Textbook of pediatric dermatology [3ed.] 9781405176958, 1405176954

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Harper’s Textbook of Pediatric Dermatology

From left to right: The Founding and current Editors in a sweltering Chicago hotel room, Summer 2007 as they plan the third Edition. Left to right: Neil Prose, Peter Hoeger, Arnold Oranje, Alan Irvine, John Harper, Albert Yan.

For Michele, Steffi, Zara and Conal. ADI For Grace, Lucy, and our one on the way. AY

Harper’s Textbook of Pediatric Dermatology EDITED BY

Alan D. Irvine MD, FRCPI, FRCP Trinity College, Dublin and Our Lady’s Children’s Hospital Dublin, Ireland

Peter H. Hoeger MD University of Hamburg and Catholic Children’s Hospital Wilhelmstift Hamburg, Germany

Albert C. Yan MD, FAAP, FAAD University of Pennsylvania School of Medicine and The Children’s Hospital of Philadelphia Philadelphia, PA, USA

IN TWO VOLUMES

VOLUME 1 THIRD EDITION

A John Wiley & Sons, Ltd., Publication

This edition first published 2011, © 2000, 2006, 2011 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. ISBN: 978-1-4051-7695-8 A catalogue record for this book is available from the British Library. Set in 9.5/12 pt Palatino by Toppan Best-set Premedia Limited, Hong Kong

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2011

v

Contents

List of Contributors, xiii Preface to the Third Edition, xxv Acknowledgements, xxvii List of Abbreviations, xxix

8 Cutaneous Manifestations of Congenital

Infections, 8.1 Peter H. Hoeger 9 Acquired Neonatal Infections, 9.1

Nico G. Hartwig, Arnold P. Oranje, Dirk Van Gysel & Marinus C.G. van Praag 10 Developmental Abnormalities, 10.1

Henning Hamm

V OL U ME 1 Part 1

The Development of Paediatric Dermatology as a Medical Sub-speciality

1 The History of Paediatric Dermatology, 1.1

John Harper

11 Differential Diagnosis of Neonatal

Erythroderma, 11.1 Hagen Ott & Peter H. Hoeger, 12 Collodion Baby, 12.1

Edel A. O’Toole & David P. Kelsell 13 Harlequin Ichthyosis, 13.1

Edel A. O’Toole & David P. Kelsell

Part 2

The Newborn

2 Embryogenesis of the Skin, 2.1

Karen A. Holbrook 3 Physiology of Neonatal Skin, 3.1

Peter H. Hoeger 4 The Role of Histopathology in Paediatric

Dermatopathology, 4.1 Marian Malone

14 Neonatal Lupus Erythematosus, 14.1

Sara J. Brown & Rosemarie M. Watson 15 Restrictive Dermopathy, 15.1

David G. Paige 16 Congenital Erosive and Vesicular

Dermatosis, 16.1 Bernard A. Cohen 17 Iatrogenic Disorders of the Newborn, 17.1

Elia F. Maalouf & Wilson B. Lopez

5 Skin Care of the Newborn, 5.1

Jean-François Stalder

Part 3

Napkin Dermatitis

6 Common Transient Neonatal Dermatoses, 6.1

Franck Boralevi & Alain Taïeb 7 Disorders of Subcutaneous Tissue in the

Newborn, 7.1 Susan J. Bayliss & Roy Colven

18 General Aspects of Napkin Dermatitis, 18.1

Arnold P. Oranje 19 Causative Factors of Napkin Dermatitis, 19.1

Ernesto Bonifazi

vi

Contents

20 Clinical Features and Differential Diagnosis of

Napkin Dermatitis, 20.1 Albert C. Yan & Paul J. Honig 21 Management of Napkin Dermatitis, 21.1

Arnold P. Oranje

Part 4

Atopic Dermatitis

36 Hypereosinophilic Disorders, 36.1

Nerys M. Roberts & Richard Staughton 37 Pityriasis Alba, 37.1

Nanette B. Silverberg 38 Perioral Dermatitis, 38.1

Ki-Young Suh & Ilona J. Frieden 39 Pompholyx, 39.1

22 Epidemiology of Atopic Dermatitis, 22.1

Carsten Flohr & Hywel C.G. Williams 23 Genetics of Atopic Dermatitis, 23.1

Stephan Weidinger & Alan D. Irvine 24 Immunology of Atopic Dermatitis, 24.1

Aideen M. Byrne & Donald Y.M. Leung 25 Immunopharmacological Mechanisms in Atopic

Dermatitis, 25.1 Clive B. Archer 26 Microbiology in Atopic Eczema, 26.1

Christina Schnopp & Martin Mempel 27 The Skin Barrier in Atopic Dermatitis, 27.1

Simon G. Danby & Michael J. Cork

Carlo M. Gelmetti 40 Nummular or Discoid Dermatitis, 40.1

Linda E. De Raeve 41 Seborrhoeic Dermatitis of Adolescence, 41.1

James A.A. Langtry 42 Lichen Simplex Chronicus and Prurigo, 42.1

Howard B. Pride & Mercedes E. Gonzalez 43 Juvenile Plantar Dermatosis, 43.1

John Browning & Alanna Bree 44 Allergic Contact Dermatitis, 44.1

Carsten Flohr & John S. C. English 45 Phytodermatoses, 45.1

Christopher R. Lovell

28 Clinical Features and Diagnostic Criteria of Atopic

Dermatitis, 28.1 Sinéad M. Langan & Hywel C.G. Williams 29 Atopic Dermatitis: Scoring Severity and Quality of

Life Assessment, 29.1 M. Susan Lewis-Jones & Carolyn R. Charman

Part 6

Infections

46 Molluscum Contagiosum, 46.1

Ali Alikhan & Tor Shwayder 47 Human Papillomavirus Infection, 47.1

30 Guidelines to Management of Atopic

Dermatitis, 30.1 John Harper, Kathrin Giehl & E. Ann Bingham

Zsuzsanna Z. Szalai 48 Herpes Simplex Virus Infections, 48.1

Helen M. Goodyear 31 Food Allergy and Eczema, 31.1

Helen E. Cox & Jonathan Hourihane 32 Aeroallergies and Atopic Eczema, 32.1

49 Viral Exanthems, 49.1

Wynnis L. Tom & Sheila Fallon Friedlander

Ann-Marie Powell, Gideon Lack & Adam Fox 50 Gianotti–Crosti Syndrome, 50.1 33 Eczema Herpeticum, 33.1

Carlo M. Gelmetti

Helen M. Goodyear 51 Poxviruses, 51.1 34 Psychosocial Aspects of Atopic Dermatitis, 34.1

M. Susan Lewis-Jones

Margaret DeJong, Ereni Skouta & Mary T. Glover 52 HIV Infection, 52.1

Part 5

Other Types of Dermatitis

Neil S. Prose & Coleen K. Cunningham 53 Infective Dermatitis (Skin Manifestations of HTLV

35 Infantile Seborrhoeic Dermatitis, 35.1

Carlo M. Gelmetti & Ramon Grimalt

Infection), 53.1 Rosalia A. Ballona & Neil B. Prose

Contents 54 Pyodermas and Toxin-mediated Syndromes, 54.1

Christian R. Millett, Warren R. Heymann & Steven M. Manders 55 Skin Manifestations of Meningococcal

Infection, 55.1 Saul N. Faust, Parviz Habibi & Robert S. Heyderman

vii

68 Cutaneous Larva Migrans, 68.1

Antonia K. Kienast 69 Myiasis, 69.1

Peter H. Hoeger 70 Leprosy (Hansen Disease), 70.1

Sunil Dogra & Amrinder J. Kanwar

56 Pitted Keratolysis, Erythrasma and

Erysipeloid, 56.1 Anita P. Sheth 57 Mycobacterial Infections of the Skin, 57.1

Lisa McNally, Huda Al-Ansari & Vas Novelli 58 Bartonella Infections: Bacillary Angiomatosis,

Cat Scratch Disease and Bartonellosis, 58.1 Diana B. McShane, Heidi H. Kong & Sarah A. Myers 59 Lyme Borreliosis, 59.1

Susan O’Connell

Part 9

Stings and Infestations

71 Papular Urticaria, 71.1

Ian F. Burgess 72 Scabies and Lice, 72.1

Julie S. Prendiville 73 Other Noxious and Venomous Creatures, 73.1

Dirk M. Elston

60 Endemic Treponematoses: Yaws, Pinta and

Endemic Syphilis, 60.1 Herman Jan H. Engelkens 61 Rocky Mountain Spotted Fever and Other

Rickettsial Infections, 61.1 Daniel J. Sexton 62 Superficial Fungal Infections, 62.1

Peter P.M. Mayser & Yvonne Gräser 63 Deep Mycoses and Opportunistic Infections, 63.1

Adrián-Martín Pierini,, María Marta Bujan & Agustina Lanoël 64 Cutaneous Infections in

Immunocompromised Children, 64.1 Hagen Ott & Peter H. Hoeger

Part 10 Urticaria and the Erythemas 74 Urticaria, 74.1

Christine Léauté-Labrèze, Franck Boralevi & Alain Taïeb 75 Mastocytosis, 75.1

Dirk Van Gysel, Ron H.N. van Schaik & Arnold P. Oranje 76 Annular Erythemas, 76.1

Kimberly A. Horii & Amy J. Nopper 77 Erythema Nodosum and Other Forms of

Panniculitis, 77.1 Heather A. Brandling-Bennett & Maria C. Garzon 78 Erythema Multiforme, Stevens–Johnson Syndrome

Part 7

Nutritional Disorders

65 Skin Manifestations of Nutritional Disorders, 65.1

Luz Orozco-Covarrubias & Carola Durán McKinster

and Toxic Epidermal Necrolysis, 78.1 Lizbeth Ruth A. Intong & Dédée F. Murrell

Part 11 Acne 79 Acne, 79.1

Part 8

Tropical Dermatoses

66 Tropical Ulcer, 66.1

Vibhu Mendiratta

Bodo C. Melnik

Part 12 Psoriasis and Other Papulosquamous Disorders

67 Leishmaniasis, 67.1

Evelyne Halpert, Gerzain Rodriguez & Carlos Arturo Hernández

80 Psoriasis, 80.1

Flora B. de Waard-van der Spek & Arnold P. Oranje

viii

Contents

81 Psoriasis: Pathogenesis, 81.1

Flora B. de Waard-van der Spek & Arnold P. Oranje 82 Psoriasis: Treatments, 82.1

Flora B. de Waard-van der Spek, Lisette W.A. van Suijlekom-Smit & Arnold P. Oranje 83 Pityriasis Rubra Pilaris, 83.1

Melinda Jen & Mary Wu Chang 84 Pityriasis Rosea, 84.1

Antonio A.T. Chuh & Vijay Zawar 85 Lichen Planus and Lichen Nitidus, 85.1

Harper N. Price & Andrea L. Zaenglein

96 Knuckle Pads, 96.1

Elaine C. Siegfried 97 Fibromatoses, Hyalinoses and Stiff

Skin Syndrome, 97.1 Grazia Mancini, Arnold P. Oranje, Jan C. den Hollander & Moise L. Levy 98 Angiolymphoid Hyperplasia with

Eosinophilia, 98.1 Alfons L. Krol 99 Skin Malignancies, 99.1

Adrián-Martín Pierini,, Andrea Bettina Cervini & Marcela Bocian

86 Lichen Striatus, 86.1

Alain Taïeb & Edouard Grosshans

Part 13 Blistering Disorders

Part 15 Lymphocytic Disorders and Histiocytosis 100 Pityriasis Lichenoides, 100.1

Ernesto Bonifazi 87 Differential Diagnosis of

Vesiculobullous Lesions, 87.1 James G.H. Dinulos & Joi B. Carter 88 Infantile Acropustulosis, 88.1

Richard J. Antaya 89 Linear IgA Associated Bullous Disease in

Children: Childhood Linear IgA Disease/Chronic Bullous Disease of Childhood, Mixed Immunobullous Disease and IgA Mucous Membrane Pemphigoid, 89.1 Gudula Kirtschig & Fenella Wojnarowska 90 Dermatitis Herpetiformis, 90.1

Jonathan N. Leonard 91 Pemphigus, Pemphigoid and Epidermolysis

Bullosa Acquisita, 91.1 J. Henk Sillevis Smitt & Marcel F. Jonkman

Part 14 Skin Nodules

101 Jessner’s Lymphocytic Infiltrate of the Skin, 101.1

R.M. Ross Hearn 102 Cutaneous Lymphomas, 102.1

Elena Pope & Kenneth Chang 103 Histiocytosis, 103.1

Irene Lara-Corrales and Elena Pope

Part 16 Disorders of Pigmentation 104 Disorders of Pigmentation, 104.1

R.M. Ross Hearn 105 Vitiligo, 105.1

Juliette Mazereeuw-Hautier & Alain Taïeb

Part 17 Photodermatoses and Photoprotection 106 The Idiopathic Photodermatoses, 106.1

James Ferguson 92 Differential Diagnosis of Skin Nodules

and Cysts, 92.1 Peter H. Hoeger 93 Granuloma Annulare, 93.1

Cameron T.C. Kennedy 94 Adnexal Disorders, 94.1

Andrew Wang & Robert Sidbury 95 Calcification and Ossification in the Skin, 95.1

Eulalia T. Baselga

107 Porphyrias, 107.1

Jose M. Mascaro & Henry W. Lim 108 Photoprotection, 108.1

Robin L. Hornung

Part 18 Melanocytic Naevi and Melanoma 109 Melanocytic Naevi and Melanoma, 109.1

Julia A. Newton Bishop

Contents

Part 19 Epidermal Naevi and Associated Syndromes

123 Keratosis Pilaris, 123.1

110 Epidermal Naevi, 110.1

124 Netherton Syndrome, 124.1

Jon A. Dyer 111 Proteus Syndrome, 111.1

John Harper, Kathrin Giehl & Raoul Hennekam

ix

Arnold P. Oranje & Dirk Van Gysel

Wei-Li Di & John Harper, 125 Darier Disease, 125.1

Susan M. Burge 126 Porokeratosis, 126.1

Part 20 Vascular and Lymphatic Anomalies 112 Vascular Malformations, 112.1

Laurence M. Boon, Odile Enjolras, John B. Mulliken, & Miikka Vikkula 113 Infantile Haemangiomas and Other

Vascular Tumours, 113.1 Anna L. Bruckner & Ilona J. Frieden

Leslie Castelo-Soccio 127 Ectodermal Dysplasias, 127.1

Yuka Asai & Alan D. Irvine 128 The Neurofibromatoses, 128.1

Amy Theos, Kevin P. Boyd & Bruce R. Korf 129 Tuberous Sclerosis, 129.1

John P. Osborne & Andrew J. Green 114 Disorders of Lymphatics, 114.1

Sahar Mansour & Peter S. Mortimer

130 Incontinentia Pigmenti, 130.1

Dian Donnai

V OL U ME 2 Part 21 Genetic Disorders 115 Principles of Genetics, Mosaicism and Molecular

Biology, 115.1 Rudolf Happle 116 Chromosomes and the Skin, 116.1

Christopher P. Barnett & William Reardon 117 Review of Keratin Disorders, 117.1

Maurice A.M. van Steensel & Peter M. Steijlen 118 Epidermolysis Bullosa, 118.1

Jemima E. Mellerio & Jacqueline E. Denyer 119 Kindler Syndrome, 119.1

Anna E. Martinez & Dawn Siegel 120 Mendelian Disorders of Cornification (MEDOC):

the Keratodermas, 120.1 Maurice A.M. van Steensel & Peter M. Steijlen 121 Mendelian Disorders of Cornification (MEDOC):

the Ichthyoses, 121.1 Daniel Hohl & Mary Williams

131 Hypomelanosis of Ito/Pigmentary mosaicism, 131.1

Saleem M. Taibjee & Celia Moss 132 Gorlin (Naevoid Basal Cell Carcinoma)

Syndrome, 132.1 Peter A. Farndon 133 Focal Dermal Hypoplasia, 133.1

Amarilis Sanchez-Valle, V. Reid Sutton & Ignatia B. Van den Veyver, 134 Premature Ageing Syndromes, 134.1

Helga V. Toriello 135 Xeroderma Pigmentosum, Cockayne Syndrome and

Trichothiodystrophy, 135.1 Steffen Emmert 136 Rothmund–Thomson Syndrome, Bloom Syndrome,

Dyskeratosis Congenita, Fanconi Anaemia, 136.1 Celia Moss 137 Genetic Diseases that Predispose to

Malignancy, 137.1 Julie V. Schaffer 138 Inherited Disorders of Pigmentation, 138.1

Eli Sprecher & Dov Hershkovitz 122 Mendelian Disorders of Cornification (MEDOC):

the Erythrokeratodermas, 122.1 Daniel Hohl, Stephanie Christen-Zaech & Baruk Mevorah

139 Prenatal Diagnosis of Inherited Skin

Disorders, 139.1 John A. McGrath

x

Contents

140 Skin Gene and Cell Therapy, 140.1

Matthias Titeux & Alain Hovnanian

153 Sexually Transmitted Diseases in Children and

Adolescents, 153.1 Arnold P. Oranje, Robert A.C. Bilo & Nico G. Hartwig

Part 22 Disorders of Fat Tissue Part 27 Physical and Sexual Abuse in Children 141 Disorders of Fat Tissue, 141.1

Marc Lacour

154 Non-accidental Injury (Physical Abuse), 154.1

Antonia K. Kienast

Part 23 Disorders of Connective Tissue

155 Child Maltreatment: Sexual Abuse, 155.1

Sarah M. Frioux & Cindy Christian 142 Ehlers–Danlos Syndromes, 142.1

Nigel P. Burrows, Navjeet Sidhu-Malik & Heather N. Yeowell 143 Cutis Laxa, 143.1

Richard J. Antaya 144 Pseudoxanthoma Elasticum, 144.1

Anne Han & Mark Lebwohl 145 Buschke–Ollendorff Syndrome, Marfan Syndrome,

Osteogenesis Imperfecta, Anetodermas and Atrophodermas, 145.1 Marc Lacour

Part 28 Systemic Diseases 156 Sweet Syndrome, 156.1

Peter von den Driesch 157 Crohn Disease and Orofacial Granulomatosis, 157.1

Billy Bourke, Paddy Fleming, & Claire Healy 158 Sarcoidosis, 158.1

Julie L. Cantatore-Francis & Julie V. Schaffer 159 Amyloidosis, 159.1

Teri A. Kahn

146 Striae, 146.1

Manjunatha Kalavala & Magdalene Dohil

160 Schönlein–Henoch Purpura, 160.1

Hagen Ott

Part 24 The Oral Cavity 147 Diseases of the Oral Mucosa and Tongue, 147.1

Jane Luker & Crispian Scully,

161 Acute Haemorrhagic Oedema of the Skin

in Infancy, 161.1 Alain Taïeb & Valérie Legrain 162 Purpura Fulminans, 162.1

Michael Levin, Brian Eley & Saul N. Faust

Part 25 Hair and Nails 148 Hair Disorders, 148.1

Elise A. Olsen

163 Urticarial Vasculitis, 163.1

Heather A. Brandling-Bennett & Marilyn G. Liang 164 Erythema Elevatum Diutinum, 164.1

149 Alopecia Areata, 149.1

Kerstin Foitzik-Lau 150 Nail Disorders, 150.1 ,

Antonella Tosti & Bianca M. Piraccini

Aimee C. Smidt & Sarah L. Chamlin 165 Pigmented Purpura, 165.1

Allison L. Jensen & Sheryll L. Vanderhooft 166 Erythromelalgia, 166.1

Justin Daniels

Part 26 Genitourinary Problems in Children 151 Genital Disease in Children, 151.1

Gayle O. Fischer 152 Vulvovaginitis and Lichen Sclerosus, 152.1

Sallie M. Neill

167 Wegener Granulomatosis, Polyarteritis Nodosa,

Microscopic Polyangiitis, Behçet Disease and Relapsing Polychondritis, 167.1 Paul A. Brogan & E. Jane Tizard 168 Kawasaki Disease, 168.1

Wynnis L. Tom, Tomisaku Kawasaki & Jane C. Burns

Contents 169 Inherited Metabolic Disorders and the Skin, 169.1

Johannis B.C. de Klerk & Arnold P. Oranje 170 Cystic Fibrosis, 170.1

Rod Phillips 171 Carotenaemia, 171.1

Peter T. Clayton & Emma J. Footitt 172 Cutaneous Manifestations of Endocrine

Disease, 172.1 Peter A. Hogan 173 Morphoea (Localized Scleroderma), 173.1

Lisa Weibel & John Harper 174 Systemic Sclerosis in Childhood, 174.1

Christopher P. Denton & Carol M. Black

182 The Use of Emerging Biological Treatments in

Children, 182.1 Polly Livermore & Clarissa Pilkington 183 Hypersensitivity Reactions to Drugs, 183.1

Hagen Ott 184 Poisoning and Paediatric Skin, 184.1

Giuseppe Micali, Stephanie A. St Pierre, Erika E. Reid & Dennis P. West

Part 31 Dermoscopy in Pediatric Skin 185 Dermoscopy of Melanocytic Lesions in

the Paediatric Population, 185.1 Jennifer L. DeFazio, Ralph P. Braun & Ashfaq A. Marghoob

175 Juvenile Idiopathic Arthritis, Systemic

Lupus Erythematosus and Juvenile Dermatomyositis, 175.1 Despina Eleftheriou & Patricia Woo 176 Periodic Fever Syndromes, 176.1

Juan C. Salazar & Henry M. Feder Jr 177 Immunodeficiency Syndromes, 177.1

Julie V. Schaffer & Amy S. Paller 178 Graft-Versus-Host Disease, 178.1

John Harper & Paul Veys

Part 29 Psychological Aspects of Skin Disease in Children 179 Coping with the Burden of Chronic Skin

Disease, 179.1 Elisa S. Gallo & Sarah L. Chamlin 180 Physiological Habits, Self-Mutilation and Factitious

Disorders, 180.1 Arnold P. Oranje, Jeroen Novak & Robert A.C. Bilo

Part 32 Surgical and Laser Therapies 186 Surgical Principles and Techniques in Paediatric

Dermatology, 186.1 Léon N.A. van Adrichem 187 More Complex Skin Surgery, 187.1

Paul Morris, Guy Thorburn & Loshan Kangesu 188 Laser Treatment for Cutaneous Vascular

Anomalies, 188.1 Samira Syed, Jane Linward & John Harper 189 The Use of Resurfacing, Pigment and Depilation

Lasers in Children, 189.1 Andrew C. Krakowski & Lawrence F. Eichenfield 190 Sedation and Anaesthesia, 190.1

Yuin-Chew Chan & Lawrence F. Eichenfield 191 Treatment of Congenital Melanocytic Naevi, 191.1

Neta Adler & Bruce S. Bauer

Part 33 Nursing Care of Paediatric Skin Part 30 Therapeutics and Poisoning 181 Principles of Paediatric Dermatological

Therapy, 181.1 Dennis P. West, Candrice Heath, Ann Cameron Haley, Anne Mahoney & Giuseppe Micali

xi

192 Nursing Care of Paediatric Skin, 192.1

Jane White, Jane Linward, Jacqueline Denyer & Bisola Laguda Index

xiii

List of Contributors

Neta Adler

Yuka Asai

Robert A.C. Bilo

MD Attending Surgeon Department of Plastic and Reconstructive Surgery Hadassah Medical Center Hebrew University School of Medicine Jerusalem, Israel

MD Division of Dermatology McGill University Montreal, Canada

MD Forensic Physician Consultant in Forensic Pediatrics Department of Forensic Pathology and Toxicology Netherlands Forensic Institute The Hague, The Netherlands

Huda Al-Ansari MD, DTM&H Consultant in Paediatric Infectious Diseases Salmaniya Hospital Bahrain

Ali Alikhan MD Resident in Dermatology Department of Dermatology The Mayo Clinic Rochester, MN, USA

Richard J. Antaya MD, FAAD, FAAP Associate Professor of Dermatology and Pediatrics Director, Pediatric Dermatology Yale University School of Medicine New Haven, CT, USA

Clive B. Archer BSc, MBBS, MSc Med Ed, MD, PhD (Lond), FRCP (Edin, Lond) Consultant Dermatologist and Honorary Clinical Senior Lecturer St John’s Institute of Dermatology Guy’s and St Thomas’ NHS Foundation Trust and King’s College London London, UK

Rosalia A. Ballona MD Division of Dermatology Instituto de Salud del Niño Lima, Peru

Christopher P. Barnett MBBS, FRACP Clinical Fellow Division of Clinical and Metabolic Genetics The Hospital for Sick Children Toronto, Canada

Eulalia Baselga MD Medical Director Pediatric Dermatology Unit Department of Dermatology Hospital de la Santa Creu i Sant Pau Barcelona, Spain

Bruce S. Bauer MD, FACS, FAAP Director of Pediatric Plastic Surgery NorthShore University Health System Highland Park Hospital Clinical Professor of Surgery Pritzker School of Medicine University of Chicago Highland Park, IL, USA

E. Ann Bingham MB, FRCP Formerly Consultant Dermatologist Department of Dermatology Royal Belfast Hospital for Sick Children Belfast, UK

Carol M. Black MD, FRCP, FMedSci Director Centre for Rheumatology Royal Free Hospital and UCL Medical School London, UK

Marcela Bocian MD Assistant Physician Department of Dermatology Professor Juan P. Garrahan Hospital for Pediatrics Buenos Aires, Argentina

Ernesto Bonifazi MD Associate Professor of Dermatology Department of Dermatology University of Bari Bari, Italy

Susan J. Bayliss MD Professor of Internal Medicine (Dermatology) and Pediatrics Division of Dermatology Washington University School of Medicine St Louis, MO, USA

Laurence M. Boon MD, PhD Director of Vascular Anomalies Program Division of Plastic Surgery Clinique Universitaire St Luc and Université Catholique de Louvain Brussels, Belgium

xiv

List of Contributors

Franck Boralevi

Sara J. Brown

Aideen M. Byrne

MD, PhD Professor of Dermatology Pediatric Dermatology Unit Childrens’ Hospital of Bordeaux Bordeaux, France

BSc, MBChB, MRCP, MD Wellcome Trust Intermediate Clinical Fellow Clinical Senior Lecturer and Honorary Consultant Dermatologist Ninewells Hospital and Division of Molecular Medicine University of Dundee, UK

MRCPI University of Colorado Denver Medical School Aurora, CO, USA

Billy Bourke MD, FRCPI Consultant Paediatric Gastroenterologist Children’s Research Center Our Lady’s Children’s Hospital and Conway Institute University College Dublin Dublin, Ireland

John Browning MD, FAAD, FAAP Assistant Professor Pediatrics and Dermatology University of Texas Health Science Center San Antonio, TX, USA

Kevin P. Boyd

Anna L. Bruckner

MD Research Fellow Department of Dermatology University of Alabama at Birmingham Birmingham, AL, USA

MD Assistant Professor of Dermatology and Pediatrics Departments of Dermatology and Pediatrics Stanford University School of Medicine Stanford, CA, USA

Heather A. Brandling-Bennett MD Assistant Professor of Pediatrics Division of Dermatology Seattle Children’s Hospital University of Washington Seattle, WA, USA

María Marta Bujan MD Chief Resident, Department of Dermatology Professor Juan P. Garrahan Hospital for Pediatrics Buenos Aires, Argentina

Ralph P. Braun

Susan M. Burge

MD Associate Professor Dermatology Clinic University Hospital Zürich Zürich, Switzerland

OBE, BSc (Bristol), BM BCh, DM (Oxon), FRCP Consultant Dermatologist Oxford Radcliffe Hospitals NHS Trust Honorary Senior Clinical Lecturer Oxford University Oxford, UK

Alanna Bree MD Pediatric Dermatologist Dermatology Specialists of Houston Bellaire, TX, USA

Paul A. Brogan BSc (Hon), MBChB (Hon), FRCPCH, MSc, PhD Senior Lecturer and Honorary Consultant Paediatric Rheumatologist Institute of Child Health University College London London, UK

Ian F. Burgess MSc, MPhil, FRES Director, Medical Entomology Centre Insect Research & Development Limited Cambridge, UK

Ann Cameron Haley BA Research Assistant Department of Dermatology Northwestern University Feinberg School of Medicine Chicago, IL, USA

Julie L. Cantatore-Francis MD Volunteer Pediatric Dermatology State University of New York Downstate Medical Center New York, NY, USA

Joi B. Carter MD Assistant in Dermatology Department of Dermatology Massachusetts General Hospital Boston, MA, USA

Leslie Castelo-Soccio MD, PhD, FAAD Clinical Fellow in Pediatric Dermatology Children’s Hospital of Philadelphia Philadelphia, PA, USA

Andrea Bettina Cervini MD Assistant Physician Department of Dermatology Professor Juan P. Garrahan Hospital for Pediatrics Buenos Aires, Argentina

Sarah L. Chamlin

Rady Children’s Hospital University of California San Diego, CA, USA

MD Associate Professor Departments of Pediatrics and Dermatology Northwestern University Feinberg School of Medicine Children’s Memorial Hospital Chicago, IL, USA

Nigel P. Burrows

Yuin-Chew Chan

MD, FRCP Consultant Dermatologist and Associate Lecturer Department of Dermatology Addenbrookes NHS Trust Cambridge, UK

MBBS, MRCP (UK), FAMS (Dermatology) Dermatologist Dermatology Associates Gleneagles Medical Centre Singapore

Jane C. Burns

List of Contributors

Kenneth Chang

Roy Colven

Department of Pathology and Laboratory Medicine The Hospital for Sick Children Toronto, Canada

MD Harborview Medical Center Seattle, WA, USA

Michael J. Cork Mary Wu Chang MD Associate Clinical Professor Departments of Dermatology and Pediatrics University of Connecticut School of Medicine Farmington, CT, USA

Carolyn R. Charman BMBCH, MD, FRCP Consultant Dermatologist Department of Dermatology Royal Devon and Exeter NHS Foundation Trust Exeter, UK

BSc, MB, PhD, FRCP Head, Academic Unit of Dermatology Research Department of Infection and Immunity University of Sheffield and The Paediatric Dermatology Clinic Sheffield Children’s Hospital Sheffield, UK

Cindy W. Christian MD Chair, Child Abuse and Neglect Prevention Children’s Hospital of Philadelphia Philadelphia, PA, USA

Antonio A.T. Chuh MD, FRCP, MRCPCH Adjunct Associate Professor School of Public Health The Chinese University of Hong Kong Shatin, Hong Kong

Peter T. Clayton MD, FRCP, FRCPCH Professor of Paediatric Metabolic Disease and Hepatology University College London Institute of Child Health with Great Ormond Street Hospital for Children NHS Trust London, UK

Bernard A. Cohen MD Professor of Pediatrics and Dermatology Johns Hopkins University; Director of Pediatric Dermatology Johns Hopkins Children’s Center Baltimore, MD, USA

Flora B. de Waard-van der Spek MD, PhD Pediatric Dermatologist Department of Dermatology Erasmus MC Rotterdam, The Netherlands

Jennifer L. DeFazio MD Assistant Attending Department of Medicine Division of Dermatology Memorial Sloan-Kettering Cancer Center New York, NY, USA

Helen E. Cox MBChB, FRCP, FRCPCH, MD(Ldn) Consultant in Paediatric Allergy Imperial College and St Mary’s Hospital London, UK

Stephanie Christen-Zaech Attending Physician Pediatric Dermatology Department of Dermatology and Pediatrics Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland

xv

Coleen K. Cunningham MD Chief, Infectious Diseases Department of Pediatrics Duke University Medical Center Durham, NC, USA

Margaret DeJong MDCM, FRCPsych (Can), FRCPsych (UK) Consultant Child and Adolescent Psychiatrist Department of Child and Adolescent Mental Health Great Ormond Street Hospital for Children NHS Trust London, UK

Jan C. den Hollander Department of Radiology and Pathology Erasmus MC Rotterdam, The Netherlands

Simon G. Danby PhD, BSc (Hon) Research Associate The Academic Unit of Dermatology Research Department of Infection and Immunity The University of Sheffield Sheffield, UK

Justin Daniels

Christopher P. Denton Consultant Rheumatologist Centre for Rheumatology Royal Free Hospital and UCL Medical School London, UK

Jacqueline E. Denyer

Consultant Paediatrician and Honorary Senior Lecturer Pediatric Department North Middlesex University Hospital London, UK

BSc, MD, FRCP Clinical Nurse Specialist Epidermolysis Bullosa Unit Great Ormond Street Hospital for Children NHS Trust London, UK

Johannis B.C. de Klerk

Wei-Li Di

MD Consultant in Metabolic Diseases Department of Pediatrics Erasmus MC Sophia Children’s Hospital Rotterdam, The Netherlands

MBBS, PhD Lecturer in Skin Biology Immunobiology Unit Institute of Child Health University College London London, UK

Linda E. De Raeve

James G.H. Dinulos

MD, PhD Clinical Professor, Paediatric Dermatology UZ Brussel, Vrije Universiteit Brussel Brussels, Belgium

MD Residency Program Director Department of Dermatology Dartmouth-Hitchcock Medical Center Lebanon, NH, USA

xvi

List of Contributors

Sunil Dogra

Dirk M. Elston

Henry M. Feder Jr

MD, DNB, MNAMS Assistant Professor Department of Dermatology, Venereology and Leprology Postgraduate Institute of Medical Education and Research Chandigarh, India

MD Director, Department of Dermatology Geisinger Medical Center Danville, PA, USA

MD Professor of Pediatrics Division of Pediatric Infectious Diseases Connecticut Children’s Medical Center Hartford CT, USA

Magdalene Dohil MD Attending Staff Physician Pediatric and Adolescent Dermatology University of California San Diego, CA, USA

Dian Donnai Professor of Medical Genetics Department of Genetic Medicine University of Manchester and Central Manchester University Hospitals NHS Foundation Trust Manchester, UK

Jonathan A. Dyer MD Assistant Professor of Dermatology and Child Health Departments of Dermatology and Child Health University of Missouri Columbia, MO, USA

Lawrence F. Eichenfield MD Professor of Clinical Pediatrics and Medicine (Dermatology) University of California San Diego School of Medicine and Chief, Pediatric and Adolescent Dermatology Rady Children’s Hospital San Diego, CA, USA

Despina Eleftheriou MBBS, MRCPCH Clinical Research Fellow Rheumatology Unit Institute of Child Health London, UK

Brian Eley BSc, FC Paed (SA) Associate Professor Paediatric Infectious Diseases Unit Red Cross Children’s Hospital Cape Town, South Africa

Steffen Emmert MD Professor of Dermatology Department of Dermatology, Venerology, and Allergology Georg-August-University Göttingen Göttingen, Germany

James Ferguson MD, FRCP Professor, Photobiology Unit Department of Dermatology Ninewells Hospital Dundee, UK

Herman-Jan H. Engelkens MD, PhD Department of Dermatology and Venereology Ikazia Hospital Rotterdam, The Netherlands

John S. C. English MBBS, FRCP Consultant Dermatologist Department of Dermatology Nottingham University Hospitals Nottingham, UK

Odile Enjolras MD Dermatologist, Centre de Référence des Pathologies Neurovasculaires Malformatives Site Hôpital d’Enfants AP-HP Armand Trousseau Département de Chirurgie Maxillofaciale et de Chirurgie Plastique Pédiatriques Paris, France

Sheila Fallon Friedlander MD Clinical Professor, Departments of Pediatrics and Medicine (Dermatology) University of California Rady Children’s Hospital San Diego, CA, USA

Peter A. Farndon MSc, MD, FRCP, DCH Professor of Clinical Genetics West Midlands Regional Clinical Genetics Service Birmingham Women’s Hospital Birmingham, UK

Saul N. Faust MA, MBBS, PhD, MRCPCH, FHEA Senior Lecturer in Child Health Consultant in Paediatric Immunology and Infectious Diseases University of Southampton Southampton, UK

Gayle O. Fischer MBBS, FACD Senior Lecturer in Dermatology The Northern Clinical School The University of Sydney Sydney, Australia

Paddy Fleming Senior Lecturer and Consultant in Paediatric Dentistry Dental Department Our Lady’s Children’s Hospital Dublin, Ireland

Carsten Flohr BM, BCh, MRCPCH, MSc, PhD National Institute for Health Research (NIHR) Clinician Scientist Senior Lecturer and Consultant Dermatologist Department of Paediatric Allergy and Dermatology St John’s Institute of Dermatology St Thomas’ Hospital and King’s College London London, UK

Kerstin Foitzik-Lau MD Dermatologist Department of Pediatric Dermatology Catholic Children’s Hospital Wilhelmstift Hamburg, Germany

Emma J. Footitt MBBS, BSc, MRCPCH Clinical Research Fellow in Paediatric Metabolic Medicine Institute of Child Health University College London with Great Ormond Street Hospital for Children NHS Trust London, UK

List of Contributors

xvii

Adam T. Fox

Mercedes E. Gonzalez

Henning Hamm

FRCPCH Consultant Paediatric Allergist King’s College London MRC, Asthma UK Centre in Allergic Mechanisms of Asthma Division of Asthma, Allergy and Lung Biology Guy’s and St Thomas’ NHS Foundation Trust London, UK

MD Resident Ronald O. Perlman Department of Dermatology New York University New York, NY, USA

MD Professor of Dermatology Department of Dermatology, Venereology and Allergology University Hospital Würzburg Würzburg, Germany

Helen M. Goodyear

Anne Han

MBChB, FRCP, FRCPCH, MD, MMEd Consultant Paediatrician and Associate Postgraduate Dean West Midlands Deanery Heart of England NHS Foundation Trust Birmingham, UK

Department of Dermatology The Mount Sinai School of Medicine New York, NY, USA

Ilona J. Frieden MD Professor of Dermatology and Pediatrics Division of Pediatric Dermatology San Francisco School of Medicine University of California San Francisco, CA, USA

Sarah M. Frioux Children’s Hospital of Philadelphia Philadelphia, PA, USA

Yvonne Gräser PhD Head, National Reference Laboratory for Dermatophytes Universitätsmedizin – Charité Institute of Microbiology and Hygiene Berlin, Germany

Elisa S. Gallo MD Board Certified Dermatologist Department of Dermatology Mayo Clinic Health System La Crosse, WI, USA

Andrew J. Green National Centre for Medical Genetics Our Lady’s Hospital Dublin, Ireland

Ramon Grimalt Maria C. Garzon MD Professor of Clinical Dermatology and Clinical Pediatrics Departments of Dermatology and Pediatrics Columbia University New York, NY, USA

Carlo M. Gelmetti MD Department of Anesthesia, Intensive Care and Dermatologic Sciences Università degli Studi di Milano Head, Unit of Pediatric Dermatology Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milan, Italy

Kathrin A. Giehl MD Dermatologist, Department of Dermatology Ludwig-Maximilians-University Munich, Germany

Mary T. Glover MA, FRCP, FRCPCH Consultant Paediatric Dermatologist Department of Dermatology Great Ormond Street Hospital for Children NHS Trust London, UK

MD Department of Dermatology Hospital Clínic University of Barcelona Barcelona, Spain

Edouard Grosshans Former Head, Strasbourg Dermatology Clinic Department of Dermatology CHU de Strasbourg Strasburg, France

Rudolf Happle Professor Emeritus Department of Dermatology Philipp University of Marburg Marburg, Germany

John Harper MD, FRCP, FRCPCH Professor of Paediatric Dermatology Great Ormond Street Hospital for Children NHS Trust London, UK

Nico G. Hartwig MD, PhD Pediatric Infectious Disease Specialist Department of Pediatrics Erasmus MC Sophia Children’s Hospital Rotterdam, The Netherlands

Claire Healy MBBCh, B Dent Sc, FDS RCS (Eng), FFD RCSI, PhD Senior Lecturer and Consultant in Oral Medicine Dublin Dental School and Hospital Trinity College Dublin Dublin, Ireland

Parviz Habibi PhD, FRCPCH Clinical Reader, Division of Medicine Imperial College London London, UK

Evelyne Halpert MGS Clinical Epidemiology Head, Pediatric Dermatology Department of Pediatrics Fundación Santafé de Bogotá Bogotá, Colombia

R.M. Ross Hearn Specialist Registrar Department of Dermatology and Photobiology Ninewells Hospital and Medical School Dundee, UK

Candrice Heath MD Clinical Research Fellow Department of Dermatology Northwestern University Feinberg School of Medicine Chicago, IL, USA

xviii

List of Contributors

Raoul Hennekam

Paul J. Honig

Marcel F. Jonkman

Professor of Pediatrics and Translational Genetics Academic Medical Center University of Amsterdam Amsterdam, The Netherlands

MD Emeritus Professor of Pediatrics and Dermatology University of Pennsylvania School of Medicine The Children’s Hospital of Philadelphia Philadelphia, PA, USA

MD, PhD Full Professor of Dermatology Department of Dermatology University Medical Centre Groningen Groningen, The Netherlands

Carlos Arturo Hernández BA, MD, MPH Editor, Revista Biomédica Instituto Nacional de Salud Bogotá, Colombia

Dov Hershkovitz Department of Pathology Rambam Medical Center Haifa, Israel

Robert S. Heyderman PhD, FRCP, DTM&H Professor of Tropical Medicine Wellcome Trust Tropical Centre University of Liverpool Liverpool, UK

Warren R. Heymann MD Head, Division of Dermatology Clinical Professor of Dermatology, University of Pennsylvania School of Medicine Professor of Medicine and Pediatrics, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School Camden, NJ, USA

Peter A. Hogan Head, Department of Dermatology Children’s Hospital at Westmead Sydney, Australia

Daniel Hohl MD Associate Professor and Chief Physician Service de Dermatologie et Vénéréologie CHUV Hopital de Beaumont Lausanne, Switzerland

Karen A. Holbrook Professor Department of Physiology and Cell Biology Ohio State University Columbus, OH, USA

Kimberly A. Horii MD Associate Professor of Pediatrics Section of Dermatology Children’s Mercy Hospitals and Clinics Kansas City, MO, USA

Robin L. Hornung MD Staff Physician Department of Dermatology The Everett Clinic Everett, WA, USA

Teri A. Kahn MD Pediatric Dermatologist Department of Dermatology University of Maryland Baltimore, MD, USA

Manjunatha Kalavala MD, MRCP(UK) Consultant in Dermatology and Pediatric Dermatology Department of Dermatology University Hospital of Wales Cardiff, UK

Loshan Kangesu Jonathan O’B Hourihane MB, DM, MRCPI, FRCPCH Professor of Paediatrics and Child Health Consultant in Paediatric Allergy Departments of Paediatrics and Child Health University College Cork Cork, Ireland

Alain Hovnanian MD, PhD Professor of Genetics Department of Dermatology and Genetics Inserm U781, Necker Hospital for Sick Children University Paris V – Rene Descartés Paris, France

Lizbeth Ruth A. Intong MD Dermatology Fellow Department of Dermatology St. George Hospital and University of New South Wales Sydney, Australia

Melinda Jen MD Dermatology Resident Departments of Dermatology and Pediatrics University of Connecticut School of Medicine Farmington, CT, USA

Allison L. Jensen MD Dermatology Resident Department of Dermatology University of Utah School of Medicine Salt Lake City, UT, USA

Consultant Plastic Surgeon Department of Plastic Surgery Great Ormond Street Hospital for Children NHS Trust London, UK

Amrinder J. Kanwar MD, FAMS Professor and Head Department of Dermatology, Venereology and Leprology Postgraduate Institute of Medical Education and Research Chandigarh, India

Tomisaku Kawasaki Japan Kawasaki Disease Research Center Tokyo, Japan

David P. Kelsell BSc, PhD Professor of Human Molecular Genetics Centre for Cutaneous Research Blizard Institute of Cell and Molecular Science Barts and the London School of Medicine and Dentistry London, UK

Cameron T.C. Kennedy MA, MBBChir, FRCP Consultant Dermatologist and Clinical Senior Lecturer Department of Paediatric Dermatology Bristol Royal Hospital for Children Bristol, UK

List of Contributors

xix

Antonia K. Kienast

Bisola Laguda

Donald Y.M. Leung

MD Resident, Department of Dermatology BUK Hamburg-Boberg Germany

MBBch, MSc, MRCPCH/MRCP Consultant Paediatrician in Paediatric Dermatology Paediatric Dermatology Chelsea and Westminster Hospital London, UK

MD, PhD Edelstein Chair of Pediatric Allergy-Immunology Department of Pediatrics National Jewish Health Denver, CO, USA

Sinéad M. Langan

Michael Levin

MRCP, MSc, PhD Visiting Scholar, Department of Dermatology University of Pennsylvania Philadelphia, PA, USA

PhD, FRCPCH, FMedSci Chair in Paediatrics and International Child Health Imperial College London London, UK

Gudula Kirtschig Consultant Dermatologist VU University Medical Center Amsterdam, The Netherlands

Heidi H. Kong MD Assistant Clinical Investigator Dermatology Branch National Institutes of Health Bethesda, MD, USA

Bruce R. Korf MD, PhD Professor and Chair Department of Genetics University of Alabama at Birmingham Birmingham, AL, USA

Andrew C. Krakowski MD Department of Dermatology University of California San Diego, CA, USA

Alfons L. Krol MD, FRCPC Professor of Dermatology and Pediatrics Departments of Pediatrics and Dermatology Doernbecher Children’s Hospital Oregon Health and Science University Portland, OR, USA

Gideon Lack MBBCH (Oxon), MA (Oxon), FRCPCH Professor of Paediatric Allergy, King’s College London MRC and Asthma UK Centre in Allergic Mechanisms of Asthma Division of Asthma, Allergy and Lung Biology Guy’s and St Thomas’ NHS Foundation Trust London, UK

Marc Lacour Paediatrician Swiss Group for Pediatric Dermatology Geneva, Switzerland

James A.A. Langtry MBBS, FRCP Consultant Dermatologist Department of Dermatology Royal Victoria Infirmary Newcastle-upon-Tyne, UK

Moise L. Levy Baylor College of Medicine and Texas Children’s Hospital Houston, TX, USA

M. Susan Lewis-Jones Agustina Lanoël MD Assistant Physician Department of Dermatology Professor Juan P. Garrahan Hospital for Pediatrics Buenos Aires, Argentina

MBChB, FRCP, FRCPCH Consultant Dermatologist and Honorary Clinical Senior Lecturer Department of Dermatology Ninewells Hospital and Medical School Dundee, UK

Marilyn G. Liang Irene Lara-Corrales Fellow, Pediatric Dermatology Division of Paediatric Medicine Hospital for Sick Children Toronto, Canada

MD Assistant Professor in Dermatology Department of Dermatology Harvard Medical School Children’s Hospital Boston Boston, MA, USA

Christine Léauté-Labrèze Department of Dermatology Hôpital Pellegrin-Enfants and Hôpital Saint-André Bordeaux, France

Henry W. Lim MD Chairman, Department of Dermatology Henry Ford Health System Detroit, MI, USA

Mark Lebwohl MD Chairman, Department of Dermatology The Mount Sinai School of Medicine New York, NY, USA

Valérie Legrain MD Consultant Dermatologist Department of Dermatology Hôpital Saint-André Bordeaux, France

Jonathan N. Leonard Consultant Dermatologist Department of Dermatology St Mary’s Hospital London, UK

Jane Linward MD Clinical Nurse Specialist, Paediatric Dermatology Great Ormond Street Hospital for Children NHS Trust London, UK

Polly Livermore MSc, ANP V300 Nurse Prescriber, BSc, RN child Advanced Nurse Practitioner Paediatric Rheumatology Great Ormond Street Hospital for Children NHS Trust London, UK

xx

List of Contributors

Wilson B. Lopez

Sahar Mansour

Lisa McNally

MD, MRCPCH, MSc Locum Consultant Queens Hospital BHR Hospitals NHS Trust London, UK

MD Consultant Clinical Geneticist SW Thames Regional Genetics Service St George’s University of London London, UK

MBBS, MRCPCH Nelson R. Mandela School of Medicine University of Kurazulu Durban, South Africa

Christopher R. Lovell

Ashfaq A. Marghoob

MBChB, MD, FRCP Consultant Dermatologist Kinghorn Dermatology Unit Royal United Hospital Bath, UK

MD Associate Attending Physician Department of Dermatology Memorial Sloan-Kettering Skin Cancer Center New York, NY, USA

Jane Luker

Anna E. Martinez

BDS, FDSRCS, PhD, DDRRCR Consultant Senior Lecturer Bristol Dental Hospital University Hospitals Bristol NHS Foundation Trust Bristol, UK

MBBS, MRCP, MRCPCH Consultant Paediatrician Paediatric Dermatology Great Ormond Street Hospital for Children NHS Trust London, UK

Elia F. Maalouf

Jose M. Mascaro

MB ChB, MRCP, FRCPCH, MD Consultant in Neonatal Medicine Neonatal Unit Homerton University Hospital NHS Foundation Trust London, UK

Professor Emeritus of Dermatology Department of Dermatology Hospital Clinic Barcelona, Spain

MD Professor of Dermatology Department of Dermatology Environmental Medicine and Health Theory University of Osnabrück Osnabrück, Germany

Peter A. Mayser

Martin Mempel

Department of Dermatology Northwestern University Feinberg School of Medicine Chicago, IL, USA

MD Vice Director Clinic of Dermatology, Allergology and Venerology Justus Liebig University (UKGM) Giessen, Germany

MD Professor of Dermatology, Allergic Diseases, and Infectious Diseases Department of Dermatology, Venereology, and Allergology Georg-August-Universität Göttingen Göttingen, Germany

Marian Malone

Juliette Mazereeuw-Hautier

MBBCh, BAO, FRCPath Consultant Paediatric Pathologist Department of Histopathology Great Ormond Street Hospital for Children NHS Trust London, UK

Professor of Dermatology Dermatology Department Reference Center for Rare Skin Diseases Larrey Hospital Toulouse, France

Diana B. McShane

Anne Mahoney

John A. McGrath Grazia Mancini Department of Neonatology Wilhelmina Children’s Hospital UMC Utrecht The Netherlands

MD, FRCP Professor of Molecular Dermatology St John’s Institute of Dermatology St Thomas’ Hospital and King’s College London London, UK

Steven M. Manders MD Professor of Medicine and Pediatrics Division of Dermatology University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School Camden, NJ, USA

Resident Department of Dermatology Duke University Medical Center Durham, NC, USA

Jemima E. Mellerio BSc, MD, FRCP Consultant Dermatologist Paediatric Dermatology Great Ormond Street Hospital for Children NHS Trust London, UK

Bodo C. Melnik

Vibhu Mendiratta MD, FIMSA Professor, Pediatric Dermatology Lady Hardinge Medical College Sucheta Kriplani and Kalawati Saran Children’s Hospital New Delhi, India

Baruk Mevorah Department of Dermatology Tel Aviv Sourasky Medical Center Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel

Carola Durán McKinster MD, PhD Professor of Paediatric Dermatology Department of Dermatology National Institute of Paediatrics Mexico City, Mexico

Giuseppe Micali MD Full Professor Chair Dermatology Clinic University of Catania Catania, Italy

List of Contributors

xxi

Christian R. Millett

Julia A. Newton Bishop

John P. Osborne

MD Chief Resident, Division of Dermatology University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School Camden, NJ, USA

MD Professor of Dermatology Division of Epidemiology and Biostatistics University of Leeds Leeds, UK

Formerly of the, Department of Paediatrics The Royal United Hospital Bath, UK

Amy J. Nopper Paul H. Morris MBChB, FRCS (Ed), FRCS (Plast), MD Consultant Cleft Lip and Palate and Reconstructive Plastic Surgeon Department of Plastic Surgery Great Ormond Street Hospital for Children NHS Trust London, UK

Peter S. Mortimer MD, FRCP Professor of Dermatological Medicine, Cardiac and Vascular Sciences (Dermatology) St George’s, University of London London, UK

Celia Moss Professor of Paediatric Dermatology Department of Dermatology Birmingham Children’s Hospital Birmingham, UK

John B. Mulliken MD Professor of Surgery, Harvard Medical School and Vascular Anomalies Center Department of Plastic and Oral Surgery Children’s Hospital Boston, MA, USA

Dédée F. Murrell MA, BMBCh, FAAD, MD Professor and Head, Department of Dermatology St George Hospital and University of New South Wales Sydney, Australia

Sarah A. Myers Associate Professor Department of Dermatology Duke University Medical Center Durham, NC, USA

MD Associate Professor of Pediatrics Chief, Section of Dermatology Children’s Mercy Hospitals and Clinics Kansas City, MO, USA

MBChB, FRCP Consultant Dermatologist St John’s Institute of Dermatology St Thomas’ Hospital and King’s College London London, UK

MB, PhD, FRCPI Professor of Molecular Dermatology Centre for Cutaneous Research Blizard Institute of Cell and Molecular Science Bart’s and the London School of Medicine and Dentistry London, UK

Jeroen Novak Department of Pediatrics Erasmus MC Sophia Children’s Hospital Rotterdam, The Netherlands

Vas Novelli FRCP, FRACP, FRCPCH Consultant in Paediatric Infectious Diseases Great Ormond Street Hospital for Children NHS Trust London, UK

Susan O’Connell LRCP&SI, DipClinMicro Consultant Medical Microbiologist and Head, Lyme Borreliosis Unit Health Protection Agency Microbiology Laboratory Southampton University Hospitals Trust Southampton, UK

Elise A. Olsen MD Professor of Dermatology and Oncology Departments of Dermatology and Medicine (Oncology) Duke University Medical Center Durham, NC, USA

Arnold P. Oranje MD, PhD Professor of Pediatric Dermatology Department of Pediatrics Erasmus MC Sophia Children’s Hospital Rotterdam, The Netherlands

Luz Orozco-Covarrubias Sallie M. Neill

Edel A. O’Toole

MD Associate Professor of Paediatric Dermatology Department of Dermatology National Institute of Paediatrics Mexico City, Mexico

Hagen Ott MD Consultant in Pediatric Dermatology and Allergology Department of Pediatric Dermatology and Allergology Catholic Children’s Hospital Wilhelmstift Hamburg, Germany

David G. Paige MA, FRCP Consultant Dermatologist Department of Dermatology Bart’s and the London NHS Trust London, UK

Amy S. Paller MD Walter J. Hamlin Professor and Chair of Dermatology and Professor of Pediatrics Departments of Dermatology and of Pediatrics Northwestern University Feinberg School of Medicine Chicago, IL, USA

Rod Phillips MBBS, FRACP, PhD Paediatric Dermatologist Royal Children’s Hospital Melbourne, Australia

Adrián-Martín Pierini MD, PhD Professor of Dermatology University of Buenos Aires, and Head, Department of Dermatology Professor Juan P. Garrahan Hospital for Pediatrics Buenos Aires, Argentina

xxii

List of Contributors

Clarissa Pilkington

Erika E. Reid

Crispian Scully

MBBS, BSc, MRCP(paeds) Consultant Rheumatologist Paediatric Rheumatology Great Ormond Street Hospital for Children NHS Trust London, UK

Department of Dermatology Northwestern University Feinberg School of Medicine Chicago, IL, USA

MD, PhD, MDS, MRCS, BSc, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FRCPath, FMedSci, FHEA, FUCL, DSc, DChD, DMed(HC) Professor of Oral Medicine, Pathology and Microbiology University of London Professor of Special Needs Dentistry University College London London, UK

Bianca M. Piraccini MD, PhD Researcher in Dermatology Department of Dermatology University of Bologna Bologna, Italy

Elena Pope MD Head, Section of Dermatology Division of Pediatric Medicine The Hospital for Sick Children Toronto, Canada

Nerys M. Roberts FRCP, MRCPCH, MD, BSc Consultant Paediatric Dermatologist Department of Dermatology Chelsea & Westminster Hospital London, UK

Gerzaín Rodríguez MD Professor, School of Medicine La Sabana University Chía, Colombia Consultant Dermatopathologist Centro Dermatológico Nacional Federico Lleras Acosta Bogotá, Colombia

Ann-Marie Powell MD, FRCPI Consultant Dermatologist Department of Paediatric and Genetic Dermatology St John’s Institute of Dermatology Guy’s and St Thomas’ NHS Foundation Trust London, UK

Juan C. Salazar MD, MPH Associate Professor of Pediatrics University of Connecticut School of Medicine Division of Pediatric Infectious Diseases Connecticut Children’s Medical Center Hartford, CT, USA

Julie S. Prendiville

Amarilis Sanchez-Valle

MB, FRCPC Clinical Professor in Pediatrics University of British Columbia, and British Columbia’s Children’s Hospital Vancouver, Canada

MD Postdoctoral Fellow in Clinical Genetics Department of Human and Molecular Genetics Baylor College of Medicine Houston, TX, USA

Daniel J. Sexton MD Professor of Medicine Duke University Medical Center Durham, NC, USA

Anita P. Sheth MD Staff Physician, Division of Pediatric Dermatology Cincinnati Children’s Hospital Cincinnati, OH, USA

Tor Shwayder MD, FAAP, FAAD Director of Pediatric Dermatology Department of Dermatology Henry Ford Hospital Detroit, MI, USA

Robert Sidbury MD Chief, Division of Dermatology Seattle Children’s Hospital University of Washington School of Medicine Seattle, WA, USA

Harper N. Price Physician, Department of Dermatology Phoenix Children’s Hospital Phoenix, AZ, USA

Howard B. Pride MD, ScB Departments of Dermatology and Pediatrics Geisinger Medical Center Danville, PA, USA

Neil S. Prose MD Professor of Pediatrics and Dermatology Duke University Medical Center Durham, NC, USA

William Reardon MD, MRCPI, DCH, FRCPCH, FRCP(Lond) Consultant Clinical Geneticist Our Lady’s Children’s Hospital Dublin, Ireland

Julie V. Schaffer

Navjeet Sidhu-Malik

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

MD Associate Professor Department of Dermatology Duke University Medical Center Durham, NC, USA

Christina M. Schnopp MD Dermatologist, Allergologist Pediatric Dermatologist Department of Dermatology and Allergy Biederstein, Technische Universität München München, Germany

Dawn Siegel MD Assistant Professor Department of Dermatology Oregon Health and Science University Portland, OR, USA

Elaine C. Siegfried Saint Louis University Cardinal Glennon Children’s Hospital St. Louis, MO, USA

List of Contributors

xxiii

J. Henk Sillevis Smitt

Ki-Young Suh

Guy Thorburn

Senior Consultant Department of Pediatric Dermatology Academic Medical Center University of Amsterdam Amsterdam, The Netherlands

MD Assistant Clinical Professor Division of Dermatology Department of Medicine David Geffen School of Medicine at University of California Los Angeles, CA, USA

BMBS, BMedSci, MA, FRCS(Plast) Consultant Cleft Lip and Palate and Reconstructive Plastic Surgeon Department of Plastic Surgery Great Ormond Street Hospital for Children NHS Trust London, UK

V. Reid Sutton

Matthias Titeux

MD Associate Professor Department of Human and Molecular Genetics Baylor College of Medicine Houston, TX, USA

Researcher Department of Dermatology and Genetics Inserm U781, Necker Hospital for Sick Children University Paris V – Rene Descartés Paris, France

Samira B. Syed

E. Jane Tizard

MBBS, DCH(Lond),DCCH, RCPEd, RCGP, FCM, BTEC Adv Laser Associate Specialist in Paediatrics (Dermatology) Paediatric Dermatology Great Ormond Street Hospital for Children NHS Trust London, UK

Consultant Paediatric Nephrologist Bristol Royal Hospital for Children Bristol, UK

Nanette B. Silverberg MD Clinical Professor of Dermatology Columbia University College of Physicians and Surgeons St. Luke’s-Roosevelt Hospital Center New York, NY, USA

Ereni Skouta MMBS, MRCPsych, MSc Specialist Registrar in Child and Adolescent Psychiatry Department of Child and Adolescent Mental Health Great Ormond Street Hospital for Children NHS Trust London, UK

Aimee C. Smidt MD Assistant Professor, Departments of Dermatology and Pediatrics University of New Mexico School of Medicine Albuquerque, NM, USA

Zsuzanna Z. Szalai MD, PhD Head, Department of Dermatology Heim Pál Children’s Hospital Budapest, Hungary

Wynnis L. Tom MD Assistant Clinical Professor Departments of Pediatrics and Medicine (Dermatology) University of California, San Diego and Rady Children’s Hospital San Diego, CA, USA

Helga V. Toriello

Eli Sprecher

Saleem M. Taibjee

MD, PhD Associate Professor, Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv, Israel

Consultant Paediatric Dermatologist Department of Dermatology Birmingham Children’s Hospital Birmingham, UK

PhD Professor, Department of Pediatrics/Human Development, Michigan State University College of Human Medicine Grand Rapids, MI, USA

Alain Taïeb

Antonella Tosti

MD Professor of Dermatology Department of Dermatology and Pediatric Dermatology Hôpital Saint-André Bordeaux, France

MD Professor in Dermatology Department of Dermatology and Cutaneous Surgery Miller School of Medicine University of Miami Miami, FL, USA

Stephanie A. St Pierre Cook County Hospital Chicago, IL, USA

Jean-François Stalder Department of Dermatology Nantes University Hospital Nantes, France

Richard Staughton Lister Hospital Chelsea Bridge Road London, UK

Peter M. Steijlen RGN, RSCN, RHV Chair, Department of Dermatology Maastricht University Medical Center Maastricht, The Netherlands

Amy Theos MD Assistant Professor Department of Dermatology University of Alabama at Birmingham Birmingham, AL, USA

Léon N.A. van Adrichem Plastic Surgeon, Head of Paediatric Section Department of Plastic Surgery Erasmus MC Sophia Children’s Hospital Rotterdam, The Netherlands

Ignatia B. Van den Veyver MD Associate Professor Department of Obstetrics and Gynecology Baylor College of Medicine Houston, TX, USA

xxiv

List of Contributors

Dirk Van Gysel

Peter von den Driesch

Hywel C. Williams

MD, PhD Director Department of Pediatrics O.L. Vrouw Hospital Aalst, Belgium

MD Dermatologist, Allergologist Dermatopathologist, Phlebologist and Head, Department for Dermatology and Allergy Center for Dermatology Stuttgart, Germany

MSc, PhD, FRCP Professor of Dermato-Epidemiology Centre of Evidence-Based Dermatology University of Nottingham Nottingham, UK

Marinus C. G. van Praag Department of Dermatology Saint Franciscus Gasthuis Rotterdam, The Netherlands

Ron H.N. van Schaik Department of Clinical Chemistry Erasmus MC Rotterdam, The Netherlands

Maurice A.M. van Steensel MD, PhD Vice-chair, Department of Dermatology Maastricht University Medical Center Maastricht, The Netherlands

Lisette W.A. van Suijlekom-Smit MD, PhD, MsCE Pediatric Rheumatologist Department of Pediatrics/Pediatic Rheumatology Erasmus MC Sophia Childrens Hospital Rotterdam, The Netherlands

Sheryll L. Vanderhooft MD Associate Professor of Dermatology and Adjunct Associate Professor of Pediatrics Departments of Dermatology and Pediatrics University of Utah School of Medicine Salt Lake City, UT, USA

Paul Veys Director, Bone Marrow Transplantation Unit Great Ormond Street Hospital for Children NHS Trust London, UK

Miikka Vikkula MD, PhD Professor of Human Genetics Laboratory of Human Molecular Genetics de Duve Institute Université Catholique de Louvain Brussels, Belgium

Andrew Wang MD Dermatology Resident Department of Dermatology Tufts Medical Center Boston, MA, USA

Rosemarie M. Watson MD, FRCPI, FACP Consultant Paediatric Dermatologist Department of Dermatology Our Lady’s Childrens Hospital Dublin, Ireland

Lisa Weibel MD Consultant for Pediatric Dermatology University Children’s Hospital Zürich Zürich, Switzerland

Stephan Weidinger MD Professor of Dermatogenetics Department of Dermatology University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany

Dennis P. West MD, PhD Professor of Dermatology Director of Dermatopharmacology Program Department of Dermatology Northwestern University Feinberg School of Medicine Chicago, IL, USA

Jane White MD Clinical Nurse Specialist in Paediatric Dermatology Paediatric Dermatology Great Ormond Street Hospital for Children NHS Trust London, UK

Mary Williams University of California San Francisco, CA, USA

Fenella Wojnarowska Professor Emeritus Nuffield Department of Medicine University of Oxford Oxford, UK

Patricia Woo CBE Professor of Paediatric Rheumatology University College London London, UK

Heather N. Yeowell MD Professor of Medicine Department of Dermatology Duke University Medical Centre Durham, NC, USA

Andrea L. Zaenglein MD Associate Professor of Dermatology and Pediatrics Penn State/Milton S. Hershey Medical Center Hershey, PA, USA

Vijay Zawar MD, FAAD, DNB, DV&D Skin Diseases Centre Nashik, India

xxv

Preface to the Third Edition

We are delighted to have the opportunity to present the third edition of this textbook. While we have made many changes in third edition, we have retained the familiar format of prior editions including detailed coverage of common diseases such as atopic dermatitis and the many rare disorders of the skin which occur in children. This third edition has been extensively rewritten; out of a total of 277 contributors from 24 countries, 165 are new contributors, bringing a truly global perspective to the work. Since publication of the first edition in 2000, there have been significant advances in many aspects of the specialty, in particular molecular genetics. This third edition provides state of the art information across the genodermatoses and includes new thinking and classifications of the disorders of cornification and the ectodermal dysplasias as well as totally updated chapters on rapidly advanc-

ing areas such as genetic mechanisms of disease, prenatal diagnosis, and gene therapy. In addition to a total rewrite of many chapters by new authors there are 18 additional new chapters including ones that reflect on new and emerging aspects of paediatric dermatology such as the role of dermoscopy and the use of biological drugs in children. We hope that this third edition will be as warmly received as its two predecessors and that it will continue to provide a definitive reference text for paediatricians, dermatologists, clinician scientists, research workers and all other individuals involved in the care of children with skin disease. ADI PH AY

xxvii

Acknowledgements

The editors wish to acknowledge the work of the three founding editors, John Harper, Arnold Oranje and Neil Prose, who expertly developed the first two editions of this book and established it as an important reference work in paediatric dermatology. We would like to thank the patients and their families who gave permission for their photographs to be reprinted; these images greatly enhance the book. Our patients provide the motivation for this work. It is our great hope that the knowledge presented here will improve patient care in paediatric dermatology around the world. We also wish to thank the many people involved in the production team at Wiley-Blackwell. ADI PH AY I was very fortunate to have wonderful mentors early in my career in paediatric dermatology. Through their excellence, these physicians inspired me to develop clinical and research interests in childhood skin disease: Ann Bingham, John Harper, David Atherton, Amy Paller, Tony Mancini and Annette Wagner. ADI

John Harper is not only one of the founders of this textbook, but one of the godfathers of paediatric dermatology as a speciality. I am very grateful for his encouragement, inspiration and support. PH I am grateful to exceptional mentors and wonderful teachers from whom I have learned much throughout my training and career. Their examples continue to inspire me to work harder to be a better physician. Among them, my thanks go especially to my parents who were my first teachers, as well as Paul Honig, Lawrence Eichenfield, William James, Julie Francis and the late Walter Tunnessen. AY

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List of Abbreviations

AA AAD ABC ACA ACC ACE ACR ACTH AD AD ADA ADHD ADR AEDS AGA AGEP aGVHD AGM AHA AHO AIDS ALL ALT AML AMMoL AMoL ANA AP APC APECED

APSS AR ARCI ARD AR-HIES AST

alopecia areata American Academy of Dermatology ATP-binding cassette anticentromere antibodies aplasia cutis congenita angiotensin-converting enzyme American College of Rheumatology adrenocorticotropic hormone atopic dermatitis autosomal dominant adenosine deaminase attention deficit hyperactivity disorder adverse drug reaction atopic eczema/dermatitis syndrome androgenetic alopecia acute generalized exanthematous pustulosis acute GVHD acrylate gelling material antihistone antibody Albright’s hereditary osteodystrophy acquired immune deficiency syndrome acute lymphoblastic leukaemia alanine transaminase acute myeloid leukaemia acute myelomonocytic leukaemia acute monocytic leukaemia antinuclear antibody adaptor protein complex antigen-presenting cell autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (syndrome) acral peeling skin syndrome autosomal recessive autosomal recessive congenital ichthyosis adult Refsum disease autosomal recessive hyperimmunoglobulin E syndrome aspartate transaminase

AT ATG ATGL ATPase AUC AZA BAL BCC BCG BCIE BDNG BMP BMT BO BOR BP CAM C-ALCL CBCL CCC CDP CDPX2 CE CEA CEDNIK CFC CGD CGRP CGS CHAND CHH CHH CHILD

ataxia telangiectasia anti-thymocyte globulin adipose triglyceride lipase adenosine triphosphatase area under the concentration-time curve azathioprine bronchoalveolar lavage basal cell carcinoma bacille Calmette–Guérin bullous congenital ichthyosiform erythroderma British Dermatological Nursing Group bone morphogenetic protein bone marrow transplants branchio-otic branchio-oto-renal blood pressure cell adhesion molecule cutaneous anaplastic large cell lymphoma cutaneous B-cell lymphoma congenital cutaneous candidiasis chondrodysplasia punctata X-linked dominant chondrodysplasia punctata cell envelope carcinoembryonic antigen cerebral dysgenesis, neuropathy, ichthyosis, keratoderma (syndrome) cardiofaciocutaneous syndrome chronic granulomatous disease calcitonin gene-related product contiguous gene syndrome curly hair, ankyloblepheron, nail dysplasia (syndrome) Conradi–Hünermann–Happle syndrome cartilage–hair hypoplasia congenital hemidysplasia with ichthyosiform erythroderma and limb defects (syndrome)

xxx

List of Abbreviations

CHIME

CHS CIE CLM CLOVE

CMC CML CMN CMTC CMV CNS CNTP CNV CRP CSF CSMH CT CTCL CTGF CTL CTLA-4 CVG CVI Cx DBPCDC DEJ DFSP DHEA DIHS/AHS DMARD DMSO DOC DOPA DRESS DSAP DSP DTE EAACI EBP EBV EBS-DM ECF ECP

colobomas, congenital heart disease, early-onset ichthyosiform dermatosis, mental retardation and ear abnormalities Chédiak–Higashi syndrome congenital ichthyosiform erythroderma cutaneous larva migrans congenital lipomatous overgrowth, vascular malformations and epidermal naevi (syndrome) chronic mucocutaneous candidiasis chronic myeloid leukaemia congenital mesoblastic nephroma cutis marmorata telangiectatica congenita cytomegalovirus central nervous system connective tissue naevus of the proteoglycan type chromosome copy number variations C-reactive protein cerebrospinal fluid congenital smooth muscle hamartoma computed tomography cutaneous T-cell lymphoma connective tissue growth factor cytotoxic T-lymphocyte cytotoxic T-lymphocyte antigen-4 cutis verticis gyrata common variable immunodeficiency connexin double-blind placebo-controlled drug challenge dermoepidermal junction dermatofibrosarcoma protuberans dihydroepiandrosterone drug-induced or anticonvulsant hypersensitivity syndrome disease modifying antirheumatic drugs dimethyl sulphoxide disorders of cornification dihydroxyphenylalanine drug rash with eosinophilia and systemic symptoms disseminated superficial actinic porokeratosis disseminated superficial porokeratosis desmoplastic trichoepithelioma European Academy of Allergy and Clinical Immunology emopamil binding protein Epstein–Barr virus epidermolysis bullosa simplex Dowling–Meara eosinophil chemotactic factor extracorporeal photopheresis

EDP EEG EGA EGF EHK EKA EKC EKV ELISA EMLA EN EN-D ENDA EOS EP ERA ESPD ESR ETN EULAR EV-HPV FADH FALDH FATP FDA FDE FFD FFM FGFR FISH FITC FMF FOP FTC FTG 5-FU GABA GBFDE GCDFP GFR GI GM-CSF GMS GNCST GOSH GPP GS GVH GVHD GVHR

erythema dyschromicum perstans electroencephalogram estimated gestational age epidermal growth factor epidermolytic hyperkeratosis erythrokeratoderma with ataxia erythrokeratoderma en cocardes erythrokeratoderma variabilis enzyme-linked immunosorbent assay eutectic mixture of local anaesthetics epidermal naevus epidermal naevus – Darier type European Network for Drug Allergy early-onset sarcoidosis eccrine poroma enthesitis-related arthritus European Society of Pediatric Derrmatology erythrocyte sedimentation rate erythema toxicum neonatorum European League Against Rheumatism epidermodysplasia verruciformisassociated human papillomavirus fatty alcohol dehydrogenase fatty aldehyde dehydrogenase fatty acid transport protein Food and Drug Administration (USA) fixed drug eruptions Fox-Fordyce disease focus-floating microscopy fibroblast growth factor receptor fluorescence in situ hybridization fluorescein isothiocynate familial Mediterranean fever fibrodysplasia ossificans progressive familial tumoral calcinosis full-thickness skin graft 5-fluoracil γ-aminobutyric acid generalized bullous fixed drug eruption gross cystic disease fluid protein glomerular filtration rate gastrointestinal granulocyte-macrophage colonystimulating factor Gomori’s methenamine silver granular nerve cell sheath tumour Great Ormond Street Hospital for Children generalized pustular psoriasis Griscelli syndrome graft-versus-host graft-versus-host-disease graft-versus-host reaction

List of Abbreviations

GVL HAE HCC HCG HCT HDL HHD HI HID HIES HIMS HIP HIV HLA HPC HPS HPETE HPV HS HSV HTLV HTP IBIDS

IBS ICAM ICD IF IFAP IFN Ig IgA1 IgM IGF IGFBP IGRA IgεRI IHCM HIS IHSC IL IL-1β ILAR ILC ILVEN IPEX

graft-versus-leukaemia hereditary angioedema harlequin colour change human chorionic gonadotropin hemopoietic cell transplantation high-density lipoprotein Hailey–Hailey disease harlequin ichthyosis hystrix-like ichthyosis with deafness (syndrome) hyperimmunoglobulin E syndrome hyperimmunoglobulin M syndrome helix initiation peptide human immunodeficiency virus human leucocyte antigen haemangiopericytoma Hermansky-Pudlak syndrome hydroperoxyeicosatetraenoic acid human papillomavirus hidradenitis suppurativa herpes simplex virus human T-lymphotropic type 1 helix termination peptide ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature ichthyosis bullosa of Siemens intracellular adhesion molecule irritant contact dermatitis infantile fibrosarcoma ichthyosis follicularis with atrichia and photophobia interferon immunoglobulin IgA subtype 1 immunoglobulin M insulin-like growth factor IGF binding protein interferon-gamma release assay high-affinity IgE receptor ichthyosis hystrix of Curth–Macklin ichthyosis hypotrichosis syndrome ichthyosis-hypotrichosis-sclerosing cholangitis (syndrome) interleukin interleukin-1β International League of Associations for Rheumatology ichthyosis linearis circumflexia inflammatory linear verrucous epidermal naevus immune dysregulation, polyendocrinopathy, enteropathy, X-linked

IPS ISAAC ISD IV IVIG JDM JIA JSPD KFSD KID KIF KLK KTS KWE LAD LAS LCD LCH LD LDF LDL LEC LEKTI LFA-3 LI/CIE LMP1 LMX LOH LOSSI LOX LT-β LTT LyP MAC MACS MAIC MBL MBTPS2 MC MC MC&S MDM MEDNIK

MEDOC mHA MHC

xxxi

ichthyosis prematurity syndrome International Study of Asthma and Allergies in Childhood infantile seborrhoeic dermatitis ichthyosis vulgaris intravenous immunoglobulin juvenile dermatomyositis juvenile idiopathic arthritis Japanese Society for Pediatric Dermatology keratosis follicularis spinulosa decalvans keratitis, ichthyosis and deafness (syndrome) keratin intermediate filaments kallikrein Klippel–Trenaunay syndrome keratolytic winter erythema leucocyte adhesion deficiency loose anagen syndrome liquor carbonis detergens Langherhans’ cell histiocytosis lymphoedema-distichiasis laser Doppler flowmetry low-density lipoprotein lymphatic endothelial cells lymphoepithelial Kazal-type inhibitor lymphocyte function-associated antigen-3 lamellar ichthyosis/congenital ichthyosiform erythroderma latent membrane protein 1 liposomal lignocaine loss of heterozygosity localized scleroderma severity index lipoxygenase lymphotoxin- β lymphocyte transformation test lymphomatoid papulosis membrane attack complex magnetic-activated cell sorting M. avium-intracellulare complex mannose-binding lectin membrane-bound transcription factor protease, site 2 mast cells molluscum contagiosum microscopy, culture and (antibiotic) sensitivity minor determinant mixture mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia mendelian disorders of cornification minor histocompatibility antigen major histocompatibility complex

xxxii

List of Abbreviations

MMF MMP MPE MRI MRSA MSD MSH NADPH

mycophenolate mofetil matrix metalloproteinases maculopapular exanthems magnetic resonance imaging methicillin-resistant Staphylococcus aureus multiple sulphatase deficiency melanocyte-stimulating hormone nicotinamide adenine dinucleotide phosphate NBD nucleotide-binding domain NBS Nijmegan breakage syndrome NBT nitroblue tetrazolium NB-UVB narrow-band UVB NCAM neural cell adhesion molecule ND naevus depigmentosus NF1 neurofibromatosis type 1 NFκB nuclear factor κB NGCO non-gestational ovarian choriocarcinoma NGFR nerve growth factor receptor NICE National Institute of Health and Clinical Excellence (UK) NICU neonatal intensive care unit NIH National Institutes of Health (USA) NISCH neonatal ichthyosis-sclerosing cholangitis (syndrome) NK natural killer (cell) NLSD neutral lipid storage disease nitrous oxide N 2O NPSA National Patient Safety Agency (UK) NPY neuropeptide Y NS naevus sebaceous NS Netherton syndrome NSAIDs non-steroidal anti-inflammatory drugs NSV non-segmental vitiligo NTM non-tuberculous mycobacteria OA ocular albinism OC osteoma cutis OL-EDA-ID osteopetrosis, lymphoedema, ectodermal dysplasia anhydrotic and immune deficiency O/W oil in water P1cp procollagen type 1 carboxy-terminal peptide PA phytanic acid PAHX phytanoyl CoA hydroxylase p-ANCA perinuclear antineutrophilic cytoplasmic antibody PAR2 protease-activated receptor 2 PAS periodic acid–Schiff PASI psoriasis area and severity index PCFCL primary cutaneous follicle-centre lymphoma PCFH precalcaneal congenital fibrolipomatous hamartoma

PCLBCL PCMZL PCOS PCR PCT PCT PDGF PDL PEPD PEN PEODDN PGP 9.5 PH PHA PHP PhyH pI PI3 PIP PL PLC PLEVA PM PML POEMS

PPAR PPK PPL POH PPPD PRES PRINTO PRP PSEK PSH PSS PTC PTH PTHrP PUVA PXE PWS

primary cutaneous diffuse large B-cell lymphoma primary cutaneous marginal zone B-cell lymphoma polycystic ovarian syndrome polymerase chain reaction porphyria cutanea tarda primary care trust platelet-derived growth factor pulsed-dye laser paroxysmal extreme pain disorder porokeratotic eccrine naevus porokeratotic eccrine ostial and dermal duct naevus protein gene product 9.5 palmoplantar hidradenitis phytohaemagglutinin pseudo-hypoparathyroidism phytanoyl-CoA 2-hydroxylase isoelectric point proteinase inhibitor 3 proximal interphalangeal pityriasis lichenoides pityriasis lichenoides chronica pityriasis lichenoides et varioliformis acuta porokeratosis of Mibelli progressive multifocal leucoencephalopathy polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (syndrome) peroxisome proliferator-activated receptor palmoplantar keratodermas penicilloyl-polylysine progressive osseous heteroplasia porokeratosis palmaris et plantaris disseminata Paediatric Rheumatology European Society Paediatric Rheumatology International Trials Organization pityriasis rubra pilaris progressive symmetric erythrokeratoderma premature sebaceous hyperplasia peeling skin syndromes premature termination codon parathyroid hormone parathyroid-hormone-related peptide psoralens plus UVA pseudo-xanthoma elasticum port wine stain

List of Abbreviations

QUADAS RAMBA RCDP RCT RF RMH ROS RTX RXLI SCC SCCE SCID SCT SCTE SD SEI SFT SHP SIB SID sIgE SJS SLADP SLC27 SLE SLN SLOS SLPI SLS SNP SP SPD SPECT SPF SPINK SPRR SPTL SSG SSLR SSRI

Quality Assessment of Diagnostic Accuracy tool retinioic acid metabolism blocking agent rhizomelic chondrodysplasia punctata randomized controlled trial rheumatoid factor rhabdomyomatous mesenchymal hamartoma reactive oxygen species rituximab recessive X-linked ichthyosis squamous cell carcinoma stratum corneum chymotryptic enzyme severe combined immunodeficiency stem cell transplantation stratum corneum tryptic enzyme seborrhoeic dermatitis superficial epidermolytic ichthyosis solitary fibrous tumour Schönlein–Henoch purpura self-injurious behaviour sudden infant death (syndrome) drug-specific IgE antibodies Stevens–Johnson syndrome Latin American Society for Pediatric Dermatology solute carrier family 27 systemic lupus erythematosus speckled lentiginous naevus Smith–Lemli–Opitz syndrome secretory leucocyte protease inhibitor Sjögren–Larsson syndrome single nucleotide polymorphism syringocystadenoma papilliferum Society for Pediatric Dermatology single-photon emission computerized tomography sun protection factor serine protease inhibitor Kazal type small proline-rich proteins subcutaneous panniculitis-like T-cell lymphoma split-thickness skin graft serum sickness-like reactions selective serotonin reuptake inhibitors

SSSS STI STS TAC TBSA TCS TCR TEN TEWL TG TG TG1 TGF TJ TLR TMD TMP-SMX TNF TPM TPMT TRAPS TRT TS TTD UD uE3 UV UVB VEGF VEGFR3 VLCFA VZIG VZV WAO WAS WHO W/O XD XLMR XR ZIG ZNS

xxxiii

staphylococcal scalded skin syndrome sexually transmitted infection steroid sulphatase tetracaine/adrenaline/cocaine total body surface area topical corticosteroids T-cell receptor toxic epidermal necrolysis transepidermal water loss transglutaminase triacylglycerol transglutaminase 1 transforming growth factor tight junction toll-like receptor transmembrane domains trimethoprim-sulfamethoxazole tumour necrosis factor transient pustular melanosis thiopurine methyltransferase TNF receptor superfamily 1A-associated periodic fever syndrome thermal relaxation time tuberous sclerosis trichothiodystrophy unrelated donor unconjugated oestriol ultraviolet ultraviolet light vascular endothelial growth factor vascular endothelial growth factor receptor 3 very-long-chain fatty acid varicella zoster immunoglobulin varicella zoster virus World Allergy Organization Wiskott-Aldrich syndrome World Health Organization water in oil X-linked dominant X-linked mental retardation X-linked recessive zoster immune globulin Zunich neuroectodermal syndrome

1.1

CHAPTER 1

The History of Paediatric Dermatology John Harper Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Trust, London, UK

Ancient origins of paediatric

Paediatric dermatology in North America

dermatology, 1.1 The global establishment of paediatric

(USA and Canada), 1.3 Paediatric dermatology in Latin

dermatology as a recognized

America, 1.4

Paediatric dermatology in Japan, 1.4 Paediatric dermatology in Europe, 1.4 The future for paediatric dermatology, 1.5

subspecialty, 1.2

Ancient origins of paediatric dermatology Visible skin abnormalities have been recognized since the dawn of history, dating back about 5000 years to the oldest medical text of Sumer, an ancient city of Mesopotamia. The text, in the form of a clay tablet, is a pharmacopoeia in which many salves (a medical ointment used to soothe the head or other body surface) and lotions are listed. There are other Mesopotamian medical tablets that mention conditions relating to itching, leprosy, impetigo, erysipelas and jaundice. Specifically in the newborn are recorded the vernix caseosa and some congenital skin abnormalities. Other evidence of early records of skin ailments and their treatment is found in the Egyptian papyri of 1500 bc, in the sacred books of the Hindus of ancient India and in the Hippocratic writings of the Greeks. Hippocrates drew attention to cutaneous disorders in children, restricted largely to clinical observation. In the Hippocratic writings at least six passages deal specifically with skin ailments in children. He refers to leprosy, lichen and leuke. Leuke was considered by many scholars to be a form of leprosy or vitiligo, and lichen has been variously interpreted as representing a variety of skin conditions – ringworm, eczema, psoriasis, herpes – characterized by eruptions and itching. Rhazes (865–925), a Persian physician, alchemist, philosopher and scholar, is considered to be the father of paediatrics for writing The Diseases of Children, the first book of paediatrics. He describes infantile eczema (cradle cap), which he called ‘sahafati’ … lesions exuding fluid spread over the head and face causing the child to cry and

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

scratch … he concluded the affliction proceeded from superfluidities of the blood and excess moisture of the skin … he recommended depilation of the scalp followed by the application of atriplex leaves to draw out the ‘poison’ … he also mentioned the use of lead ointment. His classic work was to distinguish smallpox and measles, as well as chickenpox, through his clinical characterization of these diseases. Avicenna (980–1037), whose Canon of Medicine exerted a great influence on medieval medicine, described an eruptive condition now considered to be scarlet fever. Avenzoar (1113–62), another Arabian philosopher, was the first to be credited with describing the itchy mite of scabies. The first monograph on dermatology is Galen’s (129–200 ad) De Tumoribus Praeter Naturam on abnormal swellings. In 1572, Geronimo Mercuriali of Forlì, Italy, completed De morbis cutaneis (‘Diseases of the Skin’), and this is recognized as the first scientific work to be dedicated to dermatology. Robert Willan (1757–1812) is considered the founder of dermatology as a medical specialty. Thomas Bateman (1778–1821) was a British physician and a pioneer in the field of dermatology. Willan died leaving Bateman to continue and expand on the work of his mentor. In 1817 Bateman published an atlas called Delineations of Cutaneous Disease (Fig. 1.1). The first treatise exclusively devoted to paediatric dermatology was Cutaneous Diseases Incidental to Childhood by Walter C. Dendy, published in London in 1827 (Fig. 1.2). The author was Surgeon to the Royal Universal Dispensary for Children, later to become the Royal Waterloo Hospital for Children and Women, part of St Thomas’ Hospital. Two decades later Charles West worked at the same hospital, where only ambulatory patients attended. In 1852 Dr Charles West played a significant role in

1.2

Chapter 1

Fig. 1.2 A Treatise on the Cutaneous Diseases Incidental to Childhood. Walter C. Dendy, John Churchill, London, 1827. The first textbook of pediatric dermatology. Courtesy of the Wellcome Library, London.

Fig. 1.1 From Delineations of Cutaneous Diseases. Thomas Bateman. Henry G. Bohn, London 1st edn. 1817; 2nd edn 1840: PLATE 1. The STROPHULUS intertinctus; popularly termed the Red Gum, or Gown; a pimply eruption of a vivid red colour, rising sensibly above the level of the skin, and intermixed often with dots and red patches which have no elevation. It is peculiar to very young infants; and often consistent with good health.

establishing the Hospital for Sick Children, Great Ormond Street, London. In the Western world, the first generally accepted paediatric hospital is the Hôpital des Enfants Malades, opened in Paris in June 1802, on the site of a previous orphanage. From its beginning, this famous hospital accepted patients up to the age of 15 years and it continues to this day as the paediatric division of the NeckerEnfants Malades Hospital, created in 1920 by merger with the Necker Hospital, founded in 1778 for adults.

The global establishment of paediatric dermatology as a recognized subspecialty

Fig. 1.3 Poster advertising the first International Symposium on Pediatric Dermatology held in Mexico City in 1973.

It was not until 1972 that paediatric dermatology was ‘officially born’ at the first International Symposium of Paediatric Dermatology in Mexico City (Fig. 1.3). Distinguished physicians met at the famous San Angelin Restaurant and founded the International Society of Pediatric Dermatology. These pioneers included: Martin Beare (Ireland); Ferdinando Gianotti (Italy); Joan Hodgeman (USA); Coleman Jacobson (USA); Guinter Kahn (USA); Andrew Margileth (USA); Edmund Moynahan (England); Dagoberto Pierini (Argentina); Ramon Ruiz-Maldonado

(Mexico); Lawrence Solomon (USA); Eva Torok (Hungary) and Kazuya Yamamoto (Japan). Prior to this children and adolescents with skin maladies were mainly looked after by paediatricians and primary care physicians, with only a few dermatologists and academics interested in the research and management of these children. Following that historic meeting in Mexico City, interest in this discipline of medicine has grown dramatically throughout the world and is now integral to all major dermatological and paediatric meetings. Since then, 10 World Congresses of

The History of Paediatric Dermatology

1.3

Paediatric dermatology in North America (USA and Canada)

Fig. 1.4 Delegates attending the Second International Congress of Pediatric Dermatology in Chicago, including Ruggero Caputo, Nancy Esterly, Sidney Hurwitz, Alvin Jacobs, Coleman Jacobson, Gunter Kahn, Al Lane, Marc Larregue, Arthur Norins, Jim Rasmussen, Ramon Ruiz Maldonado, Jean-Hilaire Saurat, Laurence Schachner, Lawrence Solomon, Loudes Tamayo, Sam Weinberg, William Weston. Courtesy of Dr Susan Bayliss.

Paediatric Dermatology have taken place: Chicago (Fig. 1.4), Monte Carlo, Tokyo, Milan, Toronto, Buenos Aires, Paris, Cancun, Rome and Thailand. There are now journals specifically dedicated to the subject published in the USA, Japan and Europe. The Society of Pediatric Dermatology in the USA was founded in 1975, the Japanese Society for Pediatric Dermatology in 1977 and the European Society for Pediatric Dermatology in 1983. The past two decades have seen a plethora of textbooks on paediatric dermatology, but it is important to highlight two authors, Sidney Hurwitz and William Weston, whose books respectively had a profound influence on the establishment of the specialty and its teaching. There are two up-to-date encyclopaedic textbooks of pediatric dermatology; one edited by Schachner and Hanson and the other edited by Harper, Oranje and Prose (first two editions) and Irvine, Hoeger and Yan (third edition). Mexico has led the way in training with a programme for both paediatricians and dermatologists, founded in 1973 by Ramon Ruiz Maldonado and Lourdes Tamayo. More than 100 specialists now working in most Latin American countries have been trained in that programme. In the USA paediatric dermatology became an independent board-certified subspecialty as recently as 2004. Elsewhere in the world training remains ad hoc and includes paediatricians with a special interest in dermatology, dermatologists with a special interest in children, and a select handful who have a full training in both specialties. In some countries the lack of cooperation between the two disciplines can be a stumbling block to the establishment of the specialty.

Henry Harris Perlman was the first physician to be board certified by both the American Academy of Pediatrics and the American Academy of Dermatology (AAD), the first to limit his practice to diseases of the skin in children (1946) and the first in the USA to write a textbook dedicated solely to Pediatric Dermatology (see Moynahan, 1961, p. 954 for a review). In the 1960s and 1970s interest in pediatric dermatology was pursued by a group of physicians in the USA, who made a major contribution to the establishment of the subject as a recognized specialty (in alphabetical order): Carroll Burgoon Jr, Philadelphia; Sidney Hurwitz, New Haven, Connecticut; Alvin Jacobs, Palo Alto, California; Gunter Kahn, Miami, Florida; Peter Koblenzer, Morristown, New Jersey; Arthur Norins, Indianapolis, Indiana; James Rasmussen, Buffalo, New York; Lawrence Solomon and Nancy Esterly, Chicago; Samuel Weinberg, New York City; and William Weston, Denver, Colorado. At the AAD meeting in Chicago in December 1974, four paediatric dermatologists met for the purpose of starting a Society for Pediatric Dermatology (SPD). They were Sidney Hurwitz, Sam Weinberg, William Weston and Alvin Jacobs. A meeting was organized in Dallas, Texas, in February 1976, hosted by Coleman Jacobson. Thirty-eight interested in membership attended. Sidney Hurwitz was elected President, Sam Weinberg and Alvin Jacobs VicePresidents, and William Weston Secretary-Treasurer (Fig. 1.4). The first Scientific Meeting of the Society was hosted by William Weston in Aspen, Colorado, in July 1976. Subsequent annual meetings attracted more and more individuals and now the SPD is recognized internationally to be one of the leading groups representing our specialty worldwide. In addition to the summer annual meeting, the one-day meeting prior to the AAD has been very successful and attracts a high attendance. At the 10th annual meeting in Cape Cod, the first annual Sidney Hurwitz lectureship was inaugurated. Dr Tomisaku Kawasaki of Tokyo, who first described the disorder that bears his name, gave an update on Kawasaki’s disease. The AAD now recognizes paediatric dermatology as a board certified subspecialty, for which there are designated training programmes with defined certification requirements (http://www.abderm.org/subspecialties/ qualification.html). The Journal of Pediatric Dermatology was first published in 1983 with Lawrence Solomon and Nancy Esterly as editors. It is the main journal worldwide for the subspecialty with a high profile of clinical and research contributions. It is published by Wiley Blackwell and the current editors are Ilona Frieden and Lawrence Eichenfield.

1.4

Chapter 1

Paediatric dermatology in the USA has seen a rapid growth of interest, with many new young paediatric dermatologists (too many to list) who are making significant contributions to our understanding and treatment of skin ailments in children and adolescents. Many of these clinicians and research workers have contributed to this textbook. In Canada, paediatric dermatology has been led by Bernice Krafchik in Toronto, with Julie Prendiville (Vancouver) and Julie Powell and Danielle Marcoux (Montreal). In 1981, Bernice Krafchik hosted the meeting of the Society of Pediatric Dermatology, with over 150 attendees from Canada and the USA. In 1992, Bernice Krafchik and Jim Rasmussen organized the sixth World Congress of Pediatric Dermatology in Toronto.

Paediatric dermatology in Latin America Modern day paediatric dermatology owes much to the dedication, enthusiasm and commitment of Ramon Ruiz Maldonado and Lourdes Tamayo of Mexico City in establishing paediatric dermatology as a subspecialty, not just in Mexico but throughout Latin America. Their influence, in promoting and supporting paediatric dermatology, has been worldwide. The first Symposium of Pediatric Dermatology was in 1972 in Mexico City (Fig. 1.3) and at that time the International Society of Pediatric Dermatology was founded. The first training programme in the world was established at the National Institute of Pediatrics in Mexico City in 1973, for both paediatricians and dermatologists. Certified paediatricians do 3 years of training in paediatric dermatology, and certified dermatologists do 1 year ’s training in paediatric dermatology to obtain a diploma in paediatic dermatology. Subsequently, Dagoberto Pierini launched the Paediatic Dermatology training programme in Argentina, where there are currently two training institutes, headed by Adrian Pierini and Margarita Larralde. The seventh World Congress of Pediatric Dermatology was held in Buenos Aires under the Presidency of Adrian Pierini. Paediatic dermatology is now a recognized subspecialty in most Latin American countries. Past and present leading paediatric dermatologists include: Evelyne Halpert (Colombia); Hector Caceres, Leonardo Sanchez (Peru); Luiz Alfredo Gonzales Aveledo (Venezuela); Adrian Pierini, Margarita Larralde, Rita Garcia Diaz, Maria Rosa Cordisco, Jose Antonio Massimo (Argentina); Ramon Ruiz Maldonado, Lourdes Tamayo, Carola Duran McKinster (Mexico); Fausto Forin Alonso, Susana Giraldi (Brazil); Julia Oroz, Winston Martinez, Sergio Silva (Chile); and Raul Vignale, Marcelo Ruvertoni (Uruguay).

In 1996 in Lima, the Latin American Society for Pediatric Dermatology (SLADP) was founded. The first Congress was held in Bogota in 1997, organized by Evelyne Halpert. The SLADP has grown significantly over the years and now includes representation of 15 countries, meeting every 3 years. Hector Caceres and his working group are responsible for the journal Revista de Dermatología Pediátrica Latinoamericana.

Paediatric dermatology in Japan Kazuya Yamamoto was Head of the Department of Dermatology at the National Children’s Hospital in Tokyo and in 1977 established the Japanese Society for Pediatric Dermatology (JSPD). The first President was Professor Toshiaki Yasuda. The JSPD met annually and at each meeting invited both national and international guest speakers. The number of members of the JSPD has risen to over 1000. In 1986 Tokyo hosted the fourth World Congress of Pediatric Dermatology, with Professor Harukuni Urabe as President and Kazuya Yamamoto as the Head of the Secretariat. The Journal of the JSPD was first published in 1982 and has continued biannually to the present time.

Paediatric dermatology in Europe This new medical discipline has become established in most European countries over the past 25 years. Physicians who have made major contributions to paediatric dermatology in Europe include: Jean-Hilaire Saurat, Marc Larregue, Jean Maleville, Yves de Prost and Alain Taieb (France); Ruggero Caputo, Carlo Gelmetti, Giuseppe Fabrizi and Ernesto Bonifazi (Italy); Rudolph Happle, Heiko Traupe (Germany); Martin Beare, Edmund Moynahan, Charles Wells, David Atherton and John Harper (UK); Micheline Song and Linda de Raeve (Belgium); Arnold Oranje, Flora de Waard-van der Spek and Henk Sillevis Smit (The Netherlands); Talia Kakourou (Greece); Juan Ferrando, Ramon Grimalt, Antonio Torrelo (Spain); and Daniel Hohl (Switzerland). This list does not include a number of eminent physicians who predate the past 25 years, physicians in other European countries and new young doctors trained in paediatric dermatology. National societies have been established in many European countries: Belgium, Croatia, France, Germany, Greece, Hungary, Italy, The Netherlands, Portugal, Spain, Switzerland, Turkey and the UK. Research in Europe has made major contributions to our understanding and treatment of skin conditions in children. Examples include: acrodermatitis enteropathica

The History of Paediatric Dermatology

and zinc deficiency (Edmund Moynahan); graft-versushost disease of the skin (Jean-Hilaire Saurat); the histiocytoses (Ruggero Caputo) and most recently propranolol treatment for haemangiomas (Alain Taieb). The European Society of Pediatric Derrmatology (ESPD) was established in 1983. European Congresses have been held in: Munster, 1984; Bari, 1987; Bordeaux, 1990; Bournemouth, 1993; Rotterdam, 1996; Rome, 1999; Barcelona, 2002; Budapest, 2005; and Athens, 2008. The first paediatric dermatology course in Europe was set up in 1977 by Marc Larregue and Jean Maleville, held in Arcachon in France and continued annually. Other courses have since been established in Paris, Bari, Rome, Rotterdam, Dundee and Birmingham. As well as the journal Pediatric Dermatology to which the ESPD is affiliated, the first edition of Pediatric Dermatology News, edited by Ernesto Bonifazi, was in 1982. In 1991 this publication became the European Journal of Pediatric Dermatology.

The future for paediatric dermatology The inspired vision of our predecessors has firmly established paediatric dermatology as a recognized subspecialty internationally. Compared to other medical subspecialties, paediatric dermatology is in its infancy in development. The main issue that needs addressing is an agreed international training programme. This has been achieved in Mexico and in the USA and must be a priority for the International Society for Pediatric Dermatology (ISPD) as we strive forward in this new millennium. To quote Sidney Hurwitz, in Pediatric Dermatology in 1988:

1.5

‘Those of us who have committed ourselves to this discipline are proud of the accomplishments of the past, appreciate the rapidly growing interest in this field in the present and look forward to the challenges of the future with continued optimism and enthusiasm.’ Further reading Copeman PWM. The creation of global dermatology. J Roy Soc Med 1995;88:78–84. Galimberti R, Pierini AM, Cervini AB. (eds) History of Latin American Dermatology. Toulouse: Edicions Privat, 2007. Hurwitz S. The history of pediatric dermatology in the United States. Pediatr Dermatol 1988;5:280–5. Moynahan EJ. Review of Pediatric Dermatology by Henry H Perlman. BMJ;1961(1 April):954. Radbill SX. Pediatric dermatology in antiquity: part I. Int J Dermatol 1975;14:363–8. Radbill SX. Pediatric dermatology in antiquity: part II. Roman Empire. Int J Dermatol 1976;15:303–7. Radbill SX. Pediatric dermatology in antiquity: part III. Int J Dermatol 1978;17:427–34. Radbill SX. Pediatric dermatology: chronological excursions into the literature. Part I. Pediatric dermatology in general medical texts. Int J Dermatol 1985;26:250–6. Radbill SX. Pediatric dermatology: chronological excursions into the literature. Part II. Pediatric dermatology in pediatric texts. Int J Dermatol 1987;26:324–31. Radbill SX. Pediatric dermatology: chronological excursions into the literature. Part III. DermatologicTexts. Int.J Dermatol. 1987; 26(6): 394–400. Radbill SX. Pediatric Dermatology: chronological excursions into the literature. Part IV. Pediatric dermatology texts. Int J Dermatol 1987;26:474–9. Ruiz-Maldonado R. Pediatric dermatology accomplishments and challenges for the 21st century. Arch Dermatol 2000;136:84. Taieb A, Larregue M, Maleville J. The development of paediatric dermatology. In: Wallach D, Tilles G (eds) Dermatology in France. Toulouse: Editions Privat, 2002; 127–31. http:www.bium.univ-paris 5.fr/histmed/medica/cote?extwall00001. Yamamoto K. The Society: early days. J Jpn Soc Pediatr Dermatol 2009;28:158–162 [in Japanese].

2.1

CHAPTER 2

Embryogenesis of the Skin Karen A. Holbrook Department of Physiology and Cell Biology, Ohio State University, Columbus, OH, USA

Introduction, 2.1

Embryonic–fetal transition, 2.12

Time-scale of skin development, 2.2

Fetal skin, 2.19

Embryonic skin, 2.4

Introduction The skin is an ideal organ in which to study development through ageing because it is readily accessible for observation, sampling and evaluation. As an interface, it straddles the internal, systemic world of the individual and the external environment and is vulnerable to and can be modified by both. The skin itself is a remarkably complicated and complex organ, with the normal structure and function of each ‘part’ highly dependent upon what happens in other parts of the skin. In other words, one cannot understand, for example, changes that occur in the epidermis without understanding the nature of the dermis since the dermis has major influences on the activities and functions of the epidermis. This is the case for each region or structure of the skin. Development, however, offers an opportunity to study skin structure and function under more ‘controlled’ conditions because, except for changes in the composition of the amniotic fluid (similar to maternal plasma in the embryo but more characteristic of fetal urine in the second trimester [1,2]), the environment of the developing skin is reasonably constant (controlled light, temperature, pressure, etc.). It is possible therefore to investigate how the properties of the different regions and structures of the skin are coordinately established, presumably under the directions of a genetic program, and spared from the assaults of the external world. For the sake of simplicity, the period of skin development can be correlated with the in utero life of the individual. This is not an absolute correspondence, however, because some of the structures of the skin may be fully formed early in the fetal period whereas other structures or regions are not complete until well into the postnatal

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Unique features of developing human skin, 2.23 Conclusion, 2.41

years. Also, full establishment of adult functions of the skin always requires an extended period of development beyond the stages in utero. Development is therefore the first period in a continuum of events that modifies the skin; it is characterized by morphogenetic processes, the activation of new genes and the gain of function. In contrast, ageing may involve morpholytic processes in which genes are turned off, resulting in a loss of function. Consideration of this continuum, and the genetic and environmental interactions that come into play at progressive ages throughout life, provides a conceptual framework for discussing the place and role of the events in skin morphogenesis. Understanding the stages and events of normal human skin development is also important from a biomedical perspective: it allows the definition of critical periods when the skin may be more vulnerable to developmental errors; it provides an opportunity to study the evolution of skin function, establishing a background for understanding the natural history of expression of genetic skin disease in its earliest form; and it provides the essential information for the evaluation of skin samples used in the prenatal diagnosis of genodermatoses for which molecular methods are still not adaptable. Studies of skin development can also shed light on a number of basic problems in contemporary biology: epithelial–mesenchymal interactions that establish organs (in skin, these tissue interactions occur in follicle, sweat gland and nail formation); cell–cell interactions through soluble mediators; gene regulation; apoptosis; differentiation (structural, biochemical and functional); and certain longstanding basic phenomena of development such as induction, pattern formation and differentiation. They provide an opportunity to ask how a molecule is expressed and how expression of that molecule may modify the properties of the tissue over a time sequence that begins in the simple embryonic environment and builds progressively to more complex fetal conditions. Samples of fetal skin and fetal

2.2

Chapter 2

skin-derived cells are easily established in culture for experimental studies designed to probe some of these questions, and many of the studies of skin development can be performed in animal models. But the animals that are typically used for this work (primarily rodents) lack the advantage of the long gestation period of the human, which allows for the events of development to unfold slowly and thus permits a more systematic analysis of change. The unique morphological properties of developing human skin have always intrigued investigators who have had access to this tissue. Specific aspects of the skin that are found only in the fetus, such as the periderm, and specific events that result in the formation of complex structures, such as follicle or sweat gland, were often described for specific ages only (reviewed in refs [3–6]). These descriptions, coupled with speculation as to function, led inevitably to more systematic and comprehensive studies to characterize the complete ontogeny of the tissue, region or structure (reviewed in refs [3–6]). Such studies then began to include data derived from biochemical or immunohistocytochemical assays for the expression of specific molecules that were known to correlate with the state of differentiation or with a specific property such as barrier function adhesion and so on. Culturing and grafting human embryonic and fetal skin (reviewed in refs [7–10]) and skin-derived cells [11,12] and evaluation of skin from fetuses affected with genodermatoses (reviewed in refs [13–15]), or under conditions of growth retardation, have also provided insight into human skin development. Our understanding of skin development continues to increase as we apply more modern tools of biology to study the skin at all stages of life. References 1 Lind R, Parkin FM, Cheyne GA. Biochemical and cytological changes in liquor amnii with advancing gestation. J Obstet Gynaecol Br Commonw 1971;76: 673–83. 2 Benzie RJ, Doran TA, Harkins JL et al. Composition of the amniotic fluid and maternal serum in pregnancy. Am J Obstet Gynecol 1974; 119:798–810. 3 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110. 4 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51. 5 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144. 6 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R (eds) Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995. 7 Holbrook KA, Minami SA. Hair follicle morphogenesis in the human: characterization of events in vivo and in vitro. NY Acad Sci 1991; 642:167–96.

8 Zeltinger J, Holbrook KA. A model system for long term, serum-free, suspension organ culture of human fetal tissues: experiments using digits and skin from multiple body regions. Cell Tissue Res 1997; 290:51–60. 9 Lane AT, Scott GA, Day KH. Development of human fetal skin transplanted to the nude mouse. J Invest Dermatol 1989;93:787–91. 10 Gilhar A, Gershoni-Baruch R, Margolis A et al. Dopa reaction of fetal melanocytes before and after skin transplantation onto nude mice. Br J Dermatol 1995;133:884–9. 11 Oliver AM. The cytokeratin expression of cultured human foetal keratinocytes. Br J Dermatol 1990;123:707–16. 12 Scott G, Ewing J, Ryan D et al. Stem cell factor regulates human melanocyte–matrix interactions. Pigment Cell Res 1994;7: 44–51. 13 Holbrook KA, Smith LT, Elias S. Prenatal diagnosis of genetic skin disease using fetal skin biopsy samples. Arch Dermatol 1993;129:1437–54. 14 Sybert VP, Holbrook KA, Levy M. Prenatal diagnosis of severe dermatologic diseases. Adv Dermatol 1992;7:179–209. 15 Sybert VP, Holbrook KA. Antenatal pathology of the skin. In: Claireaux AE, Reed GB (eds) Diseases of the Fetus and Newborn: Pathology, Radiology and Genetics. New York: Cockburn, Chapman & Hall, 1995: 755–68.

Time-scale of skin development There are several schemes for categorizing stages of skin development (Fig. 2.1). All of them are arbitrary and overlapping, and based on some parameter that is relevant to human development per se, to a period defined for purposes of medical intervention, a specific event that is considered a landmark in the evolution of skin structure, composition and function, or on the basis of the surface properties of the developing skin [1]. Human development is separated into embryonic (before the onset of bone marrow function) and fetal periods, corresponding, respectively, to conception until approximately 2 months estimated gestational age (EGA), and to 2 months EGA until birth. The first trimester includes the entire embryonic period and the first stages of the fetal period. Histogenesis of all skin regions is initiated in the embryo, and differentiation of some of those tissues begins to occur [2]. The boundary between the first and second trimesters, at 3 months of age, is based only on fetal age and not on any remarkable changes in structure, composition or function of any region of the skin. The second trimester includes many important events in skin development that can be correlated with changes in function and, at the same time that morphogenesis of new structures is initiated, there is terminal differentiation of others. During the third trimester, as far as we know, all parts of the skin are assembled and the functions of each of them are unfolding. The end of this period

Embryogenesis of the Skin

2.3

Fig. 2.1 Time-scale diagram identifying specific stages of skin development and identifying the ages at which prenatal diagnosis can be performed using each of the various methods currently employed. Modified from Polin RA, Fox WW. Fetal and Neonatal Physiology, 2nd edn, Vol. 1. Philadelphia: W.B. Saunders, 1998: 730.

is not the final state of the skin, as there is significant reorganization of certain units of the skin (e.g. the vasculature), additions to the skin in volume (e.g. the dermal matrix) and functional maturation of many structures of the skin (e.g. nerves, sweat glands and stratum corneum) after the newborn faces the environment of the external world [3–6,7]. Other important times that should be recognized in skin development are the ages at which chorionic villus sampling, amniocentesis and fetal skin biopsy are performed for the purpose of evaluating the condition of a fetus at risk for a genetic skin disease. Fetal DNA can be extracted from chorionic villi sampled around 10 weeks EGA, amniotic fluid cells can be obtained at around 14–16 weeks EGA, and fetal skin can be sampled as early as 16 weeks EGA. More typically, the skin is biopsied at 19–21 weeks [8–10]. The older age is necessary when diseases of keratinization are in question. This chapter is organized to describe specific periods, unique features and special events or processes of skin development using EGA, the age from the date of conception, to represent the age of the embryo or fetus in utero. In the literature gestational age is used interchangeably with menstrual age, which is calculated from the date of the last known menstrual period and thus records the timing of developmental events about 2 weeks later than EGA. Unanswered questions will be raised for the reader ’s thoughtful consideration.

References 1 Holbrook KA, Odland GF. The fine structure of developing human epidermis: light, scanning and transmission electron microscopy of the periderm. J Invest Dermatol 1975;65:16–38. 2 Holbrook KA, Dale BA, Smith LT et al. Markers of adult skin expressed in the skin of the first trimester fetus. Curr Prob Dermatol 1987;16:94–108. 3 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110. 4 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51. 5 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144. 6 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R (eds) Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995. 7 Holbrook KA. A histologic comparison of infant and adult skin. In: Boisits E, Maibach HI (eds) Neonatal Skin: Structure and Function. New York: Marcel Dekker, 1982: 3–31. 8 Holbrook KA, Smith LT, Elias S. Prenatal diagnosis of genetic skin disease using fetal skin biopsy samples. Arch Dermatol 1993;129: 1437–54. 9 Sybert VP, Holbrook KA, Levy M. Prenatal diagnosis of severe dermatologic diseases. Adv Dermatol 1992;7:179–209. 10 Sybert VP, Holbrook KA. Antenatal pathology of the skin. In: Claireaux AE, Reed GB (eds) Diseases of the Fetus and Newborn: Pathology, Radiology and Genetics. New York: Cockburn, Chapman & Hall, 1995: 755–68.

2.4

Chapter 2

Embryonic skin The primitive ectoderm of the developing blastocyst is established at 1 week EGA, and by 20–50 days EGA the major organs and organ systems of the human embryo are becoming established. The integumentary system exhibits characteristics of the skin at 30 days EGA, the earliest age at which specimens can be realistically obtained for study. Sampling of skin at this age is remarkable considering that the 6-week-old embryo has a crown– rump length of only 20 mm – no larger than a 20 pence piece (or a dime). Nonetheless, the epidermis, dermoepidermal junction (DEJ) and dermis are well delineated and the tissue is innervated and vascularized (Fig. 2.2). The boundary between the dermis and subcutaneous tissue is not clearly defined in all body sites, but in some regions these two zones are distinct from one another on the basis of a greater density of cells and matrix in the dermis compared with the hypodermis. The skin is closely asso-

(a)

(b) Fig. 2.2 (a) Tissue of the body wall of a 36-day EGA human embryo and (b) the skin from a 45-day EGA human embryo. Note the two-layered epidermis, dermis and subcutaneous tissue and the more linear orientation of dermal cells in contrast to the pleiomorphic shapes of the subcutaneous mesenchyme. In (b) note the periderm and basal cells of the epidermis, the closely associated fibroblastic cells in the dermis proximal to the epidermis and a nerve–vascular plane separating the dermis from the subcutaneous tissue (×200).

ciated with the underlying developing striated muscle or cartilage on the appendages. There is no morphological evidence that epidermal appendages have begun to form. In most regions of the embryo, the epidermis is a simple, flat, two-layered epithelium consisting of basal and periderm cells (see below) (Figs 2.2 and 2.3). Both types of cells are mostly filled with glycogen, a molecule that is characteristic in the cytoplasm of developing and regenerating tissues, where it most likely serves as a source of energy [1] (Fig. 2.3). The nucleus is centrally located in periderm and basal cells, and the cytoplasmic organelles are sparse and distributed either around the nucleus or at the periphery of the cell (Fig. 2.3b). The structural characteristics of these cells therefore fail to reveal significant differences between the two layers or to verify that either layer is composed of keratinocytes. Evaluation of the structural proteins, however, indicates that both contain keratin intermediate filament proteins (Fig. 2.4), but different species [2,3], and some cell-surface molecules are unique to each layer [4]. The latter markers may reflect the differences in environments surrounding each layer. The columnar-shaped basal cells of the embryonic epidermis express the keratins that are characteristic of adult basal layer keratinocytes – K5 (58 kDa) and K14 (50 kDa) [2,3] – and additional keratin polypeptides – K19 (40 kDa) and K8 (52 kDa) – are specific to embryonic/fetal basal cells and periderm cells [2,3]. The latter keratins are not characteristic of normal adult basal keratinocytes, but they are identified in glandular and simple epithelial cells [5]. In contrast to the adult tissue, the filaments in fetal embryonic epidermis are dispersed in the cytoplasm or assembled in small, seemingly short, bundles that are associated primarily with desmosomes and hemidesmosomes (see Fig. 2.3b). Periderm cells and basal cells also differ in the expression of many growth factors, growth factor receptors (Fig. 2.5) [6,7], cell adhesion molecules [8] and other cytoplasmic and cell-surface molecules. About 15–19% of the basal cells incorporate label when viable tissue is incubated in culture medium containing [3H]-thymidine for 1 h, rinsed and then processed for autoradiography. This is a higher labelling index than the fetal or adult epidermis, which was recorded at 10% and 6.7% labelling, respectively, under the same conditions [9]. It is possible that only the basal layer is truly epidermis. A thin, flattened layer of periderm cells covers the basal layer, with no apparent correspondence in number with the cells beneath it, i.e. one polygonal periderm cell lies above several basal cells. Microvilli project from the peridermal surface into the amniotic fluid (Figs 2.3b and 2.6). At least one keratin polypeptide expressed in periderm cells is different from those in the basal cells, K18 (45 kDa), although it is a marker for Merkel cells [10,11].

Embryogenesis of the Skin

2.5

Fig. 2.3 Transmission electron micrographs of the embryonic epidermis. In (a) note the glycogen (G)-filled basal (B) and periderm (P) layer cells. Desmosomes are evident between basal cells and between basal cells and periderm cells. The DEJ is flat and shows few sites of increased density, suggesting sites of desmosome formation. In (b) one periderm cell and portions of two basal cells are shown. Note the nature and disposition of cytoplasmic organelles within both cell types, the keratin filaments associated with desmosomes (arrow) and the microvilli extending from the periderm surface (a, ×11,525; b, ×25,000).

(a)

(a)

(b)

(c)

(d)

(b)

Fig. 2.4 Immunostained samples of (a) early (∼50-day EGA) and (b–d) later (∼60-day) human embryonic epidermis showing positive staining of both periderm and basal layers with the AE1 (a) and AE3 (d) monoclonal antibodies that recognize keratins. Both layers are negative when reacted with the AE2 (c) antibody, which recognizes the differentiation-specific keratins (×350).

2.6

Chapter 2

Fig. 2.5 Section of skin from a 78-day EGA human fetus showing differential expression of the A-chain of PDGF in the basal and intermediate cell layers (green) and an absence of staining in peridermal cells. The receptor for PDGFA, PDGFR-α (red), is expressed by cells in the dermis (×350).

(a)

Fig. 2.6 Scanning electron micrograph of the surface of 55-day EGA embryonic skin from the surface of the developing foot. The layer of cells shown is the periderm. Note the microvilli and the variable size and shape of the cells (×1000).

Two of the immigrant cells that are prominent in adult epidermis, melanocytes (neural crest in origin) and Langerhans cells, are present in the embryonic epidermis among basal cells and associated with the basement membrane. Sheets of embryonic epidermis immunostained with an antibody that recognizes melanocytes specifically (HMB-45, an inducible, cytoplasmic antigen common to melanoma and embryonic/fetal melanocytes [12,13]) show a remarkably high density (∼1000 cells/ mm2) of these cells organized in a regular pattern of distribution (Fig. 2.7). They are dendritic as early as 50 days

(b) Fig. 2.7 Embryonic skin from a 54-day EGA human embryo immunostained with the HBM-45 monoclonal antibody, which recognizes an antigen in the melanocyte. (a) Section of skin. Note the abundance and position of these cells within the two-layered epidermis. (b) Epidermal sheet. Note the density, spacing and dendritic morphology of these cells (a, ×350; b, ×25).

EGA in general body skin but there is no evidence of melanosomes in the cytoplasm [14]. Langerhans cells are recognized in embryonic skin as early as 42 days EGA on the basis of a reaction product for membrane-bound Mg2+ adenosine triphosphatase (ATPase) and histocompatibility locus antigen (HLA-DR) on the plasma membrane

Embryogenesis of the Skin

[15–17] and by their truncated or dendritic morphology (Fig. 2.8). They are probably derived from the yolk sac or fetal liver at this age because they are present in skin before the bone marrow begins to function. At 7 weeks EGA, the density of Langerhans cells is about 50 cells/ mm2 [16,17]. The third immigrant cell, the Merkel cell, can be recognized in embryonic palmar skin as early as 55–60 days EGA (see Eccrine sweat gland formation) at a density of ∼130 cells/mm2 [10,18], using as a marker any one of the set of keratins expressed by Merkel cells (K8, K18, K10 and K20) [10,11,19–21]. K20 is the only keratin found exclusively in Merkel cells [21]. At this embryonic age, they are distributed randomly and in a suprabasal position. Merkel cells are neuroendocrine cells that were originally thought to function primarily as slow-adapting mechanoreceptors. More recently, studies that have catalogued soluble mediators produced by these cells, for example nerve growth factor (NGF) [22], suggest that it is likely that Merkel cells are targets for ingrowing nerve

Fig. 2.8 Epidermal sheet from a 53-day EGA human embryo immunostained to recognize HLA-DR antigen in epidermal Langerhans cells (×400). Micrograph courtesy of Dr Carolyn Foster.

2.7

fibres or other cells such as the smooth muscle cells of the arrector pili muscle [23,24]. Their presence in selected sites of developing epidermal appendages (e.g. sweat glands and hair follicles) has also been suggested to stimulate or to correlate with active proliferation of the tissue. It is generally accepted that Merkel cells are derived from keratinocytes in situ [10,19,21,25,26]. A continuous basal lamina (lamina densa) underlies the two-layered epidermis and defines, morphologically, one structural component of the basement membrane zone [27–29]. The basal lamina is patchy, however, in regions of the body where the epidermis may be only a single layer, for example superior to the spinal cord. The molecules and antigens characteristic of all basal laminae (type IV collagen, laminin, heparan sulphate proteoglycan, nidogen/entactin) are present in the earliest recognized basal lamina of the skin; skin-specific molecules are recognized later during the first trimester in accord with the more prominent development of the attachment structures (see below) [30,31]. A thin, mat-like layer of microfilaments lies just inside the basal plasma membrane of the basal cell keratinocytes (Fig. 2.9). It may reinforce this surface of the epidermis and add to the strength of the DEJ at this stage when the structural modifications associated with dermoepidermal adhesion (hemidesmosomes, anchoring filaments, anchoring fibrils) are rudimentary [32]. The same organization of filaments is observed in cultured keratinocytes, which do not typically form hemidesmosomes and anchoring fibrils in vivo, and in basal keratinocytes under pathological situations, such as junctional epidermolysis bullosa, in which the epidermis separates from the dermis. The antigens associated with the attachment structures (laminin 5/epiligrin/kalinin and 19 DEJ-1 for hemidesmosomes and anchoring filaments [33–36]; type VII collagen for anchoring fibrils [37]) are not seen by light

Fig. 2.9 Enlarged view of the DEJ of human embryonic epidermis showing the microfilament network within the basal epidermal cell (arrows), sites where desmosomes are forming (arrowheads) and the lamina densa. Note collagen fibrils (C) surrounding the dermal fibroblastic cells (×11,625).

2.8

Chapter 2

microscopic immunostaining methods until early in the fetal period. It is likely, however, that keratinocytes begin to synthesize these proteins in the embryonic period but that the methods used for detection are not sensitive enough to demonstrate their low levels of expression. The dermoepidermal boundary is flat in the embryonic skin (Figs 2.2, 2.3 and 2.9) and thus presents a limited surface area for nutrients to traverse between the dermis and the epidermis. This may be relatively less important in the developing skin than in infant and adult skin because the dermis is thin and the small, dispersed bundles of dermal matrix proteins and the hydrated condition of the interstitial matrix permit more rapid diffusion of substances than the mature skin. The dermis in the embryo is highly cellular (Figs 2.2 and 2.10), but it also contains the extracellular fibrous matrix proteins, types I, III, V and VI interstitial collagens, characteristic of adult dermis [32,38–40,41–45]. Small bundles of collagen accumulate in a thin, dense layer, called the reticular lamina, immediately beneath the dermoepidermal interface (Figs 2.2b, 2.5 and 2.9). They are also dispersed throughout the dermis in varying densities according to the collagen type and age of the embryo. Types I, III and VI collagen are distributed uniformly throughout the dermis whereas type V collagen is concentrated primarily along basement membranes (at the DEJ and around blood vessels) and surrounding cells (Fig. 2.11). Fibre bundles within the interstitial spaces are widely dispersed by a hydrated, hyaluronic acid-rich proteoglycan matrix [46–48] (Fig. 2.12). The fluidity of the matrix at this stage permits migration of mesenchymal cells to sites of active tissue morphogenesis. A broader zone of sulphated proteoglycan-rich matrix, called the compact mesenchyme, is delineated beneath the epidermis on the basis of its rich concentration of cells that express growth factor receptors – the platelet-derived growth factor receptor β (PDGFR-β) and PDGFR-α (see Fig. 2.5), nerve growth factor receptor (NGFR) – and cell adhesion molecules (e.g. neural cell adhesion molecule, NCAM) [49,50]. Evidence from the skin of non-human species during development has shown enlargement of the composition of growth factors and receptors and adhesion molecules that are included in this dermal zone (reviewed in refs [49] and [51–53]). The compact mesenchyme may be involved in the exchange of signals between the epidermis and dermis and may be very important in stimulating the onset of appendage formation. Many of the growth factors that correspond to the receptors on the mesenchymal cells are produced by cells of the developing epidermis (e.g. PDGF-AA, PDGF-BB and NGF) (Fig. 2.5). The compact mesenchyme may also be the earliest evidence of a papillary dermis. In the adult, the modified composition and structure of the papillary dermis probably reflects molecular interactions between

(a)

(b) Fig. 2.10 Transmission (a) and scanning (b) electron micrographs of the embryonic dermis at 48 days EGA beginning at the DEJ. The matrix is less evident in the sectioned sample (a) than in the whole-mount specimen (b) (a, ×4500; b, ×1500).

Embryogenesis of the Skin

(a)

(b)

(c)

(d)

2.9

Fig. 2.11 Samples of embryonic skin immunostained with antibodies that recognize type I (a), III (b), V (c) and VI (d) collagens. Note that all of the collagens are concentrated beneath the DEJ but types III and V, especially, are found in association with all basement membranes. Types I, III and VI are found in the matrix throughout the dermal and subcutaneous tissue (a–c, ×150; d, ×300). Immunostaining courtesy of Dr Lynne T. Smith.

the epidermal and dermal cells, similar to the situation of the compact mesenchyme. Elastic fibres per se are not formed in the embryonic skin, but fibrillin (the microfibrils of elastic fibres) (Fig. 2.13) and elastin proteins of the elastic fibre can be identified immunohistochemically [32,38–42,44] and microfibrils can be seen by electron microscopy [32]. Fine nerve fibres and capillaries are present within the compact mesenchyme and deeper dermis (Fig. 2.14a), and large nerve trunks and vessels are readily apparent in the subcutaneous region. Reconstructions of vessels from serial sections of developing first-trimester skin have shown that the the basic pattern of cutaneous vasculature is established in the first trimester [54]. New vessels presumably both form de novo from dermal mesenchyme and sprout from deeper, established vessels

through a process that includes endothelial cell migration, capillary budding and vessel remodelling [55]. The events and mechanisms of these processes have not been explored beyond the morphological descriptions and antigenic characterization of the endothelial cells at various ages during development [55,56]. Pieces of fullthickness skin and sections of skin immunostained with an antibody that demonstrates all cutaneous nerves (protein gene product 9.5 or PGP 9.5) [57,58] reveal finely beaded nerve filaments distributed in an impressive density in the subepidermal region and in association with blood vessels (Fig. 2.14b and c). The number of fibres recognized by this antibody increases during development as the fibres become organized in networks throughout the dermis and in relation to developing epidermal appendages [59]. At 7 weeks EGA, a few calcitonin

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(a)

(b) Fig. 2.12 Section of the body wall from a 57-day EGA embryo treated with the Alcian blue/periodic acid–Schiff (PAS) histochemical stains. The bright pink staining of the epidermis (glycogen) and DEJ (glycoproteins) indicates a PAS-positive reaction. The blue dermis reflects the high content of hyaluronic acid. The dermal–subcutaneous boundary is marked by a transition to a lighter slightly purple reaction indicating more of the collagen–glycosaminoglycan complex (×300). Immunohistochemistry courtesy of Dr Richard Frederickson.

(c) Fig. 2.14 Sections of human embryonic skin at 42 days EGA (a) and 59 days EGA (b) immunostained with PGP 9.5, which recognizes all cutaneous nerves, and of a sample of 52-day EGA embryonic skin (c) immunostained with p75 antibody, which recognizes the low-affinity NGFR. Note the large nerve trunks deep in the subcutaneous tissue (a), the significant density of the fine fibres in the tangential section of the dermis of (b) and the distribution of both nerves and vessels (c) (a, ×100; b, ×200; c, ×200). Fig. 2.13 Section of skin from a 57-day EGA human embryo immunostained with an antifibrillin antibody. Note staining throughout the dermis (×200). Immunostaining courtesy of Dr Lynne T. Smith.

Embryogenesis of the Skin

Fig. 2.15 Nerves and vessels in the skin of a 79-day EGA human fetus immunostained with an anti-neurofilament antibody. Note the positively stained nerve network, the immunopositive cells (presumably Merkel cells) and the vascular network (clear) (×25). Immunostaining courtesy of Dr Mark Bressler.

gene-related product (CGRP)-immunopositive fibres, denoting sensory fibres, are also evident [59], but autonomic nerves are not yet recognized in the skin. Staining the tissue with the p75 low-affinity NGFR antibody also reveals the patterns of nerve fibres and specific concentrations of mesenchymal cells (e.g. around developing hair follicles; see below) [60]. Both nerves and vessels are visible in stained, full-thickness samples of the nearly transparent skin (Fig. 2.15). References 1 Sharp F. A quantitative study of the glycogen content of human fetal skin in the first trimester. J Obstet Gynaecol Br Commonw 1971;78: 981–6. 2 Dale BA, Holbrook KA, Kimball JR et al. Expression of the epidermal keratins and filaggrin during fetal human development. J Cell Biol 1985;101:1257–69. 3 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 1983;23:170–8. 4 Dabelsteen E, Holbrook KA, Clausen H et al. Cell surface carbohydrate changes during embryonic and fetal skin development. J Invest Dermatol 1986;87:81–5. 5 Moll R, Franke WW, Schiller DL. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982;31:11–24. 6 Piepkorn M, Underwood RA, Henneman C et al. Expression of amphiregulin is regulated in cultured human keratinocytes and in developing fetal skin. J Invest Dermatol 1996;105:802–9. 7 Nanney LB, Stoscheck CM, King LE et al. Immunolocalization of epidermal growth factor receptors in normal developing human skin. J Invest Dermatol 1990; 94: 742–8. 8 Fujita M, Furukawa F, Fujii K et al. Expression of cadherin molecules during human skin development: morphogenesis of epidermis, hair follicles and eccrine sweat ducts. Arch Dermatol Res 1992;284: 159–66. 9 Bickenbach JR, Holbrook KA. Label retaining cells (LRCs) in human embryonic and fetal epidermis. J Invest Dermatol 1986;88:42–6.

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10 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: 136–54. 11 Moll R, Moll I. Early development of human Merkel cells. Exp Dermatol 1992;1:180–4. 12 Gown AM, Vogel AM, Hoak D et al. Monoclonal antibodies specific for melanocytic tumors distinguish populations of melanocytes. Am J Pathol 1986;123:195–203. 13 Smoller BR, Hsu A, Krueger J. HMB-45 monoclonal antibody recognizes an inducible and reversible melanocyte cytoplasmic protein. J Cutan Pathol 1991;8:315–22. 14 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, HMB45. Anat Embryol 1989;180:443–55. 15 Foster CA, Holbrook KA, Farr AG. Ontogeny of Langerhans cells in human embryonic and fetal skin: expression of HLA-DR and OKT-6 determinants. J Invest Dermatol 1986;86:240–3. 16 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;4:11–17. 17 Foster CA, Holbrook KA. Ontogeny of Langerhans cells in human embryonic and fetal skin: cell densities and phenotypic expression relative to epidermal growth. Am J Anat 1989;84:157–64. 18 Kim D-G, 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; 104:411–16. 19 Moll I, Moll R, Franke W. Formation of epidermal and dermal Merkel cells during human fetal skin development. J Invest Dermatol 1986; 87:779–87. 20 Moll R, Löwe A, Laufer J et al. Cytokeratin 20 in human carcinomas: a new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 1992;140:427–47. 21 Moll I, Kuhn C, Moll R. Cytokeratin 20 is a general marker of cutaneous Merkel cells while certain neuronal proteins are absent. J Invest Dermatol 1995;104:910–15. 22 Vos P, Stark F, Pittman RN. Merkel cells in vitro: production of nerve growth factor and selective interactions with sensory neurons. Dev Biol 1991;144:281–300. 23 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;285:261–8. 24 Moore SJ, Munger BL. The early ontogeny of the afferent nerves and papillary ridges in human digital and glabrous skin. Dev Brain Res 1989;48:119–41. 25 Moll I, Lane AT, Franke WW et al. Intraepidermal formation of Merkel cells in xenografts of human fetal skin. J Invest Dermatol 1990; 94:359–64. 26 Narisawa Y, Hashimoto K. Immunohistochemical distribution of nerve–Merkel cell complex in fetal human skin. J Dermatol Sci 1991;2:361–70. 27 Marinkovich MP, Keene DR, Rimberg CL. Cellular origin of the dermal–epidermal basement membrane. Dev Dyn 1993;196:255–67. 28 Christiano AM, Uitto J. Molecular complexity of the cutaneous basement membrane zone: revelations through the paradigms of epidermolysis bullosa. Exp Dermatol 1996;5:1–11. 29 Uitto J, Pulkkinen L. Molecular complexity of the cutaneous basement membrane zone. Mol Biol Rep 1996;23:35–46. 30 Fine JD, Smith LT, Holbrook KA et al. The appearance of four basement membrane zone antigens in developing human fetal skin. J Invest Dermatol 1984;83:66–9.

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31 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;90:480–5. 32 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110. 33 Hopkinson SB, Riddelle KS, Jones JCR. Cytoplasmic domain of the 180-kD bullous pemphigoid antigen, a hemidesmosomal component: molecular and cell biologic characterization. J Invest Dermatol 1992;99:264–70. 34 Ishiko A, Shimizu H, Kikuchi A et al. Human autoantibodies against the 230 kD bullous pemphigoid antigen (BPAG1) bind only to the intracellular domain of hemidesmosome, whereas those against the 180 kD bullous pemphigoid antigen (BPAG2) bind along the plasma membrane of hemidesmosome in normal human and swine skin. J Clin Invest 1993;91:1608–15. 35 Verrando P, Blanchet-Bardon C, Pisani A et al. Monoclonal antibody GB3 defines a widespread defect of several basement membranes and a keratinocyte dysfunction in patients with lethal junctional epidermolysis bullosa. Lab Invest 1991;64:85–92. 36 Fine J-D, Horiguchi Y, Couchman JR. 19-DEJ-1, a hemidesmosomal– anchoring filament complex associated monoclonal antibody: definition of a new skin basement membrane antigenic defect in junctional and dystrophic epidermolysis bullosa. Arch Dermatol 1989; 125:520–3. 37 Burgeson RE. Type VII collagen, anchoring fibrils and epidermolysis bullosa. J Invest Dermatol 1993;101:252–5. 38 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51. 39 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144. 40 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R (eds) Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995. 41 Smith LT, Holbrook KA, Byers PH. Structure of the dermal matrix during development and in the adult. J Invest Dermatol 1982;79:93S–104S. 42 Smith LT, Holbrook KA. Development of dermal connective tissue in human embryonic and fetal skin. Scan Electron Microsc 1982: 1745–51. 43 Smith LT, Holbrook KA, Madri JA. Collagens types I, III and V in human embryonic and fetal skin. Am J Anat 1986; 175:507–22. 44 Smith LT, Holbrook KA. Embryogenesis of the dermis. Pediatr Dermatol 1986;3:271–80. 45 Smith LT. Patterns of type VI collagen compared to types I, III, and V collagen in human embryonic and fetal skin and in fetal skinderived cell cultures. Matrix Biol 1994:14:159–70. 46 Breen M, Weinstein HG, Johnson RL et al. Acid glycosaminoglycans in human skin during fetal development and in adult life. Biochim Biophys Acta 1970;201:54–60. 47 Varma RS, Varma R. Glycosaminoglycans and proteoglycans of skin. In: Varma RS, Varma R (eds) Glycosaminoglycans and Proteoglycans in Physiological and Pathological Processes of Body Systems. Basle: Karger, 1982: 151–64. 48 Widdowson EM. Changes in the extracellular compartment of muscle and skin during normal and retarded development. Bibl Nutr Dieta 1969;13:60–8. 49 Holbrook KA, Smith LT, Kaplan ED et al. The expression of morphogens during human follicle development in vivo and a model for

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studying follicle morphogenesis in vitro. J Invest Dermatol 1993; 101:39S–49S. Kaplan ED, Holbrook KA. Dynamic expression patterns of tenascin, proteoglycans and cell adhesion molecules during human hair follicle morphogenesis. Dev Dyn 1994;199:141–55. Chuong C-M, Widelitz RB, Jiang T-X. Adhesion molecules and homeoproteins in the phenotypic determination of skin appendages. J Invest Dermatol 1993;101:10S–15S. Chuong C-M, Widelitz RB, Ting-Berreth S et al. Early events during avian skin appendage regeneration: dependence on epithelial– mesenchymal interaction and order of molecular reappearance. J Invest Dermatol 1996;107:639–46. Widelitz RB, Jiang T-X, Noveen A et al. FGF induces new feather buds from developing avian skin. J Invest Dermatol 1996;107:797–803. Johnson CL, Holbrook KA. Development of human embryonic and fetal dermal vasculature. J Invest Dermatol 1989;93:10S–17S. Karelina TV, Goldberg GI, Eisen AZ. Matrix metalloproteinases in blood vessel development in human fetal skin and in cutaneous tumors. J Invest Dermatol 1995;105:411–17. McGowan KA, Bauer EA, Smith LT. Localization of type I human skin collagenase in developing embryonic and fetal skin. J Invest Dermatol 1994;102:951–7. Dalsgaard CJ, Rydh M, Haegerstrand A. Cutaneous innervation in man visualized with protein gene product 9.5 (PGP 9.5) antibodies. Histochemistry 1989;92:385–9. Gulbenkain S, Wharton J, Polak JM. The visualization of cardiovascular innervation in the guinea pig using an antibody to protein gene-product 9.5. J Autonom Nerv Syst 1987;18:235–47. Terenghi G, Sundaresan M, Moscoso G et al. Neuropeptides and a neuronal marker in cutaneous innervation during human foetal development. J Comp Neurol 1993;328:595–603. Holbrook KA, Bothwell MA, Schatteman G et al. Nerve growth factor receptor labelling defines developing nerve networks and stains follicle connective tissue cells in human embryonic and fetal skin. J Invest Dermatol 1988;90:609A.

Embryonic–fetal transition The most remarkable time in skin development is the embryonic–fetal transition, which occurs at approximately 2 months’ gestation, when the embryo measures about 31 mm in length (crown–rump), weighs about 2.5 g and has a humanoid appearance. The skin and the underlying tissues of the body wall are translucent, revealing the ribs and solid organs. The skin has a mucoid quality when removed from the body (Fig. 2.16). In spite of this structural simplicity, with few exceptions, the cells in the skin begin to express nearly every characteristic of adult skin. The 2-month age is thus identified as an important landmark in skin development (see Fig. 2.1). It is unlikely that the changes occurring around this period are triggered simultaneously and more probable that they unfold over a period of time. What initiates these changes in all regions of the skin is unclear, but the results are dramatically evident when the tissues are assayed for expression of the markers of differentiation – as we understand differentiation in the adult skin – that were not expressed in the embryonic skin. It is likely that a constellation of genes is triggered, but in response to

Embryogenesis of the Skin

2.13

c

n

c n

(a)

M Fig. 2.16 Sample of human fetal skin of 80-days EGA held at the tips of a forceps and demonstrating the mucoid quality of the tissue.

what signals? Since this period of development appears to be very much concerned with the establishment of adult characteristics of the skin, it is perhaps also a stage that is vulnerable to errors in development. The embryonic–fetal transition needs to be studied with modern techniques of molecular biology to gain a better understanding of the coordinated onset of expression of new properties of all regions of the skin and the introduction of another set of morphogenetic processes that result in the formation of skin appendages (hair follicles, sweat glands, teeth and nails). The most apparent change in the skin that is recognized at the embryonic–fetal transition is stratification of the epidermis from two to three cell layers (Fig. 2.17a and b). An intermediate cell layer is added as the product of basal cell mitoses. Basal cells divide asynchronously to produce an epidermis that, initially, remains two-layered at some sites and at others become three layers thick. Intermediate cells are both similar to and distinct from basal and periderm cells. Keratins are more abundant and distributed in a more specific distribution than the cells in the basal and periderm layers; small bundles of keratin filaments associated with desmosomes outline the boundaries of the intermediate cells (Fig. 2.17b). The expression of the major keratin pairs in both basal- and intermediate-

n

(b) Fig. 2.17 Skin from a human fetus of approximately 70–89 days EGA shown at the light (a) and electron (b) microscopic levels. Note the intermediate layer of cells between basal and periderm epidermal layers, the distinction between dermis and subcutaneous tissue based on differences in the orientation of fibroblastic cells, the density of collagenous matrix and the subcutaneous vascular plane. Small nerves (n) and capillaries (c) are evident in the dermis. Segments of melanocytes (M) are evident within the basal layer and collagen is accumulated beneath the DEJ (×3675).

layer keratinocytes in the early fetal epidermis is now identical to the expression of the keratins in the fully keratinized adult epidermis. The K5 and K14 basal cell keratins are downregulated in the intermediate cells and a new keratin pair, K1 (56.5 kDa) and K10 (67 kDa), the high-molecular-weight differentiation-specific keratins, is synthesized [1,2] (Fig. 2.18). Other markers of keratino-

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(a) Fig. 2.19 Skin from a 72-day EGA fetus immunoreacted with an anti-epidermal growth factor receptor showing a reaction pattern on the membranes of basal and intermediate layer cells and on the basal and lateral borders of periderm cells (×120). (b) Fig. 2.18 Keratin filaments in the cells of the intermediate layer of 77-day EGA fetal skin stain positively with the AE-2 monoclonal antibody, which recognizes the K1 and K10 differentiation-specific keratins (a). The reaction pattern is even stronger when a second intermediate layer is added at the beginning of the second trimester (b) (a, ×120; b, ×120).

cyte differentiation (e.g. pemphigus antigen [3], cornified cell envelope proteins [4,5], blood group antigens [6] and cell-surface glycoproteins [7]; also reviewed in refs [8–11]) are also expressed in the cytoplasm or on the surface of intermediate layer cells. Like the periderm and basal cells, the first intermediate cells still contain glycogen as the primary cytoplasmic component (Fig. 2.17a and b). Thus, at this stage, when the epidermis is only a few cell layers thick, and has few similarities in morphology to adult epidermis, it nonetheless possesses all of the keratins and many of the other markers that are typical of the epidermis throughout life. It is important to understand this because it indicates that genetic diseases that involve mutations in keratin proteins have the potential of being expressed, and recognized, as early as the first trimester in development. Initially, the keratinocytes of both basal and intermediate cell layers express epidermal growth factor (EGF) receptors [12] (Fig. 2.19), respond to EGF and retain the ability to proliferate [13,14]. Near the end of the first trimester, however, the proliferative cells become restricted primarily, if not exclusively, to the basal layer [13,14]; only the basal cells express P-cadherin [24], a marker of proliferative ability. Basal cells change in morphology and cellsurface properties after stratification. A greater volume of the cytoplasm is occupied by organelles and keratin filaments than with glycogen, and cell-surface carbohydrates that correlate with stratification and differentiation are differentially expressed by cells of the basal and intermediate layers [7,16]. Selected basal- and intermediate-layer keratinocytes participate in the formation of the epidermal appendages: the pilosebaceous structures, nails and teeth and the eccrine sweat glands in thick skin. The morphogenesis of these structures will be taken up in a separate section of this chapter (see below).

Fig. 2.20 Scanning electron micrograph of the periderm of a 60- to 70-day EGA human fetus showing the blebs and microvilli that modify the amniotic surface (×8000).

The cells of the periderm increase in size and begin to develop microvilli-covered blebs that extend from the outermost surface of the cell into the amniotic cavity (Fig. 2.20). It is likely that these modifications to increase cellsurface area have functional significance, but none has been specifically documented for this cell type. Function is implied only from structure (see below). The molecular species of keratins remain the same as they were in the embryonic periderm cells, but the cells lose their ability to divide and to express P-cadherin [13,15]. Because the epidermal cells that are located in the more superficial layers express differentiation-related antigens, it is appealing to link stratification and the onset of differentiation. There must be more processes involved, however, than simply the addition of cell layers because embryonic skin maintained in suspension organ culture stratifies to become several layers thick but will not differentiate in the manner characteristic of early fetal skin in vivo [17,18]. It remains unclear how stratification and the onset of expression of markers of differentiation in the epidermis (and the DEJ) are tied mechanistically.

Embryogenesis of the Skin

2.15

Fig. 2.21 Section of skin from an 82-day EGA fetus immunostained with the HMB-45 antibody, which recognizes melanocytes. Note the high density of the cells and their position within the basal epidermal layer (×200).

Melanocytes are easily recognized in sections of fetal epidermis at 8 weeks EGA by their position along the basement membrane, dense cytoplasm, an absence of glycogen and a heterochromatic nucleus [19]. Around 80 days EGA, they are present in the epidermis in maximal density (∼3000 cells/mm2) [19] compared with all other stages of skin development, and in a non-random distribution among cells of the basal layer (Fig. 2.21). The numbers decrease towards birth [20], then continue to decline over the decades of postnatal life. The high numbers of melanocytes around the embryonic–fetal transition may reflect the fact that these cells arrive early in the skin, proliferate and remain close together before there is substantial growth of the fetus. The labelling index of keratinocytes is also high [13] at this stage, suggesting that the paracrine interactions between melanocytes and keratinocytes that occur in the adult skin may be established early in development [19]. Melanosomes are recognized late in the third month of development (Fig. 2.22) and show some evidence of pigment formation in selected sites of the body [21,22]. The importance of understanding the density of melanocytes and the onset of pigment synthesis relates to appropriate fetal skin sampling for the prenatal diagnosis of tyrosinase-negative oculocutaneous albinism [23]. Samples with a low density of cells are apt to have few cells available for examination in thick or thin sections. In such cases, it is possible to adopt methods to amplify the synthesis of melanin (dihydroxyphenylalanine, or DOPA, reaction) in the tissue samples [24], otherwise biopsies must be obtained at the time when and site where melanocytes are concentrated selectively (e.g. the bulb of the hair follicle at the bulbous hair peg stage). Langerhans cells are also more abundant in the epidermis at this stage (∼50/mm2) [25,26]. Unlike melanocytes, which migrate into the epidermis only during the embryonic period, the bone marrow-derived Langerhans cells migrate into the epidermis continually throughout life; their numbers do not increase significantly, however, until the third trimester and after birth [25,26]. Langerhans cells at 80 days EGA are highly dendritic (Fig. 2.23),

Fig. 2.22 Section through late embryonic–early fetal skin showing developing melanosomes in a melanocyte positioned between keratinocytes in the basal layer. The early age of the tissue is confirmed by the immature structure of the DEJ (×25,000).

Fig. 2.23 Epidermal sheet from an 80-day EGA fetus reacted to demonstrate ATPase. Note the regular distribution and density of these highly dendritic cells (×120).

begin to express CD1a at the surface [25–27] and develop Birbeck granules in the cytoplasm, suggesting that they may be capable of processing and presenting antigen in utero. The number of cells that are HLA-DR positive is significantly greater than the number that express CD1a at this stage; however, by about 13 weeks EGA Langerhans cells seem to express both markers with reasonable consistency. By the end of the first trimester, Merkel cells are located along the primary epidermal ridges of palmar skin in regular alignment relative to the sites of origin of the sweat duct primordia (see below) and at a maximum density of ∼1400) cells/mm2 [28,29] (Fig. 2.24). In hairy

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Fig. 2.24 Section of skin from the palm of an 83-day EGA fetus immunostained to recognize keratin 18 (green), an antibody that recognizes Merkel cells within the basal layer. Note the regular distribution of cells, presumably marking the sites of primary epidermal ridge location. The skin of the hand is more advanced in development than that of the trunk at an equivalent age (×300). Immunostaining courtesy of Dr Dong-Kun Kim.

skin, they first become evident in association with the developing hair germs. At later stages in follicle development, they concentrate in the infundibulum and bulge regions of the hair pegs and bulbous hair pegs [30,31]. Merkel cells are also present in the dermis of both thick (palms and soles) and hairy skin. It is likely that the dermal Merkel cells originate in the follicular or interfollicular epidermis and migrate into the dermis, where they are suggested to play a role at early stages of development in attracting and organizing nerve fibres in the upper dermis and around developing appendages [32]. Merkel cells in the interfollicular epidermis lack NGF receptors (and produce NGF [33]), but dermal Merkel cells and Merkel cells of the developing follicle are immunopositive when the tissue is reacted with the p75 NGF antibody [32]. It must be recognized, however, that nerve fibres are already apparent in the embryonic dermis before dermal Merkel cells are detectable; thus, other factors must also attract or direct nerves into the skin. Other morphological markers that are characteristic for Merkel cells in postnatal skin, such as dense core granules, are not apparent in dermal Merkel cells at this stage. Merkel cells decrease in number during the later stages of fetal development [32]. The DEJ has acquired all of the adult features that are characteristic for this region (Fig. 2.25). Hemidesmosomes, anchoring filaments and anchoring fibrils are structurally complete, and the antigens related to these attachment structures, the skin-specific markers of the DEJ, are also expressed [34–36]. Immunostaining with an antibody to type VII collagen outlines the DEJ with high intensity [35] and stains basal cell cytoplasm (the primary source of this protein) with low intensity. Nonetheless, the structural organization of the DEJ appears delicate in

Fig. 2.25 Transmission electron micrograph of the DEJ of a 78-day EGA human fetus. Note the well-formed hemidesmosomes and associated keratin filaments, anchoring filaments within the lamina lucida and fine anchoring fibrils (×47,500).

contrast to the robust structure of the basal lamina and anchoring fibrils in adult skin. One might presume that the strength of the dermoepidermal attachment would parallel its development structurally. The relative strength of this interface, however, may not be too different from the adult since the thicknesses of the dermis and epidermis are proportionately less, the density of matrix and intermediate filament proteins is less and thus there is probably coordinate flexibility of both regions. The dermoepidermal interface is still flat although modifications of individual basal cells begin to alter the smoothness of this junction. The dermis and subcutaneous tissue are distinguished on a morphological basis by differences in the organization and composition of the matrix (Fig. 2.26). Dermal and subcutaneous mesenchymal cells still retain glycogen in the cytoplasm, but they have assumed a distinctly fibroblastic morphology and are responsible for the synthesis of all of the matrix molecules that are characteristic of adult dermis. There is significantly greater accumulation of small bundles of fibrous proteins within the interstitial space (compared with the primary deposition of fibrils at tissue interfaces and cell surfaces in embryonic skin) and papillary and reticular regions of the dermis are demarcated on the basis of increased cell density proximal to the epidermis (the papillary region) and larger collagen fibril diameter and fibre bundle size in the reticular region [9,37–39] (Fig. 2.27b). The position of the subpapillary vascular plexus of arterioles and postcapillary venules also forms an approximate boundary between these two dermal zones. In spite of the significant accumulation of matrix protein, the dermis remains highly cellular, with the matrix accounting for substantially less of the bulk of the skin than it does in the postnatal infant and the adult.

Embryogenesis of the Skin

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(a)

Fig. 2.26 Light micrograph of 72-day EGA fetal dermis stained with the Alcian blue/periodic acid–Schiff (PAS) histochemical stain. The lowmagnification image shows the clear demarcation between the dermal and subcutaneous tissue and the different concentrations of fibrous and glycosaminoglycan matrix proteins in the two regions. A vascular plane also demarcates the two regions. Skeletal muscle is evident in the lower right corner of the micrograph (×200). Histochemical staining courtesy of Dr Richard Frederickson.

Fig. 2.27 Whole-mount sample of unfixed 74-day EGA fetal skin showing the vascular network of the skin through the translucent tissue of the body wall (×63). Micrograph courtesy of Dr Carole Johnson.

The skin is still transparent enough to permit the networks of vessels and nerves to be seen through the body wall of the fetus (see Fig. 2.27). The vessels are organized in the dominant pattern of adult skin, with one plexus

(b) Fig. 2.28 Light micrograph of 78-day EGA human skin showing the vascular pattern organized in a series of horizontal plexuses and vertical connecting vessels (a, b). Note that the diameters of the vessels become increasingly smaller towards the epidermal surface. In the highermagnification image, the difference between the rounder cells of the papillary dermis are distinct from the more elongated fibroblastic cells of the reticular dermis and subcutaneous region (a, ×25; b, ×100). Micrographs courtesy of Dr Greg Hébert.

located at the dermosubcutaneous boundary and another at the boundary between the papillary and reticular dermis (Fig. 2.28). Vertically orientated vessels connect the two horizontal plexuses, and fine capillaries extend into the papillary dermis [8–11]. Nerves are also readily apparent in both sections and whole-mount preparations of skin that are immunostained with the p75 antibody to NGFR [40] (Fig. 2.29), neurofilament protein, PGP 9.5, CGRP and neuropeptide Y (NPY). NPY recognition of certain fibres associated with blood vessels signifies the presence of autonomic fibres [41]. Like the vessels, large subcutaneous nerve trunks branch to finer and finer fibres that terminate beneath the DEJ. The nerve and vascular networks are at times parallel but are also separate from one another (see Fig. 2.15). The hypodermis appears to have markedly fewer cells than either region of the dermis, and smaller bundles

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Chapter 2

Fig. 2.29 Section of skin from a 77-day EGA fetus immunostained with the PGP 9.5 antibody, which recognizes all cutaneous nerves. Note the larger trunks deep in the dermis and the fine network of fibres that supplies the epidermis (×100). Immunostaining courtesy of Dr Dong-Kun Kim.

of fibrous matrix. Dilated channels course through the hypodermis, distinguishing it from deeper tissue of the body wall (see Figs 2.26 and 2.28). Red blood cells within the lumina of some of these structures suggest that they may belong to the venous side of the vasculature although the simplicity of the wall structure would suggest they could be lymphatics. Three-dimensional reconstruction of this network would be of interest as it is not recognized in the later stages of skin development and may be important in the understanding of how the vasculature assembles during development. References 1 Dale BA, Holbrook KA, Kimball JR et al. Expression of the epidermal keratins and filaggrin during fetal human development. J Cell Biol 1985;101:1257–69. 2 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 1983;23:170–8. 3 Lane AT, Helm HF, Goldsmith LA. Identification of bullous pemphigoid, pemphigus, laminin and anchoring fibril antigens in human fetal skin. J Invest Dermatol 1985;84:27–30. 4 Holbrook KA, Underwood RA, Dale BA et al. Formation of the cornified cell envelope in human fetal skin: presence of involucrin, keratolinin, loricrin and transglutaminase correlated with the onset of transglutaminase activity. J Invest Dermatol 1991;96:542A. 5 Akiyama M, Smith LT, Yoneda K et al. Expression of transglutaminase 1 (TG1) and cornified cell envelope (CCE) proteins during human epidermal development. J Invest Dermatol 1997;108:598 (Abstract). 6 Dabelsteen E, Holbrook KA, Clausen H et al. Cell surface carbohydrate changes during embryonic and fetal skin development. J Invest Dermatol 1986;87:81–5. 7 Watt FM, Keeble S, Fisher C et al. Onset of expression of peanut lectin binding glycoproteins is correlated with stratification of keratinocytes during human epidermal development in vivo and in vitro. J Cell Sci 1989;94:355–9.

8 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110. 9 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51. 10 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144. 11 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R (eds) Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995. 12 Nanney LB, Stoscheck CM, King LE et al. Immunolocalization of epidermal growth factor receptors in normal developing human skin. J Invest Dermatol 1990;94:742–8. 13 Bickenbach JR, Holbrook KA. Label retaining cells (LRCs) in human embryonic and fetal epidermis. J Invest Dermatol 1986; 88:42–6. 14 Bickenbach JR, Holbrook KA. Proliferation of human embryonic and fetal epidermal cells in organ culture. Am J Anat 1986;177:97–106. 15 Piepkorn M, Underwood RA, Henneman C et al. Expression of amphiregulin is regulated in cultured human keratinocytes and in developing fetal skin. J Invest Dermatol 1996;105:802–9. 16 Fisher C, Holbrook KA. Cell surface and cytoskeletal changes associated with epidermal stratification in organ cultures of embryonic human skin. Dev Biol 1987;119:231–41. 17 Holbrook KA, Minami SA. Hair follicle morphogenesis in the human: characterization of events in vivo and in vitro. NY Acad Sci 1991;642:167–96. 18 Holbrook KA, Smith LT, Kaplan ED et al. The expression of morphogens during human follicle development in vivo and a model for studying follicle morphogenesis in vitro. J Invest Dermatol 1993; 101:39S–49S. 19 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, HMB45. Anat Embryol 1989;180:443–55. 20 Hamada H. Age changes in melanocyte distribution of the normal, human epidermis. Jpn J Dermatol 1972;2:223–32. 21 Becker SW, Zimmerman AA. Further studies on melanocytes and melanogenesis in human fetus and newborn. J Invest Dermatol 1955;25:103–12. 22 Barla-Szabó L. Ejection of melanocytes and melanin from fetuses and newborn mammalian animals. Acta Morph Acad Sci Hung 1970; 18:213–25. 23 Eady RAJ, Gunner DB, Garner A et al. Prenatal diagnosis of oculocutaneous albinism by electron microscopy. J Invest Dermatol 1983;80:210–12. 24 Gershoni-Baruch R, Benderly A, Brandes JM et al. Dopa reaction test in hair bulbs of fetuses and its application to the prenatal diagnosis of albinism. J Am Acad Dermatol 1991;24:220–2. 25 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; 4:11–17. 26 Foster CA, Holbrook KA. Ontogeny of Langerhans cells in human embryonic and fetal skin: cell densities and phenotypic expression relative to epidermal growth. Am J Anat 1989;84:157–64. 27 Foster CA, Holbrook KA, Farr AG. Ontogeny of Langerhans cells in human embryonic and fetal skin: expression of HLA-DR and OKT-6 determinants. J Invest Dermatol 1986;86:240–3. 28 Moll R, Moll I, Franke W. Identification of Merkel cells in human skin by specific cytokeratin antibodies: changes in cell density and distri-

Embryogenesis of the Skin

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31

32

33

34

35

36

37

38 39 40

41

bution in fetal and adult plantar epidermis. Differentiation 1984; 28:136–54. Moll R, Moll I. Early development of human Merkel cells. Exp Dermatol 1992;1:180–4. Kim D-G, 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;104:411–16. 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;285:261–8. Narisawa Y, Hashimoto K, Pietruk T. Biological significance of dermal Merkel cells in development of cutaneous nerves in human fetal skin. J Histochem Cytochem 1992;40:65–71. Vos P, Stark F, Pittman RN. Merkel cells in vitro: production of nerve growth factor and selective interactions with sensory neurons. Dev Biol 1991;144:281–300. Fine JD, Smith LT, Holbrook KA et al. The appearance of four basement membrane zone antigens in developing human fetal skin. J Invest Dermatol 1984;83:66–9. 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;90:480–5. Hertle MD, Adams JC, Watt FM. Integrin expression during human epidermal development in vivo and in vitro. Development 1991; 112:193–206. Smith LT, Holbrook KA, Byers PH. Structure of the dermal matrix during development and in the adult. J Invest Dermatol 1982; 79:93S–104S. Smith LT, Holbrook KA, Madri JA. Collagens types I, III and V in human embryonic and fetal skin. Am J Anat 1986;175:507–22. Smith LT, Holbrook KA. Embryogenesis of the dermis. Pediatr Dermatol 1986; 3: 271–80. Holbrook KA, Bothwell MA, Schatteman G et al. Nerve growth factor receptor labelling defines developing nerve networks and stains follicle connective tissue cells in human embryonic and fetal skin. J Invest Dermatol 1988;90:609A. Terenghi G, Sundaresan M, Moscoso G et al. Neuropeptides and a neuronal marker in cutaneous innervation during human foetal development. J Comp Neurol 1993;328:595–603.

Fetal skin Conclusion of the first trimester The first stages of fetal skin development occur from the time of the embryonic–fetal transition at 2 months to the end of the first trimester at 3 months, when a template of the adult skin is established. Rather than summarize what has been formed by this stage, it is more useful to point out what features of adult skin are still lacking: • The dermoepidermal interface lacks rete ridges and rete pegs. • The epidermis has yet to keratinize and one of the key proteins of keratinization, filaggrin, is not yet expressed in any region of the skin. • The dermis lacks fully formed elastic fibres and an elastic fibre network. • Sweat glands are initiated only on the palms and soles.

2.19

• Apocrine glands have not begun to develop. • Hair and nails are not synthesized. • Adipose tissue has not differentiated within the mesenchyme of the hypodermis. All of these features will be initiated and/or fully acquired during the second trimester, and changes will continue to occur in the structures and regions of the skin that have been established but not finalized.

Second-trimester fetal skin At 12 weeks’ gestation, the fetus measures about 85 mm in length (crown–rump) and has a body form similar to that of the newborn. The skin and body wall are opaque. All of the events in skin morphogenesis initiated during the first trimester continue in the second trimester in parallel with the onset of formation of those structures that were identified as lacking in first-trimester skin. Landmark events in the second trimester include completion of the formation of the lanugo hair follicle and synthesis of the hair (around 17–19 weeks EGA), completion of the formation of the nail (around 20–22 weeks EGA) and keratinization of the interfollicular epidermis (around 22–24 weeks EGA). The timing is variable because the formation of the hair follicle and epidermal keratinization are region dependent. One or two additional intermediate cell layers are added to the epidermis by proliferation of basal keratinocytes and upward migration of the first intermediate cells. By 100–110 days EGA, there are typically three suprabasal, intermediate cell layers, which become progressively more flattened towards the epidermal surface (Fig. 2.30). The cells of the most superficial layer have large bundles of keratin filaments, which can be seen in stained specimens at the light microscopic level as a reticulate cytoskeleton (Fig. 2.30). Glycogen is still a major constituent of the cytoplasm. As the epidermis thickens, the interface it forms with the dermis becomes less flattened and smooth, due largely to changes in the basal surface of each keratinocyte rather than to convolutions of the layer itself. Basal cells stain with less intensity than the intermediate-layer cells because there is less glycogen, the bundles of keratin filaments are smaller and the cytoplasm is more ribosome rich, dense and organelle filled (Fig. 2.30). At the end of the second trimester, the five-layered interfollicular epidermis keratinizes. Skin of the trunk shows signs of the onset of keratinization around 21 weeks EGA in the uppermost intermediate cell layers and the overlying periderm (Fig. 2.31). One can infer a sequence of events from the various morphologies of the uppermost cells prior to the appearance of true keratinized squames. Changes in the structure and composition of the plasma membrane mark the formation of a cornified cell enve-

2.20

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(a)

(b)

Fig. 2.30 Light (a) and electron (b) micrographs of a section of skin from a 104-day EGA human fetus showing additional intermediate cell layers, changes in periderm morphology, the reticulate keratin cytoskeleton in upper intermediate cells, less intense staining of basal cells (a, b) and the smaller bundles of collagen fibrils in the papillary dermis (a). A melanocyte is evident (a, arrow). Several capillaries (a) and nerves (b, n) lie within the papillary region (a, ×300; b, ×3500).

lope [1,2], and lamellar granules are identified in the cytoplasm (Fig. 2.31) and in the spaces between intermediate and periderm layers. The modified intermediate cells remain associated with the overlying periderm cells by infrequent and tenuous-appearing desmosomal attachments. Cells are also evident in which the nucleus is pyknotic and the cytoplasm contains dense bundles of filaments, vacuoles and other remnants of the cytoplasm. Cells beneath these seemingly incompletely keratinized squames contain very small, stellate keratohyalin granules and react immunopositively with an antibody that recognizes profilaggrin and filaggrin proteins of the granule [3] (Fig. 2.31). The two or three subjacent intermediate cell layers can now be called spinous cells. At this stage, periderm cells are very large in diameter, flattened and also display a thickened cell envelope. Each cell covers a cluster of underlying epidermal cells. The periderm stains differently from the underlying epidermal cells, probably owing to a lesser amount of structural protein within the cytoplasm. A few layers of thin, flattened, keratinized cells, organized in the manner of a true stratum corneum, are appar-

ent around 22–24 weeks EGA (Fig. 2.32). The granular cell layer is now more typical of an adult granular layer in that keratohyalin granules are larger and the cytoplasm contains less glycogen. The numbers of layers of the stratum corneum continue to increase in the third trimester. By 22–24 weeks EGA, 1700 Merkel cells/mm2 can be measured in the epidermis [4,5] and the number of Langerhans cells begins to increase (∼200 cells/mm2), although the adult level of approximately 650 cells/mm2, or about 8500 cells/mm3, is not achieved until after birth [6]. Melanosomes are transferred to keratinocytes in the fifth month of gestation. All of the structures of the DEJ were formed in the first trimester, and only a few antigens of the DEJ (AF-1 and AF-2 associated with anchoring fibrils) remain to be recognized at this age [7]. By 19–21 weeks EGA, the hemidesmosomes are present at the basal keratinocyte plasma membrane with adult-like frequency and show a strong association with basal cell keratin filaments. Anchoring filaments and banded anchoring fibrils are well formed (reviewed in refs [8–11]).

Embryogenesis of the Skin

2.21

(a)

Fig. 2.32 Electron micrograph of the keratinized epidermis from a fetus at the end of the second trimester. There are a few layers of cornified cells, a single granular cell layer and three layers of spinous cells, which retain a significant quantity of glycogen. Note the greater irregularity in the basal border of the basal cells at the DEJ (×3000).

(b) Fig. 2.31 Electron micrographs of the skin from two 21-week EGA fetuses showing early (a) and late (b) changes in the upper intermediate layers (spinous) at the onset of keratinization. Note the regressed periderm separating from the upper epidermal layers (a), lamellar granules in the top few layers (arrows), the small particulate (a) then stellate (b) keratohyalin granules, and the few layers of incompletely keratinized cell (black material) to demonstrate the permeability of the epidermis to tracers (a, ×12,150; b, ×9500). Micrograph (b) courtesy of Dr Richard Frederickson.

The hair follicles complete development and synthesis of the hair; sweat glands on the general body surface only begin to form around 17–18 weeks EGA (see below). Small bundles of interwoven, fibrous connective tissue occupy the interstitial space within the dermis (Fig. 2.33a), although they remain loosely organized because the sulphated proteoglycans and fibrous proteins of the interstitial matrix are still very hydrated. Elastin is detectable biochemically, and elastic fibres can be recognized as

granular-appearing structures along the borders of collagen fibre bundles in immunostained samples of skin and by electron microscopy. The structure of the elastic fibres, however, even in the deepest portions of the reticular dermis, is similar to that of the elaunin fibres of adult skin, which have only sparse amounts of elastin associated with the microfibrillar bundles. The extent to which elastic fibres are developed is dependent upon the region of the skin. In addition to fibroblasts, mast cells, macrophages and smooth muscle cells are present in the dermis [8–11]. The hypodermis remains distinct from the dermis by its less dense matrix and cellularity. Around 15–16 weeks EGA, mesenchymal cells collect in globular arrays surrounded by a capsule-like assembly of matrix (Fig. 2.33b). This is the first stage of adipose tissue formation. Small vessels are present within these cellular aggregations. By 18 weeks EGA, lipid droplets are evident within some of the mesenchymal cells, and by 20 weeks lobules of fat are established. The 24-week-old fetus is fully formed and has hair on the scalp and body surface. The length is about 228 mm (crown–rump).

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(a)

Fig. 2.34 A section through skin obtained from a third-trimester (34-week) human fetus showing all regions of the skin and the presence of hair follicles and eccrine sweat glands (×40).

Third-trimester fetal skin

(b) Fig. 2.33 Scanning electron (a) and light (b) micrographs of the human fetal dermis at 15 weeks EGA showing the density of the fibrous matrix, the differences in textures between papillary and reticular regions (a), and the boundary between the dermis and subcutaneous regions (a, b). The developing hair follicles are evident in cross-section in (a) and in longitudinal section in (b). A lobule of subcutaneous fat (arrows) is evident in (b) (a, ×80; b, ×100).

The skin in the third trimester appears structurally similar to postnatal skin (reviewed in refs [8–12]) (Fig. 2.34). The epidermis is fully keratinized, contours are beginning to form at the DEJ, the regions of the dermis are well defined, the adnexae are fully formed and reside deeply in the dermis, and large fat lobules fill the hypodermis. There are, however, some notable differences in structure in all regions: suprabasal epidermal cells retain a significant amount of glycogen in the cytoplasm and the dermis remains relatively thin. The bundles of collagen matrix are small elastic fibres and are immature in structure and composition, and the stratum corneum has fewer cell layers than infant or adult skin. Fetuses are often born prematurely during this period and their morbidity and mortality correlate significantly with gestational age (reviewed in ref [13]). It is therefore valuable to understand how the structure of the skin can be used to assess the gestational age, particularly at the gross observational level. Obstetrical dates, measurements made in utero, assessment of the redness of the skin (the Dubowitz scoring system) [14] and examination of the infant have all been used. Studies of the optical reflectance of light delivered at specific wavelengths to the skin, collected by optical fibres and measured by an

Embryogenesis of the Skin

optical fibre spectrophotometer, revealed a strong correlation between skin reflectance and gestational age and maturity [13]. Studies of the function of skin of the premature infant provide some understanding of the status of the skin during the third trimester. In general, various functions of the skin, such as barrier properties, temperature regulation, sweating, response to tactile and mechanical stimuli [15], that have been measured reflect the gestational age more than the birthweight. The epidermis, even though keratinized and possessing several layers of stratum corneum cells, is a less effective barrier than the infant epidermis. Transepidermal water loss, for example, decreases in a steep slope from 26 weeks EGA to 38 weeks EGA. It decreases even further and with a similarly rapid decline over the first 10–15 postnatal days (reviewed in ref [16]). Disorders of keratinization or infection of the skin may give an even greater disadvantage to the premature newborn in its ability to regulate substances crossing the skin. The stratum corneum of the preterm infant is more permissive to absorption of substances from the external environment and those applied to skin to protect, treat or cleanse it in the neonatal nursery (reviewed in ref [16]). These compromised epidermal barrier properties, coupled with the fact that the preterm/neonatal infant’s body surface-tovolume ratio is very high, can place the premature infant at significant risk. Although the structure and cellular differentiation of the sweat glands in the preterm infant and term newborn (see below) appear little, if any, different from those of the infant, the sweating function requires a period of maturation after birth, presumably for the innervation to become fully established. The sweating response is limited or absent in the preterm infant to an extent that correlates with the gestational age (reviewed in ref [12]). Apocrine glands begin to secrete during this trimester [8–11]. Some aspects of the vasculature are less organized in the third-trimester fetus and the newborn than is characteristic in the infant. The marked redness of the newborn reflects the high density of superficial vessels in the dermis and the thinness of the epidermis. Remodelling of the microcirculation occurs as appendages and regions of the skin are completed. At birth, the capillary network is still disorganized and will stabilize only after birth (reviewed in refs [8–11]). References 1 Holbrook KA, Underwood RA, Dale BA et al. Formation of the cornified cell envelope in human fetal skin: presence of involucrin, keratolinin, loricrin and transglutaminase correlated with the onset of transglutaminase activity. J Invest Dermatol 1991;96:542A. 2 Akiyama M, Smith LT, Yoneda K et al. Expression of transglutaminase 1 (TG1) and cornified cell envelope (CCE) proteins during human epidermal development. J Invest Dermatol 1997;108:598 (Abstract).

2.23

3 Dale BA, Holbrook KA, Kimball JR et al. Expression of the epidermal keratins and filaggrin during fetal human development. J Cell Biol 1985;101:1257–69. 4 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;28:136–54. 5 Kim D-G, 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;104:411–16. 6 Foster CA, Holbrook KA. Ontogeny of Langerhans cells in human embryonic and fetal skin: cell densities and phenotypic expression relative to epidermal growth. Am J Anat 1989;84:157–64. 7 Lane AT, Helm HF, Goldsmith LA. Identification of bullous pemphigoid, pemphigus, laminin and anchoring fibril antigens in human fetal skin. J Invest Dermatol 1985;84:27–30. 8 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110. 9 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51. 10 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144. 11 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R, eds. Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995. 12 Holbrook KA. A histologic comparison of infant and adult skin. In: Boisits E, Maibach HI (eds) Neonatal Skin: Structure and Function. New York: Marcel Dekker, 1982: 3–31. 13 Lynn CJ, Saidi IS, Oelberg DG et al. Gestational age correlates with skin reflectance in newborn infants of 24–42 weeks gestation. Biol Neonate 1993;64:69–75. 14 Dubowitz LMS, Dubowitz V, Golberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970;77:1–10. 15 Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation. Pain 1994;56:95–101. 16 Cartlidge PAT, Rutter N. Skin barrier function. In: Polin RA, Fox WW (eds) Fetal and Neonatal Physiology, Vol. 1. Philadelphia: W.B. Saunders, 1992: 3133–42.

Unique features of developing human skin Periderm The periderm is the outermost, transient cellular layer of the developing skin of some mammals and birds. It is one of the most interesting aspects of human skin development from the perspective of its origin, its uniqueness in biochemical composition and structural modifications (although an integrated part of the developing epidermis), and its possible function(s) during the first two trimesters of human development. The periderm is released as single cells and as sheets of cells into the amniotic fluid

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Chapter 2

at the end of the second trimester when the epidermis keratinizes (reviewed in refs [1–4]). The origin of the periderm is uncertain. A reasonable hypothesis would be that the cells of the original, single, ectodermal layer of the early embryo divide and give rise to a second cell layer that becomes superficial to the basal layer. Studies of mouse embryos provide some evidence in support of this hypothesis [5]. If this is the case, then one might expect to find the predominant keratins of the basal cell also in the periderm cell in a manner comparable to the suprabasal cells of adult epidermis, which have the basal cell keratins plus additional keratins that are expressed after these cells leave the basal layer. Periderm cells do not express the primary K5 and K14 proteins of basal keratinocytes (or the K1/K10 keratins of differentiated keratinocytes) but they do express other keratins in common with the fetal basal cells, and at least one keratin that is expressed in common with another presumed keratinocyte derivative, the Merkel cell [6]. Alternative explanations can also be considered: before giving rise to periderm the single-layered ectoderm could express low levels of keratins that are undetectable by the methods used; basal cells could express only the peridermtype keratins before giving rise to the periderm then, following this event, synthesize K5 and K14; or K5 and K14 could be completely downregulated in the periderm cells after they form. K5 and K14 are downregulated in suprabasal keratinocytes after moving out of the basal layer in postnatal epidermis. None of these possibilities has been tested. Samples of skin at the age when the epidermis is a single-cell layer would be required for such studies, and these are very rare among the embryonic specimens collected. All of the possibilities are consistent with the fact that fetal basal cells acquire and/or lose characteristics after they give rise to intermediate layer cells. It is also possible that the periderm arises from cells of the amnion that grow over the single-layered epidermis. The amnion and periderm are similar in keratin composition [7,8] and surface morphology and in the expression of other antigens [9,10]. Studies from early mouse embryos, however, suggest that a continuous sheet of tissue may not cover the epidermis as proposed by this model, because patches of periderm cells are present in some sites, thus making a moving sheet model difficult to envisage [11]. A third possibility is that the periderm layer is the original ectodermal layer that covers the very early blastocyst and embryo and that it gives rise to the basal cell layer, which then acquires characteristics as it associates with, or perhaps establishes, the first complete basal lamina. There is no evidence for this other than a few observations of single-layered ectoderm of very early embryos in which the basal lamina is incomplete.

The most remarkable features of the periderm are the morphological changes that the periderm cells undergo with progressive stages of development [12]. Studies of the surface of the developing skin using scanning electron microscopy, and of corresponding tissue sections examined by light and transmission electron microscopy from consistent regions of the body, have established the stages of human skin development [12] (Fig. 2.35). The early embryo is covered by a thin, flattened pavement epithelium that is the periderm (Fig. 2.6). Around 8–11 weeks, when the epidermis stratifies, the periderm cells increase in volume and develop a rounded external surface. By 10–14 weeks, single blebs extend from the amniotic surface of each cell and the cell increases in diameter (see Fig. 2.20). All of the cell surface, including the blebs, is modified by microvilli. A network of microfilaments is organized beneath the plasma membrane. Later in the second trimester, the surfaces of the periderm cells project multiple blebs, the larger of which have the configuration of a blackberry (Figs 2.30 and 2.36). The cell diameter continues to increase as the cells become thinly stretched over the epidermis. By 16–23 weeks EGA, the blebs flatten and the periderm regresses (Fig. 2.37). It once again becomes a very thin layer of cells, which, at this stage, rarely contain a nucleus, have few if any organelles and are composed largely of disorganized, fine filaments [12]. The periderm cells do not undergo the events of differentiation that are typical for the keratinocyte. The composition of keratins in the periderm cells remains unchanged throughout development and, since neither the K1/K10 keratin proteins nor profilaggrin are present in the periderm cells of any stage, it is clear that they do not undergo keratinization. The plasma membrane of the early second-trimester fetal periderm cell, however, appears similar to a cornified envelope (Fig. 2.38a) and, in accord with this morphology, it is possible to demonstrate the presence of several cornified cell envelope proteins – e.g. involucrin, loricrin, keratolinin (cystatin) – small proline-rich proteins (SPRR) 1 and 2, and the transglutaminase 1 (TG1) enzyme in the cytoplasm [13,14] of these cells (Fig. 2.38b–d). Some of the envelope proteins, however, are also expressed in the periderm of the embryo even when the membrane morphology does not reveal the thickened nature of a cornified envelope. This may correlate with the observations that TG1 protein is not detected in embryonic-fetal skin by immunohistochemistry until approximately 8–10 weeks EGA and that the enzyme becomes active only around the end of the first trimester, and then only in occasional cells of the periderm layer [13,14]. Thus, the envelope proteins, although present, may not be crosslinked into the morphologically recognizable envelope structure.

Embryogenesis of the Skin

2.25

Fig. 2.35 Stages of epidermal development proposed on the basis of periderm structure.

Fig. 2.36 Scanning electron micrograph of the periderm from a mid-second-trimester fetus showing multiple, complex blebs and microvilli extending from the amniotic surface (×1500).

Fig. 2.37 Scanning electron micrograph of the surface of the flexor forearm of a late second trimester fetus showing the large, thin, regressed periderm cells (×800).

The presence of transglutaminase in periderm cells ahead of other cells of the epidermis may have other implications for the fate of the periderm cell in as much as this enzyme is a feature of cells undergoing pro-

grammed cell death, or apoptosis [15,16]. The finding that other markers of apoptosis are expressed in these cells, e.g. DNA fragmentation, and the fact that periderm ceases to divide in the first trimester have led to the suggestion

2.26

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(a)

(b)

(c) (d) Fig. 2.38 Transmission image of the periderm cornified cell envelope from fetal skin of 21 weeks EGA (a). The periderm expresses involucrin early in the first trimester. (b) Data from a 98-day EGA fetus. Epidermal transglutaminase (c) is also expressed early in the periderm but does not appear to function until the end of the first trimester, when it first demonstrates cross-linking of dansyl cadaverine to substrate in the tissue (d) (a, ×41,250; b, ×300; c, ×300; d, ×300).

that the periderm is a tissue layer that undergoes apoptosis. Towards the end of the second trimester, individual periderm cells loosen from the underlying epidermal cells and are desquamated over the sites of elevated and exposed hair canals (follicular epidermis) (see below). They remain associated, however, with the interfollicular epidermis until the stratum corneum is formed. At this time, the periderm is mostly gone from the skin surface. The events that lead to disengagement of this layer are not known. The structural properties of periderm cells may provide clues as to the function of the layer. The blebs and microvilli increase the surface area of the periderm as it faces the amniotic fluid, suggesting that these cells may be important in the exchange of substances between the fetus and the amniotic fluid, across the skin, in one or both directions. Direct evidence for this role in humans is

limited. A morphological study of the intramembranous modifications of the periderm plasma membrane suggests that the cells have a role in regulating water transport [18], and Koren [19] has suggested that the skin absorbs nicotine dissolved in amniotic fluid; in the sheep fetus, the periderm has been shown to be involved in the uptake of drugs from the amniotic fluid [20]. It has also been postulated that the periderm is a secretory epithelium that adds material to the amniotic fluid [21] and that it serves as a protective layer for the developing epidermis (also reviewed in refs [1–4]). The periderm, like many features of the developing skin, is regionally variable in its properties and timing of development [12]. Periderm of the plantar surface of the toe, for example, shows a very late stage of development at 70 days compared with trunk skin. At this time, the epidermis of the appendage is thicker and more differentiated than trunk skin. This suggests that the nature of the

Embryogenesis of the Skin

underlying epidermis – perhaps its status of differentiation – affects the rate of modification of the periderm, but what factors promote this change are unknown. The periderm is thus a distinct layer of cells that is set apart early in development from the remainder of the epidermis. Although attached first to the basal cells and then to the intermediate-layer cells by typical desmosomes, the periderm appears to be unaffected by events in the epidermis other than the rate of differentiation. Genetic disorders, for example, that modify cells of the basal and intermediate layers during development appear to have no direct or indirect consequences for periderm cells. Keratin filaments are aggregated in the secondtrimester skin of fetuses affected with epidermolytic hyperkeratosis (EHK) [22] and epidermolysis bullosa simplex Dowling–Meara (EBS-DM) [23], but none of the filaments clump in periderm cells, nor are there other consequences for the periderm layer. The absence of clumping would be expected in the case of EHK since the keratins involved in this disorder are not keratins that are present in periderm cells, but basal cells and periderm cells do share keratins in common; thus, it might be possible to see alterations in a fetus affected with EBS-DM. The persistence of periderm cells with no adverse outcome in an environment of severe cell destruction in layers proximal to the periderm (in EHK) is surprising and argues for autonomy of this layer. Monoclonal antibodies have been developed that recognize only peridermal cells in the developing skin [10,24]. These reagents might be useful when separating periderm cells from disaggregated fetal epidermis. Efforts to culture them could then be undertaken for the purpose of evaluating their potential to divide, stratify and differentiate in vitro when cultured on various substrates, including extracellular matrices and cultured keratinocytes of all ages and states of differentiation.

Regionalization in developing skin Regional differences in properties of the skin are well documented in adult skin. Throughout this discussion of skin development, it has been mentioned that regionalization is also a phenomenon of developing skin even at very early ages of gestation. Few systematic studies have been done to document these regional differences consistently throughout development [12,25], but the concept is important because samples of fetal skin are still used to diagnose diseases of the epidermis, DEJ, epidermal appendages and pigment cells in utero. Without a clear appreciation and accurate knowledge of differences in normal morphology at various sites, structural evaluation of skin samples that may be from unknown regions can be risky. At the same time, it is essential to appreciate whether the disease of concern is also expressed with regional variation not only in the adult but also at the

2.27

(a)

(b) Fig. 2.39 Sections of skin obtained in utero by fetal skin biopsy from a fetus at risk of lamellar ichthyosis. Note the difference in morphology between the two samples. One sample shows an epidermis of normal thickness and state of development for 19 weeks EGA (a). The second sample shows a thickened epidermis, still covered by periderm (b). In both samples, hair canals were excessively keratinized. This disorder is expressed in utero with regional variation (a, ×300; b, ×300).

onset of expression of the disease during development [26,27]. In at least one situation, the understanding of regional variability of expression of a disease at its first presentation was gained from samples obtained for prenatal diagnosis [28] (Fig. 2.39). Systematic studies of affected fetal skin from multiple regions are valuable to undertake when tissue becomes available, especially in situations where fetal biopsy remains the only current method available to diagnose a severe genetic disease in utero. Such efforts also expand our knowledge of the natural history of the disorder.

Keratinization Keratinization of the nails, hair follicles (follicular epidermis), intraepidermal sweat duct and the interfollicular

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Chapter 2

epidermis occurs at different times during gestation. The nails are the earliest structures of the skin to keratinize in utero, with the appearance of cornified cells as early as 11–12 weeks EGA. The timing of keratinization of follicular epidermis is consistent with the cephalocaudal direction of follicle morphogenesis [27]; the interfollicular epidermis keratinizes first in thick skin and then in thin skin, with the latter also proceeding in a regionally dependent manner. The timing of keratinization for a given region appears to follow a rigidly specified programme during development. Even in situations in which keratinization is abnormal, for example in fetuses affected with lamellar ichthyosis, harlequin ichthyosis and EHK, there is no evidence for early or delayed onset of the keratinization process in either the follicular or interfollicular epidermis (reviewed in refs [29–31]).

Appendage formation After the embryonic fetal transition, around 10–11 weeks EGA, basal epidermal cells, through various molecular events, undergo proliferation at specifically patterned sites to form buds that grow down into the dermis as hair germs and sweat ducts, or as a fold of tissue that establishes the nail fold. These structures are thought to develop in response to epithelial–mesenchymal interactions that initiate the process through instructive messages, sustain the process through permissive interactions, then support differentiation and maintenance of the fully developed appendage. Nerves and vessels, cellular adhesion molecules (CAMs), soluble mediators and homeobox genes (homeoproteins) have been implicated in the pattern formation of certain appendages (reviewed in refs [32–37]). The evidence for these interactions in the development of the epidermal appendages in human skin is best documented for formation of the pilosebaceous apparatus. Studies of hair follicles in other mammals (primarily the rodent and sheep [38,39]) and of feather and scale formation in other species [35–37,40–42] provide additional evidence that may be extrapolated to the situation of human skin appendage development. The dermis is thought to be responsible for initiating appendage formation, establishing the pattern in which the appendages assemble and specifying their properties according to the region of the skin. Conversely, the epidermis has been shown to determine the class specificity of the appendage (i.e. feather, hair, sweat gland), its orientation and the species specificity of the keratins expressed by the appendageal (epithelial) cells. The epidermis is thought to convey signals to the dermis to initiate appendage formation, initially by effecting changes in the mesenchyme. Experimental studies of appendage formation in non-mammalian skin, for example of feather formation in the chick, are beginning to reveal the early molecular events that occur stepwise to control various

Fig. 2.40 Developing hair germ showing the close proximity between the epithelial cells of the germ and the mesenchymal cells of the dermis, which will follow the developing appendage and influence its development and differentiation (×8250).

aspects of feather formation such as the domain of the appendage, its orientation, the regulation of its growth and the determination of appendage phenotype [40]. Epithelial and mesenchymal cells lie in close proximity at the sites of appendage formation, and in some cases make physical contact (Fig. 2.40).

Nail formation The distal rays of the digit are evident on the hand of the 50-day EGA embryo, and within the next 7 days the digits separate [43]. Formation of the nail on the dorsal surface of the digits and the eccrine sweat glands on the ventral surface (see below) is initiated at approximately the same time after embryo–fetal transition. By 70 days’ gestation, the boundaries of the nail field are established externally by proximal, lateral and distal folds (Fig. 2.41a) and sections through the digit reveal a shallow nail fold (Fig. 2.41b). Development of the epidermis over the nail bed is furthest advanced at its distal-most margin [44,45]. By 90 days EGA, the dorsal ridge is evident superficially and is delineated from the plantar surface of the digital pad by a deep constriction (Fig. 2.42a). The nail fold has invaginated deeply into the dermis and orga-

Embryogenesis of the Skin

2.29

and over the dorsal ridge. By 15 weeks EGA, a thick cornified layer covers the nail bed (Fig. 2.42c). This preliminary ‘nail’ is easy to slough from the surface and thus may be composed to a greater extent of keratinized epidermal cells from the nail bed rather than derived from the matrix of the nail fold. The nail of a 19-week EGA fetus is established by both the nail matrix and the nail-bed epidermis, although the nail is still fragile (also reviewed in refs 1–4) (Fig. 2.42d). The nail that is present at birth is actually a composite of layers of cells derived from the dorsal nail fold (contributes the outermost layer of the nail) and the nail matrix (contributes the intermediate layer of the nail); the distal half to two-thirds of the nail bed contributes the inner layer of the nail. The layers are more evident in the fetus than in the postnatal individual [46].

Eccrine sweat gland formation on the digits

(a)

(b) Fig. 2.41 Developing nail. (a) Scanning electron micrograph of a digit from an 85-day EGA fetus showing the boundaries of the nail field recognized by proximal (identifying the position of the nail fold), lateral and distal folds. (b) A section through the digit of a 70-day EGA fetus shows the position of the nail fold and the thicker and more advanced epidermis over the nail bed (a, ×100; b, ×150).

nized into dorsal (roof of the fold) and ventral (floor of the fold) layers that are distinguished from one another morphologically and functionally (Fig. 2.42b). The ventral fold becomes the nail matrix, which is primarily responsible for the synthesis of the nail plate. The earliest nail, which is formed late in the first trimester, consists of several layers of keratinized cells that are evident primarily at the distal margin of the nail bed

The development of the digits and the morphogenesis of eccrine sweat glands and nails proceeds on the hand in advance of the foot and on the distal pads ahead of the middle and proximal phalanges and the palm [32,43]. About 8.5–9 weeks EGA, the shape of the terminal digit is evident. Volar pads, transient mounds of mesenchyme that accumulate beneath the epidermis on the ventral surface of the digits, are well formed (Fig. 2.42a). Their presence in the first trimester is presumed to influence the dermatoglyphic patterns [47,48] and the development of those flexion creases that are not considered to be dependent upon movements of the hand [43,49,50]. Interest in the development of flexion creases relates to the aberrant patterns they assume in certain congenital disorders. How the volar pad tissue actually influences development of these structures is not understood and has not been studied experimentally. Volar pads begin to regress around 10.5–11 weeks EGA and are nearly gone by 12.5– 13 weeks EGA [43] when, presumably, their influence is no longer needed for morphogenesis. It is of interest that this tissue appears to be unique to the volar surfaces at the time of sweat gland initiation on the appendages, but it has not been correlated with this morphogenetic event in any definitive manner. The primary epidermal ridges are first formed around 10–11 weeks EGA [51]. They are recognized in sectioned specimens as localized aggregations of basal epidermal cells on the digits, palms and soles (Fig. 2.43a); in sheets of epidermis viewed basally, they appear first as discontinuous then as continuous ridges [52]. At this stage, the epidermis on the plantar surface consists of five or six layers of intermediate cells and the periderm. Merkel cells containing the characteristic granules are distributed along the primary epidermal ridges, where they may attract periglandular nerve fibres to this position of the structure [53] (Fig. 2.43b). Electron microscopy has

2.30

Chapter 2

(b)

(a)

(c)

(d) Fig. 2.42 Developing digit and nail. (a) Scanning electron micrograph of the ventral surface of the developing digit of an 80-day EGA fetus showing the dorsal ridge and the large volar pads. (b) Transverse section through the nail fold of a digit from an 85-day EGA fetus showing the distinction between dorsal and ventral (presumptive nail matrix) surfaces of the nail fold. The higher-magnification section shows more detail of

the epidermal surface and the mesenchyme beneath the nail fold. (c) Transverse sections through the digit and distal-most tip of the nail bed of a digit from a 105-day fetus showing keratinization of the superficial cells forming the ‘preliminary’ nail. (d) Scanning electron micrograph of a nail of a 140-day EGA fetus showing the fragile nature of the nail plate (a, ×60; b, ×100; c, ×200; d, ×100).

revealed nerve fibres associated with basal laminae underlying the ridges and Merkel cells, and occasionally extending into the epidermal tissue [32]. Merkel cell– nerve complexes are evident in digital skin before the primary ridges begin to form, and remain prominent in the primary ridges after the appearance of the sweat gland anlagen (Fig. 2.43a). They do not appear to migrate, however, into any region of the developing appendage. The sweat gland primordia are recognized around 13–14 weeks at regular sites along the now flattened ridges as narrowed, solid, epithelial cords of cells that contain basal

cell keratins and express classical carcinoembryonic antigen (CEA) on all cells [51,53]. There is no evidence of condensed mesenchyme associated with the onset of sweat gland development as there is in follicle development, thus suggesting that other sources of signalling molecules, possibly the volar pad mesenchyme, or nerves and/or other cell–cell interactions (perhaps within the epithelium) may instruct the sites for appendage formation and trigger the onset of gland development. As the cords of epithelial cells elongate into the dermis, a thickening at the terminus defines the glandular segment

Embryogenesis of the Skin

2.31

Fig. 2.43 Developing sweat glands on the ventral surfaces of the digit. (a) Cross-section through the digit of a 95-day EGA fetus showing the primary epidermis ridges organized from the basal layer of the epidermis. Note the abundance of nerves and vessels in the proximal dermis. (b) Immunolabelled section through the palm of a 105-day fetal hand showing the position of Merkel cells (green) marked by an antibody that recognizes keratin 18. The red labelling recognizes neurofilaments in dermal nerve fibres (micrograph courtesy of Dr Dong Kun Kim). (c) Immunolabelled section through the palm of a 163-day fetal hand showing the position of Merkel cells (green) marked by an antibody that recognizes keratin 20. The red labelling recognizes neurofilaments in dermal nerve fibres. Note the well-established sweat ducts and the secondary epidermal ridges alternating with the primary ridges from which the ducts are formed (micrograph courtesy of Dr Dong-Kun Kim) (a, ×300; b, ×300; c, ×100).

(a)

within the gland; myoepithelial cells are evident at the periphery of the structure. Cells of layers of the duct and of the gland are distinct from one another at 15 weeks EGA by their morphological properties and by differences in expression of keratins (duct) and vimentin (gland) and CAMs [54,55]. Coexpression of the two intermediate filament proteins in the same cells of the secretory segment of the developing gland is unique to this appendage, but it is characteristic of other glandular tissues such as mammary and salivary glands [54]. Secondary ridges form between the primary ridges (see Figs 2.43c and 2.44d). They do not give rise to sweat glands or contain Merkel cells. Globular keratohyalin granules are evident in the cytoplasm of the circumferentially organized cells of the intraridge, intraepidermal portion of the duct (the acrosyringium) at about 15 weeks EGA, signalling the onset of canalization in the acrosyringium (Fig. 2.45). The lumen of the duct forms by the fusion of cytoplasmic vesicles within ductal cells. The duct remains partially occluded even in the third trimester [56]. By 22–24 weeks EGA, the sweat glands on the palms and soles have attained the structure of the adult glands, with a coiled secretory segment positioned deeply within the dermis.

(b)

Eccrine sweat gland formation on the general body surface (c)

from the duct [54] (Fig. 2.44a). Ductal, secretory, myoepithelial and acrosyringial cell types differentiate in the dermal and intraepidermal regions of the gland and duct, and are easily distinguished from one another by light and electron microscopy (Fig. 2.44b and c) and by immunostaining patterns using antibodies to keratin intermediate filament proteins [54]. All cells continue to express CEA [51]. The secretory cells border a central lumen

Eccrine sweat glands form on the general body surface at least 4–6 weeks later than on the palms and soles. They are the last of the epidermal appendages to be formed during ontogeny. The difference in timing of appearance of the same structure in the two regions is not understood and bears investigation. If the origin of the eccrine sweat gland is like that of the follicle, and reflects a response to signals between epithelial and mesenchymal cells, the messages between the two could hardly be expected to be similar because the interappendageal epidermis and dermis at 18 weeks are considerably more advanced in properties and distinctly different from the plantar digits

2.32

Chapter 2

(a)

(c)

(d)

(b) Fig. 2.44 Developing sweat glands and ducts. (a) Scanning electron micrograph of the palm of a 19-week EGA fetus showing the elongated ducts and the club-like terminal gland. (b) A section through the palm of a 147-day EGA fetus shows the position of the duct and gland in the dermis and the canalization (keratinization) of the intraepidermal portion of the duct. A higher-magnification image of the gland and duct in the

palmar dermis of a 126-day EGA fetus (c) shows the cell layers of the duct and the cells of the gland (arrows). (d) Scanning electron micrograph of the undersurface of palmar epidermis of a 19-week EGA fetus showing the primary epidermal ridges with the remnants of torn sweat ducts spaced periodically and the secondary ridges that do not give rise to sweat ducts (a, ×80; b, ×120; c, ×300; d, ×80).

Embryogenesis of the Skin

2.33

(a)

Fig. 2.46 Scanning electron micrograph of the undersurface of the epidermis from a 15-week EGA fetus showing the pattern of hair follicles in the hair peg and hair germ stages of development. Note the longitudinal grooves in the epidermis that mark the position of intraepidermal hair canals (×100). (b) Fig. 2.45 Formation of the intraepidermal sweat duct by the development and coalescence of vesicles and subsequent keratinization of the lining cells (a). Note the globular keratohyalin granules that are characteristic of acrosyringial keratinization (×9100). Micrograph originally published in Odland G, Holbrook K. Curr Prob Derm 1981;9:29–49.

and palms and soles, which have the unique features of the volar pads and the thickened epidermis. In addition, the DEJ is more highly skin specific in terms of molecular composition, and the dermis is more adult-like in cellular and matrix composition and organization than the 12week skin. The primary work that has been done to investigate possible mechanisms concerning the onset of eccrine sweat gland formation relates to the potential of nerves, but this remains controversial (reviewed in ref [32]). The structural events have been much better characterized for the ridged skin of the palmar plantar and digital skin than for trunk skin (reviewed in refs [1–4]). The absence of sweat glands, or the delayed or hypoplastic development of sweat glands, is a hallmark of the ectodermal dysplasias [57]. Thus, one might like to assess

the nature of these structures in skin from fetuses at risk of some forms of this disorder [58]. The late onset of formation of these structures in sites other than the palms and soles rules out this possibility. Other features of the ectodermal dysplasias, however, such as alterations in hair follicle formation, can be of value in this prenatal diagnosis (reviewed in refs [29–31]).

Pilosebaceous apparatus formation The pilosebaceous apparatus is an epidermal appendage whose origin requires dermal participation throughout development and is best described as a composite epithelial–mesenchymal structure. Morphogenesis of the hair follicle begins on the head and face at around 70–80 days EGA, shortly after the epidermis stratifies, then proceeds in a cephalocaudal direction [28]. The process is completed at around 19–20 weeks EGA, when hairs extend from the lanugo follicle through the peridermcovered surface of the skin. Follicles form in regular patterns in all body regions, with the distances separating each dependent upon the specific site (Fig. 2.46). The descriptions of the hair germ, hair peg, bulbous hair peg

2.34

Chapter 2

Fig. 2.47 Diagram of the stages of hair follicle formation including the prefollicle two-layered epidermis, pregerm, hair germ, early hair peg, late hair peg/early bulbous hair peg and lanugo follicle stages.

and lanugo follicle stages of follicle formation (Fig. 2.47) are based on the appearance of vellus hairs on the trunk [1–4,33,34,59,60]. Follicles form only during development and decline in numbers as a function of ageing. The induction of follicles, their stages of development, maintenance in the adult and the cyclic growth and regression of the scalp follicles are all dependent upon an association of the follicle epithelium with dermal mesenchymal (fibroblastic) cells that form a cellular and matrix sheath around the developing and mature follicle and establish the dermal papilla as a special collection of mesenchymal cells that modulate the production and elongation of hairs [61–63]. Little is understood about the events that establish the patterns of human follicles or the molecular nature of the inductive messages that start the process. The epithelial and mesenchymal cells have been extensively characterized at each stage of follicle formation with regard to the expression of growth factors, growth factor receptors, cytokines, other signalling molecules and growth regulators, and structural proteins and enzymes [41,62,63,64–66]. Experimental studies in animal models, transgenic animals, tissue recombination preparations and various cell and organ culture systems have revealed the functions of specific populations of cells in developing follicles (e.g. dermal papilla and cells of the bulge) and events that signal early and sequential steps in the induction of other appendage primordia [36,37,40– 42,66,67]. Using these data, a story can be pieced together to suggest the influences over follicle formation and elongation, but the story remains inexact for human skin as the experimental work is most often done on postnatal follicles, typically in the rodent, or on isolated follicles, or

follicle and follicle-associated cells, also typically from the postnatal rodent. Thus, the data can be used only to infer what may be occurring in utero at the time the human follicles form de novo. The sites of follicle formation can be recognized, even before the hair germs are visible, in sections of fetal skin by immunostaining the tissue with an antibody that recognizes the matrix molecule tenascin [33,34]. Patches of reaction product at the basement membrane zone correspond to pregerms, or sites where basal keratinocyte nuclei are closely spaced and mesenchymal cells are aggregated (Fig. 2.48). Tenascin is typically expressed in tissues where there is evidence of matrix remodelling, cell migration and proliferation. It is also associated with the formation of patterned structures, and in other developing organs tenascin is prominent at sites of epithelial– mesenchymal interaction and mesenchyme condensation [68,69]. Tenascin and other CAMs appear to be important in defining the boundary of the epithelial cell clusters that will participate in appendage formation [35]. Cells from the basal epidermal layer bud into the dermis at the tenascin-rich sites to become hair germs (Fig. 2.48b). Condensed mesenchymal cells associate closely with the germs, often extending processes that contact the basal lamina (Fig. 2.40); this collection of mesenchymal cells is intensely immunoreactive with antibodies to NGFR (p75) (Fig. 2.49), NCAM and other growth factor receptors. Little if any collagenous matrix is present around the cells as a consequence of either downregulated production or enhanced degradation (reviewed in refs [33, 34 and 66]). Merkel cells are recognized in some of the developing germs. As is the case with the other appendages in which Merkel cells are prominent, they

Embryogenesis of the Skin

2.35

(a)

(b) Fig. 2.48 Immunolabelled section of human fetal skin at 70–75 days EGA showing tenascin-positive sites where hair germs have formed or are expected to form (a and b). The clustering of basal keratinocytes is apparent at sites where tenascin is strongly expressed in the basement membrane zone (a) (a, ×100; b, ×350). Micrograph courtesy of Dr Beth Kaplan.

(a)

(b)

(c)

Fig. 2.49 Hair germs in the skin of a 97-day fetus immunostained to recognize the p75 neurotrophic receptor, which recognizes NGFR. Note the concentration of this immunoreactive material within the mesenchymal cells surrounding the hair germ (×120).

may play a role in targeting nerve fibres towards the developing appendage. At around 13–14 weeks EGA, the hair germs elongate into the dermis as cords of cells called hair pegs (Figs 2.46 and 2.50). The hair peg consists of an inner core of cuboidal cells and outer layer of columnar cells that is associated with the basal lamina surrounding the follicle and continuous with that of the interfollicular epidermis. Cells of the outer layer contain the same keratins as the basal epidermal keratinocytes and the cells of the inner

Fig. 2.50 Late-stage hair pegs (a, b) showing the continuity of the intermediate layer keratins into the upper core cells of the follicle (a), the regions of the peg and the mesenchymal cells surrounding the peg and aggregated at its tip (the presumptive dermal papilla) in association with the presumptive matrix of the follicle. Note the differences in cell orientation in the inner and outer and the distal and proximal regions of the peg (b). (c) Section through the upper end of a hair peg showing the continuation of cells into the epidermis as the hair track (a, ×300; b, ×300; c, ×300).

core contain intermediate cell keratins (Fig. 2.50a), thus implicating the origins of follicle cells from two epidermal layers. Merkel cells are distributed among the outer root sheath keratinocytes. Early hair pegs are cylindrical, but as they elongate further they develop three regions: (i) a constricted, necklike connection with the epidermis (the presumptive infundibulum); (ii) a central, cylindrical region (the presumptive isthmus); and (iii) a terminal zone that becomes widened at its most distal end (the lower follicle and the

2.36

Chapter 2

presumptive bulb) (Fig. 2.50). The length of the hair peg and the three zones of the developing follicle are exaggerated in some regions of the skin but more subtle in others. Changes occur in all three regions, with the first notable events taking place at the proximal and distal ends. Elongated core cells in the neck of the follicle continue into the epidermis, where they form a strand of cells that lies between the basal and intermediate cell layers (see Fig. 2.50). This is the hair tract that marks the position and pathway of the presumptive hair canal (Fig. 2.50c) [70]. The distal end of the hair peg flattens and the epithelial cells along this basal border elongate to form a distinct layer that establishes the matrix (Fig. 2.50a and b). The flattened end of the follicle begins to invaginate into the cord, shaping the bulb with the matrix as the roof of the bulb. Mitotic figures are evident in matrix cells, and longitudinally orientated cells, presumably the progeny of the dividing matrix cells, move out of the matrix into the centre of the cord, thereby establishing the first layers of the inner root sheath and the hair (the hair cone). Cells of the outer layer of the follicle located adjacent and lateral to the matrix appear to become more loosely associated with one another, perhaps permitting the inward migration of the cells derived from the matrix. Melanocytes aggregate in the matrix and produce melanin ahead of melanocytes in the general body skin, thus making the bulbs of developing hair follicles ideal sites to examine when evaluating skin biopsy samples from a fetus at risk of tyrosinase-negative oculocutaneous albinism (reviewed in ref [29]) (Fig. 2.51). Such samples can be induced to synthesize melanin by the DOPA reaction if the fetus is normal [71,72]. The fate of the original K1/K10-positive core cells after the matrix begins to function is not clear, but it is possible that they remain as the layer of cells that lies interior from and perpendicular to the columnar cells of the outer layer of the outer root sheath. Once the follicle is fully differentiated, however, only cells within the infundibulum stain with antibodies that recognize the K1 and K10 keratins of the intermediate layer of fetal epidermal cells. During these events, the cord is surrounded in its entirety by several layers of elongated mesenchymal cells that form a sheath. The connective tissue matrix is sparse within this cellular sheath and appears to be devoid of the fibrillar collagens that are present in the surrounding subepidermal and interstitial matrix (Fig. 2.52). Differences in matrix molecules are observed at different levels of the hair peg and when comparing the dermal papilla with the follicle sheath [33,34]. Between 15 and 17 weeks EGA, bulges of epithelial cells begin to grow out from the epithelial cord on the posterior surface of the follicle and the adult layers of the follicle differentiate into the hair and internal root sheath. Once these bulges form, the follicle is called a bulbous

(a)

(b) Fig. 2.51 The bulb of a hair peg (a) and lanugo follicle (b) in skin from different regions obtained at ages 115 days and 125 days EGA. Note the concentration of melanocytes in the matrix of the follicle (a, ×300; b, ×300).

hair peg (Fig. 2.53a). The factors that stimulate the development of these structures to arise from the follicle, at a precise stage in the hair peg formation and at precise sites along the hair peg, are unknown. There are no obvious landmarks along the hair peg that provide morphological clues as to how the bulges might originate. The most superior bulge is the primordium of the sebaceous gland (Fig. 2.53a). Cells begin to produce sebum soon after this structure is evident. Analysis of epidermal lipids from fetal skin at this stage reveals a sterol/wax ester content, which suggests that the material is similar to adult sebum [73]. The second bulge, the ‘true bulge’, forms concurrently with and slightly distal to the sebaceous gland. It is thought to be the site of follicular stem cells [74] and the point of attachment of the arrector pili muscle (Fig. 2.53a). The morphological properties of the cells are suggestive of an undifferentiated population, and their keratin composition and expression of growth factor and growth factor receptors are more similar to

Embryogenesis of the Skin

2.37

(a)

(b)

(a)

(b)

Fig. 2.53 Bulbous hair peg in the skin of a 15-week EGA fetus. (a) In the longitudinal section through the follicle, note the sebaceous gland, the bulge located just distal to the sebaceous gland, the cell layers of the inner root sheath (inner bar) and the outer layers of the outer root sheath (outer bar). The infundibulum is the region of the follicle that lies between the sebaceous gland and the epidermis. Note the cells of the dermal papilla within the bulb. (b) A cross-section through a region between the two bars shows the layers of the outer root sheath and the inner root sheath (a, ×300; b, ×300).

(c) Fig. 2.52 Sections of fetal skin immunolabelled with antibodies to collagens of the dermis. Note the decreased staining for types I (a), III (b) and V (c) collagens in the developing hair germs (a, ×300; b, ×300; c, ×300). Immunolabelling studies by Dr Lynne T. Smith.

basal keratinocytes than to cells of the outer root sheath [75,76]. There is no information about the origin of the stem cells in the bulge nor about how they are set aside in this compartment during development. Since the bulge is unusually large and well demarcated in the developing fetal follicle, it might be relatively easy to dissect these cells from the follicle and grow them in culture to learn more about their properties and differentiative potential. Merkel cells also concentrate in the bulge at early stages

2.38

Chapter 2

of bulge formation. They may be important in establishing this structure, stimulating proliferation or attracting nerve fibres and smooth muscle cells to the site. A third bulge may form superior to the sebaceous gland as the primordium of the apocrine sweat gland. These structures are located in the restricted sites of the body where apocrine sweat glands are present in the postnatal infant (axilla, areola, scalp, external eyelid, auditory meatus and anogenital regions) [77]. The cylindrical layers of the follicle differentiate and keratinization begins in several different structures of the follicle concurrently: the outer layer of cells of the inner root sheath (layer of Henle); the cuticle and cortex of the hair (Fig. 2.53b); the sebaceous duct; and the hair canal. Continued production of cells of the three layers of the inner root sheath and the hair gradually creates the keratinized tube of the inner root sheath and the hair. Production of the hair marks the establishment of the lanugo follicle (Figs 2.54 and 2.55). The hair and its cells of origin are well outlined in the whole-mount preparations of tissue at this stage by the presence of melanin-producing melanocytes in the matrix and the melanin pigment in the hair (Fig. 2.51b). Antibodies to hair keratins also highlight the forming hair in sections of skin (Fig. 2.54). The first hairs of the fetus are in the anagen phase of the hair cycle. In some newborns, a significant number of them will enter telogen and be shed, creating an alopecia that can last up to 6 months.

Keratinization within the hair tract canalizes the cord of cells and forms a keratin-lined channel that courses diagonally through the epidermis (Figs 2.50c and 2.56a) [73]. The granular and cornified cell layers of the hair canal form a sharp contrast with the remainder of the, as yet non-keratinized, epidermis (Fig. 2.56a). The angle of the canal with the epidermis and the intraepidermal length of the canal are regionally variable. On the eyebrow, for example, the hair canals are closely spaced and their paths are very short. In other regions of the body, such as the appendages, the canals can be very long. By examining the surface of the fetal skin at this stage, even with a hand lens, it is possible to see these canals (Fig. 2.56b). Scanning electron microscopy reveals sites where the roof of the canal is eroded and the hair is visible (Fig. 2.56b). These sites expose the keratinized lining of the hair canal and loose squames attached to the portion of the hair that lies within the canal. It is important to understand that keratinization of the canals occurs earlier in the follicular epidermis than in the interfollicular epidermis because this information permits the hair canals to be used for evaluating fetal skin biopsies obtained for prenatal diagnosis of one of the severe disorders of keratinization (Fig. 2.57). The presence of well-keratinized structures within the epidermis can also lead to misinterpretation of the status of the skin if not carefully compared with the non-keratinized interfollicular epidermis.

Fig. 2.54 A lanugo follicle associated with an epidermal sheet from a 126-day EGA trimester fetus. Note the hair, sebaceous gland, bulge and sebum-filled infundibulum (×150). Micrograph courtesy of Dr Carolyn Foster.

Fig. 2.55 Skin from a 117-day EGA fetus, immunostained with the AE-13 antibody, which recognizes a hair keratin (×120).

Embryogenesis of the Skin

(a)

(b) Fig. 2.56 The hair canal. (a) Section through the skin of a 138-day EGA fetus showing the floor of an opened hair canal. Keratinization of this structure stands out in contrast to the non-keratinized epidermis. (b) Scanning electron micrograph of the skin of a 21-week EGA fetus showing hair canals within (beneath the surface of) the epidermis. Note that one hair has emerged and others are evident through the thinned epidermal layers above the canal (a, ×100; b, ×185).

Fig. 2.57 Cross-section of the hair canals from a fetal skin sample obtained at 23 weeks EGA from a fetus affected with harlequin ichthyosis. Keratinization of these structures is extraordinarily thick (×300).

2.39

At this stage, the connective tissue sheath of the follicle contains all of the interstitial, fibrillar collagens characteristic of the dermis. One might interpret the absence of supportive collagens in the sheath during the downward growth and development as a supportive environment for tissue invasion of the dermis, and re-establishment of the matrix surrounding the bulbous hair peg and lanugo follicle as a stabilizing environment for the fully formed structure. References 1 Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LA (ed.) Physiology, Biochemistry and Molecular Biology of the Skin, 2nd edn. Oxford: Oxford University Press, 1991: 63–110. 2 Holbrook KA. Structural and biochemical organogenesis of skin and cutaneous appendages in the fetus and neonate. In: Polin RA, Fox WW (eds) Neonatal and Fetal Medicine Physiology and Pathophysiology. New York: Grune & Stratton, 1992: 527–51. 3 Holbrook KA, Wolff K. The structure and development of skin. In: Fitzpatrick TB, Eisen AZ, Wolff K et al. (eds) Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 1993: 97–144. 4 Holbrook KA, Sybert VP. Basic science. In: Schachner L, Hansen R (eds) Pediatric Dermatology, 2nd edn. New York: Churchill Livingstone, 1995. 5 Sanes JR, Rubenstein JLR, Nicolas J-F. Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J 1986;5:3133–42. 6 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;28:136–54. 7 Dale BA, Holbrook KA, Kimball JR et al. Expression of the epidermal keratins and filaggrin during fetal human development. J Cell Biol 1985;101:1257–69. 8 Regauer S, Franke WW, Virtanen I. Intermediate filament cytoskeleton of amnion epithelium and cultured amnion epithelial cells: expression of epidermal cytokeratins in cells of a simple epithelium. J Cell Biol 1985;100:997–1009. 9 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;161:462–7. 10 Lane AT, Negi M, Goldsmith LA. Human periderm: a monoclonal antibody marker. Curr Prob Dermatol 1987;16:83–93. 11 M’Boneko V, Merker H-J. Development and morphology of the periderm of mouse embryos (days 9–12 of gestation). Acta Anat 1988;133:325–36. 12 Holbrook KA, Odland GF. The fine structure of developing human epidermis: light, scanning and transmission electron microscopy of the periderm. J Invest Dermatol 1975;65:16–38. 13 Holbrook KA, Underwood RA, Dale BA et al. Formation of the cornified cell envelope in human fetal skin: presence of involucrin, keratolinin, loricrin and transglutaminase correlated with the onset of transglutaminase activity. J Invest Dermatol 1991;96:542A. 14 Akiyama M, Smith LT, Yoneda K et al. Expression of transglutaminase 1 (TG1) and cornified cell envelope (CCE) proteins during human epidermal development. J Invest Dermatol 1997;108:598 (Abstract). 15 Arends MJ, Wyllie AH. Apoptosis: mechanisms and roles in pathology. Int Rev Exp Pathol 1991;32:223–54. 16 Paus R, Rosenbach T, Haas N et al. Patterns of cell death: the significance of apoptosis for dermatology. Exp Dermatol 1993;2: 3–11.

2.40

Chapter 2

17 Polakowska RR, Piacentini M, Bartlett R et al. Apoptosis in human skin development: morphogenesis, periderm and stem cells. Dev Dyn 1994;199:176–88. 18 Riddle CV. Intramembranous response to cAMP in fetal epidermis. Cell Tissue Res 1985;241:687–9. 19 Koren G. Fetal toxicology of environmental tobacco smoke. Curr Opin Pediatr 1995;7:128–31. 20 Mears GJ, Van Petten GR. Fetal absorption of drugs from the amniotic fluid. Proc West Pharmacol Soc 1977;20:109–14. 21 Lind T, Kendal A, Hytten FE. The role of the fetus in the formation of amniotic fluid. J Obstet Gynaecol Br Commonw 1972;79:289–98. 22 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;81:222–7. 23 Holbrook KA, Wapner R, Jackson L et al. Diagnosis and prenatal diagnosis of epidermolysis bullosa herpetiformis (Dowling–Meara) in a mother, two affected children and an affected fetus. Prenatal Diagn 1992;12:725–39. 24 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;282:143–8. 25 Holbrook KA, Odland GF. Regional development of the human epidermis in the first trimester embryo and the second trimester fetus (ages related to the timing of amniocentesis and fetal biopsy). J Invest Dermatol 1980;80:161–8. 26 Akiyama M, Dale BA, Smith LT et al. Regional difference in expression of characteristic abnormality of harlequin ichthyosis in affected fetuses. Prenat Diagn 1998;18:425–36. 27 Pinkus H. Embryology of hair. In: Montagna W, Ellis RA (eds) The Hair Growth. New York: Academic Press, 1958: 1–32. 28 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;91:521–31. 29 Holbrook KA, Smith LT, Elias S. Prenatal diagnosis of genetic skin disease using fetal skin biopsy samples. Arch Dermatol 1993;129:1437–54. 30 Sybert VP, Holbrook KA, Levy M. Prenatal diagnosis of severe dermatologic diseases. Adv Dermatol 1992;7:179–209. 31 Sybert VP, Holbrook KA. Antenatal pathology of the skin. In: Claireaux AE, Reed GB (eds) Diseases of the Fetus and Newborn: Pathology, Radiology and Genetics. New York: Cockburn, Chapman & Hall, 1995: 755–68. 32 Moore SJ, Munger BL. The early ontogeny of the afferent nerves and papillary ridges in human digital and glabrous skin. Dev Brain Res 1989;48:119–41. 33 Holbrook KA, Smith LT, Kaplan ED et al. The expression of morphogens during human follicle development in vivo and a model for studying follicle morphogenesis in vitro. J Invest Dermatol 1993;101:39S–49S. 34 Kaplan ED, Holbrook KA. Dynamic expression patterns of tenascin, proteoglycans and cell adhesion molecules during human hair follicle morphogenesis. Dev Dyn 1994;199:141–55. 35 Chuong C-M, Widelitz RB, Jiang T-X. Adhesion molecules and homeoproteins in the phenotypic determination of skin appendages. J Invest Dermatol 1993;101:10S–15S. 36 Noveen A, Jiang T-X, Ting-Berreth SA et al. Homeobox genes Msx-1 and Msx-2 are associated with induction and growth of skin appendages. J Invest Dermatol 1995;104:711–9. 37 Noveen A, Jiang T-X, Chuong C-M. Protein kinase A and protein kinase C modulators have reciprocal effects on mesenchymal condensation during skin appendage morphogenesis. Dev Biol 1995;171:677–93.

38 du Cros DL. Fibroblast growth factor influences the development and cycling of murine hair follicles. Dev Biol 1993;156:444–53. 39 Moore GPM, du Cros DL, Isaacs K et al. Hair growth induction: roles of growth factors. Ann NY Acad Sci 1991;624:308–25. 40 Chuong C-M, Widelitz RB, Ting-Berreth S et al. Early events during avian skin appendage regeneration: dependence on epithelial– mesenchymal interaction and order of molecular reappearance. J Invest Dermatol 1996;107:639–46. 41 Widelitz RB, Jiang T-X, Noveen A et al. FGF induces new feather buds from developing avian skin. J Invest Dermatol 1996;107:797–803. 42 Ting-Berreth SA, Chuong C-M. Local delivery of TGF ?2 can substitute for placode epithelium to induce mesenchymal condensation during skin appendage morphogenesis. Dev Biol 1996;179:347–59. 43 Kimura S. Embryologic development of flexion creases. Birth Defects: Original Article Series 1991;27:113–29. 44 Zaias N. Embryology of the human nail. Arch Dermatol 1996;87:37–53. 45 Hashimoto K, Gross BG, Nelson R et al. The ultrastructure of the skin of human embryos. III. The formation of the nail in the 16–18 weeks old embryo. J Invest Dermatol 1996;47:205–17. 46 Lewis BL. Microscopic studies, fetal and mature nail and surrounding soft tissue. Arch Dermatol 1954;70:732–47. 47 Mulvihill JJ, Smith DW. The genesis of dermatoglyphics. J Pediatr 1969;75:597–9. 48 Hirsch W, Schweichel JU. Morphological evidence concerning the problem of skin ridge formation. J Ment Defic Res 1973;17:58–72. 49 Kimura S, Kitagawa T. Embryological development of human palmar, plantar and digital flexion creases. Anat Rec 1990;226:249–57. 50 Hale AR. Morphogenesis of volar skin in the human fetus. Am J Anat 1952;91:147–81. 51 Metze D, Bhardwaj R, Amann U et al. Glycoproteins of the carcinoembryonic antigen (CEA) family are expressed in sweat and sebaceous glands of human fetal and adult skin. J Invest Dermatol 1966;106:64–9. 52 Kim D-G, 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;104:411–16. 53 Narisawa Y, Hashimoto K, Pietruk T. Biological significance of dermal Merkel cells in development of cutaneous nerves in human fetal skin. J Histochem Cytochem 1992;40:65–71. 54 Moll I, Moll R. Changes of expression of intermediate filament proteins during ontogenesis of eccrine sweat glands. J Invest Dermatol 1992;98:777–85. 55 Fujita M, Furukawa F, Fujii K et al. Expression of cadherin molecules during human skin development: morphogenesis of epidermis, hair follicles and eccrine sweat ducts. Arch Dermatol Res 1992;284:159–66. 56 Hashimoto K, Gross BG, Lever WF. The ultrastructure of the skin of human embryos. I. The intraepidermal eccrine sweat duct. J Invest Dermatol 1965;45:139–51. 57 Freire-Maia N, Pinheiro M. Ectodermal Dysplasias: a Clinical and Genetic Study. New York: Alan R. Liss, 1984. 58 Holbrook KA. Structural abnormalities of the epidermally derived appendages in skin from patients with ectodermal dysplasia: insight into developmental errors. Birth Defects Original Article Series 1988:24(2):15–44. 59 Holbrook KA, Minami SA. Hair follicle morphogenesis in the human: characterization of events in vivo and in vitro. NY Acad Sci 1991;642:167–96. 60 Holbrook KA, Fisher CF, Dale BA et al. Morphogenesis of hair follicles during the ontogeny of the human skin. In: Rogers GE (ed.) The Biology of Wool and Hair. New York: Chapman & Hall, 1988: 15–35.

Embryogenesis of the Skin 61 Reynolds AJ, Oliver RF, Johoda CAB. Dermal cell populations show variable competence in epidermal support: stimulatory effects of hair papilla cells. J Cell Sci 1991;98:75–83. 62 Messenger A. The control of hair growth: an overview. J Invest Dermatol 1993;201:4S–9S. 63 Jahoda CAB, Reynolds AJ, Forrester JC et al. Hair follicle regeneration following amputation and grafting into the nude mouse. J Invest Dermatol 1996;107:904–7. 64 Breen M, Weinstein HG, Johnson RL et al. Acid glycosaminoglycans in human skin during fetal development and in adult life. Biochim Biophys Acta 1970;201:54–60. 65 Varma RS, Varma R. Glycosaminoglycans and proteoglycans of skin. In: Varma RS, Varma R (eds) Glycosaminoglycans and Proteoglycans in Physiological and Pathological Processes of Body Systems. Basle: Karger, 1982: 151–64. 66 Karelina TV, Goldberg GI, Eisen AZ. Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. J Invest Dermatol 1994;103:482–7. 67 Scandurro AB, Wang Q, Goodman L et al. Immortalized rat whisker dermal papilla cells cooperate with mouse immature hair follicle buds to activate type IV procollagenases in collagen matrix coculture: correlation with ability to promote hair follicle development in nude mouse grafts. J Invest Dermatol 1995;105:177–83. 68 Chiquet-Ehrismann R, Mackie EJ, Pearson CA et al. Tenascin: an extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell 1986;47:131–9. 69 Erickson HP, Bourdon MA. Tenascin: an extracellular matrix protein prominent in specialized embryonic tissues and tumors. Annu Rev Cell Biol 1989;5:71–91. 70 Holbrook KA, Odland GF. Structure of the hair canal and the initial eruption of hair in the human fetus. J Invest Dermatol 1978;71:385–90.

2.41

71 Eady RAJ, Gunner DB, Garner A et al. Prenatal diagnosis of oculocutaneous albinism by electron microscopy. J Invest Dermatol 1983;80:210–12. 72 Kikuchi A, Shimizu H, Nishikawa T. Epidermal melanocytes in normal and tyrosinase-negative oculocutaneous albinism fetuses. Arch Dermatol Res 1995;287:529–33. 73 Williams ML, Hincenbergs M, Holbrook KA. Skin lipid content during early fetal development. J Invest Dermatol 1988;91:263–8. 74 Cotsarelis G, Sun T-T, 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;61:1329–37. 75 Akiyama M, Dale BA, Sun T-T 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;105:844–50. 76 Akiyama M, Smith LT, Holbrook KA. Growth factor and growth factor receptor localization in the hair follicle bulge and associated tissue in human fetus. J Invest Dermatol 1966;106:391–6. 77 Hashimoto K. The ultrastructure of the skin of human embryos. VII. Formation of the apocrine gland. Acta Dermatovener 1970;50: 241–51.

Conclusion The understanding of human skin development has been based largely on the foundation of descriptive work. Fortunately, many of the methods for developing these data also provide information about composition, and thus the morphological approaches have allowed a reasonable story of skin development to unfold.

3.1

CHAPTER 3

Physiology of Neonatal Skin Peter H. Hoeger Department of Pediatric Dermatology, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany

Vernix caseosa, 3.1

Epidermis, 3.2

The transition from an aqueous, but sterile, atmosphere to a dry one rich in pathogens represents a dramatic challenge to the skin of the newborn infant. Intactness of the epidermal barrier is of utmost importance both for the prevention of water loss and for the defence against micro-organisms that start to colonize the neonatal skin from the moment of birth. The efficacy of this barrier is proportional to its thickness and lipid composition. During late gestation, the number of epidermal layers and the thickness of the stratum corneum increase with fetal age. The extent of transepidermal water loss and the risk of infections with skin-colonizing micro-organisms in preterm infants are thus directly proportional to the infant’s degree of prematurity. Although the gross anatomy of epidermal and dermal structures in neonatal skin is similar to that in older skin (Table 3.1), the process of postnatal maturation and adaptation affects virtually all compartments and structures of the skin.

Vernix caseosa During the last trimester of gestation, the fetus is covered by a protective biofilm called vernix caseosa. It forms a mechanical ‘shield’ against maceration by amniotic fluid and bacterial infection. Vernix is composed mainly of water (80.5%), proteins and lipids (8–10%) (Fig. 3.1) [1,2]. These lipids are derived from two sources: wax esters formed in sebaceous glands [3] and epidermal barrier lipids derived from keratinocytes [2]. Vernix contains all major stratum corneum lipids, including ceramides [4], which are not synthesized by sebaceous glands. Similar to postnatal skin, sebum and epidermal lipids apparently mix within vernix in order to provide on the fetal skin surface what has been referred to as the skin surface lipid film [5]. Interestingly, the lipid composition of vernix

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Dermis, 3.5

Table 3.1 A comparison of skin anatomy between preterm and term neonates and older children Premature baby

Full-term neonate

Infants/ children

Skin thickness (mm)

0.9

1.2

2.1

Diameter of epidermis (μm)

20–25

40–50

>50

Diameter of stratum corneum (μm) (number of layers)

4–5 (5 or 6)

9–10 (≥10–15)

10–15 (≥10–15)

Dermoepidermal junction

Flat, no rete ridges

Rete ridges start to form

Deep rete ridges

Eccrine sweat glands

Upper dermis, inactive

Upper dermis, barely active

Deeper dermis, fully active

Elastic fibres

Microfibrils, no elastin

Elastic fibre network, immature

Elastic fibre network, mature

Fig. 3.1 Composition of human vernix caseosa. FFA, free fatty acid. Modified from Pickens WL, Warner RR, Boissy YL et al. Characterization of vernix caseosa: water content, morphology, and elemental analysis. J Invest Dermatol 2000;115:875–81 and Hoeger PH, Schreiner V, Klaassen IA et al. Epidermal barrier lipids in human vernix caseosa: corresponding ceramide patterns in vernix and fetal epidermis. Br J Dermatol 2002;146:194–201.

3.2

Chapter 3

closely resembles that found in fetal skin [2]. Unlike postnatal skin, sebum and keratinocytes are not shed in the fetal period but adhere to the skin; accumulation of vernix might thus compensate for the relative lack of barrier lipids in fetal skin. Application of vernix to normal adult skin has been shown to increase surface hydration [6]. Shedding of vernix towards the end of gestation coincides with maturation of the transepidermal barrier. References 1 Pickens WL, Warner RR, Boissy YL et al. Characterization of vernix caseosa: water content, morphology, and elemental analysis. J Invest Dermatol 2000;115:875–81. 2 Hoeger PH, Schreiner V, Klaassen IA et al. Epidermal barrier lipids in human vernix caseosa: corresponding ceramide patterns in vernix and fetal epidermis. Br J Dermatol 2002;146:194–201. 3 Stewart ME, Quinn MA, Downing DT. Variability in the fatty acid composition of wax esters from vernix caseosa and its possible relation to sebaceous gland activity. J Invest Dermatol 1982;78:291–5. 4 Oku H, Mimura K, Tokitsu Y. Biased distribution of the branched-chain fatty acids in ceramides of vernix caseosa. Lipids 2000;35:373–81. 5 Sheu H-M, Chao S-C, Wong T-W et al. Human skin surface lipid film: an ultrastructural study and interaction with corneocytes and intercellular lipid lamellae of the stratum corneum. Br J Dermatol 1999; 140:385–91. 6 Bautista MIB, Wickett RR, Visscher MO et al. Characterization of vernix caseosa as a natural biofilm: comparison to standard oil-based ointments. Pediatr Dermatol 2000;17:253–60.

Epidermis The epidermis protects against evaporation, percutaneous absorption of toxic substances, physical damage and microbial infection. These properties depend largely on the thickness and barrier lipid content of the epidermis, both of which are directly related to gestational age [1,2]. As shown in Fig. 3.2, the number of epidermal cell layers and, from about the beginning of the third trimester, the thickness of the stratum corneum increase progessively with age. The most important lipids required for barrier function (i.e. ceramides, cholesterol and free fatty acids) are synthesized in the lamellar bodies within the granular layer. There is a patterned succession of epidermal expression of mRNA and of enzymes involved in lipid synthesis preceding the formation of an effective epidermal barrier [3,4]. Among the most important factors regulating the sequence of epidermal differentiation and stratum corneum formation is the peroxisome proliferatoractivated receptor-α (PPAR-α). PPARs are expressed abundantly in early fetal epidermis; they regulate the activity of key enzymes required for barrier ontogenesis (e.g. β-glucocerebrosidase and steroid sulphatase) [4,5]. Similar to what happens in maturation of the lung, glucocorticoids, thyroid hormones and oestrogens accelerate barrier formation, while androgens retard it [4]. Initiation of skin barrier formation in the human fetus starts at

around 20–24 weeks’ gestation [6]. The process of keratinization reveals an interesting temporal and spatial pattern, starting at and spreading from distinct epidermal initiation sites such as forehead, palms and soles [6,7].

Transepidermal water loss The intactness of the epidermal barrier can be assessed by measuring the transepidermal water loss (TEWL). The TEWL is proportional to the vapour pressure gradient measured with an evaporimeter [8,9]. It is influenced by gestational age, site and ambient humidity [8–10]. In term neonates, the TEWL ranges from 4 to 8 g/m2/h. This is slightly lower than in adults [11] owing to the fact that eccrine sweating is low or absent in the newborn infant. In the premature infant, TEWL is inversely proportional to gestational age (Fig. 3.3). In very immature infants (24–26 weeks’ gestation), it can be as high as 100 g/m2/h, which means that these infants, if left in a dry atmosphere, could lose 20–50% of their body weight within 24 h. This degree of TEWL would rapidly lead to hypernatraemia, polyglobulia and hypothermia, resulting eventually in intracranial haemorrhage and death. As TEWL represents passive diffusion of water along a water vapour gradient, it can be prevented by raising the ambient humidity. It is now common practice to humidify incubators for premature babies, particularly those of less than 32 weeks’ gestation [12]. Humidity needs to be as high as 80–90% within the first days in order to prevent heat and fluid loss. Prevention of hypothermia and TEWL can also be ascertained by using polyethylene caps or wraps immediately after delivery [13]. In underdeveloped countries where incubators are not readily available, postnatal topical emollient therapy with sunflower seed oil or mineral oils (petrolatum) has been shown to significantly reduce mortality rates in premature infants [14]. There is a striking regional variability on the skin surface regarding TEWL; it is usually highest through the abdominal skin, where maturation of the epidermal barrier occurs latest [6,7]. Preterm infants nursed under a radiant heater exhibit higher rates of evaporation because the level of ambient water vapour is lower [15]. It is likewise increased (by 20%) during phototherapy, even if relative humidity and ambient temperature are tightly controlled; this is probably caused by increased dermal blood flow during phototherapy [16,17]. Maintenance fluid intake of preterm infants should therefore be adequately increased during phototherapy. Neonatal epidermis can easily be hurt (e.g. by removal of plastic adhesives), which induces a measurable disruption of the skin barrier function [18]. Interestingly, air exposure leads to acceleration of postnatal barrier maturation. As depicted in Fig. 3.4, TEWL in most premature infants approaches that of term infants

Physiology of Neonatal Skin

3.3

(a) (b)

(d)

(c) Fig. 3.2 Embryonic, fetal and neonatal skin: (a) at 13 weeks’ gestation; (b) at 18 weeks’ gestation; (c) at 25 weeks’ gestation; (d) in a mature neonate.

Fig. 3.3 The effect of gestational age on transepidermal water loss (TEWL). Serial measurements from abdominal skin in 17 infants of 25–29 weeks’ gestation. Shaded bar represents TEWL in term infants. From Cartlidge PHT, Rutter N. Skin barrier function. In: Polin RA, Fox WW, eds. Textbook of Fetal and Neonatal Physiology, 2nd edn. Philadelphia: W.B. Saunders, 1998:771–88.

Fig. 3.4 The effect of gestational age on percutaneous absorption of phenylephrine. The blanching response was observed on the abdominal skin of infants in the early newborn period. From Cartlidge PHT, Rutter N. Skin barrier function. In: Polin RA, Fox WW, eds. Textbook of Fetal and Neonatal Physiology, 2nd edn. Philadelphia: W.B. Saunders, 1998:771–88.

3.4

Chapter 3

within 10–15 days. Studies in rodents have shown that this functional maturation is paralleled by an increase in stratum corneum thickness, the number of lamellar bodies in stratum granulosum cells and the barrier lipid content of the stratum corneum [19,20]. In ultra-lowbirthweight infants (23–25 weeks of gestational age), this process can, however, take significantly longer [21]. As demonstrated recently, even in mature babies it takes up 12 months until TEWL normalizes to levels seen in older children and adults; this process is paralleled by a constant increase of natural moisturizing factor levels within the epidermis [22].

permeability is inversely proportional to gestational age [23]. Even in the term infant, transcutaneous absorption is more readily achieved because the body surface area to weight ratio is two- to threefold higher than in older children and adults [24]. Low-molecular-weight chemicals (3000 families

Yes

2 plus >20 reports (reviewed in 3,4)

CMA1 (chymase)

14q11

rs1800875 (A-1903G) rs1800875 rs1800875

Adult eczema Childhood eczema Non-atopic eczema Adult eczema Eczema

Japanese Japanese Japanese

100:100 145/851 47:100

Yes Yes Yes

5 6 7

German Japanese

242/1875 100:101

Yes No

8 9

Eczema

Japanese

101:75

Yes

10

Adult eczema Infantile flexural eczema Adult eczema

Japanese British

27:29 XXX/1051

Yes Yes

11 12

Japanese

27/29

No

11

Atopic eczema Eczema Eczema

Japanese Japanese Chinese

302:122 101:75 94/186

No No No

13 10 14

rs1800875 rs1800875 IL4RA

16p12–11

rs2057768 (-3112C>T), rs2107356 (-1803T>C), rs8060798 (-327C>A), rs8060938 (-326A>C), rs12927172 (-186G>A) rs1805011 (Glu375Ala) rs1801275 (Glu551Arg) rs1805010 (Val75Ile), rs1805012 (Cys406Arg) rs1805010, rs1805011, rs1801275 rs12927543 (-184A>G) rs1805011, rs2234898 (Leu389Leu), rs1805012, rs1801275 (Gln576Arg), rs1805015 (Ser503Pro)

IL13

5q31

rs20541 (Arg130Gln) rs1800925 (C-1024T) rs20541 rs20541 rs1800925 rs1800925, rs20541 rs1800925, rs1881457 (A-1512C) rs1800925, rs2066960, rs1295686, rs20541, rs1295685

Childhood eczema Eczema Eczema Eczema Childhood eczema Eczema Eczema Childhood eczema

White Canadian Dutch Japanese German White Canadian Chinese Japanese British

52:288 238:104 185:102 187:98 52:288 94:186 185:102 178/1358

Yes Yes Yes Yes No No No No

15 16 17 18 15 14 17 19

NOD1 (CARD4)

7p15-p14

rs2736726, rs2075817, haplotype rs2975632, rs2075822, rs2907749, rs2907748 haplotype

Adult eczema Eczema

German German

457/1417 189 trios

Yes Yes

20 20

Eczema

German

392:297

Yes

21

rs5743836 (C-1237T) rs5743836 rs5743836 rs187084 (C-1486T), rs352139 (G1174A), rs352140 (G2848A) rs187084, rs352139, rs352140 rs187084, rs5743836

Eczema Eczema Adult eczema Eczema

German German German German

281 trios 202 trios 274:252 281 trios

Yes Yes No No

22 22 22 22

Eczema Adult eczema

German German

202 trios 136:129

No No

22 23

rs2107538 (G-403A) rs2107538 rs2107538, rs2280788 (C-28G) rs2107538, rs2280788

Childhood eczema Eczema Atopic eczema Childhood atopic eczema

German Japanese Japanese Hungarian

188:98 62:14 389:177 128:303

Yes Yes Yes No

24 25 26 27

TLR9

RANTES (CCL5)

3p21.3

17q11.2q12

(Continued)

23.10

Chapter 23

Table 23.1 Continued Gene

Location

Variant(s)

Phenotype(s)

Population

No. of subjects* Ass.¥

Reference

SPINK5 (LEKTI)

5q32

rs2287774 (G-206A) rs2303067 (Glu420Lys) rs2303067 rs2303067, rs2303063 (Asn368Ser), rs2303061 (IVS12-26C>T), rs2303062 (IVS12-10A>G), rs2303066 (IVS13-50G>A), rs2303068 (IVS14+19G>A) rs2303067, rs2303063, rs2303064, rs17860502 (Asp106Asn), rs2303070 (Glu825Asp) rs2303067 rs2303067 rs2303067 rs2303067 rs2303067 rs2303067, rs2303063, rs3756688 (A-785G) rs2303067, rs2303063, rs3756688 rs2303067 rs2303063, rs2303064 (Asp386Asn) rs2303063, rs2303064 rs2303063, rs2303065 (His396His) rs2303067, rs2303064, rs2303063, rs2303070 (G2475T) rs2303067, rs2303063, rs2303064, rs17860502

Asthma Childhood eczema Childhood eczema Eczema

Chinese British British Japanese

669:711 148 families 73 families 124:110

Yes Yes Yes Yes

28 29 29 30

Eczema+asthma

Japanese

41 families

Yes

31

Eczema Eczema Childhood eczema Childhood eczema Childhood eczema Eczema+asthma

German German Irish/UK UK German Dutch

486 trios 773:3992 418:552 1583/7746 220/1161 78:200

Yes No No No No No

32 32 32 32 33 34

Eczema+asthma Eczema Childhood eczema

Dutch French British

175 trios 99:102 148 families

No No No

34 35 29

Childhood eczema Eczema Asthma

British Japanese Chinese

73 families 124:110 669:711

No No No

29 30 28

Eczema

German

308 trios

No

36

* Cases:controls, cases/population; ¥, association.

more distal mutations allow limited expression of profilaggrin but no production of functional filaggrin subunits, implying a critical role of the C-terminus for FLG processing; there is also some early evidence of a trend towards reduced penetrance of more distal mutations [39]. The combined allele frequency of the initial mutations translates into a carrier frequency of almost 10% in individuals of European ancestry [39]. This unexpected finding combined with the known clinical association of IV with eczema, and decreased expression of FLG in eczema pointed to a possible association in the pathogenesis of eczema. This association has now been unambiguously established in a series of replication studies, making this one of the most robust gene associations so far identified in complex trait genetics [39–44], reviewed in Irvine [45] and Baurecht et al. [46]. Overall, between 18% and 48% of all eczema collections carry FLG null alleles [45]. The relatively high allele frequency of several haplotypically independent null alleles in the population is intriguing and suggests that these have not arisen by genetic drift

alone but may be as a result of balanced selection due to an as yet unclear evolutionary heterozygote advantage [47]. The FLG mutation findings were corroborated in two recent large population-based studies on more than 6700 English children [48] and 3000 German children, in whom the two common FLG mutations R501X and 2282del4 and three rare variants were analysed [49]. In the German study, FLG variants increased the risk for eczema threefold (OR 3.12, 95% CI 2.33–4.17, p 2.5 × 10−14) with a population attributable risk of 13.5%. Importantly, these mutations are highly associated with allergen sensitization and the subsequent development of asthma associated with eczema, an association that has been consistently reported [45]. At a population level, FLG mutations appear to confer an overall risk of asthma of approximately 1.8, but only in the context of prior eczema [50]. As FLG is not expressed in bronchial mucosa, transcutaneous sensitization is one suggested mechanistic possibility by which filaggrin could confer asthma risk [40,51].

Genetics of Atopic Dermatitis

Environment allergens, bacteria, viruses, etc.

European mutations Asian mutations

S100-like domain

Partial filaggrin repeats

Detected both in European and Asian populations

B domain

Filaggrin repeats 1–10

2282del4 R501X 441delA

(Pro)Filaggrin

1249insG

3321delA

E2422X R2447X

3222del4 3702delG Q1701X Q1790X

Q2471X

C-terminal domain

S3269X

S2554X

6950del8

4271delAA

R826X

23.11

S3247X

K4671X

S2889X

K4021X

N

C 3673delC

R1474X

R1140X

S1695X

6834delS

Genetic factors physicobiochemical barrier

E1795X 5360delG

TLR1/6TLR2

7945delA

5757del4

Q1256X

S2706X

11029delCA R4307X

7267delCA

Q3683X

11033del4

6867delAG

CD14 TLR4 TLR5

LC

Plasma membrane

Cytosol

TSLP

Skin

Ag IgE

Mast cell/ Basophil

CARD NOD

LRR

NOD1

CARD CARD NOD

LRR

NOD2

TLR3 TLR7 TLR9 Endosome

FcεRI IL4

Genetic factors immunological barrier

APC

IL12, IL18

Lymphoid tissue

Th1

IL2 IL10 IL23 ITGFβ

IL-4Ra

IL4

T naive

Jak1

IL4

IL2 IL10 ITGFβ

IL4 IL13

Th2

Bcell

IgE

Stat-6

IL13 gc

IL-4Ra

Jak3

Jak1

B cell

IL-13Ra1 Tyk2 Stat-6

IL4 IL13

Th17

Treg

IgE Blood Basophil

Figure 23.3 Simplified model integrating the genetics and pathophysiology of eczema. A deficient epidermal barrier, e.g. through filaggrin deficiency, facilitates the entry of allergens and antigens, which can gain access to immunocompetent cells. Depending on the host’s immunological properties, an allergic immune response is initiated.

Filaggrin and atopic dermatitis pathogenesis: mechanisms and speculations While the very strong genetic association of FLG mutations with eczema is now clear, the mechanistic pathways from inherited filaggrin haploinsufficiency to the typical inflammatory lesions of eczema require further elucidation. Filaggrin deficiency leads to reduced NMF [52], which is probably a contributor to the xerotic phenotype seen in many patients with eczema. The initiation of the typical inflammatory response is of great interest and with this in mind, it should be remembered that around 40% of all carriers of FLG null alleles never develop any signs of eczema [48]. The environmental and genetic modifiers of this risk are currently unclear, although recent evidence also indicates that filaggrin skin expression could be modulated by the atopic inflammatory response mediated by cytokines IL-4 and IL-13 [53], thus providing a link between this structural molecule and the inflammatory response in eczema (Fig. 23.3). Other currently speculative mechanisms include the possibility that FLG haploinsufficiency may critically modify pH-related altered commensal bacteria expression, thus manipulating host immunity. Altered host

immunity to bacterial infections is a notable feature of atopic dermatitis [54]. Growth of Staph. aureus is facilitated by increased pH, which colonizes the skin of over 90% of eczema patients. Exposure of a naive immune system to Staph. aureus superantigens may trigger and establish a permanent Th2 immune response, through activation and amplification of innate immune responses. The neutralizing acid SC pH has also been shown to independently facilitate excessive protease activity and reduce the activity of key lipid-processing enzymes, resulting in the formation of defective lamellar membranes, and a disrupted permeability barrier.

SPINK5 SPINK5 is the gene defective in Netherton syndrome and encodes the serine proteinase inhibitor LEKTI, which has been implicated in the regulation of SSCE activity. An association of a SPINK5 SNP (Lys420Ser) with eczema has previously been reported [55] but was not confirmed in a recent study [56]. In a large-scale study on several cohorts, the SPINK5 420LysSer mutation conferred a risk of eczema only when maternally inherited, but did not appear to be a major eczema risk factor [57].

23.12

Chapter 23

Genes implicated in immunoregulation Genes encoding cytokines and cytokine receptors One of the regions most consistently linked to asthma and atopy-related phenotypes is 5q23–31 [58,59]. The interval on human 5q31 is particularly intriguing because it harbours a cluster of cytokine and immune-related genes, including interleukin (IL) genes IL3, IL4, IL5 and IL13, interferon regulatory factor-1 (IRF-1), the glucocorticoid receptor, leukotriene C4 synthase (LTC4 syntase), CD-14, colony-stimulating factor-2 (CSF2) and T-cell transcription factor-7 (TCF7). Most of these molecules influence the T-cell development/polarization towards Th1 or Th2 and modulate features like recruitment of eosinophils, mast cells, neutrophils, etc. to the site of inflammation, and are thus excellent biological candidate genes. However, association studies have shown conflicting and inconsistent results. Assuming that at least some of the reported genetic effects are real, it appears that they might be more relevant for the atopic state sensu latu than for any individual distinct atopic disease. In addition, due to the extended marker–marker correlation in this genomic region and the potential for gene–gene interactions through overlapping functional pathways, it is difficult to reliably differentiate the specific sources of signals and to identify causal variants. The gene most consistently associated with allergic phenotypes is IL13. Notably, two functional IL13 polymorphisms, IL13–1112CT (rs1800925) in the promoter region and IL13+2044GA (IL13 Arg130Gln, rs20541) in exon 4, have been shown to be associated with a range of atopy-related disorders, including asthma, bronchial hyper-responsiveness, total IgE levels and ‘atopy’ (reviewed in Vercelli [59]). IL13 has been reported to be overexpressed in both subacute and lichenified eczema lesions [60] and association of the Arg130Gln variation with eczema was reported in Canadian [61], Japanese [62] and German cohorts [63]. The promoter polymorphism was associated with eczema in a Dutch cohort [64], a finding that could not be replicated in the aforementioned Japanese cohort [62]. IL13 and IL4 share overlapping biological functions, and both signal via a complex network of receptors [65]. A functional SNP in the promoter of IL4 (C-589T) has been associated with total serum IgE level, asthma, and asthma-related phenotypes (reviewed in Scirica & Celedon [66] and Hoffjan et al. [67]). Concerning eczema, in a Japanese study on 377 individuals from 88 nuclear families, markers flanking the IL4 gene showed evidence for linkage, and significant transmission distortion was observed for the C-589T variant [68]. However, this association could not be confirmed in a larger Japanese study [69]. In another study investigating 406 affected sibling families from Sweden, neither linkage nor association of AE to the IL4 promoter region was observed, but there

was association of C-589T with AE severity [70]. Likewise, in an Australian cohort of 76 small nuclear families and 25 triads and in a Chinese study, neither the C-589T variant nor a newly identified IL4 promoter polymorphism was associated with eczema [71,72]. The pleiotropic effects of IL-4 and IL-13 are mediated through the IL4R, which is composed of an IL4Rα subunit and an IL4Rγ subunit. IL4RA is located at 16p12–11 and several IL4RA polymorphisms have been explored for associations with total serum IgE levels, with conflicting results (reviewed in Franjkovic et al. [73]). Association of coding variants was reported for severe eczema in a small American cohort [74] and with adult eczema in a Japanese population [75] but were not confirmed in a larger Japanese sample [69]. Several promoter polymorphisms were associated with eczema in a small Japanese case– control cohort [76] but this finding so far lacks independent replication. In a small Chinese case–control study investigating several coding polymorphisms, no associations with eczema were found [72].

RANTES Chemotactic cytokines or C-C chemokines are small signalling proteins that mainly regulate trafficking of leucocytes through interaction with a subset of transmembrane G-protein coupled receptors [77]. RANTES (regulated on activation of normal T-cell expressed and secreted) is mainly produced in dermal fibroblasts, is a potent eosinophil, monocyte, basophil and lymphocyte chemoattractant at the site of inflammation, and has been reported to be overexpressed in lesional eczema skin [78]. The RANTES gene is located within the C-C chemokine cluster on 17q11–12, but is some distance from the region of linkage to eczema and psoriasis described above. Association of a functional mutation in the proximal promoter of the RANTES gene with eczema has been reported in 188 children with eczema and 98 controls from the German multicentre study (MAS-90) [79] and two Japanese cohorts [80,81] but could not be replicated in a Hungarian [82].

Mast cell chymase Mast cells represent key effector cells of IgE-dependent immediate reactions, and also contribute significantly to certain features of IgE-associated late-phase reactions and chronic allergic inflammation (reviewed in Williams & Galli [83]). Mast cell chymase is a proinflammatory serine protease that is present in large quantities in the secretory granules. A variety of features have rendered the gene encoding chymase, CMA1, a premier candidate gene for atopy and eczema. Together with tryptase and histamine, it appears to exert a plethora of actions consistent with key roles in inflammation, tissue remodelling and bronchial hyper-responsiveness (reviewed in Caughey [84]).

Genetics of Atopic Dermatitis

Enhanced expression has been observed in lesional as well as non-lesional eczema skin [85,86]. Finally, CMA1 maps to chromosome 14q11, which has been linked with specific allergic reactions, asthma, total IgE and AE [87–90]. Several studies have reported a significant association between a variant (rs1800875) within the CMA1 promoter and eczema. Initially, an association was observed in a cohort of Japanese adults [91]. In two subsequent studies on individuals with the same ethnic background, this observation was confirmed, with the strongest effect on eczema with low total serum IgE levels (‘non-atopic’ eczema) [92,93], indicating that the effect might be independent of IgE. In a larger German association study, a significant association of this polymorphism with eczema was replicated, but no effects on serum IgE levels or other atopic phenotypes were obeserved [94]. In contrast, in a UK Caucasian family cohort for asthma, associations with total IgE levels were found [95]. Although these data appear convincing, it has to be noted that two smaller studies on Japanese [96] and Italian [97] individuals failed to replicate the associations, possibly due to low statistical power and limited comparability of Asian and Caucasian populations. On the balance of data to date, CMA1 remains an interesting player in eczema susceptibility but further replication would be helpful in clarifying the precise role for this candidate gene.

Innate immunity receptors Innate immunity represents the first line of host defence, recognizing a few highly conserved structures present in many different micro-organisms. These pathogen-associated molecular patterns (PAMPs) are recognized through a set of germline-encoded pattern recognition receptors (PRRs). PRRs located in the cell membrane, such as tolllike-receptors (TLRs) or CD14, respond to extracellular PAMPs. Cytosolic PPRs like NOD1 (nucleotide-binding oligomerization domain protein 1, also designated CARD4) and NOD2 (also designated CARD15) recognize PAMPs that cross the plasma membrane (reviewed in Athman & Philpott [98]). Genetic variations in innate immunity genes have been reported to be associated with a range of inflammatory disorders, including both Th2driven atopic and Th1-dominated autoimmune diseases (reviewed in Lazarus et al. [99]). Polymorphisms in the NOD2 gene have been identified at the IBD1 locus. These DNA variants have been found to be associated with Crohn disease and are considered causative for the aetiology of the disease in a subgroup of patients [100–102]. Evaluation of three functionally relevant NOD2 polymorphisms related to Crohn disease (3020insC, C2104T, G2722C) in two cross-sectional populations from Germany (total n = 1872) indicated a role for these NOD2 variants also for atopy, with a significant

23.13

effect of G2772C on eczema risk [103]. In a more recent study on 392 eczema patients and 297 controls, the NOD2 variant R702W showed association with eczema, but significance was lost after Bonferroni correction for multiple testing [104]. In a population-based study on German adults, an association of G2772C with total IgE levels as well as associations of non-coding polymorphisms and a NOD2 haplotype with asthma, but no specific effects on eczema risk, were observed [105]. NOD1 shares many structural and functional similarities with NOD2, and is located on chromosome 7p14-p15, a region which was reported to contain an atopy susceptibility locus [106]. NOD1 polymorphisms showed effects on increased IgE levels and asthma in British and Australian cohorts [107], with a complex indel polymorphism displaying the strongest associations. This variant was associated with irritable bowel disease in a subsequent study performed by the same group [108]. In a large German study involving three independent samples, associations of several NOD1 variants with increased IgE levels and/or eczema were observed [109] and in another smaller study from Germany, a rare haplotype was associated with eczema [104]. However, despite these promising results for NOD1 and NOD2, further clarification is needed. Other innate immune receptor genes that have been investigated for association with atopic traits are TLR2, TLR4 and TLR9. TLR2 recognizes peptidoglycan, a predominant component of the cell wall of Staph. aureus[98], a pathogen with important implications for AE. TLR4 is the principal receptor for bacterial endotoxin, exposure to which has been suggested to protect from the development of asthma and atopy. TLR9 ligands are immunostimulatory sequence oligonucleotides (ISS-ODN) containing unmethylated CpG dinucleotides (also known as CpG-ODN) (reviewed in Upham & Holt [110]). Associations between the TLR2 polymorphism rs4696480 [111] and the TLR4 polymorphism rs4986790 [112] with asthma, and the TLR4 variant rs4986791 with a modified response to endotoxin [113], have been reported. In a study on 78 AE patients and 39 controls [114] and in a subsequent extension of the case series to 175 patients (no controls), an over-representation of the heterozygous genotype of the TLR2 variant R753Q (rs5743708) in eczema cases (frequency 11%) was reported. However, this finding appears to be a false positive due to a number of methodological issues. Supportive of this assumption is the lack of association of rs5743708 and TLR2 tagSNPs in a large-scale study on 275 eczema families [115] and in a more recent small German eczema case–control study [116]. The latter study reported an over-representation of the above-mentioned TLR2 promoter variant rs4696480 in severe eczema cases, although there was no association independent of disease severity [116].

23.14

Chapter 23

In another large-scale study on two independent panels of eczema families as well as a case–control sample analysing four common TLR9 SNPs, a significant overtransmission of the common T-allele of a functional TLR9 promoter polymorphism (rs5743836) was observed in both family panels, but in neither the case–control cohort nor a more recent smaller German eczema case–control study [116]. As one possible explanation for this lack of replication, the higher age of cases in the case–control samples might be assumed. Interestingly, in a study involving 210 asthmatic children, 224 controls and 80 asthma families from Tunisia, the −1237C allele in TLR9 gene polymorphisms was associated with increased risk of asthma [117], supporting a potential role for TLR9 variation in atopy. Overall, the case for a strong role for genetic susceptibility to AE conferred by polymorphisms in the innate immune system, while an intriguing possibility, remains to be proven. References 1 Barnes KC. An update on the genetics of atopic dermatitis: Scratching the surface in 2009. J Allergy Clin Immunol 2010;125:16–29. 2 Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Common lossof-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38: 441–6. 3 Rodriguez E, Baurecht H, Herberich E et al. Meta analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol 2009;123(6):1361–70. 4 O’Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol 2009;124:R2–6. 5 Mao XQ, Shirakawa T, Yoshikawa T et al. Association between genetic variants of mast-cell chymase and eczema. Lancet 1996; 348(9027):581–3. 6 Mao XQ, Shirakawa T, Enomoto T et al. Association between variants of mast cell chymase gene and serum IgE levels in eczema. Hum Hered 1998;48:38–41. 7 Tanaka K, Sugiura H, Uehara M, Sato H, Hashimoto-Tamaoki T, Furuyama J. Association between mast cell chymase genotype and atopic eczema: comparison between patients with atopic eczema alone and those with atopic eczema and atopic respiratory disease. Clin Exper Allergy 1999;29(6):800–3. 8 Weidinger S, Rummler L, Klopp N et al. Association study of mast cell chymase polymorphisms with atopy. Allergy 2005;60:1256–61. 9 Kawashima T, Noguchi E, Arinami T, Kobayashi K, Otsuka F, Hamaguchi H. No evidence for an association between a variant of the mast cell chymase gene and atopic dermatitis based on casecontrol and haplotype-relative-risk analyses. Hum Hered 1998; 48:271–4. 10 Hosomi N, Fukai K, Oiso N et al. Polymorphisms in the promoter of the interleukin-4 receptor alpha chain gene are associated with atopic dermatitis in Japan. J Invest Dermatol 2004;122:843–5. 11 Oiso N, Fukai K, Ishii M. Interleukin 4 receptor alpha chain polymorphism Gln551Arg is associated with adult atopic dermatitis in Japan. Br J Dermatol 2000;142(5):1003–6. 12 Callard RE, Hamvas R, Chatterton C et al. An interaction between the IL-4Ralpha gene and infection is associated with atopic eczema in young children. Clin Exp Allergy 2002;32:990–3. 13 Tanaka K, Sugiura H, Uehara M, Hashimoto Y, Donnelly C, Montgomery DS. Lack of association between atopic eczema and the genetic variants of interleukin-4 and the interleukin-4 receptor alpha

14

15

16

17

18

19

20

21

22 23

24

25

26

27

28

29

30

31

32

chain gene: heterogeneity of genetic backgrounds on immunoglobulin E production in atopic eczema patients. Clin Exp Allergy 2001; 31:1522–7. Chang YT, Lee WR, Yu CW et al. No association of cytokine gene polymorphisms in Chinese patients with atopic dermatitis. Clin Exp Dermatol 2006;31:419–23. He JQ, Chan-Yeung M, Becker AB et al. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immunol 2003;4:385–9. Hummelshoj T, Bodtger U, Datta P et al. Association between an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet 2003;30:355–9. Tsunemi Y, Saeki H, Nakamura K et al. Interleukin-13 gene polymorphism G4257A is associated with atopic dermatitis in Japanese patients. J Dermatol Sci 2002;30(2):100–7. Liu X, Nickel R, Beyer K et al. An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). J Allergy Clin Immunol 2000;106(1 Pt 1):167–70. Arshad SH, Karmaus W, Kurukulaaratchy R, Sadeghnejad A, Huebner M, Ewart S. Polymorphisms in the interleukin 13 and GATA binding protein 3 genes and the development of eczema during childhood. Br J Dermatol 2008;158:1315–22. Weidinger S, Klopp N, Rummler L et al. Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 2005;116:177–84. Macaluso F, Nothnagel M, Parwez Q et al. Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp Dermatol 2007; 16:692–8. Novak N, Yu C, Bussmann C et al. Association of a TLR9 promoter polymorphism with atopic eczema. Allergy 2007;62(7):766–72. Oh DY, Schumann RR, Hamann L, Neumann K, Worm M, Heine G. Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 2009;64(11):1608–15. Nickel R, Casolaro V, Wahn U et al. Atopic dermatitis is associated with a functional mutation in the promoter of the CC chemokine RANTES. J Immunol 2000;164:1612–16. Bai B, Tanaka K, Tazawa T, Yamamoto N, Sugiura H. Association between RANTES promoter polymorphism -401A and enhanced RANTES production in atopic dermatitis patients. J Dermatol Sci 2005;39:189–91. Tanaka K, Roberts MH, Yamamoto N, Sugiura H, Uehara M, Hopkin JM. Upregulating promoter polymorphisms of RANTES relate to atopic dermatitis. Int J Immunogenet 2006;33:423–8. Kozma GT, Falus A, Bojszko A et al. Lack of association between atopic eczema/dermatitis syndrome and polymorphisms in the promoter region of RANTES and regulatory region of MCP-1. Allergy 2002;57:160–3. Liu Q, Xia Y, Zhang W et al. A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population. BMC Med Genet 2009;10:59. Walley AJ, Chavanas S, Moffatt MF et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29(2): 175–8. Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 2003;48(4):665–9. Nishio Y, Noguchi E, Shibasaki M et al. Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Genes Immunol 2003;4:515–17. Weidinger S, Baurecht H, Wagenpfeil S et al. Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J Allergy Clin Immunol 2008;122:560–8.

Genetics of Atopic Dermatitis 33 Kabesch M, Carr D, Weiland SK, von Mutius E. Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample. Clin Exp Allergy 2004;34:340–5. 34 Jongepier H, Koppelman GH, Nolte IM et al. Polymorphisms in SPINK5 are not associated with asthma in a Dutch population. J Allergy Clin Immunol 2005;115:486–92. 35 Hubiche T, Ged C, Benard A et al. Analysis of SPINK 5, KLK 7 and FLG genotypes in a French atopic dermatitis cohort. Acta Derm Venereol 2007;87:499–505. 36 Folster-Holst R, Stoll M, Koch WA, Hampe J, Christophers E, Schreiber S. Lack of association of SPINK5 polymorphisms with nonsyndromic atopic dermatitis in the population of Northern Germany. Br J Dermatol 2005;152:1365–7. 37 Rawlings AV, Harding CR. Moisturization and skin barrier function. Dermatol Ther 2004;17 Suppl 1:43–8. 38 Smith FJ, Irvine AD, Terron-Kwiatkowski A et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 2006;38:337–42. 39 Sandilands A, Terron-Kwiatkowski A, Hull PR et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007; 39:650–4. 40 Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Common lossof-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38: 441–6. 41 Weidinger S, Illig T, Baurecht H et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006;118: 214–19. 42 Marenholz I, Nickel R, Ruschendorf F et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 2006;118:866–71. 43 Ruether A, Stoll M, Schwarz T, Schreiber S, Folster-Holst R. Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany. Br J Dermatol 2006;155: 1093–4. 44 Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol 2007; 127(3):722–4. 45 Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol 2007;127:504–7. 46 Baurecht H, Irvine AD, Novak N et al. Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J Allergy Clin Immunol 2007;120(6):1406–12. 47 Irvine AD, McLean WH. Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis. J Invest Dermatol 2006;126: 1200–2. 48 Henderson J, Northstone K, Lee SP et al. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol 2008;121:872–7. 49 Weidinger S, O’Sullivan M, Illig T et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 2008;121:1203–9. 50 McLean WH, Palmer CN, Henderson J, Kabesch M, Weidinger S, Irvine AD. Filaggrin variants confer susceptibility to asthma. J Allergy Clin Immunol 2008;121:1294–5; author reply 5–6. 51 Hudson TJ. Skin barrier function and allergic risk. Nat Genet 2006; 38:399–400. 52 Kezic S, Kemperman PM, Koster ES et al. Loss-of-function mutations in the filaggrin gene lead to reduced level of natural moisturizing factor in the stratum corneum. J Invest Dermatol 2008;128(8): 2117–19.

23.15

53 Howell MD, Kim BE, Gao P et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007; 120:150–5. 54 Schauber J, Gallo RL. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 2008;124(3 Suppl 2): R13–18. 55 Walley AJ, Chavanas S, Moffatt MF et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29: 175–8. 56 Folster-Holst R, Stoll M, Koch WA, Hampe J, Christophers E, Schreiber S. Lack of association of SPINK5 polymorphisms with nonsyndromic atopic dermatitis in the population of Northern Germany. Br J Dermatol 2005;152:1365–7. 57 Weidinger S, Baurecht H, Wagenpfeil S et al. Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J Allergy Clin Immunol 2008;122:560–8. 58 Denham S, Koppelman GH, Blakey J et al. Meta-analysis of genomewide linkage studies of asthma and related traits. Respir Res 2008; 9:38. 59 Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 2008;8:169–82. 60 Tazawa T, Sugiura H, Sugiura Y, Uehara M. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch Dermatol Res 2004;295:459–64. 61 He JQ, Chan-Yeung M, Becker AB et al. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immunol 2003;4:385–9. 62 Tsunemi Y, Saeki H, Nakamura K et al. Interleukin-13 gene polymorphism G4257A is associated with atopic dermatitis in Japanese patients. J Dermatol Sci 2002;30:100–7. 63 Liu X, Nickel R, Beyer K et al. An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). J Allergy Clin Immunol 2000;106:167–70. 64 Hummelshoj T, Bodtger U, Datta P et al. Association between an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet 2003;30:355–9. 65 Munitz A, Brandt EB, Mingler M, Finkelman FD, Rothenberg ME. Distinct roles for IL-13 and IL-4 via IL-13 receptor alpha1 and the type II IL-4 receptor in asthma pathogenesis. Proc Natl Acad Sci USA 2008;105:7240–5. 66 Scirica CV, Celedon JC. Genetics of asthma: potential implications for reducing asthma disparities. Chest 2007;132:770S–81S. 67 Hoffjan S, Nicolae D, Ober C. Association studies for asthma and atopic diseases: a comprehensive review of the literature. Respir Res 2003;4:14. 68 Kawashima T, Noguchi E, Arinami T et al. Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. J Med Genet 1998;35:502–4. 69 Tanaka K, Sugiura H, Uehara M, Hashimoto Y, Donnelly C, Montgomery DS. Lack of association between atopic eczema and the genetic variants of interleukin-4 and the interleukin-4 receptor alpha chain gene: heterogeneity of genetic backgrounds on immunoglobulin E production in atopic eczema patients. Clin Exp Allergy 2001; 31:1522–7. 70 Soderhall C, Bradley M, Kockum I, Luthman H, Wahlgren CF, Nordenskjold M. Analysis of association and linkage for the interleukin-4 and interleukin-4 receptor b;alpha; regions in Swedish atopic dermatitis families. Clin Exp Allergy 2002;32:1199–202. 71 Elliott K, Fitzpatrick E, Hill D et al. The −590C/T and −34C/T interleukin-4 promoter polymorphisms are not associated with atopic eczema in childhood. J Allergy Clin Immunol 2001;108: 285–7.

23.16

Chapter 23

72 Chang YT, Lee WR, Yu CW et al. No association of cytokine gene polymorphisms in Chinese patients with atopic dermatitis. Clin Exp Dermatol 2006;31:419–23. 73 Franjkovic I, Gessner A, Konig I et al. Effects of common atopyassociated amino acid substitutions in the IL-4 receptor alpha chain on IL-4 induced phenotypes. Immunogenetics 2005;56:808–17. 74 Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 1997;337: 1720–5. 75 Oiso N, Fukai K, Ishii M. Interleukin 4 receptor alpha chain polymorphism Gln551Arg is associated with adult atopic dermatitis in Japan. Br J Dermatol 2000;142:1003–6. 76 Hosomi N, Fukai K, Oiso N et al. Polymorphisms in the promoter of the interleukin-4 receptor alpha chain gene are associated with atopic dermatitis in Japan. J Invest Dermatol 2004;122:843–5. 77 Pease JE, Williams TJ. Chemokines and their receptors in allergic disease. J Allergy Clin Immunol 2006;118:305–18; quiz 19–20. 78 Kato Y, Pawankar R, Kimura Y, Kawana S. Increased expression of RANTES, CCR3 and CCR5 in the lesional skin of patients with atopic eczema. Int Arch Allergy Immunol 2006;139:245–57. 79 Nickel RG, Casolaro V, Wahn U et al. Atopic dermatitis is associated with a functional mutation in the promoter of the C–C chemokine RANTES. J Immunol 2000;164:1612–16. 80 Bai B, Tanaka K, Tazawa T, Yamamoto N, Sugiura H. Association between RANTES promoter polymorphism −401A and enhanced RANTES production in atopic dermatitis patients. J Dermatol Sci 2005;39:189–91. 81 Tanaka K, Roberts MH, Yamamoto N, Sugiura H, Uehara M, Hopkin JM. Upregulating promoter polymorphisms of RANTES relate to atopic dermatitis. Int J Immunogenet 2006;33:423–8. 82 Kozma GT, Falus A, Bojszko A et al. Lack of association between atopic eczema/dermatitis syndrome and polymorphisms in the promoter region of RANTES and regulatory region of MCP-1. Allergy 2002;57:160–3. 83 Williams CM, Galli SJ. The diverse potential effector and immunoregulatory roles of mast cells in allergic disease. J Allergy Clin Immunol 2000;105:847–59. 84 Caughey GH. Mast cell tryptases and chymases in inflammation and host defense. Immunol Rev 2007;217:141–54. 85 Badertscher K, Bronnimann M, Karlen S, Braathen LR, Yawalkar N. Mast cell chymase is increased in chronic atopic dermatitis but not in psoriasis. Arch Dermatol Res 2005;296:503–6. 86 Jarvikallio A, Naukkarinen A, Harvima IT, Aalto ML, Horsmanheimo M. Quantitative analysis of tryptase- and chymase-containing mast cells in atopic dermatitis and nummular eczema. Br J Dermatol 1997;136:871–7. 87 Soderhall C, Bradley M, Kockum I, Wahlgren CF, Luthman H, Nordenskjold M. Linkage and association to candidate regions in Swedish atopic dermatitis families. Hum Genet 2001;109:129–35. 88 Moffatt MF, Hill MR, Cornelis F et al. Genetic linkage of T-cell receptor alpha/delta complex to specific IgE responses. Lancet 1994;343: 1597–600. 89 No authors listed. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The Collaborative Study on the Genetics of Asthma (CSGA). Nat Genet 1997;15:389–92. 90 Deichmann KA, Heinzmann A, Forster J et al. Linkage and allelic association of atopy and markers flanking the IL4-receptor gene. Clin Exp Allergy 1998;28:151–5. 91 Mao XQ, Shirakawa T, Yoshikawa T et al. Association between genetic variants of mast-cell chymase and eczema. Lancet 1996;348: 581–3. 92 Mao XQ, Shirakawa T, Enomoto T et al. Association between variants of mast cell chymase gene and serum IgE levels in eczema. Hum Hered 1998;48:38–41.

93 Tanaka K, Sugiura H, Uehara M, Sato H, Hashimoto-Tamaoki T, Furuyama J. Association between mast cell chymase genotype and atopic eczema: comparison between patients with atopic eczema alone and those with atopic eczema and atopic respiratory disease. Clin Exp Allergy 1999;29:800–3. 94 Weidinger S, Rummler L, Klopp N et al. Association study of mast cell chymase polymorphisms with atopy. Allergy 2005;60: 1256–61. 95 Iwanaga T, McEuen A, Walls AF et al. Polymorphism of the mast cell chymase gene (CMA1) promoter region: lack of association with asthma but association with serum total immunoglobulin E levels in adult atopic dermatitis. Clin Exp Allergy 2004;34:1037–42. 96 Kawashima T, Noguchi E, Arinami T, Kobayashi K, Otsuka F, Hamaguchi H. No evidence for an association between a variant of the mast cell chymase gene and atopic dermatitis based on case– control and haplotype-relative-risk analyses. Hum Hered 1998;48: 271–4. 97 Pascale E, Tarani L, Meglio P et al. Absence of association between a variant of the mast cell chymase gene and atopic dermatitis in an Italian population. Hum Hered 2001;51:177–9. 98 Athman R, Philpott D. Innate immunity via Toll-like receptors and Nod proteins. Curr Opin Microbiol 2004;7:25–32. 99 Lazarus R, Vercelli D, Palmer L et al. Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease. Immunol Rev 2002;190:9–25. 100 Hugot JP, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599–603. 101 Hampe J, Frenzel H, Mirza MM et al. Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p. Proc Natl Acad Sci USA 2002;99:321–6. 102 Ogura Y, Bonen DK, Inohara N et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001;411: 603–6. 103 Kabesch M, Peters W, Carr D, Leupold W, Weiland SK, von Mutius E. Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 2003;111:813–17. 104 Macaluso F, Nothnagel M, Parwez Q et al. Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp Dermatol 2007; 16:692–8. 105 Weidinger S, Klopp N, Rummler L et al. Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults. Clin Exp Allergy 2005;35:866–72. 106 Laitinen T, Daly MJ, Rioux JD et al. A susceptibility locus for asthmarelated traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat Genet 2001;28:87–91. 107 Hysi P, Kabesch M, Moffatt MF et al. NOD1 variation, immunoglobulin E and asthma. Hum Mol Genet 2005;14:935–41. 108 McGovern DP, Hysi P, Ahmad T et al. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet 2005;14: 1245–50. 109 Weidinger S, Klopp N, Rummler L et al. Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 2005;116:177–84. 110 Upham JW, Holt PG. Environment and development of atopy. Curr Opin Allergy Clin Immunol 2005;5:167–72. 111 Eder W, Klimecki W, Yu L et al. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 2004;113:482–8. 112 Fageras Bottcher M, Hmani-Aifa M, Lindstrom A et al. A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol 2004;114:561–7.

Genetics of Atopic Dermatitis 113 Werner M, Topp R, Wimmer K et al. TLR4 gene variants modify endotoxin effects on asthma. J Allergy Clin Immunol 2003;112: 323–30. 114 Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K et al. The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J Allergy Clin Immunol 2004;113:565–7. 115 Weidinger S, Novak N, Klopp N et al. Lack of association between Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and atopic eczema. J Allergy Clin Immunol 2006;118:277–9. 116 Oh DY, Schumann RR, Hamann L, Neumann K, Worm M, Heine G. Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 2009;64(11): 1608–15. 117 Lachheb J, Dhifallah IB, Chelbi H, Hamzaoui K, Hamzaoui A. Tolllike receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children. Tissue Antigens 2008;71:417–25.

Conclusions and future directions Despite much effort and progress over the past two decades, our understanding of the complex genetic susceptibility to eczema remains in the early stages, compared to other complex diseases. Initial reports of intriguing and biologically plausible linkages to candidate genes have more often than not failed to replicate. Based on reported data, so far only FLG appears to clearly convey a strong and consistent eczema risk across all collections in all populations and in multiple large independent studies.

23.17

Therefore there is a need for large-scale and detailed whole-genome studies both to clarify the roles of previously suggested candidate genes and, more hopefully, to identify additional novel susceptibility loci. For many complex diseases, the application of GWAS to large samples has met with considerable gains, and the early results suggest this will also be true for eczema. The application of genome-wide approaches, in particular with the use of technologies with higher resolution or that are better designed to assay other sources of variation such as common copy number variations, seems promising. The success of future genetic studies will, however, depend upon the assembly of large and well-phenotyped patient samples and the ability to handle and analyse increasingly large and complex data sets. However, given the clinical heterogeneity of eczema, it will remain important to study smaller samples that might be more homogeneous. In addition, it will be necessary to revisit traditional phenotype definitions based on familial components, heritable endophenotypes and genetic markers. Holistic approaches integrating phenotypic variables and information from genomic, transcriptional, proteomic, metabolomic and other sources will greatly enhance our understanding of the complex disease eczema and its relationships with asthma and atopy. The final frontier will certainly be to translate genetic findings into an improved classification and the development of more targeted interventions. The future for eczema genetics looks very exciting and full of promise.

24.1

C H A P T E R 24

Immunology of Atopic Dermatitis Aideen M. Byrne1 & Donald Y.M. Leung2 1

University of Colorado Denver Medical School, Aurora, CO, USA Department of Pediatrics, National Jewish Health, Denver, CO, USA

2

Introduction, 24.1 The systemic immune response, 24.1

Immune response in atopic dermatitis skin, 24.3

Immunological triggers, 24.6 Clinical implications and conclusions, 24.8

Histopathological skin reaction patterns, 24.3

Introduction Atopic dermatitis (AD) is a complex skin disease that has its onset most commonly during early infancy and childhood [1,2]. The majority of patients have evidence of immunological abnormalities including elevated serum IgE, recurrent skin infections and systemic allergen sensitization that predisposes to allergic rhinitis, food allergy or asthma. There is no single mechanism that can account for all aspects of AD. This common skin condition probably represents a final clinical phenotype that results from many factors including gene–environment interactions, defective skin barrier function, neuropharmacological abnormalities and immune dysfunction. This chapter will focus on the role that immunological mechanisms play in this skin disease. The reader is referred to other chapters in this textbook for a review of additional factors that contribute to AD. Figure 24.1 summarizes in schematic format the key immunological mechanisms to be discussed below. References 1 Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94. 2 Leung DY, Bieber T. Atopic dermatitis. Lancet 2003;361:151–60.

The systemic immune response (see Box 24.1) Atopy may be considered a systemic illness with AD as the cutaneous manifestation [1] of this condition. The majority of children with AD undergo the so-called atopic march, developing asthma and allergic rhinitis later in Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

life. In murine models, epicutaneous sensitization has been shown to increase serum IgE levels and induce eosinophilia and airway hyper-reactivity characteristic of asthma [2]. That said, many children develop asthma in the absence of a history of AD, and children can outgrow AD without developing respiratory allergy. Therefore, different genes probably drive systemic atopy versus local barrier dysfunction [3–5]. Serum IgE levels are elevated in the majority of patients with AD [6,7]. Approximately 80% of patients have positive immediate skin tests or serum IgE antibody directed to a variety of foods, aeroallergens, microbial allergens and skin autoantigens. It has been proposed that AD patients should be segregated into two groups: those with elevated serum IgE (so-called extrinsic AD) and those with normal serum IgE (so-called intrinsic AD). The potential problem with this approach is that it ignores the primary defect in skin barrier that characterizes AD [4] and most physicians only focus on IgE directed to foods and aeroallergens. However, several studies have found the presence of IgE to microbial antigens and autoantigens in patients originally characterized as intrinsic AD [8,9]. The majority of patients with AD also have peripheral blood eosinophilia. Unlike eosinophils from normal donors, peripheral blood eosinophils from AD patients are primed for chemotaxis and transendothelial transmigration [10,11]. Furthermore, serum levels of eosinophil cationic protein and urinary eosinophil protein X are elevated in AD and levels of these markers of eosinophil activation correlate with the severity of skin disease [12]. These findings probably reflect a systemic T helper type 2 (Th2) immune response in AD. Importantly, the peripheral blood skin homing CLA+ T cells in AD spontaneously secrete interleukin (IL)-5 and IL-13, which functionally prolong eosinophil survival and induce IgE synthesis.

24.2

Chapter 24

Allergens Microbes P

P

P

Microbial pattern recognition receptors

P

Filaggrin

LC CCL27

SCTE SCCE

CCL27

P

MC

CCL26

CCL1 LC

CCL22

TSLP IL-10 Th2

Th0 IL-4

T

T

P

HBD LL37

CCL11

CCL18

P

P P

LC

CCL17

FcεRI signaling

P Proteases

IL-4 IL-5 IL-13 IL-31

MC

CCL17

CCL1

CCL11

CCL26 EOS

T

T

T

CCR4 CCR8 CCR10

CLA+Th2 cells

IgE

CCR3

EOS PMN

EOS Circulation

Uninvolved

Acute atopic dermatitis

Fig. 24.1 Immunology of atopic dermatitis. This figure depicts the two initial phases of AD. Non-lesional or uninvolved skin is not normal as it manifests cutaneous hyper-reactivity resulting from a genetically defective skin barrier that allows the penetration of allergens and microbial colonization, as well as a ‘primed’ cutaneous immune response poised to over-react to environmental stimuli. The acute phase that ensues is facilitated by IgE receptor-bearing Langerhans cells armed with IgE to allergens and facilitates allergen capture as well as the chronic infiltration of skin-homing Th2 memory T cells. In this second phase of AD progression, the acute skin lesion develops as the result of a complex immune and inflammatory response driven by the release of proinflammatory cytokines and chemokines from multiple resident cell types, including keratinocytes, Langerhans cells, monocytes-macrophages, and the cutaneous vascular system. Reproduced from Leung DYM. Issue cover. J Allergy Clin Immunol 2006; 118(1):A5, with permission from Elsevier.

Box 24.1 Systemic immune response in atopic dermatitis • • • • • •

Elevated total serum IgE in majority of patients Increased IgE response to specific allergens Eosinophilia Increased IL-4, IL-5 and IL-13 expression in skin-homing T cells Reduced interferon-γ expression in skin-homing T cells Decreased NK cell number and function

Ig, immunoglobulin; IL, interleukin, NK, natural killer.

Peripheral blood mononuclear cells (PBMC) from AD patients have a decreased capacity to produce interferons (IFN) [13]. IFN-γ generation ex vivo is inversely correlated with serum IgE levels in AD. The peripheral blood of AD also has an increased frequency of allergen-specific T cells producing increased IL-4, IL-5 and IL-13, but low levels of IFN-γ. These immunological alterations are important because IL-4 and IL-13 promote isotype switching to IgE,

downregulate T helper type 1 (Th1) cell function and induce the expression of vascular adhesion molecules involved in eosinophil infiltration. In contrast, IFN-γ inhibits IgE synthesis as well as the proliferation of Th2 cells. Peripheral blood monocytes from AD patients are activated and have an abnormally low incidence of spontaneous apoptosis. The likely cause of this low level of apoptosis is increased production of granulocyte macrophage-colony stimulating factor (GM-CSF) by circulating monocytes of AD patients [14]. Cytokine production in AD patient-derived monocytes has also been demonstrated to be impaired in response to bacterial and viral insult. The decreased inflammatory cytokine response by AD monocytes may be due to impairment of toll-like receptors (TLRs) [15,16]. References 1 Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113:651–7.

Immunology of Atopic Dermatitis 2 Spergel JM, Mizoguchi E, Brewer JP et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998;101:1614–22. 3 Cookson WO, Ubhi B, Lawrence R et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 2001;27:372–3. 4 Baurecht H, Irvine AD, Novak N et al. Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J Allergy Clin Immunol 2007;120:1406–12. 5 Rogers AJ, Celedon JC, Lasky-Su JA, Weiss ST, Raby BA. Filaggrin mutations confer susceptibility to atopic dermatitis but not to asthma. J Allergy Clin Immunol 2007;120:1332–7. 6 Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94. 7 Leung DY, Bieber T. Atopic dermatitis. Lancet 2003;361:151–60. 8 Novak N, Allam JP, Bieber T. Allergic hyperreactivity to microbial components: a trigger factor of “intrinsic” atopic dermatitis? J Allergy Clin Immunol 2003;112:215–16. 9 Altrichter S, Kriehuber E, Moser J et al. Serum IgE autoantibodies target keratinocytes in patients with atopic dermatitis. J Invest Dermatol 2008;128:2232–9. 10 Gleich GJ. Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol 2000;105:651–63. 11 Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy 2004;59:561–70. 12 Taniuchi S, Chihara J, Kojima T et al. Serum eosinophil derived neurotoxin may reflect more strongly disease severity in childhood atopic dermatitis than eosinophil cationic protein. J Dermatol Sci 2001;26:79–82. 13 Akdis M, Trautmann A, Klunker S et al. T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells. FASEB J 2003;17:1026–35. 14 Bratton DL, Hamid Q, Boguniewicz M et al. Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis. J Clin Invest 1995;95:211–18. 15 Hasannejad H, Takahashi R, Kimishima M, Hayakawa K, Shiohara T. Selective impairment of Toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. J Allergy Clin Immunol 2007;120:69–75. 16 Niebuhr M, Langnickel J, Draing C et al. Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy 2008;63:728–34.

Histopathological skin reaction patterns Several skin reaction patterns are seen in AD. Clinically unaffected skin of AD patients exhibits mild epidermal hyperplasia and a sparse perivascular T cell infiltrate [1]. Acute AD skin lesions are characterized by intensely pruritic, erythematous papules associated with excoriation, vesicles over erythematous skin and marked intercellular edema (spongiosis) of the epidermis. In the dermis of the acute lesion, there is a marked perivenular T cell infiltrate with occasional monocyte-macrophages. Chronic lichenified AD lesions are characterized by a hyperplastic epidermis with elongation of the rete ridges, prominent hyperkeratosis and minimal spongiosis. There are an increased number of dendritic cells in the epider-

24.3

mis and macrophages dominate the dermal mononuclear cell infiltrate. Mast cells are increased in number but are generally fully granulated. Increased numbers of eosinophils are observed. These eosinophils undergo cytolysis with release of granule protein contents into the upper dermis of lesional skin. In patients with established AD, all three stages of skin reactions frequently co-exist in the same individual. At all stages of AD, patients usually have dry, lacklustre skin. Pruritus is an important feature of AD and is thought to be induced by various products of inflammatory effector cells including histamine, neuropeptides, leukotrienes, proteolytic enzymes and the Th2 cytokine, IL-31 [2,3]. References 1 Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994;94:870–6. 2 Bilsborough J, Leung DY, Maurer M et al. IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol 2006;117:418–25. 3 Raap U, Wichmann K, Bruder M et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 2008;122:421–3.

Immune response in atopic dermatitis skin Role of cytokines The onset of atopic skin inflammation is orchestrated by the local expression of proinflammatory cytokines and chemokines [1]. Physical or chemical damage to the epithelial barrier triggers the release of preformed cytokines such as tumour necrosis factor-α (TNF-α), IL-1 and GM-CSF from resident cells (keratinocytes, mast cells, dendritic cells). Allergens can also directly trigger inflammatory cytokine production. Proteolytic activity of dust mites upregulates GM-CSF and IL-8 release from keratinocytes [2]. These cytokines in turn bind to receptors on the vascular endothelium, activating cellular signalling pathways which lead to the induction of vascular endothelial cell adhesion molecules. These events initiate the process of tethering, activation and adhesion to vascular endothelium followed by extravasation of inflammatory cells into the skin. Th2and Th1-type cytokine expression varies in AD with chronicity of the skin lesion (Box 24.2). As compared with the skin of normal controls, the unaffected skin of AD patients has an increased number of cells expressing IL-4 and IL-13 [3] but not IL-5, IL-12 or IFN-γ [4,5]. Acute and chronic skin lesions, when compared to normal skin or uninvolved skin of AD patients, have a significantly greater numbers of cells that are positive for IL-4, IL-5

24.4

Chapter 24

Box 24.2 Skin adaptive immune response in atopic dermatitis • TSLP expression in AD skin enhancing Th2 cell differentiation • Dendritic cells expressing high-affinity IgE receptor • Increased numbers of IL-4 and IL-13 expressing Th2 cells in acute AD • Decreased interferon-γ and IL-12 in acute as compared to chronic AD • Increased IL-31 in AD skin • Increased IL-17 expression in AD lesions, compared to normal skin, but decreased compared to psoriatic skin lesion • Reduced numbers of T regulatory cells in AD skin AD, atopic dermatitis; Ig, immunoglobulin; IL, interleukin; Th2, T helper type 2; TSLP, thymal stromal lymphopoietic.

and IL-13. However, acute AD does not contain significant numbers of cells expressing IFN-γ or IL-12. The lymphocytic infiltrate consists predominantly of activated memory T cells bearing CD3, CD4 and CD45 RO (suggesting previous encounter with antigen). Chronic AD has significantly fewer cells expressing IL-4 and IL-13 but increased numbers of cells expressing IL-5, GM-CSF, IL-12 and IFN-γ than does acute AD. Thus, acute T cell infiltration in AD is associated with a predominance of IL-4 and IL-13 expression, whereas maintenance of chronic inflammation is associated with increased IL-5, GM-CSF, IL-12 and IFN-γ expression, and is accompanied by the infiltration of eosinophils and macrophages. The increased expression of IL-12 in chronic AD skin lesions is of interest as that cytokine plays a key role in Th1 cell development and its expression in eosinophils and/or macrophages may initiate the switch to Th1 or Th0 cell development in chronic AD. Interleukin-31 is a newly characterized cytokine, produced by activated T cells preferentially skewed toward a Th2 type phenotype [6]. Its receptor is a member of the IL-6R group and is constitutively expressed on epithelial cells including keratinocytes. IL-31 has recently been implicated as a major factor in the origin of pruritus in AD. Overexpression of IL-31 in lymphocytes induces severe pruritus and dermatitis in mice. IL-31 mRNA levels are increased in AD skin and this increase correlates with IL-4 and IL-13 levels [7]. It has also been recognized that AD skin lesions have increased expression of IL-17 [8]. IL-17 stimulates keratinocytes to produce GM-CSF, TNF-α, IL-8 and antimicrobial peptides [9]. Recent studies suggest that the source of IL-17 in AD skin lesions is CD4+ Th17+ cells. However, the level of IL-17 expression in AD skin is significantly lower than that observed in psoriasis [10]. Activated T cells infiltrating the skin of AD patients have also been found to induce keratinocyte apoptosis,

contributing to the spongiotic process found in AD skin lesions [11]. This process is mediated by IFN-γ released from activated T cells that upregulates Fas on keratinocytes. The lethal hit is delivered to keratinocytes by Fasligand expressed on the surface of T cells that invade the epidermis and soluble Fas-ligand released from T cells.

Notable cells in atopic dermatitis Keratinocytes Epidermal keratinocytes from AD patients express significantly higher levels of RANTES (also known as chemokine (C-C motif) ligand 5) following stimulation with TNF-α and IFN-γ than keratinocytes from psoriasis patients [12]. Activated keratinocytes also produce and release thymic stromal lymphopoietin (TSLP) [13]. This IL-7-like cytokine promotes survival, maturation and migration of human dendritic cells (DCs) including Langerhans cells which reside in the skin. More importantly, it enhances Th2 cell differentiation by inducing expression of OX40L on immature myeloid DCs in the absence of IL-12 production. Its expression has been shown to be increased in keratinocytes in skin lesions of patients with AD [14]. A role for TSLP in AD pathogenesis is supported by the observation that mice genetically manipulated to overexpress TSLP in the skin develop AD-like skin inflammation [15].

Dendritic cells Atopic dermatitis skin contains an increased number of IgE-bearing Langerhans cells (LC) that appear to play an important role in cutaneous allergen presentation to Th2 cells [16]. Importantly, IgE-bearing LC from AD skin lesions, in contrast to LC which lack surface IgE, are capable of presenting low concentrations of allergen to T cells. These data indicate that cell-bound IgE on LC facilitates capture and internalization of allergens prior to their processing and antigen presentation to T cells. IgEbearing LC are thought to activate memory Th2 cells in atopic skin but they may also migrate to the lymph nodes to stimulate naïve T cells there to further expand the pool of systemic Th2 cells. Binding of IgE to LC occurs primarily via high-affinity IgE receptors. The clinical importance of these IgE receptors on LC is supported by the observation that the presence of FcεRI-expressing, LC-bearing IgE molecules is required for induction of eczematous skin lesions after application of aeroallergens to atopic skin. Normal individuals and patients with respiratory allergy have lowlevel surface expression of FcεRI on their LC, whereas FcεRI is expressed at high levels in the inflammatory environment of AD [17]. High-level FcεRI expression enhances not only binding and uptake of allergens but the activation of LC upon receptor ligation [18].

Immunology of Atopic Dermatitis

T cells As noted above, a variety of T cells infiltrate the skin lesions of patients with AD. These include Th2 cells, particularly in the acute skin lesion, as well as Th1 and Th17 cells, particularly in chronic skin lesions. A reduction in numbers of skin regulatory T cells may contribute to enhanced skin inflammatory responses in AD [19,20]. Although regulatory T cells can be found in the peripheral blood of AD subjects, it appears these cells have a distinct Th2 phenotype in AD related to severity of skin disease and may therefore contribute to the atopic immune response [21].

Skin barrier dysfunction in atopic dermatitis Atopic dermatitis is associated with a marked decrease in skin barrier function due to the downregulation of cornified envelope genes (filaggrin, involucrin and loricrin), reduced ceramide levels, increased levels of endogenous proteolytic enzymes and enhanced transepidermal water loss [22]. Mutations in the filaggrin gene (FLG) result in loss of function of the filaggrin molecule, which is responsible for several barrier structure functions, not the least of which is the structural matrix of the epidermal differentiation complex. Filaggrin gene mutations are associated with persistent and more severe eczema, early onset of AD, increased allergen sensitization and an increased risk of asthma in patients with a previous history of eczema, i.e. the so-called atopic march. A loss of barrier function can also result from Th2 immune activation. In this regard, it has been demonstrated that Th2 cytokines can downregulate innate immune responses in AD [23]. This dysfunctional barrier is further damaged by mechanical and chemical injury. Addition of soap and detergents to the skin raises its pH, thereby increasing activity of endogenous proteases, leading to further breakdown of epidermal barrier function. Mechanical injury through scratching is known to be a critical factor in the development of dermatitis. Exogenous proteases from environmental allergens, such as house dust mites and cockroaches, can inhibit neutral lipid deposition from lamellar bodies in the stratum corneum, further delaying epidermal barrier repair. Recovery is compromised by the lack of certain endogenous protease inhibitors in atopic skin. These epidermal changes probably contribute to increased allergen absorption into the skin and microbial colonization. References 1 Homey B, Steinhoff M, Ruzicka T, Leung DY. Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 2006;118:178–89. 2 Ogawa T, Takai T, Kato T et al. Upregulation of the release of granulocyte-macrophage colony-stimulating factor from keratino-

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cytes stimulated with cysteine protease activity of recombinant major mite allergens, Der f 1 and Der p 1. Int Arch Allergy Immunol 2008;146:27–35. Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994;94:870–6. Hamid Q, Naseer T, Minshall EM et al. In vivo expression of IL-12 and IL-13 in atopic dermatitis. J Allergy Clin Immunol 1996;98: 225–31. 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: 1195–202. Dillon SR, Sprecher C, Hammond A et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 2004;5:752–60. Neis MM, Peters B, Dreuw A et al. Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol 2006;118:930–7. 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;111:875–81. Eyerich K, Pennino D, Scarponi C et al. IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response. J Allergy Clin Immunol 2009;123:59–66. Guttman-Yassky E, Lowes MA, Fuentes-Duculan J et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol 2008;181:7420–7. Trautmann A, Akdis M, Kleemann D et al. T cell-mediated Fasinduced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 2000;106:25–35. Giustizieri ML, Mascia F, Frezzolini A et al. Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines. J Allergy Clin Immunol 2001;107:871–7. Bogiatzi SI, Fernandez I, Bichet JC et al. Cutting Edge: Proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol 2007;178:3373–7. Soumelis V, Reche PA, Kanzler H et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673–80. Yoo J, Omori M, Gyarmati D et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 2005;202:541–9. Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94. Novak N, Tepel C, Koch S et al. Evidence for a differential expression of the FcepsilonRIgamma chain in dendritic cells of atopic and nonatopic donors. J Clin Invest 2003;111:1047–56. Lebre MC, van Capel TM, Bos JD et al. Aberrant function of peripheral blood myeloid and plasmacytoid dendritic cells in atopic dermatitis patients. J Allergy Clin Immunol 2008;122:969–76. Lin W, Truong N, Grossman WJ et al. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 2005;116:1106–15. 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;117:176–83. Reefer AJ, Satinover SM, Solga MD et al. Analysis of CD25hiCD4+ “regulatory” T-cell subtypes in atopic dermatitis reveals a novel T(H)2-like population. J Allergy Clin Immunol 2008;121: 415–22. O’Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol 2008;122:689–93.

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23 Howell MD, Kim BE, Gao P et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007;120:150–5.

Immunological triggers Infection Patients with AD have an increased propensity to develop bacterial, viral and fungal skin infections [1]. The density of Staphylococcus aureus on acute AD lesional skin without clinical superinfection can reach up to 107 colony-forming units per cm2. The importance of Staph. aureus is supported by the observation that even AD patients without overt infection show a greater reduction in severity of skin disease when treated with a combination of antistaphylococcal antibiotics and topical corticosteroids as compared to topical corticosteroids alone. One strategy by which Staph. aureus exacerbates or maintains skin inflammation in AD is by secreting toxins known to act as superantigens that stimulate marked activation of T cells and macrophages. AD skin lesions are frequently colonized or infected with Staph. aureus that secrete superantigens such as staphylococcal enterotoxins and toxic shock syndrome toxin-1. Examination of staphylococci isolated from AD skin has shown that these microbes produce more superantigens than staphylococci isolated from the normal population. They are also more likely to produce unusual combinations of superantigens [2]. An analysis of the peripheral blood skin homing CLA+ T cells from these patients, as well as T cells in their skin lesions, reveals that they have undergone a T cell receptor (TCR) Vβ expansion consistent with superantigenic stimulation. Most AD patients make specific IgE antibodies directed against the staphylococcal superantigens found on their skin. Basophils from patients with IgE antibodies directed to superantigens release histamine on exposure to the relevant superantigen, but not in response to superantigens to which they have no specific IgE. This raises the interesting possibility that superantigens induce specific IgE in AD patients and mast cell degranulation in vivo when the superantigens penetrate the disrupted epidermal barrier. This promotes the itch–scratch cycle critical to the evolution of AD. These superantigens may also induce systemic immunological changes. Staphylococcus enterotoxin B (SEB) has recently been shown to abrogate T regulatory cell activity through the induction of glucocorticoid-induced TNFR-related ligand (GITRL) on monocytes. A correlation has also been found between the presence of IgE anti-superantigens and severity of AD (reviewed in references 3,4). Using murine models of skin inflammation, the combination of Staph. aureus superantigen plus aller-

gen has been shown to have an additive effect in inducing skin inflammation. Superantigens also augment allergenspecific IgE synthesis and induce steroid resistance, suggesting that several mechanisms exist by which superantigens could aggravate AD severity. Fulfilling Koch’s postulates, application of the superantigen SEB to the skin can induce skin changes of erythema and induration accompanied by infiltration of T cells that are selectively expanded in response to SEB. Aside from superantigens, staphylococci can produce other toxins that probably contribute to skin inflammation. AD-associated Staph. aureus isolates that do not secrete superantigenic toxins produce α-toxin. All staphylococcal strains also express staphylococcal protein A. There are significant differences in the action of these staphylococcal products on keratinocytes. Superantigenic toxins as well as protein A do not induce significant cytotoxic damage on keratinocytes but cause the delayed release of TNF-α. In contrast, α-toxin induces profound keratinocyte cytotoxicity and immediate release of TNFα. Keratinocyte cytotoxicity induced by α-toxin demonstrates the morphological and functional characteristics of necrosis, but not apoptosis. Increased binding of Staph. aureus to AD skin is probably related to underlying atopic skin inflammation. This concept is supported by several lines of investigation. First, it has been found that treatment with topical steroids or calcineurin inhibitors will reduce Staph. aureus counts on atopic skin. Second, acute inflammatory lesions have more Staph. aureus than chronic AD skin lesions or normal-looking atopic skin. Scratching enhances Staph. aureus binding by disturbing the skin barrier and exposing extracellular matrix molecules known to act as adhesins for Staph. aureus. Finally, in studies of Staph. aureus binding to skin lesions of mice undergoing Th1 versus Th2 inflammatory responses, bacterial binding was significantly greater at skin sites with Th2-mediated inflammation characteristic of acute AD exacerbations. Importantly, this increased bacterial binding did not occur in IL-4 gene knockout mice, indicating that IL-4 plays a crucial role in the enhancement of Staph. aureus binding to skin. IL-4 appears to enhance Staph. aureus binding to the skin by inducing the synthesis of fibronectin, an important Staph. aureus adhesin. Interestingly, in studies of human AD, a role for fibrinogen in the binding of Staph. aureus to atopic skin has been found. Because acute exudative lesions are likely have increased plasmaderived fibrinogen, this may provide a mechanism for further binding of Staph. aureus to acute AD lesions. A key component of the skin’s innate immune response to invading organisms is the mobilization of antimicrobial peptides (AMPs). AMPs are endogenous low molecular weight proteins produced primarily by keratinocytes [5]. Two major classes of AMPs have been identified in

Immunology of Atopic Dermatitis

Box 24.3 Innate immune response in atopic dermatitis • • • • • •

Decreased skin barrier function Reduced generation of antimicrobial peptides by keratinocytes Chemokine release driving inflammatory skin response Absence of neutrophils in AD skin lesions Reduced TLR2 signalling by monocytes Diminished numbers of interferon-producing plasmacytoid dendritic cells in skin lesion

AD, atopic dermatitis; TLR2, toll-like receptor 2.

mammalian skin: (β)-defensins, which contain six cysteine residues that form three disulphide bridges, and cathelicidins, which have a highly conserved N-terminal cathelin domain and a C-terminal cationic domain. To date, four human (β)-defensins (HBDs) and one human cathelicidin LL-37 have been described. AMPs are cationic and therefore interact with the anionic components of bacteria, leading to permeabilization of the microbial membrane and cell lysis. Stimulation of normal keratinocytes with Staph. aureus has been shown to induce the expression of AMPs, including HBD-2, HBD-3 and LL-37. The ability of keratinocytes to kill Staph. aureus is particularily dependent on HBD-3. However, the expression of HBD-2, HBD-3 and LL-37 is reduced in the skin of atopic dermatitis patients. AD skin is characterized by the overexpression of IL-4, IL-10 and IL-13. Overexpression of Th2 cytokines IL-4 and IL-13 inhibits production of AMPs and antagonism of IL-4/10/13 with antibodies significantly improved mobilization of HBD-3 by skin from patients with AD [6]. Thus it is proposed that the increased rate of Staph. aureus colonization seen in AD is due in part to suppression of AMPs levels by an altered local cytokine milieu. Please see Box 24.3 for a summary of defects in the innate immune response that may contribute to infection in AD. Atopic dermatitis can also be complicated by recurrent viral skin infections that may reflect local defects in T cell function and innate immune response. The most serious viral infection is herpes simplex virus (HSV), which can affect patients of all ages, resulting in Kaposi’s varicelliform eruption (eczema herpeticum). The role of AMPs in the defence against HSV has been explored, revealing that the human cathelicidin LL-37 exhibits potent antiviral activity against HSV [7]. Additionally, it was found that there is an inverse relationship between serum IgE levels and skin LL-37 expression. This suggests that serum IgE and skin LL-37 expression could be markers for identifying those at risk of developing eczema herpeticum. Although smallpox infections have been eradicated worldwide since the late 1970s, threats of bioterrorism

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(with smallpox and other infectious agents) have made nations reconsider their policies toward initiating vaccination programmes. In AD patients, smallpox vaccination (or even exposure to vaccinated individuals) may cause a severe widespread eruption called eczema vaccinatum. Thus, in patients with AD, vaccination is contraindicated unless there is a clear risk of smallpox. In addition, decisions regarding vaccination of family members should take into consideration the potential of eczema vaccinatum in household contacts. Several recent studies have demonstrated that the AMPs play an important role in the innate immune response against vaccinia virus. Studies show that AD skin biopsies have a reduced ability to express LL-37 and HBD-3 following stimulation with vaccinia virus and correspondingly support vaccinia virus replication to a greater extent than skin from normal individuals or psoriasis patients. Further investigation has demonstrated that IL-4 and IL-13 inhibit vaccinia virus-mediated induction of LL-37 [8]. AD skin is also deficient in MIP-3α which exhibits antiviral activity against vaccinia virus. This deficiency is also partly because of the overexpression of Th2 cytokines in AD skin. Superficial fungal infections are also more common in atopic individuals and may contribute to the exacerbation of AD. There has been particular interest in the role of Malassezia furfur (Pityrosporum ovale or P. orbiculare) in AD. M. furfur is a lipophilic yeast commonly present in the seborrhoeic areas of the skin. IgE antibodies against M. furfur are commonly found in AD patients and most frequently in patients with head and neck dermatitis [9]. Positive allergen patch test reactions to this yeast have also been demonstrated. The potential importance of M. furfur as well as other dermatophyte infections is further supported by the reduction of AD skin severity in such patients following treatment with antifungal agents.

Foods Food allergens have been reported to induce skin rashes in approximately 40% of infants and young children with moderate to severe AD. Food allergies in AD patients may induce eczematous dermatitis in some while in others, urticaria or non-cutaneous symptoms are elicited. In a study of 250 children with AD, Guillet & Guillet [10] found that increased severity of AD symptoms and younger age of patients were correlated directly with comorbid food allergy. Removal of food allergens from the patient’s diet can lead to significant clinical improvement but requires a great deal of vigilance because common allergens (e.g. egg, milk, wheat, soy and peanut) contaminate many foods and are difficult to avoid [11]. Laboratory studies also support a role for food allergy in AD. Infants and young children with moderate to severe AD often have positive immediate skin tests or

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Chapter 24

serum IgE directed to various foods. Positive food challenges are accompanied by significant increases in plasma histamine levels and eosinophil activation. Children with AD who chronically ingest foods to which they are allergic have increased spontaneous basophil histamine release compared with children without food allergy. Of note, immediate skin tests to specific allergens do not always indicate clinical sensitivity. Therefore, clinically relevant food allergy must be verified by controlled food challenges or carefully investigating the effects of a food elimination diet. Most food-allergic children, however, outgrow their food allergy in the first few years of life, so food allergy is not a common trigger factor in older patients with AD.

Inhalant allergens Exacerbation of AD has been reported following exposure to horse dander, timothy grass and ragweed pollen. Double-blind, placebo-controlled challenges have also demonstrated that inhalation of house dust mites by bronchial challenge can result in new AD skin lesions and exacerbation of a previous skin rash [12]. Topical application of inhalant allergens by patch test techniques on unaffected atopic skin can also elicit eczematoid reactions in patients with AD. In contrast, patients with respiratory allergy and healthy volunteers rarely have positive allergen patch tests. Elimination of inhalant allergens from patient environments can also improve AD in patients with documented inhalant allergy. Most of these studies have involved uncontrolled trials in which patients were placed in environments, such as hospital rooms, made mite free through the use of acaricides or impermeable mattresses covers. A recent study demonstrating that sublingual immunotherapy to house dust mites can improve AD further supports a potential role for inhalant allergy in driving this skin disease [13].

Autoallergens In the 1920s, it was first reported that human skin dander could trigger immediate hypersensitivity reactions in AD skin. The potential molecular basis for these observations was subsequently demonstrated by Valenta et al. [14] who reported that the majority of sera from patients with severe AD contain IgE antibodies directed against human proteins. These IgE-reactive autoantigens appear to target skin keratinocyte-derived antigens [15]. Such antibodies are not detected in patients with chronic urticaria, systemic lupus erythematosus (SLE) or graft versus host disease (GVHD), or in healthy controls. Although the autoallergens characterized to date have mainly been intracellular proteins, they have been detected in IgE immune complexes of AD sera, suggesting that release of these autoallergens from damaged tissues could trigger

IgE responses. These data suggest that while IgE immune responses are initiated by environmental allergens, allergic inflammation can be perpetuated by human skinderived antigens, particularly in severe AD. References 1 De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA. Atopic dermatitis: a disease caused by innate immune defects? J Invest Dermatol 2009;129:14–30. 2 Schlievert PM, Case LC, Strandberg KL, Abrams BB, Leung DY. Superantigen profile of Staphylococcus aureus isolates from patients with steroid-resistant atopic dermatitis. Clin Infect Dis 2008;46:1562–7. 3 Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94. 4 Leung DY, Bieber T. Atopic dermatitis. Lancet 2003;361:151–60. 5 Schauber J, Gallo R. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 2008;122:261–6. 6 Kisich KO, Carspecken CW, Fieve S, Boguniewicz M, Leung DY. Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3. J Allergy Clin Immunol 2008;122:62–8. 7 Howell MD, Wollenberg A, Gallo RL et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol 2006;117:836–41. 8 Howell MD, Gallo RL, Boguniewicz M et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 2006;24:341–8. 9 Lange L, Alter N, Keller T, Rietschel E. Sensitization to Malassezia in infants and children with atopic dermatitis: prevalence and clinical characteristics. Allergy 2008;63:486–7. 10 Guillet G, Guillet MH. Natural history of sensitizations in atopic dermatitis. A 3-year follow-up in 250 children: food allergy and high risk of respiratory symptoms. Arch Dermatol 1992;128:187–92. 11 Lever R, MacDonald C, Waugh P, Aitchison T. Randomised controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs. Pediatr Allergy Immunol 1998;9:13–19. 12 Tupker RA, de Monchy JG, Coenraads PJ, Homan A, van der Meer JB. Induction of atopic dermatitis by inhalation of house dust mite. J Allergy Clin Immunol 1996;97:1064–70. 13 Werfel T, Breuer K, Rueff F et al. Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose-response study. Allergy 2006;61:202–5. 14 Valenta R, Seiberler S, Natter S et al. Autoallergy: a pathogenetic factor in atopic dermatitis? J Allergy Clin Immunol 2000;105:432–7. 15 Altrichter S, Kriehuber E, Moser J et al. Serum IgE autoantibodies target keratinocytes in patients with atopic dermatitis. J Invest Dermatol 2008;128:2232–9.

Clinical implications and conclusions Atopic dermatitis involves a defective skin barrier allowing water loss and penetration by allergens and mirobial toxins to evoke a T cell response, resulting in a constant cycle of inflammation. This is aggravated by a defective innate response which fails to control microbial colonization and infection as well as a polarized Th2 response further exaggerated by defective T regulatory cells. Successful treatment of AD requires a systematic, multi-

Immunology of Atopic Dermatitis

pronged approach that incorporates skin hydration, anti-inflammatory therapy, and the identification and elimination of flare factors such as irritants, allergens and infectious agents. Many factors lead to the symptom complex characterizing AD. Thus, treatment plans should be individualized

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to address each patient’s skin disease reaction pattern, including the acuity of the rash and the trigger factors that are unique to that particular patient. See Chapter 30 for further details on therapeutic approaches in the management of AD.

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C H A P T E R 25

Immunopharmacological Mechanisms in Atopic Dermatitis Clive B. Archer St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK

Impaired β-adrenoceptor reactivity and atopy: interpretation of in vivo observations, 25.1

Cytokines in atopic dermatitis, 25.5 Cell regulatory abnormalities in atopic dermatitis, 25.6

Therapeutic implications and advances, 25.9 Conclusion, 25.13

Inflammatory mediators in atopic dermatitis, 25.2

The aim of this chapter is to review a number of altered in vivo physiological and pharmacological responses in atopic dermatitis, taking care not to overinterpret findings that are sometimes non-specific. Immunopharmacological mechanisms will be considered with particular reference to the role of inflammatory mediators and cytokines in the pathogenesis of atopic dermatitis, in the context of epidermal barrier dysfunction. In addition, the evidence for abnormal cell regulatory mechanisms in atopic dermatitis is discussed, before considering some interesting therapeutic implications and advances.

Impaired β-adrenoceptor reactivity and atopy: interpretation of in vivo observations The proposition by Szentivanyi [1] that impaired βadrenoceptor reactivity is a primary determinant of bronchial asthma and atopy stimulated extensive studies that were designed to confirm or refute it. The virtue of this controversial hypothesis was an attempt to look beyond the trigger factors of atopy in order to explain the altered pharmacological and immunological reactivity observed in such subjects [2–5]. Following Szentivanyi’s hypothesis [1] and its subsequent modifications based on current concepts of receptor function [6], a number of in vivo manifestations in atopic dermatitis have been considered to be consistent with altered adrenoceptor function, that is, impaired βadrenoceptor reactivity accompanied by enhanced αHarper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

adrenoceptor reactivity [6]. These include white dermographism [7], a delayed blanch response to cholinergic agents (thought to be mediated, in part, by noradrenaline [8,9]) and increased pilomotor muscle sensitivity to β-adrenergic stimuli [10]. Patients with atopic dermatitis do not exhibit the enhanced sweat response to acetylcholine following propranolol administration that is seen in normal subjects [11]. Some of these phenomena are non-specific, however, and observations in patients with atopic dermatitis should be interpreted with caution. The white-line response of white dermographism can be elicited on the erythematous, involved skin of patients with atopic dermatitis but may be seen in a number of other erythematous conditions [12,13]. The delayed blanch response that follows intradermal injection of acetylcholine or methacholine occurs in about 70% of patients with atopic dermatitis and can be blocked by atropine [14]. Juhlin [9] suggested the involvement of noradrenaline (norepinephrine) because (a) noradrenaline could induce the blanch response to acetylcholine in normal subjects; (b) smaller quantities of noradrenaline were required to blanch the skin of patients with atopic dermatitis; and (c) the response was abolished if the skin was depleted of noradrenaline by pretreatment with guanethidine. Delayed blanching to cholinergic agents also occurs in seborrhoeic and allergic contact dermatitis [15] and, like white dermographism, seems to be secondary to cutaneous inflammation. A major criticism of the ‘partial β-adrenoceptor blockade’ hypothesis in asthma has been the difficulty in demonstrating consistent evidence in vivo of β-adrenoceptor hyporesponsiveness. There is, therefore, a need to examine the question of altered adrenoceptor function in atopic dermatitis by performing in vivo studies, in parallel

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with in vitro investigation. In an electrophysiological study of autonomic function in atopic dermatitis, prolonged sympathetic skin response (SSR) latency in patients with active disease was interpreted as evidence for impaired sympathetic sudomotor activity, this mechanism in unmyelinated C fibres perhaps contributing to dryness of the skin via sweat gland dysfunction [16]. In guinea pig skin, bradykinin-induced responses can be inhibited by both α-adrenergic and β-adrenergic agents [17] and corresponding observations of αadrenergic and β-adrenergic actions have been reported for human skin, in which propranolol blocks the inhibitory action of salbutamol on histamine weal formation [18]. This simple in vivo method for detecting adrenoceptor reactivity in the skin has been used in patients with atopic dermatitis [19]. Histamine weal responses were reduced both by concurrent intradermal injection of noradrenaline and by salbutamol in patients with atopic dermatitis and normal subjects, but there was no significant difference between atopic and control groups for either α-adrenergic or β2-adrenergic inhibition of weal volume. Thus, within the limits of in vivo measurement sensitivity, there was no evidence of altered adrenoceptor function in the cutaneous vessels of patients with atopic dermatitis [20]. References 1 Szentivanyi A. The beta adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203–32. 2 Coca AF, Cook RA. On the classification of the phenomena of hypersensitiveness. J Immunol 1923;8:163–70. 3 Chai H, Farr RS, Froehlic LA et al. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975;56:323–7. 4 Kaliner M. The cholinergic nervous system and immediate hypersensitivity: eccrine sweat response in allergic patients. J Allergy Clin Immunol 1976;58:308–15. 5 Platts-Mills TAE, Mitchell EB, Rowntree S et al. The role of dust mite allergens in atopic dermatitis. Clin Exp Dermatol 1983;8:233–47. 6 Szentivanyi A, Heim O, Schultze P et al. Adrenoceptor binding studies with 3H (dihydroalprenolol) and 3H (dihydroergocryptine) on membranes of lymphocytes from patients with atopic disease. Acta Dermatol Venereol (Stockh) 1980;92:19–21. 7 Whitfield A. On the white reaction (white line) in dermatology. Br J Dermatol 1938;50:71–82. 8 Lobitz WC, Campbell CH. Physiologic studies in atopic dermatitis (disseminated neurodermatitis). 1. The local cutaneous response to intradermally injected acetylcholine and epinephrine. Arch Dermatol 1953;67:575–89. 9 Juhlin L. Vascular reactions in atopic dermatitis. Acta Dermatol Venereol (Stockh) 1962;42:218–29. 10 Juhlin L. Skin reactions to iontophoretically administered epinephrine and norepinephrine in atopic dermatitis. J Invest Dermatol 1961;37:201–5. 11 Hemels HGWM. The effect of propranolol on the acetyl-cholineinduced sweat response in atopic and non-atopic subjects. Br J Dermatol 1970;83:312–14. 12 Reed WB, Kierland RR, Code CF. Vascular reactions in chronically inflamed skin. 1. Mechanical stimuli to the skin: inhibition of white dermographism. Arch Dermatol 1958;77:91–6.

13 Uehara M, Ofuji S. Abnormal vascular reactions in atopic dermatitis. Arch Dermatol 1977;113:627–9. 14 Champion RH. Abnormal vascular reactions in atopic eczema. Br J Dermatol 1963;75:12–15. 15 Uehara M, Ofuji S. Delayed blanch reactions in atopic dermatitis. Arch Dermatol 1978;114:1098–9. 16 Cicek D, Kandi B, Berilgen MS et al. Does autonomic dysfunction play a role in atopic dermatitis? Br J Dermatol 2008;159:834–8. 17 Beets JL, Paul W. Actions of locally administered adrenoceptor agonists on increased plasma protein extravasation and blood flow in guinea-pig skin. Br J Pharmacol 1980;70(suppl 23):461–7. 18 Basran GS, Paul W, Morley J et al. Adrenoceptor-agonist inhibition of the histamine-induced cutaneous response in man. Br J Dermatol 1982;107:140–2. 19 Archer CB, Paul W, Morley J et al. Actions of locally administered adrenoceptor agonists on histamine induced cutaneous responses in atopic eczema. Clin Exp Dermatol 1984;9:358–63. 20 Archer CB, Hanson JM, Morley J et al. Adrenoceptor function in atopic dermatitis: in vitro and in vivo observations. Acta Dermatol Venereol (Stockh) 1985;114(suppl):93–6.

Inflammatory mediators in atopic dermatitis The pathophysiological role of inflammatory mediators in atopic dermatitis and other inflammatory skin diseases is not fully established. Candidate inflammatory mediators include histamine, arachidonic acid metabolites and platelet-activating factor (PAF). It is important not to consider each mediator in isolation, as there is evidence for synergistic interaction between a number of putative inflammatory mediators [1,2]. Much interest has focused on the concept of altered releasability of vasoactive mediators in atopic dermatitis, particularly of histamine and arachidonic acid metabolites [3]. This section reviews the findings of in vitro studies, attempts to quantify the presence of inflammatory mediators in plasma and skin, and the cutaneous effects of inflammatory mediators in vivo in patients with atopic dermatitis.

In vitro studies In most studies, atopic basophils have been shown to release increased amounts of histamine compared with control subjects, particularly after stimulation with antiimmunoglobulin E (IgE) but also other stimuli [4–9]. In addition, release of histamine from basophils of patients with atopic dermatitis was more rapid than in normal cells, probably due to a more slowly acting endogenous feedback mechanism by prostaglandin E2 [10]. The subject of histamine releasability from basophils in atopic dermatitis is reviewed by Ring & Dorsch [11]. Sweating may exacerbate itch in atopic dermatitis by an allergic mechanism, since skin tests with autologous sweat were positive in 56 of 66 patients with atopic dermatitis, but in only three of 27 healthy volunteers [12].

Immunopharmacological Mechanisms in Atopic Dermatitis

The semi-purified sweat antigen consists of a protein that induces degranulation of basophils and mast cells (i.e. histamine release) via antigen-specific IgE in patients with atopic dermatitis [13]. Eicosanoid release from mixed peripheral blood leucocytes was measured in 27 patients with atopic dermatitis and 22 non-atopic healthy control subjects [14]. Cells from atopic individuals showed enhanced spontaneous production of leukotriene C4. Immunological challenge of cells with C5a and anti-IgE resulted in increased production of prostaglandin E2, leukotriene B4 and leukotriene C4 in the atopic group, supporting the concept of enhanced generation of vasoactive mediators in atopy. Stimulation with the calcium ionophore A23127 led to maximal synthesis of all eicosanoids, of similar magnitude in the atopic and control groups. Ferreri et al. [15] found that leukotriene C4 release from monocytes after stimulation with the calcium ionophore, IgG, IgA and IgE was not significantly different in atopic dermatitis patients and control subjects. In addition, it has been shown that monocytes, but not granulocytes, from patients with atopic dermatitis and psoriasis exhibit enhanced chemotaxis towards leukotriene B4 [16]. In patients with atopic dermatitis, basophils secreted significantly higher amounts of histamine and leukotriene C4 following stimulation with Staphylococcus aureus enterotoxins compared with healthy controls [17].

Measurement of inflammatory mediators in vivo Elevated plasma histamine levels in atopic dermatitis are seen in some patients, usually those with severe disease, and then as a transient finding only [18,19]. Ring [20] found raised histamine levels in 17 out of 54 patients with atopic dermatitis, elevated histamine concentrations being demonstrated mainly in patients with severe disease and high serum IgE levels. Earlier methods of histamine estimation are considered to be unreliable, and evidence related to histamine levels in the skin is conflicting. Johnson et al. [21] found an increased concentration of histamine in patients with atopic dermatitis. Juhlin [22] found increased histamine levels in patients with atopic dermatitis, with no significant difference between affected and normal-appearing skin. More recently, using a sensitive and specific enzymatic double-isotope assay, Ruzicka & Gluck [23] measured the histamine concentrations in biopsies of lesional skin and found levels above the normal range in only three out of 22 patients with atopic dermatitis, with no significant difference between the two groups. In contrast, a single patient with the hyper-IgE syndrome showed extremely high histamine concentrations in skin. Both in atopic dermatitis patients and in the hyper-IgE patient, histamine

25.3

catabolism in skin via methyltransferase was normal. In this study, histamine release from skin slices after immunological challenge with anti-IgE was almost twice as high in atopic dermatitis patients as in control subjects, supporting the concept of enhanced releasability of vasoactive mediators in atopy. However, histamine release induced by compound 48/80, a non-immunological stimulus, was similar in atopic dermatitis patients and control subjects. These findings of normal histamine concentrations in skin biopsies in atopic dermatitis patients were confirmed in a subsequent study performed on suction blister fluid samples [24]. Hence, although increased histamine releasability in atopic dermatitis is regarded as a marker of mast cell and basophil activation [25], histamine itself is not considered to play a central role in the primary cutaneous inflammatory events of atopic dermatitis. However, histamine is likely to have a more important function in contributing to the itch of atopic dermatitis and, consequently, those events in the skin secondary to scratching, such as cytokine release [26]. Monocytes from patients with atopic dermatitis have been shown to produce increased levels of prostaglandin E2 [27]. Increased levels of leukotriene B4 have been found in suction blister fluid from lesional, but not uninvolved, atopic dermatitis skin [24], concentrations of leukotriene B4 in psoriatic lesions being even higher. Although leukotriene B4 elevation is not specific to atopic dermatitis, it is not due to skin inflammation per se because in patients with ultraviolet B erythema, leukotriene B4 concentrations are within the normal range [28]. Levels of leukotriene B4 have been found to be increased in suction blister fluid compared with late cutaneous reactions [29] but no elevation of leukotriene B4 levels was seen in immediatetype hypersensitivity skin reactions induced in atopic individuals by ragweed or grass pollen [30]. As, to an extent, similar inflammatory mechanisms are likely to be involved in different types of inflammatory skin diseases, lack of specificity should not be equated with lack of biological importance. Fogh et al. [31] found that in patients with atopic dermatitis, lesional and perilesional skin contained elevated concentrations of leukotriene B4, prostaglandin E2, 12-HETE (hydroxyeicosatetraenoic acid) and 15-HETE, eicosanoid levels in uninvolved skin being similar to those in control subjects.

Intradermal effects of inflammatory mediators Whether individuals with atopic dermatitis are more sensitive to intradermal histamine is controversial. One study reported increased weal volumes in atopic patients in response to histamine plus the protein carrier bovine serum albumin (BSA) [32]. However, some patients developed allergic reactions to the BSA and were withdrawn from the study, and the possibility that data for

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the whole group were influenced by the presence of BSA was not excluded. Using a single dose of histamine, weal volume responses to intradermal histamine were not significantly higher in atopic dermatitis patients than in control subjects [33] and two subsequent studies, one with and one without the protein carrier human serum albumin (HSA), found no differences between atopic and control groups [34,35]. Intradermal injection of leukotriene C4 produced larger weals in atopic patients than in control subjects [36]. Intradermal injection of PAF in atopic patients with no evidence of dermatitis induced weal and flare responses, with accumulation of eosinophils in the dermis, present 30 min after injection and maximal at 12 h [37], confirming the effect of PAF on eosinophil recruitment in atopic patients, observed by Henocq & Vargaftig [38]. PAFinduced flare responses were reduced by the oral administration of a PAF antagonist, BN 52063 [37,39]. References 1 Archer CB, Page CP, Paul W et al. Inflammatory characteristics of platelet activating factor (PAF-acether) in human skin. Br J Dermatol 1984;110:45–50. 2 Archer CB, Page CP, Juhlin L et al. Delayed onset synergism between leukotriene B4 and prostaglandin E2 in human skin. Prostaglandins 1987;33:799–805. 3 Lichtenstein LM, Conroy MC. The ‘releasability’ of mediators from human basophils and granulocytes. In: Mathov E, Sindo T, Naranjo P (eds) Allergy and Clinical Immunology. Amsterdam: Excerpta Medica, 1977: 109–15. 4 Lebel B, Venencie PY, Saurat JH et al. Anti-IgE induced histamine release from basophils in children with atopic dermatitis. Acta Dermatol Venereol 1980;92(suppl):57–9. 5 Assem ESK, Attallah NA. Increased release of histamine by anti-IgE from leukocytes of asthmatic patients and possible heterogenicity. Clin Allergy 1981;11:367–73. 6 Butler JM, Chan SC, Stevens SR et al. Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol 1983;71:490–7. 7 Marone G, Poto S, Giugliano R et al. Studies on human basophil releasability. Int Arch Allergy Appl Immunol 1985;77:103–6. 8 Ring J, Walz U. Indomethacin enhances in vitro histamine release induced by anti-IgE and Ca-ionophore but inhibits C5a-induced release reactions from basophils of atopics and normals. Int Arch Allergy Appl Immunol 1985;77:225–7. 9 Marone G, Poto S, Giugliano R et al. Human basophil releasability in patients with atopic dermatitis. J Invest Dermatol 1986;87: 19–23. 10 Von der Helm D, Ring J, Dorsch W. Comparison of histamine release and prostaglandin E2 production of human basophils in atopic and normal individuals. Arch Dermatol Res 1987;279:536–42. 11 Ring J, Dorsch W. Altered releasability of vasoactive mediator secreting cells in atopic eczema. Acta Dermatol Venereol (Stockh) 1985;114(suppl):9–24. 12 Hide M, Tanaka T, Yamamura Y et al. IgE-mediated hypersensitivity against human sweat antigen in patients with atopic dermatitis. Acta Derm Venereol 2002;82(5):335–40. 13 Tanaka A, Tanaka T, Suzuki H et al. Semi-purification of the immunoglobulin E-sweat antigen acting on mast cells and basophils in atopic dermatitis. Exp Dermatol 2006;15(4):283–90.

14 Ruzicka T, Ring J. Enhanced releasability of prostaglandin E2 and leukotrienes B4 and C4 from leukocytes of patients with atopic eczema. Acta Dermatol Venereol (Stockh) 1987;67: 469–75. 15 Ferreri NR, Zeiger RS, Spiegelberg HL. IgG-, IgA-, and IgE-induced release of leukotriene C4 by monocytes isolated from patients with atopic dermatitis. J Allergy Clin Immunol 1988;82:556–67. 16 Czarnetzki B. Increased monocyte chemotaxis towards leukotriene B4 and platelet activating factor in patients with inflammatory dermatoses. Clin Exp Immunol 1983;54:486–92. 17 Wehner J, Neuber K. Staphylococcus aureus enterotoxins induce histamine and leukotriene release in patients with atopic eczema. Br J Dermatol 2001;145:302–5. 18 Hanifin JM. Type I hypersensitivity diseases of the skin: divergent aspects of urticaria and atopic dermatitis. Ann Allergy 1977;39:153–60. 19 Ring J, Senter T, Cornell RC et al. Plasma complement and histamine changes in atopic dermatitis. Br J Dermatol 1979;100:521–30. 20 Ring J. Plasma histamine concentrations in atopic eczema. Clin Allergy 1983;13:545–52. 21 Johnson HH, de Oreo G, Lascheid WP et al. Skin histamine levels in chronic atopic dermatitis. J Invest Dermatol 1960;34:237–8. 22 Juhlin L. Localisation and content of histamine in normal and diseased skin. Acta Dermatol Venereol 1967;47:383–91. 23 Ruzicka T, Gluck S. Cutaneous histamine levels and histamine releasability from the skin in atopic dermatitis and hyper-IgE syndrome. Arch Dermatol Res 1983;275:41–4. 24 Ruzicka T, Simmet T, Peskar BA et al. Skin levels or arachidonic acidderived inflammatory mediators and histamine in atopic dermatitis and psoriasis. J Invest Dermatol 1986;86:105–8. 25 Ring J, Thomas P. Histamine and atopic eczema. Acta Dermatol Venereol (Stockh) 1989;144:70–7. 26 Nickoloff BJ, Naidu Y. Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin. J Am Acad Dermatol 1994;30:535–46. 27 Chan SC, Kim JW, Henderson WR et al. Altered prostaglandin E2 regulation of cytokine production in atopic dermatitis. J Immunol 1993;151:3345–52. 28 Ruzicka T, Przybilla B. Eicosanoids in skin UV-inflammation: lack of leukotriene B4 elevation in UVB-induced dermatitis. Photodermatology 1986;2:306–7. 29 Dorsch W, Ring J, Weber PC et al. Detection of immunoreactive leukotrienes LTC4/D4 in skin blister fluid after allergen testing in patients with late cutaneous reactions (LCR). Arch Dermatol Res 1985;277:400–1. 30 Talbot SF, Atkins PC, Goetzl EJ et al. Accumulation of leukotriene C4 and histamine in human allergic skin reactions. J Clin Invest 1985;75:650–6. 31 Fogh K, Herlin T, Dragballe K. Eicosanoids in skin of patients with atopic dermatitis: prostaglandin E2 and leukotriene B4 are present in biologically active concentrations. J Allergy Clin Immunol 1989;83:450–5. 32 Coulson I, Holden CA. Cutaneous responses to substance P and histamine in atopic dermatitis. Br J Dermatol 1990;122:343–9. 33 Archer CB, Paul W, Morley J et al. Actions of locally administered adrenoceptor agonists on histamine induced cutaneous responses in atopic eczema. Clin Exp Dermatol 1984;9:358–63. 34 Archer CB, Kavanagh GM. Effects of human serum albumin on PAFand histamine-induced inflammatory responses in the skin of normal and atopic subjects. Br J Clin Pharmacol 1992;33:566P. 35 Sabroe RA, Kennedy CTC, Archer CB. The effects of topical doxepin cream and oral terfenadine on the cutaneous responses to histamine and substance P in human skin. Br J Clin Pharmacol 1997;43:530P–1P.

Immunopharmacological Mechanisms in Atopic Dermatitis 36 Hammarstrom JL. Effects of intradermally injected leukotriene C4 and histamine in patients with urticaria, psoriasis, and atopic dermatitis. Br J Dermatol 1982;107(suppl):106–10. 37 Markey AC, Barker JNWN, Archer CB et al. Platelet activating factorinduced clinical and histopathological responses in atopic skin and their modification by the platelet activating factor antagonist BN 52063. J Am Acad Dermatol 1990;23:263–8. 38 Henocq E, Vargaftig BB. Accumulation of eosinophils in response to intracutaneous PAF-acether and allergens in man. Lancet 1986;i:1378–9. 39 Archer CB. Platelet activating factor (PAF) and skin inflammation. London: PhD thesis, 1991.

Cytokines in atopic dermatitis A number of studies have demonstrated increased numbers of allergen-specific T-cells producing increased interleukin 4 (IL-4) and IL-5 but little interferon-γ (IFN-γ) (the type 2 T helper cell or Th2 cytokine profile) in peripheral blood and skin lesions of patients with atopic dermatitis [1–4]. This Th2 cytokine shift is accompanied by downregulation of the IFN-γ gene [5] and upregulation of IL-4, IL-5, IL-10 and IL-13 genes [6–8]. Travers and coworkers studied the immunomodulatory role of Staphylococcus aureus in mice, lipoteichoic acid (LTA) being a constituent of Gram-positive bacteria cell walls. LTA inhibited delayed-type hypersensitivity reactions via the PAF receptor, through the production of the Th2 cytokine IL-10 [9], providing a mechanism whereby staphylococcal infections can inhibit Th1 reactions and thus worsen Th2 skin diseases such as atopic dermatitis. Interferon-γ usually inhibits IgE synthesis and the proliferation of Th2 lymphocytes [10]. IL-4 is able to induce the low-affinity receptor for IgE on Langerhans cells and regulates IgE synthesis [11–13]. In addition, it inhibits IFN-γ production and downregulates the differentiation of Th1 cells [14]. Monocytes from patients with atopic dermatitis have also been shown to secrete increased levels of IL-10 and prostaglandin E2 [14,15], both of which inhibit IFN-γ production, IL-10 being overexpressed in atopic dermatitis skin [16]. Further, Lacy et al. have shown an association between a common distal IL-10 promoter haplotype and the production of IgE in atopic dermatitis [17]. Lesional skin in atopic dermatitis contains an increased number of IgE-bearing Langerhans cells and inflammatory dendritic epidermal cells expressing the high-affinity receptor for IgE [18]. These antigen-presenting cells play an important role in the development of naive T-cells into Th2 cells. Downregulation of dendritic cell function has been found after treatment with the topical calcineurin inhibitor tacrolimus [19,20]. In addition, histamine downregulates IL-12 production by human monocyte-derived dendritic cells and may enhance the development of the Th2 cells [21].

25.5

There is some evidence for a predominance of IL-4 messenger RNA (mRNA) expression in early lesions (present for less than 3 days) of atopic dermatitis, whereas persistent lesions (present for over 2 weeks) are associated with increased IL-5 mRNA and eosinophil infiltration [22], better demonstrated by immunostaining for major basic protein than by routine histological techniques [23]. The recruitment of Th2 lymphocytes and eosinophils into atopic skin is thought to be influenced by the chemokines RANTES, monocyte chemotactic protein 4 and eotaxin, which are increased in lesional skin in atopic dermatitis [24,25]. There is also increased expression of IL-16, a chemoattractant for CD4 T-cells, in the skin lesions of atopic dermatitis [26]. As a non-specific marker of cellular activation, the serum level of soluble IL-2 receptor is elevated in atopic dermatitis [27]. Perpetuation of the lesions by scratching seems to be associated with release of keratinocytederived cytokines [28], including IL-1, tumour necrosis factor-α (TNF-α) and IL-4, which, via cell adhesion molecules, induce infiltration with lymphocytes, macrophages and eosinophils. Keratinocytes from patients with atopic dermatitis produce significantly higher levels of RANTES after stimulation with TNF-α and IFN-γ [29]. Keratinocytes from atopic dermatitis patients also produce thymic stromal lymphopoietin, which activates dendritic cells to prime naive Th cells to produce IL-4, IL-13 and TNF-α [30]. However, the role of T-cells in atopic dermatitis is more complicated than it first seemed. Studies attempting to sample ‘acute’ and ‘chronic’ lesions in atopic dermatitis showed Th2 and Th1 profiles respectively [31]. Atopic dermatitis lesional skin contains relatively few Th2 cells, and clonally expanded T-cells from lesional skin comprise mixed Th0/Th1 cytokine profiles producing high levels of IFN-γ, Fas ligand, TNF-α, IL-5 and IL-13 but not IL-4 [32–34]. The role of T-cells in the pathogenesis of atopic dermatitis has recently been reviewed [35]. Leung’s group have suggested that IL-4 and IL-13, overexpressed in atopic dermatitis lesional skin, may lead to reduced filaggrin gene expression, thereby contributing to the skin barrier defect [36]. The relevance of epidermal barrier function and its interaction with components of the innate and adaptive immune responses in patients with atopic dermatitis have also been reviewed [34,37,38]. References 1 Wierenga EA, Snoek M, Bos JD et al. Comparison of diversity and function of house dust mite-specific T-lymphocyte clones from atopic and non-atopic donors. Eur J Immunol 1990;20:1519–26. 2 Van der Heijden F, Wierenga EA, Bos JD et al. High frequency of IL-4 producing CD4 allergen-specific T lymphocytes in atopic dermatitis lesional skin. J Invest Dermatol 1991;97:389–94. 3 Van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff FS et al. Skinderived aeroallergen-specific T-cell clones of the Th2 phenotype

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in patients with atopic dermatitis. J Allergy Clin Immunol 1992;90:184–93. Chan SC, Li S-H, Hanifin JM. Increased interleukin-4 production by atopic mononuclear leukocytes correlates with increased cyclic adenosine monophosphate-phosphodiesterase activity and is reversible by phosphodiesterase inhibition. J Invest Dermatol 1993;100:681–4. Campbell DE, Fryga AS, Bol S et al. Intracellular interferon-gamma (IFN-gamma) production in normal children and children with atopic dermatitis. Clin Exp Immunol 1999;115:377–82. Chan SC, Brown MA, Willcox TM et al. Abnormal IL-4 gene expression by atopic dermatitis T lymphocytes is reflected in altered nuclear protein interactions with IL-4 transcriptional regulatory element. J Invest Dermatol 1996;106:1131–6. Koning H, Neijens HJ, Baert MR et al. T cell subsets and cytokines in allergic and non-allergic children. II. Analysis of IL-5 and IL-10 mRNA expression and protein production. Cytokine 1997;9:427–36. Hamid Q, Naseer T, Minshall EM et al. In vivo expression of IL-12 and IL-13 in atopic dermatitis. J Allergy Clin Immunol 1996;98:225–31. Zhang Q, Mousdicas N, Yi Q et al. Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity reactions via the plateletactivating factor receptor. J Clin Invest 2005;115(10):2855–61. Jujo K, Renz H, Abe J et al. Decreased gamma interferon and increased interleukin-4 production promote IgE synthesis in atopic dermatitis. J Allergy Clin Immunol 1992;90:323–30. O’Garra A, Warren DJ, Holman M et al. Interleukin 4 (B-cell growth factor II/eosinophil differentiation factor) is a mitogen and differentiation factor for preactivated murine B lymphocytes. Proc Natl Acad Sci USA 1986;83:5228–32. Delespesse G, Sarfatti M, Peleman R. Influence of recombinant IL-4, IFN-alpha, and IFN-gamma on the production of human IgE-binding factor (soluble CD23). J Immunol 1989;142:134–8. Bieber T, de la Salle H, Wollenberg A et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc?RI). J Exp Med 1992;175:1285–90. Vercelli D, Jabara HH, Lauener RP et al. IL-4 inhibits the synthesis of IFN-? and induces the synthesis of IgE in human mixed lymphocyte cultures. J Immunol 1990;144:570–3. Chan SC, Kim JW, Henderson WR et al. Altered prostaglandin E2 regulation of cytokine production in atopic dermatitis. J Immunol 1993;151:3345–52. Ohman JD, Hanifin JM, Nickoloff BJ et al. Overexpression of IL-10 in atopic dermatitis: contrasting cytokine patterns with delayed-type hypersensitivity reactions. J Immunol 1995;154:1956–63. Lacy K, Archer C, Wood K et al. Association between a common IL10 distal promoter haplotype and IgE production in individuals with atopic dermatitis. Int J Immunogenet 2009;36:213–16. Von Bubnoff D, Geiger E, Bieber T. Antigen-presenting cells in allergy. J Allergy Clin Immunol 2001;108:329–39. Wollenberg A, Sharma S, von Bubnoff D et al. Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2001;107:519–25. Panhans-Gross A, Novak N, Kraft S et al. Human epidermal Langerhans cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001;107:345–52. Gutzmer R, Langer K, Lisewski M et al. Expression and function of histamine receptors 1 and 2 on human monocyte-derived dendritic cells. J Allergy Clin Immunol 2002;109:524–31. Hamid Q, Boguniewicz M, Leung DYM. Differential in situ cytokine gene expression in acute vs. chronic atopic dermatitis. J Clin Invest 1994;94:870–6. Leiferman KM, Ackerman SJ, Sampson HA et al. Dermal deposition of eosinophil granule major basic protein in atopic dermatitis: comparison with onchocerciasis. N Engl J Med 1985;313:282–5.

24 Taha RA, Minshall EM, Leung DY et al. Evidence for increased expression of eotaxin and monocyte chemotactic protein-4 in atopic dermatitis. J Allergy Clin Immunol 2000;105:1002–7. 25 Yawalkar N, Uguccioni M, Scharer J et al. Enhanced expression of eotaxin and CCR3 in atopic dermatitis. J Invest Dermatol 1999;113:43–8. 26 Reich K, Hugo S, Middel P et al. Evidence for a role of Langerhans cell-derived IL-16 in atopic dermatitis. J Allergy Clin Immunol 2002;109:681–7. 27 Colver GB, Symons JA, Duff GW. Soluble IL-2 receptor in atopic eczema. BMJ 1989;298:1426–8. 28 Nickoloff BJ, Naidu Y. Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin. J Am Acad Dermatol 1994;30:535–46. 29 Giustizieri ML, Mascia F, Frezzolini A et al. Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T-cell-derived cytokines. J Allergy Clin Immunol 2001;107:871–7. 30 Soumelis V, Reche PA, Kanzler H et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nature Immunol 2002;3:673–80. 31 Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic dermatitis. J Clin Invest 1994;94:870–6. 32 Akdis CA, Akdis M, Simon D et al. T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis. J Invest Dermatol 1999;113:628–34. 33 Verhagen J, Akdis M, Kleemann D et al. Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol 2006;117:176–83. 34 Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol 2009;129:320–2. 35 Ogg G. Role of T cells in the pathogenesis of atopic dermatitis. Clin Exp Allergy 2009;39:310–16. 36 Howell MD, Kim BE, Gao P et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2009;124:R7–R12. 37 Jung T, Stingl G. Atopic dermatitis: therapeutic concepts evolving from new pathophysiologic insights. J Allergy Clin Immunol 2008;122:1074–81. 38 Oyoshi MK, He R, Kumar L et al. Cellular and molecular mechanisms in atopic dermatitis. Adv Immunol 2009;102:135–226.

Cell regulatory abnormalities in atopic dermatitis It has long been understood that cyclic nucleotides play an important role in cell regulation and that cyclic adenosine monophosphate (cAMP) is a modulator of inflammation and immune responses [1,2]. The subject of cyclic nucleotide metabolism in atopic dermatitis has been extensively reviewed [2,3]. Other cell regulatory mechanisms include the calcium–calmodulin system [4,5] and the phosphoinositide system [6,7].

Cyclic nucleotide cell signalling Peripheral blood mononuclear leucocytes have frequently been studied, partly for convenience, but the relevance of these bone marrow-derived cells to the pathogenesis of atopic dermatitis has been emphasized by the findings

Immunopharmacological Mechanisms in Atopic Dermatitis

that bone marrow transplantation for other indications can either confer a state of atopy [8,9] or induce clearance of atopic dermatitis in patients with immunodeficiency disorders who are followed for up to 5 years [10]. Generally, cAMP inhibits cellular activation, for example mast cell secretion, so that impaired cAMP production might lead to increased activation of a number of cell types. Peripheral blood leucocytes can be stimulated by zymosan granules to release lysosomal enzymes, a process that can be inhibited by both β-adrenoceptor agonists and prostaglandins of the E series. Leucocytes from patients with atopic dermatitis have shown impaired βadrenoceptor effects on secretory responses and on cAMP responses [11], a reduced affinity of β-adrenoceptor binding sites [12] and an increased ratio of α- to β2adrenoceptor binding sites [13]. Differences between cells from patients with atopic dermatitis and those from normal subjects have commonly been observed, although others have failed to confirm abnormal β-adrenoceptor numbers on peripheral blood leucocytes [14,15]. Using a different approach, Carr et al. [16] demonstrated impaired inhibition of DNA synthesis in response to β-adrenoceptor agonists in cultured epidermis from the skin of patients with atopic dermatitis. In some studies, normal reactivity to prostaglandin E1 in leucocytes has accompanied reduced reactivity to βadrenoceptor stimulation [11]. However, the selectivity of this impaired reactivity can be disputed as it has been independently reported that in atopic dermatitis cAMP responses of mononuclear leucocytes are reduced not only to β-adrenoceptor stimulants, but also to histamine [17] and to prostaglandin E1 [18]. In one series of experiments, Archer et al. [19] found that mononuclear leucocytes from patients with atopic dermatitis exhibited impaired cAMP responses to prostaglandin E2 and histamine, as well as to isoprenaline, implying that impaired reactivity is not confined to the β-adrenoceptor, as suggested by Szentivanyi [20], but lies at a site common to all three agonists. In the same study, differences between cells from atopic and control groups were exaggerated by the omission of a potent phosphodiesterase inhibitor, providing indirect evidence consistent with the suggestion that non-selective impairment of responses may be secondary to increased cAMP phosphodiesterase activity observed in mononuclear leucocytes in atopic dermatitis [21] (Fig. 25.1). By studying atopic dermatitis, it is possible to select patients with no previous history of asthma or, at least, no previous history of adrenergic medication, so that drug-induced desensitization can be discounted as an explanation for altered β-adrenoceptor responses. In addition, non-selective impairment of mononuclear leucocyte cAMP responses in atopic dermatitis would not be explained either by the presence of a circulating β-

25.7

Fig. 25.1 Proposed cyclic nucleotide abnormalities in atopic dermatitis. Altered responses associated with decreased β-adrenoceptor and increased α-adrenoceptor numbers and increased cAMP phosphodiesterase activity would result in impaired cAMP responses and unimpaired cellular activation (for example, increased mast cell secretion). Adrenoceptor interconversion with decreased β-adrenoceptor responsiveness linked to increased α-adrenoceptor responsiveness is no longer advocated.

adrenoceptor antibody [22] or by a reversal of the α- to β-adrenoceptor ratio on mononuclear leucocytes. Adrenoceptor interconversion with decreased β-adrenoceptor responsiveness linked to increased α-adrenoceptor responsiveness is no longer advocated. Increased mononuclear leucocyte cAMP phosphodiesterase activity in atopic dermatitis may, in part, be due to in vivo desensitization owing to chronic exposure to circulating histamine and other mediators [23,24]. Mononuclear leucocyte adrenoceptor function will also partly depend on circulating adrenaline (epinephrine) levels, but there is no evidence for desensitization at the level of the adrenal medulla in atopic dermatitis, as adrenaline responses to intravenous histamine infusions are not significantly different from normal responses [25]. Some of the studies on impure mononuclear leucocyte populations have been repeated following isolation of

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monocytes and lymphocytes, and elevated phosphodiesterase activity has been reported to reside predominantly in the monocyte fraction [26], although Cooper et al. [27], in studies carried out in the same laboratory, also demonstrated elevated phosphodiesterase activity in the lymphocyte fraction. Whether elevated mononuclear leucocyte phosphodiesterase activity in atopic dermatitis is a primary or secondary event is debatable, but elevated levels in the cord blood of neonates from atopic parents [28] does not seem to be a sufficiently specific finding for this biochemical abnormality to be considered a genetic marker for atopy. However, increased phosphodiesterase activity could underlie defective immune regulation in atopic dermatitis, as increased synthesis of IgE and increased histamine release by atopic leucocytes (presumably basophils) in culture have been shown to correlate with elevated phosphodiesterase activity in the same cells [29,30]. Cooper et al. [29] further demonstrated that a phosphodiesterase inhibitor significantly reduced both the increased cAMP phosphodiesterase activity and the raised spontaneous IgE synthesis in vitro of mononuclear leucocytes from patients with atopic dermatitis. It has been suggested that altered cyclic nucleotide metabolism in T helper lymphocytes in atopic dermatitis could result in abnormalities of T-cell immunoregulation [31]. Alternatively, impaired monocyte control of T-lymphocyte activation might be a consequence of abnormal monocyte cyclic nucleotide metabolism. There are, in fact, many cyclic AMP-phosphodiesterase isoforms, phosphodiesterase 4 being the predominant enzyme in a variety of inflammatory cells including eosinophils, neutrophils, monocytes and T cells [32]. Intracellular cAMP levels have been shown to regulate house dust mite-induced IL-13 production by T-cells from mite-sensitive patients with atopic dermatitis, this role being blocked in vitro by the phosphodiesterase 4 inhibitor rolipram [33]. The increased production of IgE by B-lymphocytes in atopic dermatitis can be corrected in vitro by exposure of cells to the cAMP phosphodiesterase inhibitor Ro 20-1724 [29]. As discussed above, B-cell IgE synthesis is also regulated by cytokines, increased IL-4 from T-cells in atopic dermatitis being associated with increased synthesis of IgE and decreased production of IFN-γ [34,35]. Evidence for interaction between the cyclic nucleotide cell regulatory system and cytokine-mediated immune dysregulation in atopic dermatitis has been put forward by Chan et al. [36]. Increased IL-4 production was demonstrated in 24-h cultures of mononuclear leucocytes and purified T-cells from patients with atopic dermatitis, there being a strong correlation between phosphodiesterase activity and IL-4 production in the atopic mononuclear leucocyte fraction. IL-4 production in mononuclear leucocytes from

patients with atopic dermatitis but not from normal subjects could be reduced by the phosphodiesterase inhibitor Ro 20-1724, this inhibitory effect acting primarily on the monocyte fraction and correlating with increased levels of cAMP. This mechanism, and the apparent increased sensitivity of the phosphodiesterase isoform in atopic dermatitis [36,37], may prove useful in the development of future drug therapy for atopic dermatitis.

Other cell regulatory mechanisms With regard to the calcium–calmodulin [4,5] and phosphoinositide [6,7] cell regulatory systems, there have been relatively few published studies in atopic dermatitis. The second messengers of the phosphoinositide system, diacylglycerol and inositol 1,4,5-triphosphate, are responsible for the activation of protein kinase C and mobilization of calcium ions respectively. There is some evidence of aberrant protein kinase A and protein kinase C activity in the mononuclear leucocytes of patients with atopic dermatitis [38]. In addition, there is likely to be some degree of interaction between the phosphoinositide and cyclic nucleotide cell regulatory systems. Mallett et al. showed increased mononuclear leucocyte membranebound phospholipase C activity in atopic dermatitis compared with healthy controls, suggesting that the phospholipase C enzyme of atopic patients was more sensitive to substrate-driven activity than in non-atopic subjects [39]. References 1 Bourne HR, Lichtenstein LM, Melmon KL et al. Modulation of inflammation and immunity by cyclic AMP. Receptors for vasoactive hormones and mediators of inflammation regulate many leukocyte functions. Science 1974;184:19–28. 2 Archer CB. Adrenoceptor function in atopic dermatitis. London: MD thesis, 1986. 3 Archer CB. Cyclic nucleotide metabolism in atopic dermatitis. Clin Exp Dermatol 1987;12:424–31. 4 Tomlinson S, MacNeil S, Walker SW et al. Calmodulin and cell function. Clin Sci 1984;66:497–508. 5 Rassmussen H, Goodman DBP. Relationship between calcium and cyclic nucleotides in cell activation. Physiol Rev 1977;57:421–509. 6 Berridge MJ. Inositol triphosphate and diacylglycerol as second messengers. Biochem J 1984;220:345–60. 7 Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 1984;308:693–7. 8 Saarinen UM. Transfer of latent atopy by bone marrow transplantation? A case report. J Allergy Clin Immunol 1984;74:196–200. 9 Tucker J, Barnetson R, Eden OB. Atopy after bone marrow transplantation. BMJ 1985;290:116–17. 10 Saurat JH. Eczema in primary immune deficiencies. Clue to the pathogenesis of atopic dermatitis with special reference to the Wiskott–Aldrich syndrome. Acta Dermatol Venereol (Stockh) 1985;114(suppl):125–8. 11 Reed CE, Busse WW, Lee TP. Adrenergic mechanisms and the adenyl cyclase system in atopic dermatitis. J Invest Dermatol 1976;67:333–8. 12 Pochet R, Delespesse G, Demaubeuge J. Characterization of betaadrenoceptors on intact circulating lymphocytes from patients with atopic dermatitis. Acta Dermatol Venereol (Stockh) 1980;92:26–9.

Immunopharmacological Mechanisms in Atopic Dermatitis 13 Szentivanyi A, Heim O, Schultze P et al. Adrenoceptor binding studies with 3H (dihydroalprenolol) and 3H (dihydroergocryptine) on membranes of lymphocytes from patients with atopic disease. Acta Dermatol Venereol (Stockh) 1980;92:19–21. 14 Galant SP, Underwood S, Allred S et al. Beta-adrenergic receptor binding on polymorphonuclear leukocytes in atopic dermatitis. J Invest Dermatol 1979;72:330–2. 15 Ruoho AE, DeClerque JL, Busse WW. Characterization of granulocyte beta-adrenergic receptors in atopic eczema. J Allergy Clin Immunol 1980;66:46–51. 16 Carr RH, Busse WW, Reed CE. Failure of catecholamines to inhibit epidermal reactions in vitro. J Allergy Clin Immunol 1973;55:255–62. 17 Busse WW, Lantis SDH. Impaired H2 histamine granulocyte release in active atopic eczema. J Invest Dermatol 1979;73:184–7. 18 Parker CW, Kennedy S, Eisen AZ. Leukocyte and lymphocyte cyclic AMP responses in atopic eczema. J Invest Dermatol 1977;68:302–6. 19 Archer CB, Morley J, MacDonald DM. Impaired lymphocyte cyclic adenosine monophosphate responses in atopic eczema. Br J Dermatol 1983;109:559–64. 20 Szentivanyi A. The beta adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203–32. 21 Grewe SR, Chan SC, Hanifin JM. Elevated leukocyte cyclic AMPphosphodiesterase in atopic disease: a possible mechanism of cyclic AMP agonist hyporesponsiveness. J Allergy Clin Immunol 1982;70:452–7. 22 Venter JC, Fraser CM, Harrison IC. Autoantibodies to beta-2-adrenergic receptors: a possible cause of hyporesponsiveness in allergic rhinitis and asthma. Science 1980;207:1361–3. 23 Safko MJ, Chan SC, Cooper KD et al. Heterologous desensitization of leukocytes: a possible mechanism of beta-adrenergic blockade in atopic dermatitis. J Allergy Clin Immunol 1981;68:218–25. 24 Chan SC, Grewe SR, Stevens SR et al. Functional desensitization due to stimulation of cyclic AMP-phosphodiesterase in human mononuclear leukocytes. J Cycl Nucl Res 1982;8:211–24. 25 Archer CB, Dalton N, Turner C et al. Investigation of adrenomedullary function in atopic dermatitis. Br J Dermatol 1987;116:793–800. 26 Holden CA, Chan SC, Hanifin JM. Monocyte localization of elevated cAMP phosphodiesterase activity in atopic dermatitis. J Invest Dermatol 1986;87:372–6. 27 Cooper KD, Chan SC, Hanifin JM. Lymphocyte and monocyte localization of altered adrenergic receptors, cAMP responses, and cAMP phosphodiesterase in atopic dermatitis. A possible mechanism for abnormal radiosensitive helper T-cells in atopic dermatitis. Acta Dermatol Venereol (Stockh) 1985;114(suppl):41–7. 28 Heskel NS, Chan SC, Thiel ML et al. Elevated umbilical cord blood leukocyte cyclic adenosine monophosphate–phosphodiesterase activity in children with atopic parents. J Am Acad Dermatol 1984;11:422–6. 29 Cooper KD, Kang K, Chan SC et al. Phosphodiesterase inhibition by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis cells in vitro. J Invest Dermatol 1985;84:477–82. 30 Butler JM, Chan SC, Stevens SR et al. Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol 1983;71:490–7. 31 Cooper KD, Kazmierowski JA, Wuepper KD et al. Immunoregulation in atopic dermatitis: functional analysis of T–B cell interactions and the enumeration of Fc receptor bearing T cells. J Invest Dermatol 1983;80:139–45. 32 Baumer W, Hoppmann J, Rundfeldt C et al. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets 2007;6:17–26. 33 Kanda N, Watanabe S. Intracellular 3’,5’-adenosine cyclic monophosphate level regulates house dust mite-induced interleukin-13 produc-

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tion by T cells from mite-sensitive patients with atopic dermatitis. J Invest Dermatol 2001;116:3–11. Trask DM, Chan SC, Hirshman CA et al. Effect of histamine on phosphorylation by protein kinases A and C in normal and atopic leukocytes. J Invest Dermatol 1985;84:330. Delespesse G, Sarfatti M, Peleman R. Influence of recombinant IL-4, IFN-alpha, and IFN-gamma on the production of human IgE-binding factor (soluble CD23). J Immunol 1989;142:134–8. Chan SC, Li S-H, Hanifin JM. Increased interleukin-4 production by atopic mononuclear leukocytes correlates with increased cyclic adenosine monophosphate-phosphodiesterase activity and is reversible by phosphodiesterase inhibition. J Invest Dermatol 1993;100:681–4. Delprete G, Maggi E, Parronchi P et al. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol 1988;140:4193–8. Chan SC, Hanifin JM. Differential inhibitor effects on phosphodiesterase isoforms in atopic and normal leukocytes. J Lab Clin Med 1993;121:44–51. Mallett RB, Myint S, Holden CA. Measurement of phosphoinositidespecific phospholipase C activity in mononuclear leucocytes from atopic and normal subjects. Br J Dermatol 1992;127:97–102.

Therapeutic implications and advances Future therapeutic measures for atopic dermatitis might include those based on better pharmacological understanding of the disease.

Drugs acting on inflammatory mediators With regard to histamine metabolism, pharmacological intervention is possible at various levels, including inhibition of histamine synthesis, blockade of histamine release at different steps of the release reaction and use of specific receptor antagonists. The efficacy of the low- or non-sedating antihistamines astemizole and terfenadine in atopic dermatitis is disputed [1], and the sedating effect of the earlier antihistamines seems clinically beneficial. It would also seem worthwhile exploring the possibility of using H3-receptor agonists to inhibit histamine synthesis and release in atopic dermatitis and other disorders such as urticaria [2]. More recently, the non-sedating secondgeneration antihistamine fexofenadine was shown to reduce plasma tryptase but not histamine levels in patients with atopic dermatitis [3] although serum tryptase does not seem to be a useful marker for disease severity in atopic dermatitis [4]. Potentially useful pharmacological approaches regarding altered eicosanoid metabolism in atopic dermatitis are numerous (for a review, see reference [5]). A diet enriched in fish oil (containing eicosapentaenoic acid), which is produced at an early stage of the arachidonic acid pathway, or evening primrose oil (containing linoleic and γ-linolenic acids) may, in theory, be of some value as adjuvant therapy in atopic dermatitis [6–8] although

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double-blind studies have demonstrated lack of effect with evening primrose oil [9] or eicosapentaenoic acid [10] in atopic dermatitis. More selective inhibition of phospholipase A2 (than occurs with glucocorticoids) may be of considerable value in inflammatory skin diseases. Clinical studies of dual inhibitors of 5-lipoxygenase and cyclo-oxygenase would be of interest. An alternative approach would be to take advantage of the anti-inflammatory [11] and tissue-protective effects in skin, gastrointestinal tract and other organs of prostaglandin E2 [12]. As in the treatment of gastric ulcers with prostanoids, the use of stable prostaglandin analogues may prove to be rewarding in inflammatory skin diseases. Endogenous aliamides have a number of antiinflammatory effects, including downregulation of mast cell reactivity through vanilloid (VR1) receptors, and a preliminary study has demonstrated improvement of mild atopic dermatitis using topical adelmidrol 2% emulsion, a novel aliamide [13].

Drugs acting on cyclic nucleotide cell signalling Following the demonstration that patients with atopic dermatitis can respond normally to the anti-inflammatory effects of intradermal salbutamol [14], a comparison of the effects of topically and orally administered salbutamol in atopic dermatitis was performed [15]. Treatment of atopic dermatitis with salbutamol ointment (1% salbutamol base in white soft paraffin) twice daily for 2 weeks resulted in a decreased clinical score for redness, but no marked clinical improvement was observed following either topical or oral therapy. Although salbutamol itself would not appear to be clinically useful in the treatment of atopic dermatitis, it would be of interest to carry out clinical studies using other β2-adrenoceptor agonists with improved skin penetration. There is some evidence that a topical phosphodiesterase inhibitor is beneficial in atopic dermatitis [16,17] and that, in vitro, mononuclear leucocyte phosphodiesterase activity is more sensitive to the effects of phosphodiesterase inhibitors in atopic patients than in normal subjects [18]. Theophylline, given in therapeutic doses in asthma, has not been useful in the treatment of atopic dermatitis [17] However, in asthma, it seems that theophylline is unlikely to act as a phosphodiesterase inhibitor in therapeutic doses [19]. Phosphodiesterase 4 inhibitors have broad antiinflammatory and immunomodulatory actions, raising the possibility of their development for the treatment of atopic dermatitis. Early clinical trials with both topically and systemically active phosphodiesterase 4 inhibitors were reported to demonstrate efficacy in atopic dermatitis and the results of confirmatory studies are awaited [20].

Drugs acting on epidermal barrier dysfunction It is clear that in atopic dermatitis, xerosis and permeability epidermal barrier abnormalities play an important role in driving disease activity [21]. In patients with atopic dermatitis, barrier function in both involved and clinically uninvolved skin is impaired [22], with the degree of impairment being correlated with a reduction in the stratum corneum ceramide fraction [23]. Elias & Seinhoff have suggested an ‘outside-inside-outside’ model of atopic dermatitis pathogenesis, whereby inflammation in atopic dermatitis results firstly from inherited and acquired insults that converge to alter epidermal structure and function, followed by activation of the immune system, which in turn has negative consequences for epidermal barrier function [24]. Changes in groups of genes encoding structural proteins, epidermal proteases and protease inhibitors predispose to epidermal barrier dysfunction and increase the risk of developing atopic dermatitis [25]. Loss-of-function mutations within the FLG gene encoding the structural protein filaggrin represent the most significant genetic factor predisposing to atopic dermatitis identified so far, as reviewed by O’Regan et al. [26]. Increased stratum corneum serine protease activity has been shown in acute eczematous skin in atopic dermatitis [27]. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to further breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier dysfunction due to the elevation of the pH of the stratum corneum. A sustained increase in pH enhances the activity of the lipid synthesis enzymes [25]. Emollients do not usually correct the underlying stratum corneum lipid abnormality, but preliminary studies showed that ceramide-dominant barrier repair lipids improve atopic dermatitis in children [28]. Topical synthetic ceramides, referred to as pseudo-ceramides, have been used to improve barrier function in atopic dermatitis [29], and maintenance of an acidic stratum corneum prevents emergence of murine atopic dermatitis [30].

Drugs acting on antimicrobial peptides Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins protect the skin both by direct antimicrobial activity and by initiation of the adaptive immune response, and cathelicidins have been reported to be suppressed in atopic dermatitis [31]. Impaired production of endogenous AMPs was observed in the epidermis in atopic dermatitis, and Th2 cytokines inhibit the expression of human β-defensin 2, one of the antimicro-

Immunopharmacological Mechanisms in Atopic Dermatitis

bial peptides deficient in atopic skin [32]. Correction of AMP abnormalities seemed to offer a potential approach to the treatment of Staphylococcus aureus colonization and infection in atopic dermatitis but recent findings have been conflicting. By measuring the cathelicidin protein hCAP18/LL-37 in non-lesional skin, Mallbris et al. [33] showed no difference between atopic dermatitis, psoriasis and healthy subjects, indicating that there is no constitutive defect in the production of hCAP18 in patients with atopic dermatitis. In atopic dermatitis lesions, however, the expression of hCAP18 mRNA was suppressed following wounding, suggesting that injury from scratching is likely to affect antimicrobial protection and tissue repair in atopic dermatitis [33]. Conversely, Asano and colleagues [34] showed that β-defensin-2 is, in fact, more than adequately induced in response to bacteria, injury or inflammatory stimuli in the stratum corneum of patients with atopic dermatitis, suggesting that impairment of this mechanism is not associated with vulnerability to Staphylococcus aureus infection. Others have reported that patients with atopic dermatitis have enhanced expression of LL-37 in lesional compared with non-lesional skin, suggesting a role of LL-37 in the process of re-epithelialization [35].

Drugs acting on immunological mechanisms: topical calcineurin inhibitors Following the use of systemic immunosuppressive drugs in severe atopic dermatitis, the development of a new

25.11

class of topical non-steroidal anti-inflammatory agents, the topical calcineurin inhibitors, represented a significant advance in the management of atopic dermatitis. However, the potential side-effects of appropriate topical corticosteroids, currently the mainstay of treatment (along with emollients, sedative antihistamines and antibiotics when required), should not be exaggerated [36]. The calcineurin inhibitors tacrolimus and pimecrolimus have a similar mode of action and penetrate the T-cell membrane and bind to endogenous cytoplasmic receptors, immunophilins (Fig. 25.2). Tacrolimus binds to the 12 kDa macrophilin (macrophilin-12) and inhibits the actions of a number of important cells involved in the pathogenesis of atopic dermatitis, including T-cells, dendritic cells, mast cells and keratinocytes [37,38]. The ascomycin macro-lactam pimecrolimus inhibits Th1 and Th2 cytokine production and mediator release from mast cells and basophils [39]. Multicentre, blinded, vehicle-controlled phase III trials with tacrolimus ointment (0.03% and 0.1%) showed tacrolimus to be effective for adults and children with moderate to severe disease [40–42]. Multicentre, blinded, vehicle-controlled studies showed pimecrolimus cream 1% to be effective in adults and children with mild to moderate disease [43]. As a maintenance therapy, topical pimecrolimus cream 1% decreased the number of flares of atopic dermatitis and reduced requirements for corticosteroid therapy [44]. Both topical preparations appear to be safe, and the most common side-effects with each

Fig. 25.2 Mode of action of the calcineurin inhibitors tacrolimus and pimecrolimus. Normally, T-cells are activated after antigen presentation through a cytoplasmic process involving the calcineurin-mediated dephosphorylation of the cytoplasmic subunit of the nuclear factor of activated T-cells (NF-ATc). NF-ATc enters the nucleus and binds to its nuclear subunit (NF-ATn), and the resulting complex promotes cytokine gene transcription. Tacrolimus and pimecrolimus bind to macrophilin-12 and this complex binds to and competitively inhibits calcineurin.

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are sensations of burning and itching. From comparison studies with other recognized treatments for atopic dermatitis, it seems that tacrolimus ointment 0.03% and 0.01% is as effective as mild (hydrocortisone acetate) and potent (hydrocortisone butyrate) topical corticosteroids, respectively, without causing atrophy of the skin [45,46]. The role of topical calcineurin inhibitors in the treatment of atopic dermatitis has been reviewed elsewhere [47–49] and pimecrolimus cream 1% has been reported to effectively control eczema and itching in children with facial dermatitis intolerant of or dependent on topical corticosteroids [50]. In addition, different effects of pimecrolimus and betametasone on the skin barrier have been shown in patients with atopic dermatitis [51]. References 1 Ring J, Przybilla B, Eberlein B. Ultraviolet A inhibits histamine release from human peripheral leukocytes. Int Arch Allergy Appl Immunol 1989;88:136–8. 2 Archer CB, Greaves MW. H3 receptors and regulation of histamine turnover in skin:a new approach. Skin Pharmacol 1993;6:81–4. 3 Kawakami T, Kaminishi K, Soma Y et al. Oral antihistamine therapy influences plasma tryptase levels in adult atopic dermatitis. J Dermatol Sci 2006;43:127–34. 4 Gerdes S, Kurrat W, Mrowietz U. Serum mast cell tryptase is not a useful marker for disease severity in psoriasis or atopic dermatitis. Br J Dermatol 2009;160:736–40. 5 Ruzicka T, Ring J. Role of inflammatory mediators in atopic eczema. In: Ruzicka T, Ring J, Przybilla B (eds) Handbook of Atopic Eczema. Berlin: Springer-Verlag, 1991: 245–55. 6 Wright S, Burton JL. Oral evening primrose seed oil improves atopic eczema. Lancet 1982;88:524. 7 Bjorneboe A, Soyland E, Bjorneboe G-EA et al. Effect of dietary supplementation with eicosapentaenoic acid in the treatment of atopic dermatitis. Br J Dermatol 1987;117:463–9. 8 Morse PF, Horrobin DF, Manku MS et al. Meta-analysis of placebocontrolled studies of the efficacy of Epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acid changes and clinical response. Br J Dermatol 1989;121:75–90. 9 Bamford ITM, Gibson RW, Renier CM. Atopic eczema unresponsive to evening primrose oil (linoleic acid and gamma linolenic acids). J Am Acad Dermatol 1985;13:959–66. 10 Kunz B, Ring J, Braun-Falco O. Eicosapentaenoic acid (EPA) treatment in atopic eczema (AE): a prospective double-blind trial. J Allergy Clin Immunol 1989;83:196. 11 Bonta IL, Parnham MJ. Prostaglandins and chronic inflammation. Biochem Pharmacol 1978;27:1611–23. 12 Ruzicka T. The physiology and pathophysiology of eicosanoids in the skin. Eicosanoids 1988;1:59–72. 13 Pulvirenti N, Nasca MR, Micali G. Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects:a pilot study. Acta Dermatovenerol Croat 2007;15:80–3. 14 Archer CB, Paul W, Morley J et al. Actions of locally administered adrenoceptor agonists on histamine induced cutaneous responses in atopic eczema. Clin Exp Dermatol 1984;9:358–63. 15 Archer CB, MacDonald DM. Treatment of atopic dermatitis with salbutamol. Clin Exp Dermatol 1987;12:323–5. 16 Kaplan RJ, Daman L, Rosenberg EW et al. Topical use of caffeine with hydrocortisone in the treatment of atopic dermatitis. Arch Dermatol 1978;114:60–2.

17 Hanifin JM. Atopic dermatitis. J Am Acad Dermatol 1982;6:1–13. 18 Giustina TA, Chan SC, Thiel ML et al. Increased leukocyte sensitivity to phosphodiesterase inhibitors in atopic dermatitis: tachiphylaxis after theophylline therapy. J Clin Allergy Immunol 1984;74:252–7. 19 Bergstrand H. Phosphodiesterase inhibition and theophylline. Eur J Respir Dis 1980;61(suppl 109):37–44. 20 Baumer W, Hoppmann J, Rundfeldt C et al. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets 2007;6:17–26. 21 Elias PM, Wood LC, Feingold KR. Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermatol 1999;10:119–26. 22 Seidenari S, Giusti G. Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance, and TEWL in eczematous and clinically uninvolved skin. Acta Dermatol Venereol (Stockh) 1995;75:429–33. 23 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;96:523–6. 24 Elias PM, Steinhoff M. ‘Outside-to-inside’ (and now back to ‘outside’) pathogenic mechanisms in atopic dermatitis. J Invest Dermatol 2008;128:1067–70. 25 Cork MJ, Danby SG, Vasilopoulos Y et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 2009;129:1892–908. 26 O’Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol 2009;124(3S2):R2– R6. 27 Voegeli R, Rawlings AV, Breternitz M et al. Increased stratum corneum serine protease activity in acute eczematous atopic skin. Br J Dermatol 2009;161:70–7. 28 Chamlin S, Frieden IJ, Fowler A et al. Ceramide-dominant, barrierrepair lipids improve childhood atopic dermatitis. Arch Dermatol 2001;137:1110–12. 29 Uchida Y, Holleran WM, Elias PM. On the effects of topical synthetic pseudoceramides: comparison of possible keratinocyte toxicities provoked by the pseudoceramides, PC104 and BIO391, and natural ceramides. J Dermatol Sci 2008;51:37–43. 30 Hatano Y, Man MQ, Uchida Y et al. Maintenance of an acidic stratum corneum prevents emergence of murine atopic dermatitis. J Invest Dermatol 2009;129:1824–35. 31 Schauber J, Gallo RL. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 2009;124(3S2):R13–R18. 32 Ong PY, Ohtake T, Brandt C et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002;347:1151–60. 33 Mallbris L, Carien L, Wei T et al. Injury downregulates the expression of the human cathelicidin protein hCAP18/LL-37 in atopic dermatitis. Exp Dermatol 2009;July 23 (epub ahead of print). 34 Asano S, Ichikawa Y, Kumagai T et al. Microanalysis of an antimicrobial peptide, beta-defensin-2, in the stratum corneum from patients with atopic dermatitis. Br J Dermatol 2008;159:97–104. 35 Ballardini N, Johansson C, Lilja G et al. Enhanced expression of the antimicrobial peptide LL-37 in lesional skin of adults with atopic dermatitis. Br J Dermatol 2009;161:40–7. 36 Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol 2000;142:931–6. 37 Wollenberg A, Sharma S, von Bubnoff D et al. Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2001;107:519–25. 38 Panhans-Gross A, Novak N, Kraft S et al. Human epidermal Langerhans cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001;107:345–52. 39 Zuberbier T, Chong SU, Grunow K et al. The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator

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release from human dermal mast cells and peripheral blood basophils. J Allergy Clin Immunol 2001;108:275–80. Hanifin JM, Ling MR, Langley R et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part 1, efficacy. J Am Acad Dermatol 2001;44:S28–S38. Paller A, Eichenfield LF, Leung DY et al. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001;44:S47–S57. Allen BR. Tacrolimus ointment: its place in the therapy of atopic dermatitis. J Allergy Clin Immunol 2002;109:401–3. Eichenfield LF, Lucky AW, Boguniewicz M et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46:495–504. Kapp A, Papp K, Bingham A et al. Long-term management of atopic dermatitis infants with topical pimecrolimus, a non-steroid antiinflammatory drug. J Allergy Clin Immunol 2002;110:277–84. 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;109:539–46. 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;109:547–55. Alomar A, Berth-Jones J, Bos JD et al. The role of topical calcineurin inhibitors in atopic dermatitis. Br J Dermatol 2004;151(suppl 70):3–27. 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. Williams HC, Grindlay DJ. What’s new in atopic eczema? An analysis of the clinical significance of systematic reviews on atopic eczema published in 2006 and 2007. Clin Exp Dermatol 2008;33:685–8. Hoeger PH, Lee KH, Jautova J et al. The treatment of facial atopic dermatitis in children who are intolerant of, or dependent on, topical

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corticosteroids: a randomized, controlled clinical trial. Br J Dermatol 2009;160:415–22. 51 Jensen JM, Pfeiffer S, Witt M et al. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol 2009;123:1124–33.

Conclusion There are a number of altered in vivo physiological and pharmacological responses in atopic dermatitis, but one should take care not to overinterpret findings that are sometimes non-specific. The relative roles of inflammatory mediators, cytokines and abnormal cell regulatory mechanisms in the pathogenesis of atopic dermatitis have been discussed. Preventive treatment of atopic dermatitis comprises daily emollient therapy. Most patients require treatment with topical corticosteroids and/or topical calcineurin inhibitors, and topical therapies are being developed to improve epidermal barrier dysfunction. There remains a need to develop safer anti-inflammatory medications. There is no shortage of potential targets for drug therapy in atopic dermatitis. As with other complex disorders, drugs with defined but relatively non-selective mechanisms of action (e.g. tacrolimus and pimecrolimus) are proving to be more successful than selective agents, which are nevertheless important, in the context of research, in determining the contribution of a particular immunopharmacological mechanism to the overall disease process.

26.1

C H A P T E R 26

Microbiology in Atopic Eczema Christina Schnopp1 & Martin Mempel2 1

Department of Dermatology and Allergy, Biederstein, Technische Universität München, München, Germany Department of Dermatology, Venereology, and Allergology, Georg-August-Universität Göttingen, Göttingen, Germany

2

Introduction, 26.1

Malassezia species, 26.5

Conclusion, 26.9

Staphylococcus aureus and atopic eczema, 26.1

Introduction The skin in atopic eczema is prone to a particular colonization pattern, with high numbers of Staphylococcus aureus being present and an almost complete displacement of the physiological skin flora. Moreover, patients with atopic eczema often show sensitization to microbial products from bacteria and yeasts. The most important germs in this context are Malassezia species and again Staphylococcus aureus. This chapter will therefore focus on the role of these particular microbes.

Staphylococcus aureus and atopic eczema The high degree of bacterial colonization with Staphylococcus (Staph.) aureus on lesional and non-lesional skin represents a hallmark of atopic eczema (AE). Several studies have determined a colonization rate with Staph. aureus as high as 90% of all analysed patients [1–3]. Besides lesional skin, several reservoirs such as the nares, the axillae and the perianal region have been identified [3]. Moreover, clinically apparently unaffected body areas in patients with AE repeatedly screen positive for Staph. aureus. Even extensive eradication strategies are only transiently successful, with recurrence rates of almost 100% in AE patients [4]. Pathogenic strains seem to persist for a long time and can be re-isolated even months after adequate treatment [5]. In addition, patients can be colonized by several genetically different strains, a phenomenon which has not been studied in detail so far [3].

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

When analysing the role of Staph. aureus in AE, several factors have to be taken into account. First, there seem to be crucial factors for preferential adherence and continuous colonization on atopic skin [6]; second, defence factors are impaired in atopic individuals, including diminished defensin expression and possibly polymorphisms in pattern recognition receptors [7,8]; and third, there is a preferential induction of IgE antibodies against staphylococcal components in atopic patients, leading to aggravation of clinical symptoms [9].

Skin colonization The skin of patients with atopic eczema shows striking differences in colonization frequency as compared to healthy individuals. Whereas normal skin is rarely (2– 25%) colonized with Staph. aureus (with the exception of healthy chronic Staph. aureus carriers in endemic areas), 76–100% of patients with AE are found to be colonized, depending on the study [1,2,10], with some patients carrying up to four different strains [3]. In most studies, colonization with Staph. aureus also correlated with higher disease scores [3,11]. Staphylococcus aureus is usually recovered in densities of 105 colony-forming units (cfu)/cm2 from lesional atopic eczema sites but can reach concentrations of up to 107 cfu/cm2 [12], a density which is 1000 times higher than on non-lesional skin. The exacerbation of Staph. aureus colonization (impetiginized eczema) is a known complication in AE patients but colonization cannot be proportionally correlated to the degree of disease activity, although cut-off levels have been proposed [1].

Mechanisms of adherence The mechanisms by which Staph. aureus gains permanent access to the skin have been partially identified in recent years. The bacteria produce several adhesins, including protein A, clumping factor, coagulase and matrix-binding

26.2

Chapter 26

proteins, among which fibronectin-binding protein seems to be the most important [13,14]. Experiments using knockout mutants for several adhesins have shown that the binding of Staph. aureus to the matrix protein fibronectin via its binding protein enables the bacteria to attach to cultured human keratinocytes [13] and that production of this protein is also required for the colonization of inflamed skin [6,14]. Interestingly, pH values between 7 and 8 are more likely to support this adhesion process, values which are usually found in AE after disruption of the skin barrier [13]. Furthermore, the expression of fibronectin is regulated by IL-4, the crucial Th2-promoting cytokine which is present in higher concentrations in AE patients [15]. Besides fibronectin, fibrinogen, which is bound by the staphylococcal clumping factor and coagulase, plays a major role in the adhesion of bacteria to the keratinocytes. This is of particular importance when large quantities of plasma proteins are produced, such as in weeping eczemas, and in this situation, fibrinogen might function as molecular glue for the bacteria. This is even more relevant as it has recently been demonstrated that sequences within the fibronectin-binding protein of Staph. aureus can react with both fibronectin and fibrinogen [16]. Whether polymorphisms in filaggrin, the strongest genetic association factor for AE [17] and a hallmark protein of epidermal barrier generation, play a role in Staph. aureus adhesion is not clear yet but these mechanisms could be of special interest because of possible differences in the penetration of Staph. aureus compounds into deeper layers of the epidermis. After initial attachment of staphylococci to atopic skin, a stable connection between the host cell and the bacterium is established. Bacteria can adhere via pilus-like extrusions of the keratinocytes or can be embedded into surface grooves of the cells [18]. As Staph. aureus is a very potent stimulator of cellular defence mechanisms and is equipped with numerous hazardous toxins, this adhesion step is soon followed by signs of keratinocyte cell damage or by host cell attempts to inactivate the staphylococci by uptake in endosomal structures [18]. Although the α-haemolysin produced by Staph. aureus seems to be the most effective inducer of keratinocyte cell death by forming pores into the cell membrane [19], cell damage is also seen in the absence of this virulence factor [18]. Besides the haemolysins, a large number of bacterial toxins and/or enzymes have to be considered. Thus, a number of proteases, lipases, nucleases and exfoliative toxins (which act in fact as proteases), as well as the cell wall components protein A, peptidoglycan (PGN) and lipoteichoic acid (LTA), have been described in different models of cellular damage, although their exact role in atopic eczema has not be elucidated in detail so far.

Virulence factors Special attention should be paid to the staphylococcal superantigens. These proteins belong to a very particular group of promitotic and proinflammatory antigens for both human and murine T-cells. Because they bind outside the conventional MHC groove but still cross-link certain MHC II molecules with a panel of defined T-cell receptor β-chains and thereby activate many T-cells in a clonally unrestricted way, they are implicated in a variety of immune processes which take place in the course of AE. First, the T-cells of atopic patients have been shown to express the crucial skin homing receptor CLA after activation by staphylococcal superantigens [20], a process which depends on the production of IL-12. Second, patients with AE tend to develop IgE antibodies against the staphylococcal superantigens, rendering these proteins not only effective toxins but also potent allergens [21–24]. Third, the application of superantigens onto atopic skin itself can induce the clinical symptoms of erythema and induration, two major symptoms of eczema [25,26]. This particular initiation of skin symptoms can also be seen in Balb/c mice after injection of the superantigen SEB [27]. When SEB is applied onto atopic skin using the patch test technique, an infiltration of T-cells with superantigen-susceptible T-cell receptor (TCR) βchains is seen (TCR Vβ 3, 12 and 17). Most of these T-cell Vβ families are also overexpressed in the peripheral blood and lesional skin of atopic eczema [28]. Finally, because they bind to the MHC II molecules on B-cells (which are also potent antigen-presenting cells), the superantigens are capable of directly stimulating B-cells to increase IgE production [29]. Whereas there is little doubt about the immunological mechanisms leading to initiation and aggravation of atopic eczema by staphylococcal superantigens, there is ongoing debate over whether the extent of skin symptoms can be correlated to the presence of superantigenproducing Staph. aureus strains on the skin. Whereas some authors have found an association [22,23,30], we [3] and others [31] failed to establish a correlation. This difference might be in part explained by the different techniques used to determine the degree of superantigen production. Most of the studies used agglutination tests to identify toxin production in vitro. Using PCR analysis in contrast allows not only screening for the recently identified superantigens of the seg-seo genes (which are encoded by the enterotoxin gene cluster (egc)) [32] but also identification of Staph. aureus isolates that have downregulated their superantigen production. As a consequence, in a group of patients more than 70% of the Staph. aureus-colonized individuals harboured a strain positive for at least one superantigen but showed no significant difference in the SCORAD values as compared to patients with superantigen-negative Staph. aureus on their skin.

Microbiology in Atopic Eczema

Independent of their direct immunological effect, superantigens together with additional microbial components serve as strong inducers of IgE antibodies. Some authors even favour the opinion that IgE sensitization to Staph. aureus superantigens is more closely linked to the level of skin symptoms than the positivity of superantigenproducing strains on the skin itself [23]. In this context, it has been suggested that IgE sensitizations to Staph. aureus superantigens and/or fungal proteins predominantly characterizes patients with the so-called ‘intrinsic’ form of atopic eczema [33]. However, these results have not been confirmed in larger groups of adult and paediatric patients in whom instead a clear association with the total IgE level has been established [34,35].

Staph. aureus and skin defence The immunological response of the skin is mainly directed against the staphylococcal cell wall components such as protein A, PGN and LTA but also against toxins such as the haemolysins [36]. These products usually activate the skin cells through recognition by pathogen-associated molecular pattern recognition molecules, of which the family of toll-like receptors (TLRs) probably represents the most important members. It has recently been shown that for the activation of keratinocytes by staphylococci, TLR2 plays the most important role although other members of this family are expressed in human skin [37,38]. It is currently not clear whether polymorphisms in TLRs are associated with atopic eczema or not; the single nucelotide polymorphisms (SNP) identified so far seem especially to account for a differential response of cellular subsets to microbial stimuli, with the 753TLR2 polymorphism being best characterized [8]. After immune recognition of the bacteria, several defence mechanisms are activated, including the production of IL-8 and iNOS as well as antimicrobial peptides such as human β-defensins (HBD) 2 and 3 and LL37 [39– 42]. Most of these defence factors are positively regulated by the Th1 cytokins IL-1β, IFN-γ and TNF-α. It is known, however, that these Th1 cytokines are produced at lower levels in the skin of atopic patients [43]. Consequently, the skin of AE patients produces lower amounts of the antistaphylococcal compounds HBD2, HBD3, LL37, iNOS and IL-8 [44,45], compared to psoriasis. This correlation has been recently established and has been characterized as a major factor of staphylococcal colonization in AE patients. It is not clear at the moment whether there is a constant downregulation of these defensins in atopics or only a defect in the induction when challenged by microbes [46].

26.3

whether a (supplemental) antimicrobial therapy makes sense or not. Several studies have found a beneficial effect of adequate antibiotic treatment on the degree of skin symptoms but there are also good arguments against such a therapeutic intervention. First, the degree of Staph. aureus colonization correlates with the degree of skin inflammation and consequently, the number of bacteria can be reduced by exclusive anti-inflammatory therapy using either corticosteroids [47] or calcineurin inhibitors without additional antimicrobial therapy [48]. Second, even after extensive eradication strategies, recolonization occurs rapidly [4] and pathogenic strains tend to persist for a long period [5] regardless of the therapeutic approaches used. In contrast, strategies to reduce bacterial load using antiseptic measures [49], antibacterial clothes or dressings [50] or antibacterial dyes [51] have proved effective in the management of AE. Systemic antibiotic therapy should, however, be applied in cases of severely oozing eczema (Fig. 26.1), impetigenized eczema, and signs of systemic infections such as fever, chills or raised serum inflammation markers. As resistance patterns strongly vary between different geographic regions, a systemic treatment should be chosen based on the locally observed resistance findings. As for other staphylococcal infections, penicillinase-resistant βlactam antibiotics such as oxacillin and flucloxacillin and the first-generation oral cephalosporins such as cephalexin are good candidates for initial treatments. In cases of MRSA infections, cotrimoxazol and clindamycin often represent suitable alternatives. If the MRSA strains are found to be resistant to both antibiotics, necessary therapeutic interventions should include MRSA standard medications such as vancomycin and linezolid. A targeted topical antibiotic treatment in AE can be indicated in localized nummular eczema which often responds nicely to the combination of anti-inflammatory

Therapeutic strategies Ever since the description of Staph. aureus as an aggravating factor in AE, there has been an ongoing debate as to

Fig. 26.1 Oozing eczema showing large erosive lesions with pustular crusts typically seen in heavily Staph. aureus colonized atopic eczema.

26.4

Chapter 26

and antibacterial therapy. Suitable agents are mupirocin, fusidic acid and retapamulin. While in some countries there is a tendency to reserve mupirocin for eradication strategies in intensive care units and high-risk medical centres, others continue to use mupirocin as routine medication for infected skin disease. Fusidic acid is commonly used for cutaneous Staph. aureus infection but resistance is increasingly induced and in several areas, up to 50% show unresponsiveness [52]. Whether this in vitro resistance is also clinically relevant or whether it can be overcome by increased doses of fusidic acid remains a matter of debate. Retapamulin is a drug recently introduced for the treatment of cutaneous Staph. aureus infection which also shows excellent efficacy against streptococci for which the induction of resistance patterns has not yet been documented [53]. References 1 Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90(5):525–30. 2 Aly R, Maibach HI, Shinefield HR. Microbial flora of atopic dermatitis. Arch Dermatol 1977;113(6):780–2. 3 Mempel M, Lina G, Hojka M et al. High prevalence of superantigens associated with the egc locus in Staphylococcus aureus isolates from patients with atopic eczema. Eur J Clin Microbiol Infect Dis 2003;22(5):306–9. 4 Breuer K, Kapp A, Werfel T. Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol 2002;147(1):55–61. 5 Hoeger PH, Lenz W, Boutonnier A, Fournier JM. Staphylococcal skin colonization in children with atopic dermatitis: prevalence, persistence, and transmission of toxigenic and nontoxigenic strains. J Infect Dis 1992;165(6):1064–8. 6 Cho SH, Strickland I, Tomkinson A, Fehringer AP, Gelfand EW, Leung DY. Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model. J Invest Dermatol 2001;116(5):658–63. 7 Kisich KO, Carspecken CW, Fieve S, Boguniewicz M, Leung DY. Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3. J Allergy Clin Immunol 2008;122(1):62–8. 8 Mrabet-Dahbi S, Dalpke AH, Niebuhr M et al. The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis. J Allergy Clin Immunol 2008; 121(4):1013–19. 9 Bunikowski R, Mielke ME, Skarabis H et al. Evidence for a diseasepromoting effect of Staphylococcus aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol 2000;105(4):814–19. 10 Dahl MV. Staphylococcus aureus and atopic dermatitis. Arch Dermatol 1983;119(10):840–6. 11 Williams RE, Gibson AG, Aitchison TC, Lever R, Mackie RM. Assessment of a contact-plate sampling technique and subsequent quantitative bacterial studies in atopic dermatitis. Br J Dermatol 1990; 123(4):493–501. 12 Leung D. Role of Staphylococcus aureus in atopic dermatitis. In: Bieber TL (ed) Atopic dermatitis, vol. 1. New York: Marcel Dekker, 2002. 13 Mempel M, Schmidt T, Weidinger S et al. Role of Staphylococcus aureus surface-associated proteins in the attachment to cultured HaCaT keratinocytes in a new adhesion assay. J Invest Dermatol 1998;111(3):452–6.

14 Cho SH, Strickland I, Boguniewicz M, Leung DY. Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol 2001;108(2): 269–74. 15 Postlethwaite AE, Holness MA, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest 1992;90(4):1479–85. 16 Wann ER, Gurusiddappa S, Hook M. The fibronectin-binding MSCRAMM FnbpA of Staphylococcus aureus is a bifunctional protein that also binds to fibrinogen. J Biol Chem 2000; 275(18):13863–71. 17 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(4):441–6. 18 Mempel M, Schnopp C, Hojka M et al. Invasion of human keratinocytes by Staphylococcus aureus and intracellular bacterial persistence represent haemolysin-independent virulence mechanisms that are followed by features of necrotic and apoptotic keratinocyte cell death. Br J Dermatol 2002;146(6):943–51. 19 Walev I, Martin E, Jonas D et al. Staphylococcal alpha-toxin kills human keratinocytes by permeabilizing the plasma membrane for monovalent ions. Infect Immun 1993;61(12):4972–9. 20 Leung DY, Gately M, Trumble A, Ferguson-Darnell B, Schlievert PM, Picker LJ. Bacterial superantigens induce T cell expression of the skinselective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production. J Exp Med 1995;181(2):747–53. 21 Leung DY, Harbeck R, Bina P et al. Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens. J Clin Invest 1993; 92(3):1374–80. 22 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(1 Pt 1):119–24. 23 Nomura I, Tanaka K, Tomita H et al. Evaluation of the staphylococcal exotoxins and their specific IgE in childhood atopic dermatitis. J Allergy Clin Immunol 1999;104(2 Pt 1):441–6. 24 Lin YT, Shau WY, Wang LF et al. Comparison of serum specific IgE antibodies to staphylococcal enterotoxins between atopic children with and without atopic dermatitis. Allergy 2000;55(7):641–6. 25 Strange P, Skov L, Lisby S, Nielsen PL, Baadsgaard O. Staphylococcal enterotoxin B applied on intact normal and intact atopic skin induces dermatitis. Arch Dermatol 1996;132(1):27–33. 26 Skov L, Olsen JV, Giorno R, Schlievert PM, Baadsgaard O, Leung DY. Application of Staphylococcal enterotoxin B on normal and atopic skin induces up-regulation of T cells by a superantigen-mediated mechanism. J Allergy Clin Immunol 2000;105(4):820–6. 27 Saloga J, Leung DY, Reardon C, Giorno RC, Born W, Gelfand EW. Cutaneous exposure to the superantigen staphylococcal enterotoxin B elicits a T-cell-dependent inflammatory response. J Invest Dermatol 1996;106(5):982–8. 28 Neuber K, Loliger C, Kohler I, Ring J. Preferential expression of T-cell receptor V beta-chains in atopic eczema. Acta Derm Venereol 1996;76(3):214–18. 29 Hofer MF, Harbeck RJ, Schlievert PM, Leung DY. Staphylococcal toxins augment specific IgE responses by atopic patients exposed to allergen. J Invest Dermatol 1999;112(2):171–6. 30 McFadden JP, Noble WC, Camp RD. Superantigenic exotoxinsecreting potential of staphylococci isolated from atopic eczematous skin. Br J Dermatol 1993;128(6):631–2. 31 Jappe U, Heuck D, Witte W, Gollnick H. Superantigen production by Staphylococcus aureus in atopic dermatitis: no more than a coincidence? J Invest Dermatol 1998;110(5):844–6.

Microbiology in Atopic Eczema 32 Jarraud S, Peyrat MA, Lim A et al. egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureus. J Immunol 2001;166(1):669–77. 33 Novak N, Allam JP, Bieber T. Allergic hyperreactivity to microbial components: a trigger factor of “intrinsic” atopic dermatitis? J Allergy Clin Immunol 2003;112(1):215–16. 34 Reefer AJ, Satinover SM, Wilson BB, Woodfolk JA. The relevance of microbial allergens to the IgE antibody repertoire in atopic and nonatopic eczema. J Allergy Clin Immunol 2007;120(1):156–63. 35 Schnopp C, Grosch J, Ring J, Ollert M, Mempel M. Microbial allergenspecific IgE is not suitable to identify the intrinsic form of atopic eczema in children. J Allergy Clin Immunol 2008;121(1):267–8 e1; author reply 268. 36 Iwatsuki K, Yamasaki O, Morizane S, Oono T. Staphylococcal cutaneous infections: invasion, evasion and aggression. J Dermatol Sci 2006;42(3):203–14. 37 Curry JL, Qin JZ, Bonish B et al. Innate immune-related receptors in normal and psoriatic skin. Arch Pathol Lab Med 2003;127(2):178–86. 38 Kollisch G, Kalali BN, Voelcker V et al. Various members of the Tolllike receptor family contribute to the innate immune response of human epidermal keratinocytes. Immunology 2005;114(4):531–41. 39 Frohm M, Agerberth B, Ahangari G et al. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J Biol Chem 1997; 272(24):15258–63. 40 Harder J, Siebert R, Zhang Y et al. Mapping of the gene encoding human beta-defensin-2 (DEFB2) to chromosome region 8p22-p23.1. Genomics 1997;46(3):472–5. 41 Harder J, Bartels J, Christophers E, Schroder JM. Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 2001;276(8):5707–13. 42 Stolzenberg ED, Anderson GM, Ackermann MR, Whitlock RH, Zasloff M. Epithelial antibiotic induced in states of disease. Proc Natl Acad Sci USA 1997;94(16):8686–90. 43 Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994;94(2):870–6. 44 Ong PY, Ohtake T, Brandt C et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347(15):1151–60. 45 Nomura I, Goleva E, Howell MD et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 2003;171(6):3262–9. 46 Glaser R, Meyer-Hoffert U, Harder J et al. The antimicrobial protein psoriasin (S100A7) is upregulated in atopic dermatitis and after experimental skin barrier disruption. J Invest Dermatol 2009; 129(3):641–9. 47 Stalder JF, Fleury M, Sourisse M, Rostin M, Pheline F, Litoux P. Local steroid therapy and bacterial skin flora in atopic dermatitis. Br J Dermatol 1994;131(4):536–40. 48 Pournaras CC, Lubbe J, Saurat JH. Staphylococcal colonization in atopic dermatitis treatment with topical tacrolimus (Fk506). J Invest Dermatol 2001;116(3):480–1. 49 Wohlrab J, Jost G, Abeck D. Antiseptic efficacy of a low-dosed topical triclosan/chlorhexidine combination therapy in atopic dermatitis. Skin Pharmacol Physiol 2007;20(2):71–6. 50 Gauger A, Mempel M, Schekatz A, Schafer T, Ring J, Abeck D. Silvercoated textiles reduce Staphylococcus aureus colonization in patients with atopic eczema. Dermatology 2003;207(1):15–21. 51 Brockow K, Grabenhorst P, Abeck D et al. Effect of gentian violet, corticosteroid and tar preparations in Staphylococcus-aureus-colonized atopic eczema. Dermatology 1999;199(3):231–6. 52 Mitra A, Mohanraj M, Shah M. High levels of fusidic acid-resistant Staphylococcus aureus despite restrictions on antibiotic use. Clin Exp Dermatol 2009;34(2):136–9.

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53 Yang LP, Keam SJ. Retapamulin: a review of its use in the management of impetigo and other uncomplicated superficial skin infections. Drugs 2008;68(6):855–73.

Malassezia species Malassezia (M.) species, a lipophilic yeast, earlier denoted as Pityrosporum ovale, is part of the commensal microflora of normal skin. Currently, 11 species are recognized (M. dermatitis, M. furfur, M. globosa, M. japonica, M. obtusa, M. restricta, M. sloofiae, M. sympodialis, M. yamamotoensis, M. nana and M. pachydermatis) [1,2]. The first nine colonize human skin with variable frequency, while M. nana and M. pachydermatitis show affinity to animal furs. The head and neck area is 7–12 times more likely to be colonized than other areas of the body as the microorganism depends on lipids for growth [3]. Malassezia colonization takes place immediately after birth and the presence of different M. species and density of colonization vary significantly over the age groups, with the highest rates between 2 and 23 months and after 9 years of age [4,5]. Malassezia species cause pityriasis versicolor and play an important role in seborrhoeic dermatitis, although the exact mechanisms are not fully elucidated. Inflammatory processes due to infection or immunization have been identified as trigger factors in AE.

Malassezia and AE Adult AE patients are equally or less often colonized with Malassezia species than healthy controls, and lesional skin seems to be less affected than non-lesional skin [4,6]. In children, no difference between atopic and healthy children was noted, whereas in children with infantile seborrhoeic dermatitis, cultures for Malassezia were positive in the majority of cases [4]. There are conflicting data on whether the pattern of colonization with different Malassezia species in AE (mostly M. globosa and M. restricta, followed by M. sympodialis and M. furfur) is different from healthy controls and patients with other dermatoses [3,7,8]. The same applies to infections with Candida albicans, which are neither more frequent nor more severe in AE patients. To explain the particular immune response to Malassezia in AE, it has been speculated that alkaline skin pH, reduced endogenous antimicrobials and impaired barrier function in AE impose increased Malassezia antigen load, thus stimulating both innate and adaptive immune responses [9].

Sensitization to Malassezia antigens in AE Malassezia species are capable of inducing specific IgEand T-cell mediated responses in AE patients [10–12]. About 50% of adult AE patients display elevated IgE

26.6

Chapter 26

and/or positive patch test reactions to Malassezia species [13-16]. Patients with sensitization to Malassezia tend to have more severe disease [14,17]. It has been shown very clearly that sensitization to Malassezia is almost completely restricted to AE patients and this phenomenon is not found in healthy controls or patients with other atopic diseases and other skin diseases such as allergic contact dermatitis, tinea versicolor or seborrhoeic eczema [18–20]. In the study by Scalabrin and co-workers, the finding of specific IgE to Malassezia antigens was 132 times more likely in AE patients compared to asthmatics and healthy controls. For atopy patch tests with Malassezia extract or recombinant Malassezia, the correlation to AE is less consistent in different studies (for review, see Darabi 2009 [7]). Interestingly, a recent study did not find a correlation between IgE reactivity and positive atopy patch test results [10] for Malassezia spp. A study from Sweden detected specific IgE to M. sympodialis in 34/64 (53%) adult patients and none of 24 healthy controls. In 19 patients, atopy patch tests with Malassezia antigen elicited positive reactions, five of which with no detectable specific IgE. In contrast, only 61% of patients with elevated specific IgE (cut-off 0.35kU/L) were patch test positive. An elevated IL-5 response to Malassezia extract in peripheral blood mononuclear cells (PBMCs) as analysed by the ELISpot method was restricted to atopy patch test-positive patients, indicating a crucial role for a cellular (Th2 helper cell) allergenspecific immune response [10]. It has been shown before that proliferative responses of PBMCs from sensitized patients are significantly higher than from non-sensitized patients [13,21]. As the cellular infiltrate of atopy patch test reactions with infiltrating lymphocytes and eosinophils mimics the early stages of AE lesions, and is reflected by corresponding activated allergen specific T-cells, the atopy patch test might be more appropriate for predicting relevant reactions. Of note, differences in sensitization rates can be explained by differences in patient characteristics (age, severity, extrinsic or intrinsic type) but also by different antigens to detect specific IgE antibodies. Over time, crude Malassezia extracts, M. furfur antigen (Phadia ImmunoCAP m70), a combination of M. sympodialis, M. globosa and M. restricta (Phadia ImmunoCAP m227) and a variety of recombinant antigens have been used.

Clinical significance of Malassezia sensitization Head and neck type AE It has been suggested that the distribution of skin lesions in different age groups reflects Malassezia colonization rates. The head and neck area, which is heavily colonized with Malassezia due to its higher lipid content, is the area

Fig. 26.2 Head and neck type of atopic eczema preferentially affecting the neck. These patients often show high IgE titres to Malassezia allergens and other microbial compounds.

preferentially affected in postpubertal atopic dermatitis (AD) patients (Fig. 26.2), whereas children before puberty show a different pattern. In infants, eczema of the face and scalp is very common, reflecting the first colonization with Malassezia under the influence of maternal hormones. In adult patients with a head and neck and upper trunk distribution of their eczema, higher rates of sensitization to M. furfur antigens have been found, as demonstrated by positive skin prick tests and elevated specific IgE [22,23] or atopy patch test [14,24].

Sensitization to microbial antigens in intrinsic and extrinsic AE As mentioned before, microbial allergens, namely staphylococcal superantigens and the yeasts of the species Candida and Malassezia, have been postulated to identify intrinsic-type AE patients [25]. Casagrande and co-workers analysed reactivity to Malassezia antigens in 97 adult AE patients and 571 controls. Eighty-three were extrinsic-type patients and 14 intrinsictype, with a comparable percentage of head and neck type in both groups (36/83 and 5/14 respectively). They found a positive skin prick test in 36% and positive atopy patch test (APT) in 38% of the intrinsic-type patients. Serologically, 7/14 (50%) had elevated IgE to M. furfur and in the PBMC proliferation assay, 5/8 reacted to

Microbiology in Atopic Eczema

natural Malassezia extract. The numbers were comparable to the extrinsic group. The authors conclude that sensitization to Malassezia occurs in a substantial proportion of intrinsic AE patients [18]. In our own study of paediatric patients [26], sensitizations to microbial allergens were almost exclusively restricted to patients with high IgE. We found reactivity to Malassezia species in 40% of extrinsic-type patients while 28% of high-IgE patients reacted to Candida albicans. These results support the previously published observation that the sensitization to microbial allergens generally reflects a more severe course of atopic eczema with higher disease scores and the disposition to elaborate IgE in response to various allergenic challenges [27]. In line with these findings, a study from Cologne found no correlation to disease duration or onset of disease, but patients with more severe disease and higher total IgE levels were more likely to be sensitized to Malassezia species [28].

Microbial antigens and autoreactivity IgE-mediated autoreactivity is a phenomenon observed in severe long-standing disease; however, the development and clinical impact of IgE remain unclear. Autoreactivity can result from molecular mimicry between common B-cell epitopes between self antigens and microbial antigens [29,30]. As for Malassezia, the enzyme manganese superoxide dismutase (Mal s 11) has been found to share substantial epitopes with human superoxide dismutase, thus possibly inducing autoreactivity. Manganese superoxide dismutase is a stress-induced enzyme which is upregulated in eczematous skin, most likely as a consequence of scratching. Patch testing with human MnSOD induced eczematous reactions on unaffected skin in patients sensitized to M. sympodialis. These patients also showed positive skin prick tests to human MnSOD and MnSOD-specific IgE. Of note, levels of anti-MnSOD IgE correlated with disease severity [31,32]. Another Malassezia antigen (Mal s 13) shows homology to thioredoxin [30], an oxidoreductase, which is also upregulated as a consequence of cellular stress.

Effect of antifungal therapy on AE A response to antifungal therapy would confirm the clinical significance of Malassezia colonization in AE. Theoretically, antifungal treatment should have an additional and longer-lasting effect to standard treatment with antiinflammatory substances. All Malassezia species are susceptible to both ketoconazole and itraconazole, the two agents most widely used in clinical trials for Malassezia. There is a single study from Taiwan looking at the effect of antifungal therapy in paediatric AE patients. It showed no effect of additional antifungal treatment in a randomized, double-blind, placebo-controlled intra-individual comparison study in 30 paediatric patients aged 5–14

26.7

years with flexural eczema. Most of the patients had severe disease; 70% showed head and neck involvement. Miconazole was added to hydrocortisone 1% cream on one side and the corresponding area (knees or elbows) was treated with hydrocortisone 1% twice daily for 2 weeks. Patients were followed for 6 weeks after treatment to detect any prolonged or delayed effects [33]. Choosing knees and elbows as the target area might account for the lack of effectiveness, as these areas are not preferential sites for Malassezia colonization. A group from Sweden has analysed the effect of miconazole in addition to hydrocortisone 1% for adult AE patients with head and neck involvement. Furthermore, the treatment group was provided with ketoconazole shampoo for twice-weekly use for a total of 4 weeks. The authors noted a decrease of Malassezia colonies on the skin, but no effect on eczema severity [34]. In contrast, a randomized placebo-controlled trial including adult AE patients with head and neck involvement and M. furfur sensitization (≥class 1) showed significant improvement of AE severity as measured by IGA score with twice-daily application of ciclopiroxolamine compared to application of the corresponding ointment base. Unfortunately, from the initial 50 patients only 29 (16 in the treatment group, 13 in the placebo group) finished the study [35].

Systemic treatment Ketoconazole 200 mg daily for 1 month was superior to placebo in 14 Malassezia skin prick test-positive patients with head and neck dermatitis in a double-blind, placebocontrolled cross-over study [36]. The same study design was used in a larger trial: 75 AE patients with head and neck involvement and elevated IgE to Malassezia or Candida, treated with ketoconazole 200 mg daily for 1 month, showed significant improvement in the treatment group compared to the placebo group at 1 month [37]. Back and co-workers included patients with established AE, predominant head and neck involvement, elevated total IgE and elevated IgE to M. furfur. Fifteen patients were treated with ketoconazole 200 mg/d over 3 months, while 14 control patients received placebo. Betametasone was allowed as a topical steroid. All patients improved, but the treatment group used less topical steroid. In the treatment group, levels of specific IgE to M. furfur and C. albicans, as well as total serum IgE, decreased [38]. Similar results were shown in two studies with itraconazole treatment in adult atopic head and neck dermatitis. Ikezawa and co-workers performed a randomized crossover study with 34 patients, adding itraconazole 100 mg/ daily for 2 months to a lactobacillus preparation; topical steroids were allowed. After 2 months of active treatment

26.8

Chapter 26

with itraconazole, they observed decreased specific IgE levels to Malassezia and reduced eosinophils. Concomitant use of topical steroids was less in the treatment group [39]. Svejgaard and co-workers [40] compared the effect of 400 mg itraconazole daily or 200 mg itraconazole daily for 7 days with placebo. They found weak but significant improvement in both treatment groups. In summary, all studies on systemic antifungal treatment with ketoconazole and itraconazoles show effects on either blood parameters and/or clinical severity. There are no convincing data on additional topical treatment with antifungals in AE patients. As imidazole antimycotics also have anti-inflammatory properties [41], it remains questionable whether clinical effects on AE are related to the specific antifungal properties. In stable allergic bronchopulmonary aspergillosis, itraconazole has been shown to reduce sputum eosinophilic cationic protein (ECP) and total IgE [42]. In vitro, anti-inflammatory effects of itraconazole are more pronounced than ketocoanzole; least effective was fluconazole [43].

Other micro-organisms Although associations of AE with other bacteria and fungi apart frm Staph. aureus and Malassezia have been occasionally reported, there has not yet been confirmation of these data in larger studies. References 1 Sugita T, Tajima M, Ito T, Saito M, Tsuboi R, Nishikawa A. Antifungal activities of tacrolimus and azole agents against the eleven currently accepted Malassezia species. J Clin Microbiol 2005;43(6): 2824–9. 2 Kato H, Sugita T, Ishibashi Y, Nishikawa A. Detection and quantification of specific IgE antibodies against eight Malassezia species in sera of patients with atopic dermatitis by using an enzyme-linked immunosorbent assay. Microbiol Immunol 2006;50(11):851–6. 3 Sugita T, Tajima M, Tsubuku H, Tsuboi R, Nishikawa A. Quantitative analysis of cutaneous malassezia in atopic dermatitis patients using real-time PCR. Microbiol Immunol 2006;50(7):549–52. 4 Broberg A. Pityrosporum ovale in healthy children, infantile seborrhoeic dermatitis and atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1995;191:1–47. 5 Takahata Y, Sugita T, Kato H, Nishikawa A, Hiruma M, Muto M. Cutaneous Malassezia flora in atopic dermatitis differs between adults and children. Br J Dermatol 2007;157(6):1178–82. 6 Sandstrom Falk MH, Tengvall Linder M, Johansson C et al. The prevalence of Malassezia yeasts in patients with atopic dermatitis, seborrhoeic dermatitis and healthy controls. Acta Derm Venereol 2005; 85(1):17–23. 7 Darabi K, Hostetler SG, Bechtel MA, Zirwas M. The role of Malassezia in atopic dermatitis affecting the head and neck of adults. J Am Acad Dermatol 2009;60(1):125–36. 8 Sugita T, Suto H, Unno T et al. Molecular analysis of Malassezia microflora on the skin of atopic dermatitis patients and healthy subjects. J Clin Microbiol 2001;39(10):3486–90. 9 Selander C, Zargari A, Mollby R, Rasool O, Scheynius A. Higher pH level, corresponding to that on the skin of patients with atopic eczema, stimulates the release of Malassezia sympodialis allergens. Allergy 2006;61(8):1002–8.

10 Johansson C, Ahlborg N, Andersson A et al. Elevated peripheral allergen-specific T cell response is crucial for a positive atopy patch test reaction. Int Arch Allergy Immunol 2009;150(1):51–8. 11 Tengvall Linder M, Johansson C, Zargari A et al. Detection of Pityrosporum orbiculare reactive T cells from skin and blood in atopic dermatitis and characterization of their cytokine profiles. Clin Exp Allergy 1996;26(11):1286–97. 12 Selander C, Engblom C, Nilsson G, Scheynius A, Andersson CL. TLR2/MyD88-dependent and -independent activation of mast cell IgE responses by the skin commensal yeast Malassezia sympodialis. J Immunol 2009;182(7):4208–16. 13 Scheynius A, Johansson C, Buentke E, Zargari A, Linder MT. Atopic eczema/dermatitis syndrome and Malassezia. Int Arch Allergy Immunol 2002;127(3):161–9. 14 Johansson C, Sandstrom MH, Bartosik J et al. Atopy patch test reactions to Malassezia allergens differentiate subgroups of atopic dermatitis patients. Br J Dermatol 2003;148(3):479–88. 15 Wessels MW, Doekes G, Van Ieperen-Van Kijk AG, Koers WJ, Young E. IgE antibodies to Pityrosporum ovale in atopic dermatitis. Br J Dermatol 1991;125(3):227–32. 16 Kim TY, Jang IG, Park YM, Kim HO, Kim CW. Head and neck dermatitis: the role of Malassezia furfur, topical steroid use and environmental factors in its causation. Clin Exp Dermatol 1999;24(3):226–31. 17 Lindgren L, Wahlgren CF, Johansson SG, Wiklund I, Nordvall SL. Occurrence and clinical features of sensitization to Pityrosporum orbiculare and other allergens in children with atopic dermatitis. Acta Derm Venereol 1995;75(4):300–4. 18 Casagrande BF, Fluckiger S, Linder MT et al. Sensitization to the yeast Malassezia sympodialis is specific for extrinsic and intrinsic atopic eczema. J Invest Dermatol 2006;126(11):2414–21. 19 Nordvall SL, Lindgren L, Johansson SG, Johansson S, Petrini B. IgE antibodies to Pityrosporum orbiculare and Staphylococcus aureus in patients with very high serum total IgE. Clin Exp Allergy 1992;22(8):756–61. 20 Scalabrin DM, Bavbek S, Perzanowski MS, Wilson BB, Platts-Mills TA, Wheatley LM. Use of specific IgE in assessing the relevance of fungal and dust mite allergens to atopic dermatitis: a comparison with asthmatic and nonasthmatic control subjects. J Allergy Clin Immunol 1999;104(6):1273–9. 21 Tengvall Linder M, Johansson C, Bengtsson A, Holm L, Harfast B, Scheynius A. Pityrosporum orbiculare-reactive T-cell lines in atopic dermatitis patients and healthy individuals. Scand J Immunol 1998;47(2):152–8. 22 Kieffer M, Bergbrant IM, Faergemann J et al. Immune reactions to Pityrosporum ovale in adult patients with atopic and seborrheic dermatitis. J Am Acad Dermatol 1990;22(5 Pt 1):739–42. 23 Bayrou O, Pecquet C, Flahault A, Artigou C, Abuaf N, Leynadier F. Head and neck atopic dermatitis and malassezia-furfur-specific IgE antibodies. Dermatology 2005;211(2):107–13. 24 Tengvall Linder M, Johansson C, Scheynius A, Wahlgren C. Positive atopy patch test reactions to Pityrosporum orbiculare in atopic dermatitis patients. Clin Exp Allergy 2000;30(1):122–31. 25 Novak N, Allam JP, Bieber T. Allergic hyperreactivity to microbial components: a trigger factor of “intrinsic” atopic dermatitis? J Allergy Clin Immunol 2003;112(1):215–16. 26 Schnopp C, Grosch J, Ring J, Ollert M, Mempel M. Microbial allergenspecific IgE is not suitable to identify the intrinsic form of atopic eczema in children. J Allergy Clin Immunol 2008;121(1):267–8 e1; author reply 268. 27 Reefer AJ, Satinover SM, Wilson BB, Woodfolk JA. The relevance of microbial allergens to the IgE antibody repertoire in atopic and nonatopic eczema. J Allergy Clin Immunol 2007;120(1):156–63. 28 Lange L, Alter N, Keller T, Rietschel E. Sensitization to Malassezia in infants and children with atopic dermatitis: prevalence and clinical characteristics. Allergy 2008;63(4):486–7.

Microbiology in Atopic Eczema 29 Zeller S, Glaser AG, Vilhelmsson M, Rhyner C, Crameri R. Immunoglobulin-E-mediated reactivity to self antigens: a controversial issue. Int Arch Allergy Immunol 2008;145(2):87–93. 30 Glaser AG, Menz G, Kirsch AI, Zeller S, Crameri R, Rhyner C. Autoand cross-reactivity to thioredoxin allergens in allergic bronchopulmonary aspergillosis. Allergy 2008;63(12):1617–23. 31 Schmid-Grendelmeier P, Scheynius A, Crameri R. The role of sensitization to Malassezia sympodialis in atopic eczema. Chem Immunol Allergy 2006;91:98–109. 32 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(5): 1068–75. 33 Wong AW, Hon EK, Zee B. Is topical antimycotic treatment useful as adjuvant therapy for flexural atopic dermatitis: randomized, doubleblind, controlled trial using one side of the elbow or knee as a control. Int J Dermatol 2008;47(2):187–91. 34 Broberg A, Faergemann J. Topical antimycotic treatment of atopic dermatitis in the head/neck area. A double-blind randomised study. Acta Derm Venereol 1995;75(1):46–9. 35 Mayser P, Kupfer J, Nemetz D et al. Treatment of head and neck dermatitis with ciclopiroxolamine cream – results of a doubleblind, placebo-controlled study. Skin Pharmacol Physiol 2006;19(3): 153–8. 36 Clemmensen S, Hjorth N. Treatment of dermatitis of head and neck with ketoconazole in patients with type 1 sensitivity to Pityrosporum ovale. Semin Dermatol 1983;2: 26–9. 37 Lintu P, Savolainen J, Kortekangas-Savolainen O, Kalimo K. Systemic ketoconazole is an effective treatment of atopic dermatitis with IgEmediated hypersensitivity to yeasts. Allergy 2001;56(6):512–17. 38 Back O, Bartosik J. Systemic ketoconazole for yeast allergic patients with atopic dermatitis. J Eur Acad Dermatol Venereol 2001;15(1):34–8. 39 Ikezawa Z, Kondo M, Okajima M, Nishimura Y, Kono M. Clinical usefulness of oral itraconazole, an antimycotic drug, for refractory atopic dermatitis. Eur J Dermatol 2004;14(6):400–6. 40 Svejgaard E, Larsen PO, Deleuran M, Ternowitz T, Roed-Petersen J, Nilsson J. Treatment of head and neck dermatitis comparing itraconazole 200 mg and 400 mg daily for 1 week with placebo. J Eur Acad Dermatol Venereol 2004;18(4):445–9.

26.9

41 Steel HC, Anderson R. Itraconazole antagonizes store-operated influx of calcium into chemoattractant-activated human neutrophils. Clin Exp Immunol 2004;136(2):255–61. 42 Wark PA, Hensley MJ, Saltos N et al. Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: a randomized controlled trial. J Allergy Clin Immunol 2003;111(5):952–7. 43 Steel HC, Tintinger GR, Anderson R. Comparison of the antiinflammatory activities of imidazole antimycotics in relation to molecular structure. Chem Biol Drug Des 2008;72(3):225–8.

Conclusion The colonization of lesional and non-lesional atopic eczema skin with Staph. aureus represents an important trigger factor for the severity and exacerbation frequency of skin symptoms. Atopic skin is preferentially prone to bind Staph. aureus and this binding is followed by a repetitive stimulation of the atopic immune system mainly by staphylococcal superantigens, leading to enhanced T-cell homing as well as increased IgE synthesis. Atopic skin shows reduced induction of crucial skin defence peptides such as LL37, HBD2 and HBD3. Sensitivity to Malassezia antigens is a phenomenon specific to atopic eczema. Up to 50% of adult patients and more than 30% of paediatric patients are sensitized to Malassezia, with higher rates in adults with predominance of head and neck disease, more severe atopic eczema and high total IgE. Higher rates of Malassezia sensitization in adults can be attributed to higher proportion of extrinsictype eczema. Thus, sensitization to Malassezia and other microbial allergens seems to reflect the tendency towards a Th2immune response in extrinsic-type AE rather than being a specific response.

27.1

C H A P T E R 27

The Skin Barrier in Atopic Dermatitis Simon G. Danby1 & Michael J. Cork1,2 1

The Academic Unit of Dermatology Research, Department of Infection and Immunity, The University of Sheffield, Sheffield, UK The Paediatric Dermatology Clinic, Sheffield Children’s Hospital, Sheffield, UK

2

Introduction, 27.1

Skin barrier homeostasis, 27.5

Development of the skin barrier, 27.12

The normal skin barrier, 27.1

Skin barrier dysfunction, 27.9

Conclusion, 27.17

Introduction

The normal skin barrier

Atopic dermatitis (AD) is a chronic relapsing disease of the skin associated with a defective skin barrier. Environmental insults, such as the use of soap and detergents, interact with inherited skin barrier abnormalities to reduce stratum corneum (SC) hydration, integrity and cohesion, leading to xerosis [1]. The reduction in skin barrier integrity is characterized by elevated transepidermal water loss (TEWL) and an increased susceptibility to irritant and allergen penetration. In some cases, allergen penetration leads to immune system hyper-reactivity and progression to ‘true’ AD (as opposed to non-atopic dermatitis) characterized by elevated IgE levels [2]. Inflammation associated with flares of AD results from disruption of the skin barrier, which triggers cytokine production, release and activation [3]. In the ‘outside-inside-outside’ model of AD proposed by Elias in 2008, cytokines released following barrier disruption by environmental agents direct further damage to the barrier and inhibit barrier recovery, creating a self-perpetuating cycle of skin barrier damage and inflammation [4]. The aim of this chapter is to provide an overview of the skin barrier, its dysfunction in AD, and the implications of skin barrier dysfunction on treating AD.

Structure of the primary skin barrier

References 1 Cork MJ, Danby SG, Vasilopoulos Y et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 2009;129(8):1892–908. 2 Bieber T. Atopic dermatitis. N Engl J Med 2008;358(14):1483–94. 3 Wood LC, Stalder AK, Liou A et al. Barrier disruption increases gene expression of cytokines and the 55 kD TNF receptor in murine skin. Exp Dermatol 1997;6(2):98–104. 4 Elias PM, Steinhoff M. ‘Outside–to–inside’ (and now back to ‘outside’) pathogenic mechanisms in atopic dermatitis. J Invest Dermatol 2008;128(5):1067–70.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

The epidermis is the outermost compartment of the skin and acts as an important barrier against the outside environment. It is made up of distinct layers of keratinocytes (Fig. 27.1). The basal layer (stratum basale) consists of proliferating cells required for the continual regeneration of the epidermis. New cells migrate upwards, undertaking a process of terminal differentiation [1]. During the early stages of differentiation, the keratinocytes in the stratum spinosum are linked together by specialized junctions, called desmosomes [2]. These disc-shaped junctions consist of the cadherin family of extracellular transmembrane glycoproteins, desmoglein (DSG) and desmocollin (DSC). The intracellular domains of DSG and DSC are fused to the cell cytoskeleton via interaction with the armadillo proteins plakoglobin and plakophillin and the plakin desmoplakin. The cytoskeleton itself is reinforced with keratins, which together with the desmosomal junctions enhances the integrity and tensile strength of the skin. In the stratum granulosum (SG), the large stores of proteins and lipids produced during differentiation are visible and form the keratohyalin granules and lamellar bodies (LB). Upon transition from the SG to the SC, the contents of these granules are released, resulting in the remodelling of the keratinocytes into corneocytes, a process termed cornification. This transition is accompanied by the loss of their intracellular organelles and nuclei. The proteins derived from the keratohyalin granules reinforce the plasma membrane, forming an insoluble layer referred to as the cornified envelope (CE) [reviewed by [1]. The CE is mainly composed of loricrin, involucrin, filaggrin and small proline rich proteins (SPRs), which are cross-linked together by the action of transglutaminases. Filaggrin also aggregates the keratin

27.2

Chapter 27

B

A

C

pH4.5 Cornified envelope

Low Ca2+

Corneodesmosomes Corneocyte

Stratum corneum

1° barrier

Lipid lamellae

SC:SG interface High Ca2+

Keratohyalin granules

Lamellar granules

pH7.0

Stratum granulosum

Nucleus

Desmosome

Stratum spinosum

Stratum basale

Low Ca2+

Fig. 27.1 The epidermis. (Panel A) Illustration of the epidermis showing the arrangement of keratinocyte cells at various stages of differentiation. The primary barrier to the penetration of irritants and allergens is located in the intact portion of the inner SC. (Panel B) The calcium gradient across the epidermis. Differentiation of keratinocytes is driven by the increasing concentration of calcium. The transition of differentiated keratinocytes into corneocytes is triggered by a rapid decline in calcium concentration at the interface between the SG and the SC. (Panel C) The pH gradient across the SC.

fibres of the cellular cytoskeleton into bundles, collapsing the corneocytes into flattened discs with a large surface area (approximately 1000 μm2 for mature surface corneocytes). The resulting corneocytes have a geometrical morphology and interlock together in layers of approximately 20 corneocytes deep, spanning between 10 and 20 μm, depending on the body site [3] The majority of filaggrin protein does not persist beyond the deepest two layers of the SC [4]. As the corneocytes mature, filaggrin is extensively deiminated through the actions of the enzyme peptidyl-deiminase to reduce keratin-binding affinity, and subsequently degraded into small peptides and then free amino acids. The free amino acids are then catabolized into the constituents of natural moisturizing factor (NMF), including

sodium pyrrolidone carboxylic acid (NaPCA) and transurocanic acid (tUCA); NMF also contains lactic acid and urea from other prescursors [4]. NMF is essential for the retention of water within corneocytes and results in their optimal hydration and tumidity. NaPCA and lactic acid, in particular, are intensely hydroscopic; they both absorb water and dissolve in their own water, acting as very efficient humectants, which leads to a swelling of corneocytes, preventing the development of gaps between them. To help prevent the loss of water from the swollen corneocytes, they are surrounded by lipid lamellae, crystalline substances composed of ceramides, cholesterol, fatty acids and cholesterol esters [5]. The lipid lamellae are extruded into the extracellular space between the corneocytes from the secretory LB, which are thought to be

The Skin Barrier in Atopic Dermatitis

(a)

27.3

(b)

Fig. 27.2 The ‘brick wall’ analogy of the skin barrier [14,15]. The wall represents the barrier to the loss of water and to the penetration of irritants/ allergens. It is made up of bricks, representing the corneocytes, held together by iron rods, representing the corneodesmosomal junctions, and surrounded by mortar, representing the lipid lamellae. (a) The intact ‘healthy’ skin barrier. The rusting of the iron rods in the uppermost layers represents desquamation. (b) The defective skin barrier present in AD. The broad skin barrier defect described in the text can be visualized as a broken wall built with an insufficient amount of poor-quality mortar. There is an increased rate of desquamation represented by the increased rusting of the iron rods. The poor construction leads to the development of cracks that permit the entry of irritants and allergens.

branched tubular structures extending from the granular keratinocyte trans-Golgi network [6]. In addition to preventing water loss, the lipid lamellae restrict the penetration of water-soluble materials. The CE acts as a scaffold for the attachment of lipids, including ceramides, from the lamellar matrix, which aggregate to form the lipid envelope [1]. The corneocytes are therefore enmeshed in what is believed to be a single and coherent lamellar gel that confers flexibility to the barrier. The intercellular desmosomal junctions connecting the corneocytes together are also reinforced following the association with corneodesmosin (CDSN). The incorporation of corndeodesmosin marks the transition from desmosome to corneodesmosome [7]. This locks the corneocytes together, providing tensile strength for the SC to resist shearing forces. Corneodesmosin is a 52 kDa protein, packaged in LB and secreted into the extracellular space at the transition between the SG and SC [8]. LB also deliver a cocktail of proteases which progressively break down the corneodesmosomal junctions as the corneocytes mature. This results in the disassociation of mature corneocytes (or squames) in the uppermost layers of the SC. This process of corneocyte shedding, known as desquamation, counterbalances the generation of new keratinocytes in the basal layer so that the whole epidermis is continually renewed [9]. The primary barrier to the penetration of irritants and allergens through the skin, the skin barrier, is located in

the lower part of the SC. This is the point at which the integrity of the barrier is greatest, where cornification culminates prior to its ensuing breakdown. Elias described this barrier as being like a brick wall, where the corneocytes are analogous to bricks and the lipid lamellae to cement sealing the bricks together [10]. Extending this model, Cork et al. likened the corneodesmosomes to iron rods that pass down through the bricks to add strength to the wall (Fig. 27.2) [11]. Desquamation can be envisaged as rusting of these iron rods in the upper layers of the brick wall.

Desquamation Desquamation involves a network of degradatory proteases, regulated by protease inhibitors, which break down the extracellular corneodesmosome adhesion proteins securing the corneocytes together [9]. This process is largely attributed to the kallikrein-related peptidases (KLK), a family of serine proteases possessing either trypsin-like or chymotrypsin-like activity. To date, seven trypsin-like KLKs, KLK5 (previously SCTE), KLK6, KLK8, KLK10, KLK11, KLK13 and KLK14, and one chymotrypsinlike KLK, KLK7 (previously stratum corneum chymotryptic enzyme, SCCE), have been specifically identified in the SC [12]. At least a further three, including KLK1, KLK3 and KLK9, have been found in total skin extracts. Of these, KLK5 has been shown to hydrolyse DSG, DSC and CDSN, whereas KLK7 cleaves DSC and CDSN only.

27.4

Chapter 27

KLK6 and KLK14, exhibiting the highest level of activity, are also capable of cleaving DSG. All of the KLKs are expressed as inactive precursors, whereby removal of pro-peptides by trypsin digestion is required for the formation of proteolytically active enzymes [12]. The ability of the KLK with trypsin-like activity to activate other family members, coupled with their different levels of expression and activity within the SC, creates a complex system of hierarchical activation. KLK5, which is capable of self-activation, is thought to trigger this proteolytic cascade, ultimately leading to the breakdown of corneodesmosomes. Other enzymes found in the SC and capable of degrading corneodesmosomal adhesion proteins include the cysteine proteases cathepsin L2 (stratum corneum thiol protease) and stratum corneum L-like enzyme [13], and the aspartate protease cathepsin D [14]. The activity of this proteolytic network is strictly regulated by a number of protease inhibitors, including the pH-dependent lymphoepithelial kazal-type 5 serine protease inhibitor (LEKTI) [15]. LEKTI is composed of 15 potential serine proteinase inhibitory domains, at least four of which have confirmed activity against members of the kallikrein family, including KLK5, KLK6, KLK7 and KLK14. It is expressed by granular cells and delivered by LB vesicles to the superficial SG layers, ahead of its target proteases, prohibiting undesired proteolytic activity in the lower layers of the SC [8]. This is achieved owing to the highly organized and compartmentalized nature of LB trafficking. At the SG–SC interface. LEKTI is colocalized with KLKs in the extracellular space where the pH is near neutral. Under these conditions, LEKTI was found to be a potent inhibitor of both KLK5 and KLK7 [15]. As the pH becomes more acidic, the inhibitory potential of LEKTI is reduced. In the superficial layers of the SC, inhibition by LEKTI is sufficiently reduced to support localized desquamation.

LEKTI, encoded by the SPINK5 gene, is a member of a group of serine protease inhibitors of the Kazal type (SPINK), of which a second member has recently been identified in human skin [14]. Encoded by the SPINK9 gene, LEKTI-2 was found to inhibit KLK5, but not KLK7 and KLK14, proteolytic activity. Human epidermis also expresses serine leucoprotease inhibitor (SLPI) and elafin, otherwise known as skin-derived antileucoprotease (SKALP), which specifically inhibits KLK7, and the cystatin protease inhibitors A, C and M/E, which are specific for cysteine proteases [14]. Cystatin A is also secreted in sweat and forms a protective layer over the surface of the skin against exogenous cysteine proteases such as those produced by house dust mites and Staphylococcus aureus (Staph. aureus) [16].

Stratum corneum pH A pH gradient exists across the SC, starting with a pH close to 7 at the SG–SC interface and changing to an acidic pH, of around 5, in the superficial layers of the SC (see Fig. 27.1c) depending on age, sex and the anatomical site tested [17]. This is a simplified view of the spatial distribution of the pH gradient, which in fact occurs through the progressive accumulation of acidic micro-domains. At least three endogenous pathways contribute to SC acidification (Fig. 27.3): the generation of free fatty acids (FFA) from phospholipids via the action of secretory phospholipase A2 (sPLA2) or from ceramide via the action of epidermal ceramidase; the activity of the non-energy dependent sodium-proton exchanger-1 (NHE1); and the degradation of filaggrin into NMF [17–19]. In the latter pathway, filaggrin degradation yields free amino acids including histidine, which is catabolized into tUCA by histidase. The resulting acidic pH of the skin has a strong antimicrobial effect, decreasing skin colonization by pathogenic bacteria and favouring the adhesion of nonpathogenic bacteria to the SC [17]. Homeostasis

Filaggrin

Histidine

tUCA

Na/H proton pump

Phospholipids

pH

Desquamation

Enzyme activity: βGCCase SMase

Lipid lamellae synthesis

PLA2 FFA

Ceramide

SC Proteases KLKs

CDase

Antimicrobial activity

Fig. 27.3 Stratum corneum pH is centrally involved in the regulation of key skin barrier functions. Histidase (HDase) catalyses the conversion of histidine into trans-urocanic acid (tUCA), a component of NMF. Essential FFA are generated from phospholipids and ceramide by the actions of secretory phospholipase A2 (PLA2) and ceramidase (CDase) respectively. The lipid biosynthetic enzymes β-glucocerebrosidase (βGCase) and acid sphingomyelinase (SMase) are inhibited at high pH, whereas the degradatory serine proteases, including the kallikreins, are activated.

The Skin Barrier in Atopic Dermatitis

The pH gradient is also vital for maintaining normal barrier function, including the regulation of lipid lamellae biosynthesis and desquamation. The generation of lamellar components relies on the conversion of glycosylceramides and sphingomyelin into ceramides by β-glucocerebrosidase (β-GlucCer ’ase) and acid sphingomyelinase, both of which have an acid optimum pH [17]. Furthermore, desquamation is largely dependent on the activity of serine proteases with alkaline pH optima [9], and regulated by the pH-sensitive inhibitor LEKTI [15]. For instance, a change in pH from 5.5 to 7.5 increases KLK7 activity by 50% [9]. When the skin pH is increased by blocking either sPLA2 or NHE1, barrier abnormalities are observed, which can be corrected by co-exposure of inhibitor-treated areas to an acidic buffer [20,21]. Moreover, a delay in skin barrier recovery occurs when the skin is immersed in neutral pH buffers [22]. When hairless mice were treated with ‘superbases’ that neutralize skin surface pH, a rapid activation of serine protease activity was observed, with consequent degradation of corneodesmosomes [23]. This was accompanied by decreased β-GlucCer ’ase activity, resulting in incompletely processed lipid lamellae membranes. References 1 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):328–40. 2 Al-Amoudi A, Frangakis AS. Structural studies on desmosomes. Biochem Soc Trans 2008;36(Pt 2):181–7. 3 Ya-Xian Z, Suetake T, Tagami H. Number of cell layers of the stratum corneum in normal skin – relationship to the anatomical location on the body, age, sex and physical parameters. Arch Dermatol Res 1999;291(10):555–9. 4 Harding CR, Watkinson A, Rawlings AV et al. Dry skin, moisturization and corneodesmolysis. Int J Cosmet Sci 2000;22(1):21–52. 5 Rawlings AV. Trends in stratum corneum research and the management of dry skin conditions. Int J Cosmet Sci 2003;25(1–2):63–95. 6 Norlen L, Al-Amoudi A, Dubochet J. A cryotransmission electron microscopy study of skin barrier formation. J Invest Dermatol 2003;120(4):555–60. 7 Serre G, Mils V, Haftek M et al. Identification of late differentiation antigens of human cornified epithelia, expressed in re-organized desmosomes and bound to cross-linked envelope. J Invest Dermatol 1991;97(6):1061–72. 8 Ishida-Yamamoto A, Simon M, Kishibe M et al. Epidermal lamellar granules transport different cargoes as distinct aggregates. J Invest Dermatol 2004;122(5):1137–44. 9 Caubet C, Jonca N, Brattsand M et al. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/ KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol 2004; 122(5):1235–44. 10 Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol 1983;80 Suppl:44s–9s. 11 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(1):3–21; quiz 2–3. 12 Eissa A, Diamandis EP. Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions. Biol Chem 2008;389(6):669–80.

27.5

13 Bernard D, Mehul B, Thomas-Collignon A et al. Analysis of proteins with caseinolytic activity in a human stratum corneum extract revealed a yet unidentified cysteine protease and identified the socalled “stratum corneum thiol protease” as cathepsin l2. J Invest Dermatol 2003;120(4):592–600. 14 Meyer-Hoffert U. Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases. Arch Immunol Ther Exp (Warsz) 2009;57(5):345–54. 15 Deraison C, Bonnart C, Lopez F et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 2007;18(9):3607–19. 16 Kato T, Takai T, Mitsuishi K et al. Cystatin A inhibits IL-8 production by keratinocytes stimulated with Der p 1 and Der f 1: biochemical skin barrier against mite cysteine proteases. J Allergy Clin Immunol 2005;116(1):169–76. 17 Fluhr J, Bankova LG. Skin surface pH: mechanism, measurement, importance. In: Serup J, Jemec GB, Grove GL (eds) Handbook of NonInvasive Methods and the Skin. Boca Raton, FL: CRC Press, 2006, pp. 411–20. 18 Nakagawa N, Sakai S, Matsumoto M et al. Relationship between NMF (lactate and potassium) content and the physical properties of the stratum corneum in healthy subjects. J Invest Dermatol 2004;122(3):755–63. 19 Houben E, Hachem JP, de Paepe K et al. Epidermal ceramidase activity regulates epidermal desquamation via stratum corneum acidification. Skin Pharmacol Physiol 2008;21(2):111–18. 20 Behne MJ, Meyer JW, Hanson KM et al. NHE1 regulates the stratum corneum permeability barrier homeostasis. Microenvironment acidification assessed with fluorescence lifetime imaging. J Biol Chem 2002;277(49):47399–406. 21 Fluhr JW, Kao J, Jain M et al. Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity. J Invest Dermatol 2001;117(1):44–51. 22 Mauro T, Holleran WM, Grayson S et al. Barrier recovery is impeded at neutral pH, independent of ionic effects: implications for extracellular lipid processing. Arch Dermatol Res 1998;290(4):215–22. 23 Hachem JP, Man MQ, Crumrine D et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol 2005;125(3):510–20.

Skin barrier homeostasis Regulation of skin barrier structure and function A distinct gradient of calcium ions (Ca2+) exists across the epidermis (see Fig. 27.1b), starting with low levels in the basal layer(s) and progressively increasing towards the upper SG, where it peaks, before sharply declining across the SC [1,2]. Ca2+ regulates the expression of differentiationdependent genes in keratinocytes, such as those encoding proteins of the CE [3]. As such, the Ca2+ gradient plays a key role in maintaining the different stages of differentiation. Other ions, including potassium, also exhibit specific gradients across the epidermis, which play important roles in regulating barrier homeostasis [4]. The maintenance of these ion gradients across the epidermis is interdependent on the ability of the epidermis, specifically the SC, to act as a permeability barrier [1]. Poor permeability barrier function, defined by a decreased ability to retain

27.6

Chapter 27

Exogenous calcium (hard water)

Extracellular Ca2+ flux

Acute barrier disruption

IL-1β activation

Soap and detergents

Exogenous proteases

pH

SP

LG secretion

PAR2

Desquamation

(house dust mite, S. aureus)

Olive oil

Cornification

Inflammation and pruritus

Unsaturated fatty acids

NMDA

water (increased permeability), is accompanied by increased ion flux with consequent perturbation of epidermal ion gradients. Acute barrier damage, by tapestripping for example, causes rapid ion flux, resulting in the loss of Ca2+ in the SG. This disruption of the Ca2+ gradient triggers rapid secretion of LB contents in the upper SG and restoration of permeability barrier function. The reduced level of Ca2+ in the SG also precludes the expression of differentiation-dependent genes, thereby promoting proliferation [3]. If the permeability barrier is artificially restored using a vapour-permeable membrane barrier, repair does not take place, but the Ca2+ gradient is rapidly restored [1]. Similarly, if exogenous Ca2+ is applied to the skin, the repair process is inhibited [4]. This highlights the role of the Ca2+ gradient in regulating the release of LB contents at the transition between the SG and SC in addition to the barrier repair process following disruption. Barrier disruption also results in elevation of pH within the uppermost layers of the epidermis (Fig. 27.4), and the subsequent elevation of serine protease activity [5]. Alterations in trypsin-like serine protease activities, including KLK5 and KLK14, play a key role in skin barrier homeostasis through their ability to activate the PAR2 signalling cascade by direct cleavage of PAR2 [5,6]. PAR2 is a member of the protease-activated receptor (PAR) family of G-coupled receptors, involved in innate immune inflammatory responses and pruritus [7]. Its activation, as a result of acute disruption or chronic abrogation of the skin barrier, triggers release of the proinflammatory cytokines interleukin (IL)-8, ICAM-1, TNF-α and thymic stromal lymphopoietin (TSLP) [8]. TSLP, an IL-7-like cytokine, is a mediator of proallergic inflammation [9]. Inducible expression of TSLP in mice results in the development of AD-like lesions [10]. Activation of PAR2 also results in

Fig. 27.4 The serine protease (SP)-PAR2 pathway (red) and associated mechanisms of regulating barrier homeostasis (blue and green). Environmental factors (left-hand boxes and dashed lines) influence barrier homeostasis, resulting in exacerbated skin barrier breakdown and inhibition of barrier repair.

the inhibition of LB secretion and promotion of cornification (terminal differentiation), albeit with a delay of about 30 minutes [11]. This delay permits the secretion of the preformed pool of LB, triggered by extracellular Ca2+ flux. After this initial release of lamellar lipids, PAR2 activation prevents further LB secretion and promotes rapid cornification of the uppermost granular cells. This enhancement of cornification is thought to arise due to the PAR2-triggered increase in intracellular calcium, derived from internal stores, which occurs independently of extracellular Ca2+ levels [12]. In short, the simultaneous disruption of the Ca2+ gradient and activation of the serine protease-PAR2 pathway following acute barrier disruption results in the fortification of the skin barrier by the co-ordinated and rapid transition of granular cells into corneocytes encased in a preformed lamellar mesh (see Fig. 27.4). Notably, inhibition of the serine protease-PAR2 pathway using serine protease inhibitors was found to facilitate recovery of the permeability barrier following acute disruption [5]. This is in agreement with the opposing effect resulting from activation of this pathway by elevation of SC pH [13]. Activation of the serine protease-PAR2 pathway is therefore detrimental in terms of rapidly repairing permeability barrier function. Activation of calcium-permeable ionotropic channels expressed by keratinocytes was also found to inhibit barrier recovery [14]. Of these, the NMDA-type glutamate receptor, upon activation by glutamate or the specific agonist NMDA, triggers the influx of calcium into keratinocytes. The topical application of certain unsaturated fatty acids exhibited similar effects, resulting in altered differentiation [14]. This led to the finding that the unsaturated fatty acid oleic acid mediates its effect on the skin barrier through NMDA-type glutamate receptors

The Skin Barrier in Atopic Dermatitis

(see Fig. 27.4). This may be surprising because oleic acid is the main component of olive oil (55–83%), which is widely used topically as a skin protector and softener. However, olive oil, and oleic acid, have been shown to adversely affect the water-retaining properties of the skin, induce scaling and trigger an inflammatory response [14,15]. Not all fatty acids have this effect, and linoleic acid in particular was shown to improve barrier function. This is attributed to its potent activation of perioxisome proliferator-activated receptor α (PPARα) [16]. PPARα is a member of the nuclear hormone family of receptors involved in regulating proliferation, inflammation and barrier homeostasis in response to a range of lipid metabolites. A greater knowledge of the mechanisms underlying skin barrier homeostasis helps us to understand the effect of the environment on barrier function. For instance, the use of soap and harsh ionic detergents has a profound effect on the surface pH of skin, and thereby significant detrimental effect on skin barrier function (see Fig. 27.4) [17]. Mucke and colleagues reported that washing the skin with soap causes an increase in pH by 3 units on the palms for more than 90 minutes [18]. Increases in skin surface pH, resulting from the use of soap and harsh detergents, cause significant structural damage indicated by a decreased ability of the barrier to retain water [19]. Significant thinning of the SC was also observed following washing with soap, consistent with altered activity of epidermal proteases [20].

Our environment also contains a number of different sources of exogenous proteases with the potential to degrade the skin barrier (facilitate desquamation) and activate PAR2 (see Fig. 27.4). For instance, Staph. aureus releases several serine proteases known as exfoliative toxins, which break down the skin barrier via cleavage of DSG to facilitate colonization [21]. An association with a defective skin barrier is evident from the dramatically elevated colonization of patients suffering from AD with Staph. aureus (more than 90%) compared to healthy control subjects, with a mean density of up to ∼20 million organisms per cm2 in acute lesions [22]. In addition to degrading the skin barrier, house dust mite, cockroach and scabies mite allergens with proteolytic activity were found to activate PAR2, resulting in delayed permeability barrier recovery and LB secretion following acute barrier disruption [23].

Variations in skin barrier structure and function Although AD can affect any area of the body, it preferentially affects the flexures and the face. In babies aged less than 6 months, the face and scalp are the most common sites affected [24]. In older children, the most common sites affected are the antecubital and popliteal fossae [25,26]. Many factors could explain the areas of predisposition to AD, including the thickness of the SC and the variation in exposure to exogenous substances, such as irritants and allergens (Fig. 27.5). The eyelids and the Allergens

Allergens

Fig. 27.5 There is a wide difference in the thickness of the SC at different body sites. The skin sites that are not predisposed to AD have a much thicker SC where the uppermost corneocytes have been permitted to mature (left-hand panel), and as a result have a higher ‘skin barrier reserve’ (indicated in pink shading) to protect against allergen penetration. In contrast, the sites of predisposition to AD, such as the face and flexures, have the thinnest SC (right-hand panel) and can be visualized as having a very low ‘skin barrier reserve’.

TH1

27.7

TH2

TH1

TH2

27.8

Chapter 27

genitals have the thinnest epidermis, followed by the flexor forearm and posterior auricular areas [27–29]. The number of cell layers in the SC also varies between different body sites and correlates with epidermal thickness [30]. A greater penetration of topical corticosteroids was observed through the skin of these areas with the thinnest epidermis [31–34]. The size of the corneocytes that make up the skin barrier also varies between different body sites [35,36]. This variation correlates with skin permeability; for example, the postauricular and forehead SC were found to have the smallest corneocytes and the highest permeability compared to the upper arm, the forearm and the abdomen [36]. Furthermore, it was demonstrated that corneocytes from patients with AD are significantly smaller compared to those found in normal skin [35,37]. Taken together, variations in epidermal thickness, the layers of cells comprising the epidermal permeability barrier, and the size of the cells suggest region-specific variations in the function of the SC as a permeability barrier and therefore variations in the susceptibility to allergen penetration (see Fig. 27.5). The thickness of the barrier and the size of the corneocytes can be attributed to the rate of desquamation. Increased desquamation results in the early loss of immature corneocytes, thereby restricting or even reducing the number of corneocyte layers, whereas reduced desquamation permits the accumulation of corneocyte layers and the extended maturation of corneocytes, which includes further flattening of their morphology, leading to a greater surface area. In agreement with this, the level of SC protease activity associated with desquamation was found to vary between different body sites [38]. This variation in activity correlated with both the thickness of the SC and the size of the corneocytes. The activity of the desquamatory proteases KLK5 and KLK7 was found to be 2–4 times higher on the cheek compared to the forearm. Notably, skin surface pH was also higher on the cheek. The surface pH of the skin is known to vary between body sites, and may provide an explanation for the differences in protease activity [39]. Measurement of TEWL is an important method of assessing barrier functionality (its ability to retain water). Nikolovski and colleagues found that the level of TEWL is associated with the thickness of the barrier, using Raman confocal microscopy [40]. Furthermore, TEWL was found to positively correlate with certain protease activities [41]. Taken together, one interpretation of these data suggests that the level of protease activity determines the rate of desquamation and thereby the structure of the barrier on a regional basis, which may involve varying degrees of PAR2 pathway activation (discussed above). Areas with low protease activity are associated with a resilient skin barrier, which retains moisture and

repels allergens. On the other hand, areas with high protease activity are associated with a thin SC with low permeability barrier function – these areas can be described as having a low skin barrier reserve (see Fig. 27.5), which predisposes sites to the development of AD. References 1 Elias P, Ahn S, Brown B et al. Origin of the epidermal calcium gradient: regulation by barrier status and role of active vs passive mechanisms. J Invest Dermatol 2002;119(6):1269–74. 2 Forslind B, Werner-Linde Y, Lindberg M et al. Elemental analysis mirrors epidermal differentiation. Acta Derm Venereol 1999;79(1): 12–7. 3 Elias PM, Ahn SK, Denda M et al. Modulations in epidermal calcium regulate the expression of differentiation-specific markers. J Invest Dermatol 2002;119(5):1128–36. 4 Lee SH, Elias PM, Proksch E et al. Calcium and potassium are important regulators of barrier homeostasis in murine epidermis. J Clin Invest 1992;89(2):530–8. 5 Hachem JP, Houben E, Crumrine D et al. Serine protease signaling of epidermal permeability barrier homeostasis. J Invest Dermatol 2006;126(9):2074–86. 6 Stefansson K, Brattsand M, Roosterman D et al. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol 2008;128(1):18–25. 7 Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol 2008;153 Suppl 1:S263–82. 8 Briot A, Deraison C, Lacroix M et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 2009; 206(5):1135–47. 9 He R, Geha RS. Thymic stromal lymphopoietin. Ann N Y Acad Sci 2010;1183:13–24. 10 Yoo J, Omori M, Gyarmati D et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 2005;202(4):541–9. 11 Demerjian M, Hachem JP, Tschachler E et al. Acute modulations in permeability barrier function regulate epidermal cornification: role of caspase-14 and the protease-activated receptor type 2. Am J Pathol 2008;172(1):86–97. 12 Macfarlane SR, Sloss CM, Cameron P et al. The role of intracellular Ca2+ in the regulation of proteinase-activated receptor-2 mediated nuclear factor kappa B signalling in keratinocytes. Br J Pharmacol 2005;145(4):535–44. 13 Hachem JP, Man MQ, Crumrine D et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol 2005;125(3):510–20. 14 Katsuta Y, Iida T, Hasegawa K et al. Function of oleic acid on epidermal barrier and calcium influx into keratinocytes is associated with N-methyl D-aspartate-type glutamate receptors. Br J Dermatol 2009;160(1):69–74. 15 Darmstadt GL, Mao-Qiang M, Chi E et al. Impact of topical oils on the skin barrier: possible implications for neonatal health in developing countries. Acta Paediatr 2002;91(5):546–54. 16 Hanley K, Jiang Y, Crumrine D et al. Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier. J Clin Invest 1997; 100(3):705–12. 17 Cork MJ, Danby SG, Vasilopoulos Y et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 2009;129(8): 1892–908.

The Skin Barrier in Atopic Dermatitis 18 Mucke H, Mohr KT, Rummler A et al. [Skin pH value on hands after application of soap, cleaners and hand disinfectants]. Pharmazie 1993;48(6):468–9. 19 Voegeli D. The effect of washing and drying practices on skin barrier function. J Wound Ostomy Continence Nurs 2008;35(1):84–90. 20 White MI, Jenkinson DM, Lloyd DH. The effect of washing on the thickness of the stratum corneum in normal and atopic individuals. Br J Dermatol 1987;116(4):525–30. 21 Hirasawa Y, Takai T, Nakamura T et al. Staphylococcus aureus extracellular protease causes epidermal barrier dysfunction. J Invest Dermatol 2010;130(2):614–17. 22 Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90(5):525–30. 23 Jeong SK, Kim HJ, Youm JK et al. Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery. J Invest Dermatol 2008;128(8):1930–9. 24 Kunz B, Ring J. Clinical features and diagnostic criteria of atopic dermatitis. In: Harper JI, Oranje A, Prose N (eds) Textbook of Pediatric Dermatology. Oxford: Blackwell Science, 2002. 25 Dotterud LK, Kvammen B, Lund E et al. Prevalence and some clinical aspects of atopic dermatitis in the community of Sor-Varanger. Acta Derm Venereol 1995;75(1):50–3. 26 Schudel P, Wuthrich B. [Clinical course of childhood atopic neurodermatitis. A catamnestic study of 121 cases]. Z Hautkr 1985; 60(6):479–86. 27 Lee Y, Hwang K. Skin thickness of Korean adults. Surg Radiol Anat 2002;24(3–4):183–9. 28 Barker DE. Skin thickness in the human. Plast Reconstr Surg 1951;7(2):115–16. 29 Southwood WF. The thickness of the skin. Plast Reconstr Surg 1955;15(5):423–9. 30 Ya-Xian Z, Suetake T, Tagami H. Number of cell layers of the stratum corneum in normal skin – relationship to the anatomical location on the body, age, sex and physical parameters. Arch Dermatol Res 1999;291(10):555–9. 31 Feldmann RJ, Maibach HI. Regional variation in percutaneous penetration of 14C cortisol in man. J Invest Dermatol 1967;48(2):181–3. 32 Marzulli FN. Barriers to skin penetration. J Invest Dermatol 1962;39:387–93. 33 Schaefer KE, Scheer K. Regional differences in CO2 elimination through the skin. Exp Med Surg 1951;9(2–4):449–57. 34 Cronin E, Stoughton RB. Percutaneous absorption of nicotinic acid and ethyl nicotinate in human skin. Nature 1962;195:1103–4. 35 Kashibuchi N, Hirai Y, O’Goshi K et al. Three-dimensional analyses of individual corneocytes with atomic force microscope: morphological changes related to age, location and to the pathologic skin conditions. Skin Res Technol 2002;8(4):203–11. 36 Rougier A, Lotte C, Corcuff TP et al. Relationship between skin permeability and corneocyte size according to anatomic site, age and sex in a man. J Soc Cosmet Chem 1988;39:15–26. 37 Holzle E, Plewig G. Effects of dermatitis, stripping, and steroids on the morphology of corneocytes. A new bioassay. J Invest Dermatol 1977;68(6):350–6. 38 Voegeli R, Rawlings AV, Doppler S et al. Profiling of serine protease activities in human stratum corneum and detection of a stratum corneum tryptase-like enzyme. Int J Cosmet Sci 2007;29(3):191–200. 39 Fluhr J, Bankova LG. Skin surface pH: mechanism, measurement, importance. In: Serup J, Jemec GB, Grove GL (eds) Handbook of NonInvasive Methods and the Skin. Boca Raton, FL: CRC Press, 2006, pp. 411–20. 40 Nikolovski J, Stamatas GN, Kollias N et al. Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life. J Invest Dermatol 2008;128(7):1728–36.

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41 Voegeli R, Rawlings AV, Doppler S et al. Increased basal transepidermal water loss leads to elevation of some but not all stratum corneum serine proteases. Int J Cosmet Sci 2008;30(6):435–42.

Skin barrier dysfunction Disturbed skin differentiation Atopic dermatitis is characterized by a skin barrier defect evident from the increased TEWL. A number of changes in the structure and function of the barrier contribute to this reduced permeability barrier function (Fig. 27.6). The most significant structural defect identified is the reduced level of filaggrin in the skin of patients with AD. Loss-offunction mutations found within the FLG gene, encoding the inactive proform of filaggrin, strongly associate with AD and constitute the most important predisposing genetic factors identified so far [1,2]. Approximately 20% of all patients with AD carry a FLG loss-of-function mutation, which increases to 50% of all patients with severe AD. Mutations of the FLG gene were primarily identified as the underlying cause of ichthyosis vulgaris (IV), which often occurs concomitantly with AD. A deficiency of filaggrin is associated with dry and scaly skin, both characteristics of IV, and correlates with clinical severity and the barrier impairment in AD. The FLG gene is located within the epidermal differentiation complex (chromosomal location 1q21), a cluster of genes encoding a range of proteins involved in epidermal differentiation, many of which are incorporated into the CE, such as loricrin and involucrin. This region is strongly associated with a number of skin disorders including AD and psoriasis [2]. Several large-scale genetic studies have revealed extensive defects in epidermal differentiation in AD, which predominantly includes altered expression of genes encoded in this region [2–5]. Most notably, in addition to filaggrin, gene expression of involucrin, loricrin and corneodesmosin is decreased in patients with AD, concomitant with altered protein expression, compared to healthy controls. These defects have been observed in both lesional and non-lesional skin of patients with AD. On the other hand, the differentiation-dependent proteins transglutaminase 1 (14q12), a key enzyme involved in the formation of the CE, and the S100 proteins A7 (1q21), with antimicrobial and chemoattractant properties, for example, were found to be elevated in the lesional skin of patients with AD. These dramatic alterations in expression are evidence that differentiation, like the epidermal calcium gradient that regulates it, is broadly disturbed in AD. This broad disturbance results in the observed abnormal corneocyte morphology, reduced barrier function and a defective CE. The barrier defect resulting from filaggrin deficiency is augmented by the reduced abundance of NMF, the

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Chapter 27

Hydrated corneocytes

Intact corneodesmosomes

High levels of NMF

NMF

NMF

NMF

H2O

H2O

H2O

product of filaggrin catabolism [6]. The hygroscopic components of NMF are essential for maintaining SC hydration and the structure of the skin barrier by the swelling of corneocytes. Notably, their concentration in the skin generally correlates with dry skin conditions [7,8]. The deficiency of NMF in AD leads to decreased retention of moisture and increased TEWL.

Altered lipid metabolism Protease inhibitors

Degradatory proteases

Profilaggrin

(a)

Defective lipid lamellae

Degraded corneodesmosomes

Abnormal cornified envelope

NMF

NMF

NMF

H 2O

H2O

H2O

Protease inhibitors

(b)

Filaggrin

Degradatory proteases

Filaggrin

Profilaggrin

Fig. 27.6 (a) The structure of the intact skin barrier. The corneocytes (blue rectangles) of the SC are reinforced by a cornified envelope (dark blue), and contain NMF. NMF, derived from filaggrin catabolism, is a collection of natural humectants required to maintain optimal SC hydration. The corneocytes are joined together by specialized junctions known as corneodesmosomes (orange spheres) and encapsulated in the lipid lamellae (pink). To balance the proliferation of basal keratinocytes, a cocktail of proteases degrades the corneodesmosomal junctions to liberate fully mature corneocytes in a process referred to as desquamation. The presence of protease inhibitors ensures that desquamation is restricted to only the uppermost layers of the SC. (b) The defective skin barrier present in AD. Altered differentiation leads to a defective cornified envelope (dark blue) and reduced levels of NMF. The composition of the lipid lamellae (pink) is abnormal and contains significantly reduced ceramide levels. The degradation of corneodesmosomes (orange spheres) is enhanced owing to the decreased expression of protease inhibitors, increased expression of degradatory proteases, and the elevated skin surface pH associated with AD. The consequence of this broad skin barrier defect is elevated TEWL, a reduced capacity of the SC to hold water (reduced moisturization), and increased penetration of irritants and allergens.

The lipid content of the SC consists of equimolar concentrations of cholesterol phospholipids and ceramides required to maintain the lamellar mesh, which encases the corneocytes and prohibits water loss [9]. In AD, there is a reduction in the amount of total lipids owing to a significant deficit in ceramides found in both lesional and non-lesional skin of patients with AD compared to controls (reviewed in [10]). Ceramide insufficiency is partly attributed to the increased activity of glucosylceramide sphingomyelin deacylase, which breaks down the ceramide precursors glucosylceramide and sphingomyelin to yield FFA. The types of bacteria colonizing the skin of patients with AD was also found to produce elevated levels of ceramidase, an enzyme which cleaves ceramides into FFA and sphingosine. Ceramides, particularly ceramide 1 and 4, play an important role in the organization of the lamellar membrane sheets and the formation of the lipid envelope, which forms a protective sheath around the corneocytes by attachment to involucrin incorporated in the CE [10]. This interaction with the CE physically intertwines the corneocytes into the lipid lamellae, creating a cohesive and dynamic barrier. The ceramide insufficiency associated with AD results in the defective formation of the lipid lamellae and the lipid envelope, and was found to correlate with xerosis and reduced barrier function based on TEWL measurements [11]. Despite the decrease in total lipids, phospholipid levels were found to be elevated in the lesional and non-lesional skin of AD patients compared to healthy skin [12]. The amount of FFA was also increased and attributed to the enhanced activity of PLA2, which breaks down phospholipids, and the degradation of ceramides. Intriguingly, there was a distinct alteration in the pattern of fatty acids (free and as constituents of phospholipids), with a reduction of omega-6 unsaturated fatty acids (ω-6 USFA) and an elevation of monounsaturated fatty acids (MUSFA) [12]. This pattern may correlate with disease severity; for example, a decrease in ω-6 USFA is associated with an increased severity of AD. Moreover, a reduction in ω-6 USFA and an elevation in MUSFA are associated with pruritus, xerosis and increased TEWL [12]. Ceramides synthesized with ω-6 USFA, such as linoleic acid used in the synthesis of ceramide 1, play a key role in the structure of the lamellar membranes [10]. The substitution of

The Skin Barrier in Atopic Dermatitis

ω-6 USFA-derived ceramides with those synthesized with MUSFA, such as oleic acid, adversely affects barrier structure. In addition, the role of these FFA in barrier homeostasis suggests a possible shift from PPARα activation, which promotes barrier repair, to NMDA-directed inhibition of barrier repair [13].

Elevated SC pH The altered metabolism of lipids in the epidermis can be explained, at least in part, by the altered skin pH in AD. The uninvolved skin of patients with AD is significantly elevated, with further increase towards a near neutral surface pH in involved areas [14]. As introduced earlier, pH plays an important role in the maintenance of skin barrier homeostasis. An increase in skin pH is thought to inhibit the activity of β-GlucCer ’ase and acid sphingomyelinase required for the synthesis of ceramide, which exhibit optimum activity at acidic pH [15]. The expected alteration in enzyme activity is independent of βGlucCer ’ase levels that were found to be similar in skin samples from patients with AD and normal controls [10]. Recently, Hatano and colleagues reported that the maintenance of an acidic SC prevents the emergence of hapteninduced murine AD (mAD) [16]. Hapten-induced mAD bears many of the characteristics associated with AD including a chronic, pruritic, inflammatory dermatosis and increased TEWL. The maintenance of an acidic pH reduced the appearance of these characteristics in response to repeated treatment with the hapten oxazalone, and was shown to affect a number of mechanisms already associated with the development of AD, including the attenuation of T helper type 2 cell (Th2) dominant inflammation, and normalization of protease and lipid synthesis enzyme activities. The lipid abnormalities associated with AD, resulting from hapten-induced mAD, included an inhibition of lipid processing and reduction in LB secretion, required for the delivery of lipids to the SC. SC acidification was shown to partially restore activity of the lipid processing enzyme β-GlucCer ’ase and reinstate LB secretion, thereby repairing the lipid defect. As discussed above, serine protease-PAR2 signalling regulates LB secretion [17]. Notably, serine protease activity was substantially upregulated in the SC following hapten-induced mAD, which could be prevented by maintaining an acidic SC. Activation of PAR2 by serine proteases triggers inflammation, pruritus and a delay in permeability barrier repair [18], suggesting a key role in the development of hapteninduced mAD, and by inference AD.

Increased SC protease activity Elevated serine protease activities are strongly associated with AD due to the increased rate of desquamation

27.11

observed compared to normal skin. Increased levels of seven KLKs involved in desquamation are associated with AD [19,20]. It has been demonstrated that transgenic mice overexpressing human KLK7, with chymotryptic activity, develop changes in their skin similar to those seen in chronic AD [21]. Vasilopoulos and colleagues reported a significant association between a genetic variant of the KLK7 gene, which could potentially result in elevated expression of KLK7, and non-atopic dermatitis [22]. Two subsequent studies, however, have failed to confirm an association with AD [23]. Despite this KLK7 expression does appear to be elevated in the skin of patients with AD compared to controls [3,19,20]. It has been suggested that the level of protease activity at the SC is an important indicator of milder forms of barrier disruption, including sensitive skin, in addition to AD [24]. The level of proteases quantified in samples of human SC was found to correlate with biophysical measures of skin condition including hydration and TEWL [24]. Trypsin-like (including KLK5 and KLK14), tryptaselike, plasmin and urokinase activities, but not chymotrypsin-like activities (including KLK7), were positively correlated with TEWL and negatively correlated with hydration. Interestingly, the type of protease activity that correlates with barrier integrity is consistent with the types of protease capable of activating PAR2, involved in barrier homeostasis [25]. The lesional skin of patients with AD is characterized by the increased presence of PAR2 receptors and an overproduction of TSLP [25,26]. Combined with the increased levels of proteases capable of activating PAR2, at an elevated pH, in AD, this suggests that the serine protease PAR2 pathway is potently activated, and that it plays a role in the development of AD lesions. A reduced expression of protease inhibitors is also associated with AD. For instance, several studies have linked mutations within the SPINK5 gene, encoding the serine protease inhibitor LEKTI, with AD when maternally inherited [27,28]. Mutations of the SPINK5 gene are the underlying cause of Netherton’s syndrome (NS), a severe autosomal recessive disorder of the skin with atopic manifestations. Individuals with this disorder display marked barrier dysfunction, involving altered desquamation and impaired keratinization as a result of elevated KLK5 and KLK7 activity [29]. Furthermore, elevated KLK5 activity in the SC of patients with NS was directly linked to the development of AD-like inflammatory lesions, by triggering PAR2-mediated release of TSLP [29]. Expression of the cystatin A protease inhibitor, with dual roles in epidermal differentiation and desquamation, was also found to be decreased in AD, and attributed to a genetic variant of the CSTA gene associated with the development of AD [30].

27.12

Chapter 27

References 1 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(4): 441–6. 2 Brown SJ, McLean WH. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 2009;129(3):543–52. 3 Saaf AM, Tengvall-Linder M, Chang HY et al. Global expression profiling in atopic eczema reveals reciprocal expression of inflammatory and lipid genes. PLoS ONE 2008;3(12):e4017. 4 Guttman-Yassky E, Suarez-Farinas M, Chiricozzi A et al. Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J Allergy Clin Immunol 2009;124(6):1235– 44 e58. 5 Sugiura H, Ebise H, Tazawa T et al. Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br J Dermatol 2005;152(1):146–9. 6 Kezic S, Kemperman PM, Koster ES et al. Loss-of-function mutations in the filaggrin gene lead to reduced level of natural moisturizing factor in the stratum corneum. J Invest Dermatol 2008;128(8): 2117–19. 7 Harding CR, Watkinson A, Rawlings AV et al. Dry skin, moisturization and corneodesmolysis. Int J Cosmet Sci 2000;22(1):21–52. 8 Nakagawa N, Sakai S, Matsumoto M et al. Relationship between NMF (lactate and potassium) content and the physical properties of the stratum corneum in healthy subjects. J Invest Dermatol 2004;122(3):755–63. 9 Schurer NY, Elias PM. The biochemistry and function of stratum corneum lipids. Adv Lipid Res 1991;24:27–56. 10 Proksch E, Jensen JM, Elias PM. Skin lipids and epidermal differentiation in atopic dermatitis. Clin Dermatol 2003;21(2):134–44. 11 Meguro S, Arai Y, Masukawa Y et al. Relationship between covalently bound ceramides and transepidermal water loss (TEWL). Arch Dermatol Res 2000;292(9):463–8. 12 Schafer L, Kragballe K. Abnormalities in epidermal lipid metabolism in patients with atopic dermatitis. J Invest Dermatol 1991;96(1): 10–15. 13 Katsuta Y, Iida T, Hasegawa K et al. Function of oleic acid on epidermal barrier and calcium influx into keratinocytes is associated with N-methyl D-aspartate-type glutamate receptors. Br J Dermatol 2009;160(1):69–74. 14 Fluhr J, Bankova LG. Skin surface pH: mechanism, measurement, importance. In: Serup J, Jemec GB, Grove GL (eds) Handbook of NonInvasive Methods and the Skin. Boca Raton, FL: CRC Press, 2006, pp. 411–20. 15 Hachem JP, Man MQ, Crumrine D et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol 2005;125(3):510–20. 16 Hatano Y, Man MQ, Uchida Y et al. Maintenance of an acidic stratum corneum prevents emergence of murine atopic dermatitis. J Invest Dermatol 2009;129(7):1824–35. 17 Demerjian M, Hachem JP, Tschachler E et al. Acute modulations in permeability barrier function regulate epidermal cornification: role of caspase-14 and the protease-activated receptor type 2. Am J Pathol 2008;172(1):86–97. 18 Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol 2008;153 Suppl 1:S263–82. 19 Komatsu N, Saijoh K, Kuk C et al. Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients. Exp Dermatol 2007;16(6):513–19.

20 Voegeli R, Rawlings AV, Breternitz M et al. Increased stratum corneum serine protease activity in acute eczematous atopic skin. Br J Dermatol 2009;161(1):70–7. 21 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):444–9. 22 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 2002;123(1):62–6. 23 Weidinger S, Baurecht H, Wagenpfeil S et al. Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J Allergy Clin Immunol 2008;122(3):560–8 e4. 24 Voegeli R, Rawlings AV, Doppler S et al. Increased basal transepidermal water loss leads to elevation of some but not all stratum corneum serine proteases. Int J Cosmet Sci 2008;30(6):435–42. 25 Stefansson K, Brattsand M, Roosterman D et al. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol 2008;128(1):18–25. 26 Soumelis V, Reche PA, Kanzler H et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3(7):673–80. 27 Walley AJ, Chavanas S, Moffatt MF et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29(2):175–8. 28 Morar N, Willis-Owen SA, Moffatt MF et al. The genetics of atopic dermatitis. J Allergy Clin Immunol 2006;118(1):24–34. 29 Briot A, Deraison C, Lacroix M et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 2009; 206(5):1135–47. 30 Vasilopoulos Y, Cork MJ, Teare D et al. A nonsynonymous substitution of cystatin A, a cysteine protease inhibitor of house dust mite protease, leads to decreased mRNA stability and shows a significant association with atopic dermatitis. Allergy 2007;62(5):514–19.

Development of the skin barrier Normal development of the skin barrier from birth Early development of AD is considered the first step along the ‘atopic march’ that can lead onto asthma and allergic rhinitis [1]. The condition and functionality of the skin barrier are therefore most important during these early years. It has been suggested that the SC reaches maturity anywhere between 30 and 37 weeks of gestational age, but this contradicts the generally acknowledged ‘sensitive’ nature of infant skin [2]. To emphasize this, 78% of participants in one study reported a ‘rash’ in the first month of their newborn’s life. Infant skin is prone to the development of irritant/allergic contact dermatitis, suggesting that the permeability barrier function of the SC is not fully developed [2]. Research into the biophysical properties of the neonatal skin barrier has yielded varying findings depending heavily on the experimental design [2]. Disparate TEWL measurements are largely accountable for this and can in

The Skin Barrier in Atopic Dermatitis

part be attributed to the use of different experimental procedures and instrumentation (open- versus closedchamber TEWL measurement devices). For instance, open-chamber measurement probes are prone to underestimate TEWL compared with the newer closed chamber probes due to a greater dependency on the external environment [3]. The extensive use of TEWL to assess skin barrier function has greatly advanced our understanding of the technique and its application. For instance, it is clear that the experimental procedure followed greatly influences the results; in particular, the environmental conditions of the room in which the readings are taken must be controlled [3]. On review of the current literature, taking into account our current understanding of the technique, the most convincing data suggest wideranging TEWL readings during infancy that are generally elevated compared to adult values, and also to those of neonates [2,4]. This increased variability, compared to TEWL measurements taken from adults, fits with the suggestion that infant skin is in a state of flux, and requires a period of time to adjust to the extrauterine environment. Increased TEWL reported during the first year of life was confirmed by measuring the rate of water absorption and desorption from the skin [4]. A similar trend for increased TEWL was also reported for newborn rats, in which a concurrent delay in skin barrier repair in response to injury (tape-stripping or acetone treatment) was observed compared to 5–6-day old rats [5]. The increase in TEWL may indicate increased percutaneous absorption and thereby an increase in the risk to allergen and irritant penetration [6]. An inverse relationship has been reported between postnatal age and the percutaneous absorption of isotope-labelled benzoic acid [7]. This may account, at least in part, for the increased prevalence of allergic/ irritant contact dermatitis in infants. Stratum corneum hydration (SCH) was found to be reduced in term infants compared to adults. However, it increases with increasing postnatal age, resulting in higher, more varied levels in infants (3–12 months old) compared to adults [2,4,8]. This finding was confirmed using in vivo Raman confocal microscopy to quantify the amount of water present in the SC [4]. Notably, the gradient of water through the skin was also steeper in infants compared to adults, which can, at least in part, be attributed to the thinner SC in infants [9]. Taken together, the water-handling properties of the infant SC appear to be very different to those of an adult. One of the causes of this may be the reduced amount of NMF found within the skin of infants compared to adults [4]. As mentioned earlier, NMF is a key skin barrier component involved in moisture retention, the levels of which in the SC correlate with TEWL, amongst other biophysical parameters of permeability barrier function [10].

27.13

Components of NMF also play a role in maintaining the acidic pH of the skin surface [10]. Pertinently, skin surface pH is neutral at birth in humans and only gradually develops an acid pH over a period of at least 3 months, and may not reach normal/adult pH levels until 2 years of age [2]. As already discussed, pH is a key factor governing skin barrier homeostasis, including regulation of desquamation and lipid synthesis. Elevated skin surface pH in newborn rats was found to be responsible for a reduced abundance of CDSN and DSG1, owing to an increased activity of serine proteases [5,11]. In humans, the size of the uppermost corneocytes was 20% smaller in infants (3–24 months) compared to adults, which suggests an increased rate of desquamation resulting from elevated protease activities [9]. Furthermore, the activity of β-GlucCer ’ase, present at normal levels in neonatal epidermis, is reduced due to the elevated pH, leading to impaired lipid synthesis [8]. The nuclear receptor PPARα was shown to play a pivotal role in regulating postnatal SC acidification in the rat, whereby its targeted inhibition delayed SC acidification [11]. Activation of PPARα in newborn rats with clofibrate resulted in the normalization of barrier homeostasis, including the inhibition of serine protease activity and restoration of β-GlucCer ’ase activity [11]. Ultimately, PPARα activation improved skin barrier integrity assessed as reduced TEWL, with visual improvement in the maturation of the lamellar membranes and density of corneodesmosomal junctions. Both NHE1 and sPLA2 were also found to contribute to postnatal acidification in rats. Activity of sPLA2 is directly regulated via PPARα and is associated with skin barrier structure and function [11]. Inhibition of sPLA2 results in a barrier defect consistent with the incompletely processed extracellular lamellar membranes present in the SC of newborn rats [5,8]. sPLA2 catalyses the breakdown of phospholipids into FFA, of which very low levels have been reported in human samples taken from the forehead at birth [12]. In infants, however, from the age of 1 month to 4 years, FFA levels were elevated compared to adult levels. These observations suggest that delayed activation of PPARα may contribute to the gradual acidification of the human SC from birth onwards. However, the increased composition of FFA in the SC of infants compared to adults suggests the involvement of additional mechanisms. PPARα also appears to regulate the expression of proteins involved in the structure and formation of the CE, including filaggrin [13]. The constituents of NMF are derived from the catabolism of filaggrin, but despite prenatal expression of this protein, there is a deficit of filaggrin breakdown products (NMF) in the SC of infants compared to adults [4]. The acidic components of NMF correlate with SC pH, suggesting that this early lack of NMF may also contribute to the abnormal barrier

27.14

Chapter 27

function associated with increased surface pH in infants [10]. The composition and type of total lipids in the SC appear to be dynamic during infancy, and can be expected to alter the structure of the lamellar membranes, affecting their ability to prevent the loss of water and the ingress of irritants and allergens [12,14]. In addition to elevated FFA levels, the composition of cholesterol in human SC is increased during infancy compared to adults, and is associated with the reduced production of sebum before puberty [12]. Studies in mice demonstrated that there is a deficiency in ester-linked FA containing linoleate at birth, which progressively increases with increasing postnatal age [14]. As introduced above, an absence of linoleate is associated with abnormal formation and packing of lamellar membranes and a reduction in skin barrier function. Linoleic acid is also a potent activator of PPARα, so the levels of this FFA in the epidermis may be important in regulating postnatal skin barrier homeostasis [13]. The composition of lipids is also associated with susceptibility to skin infections, which more commonly afflict children than adults [2,15]. The altered production and lipid composition of sebum, which varies with age, are associated with the development of acne, including acne infantum, relevant during the development of the barrier [16]. In AD, increased Staph. aureus colonization correlates with a reduction in the composition of antibacterial lipids in the SC [15]. Skin surface pH also plays an important role in the antimicrobial barrier. For example, the normal acidic pH of the skin limits the growth of propionibacteria and Staph. aureus [17]. Staph. aureus infection is the most common complication of AD and, as mentioned, plays an important role in determining the severity of the disease [18–20]. The elevated surface pH of infant skin and altered lipid profile may therefore play an important role in the development of AD by altering the properties of the antimicrobial barrier.

Barrier development and AD Although there is still a lack of research on the structure of the human skin barrier from birth and into infancy compared to adult skin, the evidence reviewed above supports a period of reduced integrity and permeability barrier function during the first weeks to months of life. This temporary impairment of barrier function can be interpreted as a period of optimization and adjustment [2,4]. The mechanisms involved appear to be the same as those that are dysfunctional in conditions such as AD, including altered pH and water-handling properties of the stratum corneum. One can hypothesize that the genetic predisposition to the barrier defect associated with AD will further disrupt and/or delay barrier ‘optimization’ following birth. As such, the risk of developing AD would be greatest during this time. Indeed, 45% of

AD cases arise during the first 6 months of life, and 60% by the first 12 months [21]. Pertinently, the period required for normalization of SC pH appears to coincide with the age by which the majority of cases of AD, particularly severe AD, first develop [2] (Fig. 27.7). Furthermore, Illi and colleagues reported that 43.2% of children with earlyonset AD were in complete remission by the age of 3 [22]. This may reflect the progressive development of the barrier, perhaps delayed by a predisposed defect and the interaction of adverse environmental factors, over the first months of life. Further research is absolutely required to ascertain both the contribution of the immature skin barrier to the risk of developing AD, and the effect of the underlying barrier defect associated with AD on maturation of the barrier.

Clinical implications of a defective skin barrier The sites of predisposition to the development of AD in unaffected individuals are the face and flexures, where the stratum corneum is at its thinnest [23] (Fig. 27.8). The stratum corneum is 30% thinner in a baby at birth compared to an adult [9]. This has functional significance because the TEWL in a normal baby at birth is five times higher than in an adult [4]. This indicates that the skin barrier in a normal baby at birth is severely defective compared to an adult. The combination of a thin skin barrier in normal skin on the face means that a baby’s face has the lowest ‘skin barrier reserve’ and therefore, considering this hypothesis, is the area most likely to develop AD. Furthermore, the skin barrier in non-lesional AD skin is up to 35% thinner than in the skin of an individual without AD [24]. Environmental factors on the face, such as saliva, nasal secretions and some foods, interact with the genetic variants to exacerbate the skin barrier defect [25]. Saliva contains proteases and lipases and has a pH of 7.42 (±0.4) with a substantial buffering capacity [26]. This provides an optimal pH for protease activity and therefore facilitates skin barrier breakdown. Similarly, breast milk has a pH of 7.29 (±0.19) [27], and nasal secretions have a pH of 6.91 (±0.06) [28], which is optimal for protease activity. The combination of saliva, breast milk and nasal secretions caught under a dummy (pacifier) in a baby with AD leads to a localized drooling dermatitis around the mouth and onto the cheeks [25]. A combination of adverse environmental factors also constitutes the mechanism by which napkin dermatitis arises, in which case urine and faeces, in conjunction with napkin occlusion, are responsible for the elevation of skin surface pH and are the source of additional degradatory proteases and lipases [29]. Drooling dermatitis may play a role in the development of food allergy. The route of sensitization to some

The Skin Barrier in Atopic Dermatitis

∗

45%

∗

60%

Epidermal Barrier Function

Developed skin barrier

Positive Intervention

27.15

No predisposition Mild predisposition Severe predisposition

Most at risk age group Developed skin barrier

Negative Environment Interaction

6

12 18 Age (Months)

24

Fig. 27.7 An illustrative representation of the proposed development of AD with age. Skin barrier function, assessed by TEWL, does not achieve adult status until after 1 year of age [63]. The stratum corneum does not appear to reach maturity on average until after 24 months [92]. A predisposition to a defective skin barrier, the severity of which is thought to be dependent on gene-gene (and gene-environment) interaction, is thought to delay skin barrier development (amber and red lines), compared to having no predisposition (green line). The function of the fully developed barrier is similarly dependent on the inherited predisposition and will determine the life-long susceptibility of an individual to environmental insults. The effect of a given predisposing factor may be compensated for by the epidermal barrier reserve, which is present in normal skin, and may therefore appear normal until challenged. For instance a KLK7 mutation has been associated with mild ‘non-atopic’ AD [79] and the expected elevation in KLK7 levels has been associated with ‘sensitive skin’ [64] – skin with an increased susceptibility to environmental challenges. On the other hand carriers of FLG loss-of-function mutations who are also exposed to cat allergens are at the highest risk of developing severe AD [116]. *45% of AD cases will arise by the age of 6 months, and *60% by 12 months [2]. The prevalence of AD in the first 2 years of life is 21.5% [100]. Positive intervention that improves skin barrier function towards the fully developed barrier is expected to decrease the risk of developing AD (green arrow). The interaction of negative environmental factors, such as cat allergens, with genetic factors associated with AD is known to increase the risk of developing the condition (red arrow). Please refer to the text for additional explanation.

Fig. 27.8 Sites of predisposition to AD such as the face have the lowest skin barrier reserve and are most vulnerable to allergen penetration.

food allergens, such as peanut, is thought to be through the skin rather than by ingestion [30]. This highlights the importance of more effective treatment of facial AD in babies. Avoiding dummies (pacifiers) and using barrier emollients to reduce epidermal damage by saliva (and some foods) should be combined with effective, ‘nondestructive’ cleansing of the face using products that do not damage the skin barrier. A major environmental factor in the development of AD may be the use of soap and harsh ionic detergents, such as the surfactant sodium lauryl sulphate (SLS). Harsh surfactants damage the skin barrier by multiple mechanisms, the most important of which may involve an elevation of skin-surface pH [17]. The combination of environmental factors affecting skin-surface pH synergizes with the effect of reduced NMF levels (in some cases resulting from FLG loss-of-function mutations in AD, and inherently reduced levels during infancy) on SC pH, leading to optimal conditions for skin barrier breakdown. This breakdown of the barrier results from the elevated activity of both endogenous (desquamatory proteases) and exogenous proteases and

27.16

Chapter 27

lipases (from saliva, Staph. aureus, house dust mite, for example) and the reduced activity of lipid synthesis enzymes. Avoiding harsh surfactants such as SLS in wash products makes sense as an important first step in treating AD [31]. These should be replaced with positive emollient products. Surfactants are required to produce an emulsion in an emollient cream or wash product, but they are available in a spectrum from harsh anionic surfactants (e.g. SLS) to mild non-ionic surfactants [32]. It is essential to know the formulations of all products that are put onto the skin because even some emollient formulations contain harsh surfactants. Aqueous cream BP, for instance, contains 1% SLS and has been reported to cause irritant reactions in children with AD [33]. In adult volunteers, aqueous cream BP has also been shown to cause severe skin barrier breakdown as a result of enhanced protease activity [34]. The negative effects of washing are not limited to surfactants. The repeated exposure to the wash water itself, in the absence of surfactants, can be damaging to the barrier [35]. Part of the mechanism may be that water alone has a pH around 7.0 and no buffering capacity [35]. This would therefore enhance protease activity and skin barrier breakdown. Water alone is also not an effective cleanser, as it leaves fat-soluble substances on the skin surface that may damage the barrier, including some foods, saliva and nasal secretions. Hard water in particular, which contains high levels of calcium, was found to significantly increase dryness and erythema, indicating skin irritation [36]. It is thought that the presence of exogenous Ca2+ might inhibit the cutaneous homeostatic repair response (see Fig. 27.4). Areas with hard water are associated with an increased prevalence of AD in epidemiological studies [37]. Another example of a topical product that can damage the skin barrier is olive oil [38]. Olive oil and other oils, such as mustard seed oil, are used as massage oils for babies throughout the world and both of these oils have been shown to damage the skin barrier in a normal volunteer study [38]. The negative effects of these oils have been attributed, at least in part, to their high oleic acid to linoleic acid content. Oleic acid, as discussed earlier, inhibits skin barrier repair by targeting the NMDA receptor [39]. In contrast, the topical application of sunflower seed oil, which has a high linoleic acid to oleic acid content, resulted in enhanced skin barrier repair in normal volunteers [38]. This is attributed to the activation of PPARα by linoleic acid [40]. In addition to the divergent effects of linoleic acid and oleic acid on homeostatic mechanisms for skin barrier repair, the relative content of these fatty acids is important in determining the structure and function of the lipid lamellae [41]. Thus the ratio between linoleic acid and oleic acid in the skin appears

to be important in maintaining a healthy intact skin barrier. Exposure of the skin to individual negative environmental factors such as olive oil, hard water and harsh surfactants can cause significant damage alone, but these environmental exposures often occur in combination. The interaction between surfactants and the calcium in hard water used during washing, for example, is thought to amplify their negative effects by simultaneously inhibiting the repair response and promoting skin barrier breakdown [24,34,35,42]. Subsequent use of negative massage oils, such as olive oil, after washing, is likely to inhibit the skin’s recovery after the use of harsh surfactants and cause further damage to the structure of the skin barrier [38]. As an efficient penetration enhancer, oleic acid in olive oil is also likely to enhance the penetration of surfactants present in the residue left on the skin, or indeed the penetration of other environmental factors with the potential to cause irritation [43]. The very negative and very positive effects of different topical products on the structure and function of the skin barrier highlight the need to assess the properties of everything we apply to the skin, particularly where there is a predisposition to a defective skin barrier. This is especially important during the very first months of life where the barrier is not yet fully developed and the risk of developing AD is highest. It is pertinent to observe that up to 60% of carriers of FLG loss-of-function mutations never develop AD [44], suggesting the importance of gene–environment interaction [45] and, moreover, that a positive environment could prevent AD from ever occurring.

References 1 Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol 2003;112(6 Suppl):S118–27. 2 Chiou YB, Blume-Peytavi U. Stratum corneum maturation. A review of neonatal skin function. Skin Pharmacol Physiol 2004; 17(2):57–66. 3 Nuutinen J. Measurement of transepidermal water loss by closedchamber systems. In: Serup J, Jemec GBE, Grove GL (eds) Handbook of Non-Invasive Methods And The Skin, 2nd edn. Boca Raton, FL: CRC Press, 2006, pp. 393–6. 4 Nikolovski J, Stamatas GN, Kollias N et al. Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life. J Invest Dermatol 2008;128(7):1728–36. 5 Fluhr JW, Mao-Qiang M, Brown BE et al. Functional consequences of a neutral pH in neonatal rat stratum corneum. J Invest Dermatol 2004;123(1):140–51. 6 Levin J, Maibach H. The correlation between transepidermal water loss and percutaneous absorption: an overview. J Control Release 2005;103(2):291–9. 7 West DP, Halket JM, Harvey DR et al. Percutaneous absorption in preterm infants. Pediatr Dermatol 1987;4(3):234–7. 8 Behne MJ, Barry NP, Hanson KM et al. Neonatal development of the stratum corneum pH gradient: localization and mechanisms leading

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to emergence of optimal barrier function. J Invest Dermatol 2003;120(6):998–1006. Stamatas GN, Nikolovski J, Luedtke MA et al. Infant skin microstructure assessed in vivo differs from adult skin in organization and at the cellular level. Pediatr Dermatol 2010;27(2):125–31. Nakagawa N, Sakai S, Matsumoto M et al. Relationship between NMF (lactate and potassium) content and the physical properties of the stratum corneum in healthy subjects. J Invest Dermatol 2004;122(3):755–63. Fluhr JW, Man MQ, Hachem JP et al. Topical peroxisome proliferator activated receptor activators accelerate postnatal stratum corneum acidification. J Invest Dermatol 2009;129(2):365–74. Ramasastry P, Downing DT, Pochi PE et al. Chemical composition of human skin surface lipids from birth to puberty. J Invest Dermatol 1970;54(2):139–44. Hanley K, Jiang Y, He SS et al. Keratinocyte differentiation is stimulated by activators of the nuclear hormone receptor PPARalpha. J Invest Dermatol 1998;110(4):368–75. Wertz PW, Downing DT. Linoleate content of epidermal acylglucosylceramide in newborn, growing and mature mice. Biochim Biophys Acta 1986;876(3):469–73. Drake DR, Brogden KA, Dawson DV et al. Thematic review series: skin lipids. Antimicrobial lipids at the skin surface. J Lipid Res 2008;49(1):4–11. Basta M, Wilburg J, Heczko PB. In vitro effects of skin lipid extracts on skin bacteria in relation to age and acne changes. J Invest Dermatol 1980;74(6):437–9. Fluhr J, Bankova LG. Skin surface pH: mechanism, measurement, importance. In: Serup J, Jemec GBE, Grove GL (eds) Handbook of Non-Invasive Methods and the Skin, 2nd edn. Boca Raton, FL: CRC Press, 2006, pp. 411–20. Hirasawa Y, Takai T, Nakamura T et al. Staphylococcus aureus extracellular protease causes epidermal barrier dysfunction. J Invest Dermatol 2010;130(2):614–17. Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90(5):525–30. Huang JT, Abrams M, Tlougan B et al. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 2009;123(5):e808–14. Bieber T. Atopic dermatitis. N Engl J Med 2008;358(14):1483–94. Illi S, von Mutius E, Lau S et al. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004;113(5):925–31. Lee Y, Hwang K. Skin thickness of Korean adults. Surg Radiol Anat 2002;24(3–4):183–9. White MI, Jenkinson DM, Lloyd DH. The effect of washing on the thickness of the stratum corneum in normal and atopic individuals. Br J Dermatol 1987;116(4):525–30. Paller AS, Mancini A. Hurwitz Clinical Pediatric Dermatology, 3rd edn. Phildelphia: Saunders, 2006. Siqueira WL, Bermejo PR, Mustacchi Z et al. Buffer capacity, pH, and flow rate in saliva of children aged 2–60 months with Down syndrome. Clin Oral Invest 2005;9(1):26–9. Harrison VC, Peat G. Significance of milk pH in newborn infants. BMJ 1972; 4(5839):515–18. Ireson NJ, Tait JS, MacGregor GA et al. Comparison of nasal pH values in black and white individuals with normal and high blood pressure. Clin Sci (Lond) 2001;100(3):327–33. Adam R. Skin care of the diaper area. Pediatr Dermatol 2008; 25(4):427–33. Lack G, Fox D, Northstone K et al. Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348(11):977–85. Lewis-Jones S, Cork MJ, Clark C et al. Atopic eczema in children – guideline consultation: a systematic review of the treatments for

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atopic eczema and guideline for its management [electronic article]. London: National Institute for Clinical Excellence (NICE), Department of Health, 2007. Available from: http://guidance.nice.org.uk/ page.aspx?o=434713. Kuehl BL, Fyfe KS, Shear NH. Cutaneous cleansers. Skin Therapy Lett 2003;8(3):1–4. Cork MJ, Timmins J, Holden C et al. An audit of adverse drug reactions to aqueous cream in children with atopic eczema. Pharmaceut J 2003;271:746–7. Al Enezi T, Sultan A, Chittock J et al. Breakdown of the skin barrier induced by aqueous cream: implications for the management of atopic eczema. 89th Annual Meeting of the British Association of Dermatologists, Glasgow, 2009. Tsai TF, Maibach HI. How irritant is water? An overview. Contact Dermatitis 1999;41(6):311–14. Warren R, Ertel KD, Bartolo RG et al. The influence of hard water (calcium) and surfactants on irritant contact dermatitis. Contact Dermatitis 1996;35(6):337–43. McNally NJ, Williams HC, Phillips DR et al. Atopic eczema and domestic water hardness. Lancet 1998;352(9127):527–31. Darmstadt GL, Mao-Qiang M, Chi E et al. Impact of topical oils on the skin barrier: possible implications for neonatal health in developing countries. Acta Paediatr 202;91(5):546–54. Katsuta Y, Iida T, Hasegawa K et al. Function of oleic acid on epidermal barrier and calcium influx into keratinocytes is associated with N-methyl D-aspartate-type glutamate receptors. Br J Dermatol 2009;160(1):69–74. Hanley K, Jiang Y, Crumrine D et al. Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier. J Clin Invest 1997; 100(3):705–12. Proksch E, Jensen JM, Elias PM. Skin lipids and epidermal differentiation in atopic dermatitis. Clin Dermatol 2003;21(2):134–44. Lee SH, Elias PM, Proksch E et al. Calcium and potassium are important regulators of barrier homeostasis in murine epidermis. J Clin Invest 1992;89(2):530–8. Naik A, Pechtold LARM, Potts RO et al. Mechanism of oleic acidinduced skin penetration enhancement in vivo in humans. J Control Release 1995;37(3):299–306. Brown SJ, McLean WH. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 2009;129(3):543–52. Cork MJ, Danby SG, Vasilopoulos Y et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 2009;129(8):1892–908.

Conclusion Skin barrier structure and function are inherently dependent on the activities of myriad degradatory proteases and lipid synthesis enzymes found within the SC. The natural variations between different body sites, pigmenttype differences, and age-related changes in skin barrier structure and function are accompanied by changes in the activities of these enzymes. Moreover, the skin barrier abnormality associated with AD is accompanied by increased expression and activity of proteases, responsible for desquamation, and the altered activity of enzymes involved in the synthesis and degradation of the lipid lamellae. Importantly, pH is a central regulator of enzymatic activity within the SC. Skin-surface pH correlates

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with the general structure and function of the skin barrier, and is elevated in patients with AD. Elevation of skin surface pH is one of the proposed effects of FLG loss-of-function mutations, which show a strong association with AD. This indirect mechanism by which FLG mutations increase the risk of AD is attractive given that a filaggrin deficit per se does not necessarily cause AD. In fact, FLG mutations account for approximately 50% of moderate-to-severe cases of AD, and only up to 20% of mild-to-moderate cases, suggesting a role for additional genetic factors and gene–gene interaction [1,2]. Mutations of the SPINK5 have been associated with AD, albeit with a lower effect size, and are expected to alter protease activity within the SC. Environmental factors, such as the use of soap and harsh detergents, also play an important role in the development of AD and all appear to affect or contribute to the profile of activities within the skin barrier. Washing with SLS, for example, is associated with an elevation of skin surface pH [3], known to alter the activity of degradatory proteases and lipid-metabolizing enzymes [4]. All the contributing factors mentioned above support the theory of a defective skin barrier as the primary event in the development of AD. This primary defect then triggers local inflammation and pruritus. For instance, elevated trypsin-like serine protease activity results in PAR2 activation, which in turn triggers the release of the proinflammatory cytokines, including TSLP [5]. Recent evidence has demonstrated a link between the elevated levels of TSLP in response to skin barrier disruption and the development of asthma [6]. The role of the skin barrier in the development of atopy is twofold. Its disruption/abrogation permits the pene-

tration of allergens that trigger immune responses, and the mechanisms that sense skin barrier disruption direct local inflammation. Together, these mechanisms synergistically drive a strong Th2 inflammatory response [7]. This suggests that a skin barrier defect is not only a primary event in the development of AD, but also the first event along the so-called atopic march. Changing the environment of a genetically predisposed baby from birth may therefore not only influence the development of AD but also the progression of some babies along the atopic march. References 1 Brown SJ, McLean WH. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 2009;129(3):543–52. 2 Morar N, Willis-Owen SA, Moffatt MF et al. The genetics of atopic dermatitis. J Allergy Clin Immunol 2006;118(1):24–34. 3 Fluhr J, Bankova LG. Skin surface pH: mechanism, measurement, importance. In: Serup J, Jemec GB, Grove GL (eds) Handbook of NonInvasive Methods and the Skin. Boca Raton, FL: CRC Press, 2006, pp. 411–20. 4 Hachem JP, Man MQ, Crumrine D et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol 2005;125(3):510–20. 5 Briot A, Deraison C, Lacroix M et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 2009; 206(5):1135–47. 6 Demehri S, Morimoto M, Holtzman MJ et al. Skin-derived TSLP triggers progression from epidermal barrier defects to asthma. PLoS Biol 2009;7(5):e1000067. 7 Bieber T. Atopic dermatitis. N Engl J Med 2008;358(14):1483–94.

28.1

C H A P T E R 28

Clinical Features and Diagnostic Criteria of Atopic Dermatitis Sinéad M. Langan1 & Hywel C.G. Williams2 1

Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA The Centre of Evidence-Based Dermatology, University of Nottingham, Nottingham, UK

2

Clinical features of atopic dermatitis that may be useful for clinical practice, 28.1

Diagnostic criteria for atopic dermatitis used in clinical studies, 28.10

This chapter is divided into two sections: the first lists the common and less common clinical features of atopic dermatitis (AD) with the aim of helping those less familiar with diagnosing atopic dermatitis in a clinical setting. The second part deals with diagnostic criteria for atopic dermatitis that may be used in research studies. The two sections are set apart deliberately since the requirements of a disease definition for making a group definition for use in research purposes may be somewhat different from those that may be useful in making a clinical diagnosis in an individual. For example, a clinical sign such as thinning of the lateral eyebrows may be associated with AD, and possibly useful in the context of tipping a clinician to make an operating diagnosis of AD in a child with indeterminate skin inflammation, yet it is too difficult to define reliably and too infrequent to be of use when examining groups of individuals, especially when it adds very little to the predictive ability of existing cardinal features such as flexural involvement and dry skin. Likewise, diagnostic criteria that may produce acceptable results for estimating the prevalence of AD in a country may not be suitable when trying to diagnose AD in an individual, since every set of diagnostic criteria will have limitations in sensitivity (proportion of true cases correctly identified) and specificity (proportion of non-cases correctly identified). All current diagnostic criteria will therefore misclassify some individuals who have AD as not having AD, and some who do not have AD as having AD. Such misclassification may be acceptable in research studies providing the degree of misclassification is understood in relation to the objective of the study.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Clinical features of atopic dermatitis that may be useful for clinical practice The evidence for the first section of this chapter is largely based on classical descriptions in textbooks and scholarly articles by pioneers in the field of atopic dermatitis, supplemented by clinical experience. An excellent historical account of the concepts that formed the notion of what is recognized today as AD may be found elsewhere [1]. Multiple factors including age, ethnic origin, level of disease activity, therapeutic interventions and infectious complications influence both distribution and morphology of AD leading to variations in disease presentation. The characteristic clinical features of AD distribution and morphology described here aid clinical diagnosis in the absence of a specific laboratory test for AD.

Distribution The distribution of AD is dependent on the age of onset and disease activity. Infantile eczema usually starts at 3 months or younger and typically affects the face and scalp first (Fig. 28.1a,b), then spreads to involve the extensor surfaces (Fig. 28.2) of the limbs and trunk in a symmetrical distribution [2]. Truncal lesions are diffuse while limb lesions tend to be discrete and localized (Fig. 28.3). The nappy area is frequently spared for reasons that are unclear, although local humidity has been suggested. In childhood, AD distribution changes from an extensor to a flexural pattern at around 2–3 years of age. The tendency for skin inflammation and the effects of chronic rubbing (lichenification) to become accentuated in the flexures is one of the classical hallmarks of AD (Fig. 28.4) [3]. Flexures refer to bends in the articular skeleton where skin apposes skin. What exactly constitutes a flexure varies from text to text, but most agree that the fronts of

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(a)

Fig. 28.2 Infantile facial eczema and diffuse truncal erythema. Courtesy of Dr Paula E. Beattie.

(b) Fig. 28.1 Scalp involvement in infantile atopic dermatitis. Courtesy of Dr Paula E. Beattie.

Fig. 28.3 Symmetrical eczema involving the trunk and extensor surfaces in infantile atopic dermatitis. Courtesy of Professor Hywel C. Williams.

Fig. 28.4 Thickened lichenified atopic dermatitis on the lower leg and dorsal foot in darkly pigmented skin. Courtesy of Professor Hywel C. Williams.

Clinical Features and Diagnostic Criteria of Atopic Dermatitis

(a)

28.3

(b)

Fig. 28.5 (a,b) Flexural subacute atopic dermatitis involving the antecubital and popliteal fossae with erythema and excoriations. Courtesy of Professor Hywel C. Williams.

the elbows, backs of the knees, around the neck and in front of the ankles are the commonly affected flexures. All of the flexure is not always involved – lichenification as a result of prolonged rubbing typically occurs most prominently behind the knees along the most prominent tendons (semimembranosus and semitendinosus) and likewise overlying the brachioradialis muscle group on the antecubital fossae (Fig. 28.5a,b). Other less commonly affected areas include the wrists and folds beneath the buttocks (infragluteal folds). Why the axillae are infrequently involved is unclear, and the presence of axillary involvement may be a marker of seborrhoeic as opposed to atopic dermatitis. Two points are worthy of note with regards to flexural involvement; the first is that AD can affect any part of the body. The fact that a child presents with an itchy scalp and diffuse patches of skin inflammation on extensor parts of the limbs should not put one off diagnosing AD since it is the most common inflamed itchy chronic skin eruption in developed countries. From puberty onwards, AD tends to affect the face, hands, back, wrists and dorsal feet. The hands and fingers are frequently involved probably as a result of constant irritant exposure, which may result in fissures overlying the finger joints (Fig. 28.6) and scaling on the palms adjoining the fingers (apron sign). Adults may only have persisting hand eczema and skin that is sensitive to irritant exposure, or they may have persistent chronic AD. Specific sites that are frequently involved by AD are as follows: lips with cheilitis in childhood (Fig. 28.7), which can lead to secondary ‘lip-lick cheilitis’ or exfoliating cheilitis with perlèche (single or multiple fissures and cracks at the labial commissures) and involvement of the vermillion border in adult AD. The retroauricular region is frequently affected by fissures (rhagades) in children

Fig. 28.6 Chronic hand eczema with loss of cuticles, nail dystrophy, fissuring and scaling. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

(Fig. 28.8) while eyelids are frequently involved in adolescents and adults. Nipple eczema is frequently seen from puberty onwards (Fig. 28.9). Some sites of predilection of AD such as around the eyes, mouth or nose (Fig. 28.10) or under the ear also occur probably as a result of influences other than skin-to-skin contact such as airborne allergens and irritants, or irritant contact dermatitis around the mouth from saliva and wet foods in early age.

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Fig. 28.7 Acute cheilitis in a child with atopic dermatitis with erythema and swelling of the vermillion border and perioral region and fissuring of the commissures. Courtesy of Professor Dr Thomas Diepgen and Dermis. net.

Fig. 28.9 Acute nipple eczema with erythema, erosions, oozing and secondary impetiginization. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

Fig. 28.10 Subacute eczema with fissuring and oedema. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

Fig. 28.8 Rhagades of the infra-auricular region in childhood atopic dermatitis. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

Configuration In addition to the distributions described, AD can occasionally demonstrate a Koebner phenomenon, whereby new lesions develop at the site of skin injury.

Morphology The morphology of AD can be variable and depends on the stage of the lesion. Acute lesions are characterized by ill-defined erythema, papules, papulovesicles, erosions

and weeping (Fig. 28.11a). Subacute lesions are erythematous scaly excoriated plaques and papules (Fig. 28.11b) while thickened purple/grey lichenified plaques and fibrotic papules (prurigo) are seen in chronic lesions (Fig. 28.11c). During infancy, AD tends to be acute and exudative with chronic forms of AD developing later in childhood. In longstanding AD, individuals may manifest all three stages of AD concurrently or at different times depending on the level of disease activity, reflecting the relapsing and remitting nature of eczema.

Associated physical signs A number of clinical signs frequently accompany AD and may be clues to the diagnosis when the distribution and morphology are not classical, although they may not be pathognomonic of AD. A number of these will be briefly discussed here.

Clinical Features and Diagnostic Criteria of Atopic Dermatitis

28.5

(b) (a)

(c) Fig. 28.11 (a) Acute, (b) subacute and (c) chronic eczema. Courtesy of Professor Hywel C. Williams.

Periocular and ocular signs Infraorbital folds (Dennie–Morgan lines) are frequently seen in AD, with most studies reporting their presence in 50–60% of cases of AD. However, this sign appears to vary depending on ethnicity and shows significant variability even within individuals (Fig. 28.12). Periorbital pigmentation, ‘atopic shiners’, describes a periorbital brown to grey discoloration [4]. As previously discussed, thinning or absence of the outer eyebrows (Hertoghe’s sign), a sign originally described in hypothyroidism, may also be seen although its prevalence has not been extensively studied (Fig. 28.13). Specific ocular signs such as keratoconjunctivitis, keratoconus and anterior subcapsular cataracts may be associated with AD although their population-based frequency is difficult to identify from the literature.

Other cutaneous ‘minor’ signs Two features are described in the neck region, namely the anterior neck folds and atopic ‘dirty neck’ (Fig. 28.14). The ‘dirty neck’ refers to rippled hyperpigmentation of

Fig. 28.12 Symmetrical infraorbital Morgan–Dennie folds. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

the anterior and lateral neck, which clinically resembles macular amyloid. Facial pallor and white dermographism (blanching of the skin at the site of stroking with a blunt instrument rather than developing a partial or full triple response of Lewis with reflex erythema), are frequently

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Fig. 28.13 Thinning of the outer eyebrows (Hertoghe’s sign) with extensive scaling and lichenification of the forehead. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

described in AD and are thought to represent abnormal vascular responses (Fig. 28.15). Dry skin (xerosis) is seen in all age groups with AD and is considered a hallmark of AD (Fig. 28.16). This is characterized by fine scaling without associated inflammation and roughness on palpation. Dry skin may be associated with ichthyosis vulgaris, an autosomal dominant condition seen in 8% of individuals with AD [5,6]. However, studies show that dry skin is also independently associated with AD in the absence of icthyosis vulgaris [7]. Hyperlinear palms are a frequent finding in AD (Fig. 28.17). Recent studies have shown that palmar hyperlinearity is more frequently seen in AD compared to atopiform dermatitis (AD without raised IgE levels) and that this sign is strongly associated with filaggrin null mutations and ichthyosis vulgaris [8,9]. Pityriasis alba describes a condition frequently associated with AD characterized by poorly defined slightly scaly hypopigmented patches on the cheeks and upper arms (Fig. 28.18). This clinical sign is more obvious in dark skin and can be mistaken for tinea corporis.

Fig. 28.14 Rippled hyperpigmentation of the lateral neck (atopic ‘dirty neck’). Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

Atopic dermatitis in dark skin types The diagnosis of eczema in dark skins is complicated by the lack of visible erythema. The diagnosis is made based on the presence of a typical history accompanied by lesions demonstrating a distribution and morphology consistent with AD. Other features classically seen in African skin are enhanced follicular lichenification with a papular appearance and postinflammatory hypo- and hyperpigmentation (Fig. 28.19).

Clinical features of specific subtypes of atopic dermatitis Specific subtypes of childhood AD deserve a mention as their morphology and distribution have not been previously discussed in this chapter.

Fig. 28.15 White dermographism with blanching of the skin at the site of stroking with a blunt instrument rather than developing a partial or full triple response of Lewis with reflex erythema. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

Clinical Features and Diagnostic Criteria of Atopic Dermatitis

Fig. 28.16 Xerosis in infantile atopic dermatitis. Courtesy of Dr Paula E. Beattie.

Fig. 28.17 Hyperlinear palms with exaggerated wrinkling of the palms. Courtesy of Professor Alan Irvine.

28.7

Fig. 28.18 Pityriasis alba with poorly defined slightly scaly hypopigmented patches on the torso, arms and cheeks. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

Fig. 28.19 Postinflammatory hypo- and hyperpigmentation in darkly pigmented skin. Courtesy of Professor Hywel C. Williams.

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Chapter 28

Fig. 28.21 Clinically infected infantile atopic dermatitis affecting the extensor aspects of the limbs and trunk. Courtesy of Professor Hywel C. Williams Fig. 28.20 Nummular atopic dermatitis affecting the torso in a young child. Courtesy of Professor Hywel C. Williams.

Nummular or discoid atopic dermatitis This type of AD presents with sharply demarcated circular lesions (Fig. 28.20) often located on the trunk and distal extensor limbs including dorsal hands, lower legs and forearms. The individual lesions are frequently dry and infiltrated plaques. This type of AD is reported to worsen in winter time. In adults, nummular eczema may be independent of atopy.

Diffuse ‘dry type’ AD This type of AD was first described in Japan and refers to a diffuse dry type AD, sometimes called patchy pityriasiform lichenoid eczema, which is slightly irritating and clinically consists of confluent scaly non-hyperkeratotic skin-coloured papules or ‘chicken-skin spots’ mainly on the trunk region [10]. Seasonal variations are described, with worsening in winter.

Possible future subtypes Recent advances in our understanding of the genetic basis for AD are likely to lead to new subtypes of AD. Specific emerging subtypes include eczema associated with null filaggrin mutations. These mutations appear to be associated with severe early-onset extrinsic (elevated IgE levels) eczema with palmar hyperlinearity and keratosis pilaris [11]. Recent studies of asthma in the context of filaggrin mutations have identified a complex asthma and eczema phenotype whereby filaggrin mutations are associated with asthma but only when it is associated with AD [12].

Complications Bacterial infections Staphylococcus aureus colonization can be demonstrated in 90% of eczema lesions and its density is associated with disease severity [13]. Clinically infected AD is characterized by honey-coloured crusted impetigo, folliculitis and pyoderma or as worsening of AD with increased erythema, oozing and pain (Fig. 28.21). Infections are usually caused by Staphylococcus aureus but β-haemolytic streptococci may also be isolated from infected AD.

Viral infections Infections with herpes simplex virus (HSV) in individuals with AD can result in eczema herpeticum (also known as Kaposi varicelliform eruption). This is a serious but infrequent complication, occurring in 3% of AD patients characterized by disseminated HSV infections and associated with significant morbidity, including multiorgan involvement, and rarely mortality. Clinically this presents with grouped or widespread umbilicated vesicopustules and eroded vesicles (Fig. 28.22). This complication is usually secondary to HSV-1 infection and recent studies suggest that there may be an association with filaggrin mutations [14]. A clinically similar eruption (eczema vaccinatum) can be seen following smallpox vaccination in susceptible individuals, hence AD or household AD contacts is a contraindication for smallpox vaccination. Molluscum contagiosum (MC) is a common childhood cutaneous poxvirus infection that presents with single or

Clinical Features and Diagnostic Criteria of Atopic Dermatitis

28.9

Differential diagnosis While AD is one of the commonest causes of an itchy rash in childhood, and in the vast majority of individuals the diagnosis is straightforward, it is important to consider other differential diagnoses. Table 28.1 lists diagnoses that can present in a similar manner to AD. A specific situation in which other differential diagnoses should be considered is when infants present with a severe eczematous rash with failure to thrive, recurrent infections or petechiae [16]. In this scenario, it is important to exclude immunodeficiency states. In children from the Caribbean, severe infected AD may be a manifestation of human T-lymphotropic virus-1 (HTLV1) infection [17]. Fig. 28.22 Periorbital eczema herpeticum displaying grouped punchedout erosions with secondary impetiginization. Courtesy of Professor Hywel C. Williams.

Fig. 28.23 Molluscum contagiosum presenting as infraorbital umbilicated and crusted papules. Courtesy of Professor Dr Thomas Diepgen and Dermis.net.

grouped skin-coloured papules and is frequently seen in children with AD (Fig. 28.23). Studies have reported an increased incidence of MC with AD, with a recent crosssectional study showing that 24% of children with MC from a tertiary centre had AD [15].

Exfoliative dermatitis Exfoliative dermatitis is a life-threatening dermatosis that rarely develops in AD (0.61)

Truncal dermatitis

MODERATE (kappa 0.41–0.60)

Flexural dermatitis, hand/foot dermatitis, facial dermatitis, hypopigmented patches, orbital fold, periorbital dermatitis, ear fissure, hyperlinear palms

FAIR (kappa 0.21–0.40)

Follicular accentuation, periaural dermatitis, cheilitis

SLIGHT (kappa 0.01–0.20)

Keratosis pilaris, fine hair, periorbital pigmentation, dry skin, extensor dermatitis (visible dermatitis)

as the kappa statistic, which usually varies from 0 (no better than chance) to 1 (perfect agreement), with values of 0.6 or more indicating substantial agreement. As can be seen from the data on signs of AD recorded by UK dermatologists in Table 28.3, even experienced physicians may exhibit poor agreement over classical features of a skin disease [1]. Many minor signs such as infraorbital crease can vary according to a number of factors such as the time of day (Fig. 28.25) or ethnic group [2]. Repeatability can be improved by keeping the number of criteria small and by clear instructions and training of field workers. Whilst it is true that good validity usually implies good repeatability, the converse is not always true; for example, two clocks that are both 10 minutes slow may well agree with each other, but neither is telling the correct time.

Acceptable to the population Whilst it may be possible and appropriate for physicians to perform quite invasive tests on patients in a hospital setting, even relatively non-invasive procedures such as examining the skin in covered areas or taking nail clippings may result in a low response rate when attempted in a population setting. The criteria should also be easy and rapid to apply. Complicated and time-consuming procedures will lead to observer fatigue, errors and lower response rates if conducted as part of a large study.

Coherence with prevailing clinical concepts Criteria should demonstrate a degree of face validity, i.e. they should contain features that clinicians identify as key elements for the disease syndrome. It is here that the seminal work of Hanifin and Rajka stands out [3]. They suggested a list of major features and a long list of minor features that characterize the clinical syndrome of AD based on clinical experience. Whilst the long list is too

Clinical Features and Diagnostic Criteria of Atopic Dermatitis

28.15

Fig. 28.25 Images of the same atopic person taken 12 hours apart. Although signs like infraorbital crease (defined as one or more prominent creases that extend beyond the midline when the pupil gazes forward) may sound straightforward to ascertain, these images show how unreliable such a sign can be.

cumbersome and imprecisely defined to be used as a research instrument, they have formed a good basis for subsequent scientific refinements such as the UK Working Party’s minimum list of reliable criteria [4]. It is also worth pointing out that diagnostic criteria for AD should also reflect some degree of morbidity; for example, it may be possible to develop criteria that measure very minor degrees of eczematous inflammation, but if such people are not itchy or bothered by those features, then it is questionable whether such a disease is worth studying. This is the main reason for making ‘an itchy skin condition’ a necessary criterion for the UK diagnostic criteria.

Comprehensiveness Criteria need to be applicable to a wide range of groups such as children and adults, those with dark skins (where erythema may be less obvious) and in different ethnic groups who may have a different cultural understanding of terms like ‘itching’, especially when compounded by difficulties in translation [5]. References 1 Williams HC, Burney PGJ, Strachan D, Hay RJ. The UK Working Party’s diagnostic criteria for atopic dermatitis II: Observer variation of clinical diagnosis and signs of atopic dermatitis. Br J Dermatol 1994;131:397–405. 2 Williams HC, Forsdyke H, Pembroke AC. Infraorbital crease, ethnic group and atopic dermatitis. Arch Dermatol 1996;132:51–4. 3 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta Dermatol Venereol (Stockh.) 1980;92:44–7.

4 Williams HC, Burney PGJ, Pembroke AC, Hay RJ. The UK working party’s diagnostic criteria for atopic dermatitis III: Independent hospital validation. Br J Dermatol 1994;131:406–16. 5 Chalmers DA, Todd G, Saxe N et al. Validation of the U.K. Working Party diagnostic criteria for atopic eczema in a Xhosa-speaking African population. Br J Dermatol 2007;156:111–16.

The systematic review The last section highlighted the need for a small list of reliable and valid criteria that can be used widely. Very few studies have developed and tested diagnostic criteria scientifically. Many groups have suggested diagnostic criteria based on a hunch or show of hands, but many remain untested. It is also worth noting that instead of focusing on the really important questions about the diagnostic criteria for AD, i.e. which criteria are the best discriminators and which can be lost in order to make a minimum list of reliable ones, lots of studies have focused on the long list of minor features and whether or not they apply to a particular study population [1–3]. Whilst these studies are helpful in showing some possible variation in the minor phenotypic features that may be more or less prevalent in some countries and ethnic groups, they add little to the main quest for a minimum list of reliable and valid major criteria. At least 10 different sets of diagnostic criteria for AD had been proposed by 2007 [4–13], prompting Brenninkmeijer and colleagues to undertake a systematic review of the validity of such studies [14]. Following an extensive

28.16

Chapter 28

search of three databases and citations from retrieved papers, they identified 27 validation studies that were then quality-assessed by two independent data extractors using the Quality Assessment of Diagnostic Accuracy (QUADAS) tool, which assesses the risk of bias by means of 14 different items [15]. The authors also compared sensitivity and specificity parameters and optimum cut-offs for different criteria using receiver-operator curves. They found that some of the proposed diagnostic criteria such as those of the Japanese Dermatological Association, the Danish Allergy Research Centre criteria and the Lillehammer criteria had not undergone any form of validation at all. The original Hanifin and Rajka criteria had only been validated in two hospital studies, those of Schultz Larsen in two studies, those of Diepgen et al. and those of Kang and Tian in one study each, and the UK refinement of Hanifin and Rajka’s criteria in 19 studies. Overall, sensitivity and specificity of the various criteria ranged from 10% to 95% and from 77.6% to 100%, respectively, in hospital-based studies, and from 42.8% to 100% and from 44.7% to 96.6%, respectively, in population studies. The two hospital-based studies that evaluated the Hanifin and Rajka criteria showed a sensitivity of 87.9% and 96.0% respectively, and specificity of 77.6% and 93.8%. The eight hospital-based studies validating the UK refinement of the Hanifin and Rajka criteria showed a sensitivity ranging from 10% to 95.5% and specificity from 90.4% to 98.3%. The 13 population-based validation studies showed a sensitivity ranging from 42.8% to 100% and specificity from 89.3% to 99.1%. No meta-analytic summary estimates could be given due to the major differences between studies in terms of participants, setting and study design. Validity was particularly poor in one community validation study of the UK criteria that had been translated in the Xhosa language [16], although other studies of translated versions in China, Italy and Romania seemed to show good results [17–19], suggesting that cultural factors rather than just translation issues are important. One study from Ethiopia showed that the questionnaire used in the International Study of Asthma and Allergies in Childhood (ISAAC) showed a positive predictive value of 48.8% and a negative predictive value of 91.1% [20]. The methodological quality of the validation studies varied considerably, making comparisons difficult. Common methodological problems included an inappropriate reference standard, lack of blinding of those determining the index test results from the reference test results, lack of reporting of intermediate or uninterpretable results, and failure to provide details on participant withdrawals. The authors of the systematic review also point to problems such as the reference standard of clinical diagnosis residing with just one clinician whose perception of what constitutes AD might be very different

from others [21,22]. Another problem when validating criteria that refer to symptoms over the course of a year (to overcome seasonal variations when making comparisons) was that they were often validated by clinical examination at just one point in time, a procedure that will always underestimate genuine cases that are not active at the time of examination. The authors concluded that the UK diagnostic criteria are the most extensively validated in hospital and community settings, and that this set of criteria for AD should be recommended in future intervention studies. They point out that the ideal set of diagnostic criteria still has to be established, and there is considerable scope for improvement of methodological design for validation studies. Guidances on how to design a good validation study for diagnostic criteria for AD can be found elsewhere [22]. Guidance on what makes a good prevalence study have been suggested by Radalescu et al. [23]. An interactive website is available in the public domain for those interested in finding out more about using the UK Working Party’s diagnostic refinement of the Hanifin and Rajka criteria, including translations, detailed field instructions, training images and a quality control test [24]. References 1 Mevorah B, Frenk E, Wietlisbach V et al. Minor clinical features of atopic dermatitis. Evaluation of their diagnostic significance. Dermatologica 1988;177:360–4. 2 Nagaraja, Kanwar AJ, Dhar S et al. Frequency and significance of minor clinical features in various age-related subgroups of atopic dermatitis in children. Pediatr Dermatol 1996;13:10–13. 3 Hiletework M. Evaluation of Hanifin and Rajka atopic eczema diagnostic guidelines for reduced minor criteria. Ethiop Med J 2009;47: 39–47. 4 Asher MI, Keil U, Anderson HR et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8:483–91. 5 Bos JD, Van Leent EJ, Sillevis Smitt JH. The millennium criteria for the diagnosis of atopic dermatitis. Exp Dermatol 1998;7:132–8. 6 Diepgen TL, Sauerbrei W, Fartasch M. Development and validation of diagnostic scores for atopic dermatitis incorporating criteria of data quality and practical usefulness. J Clin Epidemiol 1996;49:1031–8. 7 Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980;92:44–7. 8 Johnke H, Vach W, Norberg LA et al. A comparison between criteria for diagnosing atopic eczema in infants. Br J Dermatol 2005;153: 352–8. 9 Schultz Larsen F, Hanifin JM. Secular change in the occurrence of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1992;176:7–12. 10 Schultz Larsen F, Diepgen T, Svensson A. Clinical criteria in diagnosing atopic dermatitis: the Lillehammer criteria 1994. Acta Derm Venereol Suppl (Stockh) 1996;96:115–19. 11 Williams HC, Burney PG, Hay RJ et al. The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol 1994;131: 383–96. 12 Kang KF, Tian RM. Criteria for atopic dermatitis in a Chinese population. Acta Derm Venereol Suppl (Stockh) 1989;144:26–7. 13 Tagami H. Japanese Dermatology Association criteria for the diagnosis of atopic dermatitis. J Dermatol 1995;22:966–7.

Clinical Features and Diagnostic Criteria of Atopic Dermatitis 14 Brenninkmeijer EEA, Schram M, Leeflang MMG, Bos JD, Spuls PH. Diagnostic criteria for atopic dermatitis: a systematic review. Br J Dermatol 2008;158:754–65. 15 Whiting P, Rutjes AW, Reitsma JB et al. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003;3:25. 16 Chalmers DA, Todd G, Saxe N et al. Validation of the U.K. Working Party diagnostic criteria for atopic eczema in a Xhosa-speaking African population. Br J Dermatol 2007;156:111–16. 17 Gu H, Chen XS, Chen K et al. Evaluation of diagnostic criteria for atopic dermatitis: validity of the criteria of Williams et al. in a hospitalbased setting. Br J Dermatol 2001;145:428–33. 18 Girolomoni G, Abeni D, Masini C et al. The epidemiology of atopic dermatitis in Italian schoolchildren. Allergy 2003;58:420–5. 19 Popescu CM, Popescu R, Williams H et al. Community validation of the United Kingdom diagnostic criteria for atopic dermatitis in Romanian school children. Br J Dermatol 1998;138:436–42. 20 Haileamlak A, Lewis SA, Britton J et al. Validation of the International Study of Asthma and Allergies in Children (ISAAC) and U.K. criteria for atopic eczema in Ethiopian children. Br J Dermatol 2005;152: 735–41. 21 Firooz A, Davoudi SM, Farahmand AN, Majdzadeh R, Kashani N, Dowlati Y. Validation of the diagnostic criteria for atopic dermatitis. Arch Dermatol 1999;135:514–16. 22 Williams HC. Defining atopic dermatitis – where do we go from here? Arch Dermatol 1999;135:583–6. 23 Radalescu M, Diepgen T, Williams H. What makes a good prevalence survey? In: Williams HC, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B (eds) Evidence-Based Dermatology, 2nd edn. Oxford: Blackwell Publishing and BMJ Publishing Group, 2008;61–7. 24 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical Manual for Researchers Wishing to Define Atopic Eczema. University of Nottingham, 1995 (http://www.nottingham.ac.uk/ dermatology/eczema/contents.html).

Other studies that have emerged since the systematic review A few other relevant validation studies have emerged since the systematic review by Brenninkmeijer et al. [1]. The first is a study of validation of the UK diagnostic criteria in adults in Japan [2] – a useful study as nearly all work to date has involved children. Saeki et al. compared the validity of the UK criteria with clinical examination [2]. Such a comparison will always underestimate the true validity of the criteria since a 1-year period prevalence is being compared against a point prevalence. In other words, many of those who were ‘positive’ for the UK criteria in the last year, may not have had add active eczema at the time of examination. Nevertheless, the study found that the the UK criteria showed a sensitivity of 68.8% (88/128) and specificity of 93.5% (1863/1992) in an adult Japanese population. In an earlier study of community validation of diagnostic criteria for AD in schoolchildren, Saeki and colleagues illustrated how validity of the UK criteria can appear to improve if the time period for assessing symptoms is restricted to the last week to make them more like a point prevalence measure, which could then be more realistically compared with a clinical examination at one point in time [3]. They found in 2002

28.17

that when the UK diagnostic criteria were used as a 1-year prevalence measure, sensitivity and specificity were 71.8% and 89.3%, respectively, with a positive predictive value of 44.7%. When used as a point prevalence estimate in 2004/5 in a different sample, sensitivity had dropped slightly to 58.9% but specificity had increased to 95.4%, which led to an increase in the positive predictive value to 59.9% [3]. A further validation study concerning adults was conducted on 1131 nursing staff in a Taiwanese teaching hospital; this achieved a good 93% response rate [4]. The Taiwanese study compared the validity of the UK criteria and the ISAAC criteria in the last year against a dermatologist’s opinion of whether the person had AD in the last year (using guidance that broadly followed the Hanifin and Rajka list). They found that sensitivity and specificity of the UK criteria were 42.2% and 99.6%, respectively, and for the ISAAC criteria they calculated a sensitivity and specificity of 36.7% and 92.9%, respectively. Further analysis by means of receiver operator curves indicated that dropping the criterion of ‘onset under the age of 2 years’ resulted in better discrimination for the UK criteria (sensitivity and specificity of 82.2% and 94.2%, respectively). It should be pointed out, however, that the original instructions on the use of the UK diagnostic criteria in adults on the online manual clearly state ‘Recall of onset of eczema under the age of 2 is likely to be inaccurate in adults’, and should be replaced by ‘Did your eczema start when you were a child?’ as few adults will be able to remember what happened in the first two years of their life [5]. Another study of 518 children in Spain found that the UK criteria when administered in a telephone interview along with other questions about possible diseases causes, agreed with physician diagnosis in 75.3% of cases [6]. Within Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC), 30,358 schoolchildren aged 8–12 years from 18 countries were examined for flexural eczema and their parents completed the ISAAC eczema symptom questionnaire [7]. As might be expected, the point prevalences for flexural eczema based on a single examination were lower than the questionnairebased 12-month period prevalences (mean centre prevalence 3.9% vs 9.4%), yet both were highly correlated (r = 0.77, p < 0.001). When analysed at an individual level, questionnaire-derived symptoms of ‘persistent flexural eczema in the past 12 months’ missed less than 10% of cases of flexural eczema detected on physical examination, although between 33% and 100% of questionnairebased symptoms of ‘persistent flexural eczema in the past 12 months’ were not confirmed on examination. The authors concluded that prevalences derived using the ISAAC questionnaires were sufficiently robust for comparing disease prevalence between populations. They

28.18

Chapter 28

went on to say that when diagnostic precision at the individual level is important, questionnaires should always be validated first, or a standardized skin examination protocol should be used such as that used by the UK working party (Fig. 28.26) [8].

One study has tried to see whether there are differences in diagnostic features in children with AD (i.e. truly atopic with IgE antibodies) versus those who look similar but who do not have evidence of IgE reactivity (called ‘atopiform’ by some). The authors found that the atopi-

A. Subjects aged 4 years and over Your task is to record as consistently as possible the presence/absence of physical signs - "visible flexural dermatitis". To decide whether this sign is present or not, there are two components to consider:

Step 1 What dermatitis looks like Definition of dermatitis: Poorly demarcated erythma (redness) with surface change "Surface change" can mean fine scaling, vesicles, oozing, crusting or lichenification.

Here are some photographs to help you. Click on the photograph for a larger image.

1. This is dermatitis. Note it is red, has an indistinct margin and there is a surface change (in this case fine scaling)

4. This is lichenification in a white skin. lichenification means a thickening of the skin in response to scratching. The skin markings are exaggerated and the skin feels thickened.

2. This is dermatitis showing another type of surface change, in this case oozing (clear fluid leaking from the skin) and crusting (scabs).

5. This is lichenification in a black skin. Note the exaggerated skin creases and post-inflammatory pigmentation

3. These are vesicles (tiny clear "water" blisters).

6. This is also lichenification in a black skin. In this case, the thickening is comprised of smaller flat topped bumps corresponding to hair follicles - so called "follicular lichenification".

Fig. 28.26 Extract from the UK Working Party’s visible flexural dermatitis protocol.

Clinical Features and Diagnostic Criteria of Atopic Dermatitis

form children had later disease onset, an absence of other atopic diseases, fewer Dennie–Morgan creases, less hand/ foot eczema and a variety of other features, yet some of these differences could be due to the fact that the atopiform cases were milder, an important confounder that was not taken into account in the selection of cases or analysis [9]. References 1 Brenninkmeijer EEA, Schram M, Leeflang MMG, Bos JD, Spuls PH. Diagnostic criteria for atopic dermatitis: a systematic review. Br J Dermatol 2008;158:754–65. 2 Saeki H, Oiso N, Honma M, Iizuka H, Kawada A, Tamaki K. Prevalence of atopic dermatitis in Japanese adults and community validation of the U.K. diagnostic criteria. J Dermatol Sci 2009;55:140–1. 3 Saeki H, Iizuka H, Mori Y et al. Community validation of the UK diagnostic criteria for atopic dermatitis in Japanese elementary schoolchildren. J Dermatol Sci 2007;47:227–31. 4 Lan CC, Lee CH, Lu YW et al. Prevalence of adult atopic dermatitis among nursing staff in a Taiwanese medical center: a pilot study on validation of diagnostic questionnaires. J Am Acad Dermatol 2009; 61:806–12. 5 Williams HC, Flohr C. So How Do I Define Atopic Eczema? A Practical Manual for Researchers Wishing to Define Atopic Eczema. University of Nottingham, 1995 (http://www.nottingham.ac.uk/dermatology/ eczema); Section5-3. 6 García-Díez A, Puig L, Ortiz J, Blanco A. [Validity of a telephone survey for determining the prevalence of atopic dermatitis and its seasonal variation in Spain]. Actas Dermosifiliogr 2009;100:298–306. 7 Flohr C, Weinmayr G, Weiland SK et al. and the ISAAC Phase Two Study Group. How well do questionnaires perform compared with physical examination in detecting flexural eczema? Findings from the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two. Br J Dermatol 2009;161:846–53. 8 Williams HC, Forsdyke H, Boodoo G, Hay RJ, Burney PGF. A protocol for recording the sign of visible flexural dermatitis. Br J Dermatol 1995;133:941–9. 9 Brenninkmeijer EE, Spuls PI, Legierse CM, Lindeboom R, Smitt JH, Bos JD. Clinical differences between atopic and atopiform dermatitis. J Am Acad Dermatol 2008;58:407–14.

Summary • Atopic dermatitis is a difficult disease to define since it is variable in morphology and distribution according to age, skin type and whether the skin is acutely or chronically affected. • Whilst a ‘clinical diagnosis’ is appropriate in clinical practice, standardized diagnostic criteria for AD are essential when comparing groups of people in clinical studies. • Although the term ‘atopic dermatitis’ is used throughout this book, most cases of ‘atopic’ dermatitis are not atopic when tested in populations. • The World Allergy Organisation has suggested the term ‘eczema’ should be used to denote the clinical phenotype of ‘atopic’ dermatitis and that the prefix ‘atopic’ should only be used when there is evidence of IgE reactivity.

28.19

• The division of AD into an atopic and non-atopic (intrinsic or atopiform) dermatitis is premature as it may be confounded by disease severity and because other determinants such as filaggrin status might be more useful predictors of disease subtypes. • It is crucial to consider the type of clinical study before deciding which diagnostic criteria can be used. Surveys will need a trade-off between sensitivity and specificity whereas clinical trials will require very specific criteria. • The positive predictive value of diagnostic criteria will fall with low disease prevalence even though sensitivity and specificity might appear to be high. • There is currently no well-developed definition of an incident case of AD. • All binary disease definitions will always result in some degree of misclassification of study participants. • What is recognized as one disease today may turn out to be four or five different subtypes in years to come if further discoveries lead to disease subtypes that increase our predictive ability in terms of prognosis, disease associations or response to treatments. • A good disease definition should be valid, reliable, acceptable to the population, be coherent with prevailing clinical concepts and comprehensive in its application. • The Hanifin and Rajka list of diagnostic features was an important landmark in suggesting major and minor criteria for the AD phenotype. • A recent systematic review has identified at least 10 sets of diagnostic criteria for AD. • Some such as those of the Japanese Dermatological Association, the Danish Allergy Research Centre criteria and the Lillehammer criteria had not undergone any form of validation. • The systematic review suggested that most extensively tested criteria (the UK Working Party’s refinement of the Hanifin and Rajka criteria) should be used in future intervention studies, although there is room for improvement. • Many validation studies are flawed by issues such as lack of blinding and because they try to validate period prevalence measures (symptoms in the last year) against a point prevalence measure (examination by a doctor at one time point). • Ideally, diagnostic criteria should be tested beforehand for validity in the setting where they are to be used. If translation or transcultural interpretation becomes a problem, then question-free methods of assessing visible flexural dermatitis in a standardized way are an option for comparative research. • The questionnaire criteria used in the International Study of Asthma and Allergies in Childhood (ISAAC) are adequate for comparing prevalences between populations.

29.1

C H A P T E R 29

Atopic Dermatitis: Scoring Severity and Quality of Life Assessment M. Susan Lewis-Jones1 & Carolyn R. Charman2 1

Department of Dermatology, Ninewells Hospital and Medical School, Dundee, Scotland, UK Department of Dermatology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

2

The measurement of disease severity, 29.1

Measuring quality of life in children with

Conclusion, 29.14

atopic dermatitis, 29.9

The measurement of disease severity Measuring atopic dermatitis severity and its impact on children’s lives is of great importance, both in the clinical trial setting and for monitoring response to therapy in everyday clinical practice. Outcome measures for assessing healthcare intervention form the basis of evidencebased practice and can play a central role in the allocation of health service resources. The measurement of disease severity in atopic dermatitis can present difficulties because there is no accepted laboratory test of disease activity [1,2]. In the absence of a single objective marker, a number of different outcome measures have been used to try to capture changes in atopic dermatitis severity. This chapter discusses the various measurement tools for atopic dermatitis that are currently available to both the practising clinician and researcher.

What to measure in atopic dermatitis? In the absence of a gold-standard measure of atopic dermatitis severity, opinion on which aspects of the disease are most important will always vary between physicians, and also between physicians and patients. However, it is generally accepted that subjective indicators perceived by the patient (symptoms and quality of life) as well as physical features of the disease visible to the physician (clinical signs) and estimations of body surface area involvement (disease extent) are all important when attempting to measure atopic dermatitis severity, with extent measurements usually being given less weighting than clinical signs of disease intensity [3]. The precise outcome mea-

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

sures chosen will depend on the requirements of the clinical setting. In clinical trials, it is often appropriate to include all these parameters, whereas for routine clinical use in primary or secondary care, simple subjective indices or global measurements of disease severity may be more useful.

Validity and reliability Measurement tools for assessing disease severity should be tested for validity, reliability and sensitivity to change before being introduced into clinical practice. The extent to which this has been applied to existing severity scales for atopic dermatitis is variable, and there is widespread use of untested scales, making accurate interpretation difficult [4–6]. Although varying terminologies exist surrounding the assessment of validity, this can be defined as the degree of confidence that can be placed in inferences drawn from the severity index (Table 29.1). Reliability studies provide information on the repeatability of the scoring system in different circumstances, for example when being used by different observers. Whereas intraobserver variation is usually low with the majority of atopic dermatitis scoring systems that have been tested, interobserver variation can be a problem, and in some trials this variation could potentially overshadow therapeutic effects [4,5]. This problem can be minimized by employing a single observer in clinical trials wherever possible, or training observers before multicentre studies to improve standardization. Severity indices designed for use in clinical trials also need to be sensitive enough to detect short-term changes in disease severity; for example, one would expect that an objective scale based on the measurement of skin dryness and lichenification would be less sensitive to change in a 4-week trial of ciclosporin than an index including features of acute eczema such as

29.2

Chapter 29

Table 29.1 Atopic dermatitis: validity and reliability Properties of measurement scales

Definition

Validity–Does the scale measure what it is intended to measure? Content

Does the scale appear to be assessing all the relevant content or domains, based on judgement by one or more experts?

Construct

Does the scale agree with other related variables and measures of the same construct with which, in theory, it ought to agree?

Criterion

Does the scale correlate with some other measure of the disease, ideally a ‘gold standard’ that has been used and accepted in the field?

Reliability–Does the scale measure what it is intended to measure in a reproducible fashion? Interobserver reliability

Do measurements made by two or more observers produce the same or similar results?

Intraobserver reliability

Do measurements made by the same observer on two or more occasions produce the same or similar results?

Internal consistency

Do the scores from different items in the scale correlate with each other and with the total scale score, i.e. are all items in the scale measuring the same attribute?

erythema, oozing and excoriations. Similarly, a crude scoring system based on the measurement of three clinical signs at a single body site may be less able to detect small changes in disease activity than a tool based on the measurement of six clinical signs at six body sites, although interobserver variation is likely to be greater with the more complex system.

Measuring clinical signs A number of eczema severity indices are based on the assessment of visible clinical signs of disease activity. These indices are often regarded as being less subject to social or cultural factors than outcome measures based on patient symptoms or quality of life, and are frequently employed as the primary outcome measure in clinical trials [4–6]. Some of these ‘objective’ scoring systems also include measurements of patients’ symptoms, with scores on scales of individual parameters being combined to form an overall composite severity index. The two most tested ‘objective’ clinical indices are the SCORAD index [7] and the Eczema Area and Severity Index (EASI) [8].

SCORAD The SCORAD index was developed by the European Task Force on Atopic Dermatitis in 1983 as a simple tool for measuring disease severity in clinical trials [7]. The index comprises a measurement of six clinical signs of disease intensity on a scale of 0–3, each measured at a single representative body site (Fig. 29.1). The resulting score is then combined with a measurement of disease extent using the ‘rule of nines’, plus a visual analogue score for itch and sleep loss (maximum score 103) (Fig. 29.2). It has been suggested that disease severity can be categorized as mild (40), according to the objective components of the index (clinical signs and disease extent) [9,10]. Extensive published data on the validity, reliability and sensitivity to change of the SCORAD index in children and adults are available [4,5,11], both from studies designed specifically to assess the index [9–19] and from a number of clinical trials [6] and epidemiological studies [20,21] in which it has been successfully employed. As with most ‘objective’ atopic dermatitis indices, inter- and intraobserver variation can occur, with lichenification and disease extent being among the most difficult features to score consistently [9,12]. When SCORAD is used in black children, assessments of erythema can be difficult and can lead to underestimation of disease severity; this is also likely to occur with other scoring systems in which erythema is included as a severity parameter [22]. Training has been recommended before using the index, and is freely available on the SCORAD website (http://adserver.sante.univ-nantes.fr). In addition, a computer software program called ScoradCard® has been developed to assist with SCORAD assessments (http:// www.tpsproduction.com) [23]. Assessments can be made in less than 10 min, after training [12,20]. SCORAD is a composite score, and combining both objective and subjective measurements made by both the physician and the patient may be seen as disadvantageous, although the measurements of signs, symptoms and disease extent can easily be presented separately if required. It has been recommended that only the objective components of the SCORAD index (disease intensity and extent) be used for inclusion and categorization of patients into clinical trials, but that the complete index (including subjective criteria) should remain the major follow-up and end-point study criterion [9,10]. A selfassessed patient-oriented version of SCORAD has recently been described (PO-SCORAD) [24]. The POSCORAD has undergone preliminary validation, although some clinical signs were found to be difficult for patients to measure accurately, particularly disease extent, lichenification, and oedema/swelling of the skin. An illustrated document has been proposed to accompany the index in further validation studies.

Atopic Dermatitis: Scoring Severity and Quality of Life Assessment

(a)

(d)

(b)

(e)

29.3

(c) Fig. 29.1 Examples of grading of clinical signs in the SCORAD index. (a) Erythema, grade 3; (b) oedema/papulation, grade 2; (c) oozing/crusting, grade 1; (d) excoriations, grade 3; (e) lichenification, grade 3. Reproduced with permission from the SCORAD website.

Eczema Area and Severity Index The Eczema Area and Severity Index (EASI) score was described in 1998 as a new tool for assessing atopic dermatitis severity and response to therapeutic interventions [8,25]. The index involves an assessment of the average intensity of four clinical signs – erythema, induration/ papulation, excoriations and lichenification (0–3) – each

assessed at four defined body sites (Table 29.2). Disease extent is also assessed in each of the four regions on a scale of 0–6. The total score for each body region is obtained by multiplying the sum of the severity scores of the four key signs by the area score, and then multiplying the result by a constant weighted value. The constant weighted value represents the contribution of each body

29.4

Chapter 29

Fig. 29.2 SCORAD evaluation sheet. Reproduced from Charman & Williams 2000 [5] with permission from American Medical Association.

region to the total body surface area, with a modification for young children. The sum of the scores for each body region gives the EASI total (maximum score 72). The index has been widely used and validated against other measures of disease activity in trials involving chil-

dren and adults [26–28]. EASI and SCORAD scores have shown high correlation in children and adults [18,19]. Reliability studies have shown reasonably good interand intraobserver agreement, with induration/papulation assessments showing the most interobserver variability

Atopic Dermatitis: Scoring Severity and Quality of Life Assessment Table 29.2 The Eczema Area and Severity Index (EASI). Body region

EASI score in patients ≥ 8 years

Head/neck (H) Upper limbs (UL) Trunk (T) Lower limbs (LL)

(E (E (E (E

I I I I

Ex Ex Ex Ex

L) L) L) L)

× × × ×

area area area area

× × × ×

0.1 0.2 0.3 0.4

EASI score in patients ≤ 7 years (E (E (E (E

I I I I

Ex Ex Ex Ex

L) L) L) L)

× × × ×

area area area area

× × × ×

0.2 0.2 0.3 0.3

EASI = sum of the above four body region scores. E, erythema; I, induration/papulation; Ex, excoriation; L, lichenification. Area is defined on a seven-point ordinal scale: 0 = no eruption; 1 = 60% improvement and four achieving complete clearance within 12 weeks. It was well tolerated and reported as being a promising therapeutic alternative treatment for refractory atopic dermatitis. Methotrexate There are several published papers on the use of methotrexate for treating moderate to severe atopic dermatitis [96–98] but no clinical trial as yet in children. From per-

30.11

sonal experience and anecdotal reports of its use in children, the results are variable. Methotrexate is usually well tolerated in children and warrants further investigation for severe recalcitrant atopic dermatitis in the younger age group.

Traditional Chinese medicine Traditional Chinese herbal medicine has always claimed success in the management of atopic dermatitis but scientific evidence has been lacking and there are serious concerns about the risk of hepatoxicity [99]. Sheehan and Atherton [100] attempted scientifically to validate the efficacy of traditional Chinese herbal therapy. They used a specific group of herbs that were wrapped in tea bags and infused in a liquid. They studied 37 children with nonexudative atopic dermatitis in a double-blind crossover trial with 8 weeks each of placebo and active therapy and a 4-week washout period in between. They proved efficacy with the treatment in approximately 60% of children and followed up the children for 1 year; 18 showed a 90% improvement in their eczema; one child developed abnormal liver function tests and 14 withdrew either because of a lack of efficacy or because of the unpalatability of the long-term treatment [101]. Much work has been done in an effort to identify the chemicals in the traditional Chinese herbal teas and to try to understand the method of effect, but to date it remains shrouded in mystery. Other treatments The following have been tried but are of questionable benefit for treating atopic dermatitis: probiotics [102], killed Mycobacterium vaccae suspension given by intradermal injection [103], thymostimulin (TP-1) [104] and thymopentin [105,106]. References 1 Williams HC. Is the prevalence of atopic dermatitis increasing? Clin Exp Dermatol 1992;17:385–91. 2 Williams HC, Pembroke AC, Fosdyke H et al. London-born black Caribbean children are at increased risk of atopic dermatitis. J Am Acad Dermatol 1995;32:212–17. 3 Kay J, Gawkrodger DJ, Mortimer MJ et al. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol 1994;30:35–9. 4 Darsow U, Wollenberg A, Simon D et al. ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol 2010;24(3):317–28. 5 Hoare C, Li Wan Po A, Williams H. Systemic review of treatments for atopic eczema. Health Technol Assessment 2000;4:1–187. 6 Simpson EL. Atopic dermatitis: a review of topical treatment options. Curr Med Res Opin 2010;26(3):633–40. 7 Long CC, Funnell CM, Collard R et al. What do members of the National Eczema Society really want? Clin Exp Dermatol 1993;18: 516–22. 8 Eriksson G, Forsbeck M. Smallpox outbreak and vaccination problems in Stockholm, Sweden 1963. The assessment and the vaccination of patients with cutaneous disorders. Acta Med Scand 1966; 464(Suppl):147–57.

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9 Engler RJ, Kenner J, Leung DY. Smallpox vaccination: risk considerations for patients with atopic dermatitis. J Allergy Clin Immunol 2002;110:357–65. 10 Cono J, Casey CG, Bell DM. Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR Recomm Rep 2003;52:1–28. 11 Kristmundsdottir F, David TJ. Growth impairment in children with atopic eczema. J Roy Soc Med 1987;80:9–12. 12 David TJ. Conventional allergy tests. Arch Dis Child 1991;66:281–2. 13 Juhlin L, Johansson SGO, Bennich H et al. Immunoglobulin E in dermatoses. Arch Dermatol 1969;100:12–16. 14 Hanifin JM, Rajka G. Diagnostic features of atopic eczema. Acta Dermatol Venereol (Stockh) 1980;92:44–7. 15 Williams HC, Burney PGJ, Hay RJ et al. The UK Working Party’s diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol 1994;131: 383–96. 16 Lever R, Forsyth A. Allergic contact dermatitis in atopic dermatitis. Acta Dermatol Venereol (Stockh) 1992;176(Suppl):95–8. 17 Tada J, Toi Y, Arata J. Atopic dermatitis with severe facial lesions exacerbated by contact dermatitis from topical medicaments. Contact Derm 1994;31:261–3. 18 English J, Ford G, Beck MH et al. Allergic contact dermatitis from topical and systemic steroids. Contact Derm 1990;23:196–7. 19 White MI, McEwan J, Jenkinson D et al. The effect of washing on the thickness of the stratum corneum in normal and atopic individuals. Br J Dermatol 1987;116:525–30. 20 Chiang C, Eichenfield LF. Quantitative assessment of combination bathing and moisturizing regimens on skin hydration in atopic dermatitis. Pediatr Dermatol 2009;26(3):273–8. 21 Blume-Peytavi U, Cork MJ, Faergemann J et al. Bathing and cleansing in newborns from day 1 to first year of life: recommendations from a European round table meeting. J Eur Acad Dermatol Venereol 2009;23(7):751–9. 22 La Rosa M, Ranno C, Musarra I et al. Double-blind study of cetirizine in atopic eczema in children. Ann Allergy 1994;73: 117–22. 23 Kemp JP. Tolerance to antihistamines: is it a problem? Ann Allergy 1989;63:621–3. 24 McFadden JP, Noble WC, Camp RDR. Super-antigenic exotoxinsecreting potential of staphylococci isolated from atopic eczematous skin. Br J Dermatol 1993;128:631–2. 25 Zienicke H. Topical glucocorticoids and anti-infectives: a rational combination? Curr Prob Dermatol 1993;21:186–91. 26 Korting HC, Zienicke H, Braun-Falco O et al. Modern topical glucocorticoids and anti-infectives for superinfected atopic eczema: do prednicarbate and didecyldimethylammonium chloride form a rational combination? Infection 1994;22:390–4. 27 Huang JT, Abrams M, Tlougan B et al. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 2009;123(5):e808–14. 28 Craig FE, Smith EV, Williams HC. Bleach baths to reduce severity of atopic dermatitis colonized by Staphylococcus. Arch Dermatol 2010;146(5):541–3. 29 Thomas KS, Armstrong S, Avery A et al. Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema. BMJ 2002;324:768. 30 David TJ. Steroid scare. Arch Dis Child 1987;62:876–8. 31 Patel L, Clayton PE, Addison GM et al. Adrenal function following topical steroid treatment in children with atopic dermatitis. Br J Dermatol 1995;132:950–5. 32 Nielsen NV, Sorensen PN. Glaucoma induced after corticosteroid treatment of periorbital eczema. Ugeskr-Laeger 1977;139:1788–9. 33 Cubey RB. Glaucoma following the application of corticosteroid to the skin of the eyelids. Br J Dermatol 1976;95:207–8.

34 Howell JB. Eye diseases induced by topically applied steroids. Arch Dermatol 1976;112:1529–30. 35 Chu AC, Munn S. Fluticasone propionate in the treatment of inflammatory dermatoses. Br J Clin Pract 1995;49:131–3. 36 Berth-Jones J, Damstra 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(7403):1367. 37 Long CC, Finlay AY. The finger tip unit: a new practical measure. Clin Exp Dermatol 1991;16:444–7. 38 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;141:264–73. 39 Zuberbier T, Chong S. The ascomycin macrolactam pimecrolimus (Eridel, SD2 ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. J Allergy Clinic Immunol 2001;108:275–80. 40 Mayer K, Reinhard T, Reis A et al. FK506 ointment 0.1%. A new therapeutic option for atopic blepharitis: clinical trial with 14 patients. Klin Monatsbl Augenheilkd 2001;218:733–6. 41 Bekersky I, Fitzsimmons W, Tanase A et al. Non clinical and early clinical development of tacrolimus ointment for the treatment of atopic dermatitis. J Am Acad Dermatol 2001;44(1):S17–27. 42 Meingassner JG, Grassberger M, Fahrngruber H et al. A novel antiinflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol 1997;137: 568–76. 43 Queillen-Roussel C, Paul C, Duteil L et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double blind controlled study. Br J Dermatol 2001;144:507–13. 44 Kang S, Lucky AW, Pariser D et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001;44(Suppl 1):558–64. 45 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: 539–46. 46 Eichenfield LF, Lucky AW, Boguniewiez M et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46:495–504. 47 Kapp A, Papp K, Bingham A et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a non-steroid antiinflammatory drug. J Allergy Clin Immunol 2002;110:277–84. 48 Kawashima M, Nakagawa H, Ohtsuki M et al. Tacrolimus concentrations in blood during topical treatment of atopic dermatitis. Lancet 1996;348:1240–1. 49 Alaiti S, Kang S, Fiedler VC et al. Tacrolimus (FK506) ointment for atopic dermatitis: a phase 1 study in adults and children. J Am Acad Dermatol 1998;38:69–76. 50 Van Leent EJM, Ebelin ME, Bartin P et al. Low systemic concentrations of SDZ ASM 981 after topical treatment of extensive atopic dermatitis lesions. J Eur Acad Dermatol Venereol 1998;11(Suppl 2):133–4. 51 Harper J, Lakhanpaul M, Wahn U et al. Pimecrolimus (Elidel, SDZ ASM 981) cream 1% blood levels are consistently low in children with extensive atopic eczema. J Dermatol Venereol 2001;15(Suppl 2):S109. 52 Fleischer AB Jr, Ling M, Eichenfield L et al. Tacrolimus ointment for the treatment of atopic dermatitis is not associated with an increase in cutaneous infections. J Am Acad Dermatol 2002;47:562–70. 53 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(1):e2.

Guidelines to Management of Atopic Dermatitis 54 Thaçi D, Salgo R. Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies. Clin Dermatol 2010;28(1):52–6. 55 Thaçi D, Reitamo S, Gonzalez Ensenat MA et al. 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(6):1348–56. 56 Thaci D, Chambers C, Sidhu M et al. Twice-weekly treatment with tacrolimus 0.03% ointment in children with atopic dermatitis: clinical efficacy and economic impact over 12 months. J Eur Acad Dermatol Venereol 2010;24(9):1040–6. 57 Oranje AP, Devillers AC, Kunz B et al. Treatment of patients with atopic dermatitis using wet-wrap dressings with diluted steroids and/or emollients. An expert panel’s opinion and review of the literature. J Eur Acad Dermatol Venereol 2006;20(10):1277–86. 58 Goodyear HM, Spowart K, Harper JI. ‘Wet wrap’ dressings for the treatment of atopic eczema in children. Br J Dermatol 1991;125:604. 59 Steinman HA, Potter PC. The precipitation of symptoms by common foods in children with atopic dermatitis. Allergy Proc 1994;14: 203–10. 60 Fuglsang G, Madsen C, Halken S et al. Adverse reactions to food additives in children with atopic symptoms. Allergy 1994;49:31–7. 61 Atherton DJ, Sewell M, Soothill JF et al. A double blind controlled cross-over trial of antigen avoidance diet in atopic eczema. Lancet 1978;1:401–3. 62 Neild VS, Marsden RA, Bailes JA et al. Egg and milk exclusion diets in atopic eczema. Br J Dermatol 1986;114:117–23. 63 Webber SA, Graham-Brown RAC, Hutchinson PE et al. Dietary manipulation in childhood atopic dermatitis. Br J Dermatol 1989; 121:91–8. 64 Fergusson DM, Horwood LJ. Early solid food diet and eczema in childhood: a 10 year longitudinal study. Pediatr Allergy Immunol 1994;5(Suppl 1):44–7. 65 Chandra RK, Puri S, Suraiya C et al. Influence of natural food antigen avoidance during pregnancy and lactation on incidence of atopic eczema in infants. Clin Allergy 1986;16:563–9. 66 Hide DW, Matthews S, Matthews L et al. Effect of allergen avoidance in infancy on allergic manifestations at age 2 years. J Allergy Clin Immunol 1994;93:842–6. 67 Warner JA, Miles EA, Jones AC et al. Is deficiency of interferon gamma production by allergen triggered cord blood cells a predictor of atopic eczema? Clin Exp Allergy 1994;24:423–30. 68 Kondo N, Kobayashi Y, Shinoda S. Reduced interferon gamma production by antigen-stimulated cord blood mononuclear cells is a risk factor of allergic disorders: 6 year follow-up study. Clin Exp Allergy 1998;28:1340–4. 69 Platts-Mills TAE, Mitchell EB, Rowntree S et al. The role of house dust mite allergens in atopic dermatitis. Clin Exp Dermatol 1983; 8:233–47. 70 Norris PG, Schofield OM, Camp RDR. A study of the role of house dust mite in atopic dermatitis. Br J Dermatol 1988;118:435–40. 71 Colloff MJ, Ayres J, Carswell F et al. The control of allergens of dust mites and domestic pets: a position paper. Clin Exp Allergy 1992; 22(Suppl 2):1–28. 72 Oosting AJ, de Bruin-Weller MS, Terreehorst I et al. Effect of mattress encasings on atopic dermatitis outcome measures in a double-blind, placebo-controlled study: the Dutch mite avoidance study. J Allergy Clin Immunol 2002;110:500–6. 73 Koopman LP, van Strien RT, Kerkhof M et al. Placebo-controlled trial of house dust mite-impermeable mattress covers: effect on symptoms in early childhood. Am J Respir Crit Care Med 2002;166: 307–13. 74 Ricci G, Patrizi A, Speechia F et al. Effect of house dust mite avoidance measures in children with atopic dermatitis. Br J Dermatol 2000;143:379–84.

30.13

75 Tan BB, Strickland I, Weald D et al. House dust mite allergen avoidance in atopic dermatitis: a double-blind controlled study. Br J Dermatol 1995;133:18. 76 Melin L, Frederiksen T, Noren P et al. Behavioural treatment of scratching in patients with atopic dermatitis. Br J Dermatol 1986; 115:467–74. 77 Noren P, Melin L. The effect of combined topical steroids and habitreversal treatment in patients with atopic dermatitis. Br J Dermatol 1989;121:359–66. 78 Sokel B, Kent CA, Lansdown R et al. A comparison of hypnotherapy and biofeedback in the treatment of childhood atopic eczema. Contemp Hypnosis 1993;10:81. 79 Ehlers A, Stangier U, Gieler U. Treatment of atopic dermatitis: a comparison of psychological and dermatological approaches to relapse prevention. J Consult Clin Psych 1995;63:624–35. 80 Stewart AC, Thomas SE. Hypnotherapy as a treatment for atopic dermatitis in adults and children. Br J Dermatol 1995;132:778–83. 81 Noren P. Habit reversal: a turning point in the treatment of atopic dermatitis. Clin Exp Dermatol 1995;20:2–5. 82 Tan BB, Lear JT, Gawkrodger DJ et al. Azathioprine in dermatology: a survey of current practice in the UK. Br J Dermatol 1997;136: 351–5. 83 Lear JT, English JS, Jones P et al. Retrospective review of the use of azathioprine in severe atopic dermatitis. J Am Acad Dermatol 1996; 35:642–3. 84 Wolverton SE. Optimizing clinical use of azathioprine with newer pharmacogenetic data. Arch Dermatol 2009;145(6):707–10. 85 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;142:308–15. 86 Berth-Jones J, Finlay AY, Zaki H et al. Cyclosporin in severe childhood atopic dermatitis: a multicentre study. J Am Acad Dermatol 1996;34:1016–21. 87 Camp RDR, Reitamo S, Friedmann PS et al. Cyclosporin A in severe, therapy-resistant atopic dermatitis: report of an international workshop. Br J Dermatol 1993;129:217–20. 88 Harper JI, Berth-Jones J, Camp RD et al. Cyclosporin for atopic dermatitis in children. Dermatology 2001;203(1):3–6. 89 Munro CS, Levell NJ, Shuster S et al. Maintenance treatment with cyclosporin in atopic eczema. Br J Dermatol 1994;130:376–80. 90 Harper JI, Ahmed I, Barclay G et al. Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 2000;142:52–8. 91 Jury GS, Lever R, Burden AD et al. Narrowband ultraviolet B phototherapy in children. Br J Dermatol 2003;149(Suppl 64): 74–5. 92 Sheehan MP, Atherton DJ, Norris P et al. Oral psoralen photochemotherapy in severe childhood atopic eczema: an update. Br J Dermatol 1993;129:431–6. 93 Stern RS, Lairn N, Melski J et al. Cutaneous squamous cell carcinoma in patients treated with PUVA. N Engl J Med 1984;310:1156–61. 94 Stern RS, Nichols KT. Therapy with orally administered methoxsalen and ultraviolet A radiation during childhood increases the risk of basal cell carcinoma. The PUVA follow-up study. J Pediatr 1996; 129:915–17. 95 Heller M, Shin HT, Orlow SJ et al. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 2007;157(1):127–32. 96 Lyakhovitsky A, Barzilai A, Heyman R et al. Low-dose methotrexate treatment for moderate-to-severe atopic dermatitis in adults. J Eur Acad Dermatol Venereol 2010;24(1):43–9. 97 Bateman EA, Ardern-Jones M, Ogg GS. Dose-related reduction in allergen-specific T cells associates with clinical response of atopic dermatitis to methotrexate. J Dermatol 2007;156(6):1376–7.

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98 Balasubramaniam P, Ilchyshyn A. Successful treatment of severe atopic dermatitis with methotrexate. Clin Exp Dermatol 2005;30(4): 436–7. 99 Graham-Brown RAC. Toxicity of Chinese herbal remedies. Lancet 1992;340:673. 100 Sheehan MP, Atherton DJ. A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema. Br J Dermatol 1992;126:179–84. 101 Sheehan MP, Atherton DJ. One-year follow up of children treated with Chinese medicinal herbs for atopic eczema. Br J Dermatol 1994;130:488–93. 102 Gerasimov SV, Vasjuta VV, Myhovych OO et al. Probiotic supplement reduces atopic dermatitis in preschool children: a randomized, double-blind, placebo-controlled, clinical trial. Am J Clin Dermatol 2010;11(5):351–61.

103 Berth-Jones J, Arkwright PD, Marasovic D et al. Killed Mycobacterium vaccae suspension in children with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled trial. Clin Exp Allergy 2006;36(9):1115–21. 104 Harper JI, Mason UA, White TR et al. A double-blind placebocontrolled study of thymostimulin (TP-1) for the treatment of atopic eczema. Br J Dermatol 1991;125(4):368–72. 105 Leung DY, Hirsch RL, Schneider L et al. Thymopentin therapy reduces the clinical severity of atopic dermatitis. J Allergy Clin Immunol 1990;85(5):927–33. 106 Stiller MJ, Shupack JL, Kenny C et al. A double-blind, placebocontrolled clinical trial to evaluate the safety and efficacy of thymopentin as an adjunctive treatment in atopic dermatitis. J Am Acad Dermatol 1994;30(4):597–602.

31.1

C H A P T E R 31

Food Allergy and Eczema Helen E. Cox1 & Jonathan Hourihane2 1

Imperial College and St Mary’s Hospital, London, UK Departments of Paediatrics and Child Health, University College Cork, Cork, Ireland

2

Introduction, 31.1 Food-allergic sensitization and the allergic march, 31.1 The epithelial skin barrier as a route for

Phenotypes of food allergy in patients with eczema, 31.5

eczema, 31.11

The diagnosis of food allergy in patients with eczema, 31.7

allergic sensitization, 31.2

Elimination diets in patients with Practical approach to specific dietary allergen exclusion in eczema, 31.13 Conclusion, 31.18

Food-allergic disease in patients with eczema, 31.3

Introduction Eczema has been proposed as the cutaneous manifestation of a systemic disorder that also gives rise to asthma, food allergy and allergic rhinitis [1]. This observed pattern is frequently referred to as ‘the allergic march’. Sensitization to food and inhalant allergens is present in 70–80% of patients with moderate-to-severe eczema and when present in early childhood, precedes and anticipates the development of allergic asthma and rhinitis [2]. The early onset of food-allergic sensitization and prevalence of food allergy mirror the course of eczema, with both diseases peaking at 2 years followed by a steady decline thereafter. The role of allergen sensitization and food allergy in eczema pathogenesis and management has been debated since the turn of the last century. Opinions are polarized into those that believe that sensitization, food allergy and dietary avoidance are irrelevant in the pathogenesis and management of eczema, and those that believe that they are highly relevant in selected patients with eczema. This has caused considerable confusion and the issues of when to undertake allergy testing and dietary manipulations in eczema are still debated. It is important to recognize that food allergy and eczema co-exist due to their common origins as manifestations of an allergic diathesis. Infants and children with eczema need their skin treatment optimized before confident conclusions can be drawn about a specific food being a specific trigger of their eczema.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

This chapter explores the relationship between food allergy and eczema, drawing on the considerable advances that have been made at a clinical, cellular and molecular level in recent years. The following areas are covered. • Food allergic sensitization and the allergic march • The epithelial skin barrier as a route for allergic sensitization • Prevalence of food-allergic disease in eczema • Food-allergic phenotypes in eczema • Diagnosis of food allergy in patients with eczema • Elimination diets in patients with eczema • Practical approach to specific dietary allergen exclusion in eczema

Food-allergic sensitization and the allergic march Allergic sensitization to food allergens is a frequent but not universal finding in infants and children with eczema. The highest rates of food-allergic sensitization occur during the first 2 years of life, and they closely parallel the onset of eczema. Although food-allergic sensitization is not synonymous with food-allergic disease, the onset of food-allergic sensitization in infancy reflects the slightly later onset of food-allergic disease with a peak incidence of food allergy of 5–6% at 1 year with a gradual decline during childhood to an incidence of 1–2% in adults [3–6]. There is a direct correlation between eczema severity and food allergen sensitization, with food allergen sensitization rates increasing in infants and children with more

31.2

Chapter 31

severe eczema and falling in those with milder disease variants [7]. Hill et al. studied the prevalence of foodallergic sensitization and food-allergic disease confirmed by open challenge testing in a cohort of infants selected on the basis of parental atopy at birth. Positive challenges were seen in 10% of infants with mild eczema and in 65% with severe disease [8]. In a large multicentre, international cohort study of 2184 infants with active eczema (SCORAD 5–59), 55% were found to be atopic [9]. Infants deemed at high risk for food allergy were those in whom specific IgE levels exceeded previously reported age-specific cut-off levels for 95% positive predictive values (PPVs) for milk, egg and peanut, confirmed on double-blind placebocontrolled food challenge testing. The group at highest risk were infants with eczema onset 12 months of age (P 3 hours per day) at least 3 days per week over a period >3 weeks

Adapted from Host et al. 1988 [14] and Vandenplas et al. 2007 [15].

Food Allergy and Eczema

feeding aversion). The absence of diarrhoea or growth failure does not preclude the diagnosis of cow’s milk allergy. Furthermore, it should be recognized that infants can react to minute amounts of milk and other food proteins transmitted within their mother ’s breast milk. These proteins are capable of driving allergic inflammation in both the skin (eczema) and gut (e.g. diarrhoea) [14,16,17]. Maternal dietary exclusions may be justified if symptoms are attributed to maternal ingestion but they are no longer advised as a preventive strategy [18]. A clinical phenotype of severe eczema, multiple food allergies, failure to thrive, diarrhoea, hypoalbuminaemia and protein-losing enteropathy has been described in breast- and bottlefed infants at around 3–6 months of age. The clinical features can be confused with Netherton syndrome or severe immunodeficiency syndromes (severe combined immunodeficiency, Omenn syndrome), particularly as serum immunogloblins (IgG, A and M) are invariably low, secondary to protein loss in the gut. Response to an extensively hydrolysed formula is poor. Most infants respond dramatically to the removal of causative food proteins from the infant diet and institution of amino acid-based feeds [19]. References 1 Johansson S, Hourihane J, Bousquet J et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI Nomenclature Task Force. Allergy 2001;56(9):813–24. 2 Muraro A, Roberts G, Clark A et al., for the EAACI Task Force on Anaphylaxis in Children. The management of anaphylaxis in childhood: position paper of the European Academy of Allergology and Clinical Immunology. Allergy 2007;62(8):857–71. 3 Sampson HA, Munoz-Furlong A, Campbell RL et al. Second symposium on the definition and management of anaphylaxis: summary report – Second National Institute of Allergy and Infectious Disease/ Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391–7. 4 Bock SA, Atkins FM. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges. J Pediatr 1990;117(4):561–7. 5 Flinterman AE, Knol EF, Lencer DA et al. Peanut epitopes for IgE and IgG4 in peanut-sensitized children in relation to severity of peanut allergy. J Allergy Clin Immunol 2008;121(3):737–43, e710. 6 Sampson H. Role of immediate food hypersensitivity in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 1983;71(5):473–80. 7 Sampson H, McCaskill C. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 1985;107(5):669–75. 8 Worm M, Ehlers I, Sterry W, Zuberbier T. Clinical relevance of food additives in adult patients with atopic dermatitis. Clin Exp Allergy 2000;30:407–14. 9 Ehlers I, Worm M, Sterry W, Zuberbier T. Sugar is not an aggravating factor in atopic dermatitis. Acta Dermatol Venereol 2001;81:282–4. 10 Niggemann B, Sielaff B, Beyer K, Binder C, Wahn U. Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. Clin Exp Allergy 1999;29:91–6. 11 Celik-Bilgili S, Mehl A, Verstege A et al. The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges. Clin Exp Allergy 2005;35(3):268–73.

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12 Breuer K, Heratizadeh A, Wulf A et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy 2004;34(5):817–24. 13 Hill D, Firer J, Shelton M, Hosking C. Manifestations of milk allergy in infancy: clinical and immunologic findings. J Pediatr 1986;109(2):270–6. 14 Host A, Husby S, Osterballe O. A prospective study of cow’s milk allergy in exclusively breast-fed infants. Incidence, pathogenetic role of early inadvertent exposure to cow’s milk formula, and characterization of bovine milk protein in human milk. Acta Paediatr Scand 1988;77(5):663–70. 15 Vanderhoof J, Murray N, Kaufman S et al. Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants. J Pediatr 1997;131(5):741–4. 16 Wilson N, Self T, Hamburger R. Severe cow’s milk induced colitis in an exclusively breast-fed neonate. Case report and clinical review of cow’s milk allergy. Clin Pediatr (Phila) 1990;29(2):77–80. 17 Jarvinen KM, Suomalainen H. Development of cow’s milk allergy in breast-fed infants. Clin Exp Allergy 2001;31(7):978–87. 18 Greer FR, Sicherer S, Burks AW. American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Allergy and Immunology. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008;121(1):183–91. 19 Hill DJ, Cameron D, Francis DE, Gonzalez-Andaya AM, Hosking CS. Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. Allergy Clin Immunol 1995;96(3):386–94.

The diagnosis of food allergy in patients with eczema An accurate diagnosis of food allergy is important as it allows for a targeted approach to allergen avoidance and the implementation of an appropriate management plan. Conversely, a negative allergy diagnosis allows for relaxation of dietary restrictions, which are often erroneously imposed on children in the absence of a specific allergy diagnosis [1]. The gold standard test for food allergy diagnosis is the DBPCFC. These tests are time-consuming and expensive and not accessible to most patients outside research studies. The diagnosis therefore needs to rely on a stepwise approach which includes a detailed allergy-focused history and food-specific allergy tests which are interpreted within the context of the allergy history. When there is still doubt about the diagnosis of food allergy, oral provocations tests are required after a trial period of dietary elimination.

The history A detailed allergy-focused history should focus on the following areas.

Infant feeding A history of breast versus formula feeding, detailing the time period of exclusive breastfeeding. The relationship

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Chapter 31

of eczema onset to the introduction of formula feeds. The type of formula feed and the infant’s acceptance thereof. The onset of severe eczema during a period of exclusive breastfeeding may be secondary to food proteins excreted within breast milk which are capable of causing adverse reactions [2].

Gastrointestinal symptoms This should explore the presence of gut dysmotility in infancy as well as a current history of colic, abdominal pain, vomiting, reflux, feeding aversion, diarrhoea, constipation, blood or mucus in stools and failure to thrive. The presence of gastrointestinal symptoms in a patient with eczema should raise awareness of the possibility of food allergy.

History of immediate reactions to specific foods (past or present) A history of type 1 reactions to foods is important to ascertain. This should explore the time of onset in relation to ingestion, the quantity of food required to cause a reaction, any previous reaction or prior tolerance of that food and whether the reaction was of sufficient severity to cause anaphylaxis. As the natural history is for children to acquire tolerance to food allergens over time, it is necessary to determine reactions to foods in infancy as well as current reactions to establish a meaningful picture of the child’s allergic status. A useful approach is to establish whether the patient is able to ingest a normal portion size of common food allergens in order to ascertain oral tolerance, e.g. a healthy 6 year old should be able to tolerate a glass of milk, whole egg, slice of bread, peanut butter sandwich, piece of fish, tablespoon of pulses, seeds on bread and one kiwi fruit. A history of food aversion may be due to dislike of a particular food or an underlying food allergy. Young children with egg allergy frequently refuse to eat egg but receive small amounts of heated or baked egg within food products, e.g. cakes. In response to the question ‘Does your child eat egg?’, parents will frequently reply ‘yes’ as they are aware of their child’s ingestion of certain egg products but fail to recognize the possible importance of their child’s refusal to eat scrambled egg or raw egg within mayonnaise.

History of eczematous or gastrointestinal reactions to specific foods (past or present) Is there a history of foods causing an eczematous flare or onset of gastrointestinal symptoms? A history of food causing an eczematous flare in patients with persistent eczema is frequently absent. This has been shown in many clinical investigations. In a placebo-controlled study which demonstrated a 60% improvement in eczema patients adhering to a milk- and egg-free elimination diet,

there was no correlation between the parents’ suggestions that milk and/or eggs triggered their child’s eczema [3]. Retrospective analyses by Niggemann & Breuer have shown that the patients’ history of food-related eczema does not have a high diagnostic specificity [4,5].

Current diet and prior history of tolerance to foods Which of the main allergenic foods are included within the current diet? Are these foods present in normal portion sizes? Has there been any previous attempt to eliminate foods from the patient’s diet? Was this done with any specialist dietetic supervision? Up to 75% of children with eczema have undergone some form of dietary exclusion, usually without the supervision of a health professional or dietitian [6]. Unsupervised dietary elimination is potentially hazardous and can cause iron deficiency anaemia, rickets and symptoms associated with deficiency of vitamins A, C, B, zinc and selenium [7]. It is therefore important to establish the nutritional adequacy of the patient’s current diet as well as any proposed elimination diet, ensuring that they are meeting their calcium, vitamin, mineral and protein requirements.

Could cross-reacting allergens be relevant? Certain foods display a high degree of allergen crossreactivity which may be clinically relevant, e.g. the association between peanut allergy and allergy to sesame and tree nuts. In the absence of a history of oral tolerance to cross-reacting allergens, allergy testing is indicated to screen for potential, clinically relevant cross-reactivity.

Age of onset of eczema Eczema onset in infancy is far more likely to be associated with food allergy than eczema onset in a child >5 years [8]. A history of late eczema onset can therefore be helpful in ‘ruling out’ the possibility of allergy to certain foods (milk, soya, egg, wheat) previously tolerated in good amounts in infancy.

Eczema severity The probability of food allergy is greater in younger children and infants and those with severe disease. This is particularly true in infancy where the prevalence of food allergy ranges from 10% to 65% depending on infant severity [8]. When associated with symptoms of gut dysmotility, the association between food allergy and eczema is strengthened.

Co-morbid associations Asthma is a specific risk factor for anaphylaxis particularly within the context of poor asthma control [9]. It is important to be aware of a patient’s asthma status prior to embarking on elimination diets and challenge testing

Food Allergy and Eczema

within the context of positive allergy-specific IgE tests to foods. Patients with chronic asthma and co-existing or suspected food allergy are best managed by specialists with allergy training.

Family history of atopy The risk of atopy increases if a parent or sibling has atopic disease (20–40% and 25–35%, respectively), and is higher still if both parents are atopic (40–60%) [10].

Allergy-specific tests Available tests for the diagnosis of food allergy include skinprick tests (SPT), specific IgE tests (sp IgE) and the atopy patch test (APT). None of these tests, however, confirms or refutes the diagnosis of food allergy in the absence of an individual patient history which seeks to establish the prior probability of the allergen being causal. In order to minimize the number of false-positive tests, the selection of candidate allergens for testing should not be open-ended and should include relevant allergens based on the clinical history, patient’s age, allergic condition and geographical location. In the absence of a history of food allergy or prior exposure to a food, it may be necessary to select a screening panel of relevant food allergens, e.g. for an infant this would typically include cow’s milk, hen’s egg, wheat, soya, fish (cod or salmon), peanut and sesame. When applying normal ranges for test positivity (i.e. SPT wheal diameter of 3 mm or greater and/or specific IgE >0.35 KU/L), allergy tests show good sensitivity and negative predictive value (generally >90%) but moderate specificity and PPV (30–50%) in identifying a food hypersensitivity reaction. A negative test, in the presence of a good response to a histamine positive control, is therefore good at ruling out an IgE-mediated reaction whereas a positive test will overestimate IgE-mediated allergy 50% of the time if used as a screening test (Fig. 31.1). When the index of suspicion is high, the tests are useful for confirming allergy and conversely when the index of suspicion is low, the tests are useful for ruling out a diagnosis

Fig. 31.1 Positive skinprick tests.

31.9

of allergy. When there is a lack of correlation between the history and tests of specific IgE or when the history and tests are equivocal, confirmation by way of an open or blinded provocative challenge test is usually required to reach the diagnosis [11,12]. The specificity of a SPT can be increased by utilizing fresh foods for testing [13] and by raising the wheal diameter considered positive [14]. Changing the parameters for sIGE positivity to certain allergens (milk, egg, cod, peanut) but not others (wheat, soya) can similarly increase the specificity and performance of allergy tests [15] (Table 31.4). The larger the SPT mean wheal diameter, or quantity of sIgE, the more likely that the child has clinical allergy as opposed to sensitization. This relationship has allowed the development of predictive diagnostic cut-off values, which have been validated in specific patient populations for selected foods. These diagnostic cut-off values represent the SPT diameter or sIgE value at which a certain proportion (usually 95%) of patients were demonstrated as having proven (by DBPCFC) clinical allergy. Published 95% PPVs are, however, population specific and may vary in different populations [16–18]. There are no decision points yet for eczematous reactions to foods and these PPVs have not been calculated specific to an eczematous population. These published PPV values may therefore serve as a guide only when making decisions on whether oral food provocation challenge test is needed.

Table 31.4 Positive predictive values for food-specific IgE and skinprick tests Allergen 95% specific IgE levels (U/mL) positive predictive values Egg Infants Alternaria mould) [3]. References 1 Flohr C, Johansson SGO, Wahlgren CF et al. How “atopic” is atopic dermatitis? J Allergy Clin Immunol 2004;114:150–8. 2 Roberts G, Peckitt C, Northstone K et al. Relationship between aeroallergen and food allergen sensitization in childhood. Clin Exp Allergy 2005;35:933–40. 3 De Benedictis FM, Mranceshini F, Hill D et al. The allergic sensitisation in infants with atopic eczema from different countries. Allergy 2009;64:295–303.

32.3

Timing of sensitization In general, sensitization evolves in the order of exposure: food, indoor allergens, outdoor allergens. Sensitization to milk and egg most frequently occurs during the first year of life, while sensitization to aeroallergens occurs later in childhood, with increasing prevalence with age [1]. Sensitization to indoor airborne allergens (HDM and pets) often occurs at an earlier age than sensitization to pollens (tree and grass). Beyond the age of 3 years, food allergy is frequently outgrown but sensitization to aeroallergens increases, such that although the prognosis of food allergy (particularly to egg and milk) is in general good, children with atopic eczema and sensitization to aeroallergens are likely to progress to rhinoconjunctivitis and/or asthma. Furthermore, the number and type of allergic sensitizations serve as negative prognostic factors predicting a more chronic and recalcitrant course of atopic eczema [2]. References 1 Illi S, von Mutius E, Lau S et al. The pattern of atopic sensitisation is associated with the development of asthma in childhood. J Allergy Clin Immunol 2001;108:709–14. 2 Akdis CA, Akdis M, Bieber T et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2006;118:152–69.

Pathophysiology of allergic sensitization One current disease model for the pathogenesis of atopic eczema postulates that allergen uptake by IgE receptorbearing dendritic cells, followed by skin homing of cutaneous lymphocyte antigen (CLA)-bearing T-cells, plays a central role in initiating the inflammatory process [1]. Dendritic cells found in atopic eczema lesional skin express the high-affinity receptor for IgE (FcεRI) [2]. Allergy is thought to be triggered initially by encounter with an allergen. The first contact with this antigen leads to the formation of antigen-specific T-cells, predominantly Th2, and the consecutive induction of IgEproducing B-cells (Fig. 32.1). A second encounter with the allergen results in an inflammatory reaction which in turn leads to the clinical manifestations of the disease (Fig. 32.2) [3,4]. Dendritic cells are essential for priming and Th2 differentiation of naïve T-cells towards aeroallergens. Contamination of antigens with pattern-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) as well as locally produced damage-associated molecular patterns (DAMPs), such as uric acid and adenosine triphosphate (ATP), will augment an immune

32.4

Chapter 32

Allergen properties Skin factors

• Concentration

• Barrier disruption

• Association with ‘adjuvant’

• Pre-existing pro-inflammatory milieu

• Protease expression and disruption of skin barrier

• Infection

• Cross-reactivity other antigens

Allergen MHC Class II

IL-4, IL-3

TCR

IgE IL-4 Dendritic cell

Naïve T-cell

Th2 cells

Naïve B-cell

IgE memory B-cell

Fig. 32.1 A simple schematic representation of allergen sensitization. Dendritic cells are essential for priming and Th2 differentiation of naïve T-cells towards aeroallergens. Contamination of antigens with pattern-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) as well as locally produced damage-associated molecular patterns (DAMPs), such as uric acid and adenosine triphosphate (ATP), will augment an immune response.

response (see Fig. 32.1). Several studies have recently demonstrated an important role of endogenous danger signals at the inception and maintenance phase of allergic disease. These factors may also contribute to the transition toward chronic disease [5]. There is a complex interaction between allergen exposure, sensitization and subsequent disease development. It has been shown to be influenced by several factors, including genetic susceptibility, route of exposure, dose of allergen and in some cases by the structural characteristics of the allergen [6]. Populations and individuals, furthermore, are exposed to a mixture of several allergens, irritants and pollutants and their possible synergistic effects. References 1 Kraft S, Kinet JP. New developments in FcεRI regulation, function and inhibition. Nat Rev Immunol 2007;7:365–78. 2 Bieber T. The pro- and anti-inflammatory properties of human antigenpresenting cells expressing the high affinity receptor for IgE (Fc epsilon RI). Immunobiology 2007;212:499–503. 3 Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med 2001;344:30–7. 4 Kay AB. Allergy and allergic diseases. Second of two parts. N Engl J Med 2001;344:109–13. 5 Willart MA, Lambrecht BN. The danger within: endogenous danger signals, atopy and asthma. Clin Exp Allergy 2009;39:12–19. 6 Larché M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 2006;6:761–71.

The skin as a route of sensitization Epicutaneous sensitization is a possible major route of penetration for allergens and antigens that may pertain to later mucosal allergic disorders, as already suggested in animal models [1]. ‘Human disease models’ such as those observed within the context of occupational lung disease showed that despite reductions in workplace respiratory exposures, isocyanate and chronic beryllium lung disease continue to occur, prompting a focus on skin as a route of exposure [2]. It has long been recognized that individuals with Netherton syndrome, an autosomal recessive disorder with defective LEKTI expression, loss of stratum corneum adhesion, defective skin barrier function and increased skin permeability, are susceptible to allergy [3]. Transepidermal water loss (TEWL) is associated with prevalence of sensitization to aeroallergens [4]. Two comprehensive meta-analyses of published studies confirmed a strong risk of asthma in individuals with FLG null mutations, particularly in the context of eczema [5,6]. Filaggrin is only expressed in cornified skin and is not present in transitional or respiratory epithelia [7], supporting a role for epicutaneous sensitization in the development of asthma and allergic rhinitis. Furthermore, the development of food (such as peanut) allergies is also thought to be associated with allergen exposure through

Aeroallergies and Atopic Eczema

32.5

Atopic dermatitis T-cell mediated keratinocyte apoptosis Epithelial cell activation with release of proinflammatory cytokines

Allergic airways disease

Th1 cells

Th2 cell Th2 cells promote IgE production and activate eosinophils and mast cells locally

Allergen

MHC Class II

FcεRI receptor

TCR

Dendritic cells can present allergens via MHC molecule or IgE bound allergen via FcεRI receptor T-cell activation and proliferation

IgE antibodies

Dendritic cell

Allergen specific T helper cell

Fig. 32.2 A schematic representation of the mechanism of eczematous and/or delayed asthmatic reaction to aeroallergens after either skin and/or airway exposure. This process may occur with or without immediate type hypersensitivity reactions due to mast cell or basophil degranulation. It typically begins 2–3 hours after exposure, peaking by 10 hours and receding within 24–48 hours, unless complicated by further exposure, skin damage due to excoriations or secondary infections.

abraded skin, further implicating antigen sensitization through atopic skin in early life [8]. On the other hand, in patients with AD without filaggrin mutations, the cytokines IL-4 and IL-13 (typical of the Th2 profile) are able to inhibit filaggrin expression, thus indicating that if filaggrin deficiency favours atopic manifestations, an atopic pattern of response may also alter the filaggrin-mediated skin barrier [9]. References 1 Spergel JM, Mizoguchi E, Brewer JP et al. Epicutaneous sensitisation with protein antigen induces localised allergic dermatitis and hyperresponsiveness to metacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998;101:1614–22. 2 Redlich CA, Herrick CA. Lung/skin connection in occupational lung disease. Curr Opin Allergy Clin Immunol 2008;8:115–19. 3 Callard RE, Harper JI. The skin barrier, atopic dermatitis and allergy: a role for Langerhans cells? Trends Immunol 2007;28:294–8. 4 Boralevi F, Hubiche T, Léauté-Labrèze C et al. Epicutaneous aeroallergen sensitization in atopic dermatitis infants – determining the role of epidermal barrier impairment. Allergy 2008;63:205–10.

5 Rodríguez E, Baurecht H, Herberich E et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol 2009;123:1361–70. 6 Van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ 2009;339, b2433. 7 Hudson TJ. Skin barrier function and allergic risk. Nat Genet 2006;38:399–400. 8 Lack G, Fox D, Northstone K et al. Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348:977–85. 9 Incorvaia C, Fratu F, Verna N et al. Allergy and the skin. Clin Exp Immunol 2008;153(suppl 1):27–9.

Evidence to support the role of aeroallergens in atopic eczema flares The atopy patch test Eczematous lesions can be induced by the epicutaneous application of airborne allergens in a concentrationdependent fashion, in the so-called atopy patch test (APT)

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[1–3]. This test has been used as an experimental model for studying allergen-induced changes in atopic eczema lesions and is performed with protein extracts of the relevant allergen. There is some evidence to support its validity in determining the clinical relevance of IgE sensitization for eczematous skin lesions (e.g. for patients with flares of atopic eczema over air-exposed sites during the pollen season) [2,4]. Aeroallergen-specific T-cells have been isolated from lesional skin following the APT [5].

Immunological data Even more convincing evidence of the role of aeroallergens in the immunopathogenesis of a subgroup of patients with atopic eczema is the finding that aeroallergenspecific T-cells can be isolated from spontaneous lesional skin [6].

Impact of aeroallergen load and atopic eczema severity It is common knowledge that the symptoms of hay fever become more frequent and severe when the relevant pollen count rises beyond a certain threshold. There is evidence that for children with summer-pattern eczema, an association can be observed between disease severity and outdoor grass pollen counts (particularly for patients with specific IgE to grass pollens) [7]. Housedust mite is found in all homes but there is evidence that the homes of patients with AD have higher numbers of HDM than normal [8]. Patients with eczema often improve on admission to hospital where HDM antigen load is low [9,10]. As tests became available to measure environmental allergen load and document hypersensitivity, interest then developed in environmental modification to reduce HDM exposure, either by removal of the housedust [11–13] or by hospitalization of the patient [10]. A combination of effective measures to control HDM has been reported to improve atopic eczema, with variable clinical effect depending on the study, but in general with greatest improvement being seen in children [13–15]. References 1 Adinoff AD, Tellez P, Clark RA. Atopic dermatitis and aeroallergen contact sensitivity. Clin Immunol 1988;81:736–42. 2 Darsow U, Vieluf U, Ring J. Evaluating the relevance of aeroallergen sensitisation in atopic eczema with the atopy patch test: a randomised, double-blind multicenter study. Atopy Patch Study Group. J Am Acad Dermatol 1999;40:187–93. 3 Ring J, Darsow U, Behrendt H. Role of aeroallergens in atopic eczema: proof of concept with the atopy patch test. J Am Acad Dermatol 2001;45:49–52. 4 Kerschenlohr K, Günther S, Darsow U et al. Clinical and immunological reactivity to aeroallergens in ‘intrinsic’ atopic dermatitis patients. J Allergy Clin Immunol 2003;111:195–7.

5 Van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff FS et al. Skin derived aeroallergen-specific T cell clones of Th2 phenotype in patients with atopic dermatitis. J Allergy Clin Immunol 1992;90:184–93. 6 Werfel T. The role of leukocytes, keratinocytes and allergen-specific IgE in the development of atopic dermatitis. J Invest Dermatol 2009;129(8):1878–91. 7 Krämer U, Weidinger S, Darsow U et al. Seasonality in symptom severity influenced by temperature or grass pollen: results of a panel study in children with eczema. J Invest Dermatol 2005;124:514–23. 8 Colloff MJ. Exposure to house dust mite in homes of people with atopic dermatitis. Br J Dermatol 1992;127:322–7. 9 Blythe ME, Ubaydi FAL, Williams JD et al. Study of dust mites in three Birmingham hospitals. BMJ 1975; 11:62–4. 10 Platts-Mills TAE, Mitchell EB, Rowntree S et al. The role of dust mite allergens in atopic dermatitis. Clin Exp Dermatol 1983;118:229–38. 11 August PJ. House dust mite causes atopic eczema: a preliminary study. Br J Dermatol 1984;110:10–11. 12 Roberts DLL. House dust mite avoidance and atopic dermatitis. Br J Dermatol 1984;110:735–6. 13 Tan BB, Weald D, Strickland I et al. Double-blind controlled trial of effect of housedust-mite allergen avoidance on atopic dermatitis. Lancet 1996;347:15–18. 14 Holm L, Bengtsson A, Hage-Hamsten M et al. Effectiveness of occlusive bedding in the treatment of atopic dermatitis – a placebocontrolled trial of 12 months duration. Allergy 2001;56:152–8. 15 Oosting AJ, Bruin-Weller MS, Terreehorst I et al. Effects of mattress encasings on atopic dermatitis outcome measures in a double-blind, placebo controlled study: the Dutch mite avoidance study. J Allergy Clin Immunol 2002;110:500–6.

Properties of aeroallergens can promote sensitization Allergens may not be as innocuous or inert as previously thought. Pollens themselves not only release allergens but contain myriad biochemically active substances, including proteases and the recently described proinflammatory and immunomodulatory lipid mediators which can skew the immune system in a Th2 direction [1]. HDM (Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f)) express factors (generally proteases) that are capable of compromising epidermal tight junction integrity while also contributing to their allergenicity [2]. References 1 Traidl-Hoffmann C, Kasche A, Jakob T et al. Lipid mediators from pollen act as chemoattractants and activators of polymorphonuclear granulocytes. J Allergy Clin Immunol 2002;109:831–8. 2 Wan H, Winton HL, Soeller C et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999;104:123–33.

Specific allergens Housedust mite allergy Housedust mite is the top-ranking indoor allergen due to

Aeroallergies and Atopic Eczema

the high rate of sensitization against them, their perennial prevalence and their additional enzymatic properties. HDM are arachnids (members of the spider family) with Dermatophagoides farinae the species most often encountered in North America and Dermatophagoides pternoyssinus common in Europe, although both species are found world-wide. Their principal habitat is fomites and their diet consists of human epidermal scale, animal dander and micronutrients. They are found in carpets, fabric, pillows and mattresses. Up to 100 living mites can be found in 1 g of housedust. HDM survive best at ambient humidities between 50% and 80%. The most allergenic materials derive from their excrement (Der p1 and Der f1: water-soluble and heat-unstable glycoproteins) and from the body of the mite (Der p2 and Der f2; water-soluble and heat-stable glycoproteins). A person with normal skin leaves behind 0.5–1 g of epidermal scale in their bedding per week, providing enough food for thousands of mites for months. HDM allergen reduction is difficult to achieve and maintain due to the near ubiquitous exposure to HDM and encasing strategies do not always lead to an improvement in symptoms.

Birch pollen allergy

32.7

A practical approach to the patient with suspected aeroallergenexacerbated atopic eczema A contribution of aeroallergens is suggested by a history of environmental or seasonal exacerbation of atopic eczema and a clinical distribution particularly over air-exposed skin (Fig. 32.3). Associated symptoms of rhinoconjunctivitis or asthma may provide additional supportive evidence and will need separate specific therapy. Knowledge of local pollen counts and the flowering seasons of the major allergenic plants is helpful in defining a culprit pollen. In general, tree species flower through the spring and early summer, while the grass species flower throughout the summertime. Mould spores tend to be most abundant in the autumn but they may be found indoors under certain conditions all year. Confirming an association in patients with a history and clinical features suggestive of aeroallergenexacerbated eczema is challenging and at best indirect. A positive skinprick test (SPT) and/or specific IgE test (RAST) will support a suspected diagnosis but a negative test does not rule it out. The use of APT may improve diagnostic power, with proponents suggesting a contri-

Several studies have documented sensitization to birch pollen as one of the most important aeroallergen sensitizations impacting on eczema. Water-soluble mediators from birch pollen physiologically resemble prostaglandin E2 and are capable of promoting a Th2 response [1]. In addition, up to 70% of birch pollen-allergic patients experience allergic symptoms after ingestion of certain fruit and vegetables. The majority of these reactions are caused by cross-reaction with birch pollen proteins, in particular the Bet v 1 (and less frequently Bet v 6) epitope, which also occurs in the pollens of several other tree species, notably apples, stone fruit and nuts, as well as in celery, carrots and soybeans. These crossreactions in general do not cause severe food allergy, but unpleasant sensations within the oropharynx (termed the oral allergy syndrome) [2]. Importantly for some patients, consumption of birch pollen-related foods can provoke allergic symptoms and/or lead to an exacerbation of eczema [3]. References 1 Mariani V, Gilles S, Jakob T et al. Immunomodulatory mediators from pollen enhance the migratory capacity of dendritic cells and license them for Th2 attraction. J Immunol 2007;178:7623–31. 2 Vieths S, Scheuer S, Ballmer-Weber B. Current understanding of crossreactivity of food allergens and pollen. Ann N Y Acad Sci 2002;964:47–68. 3 Werfel T. The role of leukocytes, keratinocytes and allergen-specific IgE in the development of atopic dermatitis. J Invest Dermatol 2009;129(8):1878–91.

Fig. 32.3 This 8 year old with hay fever notices a flare of his eczema particularly over air-exposed sites during the grass pollen season. Courtesy of St John’s Institute of Dermatology, London, UK.

32.8

Chapter 32

Table 32.2 Strategies to minimize exposure to indoor aeroallergens Allergen

Avoidance strategies

Housedust mite

Impermeable covers for mattress and pillow Remove dust reservoirs (carpets, upholstery and soft toys) Reduce dust: regular vacuuming (weekly) Hot-wash (>55°C) bedclothes and soft toys weekly Reduce ambient humidity (30 minutes after closing windows Avoid drying washing outside

Personal

Wear brimmed hat and glasses while outdoors Change clothes and wash skin and hair after being outdoors

The role of aeroallergen-specific immunotherapy in the treatment of atopic eczema Specific immunotherapy (SIT) involves the repeated administration of the sensitizing allergen in a diseasemodifying manner. The duration of efficacy exceeds the treatment period. It is administered by subcutaneous (SCIT) or sublingual (SLIT) routes and potentially in the not toodistant future by the epicutaneous route. SIT modulates the responses of T-cells, B-cells and antigen-presenting cells on different levels, inducing epitope-specific T-cell anergy and by the generation of allergen-specific regulatory T-cells that can suppress the responses of effector T-cells leading ultimately to hyposensitization [2]. Hyposensitization therapy is well established in the treatment of allergic rhinitis [3] and insect venom allergy. However, although there have been promising results from small studies [4], it is not yet an established treatment for atopic eczema. Specific immunotherapy with mite allergens in children with eczema was recently shown to be effective only in patients with mild eczema in one study [5], while a second larger multicentre trial revealed a significant dose-dependent benefit for symptoms and disease severity [6]. The only meta-analysis of the use of SIT revealed positive effects on the management of atopic eczema in the majority of studies [4].

Aeroallergies and Atopic Eczema

Specific immunotherapy is generally safe and welltolerated although it may be associated with risk of anaphylaxis, especially by the subcutaneous route. For some patients with aeroallergy-associated atopic eczema, SIT itself may be associated with disease flare. SIT may be expensive and it requires frequent physician visits although immunotherapy by the sublingual route can reduce this latter requirement; cost and availability commonly limit its wider application. The major advantages of SIT are that the duration of efficacy significantly exceeds the treatment period. Furthermore, it can prevent the onset of new sensitizations to different allergens [7], and has been demonstrated to reduce the development of asthma among patients with allergic rhinoconjunctivitis, suggesting a possible role in halting the atopic march [8]. References 1 Darsow U, Vieluf U, Ring J. Evaluating the relevance of aeroallergen sensitisation in atopic eczema with the atopy patch test: a randomised, double-blind multicenter study. Atopy Patch Study Group. J Am Acad Dermatol 1999;40:187–93.

32.9

2 Larché M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 2006;6:761–71. 3 Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systmatic review and meta-analysis. Allergy 2005;60:4–12. 4 Bussmann C, Bockengoff A, Henke H et al. Does allergen-specific immunotherapy represent a therapeutic option for patients with atopic dermatitis? J Allergy Clin Immunol 2006;118:1292–8. 5 Panjo GB, Caminiti L, Vita D et al. Sublingual immunotherapy in mite-sensitized children with atopic dermatitis : a randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol 2007;120:164–70. 6 Werfel T, Breuer K, Rueff F et al. Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitisation to house dust mites: a multi-centre, randomised, dose-response study. Allergy 2006;61:202–5. 7 Panjo GB, Barberio G, de Luca F et al. Prevention of new sensitisations in asthmatic children monosensitised to house dust mite by specific immunotherapy. A six year follow-up study. Clin Exp Allergy 2001;31:1392–7. 8 Möller C, Dreborg S, Ferdousi HA et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT study). J Allergy Clin Immunol 2002;109:251–6.

33.1

C H A P T E R 33

Eczema Herpeticum Helen M. Goodyear West Midlands Deanery, Heart of England NHS Foundation Trust, Birmingham, UK

Definition. Eczema herpeticum is acute disseminated herpes simplex virus (HSV) infection in a patient with atopic dermatitis, often associated with systemic symptoms. History. The traditional description of HSV infection of atopic dermatitis comes from Kaposi [1], who described ‘a widespread eruption of lentil-shaped vesicles in patients with a pre-existing dermatitis’. Although the term ‘Kaposi’s varicelliform eruption’ (KVE) became widely used, Kaposi was uncertain of what to call the ‘varicella-like eruption’ he had described and suggested the name ‘eczema herpetiforme’. In 1941, HSV was first isolated from patients with KVE [2,3] and subsequently vaccinia virus [4] and coxsackie A16 [5]. Other dermatoses that predispose to cutaneous HSV infection include Darier disease [6], ichthyosis vulgaris [7], congenital ichthyosiform erythroderma [8], second-degree burns [9] and pemphigus foliaceus [10]. The term ‘eczema herpeticum’ was proposed by Lynch in 1945 [11] for extensive HSV infection complicating eczema and other dermatoses. To avoid confusion, the term ‘eczema herpeticum’ is now used to refer only to cutaneous HSV infection of atopic dermatitis [12]. Aetiology. The majority of children with atopic dermatitis come into contact with HSV and do not have a problem in dealing with the virus [13]. The reason why some children with atopic dermatitis are susceptible to widespread cutaneous HSV infection appears to be multifactorial [14,15]. Although multiple abnormalities of both cellmediated and humoral immunity have been found in atopic dermatitis [16,17], HSV-specific immunity appears to be intact [14]. Although in vitro lymphoproliferation to HSV antigen was decreased in three adults following eczema herpeticum [18,19], no defect in lymphoproliferation to HSV antigen was found on follow-up of 10 children with eczema herpeticum [14].

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Natural killer cells provide a first line of defence against HSV infection [20], and reduced natural killer cell activity in atopic dermatitis is well documented [14,21–23]. Decreased interleukin 2 (IL-2) receptors have also been found at the time of eczema herpeticum [14]. Herpes simplex virus is known to transiently suppress cellular immune responses in acute episodes of HSV infection [20]. One possibility is that the decrease in natural killer activity in atopic dermatitis may allow HSV to proliferate sufficiently to have a suppressive effect on immune mechanisms such as IL-2 receptors, resulting in HSV infection becoming extensive and disseminated [14]. There is also decreased interferon-γ and IL-18 [24]. The cathelicidin family of antimicrobial peptides which exhibit activity against viral infections have reduced levels in the skin of patients with atopic dermatitis but are lower still in skin biopsy samples from patients with eczema herpeticum [25]. The role of antibody to HSV infection is less well defined but appears to limit the severity of infection and play a part in cell-mediated cytotoxicity [26]. No defects in antibody responses measured by enzyme-linked immunosorbent assay (ELISA), Western blotting and neutralizing antibodies were found in 10 children [14], although there is one report of persistently low ELISA (12 years and in vitro penetrates deeper into the epidermal cells than aciclovir, but needs to be applied every 2 hours for 4 days [104,105]. Topical idoxuridine in adults has also been used to decrease pain and duration of recurrences [106] and more recently docosonal, which inhibits fusion of the human host cell with the viral envelope of HSV, preventing viral replication [107]. More severe recurrences, particularly in immunocompromised children or those with an underlying skin disorder or genital HSV, may require therapy with systemic aciclovir. Effective prophylaxis against recurrent HSV infections, occurring at monthly intervals or more frequently, can be achieved with systemic aciclovir. The usual starting dose is 800 mg daily (400 mg twice daily or 200 mg four times daily), decreased to 200 mg 2–3 times daily, with one-half of the dose being given to children under 2 years. Therapy should be interrupted every 6–12 months to see if the natural frequency of recurrences has decreased. Prevention. An ideal vaccine would prevent primary infection and colonization of the sensory ganglion [108,109]. Most vaccines aim to decrease the frequency of recurrences [109]. Vaccination with inactivated HSV DNA has been protective to patients at risk of genital HSV infection [110] and whole HSV vaccines have been found to decrease the rate and duration of recurrences [111]. An untested approach is the use of plasmid DNA encoding viral proteins [108]. Research in animals continues [112] but clinical trials and long-term follow-up are needed to evaluate the role and safety of vaccines in prevention of HSV infection. References 1 Longson M. Herpes simplex. In: Zuckerman AJ, Banatvala JE, Pattison JR (eds) Principles and Practice of Clinical Virology, 2nd edn. Chichester: John Wiley, 1990: 3–42. 2 Mindel A. Herpes Simplex Virus. The Bloomsbury Series in Clinical Science. London: Springer-Verlag, 1990: 1–164. 3 Corey L, Spear PG. Infections with herpes simplex viruses (first of two parts). N Engl J Med 1986;314:686–91. 4 Kieff ED, Bachenheimer SL, Roizman B. Size, composition and structure of the deoxyribonucleic acid of herpes simplex subtypes 1 and 2. J Virol 1971;8:125–32. 5 Chang T-W. Herpes simplex. Clin Dermatol 1984;2:5–7.

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6 Snavely SR, Liu C. Clinical spectrum of herpes simplex virus infections. Clin Dermatol 1984;2:8–22. 7 Rawls WE, Hammerberg O. Epidemiology of the herpes simplex viruses. Clin Dermatol 1984;2:29–45. 8 Jarrett M. Herpes simplex infection. Arch Dermatol 1983;119: 99–103. 9 Vestey JP, Norval M. Mucocutaneous infections with herpes simplex virus and their management. Clin Exp Dermatol 1992;17:221–37. 10 Buddingh GJ, Schrum DR, Lancier JC et al. Studies of the natural history of herpes simplex infections. Pediatrics 1953;11:595–610. 11 Kohl S. Herpes simplex virus infection – the neonate to the adolescent. Isr J Med Sci 1994;30:392–8. 12 Buchman TG, Roizman B, Nahmias AJ. Demonstration of exogenous genital reinfection with herpes simplex virus type 2 by restriction endonuclease fingerprinting of viral DNA. J Infect Dis 1979;140: 295–304. 13 Scott TFM, Coriell L, Blank H et al. Some comments on herpetic infection in children with special emphasis on unusual clinical manifestations. J Pediatr 1952;41:835–43. 14 Nahmias AJ, Josey WE, Naib ZM et al. Antibodies to herpesvirus hominis types 1 and 2 in humans. Am J Epidemiol 1970;91:539–46. 15 Cunningham AL, Turner RR, Miller AC et al. Evolution of recurrent herpes simplex lesions. An immunohistologic study. J Clin Invest 1985;75:226–33. 16 Megyeri K, Orosz L, Kormos B et al. The herpes simplex virusinduced demise of keratinocytes is asssoicated with a dysregulated pattern of p63 expression. Microbes Infect 2009;11(8–9):784–94. 17 Rinaldo CR, Torpey DJ. Cell-mediated immunity and immunosuppression in herpes simplex virus infection. Immunodeficiency 1993;5:33–90. 18 Lopez C, O’Reilly RJ. Cell-mediated immune responses in recurrent herpesvirus infections. J Immunol 1977;118:895–902. 19 Vestey JP, Norval M, Howie S et al. Variation in lymphoproliferative responses during recrudescent orofacial herpes simplex virus infections. Clin Exp Immunol 1989;77:384–90. 20 Tsutsumi H, Bernstein JM, Riepenhoff-Talty M et al. Immune responses to herpes simplex virus in patients with recurrent herpes labialis. 1. Development of cell-mediated cytotoxic responses. Clin Exp Immunol 1986;66:507–15. 21 Rasmussen LE, Jordan GW, Stevens DA et al. Lymphocyte interferon production and transformation after herpes simplex infection in humans. J Immunol 1974;112:728–36. 22 Rabie-Finger H, Valentine-Thon E, Steinmann J et al. Serological responses to herpes simplex virus type 1 (HSV-1) analysed with enzyme-linked immunosorbent assay (ELISA) and western blot (WB). Acta Virol 1991;35:113–26. 23 Eberle R, Mou S-W. Relative titers of antibodies to individual polypeptide antigens of herpes simplex type 1 in human sera. J Infect Dis 1983;148:436–44. 24 Kalimo KOK, Joronen IA, Havu VK. Cell-mediated immunity against herpes simplex virus envelope, capsid, excreted, and crude antigens. Infect Immunol 1983;39:24–8. 25 Douglas RG Jr, Couch RB. A prospective study of chronic herpes simplex virus infection and recurrent herpes labialis in humans. J Immunol 1970;104:289–95. 26 Bernstein DI, Lovett MA, Bryson YJ. The effects of aciclovir on antibody response to herpes simplex virus in primary genital herpetic infections. J Infect Dis 1984;150:7–13. 27 Ashley R, Mack K, Critchlow C et al. Differential effect of systemic aciclovir treatment of genital HSV-2 infections on antibody responses to individual HSV-2 proteins. J Med Virol 1988;24:309–20. 28 Lenette EH, Schmidt NJ (eds) Diagnostic Procedures for Viral Rickettsial and Chlamydial Infections, 5th edn. Washington, DC: American Public Health Association, 1979.

29 Goodyear HM, Wilson P, Cropper L et al. Rapid diagnosis of cutaneous herpes simplex infections using specific monoclonal antibodies. Clin Exp Dermatol 1994;19:294–7. 30 Benjamin DR. Use of immunoperoxidase for rapid diagnosis of mucocutaneous herpes simplex virus infections. J Clin Microbiol 1977;6:45–56. 31 Zimmerman SJ, Moses E, Sofat N et al. Evaluation of a visual, rapid, membrane enzyme immunoassay for the detection of herpes simplex virus antigen. J Clin Microbiol 1991;29:842–5. 32 Halstead DC, Beckwith DG, Sautter RL et al. Evaluation of a rapid slide agglutination test for herpes simplex virus as a specimen screen and culture identification method. J Clin Microbiol 1987;25:936–7. 33 Corey L, Spear PG. Infections with herpes simplex viruses (second of two parts). N Engl J Med 1986;12:749–57. 34 Aurelius E, Johansson B, Skoldenberg B et al. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 1991;337:189–221. 35 Lonsdale DM. A rapid technique for distinguishing herpes simplex virus type 1 from type 2 by restriction-enzyme technology. Lancet 1979;i:848–52. 36 Wheeler CE. The herpes simplex problem. J Am Acad Dermatol 1988;18:163–8. 37 Higgins CR, Schofield JK, Tatnall FM et al. Natural history, management and complications of herpes labialis. J Med Virol 1993;1(suppl):22–6. 38 Lafferty WE, Coombs RW, Benedetti J et al. Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type. N Engl J Med 1987;316:1444–9. 39 Taieb A, Diris N, Boralevi F et al. Herpes simplex in children. Clinical manifestations, diagnostic value of clinical signs, clinical course. Ann Dermatol Venereol 2002;129:603–8. 40 Joseph R, Rose FC. Cluster headache and herpes simplex: association? BMJ 1985;290:1625–6. 41 Shearer ML, Finch SM. Periodic organic psychosis associated with recurrent herpes simplex. N Engl J Med 1964;271:494–7. 42 Gill MJ, Arlette J, Tyrell DL. Herpes simplex virus infection of the hand: clinical features and management. Am J Med 1988;85(suppl 2A):53–6. 43 Gill MJ, Arlette J, Buchan KA. Herpes simplex virus infections of the hand. J Am Acad Dermatol 1990;22:111–16. 44 Feder HM, Long SS. Herpetic whitlow. Epidemiology, clinical characteristics, diagnosis and treatment. Am J Dis Child 1983;137:861–3. 45 Novick NL. Autoinoculation herpes of the hand in a child with recurrent herpes labialis. Am J Med 1985;79:139–42. 46 Szinmai G, Schaad UB, Heininger U. Multiple herpetic whitlow lesions in a 4-year-old girl: case report and review of the literature. Eur J Pediatr 2001;160:528–33. 47 Muller SA, Herrmann EC. Association of stomatitis and paronychias due to herpes simplex. Arch Dermatol 1970;101:396–402. 48 Glogau R, Hanna L, Jawetz E. Herpetic whitlow as part of genital virus infection. J Infect Dis 1977;136:689–92. 49 Crane LR, Lerner AM. Herpetic whitlow: a manifestation of primary infection with herpes simplex virus type 1 or type 2. J Infect Dis 1978;137:855–6. 50 Polayes IM, Arons MS. The treatment of herpetic whitlow – a new surgical concept. Plast Reconstr Surg 1980;65:811–17. 51 Corey L. First episode, recurrent and asymptomatic herpes simplex infections. J Am Acad Dermatol 1988;18:167–72. 52 Kinghorn GR. Genital herpes: natural history and treatment of acute episodes. J Med Virol 1993;1(suppl):33–8. 53 Vermillion ST, Holmes MM, Soper DE. Adolescent and sexually transmissible diseases. Obstet Gynecol Clin North Am 2000;27:163–79.

Herpes Simplex Virus Infections 54 Nahmias AJ, Dowdle WR, Naib ZM et al. Genital infection with herpesvirus hominis types 1 and 2 in children. J Pediatr 1968;42:659–66. 55 Stanberry LR, Rosenthal SL. Genital herpes simplex virus infection in the adolescent: special considerations for management. Paediatr Drugs 2002;4:291–7. 56 Lazar MP. Primary herpetic vulvovaginitis. Arch Dermatol Syph 1955;72:272–6. 57 Jaffe AC. Sexual abuse and herpetic genital infection. J Pediatr 1976;89:338. 58 Gardner M, Jones JG. Genital herpes acquired by sexual abuse of children. Pediatrics 1984;104:243–4. 59 Kaplan KM, Fleischer GR, Paradise JE et al. Social relevance of genital herpes simplex in children. Am J Dis Child 1984;138:872–4. 60 Reeves WC, Corey L, Adams HG et al. Risk of recurrence after first episodes of genital herpes. Relation to HSV type and antibody response. N Engl J Med 1981;305:315–19. 61 Lynch PJ. Psychiatric, legal and moral issues of herpes simplex infections. J Am Acad Dermatol 1988;18:173–5. 62 White WB, Grant-Kels JM. Transmission of herpes simplex virus type 1 infection in rugby players. JAMA 1984;252:533–5. 63 Belongia EA, Goodman JL, Holland EJ et al. An outbreak of herpes gladiatorum at a high school wrestling camp. N Engl J Med 1991;325:906–10. 64 Brett EM. Herpes simplex virus encephalitis in children. BMJ 1986;293:1388–9. 65 Kohl S. Herpes simplex virus encephalitis in children. Pediatr Clin North Am 1988;35:465–83. 66 Editorial. Herpes simplex encephalitis. Lancet 1986;i:535–6. 67 Parier EH. Herpetic ocular infections of childhood. Arch Ophthalmol 1980;98:704–6. 68 Auch Moedy JL, Lerman SJ, White RJ. Fatal disseminated herpes simplex virus infection in a healthy child. Am J Dis Child 1981;135:45–7. 69 Jaworski MA, Moffatt MEK, Ahronheim GA. Generalized HSV 1 infection during H. influenzae epiglottitis. J Pediatr 1980;96: 426–9. 70 Inoda S, Wakakura M, Hirata J et al. Stromal keratitis and anterior uveitis due to herpes simplex virus-2 in a young child. Jap J Ophthalmol 2001;45:618–21. 71 Becker WB, Kipps A, McKenzie D. Disseminated herpes simplex virus infection. Am J Dis Child 1968;115:1–8. 72 Doeglas HMG, Moolhuysen TMGF. Kaposi’s varicelliform eruption. Two cases caused by herpes virus hominis infection complicating Darier ’s disease. Arch Dermatol 1969;100:592–5. 73 Verbov J, Munro DD, Miller A. Recurrent eczema herpeticum associated with ichthyosis vulgaris. Br J Dermatol 1972;86:638–40. 74 Nishimura M, Maekawa M, Hino Y et al. Kaposi’s varicelliform eruption. Development in a patient with a healing second-degree burn. Arch Dermatol 1984;120:799–800. 75 McGill SN, Cartotto RC. Herpes simplex virus infection in a paediatric burn patient: case report and review. Burns 2000;26:194–9. 76 Meuli M, Lips U, Nadal D. A toddler with burns, stomatitis and skin graft loss. Burns 2000;26:625–7. 77 Fitzgerald WC, Booker AP. Congenital ichthyosiform erythroderma: a report of two cases in siblings, one complicated by Kaposi’s varicelliform eruption. Arch Dermatol Syph 1951;64:611–19. 78 Fromer ES, Lynch PJ. Neonatal herpes simplex and incontinentia pigmenti. Pediatr Dermatol 2001;18:86–7. 79 Silverstein EH, Burnett JW. Kaposi’s varicelliform eruption complicating pemphigus foliaceus. Arch Dermatol 1968;95:214–16. 80 Jordan SW, McLaren LC, Crosby JH. Herpetic tracheobronchitis. Cytologic and virologic detection. Arch Intern Med 1975;135:784–8.

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81 Nash G, Foley FD. Herpetic infection of the middle and lower respiratory tract. Am J Clin Pathol 1970;54:857–63. 82 Ramsey PG, Fife KH, Hackman RC et al. Herpes simplex virus pneumonia. Clinical, virologic and pathologic features in 20 patients. Ann Intern Med 1982;97:813–20. 83 Delis S, Kato T, Ruiz P et al. Herpes simplex colitis in a child with combined liver and small bowel transplant. Pediatr Transplant 2001;5:374–7. 84 Leigh IM. Management of non-genital herpes simplex virus infections in immunocompetent patients. JAMA 1985;2A(suppl):34–8. 85 Brown TJ, Straten MV, Tyring SK. Antiviral agents. Dermatol Clin 2001;19:23–34. 86 Wood AJJ. Antiviral drugs. N Engl J Med 1999;340:1255–68. 87 Snoeck R. Antiviral therapy of herpes simplex. Antimicrob Agents Chemother 2000;16:157–9. 88 Whitley RJ. Herpes simplex virus in children. Curr Treat Options Neurol 2002;4:231–7. 89 Kimura H, Aso K, Kuzushima K, et al. Relapse of herpes simplex encephalitis in children. Pediatrics 1992;89:891–4. 90 Elion GB. Aciclovir: discovery, mechanism of action and selectivity. J Med Virol 1993;1(suppl):2–6. 91 Arndt KA. Adverse reactions to aciclovir. topical, oral and intravenous. J Am Acad Dermatol 1988;18:188–90. 92 Gould JM, Chessells JM, Marshall WC et al. Aciclovir in herpesvirus infections in children: experience in an open study with particular reference to safety. J Infect 1982;5:283–9. 93 Levin MJ, Weinberg A, Leary JJ et al. Development of aciclovirresistant herpes simplex virus early during the treatment of herpes neonatorum. Pediatr Infect Dis 2001;20:1094–7. 94 Mertz GJ. Herpes simplex virus. In: Galasso GJ, Whitley RJ, Merigan TC (eds) Antiviral Agents and Viral Diseases of Man, 3rd edn. New York: Raven Press, 1990: 265–300. 95 Erlich KS, Mills J, Chatis P et al. Aciclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989;320:293–6. 96 Laiskonis A, Thune T, Neldam S et al. Valaciclovir in the treatment of facial herpes simplex virus infection. J Infect Dis 2002;186(suppl 1):S66–70. 97 Dignani MC, Mykietiuk A, Michelet M et al. Valaciclovir prophylaxis for the prevention of Herpes simplex virus reactivation in recipients of progenitor cells transplantation. Bone Marrow Transplant 2002;29:263–7. 98 Chan PKS. Use of oral valaciclovir in a 12-year-old boy with herpes simplex encephalitis. Hong Kong Med J 2000;6:119–21. 99 Saltzman R, Jurewicz R, Boon R. Safety of famciclovir in patients with herpes zoster and genital herpes. Antimicrob Agents Chemother 1994;38:2454–7. 100 Sáez-Llorens X, Yogev R, Arguedas A et al. Pharmacokinetics and safety of famciclovir in children with herpes implex or varicellazoster virus infection. Antimicrob Agents Chemother 2009;53: 1912–20. 101 Superti F, Ammendotia MG, Merchetti M. New advances in antiHSV chemotherapy. Current Med Chem 2008;15:900–11. 102 Blot N, Schneider P, Young P et al. Treatment of an aciclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant. Bone Marrow Transplant 2000;200:903–5. 103 Kleymann G, Fischer R, Betz UA et al. New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nature Med 2002;8:327–8. 104 Lin L, Chen XS, Cui PG et al. Topical application of penciclovir cream for the treatment of herpes simplex facialis/labialis: a randomized, double-blind, multicentre, aciclovir-controlled trial. J Dermatol Treat 2002;13:67–72.

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105 Hasler-Nguyen N, Shelton D, Ponard G et al. Evaluation of the in vitro skin permeation of antiviral drugs from penciclovir 1% cream and acyclovir 5% cream sued to treat herpes simplex virus infection. BMC Dermatol 2009;9:3. 106 Hamuy R, Berman B. Treatment of herpes simplex virus infections with topical antiviral agents. Eur J Dermatol 1998;8:310–19. 107 Sacks SL, Thisted RA, Jones TM et al. Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: a multicenter, randomized, placebo-controlled trial. J Am Acad Dermatol 2001;45: 222–30. 108 Eo SK, Pack C, Kumaraguru U et al. Optimisation of DNA vaccines for the prophylaxis and modulation of herpes simplex virus infections. Expert Opin Biol Ther 2001;1:213–25.

109 Whitley RJ, Roizman B. Herpes simplex viruses: is a vaccine tenable? J Clin Invest 2002;110:145–51. 110 Skinner GRB, Fink C, Melling J et al. Report of 12 years experience in open study of Skinner herpes simplex vaccine towards prevention of herpes genitalis. Med Microbiol Immunol 1992;180: 305–20. 111 Dundarov S, Andonov P. Seventeen years of application of herpes vaccines in Bulgaria. Acta Virol 1994;38:205–8. 112 Lu Z, Brans R, Akhrameyeva NV et al. High-level expression of glycoprotein D by a dominant-negative HSV-1 virus augments its efficacy as a vaccine against HSV-1 infection. J Invest Dermatol 2009;129:1174–84.

49.1

C H A P T E R 49

Viral Exanthems Wynnis L. Tom & Sheila Fallon Friedlander Departments of Pediatrics and Medicine (Dermatology), University of California, Rady Children’s Hospital, San Diego, CA, USA

Introduction, 49.1 Classic viral exanthems, 49.1 Other well-recognized viral eruptions, 49.8

Eruptions considered viral but without exact aetiology, 49.19 Conclusion, 49.21

Introduction Viral-induced exanthems are diffuse cutaneous eruptions often accompanied by systemic symptoms such as fever, malaise and headache. Some viruses cause well-recognized, distinct eruptions, while others cause non-specific skin findings that do not allow clinical differentiation of origin.

Classic viral exanthems Exanthems were previously numbered in the order of their historical appearance and description: first disease being measles; second disease, scarlet fever; third disease, rubella; fourth disease, ‘Dukes’ disease’ (now no longer considered a distinct entity); fifth disease, erythema infectiosum; and sixth disease, roseola infantum [1]. Of these six classic infectious exanthems, scarlet fever is the only non-viral rash and is due to group A streptoccocal infection (see Chapter 54). These infections once affected children throughout much of the world. Fortunately, their incidence has markedly declined as a result of preventive measures and immunization programmes, but they do remain endemic in some areas, particularly those with poor healthcare systems.

Measles (rubeola) Measles, or rubeola, is caused by the measles virus, a single-stranded RNA virus in the Paramyxovirus family. References to the disease extend as far back as the seventh century [2]. Before a vaccine became available, infection with measles virus was nearly universal during childHarper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

hood, with more than 90% of persons afflicted by age 15 years [3]. Despite significant progress in combating the disease, measles is still common and often fatal in developing countries: the World Health Organization estimated more than 197,000 deaths worldwide from measles in 2007 [4]. Even in the United States and other countries where endemic disease has been virtually eliminated, cases are still imported by foreign visitors or returning travellers. Affected children often have failed to receive the recommended immunizations due to parental fears. This is illustrated by an incident in 2008, where unvaccinated American children travelled to Switzerland and returned while in the prodromal phase of infection; the disease was spread to other unvaccinated children and transported to the Hawaiian islands before the condition was recognized [5]. Thus, continued worldwide efforts in vaccine education and coverage are needed to achieve disease eradication. Epidemiology and pathogenesis. Measles is more common in the winter months. The virus is highly contagious, with secondary attack rates near 90% for unvaccinated contacts [6]. It is predominantly spread by respiratory droplets and occasionally through the conjunctiva. Measles can be communicated from 1–2 days before the beginning of the prodromal period to 4 days after appearance of the rash. The virus invades and replicates in the respiratory epithelium and local lymphoid tissues. This results in a primary viraemia with spread to the reticuloendothelial system. A second viremia occurs 5–7 days later to involve the skin and multiple other organs [7]. Clinical features. Prodromal symptoms usually occur about 10–14 days after exposure and consist of progressive fever (to 39–40.5°C) and a severe, brassy cough,

49.2

Chapter 49

continuous coryza and conjunctivitis (the classic 3 Cs of measles). Koplik’s spots are blue-white spots with a red halo that appear intraorally, particularly on the buccal mucosa opposite the molar teeth (Fig. 49.1). They are often missed as they quickly resolve over 2–4 days with the onset of a generalized exanthem [2,8]. The characteristic eruption of measles consists of red macules and papules starting on the face and neck, especially behind the ears and along the hairline. It then spreads caudally to the rest of the body, often becoming confluent on the face and trunk (Fig. 49.2). Lesions gradually fade in the same order after 4–5 days, leaving behind coppery macules and a fine desquamation. The fever usually resolves 2–3 days after onset of the rash, but cough can persist for 10 days or longer [2,9]. Other possible symptoms include photosensitivity, anorexia and generalized lymphadenopathy. Secondary complications are seen in up to 40% of cases [10]. Morbidity and mortality are directly related to the nutritional status of the patient and age of disease acquisition. Children less than 5 years of age and adults 20 years of age and older are particularly affected. The most frequent complications are diarrhoea, otitis media and bronchitis. Death occurs in 0.3% of patients, with pneumonia accounting for the most cases. Acute encephalitis can affect 0.1% of persons within 2 weeks of the rash and give fever, seizures, headache and even coma. A higher incidence is seen in adolescents and adults, causing death in 15–25% and lifelong neurological sequelae such as motor impairment and mental retardation in 33% of survivors [10,11]. While conjunctivitis and keratitis are common and generally self-limited, corneal ulceration and blindness may manifest in individuals in developing countries [12], where vitamin A deficiency is prevalent, and appears to predispose to more severe infection.

Months to years after the acute disease, there can be a rare complication called subacute sclerosing panencephalitis from persistent measles virus infection. It most often occurs in those infected under the age of 2 years and slowly progresses from seizures to deterioration of cognitive and motor functions, followed by death. Individuals with defective cellular immunity may develop measles inclusion body encephalitis 5 weeks to 6 months after acute measles. Mental status changes and seizures develop without fever and over 80% of deaths occur within 1 week [13,14]. In addition to typical measles, mild/modified and atypical forms also occur. Modified measles can occur in young infants with residual maternal antibodies, in those receiving immunoglobulin therapy and in adults with partial immunity from prior vaccination. The incubation period is longer, the prodrome milder and the eruption sparse. Atypical measles occurred in children from the 1960s to the 1980s when formalin-inactivated (killed) measles vaccines were in use. They developed high fever, a rash most prominent on the extremities that often included petechiae and a high rate of pneumonitis. This was thought to be from antigen-antibody immune complexes resulting from incomplete maturation of the antibody response to the vaccines [9,15]. It is now rare with the substitution of live, attenuated vaccines for the previously utilized killed form.

Fig. 49.1 Koplik’s spots on the buccal mucosa: irregularly shaped, bright red spots with a bluish-white centre. Reproduced with permission from the Centers for Disease Control and Prevention.

Fig. 49.2 The measles exanthem at day 3, showing confluence on the face and upper trunk. Reproduced with permission from the Centers for Disease Control and Prevention.

Viral Exanthems

Differential diagnosis. Koplik’s spots are considered pathognomonic for measles, though their presence has also been documented with erythema infectiosum [16]. The latter, however, has a distinct eruption characterized by a generalized, reticulated erythematous rash and confluent erythema of the face (‘slapped cheeks’). Rubella has a less striking rash and shorter course, fading as it spreads. Rocky Mountain spotted fever should also be considered in the differential for atypical measles, but the rash typically spares the face. Other infections, such as Epstein–Barr virus and Mycoplasma infections, may mimic measles as well, but without the complete set of features. Drug eruptions often have a morbilliform appearance, but in uncomplicated cases lack cough or other prodromal symptoms. Kawasaki’s disease has fever, irritability, conjunctivitis and a morbilliform eruption, but also peripheral oedema of the extremities and palmoplantar erythema; Koplik’s spots do not occur. Laboratory findings. Histological findings from skin include a non-specific superficial perivascular lymphocytic infiltrate, with variable spongiosis and dyskeratosis. Finding multinucleated keratinocytes is helpful for diagnosis of measles. Giant cells, called Warthin–Finkelday cells, may be seen in the tonsils, lymph nodes and other reticuloendothelial tissues [17]. Serological testing for immunoglobulin M (IgM) antibody and examination of throat/nasopharyngeal cells for viral antigens by immunofluorescent microscopy may aid diagnosis. Polymerase chain reaction (PCR) may be used to detect the measles virus in nasopharyngeal and urine samples; viral culture, however, is difficult and much less sensitive [7]. Treatment and prevention. Symptomatic care with attention to hydration and nutrition is required. Natural disease confers lifelong immunity in immunocompetent individuals. To prevent spread, otherwise healthy children with measles should be isolated until 4 days after the onset of the eruption, whereas immunocompromised individuals need to be isolated for the duration of the illness. Active immunization is advocated to prevent measles. Current recommendations are two doses of live, attenuated virus vaccine given after 12 months of age; waning immunity is rare with this schedule. Because of the high transmissibility of measles virus, immunization levels of the order of 95% are necessary to prevent outbreaks within a particular population [18,19]. Some parents have declined vaccination of their children because of concerns relating to autism, but numerous studies do not support either the measles-mumps-rubella vaccine or thimerosal,

49.3

a vaccine preservative, as a primary cause of this condition [20–22]. In suspected or confirmed exposures, the measles vaccine may provide some protection if given within 72 hours. Susceptible household contacts and persons at high risk of complications (e.g. immunosuppressed individuals, infants 400 cases since 1970, c.90% in children with c.15% mortality; limited case-to-case spread. Recent USA outbreak from infected imported rodents

Buffalopox (orthopoxvirus)

India

Buffalo (R?)

Occupational hazard, painful skin lesion; virus is subspecies of vaccinia

Cattlepox (orthopoxvirus)

Brazil and South America

Cattle (R?)

Occupational. Resembles cowpox. Araçatuba and Cantagalo viruses (subspecies of vaccinia)

Orf/milker’s nodes (parapoxvirus)

Worldwide

Sheep (R), goats (R), cattle (R)

Relatively painless granulomatous skin lesions; occupational hazard of those in contact with reservoir hosts

Sealpox (parapoxvirus)

Europe and USA (and regions frequented by seals)

Seals (R?)

Resembles orf. Newly confirmed by PCR as human zoonosis in seal handlers

Tanapox (yatapoxvirus)

Zaire, Kenya

Monkeys (R)

Nodular skin lesions usually singular, with pyrexia

R, reservoir hosts.

(a)

(b)

(c)

Fig. 51.1 Electron micrographs of (a) cow poxviruses showing the common ‘mulberry’ (M) form with conspicuous short randomly arranged surface tubules and the less common ‘capsule’ (C) form with deeper stain penetration. (b) Whole M and C forms of parapoxvirus, showing the characteristic long spiralling of the surface tubule of the former. (c) Whole herpesviruses showing one particle with intact nucleocapsid and one broken, allowing stain penetration (phosphotungstic acid, ×120,000) Reproduced with permission from Baxby D, Bennett M. Cowpox: a re-evaluation of the risks of human cowpox based on new epidemiological information. In: Kaaden OP, Czerny CP, Eichorn W. (eds) Viral Zoonoses and Food of Animal Origin. Vienna: Springer, 1997: 1–12.

Poxviruses 2 Baxby D. Poxviruses. In: Mahy BWJ, Collier LH (eds) Topley and Wilson’s Microbiology and Microbial Infections, vol. 1, 9th edn. London: Arnold, 1998: 367–83. 3 Stanford MM, McFadden G, Karupiah G, Chaudhri G. Immunopathogenesis of poxvirus infections: forecasting the impending storm. Immunol Cell Biol 2007;85(2):93–102. 4 Nakano JH, Esposito JJ. Poxviruses. In: Schmidt NJ, Emmons RW (eds) Diagnostic Procedures for Viral, Rickettsial and Chlamydial Diseases, 6th edn. Washington, DC: American Public Health Association, 1989: 224–65. 5 Baxby D, Bennett M, Getty B. Human cowpox 1969–93: a review based on 54 cases. Br J Dermatol 1994;113:598–607. 6 Ropp SL, Jin Q, Knight JC et al. PCR strategy for identification and differentiation of smallpox and other orthopoxviruses. J Clin Microbiol 1995;33:2069–76. 7 Naidoo J, Baxby D, Bennett M et al. Characterisation of orthopoxviruses isolated from feline infections in Britain. Arch Virol 1992;125:261–72. 8 Loparev VN, Massung RF, Esposito JJ et al. Detection and differentiation of old world orthopoxviruses: restriction fragment length polymorphism of the crmB gene region. J Clin Microbiol 2001;39: 94–100. 9 Lapa S, Mikheev M, Shelkunov S et al. Species-level identification of orthopoxviruses with an oligonucleotide microchip. J Clin Microbiol 2002;40:753–7. 10 Espy MJ, Cockerill FR III, Meyer RF et al. Detection of smallpox virus DNA by LightCycler PCR. J Clin Microbiol 2002;40: 1985–8. 11 Inoshima Y, Morooka A, Sentsui H. Detection and diagnosis of parapoxvirus by the polymerase chain reaction. J Virol Methods 2002;84:201–8. 12 Lewis-Jones MS. Zoonotic pox virus infections in man: review article. Curr Opin Infect Dis 2004;17:81–9.

Orthopox infection in humans Smallpox Historical aspects. Smallpox (variola major) has altered the course of world history [1,2]. For centuries an endemic disease throughout the world, it caused millions of deaths and frequently left survivors with damaged health, unsightly pock-marked skin and blindness. In mediaeval times, the overall mortality ranged from 10% to 60%, with an average of about 25–30%. By the 20th century, mortality had fallen to between 5% and 25%, although the childhood mortality rate remained as high as 40% [2,3]. The origins of smallpox are uncertain. During the first millennium ad, the disease spread through Asia into Europe and, around 700 ad, into North Africa [1–3]. The Spanish Conquistadors carried it to the New World in the 1500s, where it spread rapidly in the ‘virgin population’. It is estimated that over 3.5 million native South Americans died in smallpox epidemics. A similar epidemic occurred in North America when smallpox wiped out millions of the members of native tribes [1–4]. The annual smallpox mortality rate in Europe in the 18th century was estimated at about 200,000–600,000, making up 7–12% of all deaths. The majority of these mortalities occurred in

51.3

children, especially infants, and the disease accounted for one-third of all childhood deaths [1]. The succession of the European monarchy was considerably altered by smallpox deaths [1]. In the early 20th century, a minor form of smallpox, alastrim, with a mortality of 1% or less, appeared in Africa and spread throughout the USA and Europe [3–6]. Vaccination alone was unsuccessful in eradicating smallpox and in 1967, when the estimated world prevalence was 10–15 million, the World Health Organization (WHO) commenced a global programme of identification, isolation and containment of cases and contacts [2,3]. As a result, the last naturally occurring case of smallpox was recorded in Somalia in 1977, although a small UK laboratory outbreak did occur in 1978 [3]. In 1980, the WHO declared the world to be free from smallpox, the first and to date the only virus infection to have been successfully eradicated [2,3]. After this, all stocks of smallpox virus were destroyed except for those held in specialized laboratories in the USA and the former USSR for research purposes [4]. Aetiology. The smallpox virus is a large brick-shaped orthopox virus measuring 240 × 300 nm (Fig. 51.1a). The virus is very stable and in the past attempts to attenuate it proved largely unsuccessful [3,7]. Epidemics were most common in winter and spring, transmission occurring by inhalation of infected droplets in aerosolized form or indirectly from fomites in clothes and bedding [2–6]. The infectious dose is unknown but is likely to be very small [4,8]. There are no known animal or insect vectors [2–4]. The virus enters through the mucosal surfaces of the nasopharyngeal tract and is transmitted to the local lymph nodes, where it replicates. After 3 or 4 days, an asymptomatic viraemia occurs, transmitting the smallpox virus to the rest of the reticuloendothelial system. Further replication occurs in the spleen, bone marrow and lymph nodes. Between 8 and 10 days after exposure, infected leucocytes cause a second symptomatic viraemia, homing particularly to the vessels in the papillary dermis and infecting local epidermal cells to produce cutaneous lesions. Persons incubating the disease become infectious only at this point. Their saliva is most infectious during the first week of illness and especially when oral lesions rupture. Ruptured pustules are also very infectious, but scabs much less so [2–4]. The virus is not as contagious as chickenpox or influenza and the secondary attack rate among unvaccinated contacts ranges from 37% to 88% [3]. Transmission usually occurs among close contacts, but occasionally there are more extensive outbreaks [8]. Clinical features. The most recent contemporary illustrated accounts of the clinical features of smallpox are

51.4

Chapter 51

found in publications by Dixon in 1962 [6], Rao in 1972 [9] and Fenner et al. in 1988 [3]. Rao [9] studied 3544 cases in India and reclassified smallpox into five types (Table 51.2). This classification was later adopted by the WHO [3]. 1 ‘Ordinary’ smallpox accounted for the majority of cases: 88.8% of unvaccinated patients and 70% of vaccinated patients. There are three subtypes. The confluent subtype was the most serious, with a mortality of 62% in the unvaccinated, and was characterized by lesions that were confluent on the face and forearms but discrete elsewhere. Patients with the semi-confluent subtype had confluent lesions only on the face (37% mortality), while those with the discrete form, the most common type, had no confluent lesions (9.3% mortality). 2 A milder, modified type, rarely fatal and with an accelerated course, occurred in 2% of unvaccinated persons and 25% of those previously vaccinated. 3 The rare purpuric or haemorrhagic-type smallpox (3%, usually adults), with widespread haemorrhage into skin and mucous membranes, caused early death from septicaemia. Subconjunctival haemorrhages and bleeding from any orifice could occur. Characteristically, the incubation period was short and the prodromal illness was severe and accompanied by abdominal pain. The ‘early type’ was always fatal and the ‘later ’, with haemorrhage into pustules, usually fatal. It occurred more commonly in pregnancy.

Table 51.2 A classification of clinical types of variola major Type

Features

Ordinary type

Raised pustular skin lesions • Confluent: confluent rash on face and forearms • Semi-confluent: confluent rash on face, discrete elsewhere • Discrete: areas of normal skin between pustules, even on face

Modified type

Like ordinary type but with an accelerated course

Variola sine eruptione

Fever without rash caused by variola virus; serological confirmation

Flat type

Pustules remained flat; usually confluent or semi-confluent; usually fatal

Haemorrhagic type

Widespread haemorrhages in skin and mucous membranes • Early: purpuric rash; always fatal • Late: haemorrhages into base of pustules; usually fatal

Reproduced from Fenner et al. 1988 [3] (based on Rao 1972 [9]) published with permission of the World Health Organization.

4 The flat type (7%), fatal in 66% of cases, occurred mainly in children (72%). A short incubation period and severe prostrating illness was followed by confluent or semiconfluent, slowly developing lesions. These lesions never formed pustules but remained soft and flattened with an erythematous and velvety appearance. The distribution was not always centrifugal. In survivors, the skin healed without scab formation and widespread epidermal peeling sometimes occurred. 5 In variola sine eruptione, fever occurred without rash in previously vaccinated persons or in infants with maternal antibodies. This form of smallpox could only be confirmed by serological testing. This last type may not cause transmissible smallpox. The incubation period for ‘ordinary’ smallpox is around 10–14 days (range 7–17 days) [2–6]. Patients are largely asymptomatic and remain non-infectious until the end of the second week, when there is an abrupt onset of a high prodromal fever associated with severe malaise and ‘flulike’ symptoms. Most have severe headache, usually frontal, and backache is common. Vomiting occurs in about half of patients, sometimes with severe abdominal pain. About 10% of patients, especially infants, develop diarrhoea. Very rarely, infants develop acute dilation of the stomach, which is usually fatal. Some adults become delirious and convulsions may occur in children. The fever falls by the second or third day and erythematous mucosal lesions (enanthema) appear in the mouth and pharynx, often associated with pharyngitis. The exanthema develops the following day and consists of small cutaneous erythematous macules [3–6,9]. The eruption is characteristically centrifugal, developing initially on the face, hands and palms and then spreading distally to the trunk and limbs and the soles (Figs 51.2–51.4). The lesions evolve more slowly than in chickenpox, developing over a period of 4–7 days. The lesions begin as small ‘papules’, in reality early vesicles, which are firm and hard. They evolve briefly into 2–4 mm vesicles and then into deep, firm, circular pustules (4–6 mm). In severe cases, these lesions become confluent. At any one time, unlike chickenpox, all lesions are in the same stage of evolution. By the seventh or eighth day of the rash, the pustules start to flatten and become umbilicated (Fig. 51.3) and then gradually crust by the end of the second week, lasting longest on the palms and soles. Final resolution of lesions occurs at about the end of the third week of the rash, leaving postinflammatory hyperand/or hypopigmentation initially. Although this gradually fades, a proportion develop fibrosis, causing deeply pitted scars or ‘pock’ marks of 2 mm or more. Destruction of sebaceous glands causes the face to be particularly affected in 65–80% (Fig. 51.5) [3–6]. Involvement of organs other than the skin, mucous membranes and reticuloendothelial system is uncommon and most deaths (usually

Poxviruses

(a)

(b)

51.5

(c)

Fig. 51.2 (a–c) ‘Ordinary’ smallpox, discrete type, demonstrating the centrifugal distribution of lesions, particularly on the face and distal limbs, hands and feet with fewer lesions on the trunk. Reproduced from the Smallpox Eradication Campaign identification pamphlet, with permission from the World Health Organization.

between days 10 and 16) result from toxaemia and hypotension, probably caused by circulating immune complexes and soluble variola antigens [3,4]. Smallpox infection confers lifelong immunity in most cases, but occasional subclinical smallpox was reported in patients who had previously had smallpox [3]. The fever of ordinary-type smallpox is bimodal. In the prodromal stage, there is a peak of around 40°C, followed by low-grade pyrexia for a few days. The second peak of around 39°C occurs during the maximum evolutional or pustular stage in the second week of the rash and gradually subsides, often in a swinging pattern [3–6]. Persistence of fever after scab formation is a poor prognostic indicator [3]. Respiratory involvement and cough, with death from pneumonia, is more likely to occur in severe cases. Blindness was reported as common in the older literature but occurred in only about 1% of patients in the 20th century [3,6,10]. It was usually as a result of keratitis, corneal ulceration and scarring and rarely secondary infection or panophthalmitis. Encephalitis was reported in 1 in 500 cases of variola major and 1 in 2000 of variola minor [3]. It usually resolved slowly without complications, but very rarely (1%) a typical perivascular demyelination developed, similar to that occurring with vaccinia, measles or varicella [6]. Arthritis and osteomyelitis developed in about 2% of children, possibly as a result of viral involvement of the metaphyses [3,10]. Signs may be

missed in the acute stages, but later sequelae of limb shortening, flail joints, subluxations and gross deformities may occur [3]. As variola is cytocidal, most pregnant women miscarry in the early stages of smallpox; however, if the fetus survives to term it has temporary immunity from maternal antibodies [3]. Congenital smallpox is usually fatal [3,9]. In a few vaccinated patients, there may be a fleeting erythematous rash during the prodromal stage, particularly around the vaccination scar and in the axillae, groins and popliteal fossae [3,4]. The more toxic forms of smallpox, apart from the haemorrhagic type, are less common in vaccinated individuals [3]. ‘Modified-type’ smallpox sometimes occurs in previously vaccinated individuals and is hardly ever fatal. The prodrome may still be severe but the course of the disease is accelerated, the lesions often being smaller and fewer and the secondary eruptive fever absent [3,9]. Differential diagnosis. Early lesions or milder forms of smallpox could be confused with many eruptive exanthems, especially chickenpox, but a full-blown case of ordinary-type smallpox is unlikely to be missed. Children are usually extremely toxic and display the typical centrifugal distribution of lesions [3–6,9,10]. In chickenpox, the rash is centripetal, seen mainly on the trunk and rarely on the palms and soles. Unlike smallpox, there is

51.6

Chapter 51

(a)

Fig. 51.4 ‘Ordinary’ smallpox in a child at the umbilicated/crusted stage. Note the confluent lesions on the face. Courtesy of Dr Derrick Baxby.

(b) Fig. 51.3 Close-up of typical lesions on the hands and feet showing involvement of the palms and soles with early umbilication of lesions in (a). Reproduced with permission from the World Health Organization.

a rapid evolution and healing of lesions in recurrent crops, so that many lesions are in different phases in the same body site. Monkeypox is almost identical to smallpox, with the same acral distribution, but with more marked adenopathy. Lesions of eczema herpeticum may all be at the same stage of development (Fig. 51.6) but are smaller and more superficial, rupturing easily and crusting within the first week. Scanning electron microscopy will rapidly differentiate between herpes- and poxviruses. Other acral blistering disorders, such as hand-foot-andmouth disease, are sufficiently distinctive to make confusion unlikely. In bullous erythema multiforme major, the lesions are not uniform in size or shape. The lesions on the palms and soles of secondary syphilis are of varying sizes and do not progress to form blisters. Haemorrhagic smallpox, however, could easily be mistaken for leukaemia or other purpuric conditions such as meningitis, vas-

Fig. 51.5 Granulomatous smallpox lesions of the face causing destruction of the sebaceous glands. Reproduced from Dixon [6] with permission from Elsevier.

Poxviruses

51.7

orthopox virus, but polymerase chain reaction (PCR) will be required for rapid diagnosis of variola virus [12,13]. Isolation of virus on live cell cultures or growth on chorioallantois is slow and outdated and nucleic acid identification is still required to distinguish between different orthopoxviruses. At present, serological testing does not differentiate between orthopox species or between recent infection and past vaccination, although in the future newer IgM detection methods may help to do so [10].

(a)

(b) Fig. 51.6 Eczema herpeticum of the distal arm and hand. (a) The distribution mimics smallpox in this case. (b) A close-up shows the typical lesion of herpes, some of which are at the same stage of evolution, but there is already early crusting at day 4 and the lesions are smaller and less firm than smallpox (authors’ collection).

culitis or even drug reactions. Breman & Henderson [10] give a clear account of the differential diagnosis and management of smallpox. In addition, public health websites such as those of the WHO [11] or the USA Centers for Disease Control and Prevention (CDC) [5] have excellent photographic images and an algorithm for the differential diagnosis of smallpox. Investigations. The variola virus can sometimes be detected in swabs from the nasopharynx as early as 5–6 days before the development of rash. The patient is not infectious at this time [4]. In addition, lesional swabs, blister fluid, scabs, blood and urine should be taken, using the precautions and equipment supplied by regional smallpox teams. These should be transported by special arrangements to a designated reference laboratory. Electron microscopy will quickly identify the presence of an

Pathology. Multiplication of virions within the cellular cytoplasm of the basal and lower spinous keratinocytes produces the typical cytoplasmic eosinophilic inclusion bodies common to all orthopox infections [14]. In variola, they are small and located close to the nucleus, surrounded by a clear halo (Guarnieri’s bodies) [14]. Similar bodies occur in vaccinia. Severe intracellular oedema, ballooning and cell necrosis occur, producing microscopic vesicles, which enlarge and coalesce to form large unilocular vesicles. During the pustular phase, the vesicles become filled with large numbers of neutrophils. Destruction occurs mainly in the epidermis and superficial dermis, so that hair follicles and eccrine tissue can recover. However, the more superficial sebaceous glands are destroyed. In the later stages, granulation tissue is seen around the necrotic areas and causes deeply pitted scars. Electron microscopy demonstrates two forms, the encapsulated or ‘C’ form (the most infectious) and the nonencapsulated or mulberry ‘M’ form, which is more common (approximately 80%) (Fig. 51.1a). Treatment. Smallpox is a hazard group 4 organism and suspected cases should be treated as an international health emergency [4,5,10], with immediate isolation at the place of diagnosis and notification to locally designated smallpox teams. Protocols are now in place in most countries for the management of suspected cases of smallpox, with designated regional teams for isolation, assessment, treatment, decontamination and vaccination of contacts. Detailed descriptions are beyond the scope of this article and readers are referred to the appropriate public health authority guidelines or website in their own country. Hospital patients should be nursed in an environment of high-efficiency particulate air (HEPA) filtration by previously vaccinated staff [4]. Vaccination of all contacts and their contacts, a process known as ring vaccination, should be undertaken [3,4,10]. Fluid replacement and attention to skin and eye care are essential. Although its effect in smallpox is unproven, topical idoxuridine could be used for corneal lesions [3,10]. Patients should be observed for signs of septicaemia, hypotension or purpura and treated appropriately with general supportive measures. Secondary infection and pneumonia require anti-

51.8

Chapter 51

biotic therapy. Vaccinia immune globulin (VIG), which was used in the treatment of smallpox and complications of vaccination in the 1970s [3], is not currently recommended during either the incubation period or clinical stages of smallpox and should be reserved for the complications of vaccination [4,5]. In the 1960s, semithiocarbazone (marboran) derivatives were used to treat smallpox, but their benefit was not substantiated [4]. The DNA polymerase inhibitor cidofovir given intravenously in the first days after exposure has been shown to be effective against most poxviruses in the laboratory [15] and in theory could be used to treat smallpox. However, this medication has significant renal toxicity and should be administered with probenecid and hydration. It is not known to be more effective than vaccination in the immediate postexposure phase [4]. Patients who die from smallpox should be cremated as soon as possible and mortuary workers vaccinated [4]. References 1 Hopkins DR. Princes and Peasants. Smallpox in History. Chicago: University of Chicago Press, 1983. 2 Henderson DA, Moss B. Smallpox and vaccinia. In: Plotkin SA, Orenstein WA (eds) Vaccines, 3rd edn. 1999. 3 Fenner F, Henderson DA, Arita I et al. Smallpox and its Eradication. Geneva: World Health Organization, 1988. www.who.int/emc/ diseases/smallpox/Smallpoxeradication.html. 4 Henderson DA, Inglesby TV, Bartlett JG et al. Smallpox as a biological weapon. JAMA 1999;281:2127–37. 5 Centers for Disease Control and Prevention. Smallpox home page. http://www.bt.cdc.gov/agent/smallpox/index.asp. 6 Dixon CW. Smallpox. London: Churchill, 1962. www.nlm.nih.gov/ nichsr/esmallpox/esmallpox.html. 7 Baxby D. Jenner ’s Smallpox Vaccine: the Riddle of Vaccinia Virus and its Origin. London: Heinemann Educational Books, 1981. 8 Wehrle PF, Posch J, Richter KH et al. An airborne outbreak of smallpox in a German hospital and its significance with respect to other recent outbreaks in Europe. Bull World Health Organ 1970;43:669–79. 9 Rao AR. Smallpox. Bombay: Kothari Book Depot, 1972. www.nlm.nih.gov/nichsr/esmallpox/esmallpox.html. 10 Breman JG, Henderson DA. The diagnosis and management of smallpox. N Engl J Med 2002;346:1300–8. 11 WHO Slide Set on Diagnosis of Smallpox. www.who.int/emc/ diseases/smallpox/slideset/. 12 Espy MJ, Cockerill FR III, Meyer RF et al. Detection of smallpox virus DNA by LightCycler PCR. J Clin Microbiol 2002;40:1985–8. 13 Ropp SL, Jin Q, Knight JC et al. PCR strategy for identification and differentiation of smallpox and other orthopoxviruses. J Clin Microbiol 1995;33:2069–76. 14 McKee PH. Pathology of the Skin with Clinical Correlations, 2nd edn. London: Mosby-Wolfe, 1996: 4–14. 15 De Clercq E. Cidovir in the therapy and short-term prophylaxis of the poxvirus infections. Trends Pharmacol Sci 2002;23:456–8.

Vaccinia and vaccination Historical aspects of vaccination. Variolation, which originated in the East, was widely used in the second half of the 18th century as a method of introducing live small-

pox material superficially into the skin. The intention was to produce a milder form of the disease. However, it was not without hazard and often led to full-blown clinical smallpox, with considerable morbidity and a mortality of between 1 in 70 and 1 in 200 [1,2]. Non-immune contacts were particularly at risk. Edward Jenner (1749–1823) was the first to publish work on the use of cowpox material as a protective inoculation against smallpox [1,2]. This later became known as vaccination (vacca is Latin for cow). Jenner had noted that dairy maids who had previously contracted cowpox appeared to be immune to smallpox. In 1796, he used material taken from a cowpox lesion on a dairy maid’s hand to inoculate 8-year-old James Phipps, protecting him from subsequent variolation. News of Jenner ’s ‘vaccination’ spread rapidly throughout Europe and then the world. Despite initial opposition, it was quickly adopted in preference to variolation and this resulted in virtual eradication of smallpox in many countries [1,2]. The original vaccinators used either cowpox or horsepox material and supplies were shared and replenished when possible, so that many vaccines existed at this time [1–3]. Cowpox was rare even in Jenner ’s time and vesicle fluid from successful vaccinees was used for arm-to-arm transfer, dried on cotton threads and ivory stylets or stored in quills [1–3]. Supplies of vaccine were later assured by growth on calf skin, a practice which resulted in particular outrage from the antivaccination lobby [2]. Secondary infection was common and reduced the vaccines’ effectiveness. In order to counteract this phenomenon, vaccination was often performed at multiple sites until the 1930s. The introduction of glycerated calf serum considerably reduced the risk of infection and in the 20th century mass vaccination with stable freeze-dried vaccines using vaccinia virus was both more effective and less dangerous. This replaced the older vaccines [2–4]. Vaccinia and modern vaccination. Vaccinia is an orthopox virus 300–400 nm in diameter. Its origins are unknown but it possibly originated from an extinct form of horsepox [1,2]. Several different strains of a lyophilized preparation of live Vaccinia virus (VACV) are available for use [5,6]. During vaccination, VACV is inserted into the basal layers of the epidermis for maximum effect. Many different techniques have been employed with varying effectiveness and morbidity. In the 1960s and 1970s, scarring following vaccination with rotary methods, commonly employed in India, was sometimes due to trauma rather than successful vaccination [3]. Latterly, superficial scarification or multiple punctures (usually 5–15) with a two-tined or bifurcated needle (Fig. 51.7a) were the most common procedures [3–5]. Currently, 2–3 punctures are recommended for primary vaccination and

Poxviruses

51.9

(a)

(d)

(b)

(e)

(c) Fig. 51.7 (a) Bifurcated needle. (b) Typical primary take reaction at days 6–10. (c) Lymphangitis around vaccination site sometimes occurs and is associated with localized lymphadenopathy. (d) Smallpox vaccination scars. (e) Satellite scars around vaccination site are considered a variant of normal. (a) Courtesy of Dr Derrick Baxby. (b,c,e) Reproduced with permission from the CDC, Atlanta, GA, USA. (d) Author’s collection.

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15 for revaccination. Prior treatment of the skin with alcohol inactivates the virus and should not be used. In primary vaccination [4,7], an initial papule evolves to a vesicle and then a pustule. The erythematous areola reaches a maximal size at 8–10 days (Fig. 51.7b). Systemic symptoms, with malaise, myalgia, mild pyrexia (up to 39°C) and localized soreness and itching, occur between days 4 and 14 in over 70% of children. Regional lymphadenopathy is common and may be associated with localized lymphangitis (Fig. 51.7c). The scab separates between 14 and 21 days, leaving a puckered scar (Fig. 51.7d). Not infrequently, there are small satellite lesions around the primary site (Fig. 51.7e). Vaccination site reactions are classified into two categories: major reactions and equivocal or ‘non-take’ reactions. Response to vaccination should be observed between days 6 and 8 and anything less than a major reaction should be considered as equivocal and the individual should be revaccinated. There are several reasons for ‘non-takes’, including suboptimal techniques, suboptimal vaccine quality or persistence of residual immunity in previously vaccinated individuals [7]. Hypersensitivity reactions with localized erythema, maximal at 48 h, indicate a failure of ‘primary take’ and these individuals should also be revaccinated [4]. In about 10% of patients, around 8–10 days after vaccination, there may be considerable oedema and severe erythema greater than 10 cm. This is indicative of a viral cellulitis, known as a robust take (RT) and is considered a normal variant rather than an adverse reaction. This must be differentiated from much rarer secondary bacterial cellulitis, which is more common in children and usually occurs within 5 days of vaccination [7]. Smallpox vaccination is successful in producing some immunity in over 95% of patients, but there is wide individual variation and protection is limited to a few years in some vaccinees [4]. Laboratory workers in contact with vaccinia should be revaccinated every 10 years [6,8], but current recommendations for health workers is every 3 years. Information on smallpox vaccination and its complications can be found on the CDC website [7]. Genetically engineered smallpox vaccine, which codes for the immunizing antigen of rabies virus, has been used to control wild fox rabies in Belgium. This attenuated vaccinia vector has limited capacity for replication and is not thought to represent a public health hazard [9]. Other recombinant vaccinia viruses are being studied but none has yet been licensed for use in humans [10]. Protective immune responses to variola and vaccinia. Infection with variola produces various immune responses of both innate and adaptive types in the host [8]. These involve neutrophils, natural killer cells, γ-δ T

cells and cytotoxic T cells (innate), or interferon-γ and neutralizing antibodies (adaptive). Innate responses are important in limiting viral invasion in the early stages of infection. High titres of neutralizing antibodies are found by day 6 of the illness (approximately 18 days after exposure) and persist for years [4,6,11]. Haemagglutinininhibiting (HI) antibodies appear at the same time but gradually decline to low levels by 5 years. Complementfixing (CF) antibodies appear about 8 days after the rash starts but are short-lived and rarely found after 6 months [4,8]. They occur in only half of those vaccinated against smallpox [8]. Animal studies suggest that cell-mediated immunity occurs earlier than antibody production and that virusspecific T cells are detectable in lymphoid tissue 4 days after infection [4,12]. Individuals with defects of immunity of T cells developed rapidly fatal smallpox, suggesting that cell-mediated immunity is of great importance [4,13]. Because many immunological investigative techniques were not available during the era of endemic smallpox, more is known about the immune response to vaccinia than to variola itself. Replication of the vaccinia virus within the lower epidermis appears to be critical for the development of effective immunity [8]. Neutralizing and HI antibodies to vaccinia appear about 10 days after vaccination [4]. Neutralizing antibodies may last for decades and are quickly boosted by revaccination [4,8]. Over 95% of those vaccinated achieve antibody titres of more than 1:10, a level believed to provide sufficient protection. Virus-specific cytotoxic activity appears in peripheral blood mononuclear cells 5 days after vaccination, waning by the 12th day. Memory T cells persist for at least 4 years and possibly for decades [8]. Adverse reactions to vaccinia vaccination. Complications from using live vaccinia virus occur more commonly and are more severe than vaccinations for other diseases which use killed or attenuated viruses (Table 51.3). Data from a 10-state US study found a mortality of 1 per million in primary vaccinees, with a rate of approximately 1.3 serious complications per 100,000 vaccinated [14]. Complications were 10 times more common in primary vaccinees, with the highest mortality in infants under 12 months, who were not vaccinated routinely [7,8,15]. Lane et al. [17] examined all reported deaths from smallpox vaccination in the USA from the years 1959–66 and 1968; there were 68 in total, 24 of which were in infants (only 12% of this age group received primary vaccinations). The three main complications causing fatalities were postvaccinial encephalitis (36 cases), vaccinia necrosum or progressive vaccinia (19 cases) and eczema vaccinatum (12 children, all secondarily acquired).

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Table 51.3 Complications of vaccination with vaccinia Type of complication

Comments

Frequency

Local bacterial infections

Occasionally severe, potential for septicaemia (rare)

Uncommon, distinguish from robust take

Generalized vaccinia [7,8,13–15]

Bloodborne dissemination; usually occurs in the immunosuppressed after primary vaccination Mortality up to 36% [12–14]

Rare, occasionally recurrent

Roseola vaccinatum

First described by Robert Willan in 1808

Transient, not uncommon

Urticaria

Fairly common

Erythema multiforme (EM) minor [14,15]

1–2 weeks after vaccination

Quite common

EM major/Stevens Johnson syndrome (SJS) [14–16]

Potentially lethal

Very rare

Autoinoculation [15,16,19,20]

Local/generalized: particularly face, genitals, ocular

Probably under-reported in the past but common, especially in children Strict attention to vaccination site should reduce risks

Accidental inoculation (contact vaccinia) [15,16,19,20]

Frequently from family members, usually primary vaccinees

2–6 per 100,000 primary vaccinations, especially infants; probably under-reported

Eczema vaccinatum (EV) [7,8,13–16,19,20]

Occurs mainly in children, almost exclusively in atopic individuals, often with no active eczema at time of vaccination Frequently due to accidental inoculation from primary vaccinees

Approximately 123 per million vaccinated [17]. Mortality 1–6%; mostly infants [17,18]. 1–2 cases per 100,000

Progressive vaccinia (PV) [4,7,14,16]

Usually occurs in the immunosuppressed Extension of necrosis to involve deeper local structures with gradual widespread dissemination Includes the terms vaccinia necrosum and vaccinia gangrenosum

Rare; potentially lethal [12–14]

Ophthalmological complications [12,14]

Auto- or accidental inoculation Keratitis causes corneal scarring with potential blindness

Not very common

Postvaccinia encephalitis [6,13,14,16,19]

Idiosyncratic Permanent neurological damage in 25% affected

1 per 300,000 vaccinated Mortality of 15–25%

Other systemic complications [7,14]

Cardiac, rheumatological

Very rare. Pericarditis may be mild and transient but more serious cardiac complications including myopericarditis appears to be increased in older vaccinees

It appears that some strains of vaccinia are more likely than others to cause adverse reactions [4,7,15,16]. This was certainly true in the early days of vaccination [2]. By the 1970s, in non-endemic areas, the risks of vaccination far outweighed those of contracting smallpox and vaccination was discontinued [4–6,8]. After 1980, only those individuals at risk, such as members of the armed forces and smallpox laboratory workers, continued to receive smallpox vaccination. However, recently, pre-event vaccination programmes among healthcare volunteers have

been implemented in the USA and other countries in the light of the possible use of smallpox as a weapon of bioterrorism. Local reactions (see Modern vaccination) are common and should not usually be considered as adverse events. Secondary infection was uncommon in the later US vaccination surveys [14,15]. However, in a recent vaccination programme, Frey et al. [18] found rates of infection to be greater than 30% among vaccinees and the incidence of cellulitis increased from 3.9% in 2001 to 10.2% in 2002

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Fig. 51.8 Autoinoculation of the genital area. Courtesy of Dr Stewart Douglas.

Fig. 51.10 Eczema vaccinatum on the scalp of an infant contracted by close contact with a primary vaccinee. Courtesy of Dr Stewart Douglas.

Fig. 51.9 Accidental vaccinia causing severe blepharoconjunctivitis. Reproduced with permission from CDC, Atlanta, GA, USA.

[18]. It has been suggested that this increase was as the result of alterations in vaccination technique [19]. When vaccination was widespread, autoinoculation was common, particularly to the face, mouth, eyes and genitalia (Fig. 51.8). Accidental transmission or contact vaccinia was probably under-reported and occurred mainly from primary vaccinations at a rate of 2–6 per 100,000 [15,17,20,21]. This usually produces widespread lesions, particularly in young children, and is frequently acquired from family members or playmates. Contact vaccinia (Figs 51.9, 51.10) is an important cause of eczema vaccinatum and progressive vaccinia and is associated with a significant mortality [15,17,18,21]. Although modern infection control techniques should help to reduce contact vaccinia, Sepkowitz [22] has examined past reports of nosocomial spread and concludes that the route of vaccinia transmission is unknown. This has significant implications for vaccination policies in view of the huge numbers of immunocompromised

people within today’s society. Ophthalmological complications from auto- or accidental inoculation include blepharitis (Fig. 51.9), conjunctivitis, keratitis and iritis, which may result in corneal scarring and blindness [7,13,15,23]. During recent vaccination programmes an incidence of ophthalmological complications of 3.6 per 100,000 inoculations was reported (25% contact) and topical trifluridine 1% was most frequently used [23]. To prevent viral shedding and accidental vaccinia, it is important to cover the vaccination site with a dressing such as Mepore® or Tegederm® until the scab has dropped off. Protective gloves should be worn while changing dressings and used dressings should be disposed of as clinical waste. Touching or scratching of the site must be avoided. Care should be taken to protect non-vaccinated persons, especially children, pregnant women, atopic or immunosuppressed individuals and those with extensive burns or erosive skin diseases such as Darier ’s disease, from coming into contact with vaccinees during the early postvaccination period. Such individuals are unsuitable for vaccination unless there is a definite risk of smallpox and cover with VIG may be necessary [7]. Atopic individuals are at particular risk of eczema vaccinatum (EV) (Figs 51.10 and 51.11) and, unless there is a definite risk of smallpox, a history of atopic dermatitis,

Poxviruses

51.13

Fig. 51.11 Severe facial eczema vaccinatum in a young infant. Courtesy of Professor J. Hunter, Department of Dermatology, Edinburgh University.

even if it is no longer present, is a relative contraindication to vaccination. EV causes severe scarring, blindness and occasional death, almost exclusively in young children [7,8,13–17,20]. It was particularly common in patients with contact vaccinia, with a frequency of about 1–2 per 100,000 primary vaccinations and a case fatality rate of 1%, mostly infants [17,20]. A retrospective study by Copeman & Wallace [21] of a 1962 mass vaccination campaign of 3.2 million primary vaccinees in England and Wales found 185 cases of EV, with 11 deaths (6%). Accidental inoculation had occurred in 65% of cases, usually from family members. The majority of deaths occurred in children under 5 years and most (80%) had a history of atopic dermatitis. However, two-thirds had not had active atopic dermatitis for up to 10 years. Generalized vaccinia (GV), with a maculopapular or vesicular rash which may be mistaken for chickenpox or erythema multiforme, occurs rarely, around 6–10 days after vaccination and may be due to haematogenous spread. Immunocompetent patients are not usually ill and the disease is often self-limiting but immunosuppressed patients are at risk of severe disease, with a mortality rate of up to 33% [7,8,13–15]. The term ‘progressive vaccinia’ (PV) is used to describe a rare, severe but painless ulceration/necrosis with minimal inflammation (often referred to as vaccinia necrosum, VN) (Fig. 51.12), usually occurring in immunosuppressed adults [4,7,14,15,17], but several children with VN have also been described [13]. It progresses slowly but inexorably, sometimes involving bone and viscera (vaccinia gangrenosum, VG) and is usually fatal, often responding poorly to VIG [4,7,13–15]. Other cutaneous complications of vaccination include local contact allergic dermatitis to adhesive dressing tape, a transient rash, roseola vaccinatum and other reactive erythemas such as urticaria and erythema multiforme. Lane et al. [15] found 48 cases of

Fig. 51.12 Early progressive vaccinia showing severe localized necrosis at vaccination site with little surrounding inflammation. Courtesy of Dr Stewart Douglas.

erythema multiforme (EM), nine cases of EM major/ Stevens Johnson syndrome and one case of toxic epidermal necrolysis in a child. One infant died from Stevens Johnson syndrome [17]. Non-cutaneous complications include postvaccinial encephalopathy (PVE) and postvaccinial encephalomyelitis (or encephalitis) (PVEM), occurring in 1 per 300,000 vaccinees and particularly in children under 5 years [6,7,14–17]. These are not thought to be due to vaccinia replication. PVE is most common in infants less than 12 months old. Clinical symptoms include headache, fever, vomiting, altered mental status, lethargy, seizures and coma. Permanent neurological damage occurs in 25% of those affected and the mortality may be 15–25%. Two severe adult cases have occurred in the USA vaccination programme between 2002 and 2009 and both responded dramatically to early treatment with IVIG and VIG and corticosteroids [24]. Fetal vaccinia is rare and there are no known diagnostic confirmatory tests. Involvement of the skin and systemic organs frequently results in intrauterine or neonatal fatality [7]. Pericarditis and cardiac problems appeared to be rare in past vaccination programmes, although transient minor complications probably went unrecognized. Lane et al. [15] reported one case of transient pericarditis in a

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child. However, in the current US pre-event vaccination programme, there have been reports of several deaths in middle-aged adults shortly after vaccination due to cardiac complications, especially myopericarditis, mainly in those with associated risk factors [7,25]. Therefore, cardiac disease is now included as a contraindication to vaccination. Other (relative) contraindications include: allergy to vaccinia vaccine or its constituents (including latex allergy), pregnancy and breastfeeding, immunosuppression or the use of immunosuppressive agents including steroid eye-drops, individuals younger than 18 years or over 65 years. In addition, three or more of the following risk factors: hyperlipidaemia, hypertension, smoking, diabetes, first-degree relative with heart disease before age 50 years. Until routine smallpox vaccination ceased in the 1970s, the majority of primary vaccinees were children or young people and this group had the highest rate of adverse events. However, a return to vaccination in this century may result in an increase in adverse events among the older population. More information on vaccinia-related complications is available from the CDC smallpox home page (www.bt.cdc.gov/agent/smallpox/) [7]. Treatment of severe complications of vaccinia vaccination. Handwashing protocols with soap or alcohol rubs help to prevent accidental inoculation. Strict attention to haemodynamic support, hydration and electrolyte balance plus meticulous skin management to avoid sepsis, as in burn patients, is paramount. The development of secondary infection or septicaemia necessitates appropriate antimicrobial therapy. The effectiveness of cidofovir is unknown. It is proposed as a possible therapy in severe cases when VIG is either unavailable or unsuitable [7]. Topical trifluridine and vidarabine, if available, could be tried for severe ophthalmological complications [7]. There is no specific therapy for neurological complications but fits should be controlled with anticonvulsants and supportive therapy and intensive care may be required. Vaccinia immune globulin treatment for complications of smallpox vaccination. Vaccinia immune globulin has been found to be helpful in the treatment of accidental vaccinia, EV, GV, progressive vaccinia and VG [4,6,7,13,15]. It should be reserved for severe cases or those at significant risk. Kempe [13] found that use of VIG in EV reduced mortality from between 30% and 40% to 7%. Vaccinia keratitis is a contraindication to VIG because of potentially increased risk of severe corneal opacities, but VIG can be used in other types of severe eye complications without keratitis. VIG is given intramuscularly in a dose of 0.6 mL/kg bodyweight in divided doses over 24–36 h and repeated if necessary after 2–3 days [6,7,13]. In severe

life-threatening cases, doses of up to 1–10 mL/kg have been used [7]. In cases of vaccination for those with a high risk of severe complications, VIG can be given in a dose of 0.3 mL/kg at the time of vaccination [6]. There is a spectrum of severity of side-effects from VIG, including local pain, tenderness, oedema and erythema persisting for 1–2 h at the injection site [7]. Moderate reactions include nausea and vomiting, back pain and abdominal pain within 10 min of injection and flu-like symptoms lasting several hours. Arthralgia, hyperkinesis, drowsiness, pruritus and erythematous rash, sweating and vasodilation may also occur. Serious side-effects are similar to those seen with any intravenous immune globulin preparation and include hypotension, anaphylaxis and associated reactions, renal dysfunction and aseptic meningitis syndrome (AMS). AMS is associated with high dosage (2 g/kg bodyweight) and occurs from 2 h to 2 days after injection but may remit if VIG is stopped. Investigation into the production and standardization of intravenous VIG is ongoing. The implications of the use of smallpox as a bioterrorist weapon. One of the first documented reports of early biological warfare concerned the gift of smallpox-infected blankets to Amerindians during the mid-1700s wars. This practice caused epidemics with up to 50% mortality [26]. The suggestion that smallpox might again be used for biological warfare has prompted considerable debate concerning the benefits and risks of vaccination [4,6,8,20,27–31]. It is likely that the increased numbers of those with atopic dermatitis and immunosuppression in today’s society might lead to considerably higher vaccination complication rates than occurred in the 1960s and 1970s. It is not known how effective a bioterrorist attack using variola virus would be. Vaccinia and variola viruses do not survive long in aerosol form, although survival is longer in cooler climates with low humidity, on clothes or bedding and in crusts/scabs [32,33,34]. Scabs, however, are not believed to be infectious to humans under normal circumstances of contact because the virus is tightly bound in the protein matrix. Various mathematical models have been used to estimate the possible numbers of cases that could arise from the deliberate release of variola virus [30,31]. At the time of writing, many countries have bought in stocks of smallpox vaccine and VIG as a precaution and each has its own implementation plan for distribution and vaccination. It is unlikely that persons vaccinated before 1970 will maintain enough protection to prevent reinfection, but previous vaccination may well protect against death [4,8]. However, most of the world is no longer immune to smallpox and in the USA alone, there are now at least 119 million unvaccinated people (over 40% of the population) [7,27]. ‘Ring vaccination’ of direct contacts and their

Poxviruses

secondary contacts was successful in the WHO eradication campaign [4] and vaccination within the first 4 days after contact with smallpox can protect against infection or, in those developing smallpox, can significantly reduce mortality [35]. However, it has been suggested that in the event of a widespread bioterrorist attack, it might be difficult to find and vaccinate all contacts within this period. Therefore, voluntary pre-event vaccination of key public health workers has started in the USA and some other countries. References 1 Baxby D. The Jenner bicentenary: the introduction and early distribution of smallpox vaccine. FEMS Immunol Med Microbiol 1996;16:1–10. 2 Baxby D. Jenner ’s Smallpox Vaccine: the Riddle of Vaccinia Virus and its Origin. London: Heinemann Educational Books, 1981. 3 Baxby D. Smallpox vaccination techniques; from knives and forks to needles and pins. Vaccine 2002;20:2140–9. 4 Fenner F, Henderson DA, Arita I et al. Smallpox and its Eradication. Geneva: WHO, 1988. 5 Henderson DA, Moss B. Smallpox and vaccinia. In: Plotkin SA, Orstein WA (eds) Vaccinia, 3rd edn. Philadelphia: W.B. Saunders, 1999. 6 Henderson DA, Inglesby TV, Bartlett JG et al. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999;281:2127–37. 7 Cono J, Casey CG, Bell DM. Smallpox vaccination and side effects. Guidance for clinicians. CDC smallpox home page: www.bt.cdc.gov/ agent/smallpox/index.asp. 8 Engler RMJ, Kenner J, Leung DYM. Smallpox vaccination: risk considerations for patients with atopic dermatitis. J Allergy Clin Immunol 2002;110:357–65. 9 Pastoret P-P, Brochier B. The development and use of a vaccinia– rabies recombinant oral vaccine for the control of wildlife rabies. Epidemiol Infect 1996;116:235–40. 10 Moss B. Genetically engineered poxviruses for recombinant gene expression, vaccination and safety. Proc Natl Acad Sci USA 1996;93:11341–8. 11 Downie AW, Saint Vincent L, Goldstein L et al. Antibody response in non-haemorrhagic smallpox patients. J Hyg (Lond) 1969;67:609–18. 12 Cole G, Blanden RV. Immunology of poxviruses. In: Hamias AJ, O’Reilly RJ (eds) Comprehensive Immunology. New York: Plenum Press, 1982: 1–19. 13 Kempe CH. Studies on smallpox and complications of vaccination. Pediatrics 1960;26:176–89. 14 Lane JM, Ruben FL, Neff JM et al. Complications of smallpox vaccination, 1968. Results of ten statewide surveys. J Infect Dis 1970;122:303–9. 15 Lane JM, Ruben FL, Neff JM et al. Complications of smallpox vaccination, 1968. National surveillance in the United States. N Engl J Med 1969;281:1201–8. 16 Kretzschmar M, Wallinga J, Teunis P et al. Frequency of adverse events after vaccination with different vaccinia strains. PLoS Med 2006;3(8):e272. 17 Lane JM, Ruben FL, Abrutyn E et al. Deaths attributable to smallpox vaccination: 1959–66 and 1968. JAMA 1970;212:441–4. 18 Frey SE, Couch RB, Tacket CO et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002;346: 1265–74. 19 Sauri M. Responses to smallpox vaccine [letter]. N Engl J Med 2002;347:689.

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20 Neff JM, Lane JM, Fulginiti VA et al. Contact vaccinia – transmission of vaccinia from smallpox vaccination. JAMA 2002;288:1901–5. 21 Copeman PMW, Wallace HJ. Eczema vaccinatum BMJ 1964;2: 906–8. 22 Sepkowitz KA. How contagious is vaccinia? N Engl J Med 2003;348:439–46. 23 Fillmore GL, Ward TP, Bower KS. Ocular complications in the Department of Defense Smallpox Vaccination Program. Ophthalmology 2004;111(11):2086–93. 24 Van Dam CN, Syed S, Eron JJ et al. Severe postvaccinia encephalitis with acute disseminated encephalomyelitis: recovery with early intravenous immunoglobulin, high-dose steroids and vaccinia immunoglobulin. Clin Infect Dis 2009;48(4):e47–9. 25 Eckart RE, Love SS, Atwood JE et al. Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination. J Am Coll Cardiol 2004;44(1):201–5. 26 Stearn EW, Stearn AE. The Effect of Smallpox on the Destiny of the Amerindian. Boston: Humphries, 1945. 27 Bicknell WJ. The case for voluntary smallpox vaccination. N Engl J Med 2002;346:1323–5. 28 Lane JM. Smallpox and smallpox vaccination [letter]. N Engl J Med 2002;347:691. 29 Mack T. A different view of smallpox and vaccination. N Engl J Med 2003;348:460–3. 30 Meltzer MI, Damon I, LeDue JW et al. Modelling potential responses to smallpox as a bioterrorist weapon. Emerg Infect Dis 2001;7:959–69. 31 Bozzette SA, Boer R, Bhatnagar V et al. A model for a smallpox vaccination policy. N Engl J Med 2003;384:416–25. 32 Harper GJ. Airborne micro-organisms: survival test with four viruses. J Hyg 1961;59:479–86. 33 Huq F. Effect of temperature and relative humidity on variola virus in crusts. Bull WHO 1976;54:710–12. 34 Dixon CW. Smallpox. London: Churchill, 1962. www.nlm.nih.gov/ nichsr/esmallpox/esmallpox.html. 35 World Health Organization. World Health Organization announces updated guidance on smallpox vaccination. www.who.int/inf-pr2001/en/state2001-16html.

Cowpox Aetiology. Human cowpox is an uncommon zoonosis occurring sporadically in the UK, across Europe and in adjacent areas of the former USSR. The causative agent, an orthopoxvirus (see Table 51.1), has not been found elsewhere. Although the first strains were isolated from cattle and farm workers, it is most frequently reported after contact with cats [1]. However, cases of bovine and feline cowpox are not sufficiently common for the virus to be maintained in those species and it is therefore likely that the reservoir host is a small wild mammal. This is supported by reports of cowpox in wild rodents in the Russian subcontinent [2] and detection of antibody in British woodmice and bankvoles [3,4]. There are three reports of children developing cowpox following contact with rodents: an 11-year-old boy bitten by a small animal while swimming in a canal [5], a 15-year-old girl (Fig. 51.13) who handled a sick wild mouse [6] and a 14-yearold girl who cared for a sick wild rat with proven cowpox [7]. Cases of cowpox occurring in zoo animals such as

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Chapter 51

elephants, okapis and rhinoceros have sometimes resulted in transmission to humans [8]. The common vector is considered to be a rodent and fatal infections in cheetahs in an English zoo were attributed to contact with wild rodents [9]. Of 54 cases of cowpox reported from 1969 to 1993, 23 occurred in children less than 16 years old and another five in older teenagers [1]. The hands and face are the commonly affected sites, although four children had ocular infections, two with severe conjunctivitis. In approximately half of the cases, the source of contact was unknown; cats were implicated in 18 cases, four cases occurred in veterinary workers and a bovine contact was reported in only three cases. Among children, it was twice as common in girls. Eight cases in children were due to contact with cats and in two rodents were implicated; in the remainder the source was unknown. Infection probably occurs through small abrasions in the skin when handling infected animals. However, there is a report of cowpox infection in a 12-year-old boy whose apparently healthy cat carried serological evidence of infection [10]. This might explain the high percentage of infections with no obvious animal vector.

(a)

(b) Fig. 51.13 Cowpox in a 15-year-old girl at the early eschar stage. (a) Co-primary lesions with left-sided swelling and periorbital oedema but relatively little obvious inflammation. (b) Enlarged view of the chin lesion; compare with Fig. 51.20. Reproduced from Lewis-Jones et al. 1993 [6] with permission from John Wiley & Sons.

Pathology. Most pathological data pertain to feline infection [9]. The light microscopic appearances are characterized by hypertrophy and proliferation of the basal keratinocytes [11]. Large, eosinophilic, cytoplasmic inclusion bodies resembling the smaller Guarnieri’s bodies seen in variola and vaccinia are found in many keratinocytes. In the dermis, there is a mixed inflammatory cell infiltrate with marked extravasation of red cells. Clinical features. The incubation period of cowpox is about 7 days, after which an erythematous papule develops, most commonly on the hands or face. Multiple lesions due to self-inoculation occur in about a quarter of cases [1]. The lesions quickly progress to the vesicular and pustular stage, often with central umbilication and a surrounding zone of erythema and oedema (Fig. 51.14). The latter may be marked and persist for 1–2 weeks, particularly on the face and periorbital regions [6] (see Fig. 51.13a). There is considerable local pain and the surrounding tissues are indurated with a woody-hard feel to them. In the first week, constitutional symptoms are often severe and there is usually pyrexia, general malaise and often myalgia and vomiting. Regional lymphangitis is marked and can persist for some weeks. After the pustular stage, lesions develop a firmly adherent crusted eschar (Figs 51.13b, 51.15) which may be quite deep. Healing takes place slowly over 1–2 months, leaving a depressed pock-like scar. Complications include secondary bacterial infections and cellulitis.

Poxviruses

Fig. 51.14 Cowpox in a 9-year-old girl about 11 days after infection showing haemorrhagic vesicular lesion with marked inflammation and oedema. Reproduced with permission from Baxby 1982 [17].

Fig. 51.15 Cowpox lesion in a 17-year-old male at the late eschar stage showing the hard black eschar and conspicuous inflammation. Reproduced from Baxby et al. 1994 [1] with permission from Wiley-Blackwell.

Ocular cowpox usually results from autoinoculation and can be serious with severe ulcerative conjunctivitis [1]. An unusual case of nasal inoculation causing severe facial cellulitis resulted in several areas of subcutaneous, necrotizing lymphadenitis and abscess formation with prolonged adenopathy. [12] Widespread lesions mimicking eczema herpeticum have been reported in an adult

51.17

with atopic dermatitis [13]. Generalized cowpox was reported in a 17-year-old male with chronic use of recreational drugs and alcohol excess [14]. He recovered but without proper seroconversion, which was attributed to drug-induced immunosuppression. This has implications for all immunosuppressed individuals. There have been occasional fatalities from generalized cowpox and one case of fatal encephalitis [1]. An 18-yearold youth, immunosuppressed by virtue of his medication for severe eczema and asthma, contracted cowpox from a cat and died after developing disseminated confluent poxvirus lesions similar to haemorrhagic smallpox [15]. However, the direct cause of death was thought to be heart failure. He had never been vaccinated against smallpox, which would have provided some protection against cowpox. Similarly, individuals who have had cowpox have good immunity against smallpox infection, although this wanes with time. Diagnosis. In most cases, the lesions have the typical appearance described above and diagnosis relies on clinical suspicion, a history of contact with cats, cattle or rodents and laboratory confirmation. In areas of the world where cowpox is not found, anthrax is the most likely diagnosis. The differential diagnosis also includes orf or milker ’s nodules and herpesvirus infections [6]. Widespread lesions may be mistaken for eczema herpeticum but the lesions are somewhat larger. Tissue swabs in viral culture medium or preferably scrapes from the eschar should be taken for culture and electron microscopy (see Fig. 51.1). Rapid analysis using PCR is now being utilized [10]. Treatment. Treatment usually consists of supportive measures with antipyretics and analgesia in the initial stages. Antibiotics may be necessary for secondary infection. Specific treatment with systemic cidofovir in the early stages is a possible treatment of choice in immunosuppressed patients but there is risk of renal toxicity and cowpox fatalities are very rare, the majority of lesions resolving without significant morbidity [16]. Cowpox should respond to treatment with VIG if available and this could also be considered in severe cases.

References 1 Baxby D, Bennet M, Getty B. Human cowpox 1969–93: a review based on 54 cases. Br J Dermatol 1994;131:598–607. 2 Marrenikova S, Ladnyi I, Ogorodnikova Z et al. Identification and study of a poxvirus isolated from wild rodents in Turkmenia. Arch Virol 1978;56:7–14. 3 Crouch AC, Baxby D, McCracken CM et al. Serological evidence for the reservoir hosts of cowpox virus in British wildlife. Epidemiol Infect 1995;115:185–91. 4 Baxby D, Bennett M. Cowpox: a re-evaluation of the risks of human cowpox based on new epidemiological information. In: Kaaden OP,

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Czerny CP, Eichhorn W (eds) Viral Zoonoses and Food of Animal Origin. Vienna: Springer, 1997: 1–12. Postma BH, Diepersloot RJA, Niessen GJCM et al. Cowpox-virus-like infection associated with a rat bite. Lancet 1991;337:733–4. Lewis-Jones MS, Baxby D, Cefai C et al. Cowpox can mimic anthrax. Br J Dermatol 1993;129:625–7. Wolfs TF, Wagenaar JA, Niesters HG et al. Rat-to-human transmission of cowpox infection. Emerg Infect Dis 2002;8: 1495–6. Pilaski J, Rosen-Wolff A. Poxvirus infection in zoo-kept mammals. In: Darai G (ed) Virus Diseases in Laboratory and Captive Animals. Boston: Martin Nijhoff, 1988: 83–100. Baxby D, Ashton DG, Jones DM et al. An outbreak of cowpox in captive cheetahs: virological and epidemiological studies. J Hyg 1982;89:365. Schupp P, Pfeffer M, Meher H et al. Cowpox virus in a 12-year-old boy: rapid identification by an orthopoxvirus-specific polymerase chain reaction. Br J Dermatol 2001;145:146–50. Baxby D. Poxviruses. In: Zuckerman AJ, Banatvala JE, Pattison JR (eds) Principles and Practice of Clinical Virology. Chichester: John Wiley, 1995: 441–66. Pahlitzsch R, Hammarin AL, Widell A. A case of facial cellulitis and necrotizing lymphadenitis due to cowpox virus infection. Clin Infect Dis 2006;43(6):737–42. Blackford S, Roberts DL, Thomas PD. Cowpox infection causing a generalized eruption in a patient with atopic dermatitis. Br J Dermatol 1993;129:628–9. Huemer HP, Himmelreich A, Hönlinger B et al. “Recreational” drug abuse associated with failure to mount a proper antibody response after a generalized orthopoxvirus infection. Infection 2007;35(6) :469–73. Czerny CP, Eis-Hubinger AM, Mayr A et al. Animal poxviruses transmitted from cat to man: current event with lethal end. Zentralbl Veterinarmed [B] 1991;38:421–31. De Clercq E. Cidovir in the therapy and short-term prophylaxis of the poxvirus infections. Trends Pharmacol Sci 2002;23:456–8. Baxby D. The natural history of cowpox. Brist Med Chirurg J 1982;97:12–16.

Monkeypox Aetiology. Monkeypox virus (see Table 51.1) was so named because it was first isolated from captive Asiatic monkeys in 1958 [1], but there is no evidence that monkeys form the reservoir in the endemic areas of Africa. Serological surveys found specific antibodies to monkeypox virus in 25% of two species of African squirrels but not in other rodents [2,3]. Children are probably infected by playing with the carcasses used for food and public education is important in disease control. The disease was of little interest until 1970, when human monkeypox, clinically indistinguishable from smallpox, was first described in Africa, where it appears to be confined to the tropical rainforests, mainly in Zaire. Most cases occurred in children not vaccinated against smallpox. Of 338 cases occurring in Zaire between 1981 and 1986, 291 (86%) were in children under the age of 10 years, only 4% of whom had vaccination scars [1]. Threequarters of patients had over 100 lesions and were totally incapacitated, requiring intensive nursing. A total of 33

Fig. 51.16 (a) Lesions of monkeypox on the hand of a 3-year-old girl arising at the site of a prairie dog bite. (b) Similar lesions on her mother’s hand, also from a prairie dog bite. Reproduced with permission from Fenner et al. 1988 [10].

children (11%) died; the mortality in unvaccinated children was 15%. This high mortality rate was probably due in part to malnutrition and lack of suitable medical care. Sporadic outbreaks continue to occur [3], particularly in areas where there is civil unrest [4]. Human-to-human transmission was reported to be uncommon in the 1980s outbreaks but during an outbreak in Zaire in 1996, most cases resulted from direct contact with infected people [3]. An increase in holiday travel to Africa may result in unrecognized cases [5]. Several outbreaks have occurred at the same time as outbreaks of varicella, which can lead to difficulties in differential diagnosis in the early stages, but in chickenpox the rash is centripetal and lesions occur in crops at different stages of evolution [6]. An outbreak of monkeypox in the US mid-west in 2003, with 35 confirmed cases, was traced to pet prairie dogs, which contracted the infection from an imported Gambian giant rat housed adjacently in the pet shop [7]. The index case was a 3-year-old girl from Wisconsin who was bitten by her pet (Fig. 51.16a), which later died. The girl’s mother (Fig. 51.16b) was also bitten and electron microscopy of a skin biopsy confirmed an orthopox virus. Monkeypox was isolated from the dead animal and confirmed by

Poxviruses

culture and PCR. Both patients survived. They had severe flu-like symptoms, lasting several days, associated with adenopathy and acral pustular lesions resembling smallpox. These cases were linked to similar cases in adjacent states all traced back to the same pet shop. Five cases (15%), incuding two children, were severely ill and nine hospitalized (26%) but no deaths and no definite person-to-person transfer occurred. Previous smallpox vaccination did not correlate with disease severity or hospitalization [8]. Concerns were raised that if the virus should become established among indigenous US rodents, they could act as a reservoir for the disease within the USA. This would be dependent upon the virus finding a suitable host for which it is non-lethal and then surviving transfer among animals without eventually dying out. The possible use of smallpox as an agent for biological warfare and the apparent change to human-to-human transmission of monkeypox continues to make it essential that suspected cases are confirmed by laboratory testing such as virus isolation, PCR techniques and serology. Further information can be obtained from the monkeypox web page on the CDC website [7]. Clinical features. The incubation period is about 12 days [1,4,10]. A prodromal fever heralds the appearance of multiple monomorphic blisters/pustules distributed centrifugally on the face, hands and feet. There is more marked adenopathy than is seen in smallpox, particularly of the submandibular, cervical and sublingual regions (Fig. 51.17). Systemic malaise and total prostration have occurred in the majority of childhood cases reported from Africa and complications include secondary bacterial infection, respiratory and gastrointestinal problems and death. The disease appears to have been less severe in the recent US outbreak, probably because of improvements in healthcare and nutrition. Prior smallpox vaccination with vaccinia virus protects against or modifies the severity of the disease to some extent but is not recommended for routine use. Treatment. The same protective precautions should be used as in cases of smallpox. Intensive supportive therapy is essential in severe cases and will depend on the individual complications. Parenteral fluids and antibiotic therapy for secondary infection may be necessary. VIG, if available, could be given in severe cases. During epidemics, protection with smallpox vaccination should be used and can also be given within 4 days of contact with infected animals or humans. Intravenous cidofovir [11] could be used to attempt to prevent infection in contacts at significant risk. However, this medication has the disadvantage of causing renal toxicity and is not currently recommended.

51.19

(a)

(b) Fig. 51.17 Monkeypox in a 7-year-old girl on the eighth day of the rash; note the submaxillary and inguinal lymphadenopathy. Courtesy of Dr Erik Stratman.

References 1 Jezek Z, Fenner F. Human monkeypox. In: Monographs in Virology, vol. 17. Basle: Karger, 1988. 2 Khodakevich L, Szceniowski M, Manbu-ma-Disu et al. The role of squirrels in sustaining monkeypox virus transmission. Trop Geogr Med 1987;39:115–27. 3 Hutin YJ, Williams RJ, Malfait P et al. Outbreak of human monkeypox, Democratic Republic of Congo, 1996–97. Emerg Infect Dis 2001;7:434–8. 4 Heymann DL, Szcezeniowsky M, Esteves K. Reemergence of monkey pox in Africa: a review of the past 6 years. Br Med Bull 1998;54:693–702. 5 Weber DJ, Rutala WA. Risks and prevention of nosocomial transmission of rare zoonotic diseases. Clin Infect Dis 2001;32: 446–56. 6 Meyer H, Perrichot M, Stemmler M et al. Outbreaks of disease suspected of being due to human monkeypox virus infection in the Democratic Republic of Congo in 2001. J Clin Microbiol 2002;40:2919–21. 7 Centers for Disease Control website: www.cdc.gov/ncidod/ monkeypox/. 8 Huhn GD, Bauer AM, Yorita K et al. Clinical characteristics of human monkeypox and risk factors for severe disease. Clin Infect Dis 2005;41(12):1742–51.

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9 Jezek Z, Szczeniowski M, Paluka KM et al. Human monkeypox: clinical features of 282 patients. J Infect Dis 1987;156:293–8. 10 Fenner F. Henderson DA, Arita A et al. Smallpox and its Eradication. Geneva: WHO, 1988. 11 De Clercq E. Cidovir in the therapy and short-term prophylaxis of the poxvirus infections. Trends Pharmacol Sci 2002;23:456–8.

Buffalopox Aetiology. When smallpox vaccination was common, vaccinia virus was occasionally transmitted from recently vaccinated individuals to domestic species such as cows, buffaloes and pigs and then back to humans. However, there was no evidence that vaccinia became established in such animal species. In India, the position was complicated by the existence of an orthopoxvirus, also pathogenic for buffaloes and humans, referred to as buffalopox virus [1] (see Table 51.1). This virus is very closely related to vaccinia virus and is now regarded as a subspecies of it [2].

Clinical features. Buffalopox virus causes localized vesicular skin lesions, usually on the hands and arms of those in contact with infected animals with lesions on the teats and udders [3–5]. The painful lesions are not as haemorrhagic as those of cowpox but may be accompanied by pyrexia and other systemic reactions [3,4]. However, a report of outbreaks in Maharashtra state during 1992–6 suggests that subclinical infection may be common [5]. Young people with no contact with infected buffalo and not previously vaccinated against smallpox showed serological evidence of neutralizing antibodies to buffalopox virus. There were also a few children with disseminated buffalopox lesions on the face, arm and buttocks, similar to contact vaccinia, who had not had contact with infected animals, suggesting a possible human-tohuman transmission via infected family members. Further careful epidemiological studies are necessary. Lesions are usually self-limiting and do not require specific treatment although secondary infection may require antibiotic therapy. References 1 Baxby D, Hill BJ. Characteristics of a new poxvirus isolated from Indian buffaloes. Arch Ges Virusforch 1971;35:70–9. 2 Dumbell KR, Richardson M. Virological investigations of specimens from buffaloes affected by buffalopox in Maharashtra State, India between 1985 and 1987. Arch Virol 1993;128:257–67. 3 Lal SM, Singh IP. Buffalopox – a review. Trop Anim Hlth Prod 1977;9:107–12. 4 Sehgal CL, Ray SN, Ghosh TK et al. An investigation of an outbreak of buffalopox in animals and humans in Dhulia district, Maharashtra. J Commun Dis 1977;9:49–58. 5 Kolhapure RM, Deolanker RP, Tupe CD et al. Investigation of buffalopox outbreaks in Maharashtra State during 1992–6. Ind J Med Res 1997;106:441–6.

Human cattle pox in Brazil Newly described Cantagalo [1] and Araçatuba viruses [2] causing cowpox-like infections in cattle and cattle workers in Brazil share 99% homology with vaccinia virus genes. They almost certainly became established within herds from contact with vaccinated cattle workers at the time of the World Health Organization smallpox vaccination programme in the 1960s and 1970s. References 1 Damaso CRA, Esposito JJ, Condit RC et al. An emergent pox-virus from humans and cattle in Rio de Janeiro state: Cantagalo virus may derive from Brazilian smallpox vaccine. Virology 2000;277:439–49. 2 Trindade GdS, da Fonseca FG, Marques JT et al. Araçatuba virus: a vaccinia- like virus associated with infection in humans and cattle. Emerg Inf Dis 2003;9:155–60.

Human parapox infections Orf Aetiology. Orf (synonyms: ecthyma contagiosum, contagious pustular dermatitis) is endemic worldwide and human infection is a relatively common occupational hazard in the sheep industry in Europe and Australasia but less so in the USA [1]. It is caused by a parapoxvirus (see Table 51.1), clinically and morphologically identical to the virus causing milker ’s nodules (see Fig. 51.1). The two can, however, be differentiated by subtle differences in tissue culture [2]. The word ‘orf ’ may come from the old Nordic word Hrufa meaning a scab or boil [3], but it is also an Anglo-Saxon word for cattle [4]. The infection occurs through small cutaneous abrasions from contact with young sheep or goats with ‘scabby mouth’ and is particularly common in shepherds, farm workers, veterinary personnel and abattoir workers. It is uncommon in children, who accounted for only 6% of all reported cases in the UK between 1975 and 1981 [5]. They may contract it by bottlefeeding lambs with infected sores on their mouths, often on school educational visits. The virus is relatively stable under normal environmental conditions and can survive for long periods on pastures, wool, fences, barbed wire, etc., which can act as the source of infection [3]. There is an early report of a child falling in a contaminated pasture and developing orf on one knee [6]. The first detailed report of orf in humans was in 1934 [7] and experimental infection of volunteers later confirmed the cause [8]. In the past, one infection was thought to confer lifelong immunity, but in a large series of 231 cases from New Zealand there were 18 cases of reinfection [3]. This has been confirmed by other workers; Yirrell & Vestey [9] have reviewed the literature on orf. Most reported cases of orf are in adults and in a large series of 119 cases, only two patients were children [10].

Poxviruses

51.21

Pathology. Identical histopathological features are found in both orf and milker ’s nodules [2]. Low-power examination of the epidermis shows endophytic strand-like proliferations with distension of the dermal papillae by oedema. Epidermal viral cytopathic changes with inclusion bodies are seen under high-power examination, together with clumping of keratohyalin and cytoplasmic vacuolation with a distinctive spongiform appearance within follicular structures. Leavell et al. [4] have correlated the histopathological features with the various clinical stages. Clinical features. The incubation period for orf is approximately 3–7 days. Thereafter, an erythematous macule develops, often with intense local itching. This is the first of six well-recognized stages [4] (Table 51.4). The second stage is papular and at about 1–2 weeks the target stage develops, with a central erythema surrounded by a white ring and a red halo (Fig. 51.18). There then follows a weeping stage, often with central umbilication and vesiculation at 2–3 weeks (Fig. 51.19). The lesions then become nodular at 3–4 weeks and, finally, granulomatous or papillomatous (Fig. 51.20) before regressing spontaneously after 5 weeks. Occasionally, lesions become ulcerative and secondary bacterial infections can be a problem. Healing usually takes place by 6 weeks but can take as long as 24 weeks [1]. The illness is usually mild without systemic symptoms, although a minority of patients may have a transient low-grade fever and general malaise with local pain and itching and regional adenopathy are features in up to one-third of cases [10]. Erythema multiforme has been reported in 25% [10], but because most cases of orf go unreported [11], this may be a falsely high figure. However, it is probably the most common cause of referral to the dermatologist. Stevens Johnson syndrome (SJS) develops very rarely; an unreported case of SJS progressing to severe toxic epidermal necrolysis (TEN) occurred in a farmer ’s wife who had developed orf from suckling lambs (S. Mendelsohn and

Fig. 51.18 Parapoxvirus infection at the ‘target’ stage. Reproduced with permission from Baxby 1982 [21].

Fig. 51.19 Parapoxvirus infection at the ‘weeping’ stage contracted after bottlefeeding a sick lamb with sores around the mouth.

Table 51.4 Clinical stages of orf lesions Incubation period Type of lesions

3–7 days

Macular Papular Target-like Nodular Granulomatous/papillomatous Ulcerative (occasionally) Spontaneous healing

1–3 3–7 1–2 2–3 3–4 4–6 1–6

days days weeks weeks weeks weeks months

Fig. 51.20 Parapoxvirus infection showing a granulomatous lesion at the crusting stage; compare with Fig. 51.13b. Reproduced from Baxby et al. 1994 [22] with permission from Wiley-Blackwell.

51.22

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M.S. Lewis-Jones, personal communication, 1987). She eventually survived after supportive therapy in intensive care. Giant orf occasionally occurs and has been reported in a 12-year-old boy following a rope burn to the neck [12] (Fig. 51.21). Amputation of a finger with a giant orf lesion mistaken for malignancy has occurred [10]. A widespread papulovesicular rash with systemic symptoms occurred in a mother and daughter but no immune defect was found [13]. The hand is the most common site of lesions: 95% in one study [3]. They are usually solitary but can be multiple and the face is the second most common site. A 16-month-old girl with severe generalized atopic dermatitis is reported to have developed a large granulomatous lesion of orf on the chin with multiple smaller lesions at the periphery and on the face, wrists and dorsal hands [14]. There is a report of two cases of perianal orf in children [15] (Fig. 51.22). Blindness due to ocular orf in an adult has occurred [16]. Case-to-case transmission of orf has occasionally been reported [9,10] and the author has seen vulval orf in a farmer ’s wife, transmitted from a lesion of orf on her husband’s finger. Diagnosis. Diagnosis is made from the clinical features and history of exposure to sheep or goats. It is usually recognized by susceptible workers and family practitioners in rural areas [11]. Problems arise when it occurs in suburban areas. A 7-year-old girl underwent unnecessary surgical drainage of a finger because of suspected abscess despite a clear-cut history of sheep bite [17]. Electron microscopy of material taken from crusts is the best method of detecting the virus as culture techniques are

Fig. 51.21 Giant orf in a 12-year-old boy showing the very large granulomatous lesion approximately 3 weeks after the lesion first appeared. Reproduced from Pether et al. 1986 [12] with permission from Wiley-Blackwell.

slow and unreliable and there are no serological tests available. Orf can be identified by PCR techniques, but these are not yet routinely available. In children, the most important differential diagnosis is pyogenic granuloma. Other diagnoses have included herpetic whitlow or giant molluscum contagiosum, but large granulomatous lesions can be mistaken for tumours, particularly keratoacanthoma (Fig. 51.23). Anthrax and cowpox are usually asso-

Fig. 51.22 Parapoxvirus infection showing multiple perianal lesions at various stages which could be mistaken for eczema herpeticum. Reproduced from Kennedy & Lyell 1984 [15] with permission from Elsevier.

Fig. 51.23 Parapoxvirus infection in an adult showing a severe ulcerated granulomatous lesion which could be mistakenly diagnosed as a keratoacanthoma.

Poxviruses

ciated with more severe systemic symptoms. More generalized lesions of orf might be mistaken for eczema herpeticum. Treatment. Supportive therapy in symptomatic cases is usually all that is necessary, but secondary infection may require antibiotics. Cases with severe SJS/TEN might benefit from intravenous γ-globulin. Topical idoxuridine in dimethylsulphoxide has been used to treat a local recurrence after surgery in an immunosuppressed patient [18]. Although surgery has been advocated by some authors, the effects are variable and it is not always appropriate for children [10]. However, shave biopsy or curettage and cautery can leave good results with much more rapid healing than natural resolution (Fig. 51.24). A 2-year-old boy responded well to shave excision [19], whereas giant orf on the nose in a 9-year-old child took 3 months to heal spontaneously [20]. References 1 Gill JM, Arlette J, Buchan KA et al. Human orf. Arch Dermatol 1990;126:356–8. 2 Groves RW, Wilson-Jones E, MacDonald DM. Human orf and milkers’ nodule: a clinicopathologic study. J Am Acad Dermatol 1991;25:706–11. 3 Robinson AJ, Petersen GV. Orf virus infection of workers in the meat industry. NZ Med J 1983;96:81–5. 4 Leavell UW, McNamara MJ, Muelling R et al. Orf – report of 19 human cases with clinical and pathological observations. JAMA 1968;204:657–64. 5 PHLS, Communicable Disease Surveillance Centre, Communicable Disease (Scotland) Unit. Orf paravaccinia infections, British Isles: 1975–81. BMJ 1982;284:1958.

Fig. 51.24 Orf on a young boy’s face before and after surgery. Courtesy of Dr Colin Clark.

(a)

51.23

6 Ward CW. Four cases of orf. Med Wld Lond 1956;84:25–8. 7 Newsom IE, Cross F. Sore mouth in sheep transmissible to man. J Am Vet Med Assoc 1934;84:799–802. 8 Pask VM, Mackerras IM, Sutherland AK et al. Transmission of contagious ecthyma from sheep to man. Med J Aust 1951;2:628–32. 9 Yirrell DL, Vestey JP. Human orf infections. J Eur Acad Dermatol Venereol 1994;3:451–9. 10 Johannessen JV, Krogh HK, Solberg I et al. Human orf. J Cutan Pathol 1975;2:265–83. 11 Baxby D, Bennett M. Poxvirus zoonoses. J Med Microbiol 1997;46:17–20. 12 Pether JVS, Guerrier CJW, Jones SM et al. Giant orf in a normal individual. Br J Dermatol 1986;115:497–9. 13 Wilkinson JD. Orf: a family with unusual complications. Br J Dermatol 1977;97:447–50. 14 Dupre A, Christol B, Bonafe JL et al. Orf and atopic dermatitis. Br J Dermatol 1981;105:103–4. 15 Kennedy CTC, Lyell A. Perianal orf. J Am Acad Dermatol 1984;11:72–4. 16 Royer J, Joubert L, Prave M. Grave ocular damage in man due to ovine contagious pustular dermatitis. Bull Soc Sci Vet Med Comp Lyon 1970;72:93–104. 17 Waldran MA. A 7-year-old girl with orf of the hand. J Hand Surg 1986;11B:467–8. 18 Hunskaar S. Giant orf in a patient with chronic lymphocytic leukaemia. Br J Dermatol 1986;114:631–4. 19 Rogers M, Bale P, de Silva LM et al. Giant parapox infection in a twoyear-old child. Australas J Dermatol 1989;30(2):87–91. 20 Gurel MS, Ozardali I, Bitiren M et al. Giant orf on the nose. Eur J Dermatol 2002;12:183–5. 21 Baxby D. The natural history of cowpox. Brist Med Chirurg J 1982;97:12–16. 22 Baxby D, Bennett M, Getty B. Human cowpox 1969–93: a review based on 54 cases. Br J Dermatol 1994;131:598–607.

(b)

51.24

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Milker’s nodules Aetiology. Milker ’s nodules (synonym: pseudocowpox, paravaccinia) (see Table 51.1), as the name suggests, occur usually on the hands of humans in contact with the teats or occasionally other parts of cows infected with parapoxvirus [1]. The clinicopathological features are identical to those seen in orf [2] and the viruses are very closely related [3]. As with orf, laboratory diagnosis is made by electron microscopy but most cases probably go unreported [4]. The condition has been described in children only rarely and usually after milking cows. In a report of 10 cases, three were children, aged 10, 14 and 16 years, with no systemic symptoms; lesions healed within 1 month to leave a small scar [5]. Three of 15 Danish patients with milker ’s nodules developed erythema multiforme [6]. References 1 Leavell UW, Phillips IA. Milker ’s nodules. Arch Dermatol 1975;111:1307–11. 2 Groves RW, Wilson-Jones E, MacDonald DM. Human orf and milker ’s nodule: a clinicopathologic study. J Am Acad Dermatol 1991;25:706–11. 3 Mercer A, Fleming S, Robinson A et al. Molecular genetic analysis of parapoxviruses pathogenic for humans. In: Kaaden OP, Czerny CP, Eichhorn W (eds) Viral Zoonoses and Food of Animal Origin. Vienna: Springer, 1997: 25–34. 4 Baxby D, Bennett M. Poxvirus zoonoses. J Med Microbiol 1997;46:17–20. 5 Nomland R, McKee AP. Milker ’s nodules. Arch Dermatol Syph 1952;65:663–74. 6 Hansen SK, Mertz H, Krogdahl AS et al. Milker ’s nodules. Ugeskr Laeger 1997;159:436–7.

Other parapox infections Parapox infections have been reported to occur in other mammals [1] such as red deer, seals [2], camels, reindeer [3] and musk ox, and occasional human infection has occurred, usually in adults. Sealpox has previously been reported in human seal workers but could not be differentiated from orf. However, a recent case of sealpox in an adult marine worker bitten by an infected seal has been confirmed by PCR [2]. There is a report of case-to-case transmission in a 2-year-old child who developed a crusted lesion below her lip associated with fever, nausea and cervical adenopathy, caused by a parapox infection which her father had contracted from reindeer [3]. References 1 Yirrell DL, Vestey JP. Human orf infections. J Eur Acad Dermatol Venereol 1994;3:451–9. 2 Clark C, McIntyre PG, Evans AT, McInnes CJ, Lewis-Jones MS. Human sealpox resulting from a seal bite: confirmation that sealpox virus is zoonotic. Br J Dermatol 2005;152:791–3. 3 Falk ES. Parapox infections of reindeer and musk ox associated with unusual human infections. Br J Dermatol 1978;99:647–54.

Fig. 51.25 Tanapox in a 4-year-old girl showing ulcerated lesions and marked oedema approximately 20 days after onset. Reproduced from Jezek et al. 1985 [2] with permission from WHO.

Tanapox Aetiology. Tanapoxvirus (see Table 51.1), serologically unrelated to orthopoxvirus or parapoxvirus, was first isolated in Kenyans living on the flood plains of the River Tana in 1962 during an epidemic [1]. It produces a mild, non-fatal, febrile illness associated with one or two skin lesions superficially similar to smallpox and monkeypox (Fig. 51.25). Serological studies in human and monkey populations suggest that it is endemic in several countries in equatorial Africa [2,3]. Among 264 patients with laboratory-confirmed disease in Zaire between 1979 and 1983, 76 (29%) were less than 15 years of age [2]. It was most common from November to March and there was clustering of cases geographically but no evidence of person-to-person transmission. Although animal handlers may acquire the infection through cuts caused by monkeys, the majority of patients have no contact with monkeys and the vector is suspected but not proven to be a biting insect, particularly as lesions occur in exposed sites. There has been a report of tanapox infection in a European traveller, identified using PCR [4]. Clinical features. The majority (60%) start with preeruptive symptoms, such as fever, for 2–4 days, and systemic malaise, severe headache, backache and prostration can occur. Skin lesions appear a few days later and are solitary in 80% of cases. They usually occur on the legs and lower trunk, rarely on the face or covered sites [2]. However, in a recent outbreak in Moshi, Tanzania, the majority of lesions were on the fingers or face (B. Leppard, personal communication). They start as itchy areas,

Poxviruses

developing raised circles, which quickly become dark and papular with marked central necrosis, umbilication, frequent crusting and surrounding oedema (Figs 51.25, 51.26). There is local lymphangitis and regional lymphadenitis, often with secondary infection. Involution of nodules usually starts after 2 weeks but larger nodules, on the legs particularly, break down to form itchy, painful ulcers up to 2 cm in diameter. Gradual healing occurs over 2 months to leave circular cicatrized scars. Differential diagnosis includes insect bites in the early stages, monkeypox, in which the evolution of large numbers of lesions is usually rapid, and tropical ulcers which are usually larger with foul, green slough and are slow to heal. Early tanapox and smallpox could be confused so it is important to make the correct diagnosis. Crusted lesions could be mistaken for anthrax but the evolution in tanapox is much slower.

51.25

(a)

Treatment. Little is necessary except analgesia and antibacterial measures where secondary infection is a problem. References 1 Downie AW, Taylor-Robinson C, Caunt AE. Tanapox: a new disease caused by a pox virus. BMJ 1971;1:363–8. 2 Jezek Z, Arita I, Szczeniowski M et al. Human tanapox in Zaire: clinical and epidemiological observations on cases confirmed by laboratory studies. Bull WHO 1985;63:1027–35. 3 Fenner F, Henderson DA, Arita I et al. Smallpox and its Eradication. Geneva: WHO, 1988. 4 Stich A, Meyer H, Kohler B et al. Tanapox: first report in a European traveler and identification by PCR. Trans R Soc Trop Med Hyg 2002;96:178–9.

(b) Fig. 51.26 (a) Tanapox lesion on the finger of a young child at an early stage, showing similarities to orf. (b) Same lesion at the eschar stage. Courtesy of Dr Barbara Leppard.

52.1

C H A P T E R 52

HIV Infection Neil S. Prose & Coleen K. Cunningham Department of Pediatrics and Dermatology, Duke University Medical Center, Durham, NC, USA

Definition. The human immunodeficiency virus (HIV) is an RNA virus that belongs to the lentivirus family of cytopathic viruses [1]. This virus has a specific tropism for cells bearing the CD4 surface antigen, including helper T-lymphocytes [2]. HIV is the cause of acquired immune deficiency syndrome (AIDS), a disease that can affect children. Paediatric AIDS is characterized by wasting, neurological degeneration and loss of immune function. History. In 1981, a number of cases of Pneumocystis carinii (now P. jiroveci) pneumonia and Kaposi sarcoma in previously healthy homosexual men were reported to the United States Centers for Disease Control [3]. Shortly thereafter, a syndrome characterized by progressive deterioration of the immune system was conclusively shown to be the result of infection with the RNA retrovirus, HIV-1 [4,5]. Within several years, numerous cases of AIDS in children were observed and reported [6,7]. Epidemiology. The epidemic of AIDS in children is part of a worldwide epidemic of HIV infection. At the end of 2008, 33 million people, including more than 2 million children, were living with HIV [8]. HIV infection is particularly common in sub-Saharan Africa and parts of South-East Asia. However, cases of HIV infection have been reported in virtually all countries in the world. Children may acquire HIV infection through several well-established modes of transmission. In most parts of the world, perinatal transmission is by far the most common. Without treatment to interrupt mother-to-child transmission of the virus, approximately 30% of the children of mothers who are infected with HIV will themselves be infected [9]. Paediatric HIV infection may also be the result of receiving contaminated blood or blood products. HIV infection is also transmitted by breastfeeding [10]. Studies of the parents and siblings of infected children indicate that routine household contact is not a mode of disease spread [11,12].

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Clinical features

General features Paediatric HIV infection results in a wide variety of clinical manifestations [13]. Common non-specific manifestations include lymphadenopathy, hepatosplenomegaly, fever, weight loss, diarrhoea, chronic parotitis, thrush and failure to thrive. Bacterial sepsis, meningitis and pneumonia are frequent causes of morbidity and mortality in these children [14]. Numerous opportunistic infections are associated with deterioration of cell-mediated immunity. P. jiroveci pneumonia is by far the most common. Others include Candida oesophagitis, disseminated cytomegalovirus (CMV) infection, disseminated Mycobacterium aviumintracellulare infection and cryptosporidiosis [15]. While not strictly an opportunistic infection, Mycobacterium tuberculosis is a common serious bacterial co-infection. An encephalopathy results from HIV infection in the brain. Symptoms include abnormalities in behaviour, developmental delays and deterioration of motor and intellectual function. Spastic paresis and ataxia may also be present [16]. Lymphocytic interstitial pneumonitis (LIP) is seen in almost 50% of children with AIDS. LIP usually presents with hypoxaemia without fever and may be accompanied by nail clubbing. Cutaneous manifestations A wide variety of mucocutaneous disorders have been associated with the presence of HIV infection in children [17]. The presence of these findings correlates with the degree of AIDS-related immunosuppression [18]. Acute HIV infection. A generalized cutaneous eruption has been observed in a number of young adults in association with the infectious mononucleosis-like symptoms of acute HIV infection [19]. The lesions are generalized, may be either papulosquamous or morbilliform and last 2–3 weeks. This seroconversion illness appears to be unusual in young children although it may be more common in youth with HIV acquired as an adolescent. Bacterial infections. In studies of large groups of HIVinfected patients, increased cutaneous colonization with

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Staphylococcus aureus has been noted [20]. In addition, the incidence of Staph. aureus infections correlates with the progression of HIV-related immune dysfunction [21]. Impetigo, ecthyma and cellulitis due to infection with Staph. aureus appear to be more common in children with HIV infection [22]. Staphylococcal folliculitis, presenting with pustules or plaques, and severe scalp infection have also been observed [23,24]. Toxic shock syndrome, as a result of cutaneous Staph. aureus infection, may occur in children with HIV infection [25]. Other documented bacterial infections of the skin include Haemophilus influenzae cellulitis and external otitis due to Pseudomonas aeruginosa [26,27]. In a report of eight children with AIDS and bacteraemia due to Ps. aeruginosa, four were noted to develop skin lesions [28]. The lesions ranged from a generalized papular eruption to ecthyma gangrenosum. Macular lesions and oral ulcers due to M. aviumintracellulare and atypical ecthymatous lesions due to Mycobacterium marinum have been described [29,30]. Miliary tuberculosis of the skin may present with widespread follicular papules [31]. Disseminated Listeria monocytogenes infection in a neonate born to an HIV-infected woman has been reported [32]. The skin lesions were petechiae and pustules; Gram-positive coccobacilli were present on skin biopsy. Bacillary angiomatosis. Bacillary angiomatosis is characterized by the development of red to purple papules and nodules over the entire skin surface [33]. Systemic symptoms may include weight loss and fever. This disorder was first recognized in adult patients with AIDS, and was attributed to infection with the cat scratch disease bacillus. The cause of bacillary angiomatosis is now recognized to be Bartonella henselae, a rickettsia-like organism [34] (see Chapter 58). Bacillary angiomatosis appears to be rare in children with HIV infection, but it has been reported to occur [35]. Fungal infections. Oral candidiasis is the single most common oral manifestation of HIV infection in children [36]. This disorder may present with creamy white or yellowish plaques (thrush), areas of atrophy or angular cheilitis [37]. Oral candidiasis appears to be more common among children with low CD4 counts and symptomatic HIV disease than those with normal counts and no symptoms [38]. Recurrences of oral candidiasis following treatment may be associated with changes in C. albicans biotype and reduced susceptibility to antifungal agents [39,40]. Cutaneous infection with Candida may also occur in the napkin area. Most typically, Candida napkin dermatitis presents as an area of confluent, bright red erythema with

Fig. 52.1 Trichophyton tonsurans tinea capitis with scarring in a 7-year-old girl with AIDS.

satellite pustules extending beyond the periphery of the lesion. Simultaneous infection may occur in the axilla or neck folds. Children with HIV infection may also develop chronic candidal paronychiae and nail dystrophy [41]. A number of common dermatophytes may also cause severe cutaneous disease in children with HIV infection. Severe tinea capitis (Fig. 52.1), widespread tinea corporis and onychomycosis have been observed. In addition to C. albicans and the common dermatophytes, a number of other fungi infect the skin either locally or as part of a systemic infection. HIV-infected patients with cryptococcosis may develop a variety of cutaneous lesions, including papules, nodules, infiltrated plaques, ulcers and subcutaneous abscesses. Herpetiform lesions and small, umbilicated papules resembling molluscum contagiosum have also been reported. Disseminated sporotrichosis, associated with numerous painful ulcers, has been reported in a number of patients with AIDS [42]. Disseminated histoplasmosis may lead to a wide variety of cutaneous lesions. Patients presenting with inflammatory dermatoses, widespread keratinous papules and granulomatous ulcers have been described [7].

Viral infections Herpes simplex. Mucocutaneous infection with herpes simplex is sometimes a severe problem in the child with AIDS [43]. Chronic or recurrent herpetic gingivostomatitis is characterized by painful vesicles and superficial ulcerations on the lips, tongue, buccal mucosa and palate. Without proper treatment, these lesions may progress to large, black eschars. Not infrequently, children with oral herpes simplex develop infection of the fingers, and chronic herpetic ulcers at other locations have also been observed. Varicella zoster virus infection. The course of varicella zoster virus infection in children with AIDS is variable

HIV Infection

[44,45]. For many children with HIV infection, varicella is a benign and uncomplicated infection. However, some of these patients go on to have recurrent episodes of varicella, which may or may not be more severe than the original episode. Children with HIV infection have a higher incidence of herpes zoster than do healthy individuals of the same age. Herpes zoster in the child with HIV infection tends to be more severe and painful than in the healthy child; the incidence of permanent scarring (Fig. 52.2) and of recurrence seems to be higher. Some HIV-infected children who develop varicella go on to have chronic and persistent infection with varicella zoster virus. The skin lesions in these patients are characteristically hyperkeratotic nodules and plaques (Fig. 52.3), which may be widespread [46,47]. Children with this form of chronic infection may develop pneumonia or central nervous system infection due to varicella zoster virus.

52.3

Measles. In children with HIV infection, measles is often complicated by pneumonia, and the disease can be lifethreatening [48]. In most cases, the exanthem is typical (see Chapter 49), although patients with atypical eruptions or without skin disease have been reported. In cases in which the rash is atypical or the patients do not develop antibodies, examination of the skin biopsy can be helpful in confirming the diagnosis [49]. Cytomegalovirus. A case of napkin dermatitis (nappy rash) from infection with CMV has been reported [50]. The patient, a 6-month-old infant with AIDS, developed an erythematous eruption in the perineum, with crusting, erosions and bullae. Conspicuous viral inclusions were noted on the skin biopsy and CMV was cultured from the skin. Oral hairy leucoplakia. Oral hairy leucoplakia is induced by the presence of Epstein–Barr virus infection within the oral mucosal epithelium. This disorder is characterized by the appearance of corrugated white plaques, which are usually located on the sides of the tongue. Although oral hairy leucoplakia appears to be relatively unusual in paediatric AIDS, occurrence in children has been reported [51]. Molluscum contagiosum. Widespread lesions of molluscum contagiosum are frequently associated with HIV infection (Fig. 52.4). In some children with AIDS, giant and confluent lesions have been reported [30,52].

Fig. 52.2 Scarring secondary to herpes zoster in a child with HIV infection.

Fig. 52.3 Hyperkeratotic nodules due to chronic varicella-zoster infection.

Fig. 52.4 Widespread molluscum contagiosum in a child with AIDS.

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Chapter 52

Fig. 52.5 Confluent flat warts on the forehead of an 8-year-old boy with HIV infection.

Human papillomavirus (HPV). Children with immune suppression secondary to HIV infection may develop widespread common warts. A patient with widespread flat warts due to HPV5 has been reported (Fig. 52.5) [53]. In this case, the appearance of the lesions resembled the phenotype of epidermodysplasia verruciformis. Children with HIV infection may also develop genital or perianal condyloma acuminata [54,55]. In some cases, these lesions are extremely large and difficult to treat. Gianotti–Crosti syndrome. The occurrence of Gianotti– Crosti syndrome in children with HIV infection has been reported [56]. These cases may have been triggered by CMV, hepatitis C virus or by HIV itself.

Infestations In children with AIDS, scabies usually presents with nodules and crusted papules. However, some patients develop a generalized papulosquamous eruption, with diffuse areas of crusting and scale [57]. Patients with crusted scabies (sometimes termed ‘Norwegian scabies’) are infested with numerous mites, and are highly contagious to family members and health personnel [58]. Demodex infestation has been noted to occur in patients with HIV infection. A facial papular follicular eruption due to Demodex infestation was observed in such a child [59]. Histological examination revealed the presence of tuberculoid granulomas. Parasitic infection. Acanthamoeba infection of the skin may rarely occur in patients with HIV infection [60]. The lesions are pustules, subcutaneous and deep dermal nodules, and ulcers, most often on the extremities and face [61].

Inflammatory disorders The incidence of atopic dermatitis may be higher among children with HIV infection. The onset or worsening of this disorder was observed among haemophiliacs after seroconversion [62,63]. The onset or worsening of atopic dermatitis in children with HIV infection may be due to an increased atopic diathesis or to xerosis, bacterial or viral superantigens, or epidermal barrier disruption [64]. Seborrhoeic dermatitis also appears to be somewhat more severe in children with HIV infection. The presentation of this disorder varies markedly with the age of the patient. Among infants, diffuse scaling of the scalp (‘cradle cap’) may progress to widespread involvement of the intertriginal folds and napkin area. Older children develop erythema and scaling of the scalp, nasolabial folds and postauricular skin. Psoriasis may develop and turn into a severe form during the course of HIV infection [65]. This may occasionally occur in children and adolescents. Children with HIV infection are at significant risk for drug eruptions, especially due to trimethoprim– sulphamethoxazole. In a single study, 16% of 50 children with AIDS developed a cutaneous eruption from this medication [66]. Lesions may be macular and papular, or morbilliform. Although most HIV-related drug eruptions resolve rapidly after discontinuing the causative medication, severe Stevens–Johnson syndrome and toxic epidermal necrolysis have been observed [67,68]. Hypersensitivity reactions to antiretroviral agents may also result in skin changes. The two most notable reactions are those to nevirapine and abacavir. These reactions are critical to recognize because either can be fatal; stopping the offending agent can be life-saving. Skin reactions to nevirapine, a non-nucleoside reverse transcriptase inhibitor, were recognized during the initial treatment trials of this agent. This drug primarily produces two types of reactions. The first type occurs commonly (32% in one study) and includes moderate-to-severe diffuse maculopapular lesions or dry desquamation generally occurring within the first 2 weeks of starting the medication. The frequency and severity of these lesions can be decreased by increasing the medication dose slowly; hence the 2-week lead-in period where nevirapine is administered once per day instead of twice [69]. If this rash is mild and there are no manifestations suggesting Stevens–Johnson syndrome, then treatment can continue and the rash will generally resolve. The second and more serious reaction that occurs with nevirapine is a typical Stevens–Johnson reaction which does require immediate treatment discontinuation [70]. Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) can also occur as a side-effect of nevirapine in children [71]. Similar rashes can occur with other drugs in this

HIV Infection

class, including efavirenz; however, skin reactions to these other agents occur less frequently than with nevirapine. Abacavir produces a significant hypersensitivity reaction in about 5% of recipients, usually beginning within 6 weeks of starting the medication. The reaction is strongly correlated with the presence of the HLA-B57 antigen [72]. This reaction includes fever in 80% and rash in 70% [73]. Multiple organ systems are often involved. The eruption is papular and diffuse, but may include macules. It is only occasionally itchy, and is often mild; sometimes the rash is not noticed by the patient [74]. If abacavir hypersensitivity is suspected, the medication must be stopped immediately and never restarted. Patients with suspected abacavir hypersensitivity should never be rechallenged as the reactions with repeat exposure are rapid, severe and often fatal. Other reported adverse cutaneous effects of highly active antiretroviral therapy (HAART) in children include xanthomas and hyperlipidaemia [75] and lipodystrophy syndrome [76]. Lipodystrophy syndrome is characterized by fat redistribution, with peripheral fat wasting and abdominal adiposity. Chronic leucocytoclastic vasculitis has been observed in a number of children with HIV infection. In one child, chronic palpable purpura of the lower extremities was the sole manifestation of HIV infection [77]. Pyoderma gangrenosum has been reported in two children with AIDS [78]. In one patient, this skin disease responded to treatment with dapsone. Pityriasis rubra pilaris (PRP) has been reported in both children and adults with HIV infection. In these patients, PRP appears to have a poor response to treatment; nodulocystic and lichen spinulosus lesions may occur [79,80]. Ashy dermatosis (erythema dyschromicum perstans) has also been observed in children with HIV infection [81]. Children with chronic HIV infection may develop cutaneous manifestations of nutritional deficiencies. Eruptions resembling those seen in kwashiorkor and pellagra have been observed in some children. In addition, acrodermatitis enteropathica may develop in children with HIV infection [82].

Neoplasms The epidemic form of Kaposi sarcoma was first described in 1981 [83]. This neoplastic disorder is characterized by violaceous nodules or plaques that occur on any skin or mucous membrane surface. Growing data indicate that Kaposi sarcoma is caused by HHV8 [84]. Cutaneous Kaposi sarcoma is most common in homosexual men with AIDS, and was originally thought to be unusual in HIV-infected children. In western countries only a few such patients have been reported [85–87]. However, HIV-

52.5

associated Kaposi sarcoma in children appears to be a common entity in Zambia and other countries of sub-Saharan Africa [88–90] and Asia. Skin, oral and gastrointestinal lesions are the most frequent manifestations [91]. Various tumours of smooth muscle origin have also been described in children with HIV infection [92,93]. A case of multiple subcutaneous leiomyosarcomas in an adolescent with HIV infection has been reported [94]. The lesions presented with localized pain, and there was minimal elevation and firmness of the overlying skin. Differential diagnosis. In infants, HIV infection must be differentiated from congenital immune disorders. The clinical presentation in older children, which often includes generalized lymphadenopathy, must be distinguished from Hodgkin disease and other haematological malignancies. Prognosis and treatment. Over the past decade, there has been significant progress in the treatment of HIV infection in children. In a number of countries, the mortality rate has dramatically decreased and the disorder can be approached as a chronic disease. Unfortunately, the developing countries most severely affected by the HIV/AIDS epidemic have often been unable to access the relevant medications and, in those areas, large numbers of children continue to die from AIDS. Treatment consists of a combination of antiretroviral agents commonly referred to as as ‘highly active antiretroviral therapy’ (HAART) [95]. HAART usually includes two nucleoside reverse transcriptase inhibitors and either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor; however, several new classes of antiretroviral agents are now available including integrase inhibitors, entry inhibitors and a fusion inhibitor. The choice of drug combinations is dictated by the patient’s overall state of health, viral resistance or susceptibility to specific drugs, and by viral load. The skin manifestations, whether they are a direct result of HIV or of secondary infections, are usually best treated by suppressing the HIV to undetectable levels. Caution must be exercised, however, because sometimes the antiretroviral agents are the cause of the skin rashes. Further, the skin reactions may herald a severe hypersensitivity reaction that requires immediate intervention. Immune restoration disease (IRIS) is an additional complication of antiretroviral treatment. The restoration of CD4+ lymphocytes results in a reactivation of inflammatory conditions or an increased immune response to opportunistic infections. The development of herpes zoster as a manifestation of IRIS has been described in a number of children [96].

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70 Metry DW, Lahart CJ, Farmer KL, Hebert AA. Stevens–Johnson syndrome caused by the antiretroviral drug nevirapine. J Am Acad Dermatol 2001;44(2 suppl):354–7. 71 Santos RP, Ramilo O, Barton T. Neviapine-associated rash with eosinophilia and systemic symptoms in a child with human immunodeficiency virus infection. Pediatric Inf Dis 2007;26:1053–6. 72 Saag M, Balu R, Phillips E et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. AIDS 2008;22:1673–5. 73 Clay PG. The abacavir hypersensitivity reaction: a review. Clin Therapeut 2002;24:1502–14. 74 Hewitt RG. Abacavir hypersensitivity reaction. Clin Infect Dis 2002;34:1137–42. 75 Babl F, Regan AM, Pelton S. Xanthomas and hyperlipidemia in a human immunodeficiency virus-infected child receiving highly active antiretroviral therapy. Pediatr Infect Dis J 2002;21:259–60. 76 Amaya R, Kozinetz C, Mcmeans A et al. Lipodystrophy syndrome in human immunodeficiency virus infected children. Pediatr Infect Dis J 2002;21:404–10. 77 Chren MM, Silverman RA, Sorensen RU et al. Leukocytoclastic vasculitis in a patient infected with human immunodeficiency virus. J Am Acad Dermatol 1989;21:1161–4. 78 Paller AS, Sahn EE, Garen PD et al. Pyoderma gangrenosum in pediatric acquired immunodeficiency syndrome. J Pediatr 1990;117:63–6. 79 Menni S, Barncaleone W, Grimalt R. Pityriasis rubra pilaris in a child seropositive for the human immunodeficiency virus. J Am Acad Dermatol 1992;27:1009. 80 Miralles ES, Numez M, de las Heras ME et al. Pityriasis rubra pilaris and human immunodeficiency virus infection. Br J Dermatol 1995;133:990–1. 81 Venencie PY, Foldes C, Laurain Y et al. Erythema dyschromicum perstans following human immunodeficiency virus seroconversion in a child with hemophilia B. Arch Dermatol 1988;124:1013. 82 Tong TK, Andrew LR, Albert A et al. Childhood acquired immunodeficiency syndrome manifesting as acrodermatitis enteropathica. J Pediatr 1986;108:426–8. 83 Hymes K, Cheung T, Green JB et al. Kaposi’s sarcoma in homosexual men: report of eight cases. Lancet 1981;ii:598–600. 84 Chang Y, Cesarman E, Pessin MS et al. Identification of herpesviruslike DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 1994;266:1863–4. 85 Malekzadeh MH, Church J, Siegel SE et al. Human immunodeficiency virus-associated Kaposi’s sarcoma in a pediatric renal transplant recipient. Nephron 1987;42:62–5. 86 Guiterrez-Ortega P, Hierro-Orozoco S, Sanchez-Cisneros R et al. Kaposi’s sarcoma in a 6-day-old infant with human immunodeficiency virus. Arch Dermatol 1989;125:432–3. 87 Orlow SJ, Cooper D, Petrea S et al. AIDS-associated Kaposi’s sarcoma in Romanian children. J Am Acad Dermatol 1993;28:449– 53. 88 Pruksachatkunakorn C, Uruwannakul K, Bhoopat L. Kaposi sarcoma in a Thai boy with acquired immunodeficiency syndrome. Pediatr Dermatol 1995;12:252–5. 89 Athale UH, Patil PS, Chintu C et al. Influence of HIV epidemic on the incidence of Kaposi’s sarcoma in Zambian children. J AIDS Hum Retrovirol 1995;8:96–100. 90 Arkin LM, Cox CM, Kovarik CL. Kaposi’s sarcoma in the pediatric population: the critical need for a tissue diagnosis. Pediatr Infect Dis 2009;28(5):426–8. 91 Cairncross LL, Davidson A, Millar AJW, Pillay K. Kaposi sarcoma in children with HIV: a clinical series from Red Cross Children’s Hospital. J Pediatr Surg 2009;44:373–6. 92 Chadwick E, Conner EG, Guerra Hanson IC et al. Tumors of smooth muscle origin in pediatric HIV-infected children: an association of AIDS and cancer. JAMA 1990;263:3182–5.

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93 McLoughlin LC, Nord KS, Joshi JV et al. Disseminated leiomyosarcomas in a child with acquired immunodeficiency syndrome. Cancer 1991;67:2618–21. 94 Orlow SJ, Kamino H, Lawrence RL. Multiple subcutaneous leiomyosarcomas in an adolescent with AIDS. Am J Pediatr Hematol Oncol 1992;14:265–8.

95 Palumbo PE. Antiretroviral therapy in HIV infection in children. Pediatr Clin North Am 2000;47:155–69. 96 Tangsinmankong N, Kamchaisatian W, Lujan-Zilbermann J et al. Varicella zoster as a manifestation of immune restoration disease in HIV-infected children. J Allergy Clin Immunol 2004;113:742–6.

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Infective Dermatitis (Skin Manifestations of HTLV Infection) Rosalia A. Ballona1 & Neil S. Prose2 1

Division of Dermatology, Instituto de Salud del Niño, Lima, Peru Department of Pediatrics and Dermatology, Duke University Medical Center, Durham, NC, USA

2

Definition. Infective dermatitis (ID) is a form of severe and recurrent infantile eczema that involves the nasal vestibule, earlobes and scalp, and is associated with infection with human lymphtrophic virus type 1 (HTLV-1) [1,2]. History. Infective dermatitis was first described in 1966 by Sweet, and was characterized as a severe exudative dermatitis, with crusting and a fine generalized popular rash. It was noted to respond to prolonged treatment with systemic antibiotics and topical corticosteroids [1]. In 1967, Walshe established the consistent presence of Staphylococcus aureus and β-haemolytic streptococcus in this clinical entity [2,3]. In 1990, LaGranade demonstrated the association with HTLV-1 infection and in 1998 proposed the diagnostic criteria which are accepted to this day [3]. HTLV-1 was isolated from red blood cells of a patient with adult T-cell lymphoma/leukaemia in 1990. Epidemiology. HTLV-1 belongs to the family Retroviridae, subfamily oncovirus [1]. The largest endemic areas are the Caribbean (Trinidad, Jamaica), southern Japan, southern Africa and South America (especially Brazil). The virus has also been found in southern India, northern Iran and among aboriginal people in northern Australia [4,5]. Transmission of HTLV-1 has been reported in immigrants from endemic areas to the United States and Europe [4]. Seroprevalence varies from 3–6% in the Caribbean (Trinidad and Jamaica) to 30% in rural areas of Japan, such as Miyazaki. Seroprevalence studies also show an unequal distribution among populations in the same area [1,4,5]. The nature of the epidemic is influenced by changes in environment and lifestyle, and incidence tends to decline with overall economic improvement. Seroprevalence increases with age and is two times higher in women. This disparity has increased over the past 30 years and is attributed to changes in lifestyle and increased risk of male-to-female sexual transmission in certain regions [1].

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

The most important routes of transmission are sexual contact, blood transfusion and vertical transmission from mother to child [6]. Intrauterine infection is less common than perinatal infection, and the rate of transmission is increased in children born to mothers with high titres of maternal antibodies and premature rupture of membranes, and is associated with breastfeeding for more than 6 months [1,4–6]. Parenteral transmission is due to blood transfusion in 50–60% of cases, and decreases with storage of blood for more than 7 days. Fresh plasma and cryoprecipitates are not associated with transmission of HTLV-1 [5,6]. Transmission via intravenous drug use appears to be less common [5]. Pathophysiology. The pathogenetic mechanism of HTLV-1 has been closely related to its structural proteins, Tax and Rex. There is also evidence that the accessory protein p12 plays a fundamental role in establishing persistent infection [7,8]. The protein HTLV-1 p12, located in the endoplasmic reticulum and its Golgi apparatus, causes release of calcium into the cytoplasm and forms a complex with the cytoplasmic protein calreticulin. This process in turn activates T-cell nuclear factor (TCNF). In the presence of calcium, the complex enters the nucleus where it joins with TCNF and causes the transcription of cytokines interleukin 1, 2 and 6, and tumour necrosis factor-α. These continue to cause recurrent inflammatory reactions and disease recurrences [7–9] (Fig. 53.1). Clinical features. Infective dermatitis begins with rhinitis which resembles a common respiratory infection. This is followed by a generalized erythematous eruption, with crusting in the nares and an exudative eczematous dermatitis affecting the scalp, earlobes, neck, axillae, and inguinal and periumbilical skin. The disorder is associated with variable degrees of pruritus and regional lymphadenopathy [9] (Figs 53.2–53.4). Diagnosis. In most cases, diagnosis is suspected well before the performance of serological testing. ID is always associated with staphylococcal and streptococcal infection.The diagnosis is now based on the diagnostic criteria delineated by LaGrenade (Box 53.1).

53.2

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HTVL

T cell

NFAT

HTVL1 IP3 Ca++ RE + Ca

Protein kinase

n

duli

o Calm

PPP NFA T

Golgi

Calcineurin

P P P

Nucleus DNA

IL1-1L2-1L3-1L4-1L6 FSCG-FNT

Fig. 53.1 Pathogenic mechanism of HTLV-1.

Box 53.1 Diagnostic criteria for ID according to LaGrenade Major criteria (1,2, and 5 are required)

Minor criteria

• Eczema of scalp, axillae, groin, external ears, retroauricular skin, eyelids, and skin around the nose and/or neck. (Two areas are required.) • Watery chronic nasal discharge without other signs of rhinitis and/or desquamation of the nares. • Chronic recurrent dermatitis that rapidly responds to treatment with appropriate antibiotic therapy, but with rapid recurrence after discontinuation of antibiotics. • Onset in early infancy. • HTLV-1 seropositivity.

• Skin culture positive for Staphylococcus aureus or β-haemolytic streptococcus. • Generalized fine papular rash (in the most severe cases). • Generalized lymphadenopathy and dermatopathic lymphadenopathy. • Anaemia. • Increased erythrocyte sedimentation rate. • Hyperimmunoglobulinaemia (IgD or IgE). • Increased levels of CD4 and CD8, and increased CD4 to CD8 ratio.

Infective Dermatitis (Skin Manifestations of HTLV Infection)

Fig. 53.2 Facial erythema and desquamation in infective dermatitis.

(a) Fig. 53.3 (a,b) Generalized erythema in a child with HTLV-1 infection.

(b)

53.3

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Infective dermatitis cannot be diagnosed by histopathology. However, in some cases, hyperkeratosis, parakeratosis, epidermotropism and even Munro-like microabcesses are observed [9,10]. Differential diagnosis. The differential diagnosis consists of atopic dermatitis in children, and seborrhoeic dermatitis in adolescents [6,9]. Prognosis and treatment. Progression of ID to adult T-cell leukaemia-lymphoma (ATL) and HTLV-1 associated myelopathy (HAM) or tropical spastic paraparesis (TSP) has been reported [11,12]. ATL is a severe form of leukaemia-lymphoma that does not respond to chemotherapy and HAM/STP is a severe disorder of the central nervous system. Due to the frequent recurrence of bacterial infection, patients must receive chronic treatment, with antibiotic therapy maintained at a minimum effective dose. Most frequently prescribed is trimethoprim/ sulphamethoxazole. Because ID is a risk factor for malignancy, close follow-up is required.

(a)

(b) Fig. 53.4 (a,b) Severe exudative eczematous dermatitis due to HTLV-1 infection.

References 1 Manns A, Hisada M, LaGranade L. Human T-lymphotropic virus type I infection. Lancet 1999;353:1951–8. 2 LaGranade L, Manns A, Fletcher V et al. Clinical, pathologic and immunologic features of human T lymphotrophic virus type I associated infective dermatitis in children. Arch Dermatol 1998;134:439–44. 3 LaGranade L, Hanchard B, Fletcher V, Cranston B, Blattner W. Infective dermatitis of Jamaican children: a marker for HTLV-1 infection. Lancet 1990;336:1345–7. 4 Bangham CR. HTLV-1 infections. J Clin Pathol 2000;53:581–6. 5 Gotuzzo E, Arango C, de Queiroz-Campos A, Isturiz RE. Human T cell lymphotropic virus in Latin America. Infect Dis Clin North Am 2000;14(1):211–39. 6 Bittencourt AL. Vertical transmission of HTLV-1: a review. Rev Inst Med Trop S Paulo 1998;40:245–51. 7 Ding W, Albrecht B, Kelley R et al. Human T cell lymphotropic virus type1 p12 expression increases cytoplasmic calcium to enhance the activation of nuclear factor of activated T cells. J Virol 2002;76(20):10374–82. 8 Kim SJ, Ding W, Albrecht B, Green PL, Lairmore MD. A conserved calcineurin-binding motif in human T lymphotropic virus type 1 p12 functions to modulate nuclear factor of activated T cell activation. J Biol Chem 2003;278(18):15550–7. 9 Bittencourt AL. Infective dermatitis associated with HTLV-1: a review. An Bras Dermatol 2001;76(6):723–32. 10 Bittencourt AL, Oliveira MF, Brites C, van Weyenbergh J, Vieira M, Araujo I. Histopathological and immunohistochemical studies of infective dermatitis associated with HTLV-1. Eur J Dermatol 2005;15(1):26–30. 11 Hanchard B, LaGrenade L, Carberry C, Fletcher V, Williams E, Cranston B. Childhood infective dermatitis evolving into adult T cell leukaemia after 17 years. Lancet 1991;338:1593–4. 12 LaGranade L, Morgan O, Carberry C et al. Tropical spastic paraparesis ocurring in HTLV1 associated infective dermatitis. West Ind Med J 1995;44(1):34–5.

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C H A P T E R 54

Pyodermas and Toxin-mediated Syndromes Christian R. Millett, Warren R. Heymann & Steven M. Manders Division of Dermatology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, NJ, USA

Pathophysiology, 54.1 Epidemiology, 54.3

Localized cutaneous staphylococcal and streptococcal infections: pyodermas, 54.3

Pathophysiology Streptococci Group A streptococcus (GAS) is a common infectious agent in children, having a large number of virulence factors responsible for a broad range of disease. It is a Gram-positive organism that is seen in chains on Gram stain. On blood agar, GAS displays characteristic βhaemolysis due to the haemolysin streptolysin S. The GAS has numerous surface and extracellular factors that confer virulence, of which the cell surface M protein is the main antigenic determinant. It aids in adherence but most importantly enables the bacterium to evade phagocytosis. GAS classification is based on genotyping of the M protein (emm sequence typing). There are currently approximately 180 emm sequence types and 800 emm subtypes described, but new types and subtypes are still being identified [1]. Invasive GAS disease is defined by the isolation of GAS from a normally sterile body site, and includes entities such as streptococcal toxic shock syndrome (TSS) and necrotizing fasciitis [2]. These infections depend in large part on the ability of the bacteria to produce streptococcal exotoxins, which are particularly potent virulence factors because they function as superantigens. Unlike traditional antigens, superantigens have the ability to stimulate immune cells without undergoing antigen processing and presentation by antigen-presenting cells (APCs) [3]. Conventional antigens are processed within the APC, and protein fragments of the antigen are then expressed on the cell surface in the groove of the major histocompatibility type II complex (MHCII). The antigen-MHCII complex then interacts with the T cell receptor in a very specific, antigen-restricted fashion. The segment of T cells bearing the receptor that corresponds to the antigen is

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Toxin-mediated staphylococcal and streptococcal disease, 54.8

then activated, with resultant cytokine production and specific immune activation. Superantigens, however, are able to bypass many elements of the typical immune response sequence. Superantigens are not processed by APCs but bind directly to the MHCII complex outside the groove and therefore are able to interact with T cells in a relatively non-specific fashion. Whereas conventional antigens require recognition of all five elements of the T cell receptor (Va, Ja, Vb, Db, Jb), the recognition sequence for superantigens is almost entirely dependent on Vb only. Because only a limited amount of Vb genes exists, a given superantigen–T cell interaction may lead to the activation of 5–30% of the entire T cell population, whereas conventional antigens activate approximately 0.01–0.1% of the body’s T cells. This large-scale activation of T cells by superantigens leads to massive cytokine production, especially that of tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6. These cytokines, especially TNF-α and IL-1, have been shown to mediate clinical effects such as fever, erythematous rash, emesis, hypotension, tissue injury and shock. Certain superantigen-mediated illnesses appear to induce a large-scale depletion of particular Vb subsets; this may result from apoptosis of initially activated T cells [4]. Host antibacterial and antitoxic immunity to GAS is an important aspect in the pathogenesis of cutaneous and systemic infections. Antibacterial immunity is related to the type-specific M component of GAS. For example, infection with type 4 Streptococcus is followed by development of specific neutralizing antibody for M type 4-bearing organisms, but not against heterologous types. Antitoxic immunity follows exposure to erythrogenic toxins such as the streptococcal pyrogenic exotoxins (SPEs). Most commonly, these toxins produce the exanthem and constitutional manifestations of scarlet fever; rarely they may cause TSS. A child with antibacterial immunity to a strain with a particular M type will not develop clinical disease. Conversely, in the absence of

54.2

Chapter 54

M-type specific immunity, an infected child will develop scarlet fever if he or she lacks immunity to the specific erythrogenic toxin. Furthermore, failure to produce an adequate humoral immunity to toxins can lead to recurrent toxin-mediated disease. The immune response to various streptococcal exoproducts has been used in several diagnostic serological tests, most notably the response to streptolysin O. The antistreptolysin O (ASO) titer is generally elevated in patients recovering from a recent streptococcal infection. This test may be useful in certain settings to confirm or support a diagnosis. In addition, there are two important late sequelae of GAS infections that appear 1–3 weeks later: glomerulonephritis and rheumatic fever. The pathogenesis remains poorly understood, and appears to be best explained by an abnormal immune response or hypersensitivity to streptococcal antigens.

Staphylococci Staphylococci are Gram-positive cocci found in clusters on Gram stain. Staphylococcus aureus is usually a transient pathogenic organism on the skin, and can be found to asymptomatically colonize the nasal mucosa. In certain situations, however, Staph. aureus can cause skin or invasive infections via expression of a wide array of virulence factors, including wall teichoic acid (TA) and surface proteins. These promote adherence to damaged tissue and diminish neutrophil function and immune response. Staph. aureus also secretes exotoxins and enzymes that can contribute to a variety of cutaneous and systemic infections, including four haemolysins (a-, b-, d- and g-toxins). Staphylococcal exfoliative toxins (ETs), including ETA, ETB, and ETD, disrupt desmoglein 1, a desmosomal cadherin expressed in the upper epidermis. This results in staphylococcal scalded skin syndrome (SSSS) and bullous impetigo [5]. TSST-1, among other toxins produced by Staph. aureus, can also cause TSS, an acute life-threatening illness.

Methicillin-resistant Staphylococcus aureus (MRSA) In 1942, the first penicillin-resistant Staph. aureus isolate was observed, and in 1961, Staph. aureus developed methicillin resistance due to the acquisition of the mecA gene. It has been suggested that MRSA originated in vivo through the horizontal transfer of the mecA gene between two staphylococcal species. During the last 45 years, various hospital-associated MRSA (HA-MRSA) clones have disseminated worldwide. In addition, communityassociated MRSA (CA-MRSA) clones have also become much more prevalent [6]. Methicillin resistance occurs by the presence of the mecA gene, which encodes penicillin-binding protein 2a. Penicillin-binding protein is a transpeptidase that restores

cell wall biosynthesis of MRSA in the presence of βlactams. The mecA gene is carried on the staphylococcal methicillin resistance gene cassette, or staphylococcal cassette chromosome mec (SCCmec). CA-MRSA and HAMRSA have different types of cassettes and antibiotic resistance. CA-MRSA typically has SCCmec type IV, and is generally susceptible to most non-β-lactam antibiotics. In contrast, HA-MRSA usually carries SCCmec types I, II or III, and is resistant to aminoglycosides, clindamycin and macrolides. A recently cloned strain of CA-MRSA called USA300 defies this generalization of antibiotic resistance. USA300 carries the genes that encode resistance to macrolides, lincosamides, streptogranin B, tetracycline, doxycycline and mupirocin [7]. The USA300 strain has predominated in outbreaks throughout the USA, suggesting that it possesses virulence or transmissibility factors that confer unusual pathogenicity. Recent sequencing of the complete genome of this strain identified a mobile genetic element, termed arginine catabolic mobile element (ACME). It has been hypothesized that the products of this gene cluster enhance the capacity of USA300 strains to survive at low pH on human skin and within phagocytic cells [8]. Other toxins produced by MRSA also contribute to the pathogenesis of skin and soft tissue infections. PantonValentine leukocidin (PVL) is a cytotoxin of CA-MRSA involved in the development of abscesses, cellulitis and furuncles. PVL lyses leucocytes by facilitating calcium channel opening and pore formation, and increases IL-8 secretion which leads to an inflammatory response and tissue necrosis. The genes that encode PVL have been found in almost all CA-MRSA isolates [7]. Risk factors for acquisition of HA-MRSA include a history of hospitalization, surgery, dialysis or residence in a long-term care facility within 1 year before the MRSA culture date, presence of an indwelling device at the time of culture, or a previous history of MRSA infection or colonization. CA-MRSA has been defined by some as a MRSA infection with onset in the community in a patient lacking established HA-MRSA risk factors. However, it is generally not possible to determine with certainty where MRSA was initially acquired [8]. Staph. aureus can persist as a colonizer for years, leading to misclassification of the source. Indeed, some ‘community-onset’ infections may in fact be caused by hospital-acquired strains, leading to a blurring of the distinction between CA-MRSA and HAMRSA. Nevertheless, the presence of SCCmec type IV and PVL have been useful molecular markers to identify true CA-MRSA strains. Infections caused by CA-MRSA predominantly affect children and young adults. Direct contact with infected patients, colonized subjects or a contaminated environment is implicated in the transmission of CA-MRSA

Pyodermas and Toxin-mediated Syndromes

infection. Crowding and sharing of personal items appear to be important factors. Transmission has occurred through activities in which direct contact is common, such as among football players, wrestlers and military personnel [9]. Nasal colonization has also been identified as a risk factor for infection [8]. References 1 Steer A, Danchin M, Carapetis J. Group A streptococcal infections in children. J Pediatr Child Health 2007;43:209–13. 2 Martin J, Green M. Group A streptococcus. Semin Pediatr Infect Dis 2006;17:140–8. 3 Burnett A, Domachowske J. Therapeutic considerations for children with invasive group A streptococcal infections: a case series report and review of the literature. Clin Pediatr 2007;46:550–5. 4 Manders S. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998;39:383–98. 5 Iwatsuki K, Yamasaki O, Morizane S, Oono T. Staphylococcal cutaneous infections: invasion, evasion, and aggression. J Dermatol Sci 2006;42:203–14. 6 Deurenberg R, Stobberingh E. The evolution of Staphylococcus aureus. Infect Genet Evol 2008;8(6):747–63. 7 Kil E, Heymann W, Weinberg J. Methicillin-resistant Staphylococcus aureus: an update for the dermatologist. Cutis 2008;81:227–32, 247–52. 8 Gorwitz R. A review of community-associated methicillin resistant Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J 2008;27:1–7. 9 Stryjewski M, Chambers H. Skin and soft tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008;46:S368–77.

Epidemiology Streptococci In the past two decades, there has been a re-emergence of serious streptococcal infections. Surface proteins, host factors and toxin production have all contributed to the renewed virulence of these bacteria. The re-emergence of invasive GAS infections, such as necrotizing fasciitis and streptococcal TSS, has been closely linked with the renewed prevalence of GAS bearing M-1 and M-3 surface proteins. Host factors in the general population appear to be partially responsible for the re-emergence of streptococci as major pathogens, as very young or immunocompromised persons are at high risk for infection with these bacteria. However, a large percentage of patients who have serious disease are otherwise healthy. This is postulated to be due to the absence of previous exposure to these more virulent strains of bacteria, as an absence of protective antibody appears to predispose persons to infection. Bacterial toxin production has also been shown to be a highly important factor in the increased frequency of serious streptococcal and staphylococcal disease, with toxins such as streptococcal pyrogenic exotoxin-A (SPEA) being linked with the increased prevalence of serious invasive GAS infections in the United States [1].

54.3

Around the world, there are an estimated 1.7 million new cases per year and 500,000 deaths per year from serious GAS disease. In addition, there are over 100 million cases of less serious skin infections per year. Since the 1980s, severe GAS diseases have been increasing in incidence and severity. The incidence of invasive GAS disease in most industrialized countries is between 2.5 and 3 per 100,000, and mortality rates vary between 10% and 20%. The burden of severe GAS disease is predominantly in developing countries and impoverished populations. It is estimated that more than 660,000 cases of invasive disease resulting in more than 160,000 deaths occur globally each year, most in developing countries. The peak incidence of these infections occurs in infants and the elderly [2].

Staphylococci The incidence and prevalence of MRSA infections have also been increasing. Over the last 20 years, there have been reports from many healthcare facilities documenting increasing numbers of CA-MRSA infections treated at the facility, increasing proportions of all MRSA infections that are community associated, and increasing proportions of all community-acquired Staph. aureus infections that are methicillin resistant. To date, reported CA-MRSA infections have disproportionately affected children, young adults, and people from racial or ethnic minorities and low socio-economic groups [3]. Between 1998 and 2004, 44.9% of non-intensive care unit Staph. aureus strains were methicillin resistant. Furthermore, the percentage of methicillin resistance among patients in intensive care units infected with Staph. aureus was 59.5% in 2003, an 11% increase in resistance from 1998–2002. Methicillin resistance has also spread to the outpatient setting and between 1998 and 2004, 25% of Staph. aureus infections were methicillin resistant [4]. References 1 Manders S. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998;39:383–98. 2 Steer A, Danchin M, Carapetis J. Group A streptococcal infections in children. J Pediatr Child Health 2007;43:209–13. 3 Gorwitz R. A review of community-associated methicillin resistant Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J 2008;27:1–7. 4 Kil E, Heymann W, Weinberg J. Methicillin-resistant Staphylococcus aureus: an update for the dermatologist. Cutis 2008;81:227–32, 247–52.

Localized cutaneous staphylococcal and streptococcal infections: pyodermas Impetigo Pyoderma refers to a localized purulent infection of the skin and soft tissues. Impetigo is a common type of superficial pyoderma that is characterized by inflammation

54.4

Chapter 54

and infection localized in the epidermis. Non-bullous impetigo (impetigo contagiosa) is the most common form of pyoderma and is usually due to GAS, whereas bullous impetigo is usually due to Staphylococcus aureus [1]. Non-bullous impetigo represents a host response to the infection, whereas a staphylococcal toxin causes bullous impetigo. Impetigo most often affects children 2–5 years of age, although it can occur in any age group. Non-bullous impetigo accounts for approximately 70% of cases. Impetigo is the most common bacterial skin infection among children and is more common in those receiving dialysis. The diagnosis usually is made clinically and can be confirmed by Gram stain and culture. The infection usually heals without scarring and can resolve within several weeks even if left untreated [2]. Impetigo usually is transmitted through direct contact. In many cases, antecedent cutaneous trauma, such as insect bites or minor scratch injuries, is necessary for clinical infection. Bacterial colonization of the nares, axilla or perineum may serve as a reservoir for infection. Impetigo is more common in tropical climates and in crowded living conditions, and can be associated with poor hygiene. Certain dermatoses, most notably atopic dermatitis, are associated with Staph. aureus colonization rates as high as 90%, leading to frequent bacterial superinfection. Epidemic impetigo may also occur in the newborn nursery setting. Non-bullous impetigo begins as an erythematous macule or papule, which rapidly evolves into a vesicle or pustule and then possibly an erosion. Serous and purulent drainage forms a characteristic honey-coloured crust. Individual lesions can enlarge to 1 or 2 cm, but satellite lesions typically appear in the vicinity due to spread by autoinoculation. Coalescence of these lesions may produce wider areas of crusted involvement. The face is the usual location, especially around the mouth and nares, but extremity lesions as well as buttock involvement are not uncommon. Although typically localized, widespread impetigo may occur, especially in the setting of underlying atopic dermatitis. Itching and mild discomfort may occur with impetigo, but systemic complaints are rare. Bullous impetigo is mainly caused by toxin-producing phage group II Staph. aureus. It is a localized form of SSSS, with subcorneal epidermolysis caused by one of the two staphylococcal exfoliative toxins. These toxins are localized to the area of infection and Staph. aureus can be cultured from the blister contents (unlike the blisters in generalized SSSS). Superficial vesicles progress to rapidly enlarging, flaccid bullae with sharp margins. Ruptured bullae are replaced with yellow crusting. Bullous impetigo is most frequently seen in infants and favours moist, intertriginous areas, such as the nappy area, axillae and

neck folds. It appears to be less contagious than nonbullous impetigo, and cases usually are sporadic. Impetigo has an excellent prognosis. The infection may be self-limited, but it can spread and persist on the skin, remaining contagious to others. Acute poststreptococcal glomerulonephritis is a serious complication that affects between 1% and 5% of patients with non-bullous impetigo. Treatment with antibiotics does not have any effect on this risk. Other rare but potential complications include sepsis, osteomyelitis, arthritis, endocarditis, pneumonia, cellulitis, lymphadenitis, guttate psoriasis, TSS and SSSS [2]. However, most of these complications are usually limited to children with acquired or inherited immune deficits. Treatment of impetigo is not always necessary, as the problem is potentially self-limited. In the majority of cases, however, intervention is appropriate to achieve a faster resolution of infection, prevent more serious complications, and limit the spread of infection to others. Patients with localized disease may be treated with topical antiseptics, mupirocin or retapamulin. There are good arguments to limit the use of mupirocin to the elimination of MRSA carriership. Oral antibiotics are recommended for more extensive disease. Given the relative prevalence of staphylococcal impetigo, penicillin VK is not a good choice for oral therapy. The most appropriate oral antibiotics for the majority of cases of impetigo include penicillinase-resistant penicillins and cephalosporins. Oral erythromycin may be an acceptable alternative, although resistance to this agent is rising in many areas (mostly >20%). Cultures and sensitivities should dictate therapy in recalcitrant cases. Ecthyma is considered to be an ulcerated form of impetigo, and can be a consequence of failure to effectively treat impetigo. The infection extends into the dermis to produce shallow ulcerations that may heal with scarring. It is mainly caused by Strep. pyogenes. Treatment for ecthyma usually requires systemic antibiotics such as βlactamase-resistant penicillins or cephalosporins, particularly since ecthyma is more commonly seen in patients with underlying immunodeficiency or widespread atopic eczema and in those living under poor hygienic conditions.

Folliculitis Bacterial folliculitis is a specialized form of pyoderma in which the infection is anatomically confined to the hair follicle and perifollicular structures. By far the most common bacterial pathogen in cases of childhood folliculitis is Staph. aureus. Superficial staphylococcal folliculitis is very common and is also known as Bockhart’s impetigo. Predisposing conditions which increase the number of skin surface bacteria, such as occlusion, overhydration and maceration, may lead to the development of follicu-

Pyodermas and Toxin-mediated Syndromes

litis. Similar to impetigo, folliculitis is more common in tropical climates, and in settings characterized by crowded living conditions and poor hygiene. The clinical lesions of folliculitis begin as small pustules in follicular orifices, often accompanied by a halo of perifollicular erythema. Pustules may rupture followed by crust formation at the follicular opening. The papulopustular eruption is often regionalized, and lesions are typically located on the trunk, buttocks and extremities. Pruritus is the most common symptom of folliculitis, although prominent excoriations are usually not seen. Systemic signs and symptoms are rare. The histopathology of folliculitis reveals neutrophilic pustules within the hair follicle. A perifollicular infiltrate composed of lymphocytes and histiocytes may also be present. Folliculitis may be acute or chronic with a tendency for recurrence. The prognosis for superficial folliculitis is excellent, and the process may be self-limited. Deeper forms of folliculitis can result in dermal scarring and alopecia. Although uncommon, folliculitis can progress to cellulitis or lymphadenitis. Rarely, folliculitis caused by toxigenic staphylococcal strains can produce TSS. In normal hosts, folliculitis usually resolves spontaneously without systemic treatment. Good hygiene is the best way to prevent this type of infection. For superficial and limited folliculitis, topical antiseptics (e.g. chlorhexidine, polyhexanide or antiseptic dyes such as methyl violet or eosin) or topical preparations of erythromycin or clindamycin are usually effective. Mupirocin ointment is also effective, but the rate of mupirocin resistance is increasing in proportion to its use in mild cutaneous infections which has negative impact on its capacity to eliminate nasal MRSA carriership. Widespread or deep inflammatory folliculitis usually requires oral antistaphylococcal antibiotics.

Furunculosis Deep folliculitis with extensive perifollicular inflammation and abscess formation produces a lesion known as a furuncle (boil). Isolated furuncles are common, and the term ‘furunculosis’ refers to a condition with multiple, recurrent furuncles. Furuncles are inflammatory nodules associated with a hair follicle that extend into the dermis and the subcutaneous tissue. They usually affect moist, hairy, friction-prone areas of the body, such as the face, axilla, neck and buttocks. These lesions are firm and tender, and may spontaneously drain purulent material. Fever and other constitutional symptoms are rarely present. The most common causative micro-organism is Staph. aureus. When the subcutaneous infection extends to involve multiple furuncles, the lesions are called carbuncles. This multiseptate coalescence can be painful, and constitu-

54.5

tional signs and symptoms, including fever and malaise, are often present. Severe complications, such as bacterial endocarditis, have been reported. If systemic involvement of any type is suspected, evaluation should include blood cultures as well as Gram stain and culture of purulent material [3]. Smaller furuncles can be treated with the application of warm, moist towels. Incision and drainage is usually required for larger furuncles and carbuncles. In addition, the increased incidence of MRSA dictates a consideration of empiric coverage of MRSA in these infections in addition to incision and drainage. Antibiotic choices include clindamycin, doxycycline (in children older than 9 years) and trimethoprim-sulphamethoxazole (TMP-SMX). Patients who have recurrent furuncles may require eradication of Staph. aureus from the nares, axilla and perineum with agents such as mupirocin ointment or oral clindamycin to decrease risk for future infection.

Cellulitis and erysipelas Cellulitis is an infection of the dermis and subcutaneous fat that typically manifests as warm, tender, poorly demarcated areas of erythema. Occasionally, bullae and even necrosis may be present. Constitutional symptoms may include malaise, fever and chills. In adults, cellulitis is often caused by Staph. aureus or Strep. pyogenes and is typically located on the lower extremities. In paediatric patients, cellulitis is most often caused by Staph. aureus and frequently affects the face and neck, although any area can be involved. Multiorganism cellulitis with anaerobes and Gram-negatives tends to occur in patients with chronic ulcers secondary to diabetes, venous insufficiency or pressure. Small breaks in the skin, as can occur with minor trauma, injection drug use, body piercing or bites, serve as portals of entry for bacteria. Tinea pedis is a common fungal infection that predisposes to bacterial cellulitis. Haematogenous spread of bacteria from other sites to the skin occurs most commonly in the immunosuppressed patient. Lymphadenitis, subacute bacterial endocarditis and glomerulonephritis are potential, but uncommon, complications of cellulitis. In most cases, the clinical presentation is sufficient for an accurate diagnosis. Blood cultures and cultures of bullae or ulcers should be obtained. Imaging is not usually necessary, but can be helpful in distinguishing cellulitis from more severe infections such as necrotizing fasciitis [4]. Treatment in immunocompetent patients involves oral antibiotic therapy targeting Staph. aureus and Strep. pyogenes. Options include cephalexin, clindamycin, dicloxacillin (for Staph. aureus) or erythromycin (resistance in >20% of Staph. aureus). In those who are more severely ill, initial intravenous antibiotics are indicated, such as cefazolin, clindamycin or oroxacillin (Staph. aureus). If

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MRSA is suspected, agents such as clindamycin, TMPSMX or doxycycline (in children >9 years of age) should be used [3]. Gram-negative bacteria and opportunistic organisms should be considered in immunocompromised individuals and people with diabetes. When multiorganism cellulitis is suspected, broad-spectrum antibiotics should be instituted [4]. Erysipelas is a distinctive superficial variant of cellulitis, characterized by striking erythema and a firm, welldefined, advancing border. It is primarily caused by group A β-haemolytic streptococci. Infants, young children and older adults are most commonly affected by erysipelas. Fever, chills, nausea and vomiting are frequent, and may be associated with bacteraemia. Although most common on the lower legs, erysipelas may occur in any location. It is particularly dangerous on the face due to the risk of septic sinus thrombosis. Recurrent erysipelas most frequently occurs in lymphoedematous extremities. Prompt, aggressive treatment is indicated for erysipelas, and parenteral antibiotics are generally preferred for initial management. Once stabilized, patients can be treated with oral therapy. Penicillin remains the treatment of choice for erysipelas, but numerous alternatives are available, including the penicillinase-resistant penicillins and cephalosporins.

Botryomycosis Botryomycosis is a chronic suppurative granulomatous bacterial infection of the skin and subcutaneous tissue. It presents with clinical and histological features similar to actinomycosis or mycetoma, although the causative organism is usually Staph. aureus. The bacteria become encapsulated, which not only protects them from systemic antibiotics but also prevents proliferation to a full pathological state. The bacterial inoculum usually remains low enough that abscesses do not develop but a chronic granulomatous reaction develops with sinuses, fistulas and ulceration. Small yellow granules may be noted in the exudate, and the causative bacteria are embedded within these granules. The extremities are most commonly affected, while head and neck involvement is unusual [5]. The term ‘botryomycosis’ came from the Greek botrys, meaning bunch of grapes, because of the characteristic groups of granules that resemble grapes, and mycosis, because the origin of the disease was first thought to be a fungus. However, botryomycosis is now known to mainly be caused by Staph. aureus, with Pseudomonas aeruginosa ranking second in frequency. Most cases are reported in hospitalized patients with concomitant diseases. The major associated predisposing factors are: skin trauma, previous surgery, diabetes mellitus, liver disorders, systemic steroids, alcoholism and cystic fibrosis.

Whenever botryomycosis is suspected, a Gram stain should be used to look for bacterial masses. Two cultures should be done: one for fungi and one for bacteria. A biopsy should be taken for histopathological examination and to determine the shape and staining characteristics of the granule, which differentiate it from actinomycosis and mycetoma [6]. Histopathological findings of botryomycosis include eosinophilic granules in a suppurative focus. The centre of the granules is basophilic, but the periphery is eosinophilic. They are usually 1–3 mm and stain with periodic acid-Schiff (PAS), Gram and Giemsa stains. A chronic inflammatory response composed of neutrophils, lymphocytes, eosinophils, plasma cells, fibroblasts and histiocytes is present [5]. Treatment of botryomycosis traditionally involves a combination of antibiotic and surgical therapy. Antibiotic treatment should be prolonged, usually for weeks, and based on the causal agent isolated. Surgical excision and drainage of lesions are also usually recommended.

Blastomycosis-like pyoderma Blastomycosis-like pyoderma is a rare chronic pyoderma that presents as verrucous plaques with multiple draining sinuses, and heals with a cribriform scar [7]. Typical vegetating skin lesions are difficult to distinguish clinically from blastomycosis. Staphylococcus aureus is the most common cause but β-haemolytic streptococci, Pseudomonas spp, Proteus mirabilis and E. coli have also been reported [8]. Blastomycosis-like pyoderma most likely represents a hyperinflammatory tissue reaction in the context of a reduced immunological capacity. It has been reported in patients with systemic immunosuppression due to malnutrition, alcoholism, lymphoma, chronic myeloid leukaemia and HIV [7]. The initial lesion usually begins at sites of trauma, and presents as large verrucous plaques with multiple pustules and elevated borders. Histology shows pseudoepitheliomatous hyperplasia and multiple abscesses [8]. Cultures and biopsy may be helpful in distinguishing blastomycosis-like pyoderma from blastomycosis. Treatment for blastomycosis-like pyoderma includes topical and systemic antibiotics, intralesional corticosteroids, surgical excision and local ablative measures such as electrodesiccation and curettage or carbon dioxide laser. There are also several case reports of response to acitretin [7].

Necrotizing fasciitis Necrotizing fasciitis (NF) is an aggressive soft tissue infection involving the subcutis and fascia, with a rapid and fulminant progression. Necrotizing fasciitis in adults is frequently polymicrobial but in children, it is usually a monomicrobial infection most commonly caused by GAS. Due to a significant mortality rate, early diagnosis and

Pyodermas and Toxin-mediated Syndromes

initiation of aggressive surgical and supportive therapy are critical for survival. Any suspicion of NF warrants immediate hospitalization and critical care support [9]. Predisposing conditions for the acquisition of NF include trauma, previous surgery, diabetes mellitus, immunosuppression, renal failure, arteriosclerosis, odontogenic infection and malignancy. Although NF usually involves an extremity, it can often involve the trunk in children. Localized painful erythema and edema rapidly progress over hours to days, with development of cyanosis, blistering and necrosis. Untreated, NF may progress to deep gangrene and sloughing of tissue. Systemic signs and symptoms include high fever, anxiety, altered mental status, tachypnoea, tachycardia and hypocalcaemia [10]. Vesiculation, ecchymosis, crepitus, anaesthesia and necrosis are indicative of advanced disease. Severe pain out of proportion to skin findings, rapidly spreading oedema, bullae formation, mental status changes, marked leucocytosis or elevated creatinine kinase level all suggest NF more than cellulitis. Anaesthesia of overlying skin may be present prior to the appearance of skin necrosis [9]. In cases of suspected NF, an MRI scan of the affected extremity should be urgently requested. It typically shows widespread soft tissue oedema and subfascial gas formation. Frozen tissue sections showing massive polymorphonuclear infiltrate in the fascia and subcutaneous tissue. Early surgical intervention for fasciotomy and debridement, along with an aspirate for Gram stain and culture, are usually indicated. Antibiotic choices should cover the variety of potential causative organisms, unless a definite bacterium can be isolated. For primary treatment, a combination of penicillin G (or cefalexin) and clindamycin covers the most relevant pathogens. In cases caused by Strep. pyogenes, penicillin G remains the antibiotic of choice The mortality rate for NF ranges from 35% to 40%; however, prompt intervention lowers the rate to 12% [10].

Blistering distal dactylitis Blistering distal dactylitis (BDD) is an infection with Gram-positive bacteria that most commonly occurs in infants and children; cases in adults have mainly been reported in people with diabetes and the immunocompromised. BDD manifests as acral bullae on erythematous bases and, classically, as an individual bulla on the distal finger. However, it can occur on the proximal phalanx, palm or sole, and can present as multiple bullae. The bullae are typically oval and 1–3 cm in diameter. They are usually asymptomatic, but can evolve into erosions. Diagnosis of BDD is usually made on clinical grounds alone. Group A streptococcus is the most frequently reported cause of BDD, although occasional cases are linked to Staph. aureus, especially if multiple bullae or erosions are present. BDD is associated with very low morbidity.

54.7

When it is suspected, treatment should involve incision and drainage of bullae, wet to dry compresses to the erosions, and a course of β-lactamase-resistant antibiotics [11].

Perianal streptococcal dermatitis Perianal streptococcal dermatitis (PSD) is an infection that predominantly affects younger children and is most frequently caused by GAS. It has a male preponderance, and the typical age group is between 6 months and 10 years. The signs and symptoms of PSD include rectal irritation, pruritus ani, painful defaecation, rectal bleeding and encopresis. The cutaneous findings in acute infections are patchy or plaque-like, sharply demarcated, moist erythema in a uniform perianal distribution extending 2–4 cm from the anal verge. Satellite pustules may also be observed. Perianal bacterial cultures can confirm the diagnosis. Staphylococcal perianal dermatitis can occur, but is far less common than PSD. Oral therapy with penicillin V is considered first-line therapy. Alternatives include cefalexin, erythromycin or other macrolides. A duration of therapy from 14 to 21 days is recommended. Additional topical therapy with antiseptics (e.g. chlorhexidine) is widely used and may accelerate bacterial clearance [12].

Streptococcal intertrigo Intertrigo is caused by friction of opposing skin surfaces in a moist environment. Young infants are especially susceptible because of their short necks, relative chubbiness and flexed posture, all of which produce deep skinfolds. Secondary infection with Candida albicans is common, but GAS must also be considered. A sharply demarcated, intensely erythematous, weeping eruption in intertriginous areas is characteristic of both candidal and GAS intertrigo. Certain clinical features can help to differentiate these two conditions. The appearance of satellite lesions surrounding the main eruption favours Candida infection, whereas the presence of a distinct, foul odour suggests GAS intertrigo. Patients with GAS intertrigo may also be irritable or have low-grade fevers. Bacterial culture can most clearly establish the diagnosis. Simple intertrigo will respond to measures that minimize moisture and reduce friction, such as drying of the skinfolds, barrier creams or zinc pastes. Candidal intertrigo can be treated with topical anti-yeast medications such as ketoconazole or nystatin. For GAS intertrigo, a 10-day course of penicillin successfully eliminates the infection in most instances. Recurrences may occur and require retreatment [13]. References 1 Steer A, Danchin M, Carapetis J. Group A streptococcal infections in children. J Pediatr Child Health 2007;43:209–13.

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2 Cole C, Gazewood J. Diagnosis and treatment of impetigo. Am Fam Physician 2007;75:859–64. 3 Lopez F, Lartchenko S. Skin and soft tissue infections. Infect Dis Clin North Am 2006;20:759–72. 4 Kroshinsky D, Grossman M, Fox L. Approach to the patient with presumed cellulitis. Semin Cutan Med Surg 2007;26:168–78. 5 Ellerbe D, Parsons D, Cook P. Botryomycosis: improved therapy for a difficult infection. Int J Pediatr Otorhinolaryngol 1997;41:363–9. 6 Bonifaz A, Carrasco E. Botryomycosis. Int J Dermatol 1996;35:381–8. 7 Nguyen R, Beardmore G. Blastomycosis-like pyoderma: successful treatment with low-dose acitretin. Austral J Dermatol 2005;46:97–100. 8 Sawalka S, Phiske M, Jerajani H. Blastomycosis-like pyoderma. Ind J Dermatol Venereol Leprol 2007;73:117–19. 9 Bingol-Kologlu M, Yildiz R, Alper B et al. Necrotizing fasciitis in children: diagnostic and therapeutic aspects. J Pediatr Surg 2007;42:1892–7. 10 Manders S. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998;39:383–98. 11 Scheinfeld N. Is blistering distal dactylitis a variant of bullous impetigo? Clin Exper Dermatol 2007;32:314–16. 12 Jongen J, Eberstein A, Peleikas H et al. Perianal streptococcal dermatitis: an important differential diagnosis in pediatric patients. Dis Colon Rect 2008;51(5):584–7. 13 Honig P, Frieden I, Kim H, Yan A. Streptococcal intertrigo: an underrecognized condition in children. Pediatrics 2003;112:1427–9.

Toxin-mediated staphylococcal and streptococcal disease Toxic exanthems in children represent a common clinical problem. While viral exanthems account for the majority, staphylococcal and streptococcal toxin-mediated diseases are important disorders to identify. Early recognition and treatment of these syndromes can significantly reduce the morbidity and potential mortality. In this section, staphylococcal scalded skin syndrome, staphylococcal TSS, streptococcal TSS, streptococcal scarlet fever and recurrent toxin-mediated erythema will be discussed. In all of these cases, route of admininistration and dose of toxin have been shown to directly influence the clinical response. In addition, host factors such as local pH, glucose level, oxygen level, age, and presence or absence of antibodies will have a direct impact on the clinical expression of toxin-mediated illness. Certain physical signs are frequently present in toxin-mediated illness. These include strawberry tongue, acral erythema with desquamation, and an erythematous eruption with frequent perineal accentuation; they have been described in TSS, scarlet fever and recurrent perineal erythema, among others. The frequent clinical overlap between toxinmediated diseases has been attributed to the significant degree of sequence homology not only between toxins produced by the same bacterial strain, but also due to the similarities at a molecular level between many streptococcal and staphylococcal toxins. Ultimately, though, the phenotypic expression of a given toxin-mediated disease

is dependent not only on the toxin itself, but also on host factors [1].

Staphylococcal scalded skin syndrome The SSSS is a potentially life-threatening, toxin-mediated manifestation of localized infection with certain strains of staphylococci. The syndrome may range from limited to extensive cutaneous involvement characterized by tenderness, blistering and superficial denudation of the skin. In more severe cases, systemic involvement may be present. Staphylococcal scalded skin syndrome is predominantly a disease of infancy and early childhood, with most cases seen before the age of 5 years. Factors responsible for the age distribution include renal immaturity, leading to decreased toxin clearance in the very young. Adults with SSSS have rarely been reported; predisposing factors in this population include renal failure, malignancy, immunosupression, chronic alcohol abuse and HIV-1 infection. Most toxigenic strains of Staph. aureus causing SSSS belong to phage group II, types 71 and 55. Staphylococcal scalded skin syndrome results from the effects of one of the two exfoliative (also known as epidermolytic) toxins (ETs): ETA and ETB. As noted previously, bullous impetigo results when toxin is produced and exerts its effect locally. In generalized forms of SSSS, toxin diffuses from an infected focus and, in the absence of specific antitoxin antibody, spreads haematogenously to produce its widespread effects. In children the infectious focus is usually in the nasopharynx or conjunctivae. Staphylococcal pneumonia or bacteraemia may be present in adults. An appropriate antibody response to ET appears to limit clinical disease expression to bullous impetigo; an inadequate humoral immune response may predispose patients to development of SSSS. Childhood cases of SSSS are primarily associated with solely ETA production, but the frequency of the different toxins in adult cases is unclear [1]. Both ETs produce blistering and denudation by disruption of the epidermal granular cell layer through interdesmosomal splitting. ETs have been shown to be glutamate-specific serine proteases that specifically bind and cleave desmoglein 1. Desmogleins are cadherin-type cell–cell adhesion molecules found in desmosomes, and play a critical role in maintaining epithelial integrity. Desmogleins are also affected in the autoimmune blistering disease pemphigus. Desmoglein 1 is targeted by IgG autoantibodies in pemphigus foliaceus, which shows superficial epidermal blisters with identical histological findings to SSSS [2]. Clinical features of SSSS include fever, irritability, skin tenderness and scarlatiniform erythema with accentuation in flexural areas. Within 24–48 hours, flaccid blisters and erosions develop. These blisters are sterile and yield

Pyodermas and Toxin-mediated Syndromes

no organisms when sampled for bacterial culture. Nikolsky’s sign is characteristically present. Intraoral lesions do not occur because of the absence of a granular layer to which the toxin may bind; however, involvement of the keratinized external lip with crusting and fissuring is frequently encountered. Sepsis is rare in children but common in (immunocompromised) adults. The major entity in the differential diagnosis is toxic epidermal necrolysis (TEN), a life-threatening but rare disease in infancy. In contrast to SSSS, TEN produces full-thickness epidermal necrosis and histologically demonstrates subepidermal separation, rather than the intraepidermal split characteristic of SSSS. Therapy for SSSS should be directed towards eradication of staphylococci from the focus of infection, which generally involves intravenous penicillinase-resistant penicillins. Usually, oral antibiotic therapy can be substituted within several days. In addition to antibiotics, topical supportive skin care and appropriate attention to fluid and electrolyte management in the face of disrupted barrier function will usually ensure rapid recovery. The mortality rate is low in children (3%) but exceeds 50% in adults, especially in the setting of immunocompromise [1]. It is vital to recognize the potential for epidemic SSSS in newborn nurseries, and identification of healthcare workers who are colonized or infected with toxigenic Staph. aureus is an integral part of management. Control measures should be applied, including strict enforcement of chlorhexidine handwashing, oral antibiotic therapy for infected workers, and mupirocin ointment for eradication of persistent nasal carriage.

Staphylococcal toxic shock syndrome Toxic shock syndrome (TSS) is defined as an acute and potentially fatal illness characterized by high fever, a diffuse erythematous rash, desquamation of the skin 1–2 weeks after onset, hypotension, and involvement of three or more organ systems. Toxic shock syndrome is usually classified into two categories: menstrual TSS, originally described in association with tampon use, and nonmenstrual TSS, which occurs in a variety of clinical settings and has a tendency to recur [3]. Currently, the incidence of non-menstrual TSS exceeds that of menstrual TSS. Most cases of non-menstrual TSS occur in the postoperative setting but TSS has also been described in association with influenza, sinusitis, tracheitis, intravenous drug use, HIV infection, cellulitis, burn wounds, allergic contact dermatitis, gynaecological infection, and the postpartum period. In both settings, TSS occurs when infection with toxinproducing strains of Staph. aureus induce a systemic inflammatory response in those lacking protective antibodies.

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TSST-1 is one of the significant mediators of pathogenicity in TSS, and it is generated by strains from virtually all menstrual and many non-menstrual cases of TSS. However, non-menstrual cases of TSS can be due to strains of Staph. aureus that do not produce TSST-1, but instead produce staphylococcal enterotoxins. TSST-1 and staphylococcal enterotoxin B act as superantigens, and can lead to large-scale activation of T cells as well as massive cytokine production. Clinically, both menstrual and non-menstrual TSS have similar features. Fever, rash, desquamation, hypotension and multiple organ involvement are the hallmarks of both variants. The eruption of TSS is defined as ‘diffuse macular erythroderma’; however, a scarlatiniform eruption, often with flexural accentuation, is frequently present. Erythema and oedema of palms and soles, hyperaemia of conjunctiva and mucous membranes, and strawberry tongue are often noted. Desquamation of the palms and soles, as seen in many bacterial toxin-mediated disorders, usually follows the onset of the illness by 1–2 weeks. Importantly, in non-menstrual TSS caused by a postoperative infection, the classic signs of localized infection such as erythema, tenderness and purulence may be absent from the site of infection, thereby making clinical diagnosis challenging. Multiple organ involvement may include the gastrointestinal, muscular, renal, hepatic, haematological or central nervous systems [1]. Intense conjunctival hyperaemia is a very frequent and characteristic finding in TSS, but it also occurs in Kawasaki’s disease, erythema multiforme, Rocky Mountain spotted fever, adenoviral and enteroviral infections. These diseases, along with streptococcal toxic shock syndrome (STSS) and early SSSS, constitute the differential diagnosis of TSS. In children, the distinction between Kawasaki’s disease and TSS can be very difficult, especially early in the course of illness. The characteristic thrombocytosis and lymphadenopathy of Kawasaki’s disease are the most helpful distinguishing features, but may not always be present. Prompt intervention is the key to the successful management of the multiorgan involvement in TSS. Removal of infected foreign bodies, drainage of infected sites and institution of penicillinase-resistant antistaphylococcal antibiotics are essential to eradicate the focus of toxinproducing organisms. Massive volume replacement may be needed in the setting of severe intravascular volume depletion. Cardiovascular support may be necessary, including both inotropic and antiarrhythmic measures. Paediatric patients may require ventilatory support for respiratory distress more often than adult patients. Metabolic acidosis, hypomagnesaemia, hypocalcaemia and hypophosphataemia may accompany renal disease, requiring aggressive monitoring and management.

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Streptococcal toxic shock syndrome In the late 1980s, a disease similar in appearance to TSS, yet caused by invasive streptococci, was recognized. This streptococcal toxic shock syndrome (STSS) was found to share many clinical features with staphylococcal TSS, including multiorgan involvement, toxicity, conjunctival hyperaemia and profound hypotension. In the majority of cases, toxin-producing group A streptococci have been isolated, with SPE-A production being most closely linked with invasive disease. However, group A streptococci producing SPE-B, SPE-C, streptococcal superantigen and mitogenic factor, as well as non-group A streptococci, have been found to be causative in individual cases of STSS as well. In a similar manner to classic TSS, the clinical signs of STSS are postulated to be mediated by massive cytokine release as a result of toxin/ superantigen activity. In addition, streptolysin O, produced by 100% of streptococcal strains associated with STSS, has been demonstrated to act synergistically with SPE-A [1]. The majority of cases of STSS have occurred in young, otherwise healthy persons between 20 and 50 years of age. Most are associated with invasive streptococcal infections with virulent (i.e. M types 1 and 3) strains causing extensive soft tissue infections and leading to bacteraemia. (In contrast with STSS, staphylococcal TSS typically is associated with occult or minor focal infections.) The factors that determine whether infections with SPE-A lead to STSS or classic scarlet fever are uncertain. The host’s immune status for the infecting strain’s M type and toxin type is clearly important. It appears that lack of immunity to both streptococcal M type and toxin is required for both scarlet fever and STSS. Clinically, STSS shares many features with TSS. Fever, hypotension, myalgias, liver abnormalities, diarrhoea, emesis, renal dysfunction and haematological abnormalities may be present in TSS caused by either staphylococci or streptococci. Diffuse macular erythroderma likewise is frequently present in disease caused by both bacteria, and is often accompanied by mucous membrane findings, such as conjunctival injection and delayed desquamation of palms and soles. Nonetheless, certain important differences exist between STSS and TSS. The skin is often the portal of entry in STSS, with soft tissue infections developing in 80% of patients. The initial presentation of STSS is often localized pain in an extremity, which rapidly progresses over 48–72 hours to manifest both local and systemic signs of STSS. Cutaneous signs may include localized oedema and erythema, a bullous and haemorrhagic cellulitis, necrotizing fasciitis or myositis, and gangrene. Soft tissue involvement of this nature is distinctly uncommon in staphylococcal TSS. STSS may uncommonly occur in the absence of cutaneous involvement; in these cases differentiation from staphylococcal TSS

becomes more difficult. Blood cultures are positive in more than 50% of patients with STSS, as compared with less than 15% in TSS. In addition, mortality rates are more than five times higher in STSS. Management of STSS is similar to that of TSS. Supportive therapy, vasopressors and antibiotics are the cornerstones of treatment. The increasingly reported clinical resistance of streptococci to penicillin, as well as the difficulty in distinguishing STSS from TSS in some cases, suggests the need for adequate antimicrobial coverage for both staphylococci and penicillin-resistant streptococci. Consideration should be given to clindamycin, erythromycin, cephalosporins or other agents as deemed appropriate by clinical presentation and culture results [1]. Surgical drainage, debridement, fasciotomy or amputation may be necessary.

Streptococcal scarlet fever Scarlet fever is caused by pyrogenic exotoxin-producing group A β-haemolytic streptococcal infections. Epidemics of scarlet fever occurred in the first half of the 20th century, but it is no longer the major public health threat that it was in the past. Morbidity,mortality and sequelae are much less serious today not only because of the development of antibiotics, but also because of changes in the streptococci responsible for the majority of cases of scarlet fever. Whereas the bacteria that caused scarlet fever in the past primarily produced the more virulent SPE-A toxin, currently SPE-B and SPE-C are produced by most Strep. pyogenes organisms isolated from patients with scarlet fever. Scarlet fever remains primarily a disease of children, with most cases occurring between the ages of 1 and 10 years. SPEs have been shown to elicit the cutaneous manifestations of scarlet fever by enhancing delayed-type hypersensitivity to streptococcal products, thereby requiring previous exposure for expression of disease. This explains the rarity of cases of scarlet fever in infancy because most infants have not had previous exposure to these streptococcal toxins and therefore have not generated antitoxin antibody. Clinical findings include the abrupt onset of fever, sore throat, headache and chills. Mucocutaneous findings include a finely papular erythematous ‘sandpaper ’ rash on the trunk and extremities, with circumoral pallor. Pastia’s lines represent linear petechial streaks found especially in flexural locations such as the antecubital fossae, the axilla and the inguinal region. Erythema and oedema of the pharyngotonsillar area, punctate erythematous and petechial macules on the palate, and strawberry tongue are commonly present. Large, thick sheets of skin may desquamate from the hands and feet, especially in the convalescent phase. Uncommon complications include pneumonia, pericarditis, meningitis, hepatitis, glomerulonephritis and rheu-

Pyodermas and Toxin-mediated Syndromes

matic fever. Recurrence rates of scarlet fever have been reported to be as high as 18%. Diagnosis of scarlet fever is usually apparent clinically, but can be further confirmed by supportive serologies and isolation of group A streptococci from the pharynx. First-line treatment is with penicillin; cephalosporins, erythromycin and other macrolides are alternatives [1].

Recurrent toxin-mediated (perineal) erythema Recurrent toxin-mediated perineal erythema (RPE) is caused by the action of toxins produced by both staphylococci and streptococci. Due to a homology at the molecular level between the toxins produced by these bacteria, there is a substantial clinical overlap. Furthermore, a single bacterial toxin acting as a superantigen can lead to a broad spectrum of clinical diseases. Testing for these toxins in cases of RPE has revealed streptococcal pyrogenic exotoxins A and B as well as TSST-1 [4]. The hallmark of RPE is a striking diffuse macular erythema in the perineum occurring within 24–48 hours after a bacterial pharyngitis. Oral mucosal changes, such as strawberry tongue, as well as erythema, oedema and convalescent desquamation of the hands and feet are usually present as well. Systemic signs such as fever or hypotension are absent; however, diarrhoea may occur. Recurrences are frequent, occurring as many as 40 times.

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Culture of the pharynx during the acute episodes reveals toxin-producing Staph. aureus or Strep. pyogenes. It has become clear that RPE is part of an expanding clinical spectrum of toxin-mediated skin diseases that do not easily fit into previously described clinical entities. Recurrent erythroderma associated with a preceding bacterial pharyngitis, isolated episodes of toxin-mediated erythema without recurrences, and patients with episodic mild hypotension, fever and typical mucocutaneous findings in the absence of full criteria for TSS have been described. The common feature, aside from a large degree of clinical overlap, has been the repeated ability to isolate toxin-producing bacteria from normally sterile sites. Given the clinical variations, it is more appropriate to refer to this group of entities as ‘toxin-mediated erythema’ although most cases are recurrent with a propensity for perineal involvement [1]. References 1 Manders S. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998;39:383–98. 2 Anzai H. Production of low titers of anti-desmoglein 1 IgG autoantibodies in some patients with staphylococcal scalded skin syndrome. J Invest Dermatol 2006;126:2139–41. 3 Iwatsuki K, Yamasaki O, Morizane S, Oono T. Staphylococcal cutaneous infections: invasion, evasion, and aggression. J Dermatol Sci 2006;42:203–14. 4 Patrizi A, Raone B, Savoia F et al. Recurrent toxin-mediated perineal erythema. Arch Dermatol 2008;144:239–43.

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C H A P T E R 55

Skin Manifestations of Meningococcal Infection Saul N. Faust1, Parviz Habibi2 & Robert S. Heyderman3 1

Division of Infection, Inflammation and Immunity, University of Southampton, Southampton, UK Division of Medicine, Imperial College London, London, UK 3 Wellcome Trust Tropical Centre, University of Liverpool, Liverpool, UK 2

Neisseria meningitidis is one the most common causes of severe infection in childhood [1–3]. First described by Vieusseux [4] in 1805 following an outbreak of epidemic meningitis in Geneva, meningococcal disease remains an important cause of both morbidity and mortality [3,5]. Meningococcaemia is characterized by the development of a widespread purpuric rash and the progression to vascular collapse and death in up to 20% of cases. In his description of the rapid onset and fulminant progression of meningococcal disease, Herrick [6] remarked that ‘no other infection so quickly slays’. Nearly 80 years later, improved awareness, the availability of highly active antibiotics and advances in intensive care management have failed to alleviate our fear of meningococcal infection. Aetiology. The aetiological agent N. meningitidis is a small Gram-negative diplococcus that is surrounded by an outer polysaccharide capsule, an outer membrane and an underlying peptidoglycan layer. The cell wall is rich in lipopolysaccharide (LPS) which, together with outer membrane proteins, is released as vesicles or ‘blebs’. These blebs are thought to facilitate immune avoidance by binding antibodies that would otherwise bind to whole organisms and also mediate endotoxic shock. Different strains of N. meningitidis may be distinguished by their serogroups, which are based on the 12 recognized variations in capsular polysaccharide antigens (A, B, C, E, H, I, K, L, W135, X, Y, Z). Worldwide, most infections are due to organisms of serogroup A, B or C, although Y and W135 are becoming more prevalent [7,8]. N. meningitidis may be further serotyped, serosubtyped and immunotyped on the basis of outer membrane protein and LPS expression. Characterization of bacterial genome by multilocus sequence typing (MLST) is now the gold standard technique in defining the epidemic spread of the disease [9].

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Meningococcal carriage Colonization of the nasopharynx by meningococci predominantly follows transmission from asymptomatic close contacts through respiratory droplets. Although carriage rates range between 4% and 40%, meningococcal invasion usually occurs within 2–10 days of acquisition and is rare following prolonged carriage. Why one individual out of several hundred harbouring the same strain of meningococcus develops invasive disease is one of the unexplained paradoxes of meningococcal research. Important bacterial properties that might influence this process include the presence of a capsule, pili, outer membrane proteins and immunoglobulin (Ig) A1 proteases [10–13]. Host factors implicated in the development of invasive disease include poor socio-economic circumstances, overcrowding, secretor status, smoking, respiratory tract infection, nasopharyngeal colonization by inhibitory flora, and mucosal and systemic immunity [14–21]. No increased risk of invasive meningococcal disease is associated with human immunodeficiency virus (HIV) infection [22,23]. Epidemiology. Meningococcal disease remains a major health problem worldwide. It is endemic in most countries (attack rates of approximately one in 100,000 of the population), but may occur in epidemics in both developing and industrialized countries [2,5]. Although we no longer see the large epidemics that used to occur in 5–10yearly cycles in Europe and North America before the Second World War [2,5], the annual incidence of invasive meningococcal disease in Europe rose in the mid-1980s and remained higher during the 1990s in countries such as the UK [2,24,25]. In industrialized countries, serogroup B predominates, with serogroup C accounting for the majority of the remaining sporadic cases and a number of recent small outbreaks [2,24–26]. Since the successful introduction of a new conjugate vaccine against serogroup C in the UK in 1999, the disease in the population has been predominantly group B [27,28]. In the African ‘meningitis belt’ large epidemics of serogroup A and, more recently, serogroup W135 disease occur every 5–10

55.2

Chapter 55

Fig. 55.1 The molecular pathogenesis of disseminated intravascular coagulation of bacterial septicaemia.

years, affecting up to 100,000 people in a single outbreak [29–32]. In the ‘meningitis belt’ of Africa the incidence of meningococcal disease rises dramatically towards the end of the dry season and falls with the onset of the rains [2,29]. In temperate climates this seasonal peak in incidence can be seen in the first quarter of the year [2]. Although meningococcal disease can occur at any age, children under 5 years of age are predominantly affected, with the highest attack rates being seen in those less than 1 year. In many countries, a second smaller peak in incidence has also been observed amongst teenagers aged 15–19 years [2,33]. At the beginning of the 20th century when the only treatment available was a crude horse serum, the mortality amongst patients with meningococcal septicaemia was often over 90% [5,34]. With the introduction of sulphonamides and penicillin in the late 1930s and 1940s, there was a dramatic reduction in this mortality in countries around the world [5]. Until the mid 1990s the mortality associated with meningococcal infection remained unchanged at around 10% overall, rising to between 40% and 70% in those patients in severe shock [5,34]. More

recently, in industrialized countries where early disease recognition and aggressive intensive care have become common, the mortality even in children presenting in shock has decreased to between 5% and 10% [3,35]. Pathophysiology. Between 1947 and 1976, the cutaneous manifestations of fulminant meningococcal septicaemia were investigated in a series of postmortem and skin biopsy studies [36–42]. Although the appearances described probably represent the final common pathway for a number of possible pathogenic mechanisms, a wide spectrum of histological changes were observed. These ranged from fibrin-platelet thrombi, endothelial swelling and necrosis, and granulocytic infiltrates to occlusion of blood vessels, extravasation of red blood cells and extensive full-thickness necrosis. In recent years, our understanding of the mechanisms underlying meningococcal sepsis has improved. It has become apparent that much of the disease process that follows meningococcal invasion is not due to direct toxicity by the meningococcus itself but results from the release of endotoxin into the circulation. This triggers the activation of inflammatory

Skin Manifestations of Meningococcal Infection

55.3

Fig. 55.2 The coagulation and fibronolytic pathways rely on the function of endothelial proteins and protein complexes. Dysfunctional regulatory mechanisms in meningococcal disease include endothelial (protein C pathway) and plasma (tissue factor pathway inhibitor (TFPI), antithrombin, PAI) factors. PGI2, prostacyclin; TFPI, tissue factor pathway inhibitor; AT, antithrombin; GAGs, glycosaminoglycans; CS, chondroitin sulphate; HS, heparin sulphate; DS, dermatan sulphate; PC, protein C; PS, protein S; TM, thrombomodulin; EPCR, endothelial protein C receptor; PAI, plasminogen receptor inhibitor; tPA, tissue plasminogen activator.

cells and the elaboration of a wide range of cytokines and other mediators [43–48]. This intense inflammatory response is commonly associated with platelet consumption, a coagulopathy and intravascular thrombosis, which are all important markers of disease progression and a poor prognosis [49]. However, the coagulopathy and the microvascular consequences of meningococcal sepsis are more complex than originally thought (Fig. 55.1) [50]. With the appreciation that the vessel wall is not simply an inert conduit [51] but performs a wide range of important homeostatic functions, it has become recognized that dysfunction of the vascular endothelium is key to the development and progression of both the haemostatic and inflammatory disorders associated with severe sepsis [50,52–54]. A haemostatic imbalance occurs following the activation of coagulation and dysfunction or dysregulation of the natural regulatory pathways (Fig. 55.2) [48,50]. Endothelial prostacyclin production and the expression of anticoagulant glycosaminoglycans may be impaired [55,56]. Patients with meningococcal disease have increased monocyte tissue factor activity [57], decreased tissue factor pathway inhibitor [58], a deficiency of antithrombin, protein C and protein S, and significant disruption of the fibrinolytic pathway [45,54,59–64]. We have demonstrated that disruption of the endothelial activation of protein C in meningococcal sepsis is caused by downregulation of thrombomodulin and endothelial protein C receptor on the endothelial cell surface (Figs 55.3, 55.4) [54]. The dysregulation of the coagulation and fibrinolysis pathways described above occurs together with activation of inflammatory pathways including innate,

(a)

(b)

(c)

Fig. 55.3 Skin-biopsy specimen from a patient with meningococcal sepsis. A biopsy specimen from a purpuric lesion shows areas containing thrombosed vessels (right-hand arrow in (a) and arrow in (b)) and a perivascular infiltrate (left-hand arrow in (a)) (haematoxylin and eosin, ×100 (a) and ×400 (b)). (c) shows inflammatory cells (arrow) around non-thrombosed vessels (haematoxylin and eosin, ×400). The cellular infiltrate consisted of both neutrophils (identified by neutrophil-elastase staining) and monocytes and macrophages (identified by CD68 staining).

55.4

Chapter 55

(a)

(b)

(c)

(d)

(e)

Fig. 55.4 Immunostaining for thrombomodulin in skin biopsy specimens from patients with meningococcal sepsis during the initial infection and 3 months later (immunoperoxidase stain, ×200). Thrombomodulin immunostaining of skin biopsy specimens from a patient with acute meningococcal sepsis during the initial infection (a) and 3 months later (b) is shown. The same sequence is shown for a second patient (c, d). (e) shows another initial specimen from the second patient. The arrows in (a) and (e) show unthrombosed vessels with reduced thrombomodulin staining, and the arrow in (c) shows a thrombosed vessel with reduced thrombomodulin staining. Partial recovery of thrombomodulin expression (arrows in (b) and (d)), together with some residual inflammatory infiltrate, is seen in both patients after 3 months.

Fig. 55.5 The inflammatory, coagulation and fibrinolytic pathways are linked at many levels, leading to organ failure and eventually death.

Skin Manifestations of Meningococcal Infection

(a)

(c)

cell-mediated and humoral immunological processes, involving the complement cascade, the kallikreinbradykinin system, monocytes, neutrophils and cytokines (Fig. 55.5) [48,50,65–69]. The pathways are linked at many levels [48], together leading to the capillary leak, defects in vascular tone, hypoperfusion, myocardial dysfunction and focal thrombosis that are responsible for the tissue damage commonly observed in association with fulminant meningococcal sepsis [48]. Although the release of meningococcal LPS seems to be an important trigger for the inflammatory and haemostatic processes seen in fulminant disease, the importance of direct invasion of the skin by the organism remains uncertain. However, in view of the large numbers of meningococci detected in the dermal vessels of purpuric

55.5

(b)

Fig. 55.6 Skin biopsy specimen from a patient with meningococcal septicaemia. (a, b) Gram-stained sections reveal meningococci associated with a leucocyte (a, electronically enlarged) and within blood vessels (b, electronically enlarged). Figures were processed with Adobe Photoshop and illustrator software. Arrows indicate Gram-stained meningococci. (c) Immunohistochemical staining of N. meningitidis in a skin biopsy sample from a patient with meningococcal disease showing PorA-stained bacteria in the interstitium and blood vessel. V, blood vessel. Arrows indicate immunoperoxidase-positive staining of meningococci (brown) with the appropriate specific mouse monoclonal antimeningococcal antibody (nuclei were counterstained in haematoxylin).

skin lesions [36,39,42,70], direct involvement by the organism is likely. There is increasing evidence that meningococci adhere to the endothelium through a number of mechanisms, and may not only be directly toxic but act as a focus for both the inflammatory and haemostatic responses on the vessel wall [69,71–73]. We have identified meningococci in a number of different cellular environments expressing key virulence factors (Fig. 55.6) [70]. While many single-gene defects are known to affect the immune and coagulation responses to infection [74], a combination of genetic predisposition and bacterial virulence factors is likely to be responsible for any one individual’s susceptibility to invasive disease. In meningococcal disease, many such single-nucleotide polymor-

55.6

Chapter 55

phisms have now been identified. Genetic variants of mannose-binding lectin might account for nearly onethird of cases of invasive disease [75] and an innate antiinflammatory cytokine profile contributes to the likelihood of death [76]. A specific Fc-γ receptor polymorphism may be essential in protecting against fulminant meningococcal infection [77]. Although the factor V Leiden mutation confers a specific genetic predisposition to thrombotic disease [78], it has not been shown to be associated with increased mortality in meningococcaemia, although patients with this mutation may be at higher risk of thrombotic complications such as amputations and skin grafting [79]. An increased PAI-1 response to TNF-α has been associated with death in meningococcal septicaemia [80], demonstrated to be due to a polymorphism in the PAI-1 gene [63,64]. Clinical features. Meningococcal meningitis is the most common form of the disease, is indistinguishable from other forms of childhood bacterial meningitis, usually responds rapidly to antibiotics and is associated with little long-term morbidity [81]. Meningococcal septicaemia with shock is more devastating, commonly presenting with non-specific symptoms of fever, vomiting, headache, abdominal pain and muscle aches. The rash of meningococcal septicaemia may be very subtle in the early stages (Fig. 55.7) and its recognition is imperative if this life-threatening condition is to be diagnosed early and treated effectively. In the early stages of meningococcal infection the rash may resemble a viral exanthem such as rubella (see Fig. 55.7). This erythematous maculopapular rash is nonpurpuric, non-pruritic and often very transient [36,82]. Following a diligent search of all areas of the body, the purpuric lesions of meningococcal septicaemia are seen in 80–90% of patients [83]. The rash usually occurs within 12–36 hours of the onset of the disease and is characteristically petechial but may blanch early in the course of the infection. In the classic presentation of meningococcal septicaemia, the petechiae are irregular, small and often have raised centres (Fig. 55.8). Lesions commonly occur on the limbs and trunk but may be found on the head, palms, soles and mucous membranes. They may also occur on areas subjected to friction or under pressure by clothing. Progression of the rash of meningococcal septicaemia has been shown to relate to the severity of the coagulopathy and prognosis [41,49,84–87]. As the disease becomes more fulminant, lesions coalesce to form large ecchymoses and become haemorrhagic and bullous (see Fig. 55.8). These areas of extensive skin involvement may progress to gangrene of the digits or whole limbs (Fig. 55.9). In such severe purpura fulminans, the gangrenous regions are gunmetal grey or blue-black and are well demarcated

(a)

(b) Fig. 55.7 Early stages of meningococcal septicaemia. (a) Fine maculopapular rash with one early purpuric lesion on the forearm of a young infant. (b) Fine maculopapular rash with a few early purpuric lesions on the trunk of a young child with septic shock.

[37]. The arterial pulses are usually intact but the capillary perfusion is very poor. Thrombosis, extensive skin involvement, venous congestion and tissue oedema may lead to the development of a limb compartment syndrome (see Fig. 55.9). Severe tissue destruction may be associated with muscle infarction and rhabdomyolysis.

Skin Manifestations of Meningococcal Infection

55.7

(a)

(b)

(d)

(c) (e) Fig. 55.8 Purpuric lesions of meningococcal sepsis. (a) Purpuric lesions on trunk and limbs. (b) Close-up of abdominal purpuric lesions. (c) Haemorrhagic rash with central necrosis. (d) Severe purpura fulminans. (e) Bullous formation on a large ecchymotic area.

The development of shock associated with meningococcal septicaemia may be insidious, and is manifested initially by poor peripheral perfusion, confusion and an increased respiratory rate. Hypotension is a late sign as children and young adults may maintain their blood pressure by vasoconstriction, despite severe hypovolaemia [3]. It is important to recognize meningococcal shock

in the early phases, well before hypoxia, acidosis and hypovolaemia lead to multiorgan failure (Fig. 55.10). An algorithm for the early recognition and management of meningococcal infections is given in Figure 55.11. Differential diagnosis. Bacteraemia with Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas spp. and

55.8

Chapter 55

(a)

(b)

(d)

(e) (c) Fig. 55.9 Extensive cutaneous involvement in meningococcal sepsis. (a) Severe digital hypoperfusion in the early stages of meningococcal septicaemia. (b) Digital hypoperfusion that has progressed to gangrene with demarcation 2 weeks after onset of the illness. (c) Gangrene over a proximal ecchymotic area associated with dermal vascular thrombosis. (d) A child with septicaemic shock in the first 24 h of the illness, showing purpura fulminans, severe bilateral lower limb ischaemia and bilateral compartment syndromes. (e) Extensive gangrene with marked venous thrombosis of superficial and deep vessels.

Skin Manifestations of Meningococcal Infection

55.9

skin lesions of meningococcal disease provide a rich source of organisms and have been advocated by some workers for rapid diagnosis, but this is not usually considered routine owing to the advent of modern molecular techniques now available [88,90–94]. An array of rapid tests is now available to detect N. meningitidis group A, B, C, Y and W135 antigens from blood, CSF and urine, which may establish the diagnosis although the sensitivity is poor [95,96]. The highly sensitive polymerase chain reaction (PCR) of blood (or CSF where available) can make the diagnosis in an additional 60% of cases in which no positive culture has been obtained [97–100]. The sensitivity of the new WB-Taqman PCR on EDTA-treated samples of whole blood has been demonstrated to be 87%, increasing case confirmation compared with previous PCR techniques from 72% to 94% [100]. Management of acute meningococcal septicaemia. The management of meningococcal disease has been reviewed in detail elsewhere [3,83] and is detailed in Figure 55.11. However, a number of important management points will be emphasized.

Fig. 55.10 Severe meningococcal sepsis associated with a capillary leak syndrome and multiorgan failure. This child had widespread purpuric lesions, poor peripheral perfusion and marked tissue oedema and required mechanical ventilation, inotropic support and peritoneal dialysis.

overwhelming viral and fungal infections may all rarely present with shock and purpuric rash (Fig. 55.12). Other congenital and immune causes of a purpura fulminans may present with the characteristic rash but these patients are rarely cardiovascularly compromised (see Chapter 162). Laboratory diagnosis. Meningococci are very sensitive to chilling or drying, and must be inoculated and cultured soon after collection. Cerebrospinal fluid (CSF) examination and culture are likely to provide confirmation of the diagnosis of meningococcal meningitis in about 80–90% of cases [88]. However, blood cultures are positive in only one-third to one-half of untreated patients, even when accompanied by a characteristic rash or positive CSF microscopy and culture [88]. Lumbar puncture is now usually considered contraindicated when the clinical diagnosis is meningococcal septicaemia or is often delayed when a characteristic rash suggests meningococcal meningitis, as it is frequently associated with clinical deterioration and death [3,89]. Nasopharyngeal swabs may provide evidence of meningococcal infection. Biopsy material and aspirates from the characteristic purpuric

Recognition and initial therapy It is crucial that, in the absence of another diagnosis, any febrile, ill child with a petechial rash should be considered to have meningococcal septicaemia and treatment should be commenced without awaiting further confirmation. Although the majority of children may not appear desperately ill when first seen, they may deteriorate suddenly and therefore should be observed carefully during the first 48 hours, ideally on a paediatric intensive care unit. Choice of antibiotic Penicillin remains the treatment of choice for meningococcal sepsis. However, since other infections may also occasionally cause shock and a petechial rash, a thirdgeneration cephalosporin should be employed until the diagnosis has been confirmed. Penicillin-resistant strains of N. meningitidis have become a problem in Spain and South Africa [101–103] but fortunately only a handful of insensitive strains have been detected in the UK, the rest of Europe and North America [104–111]. Supportive care Children who present in meningococcal shock need immediate resuscitation, restoration of circulating volume and adequate oxygenation [3]. In those patients with concomitant meningitis, cerebral oedema and raised intracranial pressure may occur. Elective ventilation, control of the PCO2, improvement of cardiac output and thus cerebral perfusion are important aspects of treatment of such patients.

2 seconds Cold hands/feet; pale or blue skin Respiratory distress/ oxygen saturation 2 mmol/l)

SIGNS OF SHOCK?

Call consultant in A&E, Paediatrics, Anaesthesia or Intensive Care Initial assessment looking for shock/raised ICP Do not perform Lumbar Puncture

May present with predominant SEPTICAEMIA (with shock), MENINGITIS (with raised ICP) or both. Purpuric/petechial non- blanching rash is typical. Some may have neither shock nor meningitis. Rash may be atypical or absent in some cases.

RECOGNITION

incorporates NICE Bacterial Meningitis and Meningococcal Septicaemia Guideline CG102

Management of Meningococcal Disease in Children and Young People

Fig. 55.11 Early management of meningococcal disease in children. Reproduced with permission from the Meningitis Research Foundation. © Meningitis Research Foundation (www.meningitis.org).

Based on Early Management algorithm, Dept Paediatrics, Imperial College at St Mary’s Hospital as described in Arch Dis Child 1999;80:290 & 2007;92;283 & on NICE CG102 http://guidance.nice.org.uk/CG102/Guidance http://guidance.nice.org.uk/CG102/QuickRefGuide/pdf/English Authors AJ Pollard (GDG chair), A Cloke, L Glennie, SN Faust, C Haines, PT Heath, JS Kroll, M Levin, I Maconochie, S McQueen, P Monk, S Nadel, N Ninis, MP Richardson, MJ Thompson, AP Thomson, D Turner. Further copies from www.meningitis.org or 01454 281811.

for confirmed and unconfirmed (but clinically suspected) meningococcal disease: i.v. Ceftriaxone for 7 days unless contraindicated BM 3 (see bacterial meningitis algorithm for antibiotics against other pathogens)

MD12 Antibiotics

Urgently notify public health of any suspected case of meningitis or meningococcal disease Prophylaxis of household contacts of MD http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1194947389261 Rifampicin bd for 2 days: < 1yr 5 mg/kg; 1-12yrs 10 mg/kg; > 12yrs 600 mg or Ceftriaxone single im dose: < 12yrs 125 mg; > 12yrs 250 mg or Ciprofloxacin single dose (not in children 12yrs 500 mg For index case not treated with Ceftriaxone, prophylaxis when well enough. Hib: prophylaxis may be indicated – consult public health

MD11

MD10 If Mg++< 0.75 mmol/l Give 0.2 ml/kg of 50% MgSO4 over 30 mins i.v. (max 10 ml).

MD9

If total Calcium < 2 mmol/l or ionized Ca ++ < 1.0 Give 0.1 ml/kg 10% CaCl2 (0.7 mmol/ml) over 30 mins i.v. (max 10 ml) or 0.3 ml/kg 10% Ca gluconate (0.22 mmol/ml) over 30 mins (max 20 ml). Central line preferable.

MD8 If K+< 3.5 mmol/l Give 0.25 mmol/kg over 30 mins i.v. with ECG monitoring. Central line preferable. Caution if anuric.

Correction of metabolic acidosis pH < 7.2 Give half correction NaHCO3 i.v. Volume (ml) to give = (0.3 x weight in kg x base deficit ÷2) of 8.4%NaHCO3 over 20 mins, or in neonates, volume (ml) to give = (0.3 x weight in kg x base deficit) of 4.2% NaHCO3.

MD7

MD6

Inotropes Dopamine at 10-20 mcg/kg/min. Make up 3 x weight (kg) mg in 50 ml 5% dextrose and run at 10 ml/hr = 10 mcg/kg/min. (These dilute solutions can be used via a peripheral vein). Start Adrenaline via a central or IO line only at 0.1 mcg/kg/min. Start Noradrenaline via a central or IO line only at 0.1 mcg/kg/min. for ‘warm shock’. Adrenaline & Noradrenaline: Make up 300 mcg/kg in 50 ml of normal saline at 1 ml/hour = 0.1 mcg/kg/min.

MD5

Intubation (call anaesthetist and consult PICU) see BM 5 Consider using: Atropine 20 mcg/kg (max 600 mcg) AND Ketamine 1-2 mg/kg in shock or Thiopental (thiopentone) 3-5 mg/kg in RICP AND Suxamethonium 2 mg/kg (caution, high potassium). ETT size = age/4 + 4, ETT length (oral) = age/2 + 12 (use cuffed ET tube if possible). Then: Morphine (100 mcg/kg) and Midazolam (100 mcg/kg) every 30 min. Do not use Ketamine in children with raised ICP.

MD4

Take bloods for Glucose, FBC, CRP, Clotting, U&E, Ca++, Mg++, PO 4, Lactate, Blood cultures, Whole blood (EDTA) for PCR, Blood gas (bicarb, base deficit), X-match.

MD3

Normal systolic blood pressure = 80 + (age in years x 2) N.B. Low BP is a pre-terminal sign in children

Conscious Level Alert Responds to Voice Responds to Pain Unresponsive

Observe HR, RR, BP, perfusion, conscious level Cardiac monitor & pulse oximetry.

MD2

Estimate of child’s weight (1–10 years) Weight (kg) = 2 x (age in years + 4)

MD1

55.10 Chapter 55

Skin Manifestations of Meningococcal Infection

Fig. 55.12 Differential diagnosis of meningococcal sepsis. The hand of a child with a Streptococcus pneumoniae septicaemia. Although this presentation is rare, the confluent purpuric lesions, tissue oedema and compartment syndrome are very similar to those seen in meningococcal septicaemia.

Management of the skin lesions Although the majority of purpuric skin lesions heal well following the resolution of meningococcal sepsis, in fulminant disease it is important to prevent the extensive skin damage, limb loss and associated multiorgan failure that often occur despite prompt antibiotic therapy. Although there is no evidence from randomized controlled trials, fresh frozen plasma (FFP) infusions are indicated to correct hypofibrinogenaemia and specific clotting factor deficiency, and to reduce the risk of haemorrhage [50,112]. Cryoprecipitate may be used in patients where hypofibrinigenaemia persists despite multiple FFP infusions. In addition, prostacyclin has been used to try to reverse some vasoconstriction where impending gangrene is seen in a ‘glove and stocking’ distribution. However, there is no clinical trial supporting its use and, when used in large doses, this agent may cause further hypotension [50,55]. Faced with a devastating illness, and the prospect of limb loss and death in young children, many clinicians have felt justified in attempting to utilize experimental treatments outside controlled trials. Purified inhibitors such as antithrombin, fibronectin, protein C or variants of α1-antitrypsin have been advocated by a number of authors [59,113–120], as have blockers of the initial phases of coagulation [121–123]. Others have suggested fibrinolytic agents [124]. Heparin has been promoted in the past as rational therapy for disseminated intravascular coagulation DIC [39,125,126]. However, the agent has failed to produce obvious benefit in a limited number of open clinical trials [40,127,128] and has been associated with uncontrolled bleeding. In recent years, understanding of the pathophysiology of the coagulation and inflammatory abnormalities has

55.11

led to a number of large randomized controlled trials of adjunctive agents in adult and childhood sepsis and in meningococcal disease. No survival or morbidity benefit has been demonstrated for most of these agents, including antithrombin [129], antiendotoxin monoclonal antibody [130] and recombinant bactericidal permeabilityincreasing protein [131]. Although previous trials of steroids in sepsis have been disappointing [132,133] and a very old study suggested a worse prognosis in meningococcaemia [134], more recent data have renewed interest in low-dose steroid therapy [135]. A phase III trial of recombinant activated protein C was shown to reduce the mortality in adult sepsis [136], although a recently completed phase III trial in childhood sepsis did not show similar benefit [137]. On the basis of small pharmacological series using unactivated protein C concentrate, some have advocated using this form of the drug [119,120,138]. However, it is currently not possible to predict which patients who have been administered protein C concentrate will be able to activate the drug [54,138]. Even when activated protein C is detectable in the plasma, there is evidence of an activation defect in the dermal vascular endothelium and a theoretical risk that unactivated protein C in excess may displace activated protein C at the endothelial protein C receptor and thus worsen dermal vessel thrombosis [54,139]. Finally, although the use of recombinant tPA to treat severe meningococcaemia has an apparently sound theoretical basis [61,63,64,80], in a retrospective European study of 62 children with meningococcal disease treated with tPA, 8% suffered serious intracerebral bleeding and its use cannot now be recommended [140]. The adverse clinical experience demonstrated in evaluating tPA and the lack of benefit of most of the other adjunctive therapies used to treat severe sepsis strongly reinforce the need for new or experimental agents to be introduced only after properly controlled randomized clinical trials.

Surgical intervention In the acute phase of fulminant meningococcaemia, surgical intervention has been attempted in the authors’ units to relieve compartment syndromes that may develop in severely affected limbs [141] (Fig. 55.13). Whilst this approach has had some success, the procedure requires further formalized evaluation. As discussed more fully in Chapter 162, surgical intervention to remove necrotic skin or amputate limbs or digits is generally not indicated during the acute phase of the disease. During recovery, surgery to repair damaged skin and extremities may be required in up to 72% of patients [142]. These procedures range from skin grafting and local debridement to microvascular flaps and amputations [142–144]. Multiple grafting procedures and scar revision may also be required [141,143–146] (see Fig. 55.13). Nutritional support and the

55.12

Chapter 55

were reported to have effective compensation strategies with a generally good quality of life [149]. However, others report considerable lasting effects on health and health-related quality of life 2 years following severe meningococcal sepsis [150].

(a)

(b) Fig. 55.13 Surgical intervention in meningococcal sepsis. (a) Fasciotomy following the development of a compartment syndrome in a child with purpura fulminans. (b) Extensive skin necrosis following meningococcal septicaemia requiring multiple grafting procedures.

avoidance of nosocomial wound infection are essential in the management of such patients [143]. Recently, a new microsurgical technique has been proposed to benefit outcome, but this remains to be tested in a larger study or reported from other centres [147].

Outcome of skin disease Recently, a large study from The Netherlands showed the incidence of long-term skin scarring to be 48% and of orthopaedic sequelae 14% in children surviving meningococcal sepsis. Although the severity of these sequelae varied, children with more severe scarring or who had suffered orthopaedic sequelae were demonstrated to have had more severe disease [148]. Despite such high morbidity, a group of UK children who had suffered amputation were studied from a daily living functions and quality of life perspective for 3–5 years following their disease. Importantly, the degree of amputation did not predict the functional outcome, and most children

Allergic complications Approximately 5 days after the presentation of acute meningococcal disease, between 1.7% and 4.7% of patients may develop a vasculitic rash that may be accompanied by arthritis or episcleritis [151,152]. Typically, the rash occurs either as a single lesion or as crops on the trunk, lower limbs, deltoid areas and dorsum of the hand. Often associated with persistence of fever, the lesions appear as darkened skin with a blistered edge, are slightly swollen, warm and tender. These progress to sterile bullae containing red cells and leucocytes, which ulcerate but usually heal quickly. A few patients develop tender warm nodules similar to Osler ’s nodes. Histologically, the dermal lesions appear oedematous and consist of dilated small blood vessels with polymorph and mononuclear infiltrates. Thrombosis, necrosis and haemorrhage may be seen in association with these changes and typically organisms are neither seen nor cultured. The epidermal changes range from hyperkeratosis to an intense mononuclear infiltration of the basal layer with overlying atrophy. Meningococcal antigen, anti-meningococcal antibody and complement (C3) have been demonstrated in the skin and synovium of these patients. Greenwood et al. [153] suggested that these skin lesions occur as a result of Arthus-like immune complex deposition. Prolonged antibiotic therapy offers no benefit to patients with this allergic phenomenon and the use of systemic corticosteroids has not been evaluated in controlled trials. Chronic meningococcaemia In addition to meningitis and fulminant septicaemia, occasional cases of meningococcal infection may present as chronic meningococcaemia, pneumonia, arthritis or ophthalmitis [154–156]. More common in teenagers and adults [154], chronic meningococcaemia has become a rare entity since the widespread use of antibiotics. Untreated, the disease was often self-limiting with a small mortality associated with supervening meningitis or endocarditis. Underlying immunological disorders, other chronic diseases or specific bacterial virulence factors have not been confirmed in the pathogenesis of this syndrome [154,157]. However, some have suggested that chronic infection may be caused by less virulent meningococci producing a milder host immune response [158]. Chronic meningococcaemia is an insidious disease, classically presenting with a low-grade fever lasting for at least 1 week, flitting arthralgias or, less commonly,

Skin Manifestations of Meningococcal Infection

arthritis [154,155]. The rash is recurrent and may be maculopapular, nodular or petechial. There is little systemic toxicity and no significant coagulopathy, and the presence of meningeal signs suggests that the disease has become fulminant [154,156]. Histology shows a perivascular infiltration of lymphocytes, macrophages and a few neutrophils. Vessel wall destruction has not been reported. Meningococci are rarely detected in the cutaneous lesions. Multiple blood cultures are required for the diagnosis of chronic meningococcaemia and may not be positive until between 2 and 8 weeks into the illness. Chronic meningococcaemia responds rapidly to systemic antibiotics and therefore should always be considered in the differential diagnosis of vasculitic disorders, particularly Henoch– Schönlein purpura, acute rheumatic fever and infective endocarditis [154,156].

Prevention Prevention of meningococcal disease is a major priority worldwide and remains the focus of an intense research effort. Until eradication of N. meningitidis has been achieved, prevention rests on chemoprophylaxis and the selective use of vaccines. At present, recommendations are that household members and hospital workers who have come into close contact with secretions and the index case (unless already treated with ceftriaxone) should receive 2-day rifampicin or single-dose ciprofloxacin [159] chemoprophylaxis [24,83,160]. In the UK, routine prophylaxis for day nursery contacts is not recommended. It is important to recognize that eradication of the meningococcus is not always successful and that recolonization of the nasopharynx may occur after initial clearance. Single-dose intramuscular ceftriaxone or oral ciprofloxacin have proved very effective in adults and children but require further evaluation [159,161,162]. In cases due to vaccine-preventable strains, chemoprophylaxis should be followed by vaccination where possible. Bivalent (A and C) and tetravalent (A, C, W135, Y) polysaccharide vaccines have been shown to be both safe and effective in containing small outbreaks and more widespread epidemics of meningococcal disease [163]. However, the immunological response to these polysaccharides does not provide complete protection for all age groups, and does not induce immunological memory (immunity lasts for a maximum of 3 years). Following the outstanding successes of the H. influenzae type b vaccine [164,165], a conjugate vaccine against the group C meningococcus has been introduced successfully in the UK and in other European countries [27,28,166–168]. Quadravalent conjugate ACW135Y vaccines have been licensed for use in the USA and Europe [169], and promising new vaccines against group B meningococcal subcapsular antigens are currently undergoing late phase clinical trials [170].

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125 Colman RW, Robboy SJ, Minna JD. Disseminated intravascular coagulation (DIC): an approach. Am J Med 1972;52(5):679–89. 126 Corrigan JJ, Ray WL, May N. Changes in the blood coagulation system associated with septicemia. N Engl J Med 1968(279):851–6. 127 Gerard P, Moriau M, Bachy A, Malvaux P, de Meyer R. Meningococcal purpura: report of 19 patients treated with heparin. J Pediatr 1973;82(5):780–6. 128 Ockelford P. Heparin 1986. Indications and effective use. Drugs 1986;31(1):81–92. 129 Warren BL, Eid A, Singer P et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286(15):1869–78. 130 Derkx B, Wittes J, McCloskey R. Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. European Pediatric Meningococcal Septic Shock Trial Study Group. Clin Infect Dis 1999;28(4):770–7. 131 Levin M, Quint PA, Goldstein B et al. Recombinant bactericidal/ permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet 2000;356(9234):961–7. 132 Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987(317):653–8. 133 Jafari HS, McCracken GH Jr. Sepsis and septic shock: a review for clinicians. Pediatr Infect Dis J 1992;11(9):739–48. 134 Margaretten W, McAdams AJ. An appraisal of fulminant meningococcemia with reference to the Schwartzman phenomenon. Am J Med 1958;25:868–76. 135 Annane D, Sebille V, Charpentier C et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7):862–71. 136 Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344(10):699–709. 137 Nadel S, Goldstein B, Williams MD et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007;369(9564):836–43. 138 De Kleijn ED, de Groot R, Hack CE et al. Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study. Crit Care Med 2003;31(6):1839–47. 139 Bernard G, Artigas A, Dellinger P et al. Clinical expert round table discussion (session 3) at the Margaux Conference on Critical Illness: the role of activated protein C in severe sepsis. Crit Care Med 2001;29(7 suppl):S75–7. 140 Zenz W, Zöhrer B, Faust SN et al. (eds). Use of tissue plasminogen activator (t-PA) in children with fulminant meningococcaemia. Royal College of Paediatrics and Child Health Annual Meeting, 2001, York, UK. London: Royal College of Paediatrics and Child Health. 141 Hunt DM. The orthopaedic management of purpura fulminans in meningococcal disease in children. Care Crit Ill 2001;17(4): 118–20. 142 Herrera R, Hobar PC, Ginsburg CM. Surgical intervention for the complications of meningococcal-induced purpura fulminans. Pediatr Infect Dis J 1994;13(8):734–7. 143 Hudson DA, Goddard EA, Millar KN. The management of skin infarction after meningococcal septicaemia in children. Br J Plast Surg 1993;46(3):243–6. 144 Harris NJ, Gosh M. Skin and extremity loss in meningococcal septicaemia treated in a burn unit. Burns 1994;20(5):471–2.

Skin Manifestations of Meningococcal Infection 145 Arevalo JM, Lorente JA, Fonseca R. Surgical treatment of extensive skin necrosis secondary to purpura fulminans in a patient with meningococcal sepsis. Burns 1998;24(3):272–4. 146 Huang DB, Price M, Pokorny J, Gabriel KR, Lynch R, Paletta CE. Reconstructive surgery in children after meningococcal purpura fulminans. J Pediatr Surg 1999;34(4):595–601. 147 Boeckx WD, Nanhekhan L, Vos GD, Leroy P, van den Kerckhove E. Minimizing limb amputations in meningococcal sepsis by early microsurgical arteriolysis. J Pediatr Surg 2009;44(8):1625–30. 148 Buysse CM, Oranje AP, Zuidema E et al. Long-term skin scarring and orthopaedic sequelae in survivors of meningococcal septic shock. Arch Dis Child 2009;94(5):381–6. 149 Allport T, Read L, Nadel S, Levin M. Critical illness and amputation in meningococcal septicemia: is life worth saving? Pediatrics 2008;122(3):629–32. 150 Buysse CM, Raat H, Hazelzet JA, Hop WC, Maliepaard M, Joosten KF. Surviving meningococcal septic shock: health consequences and quality of life in children and their parents up to 2 years after pediatric intensive care unit discharge. Crit Care Med 2008;36(2): 596–602. 151 Whittle HC, Abdullahi MT, Fakunle FA et al. Allergic complications of meningococcal disease. I. Clinical aspects. BMJ 1973;2(869): 733–7. 152 Edwards MS, Baker CJ. Complications and sequelae of meningococcal infections in children. J Pediatr 1981;99(4):540–5. 153 Greenwood BM, Whittle HC, Bryceson AD. Allergic complications of meningococcal disease. II. Immunological investigations. BMJ 1973;2(869):737–40. 154 Benoit FL. Chronic meningococcemia. Am J Med Sci 1963;206: 566–76. 155 Applebaum E. Chronic meningococcus septicaemia. Am J Med 1937;193:96–108. 156 Leibel RL, Fangman JJ, Ostrovsky MC. Chronic meningococcemia in childhood. Case report and review of the literature. Am J Dis Child 1974;127(1):94–8. 157 Nielsen HE, Koch C, Mansa B, Magnussen P, Bergmann OJ. Complement and immunoglobulin studies in 15 cases of chronic meningococcemia: properdin deficiency and hypoimmunoglobulinemia. Scand J Infect Dis 1990;22(1):31–6. 158 Prins JM, Lauw FN, Derkx BH et al. Endotoxin release and cytokine production in acute and chronic meningococcaemia. Clin Exp Immunol 1998;114(2):215–19.

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159 Visakorpi R. Ciprofloxacin in meningococcal carriers. Scand J Infect Dis 1989;60(suppl):108–11. 160 Pollard AJ, Begg N. Meningococcal disease and healthcare workers. The risks to healthcare workers are very low. BMJ 1999;319(7218):1147–8. 161 Cuevas LE, Kazembe P, Mughogho GK, Tillotson GS, Hart CA. Eradication of nasopharyngeal carriage of Neisseria meningitidis in children and adults in rural Africa: a comparison of ciprofloxacin and rifampicin. J Infect Dis 1995;171(3):728–31. 162 Schwartz B, Al-Tobaiqi A, Al-Ruwais A et al. Comparative efficacy of ceftriaxone and rifampicin in eradicating pharyngeal carriage of group A Neisseria meningitidis. Lancet 1988;1(8597):1239–42. 163 Frasch CE. Meningococcal vaccine: past, present and future. In: Cartwright K (ed) Meningococcal Disease. Chichester: John Wiley, 1995: 246–83. 164 Shinefield HR, Black S. Postlicensure surveillance for Haemophilus influenzae type b invasive disease after use of Haemophilus influenzae type b oligosaccharide CRM197 conjugate vaccine in a large defined United States population: a four-year eight-month follow-up. Pediatr Infect Dis J 1995;14(11):978–81. 165 Hargreaves RM, Slack MP, Howard AJ, Anderson E, Ramsay ME. Changing patterns of invasive Haemophilus influenzae disease in England and Wales after introduction of the Hib vaccination programme. BMJ 1996;312(7024):160–1. 166 Bose A, Coen P, Tully J, Viner R, Booy R. Effectiveness of meningococcal C conjugate vaccine in teenagers in England. Lancet 2003;361(9358):675–6. 167 Lakshman R, Jones I, Walker D et al. Safety of a new conjugate meningococcal C vaccine in infants. Arch Dis Child 2001;85(5):391–7. 168 Salleras L, Dominguez A, Cardenosa N. Impact of mass vaccination with polysaccharide conjugate vaccine against serogroup C meningococcal disease in Spain. Vaccine 2003;21(7–8):725–8. 169 Pollard AJ, Perrett KP, Beverley PC. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat Rev Immunol 2009 Mar;9(3):213–20. 170 Sadarangani M, Pollard AJ. Serogroup B meningococcal vaccines— an unfinished story. Lancet Infect Dis 2010 Feb;10(2):112–24.

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C H A P T E R 56

Pitted Keratolysis, Erythrasma and Erysipeloid Anita P. Sheth Division of Pediatric Dermatology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

Pitted keratolysis, 56.1

Erythrasma, 56.3

Pitted keratolysis Definition. Pitted keratolysis is a superficial infection of the skin that is most commonly caused by a Corynebacterium species. It is characterized by circular, shallow erosions, primarily on the soles. Aetiology and pathogenesis. The circular erosions are thought to be due to the invasion of the softened keratin by the causative organism. Multiple organisms have been isolated from these lesions, including various species of Streptomyces, Dermatophilus congolensis and Micrococcus sedentarius [1–5]. Zaias et al. [6] identified a Corynebacterium as an aetiological agent and also experimentally reproduced the condition by inoculating the organism into the soles of normal volunteers. Lesions of pitted keratolysis have also been reproduced by applying M. sedentarius under an occlusive dressing on the heel and in 53% of 387 volunteers whose feet were continuously wet for 3 days [2,3]. History. Castellani [7] first reported this condition from Sri Lanka in 1910 and termed it ‘keratoma plantare sulcatum’. Although initially thought to be a condition found only in tropical climates, it has also been described in temperate zones. The term ‘pitted keratolysis’ was coined by Zaias et al. [6] in 1965 and is universally accepted. Pathology. Histological examination of a lesion will show multiple superficial erosions confined to the upper layers of the stratum corneum. These shallow, crater-like defects have sharply inclined walls and a flat base consisting of a thin layer of stratum corneum. Numerous branching, filamentous bacterial forms can be seen confined to

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Erysipeloid, 56.4

these erosions. The ultrastructure of pitted keratolysis has been characterized by transmission and scanning electron microscopy, which has revealed ‘tunnel openings’ of the floor of the crateriform pits where bacteria reside. Bacterial colonies with tunnels without keratin loss have also been observed in normal-appearing plantar skin [8]. The organisms can be observed in tissue sections stained with haematoxylin and eosin or special stains such as silver methenamine. A sparse, superficial perivascular lymphocytic infiltrate may be noted in the dermis [3,6,9]. Clinical features. Pitted keratolysis occurs in both sexes and in most age groups. Multiple circular, discrete and coalescing superficial erosions are seen on the soles and undersurface of the toes (Fig. 56.1). The lesions are more common on the weight-bearing surfaces such as the toes, balls of the feet and the heels. However, involvement of non-weight-bearing areas has been described recently. The areas involved were the instep of the foot and dorsal aspect of the toes [10]. Palmar involvement can rarely occur and is seen more commonly in the tropics. On the palms, the lesions may present as scaly collarettes instead of pits [9,11]. A case of pitted keratolysis on the palm arising after herpes zoster infection has been described. This individual had postherpetic neuralgia of the affected, left hand and presented with asymptomatic pits and a foul odour on her left palm [12]. The lesions of pitted keratolysis are more apparent after soaking the involved areas in water for a short period of time. Hyperhidrosis and malodour are often present and maceration may be an associated feature. In one review of 53 patients with pitted keratolysis, hyperhidrosis was present in 51 patients (96.2%) and malodour in 47 patients (88.7%) [13]. A mixture of thiols, sulphides and thio-esters has been shown to be the cause of the unpleasant odour [2]. Yellowish-brown discoloration of involved skin has been reported [14]. Although most cases are symptom free, painful lesions have been described in children [9,15] (Fig. 56.2). In the

56.2

Chapter 56

Fig. 56.1 Pitted keratolysis in an adolescent girl.

painful variant, erythematous to violaceous tender plaques are often present in addition to the typical pitted lesions. There is no evidence for deeper invasion into the stratum corneum by the bacterium in these symptomatic cases. Therefore, the exact reason for the pain in some patients is not known. Predisposing factors for painful lesions include occlusive footwear such as tennis shoes made of synthetic materials and prolonged exposure to moisture. The organism may be rarely seen on a potassium hydroxide preparation but is more easily demonstrated on Gram-stained scrapings or thin tissue sections [14]. The organism can be cultured on appropriate medium if specific identification is desired, but this is usually not necessary. Prognosis. The condition is rapidly responsive to an adjustment in the contributing environmental factors (prolonged exposure to moisture, occlusive footwear and hyperhidrosis), various topical preparations and systemic antibiotics. Differential diagnosis. The characteristic clinical presentation is easily recognized and diagnosed but isolated hyperhidrosis and tinea pedis (dermatophyte) infection must be considered as a cause of maceration and bromhidrosis. Pitting associated with the basal cell naevus syndrome can be distinguished by the presence of other specific clinical features seen in this syndrome. Treatment. Therapy for pitted keratolysis is simple and efficacious. Although, in the past, various treatments

Fig. 56.2 Large area of pitted keratolysis on the lateral sole in an adolescent boy. Smaller, more typical lesions, are seen near the heel of the foot. Courtesy of Dr Neil Prose.

(20% aluminium chloride, formalin ointment, various topical antibiotics and imidazoles) were used with some success, topical antibiotics such as erythromycin and clindamycin are safe and rapidly effective and should be the first line of treatment. Mupirocin ointment has been found to be effective when conventional therapy has failed [16], but its use should be restricted to elimination of MRSA carriership. Systemic treatment with erythromycin has been successful. The painful variant also responds well to these therapies [9,11,15,17]. Therapy should also include an effort to reduce predisposing factors such as hyperhidrosis, frequent and prolonged contact with water and wearing of occlusive footwear. References 1 Acton HW, McGuire C. Keratolysis plantare sulcatum; lesion due to actinomycetic fungus. Ind Med Gaz 1930;65:61–5. 2 Nordstrom KM, McGinley KS, Cappiello L et al. Pitted keratolysis: the role of Micrococcus sedentarius. Arch Dermatol 1987;123:1320–5. 3 Gill KA, Buckels LJ. Pitted keratolysis. Arch Dermatol 1968;98:7–11. 4 Gillum RL, Qadri SM, Al-Ahdal MN et al. Pitted keratolysis: a manifestation of human dermatophilosis. Dermatologica 1988;177:305–8. 5 Woodgyer AJ, Baxter M, Rush-Munro FM et al. Isolation of Dermatophilus congolensis from two New Zealand cases of pitted keratolysis. Australas J Dermatol 1985;26:29–35. 6 Zaias N, Taplin D, Rebell G. Pitted keratolysis. Arch Dermatol 1965;92:151–4.

Pitted Keratolysis, Erythrasma and Erysipeloid 7 Castellani A. Keratoma plantare sulcatum. J Ceylon Br Med Assoc 1920;1:12–14. 8 De Almeida HL Jr, de Castro LA, Rocha NE et al. Ultrastructure of pitted keratolysis. Int J Dermatol 2000;39:698–701. 9 Shah AS, Kamino H, Prose NS. Painful, plaque-like pitted keratolysis occurring in childhood. Pediatr Dermatol 1992;9:251–4. 10 Takama H, Tamada Y, Yokochi K et al. Pitted keratolysis: a discussion of two cases in non-weight-bearing areas. Acta Dermatol Venereol 1998;78:225–6. 11 Zaias N. Pitted and ringed keratolysis: a review and update. J Am Acad Dermatol 1982;7:787–91. 12 Lee HJ, Roh KY, Ha SJ et al. Pitted keratolysis of the palm arising after herpes zoster. Br J Dermatol 1999;140:974–5. 13 Takama H, Tamada Y, Yano K et al. Pitted keratolysis: clinical manifestations in 53 cases. Br J Dermatol 1997;137:282–5. 14 Sehgal VN, Ramesh V. Crateriform depression – an unusual clinical expression of pitted keratolysis. Dermatologica 1983;166:209–11. 15 Lamberg SI. Symptomatic pitted keratolysis. Arch Dermatol 1969;100:10–11. 16 Vazquez-Lopez F, Perez-Oliva N. Mupirocine ointment for symptomatic pitted keratolysis. Infection 1996;24:55. 17 Burkhart CG. Pitted keratolysis: a new form of treatment [letter]. Arch Dermatol 1980;116:1104.

56.3

bacterium species, C. afermentans, was the only organism isolated from the skin of an individual with disseminated erythrasma involving the abdomen, arms, thighs, legs, neck and back, as well as the axillae and groin [5]. Pathology. On histological examination, corynebacteria are seen in the horny layer in small amounts as Gram-positive rods and filaments. Electron microscopic examination of thin-sectioned skin from patients with erythrasma has also demonstrated ‘diphtheroids’ in the horny layer [6]. Skin biopsy is rarely performed to diagnose erythrasma as the diagnosis is easily made by Wood’s light examination.

History. Before 1960, the aetiological agent of erythrasma was presumed to be a fungal organism. Lagana first indicated that a diphtheroid bacterium isolated from an erythrasma lesion was the cause of this condition. In 1961, Sarkany et al. [1] confirmed that C. minutissimum was the cause of erythrasma.

Clinical features. Erythrasma occurs in all age groups and both sexes and the incidence increases with age. It is uncommon in the general paediatric population, although the incidence is notably higher among institutionalized children and children in boarding school as well as people living a communal lifestyle [4]. Erythrasma occurs most commonly in moist, occluded, intertriginous areas that favour the growth of C. minutissimum. The common locations for erythrasma are the axillae, groin, toe webs, intergluteal and crural folds and inframammary areas. However, disciform erythrasma, a more generalized form, occurs in non-intertriginous areas as well as intertriginous areas and is more commonly seen in the tropics [7]. The characteristic skin lesions are well-demarcated, irregular, reddish-brown scaly patches (Fig. 56.3). However, in the toe webs, maceration is most commonly seen. Mild, subclinical cases are not uncommon and are diagnosed only by the typical fluorescence on Wood’s light examination. Lesions of disciform erythrasma may have shiny, atrophic-appearing surfaces and may resemble lesions of parapsoriasis en plaque or lichen sclerosis

Aetiology and pathogenesis. A warm humid climate is believed to be a predisposing factor for erythrasma and therefore more extensive involvement is seen in the tropics and during the hot summer months. The incidence of the disease is also higher among diabetic subjects [2,3]. Hyperhidrosis, obesity, advanced age and compromised host status are additional risk factors. Poor hygiene has historically been thought to be a predisposing factor, but Somerville et al. [4] found the incidence to be unaffected by the state of personal cleanliness, the use of deodorants and antibacterial soaps. Because C. minutissimum, the bacterium most commonly implicated in erythrasma, has been grown from normal human skin flora, it seems probable that some local or systemic alteration must occur before this normal bacterium can act as a pathogen. The exact nature of these alterations has not been elucidated. An unusual Coryne-

Fig. 56.3 Erythrasma. Well-demarcated scaly plaque in axilla. Courtesy of Dr Samuel Bean.

Erythrasma Definition. Erythrasma is a mild chronic superficial infection of the skin resembling dermatophyte infection. It is caused by Corynebacterium minutissimum. The skin lesions show a characteristic ‘coral-red’ fluorescence when viewed under a Wood’s light.

56.4

Chapter 56

et atrophicus [7]. Vesiculobullous lesions have been described [8]. Gentle scraping of the lesions may yield scale that can be stained with methylene blue or Gram stains and examined under an oil immersion lens. Coccoid and rod-like organisms with long filaments will be seen. Cultures of skin swabs or skin scrapings from involved areas may be helpful [9,10] but are not routinely undertaken. Skin biopsy is rarely indicated but may be performed when the lesions are atypical in morphology and distribution, as may be seen with disciform erythrasma. Prognosis. Erythrasma responds quickly to treatment with a variety of topical preparations and to topical and systemic antibiotics. The subclinical form may remain asymptomatic for years or undergo periodic exacerbation. Relapses may occur even after successful treatment. Differential diagnosis. Erythrasma must be distinguished from tinea corporis. The interdigital variety may mimic tinea pedis or other bacterial infection. A potassium hydroxide stain and Wood’s light examination are valuable in differentiating these entities, but both entities may be present simultaneously [11]. The disciform type may be confused with lichen sclerosis et atrophicus, plaque-type parapsoriasis or tinea versicolor [12]. Treatment. Although, historically, various topical treatments have been used for erythrasma, currently topical and/or systemic antibiotics are most commonly used and are very effective [9]. Topical erythromycin, clindamycin and tetracycline have all been used successfully [13]. In most cases, oral erythromycin taken for 7 days is curative. A single 1 g dose of clarithromycin has been reported to be effective for the treatment of erythrasma [14]. A combination of topical and oral therapy may prove beneficial in severe cases [7].

References 1 Sarkany I, Taplin D, Blank H. The etiology and treatment of erythrasma. J Invest Dermatol 1961;37:283–90. 2 Henslee TM, Tanaka TJ, Hodson SB et al. Interdigital erythrasma: an incidence study. J Am Podiatr Med Assoc 1988;78:559–62. 3 Montes LF, Dobson H, Dodge BG et al. Erythrasma and diabetes mellitus. Arch Dermatol 1969;99:674–80. 4 Somerville DA, Seville RH, Cunningham RC et al. Erythrasma in a hospital for the mentally subnormal. Br J Dermatol 1970;82:355–60. 5 Dellion S, Morel P, Vignon-Pennamen D et al. Erythrasma owing to an unusual pathogen. Arch Dermatol 1996;132:716–17. 6 Montes LF, Black SH. The fine structure of diphtheroids of erythrasma. J Invest Dermatol 1967;48:342–51. 7 Tchen JA, Ramsdell WM. Disciform erythrasma. Cutis 1983;31:541–7. 8 Grigoriu D, Delacrétaz J. La forme vesiculo-bulleuse de l’érythrasma interdigito-plantaire. Dermatologica 1976;152:1–7.

9 Sindhuphak W, MacDonald E, Smith EB. Erythrasma. Overlooked or misdiagnosed? Int J Dermatol 1985;24:95–6. 10 Bowyer A, McColl I. Erythrasma and pruritus ani. Acta Dermatol Venereol 1971;51:444–7. 11 Schlappner OL, Rosenblum GA, Rowden G. Concomitant erythrasma and dermatophytosis of the groin. Br J Dermatol 1979;100:147–51. 12 Gorani A, Oriani A, Falconi Klein E et al. Erythrasmoid pityriasis versicolor. Mycoses 2001;44:516–17. 13 Cochran RJ, Rosen T, Landers T. Topical treatment of erythrasma. Int J Dermatol 1981;20:562–4. 14 Wharton JR, Wilson PL, Kincannon JM. Erythrasma treated with single-dose clarithromycin. Arch Dermatol 1998;134:672.

Erysipeloid Definition. Erysipeloid is an acute skin infection caused by Erysipelothrix rhusiopathiae. It occurs primarily in individuals who handle animals and animal products, especially fish, shellfish, meat and poultry. History. Erysipeloid infection has been recognized since the late 1800s. It was initially described by Fox in 1873. A multitude of terms, including erythema serpens, erythema migrans, erysipelas chronicum, crab cellulitis and swine erysipelas, had been used to describe the condition prior to the identification of the infectious organism [1–3]. The term ‘erysipeloid’ was coined in 1887 by Rosenbach, who recognized that there was a common causative agent for these various entities, the bacillus Erysipelothrix rhusiopathiae [4]. Aetiology and pathogenesis. Erysipeloid is most commonly seen as a skin and soft tissue infection in fishermen and meat handlers but can occur in anyone coming into contact with the appropriate infectious material. Poultry, fish, crab and swine are most frequently infected with E. rhusiopathiae (formerly known as Erysipelothrix insidiosa), but the organism has been found to cause infection in several dozen species of mammals and other animals. Direct contact with infected animals or animal products is the most significant mode of transmission. A rare case of presumed systemic infection due to eating infected meat has been reported [5]. It has also been reported to occur in a surgical wound in a patient without known exposure to animals [6]. In some instances, the source of infection is an enigma [7,8]. The Erysipelothrix organism is a facultatively anaerobic, non-motile, non-encapsulated, non-sporulating Grampositive rod. It is ubiquitous in nature, being found wherever nitrogenous substances decompose. The organism remains viable and virulent for months in putrid, decomposing material and survives smoking, pickling and salting for prolonged periods. Exposure to moist heat at 55°C for 15 min is usually bactericidal [9].

Pitted Keratolysis, Erythrasma and Erysipeloid

56.5

Pathology. Skin biopsy reveals varying degrees of spongiosis and intraepidermal vesiculation. The papillary dermis shows oedema, lymphangitis and capillary engorgement. A polymorphous infiltrate of neutrophils, lymphocytes, eosinophils and plasma cells is seen in the dermis. Gram staining of tissue sections usually does not demonstrate the organism [3]. Clinical features. Erysipeloid occurs predominantly in fishermen, butchers, farmers, veterinarians and homemakers. An increased incidence of infection is noted in the summer and early autumn. Occurrence in adolescents is usually associated with the individual being engaged in an occupation with a high risk of exposure to E. rhusiopathiae [10]. Erysipeloid and Erysipelothrix infection has been reported in a 7-week-old infant and a 6-year-old child, but this is uncommon. Both of these cases had some degree of systemic involvement [7,8]. The source of infection in these cases was not determined, but it was suggested that a possible source of infection was food contaminated by an animal which was excreting these organisms. Systemic infection with endocarditis has been reported in children [9,11]. There are three clinical presentations of E. rhusiopathiae infections in humans: a localized cutaneous form; a diffuse cutaneous type; and a systemic form with or without cutaneous lesions and often with endocarditis. Systemic disease with cerebral abscess formation, arthritis and empyemas has also been reported [7,9,11]. The most common form of infection is the localized cutaneous type. The onset of the skin lesion is 2–7 days after inoculation. Inoculation of the organism commonly occurs through an area of minor skin trauma.Typically, a glistening violaceous or purplish-red plaque with welldemarcated, raised borders is seen on the hands (Fig. 56.4). However, lesions can occur elsewhere and have been reported on the sole and neck. The initial lesion typically expands peripherally with clearing of the centre. Vesicles and bullae may be present. The hand and fingers can swell and become stiff, causing tenderness and limited motion. Arthritis of underlying and adjacent joints may occur. Symptoms include pain, itching and local burning. Lymphangitis and regional lymphadenopathy are seen in 20–30% of patients. Other constitutional symptoms such as fever and malaise occur infrequently [4,12]. This localized form of the disease is usually selflimited and may resolve spontaneously. However, therapy with penicillin is curative in 7 days. Prior to penicillin therapy, relapses were sometimes seen from 4 days to 2 weeks after the lesion had completely resolved [4,12]. The diffuse cutaneous form of the disease usually manifests with violaceous lesions on multiple areas of the body. The lesions are characterized by a variable advanc-

(a)

(b) Fig. 56.4 Erysipeloid in a 16-year-old boy employed in a fish market. Courtesy of Dr Ilona Frieden.

ing pink border and have central resolution. Constitutional symptoms are usually present, but blood cultures are negative. This form of the disease is also self-limited, but long-term disease has been documented. In the systemic form of E. rhusiopathiae infection, blood cultures are usually positive and patients are quite ill with prominent constitutional symptoms. Clinical manifestations include septic arthritis, osseous necrosis, cerebral infarction or abscess, pulmonary effusion and, most commonly, bacterial endocarditis. Skin lesions can also be seen and they have varied from a localized swelling with raised edges around the central necrotic areas to a generalized purpuric and petechial eruption simulating meningococcaemia.

56.6

Chapter 56

The organism is rarely demonstrable by Gram staining and is difficult to culture. Attempts to culture the organism from small amounts of serum from the wound or aspirated material are usually unsuccessful. In contrast, culture of a skin biopsy specimen is more likely to demonstrate the organism. It has been proposed that conversion of the bacteria to a cell wall-deficient ‘L’ form may be responsible for the difficulty in identifying the bacteria by Gram staining or culturing. This ability to convert back and forth from this ‘L’ form morphology may also confer antibiotic resistance to cell wall-active antibiotics and contribute to recurrent disease [3]. Prognosis. Patients with the localized cutaneous form and diffuse cutaneous type have a self-limited course with disease resolution. When systemic infection occurs, morbidity and mortality are greatly increased, especially in those who manifest endocarditis. Differential diagnosis. As indicated by the name, erysipeloid can clinically mimic erysipelas and may therefore be mistaken for a cutaneous streptococcal infection. Erysipelas more commonly occurs on the face and lower extremity and is more likely to be associated with constitutional symptoms. Culturing a skin biopsy specimen may prove useful. Other infectious cellulitides need to be differentiated from erysipeloid. Because of the tendency to form annular lesions, erythema chronicum migrans (ECM) may infrequently be confused with erysipeloid lesions. These lesions are more commonly seen on the trunk and proximal extremities and are often asymptomatic. Treatment. Although many therapeutic modalities have been tried in the treatment of erysipeloid, systemic antibiotics are most effective. Penicillin is the antibiotic of choice. Doses and treatment regimens have varied [3]. Cure has also been achieved with oral erythromycin [6]. E. rhusiopathiae has been reported to be sensitive in vitro to clindamycin, lincomycin, erythromycin and cephalosporin. Incision and drainage of skin lesions is contrain-

dicated because surgery has been noted to prolong the duration of erysipeloid lesions [13]. Cases of endocarditis due to E. rhusiopathiae have been successfully treated with IV penicillin G. E. rhusiopathiae is resistant to vancomycin, which is often used as empirical therapy for presumed endocarditis. It is therefore important to differentiate E. rhusiopathiae from other Gram-positive organisms to avoid delays in the initiation of appropriate antibiotic therapy [14]. Although in many instances the cutaneous forms of the disease run a self-limited course, all patients should receive antibiotics to prevent progression to systemic disease and endocarditis. References 1 Gilchrist TC. Erysipeloid with a record of 329 cases of which 323 were caused by crab bites or lesion produced by crabs. J Cutan Dis 1904;22:507–19. 2 Klauder JV, Righter LL, Harkins MJ. A distinctive and severe form of erysipeloid among fish handlers. Arch Dermatol 1926;14:667–78. 3 Barnett JH, Estes SA, Wirman JA et al. Erysipeloid. J Am Acad Dermatol 1983;9:116–23. 4 Klauder JV. Erysipeloid and swine erysipelas in man. JAMA 1926;86:536–42. 5 Woodbine M. Erysipelothrix rhusiopathiae bacteriology and chemotherapy. Bacteriol Rev 1950;14:161–78. 6 Ary KR, Maxwell JR, Printz DW. Erysipeloid of Rosenbach: a postoperative complication. J Am Podiatr Med Assoc 1981;71:40–1. 7 Panhotra BR, Agarwal KC, Kumar L et al. Erysipelothrix rhusiopathiae infection in a child (a case report with review of literature). Indian Pediatr 1979;16:547–9. 8 Lacroix J, Delage G, Mitchell G. Erysipeloid in an infant. J Pediatr 1981;99:745–6. 9 Grieco MH, Sheldon C. Erysipelothrix rhusiopathiae. Ann N Y Acad Sci 1970;174:523–31. 10 King PF. Erysipeloid: survey of 115 cases. Lancet 1946;2:196–8. 11 Gorby GL, Peacock JE. Erysipelothrix rhusiopathiae endocarditis: microbiologic, epidemiologic and clinical features of an occupational disease. Rev Infect Dis 1988;10:317–25. 12 Nelson E. Five hundred cases of erysipeloid. Rocky Mountain Med J 1955;52:40–2. 13 Lamphier TA. Erysipeloid infection of digits. J Fla Med Assoc 1971;58:39–41. 14 Venditti M, Gelfusa V, Tarasi A. Antimicrobial susceptibilities of Erysipelothrix rhusiopathiae. Antimicrob Agents Chemother 1990;34:2038–40.

57.1

C H A P T E R 57

Mycobacterial Infections of the Skin Lisa McNally1, Huda Al-Ansari2 & Vas Novelli3 1

Nelson R. Mandela School of Medicine, University of Kurazulu, Durban, South Africa Department of Paediatrics, Salmaniya Hospital, Bahrain 3 Great Ormond Street Hospital for Children NHS Trust, London, UK 2

Introduction, 57.1 Cutaneous tuberculosis, 57.2

Non-tuberculous mycobacterial infections, 57.5

Introduction Human disease due to mycobacteria is a major cause of mortality and morbidity worldwide. In 1993, the World Health Organization (WHO) declared tuberculosis a global emergency after it became clear that there was a major resurgence of the disease. It is estimated that onethird of the world’s population is infected with tuberculosis, with around 5–10% manifesting disease. Each year worldwide there are an estimated 9 million new cases with around 2 million deaths, the vast majority occurring in resource-poor countries [1,2]. The reasons for the increased incidence of tuberculosis, which has also occurred in resource-rich countries, include deteriorating socioeconomic conditions, with rising poverty and homelessness, breakdown of tuberculosis control programmes, the human immunodeficiency virus (HIV) epidemic and the emergence of multidrug-resistant tuberculosis [3]. Infection with HIV has been estimated to account for an excess of 34% of new cases of tuberculosis in sub-Saharan Africa [4]. Other species of mycobacteria, other than Mycobacterium tuberculosis, may cause human disease. These are often referred to as atypical mycobacteria. They are ubiquitous in nature and although they tend to cause major problems in patients with chronic lung disease and immunodeficiency states (especially HIV), infection may also occur in patients without predisposing conditions [5]. Mycobacteria belong to the genus Mycobacterium and are aerobic, non-motile, non-spore-forming, pleomorphic rods (1–5 μm long) that contain, as a major constituent, lipid substances called mycolic acids. Each different species of mycobacteria has a distinct mycolic acid distribution. It is these fatty acids and other lipids in the cell wall that are responsible for the acid-fastness [6]. There are more than 50 species of Mycobacterium, of which about Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

one-half are recognized as human pathogens. A classification scheme for the various mycobacteria (excluding M. tuberculosis and M. bovis) was originally proposed by Runyon [7]; he sought to group them according to their speed of growth and whether they produced any pigment. He described three groups of slow growers and one group of rapid growers: 1 Organisms from group I produce pigment only in the light (photochromogens), e.g. M. marinum, M. kansasii. 2 Organisms from group II produce pigment in the absence of light (scotochromogens), e.g. M. scrofulaceum. 3 Organisms from group III produce no pigment (nonphotochromogens), e.g. M. avium-intracellulare and M. ulcerans. 4 Group IV are termed rapid growers as colony maturation occurs in 1 week, e.g. M. fortuitum and M. chelonae. An updated Runyon classification of mycobacteria is shown in Table 57.1, with the tuberculosis group included [8]. References 1 Dyer C. Global epidemiology of tuberculosis. Lancet 2006;367: 938–40. 2 WHO. Global Tuberculosis Control. Geneva: World Health Organization, 2001. 3 Inselman LS. Tuberculosis in children: an update. Pediatr Pulmonol 1996;21:101–20. 4 Corbett EL, Watt CJ, Walker N et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009–21. 5 Cross JT Jr, Jacobs JF. Other mycobacteria. In: Feigin RD, Cherry JD, Demmler G, Kaplan SL (eds) Textbook of Pediatric Infectious Diseases, 5th edn. Philadelphia: W.B. Saunders, 2004:1379–90. 6 Starke JR, Jacobs RF. Mycobacterium tuberculosis. In: Long SS, Pickering LK, Prober CG (eds) Principles and Practice of Pediatric Infectious Diseases. 3rd edn. Philadelphia: Churchill Livingstone, 2008:770–88. 7 Runyon EH. Pathogenic mycobacteria. Adv Tuberc Res 1965;14: 235–87. 8 Starke JR. Non-tuberculous mycobacterial infections in children. Adv Pediatr Infect Dis 1992;7:123–59.

57.2

Chapter 57

Non-pathogens /rare pathogens

3 Cutaneous tuberculosis arising from a haematogenous source: (a) miliary form (papulonecrotic tuberculids); (b) subcutaneous abscesses; or (c) lupus vulgaris. 4 Erythema nodosum.

M. marinum M. kansasii M. simiae

M. asiaticum

Inoculation cutaneous tuberculosis from an exogenous source

Group II (scotochromogens)

M. scrofulaceum M. szulgai M. xenopi

M. gordonae M. flavescens M. thermoresistibile

Group III (nonphotochromogens)

M. M. M. M. M. M.

M. M. M. M.

Group IV (rapid growers)

M. fortuitum M. chelonae M. abscessus

Table 57.1 Updated Runyon classification for mycobacteria. Group

Common human pathogens

Tuberculosis

M. tuberculosis M. bovis M. africanum

Group I (photochromogens)

avium intracellulare malmoense haemophilum shimoidei ulcerans

terrae triviale gastri non-chromogenicum

M. smegmatis M. phlei M. vaccae

Cutaneous tuberculosis Although tuberculous involvement of the skin may occur at any stage of the natural history of the infection, cutaneous tuberculosis is rare. First described in 1826 by Laennec, who recognized his own ‘prosector ’s wart’, it is estimated that fewer than 3% of children with tuberculosis manifest skin lesions [1]. The skin can become infected with tuberculosis as an extension of disease from the primary complex, or from haematogenous dissemination. It can also be involved as part of a generalized hypersensitivity process to the tubercle bacillus. Previously, much of the confusion regarding cutaneous tuberculosis has been due to a cumbersome nomenclature and classification. The following classification scheme seems to be the most useful in children [2,3]. 1 Inoculation cutaneous tuberculosis from an exogenous source: (a) in a previously uninfected child (primary disease); (b) in a previously infected child (postprimary disease); or (c) associated with inoculation of bacille Calmette– Guérin (BCG). 2 Cutaneous tuberculosis from an endogenous source: (a) contiguous spread; or (b) autoinoculation.

In a child not previously infected with tuberculosis, primary inoculation of tuberculosis occurs as a result of entry of mycobacteria into the skin through a recent cut or abrasion, with the resultant development of a nodule, which then ulcerates; regional lymph nodes slowly enlarge and generally suppurate (primary disease) [4]. It is usually these that bring the patient to seek medical attention. The areas most commonly involved tend to be the face, scalp, legs below the knees and the feet [5]. Fever and systemic reactions are usually minimal; low-grade pyogenic infections and cat-scratch disease need to be considered in the differential diagnosis. The skin lesions associated with the primary complex develop following direct inoculation of tubercle bacilli into traumatized areas present on the soles of a child’s bare feet or, as in the authors’ experience, in an area of superficial burn present on the sole of a child’s foot. Tubercle bacilli may also gain entry into the skin at sites of mosquito bites on the face, or on the foreskin at the time of ritual circumcision [6,7]. The lesion usually starts as a reddish-brown painless papule that appears at the site of the healed wound. Subsequently, a small, shallow, dry ulcer develops at the eroded centre. It is often surrounded by tiny satellite lesions and usually passes unnoticed until 3–4 weeks later, when the regional lymph nodes enlarge, soften and drain through a sinus. Initially, the bacilli are readily stained and cultured from the lesion, but later biopsy will show the typical histological picture of a granulomatous infiltrate with caseation necrosis [7]. The pathogenesis is similar to primary tuberculous complex in the lung, except that the portal of entry is the skin. On healing, what is left is deep, smooth scar tissue with sharply defined irregular edges surrounded by defined little pits [5]. Inoculation of the abraded skin in a previously infected or immunized person (postprimary disease) is extremely rare in children. A purplish encrusted lesion, 2–5 cm in diameter, appears at the site of inoculation, which occurs mainly on the hands or arms. It is a painless and selflimiting lesion, which is covered with rough scaly skin; it does not ulcerate and is not associated with lymphangitis or lymphadenitis [8]. The lesion resembles the ‘prosector ’s wart’, which is an occupational hazard of pathologists [9]. This is described as a hyperkeratotic papule,

Mycobacterial Infections of the Skin

which eventually becomes verrucous (tuberculosis cutis verrucosa or ‘warty tuberculosis’). The cutaneous lesion associated with BCG vaccination occurs some 2–4 weeks after the intradermal inoculation of the vaccine. The BCG vaccine is derived from M. bovis. At the site of the inoculation, a small papule develops, which slowly enlarges to a size of 5–10 mm and then ulcerates. There is often discharge of pus at this stage. Spontaneous healing occurs after this, usually with formation of a small scar; the whole process takes around 8–10 weeks. Between 1% and 2% of vaccinees will develop local lymphadenitis in association with ulceration at the BCG site; a smaller proportion of children will develop severe or prolonged ulceration at the site, subcutaneous abscess or plaques of lupus vulgaris [10]. These complications are said to occur more frequently if the vaccine is injected subcutaneously. If children with severe immunodeficiency are inadvertently given BCG vaccine, disseminated BCG infection may result. This may be characterized by the development of widespread cutaneous nodules (as well as systemic involvement), in the absence of any local reaction at the site of BCG vaccination [11].

Cutaneous tuberculosis from an endogenous source Cutaneous tuberculosis may result from contiguous involvement of the skin from an underlying subcutaneous caseous focus, generally a tuberculous lymph node, bone or epididymis [3]. ‘Scrofuloderma’ is the old term used to describe this condition. The skin overlying the cervical lymph nodes was most often affected. Initially, a mobile subcutaneous swelling or nodule would appear; this would then become fixed to overlying skin. The contents of the lymph node would then rupture to the outside, leaving either a shallow ulcer or a deep sinus, often surrounded by a cluster of nodules [3]. Extensive scarring was the inevitable outcome after some years of slow healing. In a paper from India, analysing the pattern of childhood cutaneous tuberculosis in 75 patients diagnosed over a 25-year period, more than 50% of children had a scrofuloderma pattern of disease, with the neck being the most common site affected [12]. Lupus vulgaris (see below), affecting mainly the face, was the next most common presentation, being seen in 40% of children. Autoinoculation of tubercle bacilli may occasionally occur into mucocutaneous areas adjacent to the major orifices (orificial tuberculosis) [3]. This occurs following the expectoration of secretions containing tubercle bacilli from the nose, mouth, rectum or genitalia. This form of cutaneous tuberculosis generally occurs in the older patient with advanced pulmonary, intestinal or genitourinary tuberculosis. Ulcerative lesions may occur in the oral or perineal regions, or in the perirectal skin [2,3,13]. They do not heal spontaneously.

57.3

Cutaneous tuberculosis arising from a haematogenous source In babies and young children, multiple small purplish papules may develop on the skin in association with early haematogenous spread of tubercle bacilli (papulonecrotic tuberculids) [5,14]. These used to be the most common manifestation of tuberculous skin disease seen in infants and children. They are more common on the face but may appear anywhere on the body. The lesions, which appear in crops, are small bluish papules with central nodules of semitranslucent ‘apple jelly’ [15]. Some of the lesions are associated with silver scales that are easily scraped off, leaving a crater. They resemble chickenpox in appearance and distribution. Histological examination shows tubercle formation with giant cells and scanty tubercle bacilli. Response to antituberculous chemotherapy is rapid. Without treatment, the lesions remain unchanged for a long time but eventually heal, leaving small, deep pits. Metastatic subcutaneous tuberculous abscesses may develop in some children, often at sites of previous trauma, for up to 2 years following primary infection [5]. They most likely represent a late dissemination of tubercle bacilli. The lesions tend to erode into the skin and discharge, resulting in a superficial ulcer (often multiple) or in a brown pigmented area [16]. An important differential diagnosis is staphylococcal abscesses; the diagnosis is made by Gram’s stain and culture. Although lupus vulgaris is the best known form of cutaneous tuberculosis, it is rare in children. It is a chronic and progressive skin tuberculosis occurring in a sensitized individual and characterized by the appearance of reddish-brown plaques, which take some years to develop [3,5]. Most cases follow haematogenous or lymphatic seeding. The lesions may be psoriasiform in nature, with a plaque-like configuration. There is involvement of the head, face and extremities. A mutilans form exists, which results in progressive destruction of the skin and cartilage of the ears and nose with significant deformity. The mouth may be distorted by atrophic scars. Malignant skin changes may occur in patients with longstanding lupus vulgaris.

Erythema nodosum This is the most common form of skin hypersensitivity to tuberculosis that is present elsewhere in the body. It usually occurs at the same time as the primary tuberculous infection, and is an important marker of the onset of infection. It is rare before the age of 7 years. At the onset there may be fever and joint swelling. The eruption is characterized by the development of painful, reddish or violaceous nodules on the anterior surface of one or both legs below the knee (Fig. 57.1), but may occur over the thighs, buttocks and upper extremities [5]. The nodules are of different sizes but may coalesce. They tend to be

57.4

Chapter 57

Fig. 57.1 Erythema nodosum in a young girl with primary tuberculosis.

up to 5–20 mm in diameter, with ill-defined margins; recurrent crops occur over a number of weeks. Lesions then become more ecchymotic in appearance prior to gradually fading in the manner of a bruise. Erythema nodosum may also be associated with other conditions apart from tuberculosis: streptococcal infections, sarcoidosis, chronic inflammatory bowel disease, some fungal infections and administration of certain drugs (e.g. sulphonamides, phenytoin) [17]. The pathogenesis is thought to be due to an allergic vasculitis induced by circulating immune complexes; biopsy only reveals a septal panniculitis. A tuberculin test will be positive, as may one of the interferon-gamma release assays (IGRA); chest radiograph changes may be suggestive of tuberculosis. Differential diagnosis should include insect bites, cellulitis or anaphylactoid purpura. Diagnosis. To make a diagnosis of cutaneous tuberculosis, a high index of suspicion is required when considering the aetiology of chronic eruptions in children. The history and epidemiological circumstances will be helpful, as will results of tuberculin testing and chest radiography. The important differential diagnosis to consider is whether the cutaneous lesions are caused by one of the atypical mycobacteria, such as M. marinum, M. kansasii, M. fortuitum or M. chelonae (see below). The following should also be considered in the differential diagnosis: impetigo, cat-scratch disease, sporotrichosis, syphilis and tularaemia. In those patients coming from endemic areas, cutaneous leishmaniasis, leprosy and cutaneous diphtheria also need to be considered. A definitive diagnosis of cutaneous tuberculosis will require biopsy of a lesion; histopathology examination

may reveal epithelioid granulomas and/or the presence of acid-fast bacilli. Subsequent mycobacterial cultures would identify M. tuberculosis as the aetiological agent. Culture media for M. tuberculosis include Lowenstein– Jensen, which requires 6–8 weeks for growth; Bactec systems can detect M. tuberculosis within 2 weeks but are more useful for culturing blood, urine and respiratory secretions. In general, the culture yield from tissues in children with extrapulmonary tuberculosis is around 50%, due to the paucibacillary nature of the disease [18]. Microscopy using Ziehl–Neelsen staining can detect 40– 60% of culture-positive samples, with a lower limit of detection of 5000 organisms per millilitre. Newer techniques, such as fluorescent staining of samples with auramine or rhodamine, are superior to the Ziehl–Neelsen stain. The amplification of small amounts of bacterial nucleic acid, using techniques such as polymerase chain reaction (PCR), allows the detection of mycobacteria directly from clinical specimens. Several studies in children have found the PCR test on clinical samples to have a sensitivity of 40–60%, which compares favourably with standard culture [19]. Polymerase chain reation is especially useful in making a rapid diagnosis in the paucibacillary form of cutaneous tuberculosis [20]. Recently new diagnostic blood tests for tuberculosis have become commercially available. These tests, termed interferon-gamma release assays (IGRA), either measure the amount of interferon-gamma released by TB-specific T-lymphocytes or enumerate these cells. Although these tests are considered superior to tuberculin skin testing and do not require follow-up, clinical experience in children with extrapulmonary tuberculosis, such as cutaneous diseases, is limited. A high positive predictive value was observed for IGRA in diagnosing extrapulmonary tuberculosis [21]. Treatment. There are no clinical efficacy trials for the treatment of extrapulmonary tuberculosis in children; however, most authorities recommend standard shortcourse chemotherapy for treatment of cutaneous tuberculosis. This involves the administration of four antituberculous drugs for the first 2 months (isoniazid 10 mg/kg, rifampicin 10 mg/kg, pyrazinamide 35 mg/kg, ethambutol 15 mg/kg), followed by 4 months of isoniazid and rifampicin [22,23]. Ethambutol has been associated with retrobulbar neuritis, although Trebucq [24] reviewed the literature and concluded that ethambutol, at a dose of 15 mg/kg/day, was safe in children older than 5 years, and in younger children. It is appropriate to obtain a baseline ophthalmological assessment in younger children before starting therapy, and repeat the assessment after 1–2 months. In older children, routine colour vision and visual acuity should be assessed at follow-ups using special charts. Treatment should be started as soon

Mycobacterial Infections of the Skin

57.5

as the diagnosis is thought to be a definite possibility, based on the epidemiological history, clinical examination and the results of Mantoux testing, chest radiograph and skin biopsy. Results of drug susceptibility testing should become available within the first 2 months of the treatment period, and hence appropriate changes can be made to the antituberculous regimen if necessary. If besides cutaneous tuberculosis there is initial evidence of meningeal involvement, total treatment should be for 12 months. Local complications following BCG vaccination (e.g. excessive ulceration, subcutaneous abscess) can probably be treated with short courses of isoniazid.

21 Winqvist N, Bjorkman P, Noren A, Miorner H. Use of a T cell interferon gamma release assay in the investigation for suspected active tuberculosis in a low prevalence area. BMC Infect Dis 2009;9:105. 22 American Academy of Pediatrics. Tuberculosis. In: Pickering L, Baker CJ (eds) Red Book: Report of the Committee on Infectious Diseases, 28th edn. ELK Grove Village: American Academy of Pediatrics, 2009. 23 National Institute of Clinical Excellence (NICE). Tuberculosis: Clinical Diagnosis and Management of Tuberculosis, and Measures for its Prevention and Control. London: Royal College of Physicians of London, 2006. 24 Trebucq A. Should ethambutol be recommended for routine treatment of tuberculosis in children? A review of the literature. Int J Tuber Lung Dis 1997;1:12–15.

References 1 Lincoln EM, Sewell EM. Tuberculosis in Children. New York: McGraw-Hill, 1963. 2 Beyt BE Jr, Ortbals DW, Santa Cruz DJ et al. Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of disease. Medicine 1981;60:95–109. 3 Hill MK, Sanders CV. Cutaneous tuberculosis. In: Schlossberg D (ed.) Tuberculosis, 4th edn. Philadelphia: W.B. Saunders, 1999: 264–70. 4 Pereira CA, Webber B, Orson JM. Primary tuberculous complex of the skin. J Am Med Assoc 1976;235:942–6. 5 Miller FJW. Tuberculosis in Children. Edinburgh: Churchill Livingstone, 1982:144–55. 6 Hole LE. Tuberculosis acquired through ritual circumcision. J Am Med Assoc 1913;61:99. 7 Sehgal VN, Wagh SA. Cutaneous tuberculosis: current concepts. Int J Dermatol 1990;29:237–40. 8 Montgomery H. Histopathology of various types of cutaneous tuberculosis. Arch Dermatol 1961;35:698–702. 9 Minkowitz S, Brandt IJ, Rapp Y et al. Prosector ’s wart (cutaneous tuberculosis) in a medical student. Am J Clin Pathol 1969;51:260–2. 10 Dennehy PH, Peter G. Active immunizing agents. In: Feigin RD, Cherry JD, Demmler G, Kaplan SL (eds) Textbook of Pediatric Infectious Diseases, 5th edn. Philadelphia: W.B. Saunders, 2004:3136–82. 11 Gonzalez B, Moreno S, Burdach R et al. Clinical presentation of bacillus Calmette–Guérin infections in patients with immunodeficiency syndromes. Pediatr Infect Dis J 1989;8:201–6. 12 Kumar B, Rai R, Kaur I et al. Childhood cutaneous tuberculosis; a study over 25 years from northern India. Int J Dermatol 2000;40:26–32. 13 Nepomuceno OR, O’Grady JF, Eisenberg SW et al. Tuberculosis of the anal canal: report of a case. Dis Colon Rectum 1971;14:313–15. 14 Kennedy C, Knowles GK. Miliary tuberculosis presenting with skin lesions. Br Med J 1975;3:356. 15 Sloan JB. Papulonecrotic tuberculid in a 9-year-old American girl: case report and review of the literature. Pediatr Dermatol 1990;7:191–5. 16 Ward AS. Superficial abscess formation: an unusual presenting feature of tuberculosis. Br J Surg 1971;58:540. 17 Miller ML. Evaluation of suspected rheumatic disease. In: Kliegman RM, Behrman RE, Jensen HB, Stanton BF (eds) Nelson Textbook of Pediatrics, 18th edn. Philadelphia: W.B. Saunders, 2007:995–7. 18 Shingadia D, Novelli V. Diagnosis and treatment of tuberculosis in children. Lancet Infect Dis 2003;3:624–32. 19 Smith KC, Starke JR, Eisenach K et al. Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction. Pediatrics 1996;97:155–60. 20 Hsiao PF, Tzen CY, Chen HC et al. Polymerase chain reaction based detection of mycobacterial tuberculosis in tissues showing granulomatous inflammation without demonstrable acid-fast bacilli. Int J Dermatol 2003;42:281–6

Non-tuberculous mycobacterial infections Non-tuberculous mycobacteria (NTM), also known as atypical mycobacteria, mycobacteria other than tuberculosis and anonymous mycobacteria, are acid-fast bacilli that are found in our environment, in dust, soil and water (taps, water tanks and swimming pools), in foodstuffs, and in both wild and domestic animals [1]. Studies in the USA have estimated the prevalence of NTM to be around 20% that for tuberculosis (1–2 per 100,000). Transmission of NTM occurs from these environmental sources, aerosols and animals; however, there is no evidence of personto-person transmission. Nosocomial outbreaks (usually by rapid growers) have been reported following surgical procedures, for example sternal wound infections after cardiac surgery, respiratory manipulations and intravenous catheter insertion [2]. Infections have also occurred, iatrogenically, after vaccination with infected needles [3]. In recent years, NTMs have represented an increasing problem in industrialized countries. This situation has been exacerbated by the AIDS pandemic, which has led to infections, especially from the M. avium-intracellulare complex (MAIC), occurring quite frequently in patients with HIV and very low CD4 counts. It may be difficult to distinguish disease from colonization, as isolating NTM from a clinical specimen does not necessarily indicate it is causing disease. Although most reports have concentrated on the pathogenicity of these organisms in immunocompromised hosts, they continue to be uncommon but important pathogens in children with intact immune systems [4]. In contrast with adults and immunocompromised individuals in whom pulmonary and bone involvement is common, the most frequent sites for NTM infection in children are the skin and lymph nodes. Indeed, in developed countries the NTM are causing an increasing proportion of all mycobacterial infections in children and cause skin infections much more commonly than M. tuberculosis [5]. Cervical lymphadenitis is the most common nontuberculous mycobacterial infection in immunocompe-

57.6

Chapter 57

tent children, with the majority of cases occurring in children under 5 years of age. In contrast with tuberculous adenitis, there is usually unilateral lymph node swelling (most commonly submandibular) and there are no clinical or radiological manifestations of pulmonary disease. The node and its overlying skin are seldom painful to the child. Because of the chronicity of the infection, the skin overlying the infected node(s) is indurated, with a dark-red to purplish hue; often the affected node may be fluctuant or there may be a draining sinus present. Cutaneous infections caused by the NTM are less common than adenitis but are often more difficult to diagnose and require the paediatrician to have a high index of suspicion. They are generally indolent and present as non-healing lesions, which are often not diagnosed until the patient has failed several attempts at treatment. In 1969, Wayne and Runyon [6] published a classification for mycobacteria, based on their rate of growth and pigmentation (see Table 57.1). Most infections in humans involve either group I or III. The slow-growing mycobacteria (group I) cause the most cutaneous disease. Antigenic analysis and DNA studies have shown that the rapid growers and slow growers are two distinct subgenera that probably split very early in the evolution of the genus. The rapid growers show significant overlap with the genus Nocardia. As NTM organisms are free living within the environment, in contrast to M. tuberculosis, which is an obligatory parasite, it is incorrect to consider them as a variant of tuberculosis, and because person-toperson spread is unlikely, the public health implications are also quite different. The prevalence of the different organisms depends on the country and even varies from region to region within a country. In the UK, M. kansasii is commonest overall, although M. xenopi is more common in the south, whereas M. malmoense is more common in the north [7]. In West and Central Africa, M. ulcerans predominates [8]. The incidence of infection depends on the occurrence of these organisms within the environment. In the USA, NTM are identified in almost one-half of the cultures reported for mycobacteria in clinical laboratories, although due to their ubiquitous nature some of these are presumably contaminants. Due to the wide distribution of these organisms, it is not surprising that there is a broad base of latent, inapparent infection [9]. A large proportion of the population probably becomes infected at some time, although owing to the low pathogenicity of the organisms, disease is probably confined to people with impaired local or systemic immune responses. The identification of these organisms is difficult and generally requires skin biopsy and culture. Most laboratories use the radiometric BACTEC culture system to culture the organisms. DNA probes are then used to identify the species of NTM isolated. More rapid tests, such

as PCR, are being increasingly used to identify NTB in clinical specimens [2]. Moreover, NTB share common antigens with M. tuberculosis, and it is therefore common to have a false positive Mantoux test, although the response is usually smaller than 10 mm. Interferongamma release assays are usually negative for NTB, although for some atypical mycobacteria (M. kansasii, M. marinum, M. szulgai), IGRAs are positive, as these species share common antigens with M. tuberculosis [10]. Specific treatment will be discussed in the relevant sections; however, in virtually all cases of localized disease, complete surgical excision of the infected lesion(s) is the preferred option and is usually curative. When operative procedures are not possible or have not been successful, or there is more widespread disease, medical treatment can be instituted based on the results of culture and sensitivity testing. Unfortunately results of in vitro sensitivity testing do not always correlate with clinical response.

Mycobacterium marinum infections (swimming pool or fish tank granuloma) This organism was first isolated from fish in 1926 by Aronson [11], and has been shown to be identical to M. balnei, named by Linell and Norden [12] in the Swedish literature in 1954; the latter authors described 80 cases of ‘swimming pool granuloma’ amongst swimmers who used a pool filled with water from hot springs. M. marinum has a widespread distribution but is only viable in heated water in temperate areas and pool or sea water from tropical areas. Although the bacterium may colonize the skin, there is evidence that a break in the epidermal barrier is required for disease to occur [13]. In the majority of cases, infection is clinically manifest between 3 and 8 weeks after inoculation of the organism into an abrasion or puncture wound. M. marinum infection normally follows trauma, often trivial, in water or from marine life. More infections are acquired from home aquariums than from swimming pools. The most common sites for infection are the elbows, knees, fingers and dorsum of the hand. Brady and colleagues [14] described an otherwise healthy 2-year-old child with M. marinum facial infection, presumed to be from contact with his aquarium pets, and there is even a reported finger infection after a dolphin trainer was bitten by his ‘pupil’ [15]. The skin infection usually presents as a solitary granulomatous nodule or pustule, which may ulcerate and discharge, or form a suppurative mass. There are often multiple lesions, and it is not uncommon for one or more nodules to extend along the line of the lymphatic vessels (sporotrichoid form). Immunocompromised individuals can develop disseminated skin lesions [16]. There is also a report of intra-articular infection after a puncture wound to the hand by the spines of a dead fish [17]. The disease is diagnosed by biopsy at the border of the ulcer (reveal-

Mycobacterial Infections of the Skin

ing non-caseating granulomas with sparse acid-fast bacilli) and definitively by culturing the organism. The culture may take several weeks. A special culture process is required with the biopsy specimens being cultured at 30°C. There will be no growth at 37°C, the usual temperature for culture of mycobacteria, and therefore the laboratory must be informed of the possible diagnosis. Tests to determine full identification and sensitivity take a further few weeks. Unfortunately, in general the yield from culture is rather low, and a definitive microbiological diagnosis is only possible in around 20% of patients [18]. Interferon-gamma release assays may prove to be be useful in diagnosing M. marinum infections because of the antigens shared with M. tuberculosis [19]. Minor cutaneous lesions may resolve spontaneously, usually within 3 or 4 months of infection. More extensive lesions are usually treated with systemic antimicrobial agents. Unfortunately, as mentioned previously, results of in vitro sensitivity testing do not always correlate with the clinical response. By standard susceptibility testing, M. marinum isolates are susceptible to rifampicin, rifabutin and ethambutol [20]. They are also susceptible to clarithromycin, sulphonamides and tetracyclines. There have been no comparative trials of treatment regimens for M. marinum infections. An approach has been to treat with two active agents for 1–2 months until after resolution of symptoms. These agents can be a combination of clarithromycin and either rifampicin or ethambutol [21,22]. The three drugs can be used together for severe infections, or for those with deep structure involvement. Therapy is generally required for at least 3–6 months. Response to treatment is slow, but an alternative antibiotic regimen should be considered if there is no response after 1 month. Surgical debridement may be required for those patients with resistant disease, persistent pain or a discharging sinus [23]. Although infection is usually fairly indolent and non-progressive, some patients have presented with a more rapidly progressive disease [24]. Other therapeutic modalities that have been used include curettage, cryotherapy and radiation therapy. In fish-keeping circles, M. marinum infection is known as fish tuberculosis, and fish can live for up to a year once infected. Simple manoeuvres such as ensuring that children wear gloves while cleaning their fish tanks will reduce the risk of infection.

Mycobacterium ulcerans (Buruli ulcer) Mycobacterium ulcerans infection was probably first described in 1897 in Uganda by Sir Albert Cook. After tuberculosis and leprosy, M. ulcerans infection (Buruli ulcer) is the third most important and probably the third most common mycobacterial disease of immunocompetent humans. Buruli ulcers are associated with nonspecific clinical signs and an indolent course, often

57.7

causing massive destruction of the skin and subcutaneous tissue before diagnosis is made, leaving grossly deforming sequelae [25]. M. ulcerans produces a toxin, mycolactone, which induces necrosis and ulceration by its cytotoxic and immunosuppressive properties. Osteomyelitis and joint disease may develop through contiguous or haematogenous spread of M. ulcerans. The distribution of M. ulcerans infection is limited but where it is endemic the infection has been reported to have a point prevalence as high as 150–280/100,000 population [26]. Buruli ulcers occur most commonly in tropical rainforests and swampy regions such as West and Central Africa, Central and South America, Indonesia and Australia. The highest incidence is reported in an area of the upper Nile region of Uganda. Southeastern Australia, which also has some pockets of residual rainforest, is the only temperate region where the infection has been found (Bairnsdale ulcer). Apart from Malaysia, the areas in which the organism is found have a common prehistoric derivation from Gondwanaland, a single land mass that included Africa, Australia and South America [27]. M. ulcerans has not been cultured from the environment and, although no known reservoir has been identified, it is assumed that water could be a source or perhaps the spines of a tall prickly grass, Eosincloa pyrimidalis. Personto-person spread is not thought to occur. Clusters of cases within households have been reported; however, this is thought to be due to exposure to a common source. Mycobacterium ulcerans shares many of the characteristics of other slow-growing mycobacteria, with 4–12 weeks of incubation often being required before growth is visible. However, it differs from most other pathogenic mycobacteria in that it grows best at 30–33°C and not above 35–37°C. It is a non-photochromogen and is morphologically similar to M. tuberculosis, to which it is antigenically related. Children are most commonly affected by M. ulcerans infection. In most reported series the majority of patients are aged between 5 and 15 years, with an almost equal gender distribution [26]. Patients often do not present for several months after the lesion is first noticed, reflecting both the indolent course of the disease and the remoteness of medical care in the countries where it is endemic. The incubation period is usually less than 3 months. The lesions are distributed centrifugally, especially on the extensor surfaces of limbs, and often at sites of minor trauma. Direct inoculation is the likely mode of entry, probably through scraping of the skin by thorns or pieces of wood. Lesions have a tendency to occur on the extremities but have also been reported on the face and trunk. The lesion begins as a small, persistent, painless and occasionally pruritic intradermal papule or subcutaneous nodule; over a period of weeks it becomes fluctuant then indurated – particularly in fatty areas – before ulcerating.

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Chapter 57

The ulcer enlarges over weeks or months, with progressive skin necrosis. There is then extensive undermining of sharply defined ulcer margins, necrotic fat appears dry and white, and there is hyperpigmentation of surrounding skin. The ulcers usually appear singularly but multiple lesions may occur. Necrosis can extend below deep fascia and may involve tendons or muscles, nerves and bones. However, this is unusual as the higher temperature of deeper tissues inhibits replication of the mycobacteria. Bone necrosis occurs later and usually involves small lytic lesions with sequestra and no new bone formation. The infection is accompanied by remarkably few systemic symptoms, but occasionally secondary infections resulting in sepsis or tetanus cause severe systemic disease and death [28]. Healing of untreated ulcers may lead to extensive scarring and contractures, and healed ulcers can break down years later, even after medical and surgical treatment. Diagnosis is usually made based on the clinical and histopathological features without requiring culture of the organisms, which are plentiful early in the disease but difficult to detect in more chronic disease. Even if necrosis is minimal, the presence of acid-fast bacilli and giant cell granulomas in the subcutaneous fat is virtually diagnostic of M. ulcerans infection. Unlike M. leprae, organisms of which are seen within macrophages, sometimes aggregates of M. ulcerans are extracellular and free in the necrotic subcutaneous fat. It is possible to culture the organism and the diagnosis may also be made by PCR amplification of the 16S rRNA gene from the biopsy specimens [22,26]. Mycobacterium ulcerans is variably susceptible in vitro to streptomycin, dapsone, ethambutol and rifampicin but resistant to isoniazid. Initial medical treatment with various combinations of antibiotics was abandoned in favour of wide surgical excision of affected skin and surrounding normal tissue. For small lesion excision, primary closure was all that was required, but more often radical resection to healthy tissues with immediate grafting was preferable. A reappraisal of treatment strategies led to WHO recommending the combination of streptomycin and rifampicin as standard therapy for M. ulcerans infection, with or without additional surgical debridement or skin grafting [29]. In a recent clinical trial in Ghana, antimicrobial therapy with streptomycin and rifampicin for 8 weeks, or streptomycin and rifampicin for 4 weeks, followed by 4 weeks of clarithromycin and rifampicin, for early, limited M. ulcerans infection, was shown to be effective. More than 95% of patients had healed lesions at 1 year, and there were no lesion recurrences at 1 year [30].

Mycobacterium kansasii Like other Runyon group I mycobacteria, M. kansasii is slow growing and produces pigment on exposure to light.

Tap water is likely to be the major reservoir for M. kansasii causing human disease. It is the antigenically most closely related mycobacterium to M. tuberculosis. Mycobacterium kansasii is a common chest pathogen, producing a tuberculosis-like illness in patients with damaged lungs and in the immunocompromised. Rarely, however, M. kansasii may involve the skin. The disease not infrequently affects the immunosuppressed, and there have been reports of the disease presenting as verrucous papules, ulcerative, nodular and sporotrichoid lesions. There have also been reports of the disease presenting as a cellulitic picture in two renal homograft patients [31]. As with M. avium-intracellulare, there may also be haematogenous spread to the skin and bones. With bony involvement, tracts to the skin may occur, which may be diagnosed as apparent cutaneous infection. Histologically, the lesions may vary in appearance, from a granulomatous picture to a dense polymorphic infiltrate with epidermal necrosis; abscess formation may also occur [32]. Usually, no acid-fast bacilli can be seen but when present they may give a clue as they are longer and thicker than other mycobacteria. Infections due to M. kansasii can be treated with a regimen containing rifampicin, isoniazid and ethambutol for a minimum of 12 months [21,33]. Reports from the UK suggest that treatment with rifampicin and ethambutol, for a total of 9 months, is sufficient [34,35].

Mycobacterium scrofulaceum Like other Runyon group II organisms, M. scrofulaceum rarely involves the skin. It is found in the environment in house dust, soil and water, and is an opportunistic pathogen that is most commonly associated with lymphadenitis in children 1–5 years of age. Reports of skin involvement include single nodules, a thigh abscess and localized sporotrichoid lesions. There are several reports of cutaneous presentation of systemic disease [36]. It has also been reported to cause disseminated infection in patients with AIDS [37]. Treatment depends on the sensitivity of the organism but includes rifampicin, ethambutol and clarithromycin. Usually, dual therapy is required, although treatment with one drug (clarithromycin) has been reported to be successful [38]. Gorse reported the successful treatment of a thigh abscess in a child by local excision alone [39]. Lymphadenitis can be cured with complete excision of the lymph nodes.

Mycobacterium avium-intracellulare complex Organisms of the MAIC are found in many environmental sites, including water and soil, and in animals. It is believed that these sources, especially natural waters, are the reservoir for most human infections caused by MAIC [21]. Disseminated infections with MAIC in healthy indi-

Mycobacterial Infections of the Skin

57.9

the treatment of choice. Medical therapy may be necessary for extensive cutaneous diseases, incomplete surgical excision or recurrence of disease. Some authorities recommend treatment with combinations of rifampicin, ethambutol and clarithromycin for up to 2 years [35]. Success has been achieved in some children with M. avium-intracellulare adenitis, using shorter courses of therapy [48,49].

Mycobacterium fortuitum

Fig. 57.2 Atypical mycobacterial adenitis (pre-eruptive stage) due to Mycobacterium avium-intracellulare complex.

viduals are rare, and the usual setting is in an immunocompromised host (particularly impaired cell-mediated immunity); infection is common in patients with AIDS [40,41]. Up to the advent of AIDS, skin infections from this group were rare, but their incidence is now increasing. In immunocompetent children, lymph node infection of the neck and the overlying skin is the most clinically significant presentation [42]. It tends to be a unilateral, chronic adenitis, with transmission of the MAIC occurring as a result of children’s tendency to put objects contaminated with soil, dust or water into their mouth. Eventually the nodes soften and the overlying skin usually becomes shiny and flaky with a characteristic reddish to violaceous hue (Fig. 57.2). A persistent discharging sinus may then develop following rupture of the nodes through the skin. Without treatment, healing may take several months and the child is often left with an area of skin fibrosis and scarring. Although MAIC most commonly affects the lungs, other extrapulmonary sites include the bone marrow and gastrointestinal tract, as well as the lymph nodes [43,44]. Cutaneous manifestations have included nodules, ulcerations, erythematous lesion, abscess and panniculitis. Skin disease most commonly represents disseminated disease, and 20% of disseminated cases reviewed by Wolinsky [45] had cutaneous involvement. In some patients with AIDS, the initiation of antiretroviral therapy has led to the development of MAIC disseminated cutaneous disease, due to the ‘immune reconstitution syndrome’. This represents a response of the recovering immune system to a new or previously subclinical infection with MAIC [46,47]. Because many species of MAIC are reported as resistant to standard antimycobacterial agents, surgical excision of the involved tissues (nodes and skin) has become

One of the rapid-growing atypical mycobacteria, this is widely distributed in the environment. It was first reported in 1938, after its isolation from a post-injection skin abscess [50]. Infection normally occurs after a minor penetrating injury to the skin by a contaminated foreign body [51]. Suspicion should be aroused when there is failure of a simple wound to heal despite adequate treatment. The first indications of continuing infection are a violaceous discoloration of the primary wound edges and the appearance of satellite lesions. The degree of regional lymph node involvement gives an idea of the depth to which the infection has spread. At this stage aggressive surgical intervention is required to avoid the development of subcutaneous abscesses, cutaneous fistula from involved nodes and even osteomyelitis [52]. The resulting wound should be left to heal by secondary intention, although secondary split-skin grafting may be considered once the wound looks clean [53]. Recently, whirlpool footbaths, commonly used in nail salons during pedicures, have been implicated as a source of M. fortuitum furunculosis. The disease in these patients lasted from several months to a year, and either healed spontaneously or required antibiotic therapy [54]. In immunocompromised patients, disseminated disease may occur with primarily skin involvement (Fig. 57.3); presentation may occur some time after the period of immunosuppression [55]. The lesions may be subcutaneous nodules, ulcers or skin papules. Medical treatment can be difficult. In general, M. fortuitum is resistant to standard antituberculous chemotherapy, but sensitive to amikacin, imipenem, ciprofloxacin, co-trimoxazole and clarithromycin. Combination therapy with two agents is usually recommended, and optimal treatment time is generally thought to be 4–6 months [21].

Mycobacterium chelonae Mycobacterium chelonae has been implicated in pulmonary disease and in many extrapulmonary infections, most following documented breaks in body surface barriers. The extrapulmonary infections usually consist of localized skin lesions (painful erythematous nodules that may be superficial or deep), joint infections, bone infections and ocular disease [21,56–58]. However, disseminated lesions have been described, as has sporotrichoid spread [59].

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(a)

(b) Fig. 57.3 (a,b) Disseminated skin lesions due to Mycobacterium fortuitum in a child on chemotherapy for neuroblastoma.

Infection is characteristically acquired via direct contact between a broken skin surface and contaminated water or soil. The most commonly reported events are local trauma to the skin, cutaneous injection (especially in people with diabetes) and median sternotomy. Acupuncture treatment with resulting multiple cutaneous lesions has also been implicated in the transmission of M. chelonae [60]. A review of skin infections caused by M. chelonae reported that 60% occurred in immunocompromised hosts [61]. The incubation period can be from 1 week to 2 years, although clinical manifestation within 1 month is most typical. Local infection resembles a pyogenic abscess; occasionally, there is low-grade inflammation that evolves into an ulcer or a sinus tract. Sporotrichoid and disseminated disease is usually only found in the immunocompromised host. Like all rapid growing mycobacteria, M. chelonae is resistant to conventional antituberculous medications. Isolates of M. chelonae are susceptible or intermediate in susceptibility to tobramycin, clarithromycin, linezolid,

imipenem, amikacin, clofazimine and ciprofloxacin [21]. The only treatment trial for M. chelonae skin disease used clarithromycin alone. Of the immunosuppressed patients treated for 6 months with monotherapy, only 1 out of 14 patients relapsed; all the rest were cured [62]. Clarithromycin has been suggested as a drug of choice in children with M. chelonae infection; it is well tolerated and it penetrates into deeper tissues. However, it should be noted that there are increasing reports of drug resistance, developing during or following clarithromycin monotherapy [63,64]. In general, for serious skin and soft tissue infection, a minimum of 4 months of combination therapy, to minimize the possibility of clarithromycin resistance, is required [21]. Adjunctive surgery is necessary with extensive disease, abscess formation, or where drug therapy is difficult. Removal of foreign bodies and central venous catheters is essential. References 1 Editorial. Opportunistic mycobacteria. Lancet 1981;i:424–5. 2 Wallace RJ. Mycobacteria species: non tuberculosis. In: Long SS, Pickering LK, Prober CG (eds) Principles and Practice of Pediatric Infectious Diseases, 3rd edn. Philadelphia: Churchill Livingstone, 2008:788–92. 3 Borghans JG, Stanford JR. Mycobacterium chelonei in abscesses after infection of diphtheria-pertussis-tetanus-polio vaccine. Am Rev Resp Dis 1973;107:1. 4 Amir J. Non-tuberculous mycobacterial lymphadenitis in children: Diagnosis and management. Isr Med Assoc J 2010;12:49–52. 5 Daloviso JR, Pankey GA. Dermatologic manifestations of nontuberculous mycobacterial diseases. Infect Dis Clin N Am 1994;8:677–88. 6 Wayne LG, Runyon EH. Mycobacteria: a guide to nomenclatural usage. Am Rev Resp Dis 1969;100:732–4. 7 Davies PDO. Infection with non-tuberculous mycobacteria. Br J Hosp Med 1994;52:375–7. 8 Smith JH. Epidemiologic observations on cases of Buruli ulcer seen in a hospital in the lower Congo. Am J Trop Med Hyg 1970; 19:657–63. 9 Owens DW. Atypical mycobacteria. Int J Dermatol 1978;17: 180–5. 10 Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection – United States, 2010. MMWR Recomm Rep 2010;59:1–25. 11 Aronson JD. Spontaneous tuberculosis in salt water fish. J Infect Dis 1926;39:315. 12 Linell F, Norden A. Mycobacterium balnei. A new acid fast bacillus occurring in swimming pools and capable of producing skin lesions in humans. Acta Tuberc Scand 1954;33(Suppl.): 1. 13 Ginsburg CM. Superficial fungal and mycobacterial infections of the skin. Pediatr Infect Dis J 1985;4:S19–20. 14 Brady RC, Sheth A, Mayer T et al. Facial sporotrichoid infection with Mycobacterium marinum. J Pediatr 1997;130:324–6. 15 Flowers DJ. Human infection due to Mycobacterium marinum after a dolphin bite. J Clin Pathol 1970;23:475. 16 Parent LJ, Salam MM, Appelbaum PC et al. Disseminated Mycobacterium marinum infection and bacteremia in a child with severe combined immune deficiency. Clin Infect Dis 1995;21:1325–7. 17 Bailey JP, Stevens SJ, Bell WM et al. Mycobacterium marinum infection. A fishy story. J Am Med Assoc 1982;247:1314.

Mycobacterial Infections of the Skin 18 Ang P, Rattana-Apiromyakij N, Goh CL. Retrospective study of Mycobacterium marinum skin infections. Int J Dermatol 2000;39: 343–7. 19 Arend SM, van Meijgaarden KE, de Boer K et al. Tuberculin skin testing and in-vitro T cell responses to ESAT-6 and CFP10 after infection with Mycobacterium marinum or M. kansasii. J Infect Dis 2002:186:1797–807. 20 Stone MS, Wallace RJ, Swenson JM et al. Agar disc elution method for susceptibility testing for Mycobacterium marinum and Mycobacterium fortuitum complex to sulfonamides and antibiotics. Antimicrob Agents Chemother 1983;24:486–93. 21 Griffith DE, Askamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175: 367–416. 22 Piersimoni C, Scarparo C. Extrapulmonary infections associated with nontuberculous mycobacteria in immunocompetent persons. Emerg Infect Dis 2009;15:1351–8. 23 Aubry A, Chosidow O, Caumes E, Robert J, Cambau E. Sixty-three cases of Mycobacterium marinum infection. Arch Intern Med 2002;162: 1746–52. 24 Wendt JR, Lamm RC, Altman DI et al. An unusually aggressive Mycobacterium marinum hand infection. J Hand Surg (Am) 1986;11: 753–5. 25 Sizaire V, Nackers F, Comte E, Portaels F. Mycobacterium ulcerans infection: control, diagnosis and treatment. Lancet Infect Dis 2006;6: 288–96. 26 van der Werf T, Stienstra Y, Christian Johnson R et al. Mycobacterium ulcerans disease. Bull World Health Organ 2005;83:785–91. 27 Hayman J. Postulated epidemiology of Mycobacterium ulcerans infection. Int J Epidemiol 1991;20:1093–8. 28 van der Werf TS, van der Graaf WT, Tappero JW et al. Mycobacterium ulcerans infection. Lancet 1999;354:1013–18. 29 Chauyt A, Ardant MF, Adeye A et al. Promising clinical efficacy of streptomycin–rifampicin combination for treatment of Buruli ulcer (Mycobacterium ulcerans disease). Antimicrob Agents Chemother 2007;51:4029–35. 30 Nienhuis WA, Stienstra Y, Thompson WA et al. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet 2010;37:664–72. 31 Groves RW, Newton JA, Hay RJ. Cutaneous Mycobacterium kansasii infection: treatment with erythromycin. Clin Exp Dermatol 1991; 16:300–2. 32 Liao CH, Lai CC, Ding LW et al. Skin and soft tissue infection caused by non-tuberculous mycobacteria. Int J Tuberc Lung Dis 2007; 11:96–102. 33 Cross JT Jr, Jacobs JF. Other mycobacteria. In: Feigin RD, Cherry JD, Demmler G, Kaplan SL (eds) Textbook of Pediatric Infectious Diseases, 5th edn. Philadelphia: W.B. Saunders, 2004:1379–90. 34 Research Committee of the British Thoracic Society. Mycobacterium kansasii pulmonary infection: a prospective study of the results of nine months of treatment with rifampicin and ethambutol. Thorax 1994;49:442–5. 35 Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunistic mycobacterial infection: JTC guidelines 1999. Thorax 2000;55:210–18. 36 Murray Leisure KA, Egan N, Weitekamp MR. Skin lesions caused by Mycobacterium scrofulaceum. Arch Dermatol 1987;123:369–70. 37 Sanders JW, Walsh AD, Snider RL et al. Disseminated Mycobacterium scrofulaceum infection: a potentially treatable complication of AIDS. Clin Infect Dis 1995;20:549. 38 Jang HS, Jo JH, Oh CK et al. Successful treatment of localized cutaneous infection caused by Mycobacterium scrofulaceum with clarithromycin. Pediatr Dermatol 2005;22:476–79.

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39 Gorse GJ. Non-tuberculous mycobacterial disease. Experience in a southern Californian hospital. Arch Intern Med 1983;143:225–8. 40 Hawkins CC, Gold JW, Whimbey E et al. Mycobacterium avium complex infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986;105:184–8. 41 Sohn CC, Schroff RW, Kliewer KE et al. Disseminated Mycobacterium avium-intracellulare infection in homosexual men with acquired cellmediated immunodeficiency; a histologic and immunologic study of two cases. Am J Clin Pathol 1983;79:247–52. 42 Lincoln EM, Gilber LA. Diseases in children due to mycobacteria other than Mycobacterium tuberculosis. Am Rev Resp Dis 1972;105: 683–714. 43 Chicoine L, Lapointe N, Simenau R et al. Anonymous mycobacterial infection causing disseminated osteomyelitis and skin lesions. Can Med Assoc J 1968;98:1059–62. 44 Sanderson TL, Moskowitz L, Hensley GT et al. Disseminated Mycobacterium avium-intracellulare infection appearing as a panniculitis. Arch Pathol Lab Med 1982;106:112–14. 45 Wolinsky E. State of the art: non-tuberculous mycobacteria and associated diseases. Am Rev Resp Dis 1979;119:107–59. 46 Lange CG, Lederman MM. Immune reconstitution with antiretroviral therapies in chronic HIV-1 infection. J Antimicrob Chemother 2003;51:1–4. 47 Nalaboff KM, Rozenshtein A, Kaplan MH. Imaging of MAI infection in AIDS patients on HAART. Am J Roentgenol 2000;175:387–90. 48 Green PA, Fordham von Reyn C, Smith RP Jr. Mycobacterium avium complex parotid lymphadenitis: successful therapy with clarithromycin and ethambutol. Pediatr Infect Dis J 1993;7:615–17. 49 American Academy of Pediatrics. Diseases caused by nontuberculous mycobacteria. In: Pickering L, Baker CJ (eds) Red Book: Report of the Committee on Infectious Diseases, 28th edn. Elk Grove Village, IL: American Academy of Pediatrics, 2009. 50 Cruz J da C. A new acid resistant bacillus pathogenic for man. Acta Med Bras 1938;1:297–301. 51 Runyon EH. Whence mycobacteria and mycobacterioses? Ann Intern Med 1971;75:467. 52 Wallace RJ, Swenson JM, Silcox VA et al. Spectrum of disease due to rapidly growing mycobacteria. Rev Infect Dis 1983;5:657. 53 Plaus WJ, Hermann G. The surgical management of superficial infections caused by atypical mycobacteria. Surgery 1991;100:99–103. 54 Winthrop KL, Albridge K, South D et al. The clinical management and outcome of nail salon-acquired Mycobacterium fortuitum skin infection. Clin Infect Dis 2004;38:38–44. 55 Okano A, Shimazaki C, Ochiai N et al. Subcutaneous infection with Mycobacterium fortuitum after allogenic bone marrow transplantation. Bone Marrow Transplant 2001;28:709–11. 56 Heironimus J, Winn RE, Collins CB. Cutaneous non-pulmonary Mycobacterium chelonei infection. Arch Dermatol 1984;120:1061–3. 57 Moore M, Frerichs JR. An unusual acid-fast infection of the knee with subcutaneous abscess like lesions of the gluteal region. J Invest Dermatol 1953;20:133–69. 58 Gremillion DH, Mursch SB, Lerner CJ. Injection site abscesses caused by Mycobacterium chelonei. Infect Control 1983;4:25–8. 59 Jopp-McKay AG, Randell P. Sporotrichoid cutaneous infection due to Mycobacterium chelonei in a renal transplant patient. Australas J Dermatol 1990;31:105–9. 60 Woo PC, Leung KW, Wong SS et al. Relatively alcohol-resistant mycobacteria are emerging pathogens in patients receiving acupuncture treatment. J Clin Microbiol 2002;40:1219–24. 61 Wallace RJ, Brown BA, Onyi GO. Skin, soft tissue and bone infections due to Mycobacterium chelonae; importance of prior corticosteroid therapy, frequency of disseminated infections and resistance to oral antimicrobials other than clarithromycin. J Infect Dis 1992;166: 405–12.

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62 Wallace RJ Jr, Tanner D, Brennan PJ, Brown BA. Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 1993;119:482–6. 63 Vemulapalli RK, Cantey JR, Steed LL et al. Emergence of resistance to clarithromycin during treatment of disseminated cutaneous Myco-

bacterium chelonae infection: case report and review of literature. J Infect 2001;43:163–8. 64 Driscoll MS, Tyring SK. Development of resistance to clarithromycin after treatment of cutaneous Mycobacterium chelonae infection. J Am Acad Dermatol 1997;36:495–6.

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C H A P T E R 58

Bartonella Infections: Bacillary Angiomatosis, Cat Scratch Disease and Bartonellosis Diana B. McShane1, Heidi H. Kong2 & Sarah A. Myers1 1

Department of Dermatology, Duke University Medical Center, Durham, NC, USA Dermatology Branch, National Institutes of Health, Bethesda, MD, USA

2

Bacillary angiomatosis, 58.1

Cat scratch disease, 58.5

Bacillary angiomatosis Definition. Bacillary angiomatosis is an infectious disease caused by organisms of the genus Bartonella. It primarily occurs in immunocompromised patients, especially in those with the acquired immune deficiency syndrome (AIDS), but it also occurs in immunocompetent hosts. The disease is characterized by vascular papules or nodules that respond to antibiotic treatment. If left untreated, however, the disease can have systemic involvement and even a fatal outcome. History. Bacillary angiomatosis is a more recently recognized infectious disease. Understanding of bacillary angiomatosis has led to new discoveries about cat scratch disease and other Bartonella-associated diseases. The first clinical and histopathological description of bacillary angiomatosis was reported by Stoler et al. in 1983 [1]. Additional cases were not described until 1987, when ‘epithelioid angiomatosis’ was diagnosed in several patients with human immunodeficiency virus (HIV) infection [2]. In these early descriptions, distinction from Kaposi sarcoma or pyogenic granuloma was difficult. As bacillary forms were observed in tissue stained with Warthin–Starry and immunoperoxidase with the antiserum raised against the cat scratch disease bacillus, a variant of the cat scratch disease bacillus was originally postulated to be the causative agent of bacillary angiomatosis. Clinical and histological differences observed between bacillary angiomatosis and cat scratch disease as well as the rapid response of bacillary angiomatosis to erythromycin argued against cat scratch bacillus as the

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Bartonellosis (Carrión disease), 58.8

aetiology of bacillary angiomatosis. Attempts at culturing an organism were unsuccessful. In 1990, DNA sequences closely related to Bartonella quintana were identified in the lesions of patients with bacillary angiomatosis [3]. Independently, a Gramnegative bacillus was isolated from HIV-infected patients with fever and bacteraemia [4], and similar bacilli were noted in tissue from patients with peliosis hepatis [5]. A novel species, Bartonella henselae, was later isolated and fully characterized and found to be identical to the organism identified in biopsied tissues from patients with bacillary angiomatosis and peliosis hepatis [6,7]. Subsequently, both B. henselae and B. quintana were cultured from cutaneous and visceral lesions of bacillary angiomatosis [8]. It is now known that the spectrum of Bartonella infection encompasses several different diseases including bacillary angiomatosis (cutaneous and extracutaneous), bacillary peliosis hepatis and splenitis, bacteraemia and endocarditis [9]. Aetiology. Many original descriptions of the causative organisms of bacillary angiomatosis refer to the species of the genus Rochalimaea (R. quintana, R. henselae, R. elizabethae and R. vinsonii). The four species were subsequently shown to be closely related to the sole member of the genus Bartonella (B. bacilliformis) and have been reclassified as B. quintana, B. henselae, B. elizabethae and B. vinsonii [10]. Both B. quintana and B. henselae have been associated with bacillary angiomatosis. Infection with the remaining three Bartonella species has not been reported in HIVinfected patients, although seropositivity to B. elizabethae has been demonstrated among HIV-infected IV drug users in Sweden [11]. B. elizabethae and B. vinsonii have been isolated as a rare cause of endocarditis. B. bacilliformis causes bartonellosis, an illness endemic to South America. The acute febrile phase is Oroya fever, and the

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chronic phase, verruga peruana, is associated with cutaneous vascular lesions that can be indistinguishable from those of bacillary angiomatosis. Bacillary angiomatosis occurs primarily in patients with AIDS. However, the condition may occur in immunocompetent patients and in HIV-negative immunocompromised individuals [9]. Bacillary angiomatosis in children appears to be extremely rare. The several reports of AIDS-associated bacillary angiomatosis include only two paediatric cases [12,13]. The reason for the paucity of reported cases in this population is unclear; however, the diagnosis of bacillary angiomatosis should be considered in HIV-positive children in the appropriate clinical setting. Paediatric bacillary angiomatosis has also been reported in a child who was undergoing chemotherapy for leukaemia [14] and in two immunocompetent children [15,16]. No perinatal cases have been described, although bacillary angiomatosis in pregnancy has been reported in an HIV-positive patient. Recently, B. henselae was found to be the cause of cat scratch disease in addition to some cases of bacillary angiomatosis. The reason for the different host responses to infection with B. henselae is unknown, but cat scratch disease is commonly acquired in childhood. Similar to the epidemiology of cat scratch disease, bacillary angiomatosis is associated with a traumatic exposure to cats (bite or scratch) [17]. Further implicating cats as a reservoir of the disease, B. henselae has been repeatedly isolated from the blood of cats [18]. Many patients with bacillary angiomatosis, however, have no history of exposure to cats, suggesting that the organism may also be acquired from other sources. Arthropod vectors, specifically fleas, ticks and lice, have also been suggested as vectors of B. henselae.

Fig. 58.1 Histological examination of bacillary angiomatosis demonstrates vascular proliferations lined with plump endothelial cells, scattered lymphocytes, neutrophils and leucocytoclastic debris. Reproduced with permission from Myers et al. 1992 [14].

Fig. 58.2 Clusters of extracellular argyrophilic bacilli in bacillary angiomatosis (Warthin–Starry stain). Reproduced with permission from Myers et al. 1992 [14].

Pathology. Histologically, the most characteristic features in skin lesions of patients with bacillary angiomatosis are lobular vascular proliferations consisting of plump epithelioid endothelial cells lining vessels and protruding into vascular lumina (Fig. 58.1) [19]. Neutrophils and leucocytoclastic debris are scattered throughout lesions and especially around eosinophilic granular aggregates. Staining of the aggregates with Warthin– Starry reveals masses of bacteria (Fig. 58.2). Electron microscopy demonstrates pleomorphic bacilli with a Gram-negative trilaminar wall (Fig. 58.3). Clinical features

Cutaneous bacillary angiomatosis Most reported cases of bacillary angiomatosis describe lesions that are dermal or subcutaneous. Lesions may be solitary or multiple and may even number more than 1000. Initially, lesions are usually small, red-to-purple

Fig. 58.3 Transmission electron microscopic study of tissue in bacillary angiomatosis demonstrates bacilli between collagen fibres. Inset: trilaminar structure of bacterial wall. Reproduced with permission from Myers et al. 1992 [14].

Bartonella Infections: Bacillary Angiomatosis, Cat Scratch Disease and Bartonellosis

pinpoint papules, which can evolve into vascularappearing nodules and tumours that may bleed profusely with trauma (Fig. 58.4). The surface may be smooth or ulcerated with crusting. Often, individual lesions resemble pyogenic granulomas. Subcutaneous lesions are deeper seated skin-coloured or dusky nodules that may be freely mobile or fixed to underlying structures. These nodules are often tender and may exhibit some overlying skin changes, resembling cellulitis. Additional descriptions include plaque-like lesions and a suppurative ulcer. The few case reports of bacillary angiomatosis in children were isolated lesions described as a crusted and ulcerated violaceous nodule, a crusted erythematous papule and a red papular lesion (Fig. 58.5) [12,14,16]. Constitutional symptoms including fever, chills, malaise, headache and anorexia with or without weight loss may be present.

58.3

Extracutaneous bacillary angiomatosis Extracutaneous bacillary angiomatosis can involve numerous different internal organs leading to local complications or overwhelming fatal disseminated infection. Constitutional signs and symptoms as described for cutaneous bacillary angiomatosis are usually present in extracutaneous bacillary angiomatosis. Both respiratory and gastrointestinal mucosal surfaces can be involved. Laryngeal and endobronchial lesions may cause obstruction and respiratory compromise. Lesions in the oral cavity may be the presenting sign of HIV infection [20]. Most organ systems have been reported to be involved with lesions of bacillary angiomatosis, including heart, lymph nodes, liver and spleen, lung pleura, muscles and soft tissues, bone marrow, brain and bone [9]. Bone infection, asymptomatic or manifested as focal bone pain, which appears as osteolytic lesions on radiographs, is relatively frequent. Bacillary peliosis hepatis and splenitis Hepatic involvement in patients with Bartonella infection may present as blood-filled cystic spaces [5]. Peliosis may present as an isolated condition or in association with cutaneous and extracutaneous bacillary angiomatosis. Accompanying signs and symptoms include nausea, vomiting, diarrhoea, abdominal distension, fever, chills and hepatosplenomegaly. Thrombocytopenia or pancytopenia can develop in patients with peliosis hepatitis and splenitis. Splenitis may occur as an acute necrotizing inflammatory response without evidence of angiomatosis.

Fig. 58.4 Smooth-surfaced vascular nodule with peripheral scale in a child with bacillary angiomatosis and AIDS. Courtesy of Dr Annette Wagner, Children’s Memorial Hospital, Chicago, IL, USA.

Fever with bacteraemia Some patients with Bartonella infection develop a symptom complex of malaise, fatigue, anorexia, weight loss and recurring progressive fevers with eventual isolation of the organism in blood cultures [4,7]. In these patients, there is no obvious site of focal infection. Prognosis. All patients with bacillary angiomatosis should be treated promptly because of the potential morbidity and mortality associated with untreated progressive disease. Appropriate antibiotic therapy usually leads to resolution of the potentially disfiguring cutaneous lesions and visceral disease, including bone lytic lesions. Even when the therapy is prolonged, recurrent disease can occur after successful treatment. It is not known whether this represents relapse or reinfection.

Fig. 58.5 Violaceous papule with ulceration and crusting in a child with bacillary angiomatosis and immunosuppression from chemotherapy for leukaemia. Reproduced with permission from Myers et al. 1992 [14].

Diagnosis. The diagnosis of cutaneous bacillary angiomatosis is most often made by suggestive clinical features combined with histological confirmation. Blood cultures should be performed, as both B. henselae and B. quintana can be isolated from blood using paediatric or adult isola-

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tor tubes or tubes containing ethylenediaminetetra-acetic acid (EDTA). Both organisms can also be isolated from cutaneous tissue by co-cultivation with an endothelial cell monolayer [8]. Furthermore, Bartonella DNA from tissue or blood can be amplified by polymerase chain reaction (PCR). Indirect fluorescence assay (IFA) and enzyme immunosorbent assay (EIA) have been tested for serological diagnosis of B. henselae and B. quintana. Difficulties with the IFA test include significant cross-reactivity between B. henselae and B. quintana immunoglobulin G (IgG) assays, suboptimal sensitivity and false-positive tests due to a 4–6% prevalence of positive Bartonella serology in the general population. Although serological studies are traditionally available in the USA through the Centers for Disease Control and Prevention or through a commercially available IFA test, positive results must be interpreted with respect to the clinical context and should not be used as the sole method of diagnosis [21]. Differential diagnosis. The differential diagnosis of the cutaneous lesions of bacillary angiomatosis includes infectious and non-infectious entities [22]. The noninfectious disorders include pyogenic granuloma, cherry angioma, dermatofibroma and haemangioma. Distinguishing solitary lesions and pyogenic granuloma can be difficult clinically and may require biopsy for diagnosis. Kaposi sarcoma is an important infectious disease to distinguish from bacillary angiomatosis as they are both more common in the immunocompromised patient setting. Given the rarity of Kaposi sarcoma in children, Kaposi-like lesions should be biopsied in this population of patients. In addition, the absence of macules, patches and plaques in most cases distinguishes bacillary angiomatosis from Kaposi sarcoma, but the diseases can occur simultaneously. With respect to other infectious diseases, bacillary angiomatosis is most similar to bartonellosis, but infection with B. bacilliformis occurs almost entirely in endemic areas of Peru. The nodular and plaque forms of bacillary angiomatosis may need to be differentiated from other deep mycobacterial and fungal infections that can present similarly, including atypical Mycobacterium infections, tuberculosis, coccidioidomycosis, cryptococcosis, histoplasmosis and sporotrichosis. Treatment. The treatment of choice for bacillary angiomatosis, bacillary peliosis hepatis and the bacteraemic syndrome associated with Bartonella infection for both immunocompetent and immunocompromised patients is erythromycin (500 mg four times daily in adults) [23]. Excellent responses have also been obtained with doxycycline, tetracycline, azithromycin, clarithromycin and minocycline, which may be used as alternative therapy in patients who cannot tolerate erythromycin. The optimal

duration of therapy is unknown, but a recent review suggests that therapy should be extended to 3 months [24]. Therapy should be guided by clinical response and, especially in immunocompromised patients, should be extended beyond clearance of lesions to decrease the likelihood of relapse. In severe or refractory cases, combination parenteral antibiotics with erythromycin or doxycycline and rifampin (300 mg twice daily in adults) should be used [24]. After antibiotic therapy is stopped, patients should be followed closely for relapse; if relapse occurs these individuals may require indefinite suppressive antibiotics.

References 1 Stoler MH, Bonfiglio TA, Steigbigel RT et al. An atypical subcutaneous infection associated with acquired immune deficiency syndrome. Am J Clin Pathol 1983;80:714–18. 2 Cockerell CJ, Whitlow MA, Webster GF et al. Epithelioid angiomatosis: a distinct vascular disorder in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Lancet 1987;ii:654–6. 3 Relman DA, Loutit JS, Schmidt TM et al. The agent of bacillary angiomatosis: an approach to the identification of uncultured pathogens. N Engl J Med 1990;323:1573–80. 4 Slater LN, Welch DF, Hensel D et al. A newly recognized fastidious Gram-negative pathogen as a cause of fever and bacteremia. N Engl J Med 1990;323:1587–93. 5 Perkocha LA, Geaghan SM, Yen TSB et al. Clinical and pathological features of bacillary peliosis hepatis in association with human immunodeficiency virus infection. N Engl J Med 1990;323:1581–6. 6 Regnery RL, Anderson BE, Clarridge JE III et al. Characterization of a novel Rochalimaea species, R. henselae sp. nov., isolated from blood of a febrile, human immunodeficiency virus-positive patient. J Clin Microbiol 1992;30:265–74. 7 Welch DF, Pickett DA, Slater LN et al. Rochalimaea henselae sp. nov., a cause of septicemia, bacillary angiomatosis, and parenchymal bacillary peliosis. J Clin Microbiol 1992;30:275–80. 8 Koehler JE, Quinn FD, Berger TG et al. Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis. N Engl J Med 1992;327:1625–31. 9 Adal KA, Cockerell CJ, Petri WA Jr. Cat scratch disease, bacillary angiomatosis, and other infections due to rochalimaea. N Engl J Med 1994;330:1509–15. 10 Brenner DJ, O’Connor SP, Winkler HH et al. Proposals to unify the genera Bartonella and Rochalimaea, with descriptions of Bartonella quintana comb. nov., Bartonella vinsonii comb. nov., Bartonella henselae comb. nov. and Bartonella elizabethae comb. nov. and to remove the family Bartonellaceae from the order Rickettsiales. Int J Syst Bacteriol 1993;43:777–86. 11 McGill S, Hjelm E, Rajs J, Lindquist O, Friman G. Bartonella spp. antibodies in forensic samples from Swedish heroin addicts. Ann NY Acad Sci 2003;990:409–13. 12 Malane MS, Laude TA, Chen GK et al. An HIV-1-positive child with fever and a scalp nodule. Lancet 1995;346:1466. 13 Chitsike I, Muronda C. Bacillary angiomatosis in an HIV positive child. First case report in Zimbabwe. Cent Afr J Med 1997;43:238–9. 14 Myers SA, Prose NS, Garcia JA. Bacillary angiomatosis in a child undergoing chemotherapy. J Pediatr 1992;121:574–8. 15 Paul MA, Fleischer AB Jr, Wieselthier JS et al. Bacillary angiomatosis in an immunocompetent child: the first reported case. Pediatr Dermatol 1994;11:338–41.

Bartonella Infections: Bacillary Angiomatosis, Cat Scratch Disease and Bartonellosis 16 Smith KJ, Skelton HG, Tuur S et al. Bacillary angiomatosis in an immunocompetent child. Am J Dermatopathol 1996;18:597–600. 17 Tappero JW, Mohle-Boetani J, Koehler JE et al. The epidemiology of bacillary angiomatosis and bacillary peliosis. JAMA 1993;269:770–5. 18 Koehler JE, Glaser CA, Tappero JW. Rochalimaea henselae infection: new zoonosis with the domestic cat as reservoir. JAMA 1994;271:531–5. 19 LeBoit PE, Berger TG, Egbert BM et al. Bacillary angiomatosis: the histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease. Am J Surg Pathol 1989;13:909–20. 20 Speight PM, Zakrzewska J, Fletcher CDM. Epithelioid angiomatosis affecting the oral cavity as a first sign of HIV infection. Br Dent J 1991;171:367–70. 21 Regnery RL, Childs JE, Koehler JE. Infections associated with Bartonella species in persons infected with immunodeficiency virus. Clin Infect Dis 1995;21(suppl 1):S94–8. 22 Spach DH. Bacillary angiomatosis. Int J Dermatol 1992;31:19–24. 23 Koehler JE, Tappero JW. Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1993;17:612–24. 24 Maguina C, Guerra H, Ventosilla P. Bartonellosis. Clin Dermatol 2009;27(3):271–80.

Cat scratch disease Definition. Cat scratch disease is an infectious disease typically characterized by self-limited regional lymphadenopathy occurring after a cat scratch or bite distal to the affected node. Afipia felis was the original organism isolated from patients with cat scratch disease, but B. henselae is now considered the primary causative organism. In contrast to bacillary angiomatosis (also caused by B. henselae), cat scratch disease manifests as granulomatous lesions in immunocompetent individuals and is rarely a serious illness. History. Cat scratch disease was first described in 1950 by Debré et al. [1] in patients with a history of cat contact followed by regional adenitis that spontaneously resolved. Similar symptoms of fever, conjunctival granulomas and pre-auricular lymphadenopathy, known as oculoglandular syndrome, were described by Parinaud in 1889 [2]. Epidemiological features of the disease strongly suggested an infectious aetiology, but attempts to isolate bacteria, acid-fast organisms, viruses, spirochaetes, fungi and chlamydiae failed. In 1983, a Gram-negative bacillus was detected in lymph nodes of patients with cat scratch disease [3]. The presumed causative agent was isolated and cultured from lymph node culture of 10 patients with cat scratch disease in 1988 [4]. The organism was eventually named A. felis. At the same time, many investigators had noted similarities between cat scratch disease and bacillary angiomatosis and speculated that the two diseases might be caused by the same organism. During the development of a serological test for B. henselae (the agent found in

58.5

many patients with bacillary angiomatosis), sera from 36 out of 41 patients (88%) with suspected cat scratch disease were found to have high titres of B. henselae antigens [5]. Furthermore, sera with high-titre B. henselae antibodies did not cross-react with A. felis, and only 24% of patients with cat scratch disease had detectable antibodies to A. felis. Other investigators confirmed the positive serologies to B. henselae in patients with cat scratch disease and also found that 81% of the cats owned by patients with cat scratch disease had serum antibodies that reacted with B. henselae [6]. Subsequently, B. henselae has been cultured from involved lymph nodes in immunocompetent patients with cat scratch disease and detected by PCR in preparations of the cat scratch disease antigen and in lymph nodes from patients with cat scratch disease. Aetiology. The exact proportion of cases of cat scratch disease caused by A. felis and B. henselae is unknown, but it is now widely accepted that B. henselae is the primary cause. Bartonella species are morphologically very similar to A. felis when examined by Warthin–Starry staining; however, A. felis and B. henselae have been classified as members of different genera. Two reports have also described cases of cat scratch disease caused by B. clarridgeiae [7,8]. Cat scratch disease occurs in immunocompetent patients of all ages, with 80% of patients under 21 years of age [9]. It is considered the most common cause of chronic benign lymphadenopathy in children and adolescents. More than 90% of the patients have a history of some type of contact with cats. More specifically, patients are more likely than healthy cat-owning control subjects to have at least one kitten of 12 months old or younger, to have been scratched or bitten by a kitten, and to have at least one kitten with fleas [6]. Rarely, cases of cat scratch disease have occurred following skin injury from a foreign body such as a wood splinter or thorn. As suggested in bacillary angiomatosis, fleas and ticks may also be vectors in some cases of cat scratch disease. Family outbreaks have been described, often involving the children and rarely a parent. These households have cats or kittens, and cases present within a few weeks of each other. It is thought that the animals probably transmit the bacillus for only a short period of time [9]. No human-to-human transmission has been documented. Recently, B. henselae was found to be viable in red blood cell units after storage at 4° for 35 days, suggesting the possibility of transmission by blood transfusion [10], though no reported cases exist. Pathology. Histological examination of the primary inoculation site in the skin reveals one to several acellular areas of necrosis in the dermis. Histiocytes and epithelioid cells surround the areas of necrosis in multiple layers,

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Chapter 58

with the innermost layer often in a palisading arrangement. A zone of lymphocytes surrounds the histiocytes and multinucleated giant cells are variably present. The histopathological findings in involved lymph nodes are non-specific and depend on the stage of the disease. Lymphoid hyperplasia is present initially and is followed by the development of stellate granulomas. The centres are acellular and necrotic and surrounded by histiocytes and peripheral lymphocytes similar to those observed in the skin. Later, microabscesses develop and may become confluent. Warthin–Starry silver impregnation stain within areas of necrosis of involved lymph nodes and in the primary inoculation site of the skin may demonstrate delicate pleomorphic bacilli in chains, clumps or filaments. Clinical features. An inoculation lesion develops 3–10 days after the introduction of the organism into the skin in 60–90% of patients [9]. This lesion can present as a papule, pustule, vesicle or nodule that lasts for days to months (Fig. 58.6). Careful examination of interdigital web spaces, skin creases and scalp may reveal the inoculation lesion and provide clues to the diagnosis. Other inoculation sites (5–10%) include the eye (non-suppurative conjunctivitis, ocular granuloma) and mucous membranes (oral ulcer). Paronychia has also been described as an inoculation site lesion [11]. Within 2 weeks (range 7–60 days) of the inoculation, enlarged tender lymph nodes appear proximal to the inoculation site (Fig. 58.7). Over 80% of the involved nodes are in the axillary, epitrochlear, cervical, supraclavicular and submandibular areas. Approximately twothirds of patients have regional single or multiple nodes and the other one-third of patients have enlarged nodes in several anatomical sites [9]. Generalized lymphadenopathy may occur in severe systemic cat scratch disease.

Fig. 58.6 Cat scratch disease inoculation lesion on the right cheek and associated subauricular lymphadenopathy in a 16-month-old infant. Courtesy of Dr Andrew Margileth.

The nodes are initially tender, often erythematous and occasionally suppurate, requiring drainage or removal [12,13]. Node size is usually between 1 and 5 cm; however, some may enlarge to 8–10 cm. The lymphadenopathy usually resolves in 2–4 months. Despite impressive lymphadenopathy, patients are usually not ill. Fever greater than 38.3°C occurs in 30–60% of patients. Other associated symptoms may include malaise, fatigue, headache, anorexia, nausea, vomiting, myalgias and arthralgias. A transient macular and papular eruption, erythema multiforme, erythema nodosum, leucocytoclastic vasculitis and thrombocytopenic purpura have also been infrequently observed. Presentations of cat scratch disease other than regional adenopathy with or without fever have been reported in large case series. Parinaud oculoglandular syndrome is an atypical form of cat scratch disease that presents as a conjunctival granuloma at the inoculation site with preauricular lymphadenopathy and often with fever. Several reports have described cat scratch disease patients with visceral lesions, including hepatic and splenic granulomas [14–16]. Neurological symptoms occur in approximately 2% of patients and include encephalopathy with coma and/or seizures, myelitis, radiculitis, polyneuritis, paraplegia, neuroretinitis, cerebral arteritis and Guillain– Barré [17,18 ]. Other atypical presentations of cat scratch disease include osteolytic lesions, hepatosplenomegaly, primary atypical pneumonia, endocarditis and a more pronounced systemic illness [9,19]. Prognosis. The prognosis for cat scratch disease is excellent, with spontaneous recovery in 2–6 months in the majority of patients. A small percentage of patients (1– 2%) may have persistent lymphadenopathy for 1–3 years [9]. Lifelong immunity is generally conferred in patients

Fig. 58.7 Three primary cat scratch disease inoculation pustules on dorsal hand with associated epitrochlear lymphadenitis in a young adult. Courtesy of Dr Andrew Margileth.

Bartonella Infections: Bacillary Angiomatosis, Cat Scratch Disease and Bartonellosis

with overt disease; however, there are cases of adult patients with recurrent lymphadenopathy 6–13 months after their initial diagnosis of cat scratch disease [20]. Death has been associated with encephalitis and endomyocarditis in patients with evidence of B. henselae infection [21,22]. Diagnosis. The diagnosis of cat scratch disease is primarily clinical. Laboratory testing with serological analysis, Warthin–Starry stains or PCR provides supportive data. Isolating B. henselae through culture is very difficult but diagnostic. Traditional criteria for diagnosis, including the cat scratch skin test, are no longer used in clinical settings. In an atypical case, the diagnosis can be confirmed by demonstrating the bacilli by Warthin–Starry stain in tissue specimens. However, lymph node biopsies are not routinely recommended. Available serological tests for B. henselae include IFA and EIA. Serological assays are discussed in the previous section on bacillary angiomatosis. The sensitivity and specificity of these assays are variable and not reliable in immunosuppressed patients. It is recommended that the results of serological studies be used as an adjunct to clinical information. Differential diagnosis. Other infectious and malignant causes of lymphadenopathy should be considered in the differential diagnosis of cat scratch disease. If the lymph nodes are tender, an infectious aetiology is more likely. Bacterial adenitis can be secondary to many different organisms, including Staphylococcus aureus, group A βhaemolytic streptococci, anaerobes, atypical mycobacteria, Mycobacterium tuberculosis, Francisella tularensis or Brucella species. Fungal aetiologies such as histoplasmosis, sporotrichosis, toxoplasmosis and nocardial infection may also need to be considered. Viral illnesses secondary to cytomegalovirus, HIV and Epstein–Barr virus infection usually cause generalized lymphadenopathy, which is an infrequent cat scratch disease presentation. Malignancy may need to be ruled out at the onset or in more typical clinical presentations that are slow to resolve. Other noninfectious causes. including congenital and acquired cysts, Kawasaki disease and sarcoidosis. may also be considered in the differential diagnosis. Treatment. The majority of patients need no treatment as the disease resolves spontaneously over 2–4 months. Compresses, analgesics and avoidance of trauma to the involved nodes provide symptomatic relief. If suppuration occurs, aspiration (but not incision and drainage due to concern for sinus tract formation) or removal may be necessary. In vitro antibiotic susceptibility testing often does not correlate with clinical response. Unlike patients with bac-

58.7

illary angiomatosis, patients with cat scratch disease respond less favourably to antibiotic therapy. In cat scratch disease patients with prolonged fever, systemic symptoms and/or severe lymphadenitis, systemic antibiotics may be helpful. Out of 18 antibiotics studied in an uncontrolled retrospective study, only rifampicin, ciprofloxacin, trimethoprim-sulphamethoxazole and gentamicin provided significant clinical benefit [12]. A prospective, randomized, placebo-controlled trial of a 5-day course of azithromycin resulted in more rapid decrease in lymph node volume during the first month of treatment [23]. Although the azithromycin study provided data in favour of antibiotic treatment, there is no general agreement on antibiotic necessity for all cases. References 1 Debré R, Lamy M, Jammet ML et al. La maladie des griffes de chat. Semin Hop Paris 1950;26:1895–901. 2 Parinaud H. Conjunctivite infectieuse transmise par les animaux. Ann d’Oulistique 1889;101:252–3. 3 Wear DJ, Margileth AM, Hadfield TL et al. Cat-scratch disease: a bacterial infection. Science 1983;221:1403–5. 4 English CK, Wear DJ, Margileth AM et al. Cat-scratch disease: isolation and culture of the bacterial agent. JAMA 1988;259:1347–52. 5 Regnery RL, Olson JG, Perkins BA et al. Serological response to Rochalimaea henselae antigen in suspected cat-scratch disease. Lancet 1992;339:1443–5. 6 Zangwill KM, Hamilton DH, Perkins BA et al. Cat-scratch disease in Connecticut: epidemiology, risk factors and evaluation of a new diagnostic test. N Engl J Med 1993;329:8–13. 7 Kordick DL, Hilyard EJ, Hadfield TL et al. Bartonella clarridgeiae, a newly recognized zoonotic pathogen causing inoculation papules, fever, and lymphadenopathy (cat scratch disease). J Clin Microbiol 1997;35:1813–18. 8 Margileth AM, Baehren DF. Chest wall abscess due to cat scratch disease (CSD) in an adult with antibodies to Bartonella clarridgeiae. Case report and review of the thoracopulmonary manifestations of CSD. Clin Infect Dis 1998;27:353–7. 9 Moriarty RA, Margileth AM. Cat-scratch disease. Infect Dis Clin North Am 1987;1:575–90. 10 Magalhaes RF, Pitassi LH, Salvedego M et al. Bartonella henselae survives after the storage of red blood cell units; is it transmissible by transfusion? Transfus Med 2008;18(5):287–91. 11 Sander A, Frank B. Paronychia caused by Bartonella henselae. Lancet 1997;350:1078. 12 Margileth AM. Antibiotic therapy for cat-scratch disease: clinical study of therapeutic outcome in 268 patients and a review of the literature. Pediatr Infect Dis J 1992;11:474–8. 13 Munson P, Boyce T, Salomao D et al. Cat-scratch disease of the head and neck in a pediatric population: surgical indications and outcomes. Otolaryngol Head Neck Surg 2008;139:358–63. 14 Lenoir AA, Storch GA, DeSchryver-Kecskemeti K et al. Granulomatous hepatitis associated with cat scratch disease. Lancet 1988;1:1132–6. 15 Delahoussaye PM, Osborne BM. Cat-scratch disease presenting as abdominal visceral granulomas. J Infect Dis 1990;161:71–8. 16 Fretzayas A, Papadopoulos NG, Moustaki M et al. Unsuspected extralymphocutaneous dissemination in febrile cat scratch disease. Scand J Infect Dis 2001;33:599–603. 17 Carithers HA, Margileth AM. Cat-scratch disease: acute encephalopathy and other neurologic manifestations. Am J Dis Child 1991;145:98–101.

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18 Massei F, Gori L, Taddeuci G et al. Bartonella henselae infection associated with Guillain–Barre syndrome. Pediatr Infect Dis 2006;25(1):90–1. 19 Fournier P-E, Lelievre H, Ekkyn S. Epidemiology and clinical characteristics of Bartonella quintana and Bartonella henselae endocarditis. Medicine 2001;80:245–51. 20 Margileth AM. Cat-scratch disease: etiology, diagnosis, and therapy. Infect Med 1993;10(38–43):46. 21 Fouch B, Coventry S. A case of fatal disseminated Bartonella henselae infection (cat-scratch disease) with encephalitis. Arch Pathol Lab Med 2007;131(10):1591–4. 22 Raoult D,Fournier PE, Vandenesch F et al. Outcome and treatment of Bartonella endocarditis. Arch Intern Med 2003;163(2):226–30. 23 Bass JW, Freitas BC, Freitas AD et al. Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease. Pediatr Infect Dis J 1998;17:447–52.

Bartonellosis (Carrión disease) Definition. Bartonellosis is a disease caused by B. bacilliformis, transmitted by sand flies of the genus Phlebotomus. The disease is limited geographically to certain areas of the Andean regions of Peru, Colombia and Ecuador. Bartonellosis occurs in acute and chronic phases, known as Oroya fever and verruga peruana respectively. History. The discovery of pre-Colombian ceramic figurines bearing wart-like excrescences apparently representative of verruga peruana suggests that bartonellosis existed in South America before the arrival of the Spaniards. The first Spanish colonizers to arrive in Ecuador described a disease called bubas or berrugas, which greatly resembles bartonellosis. All references to the disease mentioned only cutaneous manifestations, until 1870, when an outbreak of severe anaemia and fever occurred in workers constructing a railway from Lima to Oroya [1]. This disease was given the name of Oroya fever but its aetiology was unknown. In 1885, Daniel A. Carrión, a medical student at the University of San Marcos in Lima, Peru, allowed himself to be injected with material taken from a patient with verruga peruana [2]. He subsequently died from Oroya fever, demonstrating the connection between the two different manifestations of the same disease. In the early 1990s, B. bacilliformis was demonstrated to be the pathogenic agent. A recent report describes the isolation of a newly discovered Bartonella species, B. rochalimae, causing symptoms similar to Oroya fever in a traveller to Peru [3]. Aetiology. Bartonella bacilliformis is a motile, aerobic, Gram-negative bacterium that lives within cells of the human reticuloendothelial system and attaches to erythrocytes. The only known vectors of B.bacilliformis are phlebotomine sand flies of the genus Lutzomyia. Specifically, Lutzomyia verrucarum is the most common vector in

Peru; however, the disease is not limited to this area and occurs in areas where L. verrucarum is absent. Lutzomyia colombiana is the most likely vector in Colombia; the identity of the species that transmits Bartonella in Ecuador remains unknown [4]. Pathology. The histological findings of the skin lesions in bartonellosis reveal capillary and endothelial cell proliferation, often resembling pyogenic granuloma (Figs 58.8, 58.9) [5]. The tissue is predominantly infiltrated by polymorphonuclear leucocytes but histiocytes, plasma cells, lymphocytes and mast cells are also variably present. Organisms are not usually detected in sections, even with the use of various special stains. Electron microscopic studies reveal the B. bacilliformis organism extracellularly in the stroma. Phagocytosed Bartonella has been reported in neutrophils by some authors and in histiocytes and endothelial cells by others [6].

Fig. 58.8 Histopathology of verruga peruana skin lesion demonstrating pyogenic, granuloma-like appearance. Courtesy of Dr Hector CaceresRios, Instituto de Salud del Niño, Lima, Peru.

Fig. 58.9 Histopathology of verruga peruana demonstrating capillary proliferation and mixed cellular infiltrate. Courtesy of Dr Hector Caceres-Rios, Instituto de Salud del Niño, Lima, Peru.

Bartonella Infections: Bacillary Angiomatosis, Cat Scratch Disease and Bartonellosis

Clinical features. Those infected either live in endemic areas or have visited endemic areas. The incubation period varies from 2 to 6 weeks and often the patient does not recall being bitten by sand flies. Oroya fever, the first stage of the disease, is most often characterized by intermittent fever, pallor, malaise, non-painful hepatomegaly and lymphadenopathy [7]. Other manifestations include myalgias, arthralgias, headache and abdominal pain. During this acute phase, the organisms invade the bloodstream, where they attach to the surface of up to 90% of the erythrocytes and cause a severe haemolytic anaemia [4]. Coma and death can occur in up to 40% of untreated patients. Many cases can be accompanied by other infections, especially Salmonella septicaemia, resulting in a more severe disease and an increase in fatality rate. Verruga peruana usually appears 2–8 weeks after the patient has apparently recovered from Oroya fever, but may present with no prior symptoms. The cutaneous lesions appear in crops and consist of non-tender erythematous and vascular macules and papules on the face and extremities (Figs 58.10–58.12). They may become nodular or pedunculated, tend to bleed easily and can ulcerate. In Maguina’s review of ‘modern era’ bartonellosis in Peru, three types of lesions are described: miliary, nodular (subdermic) and mular (>5 mm erythematous lesions, which bleed easily and may be associated with mild pruritus) [7]. The miliary form is most commonly observed and typically located on the lower extremities. Involvement of the mucous membranes can also occur. The lesions may persist for months or years and can be accompanied by mild constitutional symptoms and fever in at least 50% of patients. The eruption heals without scarring. Prognosis. The severity of the disease depends on the severity of the anaemia and concurrent infections (salmonellosis, malaria, tuberculosis, etc.). If untreated, the fatality rate is near 40%. A non-endemic population-based study suggests that this fatality rate may be significantly lower due to prior hospital-based data reflecting more seriously ill patients and recent data from less virulent strains [8]. In treated cases, the response is typically rapid. The cutaneous phase is not significantly altered by antibiotics but does not have long-term sequelae. Bartonellosis usually confers immunity for a lifetime, although rarely the immunity is only transitory [1]. Diagnosis. The diagnosis should be considered if the patient lives in the endemic area or has appropriate travel history. In Oroya fever, the organism can be seen in blood films and isolated in blood cultures. The organism may also be isolated from blood during the verruga peruana

58.9

(a)

(b) Fig. 58.10 Isolated facial lesions of verruga peruana in Peruvian children. Courtesy of Dr Hector Caceres-Rios, Instituto de Salud del Niño, Lima, Peru.

phase and/or observed in and isolated from a cutaneous lesion. Antibody tests for B. bacilliformis have been developed and may be useful for diagnosis and epidemiological studies [9]. Differential diagnosis. Acute Oroya fever may need to be distinguished from other systemic haemotropic bacterial infections, but the geographical confines of bartonellosis usually help eliminate these other causes. The distinctive lesions of verruga peruana appear strikingly similar to those of bacillary angiomatosis and may also

58.10

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Fig. 58.12 Conjunctival lesion of verruga peruana in a girl from Peru. Courtesy of Dr Hector Caceres-Rios, Instituto de Salud del Niño, Lima, Peru. Fig. 58.11 Multiple vascular papules of verruga peruana on the legs of a 15-year-old boy from Peru. Courtesy of Dr Hector Caceres-Rios, Instituto de Salud del Niño, Lima, Peru.

need to be differentiated from yaws, pyogenic granulomas, acquired haemangiomas and Kaposi sarcoma. Treatment. Antimicrobial therapy with penicillin, streptomycin, tetracycline and chloramphenicol rapidly terminates the acute febrile phase. Chloramphenicol is preferred because of its effectiveness against often associated Salmonella infections. Rifampicin is the drug of choice for the treatment of the eruptive phase of bartonellosis. Ciprofloxacin (500 mg twice daily for 7–10 days) has also been effective [10]. Blood transfusions and other supportive measures may also be necessary for severely anaemic patients. Prevention of the disease is mostly through insecticides for control of sand flies. References 1 Ricketts WE. Clinical manifestations of Carrión’s disease. Arch Intern Med 1949;84:751–81.

2 Garcia-Caceres U, Garcia FU. Bartonellosis: an immunodepressive disease and the life of Daniel Alcides Carrión. Am J Clin Pathol 1991;95(suppl 1):S58–66. 3 Eremeeva ME, Gerns HL, Lydy SL et al. Bacteremia, fever, and splenomegaly caused by a newly recognized bartonella species. N Engl J Med 2007;356(23):2381–7. 4 Alexander B. A review of bartonellosis in Ecuador and Colombia. Am J Trop Med Hyg 1995;52:354–9. 5 Arias-Stella J, Lieberman PH, Erlandson RA et al. Histology, immunohistochemistry, and ultrastructure of the verruga in Carrión’s disease. Am J Surg Pathol 1986;10:595–610. 6 Bhutto AM, Nonaka S, Hashiguchi Y et al. Histopathological and electron microscopical features of skin lesions in a patient with bartonellosis (verruga peruana). J Dermatol 1994;21:178–84. 7 Maguina C, Garcia PJ, Gotuzzo E et al. Bartonellosis (Carrión’s disease) in the modern era. Clin Infect Dis 2001;33:772–9. 8 Kosek M, Lavarello R, Gilman RH et al. Natural history of infection with Bartonella bacilliformis in a nonendemic population. J Infect Dis 2000;182(3):865–72. 9 Chamberlin J, Laughlin L, Gordon S et al. Serodiagnosis of Bartonella bacilliformis infection by indirect fluorescence antibody assay: test development and application to a population in an area of bartonellosis endemicity. J Clin Microbiol 2000;38:4269–71. 10 Maguina C, Gotuzzo E. Bartonellosis. New and old. Infect Dis Clin North Am 2000;14:1–22, vii.

59.1

C H A P T E R 59

Lyme Borreliosis Susan O’Connell Lyme Borreliosis Unit, Health Protection Microbiology Laboratory, Southampton University Hospitals NHS Trust, Southampton, UK

Definition and cause. Lyme borreliosis (Lyme disease) is a multisystem spirochaetal infection caused by Borrelia burgdorferi sensu lato, transmitted by hard-bodied ticks of the Ixodes ricinus complex. History. The term Lyme arthritis was used initially in the mid-1970s, after a cluster of cases of juvenile arthritis occurred in the area of Old Lyme and neighbouring communities in rural Connecticut. Two mothers became concerned about the extremely high rate of ‘juvenile rheumatoid arthritis’ diagnosed in the locality and alerted the local public health authorities, prompting investigations by clinicians and scientists from Yale University [1]. They noted that the arthritis had been preceded by tick bites and slowly spreading erythematous skin lesions in a significant number of patients, thus raising suspicions of a tick-transmitted infection. It also became apparent that the disease could affect other organs and systems, including the nervous system and the heart, and the term Lyme disease was used to denote this expanded clinical spectrum. The causative organism was a previously unknown spirochaete, subsequently named Borrelia burgdorferi, which was isolated initially from Ixodes scapularis ticks (deer ticks) and then from skin biopsies, blood and cerebrospinal fluid of affected patients. Similar rashes following tick bites, termed erythema migrans or erythema chronicum migrans, had been recognized in European countries for many years, and clinicians had noted associations of tick bites with neurological presentations such as facial palsy, meningitis and radiculoneuritis. Many physicians suspected an infectious cause, and some had used empirical penicillin treatment, with good results. Another skin condition, acrodermatitis chronica atrophicans, had been described by German, Swedish and Austrian clinicians from the late 19th century onwards, and was also found to be responsive to empirical penicillin treatment. In the early 1980s Swedish researchers, using culture media developed by the American workers,

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

established that B. burgdorferi was the cause of acrodermatitis chronica atrophicans, erythema migrans and a third skin manifestation also seen in Europe, borrelial lymphocytoma. The disease is now generally known in Europe as Lyme borreliosis [2]. Epidemiology and ecological factors. Lyme borreliosis (LB) is the most common arthropod-borne infectious disease in temperate areas of the northern hemisphere [3,4]. Its incidence is strongly dependent on ecological and climatic factors affecting vector ticks and small mammals and birds that are reservoir hosts for Borrelia burgdorferi, and on human behavioural factors leading to risk of tick bite. In North America the regions of highest LB incidence are north-eastern and mid-Atlantic seaboard states, from Maine to Virginia, the upper midwest states of Wisconsin and Minnesota and some coastal areas of northern California. About 27,000 cases were reported in 2007, but the true incidence may be over three times greater [4]. Few cases have been reported from Canada, mainly from southern Ontario [5]. In Europe the infection occurs in woodland and forested regions mainly between latitudes 62o and 42o North (southern Scandinavia to northern Mediterranean countries), with an increasing incidence from west to east. There is no standardized case-reporting system for Europe, but a review of numerous data sources suggests that there may be as many as 200,000 European cases annually [3,6]. Prospective studies in several highendemic areas showed that about 90% are likely to be erythema migrans [7,8]. Within endemic regions of both continents there is considerable variation in incidence, with focal areas of hyperendemicity. Hard-bodied ticks of the Ixodes ricinus complex are the only vectors for Lyme borreliosis. In North America the infection is transmitted by the black-legged or deer tick I. scapularis (formerly called I. dammini) and I. pacificus in the Pacifc coastal states [4]. The main European vector is Ixodes ricinus (commonly called the deer, sheep or castor bean tick). In Russia and the Baltic republics the range of I. ricinus overlaps with that of another vector, I. persulcatus (the taiga tick), which is also widespread throughout temperate Asia to the Far East, including Japan [6].

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Ixodid ticks are very susceptible to desiccation and require a high relative humidity [9]. The most favourable tick habitats are forested areas and heathland where leaf litter and undergrowth provide protection against drying. These habitats also support animals and birds that are the natural feeding hosts for ticks [6]. Ticks have a three-stage lifecycle (larva, nymph and adult), usually over 2–3 years (Fig. 59.1). At each stage they take a single blood meal lasting about 3–7 days. The common feeding hosts for larvae and nymphs are small and medium-sized mammals such as field mice, voles, squirrels and hares, and groundfeeding birds including blackbirds, robins and pheasants. These creatures are reservoir-competent hosts for B. burgdorferi. Ticks can become infected during the course of a blood meal taken from a spirochaetemic animal and in turn can transmit infection to hosts during feeds at later stages in their lifecycle, thus maintaining the spirochaetal reservoir in nature [6]. Spring and early summer is the peak period for tick feeding and there can be a secondary peak during autumn. Deer are strongly associated with the presence of ticks. They are preferred feeding hosts for adult female ticks,

who mate after feeding, drop back into the undergrowth and lay between 1000 and 2000 eggs before dying. Deer are important in the maintenance and expansion of tick populations because of their feeding role at the tick’s reproductive stage but they are not competent reservoir hosts for B. burgdorferi. Increased numbers and geographic ranges of deer in some regions of Europe and North America have been linked to significant increases in tick populations and Lyme borreliosis incidence. Human beings can be incidental feeding hosts for ticks. Larval ticks pose minimal risk for borrelial transmission, as it is rare for them to have been infected transovarially. Nymphal ticks are most likely to transmit infection to people, as they are very small (about the size of a poppyseed) and may not be noticed, even after feeding. Their major feeding period is during late spring and early summer, when human outdoor recreational activity is also likely to be at its peak. The larger adult ticks are more likely to be spotted and removed before completing their feeds (Fig. 59.2). Most ticks do not carry borreliae. Infected I. ricinus ticks are unlikely to transmit infection in the first 18–24 hours

Larva feeds on host 1 Larvae seek new host Fully fed larva drops to ground

Eggs hatch to larva Host 1 Eggs laid by female

Larva moults to nymph

Fully fed female drops from host to ground

Life cycle of the deer tick (Ixodes ricinus)

Host 3

Host 2

Nymph attaches and feeds on host 2

Female attaches and feeds on host 3

Nymph moults to adult Fig. 59.1 Lifecycle of Ixodes ricinus ticks (after Professor Jeremy Gray and Mr Bernard Kaye). The relative size of the animals approximates their significance as hosts forthe different life-cycle stages in a typical woodland habitat.

Lyme Borreliosis

Fig. 59.2 Ixodid tick on nail of little finger.

of feeding and I. scapularis ticks within the first 36 hours, but transmission risk rises steadily as feeding continues. Early removal of attached ticks greatly reduces human infection risk [4,6]. There is some evidence that transmission may take place at an earlier stage during I. persulcatus blood meals [6]. Most cases of Lyme borreliosis are reported in the summer months, between May and September, but some patients with disseminated and later presentations are diagnosed at other times of the year. In many studies there is a bimodal age distribution, with higher incidences in the 5–19 year age group and in people over age 40. Male:female incidence ratios seem to be about equal or with a slight preponderance of cases in males in some studies [3,4,6–8]. The major risk factors for infection are residential or recreational activities in tick habitats. Causative organisms and pathogenetic factors. At least 15 genospecies of Borrelia burgdorferi sensu lato have been identified; the majority are not pathogenic. The only pathogenic genospecies found in North America is B. burgdorferi sensu stricto. A wider range of pathogenic genospecies is found in Europe, predominantly B. garinii and B. afzelii, but B. burgdorferi sensu stricto occurs in some areas [10,11]. All pathogenic strains can cause erythema migrans, the early skin lesion. There is evidence for some genospecies-dependent variations associated with later manifestations and for within-genospecies variation in pathogenicity [12]. B. burgdorferi sensu stricto is strongly linked with arthritic and neurological complications, B. garinii and B. bavariensis with neuroborreliosis and B. afzelii with acrodermatitis chronica atrophicans (ACA). Occasional cases of erythema migrans are caused by B. spielmanii and there have been only rare reports of disease linked to B. valaisiana and B. lusitaniae. Genospecies differences also have implications for vaccine development.

59.3

Variations in the geographic distribution of European borrelial genospecies affect the incidence and types of clinical presentations of later disease seen in different locations. For example, ACA frequently occurs in Scandinavia and central Europe, where B. afzelii is commonly found. The condition is infrequently seen in the UK, where B. afzelii is uncommon. The most commonly identified pathogenic genospecies in the UK is B. garinii, and acute neuroborreliosis is the main complication seen there. A high proportion of infected ticks in the UK carry B. valaisiana, which is essentially non-pathogenic. This may have some bearing on the lower overall incidence of clinically significant disease there compared to other parts of Europe where a higher proportion of infected ticks carry more pathogenic genospecies. Borrelia burgdorferi is an obligate parasite with limited biosynthetic ability, relying on its host for many nutrients. It does not possess the virulence factors such as toxins, lipopolysaccharides and enzymes that are associated with many bacterial pathogens [10]. Borreliae are highly motile and can disseminate through tissues and bind closely to host cell surfaces, affecting their function [13]. Borreliae must adapt to life in very different environments: the midgut of the tick vector at ambient temperature and the mammalian or avian natural reservoir host from about 35o to 39oC. They vary in gene expression, leading to production of different protein components. Some help the organisms to evade the initial defences of the host’s innate immune system, others contribute to evasion of the subsequent acquired immune response, at least for some time. For example, borreliae express an outer surface protein (Osp) called OspA within the tick, but OspC is preferentially expressed during the early stages of mammalian. Expression of another protein, VlsE, which has an elaborate system for extensive variation over time, is required to maintain persistent infection. Synthesis of VlsE starts at about the time that OspC production ceases and helps the organism to evade the host’s humoral immune response, at least for some time [10,13]. Many clinical manifestations of Lyme borreliosis occur largely as a consequence of the human immunopathological response to infection. Some borrelial lipoproteins can activate a variety of cells, including macrophages, B-cells, dendritic cells and endothelial cells, triggering inflammatory responses that contribute to pathogenesis [10,13,14]. There is also some in vitro evidence that antibodies produced in response to B. burgdorferi infection may also bind to human neural and other antigens [13].

Ixodid tick bites Ixodid ticks attach to their hosts by barbed mouth parts. Their saliva contains anaesthetic, anti-inflammatory and anticoagulant substances that allow them to attach and

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complete their feed without their hosts becoming aware of their presence [15]. The bites are not usually significantly painful or itchy, although some people who have had many bites over a prolonged period, such as forestry

workers, can become sensitized to tick saliva and develop itchy skin reactions. This can provide some protection against B. burgdorferi infection, by drawing early attention to the tick before there is significant risk of spirochaetal transmission. Clinical features. Borrelia burgdorferi infection can be asymptomatic or minimally symptomatic, as shown by prospective studies in areas of high prevalence [7,8,16,17]. Clinically significant disease has been customarily divided into three stages – early localized, early disseminated and late Lyme borreliosis – but the process should be regarded as a continuing pathological evolution in some untreated patients rather than having distinct phases or processes. Progression to later stage disease is not inevitable. The most frequently affected tissues and organs are the skin, nervous system and joints. Case definitions have been published, primarily for epidemiological purposes in the USA and for clinical use in Europe [18,19].

Skin manifestations Erythema migrans (Figs 59.3, 59.4). Erythema migrans (EM) is the most characteristic presentation of Lyme borreliosis, occurring in about 90% of symptomatic infections [7,8,20]. It is an erythematous, usually annular lesion spreading slowly from the site of a tick bite (often unnoticed) that had occurred 2 or more days previously. This lag phase occurs because spirochaetal replication is relatively slow by comparison to pyogenic bacteria. Localized

Fig. 59.3 Erythema migrans in a child.

(a)

(b)

Fig. 59.4 Erythema migrans in adults. Courtesy of the late Dr John White.

Lyme Borreliosis

redness appearing within a few hours of a tick bite is likely to be caused by an immediate inflammatory response or hypersensitivity reaction and usually fades within several days. Common sites for tick attachment and undisturbed blood meals which can result in borrelial transmission include skinfolds (groins, armpits, backs of knees, waistband area, under breasts), back and scalp. Tick bites are more frequent around the head and neck areas of children than adults. Most EM rashes become evident within about 5–14 days of a bite. They are usually round or oval but some can have a more triangular or linear appearance, presumably determined in part by lines of skin tension. A central punctum may be present at the tick attachment site. The leading edge can have a stronger colour, giving the appearance of an outer ring or border, but is not significantly raised. They are not usually particularly pruritic or painful [20]. Very itchy or painful lesions should raise suspicion of other conditions, including severe insect bite reactions or pyogenic infections. Most EM rashes are homogeneous in the early stages but with longer duration, some can develop an area of central clearing, giving a so-called ‘bull’s-eye’ or target-like appearance. Very pale lesions may be seen more easily when the skin is warm, e.g. after exercise or bathing. If left untreated, EM rashes eventually resolve over weeks to months, but usually clear within a few days of commencing appropriate treatment. There can be variations in EM appearance, related to the infecting genospecies. In North American-acquired infections, caused exclusively by B. burgdorferi sensu stricto, rashes tend to evolve more quickly and are less likely to have central clearing than European-acquired infections caused by B. afzelii and are more likely to be accompanied by systemic symptoms and signs including malaise, myalgia, arthralgia, headache, fever and regional lymphadenopathy [21]. Some have central vesiculation, which can cause difficulties in differentiation from cellulitis, arthropod bites or herpesvirus infections [22]. Some EM lesions caused by B. afzelii develop slowly, with little systemic upset, and can reach large sizes with high rates of central clearing. Infections caused by B. garinii seem to be more virulent than those caused by B. afzelii, with more homogeneous and faster evolving rashes and a higher likelihood of systemic symptoms and signs [23]. Multiple erythema migrans can occur, principally in infections caused by B. burgdorferi sensu stricto. Affected patients have multiple smaller lesions resulting from haematogenous spread of spirochaetes from the initial lesion. They usually have significant systemic symptoms and may also have other objective extracutaneous manifestations of Lyme borreliosis, which include facial nerve palsy, meningitis, carditis and arthritis [24].

59.5

Differential diagnosis of erythema migrans includes reactions to tick bites or other arthropod bites, urticaria, cellulitis, granuloma annulare, ringworm, herpes simplex or zoster, fixed drug eruptions or contact dermatitis [20,25,26]. The histological appearance of erythema migrans is characterized by patchy perivascular infiltrates, predominantly lymphocytic, with plasma cells, mast cells and occasionally eosinophils, mainly affecting the superficial dermis. Immunohistochemical staining may demonstrate occasional spirochaetes, but silver staining is prone to artefact [27,28]. Borrelial lymphocytoma (Fig. 59.5). Borrelial lymphocytoma (also termed lymphadenosis benigna cutis) is an uncommon early manifestation of European Lyme borreliosis; only rare cases have been reported in the USA. It may develop several weeks to months after a tick bite and occurs more frequently in children than adults. It presents as a bluish-red tumour-like skin infiltrate several centimetres in diameter. The most common sites are earlobe, ear helix, nipple or scrotum. If untreated, it can persist for some months but usually resolves rapidly with antibiotic treatment [29,30]. Histological examination shows dense lymphocytic and histiocytic infiltrates, frequently with germinal centres [31]. Borrelial lymphocytoma lesions have occasionally been misdiagnosed as B-cell lymphomas. Acrodermatitis chronica atrophicans (Fig. 59.6). Acrodermatitis chronica atrophicans (ACA) is an uncommon manifestation of long-standing infection, seen almost exclusively in European-acquired infections. It occurs mainly in older people, with only rare reports of ACAlike lesions in children [2,32]. Most cases are caused by B. afzelii infection. It usually occurs on extensor sites of the extremities, most commonly on the lower legs, causing

Fig. 59.5 Borrelial lymphocytoma.

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Fig. 59.6 Acrodermatitis chronica atrophicans. Courtesy of the late Dr John White.

localized livid red colour changes, doughy swelling and induration of the affected skin. Untreated lesions may progress over years, with development of hyperpigmentation and atrophy, giving a cigarette paper-like appearance [2]. There may be an associated peripheral neuropathy. If severe, this can lead to joint damage secondary to the neurological deficit. The differential diagnosis depends on the duration of the condition and includes vascular insufficiency, acrocyanosis, livedo reticularis, lymphoedema or chilblains. The infection responds to treatment but completeness of recovery depends on the degree of underlying tissue damage. Histological appearance depends on the duration of the lesion, with earlier inflammatory lesions showing perivascular infiltrates of lymphocytes and plasma cells, dermal oedema and telangiectasia. Epidermal atrophy and loss of epidermal appendages are characteristic findings in late-stage ACA [28,33]. Other skin manifestations. Several other skin conditions, including morphea and lichen sclerosis et atrophicus, have been linked to Borrelia burgdorferi infection in a few case reports and small studies, predominantly from high-endemic areas of Europe. Other European and North American studies have shown no link with these conditions. These mainly early reports should be interpreted cautiously, as the laboratory tests used in support of some cases relied on methods such as silver staining, which is prone to artefact, or IgM antibody tests, which are known to have a significant risk of false-positive reactions. Positive serology, especially in areas of high prevalence (where background seroprevalence in the population can be as high as 10%), should not be interpreted as evidence for causation of atypical lesions without additional support from direct detection of the organism. More recent studies and reviews suggest that B. burgdorferi is rarely associated with these presentations [28,34–36].

Nervous system manifestations Neuroborreliosis is a common complication of European and North American-acquired Lyme borreliosis, mainly presenting within a few weeks to months of infection, in about 10% and 20% of previously untreated patients, often with concurrent or recent erythema migrans. It can affect both peripheral and central nervous systems. The most common manifestation in children is isolated facial nerve palsy without clinical signs of meningitis, although CSF examinations of some patients show mononuclear pleiocytosis [37,38]. It has been postulated that the higher rate of tick bites occurring on the head and neck region of young children causes a relatively higher incidence of facial palsies in children than in adults [39]. Other neurological presentations in children include ‘viral-like’ meningitis with or without facial or other cranial nerve palsies, including sixth nerve palsy [37,38]. Rare cases have been reported of children with previously untreated Lyme neuroborreliosis presenting with raised intracranial pressure and very high CSF protein levels, leading to sight-threatening complications [40]. Other uncommon complications include meningoencephalitis and encephalopathy. Garin–Bujadoux–Bannwarth (GBB) syndrome is the most common neurological complication in adults. Features include facial palsy, meningitis and radiculoneuritis, usually presenting as a painful radiculopathy similar to that of shingles or mechanical radiculopathy. It was originally described by French physicians in 1922 and a German neurologist in 1941 [41,42]. A more indolent form of radiculopathy has been recognized in some European patients, mainly in older age groups, who present with a gradual onset of pain increasing over months after infection acquisition. This may result from direct spirochaetal invasion of peripheral nerves from the initial skin inoculation site, gradually extending to the nerve roots, in contrast to the more rapid onset and wider effects seen in classic GBB syndrome, resulting from haematogenous spread [13]. In both situations radicular pain can be severe and patients may require opiates, but analgesia requirements usually reduce very significantly within a short time of commencing antibiotic treatment. Painful radiculopathy is rare in children. Meningoencephalitis is an uncommon complication in both children and adults. Encephalomyelitis is rare, mainly seen in older adults. It appears to affect white matter disproportionately and may be confused with multiple sclerosis or, if particularly acute, with acute disseminated encephalomyelitis. Virtually all patients have an inflammatory CSF and intrathecal production of B. burgdorferi antibodies, indicating the value of CSF examination [30,43]. European experts have estimated that it occurs in less than one in 1000 cases of untreated infection [44].

Lyme Borreliosis

Musculoskeletal manifestions Myalgias and arthralgias are common features of early disseminated Lyme borreliosis. Frank arthritis with synovitis was the presentation that initially drew attention to the infection in Connecticut. As with other later manifestations, it has become less common in recent years, probably because high awareness of Lyme borreliosis in endemic areas has led to earlier recognition and treatment. Arthritis is strongly associated with infection caused by B. burgdorferi sensu stricto, but other pathogenic genospecies also cause occasional cases in Europe [45]. Patients present initially with migratory arthralgias, developing later into an asymmetrical mono- or oligoarthritis, most commonly affecting the knee. Other large joints are less frequently affected, and small joints of the hands and feet are rarely involved. Synovial effusion can cause marked joint swelling, out of proportion to the degree of pain. Patients do not have symptoms suggesting acute sepsis, and serum inflammatory markers are usually only mildly elevated [46,47]. Tests for serum IgG antibodies to B. burgdorferi are almost always very strongly positive, and laboratory examination of synovial fluid usually demonstrates a polymorphonuclear infiltrate and presence of borrelial DNA in patients who have not received antibiotics. Antibiotic treatment is usually effective in eradicating infection from the affected joint(s) but inflammation may not resolve completely by the end of treatment, taking some weeks or months for complete resolution. A minority of patients have persistent arthritis even after re-treatment, without objective evidence of active infection. This has been termed ‘antibiotic-refractory’ arthritis and appears to have an autoimmune component. Patients with antibiotic-refractory arthritis are more likely than those with antibiotic-responsive arthritis to have HLA-DR molecules that bind B. burgdorferi outer surface protein A163–175, and in some patients there is also an association with intra-articular steroid use prior to antibiotic treatment [48]. An early longitudinal study of 21 patients who did not receive any antibiotics showed that they had attacks of arthritis for a median of 43 months (range 4–76 months) [46]. A later study of patients who received antibiotic treatment showed that those with antibioticresponsive disease had episodes of arthritis during a median total time period of 4 months (range 1–51 months) and those with antibiotic-refractory disease had episodes for a median total period of 16 months (range 4–73 months), suggesting that antibiotic treatment reduces the duration of inflammation even in antibiotic-refractory arthritis [48]. Non-steroidal anti-inflammatory agents are also helpful. Lyme disease in pregnancy Three cases of maternal-to-fetal transmission of Borrelia

59.7

burgdorferi were documented in early reports, with the babies stillborn or dying within the first 48 hours after delivery. The mothers had received inadequate or no treatment for EM during pregnancy. Since then several large studies have shown no increased rates of adverse outcomes of pregnancies and no excess of congenital abormalities in Lyme-endemic areas by comparison to non-endemic areas. An extensive review of published data concluded that an adverse fetal outcome due to maternal infection with Borrelia burgdorferi at any point during pregnancy in humans is at most extremely rare [49]. Recommendations for treatment of Lyme borreliosis in pregnant women are the same as those for non-pregnant adults, with the exception that doxycycline is contraindicated [50,51]. Diagnosis. Diagnosis of EM is primarily clinical, based on recognition of the characteristic skin lesion in a patient who has had recent exposure to ticks. A specific history of tick bite is not an essential criterion, as many tick bites go unnoticed. No later stage manifestation of Lyme borreliosis is unique to the infection; supporting evidence from the laboratory should be obtained to confirm a diagnosis of disseminated or late infection [19,50].

Direct detection methods Direct detection methods include borrelial culture and DNA detection. Culture is not routinely available for diagnostic purposes, as it requires complex culture media and may take 3–6 weeks. It is valuable in providing isolates of proven pathogenicity for research purposes. It has an overall success rate of about 70% when applied to skin biopsies from patients with untreated erythema migrans or ACA, but much lower rates (40 kg, 250 mg per day; 20–40 kg, 125 mg per day; and 20 ng/mL (in case of an associated clonal haematological non-mast cell lineage disease (AHNMO), d. is not valid)b If one major and one minor, or three minor criteria are fulfilled then the diagnosis is systemic mastocytosis a

See Table 75.4 for morphological criteria and suggested terms. In acute myeloid leukaemia, myelodysplastic syndrome or myeloproliferative syndrome, elevated serum tryptase levels have been detected without increase in mast cell numbers or signs of mastocytosis.

b

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

75.2

Chapter 75

Table 75.1 Classification and characteristics of the different categories of mastocytosis – overview. Modified from Horny et al. 2008 [2] Disease entities

Investigation(s)a

Typical finding(s)

Cutaneous mastocytosisa (CM) including mastocytoma, maculopapular CM and diffuse CM

SM criteriaa Skin lesions Bone marrow histologya Peripheral blood counts Serum tryptase

Not fulfilled Present, MC infiltrates, c-kit mutation in lesional skin Negative, no MC infiltrates Normala q21.1): a newly recognised chromosomal syndrome in a child with Klinefelter ’s syndrome. J Med Genet 1993;30(5):436–7. 7 Gohlke BC, Haug K, Fukami M et al. Interstitial deletion in Xp22.3 is associated with X linked ichthyosis, mental retardation, and epilepsy. J Med Genet 2000;37(8):600–2. 8 Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod 1996;11(10):2217–22. 9 American Academy of Pediatrics. Health supervision for children with Down syndrome. Pediatrics 2001;107(2):442–9. 10 Madan V, Williams J, Lear JT. Dermatological manifestations of Down’s syndrome. Clin Exp Dermatol 2006;31(5):623–9. 11 Sybert VP, McCauley E. Turner ’s syndrome. N Engl J Med 2004;351(12):1227–38. 12 Hook EB, Warburton D. The distribution of chromosomal genotypes associated with Turner ’s syndrome: livebirth prevalence rates and

23 24 25

26

27

28 29

30

31

32

33

116.17

evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet 1983;64(1):24–7. Aldred MA, Sanford RO, Thomas NS et al. Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes. J Med Genet 2004;41(6):433–9. Cody JD, Ghidoni PD, DuPont BR et al. Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q. Am J Med Genet 1999;85(5):455–62. Elias-Jones AC, Habibi P, Larcher VF, Spencer T, Butler LJ. The trisomy (5)(q31-qter) syndrome: study of a family with a t(5:14) translocation. Arch Dis Child 1988;63(4):427–31. Stalker HJ, Ayme S, Delneste D, Scarpelli H, Vekemans M, der Kaloustian VM. Duplication of 9q12-q33: a case report and implications for the dup(9q) syndrome. Am J Med Genet 1993;45(4): 456–9. Telvi L, Bernheim A, Ion A, Fouquet F, Le Bouc Y, Chaussain JL. Gonadal dysgenesis in del(18p) syndrome. Am J Med Genet 1995;57(4):598–600. Alperin ES, Shapiro LJ. Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein. J Biol Chem 1997;272(33):20756–63. Stewart H, Smith PT, Gaunt L et al. De novo deletion of chromosome 18q in a baby with harlequin ichthyosis. Am J Med Genet 2001;102(4):342–5. Root S, Carey JC. Survival in trisomy 18. Am J Med Genet 1994;49(2):170–4. Tajara EH, Varella-Garcia M, Gusson AC. Interstitial long-arm deletion of chromosome 7 and ectrodactyly. Am J Med Genet 1989;32(2):192–4. Marion JP, Fernhoff PM, Korotkin J, Priest JH. Pre- and postnatal diagnosis of trisomy 4 mosaicism. Am J Med Genet 1990;37(3):362–5. Watson MS, McAllister-Barton L, Mahoney MJ, Breg WR. Deletion (12)(q15q21.2). J Med Genet 1989;26(5):343–4. Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis 2006;1:42. Houlston RS, Renshaw RM, James RS, Ironton R, Temple IK. Duplication of 16q22–>qter confirmed by fluorescence in situ hybridisation and molecular analysis. J Med Genet 1994;31(11):884–7. Kulharya AS, Michaelis RC, Norris KS, Taylor HA, Garcia-Heras J. Constitutional del(19)(q12q13.1) in a three-year-old girl with severe phenotypic abnormalities affecting multiple organ systems. Am J Med Genet 1998;77(5):391–4. Metaxotou C, Tsenghi C, Bitzos I, Strataki-Benetou M, KalpiniMavrou A, Matsaniotis N. Trisomy 3 mosaicism in a liveborn infant. Clin Genet 1981;19(1):37–40. Lowenstein EJ, Kim KH, Glick SA. Turner ’s syndrome in dermatology. J Am Acad Dermatol 2004;50(5):767–76. Brand–Saberi B, Floel H, Christ B, Schulte-Vallentin M, Schindler H. Alterations of the fetal extracellular matrix in the nuchal oedema of Down’s syndrome. Ann Anat 1994;176(6):539–47. Chitayat D, Hodgkinson K, Luke A, Winsor E, Rose T, Kalousek D. Prenatal diagnosis and fetopathological findings in five fetuses with trisomy 9. Am J Med Genet 1995;56(3):247–54. Mowat D, Jauch A, Robson L, Smith A. Duplication within chromosome 5q characterized by fluorescence in situ hybridization. Am J Med Genet 1999;83(5):361–4. Fryns JP, Kleczkowska A, Limbos C, Vandecasseye W, Van den Berghe H. Centric fission of chromosome 7 with 47,XX,del(7)(pter— cen::q21—qter)+cen fr karyotype in a mother and proximal 7q deletion in two malformed newborns. Ann Genet 1985;28(4):248–50. Galan F, Aguilar MS, Gonzalez J et al. Interstitial 15q deletion without a classic Prader–Willi phenotype. Am J Med Genet 1991;38(4):532–4.

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34 Van Dyke DL, Wiktor A, Palmer CG et al. Ullrich–Turner syndrome with a small ring X chromosome and presence of mental retardation. Am J Med Genet 1992;43(6):996–1005. 35 Mefford HC, Sharp AJ, Baker C et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 2008;359(16):1685–99. 36 McLeod DR, Fowlow SB, Robertson A, Samcoe D, Burgess I, Hoo JJ. Chromosome 6q deletions: a report of two additional cases and a review of the literature. Am J Med Genet 1990;35(1):79–84. 37 Cohen MM, Lin CC, Sybert V, Orecchio EJ. Two human X–autosome translocations identified by autoradiography and fluorescence. Am J Hum Genet 1972;24(5):583–97. 38 Turleau C, Niaudet P, Cabanis MO, Plessis G, Cau D, de Grouchy J. X-linked hypohidrotic ectodermal dysplasia and t(X;12) in a female. Clin Genet 1989;35(6):462–6. 39 Redheendran R, Neu RL, Bannerman RM. Long survival in trisomy 13 syndrome: 21 cases including prolonged survival in two patients 11 and 19 years old. Am J Med Genet 1981;8(2):167–72. 40 Battaglia A, Filippi T, Carey JC. Update on the clinical features and natural history of Wolf–Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision. Am J Med Genet C Semin Med Genet 2008;148C(4):246–51. 41 Khan JY, Moss C, Roper HP. Aplasia cutis congenita with chromosome 12q abnormality. Arch Dis Child Fetal Neonatal Ed 1995;72(3):F205–6. 42 Happle R. Deletion 3q27—-3qter associated with a new skin disorder? Hum Genet 1990;85(5):563–4. 43 Chitayat D, Babul R, Silver MM, Jay V, Teshima IE, Babyn P, Becker LE. Terminal deletion of the long arm of chromosome 3 [46,XX,del(3) (q27–>qter)]. Am J Med Genet 1996;61:45–8. 44 Curtis Rogers R. Unknown cases. Proc Greenwood Genetic Center 1988;7:57. 45 Campbell WA, Newton MS, Price WH. Hypostatic leg ulceration and Klinefelter ’s syndrome. J Ment Defic Res 1980;24(2):115–7. 46 Zollner TM, Veraart JC, Wolter M et al. Leg ulcers in Klinefelter ’s syndrome – further evidence for an involvement of plasminogen activator inhibitor-1. Br J Dermatol 1997;136(3):341–4. 47 Dissemond J, Knab J, Lehnen M, Goos M. Increased activity of factor VIII coagulant associated with venous ulcer in a patient with Klinefelter ’s syndrome. J Eur Acad Dermatol Venereol 2005;19(2):240–2. 48 Lapecorella M, Marino R, de Pergola G, Scaraggi FA, Speciale V, de Mitrio V. Severe venous thromboembolism in a young man with Klinefelter ’s syndrome and heterozygosis for both G20210A prothrombin and factor V Leiden mutations. Blood Coagul Fibrinolysis 2003;14(1):95–8. 49 Ozbek M, Ozturk MA, Ureten K, Ceneli O, Erdogan M, Haznedaroglu IC. Severe arterial thrombophilia associated with a homozygous MTHFR gene mutation (A1298C) in a young man with Klinefelter syndrome. Clin Appl Thromb Hemost 2008;14(3):369–71. 50 Larralde M, Gardner SS, Torrado MV et al. Lymphedema as a postulated cause of cutis verticis gyrata in Turner syndrome. Pediatr Dermatol 1998;15(1):18–22. 51 Insley J. Syndrome associated with a deficiency of part of the long arm of chromosome no. 18. Arch Dis Child 1967;42(222):140–6. 52 Mehta RK, Burrows NP, Payne CM, Mendelsohn SS, Pope FM, Rytina E. Elastosis perforans serpiginosa and associated disorders. Clin Exp Dermatol 2001;26(6):521–4. 53 Becuwe C, Roth B, Villedieu MH, Chouvet B, Kanitakis J, Claudy A. Milia-like idiopathic calcinosis cutis. Pediatr Dermatol 2004;21(4):483–5. 54 Daneshpazhooh M, Nazemi TM, Bigdeloo L, Yoosefi M. Mucocutaneous findings in 100 children with Down syndrome. Pediatr Dermatol 2007;24(3):317–20. 55 Schepis C, Barone C, Siragusa M, Pettinato R, Romano C. An updated survey on skin conditions in Down syndrome. Dermatology 2002;205(3):234–8.

56 Nazarenko SA, Ostroverkhova NV, Vasiljeva EO et al. Keratosis pilaris and ulerythema ophryogenes associated with an 18p deletion caused by a Y/18 translocation. Am J Med Genet 1999;85(2): 179–82. 57 Fridman C, Hosomi N, Varela MC, Souza AH, Fukai K, Koiffmann CP. Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene. Am J Med Genet A 2003;119A(2):180–3. 58 Slavotinek A, Kingston H. Interstitial deletion of bands 4q12–>q13.1: case report and review of proximal 4q deletions. J Med Genet 1997;34(10):862–5. 59 Fujimoto A, Allanson J, Crowe CA, Lipson MH, Johnson VP. Natural history of mosaic trisomy 14 syndrome. Am J Med Genet 1992;44(2):189–96. 60 English CJ, Goodship JA, Jackson A, Lowry M, Wolstenholme J. Trisomy 12 mosaicism in a 7 year old girl with dysmorphic features and normal mental development. J Med Genet 1994;31(3):253–4. 61 Becker B, Jospe N, Goldsmith LA. Melanocytic nevi in Turner syndrome. Pediatr Dermatol 1994;11(2):120–4. 62 Gibbs P, Brady BM, Gonzalez R, Robinson WA. Nevi and melanoma: lessons from Turner ’s syndrome. Dermatology 2001;202(1):1–3. 63 Zvulunov A. Growth hormone treatment in Turner syndrome. Eur J Pediatr 1994;153(12):919. 64 Maraschio P, Tupler R, Barbierato L et al. An analysis of Xq deletions. Hum Genet 1996;97(3):375–81. 65 Aughton DJ, Al Saadi AA, Transue DJ. Single maxillary central incisor in a girl with del(18p) syndrome. J Med Genet 1991;28(8):530–2. 66 Price SM, Stanhope R, Garrett C, Preece MA, Trembath RC. The spectrum of Silver–Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet 1999;36: 837–42. 67 Netchine I, Rossignol S, Dufourg MN et al. 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell–Silver syndrome: clinical scoring system and epigenetic– phenotypic correlations. J Clin Endocrin Metab 2007;92:3148–54. 68 Lai MM, Robards MF, Berry AC, Fear CN, Hart C. Two cases of interstitial deletion 1p. J Med Genet 1991;28(2):128–30. 69 Yoshino M, Watanabe Y, Harada N, Abe K. De novo interstitial deletion of 1p (pter----p34.1::p32.3----qter). J Med Genet 1991;28(8):539–40. 70 Shapira SK, McCaskill C, Northrup H et al. Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet 1997;61:642–50. 71 Podruch PE, Yen FS, Dinno ND, Weisskopf B. Yq- in a child with livedo reticularis, snub nose, microcephaly, and profound mental retardation. J Med Genet 1982;19(5):377–80. 72 Buysse K, Reardon W, Mehta L et al. The 12q14 microdeletion syndrome: additional patients and further evidence that HMGA2 is an important genetic determinant for human height. Eur J Med Genet 200;52(2–3):101–7. 73 Togawa Y, Nohira G, Shinkai H, Utani A. Collagenoma in Down syndrome. Br J Dermatol 2003;148(3):596–7. 74 Beemer FA, Klep-de Pater JM, Sepers GJ, Janssen B. Two cases of interstitial deletion of the long arm of chromosome 1: del(1) (q21----q25) and del(1)(q41----q43). Clin Genet 1985;27(5):515–19. 75 Schrander-Stumpel CT, Govaerts LC, Engelen JJ et al. Mosaic tetrasomy 8p in two patients: clinical data and review of the literature. Am J Med Genet 1994;50(4):377–80. 76 Brady AF, Elsawi MM, Jamieson CR et al. Clinical and molecular findings in a patient with a deletion on the long arm of chromosome 12. J Med Genet 1999;36(12):939–41. 77 Casamassima AC, Klein RM, Wilmot PL, Brenholz P, Shapiro LR. Deletion of 16q with prolonged survival and unusual radiographic manifestations. Am J Med Genet 1990;37(4):504–9.

Chromosomes and the Skin 78 Koolen DA, Sharp AJ, Hurst JA et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet 2008;45:710–20. 79 Breslau-Siderius LJ, Beemer FA, Boom BW. Pili bifurcati: occurring in association with the mosaic trisomy 8 syndrome. Clin Dysmorphol 1996;5(3):275–7. 80 Ishikiriyama S, Goto M. Blepharophimosis sequence (BPES) and microcephaly in a girl with del(3) (q22.2q23): a putative gene responsible for microcephaly close to the BPES gene? Am J Med Genet 1993;47(4):487–9. 81 Breg WR, Steele MW, Miller OJ, Warburton D, DeCapoa A, Allderdice PW. The cri du chat syndrome in adolescents and adults: clinical finding in 13 older patients with partial deletion of the short arm of chromosome No. 5(5p-). J Pediatr 1970;77(5):782–91. 82 Donnai D, Karmiloff–Smith A. Williams syndrome: from genotype through to the cognitive phenotype. Am J Med Genet (Semin Med Genet) 2000;97:164–71. 83 Wuyts W, Roland D, Ludecke HJ et al. Multiple exostoses, mental retardation, hypertrichosis, and brain abnormalities in a boy with a de novo 8q24 submicroscopic interstitial deletion. Am J Med Genet 2002;113(4):326–32. 84 Baumeister FA. Differentiation of Ambras syndrome from hypertrichosis universalis. Clin Genet 2000;57(2):157–8. 85 Vogt J, Ryan E, Tischkowitz MD, Reardon W, Brueton LA. The tale of a nail sign in chromosome 4q34 deletion syndrome. Clin Dysmorphol 2006;15(3):127–32.

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86 Taysi K, Sekhon GS, Hillman RE. A new syndrome of proximal deletion of the long arm of chromosome 1: 1q21–23 leads to 1q25. Am J Med Genet 1982;13(4):423–30. 87 Zackai EH. Deletion 4q34.2. Am J Med Genet 1999;86(2):197–8. 88 Prothero J, Hawes-Collins E, Ellis RJ, Gupta R, Brady AF. Another nail tale: volar nail–like finding associated with interstitial deletions of chromosome 6q. J Med Genet 2007;44(suppl 1):abstract 1.60.

Conclusion Significant changes have occurred in the last 10 years in the diagnosis of chromosomal disorders and a clearer understanding of the phenotypes associated with these disorders has emerged. Chromosomal disorders can cause a broad range of dermatological disease and the association of dysmorphic features, developmental delay and congenital abnormalities in a child with skin manifestations should alert the clinician to a possible underlying chromosomal aetiology.

117.1

C H A P T E R 117

Review of Keratin Disorders Maurice A.M. van Steensel & Peter M. Steijlen Department of Dermatology, Maastricht University Medical Center, Maastricht, The Netherlands

Introduction, 117.1 Keratin biology, 117.1

Disorders caused by keratin

Conclusion, 117.8

mutations, 117.3

Introduction In recent years, rapid progress has been made in our understanding of the molecular basis of many genetic skin diseases. Among these are a number of often distressing and sometimes even life-threatening disorders in which the process of keratinization is disturbed. Keratinization, defined as the process of stratum corneum formation, is a complex process and many molecules are involved in it. This chapter discusses epithelial keratins and disorders that result from mutations in them. There are still many gaps in our knowledge, but modern genetics is giving us increasing insight into the function of keratins themselves, as well as the effects of keratin mutations. To properly understand the effects of keratin mutations, some basic knowledge of keratin biology is necessary.

Keratin biology There are at least 54 different keratins. They belong to the family of intermediate filament (IF) molecules [1]. These evolutionarily conserved molecules are a major part of the cytoskeleton in many organisms and as such play an important role in maintaining the structural integrity of the cells and their surroundings, in addition to having an emerging function in signal transduction and metabolic control [2]. This overview is concerned with the so-called soft keratins that are found in multilayered and simple epithelia and the hard keratins that form the bulk of appendicular structures such as hairs and nails. Hard keratins differ from their soft counterparts by the number of cysteine residues they contain [3]. Having more, they

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

can form more extensive cross-links between individual keratins and between filaments. This results in stiffer keratin intermediate filament (KIF) networks. There are 15 hard keratins in humans. Like all other IF molecules, keratins have a central αhelical ‘rod’ domain, flanked by end domains that are particular to the type of keratin in question (Fig. 117.1) [4]. This basic structure is strongly conserved throughout evolution in all IF proteins, which suggests that it is essential to normal IF function. Skin and hair/nail keratins are subdivided on the basis of their end domains and their charge: acidic (soft keratins 10–21 and hard keratins 31–38, type I) or basic/ neutral (soft keratins 1–9 and hard keratins 81–86, type II). The acidic keratins are coded for by a gene cluster on chromosome 17, the basic ones by genes on chromosome 12. The two forms also differ slightly in their basic structure: type I keratins lack H1 and H2 domains [4]. Keratins exist as obligate heterodimers of type I and type II chains [5]. The association between the chains is thought to take place through the rod domain, which shows a motif of seven amino acids (the ‘heptad motif ’), thought to mediate the association of the helices. Short, strongly conserved sequences at the beginning and end of the rod domains, the helix initiation and helix termination motifs, respectively, are essential for the initiation and proper termination of the dimerization process. Alterations in this motif perturb keratin function and are generally associated with severe skin disease. The keratin filaments aggregate into a network (Fig. 117.2), that interacts through specialized molecules called plakins [6] with adhesion structures in the keratinocytes: desmosomes and hemi-desmosomes [7]. Thus the cytoskeleton of each cell is linked to its membrane and, via this membrane, to other cells. Emerging evidence suggests that other motifs in keratins mediate interactions with various signalling pathways in the cell, thus implying the cytoskeleton in signal transduction.

117.2

Chapter 117 Table 117.1 Differentiation-specific expression of keratins

(a)

Layer of epidermis

Expression of keratins

Stratum spinosum Upper Lower

K2e K1/K10, K6/K16, K4/K13, K9*

Stratum basale

K5/K14, K6b, K17

* Expression in palmoplantar skin only. (b) Fig. 117.1 Central α-helical rod domain. (a) Type I; (b) type II.

Fig. 117.2 HaCaT cell transfected with a green fluorescent proteinlabelled keratin 1 construct. The intermediate filament network is clearly visible.

During differentiation of the epidermal cells, the expression of keratins in the keratinocytes changes as the cells move upwards (Table 117.1). Basal keratinocytes express K4 and K15. Upon their maturation to spinous layer cells, K5 and K14 are downregulated and K1, K2e and K10 are expressed [8]. Nail and hair progenitor cells express mainly K6, K16 and K17. These keratins are also expressed in other regions in response to keratinocyte stress or injury. Because of this, they can also be found in the palms and soles. K6a and K16 are also expressed in mucosal epithelia. K9 is expressed in the palms and soles only [9]. Non-epidermal keratins are expressed in mucous membranes and two of these, K4 and K13, have been implicated in a disorder of the mucosa (see below). As the keratinocytes reach the stratum granulosum, the expression of keratins ceases. Among the many proteins produced in the upper layer are loricrin and filaggrin [10]. These two are a major part of the so-called cornified enve-

lope (CE), an insoluble hydrophobic layer on the inner surface of the plasma membrane of the keratinocytes in the stratum corneum. This layer is made by cross-linking of the proteins mentioned, both to each other and to the KIF network [10]. A number of enzymes are involved in this process, mainly transglutaminases [10]. Keratins and other members of the IF family are involved in maintaining the structural integrity of the epidermis. Disruption of the IF network has been proposed to cause abnormal formation of the corneal layer and/or decreased resistance of the epidermis to mechanical stress. However, recent research is providing evidence to suggest that the diseases associated with keratin (and other IF) mutations do not result from epithelial fragility alone. For example, it has been shown that loss of keratin 17 correlates with decreased Akt/mTOR signalling activity. Furthermore, two amino acids in K17 are required to relocalize the adaptor protein 14-3-3-σ from the nucleus to the cytoplasm [2]. These findings reveal a new role for the cytoskeleton in regulating cell growth and metabolism. It is to be expected that further research will continue to deepen our insight in this manner. Symptoms caused by keratin mutations may also be related to the affected cells’ response to the presence of misfolded (mutant) keratin proteins. Meanwhile, the number of disorders due to keratin mutations is growing and now includes liver and ocular disease, showing that keratins are also involved in the maintenance of simple epithelia (see, for example, reference [11]). References 1 McLean WH, Irvine AD. Disorders of keratinisation: from rare to common genetic diseases of skin and other epithelial tissues. Ulster Med J 2007;76(2):72–82. 2 Kim S, Wong P, Coulombe P. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 2006;441(7091): 362–5. 3 Yu J, Yu DW, Checkla DM et al. Human hair keratins. J Invest Dermatol 1993;101(1 suppl):56S–9S. 4 Strelkov SV, Herrmann H, Aebi U. Molecular architecture of intermediate filaments. Bioessays 2003;25(3):243–51. 5 Herrmann H, Hesse M, Reichenzeller M et al. Functional complexity of intermediate filament cytoskeletons: from structure to assembly to gene ablation. Int Rev Cytol 2003;223:83–175.

Review of Keratin Disorders Table 117.2 Keratin disorders Disorder (and subtypes)

Keratins affected

Epidermolysis bullosa, simplex type; Naegeli–Franchescetti–Jadassohn syndrome, dermatopathia pigmentosa reticularis Dowling–Degos disease Epidermolytic ichthyosis (cullous congenital ichthyosiform erythroderma of Brocq) Epidermolytic epidermal naevus Epidermolytic palmoplantar hyperkeratosis (Vörner) Ichthyosis bullosa Siemens Pachyonychia congenital Focal NEPPK Steatocystoma multiplex White sponge naevus Cryptogenic liver cirrhosis Meesmann’s corneal dystrophy Monilethrix Ectodermal dysplasia, ‘pure’ hair-nail type Pseudo-folliculitis barbae

K5/14

K55 K1/10 K1/10 (mosaic) K1/9 K2e K6a/6b/16/17 K16 K17/6b K4/13 K8/18 K3/12 K83, 81, 86 K85 K75

NEPPK, non-epidermolytic palmoplantar keratoderma.

6 Sonnenberg A, Liem RK. Plakins in development and disease. Exp Cell Res 2007;313(10):2189–203. 7 Holthofer B, Windoffer R, Troyanovsky S et al. Structure and function of desmosomes. Int Rev Cytol 2007;264:65–163. 8 Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol 2008;129(6):705–33. 9 Knapp AC, Franke WW, Heid H et al. Cytokeratin No. 9, an epidermal type I keratin characteristic of a special program of keratinocyte differentiation displaying body site specificity. J Cell Biol 1986;103(2):657–67. 10 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(30):17702–11. 11 Ku NO, Strnad P, Zhong BH et al. Keratins let liver live: mutations predispose to liver disease and crosslinking generates Mallory–Denk bodies. Hepatology 2007;46(5):1639–49.

Disorders caused by keratin mutations Known disorders caused by keratin mutations are listed in Table 117.2. These are discussed below. Note that several keratin diseases are grouped under other nosological headings and are discussed in more detail elsewhere. Therefore, this chapter will provide an overview of these disorders; for details the reader is referred to the appropriate chapters. Keratin gene mutations are catalogued in the Human Intermediate Filament database: www.interfil.org [1]. A note on terminology: keratin genes are indicated by ‘KRT’, the proteins by ‘K’.

117.3

Epidermolysis bullosa simplex (MIM #131760, #131800, #131900, KRT5/14) The inherited forms of epidermolysis bullosa (EB) have recently been reclassified and EB simplex (EBS) is no longer subdivided into three entities (Weber–Cockayne, Dowling–Meara and Koebner) [2]. Nowadays, EBS is considered as a single entity with variable expressivity, which is caused by mutations in KRT5 and KRT14. The term ‘simplex’ refers to the level of blistering. EB with mottled pigmentation can be caused by mutations in KRT5/14 [3,4] and likewise is assigned to the EBS group. It is of interest to note here that there are some forms with associated symptoms that must be distinguished because they have a different molecular background. EBS with muscular dystrophy and/or pyloric atresia is caused by mutations in the PLEC1 gene coding for the intermediate filament-binding protein plectin [5]. Mutations in the ITGB4 gene coding for integrin-β4 have also been reported in EBS but are associated with nail dystrophy and enamel hypoplasia [6]. Both keratins 5 and 14 are expressed in basal epidermal cells. Different mutations can give rise to phenotypes of varying severity; there are also strong environmental influences such as ambient heat and humidity. It has been shown that disturbed network formation is an essential component of EBS [7]. Interestingly, a number of disorders formerly though to be distinct have now been shown to be allelic to EBS. From a nosological point of view, one might argue that they should perhaps no longer be recognized as separate disease entities. However, their clinical appearance is sufficiently distinctive and of mnemonic value to retain the separate categories. These are discussed below.

Naegeli–Franchescetti–Jadassohn syndrome and dermatopathia pigmentosa reticularis (MIM #161000, #125595, KRT14) These disorders are discussed under the same heading because their clinical features are highly similar, if not identical, and because they are allelic [8]. In the authors’ opinion, they should probably be considered as manifestations of EBS. In their typical form, though, they are sufficiently distinct to be recognized as a defined phenotype. Distinguishing symptoms of Naegeli–Franceschetti– Jadassohn syndrome (NFJS) are complete absence of dermatoglyphics (fingerprint lines), skin hyperpigmentation, palmoplantar keratoderma, reduced sweating, nail dystrophy and discoloured, yellow teeth that are lost early in life [9]. The hyperpigmentation is illustrated in Figure 117.3. Dermatopathia pigmentosa reticularis (DPR) is characterized by the triad of non-scarring alopecia, onychodystrophy and reticular hyperpigmentation. It has

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Chapter 117

haploinsufficiency [15]. As in NFJS/DPR, the pathogenesis of the hyperpigmentation is not clear.

Epidermolytic ichthyoses (formerly: bullous congenital ichthyosiform erythroderma of Brocq and ichthyosis bullosa of Siemens, MIM #113800 and #146800, KRT1/10 and KRT2e)

Fig. 117.3 Naegeli–Franceschetti–Jadassohn syndrome: inguinal reticular pigmentation.

been reported that in DPR the latter symptom is persistent [10]. Blistering can also be present in DPR [11] but dental abnormalities are supposed to be absent. However, all these differences are anecdotal and the NFJS and DPR phenotypes are so similar that it is probably no longer useful to distinguish them. In contrast with KRT14 mutations affecting the central α-helical rod domain of keratin 14, which are known to cause EBS, NFJS/DPR-associated mutations were found in a region of the gene encoding the non-helical head (E1/ V1) domain and are predicted to result in very early termination of translation [8]. It seems reasonable to assume from this that NFJS/DPR results from K14 haploinsufficiency, similar to Dowling–Degos disease (see below). It would seem that K14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to protect against proapoptotic signals [12]. There is evidence for increased susceptibility to apoptosis induced by TNF-α in keratinocytes that are haploinsufficient for KRT14, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR [13]. The pathogenesis of the hyperpigmentation is not clear but it may be pigmentary incontinence secondary to the apoptosis.

Dowling–Degos disease (MIM #179850, KRT5) Dowling–Degos disease (DDD) is a rare autosomal dominant disorder causing progressive reticular hyperpigmentation of skinfolds and flexures to appear after puberty. The pigmentation is progressive and disfiguring. Reticulate acropigmentation of Kitamura is a manifestation of DDD, as is the so-called Galli–Galli disease [14]. The disorder is caused by heterozygous loss-of-function mutations in the KRT5 gene presumably leading to

The ichthyoses were recently reclassified during the Ichthyosis Consensus Conference in Sorèze, France [16]. The entities formerly known as bullous congenital ichthyosiform erythroderma of Brocq (BCIE, MIM #113800) and ichthyosis bullosa Siemens (IBS, MIM #146800) have been grouped together as ‘epidermolytic ichthyoses’. The disorders are rare. For clinical and mnemonic purposes it is still useful to distinguish the two phenotypes. Bullous congenital ichthyosiform erythroderma of Brocq is characterized by generalized blistering at birth, accompanied by varying erythroderma and the development later in life of a generalized hyperkeratosis that is most pronounced on the large joints (Fig. 117.4). Inheritance is autosomal dominant. Various mutations in K1 and K10 have been identified (www.interfil.org). These keratins are expressed mainly in the suprabasal layers of the epidermis, where the ultrastructural abnormalities of epidermolytic hyperkeratosis (EHK) are found: clumping of intermediate filaments, vacuolation and hyperkeratosis. Keratin 1 mutations can cause palmoplantar keratoderma of varying severity. See Chapter 120. Mutations in K1 and K10 associated with severe BCIE are located at the beginning or end of the 1A rod domain, as in EBS [17]. Milder forms have mutations in the H1, L1 or L12 domain. Symptoms can be so mild that they escape attention. It is interesting to note that in three different keratin disorders (BCIE, EBS and epidermolytic palmoplantar keratodermas (EPPK), see below), the same residues are mutated in three different keratins (asparagine 160, arginine 162, methionine 156) [18]. This indicates the functional importance of the conserved heptad motif. Keratin 10 mutations can also appear in a mosaic pattern in some individuals [19]. Mosaicism means that cells carrying a mutation are intermingled with normal cells in the same individual. K10 mutations in a mosaic give rise to an epidermolytic epidermal naevus (MIM #600648), whereas the presence of the mutation in all cells gives rise to BCIE. Interestingly, mosaicism has never been described for K5/14 mutations. The reason for this is not clear but it seems that in the hypothetical case of mosaicism for K5/14 mutations, the blisters that result are healed by migration of normal stem cells expressing K5/14. In the case of K10 mutations, there is no expression in stem cells; hence the mosaic state remains (D Roop, personal communication). Meanwhile, mosacism for K1 mutations has also been demonstrated [20]. Most

Review of Keratin Disorders

117.5

(a) (b)

(c)

(e)

(d)

(f)

Fig. 117.4 Bullous congenital ichthyosiform erythroderma of Brocq. (a) Condition at birth; (b) condition after 5 months; (c) palmar hyperkeratosis in a patient with a keratin 1 mutation; (d) epidermolytic hyperkeratosis at histopathological examination; (e) condition in an adult patient; (f) patient with an epidermolytic type of epidermal naevus.

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(a)

(c)

(b)

(d)

Fig. 117.5 Ichthyosis bullosa of Siemens. (a) Mild scaling in a boy; (b) hyperkeratosis in flexural site of the knee; (c) condition in the mother of the boy; (d) epidermolytic hyperkeratosis limited to the upper layers of the stratum spinosum.

recently, revertant mosaicism has been demonstrated for K10 mutations. Ichthyosis en confetti is a very rare condition in which patients develop round blanched macules formed by normal skin on an erythrodermic background. It was shown that the normal areas represent thousands of revertant clones of normal keratinocytes. The reversion is caused by loss of heterozygosity (on chromosome 17q) via mitotic recombination [21]. BCIE and its manifestations do not generally respond well to retinoids (see also Chapter 121). Ichthyosis bullosa of Siemens (IBS) (MIM #146800) is a milder, superficial epidermolytic ichthyosis without erythroderma (Fig. 117.5). Hyperkeratosis is mild and located on the flexural areas as well as on the umbilical skin and shins. Erosions are caused by minor trauma. A very typical phenomenon is grey, scaling, almost flaky hyperkeratosis on the flexural surfaces known as ‘moulting’ or ‘Mauserung’ in German. Ultrastructural features in this disorder again are indicative of keratin mutations: KIF clumping and vacuolation, this time in the upper layers of the stratum spinosum. One of the keratins expressed in this layer, K2e, was found to harbour mutations [22]. Again, the mutations cluster within the con-

served domains. The IBS phenotype responds very well to low doses of retinoids (10 years on average) until neurological signs are manifest [32]. Retinitis pigmentosa is the most constant ocular finding and may be present in early childhood. Additional ocular findings include restriction of visual fields, decreased visual acuity, posterior subcapsular cataracts, abnormal papillary responses, nystagmus and glaucoma. Approximately one-third of patients with classic Refsum disease exhibit skeletal abnormalities [33]. Skeletal changes tend to be bilateral and symmetric. The most commonly observed is shortening of the terminal phalanx of the thumbs, resulting in a conical appearance. Shortening of the fourth metatarsal region is also characteristic. Epiphyseal flattening of the elbows and knees is also reported. The dermatological manifestations of classic Refsum disease have received little attention. Ichthyosis may not be clinically apparent until early adulthood and may resemble ichthyosis vulgaris with diffuse small white scales. One patient series reported prominent skin changes on the knees, palms and back [26]. Histological features include hyperkeratosis, hypergranulosis and lipidcontaining vacuoles within the basal and suprabasal epidermal cells [26]. A similar cutaneous phenotype has occasionally been reported in rhizomelic chondrodysplasia punctata (RCDP), a more severe phenotype also due to PEX7 mutations [34], but not in the global peroxisomal deficiency disorders, such as infantile Refsum disease and Zellweger syndrome. Genetics and pathogenesis. The biochemical defect was identified in 1963 when phytanic acid was noted in the plasma of affected patients. The defect in ARD was soon identified as being due to lack of an α-oxidase [35]. It took over 30 years for the enzyme responsible, PhyH (phytanoyl-CoA 2-hydroxylase), to be identified [27,29]. Phytanic acid (PA) is a branched-chain fatty acid, derived exclusively from dietary sources of chlorophyll. The inability to metabolize phytanic acid results in its accumulation in plasma and a variety of tissue lipids, including those of kidney, liver, skin and myelin sheath. Recent studies indicate that PA is a direct toxin to mitochondria and has a rotenone-like action in uncoupling complex I in the oxidative phosphorylation chain in the mitochondrial inner membrane, with subsequent production of reactive oxygen species. This metabolic toxicity may explain why neuronal or allied retinal pigment tissues rich in mitochondria are the prime tissues affected in

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121.49

Fig. 121.19 Classic adult Refsum disease. Courtesy of Dr Mevorah, Tel Aviv.

ARD [36,37]. With regard to skin manifestations, phytanic acid accumulates in epidermal lipids [38]. In 1997, two groups identified mutations in the PAHX gene localized to chromosome 10p13 [27,29]. PhytanoylCoA hydroxylase is a peroxisomal enzyme that catalyses the first step in the α-oxidation of phytanic acid [27,29]. Mutations in the PAHX gene account for most cases of Refsum disease. Mutations in a second gene, PEX7, located on chromosome 6q22-24 and comprising about 10% of cases, were subsequently identified [39]. The PEX7 gene encodes peroxin 7 receptor protein, required for import of certain enzymes into peroxisomes. These enzymes include not only those of branched-chain fatty acid α-oxidation, but also those of plasmalogen synthesis and peroxisomal fatty acid α-oxidation. Mutations in the PEX7 gene have also been found to underlie rhizomelic chondrodysplasia punctata (RCDP), another peroxisomal disorder with a more severe phenotype [40,41]. Because skeletal defects are common in RCDP and other global peroxisomal defiency disorders, it is possible that the presence of skeletal defects in ARD may be a clinical marker for mutations in PEX7, rather than PAHX. Correlation of phenotype with genotype will be important in future clinical studies. Ironically, one of the original patients described with ARD turns out to have the RCDP variant [30].

The peroxisomal disorders constitute a group of entities with overlapping phenotypes that are characterized by deficiency of one or multiple peroxisomal functions. The recent delineation of their underlying genetic causes has done much to clarify their nosology [31]. The first group are considered to be global peroxisomal deficiency disorders, caused by mutations in genes involving peroxisomal biogenesis [42,43]. Peroxisomes are absent or markedly reduced in this group of disorders, and ichthyosis has not been described. Infantile Refsum disease is one of the milder phenotypes in this group [31]. It is characterized clinically by mental retardation, retinitis pigmentosa, sensorineural hearing deficits, hepatomegaly, osteoporosis, failure to thrive, mild facial dysmorphism and hypocholesterolaemia, and is caused by mutations in the PEX1, PEX2, PEX12 and PEX26 genes [31]. Increased phytanic acid, very-long-chain fatty acids and pipecolic acid are biochemical markers of global peroxisomal deficiency [31]. The second group of peroxisomal disorders, with RCDP as the prototype, exhibit impairment of more than one, but not all, peroxisomal functions. The third group of disorders are those in which mutations affect a single peroxisomal enzyme. Adult Refsum disease due to PAHX gene mutations is an example of such disorders. Peroxisomal number and function are also reduced in Conradi–Hünermann–

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Table 121.6 Causes of acquired ichthyosis Category

Example

Malignancy

Hodgkin disease Lymphoproliferative disorders, including mycosis fungoides Kaposi sarcoma Soft-tissue sarcoma Solid organ tumours

Autoimmune

Systemic lupus erythematosus Dermatomyositis Mixed connective tissue disease

Infectious

Human immunodeficiency virus (HIV) Human T-cell leukaemia virus type 1 (HTLV-1) Leprosy

Endocrine

Hypothyroidism Hyperparathyroidism Insulin-dependent diabetes mellitus

Renal

Chronic renal failure

Malnutrition/ malabsorption

Coeliac disease Cystic fibrosis Pancreatic insufficiency Protein malnutrition

Other

Sarcoidosis Graft-versus-host disease Eosinophilic fasciitis

Medications

Nicotinic acid Other lipid- and cholesterol-lowering agents Others

Happle syndrome and CHILD syndrome [44,45]. These disorders are caused by mutations in enzymes of the distal cholesterol biosynthetic pathway, which locate to peroxisomes. Thus, they may also be considered members of this third group of peroxisomal disorders. Diagnosis. Patients with retinitis pigmentosa, either in isolation or with peripheral neuropathy and/or cerebellar ataxia, should be evaluated for Refsum disease. The disorder should be considered in the differential diagnosis of acquired ichthyosis (i.e. onset after infancy or early childhood) (Table 121.6), particularly in the setting of ocular or neurological abnormalities. Plasma phytanic acid levels can be determined by liquid gas chromatography [46], or decreased phytanic acid oxidase activity may be observed in cultured fibroblasts. Normal levels of phytanic acid are usually less than 33 μM, and levels are increased up to 100-fold in patients with classic Refsum disease [47]. Plasmalogen synthesis is decreased in patients with disease due to mutations in PEX7, leading to reduced erythrocyte plasmalogen levels as seen in

RCDP. Skin biopsy in classic Refsum disease shows lipid vacuoles in the basal layer of epidermis, a finding also seen in another inborn error of lipid metabolism, neutral lipid storage disease [26]. Treatment. Because phytanic acid is acquired exclusively through dietary intake, the mainstay of treatment in classic Refsum disease is dietary restriction of phytanic acid. The normal Western diet contains approximately 50–100 mg of phytanic acid per day; the compound is found particularly in dairy products, fish, some meats (e.g. mutton) and ruminant fats. The recommended dietary intake of phytanic acid in classic Refsum disease is less than 5–10 mg daily [47,48], because small amounts of phytanic acid (approximately 10 mg per day) can be metabolized by the alternative α-oxidation pathway. Exacerbations of classic Refsum disease are usually secondary to acute increases in plasma phytanic acid levels. Plasmapheresis can be employed to rapidly decrease phytanic acid levels, preventing potentially fatal complications, such as cardiac arrhythmias [47]. Dietary intervention may also improve dermatological and neurological manifestations, but it does not affect skeletal abnormalities. Whether early institution of dietary restrictions prevents progression of ocular complications remains unclear.

MEDNIK syndrome History. Saba et al. were the first to describe MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia) as an atypical form of erythrokeratoderma variabilis in three Canadian families originating from the Kamouraska region of the province of Quebec [49]. This form was similar to the one of Beare et al. [50] or Giroux and Barbeau [51] with sensorineural deafness, peripheral neuropathy and psychomotor retardation. However, in addition to these symptoms, the Kamouraska patients have congenital and often lethal diarrhoea, with an elevation of very-long-chain fatty acids (VLCFAs), and a recessive mode of inheritance. All three families shared common ancestors of French origin who settled in Quebec in the 17th and 18th centuries [49]. Epidemiology. MEDNIK families show an autosomal recessive transmission linked to chromosome 7q22. To date all cases have occurred with a relatively isolated Canadian population with an ancestral link. Pathogenesis. Homozygous mutations of the AP1S1 gene were identified and shown to perturb the development of the skin and the spinal cord. The AP1S1 gene encodes a subunit (σ1A) of an adaptor protein complex (AP-1) involved in the transport of many other proteins

MEDOC: the Ichthyoses

within the cell by clathrin-coated vesicles and its organization by protein cargo selection for transport between the trans-Golgi network, endosomes, lysosomes and the plasma membrane [52]. Mutations in the closely related AP1S2 gene encoding the σ1B subunit of AP-1 lead to X-linked mental retardation. Further, the clinical picture and the pathogenesis have striking similarities with CEDNIK, which is due to a mutation in a SNARE protein (SNAP29), also involved in intracellular protein trafficking (see below) [53]. Pathology. There are no published descriptions of the histopathology or ultrastructure.

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Gaucher disease, where a similar clinical phenotype can be observed with severe ichthyosis and neurological deficits. Pathology. Histopathological examination of affected skin shows hyperkeratosis and acanthosis. Ultrastructure reveals countless clear vesicles in the Malpighian layers and the significantly thickened stratum corneum. However, normal lamellar granules with lipid membranes that are secreted into the extracellular space are also found.

Prognosis. Potentially lethal congenital diarrhoea, and severe neurological handicaps due to ataxia, polyneuropathy, microcephaly and psychomotor retardation or unexplained cachexia are observed.

Clinical features. Palmoplantar keratoderma and lamellar ichthyosis appear between 5 and 11 months of age, with progressive worsening during the second year of life. Eye movement, poor head and trunk control, and failure to thrive develop during the first 4 months of life. By the age of 8 to 15 months progressive microcephaly, hypoplasia of the optic disc, macular atrophy, mild sensorineural deafness and facial dysmorphism are associated with major psychomotor retardation. Unaided sitting and walking are not achieved and tendon reflexes are absent. Older children exhibit severe psychomotor retardation, ichthyosis and palmoplantar keratoderma. Magnetic resonance imaging of the brain reveals various degrees of corpus callosum abnormalities and cortical dysplasia.

Differential diagnosis. Erythrokeratoderma with ataxia (see Chapter 122) and CEDNIK (see below) must be differentiated.

Prognosis. With progressive deterioration, no adult patients have been reported. Death in childhood is due to aspiration pneumonia, or cachexia.

Treatment. No effective treatments have been reported.

Differential diagnosis. Other severe neurological disorders with ichthyosis, including Neu–Laxova syndroma, MEDNIK syndrome, Gaucher type 2 disease, and Sjögren– Larsson syndrome may be considered in the differential diagnosis.

Clinical features. Patients show generalized nonconfluent erythematous, hyperkeratotic plaques with pityriasiform scaling, including the head and neck. In addition to the skin lesions, affected individuals exhibit severe psychomotor retardation, peripheral neuropathy and sensorineural hearing loss, as well as elevated very-long-chain fatty acids and severe congenital diarrhoea.

CEDNIK syndrome History. This novel neurocutaneous syndrome was described in two related consanguineous Arab families in Israel [53]. CEDNIK stands for cerebral dysgenesis, neuropathy, ichthyosis, keratoderma.

Treatment. There is no known treatment.

Zunich neuroectodermal syndrome Epidemiology. There is autosomal recessive transmission linked to chromosome 22q11. Pathogenesis. CEDNIK results from decreased expression of SNAP29, a SNARE protein involved in vesicle fusion [53]. SNAP29 plays an important role in Golgi trafficking and is instrumental in synaptic vesicle recycling. In CEDNIK lamellar granules are retained within the cornified cell layer, and the diminished secretion of lipids and proteases in the extracellular space causes impaired barrier formation and decreased desquamation. This leads to an accumulation of glucosylceramides in the stratum corneum similar to the one observed in type II

Erythrokeratodermic lesions may also be seen in the Zunich neuroectodermal syndrome (ZNS; synonyms: Zunich–Kaye syndrome, CHIME syndrome; OMIM 280000). This rare disorder was originally described by Zunich and Kaye [54,55], and rare reports have followed [56–58]. The acronym CHIME has been proposed to represent the syndrome’s most characteristic clinical manifestations: ocular colobomas, congenital heart disease, early-onset ichthyosiform dermatosis, mental retardation and ear abnormalities [57]. An autosomal recessive mode of inheritance has been postulated [59], although the underlying genetic defect has not been elucidated.

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The cutaneous phenotype in ZNS presents at birth or within the first several weeks of life as well-demarcated, erythematous, scaly plaques, which may involve the scalp, face, trunk and extremities. The lesions are usually pruritic, and wax and wane in severity. Moreover, lesions are migratory in nature and may have figurate borders similar to EKV and ichthyosis linearis circumflexa [56]. There is often an associated keratoderma of the palms and soles. The hair is usually fine and blonde [54,55]. The lesions respond minimally to topical steroids but modest improvement may be seen with emollients [57]. The facies in ZNS are distinct and include hypertelorism, a short philtrum, flat/broad nasal root and full lips. Dental anomalies include small, irregularly spaced teeth and bifid incisors. Colobomas of the retina or choroid are present in all patients. Severe mental retardation is also a constant feature, commonly accompanied by seizure disorder. Computed tomography (CT) scans often demonstrate cerebral atrophy. Episodes of rage, which coincide with dermatological exacerbations, have been reported in older children. Conductive hearing loss is another cardinal feature. A variety of congenital cardiac defects have been described [57]. Skeletal defects such as brachydactyly, club-foot and a broad second toe may also occur.

Neutral lipid storage disease with ichthyosis Neutral lipid storage disease (NLSD, triglyceride storage disease) is a genetically heterogeneous group of autosomal recessive disorders of lipid metabolism characterized by widespread intracellular accumulation of triacylglycerols in non-membrane-bound droplets [60–64]. Many patients with NLSD are associated with ichthyosis (NLSDI) and suffer from the disease described by Dorfman and Chanarin (Chanarin Dorfman syndrome; CDS). Clinical signs are variable and include hepatomegaly with steatosis, steatorrhoea, ichthyosis, discrete myopathy, cataracts, neurosensory deafness, developmental delay and short stature; none of these is observed in all cases [65–69]. The incidence of this multisystem disorder is unknown; however, most cases have been reported in consanguineous families from the Middle East and Mediterranean region, suggesting a founder effect. Some genetically distinct NLSD patients present with more severe skeletal and often cardiac myopathy (NLSDM), atypical CDS-like features but without ichthyosis [67]. One-third of NLSDM patients also suffer from diabetes [69]. Jordans initially described this disease in 1953 in two brothers with a progressive myopathy (NLSDM) and recognized the pathognomonic lipid inclusions in the leucocytes diagnostic of NLSD (Jordan anomaly) [60]. Subsequently, similar lipid droplets were

observed in the leucocytes of two family members with ichthyosis (NLSDI) [70]. In 1974, Dorfman et al. [61] expanded on this family, and one year later Chanarin et al. described the pathological and biochemical hallmarks of the disease [62]. Since the original description, about 40 NLSDI cases have been reported worldwide [71]. Igal was the first to discriminate between the two groups of patients – those affected with ichthyosis (NLSDI) or without ichthyosis (NLSDM) – a distinction genetically confirmed by Fischer et al. [67,72]. Clinical features. The cutaneous manifestations of NLSDI are variable. The most frequently observed pattern in the newborn is an erythroderma with generalized, small, whitish scales, although neonates with NLSDI may also present as collodion babies [73]. In the mature phenotype, the face often has a taut appearance and affected individuals may appear older than their actual age. Scales may be larger and more plate-like on the scalp and legs. Flexural surfaces are usually involved, and both flexures and extensors may have a lichenified appearance. Hyperkeratosis of the palms and soles is frequently present, but nails and hair are usually not involved. The phenotype resembles mildly to moderately severe congenital ichthyosiform erythroderma, and the degree of erythema varies within affected families. A peripheral blood smear on all patients with ichthyosiform erythroderma is indicated, because systemic manifestations of NLSD may be clinically silent or subtle at all ages [63,73]. Hepatomegaly is commonly observed on physical examination. Liver enzyme testing may be normal such that biopsy becomes necessary to demonstrate fatty changes. The skeletal myopathy is subtle, and weakness may be noted only upon careful examination. Muscle creatinine phosphokinase (CPK) can be elevated even in asymptomatic individuals. Muscle involvement may also be demonstrated by electromyography and/or muscle biopsy. Histopathological findings are often more striking than would be predicted by clinical symptoms or laboratory values. Neurological impairment also varies among patients and within families. Developmental delay and mild mental retardation are the most commonly observed findings. Ataxia and microcephaly have also been reported. Nuclear cataracts are the most commonly observed ocular abnormality in NLSD, but strabismus, nystagmus, retinal dysfunction and myopia have also been reported [66]. Mild ectropion is also frequently observed. Less commonly reported clinical features of NLSD include short stature, splenomegaly and intestinal malabsorption [61,62,69]. Histology. Cutaneous histopathology prepared from frozen sections stained for lipids reveals lipid droplets in the basal and granular cell layers, and in sweat glands

MEDOC: the Ichthyoses

and their acrosyringia [63]. Ultrastructural features include globular electron-lucent inclusions that disrupt the normal structure of lamellar bodies in the granular layer of the epidermis and form clefts in the interspaces of the inner stratum corneum [63,74]. Metabolic defect/genetics. The triacylglycerol content of lymphocytes, macrophages or fibroblasts cultured from patients with NLSD is approximately 2- to 20-fold higher than in normal cells [14,15,62]. The defect is in intracellular triglyceride metabolism; circulating lipoprotein-bound triacylglycerol levels are usually normal. Recently, two genes, adipose triglyceride lipase (ATGL/PNPLA2) [67] and comparative gene identification-58 (CGI-58/ABHD5) [72], have been shown to cause NLSD. The enzyme ATGL specifically hydrolyses the first fatty acid from triacylglycerols (TG) and CGI-58/ ABHD5 stimulates ATGL activity by a mechanism involving binding to perilipin [71,75]. Perilipin binds ABHD5 with high affinity and thereby suppresses the interaction of ABHD5 with ATGL [75]. Sequestration of ABHD5 appears to a major mechanism by which perilipin reduces basal lipolysis. Serine phosphorylation of perilipin rapidly releases ABHD5 from perilipin, allowing its direct interaction with ATGL [75]. Mutations in both the ATGL and the CGI-58 genes are associated with systemic TG accumulation, yet the resulting clinical manifestations are not identical, indicating an ATGL-independent function of CGI-58. Diagnostic studies. The diagnosis of NLSD may be based upon the presence of lipid-containing vacuoles in circulating granulocytes, eosinophils and monocytes [61–63]. It is important to note that automated leucocyte counts do not detect these abnormalities, and a peripheral smear must be directly examined. These changes are not present in lymphocytes, red blood cells or platelets. The lipid vacuoles do not appear to affect leucocyte function. Similar, but less pronounced, vacuoles can be demonstrated in the eosinophils of NLSD carriers [63]. Using lipid stains such as oil red-O or Sudan III, cytoplasmic lipid droplets can also be detected in unfixed skin sections. These droplets are most prominent in eccrine glands and ducts, as well as in fibroblasts and basal keratinocytes [64,74]. Similar histological findings may be observed in the basal keratinocytes of patients with Refsum disease, a peroxisomal disorder of impaired branched-chain fatty acid oxidation; however, leucocyte vacuoles are not present in that disorder [38]. Treatment. Because of the marked variability in clinical phenotype, treatment should be directed by the individual’s clinical manifestations. In patients with more severe dermatological manifestations, systemic retinoids may be

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of benefit. Some authors have reported improvement with fat-restricted diets, but others have not. The prognosis of NLSDI primarily depends upon the severity of hepatic involvement [68,69].

Conradi–Hünermann–Happle syndrome X-linked dominant chondrodysplasia punctata (syn. Conradi–Hünermann–Happle syndrome, CHH, CDPX2; OMIM 302960) is a rare X-linked dominant disorder characterized by distinctive skeletal, cutaneous and ocular anomalies distributed in a mosaic pattern [76–78]. The term chondrodysplasia punctata (CDP) refers to an anomaly of enchondral bone formation in utero at the epiphyseal plates causing stippled calcifications that can be visualized radiologically or sonographically (‘stippled epiphyses’) [76]. This finding is not specific to CDPX2, but is seen in a variety of other genetic disorders including CHILD syndrome, trisomy 21, Zellweger syndrome, Smith–Lemli–Opitz syndrome, congenital hypothyroidism and X-linked recessive chondrodysplasia punctata (CDPX1), as well as an acquired disorder following prenatal exposure to vitamin K antagonists [79]. The classification of CDP has been the source of much confusion. In 1971 Spranger and Opitz [34] recognized the heterogeneity of CDP and described the more severe, autosomal recessive rhizomelic type, which is usually lethal within the first year, and the Conradi–Hünermann type, with a dominant inheritance and better prognosis. Happle established that the dominant form occurred exclusively in females, was transmitted in an X-linked dominant mode, and was lethal for hemizygous males [77]. In 1999, mutations in the emopamil binding protein (EBP) gene encoding 3β-hydroxysteroid-Δ8,Δ7-isomerase, an enzyme in the distal steps of the cholesterol biosynthetic pathway, were identified as the cause of CDPX2 [80,81]. Clinical features. X-linked dominant chondrodysplasia punctata presents at birth with ichthyosiform erythroderma distributed along the lines of Blaschko [76–78]. There may be segmental collodion membranes particularly on the distal limbs [78]. The erythema and scaling usually regress spontaneously during the first 3–6 months of life, leaving atrophic patches (‘follicular atrophoderma’), often with post-inflammatory pigmentary changes, also in a blaschkoid distribution. A diffuse, very moderate ichthyotic scaling usually persists. Other cutaneous features of CDPX2 include coarse or lustreless hair, patches of scarring alopecia, and flattening or splitting of the nails. Neonates or young infants may exhibit the characteristic radiographic findings of CDPX2, namely epiphyseal stippling, but as with ichthyosiform erythroderma, these radiological skeletal changes resolve during the first

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several months of life. The stippling may be widespread and involve the cartilage of the vertebrae and trachea. Similar to the cutaneous findings, the radiographic findings are asymmetrical, reflecting the mosaic pattern of disease expression. This feature contrasts with most other CDPX2 syndromes, in which the findings are symmetrical, with the exception of CHILD syndrome, in which they are unilateral and ipsilateral to the ichthyosiform erythroderma (see below). As with cutaneous changes which result in atrophy, skeletal changes asymmetric, rhizomelic shortening of the limbs, scoliosis and craniofacial anomalies (frontal bossing and a flat nasal bridge) are the result of the skeletal dysplasia. Asymmetrical or sectorial cataracts are present in approximately two-thirds of patients with CDPX2 [82]. Microcornea and microphthalmia may also be present. Other, less common manifestations include hydronephrosis and other renal defects, congenital heart disease, central nervous system malformations, joint contractures, postaxial polydactyly and sensorineural hearing loss. Intelligence, however, is usually normal in CDPX2. There is considerable intra- and interfamilial variation in the severity of CDPX2. Although most affected individuals have the combination of skeletal and cutaneous abnormalities, there are occasional reports of patients lacking these distinct features [83,84]. Histology. During the neonatal period, cutaneous histopathology appears to be distinctive, showing hyperkeratosis and acanthosis with calcium deposits within the stratum corneum, particularly involving keratotic plugs of hair follicles [85–87]. Follicular calcifications are present at birth and thus are formed in utero, as are the epiphyseal and corneal calcifications. Thus, they are likely a direct consequence of the underlying biochemical defect. Focal pigmentation of the basal layer and needle-like calcium inclusions in vacuoles may be seen on electron microscopy [85]. In the follicular atrophoderma phase, dilated ostia of pilosebaceous structures or atrophy of the hair follicles is observed. Genetics. X-linked dominant chondrodysplasia punctata is due to mutations in the EBP gene, located at Xp11.22-23 [80,81]. The EBP protein, first described as a receptor for emopamil, is also a sterol isomerase involved in post-squalene cholesterol biosynthesis. It is the 3-βhydroxysteroid-Δ8-Δ7-isomerase enzyme that catalyses an intermediate step in the conversion of lanosterol to cholesterol. As a result of this defect, affected patients have elevated tissue and blood levels of cholesterol intermediates 8(9)-cholesterol and 8-dehydrocholesterol but decreased cholesterol levels [80]. Pathogenesis of disease. Cholesterol is an essential constituent of biological membranes; it regulates their integ-

rity and the activity of certain membrane proteins, it is an intermediate in steroid hormone biosynthesis and controls transcriptional pathways, e.g. the sonic hedgehog pathway (see below). Dietary cholesterol may be sufficient for most of these functions, supplying the sterol to tissues in the form of circulating low-density lipoprotein (LDL) cholesterol. However, tissues such as suprabasal epidermis that lack LDL receptors are vulnerable to mutations that impair sterol biosynthesis [88]. Thus, it not surprising that diverse human disorders due to faulty cholesterol biosynthesis have been identified, i.e. desmosterolosis, CHILD syndrome, CDPX2, lathosterolosis and Smith–Lemli–Opitz syndrome (SLOS) [43]. The latter spares the skin and is caused by a defect in the conversion of 7-dehydrocholesterol to cholesterol [89]. Because SLOS is also characterized by chondrodysplasia punctata, a cardinal feature of the CDPX2 syndrome [90], a similar metabolic defect of cholesterol biosynthesis was suspected in patients with CDPX2 [91]. Only two genes on the X-chromosome are encoding for enzymes of cholesterol biosynthesis, i.e. NSDHL, responsible for the ‘bare patches’ phenotype in mice [92], and EBP, encoding the emopamil binding protein mutant in the ‘tattered’ mouse [81]. Consequently, NSDHL mutations were found in human CHILD syndrome [86,93], and EBP mutations in CDPX2 [80,81]. Indeed, ichthyosis has been recognized as a side-effect of hypocholesterolaemic drugs that act by inhibiting the distal steps in sterologenesis [94]. Cataract formation but not skeletal defects were also associated with some of these agents. X-linked dominant chondrodysplasia punctata and CHILD syndromes may not derive from bulk requirements for cholesterol in biological membranes, but may reflect the role of cholesterol in regulating gene transcription, for example in the formation of active hedgehog proteins [95] or through activation of the nuclear hormone receptor, liver X receptor (LXR), by its oxygenated sterol precursors or metabolites [96]. Target genes of the hedgehog signalling pathway regulate some aspects of morphogenesis, such as the Wnt gene family and bone morphogenic proteins. Defective regulation of this pathway has been postulated to account for the specific skeletal and cardiac defects in Smith– Lemli–Opitz syndrome [95]. Moreover, activation of LXR by oxygenated metabolites of cholesterol regulates cellular lipogenesis [96] and also epidermal differentiation and skin permeability barrier maturation in utero [97]. Hence, perturbation of these regulatory signals may contribute to the skin phenotype. Finally, peroxisomes may be implicated in cholesterol biosynthesis [98], and earlier studies showed evidence of peroxisomal deficiency in CDPX2 patients [99] and in fibroblasts from involved skin of CHILD syndrome and its animal analogue, the Bare Patches mouse [44]. Despite the fact that the major site of cholesterologenesis is the endoplasmic reticulum,

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enzymes of this pathway also localize to peroxisomes [100]. In CDPX2, the cutaneous disorder, particularly the formation of calcified follicular spikes, is largely selfresolving, leaving atrophic residua. The most likely explanation for this process is reduced viability of the keratinocyte populations in which the mutant X chromosome is active. A similar disease pattern is observed in incontinentia pigmenti, another X-dominant, male-lethal disorder, in which the infantile phenotype ultimately resolves, leaving atrophy and/or pigmentary changes. Skewed patterns of X-inactivation may account for much of the observed intra- and inter-familial variability [101]. In sum, the precise molecular mechanistic relation between the enzymatic deficiency and the clinical picture remains unclear. Diagnosis. The diagnosis of CDPX2 is usually evident on clinical grounds and can be confirmed by genetic testing. Skin histopathology may also be diagnostic in neonates (see above) and can be used to distinguish CHH from incontinentia pigmenti and inflammatory epidermal naevi. In atypical cases, plasma sterol analysis will demonstrate an abnormal profile with increased levels of 8(9)-cholesterol and 8-dehydrocholesterol [102]. Mothers of apparent sporadic cases should be carefully examined for alopecia, mild and localized follicular atrophoderma, limb asymmetry and cataracts. Plasma sterol analysis may be abnormal in the absence of other clinical signs [102]. While it is presumed that most males with CDPX2 are somatic mutants [103], less deleterious mutations perhaps account for some surviving hemizygous males. Genetic counselling in cases that are apparently sporadic should take into account the extreme variability in severity in CDPX2. Very limited pigmentary changes or focal cataracts [104] may be the only clinical signs of the disorder in adult females. Moreover, some cases may arise as a result of gonadal mosaicism, without any parental clinical signs [104].

CHILD syndrome X-linked dominant chondrodysplasia punctata is closely related to the X-linked dominant disorder CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) [105], which is caused by mutations in the NSDHL gene, affecting the enzymatic step in cholesterol synthesis just proximal to the Δ8,Δ7sterol isomerase step linked to CDPX2 [86,106]. CHILD syndrome (discussed more fully in Chapter 115) is also characterized by cutaneous and skeletal abnormalities; however, a striking unilateral distribution of skin lesions with a sharp midline demarcation is seen [105]. Further, the skin lesions are characterized by wax-like scaling rather than the follicular spikes on an ichthyosiform

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erythroderma, and do not result in follicular atrophoderma. Indeed, assiduous clinical examination of CHILD syndromes allows for the unequivocal distinction from other epidermal naevi or CDPX2 despite a so-called CHILD syndrome reported with an EBP rather than a NSDLH mutation [93]. These skin changes usually persist throughout life, in contrast to the transient ichthyosiform erythroderma of CDPX2. Partial resolution of the dermatosis occurs rarely in CHILD syndrome [107]. Alopecia and nail abnormalities are commonly seen in CHILD syndrome. Epiphyseal stippling may be noted in both CDPX2 and CHILD syndromes. Limb reduction defects, at times resulting in the absence of a limb, occur on the same side as the skin abnormalities in CHILD syndrome, and the associated skeletal anomalies are usually more severe than those seen with CDPX2 [86]. Skeletal defects in CDPX2 are bilateral, asymmetrical and random in distribution. Cardiac, renal, inner ear and CNS malformation are more frequent in CHILD syndrome, while eye defects are more common in CDPX2 [86]. CHILD syndrome was suggested to correspond to a ‘naevus’ rather than an ‘ichthyosis’, because the skin lesions clinically resemble an inflammatory linear epidermal naevus [108]. Despite its clinical value for differential diagnostic considerations, this interpretation does not fit the molecular pathogenesis of CHILD syndrome with germline NSDHL mutations [86,109]. The pattern of lateralization with the strict midline demarcation in CHILD syndrome is unique and not easily explained. Possibly, differentiation of a small population of organizer cells coincides and interferes with the event of X-inactivation at an early stage of embryogenesis. Such organizer cells with a mutated NSDHL on the active X could determine a large developmental field including the skin, bones, brain, kidney and other organs of one side of the body [86].

Ichthyosis follicularis with atrichia and photophobia The clinical constellation of ichthyosis follicularis with atrichia and photophobia (IFAP; OMIM 308205) was described by MacLeod in 1909 [110]. He reported a family with three out of five boys affected by severe, follicular hyperkeratosis involving the scalp, extensor extremities and abdomen, associated with complete baldness. The term ‘ichthyosis follicularis’, however, may have been first used by Lesser in 1885 [110]. In 1959, Zeligman and Fleisher [111] reported two additional boys with similar clinical features. In the meantime several other cases and pedigrees have been described. They have revealed an X-linked transmission, and allowed identification of the underlying MBTPS2 mutations [112]. Clinical features. The IFAP syndrome is characterized by the triad of generalized, non-scarring alopecia of early

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onset, involving the scalp, eyelashes, eyebrows and body hair, widespread, non-inflammatory, thorn-like follicular projections, and severe photophobia. Keratotic papules are most pronounced over the extensor extremities and scalp and are symmetrically distributed. Teeth, nails and sweat production are generally normal, although isolated cases of nail dystrophy are reported [113,114]. In some patients, more pronounced keratotic papules overlying the elbows and knees have been described. The palms and soles are generally unaffected, in contrast to patients with KID syndrome, who have striking palmoplantar involvement. Photophobia may present in infancy or early childhood. Other ocular changes seen with IFAP syndrome include punctate keratopathy, erosions, corneal scarring, atopic keratoconjunctival inflammation, horizontal nystagmus and myopia [115,116]. Ocular histopathology shows avascular corneal scarring and secondary corneal amyloid deposition, and ultrastructural studies also demonstrate several abnormalities of the corneal epithelia, basement membrane and connective tissue [116]. Corneal abnormalities are the likely cause of photophobia in IFAP syndrome. Other less consistently reported findings in IFAP syndrome include delayed growth and development, seizures, increased susceptibility to respiratory infections, signs of atopy (asthma, elevated IgE levels) and possibly other anomalies [111,115–118]. Histology. Skin histopathology is non-specific and includes dilated hair follicles with keratin plugs extending above the surface of the skin, decreased or absent sebaceous glands and normal sweat glands [115]. Genetics. The IFAP syndrome has been described almost exclusively in males, and an X-linked recessive mode of inheritance has been postulated. Konig and Happle [119] described two female relatives of a boy with IFAP syndrome who had atrophoderma, hypohidrosis and ichthyotic skin lesions following the lines of Blaschko, as well as circumscribed areas of non-cicatricial hair loss. In other obligate carrier females, extreme lyonization may give rise to non-penetrance, thus blurring the difference between recessive and dominant X-linked inheritance. The cause of IFAP syndrome is functional deficiency of membrane-bound transcription factor protease, site 2 (MBTPS2), a membrane-embedded zinc metalloprotease that activates signalling proteins involved in sterol control of transcription and endoplasmic reticulum (ER) stress response. Since there are rare reports of female patients with clinical features of IFAP syndrome, genetic heterogeneity cannot be excluded [117,120].

Differential diagnosis. Ichthyosis follicularis with atrichia and photophobia syndrome must be differentiated from other ichthyoses associated with hair defects such as keratosis follicularis spinulosa decalvans (KFSD), ulerythema ophyrogenes, atrophodermia vermiculata, KID syndrome, keratosis pilaris rubra atrophicans faciei, atrichia with papular lesions, trichothiodystrophy, ichthyosis hypotrichosis syndrome and IHSC (ichthyosishypotrichosis-sclerosing cholangitis) syndrome. The most difficult condition to distinguish may be KFSD, which is characterized by follicular hyperkeratosis, corneal dystrophy and photophobia. However, the pattern of hair loss in KFSD usually develops in the first few years of life, is patchy and progressive and has associated atrophy and scarring [121]. However, since pedigrees described as KFSD [122], also link to chromosme X [123], KFSP may be allelic with or identical to IFAP.

Autosomal recessive ichthyosis with hypotrichosis (ARIH) ARIH is a recently identified ARCI [124] due to autosomal recessive mutations of the ST14 gene on chromosome 11q24 encoding matriptase, a serine protease [125–127]. Ichthyosis hypotrichosis syndrome (IHS) presents with ichthyosis and abnormal hair and hypotrichosis at birth, and a vernix-like layer covers the entire body, shedding progressively during the first month of life. Ichthyosis and hypotrichosis are generalized but the face is spared. The hair appears curly, sparse, fragile, brittle, dry and lustreless, and shows slow growth. Light microscopy and scanning electron microscopy of hair reveal abnormalities including dysplastic hair, pili torti, pili bifurcati and central pili monobifurcati. Over time, the hair phenotype improves. There is photophobia, and corneal opacities occur [125,127]. Matriptase is an epithelial-derived, type 2 transmembrane serine protease. It contains an N-terminal transmembrane sequence, followed by multiple LDL (low density lipoprotein receptor class A domain) and CUB (complement C1r/C1s, Uegf, Bmp1 domain) repeats, and the C-terminal protease domain. Matriptase-deficient mice die shortly after birth as a result of deficient epidermal-barrier function in the skin in newborns. These mice have abnormal hair-follicle development and disturbed thymic homeostasis resulting in increased lymphocyte apoptosis in the thymus of newborn mice [128,129]. Matriptase is implicated in processing of the N-terminal domains of filaggrin repeats: protease matriptase MT-SP1 has been shown to be an important player in the terminal differentiation of the epidermis, by affecting lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation. In matriptase-knockout mice, processing of the N-terminus

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Fig. 121.20 Neonatal ichthyosis-sclerosing cholangitis-hypotrichosis syndrome.

S100-regulatory protein and monomer units was altered [128], but caspase-14 has also been shown to be involved in the final processing of filaggrin [130].

Ichthyosis-hypotrichosis-sclerosing cholangitis syndrome (IHSC) syndrome Neonatal ichthyosis-sclerosing cholangitis syndrome (ISHC or NISCH syndrome, OMIM 607626) is a rare, autosomal recessive, complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, vulgar type ichthyosis and sclerosing cholangitis (Fig. 121.20). It

was described for the first time in 2002 by Baala et al. [131]. Two years later, the same group could attribute IHSC syndrome to a mutation in the gene encoding the 211-amino-acid long tight junction protein claudin-1 (CLDN1) (OMIM 603718) [132], mapping to chromosome 3q28-q29. Our own observations confirmed that IHSC syndrome is due to a complete claudin-1 deficit and is transmitted as a recessive trait [133]. Variable expressivity of hepatic disease has already been shown, ranging from liver failure requiring liver transplantation to regression of cholestasis as observed in our case [132]. Neonatal

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Fig. 121.21 Netherton Comel syndrome, note the characteristic double edged scaling.

sclerosing cholangitis invariably presents with jaundice and acholic stools, mimicking biliary atresia, as already noted by Gould in 1854 (OMIM 242400) [133]. Claudin-1 is a major element of tight junctions (TJs), which are among the components of the junctional complex that forms a physical barrier to the diffusion of solutes through the paracellular space and maintains cell polarity [134]. Furuse et al. [135] showed that mice lacking claudin-1 died within 1 day after birth with wrinkled skin, probably because of dehydration. Although the epidermal barrier was severely damaged, the TJs presented a normal morphology. Therefore, it seems that claudin-1 principally affects the function of TJs. The skin defect could be due to a physical imperfection of the TJs, or result from an indirect effect of claudin-1 on target genes involved in the control of stratum corneum permeability [136].

Netherton syndrome (NS) Netherton syndrome (NS; OMIM 256500) is characterized by elevated IgE levels with atopic manifestations including asthma, ichthyosis linearis circumflexa and/or congenital lamellar ichthyosis and trichorrhexis invaginata (Fig. 121.21) (see also Chapter 114). It is caused by recessive mutations in the serine protease inhibitor Kazal type (SPINK5; OMIM 605010) [137]. The SPINK5 gene encodes the 15-domain serine protease inhibitor lymphoepithelial Kazal-type inhibitor (LEKTI). Protease inhibition is essen-

tial to prevent an over-digestion of corneodesmosomes by the stratum corneum tryptic enzyme (SCTE or KLK5; OMIM 605643) and stratum corneum chymotryptic enzyme (SCCE; KLK7). In Netherton syndrome an enhanced desquamation evokes severe skin permeability barrier dysfunction resulting in dehydration and reactive ichthyosis [138,139]. Interestingly, profilaggrin processing is increased in Spink5-knockout mice [140]. Apart from LEKTI, the secretory leucocyte protease inhibitor (SLPI, or antileucoprotease), elafin (proteinase inhibitor 3, PI3) and alpha-2-macroglobulin-like 1 may be also important for protease inhibition. The other KLK (kallikrein) enzymes expressed in the upper layers of the epidermis (e.g. KLK6, KLK13 and KLK14) are also important for desquamation. Moreover, KLK14 purified from the stratum corneum is responsible for approximately 50% of the total trypsin-like serine protease activity in this layer [141]. KLK5 was shown to induce TSLP expression revealing the potential link of Netherton syndrome to atopic manifestations [142]. TSLP is known to drive atopic manifestations [143,144].

Trichothiodystrophy Trichothiodystrophy (TTD; syn. IBIDS syndrome, sulphur-deficient brittle hair syndrome, Tay syndrome, trichothiodystrophy with ichthyosis) is a rare autosomal recessive disorder characterized by brittle hair and also associated with various systemic symptoms [145,146] (see

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also Chapter 135). A tiger tail pattern under polarized light, trichoschisis and a low sulphur content of hair shafts define the disorder, which is associated with variable and neuroectodermal symptoms. Trichothiodystrophy is characterized by a congenital non-bullous ichthyosiform erythroderma, growth retardation, mental retardation, progeria-like facies and brittle hair. The association of ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature has been given the acronym IBIDS syndrome. Trichothiodystrophy is heterogeneous and due to mutations in ERCC2/XPD, ERCC3/XPB, GTF2H5/TTDA and, in cases without ichthyosis and photosensitivity, in C7Orf11/TTDN1 [147,148]. Approximately half of TTD patients exhibit photosensitivity, resulting from a defect in nucleotide excision repair resulting from mutations in genes encoding subunits of the transcription/repair factor TFIIH. Congenital ichthyosis and the collodionbaby phenotype are more often found in TFIIH mutated patients. Hypogonadism is significantly more frequent in the non-photosensitive group. However, there are no differences regarding osseous anomalies in photosensitive versus non-photosensitive patients. Mutations in TFIIH subunits leading to abnormal expression of genes involved in epidermal differentiation could explain the particular dermatological changes seen in photosensitive cases of TTD [149]. This disease complex is treated elsewhere in this book (see Chapter 135).

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11 Nakayama M, Tavora DG, Alvim TC, Araujo AC, Gama RL. MRI and 1H-MRS findings of three patients with Sjogren-Larsson syndrome. Arq Neuropsiquiatr 2006;64:398–401. 12 van Domburg PH, Willemsen MA, Rotteveel JJ et al. Sjogren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients. Neurology 1999;52:1345–52. 13 Jagell S, Polland W, Sandgren O. Specific changes in the fundus typical for the Sjogren-Larsson syndrome. An ophthalmological study of 35 patients. Acta Ophthalmol (Copenh) 1980;58:321– 30. 14 Willemsen MA, Cruysberg JR, Rotteveel JJ, Aandekerk AL, Van Domburg PH, Deutman AF. Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjogren-Larsson syndrome. Am J Ophthalmol 2000;130: 782–9. 15 Sharma P, Chaudhuri Z, Raina UK, Ghosh B, Sethi S. Abnormal ocular electrophysiology in Sjogren-Larsson syndrome. J Pediatr Ophthalmol Strabismus 2009;46:42–4. 16 Ito M, Oguro K, Sato Y. Ultrastructural study of the skin in SjogrenLarsson syndrome. Arch Dermatol Res 1991;283:141–8. 17 Rizzo WB, Dammann AL, Craft DA. Sjogren-Larsson syndrome. Impaired fatty alcohol oxidation in cultured fibroblasts due to deficient fatty alcohol:nicotinamide adenine dinucleotide oxidoreductase activity. J Clin Invest 1988;81:738–44. 18 Rizzo WB. Sjogren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. Mol Genet Metab 2007;90:1–9. 19 Rizzo WB, Craft DA, Somer T, Carney G, Trafrova J, Simon M. Abnormal fatty alcohol metabolism in cultured keratinocytes from patients with Sjogren-Larsson syndrome. J Lipid Res 2008;49: 410–19. 20 van den Brink DM, van Miert JM, Wanders RJ. A novel assay for the prenatal diagnosis of Sjogren-Larsson syndrome. J Inherit Metab Dis 2005;28:965–9. 21 Lucker GP, van de Kerkhof PC, Cruysberg JR, der Kinderen DJ, Steijlen PM. Topical treatment of Sjogren-Larsson syndrome with calcipotriol. Dermatology 1995;190:292–4. 22 Lacour M, Mehta-Nikhar B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol 1996;134:1023–9. 23 Willemsen MA, Lutt MA, Steijlen PM et al. Clinical and biochemical effects of zileuton in patients with the Sjogren-Larsson syndrome. Eur J Pediatr 2001;160:711–17. 24 Gloerich J, Ijlst L, Wanders RJ, Ferdinandusse S. Bezafibrate induces FALDH in human fibroblasts; implications for Sjogren-Larsson syndrome. Mol Genet Metab 2006;89:111–15. 25 Wierzbicki AS. Peroxisomal disorders affecting phytanic acid alphaoxidation: a review. Biochem Soc Trans 2007;35:881–6. 26 Davies MG, Marks R, Dykes PJ, Reynolds D. Epidermal abnormalities in Refsum’s disease. Br J Dermatol 1977;97:401–6. 27 Jansen GA, Waterham HR, Wanders RJ. Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat 2004;23:209–18. 28 Wierzbicki AS, Lloyd MD, Schofield CJ, Feher MD, Gibberd FB. Refsum’s disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem 2002;80:727–35. 29 Mihalik SJ, Morrell JC, Kim D, Sacksteder KA, Watkins PA, Gould SJ. Identification of PAHX, a Refsum disease gene. Nat Genet 1997;17:185–9. 30 Horn MA, van den Brink DM, Wanders RJ et al. Phenotype of adult Refsum disease due to a defect in peroxin 7. Neurology 2007;68:698–700. 31 Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW. Peroxisome biogenesis disorders. Biochim Biophys Acta 2006;1763:1733–48.

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32 Claridge KG, Gibberd FB, Sidey MC. Refsum disease: the presentation and ophthalmic aspects of Refsum disease in a series of 23 patients. Eye 1992;6:371–5. 33 Plant GR, Hansell DM, Gibberd FB, Sidey MC. Skeletal abnormalities in Refsum’s disease (heredopathia atactica polyneuritiformis). Br J Radiol 1990;63:537–41. 34 Spranger JW, Opitz JM, Bidder U. Heterogeneity of chondrodysplasia punctata. Humangenetik 1971;11:190–212. 35 Steinberg D, Herndon JH Jr, Uhlendorf BW, Mize CE, Avigan J, Milne GW. Refsum’s disease: nature of the enzyme defect. Science 1967;156:1740–2. 36 Kahlert S, Schonfeld P, Reiser G. The Refsum disease marker phytanic acid, a branched chain fatty acid, affects Ca2+ homeostasis and mitochondria, and reduces cell viability in rat hippocampal astrocytes. Neurobiol Dis 2005;18:110–18. 37 Schonfeld P, Reiser G. Rotenone-like action of the branched-chain phytanic acid induces oxidative stress in mitochondria. J Biol Chem 2006;281:7136–42. 38 Dykes PJ, Marks R, Davies MG, Reynolds DJ. Epidermal metabolism in heredopathia atactica polyneuritiformis (Refsum’s disease). J Invest Dermatol 1978;70:126–9. 39 Van den Brink DM, Brites P, Haasjes J et al. Identification of PEX7 as the second gene involved in Refsum disease. Adv Exp Med Biol 2003;544:69–70. 40 Wanders RJ, Komen JC. Peroxisomes, Refsum’s disease and the alpha- and omega-oxidation of phytanic acid. Biochem Soc Trans 2007;35:865–9. 41 Steinberg S, Jones R, Tiffany C, Moser A. Investigational methods for peroxisomal disorders. Curr Protoc Hum Genet 2008; Chapter 17:Unit 17 16. 42 Singh I, Johnson GH, Brown FR 3rd. Peroxisomal disorders. Biochemical and clinical diagnostic considerations. Am J Dis Child 1988;142:1297–301. 43 Wanders RJ, Waterham HR. Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 2006;75:295–332. 44 Emami S, Hanley KP, Esterly NB, Daniallinia N, Williams ML. X-linked dominant ichthyosis with peroxisomal deficiency. An ultrastructural and ultracytochemical study of the Conradi–Hunermann syndrome and its murine homologue, the bare patches mouse. Arch Dermatol 1994;130:325–36. 45 Emami S, Rizzo WB, Hanley KP, Taylor JM, Goldyne ME, Williams ML. Peroxisomal abnormality in fibroblasts from involved skin of CHILD syndrome. Case study and review of peroxisomal disorders in relation to skin disease. Arch Dermatol 1992;128:1213–22. 46 Cingolani L. Rapid gas chromatographic determination of phytanic acid from serum of a patient suffering from Refsum’s disease. J Chromatogr 1987;419:475–8. 47 Weinstein R. Phytanic acid storage disease (Refsum’s disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management. J Clin Apher 1999;14:181–4. 48 Jansen GA, Wanders RJ, Watkins PA, Mihalik SJ. Phytanoylcoenzyme A hydroxylase deficiency – the enzyme defect in Refsum’s disease. N Engl J Med 1997;337:133–4. 49 Saba TG, Montpetit A, Verner A et al. An atypical form of erythrokeratodermia variabilis maps to chromosome 7q22. Hum Genet 2005;116:167–71. 50 Beare JM, Nevin NC, Froggatt P, Kernohan DC, Allen IV. Atypical erythrokeratoderma with deafness, physical retardation and peripheral neuropathy. Br J Dermatol 1972;87:308–14. 51 Giroux JM, Barbeau A. Erythrokeratodermia with ataxia. Arch Dermatol 1972;106:183–8. 52 Montpetit A, Cote S, Brustein E et al. Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet 2008;4:e1000296.

53 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;77:242–51. 54 Zunich J, Kaye CI. New syndrome of congenital ichthyosis with neurologic abnormalities. Am J Med Genet 1983;15:331–3, 335. 55 Zunich J, Kaye CI. Additional case report of new neuroectodermal syndrome. Am J Med Genet 1984;17:707–10. 56 Zunich J, Esterly NB, Holbrook KA, Kaye CI. Congenital migratory ichthyosiform dermatosis with neurologic and ophthalmologic abnormalities. Arch Dermatol 1985;121:1149–56. 57 Shashi V, Zunich J, Kelly TE, Fryburg JS. Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases. J Med Genet 1995;32:465–9. 58 Tinschert S, Anton-Lamprecht I, Albrecht-Nebe H, Audring H. Zunich neuroectodermal syndrome: migratory ichthyosiform dermatosis, colobomas, and other abnormalities. Pediatr Dermatol 1996;13:363–71. 59 Zunich J, Esterly NB, Kaye CI. Autosomal recessive transmission of neuroectodermal syndrome. Arch Dermatol 1988;124:1188–9. 60 Jordans GH. The familial occurrence of fat containing vacuoles in the leukocytes diagnosed in two brothers suffering from dystrophia musculorum progressiva (ERB.). Acta Med Scand 1953;145:419–23. 61 Dorfman ML, Hershko C, Eisenberg S, Sagher F. Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol 1974;110:261–6. 62 Chanarin I, Patel A, Slavin G, Wills EJ, Andrews TM, Stewart G. Neutral-lipid storage disease: a new disorder of lipid metabolism. Br Med J 1975;i:553–5. 63 Elias PM, Williams ML. Neutral lipid storage disease with ichthyosis. Defective lamellar body contents and intracellular dispersion. Arch Dermatol 1985;121:1000–8. 64 Srebrnik A, Tur E, Perluk C et al. Dorfman-Chanarin syndrome. A case report and a review. J Am Acad Dermatol 1987;17:801–8. 65 Igal RA, Rhoads JM, Coleman RA. Neutral lipid storage disease with fatty liver and cholestasis. J Pediatr Gastroenterol Nutr 1997; 25:541–7. 66 Pena-Penabad C, Almagro M, Martinez W et al. Dorfman–Chanarin syndrome (neutral lipid storage disease): new clinical features. Br J Dermatol 2001;144:430–2. 67 Fischer J, Lefevre C, Morava E et al. The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 2007;39:28–30. 68 Bruno C, Bertini E, Di Rocco M et al. Clinical and genetic characterization of Chanarin-Dorfman syndrome. Biochem Biophys Res Commun 2008;369:1125–8. 69 Schweiger M, Lass A, Zimmermann R, Eichmann TO, Zechner R. Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. Am J Physiol Endocrinol Metab 2009;297:E289–96. 70 Rozenszajn L, Klajman A, Yaffe D, Efrati P. Jordans’ anomaly in white blood cells. Report of case. Blood 1966;28:258–65. 71 Yamaguchi T, Osumi T. Chanarin-Dorfman syndrome: deficiency in CGI-58, a lipid droplet-bound coactivator of lipase. Biochim Biophys Acta 2009;1791:519–23. 72 Lefevre C, Jobard F, Caux F et al. Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome. Am J Hum Genet 2001;69: 1002–12. 73 Wolf R, Zaritzky A, Pollak S. Value of looking at leukocytes in every case of ichthyosis. Dermatologica 1988;177:237–40. 74 Akiyama M, Sakai K, Takayama C et al. CGI-58 is an alpha/betahydrolase within lipid transporting lamellar granules of differentiated keratinocytes. Am J Pathol 2008;173:1349–60.

MEDOC: the Ichthyoses 75 Granneman JG, Moore HP, Krishnamoorthy R, Rathod M. Perilipin controls lipolysis by regulating the interactions of ab-hydrolase containing 5 (Abhd5) and adipose trigylceride lipase (ATGL). J Biol Chem 2009 Dec 11;284(50):34538–44. Epub 2009 Oct 22. 76 Bodian EL. Skin manifestations of Conradi’s disease. Chondrodystrophia congenita punctata. Arch Dermatol 1966;94:743–8. 77 Happle R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet 1979;53:65–73. 78 Mevorah B, Politi Y. Genodermatoses in women. Clin Dermatol 1997;15:17–29. 79 Poznanski AK. Punctate epiphyses: a radiological sign not a disease. Pediatr Radiol 1994;24:418–24, 436. 80 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-Hunermann syndrome. Nat Genet 1999;22:291–4. 81 Derry JM, Gormally E, Means GD et al. Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Nat Genet 1999;22:286–90. 82 Happle R. Cataracts as a marker of genetic heterogeneity in chondrodysplasia punctata. Clin Genet 1981;19:64–6. 83 Prendiville JS, Zaparackas ZG, Esterly NB. Normal peroxisomal function and absent skeletal manifestations in Conradi-Hunermann syndrome. Arch Dermatol 1991;127:539–42. 84 Has C, Bruckner-Tuderman L, Muller D et al. The ConradiHunermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet 2000;9:1951–5. 85 Kolde G, Happle R. Histologic and ultrastructural features of the ichthyotic skin in X-linked dominant chondrodysplasia punctata. Acta Derm Venereol 1984;64:389–94. 86 Konig A, Happle R, Bornholdt D, Engel H, Grzeschik KH. Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet 2000;90:339–46. 87 Feldmeyer L, Mevorah B, Grzeschik KH, Huber M, Hohl D. Clinical variation in X-linked dominant chondrodysplasia punctata (X-linked dominant ichthyosis). Br J Dermatol 2006;154:766–9. 88 Ponec M, Williams ML. Cholesterol sulfate uptake and outflux in cultured human keratinocytes. Arch Dermatol Res 1986;279:32–6. 89 Jira PE, Waterham HR, Wanders RJ, Smeitink JA, Sengers RC, Wevers RA. Smith-Lemli-Opitz syndrome and the DHCR7 gene. Ann Hum Genet 2003;67:269–80. 90 Fitzky BU, Witsch-Baumgartner M, Erdel M et al. Mutations in the delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A 1998;95:8181–6. 91 Kelley RI, Wilcox WG, Smith M, Kratz LE, Moser A, Rimoin DS. Abnormal sterol metabolism in patients with Conradi-HunermannHapple syndrome and sporadic lethal chondrodysplasia punctata. Am J Med Genet 1999;83:213–19. 92 Liu XY, Dangel AW, Kelley RI et al. The gene mutated in bare patches and striated mice encodes a novel 3beta-hydroxysteroid dehydrogenase. Nat Genet 1999;22:182–7. 93 Grange DK, Kratz LE, Braverman NE, Kelley RI. CHILD syndrome caused by deficiency of 3beta-hydroxysteroid-delta8, delta7isomerase. Am J Med Genet 2000;90:328–35. 94 Williams ML, Feingold KR, Grubauer G, Elias PM. Ichthyosis induced by cholesterol-lowering drugs. Implications for epidermal cholesterol homeostasis. Arch Dermatol 1987;123:1535–8. 95 Cooper MK, Wassif CA, Krakowiak PA et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 2003;33:508–13. 96 Zhao C, Dahlman-Wright K. J Endocrinol 2010 Mar;204(3):233–40. Epub 2009 Oct 16. Review. 97 Man MQ, Choi EH, Schmuth M et al. Basis for improved permeability barrier homeostasis induced by PPAR and LXR activators: lipo-

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sensors stimulate lipid synthesis, lamellar body secretion, and post-secretory lipid processing. J Invest Dermatol 2006;126:386–92. Weinhofer I, Kunze M, Stangl H, Porter FD, Berger J. Peroxisomal cholesterol biosynthesis and Smith-Lemli-Opitz syndrome. Biochem Biophys Res Commun 2006;345:205–9. Holmes RD, Wilson GN, Hajra AK. Peroxisomal enzyme deficiency in the Conradi-Hunerman form of chondrodysplasia punctata. N Engl J Med 1987;316:1608. Keller GA, Pazirandeh M, Krisans S. 3-Hydroxy-3-methylglutaryl coenzyme A reductase localization in rat liver peroxisomes and microsomes of control and cholestyramine-treated animals: quantitative biochemical and immunoelectron microscopical analyses. J Cell Biol 1986;103:875–86. Shirahama S, Miyahara A, Kitoh H et al. Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata. Hum Genet 2003;112:78–83. Herman GE. Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum Mol Genet 2003;12(Spec. No 1):R75–88. Happle R. X-linked dominant chondrodysplasia punctata/ ichthyosis/cataract syndrome in males. Am J Med Genet 1995;57:493. 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;39:182–7. Happle R, Koch H, Lenz W. The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr 1980;134:27–33. Bornholdt D, Konig A, Happle R et al. Mutational spectrum of NSDHL in CHILD syndrome. J Med Genet 2005;42:e17. Happle R. Ptychotropism as a cutaneous feature of the CHILD syndrome. J Am Acad Dermatol 1990;23:763–6. Happle R, Mittag H, Kuster W. The CHILD nevus: a distinct skin disorder. Dermatology 1995;191:210–16. Bittar M, Happle R, Grzeschik KH et al. CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. Arch Dermatol 2006;142:348–51. MacLeod J. Three cases of ichthyosis follicularis with baldness. Br J Dermatol 1909;21:165–89. Zeligman I, Fleisher TL. Ichthyosis follicularis. Arch Dermatol 1959;80:413–20. Oeffner F, Fischer G, Happle R et al. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet 2009;84:459–67. Hamm H, Meinecke P, Traupe H. Further delineation of the ichthyosis follicularis, atrichia, and photophobia syndrome. Eur J Pediatr 1991;50:627–9. Happle R. What is IFAP syndrome? Am J Med Genet A 2004;124A:328. Eramo LR, Esterly NB, Zieserl EJ, Stock EL, Herrmann J. Ichthyosis follicularis with alopecia and photophobia. Arch Dermatol 1985;121:1167–74. Cursiefen C, Schlotzer-Schrehardt U, Holbach LM, Pfeiffer RA, Naumann GO. Ocular findings in ichthyosis follicularis, atrichia, and photophobia syndrome. Arch Ophthalmol 1999;117:681–4. 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:S156–8. Megarbane H, Zablit C, Waked N, Lefranc G, Tomb R, Megarbane A. Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: report of a new family with additional features and review. Am J Med Genet A 2004;124A:323–7.

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119 Konig A, Happle R. Linear lesions reflecting lyonization in women heterozygous for IFAP syndrome (ichthyosis follicularis with atrichia and photophobia). Am J Med Genet 1999;85:365–8. 120 Rothe MJ, Lucky AW. Are ichthyosis follicularis and hereditary mucoepithelial dystrophy related diseases. Pediatr Dermatol 1995;12:195. 121 van Osch LD, Oranje AP, Keukens FM, van Voorst Vader PC, Veldman E. Keratosis follicularis spinulosa decalvans: a family study of seven male cases and six female carriers. J Med Genet 1992;29:36–40. 122 Herd RM, Benton EC. Keratosis follicularis spinulosa decalvans: report of a new pedigree. Br J Dermatol 1996;134:138–42. 123 Porteous ME, Strain L, Logie LJ, Herd RM, Benton EC. Keratosis follicularis spinulosa decalvans: confirmation of linkage to Xp22.13-p22.2. J Med Genet 1998;35:336–7. 124 Lestringant GG, Kuster W, Frossard PM, Happle R. Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis: a new genodermatosis? Am J Med Genet 1998;75:186–9. 125 Basel-Vanagaite L, Attia R, Ishida-Yamamoto A et al. Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase. Am J Hum Genet 2007;80:467–77. 126 Desilets A, Beliveau F, Vandal G, McDuff FO, Lavigne P, Leduc R. Mutation G827R in matriptase causing autosomal recessive ichthyosis with hypotrichosis yields an inactive protease. J Biol Chem 2008;283:10535–42. 127 Alef T, Torres S, Hausser I et al. Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. J Invest Dermatol 2009;129:862–9. 128 List K, Szabo R, Wertz PW et al. Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1. J Cell Biol 2003;163:901–10. 129 List K, Currie B, Scharschmidt TC et al. Autosomal ichthyosis with hypotrichosis syndrome displays low matriptase proteolytic activity and is phenocopied in ST14 hypomorphic mice. J Biol Chem 2007;282:36714–23. 130 Denecker G, Hoste E, Gilbert B et al. Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 2007;9:666–74. 131 Baala L, Hadj-Rabia S, Hamel-Teillac D et al. Homozygosity mapping of a locus for a novel syndromic ichthyosis to chromosome 3q27-q28. J Invest Dermatol 2002;119:70–6. 132 Hadj-Rabia S, Baala L, Vabres P et al. Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease. Gastroenterology 2004;127:1386–90. 133 Feldmeyer L, Huber M, Fellmann F, Beckmann JS, Frenk E, Hohl D. Confirmation of the origin of NISCH syndrome. Hum Mutat 2006;27:408–10. 134 Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2001;2:285–93. 135 Furuse M, Hata M, Furuse K et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin1-deficient mice. J Cell Biol 2002;156:1099–11. 136 Bazzoni G, Dejana E. Keratinocyte junctions and the epidermal barrier: how to make a skin-tight dress. J Cell Biol 2002;156:947–9. 137 Chavanas S, Bodemer C, Rochat A et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 2000;25:141–2. 138 Komatsu N, Takata M, Otsuki N et al. Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. J Invest Dermatol 2002;118:436–43. 139 Komatsu N, Saijoh K, Jayakumar A et al. Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients. J Invest Dermatol 2008;128:1148–59.

140 Hewett DR, Simons AL, Mangan NE et al. Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome. Hum Mol Genet 2005;14:335–46. 141 Deraison C, Bonnart C, Lopez F et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 2007;18:3607–19. 142 Briot A, Deraison C, Lacroix M et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 2009;206:1135–47. 143 Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci U S A 2006;103:11736–41. 144 Zhang Z, Hener P, Frossard N et al. Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma. Proc Natl Acad Sci U S A 2009;106:1536–41. 145 Tay CH. Ichthyosiform erythroderma, hair shaft abnormalities, and mental and growth retardation. A new recessive disorder. Arch Dermatol 1971;104:4–13. 146 Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol 2001;44:891–920. 147 Stefanini M, Botta E, Lanzafame M, Orioli D. Trichothiodystrophy: From basic mechanisms to clinical implications. DNA Repair (Amst) 2010 Jan 2;9(1):2–10. 148 Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med 2009;361:1475–85. 149 Morice-Picard F, Cario-Andre M, Rezvani H, Lacombe D, Sarasin A, Taieb A. New clinico-genetic classification of trichothiodystrophy. Am J Med Genet A 2009;149A:2020–30.

Management of the MEDOC Treatment overview Treatment of the generalized MEDOC is, for the most part, not disease specific. Its foremost goal is the prevention and treatment of complications. These are more common in the severe MEDOC phenotypes and include growth failure, fluid and electrolyte imbalance, toxicity from systemic absorption of medications, temperature dysregulation, local cutaneous and systemic infections, digital constrictions and joint contractures, as well as auditory and ophthalmological complications. A second, and often related, aim is to relieve the pain or discomfort from the skin disorder by preventing or healing losses of skin integrity, such as blisters or cracks and fissures, and by maintaining a hydrated, supple stratum corneum. Another major goal is to assist the patient, and his or her family, to ensure that the patient achieves maximal psychosocial development. Efforts to improve appearance are clearly central to the management of these disorders, but these efforts should be age-appropriate and part of an overall management strategy that considers all aspects of the disease burden. In more severe disorders with systemic complications or in the ‘syndromic’ MEDOC, a multidisciplinary team approach is often desirable. Because of their rarity, many patients with MEDOC feel isolated by their disease. Refer-

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ral to a lay organization, many of which can be located by internet-based research engines (e.g. www.ichthyosis.com, www.scalyskin.org, www.anips.net, www.roughskin.de), can provide an invaluable source of support and information for patients and their families.

Complications and their management Fluid and electrolyte imbalances An impaired permeability barrier is present in most of the MEDOC and is more pronounced in the more erythrodermic phenotypes [1]. Although the stratum corneum is thickened in most MEDOC, it is structurally abnormal, and its function is compromised [2]. Infants are particularly vulnerable to the consequences of increased evaporative water loss from the skin due to their increased surface to volume ratios. Neonates with collodion membranes and harlequin phenotypes may be particularly vulnerable, because of the frequent development of fissures and other breaks in skin integrity [3–5]. Likewise, widespread denuded skin in EI neonates also places them at great risk for fluid and electrolyte imbalance. Severe electrolyte imbalances are also reported in Netherton syndrome [3]. The development of hypernatraemia, due to loss of free water by evaporation, is the clinical consequence most frequently reported [6]. Hypernatraemic dehydration is difficult to detect by physical signs, particularly in infants with ichthyosis whose skin texture cannot be used as a clinical guide to dehydration. Hence, all neonates with ichthyosis should be monitored for the development of hypernatraemia by laboratory screening. In some disorders, particularly Netherton syndrome and harlequin ichthyosis, patients should be monitored for hypernatraemia throughout the first year of life. Maintaining these neonates in a high-humidity environment can reduce TEWL rates, as well as prevent some cracking and fissuring. Petrolatum-based emollients can also retard TEWL, but these need to be applied frequently, every 4–6 h for optimal effectiveness [7].

Percutaneous absorption of topical medications An impaired permeability barrier also permits increased absorption of topically applied medications, particularly hydrophilic molecules. Systemic absorption of corticosteroids, tacrolimus, petrolatum and urea has been observed in patients with MEDOC [8]. Therefore, it should be assumed that anything applied to the skin has the potential for systemic absorption in these patients, particularly those with severely impaired barrier function, such as in Netherton’s syndrome and harlequin ichthyosis, and other severe phenotypes. Owing to their large surface area:volume ratios, infants are particularly at risk. Except when needed to prevent complications, topical treatments should be largely restricted to bland emollients in

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infants. Lactic or glycolic acid-containing keratolytics may, if absorbed, result in systemic acidosis. Salicylic acid should be used with particular caution at all ages, and its use restricted to limited body surface areas [9]. Patients and parents should be taught the signs and symptoms of salicylism, and blood levels should be monitored while using this therapy. There is little rationale for the use of topical corticosteroids and immunomodulators, such as tacrolimus or pimecrolimus, in the MEDOC. Although they are potentially beneficial in Netherton syndrome, these drugs also pose the greatest risk in this disorder, owing to the severe permeability barrier defect [8]. Suppression of the pituitary–adrenal axis is a well-recognized complication of topical corticosteroid use in Netherton syndrome, and extremely high tacrolimus blood levels have also been reported [10]. Therefore, these agents can only be used with great caution, monitoring blood levels and restricting the concentration, duration and body surface area of application. Clinicians should also be aware that the tacrolimus package insert states a contraindication for use in Netherton syndrome.

Growth failure Another consequence of impaired barrier function is the loss of calories through heat and evaporation (2 kJ/mL) [11]. In children with severely impaired barriers, these caloric losses can be significant and are likely to underlie the growth failure observed in some children with severe forms of ichthyosis; caloric losses may exceed 4187 kJ per day or more than 167 kJ/kg. Provision of sufficient calories to support growth can be a challenge, particularly in infants. Because of the associated loss of water, these infants may be volume depleted as well [11,12] and intolerant of excessively hyperosmolar feedings. Moreover, infancy appears to be a critical time for growth failure in children with severe MEDOC; patients with normal birthweights tend to fall off their growth curves in early infancy. Many will establish a steady growth rate thereafter, but often on a low centile. Therefore, aggressive attempts to provide sufficient calories should be instituted early on, and may include supplemental night-time feedings through nasogastric tubes or external gastrostomies. The growth of all infants with severe MEDOC phenotypes should be closely monitored. Although not widely available as a clinical tool, measurement of TEWL can permit calculation of caloric losses through evaporation and provide a guide to replacement therapy [11]. Children with ichthyosis and growth failure should also be screened for nutritional deficiencies [12]. Mild fat malabsorption with steatorrhoea is present in some, but gastrointestinal function is usually preserved. In such cases acquired ichthyosis due to malnutrition, for example in cystic fibrosis, should be considered as a differential diagnosis [13].

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Temperature regulation Neonates and infants with severe MEDOC may experience temperature instability, particularly hypothermia, as a consequence of their impaired permeability barrier and evaporative energy loss (see ‘Growth failure’ above). Older children with hyperkeratotic skin are at risk for hyperthermia when the ambient temperature is high and when they are very active, due to an impaired ability to sweat across a thickened stratum corneum. This is primarily a problem for more severe, generalized phenotypes, as even relatively small areas of non-hyperkeratotic skin may be able to compensate through increased eccrine activity. Parents of children at risk, particularly those with lamellar ichthyosis/CIE phenotypes, should be instructed in the signs and symptoms of hyperthermia. Children should be taught to cool themselves by externally applying water from spray bottles or other devices or by using cooling vests.

Infectious complications Skin infections are a common complication of many MEDOC, although there is scant literature on the epidemiology or pathophysiology of cutaneous infections in these disorders. Patients may experience difficulty with bacterial, yeast or dermatophyte infections, which may be chronic or recurrent in nature. Superficial bacterial infections are particularly problematic in those MEDOC where there is also a component of epidermal fragility, such as EI, Netherton syndrome and Darier disease. Staphylococcus aureus is the most common pathogen, although Gram-negative organisms can also be involved in flexural or occluded areas. Outside the neonatal period, bacterial infection is often heralded by focal blistering in EI. In this and similar MEDOC with marked flexural hyperkeratoses and maceration, the clinical sign of foul odour is thought to be due to excessive bacterial colonization. However, in Netherton syndrome, where the stratum corneum is thin rather than thick, erosions may herald secondary infection. Because widespread cutaneous colonization and/or infection are the rule in these patients, treatment with oral rather than topical antibiotics is usually required. Antibiotics should be selected based upon culture and sensitivity profiles. Parenteral treatment should be considered if there are systemic signs, such as fever or toxicity, and in young infants. Septicaemia is a particular concern in neonates who have portals of entry due to cracks or fissures (e.g. collodion baby) or erosions (e.g. EI). Infants with Netherton syndrome and KID syndrome remain at high risk for septicaemia, even outside the neonatal period [14]. Whether this can be ascribed solely to impaired barrier function, including aberrant KLK activity, or includes a component of immunodeficiency is unclear [14,15]. Prophylactic antibiotics in patients with recurrent infections

may not be of benefit because the spectrum of potentially invasive organisms is broad, and because of the risk of emergence of resistant strains. Empirical efforts at topical antisepsis, through bathing in dilute bleach baths (two teaspoons of hypochlorite bleach per gallon of water; 65 g of 6% sodium hypochlorite into one bathtub of 150 L) may be considered in patients experiencing recurrent bacterial infections. Special care should be taken to avoid disseminated herpes simplex or varicella zoster viral infections. As in atopic dermatitis, patients with MEDOC may be at risk for more severe cases of varicella zoster infections and should be advised to vaccinate against this virus. Exposure to herpes simplex virus should be managed carefully to prevent dissemination. In some MEDOC, such as Netherton syndrome, other widespread viral skin infections, such as warts, may also develop [16,17]. Widespread or recurrent dermatophyte infections can be observed in a number of MEDOC [18–21]. It is likely that the thick stratum corneum provides a favourable culture medium for these organisms. Dermatophyte infections may be masked by the significant scaling associated with severe MEDOC, and a high index of suspicion is necessary to aid in early diagnosis and successful treatment. The acute onset or increased severity of pruritus should raise suspicion of a dermatophyte infection. Areas with unusual or annular scale patterns should be examined by KOH preparation or cultured for fungi. Pustules may indicate either bacterial or fungal infections, and their contents should be examined by KOH preparation, Gram-stained smear and culture. Multiple pustules may also signal a viral infection, such as herpes simplex virus. Hair loss, with or without scalp pustules or pruritus, should also raise the question of dermatophyte infection. Recurrent tinea capitis may underlie the progressive alopecia in some patients with lamellar ichthyosis/CIE and perhaps other phenotypes. Atypical organisms, such as Trichophyton rubrum, are often seen. Tinea capitis always requires treatment with an oral antifungal. Tinea corporis in the MEDOC is often too widespread to treat with topical agents and will also require oral medications. Once established, recurrent dermatophyte infections are common in the MEDOC, probably due to a combination of a fertile ground for growth, tolerance by the host for the organism and widespread environmental contamination with spores. Chronic cutaneous candidiasis may complicate KID syndrome and requires systemic antifungal therapy [22,23].

Digital constrictions and joint contractures When the stratum corneum is massively thickened and relatively inflexible, it may impair development of the underlying soft tissue, cartilage and even bone in acral locations. This is primarily observed as a consequence of

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the hyperkeratosis in utero in the harlequin baby or collodion baby phenotypes. Eversion of lips (eclabion) and eyelids (ectropion) results from the tension on these structures. The eclabion will resolve over time, but ectropion may persist (see below). Cartilaginous structures of ears and nose may also be underdeveloped in the more severe lamellar ichthyosis/CIE, harlequin ichthyosis (HI) and related phenotypes, producing a relatively small nose, with small alae and small pinnae. In HI, the stratum corneum may form mitten-like encasements of the hands, preventing full delineation of the digits, although the underlying bones are usually present. Constricting scales on the hands are very slowly shed after birth; in the interim, oedema may develop distally and compromise the vascular supply, requiring surgical release. Early institution of systemic retinoids may hasten the shedding of these digital bands and should be considered in neonates at risk. Older infants and children with severe MEDOC may be at risk for the development of joint contractures. Patients with dense, inflexible PPK are at risk for disabling hand contractures. Range-of-motion exercises should be instituted, ideally before contractures develop. Early referral for physical therapy is advised. Contractures of large joints may also develop and should be managed similarly.

Auditory and ocular complications In many severe, generalized MEDOC phenotypes, scales and sebaceous debris can accumulate in the external auditory canals and result in a conductive hearing deficit. The regular use of softeners and irrigation may be helpful but is often insufficient, and periodic manual removal is required. A trained professional should always perform this debridement. Persistent ectropion is a common problem in HI and lamellar ichthyosis/CIE phenotypes. It may manifest overtly or more subtly as incomplete lid closure. Ocular lubricants must be used regularly in all patients with lagophthalmos, and regular ophthalmological surveillance is needed to avoid corneal damage. Surgical correction may be required. Systemic retinoids may be beneficial in reducing tension on the lower eyelids.

Psychosocial issues It is important for the clinician to address the potential psychosocial ramifications of MEDOC. The presence of an obvious skin condition and its associated features, such as ectropion, often results in perceptions of disfigurement. As with many dermatological conditions, parents are often faced with frequent enquiries from family, friends and strangers regarding the nature of their condition. In some patients, chronic malodour of the skin may add to the social stigmata. If there is significant PPK,

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children may have difficulty participating in normal school activities, such as physical education and competitive athletics. They may also have to take special precautions because of heat intolerance. These activity limitations may further isolate affected children from their peers. An important goal of management is to normalize the child’s life experiences as much as possible. Diverse organizations (www.selbsthilfetirol.at/Selbsthilfegruppen/ Gruppen/Ichthyose.htm, www.devidts.com/ichthyosis, www.iktyosis.dk, www.iholiitto.fi/, www.anips.net/, www.ichthyose.de, www.ittiosi.it/, www.gyorinsen.com, www.aaimonaco.org, www.ictiosis.org, www.iktyos.nu/, www.ichthyose.ch, www.ichthyosis.org.uk/, www. scalyskin.org) can be an invaluable resource to patients and their families in combating the isolation associated with having a rare disease. Additionally, participation in a summer camp for children with skin conditions may be a life-changing experience.

Topical therapies Ichthyosis management revolves around improving hydration and lubrication of the skin to improve stratum corneum flexibility [1,2,24,25]. Daily or twice-daily prolonged baths are often essential to soften the skin. Mechanical debridement during or after soaking can be an effective way to remove hyperkeratotic areas. Bath oils can be used to further enhance moisturization of the skin. They should not be added until after the first 10–15 min of soaking, during which time the stratum corneum imbibes water. Bland petrolatum- or lanolin-based emollient creams or ointments should be applied after bathing while the skin is still moist to ‘seal’ in moisture before it evaporates as the skin dries. There are several classes of topical agents that may offer some benefit to the ichthyosis patient. These include: emollients, keratolytics (or corneolytics), humectants and barrier-repair formulations. Medications that alter epidermal differentiation, such as vitamin A and vitamin D analogues, are also available topically. Emollients are typically petrolatum- and/or lanolin-based lotions, creams and ointments that provide a hydrophobic film over the stratum corneum surface. Although their effect is limited to a few hours, at best, they help maintain corneocyte hydration and improve stratum corneum flexibility and barrier function. Barrier-repair formulations differ from simple emollients in that the lipids in these formulations reconstitute stratum corneum membrane lipids [2]. They are composed of physiological lipids or their analogues and are handled by the epidermis in a different manner from nonphysiological lipids. Whereas petrolatum forms a film over the outer stratum corneum layers, topically applied physiological lipids penetrate through the stratum corneum intercellular bilayers and are taken up by kera-

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tinocytes in the granular and upper spinous cell layers, where they are packaged into lamellar bodies and secreted back into the stratum corneum extracellular domain [26,27]. Normal stratum corneum lipids are composed of approximately equimolar ratios of cholesterol, free fatty acids and ceramides. If only one or two of these three lipid classes are applied, an imbalanced lipid mixture will be secreted, resulting in the formation of structurally abnormal membranes with a potentially deleterious effect on barrier function. Therefore, to be effective, barrierrepair formulations must contain the correct proportion of all three classes of stratum corneum lipids [28]. Although theoretically desirable, several factors may interfere with their use in MEDOC. First, some of the theoretically optimal formulations are not commercially available at present or, if available, may be too expensive for daily, total body applications in sufficient quantity to restore stratum corneum lipid content. Second, many products that are labelled ‘barrier repair ’ do not provide data in support of this claim. Finally, these agents have not been studied for their efficacy in the ichthyoses, and it is possible that the underlying defects in some of the MEDOC may interfere with their uptake and secretion. For example, HI lacks a lamellar body secretory system, and patients with HI may not benefit from therapy with physiological lipids that utilize this pathway [26]. Nonetheless, although perhaps a distant goal at present, rational therapy based upon correction of the abnormal stratum corneum lipid content or composition of many of the MEDOC is the direction in which future treatment of these disorders should go [2,25]. There are few studies to guide choice from the many products available. Humectants, such as urea-containing products, act by attracting and binding water, and are often used in conjunction with emollients. A recent study demonstrated superior response to combinations of 5% urea and 20% propylene glycol compared with these agents used individually ([7]. Keratolytics facilitate the shedding of squames. These include the α-hydroxy acids, lactic and glycolic acids, and salicylic acid. Their mechanism of action appears to be multifaceted [29], but may involve activation of proteases that degrade corneodesmosomes through their acidification of the stratum corneum [30]. Many formulations containing α-hydroxy acids are commercially available, and they may also be compounded (1–15%) in petrolatum. All α-hydroxy acids can cause stinging with applications, particularly through microcuts and abrasions. For this reason, they are often poorly tolerated by small children. The α-hydroxy acids are also irritants and may be poorly tolerated in ichthyosis vulgaris (IV) patients who have concomitant atopic dermatitis. Unless being used to improve function, there is little rationale for total body applications in infants who are not troubled by their appearance and who may be at

risk for acidosis with systemic absorption. Keratolytics should not be used in Netherton syndrome, because scaling in this disorder is not due to excessive stratum corneum in most instances. Salicylic acid is a very effective corneolytic. It is available in commercial formulations or can be compounded (3–10%) in petrolatum. Because of the risk of salicylism, it should only be applied to a limited percentage of the body surface [31]. If used in infants or over more extensive areas of the body, salicylate blood levels should be monitored and parents instructed in the signs/symptoms of salicylism.

Modulators of epidermal differentiation Vitamin A when given in pharmacological doses has long been recognized to have potent effects on cornifying epithelia; however, its use was therapeutically limited by long-term systemic retention of the drug with toxicity [32,33]. Prior to the development of the synthetic analogues, hypervitaminosis A presented with CNS, hepatic and/or bone toxicity. Moreover, teratogenicity was recognized in experimental animals. All of these toxicities are retained to some degree by the systemic synthetic retinoids and are discussed in greater detail below [34]. Retinoids are nuclear hormones that act through their nuclear hormone receptors to regulate gene transcription. In the MEDOC, retinoids act to produce a less adhesive stratum corneum, in part by inducing a shedding of desmosomes [35]. Their effects on stratum corneum adhesion are not disease specific. This increased skin fragility can compound an underlying problem of epidermal integrity in some MEDOC (e.g. EI and Darier disease). As with the keratolytics, retinoids should not be used in Netherton syndrome, because the stratum corneum is already too thin in this disorder. Retinoids also induce epidermal hyperproliferation and decrease barrier competence [36]. Thus, these aspects of the MEDOC are not improved by their use. Several retinoid derivatives are available in topical formulations. Although generally quite effective in removing scale, their use in the generalized MEDOC is limited by the inconvenience and expense of widespread applications and in the frequently accompanying irritancy [37]. Nonetheless, they can be very useful for more limited applications [38]. Tazarotene is a particularly effective derivative [39]. Vitamin D is also a nuclear hormone ligand that acts in the skin by altering the expression of genes involved in epidermal differentiation [40]. Topical formulations (calcipotriol), although developed for use in psoriasis, are useful in the MEDOC [41–43] but they aggravate atopic dermatitis [40]. As with retinoids, their use is limited by irritancy and expense. In addition, systemic absorption

MEDOC: the Ichthyoses

may affect systemic calcium homeostasis. If used in infants or young children, or over large areas of the body surface, blood calcium levels must be monitored.

Systemic retinoid therapy As is the case for psoriasis, retinoids have been used in the treatment of MEDOC for the past two decades, and their efficacy is well established [1,44]. Because they decrease the cohesiveness of the stratum corneum [44], retinoids are unquestionably effective therapy for removing excess scale. However, they are potent medications with many potential side-effects, and risk versus benefit needs to be carefully considered for each patient prior to their use. The main indications for systemic retinoid therapy are to help maintain self-esteem in older children and teenagers, to improve ectropion and to preserve function (e.g. maintaining hand mobility and decreasing the development of contractures). If used, systemic retinoid therapy must be supplemented by good topical regimens in order to optimize management and permit use of the lowest possible dose to minimize adverse effects. Several synthetic, oral retinoids have been developed, including isotretinoin, etretinate and acitretin. Since 1997, acitretin, the active metabolite of etretinate, has replaced its parent drug in clinical use. Retinoids are approved in Europe, but not by the US Food and Drug Administration, for the treatment of MEDOC, but this indication represents their third most common use, following acne and psoriasis. Because of their utility in treating these disorders, a growing body of literature regarding toxicity and recommended clinical monitoring is available. However, information regarding their use in younger children is more limited.

Clinical use The efficacy of oral retinoids depends upon the MEDOC, as well as baseline disease severity. In 1980, Tamayo and Ruiz-Maldonado [45] reported some of the earliest experience with retinoid therapy in children with MEDOC. They treated 33 children between the ages of 2 months and 15 years with etretinate, starting at doses of 1–2 mg/ kg/day for up to 42 months. The dose was decreased by 50% upon disease remission and further adjusted based upon disease control. They observed excellent clinical improvement in patients with lamellar ichthyosis, erythrokeratodermia progressiva symmetrica (EKPS) , Darier disease, pityriasis rubra pilaris and PPK. Patients with EI achieved a slightly lower remission rate of 70–80%. Several reports of retinoid efficacy for hyperkeratotic phenotypes, especially lamellar ichthyosis/CIE, have since followed [46–49], and the neonatal use of systemic retinoids for HI is also well described [45,50,51]. A study suggests that EI patients with K10 gene mutations may

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be more responsive to retinoid therapy than patients with K1 gene mutations [52]. Many experts feel that acitretin/etretinate is superior to isotretinoin in the management of MEDOC, but data to support this assertion are sparse [1,24]. However, due to its short half-life and lower risk of long-term teratogenicity (see below), isotretinoin should be used in females of child-bearing age. For either medication, it is advisable to start with lower doses and gradually increase drug quantity until the desired effect is reached, provided that the side-effects are tolerable. Acitretin may be initiated at 0.2–0.5 mg/kg/day and titrated accordingly. Adult patients can often be maintained on doses as low as 10– 25 mg/day. Isotretinoin doses generally range from 0.5 to 2 mg/kg/day. Therapeutic effects (peeling, desquamation) are usually noted after 1–2 weeks, but 1–2 months are needed to see maximal benefit. After maintaining the desired effect for a few months, the dose can be tapered to the lowest amount that will preserve this effect. Higher doses may be needed initially to peel off excess scale, whereas lower doses will prevent scale from reaccumulating. Unfortunately, the therapeutic effects of systemic retinoids are not maintained after discontinuation of the medication. Long-term disease control requires long-term retinoid therapy and close monitoring for adverse effects is necessary.

Adverse effects Common mucocutaneous side-effects of acitretin and isotretinoin include cheilitis, xerosis, epistaxis and dry eyes. These are dose related and, if troublesome, can be ameliorated by emolliation and/or dose adjustment. A minority of patients may also experience hair loss, nail fragility and blepharoconjunctivitis. Retinoids increase skin fragility, and this may be especially problematic in patients with EI, thus limiting their use. Other uncommon cutaneous side-effects include excessive granulation tissue, pyogenic granulomas and paronychia. Ocular side-effects are also reported, particularly with isotretinoin. For patients on long-term retinoid therapy or multiple cycles of isotretinoin, an annual eye examination is recommended with special attention to dark adaptation, colour vision, ocular sicca and signs of papilloedema. The medication should be discontinued if the patient develops pseudotumour cerebri, optic neuritis, night blindness, decreased colour vision or significant ocular sicca. Although most of these changes are reversible upon discontinuation of the drug, decreased dark adaptation may persist. Isotretinoin and acitretin both cause temporary elevations in cholesterol (LDL) and triglycerides, and patients with underlying obesity, diabetes or dyslipidaemia are likely to have more marked alterations. Although these

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changes are believed to be reversible, few studies have evaluated the long-term effects of systemic retinoids on cholesterol or triglyceride levels, or risk of coronary artery disease. One retrospective study of serum lipids in patients receiving more than three courses of isotretinoin for acne concluded that there was little risk of causing prolonged hyperlipidaemia, but similar studies for MEDOC are lacking and may be of particular concern as long-term therapy is likely. Fasting blood lipids should be determined before starting systemic retinoid therapy and checked again after 2 weeks, as rises in serum triglycerides may be rapid. Likewise, lipids should be re-evaluated when doses are adjusted upwards. As patients reach a stable dose, fasting lipids should be checked every 2–3 months. Muscular side-effects are also commonly seen, especially in physically active patients. Common complaints of patients taking isotretinoin include back pain, myalgias and arthralgias. These symptoms are reversible upon discontinuation of the drug. Elevations of creatine phosphokinase are also reported, both with and without coexistent muscle symptoms [53]. These changes appear to be transient and revert to normal within 2 weeks. Systemic retinoids also carry the potential for skeletal toxicity. Bone changes have been observed with isotretinoin, etretinate and acitretin, and may occur with both short- and long-term therapy. Adverse effects include osteopenia/osteoporosis, premature closure of the epiphyseal plate and hyperostosis or calcifications of the tendons and ligaments, similar to the changes observed in the disorder diffuse idiopathic skeletal hyperostosis [54,55]. Isotretinoin is more frequently associated with spinal skeletal changes, whereas acitretin/etretinate is associated with calcification of peripheral ligaments. DiGiovanna and colleagues [54] found radiographic evidence of calcification of the tendons and ligaments at extraspinal locations in 84% of patients treated with etretinate for an average of 5 years. Conversely, hyperostosis may occur after 6 months of isotretinoin therapy at 2 mg/ kg [56]. Another study examining six patients who were treated with retinoids for 8–9 years demonstrated osseous reabsorption of the distal phalanges in two out of six individuals. Often-times, these radiographic findings are not accompanied by clinical signs or symptoms and their significance remains unclear. Retinoid-induced skeletal toxicity may be irreversible. Premature epiphyseal closure associated with retinoid therapy has been reported in younger children [57]. Fortunately, this complication seems to be rare and has only been observed in the setting of prolonged and very highdose therapy. In children that have not met their full growth potential, height should be monitored closely throughout therapy.

Several studies suggest that lower doses, even with prolonged use, are relatively safe with regard to bony changes. Series of 19, 42 and 46 patients treated with etrinate doses of from 0.4 to 1 mg/kg/day for up to 11 years all showed no evidence of skeletal toxicity [58,59]. In general, adverse skeletal effects appear to be most associated with higher retinoid doses and/or with prolonged therapy. Careful patient selection, close monitoring and using the lowest dose possible to achieve desired effects will help to limit potential bone toxicity. All systemic retinoids are potent teratogens, and the potential for fetal deformities is of foremost concern when treating women of child-bearing age with these medications. The spectrum of retinoid-associated birth defects, known as retinoic acid embryopathy, includes CNS and ocular abnormalities, facial dysmorphism, cardiac defects, thymus gland abnormalities and bone malformations [60]. The plasma half-life of isotretinoin is 10–20 h, and it is completely cleared from the body within 1 month of discontinuing therapy. By contrast, the plasma half-life of etretinate is 100 days, and as the medication is stored in fat deposits, trace amounts can be detected in serum for up to 3 years after stopping therapy. Acitretin, the active metabolite of etretinate, has a plasma half-life of 2 days and has supplanted etretinate in clinical use. However, in the presence of ethanol it may be esterified to etrinate; therefore, it is recommended that women avoid pregnancy for at least 3 years after stopping acitretin. As these restrictions may be impractical for many women, isotretinoin is the preferred systemic retinoid for women of child-bearing age. Before beginning retinoid therapy, female patients need to understand the risk for potential deformities and should demonstrate compliance with reliable forms of contraception. Two forms of contraception for 1 month prior to therapy, during therapy and for 1 month following completion of therapy are recommended. Retinoid therapy does not appear to have an impact on spermatogenesis. A novel class of compounds that block the catabolism of endogenous vitamin A, called retinioic acid metabolism blocking agents, or RAMBAs, represent a new therapeutic avenue [61,62]. It appears that due to their favourable pharmacokinetic profile, RAMBAs have retinoid effects but with fewer side-effects and a reduction of the post-treatment teratogenicity period.

Monitoring Before beginning systemic retinoid therapy, baseline laboratory studies, including a complete blood count, liver function tests, fasting cholesterol and triglyceride levels, and a pregnancy test for females, should be obtained. These studies should be repeated within 2–4 weeks and, if normal, should be followed on a regular basis (every 3–6 months with monthly pregnancy testing when appli-

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cable). Those patients with elevated triglyceride levels require testing every 1 to 2 months. Laboratory studies should also be repeated following increases in retinoid dosing. Baseline radiological studies are recommended by most experts and can include a lateral view of the cervical and thoracic spine, a lateral view of the calcaneus and a posteroanterior view of the pelvis [3]. Follow-up studies should be done for any symptomatic joints, but the frequency of routine surveillance films remains controversial. With long-term retinoid therapy, some experts advocate serial skeletal surveys every 1–2 years. Patients should be questioned at every visit about the presence of joint pain or stiffness, and radiographs should be obtained to evaluate symptomatic bones/joints. References 1 Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm Venereol 2008;88:4–14. 2 Williams ML, Elias PM. Enlightened therapy of the disorders of cornification. Clin Dermatol 2003;21:269–73. 3 DiGiovanna JJ, Robinson-Bostom L. Ichthyosis: etiology, diagnosis, and management. Am J Clin Dermatol 2003;4:81–95. 4 Shwayder T, Akland T. Neonatal skin barrier: structure, function, and disorders. Dermatol Ther 2005;18:87–103. 5 Larregue M, Bieder C, Guillet G, Prigent F. [Cutaneous fissures in collodion babies: incidence and treatment]. Ann Dermatol Venereol 2008;135:279–85. 6 Jones SK, Thomason LM, Surbrugg SK, Weston WL. Neonatal hypernatraemia in two siblings with Netherton’s syndrome. Br J Dermatol 1986;114:741–3. 7 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;141:1027–32. 8 Allen A, Siegfried E, Silverman R et al. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 2001;137:747–50. 9 Young CJ. Salicylate intoxication from cutaneous absorption of salicylic acid. South Med J 1952;45:1075–7. 10 Allen DM, Esterly NB. Significant systemic absorption of tacrolimus after topical application in a patient with lamellar ichthyosis. Arch Dermatol 2002;138:1259–60. 11 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. 12 Fowler AJ, Moskowitz DG, Wong A, Cohen SP, Williams ML, Heyman MB. Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure. J Pediatr Gastroenterol Nutr 2004;38:164–9. 13 Patel N, Spencer LA, English JC 3rd, Zirwas MJ. Acquired ichthyosis. J Am Acad Dermatol 2006;55:647–56. 14 Gilliam A, Williams ML. Fatal septicemia in an infant with keratitis, ichthyosis, and deafness (KID) syndrome. Pediatr Dermatol 2002;19:232–6. 15 Yamasaki K, Schauber J, Coda A et al. Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J 2006;20:2068–80. 16 Folster-Holst R, Swensson O, Stockfleth E, Monig H, Mrowietz U, Christophers E. Comel-Netherton syndrome complicated by papillomatous skin lesions containing human papillomaviruses 51 and 52

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and plane warts containing human papillomavirus 16. Br J Dermatol 1999;140:1139–43. Weber F, Fuchs PG, Pfister HJ, Hintner H, Fritsch P, Hoepfl R. Human papillomavirus infection in Netherton’s syndrome. Br J Dermatol 2001;144:1044–9. Kamalam A, Thambiah AS. Genetic ichthyosis and Trichophyton rubrum infection in infants. Mykosen 1982;25:281–3. Shelley ED, Shelley WB, Schafer RL. Generalized Trichophyton rubrum infection in congenital ichthyosiform erythroderma. J Am Acad Dermatol 1989;20:1133–4. Ludwig RJ, Woodfolk JA, Grundmann-Kollmann M et al. Chronic dermatophytosis in lamellar ichthyosis: relevance of a T-helper 2-type immune response to Trichophyton rubrum. Br J Dermatol 2001;145:518–21. Christen-Zaech S, Patel S, Mancini AJ. Recurrent cutaneous Geomyces pannorum infection in three brothers with ichthyosis. J Am Acad Dermatol 2008;58:S112–13. Hazen PG, Walker AE, Stewart JJ, Carney JF, Engstrom CW, Turgeon KL. Keratitis, ichthyosis, and deafness (KID) syndrome: management with chronic oral ketoconazole therapy. Int J Dermatol 1992;31: 58–9. Mansur AT, Aydingoz IE, Uygur T, Gunduz S. Long-term use of fluconazole for verrucous plaques of cutaneous candidiasis in KID syndrome. Eur J Dermatol 2008;18:469–70. Fleckman P. Management of the ichthyoses. Skin Therapy Lett 2003;8:3–7. Proksch E. The role of emollients in the management of diseases with chronic dry skin. Skin Pharmacol Physiol 2008;21:75–80. Mao-Qiang M, Brown BE, Wu-Pong S, Feingold KR, Elias PM. Exogenous nonphysiologic vs physiologic lipids. Divergent mechanisms for correction of permeability barrier dysfunction. Arch Dermatol 1995;131:809–16. Schmuth M, Ortegon AM, Mao-Qiang M, Elias PM, Feingold KR, Stahl A. Differential expression of fatty acid transport proteins in epidermis and skin appendages. J Invest Dermatol 2005;125:1174–81. Man MM, Feingold KR, Thornfeldt CR, Elias PM. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol 1996;106:1096–101. Van Scott EJ, Yu RJ. Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids. J Am Acad Dermatol 1984;11:867–79. Hachem JP, Crumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM. pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 2003;121:345–53. Abdel-Magid, EH, el-Awad Ahmed FR. Salicylate intoxication in an infant with ichthyosis transmitted through skin ointment – a case report. Pediatrics 1994;94:939–40. Thomas JR 3rd, Doyle JA. The therapeutic uses of topical vitamin A acid. J Am Acad Dermatol 1981;4:505–13. Elias PM, Williams ML, Maloney ME et al. Stratum corneum lipids in disorders of cornification. Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis. J Clin Invest 1984;74:1414–21. Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am Acad Dermatol 2003;49:171– 82; quiz 183–176. Williams ML, Elias PM. Nature of skin fragility in patients receiving retinoids for systemic effect. Arch Dermatol 1981;117:611–19. Fritsch P. Oral retinoids in dermatology. Int J Dermatol 1981;20: 314–29. Steijlen PM, Reifenschweiler DO, Ramaekers FC et al. Topical treatment of ichthyoses and Darier ’s disease with 13-cis-retinoic acid. A clinical and immunohistochemical study. Arch Dermatol Res 1993;285:221–6.

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38 Muller SA, Belcher RW, Esterly NB et al. Keratinizing dermatoses. Combined data from four centers on short-term topical treatment with tretinoin. Arch Dermatol 1977;113:1052–4. 39 Marulli GC, Campione E, Chimenti MS, Terrinoni A, Melino G, Bianchi L. Type I lamellar ichthyosis improved by tazarotene 0.1% gel. Clin Exp Dermatol 2003;28:391–3. 40 Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci U S A 2006;103:11736–41. 41 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;131:556–60. 42 Lucker GP, Steijen PM, Suykerbuyk EJ, Kragballe K, Brandrup F, van de Kerkhof PC. Flow-cytometric investigation of epidermal cell characteristics in monogenic disorders of keratinization and their modulation by topical calcipotriol treatment. Acta Derm Venereol 1996;76:97–101. 43 Thiers BH. The use of topical calcipotriene/calcipotriol in conditions other than plaque-type psoriasis. J Am Acad Dermatol 1997;37:S69–71. 44 Peck GL, Yoder FW. Treatment of lamellar ichthyosis and other keratinising dermatoses with an oral synthetic retinoid. Lancet 1976;ii:1172–4. 45 Tamayo L, Ruiz-Maldonado R. Oral retinoid (Ro 10-9359) in children with lamellar ichthyosis, epidermolytic hyperkeratosis and symmetrical progressive erythrokeratoderma. Dermatologica 1980;161: 305–14. 46 Lacour M, Mehta-Nikhar B, Atherton DJ, Harper JI. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol 1996;134:1023–9. 47 Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, Puissant A. Acitretin in the treatment of severe disorders of keratinization. Results of an open study. J Am Acad Dermatol 1991;24:982–6. 48 Steijlen PM, van Dooren-Greebe RJ, Happle R, Van de Kerkhof PC. Ichthyosis bullosa of Siemens responds well to low-dosage oral retinoids. Br J Dermatol 1991;125:469–71.

49 Steijlen PM, Van Dooren-Greebe RJ, Van de Kerkhof PC. Acitretin in the treatment of lamellar ichthyosis. Br J Dermatol 1994;130:211–14. 50 Rogers M, Scraf C. Harlequin baby treated with etretinate. Pediatr Dermatol 1989;6:216–21. 51 Singh S, Bhura M, Maheshwari A, Kumar A, Singh CP, Pandey SS. Successful treatment of harlequin ichthyosis with acitretin. Int J Dermatol 2001;40:472–3. 52 Virtanen M, Gedde-Dahl T Jr, Mork NJ, Leigh I, Bowden PE, Vahlquist A. Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression. Acta Derm Venereol 2001;81:163–70. 53 Mevorah B, Landau M, Gat A, De Viragh P, Brenner S. Adolescentonset ichthyosiform-like erythroderma with lichenoid tissue reaction: a new entity? Br J Dermatol 2001;144:1063–6. 54 DiGiovanna JJ, Helfgott RK, Gerber LH, Peck GL. Extraspinal tendon and ligament calcification associated with long-term therapy with etretinate. N Engl J Med 1986;315:1177–82. 55 Rothnagel JA, Dominey AM, Dempsey LD et al. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 1992;257:1128–30. 56 Ruiz-Maldonado R, Tamayo L. Retinoids in keratinizing diseases and acne. Pediatr Clin North Am 1983;30:721–34. 57 Prendiville J, Bingham EA, Burrows D. Premature epiphyseal closure––a complication of etretinate therapy in children. J Am Acad Dermatol 1986;15:1259–62. 58 Glover MT, Peters AM, Atherton DJ. Surveillance for skeletal toxicity of children treated with etretinate. Br J Dermatol 1987;116:609– 14. 59 Paige DG, Judge MR, Shaw DG, Atherton DJ, Harper JI. Bone changes and their significance in children with ichthyosis on long-term etretinate therapy. Br J Dermatol 1992;127:387–91. 60 Lammer EJ, Chen DT, Hoar RM et al. Retinoic acid embryopathy. N Engl J Med 1985;313:837–41. 61 van Steensel MA. Emerging drugs for ichthyosis. Expert Opin Emerg Drugs 2007;12:647–56. 62 Verfaille CJ, Borgers M, van Steensel MA. Retinoic acid metabolism blocking agents (RAMBAs): a new paradigm in the treatment of hyperkeratotic disorders. J Dtsch Dermatol Ges 2008;6:355–64.

122.1

C H A P T E R 122

Mendelian Disorders of Cornification (MEDOC): the Erythrokeratodermas Daniel Hohl1, Stephanie Christen-Zaech2 & Baruk Mevorah3 1

Service de Dermatologie et Vénéréologie, CHUV Hopital de Beaumont, Lausanne, Switzerland Department of Dermatology and Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland 3 Department of Dermatology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2

Definition. Erythrokeratodermas are a clinically and genetically heterogeneous group of rare inherited disorders of cornification. They are usually present at birth but may also develop during infancy or childhood. Skin lesions are well-demarcated erythematous patches and hyperkeratotic plaques of variable distribution. Scaling, as in the other disorders of cornification (DOC), is usually not prominent; instead lesions appear hyperkeratotic clinically. Light microscopy typically shows a papillated epidermal hyperplasia with hyperkeratosis, acanthosis and in some instances, a ‘church-spire’ pattern. Based on clinical features, two major types were initially defined: a variable form, erythrokeratoderma variabilis (EKV), described by Mendes da Costa; and a fixed form, progressive symmetric erythrokeratoderma (PSEK) first documented by Darier and later by Gottron [1]. Over the years, Cram, Kelly, Giroux-Barbeau, Degos, Kogoj and Schnyder reported additional atypical variants, which are now considered to form the phenotypic spectrum of KID (keratitis, ichthyosis and deafness) syndrome [2,3]. The variability of the clinical presentation during a patient’s lifetime, within families and between families, as well as the existence of transitional forms of erythrokeratodermas, make their classification challenging. Genetic heterogeneity also adds to the complexity of this group. Finally, subjective definitions put forward by different authors have added to the confusion. For these reasons the classification of erythrokeratodermas remains controversial. In this perspective, antiquarian clinical entities such as erythrokeratoderma annularis migrans or erythrokeratoderma en cocardes should be questioned. Only precise correlation of clinical phenotypes with molecular genetics will allow a reliable nosological classification. Although research has led to advances in molecular understanding, the classification is currently incomplete (Table 122.1). Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

On a pathogenetic basis, the bulk of erythrokeratodermas are due to genetic modifications of the gap junction protein family, the connexins. Gap junctions are clusters of intercellular plasma membrane channels connecting the cytoplasm of neighbouring cells and allowing free transfer of small molecules of less than 1 kDa. Gap junctions are essential for intercellular communication and thus for control of cell fate and tissue homeostasis. Connexins are components of connexons, which form gap junctions. These intercellular channels are formed by the docking of two connexons consisting of six connexins. All the connexins within a connexon can be the same (homomeric) or different (heteromeric); and the two connexons docking together can be identical (homotypic junctions) or different (heterotypic junctions). In the epidermis, nine different connexins (Cx) are expressed. In the basal cell layer, Cx26 is the predominant connexin, while in the suprabasal compartment the most expressed connexins are Cx43, Cx31, Cx30.3 and Cx37 (see Table 122.2).

Keratitis-ichthyosis-deafness syndrome Syn. Atypical ichthyosiform erythrokeratoderma

History. The keratitis-ichthyosis-deafness (KID) syndrome was initially delineated by Burns [4]. Schnyder rediscovered KID syndrome in the 1960s [2,3] as a new neurocutaneous syndrome characterized by a partial PSEK, neurosensory deafness, myopathy and peripheral neuropathy. Similar cases were described by others [5–7], and Skinner et al. coined the term KID syndrome [8]. Ichthyosis hystrix of Rheydt also is probably a case of KID syndrome as the patient suffered from deafness. Additionally, the so-called HID (hystrix-like ichthyosis with deafness) syndrome and the Bart–Pumphrey syndrome were confirmed to share the same genetic mutations and represent clinical variants or variable expression of KID syndrome.

122.2

Chapter 122

Table 122.1 Connexin defects Protein Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin Connexin

26 26 26 30 30 30.3 30.3 31 31 32 40 43 43 43 46 47 50

Gene

Disorder

Inheritance

GJB2 GJB2 GJB2 GJB6 GJB6 GJB4 GJB4 GJB3 GJB3 GJiB1 GJA5 GJA1 GJA1 GJA1 GJA3 GJC2 GJA8

Keratitis-ichthyosis-deafness syndrome Vohwinkel syndrome with or without deafness Non-syndromic hearing loss Hidrotic ectodermal dysplasia (Clouston syndrome) Keratitis-ichthyosis-deafness syndrome with or without atrichia Erythrokeratodermia variabilis Cram–Mevorah Erythrokeratodermia variabilis Mendes da Costa Erythrokeratodermia variabilis Mendes da Costa Deafness and progressive high-tone hearing impairment X-linked Charcot–Marie–Tooth syndrome Atrial fibrillation Oculodental digital dysplasia Syndactyly type III Hypoplastic left heart syndrome Cataract, zonular pulverulent Leucodystrophy, hypomyelinating Cataract, zonular, nuclear, microcornea

AD AD AR/AD AD AD AD AD AD AD/AR XD AD AD AD AD AD AD AD

AD, autosomal dominant; AR, autosomal recessive; XD, X-linked dominant.

Epidemiology. Over 100 cases have been reported in the literature, mostly sporadic, rarely of autosomal dominant or recessive inheritance. Pathogenesis. The KID syndrome is due to connexin 26 mutations (GJB2) [9]. A case bearing a connexin 30 mutation (GJB6) has been claimed to correspond to KID syndrome with atrichia [10]. In our view, such cases should be diagnosed as Clouston syndrome. The dermatopathological changes are non-specific with acanthosis and hyperkeratosis, similar to the papillated epidermal hyperplasia seen in PSEK and EKV. Clinical features. The phenotype of KID syndrome is variable, which can be understood in the context of the wide clinical spectrum of allelic connexin 26 defects, which includes Vohwinkel syndrome, hystrix-likeichthyosis-deafness (HID) syndrome [11], the Bart– Pumphrey syndrome, and autosomal recessive type1 and autosomal dominant type 3 deafness. The HID phenoytpe differs from KID by its marked generalized spiky and cobblestone-like hyperkeratoses and only a mild palmoplantar keratoderma. The Bart–Pumphrey syndrome is characterized by sensorineural deafness, knuckle pads, palmoplantar keratoderma and leukonychia. Most KID syndrome patients have skin manifestations at birth, and all develop skin changes by 1 year of age [12]. Neonates present with erythroderma and/or a vernix-like hyperkeratosis. The neonatal erythroderma rapidly clears and symmetric erythematous and verru-

cous plaques develop in the first months or years of life, and progress until puberty. The fixed irregularly shaped, erythematous keratotic plaques typically involve the face and are accentuated over joints, somewhat reminiscent of the starfish-shaped keratoses of Vohwinkel syndrome. The lesions have a particular grainy or cobblestone surface (Fig. 122.1), which is also found on the palmoplantar keratoderma. Most patients with KID syndrome have absent or sparse scalp hair, and may also have abnormal eyelashes, eyebrows, axillary and pubic hair. Alopecia may be present at birth, or may progress over time secondary to recurrent infections and subsequent scarring. Other features are follicular keratoses with spiny projections, verrucous hyperkeratoses, perioral furrowing, leuconychia and nail dystrophy. Occasionally, nails may be absent at birth [13]. Teeth may be small or malformed [14] with a tendency for increased dental caries. There are rare reports of oral leucokeratosis and scrotal tongue [1]. Lazic et al. have reported a variant with a specific connexin 26 mutation in which fissured lips and gingival erythema are prominent clinical features [15]. Bilateral non-progressive, congenital sensorineural hearing defects are present that range in severity from mild to profound [16]. In contrast with the congenital hearing impairment, ocular changes may not be observed until the second or third decade of life and are usually progressive. Photophobia may uncommonly be present at birth [12]. Early ocular findings include photophobia, tearing and conjunctivitis. Over time, patients develop a typical, progressive proliferating vascular keratitis [17],

AD or Birth, sporadic childhood

AD

Genodermatose en cocardes OMIM: none

Keratolytic winter erythema, Oudtshoorn disease OMIM 148370 Infancy to early adulthood

Hyperkeratosis, erythema, target-like peeling

Mainly target-like erythrosquamous plaques with central exfoliation Variability within lesions

Symmetrical, fixed erythrokeratotic plaques_

AD_

EKV with ataxia OMIM 133190

Soon after birth

Early Variable annular childhood_ erythema or erythema gyratum repens-like, fixed hyperkeratosis

AD

EKV with erythema gyratum repens OMIM 133200

Usually variable erythema, fixed hyperkeratosis or erythrokeratosis, often induced by trauma, stress or temperature changes

Type of lesions other than PPI

Birth, early childhood

Onset

Erythrokeratodermia AD, rarely variabilis, (EKV) AR OMIM 133200

Heredity

Legs, knees. Rarely thighs, upper arms, shoulders, trunk

Lower extremities

Focal erythema and centrifugal peeling/No

In 6.2% non-specific anomalies

Associations

Skin: better with age, slowly progressive neurological syndrome/ Unknown

Repeating cycles, seasonal variation, improves with age/No effect

Focal spongiosis, no granular layer, elimination of necrotic cell layers in hyperkeratosis

In two cases: hyperkeratosis, thickened capillary walls, congested vessels surrounded by lymphocytes or histiocytes

None

None_

Orthokeratotic hyperkeratosis with foci of parakeratosis_

Identical to classic EKV

Orthohyperkeratosis with rare foci of parakeratosis, irregular acanthosis, mild inflammatory infiltrate

Histology

Spinocerebellar symptoms in adulthood with gait ataxia, nystagmus, dysarthria, decreased reflexes

Chronic or None better with age/Effective

Chronic better with age/ Effective

Course/ Response to systemic retinoids

PPI possible. Chronic/ Brachyonichia in possible one case_ remission/?

None/None

In 1/3 of cases/ None; frequent caries_

Face, neck, limbs, trunk, axillae, buttocks

Extensor surfaces of hands, feet, big joints

In about 1/3 of cases/Very rare

PPI/Involved adnexae

Face, limbs, folds, trunk, neck, buttocks

Distribution of lesions

Table 122.2 Synopsis of genodermatoses with erythrokeratotic or erythrosquamous component

(Continued)

Chromosome 8p22-p23, cathepsin B gene excluded_

Unknown

Chromosome 1p34-35

Chromosome 1p34-35 Some Cx30.3 mutations

Chromosome 1p34-35 Cx31 and Cx30.3 mutations cause faulty gap junctions

Molecular biology

MEDOC: the Erythrokeratodermas 122.3

AD

Vohwinkel syndrome OMIM 604117 Early childhood

Birth, infancy

AD

Loricrin keratoderma OMIM 152445

Birth

Birth, early childhood

Sporadic, rarely AD or AR

Onset

Erythrokeratodermia AD progessiva symmetrica (PSEK) OMIM 602036

Keratitis, ichthyosis, deafness, KID syndrome OMIM 148210, 242150

Heredity

Table 122.2 Continued

Starfish-like or warty hyperkeratosis

Generalized scaling with fixed erythema and fixed erythrokeratosis_

Erythrokeratotic or erythrosquamous plaques. No variability except for progressive peripheral extension of lesions

Erythrokeratoses in lines, plaques, nodules; follicular plugs

Type of lesions other than PPI

Honeycomb PPK with, pseudoainhum/None_

In 50% of cases / Rare_

Reticulate or cobblestone PPK/Scarring alopecia, nails

PPI/Involved adnexae

Over joints Honeycomb PPK, (hands > elbows) pseudo-ainhum, trans-gression/ Nail, hair

Face, flexor and extensor surfaces of limbs_

Face, limbs, dorsa of hands and feet, but-tocks

Scalp, ears, face, flexures, limbs, trunk

Distribution of lesions Associations

Goitre in some

Variable sensorineural deafness/ Spastic paraplegia, myopathy

Chronic progressive/ Effective

In 7.3% non-specific anomalies

Chronic progressive/ Effective

Chronic progressive/ Effective

Chronic/ Keratitis, Variable sensorineural response; deafness, keratitis may microbial get worse infections, SCC, leukoplakia, cryptorchidism, peripheral neuropathy

Course/ Response to systemic retinoids

Hyperkeratosis with focci-parakeratosis; acantosis. No nuclear expression of loricrin

Hyperparakeratosis with retained round nuclei – containing loricrin granules, hypergranulosis, acanthosis

As in EKV, but with focal parakeratosis in all cases

Hyperorthokeratosis often bacteria and fungi, acanthosis, vacuolated keratinocytes, plugged atrophic follicles

Histology

Chromosome 13q12 Cx26 mutations

Chromosome 1q21 C-terminal loricrin Missense mutations: basic nuclear import signal

Unknown, Cx30.3, Cx31 and loricrin excluded

Cx26

Molecular biology

122.4 Chapter 122

AR

AD

AR

Ichthyosis linearis circumflexa (ILC) OMIM 256500

Hereditary pityriasis rubra pilaris (PRP) OMIM 173200

Mal de Meleda OMIM 248300

Early infancy

Early infancy or adulthood

Birth, infancy

After age of 3 years_

Onset

Erythrokeratotic lichenoid papules

Erythroderma, plaster-like scaling, hyperkeratotic follicular papules

Congenital erythroderma, ILC, flexural lichenification, angioedema

Erythrosquamous or erythrokeratotic

Type of lesions other than PPI

Perioral, flexor wrists, less often knees and elbows

Cephalocaudal spread

Generalized

Distal limbs, elbows, knees, rarely forearms, thighs

Distribution of lesions

Diffuse macerated transgrediens PPK/ Hyperhidrosis, nails

Diffuse yellow PPK/Nails

PPK rarely/ Trichorrhexis invaginata

Diffuse PPK/ Hyperhidrosis_

PPI/Involved adnexae Associations

Slowly progressive/ May be effective

Usually resolution/ Effective

May improve with age/ May improve with low doses

Brachyphalangia, lingua plicata, syndactyly, hair on palms/soles, left-handedness

Isolated reports of myasthenia, hypothyroidism, arthritis, malignancies

Early: failure to thrive, hypernatraemic dehydration, systemic infections. Late: atopy, transient aminoaciduria, rarely cutaneous SCC

Improves with Association with age/Effective EKV in one case

Course/ Response to systemic retinoids

Acanthosis, Chromosome orthohyperkeratosis, 8q24 slight inflammation SLURP-1 mutations

Unknown

Chromosome 5q32 Mutations of SPINK/LEKTI 5 protease inhibitor gene

ILC (active border): hyperparakeratosis, with fibrin deposits and hypogranulosis

Follicular keratotic plugging, foci of parakeratosis, acanthosis, mild inflammation_

Unknown, not linked to 1p34 (connexins)

Molecular biology

Acanthosis, hyperorthokeratosis

Histology

PPI, palmoplantar involvement; AD, autosomal dominant; AR, autosomal reccesive; Cx, connexin; PPK, palmoplantar keratoderma; SCC, squamous cell carcinoma. * In two members of an Iranian family EKV and neurological anomalies appeared in early life and rapidly evolved toward death.

AD

PPK progrediens et transgrediens OMIM 133200

Heredity

MEDOC: the Erythrokeratodermas 122.5

122.6

Chapter 122

Fig 122.1 Keratitis-Ichthyosis-Deafness (KID) syndrome with its characteristic verrucous widespread hyperkeratosis and deafness. Note that the clinical aspect is keratodermic, not ichthyotic. Upper panel courtesy of Dr M. Harms, Geneva.

which leads to decreased visual acuity and potential blindness. For reasons that remain poorly understood, approximately one-half of reported patients have problems with severe and recurrent cutaneous bacterial and fungal infections [12,18]. Finally, close to 20% of patients develop cutaneous or oral squamous cell carcinomas [19].

Prognosis. There is a chronic disease course. Recurrent squamous cell carcinomas may reduce life expectancy. Differential diagnosis. Hidrotic ectodermal dysplasia (Clouston syndrome), also due to connexin 30 mutations, shows more severe ectodermal defects, notably hair and

MEDOC: the Erythrokeratodermas

nail defects. Likewise, atrichia with KID-like symptoms due to a dominant connexin 30 mutation has been described [10]. The allelic Vohwinkel syndrome, HID syndrome [11], the Bart–Pumphrey syndrome or autosomal recessive type 1 and autosomal dominant type 3 deafness can be distinguished based on clinical features. Treatment. The treatment is challenging, and emollients and keratolytic agents are of limited value. Oral retinoids may improve hyperkeratoses but lead to eye irritation.

Erythrokeratodermia variabilis Mendes da Costa Syn. Keratosis rubra figurata, erythrokeratodermia figurata variabilis, Mendes da Costa disease, erythrokeratodermia figurata variabilis type 1

History. DeBuy Wenniger [20] reported the disease first in 1907, followed in 1922 by Rille [21] (keratosis rubra figurata) and Jeanselme [22]. In 1925, Mendes da Costa [23] coined the term ‘Erythro- et Keratodermia variabilis in a mother and daughter ’ (EKV) to describe a heritable disorder characterized by fixed hyperkeratotic plaques and by erythematous areas with outlines ‘like the boundary lines of seacoasts’ that moved ‘in the course of an hour ’. Epidemiology. Erythrokeratodermia variabilis Mendes da Costa accounts for about two-thirds of all EKV. This rare genodermatosis has been reported in all races with an equal gender incidence. The pattern of inheritance, studied in some large families, was reported to be autosomal dominant [24,25]. However, some very rare cases of autosomal recessive inheritance have also been described [26]. Its estimated incidence in Switzerland is about 1:500,000. Pathogenesis. Cases of EKV are due to germline mutations in the gap junction protein beta 3 and beta 4 genes (GJB3, GJB4) that code for the gap junction proteins connexin 31 (Cx31) and 30.3 (Cx30.3), respectively [27,28]. About half of all EKV are due to mutations in Cx31, onethird to mutations in Cx30.3 [29,30]. Connexin 30.3 mutations cause less severe phenotypes generally and account also for EKV Cram–Mevorah (see below). On a molecular level, Cx31 has been suggested to interact with Cx43 (oculodentodigital dysplasia) and 30.3 [31]. In most cases of EKV, mutations are thought to cause disease by a dominant-negative mechanism disturbing intercellular coupling of connexons and trafficking. More recently, a family has been described with EKV showing autosomal

122.7

recessive inheritance being caused by a homozygous mutation in the GJB3 gene [32]. Pathology. The dermatopathological changes are nonspecific. They show a compact hyperkeratosis with papillomatosis and acanthosis as well as a sparse, mononuclear perivascular infiltrate in the upper dermis [33–35]. Electron microscopy and immunohistological studies have shown inconsistent results, with a decrease in lamellar bodies or dense perinuclear tonofilament and keratohyalin granules [33–36]. Clinical features. Erythrokeratodermia variabilis Mendes da Costa has two morphologically different types of skin lesions: migratory erythematous areas and fixed hyperkeratotic plaques. Skin lesions are usually present at birth or develop during the first year of life but may rarely develop during late childhood or early adulthood [24,37– 39]. The disease presents first as erythema and only with time do hyperkeratotic lesions appear. Although characteristically these components do not occur on the same skin area, hyperkeratotic plaques are often surrounded by erythema. The erythematous patches have irregular borders, occur at any site and migrate slowly over the body (Fig. 122.2). They last from hours to days, may cause slight pruritus or burning sensation, and may show some fine scaling. They are influenced by emotions, physical stressors such as temperature changes, friction or pressure, and hormonal changes. The fixed geographical, hyperkeratotic plaques develop primarily on the extremities, buttocks and face. They are well demarcated, range from red to yellowish-brown in colour and extend over the years. Erythrokeratodermia variabilis may flare under the influence of oral contraceptive pills or pregnancy and may improve after menopause [34]. Thus, the clinical features vary not only within a patient but also within the affected family members. Thus, there is considerable variability both within the patient over time and also between affected family members. Palmoplantar keratoderma, usually in the form of a fine erythematous scaling, may be associated [38–40], although severely affected patients may exhibit diffuse keratoderma (M. Williams and D. Hohl, unpublished observations). Prognosis. Erythrokeratodermia variabilis normally continues into adulthood [38,41]. The hyperkeratotic plaques tend to appear or extend until puberty and then remain stable. In contrast, the erythematous lesions may decrease in intensity or even disappear after puberty [38,39]. Differential diagnosis. The transient and migratory nature of the erythematous lesions distinguishes EKV from other erythrokeratodermas and from pityriasis rubra pilaris, which is characterized by its folliculocentric

122.8

Chapter 122

Fig 122.2 Erythrokeratoderma variabilis Mendes da Costa due to mutated Cx 31 in a family followed over four generations. Lesions become more fixed and hyperkeratotic with age.

involvement and an orange-coloured palmoplantar keratoderma. Older patients with EKV may present only with symmetric hyperkeratotic plaques such that differential diagnosis from progressive symmetric erythrokeratoderma is difficult without medical history or molecular genetic analysis. The differential diagnosis also includes non-classical variants of autosomal recessive congenital ichthyosis, Netherton syndrome, Greither palmoplantar keratoderma and keratolytic winter erythema (KWE; syn. erythrokeratolysis hiemalis). The latter two predominate on the palms and soles, and in KWE intermittent annular

lesions with an exfoliative border can be seen on the distal limbs. Psoriasis and seborrhoeic dermatitis should be excluded by their classical clinical findings. Treatment. Before the development of the retinoids, a variety of therapies were tried, such as oral vitamin A, radiotherapy and intralesional steroids [42–45] with limited success and considerable side-effects such that they are not recommended. Historically, etretinate [46– 48], and now acitretin [49,50] and isotretinoin have been shown to be effective treatments for both types of skin

MEDOC: the Erythrokeratodermas

lesion of EKV. Emollients, topical retinoic acid and 5% lactic acid may be of some use in those intolerant of retinoids [34].

Erythrokeratodermia variabilis Cram–Mevorah Syn. Annular erythrokeratodermia figurata variabilis, keratosis rubra figurata, erythrokeratodermia figurata variabilis type 2

History. Cases of atypical EKV with distinctive circinate lesions were reported by Cram [37] and Hacham [51,52]. Identical cases may have been described as EKV of Degos, notably by Barrière [53]. Finally, similar families have been reported as ‘congenital ichthyosis with erythema centrifugum’ [54], ‘familial annular erythema’ [55] and ‘erythrokeratodermia anularis migrans’ [56]. Epidemiology. About one-quarter of all EKV cases are due to mutations in Cx30.3 [28]. Of these at least one-

122.9

quarter are characterized by circinate or erythema gyratum repens-like lesions [29]. Mevorah suggested that erythema repens-like lesions are characteristic of EKV cases with Cx30.3 mutations [52]. Pathogenesis. Erythrokeratodermia variabilis Cram– Mevorah (EKV 2) is due to germline mutations (e.g. T85P or F137L) in the gap junction beta 4 gene (GJB4) that encode the gap junction protein connexin 30.3 (Cx30.3). On a molecular level, 30.3 mutations exert a dominant negative effect on connexin assembly with Cx31 [31]. Pathology. Histology is non-specific and identical to EKV Mendes da Costa. Clinical features. Skin lesions are present at birth or shortly thereafter. Migratory erythematous lesions tend to gradually turn into more or less fixed hyperkeratotic plaques. Some of these erythematous lesions appear as erythema gyratum repens and are characterized by rapidly migrating figurate erythema in an annular, garland or spiral arrangement (Fig. 122.3). Furthermore,

Fig 122.3 Erythrokeratoderma variabilis of the Cram–Mevorah type. Note the fractal like gyrate erythematous lesions.

122.10

Chapter 122

slight peeling may be observed. Palms and soles are intact and audiograms are normal [52]. Prognosis. Erythrokeratodermia variabilis Cram– Mevorah starts shortly after birth and continues into adulthood [37,52]. The hyperkeratotic plaques appear or extend until puberty and then remain stable. The erythematous lesions have a recurrent lifelong course. Nevertheless, EKV Cram–Mevorah tends to improve with age. Differential diagnosis. Erythrokeratodermia variabilis Mendes da Costa does not show circinate, gyratum repens-like lesions. In early cases without fixed hyperkeratosis, erythema gyratum repens (exceedingly rare in infancy), acute or subacute lupus erythematosus and erythema multiforme have to be considered. Tinea corporis, erythema annulare centrifugum and Netherton syndrome can be distinguished based on clinical and histological features. Erythrokeratoderma en cocardes may be similar to EKV Mendes da Costa; however, it is exclusively annular, limited to the lower limbs, and can involve the plantar surface. Treatment. Treatment is as for EKV Mendes da Costa.

Erythrokeratoderma en cocardes Syn. Genodermatose en cocardes, genodermatose erythematosquameuse circinée variable, maladie de Degos, Degos disease

History. In 1947, Degos and colleagues [57] described a new genodermatosis in a 13-year-old girl, her father and her paternal uncle. The skin lesions were variable erythematosquamous plaques with an annular or ‘en cocardes’ appearance strictly localized to the lower limbs, and included also some fixed erythematous and hyperkeratotic plaques. During the following decade, other reports of the same condition appeared in the French literature [58–60]. The cases described by Barrière as ‘Eruption congénital, erythèmato-squameuse, variable. Génodermatose de Degos’ [53] are not limited to the lower limbs and thus correspond better to EKV Cram–Mevorah. Pathogenesis. The aetiology of erythrokeratoderma en cocardes (EKC) is unknown. The original family of Degos et al. suggests an autosomal dominant inheritance [57]. Erythrokeratoderma en cocardes may be identical to keratolytic winter erythema, a condition mapped to 8p22 [61]. In one family with EKC, connexin 30.3 and transglutaminase 5 mutations have been excluded (J. Fischer, A. Taieb and D. Hohl, unpublished findings).

Pathology. Light microscopic findings of changes in affected skin are non-specific. They show hyperkeratosis, occasional parakeratosis, acanthosis and a mild perivascular monocytic infiltrate in the upper dermis [53]. Clinical features. Erythrokeratoderma en cocardes is similar to EKV in that fixed erythematous patches and hyperkeratotic plaques are present at birth or develop during infancy. However, in EKC the skin lesions remain strictly located to extensor surfaces, as well as palms and soles. Erythrokeratoderma en cocardes is characterized by intermittent annular lesions, with central exfoliative scaling, and surrounding erythema, giving them a targetoid or ‘en cocardes’ appearance [57]. The eruption may clear at times but it tends to progress during childhood. An ichthyosiform scaling may remain after lesions have resolved. Intercurrent infections may exacerbate the condition, whereas sunlight tends to improve it. There may be an associated mild peeling of the palms [57] or rarely a more severe palmoplantar keratoderma [54]. Prognosis. The condition normally progresses into adulthood. Differential diagnosis. Erythema annulare centrifugum can be differentiated based on clinical and histological features. Keratolytic winter erythema can appear similar with intermittent annular lesions but does not normally show fixed hyperkeratotic plaques. Greither palmoplantar keratoderma lacks the annular intermittent erythematous lesions. Annular lesions with central exfoliation on the legs occur also in the acral peeling skin syndrome, which is due to TGM5 mutations. Treatment. Treatment is as for EKV.

Progressive symmetric erythrokeratoderma Syn. Erythroderma progressiva symmetrica, Gottron syndrome, Darier– Gottron syndrome

History. Progressive symmetric erythrokeratoderma (PSEK) was first described by Darier in 1886 and 1911 [62] as ‘progressive and symmetrical verrucous erythrokeratodermia’, the first case of which was later reported by Brocq and Dubreuilh in 1908 [63]. Gottron [64,65] reported a patient with symmetrical erythematous plaques over extensor surfaces and shortened the name of this condition to ‘symmetrical progressive erythrokeratoderma’. Subsequently, numerous isolated cases and some affected families have been described [66–69] but it remains a very rare condition. Some of these cases do not corre-

MEDOC: the Erythrokeratodermas

spond completely to the initial description of Darier and Gottron. Epidemiology. With only about 40 cases described in the literature, PSEK appears to be a rare genodermatosis. However, in the absense of biochemical or genetic markers, misdiagnosis as pityriasis rubra pilaris (PRP), psoriasis and other genetic erythrokeratodermas is likely to obscure its true incidence. The inheritance is variable, but mostly follows an autosomal dominant pattern with variable penetrance and variable expressivity. RuizMaldonado [70] reported two sporadic cases of PSEK from consanguineous parents, suggesting a recessive transmission. He also observed six other cases from three families with an autosomal dominant inheritance. Similarly, Rodriguez-Pichardo [71] reported a kindred with seven affected members spanning five generations, which followed an autosomal dominant pattern.

122.11

Pathogenesis. Progressive symmetric erythrokeratoderma is heterogeneous with considerable phenotypic variability. Some cases may correspond to the KID syndrome, others are adult patients with EKV Mendes da Costa with fixed and stable symmetrically distributed hyperkeratotic plaques over the extremities. Accordingly, recently described cases of EKV/PSEK overlap, and some authors question the PSEK phenotype as a disease bona fide [72,73]. One case with a PSEK phenotype exhibited a loricrin mutation [74,75] (see below). Nevertheless, several cases of Richard [76] with neither connexin 31 nor loricrin mutations imply that additional genes for PSEK exist. One of our patients with a phenotype between congenital non-bullous ichthyosiform erythroderma/lamellar ichthyosis and PSEK was identified as carrying homozygous mutations in the ichthyin gene (D. Hohl, J. Fischer et al., unpublished observations) (Fig. 122.4). Since this patient’s

Fig 122.4 Progressive symmetric erythrokeratoderma as described by Maldonado and Rünger with fine ichthyosiform erythrodermic scaling in the face and on the dorsal surfaces of the hands, psoriatic features on the trunk and keratoderma of the axilla and palms.

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Chapter 122

phenotype is more severe than the phenotype of other patients with the same ichthyin mutation, an additional genetic defect cannot be excluded. Finally, a novel PSEK locus has been described on chromosome 21q11. However, the clinical picture in this five-generation Chinese pedigree shows only well-demarcated, slightly raised, hyperkeratotic, erythematous plaques on the dorsum of hands and feet accompanied by palmoplantar keratoderma. Thus, the phenotype is more consistent with an autosomal dominant form of transgedient keratoderma or Greither palmoplanar keratoderma than with PSEK [77]. Pathology. The histopathology is non-specific and shows hyperkeratosis with patchy parakeratosis overlying an acanthotic epidermis with intact granular layer. Vacuolation around the nuclei has been reported in the granular layer. A sparse, lymphohistiocytic, perivascular infiltrate is seen in the upper dermis [70,78]. Electron microscopy shows markedly swollen mitochondria in the granular cells and vacuolation in the cells of the lower stratum corneum. Desmosomes, keratohyalin granules and tonofilament bundles appear normal [78]. Clinical features. Progressive symmetric erythrokeratoderma usually appears in infancy, and shows an equal sex incidence. Skin lesions are characterized by fixed, large, well-defined hyperkeratotic plaques [70]. They are normally of symmetrical distribution, a reddish-orange or brownish colour, and a more marked erythema at their periphery. Lesions commonly occur on the limbs, buttocks, shoulders and fingers, and may also involve the face. The chest and abdomen are usually spared, unlike in EKV. The plaques tend to extend during the first decade of life and then remain stable. They may improve during summer. An erythematous, palmoplantar keratoderma is seen in about 50% of patients. The clinical severity shows a marked variation even within individual families [70]. Due to the overlap with other diseases, notably the KID syndrome, diverse associations have been described. Prognosis. Skin lesions tend to improve after puberty, but may persist into adulthood [67,70,71]. Differential diagnosis. Erythrokeratoderma variabilis and pityriasis rubra pilaris can be distinguished by the clinical features, and psoriasis by histological differences. Moreover, psoriasis and PRP are responsive to antiinflammatory treatments, whereas PSEK is resistant [70]. Treatment. Topical therapies are of limited benefit but oral retinoid therapy leads to satisfying results [67,70,71,78].

Loricrin keratoderma Syn. Mutilating keratoderma with ichthyosis, Camisa palmoplantar keratoderma, variant form of Vohwinkel syndrome

History. Loricrin keratoderma was initially described by Camisa as a variant of mutilating keratoderma but unfortunately incorrectly labelled as ‘Vohwinkel palmoplantar keratoderma’ [79]. It is now well accepted that ‘Vohwinkel keratoderma’ should only be used for classic cases due to connexin 26 mutations (GJB2). Epidemiology. The inheritance is autosomal dominant and linked to chromosome 1q21. With only nine cases described in the literature this appears to be an exceedingly rare disorder [80]. However, milder phenotypes may masquerade as autosomal recessive congenital ichthyosis (ARCI), and the disorder should be considered when patients with lamellar ichthyosis/congenital ichthyosiform erythroderma (LI/CIE) phenotypes exhibit disproportionately severe PPK (M. Williams, unpublished observations). Pathogenesis. Loricrin keratoderma is due to mutations in the loricrin gene, LOR. Frameshift 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 that 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 [81]. Thus, the deposition of mutant protein in the nucleus interferes with late stages of epidermal differentiation. There is evidence that loricrin deficiency per se has a pathogenic defect [82]. As loricrin is the major protein constituent of the cornified cell envelope, in loricrin keratoderma, as in transglutaminase 1 (TG1)-deficient ARCI, the cornified cell envelope exhibits foci of attenuation or absence. In these areas, lamellar bilayers are not formed. These regions of amorphous lipid provide lacunae through which the water-soluble tracer lanthanum permeates. Thus, as in the keratinopathic ichthyoses, a structural protein mutation results in a permeability barrier defect of the intercellular lipid lamellae. The barrier defect in this disorder, as in others, also drives the clinical phenotype. Pathology. Light microscopy shows a characteristic, particular type of hyperparakeratosis with retained, round

MEDOC: the Erythrokeratodermas

or oval, condensed nuclei, which are conserved to the uppermost layers of the stratum corneum. Ultrastructurally, loricrin granules are found within the nuclei of the stratum corneum. The cornified cell envelope is attenuated in foci, primarily in the inner layers of the stratum corneum. By the outer layers it is more complete, probably due to ongoing cross-linking of other peptides to the cornified envelope 9 (CE) [82]. Ruthenium tetroxide fixation demonstrates disruption of lamellar lipid formation subjacent to these regions of attenuated CE, with amorphous material filling the intercellular domain. Clinical features. Some patients are born as collodion babies, others may show a non-erythrodermic exaggerated desquamation (M. Williams, unpublished observations). Later in life, loricrin keratoderma shows palmoplantar honeycomb keratoderma and knuckle pads with a mild, finely scaling lamellar ichthyosis/CIE phenotype. More mildly affected patients exhibit a PPK that is disproportionately severe to their generalized mild CIE-like phenotype, often with tapered fingertips. Pseudo-ainhums, similar to those seen in Vohwinkel mutilating palmoplantar keratoderma, may develop [83]. Loricrin keratoderma shows generalized, mild, non-

122.13

erythrodermic ichthyosis but neither starfish-shaped hyperkeratoses over the joints nor deafness [75]. Loricrin keratoderma can present with PSEK-like features [74], and should also be considered in the differential diagnosis of more focal cornification disorders like PSEK. However, the lesions on the extremities in these patients are erythematous with psoriasiform scaling [74]. Prognosis. The course of the disease is chronic, and in some cases the PPK becomes mutilating. Differential diagnosis. Vohwinkel syndrome, caused by mutations in the connexin 26 gene (GJB2) [84], is characterized by honeycomb palmoplantar keratoderma, but unlike loricrin keratoderma, is accompanied by starfishshaped hyperkeratoses over joints and knuckles and sensorineural deafness (Fig. 122.5). A generalized ichthyosis is not present in Vohwinkel syndrome. This dominant disorder may masquerade as a form of ARCI, and should be considered if a prominent PPK is present with tapered digits or constrictions. Treatment. Loricrin keratoderma responds well to systemic retinoids [79].

Fig 122.5 Vohwinkel syndrome is characterized not only by honeycomb palmoplantar keratoderma and pesdudoainhum, but unlike loricrin keratoderma by starfish shaped hyperkeratoses over joints and knuckles.

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Chapter 122

Erythrokeratoderma with ataxia (EKA) Syn. Giroux–Barbeau syndrome

History. This syndrome was described by Giroux and Barbeau in 1972. They discovered symmetrical erythrokeratoderma associated with neurocutaneous features in 25 members of a Montreal family in over five generations [85]. Epidemiology. Erythrokeratoderma with ataxia is of exceedingly rare incidence, and autosomal dominant inheritance. Pathogenesis. Erythrokeratodermia with ataxia has been mapped to the same locus on chromosome 1 as EKV, where a cluster of several connexin genes is located that are also expressed in the epidermis. However, no GJB3 mutations have been identified [86]. Pathology. The dermatopathological findings of EKA are similar to those seen in EKV. Clinical features. In EKA symmetrical erythrokeratoderma plaques develop in infancy on extensor surfaces; these plaques tend to improve in summer. During adulthood the skin involvement decreases or even clears, with occasional relapses later in life. From the fourth decade on, spinocerebellar symptoms develop, with severe ataxia, nystagmus, dysarthria and decreased tendon reflexes. Prognosis. Progressive neurological degeneration starts developing from the age of 40 years on and can lead to severe handicap. Differential diagnosis. The transient erythemas of EKV do not occur in EKA. Neurological symptoms develop later in life allowing a clear distinction between EKA and other erythrokeratodermas. MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia), previously described as EKV3 (see below), differs by its congenital, sometimes lethal diarrhoea [87] and its early onset of severe neurological involvement. Treatment. The skin lesions of EKA are treated as the other erythrokeratodermas. The neurological symptoms require supportive care. References 1 Nazzaro V, Blanchet-Bardon C, Lorette G, Civatte J. Familial occurrence of KID (keratitis, ichthyosis, deafness) syndrome. Case reports of a mother and daughter. J Am Acad Dermatol 1990;23:385–8.

2 Schnyder U, Sommacal-Schopf D. Erythrokeratodermia progressiva (krankendemonstration). Arch Klin Exp Dermatol 1964;219:973–6. 3 Schnyder UW, Wissler H, Wendt GG. [An additional form of atypical erythrokeratoderma with deafness and brain damage]. Helv Paediatr Acta 1968;23:220–30. 4 Burns FS. A case of generalized congenital karatoderma with unusual involvement of eyes, ears, and nasal and buccous membranes. J Cutan Dis 1915;33:225–60. 5 Baden HP, Alper JC. Ichthyosiform dermatosis, keratitis, and deafness. Arch Dermatol 1977;113:1701–4. 6 Beare JM, Nevin NC, Froggatt P, Kernohan DC, Allen IV. Atypical erythrokeratoderma with deafness, physical retardation and peripheral neuropathy. Br J Dermatol 1972;87:308–14. 7 Rycroft RJ, Moynahan EJ, Wells RS. Atypical ichthyosiform erythroderma, deafness and keratitis. A report of two cases. Br J Dermatol 1976;94:211–17. 8 Skinner BA, Greist MC, Norins AL. The keratitis, ichthyosis, and deafness (KID) syndrome. Arch Dermatol 1981;117:285–9. 9 Richard G, Rouan F, Willoughby CE et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitisichthyosis-deafness syndrome. Am J Hum Genet 2002;70:1341–8. 10 Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. 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;122:1108–13. 11 van Geel M, van Steensel MA, Kuster W et al. HID and KID syndromes are associated with the same connexin 26 mutation. Br J Dermatol 2002;146:938–42. 12 Caceres-Rios H, Tamayo-Sanchez L, Duran-Mckinster C, de la Luz Orozco M, Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology. Pediatr Dermatol 1996;13:105–13. 13 Langer K, Konrad K, Wolff K. Keratitis, ichthyosis and deafness (KID) syndrome: report of three cases and a review of the literature. Br J Dermatol 1990;122:689–97. 14 Wilson GN, Squires RH Jr, Weinberg AG. Keratitis, hepatitis, ichthyosis, and deafness: report and review of KID syndrome. Am J Med Genet 1991;40:255–9. 15 Lazic T, Horii KA, Richard G, Wasserman DI, Antaya RJ. A report of GJB2 (N14K) Connexin 26 mutation in two patients – a new subtype of KID syndrome? Pediatr Dermatol 2008 Sep–Oct;25(5):535–40. 16 Todt I, Hennies HC, Kuster W et al. Neurotological and neuroanatomical changes in the connexin-26-related HID/KID syndrome. Audiol Neurootol 2006;11:242–8. 17 Messmer EM, Kenyon KR, Rittinger O, Janecke AR, Kampik A. Ocular manifestations of keratitis-ichthyosis-deafness (KID) syndrome. Ophthalmology 2005;112:e1–6. 18 Gilliam A, Williams ML. Fatal septicemia in an infant with keratitis, ichthyosis, and deafness (KID) syndrome. Pediatr Dermatol 2002;9:232–6. 19 Nyquist GG, Mumm C, Grau R et al. Malignant proliferating pilar tumors arising in KID syndrome: a report of two patients. Am J Med Genet A 2007;143:734–41. 20 DeBuy Wenniger LM. Erythrodermie congénitale ichthyosiforme avec hyperépidermotrophie. Ned Tijdschr Geneesk 1907;1A: 510–15. 21 Rille J. Krankenvorstellung. Zentbl Haut Geschl Krankh 1922;7:161. 22 Jeanselme E. Un cas d’erythrokératodermie symétrique, en placards à extension géographique. Bull Soc Fr Dermatol Syph 1922;29: 150–6. 23 Mendes da Costa S. Erythro- et keratodermia variabilis in a mother and daughter. Acta Dermatol Venereol (Stockh) 1925; 6:225–61. 24 Bijdendijk A, Noordhoek FJ. Massive doses of vitamin E in the treatment of crural ulcer. Ned Tijdschr Geneeskd 1951 Apr 7;95(14):1039–42.

MEDOC: the Erythrokeratodermas 25 Schnyder UW, Sommacal-Schopf D. Fourteen cases of erythrokeratodermia figurata variabilis within one family. Acta Genet Stat Med 1957;7:204–6. 26 Armstrong DK, Hutchinson TH, Walsh MY, McMillan JC. Autosomal recessive inheritance of erythrokeratoderma variabilis. Pediatr Dermatol 1997;14:355–8. 27 Richard G, Smith LE, Bailey RA et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 1998;20:366–9. 28 Macari F, Landau M, Cousin P et al. Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis. Am J Hum Genet 2000;67:1296–301. 29 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;120:601–9. 30 Common JE, O’Toole EA, Leigh IM et al. Clinical and genetic heterogeneity of erythrokeratoderma variabilis. J Invest Dermatol 2005;125:920–7. 31 Plantard L, Huber M, Macari F, Meda P, Hohl D. Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. Hum Mol Genet 2003;12:3287–94. 32 Gottfried I, Landau M, Glaser F et al. A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein. Hum Mol Genet 2002;11:1311–16. 33 Gewirtzman GB, Winkler NW, Dobson RL. Erythrokeratodermia variabilis. A family study. Arch Dermatol 1978;114:259–61. 34 Rappaport IP, Goldes JA, Goltz RW. Erythrokeratodermia variabilis treated with isotretinoin. A clinical, histologic, and ultrastructural study. Arch Dermatol 1986;122:441–5. 35 Vandersteen PR, Muller SA. Erythrokeratodermia variabilis. An enzyme histochemical and ultrastructural study. Arch Dermatol 1971;103:362–70. 36 Jurecka W. Erythrokeratodermia variabilis. Arch Dermatol 1986;122:1356. 37 Cram DL. Erythrokeratoderma variabilis and variable circinate erythrokeratodermas. Arch Dermatol 1970;101:68–73. 38 Brown J, Kierland RR. Erythrokeratodermia variabilis. Report of three cases and review of the literature. Arch Dermatol 1966;93:194–201. 39 Itin P, Levy CA, Sommacal-Schopf D, Schnyder UW. [Family study of erythrokeratodermia figurata variabilis]. Hautarzt 1992;43:500–4. 40 Wollina U, Knopf B, Schaaschmidt H, Frille I. [Familial coexistence of erythrokeratodermia variabilis and keratosis palmoplantaris transgrediens et progrediens]. Hautarzt 1989;40:169–72. 41 Schnyder U, Sommacal-Schopf D. Fourteen cases of erythrokeratodermia figurata variabilis within one family. Acta Genet Stat Med 1957;7:204–6. 42 Budlovsky G. Kerato- et erythrodermia variabilis. Zbl Haut Geschlechtskr 1935;51:32–3. 43 Carteaud A, Dorfman L. Erythrokératodermie variable de Mendes da Costa. Presse Méd 1963;71:2685–7. 44 Kanaar P. Zur histochemie und symptomatischen therapie der erythro- et keratodermia variabilis (Mendes da Costa). Hautarzt 1965;16:126–9. 45 Wulf K, Koch H, Schulz KH. [Erythrokeratoderma figurata variabilis of the Mendes da Costa type, a dermatosis controllable by vitamin A]. Dermatol Wochenschr 1960;142:1012–16. 46 Marks R, Finlay A, Holt P. Severe disorders of keratinization: effects of treatment with Tigason (etretinate). Br J Dermatol 1981;104:667–73. 47 Magyarlaki M, Drobnitsch I, Zombai E, Schneider I. [A case of erythrokeratodermia figurata variabilis successfully treated with tigason]. Z Hautkr 1989;64:881–2, 885–7.

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48 Larregue M, Bressieux JM, Titi A et al. [Mendes Da Costa erythrokeratoderma variabilis. Effect of RO 10-9359 (Tigason)]. Ann Dermatol Venereol 1988;115:1123–5. 49 van de Kerkhof PC, Steijlen PM, van Dooren-Greebe RJ, Happle R. Acitretin in the treatment of erythrokeratodermia variabilis. Dermatologica 1990;181:330–3. 50 Graham-Brown RA, Chave TA. Acitretin for erythrokeratodermia variabilis in a 9-year-old girl. Pediatr Dermatol 2002;19:510–12. 51 Hacham-Zadeh S, Even-Paz Z. Erythrokeratodermia variabilis in a Jewish Kurdish family. Clin Genet 1978;13:404–8. 52 Landau M, Cohen-Bar-Dayan M, Hohl D et al. Erythrokeratodermia variabilis with erythema gyratum repens-like lesions. Pediatr Dermatol 2002;19:285–92. 53 Barrière, H. Eruption congénital, erythèmato-squameuse, variable. Génodermatose de Degos. Bull Soc Fr Dermatol Syph 1950;57:547–8. 54 Kelly LJ, Kocsard B, Kocsard E. Congenital ichthyosis with erythema anulare centrifugum. A new form of ichthyosis affecting 12 members of a family of 31 in 5 generations. Dermatologica 1970;140:75– 83. 55 Beare J, Froggatt P, Jones J et al. Familial annular erythema. An apparently new dominant mutation. Br J Dermatol 1966;78:59–68. 56 Vakilzadeh F, Rose I. [Erythrokeratodermia anularis migrans – a new genetic dermatosis?] Hautarzt 1991;42:634–7. 57 Degos R, Delzant O, Morival H. Erythème desquamatif en plaques congénital et familial. Bull Soc Fr Dermatol Syphiligr 1947;54:442. 58 Gougerot H, Grupper C. Génodermatose erythèmato-squameuse circinée, variable. ‘Maladie de Degos’ (Variable circinate erythematosquamous genodermatosis: ‘Degos disease’). Bull Soc Fr Dermatol Syphiligr 1948;55:396. 59 Bazex A, Dupré A. Génodermatose à erythèmes circinés variables. Ann Dermatol Syph 1956;83:612–17. 60 Bureau Y, Jarry H, Barrière H. Génodermatose à type d’erythème desquamatif récidivant par poussées depuis l’enfance. Bull Soc Fr Dermatol Syph 1955;62:25. 61 Starfield M, Hennies H, Jung M et al. Localization of the gene causing keratolytic winter erythema to chromosome 8p22-p23, and evidence of a founder effect in South African Afrikaans speakers. Am J Hum Genet 1997;61:370–8. 62 Darier J. Erythrokératodermie verruceuse en nappe symétrique et progressive. Bull Soc Fr Dermatol Syph 1911;22:252–64. 63 Brocq M, Dubreuilh W. Erythrokératodermie symétrique en placards. Bull Soc Fr Dermatol Syph 1908;19:327–32. 64 Gottron, H. Congenital angelegte symmetrische progressive Erythrokeratodermie. Zentbl Haut Geschl Krankh 1922;4:493–4. 65 Gottron H. Congenital symmetrical progressive erythrokeratoderma. Arch Dermatol Syph 1923;7:416. 66 Hopsu-Havu VK, Peltonen L. Erythrokeratodermia congenitalis progressiva symmetrica (Gottron). Dermatologica 1970;141:321–8. 67 Nir M, Tanzer F. Progressive symmetric erythrokeratodermia. Dermatologica 1978;156:268–73. 68 Kudsi S, Naeyaert JM. Progressive symmetric erythrokeratodermia of Darier Gottron. Dermatologica 1990;180:196–7. 69 Dupertuis MC, Laroche L, Huault MC, Blanchet-Bardon C. [Progressive and symmetrical erythrokeratoderma of Darier–Gottron]. Ann Dermatol Venereol 1991;118:775–8. 70 Ruiz-Maldonado R, Tamayo L, del Castillo V, Lozoya I. Erythrokeratodermia progressiva symmetrica: report of 10 cases. Dermatologica 1982;164:133–41. 71 Rodriguez-Pichardo A, Garcia-Bravo B, Sanchez-Pedreno P, Camacho Martinez F. Progressive symmetric erythrokeratodermia. J Am Acad Dermatol 1988;19:129–30. 72 Macfarlane AW, Chapman SJ, Verbov JL. Is erythrokeratoderma one disorder? A clinical and ultrastructural study of two siblings. Br J Dermatol 1991;124:487–91.

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73 van Steensel M. Does progressive symmetric erythrokeratoderma exist? Br J Dermatol 2004;150:1043–5. 74 Ishida-Yamamoto A, McGrath JA, Lam H, Iizuka H, Friedman RA, Christiano AM. 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;61:581–9. 75 Ishida-Yamamoto A. Loricrin keratoderma: a novel disease entity characterized by nuclear accumulation of mutant loricrin. J Dermatol Sci 2003;31:3–8. 76 Richard G. Connexins: a connection with the skin. Exp Dermatol 2000;9:77–96. 77 Cui Y, Yang S, Gao M et al. Identification of a novel locus for progressive symmetric erythrokeratodermia to a 19.02-cM interval at 21q11.221q21.2. J Invest Dermatol 2006;126:2136–9. 78 Nazzaro V, Blanchet-Bardon C. Progressive symmetric erythrokeratodermia. Histological and ultrastructural study of patient before and after treatment with etretinate. Arch Dermatol 1986;122:434–40. 79 Camisa C, Rossana C. Variant of keratoderma hereditaria mutilans (Vohwinkel’s syndrome). Treatment with orally administered isotretinoin. Arch Dermatol 1984;120:1323–8. 80 Song S, Shen C, Song G et al. A novel c.545-546insG mutation in the loricrin gene correlates with a heterogeneous phenotype of loricrin keratoderma. Br J Dermatol 2008;159:714–19.

81 Suga Y, Jarnik M, Attar PS et al. Transgenic mice expressing a mutant form of loricrin reveal the molecular basis of the skin diseases, Vohwinkel syndrome and progressive symmetric erythrokeratoderma. J Cell Biol 2000;151:401–12. 82 Schmuth M, Fluhr JW, Crumrine DC et al. Structural and functional consequences of loricrin mutations in human loricrin keratoderma (Vohwinkel syndrome with ichthyosis). J Invest Dermatol 2004;122: 909–22. 83 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;13:70–7. 84 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;8:1237–43. 85 Giroux JM, Barbeau A. Erythrokeratodermia with ataxia. Arch Dermatol 1972;106:183–8. 86 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;109:666–71. 87 Saba TG, Montpetit A, Verner A et al. An atypical form of erythrokeratodermia variabilis maps to chromosome 7q22. Hum Genet 2005;116:167–71.

123.1

C H A P T E R 123

Keratosis Pilaris Arnold P. Oranje & Dirk Van Gysel 1

Department of Pediatrics, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands Department of Pediatrics, O.L. Vrouw Hospital, Aalst, Belgium

2

Definition. Keratosis pilaris is a cutaneous abnormality associated with a variety of diseases. It is defined by the presence of keratotic plugging of hair follicles, surrounded by varying degrees of erythema. When keratosis pilaris is accompanied by atrophy, it is referred to as keratosis pilaris atrophicus [1,2]. History. The clinical entities of keratosis pilaris and keratosis pilaris atrophicus have been a source of historical confusion. This is the result of overlap among syndromes, the presence of intermediate forms and the existence of numerous synonyms in the dermatology and genetics literature [3]. Particularly confusing is the entity ‘ichthyosis follicularis’, a term coined by Lesser in 1885 [4,5]. Another disorder that, historically, has received much attention is keratosis follicularis spinulosa decalvans (also initially described as ichthyosis follicularis). This entity was first described in the Dutch literature by Lameris in 1905 and Rochat in 1906 in a Dutch-German family [6,7]. In 1925, Siemens investigated this same family clinically [8]. Van Osch et al. performed an update of the clinical study with the goal of performing a linkage study [9]. Aetiology and pathogenesis. In the isolated form, keratosis pilaris is essentially a normal physiological finding. About 40% of children suffer from mild keratosis pilaris. In a questionnaire study undertaken by Poskitt & Wilkinson, the mean age of improvement was 16 years [10]. Keratosis pilaris may also be seen in relation to malnutrition/nutritional deficiency, xerosis and ichthyosis vulgaris [11,12]. Keratosis pilaris atrophicans occurs in a number of syndromes with different inheritance patterns: (a) keratosis pilaris atrophicans faciei; (b) atrophoderma vermiculata; (c) keratosis follicularis spinulosa decalvans, and (d) folliculitis spinulosa decalvans [13]. Keratosis pilaris atrophicans faciei, or ulerythema ophryogenes, is inherited in an autosomal dominant

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

fashion. Physical findings demonstrate follicular keratotic papules associated with alopecia and occur predominantly in the eyebrows. Genetic linkage studies have not yet been performed. Atrophoderma vermiculata, also known as atrophoderma reticulata, acne vermoulante, folliculitis ulerythema reticulata, folliculitis ulerythematosa and honeycomb atrophy, is characterized by reticulate scarring on the cheeks. The disease is inherited as an autosomal recessive trait, and genetic linkage has not yet been performed. Keratosis follicularis spinulosa decalvans (KFSD) has been extensively studied. Families have been described in Finland, Switzerland and The Netherlands. In all three family studies, pedigree analysis shows an X-linked inheritance pattern[9,14,15]. Nearly complete expression in women can be explained by skewed lyonization. Richard & Harth have described fully expressed keratosis follicularis spinulosa decalvans in a woman [16]. In a large Dutch family which descends from the cohort originally investigated by Lameris and Siemens, Oosterwijk et al. localized the gene to Xp21.2–p22.2 [9,17]. In 54 individuals (including 21 affected males), DNA linkage analysis was performed using DNA probes of the X chromosome. Multipoint analysis placed the gene defect between DXS16 and DXS269. The gene locus has since been narrowed to Xp22.13–p22.2 [18] but in another German family, the same research team could not confirm these results and suggested the possibility of genetic heterogeneity [19]. The KFSD candidate region Xp 22 B-p 22.2 was confirmed in a recent linkage study by Porteous et al. [20] but they failed to narrow the candidate interval for the KSD locus. Interestingly, KFSD has also been described with possible autosomal dominant interitance and a slightly different clinical presentation [19,21]. Pathology. The histopathology is non-specific and is generally not useful in diagnosis. The follicular orifice is distended by a keratin plug [22]. In keratosis pilaris, mild inflammation is present. In keratosis pilaris atrophicans, severe inflammation may occur in the early stages and in the late stages, atrophy of the epidermis is noted [9,22].

123.2

Chapter 123

Clinical features

Keratosis pilaris Lesions occur predominantly on the extensor surfaces of the arms (Fig. 123.1) and legs, but may also involve the face, buttocks and trunk. Keratosis pilaris often improves in the summer months and flares in the winter. Clinical signs of atopy are observed in at least one-third of patients [2,10]. Keratosis pilaris is characterized by the presence of rough, follicular papules and varying degrees of erythema. Erythema may be particularly severe in children with extensive facial involvement (keratosis pilaris rubra faciei). A number of diseases are associated with keratosis pilaris (Box 123.1) [11–13,23–26]. Monilethrix is characterized by beaded hair shafts that break easily (see Chapter 148). The hair is often unremarkable at birth and becomes abnormal during the first year of life. Follicular hyperkeratosis is seen on the neck and occipital scalp. The eyebrows may also be affected [27]. Genetic mutations have been described in the trichocyte and epithelial keratin gene cluster on 12q11-q13 [28]. For those with autosomal recessive hypotrichosis, mutations have also been identified in desomoglein 4 [29,30]. Lichen spinulosa or keratosis spinulosa is characterized by grouped follicular papules with keratotic spines in nummular patches, on the trunk and extremities. Boys are most often affected, and the disorder usually disappears at puberty [31]. There are no known associations with syndromes or systemic diseases.

Keratosis pilaris atrophicans Keratosis pilaris atrophicans faciei is characterized by redness and atrophic scarring of the eyebrows (Fig. 123.2). The symptoms are present at birth or begin during infancy. Typical keratosis pilaris is observed at other sites. Combinations of keratosis pilaris atrophicans faciei and Noonan syndrome or woolly hair have been described [32–34]. The association with Noonan syndrome has been designated as cardiofaciocutaneous syndrome [26]. Atrophoderma vermiculata is characterized by symmetrical reticulate atrophy and scarring of the cheeks. Small pits with sharp edges give the skin a ‘worm-eaten’

Box 123.1 Keratosis pilaris and keratosis pilaris atrophicans associated disorders and syndromes in childhood Keratosis pilaris • • • • • • • • • • •

Physiological Atopic dermatitis Lichen spinulosa Ichthyosis vulgaris Other ichthyoses (Mevorah et al. [12]) Renal insufficiency (Guillet et al. [11]) Prolidase deficiency (Larrègue et al. [23]) Down syndrome (Finn et al. [24]) Monilethrix Fairbank syndrome (Marks [25]) Keratosis pilaris follicularis non-atrophicans

Keratosis pilaris atrophicans • • • • •

Keratosis pilaris atropicans faciei (ulerythema ophryogenes) Atrophoderma vermiculata Keratosis follicularis spinulosa decalvans Folliculitis spinulosa [13] Noonan syndrome (now called cardiofaciocutaneous syndrome) (Ward et al. [26]) • Woolly hair

Fig. 123.1 Keratosis pilaris on the arms.

Fig. 123.2 Keratosis pilaris atrophicans faciei.

Keratosis Pilaris

123.3

Fig. 123.4 Patchy corneal dystrophy in keratosis follicularis spinulosa decalvans.

(a)

Fig. 123.5 Hyperkeratosis on the knees in keratosis follicularis spinulosa decalvans.

(b) Fig. 123.3 Keratosis follicularis spinulosa decalvans in the face.

appearance. Lesions are always limited to the face, and begin after the age of 5 years. Asymmetrical forms limited to one cheek have been described [35]. Keratosis follicularis spinulosa decalvans (KFSD) is a rare X-linked disease that affects both the skin (Fig. 123.3) and the eyes (Fig. 123.4). It is characterized by follicular hyperkeratosis of the skin and corneal dystrophy. Several families have been described, the largest one being of German-Dutch origin [9,14,15]. The follicular papules are associated with loss of hair, especially of the scalp, eyebrows and eyelashes. Marked photophobia may result from the corneal dystrophy. Other prominent findings are scarring alopecia of the scalp and absence of the eyebrows and eyelashes. X-linked KFSD lacks severe inflammation. In our study of the largest known pedigree,

hyperkeratosis of the knees (Fig. 123.5) and calcaneal region of the soles was noted, together with a high cuticle on the nails (Fig. 123.6) [9]. Symptoms are never present at birth and generally develop in early childhood. Complete spontaneous improvement often occurs at puberty [9]. Full expression of KFSD in a woman has been described [36]. An autosomal dominant variant has also been described. In these cases, the inflammation becomes worse in adulthood [21]. Of female carriers of X-linked KFSD, 50% are asymptomatic [9,14,35]. Symptomatic female carriers develop dry skin, minimal follicular hyperkeratosis and mild hyperkeratosis of the soles, but have no eye findings.

Phrynoderma Nicholls observed hyperkeratotic folliculitis in some African labourers who suffered from vitamin A deficiency [37]. More recently, the same physical finding has been noted to occur after intestinal bypass [38]. Phrynoderma has not been described extensively in children.

123.4

Chapter 123

Fig. 123.6 A prominent cuticle of the nails in keratosis follicularis spinulosa decalvans (aspecific sign).

Prognosis. Keratosis pilaris resolves completely in at least one-third of the cases. Lesions involving the arms and legs are more likely to persist into adulthood than facial lesions. Most cases of keratosis pilaris atrophicans eventuate in atrophy, without persistent inflammation [10,13,35]. Differential diagnosis. Normally, the diagnosis of keratosis pilaris is not difficult. Keratosis pilaris involving the face may mimic milia, miliaria and acne vulgaris. Other childhood causes of follicular keratoses include pityriasis rubra pilaris and Darier disease. Early cases of keratosis pilaris atrophicans faciei may be confused with the common form of keratosis pilaris, and late forms with seborrhoeic dermatitis. Atrophoderma vermiculata may be misdiagnosed as acne vulgaris or lupoid sycosis. Treatment. There is no effective therapy for keratosis pilaris. Emollients are rarely effective. Mild, temporary relief can be obtained with keratolytic agents, such as 10% urea. Topical corticosteroids may also temporarily reduce the keratotic and inflammatory components [39]. Similar results with topical therapy are seen in keratosis pilaris atrophicans. Dermabrasion is helpful in selected cases [2]. End-stage atrophy can be treated only by grafting [9]. Isotretinoin and etretinate are not useful in the treatment of keratosis pilaris atrophicans [35,39]. Response to all therapies (keratolytics, antibiotics, corticosteroids and retinoids) is limited. Treatment with the pulsed dye laser was proven to be effective in a study of 12 patients with respect to erythema but did not improve skin roughness [40].

References 1 McKusick VA. Mendelian Inheritance in Man, 13th edn. Baltimore: Johns Hopkins University Press, 1995. 2 Rand RE, Arndt KA. Follicular syndromes with inflammation and atrophy. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF (eds) Dermatology in General Medicine, 3rd edn. New York: McGraw Hill, 1979: 717–21. 3 Touraine A. Essai de classification des keratoses congenitales. Ann Dermatol 1958;85:257–66. 4 Eramo LR, Burton Esterly N, Zieserl EJ, Stock EL, Herrmann J. Ichthyosis follicularis with alopecia and photophobia. Arch Dermatol 1985;121:1167–74. 5 Lesser E. Ichthyosis follicularis. In: Eiemssen N (ed) Handbook of Skin Diseases. New York: William Wood, 1885. 6 Lameris HJ. Ichthyosis follicularis. Ned Tijdschr Geneeskd (Dutch J Med) 1905;41:1524. 7 Rochat GF. Familiaire cornea degeneratie. Ned Tijdschr Geneeskd (Dutch J Med) 1906;42:515–18. 8 Siemens HW. Keratosis follicularis spinulosa decalvans. Arch Dermatol Syph 1926;151:384–7. 9 Van Osch LDM, Oranje AP, Keukens FM et al. Keratosis follicularis spinulosa decalvans. J Med Genet 1992;29:36–40. 10 Poskitt L, Wilkinson JD. Natural history of keratosis pilaris. Br J Dermatol 1994;130:711–13. 11 Guillet G, Sanciaume C, Hennunestre JP et al. Keratose pilaire generalisée. Ann Dermatol Vénéréol 1982;109:1061–6. 12 Mevorah B, Marazzi A, Frenk E. The prevalence of accentuated palmoplantar marking and keratosis pilaris in atopic dermatitis, autosomal dominant ichthyosis and control dermatological patients. Br J Dermatol 1985;112:679–85. 13 Oranje AP, van Osch LDM, Oosterwijk JC. Keratosis pilaris atrophicans. Arch Dermatol 1994;130:500–2. 14 Franceschetti A, Jaccottet M, Jadassohn W. Manifestations cornéennes dans la keratosis follicularis spinulosa decalvans (Siemens). Ophthalmologica 1957;133:259–63. 15 Kuokkanen K. Keratosis follicularis spinulosa decalvans in a family from northern Finland. Acta Derm Venereol (Stockh) 1971;51:146–50. 16 Richard G, Harth W. Keratosis follicularis spinulosa decalvans. Therapie mit Isotretinoin und Etretinat im entzundlichen Stadium. Hautarzt 1993;44:529–34. 17 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;50:801–7. 18 Oosterwijk JC, van der Wielen MJ, van de Vosse E et al. Refinement of the localisation of the X linked keratosis follicularis spinulosa decalvans (KFSD) gene in Xp22.13–p22.2. J Med Genet 1995;32:736–9. 19 Oosterwijk JC, Richard G, van der Wielen MJ et al. Molecular genetic analysis of two families with keratosis follicularis spinulosa decalvans: refinement of gene localisation and evidence for genetic heterogeneity. Hum Genet 1997;100:520–4. 20 Porteous ME, Strain L, Logie LJ et al. Keratosis follicularis spinulosa decalvans: confirmation of linkage to Xp22.13-p22.2. J Med Genet 1998;35(4):336–7. 21 Khumalo NP, Loo WJ, Hollowood K et al. Keratosis pilaris atrophicans in mother and daughter. J Eur Acad Dermatol Venereol 2002;16 (4):397–400. 22 Sallakachart P, Nakjang Y. Keratosis pilaris: a clinicohistopathologic study. J Med Assoc Thai 1987;70:386–9. 23 Larrègue M, Charpentier C, Laidet B et al. Déficit en prolidase et en manganese. Ann Dermatol Vénéréol 1982;109:667–8. 24 Finn OA, Grant PW, McCallum DI et al. A singular dermatosis of Mongols. Arch Dermatol 1978;114:1493–4.

Keratosis Pilaris 25 Marks R. Follicular hyperkeratosis and ocular abnormalities associated with Fairbank’s syndrome. Br J Dermatol 1967;79:118–19. 26 Ward KA, Moss C, McKeown C. The cardio-facio-cutaneous syndrome: a manifestation of the Noonan syndrome? Br J Dermatol 1994;131:270–4. 27 Despontin K, Krafchik B. What syndrome is this? Monilethrix. Pediatr Dermatol 1993;10:192–4. 28 Stevens HP, Kelsell DP, Bryant SP et al. Linkage of monilethrix to the trychocyte and epithelial keratin gene cluster on 12q11-q13. J Invest Dermatol 1996;106:795–7. 29 Schaffer JV, Bazzi H, Vitebsky A et al. Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. J Invest Dermatol. 2006;126(6):1286–91. 30 Shimomura Y, Sakamoto F, Kariya N et al. Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis. J Invest Dermatol 2006;126(6);1281–5. 31 Boyd AS. Lichen spinulosus: case report and overview. Cutis 1989;43:557–60. 32 McKusick VA. Mendelian Inheritance in Man, 10th edn. Baltimore: Johns Hopkins University Press, 1992.

123.5

33 Pierini DO, Pierini AM. Keratosis pilaris atrophicans faciei (ulerythema oophryogenes): a cutaneous marker of Noonan’s syndrome. Br J Dermatol 1979;100:409–16. 34 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;110:357–62. 35 Arrieta E, Milgram-Sternberg Y. Honeycomb atrophy on the right cheek. Arch Dermatol 1994;130:481–2. 36 Harth W, Richard G, Schubert H. Keratosis follicularis spinulosa decalvans: the complete syndrome in a female (in German). Z Hautkr 1992;67:1080–4. 37 Nicholls L. Phrynoderma: a condition due to vitamin deficiency. Ind Med Gazette 1933;68:681–7. 38 Barr RJ, Riley RJ. Bypass phynoderma. Arch Dermatol 1984;120:919–21. 39 Baden HP, Byers R. Clinical findings, cutaneous pathology and response to therapy in 21 patients with keratosis pilaris atrophicans. Arch Dermatol 1994;130:469–75. 40 Clark SM, Mills CM, Lanigan SW. Treatment of keratosis pilaris atrophicans with the pulsed tunable dye laser. J Cutan Laser Ther 2000;2:151–6.

124.1

C H A P T E R 124

Netherton Syndrome Wei-Li Di1 & John Harper1,2 1

Immunobiology Unit, Institute of Child Health, University College London, London, UK Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Trust, London, UK

2

Definition and history. Netherton syndrome (OMIM 256500), also known as Comel–Netherton syndrome, is a rare autosomal recessive disorder characterized by the triad of ichthyosiform erythroderma, a specific hair shaft defect known as trichorrhexis invaginata, and atopic manifestations. It was first described by Comel [1] in 1949 as a new type of congenital ichthyosis, when he wrote about a young woman with erythematous, serpiginous and migratory plaques that had a characteristic doubleedged scale at the margin of the erythema, which he termed ichthyosis linearis circumflexia (ILC). In 1958, Netherton reported a case of a girl who presented at 4 years of age with congenital ichthyosiform erythroderma (CIE) associated with sparse brittle hair, which, on examination, revealed unique nodular fragile deformities that he called bamboo hairs [2]; some hairs also showed pili torti. This patient also had recurrent respiratory infections and later angioedema. In 1961, Marshall and Brede [3] also described a child with a similar clinical history. In 1964, Wilkinson et al. [4] proposed the eponym of Netherton’s disease for this combination of congenital ichthyosis, bamboo hairs and atopy. They suggested naming the hair shaft abnormality as trichorrhexis invaginata for the ball-and-socket deformity noted on the hair [4]. As an increasing number of Netherton syndrome cases were reported in the literature, Altman and Stroud [5] recognized the association of Netherton syndrome with specific skin changes called ichthyosis linearis circumflexia (ILC) and they suggested that these two were the same entity. In 1974, Mevorah and colleagues [6] established the clinico-statistical relationship between Netherton syndrome and ILC. All cases of ILC in which the hair had been carefully examined showed trichorrhexis invaginata. The atopic manifestations occur in all patients. Aetiology and pathogenesis. Netherton syndrome affects an estimated 1 in 200,000 babies [7] but may

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

account for up to 18% of congenital erythrodermas [8]. A high neonatal mortality rate and frequent misdiagnosis of this condition may result in underestimation of the true incidence. Netherton syndrome has an equal sex distribution although it was initially thought to have a female predominance [9]. Traupe [10] argued, however, that the higher incidence in females was usually seen in the mild ILC cases, whereas the most severe congenital ichthyosiform erythroderma that sometimes caused death at an early age affected more men than women. The condition appears to take a more severe course in males than in females [10,11]. Netherton syndrome has an autosomal recessive mode of transmission, occurring in offspring of unaffected parents and consanguineous families as well as in siblings [9,12]. The gene responsible for Netherton syndrome is known as SPINK5 (serine protease inhibitor Kazal type 5) and is located on chromosome 5q32 [13,14]. The premessenger SPINK5 has 34 exons and spans a region of 73.31 kb on the genome (NCBI: www.ncbi.nlm.nih.gov). The gene also contains 38 different gt-ag introns, which flank the beginning and end of the majority of vertebrate exons. To date, 61 mutations in the SPINK5 gene have been reported [7,13–25]. Except for exons 28 to 34, mutations are distributed in every exon and intron–exon boundary, with high mutation frequencies in exons 2 to 8 and exons 21 to 26. The mutations include nonsense mutations, splice-site mutations, small nucleotide deletions and insertions. All mutations cause either an immediate premature termination codon (PTC) or a frameshift/PTC in the encoding region, resulting in null or very low expression of the gene SPINK5, presumably via accelerated mRNA decay [7]. The complete mRNA of SPINK5 is 3648 bp long and encodes for a 1094-amino-acid protein, lymphoepithelial Kazal type-related inhibitor (LEKTI), which has the molecular weight of 124.1 kDa and isoelectric point (pI) of 7.7. The LEKTI protein is a serine protease inhibitor containing 15 Kazal-type related inhibitory domains. It is expressed in many tissues including the thymus, epithelial tissues, oral mucosa, tonsils, parathyroids and Bartholin glands [13,16,26]. Since patients with Netherton syndrome have a severe skin phenotype, the biological

124.2

Chapter 124

role of LEKTI in the skin and keratinocytes has been extensively investigated in the past decade. In situ hybridization and immunohistochemistry have indicated that the gene SPINK5 and its encoded protein LEKTI are localized in the uppermost spinous and granular layers of normal human epidermis [13,27]. In keratinocytes, proLEKTI synthesized in cells is rapidly processed into proteolytic fragments and secreted into extracellular compartments. More than five secreted LEKTI fragments with heterogeneous molecular weights have been found in the epidermis and conditional culture medium [28,29]. In vitro studies have confirmed that full-size LEKTI and its fragments are able to inhibit various serine proteases such as plasmin, trypsin, elastase and tissue kallikreins (KLKs), in particular KLK5 and 7 [28,30–32]. Kallikrein 5 is one of the major serine proteases expressed in the uppermost layers of the epidermis. It has a typical serine protease catalytic domain and its major biological role in the epidermis is in desquamation by degrading the adhesive ectodomain of desmoglein I, which is one of the corneodesmosomal proteins, to maintain epidermal tissue integrity in the superficial layers. Activated KLK5 further activates other KLKs including KLK6, 7, 8, 11, 13 and 14, most of which can coordinate to destabilize corneodesmosomes, subsequently resulting in a proteolytic cascade in the skin [33,34]. The LEKTI protein controls the activity of KLK5 by forming an inhibitory complex with KLK5 in a pH-dependent manner [28]. Under acidic pH, which occurs in the upper epidermal layers in normal skin, the LEKTI–KLK5 inhibitory complex is dissociated to allow inhibitor-free KLK5 to degrade corneodesmosomes [35]. In patients with Netherton syndrome, deficient LEKTI expression causes increased inhibitor-free KLK5 in the epidermis, resulting in premature degradation of corneodesmosomes in the granular layer as well as in the lower stratum corneum, where an inflammatory cascade mediated by the protease-activated receptor (PAR2)– nuclear factor κB (NFκB) pathway can be activated and further impair skin barrier formation [35–38]. Understanding of the pathophysiological pathway of loss of function of LEKTI in the epidermis has been further expanded by two recent studies: (i) apart from degrading corneodesmosomes, hyperactivated KLK5 mediated by deficient LEKTI expression can upregulate the epidermal protease elastase 2, resulting in excessive degradation of (pro-)filaggrin and alteration of intercorneocyte lipid formation in the skin barrier [39]; and (ii) once the LEKTI– KLK5 complex is dissociated, the inhibitor-free KLK5 is activated by matriptase, a transmembrane serine protease having the ability to undergo efficient autoactivation to initiate proteolytic cascades [35,40,41]. There are other studies indicating that LEKTI can also target caspase 1 [42] and caspase 14 [43], but the actual pathophysiological relationship needs to be further elucidated.

Since Netherton syndrome shares a number of clinical features with atopic dermatitis (AD), single nucleotide polymorphisms (SNPs) in SPINK5 in atopic dermatitis individuals have been sought. Earlier studies showed that the c.1258 G > A polymorphism in SPINK5 resulting in the p.Glu420Lys substitution in LEKTI was significantly associated with atopy and atopic dermatitis [44– 47]. Another study has also shown the association of SPINK5 polymorphism with disease severity and food allergy in children with AD [48]. However, recent studies carried out in French, German and Irish/English cases of AD showed no significant relationship between SPINK5 Glu420Lys SNP and AD, but an association with high immunoglobulin E (IgE) serum levels and a weaker effect with maternal transmission in the family-based study, suggesting the SPINK5 polymorphism may modulate systemic immune effects through the IgE response and carry a risk of AD when maternally inherited [49,50]. Pathology. Light microscopic examination of the skin reveals marked dermal inflammatory processes and exocytosis of the lymphocytes, macrophages and neutrophils. The epidermis shows a varying degree of epidermal acanthosis and hyperkeratosis, accentuated rete ridges and occasional long, narrow rete ridges similar to psoriasiform features. A marked parakeratotic stratum corneum with a patchy granular layer is commonly observed [10,51], although Altman and Stroud [5] found an increased granular layer. The outermost nucleated cell layer does not appear to flatten normally, instead showing irregularly distributed intracellular vacuolization and/or extracellular oedema. Spongiosis may also be pronounced in the lower epidermal cell layers. Ultrastructural studies of the skin show evidence of inhibition of terminal differentiation of the keratinocytes and impaired cornification. On electron microscopy, cells in the outer nucleated layer appear in various stages of transition into corneocytes. The stratum corneum is less cohesive than normal with the corneocytes containing numerous intracellular lipid droplets, nuclear membrane and inclusions. There are decreased numbers of desmosomal connections and tonofilaments resulting in loosening of the stratum corneum [51,52]. The granular layer shows signs of suppressed or incomplete keratinization, indicated by low amounts of irregularly dispersed keratin filaments and a near complete absence of keratohyalin. Keratinocytes in the granular layer are not flattened, as occurs in normal skin, and contain numerous inclusion bodies [10,52–54], which is not reported in other ichthyoses [10]. The formation and discharge of epidermal lipids at the stratum corneum– granulosum interface, which provide the lamellar sheets important for epidermal barrier function, is also disturbed [55].

Netherton Syndrome

124.3

Lamellar body secretion also occurs into the extracellular spaces in four or more layers of the stratum granulosum and upper spinosum. The prematurely secreted lamellar body contents remain unprocessed. In some areas where the cornified envelope is present, elongated membrane sheets are evident, but fully processed mature lamellar membrane structures, as observed in normal skin, do not occur [51]. In the extracellular compartment of the lower stratum corneum, fusiform dilations are present containing foci of electron-dense material, which may disturb the transformation to mature lamellar membrane structures. These electron-dense materials create clefts in the mid to upper stratum corneum. The defective skin barrier accounts for many of the clinical findings in Netherton syndrome, such as increased transepidermal water loss, hypernatraemic dehydration, susceptibility to skin infections and allergy. Clinical features. The clinical features are described as follows.

Features in infancy Netherton syndrome usually presents within the first few days of life with a congenital ichthyosiform erythroderma (Fig. 124.1). The neonatal course is often stormy and complicated by life-threatening events. Neonatal hypernatraemia, hypothermia, seizures, diarrhoea and recurrent sepsis contribute to the high mortality and morbidity rate in the first year of life [55–59]. The condition tends to improve thereafter.

Fig 124.2 Netherton syndrome: same boy as in Fig. 124.1 aged 3 years, exhibiting the characteristic facial appearance and short hair.

Skin manifestations Ichthyosiform erythroderma presents at or soon after birth and can range from mild patchy involvement to severe generalized ichthyosiform erythroderma. The severe cases usually persist as generalized erythroderma (Fig. 124.2), whereas milder cases often evolve into characteristic ichthyosis linearis circumflexia (ILC) (Fig. 124.3)

Fig 124.1 Netherton syndrome presenting as congenital erythroderma.

Fig 124.3 Ichthyosis linearis circumflexia: erythematous, serpiginous and migratory plaques that have a characteristic double-edged scale at the margin of the erythema.

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on the trunk and limbs after 1–2 years [10,56,57,60]. Ichthyosis linearis circumflexia may be episodic, with flares lasting up to 2–3 weeks and then clearing for weeks and months at a time [57]. Patients with predominantly ILC have normal physical development in general, whereas those with persistent generalized erythroderma have a more severe course, with failure to thrive and lifethreatening events occurring in early childhood [10,56,57]. Skin erosions with peeling of the skin, itchiness and redness can give rise to the misdiagnosis of peeling skin syndrome [10,61]. There is a tendency for spontaneous improvement of the skin with the transition from generalized erythroderma to patchy or episodic involvement. Despite the improvement, some patients remain severely affected with a fluctuating course throughout childhood and adulthood [57]. Pruritus is a common feature in Netherton syndrome, causing irritability especially in infancy [7,57]. Other skin manifestations include lichenification similar to that seen in AD [11,57]. The palms and soles are normally spared but may appear hyperkeratotic [62]. Although the nails are usually unaffected, nail dystrophy, pterygia and loss of several fingernails have been reported [57]. Papillomatous skin lesions can present at various sites such as the groin, axillae and genitoanal regions [63–65]. Squamous cell carcinoma has also been reported on the dorsum of the hand, the upper arm and the vulva [66–68]. Krasagakis and colleagues [69] reported a case of early aggressive cutaneous neoplasia in an area of papillomatous lesions on sun-exposed skin, and suggested that the underlying genetic defect may be the cause of the malignancy in these patients. Weber and colleagues [65] suggested that the non-melanoma skin cancer in Netherton syndrome patients might be associated with EV-HPV (epidermodysplasia verruciformis-associated human papillomavirus)-type infection, similar to that seen in immunosuppressed transplant recipients.

Hair abnormalities Hair growth is often sparse and delayed in Netherton syndrome patients. Individual hairs are short, dry, lustreless and brittle, growing a few centimetres before breaking and displaying a characteristic spiky appearance (Fig. 124.4) [57,70]. The hair abnormalities can affect all parts of the body, including scalp, eyebrow, eyelashes and body hair. The type of abnormalities seen include trichorrhexis invaginata, trichorrhexis nodosa and pili torti [3,4,70]. Trichorrhexis nodosa and pili torti can feature in various other medical conditions and syndromes ranging from hypothyroidism [71], Menkes hair disease [72], ectodermal dysplasia [73], mitochondrial disorders [74] to argininosuccinic aciduria [75]. Trichorrhexis invaginata, on the other hand, is considered to be pathognomonic for Netherton syndrome [60].

Fig 124.4 Netherton syndrome: short broken hairs displaying a characteristic spiky appearance.

Fig 124.5 Trichorrhexis invaginata: a ball-and-socket hair shaft deformity caused by the invagination of the distal hair shaft into the cup formed by the proximal hair shaft, pathognomonic for Netherton syndrome.

Trichorrhexis invaginata can be identified on light microscopy but is best demonstrated on electron microscopy. It is a ball-and-socket hair shaft deformity caused by the invagination of the distal hair shaft into the cup formed by the proximal hair shaft (Fig. 124.5) [4]. In trichorrhexis invaginata, the invagination occurs at the site of a transient keratinizing defect of the hair cortex resulting from incomplete conversion of sulphydryl groups into the disulphide bonds in the protein of the cortical fibres. The incomplete conversion means fewer cross-linkages of the keratin structures, thus resulting in a weak architectural structure of the cortical cells. This defect leads to cortical softness, which, when driven upwards by growing, is forced to fold around the more stable distal hair shaft forming the typical trichorrhexis invaginata deformity [70,76,77]. Trichorrhexis invaginata has been reported to be present in an 11-day-old infant [78] but is usually not obvious in early infancy. It may also be difficult to detect given the sparsity of hair in patients

Netherton Syndrome

with Netherton syndrome, making it difficult to obtain adequate samples. Even when hairs are examined microscopically, not all of them will have the obvious abnormality required to make the diagnosis. Hair microscopy often has to be repeated on several occasions over a period of time before the diagnosis is made [79]. In some instances, only the proximal half of the invaginate node is seen under electron microscopy, representing the golf tee sign, which may be the only clue to the diagnosis of trichorrhexis invaginata [79]. Powell and colleagues [80] described an increased density of trichorrhexis invaginata in eyebrow hair compared with scalp hair (about 10 times) in patients with Netherton syndrome. Hence examination of both the eyebrow and scalp hair will increase the chances of making a positive diagnosis. In some cases of Netherton syndrome only vellus [81] or eyebrow hairs [5,76,82,83] are abnormal. Improvement of hair growth can occur during childhood [83,84] but although it may approach a normal-looking appearance the hair never returns completely to normal [36]. There is currently no known treatment for trichorrhexis invaginata. If there is significant hair loss, a wig may be considered. Pili torti and trichorrhexis nodosa are the two other most common hair abnormalities in Netherton syndrome. Trichorrhexis nodosa is a disorder of the hair shaft in which there is a distinctive response to injury. The hair is fragile and on examination regularly spaced pale nodelike swellings are observed [84]. It may affect normal hair following injury or occur after minimal trauma in cases of inherent defects in keratin synthesis, leading to abnormally brittle hair. When the cuticle of the hair is absent, the hair cortex is exposed and its integrity is broken down. The hair can then split and fray into strands at the point of the break. Trichorrhexis nodosa may be localized or generalized to all hair [85,86]. Pili torti is the twisting of the hair fibre at focal points along its length. The hair cuticle is still intact but the twisting creates stress in the fibre, causing longitudinal fractures in the cuticle and internal hair cortex. This results in weak points in the hair fibre, which subsequently break [87,88].

Atopic manifestations and allergy Atopy is a feature of all patients with Netherton syndrome [57,62]. Atopic dermatitis, asthma, urticaria, angioedema and allergic rhinitis occur in some form or other in patients with Netherton syndrome [7,57,62,89]. A positive family history of atopy is also frequently observed [57]. Some patients may even have concomitant presentation of several atopic features. Reaction to food allergens, particularly nuts, egg and milk, is common [9,62,86]. In some cases, the patients may have a delayed response as seen in atopic dermatitis [5,90,91] but more often anaphylactoid-type reactions with angioedema occur

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[7,57]. Positive skin tests or radioallergosorbent test (RAST) responses to allergens such as house dust mite, grass pollen and cat dander are frequent [9,57]. Peripheral eosinophilia is present in the blood and the IgE level is high, ranging from 400 to 15,000 IU/mL [9,57,62,83,92,93].

Immunological abnormalities and infections Recurrent cutaneous, sinus and chest infections are frequent in Netherton syndrome patients [7,57]. It has been suggested that the recurrent infections are due to an underlying immunodeficiency [10,66,94]. Greene and Muller [9] reported that 12 out of the 45 patients they reviewed had recurrent infections, with six having decreased serum IgG levels. Judge and colleagues [57] in 1994 reported that two Netherton syndrome patients had decreased IgG2 subclasses, and two others who did not show clinically significant viral infections also had a reduced number of natural killer cells. However, most patients with Netherton syndrome have normal immunoglobulins apart from a high level of IgE. Stryk and colleagues [95] reported selective antibody deficiency to bacterial polysaccharide antigens in three of their patients with Netherton syndrome, who had recurrent sinopulmonary infections. The study emphasized the importance of checking for functional antibody response to both protein and bacterial polysaccharide, and not simply relying on IgG subclass levels alone. In these patients, prophylactic antibody can usually control the rate of infection [96], but in some patients intravenous immunoglobulin therapy may be required to prevent infections. Serial immunological evaluation is important as the deficient antibody response may simply represent maturation delay. Severe recurrent or chronic skin infections suffered by patients with Netherton syndrome include: bacterial infections such as Staphylococcus aureus, including methicillin-resistant S. aureus; Candida albicans and viral infections (herpes simplex and human papillomavirus) [10,97]. Other infections such as conjunctivitis, otitis media and bacterial vaginosis [98] have also been reported [57,57,59,99]. Gross and colleagues [100] documented a case of vaccine-associated poliomyelitis. Some of these infections can lead to severe sepsis and in some cases life-threatening septicaemia, especially in early childhood, accounting for the high mortality rate seen in this age group [7,59,101]. Recently, Renner and colleagues [23] carried out an extensive immunological study in patients with Netherton syndrome and revealed reduced memory B-cells and defective response to vaccination with Pneumovax and bacteriophage phiX174. They also reported that patients with Netherton syndrome had a skewed T-helper 1 (Th1) phenotype, elevated proinflammatory cytokine levels – interleukin 1β (IL-1β), IL-12, tumour necrosis factor α (TNF-α), granulocyte-macrophage

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colony-stimulating factor (GM-CSF), IL-1 receptor antagonist – and decreased natural killer (NK) cell cytotoxicity although the absolute numbers of NK cells were normal or elevated in patients.

Growth and development Failure to thrive is a major problem especially in the first year of life. This is attributed to a combination of a high catabolic rate and a defective skin barrier, leading to fluid loss and increased susceptibility to recurrent infections [57]. These children usually have chronic diarrhoea and malabsorption, which further exacerbates the failure to thrive. Jejunal biopsy has revealed villous atrophy in a significant proportion of patients: three out of five in the report by Pradeaux and colleagues [102] and 26% in the series by Bitoun and colleagues [7]. The high frequency of villous atrophy suggests that a gut biopsy should be considered in Netherton syndrome. Nutritional support is a significant part of management from an early stage in order to maintain adequate growth and development. For most patients a hypoallergenic diet is advised, and for infants, especially those with diarrhoea and failure to thrive, Neocate®, an amino acid-based formula milk substitute, is recommended. The input of a dietitian is essential. By the second year of life most children show an improved weight gain, but some degree of growth retardation persists and those who are most severely affected in early infancy remain below the 25th centile [6,54,55,57,82,103]. Greig and Wishart [103] reviewed the growth of 34 patients with Netherton syndrome and found 12 to be less than third percentile and two less than tenth percentile. Short stature is a characteristic of Netherton syndrome. Neurodevelopment is usually normal in Netherton syndrome. Mild mental retardation has been reported in a minority of patients and may be a consequence of neonatal events, such as cerebral haemorrhage following hypernatraemic dehydration [57,62,104]. Other clinical features Hypernatraemic dehydration and hypothermia are major causes of neonatal morbidity and mortality in Netherton syndrome [7,9,55,105]. These features are a consequence of the markedly increased transepidermal water loss [9,55] resulting from the impaired skin permeability barrier [51]. Intermittent aminoaciduria has been reported in Netherton syndrome patients, although no related specific renal problem has been identified [9]. Other features that have been described in patients with Netherton syndrome are: hydroureter; hypoplastic left heart; atresia of the pulmonary artery; hemihypertrophy; and acute bilateral renal thrombosis [6,55,106–108]. Diagnosis. Confirming the diagnosis of Netherton syndrome is often difficult in early infancy, in a baby who is

usually very unwell with erythroderma and profound failure to thrive. The main important differential diagnosis is Omenn syndrome, but in practice a frequent misdiagnosis is atopic dermatitis. In this situation a significant clue is the lack of response to topical steroids, and indeed this is one situation that can rapidly lead to steroid toxicity and cushingoid features. Investigations should include: a routine haematological and biochemical profile; a full immunological screen to exclude an underlying immunodeficiency; total IgE and specific IgE to a panel of common atopic allergens; a skin biopsy; and microscopic examination of a sample of hair (cut, not plucked). Unfortunately, erythrodermic babies have little or no scalp hair and examination of eyebrow hair is recommended [80]; however, trichorrhexis invaginata is rarely detectable at presentation. A presumptive diagnosis of Netherton syndrome is made and repeated hair samples need to be taken. Usually, trichorrhexis invaginata is confirmed from the age of about 6 months, but diagnosis can certainly take much longer, even several years. In the latter situation only a small proportion of hairs are affected and it is necessary to take samples from different sites on the scalp. ‘Leiner disease’ is an old term that was used for infants with erythroderma, sparse hair, diarrhoea and failure to thrive. Many of these babies have Netherton syndrome. In a clinical study by Glover and colleagues [109] of five patients with ‘erythroderma, failure to thrive and diarrhoea’, four developed clinical features consistent with Netherton syndrome. These infants are often subjected to extensive investigations for immunological, metabolic or nutritional deficiencies. With the identification of the gene responsible for Netherton syndrome (SPINK5), DNA analysis for known mutations in Netherton syndrome is now possible and would assist in the diagnosis of these patients. A more rapid investigation is to look for the presence of LEKTI in the skin by immunohistochemistry using an antibody with a specific epitope for the LEKTI protein (C-terminus). As in Netherton syndrome, heterozygous or homozygous compound mutations cause premature termination codons in both alleles of the SPINK5 gene, resulting in truncated expression of its encoded protein LEKTI. Absence of LEKTI expression can be detected using this anti- LEKTI antibody (Fig. 124.6a,b). Therefore, if LEKTI expression is absent or significantly decreased, when compared with normal skin as a control, this is strongly suggestive of Netherton syndrome. The immunostaining test can be done on paraffin-embedded tissue and provides a result within 24 h [110]. Treatment. To date, there is no curative therapy for Netherton syndrome. Regular application of ointment-based emollients (such as a 50 : 50 mixture of white soft paraffin and liquid paraffin) is the mainstay of treatment. Topical

Netherton Syndrome

Normal skin (a)

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Netherton syndrome (b)

Fig 124.6 Staining for LEKTI protein in (a) normal skin and (b) the skin of a patient with Netherton syndrome, using a polyclonal antibody. It shows almost complete absence of LEKTI in Netherton syndrome.

steroids do not help in this condition and there is the risk of increased percutaneous absorption. This aspect is particularly relevant in infancy, as it can result in systemic side-effects and cushingoid features [57]. The use of topical calcineurin inhibitors, tacrolimus and pimecrolimus, for the treatment of the skin in Netherton syndrome is controversial. Allen and colleagues [111] reported significantly high blood levels of tacrolimus in three patients with Netherton syndrome who were treated with topical tacrolimus, due to increased absorption through the skin. Bens and colleagues [112], on the other hand, described effective treatment with careful monitoring of blood levels. Renner and colleagues also used intravenous immunoglobulin therapy for patients with Netherton syndrome and reported clinical benefit from the treatment [23]. Retinoid therapy is uncertain, with some groups reporting success [10] and others showing no real improvement [57]. In our experience, oral retinoid treatment (acitretin) has no therapeutic role and in some cases can make the skin worse, causing extensive skin erosions.

The potential for gene therapy With the development of a high-efficiency gene transfer system, which has allowed delivery of foreign DNA into keratinocyte stem cells, and advances in culture techniques, which have allowed keratinocyte stem cells to be cultured as sheets of epithelium in laboratories and grafted back onto donors [113,114], gene-based therapy

for patients with Netherton syndrome has been developing; patients’ keratinocytes obtained from small skin biopsies are transduced with wild-type SPINK5 gene using a lentiviral vector system. Theoretically, corrected cells are then cultured as epidermal sheets with the potential for this to be grafted back to patients. The therapeutic strategy has been examined in a human/murine chimaeric model in vivo and results showed that skin grafts generated from transduced patients’ cells with Netherton syndrome have a marked correction of epidermal architecture, even when relatively low numbers of LEKTI-expressing cells were present in the skin grafts [25]. Linking the result with the fact that LEKTI is a secreted protein, the genetically modified skin grafts may act as ‘protein factories’ secreting functional LEKTI to produce a generalized beneficial effect. This is particular feasible for small infants where relatively small genecorrected skin sheets could provide significant clinical benefit. Prenatal diagnosis. Prenatal diagnosis for families with known mutations has been performed by two groups [53,78]. Prognosis. The mortality rate is high in the first year of life, especially in the neonatal period. Thereafter there is a tendency towards improvement, although Netherton syndrome remains a lifelong condition. The generalized

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skin condition and hair abnormality persist and the course is punctuated by acute exacerbations.

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19 Kilic G, Guler N, Ones U, Tamay Z, Guzel P. Netherton syndrome: report of identical twins presenting with severe atopic dermatitis. Eur J Pediatr 2006;165:594–7. 20 Mizuno Y, Suga Y, Muramatsu S, Hasegawa T, Shimizu T, Ogawa H. A Japanese infant with localized ichthyosis linearis circumflexa on the palms and soles harbouring a compound heterozygous mutation in the SPINK5 gene. Br J Dermatol 2005;153:661–3. 21 Mizuno Y, Suga Y, Haruna K et al. A case of a Japanese neonate with congenital ichthyosiform erythroderma diagnosed as Netherton syndrome. Clin Exp Dermatol 2006;31:677–80. 22 Zhao Y, Ma ZH, Yang Y et al. SPINK5 gene mutation and decreased LEKTI activity in three Chinese patients with Netherton’s syndrome. Clin Exp Dermatol 2007;32:564–7. 23 Renner ED, Hartl D, Rylaarsdam S et al. Comel–Netherton syndrome defined as primary immunodeficiency. J Allergy Clin Immunol 2009;124:536–43. 24 Tuysuz B, Ojalvo D, Mat C et al. A new SPINK5 donor splice site mutation in siblings with Netherton syndrome. Acta Derm Venereol 2010;90:95–6. 25 Di WL. Larcher F, Senemova E et al. Ex-vivo gene therapy restores LEKTI activity and corrects the architecture of Netherton syndrome derived skin grafts. Mol Ther 2010 Sep 28. [Epub ahead of print]. 26 Magert HJ, Standker L, Kreutzmann P et al. LEKTI, a novel 15domain type of human serine proteinase inhibitor. J Biol Chem 1999; 274:21499–502. 27 Bitoun E, Micheloni A, Lamant L et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet 2003;12: 2417–30. 28 Deraison C, Bonnart C, Lopez F et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 2007;18:3607– 19. 29 Jayakumar A, Kang Y, Henderson Y et al. Consequences of C-terminal domains and N-terminal signal peptide deletions on LEKTI secretion, stability, and subcellular distribution. Arch Biochem Biophys 2005;435:89–102. 30 Egelrud T, Brattsand M, Kreutzmann P et al. hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. Br J Dermatol 2005;153:1200–3. 31 Jayakumar A, Kang Y, Mitsudo K et al. Expression of LEKTI domains 6–9’ in the baculovirus expression system: recombinant LEKTI domains 6–9’ inhibit trypsin and subtilisin A. Protein Expr Purif 2004;35:93–101. 32 Mitsudo K, Jayakumar A, Henderson Y et al. Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. Biochemistry 2003;42:3874–81. 33 Borgono CA, Michael IP, Komatsu N et al. A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 2007;282:3640–52. 34 Caubet C, Jonca N, Brattsand M et al. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol 2004; 122:1235–44. 35 Sales KU, Masedunskas A, Bey AL et al. Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat Genet 2010;42:676–83. 36 Descargues P, Deraison C, Prost C et al. Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome. J Invest Dermatol 2006;126(7):1622–32. 37 Hachem JP, Crumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM. pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 2003; 121:345–53.

Netherton Syndrome 38 Briot A, Deraison C, Lacroix M et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 2009;206: 1135–47. 39 Bonnart C, Deraison C, Lacroix M et al. Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing. J Clin Invest 2010;120:871–82. 40 Netzel-Arnett S, Currie BM, Szabo R et al. Evidence for a matriptaseprostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem 2006;281:32941–5. 41 Kilpatrick LM, Harris RL, Owen KA et al. Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase. Blood 2006;108:2616–23. 42 Hosomi N, Fukai K, Nakanishi T, Funaki S, Ishii M. Caspase-1 activity of stratum corneum and serum interleukin-18 level are increased in patients with Netherton syndrome. Br J Dermatol 2008;159: 744–6. 43 Bennett K, Callard R, Heywood W et al. New role for LEKTI in skin barrier formation: label-free quantitative proteomic identification of caspase 14 as a novel target for the protease inhibitor LEKTI. J Proteome Res 2010;9:4289–94. 44 Kabesch M, Carr D, Weiland SK, von Mutius E. Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample. Clin Exp Allergy 2004;34:340–5. 45 Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 2003;148:665–9. 46 Nishio Y, Noguchi E, Shibasaki M et al. Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Genes Immun 2003;4:515–17. 47 Walley AJ, Chavanas S, Moffatt MF et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29:175–8. 48 Kusunoki T, Okafuji I, Yoshioka T et al. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol 2005;115:636–8. 49 Hubiche T, Ged C, Benard A et al. Analysis of SPINK 5, KLK 7 and FLG genotypes in a French atopic dermatitis cohort. Acta Derm Venereol 2007;87:499–505. 50 Weidinger S, Baurecht H, Wagenpfeil S, et al. Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J Allergy Clin Immunol 2008;122:560–8. 51 Fartasch M, Williams ML, Elias PM. Altered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome: differentiation from other infantile erythrodermas and pathogenic implications. Arch Dermatol 1999;135:823–32. 52 Frenk E, Mevorah B. Ichthyosis linearis circumflexa Comel with Trichorrhexis invaginata (Netherton’s Syndrome): an ultrastructural study of the skin changes. Arch Dermatol Forsch 1972; 245:42–9. 53 Muller FB, Hausser I, Berg D et al. Genetic analysis of a severe case of Netherton syndrome and application for prenatal testing. Br J Dermatol 2002;146:495–9. 54 Thorne EG, Zelickson AS, Mottaz JH, Katz HI, Deaton BH. Netherton’s syndrome: an electronmicroscopic study. Arch Dermatol Res 1975;253:177–83. 55 Jones SK, Thomason LM, Surbrugg SK, Weston WL. Neonatal hypernatraemia in two siblings with Netherton’s syndrome. Br J Dermatol 1986;114:741–3. 56 Hausser I, Anton-Lamprecht I, Hartschuh W, Petzoldt D. Netherton’s syndrome: ultrastructure of the active lesion under retinoid therapy. Arch Dermatol Res 1989;281:165–72.

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57 Judge MR, Morgan G, Harper JI. A clinical and immunological study of Netherton’s syndrome. Br J Dermatol 1994;131:615–21. 58 Smith DL, Smith JG, Wong SW, deShazo RD. Netherton’s syndrome. Br J Dermatol 1995;133:153–4. 59 De WK, Ferster A, Sass U, Andre J, Stene JJ, Song M. Netherton’s syndrome: a severe neonatal disease. A case report. Dermatology 1996;192:400–2. 60 Plantin P, Delaire P, Guillet MH, Labouche F, Guillet G. [Netherton’s syndrome. Current aspects. Apropos of 9 cases]. Ann Dermatol Venereol 1991;118:525–30. 61 Sardy M, Fay A, Karpati S, Horvath A. Comel–Netherton syndrome and peeling skin syndrome type B: overlapping syndromes or one entity? Int J Dermatol 2002;41:264–8. 62 Smith DL, Smith JG, Wong SW, deShazo RD. Netherton’s syndrome: a syndrome of elevated IgE and characteristic skin and hair findings. J Allergy Clin Immunol 1995;95:116–23. 63 Folster-Holst R, Swensson O, Stockfleth E, Monig H, Mrowietz U, Christophers E. Comel–Netherton syndrome complicated by papillomatous skin lesions containing human papillomaviruses 51 and 52 and plane warts containing human papillomavirus 16. Br J Dermatol 1999;140:1139–43. 64 Sedlacek V, Krenar J. [Symptomatology of Comel’s linear circumflex ichthyosis (a case associated with genito-anal papillomatosis)]. Hautarzt 1971;22:390–7. 65 Weber F, Fuchs PG, Pfister HJ, Hintner H, Fritsch P, Hoepfl R. Human papillomavirus infection in Netherton’s syndrome. Br J Dermatol 2001;144:1044–9. 66 Hintner H, Jaschke E, Fritsch P. [Netherton syndrome: weakened immunity, generalized verrucosis and carcinogenesis]. Hautarzt 1980;31:428–32. 67 Kubler HC, Kuhn W, Rummel HH, Kaufmann I, Kaufmann M. [Development of cancer (vulvar cancer) in the Netherton syndrome (ichthyosis, hair anomalies, atopic diathesis)]. Geburtshilfe Frauenheilkd 1987;47:742–4. 68 Saghari S, Woolery-Lloyd H, Nouri K. Squamous cell carcinoma in a patient with Netherton’s syndrome. Int J Dermatol 2002;41: 415–16. 69 Krasagakis K, Ioannidou DJ, Stephanidou M, Manios A, Panayiotides JG, Tosca AD. Early development of multiple epithelial neoplasms in Netherton syndrome. Dermatology 2003;207:182–4. 70 Stevanovic DV. Multiple defects of the hair shaft in Netherton’s disease. Association with ichthyosis linearis circumflexa. Br J Dermatol 1969;81:851–7. 71 Lurie R, Hodak E, Ginzburg A, David M. Trichorrhexis nodosa: a manifestation of hypothyroidism. Cutis 1996;57:358–9. 72 Taylor CJ, Green SH. Menkes’ syndrome (trichopoliodystrophy): use of scanning electron-microscope in diagnosis and carrier identification. Dev Med Child Neurol 1981;23:361–8. 73 Silengo M, Pietragalla A, Jarre L. Trichorrhexis nodosa and lip pits in autosomal dominant ectodermal dysplasia–central nervous system malformation syndrome. Am J Med Genet 1997;71: 226–8. 74 Silengo M, Valenzise M, Spada M et al. Hair anomalies as a sign of mitochondrial disease. Eur J Pediatr 2003;162:459–61. 75 Shelley WB, Rawnsley HM. Aminogenic alopecia. Trans Assoc Am Physicians 1966;79:146–56. 76 Ito M, Ito K, Hashimoto K. Pathogenesis in trichorrhexis invaginata (bamboo hair). J Invest Dermatol 1984;83:1–6. 77 Taneda A, Ogawa H, Hashimoto K. The histochemical demonstration of protein-bound sulfhydryl groups and disulfide bonds in human hair by a new staining method (DACM staining). J Invest Dermatol 1980;75:365–9. 78 Bitoun E, Bodemer C, Amiel J et al. Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis. Prenat Diagn 2002;22:121–6.

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79 de Berker DA, Paige DG, Ferguson DJ, Dawber RP. Golf tee hairs in Netherton disease. Pediatr Dermatol 1995;12:7–11. 80 Powell J, Dawber RP, Ferguson DJ, Griffiths WA. Netherton’s syndrome: increased likelihood of diagnosis by examining eyebrow hairs. Br J Dermatol 1999;141:544–6. 81 Menne T, Weisman K. Canestick lesion of vellus hair in Netherton’s syndrome. Arch Dermatol 1985;121:451. 82 Adamson JE, Marten RH. Ichthyosis linearis circumflexa and Netherton’s syndrome with idiopathic dwarfism. Proc R Soc Med 1973;66: 624–5. 83 Caputo R, Vanotti P, Bertani E. Netherton’s syndrome in two adult brothers. Arch Dermatol 1984;120:220–2. 84 Brodin MB, Porter PS. Nertherton’s syndrome. Cutis 1980;26: 185–8. 85 Dawber R, Comaish S. Scanning electron microscopy of normal and abnormal hair shafts. Arch Dermatol 1970;101:316–22. 86 Leonard JN, Gummer CL, Dawber RP. Generalized trichorrhexis nodosa. Br J Dermatol 1980;103:85–90. 87 Kurwa AR, Abdel-Aziz AH. Pili torti–congenital and acquired. Acta Derm Venereol 1973;53:385–92. 88 Selvaag E, Aas AM, Heide S. Structural hair shaft abnormalities in hypomelanosis of Ito and other ectodermal dysplasias. Acta Paediatr 2000;89:610–12. 89 Krafchik BR. What syndrome is this? Netherton syndrome. Pediatr Dermatol 1992;9:157–60. 90 Nikulin A, Salamon T. [The origin of the hair nodosities in Netherton’s disease. (Polarization microscope studies)]. Z Haut Geschlechtskr 1969;44:1015–22. 91 Stankler L, Cochrane T. Netherton’s disease in two sisters. Br J Dermatol 1967;79:187–96. 92 Gupta AK, Love P, Rasmussen JE. Hair abnormalities and a rash with a double-edged scale. Netherton’s syndrome. Arch Dermatol 1986;122:1201, 1203–4. 93 Kassis V, Nielsen JM, Klem-Thomsen H, Dahl-Christensen J, Wadskov S. Familial Netherton’s disease. Cutis 1986;38:175–8. 94 Renz H, Brodie C, Bradley K, Leung DY, Gelfand EW. Enhancement of IgE production by anti-CD40 antibody in atopic dermatitis. J Allergy Clin Immunol 1994;93:658–68. 95 Stryk S, Siegfried EC, Knutsen AP. Selective antibody deficiency to bacterial polysaccharide antigens in patients with Netherton syndrome. Pediatr Dermatol 1999;16:19–22. 96 Knutsen AP. Chronic sinusitis in children. Pediatr Asthma Allerg Immunol 1997;11:147–69. 97 Arslanagic N, Arslanagic R. [Netherton syndrome with recurrent herpes of facial skin]. Medicinski Arhiv (Sarajevo) 2002;56:221–4. 98 Nicholls S, Patel HC, Jones M. Recurrent bacterial vaginosis and Netherton’s syndrome. Int J STD AIDS 1999;10:202–3.

99 De WK, Ferster A, Sass U, Andre J, Stene JJ, Song M. Netherton’s syndrome: a severe neonatal disease. A case report. Dermatology 1996;192:400–2. 100 Gross TP, Khurana RK, Higgins T, Nkowane BS, Hirsch RL. Vaccineassociated poliomyelitis in a household contact with Netherton’s syndrome receiving long-term steroid therapy. Am J Med 1987;83: 797–800. 101 Hausser I, Anton-Lamprecht I. Severe congenital generalized exfoliative erythroderma in newborns and infants: a possible sign of Netherton syndrome. Pediatr Dermatol 1996;13:183–99. 102 Pradeaux L, Olives JP, Bonafe JL, Le TC, Pigeon P, Ghisolfi J. [Digestive and nutritional manifestations of Netherton’s syndrome]. Arch Fr Pediatr 1991;48:95–8. 103 Greig D, Wishart J. Growth abnormality in Netherton’s syndrome. Australas J Dermatol 1982;23:27–31. 104 Stoll C, Alembik Y, Tchomakov D et al. Severe hypernatremic dehydration in an infant with Netherton syndrome. Genet Couns 2001; 12:237–43. 105 Ergin H, Kilic I, Tekinalp G. Netherton’s syndrome and neonatal hypernatremia. A case report. Turk J Pediatr 1997;39: 409–13. 106 Pohl M, Zimmerhackl LB, Hausser I et al. Acute bilateral renal vein thrombosis complicating Netherton syndrome. Eur J Pediatr 1998; 157:157–60. 107 Yerebakan O, Uguz A, Keser I et al. Netherton syndrome associated with idiopathic congenital hemihypertrophy. Pediatr Dermatol 2002;19:345–8. 108 Julius CE, Keeran M. Netherton’s syndrome in a male. Arch Dermatol 1971;104:422–4. 109 Glover MT, Atherton DJ, Levinsky RJ. Syndrome of erythroderma, failure to thrive, and diarrhea in infancy: a manifestation of immunodeficiency. Pediatrics 1988;81:66–72. 110 Ong C, O’Toole EA, Ghali L et al. LEKTI demonstrable by immunohistochemistry of the skin: a potential diagnostic skin test for Netherton syndrome. Br J Dermatol 2004;151:1253–7. 111 Allen A, Siegfried E, Silverman R et al. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 2001;137:747–50. 112 Bens G, Boralevi F, Buzenet C, Taieb A. Topical treatment of Netherton’s syndrome with tacrolimus ointment without significant systemic absorption. Br J Dermatol 2003;149:224–6. 113 Ferrari S, Pellegrini G, Matsui T, Mavilio F, De Luca M. Towards a gene therapy clinical trial for epidermolysis bullosa. Rev Recent Clin Trials 2006;1:155–62. 114 Mavilio F, Pellegrini G, Ferrari S et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med 2006;12:1397–402.

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C H A P T E R 125

Darier Disease Susan M. Burge Department of Dermatology, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK

Definition and history. Darier disease (Darier–White disease, keratosis follicularis) is an inherited dermatosis characterized by warty papules, keratotic plaques and a characteristic nail dystrophy [1,2] that was described in 1889 by White in the USA and Darier in France [3,4]. The histopathological changes include focal acantholysis, dyskeratosis and hyperkeratosis. Aetiology and pathogenesis. Inheritance is autosomal dominant with complete penetrance, but variable expression. Studies suggest a prevalence of around 1 in 30,000 in the United Kingdom [2,5]. ATP2A2, the defective gene in Darier disease, encodes the p-type cation pump, sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), the pump that maintains intraluminal Ca2+ in the endoplasmic reticulum (ER) of keratinocytes [6]. The ER Ca2+ pool is required for intracellular signalling as well as for the correct folding, sorting and posttranslational processing of proteins. Most mutations cause complete or partial loss of function of SERCA2 [6] and haploinsufficiency is the primary mechanism of dominant inheritance. A variety of mutations have been described but few correlations demonstrated between genotype and phenotype. Postzygotic mosaicism for ATP2A2 mutations causes unilateral or ‘segmental’ Darier disease [7]. Some cases of acrokeratosis verruciformis of Hopf can also be attributed to mutations in the Darier gene and might be better classified as a form of Darier disease [8,9]. The pathogenesis of Darier disease is incompletely understood, but one of the earliest changes is disruption of desmosomes, the adhesion junctions that mechanically couple keratinocytes. It seems likely that intracellular signalling is abnormal and that the depletion of the ER Ca2+ pool also destabilizes desmosomes by altering the folding of desmosomal proteins or their sorting and trafficking to the cell membrane. Reduced ER Ca2+ also enhances the influx of Ca2+ into the cytosol through plasma membrane Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

channels and this may stimulate cell proliferation [10]. Alterations in the epidermal calcium gradient combined with activation of apoptosis appear to contribute to abnormal differentiation [11,12]. External factors such as UVB, heat and oral lithium may exacerbate disease by reducing transcription of ATP2A2 and decreasing the already haploinsufficient SERCA2 protein to a critical level [13–15]. Pathology. Histological features include separation between suprabasal epidermal cells (acantholysis) with proliferative ‘budding’ at the base of lesions and a distinctive dyskeratosis (Fig. 125.1). Narrow intraepidermal clefts or lacunae containing acantholytic cells form above the basal cells. Dyskeratotic keratinocytes, known as corps ronds and grains, contain clumped cytokeratin filaments and cytoplasmic vacuoles [16,17]. Corps ronds in the spinous and granular layers have a central homogeneous nucleus surrounded by a clear halo. Grains with elongated pyknotic nuclei surrounded by homogeneous dyskeratotic material are seen in or just below the horny layer. Immunoelectron microscopy indicates that some desmosomal glycoproteins are quantitatively less concentrated in perilesional epidermis [18]. Lesional keratinocytes express keratins and extracellular matrix components characteristic of hyperproliferation [19,20]. Involucrin is also expressed prematurely [21]. In acantholytic cells, the extracellular domains of desmogleins are lost, whereas intracellular domains of desmogleins and desmosomal plaque proteins are distributed diffusely in the cytoplasm, where they may be trapped in tonofilament aggregates [18,22–25]. Clinical features. Expression of the disease varies, but males and females are affected with equal frequency. More than 60% of patients develop signs between the ages of 6 and 20, with onset peaking between the ages of 11 and 15. Congenital Darier disease has been reported but is rare [26]. More than 95% of patients have acral involvement and children may have hand involvement before any

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Fig. 125.1 The hyperkeratotic papule in this biopsy shows typical features of Darier disease. The suprabasal cleft contains acantholytic cells. Dyskeratotic cells are present in the granular layer and the horny plug (x200; stain H&E).

Fig. 125.3 Small flesh-coloured papules of acrokeratosis verruciformis are scattered over the dorsum of both feet in this patient with Darier disease.

Fig. 125.2 Longitudinal red and white lines in the nail are an early sign of Darier disease. These may be associated with nail fragility, notching and splitting.

Fig. 125.4 The crusted papules on the chest are yellowish-brown and rather greasy. Some are coalescing into plaques.

other signs of the disease. In one study, seven of 13 children had nail involvement, eight had palmar pits and ten had acrokeratosis verruciformis. Only three of these children had the typical rash of Darier disease [2]. The most specific acral sign of Darier disease is a combination of longitudinal red and white lines extending from the base to the free edge of the nail plate. These may be associated with V-shaped notching of the free edge of the nail, subungual hyperkeratosis or splinter haemorrhages (Fig. 125.2). The nails are fragile so they break and split, but at first these changes may be attributed to nail biting. Most patients have pits or punctate keratotic papules on palms and soles. The fine palmar pits are easier to detect in children by using palm prints [2]. Children may develop haemorrhagic macules or blisters on the hands and feet, but these are uncommon [1]. Dis-

crete flat-topped warty papules (acrokeratosis verruciformis) are an early sign on the backs of the hands and feet (Fig. 125.3). The skin-coloured papules are always bilateral. The greasy, crusted papules in Darier disease are fleshcoloured, yellow or brown (Fig. 125.4) but in pigmented skin, Darier disease may present as hypopigmented macules and papules (Fig. 125.5) [27–29]. Papules appear on seborrhoeic areas of the trunk, the supraclavicular fossae, the sides of the neck, the forehead, the ears and the scalp. At first the lesions are discrete but later may coalesce into crusted, malodorous plaques. Itching is common but not invariable. Pain is unusual in uncomplicated disease. Most patients have some flexural involvement; occasionally this is severe. The condition is usually mild in children, so the rash is often overlooked until summer, when symptoms and

Darier Disease

125.3

always have relatively mild disease, whereas in others the condition worsens inexorably. Occasionally patients do improve in old age [1]. Differential diagnosis

Fig. 125.5 Darier disease may present with hypopigmented lesions in children with pigmented skin. This child had typical hyperpigmented papules in addition to hypopigmented macules and papules.

signs are exacerbated by heat or sweating. Lesions may develop 1–2 weeks after an episode of sunburn [30,31]. Mucosal involvement has been described in some patients, including salivary gland obstruction [32]. Papules or verrucous plaques develop on the palate, alveolar ridges, buccal mucosa or tongue. Children mosaic for the Darier mutation (see above) may present with localized disease [7,33–35]. Keratotic papules appear on one side of the body in streaks or whorls following Blaschko’s lines. Palmar pits and nail changes may be present on the same side of the body. Heat, sweating and sunburn also aggravate segmental disease. Complications. Patients are prone to widespread cutaneous infections, but no specific or consistent abnormality in immune function has been demonstrated [36]. Herpes simplex infection causes erythema, vesiculation, erosions, crusting and pain. The possibility of herpetic infection should be considered in any patient with a painful exacerbation, even if vesicles are not obvious. Infection with Staphylococcus aureus may also cause blisters. Secondary bacterial overgrowth is common in the keratotic debris and may contribute to malodour. Associated conditions. Bipolar affective disorder and mental impairment have been described in some patients, but the prevalence of these conditions in Darier disease is low [1]. A gene that confers susceptibility to bipolar affective disorder may be present in the Darier region [37–39]. Lithium exacerbates Darier disease and if possible should be avoided for the treatment of bipolar affective disorder in these patients [40,41]. Prognosis. Darier disease is chronic and life-long, but severity is unpredictable and fluctuates. Some patients

Clinical Crusted plaques on the trunk, flexural papules and scaling in the scalp may suggest seborrhoeic dermatitis. Comedones with keratotic papules on the face or chest may be misdiagnosed as acne. Acrokeratosis verruciformis may simulate plane warts. Solitary longitudinal red or white lines in the nails may indicate a subungual tumour. Flexural Darier disease may simulate Hailey–Hailey disease, but Hailey–Hailey disease usually presents in the third decade and is characterized by painful erosions without keratotic papules. Nails in Hailey–Hailey disease may also have longitudinal white lines, but are not fragile as they are in Darier disease [42]. Palmar pits have also been described in Hailey–Hailey disease. Benign forms of acanthosis nigricans may develop during childhood. Flexural skin is pigmented, thickened and papillomatous, but the soft tags differ from the warty papules of Darier disease. Confluent and reticulate papillomatosis presents around puberty, usually in girls. The flat, brown papules appear between the breasts and in the middle of the back, and gradually spread across the trunk. Although the distribution and colour may suggest Darier disease, the papules are not hyperkeratotic. Histological Acantholytic dyskeratosis is a feature of Hailey–Hailey disease, but acantholysis is more widespread and dyskeratosis less severe than in Darier disease. Acantholytic dyskeratosis is also seen in transient or persistent acantholytic dermatosis (Grover disease) but this condition affects adults, not children. Localized perineal papules and plaques with acantholytic histology have been described in children and adults, but the relationship of this condition to Darier disease is uncertain [43,44]. Treatment. The child and carers need time for questions and explanations. Genetic counselling should be offered. Written information may be helpful for the family, as well as for schoolteachers or employers. Teenagers should be advised to avoid careers that will involve work in hot or sweaty conditions. Children reluctant to reveal the affected skin or to participate in activities such as swimming will need psychological support, some of which may be provided by a paediatric-trained dermatology nurse or clinical

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psychologist. Older children may appreciate cosmetic camouflage, including artificial nails. Treatment must be tailored to the child. Those with mild disease may not need specific treatment. Itching is the most troublesome symptom, but cool cotton clothing, sun avoidance and sun protection creams will reduce exacerbations in the summer. Emollients used as a soap substitute may reduce irritation and crusting. Emollients containing urea or lactic acid (for example, Aquadrate™ or Calmurid™) may reduce hyperkeratosis, but often sting. A mild or moderately potent topical corticosteroid (e.g. clobetasone butyrate) may reduce irritation. Topical corticosteroids may be prescribed in combination with an antibiotic to reduce secondary infection in crusted plaques or malodorous flexural disease. Antiseptics may be helpful in the bath. Antiviral treatment with aciclovir should be considered in any child with a painful exacerbation. Retinoids, the vitamin A derivatives, are the most effective treatments for moderate to severe Darier disease. Topical retinoids reduce hyperkeratosis, but irritation limits efficacy. Adapalene cream or tazarotene gel may be tolerated better than isotretinoin gel or tretinoin cream [45–48]. Retinoids may be combined with mild topical corticosteroids to reduce inflammation. The oral retinoids, acitretin and isotretinoin, are of value in severe Darier disease. Acitretin 0.6 mg/kg/day has been recommended for long-term treatment of inherited disorders of keratinization in children, but sideeffects must be monitored carefully, particularly liver function [49,50]. Isotretinoin, 0.5–1 mg/kg/day, is not as effective in disorders of keratinization but is a more suitable choice than acitretin for teenage girls because of the short half-life. All oral retinoids are teratogenic. Pregnancy must be avoided during treatment and for 2 years after stopping acitretin (or etretinate) or for 1 month after stopping isotretinoin. Dose-related side-effects include mucosal dryness, nosebleeds, skin fragility, itching and elevated triglycerides, cholesterol and liver enzymes. Retinoids may cause skeletal hyperostosis and extraosseous calcification, but the long-term significance of these changes is not known. Oral contraceptives have been recommended to treat females with Darier disease [51] but this strategy has not been subjected to randomized controlled trials and no consistent relationship has been demonstrated to the menstrual cycle. References 1 Burge SM, Wilkinson JD. Darier–White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol 1992;27:40–50. 2 Munro CS. The phenotype of Darier ’s disease: penetrance and expressivity in adults and children. Br J Dermatol 1992;127:126–30. 3 White J. A case of keratosis (ichthyosis) follicularis. J Cutan GenitoUrin Dis 1889;7:201–9.

4 Darier J. Psorospermose folliculaire vëgëtant. Ann Dermatol Syphilol 1889;10:597–612. 5 Tavadia S, Mortimer E, Munro CS. Genetic epidemiology of Darier ’s disease: a population study in the west of Scotland. Br J Dermatol 2002;146:107–9. 6 Hovnanian A. Darier ’s disease: from dyskeratosis to endoplasmic reticulum calcium ATPase deficiency. Biochem Biophys Res Commun 2004;322:1237–44. 7 Sakuntabhai A, Dhitavat J, Burge S et al. Mosaicism for ATP2A2 mutations causes segmental Darier ’s disease. J Invest Dermatol 2000;115:1144–7. 8 Macfarlane CS, McSween R, Sakuntabhai A et al. Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2, the gene which is defective in Darier ’s disease. Br J Dermatol 2000;143:47. 9 Braun-Falco M, Fesq H, Ring J et al. Acrokeratosis verruciformis Hopf als minimal variante des M. Darier (Acrokeratosis verruciformis Hopf as a minimal manifestation of Darier ’s disease). H + G Zeitschrift fur Hautkrankheiten 2001;76:449–52. 10 Pani B, Singh BB. Darier ’s disease: a calcium-signaling perspective. Cell Mol Life Sci 2008;65:205–11. 11 Pasmatzi E, Badavanis G, Monastirli A et al. Reduced expression of the antiapoptotic proteins of Bcl-2 gene family in the lesional epidermis of patients with Darier ’s disease. J Cutan Pathol 2007;34: 234–8. 12 Leinonen PT, Hagg PM, Peltonen S et al. Reevaluation of the normal epidermal calcium gradient, and analysis of calcium levels and ATP receptors in Hailey–Hailey and Darier epidermis. J Invest Dermatol 2009;129(6):1379–87. 13 Mayuzumi N, Ikeda S, Kawada H et al. Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1. Br J Dermatol 2005;152:697–701. 14 Mayuzumi N, Ikeda S, Kawada H et al. Effects of drugs and anticytokine antibodies on expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes. Br J Dermatol 2005;152:920–4. 15 Sule N, Teszas A, Kalman E et al. Lithium suppresses epidermal SERCA2 and PMR1 levels in the rat. Pathol Oncol Res 2006;12:234–6. 16 Gottlieb S, Lutzner M. Darier ’s disease. An electron microscopic study. Arch Dermatol 1973;107:225–30. 17 Mesquita-Guimarïes J, Mesquita-Guimarïes I. Cellular differentiation in Darier ’s disease. Ultrastructural aspects. J Submicrosc Cytol 1984;16:387–94. 18 Tada J, Hashimoto K. Ultrastructural localization of cell junctional components (desmoglein, plakoglobin, E-cadherin, and beta-catenin) in Hailey–Hailey disease, Darier ’s disease, and pemphigus vulgaris. J Cutan Pathol 1998;25:106–15. 19 Burge SM, Fenton DA, Dawber RPR et al. Darier ’s disease: an immunohistochemical study using monoclonal antibodies to human cytokeratins. Br J Dermatol 1988;118:629–40. 20 Steijlen PM, Maessen E, Kresse H et al. Expression of tenascin, biglycan and decorin in disorders of keratinization. Br J Dermatol 1994;130:564–8. 21 Kassar S, Charfeddine C, Zribi H et al. Immunohistological study of involucrin expression in Darier ’s disease skin. J Cutan Pathol 2008;35:635–40. 22 Burge SM, Garrod DR. An immunohistological study of desmosomes in Darier ’s disease and Hailey–Hailey disease. Br J Dermatol 1991;124:242–51. 23 Burge SM, Schomberg K. Adhesion molecules and related proteins in Darier ’s disease and Hailey-Hailey disease. Br J Dermatol 1992;127:335–43. 24 Hashimoto K, Fujiwara K, Tada J et al. Desmosomal dissolution in Grover ’s disease, Hailey–Hailey’s disease and Darier ’s disease. J Cutan Pathol 1995;22:488–501.

Darier Disease 25 Hakuno M, Shimizu H, Akiyama M et al. Dissociation of intra- and extracellular domains of desmosomal cadherins and E-cadherin in Hailey–Hailey disease and Darier ’s disease. Br J Dermatol 2000;142:702–11. 26 Fong G, Capaldi L, Sweeney SM et al. Congenital Darier disease. J Am Acad Dermatol 2008;59:S50–1. 27 Berth-Jones J, Hutchinson PE. Darier ’s disease with peri-follicular depigmentation. Br J Dermatol 1989;120:827–30. 28 Ohtake N, Takano R, Saitoh A et al. Brown papules and leukoderma in Darier ’s disease: clinical and histological features. Dermatology 1994;188:157–9. 29 Peterson CM, Lesher JL Jr, Sangueza OP. A unique variant of Darier ’s disease. Int J Dermatol 2001;40:278–80. 30 Baba T, Yaoita H. UV radiation and keratosis follicularis. Arch Dermatol 1984;120:1484–7. 31 Hedblad MA, Nakatani T, Beitner H. Ultrastructural changes in Darier ’s disease induced by ultraviolet irradiation. Acta DermatoVenereol 1991;71:108–12. 32 Macleod RI, Munro CS. The incidence and distribution of oral lesions in patients with Darier ’s disease. Br Dent J 1991;171:133–6. 33 Starink T, Woerdeman MJ. Unilateral systematized keratosis follicularis. A variant of Darier ’s disease or an epidermal naevus (acantholytic dyskeratotic epidermal naevus)? Br J Dermatol 1981;105:207–14. 34 Munro CS, Cox NH. An acantholytic dyskeratotic epidermal naevus with other features of Darier ’s disease on the same side of the body. Br J Dermatol 1992;127:168–71. 35 Itin PH, Buchner SA, Happle R. Segmental manifestation of Darier disease. What is the genetic background in type 1 and type 2 mosaic phenotypes? Dermatology 2000;200:254–7. 36 Patrizi A, Ricci G, Neri I et al. Immunological parameters in Darier ’s disease. Dermatologica 1989;178:138–40. 37 Jacobsen NJ, Franks EK, Elvidge G et al. Exclusion of the Darier ’s disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder. Mol Psychiatry 2001;6:92–7. 38 Jones I, Jacobsen N, Green EK et al. Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier ’s disease. Mol Psychiatry 2002;7:424–7.

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39 Green E, Elvidge G, Jacobsen N et al. Localization of bipolar susceptibility locus by molecular genetic analysis of the chromosome 12q23q24 region in two pedigrees with bipolar disorder and Darier ’s disease. Am J Psychiatry 2005;162:35–42. 40 Clark R Jr, Hammer CJ, Patterson SD. A cutaneous disorder (Darier ’s disease) evidently exacerbated by lithium carbonate. Psychosomatics 1986;27:800–1. 41 Ehrt U, Brieger P. Comorbidity of keratosis follicularis (Darier ’s Disease) and bipolar affective disorder: an indication for valproate instead of lithium. Gen Hosp Psychiatry 2000;22:128–9. 42 Burge SM. Hailey–Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 1992;126:275–82. 43 Salopek TG, Krol A, Jimbow K. Case report of Darier disease localized to the vulva in a 5-year-old girl. Pediatr Dermatol 1993; 10:146–8. 44 Wong TY, Mihm MC Jr. Acantholytic dermatosis localized to genitalia and crural areas of male patients: a report of three cases. J Cutan Pathol 1994;21:27–32. 45 Burge SM, Buxton PK. Topical isotretinoin in Darier ’s disease. Br J Dermatol 1995;133:924–8. 46 English JC 3rd, Browne J, Halbach DP. Effective treatment of localized Darier ’s disease with adapalene 0.1% gel. Cutis 1999;63: 227–30. 47 Micali G, Nasca MR. Tazarotene gel in childhood Darier disease. Pediatr Dermatol 1999;16:243–4. 48 Cianchini G, Colonna L, Camaioni D et al. Acral Darier ’s disease successfully treated with adapalene. Acta Derm Venereol 2001;81:57–8. 49 Christophersen J, Geiger JM, Danneskiold Samsoe P et al. A doubleblind comparison of acitretin and etretinate in the treatment of Darier ’s disease. Acta Dermato-Venereol 1992;72:150–2. 50 Lacour M, Atherton DJ, Harper JI. An appraisal of acetretin treatment in children with inherited disorders of keratinisation. JEADV 1995;5(suppl 1): S109. 51 Oostenbrink JH, Cohen EB, Steijlen PM et al. Oral contraceptives in the treatment of Darier–White disease – a case report and review of the literature. Clin Exp Dermatol 1996;21:442–4.

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C H A P T E R 126

Porokeratosis Leslie Castelo-Soccio Hospital of the University of Pennsylvania and Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Clinical variants, 126.1

Definition. Porokeratoses are a collection of clonal disorders of keratinization that share a histologically distinct hyperkeratotic ridgelike border called the cornoid lamella (Fig. 126.1). There are five common clinical variants: classic porokeratosis of Mibelli (PM), disseminated superficial actinic porokeratosis (DSAP), porokeratosis palmaris et plantaris disseminata (PPPD), linear porokeratosis and punctate porokeratosis. There is also an additional disseminated variant known as disseminated superficial porokeratosis and lesser known variants such as porokeratosis ptychotropica, a pustular variant of DSAP and genital porokeratosis. Aetiology. Several risk factors exist for porokeratosis including genetic inheritance, ultraviolet radiation (including electron beam, radiation therapy and artificial ultraviolet radiation) and immunosuppression. Porokeratosis has been observed in patients with HIV and lymphomas as well as patients on immunosuppressive medications for transplant or autoimmune diseases. Most patients who develop porokeratosis have less pigmented skin, although porokeratosis can be seen in more darkly pigmented individuals. The formation of non-melanoma skin cancers including squamous cell carcinomas and basal cell carcinomas have been reported for all types of porokeratosis although linear porokeratosis and large lesions of long duration appear to have the greatest risk. Reports of malignant transformation into skin tumours range from 7.5% to 11.6%. Instability in chromosome 3 has been associated with development of malignancy in cultured fibroblasts derived from porokeratosis lesions. Three genetic loci have been identified to date in patients with DSAP: 2q23.2-24.1 (DSAP1), 15q25.1-26.1 (DSAP2) and 1p31.3-p31.1 (DSAP3) and 18p11.3. Two candidate genes at the DSAP1 locus [SSH1 (slingshot homologue-1) and SART3 (squamous cell carcinoma Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

antigen recognized by T cells 3)] were characterized. It remains to be determined which one of the two genes or if a different gene is the DSAP-causing gene at this locus. Similarly, on DSAP3 eight candidate genes were sequenced, but found to be negative for functional sequence variants. Two genetic loci for other two subtypes of porokeratosis were also mapped, one for disseminated superficial porokeratosis (DSP) on 18p11.3 and one for PPPD on 12q24.1–24.2. In 2010, microarray analysis using an Illumina platform from porokeratosis patients’ lesional and non-lesional skin identified three candidate genes: SART3, SSH1 and ARPC3 (actin related protein 2/3 complex, subunit 3) which were upregulated in lesional skin. Keratin 6a was identified as a specific biomarker for porokeratotic keratinocytes as it was the most significantly upregulated gene in the nine patient samples. Previous work by Hivnor using an Affymetrix platform identified 10 upregulated genes including keratins 6A, 6B, 16, 17, S-100A7 (S-100 calcium binding proteinA7/psoriasin), A8, A9, FABP5 (fatty acid binding protein 5, psoriasis-associated), GJB2 (gap junction protein beta 2/connexin 26) and SPRP1A (small proline-rich protein 1A). The subtypes of porokeratosis arise at different time points in an individual’s lifetime with linear porokeratosis and PPPD occurring at any time between birth and adulthood, while PM develops in childhood and DSAP typically occurs in third or fourth decade of life.

Clinical variants Porokeratosis of Mibelli This entity was first reported in 1889 by Vittorio Mibelli in a 21-year-old patient with an affected father and sibling, as multiple annular and gyrate plaques with central atrophy and elevated keratotic borders containing a longitudinal furrow. Mibelli coined the term ‘porokeratosis’ to emphasize what he believed to be representative features of the lesion: abnormal keratinization and

126.2

Chapter 126

Fig. 126.1 Histology of porokeratosis. Haematoxylin and eosin stained image (x10) showing characteristic cornoid lamella. Courtesy of Dr Adam Rubin.

origination within the pores of sweat ducts. Porokeratosis of Mibelli lesions are typically asymptomatic or very slightly itchy, light brown keratotic papules that develop in childhood. While there is usually an autosomal dominant inheritance pattern, this entity can also be acquired. As the lesion progresses, papules slowly expand to form an annular plaque with a raised border and atrophic centre. These lesions may expand rapidly if the patient becomes immunosuppressed. There are reports of patients developing this entity after diagnosis of HIV. Frequently there is a history of antecedent burn, radiation therapy or other trauma to the area where the lesion first appears. For PM, the main differential diagnoses include guttate psoriasis and warts. There are rare reports of cutaneous T-cell lymphoma mimicking porokeratosis so this should be considered. Use of dermoscopy to identify the hyperkeratotic border has been proposed recently. Under dermoscopy a white peripheral rim, which corresponds to cornoid lamellae, is the essential pathognomonic feature for diagnosis.

Disseminated superficial actinic porokertosis Four years after Mibelli described porokeratosis, Respighi described the disseminated superficial variant. In 1966, Chernosky defined DSAP (also known as porokeratosis of Chernosky) as a distinct clinical entity characterized by small inconspicuous lesions occurring on sun-exposed areas in adults. A subsequent detailed light microscopic analysis of 35 clinically varied cases was published by Reed and Leone in 1970. They observed that the majority of lesions were not associated with ostia of eccrine or pilosebaceous ducts, and asserted that the well-accepted term ‘porokeratosis’ was a misnomer. A more precise term was not proposed. This entity is composed of multiple small scaly brown keratotic papules with raised borders which occur on the extensor surfaces. Lesion number ranges from a few to several hundred but typi-

cally is greater than 50 lesions. They may be asymptomatic or slightly itchy. Half of patients note exacerbation of their lesions during the summer months. Facial lesions are uncommon and occur in less than 15% of patients. Most patients who develop DSAP are women in their fourth and fifth decades with an extensive history of ultraviolet radiation exposure (such repeated tanning/ tanning bed exposure or ultraviolet exposure from phototherapy). Immunosuppression also predisposes to DSAP. For DSAP the main differential diagnoses include psoriasis, stucco keratoses, actinic keratoses, squamous cell carcinoma, warts and Darier disease. In 2002, two loci for DSAP were mapped to 12q23.2– 24.1 and 15q25.1–26.1 in two Chinese families and in 2004 an additional locus was mapped to chromosome 18p11.3. However, no disease genes for DSAP have been identified so far. In 2009, a new variant was described with neutrophilic pustules within the cornoid lamellae which corresponds to pustules on the outer rim clinically. This was the second report of porokeratosis with pustules.

Linear porokeratosis This rarer subtype was historically described in 1974 by Rahbari as an entity distinct from PM. These lesions typically occur in infancy or childhood and do not appear to be inherited. They are red–brown linear keratotic papules and annular plaques often in a Blaschkoid distribution (Fig. 126.2). Nail dystrophy has been associated with this disorder. Loss of heterozygosity may account for higher risk of malignant degeneration within these lesions. These lesions may also have increased risk for p53 mutations. For linear porokeratosis, the main differential diagnoses include linear verrucous epidermal naevus, lichen striatus, incontinentia pigmenti, linear lichen planus, linear psoriasis, linear Darier disease and warts.

Porokeratosis palmaris and plantaris disseminata This is a variant originally described by Guss in 1971. These are small keratotic papules, which are sometimes itchy, on the palms and soles which occur during adolescence and early adulthood. These may become generalized and involve the trunk and extremities. The appearance is similar to DSAP except that the lesions are not limited to sun-exposed areas. Mucosal lesions have been noted occasionally. Squamous cell carcinomas are reported to develop within these lesions. These lesions can be transmitted in an autosomal dominant mode or caused by immunosuppression. Sudden develop of these lesions should prompt a search for internal malignancy. Differential diagnoses include palmo-plantar keratodermas, calluses and warts.

Porokeratosis

126.3

Porokeratosis ptchyotropica This lesser known variant is characterized by circumferential perianal plaques. These lesions have the typical cornoid lamella histology but with underlying amyloid deposition. Differential diagnoses include inverse psoriasis, chronic contact or irritant dermatitis, acrodermatitis enteropathica, necroytic migratory erythema, chronic intertrigo, Darier disease and Hailey–Hailey disease.

Genital porokeratosis

Fig. 126.2 Photograph of linear porokeratosis on the chin of a child. Courtesy of Dr Albert Yan.

In 2003, a locus was located at chromocome 12q24.1– 24.2 but no disease genes or mechanisms were identified. Two candidate genes, SSH1 and SART3, with uncertain signifiance were isolated from one screen. Flow cytometry of cells from lesional skin have shown abnormal DNA ploidy.

Punctate porokeratosis Punctate porokeratosis is manifested by multiple small (0.2–1.0 cm) firm flesh-coloured hyperkeratotic papules on the palms and soles of adults. Papules are firmly attached at their bases. There is no inheritance pattern (although both sporadic and autosomal dominant forms have been reported) and usually these are associated with other forms of porokeratosis. Clinically, these lesions resemble punctate porokeratotic keratoderma which is considered an sign of internal malignancy. Differential diagnoses include punctate, palmo-plantar keratoderma (Buschke–Fischer disease), acrokeratoelastoidosis, punctate keratosis of palmar creases, focal acral hyperkeratosis, calluses and warts. The aetiology of this disease is not certain. In one study, keratins 6 and 16 were present in lesional skin. Lesions do not resolve spontaneously.

This variant has been considered a distinct form of porokeratosis that can be associated with diabetes, sexually transmitted disease (one report of patient with condyloma acuminata and one with syphilis) and in one case CD4/CD8 suppression in the absence of HIV infection. Porokeratosis of the genital area is extremely rare. There is a case series of 10 patients and 6 other single case reports in the literature. There does not appear to be a genetic inheritance pattern. Most lesions are confined to the genital area but some patients have involvement of the inguinal area and buttocks. This entity is difficult to diagnose clinically at first and initial clinical impressions include atopic dermatitis, gumma, condylomata lata, extramammary Paget disease, granuloma annulare, warts and lichen simplex chronicus. Biopsy can assist in differentiation. It appears to progress rapidly initially but stabilizes quickly without further extension. The majority of cases reported were in men. Malignant transformation has not been reported. Diagnosis. Overall, appearance, age of onset and distribution categorize these lesions. Biopsy will show characteristic cornoid lamella and help rule out other diagnoses. Dermoscopic examination may be of diagnostic use. Dermoscopy of disseminated porokeratosis shows a characteristic central scar-like area with a single or double ‘white track’ structure at the margin. The ‘white track’ corresponds to the cornoid lamella histologically. Key management criteria. Treatment is individualized and based on size, location and number of lesions. For many patients observation for malignant degeneration, aggressive sun protection and emollients are all that is required. Active non-intervention should always be accompanied by anticipatory guidance for patients and caregivers, along with regular follow-up to monitor for significant changes. High-quality close-up photographic images can be of value in this effort. If lesions are widespread or there is a concern for malignant degeneration, a number of surgical, topical and oral therapies can be utilized. Overall, treatments are documented as single case reports and small case series. The majority of reports are for adult patients with DSAP. There are few case

126.4

Chapter 126

reports for use of these treatments in children. The ideal treatment is pain-free, effective, safe and non-scarring. As with any genodermatosis, a genetic history should be obtained and counselling should be provided. Parents of a child with PM should be examined for skin lesions. There is a 50% risk of disease in each child born to an affected individual. The inheritance pattern of linear porokeratosis is unclear. An autosomal pattern of transmission has been reported for other genodermatoses that present as somatic mosaics.

Topical therapies Topical therapy is the most acceptable route for the majority of patients. However, long-term therapy is often required. Poor compliance will result in suboptimal results, and prolonged use of some medications (potent topical corticosteroids, calcipotriol) requires close followup, paying special attention to problems associated with systemic absorption. Topical 5-fluouracil (5-FU), an antimetabolite that inhibits DNA synthesis, can induce remission if it is used for at least 3–4 weeks and a brisk inflammatory response is achieved. This therapy is often combined with topical retinoids or salicylic acid or other keratolytics. It is thought that topical retinoids decrease abnormal keratinization. Patients will develop extreme redness and irritation and should be warned about these effects. Topical 5% imiquimod cream, an imidazoquinoline amine, has been used effectively for PM and may be beneficial for other types of porokeratosis including linear porokeratosis. The precise mechanism is not known but appears to be related to induction of cytokines such as α-interferon (IFN-α), IFN-γ, tumour necrosis factor α and interleukin-12 which results in the promotion of cellmediated immune reposnes. In these case reports and small case series, topical imiquimod (5%) is applied once per day, 5 days per week under occlusion for 2–4 months. Strong inflammatory reactions were noted but were decreased with either topical steroids or decreasing frequency of application. Good responses were noted but long-term follow-up is needed to evaluate safety and efficacy. There is one report of a patient with DPPP with a history of multiple basal cell carcinomas and squamous cell carcinomas treated with imiquimod to prevent malignancy. This patient used daily therapy for 6 months. No new carcinomas were noted in the 6-month period and clinically there was decreased scale and red–brown coloration of porokeratotic plaques. There are no data on the efficacy of topical 5-FU for the treatment of paediatric porokeratoses. Case reports have documented the relative safety of extensively applied topical 5% 5-FU cream for up to 10 years in children with other problems. A potential adverse effect is injury from inadvertent transfer to other sensitive tissues, such as the

cornea. Systemic absorption in adults is estimated to be 6 mg following a daily application of 2 g, far below the 12 mg/kg/day for cancer chemotherapy, and toxic effects have not been reported. However, enhanced absorption is expected from eroded areas, and the increased ratio of body surface area to weight in small children puts them at higher risk for systemic toxicity. Topical vitamin D3 analogues can regulate keratinocyte differentiation and can be used in this disorder. Daily topical calcipotriol or talcalcitol applied for 8 weeks to 5 months can be effective for DSAP. Caution is advised as these can potentially elevate serum calcium levels. Topical retinoids and salicylic acid alone are third-line therapies and are more typically used in combination with topical chemotherapy. Diclofenac topical gel has also been used for genital lesions and DSAP with mixed success. Diclofenac topical gel is a topical non-steroidal anti-inflammatory which is thought to block prostaglandin production by inhibiting cyclo-oxygenase. Patients who have used this therapy typically report a subjective improvement in lesions and overall skin texture. It may stabilize progression of disease, as documented in one case report of a patient with genital porokeratosis, and provide symptomatic relief. An open label study of 17 patients in which patients were enrolled for 12–24 weeks of twice daily topical treatment, a mean decrease of 4% in target area lesions after 12 weeks and 12% decrease in 24 weeks was found. Half of the patients showed a decrease in progression of disease.

Surgical management Cryotherapy is a first-line therapy for smaller lesions. Lesions are typically treated for 30 s with a spray tip after keratotic borders are removed. The main drawback of cryotherapy is that it can be painful and lead to dyschromia and atrophy. Multiple treatments are often needed for complete resolution. Surgical methods can also be used including electrodessication and curettage for small to medium lesions. Dermabrasion has been shown to be successful in one case. Surgery is needed for any lesions that have undergone malignant transformation. It is unclear if prophylactic excision reduces the incidence of malignant transformation. If a painful surgical approach is indicated, age-appropriate recommendations for control of pain and anxiety should be followed. Oral therapies Oral retinoids may reduce malignant degeneration in patients on immunosuppression. Both acitretin and etretinate have been shown to be effective in disseminated porokeratosis and PM. Doses of 30 mg/day acitretin and 75 and 50 mg/day etretinate have been used in adults. Patients noticed improvement within 2–4 weeks. Recur-

Porokeratosis

rence has been observed after cessation of therapy. Lowdose isotretinoin (20 mg/day) has also been used for PPPD. Gradual recurrence is noted 3 months after treatment. The risks of these medications usually outweigh the benefits in children but may be warranted if there is concern for malignant degeneration in immunosuppressed children.

Laser and light therapies Laser ablation using pulsed dye laser (one case report in linear porokeratosis), ND:YAG laser (one case report), Q-switched ruby (two case reports in DSAP) and CO2 laser ablation (multiple case reports) has been used but recurrence has also been observed after these therapies. There are few case reports for each of these modalities. These methods are destructive methods and can cause scarring. Overall, these case reports describe each therapy as moderately successful. Postoperative pain may be poorly tolerated, and traditional wound care, with frequent dressing changes, is not easily accomplished in young children. Light therapy, most prominently photodynamic therapy, has been used successfully for DSAP and linear porokeratosis. Photodynamic therapy uses light to activate a photosensitizer in diseased skin leading to the formation of cytotoxic reactive oxygen species and selective cell damage. There are three case reports in adults with DSAP, one case series in adults with DSAP and one case report in a child with linear porokeratosis for efficacy of this therapy. In these reports, patients were treated with methyl aminolevulinate hydrochloride cream, a sensitizer, for 2–3 h under occlusion. The area was subsequently illuminated with red light for 9–16 minutes. Authors note good tolerance of the procedure and no need for anesthesia. Two to four total sessions were performed in these cases with no recurrence noted up to 11 months after last treatment. One patient continued 5-FU during therapy and these authors felt this combination was more effective than either alone. Close observation and education about strict sun protection is important. If familial inheritance is suspected, other family members should be screened. Screening for causes of immunosuppression including haematologic malignancies and HIV is appropriate for PM, DSAP or sudden exacerbation of lesions. Further reading Agarwal S, Berth-Jones J. Porokeratosis of Mibelli: successful treatment with 5% imiquimod cream. Br J Dermatol 2002;146:331–4. Ahn SJ, Lee HJ, Chang SE. Case of linear porokeratosis: successful treatment with topical 5% imiquimod cream. J Dermatol 2007;34:146–7. Alikhan A, Burns T, Zargari O. Punctate porokeratotic keratoderma. Dermatol Online J 2010;16:13. Alster TS, Nanni CA. Successful treatment of porokeratosis with 585 nm pulsed dye laser irradiation. Cutis 1999;63:265.

126.5

Arranz-Salas I, Sanz-Trelles A, Bautista-Ojeda D. P53 alterations in porokeratosis. J Cutan Pathol 2003;30:455–8. Barnett JH. Linear porokeratosis: treatment with the carbon dioxide laser. J Am Acad Dermatol 1986;14:902–4. Beers B, Jaszcz W, Sheetz K, Hogan DJ, Lynch PJ. Porokeratosis plantaris and palmaris: report of a case with abnormal DNA ploidy in leisonal epidermis. Arch Dermatol 1992;128:236–9. Bencini PL, Tarantino A, Grimalt R, Ponticelli C, Caputo R. Porokeratosis and immunosuppression. Br J Dermatol 1995;132:74–8. Benmously Mlika R, Kenani N, Badri T et al. Localized genital porokeratosis in a female patient with multiple myeloma. Eur Acad Dermatol Venereol 2008;23:584–5. Breneman DL, Breneman JC. Cutaneous T cell lymphoma mimicking porokeratosis of Mibelli. J Am Acad Dermatol 1993;29: 1046–8. Campbell JP, Voorhees JJ. Etretinate improves localized porokeratosis of Mibelli. Int J Dermatol 1985;24:261–3. Cavicchini S, Tourlaki A. Successful treatment of disseminated superficial actinic porokeratosis with methyl aminolevulinate–photodyamic therapy. J Dermatol Treat 2006;17:190–1. Chen TJ, Chou YC, Chen CH, Kuo TT, Hong HS. Genital porokeratosis: a series of 10 patients and review of the literature. Br J Dermatol 2006;155: 325–9. Danby W. Treatment of porokeratosis with fluorouracil and salicylic acid under occlusion. Dermatol Online J 2003;9:33. De Simone C, Paradisi A, Massi G et al. Giant verrucous porokeratosis of Mibelli mimicking psoriasis in a patient with psoriasis. J Am Acad Dermatol 2007;57:665–8. Delfino M, Argenziano G, Nino M. Dermscopy for the diagnosis of porokeratosis. J Eur Acad Dermatol Venereol 2004;18:194–5. Dereli T, Ozyurt S, Ozturk G. Porokertosis of Mibelli: successful treatment with cryosurgery. J Dermatol 2004;31:223–7. Diluvio L, Campione E, Paterno EJ et al. Acute onset disseminated superficial porokeratosis heralding diffuse large B-cell lymphoma. Eur J Dermatol 2008;18:349–50. Doherty CB, Krathen RA, Smith-Zagone MJ, Hsu S. Disseminated superficial actinic porokeratosis in black skin. Int J Dermatol 2009;48:160–1. Fernandez-Guarino M, Harto A, Perez-Garcia B et al. Photodynamic therapy in disseminated superficial actinic keratosis. J Euro Acad Dermatol Venereol 2009;23:176–7. Garcia-Navarro X, Garces JR, Baselga E, Alomar A. Linear porokeratosis: excellent response to photodyamic therapy. Arch Dermatol 2009;145:526–7. Happle R. Cancer proneness of linear porokeratosis may be explained by allelic loss. Dermatology 1997;195:20–5. Hivnor C, Williams N, Singh F et al. Gene expression profiling of porokeratosis demonstrates similarities to psoriasis. J Cutan Pathol 2004;31:657–64. Hong JB, Hsiao CH, Chu CY. Systematized linear porokeratosis: a rare variant of diffuse porokeratosis with good response to systemic acitretin. J Am Acad Dermatol 2009;60:713–5. James AJ, Clarke LE, Elenitsas R, Katz K. Segmental porokeratosis after radiation therapy for follicular lymphoma. J Am Acad Dermatol 2008;58:S49–50. James WD, Rodman OG. Squamous cell carcinoma arising in porokeratosis of Mibelli. Int J Dermatol 1986;25:389–91. Jensen JM, Egberts F, Proksch E, Hauschild A. Disseminated porokeratosis palmaris and plantaris treated with imiquimod cream to prevent malignancy. Acta Derm Venereol 2005;85:550–1. Jung JY, Yeon JH, Ryu HS et al. Disseminated superficial porokeratosis developed by immunosuppression due to rheumatoid arthritis treatment. J Dermatol 2009;36:466–7. Kim C. Linear porokeratosis. Dermatol Online J 2005;11:22.

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Levitt J, Emer JJ, Emanuel PO. Treatment of porokeratosis of Mibelli with combined use of photodynamic theray and fluorouracil cream. Arch Dermatol 2010;146:371–3. Liu HT. Treatment of lichen amyloidosis (LA) and disseminated superficial porokeratosis (DSP) with frequency-doubled Q-switched Nd-YAG laser. Dermatol Surg 2000;26:958–62. Lolis MS, Marmur ES. Treatment of disseminatd superficial actinic porokeratosis (DSAP) with the Q-switched ruby laser. J Cosmeti Laser Ther 2008;10:124–7. Lorenz GE, Ritter SE. Linear porokeratosis: a case report and review of the literature. Cutis 2008;81:479–83. Ma DL, Vano-Galvan S. Squamous cell carcinoma arising from giant porokeratosis. Dermatol Surg 2009;35:1999–2000. Martin-Clavijo A, Kanelleas A, Vlachou C, Berth-Jones J. Porokeratoses. In: Lebhowl MG, Heyman WR, Berth-Jones J, Coulson I, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies, 3rd edn. Saunders Elsevier, 2010:584–6. McAllister RE, Estes SA, Yarbrough CL. Porokeratosis plantaris, palmaris et disseminata: report of a case and treatment with isotretinoin. J Am Acad Dermatol 1986;13:598–603. McDonald SG, Peterka ES. Porokeratosis (Mibelli): treatment with topical 5-fluorouracil. J Am Acad Dermatol 1983;8:107–10. Mibelli V. Porokeratosis. In: Morris MA, ed. International Atlas of Rare Skin Diseases. Hamburg: Leopold Voss, 1889:8–10. Miller DD, Ruben BS. Pustular porokeratosis. J Cutan Pathol 2009;36:1191–2. Ninomiya Y, Urano Y, Yoshimoto K. P53 gene mutation analysis in porokeratosis and porokeratosis associated squamous cell carcinomas. J Dermatol Sci 1997;14:173–8. Nova MP, Goldberg LJ, Mattison T, Halperin A. Porokeratosis arising in a burn scar. J Am Acad Dermatol 1991;25:354–6. Otsuka F, Someya T, Ishibashi Y. Porokeratosis and malignant skin tumors. Cancer Res Clin Oncol 1991;117:55–60. Paller AS, Syder AJ, Yiu-Mo Chan BS. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 1994;331:1408–15. Palleschi GM, Torchia D. Porokeratosis of Mibelli and superficial disseminated porokeratosis. J Cutan Pathol 2008;35:253–5. Pizzichetta MA, Canzonieri V, Massone C, Soyer HP. Clinical and dermscopic features of porokeratosis of Mibelli. Arch Dermatol 2009;141:91–2. Rahbari H, Cordero AA, Mehregan AH. Linear porokeratosis: a distinctive clinical variant of porokeratosis of Mibelli. Arch Dermatol 1974;109:526–8. Rodriguez EA, Jakubowicz S, Chinchilla DA, Carril A, Viglioglia PA. Porokeratosis of Mibelli and HIV infection. Int J Dermatol 1996;35:402–4.

Sasson M, Krain AD. Porokeratosis and cutaneous malignancy: a review. Dermatol Surg 1996;22:339–42. Scappaticci S, Lambiase S, Orecchia G, Fraccaro M. Clonal chromosome abnormalities with preferential involvement of chromosome 3 in patients with porokeratosis of Mibelli. Cancer Genet Cytogenet 1989;43:89–94. Schamroth JM, Zlotogorski A, Guead L. Porokeratosis of Mibelli: overview and review of the literature. Acta Derm Venereol 1997;77:207–13. Sherman V, Reed J, Hollowod K, Littlewood T, Burge SM. Poromas and porokeratosis in patients treated for solid organ and haematological malignancies. Clin Exp Dermatol 2010;35:130–2. Siegfried EC. Diagnostic and therapeutic surgical interventions in pediatric dermatology. Curr Opin Dermatol 1995;2:142–54. Siegfried EC. Diagnostic and therapeutic surgical interventions in pediatric dermatology. Curr Opin Dermatol 1995;3:169–75. Tallon B, Blumental G, Bhawn J. Porokeratosis ptychotropica: a lesser known variant. Clin Exp Dermatol 2009;34:e895–7. Varma SM, Cantrell W, Chen SC et al. Diclofenac sodium 3% gel as a potential treatment for disseminated actinic porokeratosis. J Eur Dermatol Venereol 2009;23:42–5. Vlachou C, Kanelleas AI, Martin-Clavijo A, Berth-Jones J. Treatment of disseminated superficial actinic porokeratosis with topical diclofenac gel: a case series. Eur J Dermatol Venereol 2008;22:1343–5. Wallner J, Fitzpatrick J, Brice S. Verrucous porokeratosis of Mibelli on the buttocks mimicking psoriasis. Cutis 2003;72:391–3. Wei S, Zhang TD, Zhou Y et al. Fine mapping of the disseminated superficial porokeratosis locus to a 2.7 Mb region at 18p11.3. Clin Exp Dermatol 2010;35:664–7. 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;149:261–7S. Xia JH, Yang YF, Deng H et al. Identification of a locus for disseminated superficial actinic porokeratosis at chromosome 12q23.2–24.1. J Invest Dermatol 2000;144:1071–4. Xia K, Deng H, Xia JH et al. A novel locus (DSAP2) for disseminated superficial actinic porokeratosis maps to chromosome 15q25.1–26.1. Br J Dermatol 2002;147:650–4. Yang S, Zhang XQ, Guo Y et al. The pedigree report of disseminated superficial actinic porokeratosis in China. China J Med Genet 2002;19:182. Yazkan F, Turk BG, Dereli T, Kanandi AC. Porokeratosis of Mibelli induced by topical corticosteroid. J Cutan Pathol 2006;33:516–8. Zhang ZH, Wang ZM, Crosby ME et al. Reassessment of microarray expression data of porokeratossi by quantitative real time polymerase chain reaction. J Cutan Pathol 2002;37:371–5.

127.1

C H A P T E R 127

Ectodermal Dysplasias Yuka Asai1 & Alan D. Irvine2 1

Division of Dermatology, McGill University, Montreal, Canada Paediatric Dermatology, Trinity College Dublin and Our Lady’s Children’s Hospital, Dublin, Ireland

2

What is an ectodermal dysplasia? 127.1 Ectodermal dysplasias due to mutations in tumour necrosis factor-like/NF-κB signalling pathways, 127.65

Transcription factors, homeobox genes: major regulators of gene expression, 127.73

The ectodermal dysplasias (EDs) encompass a complex and highly diverse group of heritable disorders that have in common developmental abnormalities of ectodermal appendages. This chapter briefly discusses the historical clinical perspective on defining and classifying these conditions and the impact of recent developments in molecular biology. A summary is presented of the great majority of reported ectodermal dysplasias that have a cutaneous phenotype. A more detailed description of the more common disorders that present to dermatologists is also given. Mendelian Inheritance in Man numbers (MIM) [1] are given where appropriate for ease of reference.

What is an ectodermal dysplasia? In excess of 170 different conditions have been described under the umbrella term ‘ectodermal dysplasia’. Any approach to summarizing current knowledge about this group of diverse inherited conditions presents several challenges. First, and most important, what is an ED, and which distinct conditions are encompassed by this broad term? The history of the terminology throughout the literature is instructive. The first clinical cases with features of what would now be classified as ectodermal dysplasia were reported in the literature as early as 1792, when Danz reported two Jewish boys with congenital absence of hair and teeth [2] but the term ‘ectodermal dysplasia’ did not appear in the literature until coined by Weech in

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Disorders due to mutations in structural and adhesive molecules, 127.95

Defects in the Wnt-β-catenin pathway, 127.83

Defects in gap junction proteins, 127.88

Management of ectodermal dysplasia: general overview, 127.103

1929 [3]. Prior to this report, a small series of patients with hypotrichosis, hypodontia, onychodysplasia and anhidrosis had been described under various names such as ‘dystrophy of hair and nails’, ‘imperfect development of skin, hair and teeth’ and ‘congenital ectodermal defect’. The designation outlined by Weech specified three essential aspects of EDs: 1 most of the disturbances must affect tissues of ectodermal origin 2 these disturbances must be developmental 3 heredity plays a causal role. Weech had in mind the X-linked anhidrotic form (Christ– Siemens–Touraine syndrome (CST) or hypohidrotic ectodermal dysplasia (HED) MIM 305100) in males but noted that it had also been reported in females; he also noted that this pattern of involvement was occasionally inherited as a non-sex linked trait. Some authors and clinicians still used the term ‘ectodermal dysplasia’ specifically with reference to CST syndrome and the autosomal dominant and recessive forms of HED. As more clinical reports of patients with similar but subtly distinct patterns of anomalies were recorded, the term ‘ectodermal dysplasia’ became extended to include many different genetic entities. In an attempt to encapsulate this heterogeneity and the diversity of symptoms seen, Touraine proposed the term ‘ectodermal polydysplasia’ [4]. Attempts at more formal classification soon followed; initially conditions were classified as hidrotic or anhidrotic, but this simple classification failed to reflect the complexity of nail, hair and dental anomalies associated with the various forms of ED. Currently, the most widely accepted and used definition of EDs is a group of inherited disorders that have in

127.2

Chapter 127

common developmental abnormalities of two or more of the following: hair, teeth, nails, sweat glands and other ectodermal structures. Other structures derived from embryonic ectoderm include the mammary gland, thyroid gland, thymus, anterior pituitary, adrenal medulla, central nervous system, external ear, melanocytes, cornea, conjunctiva, lacrimal gland and lacrimal duct. This author subscribes to this definition and it has definite benefits in that the problems encountered by many patients and families are similar regardless of the specific subtype of ED; parents and children can benefit by being part of larger support networks exemplified by the Ectodermal Dysplasia Society (UK-based: www.ectodermaldysplasia.org) and the National Foundation for Ectodermal Dysplasias (US-based: www.nfed.org). This wide-ranging classification is also helpful in concentrating the minds of research workers in the field, and several EDs are now known to have shared genetic mechanisms. Although the broader definition forms the basis for this chapter, many conditions that lie within this broad definition are often considered separately. For example, pachyonychia congenita, incontinentia pigmenti, dyskeratosis congenita and Goltz syndrome are all, by definition, ectodermal dysplasias, but common practice has been to consider them as separate entities; these conditions are given in-depth coverage elsewhere.

Classification of the ectodermal dysplasias Having accepted the broadest definition of an ED, a second challenge presented by this group of conditions is that of designing a meaningful and functional classification system. Until the end of the 20th century, classification systems for ectodermal dysplasias were, because of lack of molecular understanding, based on clinical features. Several authors addressed the issue of delineating nosological groups of conditions linked by shared phenotypic features. The most comprehensive accounts of clinical features and inheritance patterns of ectodermal dysplasia are to be found in the classic 1984 monograph by Freire-Maia and Pinheiro [5] and in subsequent publications [6]. Their classification designated conditions by groups depending on the presence of features in hair, nails, teeth or sweat glands, and assigned conditions to groups using a ‘1234 system’ to collate conditions that had involvement of the hair (1), teeth (2), nails (3) or sweat glands (4) to groups such as 1–2 or 1–2–3. This classification was a comprehensive attempt at ordering an unwieldy group of conditions but was difficult to use and grouped together intuitively disparate clinical entities such as Goltz syndrome and pachyonychia congenita. In common with any other classification of EDs based on clinical findings, this system is con-

founded by the subtleties of inheritance such as incomplete penetrance and variable expressivity of phenotype. This is especially true in the EDs, in which sweating is often not formally measured and teeth or nail anomalies may be subtle. A comprehensive contemporaneous consideration of the breadth of ED conditions in the tradition of Freire-Maia and Pinheiro is presented in Table 127.1. Ectodermal dysplasias may also be divided into those with isolated involvement of hair, teeth and nails – ‘pure’ EDs – while those with abnormalities of other structures and organs are referred to as ‘ectodermal dysplasia syndromes’. The construction of a practical, convenient classification of ED is made challenging due to the complex interplay between clinical presentation, mode of inheritance and the genes, proteins and molecular pathways involved.

Molecular insights and new approaches to classification The last decade has seen several important insights into the molecular basis of several of the ectodermal dysplasias. In some cases, the molecular data have confirmed clinical impressions; for example, Hay–Wells syndrome and ectrodactyly–ectodermal dysplasia–clefting (EEC) syndrome have ectodermal dysplasia and clefting of the palate and lip as common clinical features and these conditions are now known to be allelic. In a few conditions, a unifying molecular mechanism has been shown to underlie clinically very distinct conditions. In recognition of the recent advances in understanding the molecular mechanisms underlying these EDs, conditions that share molecular mechanisms are considered together below. One important concept in ectodermal appendage morphogenesis that recurs throughout the EDs is an early dermal signal initiating morphogenesis, followed by an ectodermal signal to organize the mesenchyme, with a secondary dermal signal to co-ordinate growth and development of the epithelial appendage. For a recent summary, see Fuchs et al. [7]. The molecular mechanisms delineated to date in EDs can be considered under the broad categories of defects in the nuclear factor κB (NF-κB) signalling pathway, p63 transcription factor pathway, Wnt-β-catenin pathway, gap junctions and structural/adhesive molecules. Based on these pathophysiological mechanisms, EDs can also be sorted into two broad categories: Group 1, indicating defects in developmental regulation and epithelial-mesenchymal interaction, and Group 2, indicating defects in proteins of cytoskeleton or adhesion, which are involved in cell– cell communication as well as structural integrity [27,28].

MIM Inheritance number/ primary ref AD

AR?

129200 136000

Name (alternative names)

Absence of dermal ridge patterns, onychodystrophy and palmoplantar anhidrosis (Basan syndrome)

Achondroplasia, so 200900 called, and severe combined immunodeficiency (aka short-limb skeletal dysplasia with SCID, agammaglobulinaemia, dwarfism–ectodermal dysplasia, Swiss-type ectodermal dysplasia) (?same as cartilage–hair hypoplasia (see below))

Hair

Normal

Slow growing, in one family failed to grow after initial pelage

Fingernails attached Normal distally to the hyponychium; rough in texture; horizontal and vertically grooved

Nails

Phenotypic characteristics

Table 127.1 Clinical characteristics of the ectodermal dysplasias

No data

Normal

Teeth

No data

Palmoplantar anhidrosis

Sweat glands

Skin: erythroderma; mild hyperkeratosis; generalized scaliness; ichthyosiform lesions; redundant, especially on the limbs, suggesting cutis laxa. Biopsy showed keratosis, fissuring of keratotic layer and thickening of granular layer Other: dyschondroplastic (short-limbed) dwarfism; lymphopenia; gammaglobulinaemia; prominent eosinophilia; hypoplastic thymus; microscopic alterations of thymus, spleen, lymph nodes, gastrointestinal tract, bones

Skin: at birth, multiple milia (on chin); several vesicular/ bullous lesions (on fingers and soles); leather-like texture and callosities in adults; simian creases in some patients. May also have palmoplantar fissures and flexion contractures

Other

(Continued)

Genetic basis (if known)

Ectodermal Dysplasias 127.3

200970

207780

Ackerman syndrome (dento-oculocutaneous syndrome)

Acrorenal field defect, ectodermal dysplasia, lipoatrophic diabetes (AREDYLD) syndrome AR

AR?

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Horizontal ridging of the fingernails with distal onychoschizia

Nails

Scalp hypotrichosis, scant axillary and pubic hair; normal eyebrows and lashes

Scanty body hair; vellus hairs in the moustache and beard areas

Hair

Phenotypic characteristics

Two natal and four deciduous teeth with enamel dysplasia absence of permanent teeth buds; anodontia by 11 years

Taurodontia, pyramidal or fused molar roots

Teeth

Normal

Normal

Sweat glands

Skin: hypoplastic and hypopigmented areolae; absence of DIP extension and flexion creases Face: prominent forehead and bridge of nose; slight mongoloid slant of palpebral fissures; short nasal septum with flat tip of nose; short upper lip; relatively flat philtrum; prominent chin with mandibular prognathism; posteriorly angulated auricles with broad intertragal incisure; hypoplastic tragus and small groove at antitragus

Skin: indurated and hyperpigmented over the interphalangeal joints of the fingers; Face: upper lip characterized by absence of ‘Cupid’s bow’; thickening and widening of the philtrum; ectropion of both lower lids Other: complete sensorineural hearing loss; juvenile glaucoma; syndactyly (third and fourth fingers); clinodactyly of the fifth finger

Other

Genetic basis (if known)

127.4 Chapter 127

103285

147770

Acro-dermato-unguallacrimal-tooth syndrome (ADULT syndrome) (allelic with EEC3, limb-mammary syndrome, AEC, Rapp–Hodgkin syndrome, split hand-foot malformation 4)

Alopecia–anosmia– deafness– hypogonadism (Johnson neuroectodermal syndrome) AD

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Normal

Finger- and toenail dysplasia

Nails

Absent or sparse scalp hair, eyebrows and lashes, axillary and pubic hair

Frontal alopecia

Hair

Phenotypic characteristics

Carious, leading to extensive premature loss

Hypodontia; loss of permanent teeth

Teeth

Skin: intensive freckling Other: lacrimal duct atresia; ectrodactyly, syndactyly; hypoplastic breasts and nipples

Skin: multiple café-au-lait spots Other: conductive hearing loss; protruding ears, hypogonadism; occasional congenital heart defects; cleft palate; choanal stenosis; anosmia or hyposmia; mental retardation; speech impairment; hypodontia; unilateral facial asymmetry or palsy; retro/micrognathia

Hypohidrosis

Other: short stature; difficulty in grasping with left hand; limb abnormalities; lipoatrophic diabetes; hypoplasia of mammary gland; lumbar scoliosis; hyperostosis of cranial vault; cranial dysostosis; prominent subcutaneous leg veins; hypoplasia of the middle right major renal calyx and hypotonia of the right ureter

Other

Normal

Sweat glands

(Continued)

TP63 (transcription factor)

Genetic basis (if known)

Ectodermal Dysplasias 127.5

Freire-Maia and Pinheiro [5]

Freire-Maia and Pinheiro [5]

Alopecia– onychodysplasia– hypohidrosis

Alopecia– onychodysplasia– hypohidrosis–deafness NK

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal fingernails; thick, slightly deformed toenails, with subungual hyperkeratosi; congenital anonychia

Severely dystrophic (thick and yellow)

Nails

Extensive scalp hypotrichosis; absence of eyebrows

Absence of scalp and body hair; no eyebrows or lashes; virtually no body hair

Hair

Phenotypic characteristics

Normal

Normal

Teeth

Hypohidrosis

Hypohidrosis with hyperthermia

Sweat glands

Skin: hyperpigmented, dry and slightly rough, with hyperkeratosis of palms, soles knees and elbows; dermatoglyphs with extensive ridge dissociation Face: unusual, with prominent nose; slightly anteverted auricles with broad upper antihelical region; mongoloid palpebral slanting and narrow palpebral fissures Other: sensorineural deafness; bilateral ectropia; photophobia; short stature; pectus excavatum; retarded bone age

Skin: thick, scaly skin in patches over most of the body (the scalp, soles and legs are more severely affected); eczema; scaly lesions with crusting and some open sores most pronounced around orifices Other: photophobia; horizontal nystagmus, legal blindness; short stature, low IQ; seizures; hypospadias; non-palpable testes

Other

Genetic basis (if known)

127.6 Chapter 127

203655

Lerner [8]

226750

104570

106260

Alopecia universalis congenita (ALUNC; generalized atrichia) (allelic with atrichia with papular lesions, MIM 209500)

Alopecia universalis– onychodystrophy–total vitiligo

Amelocerebrohypohidrotic syndrome (Kohlschutter–Tonz syndrome; epilepsy and yellow teeth syndrome)

Ameloonychohypohidrotic dysplasia

Ankyloblepharon– ectodermal defects– cleft lip and palate (AEC) syndrome (Hay–Wells syndrome) (allelic with EEC3, limb-mammary syndrome, ADULT syndrome, Rapp– Hodgkin syndrome, split hand-foot malformation 4) AD

AD

AR

AR?

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Severe dystrophy

Onycholysis with subungual hyperkeratosis

Normal

Dystrophic fingernails and toenails with transverse ridging

Normal

Nails

Teeth

Hypocalcified– hypoplastic enamel

Yellow owing to enamel hypoplasia

Normal

Skin: dry and smooth; palmoplantar hyperkeratosis with obliteration of dermatoglyphic patterns; occasional reticulate hyperpigmentation; supernumerary nipples; severe recurrent scalp pustulations

Skin: generally xerotic with keratosis pilaris over the buttocks and extensor surfaces of the limbs; seborrhoeic dermatitis of scalp

Skin: scarce sebaceous glands and nerve fibres Other: myopia, progressive CNS degeneration with severe epileptiform seizures appearing between 11 months and 4 years of age; muscle spasticity; abnormal EEG; ventricular enlargement; broad thumbs and toes

Hypohidrosis

Hypohidrosis

Skin: total vitiligo; skin becomes light and translucent and prone to sunburn

Other

Hyperhidrosis

Normal

Sweat glands

Hypotrichosis; Poorly formed and Slight absent or pointed; widely hypohidrosis; scanty eyebrows spaced; carious; no and lashes; severe hyperthermia coarse, wiry hypodontia hair

Normal

Normal or coarse hair

Progressive loss of body and scalp hair, eyebrows, and lashes

Complete alopecia Normal of scalp, body hair, eyelashes, eyebrows variably affected

Hair

Phenotypic characteristics

(Continued)

TP63 (transcription factor)

HR (human homologue of the mouse ‘hairless’ gene)

Genetic basis (if known)

Ectodermal Dysplasias 127.7

106990

106750

Anonychia– onychodystrophy with brachydactyly type b and ectrodactyly (same as Cook syndrome? – see below)

Anonychia with bizarre flexural pigmentation

AD

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Generalized absence on the fingers and toes; in a few instances rudimentary

Anonychia; onychodystrophy

Nails

Slow-growing and coarse scalp hair, thinning early in adult life

Normal

Hair

Phenotypic characteristics

Highly carious

Normal

Teeth

Mild hypohidrosis without hyperthermia

Normal

Sweat glands

Skin: hypo- and hyperpigmentation, particularly in the groins, axillae and breasts; distortion of epidermal ridges on palms and soles; mild palmoplantar hyperkeratosis; increased palmar markings; distorted fingertip patterns; small macular telangiectasias in a few regions

Limbs: ectrodactyly; absent/ hypoplastic metacarpals; absent/hypoplastic distal phalanges; hypoplastic metatarsals

Face: ankyloblepharon filiforme adnatum with partial fusion of eyelids at birth; broad nasal bridge; hypoplastic maxilla; auricular abnormalities; cleft lip/palate Other: lacrimal duct atresia; choana atresia; photophobia

Other

Genetic basis (if known)

127.8 Chapter 127

AR

AR

601701

209500

240300

Arthrogryposis and ectodermal dysplasia (trichooculodermovertebral syndrome; Alves syndrome)

Atrichia with papular lesions (allelic with alopecia universalis congenita MIM 203655)

Autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy (APECED) syndrome; autoimmune polyendocrinopathy syndrome, type 1

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Thickened and dystrophic

Normal

Absence at birth; later normal length; tendency toward longitudinal breaks

Nails

Teeth

Sweat glands

Occasional alopecia areata

Atrichia at birth, or hair present at birth with shedding shortly afterwards that is not replaced Alopecia may include eyebrows, eyelashes, axillary and pubic hair Hypoplastic enamel

Normal

Normal

Normal

Hypotrichosis of Enamel hypoplasia Hypohidrosis scalp (atrichia at birth) and body; scanty eyebrows and lashes

Hair

Phenotypic characteristics

Other: oral candidiasis; autoimmune endocrinopathies (hypergonadotropic hypogonadism, insulindependent diabetes mellitus, autoimmune thyroid diseases and pituitary defects); autoimmune or immunomediated gastrointestinal diseases (chronic atrophic gastritis, achalasia, pernicious

(Continued)

AIRE (autoimmune regulator gene)

Skin: skin-coloured cystic and HR (human papular lesions over the homologue of the body, primarily on elbows mouse ‘hairless’ and knees, and face gene)

Skin: dry; tendency to excessive bruising and scarring after injuries and scratching Other: bilateral epicanthic folds; slight mongoloid slant; short stature; probable low-normal intelligence level; arthrogryposis of all joints; bilateral clinodactyly; slight bilateral syndactyly of second and third toes; diabetes mellitus

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.9

Baisch [9]

119580

112300

211370

Baisch syndrome

Blepharocheilodontic syndrome (clefting, ectropion and conical teeth syndrome; Elschnig syndrome)

Book dysplasia (PHC syndrome)

Brachymetapody– anodontia– hypotrichosis– albinoidism (oculo-osteocutaneous syndrome; Tuomaala syndrome) AR

AD

AD

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Normal

Normal

Almost total absence of the finger- and toenails

Nails

Poor hair growth, distichiasis

Premature canities

Distichiasis of eyelashes in some

Normal

Hair

Phenotypic characteristics

Congenital anodontia

Hypodontia of the premolar region

Conical teeth, hypodontia

Delayed eruption; absence of lateral incisors

Teeth

Normal

Palmoplantar hyperhidrosis

Normal

Normal

Sweat glands

Skin: albinoidism Other: multiple ocular abnormalities (strabismus, nystagmus, lenticular opacities, high-grade myopia); mandibular prognathism; short stature; short metacarpals/ metatarsals

Eyes: blue irides

Other: cleft lip and palate; hypertelorism; ectropia; euryblepharon, lagophthalmia

Limbs: polydactyly with syndactyly in the hands (6/7 fingers); hypoplasia of the distal interphalangeal joints of fingers and toes; short and wide hands and feet; adduction of feet; delayed bone age

anaemia and malabsorption); chronic active hepatitis; autoimmune skin diseases (vitiligo and alopecia); keratoconjunctivitis, immunological defects (cellular and humoral); asplenia and cholelithiasis

Other

Genetic basis (if known)

127.10 Chapter 127

Freire-Maia and Pinheiro [5]

115150

Camarena syndrome

Cardiofaciocutaneous syndrome

AD

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Normal or thin opalescent nails

Dysplastic

Nails

Teeth

Sparse, brittle, slow-growing curly hair; absence of eyebrows and eyelashes, sparse body hair Normal

Thin, Anodontia hypopigmented, and very sparse; poor growth

Hair

Phenotypic characteristics

Normal

Absence of sweat glands in the scalp; anhidrosis on face and scalp

Sweat glands

(Continued)

Mutations in KRAS, Skin: severe atopic BRAF, MEK1, dermatitis, patchy to severe MEK2, (all ichthyosis; multiple palmar involved in Ras/ and plantar creases; Erk pathway) hyperkeratosis (especially extensor surfaces); keratosis pilaris, ulerythema ophryogenes Face: coarse facial features, similar to Noonan’s syndrome; relative macrocephaly; prominent forehead; bitemporal narrowing; shallow orbital ridges; prominent philtrum; posteriorly rotated ears; downslanting palpebral fissures; hypertelorism; exophthalmos; short upturned nose; depressed nasal bridge; submucous cleft palate; high-arched palate

Skin: thin and smooth; palmoplantar erythema; naevus vascularis on the right lid and above the nose; euhidrosis on the rest of the body; mild ‘cara devieja’ (old woman’s face) Other: hypertelorism; abnormal auricles; micrognathia; microstomia; bilateral clinodactyly of the fifth fingers; high-arched palate

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.11

Freire-Maia and Pinheiro [5]

250250

Carey syndrome

Cartilage–hair hypoplasia syndrome (metaphyseal chondrodysplasia, McKusick type) AR

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Dystrophy from early childhood

Nails

Sparse eyebrows, eyelashes, beard, light-coloured hair, small calibre, fine hairs

Thin, hypopigmented and very sparse

Hair

Phenotypic characteristics

Normal

Discoloration; microdontia; hypodontia

Teeth

Normal

Decreased number of sweat pore openings

Sweat glands

RMPR (RNA Other: increased risk of malignancy (non-Hodgkin’s, processing SCC, BCC); immune defect endoribonuclease (;ymphopenia, neutropenia, gene) severe varicella and HSV); short-limbed dwarfism; mild scoliosis; short hands; limited elbow extension; malabsorption; Hirschsprung’s disease; oesophageal atresia

Skin: aplasia cutis congenitalike scalp defects Other: moderate conductive hearing loss; absence of tear ducts; displacement of the inner canthi; U-shaped mouth; flat nasal bridge; maxillary hypoplasia; incomplete two- to three-toe syndactyly; cleft palate

Other: postnatal short stature; hearing loss; nystagmus; strabismus; cardiac defects (atrial septal defects, pulmonic stenosis, hypertrophic cardiomyopathy); splenomegaly; hyperextensible fingers; mild to moderate mental retardation; seizures; hypotonia or hypertonia; hydrocephalus; cortical atrophy; frontal lobe hypoplasia; brain stem atrophy

Other

Genetic basis (if known)

127.12 Chapter 127

212360

211770

225060

221320

Cataract–alopecia– sclerodactyly syndrome

Cataract, hypertrichosis, mental retardation (CAHMR) syndrome

Cleft lip/palate– ectodermal dysplasia syndrome (CLEPD1; Zlotogora–Ogur syndrome) (allelic to Margarita Island ectodermal dysplasia, see below)

Conductive deafness, with ptosis and skeletal anomalies AR

AR

AR

AR

Normal

Subungual hyperkeratosis, sulci; transverse and longitudinal striae; irregularities of free margins; hallucal nails with absence of the lamina

Normal

Normal

Normal

605676

Carvajal syndrome (palmoplantar keratoderma with left ventricular cardiomyopathy and woolly hair)

AR

Nails

Delayed hair growth

Woolly, thin, coarse, opaque and short; pili torti

Generalized congenital hypertrichosis (back, shoulders, face)

Total alopecia

Woolly hair at birth

Hair

Phenotypic characteristics

MIM Inheritance number/ primary ref

Name (alternative names)

Dysplastic teeth

Hypodontia of upper lateral incisors; transverse striation; irregularities of the free margins

Normal

Normal

Normal

Teeth

Normal

Normal; ? mild tendency to perspiration

Normal

Normal

Normal

Sweat glands

Other: conductive hearing loss from combined atresia of the external auditory canal and the middle ear space, complicated by chronic infection; ptosis; thin, pinched-nose facial appearance Skeletal: internal rotation of hips; dislocation of the radial heads; fifth finger clinodactyly

Face: cleft lip; hypoplasia of the auricular lobes; flat nasal pyramid Other: cleft palate; malformation of the genitourinary system; absence or fusion of the last lumbar vertebra; syndactyly of second and third fingers

Other: mental retardation; congenital lamellar cataracts

Skin: sclerodactyly; hyperkeratosis Other: congenital bilateral cataracts; contractures, digits; pseudo-ainhum; patients from Rodrigues in the Indian Ocean

Skin: striate palmoplantar keratoderma Other: dilated left ventricular cardiomyopathy; altered contractility

Other

(Continued)

PVRL1 encoding nectin-1 (a cell adhesion molecule)

DSP, encoding desmoplakin, a structural protein of desmosomes

Genetic basis (if known)

Ectodermal Dysplasias 127.13

135900

601553

Coffin–Siris syndrome (fifth digit syndrome)

Congenital hypotrichosis with juvenile macular dystrophy (HJMD) AR

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Absent to hypoplastic fifth fingernails and toenails; other nails occasionally hypoplastic or absent

Nails

Congenital hypotrichosis secondary to decreased ratio of terminal to vellus hairs; beading of hair shaft (flat shaft and pili torti); normal eyelashes/ eyebrows

Sparse scalp hair; bushy eyebrows and lashes; hirsutism of limbs, forehead and back

Hair

Phenotypic characteristics

Normal

Delayed eruption; microdontia

Teeth

Normal

Normal

Sweat glands

Other: not true macular dystrophy; pigmentary abnormalities extending beyond macula; prorgressive cone/rod dystrophy

Skin: dermatoglyphic changes; simian crease Other: coarse face with thick lips, wide mouth and nose, anteverted nostrils and low nasal bridge; retardation of psychomotor and growth development; hypotonia; lax joints; clinodactyly of the fifth fingers; general absence of terminal phalanges of fifth fingers and toes; general aplasia or variable hypoplasia of middle and proximal phalanges of other fingers and toes; bilateral or unilateral dislocation of the radial heads; small or absent patella; frequent respiratory infections; umbilical and inguinal hernias; cleft palate; feeding problems in infancy; six lumbar vertebrae; short sternum; sternal anomalies; microcephaly; patent ductus arteriosus

Other

CDH3 gene (encoding P-cadherin, an adhesion molecule)

Genetic basis (if known)

127.14 Chapter 127

AD

AD

256800

106995

122440

Congenital insensitivity to pain with anhidrosis (CIPA; familial dysautonomia, type II; hereditary sensory and autonomic neuropathy, type IV)

Cook syndrome (same as anonychia– onychodystrophy with brachydactyly type b and ectrodactyly? – see above)

Corneodermato-osseous syndrome

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Hypotrichosis in areas of the scalp

Hair

Distal onycholysis

Normal

Congenital Normal onychodystrophy; anonychia

Normal

Nails

Phenotypic characteristics

Soft teeth; early tooth decay

Normal

Enamel aplasia

Teeth

Normal

Normal

Hypohidrosis or anhidrosis with hyperthermia, normal sweat glands

Sweat glands

Skin: diffuse palmoplantar hyperkeratosis; erythematous scaly skin (knees, elbows, hands/ feet); generalized erythroderma Eyes: corneal dystrophy; photophobia; burning/ watering of eyes Other: brachydactyly; short distal phalanges; short stature; medullary narrowing of hand bones; premature birth

Skin: prominent finger pads Other: fifth finger brachydactyly; digitalization of thumbs; absent/ hypoplastic distal phalanges of hands and feet

Skin: dry; scars from self-inflicted bites may be present on the fingers and arms; chronic sores are common on the hands, feet and pressure points, such as the buttocks Other: irregular lacrimation; mental retardation; fever; corneal ulcers; multiple fractures from trauma resulting in deformities; joint degeneration (Charcot joints); universal sensory loss; absence of pain perception and physiological responses to painful stimuli; impaired temperature and touch perception; diminished tendon reflexes; occasional encopresis and enuresis; ulceration of the mouth and scars from biting the tongue and lips

Other

(Continued)

NTRK1, the receptor tyrosine kinase for nerve growth factor

Genetic basis (if known)

Ectodermal Dysplasias 127.15

218330

Cranio-ectodermal syndrome (Levin syndrome I; Sensenbrenner syndrome) AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Broad and short

Nails Thin, sparse and slow-growing; abnormal structure

Hair

Phenotypic characteristics

Microdontia; hypodontia; widely spaced; enamel hypoplasia; taurodontism

Teeth Normal

Sweat glands Skin: dimples over elbows and knees; bilateral hallucal creases; single flexion crease on each toe; bilateral single palmar creases Skeletal: rhizomelic shortness (greatest in upper limbs); disproportionate shortness of the fibulae; pronounced shortness of middle and distal phalanges of toes and fingers; cutaneous syndactyly; clinodactyly; increased space between first and second toes; hallux valgus; dolichocephaly; generalized osteoporosis; highly arched palate; sagittal suture synostosis; short and narrow thorax; pectus excavatum Other: hyperopia; myopia; nystagmus; frontal bossing; epicanthal folds and anti-mongoloid slant; full cheeks; posteriorly angulated pinnae with hypoplastic antihelix; hypotelorism; broad nasal bridge; anteverted anres; everted lower lip; capillary naevus on the forehead; multiple oral frenula; congenital heart defects

Other

Genetic basis (if known)

127.16 Chapter 127

214350

124480

220500

125595

Curly hair– ankyloblepharon–nail dysplasia syndrome (CHANDS)

Deafness and onychodystrophy (Robinson syndrome)

Deafness and onychodystrophy (DOOR syndrome)

Dermatopathia pigmentosa reticularis (allelic with Naegeli– Franceschetti– Jadassohn syndrome) AD

AR

AD

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Onychodystrophy

Hypoplastic and dystrophic finger- and toenails; anonychia

Absent, hypoplastic, fissured and dystrophic finger- and toenails

Hypoplastic finger- and toenails

Nails

Hypoplastic and discoloured; irregular placement

Normal

Alopecia, wiry hair No dental anomalies

Coniform; hypodontia; delayed primary and secondary dentition

Normal

Teeth

Normal

Curly

Hair

Phenotypic characteristics

Hypohidrosis or hyperhidrosis

Normal

Normal

Normal

Sweat glands

Skin: reticulate hyperpigmentation that persists throughout life (unlike NFJS); adermatoglyhpia; palmoplantar hyperkeratosis; punctate hyperkeratosis of palms and soles. Rarely digital fibromatous thickening, acral non-scarring blisters

Skin: dermatoglyphic abnormalities (arched pattern) Other: congenital sensorineural deafness; apparently low-set ears; seizures and mental retardation; triphalangy of both thumbs and halluces; hypoplasia or aplasia of terminal phalanges of fingers and toes; occasional clinodactyly and camptodactyly; ↑ 2 oxo-gutarate associated with severe phenotype

Other: syndactyly of toes; severe sensorineural hearing loss (high frequency)

Eyes: fused eyelids at birth (ankyloblepharon) Other: bilateral lip pits (at commisures of mouth), inferiorly attached frenulum, inguinal hernia

Other

KRT14

(Continued)

Genetic basis (if known)

Ectodermal Dysplasias 127.17

125640

Freire-Maia and Pinheiro [5]

Dermo-odonto-dysplasia

Dermotrichic syndrome ?related to IFAP syndrome (308205) (see below) XR

AD

Inheritance MIM number/ primary ref

Name (alternative names)

Table 127.1 Continued

Dystrophic and hyperconvex fingernails

Dysplastic; brittle

Nails

Generalized atrichia from birth

Dry; slow-growing (scalp, moustache and beard); circumscribed area of alopecia; normal eyebrows and lashes; sparse axillary and pubic hair

Hair

Phenotypic characteristics

Normal

Hypodontia; microdontia; persistence of deciduous teeth

Teeth

Hypohidrosis without hyperthermia

Normal

Sweat glands

Skin: general ichthyosiform lesions, including palmoplantar area and scalp Face: prominent forehead; large ears; small nose with mildly low nasal bridge; blepharophimosis Other: severe psychomotor retardation; abnormal EEG; frequent apyretic seizures; short stature; hemivertebrae at the dorsolumbar region; congenital aganglionic megacolon; narrow arched palate; positive Benedict and glucose oxidase tests; discrete increase in tyrosinaemia; discrete anaemia; no ocular/ respiratory disorders as in IFAP

Skin: dry and thin to variable degree (especially on palmoplantar regions); simian crease Face: left palpebral ptosis; prognathic mandible

Other

Genetic basis (if known)

127.18 Chapter 127

223370

305000

Dubowitz syndrome

Dyskeratosis congenita, X-linked (Zinsser–Cole– Engman syndrome) XR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Dystrophy with late-onset paronychia occasionally leading to anonychia; hypoplasia

Normal

Nails

Hypotrichosis; loss of cilia owing to blepharitis and ectropion; absence of eyebrows and lashes; premature cavities

Sparse scalp hair, sparse lateral eyebrows

Hair

Phenotypic characteristics

Generalized hyperhidrosis

Normal

Delayed eruption; caries

Poorly aligned; early carious degeneration

Sweat glands

Teeth

Skin: hyper- and hypomelanosis, telangiectatic erythema; ulcers; dry desquamation; atrophy; hyperkeratotic plaques (palmoplantar and over joints); premalignant lesions; absent fingerprints; malignant leucoplakia on lips, mouth, anus, urethra and conjunctiva

Skin: eczema Face: elongation of face with age; shallow supraorbital ridge; facial asymmetry; micrognathia; high, sloping forehead; prominent ears; short palpebral fissures; ptosis; blepharophimosis; microphthalmia; broad nasal tip; high-arched palate; submucous cleft palate; velopharyngeal insufficiency Other: growth retardation; short stature; pilonidal dimples; spina bfida occulta; microcephaly; mild mental retardation with behaviour problems; high-pitched, hoarse voice; recurrent infections; hypogammaglobulinaemia; IgA deficiency; neoplasia including aplastic anaemia; acute lymphatic leukaemia, lymphoma and neuroblastoma; hypospadias; cryptorchidism; low cholesterol

Other

(Continued)

DKC1 (component of the telomerase ribonucleoprotein, associated with TERC )

Genetic basis (if known)

Ectodermal Dysplasias 127.19

127550

Dyskeratosis congenita, autosomal dominant (Scoggins type) AD

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Dystrophic

Nails

Hypotrichosis

Hair

Phenotypic characteristics

Carious

Teeth

Normal

Sweat glands

Skin: hyper- and hypomelanosis; telangiectatic erythema; ulcers; dry desquamation; atrophy; hyperkeratotic plaques (palmoplantar and over joints); premalignant lesions; absence of fingerprints; premalignant leucoplakia on lips, mouth, anus, urethra and conjunctiva Eyes: blepharitis; ectropion of the lower lids;obliteration of the puncta lacrimalia; bullous conjunctivitis; continuous lacrimation

Eyes: blepharitis; ectropion of the lower lids; obliteration of the puncta lacrimalia; bullous conjunctivitis; continuous lacrimation Other: sharp facial features; occasional mental and growth retardation; Fanconi-like pancytopenia; frail skeletal structure; oesophageal dysfunction and/or diverticulum; atrophic lingual papillae; gingivitis; testicular atrophy

Other

TERC telomerase TERT (telomerase reverse transciptase) TINF2 (TRF-1 interacting nuclear factor 2) negative regulator of telomerase length

Genetic basis (if known)

127.20 Chapter 127

224230

Wallace [10] NK

Dyskeratosis congenita (autosomal recessive)

Ectodermal defect with skeletal abnormalities

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Finger- and toenails poorly developed and foreshortened

Dystrophic, hypoplastic

Nails

Scalp hair is slightly coarse; very sparse axillary hair

Hypotrichosis, sparse hair and eyelashes

Hair

Phenotypic characteristics

Hypodontia; hypoplastic teeth

Carious

Teeth

Normal

Normal

Sweat glands

Skin: thin, fine and dry; fine, light, granular pigmentation; translucent appearance; rudimentary nipples Face: striking appearance; central portion is relatively underdeveloped; the cheeks, upper jaw and nose are sunken with the ‘inverted, dish-shaped deformity’ and somewhat prominent eyes Other: low intelligence; short metacarpals; some absorption of the terminal tufts of the distal phalanges; flexion anomalies of hands and feet; absence of breasts; narrow and highly arched palate

Skin: hyper- and hypomelanosis; periorbital telangiectatic erythema; ulcers; dry desquamation Other: pancytopenia; thrombocytopenia; small platelets; T-cell abnormalities; dystrophic fingers and toes

Other: pulmonary fibrosis, hepatic fibrosis, ataxia; sharp facial features; occasional mental and growth retardation; Fanconi-like pancytopenia; frail skeletal structure; osteoporosis; genital anomalies; oesophageal dysfunction and/or diverticulum; atrophic lingual papillae; gingivitis

Other

(Continued)

NOLA2 (aka NHP2); RNA binding protein, associates with NOLA3, dyskerin, GAR1, RNPs, and telomerase NOLA3 (aka NOP10); associates with NOLA2, dyskerin, GAR1, RNPs and telomerase

Genetic basis (if known)

Ectodermal Dysplasias 127.21

224800

601345

Wesser and Vistnes [11]

Kirman [12]

Ectodermal dysplasia and neurosensory deafness (Mikaelian syndrome)

Ectodermal dysplasia with natal teeth (Turnpenny type)

Ectodermal dysplasia with palatal paralysis

Ectodermal dysplasia with severe mental retardation NK

NK

AD

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Teeth

Oligodontia by late adolescence

Normal

Absence of frontal Stunted and hair, eyebrows peg-shaped; and lashes enamel hypoplasia

Thin scalp hair; scanty body hair

Coarse and brittle; Caries hypotrichosis of scalp

Hair

Almost absent from Absent scalp fingers and toes (except for a small wisp in the centre of the head) and body hair

No data

Normal

Normal

Nails

Phenotypic characteristics

Skin: fine, thin and shiny with some desquamation over the hands, feet and the top of the head; absence of both nipples Other: blindness with bilateral cataract; abnormal ears; severe mental retardation; absence of menstruation; prepubertal vulva

Skin: absence of sebaceous glands on the face Other: conductive loss; otitis; frontal bossing; depressed nasal bridge; highly arched palate; palatal paralysis; diminished sensation in the palate, posterior pharyngeal wall and tonsillar pillar area; abnormal and distorted speech with a marked nasal component

Anhidrosis on face (absent sweat glands)

Hypohidrosis without hyperthermia

Skin: flexural acanthosis nigricans

Skin: hyperkeratotic; increased melanin in the basal layer Other: bilateral sensorineural loss; coarse facial features; arachnodactyly; contracture of fifth fingers; kyphoscoliosis

Other

Variable heat tolerance; no anhidrosis

Normal

Sweat glands

Genetic basis (if known)

127.22 Chapter 127

600906

Wiedemann [13]

129550

129540

Ectodermal dysplasia with mental retardation and syndactyly

Ectodermal dysplasia with syndactyly

Ectodermal dysplasia with adrenal cyst (odonto-onychohypohidrotic dysplasia with midline scalp defect)

Ectodermal dysplasia with distinctive facies and preaxial polydactyly

Rounded nails

Dystrophic fingernails

AD

AD

Yellowish and partially thickened

Severe onychogryposis

Nails No data

Teeth

Delayed eruption; diastemata; minor shape alterations

Scalp alopecia; Thin enamel; body alopecia; dental caries sparse eyebrows; sparse eyelashes

Alopecia cutis verticis

Hypotrichosis; Severe crown brittle scalp hypoplasia; hair; pili torti; delayed and sparse eyebrows atypical and lashes eruption of permanent teeth

Short, abundant and stiff, sparse eyebrows

Hair

Phenotypic characteristics

AR

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Normal

Hypohidrosis

Normal

Mild hypohidrosis

Sweat glands

Other: micrognathia; flat philtrum; malar hypoplasia; dystopia canthorum; flat nasal bridge; thin upper lip; thickened frenulum; fifth finger clinodactyly; preaxial polydactyly; duplicated halluces; duplicated first metatarsals; language delay

Skin: midline scalp defect (aplasia cutis vertices); hypoplastic areolae and nipples Other: breast hypoplasia (inability to lactate); hypertension of undetermined pathogenesis; large adrenal cyst

Skin: dry with hyperkeratosis, especially at the distal third of the trunk, lower limbs and palmoplantar regions (axillae and elbow are normal); transverse crease on both palms Other: mild crowding of the lenses; discrete hypermetropia; syndactyly on both fingers and toes to variable degrees; lordosis; highly arched palate

Skin: dry; large scalp defect Other: syndactyly involving the third and fourth fingers and the second and third toes; mild mental retardation; a peculiar face with large palpebral fissures, broad nasal bridge and constantly open mouth; abnormally modelled ears

Other

(Continued)

Genetic basis (if known)

Ectodermal Dysplasias 127.23

225280

602032

604292

Ectodermal dysplasia with ectrodactyly and macular dystrophy (EEM syndrome)

Ectodermal dysplasia, pure hair and nail type

Ectrodactyly–ectodermal dysplasia-cleft lip/ palate syndrome (EEC3) AD

AD AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Anodontia; hypodontia; microdontia; enamel hypoplasia; poorly formed; peg-shaped incisors

Hypotrichosis of Dysplastic, thin, scalp and body; pitted, brittle and fair and dry; striated scanty or absent eyebrows and lashes

Normal

Teeth

Normal

Hypotrichosis or normal

Hair

Congenital Brittle hair; onychodystrophy; temporal micronychia; hypotrichosis onycholysis; onychorrhexis

Dysplastic

Nails

Phenotypic characteristics

Occasional hypohidrosis without hypothermia

Normal

Dental anomalies, small wide- spaced teeth

Sweat glands

Skin: dry, translucent, palmoplantar hyperkeratosis; eczematous patches; pigmented naevi Face: cleft lip; broad nose; defective auricles; pointed chin; malar hypoplasia Other: conductive hearing loss; tear duct anomaly or malfunction; speckled iris; photophobia; strabismus; blepharitis; clouding of the cornea; congenital adhesions between the eyelids; ectrodactyly; syndactyly; clinodactyly; cleft palate; renal abnormalities; rhinitis; respiratory infections; genital anomalies

Skin: folliculitis decaIvans of neck

Other: ectrodactyly; syndactyly; cleft hand; macular dystrophy

Other

TP63 (transcription factor)

KRT85 (aka KRTHB5 – hair basic keratin 5)

CDH3 (adhesion molecule)

Genetic basis (if known)

127.24 Chapter 127

129900

129810

Ectrodactyly–ectodermal dysplasia-cleft lip/ palate (EEC1) syndrome

Ectrodactyly and ectodermal dysplasia without cleft lip/palate (EEC without cleft lip/ palate) AD

AD

MIM Inheritance number/ primary ref

Name (alternative names) Hair

Normal

Hypotrichosis

Dysplastic, thin, Sparse, brittle hair pitted, brittle and striated

Nails

Phenotypic characteristics

Abnormal dentition

Anodontia

Teeth

Normal

Hypohidrosis uncommon

Sweat glands

Other: no clefting of the lip or palate, as seen in classic EEC syndrome; ectrodactyly ranges from almost normal presentation to tetramelic clefting of hands and feet (Continued)

Skin: dry, translucent, 7q11.2-121.3 palmoplantar hyperkeratosis; eczematous patches; pigmented naevi Face: cleft lip and/or palate; low-set, posteriorly rotated ears; lacrimal duct anomalies very common (atresia, non-canalization, hypoplasia, small punctum, dysfunction), leading to secondary keratitis Other: genitourinary abnromalities; large omphalocoele; anal atresia frequent; conductive hearing loss; distal limb defects (ectodactyly, polydactyly, syndactyly, tetramelic cleft hand and foot); recurrent uper respiratory, urogenital and eye infections, secondary to structural anomalies; growth hormone deficiency secondary to hypothalamic defect

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.25

225500

Fischer [14]

Ellis–van Creveld syndrome (chondroectodermal dysplasia, mesoectodermal dysplasia) (see entry for Weyer acrofacial dysostosis below)

Fischer syndrome (Fischer–Volavsek syndrome) AD

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Onychogryposis; onycholysis

Dysplastic (brittle, furrowed and underdeveloped)

Nails

Teeth

Sparse scalp hair, eyebrows and lashes

Normal

Thin, brittle and Natal teeth; hypochromic; precocious absent or exfoliation; scanty eyebrows hypodontia; and lashes occasional hypoplastic enamel

Hair

Phenotypic characteristics

Palmoplantar hyperhidrosis

Normal

Sweat glands

Skin: occasional xeroderma; palmoplantar keratosis Other: eyelid oedema; occasional mental deficiency; clubbing of distal phalanges of the fingers and toes; syringomyelia; apathy

Skin: eczema; petechiae are EVC; EVC2 (not fully described in different elucidated, patterns putative Other: occasional strabismus; transcription cataract; coloboma of the factors) iris; microphthalmia; exophthalmia; short-limbed dwarfism; bilateral postaxial polydactyly (generally of the hands); brachymetacarpy; thick and short bones of limbs; fusion of the hamate and capitate; club-foot; genu valga; syndactyly; occasionally mild mental retardation; congenital heart disease; respiratory difficulties; gingivolabial fusion; cleft palate; epispadias; hypospadias; hypoplastic genitalia Face: broad nose; occasional cleft lip; frontal bossing and hypertelorism

Other

Genetic basis (if known)

127.26 Chapter 127

305600

Focal dermal hypoplasia syndrome (Goltz syndrome; Goltz– Gorlin syndrome) XD

MIM Inheritance number/ primary ref

Name (alternative names)

Thin, spooned, narrow, grooved hypopigmented or absent

Nails Hypotrichosis

Hair

Phenotypic characteristics

Hypodontia; microdontia; enamel hypoplasia; delayed eruption; irregular placement; dental pitting

Teeth Hypohidrosis or hyperhidrosis

Sweat glands

(Continued)

Skin: absence of skin from PORCN various parts at birth; areas (endoplasmic of underdevelopment or reticulum thinness; linear hypo- or transmembrane hyperpigmentation; protein, involved telangiectasia; herniation in development of subcutaneous fat; via wnt pathway) multiple papillomas of mucous membranes of periorificial skin; follicular hyperkeratotic papules; angiofibromatous nodules around lips, vulva and anus; palmoplantar hyperkeratosis; occasional dermatoglyphic changes Eyes: colobomas; microphthalmia; irregularity of pupils; clouding of cornea or vitreous; blue sclerae; ectopia lentis Face: lip papillomas; malformed auricles; asymmetry and notching of the alae nasi; pointed chin; triangular face; hypertelorism Other: osteopathia striata; occasional hearing loss; mental retardation; short stature; syndactyly; polydactyly; hypoplasia of the external genitalia; umbilical and/or inguinal hernia; vertebral anomalies (scoliosis, spina bifida, etc.); highly arched palate; gum papillomas; small breasts

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.27

136500

227260

Fried [15]

Focal facial dermal dysplasia, type I (FFDD type I, hereditary symmetrical aplastic naevi of temples, bitemporal aplasia cutis, Brauer syndrome) ? same as FFDD type II

Facial dermal dysplasia, type II (FFDD type II, bitemporal forceps marks syndrome, Setleis syndrome) ? same as FFDD type I

Fried tooth and nail syndrome (?same as Witkop syndrome 189500; see below) AR

?AR

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Small, thin and slightly concave

Normal

Normal

Nails

Normal

Hypodontia; Fine and short; peg-shaped scanty eyebrows teeth

Localized hypohidrosis (scarce to absence sweat glands in the focal lesions)

Sweat glands

Localized hypohidrosis (scarce to absent sweat glands in the focal lesions)

Normal

Teeth

Alopecia areata; Normal some have unruly scalp hair; generally sparse eyebrows and lashes or multiple rows of lashes on upper lids; normal to absent lashes on lower lids; upward slanting eyebrows

Alopecia areata; generally sparse eyebrows and lashes or multiple rows of lashes on upper lids; normal to absent lashes on lower lids

Hair

Phenotypic characteristics

Face: prominent lips and chin Other: branchial cyst on the left side of the neck

Skin: round, focal temporal lesions that have a smooth or wrinkled surface and may be hypo- or hyperpigmented; occasional multiple vertical linear depressions on the lower forehead; absence of sebaceous glands in the temporal lesions Eyes: chronic bilateral blepharitis in a few cases Face: leonine appearance; wrinkles periorbitally; wide nasal bridge; fleshy nose with the tip bent down; bilateral epicanthic folds; developmental delay

Skin: round, focal temporal lesions that have a smooth or wrinkled surface and may be hyperpigmented (usually bitemporal, can be unilateral); occasional multiple vertical linear depressions on the lower forehead; absence of sebaceous glands in the temporal lesions

Other

Genetic basis (if known)

127.28 Chapter 127

Gorlin–Chaudhry–Moss syndrome (craniofacial dysostosis, hypertrichosis, hypoplasia of labia majora; dental and eye anomalies, patent ductus arteriosus, normal intelligence)

233500

Gingival fibromatosis– Jorgenson sparse hair–malposition [16] of teeth

135400

Gingival fibromatosis and hypertrichosis (hypertrichosis terminalis, generalized, with or without gingival hyperplasia)

AR?

AR

AD

MIM Inheritance number/ primary ref

Name (alternative names)

No data

No data

Normal

Nails Widely spaced, dentition may be obscured by gingival fibromatosis

Teeth Normal

Sweat glands

Hypertrichosis, coarse hair, low frontal hairline

Hypodontia; microdontia; some pulp chambers small or missing

Normal

Excessively thick in Malpositioned and No data childhood; malformed; begins to thin serrated incisors out during early teens; sparse later

Generalized hypertrichosis; black and coarse (terminal hairs)

Hair

Phenotypic characteristics

Face: characteristic with ‘dished out’ appearance of middle face; ectropion of lower lid; anti-mongoloid slant; short stature Other: mild bilateral conductive hearing loss; hyperopia; microphthalmia; horizontal nystagmus; corneal ulcers; defective eyelid development; craniofacial dysostosis; patent ductus arteriosus; hypoplasia of labia majora; highly arched palate; mild umbilical hernia; short distal phalanges of fingers and toes

Face: coarse appearance; protruding lips (secondary to gingival fibromatosis); prognathic mandible; broad and flat nasal alae Other: alternating strabismus; rotating nystagmus; myopia; abnormal EEG; low IQ; large hands; broad and relatively short feet; highly arched palate

Skin: occasional pigmented naevi and hyperelasticity Other: occasional large ears, peculiar nose and coarse features; mental retardation; epilepsy; gingival fibromatosis; occasional hypoplastic breasts

Other

(Continued)

Microdeletions in 17q24.2-q24.3

Genetic basis (if known)

Ectodermal Dysplasias 127.29

230740

245010

Growth retardation– alopecia–pseudoanodontia–optic atrophy (GAPO)

Haim–Munk syndrome (kerataosis palmoplantaris with periodontopathia and onychogryphosis, Cochin Jewish disorder) (allelic with Papillon– Lefèvre syndrome) AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Generalized atrichia

Normal

Onychogryphosis

Hair

Hyperconvexity on fingers and toes in two patients

Nails

Phenotypic characteristics

Severe periodontitis with onset at young age, loss of teeth

Failure of eruption (pseudoanodontia) of both primary and permanent dentition with absence of alveolar ridges

Teeth Normal

Sweat glands

Skin; palmoplantar keratoderma Other: arachnodactyly; acro-osteolysis

Skin: dry; fragile with inadequate wound healing (small, depressed scars); depigmented areas; unusual wrinkles; leather-like and thick on nape and upper back; abnormal dermatoglyphics Face: ‘small’ and ‘characteristic’; asymmetrical; craniofacial dysostosis; micrognathia; protruding and thickened lips; protruding auricles; prominent supraorbital ridges; depressed nasal bridge; minor auricular malformations Other: sensorineural hypoacusia; optic atrophy; glaucoma; keratoconus; nystagmus; photophobia; dwarfism; occasional mental retardation; hypoplasia of mammary glands; pectus excavatum; umbilical hernia; delayed bone maturation through childhood and adolescence; respiratory infection

Other

CTSC, encodes cathepsin C enzyme

Genetic basis (if known)

127.30 Chapter 127

234100

Hallerman–Streiff syndrome (Francois dyscephalic syndrome)

Nails Thin and light; generalized or sutural alopecia of scalp

Hair

Phenotypic characteristics

AR Normal Heterogeneity?

MIM Inheritance number/ primary ref

Name (alternative names)

Natal; supernumerary; hypodontia; deciduous; premature caries; coniform teeth; hypoplastic enamel

Teeth Normal

Sweat glands Skin: cutaneous atrophy largely limited to the face and/or scalp; telangiectases; xerosis Face: characteristically bird-like; the head has an abnormal shape, usually brachycephalic or scaphocephaly with frontal and parietal bossing; micrognathia; microstomia with thin lips; apparently low-set ears; ‘double chin’; beaked nose Other: bilateral microphthalmia; congenital cataract; congenital corectopia; occasional nystagmus; strabismus; blue sclerae; optic disc coloboma; various chorioretinal pigment alterations; occasional syndactyly; winging of the scapulae; proportionate short stature; intelligence ranges from normal to mental retardation; narrow and highly arched palate; delayed ossification of craniofacial sutures; microcephaly; cardiac defects; hypogenitalism; cryptorchidism; vertebral anomalies; funnel chest

Other

(Continued)

GJA1 (encodes connexin 43, a gap junction protein)

Genetic basis (if known)

Ectodermal Dysplasias 127.31

Freire-Maia and Pinheiro [5]

158310

Hayden syndrome

Hereditary mucoepithelial dysplasia

AD

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Chronic monilial nail infection

Severe pachyonychia (hands and feet)

Nails

Non-scarring alopecia

No scalp hair, eyebrows or lashes; virtually no body hair

Hair

Phenotypic characteristics

Gingival inflammation

Normal

Teeth

Normal

Severe hypohidrosis

Sweat glands

Skin: flat red periorificial mucosal lesions; follicular keratosis Other: photophobia; nystagmus; keratoconjunctivitis; keratitis; pannus; cataracts; repeated pneumonia; fibrocystic lung disease; cor pulmonale; mucocutaneous candidiasis; diarrhoea in infancy; T- and B-cell abnormalities; abnormal Papanicolau smears; vulvovaginal erythema

Skin: follicular and plaque-like hyperkeratosis; ichthyosis-like hyperkeratosis on the shins; extremely severe palmoplantar hyperkeratosis to the point of almost complete stiffness of the fingers and toes; severe chronic scalp infection with many pustules Other: chronic external otitis leading to virtual deafness; severe chronic conjunctivitis leading to virtual blindness; saddle nose; narrow palpebral fissures

Other

Genetic basis (if known)

127.32 Chapter 127

129500

601375

Freire-Maia and Pinheiro [5]

Hidrotic ectodermal dysplasia (Clouston syndrome, ED2)

Hidrotic ectodermal dysplasia, Christianson–Fourie type

Hypertrichosis and dental defects

Dystrophic thickened nails; unattached distal half of nails

Normal

AD

Variable degrees of dystrophy; thickened and slightly discoloured; paronychia

Nails

Generalized hypertrichosis (except on palms, soles and mucous membranes)

Short, thin, sparse, pale scalp hair; absent eyebrows; short, sparse eyelashes; sparse axillary and pubic hair

Dry, fine, usually blond, slow-growing; ranging from hypotrichosis to complete alopecia; absent/scanty eyebrows and lashes

Hair

Phenotypic characteristics

AD

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Occasional persistence of deciduous teeth, delayed eruption, hypodontia, anodontia

Normal

Occasional hypodontia, anodontia, widely spaced; natal teeth; caries

Teeth

Normal

Normal

Normal

Sweat glands

Other: episodic supraventricular tachycardia; bradycardia; skin normal

(Continued)

Skin: dry and rough; GJB6 (encodes tendency towards scaliness; connexin 30, a hyperpigmentation of component of some areas; thick gap junctions) dyskeratotic palms and soles Other: occasional strabismus, cataract and myopia; occasional mental deficiency and short stature; speech difficulties; tufting of terminal phalanges; clubbing of fingers; thickening of skull bones

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.33

305100

Hypohidrotic ectodermal dysplasia-X-linked (ED1;Christ–Siemens– Tourraine (CST) syndrome) (see Lelis syndrome 608290 below) XR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Hair

Teeth

Generally normal; Fine and dry; Hypodontia; sometimes hypochromic; peg-shaped dystrophic or hypotrichosis of incisors and/or absent at birth scalp and body; canines; and/or fragile absent or persistence of and brittle with scanty eyebrows deciduous incomplete and lashes; teeth; delayed development and moustache and eruption; celonychia beard generally occasional normal anodontia

Nails

Phenotypic characteristics

Hypohidrosis with or without hyperthermia; absent or decreased number of epidermal ridge sweat pores

Sweat glands

Skin: thin, smooth and dry EDA (encodes owing to hypoplastic or ectodysplasin, absent sebaceous glands; a TNF-like occasional pigmentation intercellular and dermatoglyphic signalling changes; absent or molecule) supernumerary nipples and areolae Face: highly characteristic in persons who are severely affected (generally males) with thick and prominent lips, depressed nasal bridge (saddle nose), frontal bossing, hypoplasia of the maxilla, wrinkles beneath the eyes, or around the eyes, nose and mouth, and minor alterations of the auricles; the periorbital region is often more darkly pigmented than the rest of the body Other: occasional conductive hearing loss; photophobia; decreased function of the lacrimal glands; aplasia or hypoplasia of the lacrimal ducts; atrophic rhinitis; otitis media; decreased sense of taste and/or smell; atrophied mucous glands of the upper respiratory tract; respiratory difficulties; chronic pharyngitis and laryngitis; aplasia or hypoplasia of the mammary glands

Other

Genetic basis (if known)

127.34 Chapter 127

AR

XD

129490

224900

300291

Hypohidrotic ectodermal dysplasia–autosomal dominant (EDA3) Includes Jorgenson syndrome

Hypohidrotic ectodermal dysplasia (autosomal recessive)

HED with immune deficiency

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Generally normal; sometimes hypoplastic

Generally normal; sometimes hypoplastic

Generally normal; sometimes hypoplastic

Nails

Teeth

Sparse, fuzzy, Hypodontia; lightly anodontia; pigmented conical teeth scalp hair; absent or scanty eyebrows, lashes and body hair

Sparse, fuzzy, Hypodontia; lightly anodontia; pigmented conical teeth scalp hair; absent or scanty eyebrows, lashes and body hair

Sparse, fuzzy, Hypodontia; lightly anodontia; pigmented conical teeth; scalp hair; delayed absent or eruption of scanty teeth eyebrows, lashes and body hair

Hair

Phenotypic characteristics

Hypohidrosis with hyperthermia

Hypohidrosis with hyperthermia; hypoplastic eccrine sweat glands

Hypohidrosis with hyperthermia

Sweat glands

Other: milder ectodermal dysplasia features than classic HED; failure to thrive; recurrent infections of digestive tract; recurrent respiratory infections; dysgammaglobulinaemia; high morbidity/mortality

Skin: smooth, thin, dry and hypoplastic; hyperpigmentation; rarely palmoplantar keratoderma Other: photophobia; periorbital wrinkling; hypoplasia of lacrimal ducts; decreased function of the lacrimal glands; saddle nose; thick and protruding lips; frontal bossing and prominent auricles; chronic rhinitis; frequent respiratory infections; absence of breasts

Skin: smooth, thin, dry and hypoplastic; can be eczematous Other: photophobia; hypoplasia of lacrimal ducts; decreased function of the lacrimal glands; saddle nose; thick and protruding lips; frontal bossing and prominent auricles; chronic rhinitis, frequent respiratory infections

Other

(Continued)

IKBKG (IKKγ gene, aka NEMO) required for activation of NF-κB

EDAR (ectodysplasin A receptor gene), also EDARADD, an adapter protein for EDAR

EDAR (ectodysplasin A receptor gene) encodes EDAR, a receptor for EDA gene product; also EDARADD, an adapter protein for EDAR

Genetic basis (if known)

Ectodermal Dysplasias 127.35

300301

125050

225050

HED with immune deficiency, osteopetrosis and lymphoedema

HED with deafness

Hypohidrotic ectodermal dysplasia with hypothyroidism and ciliary dyskinesia (HEDH syndrome) (possibly a CGS with 225040; see below) (? same as ANOTHER syndrome) NK

AD

XD

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Dystrophic, ridged finger- and toenails with a shrivelled appearance

Generally normal; sometimes hypoplastic

Generally normal; sometimes hypoplastic

Nails

Teeth

Hypohidrosis with hyperthermia

Hypohidrosis with hyperthermia; low number of sweat gland pores in the palms

Scanty and wispy Normal scalp hair with a hard, hay-like consistency; scanty eyebrows and normal lashes

Hypohidrosis with hyperthermia

Sweat glands

Sparse, fuzzy, Hypodontia; lightly anodontia; pigmented conical teeth scalp hair; absent or scanty eyebrows, lashes and body hair

Sparse, fuzzy, Hypodontia; lightly anodontia; pigmented conical teeth scalp hair; absent or scanty eyebrows, lashes and body hair

Hair

Phenotypic characteristics

Skin: poorly developed palmar dermal ridges; mottled brownish skin pigmentation of the trunk during the first months of life; urticaria pigmentosalike skin and mucosal pigmentation Other: lacrimal ducts frequently blocked with resultant bilateral epiphora; frequent conjunctivitis; short stature; structural ciliary abnormalities of the respiratory tract; recurrent and severe upper and lower respiratory infections; severe cow’s milk intolerance in infancy; elevated thyrotropin;

Other: progressive hearing loss

Other: milder ectodermal dysplasia features than classic HED; failure to thrive; recurrent infections of digestive tract; recurrent respiratory infections; dysgammaglobulinaemia; osteopetrosis; generally more severe phenotype than 300291

Other IKBKG (IKKγ gene, aka NEMO) required for activation of NF-κB

Genetic basis (if known)

127.36 Chapter 127

MIM Inheritance number/ primary ref

NK ?CGS

AR

AD

225040

613102

607658

Name (alternative names)

Hypohidrotic ectodermal dysplasia with hypothyroidism and agenesis of the corpus callosum

Hypotrichosis and recurrent skin vesicles

Hypotrichosis–osteolysis– periodontitis– palmoplantar keratoderma syndrome (HOPP syndrome)

Onychogryphosis

Normal

Dystrophic, ridged finger- and toenails with a shrivelled appearance

Nails

Normal

Normal, or microdontia, enamel defect

Teeth

Hypotrichosis; pili Caries and torti et annulati; periodontitis congenital absence of eyebrows and lashes; ↓ hair follicles

Hairs present at birth, with regrowth after ritual shaving postnatally Increased hair loss at age 2–3 months, resulting in sparse and fragile scalp hair, eyebrows, eyelashes, axillary and body hair

Scanty and wispy scalp

Hair

Phenotypic characteristics

Normal

Normal

Hypohidrosis with hyperthermia

Sweat glands

Skin: severe, reticulate palmoplantar keratoderma with pits; nummular or striate palmoplantar keratoderma; acroosteolysis; psoriasis-like skin lesions; Other: lingua plicata, ventricular tachycardia

Skin: vesicles, less than 1 cm in size, on scalp and skin, which burst and heal after 34 months with scarring.

Other: severe mental retardation; agenesis of corpus callosum; primary hypothyroidism; absent normal thyroid and ectopic goitre on technetium-99 thyroid scintigram; respiratory tract and eye infections; hypoplastic maxilla; hypertelorism; protruding tongue

decreased thyroid hormone production from early childhood; 1° hypothyroidism – no evidence of thyroid tissue shown by radiolabelled iodine studies

Other

(Continued)

DSC3, desmocollin 3, a desmosomal structural protein

Genetic basis (if known)

Ectodermal Dysplasias 127.37

146520

Hypotrichosis simplex

Dystrophic in all or most of the fingers and toes in about one-tenth of cases

XL

Incontinentia pigmenti (familial male-lethal type IP, Bloch– Sulzberger syndrome) 308300

XR? Normal Heterogeneity?

Normal

Nails

Scarring alopecia in one-third

Congenital atrichia

Hair usually present at birth, but can have alopecia at birth. Gradual hair loss beginning in 1st decade, complete hair loss by 3rd decade. Facial and body hair normal

Hair

Phenotypic characteristics

Ichthyosis follicularis, 308205 atrichia and photophobia syndrome (IFAP syndrome) (? related to dermotrichicic syndrome; see above)

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Hypodontia; anodontia; peg-shaped; delayed eruption. Both deciduous and permanent teeth are affected

Enamel dysplasia

Normal

Teeth

Normal

Hypohidrosis

Normal

Sweat glands

CDSN, corneodesmosin, a protein involved in terminal differentiation

Skin: vesicular-bullous eruption in the neonatal period followed or accompanied by verrucous lesions and bizarre ‘marble cake’ pigmentation; pigmented macules may be present Other: occasional congenital hearing loss; ophthalmological alterations in about one-fifth of patients include blindness, strabismus, cataract,

IKBKG (IKKγ gene, aka NEMO) required for activation of NF-κB

Skin: ichthyosis follicularis MBTPS2 (impaired Other: photophobia; short cholesterol stature; mental retardation; homeostasis seizures; congenital – inability to cope aganglionic megacolon; with stress) inguinal hernia; vertebral anomalies; renal anomalies; recurrent respiratory infections

No other findings

Other

Genetic basis (if known)

127.38 Chapter 127

243800

Johanson–Blizzard syndrome

AR

MIM Inheritance number/ primary ref

Name (alternative names)

No data

Nails

Sparse, dry and fine or coarse; marked frontal upsweep

Hair

Phenotypic characteristics

Oligodontia of both dentitions; peg-shaped teeth; absent permanent teeth

Teeth

Normal

Sweat glands

(Continued)

Skin: pale and smooth; UBR1 (ubiquitincafé-au-lait spots on lower protein ligase E3 limbs and abdomen; component patches of vitiligo on the N-recognin) lower back and abdomen; involved in midline scalp defects ubiqutin (aplasia cutis congenita); proteolytic tiny nipples with almost no pathway areolae; transverse palmar creases Other: congenital sensorineural deafness; aplasia of the inferior puncta; strabismus; aplastic alae nasi, beak-like appearance to nose; severe mental retardation; occasional akinetic seizures; microcephaly; hypothyroidism; pancreatic dysfunction; imperforate anus; genitourinary defects; failure to thrive/ oedema; malabsorption; epiphyseal dysgenesis; dialated cardiomyopathy; nasolacrimocutaneous fistulae; highly arched palate; delayed bone age; hyperextensibility

uveitis, retrolental fibroplasias, optic nerve atrophy, microphthalmia; occasional club-foot, cleft palate, microcephaly; about one-third of the cases present severe CNS anomalies: spastic tetraplegia, hemiplegia, diplegia; epilepsy; mental retardation; occasional short stature

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.39

607654

Keratosis palmoplantaris striata III (PPKS3)

Normal

Normal

AD

612908

Keratosis palmoplantaris striata II (PPKS2)

AD

Normal

AD

148700

Keratosis palmoplantaris striata I (PPKS1)

Absence at birth; delayed development; leuconychia and thickening (most marked in the fingernails); destructive dystrophy

Nails

Normal

Normal

Normal

Hair loss varies from alopecia to fine, thin scalp hair; scanty or absent eyebrows and lashes; occasional trichorrhexis nodosa in some scalp hairs

Hair

Phenotypic characteristics

AD

MIM Inheritance number/ primary ref

Keratitis, ichthyosis and 148210 deafness (KID) syndrome, incorporates hystrix-like ichthyosis with deafness (HID) syndrome 602540

Name (alternative names)

Table 127.1 Continued

Normal

Normal

Normal

Delayed eruption of deciduous teeth; brittleness; tendency to develop caries; unspecified defects

Teeth

Normal

Normal

Normal

Hypohydrosis (with hypothermia)

Sweat glands

Skin: linear palmoplantar keratoderma of the palms, may be more diffuse on the soles

Skin: linear palmoplantar keratoderma of the palms, may be more diffuse on the soles

Skin: linear palmoplantar keratoderma of the palms, may be more diffuse on the soles

Skin: ichthyosiform erythroderma with sebaceous dysfunction; furrowing around mouth and chin; erythematous hyperkeratotic plaques on elbows, knees and dorsa of hands and feet; marked thickening (leather-like consistency) of palms and soles; increased susceptibility to squamous cell carcinoma Other: congenital sensorineural deafness; vascularization of the cornea with pannus formation resulting in loss of vision; keratitis; occasional decreased tear production; photophobia; bilateral flexion contractures at knees and elbows with tight heel cords

Other

KRT1 (keratin 1), intermediate filament

DSP (desmoplakin), desmsomal protein

DSG1 (desmoglein 1, desmosomal cadherin protein

GJB2 (encodes connexin 26, a gap junction protein)

Genetic basis (if known)

127.40 Chapter 127

221810

608290

603543

Kirghizian dermato-osteolysis

Lelis syndrome (hypohidrotic ectodermal dysplasia with acanthosis nigricans) (? manifestation of X-linked HED 305100, see above)

Limb–mammary syndrome (allelic with EEC3, ADULT syndrome, AEC, Rapp–Hodgkin syndrome, split hand-foot malformation 4) AD

AR?

AR?

MIM Inheritance number/ primary ref

Name (alternative names)

Nail dysplasia

Short and dystrophic

Some dystrophic fingernails

Nails

Normal

Generalized hypotrichosis; scalp hair is dry, fine, lustreless and slow growing; also scanty axillary, pubic hair; moustache/ beard; eyebrows and lashes

Normal

Hair

Phenotypic characteristics

Variable degrees of hypodontia

Hypoplastic and carious

Hypodontia; abnormally shaped

Teeth

Hypohidrosis

Other: hypoplasia/aplasia of the mammary glands; cleft lip/palate +/− bifid uvula; lacrimal duct atresia; absence of uterus/ovaries

Skin: dry; palmoplantar hyperkeratosis; hyperpigmented and hyperkeratotic skin with wrinkles, papillomas and a symptomatic acanthosis nigricans in the neck, axillae and genitofemoral regions; increased cornification and presence of follicular plugs on the ‘normal’ skin; unusual wrinkles around lips Other: plicate tongue with papillomatosis

Skin: multiple ulcerations on face, trunk and limbs, with healing of the more superficial ones and fistulous cicatrization of the deeper ones Other: recurrent keratitis with corneal scarring leading to visual impairment; acromegaloid enlargement of hands and feet; arthralgia; osteolysis around joints; claw hands; enlarged and deformed joints; short fingers; flexion contractures in some fingers

Normal

Hypohidrosis, small number of sweat glands (detected by biopsy)

Other

Sweat glands

(Continued)

TP63 (transcription factor)

EDA (encodes ectodysplasin, a TNF-like intercellular signalling molecule)

Genetic basis (if known)

Ectodermal Dysplasias 127.41

607903

604379

Localized autosomal recessive hypotrichosis, type 1 (LAH1)

Localized autosomal recessive hypotrichosis, type 2 (LAH2) (hypotrichosis, Mari type) AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Normal

Nails

Congenital hypotrichosis of scalp; any hairs present wiry and twisted; sparse or absent eyebrows and eyelashes. Pubic and axillary hair affected, little body hair. In men, beard hair may be normal

Hypotrichosis, localized to scalp, chest, arms and legs; facial hair may be spared; eyebrows and eyelashes may be thinned, axillary and pubic hair usually normal Thin atrophic hair shafts that are unable to penetrate through the skin surface; swelling within the base of the hair shaft at precortical region

Hair

Phenotypic characteristics

Normal

Normal

Teeth

Normal

Normal

Sweat glands

Skin: follicular hyperkeratosis in two cases, possibly unrelated to alopecia

Skin: small papules on scalp may be seen due to ingrown hairs

Other

LIPH (lipase, ?involved in cell proliferation)

DSG4 (desmoglein-4, structural protein of desmosomes)

Genetic basis (if known)

127.42 Chapter 127

AR

AD

611452

225060

Localized autosomal recessive hypotrichosis, type 3 (LAH3) (allelic with autosomal recessive woolly hair, 278150; see below)

Margarita Island ED (allelic to cleft lip/ palate–ectodermal dysplasia syndrome (CLEPD1))

Marshall syndrome (allelic 154780 to Stickler syndrome (108300), but no ectodermal dysplasia in Stickler syndrome)

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Normal

Dysplastic

Normal

Nails Normal

Teeth

Sparse scalp hair and eyelashes in some families

Normal

Normal

Sweat glands

Occasional Occasional mild hypodontia, hypohidrosis microdontia, abnormalities of eruption and malposition

Sparse, short scalp Hypodontia, hair; sparse especially upper eyebrows lateral incisors

Diffuse and progressive hair loss, beginning in childhood; sparse or absent scalp hair; sparse eyebrows and lashes, axillary and body hair. In men beard hair may be normal

Hair

Phenotypic characteristics

PVRL1 (encodes nectin, a cell adhesion molecule)

P2RY5 (purinergic receptor P2Y, G protein-coupled), receptor activation causes calcium release and downstream signalling

(Continued)

COL11A1 (structural Face: characteristic, with congenital and persistently protein) severe flat nasal bridge, anteversion of nostrils, malar hypoplasia, frontal bossing and sometimes hypertelorism; bifid uvula; large appearing eyeballs 2° to shallow orbit Other: occasional mental retardation; short to normal stature; hypoextensible joints; cranial and spondyloepiphyseal abnormalities; progressive congenital sensorineural deficit; myopia; fluid vitreous; congenital and juvenile cataracts with spontaneous and sudden maturation and absorption; calcification of falx cerebri and meninges

Other: cleft lip/palate; syndactyly of fingers; no mental retardation compared with CLEPD1

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.43

604536

246500

McGrath syndrome (ectodermal dysplasia– skin fragility syndrome)

Melanoleucoderma

AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Thickened and dystrophic

Nails

Dry and abundant scalp hair; sparse lateral eyebrows; normal eyelashes; axillary and pubic hair almost normal in women, absent in men

Short and sparse, some improvement with time

Hair

Phenotypic characteristics

Delayed eruption of deciduous and permanent teeth; hypodontia

Normal

Teeth

Mild palmoplantar hyperhidrosis

Hypohidrosis, some improvement with age

Sweat glands

Skin: pale, thin, dry, smooth, pliable and feminine; generalized mottled dyschromia consisting of various shades of hyperand hypopigmentation; aneto-poikiloderma-like lesions over the elbows, knees and proximal phalangeal articulations; pyoderma over the lower regions of the legs leading to atrophic scars; palmoplantar hyperkeratosis Face: typical ‘family’ face with flat saddle nose, thick lips with slight telangiectasia and deep furrows around the eyes and mouth Other: mental retardation; short stature; hyperextensibility of the fingers; slender legs; sexual underdevelopment in men (hypospadias, small penis and scrotum; atrophy of the testes; absence of secondary sexual characteristics)

Skin: at birth, blistering and PKP1 (desmosomal desquamation, especially structural on the face, limbs and adhesion protein) buttocks; lifelong fragility, with trauma-induced tearing and blisters on the pressure points of the soles after prolonged standing or walking; plantar hyperkeratosis

Other

Genetic basis (if known)

127.44 Chapter 127

Brunoni [17] NK

158000

161000

Mesomelic dwarfism– skeletal abnormalities– ectodermal dysplasia

Monilethrix

Naegeli–Franceschetti– Jadassohn syndrome (allelic with dermatopathia pigmentosa reticularis) AD

AD

MIM Inheritance number/ primary ref

Name (alternative names) Hair

Normal; congenital malalignment of great toenails

Occasionally dystrophic

Normal

Brittle, beaded, highly variable degrees of alopecia

Hypoplastic toenails Hypotrichosis

Nails

Phenotypic characteristics

Carious and yellowish spotted; early total loss of teeth

Normal

Dysmorphic; irregular eruption; malpositioned

Teeth

Hypohidrosis; discomfort in heat

Skin: reticular cutaneous pigmentation (appearing at age 2 and disappearing with age); diffuse palmoplantar hyperkeratosis; punctate keratoses; absent dermatoglyphics

Skin: keratosis pilaris, especially over nape of neck

Skin: extremely hypoplastic papillary dermal ridges; bilateral transitional palmar flexion creases Face: depressed nasal root; micrognathia; hypertelorism; antimongoloid palpebral slanting; epicanthal folds; long philtrum; thin lips Limbs: short forearms and hands; broad thumbs; brachymesophalangy; camptodactyly of both fifth fingers; short legs; flattened acetabular margins; broad halluces Other: esotropia; short stature; mild psychomotor retardation; brachycephaly; narrow and highly arched palate; retarded ossification of the anterior fontanelle with the presence of Wormian bones

Normal

Normal

Other

Sweat glands

(Continued)

KRT14 (keratin 14)

KRTHB1 (KRT81), KRTHB3 (KRT83) or KRTHB6 (KRT86) (structural hair keratins) DSG4 desmosomal protein

Genetic basis (if known)

Ectodermal Dysplasias 127.45

601214

164200

Naxos disease (palmoplantar keratoderma with arrhythmogenic right ventricular cardiomyopathy and woolly hair)

Oculo-dentodigital dysplasia (ODDD) syndrome, autosomal dominant AD

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Normal

Nails

Brittle, sparse and dry; slow growing

Dense, rough, bristly, woolly hair at birth; resembles steel wire, fragile hair

Hair

Phenotypic characteristics

Generalized enamel hypoplasia; occasional hypodontia; microdontia and premature loss

Normal

Teeth

Normal

Normal

Sweat glands

Eyes: microcornea; microphthalmia with small orbits; reduced lid apertures; occasional findings: optic atrophy, synechiae, disc coloboma, persistence of papillary membrane, nystagmus, congenital cataract, glaucoma, strabismus and epicanthal folds Limbs: syndactyly and camptodactyly of the fourth and fifth fingers and of one or more toes; occasional ulnar clinodactyly of the fifth fingers and syndactyly of the third and fourth toes; hip dislocation; cubitus valgus Other: face characterized by a thin nose, prominent columella, hypoplastic alae and narrow nostrils; cleft lip; orbital hypotelorism; occasional micrognathia and mild pinna defects; microcephaly; cranial hyperostosis; cleft palate; osteopetrosis; occasional conductive impairment; spastic paraplegia; neurogenic bladder; ataxia; seizures; mild mental retardation

Skin: pallmoplantar keratoderma, diffuse Other: arrhythmogenic right ventricular dysplasia and cardiomyopathy (abnormal ECG, cardiomegaly, ventricular tachycardia, sudden death)

Other

GJA1, encoding connexin 43, a gap junction protein

JUP (encodes junction plakoglobin, a structural protein)

Genetic basis (if known)

127.46 Chapter 127

257850

257960

Oculo-dentodigital dysplasia (ODDD) syndrome, autosomal recessive

Oculotrichodysplasia

AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Brittle finger- and toenails

Normal

Nails

Sweat glands

Normal

Malformed teeth; Normal abnormal enamel; delayed eruption; hypoplastic teeth; chronic infection

Teeth

Generalized Hypodontia, hypotrichosis, carious with sparse scalp, extensive axillary and extractions; pubic hair; small, pointed scanty eyelashes and widely and sparse spaced eyebrows in distal two-thirds

Sparse fine hair, delayed onset of growth (2 years)

Hair

Phenotypic characteristics

Skin: dry and scaly Other: retinitis pigmentosa

Eyes: more severe ocular disease than the dominant form; prominent epicanthal folds; microphthalmia; microcornea; telecanthus; dysplastic iris; hyaloid system remnants; deep-set eyes; persistent pupillary membrane; cataract Face: long, narrow nose; hypoplastic nasal alae; micrognathia; markedly obtuse mandibular angle; mandibular overgrowth Limbs: syndactyly of fourth and fifth fingers; bilateral distal phalanx; clinodactyly of the fifth finger; soft tissue syndactyly of the second, third and fourth toes; widening of the long bones of the limbs; wide diaphyses Other: spinal cord compression at the base of the skull; calcification of the basal ganglia fontanelles; widely separated sutures; developmental delay

Other

(Continued)

Genetic basis (if known)

Ectodermal Dysplasias 127.47

601319

257980

258360

Odontomicronychial dysplasia

Odonto-onycho-dermal dysplasia

Onychotrichodysplasia and neutropenia

Dystrophic; small thin concave toenails; thin fingernails

Hypoplastic finger- and toenails; koilonychia; onychorrhexis

AR

Short, thin, slow-growing nails

Nails Precocious eruption and shedding of deciduous teeth; precocious eruption of secondary teeth with short rhomboid roots

Teeth

Congenitally absent; later dry, fine, lustreless, short, curly, sparse on scalp, eyebrows and lashes; trichorrhexis; absent axillae and pubic hair

Normal

Dry and sparse Mis-shapen teeth; with thinning of peg-shaped eyebrows in incisors; partial some adontia; persistent deciduous teeth

Normal

Hair

Phenotypic characteristics

AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Hyperhidrosis or normal sweating

Normal

Sweat glands

Skin: thickening of the palms WNT10A (winglessand soles; erythematous type MMTV lesions of face; thickening integration site of the palmar skin with family, member painful chafing 10A), encodes a Other: mild mental signalling deficiency, chronic irritative molecule conjunctivitis secondary to important in short lashes; delayed development and psychomotor development; oncogenesis mild generalized hypotonia

Other

Genetic basis (if known)

127.48 Chapter 127

311200

167200

Orofaciodigital (OFD) syndrome type 1 (Papillon–Leage and Psaume syndrome)

Pachyonychia congenita type 1 (Jadassohn– Lewandowsky type) AD

XD

MIM Inheritance number/ primary ref

Name (alternative names)

Severe wedgeshaped thickening

Normal

Nails

Usually normal

Dryness and/or variable degree of alopecia (65%)

Hair

Phenotypic characteristics

No natal teeth

Absence of the lower lateral incisors (50%); malposition; occasional supernumerary canines and enamel hypoplasia

Teeth

Palmoplantar hyperhidrosis

Normal

Sweat glands

Skin: focal palmoplantar keratoderma; verrucous lesions on the knees, elbows, buttocks, ankles and popliteal regions; follicular keratoses/ keratosis pilaris Other: oral leucokeratosis; hoarseness

Skin: evanescent facial milia Face: broad nasal root; dystrophia canthorum; hypoplasia of alae nasi; median cleft of the upper lip; occasional short philtrum, frontal bossing; ear abnormalities Limbs: several types of malformations including brachydactyly, clinodactyly, syndactyly, polydactyly Other: occasional mental retardation (usually mild); agenesis of corpus callosum; dysarthria; gait disturbance; tremor; short stature; multiple hypertrophied lingual and labial frenula; lateral grooving of maxillary alveolar process; grooved ankyloglossia; cleft palate; hypoplasia of malar bone; hypoplasia of the base of the skull; renal abnormalities

Other

(Continued)

KRT6A and KRT 16 (keratin 6a and 16, structural proteins)

CXORF5 (function not entirely clear, ?regulation of microtubule dynamics)

Genetic basis (if known)

Ectodermal Dysplasias 127.49

167210

260130

104100

148350

Pachyonychia congenita type 2 (Jackson–Lawler type)

Pachyonychia congenita, autosomal recessive type

Palmoplantar hyperkeratosis and alopecia (alopecia congenita with keratosis palmoplantaris)

Palmoplantar keratoderma with deafness AD

AD

AR

AD

Inheritance MIM number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Short and dystrophic with onycholysis

Thickened distorted nails, or prominent white nails

Severe wedgeshaped thickening

Nails

Normal

Hypotrichosis to alopecia; absence of eyebrows and lashes; hypotrichosis of axillae and pubic regions

Normal

Usually normal

Hair

Phenotypic characteristics

Normal

Normal

Normal

Natal teeth

Teeth

Skin: palmoplantar hyperkeratosis, progressive, onset mid-childhood Other: high-frequency sensorineural deafness, onset in early childhood

Skin: palmoplantar hyperkeratosis

Normal

Normal

Skin: blistering at sites of friction; focal and punctate palmoplantar keratoderma; oral leukokeratoses; epidermal cysts; follicular keratotic papules on knees, elbows and buttocks

Skin: focal palmoplantar keratoderma; verrucous lesions on the knees, elbows, buttocks, ankles and popliteal regions; follicular keratoses/ keratosis pilaris; multiple pilosebaceous cysts (steatocysts) with onset at puberty distinguish this form from PC type 1 Other: oral leucokeratosis; hoarseness

Other

Hyperhidrosis

Palmoplantar hyperhidrosis

Sweat glands

GJB2 (encodes connexin 26) MTTS1, 7445A-G (mitochondrial point mutation)

KRT6B and KRT 17 (keratin 6b and 17, structural proteins)

Genetic basis (if known)

127.50 Chapter 127

245000

261990

Beare [18]

CalzavaraPinton [19]

262020

Papillon–Lefèvre syndrome (keratosis palmoplantaris with periodontopathia) (allelic with Haim– Munk syndrome)

Pili torti and developmental delay

Pili torti and onychodysplasia (Beare type)

Pili torti and onychodysplasia

Pilodental dysplasia with refractive errors

AR

Normal

Distal nail dystrophy

Short fragile and brittle

AD

AD

Normal

Occasionally dystrophic (spoon-shaped and striated; onychogryposis)

Nails

Normal

Periodontal degeneration with consequent shedding of all teeth

Teeth

Scalp hypotrichosis; pili annulati

Pilitorti of scalp, beard, pubic and axillary hair; absent eyebrows, eyelashes and body hair

Hypodontia; abnormally shaped teeth

Normal

Initially normal, Normal followed by hypotrichosis on the scalp, axillary and pubic areas; pili torti

Pili torti

Occasionally thin and loose

Hair

Phenotypic characteristics

AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Normal

Normal

Normal

Normal

Palmoplantar hyperhidrosis; occasional generalized hypohidrosis

Sweat glands

Other: follicular hyperkeratosis of trunk and limbs; marked hyperopia; astigmatism

Skin: normal, dry or greasy; slight atrophy on the top of the scalp Other: low IQ; severe mental retardation; ‘irresponsible personality’

Other: growth and developmental delay; mild to moderate neurological abnormalities

Skin: hyperkeratosis of the palmar and plantar surfaces with a tendency towards fissuring and cracking; dry and dirty-appearing on the dorsal surface of the arms and the ventral surface of the legs; occasional eczema and erythema of the face as well as of the sacral and gluteal regions Other: severe gingivostomatitis; occasional intracranial calcifications; abnormal liver function; renal abnormalities; generalized osteoporosis; increased susceptibility to infections; liver abscess; ocular squamous neoplasia

Other

(Continued)

CTSC (encodes the enzyme cathepsin C)

Genetic basis (if known)

Ectodermal Dysplasias 127.51

604173

175500

Poikiloderma with neutropenia (Navajo poikiloderma; poikiloderma with neutropenia, Clericuzio type)

Polyposis, skin pigmentation, alopecia and fingernail changes (Cronkhite–Canada syndrome) ?AD

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Onychodystrophy

Thickened and dystrophic; subungual hyperkeratosis

Nails

Alopecia

Normal

Hair

Phenotypic characteristics

Normal

Normal

Teeth

Normal

Normal

Sweat glands

Skin: diffuse hyperpigmentation Other: cachexia; cataracts; xerostomia; glossitis; diminution of sense of taste; gastrointestinal hamartomatous polyps (stomach, small bowel, colon); gastrointestinal carcinoma; protein-losing enteropathy; malabsorption; haematochezia; clubbing of fingers; peripheral neuropathy; thromboembolism; hypocalcaemia; hypomagnesaemia; hypokalaemia

Skin: eczematous rash at birth, becomes poikilodermatous over first 2 years of life Other: cyclical and non-cyclical neutropenia; recurrent upper respiratory tract infections and chest infections; similarity to Rothmund–Thompson syndrome but no mutations in RECQL4

Other

Genetic basis (if known)

127.52 Chapter 127

129400

225000

Rapp–Hodgkin syndrome (allelic with EEC3, limb–mammary syndrome, AEC, ADULT syndrome, split hand-foot malformation 4)

Rosselli–Gulienetti syndrome

NK

AD?

MIM Inheritance number/ primary ref

Name (alternative names)

Nail dysplasia

Small, narrow and dysplastic

Nails

Teeth

Hypotrichosis

Microdontia

Coarse and stiff Conically shaped; on scalp; pili short, square torti; absence incisors and or scarcity on canines; scalp and body; hypoplastic sparse eyebrows enamel; and lashes extensive caries; hypodontia

Hair

Phenotypic characteristics

Anhidrosis

Hypohidrosis; lower number of sweat glands

Sweat glands

Skin: tendency to desquamation with erythematous patches; popliteal and perineal pterygium (unlike CLEPD1 or Margarita Island ED; see above) Face: cleft lip and palate, aplasia or hypoplasia of thumb Other: genitourinary malformations, syndactyly (Continued)

Skin: dry and coarse; TP63 (transcription thickened over the factor) extensor surface of the elbows and knees; hypoplastic dermatoglyphics Face: cleft lip; hypoplastic maxilla; mild frontal prominence; microstomia; mildly depressed nasal bridge; prominent and malformed auricles Other: conductive loss (secondary to otitis media); chronic epiphora; corneal opacities; photophobia; atresia of puncta; ectropion; lacrimal papillae; short stature; occasional syndactyly

Other

Genetic basis (if known)

Ectodermal Dysplasias 127.53

268400

Rothmund–Thomson syndrome

AR

Inheritance MIM number/ primary ref

Name (alternative names)

Table 127.1 Continued

Frequently dystrophic

Nails Hypotrichosis of scalp and body; eyebrows and lashes usually fall out during the first year of life and remain sparse or absent

Hair

Phenotypic characteristics

Hypodontia; microdontia; supernumerary teeth; pronounced caries; delayed eruption

Teeth Normal

Sweat glands

Skin: poikiloderma including RECQL4 (DNA atrophy, irregular helicase gene) pigmentation and telangiectasias beginning during the first 3–6 months; palmoplantar hyperkeratosis; sensitivity to sunlight; initial rash is red, elevated with oedematous patches appearing symmetrically on the cheeks, hands, forearms and buttocks and subsequently on the trunk and lower limbs; after a few years the active phase persists and a dry, scaling and atrophic skin develops with areas of hyperpigmentation, hypopigmentation and telangiectasia Other: cataract, usually bilateral (onset between 3 and 6 years); occasionally degenerative lesions of the cornea; small hands and feet; short terminal phalanges; syndactyly: absence of metacarpals; rudimentary ulna and radius; increased risk of osteosarcoma; short stature; occasional mental retardation; hypogonadism; cryptorchidism; skull abnormalities; scoliosis

Other

Genetic basis (if known)

127.54 Chapter 127

AD

AR?

211390

181270

Sabina brittle hair and mental deficiency syndrome (brittle hair and mental deficit) (? same as nonphotosensitive trichothiodystrophy, Pollitt syndrome, 275550, Amish hair-brain syndrome 234050)

Scalp–ear–nipple syndrome (Finlay– Marks syndrome)

Schinzel–Giedion midface 269150 retraction syndrome

AR

MIM Inheritance number/ primary ref

Name (alternative names) Hair

Teeth

Narrow, deeply set, triangular and hyperconvex

Brittle fingernails

Generalized hypertrichosis

Congenitally denuded areas on scalp; sparse axillary and secondary sexual hair

Delayed eruption

Widely spaced/ missing teeth

No data Dystrophic (splitting Dry, brittle, coarse, wiry in and cracking texture; reduced proximally) eyebrows and lashes; absence of axillary and pubic hair

Nails

Phenotypic characteristics

No data

Reduced apocrine secretion

Normal

Sweat glands

Skin: abundant on the neck; hypoplastic nipples; hypoplastic dermal ridges; simian creases Face: saddle nose with depressed root and short bridge; high/protruding forehead; orbital hypertelorism; small/ malformed auricles; anteverted nostrils; midface hypoplasia; facial haemangiomata; alacrima; corneal hypoesthesia Limbs: mesomelic brachymelia; hypoplasia of distal phalanges in hands and feet; short metacarpals of thumbs; talipes

Skin: scalp defects at birth, later become raised firm scalp nodules Other: small tragi; cupped and protruding ears; absent/rudimentary nipples; breast aplasia; partial third/ fourth finger syndactyly; diabetes; colobomata; cataract; renal abnormalities

Skin: scalp hyperkeratosis on exposed areas Other: pigmentary retinopathy; unilateral congenital tortuosity of the retina vessels; pale optic discs and hyperopic astigmatism; maxillary hypoplasia; mental retardation; delayed bone age

Other

(Continued)

Genetic basis (if known)

Ectodermal Dysplasias 127.55

224750

606156

Schopf–Schulz–Passarge syndrome (cystic eyelids–palmoplantar keratosis–hypodontia– hypotrichosis)

Sener syndrome (frontonasal dysplasia and dilated Virchow– Robin spaces) NK

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Dystrophic nails

Brittle with longitudinal and oblique furrows; onycholysis

Nails

Thin, coarse, brittle hair

Generalized hypotrichosis of scalp and body

Hair

Phenotypic characteristics

Hypodontia; dental occlusion; natal teeth; irregular, pointed

Extensive hypodontia; persistence of deciduous teeth

Teeth

Normal

Normal or hyperhidrosis

Sweat glands

Face: hypertelorism with a wide mouth, long, smooth philtrum and small posteriorly rotated ears Other: multiple cystic areas within the white matter radiating from the ventricles into oval lobes with sparing of the basal ganglia, brainstem and corpus callosum; mild developmental delay

Skin: palmoplantar keratosis; telangiectatic facial skin; papules; multiple tumours with follicular differentiation Other: bilateral early senile cataract; arteriosclerotic fundi; myopia; cysts of eyelids developing late

Other: severe mental retardation; growth retardation; abnormal EEG and seizures; spasticity; recurrent apnoeic spells; multiple Wormian bones; wide cranial sutures and fontanelles; broad ribs, broad cortex and increased density of long tubular bones and vertebrae; hypoplastic/aplastic pubic bones choanal stenosis; short and broad neck; genitourinary abnormalities (short penis with hypospadias, megaureter, megacalycosis)

Other

WNT10A (winglesstype MMTV integration site family, member 10A), encodes a signalling molecule important in development and oncogenesis

Genetic basis (if known)

127.56 Chapter 127

234580

Schinzel [20]

607655

183600

605289

Sensorineural hearing loss, enamel hypoplasia and nail defects (Heimler syndrome)

Skeletal anomalies– ectodermal dysplasia– growth and mental retardation

Skin fragility–woolly hair syndrome

Split hand-foot malformation (SHFM1)

Split hand-foot malformation 4

AD

AD

AR

NK

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Normal

Hair

Underdeveloped, absent, dystrophic or dysplastic

Dysplastic, dystrophic, underdeveloped, absent

Progressively worsening nail dystrophy

Sparse hair, alopecia

Sparse hair, alopecia

Woolly hair; generalized alopecia; sparse eyelashes and eyebrows

Hypoplastic toenails Almost complete absence of body hair; a few curled hairs are present in the parietooccipital and pubic regions

Beau’s lines (toenails); leuconychia (fingernails)

Nails

Phenotypic characteristics Sweat glands

Oligodontia, abnormally shaped teeth

Oligodontia, abnormally shaped teeth

Abnormal teeth

Normal

Normal

Generalized Normal enamel hypoplasia; hypomineralized amelogenesis imperfecta

Teeth

Skin: freckling Face: lacrimal involvement Other: ectodermal features most common in SHFM4; SHFM3 has only dental and nail findings

Other: lacrimal involvement, ectrodactyly, preaxial involvement of the upper extremities least common in SHFM1 (most common in SHFM3)

Skin: fragile skin in the immediate newborn period, that decreases in severity; intraoral blisters with poor feeding; hyperkeratosis of palms and soles

Skin: dry and hyperkeratotic with rhomboid type of scaling, especially on the lower legs; absence of flexion creases on thumbs; fifth fingers with single flexion creases Face: large, prominent nose; upslanting palpebral fissures; short upper lip; large, poorly formed ears Other: microbrachycephaly; multiple uni- or bilateral fusion of vertebral bodies in the lower thoracic and upper lumbar regions; multiple limb abnormalities; syndactyly; bone fusions

Other: severe, early-onset sensorineural hearing loss

Other

TP63

(Continued)

7q21.2-q21.3

Genetic basis (if known)

Ectodermal Dysplasias 127.57

272980

273400

Taurodontia, absent teeth and sparse hair (? same as Witkop syndrome, 189500; see below)

Tetramelic deficiencies, ectodermal dysplasia, deformed ears and other abnormalities (odontotrichomelic syndrome) AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Platonychia, mildly dysplasitc toenails, hypoplastic?

Slow-growing nails; thin, spoonshaped nails

Nails

Severe hypotrichosis of scalp and body

Sparse hair; slow-growing hair

Hair

Phenotypic characteristics

Hypodontia; microdontia; coniform teeth; persistence of deciduous teeth

Congenital hypodontia; taurodontia; lack of permanent lateral maxillary incisors

Teeth

Normal

Normal

Sweat glands

Skin: hypoplastic nipples; hypoplastic or absent areolae; thin, dry and shiny; an unusual number of wrinkles are formed when patients smile or grimace; dermatoglyphic disturbances Face: protruding lips; enlarged nose; large, thin, prominent and deformed auricles; incomplete right cleft lip in one patient; esotropia; wide nasal root Other: bipartite right clavicle; short and distally curved left clavicle; coxa valga; steep femoral necks; synostosis of cuboid and lateral cuneiform bones; cutaneous syndactyly; EEG abnormalities; growth retardation; extensive tetramelic deficiencies; metabolic abnormalities; ECG abnormalities; mild mental retardation; short stature; microcephaly; constant tearing and repeated infections of the conjunctivae; atresia of the nasolacrimal ducts

Other

Genetic basis (if known)

127.58 Chapter 127

188150

601453

190320

129510

Thumb deformity and alopecia

Trichodental dysplasia

Trichodento-osseous syndrome

Tricho-odonto-onychial dysplasia (trichoodonto-onychial dysplasia with amastia) AR?

AD

AD

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Variable degree of dystrophy of finger- and toenails; brittle nails

Flat, thick ened, mis-shapen and striated; brittle

Normal

Normal

Nails Single central upper incisor

Teeth

Thin enamel; small, widely spaced teeth; teeth pits; taurodontism; periapical abscesses

Normal

No data

Normal

Sweat glands

Alopecia totalis; Enamel hypoplasia Normal sparse eyebrows in both and eyelashes dentitions; secondary anodontia; delayed eruption

Dry, thick, tough with short curls, often straightens in childhood; balding may occur with age in men

Slow-growing, Hypodontia; fine and peg-shaped lustreless teeth; shell appearance; teeth (thin relatively thin dentin, large shafts with a pulp chamber), slight beading missing teeth; effect; scanty or retained absent distal deciduous teeth eyebrows and sparse eyelashes

Alopecia

Hair

Phenotypic characteristics

Skin: increased number of pigmented naevi; extranumerary nipples; keratotic actinic lesions; crusts, ephelides in the scalp; mild palmoplantar hyperkeratosis; dermatoglyphic alterations; irregular hyperpigmentation of the back Other: one patient had a mixed mild hearing deficit on the left; short stature; amastia, athelia

Face: occasional frontal bossing Other: occasional clinodactyly; some of the calvarial sutures show evidence of premature fusion leading to mild to moderate dolichocephaly

Other: one case of microcephaly and mental retardation

Other: hypoplastic thumbs; short stature; mental retardation; increased groin pigmentation with raindrop depigmentation

Other

(Continued)

DLX3 (homeobox gene)

Genetic basis (if known)

Ectodermal Dysplasias 127.59

Pinheiro [21]

275450

Koshiba [22]

Tricho-odonto-onychodermal syndrome

Tricho-odonto-onychial dysplasia

Tricho-onycho-dental (TOD) dysplasia

AD

?AR

NK

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Thin with longitudinal striations and cracks

Dystrophic

Severely dystrophic or absent finger and toenails

Nails Hypodontia; persistence of deciduous teeth; enamel hypoplasia; delayed eruption

Teeth

Scanty, fine, curled; sparse eyebrows and lashes

Taurodontic molars; hypoplastic– hypomature enamel; hypodontia

Severe Enamel hypotrichosis; hypoplasia; peripheral secondary fringe of hair anodontia on the temporal and occipital regions; dry, brittle, sparse hair

Parieto-occipital hypotrichosis; aplasia cutis congenita; sparse eyelashes; sparse and irregular eyebrows

Hair

Phenotypic characteristics

Hypohidrosis with hyperthermia

Normal

Normal

Sweat glands

Skin: supernumerary nipples; naevus pigmentosus; mild palmoplantar keratoderma Other: bone deficiency in the frontoparietal region Skin: fine textured

Skin: dry with hypochromic, atrophic and poikilodermalike spots; irregular areolae; wrinkled back of hands; palmar keratosis; dermatoglyphic alterations; aplasia cutis congenita of the scalp Face: long philtrum; microstomia with thin lips; hyperpigmented eyelids and periorbital regions Limbs: bilateral clinodactyly; syndactyly; hypoplastic thumb; pronounced manus cava; hypoplastic distal and middle phalanges of both second fingers; absent middle phalanges of all toes Other: mild asymmetry of the skull; congenital hypertrophy of the frenum linguae

Other

Genetic basis (if known)

127.60 Chapter 127

190350, 190351

150230

Trichorhinophalangeal syndrome types I and III

Trichorhinophalangeal syndrome type II (Langer–Giedion syndrome) AD

AD

MIM Inheritance number/ primary ref

Name (alternative names)

Occasional thin, short, with long longitudinal grooves; flattened, koilonychia-like and normal in colour; racket thumbnails

Occasional thin, short, with long longitudinal grooves; flattened, koilonychia-like and normal in colour; racket thumbnails

Nails

Teeth

Fine, usually blond Occasional and sparse supernumerary (especially in incisors; the microdontia; frontotemporal poorly aligned areas); sparse or absent eyebrows

Fine, usually blond Occasional and sparse supernumerary (especially in incisors; the microdontia; frontotemporal poorly aligned areas); sparse or absent eyebrows

Hair

Phenotypic characteristics

As above for trichorhinophalangeal syndrome types I and III, plus multiple cartilaginous exostoses; mental retardation is common

Normal

(Continued)

Microdeletion syndrome 8q42.11 to 8q24.1 (includes TRPS1 and EXT1) zinc-finger transcription factor

Other: pear-shaped nose; TRSPS1 (zinc-finger long and wide philtrum; transcription large, prominent ears; factor) occasional exotropia and photophobia; short stature; increased susceptibility to upper respiratory tract infections; narrow palate; scoliosis; lordosis or kyphosis; pectus carinatum Limbs: brachymesophalangy; brachymetacarpy; brachymetatarsy; peripheral dysostosis with type 12 cone-shaped epiphyses at some of the middle phalanges of the hands (the joints are thickened); ulnar and radial deviation of the fingers; occasional clinodactyly; winged scapulae; coxa valga; Perthes-like abnormalities (type III: severe brachydactyly, short metacarpals, severe short stature)

Other

Normal

Sweat glands

Genetic basis (if known)

Ectodermal Dysplasias 127.61

?AR

AD

AD

275550

Trichorrhexis nodosa syndrome (Pollitt syndrome, trichothiodystrophyneurocutaneous syndrome) (? same as Sabina brittle hair and mental deficiency syndrome 211390; see above)

Ulnar mammary 181450 syndrome (Schinzel syndrome, ulnarmammary syndrome of Pallister)

Uncombable hair, retinal pigmentary dystrophy, dental anomalies and brachydactyly (Bork syndrome) 191482

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

Normal

Normal

Hypoplastic nails; spoon-shaped nails

Nails No data

Teeth

Uncombable hair; pili canaliculi; congenital hypotrichosis

Oligodontia; supernumerary inferior lateral incisors; microdontia

Sparse axillary Ectopic upper hair; scant canines; lateral eyebrows hypodontia

Trichorrhexis nodosa; short, woolly hair; stubby eyebrow hair

Hair

Phenotypic characteristics

Normal

Axillary apocrine gland hypoplasia

Normal

Sweat glands

Other: juvenile cataracts; retinal pigmentary dystrophy; brachymetacarpy; mild mental retardation

Other: delayed growth; obesity; subglottic stenosis; hypoplastic scapula; hypoplastic clavicle; breast hypoplasia; nipple hypoplasia; anal atresia or stenosis; pyloric stenosis; small penis; delayed puberty; shawl scrotum; imperforate hymen Limbs: hypoplastic/absent/ deformed ulna; hypoplastic/absent/ deformed radius; hypoplastic humerus; absent third, fourth and fifth ulnar rays; postaxial polydactyly; short fourth and fifth toes

Skin: ichthyotic skin, flexural eczema; photosensitivity Other: mental retardation; hypotonia; titubation; spastic diplegia; extensor plantar reflexes; absent deep tendon reflexes; partial agenesis of the corpus callosum; central nuclear cataracts; jerky ocular pursuit movements; growth retardation; microcephaly; receding chin; protruding ears

Other

TBX3 (transcription factor)

Genetic basis (if known)

127.62 Chapter 127

AD

AD

Walbaum [23]

189500

193530

278150

Walbaum–Dehane– Schlemmer syndrome

Witkop syndrome (tooth and nail syndrome) (? same as taurodontia, absent teeth and sparse hair (272980); see above: ? Fried tooth and nail syndrome included)

Weyer acrofacial dysostosis (acrodental dysostosis of Weyer, Curry–Hall syndrome) (? miIder AD form of Ellis–van Creveld (MIM 225500) ibid)

Wooly hair, autosomal recessive (allelic with localized autosomal recessive hypotrichosis, LAH3, 611452, see above) AR

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Normal

Hypoplastic/ dysplastic

Koilonychia; longitudinal ridging; nail pits; seen in childhood; toenails more affected than fingernails

Normal

Nails

Woolly hair; blond; coarse, lustreless, dry; tightly curled; varying hypotrichosis; reduced diameter of hair shaft normal eyebrows, lashes and beard

Normal

Fine scalp hair, normal eyelashes and eybrows

Initially thin and blond; alopecia later; hypotrichosis of body hair

Hair

Phenotypic characteristics

Normal

Incisors abnormal in shape and number; single central incisor; conical

Partial or total anodontia; permanent teeth fail to erupt; absent maxillary canines, mandibular incisors, second molars

Hypodontia; supernumerary teeth; microdontia; malposition

Teeth

Normal

Normal

Normal

Normal

Sweat glands

Other: short stature; postaxial polydactyly; short limbs; acrofacial dysostosis; abnormal mandible; hypotelorism; prominent ear antihelices

Other: lower lip eversion; polycystic ovaries

Skin: abnormal dermatoglyphics Face: swollen, with flat nasal bridge and enlarged tip of nose Other: mild gingival hypertrophy; growth retardation

Other

(Continued)

P2RY5 (purinergic receptor P2Y, G protein-coupled), receptor activation causes calcium release and downstream signalling

EVC, EVC2 (not fully elucidated, putative transcription factor)

MSX1 (homeobox gene)

Genetic basis (if known)

Ectodermal Dysplasias 127.63

278200

Moynahan [24]

300606

Zanier and Roubicek [25]

Woolly hair, hypotrichosis, everted lower lip and outstanding ears (Salamon syndrome)

Xeroderma–talipes– enamel defect (XTE syndrome)

X-linked hypodontia

Zanier–Roubicek syndrome (? same as AD HED,129490)

Hypotrichosis; normal eyebrows and lashes

Normal

Coarse and dry; slow growing; hypotrichosis; no lashes on lower lids

General hypotrichosis of scalp and body hair; woolly hair

Hair

Hypodontia; conical teeth; early loss of deciduous teeth

Congenital absence of central and lateral incisors, also canine teeth, but maxillary and permanent molars unaffected

Poorly formed; yellow enamel

Extensive hypodontia (rudimentary permanent teeth); persistence of deciduous teeth

Teeth

Hypohidrosis, often severe hyperthermia in infancy

Normal

Hypohidrosis

Normal

Sweat glands

Skin: smooth and dry Other: reduced lacrimation; normal or slightly reduced stature; hypoplasia of the mammary glands

Skin: generally dry, scaling with numerous bullae on face and limbs; scanty hair follicles Other: photophobia; hypoplasia of the ocular puncta leading to epiphora and blepharitis; EEG alterations; mild mental retardation; bilateral club foot; cleft palate

Skin: palmoplantar keratosis; telangiectatic facial skin; papules; multiple tumours with follicular differentiation Other: bilateral early senile cataract; arteriosclerotic fundi; myopia; eyelid cysts; everted lower lip; protruding ears

Other

AD, autosomal dominant; AR, autosomal recessive; CGS, contiguous gene syndrome; NK, not known; MIM, Mendelian Inheritance in Man; XL, X-linked.

Occasionally brittle

Normal

XR

AD

Deformed on fingers +/− toes

Highly dystrophic; brittle; ungues plicatae; toenails more severely affected; onycholysis

Nails

Phenotypic characteristics

NK

AR

MIM Inheritance number/ primary ref

Name (alternative names)

Table 127.1 Continued

EDA ectodysplasin A

Genetic basis (if known)

127.64 Chapter 127

Ectodermal Dysplasias References 1 Online Mendelian Inheritance in Man, OMIM™. McKusick–Nathans Institute for Genetic Medicine, Johns Hopkins University, and National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD. www.ncbi.nlm.gov/omim/. 2 Danz DFG. Sechste Bemerkung. Von Menschen ohne Haare und Zahne. Stark Arch Geburtch Frauenz Neugeb Kinderkr 1792;4:684. 3 Weech A. Hereditary ectodermal dysplasia (congenital ectodermal defect). A report of two cases. Am J Dis Child 1929;37:766–90. 4 Touraine A. L’anidrose hereditaires avec hypotrichose et anodontie (polydysplasie ectodermique héréditaire). Presse Méd 1936;44: 145–9. 5 Freire-Maia N, Pinheiro M. Ectodermal Dysplasias: a Clinical and Genetic Study. New York: Alan R. Liss, 1984. 6 Pinheiro M, Freire-Maia N. Ectodermal dysplasias: a clinical classification and a causal review. Am J Med Genet 1994;53:153–62. 7 Fuchs E, Merrill BJ, Jamora C et al. At the roots of a never-ending cycle. Dev Cell 2001;1(1):13–25. 8 Lerner AB. Three unusual pigmentary syndromes. Arch Dermatol 1961;83:151–9. 9 Baisch A. Anonychia congenita, Kombiniert mit Polydaktykie and verzogertem abnormen Zahndurchbruch. Dtsch Z Chir 1931;232: 450–7. 10 Wallace HJ. Ectodermal defect with skeletal abnormalities. Proc C Soc Med Edinb 1958;51:707–8. 11 Wesser DW, Vistnes LM. Congenital ectodermal dysplasia, anhidrotic, with palatal paralysis and associated chromosome abnormality. Plast Reconstr Surg 1969;8:396–8. 12 Kirman BH. Idiocy and ectodermal dysplasia. Br J Dermatol 1955;67:303–7. 13 Wiedemann HR, Grosse FR, Dibbern H. Caracteristicas das Sindromes em Pediatria. Atlas de Diagnostico Diferencial. São Paulo: Editoria Manole, 1978. 14 Fischer H. Familiar hereditares Vorkommen von Keratoma palamare et plantare, Nagelverandergungen, Haaranomalien und Verdickung der Endglieder der Finger und Zehen in 5 Generationen (die Beziehungen dieser Veranderungen zur inneren Sekretion). Dermatol Zeitschr 1921;32:114–42. 15 Fried K. Autosomal recessive hydrotic ectodermal dysplasia. J Med Genet 1977;14:137–9. 16 Jorgenson RJ. Gingival fibromatosis. Birth Defects 1971;VII:278– 80. 17 Brunoni D, Lederman H, Ferrari S et al. Uma sindrome malformativa com nanismo mesomelico, malformacoes esqueleticas, displasia ectodermica e facies tipica. Cienc Cult 1982;34:694. 18 Beare JM. Congenital pilar defect showing features of pili torti. Br J Dermatol 1952;64:366–72. 19 Calzavara-Pinton P, Carlino A, Benetti A et al. Pili torti and onychodysplasia. Report of a previously undescribed hidrotic ectodermal dysplasia. Dermatologica 1991;182:184–7. 20 Schinzel A. A case of multiple skeletal anomalies, ectodermal dysplasia, and severe growth and mental retardation. Helv Paediatr Acta 1980;35:243–51. 21 Pinheiro M, Pereira LC, Freire-Maia N. A previously undescribed condition: tricho-odonto-onycho-dermal syndrome. A review of the tricho-odonto-onychial subgroup of ectodermal dysplasias. Br J Dermatol 1981;105:371–82. 22 Koshiba H, Kimura O, Nakata M et al. Clinical, genetic, and histologic features of the trichoonychodental (TOD) syndrome. Oral Surg Oral Med Oral Pathol 1978;46:376–85. 23 Walbaum R, Dehaene P, Schlemmer H. Dysplasie ectodermique: une forme autosomique recessive? Arch Fr Pediatr 1971;28:435– 42.

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24 Moynahan EJ. XTE syndrome (xeroderma, talipes and enamel defect): a new heredo-familial syndrome. Proc Roy Soc Med Lond 1970;63:1–2. 25 Zanier JM, Roubicek MM. Hypohidrotic ectodermal dysplasia with autosomal dominant transmission. Fifth International Congress on Human Genetics, Mexico, 1976: Communication 273. 26 Priolo, M, Laganà C. Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet 2001;38:579–85. 27 Priolo M. Ectodermal dysplasias: an overview and update of clinical and molecular-functional mechanisms. Am J Med Genet A 2009;149A(9):2003–13.

Ectodermal dysplasias due to mutations in tumour necrosis factorlike/NF-κB signalling pathways Overview of molecular pathways The transcription factor NF-κB regulates the expression of multiple genes with functions in controlling the immune and stress responses, cell adhesion, protection against apoptosis and inflammatory reactions [1,2]. NF-κB is composed of homo- or heterodimers of five proteins belonging to the Rel family (p50, p52, c-rel, relA and relB). NF-κB is usually maintained in an inactive state within the cytoplasm by association with inhibitory proteins of the IB (IκB) family: IBα, IBβ and IBε. IB molecules are phosphorylated on two critical serine residues in response to multiple stimuli such as cytokines, various stress signals and viral and bacterial infections. An increasing number of signals that initiate this phosphorylation are identified year-on-year, but the best studied signals include the tumour necrosis factors (TNFs), lipopolysaccharides (LPS) and interleukin 1 (IL-1). Phosphorylation at these sites allows IB molecules to be recognized by a ubiquitination complex; following polyubiquitation, IBs are degraded by proteasomes, thus freeing free NF-κB to enter the nucleus and activate target genes [3]. The kinase that phosphorylates IB has been designated IKK (for IκB kinase) and has been shown to consist of two catalytic subunits (IKKα/IKK1 and IKKβ/IKK2) and a third component IKKγ (more commonly known as NEMO – NF-κB essential modulator) that provides a structural and regulatory function to the complex. Cell lines lacking NEMO are unable to activate NF-κB in response to most stimuli [4]. Extensive work with mouse models has confirmed the centrality of the NF-κB pathway in apoptosis and inflammatory and immune functions [5]. Complete absence of NF-κB leads to prenatal death owing to massive TNF-induced liver apoptosis, and more subtle knockouts that alter NF-κB activity all lead to immune defects. IKKα is also an important suppressor of skin cancer [6]. The elucidation of the NF-κB pathway has recently generated much interest in the EDs, and defects at

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Table 127.2 Genotype–phenotype correlation in disorders due to mutations in the NF-κB signalling pathway Gene

Mouse phenotype

Human disease (MIM number; abbreviation)

EDAR

Downless

Autosomal dominant hypohidrotic ectodermal dysplasia (129490) and autosomal recessive hypohidrotic ectodermal dysplasia recessive (224900)

EDA1

Tabby

X-linked hypohidrotic ectodermal dysplasia (305100)

EDARADD

Crinkled

Autosomal recessive hypohidrotic ectodermal dysplasia (606603) and autosomal dominant hypohidrotic ectodermal dysplasia (129490)

TRAF6

Hypohidrotic ED (in knockout mice), abnormal teeth, osteopetrosis

Familial osteoporosis (611739)

NEMO/IKKγ

Heterozygotes for NEMO deficiency develop: unique dermatopathy with keratinocyte hyperproliferation, skin inflammation, hyperkeratosis and increased apoptosis. +/− females recover, −/− males die in utero

Incontentia pigmenti (308300; IP)

NEMO/IKKγ (hypomorphic mutations)

As above

Hypohidrotic ectodermal dysplasia with immune deficiency (300291; ED-ID)

NEMO/IKKγ (stop codons)

As above

Anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis and lymphoedema (300248;OL-EDA-ID)

IkBα (hypermorphic dominant mutations)

Not known

Autosomal dominant ectodermal dysplasia with a severe and unique T-cell immunodeficiency (612132; EDA-ID)

IRAK (amorphic mutations)

Severe impairment in interferon-γ production and the induction of natural killer cell cytotoxicity by IL-18

None yet identified; ? lupus susceptibility

various levels have been identified in several EDs. In many cases, these predominantly phenotype-driven, mouse–human comparison studies have yielded significant new insights in molecular pathways (Table 127.2) [1]. One of the best characterized pathways in NF-κB activation is the ectodysplasin pathway, an upstream activator (Fig. 127.1). Since 1997, defects in this pathway have been demonstrated in the X-linked, autosomal dominant and recessive subtypes of hypohidrotic ED (HED). Subsequently, mutations in downstream components have been shown to underlie familial incontinentia pigmenti and HED associated with immunodeficiency and/or osteopetrosis and HED associated with T-cell immune deficiency. The X-linked HED gene, EDA, which maps to Xq12– 13.1 and is also mutated in the mouse orthologue tabby [7], was first described in 1996 [8]. Canine and bovine models for X-linked HED have mutations in the similar genes [9–11] EDA encodes two isoforms of a transmembrane protein, ectodysplasin-A (EDA), that has homology to the TNF family. The extracellular domain of EDA has a collagen-like repeat and a furin cleavage site, unique in TNF proteins. Cleavage is necessary to enable solubility and functionality of EDA. The two longest iso-

forms, EDA-A1 and EDA-A2, bind to two different receptors: EDA-A1 binds to the EDAR protein and EDA-A2 binds to another X-linked receptor, XEDAR [12]. Mutations have been identified in all domains of EDA in patients with HED; many of these mutations are thought to have an effect on solubility or cleavage of ectodysplasin-A, rendering it non-functional [13]. Mutations in the EDA Gly-X-Y domain are thought to prevent bundling of EDAR trimers but do not appear to have an effect on EDA–EDAR binding (B. Ferguson, personal communication, 2003). EDA mutations are also responsible for X-linked hypodontia (MIM 300606), a condition notable for the congenital absence of incisors but not molars [14]. The physiological role of EDA in hair follicle morphogenesis was reinforced by the isolation of the gene for autosomal dominant/recessive HED. Patients with autosomal dominant or recessive HED are phenotypically identical to those with X-linked HED. The mutated gene, previously named downless (DL) after the mouse homologue, encodes a member of the tumour necrosis factor receptor (TNFR) superfamily which functions as an ectodysplasin receptor (EDAR) [15]. Loss-of-function mutations throughout EDAR have been reported in autosomal

Ectodermal Dysplasias

127.67

AR, AD hypohidrotic ED EDA

Cytokines, stress, infection TNF family

IL1

XL, AR, AD hypohidrotic ED EDAR

PLS

EDARADD

AR, AD hypohidrotic ED

TRAF6 + +

+

IKKγ/NEMO

+

IKKα

Incontinentia pigmenti

IKKβ

+ IκBα

IKKγ/NEMO

IκBα

IκBα NFκβ

Ub

Ub NFκβ Nucleus

CYLD product

Brooke-Spiegler

Proteasome

Ubiquitination

UBR product

NFκβ

Binding and transcription

Johanson-Blizzard

Fig. 127.1 Schematic of NF-κB pathway. EDA binds to EDAR, which interacts with EDARADD. Downstream signalling from this complex, as well as input from cytokines and other stressors, leads to activation of the IKK (inhibitor κ B kinase) complex via TRAF 6 and other signalling molecules. When activated, the IKK complex, which is made up of three subunits (α, β and γ), phosphorylates IκB α (inhibitor κ B α), which results in its targeting for ubiquitination and degradation. This causes the release of NF-κB, allowing it to enter the nucleus, bind to transcriptional elements, and cause upregulation of NF-κB mediated gene targets. ED, ectodermal dysplasia; AD, autosomal dominant; AR, autosomal recessive; XL, X-linked; LPS, lipopolysaccharides; Ub, ubiquitin; EDAR, ectodysplasin A; EDARADD, EDAR-associated death domain.

recessive HED and dominant negative mutations have been reported in autosomal dominant HED within the death domain of this transmembrane protein [16]. The EDA–EDAR pathway was further refined when the molecular basis of a third mouse homologue was identified. The crinkled mouse (cr) is a spontaneous mouse mutant with an identical phenotype to downless and tabby. Using positional cloning techniques, the causative gene was identified in an adapter protein (EDAR-associated death domain, termed Edaradd) for the EDA–EDAR complex [17]. The same group also identified mutations in a family with autosomal recessive HED [17]. The Edaradd death domain interacts with the intracellular death domain of EDAR, linking it to downstream signals leading to NF-κB activation [17]. Edaradd associates with TNFR-associated factor (TRAF) 1, 2 and 3. The gene

encoding the Edaradd protein, EDARRADD, may be mutated in both autosomal recessive and dominant hypohidrotic ectodermal dysplasia [18,19]. NF-κB activation by the EDAR pathway is NEMO dependent [20], and the relevance of this interaction to human ectodermal dysplasias became clear when loss-offunction mutations were identified in the IKKγ gene (NEMO) in incontinentia pigmenti [21]. This discovery was followed by identification of less critical mutations in NEMO in several male patients with an unusual phenotype of HED associated with immune deficiency (EDAID) [20,22]. Mutations in the coding region are associated with the EDA-ID phenotype, and specific mutations in the stop codon of NEMO cause a more severe syndrome of osteoporosis and/or lymphoedema associated with EDA-ID [20].

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Recently, two other EDAR-related members of the TNFR superfamily, X-linked ectodysplasin-A2 receptor (XEDAR) [12] and TNFR superfamily member 19 (TNFRSF19), also known as TROY or TAJ (toxicity and JNK inducer) [23,24], have been reported. Signals from each of these receptors were shown to activate NF-κB, providing further candidate genes and candidate signalling systems for human HED. TRAF-6 is a cytoplasmic adapter protein that links signals from members of the TNFR superfamily to activation of transcription factors such as NF-κB through IKK activation. TRAF-6 −/− mice display HED, revealing yet more complexity to these signalling systems [25]. It is likely that several of these genes will, in time, be shown to have relevance in human HED. Regulatory modulators of the NF-κB system may also prove relevant to ectodermal dysplasia in the future; recently mutations in a gene encoding a protein involved in deubiquitinization of inhibitor proteins has been found in familial cylindromatosis (Brooke–Spiegler syndrome, MIM 605041), and its allelic disorders, familial cylindromatosis (MIM 132700) and multiple familial trichoepitheliomas (MIM 601606). Mutations in the cylindromatosis gene (CYLD) are associated with these disorders, and this protein has an important role in negative regulation of the NF-κB pathway, as it deubiquitinates multiple NF-κB regulators, including TRAF2, TRAF6 and NEMO [26–30]. Johanson–Blizzard syndrome, another ectodermal dysplasia, is due to mutations in UBR1, which encodes ubiquitin-protein ligase E3 component N-recognin, a protein that binds to a destabilizing N-terminal residue of a substrate protein and participates in the formation of a substrate-linked multiubiquitin chain [31].

X-linked, autosomal dominant and recessive hypohidrotic ectodermal dysplasia The phenotypic appearances of the X-linked (MIM 305100), autosomal recessive (MIM 606603) and autosomal dominant types (MIM 129490) are identical. Definition. X-linked HED is the most common of the ectodermal dysplasias and is characterized by hypotrichosis, hypodontia, hypohidrosis and distinctive facial features. Autosomal recessive HED is clinically identical to X-linked HED and females are as severely affected as males. History. X-linked HED was first described in 1848 by Thurnam [32]. In 1921, Thadani [33] determined that it was an X-linked disorder and later reported that female carriers manifest varying signs of the condition. Pathology. The epidermis is thin, with effacement of rete ridges. The striking finding is absent or sparse eccrine

Fig. 127.2 Skin biopsy from the trunk of an affected male with X-linked HED. Note the absence of hair follicles, sebaceous glands and eccrine glands (haematoxylin and eosin; 10× original magnification).

glands and ducts in affected males (Fig. 127.2) [34,35]. Hair follicles and sebaceous glands are variably reduced in number and may appear rudimentary [34–36]. Apocrine glands may be absent, sparse or even normal. The nasal mucosa demonstrates almost complete loss of ciliated cells [37]. Mucous glands of the upper respiratory tract may be sparse or absent [34]. Mucus-secreting glands in the duodenum may also be absent [35]. Light and scanning electron microscopic findings of hair shaft abnormalities are variable and include longitudinal clefts or grooves and transverse fissuring. The bulb of the hair shaft is dystrophic in some individuals [38]. Radiographs of the mandible reveal dental hypoplasia or aplasia [34,39]. Clinical features

Hair The scalp hair is sparse, fine and lightly pigmented, and grows slowly (Fig. 127.3). Eyebrows are scanty or absent; sometimes just the outer two-thirds are missing. The eyelashes may be normal, sparse or completely absent. Secondary sexual hair in the beard, pubic and axillary regions is variably present and may be normal. Hair on the torso and extremities is usually absent [34,36,40,41]. Approximately 70% of obligate female carriers of X-linked HED describe their hair as being sparse or fine [40]. Teeth Dental abnormalities vary from complete absence of teeth to sparse, abnormally shaped teeth. Studies reveal a mean of 24 missing teeth, out of a total of 28, in affected males [40,42]. Dentition is delayed and the erupted teeth tend to be small and widely spaced, and are frequently conical or peg-shaped. Both deciduous and permanent teeth are affected. The alveolar ridges are hypoplastic (Fig. 127.4), which gives rise to full, everted lips [39,43]. About 80%

Ectodermal Dysplasias

127.69

Fig. 127.5 This female heterozygous for X-linked HED exhibits abnormally shaped and absent permanent teeth. Courtesy of Dr Virginia Sybert.

Fig. 127.3 Young boy with X-linked HED. The hair is fine, lightly pigmented and sparse. Courtesy of Dr Virginia Sybert.

Fig. 127.4 Hypoplastic aveolar ridges and peg-shaped teeth in an affected male with X-linked HED. Courtesy of Dr Virginia Sybert.

of obligate female carriers of X-linked HED have distinct dental abnormalities, including absent permanent teeth and small or peg-shaped teeth (Fig. 127.5) [40]. Oligodontia in the primary dentition is an important clinical predictor of EDA mutation in females [44].

Nails The nails are normal in most individuals. Thin, brittle nail plates with longitudinal ridges have been described in some individuals.

Sweat glands Sweating is severely diminished or absent owing to a paucity or absence of eccrine glands. The ability to thermoregulate by evaporative cooling is inadequate and hyperthermia can occur with physical exertion or in a warm environment. This is particularly problematic in infants and young children, who may experience recurrent bouts of fever as high as 42°C. Heat intolerance does occur in older children and adults, but they learn to control their body temperature by drinking cold liquids, wetting their skin or clothing and seeking out cool surroundings [40]. About 25% of heterozygote females experience heat intolerance, and almost half notice that their ability to sweat is reduced [40]. The hypohidrotic areas of skin in carrier females of X-linked HED occur in defined linear patterns corresponding to the lines of Blaschko [45]. Diminished apocrine sweating in affected individuals is not problematic. Skin At birth, affected males may demonstrate marked scaling or peeling of their skin that may be mistaken for a collodion membrane [46]. In children and adults, the skin is fine, smooth and dry. Periorbital hyperpigmentation and fine wrinkling around the eyes are characteristic features of the disorder. Eczema is common and is prominent in flexural areas [41,47]. Small milia-like papules may be found on the face [36,48]. Other ectodermal structures Diminished or absent salivary glands and mucous glands of the nose, mouth and ears cause numerous otolaryngological complications including nasal obstruction caused by thick, foetid nasal discharge and adherent nasal crusts, sinusitis, recurrent upper respiratory tract infections, feeding problems in infancy, xerostomia, hoarse voice

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Chapter 127

and impacted cerumen [36,47–49]. Diminished production of tear film from the lacrimal glands may cause dry eyes, photophobia and corneal damage [48,50]. A third of affected males have abnormalities of the nipples including absent, simple or accessory nipples [40,51]. Female carriers may also be affected with marked breast asymmetry, inadequate breast milk production or athelia. Pituitary and adrenal insufficiency have been reported [48].

Craniofacial features The facies are distinctive with relative frontal bossing, concave midface, saddle nose and everted lips [34,36,39]. A third of affected males have ears that are described as simple or satyr [40]. The distinctive facial features may not be obvious at birth but become more noticeable with age (Figs 127.6, 127.7). Other clinical features Diminished or absent mucous glands of the tracheal, bronchial, oesophageal, gastric and colonic mucosa cause problems with recurrent bronchitis, pneumonia, dysphagia and gastro-oesophageal reflux and constipation [40,46,48]. Reactive airways associated with wheezing are a common problem [40]. There is no convincing evidence for thyroid or parathyroid abnormalities, nor for a primary immune deficiency associated with X-linked HED [40]. Prognosis. Failure to thrive occurs in up to 40% of affected males [40]. Height and weight are compromised in early childhood but appear to normalize with time. Mortality in infancy and early childhood is historically 25%, primarily owing to hyperthermia, failure to thrive

Fig. 127.6 The facial features of X-linked HED may not be obvious at birth, but become more pronounced over time. Courtesy of Dr Virginia Sybert.

and respiratory infections [40]. Febrile seizures can occur with hyperpyrexia [40,47]. Speech problems may exist as a result of hypodontia, nasal obstruction and impacted cerumen [47,49]. Differential diagnosis. Affected infants with scaling skin may be misdiagnosed as collodion babies with lamellar ichthyosis. The saddle nose and abnormal teeth have caused diagnostic confusion with congenital syphilis [36,48]. Once the characteristic facies and lack of sweating are evident, there are very few disorders to consider in the differential diagnosis. HED with hypothyroidism displays hypohidrosis with hyperthermia and hypotrichosis but the teeth are normal, the nails are significantly dystrophic and the skin has mottled-brown areas of pigmentation [52]. Fried tooth and nail syndrome manifests as hypotrichosis, hypodontia and prominent everted lips, but sweating is normal [52]. Basan syndrome is characterized by hypotrichosis, hypodontia and hypohidrosis but also by severe nail dystrophy and congenital absence of dermatoglyphics [40]. For the purposes of genetic counselling and reproductive planning, it is possible to perform DNA-based molecular genetic diagnosis in selected patients. This can help to conclusively distinguish between X-linked and autosomal forms where there is no family history to indicate the mode of inheritance. Treatment. A multidisciplinary approach to the management of these individuals is advocated [52]. Early diag-

Fig. 127.7 This female exhibits a concave midface, saddle nose and everted lips. Courtesy of Dr Virginia Sybert.

Ectodermal Dysplasias

nosis is crucial to avoid life-threatening complications in infancy, for planning long-term management and to define recurrent risks for families [53]. Female carriers may be detected in most cases by careful clinical examination for patchy distribution of scalp and body hair, sweat pores and hypodontia [47]. DNA-based molecular diagnosis in affected families can detect female carriers of X-linked HED with considerable accuracy. DNA-based prenatal diagnosis is also possible in families at risk for the disorder. Prevention of hyperthermia is critical. This is done by avoiding heat and physical overexertion, cooling the body with wet clothing and cool drinks and by airconditioning home and school environments. Early dental restoration with bonding, overdentures or implants is imperative [49,54,55]. Nasal crusting and discharge can be managed with saline nose drops and a home humidifier. Consumption of large amounts of liquids or the use of artificial saliva preparations minimizes dry mouth and swallowing difficulties [56]. Dry eyes may be treated with artificial tears. The daily use of lubricating drops facilitates the removal of impacted earwax. Pulmonary difficulties are managed by avoidance of smoky, dusty environments, adequate humidification and the use of chest physiotherapy and antibiotics when appropriate [57]. Studies on animal models of X-linked HED suggest the possibility of more targeted therapies for this condition in the future, although currently no such therapies are available. Previously, in utero administration of recombinant EDA was found to permanently correct the phenotype of newborn affected mice [58]. More recently, postnatal intravenous administration of soluble recombinant EDA to affected dogs resulted in normalization of adult teeth, improved ability to sweat, restoration of normal lacrimation, and decreased respiratory infection, due to improved mucociliary clearance from correction of glandular deficit in the trachea and bronchi [59,60].

Hypohidrotic ectodermal dysplasia with immunodeficiency (EDA–ID; MIM 300291); hypohidrotic ectodermal dysplasia with immunodeficiency with osteopetrosis and lymphoedema (MIM 300301) Both of these conditions are caused by mutations in the IKKγ gene, also known as NEMO. The observation of unusually severe recurrent infections in a small subset of patients with otherwise typical HED features led to the suggestion that there may be a specific syndrome of HED and immunodeficiency (EDA–ID). The EDA–ID syndrome was first reported in a boy with miliary tuberculosis [61]. The second reported patient had recurrent life-threatening infections caused by Pseudomonas aeruginosa, Mycobacterium avium and cytomegalovirus [62]. A

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third child had a milder phenotype with repeated infections due to Staphylococcus aureus and Streptococcus pneumoniae [63]. Three siblings from a different kindred had recurrent severe infections with Strep. pneumoniae, with impaired response to polysaccharide antigens [64]. All of these patients were male, suggesting X-linked inheritance. Further cases have extended our knowledge of the phenotype, and severe life-threatening or recurrent bacterial infections have been reported in the lower respiratory tract, skin, soft tissues, bones and gastrointestinal tract, as well as meningitis and septicaemia in early childhood. Overall, the causative pathogens have most often been Gram-positive bacteria (Strep. pneumoniae and Staph. aureus) followed by Gram-negative bacteria (Pseudomonas spp. and Haemophilus influenzae) and mycobacteria. Most patients have severe hypogammaglobulinaemia with low serum IgG levels and varied levels of other immunoglobulin isotypes (IgA, IgM and IgE) [4]. Some patients have massively elevated IgM levels [20,22,65], and an impaired antibody response to polysaccharides is the most consistent feature of this condition [4]. Impaired natural killer (NK) cell activity is reported in some, but not all, patients with EDA–ID [66,67]; the degree and range of immunological abnormalities seen may relate to the type of NEMO mutation involved. Treatment of one such case with allogenic transplantation of umbilical cord blood resulted in the resolution of the eczematous eruption, although it is not clear if the defect in cellular immunity also resolved [68].

Autosomal dominant anhidrotic ectodermal dysplasia with T-cell immunodeficiency (MIM 612132) The importance of these pathways was further emphasized when a mutation was identified in a 7-year-old boy with autosomal dominant anhidrotic ectodermal dysplasia and T-cell immunodeficiency. A 94G-T transversion resulting in a serine 32 to isoleucine (S32I) change in the IkBa gene (inhibitor of kappa light chain gene enhancer in B cells alpha), also known as NFKBIA (nuclear factor of kappa light chain gene enhancer in B cell inhibitor alpha) was found [69]. Ser32 is a key phospho-acceptor site of IκBα, and is conserved in the other two IκB proteins. The mutation appeared to be a de novo event. The patient was born to unrelated parents. From 2 months of age he had chronic diarrhoea, recurrent bronchopneumonitis, hepatosplenomegaly and failure to thrive. A diagnosis of ectodermal dysplasia with immunodeficiency was made at the age of 3 years on the basis of a dry rough skin, moderately sparse scalp hair and conical teeth. The patient had no other overt developmental defects. This patient was treated with a successful bone marrow transplant, although occasional immunoglobulin substitution was required post transplant [70]. Three other cases, including

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one female, have been described with similar immunodeficiency, presenting with recurrent infections, abnormal teeth, coarse, wrinkled or dry skin and, in some, thin hair and recessed hairline [71–73].

Familial incontinentia pigmenti (incontinentia pigmenti type 2; MIM 308300) Please see Chapter 130 for a full discussion of this condition. References 1 Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998;16:225–60. 2 Kaufman CK, Fuchs E. It’s got you covered. NF-kappaB in the epidermis. J Cell Biol 2000;149:999–1004. 3 Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination. The control of NF-[kappa]B activity. Annu Rev Immunol 2000;18:621–63. 4 Smahi A, Courtois G, Rabia SH et al. The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet 2002;11:2371–5. 5 Gerondakis S, Grossmann M, Nakamura Y et al. Genetic approaches in mice to understand Rel/NF-kappaB and IkappaB function: transgenics and knockouts. Oncogene 1999;18:6888–95. 6 Descargues P, Sil AK, Karin M. IKKalpha, a critical regulator of epidermal differentiation and a suppressor of skin cancer. EMBO J 2008;27(20):2639–47. 7 Ferguson BM, Brockdorff N, Formstone E et al. Cloning of Tabby, the murine homolog of the human EDA gene: evidence for a membraneassociated protein with a short collagenous domain. Hum Mol Genet 1997;6:1589–94. 8 Kere J, Srivastava AK, Montonen O et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996;13:409–16. 9 Drogemuller C, Distl O, Leeb T. Partial deletion of the bovine ED1 gene causes anhidrotic ectodermal dysplasia in cattle. Genome Res 2001;11:1699–705. 10 Drogemuller C, Peters M, Pohlenz J et al. A single point mutation within the ED1 gene disrupts correct splicing at two different splice sites and leads to anhidrotic ectodermal dysplasia in cattle. J Mol Med 2002;80:319–23. 11 Casal ML, Scheidt JL, Rhodes JL et al. Mutation identification in a canine model of X-linked ectodermal dysplasia. Mamm Genome 2005;16(7):524–31. 12 Yan M, Wang LC, Hymowitz SG et al. Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors. Science 2000;290:523–7. 13 Chen Y, Molloy SS, Thomas L et al. Mutations within a furin consensus sequence block proteolytic release of ectodysplasin-A and cause X-linked hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci USA 2001;98:7218–23. 14 Han D, Gong Y, Wu H et al. Novel EDA mutation resulting in X-linked non-syndromic hypodontia and the pattern of EDA-associated isolated tooth agenesis. Eur J Med Genet 2008;51(6):536–46. 15 Barsh G. Of ancient tales and hairless tails. Nat Genet 1999;22: 315–16. 16 Headon DJ, Overbeek PA. Involvement of a novel TNF receptor homologue in hair follicle induction. Nat Genet 1999;22:370–4. 17 Headon DJ, Emmal SA, Ferguson BM et al. Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature 2001;414:913–16.

18 Bal E, Baala L, Cluzeau C et al. Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus. Hum Mutat 2007;28(7):703–9. 19 Monreal AW, Ferguson BM, Headon DJ et al. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 1999;22(4):366–9. 20 Doffinger R, Smahi A, Bessia C et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 2001;27:277–85. 21 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;405:466–72. 22 Zonana J, Elder ME, Schneider LC et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet 2000;67:1555–62. 23 Kojima T, Morikawa Y, Copeland NG et al. TROY, a newly identified member of the tumor necrosis factor receptor superfamily, exhibits a homology with Edar and is expressed in embryonic skin and hair follicles. J Biol Chem 2000;275:20742–7. 24 Eby MT, Jasmin A, Kumar A et al. TAJ, a novel member of the tumor necrosis factor receptor family, activates the c-Jun N-terminal kinase pathway and mediates caspase-independent cell death. J Biol Chem 2000;275:15336–42. 25 Naito A, Yoshida H, Nishioka E et al. TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci USA 2002;99:8766–71. 26 Blake PW, Toro JR. Update of cylindromatosis gene (CYLD) mutations in Brooke–Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat 2009;30(7):1025–36. 27 Trompouki E, Hatzivassiliou E, Tsichritzis T et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 2003;424(6950):793–6. 28 Kovalenko A, Chable-Bessia C, Cantarella G et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 2003;424(6950):801–5. 29 Brummelkamp TR, Nijman SM, Dirac AM et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NFkappaB. Nature 2003;424(6950):797–801. 30 Hutti JE, Shen RR, Abbott DW et al. Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKK-epsilon promotes cell transformation. Molec Cell 2009;34:461–72. 31 Zenker M, Mayerle J, Lerch MM et al. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson–Blizzard syndrome). Nat Genet 2005;37(12):1345–50. 32 Thurnam J. Two cases in which the skin, hair and teeth were very imperfectly developed. Med Chir Trans 1848;31:71–82. 33 Thadani KI. A toothless type of man. J Hered 1921;12:87–8. 34 Clouston H. The major forms of hereditary ectodermal dysplasia (with an autopsy and biopsies on the anhydrotic type). Can Med Assoc J 1939;40:1–7. 35 Arnold ML, Rauskolb R, Anton-Lamprecht I et al. Prenatal diagnosis of anhidrotic ectodermal dysplasia. Prenat Diagn 1984;4(2): 85–98. 36 Weech A. Hereditary ectodermal dysplasia (congenital ectodermal defect). A report of two cases. Am J Dis Child 1929;37:766–90. 37 Baer ST, Coulson IH, Elliman D. Anhidrotic ectodermal dysplasia: an ENT presentation in infancy. J Laryngol Otol 1988;102:458–9. 38 Micali G, Cook B, Blekys I et al. Structural hair abnormalities in ectodermal dysplasia. Pediatr Dermatol 1990;7(1):27–32. 39 Vierucci S, Baccetti T, Tollaro I. Dental and craniofacial findings in hypohidrotic ectodermal dysplasia during the primary dentition phase. J Clin Pediatr Dent 1994;18:291–7.

Ectodermal Dysplasias 40 Clarke A, Phillips DI, Brown R et al. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child 1987;62:989–96. 41 Reed WB, Lopez DA, Landing B. Clinical spectrum of anhidrotic ectodermal dysplasia. Arch Dermatol 1970;102:134–43. 42 Crawford PJ, Aldred MJ, Clarke A. Clinical and radiographic dental findings in X linked hypohidrotic ectodermal dysplasia. J Med Genet 1991;28:181–5. 43 Clauss F, Manière MC, Obry F et al. Dento-craniofacial phenotypes and underlying molecular mechanisms in hypohidrotic ectodermal dysplasia (HED): a review. J Dent Res 2008;87(12):1089–99. 44 Levin LS. Dental and oral abnormalities in selected ectodermal dysplasia syndromes. Birth Defects Orig Artic Series 1988;24:205–27. 45 Happle R, Frosch PJ. Manifestation of the lines of Blaschko in women heterozygous for X-linked hypohidrotic ectodermal dysplasia. Clin Genet 1985;27:468–71. 46 Executive and Scientific Advisory Boards of the National Foundation for Ectodermal Dysplasias, Mascoutah, Illinois. Scaling skin in the neonate: a clue to the early diagnosis of X-linked hypohidrotic ectodermal dysplasia (Christ–Siemens–Touraine syndrome). J Pediatr 1989;114(4 Part 1):600–2. 47 Clarke A. Hypohidrotic ectodermal dysplasia. J Med Genet 1987;24:659–63. 48 Butterworth T, Ladda R. Clinical Genodermatology. Westpoint, CT: Praeger, 1981, pp. 208–17. 49 Coston GN, Salinas CF. Speech characteristics in patients with hypohidrotic ectodermal dysplasia. Birth Defects Orig Artic Series 1988;24:229–34. 50 Wright JT, Finley WH. X-linked recessive hypohidrotic ectodermal dysplasia. Manifestations and management. Ala J Med Sci 1986;23(1):84–7. 51 Soderholm AL, Kaitila I. Expression of X-linked hypohidrotic ectodermal dysplasia in six males and in their mothers. Clin Genet 1985;28:136–44. 52 Freire-Maia N, Pinheiro M. Ectodermal Dysplasias: a Clinical and Genetic Study. New York: Alan R. Liss, 1984. 53 Sybert VP. Early diagnosis in the ectodermal dysplasias. Birth Defects Orig Artic Series 1988;24:277–8. 54 Nowak AJ. Dental treatment for patients with ectodermal dysplasias. Birth Defects Orig Artic Series 1988;24:243–52. 55 Guckes AD, Brahim JS, McCarthy GR et al. Using endosseous dental implants for patients with ectodermal dysplasia. J Am Dent Assoc 1991;122(11):59–62. 56 Myer CM 3rd. The role of an otolaryngologist in the care of ectodermal dysplasia. Pediatr Dermatol 1987;4:34–5. 57 Myer CM 3rd. Otolaryngologic manifestations of the ectodermal dysplasias – clinical note. Int J Pediatr Otorhinolaryngol 1986;11: 307–10. 58 Gaide O, Schneider P. Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nat Med 2003;9:614–18. 59 Casal ML, Lewis JR, Mauldin EA et al. Significant correction of disease after postnatal administration of recombinant ectodysplasin A in canine X-linked ectodermal dysplasia. Am J Hum Genet 2007;81(5):1050–6. 60 Mauldin EA, Gaide O, Schneider P et al Neonatal treatment with recombinant ectodysplasin prevents respiratory disease in dogs with X-linked ectodermal dysplasia. Am J Med Genet A 2009;149A(9):2045–9. 61 Frix CD 3rd, Bronson DM. Acute miliary tuberculosis in a child with anhidrotic ectodermal dysplasia. Pediatr Dermatol 1986;3:464–7. 62 Sitton JE, Reimund EL. Extramedullary hematopoiesis of the cranial dura and anhidrotic ectodermal dysplasia. Neuropediatrics 1992;23:108–10. 63 Abinun M, Spickett G, Appleton AL et al. Anhidrotic ectodermal dysplasia associated with specific antibody deficiency. Eur J Pediatr 1996;155:146–7.

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64 Schweizer P, Kalhoff H, Horneff G et al. Polysaccharide specific humoral immunodeficiency in ectodermal dysplasia. Case report of a boy with two affected brothers. Klin Padiatr 1999;211:459–61. 65 Jain A, Ma CA, Liu S et al. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2001;2:223–8. 66 Orange JS, Brodeur SR, Jain A et al. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest 2002;109:1501–9. 67 Dupuis-Girod S, Corradini N, Hadj-Rabia S et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics 2002;109(6):e97. 68 Minakawa S, Takeda H, Nakano H et al. Successful umbilical cord blood transplantation for intractable eczematous eruption in hypohidrotic ectodermal dysplasia with immunodeficiency. Clin Exp Dermatol 2009;34(7):e441–2. 69 Courtois G, Smahi A, Reichenbach J et al. A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and t-cell immunodeficiency. J Clin Invest 2003;112: 1108–15. 70 Dupuis-Girod S, Cancrini C, Le Deist F et al. Successful allogeneic hemopoietic stem cell transplantation in a child who had anhidrotic ectodermal dysplasia with immunodeficiency. Pediatrics 2006;118(1):205–11. 71 Janssen R, van Wengen A, Hoeve MA et al. The same I-kappa-B-alpha mutation in two related individuals leads to completely different clinical symptoms. J Exp Med 2004;200:559–68. 72 Lopez-Granados E, Keenan JE, Kinney MC et al. A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum Mutat 2008;29:861–8. 73 McDonald DR, Mooster JL, Reddy M et al. Heterozygous N-terminal deletion of I-kappa-B-alpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency. J Allergy Clin Immunol 2007;120:900–7.

Transcription factors, homeobox genes: major regulators of gene expression TP63-related phenotypes: overview of molecular pathway The p53 gene family is a key regulator of the cell cycle and is mutated in more than 50% of human cancers. p63 and p73 are recently discovered [1–5], related genes that share high amino acid identity with p53. The role of p63 and p73 in human cancers has been extensively studied, but neither molecule is believed to play a significant role in tumorigenesis. Both p63 and p73 are distinct from p53 in that they each have a C-terminal protein–protein interacting motif (sterile α motif – SAM domain) that is not present in p53. The p63 and p73 genes also differ from p53 in that they can each encode several different isoforms by utilizing two different transcription initiation sites (for review see ref. 6). The expression of p63 is more restricted than the ubiquitous nature of p53 expression and is restricted to the embryonic ectoderm and the basal regenerative layers of epithelial tissues in adults (skin, cervix,

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tongue, oesophagus, mammary glands, prostate and urothelium [5]). p63 −/− mice die at birth and have truncation of limbs (especially the forelimbs, with complete absence of phalanges and carpals) and absence of ectodermal derivatives including the epidermis and appendages (whiskers, hair, etc.), the prostate, lacrimal, breast and urothelial tissues [7,8]. Limb defects are best explained by a failure of the apical ectodermal ridge to develop [8]. Mutations in the human p63 gene, TP63, have now been identified in six distinct human phenotypes, all of which have ectodermal dysplasia as a key feature. Some genotype–phenotype correlation is possible in that there is clustering of mutations in some of the phenotypes to specific sites of the p63 molecule (for review see ref. 6). TP63 mutations account for most cases of ectrodactylyectodermal dysplasia-clefting syndrome (EEC syndrome). In an authoritative paper, van Bokhoven et al. [9] were able to demonstrate mutations in 40 out of 43 families with EEC; all but one of these mutations were sited within the DNA-binding domain, and five amino acid residues accounted for 75% of all mutations [9]. In ankyloblepharonectodermal dysplasia-clefting syndrome (AEC syndrome, also known as Hay–Wells syndrome), in which the limb abnormalities are absent or minimal, mutations have been exclusively detected within the SAM domain and are associated with complex gain-of-function as well as loss- and change-of-function effects [9]. In limb-mammary syndrome (LMS), TP63 frameshift mutations leading to truncations of p63 protein have been reported in exon 13 in two unrelated patients [9] and an N-terminal mutation was found in a further family [6]. Mutations in acrodermato-ungual–tooth syndrome (ADULT syndrome) have yielded interesting insights in that the first mutation was identified in exon 3′, which is only expressed in the transactivating (TA) isotypes of p63 and causes an amino acid substitution outside the DNA-binding domain [10]. A subsequent report has demonstrated a mutation that confers significant transactivation activity on ΔN-p63γ, an otherwise inert isoform of p63 [6]. Non-syndromic split hand-split foot syndrome (SHFM) is a genetically heterogeneous group of conditions, but some cases (possibly around 10%) are attributable to p63 mutations [9]. Some of these mutations seem specific for SHFM, but others underlie both EEC and SHFM [6]. It is therefore understandable that of the six known types of SHFM, ectodermal dysplasia features are most commonly seen in SHFM4, which shares the same gene as EEC, while SHFM3, which maps to 10q24, has only dental and nail findings [11]. The TP63 gene product can act as an activator or a repressor, and mutations in the 5′ end of TP63 in AEC and Rapp–Hodgkin syndrome show loss of activator function, and even dominant-negative activity [12,13]. While clustering of mutations is determined in part by the char-

acteristics of the mutated residue, whether it is a CpG site, etc., the degree of clustering in this group of conditions suggests that each condition has a specific pathogenetic mechanism. This site specificity also presumably suggests that the p63 protein has several functions, each with a specific site, and that each of these functions can be disturbed in isolation from the others. However, overlapping phenotypes are not uncommon and further elucidation of TP63 may shed light on the role of this protein and its downstream pathway [14,15]. One target of p63 is PERP (p53 effector related to PMP22), a gene that has an effect on cell–cell adhesion and is a potential tumour suppressor gene [16,17]. PERP levels may vary in patients with the same TP63 mutation; therefore modifier genes and other proteins are likely to be involved in the phenotypic expression of TP63 mutations [18]. IKKα, discussed above, is a direct transcriptional target of ΔNp63α [19,20]. A mouse model may shed further light on the role of p63 in ectodermal dysplasia [21].

Ankyloblepharon-ectodermal dysplasiaclefting syndrome (AEC; Hay–Wells syndrome; MIM 106260) Definition. Ankyloblepharon-ectodermal dysplasiaclefting syndrome is characterized by cleft lip/palate, severe scalp erosions and abnormalities of the epidermal appendages including hypotrichosis, hypodontia, absent or dystrophic nails and mild hypohidrosis. One distinctive feature is ankyloblepharon filiforme adnatum, partial-thickness fusion of the eyelid margins. Recently, mutations in TP63 have also been identified in Rapp– Hodgkin syndrome (MIM 129400) (Fig. 127.8) [22], demonstrating that this disorder is allelic with AEC syndrome. Clinical distinction between these two disorders is probably not warranted. History. In 1976, Hay and Wells described seven patients from four families with an inherited disorder characterized by congenital filiform fusion of the eyelids, dysplasia of the epidermal appendages and cleft lip/palate. Five of these original seven patients had ankyloblepharon filiforme adnatum and one had small nodules removed from her eyelids as a child, presumably remnants of spontaneously lysed ankyloblepharon [23]. Pathology. Hair shafts are thin and atrophic, and show various defects, including fractures of the cuticle, bent shafts, trichoclasis, trichorrhexis nodosa, pili canaliculi, pili annulati, pili triangulati and pili torti, none of which is specific for the disorder [24,25]. Dyspigmentation of the hair is relatively common, with pigment variation both between and within hairs; pigment may be normal, clumped or nearly absent [25].

Ectodermal Dysplasias

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(b)

(a)

(d)

(c)

(e)

Fig. 127.8 (a,b) A father and daughter with Rapp–Hodgkin syndrome (AEC). Both have history of cleft palate. Note the typical facies (high forehead, hypoplastic maxilla and thin upper lip) and brittle, wiry hair in childhood, which can progress to alopecia in adulthood. The father was previously wearing a hairpiece. (c) Scalp dermatitis with alopecia seen in Rapp–Hodgkin syndrome (AEC). (d,e) Hypodontia and nail dysplasia in Rapp–Hodgkin syndrome (AEC). Courtesy of Dr Jean Bernard.

Skin biopsy of involved scalp tissue shows a thin granular layer and stratum corneum [26]. Biopsies from clinically ‘normal’ skin show mild hyperkeratosis and papillomatosis, epidermal atrophy and pigment incontinence, as well as a prominent superficial perivascular

plexus with minimal to mild perivascular lymphocyte infiltrates [25]. Hair follicles are reduced in size and arrector pili muscles appear hypertrophic [26]. Sweat stimulation tests reveal a patchy loss of sweat glands over most of the body [23].

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Clinical features

Hair Scalp hair is wiry, coarse and sparse; alopecia is common. The eyebrows and eyelashes are almost always short, brittle and sparse or absent. Body, pubic and axillary hair may be sparse or absent [23,24,27]. Some may also display scarring alopecia or ‘spun-glass’ uncombable hair [28]. Teeth Hypodontia is common. Those teeth that are present are frequently small, conical and discoloured with white or yellow spots secondary to enamel hypoplasia [23,24,27,29,30]. Maxillary and mandibular first molars are the most likely of the permanent teeth to be present, while maxillary incisors and canines tend to be absent, probably due to the alveolar cleft defect [30].

scarring, in a cribriform, reticulate, stellate or punctate pattern [28]. Over two-thirds of individuals have chronic problems with severe recurrent scalp erosions and scalp infections, which are a major feature of AEC syndrome (Fig. 127.11) [27]. Palmoplantar keratoderma was reported in four of the original seven patients described by Hays and Wells [23]. It is not a common finding in affected children but may be more pronounced in adults. Both hypopigmentation and hyperpigmentation can occur,

Nails Nail abnormalities are variable even within an individual and include distal hypoplasia and thickened, hyperconvex plates. Complete absence of nails is a frequent finding [23]. Chronic paronychia has been reported [24]. Sweat glands Decreased sweat production and heat intolerance is described by a significant number of individuals but hyperpyrexia is not a problem [27,28]. Sweat pores are reduced in a number in affected individuals [23]. Skin At birth, over three-quarters of affected newborns have red, eroded, peeling skin like a collodion membrane (Fig. 127.9) [27] or may present with erythroderma [31]. Erosions are most prominent over the scalp [28]. These symptoms resolve over the first few weeks and the underlying skin is dry (Fig. 127.10). Erosions may heal with residual

Fig. 127.9 Peeling, red, parchment-like skin in a newborn with AEC syndrome. Courtesy of Dr Virginia Sybert.

Fig. 127.10 The parchment skin resolves over the first few weeks of life and the underlying skin is dry as seen in this 1-month-old baby with AEC syndrome.

Fig. 127.11 Severe scalp erosions and extensive granulation tissue in a 5-year-old girl with AEC syndrome. Courtesy of Dr Virginia Sybert and Dr Mark Stephan.

Ectodermal Dysplasias

commonly in a reticulate pattern in intertriginous areas; this may progress with age [28].

Other ectodermal structures Ankyloblepharon filiforme adnatum (strands of epithelial tissue between the eyelids) are a cardinal feature of the disorder but are noted in only 70% of patients (Fig. 127.12) [23,24,27]. The strands may lyse spontaneously and may be difficult to detect. Lacrimal duct atresia or obstruction occurs in over half of affected individuals [27]. Supernumerary nipples may be present [24,27]. Nutritional issues are common, which are not specifically related to cleft palate and lip. One-quarter of patients require gastrostomy placement, and nutritional supplements at some point in time are required in two-thirds of patients. Low birthweight is common, although birth length is unaffected. Weight issues resolve with time, but AEC patients have significantly lower height-for-age than the reference population [32].

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media and secondary hearing loss. Atresia of the lacrimal duct can lead to excessive lacrimation, chronic conjunctivitis and photophobia. Scalp erosions and chronic scalp infections may be severe enough to warrant surgical intervention with skin engraftment [27]. Prenatal diagnosis of cleft palate/lip by ultrasound may be possible in affected families [34]. Differential diagnosis. Curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS) is a rare autosomal recessive ectodermal dysplasia with curly, kinky hair, hypoplastic nails and the defining feature of ankyloblepharon. It can be distinguished from AEC by absence of cleft palate and lack of typical craniofacial features [35,36]. In the newborn period, the eroded, peeling skin seen in AEC syndrome may be mistaken for epidermolysis bullosa [37].

Other abnormalities Other features seen occasionally in AEC syndrome include cutaneous syndactyly of the second and third toes, hypospadias and vaginal dryness and erosions [27].

Treatment. Emollients are appropriate for the collodionlike membrane in the newborn. Neonates with AEC often have extremely fragile skin and they should be handled with extreme care. Neonatal intensive care nursing protocols such as those used for neonates with epidermolysis bullosa should be used. The ankyloblepharon filiforme adnatum may require surgical correction or may lyse spontaneously. The lacrimal duct atresia may be surgically correctable [38]. The scalp requires aggressive wound care and treatment with topical or systemic antibiotics as warranted [27]. Other abnormalities, such as cleft lip/palate, hypospadias and the maxillary hypoplasia, may be surgically corrected [33]. Teeth preservation and restoration are imperative [29].

Prognosis. Abnormalities of the external ear canals and palate frequently cause problems with chronic otitis

Ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC; MIM 12990)

Craniofacial features Typical craniofacial features include a broadened nasal bridge and maxillary hypoplasia [33]. The ears may be small and low-set with deformities of the auricle [27]. The ear canals may be webbed and abnormally shaped [24]. Cleft lip is a variable feature but cleft palate is seen in most individuals [23–27].

Definition. The main features of the EEC syndrome are ectrodactyly (spilt hand or foot deformity), cleft lip/ palate, tear duct anomalies and abnormalities of the epidermal appendages including hypotrichosis, hypodontia, dystrophic nails and occasional hypohidrosis. History. The association of ectrodactyly, cleft lip/palate and ectodermal dysplasia was initially described by Rüdiger et al. [39], who recognized that this combination of defects represents a specific syndrome, termed EEC syndrome. Over 150 cases have subsequently been described [26].

Fig. 127.12 Ankyloblepharon filiforme adnatum (strands of epithelial tissue between the eyelids) in a newborn with AEC syndrome. Courtesy of Dr Virginia Sybert.

Pathology. Radiographs of hand or foot deformities show missing or hypoplastic metacarpals and metatarsals [40]. Scanning electron microscopic studies of hair shafts of affected individuals show longitudinal grooves, distorted bulbs and cuticular defects [41,42]. These findings

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can be seen in a number of other ectodermal dysplasias and are not specific to EEC syndrome. Clinical features

Hair The scalp hair is fine and sparse, light-coloured and may be wiry in texture. Eyebrows and eyelashes are short, thin and sparse. Axillary, pubic and body hair may also be affected [39–41,43]. Teeth Teeth may be small, abnormally shaped or missing [39– 41,43]. Premature loss of secondary teeth is common, presumably owing to multiple caries from enamel hypoplasia. Nails The nail plates may be dystrophic, hypoplastic or completely absent even when there are no bony defects of the involved digit [43,44]. Sweat glands Sweating is usually normal but heat intolerance is noted by a few individuals [40,43,45]. Skin Dry skin and hyperkeratosis, particularly of the lower extremities, are reported in some individuals [46,47]. Scalp dermatitis is seen rarely [41,47]. Other ectodermal structures Atresia or hypoplasia of the lacrimal duct is seen in over 90% of affected individuals [26,46,48]. Secretions from the lacrimal gland may be diminished [48]. Nipple anomalies are reported in a few individuals [46].

Fig. 127.13 Ectrodactyly of the hands in a young man with EEC syndrome. Courtesy of Dr Virginia Sybert.

finding is megaureter [50,51]. Urinary abnormalities may be more common in those cases of EEC with an Arg227Gln TP63 mutation [52]. Abnormalities of the external genitalia have also been described [51]. Mental retardation is a variable and uncommon feature of the disorder, occurring in less than 10% of affected individuals [46], and may be limited to those with chromosomal deletions as part of a contiguous gene syndrome. Hearing loss occurs in about 15% of individuals [46]. It is uncertain whether this is primary or secondary to recurrent otitis media. Isolated growth hormone deficiency has been reported in one individual [53]. Endocrine anomalies such as hypogonadotropic hypogonadism, thyroidstimulating hormone and prolactin deficiency have also been reported [54]. Cases of concomitant Hodgkin, nonHodgkin and B-cell lymphoma in EEC have also been reported [54–56].

Craniofacial features The nose may be broad, the chin pointed, and there may be minor variable ear anomalies, but the facies are not distinct. Cleft palate with or without cleft lip occurs in three-quarters of affected individuals and is a major feature of this disorder [46]. Choanal atresia has been reported [49].

Prognosis. A significant number of affected individuals experience excessive tearing, conjunctivitis and blepharitis as a result of lacrimal duct hypoplasia. Photophobia and corneal ulcers as well as corneal scarring and perforation may occur as a result of lacrimal gland hypoplasia [48]. Recurrent urinary tract infections, both symptomatic and asymptomatic, may be a problem in individuals with genitourinary anomalies [50].

Other abnormalities Ectrodactyly (lobster claw deformity) is a major feature of this disorder and occurs in over 90% of affected individuals (Fig. 127.13). About three-quarters of individuals with ectrodactyly have both hand and foot involvement [46]. Structural abnormalities of the genitourinary tract occur in about one-third of individuals, including cryptorchidism, hypospadias, hydronephrosis and hydroureters, renal agenesis, and duplication of the kidneys and collecting system [46]; the most common structural

Differential diagnosis. A few other ectodermal dysplasias involve limb abnormalities and cleft palate/lip. Although clefting is not a constant feature, odontotrichomelic syndrome may be differentiated by severe tetramelic reductions and autosomal recessive mode of inheritance [26]. Other rare syndromes, such as Martinez syndrome, Zlotogora–Ogur syndrome and Rosselli– Gulienetti syndrome, can be differentiated from EEC by specific limb abnormalities and mode of inheritance (see Table 127.1).

Ectodermal Dysplasias

Treatment. Treatment involves surgical correction of the cleft lip/palate, lacrimal duct and limb defects and genitourinary abnormalities as indicated. DNA-based prenatal diagnosis is available for selected families in which the gene defect is known.

Acro-dermato-ungual-tooth (ADULT; MIM 103285) Acro-dermato-ungual-tooth syndrome is a rare condition distinguished from EEC syndrome by an absence of facial clefting. Patients have, in addition, excessive freckling and exfoliative dermatitis of the digits [57]. Other features, such as hyperextensibility of the distal interphalangeal joints, bilateral duplicate thumbs, bifid toenails, genitourinary defects and conductive hearing loss, have also been described [58].

Limb-mammary syndrome (LMS; MIM 603543) This previously unrecognized autosomal dominant syndrome was described in a Dutch family with a constellation of features that had not previously been reported. The major features were a combination of hand and foot anomalies and mammary gland aplasia/hypoplasia. The skin and hair were normal in all affected individuals but some had lacrimal duct atresia, nail dysplasia, hypohidrosis, hypodontia or cleft palate [6]. LMS is distinguished from EEC syndrome by the consistent finding of mammary anomalies in LMS (infrequent in EEC) and the much more frequent finding of skin, nail and tooth anomalies in EEC syndrome. The clefting in LMS is of the palate only whereas in EEC syndrome the lip and palate are affected [6].

Non-syndromic split hand-split foot syndrome (SHFM; MIM 183600)

127.79

most likely transcription factors, given the hypothetical structural characteristics (nuclear localization, two DNAbinding domains, leucine-rich zipper domain). The products of these two genes are thought to function co-ordinately in cardiac development [62]. Mutations in these genes may also cause Weyer acrofacial dysostosis (MIM 193530), an autosomal dominant allelic disorder [60]. Witkop syndrome (MIM 189500) is an autosomal dominant ED with primary manifestation in the teeth (taurodontia, partial or complete anodontia) and nails (koilonychia, longitudinal ridging and nail pits) [63]. Recently, mutations have been identified in the MSX1 gene, a member of the homeobox gene family and an important regulator of transcription [63]. Of the EDs more likely to be seen by a paediatric dermatologist, trichodento-osseous (TDO) syndrome and trichorhinophalangeal syndrome (TRPS) have both been attributed to mutations in transcription factors. The causative gene for TDO is DLX3 [64], a homeodomain transcription factor that is developmentally expressed in many structures derived from epithelial–mesenchymal interactions such as teeth, hair follicle and limb buds [65]. Mutations in this gene were previously thought to cause amelogenesis imperfecta (type IV) [66]; however, this condition is now thought to simply be an attenuated phenotype of TDO [67]. The TRPS1 gene underlies TRPS types I and III [68,69] and a microdeletion syndrome (8q42.11-8q24.1), which includes TRPS1 and EXT1, underlies TRPS type II [70,71]. Computer analysis of the protein encoded by TRPS1 suggests that it is a novel transcription factor with an unusual composition of nine putative zinc-finger motifs of four different types [72]. All the mutations in TRPS1 probably act as loss-of-function mutations, meaning that haploinsufficiency is the likely mechanism in TRPS. TDO and TRPS are discussed in detail below.

This condition has no dermatological features and is not discussed in detail here.

Trichodento-osseous syndrome (MIM 190320)

Defects in transcription factors other than p63

Definition. Trichodento-osseous syndrome is a welldefined ectodermal dysplasia manifesting in kinky hair, hypoplasia of tooth enamel and asymptomatic sclerotic bone changes.

In addition to the p63 pathway, several other EDs have now been attributed to defects in transcription factors that control the expression of several target genes important in ectodermal morphogenesis. In many cases, positional cloning studies have yielded the primary mutation but the detailed molecular signalling pathways have yet to be delineated. Ellis–van Creveld syndrome (EvC) is a recessive ED that is characterized by a skeletal dysplasia with short limbs, short ribs, postaxial polydactyly and congenital heart defects [59]. Mutations in the EVC1 and EVC2 genes have been identified in this syndrome [60,61] and these proteins, although not fully characterized, are

History. Lichtenstein et al. [73] defined the features of this disorder in 107 individuals and proposed the name TDO syndrome. Robinson and Miller [74] were the first authors to describe this syndrome, but they did not detect bone involvement as part of the disorder. Some authors argue that the clinical manifestations observed in some families are sufficiently varied to suggest genetic heterogeneity and classify TDO syndrome into three subtypes that differ primarily by the degree of bone involvement

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[75,76]. Variable expression of a single gene seems a more plausible explanation for other authors [77]. Pathology. On dental radiographs, unerupted teeth and taurodontia (increased size of the tooth pulp chamber) are found [78]. Scanning electron microscopic analysis of affected teeth shows pits and depressions in the tooth enamel, uniformly thin tooth enamel and an abnormal collagenous membrane around the open apices [79]. Radiographs of the skull reveal sclerosis and sometimes thickening of the calvarium. The long bones may also be sclerotic [77].

blepharon and nail dysplasia), but ankyloblepharon makes this disorder distinct. Tooth and nail syndrome lacks kinky or curly hair. Treatment. This includes appropriate dental restoration [80].

Trichorhinophalangeal syndrome type I (MIM 190350); trichorhinophalangeal syndrome type II (Langer–Giedion syndrome; MIM 150230); trichorhinophalangeal syndrome type III (Sugio–Kajii syndrome; MIM 190531)

Clinical features [73,76,77,79]

Hair At birth, the scalp hair is thick and kinky or curly; it may straighten in later life. The eyelashes may also be curly. Teeth Teeth abnormalities are present in all patients and include pitted, hypoplastic enamel with brownish-yellow discoloration of both primary and permanent teeth, and taurodontia. Tooth eruption may be delayed and abscesses are common. Multiple dental caries occur and lead to early loss of teeth.

Definition. The trichorhinophalangeal syndrome is characterized by sparse scalp hair, bulbous pear-shaped nose, small teeth with dental malocclusion, thin nails, coneshaped epiphyses, short stature and occasional skeletal abnormalities. Clinical features [81,82]

Hair The hair is usually fine, blond and sparse; the most prominently affected areas are the frontotemporal areas. The eyebrows are sparse or absent.

Nails Fingernails are thin and brittle and peel readily. Toenails may be thickened or normal.

Teeth Dental abnormalities are frequent, with supernumerary incisors, microdontia and poorly aligned teeth.

Sweat glands Sweating abnormalities are not found in this disorder.

Nails The nails are occasionally thin and short, with long longitudinal grooves. They can be flattened, koilonychia-like and normal in colour. ‘Racket’ thumbnails have been described.

Skin The skin is normal and other ectodermal structures are normal. Craniofacial features There is frontal bossing, the jaw is square and the head is elongated. Partial premature fusion of the cranial sutures occurs in three-quarters of affected individuals. The bones of the skull are radiographically dense and may be thick. This is not problematic for the patient and may be found incidentally when radiographs of the skull are obtained for unrelated reasons. Other abnormalities Clinodactyly is rarely seen. Prognosis. Affected individuals are healthy but lose most of their teeth by the age of 30 years [73]. Differential diagnosis. Curly hair and nail dysplasia is also seen in CHANDS syndrome (curly hair, ankylo-

Sweat glands and skin There are no abnormalities of sweat glands or skin. Other ectodermal structures There is occasional exotropia and photophobia. Craniofacial features Many patients have a characteristic facies with a pearshaped nose, a long and wide philtrum and large, prominent ears. A narrow palate is often noted. Other features Short stature is common and a wide range of skeletal abnormalities have been described, including brachymesophalangy, brachymetacarpy, brachymetatarsy and peripheral dysostosis with type 12 cone-shaped epiphyses at some of the middle phalanges of the hands. Joints are often thickened, ulnar and radial deviation of the

Ectodermal Dysplasias

fingers is seen and there are occasional abnormalities such as clinodactyly, winged scapulae and coxa valga. Perthes-like abnormalities have been reported in a few cases [83]. Chest wall deformities such as pectus carinatum, lordosis or kyphoscoliosis are occasional features. Type II TRPS shares many characteristics with types I and III but is more significantly associated with mental retardation. In addition, there are multiple cutaneous exostoses and marked redundant or loose skin and more marked joint laxity. Type III TRPS differs from TRPS I by the presence of severe brachydactyly, owing to short metacarpals, and more severe short stature [84,85]. There is an emerging genotype–phenotype correlation in that mutations in the GATA DNA-binding zinc finger seem to predict a type III phenotype, whereas mutations elsewhere are associated with TRPS I [69]. References 1 Jost CA, Marin MC, Kaelin WG Jr. p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature 1997;389:191–4. 2 Kaghad M, Bonnet H, Yang A et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997;90:809–19. 3 Osada M, Ohba M, Kawahara C et al. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nat Med 1998;4:839–43. 4 Senoo M, Seki N, Ohira M et al. A second p53-related protein, p73L, with high homology to p73. Biochem Biophys Res Commun 1998;248:603–7. 5 Yang A, Kaghad M, Wang Y et al. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 1998;2:305–16. 6 Brunner HG, Hamel BC, van Bokhoven H. P63 Gene mutations and human developmental syndromes. Am J Med Genet 2002;112:284–90. 7 Mills AA, Zheng B, Wang X-J et al. p63 is a p53 homolog required for limb and epidermal morphogenesis. Nature 1999;398:708–13. 8 Yang A, Schweizer R, Sun D et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999;398:7147–8. 9 Van Bokhoven H, Hamel BC, Bamshad M et al. p63 Gene mutations in EEC syndrome, limb–mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 2001;69:481–92. 10 Amiel J, Bougeard G, Francannet C et al. TP63 gene mutation in ADULT syndrome. Eur J Hum Genet 2001;9:642–5. 11 Elliott AM, Evans JA. Genotype-phenotype correlations in mapped split hand foot malformation (SHFM) patients. Am J Med Genet A 2006;140(13):1419–27. 12 Rinne T, Bolat E, Meijer R et al. Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC). Am J Med Genet A 2009;149A(9):1948–51. 13 Rinne T, Clements SE, Lamme E et al. A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp–Hodgkin/Hay–Wells-like syndromes. Hum Mol Genet 2008;17:1968–77. 14 Chiu YE, Drolet BA, Duffy KJ et al. A case of ankyloblepharon, ectodermal dysplasia, and cleft lip/palate syndrome with ectrodactyly:

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are the p63 syndromes distinct after all? Pediatr Dermatol 2009 Oct 1. [Epub ahead of print] Slavotinek AM, Tanaka J, Winder A et al. Acro-dermato-unguallacrimal-tooth (ADULT) syndrome: report of a child with phenotypic overlap with ulnar-mammary syndrome and a new mutation in TP63. Am J Med Genet A 2005;138A(2):146–9. Hildebrandt T, Preiherr J, Tarbe N, Klostermann S, van Muijen GN, Weidle UH. Identification of THW, a putative new tumor suppressor gene. Anticancer Res 2000;20:2801–10. Ihrie RA, Marques MR, Nguyen BT et al. Perp is a p63-regulated gene essential for epithelial integrity. Cell 2005;120:843–56. Beaudry VG, Pathak N, Koster MI et al. PERP regulation by TP63 mutants provides insight into AEC pathogenesis. Am J Med Genet A 2009;149A:1952–7. Koster MI, Dai D, Marinari B et al. p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci USA 2007;104(9):3255–60. Marinari B, Ballaro C, Koster MI et al. IKKalpha is a p63 transcriptional target involved in the pathogenesis of ectodermal dysplasias. J Invest Dermatol 2009;129(1):60–9. Koster MI, Marinari B, Payne AS et al. DeltaNp63 knockdown mice: a mouse model for AEC syndrome. Am J Med Genet A 2009;149A(9):1942–7. Chan I, McGrath JA, Kivirikko S. Rapp–Hodgkin syndrome and the tail of p63. Clin Exp Dermatol 2005;30:183–6. Hay RJ, Wells RS. The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition. Br J Dermatol 1976;94:277–89. Greene SL, Michels VV, Doyle JA. Variable expression in ankyloblepharon-ectodermal defects-cleft lip and palate syndrome. Am J Med Genet 1987;27:207–12. Dishop MK, Bree AF, Hicks MJ. Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet A 2009;149A:1935–41. Fosko SW, Stenn KS, Bolognia JL. Ectodermal dysplasias associated with clefting: significance of scalp dermatitis. J Am Acad Dermatol 1992;27:249–56. Vanderhooft SL, Stephan MJ, Sybert VP. Severe skin erosions and scalp infections in AEC syndrome. Pediatr Dermatol 1993;10: 334–40. Julapalli MR, Scher RK, Sybert VP et al. Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet A 2009;149A:1900–6. Rule DC, Shaw MJ. The dental management of patients with ankyloblepharon (AEC) syndrome. Br Dent J 1988;164:215–18. Farrington F, Lausten L. Oral findings in ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome. Am J Med Genet A 2009;149A(9):1907–9. Yoo J, Beck DR, Fabre E et al. Ankyloblepharon-ectodermal dysplasiaclefting (AEC) syndrome with neonatal erythroderma: report of two cases. Int J Dermatol 2007;46:1196–7. Motil KJ, Fete TJ. Growth, nutritional, and gastrointestinal aspects of ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) syndrome. Am J Med Genet A 2009;149A(9):1922–5. Satoh K, Tosa Y, Ohtsuka S et al. Ankyloblepharon, ectodermal dysplasia, cleft lip and palate (AEC) syndrome: surgical corrections with an 18-year follow-up including maxillary osteotomy. Plast Reconstr Surg 1994;93:590–4. Bronshtein M, Gershoni-Baruch R. Prenatal transvaginal diagnosis of the ectrodactyly, ectodermal dysplasia, cleft palate (EEC) syndrome. Prenat Diagn 1993;13:519–22. Baughman FA Jr. CHANDS: the curly hair–ankyloblepharon–nail dysplasia syndrome. Birth Defects Orig Artic Series 1971;7:100–2. Toriello HV, Lindstrom JA, Waterman DF et al. Re-evaluation of CHANDS. J Med Genet 1979;16:316–17.

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37 Taieb A, Legrain V, Surleve-Bazeille JE et al. Generalized epidermolysis bullosa with congenital synechiae, associated malformations and unusual ultrastructure: a new entity? Dermatologica 1988;176: 76–82. 38 Hicks C, Pitts J, Rose GE. Lacrimal surgery in patients with congenital cranial or facial anomalies. Eye 1994;8:583–91. 39 Rüdiger RA, Haase W, Passarge E. Association of ectrodactyly, ectodermal dysplasia, and cleft lip–palate. Am J Dis Child 1970;120: 160–3. 40 Bixler D, Spivack J, Bennett J et al. The ectrodactyly–ectodermal dysplasia–clefting (EEC) syndrome. Report of 2 cases and review of the literature. Clin Genet 1972;3:43–51. 41 Trueb RM, Bruckner-Tuderman L, Wyss M et al. Scalp dermatitis, distinctive hair abnormalities and atopic disease in the ectrodactyly– ectodermal dysplasia–clefting syndrome. Br J Dermatol 1995;132:621–5. 42 Micali G, Cook B, Blekys I et al. Structural hair abnormalities in ectodermal dysplasia. Pediatr Dermatol 1990;7:27–32. 43 Kuster W, Majewski F, Meinecke P. EEC syndrome without ectrodactyly? Report of 8 cases. Clin Genet 1985;28:130–5. 44 Rosenmann A, Shapira T, Cohen MM. Ectrodactyly, ectodermal dysplasia and cleft palate (EEC syndrome). Report of a family and review of the literature. Clin Genet 1976;9:347–53. 45 Richieri-Costa A, de Vilhena-Moraes SA, Ferrareto I et al. Ectodermal dysplasia/ectrodactyly in monozygotic female twins. Report of a case-review and comments on the ectodermal dysplasia/ectrodactyly (cleft lip/palate) syndromes. Rev Brasil Genet 1986;9:349–74. 46 Rodini ES, Richieri-Costa A. EEC syndrome. Report on 20 new patients: clinical and genetic considerations. Am J Med Genet 1990;37:42–53. 47 Trueb RM, Bruckner-Tuderman L, Burg G. Ectrodactyly-ectodermal dysplasia–clefting syndrome with scalp dermatitis. J Am Acad Dermatol 1993;29:505–6. 48 McNab AA, Potts MJ, Welham RA. The EEC syndrome and its ocular manifestations. Br J Ophthalmol 1989;73:261–4. 49 Christodoulou J, McDougall PN, Sheffield LJ. Choanal atresia as a feature of ectrodactyly–ectodermal dysplasia–clefting (EEC) syndrome. J Med Genet 1989;26:586–9. 50 Nardi AC, Ferreira U, Netto NR Jr et al. Urinary tract involvement in EEC syndrome: a clinical study in 25 Brazilian patients. Am J Med Genet 1992;44:803–6. 51 Rollnick BR, Hoo JJ. Genitourinary anomalies are a component manifestation in the ectodermal dysplasia, ectrodactyly, cleft lip/palate (EEC) syndrome. Am J Med Genet 1988;29:131–6. 52 Maclean K, Holme SA, Gilmour E et al. EEC syndrome, Arg227Gln TP63 mutation and micturition difficulties: is there a genotypephenotype correlation? Am J Med Genet A 2007;143A(10):1114–19. 53 Knudtzon J, Aarskog D. Growth hormone deficiency associated with the ectrodactyly-ectodermal dysplasia–clefting syndrome and isolated absent septum pellucidum. Pediatrics 1987;79:410–12. 54 Gershoni-Baruch R, Goldscher D, Hochberg Z. Ectrodactylyectodermal dysplasia-clefting syndrome and hypothalamo-pituitary insufficiency. Am J Med Genet 1997;68(2):168–72. 55 Balci S, Engiz O, Okten G, Sipahier M, Gursu G, Kandemir B. A 19year follow-up of a patient with type 3 ectrodactyly-ectodermal dysplasia-clefting syndrome who developed non-Hodgkin lymphoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108(3):e91–5. 56 Akahoshi K, Sakazume S, Kosaki K, Ohashi H, Fukushima Y. EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma. Am J Med Genet A 2003;120A(3): 370–3. 57 Propping P, Zerres K. ADULT syndrome: an autosomal-dominant disorder with pigment anomalies, ectrodactyly, nail dysplasia, and hypodontia. Am J Med Genet 1993;45:642–8.

58 Reisler TT, Patton MA, Meagher PPJ. Further phenotypic and genetic variation in ADULT syndrome. Am J Med Genet A 2006;140A: 2495–500. 59 Ellis RWB, van Creveld S. A syndrome characterized by ectodermal dysplasia, polydactyly, chondrodysplasia and congenital morbus cordis: report of three cases. Arch Dis Child 1940;15:65–84. 60 Ruiz-Perez VL, Ide SE, Strom TM et al. Mutations in a new gene in Ellis–van Creveld syndrome and Weyer ’s acrodental dysostosis. Nat Genet 2000;24:283–6. 61 Galdzicka M, Patnala S, Hirshman MG et al. A new gene, EVC2, is mutated in Ellis–van Creveld syndrome. Mol Genet Metab 2002;77:291–5. 62 Sund KL, Roelker S, Ramachandran V, Durbin L, Benson DW. Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease. Hum Mol Genet 2009;18(10):1813–24. 63 Jumlongras D, Bei M, Stimson JM et al. A nonsense mutation in MSX1 causes Witkop syndrome. Am J Hum Genet 2001;69(1):67–74. 64 Price JA, Bowden DW, Wright JT et al. Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum Mol Genet 1998;7:563–9. 65 Robinson GW, Mahon KA. Differential and overlapping expression domains of Dlx-2 and Dlx-3 suggest distinct roles for Distal-less homeobox genes in craniofacial development. Mech Dev 1994;48:199–215. 66 Dong J, Amor D, Aldred MJ et al. DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism. Am J Med Genet 2005;133A:138–41. 67 Wright JT, Hong SP, Simmons D et al. DLX3 c.561_562delCT mutation causes attenuated phenotype of tricho-dento-osseous syndrome. Am J Med Genet 2008;146A:343–9. 68 Momeni P, Glockner G, Schmidt O et al. Mutations in a new gene, encoding a zinc-finger protein, cause tricho–rhino–phalangeal syndrome type I. Nat Genet 2000;24:71–4. 69 Ludecke HJ, Schaper J, Meinecke P et al. Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. Am J Hum Genet 2001;68:81–91. 70 Ludecke HJ, Wagner MJ, Nardmann J et al. Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer–Giedion syndrome. Hum Mol Genet 1995;4:31–6. 71 Hou J, Parrish J, Ludecke HJ et al. A 4-megabase YAC contig that spans the Langer–Giedion syndrome region on human chromosome 8q24.1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1). Genomics 1995;29:87–97. 72 Dai KS, Liew CC. Characterization of a novel gene encoding zinc finger domains identified from expressed sequence tags (ESTs) of a human heart cDNA database. J Mol Cell Cardiol 1998;30:2365–75. 73 Lichtenstein J, Warson R, Jorgenson R et al. The tricho-dento-osseous (TDO) syndrome. Am J Hum Genet 1972;24:569–82. 74 Robinson GC, Miller JR. Hereditary enamel hypoplasia: its association with characteristic hair structure. Pediatrics 1966;37:498–502. 75 Freire-Maia N, Pinheiro M. Ectodermal Dysplasias: A Clinical and Genetic Study. New York: Alan R. Liss, 1984. 76 Shapiro SD, Quattromani FL, Jorgenson RJ et al. Tricho-dento-osseous syndrome: heterogeneity or clinical variability. Am J Med Genet 1983;16:225–36. 77 Quattromani F, Shapiro SD, Young RS et al. Clinical heterogeneity in the tricho-dento-osseous syndrome. Hum Genet 1983;64:116–21. 78 Levin LS. Dental and oral abnormalities in selected ectodermal dysplasia syndromes. Birth Defects Orig Artic Series 1988;24: 205–27. 79 Melnick M, Shields ED, El-Kafrawy AH. Tricho-dento-osseous syndrome: a scanning electron microscopic analysis. Clin Genet 1977;12:17–27.

Ectodermal Dysplasias 80 Sclar AG, Kannikal J, Ferreira CF, Kaltman SI, Parker WB. Treatment planning and surgical considerations in implant therapy for patients with agenesis, oligodontia, and ectodermal dysplasia: review and case presentation. J Oral Maxillofac Surg 2009;67(11 Suppl):2–12. 81 Giedion A, Burdea M, Fruchter Z et al. Autosomal dominant transmission of the tricho-rhino-phalangeal syndrome. Report of 4 unrelated families, review of 60 cases. Helv Paediatr Acta 1973;28:249–59. 82 Beals RK. Tricho-rhino-phalangeal dysplasia. Report of a kindred. J Bone Joint Surg Am 1973;55:821–6. 83 Sugiura Y. Tricho-rhino-phalangeal syndrome associated with Perthes disease-like bone change and spondylolisthesis. Jinrui Idengaku Zasshi 1978;23:23–30. 84 Sugio Y, Kajii T. Ruvalacaba syndrome: autosomal dominant inheritance. Am J Med Genet 1984;19:741–53. 85 Niikawa N, Kamei T. The Sugio–Kajii syndrome, proposed trichorhino-phalangeal syndrome type III. Am J Med Genet 1986;24:759–60.

Defects in the Wnt-β-catenin pathway The Wnt-β-catenin pathway is highly conserved, and seen in all species from invertebrates to humans. It plays a prominent role in embryogenesis and carcinogenesis. The term ‘wnt’ is the result of a combination between ‘wingless’, also known as Wg, the identified gene in Drosophila melanogaster, and the homologous ‘int’, the murine mammary tumour virus integration site. There are at least 19 WNT genes in humans that are involved in a variety of developmental and regulatory processes, including the decision between self-renewal and differentiation [1]. They are also notably involved in hair and tooth formation [2–5]. Recently, WNT10A mis-sense mutations were associated with both odonto-onycho-dermal dysplasia syndrome (MIM 257980) and Schöpf–Schulz–Passarge syndrome (MIM 224750) [6–8]. This is understandable since one kindred exhibited both conditions among its family members [8]. Focal dermal hypoplasia, also known as Goltz syndrome (MIM 305600), is caused by mutations in the PORCN gene [9,10]. The product of this gene is homologous to Porc, which encodes an O-acyltransferase enzyme in the endoplasmic reticulum, responsible for modification of Wg in Drosophila. Due to the conservation of this pathway throughout evolution, it is likely that the product of PORCN performs a similar function for Wnt [9]. In the canonical Wnt-β-catenin pathway, the downstream effector is β-catenin, whose concentrations are altered when Wnt interacts with Frizzled, a transmembrane protein, and the LRP5/6 receptor (Fig. 127.14). In the absence of Wnt signalling, β-catenin is free in the cytoplasm and is rapidly bound by a ‘destruction complex’, followed by polyubiquitination and degradation. With Wnt binding, a downstream cascade leads to stabilization of β-catenin, allowing it to enter the nucleus and activate its target genes [11]. Mutations in the gene

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Hairless (HR) have been discovered in two conditions that feature hair loss: atrichia with papular lesions (MIM 209500) [12] and alopecia universalis congenita (MIM 203655) [13]. The HR protein is involved in the regulation of gene expression during the hair cycle, specifically by controlling Wnt signalling through its actions as a repressor of a Wnt inhibitor, Wise; thus HR increases the amount of Wnt signalling, allowing for proper regrowth of hair at the beginning of the hair cycle [14]. Wnt signalling is also involved in myriad other processes, including tooth and limb formation, myogenesis and neural development [15]. Multiple developmental signalling pathways, of which the Wnt-β-catenin pathway is one, have complex and interconnected relationships. A patient with vitamin D-resistant rickets due to a compound heterozygote mutation in the vitamin D receptor gene (VDR) had an identical phenotype to APL, suggesting its importance in the hair growth cycle [16]. Wnt is repressed by Notch signalling, another important and highly conserved protein in cell regulation. The p63 signalling pathway, discussed above, inhibits Notch, and Notch in turn represses p63 [17].

Odonto-onycho-dermal dysplasia syndrome (OODD; MIM 257980) Definition. The main features of the odonto-onychodermal dysplasia syndrome include hypotrichosis, hypodontia and nail dystrophy. Other characteristics that may be observed include hyperhidrosis, palmoplantar keratoderma and loss of lingual papillae, resulting in a smooth tongue. Patients may also exhibit mild mental retardation and recurrent infection. History. Odonto-onycho-dermal-dysplasia was initially reported by Fried in 1977 in a boy and a girl cousin who were products of consanguineous marriages. They were described as having a similar presentation to Witkop syndrome, with partial adontia, conical teeth and nail dystrophy [18]. The disease was further characterized in a large Lebanese Muslim [7,19–21] and Pakistani kindred [6]. This condition is autosomal recessive; sporadic cases have been reported [22]. Pathology. Histology of the hyperkeratotic plantar skin shows mild epidermal acanthosis with hypergranulosis, orthokeratosis, and hyperkeratosis [7,21]. A mild perivascular infiltrate in the papillary dermis may also be present [21]. Sweat glands are decreased in number, and poorly developed [8,21]. The erythematous plaques of the face show an atrophic epidermis with basophilic collagen degeneration of the upper dermis [19]. Irregular hairs with longitudinal depressions are observed on scanning

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Chapter 127

Atrichia with papular lesions Alopecia universalis congenita

Odonto-onycho-dermal dyplasia Schöpf-Schulz-Passarge syndrome

Hairless

Wnt

−

Wise

Wnt

Wnt

−

Wise

LRP

LRP Axin

Frizzled

Frizzled

GSK

βc

a te nin

APC

GSK

APC

βc

+

Axin

Axin GSK

APC

Axin

βc

a te nin

a te nin

βc

a t e nin

Stabilization Ub Nucleus FDH (Goltz) Ubiquitination

A

te

Binding and transcription

N

βca

Proteasome

PORCN

nin mR

ER

Transcription, translation, modification of βcatenin

βc

a t e nin

Fig. 127.14 Overview of the Wnt-related pathways and their role in human ectodermal dysplasias. Wnt binding to Frizzled and LRP causes stabilization of β-catenin, resulting in its translocation to the nucleus, where it binds to DNA and causes transcription of β-catenin upregulated genes. Wnt binding to Frizzled is impaired by Wise, while Wise is inhibited by the Hairless gene product. β-catenin is usually held inactive by binding of the APC destruction complex. APC, along with Axin, binds β-catenin, allowing it to be phosphorylated by GSK. Phosphorylation results in ubiquitination of β-catenin and its targeting for destruction. APC, adenomatosis polyposis coli protein; GSK, glycogen synthase kinase 3 β; ER, endoplasmic reticulum; PORCN, PORCN gene product; Ub, ubiquitin.

electron microscopy [21], at the bottom of which are cuticular cells with a longitudinal striated aspect [7].

texture [21]. Eyebrows and eyelashes may be thinned [6,7,19,22,23].

Clinical features

Teeth Severe oligodontia is nearly always present [7]; congenital absence of secondary dentition is often seen [6,21]. Deciduous teeth may be widely spaced and malformed [7,19,21]. If permanent teeth are absent, some deciduous teeth may be retained into adulthood [6]. Mis-shapen

Hair Hypotrichosis is common, and lack of hair may be congenital [6,20,21], but hair may be normal at birth [21]. Both scalp and body hair may be affected [6]. Hair that is present is often dry, thin and sparse [7,23], or has a coarse

Ectodermal Dysplasias

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teeth, including conical and bifid incisors, and five-cusped molars have been described [19,21,23]

a risk of skin cancer, as in the allelic condition of Schöpf–Schulz–Passarge.

Nails Nails may be congenitally absent [21,23]. Nail dystrophy may or may not be present; toenails are more commonly affected than fingernails [7,19,21–23]. Nails are thin, concave and may exhibit longitudinal ridging or central grooved dystrophy [7,21,23]. Thickening, tenting and onycholysis have also been described [23].

Differential diagnosis. Schöpf–Schulz–Passarge syndrome is in the differential for this condition, as it shares a common affected gene. A lack of eyelid cysts would aid the clinician, although they present later on in life. If present, a smooth tongue may also help to make the diagnosis. The facial eruption may bring to mind keratitis ichthyosis deafness syndrome (KID), discussed below, but the quality of palmoplantar keratoderma and lack of deafness would delineate OODD from KID syndrome.

Sweat glands Hyperhidrosis of the palms and soles is commonly reported, although not in all cases [7,19,21,23]. Hypohidrosis and heat intolerance are less commonly reported [6,8]. Skin Thickening of the palms and soles is common, and hyperkeratosis can range from mild to severe, causing symptoms such as pain, laceration or impaired dexterity [6–8,21–23]. The onset can be as early as 3–4 years or appear in the second or third decade. Palmar erythema is a very common finding [7,21]. A smooth tongue, due to reduced fungiform and filiform papillae, is notable for this condition, although it is not always present [6,7,21]. Diffusely dry skin is a common finding [6–8,21]. Erythematous, telangiectatic atrophic plaques in a malar distribution have been described in select patients [19,24]; these tend to become worse in the summer [19,23]. Those with OODD may have keratosis pilaris and follicular hyperkeratosis on body [6,21,24], and recurrent folliculitis has been described [7]. Some photos of these erythematous malar plaques bring to mind keratosis pilaris atrophicans rubra faciei (ulerythema ophryogenes), especially when considering the presence of keratosis pilaris. Other ectodermal structures Patients with this condition may have chronic irritative conjunctivitis secondary to short lashes [23] and a few have also reported photophobia [8,23]. One case of seizures associated with this condition has been reported [22]. Craniofacial features There are no characteristic craniofacial features. Other abnormalities Mild mental deficiency has been described [22], recurrent cutaneous dermatophytosis [21] and folliculitis [7]. Prognosis. The nail and skin dystrophies can become more pronounced over time. Physical development and lifespan are unaffected. It is unknown if this condition has

Treatment. Treatment is symptomatic. Suggested treatments have included topical keratolytic agents and physical debridement with warm water soaks and pumice stone [24]. Emollients are suggested for dry skin. It is unclear if topical corticosteroids improve the facial eruption associated with this syndrome [24].

Schöpf–Schulz–Passarge syndrome (SSPS; MIM 224750) Definition. The main features of Schöpf–Schulz–Passarge syndrome include hypodontia, persistence of deciduous teeth, generalized hypotrichosis of both scalp and body, and normal sweating. Eyelid cysts are helpful in the diagnosis, but may not always be present. Age of onset of symptoms may vary greatly. These patients have a risk of benign and malignant skin tumours. History. The condition was described by Schöpf in 1971 [25]. SSPS generally exhibits autosomal recessive inheritance; other reported forms of inheritance include one German kindred with autosomal dominant inheritance, and one case of possible uniparental isodisomy for a recessive trait [26,27]. Pathology. Eccrine syringofibroadenoma is characteristic of SSPS. This is a rare tumour that presents with anastomosing cords of pale-staining epithelial cells, extending from the epidermis into the papillary dermis, with focal luminal formation. The cords of cells are surrounded by an oedematous stroma containing dilated capillaries. Rarely, this tumour may become malignant [28]. The pale epithelial cells are negative for SMA, S100 and CAM5.2, with weak to intermediate staining for EMA. CEA is positive only at the inner border of ductal structures. In areas of malignant degeneration, more intense staining of EMA is seen, with weak CAM5.2 positivity. CEA, EMA and CAM5.2 are all strongly positive in ductal areas [28]. Biopsy of the eyelid cysts characteristic in this condition show intradermal papillary cystic stuctures composed of two layers of cells – a cuboidal inner lining of

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cells and an outer myoepithelial layer. These findings are consistent with apocrine hidrocystomas [29]. Clinical features

Hair Hair loss is common, although not always present, and may affect the scalp and body [8,27,28]. Sparse eyelashes and eyebrows have also been described [27,28]. Hair may be thin or fine [27]. Pili torti has also been associated with this syndrome [30]. Despite the many findings, hair may also be normal [29]. Teeth Extensive hypodontia is common in this condition. Primary teeth may be abnormal, lost early or retained, and permanent teeth may be missing completely or have partial development [8,25,27,28,31]. Tooth abnormalities include conical and widely spaced teeth [28,29]. Nails Both fingernail and toenail dystrophy are seen [8,27,28]. Nails may be fragile and brittle or exhibit furrowing or onycholysis [25,29,32]. Splitting, koilonychia and pterygium unguis have also been described [31]. Longitudinal narrowing of the fingernails and complete absence of the fingernails have also been noted in this condition [33]. Sweat glands Sweating is usually normal but hyperhidrosis is not uncommon [8,31,34]. Tumours and cysts of eccrine origin are common; this will be discussed further below. Skin The palmoplantar keratoderma in Schöpf ’s original description began at approximately age 12 [25]; other cases became symptomatic in their 20s and 30s [20,28,33]. The palmar and plantar findings include erythematous hyperkeratosis, scaling hyperkeratosis and a lace-like network of erythema and scale [28]. Findings may also include dyshidrotic blistering of glabrous skin and hyperkeratosis of the dorsal hands [8]. These may be symptomatic due to thickening or fissuring. Multiple eccrine tumours are noted, specifically eccrine poroma and eccrine syringofibroadenoma [28,34]. Eccrine syringofibroadenoma can present as palmoplantar keratoderma in a mosaic pattern [35]. Benign adnexal tumours, such as tumour of the follicular infundibulum, and poroma with follicular differentiation have also been reportedly associated with this condition [36]. Malignant skin tumours have also been described, suggesting an elevated risk of skin cancer in these patients requiring increased vigilance. Some of these are common tumours, such as basal cell and squamous cell carcinomas [26,28,29,37]; others are neoplastic counterparts to eccrine

tumours, such as malignant degeneration of eccrine syringofibroadenoma, and porocarcinoma [8,28]. Eyelid cysts present as milky or translucent papules located mostly along the lash border; they are bilateral and symmetrically distributed. These apocrine hidrocystomas were originally thought to originate from the glands of Moll [29], but others suggest they are ectopic remnants of fetal apocrine glands [38]. Milia on the face have also been described in a few cases [29,31]. Telangiectatic rosacea has also been reported [31].

Other ectodermal structures Photophobia has been described [29], similar to cases of OODD. Optic atrophy and hypoplastic nipples were reported in one case [31]. Vaginal dryness and decreased salivary gland secretion have also been described [32]. Craniofacial features There are generally no characteristic craniofacial features, although a ‘curious bird-like facies’ has been described in one kindred [33]. Other abnormalities Breast cancer and hypernephroma have been described in patients with this condition [28,33]. Prognosis. Patients may present during childhood [25], or during their second and third decades [20,28,29,33]. Eyelid cysts can become symptomatic much later, after the age of 50 and into the 70s [25,27,28]. As many features may have late presentation in the fifth and sixth decades, counselling younger patients or their parents on prognosis may be difficult; a milder presentation at a younger age does not necessarily predict lack of lifetime symptoms. Differential diagnosis. The main differential for this condition is odonto-onycho-dermal dysplasia, as both present with severe oligodontia, hypotrichosis, palmoplantar keratoderma and nail dystrophy. Patients with both of these conditions may also display hyperhidrosis. Significant differences between the two conditions include the presence of eyelid cysts and eccrine tumours in SSPS, and the smooth tongue due to loss of lingual papillae in OODD. Treatment. Apocrine hidrocystomas of the eyelid can present significant cosmetic impairment, and simple excision of eyelid cysts is rarely adequate. Radical excision of the anterior lamella may result in sustained improvement [32]. Treatment of hyperkeratosis involves keratolytic therapy. For lesions unresponsive to treatment, a biopsy may be warranted. Unresponsive lesions may in fact be eccrine tumours, and clinicians must remain vigilant for cutaneous malignancies.

Ectodermal Dysplasias

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Focal dermal hypoplasia (FDH; Goltz syndrome; MIM 305600)

lary and pubic hair [43], but sparse eyelashes and eyebrows may be present in some cases [45].

Definition. The main features of Goltz syndrome include linear, streaked blaschkoid arrangements of markedly thinned dermis, resulting in fat herniation. Skin is dry, and involvement of other ectodermal structures may be present, such as sparse hair, hypodontia, notched incisors and dysplastic or absent nails [39]. Ophthalmological abnormalities are common, as is cleft palate. This is an X-linked dominant condition due to mutations in the PORCN gene [8,9]; cases may also be sporadic [39]. The majority (90%) of affected patients are female, and severity may be affected by lyonization in females and by somatic mosaicism in males [40,41]. Please see Chapter 133 for a full discussion of this condition.

Teeth, nails, sweat glands and other ectodermal structures Teeth, nails and sweat glands are normal. No other ectodermal abnormalities have been reported [43,45]. Intelligence is normal [43].

Atrichia with papular lesions (APL; MIM 209500); alopecia universalis congenita (MIM 203655) Definition. These two syndromes are probably the same or a continuum of the same disease, the main feature of which is diffuse hair loss. In APL, this hair loss can be accompanied by skin-coloured papules, which are not present in alopecia universalis congenita. They are both autosomal recessive conditions, caused by mutations in the Hairless gene (HR), a co-repressor in the Wnt signalling pathway (see above) [12,13]. History. In 1952 Tillman reported two families with congenital alopecia [42]. This condition was further characterized in a large Pakistani kindred [43], in which the gene for alopecia universalis congenita was eventually mapped and identified [13,44]. Pathology. Skin biopsy of the area of alopecia shows an unremarkable epidermis, and a dermis containing hair follicles without hair [43]. Aborted follicles are seen, with only well-developed infundibula but no hair shaft or other parts of the hair follicle. The papular lesions contain small keratinous cysts surrounded by normal sebaceous glands and pilar muscle; these cysts are lined by epithelial cells similar to those that line the mid and lower portions of the hair follicle [45]. Clinical features

Hair Patients may present with a history of atrichia at birth or, more commonly, with a history of normal hair present at birth that is shed normally but is not replaced; this may occur between 3 and 24 months of age [43,45]. Alopecia may be complete and include eyebrows, eyelashes, axil-

Skin In APL, patients may present with skin-coloured to white cystic and/or papular lesions, similar to milia, ranging in size from 1 to 3 mm. These papules are primarily seen over the elbows and knees but can be present elsewhere on the body, including thighs and buttocks; if other sites are involved, the face is a common location [45]. Prognosis. As this is a defect in the hair growth cycle, hair loss does not grow back. The condition does not affect patient lifespan. Differential diagnosis. The differential diagnosis of this condition includes autoimmune-induced alopecia totalis and universalis, and localized autosomal recessive hypotrichosis, These conditions should be distinguishable upon history, with the exception of cases of APL or alopecia universalis congenita that present with congenital hair loss – these may be more difficult to distinguish from localized autosomal recessive hypotrichosis. Biopsy showing an inflammatory infiltrate would differentiate autoimmune alopecia from APL and alopecia universalis congenita. Treatment. There is currently no specific treatment for this condition. Treatment involves wigs or hats for cosmesis. References 1 Staal FJ, Tiago CL. Wnt signaling in hematopoiesis: crucial factors for self-renewal, proliferation, and cell fate decisions. J Cell Biochem 2010;109(5):844–9. 2 Wang J, Shackleford GM. Murine Wnt10a and Wnt10b: cloning and expression in developing limbs, face and skin of embryos and in adults. Oncogene 1996;13(7):1537–44. 3 Dassule HR, McMahon AP. Analysis of epithelial-mesenchymal interactions in the initial morphogenesis of the mammalian tooth. Dev Biol 1998;202(2):215–27. 4 Millar SE, Willert K, Salinas PC et al. WNT signaling in the control of hair growth and structure. Dev Biol 1999;207(1):133–49. 5 Andl T, Reddy ST, Gaddapara T et al. WNT signals are required for the initiation of hair follicle development. Dev Cell 2002;2(5): 643–53. 6 Nawaz S, Klar J, Wajid M et al. WNT10A missense mutation associated with a complete odonto-onycho-dermal dysplasia syndrome. Eur J Hum Genet 2009;17(12):1600–5. 7 Adaimy L, Chouery E, Mégarbané H et al. Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. Am J Hum Genet 2007;81:821–8.

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8 Bohring A, Stamm T, Spaich C et al. WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sexbiased manifestation pattern in heterozygotes. Am J Hum Genet 2009;85(1):97–105. 9 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;39:833–5. 10 Wang X, Sutton VR, Peraza-Llanes JO et al. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet 2007;39:836–8. 11 Cadigan KM, Peifer M. Wnt signaling from development to disease: insights from model systems. Cold Spring Harb Perspect Biol 2009;1:a002881. 12 Ahmad W, Irvine AD, Lam H et al. A missense mutation in the zincfinger domain of the human hairless gene underlies congenital atrichia in a family of Irish travelers. Am J Hum Genet 1998;63: 984–91. 13 Ahmad W, Haque MF, Brancolini V et al. Alopecia universalis associated with a mutation in the human hairless gene. Science 1998;279:720–4. 14 Thompson CC, Sisk JM, Beaudoin GM. Hairless and wnt signaling: allies in epithelial stem cell differentiation. Cell Cycle 2006;5(17): 1913–17. 15 Clements SE. Importance of PORCN and Wnt signaling pathways in embryogenesis. Am J Med Genet A 2009;149A:2050–1. 16 Miller J, Djabali K, Chen T et al. Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J Invest Dermatol 2001;117:612–17. 17 Okuyama R, Tagami H, Aiba S. Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. J Dermatol Sci 2008;49(3):187–94. Epub 18 Fried K. Autosomal recessive hydrotic ectodermal dysplasia. J Med Genet 1977;14:137–9. 19 Fadhil M, Ghabra TA, Deeb M et al. Odontoonychodermal dysplasia: a previously apparently undescribed ectodermal dysplasia. Am J Med Genet 1983;14:335–46. 20 Mégarbané A, Noujeim Z, Fabre M et al. New form of hidrotic ectodermal dysplasia in a Lebanese family. Am J Med Genet 1998;75(2):196–9. 21 Mégarbané H, Haddad M, Delague V et al. Further delineation of the odonto-onycho-dermal dysplasia syndrome. Am J Med Genet 2004;129A:193–7. 22 Arnold WP, Merkx MA, Steijlen PM. Variant of odontoonychodermal dysplasia? Am J Med Genet 1995;59:242–4. 23 Zirbel GM, Ruttum MS, Post AC et al. Odonto-onycho-dermal dysplasia. Br J Dermatol 1995;133:797–800. 24 Adams BB. Odonto-onycho-dermal dysplasia syndrome. J Am Acad Dermatol 2007;57(4):732–3. 25 Schöpf E, Schulz HJ, Passarge E. Syndrome of cystic eyelids, palmo-plantar keratosis, hypodontia and hypotrichosis as a possible autosomal recessive trait. Birth Defects Orig Artic Ser 1971;VII: 219–21. 26 Küster W, Hammerstein W. Das Schöpf-Syndrom. Hautarzt 1992;43:763–6. 27 Craigen WJ, Levy ML, Lewis RA. Schöpf-Schulz-Passarge syndrome with an unusual pattern of inheritance. Am J Med Genet 1997;71:186–8. 28 Starink TM. Eccrine syringofibroadenoma: multiple lesions representing a new cutaneous marker of the Schöpf syndrome, and solitary nonhereditary tumors. J Am Acad Dermatol 1997;36(4):569–76. 29 Font RL, Stone MS, Schanzer MC et al. Apocrine hidrocystomas of the lids, hypodontia, palmarplantar hyperkeratosis, and onychodystrophy: a new variant of ectodermal dysplasia. Arch Ophthalmol 1986;104:1811–13.

30 Szepetiuk G, Vanhooteghem O, Muller G et al. Schöpf-SchulzPassarge syndrome with pili torti: a new association? Eur J Dermatol 2009;19(5):517–18. 31 Castori M, Ruggieri S, Giannetti L et al. Schöpf-Schulz-Passarge syndrome: further delineation of the phenotype and genetic considerations. Acta Derm Venereol 2008;88(6):607–12. 32 Maillaiah U, Dickinson J. Photo essay: bilateral multiple eyelid apocrine hidrocystomas and ectodermal dysplasia. Arch Ophthalmol 2001;119(12):1866–7. 33 Monk BE, Pieris S, Soni V. Schöpf-Schulz-Passarge syndrome. Br J Dermatol 1992;127(1):33–5. 34 Nordin H, Mansson T, Svensson A. Familial occurrence of eccrine tumours in a family with ectodermal dysplasia. Acta Dermatol Venereol 1988;68:523–30. 35 Hampton PJ, Angus B, Carmichael AJ. A case of Schöpf-SchulzPassarge syndrome. Clin Exp Dermatol 2005;30(5):528–30. 36 Verplancke P, Driessen L, Wynants P et al. The Schöpf-SchulzPassarge syndrome. Dermatology 1998;196(4):463–6. 37 Perret C. Schöpf syndrome. Br J Dermatol 1989;120:131–2. 38 Alessi E, Gianotti R, Coggi A. Multiple apocrine hidrocystomas of the eyelids. Br J Dermatol 1997;137(4):642–5. 39 Leoyklang P, Suphapeetiporn K, Wananukul S et al. Three novel mutations in the PORCN gene underlying focal dermal hypoplasia. Clin Genet 2008;73(4):373–9. 40 Maas SM, Lombardi MP, van Essen AJ et al. Phenotype and genotype in 17 patients with Goltz-Gorlin syndrome. J Med Genet 2009;46(10):716–20. 41 Harmsen MB, Azzarello-Burri S, García González MM et al. GoltzGorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap. Eur J Hum Genet 2009;17(10):1207–15. 42 Tillman WG. Alopecia congenita: report of two families. BMJ 1952;2:428. 43 Ahmad M, Abbas H, Haque S. Alopecia universalis as a single abnormality in an inbred Pakistani kindred. Am J Med Genet 1993;46(4):369–71. 44 Nöthen MM, Cichon S, Vogt IR et al. A gene for universal congenital alopecia maps to chromosome 8p21–22. Am J Hum Genet 1998;62(2):386–90. 45 Sprecher E, Bergman R, Szargel R et al. Atrichia with papular lesions maps to 8p in the region containing the human hairless gene. Am J Med Genet 1998;80(5):546–50.

Defects in gap junction proteins Gap junctions facilitate efficient cell–cell communication between all cells in multicellular organisms. This system facilitates a synchronized cellular response to a variety of intercellular signals by regulating the direct passage of low molecular weight metabolites (1.5 cm as being useful in distinguishing those individuals with multiple CALMs and NF1 [8]. A prospective study evaluating the diagnostic outcome of

Introduction The neurofibromatoses encompass three distinct inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. These disorders share the propensity to develop multiple benign tumours of the peripheral and/or central nervous system, but are distinguished by specific clinical features, distinct genetic mutations, natural history and management (Table 128.1). In this chapter, NF1 is reviewed in detail and the others are discussed briefly, with emphasis on how they may present to the paediatric dermatologist.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

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Table 128.1 The neurofibromatoses NF1

NF2

Schwannomatosis

Incidence Cutaneous features

1 in 3000 Café-au-lait macules, axillary freckling, neurofibromas

1 in 25,000 Café-au-lait macules (5 mm pre-puberty, >15 mm post-puberty) 2. Two or more neurofibromas of any type, or one or more plexiform neurofibromas 3. Freckling in the axillae or groin 4. Optic glioma 5. Two or more Lisch nodules 6. Dysplasia of the sphenoid; dysplasia or thinning of long bone cortex 7. First-degree relative with NF1

children with multiple CALMs followed 41 children with at least six CALMs and 30 (73%) developed other signs of NF1 (24/41) or segmental NF1 (6/41) [9]. Café-au-lait macules are the earliest manifestation of NF1 and are present in essentially 100% of children with NF1. Conservatively, 80% of children with NF1 will manifest with multiple CALMs by the age of 1 [10]. If a child has not developed at least six CALMs by the age of 4, they

Fig. 128.1 Multiple café-au-lait macules in a 9-year-old boy. Courtesy of Professor John Harper.

The Neurofibromatoses

128.3

Neurofibromas Neurofibromas are benign tumours of the nerve sheath, which can occur at any point along any peripheral nerve, from the spinal roots to the cutaneous free nerve endings. Neurofibromas can be broadly classified as focal (localized to a single site on a nerve) or ‘plexiform’. Dermatologists will most frequently encounter focal cutaneous and

subcutaneous neurofibromas and superficial plexiform neurofibromas. Cutaneous neurofibromas are generally first noticed in adolescence and continue to increase in size and number throughout adulthood. Younger children may have neurofibromas that appear as subtle subcutaneous swellings that are best seen with side lighting. Almost all adults with NF1 will develop cutaneous neurofibromas [10]. The number an individual will ultimately develop is unpredictable, even among family members, and can range from a few to thousands of lesions. Women with NF1 often report an increase in size and number of neurofibromas during pregnancy. They appear as soft, dome-shaped, flesh-coloured to slightly hyperpigmented papules or nodules or as more subtle bluish lesions that barely project above the skin surface (Fig. 128.3). When pressed, the tumours tend to invaginate into the subcutaneous tissue, a sign called buttonholing [8]. Cutaneous neurofibromas do not have a risk of malignant degeneration, but have a negative impact on quality of life due to disfigurement from the visibility and sheer number of lesions [11]. Cutaneous neurofibromas can be pruritic and occasionally, especially if large and pedunculated, infarct, which can present with pain and swelling. Subcutaneous neurofibromas are less prevalent than cutaneous neurofibromas and arise along peripheral nerves under the skin. These lesions present as welldefined, ovoid, firm subcutaneous nodules, best appreciated with palpation. Subcutaneous neurofibromas are often painful and can cause neurological symptoms, such as paraesthesia or weakness. While the risk of malignancy in these tumours is low, it is important to recognize indi-

Fig. 128.2 Axillary freckling. Courtesy of Professor John Harper.

Fig. 128.3 Discrete and subtler bluish (arrows) cutaneous neurofibromas in a patient with NF1.

are unlikely to do so [6]. CALMs continue to appear during childhood, but stop appearing or may disappear in adulthood. The spots vary in diameter from 0.5 to 50 cm or more, but are usually less than 10 cm. They increase proportionately in size with the growth of the child. The spots usually have smooth contours but some, particularly the larger ones, have irregular outlines. The colour intensity varies with background skin pigmentation, and in children with very pale complexions they are best seen under ultraviolet light.

Skinfold freckling Skinfold freckling (Crowe’s sign) is the most specific of the diagnostic criteria for NF1. It presents as multiple (>3) 1–3 mm tan macules in the axillae and inguinal folds (Fig. 128.2). Skinfold freckling is uncommon in infants and typically becomes evident around the age of 3, reaching a prevalence of 90% by the age of 7 [6]. In children with multiple CALMs and no family history of NF1, the appearance of skinfold freckling confirms the diagnosis of NF1. In addition to the axillae and inguinal folds, freckling can occur around the neck, in the submammary region, in other skinfolds and occasionally is a generalized finding in adult patients.

128.4

Chapter 128

viduals with multiple subcutaneous tumours because they are more likely to have internal spinal or plexiform neurofibromas, which are at a higher risk for malignant change [12]. The presence of subcutaneous neurofibromas has also been reported to be associated with a higher mortality rate [13]. Plexiform neurofibromas (PNFs) are neurofibromas that develop along the length of the nerve and involve multiple nerve fascicles and even multiple branches of nerves. The term ‘plexiform’ arises from the histopathological appearance and implies a network-like growth of neurofibroma involving multiple nerve fascicles. Plexiform neurofibromas may be superficial and visible on examination, or deep and apparent only with imaging. Superficial plexiform neurofibromas are usually noticed early in life. A population study in Wales found that 27% of individuals with NF1 had a plexiform neurofibroma apparent on examination and in another study up to 44% had a plexiform neurofibroma apparent with imaging [10,14]. When they are superficial, there is often associated overlying hyperpigmentation, hypertrichosis and/ or increased vascular markings (similar in appearance to a capillary malformation) (Fig. 128.4). The skin appears thickened and there are palpable cord-like masses, often likened to a ‘bag of worms’. Overlying irregular hyperpigmentation is sometimes the earliest clue to an underlying plexiform neurofibroma and can appear before the skin thickens. Plexiform neurofibromas can be associated with soft tissue overgrowth, leading to massive hypertrophy and disfigurement. When plexiform neurofibromas involve the face they can cause facial asymmetry and there is often associated dysplasia of the greater wing of the sphenoid [15]. Unlike cutaneous neurofibromas, there is a risk of plexiform neurofibromas transforming into malignant peripheral nerve sheath tumours (MPNST).

The estimated lifetime risk of MPNST in individuals with NF1 is 8–13% [16]. Unrelenting pain, sudden growth or increased firmness in a previously stable PNF are all signs suggestive of malignant transformation and should be evaluated. Positron emission tomography (PET) and PET computed tomography have been shown to be useful for evaluating malignant transformation in symptomatic plexiform neurofibromas [17].

Other dermatological associations Juvenile xanthogranulomas (JXGs) occur at an increased frequency in the NF1 population and the triple association of JXGs, NF1 and the development of juvenile myelomonocytic leukaemia has been reported [18–21]. The exact frequency of the triple association is unknown and a source of debate [22,23]. JXGs have a similar appearance and natural history in patients with and without NF1. Routine haematological screening in patients with NF1 and JXGs is currently not recommended, but clinicians should be aware of the possibility of juvenile myelomonocytic leukaemia and be vigilant for its presenting features (hepatosplenomegaly, lymphadenopathy, pallor, petechiae). Generalized hyperpigmentation has been noted in individuals with NF1 compared to their unaffected siblings or parents [24]. Interestingly, the involved body regions of patients with segmental NF1 often have a background of hyperpigmentation. Although the cause of the generalized hyperpigmentation has not been studied, it is interesting to theorize that it is caused by a single mutation of the NF1 gene, whereas CALMS are caused by loss of both alleles. There are several case reports of multiple subungual glomus tumours occurring with NF1 [25–27]. Patients presented with severe pain localized to one or more fingers and cold intolerance. It is important to recognize the increased risk of glomus tumours in NF1 patients because surgical removal of the tumour eliminates the pain. Non-dermatological features. Neurofibromatosis type 1 can involve any organ system. Reported non-cutaneous manifestations are summarized in Table 128.3. The noncutaneous features that comprise the diagnostic criteria, those that may be recognized during physical examination, and learning disabilities are reviewed.

Fig. 128.4 Plexiform neurofibroma with characteristic overlying hyperpigmentation.

Orthopaedic Orthopaedic manifestations are frequent and include mildly short stature, skeletal dysplasia, scoliosis and more recently recognized osteopenia/osteoporosis. Sphenoid wing or long bone dysplasias are the most distinctive bony lesions in NF1. Approximately 14% of patients with NF1 fulfil this diagnostic criterion, which is usually

The Neurofibromatoses

128.5

Table 128.3 Non-cutaneous manifestations and typical period of presentation Congenital/infancy Skeletal Scoliosis Dysplasia of the long bone/sphenoid Macrocephaly Prominent brow Short stature Pectus excavatum Pseudo-arthrosis (esp. of tibia)

Early childhood

Late childhood

Adolescence

X (severe)

X

X X

X

Adult

X X X X X X

X

Neurological/psychological Headaches Learning disabilities/ADHD Astrocytoma Seizures

X X X

Ophthalmological Lisch nodules Optic glioma

X

Cardiovascular Hypertension Vascular dysplasia

X

X X

X

X

Endocrine Precocious puberty Carcinoid tumour Phaeochromocytoma

X

X

X

X X

Gastrointestinal Gastrointestinal stromal tumours (GIST) Associated malignancies Juvenile myelomonocytic leukaemia (JMML) Malignant peripheral nerve sheath tumour (MPNST) Rhabdomyosarcoma

X X

X

X X

X

X

ADHD, attention deficit hyperactivity disorder.

evident by the age of 1 [6]. Long bone dysplasia should be suspected clinically when an infant or child presents with anterolateral bowing of the lower leg or, less commonly, the distal arm. These children are at an increased risk for fractures, which often fail to heal normally and can lead to pseudo-arthrosis. Contrary to the wording of the NIH criteria, thinning of the long bone cortex is uncommon, and the characteristic radiographic finding is cortical thickening with medullary canal narrowing [28]. Sphenoid wing dysplasia presents as facial asymmetry with either enophthalmos or proptosis, depending on whether there is associated orbital plexiform neurofibroma. If physical examination does not suggest a bony abnormality, routine radiographs are not recommended. Scoliosis is also common, with an incidence of 10–25% [29]. Although the dermatologist’s role is limited, periodic screening of children and adolescents is simple and

if evidence of scoliosis is found, referral to orthopaedics is warranted.

Ophthalmological Lisch nodules (iris hamartomas) are 1–2 mm smooth dome-shaped lesions on the iris [30]. They can occasionally be detected on general examination as yellow-brown lesions, but are best viewed and distinguished from iris naevi with slit-lamp examination. Lisch nodules are innocuous, but are useful for diagnostic confirmation of NF1. They generally appear after the CALMs and skinfold freckling and are found in approximately 40% of children under 6, 85% of children under 18 and 93% of adults [31,32]. Optic pathway gliomas are classified as low-grade pilocytic astrocytomas of the optic nerve, optic chiasm, hypothalamus or optic tracts. Optic pathway gliomas are

128.6

Chapter 128

estimated to occur in 15% of children [33]; one-third to one-half of these cause clinical symptoms, such as decreased visual acuity, diminished visual fields, proptosis or precocious puberty [34]. Optic pathway gliomas are slow to progress and many never require intervention. Symptomatic optic pathway gliomas usually manifest by the age of 6, but there are an increasing number of reports of late-onset or late-progressive optic pathway gliomas in NF1 [35]. The 1997 OPG Task Force determined that there was not enough evidence to recommend routine neuroimaging in asymptomatic children. Instead, children with known or suspected NF1 should have yearly ophthalmological assessments until at least the age of 7 [36].

Learning disabilities Learning disabilities are the most common complication in children with NF1. The reported frequency of learning disability ranges between 30% and 69% [37]. Several studies have shown a consistent shift to the left of IQ but it is within 1 SD of the population mean; mental retardation (IQ 50% and ∼25% of associated cancers, respectively), typically with presentation a decade earlier (mean 50 years) and a course that is less aggressive than their sporadic counterparts [9]. Almost half of patients develop more than one internal malignancy. Patients with CMRDS syndrome usually present during early childhood with multiple café-au-lait macules (CALMs) [2]. Axillary freckling, hypopigmented macules and (less often) neurofibromas are evident in some affected children. Haematological malignancies (most often non-Hodgkin lymphoma and acute lymphoblastic leukaemia) develop at a mean age of 5 years, brain tumours (primarily glioblastomas) occur at a mean age of 8 years, and colorectal carcinoma arises at a mean age of 16 years (considerably earlier than in MTS). Other malignancies such as rhabdomyosarcoma, neuroblastoma and Wilms tumour have also been reported in young children with CMRDS [2,11]. Differential diagnosis. Sebaceous adenomas and carcinomas as well as colorectal carcinomas and other malignancies have been described in patients with autosomal recessive colorectal adenomatous polyposis caused by mutations in the MUTYH base excision repair gene [12]. Patients with multiple self-healing squamous epithelioma of Ferguson-Smith, an uncommon autosomal dominant condition initially reported in Scottish families and mapped to chromosome 9q22-q31, present with keratoacanthoma-like tumors that tend to regress spontaneously

137.15

(usually within 6 months) with residual scarring; affected individuals do not have an increased risk of internal malignancies. The time of onset varies from childhood to late adulthood (mean age = ∼25 years), and the lesions favour chronically sun-exposed sites [13]. The cutaneous findings of CMRDS overlap with those of NF1, and a subset of CMRDS patients meets clinical criteria for diagnosis of NF1 (Chapter 128). The CALMs of CMRDS tend to be more irregular in pigmentation, configuration and size than those of NF1 and are more likely to be accompanied by hypopigmented macules [2]. CMRDS should be considered in the differential diagnosis for children with multiple CALMs, especially when associated with a malignancy that is not linked to NF1. Treatment. Recognition of the cutaneous findings of MTS and CMRDS, with confirmation via analysis of tumours for loss of a mismatch repair protein and microsatellite instability, can facilitate early diagnosis and treatment of associated malignancies in patients and their family members. References 1 Ponti G, Ponz de Leon M. Muir–Torre syndrome. Lancet Oncol 2005;6:980–7. 2 Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 2008;124:105–22. 3 Mangold E, Rahner N, Friedrichs N et al. MSH6 mutation in Muir– Torre syndrome: could this be a rare finding? Br J Dermatol 2007;156:158–62. 4 Ricciardone MD, Ozçelik T, Cevher B et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 1999;59:290–3. 5 Wang Q, Lasset C, Desseigne F et al. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res 1999;59:294–7. 6 Poley JW, Wagner A, Hoogmans MM et al. Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Cancer 2007;109:2349–56. 7 Ponti G, Losi L, di Gregorio C et al. Identification of Muir–Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability and immunohistochemistry. Cancer 2005;103:1018–25. 8 Abbas O, Mahalingam M. Cutaneous sebaceous neoplasms as markers of Muir–Torre syndrome: a diagnostic algorithm. J Cutan Pathol 2009;36:613–19. 9 Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland and internal malignancy: the Muir–Torre syndrome. Am J Med 1991;90:606–13. 10 Singh RS, Grayson W, Redston M et al. Site and tumor type predicts DNA mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol 2008;32:936–42. 11 Kratz CP, Holter S, Etzler J et al. Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome. J Med Genet 2009;46:418–20. 12 Vogt S, Jones N, Christian D et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009;137:1976–85.

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13 D’Alessandro M, Coats SE, Morley SM et al. Multiple self-healing squamous epithelioma in different ethmic groups: more than a founder mutation disorder? J Invest Dermatol 2007;127:2336–44.

Peutz–Jeghers syndrome Syn. Periorificial lentiginosis

Definition. Peutz–Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by mucocutaneous lentigines with a predilection for periorificial sites, gastrointestinal hamartomatous polyps, and an increased incidence of internal malignancies [1,2]. Pathogenesis. Peutz–Jeghers syndrome is caused by heterozygous loss-of-function mutations in the serine/ threonine kinase 11 (STK11; also known as LKB1) tumour suppressor gene [3]. Some studies have found that truncating STK11 mutations are associated with the development of more gastrointestinal polyps and malignancies [4,5]. The STK11 protein activates adenosine monophosphate-activated protein kinase (AMPK) and thereby stimulates activation of tuberin (the tuberous sclerosis complex 2 (TSC2) gene product), which inhibits the mTOR pathway that promotes cellular growth and survival [6]. PJS is therefore characterized by increased mTOR signalling, and the mTOR inhibitor rapamycin has been shown to reduce gastrointestinal polyp burden in the lkb1+/- mouse model of PJS [7]. Clinical features. The brown-to-black hyperpigmented macules (lentigo simplex or mucosal melanotic macules) of PJS are present at birth or develop during early childhood [8,9]. The cutaneous lentigines typically measure 1–5 mm in diameter and favour perioral (Fig. 137.6), peri-

Fig. 137.6 Peutz–Jeghers syndrome: pigmented macules on the lip. Courtesy of Professor John Harper.

orbital and other periorificial regions (e.g. around the nares or anus) as well as the hands (especially the fingers) and feet. The lips (vermilion and mucosal) and buccal mucosa are commonly affected, and additional mucosal sites may include the gingiva, palate and tongue. Lesions on the skin and vermilion lip tend to fade after puberty, but those in mucosal areas usually persist. Longitudinal melanonychia is sometimes observed. The hamartomatous polyps of PJS have a predilection for the small intestine but can occur anywhere in the gastrointestinal tract. The majority of patients have clinical manifestations such as abdominal pain, bleeding (often leading to anaemia), intussusception and other forms of bowel obstruction during childhood [8,9]. Nasal polyposis has also been described in PJS patients. Girls with PJS occasionally develop benign ovarian sex cord tumours with annular tubules (SCTAT), which can manifest with precocious puberty or abnormal menstrual bleeding, and boys may present with gynaecomastia due to intratubular large cell hyalinizing Sertoli cell neoplasia of the testes [10]. Peutz–Jeghers syndrome patients have a 10–15-fold increase in the overall risk of cancer, with onset at younger ages than in the general population [11,12]. Predisposition to breast, colorectal, small intestinal, gastric, pancreatic, lung, ovarian, endometrial and cervical (adenoma malignum) malignancies has been documented [13,14]. Treatment. Patients with PJS should undergo periodic endoscopy beginning by age 10 years, with removal of large or otherwise troublesome polyps. Surveillance for extraintestinal as well as intestinal malignancies is required, and published protocols provide recommendations for types, starting ages and frequencies of procedures [8,9]. References 1 Peutz JL. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. Ned Maandschr Geneeskd 1921;10:134. 2 Jeghers H, McKusick BA, Katz KH. Generalised intestinal polyposis and melanin spots of the oral mucosa, lips and digits. N Engl J Med 1949;241:1031. 3 Hemminki A, Markie D, Tomlinson I et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 1998;391: 184–7. 4 Amos CI, Keitheri-Cheteri MB, Sabripour M et al. Genotype– phenotype correlations in Peutz–Jeghers syndrome. J Med Genet 2004;41:327–33. 5 Salloch H, Reinacher-Schick A, Schulmann K et al. Truncating mutations in Peutz–Jeghers syndrome are associated with more polyps, surgical interventions and cancers. Int J Colorectal Dis 2010;25(1): 97–107. 6 Shaw RJ, Kosmatka M, Bardeesy N et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 2004;101:3329–35.

Genetic Diseases that Predispose to Malignancy

137.17

7 Shakelford DB, Vasquez DS, Corbeil J et al. mTOR and HIF-1-mediated tumor metabolism in an LKB1 mouse model of Peutz–Jeghers syndrome. Proc Natl Acad Sci USA 2009;106:11137–42. 8 McGarrity TJ, Aos C. Peutz–Jeghers syndrome: clinicopathology and molecular alterations. Cell Mol Life Sci 2006;63:2135–44. 9 Giardiello FM, Trimbath JD. Peutz–Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol 2006;4:408–15. 10 Winterfield L, Schultz J, Stratakis CA et al. Gynecomastia and mucosal lentigines in an 8-year-old boy. J Am Acad Dermatol 2005;53:660–2. 11 Boardman LA, Thibodeau SN, Schaid DJ et al. Increased risk for cancer in patients with the Peutz–Jeghers syndrome. Ann Intern Med 1998;128:896–9. 12 Lim W, Hearle N, Shah B et al. Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome. Br J Cancer 2003;89:308–13. 13 Lim W, Olschwang S, Keller JJ et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 2004;126:1788–94. 14 Hearle N, Schumacher V, Menko FH et al. Frequency and spectrum of cancers in the Peutz–Jeghers syndrome. Clin Cancer Res 2006;12:3209–15.

found in BRRS, identical mutations have been described in patients with BRRS and Cowden syndrome phenotypes. Clinical features vary considerably within PHTS kindreds, and BRRS and Cowden syndrome phenotypes can be observed in different members of the same family or even in the same individual (e.g. diagnosis with BRRS as a young child and meeting Cowden syndrome criteria later in life). It has been suggested that BRRS and Cowden syndrome represent a single condition with variable expressivity, with BRRS features (often reported by paediatricians) having onset earlier in life than Cowden syndrome features (often reported by dermatologists and oncologists). In PHTS patients with congenital manifestations in a mosaic distribution (e.g. epidermal naevi and segmental vascular malformations), the presence of a postzygotic ‘second hit’ (presumably arising during embryogenesis) that results in loss of the germline wildtype PTEN allele in lesional tissue (type 2 mosaicism) has been documented [9,10].

PTEN hamartoma-tumour syndrome

Pathology. Histological examination of trichilemmomas reveals lobular proliferations of pale keratinocytes with peripheral palisading surrounded by a prominent eosinophilic basement membrane [11,12]. The surface of trichilemmomas often demonstrates papillomatosis and hyperkeratosis. Papules on the face, neck and extremities of PHTS patients can also have histological features of verrucae or acrochordons, and acral keratoses may resemble acrokeratosis verruciformis. Cutaneous and mucosal sclerotic fibromas are hypocellular lesions composed of short, thick, parallel collagen bundles arranged in plywood-like whorls embedded in abundant mucin [11,12].

Syn. Bannayan–Riley–Ruvalcaba syndrome, Bannayan–Zonana syndrome, Cowden disease, Cowden syndrome, linear Cowden naevus, multiple hamartoma syndrome, Proteus-like syndrome, Riley–Smith syndrome, Ruvalcaba–Myhre–Smith syndrome, SOLAMEN syndrome

Definition. PTEN hamartoma-tumour syndrome (PHTS) is a multisystem disorder that features hamartomatous overgrowth of tissues with ectodermal, mesodermal and endodermal origin. Bannayan–Riley–Ruvalcaba syndrome (BRRS; characterized by pigmented macules of the genitalia, lipomas and fast-flow vascular malformations) and Cowden syndrome (characterized by trichilemmomas, acral keratoses and sclerotic fibromas) are overlapping autosomal dominant genodermatoses included within the spectrum of PHTS [1–3]. Macrocephaly and an increased incidence of benign and malignant neoplasms of the thyroid gland, breast and uterus represent additional manifestations of PHTS. Pathogenesis. PTEN hamartoma-tumour syndrome is caused by heterozygous loss-of-function germline mutations in the PTEN (phosphatase and tensin homolog) tumour suppressor gene [4,5]. One important function of the PTEN lipid phosphatase is to negatively regulate the phosphatidylinositol 3-kinase/Akt pathway that stimulates (via inhibition of the tuberin tumour suppressor protein) the mTOR pathway of increased cellular growth and survival [2,3]. Most studies have failed to correlate particular germline PTEN mutations with specific phenotypic characteristics [6–8]. Although large deletions are more often

Clinical features (Fig. 137.7). The classic skin findings of BRRS are usually apparent at birth or during early childhood. Pigmented genital macules favor the glans penis and vulva. Vascular anomalies tend to be multifocal lesions with fast-flow channels, intramuscular involvement and associated ectopic fat [13]. They have variable capillary, venous and lymphatic components and are sometimes associated with regional soft tissue and bony overgrowth. Separate lipomatous tumours may also be observed, and recent studies have found a high prevalence of testicular lipomatosis in men with PHTS. Additional mucocutaneous findings in children with PHTS can include non-epidermolytic verrucous epidermal naevi and facial, acral and mucosal neuromas [14]. In contrast, the mucocutaneous hallmarks of Cowden syndrome typically develop during the second or third decade of life, although they are occasionally evident in younger children [15–17]. Trichilemmomas present as skin-coloured to yellowish-tan, verrucous or keratotic papules that favour the central face (especially the nose

137.18

Chapter 137

(d)

(a)

(b)

(e)

(c) Fig. 137.7 PTEN hamartoma-tumour syndrome: (a, b) vascular malformation with arteriovenous and lymphatic components associated with overgrowth of the affected arm; (c) facial trichilemmomas; and (d,e) acral keratoses.

Genetic Diseases that Predispose to Malignancy

and periorificial areas), ears and neck. Other papillomatous papules resembling warts or skin tags are also common in these locations. Punctate palmoplantar keratoses, which appear as translucent yellowish papules with or without a central depression, have been described in affected children as young as 3 years of age [18]. In addition, acral keratoses resembling flat warts may be seen on the dorsal aspects of the hands and feet, wrists and ankles, and extensor surfaces of the forearms and lower legs. Cutaneous sclerotic fibromas manifest as skincoloured to white, smooth-surfaced, dome-shaped, firm papules. Mucosal papules, which may represent sclerotic fibromas or (less often) glycogenic acanthosis [19], can occur anywhere in the oral cavity, including the lips, tongue, buccal mucosa and gingiva; multiple lesions frequently lead to a cobblestone-like appearance. Macrocephaly affects ≥80% of patients with PHTS, and neurological manifestations such as developmental delay, autism and seizures are occasionally observed [20]. Intracranial developmental venous anomalies have recently been recognized as a common magnetic resonance imaging finding in PHTS patients. Lhermitte– Duclos disease, a hamartomatous dysplastic gangliocytoma of the cerebellum, affects a small minority of patients with PHTS but (particularly when present in adults) is relatively specific for the condition. Craniofacial and skeletal abnormalities may include adenoid facies, a high-arched palate, scoliosis, pectus excavatum, joint hyperextensibility and digital anomalies. Neonatal macrosomia, hypotonia and lipoid storage myopathy represent early extracutaneous findings in a small subset of patients. Individuals with PHTS are at increased risk for the development of benign and malignant neoplasms of the thyroid, breast and uterus [2,3,21]. Thyroid cancer (follicular or papillary) affects 5–10% of patients, including children as young as 10 years of age. Breast cancer occurs in 25–50% of affected women at a mean age of approximately 40 years, while endometrial carcinoma develops in 5–10% of women at a somewhat older mean age. Although the majority of children and adults with PHTS have hamartomatous gastrointestinal polyps, colon cancer has been described in a relatively small number of affected individuals. Renal cell carcinoma and cutaneous melanoma have each been reported in several patients with PHTS, but data accumulated to date are not sufficient to clearly establish a predisposition to these malignancies in PHTS [2]. Differential diagnosis. The most recent diagnostic criteria for Cowden syndrome are provided in Table 137.4 [2]. Despite their designation as ‘pathognomonic’ in the Cowden syndrome criteria, a combination of facial papules, oral mucosal papules and acral (including pal-

137.19

Table 137.4 Diagnostic criteria for Cowden syndrome Major criteria Mucocutaneous lesions: • One biopsy-proven trichilemmoma, or • Multiple palmoplantar keratoses, or • Multifocal or extensive oral mucosal papillomatosis, or • Multiple verrucous facial papules, or • Pigmented macules on the glans penis Macrocephaly (>97th percentile; for adults, 58 cm in women, 60 cm in men) Breast carcinoma Thyroid carcinoma (non-medullary; especially follicular) Endometrial carcinoma Multiple gastrointestinal hamartomas or ganglioneuromas Minor criteria Fibromas Lipomas Fibrocystic breast disease Other thyroid lesions (e.g. adenoma, nodules, goitre) Uterine leiomyomas (fibroids) Single gastrointestinal hamartoma or ganglioneuroma Renal cell carcinoma Mental retardation (IQ ≤ 75) Autism spectrum disorder Indications for PTEN gene testing/provisional diagnosis (A, B or C) A Individual from a family with a known PTEN mutation B Individual with a personal history of: BRRS, or Adult Lhermitte–Duclos disease, or Autism spectrum disorder + macrocephaly, or Two or more biopsy-proven trichilemmomas, or Two major criteria, including macrocephaly, or Three major criteria, without macrocephaly, or Two major criteria + two minor criteria, or One major criterion + three minor criteria, or Four minor criteria C Individual with a first-degree relative with a clinical diagnosis of Cowden disease or BRRS plus a personal history of: One major criterion, or Two minor criteria BRRS, Bannayan–Riley–Ruvalcaba syndrome. National Comprehensive Cancer Network 2010 (www.nccn.org/ professionals/physician_gls/PDF/genetics_screening.pdf)

moplantar) keratoses can be observed in patients with Darier disease. Facial papules (e.g. angiofibromas and fibrofolliculomas) and gingival fibromas also occur together in tuberous sclerosis and Birt–Hogg–Dubé syndrome. However, these conditions can usually be easily differentiated from Cowden syndrome by their distinct clinical and histological features.

137.20

Chapter 137

PTEN hamartoma-tumour syndrome patients with manifestations such as segmental overgrowth, lipomatosis, epidermal naevi, vascular malformations and fibromas have been reported as having ‘Proteus-like’ or even Proteus syndrome. However, these individuals generally fail to meet stringently applied Proteus syndrome criteria such as a relentlessly progressive course, mosaic distribution of lesions (e.g. no disseminated/non-segmental gastrointestinal polyposis as observed in many PHTS patients), sporadic occurrence (e.g. no relatives with Cowden syndrome as observed in some PHTS patients), disproportionate as well as asymmetrical overgrowth, and truly cerebriform connective tissue naevi. A search for germline PTEN mutations has thus far yielded negative results in patients with classic Proteus syndrome. Treatment. All patients with PHTS, including individuals with a known germline PTEN mutation and those who meet diagnostic criteria for Cowden syndrome, should undergo surveillance for associated malignancies [2,21]. Current guidelines recommend an annual thyroid ultrasound beginning at age 18 years and (for women) semi-annual clinical breast examination beginning at age 25 years and annual mammography and breast magnetic resonance imaging beginning at age 30–35 years. Prophylactic mastectomy can be considered on an individual basis. Surveillance for endometrial and renal cancer is also recommended for patients with a family history of these malignancies. A clinical trial is under way to determine whether the mTOR inhibitor rapamycin can decrease the growth of benign and malignant tumours in patients with PHTS, as has been demonstrated in pten-deficient mice [21,22]. References 1 Lloyd KM, Dennis M. Cowden’s disease: a possible new symptom complex with multiple system involvement. Ann Intern Med 1963;58:136–42. 2 Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Counsel 2009;18:13–27. 3 Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet 2008;16:1289–300. 4 Liaw D, Marsh DJ, Li J et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997;16:64–7.

5 Marsh DJ, Dahia PL, Zheng Z et al. Germline mutations in PTEN are present in Bannayan–Zonana syndrome. Nat Genet 1997;16: 333–4. 6 Marsh DJ, Kum JB, Lunetta KL et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan–Riley–Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999;8:1461–72. 7 Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 2004;41:323–6. 8 Lachlan KL, Lucassen AM, Bunyan D et al. Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome represent on condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 2007;44:579–85. 9 Caux F, Plauchu H, Chibon F et al. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Eur J Hum Genet 2007;15:767–73. 10 Happle R. Linear Cowden nevus: a new distinct epidermal nevus. Eur J Dermatol 2007;17:133–6. 11 Brownstein MH, Mehregan AM, Bikowski B et al. The dermatopathology of Cowden’s syndrome. Br J Dermatol 1979;100:667–73. 12 Starink TM, Meijer CJLM, Brownstein MH. The cutaneous pathology of Cowden’s disease: new findings. J Cutan Pathol 1985;12:83–93. 13 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. 14 Schaffer JV, Kamino H, Witkiewicz A et al. Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol 2006;142:625–32. 15 Salem OS, Steck WD. Cowden’s disease (multiple hamartoma and neoplasia syndrome). J Am Acad Dermatol 1983;8:686–96. 16 Starink TM. Cowden’s disease: analysis of 14 new cases. J Am Acad Dermatol 1984;11:1127–41. 17 Starink TM, van der Veen JPW, Arwert F et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986;29:222–33. 18 Ferran M, Bussaglia E, Matias-Guiu X et al. Bilateral and symmetrical palmoplantar punctuate keratoses in childhood: a possible clinical clue for an early diagnosis of PTEN hamartoma-tumour syndrome. Clin Exp Dermatol 2009;34:e28–e30. 19 Nishizawa A, Satoh T, Watanabe R et al. Cowden syndrome: a novel mutation and overlooked glycogenic acanthosis in gingival. Br J Dermatol 2009;160:1116–18. 20 Lynch NE, Lynch SA, McMenamin J et al. Bannayan–Riley– Ruvalcaba syndrome: a cause of extreme macrocephaly and neurodevelopmental delay. Arch Dis Child 2009;94:553–4. 21 Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med 2009;11(10):687–94. 22 Squarize CH, Castilho RM, Gutkind JS. Chemoprevention and treatment of experimental Cowden’s disease by mTOR inhibition with rapamycin. Cancer Res 2008;68:7066–72.

138.1

C H A P T E R 138

Inherited Disorders of Pigmentation Eli Sprecher1 & Dov Hershkovitz2 1

Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Department of Pathology, Rambam Medical Center, Haifa, Israel

2

Disorders of hypopigmentation, 138.4

Disorders of hyperpigmentation, 138.9

Variation in skin pigmentation is one of the most distinctive and socially significant human characteristics [1]. Differences in skin and hair colour are principally the result of differences in the melanin content of skin although additional elements including other pigments and skin thickness also determine shade variation in the skin [2]. Melanocytes are responsible for the synthesis of melanin, a complex quinone/indole-quinone-derived mixture of biopolymers [3]. Melanocytes migrate from the neural crest into the epidermis during the first trimester of gestation. They produce melanin within specialized vesicles known as melanosomes. Pigmentation differences arise from variation in the number, size, composition and distribution of melanosomes [4]. The major precursor of melanins is tyrosine. Tyrosinase catalyses the hydroxylation of tyrosine to DOPA (3,4,dihydroxyphenylalanine). Once completely formed within melanocytes, melanosomes are transported along dendrites towards adjacent keratinocytes [5].This process results from the concerted action of at least three proteins: the motor protein myosin Va, Rab27a, a member of the Rab GTPases family of proteins, and melanophilin [6]. The next step involves the extrusion of the melanosomes and their transfer into neighbouring keratinocytes, most probably through phagocytosis of released melanosomes by keratinocytes [7]. Activation of PAR-2 results in increased phagocytic activity of cultured keratinocytes toward isolated melanosomes [8]. After being transferred, melanosomes are translocated to the apical pole of the keratinocyte where they are best placed to absorb UV light and protect the nucleus from mutagenic damage. This trafficking process has been shown to require microtubule-associated motor proteins such as dynein [9] and cytoskeletal elements such as keratin and keratin-associated proteins [10]. Keratinocyte

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Dyschromatoses, 138.11

terminal differentiation is accompanied by concomitant degradation of melanosomes so that no melanosomes are normally visible in the very upper part of the epidermis. In accordance with the biochemical complexity of the skin pigmentation process, more than 120 loci have been found to affect coat pigmentation in the mouse [11] and more than 100 inherited disorders of pigmentation have been described in humans, many of which have yet to be elucidated at the molecular level (Table 138.1). These disorders can be classified into three major groups: disorders of hypopigmentation, disorders of hyperpigmentation and disorders featuring combined hypo- and hyperpigmented lesions, known as dyschromatoses. References 1 Slominski A, Tobin DJ, Shibahara S et al. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 2004;84:1155–228. 2 Abdel-Malek ZA, Scott MC, Furumura M et al. The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling protein on mammalian melanocytes. J Cell Sci 2001;114,1019–24. 3 Rees JL. Genetics of hair and skin color. Annu Rev Genet 2003;37: 67–90. 4 Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007;445:843–50. 5 Boissy RE. Melanosome transfer to and translocation in the keratinocyte. Exp Dermatol 2003;12(suppl 2):5–12. 6 Hume AN, Ushakov DS, Tarafder AK et al. Rab27a and MyoVa are the primary Mlph interactors regulating melanosome transport in melanocytes. J Cell Sci 2007;120:3111–22. 7 Van Den Bossche K, Naeyaert JM, Lambert J. The quest for the mechanism of melanin transfer. Traffic 2006;7:769–78. 8 Seiberg M, Paine C, Sharlow E et al. Inhibition of melanosome transfer results in skin lightening. J Invest Dermatol 2000;115:162–7. 9 Betz RC, Planko L, Eigelshoven S et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet 2006;78:510–19. 10 Planko L, Bohse K, Hohfeld J et al. Identification of a keratinassociated protein with a putative role in vesicle transport. Eur J Cell Biol 2007;86:827–39. 11 Hoekstra HE. Genetics, development and evolution of adaptive pigmentation in vertebrates. Heredity 2006;97:222–34.

138.2

Chapter 138

Table 138.1 Disorders of pigmentation Disease name

Inheritance*

Gene

Locus

OMIM#

Clinical features

Hypopigmentation Piebaldism

AD

KIT

4q11-12

(MIM#172800)

Well-demarcated irregular hypopigmentary macules

Waardenburg syndrome (WS) WS1

AD

PAX3

2q35

(MIM#193500)

WS2A WS2B WS2C WS2D WS2E WS3

AD AD T(4p;8p) AR AR AD

MITF unknown unknown SNAI2 SOX10 PAX3

3p14.2-p14.1 1p21-p13.3 8p23 8q11 22q13.1 2q35

(MIM#193510) (MIM#600193) (MIM#606662) (MIM#608890) (MIM#611584) (MIM#148820)

Waardenburg–Shah syndrome

AR

EDN3

(MIM#277580)

AR AR

EDNRB SOX10

20q13.2q13.3 13q22 22q13.1

Congenital leucoderma with sensorineural deafness White forelock, alopecia, hypopigmented patches, dystopia canthorum, dysmorphic features and deafness Same as WS1, no facial dysmorphism

Same as WS1 with musculoskeletal anomalies Accompanied by Hirschsprung disease

(MIM#277580) (MIM#277580)

Oculocutaneous albinism (OCA) OCA1A

AR

TYR

11q14-q21

(MIM#203100)

OCA1B OCA2 OCA3 OCA4 OA1

AR AR AR AR XLR

TYR OCA2 TYRP1 SLC45A2 GPR143

11q14-q21 15q11.2-q12 9p23 5p13.3 Xp22.3

(MIM#606952) (MIM#203200) (MIM#203290) (MIM#606574) (MIM#300500)

Hermansky-Pudlak syndrome HPS1

AR

HPS1

10q23.1-q23.

(MIM#203300)

HPS2 HPS3 HPS4 HPS5 HPS6 HPS7 HPS8

AR AR AR AR AR AR AR

AP3B1 HPS3 HPS4 HPS5 HPS6 DTNBP1 BLOC1S3

5q14.1 3q24 22cen-q12.3 11p14 10q24.32 6p22.3 19q13.32

(MIM#608233) (MIM#203300) (MIM#203300) (MIM#203300) (MIM#203300) (MIM#203300) (MIM#203300)

Chediak-Higashi syndrome

AR

LYST

1q42.1-q42.2

(MIM#214500)

Griscelli syndrome GS1 GS2 GS3

AR AR AR

MYO5A RAB27A MLPH

15q21 15q21 2q37.3

(MIM#607624) (MIM#214450) (MIM#609227)

Hypopigmented to white skin and hair colour Absent skin and hair pigmentation, no ability to tan Partial albinism, hair darkens with age

Decreased pigmentation in eyes, hair and skin, easy bruisability and bleeding tendency, lung and intestinal diseases

Partial albinism (blond hair, fair skin) accompanied by immunodeficiency Silvery grey hair and fair skin Neurological defects Immunological defects

Inherited Disorders of Pigmentation

138.3

Table 138.1 Continued Disease name

Inheritance*

Gene

Locus

OMIM#

Clinical features

Hyperpigmentation Familial progressive hyperpigmentation

AD

unknown

19pter-p13.1

(MIM#145250)

Primary cutaneous amyloidosis

AD

OSMR

5p13.1

(MIM#105250)

Congenital sharply and irregular hyperpigmentary patches which increase in size and number with age Chronic skin itching and diffuse hyperpigmentation

Incontinentia pigmenti

XLD

IKBKG

Xq28

(MIM#308300)

Linear and whorled nevoid hypermelanosis Dyskeratosis congenita

SO

unknown

unknown

XLR AD AD AD AR AD

DKC1 TERC TERT TINF2 NOP10 KRT14

Xq28 3q26 5p15.33 14q12 15q14-q15 17q12-q21

(MIM#305000) (MIM#127550) (MIM#127550) (MIM#127550) (MIM#224230) (MIM#161000/ MIM#125595)

Dowling-Degos disease

AD

KRT5

12q12-q13

(MIM#179850)

Reticulate pigmentary disorder with systemic manifestations

XLD

unknown

Xp22-p21

(MIM#301220)

Reticulate acropigmentation of Kitamura

AD

unknown

unknown

AD

ADAR

1q21.3

(MIM#127400)

AD

unknown

6q24.2-q25.2

(MIM#127500)

Naegeli-FranceschettiJadassohn syndrome and dermatopathia pigmentosa reticularis

Dyschromatoses Dyschromatosis symmetrica hereditaria Dyschromatosis universalis hereditaria

Pigmentation abnormalities consisted of whorls and streaks located over the trunk Cardiovascular, neurological and musculoskeletal abnormalities Reticulated pattern of hyperpigmentation, bone marrow dysplasia, hematological and epithelial malignancies

Complete absence of dermatoglyphics, a reticulate pattern of skin hyperpigmentation, palmoplantar keratoderma, abnormal sweating, dental anomalies and nail dystrophy Postpubertal reticulate hyperpigmentation of the flexures Reticulate brown hyperpigmentation that follows the lines of Blashko in females and is generalized in males. Males also have neonatal colitis, neurological defects, hypohidrosis, dental anomalies, musculoskeletal defects and pulmonary complications Hyperpigmented atrophic macules on the hand dorsa and ‘pits’ on the palms and soles with abnormal dermatoglyphics

Small hyperpigmented and hypopigmented macules on the back of the hand and feet Hypopigmented and hyperpigmented macules distributed over the entire surface of the skin

138.4

Chapter 138

Disorders of hypopigmentation Diseases resulting from abnormal melanocyte ontogenesis This group of pigmentation disorders mostly result from aberrant development and/or migration of melanocyte precursors to the epidermis (Fig. 138.1).

Piebaldism Clinical presentation. Piebaldism is a rare autosomal dominant disorder manifesting with well-demarcated irregular hypopigmentary macules [1]. The most typical and common clinical feature of the disease is a white forelock, often associated with a V-shaped area of leuco-

(d)

derma on the mid-forehead. The hypopigmented lesions of piebaldism have a predilection for the anterior part of the body and the midportion of the limbs (Fig. 138.2a). In contrast with vitiligo lesions, in piebaldism, lesions grow in size with the patient age and remain stable in adults. In addition, small spots of hyperpigmentation can be observed within the hypopigmentary lesions or even on the background of normal skin. Although piebaldism is usually not associated with extracutaneous manifestations, mental retardation and deafness have been reported in a number of cases [2,3]. Pathophysiology. The disease results from mutations in KIT, encoding c-KIT, a membranal tyrosine kinase receptor responsible for triggering cell proliferation and migra-

(e)

(c)

(b)

(a)

Fig. 138.1 Normal physiology of skin pigmentation and molecular defects associated with hypopigmentary disorders. During embryonic development, melanocytes (yellow) migrate to the epidermis (lower middle panel). Melanin-containing melanosomes are formed within melanocytes and are transported through dendrites to neighbouring keratinocytes (pink) where they form a cap at the upper pole of the nucleus to protect it from the deleterious effects of ultraviolet light. (a) Impaired melanocyte migration during embryogenesis results in piebaldism, characterized by patches of white skin lacking melanocytes. (b) Defects in melanin production result in lack of pigment production in oculocutaneous albinism. Chediak–Higashi syndrome (CHS), Hermansky–Pudlak syndrome (HPS) and Griscelli syndrome (GS) are characterized by dysfunction of lysosomal-related organelles. (c) The hallmarks of CHS are huge intracellular melanosomes. (d) In HPS impaired protein trafficking in melanocytes causes melanosomal dysfunction. (e) Impaired melanosome transport and capture by keratinocytes causes their accumulation in melanocytes as seen in GS.

Inherited Disorders of Pigmentation

138.5

(b)

(c)

(a)

(d)

Fig. 138.2 Disorders of hypopigmentation. (a) Well-demarcated hypopigmented macules with areas of hyperpigmentation in piebaldism. Courtesy of Dr Arie Metzker. (b) Heterochromia and dystopia canthus in Waardenburg syndrome type 1. Courtesy of Professor Peter Itin. (c) Poliosis in Waardenburg syndrome type 1 (arrow). Courtesy of Professor Peter Itin. (d) Depigmented hair and skin in oculoalbinism type 1A. Courtesy of Dr Arie Metzker.

tion. The c-KIT receptor is very important for proper melanocyte and mast cell maturation [4]. A single nucleotide polymorphism in the KIT ligand (KITLG) gene was found to be associated with fair versus brown hair [5]. Additionally, the recent demonstration of pigmentation abnormalities resulting from the use of novel tyrosine kinase inhibitors attests to the importance of this system in the maintenance of the epidermal melanocyte population [6]. Dominant mutations in KIT result in impaired migration of melanocytes to the skin, as reflected by the absence of melanocytes and melanin in hypopigmented patches [1]. Differential diagnosis. Although the skin lesions in piebaldism are quite typical, the occurrence of isolated poliosis or skin hypopigmentation can suggest a number of other inflammatory (e.g. vitiligo, alopecia areata, Vogt– Koyanagi syndrome, Alezzandrini syndrome, Woolf

syndrome), monogenic (e.g. tuberous sclerosis, Waardenburg syndrome) or somatic (naevus depigmentosus) disorders. Treatment. Epidermal cell and skin grafting have both been successfully tried in piebaldism. In contrast, phototherapy is inefficacious. Sun protection is recommended.

Waardenburg syndrome Clinical features. Waardenburg syndrome features congenital leucoderma in association with sensorineural deafness of varying severity. Areas of hypopigmentation may diminish in size or even disappear with time. Four distinct subtypes of the disease have been recognized [7]. Waardenburg syndrome type 1 is inherited in an autosomal dominant fashion and is characterized by a white

138.6

Chapter 138

forelock, alopecia, hypopigmented patches, dystopia canthorum (increased distance between the inner canthi without any change in the distance between the pupils) and heterochromia irides associated with deafness in one-third to one-half of the cases (Fig. 138.2b-c). Patients often display dysmorphic features including a broad nasal root and synophrys (medial hyperplasia of eyebrows). Waardenburg syndrome type 2 (Klein–Waardenburg syndrome) is inherited in an autosomal dominant or recessive fashion. Clinical signs are similar to those seen in Waardenburg syndrome type 1 except for absence of facial dysmorphism and dystopia canthorum, and a higher frequency of deafness and heterochromia. Waardenburg syndrome type 3, an autosomal dominant disorder, is much rarer than the other types and presents the same clinical manifestations as type 1 in association with musculoskeletal anomalies (e.g. syndactyly, fusion of carpal bones, etc.). Waardenburg syndrome type 4 (Shah–Waardenburg syndrome) is inherited in an autosomal recessive fashion, features a white forelock and is accompanied by Hirschsprung disease. Pathophysiology. So far, mutations in six different genes have been associated with the four disease types. Type 1 and type 3 result from loss-of-function mutations in the PAX3 gene [8]. PAX3 is a transcription factor for the microphthalmia-associated transcription factor gene (MITF) which, in turn, activates a number of genes associated with melanogenesis such as TYR encoding tyrosinase [9], as well as mediating survival of melanocytes through Bcl-2. Mutations in MITF result accordingly in Waardenburg syndrome type 2. This is characterized by genetic heterogeneity (caused by mutations in different genes); for example, it was recently shown to also result from mutations in SNAI2 encoding a zinc-finger transcription factor [10]. Waardenburg syndrome type 4 is caused by mutations in at least three genes including EDNRB, encoding the endothelin-B receptor, EDN3, encoding the ligand of EDNRB, and SOX10 which, like PAX3, regulates the expression of MITF. Homozygous mutations in EDNRB and EDN3 result in Waardenburg syndrome type 4 whereas heterozygous mutations cause isolated Hirschsprung disease. Loss of SOX10 expression leads to abnormal expression of RET, which is known to cause Hirschsprung disease [9,11-13]. In addition, lack of SOX10 expression is associated with abnormal myelination and neurological signs. Differential diagnosis. Tietz syndrome is characterized by skin, hair and iris hypopigmentation, hypoplasia of the eyebrows and deafness, without any photophobia or nystagmus [14].

Treatment. Therapeutic options for the skin disease are identical to those for piebaldism. In addition, early detection of hearing loss allows for prompt intervention. Finally, surgical correction is mandatory in Hirschsprung disease.

Diseases resulting from abnormal melanosome biogenesis and transfer Unlike the patchy hypopigmentation typical of piebaldism and Waardenburg syndrome, mutations affecting melanosome maturation and transport (as well as melanin production, see below) are usually associated with either globally reduced or absent pigmentation of the skin, hair and eyes, with normal numbers of melanocytes in the epidermis (see Fig. 138.1).

Hermansky–Pudlak syndrome Clinical features. All eight different types of Hermansky– Pudlak syndrome are inherited in an autosomal recessive fashion [15]. All subtypes of the syndrome share common clinical manifestations including decreased pigmentation in eyes, hair and skin, easy bruisability and bleeding tendency (manifesting with menorrhagia, epistaxis, haematochezia, ecchymoses), interstitial pulmonary fibrosis and granulomatous colitis. The disorder is rare in most parts of the world except in Puerto Rico where its prevalence reaches 1:800. Pathogenesis. The disease results from abnormal biogenesis of lysosome-related organelles. Melanocytes are present within the skin and express a normal repertoire of genes. However, melanosome maturation is impaired and type IV melanosomes can only rarely be observed. Similarly, the platelet count is normal; however, dense bodies are absent in thrombocytes. Visceral involvement is due to partial or absent degradation of lipids resulting in accumulation of ceroid materials within the cell lysosomes. Hermansky–Pudlak syndrome is associated with mutations in eight distinct genes: HPS1 (type 1) and HPS4 (type 4) encode components of the BLOC3 lysosomal complex, which is essential for the proper formation of lysosome-related organelles; AP3B1 (type 2) encodes a subunit of the AP3 complex, which is responsible for mediating protein sorting to lysosomes; HPS3 (type 3), HSP5 (type 5) and HSP6 (type 6) encode components of BLOC2, and DTNBP1 (type 7) and BLOC153 (type 8) encode for components of BLOC1, which are all required for proper melanosome maturation [15,16]. Differential diagnosis. Cross–McKusick–Breen is a rare autosomal recessive disorder characterized by oculocuta-

Inherited Disorders of Pigmentation

138.7

neous albinism, silvery hair, growth retardation, gingival fibromatosis, spasticity, athetosis and nystagmus. Its underlying cause is unknown.

syndrome result in defective transport of melanosomes and consequently accumulation of melanosomes in melanocytes on electron microscopy.

Treatment. The disease has been managed with 1-desamino-8-D-arginine or platelet transfusion for the bleeding disorder. Prognosis is guarded with a life expectancy of 30–50 years.

Differential diagnosis. Elejalde syndrome is inherited in an autosomal recessive fashion and is characterized by pigment dilution, silvery grey hair, neurological defects and early demise. Some authors suggest that the disease may in fact be identical to Griscelli–Prunieras syndrome type 1 [23].

Chediak–Higashi syndrome Clinical features. Chediak–Higashi syndrome is characterized by partial albinism (blond hair, fair skin) accompanied by immunodeficiency manifesting with an increased incidence of pyogenic infections and haematophagocytic syndrome. Some patients present cerebellar signs at adulthood [17]. Pathogenesis. The disease results from loss-of-function mutations in LYST which plays an important role in vesicle trafficking [18]. As a consequence, melanocyte maturation, as well as neutrophil, monocyte and natural killer cell function are impaired. Cell dysfunction in Chediak–Higashi manifests at the ultrastructural level through the accumulation of giant melanosomes in melanocytes and inclusion bodies in other affected cell types [16,18].

Treatment. This syndrome has been successfully treated with bone marrow transplantation.

Melanin synthesis disorders Here, melanocyte and melanosome formation is normal; the defect involves abnormal synthesis of melanin (Fig. 138.1).

Oculocutaneous albinism

Clinical features. All subtypes of the disease present with typical silvery grey hair and fair skin. In Griscelli– Prunieras syndrome type 1, patients display partial albinism in association with neurological manifestations including psychomotor retardation and hypotonia; in Griscelli–Prunieras syndrome type 2, immunological abnormalities are prominent. Occasionally, only hypopigmentation is noted (Griscelli–Prunieras syndrome type 3) [7,16].

Clinical features. Oculocutaneous albinism results from absent (type 1A) or decreased (type 1B, 2, 3 and 4) production of melanin. As a consequence, patient skin and hair colour is hypopigmented (type 1B, 2,3 and 4) or white (type 1A). Visual acuity is decreased due to reduced melanin in the retinal pigment epithelium and iris, and is associated with congenital nystagmus, photophobia and foveal hypoplasia. Electrophysiological testing can demonstrate misrouting of the optic nerves, resulting in strabismus and impaired stereoscopic vision [24,25]. Patients with oculocutaneous albinism type 1A have pink skin, white hair and blue irises (Fig. 138.2d). Many of these patients are legally blind. In contrast, patients with oculocutaneous albinism type 1B (yellow albinism) show some degree of pigmentation with age and have yellow hair. Oculocutaneous albinism types 2 and 4 are characterized by the presence of pigmented hair, partial hypopigmentation and better visual acuity. In oculocutaneous albinism type 3 (known as red albinism), often seen in individuals of African origin, red hair and reddishbrown skin colour are typical.

Pathogenesis. Griscelli–Prunieras syndrome type 1 results from mutations in MYO5A, encoding myosin 5a, which together with Rab27a and melanophilin forms a complex that enables melanosomes to traffic through melanocytes and dock to the dendrite tips [19–22]. Griscelli–Prunieras syndrome type 2 results from mutations in the RAB27A gene whereas type 3 is caused by mutations in the MLPH gene encoding melanophilin or by a specific genetic defect in MYO5A. Collectively, all genetic alterations associated with Griscelli–Prunieras

Pathogenesis. The disease is inherited in an autosomal recessive fashion (except for rare instances of dominant inheritance) and is found in 1:17,000 people in the general population. Oculocutaneous albinism type 1 is caused by mutations in TYR, encoding the tyrosinase gene. Tyrosinase catalyses the first two steps in the biosynthesis of melanins, converting tyrosine to L-DOPA, and L-DOPA to DOPAquinone. Total lack of tyrosinase activity results in oculocutaneous albinism type 1A while partial activity causes oculocutaneous albinism type 1B. Of interest,

Treatment. The only curative treatment available today for Chediak–Higashi syndrome is bone marrow transplantation.

Griscelli–Prunieras syndrome

138.8

Chapter 138

some patients with type 1B oculocutaneous albinism show variation in hair and skin hypopigmentation, with dark hair being found in cooler areas of the body. This phenomenon has been related to the fact that the underlying mutations in these cases are temperature sensitive. Oculocutaneous albinism type 2 is caused by mutations in the OCA2 gene, encoding the P protein, a transmembrane protein of importance for melanin biosynthesis and for the processing and transport of other melanosomal proteins such as tyrosinase. Mutations in TYRP1 are responsible for oculocutaneous albinism type 3. The protein encoded by this gene catalyses the oxidation of DHICA monomers into eumelanin and serves also to stabilize tyrosinase. It is not required for pheomelanin production, explaining the accumulation of the latter in the skin and hair in oculocutaneous albinism type 3. Finally, oculocutaneous albinism type 4 is caused by mutations in SLC45A2, encoding the membrane-associated transporter protein (MATP), a membrane transporter in melanosomes. Interestingly, it has recently been demonstrated that a common polymorphism in the OCA2 gene can explain most human eye colour variation [26]. Additionally, polymorphisms in the TYR and MATP genes causing OCA1 and OCA4, respectively, have been associated with variation in skin pigmentation in the South Asian population [27]. Differential diagnosis. The presence of ocular albinism excludes a large number of diseases associated with pigment dilution. Diagnoses to be considered in the case of ocular and cutaneous hypopigmentation include histidinaemia, homocystinuria, phenylketonuria, Hermansky– Pudlak and Chediak–Higashi syndromes, as well as Cross and Tietz syndromes. Treatment. Sun protection is mandatory to avoid skin sunburns and skin cancers which are more frequent in patients with oculocutaneous albinism than in the general population. Early referral to an ophthalmologist is recommended. Decreased visual acuity is usually managed with corrective lenses while strabismus requires eye patching or surgical correction. Dark glasses are important to protect the eyes and prevent photophobia.

Ocular albinism This disorder manifests in the eyes only, is transmitted in an X-linked fashion and is caused by mutations in the OCA gene. A recessive form of ocular albinism has been shown to result from mutation in the OCA2 gene, which may explain why some cases of ocular albinism have been shown to be associated with mild pigment dilution of the skin and hair [28].

References 1 Thomas I, Kihiczak GG, Fox MD et al. Piebaldism: an update. Int J Dermatol 2004;43:716–19. 2 Sijmons RH, Kristoffersson U, Tuerlings JH et al. Piebaldism in a mentally retarded girl with rare deletion of the long arm of chromosome 4. Pediatr Dermatol 1993;10:235–9. 3 Spritz RA, Beighton P. Piebaldism with deafness: molecular evidence for an expanded syndrome. Am J Med Genet 1998;75:101–3. 4 Kitamura Y, Hirotab S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 2004;61:2924–31. 5 Sulem P, Gudbjartsson DF, Stacey SN et al. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 2007;39:1443–52. 6 Tsao AS, Kantarjian H, Cortes J et al. Imatinib mesylate causes hypopigmentation in the skin. Cancer 2003;98:2483–7. 7 Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet 2004;131C:75–81. 8 Kubic JD, Young KP, Plummer RS et al. Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease. Pigment Cell Melanoma Res 2008;21:627–45. 9 Sato-Jin K, Nishimura EK, Akasaka E et al. Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders. Faseb J 2008;22:1155–68. 10 Sanchez-Martin M, Rodriguez-Garcia A, Perez-Losada J et al. SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum Mol Genet 2002;11:3231–6. 11 Edery P, Attie T, Amiel J et al. Mutation of the endothelin-3 gene in the Waardenburg–Hirschsprung disease (Shah–Waardenburg syndrome). Nat Genet 1996;12:442–4. 12 Hofstra RM, Osinga J, Tan-Sindhunata G et al. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah–Waardenburg syndrome). Nat Genet 1996;12:445–7. 13 Pingault V, Bondurand N, Kuhlbrodt K et al. SOX10 mutations in patients with Waardenburg–Hirschsprung disease. Nat Genet 1998;18:171–3. 14 Smith SD, Kelley PM, Kenyon JB et al. Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. J Med Genet 2000;37:446–8. 15 Wei ML. Hermansky–Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res 2006;19:19–42. 16 Huizing M, Helip-Wooley A, Westbroek W et al. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu Rev Genomics Hum Genet 2008;9:359–86. 17 Shiflett SL, Kaplan J, Ward DM. Chediak–Higashi syndrome: a rare disorder of lysosomes and lysosome related organelles. Pigment Cell Res 2002;15:251–7. 18 Kaplan J, de Domenico I, Ward DM. Chediak–Higashi syndrome. Curr Opin Hematol 2008;15:22–9. 19 Fukuda M, Kuroda TS, Mikoshiba K. Slac2-a/melanophilin, the missing link between Rab27 and myosin Va: implications of a tripartite protein complex for melanosome transport. J Biol Chem 2002;277:12432–6. 20 Menasche G, Feldmann J, Houdusse A et al. Biochemical and functional characterization of Rab27a mutations occurring in Griscelli syndrome patients. Blood 2003;101:2736–42. 21 Menasche G, Pastural E, Feldmann J et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 2000;25:173–6. 22 Pastural E, Barrat FJ, Dufourcq-Lagelouse R et al. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nat Genet 1997;16:289–92. 23 Lambert J, Vancoillie G, Naeyaert JM. Elejalde syndrome revisited. Arch Dermatol 2000;136:120–1.

Inherited Disorders of Pigmentation 24 Gronskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis 2007;2:43. 25 Okulicz JF, Shah RS, Schwartz RA et al. Oculocutaneous albinism. J Eur Acad Dermatol Venereol 2003;17:251–6. 26 Duffy DL, Montgomery GW, Chen W et al. A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. Am J Hum Genet 2007;80:241–52. 27 Stokowski RP, Pant PV, Dadd T et al. A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet 2007;81:1119–32. 28 Young TL. Ophthalmic genetics/inherited eye disease. Curr Opin Ophthalmol 2003;14:296–303.

138.9

Linear hyperpigmentation Incontinentia pigmenti A thorough discussion of the disease is presented in Chapter 130. This X-linked dominant disorder develops in four stages: vesicular, verrucous, hyperpigmentary and hypopigmentary, and results from mutations in the NEMO gene [3]. The pigmentation abnormalities in incontinentia pigmenti are striking and consist of whorls and streaks, mainly located over the trunk. These lesions tend to fade over time.

Linear and whorled naevoid hypermelanosis

Disorders of hyperpigmentation Inherited disorders of pigmentation can be classified according to the pattern of pigmentation: diffuse, linear, reticulate and punctate. A full discussion of all inherited disorders of hyperpigmentation is beyond the scope of the present chapter. Punctate hyperpigmentation as seen in Peutz–Jeghers disease (Chapter 137) and Carney complex is discussed elsewhere (see Chapter 172).

Diffuse hyperpigmentation Important metabolic disorders associated with diffuse hyperpigmentation include congenital adrenal hypoplasia, adrenal leucodystrophy, Wilson disease, porphyria cutanea tarda and haemochromatosis which are discussed in Chapter 172. Lysosomal storage disorders can also be accompanied by diffuse hyperpigmentation (e.g. Niemann–Pick disease, especially in sun-exposed areas, and Gaucher disease type I). Two disorders are discussed here below: familial progressive hyperpigmentation and familial primary cutaneous amyloidosis.

Familial progressive hyperpigmentation This autosomal dominant disorder is characterized by congenital sharply demarcated and irregular hyperpigmentary patches which increase in size and number over time, and involve both the mucosae and the skin. The underlying cause is unknown. The disorder has been mapped to chromosome 19p13.1-pter but no specific gene has been reported yet [1].

Familial primary cutaneous amyloidosis This disease is inherited in an autosomal dominant fashion and manifests with chronic skin itching, resulting in deposition of keratin filament-derived amyloid in the upper dermis, and consequently diffuse hyperpigmentation. The disease was found to result from impaired function of the oncostatin M-specific receptor β, which is part of the oncostatin M type II receptor and of the interleukin-31 receptor [2].

The hyperpigmentation in this somatic disorder results from increased melanin content in the epidermis and is present at birth. Associated findings may include cardiovascular, neurological and musculoskeletal abnormalities [4]. A fuller discussion of this disorder is considered in Chapter 131.

Reticulate hyperpigmentation Dyskeratosis congenita and Fanconi anaemia Dyskeratosis congenita and Fanconi anaemia are fully discussed in Chapter 136. Dyskeratosis congenita can be inherited in an autosomal recessive, autosomal dominant or X-linked recessive fashion. The disorder features a reticulated pattern of hyperpigmentation predominantly on the neck, keratoderma, bullae, wrinkled skin on the extremities, nail dystrophy and leucokeratosis often undergoing malignant transformation (Fig. 138.3a-c) [5]. Bone marrow dysplasia, haematological and epithelial malignancies are frequent complications. The condition results from mutations in multiple genes encoding proteins of critical importance for proper telomere function and maintenance [6]. A related disorder is autosomal recessive Fanconi anaemia, which is also associated with reticulated hyperpigmentation, pancytopenia and an increased risk of neoplasia [7].

Naegeli–Franceschetti–Jadassohn syndrome and dermatopathia pigmentosa reticularis These disorders are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics, a reticulate pattern of skin hyperpigmentation mainly involving the trunk and face (Fig. 138.3d) palmoplantar keratoderma, abnormal sweating, and other subtle developmental anomalies including plantar bullae in early childhood, alopecia, dental anomalies and nail dystrophy. Recently, these two syndromes have been shown to result from mutations affecting the region of the KRT14 gene encoding the non-helical head domain of keratin 14 [8]. These mutations were found to result in haploinsufficiency and to be associated with increased susceptibility of

138.10

Chapter 138

(a)

(b)

(d)

(c)

(e)

Fig. 138.3 Disorders of hyperpigmentation. (a) Reticulate pigmentation, (b) nail dystrophy and (c) squamous cell carcinoma in dyskeratosis congenita. (d) Reticulate hyperpigmentation in Naegeli–Franceschetti–Jadasshon syndrome. Courtesy of Professor Gabriele Richard. (e) Flexural hyperpigmentation in Dowling–Degos syndrome.

Inherited Disorders of Pigmentation

keratinocytes to proapoptotic stimuli [9]. Interestingly, mutations affecting other keratin 14 domains cause a completely different clinical phenotype – epidermolysis bullosa simplex [10] (see Chapter 118), which in some cases is also associated with mottled pigmentation [11].

Dowling–Degos disease Dowling–Degos disease (DDD) is an autosomal dominant disorder with variable penetrance characterized by the presence of reticulate hyperpigmentation of the flexures (Fig. 138.3e) comedo-like lesions on the neck, and pitted perioral acneiform scars [12]. Onset is usually postpubertal. No abnormalities of hair or nails are seen. It has been recently shown that the disease is caused by loss-offunction mutations affecting the KRT5 gene region encoding the initial part of keratin 5 [12]. Here also, the mutations result in haploinsufficiency, causing epithelial remodelling, melanosome mistargeting and altered perinuclear organization of intermediate filaments. The fact that a mutation in KRT5 causes epidermolysis bullosa simplex (EBS) with mottled pigmentation (EBS-MP; MIM131961) suggests that keratin 5 has an important role in melanosome transport [13]. Interestingly, DDD appears to be a genetically heterogeneous disease as a genome-wide linkage analysis in a Chinese family mapped a novel DDD-associated gene to chromosome 17p13.3, suggesting that at least another gene might be associated with the disease [14]. On the other hand, Galli–Galli disease, which clinically resembles DDD and features acantholysis on histology, was shown to be allelic to this disease [15].

X-linked reticulate pigmentary disorder Reticulate brown hyperpigmentation in this disease follows the lines of Blashko in females and is generalized in males, who also suffer from systemic complications such as neonatal colitis, neurological defects, hypohidrosis, dental anomalies, musculoskeletal defects and pulmonary complications which can lead to early death [16]. Histology reveals increased melanin epidermal content, pigment incontinence and dyskeratosis.

Reticulate acropigmentation of Kitamura Reticulate acropigmentation of Kitamura is characterized by the presence of hyperpigmented atrophic macules on the hand dorsa and ‘pits’ on the palms and soles with abnormal dermatoglyphics [17]. Hyperpigmented macules tend to spread to the body in adulthood. References 1 Zhang C, Deng Y, Chen X et al. Linkage of a locus determining familial progressive hyperpigmentation (FPH) to chromosome 19p13.1pter in a Chinese family. Eur J Dermatol 2006;16:246–50. 2 Arita K, South AP, Hans-Filho G et al. Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Am J Hum Genet 2008;82:73–80.

138.11

3 Nelson DL. NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin Genet Dev 2006;16:282–8. 4 Hong SP, Ahn SY, Lee WS. Linear and whorled nevoid hypermelanosis: unique clinical presentations and their possible association with chromosomal abnormality inv(9). Arch Dermatol 2008;144:415–16. 5 Ding YG, Zhu TS, Jiang W et al. Identification of a novel mutation and a de novo mutation in DKC1 in two Chinese pedigrees with Dyskeratosis congenita. J Invest Dermatol 2004;123:470–3. 6 Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood 2008;111:4446–55. 7 Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene 2006;25:5875–84. 8 Lugassy J, Itin P, Ishida-Yamamoto A et al. Naegeli–Franceschetti– Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. Am J Hum Genet 2006;79:724–30. 9 Lugassy J, McGrath JA, Itin P et al. KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli–Franceschetti–Jadassohn syndrome. J Invest Dermatol 2008;128(6):1517–24. 10 Hovnanian A, Pollack E, Hilal L et al. A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex. Nat Genet 1993;3:327–32. 11 Harel A, Bergman R, Indelman M et al. Epidermolysis bullosa simplex with mottled pigmentation resulting from a recurrent mutation in KRT14. J Invest Dermatol 2006;126:1654–7. 12 Betz RC, Planko L, Eigelshoven S et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling–Degos disease. Am J Hum Genet 2006;78:510–19. 13 Uttam J, Hutton E, Coulombe PA et al. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc Natl Acad Sci USA 1996;93:9079–84. 14 Li CR, Xing QH, Li M et al. A gene locus responsible for reticulate pigmented anomaly of the flexures maps to chromosome 17p13.3. J Invest Dermatol 2006;126:1297–301. 15 Sprecher E, Indelman M, Khamaysi Z et al. Galli–Galli disease is an acantholytic variant of Dowling–Degos disease. Br J Dermatol 2007;156:572–4. 16 Jaeckle Santos LJ, Xing C, Barnes RB et al. Refined mapping of X-linked reticulate pigmentary disorder and sequencing of candidate genes. Hum Genet 2008;123:469–76. 17 Schnur RE, Heymann WR. Reticulate hyperpigmentation. Semin Cutan Med Surg 1997;16:72–80.

Dyschromatoses This group of diseases is characterized by both hyperpigmented and hypopigmented lesions.

Dyschromatosis symmetrica hereditaria Dyschromatosis symmetrica hereditaria, also known as reticulate acropigmentation of Dohi, is characterized by small hyperpigmented and hypopigmented macules on the back of the hands and feet. The disease has a dominant pattern of inheritance and is associated with haploinsuficiency for the adenosine deaminase RNA-specific (ADAR1) gene [1]. ADAR1 mediates a post-transcriptional modification of the messenger RNA known as RNA editing. It has been postulated that impaired RNA editing

138.12

Chapter 138

during melanoblast migration causes their differentiation into hyper- and hypoactive melanocytes. Thus the most affected melanocytes are those which migrate farthest, to the hands and feet [1].

Dyschromatosis universalis hereditaria Here hypopigmented and hyperpigmented macules are distributed over the entire surface of the skin. The aetiology of the disorder and the mode of inheritance are still not clear. Neurological, ophthalmological and haematological complications have been reported [2].

References 1 Miyamura Y, Suzuki T, Kono M et al. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet 2003;73:693–9. 2 Stuhrmann M, Hennies HC, Bukhari IA et al. Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21-q23. Clin Genet 2008;73:566–72.

Acknowledgement We wish to thank Amihai Hershkovitz for his help in the design and preparation of Figure 138.1.

139.1

C H A P T E R 139

Prenatal Diagnosis of Inherited Skin Disorders John A. McGrath St John’s Institute of Dermatology, St Thomas’ Hospital and King’s College London, London, UK

Introduction, 139.1 Progress in molecular genetics, 139.1 Development of DNA-based prenatal diagnostic testing, 139.2

Practical aspects of DNA-based prenatal diagnosis, 139.6

Non-invasive prenatal diagnosis, 139.11 Ethical issues in prenatal testing, 139.12

Fetal skin biopsy, 139.7 Preimplantation genetic diagnosis, 139.9

Introduction The purpose of prenatal diagnosis is the detection or exclusion of a hereditary disease or congenital defect in utero. To that end, the development of accurate, reliable and generally safe methods for the prenatal diagnosis of several inherited skin disorders over the last 30 years represents one of the major benefits of translational research. A consequence of early prenatal diagnosis is that many pregnancies can proceed to term with the delivery of a normal child, instead of being terminated on the basis of a high risk. Prenatal testing for several genodermatoses is now well established. Most prenatal testing for inherited skin disorders currently assesses fetal DNA derived from first-trimester chorionic villus samples [1] with relatively few indications for the analysis of fetal skin biopsy samples acquired after 16 weeks’ gestation. Preimplantation genetic diagnosis and preimplantation genetic haplotyping are additional options that have been recently introduced and which expand choice for couples at risk of having affected children [2]. In future, further technical advances are likely to lead to the development of less invasive forms of fetal screening, such as analysis of free fetal DNA or RNA in the maternal circulation at 6–7 weeks’ gestation [3] but these approaches are not currently in clinical practice for genetic skin diseases. Technical innovations, however, also introduce new financial, ethical and moral considerations, all of which need to be considered carefully in planning strategies for prenatal diagnosis. References 1 Fassihi H, Eady RA, Mellerio JE et al. Prenatal diagnosis for severe inherited skin disorders: 25 years’ experience. Br J Dermatol 2006;154:106–13.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

2 Braude P, Pickering S, Flinter F, Ogilvie CM. Preimplantation genetic diagnosis. Nat Rev Genet 2002;3:941–55. 3 Norbury G, Norbury CJ. Non-invasive prenatal diagnosis of single gene disorders: how close are we? Sem Fetal Neonatal Med 2008;13:76–83.

Progress in molecular genetics The human genome contains approximately 30,000 genes, several of which have been implicated in the pathogenesis of inherited skin diseases. Indeed, causative gene mutations have now been identified in more than 350 different genodermatoses [1]. Identification of familyspecific pathogenic molecular abnormalities has led to considerable medical and patient-related benefits. For example, advances in understanding the molecular basis of the inherited blistering skin disorder dystrophic epidermolysis bullosa have had a major impact on the accuracy of genetic counselling. Clinically, previously it was often difficult to determine whether a child with moderately severe blistering and scarring born to unaffected parents represented sporadic autosomal dominant or, alternatively, autosomal recessive disease [2]. However, recent molecular analyses have helped to provide genotype-phenotype information based on mutation detection in the type VII collagen gene (COL7A1 on 3p21.3). Specifically, the identification of specific missense, nonsense, frameshift or splice site mutations in COL7A1 has helped clarify most diagnostic dilemmas with the emergence of a new paradigm for genotypephenotype correlation [3,4]. Delineation of the molecular pathology of dystrophic epidermolysis bullosa, and a number of other inherited skin disorders, has also set the stage for the development of newer forms of treatment, including somatic gene therapy [5,6]. Although considerable technical and practical obstacles still need to be overcome, genodermatoses

139.2

Chapter 139

characterized by nonsense or premature termination codon mutations on one or both mutant alleles might be suitable diseases for the design of gene replacement therapy, as either in vivo or ex vivo procedures [7–9]. To date, however, there has only been one successful ‘proof of principle’ human gene therapy trial in which an individual with non-Herlitz junctional epidermolysis bullosa was grafted with cultured keratinocytes that had been engineered to express the LAMB3 transgene and to secrete functional laminin-332 protein [10]. Sustained expression of the transgene was noted in 18 months follow-up and the patient was free from blisters in the treated site (but not elsewhere). Genetic therapies for autosomal dominant disorders are also being introduced. In these conditions, there is often dominant-negative interference between the wild-type and the mutant protein, and therefore antisense or RNA interference approaches designed to silence the mutant alleles may be appropriate [11,12]. A clinical trial of RNAi in one individual with pachyonychia congenita caused by a mutation in keratin 6a supports the principle of this form of therapy, although optimizing delivery methods for the RNAi molecules into skin remains a considerable challenge [13]. In spite of recent progress, however, it is clear that the science of genetic therapies is still very much in its infancy. Likewise, other treatments including cell, protein and drug therapies aimed at ameliorating or correcting inherited skin diseases, are mostly still in preclinical studies. Consequently, for couples at risk of bearing children with severe inherited skin diseases, prenatal diagnosis remains a vitally important part of current clinical management. References 1 Leech SN, Moss C. A current and online genodermatosis database. Br J Dermatol 2007;156:1115–48. 2 Uitto J, Pulkkinen L. Molecular genetics of heritable blistering disorders. Arch Dermatol 2001;137:458–61. 3 Christiano AM, Uitto J. Molecular diagnosis of inherited skin disease:the paradigm of dystrophic epidermolysis bullosa. Adv Dermatol 1996;11:199–213. 4 Mallipeddi R, Bleck O, Mellerio JE et al. Dilemmas in distinguishing between dominant and recessive forms of dystrophic epidermolysis bullosa. Br J Dermatol 2003;49:810–18. 5 Pai S, Marinkovich MP. Epidermolysis bullosa: new and emerging trends. Am J Clin Dermatol 2002;3:371–80. 6 Eady RAJ. Epidermolysis bullosa: scientific advances and therapeutic challenges. J Dermatol 2001;28:638–40. 7 Chen M, Kasahara N, Keene DR et al. Restoration of type VII collagen expression and function in dystrophic epidermolysis bullosa. Nature Genet 2002;32:670–5. 8 Ortiz-Urda S, Thyagarajan B, Keene DR et al. Stable nonviral genetic correction of inherited human skin disease. Nature Med 2002;8:1166–70. 9 Mecklenbeck S, Compton SH, Mejia JE et al. A microinjected COL7A1PAC vector restores synthesis of intact procollagen VII in a dystrophic epidermolysis bullosa keratinocyte cell line. Hum Gene Ther 2002;13:1655–62.

10 Mavilio F, Pellegrini G, Ferrari S et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med 2006;12:1397–402. 11 Wraight CJ, White PJ. Antisense oligonucleotides in cutaneous therapy. Pharmacol Ther 2001;90:89–104. 12 Yu JY, DeRuiter SL, Turner DL. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci USA 2002;99:6047–52. 13 Leachman SA, Hickerson RP, Hull PR et al. Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita. J Dermatol Sci 2008;51:151–7.

Development of DNA-based prenatal diagnostic testing The immediate major benefit of the recent advances in unravelling the molecular basis of the genodermatoses has been in the development of DNA-based prenatal diagnosis in families at risk for recurrence of particular disorders (Table 139.1). In most cases, fetal DNA can be obtained from chorionic villi (Fig. 139.1) or, less frequently, amniocytes. DNA-based prenatal testing usually involves sampling of chorionic villi at 10–12 weeks’ gestation. Chorionic villi are of fetal origin and therefore a useful source of fetal DNA, as are amniotic cells that are released from various fetal epithelia [36]. Chorionic villus

Fig. 139.1 Chorionic villi sampled at 11 weeks’ gestation. These villi have had all traces of maternal decidua carefully removed so that pure fetal DNA can subsequently be extracted without the risk of maternal DNA contamination. The cleaned villi are digested using proteinase K or urea buffers, DNA is then precipitated following which previously optimized and characterized PCT protocols can be used to test for the presence or absence of mutations in a DNA-based prenatal test.

Prenatal Diagnosis of Inherited Skin Disorders

139.3

Table 139.1 DNA-based prenatal diagnosis by mutation analysis Genodermatosis

Gene

Gene locus

References

Junctional epidermolysis bullosa (Herlitz subtype)*

Laminin-332 α3 chain (LAMA3) Laminin-332 β3 chain (LAMB3) Laminin-332 γ2 chain (LAMC2)

18q11.2 1q32.2 1q25.3

1 2 3

Junctional epidermolysis bullosa with pyloric atresia†

β4 integrin (ITGB4)

17q25.1

4

Dystrophic epidermolysis bullosa (recessive)

Type VII collagen (COL7A1)

3p21.33

5–7

Dystrophic epidermolysis bullosa (dominant)

Type VII collagen (COL7A1)

3p21.33

8

Epidermolysis bullosa simplex (Dowling–Meara)‡

Keratin 14 (KRT14)

17q21.2

9

Bullous congenital ichthyosiform erythroderma§

Keratin 10 (KRT10)

17q21.2

10

Netherton syndrome

Serine protease inhibitor (SPINK5)

5q33.1

11

Lamellar ichthyosis**

Transglutaminase 1 (TGM1)

14q11.2

12

Sjögren–Larsson syndrome

Fatty aldehyde dehydrogenase (FALDH)

17p11.2

13

Ehlers–Danlos syndrome type VI

Lysyl hydroxylase I (PLOD)

1p36.22

14

Oculocutaneous albinism (tyrosinase-negative, OCA1A)

Tyrosinase (TYR)

11q14.3

15,16

Congenital erythropoietic porphyria

Uroporphyrinogen III cosynthetase (UROS)

10q26.2

17

Ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome

TP63 (p63)

3q28

18

Smith–Lemli–Opitz syndrome

Sterol δ-7-reductase (DHCR7)

11q13.4

19

Mucopolysaccharidosis (Hunter, type II)

Iduronate-2-sulphatase (IDS)

Xq28

20

Sialidosis (type II)

Lysosomal α-N-acetyl neuraminidase (NEU1)

6p21.33

21

Infantile neuronal ceroid lipofuscinosis (INCL)

Lysosomal palmitoyl-protein thioesterase (CLN1)

1p32

22

Late-infantile neuronal ceroid lipofuscinosis (LINCL)

Lysosomal tripeptidyl peptidase (CLN2)

11p15.4

23

Thanatophoric dysplasia (types I, II)

Fibroblast growth factor receptor 3 (FGFR3)

4p16.3

24

Achondroplasia–hypochondroplasia

Fibroblast growth factor receptor 3 (FGFR3)

4p16.3

25

Conradi–Hunermann–Happle syndrome

Emopamil binding protein (EBP/CDPX2)

Xp11.23

26

Xeroderma pigmentosum group A

XP group A-complementing protein (XPA)

9q22.3

27

Oculocutaneous tyrosinaemia

Tyrosine aminotransferase (TAT)

16q22.1

28

Harlequin ichthyosis

Adenosine triphosphate-binding cassette A12 (ABCA12)

2q34

29

* Junctional epidermolysis bullosa is a heterogeneous condition. Other subtypes of this disorder may result from mutations in the gene encoding type XVII collagen (COL17A1/BPAG2) on 10q24.3 [30]. † Junctional epidermolysis bullosa with pyloric atresia may also be caused by mutations in the gene for α6 integrin (ITGA6) on 2q31.1 [31]. ‡ Some cases of epidermolysis bullosa simplex are caused by mutations in the keratin 5 gene (KRT5) on 12q13.13 [32]. § Some cases of bullous congenital ichthyosiform erythroderma arise because of mutations in the gene encoding keratin 1 (KRT1) on 12q13.13 [33]. ** Some cases of lamellar ichthyosis show linkage to different loci on 2q33–35 [34], 3p21 and 19p12–q12 [35].

biopsy can be performed either transcervically or by the transabdominal route. These procedures allow for ∼10– 50 mg of tissue to be biopsied or aspirated. The risk of fetal loss following chorionic villus sampling (CVS) (performed after 10 weeks) is ∼1–2%. It is recommended that CVS is not performed before 10 weeks: this advice stems

from initial reports that suggested CVS might increase the risk of severe limb reduction defects or vascular anomalies, although this has not been borne out in subsequent studies [36]. Apart from CVS, fetal DNA can also be extracted from fetal cells obtained by amniocentesis; this is usually per-

139.4

Chapter 139

formed at about 16 weeks’ gestation [37]. Amniotic fluid and its cells can be examined for morphological, cytogenetic, biochemical or molecular abnormalities. Amniotic fluid cells are derived from fetal epidermis, alimentary and genitourinary mucosa, and amnion. These cells have been used to assess inherited disorders with abnormal DNA synthesis and repair, as well as metabolic disorders that result in abnormal protein synthesis. However, now that the molecular basis of nearly all these conditions is known, such approaches are rarely necessary and most prenatal tests can be performed by direct analysis of genomic DNA pathology in fetal DNA following CVS or amniocentesis [38]. A number of inherited skin disorders in which specific gene mutations have been identified and used as a basis for first-trimester DNA-based prenatal diagnosis have been documented and are shown in Table 139.1, and an example of DNA analysis for one of these conditions is illustrated in Figure 139.2. To these disorders, several further conditions might be added in the near future, based on recent disclosures of pathogenic molecular events. Over the last 15 years, the most common dermatological indications for DNA-based prenatal testing have been Hallopeau–Siemens recessive dystrophic epider-

molysis bullosa (EB) and Herlitz junctional EB [38]. Inherited disorders such as lamellar ichthyosis are also suitable for DNA-based prenatal testing [12], but this form of ichthyosis shows considerable genetic heterogeneity [34,35]. Therefore it is vital that specific abnormalities should first be identified in the proband, such as mutations in the keratinocyte transglutaminase gene (TGM1 on 14q11.2), before any prenatal test is planned. Clues to inherent TGM1 gene pathology in an individual case of lamellar ichthyosis can be obtained from immunohistochemical studies for the TGM1 enzyme in the proband’s skin [39,40]. Likewise, junctional EB is a heterogeneous disorder that results from autosomal recessive mutations in six different genes encoding structural components of the hemi-desmosomal anchoring filament network [41]. Therefore, determining the correct gene responsible for a specific case is crucial to the feasibility and accuracy of DNA-based prenatal testing. To that end, the development of monoclonal antibodies to candidate gene proteins and immunostaining of skin sections from affected individuals have become an integral part of the work-up for molecular studies for several recessive disorders that stem from loss-of-function mutations leading to reduced protein expression in the skin [41,42].

Fig. 139.2 DNA-based prenatal testing. Illustrated is a DNA-based prenatal test for the autosomal dominant ectrodactyly ectodermal dysplasia-clefting (EEC) syndrome. The mother had EEC syndrome, which means that the fetus had a 50% risk of also being affected. She had already had one son with EEC syndrome. (a) Sequencing of amplified DNA from the mother and the previously affected child shows a heterozygous G > A transition in exon 7 of the p63 gene, which changes an arginine residue (CGC) to histidine (CAC). The mutation is designated p.R279H. (b) Sequencing of amplified control DNA for this exon shows only the wild-type arginine codon (CGC). (c) DNA-based prenatal testing using restriction endonuclease digestion with AciI. The mutation p.R279H results in loss of a cut site for AciI. In control DNA (lanes C1 and C2), the PCR product is completely digested into fragments of 140 and 113 bp. By contrast, there is an additional undigested band of 253 bp on DNA from the affected mother and child. The fetal PCR products are digested similarly to the control DNA, indicating that the fetus has inherited two wild-type p63 alleles with respect to this mutation and is therefore predicted to be clinically unaffected with EEC syndrome. Adapted from South et al. 2002 [18].

Prenatal Diagnosis of Inherited Skin Disorders References 1 McGrath JA, Kivirikko S, Ciatti S et al. A homozygous nonsense mutation in the alpha 3 chain gene of laminin 5 (LAMA3) in Herlitz junctional epidermolysis bullosa: prenatal exclusion in a fetus at risk. Genomics 1995;29:282–4. 2 Vailly J, Pulkkinen L, Miquel C et al. Identification of a homozygous one-base pair deletion in exon 14 of the LAMB3 gene in a patient with Herlitz junctional epidermolysis bullosa and prenatal diagnosis in a family at risk for recurrence. J Invest Dermatol 1995;104: 462–6. 3 Christiano AM, Pulkkinen L, McGrath JA et al. Mutation based prenatal diagnosis of Herlitz junctional epidermolysis bullosa. Prenat Diagn 1997;17:343–54. 4 Ashton GH, Sorelli P, Mellerio JE et al. Alpha 6 beta 4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia. Br J Dermatol 2001;144:408–14. 5 Hovnanian A, Hilal L, Blanchet-Bardon C et al. DNA-based prenatal diagnosis of generalized recessive dystrophic epidermolysis bullosa in six pregnancies at risk for recurrence. J Invest Dermatol 1995;104:456–61. 6 Christiano AM, LaForgia S, Paller AS et al. Prenatal diagnosis for recessive dystrophic epidermolysis bullosa in 10 families by mutation and haplotype analysis in the type VII collagen gene (COL7A1). Mol Med 1996;2:59–76. 7 McGrath JA, Dunnill MG, Christiano AM et al. First trimester DNAbased exclusion of recessive dystrophic epidermolysis bullosa from chorionic villus sampling. Br J Dermatol 1996;134:734–9. 8 Klinberg S, Mortimore R, Parkes J et al. Prenatal diagnosis of dominant dystrophic epidermolysis bullosa by COL7A1 molecular analysis. Prenat Diagn 2000;20:618–22. 9 Rugg EL, Baty D, Shemanko CS et al. DNA-based prenatal testing for the skin blistering disorder epidermolysis bullosa simplex. Prenat Diagn 2000;20:371–7. 10 Rothnagel JA, Longley NA, Holder RA et al. Prenatal diagnosis of epidermolytic hyperkeratosis by direct gene sequencing. J Invest Dermatol 1994;102:13–16. 11 Sprecher E, Chavanas S, DiGiovanna JJ et al. The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. J Invest Dermatol 2001;117:179–87. 12 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;17:483–6. 13 Sillen A, Holmgren G, Wadelius C. First prenatal diagnosis by mutation analysis in a family with Sjogren–Larsson syndrome. Prenat Diagn 1997;17:1147–9. 14 Yeowell HN, Walker LC, Farmer B et al. Mutational analysis of the lysyl hydroxylase I gene (PLOD) in six unrelated patients with Ehlers–Danlos syndrome type VI: prenatal exclusion of this disorder in one family. Hum Mutat 2000;16:90. 15 Shimizu H, Niizeki H, Suzumori K et al. Prenatal diagnosis of oculocutaneous albinism by analysis of the fetal tyrosinase gene. J Invest Dermatol 1994;103:104–6. 16 Falik-Borenstein TC, Holmes SA, Borochowitz Z et al. DNA-based carrier detection and prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA1A). Prenat Diagn 1995;15:345–9. 17 Daika-Dahmane F, Dommergues M, Narcy F et al. Congenital erythropoietic porphyria: prenatal diagnosis and autopsy findings in two sibling fetuses. Pediatr Dev Pathol 2001;4:180–4. 18 South AP, Ashton GH, Willoughby C et al. EEC syndrome: heterozygous mutation in the p63 gene and DNA-based prenatal diagnosis. Br J Dermatol 2002;146:216–20. 19 Nowaczyk MJ, Garcia DM, Eng B et al. Rapid molecular prenatal diagnosis of Smith–Lemli–Opitz syndrome. Am J Med Genet 2001;102:387–8.

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20 Bunge S, Steglich C, Lorenz P et al. Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis. A 47,XXY male heterozygous for a missense point mutation. Prenat Diagn 1994;14:777–80. 21 Sergi C, Penzel R, Uhl J et al. Prenatal diagnosis and fetal pathology in a Turkish family harbouring a novel nonsense mutation in the lysosomal alpha-N-acetyl-neuraminidase (sialidase) gene. Hum Genet 2001;109:421–8. 22 De Vries BB, Kleijer WJ, Keulemans JL et al. First trimester diagnosis of infantile neuronal ceroid lipofuscionosis (INCL) using PPT enzyme assay and CLN1 mutation analysis. Prenat Diagn 1999;19:559–62. 23 Kleijer WJ, van Diggelen OP, Keulemans JL et al. First trimester diagnosis of late-infantile neuronal ceroid lipofuscionosis (LINCL) by tripeptidyl peptidase I assay and CLN2 mutation analysis. Prenat Diagn 2001;21:99–101. 24 Chen CP, Chern SR, Shih JC et al. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn 2001;21:89–95. 25 Chitayat D, Fernandez B, Gardner A et al. Compound heterozygosity for the achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome. Am J Hum Genet 1999;84:401–5. 26 Milunsky JM, Maher TA, Metzenberg AB. Molecular, biochemical and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi–Hunermann–Happle syndrome and a mutation in EBP. Am J Hum Genet 2003;116:249–54. 27 Yang Y, Ding B, Wang K et al. DNA-based prenatal diagnosis in a Chinese family with xeroderma pigmentosum group A. Br J Dermatol 2004;150:1190–3. 28 Maydan G, Andresen BS, Madsen PP et al. TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II: characterization of a silent exonic transversion that causes missplicing by exon 11 skipping. J Inherit Metab Dis 2006;29:620–6. 29 Akiyama M, Titeux M, Sakai K et al. DNA-based prenatal diagnosis of harlequin ichthyosis and characterization of ABCA12 mutation consequences. J Invest Dermatol 2007;127:568–73. 30 McGrath JA, Gatalica B, Christiano AM et al. Mutations in the 180-kD bullous pemphigoid antigen (BPAG2/COL17A1), a hemidesmosome transmembrane collagen, in generalized atrophic benign epidermolysis bullosa. Nature Genet 1995;11:83–6. 31 Pulkkinen L, Kimonis VE, Xu Y et al. Homozygous α6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. Hum Mol Genet 1997;6:669–74. 32 Lane EB, Rugg EL, Navsaria H et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 1992;356:244–6. 33 Rothnagel JA, Dominey AM, Dempsey LD et al. Mutations in the rod domain of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 1992;257:1128–30. 34 Parmentier L, Clepet C, Boughdene-Stambouli O et al. Lamellar ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus. Eur J Hum Genet 1999;7:77–87. 35 Fischer J, Faure A, Bouadjar B et al. Two new loci for autosomal recessive ichthyosis on chromosomes 3p21 and 19p12-q12 and evidence for further genetic heterogeneity. Am J Hum Genet 2000;66:904–13. 36 Brambati B, Tului L. Chorionic villus sampling and amniocentesis. Curr Opin Obstet Gynecol 2005;17:197–201. 37 Evans MI, Andriole S. Chorionic villus sampling and amniocentesis in 2008. Curr Opin Obstet Gynecol 2008;20:164–8. 38 Fassihi H, Eady RA, Mellerio JE et al. Prenatal diagnosis for severe inherited skin disorders: 25 years’ experience. Br J Dermatol 2006;154:106–13. 39 Hohl D, Huber M, Frenk E. Analyses of the cornified cell envelope in lamellar ichthyosis. Arch Dermatol 1993;129:618–24.

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40 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;290:621–7. 41 Fine JD, Eady RAJ, 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;58:931–50. 42 McGrath JA, Eady RAJ. The role of immunohistochemistry in the diagnosis of the non-lethal forms of junctional epidermolysis bullosa. J Dermatol Sci 1997;14:68–75.

Practical aspects of DNA-based prenatal diagnosis The clinical application of DNA-based prenatal testing has had substantial benefits for families at risk for recurrence of further affected children with inherited skin disorders in subsequent pregnancies. Nevertheless, an important prerequisite to undertaking any DNA-based prenatal test procedure is the delineation of informative genetic markers. In most instances, it is important to have DNA samples from both parents and the affected individual to determine the pathogenic mutation(s) [1,2]. Availability of all these samples then permits screening for de novo mutations, non-paternity, uniparental disomy and germline mosaicism, any of which can have an impact on the suitability and feasibility of prenatal diagnosis. Uniparental disomy refers to the inheritance of both copies of a chromosome pair from just one parent (paternal or maternal). In effect, uniparental isodisomy allows two copies of a recessive mutation to be transmitted from a heterozygous carrier parent. This phenomenon has been reported for both junctional and recessive dystrophic EB, as well as several other recessive diseases, emphasizing the importance of screening DNA from both parents to check carrier status [3,4]. It should also be stressed that delineation of informative gene mutations or genetic markers should be determined in advance of all requests for prenatal testing. It is not appropriate to undertake a DNA-based test without prior knowledge of the genetic information that is pertinent to a particular case or family. For most inherited skin disorders, it is important to base the test on mutational analysis but, for some disorders, such as dystrophic epidermolysis bullosa, indirect linkage analysis using intragenic and flanking type VII collagen gene markers may be appropriate [2,5]. This is because all cases of dystrophic epidermolysis bullosa only result from mutations in the COL7A1 gene on 3p21.2. It is also important to emphasize that in most instances molecular markers are family specific and are best determined before pregnancy is contemplated as it may take several weeks or months to complete the DNA screening analysis. Several condition-specific guidelines for prena-

tal testing in inherited skin disorders have been published [1,2], and form a useful basis for planning prenatal testing in other genodermatoses. Practically, when undertaking CVS, it is important that the villi are cleaned under a dissecting microscope to exclude maternal cells (decidua, blood) that could contaminate polymerase chain reaction (PCR) or biochemical analyses. It is also important that villi are collected in an appropriate medium, for example transport medium such as RPMI (Roswell Park Memorial Institute medium). This is relevant since the presence of heparin (beyond the initial cleaning phase) may inhibit the activity of the Taq polymerase enzyme that is fundamental to PCR amplification. Once in the laboratory, extraction of fetal DNA and molecular screening for the predetermined informative genetics markers/mutations can be completed within 72 hours. Chorionic villi can also be cultured for diagnostic confirmation of the findings obtained from direct analysis of the villi. It usually takes ∼2 weeks to culture chorionic villi for the confirmatory tests: this may improve diagnostic accuracy but there is an inevitable delay that adds to the gestational age at final diagnosis. References 1 Christiano AM, Pulkkinen L, McGrath JA et al. Mutation based prenatal diagnosis of Herlitz junctional epidermolysis bullosa. Prenat Diagn 1997;17:343–54. 2 Christiano AM, LaForgia S, Paller AS et al. Prenatal diagnosis for recessive dystrophic epidermolysis bullosa in 10 families by mutation and haplotype analysis in the type VII collagen gene (COL7A1). Mol Med 1996;2:59–76. 3 Fassihi H, Wessagowit V, Ashton GH et al. Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa. Clin Exp Dermatol 2005;30:71–4. 4 Fassihi H, Lu L, Wessagowit V et al. Complete maternal isodisomy of chromosome 3 in a child with recessive dystrophic epidermolysis bullosa but no other phenotypic abnormalities. J Invest Dermatol 2006;126:2039–43. 5 McGrath JA, Dunnill MG, Christiano AM et al. First trimester DNAbased exclusion of recessive dystrophic epidermolysis bullosa from chorionic villus sampling. Br J Dermatol 1996;134:734–9.

Fetal skin biopsy Before the era of molecular diagnostics, prenatal testing for inherited skin disorders was limited to a small number of conditions for which a diagnosis could be established through analysis of a sample of fetal skin. During the early 1980s, sampling of fetal tissue mostly relied on direct visualization of the fetus using fetoscopy [1]. However, use of the fetoscope declined with improvements in real-time ultrasonography [2]. When performed nowadays, fetal skin biopsy typically involves ultrasoundguided insertion of a 2-gauge biopsy forceps introduced through a 16–18-gauge needle. Samples are usually taken

Prenatal Diagnosis of Inherited Skin Disorders

139.7

(a) (a)

(b) Fig. 139.3 Prenatal diagnosis by fetal skin biopsy. (a) Light microscopy of normal fetal skin biopsied at 20 weeks’ gestation. The dermoepidermal junction is intact (Richardson’s stain; magnification ×160). (b) Light microscopy of a skin biopsy from a fetus affected with junctional epidermolysis bullosa. There is widespread detachment of the epidermis from the underlying dermis. The extensive separation results from the trauma of the skin forceps sampling procedure. Richardson’s stain, magnification ×140.

at 16–20 weeks’ gestation, especially in the assessment of inherited disorders of the dermal–epidermal junction, including the different subtypes of EB. However, in assessing certain ichthyoses and other disorders of keratinization, fetal skin biopsy may have to be delayed until 20–22 weeks. Biopsy sites depend on the position of the fetus and the placenta. Ideally, skin from the back or buttocks should be sampled. Wounds tend to heal by pursestring closure with minimal scarring [3]. For all tests, it is important that fetal skin samples are collected and transported to the laboratory in appropriate media and then rapidly processed for microscopic analysis. Most often, this involves light microscopy and transmission electron microscopy [4], as illustrated in Figures 139.3 and 139.4. However, immunohistochemistry (indirect immunofluorescence microscopy) is a valuable additional method of

(b) Fig. 139.4 Prenatal diagnosis by fetal skin biopsy. (a) Transmission electron microscopy of normal fetal skin at 16 weeks’ gestation. The structure of the hemi-desmosome anchoring filament adhesion complexes resembles postnatal skin and there are numerous anchoring fibrils and elastic microfibrils beneath the lamina densa (bar = 100 nm). (b) Transmission electron microscopy of a skin biopsy from a fetus with recessive dystrophic epidermolysis bullosa. There is detachment of the basal keratinocytes from the underlying dermis (blister cavity shown by asterisk). The level of separation occurs beneath the lamina densa (arrow), a characteristic finding in dystrophic forms of epidermolysis bullosa (bar = 100 nm).

analysis, especially in the prenatal diagnosis of recessive dystrophic or junctional epidermolysis bullosa [5,6]. An example of this antibody staining is shown in Figure 139.5. Moreover, the availability of a range of monoclonal and polyclonal antibodies to different components of the normal epidermal basement membrane zone, such as plectin, α6β4 integrin and type XVII collagen (also known as the 180 kDa bullous pemphigoid antigen) has proved essential in carrying out prenatal testing for other forms of epidermolysis bullosa and related disorders [7]. A schematic of the structure and protein composition of the dermoepidermal junction relevant to the pathology and prenatal diagnostic testing of epidermolysis bullosa is

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Fig. 139.5 Prenatal diagnosis by fetal skin biopsy. (a) Immunofluorescence microscopy of normal fetal skin sampled at 16 weeks’ gestation. The skin is labelled with an antibody to laminin-332. Immunostaining is present in a continuous linear pattern at the dermoepidermal junction (arrows) (magnification ×130). (b) Immunofluorescence microscopy of normal fetal skin labelled with an antibody to type IV collagen. Immunolabelling is present on basement membranes at the dermoepidermal junction and surrounding dermal blood vessels and nerves (magnification ×130). (c) Immunofluorescence microscopy of skin from a fetus affected with Herlitz junctional epidermolysis bullosa, labelled with an antibody to laminin-332. In contrast to the positive staining in normal skin shown in (a), there is a complete absence of laminin-332 staining at the dermoepidermal junction (arrows). In addition, blister formation with detachment of the epidermis from the dermis is present (asterisk) (magnification ×300). (d) Immunofluorescence microscopy of skin from a fetus affected with Herlitz junctional epidermolysis bullosa, labelled with an antibody to type IV collagen. The immunostaining pattern and intensity are similar to the control labelling shown in (b), but there is blister formation (asterisk) and all the positive immunolabelling is present in the blister base, consistent with a plane of cleavage above the lamina densa (magnification ×280). (e) Immunofluorescence microscopy of skin from a fetus affected with Herlitz junctional epidermolysis bullosa, labelled with an antibody to type VII collagen. There is linear labelling at the dermoepidermal junction, which is present at the base of the skin blister (asterisk). Although labelling intensity with this antibody probe is normal in Herlitz junctional epidermolysis bullosa, immunostaining would be expected to be reduced or absent in skin from a fetus affected with recessive dystrophic epidermolysis bullosa (magnification ×280).

shown in Figure 139.6. From a practical perspective, most fetal skin biopsies can be processed and analysed within 3 days of the sample being taken. Fetal skin biopsy was first performed for the diagnosis of congenital bullous ichthyosiform erythroderma and Herlitz junctional EB [8,9]. Over the next 12 years, severe recessive forms of epidermolysis bullosa remained the most common indications for fetal skin biopsy analysis [10]. Other disorders that were assessed included nonbullous ichthyosiform erythroderma (or lamellar ichthyosis) [11], harlequin ichthyosis [12], tyrosinase-negative oculocutaneous albinism [13], epidermolysis bullosa simplex [14], X-linked hypohidrotic ectodermal dysplasia [15], Sjögren–Larsson syndrome [16], restrictive dermopathy [17] and Chediak–Higashi syndrome [18]. For all fetal skin biopsy tests, sampling error, inadequacy of samples for analysis and difficulty in interpreting the morphological and immunohistochemical features can

pose technical or diagnostic problems. Moreover, artifact caused by the biopsy procedure, and by processing the very small fetal skin samples, can be severe or mimic true pathology. Nevertheless, fetal skin biopsy has an excellent track record, with a high degree of sensitivity and specificity of the analytical techniques used. The rate of fetal loss is probably no more than 1% over the background incidence of spontaneous abortions. Since the mid-1990s, however, the number of fetal skin biopsies performed has fallen by more than 95%, largely due to the introduction of alternative DNA-based molecular screening methods [7]. The current indications for fetal skin biopsies, therefore, are where: • the causative gene is unknown but prenatal diagnosis has been shown to be possible in similar cases using fetal skin biopsies • the causative gene is known but informative DNA markers are unavailable, perhaps because an affected

Prenatal Diagnosis of Inherited Skin Disorders

Fig. 139.6 Structures and proteins that provide adhesion between the epidermis and the dermis and which are abnormally expressed in the different forms of epidermolysis bullosa. (a) This schematic diagram illustrates the key structural components of the hemi-desmosome anchoring filament–anchoring fibril complex at the dermoepidermal junction. (b) These adhesion complexes are composed of several proteins and glycoproteins that harbour mutations in the corresponding genes in the different subtypes of epidermolysis bullosa. The development of specific antibody probes to several of these components has been helpful in developing immunohistochemical approaches to support transmission electron microscopy techniques for fetal skin biopsy assessment in the prenatal diagnosis of this group of disorders.

offspring had died before appropriate DNA samples could be obtained, or because of a late request for prenatal testing • previously attempted DNA-based prenatal diagnosis has been equivocal or technically unsatisfactory. References 1 Elias S. Use of fetoscopy for prenatal diagnosis of hereditary skin disorders. Curr Probl Dermatol 1987;16:1–13.

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2 Rodeck CH. Fetoscopy guided by real time ultrasound for pure fetal blood samples, fetal skin samples and examination of the fetus in utero. Br J Obstet Gynaecol 1980;87:449–56. 3 Adzick NS, Longaker MJ. Scarless fetal wound healing. Therapeutic implications. Ann Surg 1992;215:3–7. 4 Eady RAJ, Gunner DB, Tidman MJ et al. Rapid processing of fetal skin for prenatal diagnosis by light and electron microscopy. J Clin Pathol 1984;37:633–8. 5 Heagerty AHM, Kennedy AR, Gunner DB et al. Rapid prenatal diagnosis and exclusion of epidermolysis bullosa using novel antibody probes. J Invest Dermatol 1986;86:603–5. 6 Heagerty AHM, Eady RAJ, Kennedy AR et al. Rapid prenatal diagnosis of epidermolysis bullosa letalis using GB3 monoclonal antibody. Br J Dermatol 1987;117:271–5. 7 Fassihi H, Eady RA, Mellerio JE et al. Prenatal diagnosis for severe inherited skin disorders:25 years’ experience. Br J Dermatol 206;154:106–13. 8 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;302:93–5. 9 Rodeck CH, Eady RA, Gosden CM. Prenatal diagnosis of epidermolysis bullosa letalis. Lancet 1980;i:949–52. 10 Eady RAJ, Holbrook KA, Blanchet-Bardon C et al. Prenatal diagnosis of skin diseases. In: Burgdorf WHC, Katz SI (eds) Dermatology: Progress and Perspectives. Proceedings of the 18th World Congress of Dermatology. New York: Pantheon Publishing Group, 1993: 1159–65. 11 Perry TB, Holbrook KA, Hoff MS. Prenatal diagnosis of congenital nonbullous ichthyosiform erythroderma (lamellar ichthyosis). Prenat Diagn 1987;7:145–55. 12 Blanchet-Bardon C, Dumez Y. Prenatal diagnosis of harlequin fetus. Semin Dermatol 1984;3:225–8. 13 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;302:93–5. 14 Eady RAJ, Gunner DB, Garner A et al. Prenatal diagnosis of oculocutaneous albinism by electron microscopy of fetal skin. J Invest Dermatol 1983;80:210–12. 15 Holbrook KA, Wapner R, Jackson L et al. Diagnosis and prenatal diagnosis of epidermolysis bullosa herpetiformis (Dowling–Meara) in a mother, two affected children, and an affected fetus. Prenat Diagn 1992;12:725–39. 16 Arnold M-L, Rauskolb R, Anton-Lamprecht I et al. Prenatal diagnosis of anhidrotic ectodermal dysplasia. Prenat Diagn 1984;4:85–98. 17 Kousseff BG, Matsuoka LY, Stenn KS et al. Prenatal diagnosis of Sjogren–Larsson syndrome. J Pediatr 1982;101:998–1001. 18 Happle R, Schuurmana Stekhoven JH, Hamel BC et al. Restrictive dermopathy in two brothers. Arch Dermatol 1992;128:232–5.

Preimplantation genetic diagnosis Knowledge of precise molecular defects in particular inherited skin disorders also enables prenatal testing to be performed at a much earlier stage using preimplantation genetic diagnosis (PGD) (Fig. 139.7) [1,2]. PGD refers to the removal of a single cell from an embryo generated in vitro for genetic testing to diagnose a recurrent, serious, heritable condition and thereby to avoid the implantation of affected embryos. This approach involves in vitro fertilization and sampling of a single cell, usually at the eight-cell stage of embryonic development [1,3]. The

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(c) Fig. 139.7 Preimplantation genetic diagnosis. (a) A harvested egg is injected with a single sperm cell (intracytoplasmic sperm injection, ICSI) while being positioned by holding forceps (left). The polar body of the egg is present on its upper aspect in this image. The ICSI approach improves accuracy in subsequent single cell diagnostic tests by avoiding DNA contamination from multiple sperm cells. (b) The fertilized ovum has a diploid nucleus. (c) At the 12–16-cell stage of embryonic development, a hole is drilled in the zona pellucida using an acid solution and then a single cell is removed using the suction pipette (right). This cell can then be tested for chromosomal aberrations or used for sex typing for X-linked disorders or as a template for nested PCRs and DNA-based diagnostic procedures. Results are usually available within 12 h and unaffected embryos (a maximum of two) can then be selected and implanted into the uterus.

methodology was developed in the UK in the late 1980s and was first used to avoid transmission of adrenoleucodystrophy and X-linked mental retardation [4]. Selection of female embryos to avoid X-linked disease was initially carried out by PCR and then subsequently by fluorescence in situ hybridization (FISH), which can also be applied to testing for chromosomal rearrangements and translocations [5]. Only embryos found to be free of a specific genetic defect are then implanted in the uterus. Significantly, unlike CVS at 10–11 weeks’ gestation, the preimplantation approach obviates the need for possible termination of pregnancy of an affected fetus and may be more acceptable to couples at risk for further affected children.

Successful clinical application of PGD for an inherited skin disorder has also been described. In that case, PGD testing was performed in embryos at risk of the autosomal recessive disorder ectodermal dysplasia-skin fragility syndrome (OMIM 604536). Testing involved direct sequencing of family-specific mutations in the PKP1 gene encoding the desmosomal protein plakophilin 1 [6]. Testing protocols have also been developed for PGD testing for other inherited skin diseases. For dystrophic epidermolysis bullosa, for example, a generic test based on amplification of microsatellite markers centromeric and telomeric to the COL7A1 gene is available for clinical use [7]. Tests that can screen for junctional EB resulting from mutations in the LAMA3 or LAMB3 genes (which

Prenatal Diagnosis of Inherited Skin Disorders

encode the α3 and β3 polypeptide chains of laminin-332, respectively) are also in clinical practice. The UK-licensed tests for junctional EB are based on recent technological advances in which template DNA (typically ∼6 ng from a single cell) can undergo initial whole-genome amplification through multiple displacement amplification to create a much larger amount of DNA (∼6 µg) for genetic testing. This means that more linkage markers (microsatellites or single nucleotide polymorphisms) of mutant or wild-type alleles can be examined, thus improving both diagnostic scope and accuracy. This particular approach is known as preimplantation genetic haplotying (PGH) [8]. The main advantage of PGH is that it does not require precise details of the mutation to be known: only the gene which is implicated and the mode of inheritance are required. This makes the development of a specific test for a disease faster and the diagnosis from a single cell biopsy more secure. The clinical success of PGD/PGH is related to the number of embryos available for biopsy, which in turn is related to the number of good-quality eggs obtained after gonadotropin stimulation. If suitable embryos are available, clinical pregnancy rates are usually ∼25% in most centres [9]. References 1 Braude P, Pickering S, Flinter F, Ogilvie CM. Preimplantation genetic diagnosis. Nat Rev Genet 2002;3:941–55. 2 McGrath JA, Handyside AH. Preimplantation genetic diagnosis of severe inherited skin diseases. Exp Dermatol 1998;7:65–72. 3 Handyside AH. Preimplantation genetic diagnosis today. Hum Reprod 1996;11 (suppl 1):139–51. 4 Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990;344:768–70. 5 Ogilvie CM, Braude PR, Scriven PN. Preimplantation genetic diagnosis – an overview. J Histochem Cytochem 2005;53:255–60. 6 Fassihi H, Grace J, Lashwood A et al. Preimplantation genetic diagnosis of skin fragility-ectodermal dysplasia syndrome. Br J Dermatol 2006;154:546–50. 7 Fassihi H, Renwick PJ, Black C, McGrath JA. Single cell PCR amplification of microsatellites flanking the COL7A1 gene and suitability for preimplantation genetic diagnosis of Hallopeau–Siemens recessive dystrophic epidermolysis bullosa. J Dermatol Sci 2006;42:241–8. 8 Renwick PJ, Trussler J, Ostad-Saffari E et al. Proof of principle and first cases using preimplantation genetic haplotyping – a paradigm shift for embryo diagnosis. Reprod Biomed Online 2006:13:110–19. 9 Grace J, El-Toukhy T, Scriven P et al. Three hundred and thirty cycles of preimplantation genetic diagnosis for serious genetic disease: clinical considerations affecting outcome. Br J Obstet Gynaecol 2006;113:1393–401.

Non-invasive prenatal diagnosis All current methods for prenatal testing of fetal DNA or skin involve invasive procedures and therefore attempts are also being made to develop less invasive screening strategies, for example through analysis of fetal DNA in

139.11

the maternal circulation [1]. Fetal DNA is present in the mother ’s blood in nucleated cells (e.g. erythrocytes, lymphocytes and trophoblasts) although there is only about one fetal cell per mL of maternal blood. This makes nucleated fetal cell capture difficult and sensitivity rates for fetal cell detection in maternal blood are only ∼40% and false-positive detection rates are often more than 10%. In addition, nucleated fetal cells may also persist in the maternal circulation for months or years, and thus their detection may be of dubious value for prenatal testing [2]. In 1997, however, it was established that cell-free circulating fetal DNA was also present in the maternal circulation from as early as 4 weeks’ gestation [3]. Unlike nucleated fetal cells, there is no long-term persistence of free fetal DNA in the maternal circulation [4]. The main source of free fetal DNA in the maternal plasma is the placenta, from syncytiotrophoblasts in the form of apoptotic fragments packaged into microvesicles [5]. Once free fetal DNA is isolated, chromosomes, genes or genetic polymorphisms and mutations, inherited from the father, can be targeted. It is important to remember, however, that fetal cell or cell-free DNA cannot be used to screen for maternal alleles because of masking of the maternal allele by maternal DNA. Nevertheless, prenatal diagnosis, based on screening for paternally derived mutations, has been reported for some types of muscular dystrophy and β-thalassaemia [6]. Moreover, the use of free fetal DNA is now the basis of a widely used clinical assay to test for Rhesus blood group antigen D (i.e. from a RhD-positive fetus in the plasma of a RhD-negative mother) [7], as well as fetal sex determination in women at high risk for X-linked conditions or congenital adrenal hyperplasia. Current testing by this method is usually carried out at about 7 weeks’ gestation and false-positive rates (for fetal sexing) are ∼2%. As yet, however, there are no maternal blood testing methods currently in use for prenatal testing of severe inherited skin disorders. Analysis of cell-free fetal DNA in maternal plasma provides a potential opportunity to develop reliable, timely, safe and cost-effective prenatal diagnosis for single-gene disorders. To date, non-invasive first-trimester analysis for these conditions has been limited by assay sensitivity and specificity, mostly due to the background maternal DNA. However, the identification of fetal RNA in the maternal circulation and the detection of fetal epigenetic markers have greatly increased the number of molecular markers that could be developed for prenatal diagnosis and monitoring [8–11]. When testing very early in gestation, however, it is important to perform careful ultrasound examination to determine the number of gestational sacs because of the risk of discordant pregnancies. Nevertheless, overall, it is likely that in the future these molecular biological and technical advances will be translated into clinical prenatal

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tests for couples at reproductive risk of severe inherited skin disorders, thus increasing screening choice. References 1 Norbury G, Norbury CJ. Non-invasive prenatal diagnosis of single gene disorders: how close are we? Sem Fetal Neonatal Med 2008;13:76–83. 2 Bianchi DW, Simpson JL, Jackson LG et al. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat Diagn 2002;22:609–15. 3 Lo YM, Corbetta N, Chamberlain PF et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350:485–7. 4 Lo YM, Zhang J, Leung TN et al. Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet 1999;64:218–24. 5 Alberry M, Maddocks D, Jones M et al. Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast. Prenat Diagn 2007;27:415–18. 6 Li Y, di Naro E, Vitucci A et al. Detection of paternally inherited fetal point mutations for beta-thalassemia using size-fractionated cell-free DNA in maternal plasma. JAMA 2005;293:843–9. 7 Finning KM, Martin PG, Soothill PW, Avent ND. Prediction of fetal D status from maternal plasma: introduction of a new noninvasive fetal RHD genotyping service. Transfusion 2002;42:1079–85. 8 Poon LL, Leung TN, Lau TK, Lo YM. Presence of fetal RNA in maternal plasma. Clin Chem 2000;46:1832–4. 9 Lo YM, Chiu RW. Prenatal diagnosis: progress through plasma nucleic acids. Nat Rev Genet 2007;8:71–7. 10 Avent ND, Plummer ZE, Madgett TE, Maddocks DG, Soothill PW. Post-genomics studies and their application to non-invasive prenatal diagnosis. Sem Fetal Neonatal Med 2008;13:91–8. 11 Hahn S, Zhong XY, Holzgreve W. Recent progress in non-invasive prenatal diagnosis. Semin Fetal Neonatal Med 2008;13:57–62.

Ethical issues in prenatal testing The development of DNA-based prenatal testing for genodermatoses raises several important ethical issues. For example, until recently in epidermolysis bullosa only the severe forms of the disease could be tested for prenatally using fetal skin biopsy with analysis of the skin samples by immunohistochemistry and electron microscopy [1]. Now, not only is it possible to test for the Herlitz subtype of junctional epidermolysis bullosa and the severe, generalized form of recessive dystrophic epidermolysis bullosa using DNA analysis [2], but several of the milder subtypes, such as autosomal dominant or localized recessive dystrophic epidermolysis bullosa, non-Herlitz junctional epidermolysis bullosa or even epidermolysis bullosa simplex, can now also be assessed by gene analysis. Clearly, given the rapid accumulation of new genetic information, the clinical indications for undertaking prenatal diagnosis need to be carefully con-

sidered and precisely defined. Many healthcare personnel may feel that aborting a fetus that has tested positive for one of the ‘milder ’ disorders is unjustified [3]. However, society might say that any couple at risk has the right to know what options are available and possibly the right to have prenatal diagnosis with the intention of terminating an affected pregnancy. Such decisions are complex and often very personal although social, geographic and ethnic influences may all contribute. Notably, although informed choice is highly valued in western, individualistically orientated countries, it is less highly valued in non-western, more collectivist countries [4]. Thus moral, ethical and legal considerations may vary and may also change with further advances in biomedical technology and reproductive medicine. As well as the option to develop PGD/PGH tests for the monogenic inherited skin disorders listed in Table 139.1, it is now feasible to consider applying this technology to other clinical situations, for example to individuals who might be at risk for a disorder in later life, such as a familial malignancy. With regard to skin tumours, familial melanoma has not yet become a licensed indication for preimplantation testing but if a specific single susceptibility gene abnormality is identified in some individuals then it may well become a feasible and licensed screening test [5–7]. Likewise, psoriasis or atopic dermatitis families with clear single-gene influences on disease expression might also be candidates for these genetic susceptibility screening approaches in the future. References 1 Eady RAJ, Holbrook KA, Blanchet-Bardon C et al. Prenatal diagnosis of skin diseases. In: Burgdorf WHC, Katz SI (eds) Dermatology: Progress and Perspectives. Proceedings of the 18th World Congress of Dermatology. New York: Pantheon Publishing Group, 1993:1159–65. 2 Fassihi H, Eady RA, Mellerio JE et al. Prenatal diagnosis for severe inherited skin disorders: 25 years’ experience. Br J Dermatol 2006;154:106–13. 3 Gare M, Gosme-Seguret S, Kaminski M, Cuttini M. Ethical decisionmaking in prenatal diagnosis and termination of pregnancy: a qualitative survey among physicians and midwives. Prenat Diagn 2002;22:811–17. 4 Van den Heuvel A, Marteau TM. Cultural variation in values attached to informed choice in the context of prenatal diagnosis. Semin Fetal Neonatal Med 2008;13:99–102. 5 Retchitsky S, Verlinsky O, Chistokhina A et al. Preimplantation genetic diagnosis for cancer predisposition. Reprod Biomed Online 2002;5:148–55. 6 Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006;355:541–3. 7 Newson AJ. Ethical aspects arising from non-invasive fetal diagnosis. Semin Fetal Neonatal Med 2008;13:103–8.

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C H A P T E R 140

Skin Gene and Cell Therapy Matthias Titeux & Alain Hovnanian Department of Dermatology and Genetics, Inserm U781, Necker Hospital for Sick Children, University Paris V – Rene Descartés, Paris, France

Introduction, 140.1

Skin gene therapy applications, 140.9

Conclusion, 140.22

Delivery methods, 140.2

Introduction Because of its accessibility, the skin represents a good target for gene and cell therapy for both cutaneous and systemic diseases. However, owing to its barrier function, the obstacles to effective gene insertion into skin cells are not trivial. Preclinical studies have paved the way for the first successful clinical trials in a patient suffering from non-Herlitz junctional epidermolysis bullosa. Almost all types of currently available vectors have been used to transduce either keratinocytes or dermal fibroblasts. Applications have progressed from the correction of genetic skin disorders to treatment of systemic diseases or cancer or wound-healing enhancement. Recent studies have enlarged the field to cell-based, small antisensebased or protein-based therapies; a recent clinical trial using antisense technology in a patient with pachyonychia congenita showed clinical benefit. We will review the different approaches that have been used and the large panel of potential applications of gene transfer into skin.

Target tissue The skin comprises two major compartments: an uppermost part of ectodermal origin, the epidermis, and an underlying dermis of mesodermal origin. The epidermis is a stratified squamous epithelium composed of a multilayered array of keratinocytes organized in four layers, distinguishable by their proliferative and differentiation properties: the basal, spinous, granulous and cornified layers. The basal layer is made of proliferative keratinocytes adherent to the underlying basement membrane, whereas the suprabasal layers are dedicated to the terminal differentiation of keratinocytes and skin barrier for-

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

mation. Basal keratinocytes firmly adhere to basement membrane components by means of complex protein structures called hemi-desmosomes, they express K5/ K14 keratin pairs and constitute the germinative compartment [1]. The dermis is a supporting collagen lattice composed of embedded fibroblasts, blood vessels and epidermal appendages, such as sweat glands and hair follicles. The skin and the mucous membrane constitute the first mechanical barriers that foreign agents encounter before entering the organism. A major skin function is to respond to dangerous external agents while regulating the intensity of the response in order to maintain homeostasis. The skin has an important immune-associated function and contains numerous resident epidermal and dermal dendritic cells (Langerhans cells and dermal dendrocytes respectively). These dendritic cell populations are the most powerful antigen-presenting cell (APCs) identified so far, ensuring a strong immunological response [2].

Target cells The two major cell types in the skin, keratinocytes and fibroblasts, have been subjected to gene therapy. The choice of the target cell depends, essentially, on the goal of the gene therapy project. As the epidermis is a continuously self-renewing tissue, long-term expression of a transgene can be obtained only through the targeting of epidermal stem cells. Basal keratinocytes include stem cells which are recruited during development, epidermal turnover and wounds (burns, cuts, abrasions), which ensure continual renewal of the tissue. Perhaps one of the most spectacular illustrations of the existence of stem cells in the epidermis has relied on permanent coverage of severely burned patients by autologous grafts of epidermal sheets amplified in culture ex vivo from biopsies of a few square centimetres [3–5]. These successes have ensued from pioneering studies by Rheinwald & Green [6,7], who determined the essentials

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of keratinocyte culture conditions. Subsequently, Barrandon & Green showed that human epidermis shelters keratinocyte colony-forming cells with virtually infinite lifespan, the ‘holoclones’, which are thought to correspond to epidermal stem cells [8]. It has been shown that as long as holoclone-founding cells are transduced, transgene expression may be sustained over 150 cell generations, as demonstrated by clonal analysis [9]. References 1 Borradori L, Sonnenberg A. Structure and function of hemidesmosomes: more than simple adhesion complexes. J Invest Dermatol 1999;112(4):411–18. 2 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392(6673):245–52. 3 Gallico GG 3rd, O’Connor NE, Compton CC, Kehinde O, Green H. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984;311(7):448–51. 4 Llames SG, del Rio M, Larcher F et al. Human plasma as a dermal scaffold for the generation of a completely autologous bioengineered skin. Transplantation 2004;77(3):350–5. 5 Ronfard V, Rives JM, Neveux Y, Carsin H, Barrandon Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation 2000;70(11):1588–98. 6 Rheinwald JG, Green H. Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma. Cell 1975;6(3):317–30. 7 Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 1975;6(3):331–43. 8 Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA 1987;84(8):2302–6. 9 Mathor MB, Ferrari G, Dellambra E et al. Clonal analysis of stably transduced human epidermal stem cells in culture. Proc Natl Acad Sci USA 1996;93(19):10371–6.

Delivery methods A wide range of delivery methods are available for skin gene therapy. The choice of method depends essentially on the application of the gene therapy under consideration, and the nature of the disease and the targeted gene. For some applications, such as vaccination or cancer treatment, transient expression is required and integration of the therapeutic gene must be avoided. In contrast, the treatment of genodermatoses requires long-term expression of the transgene, which is achieved mainly through the integration of the therapeutic gene into the genome of the target somatic stem cells. Alternatively, a life-long treatment which must be repeated periodically could also be considered. There are essentially two different ways to transfer a gene into a cell or a tissue: by the use of virus or by physical methods. Both have advantages and disadvantages.

The modified viruses used as vectors are difficult and expensive to produce but they have already proven their efficacy, whereas the physical methods are cheaper but generally suffer from low gene transfer efficiency (Fig. 140.1).

Virus-mediated transfer Several viruses have been used as templates to design gene therapy vectors. Their common feature is their natural ability to infect eukaryotic cells and to carry their nucleic acids directly to the nucleus. They are used to transfer cDNAs, genes or small antisense sequences. These viruses are not equivalent, and Table 140.1 summarizes their main differences relevant for gene therapy.

Retroviruses Retroviruses belong to the Retroviridae family, which also comprises the lentiviruses such as human immunodeficiency virus (HIV). Retroviral vectors, the most widely used vectors for gene therapy, are derived from the Moloney murine leukaemia virus (MoMuLV). To generate replication-defective MoMuLV, all the proteinencoding sequences are removed from the virus and replaced by the transgene of interest. However, the sequences required for encapsidation of the vector RNA, the ψ packaging signal, have to be included in the vector construct. Retroviruses are able to transduce a large range of cell types with a high efficiency and for a long time. Progress in the design of retroviral vectors has permitted the transfer of cDNA as large as 10 kb, and the vectors can be pseudo-typed to enlarge the spectrum of potential target cells. This means that different envelope proteins can be used, each of which has its own advantages and disadvantages. For example, the glycosylated protein of the vesiculous stomatitis virus (VSV-G) is commonly used because it allows the targeting of a wide spectrum of cells. VSV-G mediates viral entry by membrane fusion via the interaction with phospholipid components of the cell membrane, and therefore it has a broad host range. Moreover, it is made of one monomer only and thus is more resistant than the MoMuLV natural amphotropic envelope protein. This resistance offers the possibility of ultracentrifuging the viral supernatant to obtain higher titres, about 100–300-fold concentrated. The major disadvantage of using VSV-G as an envelope is its toxic effects in the packaging cells, and in some cases the use of the amphotropic protein is required. Retrovirus integrate the genome only in dividing cells. Thus, one of the limitations of these vectors is that quiescent cells cannot be targeted. The other major issue is that the transgene is randomly integrated into the cell genome. This can lead to serious adverse effects such as

Skin Gene and Cell Therapy

140.3

Fig. 140.1 Different approaches to skin gene therapy. Approaches differ by the delivery method, in vivo or ex vivo, and by the vector (non-viral or viral method).

Table 140.1 Gene therapy viral vectors Virus

Integrative

Cargo capacity

Ability to transduce quiescent cells

Application

Retrovirus Lentivirus Adenovirus AAV HSV

Yes Yes No Yes‡ No*

Up Up Up Up Up

No Yes Yes Yes Yes

Genetic disorders Genetic disorders Cancer, vaccination, wound healing, genetic disorders* Genetic disorders Cancer, genetic disorders*

to to to to to

10 kb 11 kb 35 kb† 4.9 kb 140 kb

* The use of phage integrases or transposases such as φC31 or sleeping beauty could confer on these vectors the ability to integrate the therapeutic gene into the target cell’s genome. † The development of ‘gutless’ adenoviral vectors has improved the cargo capacity from 9 to 35 kb. ‡ AAV vectors lack the rep protein and thus integration is less efficient than with the wild-type virus.

the occurrence of leukaemia associated with the X-severe combined immunodeficiency (SCID) gene therapy trial [1,2]. The development of self-inactivating (SIN) vectors, in which the enhancer located in the U3 region of the 3′-long-term repeat (LTR) has been deleted, offers a

greater biosafety and should prevent oncogenic events due to an upregulation of a proto-oncogene in the close vicinity of the integration site. Recent data clearly demonstrate that transcriptionally active (i.e. non-SIN) LTRs are the major determinants of genotoxicity in retroviral

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and lentiviral vectors, and that SIN vectors have greater therapeutic potential [3–5]. Moreover, they allow for the use of tissue-specific promoters to drive transgene expression. The drawback of the inactivation of the transcriptional regulatory elements of the proviral LTRs is a substantial loss of viral titre, which was at least 10–100-fold lower than the parental retroviral vector [6,7]. SIN vectors are now mandatory for clinical applications in European countries and in the United States [8].

Lentiviruses Lentiviral vectors are derived from the human immunodeficiency virus 1 (HIV1). They share almost all their features with the retroviral vectors, with the major exception that they are able to transduce quiescent cells. Like retroviral vectors, their integration is not site specific and thus can theoretically lead to oncogenesis through insertional mutagenesis. As for the retroviral vectors, lentiviral vectors can be pseudo-typed to enlarge the spectrum of target cells. The use of the VSV-G protein also permits the production of highertitre vector preparations. The development of lentiviral SIN vectors [9,10], like the one developed first for retroviral vectors, greatly reduces this risk [3–5]. SIN lentiviral vectors have been successfully used in several preclinical studies to transfer genes of interest into primary keratinocytes [11–15].

mize the number of Ad viral genes present in the vector, increasing the cloning capacity up to 35 kb and reducing the host immune response against the Ad vectortransduced cells. Adenoviruses are not oncogenic in humans; in addition, their genomes are completely defined and can easily be modified. Recombinant Ad can readily be produced in large quantities and highly concentrated without modifying the ability of the virus to infect cells. The ability to generate high-titre (1014 particles/mL) recombinant Ad vectors and their efficient transduction of both dividing and non-dividing cells initially boded well for a very successful vector. Unfortunately, cells transduced by recombinant Ad vectors are eliminated by cytotoxic T-lymphocytes (CTLs) generated against viral proteins or the transgene [16,17]. Furthermore, Ad vectors elicit a potent humoral response that effectively eliminates all subsequent transduction. This is even more pertinent to adenoviral vectors because they do not integrate, and hence they suffer loss by cell division and by DNA degradation. The high-titre recombinant Ad vectors are potentially toxic, although the precise mechanism associated with this toxicity remains uncertain. The death of a patient as the direct result of recombinant adenoviral vector therapy is a tragic warning sign that signals the need for further improvement of viral gene therapy. Ad vectors will, however, continue to be used in situations in which a high-level but transient expression of the foreign gene is required.

Adenoviruses Human adenoviruses (Ad) are a group of double-stranded DNA viruses that infect a variety of vertebrate hosts, including rodents, chicken and non-human primates. These are divided into six subgroups according to rather arbitrary criteria of ability to transform rodent cells, pattern of haemagglutination, and GC contents of the DNA. In the context of gene therapy, serotypes 5 and 2 of the subgroup C have been used almost exclusively because these are the serotypes about which most is known regarding structure and biology, and convenient biological reagents are available to produce recombinant subgroup C Ad gene transfer vectors in large quantities. First, Ad vectors permit limited Ad gene expression and DNA replication, which probably contributes to the immune response against the vector. In addition, the possibility of making replication-competent adenovirus (RCA) during propagation is a potentially dangerous feature. By making additional mutations or deletions in the Ad genome, both of these problems can be avoided. Such second and third generations of Ad vectors avoid the presence of RCA in the preparation. The thirdgeneration Ad vectors have been termed, because of their characteristics, high-capacity, helper-dependent and ‘gutless’ adenoviral vectors. They were designed to mini-

Adeno-associated virus The human parvovirus adeno-associated virus (AAV) belongs to the Parvoviridae family. It is a dependovirus that needs a helper virus to replicate. Thus, the AAVs are naturally defective for replication. AAV has aroused considerable interest as a potential vector for human gene therapy. Among the favourable properties of the virus are its lack of association with any human disease, the wide range of cell lines derived from different tissues that can be infected and the ability of the virus to integrate into the genome of the infected cell to establish a latent infection. The last property appears to be unique among mammalian viruses because the integration can occur in quiescent cells, albeit at a lesser frequency than in dividing cells, and because AAV integration occurs at a specific site in the human genome. This site, called AAVS1, is located on chromosome 19 (19q13.3–qter). The site specificity of AAV integration is mediated by the AAV rep78 protein or by its C-terminally spliced variant Rep68 [18,19]. Although the inverse terminal repeats (ITRs) are the only genomic elements necessary for integration, efficient integration and site specificity require the presence of the viral Rep protein [20]. Because AAV vectors lack the Rep expression cassette, AAV vectors integrate with

Skin Gene and Cell Therapy

low efficacy and low specificity into the host genome. Integration of recombinant AAV (rAAV) has been observed in dividing cells [21], as well in non-dividing cells in vitro [22]. Apart from integration into the host genome, the presence of episomal forms of rAAV has been demonstrated in vivo [23–25]. Several studies have demonstrated the presence of AAV vectors DNA in an episomal circular form in muscle and brain tissue transduced with AAV vectors [23–25]. Because this form of episomal AAV DNA persists for months and maybe years, episomal AAV DNA might be a major contributor to the long-term expression of transgenes delivered by AAV vectors. The major disadvantage of the AAV vector is its low cargo capacity, between 4.1 and 4.9 kb, but a recent strategy based on hybrid dual AAV vector has allowed the transfer of the 6 kb minidystrophin cDNA [26]. Nonetheless, AAV are very valuable vectors which are now extensively used to transfer small antisense sequences to selectively knock down alleles or modulate the splicing of target genes [27,28]. Single administration of rAAV into the muscle of immunocompetent mice does not result in a detectable cellular immune response; however, a humoral response can be detected. Pre-existing humoral immunity against AAV is likely to be a hurdle for many gene therapy approaches in humans. Thus, and especially if vectors are readministered, efforts to overcome humoral immunity against AAV have to be considered.

Herpes simplex virus amplicons Transfer of large DNA constructs in gene therapy studies is being recognized for its importance in maintaining the natural genomic environment of the gene of interest and providing tissue-specific regulation and control. Recent advances in the manipulation of BAC (bacterial artificial chromosomes) and PAC (P1-derived artificial chromosomes) inserts by homologous recombination in bacteria have increased their versatility as cloning systems for genomic DNA. However, the use of these vectors in gene expression studies is hampered by the difficulty of transferring and retaining intact sequences of genomic DNA over 100 kb long in human cells. Although gene expression from the genomic DNA inserts of BACs and PACs has been demonstrated in cell culture systems and in transgenic animal models, the efficiency of physical methods of intact DNA delivery is usually low for DNA constructs more than 100 kb long [29]. Mecklenbeck et al. successfully corrected the type VII collagen expression in immortalized keratinocytes from an recessive dystrophic epidermolysis bullosa (RDEB) patient using a microinjected PAC containing the entire COL7A1 locus (32 kb), demonstrating the ‘proof of principle’ of genomic DNA vectors as a means of restoring expression of gene as large as COL7A1 [30].

140.5

Viral vectors are an efficient means of delivering genes to cells, but the size of most genomic loci generally excludes their use in the context of viral vectors. In contrast, the large size (152 kb) of herpes simplex virus type 1 (HSV-1) confers a transgene capacity that can accommodate many genomic loci. The capacity of HSV-1 exceeds that of the helper-dependent or ‘gutless’ adenoviral vectors, which have been used to express a genomic DNA locus of 19 kb in size. Infectious amplicon plasmids carrying an origin of replication (oris) and the packaging/cleavage signal (pac) from HSV-1 have been widely used for gene delivery both in vitro and in vivo [31,32]. Furthermore, the manipulation of HSV-1 in bacteria has led to the development of helper virus-free packaging systems for HSV-1 amplicons capable of high-titre amplicon production [33]. HSV-1 amplicons do not express any viral genes but depend on helper functions for replication and packaging into virions. The problems of cytotoxicity and antigenicity are largely reduced when the helper functions are provided by a packagingdefective HSV-1 genome, which results in vector stocks that are essentially free of contaminating helper virus. However, the problem remains that it is difficult to achieve stable transgene expression with HSV-1-based vectors, as with other viral vectors. The human herpes viruses represent promising candidate vectors for several types of gene therapy applications, which include neuropathological disorders, cancer, pain control, autoimmune syndromes and metabolic diseases. The primary tropism of HSV is the neurones, however experimental HSV infection is not limited to neurones. The virus is capable of infecting most mammalian cell types and does not require cell division for infection and gene expression. Accordingly, HSV may be generally useful for gene transfer to a variety of nonneuronal tissues, particularly if short-term transgene expression is required to achieve a therapeutic effect. The large cargo capacity of the herpes viral vectors permits the transduction of complete loci, preserving the normal gene regulation.

Non-viral delivery Although often effective, viral vectors have significant drawbacks, including concerns about safety, immunogenicity, scalability of production and cost-effectiveness. Non-viral transfer to skin has several key features. First, non-viral therapeutic agents are usually plasmids or oligonucleotides, which are generally inexpensive and easy to construct and manufacture. Second, they have been shown to be effective for certain applications such as immunization, in part because of dendritic and Langerhans antigen-presenting cells located in the skin [34,35]. Third, this approach results in transient and variable levels of gene expression owing to rapid turnover in renewable epithelial tissues [36–38]. In addition, delivery

140.6

Chapter 140

of naked DNA offers a safer way to transfer a therapeutic gene both in vivo or ex vivo, without the risk of inducing unwanted side-effects including infection, mutagenesis or generation of immune response against viral proteins, which can limit subsequent readministrations. The principal issues of non-viral gene therapy are the low efficiency of gene transfer, the inability to selectively deliver DNA to specific cell types and the variable levels of gene expression. Tremendous progresses have been made in the past 5 years in the development of efficient non-viral delivery methods. This is in part due to the rise of new RNA-based therapeutic approaches involving small antisense sequences such as RNA interference (RNAi), modulation of pre-mRNA splicing or trans-splicing (for review see [39]). In vivo delivery systems for siRNA include liposomes [40], lipid/alcohol-based formulation cream [41] and nanoparticles [42,43]. Until recently, non-viral gene transfer was not applicable for long-term therapy, as such a strategy would require targeting of stem cells and integration into their genome, which was a very rare event. However, Ortiz-Urda et al. [44] have recently used a polybrene shock to successfully transfer the COL7A1 cDNA into RDEB keratinocytes using the phage φC31 integrase, This ex vivo non-viral gene therapy approach combines the advantage of a non-viral system and genomic integration which allows for long-term expression. However, a recent study showed that φC31 expression led to DNA damage and chromosomal aberrations in primary human fibroblasts. These chromosomal rearrangements (translocations, aneuploidy, ring chromosomes) were not due to the puromycin treatment, as cells transfected with the pBabepuro plasmid backbone and selected with this antibiotic did not show abnormal karyotypes [45]. This observation may temper the interest of this approach. Transposable elements such as sleeping beauty have also been used to mediate permanent genetic modification into keratinocytes [46]. Despite their advantages over viral vectors (near-random integration profile), they were not as efficient and antibiotic selection was required to enrich the genetically modified population. The use of engineered hyperactive sleeping beauty transposase, allowing ∼30% of transposition in HeLa cells, may circumvent the need for selection [47]. This has been confirmed recently on more clinically relevant primary cells (CD34+ haematopoietic stem cells and in vivo liver injection), allowing for 35–50% of transposition efficiency [48]. The different non-viral gene delivery methods that have been used for skin gene therapy are illustrated in the In vivo gene therapy section, below.

Approaches to cutaneous gene delivery Two distinct approaches have been used to genetically modify keratinocytes or fibroblasts. The in vivo approach

consists of the direct administration of the genetic material into the skin using either viral or non-viral delivery vectors, whereas in the ex vivo approach, the genetic correction of cells is achieved while they are cultured (see Fig. 140.1).

Ex vivo gene therapy The cells are harvested from the host from a skin biopsy and grown in vitro and the gene is then transferred to the cells while they are growing in tissue culture. After genetic correction, the cells are expanded and grafted back onto the recipient. This approach has many advantages: targeting of the cells of interest, possible selection of the transduced cells and a high efficacy of gene transfer. The disadvantages include the need for a good cell culture method that preserves stem cells for long-term correction, the loss of the skin appendages on the treated area and the fact that the technique is labour intensive, in that it involves extensive tissue culture and grafting efforts. Gene transfer preclinical studies using this approach have been most successfully achieved with integrating retroviral or lentiviral vectors[12,49,50–61]. Non-viral vectors have also been used for ex vivo gene therapy to correct haemophilia A by injection of transfected autologous fibroblasts in a phase I trial [62]. This approach was also used to correct type VII collagendeficient keratinocytes and laminin 5 deficiency in preclinical studies [44,46]. The grafting efforts have benefited from experience acquired primarily in the treatment of burns and cutaneous ulcers [63–65]. These include refinement of approaches, ranging from the application of simple sheets of epithelium grown in vitro to the use of complex skin-equivalent grafts composed of living cells seeded in natural or synthetic matrices.

In vivo gene therapy This direct approach includes the topical application or the injection of the gene therapy compound into the skin.

Injection In this approach, the therapeutic agent is directly injected into the skin by several means: intradermal injection of naked plasmid DNA in phosphate-buffered saline (PBS) [37,66], ballistic particle (DNA-coated gold particles) bombardment using a ‘gene gun’ method, also called ‘biolistic delivery’ [67,68], electroporation [69,70], jet injection [71], puncture-mediated transfer [72,73] or tape stripping [74]. Generally, these methods are at present inefficient for gene therapy purposes, but some may be useful for DNA vaccines or anticancer applications. However, in the case of small molecules (siRNA, antisense oligoribonucleotides), the intradermal route of administration has shown some interest for the treatment of genetic skin disorders [75].

Skin Gene and Cell Therapy

Topical application The topical route of administration allows for delivery to large areas of the epidermis. The therapeutic compound is applied to the skin, either in a liposome mixture, as uncoated DNA for epicutaneous transfer into the epidermis or complexed with newly identified cell-penetrating peptides [41,76–82]. However, the stratum corneum, which is the outer protective layer of the epidermis, is hydrophobic and acts as a very efficient barrier to large negatively charged molecules such as DNA, even when complexed to liposomes. Other topical methods involve the use of viral vectors such as adenovirus and modified herpes virus [83,84], but this raised safety concerns about viral vector distribution in vivo and immune response towards the vector. Direct in vivo gene transfer is, in general, less labour intensive than ex vivo approaches and can produce biologically active levels of gene expression and protein production. However, direct approaches have been plagued by low levels of gene transfer, which achieves transgene expression in only a minority of cells for periods as short as few days [37,83]. The development of new gene therapy approaches involving small antisense compounds such as siRNA or exon skipping (see below) has raised a new interest in in vivo non-viral topical delivery. These small compounds are easier to deliver through the skin barrier than large plasmids and recent developments in lipid cream formulation, cell-penetrating peptides and nanoparticles are very promising tools for clinical application [41,79,81]. References 1 Hacein-Bey-Abina S, von Kalle C, Schmidt M et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348(3):255–6. 2 Hacein-Bey-Abina S, von Kalle C, Schmidt M et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCIDX1. Science 2003;302(5644):415–19. 3 Cornils K, Lange C, Schambach A et al. Stem cell marking with promotor-deprived self-inactivating retroviral vectors does not lead to induced clonal imbalance. Mol Ther 2009;17(1):131–43. 4 Maruggi G, Porcellini S, Facchini G et al. Transcriptional enhancers induce insertional gene deregulation independently from the vector type and design. Mol Ther 2009;17(5):851–6. 5 Montini E, Cesana D, Schmidt M et al. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J Clin Invest 2009;119(4):964–75. 6 Yee JK, Moores JC, Jolly DJ, Wolff JA, Respess JG, Friedmann T. Gene expression from transcriptionally disabled retroviral vectors. Proc Natl Acad Sci USA 1987;84(15):5197–201. 7 Yu JY, DeRuiter SL, Turner DL. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci USA 2002;99(9):6047–52. 8 De Luca M, Pellegrini G, Mavilio F. Gene therapy of inherited skin adhesion disorders: a critical overview. Br J Dermatol 2009;161(1):19–24.

140.7

9 Miyoshi H, Blomer U, Takahashi M, Gage FH, Verma IM. Development of a self-inactivating lentivirus vector. J Virol 1998;72(10): 8150–7. 10 Zufferey R, Dull T, Mandel RJ et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 1998;72(12):9873–80. 11 Baek SC, Lin Q, Robbins PB, Fan H, Khavari PA. Sustainable systemic delivery via a single injection of lentivirus into human skin tissue. Hum Gene Ther 2001;12(12):1551–8. 12 Chen M, Kasahara N, Keene DR et al. Restoration of type VII collagen expression and function in dystrophic epidermolysis bullosa. Nat Genet 2002;32(4):670–5. 13 Di Nunzio F, Maruggi G, Ferrari S et al. Correction of laminin-5 deficiency in human epidermal stem cells by transcriptionally targeted lentiviral vectors. Mol Ther 2008;16(12):1977–85. 14 Kuhn U, Terunuma A, Pfutzner W, Foster RA, Vogel JC. In vivo assessment of gene delivery to keratinocytes by lentiviral vectors. J Virol 2002;76(3):1496–504. 15 Richard E, Mendez M, Mazurier F et al. Gene therapy of a mouse model of protoporphyria with a self-inactivating erythroidspecific lentiviral vector without preselection. Mol Ther 2001;4(4): 331–8. 16 Kafri T, Morgan D, Krahl T, Sarvetnick N, Sherman L, Verma I. Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy. Proc Natl Acad Sci USA 1998;95(19):11377–82. 17 Tripathy SK, Black HB, Goldwasser E, Leiden JM. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 1996;2(5):545–50. 18 Linden RM, Ward P, Giraud C, Winocour E, Berns KI. Site-specific integration by adeno-associated virus. Proc Natl Acad Sci USA 1996;93(21):11288–94. 19 Linden RM, Winocour E, Berns KI. The recombination signals for adeno-associated virus site-specific integration. Proc Natl Acad Sci USA 1996;93(15):7966–72. 20 Weitzman MD, Kyostio SR, Kotin RM, Owens RA. Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. Proc Natl Acad Sci USA 1994;91(13):5808–12. 21 Yang CC, Xiao X, Zhu X et al. Cellular recombination pathways and viral terminal repeat hairpin structures are sufficient for adeno-associated virus integration in vivo and in vitro. J Virol 1997;71(12):9231–47. 22 Wu P, Phillips MI, Bui J, Terwilliger EF. Adeno-associated virus vector-mediated transgene integration into neurons and other nondividing cell targets. J Virol 1998;72(7):5919–26. 23 Duan D, Sharma P, Yang J et al. Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J Virol 1998;72(11):8568–77. 24 Fisher KJ, Jooss K, Alston J et al. Recombinant adeno-associated virus for muscle directed gene therapy. Nat Med 1997;3(3):306–12. 25 Nakai H, Iwaki Y, Kay MA, Couto LB. Isolation of recombinant adeno-associated virus vector-cellular DNA junctions from mouse liver. J Virol 1999;73(7):5438–47. 26 Ghosh A, Yue Y, Lai Y, Duan D. A hybrid vector system expands adeno-associated viral vector packaging capacity in a transgeneindependent manner. Mol Ther 2008;16(1):124–30. 27 Goyenvalle A, Vulin A, Fougerousse F et al. Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science 2004;306(5702):1796–9. 28 Xia H, Mao Q, Eliason SL et al. RNAi suppresses polyglutamineinduced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 2004;10(8):816–20.

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29 Compton SH, Mecklenbeck S, Mejia JE et al. Stable integration of large (>100 kb) PAC constructs in HaCaT keratinocytes using an integrintargeting peptide delivery system. Gene Ther 2000;7(18):1600–5. 30 Mecklenbeck S, Compton SH, Mejia JE et al. A microinjected COL7A1PAC vector restores synthesis of intact procollagen VII in a dystrophic epidermolysis bullosa keratinocyte cell line. Hum Gene Ther 2002;13(13):1655–62. 31 Geller AI, Breakefield XO. A defective HSV-1 vector expresses Escherichia coli beta-galactosidase in cultured peripheral neurons. Science 1988;241(4873):1667–9. 32 Spaete RR, Frenkel N. The herpes simplex virus amplicon: a new eucaryotic defective-virus cloning-amplifying vector. Cell 1982;30(1):295–304. 33 Saeki Y, Fraefel C, Ichikawa T, Breakefield XO, Chiocca EA. Improved helper virus-free packaging system for HSV amplicon vectors using an ICP27-deleted, oversized HSV-1 DNA in a bacterial artificial chromosome. Mol Ther 2001;3(4):591–601. 34 Falo LD Jr. Targeting the skin for genetic immunization. Proc Assoc Am Phys 1999;111(3):211–19. 35 Raz E, Carson DA, Parker SE et al. Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses. Proc Natl Acad Sci USA 1994;91(20):9519–23. 36 Choate KA, Khavari PA. Sustainability of keratinocyte gene transfer and cell survival in vivo. Hum Gene Ther 1997;8(8):895–901. 37 Hengge UR, Chan EF, Foster RA, Walker PS, Vogel JC. Cytokine gene expression in epidermis with biological effects following injection of naked DNA. Nat Genet 1995;10(2):161–6. 38 Vogel JC. A direct in vivo approach for skin gene therapy. Proc Assoc Am Phys 1999;111(3):190–7. 39 Wood M, Yin H, McClorey G. Modulating the expression of disease genes with RNA-based therapy. PLoS Genet 2007;3(6):e109. 40 Morrissey DV, Lockridge JA, Shaw L et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 2005;23(8):1002–7. 41 Takanashi M, Oikawa K, Sudo K et al. Therapeutic silencing of an endogenous gene by siRNA cream in an arthritis model mouse. Gene Ther 2009;16(8):982–9. 42 Li SD, Chen YC, Hackett MJ, Huang L. Tumor-targeted delivery of siRNA by self-assembled nanoparticles. Mol Ther 2008;16(1):163–9. 43 Patel PC, Giljohann DA, Seferos DS, Mirkin CA. Peptide antisense nanoparticles. Proc Natl Acad Sci USA 2008;105(45):17222–6. 44 Ortiz-Urda S, Thyagarajan B, Keene DR et al. Stable nonviral genetic correction of inherited human skin disease. Nat Med 2002;8(10):1166–70. 45 Liu J, Skjorringe T, Gjetting T, Jensen TG. PhiC31 integrase induces a DNA damage response and chromosomal rearrangements in human adult fibroblasts. BMC Biotechnol 2009;9:31. 46 Ortiz-Urda S, Lin Q, Yant SR, Keene D, Kay MA, Khavari PA. Sustainable correction of junctional epidermolysis bullosa via transposonmediated nonviral gene transfer. Gene Ther 2003;10(13):1099–104. 47 Baus J, Liu L, Heggestad AD, Sanz S, Fletcher BS. Hyperactive transposase mutants of the Sleeping Beauty transposon. Mol Ther 2005;12(6):1148–56. 48 Mates L, Chuah MK, Belay E et al. Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates. Nat Genet 2009;41(6):753–61. 49 Choate KA, Kinsella TM, Williams ML, Nolan GP, Khavari PA. Transglutaminase 1 delivery to lamellar ichthyosis keratinocytes. Hum Gene Ther 1996;7(18):2247–53. 50 Choate KA, Medalie DA, Morgan JR, Khavari PA. Corrective gene transfer in the human skin disorder lamellar ichthyosis. Nat Med 1996;2(11):1263–7. 51 Dellambra E, Pellegrini G, Guerra L et al. Toward epidermal stem cell-mediated ex vivo gene therapy of junctional epidermolysis bullosa. Hum Gene Ther 2000;11(16):2283–7.

52 Dellambra E, Prislei S, Salvati AL et al. Gene correction of integrin beta4-dependent pyloric atresia-junctional epidermolysis bullosa keratinocytes establishes a role for beta4 tyrosines 1422 and 1440 in hemidesmosome assembly. J Biol Chem 2001;276(44):41336–42. 53 Dellambra E, Vailly J, Pellegrini G et al. Corrective transduction of human epidermal stem cells in laminin-5-dependent junctional epidermolysis bullosa. Hum Gene Ther 1998;9(9):1359–70. 54 Freiberg RA, Choate KA, Deng H, Alperin ES, Shapiro LJ, Khavari PA. A model of corrective gene transfer in X-linked ichthyosis. Hum Mol Genet 1997;6(6):927–33. 55 Gache Y, Baldeschi C, del Rio M et al. Construction of skin equivalents for gene therapy of recessive dystrophic epidermolysis bullosa. Hum Gene Ther 2004;15(10):921–33. 56 Gagnoux-Palacios L, Vailly J, Durand-Clement M, Wagner E, Ortonne JP, Meneguzzi G. Functional re-expression of laminin-5 in laminingamma2-deficient human keratinocytes modifies cell morphology, motility, and adhesion. J Biol Chem 1996;271(31):18437–44. 57 Garlick JA, Katz AB, Fenjves ES, Taichman LB. Retrovirus-mediated transduction of cultured epidermal keratinocytes. J Invest Dermatol 1991;97(5):824–9. 58 Goto M, Sawamura D, Ito K et al. Fibroblasts show more potential as target cells than keratinocytes in COL7A1 gene therapy of dystrophic epidermolysis bullosa. J Invest Dermatol 2006;126(4):766–72. 59 Seitz CS, Giudice GJ, Balding SD, Marinkovich MP, Khavari PA. BP180 gene delivery in junctional epidermolysis bullosa. Gene Ther 1999;6(1):42–7. 60 Vailly J, Pulkkinen L, Miquel C et al. Identification of a homozygous one-basepair deletion in exon 14 of the LAMB3 gene in a patient with Herlitz junctional epidermolysis bullosa and prenatal diagnosis in a family at risk for recurrence. J Invest Dermatol 1995;104(4):462–6. 61 Woodley DT, Krueger GG, Jorgensen CM et al. Normal and genecorrected dystrophic epidermolysis bullosa fibroblasts alone can produce type VII collagen at the basement membrane zone. J Invest Dermatol 2003;121(5):1021–8. 62 Roth DA, Tawa NE Jr, O’Brien JM, Treco DA, Selden RF. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med 2001;344(23):1735–42. 63 Gallico GG 3rd, O’Connor NE, Compton CC, Kehinde O, Green H. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984;311(7):448–51. 64 Llames SG, del Rio M, Larcher F et al. Human plasma as a dermal scaffold for the generation of a completely autologous bioengineered skin. Transplantation 2004;77(3):350–5. 65 Ronfard V, Rives JM, Neveux Y, Carsin H, Barrandon Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation 2000;70(11):1588–98. 66 Hengge UR, Walker PS, Vogel JC. Expression of naked DNA in human, pig, and mouse skin. J Clin Invest 1996;97(12):2911–16. 67 Cheng L, Ziegelhoffer PR, Yang NS. In vivo promoter activity and transgene expression in mammalian somatic tissues evaluated by using particle bombardment. Proc Natl Acad Sci USA 1993;90(10):4455–9. 68 Rakhmilevich AL, Turner J, Ford MJ et al. Gene gun-mediated skin transfection with interleukin 12 gene results in regression of established primary and metastatic murine tumors. Proc Natl Acad Sci USA 1996;93(13):6291–6. 69 Roos AK, Eriksson F, Walters DC, Pisa P, King AD. Optimization of skin electroporation in mice to increase tolerability of DNA vaccine delivery to patients. Mol Ther 2009;17(9):1637–42. 70 Zhang L, Nolan E, Kreitschitz S, Rabussay DP. Enhanced delivery of naked DNA to the skin by non-invasive in vivo electroporation. Biochim Biophys Acta 2002;1572(1):1–9. 71 Sawamura D, Ina S, Itai K et al. In vivo gene introduction into keratinocytes using jet injection. Gene Ther 1999;6(10):1785–7.

Skin Gene and Cell Therapy 72 Ciernik IF, Krayenbuhl BH, Carbone DP. Puncture-mediated gene transfer to the skin. Hum Gene Ther 1996;7(8):893–9. 73 Hafeli UO, Mokhtari A, Liepmann D, Stoeber B. In vivo evaluation of a microneedle-based miniature syringe for intradermal drug delivery. Biomed Microdevices 2009;Apr 4 (epub ahead of print). 74 Yu WH, Kashani-Sabet M, Liggitt D, Moore D, Heath TD, Debs RJ. Topical gene delivery to murine skin. J Invest Dermatol 1999;112(3):370–5. 75 Smith FJ, Hickerson RP, Sayers JM et al. Development of therapeutic siRNAs for pachyonychia congenita. J Invest Dermatol 2008;128(1):50–8. 76 Alexander MY, Akhurst RJ. Liposome-medicated gene transfer and expression via the skin. Hum Mol Genet 1995;4(12):2279–85. 77 Domashenko A, Gupta S, Cotsarelis G. Efficient delivery of transgenes to human hair follicle progenitor cells using topical lipoplex. Nat Biotechnol 2000;18(4):420–3. 78 Fan H, Lin Q, Morrissey GR, Khavari PA. Immunization via hair follicles by topical application of naked DNA to normal skin. Nat Biotechnol 1999;17(9):870–2. 79 Jearawiriyapaisarn N, Moulton HM, Buckley B et al. Sustained dystrophin expression induced by peptide-conjugated morpholino oligomers in the muscles of mdx mice. Mol Ther 2008;16(9):1624–9. 80 Li L, Hoffman RM. The feasibility of targeted selective gene therapy of the hair follicle. Nat Med 1995;1(7):705–6. 81 Ritprajak P, Hashiguchi M, Azuma M. Topical application of creamemulsified CD86 siRNA ameliorates allergic skin disease by targeting cutaneous dendritic cells. Mol Ther 2008;16(7):1323–30. 82 Shi Z, Curiel DT, Tang DC. DNA-based non-invasive vaccination onto the skin. Vaccine 1999;17(17):2136–41. 83 Lu B, Federoff HJ, Wang Y, Goldsmith LA, Scott G. Topical application of viral vectors for epidermal gene transfer. J Invest Dermatol 1997;108(5):803–8. 84 Setoguchi Y, Jaffe HA, Danel C, Crystal RG. Ex vivo and in vivo gene transfer to the skin using replication-deficient recombinant adenovirus vectors. J Invest Dermatol 1994;102(4):415–21.

140.9

Table 140.2 Recessive skin genetic disorders corrected by gene therapy Disease

Protein

Vector

Reference

Lamellar ichthyosis

Transglutaminase I

Retrovirus

117,118

X-linked ichthyosis

Steroid sulphatase

Retrovirus

119

GABEB

BPAG2/ collagen XVII

Retrovirus

24

Herlitz junctional EB

Laminin 5 β3 Laminin 5 γ2

Retrovirus Retrovirus

23,34 21

Junctional EB with pyloric atresia

Integrin β4

Retrovirus

120

Dystrophic EB

Collagen VII Collagen VII Collagen VII

Lentivirus Retrovirus Non-viral

31 28,32 27

Table 140.3 Candidate dominant skin genetic disorders Disease

Protein

Reference

Epidermolytic hyperkeratosis (EHK)

Keratin 1 Keratin 10

2

EB simplex

Keratin 5 Keratin 14

121 3

Dystrophic EB

Collagen VII

122

Pachyonychia congenita

Keratin 6a

57,58

Skin gene therapy applications Skin genetic disorders Tremendous progress has been made in the understanding of the genetic basis of a large number of skin genetic disorders. The discovery of the underlying mutations in the defective gene–protein systems has provided the basis for the initial development of cutaneous gene therapy, and these heritable conditions appear to serve as appropriate candidate diseases for such efforts. The mode of inheritance may imply different means of correction, as in the case of recessive diseases the gain of just one copy of the normal gene can correct the phenotype of the defective cells. Thus these diseases are at present the best candidates for gene therapy. Table 140.2 summarizes the different recessive skin disorders that have been successfully corrected in preclinical or clinical studies so far. Genetic correction of dominant diseases is more complex, as the gain of one or more normal copies of the gene usually does not correct the phenotype (except for defects due to haploinsufficiency). In fact, a majority of dominant diseases are due to the dominant negative action of the mutant proteins, as in the case of keratin 1

and 10 mutants in epidermolytic hyperkeratosis [1,2]. A general strategy to treat these diseases is to eliminate enough of these mutant proteins from the cells, either by destroying the mutant mRNA or the mutant protein or directly by correcting the mutation in the genome of the targeted cells. Table 140.3 summarizes the dominant skin disorders for which a gene therapy is conceivable, even if the appropriate technology is still under development. Among the genodermatoses, most efforts have probably been devoted to prospective studies of gene-based treatments of epidermolysis bullosa, a large family of skin disorders characterized by the propensity of skin to form blisters upon minor trauma, which can be either recessively or dominantly inherited (see also Chapter 118). These mechanobullous diseases result from defects in the assembly of the cytokeratin network, in the proteins constituting the hemi-desmosomes or proteins linking these proteins to the extracellular matrix of the dermis. Mutations in the basal keratins genes K5 or K14, which are most often transmitted in a dominant manner, lead to

140.10

Chapter 140

epidermolysis bullosa simplex (EBS) [1–5]. In junctional EB (JEB), the epidermal–dermal cohesiveness is altered as a result of abnormalities of protein components of hemidesmosomes at the basement membrane zone (BMZ). JEB is caused by mutations in the genes encoding the laminin 5 subunits (LAMA3, LAMB3 or LAMC2), the α6/β4 integrins (ITGA6 or ITGB4) or the BPAG2/type XVII collagen (COL17A1) [6–13]. All forms of JEB are recessively inherited. Patients affected with the most severe form of JEB (Herlitz-type JEB) die during the first weeks of life [14,15]. Milder JEB variants thus appear to be better candidates for gene therapy [16]. Dystrophic epidermolysis bullosa (DEB) is caused by mutations in COL7A1 encoding type VII collagen [17]. It is either dominantly or recessively inherited. The recessive forms (RDEB) are among the most severe genodermatoses in children and young adults. The dominant forms (DDEB) are usually less severe. DEB patients suffer from birth from loss of adhesion between the epidermis and the dermis, resulting in severe blistering of the skin and mucosae after mild trauma. Type VII collagen is the major component of anchoring fibrils which are key attachment structures linking the hemi-desmosomes to the extracellular matrix through their interaction with laminin 5. Type VII collagen also interacts with collagen IV, another component of the dermal-epidermal junction [18]. Another genetic skin disease, pachyonychia congenita (PC), has been subjected to a gene therapy trial. PC is an autosomal dominant skin disorder characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and oral leucokeratosis. The disease is due to defects in the KRT6a, KRT6b, KRT16 and KRT17 genes encoding cytokeratins 6a, 6b, 16 and 17 respectively. Different approaches to the development of gene or cell therapy for skin genetic disorders have been tested. They aim at correcting the genetic defect by different means and at different levels.

Strategies at the DNA level The following strategies target cellular DNA either by transferring a wild-type copy of the cDNA or gene or by editing the mutation in situ in the genomic sequence.

cDNA transfer This is the oldest and most widely used gene therapy strategy. It is based on the concept that, since the target gene is mutated, the transfer into the cells of a wild-type copy will restore the synthesis of a functional protein. Thus it is only applicable to recessively inherited skin disorders, with only very few exceptions. One of these exceptions concerns the treatment of EBS keratinocytes by an original supplementation strategy [19,20]. Since a normal copy of the defective keratin will not correct the

defect, the gene encoding desmin, which has a similar protective role from mechanical stress function in the muscle, was transferred into cultured EBS keratinocytes. The newly expressed desmin protein does not suffer from the toxic dominant-negative effect of the mutant keratin protein, and the investigators have demonstrated a reversion towards wild-type responses to stress after transfection of EBS keratinocytes with human desmin [19]. In the field of skin gene therapy to treat monogenic disorders, most work using this approach has been done on recessive forms of epidermolysis bullosa. Different groups have reported functional restoration of hemi-desmosomes in JEB keratinocytes. Genetic correction of defects in the laminin 5 γ2 chain was first achieved in transformed keratinocytes [21]. Subsequently type XVII collagen or laminin β3 re-expression was reported in primary JEB keratinocytes using retroviral vectors [22–25]. Similar results were recently obtained with SIN lentiviral vectors expressing the LAMB3 cDNA under the control of the tissue-specific keratin 14 promoter [26]. Type XVII collagen or laminin 5 subunit reexpression resulted in improvement in the cell adhesion properties and colony-forming efficiency of patient keratinocytes. Corrected cells retained polarity and differentiation potential, and recovered a normal capacity of desmosome assembly. The treatment of RDEB has been hindered because of the large size of the COL7A1 cDNA that has to be transferred (9 kb). Until recently, no viral vectors were available that could efficiently transduce cells with a 9 kb cDNA and achieve long-term expression. However, as a result of recent progress in vectorology, two groups have been able to correct primary human keratinocytes derived from RDEB patients. The Khavari group used non-viral gene transfer to correct RDEB keratinocytes ex vivo. To ensure long-term expression of the transgene, they used the φC31 integrase, which permits the integration of the COL7A1 cDNA into a specific site on human chromosome 8. The keratinocytes were co-transfected with a plasmid containing the COL7A1 cDNA and the resistance gene to blasticidin, and a plasmid expressing the φC31 integrase. The keratinocytes were then selected with blasticidin [27]. Later, Gache and co-workers used a classic retroviral gene transfer to transduce primary RDEB keratinocytes, which were subsequently selected using the zeocinresistance gene present in the construct [28]. In this vector, COL7A1 expression was driven by the viral long terminal repeat (LTR) containing a strong enhancer located in its U3 region, previously associated with a higher risk of insertional mutagenesis [29,30]. In both reports, selection of transduced cells with antibiotics implied that a prokaryotic resistance gene was added to the integrated construction. For these reasons, these results were not directly applicable for clinical use.

Skin Gene and Cell Therapy

In contrast, three groups targeted both keratinocytes and fibroblasts without antibiotic selection. Woodley’s group used a self-inactivating lentiviral expressing the COL7A1 cDNA under the control of a modified MoMuLV promoter (i.e. a transcriptionally active retroviral LTR) [31]. Goto and co-workers used a classic retroviral vector to transduce both RDEB keratinocytes and fibroblasts without antibiotic selection, while Titeux et al. used a SIN retroviral vector in which the COL7A1 cDNA is expressed under the control of human promoters [32,33]. In all cases, the corrected cells were then grafted onto immunedeficient mice to demonstrate the formation in vivo of anchoring fibrils by the genetically corrected skin. Collectively, these studies have established that corrective gene transfer is feasible in epidermal recessive genodermatoses and they have provided a starting point for further refinement in future preclinical and clinical efforts. More importantly, they led to the first ever ex vivo gene therapy trial for a rare genodermatose, JEB, due to laminin 5 deficiency [34]. This phase I clinical trial aimed at assessing the overall safety of the procedure, analysing the long-term survival of transduced stem cells and persistence of transgene expression, and monitoring any humoral or cytotoxic immune response to the genetically modified cells or transgene product [35]. The patient was a 36-year-old man suffering from non-lethal JEB, compound heterozygote for a null and a missense mutation in the LAMB3 gene. Keratinocytes obtained from a punch biopsy were genetically modified ex vivo using a classic (i.e. non-SIN) retroviral vector expressing the full-length LAMB3 cDNA. Transduced epithelial sheets were grafted on both upper legs in October 2005. Skin biopsies demonstrated complete functional correction without adverse events up to 5 years after grafting [34,35]. This pilot study demonstrated the feasibility and safety of ex vivo gene therapy for severe blistering disorders and paved the way for further studies aiming at correcting other genetic skin disorders.

Genomic locus transfer This approach is similar to the cDNA transfer but involves the transfer of larger DNA fragments. The genomic approach permits the maintenance of the genomic environment of the transgene which contains regions involved in the control of gene transcription (promoter, introns, 3′UTR) and the alternative splicing diversity. The first successful gene locus transfer applied to a genetic skin disorder was achieved by microinjecting a PAC vector into a COL7A1-deficient cell line derived from a RDEB patient [36]. However, the efficiency of transfection methods for large DNA molecules is low and the pursuit of this type of approach could benefit from progress made in engi-

140.11

neering systems of high-capacity DNA vectors such as herpes virus-based vectors or non-viral approaches using newly available hyperactive transposases.

Gene editing Gene editing holds the promise of transforming a mutant allele into a normal one while maintaining the genomic organization of the gene, which is important for appropriate expression of finely regulated genes. It involves the use of zinc finger nucleases (ZFN) or meganucleases to mediate homologous recombination of a fragment containing the wild-type sequence into the target mutated gene. Another technology uses RNA/DNA oligonucleotides (RDO) to edit the mutation in situ.

Meganucleases/zinc finger nucleases Meganucleases are distinct endonucleases recognizing large (12–45 bp) DNA sequences such as I-CreI or I-SceI (Fig. 140.2a). The target locus must contain a meganuclease cleavage site, so the generation of novel engineered meganucleases with tailored specificities is under investigation [37]. Custom-designed ZFN involve the association of the non-specific cleavage domain of the FokI endonuclease with several zinc finger protein domains to confer site-specific cleavage (Fig. 140.2b) (for review see [38]). In both cases, the induced DNA double-stranded break will allow for the replacement of the mutant sequence by the wild-type sequence through a homologous recombination process (Fig. 140.2c,d). The recombination fragment can be transferred as a plasmid or encoded by non-integrative lentiviral vectors [39]. The advantages of this approach are to use smaller cDNA fragments than in the cDNA transfer strategy, it is not associated with insertional mutagenesis and it preserves the temporal and tissue-specific gene expression. Recently, Redondo and co-workers have selected a derivative of the meganuclease I-CreI to induce a specific double-strand cleavage into the XPC gene mutated in xeroderma pigmentosum [37]. This opens up a new avenue for an ex vivo-based gene therapy approach for this type of xeroderma pigmentosum. However, at present, the efficiency of gene editing through these methods is below clinical feasibility. RNA/DNA oligonucleotides RNA/DNA oligonucleotides (RDO), also called chimeraplasts, directly and specifically correct the point mutation by in vivo targeted mutagenesis. The therapeutic nucleic acid to be transferred is small and quality control of the therapeutic agent is relatively simple as manufacturers have the know-how to synthesize nucleic acids. Furthermore, the stability of RDO allows for a slow and sustained release in vivo, and gene correction by RDO does not appear to require DNA replication [40,41].

140.12 (a)

Chapter 140

Meganuclease

(b)

Zinc Finger endonuclease

Fok I

Right ZFP

Cleavage domain

Fok I 5’

3’

3’

5’ Fok I

Double strand cleavage

(c)

Left ZFP

(d)

Gene correction 4

5

Homology sequences

Donor DNA

Gene addition cDNA fragment 2

3

4

Donor cDNA

5

Homology sequences

1

2

3

4

5

Mutated pA gene

1

2

3

1

2

3

4

5

WT pA gene

1

2

3

4

4

5

pA

5

4

pA

5

Mutated gene

Modified gene

Fig. 140.2 Gene editing strategies. Meganucleases are endonucleases recognizing large sites (12–45 nt) and thus cleave very rarely in the human genome. From natural meganucleases such as I-CreI and I-SceI, bio-engineered site-specific meganucleases can be derived that induce a double-strand cleavage at the target genomic site (a). Similarly, the fusion of the non-specific FokI endonuclease cleavage domain to different zinc finger motifs recognizing specific DNA sequences can induce a double-stranded break in the target genomic DNA (b). Together with the tailored endonuclease, a DNA fragment containing homology sequences and the wild-type sequence is transferred (c,d). Each system can mediate the perfect exchange of the mutant sequence targeted (c) or can be placed in a 5′ position of the mutation (d). In the latter, the transferred DNA fragment must contain the cDNA sequence of all exons located downstream of the mutation. Adapted from Cathomen T, Joung JK. Zinc-finger nucleases: the next generation emerges. Mol Ther 2008;16:1200–7 and Miller JC et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol 2007;25:778–85.

Such a strategy has already proved its feasibility both in vitro and in vivo. Alexeev and colleagues [42,43] have successfully locally corrected the albino mutation in mouse skin by topical application or intradermal injection of an RDO directed to a point mutation in the gene encoding the tyrosinase, a key enzyme in melanin synthesis. They observed prolonged expression of tyrosinase activity lasting longer than one hair cycle, indicating that melanocyte precursors were corrected. However, the frequency of gene correction appeared to be low and to vary between individual experiments, indicating that cellular activities such as recombination and repair may vary according to the cell cycle and metabolism [44]. Moreover, primary keratinocytes did not show any detectable level

of gene conversion among at least six different targeted genes [45]. The exact mechanism of RDO-mediated sequence exchange is still unknown and needs to be clarified.

Strategies at the RNA level Apart from transferring a wild-type copy of a gene, recent technological breakthroughs have opened the field of new gene therapy strategies targeting the mutant mRNA or pre-mRNA. Some of these strategies offer many advantages over the classic gene therapy approach such as the size and nature of the compounds involved, allowing for easier in vivo delivery, and the possibility to treat dominant disorders as well as disease caused by

Skin Gene and Cell Therapy

mutations in cDNAs which are too large to fit in classic viral vectors.

Gene knockdown The concept of gene knockdown to treat genetic diseases may appear surprising but it is particularly applicable to the treatment of dominant disorders. In fact, most dominant disorders are caused by the synthesis of a mutated protein which acts in a dominant-negative manner by interfering with the function of the wild-type protein. Several approaches have thus been designed to try to selectively knock down the mutant allele, one of them, RNA interference, having been successful in treating PC.

RNA interference Gene silencing mediated by double-stranded RNAs (dsRNAs) has emerged as an important mechanism regulating exogenous and potentially endogenous gene expression. Termed post-transcriptional gene silencing in plants and fungi, and RNA interference (RNAi) in other organisms, this process induces the sustained downregulation of the target gene corresponding to the dsRNA as a result of degradation of the target mRNA. Although most work has been performed in lower eukaryotes, there is also evidence for RNAi in mouse zygotes and embryos, and in both mouse and human cells in culture, in which dsRNAs of 21–23 nucleotides have been shown to specifically inhibit gene expression [46–50]. During RNAi, long dsRNA molecules are processed into 19- to 23-nucleotide RNAs, known as short-interfering RNAs (siRNA), that serve as guides for enzymatic cleavage of complementary RNAs (Fig. 140.3a) [51]. In addition, siRNAs can function as primers for an RNA-dependent RNA polymerase that synthesizes additional dsRNA, which, in turn, is processed into siRNAs, amplifying the effects of the original siRNAs [51–53]. In 2001, Caplen et al. [46] demonstrated, for the first time, the feasibility of targeting a disease-associated transcript by RNAi. Using dsRNA of 22 nucleotides, they inhibited, in mammalian cells, the cytotoxicity induced by the expression of a plasmid encoding an expanded polyglutamine tract. The development of the siRNAproducing expression vectors using the U6 promoter provides a more effective tool than the other methods such as transfection of in vitro synthesized siRNA duplexes [51]. More recently, the development of lentivirus- and retrovirus-based systems to silence genes in primary mammalian cells by RNAi has provided the mean of long-term silencing needed for the treatment of genetic disorders [54–56]. As siRNA-mediated gene silencing should affect both the mutant and wild-type alleles, a third copy using the code degeneracy should be introduced to correct dominant skin genetic disorders. However, in the case of PC,

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the two closely related KRT6a and KRT6b genes show similar function and expression. Thus, by inducing the near-complete knockdown of both KRT6a alleles leaving the KRT6b gene untouched in a keratinocyte cell line (HaCaT), Smith and co-workers have demonstrated the feasibility of siRNA-based gene therapy for PC [57]. Alternatively, siRNA-mediated gene knockdown could be attempted to selectively destroy the mutant RNA. Using this strategy, the same group has induced the selective knockdown of the KRT6a mutant allele targeting a recurrent point mutation (c.513C>A; p.Asn171Lys) without affecting significantly the wild-type KRT6a [58]. A phase 1b clinical trial has been sucessfully completed on one patient carrying the p.Asn171Lys mutation based on intradermal injection of the siRNA. The patient showed clinical improvement at the site of injection, although the treatment had to be discontinued due to the pain caused by repetitive intradermal injections in the sole (http:// clinicaltrials.gov/ct2/show/NCT00716014). This latter study, by demonstrating the efficiency of the siRNA strategy to discriminate mutant and wild-type allele differing by only one nucleotide, pioneers future studies on other dominant skin disorders. Nonetheless, the development of siRNA which specifically silence a mutant allele differing by only one base pair with the wild-type allele is a great challenge and is sequence specific by nature. When applied to the skin, this approach should allow for an efficient in vivo delivery of the small molecules involved, by either local injections or using cream formulations [59,60], which may facilitate treatment of a large body area.

Ribozymes-mediated gene knockdown Ribozymes, such as the hammerhead ribozymes, can be used specifically to destroy mRNA in a way that differs from the RNA interference pathway. The enzymatic site that cleaves the mRNA is flanked by two sequences homologous to the target mRNA. The ribozyme will cleave the mRNA at a specific site corresponding to a codon NUX, where N is any nucleotide and X can be any nucleotide except G, and is more likely if the target codon is located in an open loop of the mRNA. One limitation to the use of ribozymes is the fact that NUG sequences are not cleaved [61]. However, this problem has been solved recently by extensive mutagenesis experiments that have led to the development of a new catalytic hammerhead core sequence that specifically cleaves NUG sequences [62,63]. Point mutations that create one of these NUX codons could thus be specifically targeted by the ribozyme. As a result, only the mutant allele will be silenced and, if no haploinsufficiency occurs, the phenotype will be corrected. For example, suppression of a mutation in codon 12 of the K-ras gene using a

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dsRNA Dicer shRNA Dicing

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Fig. 140.3 Strategies targeting the messenger RNA. (a) The RNA interference strategy involves the use of small double-stranded RNA molecules (21 mer) called siRNA (silencing RNA) or the use of plasmid or viral vector encoding shRNA (small hairpin RNA). shRNA will be processed in the cell by the DICER enzyme complex that naturally cleaves double-stranded RNAs. The siRNA produced is then recognized by the RISC complex that will degrade the sense strand. The remaining antisense strand will associate to the target mRNA through base-pairing affinity and an endonuclease present in the RISC complex called Argonaut will cleave the mRNA. (b) The trans-splicing strategy involves the transfer of a pre-mRNA trans-splicing (PTM) molecule containing a sequence homologous to an intronic sequence, a strong acceptor splice site sequence and the wild-type cDNA sequence downstream of the mutated exon. The PTM hybridizes with the target pre-mRNA and during the splicing process, edited mRNA carrying the wild-type sequence will be produced. (c) The exon skipping strategy is based on the capability of small antisense sequence like antisense oligoribonucleotides (AON) to mask splicing signals recognized by the spliceosome. These signals present along the pre-mRNA are the branch points, the acceptor sites, the donor sites and the exonic splicing enhancers (ESEs). In this example, an AON masking an ESE sequence induces the skipping of the mutated exon (exon2*). If the skipping maintains the open reading frame, and the sequence encoded by the skipped exon is dispensable for the protein function, the edited mRNA encodes a shorter albeit functional protein. Adapted from O’Connor TP, Crystal RG. Genetic medicines: treatment strategies for hereditary disorders Nat Genet 2006;7:261–76.

Skin Gene and Cell Therapy

hammerhead ribozyme that specifically cleaves the mutant RNA has been successfully achieved [64,65]. However, the probability of an appropriate site is low, given the specificity of the target site and the incidence of open-loop structures, so this approach could only be used to correct certain mutations and is less efficient and versatile than siRNA knockdown.

Exon skipping The exon skipping strategy targets the splicing process which matures the pre-mRNA into the mRNA. During this step, small antisense molecules can mask signals recognized by the spliceosome machinery, thus leading to the excision of target exon(s) carrying mutation(s). If the target exon sequence is dispensable and the process maintains the open reading frame, it produces a shortened protein partly or a completely functional protein (Fig. 140.3c). This approach has been successfully applied first to βthalassaemia [66] and then more extensively to Duchenne’s muscular dystrophy (DMD). Numerous studies have demonstrated its feasibility and efficiency in animal models (for review see [67]) and in a phase II clinical trial for DMD patients, which is currently ongoing in The Netherlands [68,69]. Among the genodermatoses, dystrophic EB is a major candidate disease for this approach. In fact, with 118 exons, COL7A1 is one of the most segmented genes in the human genome, and among them the 85 exons encoding the central collagenous domain are in the same open reading frame. Recently, the group of Hiroshi Shimizu has illustrated the feasibility of exon skipping for RDEB by demonstrating the dispensability of exon 70 of COL7A1 [32]. They have used a retroviral vector encoding a deleted COL7A1 cDNA to transduce RDEB keratinocytes and fibroblasts, and have generated skin equivalents grafted onto nude mice to demonstrate the formation of functional anchoring fibrils. Then, they have induced in vivo targeted skipping of exon 70 using intradermal injection of antisense oligoribonucleotides in RDEB skin equivalents, albeit with low efficacy. Therefore, the efficacy of this approach for RDEB and other genetic skin disorders remains to be demonstrated. The main advantages of this approach are that it is applicable to both recessive and dominant disorders, and it offers the opportunity of a non-invasive, body-wide in vivo treatment using easy-to-manufacture compounds (oligoribonucleotides) combined to local or topical delivery methods (see above). Moreover, since it targets the mutant RNA produced in situ, it preserves the physiological regulation of the gene. However, this strategy may be applicable to only a subset of genes with appropriate genomic organization, protein structure and mutation localization. In addition, this strategy may benefit only a

140.15

subset of patients carrying mutations within exons which are dispensable for the protein function.

Trans-splicing Trans-splicing is a naturally occurring process in primitive eukaryotes, plants and to a lesser extent in mammals [70,71]. It involves the splicing between two separately transcribed mRNA fragments. The trans-splicing gene therapy strategy uses the splicing process to exchange part of the target mRNA containing the mutated exons with a fragment brought in trans called PTM (pre-transsplicing-molecule), containing a binding domain (which binds to the target pre-mRNA), a splicing domain and a coding domain with the wild-type sequence (Fig. 140.3b). So far, the most efficient transfer of PTM has been done by ex vivo retroviral gene transfer. Thus, the main advantages of this approach are to be able to target very large genes (size over 10–11 kb) with cDNA which does not fit within conventional gene therapy vectors and to maintain the temporal and spatial expression of the gene. The most efficient trans-splicing strategy so far is the spliceosome-mediated RNA trans-splicing (SMaRT, trademark owned by VIRxSYS Corporation). Ribozymemediated trans-splicing has also been developed but the efficiency is at present too low to consider clinical application (for review see [72]). In skin, two genes have been targeted by SMaRT trans-splicing by Johannes Bauer ’s group: COL17A1 and PLEC1. Mutations in COL17A1 cause either JEB or generalized atrophic benign epidermolyis bullosa (GABEB), whereas mutations in PLEC1 cause a rare form of EBS associated with a late-onset muscular dystrophy (EBSMD). Over time, patients suffer mainly from the muscular dystrophy and are often wheelchair bound by the age of 40. The first paper showing a proof-of-principle approach on COL17A1 demonstrated SMaRT-mediated trans-splicing, albeit with low efficacy [73]. COL17A1 is not a particularly good candidate for trans-splicing since the cDNA is not very large (5.6 kb) and can be transferred using classic gene therapy approach, but this study opened the way for the strategy on the PLEC1 gene. PLEC1 encodes a very large cDNA of 14.2 kb which does not fit in any known integrative vector. Bauer ’s group has transferred a small PTM (about 1.4 kb) using a retroviral vector into EBS-MD immortalized fibroblasts and has shown a small increase in full-length plectin [74]. However, while plectin is ubiquitously expressed, the skin blistering defect in EBS-MD arises from the lack of interaction of the keratin filaments with hemi-desmosomes in basal keratinocytes. Thus for a clinical application, basal keratinocytes and more likely skeletal muscle cells should be targeted. This strategy is still in its infancy and more work should be done before a clinical application is feasible.

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Chapter 140

Strategies at the cell level Cell therapy is one of the first approaches which has been tested for genetic skin disorders after the conditions to culture and expand primary keratinocytes have been established. However, grafts of allogeneic or autologous epidermal sheets made of cultured keratinocytes from human skin have so far failed to produce lasting benefit in RDEB [75]. Similarly, artificial skin bio-equivalents made of allogeneic cells, such as Apligraf (Organogenesis, Canton, MA, USA), have been used in small numbers of DEB patients on acute and chronic wounds [76]. Initial results have been encouraging; however the duration of survival of such grafts has not been fully determined. As type VII collagen is synthesized by both basal keratinocytes and fibroblasts, and it has been demonstrated that fibroblasts alone can restore the dermal-epidermal defects in RDEB skin-equivalent models [32,77], it is theoretically feasible to correct the disease by using only wildtype fibroblasts.

Skin-equivalent grafting It is tempting to consider autologous grafting of either full-split skin (taken in non-blistering areas) or grafting of epithelia made from cultured autologous keratinocytes, but this has proved to be of limited value in ensuring permanent healing [78]. The cost of such treatments, considering coverage of large areas for only a limited time, means that this is not an option for most DEB patients. Still, in some particular cases the grafting of autologous cells displays promise. Revertant somatic mosaicism have been demonstrated in two forms of JEB caused by mutation in either COL17A1 [79] or LAMB3 [80]. In those patients, second point mutations occurring in vivo in a subset of cells correct the genetic defect. Apparently, in JEB this phenomenon is not as rare as was initially presumed, with an average of 35% of the patient showing revertant skin zones [81]. Thus, if those cells can be isolated, expanded and grafted back on affected areas of the patient, a long-lasting benefit could be expected without genetic engineering and without the risk of an immune rejection. Currently, research is ongoing into the development of a mixed allogeneic/autologous skin graft for RDEB by a Spanish biotechnology company (Cellerix, www.cellerix.com) which has obtained an orphan drug designation by the European Medicine Agency (EMEA, EU/3/06/369) for the treatment of EB. The product (Cx501) is a human skin equivalent made of a fibrin-based dermis containing allogenic normal fibroblasts (thus expressing wild-type type VII collagen) and an epidermis composed of autologous deficient keratinocytes. It is thought to provide long-lasting correction since the allogeneic fibroblast layer is sufficient to correct the dermalepidermal adherence, while not being rejected by the

immune system because human fibroblasts do not express HLA class II antigens in basal conditions. However, the efficacy of this product has not been disclosed yet and the lack of immune response needs to be addressed, since in certain conditions such as inflammation, human fibroblasts do express HLA class II antigens.

Allogeneic fibroblast injection Wild-type fibroblasts may be directly injected into the dermis. Following previous work which showed that injection of genetically modified RDEB fibroblasts can correct the phenotype in a model of human skin equivalent grafted onto immune-deficient mice [77,82] or in a RDEB mouse model [83], Wong et al. injected allogenic normal fibroblasts into limited areas of five RDEB patients and showed transient amelioration of the phenotype lasting for up to 3 months [84]. Strikingly, injected fibroblasts did not survive more than a few days, and the positive effect seemed to arise from a paracrine effect on patient keratinocytes which overexpressed the mutant type VII collagen protein [84]. However, this paracrine effect was not detected in the same experiment performed on a hypomorphic mouse model of RDEB [85]. Thus, while the transient clinical benefit is not fully understood, the first results are promising and a second clinical trial is ongoing with eight patients suffering from RDEB.

Bone marrow transplant Bone marrow contains stem cells that are able to reconstitute the entire haematopoietic tissue. Bone marrow transplant (BMT) is widely used to treat immune or blood genetic disorders such as severe combined immunodeficiency (SCID), sickle cell anaemia and β-thalassaemia, as well as adrenoleucodystrophy, a rare neurological genetic disorder. Remarkably, it has been shown that skin injury recruits bone marrow-derived fibroblasts to the site of injury to accelerate tissue repair [86]. Therefore, a recent study evaluated the capacity of bone marrow stem cells to ameliorate the disease in Col7a1 knockout mice, a model of RDEB [87]. Congenic bone marrow transplantation was performed, and bone marrow cells were shown to home to damaged skin, to produce type VII collagen and anchoring fibrils. Skin fragility was improved and lethality was reduced. Based on this study, a first clinical trial has been launched in the USA (http://clinicaltrials.gov/show/ NCT00478244; http://cumc.columbia.edu/news/press_ releases/stemcell-collagen-vii-RDEB-angela-christiano. html). While results look promising in one patient who had a perfect HLA-matched donor, several key points need to be addressed before this strategy can be extended to other patients: how effective is the treatment, would it allow a long-term correction, which bone marrow-derived

Skin Gene and Cell Therapy

stem cells are able to home to the skin and to synthesize type VII collagen? There are also concerns about safety of BMT in EB patients, because of the fragility of their general condition, the consequences of immune suppression on the development of infections and cancer formation. This procedure is also associated with several side-effects and it has been estimated that almost half the SCID patients treated by allogeneic haematopoietic stem cell transplantation have experienced one or more significant clinical events, including persistent chronic graft-versus-host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, chronic human papillomavirus (HPV) infections, and a requirement for nutritional support [88].

Strategy at the protein level Following the first treatment for type I diabetes using purified bovine insulin by Frederik Banting and John Macleod (Nobel Prize 1923), the use of purified then recombinant protein injections to treat human diseases including genetic disorders (pituitary dwarfism, ADASCID, Gaucher and Fabry disease) has continued to develop. However, such protein substitution treatments usually involve administration of circulating hormones or enzymes, and this approach for the treatment of a protein scaffold defect is more challenging. Chen and co-workers have demonstrated functional correction for up to 3 months after intradermal injection of purified recombinant type VII collagen RDEB reconstructed skin grafted onto nude mice [89] and later after systemic injections into Col7a1 knockout mice [90]. The injected recombinant type VII collagen moved to the dermal-epidermal junction and generated anchoring fibrils at that location and enhanced knockout mice survival. This set of experiments suggests that protein therapy may be a very attractive alternative to gene therapy for RDEB. Should type VII collagen be a relatively stable molecule, the quantity of recombinant protein needed and the turnover of anchoring fibrils are currently unknown. Therefore the density, protein quantity and frequency at which injections should be repeated remain to be established. This approach is also under development for JEB, with a defect in the β3 subunit of laminin 5. Recombinant laminin 5 transfection into cultured JEB keratinocyte allowed for the correct localization of the laminin 332 protein as demonstrated by Western blot experiments and organotypic human JEB skin reconstructs [91]. It could also be speculated that the specific elimination of the mutant protein might be a way to cure a disease. In the case of a mutation inducing a specific tertiary or quaternary structure of the mutant protein, progress in molecular design could in the future produce compounds

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that are able to specifically sequestrate or destroy mutant proteins.

The skin as an efficient secretory bioreactor Although the epidermis primarily functions as a barrier between the organism and the environment, epidermal keratinocytes also secrete a variety of proteins that have diverse roles in epidermal physiology. A study of stratified keratinocyte culture estimated that nearly 70 proteins were secreted into the medium [92]. There is also evidence that keratinocytes secrete proteins that reach the central circulation. One of the first studies of the secretory function of keratinocytes was carried out by Taichman and colleagues [93]. They first monitored secretion of apopoliprotein E (apoE) in cultured human keratinocytes. After grafting human keratinocytes onto athymic mice and rats, they detected human apoE in the systemic circulation of graft-bearing animals, as long as the graft remained on the animals [94]. These results showed that proteins as large as apoE (299 amino acids) can cross the epidermal–dermal barrier and reach the systemic circulation. Once it was established that proteins secreted in the epidermis could reach the central circulation, genetically modified keratinocytes were used to test whether such cells could deliver transgene products into the bloodstream. For example, two forms of apoE, both the endogenous human apoE and a recombinant form from transfected vector, were detected in the serum of athymic mice bearing grafts of modified human keratinocytes [95]. On the basis of their proliferative capacity and the proven value of cultured keratinocytes for skin wound coverage, autologous grafts of genetically engineered keratinocytes have been proposed as a suitable vehicle to correct deficiencies in circulating proteins. Previous studies have shown that the product of exogenous genes such as growth hormones, factor IX, interleukin 6, leptin and transferrin can reach the blood circulation after being synthesized, processed and secreted by genes transferred to human epidermal cells [96–100]. When human keratinocytes in culture were transduced with a retroviral vector carrying the gene coding for factor IX, they secreted active factor IX into the medium and when they were grafted onto nude mice, small quantities of factor IX were detected in the bloodstream [96]. Similar observations were made of human keratinocytes carrying a human growth hormone transgene [98,100,101]. In more recent experiments, not only were the transgene products detected in the serum, but the physiological effects of the transgene were observed. When an vector expressing IL-10 was injected into the dorsal skin of hairless rats, IL-10 was detected in the central circulation, and it displayed its function of inhibiting contact hypersensitivity at distant areas of the skin [102]. In

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another study, skin explants from transgenic mice overexpressing leptin were grafted onto immunodeficient ob/ ob mice, whose phenotype includes obesity, diabetes and infertility. One month later, the bodyweight of these mice had fallen to values found in lean animals while all the other biochemical and clinical parameters were also normalized [97]. Not only can the keratinocytes can be used to deliver a gene product to the systemic circulation: the results of grafting skin fibroblasts expressing erythropoietin in a variety of non-cutaneous visceral tissue sites in animal models of disorders such as mucopolysaccharidosis and anaemia have also been encouraging [103]. Recently, it has been shown that dermal fibroblasts genetically engineered to express the human Lim mineralization protein3 embedded into a biopolymer matrix can efficiently form new bone in a rodent model [104]. In addition to these ex vivo approaches, transgenic mouse studies strongly support the concept of the epidermis as an efficient secretory bioreactor [105,106]. A further boost to cutaneous gene therapy for systemic disorders came from a study of gene therapy for haemophilia A. This disease is a suitable candidate for gene therapy for several reasons: factor VIII is not regulated in response to bleeding, the broad therapeutic index of factor VIII minimizes the risk of overdose, delivery of factor VIII into the bloodstream does not require expression of the gene by a specific organ and even low levels of the protein can be beneficial. Partial correction of haemophilia A in factor VIII-deficient mice was achieved after grafting of factor VIII-expressing mouse skin from a loricrin factor VIII transgenic mouse [107] and, more recently, in a phase I trial, autologous fibroblasts from haemophilia A patients were transfected ex vivo using non-viral methods to express factor VIII [108]. In four out of six patients, plasma levels of factor VIII activity increased following the procedure. The increase in factor VIII activity coincided with a decrease in bleeding, a reduction in the requirment for exogenous factor VIII, or both. In the patient with the highest level of factor VIII activity, the clinical changes lasted approximately 10 months. Thus, cutaneous gene therapy is considered an attractive potential method to correct circulating protein deficiencies, as human keratinocytes can produce and secrete transgene products with systemic action. Protein injection is frequently used to treat peptide hormone deficiencies. Although these proteins can be delivered by this route with good results in some cases [109], the treatment may be compromised by its short duration of action and the need for repetitive daily dosing. Gene therapy is thus an attractive alternative approach for systemic protein delivery, although potential limitations due to protein size and charge are still incompletely understood.

Vaccination The combination of immunization strategies with gene therapy methods constitutes a powerful tool for the purpose of genetic immunization. The cutaneous microenvironment, rich in professional antigen-presenting cells (dendritic cells) and accessory cells capable of initiating and controlling the intensity of specific immune response, makes the skin a unique target for the expression of transgenic antigens. The fact that epidermal and dermal dendritic cells (DCs) can be directly transfected using genetically engineered vectors allows in vivo manipulation of immune responses by modifying the function of these distinctive antigen-presenting cell populations. For this purpose a high-efficiency gene transfer is not required. Despite relatively low levels and relatively short-term gene expression, immunization with plasmid DNA encoding antigenic proteins has been shown to generate effective, protective and therapeutic immune responses. Thus, the use of simple plasmid DNA has several advantages compared with viral vectors: it facilitates simultaneous delivery of multiple genes encoding different antigenic protein epitopes or immunomodulatory molecules to engineer the immune response, and is easier to produce and control. The biosafety of this technique is also greater (see above). After biolistic delivery or intradermal injection of plasmid DNA, a small number of transfected skin-derived DCs present in draining lymph nodes was enough to initiate effective and protective immunity [110–112]. Importantly, transfected cells were present in T-cell areas of local draining nodes as early as 12–24 h after vaccination, confirming that transient transfection of APCs might be sufficient for the purpose of genetic immunization. Directly transfected DCs have been shown to present trangenic peptides through both major histocompatibility complex (MHC) I- and II-restricted pathways [110–114]. Some early-phase clinical vaccination trials in patients with metastatic melanomas have been performed using transient expression of IL-12. IL-12 was expressed from a plasmid injected intratumorally [115] or using intratumoral injection of a recombinant canary pox virus [116] but with limited efficacy. DNA immunization holds great promise for providing safe and inexpensive vaccines for many infectious pathogens.

References 1 Cheng J, Syder AJ, Yu QC, Letai A, Paller AS, Fuchs E. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiationspecific epidermal keratin genes. Cell 1992;70(5):811–19. 2 Rothnagel JA, Dominey AM, Dempsey LD et al. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 1992;257(5073):1128–30.

Skin Gene and Cell Therapy 3 Bonifas JM, Rothman AL, Epstein EH Jr. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science 1991;254(5035):1202–5. 4 Fuchs E, Coulombe P, Cheng J et al. Genetic bases of epidermolysis bullosa simplex and epidermolytic hyperkeratosis. J Invest Dermatol 1994;103(5 suppl):25S–30S. 5 Rothnagel JA, Fisher MP, Axtell SM et al. A mutational hot spot in keratin 10 (KRT 10) in patients with epidermolytic hyperkeratosis. Hum Mol Genet 1993;2(12):2147–50. 6 Aberdam D, Galliano MF, Vailly J et al. Herlitz’s junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/kalinin (LAMININ-5). Nat Genet 1994;6(3):299–304. 7 Baudoin C, Miquel C, Gagnoux-Palacios L et al. A novel homozygous nonsense mutation in the LAMC2 gene in patients with the Herlitz junctional epidermolysis bullosa. Hum Mol Genet 1994;3(10):1909–10. 8 McGrath JA, Gatalica B, Christiano AM et al. Mutations in the 180kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa. Nat Genet 1995;11(1):83–6. 9 Mellerio JE, Denyer JE, Atherton DJ, Eady RA, McGrath JA. Prognostic implications of determining 180 kDa bullous pemphigoid antigen (BPAG2) gene/protein pathology in neonatal junctional epidermolysis bullosa. Br J Dermatol 1998;138(4):661–6. 10 Pulkkinen L, Christiano AM, Airenne T, Haakana H, Tryggvason K, Uitto J. Mutations in the gamma 2 chain gene (LAMC2) of kalinin/ laminin 5 in the junctional forms of epidermolysis bullosa. Nat Genet 1994;6(3):293–7. 11 Ruzzi L, Gagnoux-Palacios L, Pinola M et al. A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia. J Clin Invest 1997;99(12):2826–31. 12 Vidal F, Aberdam D, Miquel C et al. Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet 1995;10(2):229–34. 13 Vidal F, Baudoin C, Miquel C et al. Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics 1995;30(2):273–80. 14 Pulkkinen L, Christiano AM, Gerecke D et al. A homozygous nonsense mutation in the beta 3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa. Genomics 1994;24(2):357–60. 15 Vailly J, Pulkkinen L, Miquel C et al. Identification of a homozygous one-basepair deletion in exon 14 of the LAMB3 gene in a patient with Herlitz junctional epidermolysis bullosa and prenatal diagnosis in a family at risk for recurrence. J Invest Dermatol 1995; 104(4):462–6. 16 Dellambra E, Pellegrini G, Guerra L et al. Toward epidermal stem cell-mediated ex vivo gene therapy of junctional epidermolysis bullosa. Hum Gene Ther 2000;11(16):2283–7. 17 Varki R, Sadowski S, Uitto J, Pfendner E. Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet 2007;44(3):181–92. 18 Brittingham R, Uitto J, Fertala A. High-affinity binding of the NC1 domain of collagen VII to laminin 5 and collagen IV. Biochem Biophys Res Commun 2006;343(3):692–9. 19 D’Alessandro M, Morley SM, Ogden PH, Liovic M, Porter RM, Lane EB. Functional improvement of mutant keratin cells on addition of desmin: an alternative approach to gene therapy for dominant diseases. Gene Ther 2004;11(16):1290–5. 20 Magin TM, Kaiser HW, Leitgeb S et al. Supplementation of a mutant keratin by stable expression of desmin in cultured human EBS keratinocytes. J Cell Sci 2000;113(Pt 23):4231–9.

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Skin Gene and Cell Therapy 82 Ortiz-Urda S, Lin Q, Yant SR, Keene D, Kay MA, Khavari PA. Sustainable correction of junctional epidermolysis bullosa via transposon-mediated nonviral gene transfer. Gene Ther 2003;10(13): 1099–104. 83 Woodley DT, Remington J, Huang Y et al. Intravenously injected human fibroblasts home to skin wounds, deliver type VII collagen, and promote wound healing. Mol Ther 2007;15(3):628–35. 84 Wong T, Gammon L, Liu L et al. Potential of fibroblast cell therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol 2008;128(9):2179–89. 85 Kern JS, Loeckermann S, Fritsch A et al. Mechanisms of fibroblast cell therapy for dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity. Mol Ther 2009;17(9): 1605–15. 86 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(3):803–14. 87 Tolar J, Ishida-Yamamoto A, Riddle M et al. Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells. Blood 2009;113(5):1167–74. 88 Neven B, Leroy S, Decaluwe H et al. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood 2009;113(17):4114–24. 89 Woodley DT, Keene DR, Atha T et al. Injection of recombinant human type VII collagen restores collagen function in dystrophic epidermolysis bullosa. Nat Med 2004;10(7):693–5. 90 Remington J, Wang X, Hou Y et al. Injection of recombinant human type VII collagen corrects the disease phenotype in a murine model of dystrophic epidermolysis bullosa. Mol Ther 2009;17(1):26–33. 91 Igoucheva O, Kelly A, Uitto J, Alexeev V. Protein therapeutics for junctional epidermolysis bullosa: incorporation of recombinant beta3 chain into laminin 332 in beta3-/- keratinocytes in vitro. J Invest Dermatol 2008;128(6):1476–86. 92 Katz AB, Taichman LB. A partial catalog of proteins secreted by epidermal keratinocytes in culture. J Invest Dermatol 1999;112(5): 818–21. 93 Gordon DA, Fenjves ES, Williams DL, Taichman LB. Synthesis and secretion of apolipoprotein E by cultured human keratinocytes. J Invest Dermatol 1989;92(1):96–9. 94 Fenjves ES, Gordon DA, Pershing LK, Williams DL, Taichman LB. Systemic distribution of apolipoprotein E secreted by grafts of epidermal keratinocytes: implications for epidermal function and gene therapy. Proc Natl Acad Sci USA 1989;86(22):8803–7. 95 Fenjves ES, Smith J, Zaradic S, Taichman LB. Systemic delivery of secreted protein by grafts of epidermal keratinocytes: prospects for keratinocyte gene therapy. Hum Gene Ther 1994;5(10):1241–8. 96 Gerrard AJ, Hudson DL, Brownlee GG, Watt FM. Towards gene therapy for haemophilia B using primary human keratinocytes. Nat Genet 1993;3(2):180–3. 97 Larcher F, del Rio M, Serrano F et al. A cutaneous gene therapy approach to human leptin deficiencies: correction of the murine ob/ ob phenotype using leptin-targeted keratinocyte grafts. Faseb J 2001;15(9):1529–38. 98 Morgan JR, Barrandon Y, Green H, Mulligan RC. Expression of an exogenous growth hormone gene by transplantable human epidermal cells. Science 1987;237(4821):1476–9. 99 Petersen MJ, Kaplan J, Jorgensen CM et al. Sustained production of human transferrin by transduced fibroblasts implanted into athymic mice: a model for somatic gene therapy. J Invest Dermatol 1995;104(2):171–6. 100 Teumer J, Lindahl A, Green H. Human growth hormone in the blood of athymic mice grafted with cultures of hormone-secreting human keratinocytes. Faseb J 1990;4(14):3245–50.

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101 Jensen UB, Jensen TG, Jensen PK et al. Gene transfer into cultured human epidermis and its transplantation onto immunodeficient mice: an experimental model for somatic gene therapy. J Invest Dermatol 1994;103(3):391–4. 102 Meng X, Sawamura D, Tamai K, Hanada K, Ishida H, Hashimoto I. Keratinocyte gene therapy for systemic diseases. Circulating interleukin 10 released from gene-transferred keratinocytes inhibits contact hypersensitivity at distant areas of the skin. J Clin Invest 1998;101(6):1462–7. 103 Naffakh N, Henri A, Villeval JL et al. Sustained delivery of erythropoietin in mice by genetically modified skin fibroblasts. Proc Natl Acad Sci USA 1995;92(8):3194–8. 104 Lattanzi W, Parrilla C, Fetoni A et al. Ex vivo-transduced autologous skin fibroblasts expressing human Lim mineralization protein-3 efficiently form new bone in animal models. Gene Ther 2008;15(19):1330–43. 105 Alexander MY, Bidichandani SI, Cousins FM, Robinson CJ, Duffie E, Akhurst RJ. Circulating human factor IX produced in keratinpromoter transgenic mice: a feasibility study for gene therapy of haemophilia B. Hum Mol Genet 1995;4(6):993–9. 106 Wang X, Zinkel S, Polonsky K, Fuchs E. Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy. Proc Natl Acad Sci USA 1997;94(1):219–26. 107 Fakharzadeh SS, Zhang Y, Sarkar R, Kazazian HH Jr. Correction of the coagulation defect in hemophilia A mice through factor VIII expression in skin. Blood 2000;95(9):2799–805. 108 Roth DA, Tawa NE Jr, O’Brien JM, Treco DA, Selden RF. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med 2001;344(23):1735–42. 109 Farooqi IS, Jebb SA, Langmack G et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341(12):879–84. 110 Akbari O, Panjwani N, Garcia S, Tascon R, Lowrie D, Stockinger B. DNA vaccination: transfection and activation of dendritic cells as key events for immunity. J Exp Med 1999;189(1):169–78. 111 Condon C, Watkins SC, Celluzzi CM, Thompson K, Falo LD Jr. DNAbased immunization by in vivo transfection of dendritic cells. Nat Med 1996;2(10):1122–8. 112 Porgador A, Irvine KR, Iwasaki A, Barber BH, Restifo NP, Germain RN. Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization. J Exp Med 1998;188(6):1075–82. 113 Bouloc A, Walker P, Grivel JC, Vogel JC, Katz SI. Immunization through dermal delivery of protein-encoding DNA: a role for migratory dendritic cells. Eur J Immunol 1999;29(2):446–54. 114 Klinman DM, Sechler JM, Conover J, Gu M, Rosenberg AS. Contribution of cells at the site of DNA vaccination to the generation of antigen-specific immunity and memory. J Immunol 1998;160(5):2388–92. 115 Heinzerling L, Burg G, Dummer R et al. Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum Gene Ther 2005;16(1): 35–48. 116 Triozzi PL, Strong TV, Bucy RP et al. Intratumoral administration of a recombinant canarypox virus expressing interleukin 12 in patients with metastatic melanoma. Hum Gene Ther 2005;16(1):91–100. 117 Choate KA, Kinsella TM, Williams ML, Nolan GP, Khavari PA. Transglutaminase 1 delivery to lamellar ichthyosis keratinocytes. Hum Gene Ther 1996;7(18):2247–53. 118 Choate KA, Medalie DA, Morgan JR, Khavari PA. Corrective gene transfer in the human skin disorder lamellar ichthyosis. Nat Med 1996;2(11):1263–7. 119 Freiberg RA, Choate KA, Deng H, Alperin ES, Shapiro LJ, Khavari PA. A model of corrective gene transfer in X-linked ichthyosis. Hum Mol Genet 1997;6(6):927–33.

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120 Dellambra E, Prislei S, Salvati AL et al. Gene correction of integrin beta4-dependent pyloric atresia-junctional epidermolysis bullosa keratinocytes establishes a role for beta4 tyrosines 1422 and 1440 in hemidesmosome assembly. J Biol Chem 2001;276(44):41336–42. 121 Lane EB, Rugg EL, Navsaria H et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 1992 Mar 19;356(6366):244–6. 122 Ryynänen M, Ryynänen J, Sollberg S et al. Genetic linkage of type VII collagen (COL7A1) to dominant dystrophic epidermolysis bullosa in families with abnormal anchoring fibrils. J Clin Invest 1992 Mar;89(3):974–80.

Conclusion Skin gene therapy is a very dynamic field of investigation, with several successful preclinical trials and two success-

ful clinical trials. It is anticipated that the development of various different approaches and, perhaps, their combined use could benefit patients as part of the therapeutic arsenal for the treatment of skin disorders. However, there is room for further progress in the targeting of therapeutic genes to specific cells, in the development of gene therapy approaches that preserve the correct regulation of the transgene, in strategies allowing for the treatment of very large body areas and for the treatment of dominant disorders. Nonetheless, tremendous progress has been made during the last 5 years and skin gene and cell therapy will offer major new possibilities for the treatment of genetic skin disorders as well as nondermatological diseases.

141.1

C H A P T E R 141

Disorders of Fat Tissue Marc Lacour Swiss Group for Pediatric Dermatology, Geneva, Switzerland

PART ONE: DISORDERS WITH INCREASED FAT TISSUE, 141.1 Inherited localized disorders, 141.1 Acquired localized disorders, 141.2

Inherited generalized disorders, 141.9

Inherited partial disorders, 141.14

Acquired generalized disorders, 141.10

Acquired partial disorders, 141.15

PART TWO: DISORDERS WITH DECREASED

Inherited generalized disorders, 141.17

FAT TISSUE 141.10

Acquired generalized disorders, 141.19

Inherited partial disorders, 141.6

Inherited localized disorder, 141.11

Acquired partial disorders, 141.8

Acquired localized disorders, 141.11

A good classification of the disorders of fat tissue is difficult since, over the years, one particular disorder may have been described under different names, i.e. first with the name of the first reporting author (such as Dunnigan’s syndrome), then with the name of its description (familial partial lipodystrophy (FLDP)), later with the name of the pathomechanism involved (lipoatrophic diabetes), and then divided into several subtypes according to its genetic heterogeneity (i.e. FPLD type 1, type 2), with different OMIM numbers). Furthermore, it is etymologically difficult to accept that the term lipodystrophy only encompasses lipoatrophic disorders in the literature and none of the lipohypertrophic disorders. In order to avoid further confusion, this chapter is divided in two: part one focuses on disorders with increased fat tissue and part two addresses disorders with decreased fat tissue. The two parts of the chapter are then similarly divided into inherited and acquired disorders as well as localized, partial (involving several but not all parts of the body) and generalized disorders.

PART ONE: DISORDERS WITH INCREASED FAT TISSUE The classification of lipohypertrophic disorders described in this section is shown in Table 141.1.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Inherited localized disorders Multiple lipomatosis Syn. familial multiple lipomas, hereditary multiple lipomas, multiple cutaneous lipomas, discrete lipomatosis, lipomatose de Roch–Leri

Multiple lipomatosis [1–5] is characterized by the hereditary occurrence of multiple encapsulated lipomas. The disorder was first described by Brodie in 1846 and its familial nature was reported by Blaschko in 1891. With a prevalence of 2 in 100,000, there is no geographic predilection. Clinically, numerous encapsulated lipomas develop during adulthood and usually remain asymptomatic, their diameter rarely exceeding 5 cm. They occur on the mid-level of the body and are predominantly found on the lower arms, forearms, lower chest, abdomen and lumbar region. After a rapid onset lasting 1–2 years, the course of multiple lipomatosis is benign in most cases. The disorder is cytogenetically linked to translocations at 12q14 in the tumours. Differential diagnosis includes steatocystoma multiplex (cystic lesions), familial multiple angiolipomas (histologically different) [6], Dercum disease (painful lesions) and familial benign cervical lipomatosis. The French literature also reports the segmental lipomatosis of Touraine and Renault (1938), which consists of multiple encapsulated lipomas but is differentiated by its metameric distribution. Treatment requires surgical removal of functionally or aesthetically troublesome lipomas.

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Chapter 141

Table 141.1 Classification of disorders with increased fat tissue (lipohypertrophies) Inherited

Acquired

Localized

Familial multiple lipomatosis

Lipoma Lipoblastoma Hibernoma Lipoma variants

Partial

Encephalocraniocutaneous lipomatosis PTEN hamartoma tumour syndromes (Launois-Bensaude, Cowden, Banayan– Riley–Ruvalcaba, Proteus syndromes) Gardner syndrome

Multiple symmetric lipomatosis

Generalized

Genetic disorders with obesity (Prader–Willi, Alstrom syndrome, etc.)

Obesity

References 1 Leffell DJ, Braverman IM. Familial multiple lipomatosis. J Am Acad Dermatol 1986;15:275–9. 2 Stephens FE, Isaacson A. Hereditary multiple lipomatosis. J Hered 1959;50:51–3. 3 Golsch S, Worret WI. Familial multiple lipomatosis with polyneuropathy. Eur J Dermatol 1995;5:283–5. 4 Schoenmakers EPPM, Wanshura S, Mols R et al. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet 1995;10:436–44. 5 Abensour M, Jeandel C, Heid E. Lipomes et lipomatoses cutanés. Ann Dermatol Vénéréol 1987;114:873–82. 6 Kumar R, Pereira BJ, Sakhuja V et al. Autosomal dominant inheritance in familial angiolipomatosis. Clin Genet 1989;35:202–4.

Acquired localized disorders ‘Solitary’ lipoma Definition. Solitary lipomas are benign tumours of mature adipocytes with an ubiquitous localization. Classically they are well circumscribed and develop slowly. Aetiology. Lipomas are common connective tissue tumours, representing 25–50% of all soft tissue masses [1] and 80% of all lipomatous tumours [2]. They occur rarely in the first two decades of life and most often appear between 30 and 60 years. There is no ethnic predisposition. The pathogenesis of subcutaneous lipomas remains obscure except in a few situations: post trauma [3,4]; diabetes and obesity; and a genetic predisposition (familial multiple lipomatosis). Similarly, the origin of visceral lipomas remains obscure in most cases except for the development of epidural lipomatosis following prolonged corticosteroid treatment [5,6]. Probably the most interesting finding in recent years is the extremely high incidence of chromosomal abnormalities in lipomatous tumours [7]. Of 93 subcutaneous and

intramuscular lipomas, 80% were shown to harbour specific karyotypic aberrations affecting mainly 12 q, 6 p and 13 q. Other distinct karyotypic abnormalities were found in other types of lipomatous tumours. If such a specificity is confirmed, karyotype analysis of lipomas and related tumours may become a valuable diagnostic and prognostic tool. Histopathology. Lipomas are usually composed of univacuolated mature adipocytes, the nucleus of which is compressed in the cellular periphery. These features are indistinguishable from adult adipose tissue. Tumours are encapsulated by fibrous tissue and may be uni- or multilobulated. Adipocytes and lobules are thinly divided by a rich vasculature. Degenerative features within the tumour are frequent, and so are foci of fibrous tissue, such as in cervical fibrolipoma [8]. Histological variants are discussed below. Clinical features. Two main groups of lipomas can be defined according to their localization: superficial or cutaneous lipomas, which will be reviewed here, and deeply located lipomas. The latter can arise in any visceral localization such as the anterior mediastinum, bones, brain, retroperitoneal area and periarticular regions. Superficial lipomas appear as a painless subcutaneous mass that develops slowly, reaching a size up to 20 cm. Typically, the tumour is soft and freely mobile and the overlying skin remains perfectly normal. Most lipomas are found (in descending order of frequency) on the neck, scapular regions, back, abdomen, buttocks and upper thighs. More rarely, they can occupy the scalp, face or extremities. Individuals may develop one or multiple lesions. Giant lipomas can occur in children [9] but are more common in adulthood, reaching between 4.5 and as much as 58.5 kg [10]. Congenital lumbosacral lipomas are often linked with spinal dysraphism [11,12]. They are predominantly found in girls and show a bimodal distribution of age at presentation with peaks at 0–2 and 7–8 years [13]. In a series of 200 patients with spinal dysraphism, 41 had subcutaneous lipomas in the lumbosacral region, and intracanal extension of the lipoma was seen in all of them [14]. Similarly, 75% of 73 patients with intraspinal lipomas were found to have a subcutaneous lipoma [15]. Lipomas can also reveal other types of spinal abnormalities, such as filum terminale with tethered conus and hydrosyringomyelia [12,16]. Lumbosacral lipomas have specific histological features, including lack of capsule, large amounts of fibrous tissue and a variety of ectopic neuroectodermal and mesodermal tissue. This association should be suspected in even minute bulging over the lower spine in a neonate [17]. Rarely, the lipoma may not develop before

Disorders of Fat Tissue

puberty [18]. Treatment is surgical after a careful neurological assessment and magnetic resonance imaging (MRI) scan [19] and formal urological assessment [13]. Diagnosis. Clinical findings are usually sufficient to give a diagnosis of subcutaneous lipoma. In difficult cases in children, Doppler-coupled ultrasonography (exclusion of vascular tumour), MRI scan (presence of fat) and fine needle aspiration (histology) will confirm the diagnosis [20,21]. When presented with a child with an unusual lipoma (localization, number, shape, size), one should be careful to exclude associated syndromes (see below). The differential diagnosis of a subcutaneous soft tissue mass appearing in childhood or adolescence is quite large (see Chapter 92). Treatment. Most lipomas found in children are small, slow growing and of little cosmetic significance. They can be left alone. If necessary, surgical excision with minimal incision on the skin or liposuction are both effective, provided that a skilled hand carefully removes all the tumoral tissue to avoid recurrence [22–27].

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minority of diffuse lipoblastomatosis. Almost all cases presented before the age of 3 years. Predominantly involved sites are the trunk, extremities, and head and neck region. Mediastinal and abdominal lipoblastomas have also been reported [35,38]. Typically, lipoblastoma consists of a rapidly enlarging subcutaneous tumour, usually soft and painless. As opposed to common lipomas, which are extremely rare in this age group, the tumour rapidly becomes less mobile and so large that it interferes with local structures. Despite the infiltrating nature of the lipoblastomatosis form, malignant transformation of the disorder has never been reported. Local regrowth can occur after surgery, usually within the first two postoperative years. Diagnosis and treatment. A clinical diagnosis of lipoma is insufficient in this age group and all subcutaneous masses must be investigated. MRI has the advantage of confirming a mass of adipose tissue and delineating the extent of the infiltrating forms [39]. Fine needle aspiration or needle biopsy gives an accurate diagnosis [20,40]. Conservative excision should be carefully planned in order to remove the lesion in toto, therefore avoiding recurrence.

Lipoblastoma and lipoblastomatosis Definition. Lipoblastomas are rare tumours of adipocytes and their mesenchymal precursor cells, which occur almost exclusively in early childhood. The term lipoblastoma is reserved for the common type in which the tumour is well encapsulated. Lipoblastomatosis represents the diffuse infiltrating variety that is more difficult to resect completely [28–33]. Both types always remain benign and in view of this absence of malignant transformation, the term infantile lipoma has been suggested [34]. Aetiology. These lesions probably represent persistence or reactivation of fetal fat proliferation in the postnatal period. Tumoral transformation is likely as most cases harbour a rearrangement of chromosome 8q11–q13 [7,35–37]. Histology. A lipoblastoma consists of mature adipocytes, lipoblasts and prelipoblasts arranged in a lobulated pattern and separated by loose fibrous connective tissue, thus recapitulating developing fat. Peripherally, spindleshaped tumour cells (precursors) can be found in increased numbers. The histological picture may also show a striking similarity to myxoid liposarcoma, a malignancy that affects older individuals and shows pleiomorphism, atypical lipoblasts and chromosome 12 translocation [20]. Clinical features. More than 100 cases have been reported, with a majority of circumscribed lipoblastomas and a

Hibernoma Syn. fetal lipoma, embryonary fat lipoma, granular cell lipoma

Definition. The term hibernoma was proposed in 1914 by Gery [41] to describe tumours derived from brown fat or embryonary fat. Aetiology. Brown fat is a specialized form of adipose tissue that is prominent in hibernating animals. In these animals, brown fat mostly consists of two symmetrical masses on either side of the midline between the scapulae, and is thought to serve as a heat-producing tissue. Pathologically, hibernomas are tumours of brown fat. Karyotypic abnormalities (on 11 q) have been reported [7]. Histopathology. The tumour is usually well encapsulated, being yellow-brown to red in colour. This brown tan is due to increased vascularization, which also causes the tumour to be warm. The tumour mass consists of round cells with a multivacuolated or granular cytoplasm and central nuclei. Clinical features. Hibernomas are well-defined mobile, rather hard, painless and often warm subcutaneous nodules of 5–10 cm in diameter. Their elective localization is between the scapulae, but they can occur in the head

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and neck [42–44], thigh [45] or, rarely, mediastinal region. In a series of 67 patients, median age at diagnosis was 33 years with a female predominance [46]. In another report with 170 cases, median age was 38 years with a male predominance, the most common site being the thigh [47]. Hibernomas reported in children are few [48]. The youngest patient was 6 weeks old [49]. Another child’s lesion was unusually superficial [50]. The tumour is unlikely to be clinically diagnosed as it often presents as a benign lipoma. Thus, diagnosis has been histological in most reports. Treatment is surgical. Complications from local compression of the surrounding structures can occur. Malignant transformation has been reported only once.

Lipoma variants These include angiolipomas [51,52], chondroid lipomas [53], adenolipomas [54], spindle cell lipomas [55,56], pleiomorphic lipomas [57,58], liposarcomas [59–62], and angiomyolipomas [63–66]. These can occur in children, but mostly arise in adulthood. Cytogenetic analysis shows that most of these tumours harbour specific karyotypic abnormalities [7]. Angiomyolipoma is a rare benign vascular tumour that is almost exclusively found in the kidneys and in association with tuberous sclerosis. Skin angiomyolipomas are exceedingly rare, with a male predominance in adults and not linked with tuberous sclerosis [64–66].

Localized fat hypertrophy due to insulin therapy Insulin therapy in diabetes mellitus may result in local or systemic allergic cutaneous reactions, as well as fat hypertrophy and fat atrophy at sites of injections [67,68]. The prevalence of these reactions overall decreased, but did not disappear, with the introduction of highly purified bovine/pork insulins and recombinant human insulins [69,70]. Lipohypertrophy follows repeated insulin injections at the same site and is characterized by painless, soft and boggy masses progressively enlarging over several years. It was found in over 20% of diabetic patients having regular insulin injections and, as opposed to insulin lipoatrophy, its prevalence remained above 20% with the introduction of purified insulins [67,71]. Children can be affected. Most patients with lipohypertrophy admit to restricting their injections to anatomically small regions. This is partly due to the fact that the localized swelling is more convenient to aim at and is less painful for injection. Another reason is that restricting injections to one area may result in better metabolic control, as the absorption of insulin varies between anatomical sites [72]. Histologically, the dermis and epidermis are unaltered and the subcutaneous tissue consists of enlarged adipocytes [73].

This lipohypertrophy is regarded as due to a local anabolic effect of insulin, which promotes fat and protein synthesis. The main factor appears to be the constant injections at the same site, rather than the type of insulin. Indeed, all forms of insulin (soluble, isophane, zinc suspension) can cause lipohypertrophy [67,74]. Marked improvement usually follows a switch to human insulin or to insulin lispro [75], and careful rotation of injection sites [73]. Liposuction can be effective in refractory cases [76]. References 1 Rydholm A, Berg NO. Size, site and clinical incidence of lipoma. Acta Orthop Scand 1983;54:929–34. 2 Enzinger FM, Weiss SW. Soft Tissue Tumors. St Louis, MO: C.V. Mosby, 1983. 3 Penoff JH. Traumatic lipomas: pseudolipomas. J Traumatol 1982;22: 63–5. 4 Meggit BF. The battered buttock syndrome. A report of a group of traumatic lipoma. Br J Surg 1972;59:165–9. 5 Crayton HE, Partington CR, Bell CL. Spinal cord compression by epidural lipomatosis in a patient with systemic lupus erythematosus. Arthritis Rheum 1992;35:482–4. 6 Arroyo IL, Barron KS, Brewer EJ Jr. Spinal cord compression by epidural lipomatosis in juvenile rheumatoid arthritis. Arthritis Rheum 1988;31:447–51. 7 Fletcher CDM, Akerman M, Dal Cin P et al. Correlation between clinicopathological features and karyotype in lipomatous tumors. Am J Pathol 1996;148:623–30. 8 Abensour M, Jeandel C, Heid E. Lipomes et lipomatoses cutanés. Ann Dermatol Vénéréol 1987;114:873–82. 9 N’Diaye B, Guiraud M, Kane A et al. Naevus lipomateux tumoral. A propos d’un cas. Ann Dermatol Vénéréol 1984;111:737–8. 10 Sanchez MR, Golomb FM, Moy JA et al. Giant lipoma: case report and review of the literature. J Am Acad Dermatol 1993;28:266–8. 11 Serna MJ, Vazquez Doval J, Vanaclocha V et al. Occult spinal dysraphism: a neurosurgical problem with a dermatologic hallmark. Pediatr Dermatol 1993;10:149–52. 12 Finn MA, Walker ML. Spinal lipomas: clinical spectrum, embryology, and treatment. Neurosurg Focus 2007;23(2): 1–12. 13 Dorward NL, Scatliff JH, Hayward RD. Congenital lumbosacral lipomas: pitfalls in analysing the results of prophylactic surgery. Child Nerv Syst 2002;18:326–32. 14 Tavafoghi V, Ghandchi A, Hambrick GW Jr et al. Cutaneous signs of spinal dysraphism. Arch Dermatol 1978;114:573–7. 15 Pierre-Kahn JW, Lacombe J, Pichon J et al. Intraspinal lipomas with spina bifida. Prognosis and treatment in 73 cases. J Neurosurg 1986;67:756–61. 16 Davis DA, Cohen PR, George RE. Cutaneous stigmata of occult spinal dysraphism. J Am Acad Dermatol 1994;31:892–6. 17 Bodemer C, Durand C, Brunel F et al. Lipome sous-cutané révélateur d’un lipome intradural. Ann Dermatol Vénéréol 1988;115:1130–2. 18 Ryan TJ, Curri SB. Hypertrophy and atrophy of fat. Clin Dermatol 1989;7:93–106. 19 Hakuba A, Fujitani K, Hoda K et al. Lumbosacral lipoma, the timing of the operation and morphological classification. Neuroorthopedics 1986;2:34–42. 20 Leon ME, Deschler D, Wu SS et al. Fine needle aspiration diagnosis of lipo-blastoma of the parotid region. A case report. Acta Cytol 2002;46:395–404. 21 Boothroyd AE, Carty H. The painless soft tissue mass in childhood: tumour or not? Postgrad Med J 1995;71:10–16.

Disorders of Fat Tissue 22 Kenawi MM. ‘Squeeze delivery’ excision of subcutaneous lipoma related to anatomic site. Br J Surg 1995;82:1649–50. 23 Monfrecola G, Riccio G, Viola L et al. A simple cryo-technique for the treatment of cutaneous soft fibromas. J Dermatol Surg Oncol 1994;20:151–2. 24 Sharma PK, Janniger CK, Schwartz RA et al. The treatment of atypical lipoma with liposuction. J Dermatol Surg Oncol 1991;17:332–4. 25 Apesos J, Chami R. Functional applications of suction-assisted lipectomy: a new treatment for old disorders. Aesthetic Plast Surg 1991;15:73–9. 26 Pinski KS, Roenigk HH Jr. Liposuction of lipomas. Dermatol Clin 1990;8:483–92. 27 Spinowitz AL. The treatment of multiple lipomas by liposuction surgery. J Dermatol Surg Oncol 1989;15:538–40. 28 Chung EB, Enzinger FM. Benign lipoblastomas: an analysis of 35 cases. Cancer 1973;32:482–92. 29 Federici S, Cuoghi D, Sciutti R. Benign mediastinal lipoblastoma in a 14-month-old infant. Pediatr Radiol 1992;22:150–1. 30 Jimenez JF. Lipoblastoma in infancy and childhood. J Surg Oncol 1986;32:238–44. 31 Stringel G, Shandling B, Mancer K et al. Lipoblastoma in infants and children. J Pediatr Surg 1982;17:277–80. 32 Harrer J, Hammon G, Wagner T et al. Lipoblastoma and lipoblastomatosis: a report of two cases and review of the literature. Eur J Pediatr Surg 2001;11:342–9. 33 Chien AL, Song DH, Stein SL. Two young girls with lipoblastoma and a review of the literature. Pediatr Dermatol 2006;23:152–6. 34 O’Donnell KA, Caty MG, Allen JE et al. Lipoblastoma: better termed infantile lipoma? Pediatr Surg Int 2000;16:458–61. 35 Hicks J, Dilley A, Patel D et al. Lipoblastoma and lipoblastomatosis in infancy and childhood: histopathologic, ultrastructural, and cytogenetic features. Ultrastruct Pathol 2001;25:321–3. 36 Orui H, Ishikawa A, Kanazawa M et al. Lipoblastoma with aberration in the long arm of chromosome 8. J Orthop Sci 2000;407–10. 37 Moriro C, Panarello C, Russo I et al. A further case of chromosome 8 q rearrangement in lipoblastoma. J Pediatr Hematol Oncol 2000;22:484–5. 38 Whyte AM, Powell N. Case report: mediastinal lipoblastoma in infancy. Clin Radiol 1990;42:205–6. 39 Norton KI, Glajchen N, Dolgin SE. Magnetic resonance appearance in a case of lipoblastomatosis. Pediatr Surg Int 1996;11:286–7. 40 Ching AS, Lee SF, Chan YL. Diagnosing paediatric mediastinal lipoblastoma using ultrasound-guided percutaneous needle biopsy: review and report. Clin Imaging 2002;26:23–6. 41 Gery L. Discussion. Bull Mem Soc Anat Paris 1914;89:110–11. 42 Wilhelm KP, Eisenbeiss W, Wolff HH. Hibernoma of the forehead. Hautarzt 1993;44:735–7. 43 Abemayor E, McClean P, Cobb CJ et al. Hibernomas of the head and neck. Head Neck Surg 1987;9:362–7. 44 Muszynski CA, Robertson DP, Goodman JC et al. Scalp hibernoma, case report and literature review. Surg Neurol 1994;42:343–5. 45 Merlino AF, Pike RF. Hibernoma of the thigh. A case report. J Bone Joint Surg 1973;55:406–8. 46 McLane RC, Meyer LC. Axillary hibernoma: review of the literature with report of a case examined angiographically. Radiology 1978;127:673–4. 47 Furlong MA, Fanburg-Smith JC, Miettinen M. The morphologic spectrum of hibernoma: a clinicopathological study of 170 cases. Am J Surg Pathol 2001;25:809–14. 48 Ahmed SH, Schuller I. Pediatric hibernoma. A case review. J Pediatr Hematol Oncol 2008;30:900–1. 49 Cox RW. ‘Hibernoma’: the lipoma of immature adipose tissue. J Pathol Bact 1954;68:511–24. 50 Bonifazi E, Meneghini CL. A case of hibernoma in a child. Dermatologica 1982;165:647–52.

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51 Belcher RW, Czarnetzki BM, Carnery JF et al. Multiple (subcutaneous) angiolipomas. Arch Dermatol 1974;110:583–5. 52 Shea CR, Prieto VG. Mast cells in angiolipomas and hemangiomas of human skin: are they important for angiogenesis? J Cutan Pathol 1994;21:247–51. 53 Patne SC, Aryya NC, Gangopadhyay AN. Chondroid lipoma in a child. Indian J Pathol Microbiol 2008;51:541–2. 54 Del Agua C, Felipo F. Adenolipoma of the skin. Dermatol Online J 2004;10:9. 55 Eckert F, Landthaler M, Braun Falco O. Spindle cell lipoma. Hautarzt 1989;40:161–3. 56 Billings SD, Folpe AL. Diagnostically challenging spindle cell lipomas: a report of 34 ‘low-fat’ and ‘fat-free’ variants. Am J Dermatopathol 2007;29:437–42. 57 Nigro MA, Chieregato GC, Querci della Rovere G. Pleomorphic lipoma of the dermis. Br J Dermatol 1987;116:713–17. 58 Shitabata PK, Ritter JH, Fitzgibbon JF et al. Pleomorphic hamartoma of the subcutis: a lesion with possible myogenous and neural lineages. J Cutan Pathol 1995;22:269–75. 59 Enzinger FM, Winslow DJ. Liposarcoma. A study of 103 cases. Virchows Arch Pathol Anat 1962;335:367–88. 60 Mrozek K, Karakousis CP, Bloomfield CD. Chromosome 12 breakpoints are cytogenetically different in benign and malignant lipogenic tumors: localization of breakpoints in lipoma to 12q15 and in myxoid liposarcoma to 12q13. Cancer Res 1993;53:1670–5. 61 Dei Tos AP. Liposarcoma: new entities and evolving concepts. Ann Diagn Pathol 2000;4:252–66. 62 Dalal KM, Antonescu CR, Singer S. Diagnosis and management of lipomatous tumours. J Surg Oncol 2008;97:298–313. 63 Winterkorn EB, Daouk GH, Anupindi S et al. Tuberous sclerosis complex and renal angyomyolipoma: case report and review of the literature. Pediatr Nephrol 2006;21:1189–93. 64 Debloom JR, Friedrichs A, Swick BL et al. Management of cutaneous angiomyolipoma and its association with tuberous sclerosis. J Dermatol 2006;33:783–6. 65 Mehregan DA, Mehregan DR, Mehregan AH. Angiomyolipoma. J Am Acad Dermatol 1992;27:331–3. 66 Rodriguez Fernandez A, Caro Mancilla A. Cutaneous angiomyolipoma with pleomorphic changes. J Am Acad Dermatol 1993;29: 115–16. 67 McNally PG, Jowett NI, Kurinczuk JJ et al. Lipohypertrophy and lipoatrophy complicating treatment with highly purified bovine and porcine insulins. Postgrad Med J 1988;64:850–3. 68 Plantin P, Sassolas B, Guillet MH et al. Accidents cutanés allergiques aux insulines. Ann Dermatol Vénéréol 1988;115:813–17. 69 Payne R, Williams C, Wilson IV. True delayed pressure urticaria induced by human Monotard insulin. Br J Dermatol 1996;134:184. 70 Goldman JM, Wheeler MF. Lipodystrophy from recombinant DNA human insulin. Am J Med 1987;83:195–6. 71 Young RJ, Steel JM, Frier BM et al. Insulin injection sites in diabetes: a neglected area? BMJ 1981;283:349. 72 Koivisto VA, Felig P. Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients. Ann Intern Med 1980;92:59–61. 73 Samadaei A, Hashimoto K, Tanay A. Insulin lipodystrophy, lipohypertrophic type. J Am Acad Dermatol 1987;17:506–7. 74 Meier A, Weerakoon J, Dandona P. Bilateral abdominal lipohypertrophy after continuous subcutaneous infusion of insulin. BMJ 1982;285:1539. 75 Roper NA, Bilous RW. Resolution of lipohypertrophy following change of short-acting insulin to insulin lispro (Humalog). Diabet Med 1998;15:1063–4. 76 Field LM. Successful treatment of lipohypertrophic insulin lipodystrophy with liposuction surgery (letter). J Am Acad Dermatol 1988;19:570.

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Inherited partial disorders The term lipomatosis has been applied to several disorders to describe either abnormal deposition of fat tissue or multiple lipomas (see above). Inherited lipomatoses presenting in children are rare and include encephalocraniocutaneous lipomatosis, diagnosed soon after birth, and several congenital syndromes such as Proteus syndrome, Cowden disease or the Bannayan–Riley–Ruvalcaba syndrome.

lipoma of the scalp or forehead with overlying alopecia, ocular lesions and intracranial malformations associated with a cerebral lipoma. The characteristic cutaneous finding, naevus psiloliparus (hairless fat naevus), is the most conspicuous sign of ECCL [12]. There is no geographic, racial or sex predilection [13]. Intracranial involvement is usually unilateral, except in three children with bilateral lesions [14–16] and one with midline lesions [9]. Intracranial lipomas were found in 32 of 52 reviewed patients [17]. In this report, no correlation between the brain anomalies and the degree of retardation or epilepsy could be established.

Encephalocraniocutaneous lipomatosis Definition. Encephalocraniocutaneous lipomatosis (ECCL), first described in 1970 [1], is a rare congenital hamartomatous disorder classified in the neurocutaneous syndromes and characterized by unilateral skin lesions, lipomas and ipsilateral ophthalmic and cerebral malformations. Aetiology. Although the course of ECCL is unknown, several mechanisms have been proposed. A maternal viral infection, described in two cases [2,3], is probably incidental. The most widely accepted theory involves dysgenesis of the cephalic neural crest and anterior neural tube [4]. Somatic mosaicism is the most likely explanation [5], as in the Proteus syndrome [6]. Indeed, ECCL and Proteus syndrome have many overlapping manifestations and ECCL can be considered as either a localized form of Proteus syndrome [7] or a distinct entity in the same spectrum of mosaic overgrowth [8]. The finding of a mutation in the neurofibromatosis type 1 (NF1) gene in an affected child, who also has caféau-lait patches, suggests a role for this gene, either alone or in combination with another genetic or non-genetic event [7]. Further investigation has not confirmed this hypothesis and the molecular basis of ECCL remains unknown. Finally, among lipomatoses, the pathogenic mechanism leading to the development of ECCL is probably similar to the one involved in the association of a cutaneous lipoma with an underlying intradural lipoma [9,10]. Histopathology. Both the subcutaneous soft masses and the intracranial tumours are typical lipomas. The two most common ocular findings in ECCL are epibulbar choristomas, consisting of dermal elements, fatty tissue and cartilage, and small skin nodules around the eyelids, which histologically represent connective tissue naevi [11]. Clinical features. The multiple craniofacial abnormalities of ECCL are present at birth, usually consisting of a

Diagnosis. Establishing the diagnosis poses few problems because other neurocutaneous syndromes accompanied by cranial, cerebral and ocular malformations are not associated with the characteristic lipomas and alopecia seen in ECCL. Proteus syndrome with similar lesions in other parts of the body, sebaceous naevus syndrome and Bannayan–Riley–Ruvalcaba syndrome with macrocephaly and intestinal polyposis are distinguishable. On the basis of the ocular abnormalities, one should consider focal dermal hypoplasia (Goltz syndrome), oculoauricular vertebral dysplasia (Goldenhar syndrome) and oculocerebrocutaneous (Delleman) syndrome. Oculocerebrocutaneous syndrome and ECCL can only be distinguished using very specific criteria [18]. Treatment. Early surgical removal of the subcutaneous and cerebral (when feasible) lipomas, as well as the epibulbar choristomas, is advised but will probably not alter the ultimate prognosis, which mainly depends on the extent of the intracranial malformations.

PTEN hamartoma tumour syndromes Germline PTEN (Phosphatase and TENsin homologue deleted on chromosome TEN) mutations predispose to phenotypically diverse disorders that share overlapping clinical features: Cowden syndrome, Bannayan–Riley– Ruvalcaba syndrome and Proteus syndrome, collectively classified as PTEN hamartoma tumour syndromes (PHTS) [19]. Germline mutations in PTEN, on 10q23.3, have been found in 85% of Cowden syndrome cases and subsets of the unrelated syndromes, including 65% of Bannayan– Riley–Ruvalcaba syndrome cases and 20% of Proteus syndrome. As a dual-specificity tumour suppressor phosphatase, PTEN dephosphorylates both protein and lipid substrates, and mutations of the gene confirmed its fundamental role in both biology and disease. Interestingly, PTEN-related syndromes are due to mutations of one component of a large enzymatic cascade known as the mTOR pathway [20]. The mammalian target of rapamycin (mTOR) is a member of the phosphoinositide-3-kinase related kinase family, which is

Disorders of Fat Tissue

centrally involved in growth regulation, proliferation control and cancer cell metabolism. Mutations in the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of tuberous sclerosis, Peutz–Jeghers syndrome, Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Lhermitte–Duclos disease, Proteus syndrome, von Hippel–Lindau disease, neurofibromatosis type 1 and polycystic kidney disease, respectively. In addition, alterations of signalling molecules upstream and downstream of the mTOR pathway are involved in many human neoplasias.

Cowden syndrome (see Chapter 137) Cowden syndrome (CS), also known as the multiple hamartoma syndrome, is a rare autosomal dominant condition in whwich multiple tumours of ectodermal, mesodermal and endodermal origin occur [21,22]. As stated above, Cowden syndrome is due to PTEN gene mutations [23,24] and thus allelic with Bannayan–Riley– Ruvalcaba syndrome. Expression is variable among members of the same family, some members having Cowden syndrome, whereas others present with typical Bannayan–Riley–Ruvalcaba. Mucocutaneous lesions are prominent, including facial trichilemmomas, acral keratoses and oral papillomas. The danger of the disease lies in the development of malignancies in the thyroid, gastrointestinal tract, breasts and female reproductive system. In contrast to Gardner syndrome, the gastrointestinal polyps of Cowden syndrome do not represent premalignant lesions. Lipomas occur in about 25% of affected patients but it is believed that many go unnoticed. Important signs indicating Cowden syndrome in young children include progressive macrocephaly, scrotal tongue and mild to moderate mental retardation. A newly determined familial variant in two patients from distinct Cowden disease families and due to mosaic PTEN nullizygosity has been described under the name of SOLAMEN syndrome (Segmental Overgrowth, Lipomatosis, Arteriovenous malformation and Epidermal Naevus) [25]. Bannayan–Riley–Ruvalcaba syndrome Bannayan–Riley–Ruvalcaba syndrome (BRRS) is now recognized to include three phenotypes that were described earlier by Ruvalcaba (macrocephaly, intestinal polyposis, pigmented spotting of the penis), Bannayan and later by Zonana (macrocephaly with multiple subcutaneous and visceral lipomas and haemangiomas), and by Riley and Smith (macrocephaly, pseudo-papilloedema and multiple haemangiomas) [26–30]. All the phenotypes show an autosomal dominant transmission and share overlapping features, such as macrocephaly. Pigmented macules on the penile shaft occur in most males. Other features

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include cutaneous lipomas, haemangiomas and, more commonly, lymphangiomas and multiple hamartous polyps limited to the distal ileum and colon. Hashimoto thyroiditis has been added as a relatively frequent complication. Prognosis is generally good except in cases that develop aggressive, infiltrating tumours. As a result of a clinical study of PTEN mutations carriers, CS and BRRS are considered to represent one condition with variable expression and age-related penetrance [31]. Differential diagnosis includes Sotos syndrome and Peutz–Jeghers syndrome; both are easily distinguishable.

Proteus syndrome (see Chapter 111) Lipomas often develop in Proteus syndrome [32,33], which is determined by the association of asymmetrical overgrowth of body parts, vascular malformations, epidermal and naevocellular naevi, and is due to PTEN mutations (at least 20% of cases). Proteus syndrome is a highly variable, progressive overgrowth condition characterized by sporadic occurrence, mosaic distribution and a progressive course. The differential diagnosis of Proteus syndrome includes many closely related but clinically distinct conditions such as encephalocraniocutaneous lipomatosis (see above) and hemihyperplasia-multiple lipomatosis syndrome [34].

Congenital Lipomatous Overgrowth, Vascular malformations, and Epidermal naevi (CLOVE syndrome) CLOVE syndrome is a newly delineated phenotype comprising progressive, complex and mixed truncal vascular malformations, dysregulated adipose tissue, varying degrees of scoliosis and enlarged bony structures without bony overgrowth. Of note, before the description of the syndrome, all patients were previously diagnosed with Proteus syndrome. However, they did not meet diagnosis criteria for this disorder, their natural history was distinct and none had a PTEN mutation [35].

Gardner syndrome (see Chapter 137) Gardner syndrome [36,37] is an autosomal dominant disorder characterized by familial adenomatous polyposis of the colon, osteomas of the skull, mouth and long bones, desmoid tumours (usually as fibromatosis of the mesentery), dental abnormalities, epidermoid cysts, lipomas, fibromas and congenital hypertrophy of the retinal pigment epithelium. Mutations of the adenomatous polyposis coli (APC) gene on chromosome 5 q [38] account for the disorder which may now be classified among the ciliopathies [39]. Lipomas in this syndrome are a secondary feature that appear in early adulthood.

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References 1 Haberland C, Perou M. Encephalocraniocutaneous lipomatosis. Arch Neurol 1970;22:144–55. 2 Fishman MA, Chang CS, Miller JE. Encephalocraniocutaneous lipomatosis. Pediatrics 1978;61:580–2. 3 Alfonso I, Lopez PF, Cullen RF Jr et al. Spinal cord involvement in encephalocraniocutaneous lipomatosis. Pediatr Neurol 1986;2:380–4. 4 Gawel J, Schwartz RA, Joswiak S. Encephalocraniocutaneous lipomatosis. J Cutan Med Surg 2003;7:61–5. 5 Happle R, Steijlen PM. Enzephalokraniokutane Lipomatose. Ein nicht erblicher Mosaikphänotyp. Hautarzt 1993;44:19–22. 6 Cohen MM Jr. Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Neurofibromatosis 1988;1:260–80. 7 Legius E, Wu R, Eyssen M et al. Encephalocraniocutaneous lipomatosis with a mutation in the NF1 gene. J Med Genet 1995;32: 316–19. 8 McCall S, Ramzy MI, Cure JK et al. Encephalocraniocutaneous lipomatosis and the Proteus syndrome: distinct entities with overlapping manifestations. Am J Med Genet 1992;43:662–8. 9 Venencie PY, Husson B, Lacroix C et al. Lipomatose encéphalo-craniocutanée: une observation. Ann Dermatol Vénéréol 1993;120:766–7. 10 Bodemer C, Durand C, Brunel F et al. Lipome sous-cutané révélateur d’un lipome intradural. Ann Dermatol Vénéréol 1988;115:1130–2. 11 Kodsi SR, Bloom KE, Egbert JE et al. Ocular and systemic manifestations of encephalocraniocutaneous lipomatosis. Am J Ophthalmol 1994;118:77–82. 12 Sofiatti A, Cirto G, Arnone M et al. Encephalocraniocutaneous lipomatosis: clinical spectrum of systemic involvement. Pediatr Dermatol 2006;23:27–30. 13 Nosti Martinez D, del Castillo V, Duran Mckinster C et al. Encephalocraniocutaneous lipomatosis: an uncommon neurocutaneous syndrome. J Am Acad Dermatol 1995;32:387–9. 14 Sanchez NP, Rhodes AR, Mandell F et al. Encephalocraniocutaneous lipomatosis: a new neurocutaneous syndrome. Br J Dermatol 104:89–96. 15 Grimalt R, Ermacora E, Mistura L et al. (1993) Encephalocraniocutaneous lipomatosis: case report and review of the literature. Pediatr Dermatol 1981;10:164–8. 16 Al Mefty O, Fox JL, Sakati N et al. The multiple manifestations of the encephalocraniocutaneous lipomatosis syndrome. Child Nerv Syst 1987;3:132–4. 17 Moog U, Jones MC, Viskochil DH et al. Brain anomalies in encephalocraniocutaneous lipomatosis. Am J Med Genet 2007;143A: 2963–72. 18 Hunter AGW. Oculocerebrocutaneous and encephalocraniocutaneous lipomatosis syndromes: blind men and an elephant or separate syndromes? Am J Med Genet 2006;140A:709–26. 19 Orloff MS. Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene 2008;27:5387–97. 20 Rosner M, Hanneder M, Siegel N et al. The mTOR pathway and its role in human genetic diseases. Mutat Res 2008;659:284–92. 21 Hanssen AMN, Fryns JP. Cowden syndrome. J Med Genet 1995;32:117–19. 22 Pilarski R. Cowden syndrome: a critical review of the literature. J Genet Counsel 2009;18:13–27. 23 Diliberty JH. Inherited macrocephaly-hamartomata syndromes. Am J Med Genet 1998;79:284–90. 24 Marsh DJ, Kum JB, Lunetta KL et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999;8:1461–72. 25 Caux F, Plauchu H, Chibon F et al. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygocity. Eur J Hum Genet 2007;15:767–73.

26 Gorlin RJ, Cohen MM, Condon LM et al. Bannayan–Riley–Ruvalcaba syndrome. Am J Med Genet 1992;44:307–14. 27 Hayashi Y, Ohi R, Tomita Y et al. Bannayan–Zonana syndrome associated with lipomas, hemangiomas and lymphangiomas. J Pediatr Surg 1992;27:722–3. 28 Klein JA, Barr RJ. Bannayan–Zonana syndrome associated with lymphangiomyomatous lesions. Pediatr Dermatol 1990;7:48–53. 29 Marsh D, Dahia PLM, Zheng Z et al. Germline mutations in PTEN are present in Bannayan–Zonana syndrome. Nat Genet 1997;16: 333–4. 30 Buisson P, Leclair M-D, Jacquemont S et al. Cutaneous lipomas in children, 5 cases with Bannayan-Riley-Ruvalcaba syndrome. J Pediatr Surg 2006;41:1601–3. 31 Lachlan KL, Lucassen AM, Bunyan D et al. Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutations carriers. J Med Genet 2007;44:579–85. 32 Viljoen DL, Saxe N, Temple Camp C. Cutaneous manifestations of the Proteus syndrome. Pediatr Dermatol 1988;5:14–21. 33 Biesecker LG. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet 2006;14:1151–7. 34 Biesecker LG, Peters KF, Darling TN et al. Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia. Am J Med Genet 1998;79:311–18. 35 Sapp JC, Turner JT, van de Kamp JM et al. Newly delineated syndrome of Congenital Lipomatous Overgrowth, Vascular malformations, and Epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet 2007;143A: 2944–58. 36 Pereyo NG. Extra abdominal desmoid tumor. J Am Acad Dermatol 1996;34:352–6. 37 Rustgi AK. Hereditary gastrointestinal polyposis and non-polyposis syndromes. N Engl J Med 1994;331:1694–702. 38 Olschwang S, Laurent-Puig P, Melot T et al. High resolution genetic map of the adenomatous polyposis coli gene (APC) region. Am J Med Genet 1995;56:413–19. 39 Gomez Garcia EB, Knoers NV Gardner ’s syndrome (familial adenomatous polyposis): a cilia-related disorder. Lancet Oncol 2009;10: 727–35.

Acquired partial disorders Benign cervical lipomatosis Syn. multiple symmetric lipomatosis, cephalothoracic lipoatrophy, Madelung disease, maladie de launois et bensaude

This disorder [1–6] represents the occurrence of a diffuse symmetrical lipomatosis, with predilection for the neck. It was called ‘Fetthals’ (fat neck) by Madelung in 1888. Launois and Bensaude reported 95 cases in 1898 and described the three main characteristics of this fat deposition: symmetrical lesions, cervical localization and diffuse nature. The disorder starts at around 30–50 years, mainly in men. A peripheral neuropathy is often associated. Despite the familial description of the disorder, it should be noted that many cases are isolated and linked with severe alcoholism.

Disorders of Fat Tissue References 1 Abensour M, Jeandel C, Heid E. Lipomes et lipomatoses cutanés. Ann Dermatol Vénéréol 1987;114:873–82. 2 Chalk CH, Mills KR, Jacobs JM et al. Familial multiple symmetric lipomatosis with peripheral neuropathy. Neurology 1990;40:1246–50. 3 Enzi G, Angelini C, Negrin P et al. Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis. Medicine 1985;64:388–93. 4 Williams DW, Ginsberg LE, Moody DM et al. Madelung disease: MR findings. Am J Neuroradiol 1993;14:1070–3. 5 Verna G, Kefalas N, Boriani F et al. Launois–Bensaude syndrome: an unusual localization of obesity disease. Obes Surg 2008;18:1313–17. 6 Meninguaud JP, Pitak-Arnnop P, Bertrand JC. Multiple symmetric lipomatosis: a case report and review of the literature. J Oral Maxillofac Surg 2007;65:1365–9.

Inherited generalized disorders Genetic disorders associated with childhood-onset obesity The known monogenic forms of obesity can be divided into three broad categories [1]. The first category is obesity caused by mutations in genes that have a physiological role in the hypothalamic leptin-melanocortin system of energy balance. Specifically, these include obesity caused by mutations in leptin, leptin receptor, melanocortin-4 receptor (MC4R), proopiomelanocortin (POMC) and prohormone convertase 1/3 (PC1/3). The second category is obesity resulting from mutations in the three genes necessary for development of the hypothalamus: SIM1, BDNF and NKTR2. These disorders also affect neurodevelopment and emphasize the role of the hypothalamus in bodyweight regulation. However, the mechanisms through which these genes regulate bodyweight are unknown [2]. The third category is obesity presenting as part of a complex syndrome caused by mutations in genes whose functional relationship to obesity is also unclear. These include Prader–Willi syndrome and three disorders (Bardet–Biedl (BBS), Alström and Carpenter syndromes) which are linked to the dysfunction of the primary cilium. Disorders of the third category are less rare and will be briefly summarized here.

Prader–Willi syndrome (PWS) With a frequency at about 1 in 25,000, this is the most common syndromal cause of human obesity [3,4] and consists of intrauterine hypotonia, short stature, muscular hypotonia, hypogonadotropic hypogonadism, small hands and feet, fair skin and hair (hypopigmentation), failure to thrive and obesity [5–7]. It is recognized in infancy by a characteristic facies (facial diplegia with flat narrow face and triangular mouth), hypotonia and feeding problems leading to failure to thrive. During the first year of life, a marked change in activity occurs, as the child becomes much more lively and mobile.

141.9

Hyperphagia/food foraging then develops and results in secondary obesity, with the possible consequence of insulin resistance and glucose intolerance after puberty. Other cutaneous signs include abdominal striae and scars from scratching due to itching after 6 years of age. There is a male to female predominance of 5 : 2. PWS is a genomic, imprinted, contiguous gene disorder due to the loss of expression of the paternally inherited genes on chromosome 15q11.2–13, resulting from a deletion of the paternal allele (65% of cases), maternal uniparental disomy [8] (30% of cases) or an imprinting defect (2–5% of cases). The differential DNA methylation of certain maternal and paternal alleles in the 15q11.2–13 region provides a tool for assessing paternal-only, maternal-only and biparental inheritance. Of note is that the maternal deletion of the same locus causes Angelman syndrome, and families with occurrence of both syndromes have been described [9]. The exact function of the many genes located in 15q11.2–13 in the PWS phenotype remains to be elucidated. Interestingly, one of the involved genes is the human homologue for the mouse pink-eyed dilution (p locus). As mutation in both copies of the P gene account for type II oculocutaneous albinism, it has been suggested that deletion of one copy of this gene is the cause of hypopigmentation in PWS and Angelman syndrome [10]. Management of PWS is focused on anticipatory guidance and addressing the age-dependent consequences of the syndrome. Treatment with growth hormone from infancy in conjunction with good dietary management normalizes facial appearance and body habitus. Finally, with abundant fat, muscle hypotonia and small hands and feet, PWS represents the clinical opposite of congenital lipoatrophic diabetes (Berardinelli–Seip congenital lipoatrophy).

Bardet–Biedl syndrome (BBS) Now considered distinct from Laurence–Moon syndrome [11], BBS is characterized by obesity (predominantly on the trunk and proximal limbs), hypogonadism, mental retardation, blindness due to retinal atrophy and digital abnormalities (syndactyly, polydactyly). Other cutaneous features are hypertrichosis and web neck [12]. The disorder is genetically heterogeneous with linkage to 14 loci (BBS1–BBS14). All these genes code for proteins involved in the development and function of the primary cilium [13,14].

Alström syndrome (AS) Alström syndrome is manifested by childhood blindness related to retinal degeneration, infantile obesity, nerve deafness, hypogonadism in males and diabetes mellitus with insulin resistance, acanthosis nigricans and nephropathy [15–17]. It is an autosomal recessive disorder caused

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by mutations of the ALMS1 gene. The ALMS1 protein localizes to the centrosome and ciliary basal body, and probably has a role in the formation or maintenance of primary cilia.

Other disorders Other disorders in which obesity is listed as an associated feature include X-linked mental retardation with gynaecomastia and obesity, also known as the Wilson–Turner syndrome and originally described by Vasquez-Hurst and Sotos [18], Cohen syndrome with microcephaly, mental retardation, short stature, facial abnormalities and rather long, fine hands [19], acrocephalopolysyndactyly type II (Carpenter syndrome), with mental retardation, acrocephaly, polydactyly, syndactyly and obesity in older patients [20,21], and Blount disease with genu vara, tibial torsion and occasionally obesity. Non-Mendelian disorders should not be forgotten and in clinical practice one should remember that in children, acquired obesity coupled with headaches, growth disorders or endocrine dysfunction merits a lateral radiograph of the head and CT/MRI scan to search for a craniopharyngioma. References 1 Ranadive SA, Vaisse C. Lessons from extreme human obesity: monogenic disorders. Endocrinol Metab Clin North Am 2008;37:733–51. 2 Farooqi IS, O’Rahilly S. Genetics of obesity in humans. Endocrin Rev 2006;27:710–18. 3 Cassidy SB, Driscoll DJ. Prader–Willi syndrome. Eur J Hum Genet 2009;17:3–13. 4 Butler M. Prader–Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet 1990;35:319–22. 5 Wiesner GL, Bendel CM, Olds DP et al. Hypopigmentation in the Prader–Willi syndrome. Am J Hum Genet 1987;40:431–42. 6 Prader A, Labhart A, Willi H. Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus unf Oligophrenie nach Myatonieartigem Zustand im Neugeborrenealter. Schweiz Med Wschr 1956;86:1260–1. 7 Holm VA, Cassidy SB, Butler MG et al. Prader–Willi syndrome: consensus diagnostic criteria. Pediatrics 1993;91:398–402. 8 Nichols RD, Knoll JHM, Butler MG et al. Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader–Willi syndrome. Nature 1989;342:281–5. 9 Smeets DFCM, Hamel BCJ, Nelen MR et al. Prader–Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N Engl J Med 1992;326:807–11. 10 Rinchik EM, Bultman SJ, Horsthemke B et al. A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Nature 1993;361:72–6. 11 Schachat AP, Maumenee IH. The Bardet–Biedl syndrome and related disorders. Arch Ophthalmol 1982;100:285–8. 12 Green JS, Parfrey PS, Harnett JD et al. The cardinal manifestations of Bardet–Biedl syndrome, a form of Laurence–Moon–Biedl syndrome. N Engl J Med 1989;321:1002–9. 13 Tobin JL, Beales PL. Bardet–Biedl syndome: beyond the cilium. Pediatr Nephrol 2007;22:926–36. 14 Adams M, Smith UM, Logan CV et al. Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. J Med Genet 2008;45:257–67.

15 Russell-Eggitt IM, Clayton PT, Coffey R et al. Alström syndrome: report of 22 cases and literature review. Ophthalmology 1998; 105:1274–80. 16 Alström CH, Hallgren B, Nilsson LB et al. Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence– Moon–Biedl syndrome. Acta Psychiatr Neurol Scand 1959;34(Suppl 129): 1–35. 17 Joy T, Cao H, Black G et al. Alstrom syndrome: a case report and literature review. Orphan J Rare Disord 2007;2:49–57. 18 Wilson M, Mulley J, Gedeon A et al. New X-linked syndrome of mental retardation, gynecomastia, and obesity is linked to DXS255. Am J Med Genet 1991;40:406–13. 19 Cohen MM, Hall BD, Smith DW et al. A new syndrome with hypotonia, obesity mental deficiency and facial, oral, ocular and limb anomalies. J Pediatr 1973;83:280–4. 20 Cohen DM, Green JG, Miller J et al. Acrocephalopolysyndactyly type II: Carpenter syndrome: clinical spectrum and an attempt at unification with Goodman and Sumitt syndromes. Am J Med Genet 1987;28:311–24. 21 Jenkins D, Seelow D, Jehee FS et al. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Med Genet 2007;80:1162–70.

Acquired generalized disorders Obesity Obesity now affects up to 20% of the population in developed countries and is currently regarded as an epidemic. Obesity is, however, beyond the scope of this chapter and information can be found elsewhere [1–3]. References 1 Silva JM, Serra-e-Silva P. Triumph of obesity or of human insanity. Lancet 1995;346:636–7. 2 Rohner-Jeanrenaud F, Jeanrenaud B. Obesity, leptin, and the brain. N Engl J Med 1996;334:324–5. 3 Foster DW. Eating disorders: obesity, anorexia nervosa, and bulimia nervosa. In: Wilson JD, Foster DW (eds) Williams Textbook of Endocrinology. Philadelphia: W.B. Saunders, 1992, pp.1335–65.

PART TWO: DISORDERS WITH DECREASED FAT TISSUE Many disorders presenting with fat atrophy (lipoatrophy) have been reported as lipoatrophy. As stated above, the latter term will be avoided here in the interests of semantic clarification. Fat atrophy, as the loss of subcutaneous adipose tissue, can result from many congenital or acquired conditions, which are classified as localized, partial or generalized disorders (Table 141.2). The most common forms of lipoatrophy in children are localized (Fig. 141.1) and most of them are secondary, following an inflammatory or scarring process of various origins (Box 141.1). In such cases, lipoatrophy may be the only finding. Alternatively, other cutaneous modifica-

Disorders of Fat Tissue Table 141.2 Classification of disorders with decreased fat tissue (lipoatrophies) Inherited

Acquired

Localized

Centrifugal lipoatrophy Atrophy of the ankles Semi-circular lipoatrophy Annular lipoatrophy Naevoid disorders Secondary lipoatrophies

Partial

Generalized

Familial partial lipodystrophies (Köbberling–Dunnigan syndrome) Mandibuloacral dysplasia

Acquired partial lipoatrophy

Congenital generalized lipoatrophies (Berardinelli–Seip lipoatrophy, types1–3) Leprechaunism

Acquired generalized lipoatrophy (Lawrence syndrome)

(Barraquer–Simmons disease) Lipoatrophy in HIV patients

141.11

Box 141.1 Disorders causing acquired localized lipoatrophy • • • • • • •

Injections (insulin, corticosteroids, vaccinations) Neonatal subcutaneous necrosis Subcutaneous calcification/ossification Lipoatrophic panniculitis Trauma Infections (bacterial, fungal or parasitic) Connective tissue diseases (lupus erythematosus, dermatomyositis, morphoea/scleroderma) • Thrombophlebitis/liposclerosis • Granuloma necrobiosis (granuloma annulare, necrobiosis lipoidica, rheumatic nodules) • Lymphoma, leukaemia, neoplasia

insulin injection and in human immunodeficiency virus (HIV)-infected patients.

Inherited localized disorder There is no recognized disorder in this category.

Acquired localized disorders Primary localized lipoatrophies correspond to a heterogenic group of disorders whose denomination mainly depicts their clinical appearance. Insulin and centrifugal lipoatrophy can present in childhood. Annular lipoatrophy, semi-circular lipoatrophy and lipoatrophy of the ankles are clinically distinct entities mainly seen in adult women and, therefore, will only be mentioned briefly.

Centrifugal lipoatrophy Syn. lipodystrophia lipoatrophy

Fig. 141.1 Typical appearance of localized lipoatrophy with sharply delineated border and prominent subcutaneous veins.

tions may be involved, such as sclerosis in morphoea. These inflammatory disorders are discussed elsewhere (see Chapter 77). In this part of the chapter, mainly noninflammatory, primary or idiopathic lipoatrophies will be reviewed, the exception being for lipoatrophy following

centrifugalis

abdominalis

infantilis,

centrifugal

Definition. Described in 1971 by Imamura and colleagues [1] under the name ‘lipodystrophia centrifugalis abdominalis infantilis’, this form of lipoatrophy is characterized by (a) a localized loss of subcutaneous fat involving the greater part of the abdomen, (b) an onset before 3 years of age, (c) a centrifugal enlargement of the depressed area, (d) slightly reddish and scaly changes in the surrounding area, and (e) no other significant abnormalities. More than 100 cases have been reported to date, mainly among Japanese [2]. Occurrence in Caucasian children appears exceptional [3].

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Aetiology. The origin of centrifugal lipoatrophy is uncertain. Although small inflammatory findings such as lymph node enlargement and peripheral inflammatory cellular infiltrate are initially present in about two-thirds of cases, systemic signs of inflammation are usually absent [2]. These findings and the fact that corticosteroids do not stop the progressive enlargement of centrifugal lipoatrophy argue against a primary inflammatory process as in other types of panniculitis. Speculation has covered several possible mechanisms: (a) a primary loss of subcutaneous fat with reactive inflammatory infiltrate and lymphadenopathy, (b) localized trauma such as friction, contusion, inguinal hernia or congenital dislocation of the hip, which have all been reported as possible triggers in some patients, and (c) intercurrent infections. The higher expression of the disorder in Japanese children, together with the description of affected dizygotic twins and siblings [4], may suggest a genetic predisposition.

Histology. Lesions are characterized by a decrease or loss of subcutaneous fat, with the presence of inflammatory cells that are more prominent in the surrounding area. The inflammatory cell infiltrate may involve the dermis as well as the subcutaneous tissue and consists of lymphocytes, histiocytes and few plasma cells in most cases [2,3,5]. Multinucleated giant cells and foamy cells have been reported [5]. Mild vascular changes (endothelial swelling) can occur, but not apparent vasculitis.

Clinical features. With a 2 : 1 female : male ratio, 90% of cases are characterized by an onset before 8 years of age and an abdominal location, most often the groin or surrounding area. The initial presentation includes erythematous, bluish macules or ecchymoses with regional lymph node enlargement in about one-half of the cases. In the other half, the parents first notice the lesion only by a well-defined depression or atrophy of the skin. The lesion then spreads centrifugally to leave a central part of lipoatrophy, where subcutaneous veins become easily visible. A few patients have developed two or three lesions. In a follow-up review of cases, it was found that cessation of enlargement occurs within 3 years in 50% of patients and within 8 years in 90%, followed by spontaneous resolution or marked improvement in a majority of cases [2,5–7]. The clinical course appears rather uniform in most cases. However, a few variations were recently reported. These include extra-abdominal locations, such as the head [5,8], neck [7] and lumbar region [3,6] and nonregressing cases [9]. Adult cases are extremely rare [10– 12], and whether these should be classified as large unusual semi-circular lipoatrophies is disputable.

Treatment and prognosis. Topical and oral corticosteroids have been used with little benefit. They are usually effective at decreasing the peripheral inflammation/ erythema but do not halt the progressive centrifugal extension [2]. Although most cases spontaneously stop progressing before the age of 13 years and then regress, persistence into adulthood of a lesion further complicated by angioblastoma has been reported [9].

Annular lipoatrophy This entity is characterized by a circular depressed band, 1 cm wide and 0.5–2 cm deep, that encircles an upper limb, usually in women aged 40–70 years. The atrophic lesion is preceded by tenderness and swelling of the entire limb. Unexplained neuralgia and arthralgic pain with muscle weakness or myopathy are frequent. Annular lipoatrophy does not spontaneously regress and may last up to 20 years. Histological findings may be minimal or show polyarteritis and strands of connective tissue replacing the subcutaneous fat. The prevalence of ‘rheumatic’ pain and associated findings suggests an underlying connective tissue disease [13–15].

Atrophy of the ankles This is an extremely rare disorder, mainly characterized by its peculiar location. Less than 10 cases have been described with bilateral circumferential, asymptomatic, lipoatrophic bands, 9–11 cm wide, on the ankles. Local symptomatology and muscle involvement are absent. The disorder should be differentiated from acral lipoatrophy, which may develop as an autoimmune process (Fig. 141.2) [16–19].

Semi-circular lipoatrophy Semi-circular lipoatrophy occurs more frequently than annular lipoatrophy and atrophy of the ankles, and mainly in adults. Patients present with semi-annular cutaneous depressions symmetrically distributed on the anterolateral aspects of both thighs. The lesions are asymptomatic and flesh coloured. Spontaneous resolution usually occurs within 3 years of onset. Although the aetiology of the disorder may be heterogeneous, most authors believe that the lipoatrophy follows a panniculitis of traumatic origin. Histological changes include fat atrophy replaced by collagen and mild perivascular cellular infiltrate in the dermis [20–31].

Naevoid disorders Localized lipoatrophy can occasionally be associated with naevoid disorders such as Becker ’s naevus [32,33] or naevoid hypertrichosis [34].

Disorders of Fat Tissue

141.13

Clinical features. Insulin atrophy was previously seen more frequently than insulin hypertrophy, but not now. In a series of 281 patients treated with purified insulins, the prevalence of lipohypertrophy was 27% and lipoatrophy 2.5% [35]. It is a cosmetically distressing complication, which presents as a non-inflammatory, painless, small to large dimple at insulin injection sites. It usually develops within 3 years of starting insulin and is more common in children and women. Most cases are associated with higher levels of insulin requirements, as insulin absorption can be delayed or variable due to the formation of avascular, fibrous scar tissue. Lipoatrophic lesions distant from the sites of injection may occur, as well as the co-existence of both fat atrophy and hypertrophy [43].

Fig. 141.2 Diffuse, predominantly acral lipoatrophy in a girl with autoimmune hepatitis, alopecia and positive anti-liver and anti-kidney microsome antibodies.

Treatment. The use of highly purified porcine insulins with a reinforcement of careful rotational routine of injection sites resulted in a marked decrease, but not disappearance, of insulin lipoatrophy. The use of human insulin preparations, injected directly into the lipoatrophic area, is usually curative [43,44]. This often results in both a regression of the localized lipoatrophy and a reduction in insulin requirements. However, cautious optimism should prevail as lipoatrophy may occasionally complicate human insulin injections [45]. In such cases, topical cromolyn therapy may reverse early and prevent new lipoatrophic lesions [42].

Insulin lipoatrophy Aetiology. Lipoatrophy following subcutaneous insulin injections was probably one of the most common causes of localized fat atrophy when diabetic patients used conventional bovine–porcine insulin preparations. As lipoatrophy was more commonly seen with longer acting insulins rather than soluble ones, and as its occurrence was greatly reduced with the availability in the early 1980s of highly purified porcine insulins [35,36], it is considered to be an immunological reaction to impurities in the insulin preparations and/or to the xenogenic insulin [37–39]. These immunological reactions should be differentiated from allergic reactions to the content of long-acting insulins, which result in generalized urticaria and not lipoatrophy [40,41]. Histopathology. Skin biopsies show a loss of fat tissue. An increase in insulin-binding capacity is found on the edge of lipoatrophic lesions. Inflammatory changes are characteristically scant but immunofluorescence may show deposition of immunoglobulin M (IgM), C3 in the dermis and C3 in dermal blood vessels [38]. Accumulation of tryptase-positive, chymase-positive degranulated mast cells has been described with human insulin [42].

References 1 Imamura S, Yamada M, Ikeda T. Lipodystrophia centrifugalis abdominalis infantilis. Arch Dermatol 1971;104:291–8. 2 Imamura S, Yamada M, Yamamoto K. Lipodystrophia centrifugalis abdominalis infantilis. J Am Acad Dermatol 1984;11:203–9. 3 Zachary CB, Wells RS. Centrifugal lipodystrophy. Br J Dermatol 1984;110:107–10. 4 Mizoguchi M, Nanko S. Lipodystrophia centrifugalis abdominalis infantilis in dizygotic twins. J Dermatol 1982;9:139–43. 5 Hagari Y, Sasaoka R, Nishiura S et al. Centrifugal lipodystrophy of the face mimicking progressive lipodystrophy. Br J Dermatol 1992;127:407–10. 6 Caputo R. Lipodystrophia centrifugalis sacralis infantilis. Acta Dermatol Venereol 1989;69:442–3. 7 Higuchi T, Yamakage A, Tamura T et al. Lipodystrophia centrifugalis abdominalis infantilis occurring in the neck. Dermatology 1994;188:142–4. 8 Hagari Y, Ikehara A, Nuno K et al. Centrifugal lipodystrophy presenting with serpiginous erytheme and alopecia. Cutis 2002;69:281–3. 9 Hiraiwa A, Takai K, Fukui Y et al. Non-regressing lipodystrophia centrifugalis abdominalis with angioblastoma (Nakagawa). Arch Dermatol 1990;126:206–9. 10 Rowland Payne CME, Harper JI, Farthing CE et al. Lypodystrophia centrifugalis. Br J Dermatol 1985;113(Suppl):100–1. 11 Franks A, Verbov JL. Unilateral localized idiopathic lipoatrophy. Clin Exp Dermatol 1993;18:468–9. 12 Vieira Serrão V, Barata Feio A, Localized abdominal idiopathic lipodystrophy. Dermatol Online J 2008;14:15–20. 13 Bruinsma W. Lipoatrophia annularis, an abnormal vulnerability of the fatty tissue. Dermatologica 1967;134:107–12.

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14 Rongioletti F, Rebora A. Annular and semicircular lipoatrophies. J Am Acad Dermatol 1989;20:433–6. 15 Ferreira-Marques J. Lipoatrophia annularis. Ein Fall einer bisher nicht beschriebenen Krankheit der Haut. Arch Dermatol Syph (Berlin) 1953;195:479–91. 16 Jablonska S, Szczepanski A, Gorkiewicz A. Lipoatrophy of the ankles and its relation to other lipoatrophies. Acta Dermatol Venereol 1975;55:135–40. 17 Roth DE, Schikler KN, Callen JP. Annular atrophic connective tissue panniculitis of the ankles. J Am Acad Dermatol 1989;21:1152–6. 18 Shelley WB, Izumi AK. Annular atrophy of the ankles. Arch Dermatol 1970;102:326–9. 19 Dimson OG, Esterly NB. Annular lipoatrophy of the ankles. J Am Acad Dermatol 2006;54: S40–S42. 20 Baurle G, Hanke E. Lipodystrophia semicircularis: ein rein kosmetisches Problem? Artzl Kosmetol 1983;13:135–41. 21 Bloch PH, Runne U. Lipotrophia semicircularis beim Mann. Hautarzt 1978;29:270–2. 22 Karkavitsas C, Miller JA, Kirby JD. Semicircular lipoatrophy. Br J Dermatol 1981;105:591–3. 23 Hodak E, David M, Sandbank M. Semicircular lipoatrophy: a pressure-induced lipoatrophy? Clin Exp Dermatol 1990;15:464–5. 24 Ayala F, Lembo G, Ruggiero F et al. Lipoatrophia semicircularis. Dermatologica 1985;170:101–3. 25 Thiele B, Ippen H. Multilokulare progrediente Lipatrophia semicircularis. Hautarzt 1983;34:292. 26 Mascaro JM, Ferrando J. Lipoatrophia semicircularis: the perils of wearing jeans? Int J Dermatol 1982;21:138–9. 27 Leonforte JF. Lipoatrophia semicircularis associated with an osseous cyst. Cutis 1983;31:428. 28 Gshwandtner WR, Munzberger H. Lipoatrophia semicircularis. Wien Klin Wochenschr 1975;87:164–8. 29 Peters MS, Winkelmann RK. The histopathology of localized lipoatrophy. Br J Dermatol 1986;114:27–36. 30 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;39:879–81. 31 Gruber PC, Fuller LC. Lipoatrophy semicircularis induced by trauma. Clin Exp Dermatol 2001;26:269–71. 32 Van Gerwen HJ, Koopman RJ, Steijlen PM et al. Becker ’s naevus with localized lipoatrophy and ipsilateral breast hypoplasia. Br J Dermatol 1993;129:213. 33 Cox NH. Becker ’s naevus of the thigh with lipoatrophy: report of two cases. Clin Exp Dermatol 2002;27:27–8. 34 Cox NH, McClure JP, Hardie RA. Naevoid hypertrichosis: report of a patient with multiple lesions. Clin Exp Dermatol 1989;14:62–4. 35 McNally PG, Jowett NI, Kurinczuk JJ et al. Lipohypertrophy and lipoatrophy complicating treatment with highly purified bovine and porcine insulins. Postgrad Med J 1988;64:850–3. 36 Young RJ, Steel JM, Frier BM et al. Insulin injection sites in diabetes: a neglected area? BMJ 1981;283:349. 37 Kahn CR, Rosenthal AS. Immunologic reaction to insulin: insulin allergy, insulin resistance, and the autoimmune insulin syndrome. Diabetes Care 1979;2:283–95. 38 Reeves WG, Allen BR, Tattersall RB. Insulin-induced lipoatrophy: evidence for an immune pathogenesis. BMJ 1980;280:1500–3. 39 Raile K, Noelle V, Landgraf R et al. Insulin antibodies are associated with lipoatrophy but also with lipohypertrophy in children and adolescents with type 1 diabetes. Exp Clin Endocrinol Diabetes 2001;109:393–6. 40 Plantin P, Sassolas B, Guillet MH et al. Accidents cutanés allergiques aux insulines. Ann Dermatol Vénéréol 1988;115:813–17. 41 Rowland Payne CME, Williams C, Wilson IV. True delayed pressure urticaria induced by human Monotard insulin. Br J Dermatol 1996;134:178–92.

42 Lopez X, Castells M, Ricker A et al. Human insulin analog-induced lipoatrophy. Diabetes Care 2008;31:442–4. 43 Valenta LJ, Elias AN. Insulin-induced lipodystrophy in diabetic patients resolved by treatment with human insulin. Ann Intern Med 1985;102:790–1. 44 Samadaei A, Hashimoto K, Tanay A. Insulin lipodystrophy, lipohypertrophic type. J Am Acad Dermatol 1987;17:506–7. 45 Chantelau E, Reuter M, Schotes S et al. A case of lipoatrophy with human insulin therapy. Exp Clin Endocrinol 1993;101:194–6.

Inherited partial disorders Familial partial lipodystrophy (FPLD1, FPLD2, FPLD3) Syn. Köbberling–Dunnigan lipoatrophic diabetes

syndrome,

reverse

partial

lipoatrophy,

Definition and history. Familial partial lipodystrophy (FPLD) is an autosomal dominant syndrome comprising initially two clinical phenotypes with progressive loss of subcutaneous fat confined to the limbs or also involving the trunk, starting in childhood. In 1974, Dunnigan and colleagues [1] described three female members of a Scottish family and one female member of another family who showed the complete absence of fat from the limbs and trunk with normal or excessive adipose tissue of the face and neck. All four patients had hyperlipaemia and three had diabetes mellitus. In 1975, Köbberling and colleagues [2] described three female members of a German family who showed complete absence of cutaneous fat from the limbs, with normal fat on the face and trunk. Other familial cases were then reported [3–6]. In 1986, Köbberling and Dunnigan [7] reviewed all cases and delineated the two clinical phenotypes. Aetiology. Familial partial lipodystrophy 1 (Köbberling type) only affects females [8] and remains of unknown origin and transmission. FPLD2 (Dunnigan type) has now been linked to mutations of the lamin A/C (LMNA) gene [9] and is thus part of a broad spectrum of disorders called the laminopathies [10]. This is a group of heterogeneous clinical entities, including Emery–Dreifuss muscular atrophy, dilated cardiomyopathy with conduction defect, limb girdle muscular atrophy 1B, type 2B Charcot– Marie–Tooth disease, progeric syndromes, and mandibuloacral dysplasia. FPLD3 is due to mutations of the peroxisome proliferator-activated receptor γ (PPARG). The disorder is rare [11,12]. Clinical features. Patients with type 1 FPLD show the complete absence of visible or palpable subcutaneous fat

Disorders of Fat Tissue

141.15

on the arms and legs. The subcutaneous veins appear prominent and the muscles hypertrophied. Acanthosis nigricans occurs only in patients with diabetes and hyperlipoproteinaemia. Diabetes can present as the mild maturity-onset form or be more severe, complicated by nephropathy and early death [2,4,5]. In type 2 FPLD, all three members of the first described family showed the absence of subcutaneous fat from the trunk and limbs, broad facies with short thick-set necks and slight prognathism. Excess fat on the face, neck and supraclavicular fossae can occur. Hands and feet are always normal in size and shape. Associated metabolic abnormalities are mild to severe, including hyperlipoproteinaemia and insulin-resistant diabetes [1,5]. Affected males can be difficult to recognize because an apparent muscular hypertrophy may not be considered dysmorphic. Females with FPLD are more severely affected with metabolic complications of insulin resistance than are males [13]. Treatment of the metabolic disturbances associated with FPLD has been achieved with the use of recombinant human leptin. This treatment is effective for the generalized and partial (FLDP2,3) forms[14].

9 Cao H, Regele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 2003;9:109–12. 10 Worman HJ, Bonne G. Laminopathies: a wide spectrum of human diseases. Exp Cell Res 2007;313:2121–33. 11 Barroso I, Gurnell M, Crowley VEF et al. Dominant negative mutations in human PPAR-gamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999;402:880–3. 12 Hegele RA, Cao H, Frankowski C et al. PPARG F388L, a transactivationdefiecient mutant, in partial familial lipodystrophy. Diabetes 2002;51:3586–90. 13 Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 2000;84:170–4. 14 Guettier J-M, Park JY, Cochran EK et al. Leptin therapy for partial lipodystrophy linked to a PPAR-γ mutation. Clin Endocrinol 2008;68:547–54. 15 Simha V, Garg A. Body fat distribution and metabolic derangements in patients with familial partial lipodystrophy associated with mandibuloacral dysplasia. J Clin Endocrinol Metab 2002;87:776–85. 16 Novell G, Muchir A, Sangiuolo F et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 2002;71:416–31. 17 Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 2003;12(16):1995–2001.

Mandibuloacral dysplasia

Acquired partial disorders

Mandibuloacral dysplasia is a rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia (bird-like facies, acro-osteolysis, mottled cutaneous pigmentation, dental abnormalities, skin atrophy and alopecia). Affected patients have a progeroid appearance. Patients show two patterns of associated lipoatrophy: type A presents with loss of fat exclusively from arms and legs, and type B shows generalized fat loss. Some patients (type A) carry mutations of the lamin A/C (LMNA) gene [15,16]. Other patients may have mutations identified in ZMPSTE24 [17]. References 1 Dunnigan MG, Cochrane MA, Kelly A et al. Familial lipoatrophic diabetes with dominant transmission. Q J Med 1974;43:33–48. 2 Köbberling J, Wilms B, Kattermann R et al. Lipodystrophy of the extremities. Humangenetik 1975;29:111–20. 3 Ozer FL, Lichtenstein JR, Kwiterovitch PO et al. A ‘new’ variety of lipodystrophy. Clin Res 1973;21:533A. 4 Davidson MB, Young RT. Metabolic studies in familial partial lipodystrophy of the lower trunk and extremities. Diabetologia 1975;11:561–8. 5 Reardon W, Temple IK, Mackinnon H et al. Partial lipodystrophy syndromes: a further male case. Clin Genet 1990;38:391–5. 6 Burn J, Baraitser M. Partial lipoatrophy with insulin resistant diabetes and hyperlipidaemia (Dunnigan syndrome). J Med Genet 1986;23:128–30. 7 Köbberling J, Dunnigan MG. Familial partial lipodystrophy: two types of an X-linked dominant syndrome, lethal in the hemizygous state. J Med Genet 1986;23:120–7. 8 Herbst KL, Tannock LR, Deeb SS et al. Köbberling type of familial partial lipodystrophy: an underrecognized syndrome. Diabetes Care 2003;26:1819–24.

Acquired partial lipoatrophy Syn. Barraquer–Simons disease

Definition. Acquired partial lipoatrophy (APL) is a nonMendelian disorder that occurs predominantly in females, who exhibit a loss of subcutaneous adipose tissue, starting on the face and progressing downwards to the trunk, and accompanied by normal or excessive fat deposition in the pelvic girdle and lower limbs [1]. Ninety percent of the cases have low C3 levels due to the presence of C3 nephritic factor (C3NeF) and about one-half of the patients develop an associated membranoproliferative glomerulonephritis. Aetiology. The disorder may follow an acute specific fever such as measles or dermatomyositis [2–4]. Although the exact cause of APL remains obscure in most cases, the frequent relationship with C3NeF (an acquired autoantibody that binds to the C3 convertase enzyme), often associated with an immunologically related glomerulonephritis or other autoimmune diseases [4–8], supports an immunological basis for APL. The role of C3 deficiency as a primary event in PPL is further supported by the description of APL in a family with C3 deficiency [9]. Although the link between C3 deficiency (with C3NeF) and glomerulonephritis and/or later onset of systemic lupus

141.16

Chapter 141

erythematosus (SLE) can be explained [2,8], its link with lipoatrophy is unknown. Recently, impaired expression of mitochondrial and adipogenic genes in adipose tissue has been reported [10]. In contrast to other lipoatrophies, diabetes mellitus is rare in APL [11]. However, basal hyperinsulinaemia following an oral glucose tolerance test is frequent [12], implying a similarity with forms of lipoatrophic diabetes for which insulin and insulin receptor abnormalities have been described. Clinical features. With a female : male predominance of 5 : 1, patients usually present in the second decade of life although onset of APL earlier in childhood has been well described. APL is acquired in most cases and has a fairly sudden onset, characterized by the symmetrical disappearance of facial fat, producing a cadaveric-like facies, followed by the progressive loss of subcutaneous fat in the upper half of the body. Some patients may somewhat paradoxically develop fat overgrowth on the lower part of the body. Glomerulonephritis, diabetes mellitus and SLE are the most frequent complications/associations and should be sought. Occasional findings include cutaneous vasculitis and purpura, cirrhosis, myopathy and coeliac disease [13–17]. Treatment. No preventive or therapeutic measures appear effective for the lipoatrophy, and facial reconstruction may be necessary to improve the dramatic facial appearance [18]. Management of the complications (diabetes, nephritis) should follow the usual course. Closely monitored pregnancy can be successful [19].

Lipodystrophy in HIV-infected patients Lipodystrophy in HIV patients (LDHIV) [20–23] is recognized as a newly described complication in HIV patients receiving highly active antiretroviral therapies (HAARTs) that include HIV-protease inhibitors. It may soon become the most frequent form of lipoatrophy in countries with both high HIV prevalence and financial access to antiretroviral therapies. Prevalence is variable but usually ranges around 50% in patients treated for more than 1 year with protease inhibitors. Children can be affected. Lipodystrophy in HIV patients usually presents with a selective loss of fat from the face and extremities and, in some patients, accumulation of fat around the neck, dorsocervical region, abdomen and trunk. It is also linked with metabolic abnormalities such as dyslipidaemia, glucose intolerance and insulin resistance. Management of LDHIV is difficult. Lipoatrophy can be managed with the use of nucleoside reverse transcriptase inhibitor sparing regimes, thiazolidinediones, uridine and cosmetic surgery (poly-L-lactic acid injections) [24]. Lipohypertrophy and insulin resistance may be addressed with

lifestyle interventions (diet and exercise), metformin, thiazolidinediones and recombinant growth hormone. Hyperlipidaemia requires lifestyle interventions as well as statins and fibrates [25]. References 1 Barraquer-Ferré L. Lipodystrophie progressive, syndrome de Barraquer et Simons. Presse Med 1935;86:1672–74. 2 Sissons JG, West RJ, Fallows J et al. The complement abnormalities of lipodystrophy. N Engl J Med 1976;294:461–5. 3 Kavanagh GM, Colaco CB, Kennedy CT. Juvenile dermatomyositis associated with partial lipoatrophy. J Am Acad Dermatol 1993;28:348–51. 4 Torrelo A, Espana A, Boixeda P et al. Partial lipodystrophy and dermatomyositis. Arch Dermatol 1991;127:1846–7. 5 Alarcon Segovia D, Ramos Niembro F. Association of partial lipodystrophy and Sjögren’s syndrome (letter). Ann Intern Med 1976;85:474–5. 6 Font J, Herrero C, Bosch X et al. Systemic lupus erythematosus in a patient with partial lipodystrophy. J Am Acad Dermatol 1990;22:337–40. 7 Hall SW, Gillespie JJ, Tenczynski TF. Generalized lipodystrophy, scleroderma, and Hodgkin’s disease (letter). Arch Intern Med 1978;138:1303–4. 8 Walport MJ, Davies KA, Botto M et al. C3 nephritic factor and SLE: report of four cases and review of the literature. Q J Med 1994;87:609–15. 9 McLean RH, Hoefnagel D. Partial lipodystrophy and familial C3 deficiency. Hum Hered 1980;30:149–54. 10 Guallar JP, Rojas-Garcia R, Garcia-Arumi E et al. Impaired expression of mitochondrial and adipogenic genes in adipose tissue from a patient with acquired partial lipodystrophy (Barraquer–Simons syndrome): a case report. J Med Case Reports 2008;2:284–9. 11 Rifkind BM, Boyle JA, Gale M. Blood lipid levels, thyroid status, and glucose tolerance in progressive partial lipodystrophy. J Clin Pathol 1967;20:52–5. 12 West RJ, Fosbrooke AS, Lloyd JK. Metabolic studies and autonomic function in children with partial lipodystrophy. Arch Dis Child 1974;49:627–32. 13 Robertson DA, Wright R. Cirrhosis in partial lipodystrophy. Postgrad Med J 1989;65:318–20. 14 O’Mahony D, O’Mahony S, Whelton MJ et al. Partial lipodystrophy in coeliac disease. Gut 1990;31:717–18. 15 Orrell RW, Peatfield RC, Collins CE et al. Myopathy in acquired partial lipodystrophy. Clin Neurol Neurosurg 1995;97:181–6. 16 Perrot H, Delaup JP, Chouvet B. Lipodystrophie de Barraquer et Simons. Ann Dermatol Vénéréol 1987;114:1083–91. 17 Levy Y, George J, Yona E et al. Partial lipodystrophy, mesangiocapillary glomerulonephritis, and complement dysregulation. An autoimmune phenomenon. Immunol Res 1998;18:55–60. 18 Goossens S, Coessens B. Facial contour restoration in Barraquer– Simons syndrome using two free TRAM flaps: presentation of two case reports and long-term follow-up. Microsurgery 2002;22: 211–218. 19 Akhter J, Qureshi R. Partial lipodystrophy and successful pregnancy outcome. J Pak Med Assoc 1995;45:24. 20 Hengel RL, Watts NB, Lennox JL. Benign symmetric lipomatosis associated with protease inhibitors. Lancet 1997;350:1596. 21 Jaquet D, Levine M, Oertegua-Rodriguez E et al. Clinical and metabolic presentation of the lipodystrophic syndrome in HIV-infected children. AIDS 2000;14:2123–2128. 22 Chen D, Misra A, Garg A. Clinical review 153. Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab 2002;87:4845–4856.

Disorders of Fat Tissue 23 Amaya RA, Kozinetz CA, McMeans A et al. Lipodystrophy syndrome in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2002;21:405–410. 24 Mest DR, Humble GM. Retreatment with injectable poly-L-lactic acid for HIV-associated facial lipodystrophy: 24-month extension of the blue pacific study. Dermatol Surg 2009;35:350–359. 25 Pirmohamed M. Clinical management of HIV-associated lipodystrophy. Curr Opin Lipidol 2009;20:309–314.

Inherited generalized disorders Leprechaunism, Berardinelli–Seip congenital lipoatrophy and acquired generalized lipoatrophy (Lawrence syndrome) are three clinically distinct forms of generalized lipoatrophy that belong to a group of disorders associated with severe insulin resistance. This group, which also includes the partial lipoatrophies, shows a significant risk for development of severe metabolic diseases and common clinical findings (see Box 141.2).

Leprechaunism Syn. Donohue syndrome

Definition. Leprechaunism is an autosomal recessive disorder due to a mutation of the insulin receptor gene and characterized by intrauterine growth retardation, small elfin-like face with protuberant ears, distended abdomen, large hands, feet and genitalia, abnormal skin with hypertrichosis, acanthosis nigricans and decreased subcutaneous fat [1–3]. In total, 52 cases were recorded in 1993 [4]. Aetiology. The molecular defect in leprechaunism is a mutation in the insulin receptor gene (INSR). More than 10 different mutations have been described [5], including both homozygous and combined heterozygous mutations that result in either a decrease in the number of

Box 141.2 Clinical findings in lipoatrophy syndromes • Lipoatrophy • Metabolic syndrome 䊊 Insulin resistance 䊊 Hyperglycaemia 䊊 Hypertriglyceridaemia 䊊 Lactic acidosis • Acanthosis nigricans • Hepatic disease (steatosis, cirrhosis) • Hypertrichosis • Hirsutism, polycystic ovarian syndrome • Muscular hypertrophy • Mental retardation

141.17

receptors or a defective function of the receptor. Secondary defective formation of insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) receptors have been described [6,7]. As IGF-1 receptors are present on the ovary, heart and kidneys, but not fat cells, this could explain ovarian enlargement, myocardial hypertrophy and kidney enlargement reported in some patients. Finally, Psiachou and colleagues [8] suggested that growth hormone (GH) resistance was a secondary effect caused by downregulation of growth hormone receptor activity in the presence of a high concentration of insulin proximal to the cell membrane, with consequent limitation of IGF-1 formation and cellular growth. Thus, although the primary defect in leprechaunism is in the INSR gene, a secondary defect is probably responsible for an impaired response to endogenous GH and growth failure. Histopathology. Skin biopsies show the complete absence of fat. Autopsy findings often show pancreatic β-cell hyperplasia in 60% of patients, increased iron deposition in liver, and kidney calcifications, as well as other rarer features [1]. Clinical features. Leprechaunism is characterized by cessation of intrauterine growth at about 7 months’ gestation. The two sisters first described by Donohue [2] also had a peculiar facies, creating a gnome-like appearance which lead to the designation. Severe endocrine disturbance was indicated by emaciation and enlargement of the breasts and clitoris. The sisters died at 46 and 66 days of age respectively. Unequivocal cases are all characterized in addition by hypertrichosis, acanthosis nigricans and symptomatic hypoglycaemia due to insulin resistance. Most patients die before 1 year of age [1,9]. Pictures of the phenotypic appearance can be found in reference [10]. Variant syndromes with leprechaun features include patients with clinical Cushing disease, enlarged adrenals and severe bone changes [11,12]: three infants with associated generalized elastic fibre deficiency [13] and five siblings with less severe leprechaun features, survival beyond 10 years of age, normal subcutaneous fat, kidney enlargement, myocardial hypertrophy and ovarian enlargement in the female case [4]. Diagnosis and treatment. Intrauterine growth retardation, abnormal facies, hirsutism and decreased subcutaneous fat lead to the diagnosis in most cases. Treatment in leprechaunism is aimed at avoiding hypoglycaemic attacks, which are potentially fatal. However, this may not prevent sudden death at an early age. Affected patients also often demonstrate acanthosis nigricans. Rabson–Mendenhall syndrome is another condition due to insulin receptor mutation. The phenotype is

141.18

Chapter 141

different from that of leprechaunism, with pseudoacromegalic facies, dental dysplasia, ungual dysplasia, abnormal hair, cutaneous hyperkeratosis and abdominal hypotonia. The insulin receptor is present but defective (absent in leprechaunism). The quality of the remaining insulin-binding activity is correlated with survival [14,15].

Berardinelli–Seip congenital lipoatrophy Syn. congenital generalized lipoatrophy, congenital lipoatrophic diabetes, total lipoatrophy with acromegaloid gigantism

Definition. Berardinelli–Seip congenital lipoatrophy (BSCL) is a rare autosomal recessive syndrome characterized by extreme paucity of fat in adipose tissue from birth, severe insulin resistance, hyperlipaemia and increased bone growth [16–18]. Aetiology. Berardinelli–Seip congenital lipoatrophy is an autosomal recessive and genetically heterogeneous disorder. BSCL-1 is due to AGPAT2 gene mutations on 9q34, which affect the triacylglycerol synthesis in adipose tissue. BSCL-2 is caused by mutations in the gene encoding seipin on 11q13. BSCL-3 is caused by mutations of the CAV1 gene [19–22]. Clinical features. Complete loss of subcutaneous fat appears at birth or within the first 2 years of life. Nonketotic insulin-resistant diabetes mellitus usually develops during the first or second decade [23–25]. Other findings include acanthosis nigricans, acromegaloid features, marked hypertriglyceridaemia (with or without eruptive xanthoma), visceromegaly, hirsutism, virilization in female patients and possible muscular hypertrophy. Individuals with BSCL-2 gene mutations seem to have mild mental retardation and cardiomyopathy, features not found in families with AGPAT2 mutations. Generalized congenital lipoatrophy with the association of systemic angiomatosis has been separated as a distinct entity (Brunzell syndrome) [26,27]. Treatment. With good control of the diabetes and hyperlipidaemia and prevention of their complications, patients reach adult life. Management of pregnancy is difficult, as in acquired generalized lipoatrophy [28]. Promising results are described with the use of subcutaneous recombinant leptin [29,30]. References 1 Rosenberg AM, Haworth JC, William Degroot G et al. A case of leprechaunism with severe hyperinsulinemia. Am J Dis Child 1980;134:170–5.

2 Donohue WL. Leprechaunism. J Pediatr 1954;45:505–19. 3 Elsas LJ, Endo F, Strumlauf F et al. Leprechaunism: an inherited defect in a high affinity insulin receptor. Am J Hum Genet 1985;37:73–88. 4 Al Gazali LI, Khalil M, Devadas K. A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. J Med Genet 1993;30:470–5. 5 Taylor SI. Diabetes mellitus. In: Scriver CR, Beaud AL, Sly WS et al. (eds) The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill, 1995, pp.843–96. 6 Van Oberghen-Schilling E, Rechler M, Romanus J et al. Receptors for insulin like growth factor I are defective in fibroblast cultures from a patient with leprechaunism. J Clin Invest 1981;68:1358–65. 7 Reddy SS-K, Kahn CR. Epidermal growth factor receptor defects in leprechaunism: a multiple growth factor-resistant syndrome. J Clin Invest 1989;84:1569–76. 8 Psiachou H, Mitton S, Alaghband-Zadeh J et al. Leprechaunism and homozygous nonsense mutation in the insulin receptor gene. Lancet 1993;342:924. 9 Cantani A, Ziruolo MG, Tacconi ML. A rare polydysmorphic syndrome: leprechaunism: review of 49 cases reported in the literature. Ann Genet 1987;30:221–7. 10 Ozbey H, Ozbey N, Tunnessen WW Jr. Picture of the month. Arch Pediatr Adolesc Med 1998;152:1031–2. 11 David R, Goodman RM. The Patterson syndrome, leprechaunism and pseudo-leprechaunism. J Med Genet 1981;18:294–8. 12 Patterson JH, Watkin WL. Leprechaunism in a male infant. J Pediatr 1962;60:733–9. 13 Dallaire L, Cantin M, Melancon SB et al. A syndrome of generalized elastic fiber deficiency with leprechaunoid features: a distinct genetic disease with an autosomal recessive mode of inheritance. Clin Genet 1976;10:1–11. 14 Rabson SM, Mendenhall EN. Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus. Am J Clin Pathol 1956;26:283. 15 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;94:356–62. 16 Berardinelli W. An undiagnosed endocrinometabolic syndrome: report of two cases. J Clin Endocrinol Metab 1954;14:193–204. 17 Seip M. Generalized lipodystrophy. Ergeb Inn Med Kinderheilkd 1971;31:59–95. 18 Seip M, Trygstad O. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr 1996;413:2–28. 19 Magre J, Delepine M, Khallouf E et al. Identification of the gene altered in Berardinelli–Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001;28:365–70. 20 Agarwal AK, Aqrioglu E, de Almeida S et al. AGPAT? is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 2002;31:21–3. 21 Van Maldergem L, Magre J, Khallouf TE et al. Genotype–phenotype relationships in Berardinelli–Seip congenital lipodystrophy. J Med Genet 2002;39:722–33. 22 Kim C, Delepine M, Boutet E et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab 2008;93:1129–34. 23 Tsukahara H, Kikuchi K, Kuzuya H et al. Insulin resistance in a boy with congenital generalized lipodystrophy. Pediatr Res 1988;24:668–72. 24 Copeland KC, Nair KS, Kaplowitz PB et al. Discordant metabolic actions of insulin in extreme lipodystrophy of childhood. J Clin Endocrinol Metab 1993;77:1240–5. 25 Garg A, Fleckenstein JL, Peshock RM et al. Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrinol Metab 1992;75:358–61.

Disorders of Fat Tissue 26 Brunzell JD, Shankle SW, Bethune JE. Congenital generalized lipodystrophy accompanied by cystic angiomatosis. Ann Intern Med 1968;69:501–16. 27 Van Maldergem L, Bacq C, Mommen N et al. Total lipodystrophy, polycystic ovaries and cystic angiomatosis of bones (Brunzell syndrome): confirmation of a separate entity. Am J Hum Genet 1992;51 (Suppl):A109 (abstract). 28 Sturley RH, Stirling C, Reckless JP. Generalised lipodystrophy and pregnancy. Br J Obstet Gynaecol 1994;101:719–20. 29 Savage DB, O’Rahilly S. Leptin: a novel therapeutic role in lipodystrophy. J Clin Invest 2002;109:1285–6. 30 Gomes KB, Cavalcanti Pardini V, Fernandes AP. Clinical and molecular aspects of Berardinelli–Seip congenital lipodystrophy (BSCL). Clin Chim Acta 2009;402:1–6.

Acquired generalized disorders Acquired generalized lipoatrophy Syn. Lawrence syndrome, lipoatrophy

acquired

lipoatrophic

diabetes,

total

Acquired generalized lipoatrophy (AGL) comprises the same clinical features as Berardinelli–Seip syndrome,

141.19

with the difference that symptoms develop later in life. Lipoatrophy is delayed until adolescence or early adulthood. Lawrence syndrome was believed to be acquired and restricted to women, but consanguinity or family antecedents have been reported [1–3]. An episode of granulomatous panniculitis precedes the onset of lipoatrophy in 25% of cases. Another group of patients show concomitant autoimmune disease, particularly juvenile dermatomyositis, which suggests a common autoimmune basis for both diseases. However, in half of the patients, the disease is idiopathic [4]. Long-term leptin therapy is effective in the very rare cases with AGL and type 1 diabetes [5]. References 1 Lawrence RD. Lipodystrophy and hepatomegaly. Lancet 946; i:724. 2 Sasaki T, Ono H, Nakajima H et al. Lipoatrophic diabetes. J Dermatol 1992;19:246–9. 3 Robert JJ, Rakotoambinina B, Cochet I et al. The development of hyperglycaemia in patients with insulin-resistant generalized lipoatrophic syndromes. Diabetologia 1993;36:1288–92. 4 Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case report and review of the literature. Medicine 2003;82:129–46. 5 Park JY, Chong AY, Cochran EK et al. Type-1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. Clin Endocrinol Metab 2008;93:26–31.

142.1

C H A P T E R 142

Ehlers–Danlos Syndromes Nigel P. Burrows1, Navjeet Sidhu-Malik2 & Heather N. Yeowell2 1

Department of Dermatology, Addenbrookes NHS Trust, Cambridge, UK Department of Dermatology, Duke University Medical Center, Durham, NC, USA

2

Ehlers–Danlos syndrome subtypes, 142.11

Definition. The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue diseases that historically have been divided into as many as 12 different subtypes. In 1986, the Seventh International Congress of Human Genetics standardized the growing and confusing list of EDS subcategories [1]. With improved understanding of the molecular defects in many subtypes, the classification was modified further in 1997 [2]. Although this more recent system, called the Villefranche classification, attempts to simplify the nosology, some patients still do not fit into any one specific category. Furthermore, new subtypes have subsequently been delineated. The cardinal features, which are shared to varying degrees by most of the subtypes, include hyperextensible skin with a soft, doughy or velvety texture, dystrophic scarring, easy bruising, joint hypermobility and connective tissue fragility [1]. The genetic pattern of inheritance differs for the subtypes and additional systemic involvement may occur in some forms of EDS. The diagnosis is based on the history, inheritance pattern, clinical examination and biochemical or genetic testing that are available for some of the subtypes. Some EDS variants are relatively benign entities and have no significant associated morbidity; others, however, have systemic complications. There are no established figures for the incidence of EDS. In 1972, McKusick [3] estimated EDS to be one of the most common inherited diseases of connective tissue. As symptoms are often unnoticed, especially in the milder subtypes, EDS may be underdiagnosed, and a more recent estimate of the incidence is 1:5000 [4]. Up to 9% of adult general dermatology patients have been found to have a mild variant of classic EDS [5]. Many of the features, such as soft skin,

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

easy scarring and bruising, are difficult to assess during infancy and only become evident during childhood, whereas others, such as joint hypermobility, may present at birth with congenital hip dislocation, kyphoscoliosis and muscle hypotonia. History. Although there are references to EDS-like diseases in ancient literature [6], the first reported case dates to 1682, when van Meek’ren [7], a Dutch surgeon, described a patient with hyperextensible skin. Features of EDS were undoubtedly present in the contortionists exhibited at fairs and curiosity shows that were popular in the 19th century. Various reports of these performers appeared in the medical literature [8]. The first extensive clinical description of a patient with EDS should be credited to Tschernogobow [9], a Russian dermatologist who, in 1891, described two patients with hyperextensible skin with scarring and fragility, joint hyperextensibility and molluscoid pseudo-tumours. He also conjectured that this might represent a disorder of underlying connective tissue. Ehlers [10] in 1901 reported a case of a patient with hyperextensible skin, joint laxity and easy bruising, and in 1908 Danlos [11] described a second patient with the additional features of pseudo-tumours at sites of trauma. In 1936, Weber [12] reviewed the numerous case reports describing various conditions with loose skin and joints, and suggested the name EDS for the disorder encompassing skin fragility and hyperextensibility, joint laxity and molluscoid pseudo-tumours. McKusick [13], in 1960, recognized that EDS encompasses a genetically heterogeneous group of diseases. Subsequently, subtypes have been added and others have been removed; for example, EDS IX, originally called ‘X-linked cutis laxa’ and later reclassified as ‘occipital horn syndrome’, was excluded from the EDS subcategories when it was found to be a copper transport defect, and EDS XI has been renamed the ‘familial articular hypermobility syndrome’. The most recent Villefranche

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classification takes into account recent progress in the understanding of the molecular pathology of EDS and has enabled more accurate definition of some subtypes [2]. Many of the forms have been given names based on their clinical phenotype, rather than numbers, in an attempt to reduce confusion. Therefore, the Villefranche classification is used, whenever possible, in the rest of this chapter. Aetiology and pathogenesis. Ehlers–Danlos syndromes comprise a heterogeneous group of diseases, and distinct abnormalities involving abnormal collagen synthesis or processing have been described for classic, vascular, kyphoscoliosis and arthrochalasia subtypes. Causal defects in other extracellular matrix molecules are recognized in the fibronectin-deficient subtype and in a newly recognized autosomal recessive form of EDS.

Classic EDS (previously types I and II) Variable sizes of dermal collagen fibrils with large composite ‘cauliflower ’ fibrils as a result of abnormal fibrillogenesis are seen on electron microscopy. Abnormalities of type V collagen, which regulates collagen I fibril diameter, were first identified by linkage analysis in a large British EDS II family [14]. Subsequent studies confirmed that EDS I and II are allelic [15]. Mutations in the genes encoding α1 and α2 chains of type V collagen (COL5A1 and COL5A2 respectively) account for up to 50% of all classic EDS patients. The majority of mutations result in a non-functional COL5A1 allele, with fewer reports of structural mutations [16]. Signal peptide mutations in COL5A1 have also been linked to this type of EDS [17]. The cause in the remainder is unclear, but abnormalities in collagen I have been described in one family [18]. Although mouse models suggest a role for other extracellular matrix proteins, such as decorin, biglycan, fibromodulin and lumican, these have not been identified in human EDS [19,20]. Hypermobility-type EDS (previously type III) No consistent biochemical or genetic abnormality has been identified. One family has been described with a glycine substitution towards the N-terminal of type III collagen [21]. Mis-sense and truncating mutations in the TNXB gene have been reported in small numbers of patients with hypermobility-type EDS, suggesting TNXB as a candidate gene for some patients with this type of EDS [22,23]. A deficiency, or absence of, α2(I) collagen has been associated with overlap between mild hypermobilitytype EDS in childhood and a cardiac valvular form of EDS during adulthood [24]. In a recent study of 13 patients with hypermobility-type EDS, linkage to mutations in COL5A3 was excluded [25].

Vascular-type EDS (previously type IV) Vascular EDS results from a defect in type III collagen with heterogeneous mutations in the COL3A1 gene [26– 28]. These mutations lead to abnormal type III procollagen structure, synthesis or secretion, resulting in a thin dermis with variable size of collagen fibrils [29]. Fibroblast cultures demonstrate decreased synthesis or secretion of procollagen III [30]. Skin extracts also have decreased collagen III levels, and serum levels of procollagen III aminopeptide are decreased. An overlapping phenotype with Loeys–Dietz syndrome (LDS) occurs in patients with type II LDS, attributed to mutations in the transforming growth factor β receptor II (TGFBR2) gene [31]. X-linked EDS (previously type V) No biochemical or genetic abnormality has been described for this subtype. Kyphoscoliosis-type EDS (previously type VI) This was the first of the inherited disorders of collagen to be biochemically characterized [32]. The defect in most, but not all, patients consists of a deficiency of lysyl hydroxylase, an important enzyme involved in collagen cross-linking. A heterogeneous group of homozygous and compound heterozygous mutations in one of the three lysyl hydroxylase genes, lysyl hydroxylase 1(PLOD1) gene, is responsible for the abnormal enzyme activity [33]. The diagnosis is confirmed by decreased levels of lysyl hydroxylase enzyme activity in fibroblast culture. Abnormal pyridinoline cross-links can also be detected in the urine [34,35]. A rarer, clinically similar condition with normal lysyl hydroxylase activity is designated EDS VIB [36]. This has not been defined at the molecular/biochemical level. There has been a recent report of a novel spondylocheiro dysplastic form of EDS (SCD-EDS) which has an overlapping clinical phenotype with the kyphoscoliotic form and normal lysyl hydroxylase activity. This has been attributed to a mutation in the Zn++ transporter gene SLC39A13 and it remains to be determined whether some previously designated EDS VIB patients fall into this category [37]. Arthrochalasia-type EDS (previously types VIIA and B) This type consists of two subgroups, A and B. Both are caused by type I collagen gene defects, which result in a precursor procollagen molecule with an abnormal amino terminal cleavage site that cannot be processed to mature collagen. Types A and B are distinguished by mutations in COL1A1 and COL1A2 genes, respectively, which disrupt or delete exon 6 and therefore the N-proteinase (ADAMTS2) cleavage site of proα1(I) and proα2(I) collagen chains [38,39]. To date, mutations have been identi-

Ehlers–Danlos Syndromes

fied in 32 patients. Angulated collagen fibrils may be seen on electron microscopy [40,41].

Dermatosparaxis-type EDS (previously type VIIC) Mutations in the procollagen I N-proteinase (ADAMTS2) enzyme result in insufficient processing of both α1(I) and α2(I) collagen chains [42]. To date, mutations in the ADAMTS2 gene have been identified in nine patients, of which seven are homozygous. This leads to alterations in cross-link formation in the type I collagen molecule, with decreased tissue strength. Dermal collagens are thin and form hieroglyphic-like structures [43,44]. Periodontitis-type EDS (previously type VIII) No specific biochemical defect has been reported for this disorder, although reduced type III collagen has been reported in the skin [45]. It is inherited as an autosomal dominant and linkage has been shown to chromosome 12p13 in three out of five families, indicating genetic heterogeneity [46]. Fibronectin-deficient EDS (previously type X) Abnormal platelet aggregation due to a defect in fibronectin has been reported [47]. Abnormal dermal collagen fibrils occur, possibly due to impaired interaction with fibronectin. Other types Progeroid EDS. Galactosyltransferase I deficiency due to mutations in the B4GALT7 gene leads to abnormal glycosaminoglycan synthesis in patients with this subtype [48]. Different mutations in the B4GALT7 gene may result in phenotypes of variable severity, as observed in two patients with a milder form of the progeroid-like phenotype of EDS [49]. A similar phenotype occurs in decorinand biglycan-deficient mice because of impaired binding to glycosaminoglycans [19]. Tenascin-X deficient EDS. Tenascin-X (TNX) is a large extracellular matrix glycoprotein, and mutations have been identified in this gene in a small number of patients with this autosomal recessive subtype [50]. Affected skin shows abnormal elastic fibres and reduced collagen content [51]. TNX appears to regulate collagen deposition by dermal fibroblasts [52] and possibly plays a role in matrix stability and collagen fibrillogenesis by interacting with dermal extracellular matrix molecules [53,54]. Clinical features. The clinical features associated with EDS are present to differing degrees in the individual subtypes and are summarized in Table 142.1. An overview of the clinical features is presented below and the specific features associated with each subtype

142.3

will be reviewed as the individual subtypes are discussed.

Cutaneous aspects Cutaneous features of EDS include skin hyperextensibility and fragility [4,6,55]. The skin is soft, and is often described as velvety and doughy with a chamois leather texture. The skin is easily extended and, upon release, recoils back to its original shape (Fig. 142.1). Redundant skin may be present overlying elbows and knees, but this differs from the lax skin of cutis laxa which, after stretching, does not recoil. Hyperextensibility and skin softness can be difficult to assess in infants because of subcutaneous fat and are more easily evaluated in slightly older children. Skin fragility (dermatorrhexis) is manifested by tearing of the skin after minor trauma. Sites commonly involved include knees, shins, elbows and face, especially the forehead and chin (Fig. 142.2). Scarring occurs most commonly during childhood as infants begin to crawl and walk and experience minor trauma, and improves with increasing age. Cutaneous fragility also results in easy bruising, delayed wound healing and poor healing after suturing, with a higher incidence of wound dehiscence. Prominent bruising can lead to mistaken concerns about child abuse in affected children. Scars characteristically widen and develop fine ‘cigarette paper ’ or ‘papyraceous’ wrinkling in addition to a shiny surface with overlying telangiectasias. Vascular EDS typically lacks significant hyperextensibility of skin but is associated with pale skin with readily visible veins on the torso, particularly the upper chest (Fig. 142.3) and dorsum of hands and feet (acrogeric appearance). Unique cutaneous findings in some patients with EDS are molluscoid pseudo-tumours (Fig. 142.4) and spheroids. Molluscoid pseudo-tumours are fibrous nodules that occur over areas of recurrent trauma such as the elbows, knees and heels. Spheroids are small subcutaneous, cyst-like nodules that occur over bony prominences of the legs and arms. These are calcified on radiography examination and result from trauma-induced fibrosis and calcification of the subcutaneous fat lobules [56,57]. Additional cutaneous features include looseness of palmar skin and an increased number of palmar creases (Fig. 142.5). Elastosis perforans serpiginosa has been reported in some affected individuals [58,59] and is more common in the vascular subtype. Piezogenic papules, herniations of fat lobules through fascia at the medial and lateral aspects of the feet, may also be present. Pregnancyassociated striae gravidarum generally do not occur in patients with EDS.

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Table 142.1 Summary of clinical and genetic features of the main EDS subtypes Villefranche classification

Subtype

Inheritance

Clinical features

Molecular defect

Classic

I Gravis; II Mitis

AD

Skin: soft, hyperextensible with easy bruising, fragility; ‘cigarette paper’ scarring, especially during childhood; molluscoid pseudo-tumours Joints: hypermobility Other: history of premature birth

COL5A1 and COL5A2 mutations

Hypermobility

III Benign familial hypermobility

AD

Skin: soft, minimal hyperextensibility and scar formation Joints: marked hypermobility

Unknown

Vascular

IV Arterial, vascular, ecchymotic

AD

Skin: thin, translucent, veins visible, marked bruising with minimal scarring and hyperextensibility; hands and feet prematurely aged Joints: small joint hypermobility Other: bowel, arterial and uterine rupture with risk of death; premature or lowbirthweight infants

COL3A1 mutations

X-linked

V X-linked

XLR

Similar to mild classic EDS

Unknown

Kyphoscoliosis

VI Ocular-scoliotic

AR

Skin: hyperextensible, fragile, with easy bruising, no increased fragility Joints: marked hypermobility Other: hypotonia at birth, delayed development and kyphoscoliosis; possible ocular fragility

Lysyl hydroxylase deficiency due to PLOD 1 gene mutations

Arthrochalasia

VII Arthrochalasia multiplex congenita

AD

Skin: soft, mild hyperextensibility and bruising Joints: extreme laxity with dislocations Other: hypotonia.

Type I collagen gene defect: A: COL1A1 mutation, B: COL1A2 mutation. Both result in loss of exon 6 and therefore proteinase cleavage site

Dermatosparaxis

VIIC Human dermatosparaxis

AR

Skin: marked fragility, easy tearing and bruising Joints: mild hypermobility Other: growth retardation, umbilical herniae, blue sclerae

Procollagen N-proteinase deficiency due to ADAMTS2 mutations

Periodontitis

VIII Periodontal

AD

Skin: soft, mild hyperextensibility, easy bruising, scars on shins with purple-brown discoloration Joints: hypermobility Other: early-onset periodontal disease

Unknown

Fibronectin deficient

X Fibronectin deficient

AR

Skin and joints: like mild classic EDS Other: clotting defect with abnormal platelet adhesion

Fibronectin defect

Progeroid

AR

Skin and joints: similar to classic EDS Other: aged appearance, short stature, sparse hair, osteopenia, mental retardation

Galactosyltransferase deficiency due to B4GALT7 mutations

Tenascin-X

AR

Similar to classic EDS but no scarring

TNXB mutations

AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

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142.5

(a)

(a) (b) Fig. 142.1 Hyperextensibility of the skin is present with marked stretching upon gentle pulling.

Musculoskeletal aspects With the exception of vascular EDS, in which only small joints are involved, joint hypermobility is a cardinal feature of EDS and involves both large and small joints (Fig. 142.6) [60]. Generally, this is first noticed when a child exhibits a delay in beginning to walk and remains unsteady with a greater number of falls and improves with increasing age. At any age, females display greater mobility than males. Clinical evaluation of joint hyperextensibility can be made using the Beighton score [61] (Box 142.1). This includes examination of small joints by assessing the ability to dorsiflex the fifth finger beyond 90° and the ability to appose thumb to flexor forearm. Large joint hyperextensibility is evaluated by the presence of knee and elbow hyperextension. One point is given for each side of the body for these manoeuvres and a further point is added for the ability to bend and touch palms of hands flat to the floor. Hypermobility is present if a score of four out of nine or greater is achieved. Severe hypermobility as seen with kyphoscoliosis and arthrochalasia types can

(b) Fig. 142.2 Skin fragility with abnormal scarring. (a) Knee with cigarette paper or papyraceous wrinkling after trauma. (b) Scar widening after healing.

be present at birth with hypotonia, skeletal deformities and congenital hip dislocations. Early-onset osteo-arthritis can be a significant complication and usually involves weight-bearing joints such as the knees and ankles. Chronic pain is a common manifestation of EDS [62]. Other musculoskeletal complications include recurrent joint effusions, which occur most

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Fig. 142.3 Translucent skin with visible venous network over the upper chest in vascular EDS.

Fig. 142.5 Palmar aspect of hands with increased wrinkling and loose appearance of the skin.

commonly in knees, ankles and elbows, pes planus (flatfootedness) and kyphoscoliosis [63]. Haemarthrosis may occur in vascular EDS. Joint instability results in delayed walking in childhood and joint subluxation. Children and adults with hypermobility are more prone to reduced bone mineral density and DEXA screening has been advocated for this group [64,65].

Fig. 142.4 Molluscoid pseudo-tumours present on the elbow with redundant skin and bruising.

Box 142.1 Beighton scoring system Movement

Score o

Dorsiflexion of right and left 5th finger >90 Apposition of right and left thumb to forearm Hyperextension of right and left elbow >10o Hyperextension of right and left knee >10o Palms touching the floor with knees extended Total

2 2 2 2 1 9

Reproduced from Beighton et al. Ann Rheum Dis 1973;32:413–18 with permission from BMJ Publishing Group Ltd.

Cardiovascular aspects Structural cardiac abnormalities are not specifically associated with EDS and may be present as a result of random association [66,67]. Mitral valve prolapse (MVP), resulting from redundant chordae tendineae and valve cusps, has been reported, most often with hypermobile and vascular EDS [68]; however, one study suggests that the incidence of MVP in these types and classic EDS is not increased [69]. A rare, recessively inherited form of EDS due to heterozygous mutations in COL1A2, characterized by cardinal features, is also associated with cardiac valvular defects which may not present until adult life [24,70]. Vascular EDS is also associated with spontaneous and life-threatening rupture of large arteries, especially the descending aorta and other abdominal vessels [71]. Intracranial aneurysm and arteriovenous fistulae rupture may occur with vascular EDS, but have also been reported with other EDS types [72]. Genitourinary aspects Urinary bladder diverticulae are found in most EDS types but are specifically associated with occipital horn syn-

Ehlers–Danlos Syndromes

142.7

(a)

(c)

(b)

drome (formerly EDS IX). These may result in vesicoureteral reflex and have an associated risk of recurrent urinary tract infections.

Neurological aspects Autonomic nervous system-related symptoms (dysautonomia) such as syncope, palpitations, easy fatigue and postural orthostatic intolerance (POTS) occur more commonly in hypermobile patients [73]. A small subset also reports the failure of intradermal local anaesthetic [74]. Significant neurological complications include muscle hypotonia in kyphoscoliotic EDS and haemorrhage from intracranial arterial aneurysm in vascular EDS. Joint laxity, particularly of the spine, may result in nerve

Fig. 142.6 Joint hypermobility. (a,b) Small joint hypermobility with extension of fingers beyond 90°. (c) Large joint hypermobility is evidenced by hyperextension of the knees.

trauma and subsequent neurological manifestations [75,76].

Ocular aspects Minor ocular findings include epicanthal folds, ease in everting the upper eyelid (Méténier ’s sign), redundant upper eyelid skin and strabismus that is secondary to the laxity of tendons supporting the extrinsic muscles of the eyes [77]. Kyphoscoliosis-type EDS (also formerly known as ocular-scoliotic variant) has been associated with more significant ocular complications including retinal detachment and scleral perforation, which may occur during childhood [78]. Microcornea, glaucoma and keratoconus may also occur. However, a more recent review of patients

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suggests that the more serious ocular complications have been overestimated and that myopia is the most common finding in this EDS subgroup [79]. Keratoconus may be present in classic EDS and has been described cosegregating in a family with EDS II found to have a COL5A2 mutation [80].

Dental and oral aspects Gorlin’s sign, the ability to touch the tip of the nose with the tongue, has sometimes been associated with EDS; nonetheless, this finding is not specific as it occurs in 10% of unaffected individuals [81]. Periodontitis-type EDS is associated with early-onset periodontal disease and premature loss of teeth [82]. It has been suggested that absence of the inferior labial and lingual frenula may be a reliable marker for classic and hypermobile EDS [83], although this has been disputed by other authors [84,85]. Bleeding disorders Bleeding and bruising problems are seen in different forms of EDS, particularly in the vascular EDS subtype. In children with EDS, excessive bruising is often the presenting problem and a careful diagnosis is necessary to distinguish between this disorder and other potential causes of bruising [86]. Obstetric complications Complications of pregnancy occur in both mother and infant with EDS and are related to the specific type [87]. These include maternal joint subluxation, severe varicose veins and cervical insufficiency, with risk of miscarriage and preterm labour and postpartum haemorrhage. Vascular EDS is associated with the greatest risks, including uterine rupture, which has an estimated maternal mortality of 25%. Fetuses affected with EDS have a higher incidence of prematurity, resulting from maternal premature rupture of membranes, in addition to demonstrating low birthweight and short stature. Prognosis. The prognosis of the various EDS subtypes is based upon the specific associated features and their complications and has been reviewed above. Differential diagnosis. The differential diagnosis of EDS includes syndromes specifically associated with joint hypermobility, cutaneous laxity or aneurysms. Familial articular hypermobility syndrome was initially classified as EDS XI but is manifest by joint laxity alone, without any skin changes, and must be considered in patients with joint hypermobility without other stigmata of EDS. Cutis laxa has increased cutaneous laxity with acrogeric appearance but is distinguished by lack of recoil after stretching of the skin.

Occasional patients with hypermobility-type and kyphoscoliosis-type EDS have a marfanoid habitus, suggesting some overlap with Marfan syndrome [88–90]. Loeys–Dietz syndrome is a recently described aneursymal phenotype due to mutations in transforming growth factor β receptors 1 and 2 (TGFBR 1 or 2) [91]. Patients with type I LDS have overlapping features with Marfan syndrome, most noticeably aortic aneurysms, arachnodactyly and dural ectasia. Additional features of cleft palate or bifid uvula, craniosynostosis and hypertelorism occur. Type II LDS phenotype overlaps with vascular EDS although a bifid uvula may rarely be present. Although the overall prognosis is poor for both LDS and vascular EDS, the survival during, or immediately after, vascular surgery is dramatically lower in the former. The occipital horn syndrome is a rare disorder with X-linked recessive inheritance. It arises from mutations in the same gene as for Menkes syndrome [92] and has been reclassified as a disorder of copper transport. It is characterized, at birth, by soft, lax and redundant skin. The skin, however, is not hyperelastic and does not demonstrate easy bruising or abnormal scarring. During childhood, formation of bladder diverticuli may occur and skeletal changes such as exostoses at sites of tendon insertion, also called occipital horns, are typical. Arthrochalasia-type EDS can also share features with osteogenesis imperfecta [93] and a non-glycine substitution has been recently reported in the α1(I)collagen chain in a family with an osteogenesis imperfecta/EDS phenotype [94]. Investigations. The diagnosis of EDS is based primarily on clinical history, family history to clarify inheritance and careful physical examination to evaluate involvement of the various systems. Biochemical testing may be undertaken to confirm the diagnosis in several EDS subtypes. In vascular EDS, protein chemistry analysis using fibroblast cultures demonstrates decreased synthesis or secretion of procollagen III. In addition, decreased serum levels of procollagen III aminopeptide may be found [30]. If collagen III levels are normal, type II LDS should be considered and TGFBR1 and 2 genes should be screened for mutations [91]. Decreased lysyl hydroxylase enzyme activity in fibroblast culture resulting in underhydroxylated collagen causes abnormally fast migration of type I collagen on radiolabelled protein electrophoresis and confirms the diagnosis of kyphoscoliosis-type EDS [35]. Measurement of urinary excretion of lysyl- and hydroxylysyl-derived pyridinoline cross-links is a non-invasive reliable diagnostic test in this subgroup [34]. Arthrochalasia subtypes can be confirmed through evaluation of type I collagen processing, which shows abnormalities in α1, α2 or both peptides [38,39,42]. Electron microscopic studies

Ehlers–Danlos Syndromes

of skin in dermatosparaxis show markedly irregular (hieroglyphic-like) collagen fibrils. Biochemical confirmation is based on electrophoretic analysis showing the accumulation of pNα1(I) and pNα2(I) chains of type I collagen extracted from dermis [44]. Tenascin-X deficient EDS is confirmed with the complete absence of serum TNX, measured by ELISA [50]. Haploinsufficiency associated with hypermobility EDS results in reduced serum TNX levels [22]. The genetic defects have been elucidated for vascular, kyphoscoliosis, arthochalasia, dermatosparaxis, tenascin-X deficient and some classic subtypes, and molecular analysis is therefore feasible, but it is usually available only in specialized centres. Treatment. The management of an EDS patient is dependent upon which system is involved. Joint laxity may result in joint dislocations or early-onset osteo-arthritis and may require orthopaedic or rheumatological followup. Physical therapy to strengthen supporting muscles and stabilize loose joints may be necessary in children who are experiencing delay in motor development. Bracing may be required to support unstable joints and assist with walking. Sports with joint impact such as gymnastics or long-distance running are best avoided in children with significant joint hyperextensibility. Repeated hyperextension of joints to perform ‘joint tricks’ should also be discouraged as this stresses an unstable joint, increasing the risk of joint dislocation. In children with severe skin fragility, protective pads over knees, shins and elbows may be helpful in preventing lacerations. Poor wound healing and scar formation have implications for any surgical procedure to be performed, and the surgeon must be aware of the potential problems. Because of the risk of sudden, and potentially fatal, vascular or bowel haemorrhage in vascular EDS, patients should be advised to wear a medical alert tag or bracelet with their diagnosis. They should be given advice to avoid any activities that are likely to cause a sudden increase in blood pressure. Females with vascular EDS must be made aware of the complications associated with pregnancy. This also applies to females with the kyphoscoliosis type. Most importantly, counselling, reviewing the inheritance and specific features of the subtype involved, is essential for all families. The clinical and genetic heterogeneity of the EDS subtypes must be stressed with careful explanation of the expected risks and complications associated with the specific diagnosis. Clearly, the diagnosis of mild classic EDS has minimal impact on family planning or activity level of an affected individual, whereas the diagnosis of vascular, kyphoscoliosis, arthrochalasia or dermatosparaxis types has significant lifelong sequelae. The dramatic arterial complications of vascular-type EDS

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have often been stressed in the older literature on EDS, and it is essential to clarify that these are not associated with all the EDS subtypes. Patient support groups exist in the UK (www.ehlersdanlos.org) and the USA (www.ednf.org) and are a valuable source of information for patients. References 1 Beighton P, de Paepe A, Danks D et al. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 1988;29:585–94. 2 Beighton P, de Paepe A, Steinmann B et al. Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31–7. 3 McKusick VA. The Ehlers–Danlos syndrome. In: Heritable Disorders of Connective Tissue, 4th edn. St Louis: C.V. Mosby, 1972:292–371. 4 Steinmann B, Royce PM, Superti-Furga A. The Ehlers–Danlos syndrome. In: Royce PM, Steinmann B (eds) Connective Tissue and its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York: Wiley-Liss, 2002:431–523. 5 Holzberg M, Hewan-Lowe KO, Olansky AJ. The Ehlers–Danlos syndrome: recognition, characterization, and importance of a milder variant of the classical form. J Am Acad Dermatol 1998;19:656–66. 6 Beighton P. The Ehlers–Danlos syndromes. In: Beighton P (ed) McKusick’s Heritable Disorders of Connective Tissue, 5th edn. St Louis: C.V. Mosby, 1993:189–251. 7 Van Meek’ren JA. De dilatabilitate extraordinaria cutis. In: Observations Medicochirugicae. Ger Fil Medicinae Studioso. Amsterdam: Ex Officina Henrici and Viduae Theodori Boom, 1682:134–6. 8 Beighton P. The Ehlers–Danlos Syndrome. London: Heinemann Medical, 1970. 9 Tschernogobow A. Cutis laxa (presentation at first meeting of Moscow Dermatologic and Venereologic Society, 13 November 1891). Mhft Prakt Dermatol 1892;14:76. 10 Ehlers E. Cutis Laxa, Neigung zu hemorrhagien in der Haut, Loekerung mehrerer artikulationen. Dermatal Zeitschr 1901;8:173. 11 Danlos M. Un cas de cutis laxa avec tumeurs par contusion chronique des coudes et des Mace De Lepinay. Bull Soc Franc Dermatol 1908;19:70. 12 Weber FP. The Ehlers–Danlos syndrome. Br J Dermatol Syph 1936;48:609. 13 McKusick VA. The Ehlers–Danlos syndrome. In: Heritable Disorders of Connective Tissue, 2nd edn. St Louis: C.V. Mosby, 1960. 14 Loughlin J, Irven C, Hardwick LJ et al. Linkage of the gene that encodes the α1 chain of type V collagen (COL5A1) to type II Ehlers– Danlos syndrome (EDS II). Hum Mol Genet 1995;4:1649–51. 15 Burrows NP, Nicholls AC, Yates JWR et al. The gene encoding α1 (V) (COL5A1) is linked to mixed Ehlers–Danlos syndrome type I/II. J Invest Dermatol 1996;106:1273–6. 16 Malfait, A, de Paepe A. Molecular genetics in classic Ehlers–Danlos syndrome. Am J Med Genet C Semin Med Genet 2005;139C:17–23. 17 Symoens S, Malfait F, Renard M et al. COL5A1 signal peptide mutations interfere with protein secretion and cause classic Ehlers–Danlos syndrome. Hum Mutat 2009;30(2):E395–403. 18 Nuytinck L, Freund M, Lagae L et al. Classical Ehlers–Danlos syndrome caused by a mutation in type I collagen. Am J Hum Genet 2000;66:1398–402. 19 Corsi A, Xu T, Chen X-D et al. Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers–Danlos-like changes in bone and other connective tissues. J Bone Miner Res 2002;17: 1180–9. 20 Jepsen KJ, Wu F, Peragallo JH et al. A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. J Biol Chem 2002;277:35532–40.

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21 Narcisi P, Richards AJ, Ferguson SD et al. A family with Ehlers– Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen. Hum Mol Genet 1994;3:1617–20. 22 Zweers MC, Bristow J, Steijlen PM et al. Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers–Danlos syndrome. Am J Hum Genet 2003;73:214–17. 23 Zweers MC, Dean WB, van Kuppevelt TH et al. Elastic fiber abnormalities in hypermobility type Ehlers–Danlos syndrome patients with tenascin-X mutations. Clin Genet 2005;67:330–4. 24 Malfait F, Symoens S, Coucke P et al. Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers–Danlos syndrome with hypermobility and propensity to cardiac valvular problems. J Med Genet 2006;43:e36. 25 Hoffman GG, Dodson GE, Cole WG, Greenspan DS. Absence of apparent disease causing mutations in COL5A3 in 13 patients with hypermobility Ehlers–Danlos syndrome. Am J Med Genet A 2008;146A:3240–1. 26 Byers PH. Ehlers–Danlos syndrome: recent advances and current understanding of the clinical and genetic heterogeneity. J Invest Dermatol 1994;103:47S–52S. 27 Pope FM, Narcisi P, Nicholls AC et al. COL3A1 mutations cause variable clinical phenotypes including acrogeria and vascular rupture. Br J Dermatol 1996;135:163–81. 28 Pepin M, Schwarze U, Superti-Furga A et al. Clinical and genetic features of Ehlers–Danlos syndrome type IV, the vascular type. N Engl J Med 2000;342:673–80. 29 Byers PH, Holbrook KA, McGillivray B. Clinical and ultrastructural heterogeneity of type IV Ehlers–Danlos syndrome. Hum Genet 1979;47:141–50. 30 De Paepe A. Ehlers–Danlos syndrome type IV. Clinical and molecular aspects and guidelines for diagnosis and management. Dermatology 1994;189(suppl 2):21–5. 31 Loeys BL, Schwarze U, Holm T et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. N Engl J Med 2006;355:788–98. 32 Pinnell SR, Krane SM, Kenzora JE et al. A heritable disorder of connective tissue: hydroxylysine-deficient collagen disease. N Engl J Med 1972;286:1013–20. 33 Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase gene that result in enzyme deficiency and the clinical phenotype of Ehlers– Danlos syndrome type VI. Mol Genet Metab 2000;71:212–24. 34 Steinmann B, Eyre DR, Shao P. Urinary pyridinoline cross-links in Ehlers–Danlos syndrome type VI. Am J Hum Genet 1995;57:1505–8. 35 Yeowell HN, Steinmann B. Ehlers–Danlos Syndrome, Kyphoscoliotic Form. In: GeneReviews at GeneTests:Medical Genetics Information Resource. Available at www.genetests.org. 36 Walker LC, Overstreet MA, Willing MC et al. Heterogeneous basis of the type VIB form of Ehlers–Danlos syndrome (EDS VIB) that is unrelated to decreased collagen lysyl hydroxylation. Am J Med Genet A 2004;131A:155–62. 37 Giunta C, Elcioglu NH, Albrecht B et al. Spondylocheiro dysplastic form of the Ehlers–Danlos syndrome – an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet 2008;82(6):1290–305. 38 Cole WG, Chan D, Chambers GW et al. Deletion of 24 amino acids from the proα1(I) chain of type I procollagen in a patient with the Ehlers–Danlos syndrome type VII. J Biol Chem 1986;261:5496–503. 39 Wirtz MK, Glanville RW, Steinmann B et al. Ehlers–Danlos syndrome type VIIB. Deletion of 18 amino acids comprising the N-telopeptide region of a proα2(I) chain. J Biol Chem 1987;262:16376–85. 40 Holbrook KA, Byers PH. Structural abnormalities in the dermal collagen and elastic matrix from the skin of patients with inherited connective tissue disorders. J Invest Dermatol 1982;79(suppl):7–15. 41 Giunta C, Chambaz C, Pedemonte M et al. The arthrochalasia type of Ehlers–Danlos syndrome (EDS VIIA and VIIB): the diagnostic

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value of collagen fibril ultrastructure. Am J Med Genet A 2008;146A(10):1341–6. Smith LT, Wertelecki W, Milstone LM et al. Human dermatosparaxis: a form of Ehlers–Danlos syndrome that results from failure to remove the amino-terminal peptide of type I procollagen. Am J Hum Genet 1992;51:235–44. Reardon W, Winter RM, Smith LT et al. The natural history of human dermatosparaxis (Ehlers–Danlos syndrome type VIIC). Clin Dysmorphol 1995;4:1–11. Colige A, Nuytinck L, Hausser I et al . Novel types of mutation responsible for the dermatosparactic type of Ehlers–Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene. J Invest Dermatol 2004;123:656–63. Lapière CM, Nusgens BV. Ehlers–Danlos type VIII skin has a reduced proportion of type III collagen. J Invest Dermatol 1981;76:422. Rahman N, Dunstan M, Teare MD et al. Ehlers–Danlos syndrome with severe early-onset periodontal disease (EDS-VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. Am J Hum Genet 2003;73:198–204. Arneson MA, Hammerschmidt DE, Furcht LT et al. A new form of Ehlers–Danlos syndrome: fibronectin corrects defective platelet function. JAMA 1980;244:144–7. Okajima T, Fukumoto S, Furukawa K et al. Molecular basis for the progeroid variant of Ehlers–Danlos syndrome. J Biol Chem 1999;274:28841–4. Faiyaz-Ul-Haque M, Zaidi SH, Al-Ali M et al. A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers–Danlos syndrome resembling the progeroid type. Am J Med Genet A 2004;128A:39–45. Schalkwijk J, Zweere MC, Steijlen PM et al. A recessive form of the Ehlers–Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 2001;345:1167–75. Zweers MC, van Vlijmen-Willems IM, van Kuppevelt TH et al. Deficiency of tenascin-X causes abnormalities in dermal elastic fiber morphology. J Invest Dermatol 2004;122:885–91. Mao JR, Taylor G, Dean WB et al. Tenascin-X deficiency mimics Ehlers–Danlos syndrome in mice through alteration of collagen deposition. Nature Genet 2002;30:421–5. Egging D, van den Berkmortel F, Taylor G et al. Interactions of human tenascin-X domains with dermal extracelleular matrix molecules. Arch Dermatol Res 2007;298:389–96. Minamitani T, Ikuta T, Saito Y et al. Modulation of collagen fibrillogenesis by tenascin-X and type VI collagen. Exp Cell Res 2004;298:305–15. Byers PH, Holbrook KA. Ehlers–Danlos syndrome. In: Emery AEH, Rimoin DL (eds) Principles and Practice of Medical Genetics, 2nd edn. New York: Churchill Livingstone, 1990:1065–81. Beighton P, Thomas ML. The radiology of the Ehlers–Danlos syndrome. Clin Radiol 1969;20:354–61. Weber FP, Aitken JK. Nature of the subcutaneous spherules in some cases of the Ehlers–Danlos syndrome. Lancet 1938;i:198–9. Mehregan AH. Elastosis perforans serpiginosa. Arch Dermatol 1968;97:381–93. Mehta RK, Burrows NP, Royland Payne CME et al. Elastosis perforans serpiginosa and associated disorders. Clin Exp Dermatol 2001;26:521–4. Beighton P. Articular manifestations of the Ehlers–Danlos syndrome. Semin Arthr Rheum 1971;1:246–61. Beighton PH, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis 1973;32:413–18. Sacheti A, Szemere J, Bernstein B et al. Chronic pain is a manifestation of the Ehlers–Danlos syndrome. J Pain Symptom Manage 1997;14:88–93. Beighton P, Horan F. Orthopaedic aspects of the Ehlers–Danlos syndrome. Semin Arthr Rheum 1971;1:246–61.

Ehlers–Danlos Syndromes 64 Engelbert RH, Bank RA, Sakkers RJ et al. Pediatric generalized joint hypermobility with and without musculoskeletal complaints: a localized or systemic disorder? Pediatrics 2003;111:e248–54. 65 Tofts LJ, Elliot EJ, Munns C et al. The differential diagnosis of children with joint hypermobility: a review of the literature. Pediatr Rheumatol Online J 2009;7:1. 66 Beighton P. Cardiac abnormalities in the Ehlers–Danlos syndrome. Br Heart J 1969;31:227–32. 67 Pyeritz RE. Cardiovascular manifestations of heritable disorders of connective tissue. Prog Med Genet 1983;5:191–301. 68 Jaffe AS, Geltman EM, Rodey GE et al. Mitral valve prolapse: a consistent manifestation of type IV Ehlers–Danlos syndrome. The pathogenetic role of the abnormal production of type III collagen. Circulation 1981;64:121–5. 69 Dolan AL, Mishra MB, Chambers JB et al. Clinical and echocardiographic survey of the Ehlers–Danlos syndrome. Br J Rheumatol 1997;36:459–62. 70 Schwarze U, Hata R, McKusick VA et al. Rare autosomal recessive cardiac valvular form of Ehlers–Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet 2004;74:917–30. 71 McFarland W, Fuller DE. Mortality in Ehlers–Danlos syndrome due to spontaneous rupture of large arteries. N Engl J Med 1964;271: 1309–10. 72 Shohet I, Rosenbaum I, Frand M et al. Cardiovascular complications in the Ehlers–Danlos syndrome with minimal external findings. Clin Genet 1964;31:148–52. 73 Gazit Y, Nahir AM, Grahame R et al. Dysautonomia in the joint hypermobility syndrome. Am J Med 2003;115:33–40. 74 Arendt-Nielson L, Kaalund S, Hogsaa B et al. The response to local anaesthetics (EMLA®) as a clinical test to diagnose between hypermobility and Ehlers–Danlos III syndrome. Scand J Rheumatol 1991;20:190–5. 75 Moreira A, Wilson J. Non-progressive paraparesis in children with congenital ligamentous laxity. Neuropediatrics 1992;23: 49–52. 76 Galan E, Kousseff BG. Peripheral neuropathy in Ehlers–Danlos syndrome. Pediatr Neurol 1995;12:242–5. 77 Pemberton JW, Freeman HM, Schepens CL. Familial retinal detachment and the Ehlers–Danlos syndrome. Arch Ophthalmol 1966;76:817–24. 78 Beighton P. Serious ophthalmological complications in the Ehlers– Danlos syndrome. Br J Ophthalmol 1970;54:263–8. 79 Wenstrup RJ, Murad S, Pinnell SR. Ehlers–Danlos syndrome type VI. Clinical manifestations of lysyl hydroxylase deficiency. J Pediatr 1989;115:405–9. 80 Richards AJ, Martin S, Nicholls AC et al. A single base mutation in COL5A2 causes Ehlers–Danlos syndrome type II. J Med Genet 1998;35:846–8. 81 Gorlin RJ, Cohen MM, Levin LS. Ehlers–Danlos syndromes. In: Syndromes of the Head and Neck, 4th edn. New York: Oxford University Press, 1990:429–41. 82 Stewart RE, Hollister DW, Rimoin DL. A new variant of Ehlers– Danlos syndrome: an autosomal dominant disorder of fragile skin, abnormal scarring, and generalized periodontitis. Birth Defects 1977;13:85–93. 83 De Felice C, Toti P, di Maggio G et al. Absence of the inferior labial and lingual frenula in Ehlers–Danlos syndrome. Lancet 2001;357: 1500–3. 84 Bohm S, Martinez-Schramm A, Gille J et al. Missing inferior labial and lingual frenula in Ehlers–Danlos syndrome. Lancet 2001;358: 1627. 85 Shankar S, Shirley E, Burrows NP. Absence of inferior labial or lingual frenula is not a useful marker for Ehlers–Danlos syndrome in the UK. J Eur Acad Dermatol Venereol 2006;20:75–80.

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86 De Paepe A, Malfait F. Bleeding and bruising in patients with Ehlers– Danlos syndrome and other collagen vascular disorders. Br J Haematol 2004;127:491–500. 87 Hordnes K. Ehlers–Danlos syndrome and delivery. Acta Obstet Gynecol Scand 1994;73:671–3. 88 Grahame R, Bird HA, Child A et al. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol 2000;27:1777–9. 89 Walker BA, Beighton PH, Murdoch JL. The marfanoid hypermobility syndrome. Ann Intern Med 1969;71:349–52. 90 Callewaert B, Malfait F, Loeys B et al. Ehlers–Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol 2008;22:165–89. 91 Loeys BL, Chen J, Neptune ER et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275–81. 92 Levinson B, Conant R, Schnur R et al. A repeated element in the regulatory region of the MNK gene and its deletion in a patient with the occipital horn syndrome. Hum Mol Genet 1996;5:1737–42. 93 Raff ML, Craigen WJ, Smith LT et al. Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers–Danlos syndrome type VII. Hum Genet 2000;106:19–28. 94 Lund A. A novel arginine to cysteine substitution in the triple helical region of the α1(I) collagen chain in a family with an osteogenesis imperfecta/Ehlers–Danlos syndrome phenotype. Clin Genet 2008;73:97–101.

Ehlers–Danlos syndrome subtypes Classic EDS (types I and II) Classic EDS is an autosomal dominant condition comprising both EDS types I (gravis) and II (mitis), which are allelic. Together with hypermobility-type EDS, they constitute an estimated 80% of all EDS cases [1]. Cutaneous signs usually present when the child starts to crawl or walk. The skin is soft with a velvety texture and can easily be stretched, with recoil to its original form upon release. Increased fragility of the skin results in large wounds following minor trauma, and poor wound healing leads to widened scars with characteristic ‘cigarette paper ’ wrinkling and atrophy. Large scars, often with hyperpigmentation, develop during childhood in areas of repeated trauma such as knees, elbows and shins. Molluscoid pseudo-tumours and subcutaneous spheroids may also develop on areas of trauma. Delayed motor development including walking and an unsteady gait may be evident owing to marked joint hypermobility. Affected individuals tire more easily and this may relate, at least in part, to poor musculoskeletal co-ordination. Ligamentous laxity of small joints can be such that the child has difficulty holding a pen. Other findings include a history of premature rupture of fetal membranes in 50% of affected infants, scoliosis and pes planus, and lower extremity venous varicosities. Herniae due to poor muscle tone may present in infancy. Symptomatic bladder diverticulae can develop [2]. Arterial ruptures occur only rarely.

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Hypermobility-type EDS (type III) Joint hypermobility occurs in 8–39% of school-age children and it is important to determine whether it is occurring in the context of a hereditary disorder of connective tissue [3]. Hypermobility-type EDS and benign joint hypermobility syndrome overlap and are considered the same disorder by some authors [4]. Joint hypermobility is the hallmark of this autosomal dominant subtype and constitutes 10% of all cases of EDS [1]. The skin is soft but less hyperextensible and with only minimal scarring compared with classic EDS. Complications of joint dislocation, including pain and early-onset osteo-arthritis, may be present. Chronic musculoskeletal pain, orthostatic intolerance (dysautonomia) and chronic fatigue are more prevalent in hypermobility-type EDS and benign joint hypermobility syndrome [5].

Vascular-type EDS (type IV) Vascular EDS is also called the arterial–ecchymotic type of Sack–Barabas, acrogeric or ecchymotic EDS. This subtype is quite distinct in that patients lack skin and joint hyperextensibility and it is associated with life-threatening complications [6]. It is an uncommon subtype and exhibits an autosomal dominant inheritance pattern. Tissues with abundant type III collagen are most affected, namely blood vessels, bowel and uterus. The skin of patients is thin and translucent with easily visible veins on the abdomen, trunk and extremities. A minority of patients have soft skin with mild hyperextensiblity. Marked bruising of the skin after minor trauma often occurs. The skin of the hands and feet is thin and wrinkled with a resulting aged and acrogeric appearance. A characteristic facies with thin nose, thin lips, hollow cheeks, prominent eyes and thin hair has been described [7]. Life-threatening complications include rupture of medium-sized arteries and the bowel. Arterial dissection or rupture is the most common cause of death and most often occurs in abdominal mesenchymal, splenic and renal arteries, and in the descending aorta. Bowel rupture frequently involves the ascending colon. Median survival is 48 years and although significant complications are rare in childhood, 25% of patients with vascular EDS have had at least one complication by the age of 20 years [6]. Death in the peripartum period in 12 out of 81 women following 183 pregnancies was reported as a consequence of vessel and uterine ruptures [6]. Vascular EDS can present in infancy and childhood with low birthweight, prematurity, congenital hip dislocations, increased bruising and the facies described above, although without a family history it is most often not suspected until vascular, bowel or pregnancy complications occur later in life. Treatment of this EDS type con-

sists of supportive care for management of vessel or bowel rupture. Pregnancy requires close monitoring.

X-linked EDS (type V) This type is characterized by X-linked recessive inheritance and is clinically similar to mild classic EDS (type II) with findings of soft skin and mild joint and skin hyperextensibility. This disorder has been described in only two families with a total of eight affected persons [8,9]. Without a clear family history to confirm X-linked inheritance, the diagnosis of classic EDS should be considered. Some controversy exists as to whether this is a distinct subtype rather than variable expression of classic EDS [10].

Kyphoscoliosis-type EDS (type VI) Also known as ocular-scoliotic EDS, this is a rare autosomal recessive disorder manifesting as joint laxity, kyphoscoliosis and muscle hypotonia (Fig 142.7) [11]. Skin findings include fragility with easy bruising, hyperextensibility and abnormal scarring. Major complications can include severe thoracic deformity with respiratory insufficiency [12], in addition to vascular and gastrointestinal ruptures [13]. A maternal and perinatal mortality in pregnancy was recently reported in a case of kyphoscoliosis. Maternal autopsy showed a spontaneous rupture of the right iliac artery [14]. Newborns generally present with muscular hypotonia, poor cry, problems with sucking and delayed motor development. Kyphoscoliosis may be present at birth and is thought to be due to muscular hypotonia with resulting ligamentous laxity. Vertebral bodies are normal. There is marked joint laxity, which may result in joint dislocations. Ocular fragility complicated by retinal detachment and globe rupture was initially reported as a major feature [13,15], leading to the description ‘ocular form’ of EDS. A subsequent review of the clinical features in patients, with biochemical confirmation, suggests that this may be less common than initially thought [16]. Blue sclerae, microcornea, glaucoma and keratoconus may also be present. Although from a different genetic background, patients with the spondylocheiro dysplastic form of EDS (SCDEDS) have an overlapping clinical phenotype with the kyphoscoliotic type, but there are distinguishable biochemical differences [17].

Arthrochalasia-type EDS (types VIIA and B) Arthrochalasia consists of two subgroups, types A and B, also known as arthrochalasia multiplex congenita [1]. They are autosomal dominant disorders and patients exhibit severe joint laxity with bilateral congenital hip

Ehlers–Danlos Syndromes

(a)

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(b)

Fig. 142.7 (a)A 4-year-old girl with severe kyphoscoliosis and pectus excavatum due to kyphoscoliois-type EDS (type VI). Her skin is soft and hyperextensible. (b) Severe scoliosis evident on X-ray. Reproduced with permission from Nature Publishing.

(a)

(b)

Fig. 142.8 (a)A 12 month old with bilateral hip dislocation due to arthrochalasia (EDS VII). (b) Same child at 23 months post open reduction of bilateral hip dislocation. Thoracolumbar kyphosis is evident due to hypotonia and ligament laxity. Reproduced with permission from John Wiley & Sons.

dislocations and dislocation of other joints throughout life (Fig. 142.8). Some patients have short stature. Muscular hypotonia may be present at birth and is associated with delayed gross motor development. Skin features include softness, mild increase in bruising and mild hyperextensibility without significantly increased fragility. There may be phenotypic overlap with osteogenesis imperfecta, which is also caused by abnormalities of type I collagen [18].

Dermatosparaxis-type EDS (type VIIC) A very rare disorder with extreme skin fragility, called dermatosparaxis, was first identified in cattle in 1971, and only relatively recently has the human counterpart been described [19–22]. It is characterized by autosomal recessive inheritance, marked skin fragility with easy tearing of the skin, skin laxity, increased bruising, growth retardation, umbilical herniae and blue sclerae.

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Periodontitis-type EDS (type VIII)

Progeroid EDS

This rare autosomal dominant variant is associated with generalized periodontal disease [23–25]. There is early loss of teeth in the second to third decades due to gingival inflammation and alveolar bone loss. Other features include easy bruising that presents in early childhood, and a characteristic purplish-brown discoloration of scars limited to the shins (Fig. 142.9). Joint hypermobility and cutaneous hyperextensibility may be present to a minor degree.

The cardinal features of EDS are rarely seen in association with mental retardation, an aged appearance, scanty scalp hair and eyelashes, short stature, abnormal dentition and osteopenia. Patients lack the full characteristics of true progeria.

Fibronectin-deficient EDS (type X) This autosomal recessive disorder has been reported in only a single family [26]. It is characterized by mild skin hyperextensibility, poor wound healing, easy bruising and mild joint hypermobility. Excessive bleeding was noted and a platelet adhesion defect that improved with the addition of fibronectin was identified.

(a)

(b) Fig. 142.9 EDS VIII. (a) Parent (left) and child (right) with characteristic scarring on anterior shins with bruising and purple discoloration. (b) Periodontal disease is present in this child with gingival fragility and retraction of tissue.

Tenascin-X deficient EDS Originally described in a patient with 21-hydroxylase deficiency [27], this subtype is characterized by an autosomal recessive inheritance. Joint laxity, bruising and hyperextensible skin are features but notably the skin is not fragile and scars are therefore normal [28]. The relative risk of systemic symptoms is not clear although in adults, cardiovascular (mitral valve prolapse), gastrointestinal (diverticular disease) and obstetric (vaginal, uterine and rectal prolapses) complications have all been reported [29]. References 1 Beighton P. The Ehlers–Danlos syndromes. In: Beighton P (ed) McKusick’s Heritable Disorders of Connective Tissue, 5th edn. St Louis: C.V. Mosby, 1993:189–251. 2 Hordnes K. Ehlers–Danlos syndrome and delivery. Acta Obstet Gynecol Scand 1994;73:671–3. 3 Tofts LJ, Elliot EJ, Munns C et al. The differential diagnosis of children with joint hypermobility: a review of the literature. Pediatr Rheumatol Online J 2009;7:1. 4 De Felice C, Toti P, di Maggio G et al. Absence of the inferior labial and lingual frenula in Ehlers–Danlos syndrome. Lancet 2001;357:1500–3. 5 Grahame R, Hakim AJ. Hypermobility. Curr Opin Rheumatol 2008;20:106–10. 6 Pepin M, Schwarze U, Superti-Furga A et al. Clinical and genetic features of Ehlers–Danlos syndrome type IV, the vascular type. N Engl J Med 2000;342:673–80. 7 Pope FM, Narcisi P, Nicholls AC et al. Clinical presentations of Ehlers–Danlos syndrome type IV. Arch Dis Child 1988;63:1016–25. 8 Beighton P. X-linked recessive inheritance of the Ehlers–Danlos syndrome. BMJ 1968;2:409–11. 9 Beighton P, Curtis D. X-linked Ehlers–Danlos syndrome type V: the next generation. Clin Genet 1985;27:472–8. 10 Steinmann B, Royce PM, Superti-Furga A. The Ehlers–Danlos syndrome. In: Royce PM, Steinmann B (eds) Connective Tissue and its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York: Wiley-Liss, 2002:431–523. 11 Yeowell HN, Steinmann B. Ehlers–Danlos Syndrome, Kyphoscoliotic Form. In: GeneReviews at GeneTests:Medical Genetics Information Resource. Available at www.genetests.org. 12 Chamson A, Berbis P, Fabre JE et al. Collagen biosynthesis and isomorphism in a case of Ehlers–Danlos syndrome type VI. Arch Dermatol Res 1987;279:303–7. 13 Sussman M, Lichtenstein JR, Nigra TP et al. Hydroxylysine-deficient skin collagen in a patient with a form of Ehlers–Danlos syndrome. J Bone Joint Surg 1974;56:1228–34. 14 Esaka E, Golde S, Stever M et al. A maternal and perinatal mortality in pregnancy complicated by the kyphoscoliotic form of Ehlers– Danlos syndrome. Obstet Gynecol 2009;113:515–18. 15 Pinnell SR, Krane SM, Kenzora JE et al. A heritable disorder of connective tissue: hydroxylysine-deficient collagen disease. N Engl J Med 1972;286:1013–20.

Ehlers–Danlos Syndromes 16 Beighton P. Serious ophthalmological complications in the Ehlers– Danlos syndrome. Br J Ophthalmol 1970;54:263–8. 17 Giunta C, Elcioglu NH, Albrecht B et al. Spondylocheiro dysplastic form of the Ehlers–Danlos syndrome – an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet 2008;82(6):1290–305. 18 Raff ML, Craigen WJ, Smith LT et al. Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers–Danlos syndrome type VII. Hum Genet 2000;106:19–28. 19 Smith LT, Wertelecki W, Milstone LM et al. Human dermatosparaxis: a form of Ehlers–Danlos syndrome that results from failure to remove the amino-terminal peptide of type I procollagen. Am J Hum Genet 1992;51:235–44. 20 Wertelecki W, Smith LT, Byers PH. Initial observations of human dermatospraxis: Ehlers–Danlos syndrome type VIIC. J Pediatr 1992;121:558–64. 21 Nusgens BV, Verellen-Dumoulin C, Hermanns Le T et al. Evidence for a relationship between Ehlers–Danlos type VII C in humans and bovine dermatosparaxis. Nature Genet 1992;1:214–17. 22 Petty EM, Seashore MR, Braverman IM et al. Dermatospraxis in children: a case report and review of the newly recognized phenotype. Arch Dermatol 1993;129:1310–15.

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23 Stewart RE, Hollister DW, Rimoin DL. A new variant of Ehlers– Danlos syndrome: an autosomal dominant disorder of fragile skin, abnormal scarring, and generalized periodontitis. Birth Defects 1977;13:85–93. 24 Linch DC, Acton CH. Ehlers–Danlos syndrome presenting with juvenile destructive periodontitis. Br Dent J 1979;147:95–6. 25 Nelson DL, King RA. Ehlers–Danlos syndrome type VIII. J Am Acad Dermatol 1981;5:297–303. 26 Arneson MA, Hammerschmidt DE, Furcht LT et al. A new form of Ehlers–Danlos syndrome: fibronectin corrects defective platelet function. JAMA 1980;244:144–7. 27 Burch GH, Gong Y, Liu W et al. Tenascin-X deficiency is associated with Ehlers–Danlos syndrome. Nat Genet 1997;17:104–8. 28 Schalkwijk J, Zweere MC, Steijlen PM et al. A recessive form of the Ehlers–Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 2001;345:1167–75. 29 Lindor NM, Bristow J. Tenascin-X deficiency in autosomal recessive Ehlers–Danlos syndrome. Am J Med Genet A 2005;135:75–80.

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C H A P T E R 143

Cutis Laxa Richard J. Antaya Department of Pediatric Dermatology, Yale University, New Haven, CT, USA

Definition. The term ‘cutis laxa’ (dermatochalasis, dermatomegaly) denotes the clinical expression of several extremely rare, heterogeneous disorders of elastic tissue, characterized by loose, inelastic skin that is pendulous and hangs in folds, giving a prematurely aged or bloodhound-like appearance. Some forms with significant systemic involvement are better termed ‘generalized elastolysis’. Aetiology. Elastic fibres are primarily present in the extracellular matrix of the dermis, large blood vessels and lung. They are responsible for the elastic recoil of these tissues. Elastic fibres are composed of two components: the protein elastin, which imparts the elasticity, and fibulin, which is more of a structural fibrillar protein. Cutis laxa may be inherited or acquired, and both types may manifest in childhood. The mechanisms responsible for cutis laxa vary widely; however, the aetiology of a few of the major types has been elucidated. Genetic defects in fibulin-4 and -5 appear to be responsible for a severe autosomal recessive type type I cutis laxa [1]. Elevated serum elastase (neutral protease) activity has been demonstrated in a patient with recessively inherited cutis laxa and suggests a possible role for this enzyme; however, elevated activity has also been shown in normal patients [2]. Some autosomal dominant and recessive forms are caused by various mutations in the elastin gene [3–5]. Interestingly, Zhang et al. [6] demonstrated that addition of transforming growth factor-β to affected fibroblasts in vitro resulted in correction of this defect, presumably by creating an alternative splicing pattern, thereby circumventing the critical mutation in autosomal recessive cutis laxa type I. Other diseases associated with different elastin mutations include Williams syndrome and supravalvular aortic stenosis [7]. A deficiency of the copper-dependent elastase inhibitor has also been postulated, but this has not been proven [8]. The X-linked form (formerly Ehlers– Danlos syndrome IX, occipital horn type) is caused by

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

mutations in the ATPase, copper-transporting, α polypeptide gene (ATP7A), resulting in decreased serum copper and caeruloplasmin [8–10]. Diminished activity or production of the copper-dependent enzyme lysyl oxidase, critical to both collagen and elastic tissue crosslinking, may be implicated [11]. Abnormal glycosylation of extracellular matrix proteins is an aetiological factor in some forms of inherited cutis laxa. A congenital defect in glycosylation has been noted in several patients with autosomal recessive cutis laxa type II with neurological involvement, and isoelectric focusing of apolipoprotein C-III is reliably abnormal in the majority of patients [12–15]. An immunological basis is suggested for the acquired forms that have been reported following ill-defined febrile illnesses or surgery [16–19]. It has been associated with apparent hypersensitivity reactions to penicillin [20], isoniazid [18] or bacille Calmette–Guérin inoculation (in one adult only). At least one child has developed clinically significant cutis laxa after diffuse cutaneous mastocytosis, presumably from the release of elastase from accompanying neutrophilic inflammation [21]. Deposits of immunoglobulin A (IgA) and immunoglobulin G (IgG) have been observed around the elastic fibres in some patients with acquired cutis laxa [22,23]. There are similar reports of IgG and immunoglobulin light-chain deposition on elastic fibres in adults affected with cutis laxa and plasma cell dyscrasias, also supporting a role for humoral mechanisms in the pathogenesis of the acquired variants [24,25]. Drugs such as d-penicillamine may produce cutis laxa by chelating copper, which is required for the function of enzymes responsible for the cross-linking of elastin and collagen [26]. One child was shown to have an underlying genetic susceptibility to acquired cutis laxa. Investigators demonstrated that the interaction of abnormal elastin and fibulin alleles resulted in elastic fibres with enhanced susceptibility to inflammatory destruction after visceral larva migrans parasitism with Toxocara canis [27]. Pathology. Haematoxylin and eosin-stained tissue is generally unremarkable. With elastic stains (Verhoeff, Weigert) there may be diminished elastic fibres either throughout the dermis or primarily in the upper or lower

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dermis. Elastic fibres that are seen may be short, fragmented and clumped, and often display thickening centrally with tapering to a point at the ends. In advanced cases, elastic fibres may be completely absent, with only dust-like granules staining positive for elastic tissue [28]. The findings vary with the stage of the disease and location on the body, but even clinically uninvolved skin may display the characteristic changes [29]. Some cases exhibit moderate non-specific chronic inflammation with lymphocytes, histiocytes [29] and neutrophils [30]. There may be a mucinous stroma in areas of abnormal elastic tissue [8,29]. Ultrastructurally, there are various patterns of abnormal elastic fibres, of which the most significant is the presence of electron-dense amorphous or granular deposits associated with bundles of microfibrils [29,31,32]. A deficiency of elastin with normal microfibril formation has been observed in some cases [31]. Both acquired and congenital types display similar ultrastructural findings [31]. Internal organs such as lung [32], aorta and gastrointestinal (GI) tract may display similar changes in elastic fibres [8,16]. Clinical features and prognosis. Patients with cutis laxa demonstrate striking features with notably loose, redundant skin that sags and hangs in pendulous folds, giving the appearance that the skin is too large for the body (Fig. 143.1). Inelasticity is best demonstrated by lack of recoil when the skin is stretched from its resting position. This is in contrast to what is observed in Ehlers–Danlos syndrome. The highly characteristic facial features are likened to that of a bloodhound, with marked sagging of the skin, accentuation of the nasolabial and other facial folds, ectropion and blepharochalasis. Because the corners of the mouth sag, individuals often appear mournful.

Fig. 143.1 Redundant skin in an adolescent girl with cutis laxa.

Despite the senescent appearance in early ages, children may appear to ‘grow into’ their abnormal skin and have a more normal appearance in adulthood. The cutaneous manifestations among the various types of cutis laxa are fairly similar, although there exists great variability in the internal manifestations and prognoses. Cutis laxa can be inherited or acquired and there are subclassifications of each type. A self-limited congenital form has also been described. The author has also observed acquired, localized cutis laxa in two children, one with involvement limited to the intertriginous skin without evidence of cutaneous T-cell lymphoma and another confined to the upper eyelids, similar to blepharochalasis reported in adults (unpublished data).

Inherited types An autosomal dominant, three autosomal recessive forms and an X-linked recessive form, previously designated Ehlers–Danlos syndrome type IX or occipital horn syndrome, are the best characterized. There are several other autosomal recessive types with varied associated features and other disorders in which cutis laxa occurs in addition to other more conspicuous anomalies. Facial dysmorphism with hooked nose, short columella, everted nostrils and long philtrum is quite characteristic of the inherited forms of cutis laxa. The rare autosomal dominant form (OMIM #123700), which has been linked to mutations in either fibulin or elastin genes [6], has primarily cutaneous involvement, with few systemic manifestations, a relatively benign course and a normal life expectancy [33–35]. It may appear at any age from birth to adulthood, but generally has a later onset than the recessive forms. It most likely displays incomplete penetrance [34]. Bronchiectasis, emphysema, diverticula, hernias, uterine prolapse [33], hoarseness, mitral valve prolapse, dilation of the sinuses of Valsalva [35], pulmonary artery stenosis [34], dilation and tortuosity of the carotid artery, presenting as a pulsating mass in the lateral neck [34], and aortic aneurysm with or without rupture [36] have been associated with this form [33]. Facial involvement is universal and cosmesis is usually the main concern, as most affected individuals lack systemic involvement. Autosomal recessive cutis laxa type I (OMIM #219100) is the rarest and most severe form, associated in some with mutations in the gene for the fibulin-5 [1], and is associated with emphysema, which may develop in the first months of life [33]. Cutis laxa is present at birth, involves nearly the entire body surface and, unlike other forms, can worsen over time. A hoarse, low-pitched voice is thought to result from lax, redundant vocal cords. Diaphragmatic hernia may cause respiratory distress in the neonatal period [8]. Diverticula of the oesophagus, stomach, small intestine and rectosigmoid as well as

Cutis Laxa

inguinal, obturator and umbilical hernias are common. Bladder diverticula present with symptoms of enuresis and frequency but are largely asymptomatic. Some patients have developed renal failure associated with heavy chain disease [37]. At least one infant was reported to have co-existent congenital hypothyroidism due to isolated thyroid-stimulating hormone (TSH) deficiency [38]. Emphysema is associated with recurrent pulmonary infections, resulting in cor pulmonale and death in the first few years of life. Autosomal recessive cutis laxa type II (OMIM #219200) is also called Debré type or cutis laxa with growth and developmental delay as this variant is a multisystemic disorder. Cutis laxa, nearly always present at birth, may or may not involve the face but appears to be especially severe over the hands, feet and abdomen. In this variant the skin manifestations appear to improve over time [13]. Variably, infants may present with congenital dislocation of the hips and generalized laxity of the joints [15] Affected infants exhibit wide sutures and a large anterior fontanelle with delayed closure. Other craniofacial abnormalities include microcephaly, broadening of the nasal bridge, short nose, with hypertelorism, long philtrum, downslanting palpebral fissures, epicanthal folds, small mouth, low-set ears and a high-arched or cleft palate [15]. Other inconstant findings are macular coloboma, myopia, iris hypoplasia, reversed-V eyebrows, simian crease, cleft lip [39], osteoporosis [40], Dandy–Walker malformation, cobblestone-like brain dysgenesis [13], minor heart and osseous defects [41] and common variable-like immunodeficiency syndrome [42]. Most have developmental delay with transient feeding intolerance and, at least in some cohorts, seizures develop during childhood. A few of the children have died as a result of the associated seizure disorder [13]. Some patients have been products of consanguineous marriages, supporting an autosomal recessive inheritance. De Barsy syndrome (OMIM #219150) has recently been categorized as autosomal recessive cutis laxa type III. It comprises intrauterine growth retardation, wrinkled atrophic skin, open sutures, somatic and mental retardation and hypermobility of small joints. It can be differentiated from recessive cutis laxa type II by the presence of corneal opacification due to degeneration of the Bowman membrane, muscular hypotonia, athetoid posturing and brisk tendon reflexes. This form is postulated to result from decreased elastin synthesis. X-linked cutis laxa (OMIM #304150) is now classified in the group of copper transport diseases and appears to be related genetically to Menkes disease. Both diseases have mutations affecting the copper-transporting P-type ATPase [43]. Patients affected have the typical cutaneous features of cutis laxa but also exhibit joint laxity, hydronephrosis, chronic diarrhoea, soft mildly hyperextensible

143.3

skin, a long thin face with high forehead and long philtrum, occipital horn exostoses and mental deficiency. In addition, serum copper and caeruloplasmin are decreased.

Acquired types Acquired elastolysis presents as a generalized insidious disease, typically associated with internal manifestations in all adults and infrequently in children. It usually begins in adulthood but has been reported in children [9,16,18,20,44,45]. Laxity varies in distribution and is progressive over several years. Only the facial and ear involvement has been reported in patients less than 10 years of age [16,18,45], with more generalized, adult presentation in older children [9,20]. Most reported patients have been male. A host of various inflammatory skin lesions, such as generalized vesicular eruptions [16], erythema multiforme, urticaria, angio-oedema, erythema multiforme and dermatitis herpetiformis-like eruptions [20], occur before or concurrent with cutaneous laxity. Associated internal disorders include emphysema, GI and genitourinary diverticula, inguinal hernias and rectal prolapse. The GI manifestations are most common and often asymptomatic. Death from emphysema and aortic rupture has been reported. Increased serum IgA was reported in two children, but its significance is unknown [20,45]. Of the few cases reported in children, only one had systemic involvement (tracheobronchiomegaly) and one death resulted. This suggests a better prognosis for those developing this type of acquired cutis laxa in childhood. However, there have been no reports of spontaneous resolution. Its association with recent drug therapy, particularly penicillin [20] and isoniazid [18], and evidence of tuberculosis in two children [18,44] suggests a hypersensitivity reaction as a possible aetiology. Another type of acquired cutis laxa was first described by Marshall et al. (46) as postinflammatory elastolysis and cutis laxa (PECL). Almost all cases have occurred in previously healthy black girls, 4 years of age or younger, living in tropical climates [17,19,46,47]. A relapsing acute inflammatory phase lasting several months or years exhibits crops of recurrent inflammatory skin lesions resembling Sweet syndrome. The primary lesion is a non-pruritic, bright-red papule. The papules expand to well-circumscribed, erythematous oval plaques, measuring 2–10 cm. As they extend peripherally, they leave a hypopigmented centre. Some lesions consist of erythema and swelling in geographical patterns, whereas others resemble papular urticaria. Malaise, fever and peripheral eosinophilia typify the acute phase [46]. The chronic phase is characterized by localized or, less commonly, extensive areas of cutis laxa and dermal atrophy occurring in foci of prior inflammation [17]. There is no consistent systemic involvement. However, coronary

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involvement [47] has been reported and the cutaneous manifestations do not always parallel internal organ involvement [47]. The aetiology is unknown. It seems to have features intermediate between anetoderma and acquired cutis laxa. Hypersensitivity, possibly to arthropod bites, or as a result of actinic damage, has been proposed [17].

Transient neonatal cutis laxa Transient neonatal cutis laxa presents in infants born to mothers treated with penicillamine for Wilson disease [26,48], rheumatoid arthritis [49] or cystinuria [50] during gestation. Generalized cutis laxa associated with inguinal hernias is characteristic of the neonatal form and, as the name implies, cutaneous changes resolve during the first year of life in all but the most severe cases [18,26,35,48,49]. Joint mobility is usually normal. Pulmonary complications, joint hyperflexibility, severe fragility of veins, varicosities, micrognathia, low-set ears [48] and impaired wound healing [50] have been reported associations in the severely affected. Low serum zinc but normal serum copper suggests a possible role for low zinc levels in the development of this form of cutis laxa [48]. Most affected infants have normal postnatal levels of serum copper and caeruloplasmin, and it has been postulated that intermittently low serum copper levels [51] in utero induce both collagen and elastic tissue defects, which self-correct postnatally [26]. This is supported by similar findings in animal studies [52]. The effects of penicillamine are more severe in the infants of mothers treated for rheumatoid arthritis and cystinuria than for Wilson disease [49]. This may be explained on the basis that in Wilson disease, there is a high proportion of unbound copper, which is chelated by penicillamine and excreted, thus effectively reducing the penicillamine level and resultant toxicity. Differential diagnosis. Cutis laxa can be differentiated from Ehlers–Danlos syndrome by the fact that in the latter the skin is extensible but exhibits brisk recoil. This is due to the presence of normal elastic fibres in association with abnormal collagen in Ehlers–Danlos syndrome. Pseudoxanthoma elasticum (PXE) usually spares the face and presents with yellowish confluent papules, especially in flexural skin. Histologically, PXE demonstrates abnormal elastic fibres in the deeper portions of the dermis, with relative sparing of the papillary dermis. There is also calcification, which is not present in cutis laxa. Granulomatous slack skin, an atrophic patch stage of cutaneous T-cell lymphoma, is characterized by pendulous folds that hang from the axillae and groin. Anetoderma also exhibits cutaneous laxity, but it is usually a localized macular type and has not been associated with systemic elastolysis. Children with Costello syndrome usually

have high birthweights but exhibit growth retardation and developmental delay. Many patients have reported nasal and/or anal papillomata. Despite clinically lax skin, they display normal elastic tissue histologically [53]. Costello syndrome should be considered in the differential diagnosis of the recessive form of cutis laxa with developmental delay. Abnormally lax skinfolds are a manifestation of other conditions, such as various amyloidoses, trisomy 18, Patterson syndrome (pseudo-leprechaunism), wrinkly skin syndrome, gerodermia osteodysplastica, SCARF (skeletal abnormalities, cutis laxa, craniosynostosis, ambiguous genitalia, retardation and facial abnormalities) syndrome [54] and leprechaunism, which are distinguished by their associated characteristics. Treatment. Therapy is limited. Surgical repair of associated internal defects such as hernias, diverticula and rectal prolapse is sometimes necessary. Plastic surgery is effective for removal of excess skinfolds, thereby improving the appearance and limiting the emotional trauma caused by severe disfigurement [55]. Repeated surgery is often required as the redundant skin recurs over time [56]. Unlike the collagen diseases, no problems with wound healing have been reported. Injection of botulinum toxin to facial musculature has improved the facial appearance in some adults with mild cutis laxa [57]. Treatment with systemic steroids controlled the eruption of PECL well in one case and partially in another [46], and a blood transfusion along with dicloxacillin prompted regression of the inflammatory response but not the elastolysis in another patient. Dapsone controlled the inflammatory lesions in the systemic acquired form; however, methaemoglobinaemia complicated the treatment [20]. Penicillamine is not helpful [29]. Pulmonary function tests are useful for early detection of emphysema. Family members should be examined for signs of cutis laxa, and for those families with inherited forms, genetic counselling should be performed. References 1 Loeys B, van Maldergem L, Mortier G et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet 2002;11(18):2113–18. 2 Anderson LL, Oikarinen AI, Ryhanen L, Anderson CE, Uitto J. Characterization and partial purification of a neutral protease from the serum of a patient with autosomal recessive pulmonary emphysema and cutis laxa. J Lab Clin Med 1985;105(5):537–46. 3 Olsen DR, Fazio MJ, Shamban AT, Rosenbloom J, Uitto J. Cutis laxa: reduced elastin gene expression in skin fibroblast cultures as determined by hybridizations with a homologous cDNA and an exon 1-specific oligonucleotide. J Biol Chem 1988;263(14):6465–7. 4 Dasouki M, Markova D, Garola R et al. Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa. Am J Med Genet 2007;143A(22):2635–41.

Cutis Laxa 5 Rodriguez-Revenga L, Iranzo P, Badenas C, Puig S, Carrio A, Mila M. A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa. Arch Dermatol 2004;140(9):1135–9. 6 Zhang MC, He L, Giro M, Yong SL, Tiller GE, Davidson JM. Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN). J Biol Chem 1999;274(2):981–6. 7 Urban Z, Michels VV, Thibodeau SN, Donis-Keller H, Csiszar K, Boyd CD. Supravalvular aortic stenosis: a splice site mutation within the elastin gene results in reduced expression of two aberrantly spliced transcripts. Hum Genet 1999;104(2):135–42. 8 Goltz RW, Hult AM, Goldfarb M, Gorlin RJ. Cutis laxa. A manifestation of generalized elastolysis. Arch Dermatol 1965;92(4):373–87. 9 Ferreira MC, Spina V. A case of cutis laxa with abnormal copper metabolism. Br J Plast Surg 1973;26(3):283–6. 10 Das S, Levinson B, Vulpe C, Whitney S, Gitschier J, Packman S. Similar splicing mutations of the Menkes/mottled coppertransporting ATPase gene in occipital horn syndrome and the blotchy mouse. Am J Hum Genet 1995;56(3):570–6. 11 Kemppainen R, Hamalainen ER, Kuivaniemi H, Tromp G, Pihlajaniemi T, Kivirikko KI. Expression of mRNAs for lysyl oxidase and type III procollagen in cultured fibroblasts from patients with the Menkes and occipital horn syndromes as determined by quantitative polymerase chain reaction. Arch Biochem Biophys 1996;328(1):101–6. 12 Wopereis S, Morava E, Grunewald S et al. A combined defect in the biosynthesis of N- and O-glycans in patients with cutis laxa and neurological involvement: the biochemical characteristics. Biochim Biophys Acta 2005;1741(1–2):156–64. 13 Van Maldergem L, Yuksel-Apak M, Kayserili H et al. Cobblestonelike brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type. Neurology 2008;71(20):1602–8. 14 Morava E, Wopereis S, Coucke P et al. Defective protein glycosylation in patients with cutis laxa syndrome. Eur J Hum Genet 2005;13(4):414–21. 15 Morava E, Lefeber DJ, Urban Z et al. Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation. Eur J Hum Genet 2008;16(1):28–35. 16 Reed WB, Horowitz RE, Beighton P. Acquired cutis laxa. Primary generalized elastolysis. Arch Dermatol 1971;103(6):661–9. 17 Verhagen AR, Woerdeman MJ. Post-inflammatory elastolysis and cutis laxa. Br J Dermatol 1975;92(2):183–90. 18 Koch SE, Williams ML. Acquired cutis laxa: case report and review of disorders of elastolysis. Pediatr Dermatol 1985;2(4):282–8. 19 Saxe N, Gordon W. Acute febrile neutrophilic dermatosis (Sweet’s syndrome). Four case reports. S Afr Med J 1978;53(7):253–6. 20 Kerl H, Burg G, Hashimoto K. Fatal, penicillin-induced, generalized, postinflammatory elastolysis (cutis laxa). Am J Dermatopathol 1983;5(3):267–76. 21 Mahajan VK, Sharma NL, Garg G. Cutis laxa acquisita associated with cutaneous mastocytosis. Int J Dermatol 2006;45(8):949–51. 22 Grassegger A, Romani N, Fritsch P, Smolle J, Hintner H. Immunoglobulin A (IgA) deposits in lesional skin of a patient with blepharochalasis. Br J Dermatol 1996;135(5):791–5. 23 Harrington CR, Beswick TC, Susa JS, Pandya AG. Acquired cutis laxa associated with heavy chain deposition disease. J Am Acad Dermatol 2008;59(5 suppl):S99–101. 24 Nikko A, Dunnigan M, Black A, Cockerell CJ. Acquired cutis laxa associated with a plasma cell dyscrasia. Am J Dermatopathol 1996;18(5):533–7. 25 Krajnc I, Rems D, Vizjak A, Hodl S. [Acquired generalized cutis laxa with paraproteinemia (IgG lambda). Immunofluorescence study, clinical and histologic findings with review of the literature.] Hautarzt 1996;47(7):545–9. 26 Linares A, Zarranz JJ, Rodriguez-Alarcon J, Diaz-Perez JL. Reversible cutis laxa due to maternal D-penicillamine treatment. Lancet 1979;2(8132):43.

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27 Hu Q, Reymond JL, Pinel N, Zabot MT, Urban Z. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes.[erratum appears in J Invest Dermatol 2006;126(6):1426]. J Invest Dermatol 2006;126(2):283–90. 28 Mehregan AH, Lee SC, Nabai H. Cutis laxa (generalized elastolysis). A report of four cases with autopsy findings. J Cutan Pathol 1978;5(3):116–26. 29 Nanko H, Jepsen LV, Zachariae H, Sogaard H. Acquired cutis laxa (generalized elastolysis): light and electron microscopic studies. Acta Derm Venereol 1979;59(4):315–24. 30 Jablonska S. [Inflammatory changes in the skin preceding acquired cutis laxa.] Hautarzt 1966;17(8):341–6. 31 Hashimoto K, Kanzaki T. Cutis laxa. Ultrastructural and biochemical studies. Arch Dermatol 1975;111(7):861–73. 32 Sayers CP, Goltz RW, Mottiaz J. Pulmonary elastic tissue in generalized elastolysis (cutis laxa) and Marfan’s syndrome: a light and electron microscopic study. J Invest Dermatol 1975;65(5):451–7. 33 Beighton P. The dominant and recessive forms of cutis laxa. J Med Genet 1972;9(2):216–21. 34 Hayden JG, Talner NS, Klaus SN. Cutis laxa associated with pulmonary artery stenosis. J Pediatr 1968;72(4):506–9. 35 Brown FR 3rd, Holbrook KA, Byers PH, Stewart D, Dean J, Pyeritz RE. Cutis laxa. Johns Hopkins Med J 1982;150(4):148–53. 36 Szabo Z, Crepeau MW, Mitchell AL et al. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet 2006;43(3):255–8. 37 Champion P, Ryan F. A case of congenital cutis laxa (generalized elastolysis). Can Respir J 2005;12(3):151–2. 38 Koklu E, Gunes T, Ozturk MA, Akcakus M, Buyukkayhan D, Kurtoglu S. Cutis laxa associated with central hypothyroidism owing to isolated thyrotropin deficiency in a newborn. Pediatr Dermatol 2007;24(5):525–8. 39 Patton MA, Tolmie J, Ruthnum P, Bamforth S, Baraitser M, Pembrey M. Congenital cutis laxa with retardation of growth and development. J Med Genet 1987;24(9):556–61. 40 Sakati NO, Nyhan WL. Congenital cutis laxa and osteoporosis. Am J Dis Child 1983;137(5):452–4. 41 Biver A, de Rijcke S, Toppet V, Ledoux-Corbusier M, van Maldergem L. Congenital cutis laxa with ligamentous laxity and delayed development, Dandy–Walker malformation and minor heart and osseous defects. Clin Genet 1994;45(6):318–22. 42 Litzman J, Buckova H, Ventruba J, Holcikova A, Mikyska P, Lokaj J. A concurrent occurrence of cutis laxa, Dandy–Walker syndrome and immunodeficiency in a girl. Acta Paediatr 2003;92(7):861–4. 43 Kaler SG. Metabolic and molecular bases of Menkes disease and occipital horn syndrome. Pediatr Dev Pathol 1998;1(1):85–98. 44 Bernstein BA, Sorbera RS, Maloney PL, Doku HC. Cutis laxa: report of case. J Oral Surg 1971;29(3):201–4. 45 Wanderer AA, Ellis EF, Goltz RW, Cotton EK. Tracheobronchiomegaly and acquired cutis laxa in a child. Physiologic and immunologic studies. Pediatrics 1969;44(5):709–15. 46 Marshall J, Heyl T, Weber HW. Postinflammatory elastolysis and cutis laxa. A report on a new variety of this phenomenon and a discussion of some syndromes characterized by elastolysis. S Afr Med J 1966;40(42):1016–22. 47 Muster AJ, Bharati S, Herman JJ, Esterly NB, Gonzales-Crussi F, Holbrook KA. Fatal cardiovascular disease and cutis laxa following acute febrile neutrophilic dermatosis. J Pediatr 1983;102(2):243–8. 48 Harpey JP, Jaudon MC, Clavel JP, Galli A, Darbois Y. Cutis laxa and low serum zinc after antenatal exposure to penicillamine. Lancet 1983;2(8354):858. 49 Solomon L, Abrams G, Dinner M, Berman L. Neonatal abnormalities associated with D-penicillamine treatment during pregnancy. N Engl J Med 1977;296(1):54–5.

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50 Mjolnerod OK, Dommerud SA, Rasmussen K, Gjeruldsen ST. Congenital connective-tissue defect probably due to D-penicillamine treatment in pregnancy. Lancet 1971;1(7701):673–5. 51 Rosa FW. Teratogen update: penicillamine. Teratology 1986;33(1): 127–31. 52 Keen CL, Cohen NL, Lonnerdal B, Hurley LS. Teratogenesis and low copper status resulting from triethylenetetramine in rats. Proc Soc Exp Biol Med 1983;173(4):598–605. 53 Davies SJ, Hughes HE. Costello syndrome: natural history and differential diagnosis of cutis laxa. J Med Genet 1994;31(6):486–9. 54 Koppe R, Kaplan P, Hunter A, MacMurray B. Ambiguous genitalia associated with skeletal abnormalities, cutis laxa, craniostenosis, psy-

chomotor retardation, and facial abnormalities (SCARF syndrome). Am J Med Genet 1989;34(3):305–12. 55 Thomas WO, Moses MH, Craver RD, Galen WK. Congenital cutis laxa: a case report and review of loose skin syndromes. Ann Plast Surg 1993;30(3):252–6. 56 Banks ND, Redett RJ, Mofid MZ, Manson PN. Cutis laxa: clinical experience and outcomes. Plast Reconstr Surg 2003;111(7):2434–42; discussion 43–4. 57 Tamura BM, Lourenco LM, Platt A, Pertel P, Santos LF, Levites J. Cutis laxa: improvement of facial aesthetics by using botulinum toxin. Dermatol Surg 2004;30(12 Pt 2):1518–20.

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C H A P T E R 144

Pseudoxanthoma Elasticum Anne Han & Mark Lebwohl Department of Dermatology, The Mount Sinai School of Medicine, New York, NY, USA

Definition. Pseudoxanthoma elasticum is an inherited disease of connective tissue, which results in a wide array of cutaneous, ocular and systemic manifestations. Calcification of elastic tissue results in characteristic changes in the skin, eyes and cardiovascular systems. The resulting clinical picture can be quite variable, but in its most severe form is a model for accelerated ageing. The clinical presentation of pseudoxanthoma elasticum in the paediatric age group has been well described [1]. History. Felix Balzer [2] first reported a patient with yellow xanthomatous flexural skin lesions in 1884. On histopathological examination, he observed thickened and broken elastic fibres in the skin and heart. In 1896, Jean Darier [3] differentiated the skin lesions and xanthomas and called the disease ‘pseudo-xanthome elastique’. Angioid streaks were also first described at the end of the 19th century [4,5] but it was not until 1929 that the ophthalmologist Gronblad [6] and the dermatologist Strandberg [7] firmly established a link with the skin lesions of pseudoxanthoma elasticum and attributed both to an underlying elastic tissue defect. The cardiovascular calcification that occurs in pseudoxanthoma elasticum was definitively described in 1944 in a group of 29 Swedish patients with the disorder [8]. Since that time, reviews of large numbers of patients have been conducted by Connor et al. [9] at the Mayo Clinic, McKusick [10], Pope [11] and Neldner [12]. A review of the history of pseudoxanthoma elasticum would not be complete without mention of the detailed description of this disorder ’s light microscopic and ultrastructural findings published by Danielsen in her doctoral thesis in 1979 [13]. Aetiology and pathogenesis. Pseudoxanthoma elasticum has been reported in most countries and racial groups around the world [10,12]. Several published studies have reported a female-to-male ratio of approximately 2 : 1 [10,12]. An autosomal recessive inheritance

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

pattern, however, should result in an equal number of male and female cases. The discrepancy may be explained by a tendency of males to ignore cutaneous lesions or by hormonal or environmental effects that cause the disease to become more noticeable in females. The exact prevalence of the disorder is not known because we do not have a simple serological test for the diagnosis of pseudoxanthoma elasticum. In one of the earliest reviews of this disease, McKusick [10] estimated that pseudoxanthoma elasticum occurs in at least 1 in 160,000 people. In a study by Altman et al. [14] in the Seattle area, the prevalence of pseudoxanthoma elasticum was estimated at 1 in 70,000. In Denver, Neldner [12] found a prevalence from 1 in 90,000 to 1 in 100,000. He published his data in the most comprehensive review of pseudoxanthoma elasticum in a systematic 10-year study of 100 patients with the disease. A key flaw exists in all attempts to estimate the prevalence of this disease: there are patients who have skin lesions that are mild or even undetectable except on biopsy. Patients have been reported who have accelerated cardiovascular disease and angioid streaks without the skin lesions of pseudoxanthoma elasticum. On biopsy of normal-appearing flexural skin, however, these patients have been found to have histological evidence of the disease [15]. In one report, a 63-year-old man, who had had cerebral infarcts and myocardial infarctions at an early age with repeated cardiac interventions, was found to have angioid streaks and pseudoxanthoma elasticum on biopsy of normal-appearing skin 25 years after the onset of cardiovascular disease [16]. There have also been reports of patients with angioid streaks and histological evidence of pseudoxanthoma elasticum on biopsy of scars despite the absence of characteristic skin lesions [17]. Are these patients heterozygote carriers for pseudoxanthoma elasticum [18]? For many years, studies of the genetics of pseudoxanthoma elasticum (PXE) suffered from the same difficulty that plagued epidemiological studies. Pseudoxanthoma elasticum was thought by many to be an autosomal recessive disease. Meanwhile, in 1966, 20 instances of inheritance from parent to child were reported [19]. More instances of autosomal dominant inheritance

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were presented by Pope [20], who also reported autosomal recessive inheritance [21]. At the turn of the century, however, the prevailing hypothesis was that PXE was an autosomal recessive disease characterized by compound heterozygosity, or the presence of different mutations for each allele [22]. In 2000, Ringpfeil et al. reported that mutations in the ABCC6 gene on chromosome 16p13.1 were responsible for PXE [23]. That discovery was quickly confirmed by reports from several other groups looking for the genetic defect. With the availability of DNA testing, genotype analysis now confirmed the detection of two allelic mutations in affected individuals who demonstrated clinical signs of PXE, including skin findings confirmed by biopsy, the presence of angioid streaks and evidence of vascular lesions [24]. Prior reports of putative dominant inheritance could be explained by pseudodominance, as they originated in a subset of families in which inheritance occurred in two successive generations [25]. Furthermore, evidence of an autosomal recessive mode of inheritance was reinforced by recent observations on mice in which the ABCC6 gene had been inactivated by targeted ablation [26,27]. The ABCC6 gene encodes MRP6, an ATP-binding cassette transmembrane transporter protein expressed primarily in the liver and the kidneys. Researchers have identified 188 different causative mutations of this gene, which mainly consist of nonsense and mis-sense mutations or deletions and splice-site alterations occurring on exons 24–30 [28]. Although the discovery of the genetic defect for PXE answered many questions, it led to many others. How did genetic defects in the ABCC6 gene result in the clinical features of PXE? All the complications of PXE occur in elastic tissue-containing organs such as the skin, Bruch’s membrane of the eye and the internal elastic lamina of arteries. Histological and ultrastructural studies certainly corroborate the profound involvement of elastic tissue in this disease. Furthermore, why was there such marked clinical heterogeneity in PXE? Patients within the same family may differ in disease severity as well as in the number of organ systems involved [29]. No correlation between genotype and phenotype severity has yet been found [30]. To elucidate the process from genetic defect to clinical manifestations and to account for the tremendous variation in PXE phenotype, researchers regard the prevalence of heterozygosity [31] and intragenic polymorphisms as well as other modulating genes or metabolic pathways as key components that may influence clinical expression [32]. Recently, Hendig et al. identified the first modifier gene for PXE [33]. SPP1 promoter polymorphisms, as a secondary genetic risk factor, were shown to be significantly associated with PXE susceptibility. The presence of such a modulating gene also explains a mutation detec-

tion rate of PXE that ranges from 55% to 97% [34]. Studies involving murine models with ABCC6 knockout mutations support the ‘metabolic’ disease hypothesis, which describes circulating factors involved in the mineralization process of elastic fibres [30,35]. In an in vitro experiment, Le Saux et al. showed that unknown metabolites in the serum of PXE patients interfered with normal assembly of elastic fibres, rather than fibroblasts from PXE patients which deposited only normal elastic fibres [36]. More recently, the metabolic disease hypothesis has explained tissue calcification as a result of the absence of a plasma factor secreted from the basolateral hepatocytes membrane due to loss of function of ABCC6. Since vitamin K is an important co-factor for the γ-carboxylation of gla-proteins, which in the carboxylated form prevent tissue calcification, researchers now hypothesize that the missing plasma factor could be vitamin K, a vitamin K precursor or a vitamin K metabolite [37]. Another hypothesis has recently surfaced with the discovery that ABCC (-/-) mice suffer from mild chronic oxidative stress [38]. Reactive oxygen species and proteolytic degradation of matrix components are thought to play a role in the biochemical and structural alterations in PXE [39,40]. Further observations regarding disease activity include lower levels of calcification inhibitory proteins in PXE sera [41– 43] and an elevation of XT-I, a marker of tissue remodelling [44,45]. While these clues bring us closer to understanding this disease, the steps leading from the ABCC6 gene to calcification of elastic tissue remain under investigation. Pathology. On light microscopy, there is an increase in elastic tissue. Much of the elastic tissue is clumped and fragmented, particularly in the middle and deep dermis. On staining with haematoxylin and eosin, calcification of dermal components is visible as clumped, faintly basophilic material. The von Kossa stain, a calcium stain that demonstrates the negatively charged ions that bind to calcium, is useful for demonstrating the calcification that occurs in PXE, and a diagnosis of PXE should be questioned if dermal calcification cannot be demonstrated with this stain (Fig. 144.1). The Verhoeff–van Gieson stain is an elastic tissue stain that demonstrates the fragmentation of elastic fibres, which occurs in PXE (Fig. 144.2a). Figure 144.2b shows normal elastic tissue in an unaffected individual for comparison. On staining with Alcian blue, there is a marked increase in mucopolysaccharides. Upon digestion with hyaluronidase, it can be shown that much of this Alcian bluepositive material is hyaluronic acid. A number of studies have demonstrated marked increases in dermal mucopolysaccharides in lesional skin of patients with PXE. Both dermatan sulphate and hyaluronic acid are increased [46–48]. Of great interest, the increase in mucopolysac-

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charides is also demonstrable in clinically unaffected skin of patients with PXE. This has been clearly shown in nonlesional buttock skin. The authors suggested that deposition of mucopolysaccharides precedes the calcification of elastic tissue, and the negatively charged mucopolysaccharides may contribute to elastic tissue calcification by electrostatic forces [46]. This leads to the intriguing possibility that by preventing this increase in mucopolysaccharides, we may one day be able to prevent the calcification that occurs in PXE. On electron microscopy, profound changes in both elastic tissue and collagen have been described. Elastic fibres contain irregularly shaped holes and electrondense bodies. Some elastic fibres contain holes surrounded by a striking discrete electron-dense borderline [13,49]. Numerous abnormalities of collagen have also been described, including collagen fibrils that are thin, thick, laterally fused and twisted as well as decreased in number and broken down to particles [13,49–53].

Fig. 144.1 Von Kossa stain to demonstrate calcification in PXE.

(a)

Clinical features. The skin lesions of PXE are said to resemble cobblestones or plucked chicken skin. They have also been called ‘xanthoma-like’ because of their yellowish colour. The skin lesions typically begin on the neck (Fig. 144.3). The next most commonly involved sites are the axillae (Fig. 144.4), but any flexural area can be

(b)

Fig. 144.2 Van Gieson stain, showing fragmentation of elastic fibres in PXE (a) and in normal elastic fibres in the skin of an unaffected individual for comparison (b).

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Fig. 144.3 Typical ‘xanthoma-like’ skin lesions on the neck. Fig. 144.5 Affected skin above the umbilicus.

Fig. 144.4 Involvement of the axilla.

Fig. 144.6 Severe involvement with redundant folds of skin around the neck.

affected, including the skin superior to the umbilicus (Fig. 144.5). Wrists are less commonly affected. Skin lesions begin as yellow macules that can develop into yellow papules. In more severe cases, papules become confluent to form yellow plaques that simulate plane xanthomas. In very severe cases, patients develop redundant folds of skin in flexural areas (Fig. 144.6) and skin can be strikingly hyperextensible. In patients who are severely affected, the sagging of facial skin can be striking. This

results in a ‘hound dog’ appearance that has been seen in patients with cutis laxa. Characteristic folds in the chin have recently been described in a high proportion of patients with PXE. Although these can occur with normal ageing, they are often seen in PXE patients in their teens and twenties (Fig. 144.7) [54]. The skin lesions of PXE exhibit a Koebner phenomenon, having a tendency to develop within scars. This has

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Fig. 144.7 Mucosal lesions on the lower lip.

Fig. 144.8 Angioid streaks on the retina.

been used diagnostically in that biopsy of scars may aid in the diagnosis of PXE in patients without clinically apparent skin lesions [16]. Similarly, in patients with angioid streaks and accelerated cardiovascular disease who do not have skin lesions, biopsy of intertriginous areas such as the neck or axillae can establish a diagnosis of PXE [15]. Skin lesions can occasionally be quite subtle. In one patient examined at the Mount Sinai Medical Center in New York City, PXE was found incidentally in normalappearing skin around an excised naevus. The patient was subsequently found to have asymptomatic angioid streaks and mild skin lesions on the neck and in the axillae, groin and periumbilical area. Mucosal lesions develop in many patients. They are easily seen on the mucosal aspect of the lower lip (see Fig. 144.7) and under the tongue. Histological evidence of PXE has been found in rectal mucosa [55], and a patient has been reported with lesions of PXE on the dorsal aspect of the penis [12].

particularly in the periumbilical area. In several instances, perforation of the epidermis with dermal extrusion of calcified elastic fibres has been reported [61]. The reported cases have been sporadic without any family history of PXE, and the patients do not generally have other stigmata of PXE, although there has been a solitary report of a black woman with chronic renal failure who developed perforating PXE and was found to have angioid streaks [62]. Neldner & Martinez-Hernandez [60] have also reported a multiparous black woman with cirrhosis who was thought to have localized acquired PXE with skin lesions on the breasts as well as the abdomen.

Variants Perforation of calcified elastic fibres through the epidermis in patients with PXE has been called ‘perforating pseudo-xanthoma elasticum’ [56]. There have been many reports of elastosis perforans serpiginosa occurring in patients with PXE, and it is likely that many of these patients in fact had perforating PXE [57-59]. Although extrusion of dermal material is common to all the perforating disorders, perforating PXE is clearly distinct from the other disorders in that the extruded material consists of calcified elastic fibres. Another unusual form of PXE has been called ‘localized acquired cutaneous pseudo-xanthoma elasticum’ [60]. This condition appears to be more common in obese, multiparous black females, several of whom have had hypertension. Skin lesions usually occur on the abdomen,

Ocular manifestations Angioid streaks, the ocular hallmark of PXE, represent breaks in Bruch’s membrane, an elastic tissue-containing membrane of the retina that can become calcified and crack. Angioid streaks appear as blood vessel-like lines that are grey or brown in darkly pigmented individuals (Fig. 144.8) and red in fair-skinned patients. They often encircle the optic disc in a peripapillary distribution or radiate out from the optic disc. Their size is often similar to that of retinal vessels but they can occasionally be much wider than retinal vessels. Although they have been reported in patients with many different conditions, angioid streaks are most closely associated with PXE. The large majority of adults with PXE have angioid streaks [12]. Because the skin lesions of PXE can be subtle or inapparent [15,16], it is possible that many of the patients reported with angioid streaks may have occult PXE. Angioid streaks have also been reported in several patients with Paget disease and sickle cell anaemia [63,64]. In patients with PXE, angioid streaks often develop in the teenage years. Other ocular features of PXE include mottled ‘peau d’orange’, which consists of mottled pigmentation of the retinal pigment epithelium, and drusen,

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which appear as small hypopigmented holes in Bruch’s membrane. The development of subretinal neovascularization in these patients can lead to haemorrhage, scarring and loss of vision. If haemorrhage involves the macular area, patients may develop loss of central vision and can become legally blind. Peripheral vision is maintained, however, so that patients do not become totally blind.

Cardiovascular manifestations Just like other elastin-containing tissues, the internal elastic lamina of arteries can become calcified. Calcification of arteries can be seen on simple radiographs in up to one-third of patients [12]. Reduced peripheral pulses commonly result from arterial calcification in patients with PXE. Intermittent claudication, presumably due to reduced circulation, has been reported in up to 30% of patients [12]. Claudication has been reported as early as the age of 9 years in a patient with PXE [12]. Intermittent claudication of the arms can also occur and may present as aching, weakness or fatigue on upper extremity exertion. Occlusion of vessels has been demonstrated in arteriograms of the arms [53]. Calcification of the coronary arteries can lead to accelerated cardiovascular disease with symptoms and complications simulating arteriosclerosis. There have been patients with angina or myocardial infarctions in the teenage years. A patient was reported who developed angina pectoris at the age of 11 years and underwent three-vessel coronary artery bypass graft surgery at the age of 18 years [10]. An Australian journal reported three teenage patients with PXE who died of myocardial infarctions, leading the authors to call this disease the ‘sudden death syndrome’ [65]. The severity of skin lesions does not correlate with the development of cardiovascular disease. At the Mount Sinai Medical Center, the authors have seen four patients who developed cardiovascular disease at an early age in the absence of other risk factors for atherosclerosis. All had angioid streaks and histological evidence of PXE but no skin lesions [15]. This has led to the suggestion that any patient with unexplained accelerated heart disease be examined for PXE. Examination for angioid streaks by a retina specialist and skin biopsy of normal-appearing axillary skin or scars may reveal the diagnosis in patients without skin lesions [16]. Other cardiovascular complications of PXE include a restrictive cardiomyopathy reported in one patient [66] and cardiac valvular abnormalities, which are common. Heart valves contain elastic tissue, so it is not surprising that they are affected in patients with this disease. A number of cardiac valvular abnormalities can occur, including fibrous thickening of the atrioventricular valves and mitral valve prolapse. The latter abnormality occurs

in approximately two-thirds of patients [67]. Abnormal diastolic dysfunction has been found in less than half of PXE patients without clinical heart disease [68]. These changes may be due to preclinical involvement of coronary artery and endocardial disease or may be the direct consequence of ultrastructural defects of the elastic tissue in the heart. Hypertension has been reported in the region of 9–48% of patients, depending on the series of patients studied [53,69]. It is clear that hypertension increases with age. However, two sisters with PXE have been reported: one died at the age of 10 years of complications of hypertension and the other had elevated blood pressure at the age of 6 years [70]. Several additional reports of hypertension occurring in the teenage years or earlier have been published [71,72]. Elevation of blood pressure has been attributed to narrowing of the renal artery in at least some cases [73,74]. In The Netherlands, many PXE patients were found to have a specific premature truncation variant of ABCC6 known as R1141X. Because of the known association between PXE and accelerated heart disease, a case–control study was performed in which 441 patients with coronary artery disease who were under the age 50 years were compared with 1057 age- and sex-matched control subjects who did not have coronary artery disease. Patients with coronary artery disease were 4.2 times more likely to have the R1141X mutation than the control subjects, lending additional support to a role for this gene in the cardiovascular complications of PXE [75].

Other systemic manifestations In some patients, calcification of the arteries will lead to cracking of the blood vessel and haemorrhage. Bleeding has been reported in many sites, including the uterus, nose, joints, gastrointestinal tract and others. Gastrointestinal bleeding develops in almost 10% of patients [12,69]. In some women, gastrointestinal bleeding occurs during pregnancy [76]. When radiographic and endoscopic examinations are undertaken, the source of bleeding is rarely found [12]. Fortunately, bleeding is often minor and self-limited, but occasionally partial gastrectomy is required. Other consequences of arterial calcification include central nervous system complications such as stroke and dementia. These are attributed to calcification of cerebral arteries and reduced circulation or intracranial haemorrhage [77,78].Visceral calcifications are part of the phenotype of PXE. Pulmonary calcification has been noted in isolated foci on chest radiographs in a few patients with PXE [79,80]. It is quite interesting that pulmonary calcification is minor and not associated with clinical sequelae in patients with PXE, even though the lungs contain elastic tissue. A report of 17 PXE patients and 17 heterozygous carriers showed calcifications in the liver, kidneys

Pseudoxanthoma Elasticum

and spleen detected in 59% of the patients and in 23.5% of healthy carriers [81]. Male patients, including young boys, can present with bilateral testicular microlithiasis [82]. Differential diagnosis. The clinical differential diagnosis of PXE includes actinic elastosis. This is most easily seen on the posterior neck of elderly light-skinned patients, in whom the skin takes on a yellowish hue similar to that seen in PXE. Fibroelastolytic papulosis, or age-related clinicopathological patterns that include white fibrous papulosis (WFP) and papillary dermal elastolysis simulating PXE (PXE-PDE), results from progressive thinning or loss of elastic fibres in the dermis [83–85]. This syndrome occurs in late adulthood due to the intrinsic processes of ageing and appears as asymptomatic skin-toned to yellowish papules erupting on the neck. Plane xanthomas can also simulate the skin lesions of confluent plaques of PXE. Exposure of the skin to calcium salts such as calcium chloride can lead to cutaneous ulceration followed by the development of yellow papules, which may resemble PXE. Farmers have been reported with persistent yellow lesions resembling PXE following a solitary exposure to saltpetre, which they were using to fertilize their fields [86,87]. Histologically, there is calcification of elastic fibres indistinguishable from that seen in PXE. Von Kossa stains show calcification of elastic fibres in the dermis. Patients treated with penicillamine can also develop skin lesions that may resemble PXE clinically [88]. Some of these patients develop widespread redundant yellow folds of skin that are not accentuated in the typical flexural sites that are characteristically affected in PXE. Histologically, elastic tissues are not calcified in patients treated with penicillamine, distinguishing this phenomenon from true PXE. More commonly, patients treated with penicillamine develop elastosis perforans serpiginosa [89–91]. Finally, calcification of the dermis can occur in several circumstances such as electrical burns or other damaged tissue, conditions associated with hypercalcaemia or hyperphosphataemia, or idiopathic calcinosis cutis. These conditions are usually easily distinguished both histologically and clinically from PXE. Treatment. Several steps can be taken to minimize the complications of PXE. Because of the tendency to bleeding, use of anticoagulants such as warfarin or heparin should be minimized, and patients should avoid platelet inhibitors such as aspirin. Checking the stool for blood, particularly during pregnancies, has been advocated by some authors. Regular use of an Amsler grid and consultation with a retina specialist may help prevent ocular bleeding and visual loss. Similarly, avoidance of exercises that cause trauma to the head must be stressed.

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In addition to regular fundoscopy exams to monitor for ocular findings associated with PXE, imaging with fundus autofluorescence and indocyanine green angiography can better detect pathology at the level of Bruch’s membrane where calcification of this elastic layer leads to angioid streaks and choroidal neovascularization [92,93]. Early detection and treatment are essential to stabilize disease progression and even reverse visual loss in PXE. Macular haemorrhage and leakage from choroidal neovascularization secondary to angioid streaks can be treated by new modalities, including intravitreal bevacizumab [94–96] and verteporfin photodynamic therapy [97,98]. Echocardiograms can be performed to look for mitral valve prolapse or other cardiac valvular abnormalities. If heart valve abnormalities exist, it has been suggested that prophylactic antibiotics be prescribed at the time of dental work to prevent valvular infection. To prevent accelerated cardiovascular disease, a low-fat, low-cholesterol diet, avoidance of cigarette smoking, control of blood pressure and aerobic exercises have been advised. Patients who develop symptomatic coronary artery disease have been successfully treated with percutaneous transluminal coronary angioplasty with stent placement [99] as well as bypass grafting using the left internal mammary artery, although controversy over the long-term patency of arterial conduits still exists for PXE patients [100]. Balloon angioplasty has been used to treat vascular lesions that cause claudication [101]. Cosmetically deforming redundant folds of skin can be removed surgically with excellent results [102]. Despite the elastic tissue defect in PXE, patients generally heal very well after surgery. Injectable collagen has also been used to fill the chin folds and creases that have been described in patients with PXE [103]. While most visceral calcifications are benign, the presence of testicular microlithiasis is associated with testicular malignancy. Thus, regular clinical and ultrasound exams are indicated in male patients with PXE [104]. Earlier literature regarding pregnancy contained reports of severe complications such as gastric bleeding, leading some healthcare providers to advise women with PXE against pregnancy. A recent survey of over 300 PXE women who had an aggregate of approximately 800 pregnancies concluded that most pregnancies are not associated with markedly increased fetal loss or adverse reproductive outcomes [105]. The incidence of gastric bleeding, although probably higher than in the unaffected population, is much lower than previously reported, and retinal complications are uncommon. Antenatal imaging may show a markedly echogenic placenta due to extensive calcification, but this finding itself does not produce adverse obstetric outcomes [106].

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Management of pregnancy in women with PXE should include ophthalmological and cardiovascular screening at the beginning of the pregnancy and after delivery to detect changes; counselling regarding the risk of genetic transmission of the disease; discussion of the possibility of disease exacerbation and complications for the fetus; and certain precautions during labour and delivery, such as maintenance of blood pressure and heart rate in PXE women with accelerated atherosclerosis [107,108]. Efforts to avoid increased superior vena cava pressure from labour that may lead to bleeding or worsening of angioid streaks include the use of epidural anaesthesia, application of forceps or vacuum, or delivery by caesarean section [108,109]. It has also been suggested that oestrogens make PXE worse and should therefore be avoided. Researchers are currently testing the hypothesis that vitamin K may be the missing plasma factor, normally secreted from the ABCC6-encoded transporter in basolateral hepatocytes, that counteracts the calcification of connective tissue [110]. An antioxidant combination of tocopherol acetate and ascorbic acid has been used successfully to treat skin lesions in PXE patients who do not have any other clinical signs [111]. The role of dietary calcium in the development of PXE remains controversial. Patients with significant calcium intake early in life may have a worse prognosis, and this has led to the suggestion that high calcium-containing foods such as milk or calcium supplements should be avoided [112]. An open-label study of oral phosphate binders showed promise in the treatment of PXE, with marked improvement in the skin lesions of three out of six patients who completed the study [113]. Skin biopsy of treated patients showed reduction of calcification, and there was no progression of eye disease or of any other complications associated with PXE. With the era of gene therapy on the horizon, it is likely that PXE patients will be treated in much more sophisticated ways in the future. Advocacy groups, including the National Association for PXE (NAPE) (www.pxenape.org) and PXE International (www.pxe.org), continue to provide support and resources to patients suffering from this condition. PXE International has been recognized for its role as a driving force in initiating, conducting and accelerating research on this genetic disease [114]. For the time being, however, many of the therapeutic measures described are preventive in nature. It is therefore imperative that family members of patients with PXE be examined so that a diagnosis can be established as early as possible in life. References 1 Hacker SM et al. Juvenile pseudoxanthoma elasticum: recognition and management. Pediatr Dermatol 1993;10(1):19–25.

2 Balzer F. Recherches sur les caracteres anatomiques due xanthelasma. Arch Physiol 1884;4:65–80. 3 Darier J. Pseudo-Xanthome Elastique. In: Proceedings of the Third International Congress on Dermatology, London, 5 August 1896. 4 Doyne R. Choroidal and retinal changes; the result of blows on the eyes. Trans Ophthalmol Soc UK 1889;9:129. 5 Knapp H. On the formation of dark angioid streaks as an unusual metamorphosis of retinal hemorrhage. Arch Ophthalmol 1892;21:289–94. 6 Gronblad E. Angioid streaks, pseudoxanthoma elasticum. Vorlaufige Mitteilung. Acta Ophthalmol 1929;7:329. 7 Strandberg J. Pseudoxanthoma elasticum. Z Haut Geschlechtskr 1929;31:689–94. 8 Carlbourg U. Study of circulatory disturbances, pulse wave velocity and pressure pulses in larger arteries in cases of pseudoxanthoma elasticum and angioid streaks: a combination to the knowledge of the function of the elastic tissue and the smooth muscles in larger arteries. Acta Med Scand 1944;151:1–209. 9 Connor P, Juergens JL, Perry HO et al. Pseudoxanthoma elasticum and angioid streaks: a review of 106 cases. Am J Med 1961;30:537–43. 10 McKusick V. Heritable Disorders of Connective Tissue. St Louis: C.V. Mosby, 1972: 475–520. 11 Pope F. Pseudoxanthoma elasticum: an historical survey. Trans St John’s Hosp Dermatol Soc 1972;58:235–50. 12 Neldner KH. Pseudoxanthoma elasticum. Clin Dermatol 1988;6(1):1–159. 13 Danielsen L. Morphological changes in pseudoxanthoma elasticum and senile skin. Acta Derm Venereol (Stockh) 1979;83(suppl):1–79. 14 Altman LK et al. Pseudoxanthoma elasticum. An underdiagnosed genetically heterogeneous disorder with protean manifestations. Arch Intern Med 1974;134(6):1048–54. 15 Lebwohl M, Halperin J, Phelps RG. Brief report: occult pseudoxanthoma elasticum in patients with premature cardiovascular disease. N Engl J Med 1993;329(17):1237–9. 16 Araki Y et al. Pseudoxanthoma elasticum diagnosed 25 years after the onset of cardiovascular disease. Intern Med 2001;40(11):1117–20. 17 Lebwohl M et al. Diagnosis of pseudoxanthoma elasticum by scar biopsy in patients without characteristic skin lesions. N Engl J Med 1987;317(6):347–50. 18 Lebwohl M et al. Classification of pseudoxanthoma elasticum: report of a consensus conference. J Am Acad Dermatol 1994;30(1):103–7. 19 Wise D. Hereditary disorders of connective tissue. In: Galtron HA, Schnyder UW (eds) Vererbung Vo Hautkrankherten. Berlin: Julius Springer, 1966: 201–12. 20 Pope FM. Autosomal dominant pseudoxanthoma elasticum. J Med Genet 1974;11(2):152–7. 21 Pope FM. Two types of autosomal recessive pseudoxanthoma elasticum. Arch Dermatol 1974;110(2):209–12. 22 Hendig D et al. New ABCC6 gene mutations in German pseudoxanthoma elasticum patients. J Mol Med 2005;83(2):140–7. 23 Ringpfeil F et al. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci USA 2000;97(11):6001–6. 24 Ringpfeil F et al. Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity. J Invest Dermatol 2006;126(4):782–6. 25 Miksch S et al. Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. Hum Mutat 2005;26(3):235–48. 26 Gorgels TG et al. Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum. Hum Mol Genet 2005;14(13):1763–73.

Pseudoxanthoma Elasticum 27 Klement JF et al. Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues. Mol Cell Biol 2005;25(18):8299–310. 28 Plomp AS et al. ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones. Mol Vis 2008;14:118–24. 29 Chassaing N et al. Novel ABCC6 mutations in pseudoxanthoma elasticum. J Invest Dermatol 2004;122(3):608–13. 30 Chassaing N et al. Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet 2005;42(12):881–92. 31 Martin L et al. Heterozygosity for a single mutation in the ABCC6 gene may closely mimic PXE: consequences of this phenotype overlap for the definition of PXE. Arch Dermatol 2008;144(3):301–6. 32 Gheduzzi D et al. ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE). Hum Mutat 2004;24(5):438–9. 33 Hendig D et al. SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum. Clin Chem 2007;53(5):829–36. 34 Chassaing N et al. Contribution of ABCC6 genomic rearrangements to the diagnosis of pseudoxanthoma elasticum in French patients. Hum Mutat 2007:28(10):1046. 35 Jiang Q, Endo M, Dibra F et al. Pseudoxanthoma elasticum is a metabolic disease. J Invest Dermatol 2009;129(2):348–54. 36 Le Saux O et al. Serum factors from pseudoxanthoma elasticum patients alter elastic fiber formation in vitro. J Invest Dermatol 2006;126(7):1497–505. 37 Struk B. Pseudoxanthoma elasticum: are vitamin K, its precursors and metabolites the new kids on the block? PXE Awareness 2008;14(3):6–9. 38 Li Q, Jiang Q, Uitto J. Pseudoxanthoma elasticum: oxidative stress and antioxidant diet in a mouse model (Abcc6-/-). J Invest Dermatol 2008;128(5):1160–4. 39 Pasquali-Ronchetti I et al. Oxidative stress in fibroblasts from patients with pseudoxanthoma elasticum: possible role in the pathogenesis of clinical manifestations. J Pathol 2006;208(1):54–61. 40 Garcia-Fernandez MI et al. Parameters of oxidative stress are present in the circulation of PXE patients. Biochim Biophys Acta 2008;1782(7–8):474–81. 41 Hendig D et al. The local calcification inhibitor matrix Gla protein in pseudoxanthoma elasticum. Clin Biochem 2008;41(6):407–12. 42 Gheduzzi D et al. Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients. Lab Invest 2007;87(10):998–1008. 43 Jiang Q, Li Q, Uitto J. Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors. J Invest Dermatol 2007;127(6):1392–402. 44 Gotting C et al. Elevated xylosyltransferase I activities in pseudoxanthoma elasticum (PXE) patients as a marker of stimulated proteoglycan biosynthesis. J Mol Med 2005;83(12):984–92. 45 Schon S et al. Polymorphisms in the xylosyltransferase genes cause higher serum XT-I activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course. J Med Genet 2006;43(9):745–9. 46 Lebwohl M et al. Hyaluronic acid and dermatan sulfate in non-lesional pseudoxanthoma elasticum skin. Clin Chim Acta 1995;238(1):101–7. 47 Smith JG Jr, Davidson EA, Clark RL. Dermal elastin in actinic elastosis pseudoxanthoma elasticum. Nature 1962;195:716–17. 48 Fisher ER, Rodnan GP, Lansing AI. Identification of the anatomic defect in pseudoxanthoma elasticum. Am J Pathol 1958;34(5):977–91. 49 Lebwohl M et al. Abnormalities of connective tissue components in lesional and non-lesional tissue of patients with pseudoxanthoma elasticum. Arch Dermatol Res 1993;285(3):121–6.

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50 Teller H, Vester G. [Electron microscopical studies on the intercellular collagen substance of the corium in pseudoxanthoma elasticum.]. Dermatol Wochenschr 1957;136(51):1373–9. 51 Pasquali-Ronchetti I et al. Pseudoxanthoma elasticum. Biochemical and ultrastructural studies. Dermatologica 1981;163(4):307–25. 52 Ringpfeil F, Pulkkinen L, Uitto J. Molecular genetics of pseudoxanthoma elasticum. Exp Dermatol 2001;10(4):221–8. 53 Ross R, Fialkow PJ, Altman LK. Fine structure alterations of elastic fibers in pseudoxanthoma elasticum. Clin Genet 1978;13(2):213–23. 54 Lebwohl M, Lebwohl E, Bercovitch L. Prominent mental (chin) crease: a new sign of pseudoxanthoma elasticum. J Am Acad Dermatol 2003;48(4):620–2. 55 Goodman RM et al. Pseudoxanthoma elasticum: a clinical and histopathological study. Medicine (Baltimore) 1963;42:297–334. 56 Graham JH, Hunter GA. Perforating pseudoxanthoma elasticum. Arch Dermatol 1976;112:1781. 57 Bos WH. Pseudoxanthoma elasticum associated with perforating elastoma. Dermatologica 1968;136:296–7. 58 Schutt D. Pseudoxanthoma elasticum and elastosis perforans serpiginosa. Arch Dermatol 1965;91:151–2. 59 Takahashi H et al. [A case of elastosis perforans serpiginosa associated with Pseudoxanthoma elasticum (author ’s transl).] Nippon Hifuka Gakkai Zasshi 1982;92(2):91–101. 60 Neldner KH, Martinez-Hernandez A. Localized acquired cutaneous pseudoxanthoma elasticum. J Am Acad Dermatol 1979;1(6):523–30. 61 Hicks J, Carpenter CL Jr, Reed RJ. Periumbilical perforating pseudoxanthoma elasticum. Arch Dermatol 1979;115(3):300–3. 62 Nickoloff BJ, Noodleman FR, Abel EA. Perforating pseudoxanthoma elasticum associated with chronic renal failure and hemodialysis. Arch Dermatol 1985;121(10):1321–2. 63 Gass JD, Clarkson JG. Angioid streaks and disciform macular detachment in Pagets disease (osteitis deformans). Am J Ophthalmol 1973;75(4):576–86. 64 Nagpal KC et al. Angioid streaks and sickle haemoglobinopathies. Br J Ophthalmol 1976;60(1):31–4. 65 Wilhelm K, Paver K. Sudden death in pseudoxanthoma elasticum. Med J Aust 1972;2(24):1363–5. 66 Navarro-Lopez F et al. Restrictive cardiomyopathy in pseudoxanthoma elasticum. Chest 1980;78(1):113–15. 67 Lebwohl MG et al. Pseudoxanthoma elasticum and mitral-valve prolapse. N Engl J Med 1982;307(4):228–31. 68 Nguyen LD et al. Left ventricular systolic and diastolic function by echocardiogram in pseudoxanthoma elasticum. Am J Cardiol 2006;97(10):1535–7. 69 Eddy DD, Farber EM. Pseudoxanthoma elasticum. Internal manifestations: a report of cases and a statistical review of the literature. Arch Dermatol 1962;86:729–40. 70 Parker JC et al. Pseudoxanthoma elasticum and hypertension. N Engl J Med 1964;271:1204–6. 71 Kansy J et al. [Pseudoxanthoma elasticum with hypertension in a 13-year-old girl.] Pediatr Pol 1980;55(5):633–7. 72 Irani C et al. [Pseudoxanthoma elasticum with aortic insufficiency and arterial hypertension in a 12-year-old boy.] Arch Fr Pediatr 1984;41(5):337–9. 73 Farreras-Valenti P et al. Groemblad–Strandberg–Touraine syndrome with systemic hypertension due to unilateral renal angioma: cure of hypertension after nephrectomy. Am J Med 1965;39: 355–60. 74 Dymock RB. Pseudoxanthoma elasticum: report of a case with renovascular hypertension. Australas J Dermatol 1979;20(2):82–4. 75 Trip MD et al. Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease. Circulation 2002;106(7):773–5. 76 Alexander LC, McCaughey RS, Morrish JA. The Gronblad– Strandberg syndrome; a report of three cases presenting with

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massive gastrointestinal hemorrhage during pregnancy. Gastroenterology 1956;31(2):156–68. Galle G et al. [Stenoses of the cerebral arteries in pseudoxanthoma elasticum (author ’s transl).] Arch Psychiatr Nervenkr 1981;231(1): 61–70. Messis CP, Budzilovich GN. Pseudoxanthoma elasticum. Report of an autopsied case with cerebral involvement. Neurology 1970;20(7):703–9. Mamtora H, Cope V. Pulmonary opacities in pseudoxanthoma elasticum: report of two cases. Br J Radiol 1981;54(637):65–7. Jackson A, Loh CL. Pulmonary calcification and elastic tissue damage in pseudoxanthoma elasticum. Histopathology 1980;4(6):607–11. Vanakker OM et al. Visceral and testicular calcifications as part of the phenotype in pseudoxanthoma elasticum: ultrasound findings in Belgian patients and healthy carriers. Br J Radiol 2006;79(939):221–5. Bercovitch RS et al. Testicular microlithiasis in association with pseudoxanthoma elasticum. Radiology 2005;237(2):550–4. Byun JY et al. Pseudoxanthoma elasticum-like papillary dermal elastolysis developed in early middle age. J Dermatol 2007;34(10):709–11. Lee HS et al. Pseudoxanthoma elasticum-like papillary dermal elastolysis with solar elastosis. J Eur Acad Dermatol Venereol 2008;22(3):368–9. Rongioletti F, Rebora A. Fibroelastolytic patterns of intrinsic skin aging: pseudoxanthoma-elasticum-like papillary dermal elastolysis and white fibrous papulosis of the neck. Dermatology 1995;191(1):19–24. Christensen OB. An exogenous variety of pseudoxanthoma elasticum in old farmers. Acta Derm Venereol 1978;58(4):319–21. Nielsen AO et al. Salpeter-induced dermal changes electronmicroscopically indistinguishable from pseudoxanthoma elasticum. Acta Derm Venereol 1978;58(4):323–7. Light N et al. Collagen and elastin changes in D-penicillamineinduced pseudoxanthoma elasticum-like skin. Br J Dermatol 1986;114(3):381–8. Kirsch N, Hukill PB. Elastosis perforans serpiginosa induced by penicillamine. Arch Dermatol 1977;113(5):630–5. Abel M. Elastosis perforans serpiginosa associated with penicillamine. Arch Dermatol 1977;113(9):1303. Pass F et al. Elastosis perforans serpiginosa during penicillamine therapy for Wilson disease. Arch Dermatol 1973;108(5):713–15. Lee TK, Forooghian F, Cukras C et al. Complementary angiographic and autofluorescence findings in pseudoxanthoma elasticum. Int Ophthalmol 2010;30(1):77–9. Sawa M et al. Fundus autofluorescence in patients with pseudoxanthoma elasticum. Ophthalmology 2006;113(5):814–20. Finger RP et al. Intravitreal bevacizumab for choroidal neovascularisation associated with pseudoxanthoma elasticum. Br J Ophthalmol 2008;92(4):483–7. Bhatnagar P et al. Intravitreal bevacizumab for the management of choroidal neovascularization in pseudoxanthoma elasticum. Retina 2007;27(7):897–902.

96 Rinaldi M et al. Intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks. Arch Ophthalmol 2007;125(10):1422–3. 97 Browning AC et al. Verteporfin photodynamic therapy of choroidal neovascularization in angioid streaks: one-year results of a prospective case series. Ophthalmology 2005;112(7):1227–31. 98 Chung AK, Gauba V, Ghanchi FD. Photodynamic therapy (PDT) using verteporfin for juxtafoveal choroidal neovascularisation (CNV) in angioid streaks (AS) associated with pseudoxanthoma elasticum: 40 months results. Eye 2006;20(5):629–31. 99 Baglini R et al. Intracoronary ultrasound guided percutaneous coronary angioplasty using a drug eluting stent in a patient with pseudoxanthoma elasticum. Atherosclerosis 2005:180(1):205–7. 100 Song HK et al. Long-term left internal mammary artery graft patency for coronary artery disease associated with pseudoxanthoma elasticum. Ann Thorac Surg 2004;78(2):691–3. 101 Donas KP, Schulte S, Horsch S. Balloon angioplasty in the treatment of vascular lesions in pseudoxanthoma elasticum. J Vasc Interv Radiol 2007;18(3):457–9. 102 Kaplan EN, Henjyoji EY. Pseudoxanthoma elasticum: a dermal elastosis with surgical implications. Plast Reconstr Surg 1976;58(5):595–600. 103 Galadari H, Lebwohl M. Pseudoxanthoma elasticum: temporary treatment of chin folds and lines with injectable collagen. J Am Acad Dermatol 2003;49(5 suppl):S265–6. 104 Goede J et al. Testicular microlithiasis in a 2-year-old boy with pseudoxanthoma elasticum. J Ultrasound Med 2008;27(10):1503–5. 105 Bercovitch L et al. Pregnancy and obstetrical outcomes in pseudoxanthoma elasticum. Br J Dermatol 2004;151(5):1011–18. 106 Tan WC, Rodeck CH. Placental calcification in pseudoxanthoma elasticum. Ann Acad Med Sing 2008;37(7):598–600. 107 Ramos ESM et al. Connective tissue diseases: pseudoxanthoma elasticum, anetoderma, and Ehlers–Danlos syndrome in pregnancy. Clin Dermatol 2006;24(2):91–6. 108 Xiromeritis P, Valembois B. Pseudoxanthoma elasticum and pregnancy. Arch Gynecol Obstet 2006;273(4):253–4. 109 Farhi D et al. Is pseudoxanthoma elasticum with severe angioid streaks an indication for Caesarean section? J Eur Acad Dermatol Venereol 2006;20(10):1361–2. 110 Borst P, van de Wetering K, Schlingemann R. Does the absence of ABCC6 (multidrug resistance protein 6) in patients with pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery? Cell Cycle 2008;7(11):1575–9. 111 Takata T et al. Treatment of pseudoxanthoma elasticum with tocopherol acetate and ascorbic acid. Pediatr Dermatol 2007;24(4):424–5. 112 Renie WA et al. Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity. Am J Med Genet 1984;19(2):235–44. 113 Sherer DW et al. Oral phosphate binders in the treatment of pseudoxanthoma elasticum. J Am Acad Dermatol 2005;53(4):610–15. 114 Terry SF et al. Advocacy groups as research organizations: the PXE International example. Nat Rev Genet 2007;8(2):157–64.

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C H A P T E R 145

Buschke–Ollendorff Syndrome, Marfan Syndrome, Osteogenesis Imperfecta, Anetodermas and Atrophodermas Marc Lacour Swiss Group for Pediatric Dermatology, Geneva, Switzerland

Buschke–Ollendorff syndrome, 145.1

Osteogenesis imperfecta, 145.8

Marfan syndrome, 145.4

Anetodermas, 145.11

Buschke–Ollendorff syndrome Syn. familial juvenile elastoma, dermatofibrosis lenticularis disseminata with osteopoikilosis, disseminata dermatofibrosis orthopoikilosis, naevus elasticus

Definition. Buschke–Ollendorff syndrome (BOS) is an autosomal dominant disorder clinically characterized by the appearance of disseminated connective tissue naevi of the elastic type and osteopoikilosis. History. In 1928, Buschke and Ollendorff described a 41-year-old woman with pea-sized papules symmetrically distributed over the upper aspects of the back, arms, lumbar region, buttocks and thighs [1]. These skin changes, histologically compatible with connective tissue naevi, were reported as dermatofibrosis lenticularis disseminata, and were associated with osteopoikilosis. Osteopoikilosis is an uncommon cause of multiple osteosclerotic bone lesions (syn: osteopathia condensans disseminata, spotted bones, familial disseminated osteosclerosis). This bone finding was first described by Stieda in 1905 [2] and subsequently by Albers-Schoenberg in 1915 [3]. From the many further reports [4–10], it became clear that BOS could be transmitted in an autosomal dominant pattern and that, in the same family, affected individuals would usually present with both skin and bone changes, but could also present variably, and have only one of these two sites involved [11]. In 1977, Morrisson et al. [12] reported 16 patients from different

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Atrophodermas, 145.16

families in whom the skin lesions of disseminated dermatofibrosis showed the characteristic histological changes of juvenile elastoma. This confirmed earlier findings by Cairns [5] and indicated that the specific dermatological abnormality of BOS is consistent with connective tissue naevi of the elastic type (naevus elasticus). Juvenile elastoma, first described by Weidman in 1933 [13], is a hamartomatous malformation of elastic tissue which may be sporadic or inherited as an autosomal dominant trait. In the many cases reported, radiological investigations for osteopoikilosis have either not been mentioned [14–16] or were negative [17]. Familial juvenile elastoma should, however, be considered as a ‘forme fruste’ of BOS on the basis of the similar histology and the intrafamilial variation in penetration of the bone and/ or skin changes [12,18,19]. Numerous reports of BOS have been published more recently [19–27]. Aetiology and pathogenesis. In 2004, Hellemans et al. [28] mapped osteopoikilosis (OPK) and BOS to chromosome 12q12-14.3 and reported that germline mutations in LEMD3 cause OPK, BOS and melorheostosis. LEMD3 (also called MAN1), an inner nuclear membrane protein, antagonizes TGF-β and bone morphogenetic protein (BMP) signalling through interactions with Smad family proteins. All mutations causing OPK and BOS are heterozygous and cause a loss of function in the LEMD3 gene. They include nonsense and frame-shift mutations and a splice site defect that results in exon skipping [29]. Osteopoikilosis is an osteosclerotic process that can be explained by the deactivating mutations in the LEMD3 gene which results in increased TGF-β/BMP signalling, the latter known as a common pathway of several other osteosclerotic disorders such as progressive diaphyseal dysplasia and sclerosteosis.

145.2

Chapter 145

Melorheostosis is an asymmetrical, flowing hyperostosis typically of long bone cortices. The condition is usually sporadic but has occasionally been reported in BOS [30], possibly resulting from a second, postzygotic somatic mutation. Recent data, however, did not confirm this hypothesis and excluded LEMD3 mutations as a cause of sporadic melorheostosis [29]. A clear link between LEMD3 loss of function and the appearance of skin lesions in BOS remains elusive. Before the genetic characterization of BOS, the genetic mechanism leading to the localized appearance of juvenile elastoma in BOS was hypothesized as being ‘ segmental type 2 manifestation of autosome dominant skin disease’ [31,32]. This hypothesis has so far not been confirmed by genetic analysis. Indeed, fibroblasts from an elastic tissue naevus in a BOS-affected child did not show any secondhit mutation or evidence for loss of heterozygocity [33]. Pathology. Histologically and ultrastructurally, the skin lesions of BOS consist of hypertrophic, broad interlacing elastic fibres surrounding normal collagen bundles. These changes are usually present in the mid and lower dermis, sparing the papillary dermis [5,12]. Variations in the amount of both elastic and collagen fibres, as well as the peculiar branching of the elastin, have been described [9,25,34]. The adjacent uninvolved skin is morphologically normal but is not sharply demarcated from lesional skin. The lesions of BOS are therefore histologically distinct from familial cutaneous collagenoma (in which there is increased collagen and decreased, thin and fragmented elastic fibres), from the shagreen patch of tuberous sclerosis (in which there is increased collagen and paucity of elastic fibres) and from pseudo-xanthoma elasticum (in which elastic fibres show fragmentation and calcification). Clearly, careful morphometric analysis of elastic fibres in lesional skin is a valuable tool to distinguish BOS from the other inherited and acquired diseases known to display alterations of elastic fibres [26]. Osteopoikilosis histologically consists of thickened trabeculae of lamellar bone [35]. Changes in microfibrils have been described. Clinical findings. The cutaneous lesions in BOS may be present at birth but usually develop in the first or second decade. Their appearance later in adulthood is less common. They consist of multiple, pea-sized, flesh-, yellow- or white-coloured papules symmetrically distributed on the buttocks, lower extremities and lumbar region [11,12,21,31,36]. More frequently, lesions comprise larger yellowish nodules, often grouped and sometimes coalescing into plaques [12,31], or can be asymmetrically distributed [9,10,18,37]. Confluence of the lesions is frequent but only exceptionally affects the whole integument. Once

Fig. 145.1 Juvenile elastoma on the abdomen of a child with Buschke– Ollendorf syndrome.

established, the lesions usually stay unchanged and remain asymptomatic (Fig. 145.1). The radiological findings of osteopoikilosis consist of multiple, well-circumscribed round or oval opacities, each 1–10 mm in diameter. They are usually found in the epiphyses and metaphyses of long bones and the pelvis, but are also frequent in the spongiosa of the phalanges, carpal and tarsal bones. The ribs, skull and spine are very rarely affected, which is helpful in excluding other osteocondensing conditions such as metastases, mastocytosis and tuberous sclerosis [22]. Osteopoikilosis is of no pathological significance and is usually an incidental finding, found in 12 of 211,000 radiographs in one series [38]. It can occur in the fetus, but usually takes many years to develop and may not be detectable before the late adolescent or adult period. Familial osteopoikilosis in the absence of skin changes has been described [39]. Buschke–Ollendorff syndrome usually remains a benign disorder throughout life, as exemplified by a woman who gave birth to eight affected children [27]. Rarely, muscle fibrosis and contractures may complicate the disorder [40] and several associations have been described [11,41], most of which are likely to be purely coincidental. One exception to this is the association with

Buschke–Ollendorff Syndrome, Marfan Syndrome, Osteogenesis Imperfecta, Anetodermas

Box 145.1 Differential diagnosis of cutaneous elastoma in the Buschke–Ollendorff syndrome • • • • • • • • •

Shagreen patch (tuberous sclerosis) Collagenoma Pseudo-xanthoma elasticum Lichen myxoedematosus Dermal nodules of Hunter syndrome Smooth muscle hamartoma Leiomyoma Neurofibroma Lipoma

otosclerosis [5,23,42,43], possibly as a consequence of a generalized connective tissue disorder. Differential diagnosis and treatment. History, careful clinical examination and appropriate radiological investigations of the patient and whole family are essential to identify BOS. Indeed, the differential diagnosis of the cutaneous findings is quite large (Box 145.1). In the absence of bone changes in any member of the family, a biopsy will differentiate BOS from other connective tissue naevi. The lesions of BOS remain asymptomatic and rarely cause cosmetic problems, so no treatment is necessary. Informing close relatives of the diagnosis is advisable to avoid misinterpretation of incidental radiographs and allow genetic counselling of this autosomal dominant syndrome.

Papular elastorrhexis Papular elastorrhexis is a rare variant of connective tissue naevus in which there is normal collagen and a decreased amount of elastic fibres. The disorder, appearing in adolescence, has been described in three single patients [44,45]. In these non-familial cases, the cutaneous findings were distinct from papular acne scars and not associated with extracutaneous abnormalities. Although some believe that most connective tissue naevi-like lesions, including papular elastorrhexis, in adults are papular acne scars [46], it seems that the distinctive histology of papular elastorrhexis clearly separates the condition from other entities [47]. Less than 15 cases were published in 2008 [48]. Schirren et al. described three members of one family presenting with non-follicular, distributed, white papules on the trunk and extremities [49]. The clinical appearance with absence of osteopoikilosis and the histological findings (decreased, fragmented elastic fibres and normal collagen) were compatible with papular elastorrhexis. However, on the basis of the genetic background, the authors believed that papular elastorrhexis was an abor-

145.3

tive form of the Buschke–Ollendorff syndrome and suggested that connective tissue naevi with the most prominent alterations in the elastic tissue should be classified under the term elastic tissue naevi. References 1 Buschke A, Ollendorff H. Ein Fall von Dermatofibrosis disseminata und Osteopathia condensans disseminata. Dermatol Wochenschr 1928;86:257–62. 2 Stieda A. (Ueber umschriebene Knochenverdichtungen im Bereich des Substantia spongiosa im Röntgenbilde. Bruns Beitr Klin Chir 1905;45:700–3. 3 Albers-Schoenberg HE. (Eine seltene, bisher nicht bekannte Strukturanomalie des Skelettes. Fortschr Roentgenstr 1915;23:174–5. 4 Berlin R, Hedensiö B, Lilja B et al. (Osteopoikilosis – a clinical and genetic study. Acta Med Scand 1967;181:305–14. 5 Cairns RJ. (Familial juvenile elastoma, osteopoikilosis (2 cases). Proc Roy Soc Med 1967;60:1267. 6 Grupper C, Cardinne A. Disseminated lenticular dermatofibrosis with osteopecila (father and son). Buschke–Ollendorff syndrome. Ann Dermatol Syphiligr Paris 1974;101:405–407. 7 Marshall J. Osteopoikilosis and connective tissue naevi: a syndrome of hereditary polyfibromatosis. S Afr Med J 1970;44:775–7. 8 Pastinszky J, Csato Z. On skin variations in osteopoikilia (Buschke– Ollendorff syndrome). Z Haut Geschlechtskr 1968;43:313–23. 9 Schorr WF, Opitz JM, Reyes CN. The connective tissue naevus – osteopoikilosis syndrome. Arch Dermatol 1972;81:249–52. 10 Smith AD, Waisman M. Connective tissue naevi: familial occurrence and association with osteopoikilosis. Arch Dermatol 1960;81: 249–52. 11 Verbov J, Graham R. Buschke–Ollendorff syndrome – disseminated dermatofibrosis with osteopoikilosis. Clin Exp Dermatol 1986;11:17–26. 12 Morrison JG, Jones EW, MacDonald DM. Juvenile elastoma and osteopoikilosis (the Buschke–Ollendorff syndrome). Br J Dermatol 1977;97:417–22. 13 Weidman FD, Anderson NP, Ayres S. Juvenile elastoma. Arch Dermatol Syphil 1933;28:182–9. 14 Staricco RG, Mehregan AH. Naevus elasticus and naevus elasticus vascularis. Arch Dermatol 1961;84:943–7. 15 De Graciansky P, Leclerc R. Le ‘naevus elasticus’ en tumeurs disséminées. Ann Dermatol Syphil 1960;187:5–25. 16 Dammert K, Niemi KM. Naevus elasticus (elastoma juvenile Weidman) and naevus collagenicus lumbosacralis in Pringle’s disease. Dermatologica 1968;137:36–45. 17 Marguery MC, Samalens G, Pieraggi MT et al. Conjunctive nevus of the disseminated elastic type without osteopoikilosis or Weidman juvenile elastoma. Ann Dermatol Venereol 1991;118:465–8. 18 Huilgol SC, Griffiths WA, Black MM. Familial juvenile elastoma. Australas J Dermatol 1994;35:87–90. 19 Woodrow S, Pope F, Handfield-Jones S. The Buschke–Ollendorff syndrome presenting as familial elastic tissue naevi. Br J Dermatol 2001;144:890–3. 20 Ramme K, Kolde G, Stadler R. Dermatofibrosis lenticularis disseminata with osteopoikilosis. Buschke–Olldendorff syndrome. Hautarzt 11993;44:312–14. 21 Dahan S, Bonafe JL, Laroche M et al. Iconography of Buschke Ollendorff syndrome: X ray computed tomography and nuclear magnetic resonance of osteopoikilosis. Ann Dermatol Venereol 1989;116:225–30. 22 Roberts NM, Langtry JA, Branfoot AC et al. Case report: osteopoikilosis and the Buschke–Ollendorff syndrome. Br J Radiol 1993;66:468–70.

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23 Schnur RE, Grace K, Herzberg A. Buschke–Ollendorff syndrome, otosclerosis, and congenital spinal stenosis. Pediatr Dermatol 1994;11:31–4. 24 Thieberg MD, Stone MS, Siegfried EC. What syndrome is this? Buschke–Ollendorff syndrome. Pediatr Dermatol 1993;10:85–7. 25 Trattner A, David M, Rothem A et al. Buschke–Ollendorff syndrome of the scalp: histologic and ultrastructural findings. J Am Acad Dermatol 1991;24:822–4. 26 Ghomrasseni S, Dridi M, Bonnefoix M et al. Morphometric analysis of elastic fibres from patients with: cutis laxa, anetoderma, pseudoxanthoma elasticum, and Buschke–Ollendorff and Williams–Beuren syndromes. J Eur Acad Dermatol Venereol 2001;15:305–11. 27 Al Attia H, Sherif A. Buschle–Ollendorff syndrome in a grande multipara: a case report and short review of the literature. Clin Rheumatol 1998;17:172–5. 28 Hellemans J, Preobradzhenska O, Willaet A et al. Loss-of-function mutations in LEMD3 result in ostoepoikilosis, Buschke–Ollendorff syndrome and melorheostosis. Nat Genet 2004;36:1213–18. 29 Mumm S, Wenkert D, Zhang X et al. Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke–Ollendorff syndrome, but not sporadic melorheostosis. J Bone Min Res 2007;22:243–50. 30 Debeer P, Pykels E, Lammens J et al. Melorheostosis in a family with autosomal dominant osteopoikilosis: report of a third family. Am J Med Genet 2003;119:188–93. 31 Happle R. Segmentale Type-2-Manifestation autosomal dominanter Hautkrankheiten. Hautarzt 2001;52:283–7. 32 Ehrig T, Cockerell CJ. Bushke–Ollendorff syndrome: report of a case and interpretation of the clinical phenotype as a type 2 segmental manifestation of an autosomal dominant skin disease. J Am Acad Dermatol 2003;49:1163–6. 33 Gass JK, Hellemans J, Mortier G et al. Buschke–Ollendorff syndrome: a manifestation of a heterozygous nonsense mutation in the LEMD3 gene. J Am Acad Dermatol 2008;58:s103–4. 34 Giro MG, Duvic M, Smith LT et al. Buschke–Ollendorff syndrome associated with elevated elastin production by affected skin fibroblasts in culture. J Invest Dermatol 1992;99:129–37. 35 Hess W. Roentgenologische und pathologisch–anatomische Beobachtungen bei einem Fall von Osteopoikilie. Fortschr Geb Roentgenstr 1940;62:252–8. 36 Verbov J. Buschke–Ollendorff syndrome (disseminated dermatofibrosis with osteopoikilosis). Br J Dermatol 1977;96:87–90. 37 Atherton DJ, Wells RS. Juvenile elastoma and osteopoikilosis (the Buschke–Ollendorf syndrome). Clin Exp Dermatol 11982;7:109–13. 38 Jonasch E. 12 Faelle von Osteopoikilie. Fortrschr Roentgenstr 1955;82:344–53. 39 Sarralde A, Garcia Cruz D, Nazara Z et al. Osteopoikilosis: report of a familial case. Genet Couns 1994;5:373–5. 40 Walpole IR, Manners PJ. Clinical considerations in Buschke– Ollendorff syndrome. Clin Genet 1990;37:59–63.

41 Reid EM, Baker BL, Stees MA et al. Buschke–Ollendorff syndrome: a 32-month-old boy with elastomas and craniosynostosis. Pediatr Dermatol 2008;25:349–51. 42 Strosberg JM, Adler RG. Otosclerosis associated with osteopoikilosis. JAMA 1981;246:2030–1. 43 Piette Brion B, Lowy Motulsky M, Ledoux Corbusier M et al. Dermatofibromas, elastomas and deafness: a new case of the Buschke– Ollendorff syndrome. Dermatologica 1984;168:255–8. 44 Bordas X, Ferrandis C, Ribera M et al. (Papular elastorrhexis: a variety of nevus anelasticus? Arch Dermatol 1987;123:433–4. 45 Sears J, Seabury Stone M, Argenyi Z. Papular elastorrhexis: a variant of connective tissue nevus. J Am Acad Dermatol 1988;19:409–14. 46 Wilson B, Dent C, Cooper P. Papular acne scars. A common cutaneous finding. Arch Dermatol 1990;126:797–800. 47 Buechner S, Itin P. Papular elastorrhexis. report of five cases. Dermatology 2002;205:198–200. 48 Pajot C, Le Clec’h C, Hoareau F et al. Elastorrhexie papuleuse: deux cas. Ann Dermatol Venereol 2008;135:757–61. 49 Schirren H, Schirren C, Stolz W et al. Papular elastorrhexis: a variant of dermatofibrosis lenticularis disseminata (Buschke–Ollendorff syndrome)? Dermatology 1994;189:368–72.

Marfan syndrome Definition. Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue due to the abnormal expression of fibrillin-1 and is characterized by manifestations in the cardiovascular, musculoskeletal and ophthalmic systems (Table 145.1). The syndrome also shows striking pleiotropism and clinical variability. History. In 1896, the French paediatrician Marfan described a 5-year-old girl with tall stature and disproportionately long limbs and fingers [1]. He used the term ‘dolichostenomelia’ which is now referred to as the marfanoid habitus. A few years later, Marfan’s original patient developed scoliosis [2]. Another clinically similar patient was described by Achard, who introduced the word ‘arachnodactyly’ to describe the associated long, slender fingers [3]. Following reports of associated dislocation of the lens (ectopia lentis) and mitral valve regurgitation with the disorder, Weve, in 1931, proposed the name ‘dystrophica mesodermalis congenita, typus

Table 145.1 Fibrillin gene disorders

Habitus Cardiovascular manifestations Ectopia lentis Joints Cranial abnormality Gene defect

Marfan

Congenital contractural arachnodactyly

Autosomal dominant ectopia lentis

Marfan craniosynostosis syndrome

Marfanoid

Marfanoid

−

Marfanoid

+ + Looseness − FBN1

− − Contractures − FBN2

− + − − FBN1

+ (+) Looseness + FBN1

Buschke–Ollendorff Syndrome, Marfan Syndrome, Osteogenesis Imperfecta, Anetodermas

Marfanis’ [4]. This was condensed to Marfan syndrome in 1938 by Apert [5]. In 1956, McKusick, a major contributor to the characterization of MFS, suggested that elastic fibres or a component intimately associated with elastic fibres was defective in MFS. Studies initially focused on collagens, elastin and other connective tissue components and it was only in the late 1980s that fibrillin was identified as a molecule tightly linked with elastic fibres [6,7]. In a very short time, both the positional cloning approach and the candidate gene strategy resulted in the cloning and localization of two fibrillin genes [8–12]. As seen in Table 145.1, mutations in the fibrillin-1 gene (FBN1, located on chromosome 15) were identified in patients with both MFS and autosomal dominant ectopia lentis [13]; mutations in the fibrilin-2 gene (FBN2, on chromosome 5) are linked to the MFSrelated disorder called congenital contractural arachnodactyly (CCA) [14]. Finally, two anecdotes in the MFS saga are worth mentioning: it is likely that Marfan’s original patient did not have MFS but rather CCA [15], and there is quite an interest in knowing whether US President Abraham Lincoln was affected by MFS [16,17]. Aetiology. Fibrillin, an acidic glycoprotein with an estimated molecular mass of 350 kDa, is a major constituent of the 10 nm microfibrils of the extracellular matrix. Its primary structure is characterized by several cysteinerich motifs, reminiscent of the epidermal growth factor (EGF) peptide module that also has six similarly spaced cysteinyl residues [6,18,19]. The role of fibrillin as the underlying cause of MFS is supported by three independent lines of experimental evidence: firstly, antisera to fibrillin showed a decreased amount of microfibrils in MFS tissue samples [20,21]; secondly, defective synthesis and secretion of fibrillin by dermal fibroblasts were demonstrated in 26 probands with MFS [22]; thirdly, linkage and mutational analysis of several affected kindred confirmed a genetic homogeneity between MFS and the fibrillin gene [23]. Functionally, the 10 nm microfibrils, including fibrillin, serve at least three functions: as a link between elastin and other matrix structures (i.e. the basement membrane at the dermoepidermal junction); as a scaffolding upon which elastin is deposited (i.e. in the tunica media of the aorta); and as a structural component in tissues that do not contain elastin (i.e. the ciliary zonule) [24]. The pathogenic role of fibrillin in MFS was thought to be principally structural, causing a defective connective tissue. Recently, a second pathogenic role was described for fibrillin-1 deficient mice [25], which involves a metabolic pathway since these mice have marked dysregulation of transforming growth factor-β (TGF-β) activation and signalling. This is in keeping with the fact that fami-

145.5

lies with variant MFS syndrome showed mutations on the TGF-β receptor genes. Genetic analysis provided precise insights into the structural and functional features of fibrillin. Initially, however, such studies failed to define predictable genotype/phenotype correlations. This was highly in keeping with the variable expression of MFS features in affected individuals of the same family and implied that other factors are involved in the development of the clinical phenotype. Indeed, the same mutation (P1148A) was shown in individuals with MFS, isolated ectopia lentis (EL) and the MFS-related but clinically distinct Shprintzen– Goldberg syndrome [26]. The first clinicopathological correlations have now emerged through the analysis of 803 pathogenic mutations found in 1013 probands [27]. These correlations among different mutation types and clinical manifestations might be explained by different underlying genetic mechanisms (dominant-negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus as a mediator of TGF-β signalling). Clinical features. The clinical expression of MFS is highly variable, ranging from congenital presentation and death before a few months of life to long-term survival. Severe cases are often sporadic rather than familial and a few have a recessive mode of inheritance with homozygous mutations.

Musculoskeletal features Dolichostenomelia is the characteristic skeletal abnormality in MFS [28]. It includes tall stature, decreased upper to lower segment ratio (US/LS, a value 5 Fig. 147.1 Major aphthous ulceration of the palate.

Diseases of the Oral Mucosa and Tongue

Chlorhexidine gluconate (0.2%) or benzydamine hydrochloride mouthwashes or sprays are a good starting point and often give good symptomatic relief. The spray forms of these agents are particularly useful in children. Topical tetracycline mouthwash, made up from a 250 mg capsule of tetracycline in 5 mL of water, may be useful, particularly in herpetiform ulceration. However, it is unsuitable for young children as they may ingest some of the mouthwash which can cause tooth discolouration. Topical steroids such as hydrocortisone hemisuccinate pellets (Corlan® 2.5 mg four times daily) are often beneficial. Becotide 50 or 100 μg inhaler may be used as a topical mouth spray four to six times per day. A mouthwash made up of soluble betametasone tablets (0.5 mg) in 15– 20 mL of water and held in the mouth for 3 min four times per day may be of benefit to adolescents but is not suitable for young children. Very occasionally, systemic steroids or other immunosuppressive agents such as azathioprine, colchicine and thalidomide have been necessary to control ulceration; their use in children must be carefully monitored and they should be used only as a last resort. There are multiple other therapies available for RAS, including carbenoxolone, benzydamine, dapsone, cromoglycate, levamisole and many others, but generally their efficacy has not been well proven or they have unacceptable adverse effects.

Behçet syndrome Definition. Behçet syndrome is a multisystem disease in which the mouth is affected in nearly 100% of cases. Mouth lesions manifest as RAS. Other sites that may be affected include the genitals, eyes, skin and joints. There may be a number of other systemic or cutaneous manifestations. The clinical diagnosis of Behçet syndrome is dependent on the presence of at least three or more possible clinical manifestations, e.g. orogenital ulceration and uveitis (see Chapter 167). Aetiology. The aetiology of Behçet syndrome is unknown. There is increasing evidence to suggest an immunological aetiology; however, immunological findings appear to vary considerably and therefore cannot be used for the diagnosis or management of the disease. HLA-B5, HLABW51 and HLA-DR7 appear to be associated with Behçet syndrome. Behçet syndrome can occur in any age group but most commonly affects adult males in their third decade, although it may occur in childhood.There is often a positive family history. There is also a higher prevalence of the disease in people from certain geographical areas, which include Japan, China, the Mediterranean and the Middle East [3].

147.3

Clinical features. The most common clinical feature is that of oral ulceration (90–100%), which may involve especially the posterior pharynx, and is indistinguishable clinically and histopathologically from RAS. Ulcers may occur at other sites, including the anus and genitals. Skin lesions such as erythema nodosum, pustules and pathergy are also common findings. The disease process is transient and subject to spontaneous remissions. Differential diagnosis. Recurrent oral ulceration may be the first and only initial clinical feature of Behçet syndrome, but only a very few patients with RAS develop Behçet syndrome; however, Behçet syndrome must always be excluded when considering a diagnosis of RAS as, unlike RAS, it is a systemic disorder and is not self-limiting. Oral and genital ulceration may also result from folate deficiency and, together with ocular lesions, may occur in erythema multiforme and ulcerative colitis. Treatment. Oral ulceration can be managed symptomatically as in RAS. Immunosuppressive treatment is required for those with other lesions. Results using ciclosporin and dapsone have been inconclusive, colchicine appears to be of value and thalidomide may be required in cases of recalcitrant orogenital ulceration but requires extreme caution as it is teratogenic.

MAGIC syndrome A condition that overlaps with Behçet syndrome and causes large joint arthropathies consists of mouth and genital ulcers with inflamed cartilage (MAGIC) [4].

Traumatic ulceration Trauma to the oral mucosa is common and may cause localized ulceration, which resolves as long as the causative agent is removed. It may be caused by sharp broken teeth or dental appliances or be self-inflicted, particularly with disorders such as congenital insensitivity to pain, Lesch–Nyhan syndrome, epilepsy, athetosis and learning impairment. Oral ulceration may also be caused by nonaccidental injury. Radiation, thermal or chemical agents may also cause ulceration. Clinical features. The clinical appearance of a traumatic ulcer is dependent upon the causative agent. Physical trauma gives rise to a localized ulcer that may resemble a minor or major aphthous ulcer. Tongue or cheek biting gives rise to a more irregularly shaped ulcer, often with a keratotic border. Thermal and chemical trauma caused by the ingestion of hot food or drinking caustic/acidic agents gives rise to more generalized ulceration, which tends to affect the tongue and palate. Ulcers may heal

147.4

Chapter 147

with scarring, especially if loss of connective tissue has occurred. Oral ulceration due to non-accidental injury often occurs around the mouth and may involve the labial mucosa, particularly the labial fraenum, which may become torn and ulcerated by attempts to silence a child with a hand across the mouth. Differential diagnosis. The possibility of other causes of oral ulceration should always be considered as described in this section. Treatment. Usually no treatment is required other than reassurance. If soreness is a problem, benzydamine hydrochloride may be useful as either a mouthwash or a spray. If the ulcer has been caused by a sharp tooth or orthodontic appliance, appropriate modification should be carried out. If self-mutilation is a problem, the provision of polyvinyl occlusal splints may be useful. If an ulcer fails to heal within 2–3 weeks after the causative agent has been removed, a biopsy should be considered to exclude neoplasia. If child abuse is suspected, appropriate action should be taken, which is usually dependent upon local guidelines.

Infections

primary and secondary infections, and may be spread in this way. The incubation period is 3–7 days. Pathology. Well-defined fluid-filled vesicles form in the upper epithelium. The vesicles rupture, infecting the epithelium throughout its entire thickness. Ulceration is caused by shedding of the virus-damaged epithelial cells. Clinical features. The lesions consist of well-defined vesicles of about 2 mm in diameter, which may coalesce to form larger irregular lesions that may be distributed over the entire oral mucosa and gingivae but are commonly seen on the dorsum of the tongue and the hard palate. The vesicles rapidly rupture to form circular, sharply defined shallow ulcers with a yellowish-grey floor and erythematous margin (Fig. 147.2). The ulcers are very painful. The gingival margins are usually enlarged and inflamed. There is often associated cervical lymphadenopathy, pyrexia and general malaise. Diagnosis is usually made on the clinical features. Differential diagnosis. Acute ulcerative gingivitis, erythema multiforme and leukaemia may occasionally give a similar clinical appearance, as may hand, foot and mouth disease and herpangina (see below). Gingival enlargement may be seen in acute childhood leukaemia, particularly the myeloid type.

A variety of infections may give rise to oral ulceration/ stomatitis. These will be considered under three main groups: viral, fungal and bacterial.

Viral infections The acute viral infections of childhood may give rise to oral ulceration and symptoms. The symptoms of acute viral infections affecting the mouth are all very similar, but the distribution of lesions may vary. Generally, if a viral infection is suspected, the diagnosis is made on clinical and epidemiological information. It is only where virus identification is of importance, such as in immunocompromised patients, that culture and nucleic acid/ immunostaining studies to identify the virus are undertaken.

Herpetic gingivostomatitis (see Chapter 48) Aetiology. Herpes simplex virus type 1 and increasingly type 2 cause primary herpetic gingivostomatitis. Primary herpes most commonly occurs in young children (2–4 years) and is often subclinical; however, many children now reach maturity without acquiring immunity to the virus, giving rise to an increased incidence of primary herpes infections in young adults. Primary herpes infection is twice as common in lower socio-economic groups. Herpes simplex virus is found in the saliva in both

Fig. 147.2 Ulceration of the tongue and labial mucosa due to primary herpes virus infection.

Diseases of the Oral Mucosa and Tongue

Treatment. In most cases, the infection resolves spontaneously with 7–10 days. For the majority of patients the management is supportive, with antipyretic analgesics (e.g. paracetamol/acetaminophen), bed rest and adequate fluid intake. Chlorhexidine gluconate 0.2% mouthwash or spray may help to prevent secondary infection of the ulcers. Systemic aciclovir or similar antiviral agents hasten recovery but are only really useful if used in the first 3 days of onset, during the vesicular stage of infection [5]. As most cases present in the ulcerative phase, this is of little benefit. Aciclovir does have a role to play if patients are immunocompromised, and in rare complications such as encephalitis and neuropathy.

147.5

aciclovir-resistant herpes simplex infections. The clinical appearance of this condition is almost pathognomonic of the infection (Figs 147.4, 147.5). The lesions present as well-defined oral ulcers with a characteristic adherent greyish-white slough, which has a leathery texture [6]. The usual oral features of either primary or recurrent herpes are not usually present. The patients are nearly always on a prophylactic regimen of aciclovir, and many have a history of previous herpes labialis [7]. The herpes virus may also be resistant to ganciclovir and foscarnet, which is nephrotoxic and has been used to treat the virus. Valaciclovir and cidofovir are alternative treatments. Aciclovir-resistant herpes simplex virus has also been reported in immune incompetence as a result of HIV infection and Wiskott–Aldrich syndrome [8].

Recurrent herpes simplex Following primary infection, the herpes virus remains latent in the trigeminal ganglion. About one-third of patients experience recurrent herpes infections, the most common form of which is herpes labialis (cold sore) (Fig. 147.3). Typical triggering events include exposure to sunlight, infections such as the common cold, stress and trauma. Intraoral recurrence often manifests as a dendritic ulcer on the tongue or palate. Chronic ulceration of this type or nodular lesions can occur in immunosuppressed individuals and may require treatment with systemic aciclovir.

Aciclovir-resistant herpes simplex infection Severely immunocompromised children, such as those undergoing bone marrow transplantation, may develop Fig 147.4 Aciclovir-resistant herpes on the ventral surface of the tongue of a child following bone marrow transplantation. Note the well-defined lesion and the absence of an inflammatory reaction surrounding the lesion.

Fig. 147.3 Herpes labialis.

Fig. 147.5 Aciclovir-resistant herpes on the hard palate of a child following bone marrow transplantation.

147.6

Chapter 147

Chickenpox Chickenpox is caused by the varicella zoster virus. Lesions occur mainly over the trunk but may also occur intraorally. The oral lesions appear as vesicles, which break down to form discrete, well-defined ulcers. They are usually fewer in number than in primary herpes and there is no associated gingival enlargement.

Herpes zoster (shingles) Herpes zoster may give rise to oral lesions if the maxillary or mandibular branch of the trigeminal nerve is involved. Ulcers appear in the distribution of the affected nerve; the lesions do not cross the midline and are preceded by a toothache-like pain. It is rare to see herpes zoster in childhood unless the child is immunocompromised or the mother was infected during pregnancy.

pressed patients should be biopsied and sent for histopathology, microbiological culture and PCR DNA studies.

Human immunodeficiency virus Oral ulceration may occur in children who are human immunodeficiency virus (HIV) positive. Clinically, they are often aphthous-like [10] and may be treated as such. However, the possibility of another infective cause should always be considered, e.g. CMV [11].

Fungal infections Oral fungal infections rarely cause ulceration of the oral mucosa in the Western world except in immunocompromised or debilitated patients. In the tropics, otherwise healthy individuals may occasionally present with oral fungal lesions caused by endemic deep mycoses.

Herpangina Herpangina is caused by a Coxsackie A virus. The infection is usually confined to children and presents as an acute pharyngitis with lymphadenopathy and pyrexia. Oral lesions are localized to the soft palate; they resemble those of primary herpes. There is no gingival involvement. The infection resolves spontaneously in 10–14 days. Treatment is supportive, as described for primary herpes.

Hand, foot and mouth disease Hand, foot and mouth disease often causes minor epidemics among school children. It is caused by a Coxsackie A virus, usually A10 or A16, or occasionally a Coxsackie B or other enterovirus. Clinically, the oral lesions resemble those of primary herpes, although they occur in much smaller numbers and cause few symptoms. As in herpangina, the gingivae are not involved. Cutaneous lesions affect the hands and feet and consist of small deep-seated vesicles, with surrounding erythema situated on the digits or base of the phalanges. Management is as for herpangina.

Deep mycoses Deep mycotic infections are uncommon in the UK but are seen in Latin America and some parts of the southern USA. Oral lesions are most common in histoplasmosis and paracoccidioidomycosis but have been described in all mycoses. The oral lesions are not distinctive and diagnosis is usually made on biopsy. The following deep mycoses may give rise to oral ulceration in the immunocompromised child, particularly those undergoing cytotoxic chemotherapy or bone marrow transplantation, or in patients with acquired immune deficiency syndrome (AIDS). They should always be considered as part of the differential diagnosis in the immunocompromised and, if necessary, biopsied to exclude them as causative agents. Aspergillosis may cause black necrotic ulceration of the palate (Fig. 147.6). The infection usually originates from infection in the maxillary sinuses and is caused by direct

Infectious mononucleosis (Epstein–Barr viral infection) Infectious mononucleosis is caused by the Epstein–Barr virus (EBV). In the Western world, it is more common in teenagers and young adults, but it may occur in children. Oral symptoms include sore throat, and palatal petechiae are often evident. Occasionally, there may be severe ulceration of the fauces; less severe non-specific oral ulceration and pericoronitis may also occur.

Cytomegalovirus infection Cytomegalovirus (CMV) may cause a glandular fevertype illness but rarely causes oral ulceration. Persistent CMV-induced ulcers have been described in immunosuppressed patients [9]. Persistent oral ulcers in immunosup-

Fig. 147.6 Necrotic ulceration of the hard palate due to antral aspergillosis in a child following bone marrow transplantation.

Diseases of the Oral Mucosa and Tongue

invasion of the palate. Diagnosis is made from biopsy and radiographic examination of the paranasal air sinuses. Treatment is usually with intravenous itraconazole or amphotericin. Mucormycosis (zygomycosis, phycomycosis), infection with a fungus associated with mouldy bread, may give rise to a similar clinical picture to aspergillosis. It is a condition that has been associated with uncontrolled diabetes mellitus. Histoplasmosis oral lesions are uncommon and present as a non-specific ulcer or lump. They are usually seen in chronic disseminated histoplasmosis.

147.7

sis. Any chronic oral ulcer in a child with no obvious causative factors should therefore be biopsied.

Oral ulceration associated with systemic disease Oral ulceration may occasionally be the presenting feature of other systemic disease. The relationship of oral ulceration to systemic diseases will be discussed in this section with reference only to the systemic disease and oral features.

Haematological disorders Bacterial infections Acute ulcerative gingivitis Acute ulcerative gingivitis (AUG) is an uncommon disease in childhood and may be associated with immune deficiency such as AIDS and cytotoxic chemotherapy. In countries where nutrition is poor, it can manifest as cancrum oris (noma), causing massive soft tissue destruction. It is thought to be caused by a proliferation of two normal oral commensals, the Gram-negative anaerobes Borrelia vincentii and Fusobacterium nucleatum. Classically, AUG begins on the tips of the interdental papillae, causing intense pain and halitosis. Spontaneous bleeding of the gingivae may occur. The ulceration spreads along the gingival margin but is well localized. In the immunocompromised child, the ulceration may be far more destructive and spread onto the palate, and buccal sulci may occur. Histologically, there is intense inflammation and destruction of the epithelium and connective tissue. When occurring in a young child, primary herpetic gingivostomatitis may give a similar gingival appearance, but it is unusual for ulceration to be localized to the gingivae. Systemic upset is usually more severe in primary herpes. Acute ulcerative gingivitis responds rapidly to metronidazole therapy three times daily for 3 days, the dose depending upon age. If the child is immunocompromised, a longer course and higher dose may be indicated. Local measures such as improving oral hygiene and the use of an antibacterial mouthwash (e.g. chlorhexidine gluconate 0.2%) should also be considered.

Haematinic deficiencies are discussed above. Immunodeficiencies, whether congenital or acquired, may also give rise to oral ulceration. These ulcers usually resemble recurrent aphthae but if a neutropenia is present, they lack the erythematous inflammatory halo, as in cyclic or hereditary benign neutropenias (Fig. 147.7).

Gastrointestinal disease As discussed with RAS, haematinic deficiencies may give rise to oral ulceration, therefore any gastrointestinal disease causing malabsorption predisposes the child to oral ulceration.

Coeliac disease (gluten-sensitive enteropathy) Older children and adolescents with undiagnosed coeliac disease may occasionally present with sore mouths. Oral manifestations include recurrent ulcers, glossitis, angular stomatitis and dental hypoplasia, related to underlying haematinic and vitamin deficiencies.

Other bacterial infections Tuberculosis and syphilis are rare causes of chronic mouth ulcers.

Oral ulceration in association with neoplasia Oral carcinoma is extremely rare in children. Very occasionally, oral ulceration may be the presenting feature of a malignant lesion, particularly lymphoma or histiocyto-

Fig. 147.7 Neutropenic ulcers in a child with familial chronic neutropenia. Note the lack of inflammation surrounding the ulcers.

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Crohn disease Oral lesions related to Crohn disease include facial or labial swelling (orofacial granulomatosis), oral ulcers, which may be large and ragged or linear in appearance, mucosal tagging or proliferation of the oral mucosa to give a ‘cobblestone’ appearance. Other lesions, such as ulcers and glossitis, may be due to an associated nutritional deficiency caused by malabsorption or may be coincidental. Oral lesions may occur prior to any gastrointestinal symptoms. Biopsy of the oral lesions will confirm the diagnosis, histology showing non-caseating granulomas in the corium with an overlying normal or ulcerated epithelium. Differential diagnosis includes orofacial granulomatosis, sarcoidosis and tuberculosis (see below and Chapters 57, 157, 158). Treatment of the oral lesions is dependent upon whether there is active gastrointestinal disease. If systemic corticosteroid or aminosalicylate therapy for active gastrointestinal disease is used, the oral lesions may also improve; if oral lesions remain symptomatic or occur in isolation, local measures to control the symptoms, such as those used in RAS, may be adequate. Orofacial granulomatosis is a term given to labial or gingival swelling due to a granulomatous reaction but without any detectable systemic cause, e.g. Crohn disease, sarcoidosis. Some patients with this diagnosis will go on to develop a systemic disease some time later. In other cases, the granulomatous reaction is thought to be due to a food allergy, particularly to cinnamoncontaining foodstuffs. Exclusion of cinnamon from the diet of these individuals may allow resolution of the lesions. A short course of high-dose or intralesional steroids may reduce swelling [12].

Ulcerative colitis

Lichen planus, lichenoid reactions and chronic graft-versus-host disease Lichen planus is rare in childhood. It should be considered in the differential diagnosis of oral white lesions in children, particularly in children of Asian origin [13]. Drug-induced lichenoid lesions may occur; they are particularly associated with the use of anti-inflammatory agents, antihypertensives and antimalarial drugs. Graftversus-host disease (GVHD) following organ or bone marrow transplantation may also give rise to lichenoid lesions. Clinically, several forms of lichen planus may be observed. Reticular and papular lichen planus is usually asymptomatic and is usually symmetrically distributed on the buccal mucosa and lateral borders of the tongue. It may resemble oral thrush, particularly if it is plaquelike in appearance. These white forms of lichen planus often require no treatment if they are symptomless. Atrophic or erosive lichen planus is symptomatic and may be seen in GVHD. It presents as erosive, often linear ulcers, which affect any site but commonly the tongue and buccal mucosa (Fig. 147.8). It is unlikely to be the only clinical manifestation of GVHD. Skin and liver GVHD are often concurrent, requiring the use of immunosuppressive therapy. The immunosuppressive therapy does not always resolve the oral GVHD, and topical steroid therapy using Becotide 50 or 100 inhaler as a topical mouth spray four to six times per day, together with soluble betametasone 0.5 mg (Betnesol) used as a mouthwash (dissolved in 25 mL of water) and held in the mouth for 2–3 min four times per day, may aid healing and improve symptoms. Benzydamine hydrochloride mouthwash or spray may also be of symptomatic use. It is also important to keep the mouth as clean as possible, to prevent secondary infection. As tooth brushing may be painful, the use of chlorhexidine gluconate mouth-

Oral lesions associated with ulcerative colitis include aphthous-type ulceration and glossitis, which may be associated with anaemia. Other oral lesions are rare and include haemorrhagic ulceration of the mucosa, chronic oral ulceration resembling pyostomatitis gangrenosum of the skin and pyostomatitis vegetans, which clinically gives rise to hyperplastic folds of the oral mucosa between which microabscesses or fissures form; multiple yellowish pustules may also form on the mucosa. Behçet syndrome should be considered in the differential diagnosis of oral lesions. Treatment is the same as in Crohn disease, oral lesions being more apparent with exacerbations of bowel inflammation.

Dermatological disorders Dermatological disorders rarely cause mouth ulcers in children; if they do occur, skin lesions can often aid diagnosis.

Fig. 147.8 Erosive lichen planus-like lesions of the tongue due to GVHD. Note also the depapillation of the tongue.

Diseases of the Oral Mucosa and Tongue

wash 0.2% or spray twice daily may be helpful. As the GVHD responds to the immunosuppressive therapy, oral lesions usually resolve.

Vesiculobullous disorders The more common dermatological conditions that cause vesiculobullous lesions in the mouth, such as pemphigus vulgaris and mucous membrane pemphigoid, are very rare in childhood and will not be discussed. Oral vesicles or bullae may occur in childhood in benign familial chronic pemphigoid, which break down to form welldemarcated ulcers.

Epidermolysis bullosa Epidermolysis bullosa (EB) is discussed in Chapter 118. In most forms of the disease, bullae will form on the oral mucosa. They usually appear in infancy and may be precipitated by suckling. The bullae break down to form ulcers, which heal slowly, usually with scarring. The tongue becomes depapillated. Because of the sensitivity of the mucosa to trauma, oral hygiene is usually poor and the incidence of caries and periodontal disease is therefore high.

Dermatitis herpetiformis and linear immunoglobulin A disease Dermatitis herpetiformis may occur in childhood and is often associated with gluten enteropathy (see Chapter 89). Oral lesions may occur and include erythematous papules and macules, petechiae, vesicles, bullae and erosions. Similar oral lesions may occur in linear immunoglobulin A (IgA) disease. Oral lesions rarely occur in isolation and will respond to therapy for cutaneous lesions, dapsone or sulfapyridine. Diagnosis is made on biopsy.

147.9

Connective tissue disorders Connective tissue disorders that give rise to oral ulceration, e.g. systemic and discoid lupus erythematosus, rarely occur in children. Juvenile rheumatoid arthritis may be associated with anaemia, which may predispose to RAS. Felty syndrome is most likely to cause ulceration, presumably because of the associated neutropenia. Behçet syndrome may occur in childhood and is discussed above.

Iatrogenic oral ulceration Oral ulceration may regularly be caused by certain drugs, e.g. cytotoxic agents. The ulceration is usually aphthouslike in appearance but may lack an inflammatory halo if associated with neutropenia. It is self-limiting and heals within 7–10 days. It is now less commonly seen in association with methotrexate as folinic acid rescue (calcium leucovorin) is usually always given with high-dose methotrexate therapy. Aphthous-type ulceration can also occur in long-term use of some drugs, such as phenytoin or cotrimoxazole, which interfere with folate metabolism. Aplastic anaemia may also be drug induced and give rise to oral ulceration and purpura. Radiation to the head and neck, and total body irradiation for bone marrow transplantation, gives rise to mucositis, which occurs 7–10 days after beginning radiotherapy to the head and neck, and lasts for up to 4 weeks after completion of treatment. Those patients undergoing total body irradiation experience mucositis within 5–10 days and the mucositis heals within 2–3 weeks of treatment. Various agents have been used to decrease the amount of mucositis and improve healing; however, none has been particularly successful apart from oral cooling with ice. Treatment therefore remains symptomatic; benzydamine hydrochloride and chlorhexidine mouthwash may help alleviate symptoms.

Erythema multiforme Erythema multiforme is discussed in Chapter 78. Oral features characteristically include swollen, bleeding, crusted lips and widespread oral ulceration. Oral ulcers are preceded by erythematous macules, which become vesicles. Intact vesicles are rarely seen as they rapidly break down to form ill-defined ulcers. The tongue is often furred and there may be regional lymphadenitis. Oral lesions may occur in isolation or with a skin rash, which characteristically consists of ‘target’ lesions and ocular involvement. The combination of oral lesions, skin lesions and conjunctivitis is referred to as Stevens–Johnson syndrome. Biopsy may be necessary in less characteristic cases and will exclude other vesiculobullous disorders and Behçet syndrome. Aciclovir may be beneficial prophylactically in herpesprecipitated erythema multiforme.

References 1 Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc 2003;134:200–7. 2 Field AE, Brookes V, Tyldesley W. Recurrent aphthous ulceration in children: a review. Int J Paediatr Dent 1992;2:1–10. 3 Escudier M , Bagan J, Scully C. Behcets syndrome (Adamantiades syndrome). Oral Dis 2006;12:78–84. 4 Firestein GS, Gruber HE, Weisman MH et al. Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome. Am J Med 1985;79:65–71. 5 Amir J, Harel L, Smetana Z et al. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomized double blind placebo controlled study. BMJ 1997;314:1800–3. 6 Brooke AE, Eveson JW, Luker J et al. Oral presentation of a novel variant of herpes simplex in a group of bone marrow transplant patients: a report of five cases. Br J Dermatol 1999;141:381–3. 7 Venard V, Dauendorffer JN, Carrett AS et al. Infection due to aciclovir resistant herpes simplex virus in patients undergoing allogeneic haematopoetic stem cell transplantation. Pathol Biol 2001;49:553–8.

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8 Saijo M, Suzutani T, Murono K et al. Recurrent aciclovir resistant herpes simplex in a child with Wiskott–Aldrich syndrome. Br J Dermatol 1998;139:311–14. 9 Epstein J, Scully C. Cytomegalovirus: a virus of increasing relevance to oral medicine. J Oral Pathol Med 1993;22:348–53. 10 Scully C, Laskaris G, Porter SR. Oral manifestations of HIV infection and their management. II. Less common lesions. Oral Surg Oral Med Oral Pathol 1991;71:167–71. 11 Scully C. The HIV global pandemic: the development, and emerging implications. Oral Dis 1997;3(suppl 1):1–6. 12 Grave B, McCullough M, Wiesenfeld D. Orofacial granulomatosis – a 20-year review. Oral Dis 2009;15(1):46–51. 13 Alam F, Hamburger J. Oral mucosal lichen planus in children. Int J Paediatr Dent 2001;11:209–14.

White patches (leucoplakia) Definition of leucoplakia The term ‘leucoplakia’ is often used clinically to describe a chronic white lesion of the oral mucosa. However, it should really be restricted to those white lesions for which there is no identifiable cause or underlying disease process.

Normal anatomy Fordyce’s spots or granules Fordyce’s spots are sebaceous glands that are present beneath the oral mucosa. Although they are present at birth, they do not usually become clinically apparent until puberty. They appear as asymptomatic, slightly raised yellowish nodules usually on the buccal mucosa, just inside the commissure or the labial and retromolar mucosa. They may be discrete or coalescent. Diagnosis is made on the clinical appearance. Treatment involves reassurance that they are a normal feature of the oral mucosa.

Gingival cysts of infancy (Epstein’s pearls and Bohn’s nodules)

tonofilament organization. Other mucosae may be affected. The epithelium appears hyperplastic and has a thick, irregular parakeratotic layer which, as a result of epithelial oedema, has a so-called ‘basket-weave’ appearance. White sponge naevus is caused by mutations in either the KRT3 or KRT14 gene (see also Chapter 117). The clinical appearance is very distinctive and is often first noticed in childhood. The oral mucosa is irregularly thickened, folded and appears white. Unlike other white lesions, there is no clear margin to the lesion and it merges imperceptibly with normal mucosa. The buccal mucosa is usually affected but the entire oral mucosa may be involved; the attached gingivae are usually spared. The clinical appearance is usually sufficient to diagnose the condition and a positive family history is helpful. Biopsy may be necessary to eliminate other causes of white patches in less classic cases. As the condition is asymptomatic and benign, no treatment is required other than reassurance.

Darier–White disease (dyskeratosis follicularis) Inherited as an autosomal dominant disorder of keratinization, this condition manifests in early adolescence (see Chapter 125). Oral lesions occur in about 50% of affected individuals and their appearance has no significance in relation to the intensity of skin involvement. Clinically, the lesions consist of flattish initially erythematous papules, which coalesce to give a cobblestone appearance. The lesions become progressively paler until they are white. The lesions tend to occur on the tongue, palate and gingivae [1]. Palatal lesions can resemble nicotinic stomatitis.

Tylosis (palmoplantar keratoderma) and Clouston syndrome

These cysts are commonly seen in the newborn. They either rupture spontaneously or involute and are rarely apparent after 3 months or age. They arise from remnants of the dental laminae on the alveolus (Epstein’s pearls) or epithelial inclusion at a site of fusion, e.g. midline of the palate (Bohn’s nodules). Clinically, they appear as 2–3 mm diameter white nodules on the crests of the alveolar ridge or the midline of the palate. As they resolve spontaneously, no treatment is required.

Tylosis is inherited as an autosomal dominant trait and is discussed in Chapter 127. Orally, pre-leucoplakia lesions have been reported in most affected children [2]. These lesions are diffuse and greyish in colour; they go on to form non-specific leucoplakia with increasing age and do not appear to be potentially malignant. Clouston syndrome (hidrotic ectodermal dysplasia), which also causes palmoplantar hyperkeratosis, may also give rise to oral leucoplakia [3].

Congenital causes of white patches White sponge naevus (familial white folded gingivostomatitis)

Pachyonychia congenita

This is a rare condition, inherited as an autosomal dominant trait, which results in the formation of widespread white plaques of the oral mucosa caused by abnormal

Pachyonychia congenita is discussed in Chapter 117. Oral lesions occur in 60% of affected individuals and present as focal or generalized greyish-white thickening of the oral mucosa. They do not have an increased malignant potential [4]. Vesicular and ulcerative oral lesions have

Diseases of the Oral Mucosa and Tongue

also been described. Of affected individuals, 10% have angular cheilitis, and there is an increased risk of chronic candidiasis in this group. Natal or neonatal teeth may also be present in 16% of individuals [5].

Dyskeratosis congenita This is a rare disorder with both a sex-linked and a recessive form. The main features include dysplastic lesions of the oral mucosa, dermal pigmentation, nail dystrophy and aplastic anaemia (see Chapter 137). Oral lesions usually occur between the ages of 5 and 10 years and consist of white patches, usually affecting the palate or tongue, which may be preceded by vesicles or erosions [5,6]. Oral lesions may also manifest as small erythematous areas. Biopsy of the lesion shows dysplasia and there is a high risk of malignant change. Regular review and rebiopsy of lesions are essential.

Hereditary benign intraepithelial dyskeratosis This is a very rare autosomal dominant condition in which oral lesions occur in childhood and become more obvious by adolescence. They consist of milky white, smooth translucent plaques that predominantly affect the buccal mucosa, lips and ventrum of the tongue. Biopsy may be necessary to differentiate from white sponge naevus and other white lesions. No treatment is required.

Acquired transient white lesions Traumatic/frictional keratosis Frictional keratosis is caused by chronic irritation of the oral epithelium, which causes hyperkeratosis. It is often caused by a sharp tooth or restoration, or by a habit such as cheek biting. Clinically, the relationship of the keratosis to a causative factor should be established. On removal of the causative agent or cessation of the habit, resolution of the keratosis should occur. Chemical trauma to the oral mucosa may also lead to a transient white lesion. Children may occasionally ingest caustic or acidic agents, e.g. household cleaning agents, which cause epithelial cell death, clinically appearing as a soft white patch. Aspirin burns result from an aspirin being placed next to a painful tooth. In this case, the white plaque is localized.

Materia alba Debris collecting on the gingivae in uncleaned mouths may mimic thrush, and is termed materia alba.

Furred/hairy tongue See Lesions of the tongue, below.

147.11

Koplik’s spots Koplik’s spots are an oral manifestation of measles. They appear as small white lesions resembling grains of salt on the buccal mucosa. Their appearance may precede the cutaneous skin rash by 1–2 days. Measles is an uncommon childhood infectious illness in areas where there is a measles immunization programme.

Candidiasis (candidosis) This is an acute or chronic infection of the oral mucosa caused by invasion of the epithelium by candidal hyphae, which usually induce a proliferative response and cause a plaque to form. Candida species are isolated in about 50% of the population as a normal oral commensal organism, the most common species being Candida albicans. Candida krusei, C. guilliermondii, C. tropicalis and C. parapsilosis may also be implicated, especially in the immunocompromised patient. Should the balance of the oral environment be disturbed (e.g. systemic infection, use of an orthodontic or other dental appliance, suppression of cell-mediated immunity, iron deficiency, diabetes), candidal organisms may proliferate and give rise to infection. Candidiasis is the most common oral manifestation of HIV disease. Chronic mucocutaneous candidiasis is characterized by persistent candidiasis, which usually begins in early childhood, involving the skin, mucous membranes and nails. About 50% of patients have an associated endocrinopathy, which is usually preceded by candidiasis. Of all patients, 20% have a family history. The clinical features of oral candidiasis are dependent upon whether the infection is acute or chronic. The various clinical entities are discussed below.

Acute pseudo-membranous candidiasis (thrush) Thrush is typically seen in the neonatal period when immune mechanisms have not fully developed. It may also be seen in children who are compromised in some way. The lesions are usually asymptomatic and manifest as thick creamy plaques which are easily wiped off the oral mucosa, leaving an erythematous area of mucosa. The lesions may occur in any area of the mouth but are commonly seen on the soft palate and fauces (Fig. 147.9). On direct smear with a Gram or periodic acid–Schiff (PAS) stain, masses of candidal hyphae may be seen with a few yeast cells. The plaques are formed by proliferation of the epithelium in response to invasion by candidal hyphae. The plaque consists of epithelial cells that are separated by inflammatory infiltrate, making the plaque friable. The deeper epithelium is hyperplastic and there is an acute inflammatory reaction in the connective tissue. Sections stained with PAS show candidal hyphae growing downwards through the epithelium.

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Fig. 147.9 Acute pseudo-membranous candidiasis in a child undergoing chemotherapy for acute leukaemia.

Fig. 147.10 Angular stomatitis which was related to diabetes.

If no predisposing factor is evident, investigation should be undertaken to establish why candidiasis has occurred, e.g. anaemia, diabetes mellitus or immunodeficency. If the child is known to be immunocompromised, it is important to culture the lesions for species other than C. albicans, such as C. kruseii, which is inherently resistant to some antifungal agents [7]. In the majority of cases, topical antifungal therapy is usually adequate to treat the infection. Nystatin suspension or pastilles can be used or amphotericin B lozenges or miconazole oral gel used four times per day for 10–14 days. If the lesions fail to respond to topical antifungals, systemic use of fluconazole or itraconazole should be considered.

warm moist environment that favours the proliferation of candidal organisms. Histologically, the epithelium exhibits acanthosis with an oedematous superficial layer. The underlying connective tissue contains a chronic inflammatory cell infiltrate. Chronic atrophic candidiasis usually resolves if the appliance is removed from the mouth for a few hours each day, cleaned thoroughly and soaked in chlorhexidine or a mild hypochlorite solution, e.g. Milton. If this is not possible, miconazole gel can be applied to the mucosal surface of the appliance four times per day. When the appliance is no longer needed, the candidiasis will resolve spontaneously.

Erythematous candidiasis Candidal infection may cause erythematous lesions, such as in chronic denture stomatitis and candidiasis associated with xerostomia and the use of topical steroid inhalers. However, the term ‘erythematous candidiasis’ is now frequently used to describe the patchy erythematous lesions associated with HIV infection. Treatment is as for thrush. Chronic atrophic candidiasis (chronic denture stomatitis) This condition is often seen under the fitting surface of upper dentures, hence the term ‘denture-related stomatitis’. It may also occur under a removable orthodontic appliance. It is bright red in appearance and is clearly restricted to the area under the appliance. Candidal hyphae can be isolated from the mucosa and the porous acrylic surface of the appliance. The infection is caused by the continuous wearing of the appliance, which prevents debridement of the covered mucosa and forms a

Angular stomatitis Angular stomatitis describes an inflammatory lesion at the angle of the mouth. It is often bilateral and may be asymptomatic or painful. It can occur with any concurrent intraoral candidiasis but is not always due to candidal infection. Staphylococcus aureus may also cause angular stomatitis, the organisms often originating from the nares. Angular stomatitis is typically seen where a dental appliance is being worn and, in the absence of this, an underlying immune or haematinic deficiency, or diabetes may be the cause (Fig. 147.10). Angular stomatitis may also be non-infective and may be due to persistent dribbling causing maceration of the tissues. Diagnosis of the causative organism will require a microbiological swab which should be cultured for Staph. aureus and Candida species. Treatment is dependent on the causative factor [8]. Both candidal and staphylococcal infections will respond to miconazole gel. If Staphylococcus is isolated, a more rapid resolution may occur with fucidin cream and the nose may also need to be treated. If no organisms are

Diseases of the Oral Mucosa and Tongue

147.13

cultured and maceration is the cause, a barrier ointment may be of use.

Acquired persistent white lesions Chronic hyperplastic candidiasis (candidal leucoplakia) Chronic hyperplastic candidiasis in childhood is unusual and most often seen in mucocutaneous candidiasis, congenital immunodeficiencies and AIDS. Clinically, the oral lesions all have similar features: they are white, tough and firmly adherent to the underlying mucosa. They are often of irregular thickness and outline. Common sites include the buccal mucosa and dorsum of the tongue. There are four main clinical variants of chronic mucocutaneous candidiasis: • candidal leucoplakia (idiopathic limited type) • familial chronic mucocutaneous candidiasis • diffuse-type chronic mucocutaneous candidiasis • endocrine candidiasis syndrome. All give rise to persistent candidiasis in which the mouth is the sole or main site of infection. The lesions do not respond to topical antifungal therapy. Histologically, the features are similar to those seen in thrush. The plaques consist of thick layers of parakeratotic epithelium invaded by candidal hyphae. There is an inflammatory infiltrate within the plaque, which is concentrated at its base. The underlying epithelium is hyperplastic and there are chronic inflammatory changes in the dermis. Diagnosis of chronic hyperplastic candidiasis is confirmed by biopsy. Treatment is difficult and topical antifungal agents are rarely of use. Systemic agents such as fluconazole and itraconazole are beneficial but may require continued prophylactic administration if mucocutaneous candidiasis syndrome is diagnosed. If recurrence occurs with the use of long-term azole antifungals, the recurrent lesions should be cultured to check for azole resistance.

Lichen planus, lichenoid lesions and chronic graft-versus-host disease See Mouth ulcers/sore mouth, above.

Psoriasis Oral lesions are extremely rare in psoriasis and are usually associated only with pustular psoriasis. The lesions may resemble erythema migrans (see below) or take the form of translucent plaques. Macules, diffuse erythema and pustules have also been reported.

Lupus erythematosus This connective tissue disorder is very rare in childhood but may give rise to oral lesions that resemble lichen planus, particularly the atrophic type. The lesions are not symmetrical in distribution and the white striae tend to radiate centrifugally.

Fig. 147.11 Leucoplakia of the tongue. Clinically, this lesion resembles lichen planus but histologically showed only hyperkeratosis. The 17-year-old patient had undergone bone marrow transplantation 8 years previously, suggesting that the lesion may have been initially due to GVHD.

Hairy leucoplakia Hairy leucoplakia may be seen in children with severe immune defects, particularly HIV infection. EBV has been shown to be present in the epithelium, and the lesions have been reported to regress with aciclovir therapy. Histological features include severe parakeratosis, hyperplasia, koilocyte-like cells and an absence of inflammatory infiltrate. Clinically, the lesion appears more corrugated in appearance than hairy and is most often seen on the lateral borders of the tongue [9]. It is symptomless and no treatment is required. Biopsy may be necessary to confirm the diagnosis.

Chronic renal failure Stomatitis is commonly seen in uraemic patients. Leucoplakias have also been reported [10]. Clinically, the lesions resemble congenital white sponge naevus, although the lesions have well-defined margins. The ventral surface of the tongue is often the main site affected.

Leucoplakia of unknown cause Leucoplakia is uncommon in childhood. The clinical appearance is highly variable, as is the size of the lesion (Fig. 147.11). Histologically, the lesions range from simple hyperkeratosis to atrophic parakeratotic epithelium with severe dysplasia. Although the clinical appearance is no indication of the underlying histology, speckled lesions are more likely to show dysplastic changes. Any leucoplakia of unknown cause should be biopsied and kept under regular 3-monthly review. If the lesion changes in character, it should be rebiopsied because of the risk of malignant change.

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References 1 Macleod RI, Munro CS. The incidence and distribution of oral lesions in patients with Darier ’s disease. Br Dent J 1991;177:133–6. 2 Tyldesley WR. Oral leukoplakia associated with tylosis and oesophageal carcinoma. J Oral Pathol 1974;3:62–70. 3 George DI, Escobar VH. Oral findings of Clouston’s syndrome. Oral Surg Oral Med Oral Pathol 1984;57:258–62. 4 Feinstein A, Friedman J, Schewach-Millet M. Pachyonychia congenita. J Am Acad Dermatol 1988;19:705–11. 5 Scully C, Langdon JD, Evans JH. A marathon of eponyms: JadassohnLewandowsky. Oral Dis 2010;16:310–11. 6 Cannell H. Dyskeratosis congenita. Br J Oral Surg 1971;9:8–20. 7 Johnson EM, Warnock DW, Luker J. Emergence of azole resistance in Candida species from HIV-infected patients receiving prolonged fluconazole therapy for oral candidosis. J Antimicrob Chemother 1995;35:103–14. 8 Scully C, El-Kabir M, Samaranayake LP.Candida and oral candidosis. Crit Rev Oral Biol Med 1994;5:124–58. 9 Scully C, Laskaris G, Porter SR. Oral manifestations of HIV infection and their management. I. More common lesions. Oral Surg Oral Med Oral Pathol 1991;71:158–66. 10 Kellet M. Oral white patches in uraemic patients. Br Dent J 1983:154:366–8.

Red and pigmented lesions Localized lesions Amalgam and graphite tattoos Amalgam tattoos are the most common cause of localized oral pigmentation. They can occur at any age, and result from minor trauma to the oral mucosa during the placement of an amalgam restoration or during the extraction of a tooth containing an amalgam restoration, which allows amalgam particles to penetrate into the epithelium. The amalgam particles are deposited in the corium. A foreign body giant cell reaction or macrophage accumulation occurs in about 55% of cases. Clinically, amalgam tattoos are most commonly seen on the gingivae, alveolar mucosa, floor of the mouth and buccal mucosa. They appear as symptomless blue-black macules, the margins of which may be well defined or diffuse. They may vary in size from 1 to 20 mm. Similar lesions may result from trauma from a pencil and are seen mainly in the palatal vault. Radiography may aid the diagnosis as many lesions are radiopaque. If any doubt exists as to the diagnosis, biopsy should be performed.

pigmented. The hard palate and buccal mucosa are the most common sites of occurrence. Histologically, several types of naevi can be identified: junctional, compound, intramucosal, blue oral melanotic macule and melanoacanthoma. They are all benign. Malignant melanoma is rare in childhood. Diagnosis may be confirmed by biopsy.

Melanotic neuroectodermal tumour of infancy This is a rare tumour occurring in the first year of life. It is thought to arise from neural crest tissue. Clinically, lesions occur in the anterior maxilla as painless, nontender enlarging dark masses. Growth may be rapid. Radiographical examination shows underlying radiolucency and displacement of developing teeth. The lesion is benign and conservative surgical excision is curative.

Peutz–Jeghers syndrome This autosomal dominant syndrome comprises intestinal polyposis and melanotic pigmentation of the face and mouth (see Chapter 137). Oral pigmentation is usually confined to the lower lip and buccal mucosa.

Haemangiomas and vascular malformations Haemangiomas in children are localized congenital vascular tumours (described more fully in Chapter 113). Clinically, oral haemangiomas appear as superficial purple-bluish nodules or macules that blanch on pressure, the common sites of occurrence being the lips (Fig. 147.12), tongue, palate and buccal mucosa. Intraoral capillary or capillary venous malformations are also associated with certain syndromes including Sturge–Weber syndrome (Fig. 147.13), Klippel–Trenaunay– Weber syndrome and Maffucci syndrome. Excision or biopsy of the lesion may be necessary if the diagnosis is unclear or the lesion is enlarging, in order to

Oral pigmented naevi Melanocytic naevi are rare in the mouth when compared with the occurrence on the skin (see Chapters 109, 192). They are twice as common in females and tend to occur in the 30–50-year-old age group, although they may be seen in childhood. They range in size from 1 to 30 mm, the majority being less than 6 mm. They may be grey, brown, black or blue in colour; about 20% are non-

Fig. 147.12 Haemangioma of the upper lip in a 6-month-old baby. The lesion was surgically excised as it was enlarging and causing lip distortion.

Diseases of the Oral Mucosa and Tongue

147.15

Fig. 147.13 Sturge–Weber syndrome; the child also suffered epilepsy and learning impairment. Fig. 147.14 Acute gingivitis and periodontitis in a child with familial chronic neutropenia.

eliminate neoplasia. Surgery or cryotherapy may be required if repeated haemorrhage is a problem. Very large venous malformations are difficult to treat surgically and sclerotherapy may be of benefit. Problematic haemangiomas may respond to intralesional steroids or oral propranolol (see Chapter 113).

Hereditary mucoepithelial dysplasia This is a rare autosomal dominant trait that results in abnormal desmosome and gap junctions. Clinically, oral lesions appear in infancy as red macules or papules on the palate and gingivae. They are painless and may persist throughout life.

conditions such as Down syndrome, cathepsin C deficiency (Papillon–Lefevre syndrome), leucocyte adhesion deficiency (LAD) and hypophosphatasia underlie some cases. Gingivitis presents clinically as redness of the gingivae surrounding the tooth; it is usually painless, but the child may report bleeding of the gingivae on tooth brushing. There is usually a heavy accumulation of plaque around the necks of the teeth. Treatment involves removal of plaque, instigation of good oral hygiene and the use of chlorhexidine gluconate mouthwash 0.2% twice daily until gingivitis resolves.

Erythema migrans See Lesions of the tongue, below.

Kaposi’s sarcoma Rarely, Kaposi sarcoma may occur intraorally in children who have contracted HIV/AIDS by non-sexual routes, particularly in Africa [1]. Lesions are most common on the palate or gingivae and present as purple-red macules or nodules. They rarely require specific treatment.

Allergic gingivostomatitis Occasionally, gingivitis may be caused by an allergic reaction. The gingivitis tends to be diffuse and oral hygiene is often very good. Common causative agents include cinnamon-containing toothpastes, some chewing gums and mints. The gingivitis resolves when the causal agent is removed and recurs when rechallenged.

Generalized lesions Chronic atrophic candidiasis See Acquired transient white lesions (candidiasis), above.

Gingivitis Gingivitis is uncommon in preschool children (with the exception of acute viral infections), and an underlying systemic disease should always be considered in a differential diagnosis, particularly immunological deficiencies such as neutropenia (Fig. 147.14). In older children, gingivitis is usually concurrent with poor oral hygiene; however, if associated with destruction of the periodontium (the supportive tissues of the teeth), underlying disease should be eliminated, particularly diabetes mellitus and immunodeficiency [2]. Other

Racial pigmentation is the most common cause of generalized pigmentation of the oral mucosa in both children and adults; however, other causes, such as those discussed below, should be eliminated from the differential diagnosis. Other rare causes of generalized oral pigmentation include haemochromatosis, neurofibromatosis and incontinentia pigmenti.

Racial pigmentation Racial pigmentation mainly occurs in individuals of black, Asian or Mediterranean descent and 5% of Caucasians. It varies in colour from light brown to black and may occur anywhere in the mouth, particularly the gingivae and tongue.

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Drug-induced hyperpigmentation Drugs such as anticonvulsants, cytotoxic agents (especially busulphan), adrenocorticotrophic hormone (ACTH) therapy and oral contraceptives may cause brown oral pigmentation. Antimalarial drugs produce a range of mucosal pigmentation from yellow to blue-black, depending on the drug used. Minocycline may cause a blue-grey staining of the gingival margins [3].

Addison disease Oral hyperpigmentation ranging from light brown to almost black may be seen in Addison disease or in ectopic ACTH production. The pigmentation is variable in its distribution but often affects the soft palate, buccal mucosa, lateral borders of the tongue, gingivae and lips. Addison disease may be associated with chronic mucocutaneous candidiasis (see above).

Fig. 147.15 Oral purpura in a child with thrombocytopenia caused by Wiskott–Aldrich syndrome.

Albright syndrome Pigmentation of the oral mucosa has been reported in Albright syndrome, which consists of polyostotic fibrous dysplasia (facial bones affected in 25% of cases), pigmentation of the skin and precocious puberty in females.

Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu disease) This is an autosomal dominant trait characterized by multiple telangiectasia of the skin and mucous membranes. Lesions do not normally become apparent until the second or third decade. Any area of the mouth may be affected. The lesions appear as red spots or spider-like lesions, which empty on applying pressure; they are caused by the superficial dilation of small blood vessels [4]. If traumatized, they may cause bleeding, which may be difficult to control. Laser therapy to the lesions may be required. Oral telangiectasia may also be seen in scleroderma, and after radiotherapy to the head and neck region.

Fig. 147.16 Porphyria. A baby with the lower first deciduous incisors erupting. Note the red colour due to porphyrin deposition in the dentine.

Box 147.1 Causes of pigmentation of the teeth

Thrombocytopenic purpura Thrombocytopenia, whatever its aetiology (idiopathic, drug induced, etc.), may cause oral purpura or petechiae at a platelet count of below 50 × 109/L. Lesions commonly occur on mucosa that is easily traumatized, such as the tongue, palate and buccal mucosa. They are reddish-purple in colour and vary in size (Fig. 147.15). They do not blanch on pressure. Oral purpura may be the first clinical manifestation of leukaemia, aplastic anaemia or HIV disease.

Pigmentation of the teeth Pigmentation or discoloration of the teeth may be due to intrinsic or extrinsic staining (Box 147.1, Fig. 147.16).

Extrinsic • Chromogenic bacteria • Chlorhexidine gluconate • Iron preparations Intrinsic • • • • • • • •

Amelogenesis imperfecta Dentinogenesis imperfecta Tetracycline staining Fluorosis Porphyria Erythroblastosis fetalis Chronological hypoplasia Trauma

Diseases of the Oral Mucosa and Tongue References 1 Ficarra G, Berson AM, Silverman S et al. Kaposi’s sarcoma of the oral cavity: a study of 134 patients with a review of the pathogenesis, epidemiology, clinical aspects and treatment. Oral Surg Oral Med Oral Pathol 1988;66:543–50. 2 Hakki SS, Aprikyan AA, Yildirim S et al. Periodontal status in two siblings with severe congenital neutropenia: diagnosis and mutational analysis of the cases. J Periodontol 2005;75:837–44. 3 Berger RS, Mandel EB, Hayes TJ et al. Minocycline staining of the oral cavity. J Am Acad Dermatol 1989;21:432–42. 4 Flint SR, Keith O, Scully C. Hereditary haemorrhagic telangiectasia: family study and review. Oral Surg Oral Med Oral Pathol 1988;66:440–4.

Swellings/lumps in and around the mouth Lumps in the mouth may have a variety of causes ranging from normal anatomy to neoplasia. In this section, they are considered in three main groups: soft tissue swellings, bony swellings and gingival swelling.

Developmental soft tissue swellings Congenital granular cell epulis of the newborn The congenital epulis is a rare tumour occurring on the alveolar ridge and, as its name implies, is present at birth. It may form a soft, rounded, pedunculated swelling of a few millimetres in diameter or be so large as to protrude from the mouth. The aetiology is unclear but it is thought to be mesenchymal in origin and may be a hamartoma. Eighty percent of lesions occur in females, and they are more common on the maxillary alveolar ridge than the mandibular. Treatment is by excision and recurrence is very uncommon.

Lingual thyroid

147.17

Lymphangioma Lymphangiomas are hamartomas that bear a close structural resemblance to cavernous haemangiomas but contain lymph instead of blood. They are often present at birth and usually manifest before 10 years of age. Intraoral lymphangiomas are uncommon but are most likely to occur on the tongue. Clinically, they appear as a sessile swelling with a pale translucent appearance and a finely nodular surface. They may appear to turn black if bleeding occurs into the lesion and then simulate a haemangioma. Treatment is required if the lesion is symptomatic and involves surgical excision, although cryosurgery may be useful for small lesions.

Haemangioma See Red and pigmented lesions, above.

Neurofibromatosis (see Chapter 128) This syndrome comprises multiple neurofibromas, cutaneous pigmentation in the form of café-au-lait spots and skeletal abnormalities. Oral neurofibromas occur in about 10% of cases and may involve any oral soft tissues. Tuberous sclerosis complex (epiloia) (see Chapter 129) Oral lesions seen in tuberous sclerosis complex consist of fibrous outgrowths of the oral mucosa, affecting the anterior gingivae in particular [1].

Cowden syndrome (see Chapters 111, 137) Papillomatous outgrowths from the buccal mucosa and papular lesions of the palate, lips and gingivae have been described in this syndrome. Other oral lesions may include fissured tongue and hypoplasia of the maxillae, mandible and uvula.

See Lesions of the tongue, below.

Dermoid cyst See Lesions of the tongue, below.

Lingual tonsil See Lesions of the tongue, below.

Eruption cyst Eruption cysts are soft tissue follicular cysts that form over the crowns of erupting teeth of children, particularly deciduous teeth or permanent molar teeth. They appear as rounded smooth bluish swellings on the alveolar ridge. They are usually asymptomatic and resolve spontaneously as the tooth erupts. If they cause symptoms or become infected, marsupialization may be necessary.

Acquired soft tissue swellings Abscesses Intraoral abscesses are almost always dental in origin, usually originating from a carious tooth. They usually present as painful fluctuant soft tissue swelling of the gingiva or buccal sulcus, occasionally in the palate (Fig. 147.17). An associated cellulitis may also occur, giving rise to facial swelling. The abscess is often preceded by toothache and the offending tooth is usually carious and tender to pressure. The diagnosis is made on clinical findings and treatment involves draining the abscess via the tooth itself or the soft tissue. Antibiotics may be required if there is an associated regional lymphadenopathy or if treatment is delayed, as a general anaesthetic may be required to treat very young children.

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Fig. 147.17 Dental abscess causing soft tissue swelling in the upper left quadrant of a 12-year-old child.

Fig. 147.19 Giant cell granuloma.

Pyogenic granuloma Pyogenic granulomas are soft tissue swellings that are highly vascular and have a tendency to haemorrhage. They are caused by a tissue reaction to non-specific infection as a result of minor trauma to the oral mucosa. Histologically, they contain numerous thin-walled blood vessels in a loose, moderately cellular fibrous stroma. Clinically, they usually present as a painless swelling on the gingival margin, but may occur at other sites, e.g. buccal mucosa, palate. The swelling may be sessile or pedunculated with a smooth, lobulated or warty surface. They are red in colour and soft to palpation. They are variable in size from a few millimetres to a few centimetres. Differential diagnosis includes a fibroepithelial polyp and giant cell epulis. Treatment is by surgical excision. Fig. 147.18 Fibrous lump (epulis).

Giant cell epulis/granuloma

Fibroepithelial polyp/nodule Fibroepithelial polyps or nodules are the most common type of tumour-like swelling found in the mouth (Fig. 147.18). They are usually considered to be caused by chronic low-grade trauma. Often a source of trauma cannot be found. Histologically, these lesions consist of stratified squamous keratinized epithelium with underlying dense bundles of collagenous connective tissue in continuity with the corium. They are not encapsulated. There may be an inflammatory exudate and occasionally dystrophic calcification occurs. Clinically, they appear as either sessile or pedunculated, soft, pink swellings. They may occur on the gingivae, where they are referred to as epulides, palate and buccal mucosa or tongue. They are usually painless. Treatment involves surgical excision with curettage of the underlying periostium to prevent recurrence.

A giant cell granuloma is a non-neoplastic swelling of proliferating fibroblasts in a vascular stroma containing multinucleate giant cells. Its aetiology is unknown. It is more commonly seen in children than in adults and presents as a deep red-purple soft swelling, which often arises interdentally adjacent to permanent incisor or premolar teeth (Fig. 147.19). Hyperparathyroidism (brown tumours) should always be considered when a lesion containing giant cells is diagnosed. Treatment is by surgical excision and curettage of the underlying bone.

Squamous papillomas Squamous cell papillomas are common benign oral lesions caused by human papillomavirus (HPV). They may occur at any age. Clinically, they present as a welldefined exophytic mass with a warty surface. If the surface epithelium is keratinized, they appear white. Although they may occur anywhere in the mouth, they are most commonly seen at the junction of the hard and soft palates. Oral papillomas should be excised and exam-

Diseases of the Oral Mucosa and Tongue

ined histologically to confirm the diagnosis, as they may resemble a fibroepithelial polyp. Treatment is by total excision to prevent recurrence. Human papillomavirus may also cause common warts and oral papillomas, particularly on the lips, and is often seen in association with verruca vulgaris of the skin. HPV-13 and -32 are implicated in focal epithelial hyperplasia (Heck disease), which presents in certain racial groups, such as Inuits, as multiple sessile soft papules, usually on the lower labial and buccal mucosa.

147.19

Sarcomas and related conditions Oral facial sarcomas are rare tumours of childhood, the most common being rhabdomyosarcoma. Locally invasive tumours such as infantile fibromatosis may also give rise to intraoral swelling, which presents as a progressively enlarging mass. Biopsy of lesions of doubtful diagnosis should always be performed to eliminate neoplasia. Salivary gland tumours are also uncommon in childhood but should be considered in the differential diagnosis, particularly in swellings involving the upper lip, where mucocoeles are uncommon.

Molluscum contagiosum Molluscum contagiosum may occasionally affect the mouth, particularly the lips, as a result of autoinoculation from cutaneous lesions. Facial and perioral molluscum contagiosum is frequently seen in patients with AIDS.

Bony swellings

Orofacial granulomatosis and Crohn disease

Tori

See Gastrointestinal diseases, above.

Tori are slow-growing exostoses that are thought to be inherited as a dominant trait. The torus palatinus occurs in the midline of the hard palate and the torus mandibularis lingually in the premolar area of the mandible; 80% of cases are bilateral. Although they may be seen in childhood, the peak incidence is around 30 years of age.

Melkersson–Rosenthal syndrome See Lesions of the tongue, below.

Lymphoma Lymphomas are the third most common malignant disease of childhood, although it is unusual for them to occur in the mouth and jaw (with the exception of Burkitt’s lymphoma). They may present as a soft tissue enlargement, non-healing ulcer and occasionally loosening of the teeth. Radiographically, there may be evidence of bone resorption. Most lymphomas presenting in children less than 10 years of age are of the non-Hodgkin type. Any swelling of the oral tissues without obvious cause should be biopsied.

Burkitt’s lymphoma African Burkitt’s lymphoma typically affects pre-teenage children and is strongly associated with EBV. The jaw, particularly the mandible, is a common site of presentation. Clinically, there is massive swelling, which may ulcerate into the mouth.

Langerhans cell histiocytosis (histiocytosis X, eosinophilic granuloma) (see Chapter 103) This condition refers to a neoplastic-like proliferation of Langerhans cells. The spectrum of Langerhans cell histiocytosis ranges from isolated lesions, which spontaneously regress, to widespread fatal disease. Multifocal eosinophilic granuloma presents in young children and often gives rise to lytic lesions in the skull and mandible, which may involve oral soft tissue, resulting in swelling. Treatment is dependent upon the extent of dissemination of the disease and may involve surgery, chemotherapy and radiotherapy.

The majority of intraoral bony swellings in children are caused by unerupted teeth, supernumerary teeth, cysts and odontomes.

Fibrous dysplasia Fibrous dysplasias, which include familial fibrous dysplasia (cherubism), monostotic or polyostotic fibrous dysplasia as in Albright syndrome, may all give rise to expansile lesions of the jaws. On skeletal maturation, the lesions tend to cease growth (see also Red and pigmented lesions, above).

Odontogenic cysts Odontogenic cysts refer to a group of jaw cysts that are derived from the epithelium of the dental laminae. Follicular cysts are the most common odontogenic cysts seen in childhood (see Eruption cyst, above). Gorlin–Goltz syndrome, an autosomal dominant trait with variable expression, comprises multiple basal cell carcinomas, odontogenic keratocysts that may become apparent in childhood, bifid ribs and calcification of the falx cerebri (see Chapter 132).

Gardner syndrome Gardner syndrome is an autosomal dominant trait consisting of colonic polyps, which often undergo malignant change, epidermoid or sebaceous cysts, dermoid tumours, multiple supernumerary and impacted teeth, and osteomas that may cause swellings of the jaw or cranium.

Bone cysts Bone cysts, such as the aneurysmal bone cyst and solitary bone cyst, are seen almost exclusively in children and

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adolescents. They may occasionally present as a bony swelling of the mandible, but most are found as an incidental finding on routine radiography of the jaws.

Osteomyelitis Osteomyelitis affecting the jaw is rare in the UK but is occasionally seen following radiotherapy to the head and neck as a result of endarteritis obliterans. Osteosarcoma may occur in the jaw of children who have undergone irradiation of the jaw for sarcomas.

Juvenile active ossifying fibroma Juvenile active ossifying fibroma is occasionally seen in children less than 15 years of age. Unlike the ossifying fibromas of adults, it is very cellular and locally aggressive.

Generalized gingival swelling Gingivitis is the most common cause of generalized gingival enlargement. Gingival enlargement may be aggravated by local factors such as mouth breathing. Enlarged gingivae without evidence of poor oral hygiene or in preschool children may be indicative of a systemic disorder, e.g. aplastic anaemia (Fig. 147.20) or sarcoidosis.

and skeletal abnormalities [2]. Clinically, the gingivae begin to enlarge around the time of tooth eruption. The gingivae are usual firm, pink and stippled, although if oral hygiene is poor inflammation may be concurrent (Fig. 147.21). The teeth may eventually be buried by the gingivae. Treatment is by maintenance of good oral hygiene and, when aesthetically necessary, gingivectomy. Growth of the gingivae slows after puberty.

Drug-induced gingival hyperplasia Drug-induced gingival hyperplasia is associated with several drugs, including phenytoin, ciclosporin and the calcium channel blockers such as nifedipine and diltiazem. Clinically, the hyperplasia resembles that of hereditary gingival fibromatosis, although hyperplasia is particularly apparent at the interdental papillae and gingival stippling is exaggerated (Fig. 147.22). Poor oral hygiene aggravates the hyperplasia. The history and clinical features should help to distinguish it from the hereditary form.

Hereditary gingival fibromatosis Hereditary gingival fibromatosis is an autosomal dominant trait in which there is fibrous gingival enlargement, hypertrichosis and coarseness of facial features. It is occasionally associated with epilepsy, learning impairment

Fig. 147.21 Familial gingival hyperplasia (fibromatosis).

Fig. 147.20 Gingival enlargement due to acute inflammation in a 3-year-old child with aplastic anaemia.

Fig. 147.22 Drug-induced (phenytoin) gingival hyperplasia. Note that the enlargement is particularly apparent at the interdental papillae.

Diseases of the Oral Mucosa and Tongue

Acute leukaemia Generalized gingival swelling may occur with acute leukaemia. It is more frequently reported in association with acute myeloid leukaemia but may also be apparent in other forms, e.g. acute lymphoblastic leukaemia. The swelling is produced by leukaemic cell infiltrate in response to bacteria in dental plaque. The gingivae appear swollen, soft and may have a bluish-purple colour (Fig. 147.23). The surrounding mucosa may be pale (anaemia) and there may be petechiae or purpura present (thrombocytopenia).

Salivary gland swelling Historically, the most common cause of salivary gland swelling in children was mumps. However, with the introduction of the measles/mumps/rubella (MMR) vaccine in the Western world, mumps is now uncommon. Mumps infections usually give rise to bilateral parotid swelling, causing eversion of the ear lobe. Occasionally, the swelling begins unilaterally. Parotitis may be caused by other viruses, including coxsackie A, ECHOvirus, parainfluenza, EBV and CMV. Treatment is symptomatic. Other causes of salivary gland swelling are discussed below and listed in Box 147.2 [3]. Salivary gland malignancy in childhood is rare [4].

Chronic recurrent sialadenitis Chronic recurrent sialadenitis presents with recurrent painful swelling of one or more major salivary glands, usually the parotid. The attacks vary in frequency and the gland may remain enlarged between attacks. The aetiology is unclear but EBV may be involved. The condition usually resolves spontaneously at puberty.

Mucocoele/ranula Mucocoeles are mucous extravasation cysts, often resulting from trauma to the minor salivary glands. They are

Fig. 147.23 Generalized gingival swelling in a child with acute myeloid leukaemia.

147.21

common and usually occur on the lower lip (Fig. 147.24). but may occur on the palate, upper lip and buccal mucosa. They usually present as a tense, localized, fluid-filled swelling. The lesion may burst as a result of trauma from the teeth. Recurrence is common and may lead to fibrosis. The diagnosis is usually made on the history and clinical appearance. Treatment is either by cryosurgery or surgical removal of the cyst together with the offending minor salivary gland. A ranula is a form of mucous retention cyst arising in the floor of the mouth, often involving the sublingual salivary gland. It may cause both intra- and extraoral swelling (Fig. 147.25). It is usually treated by marsupialization.

HIV infection Cystic enlargement of the major salivary glands has been reported in HIV disease together with lymphocytic infiltration, giving a Sjögren syndrome appearance histologically, which may give rise to xerostomia. Swellings of this nature should be regularly observed because of the increased risk of lymphoma development. Box 147.2 Causes of salivary gland swelling in childhood • • • • • • • • • • • • •

Mumps Chronic recurrent sialadenitis Ascending parotitis Calculi HIV disease Cystic fibrosis Sjögren syndrome Sarcoidosis plus other granulomatosis Mikulicz disease Sialosis Drugs, e.g. chlorhexidine, sulphonamides, iodine Salivary gland neoplasia, e.g. juvenile haemangioma Lymphoma

Fig. 147.24 Mucocoele in the most common site.

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Fig. 147.26 Macroglossia in a baby with Beckwith–Wiedemann syndrome.

Fig. 147.25 A ranula – sublingual mucous retention cyst.

Cystic fibrosis Enlargement of the salivary glands, particularly the submandibular gland, may occasionally be seen in patients with cystic fibrosis.

Sarcoidosis Sarcoidosis is a chronic granulomatous disease of unknown aetiology described more fully in Chapter 158. Sarcoidosis causes asymptomatic enlargement of the major salivary glands in 6% of cases and involvement of the facial nerve may lead to facial palsy. Gingival enlargement may also occur. Biopsy of affected gingivae or minor salivary glands shows typical granulomas. References 1 Smith, D, Porter SR, Scully C. Gingival and other oral manifestations in tuberous sclerosis. Periodontal Clin Invest 1993;15:13–18. 2 Katz J, Guelmann M, Barak S. Hereditary gingival fibromatosis with distinct dental, skeletal and developmental abnormalities. Paediatr Dent 2002;24:253–6. 3 Lamey PJ, Lewis MAO. Oral medicine in practice: salivary gland disease. Br Dent J 1990;168:237–43. 4 Baker SR, Malone B. Salivary gland malignancies in children. Cancer 1985;55:1730–6.

Lesions of the tongue Congenital/developmental lesions Macroglossia The majority of cases of macroglossia, enlargement of the tongue, are congenital and most commonly associated with syndromes, e.g. cretinism, Down, Beckwith– Wiedemann (Fig. 147.26), Hurler and Rubenstein–Taybi

syndrome. Congenital macroglossia is due to muscle hypertrophy. Secondary macroglossia may occur and is caused by tumours, deposits or hamartomas, the most common of which in childhood is a lymphangioma. Congenital macroglossia is not usually treated, the only option being surgical.

Microglossia Microglossia, small tongue, is a rare congenital anomaly that occasionally causes difficulty in talking and eating. Only a few cases of aglossia have ever been reported.

Ankyloglossia Ankyloglossia or tongue tie affects up to 1.7% of children and is usually caused by a short lingual fraenum. Surgical intervention is rarely necessary as it is usually of little consequence and does not interfere with speech. However, the scavenging action of the tongue may be impaired.

Fissured/scrotal tongue This is a tongue with multiple small fissures or grooves on the dorsal surface, which may have a scrotal appearance (Fig. 147.27). This is thought to be a developmental anomaly affecting about 1% of children, although it is rarely seen before the age of 4 years. In surveys of the adult population, the reported frequency is between 3% and 5%, suggesting that it may not be developmental. It has an increased frequency of occurrence in children who suffer from learning impairment, particularly Down syndrome. Fissured tongue is one of the features of Melkersson– Rosenthal syndrome; the other features include facial swelling and facial palsy. The histopathology of fissured tongue is essentially normal. Clinically, fissured tongue is usually asymptom-

Diseases of the Oral Mucosa and Tongue

147.23

The foliate papillae on the lateral border also contain lymphoid tissue, which may undergo reactive hyperplasia during upper respiratory tract infections, causing the papillae to enlarge and rub against the teeth, causing inflammation (foliate papillitis).

Sublingual dermoid cyst

Fig. 147.27 A child with a mildly fissured tongue with concurrent erythema migrans, which is most evident on the right lateral border of the tongue, just anterior to the commissure.

atic except on occasions when food and debris collect in the fissures, giving rise to irritation. However, erythema migrans (geographic tongue) is very frequently found associated. If irritation occurs, food and debris should be removed by stretching and flattening the fissures and using a toothbrush, gauze or sponge to cleanse the surface.

Lingual thyroid Ectopic thyroid tissue may occasionally be found at the base of the tongue at the site of the foramen caecum. Clinically, the lesion presents as a smooth-surfaced lump. Symptoms of dysphagia may occur, but the lesion is often asymptomatic. If surgery is indicated, it is important to establish that there is normal thyroid tissue in the neck.

This is a developmental cyst derived from embryonic germinal epithelium. Sublingual dermoid cysts usually occur in the midline above the mylohyoid muscles. Although they do not occur in the tongue, they cause elevation of the tongue and may be associated with symptoms of dysphagia and dysphonia. Unlike other dermoid cysts, those arising in the floor of the mouth are seldom present at birth, becoming clinically obvious in the second decade. The histological appearance of a dermoid cyst is very variable. It is usually lined by stratified squamous epithelium and surrounded by lymphoid tissue. The cyst wall may contain sweat and sebaceous glands and hair follicles. Its contents may include keratin, sebum and matted hair. Clinically, the lesions are variable in size. They may be fluctuant to palpation or have a ‘dough-like’ feel, depending on the contents of the cyst. Several lesions may resemble a sublingual dermoid cyst, including a ranula, obstruction of the submandibular duct, thyroglossal tract cyst, cystic hygroma, branchial cleft cyst and cellulitis of the floor of the mouth.

Oral-facial-digital syndrome Oral-facial-digital type II or Mohr syndrome is characterized by facial deformities, median cleft of the upper lip, hand and feet deformities and tongue hamartomas. Tongue lipoma has also been reported in this condition [1].

Acquired lesions Swollen tongue The tongue may swell in allergic reactions (angiooedema), inflammation, haematoma formation, deposits (e.g. amyloidosis) or neoplasms.

Lingual tonsil

Glossitis

The lingual tonsil is a mass of lymphoid tissue, divided into two parts by a midline ligament, situated between the epiglottis and circumvallate papillae. If the lingual tonsil is enlarged, as in tonsillitis or in atopic individuals, symptoms such as a lump in the throat, dyspnoea and dysphonia may occur. The condition may be distinguished from other lesions of the tongue by its site, symmetry and midline ligament.

Glossitis describes an acute inflammatory reaction of the tongue. It may be localized to a particular area of the tongue or generalized. There may or may not be associated symptoms.

Median rhomboid glossitis This is a central rhomboid-shaped area of depapillation anterior to the sulcus terminalis. It is rare in children.

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Debate exists over the aetiology of median rhomboid glossitis, which affects 0.2% of the population. It was originally considered to be developmental in origin, resulting from the persistence of the tuberculum impar. However, as it is less commonly seen in children than in adults, this aetiology is unlikely. It is now thought to be infective in nature and caused by Candida (40% of lesions exhibit candidal colonization). The consistent positioning of this condition does, however, support a developmental aetiology, and it has been hypothesized that there may be a vascular anomaly in this area. Histologically, the epithelium shows loss of papillae and parakeratosis of the epithelium, with acanthosis and downward growth of the rete ridges. Polymorphonuclear lymphocytes may be seen in the superficial epithelium and candidal hyphae may be present. The underlying connective tissue is vascular and infiltrated with chronic inflammatory cells. The condition is usually asymptomatic but soreness may be reported, particularly after consumption of salty or spicy foods. The lesion presents as a rhomboid-shaped area of depapillation immediately anterior to the sulcus terminalis. It may vary in colour from pale pink to bright red. The surrounding lingual epithelium appears normal (Fig. 147.28). A swab should be taken for candidal culture. If Candida is identified, a topical antifungal agent should be prescribed, e.g. miconazole gel, nystatin suspension or pastilles or amphotericin B lozenges. If Candida is isolated, underlying systemic conditions predisposing to candidal infections should be eliminated.

Deficiency states Nutritional deficiency in the Western world is rare in childhood and usually the result of malabsorption. Hae-

Fig. 147.28 Median rhomboid glossitis in a child using a steroid inhaler for asthma. In this case, the lesion is due to candidal infection of the lingual mucosa.

matinic deficiencies (vitamin B12, ferritin, folate) may give rise to a sore tongue and atrophic glossitis. The symptoms may precede the clinical features. Classically, vitamin B12 deficiency causes a raw beefy tongue. Clinically, other oral signs of deficiency may be apparent (see Oral ulceration and candidal infection, above). If a nutritional deficiency is suspected, it is important to establish that the child is obtaining adequate dietary intake (is not vegetarian or anorexic) and to eliminate causes of malabsorption, e.g. Crohn disease, coeliac disease. If a deficiency is suspected, it may be prudent to measure full blood count, haemoglobin, serum ferritin, serum vitamin B12 and red cell folate, as a deficiency in a haematinic that has not yet given rise to anaemia may cause oral symptoms and produce glossitis.

Infections Scarlet fever, Streptococcus pyogenes infection, and Kawasaki disease (mucocutaneous lymph node syndrome [2]), of uncertain but possibly infectious aetiology, may both cause furring of the tongue and prominence of the fungiform papillae, a so-called ‘strawberry tongue’ appearance. In scarlet fever, the coating on the tongue is rapidly lost, and the tongue becomes smooth and deep red in colour (raspberry tongue). Infection with Yersinnia pseudotuberculosis has produced a similar clinical picture.

Erythema migrans (geographical tongue, benign migratory glossitis) This is a benign condition which gives rise to well-defined areas of depapillation of the tongue, which heal and recur at a different site, hence the term migratory. Erythema migrans is a common condition affecting 1–2% of the population. The aetiology is unclear. There is often a positive family history and it is often associated with fissured tongue and, possibly, with psoriasis [3]. Histologically, erythema migrans bears a striking resemblance to oral psoriasis. The lesions exhibit thinning of the epithelium, elongation of the rete ridges and a polymorphonuclear infiltrate of the superficial epithelium. The lesions may occur at any age and are often symptomless. Soreness may be a presenting symptom, which is usually aggravated by eating salty or spicy foods. Typically erythema migrans presents on the dorsum of the tongue as well-defined erythematous areas of depapillation, surrounded by a slightly raised white margin (see Fig. 147.27). The lesions are usually serpiginous in shape, giving rise to a map-like appearance; they may, however, be rounded or scalloped. The appearance of the lesions may change from day to day, hence the term ‘migratory’. Rarely, erythema migrans has been described in other sites, such as the labial mucosa and the palate [4]. Usually, the diagnosis can be made from the history and clinical appearance of the lesions. If the lesions are causing

Diseases of the Oral Mucosa and Tongue

147.25

symptoms then benzydamine hydrochloride mouth rinse or spray may be of use.

Localized enlargement of the tongue The most common cause of localized enlargement of the tongue in children is acute inflammation caused by tongue biting. Persistent localized swellings are uncommon and are most likely to be due to a lymphangioma (see Soft tissue swellings, above) or a haemangioma (see Red and pigmented lesions, above).

Hairy and furred tongue Hairy tongue is not commonly seen in childhood; it results from excessive elongation of the filiform papillae of the posterior dorsum of the tongue, caused by chronic irritation, but may be idiopathic, particularly when seen in young children (Fig. 147.29). It is asymptomatic but if it is causing aesthetic problems, brushing the dorsum of the tongue with a toothbrush, sucking a peach stone or placing an effervescent vitamin C tablet on the tongue may be beneficial. Furring of the tongue resulting from an accumulation of squames rarely occurs in healthy children but is often seen in association with acute systemic illness, particularly scarlet fever. It results from a lack of mechanical debridement and changes in the oral flora. It may be precipitated by the use of broad-spectrum antimicrobial agents. Brown or black discoloration may occur with either a furred or a coated tongue. The staining may be caused by

Fig. 147.29 Hairy tongue in a young preschool child.

chromogenic bacteria within the oral cavity or by extrinsic agents such as iron supplements or chlorhexidine gluconate, or coloured confectionery, tobacco or betel. References 1 Ghossainriant SN, Hadi U, Tawil A. Oral-facial-digital syndrome type II associated with congenital tongue lipoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:324–7. 2 Ogden GR, Kerr M. Kawasaki syndrome. Br Dent J 1988;165:327–8. 3 Morris LF, Phillips CM, Binnie WH et al. Oral lesions in patients with psoriasis: a controlled study. Cutis 1992;49:339–44. 4 Luker J, Scully C. Erythema migrans affecting the palate. Br Dent J 1983;155:385.

148.1

C H A P T E R 148

Hair Disorders Elise A. Olsen Departments of Dermatology and Medicine (Oncology), Duke University Medical Center, Durham, NC, USA

Normal hair loss/growth in childhood, 148.1

Hair loss, 148.3

Hair loss in childhood is usually fraught with overwhelming concern by parents that the condition will be permanent and/or leave psychological scars on the affected child. Conversely, physicians are more likely to focus on the potential relatedness of the hair loss to an underlying medical problem. The concerns of both are valid. There is great value in diagnosing a given case of childhood alopecia, as herein may be the necessary clue to an otherwise unfathomable multisystem illness or an explanation for an unexplained developmental delay. The treatment of hair loss presenting in childhood does include disorders for which no good therapy yet exists, but there are many conditions in which specific treatment can either reverse the hair loss or make the hair more manageable and, hence, more cosmetically acceptable. Hypertrichosis specifically refers to hair density or length beyond the accepted limits of normal for a particular age, race and sex and does not imply, as does the term hirsutism, a particular distribution of hair or a hormonal aetiology. Hypertrichosis may be generalized or localized, and may consist of lanugo, vellus or terminal hair. The presence of hypertrichosis in a child may signify an underlying physical abnormality, an associated metabolic disorder, a genetic multifocal syndrome or merely a cosmetic problem. This chapter presents an effective approach to the diagnosis of the various types of alopecia and hypertrichosis presenting in childhood. Aetiologies of hair loss or hypertrichosis presented in detail in other chapters will be mentioned only briefly and the reader is referred to these other sources of information.

Normal hair loss/growth in childhood To fully understand hair loss or excess hair growth in childhood, a basic working knowledge of normal hair Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Hypertrichosis, 148.28

growth is necessary, including the embryology and cycling of hair. Hair development begins in utero at 9–12 weeks, with the follicular units composed of epidermally derived follicles and mesodermally derived papillae [1] (Fig. 148.1). By 18–20 weeks of gestation, fine lanugo hair (unpigmented, unmedullated fine hair, which may grow to several centimetres in length [2,3]) covers the scalp and proceeds to appear elsewhere in a cephalocaudal direction, eventually covering the entire fetus. This constitutes the first anagen (growth) wave, which is followed by telogen (resting phase) and, eventually, the actual shedding of the hair at the seventh or eighth month [2,4]. The lanugo hair is replaced by vellus hair on the body and vellus or terminal hair on the scalp. The transition wave from anagen to telogen in the occipital area is delayed, however, and the expected telogen shedding in the occiput occurs at 2–3 months postpartum [2,4], accounting for the occipital alopecia normally seen in infants of this age (Fig. 148.2). Lanugo hair may also be seen on the limbs and shoulders of full-term, normally developed newborns, but this should be shed by 1–2 months of age. For the remainder of the first year of life, scalp hair growth is synchronous, taking on the adult mosaic pattern only towards the end of the first year [2]. The number of follicles does not change after birth but, rather, the follicular density decreases as the skin expands to cover an increasing surface area [4,5]. There is a gradual transition from vellus (unmedullated, lightly pigmented hair, final length less than 2 cm [5]) to terminal (usually pigmented, usually medullated, generally thicker shafts with longer anagen phase and thus longer ultimate length) hair over the scalp during the first year or two. Hair colour tends to darken with age [6]. All human scalp hairs regularly cycle through various stages of growth. In anagen, or the active growth phase, the follicular bulb embraces the dermal papillae in the dermis or subcutaneous tissue (Fig. 148.3). The division and maturation of the matrix (those cells in the centre of the hair bulb contiguous to the dermal papillae) produce columns of cells that stream superficially into the central

148.2

Chapter 148

Fig. 148.1 Embryology of the hair follicle. (a) Follicular germ illustrating the condensing mesenchyme proximal to the epidermally derived follicle cells. (b) Follicle peg stage illustrating the organization of keratinocytes in the follicle and the mesenchyme of the follicle sheath and presumptive dermal papillae. (c) Bulbous hair peg stage illustrating the regions of the differentiated follicle. The upper bulge on the right represents the sebaceous gland and duct. The ‘bulge’ area where the arrector pili muscle will insert is below this.

When a particular hair has completed its sojourn in anagen, it begins the process of transition to a resting (telogen) hair. The follicular bulb moves up in the dermis, with the dermal papillae no longer intimately associated but lagging behind (Fig. 148.3). The transition phase between the end of anagen and the beginning of telogen is referred to as catagen and lasts 2–4 weeks. With the loosening of the attachment of the root sheaths to the hair shaft, the telogen hair is now subject to being dislodged by simple pressure or traction. Once telogen is completed, and the time in telogen varies with body site, the cycle is repeated. Telogen in the scalp is normally 3–4 months. Cells in the outer root sheath of the follicle at the base of the arrector pili insertion, the bulge region, are slowcycling stem cells that are necessary for the recapitulation of anagen; this involves a downward growth of the follicle and regeneration of the matrix and lower follicle root sheaths [9,10]. The spontaneous loss of a telogen hair, termed exogen [11], generally signals the presence in the follicular canal of a new growing anagen hair. Fig. 148.2 Occipital alopecia in 4-month-old infant.

portion of the bulb and then enter the straight linear portion of the follicle [7]. The cellular keratin filaments (protein) organize into larger aggregates, which become progressively more compact as the shaft moves upwards and away from the bulb [8]. For much of the length of the follicle, the hair shaft is attached to layers of root sheaths, which serve both to anchor and to mould the newly formed hair. Anagen lasts for predetermined periods of time based on the area of the body the hair resides in; the normal time in anagen for scalp hair is longer and more variable than other body areas [9].

References 1 Pinkus H. Embryology of hair. In: Montagna W, Ellis RA, eds. The Biology of Hair Growth. New York: Academic Press, 1958:1–32. 2 Barth JH. Normal hair growth in children. Pediatr Dermatol 1987;4:173–84. 3 Danforth CH. Studies on hair. Arch Dermatol Syph 1925;11:804–21. 4 Barman JM, Pecoraro V, Astore I et al. The first stage in the natural history of the human scalp hair cycle. J Invest Dermatol 1967;48:138–42. 5 Giacometti L. The anatomy of the human scalp. In: Montagna W, ed. Advances in Biology of Skin, Vol. 6. Oxford: Pergamon Press, 1965:97–120. 6 Price ML, Griffiths WAD. Normal body hair: a review. Clin Exp Dermatol 1985;10:87–97. 7 Abel E. Embryology and anatomy of the hair follicle. In: Olsen EA, ed. Disorders of Hair Growth: Diagnosis and Treatment. New York: McGraw-Hill, 1994:1–19.

Hair Disorders

148.3

Fig. 148.3 (a–d) Normal cycling of hair. Follicular structures above the dashed line form the permanent part of the follicle. Epidermally derived cells below the bulge (B) degenerate during catagen and telogen. Note that, during catagen, the dermal papillae (DP) lags behind the ascending terminal bulb and that cells in the bulge region are poised for downward proliferation in early anagen (anagen II). When the germinative epithelium is once again in close approximation to the dermal papillae, the anagen growth cycle begins again. The preceding hair is lost as the new hair begins its growth phase. APM, arrector pili muscle; C, cortex; E, epidermis; IRS, inner root sheath; M, matrix; Md, medulla; ORS, outer root sheath; S, sebaceous gland.

8 Bertolino A, O’Guin WM. Differentiation of the hair shaft. In: Olsen EA, ed. Disorders of Hair Growth: Diagnosis and Treatment. New York: McGraw-Hill, 1994:22–5. 9 Lyle S, Cristofidou-Solomidou M, Liu Y et al. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci 1998;111:3179–88. 10 Oshima H, Rochat A, Kedzia C et al. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 2001;104: 233–45. 11 Milner Y, Sudnik J, Filippi M et al. Exogen, the shedding phase of the hair cycle: characterization of a mouse model. J Invest Dermatol 2002;119:639–44.

Hair loss Evaluation of the child with hair loss History. The evaluation of a child with scalp hair loss should always include a history, physical examination and microscopic examination of the hair bulb and/or shaft. The history should differentiate hair never coming in fully from hair that once covered the scalp but was later lost or shed. However, it is entirely within the range of normal for either the so-called second pelage (i.e. the second wave of anagen scalp hair) or the transition from vellus to terminal hair to be delayed up to 1 year of age, making it falsely appear that the affected child has congenital alopecia.

Diffuse scalp hair loss that has a hereditary basis usually manifests itself by the first or second year of life, but in some genetically based disorders the associated hair loss becomes obvious only later (e.g. dyskeratosis congenita [1], Jorgensen syndrome [2], Beare pili torti [3], androgenetic alopecia). Obviously, family history is key in determining the exact mode of inheritance of a suspected genetic disorder, but family members may have only some, but not all, of the features associated with a particular syndrome, and alopecia may not be one of them. Therefore, when suspecting a familial syndrome, or probing for one that has alopecia as one feature, multiorgan signs and symptoms should be enquired about. As the group of disorders collectively called ectodermal dysplasias commonly involve hair loss (and effects on the teeth, nails and sweating), this should be looked for in particular. Dental radiographs may be necessary to exclude tooth involvement in the very young, and formal sweat testing may be necessary to document decreased sweating. Currently, there is no standardized test protocol for the evaluation of sweating in ectodermal dysplasia syndromes, but recommended techniques are those that assess both sweat gland number and function post sweat induction [4]. Physical examination. A physical examination should be performed in all children with hair loss of uncertain

148.4

Chapter 148

(a)

Fig. 148.4 Diffuse (global) hair loss in a child with Rosselli–Gulienetti syndrome (palate–popliteal pterygia syndrome) with subgroup type 1, 2, 3 and 4 ectodermal dysplasia.

aetiology. The possibility of a syndrome must be entertained and multisystem abnormalities sought for and catalogued; those of ectodermally derived organs (epidermis-derived teeth, ears, eyes, central nervous system, mammary glands), bone, cleft lip and/or cleft palate are frequently associated with scalp hair loss. Particular attention should be paid to the child’s facial features and whether a distinctive facies is present. The scalp examination should first conclude whether the hair loss is diffuse (or global) or focal (Fig. 148.4). A diffuse loss could be secondary to an inherited abnormality in follicular or hair shaft development or an acquired problem such as alopecia areata, anagen effluvium or telogen effluvium. Focal alopecia is less likely to be inherited and much more likely to be acquired (Fig. 148.5a). The scalp in the areas of alopecia should be evaluated for the preservation of follicular openings (implying a non-scarring potentially reversible process; Fig. 148.5a) compared with smooth, poreless skin indicating attrition of follicular units and a potentially irreversible or scarring process (Fig. 148.5b). Scarring alopecia is rare in children in the absence of congenital focal scalp abnormalities, tumours or trauma. Further differentiation can be made between hair growth abnormalities secondary to: (i) failure to initiate anagen; (ii) hair fragility leading to breakage; (iii) unruly hair; and (iv) premature curtailment or interruption of anagen (abnormality of hair cycle), leading to increased hair shedding. To determine if the hair growth rate is affected, a simple hair window can be performed. In this

(b) Fig. 148.5 (a) Focal, non-scarring hair loss of alopecia areata. (b) Scarring (permanent) hair loss in a 10-year-old child, with dyspigmentation and follicular papules.

procedure, hair is clipped flush with the scalp in an arbitrarily determined target area (generally at the back of the scalp to prevent manipulation by the patient) and in a shape unlikely to occur naturally (such as a square or rectangle) and the hair length in this area observed a few weeks later. Even if there is an underlying hair shaft fragility problem that precludes the hair growing long, the hair should be able to attain a length of 0.5 cm in 2–3 weeks (1 cm/month). To determine whether abnormal shedding is occurring, a simple hair pull is performed. Approximately 50–100 hairs are grasped at the base between the thumb and forefinger and gently pulled proximally to distally. This procedure is repeated in various sections of the scalp, six to eight times in total. The number and type of shed hairs

Hair Disorders

148.5

are counted: there should normally be only telogen hairs unless the patient is a very young child or there is underlying pathology. One to two anagen hairs on a hair pull in a young child is common, and most of these hairs assume the microscopic appearance of ‘loose anagen’ hairs [5], which are devoid of the attached root sheaths characteristic of anagen hairs. Loose anagen hairs on a hair pull in postpubescent children should trigger consideration of underlying hair pathology. Microscopic examination. If increased hair shedding is present, the shed hairs collected by a hair pull should be examined under the light microscope. One to two drops of cyanoacrylic are placed on a slide and the proximal hair shafts/bulbs are lined up in the glue and a coverslip placed over them: this decreases distortion and provides a permanent record of the hairs in question. The bulbs are then examined to determine if the hair loss is telogen or anagen. Telogen bulbs are unpigmented, rounded up and devoid of an attached root sheath (Fig. 148.6a). Normal anagen hairs are not readily obtained on a hair pull test but if one or two are, they generally have attached root sheaths (Fig. 148.6b). Loose anagen hairs, which can be seen in either normal young children or in patients with loose anagen syndrome (Fig. 148.6c) or other causes of anagen hair loss such as alopecia areata, are devoid of root sheaths and have a ruffled or floppy sock appearance of the attached cuticle. Telogen versus anagen shedding should trigger very different types of work-up. If there is no abnormal shedding, but instead the hair fractures with simple trauma (rubbing the hair between the fingers is one way of precipitating this in susceptible patients), or has an abnormal texture or dullness resulting in unruliness, a sample of affected hairs should be clipped and the distal portion examined under the microscope. Most hair shaft abnormalities can be diagnosed in this manner, although some will require further examination by scanning electron microscopy to confirm findings only hinted at under light microscopy (e.g. longitudinal grooving). Polariscopic examination is necessary in cases when the particular light microscopic findings of trichoschisis with or without trichorrhexis nodosa are seen, making the diagnosis of trichothiodystrophy a possibility. The aetiology of brittle hair can be further pursued by chemical analysis of the hair for sulphur content and/or quantification of individual amino acids. Together, these simple tools (history, physical examination and microscopic examination of the hair) will help narrow the differential diagnosis of alopecia. Dermoscopy, if available, may also be used to help establish the diagnosis in some hair disorders. The various aetiologies of childhood alopecia are discussed below in further detail.

(a)

(b)

(c) Fig. 148.6 (a) Telogen bulb (light micrograph, ×40); (b) anagen bulb (light micrograph, ×40); (c) loose anagen syndrome (light micrograph, ×100). Reproduced from Olsen EA. Clinical Tools for Assessing Hair Loss. In: Olsen EA, ed. Hair Disorders: Diagnosis and Treatment. New York, McGraw-Hill, 1994.

Types of hair loss Abnormality in initiation of hair growth Diffuse loss We are only now beginning to understand the genetic abnormalities associated with hair disorders. In several

148.6

Chapter 148

conditions, near or complete universal atrichia may be present at birth, or develop within the first 1–2 years of life. Caution should be exercised to ensure that the hair abnormality is isolated, as other associations may be unveiled only with time. For example, patients with mutations in the hairless gene may present with scalp alopecia alone [6] but develop characteristic keratin-filled epithelial cysts 3–18 years after the alopecia [7,8]. This syndrome, (atrichia with papular lesions), is generally an autosomal recessive trait [9]. Total alopecia related to the hairless gene without other associated findings has been reported to be autosomal dominant, autosomal recessive or X-linked [6,10]. Patients with autosomal recessive hereditary vitamin D-dependent rickets (VDDRII) also present with total or near total hair loss within the first year of life but later develop rickets and cutaneous cysts [11]. The genetic abnormality is a mutation in the vitamin D receptor. Universal alopecia may also occur with mental retardation and either talipes [12] or seizures [13–15]. Patients with the X-linked (Xq27.3–qter region) recessive condition Mendes da Costa–van der Valk genodermatosis present with universal alopecia at birth, or within the first few months of life, accompanied by reticular brown-red pigmentation on the face and extremities [16,17]. During the first few years of life, these patients develop recurrent non-traumatic intraepidermal blisters and may have associated acrocyanosis, microcephaly with mental retardation, dwarfism, short conic fingers and nail dystrophy [16,18]. Conditions in which follicular hyperkeratosis may be associated with total alopecia in infancy are presented in Table 148.1. A few of the ectodermal dysplasias that present with universal or near total alopecia in infancy include the following: • Those associated with hair, nail and sweating abnormalities, e.g. odonto-onychodysplasia with alopecia [2,42], Hayden syndrome [2], alopecia– onychodysplasia–hypohidrosis syndrome [2,43], ectodermal alopecia with severe mental retardation [2], dermotrichic syndrome [2] and ectodermal dysplasia/ skin fragility syndrome (McGrath syndrome), caused by a mutation in the plakophilin-1 gene [17]. • Those associated with hair, teeth and sweating abnormalities under the hypohidrotic ectodermal dysplasia phenotype and related to genetic anomalies in the signaling cascade that leads to nuclear factor kB (NFkB) activation. These include autosomal recessive or autosomal dominant mutations in the EDAR (ectodysplasin receptor) gene or EDAR-associated death domain gene EDARADD, respectively, or X-linked defects in the ectodysplasin A (EDA-1) gene, the receptor for EDA-2 and the NF-kB essential modulator

(NEMO), the latter also associated with immune deficiency [44]. • Those associated with hair and teeth abnormalities, e.g. alopecia, unusual facies and preaxial polydactyly (Wilson syndrome) [45]. • Those associated with hair and nail abnormalities, e.g. tricho-onychodysplasia with xeroderma [3,46], skeletal anomalies with ectodermal dysplasia and growth and mental retardation [2,47], cataracts–alopecia– sclerodactyly [48] and pure hypotrichosis and nail dysplasia [49]. Alopecia areata is the only potentially completely reversible universal alopecia that may present in infancy. This is rare in the first year of life. There is a very long list of conditions that present with hypotrichosis, but not complete alopecia, in infancy. The hypotrichosis may be secondary to follicular hypoplasia or to faulty hair shaft production and breakage. Hypotrichosis simplex of the scalp, related to a mutation in the gene that encodes corneodesmosin, begins in the mid first decade and is associated with almost complete hair loss by the third decade [17]. Individuals with autosomal recessive localized hypotrichosis (scalp hair, largely sparing secondary sexual hair) may have sparse hair at birth that regrows poorly or not al all: this may be related to either a mutation in the LIPH (607365) gene on chromosome 3q27, desmoglein 4 on chromosome 18q12 or P2RY5 on chromosome 13q14.12-q14.2 [17,50–52]. Many of the ectodermal dysplasias are associated with hypotrichosis but, unfortunately, most of the hair shaft abnormalities have not been well characterized; the abnormal hair is generally described clinically only as ‘brittle’, ‘sparse’ or ‘lustreless’. (The ectodermal dysplasias are discussed in detail in Chapter 127.) Other nonectodermal dysplasia syndromes present in infancy with sparse, lustreless hair as one part of multiorgan abnormalities (e.g. cartilage–hair hypoplasia (mutation in the RMRP gene) [17,53], hypomelia–hypotrichosis–facial haemangioma [54] and regional choroidal atrophy and alopecia [55]). Most of the over 10 subtypes of orofaciodigital syndrome are autosomal recessive but type I is an X-linked dominant abnormality of the CXORF5 gene. The hair in the latter is either dry and wiry or demonstrates diffuse or a mosaic pattern of alopecia [17,56]. The diagnosis of the primary condition in these cases is rarely suggested by the hair abnormality, probably secondary to the dearth of available information on the hair. There are, however, a number of conditions that can be diagnosed by microscopic evaluation of the hair shaft. Depending on the type of hair shaft abnormality, they generally present as fragile or unruly hair. These will be presented here according to their microscopic description.

?AR, ?AD

AD or X-linked recessive

X-linked recessive or dominant; ?AD

AD

Atrichia with papular lesions

Ichthyosis follicularis

Keratosis follicularis spinulosa decalvans

Alopecia, keratosis pilaris, cataracts and psoriasis

Inheritance

Childhood onset hair loss without preceding inflammation or lesions → scarring alopecia; sparse lashes, brows and body hair

Progressive scarring; loss of scalp hair, lashes, brows and body hair during childhood and adolescence

Sparse, short or absent scalp hair; sparse or absent lashes, brows and body hair

Born with normal, partial or absent scalp coverage but shed by 2 years; lashes +/− sparse; usually absent brows; absent body hair

Hair

Table 148.1 Follicular hyperkeratosis with scalp alopecia

Caries

Normal

Normal

Normal

Teeth

Small and pitted

Normal

Normal

Normal

+/− Dystrophy in childhood (?secondary to infections)

Normal

Keratin-filled epithelial cysts from age 2 years

+/−

Normal

Childhood psoriasis; diffuse follicular hyperkeratosis sparing face and scalp

Generalized follicular hyperkeratosis with marked plugging, especially head and dorsum of hands and fingers; these may become atrophic at puberty; palmoplantar hyperkeratosis; may develop telangiectatic pigmentation cheeks and brows late

Extensive follicular hyperkeratosis; chronic skin infections; hyperkeratotic plaques on extensor extremities, hands and groin

Skin

Sweating

Nails

Keratoconjunctivitis; cataracts

Atopy; conjunctivitis; photophobia; corneal defects

Marked photophobia +/− conjunctivitis, blepharitis, corneal abnormalities; +/− hearing loss

Psychomotor retardation; ataxia; hypogonadism; all symptoms may be delayed a few years

Other

(Continued)

[23]

[20,22]

[20–22]

[6–9]

References

Hair Disorders 148.7

AD

AR

X-linked

?AR, ?AD

AR

Perniola syndrome

Dwarfism, cerebral atrophy and keratosis pilaris

Keratitis– ichthyosiform erythroderma– deafness syndrome (KID syndrome)

Onychotrichodysplasia with neutropenia (Cantu syndrome)

Inheritance

Marie–Unna hypotrichosis

Table 148.1 Continued

Brittle, lustreless, sparse, short, curly scalp hair; scanty eyebrows, lashes and body hair; microscopic exam hair: trichorrhexis nodosa; sparse to absent pubic and axillary hair at puberty

Diffuse, fine, sparse or absent scalp hair; +/− patchy, scarring alopecia; sparse lashes and brows; hair shaft: trichorrhexis nodosa

Almost complete absence of hair

Near universal alopecia with sparse brittle lanugo hairs

Scalp hair sparse or absent at birth, coarse hair grows in early childhood, diffuse loss (especially over vertex) at puberty; hair shaft: cuticle abnormal, longitudinal ridging and irregular twisting; sparse or absent brows, lashes and body hair

Hair

Leuconychia, +/− thickened, hypoplastic

+/− Caries; brittle, malformed, delayed

Dystrophic; koilonychia and onychorrhexis

Normal

Delayed eruption

Normal

Normal

Normal

Nails

Normal

No

Teeth

Generalized keratosis follicularis

Hyperkeratotic follicular papules

Diffuse follicular hyperkeratosis with milia-like facial lesions

Skin

Normal

Follicular hyperkeratosis

+/− Diffuse follicular decreased hyperkeratosis; leathery erythroderma (not scaly) from birth including keratoderma; plaques on face in infancy; verrucous hyperkeratosis over knees

Normal

Normal

Normal

Sweating

[15]

Seizures; +/− sensorineural deafness

[17,29–32]

[3,33,34]

Neurosensory deafness; keratitis, increased susceptibility to mucocutaneous infections

Chronic neutropenia and recurrent infections; mild hypotonia

[28]

[24–27]

+/− Atopy

Physical and psychomotor retardation, dwarfism

References

Other

148.8 Chapter 148

AR

AR, AD or spontaneous

Cystic eyelids, palmoplantar keratosis, hypodontia and hypotrichosis (Schöpf–Schulz– Passarge syndrome)

Monilethrix

Normal or absent hair at birth with development of brittle fractured hair in infancy; may include occiput only or extend to entire scalp, eyelashes, eyebrows and secondary sexual hair

Marked hypotrichosis, especially scalp; eyebrows and lashes coarse, sparse

Generalized hypotrichosis, dry hair

Hair

AD, autosomal dominant; AR, autosomal recessive. Modified from Olsen 2003 [19].

AD

Inheritance

Pachyonychia congenita

Table 148.1 Continued

Normal

Hypodontia; central incisors

Natal teeth; +/− caries; malformation

Teeth

Occasional fragility and splitting nails, longitudinal lines

Onychodystrophy; longitudinal ridging; splitting; onycholysis

Yellowish-brown discoloration; thickened nails (distal 2/3) with pinched margins and upward tilt of distal tips (all cases); paronychial infections

Nails

Normal

Normal

Increased

Sweating

Follicular hyperkeratosis on scalp and neck most commonly, also extensor limbs and periumbilical

Follicular hyperkeratosis; palmoplantar hyperkeratosis; late development eyelid aprocrine hidrocystomas

Palmoplantar hyperkeratosis; follicular keratosis, especially knees and elbows; asteatosis; painful bullae or ulceration on palms and soles; verrucous lesions extremities; +/− epidermal cysts

Skin

± Physical retardation, syndactyly, juvenile cataracts

Cataracts; hoarseness; +/− oral leucokeratosis; corneal dyskeratosis

Other

[39–41]

[19,38]

[35–37]

References

Hair Disorders 148.9

148.10

Chapter 148

Hair shaft abnormalities presenting with hair breakage Trichorrhexis nodosa The most common defect of the hair shaft leading to hair breakage is trichorrhexis nodosa [57]. The primary abnormality is a focal loss of the cuticle, which leads to exposed and eventually frayed cortical fibres [58,59]. This appears initially microscopically as a nodal swelling and is followed by fracturing and splaying of the exposed fibres in a fan-like array (Fig. 148.7). Trichorrhexis nodosa can occur in normal hair that has been abused by excessive repetitive exposure to chemicals or physical trauma but more commonly occurs in inherently weak hairs after trivial trauma (e.g. brushing, combing). Although trichorrhexis nodosa can present at birth as an isolated problem [60] or with teeth and/or nail abnormalities [61], its presence in an infant or young child should trigger a search for an underlying metabolic problem. One association is with argininosuccinic aciduria, an autosomal recessive disorder of the urea cycle caused by an abnormality in gene 7cen-q11.2 [17] in which the absence of the enzyme argininosuccinase – which normally splits argininosuccinic acid into arginine and fumaric acid – leads to acidosis, hyperammonaemia, low serum arginine, increased serum and urine citrulline and argininosuccinic acid [62,63]. In these children, seizures and hepatomegaly may begin in infancy while symptoms of psychomotor retardation, ataxia and dull brittle hair (with microscopic trichorrhexis nodosa) may first manifest after the age of 2 years [64,65]. Citrullinaemia, in which there is an abnormality of the enzyme argininosuccinic acid synthetase [66], may also present with increased serum citrulline and low arginine. Children with citrullinaemia may present with a scaly skin eruption and hair fragility, with trichorrhexis nodosa and pili torti on microscopic examination of the hair [67–69]. Patients with Menkes syndrome, or trichopoliodystrophy, an X-linked disorder of copper transport, also have trichorrhexis nodosa and pili torti on microscopic examination of the hair [70,71]. The defective gene, MKN or ATP7A, encodes a copper-translocating membrane protein adenosine triphosphatase (ATPase) that disturbs

Fig. 148.7 Trichorrhexis nodosa (light micrograph, ×100).

intracellular copper homeostasis and the function of copper-requiring enzymes [72,73]. Systemic copper deficiency occurs from trapping of copper in some tissues, particularly the intestine, kidney, fibroblasts and red blood cells, leading to failure of copper delivery to other tissues [74–77]. In affected children, the hair is normal at birth but is replaced in early infancy by sparse, brittle, depigmented hair that feels like steel wool, hence the colloquial term of ‘steely hair syndrome’ [77–79] (Fig. 148.8). The skin is characteristically pale and lax, the face expressionless and the child drowsy and/or listless. There may be associated hypothermia, mental retardation and degeneration of cerebral, cerebellar, bone and connective tissue. A low serum ceruloplasmin is diagnostic of Menkes syndrome. Treatment with copper is usually ineffective and most affected children die by the age of 3 years [80]. However, recent reports of immediate postpartum treatment with copper–histidine show a prevention or diminution in the severe neurodegeneration typical of the disease [72].

Trichoschisis Trichoschisis is a clear transverse fracture through the entire hair shaft (Fig. 148.9). Under the light microscope, the affected hairs often appear flat and may be folded over as well [81]. Trichorrhexis nodosa may also be

Fig. 148.8 Menkes syndrome. Courtesy of Dr Janet L. Roberts.

Fig. 148.9 Trichoschisis (light micrograph, ×400). Reproduced from Whiting 2003 [57].

+

+

(h) Marinesco–Sjögren syndrome

+

+

+ +

+

Ataxia, dysarthria, cataracts, abnormal teeth (primarily non-ectodermal)

Recurrent infections, folliculitis, conjunctivitis

Abnormal repair of UV-induced DNA damage

Abnormal teeth, tongue plaques, cataract, VSD

Quadriplegia, seizures, microcephaly

Marinesco–Sjögren syndrome [67,68,99,100]

ONMR [87,98], Itin syndrome

PIBI(D)S [94–97]

IBIDS [89,90], Tay syndrome [91,92] Pollitt syndrome [93]

BIDS, Amish brittle hair syndrome [87,88]

BIDS, brittle hair, impaired intelligence, decreased fertility and short shature; IBIDS, ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature; ONMR, onychotrichodysplasia, neutropenia, mental retardation; PIBI(D)S, photosensitivity, ichthyosis, brittle hair, impaired intelligence, (decreased fertility) and short stature; UV, ultraviolet; VSD, ventricular septal defect. Modified from Whiting 2003 [57].

+

+

+

+

+

+

+

(g) Most of above and chronic neutropenia

+

+

+

+

+

(f) Above and photosensitivity

+

+

+

+

+

+

(e) Above and ichthyosis

+

Sabina syndrome [85,86]

+

Astigmatism, pale optic discs, retinopathy

+

+

(d) Above and growth retardation

+

+

+

Acronym/eponym

(c) Above and mental retardation, infertility

Other findings

Trichoschisis/ onychodystrophy [81,84]

Neutropenia

+

Photosensitivity

+

Ichthyosis

(b) Hair and nail dystrophy

Short stature

Trichoschisis [83]

Decreased fertility

+

Intellectual impairment

(a) Isolated hair defect

Brittle nails

Brittle hair

Group

Table 148.2 Syndromes associated with trichothiodystrophy

Hair Disorders 148.11

148.12

Chapter 148

Fig. 148.12 Netherton syndrome. Courtesy of Professor John Harper.

Fig. 148.10 Trichothiodystrophy. Reproduced from Whiting 2003 [57].

Fig. 148.11 Trichothiodystrophy (polariscopic micrograph, ×40). Note the alternating light and dark bands. Courtesy of Dr David A. Whiting.

present. Under scanning electron microscopy, the areas of fracture are associated with localized absence of the cuticle [81]. Trichoschisis, although not absolutely pathognomonic, is nonetheless seen with regularity only in the condition termed ‘trichothiodystrophy’. Trichothiodystrophy is an autosomal recessive disorder characterized by sulphur-deficient brittle hair which may occur alone or in conjunction with other neuroectodermal abnormalities [82]. The hair abnormality identifies a group of genetic disorders in which acronyms or eponyms identify particular constellations of extratrichological findings (Table 148.2). Clinically, patients with trichothiodystrophy have, since early infancy, short brittle hair on the scalp, eyelashes or eyebrows (Fig. 148.10). The cystine content of the hair is about one-half of normal, primarily due to a major reduction and altered composition of the high sulphur matrix proteins [100–103]. Polariscopic examination of affected hairs characteristically shows alternating dark and light bands (Fig. 148.11), presumably secondary to the alternating sulphur content [104]. Sulphur and/or amino acid analysis of the hair is diagnostic.

Other abnormalities should be sought in those patients with trichothiodystrophy (Table 148.2), particularly the presence of photosensitivity. Patients with trichothiodystrophy, particularly the 50% with photosensitivity, may have a defect in excision repair of ultraviolet damage but without an increased risk of skin cancer [105]. It has recently been determined that the various clinical presentations and DNA repair characteristics of both photosensitive trichothiodystrophy and xeroderma pigmentosum can be correlated with mutations found in the ERCC2/ XPD locus on chromosome 19, with trichothiodystrophy due primarily to mutations that affect the transcriptional role of ERCC2 and xeroderma pigmentosum due to mutations that primarily alter the repair role of ERCC2 [17,105]. Photosensitive trichothiodystrophy is also uncommonly associated with mutations in gene ERCC3/XPB on chromosome 2 and TTD-A on chromosome 6. Both the XPD and XPB genes encode the two helicase subunits of transcription/repair vector TFIIH. The TTD-A gene is associated with a mutation in the 10th subunit of TFIIH. The non-photosensitive trichothiodystrophy mutation has been mapped to variations in the C70RF11 gene map locus 7p14 [17].

Trichorrhexis invaginata Trichorrhexis invaginata (bamboo hair) clinically presents in infancy with short, brittle, often sparse hair [106] (Fig. 148.12). The primary defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone allowing intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft [107,108]. This leads to a proximal cup-like or socket-like expansion embracing a ‘ball’, the typical ‘ball and socket’ deformity (Fig. 148.13). Fracture of the shaft through this area is common, but there may also be disarticulation of the distal ‘ball’, leaving a golf-tee or tulip-shaped end to the abnormal hair [109] (Fig. 148.14). These changes may be seen with dermoscopy but should be confirmed microscopically.

Hair Disorders

148.13

Fig. 148.13 Trichorrhexis invaginata (light micrograph, ×400). Reproduced from Whiting 2003 [57].

Fig. 148.15 Ichthyosis linearis circumflexa. Courtesy of Dr Neil S. Prose.

Fig. 148.14 Trichorrhexis invaginata, golf-tee fracture (light micrograph, ×200) Reproduced from Whiting 2003 [57].

Pili torti and trichorrhexis nodosa may also be seen with trichorrhexis invaginata. Sulphur content is normal in trichorrhexis invaginata and no scanning electron microscopic studies are necessary to make this diagnosis. However, the abnormal hairs may be present only in some sections of the scalp, so many areas of the scalp (or even eyebrows) may need to be evaluated to make a definitive diagnosis. Trichorrhexis invaginata can rarely occur in traumatized, otherwise normal hair or with other congenital hair shaft abnormalities. Usually, however, the hair abnormality is associated with Netherton syndrome, an autosomal recessive inherited disorder that consists of the triad of ichthyosis, atopic diathesis and trichorrhexis invaginata [110–112]. The ichthyosis is most commonly ichthyosis

linearis circumflexa, a polycyclic, ever-transforming scaly eruption with a double-edged scale on the leading edge [108,113] (Fig. 148.15]. However, some cases of trichorrhexis invaginata have instead been associated with lamellar ichthyosis or, less commonly, ichthyosis vulgaris or X-linked ichthyosis [112,114]. The atopic diathesis usually includes persistent xerosis and may include erythroderma [111,115]. The diagnosis of Netherton syndrome should always be entertained in ‘red scaly babies’ who have sparse hair. Recurrent infections, short stature and mental retardation have been reported rarely in Netherton syndrome [116]. The Netherton gene, a mutation in the gene for the serine protease inhibitor, SPINK5, has recently been localized to chromosome 5q32 [117]. The defect in the skin barrier seen in Netherton syndrome may be secondary to proteolysis, whereas the infections and atopic diathesis may be related to SPINK5-related effects on T-lymphocyte maturation and response [118]. There is no specific treatment for trichorrhexis invaginata. Retinoids and photochemotherapy have been reported to be of some value and the condition may spontaneously improve with age [119–121].

Pili torti Patients with pili torti typically present with short, brittle hair. Microscopically, the hair is flattened and twisted on its own axis, anywhere from 90° to 360° [122]. Twisted hairs on the scalp may normally be seen sporadically in

148.14

Chapter 148

Box 148.1 Infantile hair loss associated with pili torti

Fig. 148.16 Pili torti. Reproduced from Whiting 2003 [57].

Caucasians and are the norm in people of African descent and in the pubic/axillary hair of both races. For pili torti to be diagnosed, there must be multiple twists at irregular intervals on a given hair (Fig. 148.16). The affected hairs generally fracture through the twists. Pili torti, like trichorrhexis nodosa, can occur in the presence of other hair shaft abnormalities as either an inherited or an acquired finding and is also present in many different syndromes. It has been reported to occur in association with monilethrix [123], pseudomonilethrix [124], woolly hair [125], longitudinal grooving [126], trichorrhexis nodosa [59] and trichorrhexis invaginata [138]. In the classic Ronchese type of pili torti, the inheritance is usually autosomal dominant, but autosomal recessive and sporadic inheritance have also been reported [122,128–130]. The hair abnormality usually presents in infancy [127]; however, as with many inherited hair abnormalities, the first and second pelages may be normal with the pili torti not developing until the second year. Pili torti may be an isolated finding or part of an ectodermal dysplasia complex of findings. Sensorineural deafness has been described in a number of cases, and early auditory testing should be carried out in all children with pili torti [131,132]. Pili torti may also be present in many other syndromes, which are summarized in Box 148.1. The hair abnormality in these conditions may persist indefinitely or improve at puberty. Pili torti may also present as a focal area of abnormal hair. This is usually secondary to trauma or to an underlying scarring condition of the scalp.

Monilethrix Macroscopically, the hairs of monilethrix appear beaded, and with dermoscopy look like a ‘regularly bended ribbon’ [134]. Microscopically there are elliptical nodes occurring with regular periodicity every 0.7–1 mm [57] (Fig. 148.17). In between the nodes, the hair shaft is con-

• Ectodermal dysplasia:
Rapp–Hodgkins syndrome
Solamon syndrome
Arthrogryposis and ectodermal dysplasia
Ectodermal dysplasia with syndactyly
Tricho-odonto-onychodysplasia with pili torti
Pili torti and enamel hypoplasia (Ronchese type)
Pili torti and onychodysplasia (Beare type)
Ankyloblepharon–ectodermal defects with cleft lip and palate syndrome • Björnstad dysplasia • Salti and Salem syndrome • Crandall syndrome • Menkes kinky hair syndrome • Tay syndrome and other cases of trichothiodystrophy • Chondrodysplasia punctata • Bazex syndrome • Hypotrichosis with juvenile macular dystrophy [133] • Citrullinaemia Modified from Olsen, 2003 [19].

Fig. 148.17 Monilethrix (light micrograph, ×100). Courtesy of Dr David A. Whiting.

stricted, and it is at these points that the hairs usually fracture. Pili torti is often mistaken for monilethrix by the uninitiated because of the microscopic illusion of variation in diameter of the shaft due to twisting. On scanning electron microscopy of monilethrix hairs, there are structural abnormalities of both the cortex and cuticle in the zone of keratinization [135]. Most pedigrees show autosomal dominant inheritance with high penetrance [123,136] and in these cases the disorder has been found to be closely linked to the type II keratin gene cluster on chromosome 12q13, implicating a mutation in the structure or regulation of a trichocyte keratin gene in the pathogenesis of this disorder [137]. Recessively inherited cases have been reported and are

Hair Disorders

148.15

(a) Fig. 148.18 Monilethrix. Reproduced from Whiting 2003 [57].

related to defects in the desmoglein 4 (DSG4) gene, the same locus as autosomal recessive hypotrichosis [39]. The condition may result in delayed onset of hair loss with presentation at any time from infancy to the teens. Expression is variable with a spectrum of localized to global alopecia [137]. The clinical picture of monilethrix, however, can be very distinctive secondary to the appearance of extremely short brittle hairs emerging through keratotic follicular papules (Fig. 148.18). The occiput and nape of the neck are especially affected. The hair defect may occur alone or in association with keratosis pilaris, physical retardation, syndactyly, cataracts and nail/teeth abnormalities [138]. Improvement in hair brittleness may occur during the summer and with age [34]. Etretinate/acitretin and topical minoxidil may potentially be useful therapies [41,139–141]. Protection against trauma such as excessive brushing, styling and braiding is key to limiting hair breakage.

(b) Fig. 148.19 Pseudomonilethrix (light micrographs, ×200). (a) Pseudomonilethrix induced by pressure on overlapped normal hairs. (b) Image rotated 90° to demonstrate indentation. Reproduced with permission from Björnstad, 1965 [131].

Pseudomonilethrix Pseudomonilethrix is microscopic irregular beading along the hair shaft as opposed to the regular beading seen in monilethrix [124] (Fig. 148.19). Although it has been reported in patients with fragile hair [124,142], the appearance of pseudomonilethrix can be produced in normal hairs by compressing two hairs together between two glass slides [143,144]. It is likely that the nodes in pseudomonilethrix are artefactual [57].

Hair shaft abnormalities associated with unruly hair Uncombable hair syndrome Children with uncombable hair syndrome present in infancy up to puberty with slow growing, silvery-blond ‘spun-glass’ hair that is disorderly and unmanageable [145–148] (Fig. 148.20). Under light microscopy, the hairs

Fig. 148.20 Uncombable hair syndrome.

148.16

Chapter 148

The condition may be sporadic or exhibit autosomal dominant inheritance [149,152] and is generally without other associations or abnormalities. The condition of uncombable hair syndrome may improve with age. Supplemental biotin has been reported to be of use in one case [153] but generally does not affect the process. Conditioners are helpful.

Woolly hair

Fig. 148.21 Longitudinal grooving (light micrograph, ×400). Courtesy of Dr David A. Whiting.

Fig. 148.22 Cross-section of hairs on a scalp biopsy of a child with uncombable hair syndrome. Note the triangular cross-section of an affected hair (horizontal section, haematoxylin and eosin stain). Courtesy of Dr David A. Whiting.

may appear normal or may have some midline darkening suggestive of the typical longitudinal grooves so clearly seen on scanning electron microscopy [149–151]. Longitudinal grooving in itself is a relatively common hair shaft abnormality, being seen in normal hair and in many cases of ectodermal dysplasia along with other hair shaft abnormalities [57]. On scanning electron microscopy of hairs in the uncombable hair syndrome, the longitudinal grooving is generally seen in conjunction with a cross-sectional triangular shape, the basis for the term pili trianguli et canaliculi [148] (Figs 148.21 and 148.22). One potential explanation for the hair shaft abnormality is premature keratinization of the inner root sheath: normally, the inner root sheath forms a rigid casing that influences the resultant shape of the hair shaft (normally round or oval) [146]. By itself, pili trianguli et canaliculi does not lead to hair fragility.

Woolly hair is the presence of Negroid hair on the scalp of persons of non-Negroid descent. Microscopically, the hair is tightly coiled without generally going to the extremes of pili torti. However, pili torti and pili annulati (blond hair with both the clinical and microscopic findings of alternating bands of light and dark on the hair shaft) may be seen with this condition [125]. The hair in woolly hair is unruly only in the sense that it is difficult to manage, but probably not more so than the hair normally occurring in dark skinned persons of African descent. The aberrant hair growth begins at birth or infancy with excessively tight curls, making the hair appear bushy or frizzy. Hair length may be decreased secondary to brittleness, a common problem with Negroid hair in general. Woolly hair may go from curly to wavy as the child ages. Woolly hair usually appears as a solitary problem inherited in an autosomal dominant fashion [125] but has been reported in conjunction with enamel hypoplasia [154], ocular defects [155,156], deafness and ichthyosis vulgaris [157], keratosis pilaris atrophicans [158] and Noonan syndrome [159]. Woolly hair, keratoderma and various cardiac abnormalities have been reported in Naxos syndrome (mutation in the plakoblobin gene, gene map locus 17q21, arrhythmogenic right ventricular cardiomyopathy) and two syndromes associated with a mutation in the gene encoding desmoplakin, gene map locus 6p24, i.e. Carvajal syndrome (dilated cardiomyopathy) and the Naxos-like syndrome (arrhythmogenic right ventricular dysplasia) [17,57,160]. Skin fragility and woolly hair without cardiac abnormalities have been reported with another mutation of the desmoplakin gene [17]. Woolly hair has been noted to occur in a sporadic recessive form and, in these cases, the scalp hair may be fine and white-blond and may lead to severe universal hypotrichosis in childhood: mutations have been associated with gene P2RY5 [17,125,161,162]. With excessively curly hair in a non-Negroid infant, one must also consider the following syndromes: trichodento-osseous syndrome (small widely spaced teeth, frontal bossing and dolichocephaly) [163] and CHAND (curly hair, ankyloblepheron and nail dysplasia) syndrome [164].

Marie–Unna type of hereditary hypotrichosis This autosomal dominant inherited condition has a distinctive type of hair loss that varies with the child’s age

Hair Disorders

148.17

Fig. 148.24 Woolly hair naevus. Courtesy of Dr Vera H. Price.

Fig. 148.23 Marie–Unna hypotrichosis.

[23–26]. The hair is sparse or absent at birth with variable abnormal coarse scalp hair regrowth in childhood and potential scalp hair loss again at puberty (Fig. 148.23). There is associated general hypotrichosis of body hair. The coarse, wiry, twisted hair is very distinctive. Hair shaft examination shows irregular twisting and, on scanning electron microscopy, longitudinal ridging and peeling of the cuticle. Diffuse follicular hyperkeratosis with milia-like facial lesions may be present. A distinct gene has been noted close to the hairless gene in chromosome region 8p21 [165]. Recent work suggests a loss of function mutation of an inhibitory upstream ORF (U2HR) in the gene encoding the human hairless homologue [166]. Additional causes of wiry hair in childhood that can be lost after puberty include those conditions related to defects in the TP63 gene at 3q27. These all are characterized by hypohidrosis and cleft lip/palate and have been designated by the other consistent abnormalites present (Rapp–Hodgkin (none), EEC3 (ectrodactyly) and AEC (ankyloblepharon)) [17,167].

Acquired localized unruly hair Four non-inherited conditions may present as patches of scalp hair that differ from the normal texture/quality of hair for that individual. The most common is X-ray

therapy related, with the hair that regrows after treatment (and epilation) being different in quality from that seen pretreatment. Localized woolly hair naevus, occurring only in non-Negroid persons, usually develops within the first 2 years of life (although this has been first reported in adolescence), with the affected hair being finer, lighter and more tightly curled than that of the rest of the scalp hair [168] (Fig. 148.24). Microscopically, the hairs may show trichorrhexis nodosa, longitudinal grooving, flattening and twisting [169–171]. Almost 50% of patients with woolly hair naevus have an underlying linear epidermal naevus or pigmented naevus, usually other than on the scalp [172,173]. Straight hair naevus, in which a localized portion of the normally curled or kinky hair is straight, has been noted only in Negroid persons. This may also have an association with an underlying epidermal naevus [174,175]. Acquired progressive kinking occurs after puberty, generally in males with androgenetic alopecia, and presents as gradual curling and darkening of the frontal, temporal, auricular and vertex hairs [176–179]. Microscopically, the hairs of acquired progressive kinking are short with kinks and twists and may show longitudinal grooving.

Localized tufts of hair In pili multigemini, hairs from two to eight follicular bulbs, each with their own inner root sheath but surrounded by a common outer root sheath, emerge from one follicular canal [180]. In children, this condition may appear as an isolated scalp problem or may occur with classic pili torti [128] or in cleidocranial dysostosis [181]. Although compound follicles may appear similar to pili multigemini, in this condition two or three different hair

148.18

Chapter 148

Fig. 148.25 Tufted folliculitis. Reproduced from Tong and Baden 1989 [183] with permission from Elsevier.

shafts, each with their own inner root sheath and outer root sheath, eventually emerge from the same follicular opening. These two non-scarring entities must be differentiated from tufted folliculitis, in which scalp inflammation is prominent and leads to focal scarring with units of 10–15 hairs, each hair from its own follicle, emerging as tufts of hair from a single follicular canal [182,183] (Fig. 148.25).

Abnormal cycling For the purposes of facilitating diagnosis, there are two main outcomes of premature disruption of anagen and, hence, there are two types of hair loss – anagen loss or telogen loss. Both should be suspected by the clinical presentation of abnormal shedding and confirmed by histological evaluation of the proximal hair shaft/bulb. The differential diagnosis and consequent evaluation and treatment vary greatly, however, between these two conditions.

Anagen loss Anagen effluvium Anagen loss is always abnormal and, with the exception of loose anagen syndrome and alopecia areata, scalp anagen hair loss generally implies a toxic exposure. The most common and easily recognizable cause of anagen loss (or effluvium) is X-ray therapy or chemotherapy. In both cases there may be a diminution of metabolic activity in the matrix, which results in weakening of the hair shaft, which breaks off a few millimetres from the scalp surface (Fig. 148.26). If exposure is persistent or particularly toxic, anagen may be interrupted entirely and the poorly anchored dystrophic hair shed. Hair loss is profound as up to 90% of scalp hair is normally in anagen at any given time, and the loss generally occurs within days to weeks of the insult. Telogen hairs may remain in place until their usual time of loss.

Fig. 148.26 Tapered proximal portion and point of breakage in hairs involved in an anagen effluvium (light micrograph, ×100). Courtesy of Dr David A. Whiting.

In general, the hair loss from chemotherapy is reversible when treatment stops; however, ultimately, this will depend on the specific agents utilized and the toxicities of the multiple agents used in a given regimen. The potential for regrowth after X-ray therapy will depend on the type, depth and dose fractionation of the X-rays. Regrowth after hair loss from either chemotherapy or X-ray therapy may produce hair that is different in colour, curl or texture than that seen pretreatment. Other causes of anagen loss include loose anagen syndrome, alopecia areata and toxic exposure to boric acid or heavy metals. Loose anagen syndrome does not present as sudden diffuse shedding, but rarely alopecia areata does. Typically, alopecia areata may result in some focal hair loss or findings of exclamation point hairs that may help to distinguish this from other causes of anagen effluvium. Boric acid is the main ingredient in some common household pesticides and is also used as a preservative in some household products [184,185]. Boric acid poisoning is suggested by gastrointestinal, central nervous system and renal symptoms, skin findings of exfoliation, erythroderma and bullae, and a haemorrhagic diathesis [184,186,187]. Confirmation is by measuring blood boric acid levels [186]. Mercury intoxication is primarily through chronic industrial exposure, consumption of industrially polluted water or affected seafood, or inadvertent exposure to mercury used as a fungicide or antiseptic [188]. Hair loss may occur with or without the other common symptoms (particularly neurological) of mercury intoxication [189– 191]. Acrodynia is a particular constellation of findings (pain in the abdomen, extremities and joints, pink scaly palms and soles, headache, photophobia, irritability,

Hair Disorders

hyperhidrosis and hair loss) that can occur with chronic exposure to inorganic mercury [192]. Diagnosis of mercury intoxication is made by measuring urine, blood or hair levels of mercury [191,193]. Acute toxicity to arsenic may occur with suicidal or homicidal attempts or with accidental ingestion or exposure [188]. Inorganic arsenic compounds are found in insecticides, rodenticides, fungicides, herbicides and wood preservatives [193]. Acute arsenic toxification presents with gastrointestinal symptoms, hypotension, shortness of breath, central nervous system changes, haemolysis and acute tubular necrosis [194]. Approximately 6 weeks later, white transverse lines on all the nails (Mees’ lines) may appear. The importance of hair in this diagnosis is not alopecia (which is rare) but, rather, that arsenic is concentrated in the hair and is detectable for months after exposure (as opposed to being detectable in urine for 7–10 days after exposure), facilitating a diagnosis even while symptoms improve or after the patient’s demise [194,195]. The symptoms of acute thallium poisoning are insomnia, irritability, pain in the hands and feet and abdominal colic [196]. Then, 2–3 weeks later, there is a precipitous loss of all scalp hair together with peripheral and autonomic nervous system symptoms. Mees’ lines develop later. Blood and urine levels are diagnostic but must be measured as soon as possible as thallium levels tend to decrease rapidly. Very severe protein malnutrition may also give rise to anagen effluvium, as can exposure to colchicine. Ingestion of some plants, e.g. Lecythis ollaria and Leucaena glauca, can also lead to anagen hair loss [188].

Loose anagen syndrome The term loose anagen syndrome (LAS) was originally coined to describe a condition in children who had sparse hair that did not grow long, often with patches of dull, matted hair, in whom unusual anagen hairs were easily extracted. These anagen hairs had misshapen bulbs, absent root sheaths and ruffled cuticles [197–199] (see Fig. 148.6c). The term loose anagen syndrome has also come to incorporate the easy extractability of these abnormal hairs in children with either patchy, unruly hair (LAS type B) (Fig. 148.27a) or otherwise clinically normal hair with increased shedding in subjects of any age (LAS types A and C) [5] (Fig. 148.27b). The underlying abnormality is a structural defect in the inner root sheath that normally anchors the anagen hair. LAS is most common in girls (36 : 1 female to male ratio) and usually presents in children less than 6 years of age [200]. Most patients have blonde or light brown hair. Often the primary complaint is that the scalp hair does not require cutting or will not grow long. Increased shedding is less common. It is considered an autosomal dominant condition with incomplete penetrance although

148.19

(a)

(b) Fig. 148.27 Loose anagen syndrome in a child with (a) unruly hair and (b) easily extractable hair. Reproduced from Olsen et al. 1999 [5] with permission from Nature Publishing Group.

sporadic cases have been reported. Chapalain et al. reported on a K6HF keratin mutation that may be responsible for premature keratinization of the inner root sheath and leads to impaired adhesion between the cuticle of the inner root sheath and the companion layer [201]: whether this is the genetic abnormality in LAS remains to be confirmed. It is now clear that normal prepubescent children may have a few loose anagen hairs found on a gentle hair pull and that the criteria for diagnosis of LAS must include either a designated number of loose anagen hairs (at least 3 or perhaps at least 10, per hair pull [5,202]) or a percentage of all hairs obtained on hair pull (50% has been suggested) [200]. Other hair shaft abnormalites may be seen in LAS other than loose anagen hairs, including trichorhexis nodosa and tiger-tail polarization [200].

148.20

Chapter 148

Whether loose anagen hairs are markers for a distinct disorder or a common end-point seen in overlapping disorders is still unclear. LAS has been reported with a variety of syndromes [200] but it is unclear of the definition of LAS utilized in these reports, or whether there may have been artifactual creation of loose anagen hairs by too much traction on a hair pull in very young children. Two siblings with ocular colobomas, anagen hair shedding and decreased hair growth rate have been described [203]. However, the hairs in these cases did not attain the length normally seen in LAS. The differential diagnosis of loose anagen syndrome is dependent on the presenting phenotype. In patients with type B LAS who present with patches of unruly hair, the primary differential diagnosis is woolly hair nevus. In those presenting with type A LAS, the primary differential diagnosis is short anagen syndrome [204]. This latter condition also presents primarily in girls with light hair. In short anagen syndrome, the hair also does not appear to grow long but is neither brittle or otherwise abnormal. Examination of the proximal hairs obtained on hair pull in these patients do not show loose anagen hairs but may show an increased percentage of telogen hairs. If one examines the distal ends of these telogen hairs that have not been cut, they typically show tapered tips indicative of new growth and confirming that the shed hairs have had a shortened anagen phase.

Telogen loss or effluvium The stress on the anagen hair follicle necessary to trigger telogen effluvium is milder than that with anagen effluvium and, instead of triggering damage to the matrix, it precipitates an abrupt transformation of anagen hairs to telogen hairs. In telogen effluvium, about 10–40%, rarely more, of the scalp anagen hairs suddenly move in concert through the physical transformation to telogen and are shed together after the usual obligatory time in telogen. Thus, a patient with telogen effluvium generally experiences a sudden increase in hair shedding diffusely over the scalp 3–4 months after an inciting event. In situations where the aetiological factor has been removed (e.g. recovery from a severe infection), the telogen loss would be followed by a recapitulation of anagen in the affected follicles and regrowth of hair over the ensuing 6–12 months. In cases where the aetiological factor remains (e.g. untreated thyroid disease), the continued effect on the anagen follicles would cause persistence of the increased percentage of hairs in telogen, and hence decreased scalp hair density, even while those telogen hairs that are shed are being replaced in the normal cycle with anagen hairs. Once the inciting factor(s) is removed, a telogen effluvium will generally resolve over the next 6–12 months. The diagnosis of telogen effluvium is confirmed by finding a positive hair pull from multiple areas of the

Box 148.2 Causes of telogen effluvium in children and adolescents • Medical illness:
Severe infections, usually associated with high fever
Other systemic illnesses, acute or chronic
Hypo- or hyperthyroidism • Postpartum • Surgery • Medications (including but not limited to):
Anticoagulants
Beta-blockers
Lithium
Oral contraceptive pills: during use or after discontinuation
Retinoids and excess vitamin A
Valproic acid • Nutritional:
Precipitous diminution of calories or protein
Iron deficiency
Zinc deficiency
Essential fatty acid deficiency
Biotin deficiency • Psychological stress

scalp and the shed hairs all being telogen hairs. In total, 50–100 telogen hairs are normally shed per day, reflecting the 10–15% of scalp hairs in telogen at any one time [205]. In acute telogen effluvium, it is not uncommon for 200– 300 hairs per day to be shed and 20–50% of the scalp hairs may be in telogen at a given time. Telogen effluvium is less common in children than in adults, and in children is more likely to be related to a sudden and transient illness than to the drugs and hormonal fluctuations that commonly trigger this in adults (Box 148.2). It must be emphasized that any drug can trigger a telogen effluvium, just as any drug can cause a cutaneous allergic reaction. However, some drugs cause this more commonly than others, and these are listed in Box 148.2. Only those causes of telogen effluvium related to nutrition will be discussed further here. Protein malnutrition (kwashiorkor) and caloric malnutrition (marasmus) usually occur concurrently and are common in children living in developing nations [206,207]. The hair in affected individuals is slow growing, sparse and dyspigmented (Fig. 148.28). The increased telogen percentage is accompanied by relative anagen bulb atrophy and a concomitant diminution in hair shaft diameter and stability [207–211]. Zinc deficiency in childhood can lead to sparse and slow hair growth. The low serum zinc levels are caused by an autosomal recessive inherited disorder of intestinal absorption of zinc (acrodermatitis enteropathica) or may be acquired in the situation of general intestinal malabsorption with inadequate zinc replacement [212]. The hair loss may be accompanied by acral and periorificial vesiculobullous or eczematoid plaques, glossitis, stomatitis,

Hair Disorders

148.21

Fig. 148.29 Biotin deficiency. Courtesy of Dr Nancy B. Esterly.

Fig. 148.28 Protein malnutrition: flag sign. Courtesy of Dr Nancy B. Esterly.

nail dystrophy and diarrhoea [213]. Oral zinc supplementation will reverse all findings. Essential fatty acid deficiency in children usually occurs with prolonged parenteral alimentation with inadequate inclusion of supplemental essential fatty acids. The hair becomes sparse and less pigmented, and a generalized and periorificial dermatitis and thrombocytopenia may develop [214–217]. The skin returns to normal within weeks and the hair within months of either intravenous essential fatty acid replacement or treatment with topical linoleic acid [215]. Biotin deficiency may be secondary to either dietary deficiency or hereditary multiple carboxylase deficiency. The neonatal form, usually secondary to deficiency of holocarboxylase synthetase, is generally fatal, although rare cases with mild symptoms may present at several months of age [217,218]. The diagnosis is suggested by metabolic acidosis and organic aciduria; serum biotin levels may be normal [219–221]. In the late onset, infantile form of multiple carboxylase deficiency, infants develop the first symptoms at 2–3 months of age [219,222–224]. The genetic abnormality is most commonly a deficiency (7, which implies a potential functional link between the two [228]. The initial presentation of AGA may occur immediately post-puberty. Generally, hair loss presents in both boys and girls as central scalp hair thinning plus/minus frontal accentuation of hair loss. In girls, this should prompt a check for signs of hirsutism, severe acne and acanthosis nigricans and the performance of screening blood tests including thyroid function tests, complete blood count, free testosterone and dehydroepiandrosterone (DHEA) sulphate. If there is any confirmation of hyperandrogenism, a 17-OH progesterone test (best done on days 4–10 of the menstrual cycle and in the morning) and a 2 h glucose tolerance test with concomitant insulin levels should be performed to rule out diabetes and insulin resistance as part of the polycystic ovarian syndrome (PCOS): a baseline insulin level of >20 IU/mL or a glucose to insulin ratio of 12 months follow-up), developed a localized relapse during mean follow-up of 16.4 and 33.7 months. Side-effects of pulsed corticosteroid were minimal and were recorded in two patients (one with transient giddiness and headache and one with epigastric burning). Kiesch et al. [32] treated seven children with severe, rapidly evolving AA with pulse steroid therapy. Alopecia areata had been present

149.5

for 3–44 weeks and involved more than 30% of the scalp. One patient had AAT. Intravenous methylprednisolone (5 mg/kg twice a day) was administered for 3 days. No serious side-effects were noted. At the 12-month followup, complete regrowth had occurred in five patients (71%). The patient with AAT had no regrowth. Assouly et al. [33] enrolled 66 patients aged between 9 and 60 years with extensive AA. The administered treatment was methylprednisolone 500 mg/day for 3 days or 5 mg/kg twice per day for 3 days in children. These pulses were repeated after 4 and 8 weeks. Ophiasic alopecia areata did not respond to treatment. One-quarter of patients presenting with AAU had a good response (>80%) followed by a relapse in half of the cases. Half of the patients presenting with AAT had a good response. Alopecia areata presented a good response in 63.8 % (78% when it was a first episode and 90.5% if the treatment had been started less than 3 months before). The repetition of the pulses did not appear to increase the number of responders. In conclusion, highdose pulse therapy can be effective in extensive AA with rapid recent onset and did not show any serious sideeffects in the patients reported in the studies reviewed. In long-standing AA, AAT, AAU and ophiasis type, systemic corticosteroid pulse therapy did not show convincing hair growth and relapses were more frequent. Placebocontrolled studies are needed to confirm these data.

Topical immunotherapy Topical immunotherapy induces allergic contact eczema after application of contact allergens to the affected skin. The exact mechanism as to how contact sensitizers induce hair regrowth in AA remains unclear. The perifollicular lymphocytic infiltrate within the lesions is altered. While IFN-γ is reduced, IL-10 is increased after treatment with contact sensitizers. In addition, expression of MHC classes I and II is significantly down-regulated in the hair follicle epithelium. These findings indicate that contact sensitizers could be able to restore the immune privilege of the hair follicle [5]. Initially, dinitrochlorobenzene was used as topical irritant, but its mutagenic effect in the Ames test disqualified the substance for widespread use. Other topical sensitizers include squaric acid dibutyl ester (SADBE) and diphenylcyclopropenone (DPCP). Patients are first sensitized with a 2% solution on a small area of the scalp. Two weeks later, weekly half-headed treatments are started with increasing concentrations. The treatment is continued for several months until regrowth can be observed. Initial hair regrowth is usually seen after 8–12 weeks. Desired side-effects are mild eczema and mild enlargement of retroauricular lymph nodes. Other side-effects include vesicular or bullous reactions, dissemination of the allergic contact eczema, urticaria and erytheme multiformelike reactions.

149.6

Chapter 149

Contact sensitizers in the treatment of AA have been moderately effective in various studies. Cosmetically acceptable hair growth was observed in 30–70% of treated patients in different studies [34,35]. Relapse occurs in 50% of patients after cessation of therapy [36]. Studies involving children have been limited [36,37]. Schuttelaar et al. [36] observed cosmetically acceptable hair regrowth in 32% of 26 treated children. Cosmetically acceptable regrowth at the end of the study was seen in 4 of the 15 (27%) children with AAT and in 4 of the 10 (40%) children with AA. In another study, 28 patients between 10 and 35 years of age with extensive AA were treated with DPCP for 6 months. Complete remission (90–100% terminal hair regrowth) was obtained in 22.2% (6/27) and partial remission (10–90% terminal hair regrowth) in 59.3% (16/27). Partial recurrence was observed in 50.9% (13/22) of these patients after 6–12 months of follow-up [38]. Tan et al. [22] treated 58 children between 6 and 15 years with SADBE. After 6 months, 74% achieved more than 50% hair regrowth. Side-effects in these young children included itchy dermatitis, blisters and lymphadenopathy. In general, the protocols are prepared for adults and children older than 10 years with 50% or more hair loss [39]. In addition, it should be noted that DPCP and SADBE represent off-label uses of these medications.

Anthralin Anthralin is a topical irritant often used in the treatment of AA. So far no placebo-controlled double-blind studies exist for the treatment of AA in children. In adults, cosmetically acceptable hair regrowth has been found in 25% in a controlled study and in 60% in an uncontrolled study [40,41]. In a half-sided controlled study using anthralin 0.1%, no differences between treated and untreated sides could be found [42]. However, in this protocol the doses used induced only a minimal erythema that may have been subtherapeutic. The effects of anthralin on hair growth have been studied in balding C3H/HeJ mice affected by an AA-like disease. Affected C3H/HeJ mice were treated daily for 10 weeks on half of the dorsal skin with 0.2% anthralin and the contralateral side was treated with the vehicle ointment. Hair regrowth was observed in 9/14 mice on the treated sides. Four mice displayed near complete replacement. Expression of TNF-α and TNF-β were inhibited by anthralin upon successful treatment [43]. Side-effects were pruritus, skin irritation, scaling and pigmentation. For children under the age of 10 years, anthralin is a therapeutic option, but placebocontrolled studies are needed to further document safety and efficacy. Minoxidil Minoxidil is known for its potent hair growth stimulating effect in androgenetic alopecia. Its effect in AA is very

controversial. Several authors describe positive effects of topical 3% minoxidil solution in the treatment of AA. In a placebo-controlled study by Price et al. [44,45], 90 patients, aged 7–63 years, with extensive AA affecting 25–100% of the scalp were treated with minoxidil 3% for an entire year. Minoxidil-treated patients responded better than placebo-treated patients. The treatment was well tolerated and no blood pressure changes occurred [44,45]. However, in all placebo-controlled studies the effect of minoxodil was not significant compared with the placebo within the first 3 months of treatment [46,47]. Therefore, minoxidil cannot be routinely recommended for the treatment of AA in children.

Tacrolimus Tacrolimus is a topical calcineurin inhibitor. Tacrolimus has been shown to be ineffective in AA. In a recently published study, none of the patients with AA affecting 10–75% of the scalp had terminal hair growth in response to tacrolimus ointment 0.1% applied twice daily for 24 weeks. Treatment failure may reflect insufficient depth of penetration of the ointment formulation and less than optimal patient selection [48]. Psoralen plus ultraviolet A Several studies have been performed on the use of psoralen plus ultraviolet A (PUVA) in AA reporting on successful regrowth in 53–85% of treated patients in different studies. Besides the lack of controls in these studies, the reoccurrence of hair loss without continuous therapy, there is an increased risk of skin cancer that has been well documented in those receiving PUVA therapy. PUVA is therefore not a recommended treatment option in children. Experience with UVB phototherapy has been more limited; some early data suggest some efficacy in a subset of patients who receive UVB phototherapy in the form of narrowband ultraviolet light laser therapy (308 or 311 nm) [49]. Hair prostheses Some children do well with active non-intervention, and can be fitted for social reasons with hairpieces. Organizations such as the Locks of Love can provide anatomically fitted hairpieces (prostheses) which can be provided at discounted rates based on financial need. Conclusions. In summary, the possible therapeutic options for children with AA are very limited and cure of the disease or relapse prevention are not currently available. Treatment options and side-effects have to be individually balanced. Cytokines that restore the immune privilege of the hair follicle such as TGF-β, α-MSH and IL-10 could be interesting candidates for future treatment

Alopecia Areata

regimens. Recent research into agents that target NKG2D may also be a promising avenue for research. The psychological impact of the disease in young patients can be very high, and patients should be informed about support groups such as the National Alopecia Areata Foundation, the Child Alopecia Project and Locks of Love. References 1 Dudda-Subramanya R, Alexis AF, Siu K, Sinha AA. Alopecia areata: genetic complexity underlies clinical heterogeneity. Eur J Dermatol 2007;17:367–74. 2 Price VH. Alopecia areata: clinical aspects. J Invest Dermatol 1991;96:68S. 3 Kakourou T, Karachristou K, Chrousos G. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity. J Eur Acad Dermatol Venereol 2007;21: 356–9. 4 Freyschmidt-Paul P, Hoffmann R, McElwee KJ. Alopecia areata. In: Blume-Peytavi U, Tosti A, Whiting DA, Trüeb RM, eds. Hair Growth and Disorders, 1st edn. Springer, 2008:311–28. 5 Wasserman D, Guzman-Sanchez DA, Scott K, McMichael A. Alopecia areata. Int J Dermatol 2007;46:121–31. 6 Barahmani N, Schabath MB, Duvic M; National Alopecia Areata Registry. History of atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol 2009;61:581–91. 7 Jackow C, Puffer N, Hordinsky M et al. Alopecia areata and cytomegalovirus infection in twins: genes versus environment? J Am Acad Dermatol 1998;38:418–25. 8 Blaumeiser B, van der Goot I, Fimmers R et al. Familial aggregation of alopecia areata. J Am Acad Dermatol 2006;54:627–32. 9 Martinez-Mir A, Zlotogorski A, Gordon D et al. Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am J Hum Genet 2007;80:316–28. 10 Gilhar A, Paus R, Kalish RS. Lymphocytes, neuropeptides, and genes involved in alopecia areata. J Clin Invest 2007;117:2019–27. 11 Duvic M, Hordinsky MK, Fiedler VC et al. HLA-D locus associations in alopecia areata: DRw52a may confer disease resistance. Arch Dermatol 1991;27:64–8. 12 Barahmani N, de Andrade M, Slusser JP, Zhang Q, Duvic M. Major histocompatibility complex class I chain-related gene A polymorphisms and extended haplotypes are associated with familial alopecia areata. J Invest Dermatol 2006;126:74–8. 13 Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy syndrome. Br J Dermatol 2006;154:1088–93. 14 Wengraf DA, McDonagh AJ, Lovewell TR et al. Genetic analysis of autoimmune regulator haplotypes in alopecia areata. Tissue Antigens 2008;71:206–12. 15 Betz RC, König K, Flaquer A et al. The R620W polymorphism in PTPN22 confers general susceptibility for the development of alopecia areata. Br J Dermatol 2008;158:389–91. 16 Petukova L, Duvic M, Hordinsky M et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 2010;466:113–17. 17 Trautman S, Thompson M, Roberts J, Thompson CT. Melanocytes: a possible autoimmune target in alopecia areata. J Am Acad Dermatol 2009;61:529–30. 18 Tobin DJ, Fenton DA, Kendall MD. Ultrastructural observations on the hair bulb melanocytes and melanosomes in acute alopecia areata. J Invest Dermatol 1990;94:803–7. 19 Tobin DJ, Orentreich N, Fenton DA, Bystryn JC. Antibodies to hair follicles in alopecia areata. J Invest Dermatol 1994;102:721–4.

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20 Gilhar A, Pillar T, Assay B, David M. Failure of passive transfer of serum from patients with alopecia areata and alopecia universalis to inhibit hair growth in transplants of human scalp skin grafted on to nude mice. Br J Dermatol 1992;126:166–71. 21 McElwee KJ, Freyschmidt-Paul P, Zöller M, Hoffmann R. Alopecia areata susceptibility in rodent models. J Investig Dermatol Symp Proc 2003;8:182–7. 22 Tan E, Tay YK, Goh CL, Chin Giam Y. The pattern and profile of alopecia areata in Singapore: a study of 219 Asians. Int J Dermatol 2002;41:748–53. 23 Paus R, Nickoloff BJ, Ito T. A ‘hairy’ privilege. Trends Immunol 2005;26:32–40. 24 Whiting DA. Histopathologic features of alopecia areata: a new look. Arch Dermatol 2003;139:1555–9. 25 Barahmani N, Schabath MB, Duvic M; National Alopecia Areata Registry. History of atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol 2009;61:581–91. 26 Goh C, Finkel M, Christos PJ, Sinha AA. Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol 2006;20:1055–60. 27 Tosti A, Iorizzo M, Botta GL, Milani M. Efficacy and safety of a new clobetasol propionate 0.05% foam in alopecia areata: a randomized, double-blind placebo-controlled trial. J Eur Acad Dermatol Venereol 2006;20:1243–7. 28 Tosti A, Piraccini BM, Pazzaglia M, Vincenzi C. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis. J Am Acad Dermatol 2003;49:96–. 29 Mancuso G, Balducci A, Casadio C et al. Efficacy of betamethasone valerate foam formulation in comparison with betamethasone dipropionate lotion in the treatment of mild-to-moderate alopecia areata: a multicenter, prospective, randomized, controlled, investigatorblinded trial. Int J Dermatol 2003;42:572–5. 30 Dillaha CJ, Rothman S. Therapeutic experiments in alopecia areata with orally administered cortisone. J Am Med Assoc 1952;150:546–50. 31 Sharma VK, Muralidhar S. Treatment of widespread alopecia areata in young patients with monthly oral corticosteroid pulse. Pediatr Dermatol 1998;15:313–7. 32 Kiesch N, Stene JJ, Goens J, Vanhooteghem O, Song M. Pulse steroid therapy for children’s severe alopecia areata? Dermatology 1997;194:395–7. 33 Assouly P, Reygagne P, Jouanique C et al. [Intravenous pulse methylprednisolone therapy for severe alopecia areata: an open study of 66 patients.] Ann Dermatol Venereol 2003;130:326–30. 34 Hull SM, Pepall L, Cunliffe WJ. Alopecia areata in children: response to treatment with diphencyprone. Br J Dermatol 1991;125:164–8. 35 Happle R, Hausen BM, Wiesner-Menzel L. Diphencyprone in the treatment of alopecia areata. Acta Derm Venereol 1983;63:49–52. 36 Schuttelaar ML, Hamstra JJ, Plinck EP et al. Alopecia areata in children: treatment with diphencyprone. Br J Dermatol 1996;135: 581–5. 37 Weise K, Kretzschmar L, John SM, Hamm H. Topical immunotherapy in alopecia areata: anamnestic and clinical criteria of prognostic significance. Dermatology 1996;192:129–33. 38 Aghaei S. Topical immunotherapy of severe alopecia areata with diphenylcyclopropenone (DPCP): experience in an Iranian population. BMC Dermatol 2005;26:5–6. 39 Ross EK, Shapiro J. Management of hair loss. Dermatol Clin 2005;23:227–43. 40 Fiedler-Weiss VC, Buys CM. Evaluation of anthralin in the treatment of alopecia areata. Arch Dermatol 1987;123:1491–3. 41 Schmoeckel C, Weissmann I, Plewig G, Braun-Falco O. Treatment of alopecia areata by anthralin-induced dermatitis. Arch Dermatol 1979;115:1254–5.

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42 Nelson DA, Spielvogel RL. Anthralin therapy for alopecia areata. Int J Dermatol 1985;24:606–7. 43 Tang L, Cao L, Sundberg JP, Lui H, Shapiro J. Restoration of hair growth in mice with an alopecia areata-like disease using topical anthralin. Exp Dermatol 2004;13:5–10. 44 Price VH. Topical minoxidil (3%) in extensive alopecia areata, including long-term efficacy. J Am Acad Dermatol 1987;16:737–44. 45 Price VH. Topical minoxidil in extensive alopecia areata, including 3-year follow-up. Dermatologica 1987;175(Suppl 2):36–41. 46 Fransway AF, Muller SA. 3 percent topical minoxidil compared with placebo for the treatment of chronic severe alopecia areata. Cutis 1988;41:431–5. 47 Ranchoff RE, Bergfeld WF, Steck WD, Subichin SJ. Extensive alopecia areata: results of treatment with 3% topical minoxidil. Cleve Clin J Med 1989;56:149–54.

48 Price VH, Willey A, Chen BK. Topical tacrolimus in alopecia areata. J Am Acad Dermatol 2005;52:138–9. 49 Al-Mutairi N. 308-nm Excimer laser for the treatment of alopecia areata in children. Pediatr Dermatol 2009;26:547–50. 50 Price VH, Hordinsky MK, Olsen EA et al. Subcutaneous efalizumab is not effective in the treatment of alopecia areata. J Am Acad Dermatol 2008;58:395–402. 51 Abramovits W, Losornio M. Failure of two TNF-alpha blockers to influence the course of alopecia areata. Skinmed 2006;5:177–81. 52 Ochoa BE, Sah D, Wang G, Stamper R, Price VH. Instilled bimatoprost ophthalmic solution in patients with eyelash alopecia areata. J Am Acad Dermatol 2009;61:530–2. 53 Kaplan AL, Olsen EA. Topical 5-fluorouracil is ineffective in the treatment of extensive alopecia areata. J Am Acad Dermatol 2004;50:941–3.

150.1

C H A P T E R 150

Nail Disorders Antonella Tosti1,2 & Bianca M. Piraccini1 1

Department of Internal Medicine, Geriatrics and Nephrology, University of Bologna, Bologna, Italy Department of Dermatology and Cutaneous Surgery, Miller Medical School University of Miami, Miami, FL, USA

2

Nail anatomy and physiology, 150.1

Common nail disorders, 150.2

Nail anatomy and physiology The nail unit consists of four specialized epithelia: the nail matrix, the nail bed, the proximal nailfold and the hyponychium. The nail matrix is a germinative epithelial structure that gives rise to a fully keratinized multilayered sheet of cornified cells: the nail plate. In longitudinal sections, the nail matrix consists of a proximal and a distal region. Because the vertical axes of the nail matrix cells are oriented diagonally and distally, proximal nail matrix keratinocytes produce the upper portion of the nail plate whereas distal nail matrix keratinocytes produce the lower portion [1]. The peculiar kinetics of nail matrix keratinization explain why diseases of the proximal nail matrix result in nail plate surface abnormalities whereas diseases of the distal matrix result in abnormalities of the ventral nail plate or the nail free-edge or both. Nail plate corneocytes are tightly connected by desmosomes and complex digitations. The nail plate is a rectangular, translucent and transparent structure that appears pink because of the vessels of the underlying nail bed. The proximal part of the nail plate of the fingernails, especially those of the thumbs, shows a whitish, opaque, half-moon-shaped area, the lunula, that corresponds to the visible portion of the distal nail matrix. The shape of the lunula determines the shape of the free edge of the plate. The nail plate is firmly attached to the nail bed, which partially contributes to nail formation along its length. The longitudinal orientation of the capillary vessels in the nail bed explains the linear pattern of nail bed haemorrhages. Proximally and laterally, the nail plate is surrounded by the nailfolds. The horny layer of the proximal nailfold forms the cuticle, which adheres intimately to the underlying nail plate and Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Uncommon nail disorders, 150.3

prevents its separation from the proximal nailfold. Distally, the nail bed continues with the hyponychium, which marks the separation of the nail plate from the digit. The nail plate grows continuously and uniformly throughout life. Average nail growth is faster in fingernails (3 mm per month) than in toenails (1–1.5 mm per month) [2]. The nails of newborns are thin and soft, and frequently present a certain degree of expected koilonychia that is especially evident in toenails. As the nail plate of the great toenail may be relatively short, a mild distal embedding is frequently observed as soon as the nail grows. This is transitory unless there is congenital malalignment. A transient light-brown or ochre pigmentation of the proximal nailfold is frequent in newborns and may persist for a few months [3–4]. Nail growth rate in children is similar to the values observed in young adults, the fastest values of nail growth (1.5 mm per day) being reached between the ages of 10 and 14 years. The thickness and breadth of the nail plate increase rapidly in the first two decades of life [5]. The brief arrest of growth that characterizes the first days of life may involve the nail unit and result in a transitory arrest of the nail growth with development of Beau’s lines, which become visible at the base of the nails after the age of about 4 weeks. These physiological lines, however, are an inconstant phenomenon that occurs in only about 20–25% of healthy newborns [6]. References 1 Zaias N. The Nail in Health and Disease, 2nd edn. Norwalk, CT: Appleton and Lange, 1990. 2 Runne U, Orfanos CE. The human nail. Curr Prob Dermatol 1981;9:102–49. 3 Crespel E, Plantin P, Schoenlaub P et al. Hyperpigmentation of the distal phalanx in healthy Caucasian neonates. Eur J Dermatol 2001;11:120–1. 4 Iorizzo M, Oranje AP, Tosti A. Periungual hyperpigmentation in newborns. Pediatr Dermatol 2008;25:25–7.

150.2

Chapter 150

5 Hamilton JB, Terada H, Mestler GE. Studies of growth throughout the lifespan in Japanese: growth and size of nails and their relationship to age, sex, heredity and other factors. J Gerontol 1995;10:401–15. 6 Sibinga MS. Observations on growth of fingernails in health and disease. Pediatrics 1959;24:225–33.

Common nail disorders Nail diseases are a rather uncommon cause of dermatological consultation in children. They may be present at birth or be acquired. Nail signs of congenital and hereditary nail diseases usually develop early during childhood, and their presence may be a clue to the diagnosis of a syndrome or a systemic disorder. Although the acquired nail conditions observed in childhood are similar to those of adults, the prevalence of several diseases may vary in the different age groups. For instance, there are some conditions, such as parakeratosis pustulosa and twenty-nail dystrophy (TND), which are exclusively or typically seen in children. Other disorders, such as onychomycosis, are encountered only exceptionally in the first 10 years of life. The common disorders and traumatic nail abnormalities account for 90–95% of all nail abnormalities in children. This chapter reviews the nail disorders that are most commonly observed in childhood (Box 150.1), and then reviews some nail diseases that, although uncommon, are of diagnostic significance.

Transitory koilonychia • Key diagnostic criteria: thin, concave nails with everted edges • Key management features: no treatment necessary • Differentials: nail thinning due to trachyonychia Transitory koilonychia is a physiological phenomenon of the toenails in children. The nail plate is flat, thin and soft with everted edges, resulting in a spoon-shaped appearance. Lateral or distal embedding may occur and produce

mild nail ingrowing. The condition spontaneously regresses when the nail plate thickens with age.

Congenital malalignment of the big toenail • Key diagnostic criteria: the great toenail longitudinal axis is not parallel to that of the digit • Key management features: no treatment necessary except for surgery in very severe cases • Differentials: nail ingrowing In congenital malalignment, the nail plate of the big toenail deviates laterally from the longitudinal axis of the distal phalanx. The condition is always complicated by the development of lateral or distal nail embedding. The affected nail frequently shows dystrophic changes due to repetitive traumatic injuries: the nail plate may be thickened, yellow–brown in colour and present transverse ridging due to intermittent nail matrix damage (Fig. 150.1). Onycholysis is frequent. This diagnosis should always be considered in children with dystrophic or ingrowing toenails. Spontaneous improvement with complete resolution can occur. Surgical treatment produces the best results when performed before the age of 2 years [1].

Ingrown nails • Key diagnostic criteria: paronychia and pyogenic granuloma due to embedding of the nail edges into the lateral nailfold • Key management features: remove the spicula and treat the inflammation; lateral nail matrix phenolization • Differentials: nail pyogenic granulomas due to drugs or trauma Ingrown nails are a common complaint and usually affect the great toe of teenagers and young adults. Predisposing factors include congenital malalignment of the great toenails and congenital hypertrophy of the lateral nailfolds. In the latter condition, the periungual soft tissues of the great toe are hypertrophic and partially cover the nail plate, favouring nail ingrowing [2]. The development of

Box 150.1 Most commonly observed nail disorders in children • • • • • • • • • • • •

Transitory koilonychia Congenital malalignment of the big toenail Ingrown nails Herringbone (chevron) nails Acute paronychia Warts Nail biting and onychotillomania Punctate leuconychia Atopic dermatitis Parakeratosis pustulosa Psoriasis Twenty-nail dystrophy (TND, trachyonychia)

Fig. 150.1 Congenital malalignment of the toenail with mild lateral ingrowing and Beau’s lines.

Nail Disorders

nail ingrowing is favoured by incorrect nail trimming, traumatic injuries and occlusive footwear. The clinical manifestations of ingrown toenails can be divided into three stages. • Stage 1. Embedding of the nail spicula within the lateral nailfold produces painful erythema and swelling of the nailfold. Treatment is conservative with extraction of the embedded spicula and introduction of a package of non-absorbent cotton under the lateral corner of the nail. This package should be replaced every few days. • Stage 2. This stage is characterized by the formation of granulation tissue, which covers the nail plate. The affected nail is very painful and the nailfold presents a pyogenic granuloma with seropurulent exudation. In this stage, the topical application of high-potency steroids under occlusion for a few days can reduce the overgrowth of granulation tissue. Conservative treatment as for stage 1 can then be utilized. • Stage 3. The granulation tissue becomes covered by newly formed epidermis of the lateral nailfold. This stage requires surgical treatment with selective destruction of the lateral horn of the nail matrix. Newborns can develop multiple ingrown fingernails with paronychia as a result of the grasp reflex [3]. The pathogenesis of the condition is the repeated compression of the soft tissues of the lateral nailfold by the lateral edges of the nails during grasping. The condition regresses spontaneously when the grasp reflex disappears, at about 3 months of age.

Herringbone (chevron) nails This is a very common finding in fingernails of young children. The nail plate surface presents longitudinal ridges that cross its surface diagonally from the lunula to the distal margin with a V-shaped pattern [4].

Acute paronychia • Key diagnostic criteria: acute painful periungual inflammation often with pus discharge • Key management features: pus drainage, topical antibiotics • Differentials: pustular psoriasis Acute paronychia is usually caused by Staphylococcus aureus, although other bacteria and herpes simplex virus may be responsible. A minor trauma commonly precedes the development of the infection. The affected digit shows acute inflammatory changes of the nailfolds, with erythema, swelling, pus formation and pain. Whenever possible, appropriate cultures should be taken to identify the responsible organism. Treatment includes prompt incision and drainage of the abscess, local medications with antiseptics and administration of systemic antibiotics or aciclovir, depending on the causative agent.

150.3

Warts • Key diagnostic criteria: warty papules of the nailfolds or hyponychium • Key management features: topical keratolytics • Differentials: skin xerosis, subungual exostosis Periungual and subungual warts are very common in children. Warts of this type often affect more than one digit and frequently recur. Nail biting facilitates the spread of periungual warts to several digits. Periungual warts may have the typical ‘warty’ exophytic appearance, or may present as a hyperkeratotic lesion of the nailfolds. Large subungual warts may cause lifting of the nail plate and result in pain. In young children, surgical procedures should be avoided and treatment should be as conservative as possible [5]. Topical solutions containing salicylic and lactic acids are the treatment of choice. Topical immunotherapy with strong sensitizers (squaric acid dibutylester (SADBE) or diphenylcyclopropenone (DPCP)) is an effective and painless modality of treatment for multiple recalcitrant warts [6]. SADBE or DPCP 2% in acetone can be used for sensitization. After 21 days, weekly applications are carried out with dilutions selected according to the patient’s response. Complete cure usually requires 3–4 months. Similar to warts in other body sites, periungual warts may recur after cure.

Nail biting and onychotillomania • Key diagnostic criteria: paronychia with peeling scales and blood crusts, shortened nails • Key management features: topical unpleasant-tasting preparations • Differentials: paronychia due to other causes Nail biting is common in childhood and affects up to 60% of children. Conversely, onychotillomania is rather uncommon and usually associated with underlying psychological disorders. Nail biting produces short and irregular nails that show depressions and scratches. Apical root resorption may occasionally occur. The habit of picking, breaking or chewing the skin over the proximal nailfold produces paronychia and nail matrix injury with nail plate surface abnormalities. Secondary bacterial infections of the periungual tissues are common, as are periungual warts. Most children discontinue nail biting when they grow up. Frequent application of unpleasant-tasting topical preparations on the nail and periungual skin can discourage patients from biting and chewing their fingernails.

Punctate leuconychia • Key diagnostic criteria: small white spots on the fingernails

150.4

Chapter 150

• Key management features: treatment is not necessary • Differentials: drug-induced leuconychia Punctate leuconychia is a traumatic fingernail abnormality that is almost exclusively seen in children. It is usually caused by repetitive minor traumatic injuries to the nail matrix. This process produces a disturbance in nail matrix keratinization and the development of parakeratotic cells in the ventral nail plate. These modify the transparency of the nail plate and appear as white spots (Fig. 150.2). The affected nails show single or multiple small opaque white spots that move distally with nail growth and usually disappear before reaching the distal edge. The condition may involve a few or all the fingernails and there may be a variable number of white opaque spots. Although punctate leuconychia is commonly believed to be caused by calcium deficiency, there is no known relationship between this condition and the calcium content of the nail. Punctate leuconychia spontaneously regresses by avoiding trauma.

Atopic dermatitis • Key diagnostic criteria: hand and fingernail dermatitis including the periungual skin • Key management features: topical anti-inflammatory agents • Differentials: contact eczema The nails in children with atopic dermatitis may present nail plate surface abnormalities due to eczematous involvement of the nail matrix. These include irregular pitting and Beau’s lines. Onycholysis may occasionally occur as a consequence of eczematous involvement of the fingertips.

Parakeratosis pustulosa is a chronic condition that exclusively affects children and usually involves a single finger, most commonly the thumb or index finger [7]. In the early phases, the affected digit shows eczematous changes associated with mild distal subungual hyperkeratosis and onycholysis. Nail abnormalities are usually more marked on a corner of the nail. Pitting of the nail plate may be present (Fig. 150.3). Whether parakeratosis pustulosa is a limited form of nail psoriasis or a clinical manifestation of other conditions, such as contact and atopic dermatitis, is a matter of controversy. In the authors’ experience, most children with parakeratosis pustulosa develop mild nail psoriasis when they become adults [8]. As parakeratosis pustulosa and nail psoriasis produce similar nail changes, the diagnosis of parakeratosis pustulosa is based on the localization of the disease to a single digit rather than on the morphology of the nail lesions. This diagnosis should always be considered in a child with psoriasiform nail changes limited to a single finger. Patch tests can be useful to rule out contact dermatitis. The nail lesions usually resolve spontaneously. Topical treatment with steroids and/or retinoic acid may induce partial remission of the nail changes.

Psoriasis • Key diagnostic criteria: irregular pitting, salmon patches of the nail bed, onycholysis with erythematous border • Key management features: topical vitamin D derivatives or tazarotene on the nail bed after removal of the detached nail plate • Differentials: onychomycosis, alopecia areata

Parakeratosis pustulosa • Key diagnostic criteria: one digit showing onycholysis and pulp scaling • Key management features: topical steroids • Differentials: psoriasis, eczema

Fig. 150.2 Punctate leuconychia.

Fig. 150.3 Parakeratosis pustulosa: psoriasiform nail changes limited to one digit.

Nail Disorders

The prevalence of nail involvement in children with psoriasis ranges from 7% to 39%, according to different studies. The clinical manifestations of nail psoriasis in children are quite similar to those of adults, except for the fact that nail bed involvement is usually absent or mild [9,10]. Fingernails are much more commonly affected than toenails. Nail pitting is the most common sign of psoriasis in children. Pitting is the consequence of a focal psoriatic inflammatory involvement of the proximal nail matrix, which results in the persistence of clusters of parakeratotic cells within the upper layers of the nail plate. Pits usually look shiny because they reflect light. Psoriatic pits are usually large, deep and randomly scattered within the nail plate. They are rarely found in toenails. Pits may be the sole manifestation of nail psoriasis or they may be associated with distal onycholysis and salmon-pink patches of the nail bed. Onycholysis is the detachment of the nail plate from the nail bed. The onycholytic area looks whitish because of the presence of air under the detached nail plate. In psoriasis, the onycholytic area is typically separated from the normal nail plate by an erythematous border. Oily patches appear as yellowish or salmon-pink areas, easily visible through the transparent nail plate. They result from a focal psoriatic involvement of the nail bed. Subungual hyperkeratosis and splinter haemorrhages, which are commonly observed in adults with nail psoriasis, are less common in children. Subungual hyperkeratosis describes the accumulation of parakeratotic cells under the distal portion of the nail plate. Splinter haemorrhages appear as longitudinal linear red-brown areas of haemorrhage. They are almost exclusively seen in fingernails and are usually located in the distal portion of the nail plate. Splinter haemorrhages are a consequence of psoriatic involvement of the nail bed capillary loops that run in a longitudinal direction along the nail bed dermal ridges. The differential diagnosis of nail psoriasis in children mainly includes eczema and parakeratosis pustulosa. Although onychomycosis may produce nail changes very similar to nail bed psoriasis, this condition is rare in children. Nail psoriasis has an unpredictable course but, in most cases, the disease is chronic and complete remissions are uncommon. The beneficial effects of environmental factors such as sunlight are less certain than in skin psoriasis. Stressful events may precipitate relapses. There are no consistently effective treatments for nail psoriasis in children. Topical application of calcipotriol or tazarotene [11] may be useful for nail bed psoriasis.

150.5

The term TND, or trachyonychia, describes a spectrum of nail plate surface abnormalities that produce nail plate roughness. This nail symptom is the clinical manifestation of several inflammatory nail diseases including alopecia areata, lichen planus and psoriasis. The nail histopathology permits definitive diagnosis by showing the typical features of lichen planus or psoriasis in trachyonychia due to these conditions, or spongiotic changes in trachyonychia due to alopecia areata [12]. Patients affected by TND may be divided into two major groups. • Patients with a personal history or clinical evidence of alopecia areata. Up to 12% of children with alopecia areata present with this nail disorder, which may precede or follow the onset of hair loss even by several years. • Patients with isolated nail involvement (idiopathic trachyonychia). The frequency of idiopathic trachyonychia is unknown, but it is almost exclusively seen in children. It may possibly represent a variety of alopecia areata limited to the nails and is occasionally seen in association with other autoimmune diseases as vitiligo. Two clinical varieties of trachyonychia were originally described by Baran et al. in 1978: opaque trachyonychia and shiny trachyonychia [13]. Both varieties may occur in association with alopecia areata or may be idiopathic. In opaque trachyonychia, the affected nails show excessive longitudinal striations with loss of nail lustre (vertically striated sandpapered nails). Koilonychia may be present (Fig. 150.4). The disorder is symptomless and patients only complain of brittleness and cosmetic discomfort.

Twenty-nail dystrophy (TND, trachyonychia) • Key diagnostic criteria: rough nail/s due to excessive longitudinal striations • Key management features: urea-containing emollients • Differentials: psoriasis, eczema

Fig. 150.4 Opaque trachyonychia: vertically striated sandpapered nails. Note evident koilonychia.

150.6

Chapter 150

Despite the term TND, the nail changes do not necessarily involve all 20 nails. Twenty-nail dystrophy is a benign condition that usually regresses spontaneously over the years. Even in patients with TND due to lichen planus, the prognosis is favourable and nail scarring is never observed [14]. Treatment is not necessary. Nail fragility may be improved by the application of topical emollients and systemic administration of biotin. References 1 Baran R. Significance and management of congenital malalignment of the big toenails. Cutis 1996;58:181–4. 2 Piraccini BM, Parente GL, Varotti E et al. Congenital hypertrophy of the lateral nail folds of the hallux: clinical features and follow-up of seven cases. Pediatr Dermatol 2000;17:348–51. 3 Matsui T, Kidou M, Ono T. Infantile multiple ingrowing nails of the fingers induced by the grasp reflex: a new entity. Dermatology 2002;205:25–7. 4 Parry EJ. Chevron nail/herringbone nail. J Am Acad Dermatol 1999;40:497–8. 5 Tosti A, Piraccini BM. Warts of the nail unit: surgical and non surgical approaches. Dermatol Surg 2001;27:235–9. 6 Upitis JA, Krol A. The use of diphenylcyclopropenone in the treatment of recalcitrant warts. J Cutan Med Surg 2002;6:214–17. 7 Hjorth N, Thomsen K. Parakeratosis pustulosa. Br J Dermatol 1967;79:527–32. 8 Tosti A, Peluso AM, Zucchelli V. Clinical features and long term follow-up of 20 cases of parakeratosis pustulosa. Pediatr Dermatol 1998;15:259–63. 9 Nanda A, Kaur S, Kaur I et al. Childhood psoriasis: an epidemiologic survey of 112 patients. Pediatr Dermatol 1990;7:19–21. 10 Al-Mutairi N, Manchanda Y, Nour-Eldin O. Nail changes in childhood psoriasis: a study from Kuwait. Pediatr Dermatol 2007;24:7–10. 11 Diluvio L, Campione E, Paternò EJ et al. Childhood nail psoriasis: a useful treatment with tazarotene 0.05%. Pediatr Dermatol 2007;24:332–3. 12 Tosti A, Piraccini BM. Trachyonychia or twenty-nail dystrophy. Curr Opin Dermatol 1996;3:83–6. 13 Baran R, Dupre A, Christol B et al. Vertical striated sand-papered twenty nail dystrophy. Ann Dermatol Venereol 1978;105:387–92. 14 Sakata S, Howard A, Tosti A et al. Follow up of 12 patients with trachyonychia. Australas J Dermatol 2006;47:166–8.

Uncommon nail disorders

Fig. 150.5 Nail lichen planus: nail thinning, longitudinal ridging and fissuring, due to nail matrix involvement, associated with onycholysis due to nail bed involvement.

• Trachyonychia (TND) resulting from nail LP is clinically similar to trachyonychia due to other inflammatory nail disorders. Even when due to LP, trachyonychia has a benign clinical course. • Idiopathic atrophy of the nail is a rare, acute and rapidly progressing variety of nail LP that leads to painless diffuse nail destruction. It typically affects Indian patients. The nail plates are completely or almost completely absent due to the presence of dorsal pterygium and nail matrix atrophy [2]. The diagnosis of typical nail lichen planus should be considered when nail thinning is associated with longitudinal ridging and splitting. Systemic steroids (such as intramuscular triamcinolone acetonide 0.5 mg/kg per month for 3–6 months) can be effective in treating nail lichen planus and preventing destruction of the nail matrix [3]. Treatment of TND due to LP is often not necessary, as this condition improves spontaneously and never produces scarring. Pterygium and idiopathic atrophy, however, are irreversible and treatment is not effective.

Lichen planus Nail lichen planus (LP) is rare in children and is not usually associated with cutaneous or mucosal signs of the disease. Lichen planus in children may have three different clinical presentations [1]. • Typical LP, similar to that seen in adults, is characterized by nail thinning with longitudinal ridging and splitting. Nail bed involvement produces onycholysis (Fig. 150.5). Dorsal pterygium, which appears as a V-shaped extension of the skin of the proximal nailfold, is rare.

Lichen striatus Nail lichen striatus is rare and almost exclusively seen in children. It is usually associated with typical skin lesions on the affected extremity but may occur in isolation [4]. It is almost always limited to a single nail. The nail abnormalities, consisting of nail thinning associated with longitudinal ridging and splitting, closely resemble those of nail matrix lichen planus but do not involve the whole nail plate, being most frequently restricted to its medial or lateral portion. The presence of linearly arranged

Nail Disorders

papules, sometimes with verrucous scales, along the affected extremity suggests the diagnosis. The nail pathology reveals changes similar to those of lichen planus in the nail matrix. The nail lesions regress spontaneously in a few years and require no treatment.

150.7

Nail matrix naevi

Subungual exostoses are not uncommon in teenagers and are frequently precipitated by a trauma. They almost exclusively involve the toenails, especially on the great toe. Subungual exostoses are usually localized to the dorsomedial aspect of the distal phalanx. Subungual exostosis appears as a firm tender subungual nodule that elevates the nail plate and produces distal or lateral onycholysis (Fig. 150.6). Because of the gradual enlargement of the excess bone, the nail plate may be deformed or destroyed. Radiography, showing an exophytic lesion on the distal phalangeal bone, is diagnostic. The lesion should be surgically excised [5].

Nail matrix naevi in Caucasians are uncommon but not exceptional, and are usually seen in childhood [6]. They may be congenital or acquired and usually produce a pigmented longitudinal band in the nail plate (longitudinal melanonychia) (Fig. 150.7). Nail matrix naevi occur more frequently in fingernails than in toenails, the thumb being affected in about half of cases. Nail pigmentation due to nail matrix naevi may be associated with a naevus of the periungual skin. The size as well as the degree of pigmentation of the band of longitudinal melanonychia vary considerably among patients. In most cases, the naevus produces a heavily pigmented band, but it can also cause a scarcely pigmented light or brown band that may even undergo spontaneous fading, especially in children. This phenomenon, which has been exclusively reported in children, may be erroneously interpreted as a benign clinical sign [7]. However, this is not the case, as fading of the pigmentation indicates only a decreased activity of the naevus cells and not a regression of the naevus itself. From a clinical point of view, it may be difficult to distinguish longitudinal melanonychia due to a naevus from longitudinal melanonychia caused by other conditions, including nail melanoma, a rare disorder in children. A nail biopsy is necessary for definitive diagnosis [8]. Although the frequency of progression from nail matrix naevi to nail matrix melanoma is not known, some cases have been documented [9]. The role of dermoscopy in the follow-up of lesions is still not established [10,11]. The authors advise immediate excision of pigmented lesions with alarming clinical features (bands that enlarge and/ or darken, bands with irregular borders). In general, these authors always recommend excising all bands as a preventive measure, after puberty.

Fig. 150.6 Subungual exostosis: subungual nodule with onycholysis.

Fig. 150.7 Longitudinal melanonychia due to a nail matrix naevus. The pigmentation is visible through the cuticle (pseudo-Hutchinson’s sign).

Periungual fibromas Periungual fibromas in children are usually a sign of tuberous sclerosis (Koenen’s tumour). Periungual fibromas appear as firm, flesh-coloured, smooth growths that originate in the periungual groove and usually extend outwards over the nail plate. Compression of the nail matrix may produce a groove in the nail plate. Subungual lesions can also occur. In tuberous sclerosis, periungual fibromas are commonly associated with other skin signs, including facial angiofibromas, hypomelanotic macules, shagreen patches and forehead plaques. Periungual fibromas are asymptomatic and usually require no treatment. Large lesions can be surgically excised.

Subungual exostosis

150.8

Chapter 150

Anonychia/micronychia Total or partial absence of the nail at birth is rare. It may be a consequence of fetal exposure to systemic medications in early pregnancy or a sign of a genetic syndrome. Hypoplasia of the nails and terminal phalanges can occur in children whose mothers have been exposed to anticonvulsant drugs, alcohol or warfarin. Congenital syndromes associated with anonychia include DOOR syndrome (deafness, onycho-osteodystrophy, mental retardation), Iso–Kikuchi syndrome and some ectodermal dysplasias.

Iso–Kikuchi syndrome This congenital nail deformity affects one or both index fingers and occasionally other fingers [12]. The affected nails most commonly show micronychia or hemionychogryphosis (Fig. 150.8). Anonychia may also be present. Lateral radiographic views show a Y-shaped bifurcation of the distal phalanx on lateral pictures.

In 40% of all cases of nail–patella syndrome, a nephropathy develops. In total, 5.5–8% of patients eventually require haemodialysis because of renal insufficiency.

Polydactyly The frequency of polydactyly of the hands has been estimated to be 0.37%; it is more common than polydactyly of the feet. Duplication of the thumb is a manifestation of congenital polydactyly, one of the most common anomalies of the hand. Patients with type 1 (bifid distal phalanx) and 2 (duplicated) thumb polydactyly may have two distinct nails separated by a longitudinal incision or a single nail with a central indentation of the distal margin. In that situation, bone duplication is limited to the distal phalanx [14]. Thumb polydactyly may be sporadic or transmitted as an autosomal dominant trait with variable expressivity. Radiography shows bone bifurcation. Early surgical treatment is necessary to maximize functional restoration and to correct disfigurement.

Nail–patella syndrome In this condition, which is due to a mutation of the gene LMX1B [13] and is inherited in an autosomal dominant pattern, nail hypoplasia is associated with bone and kidney abnormalities. Nail abnormalities may be limited to the thumbs or affect all fingernails. When multiple nails are involved, the thumb is the most severely affected. The affected digits show absence or hypoplasia of the nail plate, usually more marked on the medial portion of the nail. Triangular lunulae are also characteristic (Fig. 150.9). The bone abnormalities characteristic of nail–patella syndrome include absent or hypoplastic patella, radial head abnormalities and iliac crest exostosis. A pelvis X-ray identifying iliac crest exostosis permits diagnosis of nail patella syndrome in children.

Fig. 150.8 Iso–Kikuchi syndrome: micronychia of the index finger.

Epidermolysis bullosa In epidermolysis bullosa, nail changes are common, even although not specific to the epidermolysis bullosa subtypes. Possible abnormalities include periungual and/or subungual blistering, onycholysis, nail thickening and shortening, pterygium and nail atrophy [15]. Extensive and repetitive blistering may produce permanent nail loss. Trauma contributes to the development of the nail dystrophy, which is more common and severe in the great toenails. Dystrophic or absent nails with periungual granulation tissue are suggestive for Herlitz EB. Dominant dystrophic epidermolysis bullosa may sometimes present with isolated nail dystrophy, characterized by thickening and yellow discoloration of the nails [16]

Fig. 150.9 Nail–patella syndrome: nail hypoplasia and triangular lunula. The thumb is more severely affected.

Nail Disorders

150.9

increase in the lateral curvature of the nail plate. Excision of the hyperkeratotic nail bed can be performed surgically or with a carbon dioxide laser.

Fig. 150.10 Only nail dominant dystrophic EB: in this child the only abnormality was the presence of thickened dystrophic great toenails.

(Fig. 150.10). Late-onset junctional epidermolysis bullosa is a subtype of autosomal recessive junctional epidermolysis bullosa, characterized by the onset of symptoms between the ages of 5 and 8 years. Nail lesions usually precede the other clinical manifestations of the disease. The nails appear thick and short, and develop recurrent periungual and subungual haemorrhagic blisters.

Ectodermal dysplasias Patients with ectodermal dysplasia develop dystrophic nails, and the presence of nail abnormalities is a major criterion for the classification of these conditions (subclass 3). The nails show variable features, which depend on the exact form of ectodermal dysplasia. Nail hypoplasia is frequently associated with thickening of the nail plate.

Pachyonychia congenita Pachyonychia congenita is an autosomal dominant disorder characterized by severe nail thickening due to nail bed hyperkeratosis. Three different types of pachyonychia congenita have been recognized, and differentiation among them depends on the clinical features and biochemical defect. Nail abnormalities are a constant feature and usually develop during childhood [17]. All the nails are thickened, difficult to trim and show an

References 1 Tosti A, Piraccini BM, Cambiaghi S et al. Nail lichen planus in children. Clinical features, response to treatment and long term follow up. Arch Dermatol 2001;137:1027–32. 2 Tosti A, Piraccini BM, Fanti PA et al. Idiopathic atrophy of the nails: clinical and pathological study of 2 cases. Dermatology 1995;190:116–18. 3 Tosti A, Peluso AM, Fanti PA et al. Nail lichen planus: clinical study of 24 patients. J Am Acad Dermatol 1993;28:724–30. 4 Tosti A, Peluso AM, Misciali C et al. Nail lichen striatus: clinical features and long-term follow-up of five cases. J Am Acad Dermatol 1997;36:908–13. 5 Lemont H, Christman RA. Subungual exostosis and nail disease and radiological aspects. In: Scher RK, Daniel CR III (eds) Nails: Therapy, Diagnosis, Surgery. Philadelphia: W.B. Saunders, 1990: 250–7. 6 Tosti A, Baran R, Piraccini BM et al. Nail matrix nevi: a clinical and pathological study of 22 patients. J Am Acad Dermatol 1996;34:765–71. 7 Tosti A, Baran R, Morelli R et al. Progressive fading of longitudinal melanonychia due to a nail matrix melanocytic nevus in a child. Arch Dermatol 1994;130:1076–7. 8 Goettmann-Bonvallot S, Andre J, Belaich S. Longitudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol 1999;41:17–22. 9 Iorizzo M, Tosti A, di Chiacchio N et al. Nail melanoma in children: differential diagnosis and management. Dermatol Surg 2008;34:974–8. 10 Ronger S, Touzet S, Ligeron C et al. Dermoscopic examination of nail pigmentation. Arch Dermatol 2002;138:1327–33. 11 Tosti A, Piraccini BM, de Farias DC. Dealing with melanonychia. Semin Cutan Med Surg 2009;28:49–54. 12 Baran R. Syndrome d’Iso et Kikuchi. Ann Dermatol Vénéréol 1980;107:431. 13 McIntosh I, Dreyer SD, Clough MV et al. Mutation analysis of LMX1B gene in nail patella syndrome patients. Am J Hum Genet 1998;63:1651–8. 14 Tosti A, Paoluzzi P, Baran R. Doubled nail of the thumb: a rare form of polydactyly. Dermatology 1992;184:216–18. 15 Dharma B, Moss C, McGrath JA et al. Dominant dystrophic epidermolysis bullosa presenting as familial nail dystrophy. Clin Exp Dermatol 2001;26:93–6. 16 Bruckner-Tuderman L, Schnyder UW, Baran R. Nail changes in epidermolysis bullosa: clinical and pathogenetic considerations. Br J Dermatol 1995;132:339–44. 17 Samman PD. Developmental anomalies. In: Samman PD, Fenton DA (eds) Samman’s The Nails in Disease, 5th edn. Oxford: ButterworthHeinemann, 1995: 183–208.

151.1

C H A P T E R 151

Genital Disease in Children Gayle O. Fischer The Northern Clinical School, The University of Sydney, Sydney, Australia

Introduction, 151.1

Blisters and ulcers, 151.12

Scrotal conditions, 151.22

Inflammatory dermatoses of the genital

Anatomical abnormalities, 151.16

Genital signs of systemic disease, 151.23

Foreign bodies, 151.19

Psychological aspects of genital disease in

region, 151.2 Birthmarks of the genital area, 151.5

Neoplasia, 151.20

children, 151.24

Non-sexually acquired genital infections in children, 151.8

Introduction Genital skin disease in children is less common than in adults and although many of the conditions that affect adults also affect children, there are some important differences between the two groups. In both adults and children of either sex, dermatitis and psoriasis are the most common causes of a chronic genital rash, and in females lichen sclerosus is also common [1]. However, acute, recurrent and chronic candidiasis are important components of female adult vulval disease that are not seen in the non-oestrogenized vulva and vagina of the child, and tinea of the groin, which is relatively common in men, is rare in children [2]. Birthmarks of the genital area, particularly haemangiomas, are an important issue in children but not in adults, in whom they are likely to have resolved long ago or have been diagnosed. Fusion of the labia is a self-limiting condition seen in small girls but it is seen in adults only in the setting of lichen sclerosus or severe lichen planus. Group A β-haemolytic streptococcal vulvovaginitis, balanitis and perianal cellulitis are diseases that affect mainly children but, apart from this, infective genital disease is rare in children. Sexual abuse is always an issue to be considered in any genital presentation in children but, in fact, is rarely a cause of genital skin disease. Malignancy of the skin of the genital skin is also very rare in children, as opposed to adults, in whom it is a real, if relatively uncommon, concern. Within the paediatric age group, genital skin disease appears to be more common in girls than in boys. Very Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

little work on the specific subject of paediatric genital disease has been published. Most of what exists focuses on infective conditions, anatomical abnormalities and tumours. Anatomical abnormalities and tumours are in fact very rare in everyday practice, and even infection is unusual. In articles on paediatric vulval disease, it is often asserted that the skin of the prepubertal vulva is fragile and sensitive because it is poorly oestrogenized. In fact, there is no evidence to back this up. It is physiological for a child’s vulva to be low in oestrogen, and the fact that children have much less trouble with vulval rashes than do adults does not support the assumption that vulval skin of a child is prone to disease. The presence of oestrogen is in fact a liability that predisposes to the vaginitis, particularly candidiasis, seen in adults. Furthermore, oestrogen creams are often very irritating when applied to children. Another common assertion is that genital and perianal disease in children is due to ‘poor hygiene’ and ‘faecal contamination’. This is a facile statement that is also poorly supported, and which trivializes and stigmatizes this problem. In fact, mothers of small children are usually highly conscientious about genital hygiene and are more likely to be doing more washing than is necessary rather than too little. Vulvovaginitis (in more detail) and lichen sclerosus are discussed in Chapter 152. References 1 Fischer GO. The commonest causes of symptomatic vulval disease: a dermatologist’s perspective. Australas J Dermatol 1996;37:12–18. 2 Fischer GO, Rogers M. Vulvar disease in children: a clinical audit of 130 cases. Pediatr Dermatol 2000;17:1–6.

151.2

Chapter 151

Inflammatory dermatoses of the genital region Dermatitis Pathogenesis. Although it is a very common assumption that candidiasis is the usual cause of genital rashes, dermatitis is a much more common cause of genital pruritus and rashes in children. Although there are no published studies that confirm this in boys, at least 30% of children with pruritus vulvae have dermatitis, and 66% of these patients are atopic [1,2]. Despite this, the medical literature has largely neglected the subject of dermatitis specifically as it affects the genital area, and many cases are simply described as ‘non-specific’ [3]. Older children wearing nappies at night may develop irritant contact dermatitis. Irritant contact dermatitis may also occur as a result of constant contact with faeces. This will most often happen in the context of the child with chronic diarrhoea or chronic constipation with soiling. Children who shower rather than bathe may miss washing the vulval area effectively, and children who wipe back to front may soil the vulval area with faeces. However, the most common causes of irritant contact dermatitis in children are overuse of soap or bubble bath, using shampoo in the bath and swimming in chlorinated swimming pools [1,2,4]. Irritation from overuse of medications and perfumed products is very common in adults but less so in children, mainly because they are not exposed to nearly so many of these products. However, it is not uncommon for children to be treated with antifungal creams on the assumption that they have candidiasis, and these are a common cause of contact irritant dermatitis. True allergic contact dermatitis of the anogenital region is most often due to topical corticosteroids, preservatives and fragrances [5] and should be considered in any persistent, treatmentresistant case. Clinical presentation. Because babies who suffer from atopic dermatitis rarely have signs of it in the wellhydrated skin under the nappy, the onset of vulval dermatitis is often delayed until the child is out of nappies. Genital dermatitis presents with itching and a fluctuating rash, which is often precipitated by contact with irritants and worsened by excessive washing and use of antifungal creams. The child’s scratching behaviour is often a source of embarrassment for parents and of unwelcome attention at school. It is common for children with vulval itching to wake in a distressed state at night with night terrors. Some girls complain of burning and stinging on urination and contact with bath water. The distribution of the rash is usually on the labia majora in girls and the base of the penis and the scrotum in boys.

Examination is often fairly unremarkable, and parents may have trouble convincing their doctor that there is anything wrong. Close inspection will reveal some erythema, scale and in girls slight rugosity of the labia majora, and increased erythema and desquamation of the minora (Fig. 151.1). The desquamation may stain the child’s underwear and be misinterpreted as a vaginal discharge. If the rash is severe, it may extend to the inguinal areas and buttocks. Superinfection with Staphylococcus aureus may occur on the skin but there is no vaginitis, and vaginal swabs and urine culture are invariably negative. Differential diagnosis. The differential diagnosis of dermatitis of the genital area includes all of the conditions that can result in an erythematous, scaly eruption. This includes psoriasis, tinea, perianal streptococcal dermatitis and pinworm infestation. Treated lichen sclerosus may appear erythematous rather than white [6]. Where examination reveals little more than a scaly, erythematous, poorly defined rash, dermatitis is the most likely diagnosis, even if signs are subtle. When the rash is erythematous but well defined, and particularly when there is perianal involvement, it is important to look for signs of psoriasis and enquire about a family history [7]. Investigations. If weeping or pustules are present, a bacteriological swab from the affected area should be performed. If there appears to be a vaginal discharge, a swab from the introitus with a moistened cotton tip can be performed, but prepubertal children tolerate vaginal swabs poorly, and they are in general not indicated. If there is suspicion of a fungal infection, a fungal scraping should be performed. Urine culture is not required unless dysuria is present. Patch testing is rarely required.

Fig. 151.1 Atopic dermatitis of the labia majora.

Genital Disease in Children

Prognosis. The prognosis of genital dermatitis is excellent, particularly when simple irritancy from an identifiable source is present, which can be easily reversed. Even when there is an underlying tendency to atopic dermatitis, the condition can easily be controlled. Remissions and exacerbations are the rule, depending on irritant exposure, but most parents rapidly learn to deal with these situations. Management. Many cases of genital itching are due to dermatitis, either atopic or the result of irritation from clothing or applied substances. Often, a much greater emotional overlay is attached to any condition of the genital area than to conditions in other parts of the skin. As a result, the degree of distress experienced by the parents and sometimes the child may be out of proportion to the actual problem. There is still a tendency for vulval disease to be poorly understood, and it is not uncommon for patients to visit many doctors without receiving what they consider a satisfactory explanation and effective treatment. As a result, parents are often angry and frustrated. This can make history taking difficult and leave the doctor wondering why the emotional reaction is so intense when there is so little to see. The first step in treating genital dermatitis involves giving parents detailed environmental advice specific to the genital area. It is preferable to bathe rather than shower. No soap or bubble bath should be used; bath oil should be used in the bath and, if the child does shower, a soap substitute should be used and the parent needs to explain that the labia have to be parted and rinsed, and in boys over the age of 3 years, the foreskin retracted. This should be supervised. Shampoo should be rinsed out after the child gets out of the bath, or soap substitute used instead of shampoo. If the child does any form of physical activity that involves wearing tight Lycra clothing, if possible this should be modified so that, at least during practice sessions, loose cotton clothes are worn. This, of course, is not possible for performances and competitions, but explain to the parents that some compromises have to be made. Even nylon tights worn as part of a school uniform may have to be discarded and parents may require a letter to take to the school. If the child is going to swimming lessons, the chlorinated water can be a powerful irritant. Applying Vaseline® (petroleum jelly) or zinc cream before swimming is helpful, and the parents should be advised to always remove the costume straight after swimming and that the child should shower before going home. If the child has an incontinence problem, either enuresis or constipation with overflow, this needs to be dealt with. Night nappies should be discarded if possible.

151.3

Always actively ask about this; it is embarrassing, is not always volunteered, and parents do not always make a connection between incontinence and the genital irritation. Enquiry should be made concerning over-the-counter topical applications as these may not be volunteered, the parent seeing them only as unsuccessful treatment and not a potential problem. Ask about perfumed products, such as toilet paper and wet wipes, as well. The use of such products should be stopped. In terms of ideal clothing, loose cotton underwear is desirable, and underpants, particularly nylon ones, should be avoided at night. Most cases of vulval dermatitis will respond to 1% hydrocortisone topically, as long as the environmental changes are also made. Ointment is preferable to creams, which may cause stinging. If the dermatitis is severe, a stronger, non-fluorinated topical steroid such as methylprednisolone aceponate 0.1% or desonide 0.05% can be used initially and be continued until the dermatitis has settled. It should be possible to reduce to 1% hydrocortisone when the rash has settled. If this is not possible, consider an alternative diagnosis. The child should be treated for possible pinworm infestation. Many parents are very apprehensive about using topical steroids on their children, and even more so on the vulva where they are concerned that the preparations will ‘thin the skin’. In practice, the above treatment is very safe and it is wise to pre-empt any objections with strong reassurance. If skin swabs show infection, which will usually be with Staph. aureus, a course of appropriate antibiotics should be given. A finding of β-haemolytic streptococcus group A requires a 10-day course of appropriate antibiotics. Much stronger reassurance is often required when skin disease affects the genital area than when it is found on other skin areas, and it is important to enquire about fears of sexually transmitted disease and child abuse. It is best to be matter of fact and help the parents to understand that the genital area is simply part of the skin and their child’s pattern is to have involvement in this area. Make them aware that children rapidly pick up their anxieties, and that an intelligent child may capitalize on this with attention-seeking or school-avoiding behaviour.

Psoriasis of the genital area Incidence. The incidence and natural history of psoriasis in childhood are unknown. However, presentation of psoriasis in children and adults differs in type and pattern [8]. Also, few data exist on psoriasis of the genital area. It

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is an accepted fact that psoriasis may be confined to this part of the skin, with little evidence of the disease elsewhere. If children with genital disease are taken as a group, psoriasis is a relatively common cause, representing about 10% of children presenting with vulval disease, and it should always be considered in the differential diagnosis of persistent genital rashes in both sexes [1,2,9]. A study in 2001 [8] indicated that the genital area was involved in 8.9% of children with childhood psoriasis. In children of less than 2 years of age, the most common type of psoriasis is nappy rash with dissemination [8]. Clinical presentation. In babies, psoriasis may present for the first time as a persistent nappy rash. The features at this age include a well-demarcated edge and involvement of the inguinal folds, but the typical scale of psoriasis is lacking under the nappy. The rash may remain confined to the nappy area or may disseminate with typical psoriatic lesions on the trunk, limbs and scalp [1,2,4,10]. In older children, the morphology of the rash is much the same, with an itchy, red, well-demarcated, symmetrical plaque. Again, there is no scale. The vulva, penis, perineum, perianal area and often natal cleft may all be involved (Fig. 151.2). The rash may not be markedly symptomatic but parents may complain that the area is persistently erythematous [7,11]. If psoriasis is confined to the genital area, it is difficult to make a definite diagnosis unless other diagnostic clues are present. A history of cradle cap or difficult nappy rashes as a baby, nail pitting, postauricular or scalp rashes and a family history are all helpful [12]. Investigations. If weeping or inflammation is present, a skin swab for bacteriology is indicated. Like psoriasis on other areas of the skin, infection of the genital area with group A streptococcus will worsen the disease and create

Fig. 151.2 Psoriasis of the penis.

treatment resistance. Other investigations are not necessary. Prognosis. Data are lacking on the outcome of childhood psoriasis. It is not known whether psoriatic nappy rash is a precursor to childhood or adult psoriasis, and the natural history of genital psoriasis in children is also not known [8]. Differential diagnosis. This includes dermatitis, erythematous lichen sclerosus and streptococcal perianal dermatitis. Management. Psoriasis tends to be more difficult to treat than dermatitis. Even psoriatic nappy rash may not respond to 1% hydrocortisone. Although some cases do respond to the weaker corticosteroids that are usually recommended for the genital area, it is not uncommon for stronger corticosteroids to be required to achieve relief of itching [13]. Topical pimecrolimas may be effective [14] but stinging is a significant side-effect in the genital area and initial control with topical corticosteroid is often required before other therapies can be initiated. Low-concentration tar-containing preparations, such as 2% liquor carbonis detergens in an emollient base, are useful on the genital area, particularly for maintenance treatment. For thickened plaques, it is possible to use low-concentration dithranol with good effect. General skin care measures specific for the genital area (as outlined in Dermatitis, above) are also an adjunct to therapy. References 1 Fischer GO. Vulval disease in pre-pubertal girls. Australas J Dermatol 2001;42:225–34. 2 Fischer GO, Rogers M. Vulvar disease in children. A clinical audit of 130 cases. Pediatr Dermatol 2000;17:1–6. 3 Paek SC, Merritt DF, Mallory SB. Pruritus vulvae in prepubertal children. J Am Acad Dermatol 2001;44:795–802. 4 Fischer G, Rogers M. Paediatric vulvovaginitis. In: Proceedings of the 3rd Symposium on Diseases of the Vulva and Vagina. Melbourne: Melbourne University, 1997: 26–9. 5 Warshaw EM, Furda LM, Maibach HI. Anogenital dermatitis in patients referred for patch testing:retrospective analysis of crosssectional data from the North American Contact Dermatitis Group. Arch Dermatol 2008;144(6):749–55. 6 Ridley CM. Genital lichen sclerosus (lichen sclerosus et atrophicus) in childhood and adolescence. J Roy Soc Med 1993;86:69–75. 7 Siegfried EC, Frasier LD. Anogenital skin disease in the pediatric population. Pediatr Ann 1997;26:321–31. 8 Morris A, Rogers M, Fischer G et al. Childhood psoriasis. A clinical review of 1262 cases. Pediatr Dermatol 2001;18:188–98. 9 Fischer G. Chronic vulvitis in pre-pubertal girls. Australas J Dermatol 2010;51:118–23. 10 Fischer GO. The commonest causes of symptomatic vulval disease: a dermatologist’s perspective. Australas J Dermatol 1996;36:166–7. 11 Farber EM, Nall L. Genital psoriasis. Cutis 1992;50:263–6. 12 Ridley CM. Vulvar disease in the paediatric population. Semin Dermatol 1996;15:29–35.

Genital Disease in Children 13 Paek SC, Merritt DF, Mallory SB. Pruritus vulvae in prepubertal children. J Am Acad Dermatol 2001;44:795–802. 14 Amichai B. Psoriasis sof the glans penis in a child successfully treated with Elidel (pimecrolimus) cream. J Eur Acad Dermatol Venereol 2004;18(6):742–3.

Birthmarks in the genital area Special considerations in the genital area Birthmarks may occur on the genital area as on any other part of the skin, but the importance of lesions in this location is that they may be mistaken for more sinister conditions. For example, pigmented naevi often raise queries of melanoma, where they might be ignored elsewhere, and epidermal naevi may be mistaken for warts or recalcitrant eczema. Any ulcerating lesion may cause queries of sexual abuse [1]. Haemangiomas and vascular malformations [2–11] are dealt with elsewhere in detail (see Chapters 112 and 113).

Melanocytic naevi Pigmented naevi may occur on the genital and perianal area; they may be congenital lesions or appear at any stage of childhood (Fig. 151.3). The congenital lesions tend to be larger than late-onset ones. Pigmented naevi of the genital region rarely present a problem but they do frequently raise fears of melanoma [4]. Despite this, melanoma in children is rare, and there have been very few reports of childhood genital melanoma [12]. There is no documented evidence that pigmented naevi of the genital area have a particular malignant potential [13]. Pigmented naevi with the histopathology of ‘atypical naevi’ occur on the genital skin but

151.5

a recent study confirms that they have a benign clinical course and cautions against overdiagnosis of melanoma [14].

Bannayan–Riley–Ruvalcaba syndrome (Ruvalcaba–Myhre–Smith syndrome) OMIM 153480 The PTEN hamartoma-tumour syndromes include at least two clinically different but overlapping cancer predisposition syndromes: Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome, both with autosomal dominant inheritance resulting from germline mutations in the PTEN tumour suppressor gene on chromosome 10q23.3 [15,16]. Bannayan–Riley–Ruvalcaba syndrome was first described in 1980 by Ruvalcaba et al. [17], as a classic triad of polyposis coli, pigmented macules of the penis and macrocephaly. The polyps, which may not appear until adult life, may occur throughout the gastrointestinal tract and have been reported on the tongue. They present with painless rectal bleeding and, sometimes, intussusception. Other features described with the syndrome include developmental delay, hypotonia, myopathy, ocular abnormalities, café-au-lait macules, lipomas, haemangiomas and vascular malformations, facial verrucous or acanthosis nigricans-like lesions and multiple skin tags of the neck, axilla and groin [18]. Musculoskeletal changes and neuropathy have been reported [19]. The pigmented macules appear during childhood or adolescence and then persist and present as a speckled lentiginosis of the penis or vulva [20]. The syndrome can be differentiated from Peutz–Jeghers syndrome by the presence in the latter of pigmented macules of the lips and buccal mucosa.

Epidermal naevi

Fig. 151.3 Melanocytic naevus of the clitoris.

Epidermal naevi are uncommon and about 50% are not present at birth although most develop within the first year of life, seldom appearing after the age of 7. They may continue to extend for up to 5 years after they first appear [21]. They usually have a warty surface and are usually arranged in whorls or streaks. Both verrucous and inflammatory epidermal naevi may involve the genital area. They may be localized or part of a larger lesion that extends to the leg and buttock. Verrucous epidermal naevi have a warty, hyperkeratotic surface (Fig. 151.4). They are usually pigmented, but when they extend onto the macerated skin of the perineum or labia minora, they may have a white appearance. They may be papillomatous in some areas (Fig. 151.5). Inflammatory epidermal naevi (ILVEN) are linear and have a scaly, erythematous surface. They are quite itchy and are therefore commonly mistaken for recalcitrant

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Fig. 151.6 Venous malformation of the vulva.

Fig. 151.4 Warty linear epidermal naevus.

queries of child abuse. If they are itchy they can be mistaken for treatment-resistant lichenified eczema or napkin dermatitis [4,38]. Naevus comedonicus has been reported on the vulva [23]. Management. Itchy genital epidermal naevi may be very resistant to topical therapy [22] and it is not uncommon for epidermal naevi of the genital region to cause enough trouble to require at least partial excision. For example, a warty perianal lesion is best removed, and sometimes recalcitrant itching is relieved only by surgically excising the lesion. However, if they are not causing problems, it is best just to reassure the patient and leave the lesions alone. There is no significant malignant potential.

Vascular naevi

Fig. 151.5 Papillomatous epidermal naevus.

eczema. ILVEN have been rarely described involving the inguinogenital region [21,22]. Because epidermal naevi have a tendency to extend with time, they may be confused with an inflammatory dermatosis. If they become large, they can interfere with function, particularly in the perianal area. Epidermal naevi can be mistaken for warts, in turn giving rise to

Haemangioma of the genital area is common in both sexes and is discussed elsewhere. Many genital vascular lesions have been described in children including venous, lymphatic and mixed venolymphatic lesions (Figs 151.6–151.8). Lymphangioma of the scrotum has been described [24,25]. Both these cases presented with a scrotal mass and were associated with other genital anomalies. Lymphangioma has also been described as a penile lesion [26] and a single case of verrucous haemangioma of the glans penis has been described [27]. In a large series of female patients with vascular anomalies, 2.6% were found to have lesions of the external genitalia. These presented with cutaneous macular stains, swelling, deformity, bleeding, fluid leakage and infection [28]. Vascular lesions may increase in size at puberty [29]. Patients with Klippel–Trenaunay syndrome, characterized by vascular malformation of capillary, venous and lymphatic systems associated with soft tissue and bone

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151.7

Papular acantholytic dyskeratosis of the vulva Papular acantholytic dyskeratosis of the vulva is a rare condition that presents with a papular eruption of the vulva [33]. The lesions are scattered, skin-coloured to white slightly keratotic papules associated with multiple grouped superficial erosions. The lesions are found on the labia majora.

Fig. 151.7 Lymphatic malformation of the vulva with associated linear epidermal naevus.

Clinical features. The condition presents in childhood with white papules and erosions found bilaterally on the labia majora. There may be associated pruritus but it has also been described as asymptomatic [34]. Both the pruritus and clinical appearance may regress with time [35]. Most previous case reports have been in adults but the condition has recently been described in a child [35]. The condition does not appear to be familial. Histology. Histopathology is distinctive with hyperkeratosis, acantholysis, dyskeratotic cells resembling corps ronds and irregular proliferation of basaloid cells. Immunofluorescence is negative [35,36]. Differential diagnosis. This condition, although rare, is important as it may be confused with multiple flat genital warts or with papular lichen sclerosus. Histologically, it needs to be differentiated from Hailey–Hailey disease, Darier disease and warty dyskeratoma. Epidermal naevi, including those found on the vulva, may show acantholysis but are usually unilateral [37].

Fig. 151.8 Lymphangioma of the vulva.

hypertrophy, frequently have genitourinary involvement, including cutaneous and anatomical genital abnormalities, the overall incidence being reported to be 30%. Bleeding from genital lesions, as well as haematuria, may occur in these patients and approximately half of them eventually require surgical intervention for genitourinary complications [30,31]. Management. Genital vascular lesions usually require magnetic resonance imaging, ultrasound, angiography and gynaecological exploration for full diagnostic clarification. They can present a very difficult therapeutic challenge and are frequently devastating for the patient and her family. Excision of these lesions may be very difficult. Treatment with direct injection venography using ethanol sclerotherapy has been described as a successful treatment for vulval venous malformation [32].

Management. This condition runs a chronic course. Treatment described so far has been disappointing. No specific treatment has been described in children and reassurance that this is a benign condition may be all that is required. References 1 Hosteller BR, Jones CE, Miram D. Capillary hemangioma of the vulva mistaken for sexual abuse. Adolesc Pediatr Gynaecol 1994;7:44–6. 2 Bouchard S, Yazbeck S, Lallier M. Perineal hemangioma, anorectal malformation, and genital anomaly: a new association? J Plastic Surg 1999;34:1133–5. 3 Goldberg NS, Hebert AA, Esterly NB. Sacral hemangiomas and multiple congenital abnormalities. Arch Dermatol 1986;122:684–7. 4 Fischer GO. Vulval disease in pre-pubertal girls. Australas J Dermatol 2001;42:225–34. 5 Morelli JG, Tan OT, Yohn J et al. Treatment of ulcerated haemangiomas in infancy. Arch Pediatr Adolesc Med 1994;148:1104–5. 6 Alter GJ, Trengove-Jones G, Horton C. Haemangioma of the penis and scrotum. Urology 1993;42:205–8. 7 Young AE, Senapati A. Intra-abdominal and pelvic vascular malformations. In: Mulliken JB, Young AE (eds) Vascular Birthmarks. Philadelphia: W.B. Saunders, 1988: 396. 8 Rodrigues D, Bourroul ML, Ferrer AP et al. Blue rubber bleb naevus syndrome. Rev Hosp Clin Fac Med Univ Sao Paulo 2000;55:29–34.

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9 Khoudary KP, Nasrallah PF, Gordon DA. Glomus tumor of the penis. J Urol 1996;155:707. 10 Ramos LM, Payon EM, Barrilero AE. Venous malformation of the glans penis: efficacy of treatment with neodymium:yttriumaluminum-garnet laser. Urology 1999;53:779–83. 11 Norouzi BB, Shanberg AM. Laser treatment of large cavernous haemangiomas of the penis. J Urol 1998;160:60–2. 12 Egan CA, Bradley RR, Logsdon V et al. Vulvar melanoma in childhood. Arch Dermatol 1997;133:345–8. 13 Christensen WN, Friedman KJ, Woodruff JD et al. Histologic characteristics of vulvar nevocellular nevi. J Cutan Pathol 1987;14:87–91. 14 Gleason BC, Hirsch MS, Nucci MR et al. Atypical genital naevi. A clinicopathologic analysis of 56 cases. Am J Surg Pathol 2008;32(1):51–7. 15 Lachlan KL, Lucassen A, Bunyan D, Temple IK. Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 2007;44(9):579–85. 16 Boccone L, Dessi V, Zappu A et al. Bannayan–Riley–Ruvalcab syndrome with reactive nodular lymphoid hyperplasia and autism and a PTEN mutation. Am J Med Genet 2006;140(18):1965–9. 17 Ruvalcaba RHA, Myhre S, Smith DW. Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clin Genet 1980;8:413–16. 18 Bishop PR, Nowicki MJ, Parker PH. What syndrome is this? Pediatr Dermatol 2000;17:319–21. 19 Erkek E, Hizel S, Sanly C et al. Clinical and histopathological findings in Bannayan–Riley–Ruvalcaba syndrome. J Am Acad Dermatol 2005;53(4):639–43. 20 Blum RR, Rahimizadeh A, Kardon L et al. Genital lentigines in a 6-year-old boy with Cowden’s disease. Clinical and genetic evidence of the genetic linkage between Bannayan–Riley–Ruvalcaba syndrome and Cowden’s disease. J Cutan Med Surg 2001;5:228–30. 21 Rogers M, McCrossin I, Commens C. Epidermal Naevi and the epidermal naevus syndrome: a review of 131 cases. J Am Acad Dermatol 1989;20:476–88. 22 Le K Wong L, Fischer G. Vulval and perianal inflammatory linear verrucous epidermal naevus. Australas J Dermatol 2009;50:115–17. 23 Gonzalez-Martinez R, Marin-Bertolin S, Martinez-Escribano J et al. Nevus comedonicus. Report of a case with genital involvement. Cutis 1996;58:418–19. 24 Joshi AV, Gupta R, Parelkar S, Gupta A, Jadhav V. An unusual congenital scrotal lymphatic malformation with absent corpora cavernosa: a case report. J Pediatr Surg 2008;43(9):1729–31. 25 Vikicevic J, Milobratovic D, Vukadinovic V, Golubovic Z, Krstic Z. Lymphangioma scroti. Pediatr Dermatol 2007;24(6):654–6. 26 Shah A, Meacock L, More B, Chandran H. Lymphangioma of the penis: a rare anomaly. Pediatr Surg Int 2005;21(4):329–30. 27 Akyol I, Jayanthi V, Luquette M. Verrucous hemangioma of the glans penis. Urology 2008;72(1):230. 28 Vogel AM, Alesbury J, Burrows PE, Fishman SJ. Vascular anomalies of the female external genitalia. J Pediatr Surg 2006;41(5):993–9. 29 Kemoinarie A, de Raeve L, Roseeuw D, Boon L, de Raeve H. Capillary–venous maformation in the labia majora in a 12-year-old girl. Dermatology 1997;194(4):405–7. 30 Husmann DA, Rathburn S, Driscoll DJ. Klippel–Trenaunay syndrome: incidence and treatment of genitourinary sequelae. J Urol 2007;177(4):1244–9. 31 Vicentini FC, Denes F, Gomes CM, Danilovic A, Silv FA, Srougi M. Urogenital involvement in the Klippel–Trenaunay Weber syndrome. Treatment options and results. Int Braz J Urol 2006;32(6):697–703. 32 Herman AR, Morello F, Strickland JL. Vulvar venous malformations in an 11-year-old girl: a case report. J Pediatr Adolesc Gynecol 2004;17(3):179–81.

33 Chorzelsky TP, Kudejko J, Jablonska S. Is papular acantholytic dyskeratosis of the vulva a new entity? Am J Dermatopathol 1984;6:557–9. 34 Bell HK, Farrar C, Curley RK. Papular acantholytic dyskeratosis of the vulva. Clin Exp Dermatol 2001;26:386–8. 35 Saenz AM, Cirocco A, Avendano M, Gonzalez F, Sardi JR. Papular Acantholytic dyskeratosis of the vulva. Pediatr Dermatol 2005;22(3):237–239. 36 Cooper P. Acantholytic dermatosis localized to the vulvocrural area. J Cutan Pathol 1989;16:81–4. 37 Cottoni F, Masala M, Cossu S. Acantholytic dyskeratotic epidermal naevus localized unilaterally in the cutaneous and genital areas. Br J Dermatol 1998;138:875–8. 38 Le K, Wong L-C, Fischer G. Vulval and perianal inflammatory linear verrucous epidermal naevus. Australas J Dermatol 2009;50:115–7.

Non-sexually acquired genital infections in children Streptococcal cellulitis, vulvovaginitis and balanitis Pathogenesis. Group A β-haemolytic streptococcus is the most common cause of acute vulvovaginitis and balanitis in prepubertal children [1]. Interestingly, adults are rarely prone to this, although very occasionally a group B streptococcus may cause a true vaginitis in an adult and perianal dermatitis and balanitis caused by group A βhaemolytic streptococcus has been described in adults [2]. Perianal streptococcal dermatitis (also known as cellulitis) is a common cause of chronic and acute-on-chronic perianal rashes in children, more commonly in boys. Presentation is with persistent perianal erythema, swelling, scale and fissuring. It is not a true cellulitis. Symptoms include itch and pain. The rash is a non-infiltrated plaque that may extend several centimetres from the anal verge. Weeping from the surface may produce a persistent discharge, and pain on defaecation may result in chronic constipation which may in turn result in bleeding on defaecation [3]. In girls with vulvovaginitis, presentation is with sudden onset of an erythematous, swollen, painful vulva and vagina, with a thin mucoid discharge. In boys with balanitis, there is acute erythema of the glans (Fig. 151.9). There may have been a preceding throat infection with the same organism or preceding perianal dermatitis. Sometimes the infection can be low grade, similar to the perianal disease, presenting as a subacute vulvitis [4]. Recurrent disease has been reported as a result of chronic pharyngeal carriage [5]. This infection does not tend to self-resolve and symptoms tend to be persistent until a diagnosis is made and appropriate treatment initiated [6]. In general, patients with this condition are systemically well; however, fever and scarlatiniform rash, followed by

Genital Disease in Children

151.9

Fig. 151.10 Staphylococcal folliculitis.

Fig. 151.9 Streptococcal balanitis.

acral desquamation in association with perianal disease, have been reported. In this case, a streptococcal pyrogenic exotoxin was assumed to be produced by the infective organism [7]. Guttate psoriasis may be precipitated by this infection [8]. The infection is easily diagnosed by introital and perianal swabs. It is not necessary to insert the swab right into the vagina, which children usually find traumatic, particularly when the area is tender. Differential diagnosis. Although a differential diagnosis of acute candidiasis would be reasonable in an adult, this is not the case in children. Psoriasis and dermatitis are also in the differential diagnosis, particularly when the vulvitis is subacute. Recurrent streptococcal infections should raise the possibility of an intravaginal foreign body [1]. Shigella species may also cause recurrent and chronic vulvovaginitis in association with diarrhoea. There is often a blood-stained vaginal discharge that may suggest a foreign body [9]. Yersinia vaginitis in conjunction with gastroenteritis has been reported [10]. Also in the differential diagnosis, but much rarer as a cause of acute vulvitis, is the fixed drug eruption. Erythema multiforme may also affect the vulva but is usually part of a generalized reaction in children. Management. Any case of acute vulvitis or balanitis and any persistent perianal rash in a child should suggest this condition; swabs should be taken and the child commenced on either oral penicillin or amoxicillin, or cephalothin if they are allergic to penicillin. The course must run for a full 10 days or recurrence may occur. Concurrent use of topical mupirocin will help to prevent recurrence. Apparent poor response to therapy, with ongoing symptoms despite resolution of infection, usually indi-

cates an underlying condition such as dermatitis, psoriasis or vaginal foreign body [1,4]. A case report has recently drawn attention to recurrent disease as a result of chronic asymptomatic pharyngeal colonization which cleared with rifampicin and amoxicillin [5].

Recurrent toxin-mediated perineal erythema (scarlatina-like) This condition, which was originally described in young men, presents with recurrent, asymptomatic erythema and desquamation of the perineum and groin area following acute pharyngitis. The eruption may be associated with swelling, erythema and desquamation of the hands and feet, or a ‘strawberry tongue’. Toxin-producing Staph. aureus or toxin-producing group A β-haemolytic streptococcus is responsible for the eruption [11]. This phenomenon is assumed to be a superantigenrelated disorder [12]. A recent series reports 11 cases of this condition in children, seven boys and four girls presenting with acute onset of perineal erythema. In this series, four patients also had erythema of the hands and feet and seven had a strawberry tongue. Only three of these cases had recurrent disease. In all cases there was evidence of group A β-haemolytic streptococcus infection although this was not recovered from perineal culture and all were treated with oral antibiotics. All of the children were well and laboratory investigations normal [13]. In young children, this condition must be differentiated from Kawasaki syndrome.

Staphylococcal folliculitis and impetigo Staphylococcal folliculitis is common on the buttocks of children, particularly those with eczema and those who are still in night nappies. It may sometimes spread to the vulva or groin or can be found there primarily (Fig. 151.10). Impetigo may also sometimes occur on the genital and perianal area.

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The presentation is with pustules and crusted lesions, which are often more itchy and irritating rather than painful. The diagnosis is made with a bacterial swab. Management. Although impetigo usually responds quickly to a course of appropriate anti-staphylococcal antibiotics, folliculitis often represents a carrier state and can be very persistent. It is often better treated with topical agents, such as bath products containing chlorhexidine or triclosan and mupirocin 2% cream. Underwear and other garments in direct contact with genital skin, such as swimming costumes and pyjamas, sheets and towels, should be hot-washed, and every attempt made to discard night nappies. If there is underlying eczema, this should be treated.

viral types [16]. The virus codes for a number of proteins that enable it to evade the immune system by blocking immune recognition and clearance [17]. These viral lesions are very common in children. The virus is spread by close physical contact, fomites and autoinoculation. Transmission in water is well recognized, and this explains the predilection for the lower body where the child sits in the bath [18]. As a result, it is not uncommon for mollusca to be found on the genital area, often as part of a more generalized eruption [14] (Fig. 151.12). Sometimes vulval mollusca can be difficult to differentiate from condylomata acuminata, and close examination with a magnifier will be needed to see the typical central core. If there is doubt, the core may be examined as a

Staphylococcal scalded skin syndrome This is an exfoliative skin condition preceded by an often minor staphylococcal infection that produces an exfoliative toxin. The child presents with fever, irritability and usually a widespread erythematous eruption, with flexural accentuation. As the illness progresses, shallow blisters evolve to raw, eroded areas, particularly in the perioral, axillary and genital areas. The eruption may begin in the genital area with a tender, erythematous eruption with superficial blistering.

Pinworm (Enterobius vermicularis) Although many children with pinworm infestation are asymptomatic, symptoms are those of perianal and vulval itching, particularly at night, when the worms migrate onto the skin to lay eggs. An eczematous rash may occur, but the skin may be normal. Vaginal discharge and irritation may also occur. Pinworm is very well known as a cause of genital itching in children, and many children will already have been treated by their parents or their pharmacist before they see a doctor [14]. Diagnosis may be made by pressing the sticky side of clear tape to the perianal area first thing in the morning and then examining the tape under a microscope for the presence of ova. Treatment requires oral mebendazole 100 mg or pyrantel pamoate 11 mg/kg up to 1 g. A further treatment in 2 weeks is recommended to kill worms that have hatched since the first treatment [15].

Fig. 151.11 Scabies nodules of the scrotum. Courtesy of Dr M. Rogers.

Scabies Scabetic nodules are common on the genital area, but are usually part of a generalized eruption. The irritable nodules occur on the vulva in girls and on the glans and scrotum in boys (Fig. 151.11).

Molluscum contagiosum Molluscum contagiosum is a large double-stranded DNA poxvirus. DNA analysis has demonstrated four major

Fig. 151.12 Molluscum contagiosum of the vulva.

Genital Disease in Children

smear stained for haematoxylin-eosin and recently a PCR technique has been described which can also genotype the virus [19]. It is important to be clear on this, as mollusca are generally not considered to be sexually transmitted in children, unlike condylomata acuminata. Sexual transmission of molluscum contagiosum is uncommon but possible [20,21]. Furthermore, studies have shown that the genotype found in children differs from that found in adults with sexually transmitted genital mollusca [22] and genital mollusca are rarely found in isolation without evidence of a more widespread infection of other parts of the skin. The appearance of these lesions can sometimes be very non-specific, as a dermal papule without an obvious core, or as a large solitary skin tag. Extensive, atypical lesions may be found in children with HIV disease and other forms of immunocompromise [23]. However, the majority even with extensive lesions are immunologically normal [24]. Giant genital mollusca are described in children [25]. In most cases, it is not necessary to treat genital mollusca. Methods that are used to extract the viral core from the centre, which may be tolerated on less sensitive parts of the skin, may prove to be very difficult. Avoidance of baths and swimming pools appears to reduce autoinoculation and topical corticosteroids reduce pruritus if present. Pimecrolimus and tacrolimus should be avoided as they have been reported to spread the lesions [26]. Spontaneous resolution invariably occurs. No study specifically examining the use of topical therapy for genital mollusca in children has been published to date.

Varicella Varicella frequently involves the genital area, and vesicles may occur on the mucosal surface, resulting in a blood-stained vaginal or penile discharge. The lesions may be localized to the area under the nappy, particularly when there is a nappy dermatitis or other dermatosis in this area, with little sign of blistering elsewhere (Fig. 151.13). Herpes zoster may also involve the genital area as a unilateral eruption.

151.11

Fig. 151.13 Varicella localized to the area under the nappy. Courtesy of Dr M. Rogers.

the nappy in a baby presents as a dermatitic rash that does not respond to treatment. The diagnosis requires a high index of suspicion but once thought of is easily confirmed by a skin scraping. Candidiasis, on the other hand, does not occur in children out of nappies. In adult women with chronic vulval symptoms, about 15% have candidiasis, but this oestrogen-dependent condition is not seen after infancy in children with normal immune systems [27,28]. This is an important point, as it is common for children with skin diseases such as dermatitis and psoriasis to be diagnosed as having ‘thrush’ and treated with antifungal creams, which may cause irritation, particularly if dermatitis is present [29].

Tuberculosis

Fungal infections

Tuberculosis of the penis and vulva, described as a genital tuberculid, has been reported in adults. However, a recent case report documents a case of lichen scrofulosorum of the vulva in an 11-year-old girl [30].

Tinea is a common cause of groin rashes in men and sometimes causes vulval rashes in women, but is rarely found on the genital area in children. When it does occur, it hardly ever has typical features, and this is often the result of treatment with topical corticosteroids. It is possible that it is more common than one would think, as so many cases of genital eruptions are assumed to be candidiasis and treated with imidazole creams. This would, in most childhood cases, fortuitously treat tinea. In cases when no antifungal has been used and the rash is treated as dermatitis, tinea of the vulva, groin or under

References 1 Fischer GO, Rogers M. Vulvar disease in children: a clinical audit of 130 cases. Pediatr Dermatol 2000;17:1–6. 2 Neri I, Bardazzi F, Marzaduri I et al. Perianal streptococcal dermatitis in adults. Br J Dermatol 1996;135:796–8. 3 Krol AL. Perianal streptococcal dermatitis. Pediatr Dermatol 1990;7:97–100. 4 Dar V, Raker K, Adhmi Z et al. Streptococcal vulvovaginitis in girls. Pediatr Dermatol 1993;10:366–7. 5 Hansen MT, Sanchez V, Eyster K, Hansen KA. Streptococcus pyognenes pharymgel colonization resultig in recurent prepubertal vulvovaginitis. J Pediatr Adolesc Gynecol 2007;20(5):315–17.

151.12

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6 Mogielnicki NP, Schwartzman J, Elliott JA. Perineal group A streptococcal disease in a pediatric practice. Pediatrics 2000;106(2):276– 81. 7 Velez A, Moreno JC. Febrile perianal streptococcal dermatitis. Pediatr Dermatol 1999;16:23–4. 8 Herbst RA, Hoch O, Kapp A. Guttate psoriasis triggered by perianal streptococcal dermatitis in a 4 year old boy. J Am Acad Dermatol 2000;42:885–7. 9 Gryngarten MG, Turco ML, Escobar ME et al. Shigella vulvovaginitis in prepubertal girls. Adolesc Pediatr Gynecol 1994;7:86–9. 10 Watkins S, Quan L. Vulvovaginitis caused by Yersinia enterocolitica. Pediatr Infect Dis 1984;3:444–5. 11 Manders SM. Toxin-mediated streptococcal and staphylococcal disease [review]. J Am Acad Dermatol 1998;39:383–98. 12 Manders SM, Heymann WR, Atillasoy E et al. Recurrent toxinmediated perineal erythema. Arch Dermatol 1996;132:57–60. 13 Patrizi A, Raone B, Savoia F, Ricci G, Neri I. Recurrent toxin-mediated perineal erythema: eleven pediatric cases. Arch Dermatol 2008;144(2):239–43. 14 Williams TS, Callen JP, Lafayette GO. Vulvar disorders in the prepubertal female. Pediatr Ann 1986;15:588–605. 15 St Georgiev V. Chemotherapy enterobiasis (oxyuriasis). Expert Opin Pharmacother 2001;2:267–75. 16 Brown J, Janniger C, Schwartz RZ, Silverberg N. Childhood molluscum contagiosum. Int J Dermatol 2006;45:93. 17 Agromayer M, Ortiz P, Lopez-Estebaranz JL, Gonzalez Nicolas J, Esteban M, Martin-Gallardo A. Molecular epidemiology of molluscum contagiosum virus and analysis of the host–serum antibody response in Spanish HIV-negative patients. J Med Virol 2002; 66:151. 18 Braue A, Ross G, Varigos G, Kelly H. Epidemiology and impact of molluscum contagiosum. Pediatr Dermatol 2005;22:287. 19 Trama JP, Adelson M, Mordechai E. Idenfification and genotyping of molluscum contagiosum virus from genital swab samples by realtime PCR and pyrosequencing. J Clin Virol 2007;40:325. 20 Porter CD, Blake NW, Archard LC et al. Molluscum contagiosum virus types in genital and non-genital lesions. Br J Dermatol 1989;120:37–41. 21 Bargman H. Is genital molluscum contagiosum a cutaneous manifestation of sexual abuse in children? J Am Acad Dermatol 1986;14:847–9. 22 Porter CD, Blake N, Archard L et al. Molluscum contagiosum virus types in genital and non-genital lesions. Br J Dermatol 1989;120:37. 23 Gur I. The epidemiology of molluscum contagiosum in HIVseropositive patients: a unique entity or insignificant finding? Int J STD AIDS 2008;19:503. 24 Dohil M, Lin P, Lee J, Lucky AW, Paller AS, Eichenfield LF. The epidemiology of molluscum contagiosum in children. J Am Acad Dermatol 2006;54:47. 25 Kim SK, Do J, Kang HY, Lee ES, Kim YC. Giant molluscum contagiosum of immunocompetent children occurring on the genital area. Eur J Dermatol 2007;17:537. 26 Goksugar N, Ozbostanci B, Goksugar SB. Molluscum contagiosum infection associated with pimecrolimus use in pityriasis alba. Pediatr Dermatol 2007;23:574. 27 Vandeven AM, Emans SJ. Vulvovaginitis in the child and adolescent. Pediatr Rev 1993;14:141–7. 28 Farrington PF. Pediatric vulvovaginitis. Clin Obstet Gynecol 1997;40:135–40. 29 Fischer G. Chronic vulvitis in pre-pubertal girls. Australas J Dermatol 2010;50:118–23. 30 Pandhi D, Mehta S, Singal A. Genital tuberculid in a female child: a new entity (childhood vulval tuberculid). Pediatr Dermatol 2007;24(5):573–5.

Blisters and ulcers Blistering and ulcerative conditions of the genital area are unusual at any age, and are probably no rarer in children than in adults. Infection with Staphylococcus aureus and herpes simplex should be kept in the differential diagnosis.

Immunobullous disease – vulval bullous and cicatricial pemphigoid Although bullous pemphigoid is very rare in children, when it does occur it may be localized to the vulva and penis [1,2]. The child presents with a history of painful and itchy blistering. The blistering lesions, which rapidly erode, occur around the labia minora and majora, glans penis and perianal area [3,4] (Fig. 151.14). Localized vulval bullous pemphigoid may be a distinct subtype of childhood bullous pemphigoid. It is a self-limited nonscarring disease with a good prognosis. It responds well to topical corticosteroids [2]. This condition is frequently misdiagnosed as herpes simplex, lichen sclerosus or sexual abuse [5]. The biopsy appearance is typical of bullous pemphigoid at any site, with linear C3 and immunoglobulin G (IgG) [4]. Cicatricial pemphigoid or benign mucous membrane pemphigoid predominantly affects the mucosal surfaces, healing with scar formation. When it involves the vulva, scarring can lead to distortion of vulval architecture with labial fusion and introital shrinkage that can mimic lichen sclerosus [6]. It has been described confined to the vulva

Fig. 151.14 Bullous pemphigoid of the vulva.

Genital Disease in Children

in children [6]. Ophthalmological examination is essential to exclude ocular involvement. In localized cases the disease is self-limiting and is easily controlled with potent topical steroid and topical tacrolimus [7]. However, severe cases may require systemic therapy with prednisone and immunosuppressive therapy [8].

Non-sexually acquired acute genital ulcers Acute non-sexually acquired genital ulcers were first described by Lipschutz in 1913. Since then the medical literature has been quite confused on the subject and these lesions are probably under-reported. Acute non-infectious ulceration can be either recurrent (most often thought to be due to aphthosis or associated with Behçet or Crohn disease) or a single event. This latter clinical situation has been termed ‘Lipschutz ulcer ’, ‘ulcus vulvae acutum’ and ‘Sutton’s ulcer ’ and has been attributed most often to Epstein–Barr infection, although it may be a response to a number of aetiological agents [9]. Acute non-sexually acquired genital ulcers are usually seen in girls in the early adolescent age range. These ulcers are of sudden onset and are frequently preceded by fever [10]. They may be very large, up to 2 cm in diameter. They are very painful and may take several weeks to heal, often with some scarring. The appearance is alarming and, not surprisingly, these patients are commonly assumed to have primary genital herpes, and are investigated for this and other sexually transmitted disease (Fig. 151.15). Epstein–Barr virus (EBV) is often implicated in these lesions and a recent study of 13 cases reported it in four [10,11]. Epstein–Barr virus has been isolated from these

151.13

ulcers by PCR. Serology is not always positive at the onset of the ulcer which can precede other signs of infection. Influenza A infection has also been implicated [12]. When there has only been one episode it is possible that such ulcers may not be part of the aphthous ulcer spectrum, but there is insufficient evidence to rule this out at the time of writing. Acute, non-sexually acquired genital ulceration is a clinical diagnosis. Biopsy is non-specific and is not indicated. The importance of this condition is that is it underreported and under-recognized. This often leads to traumatic and unnecessary investigation in these young girls. Acute genital ulceration in a girl this age should be a reason for urgent review by a dermatologist before any further action is taken.

Aphthous ulcers Aphthous ulcers are usually small, painful lesions that may begin in childhood or adolescence, and subsequently recur at intervals that can be infrequent to frequent and disabling. Oral aphthous ulcers are very common, but uncommonly these lesions may also occur on the vulva or scrotum. It is important to recognize these lesions, however, as they are commonly mistaken for genital herpes simplex and other sexually transmitted infectious diseases [11,13]. Aetiology. Aphthous ulcers have been associated with iron, ferritin, folate and vitamin B12 deficiency, Behçet disease, Crohn disease and HIV infection [14–16]. Severe, recurrent aphthosis of the oral and genital mucosa in the absence of systemic manifestations is termed ‘complex aphthosis’. It is possibly a forme fruste of Behçet disease [17] but this is speculative. The pathogenesis of this disease is unknown. Various infectious agents, such as herpes simplex virus, cytomegalovirus, EBV, Helicobacter pylori and Streptococcus species have been implicated but not reproducibly isolated [9,13]. Clinical presentation. The ulcers are usually small, round or oval, shallow lesions with a sharply defined edge and an erythematous margin. The base is yellow or grey. When they occur on the vulva, they are usually found on the mucosal surface of the labia minora. In males they are found on the scrotum. They heal spontaneously in 1–2 weeks, without scarring. Genital aphthous ulcers are rare in children but in a recent series of 20 patients aged 10–19, five were premenarchal and in the same series half the patients had associated oral aphthae and a third had recurrent lesions [13].

Fig. 151.15 Major aphthosis of the vulva.

Differential diagnosis. The diagnosis of aphthosis is a clinical one and an important one in a child presenting

151.14

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with a large painful genital ulcer, who is very likely to be traumatized by investigations for sexually transmitted disease, and to be subjected to unnecessary biopsy, which is non-diagnostic. Recurrent and major aphthosis should be differentiated from Behçet disease and Crohn disease. It is usually recommended that these patients be investigated for iron, folate and B12 deficiency; however, in the author ’s experience such investigations are often non-contributory. Management. Minor aphthosis can be managed with reassurance and topical potent corticosteroid or topical tetracycline. The situation of a child with a large, very painful genital lesion can be rapidly alleviated with oral prednisone at a dose of 0.5–1 mg/kg per day. Healing occurs within 1 week and the corticosteroid can then be rapidly tapered off. Recurrent disease may be palliated with low-dose oral tetracycline in children over the age of 8 years. Other oral medications that have been considered useful include dapsone, colchicine and thalidomide [18].

Fig. 151.16 Fixed drug eruption of the penis. Courtesy of Dr M. Rogers.

Fixed drug eruption Fixed drug eruption is an uncommon drug reaction which, when found on non-genital skin, presents as sharply demarcated round or oval plaques recurring at a fixed location. The eruption may vary from one to many involved areas. The offending drug has usually been administered within the last 12 h, and sometimes eruption will occur within 30 min of ingestion. The plaques are usually asymmetrically distributed. During the recovery phase there is often hyperpigmentation. Fixed drug eruption may occur on the genital area at any age. In this location, it presents in girls as a bilaterally symmetrical erosive eruption involving the vulva that may spread to the groins and buttocks. In boys there is usually erythema and swelling and blistering of the penis and/or scrotum [19,20] (Fig. 151.16). The eruption is itchy and sore. It may be associated with dysuria and urinary retention. The onset is sudden, and it resolves spontaneously over a period of about 2 weeks. In the genital area, hyperpigmentation does not usually occur [21]. The symmetry of the eruption and the lack of postinflammatory pigmentation on the genital area may make the diagnosis difficult. When a drug is constantly administered, genital fixed drug eruption may present as a constant erosive eruption that is puzzlingly treatment resistant. The differential diagnosis includes acute streptococcal vulvitis and balanitis, acute contact dermatitis and recurrent perineal erythema. Drugs that have most often been implicated in children include paracetamol, co-trimoxazole, hydroxyzine and methylphenidate [19].

Fig. 151.17 Erythema multiforme major involving the vulva.

Erythema multiforme and toxic epidermal necrolysis Erythema multiforme major often involves mucosal surfaces in children and may do so in a recurrent fashion when precipitated by herpes simplex infection. Other precipitants include Mycoplasma pneumoniae infection and drug reactions. It is usually part of a generalized process but can involve mucosae only [22,23] (Fig. 151.17). The vulval involvement is an erosive vulvovaginitis. Toxic epidermal necrolysis is a much more severe, multisystem disease with severe skin blistering and erosions. It is, in most cases, a drug reaction. The genital changes are similar to those encountered in erythema multiforme. If the mucosal surfaces are severely involved in either condition, vaginal adhesions may develop [24,25] and persistent mucosal erosions and ulceration have been

Genital Disease in Children

reported to occur for over 1 year after the acute episode [26]. When genital mucosal involvement is present, catheterization may be required because of urinary retention due to acute dysuria. Supportive treatment is usually all that is required.

Hidradenitis suppurativa Hidradenitis suppurativa (ectopic acne) is a chronic suppurative scarring disease resulting from non-infective inflammation of apocrine sweat gland-bearing skin. It therefore favours the axilla and anogenital area but may occur on the buttocks, breast and scalp. Although it is usually seen in young adults and older people, it may occur in children, particularly those approaching and at puberty. Children with androgen excess and premature adrenarche may suffer from the disease prematurely [27,28]. Pathogenesis. Although the true aetiology of this disease remains unknown, it does appear that follicular occlusion in apocrine gland-bearing skin is the primary event. The disease in most cases appears to be androgen dependent, and it has been postulated that these patients have an end-organ hypersensitivity to androgens. Both obesity and smoking have been reported to be exacerbating factors [29]. Clinical features. The earliest signs of the disease are tender dermal nodules that may progress to suppuration and scarring. With time, sinus tracts, comedones and fibrosing scars develop. The disease is more common in females than males, with a ratio of 4:1. Although bacterial swabs are usually negative, superinfection may result in recurrent cellulitis. The disease may become debilitating, with constant painful nodules in the groin and axilla. The connection between smoking and this condition, seen in adults, can manifest in children who are passive smokers. Differential diagnosis. Particularly in children, in whom the disease may not be suspected, recurrent folliculitis or staphylococcal boils are usually diagnosed initially. However, repeated swabs do not reveal the expected staphylococcal infection. Management. This condition may be very treatment resistant. If the area of skin affected is localized, surgical excision is probably the treatment of choice. However, such surgery is not trivial and initial management with oral tetracycline in children over the age of 8 years will often provide adequate control; recent reports of rifampicin and clindamycin in combination seem to have great promise but data are sparse in children. In postpubertal children the addition of an antiandrogen, such as cyprot-

151.15

erone acetate, may be helpful. There have been reports of the use of isotretinoin but results are unpredictable. References 1 Mirza A, Zamilpa I, Wilson JM. Localized penile bullous pemphigoid. J Pediatr Urol 2008;4(5):395–7. 2 Fisler RE, Saeb M, Liang MG, Howard RM, McKee PH. Childhood bullous pemphigoid: a clinicopathologic study and review of the literature. Am J Dermatopathol 2003;25(3):183–9. 3 Farrell AM, Kirtschig G, Dalziel KL et al. Childhood vulval pemphigoid: a clinical and immunopathological study of five patients. Br J Dermatol 1999;140:308–12. 4 Saad RW, Domloge-Hultsch N, Yancey KB et al. Childhood localized vulvar pemphigoid is a true variant of bullous pemphigoid. Arch Dermatol 1992;128:807–10. 5 Levine V, Sanchez M, Nestor M. Localised vulvar pemphigoid in a child misdiagnosed as sexual abuse. Arch Dermatol 1992;128:804–6. 6 Hoque SR, Patel M, Farrell AM. Childhood cicatricial pemphigoid confined to the vulva. Clin Exp Dermatol 2005;31:63–4. 7 Lebeau S, Mainetti C, Masouye I et al. Localized childhood vulval pemphigoid treated with tacrolimus ointment. Dermatology 2004;208:273–5. 8 Guenther LC, Shum D. Localised childhood vulvar pemphigoid. J Am Acad Dermatol 1990;22:762–4. 9 Hernandez-Nunez A, Cordoba S, Romero-Mate A, Minano R, Sanz T, Borbujo J. Lipschutz ulcers – four cases. Pediatr Dermatol 2008;25(3):364–7. 10 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. 11 Ghate JV, Jorizzo MD. Behçet’s disease and complex aphthosis. J Am Acad Dermatol 1999;40:1–18. 12 Wetter DA, Bruce A, MacLaughlin KL et al. Ulcus vulvae acutum in a 13 year old girl after influenza A infection. Skinmed 2008;7(2):95–8. 13 Huppert JS, Gerber M, Deitch HR et al. Vulvar ulcers in young females: a manifestation of aphthosis. J Pediatr Adolesc Gynecol 2006;19(3):195–204. 14 Rogers RS III. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorder. Semin Cutan Med Surg 1997;16:278–83. 15 Unal M, Yildirim SV, Akbaba M. A recurrent aphthous stomatitis case due to paediatric Behçet’s disease. J Laryngol Otol 2001;115:576–7. 16 Magalhaes MG, Bueno DF, Serra E et al. Oral manifestations of HIV positive children. J Clin Pediatr Dent 2001;25:103–6. 17 Jorizzo JL, Taylor RS, Schmalstieg FC. Complex aphthosis: a forme fruste of Behçet’s syndrome? J Am Acad Dermatol 1985;13:80–4. 18 Eisen D, Lynch DP. Selecting topical and systemic agents for recurrent aphthous stomatitis. Cutis 2001;68:201–6. 19 Nussinovitch M, Prais D, Ben-Amitai D et al. Fixed drug eruption in the genital area of 15 boys. Pediatr Dermatol 2002;19:216–19. 20 Morelli JG, Tay YK, Rogers M et al. Fixed drug eruptions in children. J Pediatr 1999;134:365–7. 21 Sehgal VH, Gangwani OP. Genital fixed drug eruptions. Genitourin Med 1986;62:56–8. 22 Salvado F, Furtado I. A case of erythema multiforme with only orogenital manifestations. Rev Port Estomatol Cirurg Maxilofac 1988;21:19–24. 23 Latsch K, Girschick H, Abele-Horn M. Stevens–Johnson syndrome without skin lesions. J Med Microbiol 2007;56(12):1696–9. 24 Graham-Brown RA, Cochrane GW, Swinhoe JR et al. Vaginal stenosis due to bullous erythema multiforme (Stevens–Johnson syndrome). Br J Obstet Gynaecol 1981;88:115–16.

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25 Bonafe JL, Thibaut I, Hoff J. Introital adhesions associated with the Stevens–Johnson syndrome. Clin Exp Dermatol 1990;15:356–7. 26 Sibaud V, Fricain J, Leaute-Labreze C, Campana F, Taieb A. Persistent mucosal ulcerations: a rare complication of toxic epidermal necrolysis. Ann Dermatol Venereol 2005;132(8–9 Pt 1):682–5. 27 Palmer RA, Keefe M. Early onset hidradenitis suppurativa. Clin Exp Dermatol 2001;26:501–3. 28 Mengesha YM, Holcombe TC, Hansen RC. Prepubertal hidradenitis suppurativa: two case reports and review of the literature. Pediatr Dermatol 1999;16:292–6. 29 Alikhan A, Lynch P, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol 2009;60:539–61.

Anatomical abnormalities

descend, is a common congenital abnormality. It results in mild scrotal swelling, which transilluminates. There is often an associated indirect inguinal hernia [6]. Chordee and penile hypospadias are also relatively common and produce abnormality of the appearance of the penis. Hypospadias is a ventral displacement of the urethral opening, which is usually associated with the presence of an incomplete foreskin with an absent ventral portion. Chordee results in a ventral curvature of the penis resulting from a deficiency of the ventral tissue distal to the abnormally placed meatus and fibrous tissue. It may occasionally occur without hypospadias. Both of these abnormalities may be associated with other abnormalities of the urinary tract [6,7].

Vulval abnormalities Abnormal-appearing genitalia present at birth in a girl has two most frequent causes: (1) masculinization due to congenital adrenocortical hyperplasia as a result of an inherited defect of steroid synthesis and (2) imperforate hymen Although these problems would not normally present to a dermatologist, they come into the differential diagnosis of fusion of the labia as discussed below. Agenesis of the labia minora and clitoris has been described as a congenital abnormality [1]. Hypertophy of the labia minora is a benign condition that may be unilateral or bilateral (Fig. 151.18). It is usually asymptomatic but very long labia may interfere with function [2]. Adolescent girls sometimes present with a great deal of anxiety about hypertrophic labia and it is becoming more common for patients to seek a surgical solution as early as puberty [3]. Ambiguous genitalia should be a reason for referral to a paediatrician for assessment [4,5].

Penile abnormalities Congenital hydrocoele caused by fluid trapped in the processus vaginalis, the tract through which the testes

CHARGE syndrome (OMIM 214800) This syndrome, first described by Pagon [8], comprises coloboma, heart defects, atresia choanae, retarded growth and development, genital hypolasia in boys, ear anomalies and deafness. Facial nerve palsy, tracheo-oesophageal fistula, hypocalcaemia and lymphopenia have also been described. A gene mutation of CHD7 on chromosome 8q12.1 is found in the majority of patients [9,10]. Although in girls hypoplastic uterus has been described, abnormalities of the external genitals have only been found in boys. Cryptorchism and micropenis are the most common anomalies [10].

Pearly penile papules Pathogenesis. Pearly penile papules are small smooth excrescences projecting from the penile corona. They are not symptomatic and are a normal variant. They are more common after puberty but may be rarely seen in children. They are found in all races [11,12]. Histopathology. The pathology is reminiscent of an angiofibroma, with a core of connective tissue containing a vascular network and a mild lymphocytic infiltrate. The covering epidermis is normal and slightly acanthotic at the periphery [13]. Clinical presentation. The complaint is only of the appearance of the papules, which are usually assumed to be genital warts. There are one to three rings of lesions, partly or completely encircling the corona of the glans. Rarely, they may cover the entire glans [14]. The papules are usually small, 1–3 mm in diameter, and flesh-coloured to white. They are usually asymptomatic.

Fig. 151.18 Hypertrophy of the labia minora.

Management. None is indicated and parents should be reassured that this is not a disease at all. Some authors have suggested treatment of these lesions with CO2 laser

Genital Disease in Children

or cryotherapy. In the author ’s opinion this should be discouraged [12,15].

151.17

behind the fusion, causing irritating maceration. Urinary tract infections are, however, rarely a complicating factor.

Fusion of the labia Incidence. Fusion of the labia is sometimes seen in young children, usually 3 years of age and under. It is not seen in adults, unless they have scarring skin diseases such as lichen sclerosus. It may be noticed from infancy to the age of 6 years, but the peak incidence is at 13–23 months of age. Once a child has had an adhesion, it may persist or recur until puberty [16]. Aetiology. The cause of labial adhesions is unknown but they are probably the result of inflammation and oedema associated with dermatological conditions such as dermatitis. Adhesions are commonly encountered with vulval lichen sclerosus and have been reported in association with calcinosis cutis [17]. Fusion of the labia is not a malformation and is acquired, but it may appear very early and has even been seen at birth. Clinical presentation. The labia minora or majora are agglutinated to a variable degree from the tip of the clitoris to the posterior fourchette. This may result in an abnormal-looking vulva with no apparent vaginal opening or the vulva may look relatively normal but there appears to be a membrane across the vagina when the labia majora are parted [18] (Fig. 151.19). Not all children with adhesions are symptomatic, but some experience soreness or itching. Urine can pool

Differential diagnosis. Fusion of the labia is important in the differential diagnosis of ambiguous genitalia and imperforate hymen and a gynaecological opinion should be sought if there is any doubt. The presence of a midline fusion line suggests the presence of this condition. Management. This is the only condition for which oestrogen cream is the treatment of choice in a prepubertal child. The cream needs to be applied only once per day, and the fusion usually resolves over a 2–6-week period. Once the fusion has separated, ongoing treatment with soap avoidance, topical lubricants and 1% hydrocortisone is recommended. The fusion may reform and have to be retreated from time to time. This can be a problem as oestrogen creams are irritating in children and they tend to sting, making co-operation difficult. Prolonged use of oestrogen creams in prepubertal girls may lead to breast budding and increased growth of hair [10,19]. When the adhesion does not resolve with oestrogen treatment, manual separation may be required [20]. This should never be attempted without anaesthesia as it is very traumatic for the child. In some patients, surgical separation under local or general anaesthesia will be required, particularly where dense fibrous adhesions have formed. The condition tends to resolve spontaneously at puberty, however, and surgery should only be undertaken if the condition is symptomatic. Dysuria, pain with activities, urinary retention and almost complete occlusion of the vestibule leading to a pinpoint opening with abnormal urinary stream are indications for such treatment [21]. The treatment of asymptomatic labial adhesions is controversial. If the adhesion is small, non-intervention is probably justified. However, an almost complete adhesion could pose difficulties in the setting when a catheterization is required, and it has therefore been suggested that large adhesions should be treated even when there are no symptoms [22].

Phimosis

Fig. 151.19 Fusion of the labia minora.

At birth the prepuce is adherent to the glans and cannot be easily retracted. Only 4% of boys have a retractable foreskin at birth, 15% at 6 months of age, 50% at 1 year and 80–90% at 3 years. It should be fully retractable by the age of 17 [23]. Dermatologists should be aware of this timeline, as inability to retract the foreskin, particularly when it has previously been retractable, may be a sign of inflammatory skin disease of the glans. The degree of phimosis may vary from difficulty retracting the foreskin to a non-retractable pinpoint

151.18

Chapter 151

opening. Persistent phimosis after this age may lead to recurring balanitis. Phimosis may be congenital or acquired. A study in 2002 found that among the group with congenital phimosis, 30% had lichen sclerosus, and in the group with acquired phimosis, this figure rose to 60%. The remainder of the boys showed inflammatory change on biopsy [24]. Thus, the aetiology of this condition, if lichen sclerosus is not present, may be similar to adhesion of the labia in girls. Phimosis has been associated with lichen planus of the glans [25]; however, lichen planus is very rare in children and this case was very unusual. Management. Although circumcision has in the past been considered the treatment of choice for phimosis, more recent studies indicate that the use of moderately potent topical corticosteroids coupled with gentle retraction has a high success rate. This should now be considered as the first-line treatment for phimosis, prior to surgery [26,27].

Infantile pyramidal perineal protrusion Although this has only quite recently been labelled as an entity in the medical literature [28], it is probably not rare. It is noticed in infancy as an asymptomatic soft protrusion of the median raphe, mostly in girls [29]. The lesion is usually anterior to the anus but may also be posterior (Fig. 151.20). The overlying skin is normal. Some cases

have been seen in association with lichen sclerosus [30] and chronic constipation [31,32]. It has been reported in families [33]. Like many innocent genital lesions, this entity may be mistaken for genital warts or sexual abuse [34]. It also comes into the differential diagnosis of a sentinel tag. No treatment is required. The natural history of the lesion in later childhood is unknown.

Median raphe cysts of the penis and scrotum Cysts of the median raphe are embryological development anomalies of the male genitalia. They are usually present at birth but may not become noticeable until adult life [31,35,36]. They are considered to be congenital alterations in embryonal development. Histology. The cysts are found in the dermis, and are lined by several layers of pseudo-stratified epithelium and contain amorphous material consisting of acid mucopolysaccharides [37]. Clinical presentation. The cyst presents as a mobile swelling with translucent contents. It may be single or multiple (Fig. 151.21). The lesions may be found anywhere between the urinary meatus and the anus (Fig. 151.22). They are usually asymptomatic. Age at first presentation is usually after the first decade but the lesion has been reported in younger children [38,39]. Differential diagnosis. This includes epidermoid cyst, dermoid, urethral diverticulum and pilonidal cyst. Management. Simple excision is recommended to avoid problems with friction in later life [40,41].

Fig. 151.20 Pyramidal perineal protrusion.

Fig. 151.21 Multiple median raphe cysts of the penis. Courtesy of Dr M. Rogers.

Genital Disease in Children

Fig. 151.22 Median raphe cyst of the perineum.

References 1 Martinon-Torres F, Martinon-Sanchez J, Martinon-Sanchez F. Clitoris and labia minora agenesis: an undescribed phenomenon. Clin Genet 2000;58(4):336–8. 2 Schroeder B. Vulvar disorders in adolescents. Obstetr Gynecol Clin 2000;27(1):5–48. 3 Rouzier R, Louis-Sylvestre C, Paniel BJ, Haddad B. Hypertrophy of labia minora: experience with 163 reductions. Am J Obstet Gynecol 2000;182(1 Pt 1):35–40. 4 Donahoe PK, Hendren WH. Evaluation of the newborn with ambiguous genitalia. Pediatr Clin North Am 1976;23:361–70. 5 Aaronson IA. The investigation and management of the infant with ambiguous genitalia: a surgeon’s perspective. Curr Probl Pediatr 2001;31:168–94. 6 Lynch PJ, Edwards L. Pediatric problems. In: Genital Dermatology. New York: Churchill Livingstone, 1994: 251–2. 7 Baskin LS. Hypospadias and urethral development. J Urol 2000;163:951. 8 Pagon RA, Graham J Jr, Zonana J, Yong SL. Coloboma, congenital heart disease and choanal atresia with multiple anomalies: CHARGE syndrome. J Pediatr 1981;99(2):223–7. 9 Aramaki M, Udaka T, Kosaki R et al. Phenotypic spectrum of CHARGE syndrome with CHD7 mutations. J Pediatr 2006;148(3):410–14. 10 Jongmans MC, Admiraal R, van der Donk KP et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet 2006;43(4):306–14. 11 Sonnex C, Dockerty WG. Pearly penile papules: a common cause of concern. Int J STD AIDS 1999;10:726–7. 12 Ackerman AB, Kronberg R. Pearly penile papules: acral angiofibromas. Arch Dermatol 1973;108:673–5. 13 Lane JE, Peterson CM, Ratz JL. Treatment of pearly penile papules with CO2 laser. Dermatol Surg 2002;28:617–18. 14 Agarwal SK, Bhattacharya S, Singh N. Pearly penile papules: a review. Int J Dermatol 2004;43(3):199–201. 15 Porter WM, Bunker CB. Treatment of pearly penile papules with cryotherapy. Br J Dermatol 2000;142:847–8. 16 Carpraro VJ, Greenburg H. Adhesions of the labia minora. Obstet Gynecol 1972;39:65–9. 17 Bernardo BD, Huettner PC, Merritt DF et al. Idiopathic calcinosis cutis presenting as labial adhesions in children: report of two cases with literature review. J Pediatr Adolesc Gynecol 1999;12:157–60. 18 Bacon JL. Prepubertal labial adhesions. Evaluation of a referral population. Am J Obstet Gynecol 2002;187:327–32.

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19 Schober J, Dulabon L, Martin-Alguacil N, Kow LM, Pfaff D. Significance of topical estrogens to labial fusion and vaginal introital integrity. J Pediatr Adolesc Gynecol 2006;19(5):337–9. 20 Soyer T. Topical estrogen therapy in labial adhesions in children: therapeutic or prophylactic? J Pediatr Adolesc Gynecol 2007;20:241–4. 21 Pokorny SF. Prepubertal vulvovaginopathies. Obstet Gynecol Clin North Am 1992;19:39–59. 22 Muram D. Treatment of prepubertal girls with labial adhesions. J Pediatr Adolesc Gynecol 1999;12:67–70. 23 Cold CJ, Taylor J. The prepuce. BJU Int 1999;83(suppl 1):34–44. 24 Mattioli G, Repetto P, Carlini C et al. Lichen sclerosus et atrophicus in children with phimosis and hypospadias. Pediatr Surg Int 2002;18:273–5. 25 Aste N, Pau M, Ferreli C et al. Lichen planus in a child requiring circumcision. Pediatr Dermatol 1997;14:129–30. 26 Orsola A, Caffaratti J, Garat JM. Conservative treatment of phimosis in children using a topical steroid. Urology 2000;5:307–10. 27 Ng WT, Fan N, Wong CK et al. Treatment of childhood phimosis with a moderately potent topical steroid. Aust NZ J Surg 2001;71:541–3. 28 Webster TM, Leonard MP. Topical steroid therapy for phimosis. Can J Urol 2002;9:1492–5. 29 Konta R, Hashimoto I, Takahashi M, Tamai K. Infantile perineal protrusion: a statistical, clinical and histopathologic study. Dermatology 2000;201(4):316–20. 30 Cruces MJ, de la Torre C, Losada A, Ocampo C, Garcia-Doval I. Infantile perineal protrusion as a manifestation of lichen sclerosus et atrophicus. Arch Dermatol 1998;134(9):1118–20. 31 Hernandez-Machin B, Almeida P, Lukan D, Montenegro T, Borrego L. Infantile pyramidal protrusion localized at the vulva as a manifestation of lichen sclerosus. J Am Acad Dermatol 2007;56(2 suppl):S49–50. 32 Kayashima KI, Kitoh M, Ono T. Infantile perianal pyramidal protrusion. Arch Dermatol 1996;132:1481–4. 33 Cruces MJ, de la Torre C, Losada A et al. Infantile pyramidal protrusion as a manifestation of lichen sclerosus et atrophicus. Arch Dermatol 1998;134:1118–20. 34 Khachemoune A, Guldbakke K, Ehrsam E. Infantile perineal protrusion. J Am Acad Dermatol 2006;54(6):1046–9. 35 Patrizi A, Raone B, Neri I et al. Infantile perianal protrusion: 13 new cases. Pediatr Dermatol 2002;19:15–18. 36 Krauel L, Tarrado X, Garcia-Aparicio L et al. Median raphe cysts of the perineum in children. Urology 2008;71(5):830–1. 37 Nagore E, Sanchez-Motilla J, Febrer MI et al. Median raphe cysts of the penis: a report of five cases. Pediatr Dermatol 1998;15:191–3. 38 Lever WF, Schaumberg-Lever G. Tumours and cysts of the epidermis. In: Lever WF, Schaumberg-Lever G (eds) Histopathology of the Skin, 7th edn. Philadelphia: J.B. Lippincott, 1990: 540. 39 Otsuka T, Ueda Y, Terauchi M et al. Median raphe (parameatal) cysts of the penis. J Urol 1998;159:1918–20. 40 Asarch RG, Golitz LE, Sansker WF et al. Median raphe cysts of the penis. Arch Dermatol 1979;115:1084–6. 41 Little JS, Keating MA, Rink RC. Median raphe cysts of the genitalia. J Urol 1992;148:1872–3.

Foreign bodies Although intravaginal foreign bodies are often mentioned as a cause of vulval disease in the medical literature, the fact is that they are not a common event. The foreign material is usually fragments of toilet paper or fluff. Small toys are less common [1].

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The presence of vaginal bleeding in a prepubertal child is highly suggestive of a foreign body [2]. Another common presentation is a persistent purulent discharge heavy enough to cause maceration of the vulval skin. A crusted, erythematous or pigmented line along the tips of the labia majora may be the result of chronic maceration. Lichenification may occur. Swabs show recurrent bacterial infection, which responds to courses of antibiotics but rapidly recurs [3]. A recent study of 24 prepubertal girls presenting with vaginal discharge or bleeding found that a foreign body was responsible in seven cases; however, six girls had malignancies, three rhabdomyosarcomas and three endodermal sinus tumours, and a further two had benign mullerian papillomas [4]. A foreign body may be in place for weeks to years before symptoms develop [5]. Radiological and ultrasound techniques fail to detect most vaginal foreign bodies. The child will require examination under anaesthesia with vaginoscopy and saline lavage. Often, there is very little to be seen on lavage, and it is likely that only small fragments can cause this clinical presentation [3,5]. Foreign bodies of the penile urethra are rare. Symptoms of dysuria, urethral discharge or bleeding may also occur. Endoscopic investigation may be required to locate and remove such objects and, rarely, surgery may be required [2].

Hair tourniquet The hair tourniquet is a well-described condition where a hair or thread becomes tightly wrapped around an end perfusion appendage, causing hypoperfusion and reducing lymphatic draininge. This results in swelling, pain and sometimes necrosis. The genital area can be involved. This phenomenon has most often been described to involve the penis [6]. A clitoral hair tourniquet has been described in a 9-year-old girl [7].

References 1 Pokorny SF. Prepubertal vulvovaginopathies. Obstet Gynecol Clin North Am 1992;19:39–58. 2 Di Meglio G. Genital foreign bodies. Pediatr Rev 1998;19:34. 3 Bacon JL. Pediatric vulvovaginitis. Adolesc Pediatr Gynecol 1989;2:86–93. 4 Striegel AM, Myers J, Sorensen MD, Furness PD, Koyle M. Vaginal discharge and bleeding in girls younger than 6 years. J Urol 2006;176(6 Pt 1):2632–5. 5 Pokorny SF. Long term intravaginal presence of foreign bodies in children: a preliminary study. J Reprod Med 1994;39:931–5. 6 Dar NR, Siddiqui S, Qayyum R, Ghafoor T. Hair coil strangulation: an uncommon cause of penile edema. Pediatr Dermatol 2007;24(4):E33–5. 7 Alverson B. A genital hair tourniquet in a 9 year old girl. Pediatr Emerg Care 2007;23(3):169–70.

Neoplasia Neoplasia of the genitalia in children is a rare event. However, the differential diagnosis of an enlarging genital mass is wide and should be promptly investigated [1]. It includes a variety of tumours of mesenchymal origin, embryonic remnants and malignancies [1].

Malignancies Langerhans cell histiocytosis may present as an erosive, purpuric and pustular recalcitrant nappy rash, usually with generalized lesions [2]. It has also been reported as a vulval eruption in an adolescent [3]. Melanoma of the vulva has been rarely reported in children and adolescents, and in three cases this has been in association with childhood lichen sclerosus [4,5]. Rhabdomyoscarcoma is the most common tumour of the lower genitourinary tract in children and has been reported on the penis, perineum and vagina as a painless firm swelling [6]. A malignant schwannoma has been described on the penis [7]. Vulval intraepithelial neoplasia has been reported in children [6] and adolescents with abnormal cervical cytology [8]. Squamous cell carcinoma of the vulva on a setting of bowenoid papulosis has been reported in a 12-year-old girl with vertically acquired HIV disease [9]. Primary malignant lymphoma is rare on the genital area but a B-cell non-Hodgkin lymphoma has been recently reported involving the penis in a 4-year-old boy [10].

Benign tumours Granular cell tumour is a rare benign soft tissue neoplasm originating from Schwann cells [11] that has been reported as a vulval, penile and scrotal lesion in children, presenting as slow-growing solitary nodules or plaques with a smooth or hyperkeratotic surface [11–15]. Syringomas of the vulva have been described in children [16] and multiple genital trichoepithelioma has been described in the setting of Bazex–Dupre–Christol syndrome [17]. A case of apocrine hidrocystoma has been described on the glans in a child [18]. Atyical fibroxanthoma, juvenile xanthogranuloma and solitary mastocytoma [19,20] may occur on the vulva. Leiomyoma may occur on the glans penis, scrotum, vulva and prepuce, and myofibroma has been described on the penis in children [21,22]. Neuroendocrine tumours, such as small cell neuroendocrine carcinomas, are more common in the female than the male genital tract; however, they may uncommonly be found on the penis, scrotum and vulva, presenting as a mass [23]. Neurilemmoma may occur as multiple swellings of the penile shaft, and neurofibromas may be found on the penis and scrotum [24–26]. Benign schwannoma

Genital Disease in Children

has been reported as a firm clitoral mass [27] and a labial mass [28]. Patients with neurofibromatosis may experience involvement of the genitals [29]. The most frequent presenting sign of genital involvement of neurofibromatosis in females is clitoromegaly with pseudo-penis formation, and enlarged penis is the most common sign in males. Rarely in girls the labia may be involved [30]. A mesenchymal tumour which has been termed ‘ prepubertal vulval fibroma’ has been described in prepubertal girls [31]. The presentation is with a non-specific unilateral labial mass ranging in size from 2 to 8 cm in diameter. This is a benign lesion showing the histopathology of spindle cells in a myxoid stroma, which can be locally recurrent after excision. Epidermoid cysts are not uncommon on the genitals in adults and have been reported in children [32]. A ciliated cyst of the vulva has been reported in a child [33]. Fibrous hamartoma of infancy is an uncommon subcutaneous proliferative lesion usually found on the trunk in the first 2 years of life. This lesion has also been reported on the vulva and scrotum [34]. Lipomas of the vulva have been described in children as sharply circumscribed soft masses of the labia [35] and in boys as masses on the penis and perineum [36]. A case of congenital perineal lipoma has been reported as presenting as ambiguous genitalia [37].

Prepubertal unilateral fibrous hyperplasia of the labium majus This recently recognized condition presents with asymptomatic rapidly growing unilateral or occasionally bilateral enlargement of the labium majus [38,39]. Clinical features. The mass is soft and has no palpable borders. The overlying skin is described as having a slightly hyperpigmented peau d’orange surface. It occurs around adrenarche and appears to be an asymmetrical physiological enlargement in response to hormonal surges of prepuberty and early puberty. It has been observed to regress if left untreated. Histology. Histology shows hypocellular fibrous tissue. Oestrogen and progesterone receptors are identified on fibroblasts. Differential diagnosis. This condition can mimic an infiltrative neoplasm because of its rapid growth [39]. References 1 Lowry DL, Guido DS. The vulvar mass in the prepubertal child. J Pediatr Adolesc Gynecol 2000;13:75–8. 2 Otis CN, Fischer RA, Johnson N et al. Histiocytosis-X of the vulva: a case report and review of the literature. Obstet Gynecol 1990;75:555–8.

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3 Mottl H, Rob L, Stary J, Kodet R, Drahokoupliova E. Langerhans cell histiocytosis of vulva in adolescent. Int J Gynecol Cancer 2007;17(2):520–4. 4 Hassanein AM, Mrstik M, Hardt NS, Morgan LA, Wilkinson EJ. Malignant melanoma associated with lichen sclerosus in the vulva of a 10-year-old. Pediatr Dermatol 2004;21(4):473–6. 5 Egan CA, Bradley RR, Logsdon VK et al. Vulvar melanoma in childhood. Arch Dermatol 1997;133:345–8. 6 Agrons GA, Wagner BJ, Lonergan JG et al. From the archives of the AFIP. Genitourinary myosarcoma in children: a radiologic-pathologic correlation. Radiographics 1997;17:919–37. 7 Mortell A, Amjad B, Breatnach F, Devaney D, Puri P. Penile malignant peripheral nerve sheath tumour (schwannoma) in a three year old child without evidence of neurofibromatosis. Eur J Pediatr Surg 2007;17(6):428–30. 8 Lara-Torre E, Perlman S. Vulvar intraepithelial neoplasia in adolescents with abnormal Pap smear results: a series report. J Pediatr Adolesc Gynecol 2004;17(1):45–8. 9 Giaquinto C, del Mistro A, de Rossi A et al. Vulvar carcinoma in a 12 year old girl with vertically acquired human immunodeficiency virus infection. Pediatrics 2000;106(4):E57. 10 Wei CC, Peng C, Chiang IP, Wu KH. Primary B cell non-hodgkin lymphoma of the penis in a child. J Pediatr Hematol Oncol 2006;28(7):479–80. 11 Godoy G, Mufarrij PW, Tsou H, Torre P, Tanjela SS. Granular cell tumour of scrotum: a rare tumor of the male external genitalia. Urology 2008;72(3):e7–9. 12 Yang JH, Mitchell K, Poppas DP. Granular cell tumor of the glans penis in a 9-year-old boy. Urology 2008;71(3):546. 13 Sidwell RU, Rouse P, Owen RA, Green JS. Granular cell tumour of the scrotum in a child with Noonan syndrome. Pediatr Dermatol 2008;25(3):341–3. 14 Gentler L, Shimmed D. Granular cell tumour of the vulva. Pediatr Dermatol 1993;10:153–5. 15 Cohen Z, Kapuller V, Maor E et al. Granular cell tumour (myoblastoma) of the labia major: a rare benign tumour in childhood. J Pediatr Adolesc Gynecol 1999;12:155–6. 16 DiLernia V, Bisighini G. Localized vulvar syringomas. Pediatr Dermatol 1996;13:80–1. 17 Yung A, Newton-Bishop J. A case of Bazex–Dupre–Christol syndrome associated with multiple genital trichoepitheliomas. Br J Dermatol 2005;153(3):682–4. 18 Samplaski MK, Somani N, Palmer JS. Apocrine hidrocystoma on glans penis of a child. Urology 2009;73(4):800–1. 19 Shuangshoti S, Shuangshoti S, Pintong J, Piyayotai V, Sukpanichnant S. Solitary mastocytoma of the vulva: report of a case. Int J Gynecol Pathol 2003;22(4):401–3. 20 Serarslan G, Atik E, Zeteroglu S. Nodular mastocytosis of the vulva: an unusual localisation. Aust NZ J Obstet Gynecol 2005;45(4):335–6. 21 Redman JF, Liang X, Ferguson MA et al. Leiomyoma of the glans penis in a child. J Urol 2000;164:791. 22 Val-Bernal J, Fernando MD, Garijo M et al. Solitary cutaneous myofibroma of the glans penis. Am J Dermopathol 1996;19:317–21. 23 Eichhorn JH, Young RH. Neuroendocrine tumours of the genital tract. Am J Clin Pathol 2001;115(suppl):S94–112. 24 Pandit SK, Rattan KN, Gupta U et al. Multiple neurilemmomas of the penis. Pediatr Surg Int 2000;16:457. 25 Kousseff BG, Hoover DL. Penile neurofibromas. Am J Med Genet 1999;87:1–5. 26 Littlejohn JO, Belman AB, Selby D. Plexiform neurofibroma of the penis in a child. Urology 2000;56:669. 27 Yegane RA, Alaee MS, Khanicheh E. Congenital plexiform schwannoma of the clitoris. Saudi Med J 2008;29(4):600–2. 28 Santos LD, Currie B, Killingsworth MC. Case report: plexiform schwannoma of the vulva. Pathology 2001;33(4):526–31.

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29 Mazdak H, Gharaati M. Plexiform neurofibroma of penis. Urol J 2007;4(1):52–3. 30 Pascual-Castroviejo I, Lopez-Pereira P, Savasta S et al. Neurofibromatosis type 1 with external genitalia involvement presentation of 4 patients. J Pediatr Surg 2008;43(11):1998–2003. 31 Iwasa Y, Fletcher C. Distinctive prepubertal vulval fibroma: a hitherto unrecognized mesenchymal tumour of prepubertal girls: analysis of 11 cases. Am J Surg Pathol 2004;28(12):1601–8. 32 Suwa M, Takeda M, Bilim V et al. Epidermoid cyst of the penis: case report and review of the literature. Int J Urol 2000;7:431–3. 33 Hamada M, Kiryu H, Ohta T, Furue M. Ciliated cyst of the vulva. Eur J Dermatol 2004;14(5):347–9. 34 Stock JA, Niku SD, Packer MG et al. Fibrous hamartoma of infancy: a report of two cases in the genital region. Urology 1995;45:130–1. 35 Williams TS, Callen JP, Lafayette GO. Vulvar disorders in the prepubertal female. Pediatr Ann 1986;15:588–605. 36 Gao H, Wang C, Wang H, Yang X, Li J, Hong T. Lipomatosis of the penis and perineum in a 6-year-old boy. Eur J Pediatr 2005;164(2):115–16. 37 Chanda MN, Jamieson M, Poenaru D. Congenital perineal lipoma presenting as ‘ambiguous genitalia’: a case report. J Pediatr Adolesc Gynecol 2000;13(2):71–4. 38 Altcheck A, Deligdisch L, Norton K, Gordon R, Greco MA, Magid MS. Prepubertal unilateral fibrous hyperplasia of the labium majus: report of eight cases and review of the literature. Obstet Gynecol 2007;110(1):1039–8. 39 Vargas SO, Kozakewich H, Boyd TK et al. Childhood asymmetric labium majus enlargement: mimicking a neoplasm. Am J Surg Pathol 2005;29(8):1007–16.

Fig. 151.23 Acute scrotal oedema in nephritic syndrome. Courtesy of Dr M. Rogers.

Scrotal conditions Idiopathic scrotal calcinosis This condition may commence in childhood. Multiple firm, asymptomatic nodules, usually grey or white, appear on the scrotum. They may discharge chalky material from time to time [1,2]. There is no systemic metabolic disturbance, and calcium and phosphorus levels are normal. Histopathology shows amorphous calcium deposits surrounded by a granulomatous reaction with foreign body giant cells. Secondary dystrophic calcinosis may be the result of local trauma or infection. The lesions may be excised surgically.

Acute scrotal oedema Acute oedema and purpura of the scrotum may occur in Henoch–Schönlein purpura (see Chapter 160) and acute haemorrhagic oedema of the newborn [3,4]. Painless bilateral scrotal oedema may be a presenting sign of nephrotic syndrome (Fig. 151.23). Idiopathic scrotal oedema is an uncommon self-limited condition seen in prepubertal children. Painless or moderately painful swelling and erythema of the scrotum occur [5]. The condition may be unilateral or bilateral, and may be recurrent. This is the most common cause of

acute disease of the scrotum in boys under the age of 10 years. It is probably an allergic phenomenon [6]. Ultrasound and Doppler studies show oedema of the scrotal skin but no increase in size of testicles and epididymis [7,8]. Patients with acute scrotal oedema must always be investigated for torsion of the testis. References 1 Gormally S, Dorman T, Powell FC. Calcinosis of the scrotum. Int J Dermatol 1992;31:75–9. 2 Song DH, Lee KH, Kang WH. Idiopathic calcinosis of the scrotum. J Am Acad Dermatol 1998;19:1095–101. 3 Gomez Parada J, Puyol Pallas M, Vila Cots J et al. Acute scrotum and Schönlein–Henoch purpura: report of 2 new cases. Arch Esp Urol 2001;54:168–70. 4 Dubin BA, Bronson DM, Eng AN. Acute haemorrhagic edema of childhood: an unusual variant of leucocytoclastic vasculitis. J Am Acad Dermatol 1990;23:347–50. 5 Van Langen AM, Gal S, Hulsmann AR et al. Acute idiopathic scrotal oedema: four cases and a short review. Eur J Pediatr 2001;160:455–6. 6 Najmaldin A, Burge DM. Acute idiopathic scrotal oedema: incidence, manifestations and aetiology. Br J Surg 1987;74:634–5. 7 Planelles Gomez J, Beltran Armada J et al. Idiopathic scrotal edema: report of two cases. Arch Esp Urol 2007;60(7):799–802. 8 Coley B. Sonography of pediatric scrotal swelling. Semin Ultrasound CT MR 2007;28(4):297–306.

Genital Disease in Children

Genital signs of systemic disease Crohn disease Crohn disease, a chronic and relapsing inflammatory bowel disorder, is often associated with skin findings. Erythema nodosum and pyoderma gangrenosum may occur as non-specific associations, but the same granulomatous process that affects the bowel may be found in the skin and can be confirmed histologically. The biopsy will demonstrate giant cells, macrophages, lymphocytes and plasma cells in sarcoidal granulomas. This is known as metastatic Crohn disease and is very uncommon [1]. Crohn disease may affect the genital area in children and does so more commonly than in adults [2]. This can be contiguous with the bowel, with perianal lesions or on the genitalia [3,4]. It may also occur prior to and without gastrointestinal involvement [5]. The usual presentation is with discomfort and soreness, associated with firm oedema and hypertrophy of the labia in girls and the penis and scrotum in boys. Ulceration may occur. Perianal erosions and fissures, swelling, fistulae, skin tags and erythema are commonly found where there is genital involvement [6]. There may be a simultaneous cheilitis [7]. The vulval and perianal changes may precede gastrointestinal symptoms [2]. The condition must be differentiated from other processes that cause painless induration of the genital area, including filiariasis and lymphogranuloma venereum. Initial management of this condition should include referral to a gastroenterologist for investigation for bowel involvement. A non-invasive investigation for gastrointestinal Crohn disease, 99Tcm-HMPAO (hexamethyl propylene amine oxime) leucocyte labelling, is a nuclear medicine technique for screening for this condition [8]. The skin lesions tend to be resistant to treatment with oral antibiotics such as metronidazole and sulphasalazine, and prednisone is usually required to induce a remission. In the long term, oral azathioprine may be required [2].

Orofacial granulomatosis and anogenital granulomatosis In this group of children, painless induration of the lips associated with a similar induration of the penis, scrotum and perianal area occurs without bowel disease. Biopsy reveals sarcoidal granulomas with lymphangiectases [9]. Anogenital granulomatosis is the same condition histologically, presenting with diffuse penile, scrotal, vulval or anoperineal swelling [10]. This condition may be a forme fruste of Crohn disease [11] but some patients appear to be exhibiting a type IV hypersensitivity reaction to dietary allergens. This may be identified by patch testing [12]. Children with this condition should be investigated for Crohn disease. Treatment with topical and intralesional

151.23

corticosteroids in association with dietary restriction is considered first-line management [13]. A report from 2002 documents three children with granulomatous periorificial dermatitis who also had involvement of the labia majora [14]. In these children, histopathology demonstrated non-caseating perifollicular granulomas. This condition presents with an erythematous papular eruption, rather than swelling and fissuring that is typical of Crohn disease, but may need to be differentiated from it because of the histological appearance. There is no systemic involvement.

Behçet disease Behçet disease is a systemic vasculitis affecting arterioles and venules. It is characterized by recurrent oral ulcers, genital ulcers and ocular inflammatory disease. Joints, gastrointestinal tract, central nervous system and skin are other sites commonly involved in this multisystem disease. Behçet disease is reported in childhood and genital signs include epididymo-orchitis [15] and genital ulceration [16,17]. The age of onset of juvenile Behçet disease is approximately 12 years and mucocutaneous and joint symptoms are the most common manifestations. A recent review showed that oral ulcers are present in all childhood cases and genital aphthous ulcers in over 90%. Familial clustering was found in 45% of cases, significantly higher than in adult cases, but in other ways childhood Behçet disease presents similarly to adult cases and is treated in the same way [18].

Zinc deficiency Zinc deficiency is seen either at birth or on weaning with acrodermatitis enteropathica, or at around 6–9 months in fully breastfed babies of mothers with low breast milk zinc. The appearance is with an eroded bilateral vulval rash with a very well-demarcated edge. There is a similar perioral rash [19]. References 1 Lehrnbecher T, Kontny H, Jeschke RJ. Metastatic Crohn’s disease in a 9-year-old boy. Pediatr Gastroenterol Nutr 1999;28:321–3. 2 Ploysangam T, Heubi JE, Eisen D et al. Cutaneous Crohn’s disease in children. J Am Acad Dermatol 1997;36:697–704. 3 Phillip SS, Baird DB, Joshi VV et al. Crohn’s disease of the prepuce in a 12-year-old boy: a case report and review of the literature. Pediatr Pathol Lab Med 1997;17:497–502. 4 Tuffnell B, Buchan PC. Crohn’s disease of the vulva in childhood. Br J Clin Pract 1991;45:159–60. 5 Bourrat E, Faure C, Vignon-Pennamen MD, Rybojad M, Morel P, Navarro J. Anitis, vulvar edema and macrocheilitis disclosing Crohn disease in a child: value of metronidazole. Ann Dermatol Venereol 1997;124(9):626–8. 6 Koluglu Z, Kansu A, Demirceken F etal. Crohn’s disease of the vulva in a 10 year old girl. Turk J Pediatr 2008;50(2):197–9.

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7 Tatnall FM, Dodd HJ, Sarkany I. Crohn’s disease with metastatic cutaneous involvement and granulomatous cheilitis. J Roy Soc Med 1987;80:49. 8 Gibson J, Neilly JB, Wray APM et al. 99Tcm-leucocyte labelling in orofacial granulomatosis and gastrointestinal Crohn’s disease in childhood and early adulthood. Nucl Med Commun 2000;21:155–8. 9 Murphy M, Kogan B, Carlson JA. Granulomatous lymphangitis of the scrotum and penis: report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation. J Cutan Pathol 2001;28:419–24. 10 Van de Scheur MR, van der Waal R, van der Waal I, Stoof TJ, Deventer S. Ano-genital granulomatosis: the counterpart of oro-facial granulomatosis. J Eur Acad Derm Venereol 2003;17(2):184–9. 11 Murphy MJ, Kogan B, Carlson JA. Granulomatous lymphangitis of the scrotum and penis. Report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation. J Cutan Pathol 2001;28(8):419–24. 12 Armstrong BK, Biagioni P, Lamey PJ et al. Contact hypersensitivity in patients with orofacial granulomatosis. Am J Contact Dermatitis 1997;8:35–8. 13 Gibson J, Forsyth A, Milligan KA. Dietary and environmental allergens in patients with orofacial granulomatosis. J Dent Reserve 1996;75:334. 14 Urbatsch AJ, Frieden I, Williams ML et al. Extrafacial and generalised granulomatous periorificial dermatitis. Arch Dermatol 2002;138: 1354–8. 15 Pektas A, Devrim I, Besbas N et al. A child with Behcet’s disease presenting with a spectrum of inflammatory manifestations including epididymoorchitis. Turk J Pediatr 2008;50(1):78–80. 16 Karincaoglu Y, Borlu M, Toker S et al. Demographic and clinical properties of juvenile-onset Behcet’s disease: a controlled multicenter study. J Am Acad Dermatol 2008;58(4):579–84. 17 Yuksel Z, Schweizer J, Mourad-Baars PE, Sukhai RN, Mearin LM. A toddler with recurrent oral and genital ulcers. Clin Rheumatol 2007;26:969–70. 18 Borlu M, Uksal U, Ferahbas A, Evereklioglu C. Clinical features of Behcet’s disease in children. Int J Dermatol 2006;45(6):713–16. 19 Stapleton KM, O’Loughlin E, Relic JP. Transient zinc deficiency in a breast-fed premature infant. Australas J Dermatol 1995;36:157–9.

Psychological aspects of genital disease in children Among adults with genital complaints, a small but significant group presents with symptoms but with no apparent abnormality. Although some of this group are malingering or somaticizing, there are many more who have a genuine complaint of neuropathy or referred pain. Neuropathic vulval pain relieved by tricyclic antidepressant medication has also been reported in preadolescent girls, but is significantly less common than in adults [1]. Children who suffer from genuine neuropathic vulval pain describe it in a similar way to adults: intolerance of wearing tight clothes, stabbing, burning and aching. They may state that they relieve the pain by pressing on the painful spot. When a child presents with symptoms but nothing to see, even after close examination when symptoms are maximal, it is more likely that there is no physical com-

plaint, particularly when they do not give a consistent description that suggests neuropathy. A common scenario is the child who is presented because of a greenish discharge noticed as staining of the underwear. There are no symptoms other than the discharge and swabs and urine culture are normal. This situation appears to be a normal variant. A somewhat less innocent situation occurs if a child constantly complains of vulval discomfort in the absence of findings and without any observable sign of being in pain. Children rapidly realize that complaining of genital pain, particularly at school or in public, attracts lots of adult attention and is a source of embarrassment for their parents. They may even find that they are rapidly sent home from school by teachers worried about sexual abuse allegations, and distraught parents are summoned to explain the behaviour. Children who do this have no idea how much real adult distress they are causing but know that it is an effective attention-seeking device. The best way to deal with it is usually to withdraw the attention, but occasionally psychiatric help is needed. In some cases, a mother with a vulval problem may project her concerns onto the child, whether or not there is a real problem present. It may be possible to enquire about this possibility when obtaining a family history. In some cases only reassurance is necessary, but a more deep-seated psychological problem may again require psychiatric help not for the child, but for the mother. Children who masturbate, and whose parents are shocked by their behaviour, often learn to explain their actions to their parents by saying that they are in pain, and their parents may need to come to terms with the normality of their actions. In most of these cases, non-intervention, reassurance and not giving in to attention-seeking behaviour is the best treatment. They represent a real trap for the unwary, however. Most parents of a girl with a vulval condition of any sort will have considered the possibility of sexual abuse, even though they often do not tend to voice it, particularly at the first visit. It is reasonable for them to do so. Child sexual abuse and paedophilia have received enormous publicity in the lay press; however, details of the evidence for abuse are never provided, and this is therefore left to the readers’ imagination. Professionals who deal with children are also made very aware of child abuse as an issue because of legal requirements to reveal criminal records as a condition of employment. It is therefore common for carers and teachers to have these concerns about children who scratch the vulval area constantly or complain of vulval pain. Their concern has to extend to the possibility that parents who suspect abuse in a child with a vulval condition may blame persons who care for the child in their absence.

Genital Disease in Children

Even in expert hands, diagnosing sexual abuse is very difficult, and impossible to prove without a disclosure from the child or a relative. Even after investigation and interview in the child protection unit setting, many cases remain unresolved [2,3]. The fact is that most children who have been sexually abused do not have any physical signs, as trauma such as bruises resolve quickly, and abusive behaviour often does not involve attempts at penetration [2,3]. Physical examination cannot confirm or exclude non-acute sexual abuse as a cause of genital trauma in prepubertal girls [4]. The presence of a rash such as eczema, psoriasis or lichen sclerosus should not raise queries of abuse in the absence of other suspicious features. When a child presents with a vulval rash it is so common for parents to have unvoiced concern about sexual abuse that it is worth enquiring about this. Parents will usually be greatly relieved that their child simply has a skin problem. The medical literature contains many cases of skin conditions being mistaken for sexual abuse, and this includes lichen sclerosus, ulcerated haemangiomas and rarer skin conditions such as bullous pemphigoid, which may cause genital ulcers [5–8]. It is important to understand that lay people may attribute almost any vulval condition to sexual abuse. Although the presence of a skin condition does not rule it out, there would have to be other grounds to suspect

151.25

it, based on household composition, parental concerns, presence of sexually acquired infections and behavioural abnormalities in the child. References 1 Reed BD, Cantoris L. Vulvodynia in preadolescent girls. J Lower Genital Tract Dis 2008;12(4):257–61. 2 Tipton A. Child sexual abuse: physical examination techniques and interpretation of findings. Adolesc Pediatr Gynaecol 1989;2:10–25. 3 Weinberg R, Sybert VP, Feldman KW et al. Outcome of CPS referral for sexual abuse children with condylomata acuminata. 1994;7:19–24. 4 Berkoff MC, Zolotor A, Makaroff KL, Thackeray JD, Shapiro RA, Runyan DK. Has this prepubertal girl been sexually abused? JAMA 2008;300(23):2779–92. 5 Jenny C, Kirby F, Fuquay D. Genital lichen sclerosus mistaken for child sexual abuse. Pediatrics 1989;4:597–9. 6 Wood PL, Bevan T. Child sexual abuse enquiries and unrecognised vulval lichen sclerosus et atrophica. BMJ 1999;319:899–900. 7 Hosteller BR, Jones CE, Miram D. Capillary hemangioma of the vulva mistaken for sexual abuse. Adolesc Pediatr Gynaecol 1994;7: 44–6. 8 Levine V, Sanchez M, Nestor M. Localised vulvar pemphigoid in a child misdiagnosed as sexual abuse. Arch Dermatol 1992;128:804–6.

Acknowledgement I would like to acknowledge and thank Dr Maureen Rogers, co-author of the original chapter, for her previous contribution to the writing and illustration of this work.

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C H A P T E R 152

Vulvovaginitis and Lichen Sclerosus Sallie M. Neill St John’s Institute of Dermatology, St Thomas’ Hospital and King’s College London, London, UK

Vulvovaginitis, 152.1

Lichen sclerosus, 152.5

Vulvovaginitis Definition. Vulvovaginitis is defined as inflammation involving both the vulval and vaginal epithelia. However, in clinical practice this term is often applied incorrectly to cases in which there is vulval inflammation alone, i.e. vulvitis. Inflammation of the vagina (vaginitis) seldom occurs in isolation as the associated discharge that accompanies it usually results in contamination of the perineum with consequent irritation and inflammation of the vulva. It is important in assessing the patient to ascertain whether there is both vulval and vaginal involvement in order to narrow down the possible diagnoses. Anatomy and physiology. The vulva in the pubescent girl comprises various anatomical sites, which include the mons pubis, paired labia majora, the labia minora, the glans clitoris and the inner vulval vestibule. The labia minora extend anteriorly to form the clitoral hood and frenulum. The vulval epithelium is cornified and stratified with the exception of the vestibule, which, although still stratified is non-cornified, i.e. a mucosa. The entire length of the vagina is lined with stratified non-cornified epithelium. In the premenarchal girl, the labia minora are often small or only partly developed but the clitoral hood and the glans clitoris are present. The labia majora have little or no hair and are less rounded than in the adult as the subcutaneous fat pads are undeveloped, leaving the vestibule and vagina more exposed to the effects of irritants and friction. The unoestrogenized vestibule is covered with a thinned epithelium and the underlying vasculature is clearly visible, giving it a bright-red appearance, which is often misdiagnosed by the inexperienced examiner as pathological inflammation. The thinner vestibular

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

epithelium is also more sensitive to irritants. The vaginal pH is neutral to alkaline and the normal flora of asymptomatic prepubescent girls consists of aerobic and anaerobic bacteria. The most common aerobic organisms are Staphylococcus epidermidis, enterococci and Escherichia coli and the predominant anaerobes were the Gram-positive cocci, Peptococcus and Peptostreptococcus [1,2]. An alkaline pH, although offering some protection against candidal infection, leaves the epithelium more susceptible to bacterial infection. In addition, the anus lies in close proximity to the vestibule, and very often perineal hygiene is inadequate, with habits such as back-tofront wiping after opening the bowels leading to bacterial contamination or irritation from faecal material. Following the thelarche, oestrogen stimulates the endocervical glands to produce mucus and a normal physiological vaginal discharge which precedes the menarche by 6–12 months. At the onset of puberty the labia majora become more rounded, the labia minora develop further, the sebaceous glands enlarge and their secretions are promoted. Hair develops on the the labia majora and a little later on the mons pubis. All these changes give more protection to the inner aspects of the vulva. The vagina becomes thickened and rugose and the vaginal and vestibular epithelial cells become glycogenated. The neutral pH of the vagina becomes acidic as a result of the fermentation of glycogen in the oestrogenized epithelium, lowering the pH to 4.0–4.5, which then supports the nonpathogenic growth of lactobacilli, haemolytic streptococci and diphtheroids. Aetiology and pathogenesis. In considering the pathogenesis of vulvovaginitis, it is helpful to categorize it into that associated with a true vaginal discharge and that without.

Vulvovaginitis associated with a vaginal discharge Vaginal discharge can be physiological, such as that seen in the newborn whose vaginal epithelium is still under

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the influence of maternal oestrogens or in the menarchal child. A physiological discharge is unlikely to be associated with inflammatory changes in either the vagina or vulva and when inflammation is present, there is likely to be pathology. Pathological discharge can be associated with infection, chemical irritants, e.g. bubble baths, congenital malformation, e.g. ectopic ureter when urine will be the cause of the discharge, rare tumours, e.g. lymphangioma producing lymph [3,4], endocrine abnormality or foreign body [5,6]. However, the majority of cases of vulvovaginitis in prepubertal girls are non-specific with an infectious cause found in about a third of cases [7]. The recognized pathogenic organisms include group A βhaemolytic streptococcus, Haemophilus influenzae, Escherichia coli and in some occasions Staphylococcus aureus [1,2,7-9]. Streptococcal vaginitis has also been reported in association with constipation [10] and glomerulonephritis [11]. There have also been reports of an associated vulvovaginal inflammation with both echo and coxsackie virus infections [12]. The enteric pathogens associated with vulvovaginitis are Shigella [13 ], which frequently occurs in the absence of diarrhoea, and Yersinia [14]. Candidal infection is rarely the cause of problems in early infancy and prepubertally and is only seen in postpubertal children, presumably due to the effects of oestrogen on the vaginal epithelium, increasing the glycogen content of the epithelial cells of both the vestibule and vagina and the presence of lactobacilli. Candida may then be a normal vaginal commensal. The rare occurrence of candidal infection in the neonatal period may be explained by the fact that maternal oestrogens still exert an effect on the infant’s mucosae from birth to 2 months. An overgrowth of Candida may, however, exacerbate a nappy dermatitis and/or vulval dermatitis in an older child, particularly if there is gastrointestinal carriage of the organism. Candidiasis in this situation is a secondary phenomenon and once the underlying dermatosis is treated, the Candida is no longer a problem. Sexually transmitted infections are seen in sexually active teenagers or younger children who are being sexually abused (see Chapter 155). The most common bacterial pathogens in this situation are Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas. The two viral infections seen are herpes simplex and human papillomavirus; however, it should be appreciated that these viruses are not always sexually transmitted. Vulval inflammation and irritation secondary to a recurrent or persistent foul-smelling discharge that fails to respond to treatment are suggestive of a foreign body. If the foreign body can be visualized, it can often be removed by irrigation. If not, then vaginoscopy and examination need to be performed under anaesthetic. A blood-stained or brown discharge is also strongly suggestive of a vaginal foreign body and this can be present for

many months to years before it is diagnosed [6]. The most common items found were tissue paper and small hard items [5,6]. All persistent, recurrent or blood-stained vaginal discharges should be fully evaluated to rule out a foreign body or other vaginal or pelvic pathology.

Vulvovaginitis without a discharge (vulvitis) This usually occurs when there is inflammation of the vulva alone and it would be more accurate to refer to the problem as vulvitis. Vulvitis may be caused by any dermatosis occurring at this site in isolation or as part of a generalized eruption. There is often the mistaken diagnosis of a vaginal discharge as the skin is wet due to the inflammatory changes, secondary infection and erosions of the affected epithelium. Diagnostic difficulties arise most frequently when vulvitis occurs in isolation because the typical morphological signs that aid in diagnosis are often lost due to the occlusive effect at this natural flexural site. The most common dermatological disorders affecting the vulval skin in infancy and childhood are eczema, psoriasis and lichen sclerosus [15]. The eczema group includes irritant contact dermatitis, seborrhoeic eczema and atopic eczema. Allergic contact eczema is very rare. It is important and helpful to examine other flexural sites, nails and scalp to see if there is evidence of these conditions elsewhere. Lichen sclerosus is the most common scarring skin disorder to affect this site exclusively as extragenital lesions are uncommon in children. Cutaneous lichen planus is very rare in childhood, with most of the cases reported occurring after the age of 10 years, and it is seen more commonly at this early age in Asian children and only a very few of these have genital involvement. Blistering disorders may also present with a macerated vulvitis such as the acquired junctional and dystrophic types of epidermolysis bullosa (see Chapter 118) and in the prebullous phase of the acquired autoimmunobullous diseases, chronic bullous disease of childhood (linear IgA disease of children) and bullous pemphigoid (see Chapters 89 and 91). Erythema and bullous lesions may also involve the vulval skin, either as part of the prodrome or simultaneously when the rest of the skin is affected by erythema multiforme, staphylococcal scalded skin syndrome, Stevens–Johnson syndrome or Kawasaki disease. A fixed drug eruption on the genital skin of young boys is well recognized and often due to paracetamol [16] but oddly, it has not been reported affecting the vulval skin in girls and this may be because it is not always recognized and diagnosed. Rarer dermatoses presenting as vulvitis include acrodermatitis enteropathica, Crohn disease, Langerhans cell histiocytosis and Hailey–Hailey disease. Irritant eczema and inflammation of the vulval skin associated with play are recognized after playing in sand

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152.3

Finally, the trauma of sexual abuse may result in inflammation with or without an associated sexually transmitted infection.

Fig. 152.1 Jacquet dermatitis, showing healing lesions that had been ulcerated nodules.

(‘sand pit vulvitis’), swimming in chlorinated pools and bathing in bubble baths [12]. Jacquet irritant erosive dermatitis describes a condition with ulcerated papules and pustules on the labia majora of the vulval skin of infants and is believed to be due to prolonged contact with soiled napkins (Fig. 152.1). This is seen less frequently with the use of disposable nappies and the recently improved absorbency of the materials used in their manufacture. A similar but quite separate entity, granuloma gluteale infantum, was first described in 1971 [17]. This condition is seen almost exclusively in infants treated with a topical corticosteroid and consists of larger non-ulcerating nodules, usually on the convexities of the nappy area. Congenital cavernous haemangiomas may occur on the vulval skin, where they are more likely to become ulcerated due to the chafing effect of nappies. A further complication with a large haemangioma in this area is obstruction of the free flow of the urine, leading to pooling and bacterial contamination. The other causes of urinary pooling are labial adhesions and a microperforate hymen. In the latter, the normal escape of urine that enters the vagina on micturition is obstructed [18]. Threadworm infestation can be a cause of vulvovaginitis and this was reported in one series in nearly one-third of the cases and in one-half of these there was also a positive vaginal swab culture for bacteria [19]. An acute vulvitis has been described as an exanthema associated with parvovirus B19 infection [20].

Clinical features. The skin signs seen in vulvovaginitis include erythema, oedema, erosions and fissuring of the vulva with an accompanying vaginal discharge. If the underlying condition is itchy, there will also be lichenification and excoriations. In severe inflammation, blisters and erosions develop. In the absence of a vaginal discharge, a vaginal infection is extremely unlikely. The main symptoms that the child complains of include itch, vulval soreness, dysuria and discharge. The discharge is often yellow, green or brown and may be reported as having an unpleasant smell. A clear odourless discharge does not exclude an infection. The symptoms may be severe enough to interfere with sleep and the parents may notice blood or evidence of a discharge on the child’s underwear. Confirmation of the discharge is important as it is often reported but found infrequently on examination. In one study, only one-half of those reportedly having a discharge were found to have one when examined [21]. The discharge due to a foreign body often has an unpleasant odour. Sometimes the vulval skin has very minimal changes of erythema but the vulval vestibule is very red and tender. This is usually the result of irritancy and the problem may be bubble baths or the harsh disinfectants used in swimming pools. The complaint is usually of a distressing stinging and/or burning sensation in the inner vulval area, often awaking the child suddenly in the night. There is usually an accompanying complaint of dysuria. Diagnosis. A careful history and thorough examination are essential to establish an accurate diagnosis. Any discharge must be fully investigated with samples for wet preparations to examine for Trichomonas and Candida, and further samples for Gram staining and bacterial culture. If herpes simplex is suspected, then viral culture and smear preparations for electron microscopy should be performed as well as serological testing. Any vaginal samples can be obtained without trauma and simple noninvasive techniques such as a swab of any discharge that has accumulated at the fourchette. If this is not possible, a vaginal specimen can be obtained using a neonatal suction catheter or a catheter within a catheter technique [22]. In this technique the hub of a butterfly infusion set with only the first 11.25 cm of the tubing still attached to it, the needle end having been cut off, is threaded into the distal end of an FG no. 12 bladder catheter that has been shortened to 10 cm. The butterfly hub is then attached to a 1 mL syringe filled with sterile saline. The uncut

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Chapter 152

front-to-back wiping may be extremely effective in treating the immediate problem and preventing further episodes. Foreign bodies may be removed with gentle vaginal lavage after first anaesthetizing the vulva with topical lidocaine but if the object is firmly embedded in the vaginal wall or the child is very young or distressed, an examination under general anaesthesia will usually be required to remove it atraumatically.

Fig. 152.2 Ova of Enterobius vermicularis.

proximal end of the catheter is inserted into the vagina and the saline is then gently flushed through and aspirated. This aspirate is then examined and cultured. It is very important bearing in mind the confounding overlap between normal flora and potential pathogens that the finding of an organism does not necessarily mean that it is the cause of the discharge [2]. If intestinal worms are suspected, a sticky tape test should be performed in the morning to try and detect parasitic ova (Fig. 152.2). However, this is not always reliable and if the symptoms and signs are highly suggestive of infestation then this should be treated empirically. An examination under anaesthetic may be required if there is a suspected foreign body, a persistent bloodstained or offensive smelling discharge and also in cases when a skin biopsy is indicated. A midstream specimen of urine should be taken for microscopy and culture and if gonorrhoea is suspected, nucleic acid amplification techniques (NAATs) can be used to detect Neisseria gonorrhoeae in the urine sample. In cases when candidiasis recurs without a background dermatosis then diabetes or immune deficiency must be excluded.

Treatment. Treatment depends upon the diagnosis. If it is due to a dermatosis, the specific topical treatment for that condition will be necessary and general measures to prevent irritation will include washing with a soap substitute such as aqueous cream or emulsifying ointment, avoiding bubble baths or shampooing the hair in the bath. Topical barriers are useful and petroleum jelly can be used when swimming in heavily disinfected pools. If there is a proven infection or infestation, the appropriate antibiotic or anthelminthic agent should be prescribed. However, a change in perineal hygiene with emphasis on

References 1 Gerstner GJ, Grunberger W, Boschitsch E, Rotter M. Vaginal organisms in prepubertal children with and without vulvovaginitis. A vaginoscopic study. Arch Gynecol 1982;231:247–52. 2 Jaquiery A, Stylianopoulos A, Hogg G, Grover S. Vulvovaginitis: clinical features, aetiology, and microbiology of the genital tract. Arch Dis Child 1999;81:64–7. 3 Allen-Davis JT, Russ P, Karrer FM et al. Cavernous lymphangioma presenting as a vaginal discharge in a six-year-old female: a case report. J Pediatr Adolesc Gynecol 1996;9:31–4. 4 Mulchahey K. Management Quandary. Persistent discharge in a premenarchal child. J Pediatr Adolesc Gynecol 2000;13:187–8. 5 Smith YR, Berman DR, Quint EH. Premenarchal vaginal discharge: findings of procedures to rule out foreign bodies. J Pediatr Adolesc Gynecol 2002;15:227–30. 6 Stricker T, Navratil F, Sennhauser FH. Vaginal foreign bodies. J Paediatr Child Health 2004;40:205–7. 7 Stricker T, Navratil F, Sennhauser FH. Vulvovaginitis in prepubertal girls. Arch Dis Child 2003;88:324–6. 8 Donald FE, Slack DB, Colman G. Streptococcus pyogenes vulvovaginitis in children in Nottingham. Epidemiol Infect 1991;106:459–65. 9 Cox RA, Slack MP. Clinical and microbiological features of Haemophilus influenzae vulvovaginitis in young girls. J Clin Pathol 2002;55:961–4. 10 Van Neer PA, Korver CR. Constipation presenting as recurrent vulvovaginitis in prepubertal children. J Am Acad Dermatol 2000;43:718–19. 11 Nair S, Schoeneman MJ. Acute glomerulonephritis with group A streptococcal vulvovaginitis. Clin Pediatr 2000;39:721–2. 12 Heller RH, Joseph JM, Davis HJ. Vulvovaginitis in the premenarcheal child. J Pediatr 1969;74:370–7. 13 Murphy TV, Nelson JD. Shigella vaginitis: report of 38 patients and a review of the literature. Pediatrics 1979;63:511–16. 14 Watkins S, Quan L. Vulvovaginitis caused by Yersinia enterocolitica. Pediatr Infect Dis 1984;3:444–5. 15 Fischer G. Vulval disease in pre-pubertal girls. Australas J Dermatol 2001;42:225–34. 16 Nussinovitch M, Prais D, Ben-Amitai D et al. Fixed drug eruption in the genital area in 15 boys. Pediatr Dermatol 2002;19:216–19. 17 Tappeiner J, Pfleger L. Granuloma gluteale infantum. Hautarzt 1971;22:383–8. 18 Capraro VJ, Dillon WP, Gallego MB. Microperforate hymen. A distinct clinical entity. Obstet Gynecol 1974;44:903–5. 19 Pierce AM, Hart CA. Vulvovaginitis: causes and management. Arch Dis Child 1992;67:509–12. 20 Delbrel X, Sibaud V, Cogrel O et al. Pseudo-cellulitis plaques and Koplick spot: a particular form of parvovirus B19 primo-infection. Revue Méd Interne 2003;24:317–19. 21 Paradise JE, Campos JM, Friedman HM et al. Vulvovaginitis in premenarchal girls: clinical features and diagnostic evaluation. Pediatrics 1982;70:193–8. 22 Pokorny SF, Stormer J. Atraumatic removal of secretion from the prepubertal vagina. Am J Obstet Gynecol 1987;156:581–2.

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152.5

Fig. 152.4 Histology of lichen sclerosus. The epidermis is thinned and effaced. The superficial dermis is hyalinized and there is a lymphocytic infiltrate immediately beneath this zone.

The incidence of lichen sclerosus is unknown but it seems to be increasingly diagnosed in children and the estimated prevalence may be between 1 in 900 in premenarchal girls [8]. Fig. 152.3 Lichen sclerosus, showing characteristic white atrophic skin with some purpura around the introitus.

Lichen sclerosus Definition. Lichen sclerosus is a chronic, lymphocytemediated inflammatory dermatosis characterized by shiny, white, atrophic patches with a predilection for the genital and perianal skin (Fig. 152.3). It is more common in females than in males and was originally described in 1887 by Hallopeau [1] as a variant of lichen planus. The peak ages of presentation are prepubertal children and menopausal women [2]. Aetiology and pathogenesis. The aetiology is unknown but familial cases are seen [3]. The evidence is increasing that it is an autoimmune-related disorder, with many affected adult female patients having circulating autoantibodies to extracellular matrix protein as well as other organ-specific autoantibodies [4,5]. There is a significant association with other autoimmune disorders, the most frequently reported being vitiligo, alopecia areata and thyroid disease. Evidence for an association with particular HLA types in lichen sclerosus is conflicting, but an increased association with DQ7 has been found in adults and children [6]. The reports of an association with Borrelia burgdorferi seem to depend on geographical location but the association is still unclear and remains controversial [7].

Pathology. The histopathological features were described first by Darier [9] and later by Hewitt [10]. The typical histological findings include a thinned, effaced epidermis, with or without an overlying hyperkeratosis. In the reticular dermis, immediately beneath the epidermis, there is a broad band of homogenized collagen. A lymphocytic infiltrate may be present just below the abnormal dermis (Fig. 152.4). In some areas this infiltrate can be seen along the dermoepidermal junction, with areas of liquefactive degeneration very similar to those changes seen in lichen planus. Clinical features. The main symptom in girls is itch, but dysuria and difficulty with defaecation are not uncommon when there is vulval or perianal fissuring. The condition is reported less in boys, occurring most frequently on the prepuce and glans. However, the condition may be under-recognized, as not all the preputial specimens from boys requiring a circumcision for medical reasons are examined histologically for lichen sclerosus. The usual presentation in young boys is a history of recurrent balanitis with erythema, fissuring and tightening of the foreskin, which can eventually lead to phimosis. Difficulty in micturating may occur because of the phimosis or, more rarely, as a result of meatal narrowing if the glans and urethral meatus are involved. In girls the initial cutaneous signs are erythema, excoriations and lichenification that may be associated with loss of pigmentation, and an acquired atrophic appearance often described in appearance as ‘cigarette paper ’

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Chapter 152

minora may fail to develop or be lost due to scarring. The clitoral hood can become tethered to the glans of the clitoris and seal over completely. Introital narrowing is an unusual complication as lichen sclerosus rarely affects the vestibule and never affects the vagina as it appears to be confined to cornified stratified squamous epithelium, sparing non-cornified (mucosal) squamous epithelium. The lesions often extend in a figure-of-eight configuration to involve the perianal skin in girls but not in boys [14] (see Fig. 152.5). If perianal involvement is severe, the associated fissuring results in painful defaecation, which can subsequently lead to constipation and faecal retention. Extragenital involvement is rare in children, occurring in less than 10%. Complications

Fig. 152.5 Early, erythematous phase of lichen sclerosus involving the vulval and perianal skin in a figure-of-eight configuration.

Scarring Scarring can lead to persistent fusion of the labia minora, causing difficulties with micturition. If there is significant introital narrowing, this may lead to problems with sexual intercourse in adult life. A pseudocyst of the clitoris may develop due to the accumulation of keratinous debris under the fused clitoral hood. However, stressing that these complications are rare is important in reassuring the parents. Malignancy Squamous cell carcinoma (SCC) may occur on a background of lichen sclerosus and the incidence is 4% or less in elderly adult women. The risk for children is unknown but likely to be negligible. However, there are very rare case reports of SCC in young adults in their late teens and early twenties who may have had lichen sclerosus in childhood [2,15,16].

Fig. 152.6 Ecchymoses of introital skin. Courtesy of Dr C.M. Ridley.

wrinkling (Fig. 152.5). There may be purpura and extensive ecchymoses that can be mistaken for child abuse [11] (Fig. 152.6). This is not usually the case, but it must be appreciated that lichen sclerosus can Koebnerize and, if a child was the subject of abuse, it could possibly exacerbate the symptoms and signs [12]. Blistering may occur and, very rarely, milia develop [13]. There may be architectural distortion as the labia

Prognosis. Children respond well to treatment and in clinical practice most of those with lichen sclerosus seem to resolve at puberty, but some may continue to have the disease beyond the menarche. The scarring and architectural changes are permanent but in most cases the scarring does not interfere with future sexual function, pregnancy or normal vaginal delivery. Untreated, the disease can continue unremittingly for many years. Phimosis that does not respond to topical treatment will require a circumcision. Differential diagnosis. In the early inflammatory stages, the disease can be mistaken for psoriasis or eczema but once the characteristic whitening occurs, these diseases can easily be excluded (Fig. 152.7). Vitiligo enters into the differential diagnosis but does not result in a textural change in the skin or scarring. Vitiligo and lichen sclerosus can occur together (Fig. 152.8). At the end-stage of disease when the lichen sclerosus is in remission, the

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152.7

Treatment

Fig. 152.7 Differential diagnosis: psoriasis extending into the genitocrural folds.

Fig. 152.8 Differential diagnosis: vitiligo results in loss of pigmentation only but on the right-hand side of the vulva, an area of textural change can be seen as the patient had lichen sclerosus as well as vitiligo.

signs of atrophy and scarring are similar to those found in other scarring inflammatory disorders and include lichen planus and the blistering disorders such as chronic bullous disease of childhood or cicatricial pemphigoid. Finally, as already mentioned, if there are extensive ecchymoses, a mistaken diagnosis of child abuse may be made.

Medical The treatment of choice is a potent topical corticosteroid such as clobetasol propionate 0.05% [17-20]. There are no randomized controlled trials comparing potency of steroid, frequency of application or length of treatment. The following regimen is currently recommended by the author. A finger tip or less measure of clobetasol propionate 0.05% is applied to the affected skin once daily, usually at night, taking care to avoid smearing onto the inner upper thighs, where striae are likely to develop with the injudicious use of a very potent steroid. Nightly application is carried out for 4 weeks followed by application on alternate nights for a further 4 weeks. In the final 4 weeks steroid is applied twice per week. The majority of children respond quickly to this regimen and then use the steroid cream as and when required, which is usually infrequently. A 30 g tube of clobetasol will usually last 1 year and the child should not experience any side-effects with this regimen. Topical testosterone and progesterone are no longer recognized treatments and have no place in the management of lichen sclerosus in children. Oral steroids are not required, and failure to respond to the potent topical steroid ointment should raise the possibility of non-compliance, another diagnosis or sexual abuse. A soap substitute such as aqueous cream is also a useful adjunct to treatment. In recent years the topical calcineurin inhibitors tacrolimus and pimecrolimus have been used for lichen sclerosus that is resistant to topical corticosteroids or in cases where there have been steroid sideeffects [21,22] but these should be used with caution [23]. Topical retinoids are helpful particularly if there are areas of hyperkeratosis but their irritant effect limits their use. Reassurance is also very important as parents now have access to medical information on the internet; some of the information is biased and may cause great concern. It is important to discuss these problems in consultations to avoid unnecessary concern. The majority of girls with uncomplicated lichen sclerosus should expect to have no problems with sexual intercourse in later life and to undergo a normal vaginal delivery at the end of any pregnancies. Significant scarring leading to marked introital narrowing can be dealt with later in life (see below). Finally, it has to be stressed that the risk of developing squamous cell carcinoma is very small. Surgical Only rarely is surgery indicated in the treatment of young girls with lichen sclerosus, as surgical excision may result in Koebnerization and exacerbation of the disease postoperatively. In a very small number of cases, surgical division of persistently fused labia minora may be necessary if there is interference with micturition or menstrua-

152.8

Chapter 152

tion; if a clitoral pseudocyst develops, surgical intervention is necessary to release the underlying collection of keratinous debris [24]. Circumcision may be necessary in boys who develop a phimosis of the prepuce that is not reversed with the use of a potent topical steroid. It is extremely unusual for the disease to affect the glans postoperatively if there was no involvement before. In later life if there is a scarred and narrowed introitus, making intercourse difficult, a perineoplasty can be performed [25]. Surgery is obviously required in the extremely rare event of a squamous cell carcinoma occurring. References 1 Hallopeau H. Lichen plan sclereux. Ann Dermatol Syph 1887;10:447–9. 2 Wallace HJ. Lichen sclerosus et atrophicus. Trans St John’s Dermatol Soc 1971;57:9–30. 3 Sahn ES, Bluestein EL, Oliva S. Familial lichen sclerosus et atrophicus in childhood. Pediatr Dermatol 1994;11:160–3. 4 Chan I, Oyama N, Neill SM et al. Characterization of IgG autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Clin Exper Dermatol 2004;29:499–504. 5 Goolamali SK, Barnes EW, Irvine WJ et al. Organ-specific antibodies in patients with lichen sclerosus. BMJ 1974;iv:78–9. 6 Powell J, Wojnarowska F, Winsey S et al. Lichen sclerosus premenarche: autoimmunity and immunogenetics. Br J Dermatol 2000;142:481–4. 7 Edmonds E, Mavin S, Francis N, Ho-Yen D, Bunker C. Borrelia burgdorferi is not associated with genital lichen sclerosus in men. Br J Dermatol 2009;160:459–60. 8 Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus: an increasingly common problem. J Am Acad Dermatol 2001;44:803–6. 9 Darier J. Lichen plan sclereux. Ann Dermatol Syph 1892;3:833–7. 10 Hewitt J. Histologic criteria for lichen sclerosus of the vulva. J Reprod Med 1986;31:781–7.

11 Handfield-Jones SE, Hinde FRJ, Kennedy CTC. Lichen sclerosus et atrophicus in children misdiagnosed as sexual abuse. BMJ 1987;294:1404–5. 12 Warrington SA, San Lazaro C. Lichen sclerosus et atrophicus and sexual abuse. Arch Dis Child 1996;75:512–16. 13 Leppard B, Sneddon IB. Milia occurring in lichen sclerosus et atrophicus. Br J Dermatol 1975;92:711–14. 14 Ridley CM. Genital lichen sclerosus (lichen sclerosus et atrophicus) in childhood and adolescence. J Roy Soc Med 1993;86:69–75. 15 Cario GM, House MJ, Paradinos FJ. Squamous cell carcinoma of the vulva in association with mixed vulvar dystrophy in an 18 yr old girl. Case report. Br J Obstet Gynaecol 1984;91:87–90. 16 Pelisse M. Lichen sclerosus. Ann Dermatol Venereol 1987;114:411–19. 17 Fischer G, Rogers M. Treatment of childhood vulvar lichen sclerosus with potent topical corticosteroid. Pediatr Dermatol 1997;14:235–8. 18 Smith YR, Quint EH. Clobetasol propionate in the treatment of premenarchal vulvar lichen sclerosus. Obstet Gynecol 2001;98:588–91. 19 Garzon MC, Paller AS. Ultrapotent topical corticosteroid treatment of childhood lichen sclerosus. Arch Dermatol 1999;135:525–8. 20 Neill SM, Tatnall FM, Cox NH. Guidelines on the management of lichen sclerosus. Br J Dermatol 2002;147:640–9. 21 Boms S, Gambichler T, Freitag M, Altmeyer P, Kreuter A. Pimecrolimus 1% cream for anogenital lichen sclerosus in childhood. BMC Dermatol 2004;4:14. 22 Matsumoto Y, Yamamoto T, Isobe T, Kusunoki T, Tsuboi R. Successful treatment of vulvar lichen sclerosus in a child with low-concentration topical tacrolimus ointment. J Dermatol 2007;34:114–16. 23 Fischer G, Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma: a case report. J Reprod Med 2007;52:329–31. 24 Paniel BJ, Rouzier R. Surgical procedures in benign vulval disease. In: Neill S, Lewis F (eds) Ridley’s The Vulva. Chichester: WileyBlackwell, 2009: 235–6. 25 Rouzier R, Haddad B, Deyrolle C et al. Perineoplasty for the treatment of introital stenosis related to vulval lichen sclerosus. Am J Obstet Gynecol 2002;186:49–52.

153.1

C H A P T E R 153

Sexually Transmitted Diseases in Children and Adolescents Arnold P. Oranje1, Robert A.C. Bilo2 & Nico G. Hartwig1 1

Department of Pediatrics, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands Department of Forensic Pathology and Toxicology, Netherlands Forensic Institute, The Hague, The Netherlands

2

Introduction, 153.1

Condyloma acuminata, 153.17

Human immunodeficiency virus, 153.20

Syphilis, 153.2

Hepatitis B in children, 153.18

Trichomonas vaginalis infection, 153.21

Gonorrhoea, 153.8

Genital herpes simplex virus

Bacterial vaginitis, 153.22

Chlamydia trachomatis infections, 153.13

infection, 153.19

Introduction

adolescent may also acquire STDs by voluntary sexual contact with another individual from their peer group. However, if STD is established in a young child, sexual abuse must always be considered. The occurrence of STDs in abused children has been reported to vary from 3% to 13% in the available literature [3,4]. Infection may sometimes be the presenting feature, although it is more often encountered during routine physical examination in suspected cases of abuse. Dealing with these problems requires particular care and expertise. A number of factors influence the risk that a child has of acquiring STD infection during abuse. The risk on acquiring a STD from sexual abuse outside the family is higher than that from abuse within the family. The final factor that is important in evaluating the manner in which the child could have acquired STD is the occurrence of intercultural differences in the mode of transmission. Whittle et al. [5], for example, describe that at present, horizontal transmission of hepatitis B from child to child is most common in certain developing countries, whereas vertical transmission from mother to child is more common in other countries, depending on the local epidemiology. HIV infections will be described in a separate chapter (see Chapter 52). In STD one should follow three rules (CCC): • correct diagnosis • contact tracing and partner treatment • counseling and education [6].

Sexually transmitted diseases (STDs) in childhood occur as a result of intrauterine infections, vertical transmission and/or postnatal infection [1]. STDs have a special implication in pregnancy [2]. They may influence the course of pregnancy and cause premature birth due to chorioamnionitis or polyhydramnios. STDs may also pose a threat to the unborn and the newborn. A number of STDs (e.g. syphilis) may result in transplacental infection and cause damage to the fetus. The newborn may also become infected during passage through the birth canal. Important infections include Chlamydia trachomatis (CT), gonorrhoea, human immunodeficiency virus (HIV) and primary genital herpes simplex virus (HSV). The newborn may also be infected via breastfeeding, as in HIV, or from bystanders, as in herpes labialis. Establishing a diagnosis of STD in a newborn forces investigation into the contacts and sexual partner(s) of the mother. It is evident that such an investigation may pose additional problems for the clinician. Concerning acquired STDs, various modes of transmission must be considered. The child may become infected via everyday contact with an infected adult, for example, through intimate but non-sexual physical contact. Infections may also occur as a result of medical interventions. The child may acquire the infection via voluntary or involuntary sexual contact. Theoretically, STDs can also be transmitted during normal sexual exploratory behaviour between an infected and a non-infected child. An

Policy on STDs in childhood

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Sexually transmitted diseases in children have two important implications: • it is essential that the correct diagnosis is made quickly and that adequate treatment is provided

153.2

Chapter 153

Box 153.1 Policy on STDs in childhood Phase 1 • Referral to a (paediatric) dermatologist and/or a paediatrician and eventually a (paediatric) gynaecologist • Contact with a child abuse doctor in suspected sexual abuse Phase 2 • Investigation and treatment of STD by a (paediatric) dermatologist and/or a paediatrician and eventually a (paediatric) gynaecologist, to ascertain the source of infection, mode of transmission, elimination of other STDs, examination of the parents and other members of the family • Supplementary examination and diagnosis by a paediatrician in connection with other physical abnormalities and psychosocial problems, in co-operation with a (medical) social worker • On indication: 䊊 hospitalization for observation, supplemented if appropriate by a paediatric psychological examination; and 䊊 gynaecological examination and investigation by a (paediatric) gynaecologist in older girls, to note any congenital abnormalities and abnormalities considered to be the result of sexual contacts/sexual abuse • Involvement of a child abuse doctor in suspected sexual abuse

• STDs provide a signal for imperative further investigation into the mode of transmission, in which sexual abuse must be considered. Therefore, a multidisciplinary approach is necessary in dealing with STDs in children (Box 153.1). Tracing of (sexual) contacts should be undertaken for both public health and epidemiological reasons. The primary aim is the diagnosis and treatment of STD and to prevent further spread [5,6]. References 1 Workowski KA, Berman S, Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59:1–110. Erratum (dosage error) in: MMWR Recomm Rep 2011;60:18. 2 Johnson HL, Ghanem KG, Zenilman JM, Erbelding EJ. Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics. Sex Transm Dis 2011;38:167–71. 3 Hobbs CJ, Wynne JM. Child sexual abuse: an increasing rate of diagnosis. Lancet 1987;ii:837–41. 4 White ST, Leda FA, Ingram DL, Pearson A. Sexually transmitted diseases in sexually abused children. Pediatrics 1983;72:16–21. 5 Whittle HC, Inskip H, Hall AJ et al. Vaccination against hepatitis B and protection against viral carriage in the Gambia. Lancet 1991;337:747–50. 6 Radcliffe K. European STD Guidelines. Int J STD AIDS 2001;12(Suppl 3):1–102.

Syphilis Definition. Syphilis is caused by infection with the bacterium Treponema pallidum and is classified as acquired or

congenital. Acquired syphilis is divided into early and late syphilis. Infection with Treponema pallidum is a systemic infection. Infection can be transmitted transplacentally (congenital syphilis) or postnatally (acquired syphilis). Congenital syphilis is always the result of maternal syphilis. Almost all acquired cases of syphilis in children are associated with sexual contact which by definition involves abuse. History. Caspar Torella in 1498 suggested that syphilis in nursing infants was acquired from syphilitic wet nurses [1]. Paracelsus in the early part of the 16th century felt that syphilis could be acquired in utero, describing the condition as hereditary syphilis. Even as late as 1901, Carpenter [2] made reference to hereditary syphilis. The pathogenesis of congenital syphilis and a clear distinction between acquired and congenital syphilis were not understood until the identification of T. pallidum by Schaudinn and Hofman in 1905, and the development of a serological test for syphilis by von Wassermann in 1906. Published reports from 1906 until 1940 mostly described childhood syphilis in the first few years of life or after the initiation of sexual activity. Cases of syphilis in the first few years of life were either congenital or acquired. Most cases seen after the initiation of sexual activity were probably acquired and unlikely to be congenital. However, if the presentation of syphilis was that of a neurological illness, the distinction between the sequelae of congenital syphilis and acquired syphilis was and still is not always possible to make. In the 1920s and 1930s, some but not all cases of syphilis described in children between the first year of life and the onset of sexual activity were reported to be associated with sexual abuse. A changing view of abuse requires a reinterpretation of these reports. It is likely that almost all cases of acquired syphilis in children were associated with abuse. Pathology. Vasculitis and plasma cell infiltration are the hallmarks of infection with T. pallidum. However, atypical findings may be seen in early fetal death [3] or with secondary syphilis. Identification of T. pallidum in suspicious cases may clarify the issue [4]. Clinical features of acquired syphilis. Acquired syphilis is unique in children in that transmission is almost always associated with abuse. Exceptions include transmission from breastfeeding and the rare instance where a primary chancre is identified at a non-genital site together with a plausible explanation such as a neck chancre from an innocent kiss. The following clinical descriptions of primary and secondary syphilis are based on data from adults with specific examples from children cited when available.

Sexually Transmitted Diseases in Children and Adolescents

Primary syphilis The initial hallmark of acquired syphilis is the chancre. Chancres are seen at the site of contact. Since transmission is usually sexual, chancres are seen on the penis, vagina and anus. Lesions can also be seen on the lips and breasts. After an incubation period of between 10 and 90 days (average 3 weeks), this usually single (but occasionally multiple) lesion develops at the site of initial infection. The chancre begins as an erythematous macule which becomes papular and then ulcerates. The resultant painless chancre has well-defined borders and a rubbery base. Associated with the chancre is regional non-tender adenopathy. Without treatment, the chancre heals within 6–12 weeks [5,6]. In children, chancres are said to be smaller than in adults and less likely to be recognized. However, in adults, as in children, the presentation may be very atypical. Frequently, chancres are not recognized either because they are atypical or because they are hidden (e.g. cervical or anal). Secondary syphilis Six weeks after the development of a chancre (2 weeks to 6 months), the rash of secondary syphilis develops as a consequence of generalized T. pallidum dissemination. The initial chancre may still be present when the secondary eruption occurs. The rash of secondary syphilis is macular, progressing to a papular eruption with a scaly component. The rash can be seen on both flexor and extensor surfaces. Associated with the rash are flat wartlike eruptions (condyloma lata) in intertriginous areas, especially the perineum. Alopecia is also associated with the secondary stage. Constitutional symptoms such as fever and malaise are common [7,8]. The descriptions of acquired syphilis in children include both papular and papulosquamous eruptions with a typical adult distribution including palms and soles as well as a description of moist verrucous plaques in the perianal area and mucous patches in the mouth [9,10]. Rash is a common initial complaint for paediatric patients with acquired syphilis. Latent syphilis By definition, syphilis becomes latent after the fading of the secondary rash. The stages are divided into early latent (1 year), based on the lower level of transmissibility in late latent syphilis. Latent syphilis in children has not been well described. Acquired syphilis in children is infrequently reported [11–20]. Most cases of acquired syphilis are consistent with abuse. A few cases had a plausible non-abuse related explanation for transmission. Since a modern interpretation of the older literature strongly suggests that most syphilis in children was associated with abuse, most evaluations of sexual abuse now involve an evaluation for syphilis [11–20]. Given the lag between infection and the

153.3

presence of detectable non-treponemal antibodies, it is suggested that a syphilis serology be performed 6 weeks after an acute episode of sexual abuse to detect a serological response. However, since much sexual abuse is chronic, even a single serological test for syphilis would detect some cases of syphilis if the infection were commonly seen in abused children. Rimsza and Niggemann [20] performed a medical evaluation on 311 sexually abused children who were seen in an emergency room over a 3-year period of time. A Venereal Disease Research Laboratory (VDRL) test was obtained on any patient who was a victim of vaginal intercourse or sodomy. None of the 104 patients who had this test performed had a reactive test. No follow-up serological tests for syphilis were performed. It should be noted that antibiotics which could have had an effect on T. pallidum were given to 83 of the 311 patients. De Jong [21] evaluated 532 victims of sexual abuse over a 3-year period. Patients were evaluated for syphilis on the initial visit and at follow-up. Only one patient had syphilis. White et al. [22] evaluated 409 cases of sexual abuse. In Wake County, North Carolina, 62 of 99 patients were evaluated for syphilis and in other counties, 46 of 310 were evaluated. Five patients had a diagnosis of syphilis in Wake County and one in the other counties. Tests were performed because of the presence of other sexually transmitted diseases in four of the children and because of a chancre in the other. Follow-up testing was not performed [22].

Congenital syphilis Congenital syphilis is transplacentally acquired and presents either early (1 : 64) probably implicate syphilis as a cause of the fetal death [25]. However, syphilitic stillbirths can be associated with lower titres. Identification of T. pallidum in fetal tissue can be used to make a definitive diagnosis. Syphilis is a multisystem disease. Congenital syphilis presents with similar features to secondary syphilis. Patients can have a rash, hepatosplenomegaly and central nervous system involvement. Although uncommon in secondary syphilis, bone findings are common in congenital syphilis and have been used to make a diagnosis before the other signs of congenital syphilis have developed [25,26]. The rash of congenital syphilis can resemble the papulosquamous eruption of secondary syphilis (Fig. 153.1) and features include condyloma lata. Involvement of the palms and soles (Fig. 153.2) may be prominent. In addition, unlike in secondary syphilis, the rash in congenital syphilis can be vesicular or bullous [5,6]. The presence of snuffles, a mucoid and sometimes bloody nasal discharge was frequently reported in the prepenicillin era but has not been common in recent congenital syphilis outbreaks [28]. The skin lesions and nasal discharge will reveal the presence of T. pallidum and may be a source of infection; appropriate precautions should therefore be taken when examining or handling affected children. Hepatosplenomegaly and findings of abnormal levels of liver enzymes or evidence of cholestasis are seen in congenital syphilis [28]. Many now believe that the hepatic abnormalities are initially made worse by therapy [29]. The liver findings

Fig. 153.1 Congenital syphilis: papulosquamous rash similar to secondary syphilis.

Fig. 153.2 Congenital syphilis: involvement of the soles.

are not specific enough to distinguish congenital syphilis from a number of other congenital infections. A positive cerebrospinal fluid (CSF) VDRL test in a newborn establishes a diagnosis of congenital syphilis but the overlap between CSF cell counts and protein determinations in infants with and without syphilis is so broad as to make the cell count and protein determination of no value [32]. Detection of T. pallidum may also be diagnostic [30,31] (Fig. 153.3). The bone lesions of congenital syphilis are those of a metaphysitis with either lucency or increased density seen in the long bones. The development of further involvement with erosion is a later finding. Erosion of the tibia is known as the cat bite or Wimberger sign. Periosteal involvement is also seen

Sexually Transmitted Diseases in Children and Adolescents

Fig. 153.3 Diagnosis by detection of Treponema pallidum.

Fig. 153.4 Syphilitic periosteal involvement.

with congenital syphilis [31] (Fig. 153.4). Inflammation of bone associated with congenital syphilis can cause pain and impairment of movement. This is known as the pseudo-paralysis of Parrot. Occasionally, fractures are seen. Similar findings can be seen in child abuse. Diffuse bone involvement suggests congenital syphilis whilst an asymmetrical finding favours trauma [32]. A serological test for syphilis performed on the infant’s serum will be reactive in cases of congenital syphilis associated with significant bone pathology. Late-onset congenital syphilis is manifest by evidence of continuing infection or evidence of stigmata. Most stigmata of congenital syphilis should be avoidable by ade-

153.5

quate treatment but since an infant with late-onset congenital syphilis may never exhibit the early signs of congenital syphilis, and since 60% of cases of late-onset congenital syphilis were initially detected by serology alone, stigmata could theoretically develop because of treatment failure or lack of therapy. The findings of lateonset congenital syphilis as summarized by the American public health service include the following. • Interstitial keratitis, a condition which leads to bilateral blindness and tends to develop around the time of puberty. • Hutchinson’s teeth, a developmental abnormality of the upper and sometimes lower central incisors in which the teeth are notched and small, resulting in a gap between them. • Mulberry molars in which the first molars show maldevelopment of the cusps and look like a mulberry. • Eighth nerve deafness, which is infrequent and tends to develop around puberty. • Neurosyphilis which has all the manifestations of neurosyphilis in acquired syphilis, including meningovascular, parenchymatous and gummatous neurosyphilis. • Bone involvement which can be sclerotic (sabre shins, frontal bossing) or lytic (gummas resulting in destruction of the nasal bridge or the palate). • Cutaneous involvement from healed syphilitic rhinitis (rhagades or cracks and fissures around the mouth). • Cardiovascular lesions as seen in acquired lesions are reported but rare. • Clutton’s joints, the painless hydrarthrosis of the knees. Hutchinson’s triad consists of keratitis, dental abnormalities and deafness. Clutton’s joints, interstitital keratitis and deafness are not infectious and do not respond to penicillin. Diagnosis. Universal testing of women during pregnancy and at delivery will identify women with syphilis and those infants at risk for congenital syphilis [33–35]. It is more difficult to eliminate the possible diagnosis of congenital syphilis in an infant born to a mother with a reactive test for syphilis, especially if previous test information is not available. Results of serological tests based on endemic treponematoses are not distinguishable from syphilis, and may lead to misinterpretation (see Chapter 60). Endemic treponematoses never lead to congenital infections. Those antibodies are always passively acquired. Without a careful history, neither reactive maternal serological findings nor the height of the maternal titre can determine infectivity [35,36]. By following the American Centers for Disease Control (CDC) criteria for STDs, one will overtreat some children but will almost never miss possible cases [25]. These criteria were developed to identify the still symptom-free infected infant [33]. See Box 153.2 [25,39].

153.6

Chapter 153

Box 153.2 Congenital syphilis: diagnostic criteria according to Centers for Disease Control and Prevention Report on Sexually Transmitted Diseases (2002) and European STD Guidelines (2001) Confirmed congenital infection • Treponema pallidum demonstrated by dark-field examination microscopy or other specific staining of specimens for histopathological examination from skin lesions, lymph nodes, autopsy material or placenta Presumed congenital infection • A stillborn neonate with a positive treponemal test for syphilis • Children with a positive treponemal test for syphilis in combination with persistent rhinitis, condylomata lata, osteitis, periostitis, osteochondritis, ascites, cutaneous and mucous membrane lesions, hepatitis, hepatosplenomegaly, glomerulonephritis, haemolytic anaemia • Radiological abnormalities of the long bones suggestive of congenital syphilis • A positive VDRL test in CSF • A fourfold increase or more of the TPHA titre in the child opposed to the mother’s serum (obtained simultaneously at birth or at a later time) • A fourfold increase or more of the titre of a cardiolipin/ non-treponemal test in the child’s as opposed to the mother’s serum (obtained simultaneously at birth or at a later time) • A positive 19S-IgM-FTA-abs test, EIA-IgM and/or IgM immunoblot for Treponema pallidum in the child’s serum • A mother in whom syphilis was confirmed during pregnancy, but who was not adequately treated either before or during pregnancy • A child >12 months of age with a positive treponemal serological test for syphilis (can also be acquired)

A diagnosis of infection with T. pallidum is made by either the detection of non-specific antibodies (nontreponemal antibodies) with confirmation by the detection of specific antibodies (treponemal antibodies) or the detection of T. pallidum. Non-treponemal antibodies are detected using the rapid plasma reagin card or the VDRL test. The tests are reactive, a quantitative titre obtained and the results are confirmed with a specific treponemal test. The specific treponemal tests are considered as confirmatory tests. Current tests include the fluorescent treponemal antibody absorbed (FTA-ABS) test or the microhaemagglutination assay for antibody to T. pallidum (MHA-TP). In Europe, immunoglobulin G (IgG) and IgM enzyme immunoassays (EIAs) are also used for the diagnosis of syphilis. Non-standardized immunoblot assays are used by some investigators [30,31]. The IgM assays have the potential to detect cases of congenital syphilis as well as cases of acquired syphilis. The IgM test may not detect

Box 153.3 Recommended evaluation of infants with proven or highly probable disease • Direct dark-field examination or fluorescent antibody test or other specific test of skin lesions, lymph nodes or body fluids • Serum quantitative non-treponemal and treponemal serological investigations. IgM serology is highly recommended • Complete blood count and differential and platelet count • CSF analysis for VDRL, cell count and protein • Other tests as clinically indicated (long bone radiographs, chest radiograph, liver function tests, cranial ultrasound, ophthalmological examination)

cases of congenital syphilis in which the patient has yet to develop symptoms [31]. Treponema pallidum is detected by dark-field examination, immunofluorescent antigen detection, the polymerase chain reaction (PCR) or the rabbit infectivity test. These tests approach 100% specificity but have variable sensitivity. They are of most value in the diagnosis of the early stages of congenital and acquired syphilis. The rabbit infectivity test is a useful standard against which to measure these other tests but it is only available in a research setting [30]. Infants suspected of highly probable disease should be thoroughly investigated. See Box 153.3 [25,39]. Prognosis. Both untreated congenital and acquired syphilis share some sequelae. Early and appropriate therapy results in a good outcome [34]. Whilst there is not a large enough experience with late congenital syphilis to evaluate the effectiveness of penicillin therapy, case reports have not shown penicillin to be helpful [37]. Failures from appropriate therapy of congenital syphilis are not reported but there have been short-term failures of benzathine penicillin therapy. All patients have been retreated appropriately [38]. Careful follow-up of all infants at risk of congenital syphilis is essential to ensure that the treatment given was effective [36]. Differential diagnosis. Syphilis is the great imitator. When acquired syphilis in children presents with a primary chancre, the differential diagnosis should be considered for a suspected bacterial skin infection which does not respond to treatment. The differential diagnosis also includes HSV and chancroid. The rash of secondary syphilis can be confused with any of the papulosquamous disorders, with the greatest likelihood of confusion with pityriasis rosea. The systemic manifestations of acquired syphilis are non-specific except for such findings as epitrochlear adenopathy. Both congenital or acquired syphilis can present with a cerebrospinal pleocytosis. There are very few findings in

Sexually Transmitted Diseases in Children and Adolescents

the CSF that would specifically indicate syphilis other than tabes dorsalis. The bullous skin findings of congenital syphilis can be seen with epidermolysis bullosa, dermatitis herpetiformis staphylococcal infection or mastocytosis [40]. Hepatosplenomegaly can be seen in any of the congenital infections such as toxoplasmosis, rubella or cytomegalovirus. The anaemia of congenital syphilis can be seen in any other cause of hydrops fetalis, especially parvovirus infection. The bone lesions of congenital syphilis can be confused with either infection or child abuse.

153.7

Box 153.4 Recommended treatment regimens for children with acquired or congenital syphilis Infants with congenital syphilis • Aqueous crystalline penicillin G 150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 8 hours during 10 days Or • Procaine penicillin G 50,000 units/kg/dose IM in a single dose during 10 days Older children

Treatment. Penicillin G, administered parenterally, is the preferred drug for treatment of all stages of syphilis [25]. First-choice treatment exists of benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose. Patients who also have symptoms or signs suggesting neurological or ophthalmic disease should have an evaluation including CSF analysis and ocular slit-lamp examination. All patients should also be tested for HIV infection [25]. Administration of IM benzathine penicillin is painful; dilution of the penicilline with 1% lidocaine HCL may reduce pain symptoms [41]. Treatment of congenital syphilis involves: • adequate treatment of the mother before pregnancy • adequate treatment of the mother during pregnancy, preferably in the first half of pregnancy but definitely before the last month of pregnancy, or • adequate treatment of the infant either at delivery or postnatally when symptoms develop. Any strategy involving maternal therapy must involve therapy of all sexual partners or the treated mother will become reinfected. Adequate maternal therapy is defined as either one injection of benzathine penicillin (2.4 million units) for early syphilis (primary and secondary syphilis) or one injection per week for 3 weeks of benzathine penicillin to a total dose of 7.2 million units. As a result of this therapy, patients with early syphilis should show a fourfold decrease in non-treponemal titre or return to become negative. Patients with late syphilis should have stable or declining titres of less than or equal to 1 : 4 [25]. Most pregnant women with reactive syphilis serologies do not fit into any of these categories, frequently because an appropriate fall in titre is not documentable before delivery. Thus, many infants at risk for congenital syphilis are treated for congenital syphilis because adequate therapy in their mother cannot be established with certainty. The therapy of congenital syphilis is 10–14 days of penicillin G (50,000/kg/dose every 12 h for the first week of life and every 8 h thereafter). Although therapy with intravenous penicillin G is one option, the authors’ experience with procaine penicillin 50,000 units/kg given intramuscularly daily for 10 days has been good. There

• Aqueous crystalline penicillin G 200,000–300,000 units/kg/day IV, administered as 50,000 units/kg every 6 hours for 10 days • No proven alternatives to penicillin are available. Erythromycin (in children) and doxycycline or tetracycline (only in adults) are claimed to be effective, but these drugs are not mentioned in the CDC STD guidelines

have been no reported treatment failures with either penicillin G or procaine penicillin while therapy with benzathine penicillin as a single injection has resulted in some treatment failures [38,42]. The cost–benefit analysis of treatment with benzathine penicillin with discharge thereafter versus 10 days of parenteral therapy has yet to be determined [43]. As in acquired syphilis, an appropriate fall in the nontreponemal serology is expected. Infants who are treated late in the course of their disease may never become seronegative [44]. Fifteen percent of patients with early syphilis treated with the recommended therapy will not achieve a twofold dilution decline in non-treponemal titre [25]. Non-penicillin therapies of congenital syphilis have not been evaluated and should not be used. Appropriate doses of ampicillin can be considered as equivalent to penicillin [25]. One should bear in mind that treatment failures can occur. References 1 Dennie CC. A History of Syphilis. Springfield, Illinois: C.C. Thomas, 1962. 2 Carpenter G. The Syphilis of Children in Every-Day Practice. New York: William Wood, 1901. 3 Harter CA, Benirschke K. Fetal syphilis in the first trimester. Obstet Gynecol 1976;124:705–11. 4 Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol 1973;107:373–7. 5 US Public Health Service. Syphilis: A Synopsis. Washington, DC: US Public Health Service, 1968. 6 Schulz KP et al. In: Holmes et al. (eds) Sexually Transmitted Diseases. New York: McGraw-Hill, 1990. 7 Chapel TA. The signs and symptoms of secondary syphilis. Sex Transm Dis 1980;7:161–4. 8 Fiumara N. Treatment of secondary syphilis: an evaluation of 204 patients. Sex Transm Dis 1977;4:96–9.

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9 Echols SK, Shupp DL, Schroeter AL. Acquired secondary syphilis in a child. J Am Acad Dermatol 1990;22(2 Pt 1):313–14. 10 Horowitz S, Chadwick DL. Syphilis as a sole indicator of sexual abuse: two cases with no intervention. Child Abuse Negl 1990;14:129–32. 11 Waugh JR. Acquired syphilis of infancy and childhood. Am J Syph Gon Ven Dis 1938;22:607–22. 12 Schoch AG, Long WE. Acquired syphilis in children. Am J Syph Gon Ven Dis 1939;23:186–7. 13 Smith FR. Acquired syphilis in children. Am J Gon Ven Dis 1938;23:165–85. 14 Ackerman AB, Goldfaden G, Cosmides JC. Acquired syphilis in early childhood. Arch Dermatol 1972;106:92–3. 15 Ginsburg CM. Acquired syphilis in prepubertal children. Pediatr Infect Dis 1983;2:232–4. 16 Aloi F. Lip syphilitic chancre in a child (letter). Pediatr Dermatol 1987;4:63. 17 Goldenring JM. Secondary syphilis in a prepubertal child. Differentiating condylomata lata from condylomata acuminata. NY State J Med 1989;89:180–1. 18 Tomeh MO, Wilfert CM. Venereal diseases of infants and children at Duke University Medical Center. N C Med J 1973;34:109–13. 19 Schwarcz SK, Whittington WL. Sexual assault and sexually transmitted diseases: detection and management in adults and children. Rev Infect Dis 1990;12(Suppl 6):S682–90. 20 Rimsza ME, Niggemann EH. Medical evaluation of sexually abused children: a review of 311 cases. Pediatrics 1982;69:9–14. 21 De Jong AR. Sexually transmitted diseases in sexually abused children. Sex Transm Dis 1986;13:123–6. 22 White ST, Loda FA, Ingram DL et al. Sexually transmitted diseases in sexually abused children. Pediatrics 1983;72:16–21. 23 Rawstron SA, Bromberg K. Comparison of maternal and newborn serologic tests for syphilis. Am J Dis Child 1991;145:1383–8. 24 Dorfman DR, Claser JH. Congenital syphilis presenting in infants after the newborn period. N Engl J Med 1990;323:1299–302. 25 Centers for Disease Control. 2002 sexually transmitted diseases treatment guidelines. MMWR 2002;51:1–78. 26 Ingraham NR. The diagnosis of infantile congenital syphilis during the period of doubt. Am J Syph Neurol 1935;19:547–80. 27 Cremin BJ, Fisher RM. The lesions of congenital syphilis. Br J Radiol 1970;43:333–41. 28 Rawstron SA, Jenkins S, Blanchard S, Li PW, Bromberg K. Maternal and congenital syphilis in Brooklyn, NY. Epidemiology, transmission, and diagnosis. Am J Dis Child 1983;147:727–31. 29 Shah MC, Barton LL. Congenital syphilitic hepatitis. Pediatr Infect Dis J 1989;8:891–2. 30 Sanchez PJ, Wendel GD Jr, Grimprel E et al. Evaluation of molecular methodologies and rabbit infectivity testing for the diagnosis of congenital syphilis and neonatal central nervous system invasion by Treponema pallidum. J Infect Dis 1993;167:148–57. 31 Bromberg K, Rawstron S, Tannis G. Diagnosis of congenital syphilis by combining Treponema pallidum-specific IgM detection with immunofluorescent antigen detection for T. pallidum. J Infect Dis 1993;168:238–42. 32 Fiser RH, Kaplan J, Holder JC. Congenital syphilis mimicking the battered child syndrome. How does one tell them apart? Clin Pediatr (Phila) 1972;11:305–7. 33 Boot JM, Oranje AP, de Groot R et al. Congenital syphilis. Int J STD AIDS 1992;3:161–7. 34 Boot JM, Menke HE, van Eijk RVW et al. Congenital syphilis in The Netherlands: cause and parental characteristics. Genito Urin Med 1988;64:298–302. 35 Boot JM, Oranje AP, Menke HE et al. Congenital syphilis in The Netherlands: diagnosis and clinical features. Genito Urin Med 1989;65:300–3.

36 Glaser JH. Centers for Disease Control prevention guidelines for congenital syphilis. J Pediatr 1996;129:488–90. 37 Wiggelinkhuizen J, Mason R. Congenital neurosyphilis and juvenile paresis: a forgotten entity? Clin Pediatr 1980;19:142. 38 Beck-Sague C, Alexander ER. Failure of benzathine penicillin G treatment in early congenital syphilis. Pediatr Infect Dis 1987;6: 1061–4. 39 Goh BT, van Voorst Vader PC. European guideline for the management of syphilis. Int J STD & AIDS 2001;12:14–26. 40 Oranje AP, Soekanto W, Sukardi A et al. Diffuse cutaneous mastocytosis mimicking staphylococcal scalded-skin syndrome: report of three cases. Pediatr Dermatol 1991;8:147–51. 41 Amir J, Ginat S, Cohen YH, Marcus TE. Lidocaine as a diluent for administration of benzathine penicillin. Pediatr Infect Dis J 1998;17(10):890–3. 42 Hardy JB, Hardy PH, Oppenheimer EH, Ryan SJ Jr, Sheff RN. Failure of penicillin in a newborn with congenital syphilis. JAMA 1970;212:1345–9. 43 De Lissovoy G, Zenilman J, Nelson KE, Ahmed F, Celentano DD. The cost of a preventable disease: estimated US national medical expenditures for congenital syphilis, 1990. Publ Health Rep 1995;110: 403–9. 44 Smith FRJ. Congenital syphilis in children, results of treatment, 521 patients. Part I. Am J Syph Neurol 1935;532–46.

Gonorrhoea Definition. Neisseria gonorrhoeae (gonococci) are nonmotile, non-spore-forming Gram-negative diplococci (they grow in pairs). Gonococcal infection in children is acquired either perinatally, from an infected mother to a newborn, or by intimate contact (almost always sexual) in older children. History. Gonorrhoea is one of the oldest known human illnesses. While references to urethral discharge are made in the Old Testament, in the fourth and fifth centuries bc Hippocrates wrote of gonorrhoea, although the term gonorrhoea (‘flow of seed/semen’) was not introduced until the second century by Galen. Neisser, who also discovered that the agent could be found in cases of ophthalmia neonatorum, finally identified the causal organism of gonorrhoea in 1879. Leistikow and Loeffler in 1882 were the first to culture the organism, and around the same time in 1881 Credé, who had been working on neonatal ophthalmia, started to use silver nitrate instillation into the eyes of newborns to prevent gonococcal ophthalmia, a common cause of blindness. The use of silver nitrate prophylaxis reduced the incidence of neonatal gonococcal ophthalmia from more than 10% to 0.5% [1]. Epidemic vulvovaginitis in girls was a common disease in the early 20th century before the advent of penicillin therapy, and was believed to be extremely contagious, requiring only superficial contact for transmission [2]. However, careful study of infected girls in controlled circumstances showed that gonococcal vulvovaginitis was not contagious (no transmission was seen from infected

Sexually Transmitted Diseases in Children and Adolescents

to non-infected girls on a ward, although there was no effective treatment at that time) [2]. The conclusion that ‘transmission of the disease requires intimate contact between an infected adult or child and non-infected child’ remains today. Aetiology and pathogenesis. Gonorrhoea is an STD which can only be acquired by intimate contact, almost always sexual [3]. Humans are the only natural host and direct mucous membrane contact is necessary to spread disease [4]. Studies of STDs in various populations of children being evaluated for sexual abuse have shown rates varying from 2.8% [5], 4.7% [6], 7.4% [7] to 18.2% and 36.8% [8], the range being a function of the prevalence of N. gonorrhoeae in the community. In addition, a heightened suspicion for sexual abuse in recent times has resulted in an apparent decreased prevalence due to more evaluations in asymptomatic children. In the neonatal period, infection is acquired perinatally from the mother by passage through an infected birth canal. In older prepubertal children, the infection is almost always sexually acquired, usually by sexual abuse from an adult, occasionally by sexual play between children [9], although even in these cases there is often abuse or exploitation of younger children by older ones who introduce the infection [10]. In older postpubertal children, consensual sexual activity is the usual source of infection, although the sexual activity can still be associated with abuse [11]. The role of fomites in the spread of disease is not clear, but is probably extremely uncommon. The only well-documented spread of gonococcal infection in a non-sexual manner was a hospital outbreak of neonatal gonococcal infection probably spread by contaminated rectal thermometers [12]. Careful interviewing enabled a history of sexual contact to be elicited in 44 of 45 1–9 year olds with gonorrhoea [13]. Similarly, a history of sexual contact was obtained in 90–100% [5,14] of children 5–12 years of age with gonorrhoea, and 35–75% [5,14] of children 1–5 years of age. If gonorrhoea is highly associated with sexual contact in verbal children, it follows that this is the most likely mode of transmission in non-verbal children. Repeated interviews by sympathetic and skilled workers may be necessary to elicit a history of abuse [15]. Sometimes the history of abuse may not be revealed until years later [16]. Pathology. Gonococcal infections start with the organism adhering to the mucosal cells which is mediated by pili and other surface proteins. Stratified squamous cells can resist invasion, but columnar epithelium is susceptible. This explains the distribution of infection: urethra, Skene and Bartholin glands, cervix and fallopian tubes in females; urethra, prostate, seminal vesicles and epididymis in males; and rectum, pharynx and conjunctivae in

153.9

both sexes. Prepubertal girls are susceptible to vaginal infections with N. gonorrhoeae because of the alkaline pH and lack of oestrogenization, whereas postpubertal girls develop cervical but not vaginal infections. The organism is engulfed by endocytosis of the cell into vacuoles, where they may replicate and eventually exit from the basal surface of the epithelial cell to the subepithelial tissues [17]. There is a marked inflammatory response at the site of inoculation with a polymorphonuclear leucocyte response, purulent material being exuded from the surface and submucosal microabscess formation. The pathology of the skin lesions in disseminated gonococcal infection (DGI) consists of haemorrhage, vasculitis and a moderately heavy inflammatory cell presence, mostly polymorphonuclear leucocytes but a variable presence of mononuclear cells [18]. Thrombosis of the small venules and arterioles of the dermis is common. Epidermal changes range from minimal oedema with few polymorphonuclear cells and red blood cells to intradermal vesicles or pustules. The organisms are only detected in the skin lesions by Gram stain or culture in about 10% of cases [19]. However, the presence of organisms can be detected in about 57% of skin lesions with the use of immunofluorescent stains [19]. Clinical features

Infection in infants In newborns, the disease is acquired perinatally from an infected mother during delivery through an infected birth canal with direct mucosal contact from infected cervical secretions of the mother to mucous membranes (conjunctiva, pharynx) of the baby. Without prophylaxis, neonatal gonococcal conjunctivitis occurred in 42% of babies born to mothers with gonorrhoea, with 7% also having orogastric contamination with N. gonorrhoeae [20]. The prevalence of maternal disease varies depending on the prevalence of gonorrhoea in the community at any particular time. The rate of maternal gonorrhoea in most American populations is less than 5%, though rates in Africa are higher (5–10% or more). Prenatal care with screening and treatment is effective at preventing neonatal infections in high-risk populations. In addition, neonatal ocular prophylaxis can reduce the incidence of gonococcal ophthalmia in newborns with infected mothers by 83–93% [21]. However, universal screening of all pregnant women and neonatal ocular prophylaxis are not cost-effective when maternal gonococcal infections are infrequent (300 cells/cm3) and elevated serum immunoglobulins [14].

Infections at other sites Infants born to Chlamydia-positive mothers may also become infected in the rectum and vagina [15]. Although infection at these sites appears to be totally asymptomatic, the infection may cause confusion if detected at a later date. Schachter et al. [15] reported finding subclinical rectal and vaginal infection in 14% of infants born to Chlamydia-positive women; some of these infants were still culture positive at 18 months of age. Harrison et al. [14] were able to follow 22 infants born to women with culture-proven chlamydial infections and found that positive cultures were detected in these children as late as 28.5 months after birth: this was the longest duration of perinatally acquired infection and it occurred in the nasopharynx or oropharynx. Nine infants had rectal or vaginal infections which persisted for slightly over 12 months. There are other anecdotal reports of perinatally acquired rectal, vaginal and nasopharyngeal infections persisting for at least 3 years [12]. This needs to be kept in mind when evaluating children for suspected sexual abuse [12]. Infections in older children Chlamydia trachomatis has not been associated with any specific clinical syndrome in older infants and children. Most attention to CT infection in these children has concentrated on the relationship to child sexual abuse. It has been suggested that the isolation of CT from a rectal or genital site in children without prior sexual activity may be a marker of sexual abuse. Although evidence for other modes of spread, such as through fomites, is lacking for this organism, as previously mentioned, perinatal maternal–infant transmission resulting in vaginal and/or rectal infection has been documented with prolonged infection for periods of up to 3 years. This is an important confounding variable. Chlamydia trachomatis infection and sexual abuse Vaginal infection with CT was uncommonly reported in prepubertal children before 1980. The possibility of sexual contact was frequently not even discussed. In 1981, Rettig et al. reported concurrent or subsequent chlamydial infection in nine of 33 (27%) episodes of gonorrhoea in a group

Sexually Transmitted Diseases in Children and Adolescents

of prepubertal children [16]. This compares with rates of concurrent infection in men and women of 11–62%, depending on the study. However, CT was not found in any of 31 children presenting with urethritis or vaginitis that was not gonococcal. No information was given about possible sexual activity. Studies have identified rectogenital chlamydial infection in 2–13% of sexually abused children, when these children were routinely cultured for the organism. The majority of those with chlamydial infection were asymptomatic. In two early studies that had control groups, similar percentages of control patients were also infected [17,18]. The control group in one study consisted of children who were also referred for evaluation of possible sexual abuse but were found to have no history of sexual contact, and siblings of abused children. The mean age of this group was 4.5 years as compared to 7.5 years for the group with a history of sexual contact, thus suggesting a bias related to the inability to elicit a history of sexual contact from young children. In the second study, the control group was selected from a well-child clinic. Three girls in this group were found to have positive chlamydial cultures; two who had positive vaginal cultures were sisters who had been sexually abused 3 years previously and had not received interim treatment with antibiotics. The implication of this observation was that these children were infected for at least 3 years and were totally asymptomatic. The remaining control child had CT isolated from her throat and rectum; no history of sexual contact could be elicited. A subsequent larger study by Ingram et al. [19,20] found a stronger association between vaginal chlamydial infection and a history of sexual abuse, but not with pharyngeal infection, which was found in a similar number of controls. Rectal infection was detected in only one of 124 abused children. The possibility of prolonged perinatally acquired vaginal or rectal carriage in the sexually abused group was minimized in the study of Hammerschlag et al. [18] since the chlamydial cultures obtained at the initial examination were negative and the infection was only detected at follow-up examination 2–4 weeks later. However, the two abused girls who developed chlamydial infection were victims of a single assault by a stranger. In the setting of repeated abuse by a family member, over long periods of time, development of infection would be difficult to demonstrate. Even among adolescents and adults who are victims of sexual assault, acquisition of CT is uncommon, less than 2% over the rate found at baseline [17,21]. The 1993 STD treatment guidelines dropped the recommendation that cultures for CT be obtained routinely from the pharynx and urethra in children who are suspected as victims of sexual abuse [22]. The major reasons were the low yield from the urethra, the tendency for longer persistence of perinatally acquired

153.15

pharyngeal infection and the potential confusion with C. pneumoniae. Diagnosis. The ‘gold standard’ remains isolation by culture of CT from the conjunctiva, nasopharynx, vagina or rectum. Chlamydia culture has been further defined by the CDC as isolation of the organism in tissue culture and confirmation by microscopic identification of the characteristic inclusions by fluorescent antibody staining [8]. Several non-culture methods have the American Food and Drug Administration (FDA) approval for diagnosis of chlamydial conjunctivitis. They include EIA, specifically Chlamydiazyme (Abbott Diagnostics, Illinois), Pathfinder (Sanofi-Pasteur, Minnesota) and SureCell (Kodak, New York), and direct fluorescent antibody tests (DFA) including Syva Micro Trak (Genetic Systems, Washington) and Pathfinder (Sanofi-Pasteur). These tests appear to perform very well with conjunctival specimens, with sensitivities over 90% and specificities over 95% compared to culture [11]. Unfortunately, the performance with nasopharyngeal specimens has not been as good, with sensitivities in infants with pneumonia at 79%, but only 30–60% in nasopharyngeal specimens from infants with conjunctivitis. The recently approved PCR assay Amplicor (Roche, New Jersey) has approval only for genital sites in adults. Preliminary studies suggest PCR is equivalent to culture for conjunctival specimens and possibly superior for respiratory specimens [23]. Non-culture tests should never be used for rectal or vaginal sites in children, or for any forensic purposes in adolescents and adults [8,11,22,23–25]. Use of these tests for vaginal and rectal specimens has been associated with a large number of false-positive results [24–26]. Faecal material can give false-positive reactions with any EIA; none are approved for this site in adults. Common bowel organisms, including Escherichia coli, Proteus species, vaginal organisms such as group B Streptococcus and Gardnerella vaginalis and even some respiratory flora such as group A Streptococcus, can also give positive reactions with EIAs [26]. These types of test are best for screening infection in adolescents and adults in high prevalence populations (prevalence of infection >7%) [8]. There are very few reports on the performance of the DNA probe, but it appears to be equivalent to most available EIAs, in terms of sensitivity and specificity compared to culture for genital specimens. Another potential problem can occur with use of an EIA for respiratory specimens. As all of the available EIAs use genus-specific antibodies, if used for respiratory specimens, these tests will also detect C. pneumoniae. Even though culture is considered the gold standard, culture of CT is not regulated and sensitivity may vary between laboratories [27].

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Polymerase chain reaction techniques are currently more reliable [28]. PCR is the gold standard for diagnosis in adults. PCR or NAAT (nucleic acid amplification tests) are somewhat controversial. The CDC advises the isolation of CT from tissue culture as a standard determination in childhood cases of suspected sexual abuse [28]. Cultures may be positive after 2–7 days. Serological investigation in suspected childhood cases is not meaningful because of the limited reliability [22]. Culturing samples from the pharynx for CT in children is also not meaningful considering the possibility of a persistent perinatal infection and confusion with C. pneumoniae [28,29]. In summary, non-culture tests for Chlamydia should not be used because of possible false-positive test results [29]. This is especially important because of the potential for a criminal investigation and legal proceedings for sexual abuse [30,31]. Treatment. Because of its long growth cycle, treatment of chlamydial infections requires multiple dose regimens. None of the currently recommended single-dose regimens for gonorrhoea is effective against CT.

Treatment of Chlamydia conjunctivitis and pneumonia in infants Oral erythromycin suspension (ethylsuccinate or sterate) 50 mg/kg/day for 10–14 days is the therapy of choice. It provides better and faster resolution of the conjunctivitis as well as treating any concurrent nasopharyngeal infection, which will prevent the development of pneumonia. Treatment with clarithromycin (15 mg/kg/day in 2 during 14 days) also is effective [32]. Additional topical therapy is not needed [33]. The efficacy of this regimen has been reported to range from 80% to 90%, so as many as 20% of infants may require another course of therapy [33]. Erythromycin at the same dose for 2–3 weeks is the treatment of choice for pneumonia and does result in clinical improvement as well as elimination of the organism from the respiratory tract. Alternative therapy consists of azithromycin 20 mg/kg/daily in a single dose [33]. Treatment of older children Chlamydial infections may be treated with oral erythromycin 50 mg/kg/day four times a day orally to a maximum of 2 g/day for 7–14 days. The newer macrolide antibiotic azithromycin is very effective as single-dose treatment for uncomplicated chlamydial urethral and cervical infection in men and non-pregnant women [8,30]. Single-dose azithromycin has also been shown to be effective in adolescents and older children [30]. In children aged 8 years and older, the treatment of choice is azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice a day for 7 days.

References 1 Schachter J. The intracellular life of Chlamydia. Curr Top Microbiol Immunol 1988;138:109–39. 2 Thygeson P, Stone W. Epidemiology of inclusion conjunctivitis. Arch Ophthalmol 1942;27:91–122. 3 Jones BR, Collier LH, Smith CH et al. Isolation of virus from inclusion blennorrhoea. Lancet 1959;i:902–5. 4 Schachter J, Rose L, Dawson CR et al. Comparison of procedures for laboratory diagnosis of oculogenital infections with inclusion conjunctivitis agents. Am J Epidemiol 1967;85:443–8. 5 Botsztejn A. Die pertussoide, eosinophile pneumonie des Sauglings. Benigne subakute afebrile hilifugale pneumonie des untergewichtigen Sauglings im ersten trimeron mit starker eosinophilie und pertussisahnlichem husten. Ann Paediatr 1941;157:28–46. 6 Schachter J, Lum L, Gooding CA et al. Pneumonitis following inclusion blennorrhea. J Pediatr 1975;87:779–80. 7 Beem MO, Saxon EM. Respiratory tract colonization and a distinctive pneumonia syndrome in infants infected with Chlamydia trachomatis. N Engl J Med 1977;296:306–10. 8 Centers for Disease Control and Prevention. Recommendations for the prevention and management of Chlamydia trachomatis infections. MMWR 1993;42(RR-12):1–39. 9 Hammerschlag MR, Golden NH, Oh MK et al. Single dose azithromycin for the treatment of genital chlamydial infections in adolescents. J Pediatr 1993;122:961–5. 10 Alexander ER, Harrison HR. Role of Chlamydia trachomatis in perinatal infection. Rev Infect Dis 1983;5:713–19. 11 Hammerschlag MR. Neonatal conjunctivitis. Pediatr Ann 1993;22: 346–51. 12 Bell TA, Stamm WE, Wang SP et al. Chronic Chlamydia trachomatis infections in infants. JAMA 1992;267:400–2. 13 Hammerschlag MR. Chlamydial infections. J Pediatr 1989;114: 727–34. 14 Harrison HR, English MG, Lee CK et al. Chlamydia trachomatis infant pneumonitis: comparison with matched controls and other infant pneumonitis. N Engl J Med 1978;298:702–8. 15 Schachter J, Grossman M, Sweet RL et al. Prospective study of perinatal transmission of Chlamydia trachomatis. JAMA 1986;255:3374–7. 16 Rettig PJ, Nelson JD. Genital tract infection with Chlamydia trachomatis in prepubertal children. J Pediatr 1981;99:206–10. 17 Glaser JD, Schachter J, Benes S et al. Sexually transmitted diseases in postpubertal female rape victims. J Infect Dis 1991;167:726–30. 18 Hammerschlag MR, Doraiswamy B, Alexander ER et al. Are rectogenital chlamydial infections a marker of sexual abuse in children? Pediatr Infect Dis 1984;3:100–4. 19 Ingram DL, Runyan DK, Collins AD et al. Vaginal Chlamydia trachomatis infection in children with sexual contact. Pediatr Infect Dis 1984;3:97–9. 20 Ingram DL, White ST, Occhiuti AR et al. Childhood vaginal infections: association of Chlamydia trachomatis with sexual contact. Pediatr Infect Dis 1986;5:226–9. 21 Jenny C, Hooton TM, Bowers A et al. Sexually transmitted diseases in victims of rape. N Engl J Med 1990;322:713–16. 22 Centers for Disease Control. 1993 Sexually transmitted diseases treatment guidelines. MMWR 1993;42(RR-14):1–102. 23 Roblin PM, Sokolovskaya N, Gelling M. Comparison of Amplicor Chlamydia trachomatis test and culture for detection of Chlamydia trachomatis in ocular and nasopharynx of specimens from infants with conjunctivitis. Pediatr Res 1996;39:301A. 24 Hammerschlag MR, Rettig PJ, Shields ME. False positive results with the use of chlamydial antigen detection tests in the evaluation of suspected sexual abuse in children. Pediatr Infect Dis J 1988;7: 11–14. 25 Hauger SB, Brown J, Agre F et al. Failure of direct fluorescent antibody staining to detect Chlamydia trachomatis from genital tract sites

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26

27 28 29 30 31 32 33

of prepubertal children at risk for sexual abuse. Pediatr Infect Dis J 1988;7:660–2. Porder K, Sanchez N, Roblin PM et al. Lack of specificity of Chlamydiazyme for detection of vaginal chlamydia infection in prepubertal girls. Pediatr Infect Dis J 1989;8:358–60. Pate MS, Hook EW III. Laboratory to laboratory variation in Chlamydia trachomatis culture practices. Sex Transm Dis 1995;22:322–6. Bechtel K. Sexual abuse and sexually transmitted infections in children and adolescents. Curr Opin Pediatr 2010;22(1):94–9. Lacey CJN. Sexually transmitted diseases in the prepubertal child. Clin Pediatr 1993;1:165–83. Centers for Disease Control. 2002 Sexually transmitted diseases treatment guidelines. MMWR 2002;51:1–78. Stary A. European guideline for the management of chlamydial infection. Int J STD & AIDS 2001;12:30–3. Zar HJ Neonatal chlamydial infections: prevention and treatment. Pediatr Drugs 2005;7:103–10. Laming AC, Currie BJ, DiFrancesco M et al. A targeted, single-dose azithromycin strategy for trachoma. Med J Aust 2000;172(4):163–6.

Condyloma acuminata (see also Chapter 47) Definition. Condyloma acuminata (CA) are anogenital warts (Fig. 153.5) caused by human papillomavirus (HPV) infection. Most commonly, these warts are caused by HPV types 6, 11, 16 and 18, though type 2 is also often found in children aged older than 3 years. In the last instance these infections are in most cases caused by manual transmission [1–3]. Aetiology. The majority of the CA in children younger than 3 years is due to vertical transmission during birth. However, within this age group, there is suspected sexual abuse in a number of cases which is difficult to estimate. Sexual transmission has been reported to be up to one in

Fig. 153.5 Condyloma acuminata.

153.17

three children older than 3 years of age [1]. Non-sexual infection via child–child contact (e.g. via exploratory sexual games) or non-sexual intimate contacts between adults and children is possible [1,4]. A careful dermatological and paediatric examination is imperative in all children with CA. Modes of non-sexual transmission include: • hand–genital contact via an infected carer of the child • non-sexual intimate behaviour • inadequate hygiene, for example via contaminated objects such as a towel. All HPV types can infect the epithelium of the anogenital region, the mucous membranes in the mouth and the adjoining skin. Typing of HPV from the warts located in the anogenital region is therefore also indicated. This typing should be done with formalin-fixed or preferably with cryobiopsies supplemented with PCR. If HPV types 6, 11, 16, 18 or (very rarely) 31 are found, then one may speak of a sexually transmissible form of the HPV types [1–3]. However, this is no proof for sexual abuse. In prepubertal children with anogenital warts, besides these HPV types, type 2 is commonly encountered. Usually, this type is also found in the warts on the hands [1,3]. HPV typing in condylomata accuminata in children is important for these reasons. Clinical features. The incubation period of HPV infections varies from 1.5 to 8 months with a peak at 3 months. However, incubation periods of up to 20 months have been reported [2]. Such a long incubation period poses difficulty in establishing the exact aetiology [3]. The average incubation period from birth is about 3 months, with a maximum of about 2 years. Usually, CA cause no complaints and are generally noticed by chance by the parents or by a doctor during physical examination [5]. CA are usually encountered in the mucocutaneous or intertriginous areas such as the anogenital region, the perineum, on the labia, around the vaginal entrance, around the anus and in the rectum. They are rarely found intravaginally in young girls. Moreover, CA may occur in and around the mouth, and in the throat cavity and between the toes. They are predominantly encountered in the perianal region (57% of the CA in boys, 37% in girls). CA are seen on the labia in 23% of the girls and on the penis and scrotum in 17% of the boys [5]. They occur more frequently in girls than in boys (2.5 : 1). The majority are children younger than 3 years of age [6]. CA may also be encountered on the lips, on the tongue and on the palate because HPV can be transmitted via orogenital contact between the victim and the perpetrator [7]. The warts usually have the shape of a cauliflower or are stemmed, although flat forms may be encountered. They are red, pink or skin-coloured. Subclinical infections

153.18

Chapter 153

may occur in teenagers and adults. Probably, such infections also occur in children. Extremely large CA may occur in children with HIV infection [8]. Condyloma acuminata as a result of a perinatal infection occur in the larynx and in the anogenital region. Juvenile papillomas of the respiratory tract (oral cavity, vocal chords, epiglottis, trachea and lungs) are a rare manifestation of such HPV infections. These are caused by HPV types 6 and 11 [9,10]. The majority of children with juvenile papillomas are diagnosed between the age of 1 and 3 years, although the disorder has been observed regularly in other children [1]. The infection presents as hoarseness or respiratory problems. In any case, the virus may remain latent in apparently normal skin. Therefore, new lesions may develop several months after treatment [6]. Treatment. The treatment of CA is difficult. It is questionable if it is really necessary. Commonly used therapeutic regimes like podophyllin toxin (toxic for infants) and liquid nitrogen are often painful, toxic (podophyllin) and of limited effectiveness. Because recurrence rates are also high, their use must be discouraged [1,11,12]. Imiquimod is a recently developed imidazoquinolin heterocyclic amine that is an immune response modifier. Topical 5% imiquimod cream has been used successfully to treat CA in adults [11]. In children, reports of successful treatment with 5% imiquimod cream have been published [12,13]. However, a ‘wait and see policy’ (non-intervention treatment) has the priority because CA show the same course of spontaneous regression as common warts (verrucae vulgares) [14]. The treatment of choice for extremely large CAs is surgery and cauterization or treatment with a CO2 laser [1]. Also, pulsed dye laser has been found to be safe, effective, satisfactory and less traumatic compared to other options for treatment of persisting CA in children [15]. Prognosis. Condyloma acuminata disappear in more than half of cases spontaneously after 2 years so that a ‘wait and see policy’ is possible [1]. Malignant transformation in young children has not been described.

References 1 Oranje AP, Waard-van der Spek FB de, Bilo RAC. Condylomata acuminata in children. Int STD & AIDS 1990;1:250–5. 2 Stewart D. Sexually transmitted diseases. In: Heger A, Emans SJ (eds) Evaluation of the Sexually Abused Child – A Medical Texbook and Photographic Atlas. Oxford: Oxford University Press, 1992, pp. 155–6. 3 Armstrong DKB. Anogenital warts in prepubertal children: pathogenesis, HPV typing and management. Int J STD & AIDS 1997;8:78–81. 4 Herman-Giddens ME, Gutman LT, Berson NL. Association of coexisting vaginal infections and multiple abusers in female children with genital warts. Sex Transm Dis 1988;15:63–7.

5 Finkel MA, DeJong AR. Medical findings in child sexual abuse. In: Reece RM (ed) Child Abuse – Medical Diagnosis and Management. Philadelphia: Lea and Febiger, 1994, pp. 229–30. 6 Lacey CJN. Sexually transmitted diseases in the prepubertal child. Clin Pediatr 1993;1:165–83. 7 Blackwell AL. Paediatric gonorrhoea: non venereal epidemic in a household. Genitourin Med 1986;62:228–9. 8 Shelton TB, Jerkins GR, Noe HN. Condylomata acuminata in the pediatric patient. J Urol 1986;135:548–9. 9 Lindeberg H, Elbrond O. Laryngeal papillomas: the epidemiology in a Danish subpopulation 1965–1984. Clin Otolaryngol 1990;15: 125–31. 10 Terry RM, Lewis FA, Robertson S et al. Juvenile and adult laryngeal papillomata: classification by in-situ hybridization for human papilloma virus. Clin Otolaryngol 1989;14:135–9. 11 Vilata JJ, Badia X, ESCCRIM Group. Effectiveness, satisfaction and compliance with imiquimod in the treatment of external anogenital warts. Int J STD & AIDS 2003;14:11–17. 12 Gruber PC,Wilkinson J. Successful treatment of perianal warts in a child with 5% imiquimod cream. J Dermatol Treat 2001;12(4): 215–17. 13 Moresi JM, Herbert CR, Cohen BA. Treatment of anogenital warts in children with topical 0.05% podofilox gel and 5% imiquimod cream. Pediatr Dermatol 2001;18:448–50. 14 Allen AL, Siegfried EC. The natural history of condyloma in children. J Am Acad Dermatol 1998;39(6):951–5. 15 Tuncel A, Gorgu M, Ayhan M et al. Treatment of anogenital warts by pulsed dye laser. Dermatol Surg 2002;28(4):350–2.

Hepatitis B in children Definition. The hepatitis B virus (HBV) belongs to the group of Hepadnaviridae. The presence of partially double-stranded DNA and the need for reverse transcriptase activity to replicate through RNA intermediates characterize this virus family. The intact and infectious HBV particle is spherical in shape and measures about 42 nm in diameter. The core particle contains RNA, the partially double-stranded DNA and the reverse transcriptase, wrapped in core proteins. An envelope surrounds the virus particle. The virus contains at least three antigenic components: hepatitis B surface antigen (HbsAg), hepatitis B core antigen (HBcAg), and hepatitis B early antigen (HbeAg). Antibodies generated against one or more of these components are helpful in determining chronic carrierstate [1]. Aetiology and pathogenesis. Hepatitis B virus is one of the most clinically important viral infection in humans. About one-third of the world’s population has been infected by HBV, and more than 250 million people are chronically infected. HBV infections occur more often in Asia, southern Europe, Africa and South America. HBV has specific tropism for human liver cells since they contain specific receptors through which they can enter the cell and start their replication. After entry, the virus produces no immediate clinical symptoms which

Sexually Transmitted Diseases in Children and Adolescents

only occur after the onset of some immune response in the host. Hepatitis B virus transmission occurs through the exchange of body fluids such as blood, semen and vaginal secretions. Prior to blood donor screening, transfusion was a common route of transmission. Today, sexual transmission is the most common route. The incubation period varies from 2 to 6 months. In children HBV infection occurs due to transplacental transmission, perinatal transmission, non-sexual transmission and transmission via sexual contact. Saliva and urine may contain small amounts of virus but this is usually too little for efficient transmission. Non-sexual transmission may occur by exposure of HBV to mucous membranes, abraded skin or unrecognized wounds. Occasionally, HBV can be transmitted through biting in daycare settings for the mentally handicapped. Most children acquire HBV infection via non-sexual contacts with infected individuals from their peer group or infected adults [2]. The criteria for testing children for HBV in suspected sexual abuse are: • a homosexual or heterosexual perpetrator with multiple sexual contacts with various partners, or • a perpetrator who is an intravenous drug abuser or has a partner who is an intravenous drug abuser [2]. Clinical features. Hepatitis B virus infection usually has an insidious onset including jaundice, malaise and urticaria. The jaundice may persist for weeks to months. Sometimes HBV infection is accompanied by arthralgia or arthritis. Three different courses of disease can be recognized. Firstly, the immune response is of such a quality that the infection is cleared. This occurs in the majority of patients. Secondly, the infection may progress into a chronic infection, which occurs in about 10–20% of patients, depending on the child’s age. Thirdly, less than 1% will develop acute liver failure, often resulting in death or liver transplant. Diagnosis. An HBV infection is proven if HBV antigens (HbsAg, HbeAg, HBcAg) and/or antibodies to HBV antigens are demonstrated. Additionally, the virus can also be demonstrated and quantitated by means of PCR techniques on serum samples. In the majority of cases antiHBs antibodies are generated by the host soon after the onset of symptoms. Probably, they play a role in clearance of the virus. Patients with chronic HBV infection usually have no or low titres of circulating anti-HBs antibodies. In these circumstances, HbsAg and HbeAg are found for a prolonged period of time (many years). In cases of suspected sexual abuse, it is not possible to demonstrate HBV antigens nor HBV antibodies immediately after the insult. After 2 months, HBV antigens can

153.19

be demonstrated. A little later, antibodies may appear but then the child may already present clinical symptoms, if no measures were taken for passive immunization. If a child is tested HbsAg and HbeAg positive, the direct (non-sexual) contacts of the child should also be tested. Prognosis. Chronic HBV infection leads to chronic active hepatitis and eventually to cirrhosis and liver failure. Also hepatocellular carcinoma is a well-known late complication. The incidence of chronic HBV infection is dependent on age at acquisition. Up to 90% of children acquiring HBV perinatally become chronic carriers, whereas 20% of older children do so. In adults 5–10% become chronic carriers after infection with HBV. Treatment. Antiviral therapy for hepatitis B is still experimental, but progress has been made with combination therapies including interferon-α2b and lamivudin [3]. Most children with chronic active hepatitis are treated within academic protocols. Passive and active immunization are by far the most effective prevention measures [4]. If risk factors for HBV transmission are present, passive immunization with HBV immunoglobulins followed by HBV vaccination is advised. Immunization and vaccination are standard in children born to HBV-positive mothers [5]. References 1 Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337: 1733–45. 2 Finkel MA, DeJong AR. Medical findings in child sexual abuse. In: Reece RM (ed) Child Abuse – Medical Diagnosis and Management. Philadelphia: Lea and Febiger, 1994, pp. 229–30. 3 Sokal E. Drug treatment of pediatric chronic hepatitis B. Pediatr Drugs 2002;4:361–9. 4 Whittle HC, Inskip H, Hall AJ et al. Vaccination against hepatitis B and protection against viral carriage in the Gambia. Lancet 1991;337: 747–50. 5 Van Damme P, Vorsters A. Hepatitis B control in Europe by universal vaccination programmes: the situation in 2001. J Med Virol 2002; 67:262–4.

Genital herpes simplex virus infection (see also Chapter 48) Definition. Genital herpes simplex virus (HSV) infections are caused by HSV type 2 and less commonly type 1. Aetiology. The transmission of HSV may occur by various methods such as intrauterine (transplacental or via an ascending infection), during delivery, after delivery via a sexual contact and via non-sexual contacts. Sexual contact should be definitely considered in acquired HSV-2 and HSV-1 genital infections in children.

153.20

Chapter 153

Transmission occurs via close contact with an infected individual from an active lesion, mucosa or secretion. It is not necessary to have a clinically recognizable lesion to be infectious [1]. Autoinoculation via the fingers from the mouth to the genitalia is also possible. Autoinoculation is less probable if there has been recovery from the primary infection or in a recurrent infection [1]. In autoinoculation, the genital infection will occur simultaneously or soon after the oral infection. It should be noted that the simultaneous occurrence of an oral and a genital infection may also be the result of orogenital and genitogenital contact. Herpes simplex virus can survive for some time, for example, on a speculum or glass slide, or on plastic and rubber objects for a maximum of 4 h [2–4]. However, transmission in this manner is unlikely because for an infection, direct contact between live virus and the mucosa or damaged skin is essential [2]. HSV is rapidly inactivated at room temperature and through drying. Clinical features. The incubation period of acquired infection is 4–20 days. HSV causes painful vesicular or ulcerating lesions on the skin or mucosae, often with fever. Sometimes, there is pruritus. An acquired infection in children is usually located around the mouth or on the fingers. Genital HSV infections are rare in children. An acute napkin rash and vulval ulceration have been reported.

Neonatal herpes In a neonatal HSV infection, several days or weeks after delivery, the infant develops one or more of the following illnesses in which fever is not prominent: • local skin infection (blisters), eyes (keratoconjunctivitis) and/or mouth • disseminated infection with the appearance of neonatal sepsis • meningoencephalitis with reduced consciousness, convulsions and/or general sickness • pneumonia with (serious) respiratory problems (cough, tachypnoea) [5]. The last three disorders have a high mortality rate because the diagnosis of ‘HSV infection’ may be delayed and only considered after an unsuccessful clinical response to empirically chosen antibiotic treatment. The consequence is a delay in initiating adequate therapy [6]. In particular, residual abnormalities may be observed after meningoencephalitis or disseminated infection [7]. Moreover, it appeared that neurological damage still occurred in about 10% of cases after local infections without neurological abnormalities and with a normal CSF [7]. The residual complaints after an infection with HSV-2 are generally more severe than those after infection with HSV-1.

About 75% of children with neonatal herpes are born to mothers who are not known to have herpes genitalis [7]. Some neonatal infections are due to postnatal transmission of HSV. Diagnosis. In principle, the same diagnostics are used in children with an acquired HSV infection as are used in a neonatal infection (see Chapters 8, 9, 48). Treatment. An uncomplicated genital HSV infection is usually not treated. A primary infection with severe symptoms is treated orally with 500 mg valaciclovir twice a day for 5 days. For very severe symptoms, including neonatal infection, intravenous treatment with aciclovir is mandatory (10 mg/kg/dose three times daily for 5–10 days). Neonatal herpes is always treated with aciclovir intravenously [8]. The recommended regimen for infants treated for known or suspected neonatal herpes is aciclovir 20 mg/kg bodyweight intravenously every 8 hours for 21 days for disseminated and CNS disease or 14 days for disease limited to the skin and mucous membranes [8]. References 1 Finkel MA, DeJong AR. Medical findings in child sexual abuse. In: Reece RM (ed) Child Abuse – Medical Diagnosis and Management. Philadelphia: Lea and Febiger, 1994, pp. 229–30. 2 Gardner M, Jones JG. Genital herpes acquired by sexual abuse of children. J Pediatr 1984;104:243–4. 3 Larson T, Bryson YJ. Fomites and herpes simplex virus (letter). J Infect Dis 1985;151:746–7. 4 Neinstein LS, Goldenring J, Carpenter S. Nonsexual transmission of sexually transmitted diseases: an infrequent occurrence. Pediatrics 1984;74:67–9. 5 Sullivan Bolyai JZ, Hull HF, Wilson C, Smith AL, Corey L. Presentation of neonatal herpes simplex virus infections: implications for a change in therapeutic strategy. Pediatr Infect Dis J 1986;5:309–14. 6 Hubell C, Dominguez R, Kohl S. Neonatal herpes simplex pneumonitis. Rev Infect Dis 1988;10:431–8. 7 Whitley R, Arvin A, Prober C et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engl J Med 1991;324:450–4. 8 Centers for Disease Control. 2002 Sexually transmitted diseases treatment guidelines. MMWR 2002;51:1–78.

Human immunodeficiency virus (see also Chapter 52) Human immunodeficiency virus infections in children may occur after medical intervention such as administration of infected blood products, via mother-to-child transmission, through intravenous drug abuse and through sexual contact. Since 1989, several reports have been published in which attention has been drawn to the dangers of HIV infection through sexual abuse of children [1–3]. In most countries, the risk that a child runs of HIV infection as a result of sexual violence, considering the epide-

Sexually Transmitted Diseases in Children and Adolescents

miological state of affairs, is still small [4]. The risk of acquiring HIV infection is slightly higher in girls than in women due to the thin vaginal epithelium before puberty and the cervical ectopy in adolescents. The risk of HIV transmission per exposure event for unprotected receptive vaginal intercourse is estimated to be 1 in 3000 to 1 in 10,000 cases, but is higher when trauma and mucous lacerations are present [5]. Bear in mind that the same perpetrator may repeatedly have abused a specific child over a long period of time. At present there are no reasons for routinely testing for HIV in cases of suspected sexual abuse. The diagnosis of HIV may be essential on indication. The criteria for HIV testing in children [4] are as follows: • a request from the victim, parents or guardians • serious concern for the possibility of infection • the child has symptoms which may be due to HIV infection • the suspicion or assurance of seropositivity of the perpetrator or risky sexual contacts of the perpetrator • intravenous drug abuse by the perpetrator • frequently occurring abuse with vaginal/anal contact • additional ‘unknown’ perpetrators (e.g. in child prostitution) • the suspicion or assurance that the perpetrator has been to high-risk areas such as Thailand and the Philippines and has had sexual contact there. One needs to realize that when a child is tested positive, no definite cure is available. Lifelong treatment is now advised, which has many concurrent problems. Therefore, children should not be tested without extensive prior consultation with others and only when appropriate guidance is available. Testing may only be undertaken after either the parents or guardians have given permission. Treatment. Postexposure prophylaxis (PEP), instituted within 72 hours after the insult and preferably sooner, is recommended to prevent transmission in cases where the perpetrator is known or suspected to have HIVinfection [5]. PEP is usually given for 28 days and consists of 2–3 antiretroviral drugs, depending on local protocols. When PEP is given, a second HIV test should be performed after 3 months to determine whether HIV transmission had actually occurred. The treatment of HIV infection in childhood must be left to a paediatrician with specialized expertise in infectious diseases. Cutaneous abnormalities should be referred to and treated by a paediatric dermatologist or a dermatologist experienced in paediatric skin diseases. References 1 Gellert GA, Mascola L. Rape and AIDS. Pediatrics 1989;83:644. 2 Gutman LT, St Claire KK, Weedy C et al. Human immunodeficiency virus transmission by child sexual abuse. Am J Dis Child 1991;145: 137–41.

153.21

3 Murtagh C, Hammill H. Sexual abuse of children: a new risk factor for HIV transmission. Adolesc Pediatr Gynecol 1993;6:33–5. 4 National Committee on the Prevention of AIDS. Children, HIV Infection and AIDS. NCAB 1989. 5 Havens PL. Postexposure prophylaxis in children and adolescents for nonoccupational exposure to human immunodeficiency virus. Pediatrics 2003;111:1457–89

Trichomonas vaginalis infection (see also Chapter 153) Trichomonas vaginalis (TV) is a flagellated protozoon, which in adults is sexually transmitted. Pokorny [1] reported that the frequency of TV infections in adults had decreased to such an extent that one would be rarely confronted with such a problem in children. The Royal College of Physicians reported later that TV infection occurs very regularly in women after puberty [2]. An infection with TV in adults is only possible through sexual contact. There are several possible explanations for infections in children [3]. Contamination of the nose/throat cavity and also of the vagina may occur during delivery. Acquired TV infections are rare before puberty because the environment in the prepubertal vagina (hypertrophic epithelium, non-glycogen-containing and alkaline environment) is a poor source of nutrition so growth and colonization are not possible. A sexual contact between a child and an adult is suspected if a TV infection is encountered in a child older than 1 year. Moreover, it indicates that the contact has occurred recently because the organism of TV does not survive for long in the prepubertal vagina. Non-sexual transmission in prepubertal children is probably very rare because the organism is highly location specific [2]. Nevertheless, in principle, non-sexual transmission because of inadequate hygiene should be excluded if abuse is suspected: the organism of TV can survive for several hours on wet towels and clothing which have been used by infected women [2]. The organism also appeared to be able to survive in samples of urine and sperm even after they had been exposed to air for several hours [2]. The period of incubation is 1–4 weeks. In adolescents there may be vulvovaginitis with purulent discharge, urethritis and cystitis. The infection may be asymptomatic. Transient vulvovaginitis is the most probable complaint in prepubertal children. Trichomonas vaginalis is demonstrated by means of a direct preparation of the exudate to which physiological saline has been added (sampling with a moist cottonwool swab). The preparation must be evaluated directly. The sensitivity of a direct preparation is moderate, but the specificity is very high; a TV culture has a sensitivity of 95% [4].

153.22

Chapter 153

Table 153.1 Diagnosis and treatment of sexually transmitted diseases in children aged less than 16 (not sexually active), based on the European and CDC STD guidelines. For syphilis see Box 153.4 Disease

Diagnosis

Therapy

Chlamydia trachomatis

Cultures urine, vagina, rectum

Children 5 red blood cells/high-power field) and/or proteinuria (0.3 g/24 h). These EULAR/PReS classification criteria permit the detection of SHP with a diagnostic sensitivity of up to 100% and a specificity of 87%, as recently determined in a large multicentre study initiated by the Paediatric Rheumatology International Trials Organization (PRINTO) [5]. Epidemiology. Schönlein–Henoch purpura represents the most common childhood vasculitis with an incidence of up to 20/100,000 children per year. It can occur at any age, but has its peak incidence between the ages of 4 and 7 years with a disease onset before the age of 5 years in 50% and before 7 years in 75% of patients. Schönlein–

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Henoch purpura has been reported to occur slightly more often in males (1.2–2 : 1 ratio) and markedly less frequently in Afro-American than in Caucasian or Asian children [6,7]. Interestingly, retrospective and prospective epidemiological studies agree on a characteristic seasonal pattern, with the highest cumulative prevalence of SHP in the late autumn and winter months [8,9]. Aetiology. The underlying mechanisms of SHP pathogenesis remain to be fully elucidated. Yet, recent investigations have clearly strengthened the concept of SHP as an immunologically mediated, externally triggered disorder occurring more frequently in genetically susceptible individuals [10]. Genetics. While familial clustering of SHP has only rarely been reported [11,12], several gene polymorphisms may confer an increased risk of developing this disease. Of note, several HLA class II alleles have been reproducibly linked to SHP in cohorts of different ethnic origin. In particular, HLA-DRB1*01 and HLA-DRB1*11 polymorphisms were shown to increase the overall risk of developing SHP in populations from Spain and Turkey, whereas the HLA-DRB1*07 genotype was inversely correlated with SHP manifestation [13–15]. Additionally, SHP patients displaying the HLA class I B35 allele developed nephritis significantly more often than HLA B35-negative control patients in a European single-centre study [16]. The link of SHP and SHP nephritis to other polymorphisms in genes encoding for angiotensin-converting enzyme [17], paraoxonase 1 [18], toll-like receptor (TLR) 2 and TLR 4 [19], nitric oxide synthase [20] or interleukin1β (IL-1β) [21] is currently less well established. Intriguingly, mutations within the MEFV gene, which is also implicated in familial Mediterranean fever (FMF), have recently been detected in nearly 40% of patients with severe SHP. Vice versa, Turkish children with FMF were reported to run a more than 70-fold increased risk of developing SHP [13,22,23]. Immunobiology. Although the intricate network of SHP immunobiology is still poorly understood, immunoglobulin A (IgA) antibodies are known to play a paramount

160.2

Chapter 160

pathogenetic role. Affected patients display increased serum IgA levels, multiorgan deposition of complementactivating IgA immune complexes and, terminally, small vessel leucocytoclastic vasculitis. Interestingly, the involved immune complexes have been shown to consist exclusively of polymeric IgA subtype 1 (IgA1), but not IgA2 antibodies. This might be attributed to an impaired glycosylation of functionally relevant proteins within the IgA1-specific hinge region, which in turn causes IgA1 aggregation and the formation of precipitating macromolecules [24,25]. In addition, a wide range of pro- and anti-inflammatory cytokines are differentially regulated in patients with SHP, depending on the clinical phenotype. For instance, serum levels of tumour necrosis factor-α (TNF-α) and IL-6 were elevated in children with acute SHP in comparison to patients with subsiding SHP or healthy controls. Similarly, transforming growth factor-β (TGF-β)-secreting regulatory T-cells have been found to be activated in acute SHP, whereas TGF-β serum levels were not significantly different in paediatric SHP patients with or without renal involvement [26,27]. Unfortunately, the clinical implications of these and other immunological findings remain unclear and, therefore, further controlled trials in larger patient populations are warranted. Trigger factors. Putatively antigen-driven, SHP has been linked to a multitude of microbial and other external eliciting factors. Consistent with its reported seasonal peak incidence, SHP is preceded by upper respiratory tract infections in up to 50% of patients [6]. Most importantly, a concomitant or previous infection with group A βhaemolytic streptococci has been ascertained by throat cultures or anti-streptolysin O serology in 30–50% of affected children [28,29]. Further incriminated bacterial and viral agents include, among others, Helicobacter pylori, Staphylococcus aureus, Bartonella henselae and Haemophilus influenzae as well as adenovirus, coxsackievirus, hepatitis B virus or parvovirus B19. While some of these microorganisms have reproducibly been linked to SHP occurrence, the significance of others in the context of SHP is still a matter of controversy. Non-infectious triggers of potential relevance in paediatric SHP comprise antibiotics (clarithromycin, ampicillin), non-steroidal anti-inflammatory drugs [paracetamol (acetaminophen)], vaccinations (influenza, hepatitis B, measles), immune response modifiers (etanercept, infliximab) and insect bites [30–34]. In contrast, sufficient evidence supporting a direct role of food-related antigens in SHP pathogenesis is currently lacking. Clinical features. Typically, SHP manifests with one or more symptoms of the ‘classical clinical tetrad’ of purpura,

Box 160.1 Infrequent complications in Schönlein–Henoch purpura Neurological • • • •

Seizures Intracranial haemorrhage Cerebral vasculitis Neuropathy

Gastrointestinal • • • • • • • •

Intussusception Gastrointestinal haemorrhage Bowel perforation Bowel infarction Protein-losing enteropathy Pancreatitis Cholecystitis Duodenal obstruction

Pulmonary • Alveolar haemorrhage • Pulmonary effusion Other • • • •

Myocarditis Myositis Orchitis Anterior uveitis

arthritis, abdominal pain and nephritis. However, as a systemic inflammatory disorder, SHP can impair further organ systems in varying frequency, sequence and severity. While SHP resolves spontaneously within 4 weeks in up to 94% of children, 33% of children may suffer one or more symptom recurrences, which usually subside within 6 months after the initial episode [35]. The following text discusses the most frequent clinical features of SHP, while rare complications occurring only in a minority of patients are summarized in Box 160.1.

Skin manifestations By definition, all patients reveal palpable purpura in one phase of the illness, and cutaneous lesions are the presenting sign in the majority (73%) of cases. Usually these are symmetrically located on the extensor surfaces of the lower extremities and the gluteal region, but may spread to other areas such as the forearms, the face and the trunk. In contrast, the palmoplantar regions and the mucous membranes are usually spared, whereas skin areas exposed to mechanical stress (sock line, belt line) represent SHP predilection sites. Characteristic skin lesions consist of a non-pruritic urticarial or maculopapular rash developing into petechiae and, terminally, non-blanching palpable purpura on the

Schönlein–Henoch Purpura

buttocks and lower extremities (Figs 160.1 & 160.2). Within several days to a few weeks, affected skin areas display a characteristic change in colour from red to purple, then turning rust-coloured or brown before spontaneous resolution [36]. In comparison to adults, paediatric patients more frequently show polymorphic SHP eruptions. Rarely, children may present with coalescent ecchymoses (Fig. 160.3) and haemorrhagic bullae that can result in ulceration and scarring. A minority of patients also display target-like lesions (Fig. 160.4) sometimes mimicking erythema multiforme. Veritable skin necrosis is observed in less than 5% of affected children [37,38]. Perhaps even more importantly, up to 5% of infants and young children (10 cells per high-power field a. If three or more supplemental laboratory criteria are positive, a diagnosis of KD is made. The child should have an echocardiogram and be treated. b. If fewer than three supplemental laboratory criteria are positive, cardiac echocardiogram should be performed. If negative but fever persists, a repeat echocardiogram may be performed. If the echocardiogram is negative and the fever abates, KD is unlikely. If the echocardiogram is positive, the child is treated for KD.

Kawasaki Disease

coronary artery aneurysms, which may lead to myocardial infarction, arrythmia, or death [1,2]. Risk factors for developing cardiac sequelae include male gender, age less than 1 year or over 5 years, CRP greater than 100 mg/L, white blood count greater than 30 × 109/L, low serum albumin and treatment after 6 days of illness [53–55]. The earliest manifestations occur within 10 days of onset of disease and can be mild to severe. Myocarditis often is observed, giving tachycardia in excess of the fever and anaemia associated with the condition and occasionally leading to acute congestive heart failure. Patients with poor myocardial function may even present with low cardiac output syndrome or shock. One centre in the United States noted this complication in 13 of 187 (7%) children with KD over a 4-year period [56]. Patients were more often female, had more severe laboratory markers of inflammation, and had impaired systolic and diastolic function. Toward the latter part of the acute phase, pericarditis/myopericarditis can cause a pericardial effusion with severe tachycardia, gallop rhythm and/or distant heart sounds on exam, although the effusion rarely progresses to tamponade and generally spontaneously resolves [55]. Diastolic dysfunction is common and aortic root dilation occurs in 15% of patients [57]. Electrocardiographic changes may include arrhythmia, prolonged PR interval or non-specific ST- and T-wave changes. Rarely, there may be severe arrhythmia leading to cardiac arrest and valvulitis with mitral and/or aortic regurgitation. In the subacute phase, congestive heart

Fig. 168.10 Right and left giant coronary aneurysms.

168.7

failure is usually caused by myocardial dysfunction stemming from ischaemia or infarction. Kawasaki disease involves an acute inflammation of medium-sized elastic arteries with a significant predilection for the coronary arteries. Coronary artery dilation is first detected after, on average, 5.4 days of illness, with peak frequency of dilation and aneurysm at 3–4 weeks of onset [9]. In some cases, dilation is transient, with regression within the first 30 days after onset of KD. However, 20–25% of these lesions progress to true aneurysms, although the rate is reduced to 4–5% with IVIG treatment [58]. Medium (5–8 mm internal diameter) and giant (>8 mm, see Fig. 168.10) aneurysms often form thrombi early in the course of disease, which may increase in size over time and result in occlusion. This may be associated with myocardial ischaemia, infarction and sudden death, although approximately two-thirds of patients with occlusion are asymptomatic [9]. Rarely giant aneurysms may rupture within the first few months after KD, also with fatal consequences. True aneurysms that persist to the convalescent phase and after do gradually decrease in size with time. Disappearance of abnormal findings on coronary angiography occurs in 50–67% of cases and within 1–2 years after onset [9,19]. The likelihood of this depends on aneurysm size, with most small aneurysms (5.6 μmol/L) than the control subjects. The carotenaemic patients were diagnosed as having metabolic or hyperlipidaemic carotenaemia. Nishimura [22] suggested that there was a close relationship between metabolic carotenaemia and biliary dyskinesia. These findings have not yet been confirmed by other investigators. It is possible that high skin and tissue concentrations of β-carotene are in fact beneficial. Carotenoids are believed to protect cells against the harmful effects of free radicals. Someya et al. [23] have shown that, in the guinea pig, carotene supplementation prevents the skin lipid peroxidation caused by ultraviolet irradiation. It has been postulated that the free radical scavenging activity of carotenoids may help to prevent atherosclerosis and

171.4

Chapter 171

cancer. Individuals with blood β-carotene levels towards the upper limit of the normal range have a lower incidence of cancer and heart disease than those with lower β-carotene levels. Conversely, two studies have shown that supplementation with β-carotene does not prevent cancer and heart disease in well-nourished individuals and, indeed, in high-risk groups (smokers and people exposed to asbestos) the morbidity and mortality appear to be increased by supplementation. However, there were no excess cases of death and disease in those who attained the highest blood β-carotene levels during supplementation [24]. Dietary carotenaemia (and some cases of hyperlipidaemia) gives rise to mildly elevated plasma concentrations of vitamin A. The hypervitaminosis A is never sufficient to cause signs of intoxication; liver function tests are normal [25]. Metabolic carotenaemia may produce low plasma vitamin A concentrations. In such individuals it may be possible to show defective dark adaptation on careful visual testing [5]. In RBP deficiency, low levels of vitamin A in plasma cause night blindness but not xerophthalmia [19]. In theory, prolonged systemic vitamin A deficiency might lead to xerophthalmia, hyperkeratosis and increased susceptibility to infection. To date, these problems have never been documented, but that may be because metabolic carotenaemia has not been described in children from developing countries. It is important to remember that such children may already be predisposed to vitamin A deficiency by their poor dietary intake of vitamin A [26].

Excessive ingestion A careful dietary history should be taken. Carotenaemia has been documented in the first year of life in breastfed infants whose mothers ingest over 1.5 kg of carrots per week or more than 10 tangerines per day [27]. It has also been documented in infants whose parents were strict vegetarians and believed that carrot juice was better for their infant than milk. Such infants may also show evidence of failure to thrive. Carotenaemia may also occur in infants who are difficult to wean onto a balanced range of solids and show a marked preference for pureed carrots and green vegetables. It has been diagnosed in infants who ingested 2–4 tangerines per day for 4 weeks. Older children may select a vegetarian diet with a high content of β-carotene, and the clinician should consider the possibility that this is part of the anorexia nervosa syndrome [28]. Dietary carotenaemia has also been recorded in areas of West Africa where red palm oil (which has high carotene content) is used for cooking. Finally, it should be recalled that β-carotene has been used for treatment of photodermatoses such as porphyria and so a careful drug history must be taken. Laboratory investigations reveal an elevated plasma β-carotene concentration and a slightly elevated plasma vitamin A concentration. Hyperlipidaemias A full medical history and examination (including urinalysis) should be undertaken. Weight loss could be the result of diabetes or anorexia nervosa. A history of polyuria and polydipsia points strongly to diabetes, which can be con-

Clinical features. Carotenaemia produces a yelloworange pigmentation of the skin that is usually most obvious on the palms, soles and nasolabial folds and is absent from the sclerae (Figs 171.2, 171.3). The urine and stools have a normal colour.

Fig. 171.2 Facies of an infant with metabolic carotenaemia. In this case the pigmentation was most obvious in the skin of the tip of the nose, the cheeks and the pinnae. Note the absence of pigmentation in the sclerae.

Fig. 171.3 Comparison of the skin colour of the palm of a child with carotenaemia (upper) and a normal palm (lower).

Carotenaemia

firmed by testing the urine for sugar. A history of lethargy, developmental delay, constipation and poor linear growth should trigger a search for features of hypothyroidism such as the coarse facies, large tongue, umbilical hernia and bradycardia. A history of periorbital swelling should lead to a general search for oedema and ascites, and the urine should be checked for the heavy proteinuria that is characteristic of nephrotic syndrome. Symptoms of fasting hypoglycaemia (pallor, sweating, jitteriness, loss of consciousness, convulsions) and poor linear growth are suggestive of one of the hepatic glycogenoses and such a diagnosis will usually be obvious from massive hepatomegaly. The hyperlipidaemia of cholestasis and of homozygous familial hypercholesterolaemia may be associated with the presence of cutaneous xanthomas. Investigations will be directed by the clinical findings but may include β-carotene, vitamin A, cholesterol, triglycerides, blood glucose, glycosylated haemoglobin, thyroid function, liver function, plasma albumin and renal function tests.

Inborn error(s) of carotene metabolism The pigmentation is identical to that produced by excessive ingestion of carotene. The age at presentation ranges from 6 months to 24 years. The β-carotene intake is normal or low; some older patients have shown an aversion to β-carotene and have adopted a low-carotene diet [14]. Some parents of affected infants and toddlers have described loose stools regularly induced by ingestion of carotene-containing foods. There may be a family history of other affected individuals. The plasma concentration of β-carotene is elevated (5–22 μmol/L) and the plasma concentration of vitamin A may be normal or low. It is now possible to look for mutations in carotenoid 15,15′-mono-oxygenase [11] and RBP [19]. This should clarify whether genetic defects in these proteins are responsible for carotenaemia. Prognosis. There are no proven adverse effects of dietary carotenaemia. The skin pigmentation can be eliminated by reducing the excessive carotene intake. In the occasional case in which there has been neutropenia or transaminaemia, these have also resolved. In children who have carotenaemia associated with hyperlipidaemia, discussion of the prognosis should focus on the cause of the hyperlipidaemia. Metabolic carotenaemia is a benign condition. Parents can be advised that any symptoms associated with ingestion of β-carotene will resolve when a low-carotene diet is instituted. Any potential effects of vitamin A deficiency can be avoided by a vitamin A supplement. Differential diagnosis. Yellowish pigmentation of the skin (xanthodermia) is most commonly due to jaundice.

171.5

Table 171.3 Differential diagnosis of carotenaemia Cause

Plasma carotene

Plasma vitamin A

Plasma cholesterol and/or triglycerides

Dietary carotenaemia Metabolic carotenaemia Hyperlipidaemia

↑ ↑ ↑

↑ N/↑ N/↑

N N ↑

N, normal.

It is occasionally seen when substances such as picric acid, saffron and mepacrine are ingested and stain the skin. In all these conditions, in contrast to carotenaemia, the sclerae are also pigmented. The diagnosis of carotenaemia and its cause can often be elucidated from the history and examination (as indicated above) but differential diagnosis is aided by measurements of plasma concentrations of β-carotene, vitamin A and lipids (Table 171.3). Treatment. Excessive ingestion of β-carotene should be managed by first reassuring the parents and the referring doctor that the child does not have jaundice or any other significant medical problem. General dietary advice should be given to ensure that the child will in future receive a balanced diet and the parents can also be told how they can eliminate the cutaneous pigmentation by cutting down the child’s excessive intake of β-carotene. Children with hyperlipidaemia should be treated on the basis of the underlying cause. Parents of children with metabolic carotenaemia should be reassured that it is a benign condition but that the pigmentation can be reduced or eliminated by the use of a low-carotene diet. This involves avoidance or restriction of certain vegetables and fruit and avoidance of foods which contain E160 carotenoid additives. The fruit and vegetables in Table 117.2 which have very high carotene content should be avoided altogether. Those with a high content should be restricted to a maximum of one portion per week, but two portions daily of those with a moderate content can be allowed. Children with metabolic carotenaemia should avoid carrot juice, apricot juice, mango juice, tomato juice and any squash or carbonated drinks with added β-carotene. Meat, fish, eggs and poultry can be used freely in the diet but ox liver should be avoided. Chilli, paprika, cayenne pepper and curry powder have high β-carotene content and should be omitted from the diet. Foods with a high content of cow’s milk fat should also be avoided, as should butter and margarine (except for products with no added β-carotene). Flour, bread, pasta and breakfast cereals can be taken freely. Cakes and

171.6

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biscuits that are made with butter or margarine should be avoided, but those made with vegetable oil as the fat source can be used in the diet. Yellow-coloured sweets, desserts, preserves and so on should be checked for added β-carotene (e.g. lemon curd has a high content). If children with metabolic carotenaemia have a low plasma vitamin A concentration, this can usually be corrected by an oral vitamin A supplement (2500 units/day).

12 13

14 15 16

Acknowledgement We are grateful to Marjorie Dixon, Chief Dietitian at Great Ormond Street Hospital, for valuable advice on the lowcarotene diet. References 1 Furr HC. Carotenoids. In: Macrae, R, Robinson, RK, Sadler, MJ (eds). Encyclopaedia of Food Science, Food Technology and Nutrition. London: Academic Press, 1993: 707–18. 2 Malvy DJ, Burtschy B, Dostalova L et al. Serum retinol, β-carotene, β-tocopherol and cholesterol in healthy French children. Int J Epidemiol 1993;22:237–46. 3 Greene CH, Blackford L. Carotenemia. M Clin N Am 1926;10:733–44. 4 Almond S, Logan RFL. Carotinaemia. BMJ 1942;ii:239–41. 5 Cohen L. Observations on carotenaemia. Ann Intern Med 1958;48:219–27. 6 Traber MG, Diamond SR, Lane JC et al. β-Carotene transport in human lipoproteins. Comparisons with β-tocopherol. Lipids 1994;29:665–9. 7 Holland B, Welch AA, Unwin ID et al. McCance and Widdowson’s The Composition of Foods, 5th edn. London: HMSO, 1991. 8 Prince MR, Frisoli JK. Beta-carotene accumulation in serum and skin. Am J Clin Nutr 1993;57:175–81. 9 Lloyd JK. Plasma lipid disorders. In: Clayton, BE, Round, JM (eds) Chemical Pathology and the Sick Child. Oxford: Blackwell Scientific Publications, 1984. 10 Mordasini R, Klose G, Greten H. Secondary type II hyperlipoproteinemia in patients with anorexia nervosa. Metabolism 1978;27:71–9. 11 Lindqvist A, Sharvill J, Sharvill DE, Anderson S. Loss-of-function mutation in carotenoid 15,15′-monooxygenase identified in a patient

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with hypercarotenaemia and hypovitaminosis A. J Nutr 2007;137:2346–50. Sharvill DE. Familial hypercarotinaemia and hypovitaminosis A. Proc Roy Soc Med 1970; 63:605–6. McLaren DS, Zekian B. Failure of enzymic cleavage of β-carotene. The cause of vitamin A deficiency in a child. Am J Dis Child 1971;121:278–80. Monk BE. Metabolic carotenaemia. Br J Dermatol 1982;106:485–7. Svensson A, Vahlquist A. Metabolic carotenemia and carotenoderma in a child. Acta Derm Venereol 1995;75:70–1. Ferruci L, Perry JRB, Matteini A et al. Common variation in the βcarotene 15,15’-monooxygenase 1 gene affects circulating levels of carotenoids: a genome wide association study. Am J Hum Gen 2009;84:123–33. Leung WC, Hessel S, Meplan C et al. Two common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15’-monoxygenase alter beta-carotene metabolism in female volunteers. FASEB J 2009;23:1041–53. Attard-Montalto S, Evans N, Sherwood RA. Carotenaemia with low vitamin A levels and low retinol-binding protein. J Inherit Metab Dis 1992;15:929–30. Seeliger MW, Biesalski HK, Wissinger B et al. Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis. Invest Ophthal Vis Sci 1999;40:3–11. Shoenfeld Y, Shaklai M, Ben-Baruch N et al. Neutropenia induced by hypercarotenaemia. Lancet 1982;i:1245. Kaspar P, Polsky A, Kudlova E et al. Carotenemia. Cesk-Pediatr 1991;46:275–7. Nishimura T. A correlation between carotenemia and biliary dyskinesia. J Dermatol 1993;20:287–92. Someya K, Totsuka Y, Murakoshi M et al. The antioxidant effect of palm fruit carotene on skin lipid peroxidation in guinea pigs estimated by the chemiluminescence–HPLC method. J Nutr Sci Vitaminol Tokyo 1994;40:315–24. Rowe PM. Beta-carotene takes a collective beating. Lancet 1996;347:249. Pollitt N. Beta-carotene and the photodermatoses. Br J Dermatol 1975;93:721–4. Favaro RM, de-Souza NV, Batistal SM et al. Vitamin A status of young children in southern Brazil. Am J Clin Nutr 1986;43:852–8. Honda T. Adverse effects of foods in genetic disorders. In: Jelliffe, EFP, Jelliffe, DB (eds) Adverse Effects of Foods. New York: Plenum Press, 1982: 389–96. Bilimoria S, Keczkes K, Williamson D et al. Hypercarotenaemia in weight watchers. Clin Exp Dermatol 1979;4:331–5.

172.1

C H A P T E R 172

Cutaneous Manifestations of Endocrine Disease Peter A. Hogan Department of Dermatology, Children’s Hospital at Westmead, Sydney, Australia

Disorders of thyroid function, 172.1

Hypopituitarism, 172.24

Disorders of the adrenal glands, 172.7

Growth hormone excess, 172.24

Disorders of sex hormones, 172.10

Growth hormone deficiency, 172.25

Insulin resistance, 172.17

Disorders of the parathyroid

Diabetes mellitus, 172.20

Polyglandular autoimmune syndromes,

gland, 172.25

Disorders of thyroid function Hypothyroidism Pathogenesis. Congenital hypothyroidism is usually due to hypoplasia or aplasia of the thyroid gland, inherited abnormalities of the thyroid-stimulating hormone (TSH) receptor, failure of the thyroid to descend properly during embryogenesis (e.g. lingual thyroid) or an inherited defect in the biosynthesis of thyroid hormone [1–4]. Uncommon causes include endemic iodine deficiency [3], unresponsiveness to thyrotropin [5], hypothalamopituitary dysfunction [6] and infiltration of the thyroid gland with histiocytosis X [7] and cystinosis [8]. Transient congenital hypothyroidism can occur for no apparent reason [1], can be due to transient hypothalamopituitary dysfunction [9], can follow the use of antithyroid drugs [1], amiodarone [10] or D-pencillamine [11] during pregnancy, can follow the cutaneous application of povidone iodine to open wounds in the neonatal period [12] and can be due to transplacental transfer of thyroxine from a hyperthyroid mother [13] or antithyroid antibodies capable of blocking the thyrotropin receptor [14]. Acquired hypothyroidism is usually due to autoimmune (Hashimoto) thyroiditis [15], endemic iodine deficiency [3], hypothalamopituitary dysfunction [16] or therapeutic ablation of the thyroid gland (radio-active iodine or surgery). In young infants, hypoplasia of the thyroid gland [15], an ectopic thyroid gland (e.g. lingual) [15] defects in the biosynthesis of thyroid hormone [17], iodine exposure [18] and Langerhans cell histiocytosis [19] are additional causes. The cutaneous findings in

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

172.28 Multiple endocrine neoplasia syndromes, 172.29 The Carney complex, 172.30

hypothyroidism result from alterations in the function and structure of the skin and alterations in the metabolism of bilirubin and β-carotene. In particular, thyroxine deficiency alters cutaneous vascular flow, decreases eccrine and sebaceous gland activity, decreases hair growth, increases production of glycosaminoglycans (GAGs) by dermal fibroblasts, prolongs neonatal jaundice and reduces the conversion of β-carotene to vitamin A. Pathology. The only distinctive histological finding in the skin of patients with hypothyroidism is the infiltration of the dermis, and occasionally the subcutaneous fat, with GAGs [20]. The infiltration is most marked around appendageal structures and consists primarily of hyaluronic acid. Identification of the infiltration requires special stains such as toluidine blue or Alcian blue. Clinical features

Congenital hypothyroidism Newborn screening programmes have found a mean incidence of congenital hypothyroidism of 1 in 3331 births in Australia, 1 in 3801 births in Europe, 1 in 4119 births in the USA [21] and 4.3 in 10,000 births in Mexico [22]. The newborn screening programme in California has found that females are more commonly affected than males in a ratio of 2:1 [23]. Most cases of congenital hypothyroidism in the western world are now diagnosed through newborn screening programmes long before the typical clinical picture develops [2,22]. Before the introduction of screening programmes, newborn infants with congenital hypothyroidism were typically quiet and initially regarded as good babies. The diagnosis was not considered until other symptoms and signs had developed during infancy and childhood [2,24,25,26] (Fig. 172.1). The characteristic symptoms of congenital hypothyroidism are feeding difficulties,

172.2

Chapter 172

lethargy, constipation, thermal instability with hypothermia and an unusual (‘hoarse’) cry [2]. Prolonged neonatal jaundice (more than 3 weeks), umbilical hernia, hypotonia, bradycardia and prominent fontanelles are the earliest signs in most cases [3,24]. Linear growth failure, developmental delay and mental retardation are features of well-established cases [25]. Although congenital hypothyroidism is an isolated problem in most patients, it has been reported in association with Alström syndrome [27], the CHARGE association (coloboma, heart disease, atresia choanae, retarded growth and retarded development and/or central nervous system (CNS) anomalies, genital hypoplasia and ear anomalies or deafness) [28], trisomy 4p [29], Beckwith– Wiedemann syndrome [30], cutis marmorata telangiectatica congenita [31], cutis laxa [32] and as part of the Young–Simpson syndrome (congenital hypothyroidism, mental retardation, blepharophimosis) [33].

(a)

(b) Fig. 172.1 A 3-month-old infant with the features of congenital hypothyroidism: myxoedematous facies, macroglossia and umbilical hernia. Courtesy of Dr Geoff Ambler, New Children’s Hospital, Sydney, Australia.

Cutaneous signs of congenital hypothyroidism. Skin involvement is initially characterized by a cool and dry feel on palpation, pronounced cutis marmorata and a translucent pallor resembling alabaster [2]. The pallor results from the combined effect of anaemia, poor peripheral perfusion, prolonged neonatal jaundice, carotenaemia and accumulated GAGs. The accumulation of GAGs in the skin and tongue eventually results in thickening of the skin (myxoedema) and macroglossia. The thickened skin is non-pitting and has a doughy, boggy feel on palpation. The thickening is most prominent around the eyes, lips, supraclavicular fossae, hands and feet. The combination of thickened facial skin, protruding tongue, depressed nasal bridge and mild hypertelorism results in a characteristic facies. Other mucocutaneous findings in established cases include lustreless, slowgrowing hair, slow-growing nails and delayed eruption of deciduous teeth.

Acquired hypothyroidism Acquired hypothyroidism is more common in females [34,35]. It usually presents with non-specific symptoms such as lethargy, constipation, cold intolerance, arthralgias and myalgias, or with specific problems such as an enlarged thyroid gland, umbilical hernia, poor linear growth, developmental delay, delayed dentition, poor school performance, delayed puberty or a neuropsychiatric illness [36–39]. Uncommon clinical manifestations include precocious puberty with multicystic ovaries [40], a polymyocitis-like syndrome with raised creatine phosphokinase (CPK) [41], pericardial tamponade [42], rhabdomyolysis with renal failure and pericardial effusion [43] and hyperprolactinaemia [44]. Acquired hypothyroidism has been reported in association with Kocher–Debre–Semelgaine syndrome [45],

Cutaneous Manifestations of Endocrine Disease

Wyck–Grumbuch syndrome [46], acanthosis nigricans and insulin resistance [47], acquired von Willebrand disease [48,49], precocious puberty [50], Schinzel– Giedion syndrome [51], allogeneic haemopoietic stem cell transplantation in children treated with fractionated total body irradiation [52], hepatic haemangioendothelioma [53,54], infants with glycogen storage disease type 1 [55], Angelman syndrome [56] and Sturge–Weber syndrome [57]. Hypothyroidism secondary to autoimmune thyroiditis can evolve rarely into hyperthyroidism [58] or patients can develop other autoimmune diseases [59]. Mucocutaneous findings in acquired hypothyroidism. The mucocutaneous findings will depend on the severity and duration of hypothyroidism at presentation [36,37]. Patients with well-established disease will have cool, dry skin, exhibiting a ‘yellow-tinged’ pallor. Myxoedematous changes are evident in the form of macroglossia and thickening of the skin on the face (‘expressionless facies’), over the supraclavicular fossae and around the hands and feet. The myxoedematous changes can be associated with purpura and poor wound healing. The lateral third of the eyebrows is characteristically lost and the scalp and body hair is sparse, brittle and lustreless in appearance. Paradoxically, some infants and children develop hypertrichosis on the back and upper arms involving dark, terminal hairs [60]. Nail growth is diminished and is associated with brittleness and ridging of the nail plates. Investigations. The clinical diagnosis of hypothyroidism is easily confirmed by measuring serum levels of free thyroxine and/or thyrotropin [1,2]. The thyrotropin level will be high in patients with primary hypothyroidism and low in patients with hypothyroidsm secondary to hypothalamopituitary dysfunction. Antithyroid antibodies may be found in neonates with transient hypothyroidism secondary to the transplacental transfer of maternal antibodies [14] and in infants and children with autoimmune thyroiditis [37]. Infants with congenital primary hypothyroidism require further evaluation (e.g. radio-isotope scan) to determine the presence and location of thyroid tissue [2]. Other investigative findings in patients with congenital hypothyroidism include absence of the long bone epiphyses [2] and pericardial effusions [61]. Prognosis. Newborn screening programmes for congenital hypothyroidism have enabled the early introduction of thyroxine replacement therapy. This has resulted in normal intelligence in infants with mild thyroxine deficiency and a significant reduction in the degree of intellectual impairment in infants with severe thyroxine deficiency [62,63]. In addition to the resolution of those

172.3

clinical features directly attributable to thyroxine deficiency (e.g. myxoedema), thyroxine replacement therapy can resolve features that are not directly attributable to thyroxine deficiency, e.g. hypertrichosis [60], acanthosis nigricans (AN) and insulin resistance (IR) [47], precocious puberty [40,48], ovarian cysts [40], rhabdomyolosis [43], myositis with raised CPK [41], pericardial tamponade [42], hyperprolactinaemia [44] and von Willebrand disease [48,49]. Differential diagnosis. The differential diagnosis of congenital hypothyroidism includes trisomy 21, gonadal dysgenesis (Turner syndrome), mucopolysaccharidoses and Beckwith–Wiedemann syndrome. Trisomy 21 and Turner syndrome are easily distinguished from congenital hypothyroidism by chromosomal studies. Infants with one of the mucopolysaccharidoses are distinguished by marked hepatosplenomegaly and normal thyroid function tests. Infants with Beckwith–Wiedemann syndrome have accelerated growth, an omphalocoele rather than an umbilical hernia, and normal thyroid function tests. Management. Congenital and acquired hypothyroidism are treated with l-thyroxine therapy. The dose will vary with the age and weight of the patient and the cause (e.g. the dose required will be greater in athyroid infants). The benefits of high-dose versus low-dose thyroxine therapy in the management of congenital hypothyroidism remain unclear [64]. Its administration should be supervised by an experienced practitioner. Care must be taken when treating congenital hypothyroidism because of the risk of inducing congestive cardiac disease in the early stages of treatment secondary to the mobilization of fluid from myxoedematous tissues. References 1 Fisher A, Dussault JH, Foley TP et al. Screening for congenital hypothyroidism: results of screening 1 million North American infants. J Pediatr 1979;94:700–5. 2 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. 3 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;83:1047–51. 4 Park SM, Chatterjee VK. Genetics of hypothyroidism. J Med Genet 2005;42:378–89. 5 Takamatsu J, Nishikawa M, Horimoto M et al. Familial unresponsiveness to thyrotropin by autosomal recessive inheritance. J Clin Endocrinol Metab 1993;77:1569–73. 6 Isichei UP, Das SC, Egbuta JO. Central cretinism in four successive siblings. Postgrad Med J 1990;66:751–6. 7 Braunstein GD, Kohler PD. Endocrine manifestations of histiocytosis-X. Am J Pediatr Hematol Oncol 1981;3:67–75. 8 Lucky AW, Howley PM, Megyesi K et al. Endocrine studies in cystinosis: compensated primary hypothyroidism. J Pediatr 1977;91:204–10.

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9 Jain R, lsaac RM, Gottschalk ME et al. Transient central hypothyroidism as a cause of failure to thrive in newborn infants. J Endocrinol Invest 1994;17:631–4. 10 Magee LA, Downer E, Sermer M et al. Pregnancy outcome after gestational exposure to amiodarone in Canada. Am J Obstet Gynecol 1995;172:1307–11. 11 Hanukoglu A, Curiel B, Berkowitz D et al. Hypothyroidism and dyshormonogenesis induced by D-pencillamine in children with Wilson’s disease and healthy infants born to a mother with Wilson’s disease. J Pediatr 2008;153:864–6. 12 Barakat M, Carson P, Hetherton AM et al. Hypothyroidism secondary to topical iodine treatment in infants with spina bifida. Acta Paediatr 1994;83:741–3. 13 Lee YS, Loke KY, Ng SC et al. Maternal thyrotoxicosis causing central hypothyroidism in infants. J Paediatr Child Health 2002;38: 206–8. 14 Matsuura N, Yamada Y, Nohara Y et al. Familial neonatal transient hypothyroidism due to maternal TSH binding inhibitor immunoglobulin. N Engl J Med 1980;303:738–41. 15 Okamura K, Salo K, Ikenoue H et al. Primary hypothyroidism manifested in childhood with special reference to various types of reversible hypothyroidism. Eur J Endocrinol 1994;131:131–7. 16 Samuels MH, Ridgeway EC. Central hypothyroidism. Endocrinol Metab Clin North Am 1992;21:903–19. 17 De Zegher F, Vanderschueren-Lodeweyckx M, Heinrichs C et al. Thyroid dyshormonogenesis: severe hypothyroidism after normal neonatal thyroid stimulating hormone screening. Acta Paediatr 1992;81:274–6. 18 Vulsma J, Menzel G, Abbad FC et al. Iodine induced hypothyroidism in infants treated with continuous cyclic peritoneal dialysis. Lancet 1990;336:812. 19 Burnett A, Carney D, Mukhopadhyay S et al. Thyroid involvement with Langerhans cell histiocytosis in a 3-year-old male. Pediatr Blood Cancer 2008;50:726–7. 20 Gabrilove JL, Ludwig AW. The histogenesis of myxoedema. J Clin Endocrinol Metab 1957;17:925–32. 21 Toublanc JE. Comparison of epidemiological data on congenital hypothyroidism in Europe with those of other parts of the world. Hormone Res 1992;38:230–5. 22 Rendon-Macias ME, Morales-Garcia I, Huerta-Hernandez E et al. Birth prevalence of congenital hypothyroidism in Mexico. Pediatr Perinat Epidemiol 2008;22:478–85. 23 Lorey FW, Cunningham GC. Birth prevalence of primary congenital hypothyroidism by sex and ethnicity. Hum Biol 1992;64:531–8. 24 Tsai WY, Lee JS, Wang TR et al. Clinical characteristics of congenital hypothyroidism detected by neonatal screening. J Formos Med Assoc 1993;92:20–3. 25 Tarim OF, Yordam N. Congenital hypothyroidism in Turkey: a retrospective evaluation of 1000 cases. Turk J Pediatr 1992;34:197–202. 26 Tahirovic H, Toromanovic A. Clinical presentation of primary congenital hypothyroidism: experience before mass screening. Bosnian J Basic Med Sci 2005;5:26–9. 27 Charles SJ, Moore AT, Yates JRW et al. Alström syndrome: further evidence of autosomal recessive inheritance and endocrinological dysfunction. J Med Genet 1990;27:590–2. 28 Marin JF, Garcia B, Quintana A et al. The CHARGE association and athyrosis. J Med Genet 1991;28:207–8. 29 Ioan DM, Ghitan T. Trisomy 4p: a new case of congenital myxedema. Endocrinologie 1991;29:111–14. 30 Chien CH, Lee JS, Tsai WY et al. Wiedemann–Beckwith syndrome with congenital central hypothyroidism in one of monozygotic twins. J Formos Med Assoc 1990;89:132–6. 31 Pehr K, Moroz B. Cutis marmorata telangiectatica congenita: longterm follow-up, review of the literature and report of a case in

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conjunction with congenital hypothyroidism. Pediatr Dermatol 1993;10:6–11. Koklu E, Gunes T, Ozturk MA et al. Cutis laxa associated with central hypothyroidism owing to isolated thyrotropin deficiency in a newborn. Pediatr Dermatol 2007;24:525–8. Stagi S, Bindi G, Lapi E et al. Congenital hypothyroidism in Young– Simpson syndrome. J Pediatr Endocrinol 2008;21:1089–92. Demirbilek H, Kandemir N, Gonc EN et al. Hashimoto’s thyroiditis in children and adolescents: a retrospective study on clinical, epidemiological and laboratory properties of the disease. J Pediatr Endocrinol 2007;20:1199–205. De Vries L, Bulvik S, Phillip M. Chronic autoimmune thyroiditis in children and adolescents: at presentation and during long-term follow-up. Arch Dis Child 2009;94:33–7. Dallas JS, Foley TP. Hypothyroidism. In: Lifshitz F (ed) Pediatric Endocrinology: A Clinical Guide, 2nd rev edn. New York: Dekker, 1990:478–93. 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;330:466–8. Keenan GF, Ostrov BE, Goldsmith DP et al. Rheumatic symptoms associated with hypothyroidism in children. J Pediatr 1993; 123:586–8. Chalk JN. Psychosis in a 15-year-old hypothyroid girl: myxoedematous madness. Aust NZ J Psychiatr 1991;25:561–2. Sanjeevaiah AR, Sanjay S, Deepak T et al. Precocious puberty and large multicystic ovaries in young girls with primary hypothyroidism. Endocr Pract 2007;13:652–5. Sbrocchi AM, Chedeville G, Scuccimarri R et al. Pediatric hypothyroidism presenting with a polymyocitis-like syndrome and increased creatinine: report of three cases. J Pediatr Endocrinol 2008;21: 89–92. Shastry RM, Shastry CC. Primary hypothyroidism with pericardial tamponade. Ind J Pediatr 2007;74:580–1. Galli-Tsinopoulou A, Stylianou C, Kokka P et al. Rhabdomyolysis, renal failure, pericardial effusion, and acquired von Willebrand disease resulting from hypothyroidism in a 10-year-old girl. Thyroid 2008;18:373–5. Alves C, Alves AC. Primary hypothyroidism in a child simulating a prolactin-secreting adenoma. Childs Nerv Syst 2008;24:1505–8. Najjar SS. Muscular hypertrophy in hypothyroid children: the Kocher–Debre–Semelaigne syndrome. A review of 23 cases. J Pediatr 1974;85:236–9. Van Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhoea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;57:416–35. Ober KP. Acanthosis nigricans and insulin resistance associated with hypothyroidism. Arch Dermatol 1985;121:229–31. Bruggers CS, McElligott K, Rallison ML. Acquired von Willebrand disease in twins with autoimmune hypothyroidism: response to desmopressin and l-thyroxine therapy. J Pediatr 1994;125:911–13. Manfredi E, van Zaane B, Gerdes VE et al. Hypothyroidism and acquired von Willebrand’s syndrome: a systematic review. Haemophilia 2008;14:423–33. Bhattacharya M, Mitra A. Regression of precocious puberty in a child with hypothyroidism after thyroxine therapy. Indian Pediatr 1992;29:96–8. Santos H, Cordeiro I, Medeira A et al. Schinzel–Giedion syndrome. A patient with hypothyroidism and diabetes insipidus. Genet Couns 1994;5:187–9. Bailey HK, Kappy MS, Giller RH et al. Time-course and risk factors of hypothyroidism following allogeneic hematopoietic stem cell transplanatation (HSCT) in children conditioned with fractionated total body irradiation. Pediatr Blood Cancer 2008;51:405–9.

Cutaneous Manifestations of Endocrine Disease 53 Kalpatthi R, Germak J, Mizelle K et al. Thyroid abnormalities in infantile hepatic hemangioendothelioma. Pediatr Blood Cancer 2007;49:1021–4. 54 Mouat F, Evans HM, Cutfield WS et al. Massive hemangioendothelioma and consumptive hypothyroidism. J Pediatr Endocrinol 2008;21:701–3. 55 Melis D, Pivonello R, Parenti G et al. Increased prevalence of thyroid autoimmunity and hypothyroidism in patients with glycogen storage disease type I. J Pediatr 2007;150:300–5. 56 Paprocka J, Jamroz E, Kalina M et al. Angelman syndrome and hypothyroidism: coincidence or unique correlation? Neuroendocrinol Lett 2007;28;545–6. 57 Comi AM, Bellamkonda S, Ferenc LM et al. Central hypothyroidism and Sturge–Weber syndrome. Pediatr Neurol 2008;39:58–62. 58 Maenpaa J. Hypothyroidism preceding hyperthyroid Graves’ disease in two children. Acta Endocrinol 1983;251(suppl):27–31. 59 Wuthrich RP. Pernicious anaemia, autoimmune hypothyroidism and rapidly progressive anti-GBM glomerulonephritis. Clin Nephrol 1994;42:404. 60 Perloff WH. Hirsutism – a manifestation of juvenile hypothyroidism. JAMA 1955;157:651–2. 61 Rondanini GF, de Panizza G, Bollati A et al. Congenital hypothyroidism and pericardial effusion. Horm Res 1991;35:41–4. 62 Tillotson SL, Fuggle PW, Smith I et al. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. BMJ 1994;309:440–5. 63 Gruters A, Krude H. Update on the management of congenital hypothyroidism. Horm Res 2007;68(suppl 5):107–11. 64 Ng Sm, Anand D, Weindling AM. High versus low dose of initial thyroid hormone replacement for congenital hypothyroidism. Cochrane Database Syst Rev 2009;1:CD006972.

Hyperthyroidism Pathogenesis. Hyperthyroidism in the paediatric population is usually due to autoimmune thyroid disease in the form of Graves disease (diffuse toxic goitre) [1–3] or Hashimoto thyroiditis [1]. In both conditions, hypersecretion of thyroxine is due to stimulation of the thyrotropin receptor on the thyroid gland by circulating antibodies. Rarely, hyperthyroidism is due to an overactive thyroid nodule [4], a multinodular goitre in association with McCune–Albright syndrome [5], increased secretion of thyrotropin from a pituitary adenoma [6], hypersecretion of thyrotropin because of pituitary unresponsiveness to thyroxine [7], iodine exposure [8], excessive intake of thyroxine or a germline mutation in the thyroid-stimulating hormone (TSH) receptor gene resulting in constitutive stimulation of the thyroid gland [9,10]. Hyperthyroidism can manifest in newborns secondary to the transplacental transfer of antithyroid antibodies from a thyrotoxic mother [11]. Although most of the cutaneous findings can be directly attributed to the hypermetabolic state induced by the increased levels of thyroxine and tri-iodothyronine, the development of pretibial myxoedema in Graves disease does not correlate with elevated thyroxine levels. These patients have a circulating factor that stimulates GAG production by fibroblasts from the pretibial and orbital

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areas [12]. Fibroblasts from unaffected body parts do not respond to the circulating factor. Pathology. Pretibial myxoedema is characterized by mucinous deposits that separate collagen in the mid- and reticular dermis [13]. The mucinous deposits are acellular and are readily identified with mucin stains such as toluidine blue and Alcian blue. Clinical features. Hyperthyroidism can develop at any age, including the newborn period [1–3,8,11,14]. Females are more commonly affected than males in a ratio of 3–5:1, and there is a family history of thyroid disease in 37–50% of cases [1–3,14,15]. The usual presentation of hyperthyroidism is with an obvious goitre or one or more of the following nonspecific symptoms: restlessness, nervousness, emotional lability, weight loss despite increased appetite, palpitations, eye prominence and/or stare, hyperactivity with reduced attention span, tremor, excessive sweating, heat intolerance and fatigue [1–3,14,15]. Many of these symptoms will lead to deterioration in school performance. Uncommon presenting symptoms include weight gain, amenorrhoea, dyspnoea on exertion and/or at night, hair loss, diarrhoea, polyuria, enuresis and accelerated linear growth [1–3,14,15]. Examination reveals a palpable goitre in all patients, with an associated bruit in approximately 50% of patients [1,2,15]. A tremor is usually evident and may be associated with choreo-athetoid like movements of the upper limbs [2]. Cardiovascular examination reveals resting tachycardia, a flow murmur and a pulse pressure of over 50 mmHg in most patients [1–3,15]. Eye involvement occurs in 60% of cases [1,2,15] and approximately 66% of prepubertal patients will be above the 75th percentile for height at the time of diagnosis [1,14,15]. Eye involvement is usually mild and consists of one or more of the following: conjunctival injection, chemosis, lid fullness, lagophthalmos and increased lacrimation. Cutaneous findings are usually restricted to a flushed appearance of the skin and a warm, clammy feel on palpation. Uncommon skin findings include thinning of the scalp hair, vitiligo, onycholysis (particularly of the fourth fingernail) and hyperpigmentation [1–3,15]. Paediatric patients with Graves disease rarely exhibit the characteristic clinical triad of pretibial myxoedema, severe ophthalmopathy and thyroid acropathy [1,2,15]. Pretibial myxoedema occurs in fewer than 2% of cases and represents mucinous infiltration of the pretibial skin. Occasionally, other sites can be affected, such as the posterior calves, the thighs, arms, trunk and the dorsum of the feet. The infiltration is usually bilateral and manifests as non-pitting nodules or plaques that can be skin

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coloured or yellow, red or brown in colour. The surface characteristically exhibits dilated follicular orifices that convey a peau d’orange appearance. Severe ophthalmopathy usually develops in association with pretibial myxoedema. It is characterized by exophthalmos, diminished eye movements, lid retraction and lid lag. The exophthalmos and diminished eye movements are due to mucinous infiltration within the orbit and extraocular muscles. Thyroid acropathy consists of clubbing and enlargement of the distal extremities. The enlargement is due to a combination of soft tissue hypertrophy and subperiosteal periostosis in the diaphyseal region of the metacarpals, metatarsals, phalanges and distal long bones. It is extremely rare in children. Investigations. The clinical diagnosis of hyperthyroidism is easily confirmed by measuring free thyroxine and tri-iodothyronine levels in the serum. The TSH levels are depressed except in those patients whose disease is due to hypersecretion of thyrotropin [6,7]. Patients with Graves disease and Hashimoto thyroiditis will have circulating thyroid-stimulating antibodies. Radio-active iodine test will distinguish Graves disease (high uptake) from thyroiditis (low uptake). Further investigation is required if an overactive thyroid nodule or pituitary dysfunction is suspected. Prognosis. The non-specific symptoms and signs of hyperthyroidism will resolve when the thyroxine level returns to normal. Pretibial myxoedema, severe ophthalmopathy and thyroid acropathy usually persist despite reduction in thyroxine levels. Differential diagnosis. The hyperthyroid child is often labelled as being anxious or suffering from a psychiatric disturbance. Pretibial myxoedema can be confused with scleromyxoedema and lichen amyloidosis. Both conditions can be distinguished on the basis of history, other physical findings and skin biopsy. Treatment. Patients with Graves disease can be treated with antithyroid drugs [1–3,14.15,16,17], subtotal thyroidectomy [16,18,19,20,21] and/or radio-active iodine [19,22]. Antithyroid drugs are used initially, and approximately 50% of patients will undergo disease remission [1–3,13,17]. If compliance is poor, side-effects develop to the medication or prolonged therapy fails to induce disease remission, the patient can be treated with subtotal thyroidectomy or radio-active iodine. Patients with Hashimoto thyroiditis are usually treated with β-blockers because of the self-limiting nature of the problem. Pretibial myxoedema is a difficult problem to treat because of its lack of response to topical steroids, intralesional steroids and oral steroids. A combination of

topical clobetasol and oral pentoxifylline [23] and a combination of shave excision and subcutaneous injections of octreotide (an insulin-like growth factor type 1 antagonist) [24] were reported to be of benefit. Although one report noted clinical and histological improvement with high-dose intravenous gammaglobulin therapy [25], another reported no response to high-dose intravenous gammaglobulin [26]. References 1 Vaidya VA, Bongiovanni AM, Parks JS et al. Twenty-two years experience in the medical management of juvenile thyrotoxicosis. Pediatrics 1974;54:565–70. 2 Barnes HV, Blizzard RM. Antithyroid drug therapy for toxic diffuse goitre (Graves’ disease). 30 years experience in children and adolescents. J Pediatr 1977;91:313–20. 3 Gorton C, Sadeghi-Nejad A, Senior B. Remission in children with hyperthyroidism treated with propylthiouracil. Am J Dis Child 1987;141:1084–6. 4 Mizukami Y, Michigishi T, Nonomura A et al. Autonomously functioning (hot) nodule of the thyroid gland. A clinical and histopathological study of 17 cases. Am J Clin Pathol 1994;101:29–35. 5 Hamilton CR Jr, Maloof F. Unusual types of hypothyroidism. Medicine (Balt) 1973;52:195–215. 6 Avramides A, Karapiperis A, Triantafyllidou E et al. TSH-secreting pituitary macroadenoma in an 11-year-old girl. Acta Paediatr 1992;81:1058–60. 7 Gershengorn MC, Weintraub BD. Thyrotropin induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. A new syndrome of inappropriate secretion of TSH. J Clin Invest 1975;56:633–45. 8 Bryant WP, Zimmerman D. Iodine induced hyperthyroidism in a newborn. Pediatrics 1995;95:434–6. 9 Alberti L, Proverbio MC, Costagliola S et al. A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism. Eur J Endocrinol 2001;145:249–54. 10 Ferrara AM, Capalbo D, Rossi G et al. A new case of familial nonautoimmune hyperthryroidism caused by the M463V mutation in the TSH receptor with anticipation of the disease across generations: a possible role of iodine supplementation. Thyroid 2007;17:677–80. 11 Smallridge RC, Wartofsky L, Chopra IJ et al. Neonatal thyrotoxicosis: alterations in serum concentrations of LATS protector, T4, T3, reverse T3, and 3, 3′T2. J Pediatr 1978;93:118–20. 12 Cheung HS, Nicoloff JT, Kamiel MB et al. Stimulation of fibroblast biosynthetic activity by serum of patients with pretibial myxedema. J Invest Dermatol 1978;71:12–17. 13 Truhan AP, Roenigk HH Jr. The cutaneous mucinoses. J Am Acad Dermatol 1986;14:1–18. 14 Bhadada S, Bhansali A, Velayutham P et al. Juvenile hyperthyroidism: an experience. Ind Pediatr 2006;43:301–7. 15 Mokhashi MH, Desai U, Desai MP. Hyperthyroidism in children. Indian J Pediatr 2000;67:653–6. 16 Dotsch J, Siebler T, Hauffa BP et al. Diagnosis and management of juvenile hyperthyroidism in Germany: a retrospective multicenter study. J Pediatr Endocrinol Metab 2000;13:879–85. 17 Kaguelidou F, Alberti C, Castanet M et al. Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab 2008;93:3817–26. 18 Desjardins JG. Treatment of hyperthyroidism in children. Can J Surg 1983;26:252–3. 19 Rivkees SA. The treatment of Grave’s disease in children. J Pediatr Endocrinol 2006;19:1095–111.

Cutaneous Manifestations of Endocrine Disease 20 Moreno P, Gomez JM, Gomez N et al. Subtotal thyroidectomy: a reliable method to achieve euthyroidism in Grave’s disease. Prognostic factors. World J Surg 2006;30:1950–6. 21 Sugino K, Ito K, Nagahama M et al. Surgical management of Grave’s disease: 10-year prospective trial at a single institution. Endocr J 2008;55:161–7. 22 Clark JD, Gelfand MJ, Elgazzar AH. Iodine-131 therapy of hyperthyroidism in paediatric patients. J Nucl Med 1995;36:442–5. 23 Pineda AM, Tianco EA, Tan JB et al. Oral pentoxifylline and topical clobetasol propionate ointment in the treatment of pretibial myxoedema, with concomitant improvement of Grave’s ophthalmopathy. J Eur Acad Dermatol Venereol 2007;21:1441–3. 24 Felton J, Derrick EK, Price ML. Successful combined surgical and octreotide treatment of severe pretibial myxoedema reviewed after 9 years. Br J Dermatol 2003;148:825–6. 25 Antonelli A, Navarrane A, Palla R et al. Pretibial myxedema and high dose intravenous immunoglobulin treatment. Thyroid 1994;4:399–408. 26 Terheyden P, Kahaly GJ, Zillikens D et al. Lack of response of elephantiasic pretibial myxoedema to treatment with high-dose intravenous immunoglobulins. Clin Exp Dermatol 2003;28:224–6.

Disorders of the adrenal glands Cushing disease and Cushing syndrome Pathogenesis. The Cushingoid phenotype results from the excessive effect of glucocorticoids on body tissues. Cushing disease refers to the clinical phenotype resulting from an overproduction of glucocorticoids by the adrenal cortex secondary to hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma [1,2]. Cushing syndrome refers to the clinical phenotype resulting from an overproduction of glucocorticoids by the adrenal cortex because of micronodular adrenal hyperplasia, an adrenal adenoma or an adrenal carcinoma or secondary to stimulation by ectopically produced ACTH [1,2] or in response to gastric inhibitory polypeptide (GIP) stimulation of adrenal cells aberrantly expressing receptors for GIP [3]. Ectopic ACTH production has been reported in children with thymic carcinoid [1], bronchial carcinoid [1,2], pancreatic tumour [4,5], and an ovarian steroid cell tumour [6]. Some of the features of Cushing syndrome can also occur with the overuse of oral steroids, potent topical steroids [7], intralesional steroids [7], inhaled steroids [8] and intranasal steroids [9]. Most of the symptoms and signs of Cushing disease and Cushing syndrome are due to the direct effect of glucocorticoids on various body tissues. Androgens may contribute to some of the cutaneous findings in patients with Cushing syndrome due to micronodular adrenal hyperplasia or an adrenal tumour. Hyperpigmentation in patients with Cushing disease is due to stimulation of melanocytes by ACTH and related peptides.

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Clinical features. Cushing disease can occur at any age. Although there is no overall predilection for either sex [1,2,10] (Fig. 172.2), one study found a predeliction for males in the prepubertal age group [11]. Patients usually present with one or more of the following problems: weight gain, growth retardation in children and young adolescents, delayed sexual maturation in prepubertal patients, menstrual irregularities in postmenarchal females, fatigue, weakness, emotional lability and one or more of the characteristic skin findings [1,2,10,12]. The weight gain is associated with redistribution of body fat, resulting in a prominent moon face, buffalo hump and truncal obesity, with relative thinning of the arms and legs [1,2,10,12] (see Fig. 172.2). The characteristic skin findings are a plethoric facies, broad purple-coloured striae at the sites of skin tension (upper thighs, buttocks, trunk, shoulder girdle, breasts) (see Fig. 172.2b), skin fragility with poor wound healing, development of purpura with minimal skin trauma, hyperpigmentation, hypertrichosis (vellus-type hair) on the cheeks and forehead of the face, acanthosis nigricans and an acneiform eruption on the face and upper trunk [1,2]. The acneiform eruption represents either steroid folliculitis or exacerbation of teenage acne vulgaris. Other clinical findings include hypertension and osteopenia in the majority of patients. The clinical features of Cushing syndrome due to ectopic ACTH production are identical to those of Cushing disease. Cushing syndrome due to an adrenal tumour or micronodular adrenal hyperplasia is identical to Cushing disease, with the exception of androgen-mediated features such as hirsutism and premature adrenarche and the absence of ACTH-mediated hyperpigmentation. Steroid-induced Cushing syndrome is characterized by weight gain with redistribution of body fat, striae, skin fragility and an acneiform eruption [7–9]. Nodular adrenal hyperplasia can be associated with myxomatous tumours in the heart, skin and breast, centrofacial lentigines, testicular tumours (Sertoli cell tumour, Leydig cell tumour, adrenocortical rest tumour), pituitary adenomas and peripheral nerve tumours (schwannomas). This constellation of clinical features is referred to as the Carney complex (see below), a multisystem tumour syndrome inherited in an autosomal dominant fashion [13,14]. Investigations. The clinical diagnosis of hypercortisolism is confirmed by measuring free cortisol levels in a 24-h urine specimen, measuring midnight sleeping plasma cortisol [15] and measuring the plasma cortisol levels after the low-dose dexametasone suppression test [1,2,11,12,16]. Patients with hypercortisolism will have elevated free cortisol levels in the urine and no decrease

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in plasma cortisol levels with low-dose dexametasone suppression [1,2,10,16]. Measurement of bedtime salivary cortisol appears to be as sensitive as urinary and plasma cortisol estimations [17]. ACTH-dependent disease can be distinguished from adrenal-mediated disease by measuring ACTH levels. If plasma ACTH levels are elevated, the high-dose dexametasone suppression test, the corticotropin-releasing hormone (CRH) stimulation test and inferior petrosal sinus sampling will distinguish pituitary and non-pituitary sources of ACTH [12,15]. If plasma ACTH levels are normal or depressed and the high-dose dexametasone suppression test fails to reduce plasma cortisol levels, imaging studies of the adrenal glands are required.

(a)

Differential diagnosis. Cushing disease needs to be excluded from physiological obesity and polycystic ovary disease. The measurement of serum cortisol and the dexametasone suppression test will distinguish Cushing disease and Cushing syndrome from physiological obesity. Polycystic ovary disease is distinguished by ultrasound of the ovaries and the presence of elevated luteinizing hormone (LH) and depressed folliclestimulating hormone (FSH) levels. Prognosis. Provided the cause is identified and removed, the prognosis is good, with a gradual reduction in body weight, normal linear growth and the development of normal fertility [1,2,10]. Treatment. Treatment depends on the underlying aetiology [1,2,10,12]. Pituitary tumours are removed surgically through the technique of trans-sphenoidal adenomectomy. Recurrent tumours can be surgically removed or treated with radiotherapy. Nodular adrenal hyperplasia and adrenal tumours are treated surgically. Nelson syndrome is a potential complication of adrenalectomy [10,18].

(b) Fig. 172.2 (a) Cushing disease exhibiting buffalo hump. (b) Cushing disease exhibiting truncal obesity and abdominal striae. Courtesy of Dr Geoff Ambler, New Children’s Hospital, Sydney, Australia.

References 1 Magiakou MA, Mastorakos G, Oldfield EH et al. Cushing syndrome in children and adolescents. Presentation, diagnosis and therapy. N Engl J Med 1994;331:629–36. 2 Leinung MC, Zimmerman D. Cushing’s disease in children. Endocrinol Metab Clin North Am 1994;23:629–39. 3 Noordam C, Hermus AR, Pesman G et al. An adolescent with fooddependent Cushing syndrome secondary to ectopic expression of GIP receptor in unilateral adrenal adenoma. J Pediatr Endocrinol Metab 2002;15:853–60. 4 Kasperlik-Zauska AA, Jeske W, Cichocki A. Cushing’s syndrome in a 16-year-old girl due to ectopic ACTH precursor production from a pancreatic tumour. Clin Endocrinol 2001;55:558–9. 5 Illyes g, Luczay A, Benyo G et al. Cushing’s syndrome in a child with pancreatic acinar cell carcinoma. Endocr Pathol 2007;18:95–102.

Cutaneous Manifestations of Endocrine Disease 6 Sawathiparnich P, Sitthinamsuwan P, Sanpakit K et al. Cushing’s syndrome caused by an ACTH-producing ovarian steroid cell tumour, NOS, in a prepubertal girl. Endocrinology 2009;35:132–35. 7 Curtis JA, Cormode E, Laski B et al. Endocrine complications of topical and intralesional corticosteroid therapy. Arch Dis Child 1982;57:204–7. 8 Priftis K, Everard ML, Milner AD. Unexpected side effects of inhaled steroids: a case report. Eur J Paediatr 1991;150:448–9. 9 Perry RJ, Findlay CA, Donaldson MD. Cushing syndrome, growth impairment and occult adrenal suppression associated with intranasal steroids. Arch Dis Child 2002;87:45–8. 10 Savage MO, Lienhardt A, Lebrethon MC et al. Cushing’s disease in childhood: presentation, investigation, treatment and long-term outcome. Hormone Res 2001;55(suppl 1):24–30. 11 Storr HL, Isidori AM, Monson JP et al. Prepubertal Cushing’s disease is more common in males, but there is no increase in severity at diagnosis. J Clin Endocrinol Metab 2004;89:3818–20. 12 Savage MO, Chan LF, Grossman AB et al. Work-up and management of pediatric Cushing’s syndrome. Curr Opin Endocrinol Diabet Obes 2008;15:346–51. 13 Carney JA, Hruska LS, Beauchamp BD et al. Dominant inheritance of the complex of myxomas, spotty pigmentation and endocrine over activity. Mayo Clin Proc 1986;61:165–72. 14 Carney JA, Gordon H, Carpenter PC et al. The complex of myxomas, spotty pigmentation and endocrine over activity. Medicine (Balt) 1985;64:270–83. 15 Batista DL, Riar J, Keil M et al. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics 2007;120:e575–86. 16 McLean M, Smith R. Cushing’s syndrome: how should we investigate in 1995? Med J Aust 1995;163:153–4. 17 Papanicolaou DA, Mullen N, Kyrou I et al. Nighttime salivary cortisol: a useful test for the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 2002;87:4515–21. 18 Thomas CG, Smith AT, Benson M et al. Nelson’s syndrome after Cushing’s disease in childhood: a continuing problem. Surgery 1984;96:1067–76.

Addison disease Pathogenesis. Addison disease in the paediatric age group can result from reduced secretion of ACTH from the pituitary gland or from failure of the adrenal cortex to respond to ACTH. Reduced secretion of ACTH can be due to hypothalamopituitary axis dysfunction (e.g. pituitary tumour) or prolonged steroid therapy [1,2]. Failure of the adrenal cortex to respond to ACTH can be due to a variety of congenital and acquired conditions. Congenital problems include adrenal hypoplasia [3], congenital unresponsiveness to ACTH [4], adrenoleucodystrophy [5,6] and congenital adrenal hyperplasia [7]. Acquired causes include destruction of the adrenal gland as a result of infection or haemorrhage, surgical removal of the adrenal gland and an idiopathic cause. The idiopathic group exhibits a high incidence of circulating autoantibodies, particularly antibodies to the adrenal cortex cells, and most patients have a personal or family history of other autoimmune diseases [8]. The cumulative risk of developing Addison disease in the presence of adrenal

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cortex autoantibodies is approximately 50% [9]. The idiopathic group now accounts for most paediatric cases of Addison disease. When glucocorticoid deficiency is associated with elevated ACTH levels, hyperpigmentation of the skin is a prominent feature. The pigmentation is due to stimulation of cutaneous melanocytes by ACTH and/or melanocyte-stimulating hormone (MSH) peptides. Clinical features. The age of the patient at presentation will depend on the cause of the Addison disease. Patients with adrenal hypoplasia and congenital adrenal hyperplasia usually present shortly after birth. Patients with inadequate ACTH production, adrenal leucodystrophy and the idiopathic form can present at any age. The usual presentation is with symptoms of lethargy, cyclic vomiting, hypotension and salt craving [7,8]. The onset of symptoms can be precipitated by an intercurrent illness [8]. Patients with gradual onset of the disease will exhibit hyperpigmentation of the skin and mucosal surfaces (gingivae, tongue, hard palate, buccal mucosa, vagina, anus) at the time of presentation [7,8]. The cutaneous pigmentation is diffuse, with accentuation on exposed areas (Fig. 172.3a), around new scars and over areas of pressure or friction (axillae, elbows, knees and perineum) (Fig. 172.3b). The development of mucosal pigmentation and palmoplantar crease pigmentation is restricted to Caucasians, as both are normal findings in black patients. The widespread hyperpigmentation is usually accompanied by darkening of the hair, darkening of existing melanocytic naevi and the appearance of longitudinal pigmented bands in the nail plate. Pubic and axillary hair may be lost in postpubertal females and vitiligo can be found in some patients. Patients with adrenoleucodystrophy will eventually develop the typical neurological features of the disease [5,6]; notably, the diagnosis of Addison disease can precede the development of the neurological features of the disease by many years [6]. Female patients with congenital adrenal hyperplasia have ambiguous genitalia, which in the newborn period alerts the doctor to the possibility of adrenal insufficiency. The 3A syndrome refers to an association between glucocorticoid deficiency, alacrima, achalasia of the cardia, fissured palms, cutis anserina, autonomic nerve dysfunction and a variety of neurological abnormalities. Some affected patients also exhibit mineralocorticoid deficiency [10,11]. Investigations. The clinical diagnosis of Addison disease is confirmed by measuring the plasma cortisol level and free cortisol levels in a 24-h urine collection [8]. Patients with Addison disease will have low plasma cortisol and urine free cortisol levels. Measurement of plasma ACTH

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increased during periods of stress and patients with circulating autoantibodies will need to be regularly monitored for the development of other autoimmune diseases.

(a)

(b) Fig. 172.3 (a) Addison disease: hyperpigmentation on the dorsal aspect of the hand with accentuation over the knuckles. (b) Hyperpigmented scratch marks in a child with Addison disease. Courtesy of Dr Geoff Ambler, New Children’s Hospital, Sydney, Australia.

levels and plasma cortisol levels following ACTH stimulation will distinguish adrenal failure from hypothalamopituitary dysfunction [8]. Most patients with the idiopathic form of Addison disease will have circulating antiadrenal antibodies [8]. Patients with adrenoleucodystrophy have raised plasma levels of hexacosanoic acid [6] and characteristic findings on magnetic resonance imaging of the brain [12]. Differential diagnosis. The early non-specific symptoms can be misdiagnosed as a wide variety of conditions. The hyperpigmentation is characteristic and readily distinguishes Addison disease from other conditions. Prognosis. All symptoms and signs will clear with appropriate glucocorticoid and mineralocorticoid replacement therapy. Patients with adrenoleucodystrophy will eventually develop neurological impairment. Treatment. Hydrocortisone and fludrocortisone are administered on a daily basis. The dose will need to be

References 1 Curtis JA, Cormode E, Laski B et al. Endocrine complications of topical and intralesional corticosteroid therapy. Arch Dis Child 1982;57:204–7. 2 Molimard M, Girodet PO, Pollet C et al. Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation. Drug Safety 2008;31:769–74. 3 Sperling MA, Wolfsen AR, Fisher DA. Congenital adrenal hypoplasia: an isolated defect of organogenesis. J Pediatr 1973;82:444–9. 4 Kelch RP, Kaplan SL, Biglieri EG et al. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. J Pediatr 1972;81:726–36. 5 Davis LE, Snyder RD, Orth DN et al. Adrenoleukodystrophy and adrenomyeloneuropathy associated with partial adrenal insufficiency in three generations of a kindred. Am J Med 1979;66:342–7. 6 Sadhegi-Nejad A, Senior B. Adrenomyeloneuropathy presenting as Addison’s disease in childhood. N Engl J Med 1990;322:13–16. 7 Lim YJ, Batch JA, Warne GL. Adrenal 21-hydroxylase deficiency in childhood: 25 years experience. J Paediatr Child Health 1995;31: 222–7. 8 Grant DB, Barnes ND, Moncrieff MW et al. Clinical presentation, growth and pubertal development in Addison’s disease. Arch Dis Child 1985;60:925–8. 9 Coco G, dal Pra C, Presotto F et al. Estimated risk for developing autoimmune Addison’s disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab 2006;1637–45. 10 Grant DB, Barnes ND, Dumic M et al. Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child 1993;68:779–82. 11 Toromanovic A, Tahirovic H, Milenkovic T et al. Clinical and molecular genetic findings in a 6-year-old Bosnian boy with triple A syndrome. Eur J Pediatr 2009;168:317–20. 12 Huckman MS, Wong PW, Sullivan T et al. Magnetic resonance imaging compared with computed tomography in adrenoleucodystrophy. Am J Dis Child 1986;140:1001–3.

Disorders of sex hormones Hypogonadism Pathogenesis. Hypogonadism in females occurs with deficiency of gonadotropin secretion or inadequate production of sex hormones by the ovary or secondary to a virilizing disorder, hypothyroidism or hyperprolactinaemia [1]. Hypogonadism in males occurs with deficiency of gonadotropin secretion, inadequate androgen production by the testis, 5α-reductase deficiency or an androgen receptor defect [2]. Clinical features. The clinical features of hypogonadism in both sexes depend on the age of onset of the problem and the severity of the hormone deficiency [1–3]. Hypo-

Cutaneous Manifestations of Endocrine Disease

gonadism in a prepubertal female results in the failure of breast development (thelarche) and the onset of menarche (primary amenorrhoea). Pubic hair, axillary hair, body odour, sebum production and acne will still develop because of the unaltered production and secretion of adrenal androgens (adrenarche). The development of hypogonadism after the onset of puberty limits breast development and results in menstrual irregularities in the form of amenorrhoea, oligomenorrhoea or dysfunctional uterine bleeding. Linear growth is unaffected if growth hormone secretion is unaffected. Additional findings relate to the underlying cause of the hypogonadism (e.g. Turner syndrome). In males, hypogonadism in utero results in abnormal (e.g. hypospadias) or ambiguous genitalia or infants who are phenotypically female. Prepubertal hypogonadism results in small testes, a small penis, lack of scrotal rugae, feminine fat distribution over the hips, face and chest, arm span 6 cm over height, eunuchoidal skeletal proportions (crown to pubis/pubis to floor ratio 90%), a marfanoid body habitus (60–75%), phaeochromocytoma (50%) and gastrointestinal ganglioneuromatosis (>30%) [3,9–13]. The mucosal neuromas are evident at birth or appear during infancy or early childhood [3,9–11]. They

Fig. 172.14 Mucosal neuromas on the dorsum of the tongue in a patient with MEN type 2b. Courtesy of Dr Geoff Ambler, New Children’s Hospital, Sydney, Australia.

manifest as a pebbly thickening of the lips and sessile or pedunculated papules on the tongue (Fig. 172.14), buccal mucosa, gingivae, palate, pharyngeal mucosa, conjunctiva, eyelid margins and skin. The marfanoid habitus consists of tall stature, long, thin limbs and an elongated face

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[3,9,12]. Unlike Marfan syndrome, the patients do not have ectopia lentis or aortic abnormalities. Gastrointestinal ganglioneuromatosis results in chronic constipation or chronic diarrhoea, feeding problems and abdominal pain [3,9,13]. The gastrointestinal symptoms can begin shortly after birth and usually precede the diagnosis of endocrine neoplasia by many years. Additional findings may include circumoral lentiginosis, café-au-lait spots, diffuse pigmentation of the hands and feet, large prominent eyebrows, thickening of the corneal nerves, arched palate and a number of musculoskeletal abnormalities (kyphosis, scoliosis, lordosis, pes cavus, slipped femoral epiphysis, proximal muscle weakness) [3,9,10,13]. A number of reports since 1989 have noted the association between MEN type 2a and cutaneous amyloidosis located unilaterally or bilaterally over the upper back [14–17]. The cutaneous amyloidosis is pruritic and consists of hyperpigmentation, scaling and small papules. Although the clinical appearance fits best with macular amyloidosis, the presence of papules and the histological findings of hyperkeratosis, acanthosis and papillomatosis are more suggestive of lichen amyloidosis. In most patients, the diagnosis of cutaneous amyloidosis precedes the diagnosis of MEN type 2a. A clinical assessment of 30 patients with MEN type 1 found that 87% had multiple facial angiofibromas, 66% had one or more white or skin-coloured collagenomas measuring 3–10 mm in diameter, 40% had café-au-lait spots and 30% had lipomas [18]. The association between facial angiofibromas, collagenomas and MEN type 1 has not been reported previously.

References 1 Wermer P. Endocrine adenomatosis and peptic ulcer in a large kindred. Inherited multiple tumours and mosaic pleiotropism in man. Am J Med 1963;35:205–12. 2 Sipple JH. The association of phaeochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163–6. 3 Carney JA, Sizemore GW, Hayles AV. C-cell disease of the thyroid gland in multiple endocrine neoplasia type 2B. Cancer 1979;44: 2173–83. 4 Larsson C, Skogseid B, Oberg K et al. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988;332:85–7. 5 Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001;1:157–62. 6 Simpson NE, Kidd KK, Goodfellow PJ et al. Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 1987;328:528–30. 7 Jackson CE, Norum RA. Genetics of the multiple endocrine neoplasia type 2B syndrome. Henry Ford Hosp Med J 1992;40:232–5. 8 Georgitsi M, Raitila A, Karhu A et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab 2007;92:3321–5. 9 Gorlin RJ, Cohen MM, Levin LS. Hamartoneoplastic syndromes. In: Gorlin RJ (ed) Syndromes of the Head and Neck. New York: Oxford University Press, 1990:385–92.

10 Nasir MA, Yee RW, Piest KL et al. Multiple endocrine neoplasia type 3. Cornea 1991;10:454–9. 11 Schenberg ME, Zajac JD, Lim-Tio S et al. Multiple endocrine neoplasia syndrome type 2B. Int J Oral Maxillofac Surg 1992;21:110–14. 12 Carney JA, Bianco AJJ, Sizemore GW et al. Multiple endocrine neoplasia with skeletal manifestations. J Bone Joint Surg Am 1981;3:405–8. 13 Carney JA, Hayles AB. Alimentary tract manifestations of multiple endocrine neoplasia type 2B. Mayo Clin Proc 1977;52:543–8. 14 Nunziata V, di Giovanni G, Lettera AM et al. Cutaneous lichen amyloidosis associated with multiple endocrine neoplasia type 2A. Henry Ford Hosp Med J 1989;37:144–6. 15 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;25:651–7. 16 Robinson MF, Furst FJ, Nunziata V et al. Characterisation 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;40:249–52. 17 Pacini F, Fugazzola L, Bevilacqua G et al. Multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis: description of a new family. Endocrinol Invest 1993;16:295–6. 18 Turner ML, Darling TN, Skarulis M. Facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. J Invest Dermatol 1996;106:889.

The Carney complex The Carney complex refers to the association of myxomas (cardiac, cutaneous, mammary fibroadenomas), spotty mucocutaneous pigmentation, endocrine abnormalities and psammomatous schwannomas [1–6]. Endocrine abnormalities include Cushing syndrome secondary to nodular adrenal hyperplasia, androgen excess due to Sertoli cell tumour of the testicle and gigantism/ acromegaly due to a pituitary adenoma. Approximately 50% of the patients have a family history of the disease, with an autosomal dominant pattern of inheritance [3]. The gene responsible is PRKAR1A, which encodes for cAMP-dependent protein kinase [7]. The mucocutaneous features of the disease can be the earliest clinical findings and often manifest during infancy and childhood [1–5]. Lentigines and/or blue naevi are responsible for the spotty mucocutaneous pigmentation [1]. Lesions vary in number and are usually distributed on the face (periocular, nose, perioral), vermilion borders of the lips, eyelids and ears. Some patients will also have lesions on the trunk, limbs, backs of the hands, genitalia and conjunctiva. Cutaneous myxomas manifest as fleshcoloured, sessile or pedunculated papules that are usually less than 1 cm in diameter [1–4]. Although they are usually smooth, they can have a rough, papillomatous surface. Most patients have multiple lesions distributed, in order of frequency, on the eyelid [3], in the external ear canal [4] and on the face, neck, trunk (especially breast and nipples), anogenital area, upper limb and lower limb. The hands and feet are notably spared [1,2]. Other cutaneous

Cutaneous Manifestations of Endocrine Disease

findings include subcutaneous nodules due to cutaneous psammomatous schwannomas [5,6], the effects of embolization from left ventricular myxomas and the effects of co-existent endocrine disease [1]. References 1 Carney JA, Gordon H, Carpenter PC et al. The complex of myxomas, spotty pigmentation and endocrine overactivity. Medicine (Balt) 1985;64:270–83. 2 Carney JA, Headington JT, Su DWP. Cutaneous myxomas. A major component of the complex of myxomas, spotty pigmentation and endocrine overactivity. Arch Dermatol 1986;122:790–8.

172.31

3 Carney JA, Hruska LS, Beauchamp GD et al. Dominant inheritance of the complex of myxomas, spotty pigmentation and endocrine overactivity. Mayo Clin Proc 1986;61:165–72. 4 Kennedy RH, Flanagan JC, Eagles RC Jr et al. The Carney complex with ocular signs suggestive of cardiac myxoma. Am J Ophthalmol 1991;111:699–702. 5 Ferreiro JA, Carney JA. Myxomas of the external ear and their significance. Am J Surg Pathol 1994;18:274–80. 6 Carney JA. Psammomatous melanotic schwannoma. A distinctive, heritable tumour with special associations, including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol 1990;14:206–22. 7 Kirschner LS, Carney JA, Pack SD et al. Mutations of the gene encoding the protein kinase A type I-A regulatory subunit in patients with the Carney complex. Nat Genet 2000;26:89–92.

173.1

C H A P T E R 173

Morphoea (Localized Scleroderma) Lisa Weibel1 & John Harper2 1

Pediatric Dermatology, University Children’s Hospital Zürich, Zürich, Switzerland Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Trust, London, UK

2

Definition and epidemiology. Morphoea or localized scleroderma is a connective tissue disorder of unknown aetiology, characterized by sclerosis of the skin and subcutaneous tissue, often affecting the underlying muscle and bone [1–3]. Although a proportion of patients with morphoea may have extracutaneous involvement it must be distinguished from systemic sclerosis (or systemic scleroderma), which is a multisystem disease. Secondary development of systemic sclerosis is exceptional [4,5]. In childhood morphoea occurs at least 10 times more commonly than paediatric systemic sclerosis. The condition has an estimated annual incidence rate of 1 to 2.7 per 100,000 individuals [6,7]. As with many other connective tissue diseases morphoea predominantly affects females, with a female : male ratio of 2–3 : 1 [2,5,8]. Usually, morphoea begins in children at early school age, sometimes even at preschool age, but rarely before then. The mean age at onset in children is between 7 and 10 years [2,5,8]. History. In 1854, Addison described areas of induration of the skin, called Addison’s keloid. The term ‘morphoea’ was first introduced by Wilson [9]. However, he interpreted the disorder as leprosy. In 1868, Fagge [10] defined Addison’s keloid as morphoea. He differentiated it from Alibert’s keloid (true keloid) [9] and described the different forms of localized scleroderma, including the ‘en coup de sabre’ variant. In 1942, Klemperer and colleagues [11] included scleroderma in the group of collagen diseases. The first data collection on the epidemiology of morphoea was presented by Peterson and colleagues [7] over a 33year period from 1960 to 1993 in the population of Olmsted County, USA. The same group proposed the first classification of morphoea [1]. Aetiology and pathogenesis. The aetiology of morphoea is still unknown. An autoimmnune activity, a genetic background and various triggers such as trauma, vaccinations and infection are the main causative factors being discussed.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

External triggers A correlation between the manifestation of the disease and trauma has been documented in many individual cases and in approximately 7–13% of the patients in larger cohorts [2,5,12]. Most often accidental trauma and insect bites have been reported but also surgery and irradiation. Of note, an increasing number of cases of morphoea have been observed after irradiation for breast cancer [13]. A limited number of cases developed morphoea following an intramuscular vaccination (tetanus–diphtheria– pertussis, mumps–measles–rubella and bacille Calmette– Guérin (BCG)) [14]. However, the fact that the skin lesions appeared at the exact site of the injection may suggest the role of trauma rather than an antigenic stimulus by the vaccine itself. The exact mechanism by which trauma can trigger a fibrotic morphoea lesion remains unknown. It has been suggested that cytokines and neuropeptides (e.g. endothelin-1), which are normally involved in wound healing, may play a causative role, however there is no confirmatory evidence [12]. Finally, accidental trauma is so common in children that it remains difficult to identify trauma as a causative trigger for the development of morphoea. A link with infection has been postulated as morphoea has been noted to start after viral and bacterial infections, such as Borrelia burgdorferi infection and Epstein– Barr virus infection [15]. The discussion on the potential causative role of B. burgdorferi infection is ongoing. The initial detection of spirochaetal organisms in morphoea lesions supported the possibility of B. burgdorferi infection [16,17]. Recently, focus-floating microscopy (FFM) has been introduced as a new method, detecting a high prevalence of Borrelia in morphoea tissue [18]. However, several further studies failed to substantiate this finding [19–21]. The autoimmune hypothesis The presence of autoantibodies, the association with a range of other autoimmune diseases, the infiltration of lymphocytes and deposition of immunoglobulins and complement C3 found in skin biopsies and the overall clinicopathological similarities with systemic sclerosis support an autoimmune hypothesis [2,8,22–24]. In

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Chapter 173

approximately 12% of cases a positive family history is found for rheumatic and/or autoimmune disorders [2]. Morphoea occurring as part of the spectrum of chronic graft-versus-host disease following bone marrow transplantation is also evidence in favour of an immune-based pathogenesis [25,26]. Activation of the immune system by an unidentified antigen may result in cytokine release and a cascade of events that stimulates fibroblast proliferation and collagen production [27]. The pathophysiological basis for fibroblast activation and the pathways that lead to the pathological fibrosis are still not clear. Early studies demonstrated that fibroblasts derived from morphoea skin synthesized increased levels of extracellular matrix proteins, particularly type I collagen, suggesting an autonomous fibroblast defect resulting from an altered pattern of gene regulation [28]. More recent studies have provided increasing evidence that cytokines and growth factors as soluble mediators of immune activation play a critical role in regulating fibroblast metabolism leading to altered fibroblast proliferation and extracellular matrix accumulation [6,29]. It appears that in patients with morphoea, antinuclear antibodies (ANAs), cytokines and soluble cell adhesion molecules are consistently raised. In addition, soluble CD23, CD8 and CD4, which are serological indicators of immune activation, have all been shown to be elevated [30,31]. Elevated levels of interleukin-2 (IL-2), IL-2R, IL-4, IL-6 and soluble CD30 suggest type 2 cytokine secreting cells to be the predominant immunological cell type involved in the pathogenesis of morphoea [27,32–35]. An interesting observation made in adults reported that serum levels of tumour necrosis factor α (TNF-α) and IL-13, potent stimulators of fibrosis, are significantly elevated in patients with morphoea [36]. Elevated serum levels of soluble vascular cell adhesion molecule-1 (VCAM-1) and E-selectin show evidence of endothelial activation by inflammatory cytokines [37]. Fibrosis of the skin relates to the activity of transforming growth factor ß (TGF-ß), its corresponding receptors and IL-4. TGF-ß selectively induces connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF) and metalloproteinase-3, all of which increase mitogenic activity in fibroblasts [29]. TGF-ß also stimulates the synthesis of several extracellular matrix proteins, such as collagens, fibronectin, tenascin, tissue inhibitor of metalloproteinase-1 and plasminogen inhibitor-1. The fibrosis is induced through the Smad pathway [38]. Several studies have confirmed the upregulation of TGF-ß, CTGF and osteonectin as well as Smad3 and Smad7 in morphoea tissue cultures [39–42]. In addition, insulin-like growth factor-I (IGF-I), which is known to be implicated in the pathogenesis of several fibrotic disorders, has been found to be increased in lesional morphoea skin [43].

Genetic background Specific evidence for genetic involvement or susceptibility is more limited. Although rare, morphoea may be familial. A few reports describe the co-occurrence of morphoea in siblings or in multiple generations [44–47]. Of interest, morphoea (e.g. linear subtype) can be present at birth, supporting evidence for a developmental/genetic background [48]. Importantly, linear morphoea has recently been described to follow Blaschko’s lines, thus strongly suggesting that early embryological events may be important in the development of the condition [49]. This leads to the hypothesis that in patients with linear morphoea susceptible cells are present in a mosaic state, potentially as a mosaic form of systemic sclerosis, and that exposure to some trigger may result in the development of the condition. Interestingly, the investigation of lesional morphoea skin revealed the presence of chimeric infiltrating cells (e.g. epithelial cells, dendritic cells and lymphocytes), which may explain the clinical and histopathological similarities with chronic graft-versus-host disease [50]. The presence of immature chimeric cells in morphoea suggests a possible role for chimerism in the pathogenesis of this condition, similar to that in other autoimmune disorders, such as juvenile dermatomyositis, neonatal lupus, Sjögren syndrome and systemic sclerosis. Histopathology. Morphoea is characterized by an early inflammatory stage with oedema and hyperaemia of the skin, followed by fibrosis, sclerosis and, finally, atrophy. The epidermis may be unchanged or flattened [51]. In the initial stage the dermis shows oedema, with swelling and degeneration of collagen fibrils and lymphocytic infiltration around small blood vessels and skin appendages [52,53]. Jablonska [54] described in detail the characteristic histological features in the different variants of the disease. There is a progressive increased thickness of the dermis with condensation of collagen and loss of dermal appendages. Elastic tissue may be fragmented. There is a homogenization of the collagen bundles parallel to the skin. Subcutaneous fat becomes replaced by hyalinized connective tissue. Subcutaneous calcification, myositis or myofibrosis and bone atrophy are possible sequelae. Electron microscopic studies have interpreted the homogenization of collagen as the result of an increased rate of collagen synthesis (neoformation of collagen), with an increased range of variation in the thickness of the collagen fibrils [55]. Immunoglobulin M (IgM) and C3 perivascular and basal membrane located deposits were described in the linear variant of localized scleroderma [24]. Xie et al. [56] recently characterized the cellular infiltrate in morphoea by immunohistochemical studies. The numbers of CD1a+, CD3+, CD4+, CD8+, CD20+, CD25+ and CD57+ cells were significantly increased in the dermal

Morphoea (Localized Scleroderma)

infiltrate of morphoea, suggesting that T lymphocytes, Langerhans’ cells and natural killer cells are involved in the pathogenesis. Classification and clinical features. In childhood, morphoea shows a greater variety of clinical presentation than in adults and the linear variant is the most common subtype [2,5]. Since 1995 the widely used classification by Peterson et al. [1] divides morphoea into five general types: plaque morphoea, generalized morphoea, bullous morphoea, linear scleroderma and deep morphoea. This classification does not include mixed forms of morphoea, which are more common than previously recognized [2]. Furthermore this classification does not distinguish the different variants of linear morphoea, and bullous morphoea is probably a very rare entity, if it exists at all. This has led to an attempt to establish a more comprehensive classification, largely based on the common clinical characteristics of the condition, proposed by a consensus conference of the Pediatric Rheumatology European Society (2nd International Workshop on Juvenile Scleroderma, June 2004, Padua, Italy) [3,57]. This new classification is summarized in Table 173.1 and includes the following five subtypes: (1) circumscribed (or plaque) morphoea including superficial and deep forms; (2) linear morphoea including ‘en coup de sabre’ lesions and Parry–Romberg syndrome; (3) generalized morphoea; (4) pansclerotic morphoea; and (5) mixed (combined) morphoea. Other forms that have been described, such as guttate and bullous morphoea, are to be considered variants of the above subsets and highlight the difficulty in classification

173.3

and the range of overlap between the different clinical types. Some conditions such as atrophoderma of Pasini and Pierini, eosinophilic fasciitis or lichen sclerosus et atrophicus are sometimes classified among the subtypes of morphoea, but this aspect is still not clearly defined [3,6]. Disease course and prognosis. In general, morphoea starts with an early inflammatory stage, and an initial erythematous patch may be seen as the first sign of the condition (Fig. 173.1). Sometimes a telangiectatic erythema is present at this stage particularly on the face. The initial stage of the disease may be unnoticed. With spreading of the lesion and initiation of fibrosis a yellow-white elevated or depressed plaque (fibrosis) develops surrounded by a blue-violet erythema (the so-called ‘lilac ring’) (Fig. 173.2). The process develops into a more solid infiltration of the skin, resulting in atrophy with loss of hair and sebaceous glands, hyper- or hypopigmentation and an ivory-like appearance of the skin. Involvement of deeper structures varies, but usually atrophy of the underlying subcutaneous fat develops simultaneously with the cutaneous changes. The disease may additionally affect underlying muscle and bone and at the more severe end of the spectrum morphoea can result in joint contractures, extremity deformity and substantial functional and cosmetic disability [6]. The progression of morphoea varies and is dependent on the clinical type, rapidly in the case of the linear variant and more gradually with the plaque type. Plaque morphoea usually shows a mild course and is self-limiting.

Table 173.1 Classification of morphoea (localized scleroderma) Main type

Subtype

Description

1. Circumscribed (or plaque) morphoea

a. Superficial

Oval or round circumscribed area of induration limited to epidermis and dermis, often with altered pigmentation and inflammatory changes. Single or multiple lesions Oval or round, circumscribed, deep induration of the skin involving subcutaneous tissue, extending to fascia; may involve underlying muscle. Localized subcutaneous atrophy may be the leading symptom with minimal involvement of overlying skin. Single or multiple lesions

b. Deep

2. Linear morphoea

a. Trunk/limbs b. Head

Linear induration involving dermis, subcutis and sometimes muscle and underlying bone ‘En coup de sabre’: linear induration or indentation that affects the face/scalp and sometimes involves muscle and bone Parry–Romberg syndrome or progressive hemifacial atrophy: loss of tissue on one side of the head that predominantly involves subcutis and bone, and to a lesser extent the dermis. Overlying skin remains mobile

3. Generalized morphoea

Widespread, confluent, often symmetrical induration and inflammation of the skin

4. Pansclerotic morphoea

Circumferential involvement of limb(s) affecting the skin, subcutis, muscle and bone with severe sclerosis. May involve large areas of the body without internal organ involvement

5. Mixed morphoea

Combination of two or more of the previous subtypes

Adapted from Laxer & Zulian 2006 [3] and based on the consensus of the Pediatric Rheumatology European Society (Zulian & Martini 2005 [57]).

173.4

Chapter 173

Fig. 173.1 Erythematous area on the cheek seen as the earliest sign of morphoea.

Fig 173.2 Active plaque morphoea: typical white lesion with an erythematous edge.

Generally, the clinical activity of morphoea persists for 3–4 years; new lesions may develop even after a longer time interval, but usually not after puberty [6]. However, as a child grows mildly atrophic lesions may become more evident. Softening of the lesions may occur, particularly with treatment, but complete resolution is rare. The residual inactive lesions often show hyperpigmentation. Occasionally, localized morphoea can be associated with mixed connective tissue disease with demonstrable autoantibodies; however lupus erythematosus or systemic scleroderma rarely develop [4,5].

Circumscribed or plaque morphoea This variant is less common in children than in adults. It comprises two subtypes: superficial and deep. Superficial

circumscribed morphoea lesions are most frequently localized on the trunk with preference for the abdominal region, especially over the iliac crests. In the initial stage the lesion shows a violaceous border, the ‘lilac ring’, and has a tendency to spread outwards. The patch has a whitish or ivory colour centrally. With time, the involved skin becomes hairless and anhidrotic, and sclerosis starts to develop [6,53]. The skin lesion becomes firmer, may show hypo- or hyperpigmentated changes and eventually signs of atrophy. Superficial circumscribed morphoea is usually associated with less physical morbity than other forms. Dissemination of the lesions is possible and is characterized by multiple, indurated, plaque-like lesions, usually on the upper trunk, abdomen, buttocks and legs, but seldom on the face, neck and arms. Associated muscle atrophy may be observed and the joints can be involved depending on the site of the overlying skin. Some authors use the term generalized morphoea if more than four plaque-like lesions occur in two or more sites of the body [3]. However, in this author ’s interpretation, generalized morphoea is characterized by widespread diffuse involvement of the body and differs from multifocal ‘en plaque’ morphoea [58]. Guttate morphoea is a term that has been used to describe multiple, small, white sclerotic lesions, which may represent multifocal circumscribed morphoea, but it needs to be differentiated from lichen sclerosus et atrophicus and atrophoderma of Pasini and Pierini. Co-existence of these diseases has been observed [59,60]. Deep, subcutaneous morphoea, referred to as ‘solitary morphoea profunda’, is localized on the upper trunk, forearms and lower legs but can also be unilateral and circular on the thigh and on the buttocks. It involves the deeper layers of the dermis and the subcutaneous fatty tissue [53,61,62], giving rise to a peau d’orange effect and sometimes ulceration. The skin is tight and immobile and arthralgia and joint contractures may result. Lesions described as morphoea profunda are likely to overlap with eosinophilic fasciitis.

Linear morphoea of the trunk and limbs Linear morphoea is the most common subtype in children, affecting approximately 65% of all paediatric patients [2]. We [49] have recently described the distribution of linear morphoea in more detail in 65 patients. Usually a limb is affected (Fig. 173.3), the legs more often than the arms. The linear lesions may sometimes affect the trunk and, rarely, half the body – face, arm, trunk and leg – resulting in hemiatrophy. In most cases linear morphoea is unilateral, and in approximately 15% bilateral lesions occur. The distribution pattern of linear morphoea has now been shown to be consistent with the lines of Blaschko, thus suggesting an early embryological devel-

Morphoea (Localized Scleroderma)

173.5

Fig. 173.4 ‘En coup de sabre morphoea’ causing facial hemiatrophy.

(a) 35.0°C

34

32

30

29.0°C (b) Fig. 173.3 (a) Linear morphoea affecting the right arm and hand with atrophy and contractures of the ring and small fingers. (b) Thermography of the same patient showing the affected side to be ‘hot’ or ‘active’. The increased heat detected is presumed to relate to the presence of inflammation.

opment [49]. These lesions may start with an inflammatory appearance, but this is often rather subtle and may be missed. The affected skin becomes indurated and there is a change in the appearance of the skin with an indentation or puckering. Associated changes in pigmentation may vary greatly depending on the ethnic skin type of the patient. The linear variant tends to involve deeper tissues such as muscle and bone and to progress rapidly, resulting in a shortened wasted limb and joint contractures [6].

‘En coup de sabre’ morphoea or linear morphoea of the head Linear morphoea of the head is termed ‘en coup de sabre’ because of the similarities of the lesions to a scar from the so-called ‘dueling sword’ injuries of the past on the forehead and scalp. ‘En coup de sabre’ morphoea in children is most often unilateral (frontoparietal or hemifacial), with a central line of demarcation [49]. After a short phase of erythema (sometimes with telangiectasia) and indurated oedema, the skin often shows early hyperpigmentation and a linear atrophic or sclerotic lesion develops, with a groove or depression [53]. The development of scarring alopecia on the scalp and partial loss of the eyebrows or eyelashes is highly characteristic. After skin and subcutis induration and atrophy, the deeper tissues may become affected with the development of facial hemiatrophy (Fig. 173.4–173.6) [63].

173.6

Chapter 173

Fig. 173.5 ‘En coup de sabre’ morphoea/linear morphoea localized to the right cheek.

Fig. 173.7 ‘En coup de sabre’ morphoea associated with unilateral atrophy of the tongue.

nervous system can be affected by seizures, headache, hemiparesis and other focal neurological symptoms [63– 65]. Approximately 8–13% of patients with ‘en coup de sabre’ morphoea experience seizures [2,64,65]. Magnetic resonance and/or computerized tomography imaging is useful: cerebral and skull atrophy, meningocortical alterations, intracranial calcification and white matter abnormality in the ipsilateral hemisphere can be detected [63–66]. Cerebral biopsy and analysis of cerebrospinal fluid have shown evidence of an intracerebral inflammation [67,68]. The neuroradiological findings and the response of the neurological manifestation to corticosteroids in several reports also support the hypothesis of an underlying inflammatory process [67,69]. In addition, the eyes may be involved (with uveitis, globe retraction, fixed pupils and other ocular and periocular changes) [63,65] and problems affecting the jaw can occur (malalignment, disturbed dentition and difficulties opening and closing the jaw). Unilateral atrophy of the tongue can also be observed (Fig. 173.7).

Fig. 173.6 Morphoea causing an area of linear scarring alopecia.

Parry–Romberg syndrome is characterized by hemifacial atrophy, mainly affecting the subcutaneous tissue, muscles and bones. In contrast to ‘en coup de sabre’ morphoea the overlying skin remains lax and movable without pigmentary changes. However, there is evidence for a close relationship and the terms Parry–Romberg syndrome and ‘en coup de sabre’ morphoea have often been used for the same clinical presentation. It is now widely accepted that Parry–Romberg syndrome represents a variant of ‘en coup de sabre’ morphoea and is not a distinct clinical entity [63,64]. These conditions share clinical, laboratorial and imaging features. The central

Generalized morphoea Generalized morphoea is defined as a rare condition in which widespread and diffuse sclerosis of the skin occurs with no systemic involvement. It is mainly seen in adults. It can start insidiously, often on the trunk, with one or more plaques, and slowly progress to a much more extensive involvement. Contractures occur in limbs and can give rise to joint pains. In contrast to systemic sclerosis, Raynaud phenomenon, nail-fold capillary dilation and telangiectasia are not characteristic features. Chronic graft-versus-host disease may result in generalized morphoea [25,70]. Disabling pansclerotic morphoea This rare form of morphoea initially presents as a linear variant, which rapidly progresses to affect large areas of

Morphoea (Localized Scleroderma)

the body [71,72]. First described in 1923 [73] as ‘progressive mutilating scleroderma’, the condition is characterized by a polymorphous appearance of lesions with involvement of the skin, deep structures, tendons, fascia and muscles. Arthralgia, joint stiffness, contractures of the hands and extremities and skin ulcerations are common features. The histological abnormalities include panniculitis and a marked lymphocytic inflammation [74]. Systemic involvement in the form of lung fibrosis and oesophageal dysmotility have been described and the condition is fatal in some cases [72,74]. Recent reports have raised awareness of the possible evolution of chronic skin ulceration to squamous cell carcinoma in pansclerotic morphoea of childhood [75,76].

Mixed morphoea (combined forms) Combined forms of morphoea are seen in approximately 14–15% of paediatric patients [2,8]. Most often combinations of circumscribed lesions on the trunk with a linear lesion on the leg or an ‘en coup de sabre’ lesion are seen. The overlap is indicative of a common pathophysiology and demonstrates the difficulty in classification on solely clinical grounds. The combined types tend to be more aggressive and usually require systemic treatment. Other combined forms are: morphoea, lichen sclerosus et atrophicus and atrophoderma of Pasini and Pierini. Extracutaneous involvement and associated conditions Morphoea is usually limited to the skin and subcutaneous tissue and, in general, internal organs are not involved. However, extracutaneous involvement is present in approximately 22% of patients, as recently described in a multicenter study of 750 children with morphoea [4]. Extracutaneous manifestations were more frequently seen in patients with linear morphoea. The extracutaneous manifestations were as follows: musculoskeletal (particularly articular) involvement 19%; neurological symptoms (including seizures, deafness, transient ischaemic attacks, migraine and headaches) 4%; other autoimmune conditions (including Raynaud phenomenon) 3%; vascular findings (vasculitic rash and deep vein thrombosis) 2%; ocular involvement 2%; and gastrointestinal symptoms (e.g. gastro-oesophageal reflux) and respiratory findings (restrictive lung disease) 1%. Very rarely cardiac findings (pericarditis and arrhythmia) have been described. The bone changes in the form of thinning, hypoplasia and shortening, as seen in linear morphoea, are usually secondary, however arthritis and musculoskeletal symptoms may occur unrelated to the site of the skin lesion. Extracutaneous involvement seems to be associated with a positive rheumatoid factor, circulating ANAs, elevated erythrocyte sedimentation rate and C-reactive

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protein [4]. In these patients the extracutaneous involvement is milder and not life threatening as usually seen in patients with systemic sclerosis. If more severe complications occur, such as pulmonary disease, pulmonary hypertension, cardiomyopathy and generalized myopathy, they should be interpreted as a sign of systemic sclerosis [77,78]. Other autoimmune syndromes may be associated with morphoea; however this is less frequent in children (3– 5%) than in adults (30%) [4,23]. The most common associated autoimmune disorders include vitiligo, alopecia areata, lichen planus, psoriasis, inflammatory bowel disease, type 1 diabetes mellitus and connective tissue diseases such as discoid and systemic lupus erythematosus, dermatomyositis. Sjögren syndrome and rheumatoid arthritis [23]. Laboratory abnormalities. There may be an increase in C-reactive protein in childhood-onset morphoea (in approximately 9%), but this is usually not paralleled by other acute phase response markers, including erythrocyte sedimentation rate, immunoglobulin and complement [2,12]. Eosinophilia may occur in 7–18% [2,5,8] and reduced complement C2 has been reported [79]. ANA, anti-Ro/SSA and rheumatoid factor are often found in children with morphoea, the clinical relevance of which is uncertain. In recent larger cohorts of patients, ANAs were found in 26–59% [2,5,8]. This frequency in children is lower than in adults with localized scleroderma but higher than in the normal population. Linear, deep and generalized morphoea seem to be the subtypes associated with a higher prevalence of ANA; however, no correlation between these antibodies and the disease course has been observed [2,8]. One of the major autoantigens for ANAs in morphoea is nuclear histone. Antihistone antibodies (AHAs) have been detected in 47% of patients with morphoea, with a different prevalence in the various subtypes – higher in generalized morphoea, lower in circumscribed morphoea [80]. Monitoring AHA titres has been proposed for assessing disease activity, however this has not been further studied in larger cohorts [81]. Anti-topoisomerase I antibodies (anti-Scl 70), a marker for systemic sclerosis, are rarely detected in children with morphoea (2–3%) [2,23,80]. Anticentromere antibodies (ACAs) are found more commonly in adult patients (12%) than in children with morphoea (1.7%) [2,82]. Whether these antibodies are markers that reflect the immunological component of the disease process or can have a prognostic significance is unclear. None of the Scl-70- or ACA-positive patients in the series of 750 morphoea cases developed signs or symptoms of internal organ involvement during a mean follow-up of 3.4 years [2]. Rheumatoid factor, a serological marker for rheumatoid arthritis, has been detected in approximately 15% of paediatric

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patients with morphoea and seems to correlate with the presence of arthritis [2]. A recent study underlined the role of anti-DNA topoisomerase IIα (antitopo-IIα) autoantibodies in morphoea. These antibodies were detected in 76% of patients with morphoea, whereas in only 14% of patients with systemic sclerosis [83]. Although it remains unknown why morphoea is associated with antitopo-IIα but not antitopo-I antibodies and vice versa in systemic sclerosis, these antibodies seem to play an important role in fibrotic disorders as shown by their presence in idiopathic pulmonary fibrosis [84]. Antibodies against anticardiolipin and lupus anticoagulant have also been found in paediatric morphoea patients with a prevalence of approximately 12%, which is lower than that reported for adult patients (46%) [2,85]. The serum concentration of procollagen type I carboxyterminal propeptide (P1cp) has been shown to correlate with the number of sclerotic lesions and the evidence of anti-single-stranded DNA and antihistone antibodies in patients with morphoea [86]. Therefore, the P1cp serum level may be an indicator for the severity and progression of morphoea. Another marker of disease activity that has been proposed is serum IL-2R [87], but another study showed no significant difference between the various disease groups and normal control subjects [12]. Disease monitoring and imaging techniques. Disease activity detection in morphoea remains challenging, both in the evaluation of the need for treatment and the assessment of its efficacy over time. The lack of reliable and standardized outcome measures has represented a significant limitation in the past for the development of therapeutic trials. To date, laboratory tests are not helpful for disease monitoring. C-reactive protein, erythrocyte sedimentation rate, ANA titres and serum levels of TGFβ1 do not correlate with the disease course. The role of P1cp serum levels, TNF-α, IL-2R and IL-13 for disease monitoring remains to be validated [3,86,87]. Clinical examination is still the mainstay of disease activity assessment; however this may be subjective and sometimes is unsatisfactory. Clinical scoring systems have been used to report the severity of morphoea; however a limited number of skin scores have been proposed and their validation is currently ongoing. Seyger et al. [88] used a modified skin score that assesses skin thickness and area involvement, but fails to describe the inflammatory aspect of the condition as well as tissue atrophy. A computerized skin score with the use of an adhesive transparent film and subsequent scanning and computer analysis has been proposed for the follow-up of circumscribed morphoea lesions [89]. This method allows accurate monitoring of the size of a lesion as one aspect of the clinical assessment; however it is not easily applicable in daily practice. A semiquantitative scoring

method, named the localized scleroderma severity index (LoSSI), has been proposed [90]. LoSSI comprises the sum of four clinical skin scores: extent of the affected area, erythema, skin thickness and new lesion development/ extension. A good inter- and intraobserver reproducibility was demonstrated for this score and to date LoSSI is probably the most useful clinical score to detect changes in morphoea over time. Our unit has been involved in evaluating objective methods to detect and monitor disease activity. Two previous studies showed thermography to be a helpful tool in assessing disease activity in morphoea, with a high sensitivity [91,92]. A morphoea lesion is judged thermographically ‘active’ if it appears to the image observer to be more than 0.5°C warmer than adjacent tissue or the contralateral limb (see Fig. 173.3b). However, the main limitation of this technique is the assessment of older lesions, characterized by marked atrophy of skin, subcutaneous fat or muscle, where the increased skin temperature more likely represents heat conduction from deeper tissues rather than active inflammation and thermography therefore reveals false-positive results [91,93]. We recently evaluated the role of laser Doppler flowmetry (LDF), a non-invasive method for the measurement of cutaneous microcirculation, for the detection of disease activity in morphoea [93]. Blood flow was shown to be significantly increased in clinically active morphoea lesions with a sensitivity of 80% and specificity of 77%. Particularly in ‘en coup de sabre’ morphoea, when inflammatory skin changes are often lacking but the disease is still progressing, LDF represents a helpful diagnostic modality to discriminate disease activity and is more accurate for this purpose than thermography. Ultrasound is another technique that has been proposed for monitoring morphoea, using a high-frequency transducer at 13–20 MHz [94–96]. Ultrasound can detect several abnormalities such as increased blood flow, increased echogenicity due to fibrosis, decreased echogenicity due to oedema and atrophy of the dermis and subcutaneous fat. However, ultrasound is operator dependent and has not been validated or standardized for the assessment of morphoea lesions as yet. Magnetic resonance imaging (MRI) is clearly useful for the assessment of central nervous system involvement, jaw deformity and deep and generalized morphoea with potential fascia, muscle and bone involvement [97]. In the inflammatory phase MRI may detect thickening of the dermis and involvement of the subcutaneous fat, fascia and muscle as increased signal intensity. Similar to other connective tissue disorders such as eosinophilic fasciitis and dermatomyositis, the reversibility of these inflammatory changes (e.g. increased signal intensity of fascia or muscle) can be demonstrated by MRI follow-up during treatment (authors’ personal observation).

Morphoea (Localized Scleroderma)

Differential diagnosis. Morphoea en plaque must be differentiated from erythema annulare, erythema migrans, fixed drug eruption, dermatophyte infection, lichen simplex chronicus and lichen sclerosus et atrophicus. The latter may particularly resemble the guttate subtype of morphoea and histological changes are helpful in differentiation. Also, morphoea-like sarcoidosis has been described [98]. Isolated deep atrophic lesions can show a similar clinical picture to the atrophoderma and subcutaneous fat atrophy sometimes shown after intramuscular injection (corticosteroids, vaccinations or vitamin K) [99– 101]. Early inflammatory morphoea lesions, particularly of the ‘en coup de sabre’ subtype may present with telangiectasia and therefore be misinterpreted as a telangiectatic capillary malformation [102]. Morphoea on the extremities in children (mainly the linear subtype) has to be differentiated from eosinophilic fasciitis (Shulman syndrome), Buschke–Ollendorf syndrome/connective tissue nevi and necrobiosis lipoidica [103–105]. Eosinophilic fasciitis in children is, however, very rare. Treatment. The aim of therapy is to arrest the disease early in its course in order to prevent the development of functional and cosmetic complications. The management and treatment of severe morphoea is challenging and the literature contains many case reports and case series but overall few randomized trials. Drugs are usually directed towards suppressing inflammation and collagen alteration.

Topical treatment and light therapy for superficial, circumscribed (plaque) morphoea For patients with mild morphoea, such as the plaque type which is confined to the skin only, topical treatment and light therapy can be used [106]. Topical corticosteroids, vitamin D3 analgogues, tacrolimus and imiquimod have been reported to be effective [3,107–109]. Over the last decade several photodermatological trials on bath psoralen plus ultraviolet A (PUVA), different dosages of ultraviolet A1 (UVA1) and narrowband ultraviolet B for the treatment of en plaque morphoea have reported a good response [110–112]. Overall treatment with UVA1 at medium and high doses, with or without psoralen (PUVA), seems to be most beneficial [110,112]. There are a variety of mechanisms of action by which ultraviolet phototherapy may work in morphoea and these include a depletion of skin-infiltrating T-cells and proinflammatory cytokines such as IL-1 and IL-6, an increase in matrix metalloproteinase-1-collagenase activity, an increased expression of interferon γ (IFN-γ) and a decrease in TGF-β, by acting on the TGF-β/Smad pathway [113,114]. Kreuter et al. [110] suggest that bath PUVA

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should be considered in the early inflammatory stages, whereas UVA1 is more beneficial in the fibrotic stage of morphoea. In clinical practice the combined use of phototherapy together with topical medium potency corticosteroids may be of value for some patients [115]. However, in children the indication for light therapy should be individually considered on the balance of benefit, potential long-term side-effects and the feasibility of conducting the time-consuming treatment.

Systemic treatment for severe morphoea In children, apart from the plaque type, all other forms of morphoea must be considered as potentially severe. In the past, numerous treatments, such as penicillamine, antimalarial drugs, retinoids, calcitriol, calcipotriol, ciclosporin, colchizine, phenytoin and azathioprine, vitamin D or E, intravenous immunoglobulin and INF-γ have been used for the treatment of severe morphoea, with varying degrees of success and often severe side-effects. Over the last years the combination of systemic corticosteroids and methotrexate has been established as firstline treatment and methotrexate is the drug most commonly used for childhood morphoea [5,58,116–119]. We recently documented our experience with a treatment protocol using intravenous methylprednisolone and then oral prednisolone in the acute phase in combination with methotrexate for the treatment of 34 children with morphoea [58]. Induction therapy includes two courses of high-dose methylprednisolone, each containing three daily pulses (30 mg/kg/day, maximum 500 mg), given on two consecutive weeks. Oral prednisolone (usually 0.5 mg/kg/day) is started after the first course of methylprednisolone, stopped during the second course of methylprednisolone and then continued on a reducing regimen over 3–6 months. Maintenance treatment with once weekly methotrexate (10–15 mg/m2/week) is started 1 week after the second course of methylprednisolone and is usually continued for 3 years. With this regimen, in 94% of the patients disease progression stopped, and a sustained prolonged good response was reported in 74% as evaluated by clinical assessment and thermography. The overall tolerability of the treatment is high. A relatively high relapse rate was noted in patients with shorter treatment duration of methotrexate, particularly in younger children [58]. We therefore now recommend continuing maintenance treatment with methotrexate for at least 3 years. It is advocated that after stopping therapy these patients are regularly monitored for at least 5 years. Recently, successful treatment of severe or methotrexateresistant localized scleroderma with mycophenolate mofetil has been reported [120]. Imatinib, a tyrosine kinase inhibitor, is currently being evaluated as a potential therapeutic agent in sclerodermatous chronic graftversus-host disease and systemic and localized

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scleroderma and further data are awaited from an ongoing phase II randomized clinical trial [121,122].

Other treatments and supportive measures Deep connective tissue massage can be helpful to improve dermal elasticity and joint movement [123]. Regular physiotherapy is essential especially for linear morphoea, to prevent the development of contractures. For established flexion deformities, splinting may be helpful. For those children with leg-length shortening, orthopaedic surgical involvement is warranted [124]. Particularly in patients with ‘en coup de sabre’ lesions, plastic surgery is an important adjunct to improve appearance, including excision of scar tissue, autologous fat transfer and the use of fillers.

Acknowledgements The authors would like to acknowledge the contributions to this chapter by Carolina Sampaio, Maria Teresa Visentin, Kevin Howell and Patricia Woo in the previous edition of the textbook and also to their care of our patients. References 1 Peterson LS, Nelson AM, Su WP. Classification of morphea (localized scleroderma). Mayo Clin Proc 1995;70:1068–76. 2 Zulian F, Athreya BH, Laxer R et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology 2006;45:614–20. 3 Laxer RM, Zulian F. Localized scleroderma. Curr Opin Rheumatol 2006;18:606–13. 4 Zulian F, Vallongo C, Woo P et al. Localized scleroderma in childhood is not just a skin disease. Arthr Rheum 2005;52:2873–81. 5 Christen-Zaech S, Hakim MD, Afsar FS, Paller AS. Pediatric morphea (localized scleroderma): review of 136 patients. J Am Acad Dermatol 2008;59:385–96. 6 Murray KJ, Laxer RM. Scleroderma in children and adolescents. Rheum Dis Clin North Am 2002;28:603–24. 7 Peterson LS, Nelson AM, Su WP, Mason T, O’Fallon WM, Gabril SE. The epidemiology of morphoea (localized scleroderma) in Olmsted County 1960–1993. J Rheumatol 1997;24:73–80. 8 Marzano AV, Menni S, Parodi A et al. Localized scleroderma in adults and children: clinical and laboratory investigations on 239 cases. Eur J Dermatol 2003;13:171–6. 9 Fox TC. Note on the history of scleroderma in England. Br J Dermatol 1892;4:101–4. 10 Fagge CH. On keloid scleriasis, morphoea. Guy’s Hosp Rep Sev 1868;3:255. 11 Klemperer P, Pollack AD, Baehr G. Diffuse collagen disease. Acute lupus erythematosus and diffuse scleroderma. J Am Med Assoc 1942;119:331–2. 12 Vancheeswaran R, Black CM, David J et al. Childhood-onset scleroderma: is it different from adult-onset disease. Arthritis Rheum 1996;39:1041–9. 13 Mosterd K, Winnepenninckx V, Vermeulen A, van Neer PA, van Neer FJ, Frank J. Morphea following surgery and radiotherapy: an evolving problem. J Eur Acad Dermatol Venereol 2009;23: 1099–101.

14 Torrelo A, Suàrez J, Colmenero I et al. Deep morphea after vaccination in two young children. Pediatr Dermatol 2006;23:484–7. 15 Longo F, Saletta S, Lepore L et al. Localized scleroderma after infection with Epstein–Barr virus. Clin Exp Rheumatol 1993;11:681–3. 16 Aberer E, Neumann R, Stanek G. Is localised scleroderma a Borrelia infection? [Letter] Lancet 1985;ii:273. 17 Aberer E, Stanek G. Histological evidence for spirochetal origin of morphea and lichen sclerosus et atrophicans. Am J Dermatopathol 1987;9:374–9. 18 Eisendle K, Grabner T, Zelger B. Morphoea: a manifestation of infection with Borrelia species? Br J Dermatol 2007;157:1189–98. 19 Weide B, Schittek B, Klyscz T et al. Morphoea is neither associated with features of Borrelia burgdorferi infection nor is the agent detectable in lesional skin by polymerase chain reaction. Br J Dermatol 2000;143:780–5. 20 Goodlad JR, Davidson MM, Gordon P et al. Morphoea and Borrelia burgdorferi: results from the Scottish Highlands in the context of the world literature. Mol Pathol 2002;55:374–8. 21 Zollinger T, Mertz KD, Schmid M, Schmitt A, Pfaltz M, Kempf W. Borrelia in granuloma annulare, morphea and lichen sclerosus: a PCR-based study and review of the literature. J Cutan Pathol 2010;37:571–7. 22 Burrows NP, Bhogal BS, Russel Jones R, Black MM. Clinicopathological significance of cutaneous epidermal nuclear staining by direct immunofluorescence. J Cutan Pathol 2993;20:159–62. 23 Leitenberger JJ, Cayce RL, Haley RW, Adams-Huet B, Bergstresser PR, Jacobe HT. Distinct autoimmune syndromes in morphea. A review of 245 adult and pediatric cases. Arch Dermatol 2009;145:545–50. 24 Vincent F, Prokopetz R, Miller RA. Plasma cell panniculitis: a unique clinical and pathologic presentation of linear scleroderma. J Am Acad Dermatol 1989;21:357–60. 25 Harper JI. Graft versus host disease: etiological and clinical aspects in connective tissue diseases. Semin Dermatol 1985;4:144–51. 26 White JM, Creamer D, du Vivier AW et al. Sclerodermatous graftversus-host disease: clinical spectrum and therapeutic challenges. Br J Dermatol 2007;156:1032–8. 27 Uziel Y, Krafchik BR, Feldman B et al. Serum levels of soluble interleukin-2 receptor. A marker of disease activity in localized scleroderma. Arthritis Rheum 1994;372:898–901. 28 LeRoy BC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast. J Clin Invest 1974;54:880–9. 29 Badea I, Taylor M, Rosenberg A, Foldvari M. Pathogenesis and therapeutic approaches for improved topical treatment in localized scleroderma and systemic sclerosis. Rheumatology 2009;48: 213–21. 30 Sato S, Fujimoto M, Kikuchi K et al. Soluble CD4 and CD8 in serum from patients with localized scleroderma. Arch Dermatol Res 1996;288:358–62. 31 Sato S, Fujimoto M, Kikuchi K et al. Elevated soluble CD23 levels in the sera from patients with localized scleroderma. Arch Dermatol Res 1996;288:74–8. 32 Ihn H, Sato S, Fujimoto M et al. Clinical significance of serum levels of soluble interleukin-2 receptor in patients with localized scleroderma. Br J Dermatol 1996;134:843–7. 33 Ihn H, Sato S, Fujimoto M et al. Demonstration of interleukin-2, interleukin-4 and interleukin-6 in sera from patients with localized scleroderma. Arch Dermatol Res 1995;28:193–7. 34 Ihn H, Yazama N, Kubo M et al. Circulating levels of soluble CD30 are increased in patients with localized scleroderma and correlated with serological and clinical features of the disease. J Rheumatol 2000;27:698–702.

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57 Zulian F, Martini G. Preliminary classification criteria for juvenile systemic sclerosis. In: Zulian F, Ruperto N, eds. Proceedings of the II Workshop on Nomenclature and Diagnostic Criteria for Juvenile Scleroderma Syndromes; 3–6 June 2004, Padua. Padua: Associazione Il Volo, 2005:5–16. 58 Weibel L, Sampaio MC, Visentin MT, Howell KJ, Woo P, Harper JI. Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children. Br J Drmatol 2006;155:1013–20. 59 Uitto J, Santa Cruz DJ, Bauer EA et al. Morphea and lichen sclerosus et atrophicus. J Am Acad Dermatol 1980;3:271–9. 60 Blaya B, Gardeazabal J, de Lagràn ZM, Diaz-Pérez JL. Patient with generalized guttate morphea and lichen sclerosus et atrophicus. Actas Dermosifiliogr 2008;99:808–11. 61 Whittaker SJ, Smith NP, Jones RR. Solitary morphoea profunda. Br J Dermatol 1989;120:431–40. 62 Person JR, Su WPD. Subcutaneous morphoea: a clinical study of sixteen cases. Br J Dermatol 1979;100:371–80. 63 Sommer A, Gambichler T, Bacharach-Buhles M, von Rothenburg T, Altmeyer P, Kreuter A. Clinical and serological characteristics of progressive facial hemiatrophy: a case series of 12 patients. J Am Acad Dermatol 2006;54:227–33. 64 Tollefson MM, Witman PM. En coup de sabre morphea and Parry– Romberg syndrome: a retrospective review of 54 patients. J Am Acad Dermatol 2007;56:257–63. 65 Stone J. Parry–Romberg syndrome: a global survey of 20 patients using the internet. Neurology 2003;61:674–6. 66 Holland KE, Steffes B, Nocton JJ et al. Linear scleroderma en coup de sabre with associated neurologic abnormalities. Pediatrics 2006;117:132–136. 67 Chang GY, Park SH, Youn YC, Kwon OS. Neuroimaging findings in scleroderma en coup de sabre. Neurology 2004;62:1585–9. 68 Chung MH, Sum J, Morrell MJ, Horoupian DS. Intracerebral involvement in scleroderma en coup de sabre: report of a case with neuropathologic findings. Ann Neurol 1995;37:679–81. 69 Unterberger I, Trinka E, Engelhardt K et al. Linear scleroderma ‘en coup de sabre’ coexisting with plaque-morphea: neuroradiological manifestation and response to corticosteroids. J Neurol Neurosurg Psychiatry 2003;74:661–4. 70 Neustadter JH, Samarin F, Carlson KR, Girardi M. Extracorporeal photochemotherapy for generalized deep morphea. Arch Dermatol 2009;145:127–30. 71 Roldan R, Morote G, Castro Mdel C, Miranda MD, Moreno JC, Collantes E. Efficacy of bosentan in treatment of unresponsive cutaneous ulceration in disabling pansclerotic morphea in children. J Rheumatol 2007;34:1786. 72 Wollina U, Looks A, Uhlemann C, Wollina K. Pansclerotic morphea of childhood follow-up over 6 years. Pediatr Dermatol 1999;16:245–7. 73 Roudinesco NN, Vallery-Radot P. Sclérodermie mutilante progressive. Bull Soc Fr Dermatol Syphilol 1923;30:151–4. 74 Diaz-Perez JL, Connolly SM, Winkelmann RK. Disabling pansclerotic morphea of children. Arch Dermatol 1980;116: 169–73. 75 Petrov I, Gantcheva M, Miteva L, Vassileva S, Pramatarov K. Lower lip squamous cell carcinoma in disabling pansclerotic morphea of childhood. Pediatr Dermatol 2009;26:59–61. 76 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 Extremity Wounds 2007;6:291–8. 77 Birdi N, Laxer RM, Thorner P et al. Localized scleroderma progressing to systemic disease. Case report and review of the literature. Arthritis Rheum 1993;36:410–15.

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78 Francisco J, Mayorquin TL, McCurley JE et al. Progression of childhood linear scleroderma to fatal systemic sclerosis. J Rheumatol 1994;21:1955–7. 79 Hulsmans RFHJ, Asghar SS, Siddiqui AH et al. Hereditary deficiency of C2 in association with linear scleroderma ‘en coup de sabre’. Arch Dermatol 1986;122:76–9. 80 Takehara K, Sato S. Localized scleroderma is an autoimmune disease. Rheumatology 2005;44:274–279. 81 el Azhary RA, Aponte CC, Nelson AM. Do antihistone autoantibodies reflect disease activity in linear scleroderma? Arch Dermatol 2004;140:759–760. 82 Ruffatti A, Peserico A, Glorioso S et al. Anticentromere antibody in localized scleroderma. J Am Acad Dermatol 1986;15:637–42. 83 Hayakawa I, Hasegawa M, Takehara K, Sato S. Anti-DNA topoisomerase IIα autoantibodies in localized scleroderma. Arthritis Rheum 2004;50:227–32. 84 Grigolo B, Mazzetti I, Borzi RM et al. Mapping of topoisomerase IIα autoantibodies in idiopathic pulmonary fibrosis. Clin Exp Immunol 1998;114:339–46. 85 Sato S, Fujimoto M, Hasegawa M, Takehara K. Antiphospholipid antibody in localized scleroderma. Ann Rheum Dis 2003;62: 771–4. 86 Kikuchi K, Sato S, Kadono T, Ihn H, Takehara K. Serum concentration of procollagen type I carboxyterminal propeptide in localized scleroderma. Arch Dermatol 1994;130:1269–72. 87 Uziel Y, Krafchik BR, Feldman B et al. Serum levels of soluble interleukin-2 receptor. A marker of disease activity in localized scleroderma. Arthritis Rheum 1994;37:898–901. 88 Seyger MM, van den Hoogen FH, de Boo T, de Jong EM. Reliability of two methods to assess morphea: skin scoring and the use of a durometer. J Am Acad Dermatol 1997;37:793–6. 89 Zulian F, Meneghesso D, Grisan E et al. A new computerized method for the assessment of skin lesions in localized scleroderma. Rheumatology 2007;46:856–60. 90 Arkachaisri T, Vilaiyuk S, Li S et al. The localized scleroderma skin severity index and physician global assessment of disease activity: a work in progress toward development of localized scleroderma outcome measues. J Rheumatol 2009;36:2819–29. 91 Martini G, Murray KJ, Howell KJ et al. Juvenile-onset localized scleroderma activity detection by infrared thermography. Rheumatology 2002;41:1178–82. 92 Birdi N, Shore A, Rush P, Laxer RM, Silverman ED, Krafchik B. Childhood linear scleroderma: a possible role of thermography for evaluation. J Rheumatology 1992;19:968–73. 93 Weibel L, Howell KJ, Visentin MT et al. Laser Doppler flowmetry for assessing localized scleroderma in children. Arthritis Rheum 2007;56:3489–95. 94 Seidenari S, Conti A, Pepe P et al. Quantitative description of echographic images of morphoea plaques as assessed by computerized image analysis on 20 MHz B-scan recordings. Acta Dermatol Venereol (Stockh) 1995;75:442–5. 95 Cosnes A, Anglade MC, Revuz J et al. Thirteen-megahertz ultrasound probe: its role in diagnosing localized scleroderma. Br J Dermatol 2003;148:724–9. 96 Li SC, Liebling MS, Ramji FG et al. Sonographic evaluation of pediatric localized scleroderma: preliminary disease assessment measures. Pediatr Rheumatol Online J 2010;8:14. 97 Horger M, Fierlbeck G, Kuemmerle-Deschner et al. MRI findings in deep and generalized morphea. Am J Rheumatol 2008;190:32–9. 98 Hess SP, Agudelo CA, White WL et al. Ichthyosiform and morpheaform sarcoidosis. Clin Exp Rheumatol 1990;8:171–5. 99 Khelifa E, Masouyé I, Chavaz P, Hauser H, Grillet JP, Borradori L. Primary atrophic solitary morphea profunda. Dermatology 2008;217:207–10.

100 Sardana K, Garg VK, Bhushan P, Relhan V Sharma S. DPT vaccineinduced lipoatrophy: an observational study. Int J Dermatol 2007;46:1050–4. 101 Holth PJA, Marks R, Waddington E. ‘Pseudomorphoea’: a side effect of subcutaneous corticosteroid injection. Br J Dermatol 1975;92:689–91. 102 Kakimoto CV, Ross EV, Uebelhoer NS. En coup de sabre presenting as a port-wine stain previously treated with pulsed dye laser. Dermatol Surg 2008;35:165–7. 103 Quintero-Del-Rio AI, Punaro M, Pasqual V. Faces of eosinophilic fasciitis in childhood. J Clin Rheumatol 2002;8:99–103. 104 Assmann A, Mandt N, Geilen CC, Blume-Peytavi U. Buschke– Ollendorff syndrome – differential diagnosis of disseminated connective tissue lesions. Eur J Dermatol 2001;11:476–9. 105 Szabo RM, Harris GD, Burke WA. Necrobiosis lipoidica in a 9-yearold girl with new onset type II diabetes mellitus. Pediatr Dermatol 2001;18:316–19. 106 Kreuter A, Altmeyer P, Gamblichler T. Treatment of localized scleroderma depends on the clinical subtype. Br J Dermatol 2007;156:1363–5. 107 Kroft EB, Groeneveld TJ, Seyer MM, de Jong EM. Efficacy of topical tacrolimus 0.1% in active plaque morphoea: randomized, doubleblind, emollient-controlled pilot study. Am J Clin Dermatol 2009;10:181–7. 108 Dytoc M, Ting PT, Man J, Sawyer D, Fiorillo L. First case series on the use of imiquimod for morphoea. Br J Dermatol 2005;153: 815–20. 109 Campione E, Paterno EJ, Diluvio L, Orlandi A, Bianchi L, Chimenti S. Localized morphea treated with imiquimod 5% and dermoscopic assessment of effectiveness. J Dermatolog Treat 2009;20:10–3. 110 Kreuter A, Hyun J, Stücker M, Sommer A, Altmeyer P, Gambichler T. A randomized controlled study of low-dose UVA1, medium-dose UVA1 and narrowband UVB phototherapy in the treatment of localized scleroderma. J Am Acad Dermatol 2006;54, 440–7. 111 Ozdemir M, Engin B, Toy H, Mevlitoglu I. Treatment of plaque-type localized scleroderma with retinoic acid and ultraviolet A plus the photosensitizer psoralen: a case series. J Eur Acad Dermatol Venereol 2008;22:519–21. 112 Andres C, Kollmar A, Mempel M, Hein R, Ring J, Eberlein B. Successful ultraviolet A1 phototherapy in the treatment of localized scleroderma: a retrospective and prospective study. Br J Dermatol 2010;162:224–7. 113 El-Mofty M, Mostafa W, Esmat S et al. Suggested mechanisms of action of UVA phototherapy in morphea: a molecular study. Photodermatol Photoimmunol Photomed 2004;20:93–100. 114 Kreuter A, Hyun J, Skrygan M et al. Ultraviolet A1 phototherapy decreases inhibitory SMAD7 gene expression in localized scleroderma. Arch Dermatol Res 2006;298:265–72. 115 Kreuter A, Gambichler T, Avermaete A et al. Combined treatment with calcipotriol ointment and low-dose ultraviolet A1 phototherapy in childhood morphea. Pediatr Dermatol 2001;18:241–5. 116 Fitch PG, Retting P, Burnham JM et al. Treatment of pediatric localized scleroderma with methotrexate. J Rheumatol 2006;33: 609–14. 117 Kreuter A, Gambichler T, Breuckmann F et al. Pulsed-high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma. Arch Dermatol 2005;141:847–52. 118 Uziel Y, Feldman BM, Krafchik BR et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr 2000;136:91–5. 119 Li SC, Feldman BM, Higgins GC, Haines KA, Punaro MG, O’Neill KM. Treatment of pediatric localized scleroderma: results of a survey of North American pediatric rheumatologists. J Rheumatol 2010;37:175–81.

Morphoea (Localized Scleroderma) 120 Martini G, Ramanan AV, Falcini F, Girschick H, Goldsmith DP, Zulian F. Successful treatment of severe or methotrexate-resistant juvenile localized scleroderma with mycophenolate mofetil. Rheumatol 2009;48:1410–13. 121 Moreno-Romero JA, Fernandez-Aviles F, Carreras E, Rovira M, Martinez C, Mascaro JM Jr. Imatinib as a potential treatment for sclerodermatous chronic graft-vs-host disease. Arch Dermatol 2008;144: 1106–9. 122 Efficacy and safety of imatinib in scleroderma (SCLEROGLIVEC). An ongoing Phase II randomized double blind clinical trial by the University of Bordeaux. www.clinicaltrials.gov/NCT00479934

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123 Black CM. Juvenile scleroderma. In: Woo P, White PH, Ansell BM, eds. Paediatric Rheumatology Update. Oxford: Oxford University Press, 1990:194–208. 124 Buckley SL, Skinner S, James P et al. Focal scleroderma in children: an orthopaedic perspective. J Pediatr Orthop 1993;13: 784–90.

174.1

C H A P T E R 174

Systemic Sclerosis in Childhood Christopher P. Denton & Carol M. Black Centre for Rheumatology, Royal Free Hospital and UCL Medical School, London, UK

Childhood-onset systemic sclerosis represents a minority of cases of scleroderma in children as localized forms of the disease are much more frequent. It is critically important to identify cases of true systemic disease as early as possible in their natural history so that appropriate investigations, monitoring and treatment can be undertaken. ‘Scleroderma’ means hard skin and is a part of many syndromes, including localized, limited and generalized scleroderma. Related to these are undifferentiated connective tissue diseases, overlap syndromes, environmentally induced scleroderma-like diseases and localized fibroses (Box 174.1). The disease we call scleroderma or systemic sclerosis (SSc) has been confused with other diseases, including scleroedema, scleromyxoedema and primary amyloidosis [1]. The pattern of scleroderma occurring in childhood differs from that in adults [2,3]. Juveniles may develop any form of scleroderma, but there is a predilection for the localized form, in which the skin, subcutaneous fascia, muscle and bone are the main organs affected [4,5]. The localized form of scleroderma will be covered elsewhere in this book. Relative to the adult disease and to juvenile chronic arthritis, childhood-onset scleroderma is rare. Less than 3% of all cases are childhood onset [6], and the disease accounts for fewer than 3% of all patients seen in a paediatric rheumatology clinic [7]. In a paediatric rheumatology centre, SSc is seen much less frequently than localized scleroderma and for every 14 cases of localized disease, there is only one case of systemic disease [8,9]. Ascertainment of scleroderma in childhood may be biased by referral patterns and subspecialty orientation. Like its adult counterpart, juvenile scleroderma occurs in all races, with a female predominance. There appears to be no significant familial incidence. HLA studies with sufficient numbers of children in each group are only now being undertaken and so definitive information is awaited. Most of the information relating to pathogenesis of SSc is derived from studies of adult disease, although

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

it is likely that many findings can be extrapolated to childhood-onset SSc [10–13]. A number of different classification systems for scleroderma have been proposed [14,15]. Central to all of them is the extent of skin involvement. Currently, the most widely used classification defines two subsets based on the extent of skin involvement, together with a number of reliable clinical laboratory and natural history associations. The two-subset model divides the disease into diffuse cutaneous systemic sclerosis (dcSSc) and limited cutaneous systemic sclerosis (lcSSc) (Box 174.2) [15]. In childhood-onset SSc, the limited cutaneous variant is exceedingly rare, contrasting with its predominance among adults with SSc. The term lcSSc is preferable to CREST syndrome (calcinosis, Raynaud phenomenon, (o)esophageal motility disorders, sclerodactyly and telangiectasis) because cutaneous manifestations often extend beyond sclerodactyly, and calcinosis may be present only late or radiologically. DcSSc, the more extensive form of the disease, is much more rapid in onset. Within each subset there is often great variability in the speed of the disease, e.g. some patients with lcSSc never develop clinically apparent pulmonary hypertension or midgut disease, whereas other individuals develop these complications, usually later on, but occasionally as early as 5–7 years after diagnosis. Some patients with dcSSc develop extensive internal organ complications within 2–4 years, whereas others have widespread skin disease but only minimal internal organ complications such as mild interstitial lung disease. Thus, there is not only disease heterogeneity, but differential progression within a subset. Notwithstanding these problems, a useful and practical scheme is to divide the disease into early and late stages (see Table 174.1). A detailed discussion of the fascinating history of this disease is found in the historical review by Rodnan, the father of modern-day clinical scleroderma [16]. The concepts of limited SSc and systemic sclerosis sine scleroderma are discussed below. Aetiology and/or pathogenesis. Although the basic aetiology of scleroderma is unknown, it is almost certainly multifactorial, with genetic and environmental factors playing a part [17]. The clinical similarities between

174.2

Chapter 174

Box 174.1 Differential diagnosis for scleroderma

Box 174.2 Clinical features of the major systemic sclerosis subsets

Skin sclerosis

Diffuse cutaneous SSc (dcSSc)

Infiltrative disorders • Amyloidosis • Scleromyxoedema • Scleroderma of Buschke • Lichen sclerosis et atrophicus

• • • • • • • •

Metabolic disorders • Myxoedema • Porphyria • Cutanea tarda • Congenital porphyrias • Acromegaly • Phenylketonuria Inflammatory • Overlap connective tissue diseases • Eosinophilic fasciitis • Chronic graft-versus-host disease • Sarcoidosis Acral vasospasm Raynaud phenomenon • Primary Raynaud phenomenon • Other autoimmune rheumatic disorders • SLE • Rheumatoid disease • Dermato/polymyositis Other vascular disease • Haematological cryoglobulinaemia • Cold agglutinin disease • Hyperviscosity syndrome • Systemic vasculitis • Buerger disease (thromboangiitis obliterans) • Macrovascular disease

the systemic forms of scleroderma in adults and children make it likely that at least some aetiopathogenetic factors are common to both age groups. Many centres, sampling different population groups, have observed abnormal frequencies of the major histocompatibility (MHC) antigens associated with adult scleroderma. The association is complex and the strongest link is between DRw52a and SSc patients with lung fibrosis (relative risk 16.7) [18]. No equivalent information is available on scleroderma in childhood and although some studies are in progress, they are extremely difficult to conduct in view of the rarity of childhood-onset SSc. There are many reports of chemical agents that may induce adult scleroderma and

Inflammatory features more prominent at onset Raynaud often develops later Skin sclerosis proximal to wrists/elbows and truncal Prominent pruritis and constitutional symptoms Tendon friction rubs associated with progressive disease Significant visceral disease more frequent than in lcSSc Renal, pulmonary fibrosis (secondary PHT), cardiac, gut Disease activity appears to remain fairly constant over many years, with prominent vasospastic symptoms. Approximately one-third of SSc cases

Limited cutaneous SSc (lcSSc) • Long-standing Raynaud, skin changes to hands, face, neck • Compared with dcSSc, renal disease less frequent, isolated pulmonary hypertension, severe gut disease and interstitial lung fibrosis (if anti-topoisomerase-1 present) • Florid telangiectasis and calcinosis (especially ACA positive). • Disease activity appears to be maximal in first 3 years from onset then often plateaus and skin involvement may stabilize or improve • The majority (approximately 60%) of cases are classified to this subset Systemic sclerosis sine scleroderma • A small proportion (less than 2%) of SSc patients exhibit vascular (Raynaud phenomenon) and visceral manifestations including gastrointestinal disease, scleroderma renal crisis or pulmonary fibrosis • Typical disease-associated autoantibodies are generally present Prescleroderma/limited systemic sclerosis • Inclusion of patients with Raynaud phenomenon, abnormal nailfold capillaroscopy and a hallmark autoantibody (e.g. ACA, anti-topoisomerase-1 or anti-RNA polymerase 1/III) within a subset of systemic sclerosis is controversial • These cases may represent a subset of ‘autoimmune Raynaud and a proportion probably remain stable • This makes the term ‘limited systemic sclerosis’ more appropriate than ‘prescleroderma’ • Frequency of this group of patients is very difficult to ascertain

this may offer some clues towards the underlying disease mechanisms although, as with immunogenetic studies, the rarity of this condition makes formal analysis difficult.

Immune dysfunction An increasing number of immune abnormalities are being reported in SSc. Most notable are the range of scleroderma-

Systemic Sclerosis in Childhood

174.3

Table 174.1 Characteristic findings in the early and late stages of systemic sclerosis Early (3 years from onset)

Minimal. Weight often regained Raynaud phenomenon more severe, increased telangiectasia Stable or regression. Tropic and ischaemic ulcers

Renal

Malaise, fatigue, weight loss Raynaud phenomenon often relatively mild Rapid progression involving arms, trunk and face Pruritus decreases Dysphagia, heartburn Maximum risk for myocarditis, pericar dial effusion, interstitial pulmonary fibrosis Maximum risk period for scleroderma renal crisis

Limited cutaneous Constitutional Vascular

None Raynaud typically severe and long-standing

Cutaneous

Mild sclerosis with little progression prominent

Gastrointestinal

Dysphagia, heartburn

Cardiorespiratory

Involvement unusual

Renal

No involvement

Diffuse cutaneous Constitutional Vascular Cutaneous Pruritus Gastrointestinal Cardiorespiratory

associated hallmark autoantibodies (Table 174.2). There is considerable evidence suggesting that abnormalities in both humoral and cell-mediated immunity occur in SSc, although the importance of these immunological events in disease pathogenesis is uncertain, paticularly in juvenile-onset SSc, in which the hallmark autoantibodies of SSc occur less frequently [19]. The lack of a generalized immune dysfunction in SSc suggests that the derangement of immune cell function may be specific to certain antigens or cell types [20,21]. The relationship of autoantibody production and HLA status is also of increasing interest in scleroderma. It would appear that some of these antibodies are closely related to particular HLA alleles; for example, it has been shown that class II MHC haplotype is an important factor in determining in vitro responsiveness to topoisomerase antigen in both SSc patients and healthy control individuals [22], and linkage with HLA-DP alleles has been demonstrated [23]. These antibodies also appear to be mutually exclusive for the different subsets of scleroderma patients and, in addition, mark out within the Raynaud population those patients who are likely to develop SSc. A pathogenic role for the antibodies which target defined epitopes remains unproven. The most

More Reduced risk of new involvement but progression of existing established visceral fibrosis Reduced risk of crisis but chronic renal impairment may be progressive

Only secondary to visceral complications Raynaud persists, often causing digital ulceration or telangiectasia gangrene Slow progression of skin involvelment. Calcinosis ulceration from ischaemia and underlying calcinosis More pronounced symptoms, midgut and anorectal complications are prevalent Isolated pulmonary hypertension occurs most often at this stage. Patients may develop interstitial lung fibrosis, especially if anti-topoisomerase-1 autoantibody positive Rarely involved

obvious targets for the immune response in SSc are endothelial cells and fibroblasts. It is possible that the aberrant properties of connective tissue cells (e.g. excess synthesis of collagen, fibronectin and glycosaminoglycans) and the endothelial cell damage and vasculopathy are in part consequences of immunological events in SSc. It is recognized that patients with localized scleroderma, including childhood disease, frequently demonstrate serum autoantibodies more typical of systemic connective tissue disease, including antinuclear antibodies and anti-double-stranded autoantibodies. This is intriguing as it suggests that common factors may underlie the development of autoantibodies in localized as well as systemic disease. This strengthens the view that they may represent a consequence rather than a cause of these conditions. Whether the clinical associations of particular hallmark reactivities determined in adult SSc are also present in childhood-onset disease is uncertain. It is remarkable that anti-centromere antibody (ACA) is very rare in children whereas it is present in more than 30% of adult SSc cases. This is intriguing as many adult patients with lcSSc describe a long history of pre-existing Raynaud phenomenon that may extend back to childhood.

174.4

Chapter 174

Table 174.2 Autoantibodies in scleroderma Antigen

Molecular identity

Immunofluorescence pattern

Frequency

Clinical association

Topoisomerase 1(Scl 70)

100 kDa protein degrades to 70 kDa

Nuclear (diffuse fine speckles)

35% dcSSc 10–15% lcSSc

Kinetochore centromere

17, 80 and 140 kDa proteins at inner and outer kinetochore plates

Centromere

60% lcSSc, up to 25% primary biliary cirrhosis

RNA polymerases I and III

Complex of proteins 13–210 kDa. Antibodies may co-exist 34 kDa protein forming a component of U3 RNP

Nucleolar (punctate)

20% dcSSc

Nucleolar (clumpy) staining coiling bodies

5%

PM-Scl

Complex of 11 proteins 20–110 kDa

Nucleolar (homogeneous)

3%

To or Th

40 kDa protein associated with 7.2 and 8.2 kDa RNAs 70 kDa protein associated with small nuclear RNP complex

Nucleolar (homogeneous)

0.5 g/24 h, or 3+ on urine dipstick • Cellular casts Neurological disorders: • Seizures • Psychosis Haematological disorders: • Haemolytic anaemia • Leucopenia 2000 IU/ mL and sometimes declining during adulthood [2]. Patients develop particularly high levels of antistaphylococcal and anti-candidal IgE and often have immediate wheal-and-flare reactions upon skin prick testing with a variety of foods and inhaled allergens as well as bacterial and fungal antigens. Serum levels of IgG, IgA and IgM are usually normal. Many patients have eosinophilia of the peripheral blood and sputum, and abnormalities of neutrophil and monocyte chemotaxis are occasionally observed. Cell-mediated immunity is often abnormal, as manifested by anergy to skin testing and impaired in vitro lymphoproliferative responses to specific antigens. Autosomal recessive HIES is a separate condition that shares some findings with classic HIES, including markedly elevated serum IgE levels, peripheral eosinophilia, chronic eczematous dermatitis, and recurrent staphylococcal and candidal infections of the skin (including cold abscesses) and respiratory tract [4,5,6]. However, instead

177.23

of pneumatoceles, osteopenia and dental abnormalities, patients with AR-HIES are at risk of severe viral (e.g. molluscum contagiosum, warts, herpes simplex and varicella-zoster) and opportunistic infections, asthma, allergies resulting in anaphylaxis, autoimmunity, central nervous system vasculitis, mucocutaneous squamous cell carcinomas and lymphomas. They have a combined immunodeficiency that is characterized by lymphopenia (deficiency of CD4 T cells > CD8 T cells > B cells), low IgM levels and variable IgG levels as well as elevated IgE levels and peripheral eosinophilia. Differential diagnosis. Diagnostic guidelines for HIES have recently been proposed [14], with criteria including IgE >1000 IU/mL and a weighted score of five clinical features (typical newborn rash, recurrent pneumonia, pathologic bone fractures, characteristic facies and a high palate); these characteristics plus a lack of Th17 cells or the detection of a heterozygous STAT3 mutation allow for a probable or definitive diagnosis, respectively. Hyperimmunoglobulin E syndrome must be differentiated from a number of other disorders that feature elevated IgE levels and dermatitis, including atopic dermatitis, Wiskott– Aldrich syndrome (WAS), Netherton syndrome, Omenn syndrome, DiGeorge syndrome, IPEX syndrome, IL-1 receptor associated kinase-4 (IRAK-4) deficiency, prolidase deficiency and GVHD. Atopic dermatitis and WAS are most easily confused with HIES because of the frequent staphylococcal superinfections, eczematous dermatitis and often very high levels of IgE. The presence of coarse facial features, osteopenia, recurrent pneumonia and cold abscesses help to differentiate HIES from these conditions, and platelet abnormalities also help to distinguish WAS. In a recent study of 70 pediatric patients over a 10-year period who had a serum IgE level of >2000 IU/ mL, 69% had atopic dermatitis and only 8% had HIES; no correlation was observed between the IgE level and diagnosis of HIES [15]. IRAK-4 deficiency leads to defective Toll-like receptor signalling and impaired antibody responses to vaccination. Affected individuals develop recurrent pyogenic sinopulmonary and skin infections, including cold abscesses, but not eczematous dermatitis. Prolidase deficiency is an autosomal recessive disorder caused by defects in the gene encoding peptidase D. In addition to eczematous dermatitis and frequent pyogenic infections, prolidase deficiency features chronic leg ulcers, facial dysmorphism and developmental delay [16]. Although bacterial and candidal abscesses are features of chronic granulomatous disease and myeloperoxidase deficiency, these conditions are not characterized by elevated IgE levels. Treatment. The mainstays of therapy for HIES are antiseptics (e.g. dilute sodium hypochlorite baths), antibiotics

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Chapter 177

(therapeutic and prophylactic), and incision and drainage of abscesses [2]. Interferon-γ has been shown to increase neutrophil chemotaxis and potentially help control infections [17], and IVIg therapy may improve the dermatitis, prevent infections and lower IgE levels [18]. There have been anecdotal reports of improvement of the eczematous dermatitis of HIES with use of omalizumab, a monoclonal antibody directed against IgE [19]. References 1 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. 2 Freeman AF, Holland SM. Clinical manifestations, etiology, and pathogenesis of the hyper IgE syndromes. Pediatr Res 2009;65:32R–7R. 3 Borges WG, Hensley T, Carey JC et al. The face of Job. J Pediatr 1998;133:303–5. 4 Renner ED, Puck JM, Holland SM et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr 2004;144:93–9. 5 Zhang Q, Davis JC, Lamborn IT et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361:2046–55. 6 Engelhardt KR, McGhee S, Winkler S et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 2009;124:1289–302. 7 Holland SM, DeLeo FR, Elloumi HZ et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357:1608–19. 8 Minegishi Y, Saito M, Tsuchiya S et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007;448:1058–62. 9 Milner JD, Brenchley JM, Laurence A et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008;452:773–6. 10 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;25:745–55. 11 Chamlin SL, McCalmont TH, Cunningham BB et al. Cutaneous manifestations of hyper-IgE syndrome in infants and children. J Pediatr 2002;141:572–5. 12 Eberting CL, Davis J, Puck JM et al. Dermatitis and the newborn rash of hyper-IgE syndrome. Arch Dermatol 2004;140:1119–25. 13 Freeman AF, Collura-Burke CJ, Patronas NJ et al. Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics 2007;119:e1121–5. 14 Woellner C, Gertz EM, Schäffer AA et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol 2010;125:424–32. 15 Joshi AY, Iyer VN, Boyce TG et al. Elevated serum immunoglobulin E (IgE): when to suspect hyper-IgE syndrome: a 10-year pediatric tertiary care center experience. Allergy Asthma Proc 2009;30:23–7. 16 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;31:435–40. 17 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;118:383–7. 18 Kimata H. High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol 1995;95:771–4.

19 Bard S, Paravisini A, Avilés-Izquierdo JA et al. Eczematous dermatitis in the setting of hyper-IgE syndrome successfully treated with omalizumab. Arch Dermatol 2008;144:1662–3.

Immunoglobulin deficiencies Several primary immunodeficiencies feature low levels of immunoglobulins. Affected individuals do not typically become symptomatic with recurrent bacterial infections until after 6 months of age, when levels of maternally transmitted antibodies wane. Major forms of immunoglobulin deficiency are discussed below, and additional information on these and other entities is presented in Table 177.7 [1–3].

Immunoglobulin A deficiency The most common immunoglobulin deficiency is selective IgA deficiency, which is found in 1 in 500 people. Between 10% and 15% of affected individuals have clinical manifestations, usually bacterial sinopulmonary infections and Giardia gastroenteritis but also mucocutaneous candidiasis, autoimmune disorders and atopy. Because half of patients have circulating anti-IgA antibodies, it is imperative that they do not receive IVIg or other blood products containing IgA-bearing lymphocytes. Fatal anaphylactic reactions have occurred from the administration of such blood products.

Hyperimmunoglobulin M syndromes Hyperimmunoglobulin M syndromes (HIMS) represent a group of conditions characterized by defective immunoglobulin class switch recombination, which leads to increased production of IgM but decreased synthesis of other immunoglobulin isotypes [4–9]. Inheritance is most often X-linked recessive, but autosomal recessive forms have also been described. Patients have recurrent skin, sinopulmonary and gastrointestinal infections with pyogenic bacteria and (in some forms of HIMS) opportunistic organisms. Other mucocutaneous manifestations include oral (Fig. 177.7) and anogenital ulcers, extensive warts and non-infectious granulomas [10]. Affected individuals are also predisposed to the development of autoimmune disorders, most often cytopenias [11], and have an increased risk of lymphoma. Hypohidrotic ectodermal dysplasia with immunodeficiency is a form of HIMS that is usually inherited in an X-linked recessive manner and caused by NF-κB essential modulator (NEMO) gene mutations that are less deleterious than the male-lethal NEMO defects that underlie incontinentia pigmenti.

Panhypogammaglobulinaemia Panhypogammaglobulinaemia is found in approximately 1 in 25,000 people, and it is classified into two major subdivisions:

Immunodeficiency Syndromes

177.25

Table 177.7 Primary immunoglobulin deficiency disorders Disorder

Gene

Protein (function)

Block in B-cell differentiation at the pro-B- to pre-B-cell transition X-linked (Bruton) BTK Bruton tyrosine agammakinase (pre-B-cell globulinaemia receptor [BCR] signalling) AR agammaglobulinaemia

IGHM

CD79A, CD79B IGLL1 BLNK

AD agammaglobulinaemia

LRRC8A

Ig levels

B cells

Infectious organisms and extracutaneous manifestations

Cutaneous manifestations

All ↓

↓↓

Recurrent infections with Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, Haemophilus influenzae, Pseudomonas aeruginosa and Mycoplasma spp. Hepatitis B and enteroviral infections Lymphomas (∼5%)

Furuncles and cellulitis Ecthyma gangrenosum Eczematous dermatitis Papular dermatitis due to lymphohistiocytic infiltration Non-infectious granulomas Dermatomyositis-like disorder associated with chronic echoviral meningoencephalitis

μ heavy chain of IgM (component of pre-BCR) Igα chain, Igβ chain (bind μ heavy chain) λ5 (surrogate light chain of pre-BCR) B-cell linker protein (binds Bruton tyrosine kinase) Leucine-rich repeat-containing 8 family member A

Defective class switch recombination (e.g. from IgM to IgG, IgA or IgE) and somatic hypermutation Common variable ICOS Inducible coIgG,A ↓; Nl or ↓ Sinopulmonary infections with immunodeficiency stimulator on +/– IgM ↓ encapsulated bacteria Gastroenteritis with Giardi and (CVID) activated T cells Campylobacter (T-cell help for Autoimmune diseases, esp. B-cell thrombocytopenic purpura differentiation) and hemolytic anaemia TNFRSF13B Transmembrane Enteropathy (AD or AR) activator and Non-infectious granulomas/ CAML interactor lymphoproliferation in the (TACI; B-cell lungs, liver, spleen, and GI isotype switching) tract TNFRSF13C B-cell activating Increased risk of lymphoma factor receptor and gastric cancer (BAFFR; B-cell isotype switching) CD19 antigen (B-cell CD19* survival and differentiation) MSH5 Mismatch repair (AD) protein (regulates class switch recombination) Selective IgA deficiency

TNFRSF13B (AD) MSH5 (AD)

See above section

IgA ↓; anti-IgA antibodies in ∼½

Nl

Clinical manifestations in only 10–15% Similar to CVID Asthma and allergic rhinoconjunctivitis

Pyodermas and mucocutaneous candidiasis Extensive warts (Fig. 177.8) and dermatophyte infections Eczematous dermatitis Non-infectious granulomas Autoimmune conditions such as vitiligo, alopecia areata and vasculitis Clonal CD8+ lymphocytic infiltration of the skin

Mucocutaneous candidiasis Eczematous dermatitis Autoimmune conditions such as SLE, vitiligo and lipodystrophia centrifugalis abdominalis

Table 177.7 Continued Disorder

Gene

Protein (function)

Ig levels

B cells

Infectious organisms and extracutaneous manifestations

Cutaneous manifestations

Selective IgM deficiency

?

?

IgM ↓

Nl

Recurrent bacterial infections Autoimmune diseases

Extensive warts Eczematous dermatitis SLE

X-linked hyper-IgM syndrome

CD40LG

CD40 ligand (on T cells)

Nl

AR hyper-IgM syndromes

CD40

CD40 (on B cells)

IgM ↑; isohaemagglutinins ↑; IgA,E,G ↓↓

Pyodermas Extensive warts Oral (Fig. 177.7) and anogenital ulcers Non-infectious granulomas Autoimmune conditions such as SLE

AICDA

Activation-induced cytidine deaminase Uracil-DNA glycosylase

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 centres), HSM and no opportunistic infections Pyogenic bacterial and opportunistic infections Subset of NEMO patients Osteopetrosis Lymphoedema

Pyodermas Ectodermal dysplasia

UNG

Hypohidrotic ectodermal dysplasia with immunodeficiency

IKBKG (NEMO) (X-linked recessive) IKBA (NFKBIA; AD, gain of function)

NF-κB essential modulator (activates NF-κB, which is involved in CD40 signalling) Inhibitor of κBα (inhibits NF-κb)

IgM ↑; +/– IgA ↑; +/– IgG ↓

Nl

Abnormal DNA methylation leading to defective B-cell negative selection and terminal differentiation Immunodeficiency, DNMT3B DNA All ↓ Nl or ↓ Bacterial sinopulmonary and centromeric methyltransferase GI infections instability and facial 3B Abnormal facies, MR anomalies (ICF) syndrome§ Aberrant chemokine signaling WHIM (warts, CXCR4 hypogamma(AD, globulinaemia, gain-ofinfections, function) myelokathexis) syndrome

CXC chemokine receptor 4 (binds CXCL12; key role in bone marrow homeostasis and lymphocyte trafficking)

Delayed maturation of helper T-cell function Transient hypo? ? gammaglobulinaemia of infancy

Pyodermas

Telangiectasias (uncommon) Naevoid hyperpigmentation

IgG ↓; +/– IgA,M ↓

↓

Recurrent bacterial sinopulmonary infections Myelokathexis (mature neutrophils fail to exit the bone marrow)

Cellulitis and pyodermas Extensive verruca vulgaris and condyloma acuminate

IgG,A ↓ (resolves by age 2–3 years)

Nl

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

* CD81 is required for CD19 expression, and a homozygous mutation in the gene encoding CD81 was reported in a patient with hypogammaglobulinemia and autoimmune vasculitis. Of note, a homozygous loss-of-function mutation in the CD20 gene can result in recurrent sinopulmonary infections associated with low IgG levels, a normal total number of B cells, decreased memory B cells and poor T cell-independent antibody responses. Autosomal recessive (AR) unless otherwise specified. 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, 2nd edn. London: Elsevier, 2007.

Immunodeficiency Syndromes

Fig. 177.7 Large ulceration on the side of the tongue in a young boy with X-linked hyperimmunoglobulin M syndrome. These oral ulcerations frequently occur during periods of neutropenia.

1 Agammaglobulinaemia (90% representing the X-linked recessive Bruton variant) resulting from failure of B-cell differentiation [12,13]; and 2 The more prevalent and heterogeneous common variable immunodeficiency (CVI). Common variable immunodeficiency can be inherited in an autosomal dominant or recessive manner, and it is characterized by variable defects in T-cell function as well as decreased levels of at least two classes of immunoglobulins (IgG, IgA > IgM) [14–16]. Some patients with CVI have family members with selective IgA deficiency. Patients with agammaglobulinaemia typically develop recurrent bacterial infections during infancy, usually beginning at around 6 months of life. Ecthyma gangrenosum in the setting of Pseudomonas bacteraemia may be the presenting sign [17]. The skin is the most frequent site of infection, and other cutaneous manifestations include eczematous or granulomatous dermatitis and a dermatomyositis-like disorder associated with chronic echoviral meningoencephalitis. Lymphoma develops in approximately 5% of patients. Flow cytometric analysis of lymphocytes revealing an absence of Bruton tyrosine kinase can confirm the diagnosis of X-linked agammaglobulinaemia. Female carriers may be detected via analysis of B-cell X-inactivation patterns, which are skewed as a reflection of preferential survival of cells with inactivation of the mutated X chromosome. DNA-based prenatal diagnosis is possible when the genetic defect in affected family members is known. Clinical onset of CVI occurs in two peaks: one in schoolaged children and the other in young adults [18]. It can present as early as 2 years of age, but distinguishing CVI from transient hypogammaglobulinaemia of infancy (see Table 177.7) may be difficult in young children. Patients with CVI are predisposed to the development of bacterial sinopulmonary infections, gastroenteritis (especially giar-

177.27

Fig. 177.8 Myriads of recalcitrant warts in a teenage girl with common variable immunodeficiency.

diasis) and skin infections including pyodermas, candidiasis, dermatophytosis and warts (Fig. 177.8). Additional manifestations include eczematous dermatitis, noninfectious granulomas of the skin and internal organs, autoimmune disorders (especially cytopenias) and inflammatory bowel disease [19]. Treatment of panhypogammaglobulinaemia includes antibody replacement with IVIg or subcutaneous immunoglobulins and antibiotic therapy for infections [20]. Tumour necrosis factor inhibitors have been successfully utilized to treat non-infectious granulomas in patients with CVI. References 1 Conley ME. Genes required for B cell development. J Clin Invest 2003;112:1636–8. 2 Grimbacher B, Schäffer AA, Peter HH. The genetics of hypogammaglobulinemia. Curr Allergy Asthma Rep 2004;4:349–58. 3 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;149:410–23. 4 Korthäuser U, Graf D, Mages HW. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 1993;361:539–40. 5 DiSanto JP, Bonnefoy JY, Gauchat JF et al. CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM. Nature 1993;361:541–3. 6 Revy P, Muto T, Levy Y et al. Activation-induced cytidine deaminase (AIS) deficiency causes the autosomal recessive form of the hyperIgM syndrome (HIGM2). Cell 2000;102:565–75. 7 Durandy A, Peron S, Fischer A. Hyper-IgM syndromes. Curr Opin Rheumatol 2006;18:369–76. 8 Lougaris V, Badolato R, Ferrari S, Plebani A. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev 2005;203:48–66. 9 Durandy A, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev 2005;203:67–79.

177.28

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10 Jesus AA, Duarte AJ, Oliveira JB. Autoimmunity in hyper-IgM syndrome. J Clin Immunol 2008;28:S62–6. 11 Chang MW, Romero R, Scholl PR et al. Mucocutaneous manifestations of the hyper-IgM Immunodeficiency syndrome. J Am Acad Dermatol 1998;38:191–6. 12 Vetrie D, Vorechovsky I, Sideras P et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of proteintyrosine kinases. Nature 1992;361:226–33. 13 Tsukada S, Saffran DC, Rawlings DJ et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993;72:279–90. 14 Castigli E, Wilson SA, Garibyan L et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 2005;37:829–34. 15 Park MA, Li JT, Hagan JB et al. Common variable immunodeficiency: a new look at an old disease. Lancet 2008;372:489–502. 16 Bonilla FA, Geha RS. Common variable immunodeficiency. Pediatr Res 2009;65:13–19R. 17 Ng W, Tan CL, Yeow V et al. Ecthyma gangrenosum in a patient with hypogammaglobulinemia. J Infect 1998;36:331–5. 18 Glocker E, Ehl S, Grimbacher B. Common variable immunodeficiency in children. Curr Opin Pediatr 2007;19:685–92. 19 Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999;92:34–48. 20 Ballow M. Immunoglobulin therapy: methods of delivery. J Allergy Clin Immunol 2008;122:1038–9.

IPEX syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is an X-linked recessive disorder caused by FOXP3 gene mutations that result in abnormal development of regulatory T cells. Affected individuals typically present during infancy with severe diarrhoea related to autoimmune enteropathy and develop a variety of autoimmune endocrinopathies, most often early-onset type 1 diabetes mellitus and thyroiditis, and cytopenias. Most IPEX patients develop widespread eczematous dermatitis and elevated IgE levels during early infancy, and this is often 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, chronic urticaria and bullous pemphigoid [1]. Autoimmune endocrinopathies, enteropathy and eczematous dermatitis have also been described in patients with IL-2 receptor α chain (CD25) deficiency (see Table 177.3) [2]. References 1 Halabi-Tawil M, Ruemmele FM, Fraitag S et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol 2009;160:645–51. 2 Caudy AA, Reddy ST, Chatila T et al. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linkedlike syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol 2007;119:482–7.

Leucocyte adhesion deficiency Leucocyte adhesion deficiency (LAD) is a group of autosomal recessive disorders that affect the ability of neutrophils, monocytes and T cells to adhere to vascular endothelial cells and migrate to sites of tissue injury and infection [1–3]. Three major subgroups have been described: LAD-I, LAD-II and LAD-III (also referred to as LAD-I variant).

Pathogenesis. The adherence of leucocytes involves a group of cell surface glycoproteins (integrins) that share a 95-kDa β2 subunit (CD18). The CD18 β2 integrin subunit can be linked to different α-chains to form three distinct cell surface glycoproteins: CD11a (lymphocyte functionassociated antigen 1 [LFA-1]), CD11b (complement receptor type 3 [iC3b receptor or CR3], Mac-1) and CD11c (complement receptor type 4 [CR4], p150,95). The principal ligand for these glycoproteins is intracellular adhesion molecule 1 (ICAM-1), which has key functions in the initiation and evolution of inflammation in skin and other tissues. LAD-I is caused by mutations in the ITGB2 gene that encodes CD18, and it presents with dysfunction of all three glycoproteins. This results in profoundly impaired leucocyte firm adhesion to the vascular endothelium and extravasation into sites of inflammation as well as defective chemotaxis and phagocytosis by neutrophils and monocytes. LAD II is caused by mutations in the FUCT1 gene, which encodes a GDP-fucose transporter that is necessary for formation of sialyl-Lewis X [4]. Fucosylated sialylLewis X on the surface of leucocytes normally interacts with E- and P-selectins on endothelial cells during processes of tethering and rolling, which target leucocytes to sites of inflammation. These contacts between leucocytes and the blood vessel wall are defective in patients with LAD-II. In order to undergo firm adhesion and subsequently extravasate, circulating leucocytes need to activate cellsurface integrins in situ and thereby increase their affinity and avidity for endothelial ligands. Patients with LAD-III have impaired integrin activation in haematopoietic cells, which leads to defective leucocyte β1 and platelet β3 integrins as well as leucocyte β2 integrins. Abnormalities in two genes on chromosome 11q13, both of which encode effectors of integrin activation in haematopoietic cells, have been identified in the same LAD-III patients from consanguineous Turkish kindreds: 1 A putative splice site mutation in RAS guanyl releasing protein 2 (RASGRP2); and 2 A nonsense mutation in kindlin-3 (FERMT3) [5,6]. However, other LAD-III patients were found to have nonsense mutations in FERMT3 but no mutations in

Immunodeficiency Syndromes

RASGRP2, demonstrating that FERMT3 mutations are the cause of LAD-III [6]. Clinical features. Patients with LAD have frequent skin infections (most often of the face and perianal area), otitis media and pneumonias caused by pyogenic bacteria. Affected individuals often present with cellulitis and necrotic abscesses with relatively little purulence. Lifethreatening bacterial, fungal or (less frequently) viral infections may develop. Approximately 80% of patients with severe LAD-I (90%. Transplantation of haploidentical parental stem cells, which can be depleted of post-thymic T cells to reduce the risk of GVHD, typically requires some chemotherapeutic conditioning to facilitate engraftment and results in ≤80% survival. In utero injection of haploidentical CD34+ cells has also been used to treat X-linked SCID [9]. SCID patients often require IVIg replacement therapy for persistent B-cell deficiency following haematopoietic stem cell transplantation, and T-cell function may decline over time. Enzyme replacement via injection of polyethylene glycol-conjugated ADA has resulted in improved immune function in infants with ADA deficiency. Gene therapy utilizing ex vivo transduction of autologous CD34+ cells with a retroviral vector has been successfully performed in more than 50 children with X-linked SCID or ADA deficiency [8,10–12]. Follow-up studies on 19 of these patients (4 months to 4 years after treatment) showed that the retrovirus preferentially integrated into transcrip-

tional start sites and coding regions of active genes in both circulating T cells and preinfusion transduced CD34+ cells. Approximately 25% of integrations in T cells were clustered at common sites, suggesting in vivo selection of transduced cells with a higher capacity for engraftment, survival and proliferation [13]. Although T- and NK-cell function was restored, at least five patients with X-linked SCID have developed T-cell leukaemias 2–6 years after treatment, which appears to be related to activation of proto-oncogenes such as LM02 by the retroviral vector [14]. This has raised concerns regarding the safety of gene therapy, leading to protocol modifications and exploration of alternative approaches such as lentiviral vectors and in situ gene transfer. References 1 Fischer A, Le Deist F, Hacein-Bey-Abina S et al. Severe combined immunodeficiency: a model disease for molecular immunology and therapy. Immunol Rev 2005;203:98–109. 2 Buckley RH. The multiple causes of human SCID. J Clin Invest 2004;10:1409–11. 3 Gaspar HB, Gilmour KC, Jones AM. Severe combined immunodeficiency: molecular pathogenesis and diagnosis. Arch Dis Child 2001;84:169–73. 4 Postigo Llorente C, Ivars Amorós J, Ortiz de Frutos FJ et al. Cutaneous lesion in severe combined immunodeficiency: two case reports and a review of the literature. Pediatr Dermatol 1991;8:314–21. 5 De Raeve L, Song M, Levy J et al. Cutaneous lesions as a clue to severe combined immunodeficiency. Pediatr Dermatol 1992;9:49–51. 6 Buckley RH, Schiff SE, Schiff RI et al. Hematopoeietic stem cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508–16. 7 Haddad E, Landais P, Friedrich W et al. Long-term immune reconstitution and outcome after HLA-non identical T-cell depleted bone marrow reconstitution for severe combined immunodeficiency, a European retrospective study of 116 patients. Blood 1998;91: 3646–53. 8 Thrasher AJ. Gene therapy for primary immunodeficiencies. Immunol Allergy Clin North Am 2008;28:457–71. 9 Flake AW, Roncarolo MG, Puck JM et al. Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. N Engl J Med 1996;335:1806–10. 10 Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000;288:669–72. 11 Aiuti A, Slavin S, Aker M et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296:2410–3. 12 Gaspar HB, Parsley KL, Howe S et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gamma retroviral vector. Lancet 2004;364:2181–7. 13 Bushman FD. Retroviral integration and human gene therapy. J Clin Invest 2007;117:2083–6. 14 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;117:3132–42.

Wiskott–Aldrich syndrome Wiskott–Aldrich syndrome is an X-linked recessive disorder that classically manifests with recurrent pyogenic

Immunodeficiency Syndromes

177.33

infections, bleeding resulting from thrombocytopenia and platelet dysfunction, and recalcitrant eczematous dermatitis [1–3]. This full triad develops in a minority of affected individuals, and platelet abnormalities are the most constant feature. Most patients are boys, but girls are occasionally affected in settings of selective inactivation of the unaffected X chromosome or homozygosity for a mild mutation. The incidence of WAS is approximately 1 in 250,000 male births in European populations, and the condition is less common in black people and Asians. Pathogenesis. Wiskott–Aldrich syndrome results from loss-of-function mutations in the WASP gene, which is constitutively expressed in cells of haematopoietic lineage. WAS protein (WASp) transduces signals from the cell surface to the actin cytoskeleton. This leads to activation of actin polymerization and facilitation of processes such as immune synapse formation, T-cell activation, phagocytosis and cellular polarization and migration [1–3]. WASp also has roles in homeostasis of peripheral B cells and activation of regulatory T cells, with the latter helping to explain the autoimmune manifestations of WAS [4]. Platelets from WAS patients are small and structurally abnormal, and they have a reduced half-life that is partly caused by increased destruction in the spleen. Some studies have shown that premature pro-platelets are released from the bone marrow because of defective podosome formation. Loss-of-function WASP mutations also underlie isolated X-linked recessive thrombocytopenia, while gain-of-function WASP mutations can cause X-linked recessive congenital neutropenia (see Table 177.4) [1]. Female carriers of WAS can be detected by their selective inactivation of the abnormal X chromosome in lymphocytes and platelets [5]. DNA-based prenatal diagnosis of WAS has been performed. Clinical features. Thrombocytopenia and platelet dysfunction are present from birth, so early clinical signs of WAS often include epistaxis and petechiae (Fig. 177.9) or ecchymoses of the skin and oral mucosa. Haematemesis, melaena and haematuria are also frequent manifestations. Eczematous dermatitis usually develops during the first few months of life and fulfils the diagnostic criteria for atopic dermatitis. The face, scalp and flexural areas are the most severely affected, although patients commonly have widespread involvement with progressive lichenification (Fig. 177.10). Excoriated areas typically have serosanguinous crusting and petechiae or purpura. Secondary bacterial infections, eczema herpeticum and molluscum contagiosum represent additional complications.

Fig. 177.9 Numerous petechiae in a boy with Wiskott–Aldrich syndrome, providing evidence of thrombocytopenia and platelet dysfunction.

Fig. 177.10 Atopic dermatitis with marked lichenification and erosions covered with serosanguinous crust in a boy with Wiskott–Aldrich syndrome.

Recurrent bacterial infections begin during infancy as levels of placentally transmitted maternal antibodies diminish, and encapsulated organisms such as Strep. pneumoniae, H. influenzae and Neiserria meningitidis predominate. Patients often develop furunculosis, otitis externa and media, pneumonia, sinusitis, conjunctivitis, meningitis and septicaemia. They also have increased susceptibility to infections with Pneumocystis jiroveci and herpes simplex virus [2]. Most children with WAS develop one or more autoimmune diseases such as cutaneous small vessel vasculitis (frequently associated with painful oedema), arthritis, cytopenias, inflammatory bowel disease and CNS vasculitis [6]. Patients with WAS are also predisposed to the development of food allergies, asthma, hepatosplenomegaly and lymphadenopathy. Non-Hodgkin lymphoma occurs in approximately 20% of individuals with WAS, with a higher risk in adults and those with a history of autoimmune disorders. Diffuse large B-cell lymphomas with extranodal and brain involvement

177.34

Chapter 177

(similar to AIDS-related lymphomas) are particularly common. Wiskott–Aldrich syndrome is characterized by persistent thrombocytopenia (typically 1000–80,000 platelets/ mm3) and a low mean platelet volume (3.5–5.0 fL). Lymphopenia and eosinophilia are occasional manifestations, and leucocyte chemotaxis is defective. Serum levels of IgM and IgG2 are usually low, but levels of IgA, IgE and IgD tend to be elevated. Antibody responses to polysaccharide antigens are severely diminished, and older patients may develop skin test anergy and decreased in vitro responses to mitogens [2]. Prognosis. The clinical course of WAS is progressive, usually resulting in death by adolescence. In patients who do not receive haematopoietic stem cell transplantation, the most common causes of death are infection (40%), bleeding (25%) and malignancy (25%) [7]. Patients with no detectable WASp in peripheral blood mononuclear cells upon flow cytometric or immunoblot analysis tend to have more severe disease and shorter survival. Differential diagnosis. Several other immunodeficiencies are characterized by eczematous dermatitis as well as increased susceptibility to infections (see Table 177.1), but WAS can usually be distinguished by the bleeding tendency and laboratory evidence of microthrombocytopenia. Treatment. Haematopoietic stem cell transplantation is the treatment of choice for WAS. Full engraftment results in normal platelet number and function, normalization of immunological status and, if T cells engraft, clearance of the dermatitis [1]. Children younger than 5 years of age who receive a transplant from an HLA-identical donor (sibling or unrelated) have a survival rate of >85%; in contrast, older patients and those with mismatched

donors have survival rates of approximately 50% [1]. Clinical trials of gene therapy using retrovirally transduced, WASp-reconstituted, autologous CD34+ cells are in progress. Minimization of infectious and haemorrhagic complications is the major goal of supportive therapy for WAS [2]. Prophylactic use of antibiotics and IVIg can decrease the incidence of serious infections and perhaps improve the eczematous dermatitis [4,8]. However, topical corticosteroids remain the mainstay for treatment of the latter. Although splenectomy can reduce the bleeding diathesis of WAS, it increases the risk of infections with encapsulated organisms [9]. Platelet transfusions should be administered prior to surgical procedures and in instances of severe haemorrhage. References 1 Notarangelo LD, Miao CH, Ochs HD. Wiskott–Aldrich syndrome. Curr Opin Hematol 2008;15:30–6. 2 Ochs HD, Thrasher AJ. The Wiskott–Aldrich syndrome. J Allergy Clin Immunol 2006;117:725–38. 3 Orange JS, Stone KD, Truvey SE, Krzewski K. The Wiskott–Aldrich syndrome. Cell Mol Life Sci 2004;61:2361–85. 4 Humblet-Baron S, Sather B, Anover S et al. Wiskott–Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest 2007;117:407–18. 5 Winkelstein JA, Fearon E. Carrier detection of the X-linked primary immunodeficiency diseases using X-chromosome inactivation analysis. J Allergy Clin Immunol 1990;85:1090–7. 6 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:e622–7. 7 Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of Wiskott–Aldrich syndrome. J Pediatr 1994;125:876–85. 8 Conley ME, Saragoussi D, Notarangelo L et al. An international study examining therapeutic options used in treatment of Wiskott–Aldrich syndrome. Clin Immunol 2003;109:272–7. 9 Litzman J, Jones A, Hann I et al. Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott–Aldrich syndrome. Arch Dis Child 1996;75:436–9.

178.1

C H A P T E R 178

Graft-Versus-Host Disease John Harper1 & Paul Veys2 1

Paediatric Dermatology and 2Bone Marrow Transplantation Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK

Graft-versus-host disease, 178.1 Graft-versus-leukaemia effect, 178.11

Conclusion: why graft-versus-host disease is important to the dermatologist, 178.11

Graft-versus-host disease Definition. Graft-versus-host disease (GVHD) is the term used to describe the clinical manifestations and histopathological features provoked by a graft-versus-host reaction (GVHR). A GVHR occurs when immunocompetent cells of the graft react with the tissues of an immunosuppressed histoincompatible recipient. Although this response has been known for many years and has been studied in several animal species, it has come to the fore as a clinical problem in humans as a major complication of hematopoietic cell transplantation (HCT), which is now widely used for the treatment of haematological malignancies, bone marrow failure, immunodeficiency, metabolic and gastrointestinal diseases. Billingham [1] described the essential conditions for the occurrence of the reaction as follows. 1 There is a profound depression of cellular immunity of the recipient, otherwise the graft is rejected. 2 The patient must have received an allograft of lymphoid immunocompetent cells in sufficient quantity. 3 There is recognition by the graft of foreign antigens in the tissues of the host. Histoincompatibility differences may be major, carried on the histocompatibility antigens of the HLA system, the major histocompatibility complex (MHC) in humans, or there may be minor differences that are more difficult to define, as in the case of HLA-identical siblings in whom a GVHR may occur despite the graft and recipient having identical major HLA antigens.

Clinical situations in which graft-versus-host disease may occur Graft-versus-host disease may occur in a human fetus with a congenital cellular immunodeficiency due to the transplacental passage of maternal lymphocytes (maternal

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

GVHD) [2]. Lymphocytes are known to cross the placental barrier either before or during birth and may react against fetal antigens. There may also be GVHD in utero following a blood transfusion for rhesus incompatibility (erythroblastosis fetalis) [3] (transfusion GVHD). In a neonate or infant with severe immune deficiency, transfusion GVHD may be provoked by administration of whole blood or blood products such as packed red cells, platelets and even fresh plasma [4,5]. Transfusion GVHD may also occur in patients with disseminated malignancies, who have a depressed immune system due to the malignancy itself and to cytotoxic drugs [6,7]. This risk must be recognized in such susceptible individuals and all blood products should be irradiated to prevent a GVHR. The risk of transfusion GVHD may have been reduced in the UK as a result of leucocyte depletion for all red cell and platelet transfusions, which was introduced in 2001 to reduce the potential transmission of Creutzfeldt–Jakob disease. Graft-versus-host disease occurs in patients who are given therapeutic grafts of haemopoietic cells, i.e. bone marrow, placental blood [8], liver and thymus. Graftversus-host disease is a common and often serious complication of HCT, and it is in this clinical context that GVHD is most frequently encountered. History

Experimental animal models of graft-versus-host disease In 1916, Murphy [9] was the first to describe the GVHR. He observed that inoculation of the chorioallantoic membranes of young (7-day) chicken embryos with fragments of certain tissues (spleen and bone marrow) from adult chicken donors resulted in enlargement of the host spleen. The effect was misinterpreted as splenic stimulation and the implications of this were not fully realized until the 1950s. When immunologically competent cells of an adult animal are injected into a newborn of a different strain, immunological immaturity of the recipient allows the

178.2

Chapter 178

graft to take, with the development of GVHD, which was originally described by Billingham and Brent [10] as runt disease. A similar situation is brought about by injecting a firstgeneration hybrid, resulting from a cross between two pure strains, with lymphoid cells of either parent. The term secondary disease denotes GVHD in a lethally irradiated animal reconstituted by the administration of foreign haematological cells. This experimental model is called a radiation chimera. The most studied animals are rodents: mice, rats and hamsters. In all of these experimental models of GVHD cutaneous lesions have been observed, the severity of which varies with the animal species.

Historical summary of human graft-versus-host disease The 1950s and 1960s saw the early attempts at human HCT, both autologous and allogeneic. Allogeneic HCT was initially plagued by the immunological problems of graft rejection and GVHD, and only 1 in 10 of the early allogeneic bone marrow transplants (BMTs) achieved a clinical improvement [11]. Much of the early pioneering work was performed by Thomas et al. [12] using dogs to develop effective total body irradiation schedules and introducing methotrexate to prevent GVHD. The characterization of the HLA system opened a new era in HCT, with transplants being carried out between matched sibling donor–recipient pairs. Throughout the 1970s and 1980s, there was a rapid expansion in the number of allogeneic HCT procedures, facilitated by the introduction of ciclosporin A prophylaxis against GVHD [13]. During the 1980s and 1990s, major advances occurred in the prophylaxis of GVHD, with the introduction of various negative depletion strategies to remove T-cells from the donor bone marrow. Most recently, the major problem of GVHD in the haploidentical (parental) donor setting has been overcome by positive selection of CD34+ progenitors from a large number of peripheral blood progenitor cells, indirectly achieving a very high level of T-cell depletion using a method of high-gradient magnetic-activated cell sorting (MACS) [14]. Finally, the antileukaemic properties of the GVHR have been recognized and a graft-versus-leukaemia (GVL) effect is deliberately employed in some patients with susceptible leukaemia. Pathogenesis

Acute disease The essential hypothesis is that GVHD occurs as a result of an interaction of donor T-lymphocytes with recipient histoincompatible antigens. The T-lymphocytes become sensitized to recipient antigens, differentiate in vivo and then directly, or through secondary mechanisms, attack

recipient cells, producing the clinical symptomatology of acute GVHD (aGVHD). In HCT, donor lymphocytes are infused into a host that has been profoundly damaged. The effects of the underlying disease, prior infection and the conditioning regime may result in substantial proinflammatory changes in endothelial and epithelial cells. Donor cells rapidly encounter not only a foreign environment, but also one that has been altered to promote the activation and proliferation of inflammatory cells by the increased expression of adhesion molecules [15], cytokines and cell surface recognition molecules [16]. Immune imbalance during recovery of immunity may also play a role in GVHD, as illustrated by an imbalance in T-cell subset recovery and the occurrence of skin GVHD following administration of ciclosporin A to patients undergoing autologous transplantation [17]. The onset of aGVHD is determined by the time required for the infused lymphocytes to proliferate and differentiate. Mature donor T-cells recognize recipient peptide– HLA complexes (alloantigens) on the surface of antigen-presenting cells (APCs), in which both the HLA molecules and the bound peptides are foreign. The peptides represent minor histocompatibility antigens (mHAs), some of which have been identified [18–20]. In mouse models of GVHD, CD4+ cells induce GVHD to MHC class II (HLA-DR, -DP, -DQ) differences, and CD8+ cells induce GVHD to MHC class I (HLA-A, -B, -C) differences [21]. In HLA-matched HCTs, GVHD may be induced by either subset or simultaneously by both. Cytokines produced in response to alloantigens are predominantly secreted by the CD4+ (T-helper type 1, or Th1) subset of T-cells [22]. Both interleukin 2 (IL-2) and interferon-γ (IFN-γ) play a central role in further T-cell activation, induction of cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cell responses, and the priming of additional donor and residual mononuclear phagocytes to produce IL-1 and tumour necrosis factor-α (TNF-α) [23]. The balance in Th1 and Th2 cytokines is critical for the development (or prevention) of aGVHD. Keratinocytes have been shown to express HLA-DR antigen during early and established GVHD. Keratinocyte HLA-DR expression can be induced in vitro by IFN-γ [24], suggesting that during GVHD sensitized T-lymphocytes release cytokines, which induce the expression of HLA-DR. The induced HLA-DR then becomes a target for CTLs directed against class II antigens. The mechanism leading to tissue damage in GVHD is complex. As well as the cellular damage caused by CTLs and NK cells, inflammatory cytokines play an important role. Tumour necrosis factor-α can cause direct tissue damage by inducing necrosis of target cells, or it may induce tissue destruction by apoptosis, or programmed cell death. The induction of apoptosis occurs after activation of the TNF-α–Fas antigen pathway [25].

Graft-Versus-Host Disease

The target organs of GVHD support the close relationship between infection and GVHD. The skin, gastrointestinal tract and liver all share exposure to endotoxin and other bacterial products that can trigger and amplify local inflammation. These tissues have a large proportion of APCs, such as macrophages and dendritic cells, that may enhance the GVHR. Similarly, viral infections, in particular cytomegalovirus (CMV), herpes viruses and Epstein– Barr virus, are frequent in patients undergoing HCT and may trigger or aggravate GVHD. Cells infected with a viral agent can induce neoantigens on their surface. The immune system may then recognize these cells as foreign and destroy them, even when both the infected cells and the immunologically competent donor cells have the same histocompatibility antigens.

Chronic disease Chronic manifestations of GVHD [26] are thought to be due to the generation of alloreactive and autoreactive T-cell clones [27]. These are derived from the engrafted donor lymphoid stem cells, which differentiate entirely within the recipient. The mechanism of the sclerotic change in the skin most likely relates to the effect of cytokines on collagen synthesis. In vitro experiments have shown that collagen synthesis by fibroblasts is increased by the cytokines present in the supernatant of a phytohaemagglutinin (PHA)-stimulated lymphocyte culture [28,29]. Holmes et al. [30] reported a patient with disseminated carcinoma, who developed cutaneous and systemic features closely resembling those seen in chronic GVHD. The authors suggested the possibility that a GVH-like reaction was induced by alteration of ‘self-antigens’, consequent upon the malignancy. This case lends support to the suggestion that GVHRs are not simply limited to patients with bone marrow grafts or blood product transfusions but may develop in a situation in which there has been an alteration in self-antigens. Such a change in selfantigens could occur as a result of viral infections, malignant disease or certain drugs. This broader concept of GVHD may help to advance our understanding of the pathogenesis of the so-called ‘idiopathic’ disorders, i.e. lichen planus, toxic epidermal necrolysis (TEN) and scleroderma. Pathology

Histopathology Histopathological features of a skin biopsy of GVHD are classified into four grades (Table 178.1). The earliest change is perivascular cuffing of lymphocytes, often seen around dilated blood vessels and swollen endothelial cells. These changes occur within the first 24 h. The next stage is marked by a mild to moderate lymphocytic infiltrate in the upper dermis and dermoepidermal junction

178.3

Table 178.1 Histopathological grades of acute cutaneous graft-versushost reaction Grade

Definition

1

Focal or diffuse vacuolar alteration of basal epidermal cells

2

Vacuolar alteration of basal epidermal cells; spongiosis and dyskeratosis of epidermal cells

3

Formation of subepidermal cleft in association with spongiosis and dyskeratosis

4

Complete loss of epidermis

Fig. 178.1 Established graft-versus-host disease: histopathology of the skin, showing basal cell vacuolation, lymphocytic infiltrate and individual cell necrosis of keratinocytes (grade 2) (haematoxylin and eosin).

at sites of focal basal cell vacuolation. Established GVHD is characterized by more extensive basal cell vacuolation with disruption of the basement membrane, lymphocytes migrating into the epidermis, and intercellular oedema of the epidermis (spongiosis) (Fig. 178.1). Degenerate keratinocytes (individual cell necrosis) are seen scattered throughout the epidermis, some with a pyknotic nucleus and eosinophilic, hyalinized cytoplasm. These necrotic keratinocytes are sometimes associated with one or more satellite lymphocytes, an association referred to as satellite cell necrosis [24] (Fig. 178.2). In fulminant GVHD there is separation of the epidermis at the dermoepidermal junction, with widespread desquamation of skin and necrosis of the overlying epidermis. Histopathological features of chronic GVHD show the epidermis to be atrophic with hyperkeratosis, thickening of the basement membrane and condensed/homogeneous connective tissue in the upper dermis. Basal layer vacuolar degeneration, inflammation and eosinophilic body formation are rare or absent. The dermis shows thickened, hyalinized collagen bundles, together with destruction of the adnexal structures.

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Chapter 178

Fig. 178.2 Satellite cell necrosis in graft-versus-host disease (haematoxylin and eosin).

In the setting of BMT, a skin biopsy is the preferred method of establishing a diagnosis of GVHD and in monitoring its course. Although GVHD can be recognized early in its course as an erythematous maculopapular rash, there is no one clinical or pathological feature that is specifically diagnostic of GVHD [31]. Individual keratinocyte cell necrosis may be induced by total body irradiation [32] and various cytotoxic drugs [33,34]. Evidence that cytotoxic agents can produce mild epidermal damage, including necrosis of occasional keratinocytes in association with a sparse lymphocytic infiltrate and some vacuolar alteration of basal epidermal cells, comes from studies of psoriatic patients treated with methotrexate and hydroxyurea [35,36]. Similar changes have been described with bleomycin, adriamycin and cyclophosphamide [34]. The author ’s results showed 7 out of 17 pretransplant skin biopsies to be abnormal [37]. The specificity of the histological features of aGVHD was questioned by Sale and the Seattle team [34]. Some 49 skin biopsy specimens taken from marrow transplant patients, who received allogeneic, syngeneic or autologous marrow, were coded and studied ‘blindly’ by three pathologists. These authors concluded the following: 1 The early cutaneous histological changes do not permit a diagnosis of GVHD, except late in its evolution (after the 35th–40th day) when the effects of the cytotoxic agents have normally disappeared. 2 The presence of eosinophilic bodies, with or without satellite lymphocytes, is a necessary criterion, but is insufficient to confirm the diagnosis of GVHD as it can be caused by cytotoxic drugs. Their presence is, however, rare after the 19th day in patients who have received only cyclophosphamide and total body irradiation. 3 Certain situations require the repetition of skin biopsies at intervals of a few days. If epidermal lesions persist,

Fig. 178.3 CD8+ T-lymphocytes at the dermoepidermal junction and in the epidermis demonstrated using an indirect immunoperoxidase technique.

the probability that they are due to cytotoxic agents decreases as the probability of GVHD increases. The histological diagnosis of GVHD therefore must take into account all other available relevant data. The author ’s findings stress the importance of taking a pretransplant skin biopsy as a baseline.

Immunopathology In a study by the author (J.H.) and co-workers, 14 skin biopsies of GVHD [38] were examined by an indirect immunoperoxidase technique using a panel of monoclonal antibodies. Controls included pretransplant skin biopsies, skin from normal healthy volunteers and skin from patients with lichen planus and cutaneous T-cell lymphoma. The results demonstrated the following immunopathological features of cutaneous GVHD: 1 The lymphoid infiltrate of aGVHD is composed of mainly T-lymphocytes. 2 Helper (CD4+) T-lymphocytes, of donor origin, appear early and accumulate around blood vessels. 3 Suppressor/cytotoxic (CD8+) T-lymphocytes are found predominantly at the dermoepidermal junction and in the epidermis (Fig. 178.3). 4 There is a significant reduction in the number of detectable Langerhans cells in aGVHD. 5 Acute GVHD is associated with HLA-DR expression of keratinocytes (Fig. 178.4). 6 There is a persistence of increased numbers of perivascular helper (CD4+) T-lymphocytes in chronic GVHD. The presence of CD8+ cells in contact with destroyed keratinocytes strongly infers a cytopathic potential of these cells. Anti-Leu-7, which stains human NK cells as well as a subset of CD8+ cells, were few in number. HLA-DR (Ia) staining of keratinocytes occurred in aGVHD, lichen planus and in two out of the six patients

Graft-Versus-Host Disease

178.5

Table 178.2 Incidence of graft-versus-host disease in patients after bone marrow transplant No. of patients Aplastic anaemia Leukaemias ALL AML Fanconi anaemia Immunodeficiency diseases Inborn errors of metabolism Total

Fig. 178.4 HLA-DR expression of basal keratinocytes.

with cutaneous T-cell lymphoma. HLA-DR expression was not observed in normal or pretransplant skin biopsies. Studies in rats have shown that Ia staining can be induced in the skin during contact hypersensitivity reactions but is absent following mechanical or chemical damage to the skin [39]. Scheynius and Tjernlund [40] have demonstrated the induction of HLA-DR on keratinocytes during the tuberculin reaction. These facts suggest that HLA-DR or Ia staining by keratinocytes is a consequence of cellular immunity. In a murine model of acute cutaneous GVHD, Breathnach and Katz [41] have shown that the keratinocytes themselves synthesize Ia antigen in aGVHD. The observation of a reduction in the number of Langerhans cells in aGVHD was first made by Lampert et al. [42] and Mason et al. [43] in F1 hybrid rats and subsequently in human GVHD [44]. However, in these studies there were no controls. The author ’s studies (J.H.) confirmed that there is a significant decrease in the number of CD1+ dendritic (Langerhans) cells detectable in the skin biopsies of aGVHD, although there was a slight reduction in the number of Langerhans cells in pretransplant skin biopsies compared with the normal controls, presumably related to chemotherapy. These results suggest that the Langerhans cell is a primary target in cutaneous GVHD [37,38]. When Campath 1H (a monoclonal antibody directed against CD52) is used in vivo to T-cell deplete the graft, it may also reduce GVHD by removing Langerhans cells from the recipient. Clinical features. Tissues that are primary targets include the epithelium of the skin, gastrointestinal tract and liver. The cutaneous signs are usually the earliest manifestation of GVHD [27,37,45]. It is traditional to divide the clinical manifestations into acute and chronic phases, occurring before and after day 100 respectively; this distinction is difficult to define precisely as acute lesions can transform

GVHD

16

12

50 5 3 11 15 100

42 3 3 4 12 76

ALL, acute lymphocytic leukaemia; AML, acute myelocytic leukaemia. Adapted from Harper 1985 [37].

and progress imperceptibly into chronic lesions, and a syndrome resembling aGVHD may develop well after day 100 and has particularly been described following the recently introduced very-low-intensity BMT procedures. New diagnostic criteria have therefore defined chronic GVHD based on actual physical manifestations rather than by the timing of its occurrence [46]. Out of the 100 BMT patients studied by the author (J.H.) [37], 76 developed GVHD (Table 178.2). Fever and skin rash occurred in all 76 patients (100%); 46 patients (61%) had acute gastrointestinal symptoms, and 28 patients (37%) had hepatic involvement. Out of the 76 patients, 23 (30%) developed chronic skin changes of GVHD.

Acute disease The most common presentation is a faint, erythematous maculopapular eruption on the trunk and limbs (Fig. 178.5), often starting on the face and affecting the palms (Fig. 178.6) and soles. Typically, aGVHD is seen at the time of haemopoietic reconstitution, 10–14 days posttransplant; in the author ’s series this ranged from day 5 to day 60 post-graft. The more severe forms of aGVHD develop an erythroderma and subsequent epidermal separation, resulting in the appearance of bullae. The occurrence of TEN as a manifestation of fulminant aGVHD in humans was reported by Peck et al. [47] and was witnessed in 3 out of the author ’s 100 patients. This has a high mortality: of the 100 patients, one died as a result of overwhelming aGVHD and the other two died of septicaemia. In areas of blister formation the separation is dermoepidermal, similar to that seen in drug-induced TEN. The severity of aGVHD is dependent on the degree of histoincompatibility and was inevitably worse when mismatched donors were used. Other manifestations of aGVHD include fever and gastrointestinal and liver disturbance. Intestinal involvement

178.6

Chapter 178 Table 178.3 Clinician’s grading of graft-versus-host disease: individual system Skin (rash, % BSA)

GI tract (diarrhoea, mL/kg/day)

Liver (bilirubin, µmol/L)

Grade

50 Desquamation

8–15 16–25 >25 Pain/ileus

12–20 20–50 >50 Raised AST/ALT

1 2 3 4

BSA, body surface area; ALT, alanine transaminase; AST, aspartate transaminase; GI, gastrointestinal.

Table 178.4 Clinician’s grading of graft-versus-host disease: overall grading

Fig. 178.5 Acute graft-versus-host disease: the early presentation of a morbilliform rash.

Skin

GI tract

Liver

Grade

1–2 1–3 2–3 2–4

– 1 2–3 2–4

– 1 2–3 2–4

I II III IV

Although there remains a considerable degree of unpredictability in the occurrence of GVHD, there are many recognized risk factors. These include: HLA disparity between donor and recipient; minor MHC antigen differences, e.g. Y chromosome in male recipients of parous female marrow [49]; intensity of the pretransplant treatment [49]; increasing donor and recipient age; and viral infection after transplant [50]. Among recipients of umbilical cord blood (UCB) transplants there was no aGVHD of severity greater than grade I in recipients who were HLA matched or mismatched for one or two antigens [51]. Depending on all of these factors, the risk of GVHD can vary from 15% to 70% [52]. Fig. 178.6 Acute graft-versus-host disease: desquamation of the palms.

is manifested by diarrhoea, nausea and vomiting. Abdominal pains and ileus are indicative of severe disease. Hepatic involvement causes an elevation in aspartate transaminase (AST) and alanine transaminase (ALT), hyperbilirubinaemia of the conjugated type and an elevation of alkaline phosphatase. Individual organ system grading and calculation of an overall GVHD grade are shown in Tables 178.3 and 178.4, respectively. Patients with GVHD limited to grade I or II severity have a 6-month transplant-related mortality similar to patients with no GVHD. Patients with grade III GVHD, however, have a 50% risk of mortality at 6 months, whereas grade IV GVHD is usually fatal [48].

Chronic disease When patients survive aGVHD and other complications, especially infections, the cutaneous lesions either disappear completely or they gradually progress and evolve into the chronic manifestations of GVHD. The incidence of chronic cutaneous GVHD in the author ’s patients was 30%. All of the patients who developed chronic skin changes had experienced previous acute manifestations. In a series of transplant patients studied by the Seattle group [53], chronic GVHD proved to be a significant problem in 19 out of 92 patients (21%) surviving 150 days or more; in five individuals, chronic GVHD apparently occurred without a preceding acute reaction. Chronic skin manifestations of GVHD include lichen planus-like lesions, pigmentary changes and sclerosis.

Graft-Versus-Host Disease

178.7

In the author ’s series, a variety of lichenoid lesions occurred from day 29 to day 350 post-graft. Involvement of the buccal mucosa is a frequent finding. Saurat and Gluckman [54] stated that oral lesions always preceded the cutaneous lesions of chronic GVHD. However, this was not substantiated by this author ’s observations. The mucosal lesions are similar to those seen in idiopathic lichen planus, with a white reticulate pattern affecting the buccal mucosa, gingiva, tongue and palate. Lichen planus lesions of the genitalia have also been reported [54,55] and were seen in one patient in the author ’s series. The appearance of lichen planus papules on the skin shows similarities to that seen in idiopathic lichen planus [56– 58], with polygonal, violaceous, shiny papules and Wickham’s striae. More often, however, the lesions are less typical of lichen planus although remaining lichenoid in nature. Lesions are often seen in a reticulate configuration, especially on the limbs (Fig. 178.7), suggesting some relationship with the underlying vascular network. The distribution, when widespread, does not tend to affect those areas of predilection seen in idiopathic lichen planus, such as the anterior aspects of the wrists. Follicular lesions resembling lichen planopilaris are seen as an early manifestation of chronic GVHD. The lichenoid lesions exhibit the Koebner phenomenon, seen in two of the author ’s patients. It has been suggested that the lichenoid lesions occur more often in the zones previ-

ously affected by the aGVHD rash. The author observed no evidence to support this, although one patient in the series did develop tiny lichenoid papules on the palms, which is unusual in idiopathic lichen planus. Nail involvement occurred in two patients. Typically nails become brittle, crack, and develop ridging [59]. Cicatricial alopecia has been reported by Touraine et al. [56] Saurat et al. [58] and Shulman et al. [55], but this was not noted in the author ’s study. Hair can become brittle and alopecia ensue even in children [60]. Premature greying of the hair is also common. A frequent finding is hyperpigmentation, which can be diffuse, reticulate or follicular. Lesions may have a poikilodermatous appearance [55,56,61]. Less commonly, areas of hypopigmentation occur. Pigmentary changes precede the development of sclerosis. Areas of induration and sclerosis of the skin develop as a late manifestation of GVHD. These sclerotic lesions tend to be localized [2,62,63], or progress to extensive sclerosis (generalized scleroderma) (Fig. 178.8). Ulceration, particularly at pressure points [56,59,64], and flexion contractures with limitation of joint movement [65,66] may result. Four patients in the author ’s series developed morphoea-like areas of skin, and in one boy these were widespread. In these patients the lesions have remained static or have gradually improved; none progressed to the more serious sequelae. This may be related to their long-

Fig. 178.7 Chronic graft-versus-host disease: lichenoid lesions in a reticulate configuration.

Fig. 178.8 Chronic graft-versus-host disease: generalized scleroderma.

178.8

Chapter 178

term treatment with prednisolone and azathioprine. Saurat et al. [58] regard these late changes to be more like lichen sclerosus et atrophicus with, in particular, characteristic genital lesions. Shulman et al. [55] noted a phimosis in 2 of their 19 patients, an observation that could possibly reinforce Saurat’s hypothesis. However, oesophageal involvement [67] and subcutaneous calcification [68] suggest that this disease process is more like scleroderma.

Other manifestations of chronic disease Chronic GVHD may manifest as a variety of autoimmune or connective tissue diseases [26], sharing overlapping features with scleroderma, lupus erythematosus, dermatomyositis, polymyositis, primary biliary cirrhosis and chronic active hepatitis. The occurrence of Sjögren syndrome is well documented [55,68]. In the author ’s study xerophthalmia, conjunctivitis and xerostomia were observed in one patient, who also had lichenoid lesions of chronic GVHD. Gratwhol et al. [68] reported cutaneous lesions, which, clinically and histologically, resembled discoid lupus erythematosus in one patient, 19 months after transplantation. The author has seen vitiligo and polymyositis associated with chronic GVHD. Visceral manifestations of chronic GVHD are essentially malabsorption and chronic hepatitis. Chronic liver damage with progressive destruction of bile canaliculi may lead to primary biliary cirrhosis [69] or to a syndrome mimicking chronic active hepatitis. Most patients with chronic GVHD tend to have prolonged humoral and cellular immune defects, with an increased susceptibility to bacterial, viral and fungal infections. Laboratory tests in chronic GVHD may show abnormal liver function, eosinophilia, hypogammaglobulinaemia with polyclonal elevation of immunoglobulin G (IgG) or IgM, and a variety of circulating autoantibodies, especially antinuclear, antismooth muscle and antimitochondrial antibodies. Differential diagnosis. The differential diagnosis of acute cutaneous GVHD includes the effects of radiotherapy, drug reactions and infections. Usually, these can be distinguished clinically, but the major practical problems of diagnosis include (i) drug-induced rashes, as a result of immunosuppressive or antibiotic therapy; and (ii) a viraemia caused by hepatitis B or CMV, which can exceptionally be responsible for an exanthematous eruption. As detailed in the section on histology, there are no features specifically diagnostic for GVHD; however, a skin biopsy may provide useful information to support the diagnosis. The diagnosis of chronic GVHD is usually straightforward, based on clinical examination of lichenoid or sclerodermatous lesions in a BMT recipient.

Treatment

Prevention There are some guidelines to the appropriate selection of prophylaxis against GVHD: identical twin transplants require no GVHD prophylaxis; ciclosporin and shortcourse methotrexate is adequate in standard risk-matched sibling donor transplants in children under 16 years of age [70], whereas in vivo T-cell depletion with Campath 1H or anti-thymocyte globulin (ATG) is usually required with unrelated donor transplants. For haplotype mismatched (parental) transplants, profound 4–5 log T-cell depletion is required, which is now readily achieved by CD34 selection techniques (e.g. CliniMACS), which usually ensure that no more than 1 × 105 CD3+ cells per kg are returned with the graft. In the absence of chronic GVHD, prophylactic immunosuppression can be discontinued at about 3–6 months after stem cell transplantation (SCT) without complications, indicating either that the originally infused T-cells, which recognize host alloantigens, have a limited lifespan, or that regulatory mechanisms develop to prevent the T-cells from causing immune damage. T-cells that develop in the host thymus after SCT do not cause GVHD because of induction of anergy and negative selection mediated by host thymic epithelial cells. A GVL effect may, to some extent, parallel GVHD, and complete abolition of GVHD may therefore not be desirable [71,72]. Acute disease Several agents have been used to treat established aGVHD, with varying degrees of success. High-dose corticosteroids given as a bolus injection of intravenous methylprednisolone produce a dramatic effect on aGVHD and are used widely as first-line treatment [73]. Although skin GVHD responds rapidly, liver and gut GVHD can be resistant, and some patients become refractory to steroids. The treatment strategy for steroid-refractory GVHD [74] is less clear and outcomes remain unsatisfactory. Some responses have been achieved in refractory disease with ATG and various monoclonal antibodies including Campath 1H, anti-IL2 receptor [75,76], anti-CD5 [77], anti-CD2 and anti-TNF (infliximab). With less aggressive disease, tacrolimus can be substituted for ciclosporin, or indeed mycophenolate mofetil (MMF) added to either drug. More recently sirolimus (rapamycin) [78] and mesenchymal stem/stromal cells [79] have been used with some benefit in steroid refractory GVHD. Chronic disease Local therapies may be sufficient to treat chronic GVHD manifestations. In fact, if the chronic GVHD is mild according to NIH Consensus Criteria, the recommendation is to attempt local therapy first [46]. Preference for

Graft-Versus-Host Disease

local therapies is also advised in patients with high-risk malignancies where a strong GVL effect is desired (see below). Topical treatments that are useful include ciclosporin in solution as a mouthwash [80] or a potent corticosteroid as an inhaler (such as beclometasone) for oral erosive lichen planus; and a potent topical steroid ointment (clobetasol propionate, Dermovate®) for phimosis or localized chronic GVHD elsewhere. Topical tacrolimus ointment is now available and could potentially be a useful treatment for skin GVHD. Other approaches include the use of artificial tears for ocular involvement and the regular application of a sunscreen. For patients with moderate or severe chronic GVHD, prednisolone is the treatment of choice, initiated at 1 mg/ kg for 2 weeks with a taper to alternate-day prednisolone by 1–2 months. Adding a calcineurin inhibitor, e.g. ciclosporin, may be beneficial as well [80]. Chronic GVHD occurring after stopping ciclosporin prophylaxis will often regress when the drug is reintroduced, but some patients develop chronic GVHD during adequate ciclosporin therapy [81]. Localized morphoea lesions may gradually improve [37]. However, the severe progressive wasting disease with immunodeficiency, liver damage and scleroderma is not always controllable; the sclerodermatous form may produce permanent deformity that persists after the GVHD process has burnt out, and requires aggressive ongoing physiotherapy and occupational health involvement. When chronic GVHD fails to respond to first-line treatment there are a number of salvage therapies available where data mostly come from adult patients: rituximab [82]; sirolimus [83]; thalidomide[84,85]; and high-dose methylprednisolone [86]. Jacobsohn [80] reviewed salvage therapies for which data in children exist, including mycophenolate mofetil (MMF) [87], pentostatin [88] and hydroxychloroquine [89], all of which showed promise, with clinical responses of around 50% permitting reduction in steroid doses. However, the main drawback remains the potential for added infection, hence careful monitoring for infections and the use of adequate antiviral and antifungal agents is mandatory. Extracorporeal photopheresis (ECP) has shown efficacy in children with steroid-refractory GVHD [90] and may be associated with less infection risk than other salvage therapies. Extracorporeal photopheresis involves the infusion of autologous peripheral blood mononuclear cells collected by apheresis and incubated with the photoactivatable drug 8-methoxypsoralen, which induces apoptosis of treated lymphocytes. Photochemotherapy (PUVA: (psoralens and UVA) may be helpful for the treatment of lichenoid GVHD inadequately controlled by systemic therapy [91]. The efficacy of PUVA treatment for sclerodermatous GVHD is more controversial and there

178.9

is a small but definite risk of developing skin malignancy [92]. The likelihood of treatment response depends upon whether single-organ or multiorgan systems are affected, and a platelet count with a thrombocytopenia of 60% occurring in a visible location on the head and neck. Complex psychosocial issues exist for parents of children with such a congenital defect and for the child themselves it is comparable to other congenital defects such as cleft lip/palate [41]. As with other skin disease, the degree of parent stress from their child’s haemangioma is variable and not correlated with the surface area or location of the lesion [42]. One mother described her experiences of having a child with a large facial hemangioma thus: ‘Our first years were filled with doctor visits, staring strangers, rude comments and pitying looks. Comments like, “What did you do during your pregnancy to cause that?” were an everyday occurrence’ [43]. Drotar et al. have studied reaction patterns and coping mechanisms for parents of children with congenital malformations. In a study of 20 parents of children with various malformations, the authors noted a predictable course of parental reactions. Despite a wide variation in the type of underlying malformation, each parent evolved through five stages: shock, denial, sadness and anger, gradual adaptation and finally reorganization with variable time spent in each stage and varying success in the reorganization period. Some parents reported difficulties in becoming attached to these children and reported a fear of not being able to care for their child appropriately. Some continued to search endlessly for a cause and remained isolated from support while others accepted the malformation as a chance occurrence and were able to seek support from friends, family and support groups [44]. The feelings of parents immediately after the birth of children with malformations include grief, guilt, sadness and a sense of loss of their expected ‘normal’ child [44,45]. The heterogeneity of disease and the uncer-

179.3

tain and often unpredictable course may lead to feelings of anxiety and a loss of control. The reactions of strangers to children with congenital malformations are another significant source of stress and anxiety for parents. This parental anxiety, along with a perception that the child is vulnerable due to their malformation, may trigger the development of indulgent and overprotective behaviours toward the affected child [46]. The adverse effects on a parent’s quality of life have also been quantified using a haemangioma-specific survey, with high scores noted for parental feelings of disbelief and panic [47]. Studies investigating the impact of appearance on behaviour and self-esteem suggest that children with craniofacial anomalies are treated differently from children without these defects. The affected children have been shown to be more introverted and to express a more negative self-concept than unaffected children and these negative self-perceptions and lack of self-esteem continue to pose problems for those with congenital anomalies as they become adults [48,49]. These psychosocial difficulties have a negative impact on social functioning and quality of life. Tanner et al. sought to understand the coping and adaptation mechanisms for children with haemangiomas and their parents [45]. The reactions of parents were similar to those observed by Drotar in parents of children with various malformations as outlined above, including feelings of loss and grief, despite the fact that haemangiomas generally follow a benign course. One particularly distressing aspect for parents noted in this and other similar studies was the reaction of strangers. In addition to negative reactions by strangers regarding the child’s appearance, many parents have reported actual accusations of child abuse. Such social stigmatization, along with a sense of panic or fear associated with the presence of the haemangioma, has a significant psychological impact on these parents [50]. Parents may choose to minimize contact with strangers and maximize contact with familiar adults as a coping mechanism for both themselves and their children.

References 1 VanBeek M, Beach S, Braslow JB et al. Highlights from the report of the working group on ‘core measure of the burden of skin disease’. J Invest Dermatol 2007;127:2701–6. 2 Chren MM. Measurement of vital signs for skin diseases. J Invest Dermatol 2005;125:viii–ix. 3 Lewis–Jones MS, Finlay AY. The Children’s Dermatology Life Quality Index: initial validation and practical use. Br J Dermatol 1995;132:942–9. 4 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;138:107–13. 5 Lewis-Jones MS, Finlay AY, Dykes PJ. The Infant’s Dermatitis Quality of Life Index. Br J Dermatol 2001;144:104–10.

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6 Chamlin SL, Cella D, Frieden IJ et al. Development of the Childhood Atopic Dermatitis Impact Scale: initial validation of a quality-of-life measure for young children with atopic dermatitis and their families. J Invest Dermatol 2005;125:1106–11. 7 McKenna SP, Whalley D, Dewar AL et al. International development of the Parents’ Index of Quality of Life in Atopic Dermatitis (PIQoL). Qual Life Res 2005;14(1):231–41. 8 Basra MKA, Sue-Ho R, Finlay AY. The family Dermatology Life Quality Index: measuring the secondary impact of skin disease. Br J Dermatol 2007;156:528–38. 9 Magin PJ, Pond CD, Smith WT et al. A cross-sectional study of psychological morbidity in patients with acne, psoriasis and atopic dermatitis in specialist dermatology and general practices. J Eur Acad Dermatol Venereol 2008;22:1435–44. 10 Al–Hoqail IA. Knowledge, beliefs and perceptions of youth toward acne vulgaris. Saudi Med J 2003;24:765–8. 11 Young M. The psychological and social burdens of psoriasis. Dermatol Nurs 2005;17:15–19. 12 Jenner N, Campbell J, Marks R. Morbidity and cost of atopic eczema in Australia. Austral J Dermatol 2004;45:16–22. 13 Higgins ET. Self-discrepancy: a theory relating to self and affect. Psychol Rev 1987;94:319–40. 14 Dalgard F, Gieler U, Holm JO et al. Self-esteem and body satisfaction among late adolescents with acne: results from a population survey. J Am Acad Dermatol 2008;59:746–51. 15 Magin P, Adams J, Heading G et al. Psychological sequelae of acne vulgaris: results of a qualitative study. Can Fam Physician 2006;52:978–9. 16 Magin P, Adams J, Heading G et al. Experiences of appearancerelated teasing and bullying in skin disease and their psychological sequelae: results of a qualitative study. Scand J Caring Sci 2008;22:430–6. 17 Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol 1998;139:846–50. 18 Laughter D, Istvan JA, Tofte SJ et al. The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol 2000;43:649–55. 19 Chamlin SL, Frieden IJ, Williams ML et al. The effects of atopic dermatitis on young American children and their families. Pediatrics 2004;114:607–11. 20 Dahl RE, Bernhisel-Broadbent J, Scanlon-Holdford S et al. Sleep disturbances in children with atopic dermatitis. Archive of Pediatric and Adolescent Medicine Arch Pediatr Adolesc Med 1995;149: 856–60. 21 Daud LR, Garralda ME, David TJ. Psychosocial adjustment in preschool children with atopic eczema. Arch Dis Child 1993;69:670–6. 22 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;137:241–5. 23 Schmitt J, Romanos M, Schmitt et al. Atopic eczema and attentiondeficit/hyperactivity disorder in a population-based sample of children and adolescents. JAMA 2009;301:724–6. 24 Moldofsky H. Evaluation of daytime sleepiness. Clin Chest Med 1992;3:417–25. 25 Smith JA. The impact of skin disease on the quality of life adolescents. Adolesc Med State Art Rev 2001;12:343–53. 26 Jowett S, Ryan T. Skin disease and handicap: an analysis of the impact of skin conditions. Soc Sci Med 1985;20:425–9. 27 Krowchuk DP, Stancin T, Keskinen R et al. The psychosocial effects of acne on adolescents. Pediatr Dermatol 1991;8:332–8. 28 Wu SF, Kinder BN, Trunnell TN et al. Role of anxiety and anger in acne patients: a relationship with the severity of the disorder. J Am Acad Dermatol 1988;18:325–33.

29 Warschburger P, Buchholz HTh, Petermann F. Psychological adjustment in parents of young children with atopic dermatitis: which factors predict parental quality of life? Br J Dermatol 2004;150: 304–11. 30 Balkrishnan R, Housman TS, Grummer S et al. The family impact of atopic dermatitis in children: the role of the parent caregiver. Pediatr Dermatol 2003;20:5–10. 31 Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol 2000;142: 931–6. 32 Ben-Gashir MA, Seed PT, Hay RJ. Are quality of family life and disease severity related in childhood atopic dermatitis? J Eur Acad Dermatol Venereol 2002;16:455–62. 33 Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol 2001;145:274–9. 34 Rapp DA, Brenes GA, Feldman SR et al. Anger and acne: implications for quality of life, patient satisfaction and clinical care. Br J Dermatol 2004;151:183–9. 35 Thomas DR. Psychosocial effects of acne. J Cutan Med Surg 2005;8:3–6. 36 Rigopoulos D, Gregoriou S, Ifandi A et al. Coping with acne: beliefs and perceptions in a sample of secondary school Greek pupils. J Eur Acad Dermatol Venereol 2007;21:806–10. 37 Chiu A, Chon SY, Kimball AB. The response of skin disease to stress. Arch Dermatol 2003;139:897–900. 38 Salek MS, Khan GK, Finlay AY. Questionnaire techniques in assessing acne handicap: reliability and validity study. qual Life Res 1996;5:131–8. 39 Motley RJ, Finlay AY. How much disability is caused by acne? Clin Exper Dermatol 1989;14:194–8. 40 Martin AR, Lookingbill DP, Botek A et al. Health-related quality of life among patients with facial acne – assessment of a new acne-specific questionnaire. Clin Exper Dermatol 2001;26: 380–5. 41 Pope AW, Ward J. Self-perceived facial appearance and psychosocial adjustment in preadolescents with craniofacial anomalies. Cleft Palate-Craniofac J 1997;34:396–401. 42 Kunkel EJS, Zager RP, Hausman CL et al. An interdisciplinary group for parents of children with hemangiomas. Pyschosomatics 1994;35:524–32. 43 Gleason T. Summer ’s strawberry. J Am Acad Dermatol 2004;51:S53–4. 44 Drotar D, Baskiewicz A, Irvin N et al. The adaptation of parents to the birth of an infant with a congenital malformation: a hypothetical model. Pediatrics 1975;56(5):710–17. 45 Tanner JL, Dechert, MP, Frieden IJ. Growing up with a facial hemangioma: parent and child coping and adaptation. Pediatrics 1998;101:446–52. 46 Tomasgard M, Metz WP. The vulnerable child syndrome revisited. Dev Behav Pediatr 1995;16:47–53. 47 Hoornweg MJ, Grootenhuis MA, van der Horst C. Healthrelated quality of life and impact of haemangiomas on childrens and their parents. J Plast Reconstr Aesthet Surg 2009;62(10): 1265–71. 48 Horton KM, Renooy L, Forrest CR. Patients with facial difference: assessment of information and psychosocial support needs. Uni Toronto Med J 2000;78:8–11. 49 Dieterich–Miller CA, Cohen BA, Liggett J. Behavioral adjustment and self-concept of young children with hemangiomas. Pediatr Dermatol 1992;9:241–45. 50 Williams EF 3rd, Hochman M, Rodgers BJ et al. A psychological profile of children with hemangiomas and their families. Arch Facial Plast Surg 2003;5:229–34.

Coping with the Burden of Chronic Skin Disease

The secondary impact of paediatric skin disease Parents, siblings and extended family members are often affected by a child’s skin disease. These effects can be emotional, physical and functional and may significantly impair healthy family functioning. Stress, anxiety, guilt and self-blame are often reported by parents and caregivers of children with skin disease. When a birthmark or skin disease is visible to strangers, these parents report a loss of anonymity due to the regular occurrence of stares and insensitive comments [1]. Some parents report the inability to effectively discipline a child afflicted with a disease [2]. In addition, the financial concerns may compound caregivers’ stress. For example, the cost of office visits, medications and treatments, including over-thecounter remedies not covered by insurance, and the significant time associated with care can be especially burdensome on caregivers [3]. Time lost from work, decreased work productivity and the necessity to quit working have all been reported by parents of children with chronic skin conditions and have broader societal ramifications beyond the family unit. References 1 Gleason T. Summer ’s strawberry. J Am Acad Dermatol 2004;51:S53–4. 2 Daud LR, Garralda ME, David TJ. Psychosocial adjustment in preschool children with atopic eczema. Arch Dis Child 1993;69:670–6. 3 Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: a systematic review. Pediatr Dermatol 2008;25:1–6.

Biopsychosocial theory Most parents expect and anticipate the birth of a healthy child and do not realistically understand the daily challenges and stress of raising a child. Moreover, when a life- or appearance-altering disorder is diagnosed, the expectation of this ‘perfect’ child is shattered and psychological adjustments must be made. As with any loss, the child, when old enough, and their parents usually go through a grieving process, best described by Elisabeth Kubler-Ross MD in her book On Death and Dying [1]. These stages of grief do not necessarily occur in a given sequence and include denial, anger, bargaining, depression and acceptance. They can be appropriately applied to the diagnosis of disease, as this is essentially a death of an ideal state of being, which affects not only the patient but also his or her loved ones. Passing through these stages may allow individuals to cope with the diagnosis and the subsequent life changes that occur. In 1977, George Engel MD, a psychiatrist, proposed the biopsychosocial model as a framework for addressing the

179.5

multidimensional components of disease [2]. The model recognizes that disease involves more than just a pathophysiological process, or what is referred to as the biomedical model. The biopsychosocial model proposes that the biomedical outlook must be expanded to account for social, psychological and behavioural considerations. This robust view of the disease process provides a more comprehensive framework within which a physician can aid the healing process. More recent models of coping and adjustment expand upon recognizing the significance of the biopsychosocial model by assessing the mechanisms which promote coping. Behaviours including early parental bonding have been associated with positive coping skills in stressful situations [3,4]. It has also been proposed that a child’s self-esteem is linked to the parent–child relationship and how the parent reacts to the child’s disease [5,6]. For children with skin disease, understanding and application of the biopsychosocial model are especially important. It ensures a wider vision of treatment, wherein the physician–caregiver–patient team recognizes the importance of a person-with-disease outlook, instead of mere treatment of the pathophysiological disease process. These models support the idea that intervention such as encouraging early parental bonding and positive parent– child relationships may improve or modify outcomes. Considering the potentially burdensome impact that paediatric dermatological diagnoses can have on the patient, family and society, a broader view of the disease course is required to achieve this. Ideally, the biopsychosocial theory applied to multidimensional paediatric dermatological disease may facilitate maximum healing potential. In addition, it is also vital to recognize the natural resilience of children in coping with challenges and the factors that promote such resilience. Resilience is determined by the ability to access psychological, social and economic resources. Positive parental and family psychological well-being has been shown to lessen the likelihood of the affected child suffering from anxiety, depression and social withdrawal [5]. Promoting general well-being may decrease these burdensome negative effects. The direct application of the biopsychosocial model to paediatric skin disease begins during the clinical exam with assessment of disease severity in order to institute appropriate treatment. However, the role of the physician in improving quality of life is not purely based on drug administration. It is equally important to address the patient’s and caregiver ’s psychosocial burden, assessing potential psychiatric co-morbidity, especially anxiety, depression and possible suicidal ideation. Depending on the findings, a psychiatric referral may be advised. However, even if psychiatric referral is not deemed necessary, other supportive strategies may be appropriate.

179.6

Chapter 179

References 1 Kubler–Ross E. On Death and Dying. New York: Simon and Schuster, 1969. 2 Engel GL. The need for a new medical model a challenge for biomedicine. Science 1977;196:129–36. 3 Wallander JL, Varni JW. Effects of pediatric chronic physical disorders on child and family adjustment. J Child Psychol Psychiatry 1998;39:29–46. 4 Thompson RJ Jr. Coping with the stress of chronic childhood illness. In: O’Quinn AN (ed) Management of Chronic Disorders of Childhood. Boston: G.K. Hall, 1985: 11–41. 5 Dennis H, Rostill H, Reed J et al. Factors promoting psychological adjustment to childhood atopic eczema. J Child Health Care 2006;10:126–39. 6 Harvey D, Greenway P. How parent attitudes and emotional reactions affect their handicapped child’s self-concept. Psychol Med 1982;12:357–70.

Coping strategies Many types of coping strategies exist and include problem-solving strategies – active efforts to alleviate a stressful occurrence – and emotion-focused coping strategies – efforts to regulate the emotional consequences of stressful events [1]. While most people use both types of strategies, one may predominate due to personal style and experience and the type of stressful event. Stressors that are less controllable, such as a chronic illness, often trigger the emotion-focused type of coping. In addition, coping can be active or avoidant with active strategies thought to be a better way to deal with stressful events [2]. Coping measurement scales exist and are often used to describe and define individual coping techniques. While some suggest that increased emotional stress correlates with disease activity, others report a poor correlation between disease severity and quality of life [3]. Therefore, the approach to each patient and family should be individualized to account for different coping strategies. In addition to traditional medical therapy, psychosocial support, including education, support groups and referral for formal psychiatric support and evaluation, can be offered to patients and families. Extensive education regarding the disease process, treatment and outcomes is required for many families coping with chronic conditions. Without such education and support, patients may ‘doctor shop’ and experiment with non-traditional or unsafe therapy. Furthermore, when the most readily available sources of information are television, parents, friends and magazines, misconceptions are likely [4]. School-based peer education can be offered for children with disfiguring skin disease or congenital lesions as a change in physical appearance increases a child’s risk of being bullied [5].

Patient advocacy groups Although scant supportive evidence exists, patient advocacy and support groups are thought to be of benefit for

children with chronic disease and their parents [6]. Many such groups exist, as seen in Table 179.1. Most patient advocacy groups offer education and support in multiple formats such as conferences, newsletters, pamphlets and trained staff. These groups may be the primary source of support for individuals with complex cutaneous disease without access to tertiary care centres. In addition, in the USA, summer camps exist for children with skin disease. Many children with chronic disease, skin or other, are not able to attend traditional summer camps because of their medical needs [7]. Camp Discovery was created in 1993 with this in mind and is sponsored by the American Academy of Dermatology. Camp Wonder, sponsored by the Children’s Skin Disease Foundation, is another such camp. Children with many different skin diseases of varying severity can attend, as it is recognized that mild disease can still greatly impact a child’s quality of life. The benefits of camps for children with chronic disease have been studied and measured. Camps may enhance healthrelated quality of life for a period of time, including physical, psychosocial, cognitive and social effects, but further study is needed on this subject [8]. References 1 Folkman S, Lazarus RS. An analysis of coping in a middle-aged community sample. J Health Soc Behav 1980;21:219–39. 2 Holahan CJ, Moos RH. Risk, resistance, and psychological distress: a longitudinal analysis with adults and children. J Abnormal Psychol 1987;96:3–13. 3 Chren MM. Measurement of vital signs for skin diseases. J Invest Dermatol 2005;125:viii–ix. 4 Tan JKL, Vasey K, Fung KY. Beliefs and perceptions of patients with acne. J Am Acad Dermatol 2001;44:439–45. 5 Pittet I, Berchtold A, Akre C et al. Are adolescents with chronic conditions particularly at risk of bullying? Arch Dis Child 2009;Mar 22; epub ahead of print. 6 Goh C, Lane AT, Bruckner AL. Support groups for children and their families in pediatric dermatology. Pediatr Dermatol 2007;24:302–5. 7 Sawin K, Lannon S, Austin J. Camp experience and attitude towards epilepsy. J Neurosci Nurs 2001;33:57–64. 8 Epstein I, Stinson J, Stevens B. The effects of camp on health-related quality of life in children with chronic illness: a review of the literature. J Pediatr Oncol 2005;22:89–103.

Conclusion This chapter has described the burden of skin disease on affected individuals and their families with a focus on atopic dermatitis, acne and infantile haemangiomas. A multidimensional individualized approach to caring for patients and their families was suggested based on theory and practical experience with management of both medical and psychosocial needs to support the trend of patient-focused care. Strategies include support of parent bonding and strong parent–child relationships, family and school-based education, and advocacy groups and camp for affected children.

Coping with the Burden of Chronic Skin Disease

179.7

Table 179.1 USA-based patient advocacy groups for children with skin disease and their families Disease

Organization

Website

Albinism

National Organization for Albinism & Hypopigmentation (NOAH)

www.albinism.org

Alopecia areata

National Alopecia Areata Foundation (NAAF)

www.naaf.org

Basal cell carcinoma naevus syndrome/Gorlin syndrome

BCCNS Life Support Network

www.bccns.org

Cicatricial alopecia

Cicatricial Alopecia Research Foundation (CARF)

www.carfinti.org

Cutaneous lymphoma

Cutaneous Lymphoma Foundation

www.clfoundation.org

Dystrophic epidermolysis bullosa

Dystrophic Epidermolysis Bullosa Research Association of America

www.debra.org

Ectodermal dysplasia

Ectodermal Dysplasia Society (ED) National Foundation for Ectodermal Dysplasias

www.ectodermaldysplasia.org www.nfed.org

Eczema

National Eczema Association (NEA)

www.nationaleczema.org

Ehlers–Danlos syndrome

Ehlers–Danlos National Foundation

www.ednf.org

Epidermolysis bullosa

Epidermolysis Bullosa Medical Research Foundation EB Info World

www.ebkids.org www.ebinfoworld.com

Hidradenitis suppurativa

Hidradenitis Suppurativa Foundation, Inc.

www.hs-foundation.org

Ichthyosis

Foundation for Ichthyosis and Related Skin Types (FIRST)

www.scalyskin.org

Incontinentia pigmenti

Incontinentia Pigmenti International Foundation (ipif)

www.medhelp.org

Inflammatory skin disease

Inflammatory Skin Disease Institute (ISDI)

www.isdionline.org

Klippel–Trenaunay syndrome

Klippel–Trenaunay Syndrome Support Group

www.k-t.org

Lupus erythematosus

Lupus Foundation of America

www.lupus.org

Mastocytosis

Pediatric Mastocytosis Organization

www.mastokids.org

Neurofibromatosis

National Neurofibromatosis Foundation

www.ctf.org

Naevi

Nevus Outreach Inc.

www.nevus.org

Pachyonychia congenita

Pachyonychia Congenita Project

www.pachyonychia.org

Parry–Romber syndrome

Parry–Romber Syndrome Resource

www.prsresource.com

Pediculosis/head lice

National Pediculosis Association

www.headlice.org

Pemphigus and pemphigoid

International Pemphigus Pemphigoid Foundation (IPPF)

www.pemphigus.org

PHACES syndrome

Faces of PHACES

www.phaces.org

Pityriasis rubra pillaris (PRP)

PRP Support Group

www.prp-support.org

Pseudo-xanthoma elasticum (PXE)

National Association for Pseudo-xanthoma Elasticum PXE International, Inc.

www.familyvillage.wisc.edu www.pxe.org

Psoriasis

National Psoriasis Foundation

www.psoriasis.org

Sturge–Weber syndrome

Sturge–Weber Foundation

www.sturge-weber.com

Tuberous sclerosis

Tuberous Sclerosis Alliance

www.tsalliance.org

Vascular anomalies

National Organzation of Vascular Anomalies (NOVA)

www.novanews.org

Vascular birthmarks

Vascular Birthmarks Foundation (VBF)

www.birthmark.org

Vitiligo

National Vitiligo Foundation, Inc. Vitiligo Support International Vitiligo Info

www.nvfi.org www.vitiligosupport.org www.vitiligoinfo.org

Xeroderma pigmentosum

Xeroderma Pigmentosum Family Support Group (XP Family Support Group)

www.xpfamilysupport.org

180.1

C H A P T E R 180

Physiological Habits, Self-Mutilation and Factitious Disorders Arnold P. Oranje1, Jeroen Novak1 & Robert A.C. Bilo2 1

Department of Pediatrics, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands Department of Forensic Pathology and Toxicology, Netherlands Forensic Institute, The Hague, The Netherlands

2

Introduction, 180.1

Self-mutilation, 180.6

Factitious disorders, 180.12

Physiological habits, 180.2

Introduction Definition. The skin, mucous membranes (mouth and genitalia), hair and nails are the most visible part of the human body. They are often also the most visible part of one’s personality. Mostly people are recognized by their fellow humans from certain characteristerics that are visible from the outside. It is no wonder that many people try to make that outside as beautiful as possible by using cosmetics, cosmetic surgery or tattoos and piercings. For that reason it is not strange that these body parts may also be direct targets for behavioral problems, in which one’s aggression is directed towards oneself. This targeting may lead to visible lesions that can be observed by (paediatric) dermatologists. Psychodermatology has emerged as an important subdiscipline of both dermatology and psychiatry. In many clinical situations, co-operation between the psychiatrist or the psychologist and the dermatologist is necessary for treatment. Five main categories of dermatological disorders with psychological components are recognized [1,2]: 1 Cutaneous disorders that result from underlying primary psychiatric disease. 2 Psychosomatic dermatoses that are mainly caused by pathological stress (such as lichen simplex chronicus). 3 Dermatological disorders in which the course is codetermined by emotional factors (e.g. atopic eczema). 4 Skin diseases caused or exacerbated by psychotropic medication. 5 Psychiatric effects of dermatological medications.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Self-mutilation and factitious disorders belong to the first category. Skin lesions caused by self-mutilation may occur in children who inflict the lesions consciously and knowingly, and in children who are satisfying a conscious or unconscious psychological need.[xnl] Factitious disorder (pathomimicry; simulation of a serious, known disease) was termed Munchausen syndrome [3,4]. In children, a factitious disorder may be produced by a parent or a parent figure [4] when it is known as factitious disorder by proxy, paediatric condition falsification or formerly Munchausen syndrome by proxy. In children and adolescents, thumb- and finger-sucking, onychotillomania, onychophagia, mutilation of the skin (dermatitis artefacta), trichotillomania, excessive obsessive hand washing and excoriated acne (acne excoriée de la jeune fille) are most common [5]. In many children, hair pulling (trichotillomania), nail biting and thumb-sucking are habitual activities that are practised spontaneously and inadvertently [6,7]. History. Prior to the 1950s, psychodermatology was confined to the study of the role of psychological factors in dermatological disorders. Diseases like urticaria and lichen simplex were the frequent targets of studies [8,9]. After the 1950s and 1960s, the character of research changed from anecdotes and descriptions to analyses of large patient series evaluated through a standardized protocol [10]. In 1953, the first psychodermatology subunit in The Netherlands was set up at the Department of Dermatology and Venereology in Amsterdam. Professor Musaph, who was a psychologist practising in that clinic, was one of the pioneers in the field. In the last 10 years, the approach to dermatological disorders caused or aggravated by psychological factors has stressed the

180.2

Chapter 180

importance of teamwork (co-operation by the dermatologist, psychiatrist, clinical psychologist, welfare worker and, in children, a child protection specialist) [11]. The term trichotillomania was introduced by Hallopeau in 1889 (the Greek thrix means hair, tillein means to pull and mania means madness). Hallopeau considered trichotillomania to be a compulsive trait in otherwise healthy individuals [12]. Little is known about the history of dermatitis artefacta and self-mutilating behaviour. Tuke (1892) stated that self-mutilation was encountered ‘not infrequently’ [13]. It was concluded that such behaviour was observed mainly in psychotic or mentally retarded subjects. Although a relationship to eating disorders exists, it was described only incidentally [14]. In 1951, Asher used the term Munchausen syndrome to describe patients exhibiting questionable symptoms and a desire for extensive diagnostic evaluation [15]. Baron Von Munchausen was an 18th century mercenary who, after his return from the Russian–Turkish war, spent his remaining years concocting embellished tales of his adventures [16,17]. The term pathomimicry, as a synonym of Munchausen or Munchausen by proxy syndrome, was introduced by Millard in 1984 [16–18]. At the moment factitious disorder as a synonym for Munchausen syndrome and factitious disorder by proxy or paediatric condition falsification as a synonom for Munchausen syndrome by proxy are the preferred terms (APA-DSM IV). References 1 Van Moffaert M. Psychodermatology: an overview. Psychother Psychosom 1992;58:125–36. 2 Locala JA. Current Concepts in Psychodermatology. Curr Psychiatr Rep 2009;11(3):211–18. 3 Folks DG, Warnock JK. Psychocutaneous disorders. Curr Psychiatr Rep 2001;3:219–25. 4 Reece RM. Child Abuse: Medical Diagnosis and Management. Philadelphia: Lea & Febiger, 1994:266–78. 5 Koo JYM, Smith LL. Obsessive–compulsive disorders in the pediatric dermatology practice. Pediatr Dermatol 1991;8:107–13. 6 Oranje AP, Peereboom-Wynia JDR, De Raeymaecker DMJ. Trichotillomania in childhood. J Am Acad Dermatol 1986;15:614–19. 7 Duke DC, Keeley ML, Geffken GR, Storch EA. Trichotillomania: a current review. Clin Psychol Rev 2010;30:181–93. 8 Wittkower E, Russell B. Emotional Factors in Skin Diseases. New York: Hoeber, 1953. 9 Alexander F, French TM. Studies in Psychosomatic Medicine. New York: Ronald Press, 1948. 10 Musaph H. Itching and Scratching. Psychodynamics in Dermatology. Basel: Karger, 1964. 11 Musaph H. Psychodermatology. Psychother Psychosom 1974;24:79. 12 Hallopeau M. Alopecie par grattage (trichomanie ou trichotillomanie). Ann Dermatol Vénéréol 1889;10:440–1. 13 Tuke DH. A Dictionary of Psychological Medicine, Vol. 2. Philadelphia: Blackiston, 1892. 14 Parry-Jones B, Parry-Jones WL. Self-mutilation in four historical cases of bulimia. Br J Psychiatr 1993;163:394–402. 15 Asher R. Munchausen syndrome. Lancet 1951;i:339–41.

16 Millard LG. Dermatologic pathomimicry: a form of patient maladjustment. Lancet 1984;ii:969–71. 17 Rosenberg DA. Munchausen syndrome by proxy. In: Reece RM, ed. Child Abuse: Medical Diagnosis and Management. Philadelphia: Lea & Febiger, 1994. 18 Meadow R. Munchausen syndrome by proxy: the hinterland of child abuse. Lancet 1977; ii:343–5.

Physiological habits Physiological habits can be defined as age-dependent behaviour that can be seen as a normal developmental stage at a certain age period. Thumb- and finger-sucking, for example, is very common in young children and soon becomes a habit, only rarely lasting to adulthood [1,2]. These habits are not rare, and are self-soothing and selfcomforting behaviour. It can be seen at all times of day, for example whenever a child is getting tired, does not feel well or experiences stress. Some of the physiological habits can even be observed during sleep. Physiological habits are never obsessive or compulsive. They disappear when they lose their function. Continuing after a certain age can be pathological. Physiological habits can result in skin lesions, caused by the habit itself or by complicating factors, e.g. the development of paronychia and warts in nail biting. An overview of physiological habits and the moment they become pathological is given in Table 180.1.

Thumb- and finger-sucking Thumb- and finger-sucking develops as a habit in 13–45% of children [1,2]. The habit is physiological in infants from the early months to 4 years (peak age about 20 months). Aetiology. The cause of thumb- or finger(s)-sucking is not fully understood [1]. It gives a feeling of warmth, pleasure and certainty. Trichotillomania in toddlers is often associated with thumb- or finger-sucking. In trichotillomania, thumb- and finger-sucking indicates the presence of inner conflicts. Sometimes the reason is simple, for example in order to avoid playing piano or playing an important tennis game. Clinical features. Sucking of the thumb or the fingers may cause maceration of the finger tips. Among children, thumb-sucking is the most common cause of paronychia. Digit-sucking is also a cause of radial angular deformity, in which a finger or the thumb is abnormally separated from the other fingers [1] (Figs 180.1, 180.2). If the habit persists, dental complications can develop [1]. Between the ages of 4 and 14 years, thumb- and finger-sucking may have a deleterious effect on dentofacial development [1,2]. A protective factor, especially against pacifier sucking, seems to be prolonged breast feeding [3].

Physiological Habits, Self-Mutilation and Factitious Disorders

180.3

Table 180.1 Dermatitis artefacta, habit phenomenona and obsessive and compulsive disorders Physiological habit/habit disorders

Body rocking, head banging, head rolling Thumb-sucking Finger(s)-sucking Nail biting Onychotillomania Trichotillomania Lip-licking/biting Cheek biting Obsessive hand washing Dermatitis artefacta Excoriated acne

Age groups Infancy

Childhood

Puberty

Adulthood

++F ++F ++F +/–P – +P – – – – –

+P +F +F +F/P +F/P ++F/P +F/P – +P +P –

– +P +P ++F/P ++F/P +P +F/P +P +P +P +P

– +P +P +P +P +P +P +P +P +P +P

F, physiological; P, pathological; –, not occurring; +/– infrequent; +, common; ++, frequent.

Fig. 180.2 Deformity of the fingers of the same girl (as an adult) as in Fig. 180.1 after prolonged sucking.

Fig. 180.1 Finger-sucking in a girl aged 3 years.

Prognosis. The prognosis is usually excellent. Only rarely will the habit continue into adulthood. Differential diagnosis. The diagnosis is very easy and simple because the habit is observed. There are no differential diagnostic problems.

Other physiological habits In neonates, reflex smile, ‘sobbing’ inspirations and myoclonic twitches are physiological habits. From birth to 1

year of age sucking of the thumb, finger(s), toe and lips is common. Other common habits are masturbation, rocking and rolling (head banging) and teeth grinding. Head banging is often dramatic and upsetting to other members of the family. Questions often asked by the parents are: (i) ‘will it cause brain damage?’ (the answer is always no); and (ii) ‘is it associated with an emotional disorder?’ (in most cases the answer is no) [1]. These habits are of pathological significance only when they persist beyond early childhood or occur in combination with other habits. In children older than 1 year of age, nail biting, nose picking and habit tics may develop. Except for nail biting and nose picking, the symptoms warrant serious attention because they can be pathological. Males are more likely to have habit tics. Any stress factor needs to be identified and treated. Habit coughs are typical tics in adolescents. Chronic tic disorders can be the first signs of Gilles de la Tourette syndrome [4]. In this syndrome,

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motor and vocal tics of variable intensity develop between the ages of 2 and 15 years. Prognosis. Many repetitive habits disappear with age and have no pathological importance. However, persistence of these repetitive behaviour problems may be a manifestation of psychological distress, side-effects of drugs or a first sign of physical disease. Differential diagnosis. The diagnosis is most often simple because the habit is observed. The clinician must distinguish between physiological and pathological behaviour. It may be difficult to diagnose early Gilles de la Tourette syndrome [4].

Onychotillomania and onychophagia Nail biting (onychophagia) and nail picking (onychotillomania) are very common, especially among children [5]. The incidence of nail biting has been reported to be 33% in children and 45% in teenagers [6–8]. Before the age of 10 years, the incidence of nail biting in the sexes is relatively equal. Thereafter it is more common in boys [9]. Its incidence in adults is much lower. Aetiology. Anxiety and stress play an important role in the aetiology of nail biting [6]. In most cases, nail biting cannot be categorized as a sign of psychological or psychiatric disease. Trichotillomania can be associated with nail biting, but rarely in children [10]. Clinical features. Damage to the cuticle, bleeding around the nails, distal onycholysis and short irregular nail plates are the clinical clues (Fig. 180.3). Nail dystrophy develops in more severe and persistent cases. Secondary periungual bacterial infection may occur as a complication. Other sequelae of persistent nail biting are paronychia, periungual warts, melanonychia and osteomyelitis [5,11,12]. Nail biting may increase nail growth by 20% [6].

Fig. 180.3 Nail-biting of the toe nails.

Rubbing the thumb nail and proximal nail fold with the index finger of the same hand results in characteristic median dystrophy. A longitudinal depression in the centre of the nail over its entire length is observed (Fig. 180.4). Prognosis. The incidence is highest in children and teenagers. This habit normally disappears in early adult life. Differential diagnosis. Nail changes because of biting should be distinguished from other physical or chemical trauma, as well as from congenital abnormalities and acquired disorders. Median nail dystrophia should be distinguished from congenital dystrophia mediana canaliformis [11]. In most cases it is not difficult; the history is most helpful.

Trichotillomania Trichotillomania is seven times more common in children than in adults. It is 2.5 times more common in girls than in boys [13–15]. It is the most common form of artefactual disease after thumb- or finger-sucking [16]. The incidence is not really known, but at a child guidance clinic three cases of trichotillomania were diagnosed among 500 children [17]. Aetiology. Trichotillomania in young children is a habit phenomenon that is not usually a sign of serious emotional disturbance. It is comparable with thumb- or finger(s)-sucking and nail biting. Trichotillomania occurring later in life, especially of long duration, tends to be more serious from a psychological perspective. Hair is an important symbol of biological maturity. Therefore, trichotillomania may indicate an unconscious, symbolic effort to deny maturity [14]. Pathology. Microscopic examination of the hair roots (the trichogram), obtained by using a standardized

Fig. 180.4 Habit phenomenon resulting in median dystrophy.

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180.5

method, shows few telogen or catagen hairs, but there is an increase in dysplastic and/or dystrophic hair shapes [18]. Trichotillomania is characterized by the presence of empty hair follicles among completely normal hairs. Residual fragments of partially extracted hair provides evidence of trauma. Clumped melanin and keratinized material is seen within the disrupted hair follicles (trichomalacia) and this picture is considered pathognomonic [14,19]. Follicular plugging with keratin debris may also be present. Hair shafts within the lower follicular duct appear small and sometimes have a corkscrew appearance. Extravasated erythrocytes are sometimes visible in the epidermis and around the follicles. Usually there is no infiltration of leucocytes, except when secondary infection develops. Completely normal anagen follicles are present in the affected areas. Clinical features. One or more areas of the scalp are affected. The areas may be quite small, or the process may involve almost the entire scalp [13]. In most cases, the areas of hair loss are not well demarcated. The eyebrows and eyelashes are sometimes affected. Most often, the areas of hair loss are contralateral to the handedness of the patient. Excoriation and crusts are sometimes visible on the scalp. The most typical pattern is an area of patchy alopecia surrounded by a rim of unaffected hair. This is called tonsure pattern alopecia or ‘Friar Tuck’ sign, for its resemblance to the hair style worn by monks [15,20] (Fig. 180.5). Complications of trichotillomania are a permanent damage to hair, and hair ingestion (trichophagia) leading to a hairball (trichobezoar) in the stomach. Trichobezoar can lead to abdominal pain, nausea, vomiting, foul breath, anorexia, obstipation, flatulence, anaemia, gastric ulcer, bowel obstruction or perforation, intestinal bleeding, obstructive jaundice and pancreatitis [20]. Trichobezoars weighing up to 412 g have been described [21]. Although trichotillomania in children usually presents as an isolated symptom, it may be associated with serious psychopathology such as mental retardation, depression, borderline disorder, schizophrenia, autism, obsessive– compulsive disorder and drug abuse [20]. However, it is commonly an anxiety condition in toddlers and is easily cured [14]. Differential diagnosis. The differential diagnosis includes alopecia areata, psoriasis and tinea capitis. Clinical differential diagnosis between trichotillomania and alopecia areata may be difficult in some cases. History of hair pulling is often lacking, except in very young children, when the parents report the symptom [14]. The presence of an initial area of almost total hair loss favours alopecia areata. Exclamation hairs, a positive hair pluck-

Fig. 180.5 Trichotillomania with ‘Friar Tuck’ sign.

ing test (loss of more than five hairs when pulled from the periphery of the bald area), pitting of the nails and depigmentation in regrowing hair in older children strongly support the diagnosis of alopecia areata. Laboratory examination will exclude tinea capitis. Prognosis. In many cases this symptom disappears with appropriate emotional support and when the child gains insight into the underlying psychological problems. However, one should not assume that trichotillomania will disappear spontaneously, therefore careful follow-up is required to establish resolution [14]. In a selected population, one-third of the patients required psychiatric treatment and guidance [14]. In serious and longstanding cases, psychological or psychiatric treatment is warranted. Repeated manipulation of the hair in trichotillomania can lead to curly hair, trichorrhexis nodosa, other hair shaft fractures and, finally, to cicatricial alopecia. Treatment. In cases where the symptoms do not disappear spontaneously it is recommended that a psychiatrist and dermatologist join the treatment team. Behavioural therapy has a longstanding tradition in the treatment of trichotillomania with successful effect. More recently, a variety of drug treatments have also been investigated.

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Psychopharmacological medications include antidepressants; serotonergic agents and antipsychotics. Selective serotonin reuptake inhibitors (SSRIs), which are known to be effective for depression, anxiety and obsessive– compulsive disorder, can also be effective in the treatment of trichotillomania. [22] In small children, oral medications will almost never be indicated or even necessary. References 1 Peterson JE, Schneider PE. Oral habits. A behavioral approach. Pediatr Oral Health 1991;38:1289–307. 2 Lubitz L. Nail biting, thumb sucking, and other irritating behaviours in childhood. Austr Fam Physician 1992;21:1090–4. 3 de Holanda AL, dos Santos SA, Fernandes de Sena M, Ferreira MA. Relationship between breast- and bottle-feeding and non-nutritive sucking habits. Oral Health Prev Dent 2009;7(4):331–7. 4 Regeur L, Pakkenberg B, Fog R et al. Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette’s syndrome. J Neurol Neurosurg Psychiatr 1986;49:791–5. 5 Oderick L, Brattstrom V. Nail biting: frequency and association with root resorption during orthodontic treatment. Br J Orthodont 1985;12:78–81. 6 Leung AKC, Robson WLM. Nail biting. Clin Pediatr 1990;29:690–2. 7 Massler M, Malone AJ. Nail biting – a review. J Pediatr 1950; 36: 523–31. 8 Wechsler D. The incidence and significance of finger-nail biting in children. Psychoanal Rev 1931;18:201–8. 9 Malone AJ, Massler M. Index of nail biting in children. J Abnorm Soc Psychol 1952;47:193–202. 10 Dimino-Emme L, Carmisa CH. Trichotillomania associated with the ‘Friar Tuck sign’ and nail biting. Cutis 1991;47:107–10. 11 Tosti A, Peluso AM, Bardazzi F. Phalangeal osteomyelitis due to nail biting. Acta Derm Venereol 1994;74:206–7. 12 Baran R. Nail biting and picking as a possible cause of longitudinal melanonychia. Dermatologica 1990;181:126–8. 13 Stroud JD. Hair loss in children. Pediatr Clin North Am 1983;30:641–57. 14 Oranje AP, Peereboom-Wynia JDR, De Raeymaecker DMJ. Trichotillomania in childhood. J Am Acad Dermatol 1986;15:614–19. 15 Muller SA. Trichotillomania. Dermatol Clin 1987;5:595–601. 16 Spraker MK. Cutaneous artifactual disease: an appeal for help. Pediatr Clin North Am 1983;30:659–68. 17 Anderson FW, Dean HC. Some aspects of child guidance clinic in policy and practice. Publ Health Rep 1956:71. 18 Peereboom-Wynia JDR. Hair root characteristics of the human scalp hair in health and disease. Thesis, Rotterdam, 1979. 19 Lachapelle JM, Pierard GE. Traumatic alopecia in trichotillomania. J Cutan Pathol 1977;4:51–67. 20 Hamdan-Allen G. Trichotillomania in childhood. Acta Psychiatr Scand 1991;83:241–3. 21 Ewert P, Keim L, Schulte-Markwort M. Der Trichobezoar. Monatsschr Kinderheilkd 1992;140:811–13. 22 Chamberlain SR, Menzies L, Sahakian BJ, Fineberg NA. Lifting the veil on trichotillomania. Am J Psychiatr 2007;164(4):568–74.

Self-mutilation Self-mutilation is defined as the deliberate alteration or destruction of one’s own body tissue without any conscious suicidal intent. The injury is done to oneself, without the aid of another person, and the injury is severe

enough for tissue damage to result. Acts that are committed with conscious suicidal intent or are associated with sexual arousal are excluded [1,2]. Synonyms for self-mutilation are self-abusive behaviour, self-harm or self-injurious behaviour. A widely accepted term in dermatology is dermatitis artefacta as a synonym for self-mutilation. However, it also is used as a term for the skin lesions that are found in children and are inflicted by another person in factitious disorder by proxy.

Classification of self-mutilation Several subgroups occur. Hollender and Abram described three groups. The first group consists of patients with an autoaggressive habitual behaviour and recognized, plausible motives, or those who are neurotic pickers and who readily admit to damaging their skin. The second group consists of patients with hysterical and obsessive impulses. The third group encompasses mentally retarded or psychotic individuals who self-mutilate frequently and in the presence of others [3]. Patients with delusions of parasitosis may also self-mutilate. The most accepted classification of self-mutilation worldwide at the moment is the one developed by Favazza, namely superficial (compulsive and impulsive), stereotypic and major self-mutilation [4]. Comparing Hollender ’s subgroups with Favazza’s classification shows that the first group consists of people/ children with the impulsive type of superficial selfmutilation. Hollender ’s second group is comparable with the compulsive type of the superficial self-mutilation group, and the third group can be compared with the stereotypic self-mutilation group. The group of patients with delusions of parasitosis can belong to either the superficial or the major self-mutilation group. Self-injurious behaviour (SIB) as seen in children with autism or developmental disabilities is not the same as self-mutilation because usually there is no deliberate intent to harm one’s own body tissue. Destruction of body tissue can be a result of repetitively stereotypic behaviour, stress due to over- or understimulation, impairment of communication skills, impairment of sensibility, somatic problems such as hearing problems or sight problems, and traumatization. The ontogenesis of SIB exhibited by young children with developmental disabilities is due to a complex interaction between neurobiological and environmental variables [5]. SIB in children with mental retardation starts at an early age: 68% starts before the age of 6 years. The prevalence of SIB in children with autism is 24–43%; the combination of both mental retardation and autism has a prevalence of more than 70% for SIB. Treatment involves behavioural therapy and/or psychomedication, depending on the liklihood of being able to change a patient’s behaviour [6,7].

Physiological Habits, Self-Mutilation and Factitious Disorders

Recently, a new classification was proposed based on adult patients: 1 Dermatitis artefacta syndrome in the narrower sense of unconscious/dissociated self-injury. 2 Dermatitis para-artefacta syndrome: admitted self-injury. 3 Malingering: consciously simulated injuries and diseases to obtain material gain. 4 Special forms, such as the Gardner–Diamond syndrome, factitious disorder (Munchausen syndrome) and the paediatric condition of falsification syndrome by proxy [8]. The authors of this chapter are not sure that this classification is useful and suitable for children.

Superficial self-mutilation Superficial self-mutilation is the most prevalent type of self-mutilation. It is estimatimed that the incidence is between 0.75% and 1.4% (750–1400 per 100,000 persons) per year [9,10]. The incidence in adolescents and young adults between the age of 15 and 35 years is estimated to be even higher at 1800 cases per 100,000 persons a year. The incidence among inpatient adolescents was estimated at about 40% [11]. Superficial self-mutilation has been described in a variety of populations with different ethnic and socioeconomic backgrounds. However, self-mutilation is three times more common in females than in males. The typical patient with self-mutilative behaviour is a Caucasian female, who started her behaviour in her teens and continues into her twenties or thirties, with a middle to upper class background. In about 50% of cases there are also eating disorders [10]. A survey done by Ensink showed that about 35% of all women who were sexually abused and were to known to self-mutilate started before the age of 12, and in total almost 50% started before the age of 18 [12]. In medical literature, children (mostly child abuse victims) are described as young as 3 years who had skin lesions as a result of superficial self-mutilation [13]. Van der Kolk et al. concluded that the earlier the abuse began, the more serious the self-mutilative behaviour will be [14]. Aetiology. Various hypotheses have been used to explain the aetiology of superficial self-mutilation. Psychoanalytical, developmental, personality and biochemical (serotonin) theories have been postulated [15]. The most serious forms of these disorders may be related to physical, emotional and sexual abuse [16]. The psychoanalytical theory stresses the importance of early emotional traumas such as illness, separation from parents and disturbances in the mother–child relationship [17]. Developmental difficulties (e.g. in school, coping problems, physical unattractiveness) also play a

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role. Van der Kolk et al. concluded that neglect is the most powerful predictor of self-destructive behaviour [14]. According to their opinion childhood trauma contributes heavily to the initiation of self-destructive behaviour and the lack of secure attachments maintains it. Developmental disturbances can lead to a poor selfimage or lack of self-esteem. The child lacks positive feelings about his or her own body (even though he or she is not conscious of this problem). The child turns his aggression against himself [18]. In children, most cases are related to distortion of the parent–child relationship. Another important factor in children is violence between family members (physical, sexual or emotional) committed by an important person, like a parent, and double messages (e.g. loving caretaking and violent behaviour by the same person). The violence and the double messages lead to confusion and the loss or disruption of the relationship. Motives. According to Malon and Berardi there is a chain of feelings that leads to self-mutilation [19]. The start seems to be a threat of separation, rejection or disappointment. A feeling of overwhelming tension and isolation, resulting from fear of abandonment, self-hatred and apprehension about being unable to control one’s own aggression, seems to take hold. The anxiety increases and culminates in a sense of unreality and emptiness that produces an emotional numbness or depersonalization [20]. The self-mutilation is a way to fight feelings of depersonalization and the immediate tension. It is also a way of dealing with feelings of anxiety, anger or sadness. It can be seen as an important coping mechanism [21]. The feeling of control is strengthened by a sense of calm that is the result of the stimulating effect of, for example, wrist cutting, on the production of the body’s endorphines [22,23]. Underlying psychiatric problems. There are many psychiatric problems in which self-mutilative behaviour can be observed. It has been described in, amongst others, personality disorders (borderline and antisocial personality disorders), post-traumatic stress disorder, eating disorders (anorexia, bulimia), mood disorders (depression, bipolar disorder), obsessive–compulsive disorders, dissociative disorders and impulse control disorders [15,24]. Many of these disorders have a link with adverse childhood experiences, such as: (i) distortion within the parent– child relationship; (ii) violent disruptions in family life; and (iii) in children who have been the victims of physical, emotional and sexual abuse or emotional neglect. Subforms of superficial self-mutilation. Two subforms of superficial self-mutilation can be recognized: compulsive and impulsive (episodic and repetitive) behaviour.

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Compulsive self-mutilation Compulsive self-mutilation is closely associated with obsessive–compulsive disorders [4]. Obsessive– compulsive disorders are characterized by obsessions and/or compulsions. An obsession is defined as an intrusive thought, urge or impulse that is experienced as repulsive, irrational and ego-distonic. Compulsion is defined by repetitive, often ritualized or stylized behaviour [17,25]. The behaviour in obsessive–compulsive disorders is meant to relieve tension or to prevent negative events. The acts can be conscious or subconscious. Obsessive–compulsive disorders may be difficult to distinguish from other causes of superficial self-mutilation [15]. Most observed behaviour in compulsive selfmutilation is trichotillomania, onychotillomania, onychophagia and acne excoriée, although these behaviours are only the result of obsessive and compulsive disorders in a small minority [18,24]. The obsessive–compulsive behaviour can be demonstrated in certain patients with trichotillomania, who pull out exact numbers of hairs, equally divided over each side of the head (front to back, left to right) to prevent negative events happening. Repeated hand washing is most often a form of obsessive–compulsive disorder, which may lead to irritative hand eczema. If this kind of hand washing tendency suddenly develops, diabetes mellitus should be ruled out. Differential diagnosis of hand eczema also includes dermatophytic infection and allergic contact eczema. One per cent of children and adolescents suffer from obsessive–compulsive disorders [26,27]. Although the behaviour is not life-threatening, the prognosis of compulsive self-mutilation and obsessive– compulsive disorder is poor, and the condition often worsens with age. The dermatologist should ask for the help of a paediatric psychiatrist in the diagnosis and treatment. Newer drug therapies, such as clomipramine and fluoxetine, have resulted in optimism regarding the treatment of obsessive–compulsive disorders [24].

her problems. It can lead to an ‘addiction’ to the selfmutilative behaviour where the patient can not resist the impulse any longer. Instead of being a symptom of an underlying psychological disorder, the behaviour becomes a disorder in itself. The patient will seen him/ herself as a self-mutilator. The acts are the same as in episodic behaviour. Episodic and repetitive behaviour is impulsive in so far that it can be a response to any positive or negative trigger [15].

Impulsive self-mutilation Impulsive self-mutilation can be episodic or repetitive. The behaviour can start in early childhood and continue for many years. Episodic self-mutilation is usually seen as a symptom of a psychological disorder. People who engage in episodic acts often do not see themselves as self-mutilators. The most common episodic acts are cutting, burning, needle sticking, bone breaking and interfering with wound healing. Repetitive self-mutilation can be the result of episodic behaviour; if the episodic behaviour leads to relief of stress or the solving of other triggers the patient may become convinced that it is the only way of solving his/

Factitious disorder Self-mutilation should be differentiated from factitious disorders. The motives for the behaviour in both situations are completely different. In self-mutilation the act of mutilating is used to relieve pain. The act is committed in privacy and is usually kept private. In factitious disorders the injuries are inflicted deliberately and are meant to produce symptoms that will attract the attention from others, like doctors, and eventually lead to hospital admissions. The lesions are not kept in privacy, although the act itself will be denied by the patient.

Differential diagnosis

Tattooing and piercing Some forms of self-mutilation are culturally and socially accepted. These can be defined as rituals and practices. Rituals reflect community traditions, very often with underlying symbolic meanings. Practices are used for cosmetic reasons or for (sub)cultural identification; they usually do not have an underlying symbolic meaning [4]. Tattoos and piercing can belong to both. These practices have varying levels of social acceptance and are seen by some as extremely mutilating. The behaviour, however, is not typical for self-mutilation. The majority of people who want to have a tattoo or piercing accept the pain of the process in order to attain a finished product. The person who shows self-mutilative behaviour seeks the pain for the purpose of feeling pain or seeing the blood as a way of escaping from unbearable feelings [28]. Suicidal behaviour Suicide and self-mutilation seem to have the same purpose, namely stopping the pain. For people who commit suicide the ultimate purpose is to end all feelings by killing oneself. For people who self-mutilate it is not the ending of life that is the purpose but to feel better after the act of self-mutilating. Self-mutilating can be a coping mechanism and a means of surviving situations in which suicide seems to be inescapable and the only way out of pain [29].

Clinical features. Depending on the methods employed by the patient, the lesions in self-mutilation are character-

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180.9

Fig. 180.6 Lip-lick dermatitis.

Fig. 180.8 Ligature around the thumb resulting in a demarcation.

Fig. 180.7 Bullous dermatosis after application of caustic substances to the skin.

Fig. 180.9 Self-inflicted burns on the arms.

ized by excoriations, ulcerations, purpura or bullae [3,30] (Figs 180.6–180.9). Methods include mechanical (e.g. rubbing, sucking, biting, use of bottles, sucking cups, scratching, picking, cutting, slashing, gouging and puncturing), thermal (burning with objects) and chemical (e.g. the application of caustic or hot agents and injections of various substances, like milk) stimuli. The lesions are single or multiple, and occur in an area accessible to the dominant hand. However, the lesions may be symmetrical and bilateral, especially after the patient has been confronted with the unilateral distribution of lesions. A significant sign is the presence of bizarre and angulated configurations. The lesions do not show any pre-stages.

The incidence is higher in females (adults and children) except for individuals involved in purposeful selfmutilation. The condition can be seen at any age, but is most common in adolescents and young adults [18]. The following are the main manifestations of self-mutilation: • Cutting: The most common form of self-mutilation is probably cutting or carving of the whole body or, in particular, body parts like the wrists. Cutting can be done with sharp objects, e.g. razorblades and glass. • Excoriations: Excoriations are probably most common in self-mutilation. Lesions are sometimes deep enough to cause ulceration and scarring. Lesions are often localized (regional), sharply bordered, deep, linear and crusted.

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• Acne excoriée de la jeune fille (excoriated acne): Acne patients often pick at their lesions. The majority of such patients are aware of and admit to their behaviour, and can be classified as neurotic excoriators. In extreme cases, the picking is more severe. Often, these patients are pubertal or adolescent girls who have only minimal acne. By manipulating their skin lesions, they transform them into excoriations or ulcers and cause scarring or postinflammatory hyperpigmentation. • Purpura: Purpura can be induced by sucking, cupping, rubbing or biting the skin, or with a bottle or a hard, rapidly moving object. • Burns: Self-induced burns are severe manifestations of a psychiatric disturbance. The skin is usually burned with a hot object, such as a cigarette. Most severe selfinduced burns are observed in adolescents, although some occur in children [31]. Friction burns can also be observed. Burn-like lesions can be the result of the application of caustic or hot agents and injections of various substances [3]. Burns in children are usually inflicted by another individual and are manifestations of child abuse or Munchausen syndrome by proxy (see Chapter 154). • Other manifestations: Lip-licking is a common and generally insignificant problem. Ligatures applied around a finger, extremity or penis may result in oedema, ulcerations or extreme demarcations and even amputations. Epistaxis and bleeding from other mucous surfaces, such as the gingiva, can be induced [32,33]. Also head banging or hitting the head or body against or with objects is seen. Self-inflicted injury of the eyes (irritation, wounding), nose, mouth or tongue can be observed. Genital mutilation, e.g. by scratching off the skin surrounding the vulva and anus or by inserting sharp objects into the vagina and/or anus, is rare.

Stereotypic self-mutilation Stereotypic self-mutilation is the result of monotonous, repetitive, sometimes rhythmic acts like head banging. Some of the acts closely resemble behaviour described as physiological habits. Also, other acts like eye poking, selfbeating and self-biting can be observed. Stereotypic self mutilation is seen in children with mental retardation, autism and Gilles de la Tourette syndrome. In Gilles de la Tourette syndrome familial occurrence is found in about 58% of the cases [34]. It can also be observed as a symptom of neurobiological disorders, such as in Lesch–Nyhan syndrome, Prader–Willi syndrome, familial dysautonomia or de Lange syndrome [34–38]. In Lesch–Nyhan syndrome lesions of the hands and lips can be seen in particular. Lesh–Nyhan syndrome is an X-linked recessive disorder caused by a deficiency of hypoxanthineguanine phosphoribosyltransferase activity [37]. The aetiology of Prader–Willi syndrome is

unknown, but associations with abnormalities of chromosome 15 (of paternal origin) and paternal exposure to hydrocarbons have been reported [36,39]. According to Ellis et al. there is an inverse relationship between the prevalence of self-injurious behaviour and intellectual abitilies: the more severe the level of mental retardation, the greater the prevalence of self-injurious behavior [37]. In a 1985 study of 10,000 mentally retarded persons by Griffin et al., 13.6% of the patients were found to engage in stereotypic self-mutilative behaviour [40]. Mostly the persons affected are not aware of their behaviour, which does not seem to have any recognizable symbolic value. Sometimes it can be interpreted as self-stimulating behaviour or as beaviour meant to suppress feelings of stress. This last idea is supported by the fact that one of the related factors seems to be institutionalization.

Major self-mutilation Major self-mutilation is rare. It refers to self-injurious behaviour leading to substantial physical and lasting damage: self-castration, severe genital mutilation, eye enucleation or amputation of fingers, hand or complete limbs. Motives for the behaviour are themes related to (sub)culture or counterculture, religious guilt or sexual themes. Major self-mutilation is seen as part of psychiatric problems, like psychosis and acute alcohol and drug abuse, religious rites and sub- and counter-cultural habits, and transsexuality. Major self-mutilation is very rare in minors, where it only occurs in combination with serious psychiatric problems or brain damage after a severe disease or trauma. In 1933 Goodhart and Savitsky described a 16-year-old girl who enucleated both her eyes without being able to explain her behaviour. She was known to have had a chronic encephalitis 8 years before the incident [41]. One of the problems in major self-mutilation is that there seems to be a ‘by proxy’ variant in which parents not only mutilate themselves, but also their children, as in female genital mutilation, which is practiced in some African countries as part of cultural rites [42].

General features of self-mutilation Pathology. Self-mutilation shows no characteristic histopathological pattern. The abnormalities are compatible with irritant dermatitis. Severity depends on the techniques used by the patient. Prognosis. Self-mutilation occurs in all age groups. It is more common in children, and has a significantly better prognosis. In some patients the clinical symptoms and signs are present for years before the diagnosis is made. Careful follow-up is indicated in all cases. Sometimes,

Physiological Habits, Self-Mutilation and Factitious Disorders

severe cases of self-mutilation in adults originate in childhood. However, in most children, the prognosis for complete recovery is excellent. Diagnosis. The morphology of the lesions and the history will usually indicate the suspected diagnosis. Organic disturbances and systemic diseases should be ruled out. When self-mutilation is denied by the patient, it is possible to establish the diagnosis by careful observation. Purpuric lesions can also be induced by stress, skin fragility, as side-effects of drugs and by applying a device to the skin (e.g. in Vietnam cao gio or coin rubbing). Purpura can be a symptom of thrombocytopenia, ‘painful bruising’ syndrome or vasculitis. Purpura may also be the result of child abuse. Treatment. There is no single treatment programme for self-mutilation, probably because self-mutilation is the result of many different causes and motives. Above all, it is the result of the complex interaction between the patient and his/her surroundings. Treatment approaches for selfmutilation can be divided into four categories: (i) behavioural modification; (ii) treatment devices and protective interventions; (iii) pharmacological treatment; and (iv) psychotherapy. Before choosing any treatment modality, it is first necessary to analyze the home and social environments, school and social influences and religious beliefs. Treatment should be directed at the causes of any precipitating stress [43,44]. Simple problems may be handled by the dermatologist [18]. A psychiatrist or psychologist should be consulted if the problem is more serious, or if early therapeutic attempts are not successful.

Behavioural modification The first step in behavioural modification is focused on building the child’s self-confidence and self-esteem [43,44]. The next steps are: (i) dispelling any threats of punishment; (ii) improving insight and understanding; (iii) maintaining authority; (iv) tackling the symptoms; and (v) recognizing positive self-actualizations. The parents are important in these stages of treatment. Interaction between the parent(s) and the child should be monitored, and keeping a diary may be helpful. A schedule of tasks and a change in attitude may have a positive effect on behaviour [43]. Up to 6 years of age the child undergoes the psychological development through which most children progress. During infancy and early childhood, oral habit phenomena are usually common, physiological and of relatively little importance [43]. In these cases, only limited therapeutic intervention is necessary. In trichotillomania, behavioural intervention may be successful [45]. In young children, trichotillomania is often accompanied

180.11

by thumb-sucking. The behavioural intervention may be aimed at the thumb-sucking and include aversive taste treatment and response-dependent alarm [46,47]. Trichotillomania is, however, not always associated with thumbsucking. Behavioural therapy is still possible in these situations and can include hypnotherapy or intensive parent–child interaction (increased physical contact, frequent praise, avoiding criticism and discussing response prevention) [48]. Nail biting can be treated with bittertasting aversive substances and competing response therapies [49].

Use of devices and protective interventions Use of devices is especially indicated in repetitive habit disorders. In trichotillomania, the child may be taught to pick hairs from a fuzzy toy [18]. Treatment of trichotillomania accompanied by thumb-sucking may also include a response-disrupting thumb-post [47]. Protective strategies (e.g. wearing a helmet in hand banging) are only supportive strategies and do not add to learning more effective strategies for handling stress or inconvenience. Pharmacological treatment Drugs include clomipramine, desipramine, fluoxetine and pimozide. In a study in 25 serious nail biting adults, clomipramine was superior to desipramine [50]. The same results were reported in the long-term treatment of serious trichotillomania [51]. Although anecdotal reports indicated that fluoxetine was effective, its efficacy could not be confirmed in a placebo-controlled, double-blind crossover study in 21 adults with trichotillomania [52]. Behavioural treatment can be combined with pharmacological modalities. This approach was reported to be successful, even in an autistic girl [53]. Psychotherapy Psychotherapy is warranted in cases in which the above approaches are unsuccessful, or after thorough psychological analysis establishes the presence of serious psychopathology. Often, a combined therapy with pharmacological agents and psychotherapy is used. Psychotherapy is more frequently indicated in cases of dermatitis artefacta and in obsessive–compulsive disorders. References 1 Favazza AR, Rosenthal RJ. Diagnostic issues in self-mutilation. Hosp Comm Psychiatr 1993;44:134–40. 2 Winchel RM, Stanley M. Self-injurious behaviour: a review of the behavior and biology of self-mutilation. Am J Psychiatr 1991;148: 306–15. 3 Hollender MH, Abram HS. Dermatitis factitia. South Med J 1973;66:1279. 4 Favazza AR. Bodies Under Siege – Self-mutilation and body modification in culture and psychiatry, 2nd edn. Baltimore, John Hopkinis University Press, 1996.

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5 Richman DM. Early intervention and prevention of self-injurious behaviour exhibited by young children with developmental disabilities. J Intellect Disabil Res 2008;52(1):3–17. 6 Parikh MS, Kolevzon A, Hollander E. Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. J Child Adolesc Psychopharmacol 2008;18(2):157–78. 7 Matson JL, Lovullo SV. A review of behavioral treatments for selfinjurious behaviors of persons with autism spectrum disorders. Behav Modif 2008;32(1):61–76. 8 Harth W, Taube KM, Gieler U. Facticious disorders in dermatology. J Dtsch Dermatol Ges 2010;12.e-pub. 9 Timofeyev AV. Self mutilation. 2002. http://wso.williams. edu/∼atimofey/self_mutilation/. 10 Favazza AR, Conterio K. Female habitual self-mutilators. Acta Psychiatr Scand 1989;78:283–9. 11 Suyemoto KL, MacDonald ML. Self-cutting in female adolescents. Psychotherapy 1995;32:162–71. 12 Ensink BJ. Confusing Realities, a Study on Child Sexual Abuse and Psychiatry. VU University Press, 1992. 13 Hobbs CJ, Wynne JM. Physical Signs of Child Abuse – A colour atlas, 2nd edn. Saunders, 2001. 14 Van der Kolk BA, Perry JC, Herman JL. Childhood origins of selfdestructive behavior. Am J Psychiatr 1991;148:1665–71. 15 Koblenzer C. Psychocutaneous Disease. Orlando, Grune-Stratton, 1987. 16 Gupta MA, Gupta AK. Dermatitis artefacta and sexual abuse. Int J Dermatol 1993;32:825–6. 17 Koo JYM, Smith LL. Obsessive–compulsive disorders in the pediatric dermatology practice. Pediatr Dermatol 1991;8:107–13. 18 Oranje AP, Peereboom-Wynia JDR, De Raeymaecker DMJ. Trichotillomania in childhood. J Am Acad Dermatol 1986;15:614–19. 19 Malon DW, Berardi D. Hypnosis with selfcutters. Am J Psychother 1987;50:531–41. 20 Cited in Martinson D. Self-injury: you are not the only one. 2002. http://www.palace.net/∼llama/psych/injury.html. 21 Stanley B, Gameroff MJ, Michalsen V et al. Are suicide attempters who self-mutilate a unique population? Am J Psychiatr 2001;158:427–32. 22 Schetky DH. A review of literature on the long-term effects of childhood sexual abuse. In Kluft RP, ed. Incest-related Syndromes of Adult Psychopathology. American Psychiatric Press, 1990:35–54. 23 Van der Kolk BA, Greenberg MS. The psychobiology of the trauma response: hyperarousal, constriction and addiction to traumatic reexposure. In Van der Kolk BA. Psychological Trauma. Washington DC, American Psychiatric Press, 1987:63–87. 24 Dulit RA, Fyer MR, Leon AC et al. Clinical correlates of self-mutilation in borderline personality disorder. Am J Psychiatr 1994;151:1305–11. 25 Stein DJ, Hollander E. Dermatology and conditions related to obsessive–compulsive disorder. J Am Acad Dermatol 1992;26:237–42. 26 Leonard HL, Rapoport JL. Pharmacotherapy of obsessive–compulsive disorders. Psychiatr Clin North Am 1989;12:963–70. 27 Rapoport JL. Annotation: childhood obsessive–compulsive disorder. J Child Psychol Psychiatr 1986;27:289–95. 28 Levenkron S. Cutting – Understanding and overcoming selfmutilation. New York, Norton, 1998. 29 Favazza AR. The coming of age of self-mutilation. J Nerv Mental Dis 1998;186:259–68. 30 Spraker MK. Cutaneous artifactual disease: an appeal for help. Pediatr Clin North Am 1983;30:659–68. 31 Stoddard FJ. A psychiatric perspective on self-inflicted burns. J Burn Care Rehabil 1993;14:480–2. 32 Tunnessen WW, Chessar IJ. Factitious cutaneous bleeding. Am J Dis Child 1984;138:354–5.

33 Rodd HD. Self-inflicted gingival injury in a young girl. Br Dent J 1995;178:28–30. 34 Regeur L, Pakkenberg B, Fog R et al. Clinical features and long-term treatment with pimozide in 65 patients with Gilles de La Tourette’s syndrome. J Neurol Neurosurg Psychiatr 1986;49:791–5. 35 Lesh M, Nyhan WL. A familiar disorder or uric acid metabolism and central nervous system function. Am J Med 1964;36:561–70. 36 Prader A, Labhart A, Willi H. Ein Syndrom von Adipositas, Kleinwuchs, Krytorchismus and Oligophrenie nach Myatonieartigem Zustand im Neugeborenalter. Schweiz Med Wochenschr 1956;86:1260–1. 37 Ellis CR, Singh NN, Jackson EV. Problem behaviors in children with develomental disabilities. In Parmelee DX. Child and Adolescent Psychiatry. St Louis: Mosby-Year Book, 1996:263–75. 38 Gadoth ME. Oro-dental self-mutilation in familial dysautonomia. J Oral Pathol Med 1994;23:273–6. 39 Butler MG, Palmer CG. Clinical and cytogenetic survey of 39 individuals with Prader–Labhart–Willi syndrome. Am J Med Genet 1986;23:793–809. 40 Griffin et al. cited in Timofeyev AV. Self mutilation. 2002. http:// wso.williams.edu/∼atimofey/self_mutilation/. 41 Goodhart S, Savitsky N. Self mutilation in chronic encephalitis. Am J Med Sci 1933;185:674–84. 42 Dorkenoo E. Cutting the Rose, Female Genital Mutilation – the practice and its prevention. London, Minority Rights Publications, 1995. 43 Peterson JE, Schneider PE. Oral habits. A behavioral approach. Pediatr Oral Health 1991;38:1289–307. 44 Leung AKC, Robson WLM. Nail biting. Clin Pediatr 1990;29:690–2. 45 Blum NJ, Barone VJ, Friman PC. A simplified behavioral treatment for trichotillomania: report of two cases. Pediatrics 1993;75: 993–5. 46 Friman PC, Finney JW, Christophersen ER. Behavioral treatment of trichotillomania: an evaluative review. Behav Ther 1984;15:249–65. 47 Watson TS, Allen KD. Elimination of thumb-sucking as a treatment for severe trichotillomania. J Am Acad Child Adoles Psychiatr 1993;32:830–4. 48 Friman PC, Finney JW, Christophersen ER. Behavioral treatment of trichotillomania: an evaluative review. Behav Ther 1984;15:249–65. 49 Silber KP, Haynes CE. Treating nail biting: a comparative analysis of mild aversion and competing response therapies. Behav Res Ther 1992;30:15–22. 50 Leonard HL, Lenage MC, Swedo SE et al. A double-blind comparison of clomipramine and desipramine treatment of severe onychophagia (nail biting). Arch Gen Psychiatr 1991;48:821–7. 51 Swedo SE, Lenane MC, Leonard HL. Long-term treatment of trichotillomania (hair pulling). N Engl J Med 1993;329:141–2. 52 Christenson GA, Mackenzie TB, Mitchell JE et al. A placebo-controlled double-blind crossover study of fluoxetine in trichotillomania. Am J Psychiatr 1991;148:1566–71. 53 Holttum JR, Lubetsky MJ, Eastman LE. Comprehensive management of trichotillomania in a young autistic girl. J Am Acad Child Adoles Psychiatr 1994;33:577–81.

Factitious disorders Factitious disorder or Munchausen syndrome Munchausen syndrome (now known as factitious disorder) was first described by Asher in 1951 [1]: ‘Here is described a common syndrome which most doctors have seen, but about which little has been written. Like the famous Baron von Munchausen, the persons affected have always travelled widely; and their stories, like those

Physiological Habits, Self-Mutilation and Factitious Disorders

attributed to him, are both dramatic and untruthful. Accordingly the syndrome is respectfully dedicated to the baron, and named after him’. According to the American Psychiatric Association, factitious disorder is characterized by the following three criteria : (i) the patient intentionally feigns physical or mental signs or symptoms; (ii) the patient’s apparent motive for this behavior is to occupy the sick role; and (iii) there are no other motives such as found in malingering (financial gain, revenge or avoiding legal responsibility) [2]. The feigning can be done by consciously self-inflicting injuries and/or falsely reporting symptoms. Until a few years ago Munchausen syndrome was almost exclusively described in adults. Only a few cases were known from children and adolescents. Libow reviewed the literature and described 42 cases of illness falsification by children [3]. The most commonly reported falsified or induced conditions were fevers, ketoacidosis, purpura and infections. The fabrications ranged from false symptom reporting to active injections, bruising and ingestions. She concluded that better understanding and identification of children with illness falsification is likely to help prevent the development of chronic adult factitious disorders. Some of the symptoms in fabricated or induced illness have known for centuries. In 2001, Bjornson and Kirk reported a case of a 12-year-old girl with artificial haemoptysis [4]. Artificial haemoptysis was already known in the Middle Ages. Hysterics were known to place leeches in their mouth to simulate haemoptysis. They also abraded their skin to simulate dermatological disorders [5]. Factitious disorder by purposeful self-mutilation must be differentiated from self-mutilation that satisfies a psychological need (see above). Contagious self-mutilation behaviour in groups has been described in prisons, schools and psychiatric institutions. These epidemics are more common in females [6] and may occur in young people without clear psychopathology [7]. The relationship between factitious disorder and factitious disorder by proxy, as already mentioned by Libow, is illustrated by a case report of a mother with dermatitis artefacta on the forearm and lower legs who produced the same lesions on her child’s face [8].

Factitious disorder by proxy, paediatric condition falsification or Munchausen syndrome by proxy Factitious disorder by proxy (also known as paediatric condition falsification or Munchausen syndrome by proxy) was first described by Meadow in 1977 [9]: ‘Here are described parents who, by falsification, caused their

180.13

children innumerable harmful hospital procedures – a sort of Munchausen syndrome by proxy’. Paediatric condition falsification is defined as a particular form of physical and psychological maltreatment whereby a disease is invented or induced in a child by a parent (mostly the mother) or someone who is responsible for the child’s welfare. The behaviour of the perpetrator leads to repeated presentation of the child within the health care system, whereby repeated medical investigations and, eventually, interventions are performed. Signs and symptoms may be actively or passively induced. Passive induction includes the presentation of a fictitious medical history and/or the description of fictitious abnormalities. Active induction is possible by causing actual abnormalities or falsifying medical records [10]. If these factitious disorders/abnormalities involve the skin, then a wide range of signals may be present, varying from clearly recognizable self-mutilation lesions, through a suggestive history (for a dermatological disorder), to frequent, very persistent ‘actual’ dermatological disorders. As mentioned before, these disorders vary from easily recognizable artefacts to complicated cutaneous infections [10]. Abnormalities that have actually been observed by physicians or reported by the perpetrator and found on the skin and mucosa in paediatric condition falsification (and factitious disorder) are [10–14]: • Haemorrhagic tendency/coagulopathies/easy bruising. • Cutaneous abscesses (sterile or infected). • Cyanosis. • Diaphoresis. • Dermatitis artefacta/(cutaneous) rashes of unknown cause. • Eczema. • Erythema. • Excoriations. • Vaginal discharge and other abnormalities, such as vaginal or anal bleeding and/or abnormalities in the anogenital area. • Abnormalities in the mouth. • Oedema. • Otitis externa. • Vesicular eruptions (clustered, chronic). • Cutaneous abnormalities in food allergy and other allergic reactions. • Painting of the skin (may mimic cellulitis of purpura). For more detailed information the reader is referred to Chapter 154. References 1 Asher R. Munchausen’s syndrome. Lancet 1951;i:339–41. 2 American Psychiatric Association. DSM-IV-TR. Washington, DC, American Psychiatric Association, 2000.

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3 Libow JA. Child and adolescent illness falsification. Pediatrics 2000;105:336–42. 4 Bjornson CL, Kirk VG. Munchausen’s syndrome presenting as hemoptysis in a 12-year-old girl. Can Respir J 2001;8:439–42. 5 Tlacuilo-Parra JA, Guevara-Gutierrez E, Garcia-De La Torre I. Factitious disorders mimicking systemic lupus erythematosus. Clin Exp Rheumatol 2000;18(1):89–93. 6 Ross RR, McKay HB. Self-Mutilation. Lexiton, MA: DC Health, 1979. 7 Fennig S, Carlson GA, Fennig S. Contagious self-mutilation. J Am Acad Child Adoles Psychiatr 1995;34:402–3. 8 Jones DPH. Dermatitis artefacta in a mother and baby as child abuse. Br J Psychiatr 1983;143:199–200. 9 Meadow R. Munchausen syndrome by proxy: the hinterland of child abuse. Lancet 1977;ii:343–5.

10 Bilo RAC. Forensic pediatric dermatology: my skin is only the top layer of the problem. In Oranje AP, de Waard – van der Spek FB, Bilo RAC. Dermatology from Young to Old. Zwolle, Isala Series No. 43, 2003:45–52. 11 Rosenberg DA. Munchausen syndrome by proxy. In Reece RM. Child Abuse: Medical diagnosis and management. Philadelphia, LeaFebiger, 1994:266–78. 12 Stankler L. Factitious skin lesions in a mother and two sons. Br Med J 1977; 97:217. 13 Johnson CF. Dermatological manifestations. In Levin AV, Sheridan MS. Munchausen Syndrome by Proxy – Issues in diagnosis and treatment. New York, Lexington Books, 1995:189–200. 14 Schreier HA, Libow JA. Munchausen by proxy syndrome: a modern pediatric challenge. J Pediatr 1994;125:S110–15.

181.1

C H A P T E R 181

Principles of Paediatric Dermatological Therapy Dennis P. West1, Candrice Heath1, Ann Cameron Haley1, Anne Mahoney1 & Giuseppe Micali2 1

Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, USA Dermatology Clinic, University of Catania, Catania, Italy

2

Principles of therapy, 181.1

Transdermal therapeutic systems, 181.5

Systemic therapeutic agents, 181.16

Barrier properties of skin, 181.1

Skin metabolism of drugs, 181.6

Conclusion, 181.20

Factors affecting drug penetration

Vehicles, 181.6

into skin, 181.2 Systemic delivery of drugs through

Topical dermatological therapeutic agents, 181.7

skin, 181.5

Principles of therapy Although general principles for the treatment of paediatric skin diseases are similar to those involving the adult, several unique aspects regarding dermatological therapeutics in the paediatric patient should be considered. The therapeutic approach to a paediatric patient, especially a newborn or an infant, differs from an older patient because of the greater difficulty in obtaining a detailed medical history, which includes time of onset of the dermatosis, original morphology of lesions at their onset and primary symptomatology. Although parents may be helpful in providing information, important symptoms may be overlooked or misunderstood. In the paediatric population, these issues may pose serious problems at the diagnostic or therapeutic decision stage. Moreover, of the innumerable topical preparations and systemic agents currently available in dermatology, only a few have been specifically designed or tested for paediatric use. As a result, topical therapy is preferred, when possible, to minimize the risk of systemic toxicity [1]. Further, treatment of skin disorders in the paediatric patient is generally aimed at restoring normal appearance and physiological state of the skin. When systemic drugs are used, the skin is just one of several possible target organs, even though it may be the only intended target organ. A systemically administered drug typically reaches the skin only after gastrointestinal absorption, biotransformation in the liver and eventual distribution to remote tissues of the body. As would be expected, the pharma-

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

cokinetics of a drug following systemic administration differ quite considerably from those following external treatment. In the latter case, the drug is applied directly to the target organ. Topical therapy, therefore, is often preferred as it may deliver medication at an optimum concentration to the target tissue, with reduced risk for systemic toxicity compared with other routes of administration. Reference 1 Siegfried EC, Shah PY. Skin care practices in the neonatal nursery: a clinical survey. J Perinatol 1999;19:31–9.

Barrier properties of skin To be effective, a topically applied drug must be absorbed through the stratum corneum, the outer layer of the skin, and into metabolically active epidermis and dermis. The stratum corneum represents the main barrier to free movement of substances through skin. It consists of flat, dead keratinocytes arranged in closely packed stacks that are approximately 12 cell layers deep. The intercellular matrix is composed predominantly of lipids, whereas the intracellular space is made of proteins. Composition of the stratum corneum is as follows: 50% protein, 20% lipid, 23% water-soluble substances and 7% water. In general, drugs permeate the stratum corneum at rates that are determined largely by their lipid–water coefficients, water-soluble ions and polar molecules [1]. Permeation through stratum corneum is thought to occur primarily through the cell membranes, for example transcellularly. Studies suggest the existence of a significant intercellular volume, which can facilitate polar drugs to

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diffuse within the aqueous region of the intercellular bilayered structure, and non-polar drugs within the hydrophobic region of the lipid chain in the same structure [2]. Although the stratum corneum acts as an effective barrier system to the penetration of exogenous substances into the skin, it also acts as a barrier to the loss of endogenous substances. This is of particular relevance when, owing to extensive tissue damage (e.g. severe burns or destruction of the epidermis), loss of water by evaporation may clinically result in life-threatening problems owing to deregulation of the normal homeostatic process. Therefore, the rate of transepidermal water loss (TEWL) may provide predictive information on the status of the skin barrier and, consequently, on the pharmacokinetics of transdermal drugs [3]. Acidification of the stratum corneum was originally thought to be central in the defence against infection [4]. However, recent studies have shown that acidfication of the stratum corneum is also necessary to the formation of a functioning permeable barrier. For example, the enzymes β-glucocerobrosidase and acid sphingomyelinase respectively metabolize glucosylceramides and sphingomyelin to ceramides, which are lipids in the extracellular membrane responsible for barrier permeability. Thus, if the pH of the stratum corneum increases, enzyme metabolism is impaired and permeability is not optimal [4]. References 1 Vecchia BE, Bunge AL. Evaluating the transdermal permeability of chemicals. In: Guy RH, Hadgraft J (eds) Transdermal Drug Delivery, 2nd edn. New York: Marcel Dekker, 2003. 2 Sznitowska M, Berner B. Polar pathway for percutaneous absorption. Curr Prob Dermatol 1995;22:164–70. 3 Aalto-Korte K, Turpeinen M. Transepidermal water loss and absorption of hydrocortisone in widespread dermatitis. Br J Dermatol 1993;128:633–5. 4 Fluhr JW, Elias PM, Man MQ et al. Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification? J Invest Dermatol 2010;130:2141–4.

Factors affecting drug penetration into skin (Box 181.1) Age The full-term infant has a well-developed epidermis, which, similar to adults, possesses excellent barrier properties. By contrast, the infant who is born prematurely, particularly before 30 weeks of gestation, has a thin epidermis with a poorly developed stratum corneum [1]. Although rapid postnatal maturation of the epidermis occurs over the first 2–3 weeks of life [2], the preterm infant’s skin is a poorly functioning barrier in this early neonatal period [3,4]. As a consequence, there is a high

Box 181.1 Factors affecting drug penetration into skin • • • • • • • •

Age Anatomical site Appendages Hydration of stratum corneum Damage to the stratum corneum Solute Vehicle Technique of application

TEWL that may correspond to problems in fluid balance and temperature control, as well as abnormal absorption of topically applied agents. The latter may have therapeutic as well as toxicological implications (see Chapter 3). Nachman and Esterly [5] applied a 10% phenylephrine solution on the skin of neonates of different gestational age and compared skin blanching as an indirect measure of skin permeability. Infants were divided into three groups: 28–34 weeks, 35–37 weeks and 38–42 weeks of gestational age. The authors demonstrate that infants in the 28–34 week age group had a rapid blanching response that lasted from 30 min to several hours. Infants in the 35–37 week gestational group had less response than the first group. Those in the 38–42 week group failed to respond in most cases. After the 21st day of postnatal age, most of the infants lost the blanching response regardless of their gestational age at birth. Harpin and Rutter [3] modified the above-mentioned study and looked at skin blanching responses using two different strengths of phenylephrine, but also studied TEWL in the infants who were classified into different gestational age groups: group A, less than 30 weeks; B, 30–32 weeks; C, 33–36 weeks; and D, 37 weeks or more. As with the previous study, the oldest group had no or minimal response to phenylephrine and TEWL was low. In group C, a mild blanching response was observed and rapidly decreased by 1 week postnatal age. TEWL was slightly greater than in group D, but at 1 week postnatally it was equivalent to the mature group D. In the younger group B, a high blanching response was initially seen, but by 2 weeks’ postnatal age it was minimally apparent. TEWL was initially elevated but was equivalent to mature levels by 10 days’ postnatal age. In the youngest gestational age group, a very high blanching response together with a very high TEWL was seen. However, by 2 weeks’ postnatal age both assessments were similar to the mature group. A correlation between response to skin blanching and TEWL was noted in group D. West and co-workers [6] applied stable, isotope-labelled benzoic acid to the skin of premature infants of various

Principles of Paediatric Dermatological Therapy

gestational and postnatal ages and measured urinary levels of the administered agent. Benzoic acid was used as it is endogenous in mother ’s milk and is considered non-toxic at the doses used, is well tolerated by the skin, readily absorbed and rapidly excreted in urine without accumulation in the body. Results of the study demonstrated that skin absorption in premature infants is most marked in the immediate postnatal period, but declines to that expected of a mature neonate within 3 weeks, with correlation to gestational age. Children may also have an increased risk of systemic toxicity from a topically applied drug because of their greater body surface area to weight ratio when a given amount of an applied drug represents a greater dose to the system (in mg/kg) compared with adults [7,8].

Anatomical site Drug penetration at different anatomical sites results from variable thickness of the stratum corneum. In general, anatomical sites can be ranked in the following order of decreased permeability: postauricular, scrotum, abdomen, scalp, forearm, foot and sole [9].

Appendages Significant penetration of drugs through an appendageal pathway (shunt route such as via hair follicles) may contribute to steady-state diffusion, although it may contribute more significantly in the very early stages of diffusion or may be more important for ions and larger molecules [10]. The extent of contribution is also limited by the fact that appendages only cover 0.1–1% of the skin surface [5]. However, the hair follicles signify invaginations, which extend deep into the dermis with a considerable increase in the actual surface area available for penetration. The extent of appendageal penetrance also depends on the solute. Highly polar non-electrolytes that are capable of binding to hydrated keratin, thus hindering diffusion across the stratum corneum, are more likely to undergo relatively prominent shunt diffusion [11]. In vivo studies have also shown that shunt diffusion could be of significance in penetration of drugs through the skin [12]. If appendages are modified by trauma, for example burned skin, the short-cut diffusion of drugs through these appendages might be impaired, even after wound healing has occurred. These observations also suggest that the targeting of a drug to appendages could be important for the treatment of some follicular disorders [13].

Hydration of the stratum corneum Hydration of the stratum corneum is a key factor in the penetration of a drug through the skin [14]. Hydration increases the rate of absorption of most substances that can permeate skin, particularly water-soluble compounds.

181.3

Immersion of the skin in water results in its uptake by corneocytes and saturation of the intercellular spaces, producing an increased thickness of the stratum corneum. Further exposure to water causes replacement of lipid covalent bonds between the corneocytes by weak hydrogen (water) bonds and separation of cells. This phenomenon also occurs in naturally occluded areas where evaporation of water is restricted, especially in the flexural sites of the axillae and groin, where absorption of drugs is likely to be increased.

Damage to the stratum corneum If the stratum corneum is damaged or removed by stripping, correlating incremental increases in drug penetration can be expected [15]. Skin diseases that disrupt the stratum corneum will similarly alter barrier function. In ichthyosis, permeability is remarkably increased because the stratum corneum alteration reduces skin barrier capability. In irritant contact dermatitis, disintegration of the stratum corneum often leads to a dry, scaly skin as a result of contact with solvents and soaps; although the barrier is altered, the thickened epidermis has little impact on the permeation process. In chronic eczema, however, there is typically a thickened epidermis and stratum corneum, which decreases absorption of drugs through the skin. In general, the thicker the stratum corneum, as in orthokeratosis, the lower the rate of influx. Psoriasis also involves a thickened stratum corneum and a generally thickened epidermis, but TEWL is increased up to 20-fold [16]. Of note, occlusion alone serves to restore barrier effect and lesions tend to respond. Recent studies have shown that ichthyosis vulgaris and atopic dermatitis result from abnormalities in the profilaggrin gene, one of the major protein components within the granular layer of the epidermis. Deficiencies in filaggrin lead to defective skin barrier function and help to explain clinical phenotypes of the diseases [17].

Solute Awareness of the pharmacological properties of the drugs used in treating dermatological diseases is essential to a rational therapeutic approach. Important determinants for the rate of diffusion of a molecule through the stratum corneum are its size and shape, its lipid– water partition coefficient and the pH of the drug and surrounding tissue. Molecular mass and size play a considerable role in stratum corneum penetration. The size of the drug particles penetrating the skin also determines the rate of cutaneous absorption, such that the smaller the particle, the greater the absorption rate. The presence of polar groups in the molecule may also significantly impair the rate of drug penetration [18]. Many simple polar electrolytes penetrate the stratum corneum at the same rate as water, with similar diffusion constants, for

181.4

Chapter 181

example ethanol and propranolol. A study on a series of corticosteroids showed that the more polar steroids have a much lower diffusion constant, and this seems to be due to increased binding to keratin [19]. For less polar compounds (lipid-soluble non-electrolytes) with similar diffusion constants, the permeability must be determined by differences in the partition coefficient (Fick’s Law) [20].

Vehicle The vehicle is a substance that forms the medium in which the active medicament is either dissolved or dispersed for application to the skin surface [21]. It is pharmacologically inert but has some important physical properties. The vehicle itself may cause sensitization reactions, although these are more often due to additives and are quite uncommon in children. The vehicle may have many functions that are sometimes conflicting: (i) to increase the penetrance of a substance through the skin; (ii) to decrease permeation and hold the substance in the upper layers of the skin (i.e. antifungals in the stratum corneum, retinoids in the epidermis); and (iii) to target the drug to the skin appendages. Vehicles that contain oleaginous solids with little or no water are called ointments; those with 20–50% water are called creams; a greater amount of water results in a lotion. Vehicles can also be categorized into ointments, emulsions (oil in water, water in oil) and gels. Ointments are usually composed of a fairly lipophilic drug in a base such as petrolatum, mineral oil, waxes or organic alcohols. They spread easily on the skin and are completely water insoluble with maximal water-retaining occlusive properties. They usually form a greasy film on the skin and can cause excessive heat retention, which may cause discomfort to the patient. An emulsion is a two-phase system of otherwise immiscible substances mixed with an oil or an emulsifier. They are generally more cosmetically acceptable. They may be water in oil (cold creams) or oil in water (vanishing creams). Gels are lotions with no oleaginous phase. They consist of fatty alcohols or fatty acids loosely aggregated with water, forming a gelatinous matrix at room temperature. When applied to the skin, gels melt and the water evaporates, leaving semi-solid particles and the active drug on the skin [22]. Other components that may be added to vehicles include emulsifiers, stabilizers, thickening agents and humectants. Some foam vehicles offer clinical and cosmetic advantages. Foam may have an ability to deliver active drug at an increased rate compared to other vehicles. It is likely that components of foam vehicles enhance penetration and alter barrier properties of the outer stratum

corneum. This is in contrast to other topical delivery vehicles that first require hydration of an intercellular space in the stratum corneum. Foam vehicles consist of oil, water and an organic solvent, and may be a liquid pressurized in an aluminium container with hydrocarbon propellant [23]. Choice of vehicle is based on clinical appearance of skin lesions and anatomical location. An oil-in-water vanishing emulsion may be best for oozing lesions, whereas an ointment that provides a mildly occlusive film is better suited to dry scaly skin. Preparations for dense follicular areas such as the scalp are more amenable to creams or gels [24]. Particular care is needed in body fold areas, where the microenvironment (temperature, humidity, pH) may be quite different from that of glabrous skin, and tissue maceration or percutaneous absorption may be significantly enhanced.

Technique of application It is important to prescribe appropriate amounts of topical medication for children. Parents and physicians should carefully monitor frequency of application of drugs that may produce systemic toxicity via percutaneous absorption. Conversely, the quantity of sunscreens usually applied is less than recommended [25,26]. Occlusive dressings increase absorption of some molecules, for example corticosteroids, up to 100-fold greater than with non-occlusion [27]. Occlusion with a plastic film dressing increases hydration and temperature, leading to enhanced drug permeation. Some compounds, i.e. topically applied corticosteroids, may induce a ‘reservoir effect’ by which the stratum corneum retains drug for several days after application [28]. Occlusive dressings may, however, increase the risk of undesirable sideeffects such as steroid atrophy and infection [27]. Certain vehicles, so-called accelerants, promoters or penetration enhancers, may also induce a stratum corneum reservoir effect [29]. References 1 Cartlidge P. The epidermal barrier. Semin Neonatol 2000;5:273–80. 2 Rutter N. Clinical consequences of an immature barrier. Semin Neonatol 2000;5:281–7. 3 Harpin VA, Rutter N. Barrier properties of the newborn infant’s skin. J Pediatr 1983;102:419–25. 4 Mancini AJ, Sookdeo-Drost S, Madison KC et al. Semipermeable dressings improve epidermal barrier function in premature infants. Pediatr Res 1994;36:306–14. 5 Nachman RL, Esterly NB. Increased skin permeability in preterm infants. J Pediatr 1971;79:628–32. 6 West DP, Halket JM, Harvey DR et al. Percutaneous absorption in preterm infants. Pediatr Dermatol 1987;4:234–7. 7 West DP, Worobec S, Solomon LM. Pharmacology and toxicology of infant skin. J Invest Dermatol 1981;76:147–50. 8 Afsar FS. Skin care for preterm and term neonates. Clin Exp Dermatol 2009;34(8):855–8.

Principles of Paediatric Dermatological Therapy 9 Rougier A, Dupuis D, Lotte C et al. Regional variation in percutaneous absorption in man: measurement by the stripping method. Arch Dermatol Res 1986;278:465–9. 10 Delgado-Charro MB, Guy RH. Iontophoresis: applications in drug delivery and noninvasive monitoring. In: Guy RH, Hadgraft J, eds. Transdermal Drug Delivery, 2nd edn. New York: Marcel Dekker, 2003. 11 Hadgraft J. Modulation of the barrier function of the skin. Skin Pharmacol Appl Skin Physiol 2001;14:72–81. 12 Otberg N, Patzelt A, Rasulev U et al. The role of hair follicles in the percutaneous absorption of caffeine. Br J Clin Pharmacol. 2008 Apr;65(4):488–92. 13 Jamoulle JC, Grandjean L, Lamaud E et al. Follicular penetration and distribution of topically applied CD-271, a new naphthoic acid derivative intended for topical acne treatment. J Invest Dermatol 1990;94:731–2. 14 Rougier A, Lotte C, Maibach HI. In vivo relationship between percutaneous absorption and transepidermal water loss. In: Bronaugh RL, Maibach HI, eds. Percutaneous Absorption, 3rd edn. New York: Marcel Dekker, 1999. 15 Anissimov YG, Roberts MS. Diffusion modeling of percutaneous absorption kinetics. 1. Effects of flow rate, receptor sampling rate, and viable epidermal resistance for a constant donor concentration. J Pharm Sci 1999;88:1201–9. 16 Ghadially R. Psoriasis and ichthyoses. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York: Marcel Dekker, 2002. 17 McGrath JA, Uitto J. The filaggrin story: novel insights into skinbarrier function and disease. Trends Mol Med. 2008;14(1):20–7. 18 Schaefer H, Redelmeier TE. Relationship between the structure of compounds and their diffusion across membranes. In: Schaefer H, Redelmeier TE, eds. Skin Barrier. Basel: Karger, 1996. 19 Vecchia BE, Bunge AL. Partitioning of chemicals into skin: results and predictions. In: Guy RH, Hadgraft J, eds. Transdermal Drug Delivery, 2nd edn. New York: Marcel Dekker, 2003. 20 Hadgraft J, Guy RH. Feasibility assessment in topical and transdermal delivery: mathematical models and in vitro studies. In: Guy RH, Hadgraft J, eds. Transdermal Drug Delivery, 2nd edn. New York: Marcel Dekker, 2003. 21 Archer CB. The skin as a barrier. In: Champion RH, Burton JL, Burns JL et al. Textbook of Dermatology, 6th edn. Oxford: Blackwell Science, 1998. 22 Ghadially R, Shear NH. Topical therapy and percutaneous absorption. In: Yaffe SJ, Aranda JV, eds. Pediatric Pharmacology. Therapeutic Principles in Practice, 2nd edn. Philadelphia: W.B. Saunders, 1992. 23 Huang X, Tanojo H, Lenn J, Deng CH, Krochmal L. A novel foam vehicle for delivery of topical corticosteroids. J Am Acad Dermatol. 2005;53(1 Suppl 1):S26–38. 24 Harper JI. Skin disorders. In: Barltrop D, Brueton MJ, eds. Paediatric Therapeutics. Principles and Practice. Oxford: ButterworthHeinemann, 1991. 25 Jungman E, Maibach HI. Enhancing sunscreen efficacy in the ‘real’ world? J Dermatolog Treat. 2009. 26 Kim SM, Oh BH, Lee YW, Choe YB, Ahn KJ. The relation between the amount of sunscreen applied and the sun protection factor in Asian skin. J Am Acad Dermatol. 2010;62(2):218–22. 27 Hepburn D, Yohn JJ, Weston WL. Topical steroid treatment in infants, children, and adolescents. In: Schachner LA, ed. Advances in Dermatology. St Louis: Mosby Year Book, 1994. 28 Strober BE, Washenik K, Shupack JL. Principles of topical therapy. In: Freedberg IM, Eisen AZ, Wolff K et al. Fitzpatrick’s Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 2003. 29 Elias PM, Feingold KR, Tsai J et al. Metabolic approach to transdermal drug delivery. In: Guy RH, Hadgraft J, eds. Transdermal Drug Delivery, 2nd edn. New York: Marcel Dekker, 2003.

181.5

Systemic delivery of drugs through skin Drugs may be delivered via the skin to the skin surface, stratum corneum, the epidermis/dermis or the systemic circulation [1]. Usually the goal of topical treatment is permeation of drug to the epidermis/dermis with minimal effect on the systemic circulation [2]. The goal of transdermal drug delivery via skin patches is to deliver drug to the systemic circulation. Some advantages of transdermal systemic drug delivery are avoidance of first-pass liver metabolism and gastrointestinal side-effects and enzyme action. Not all drugs can be delivered through or to the skin. The factors affecting skin barrier properties can be manipulated to increase drug permeation through skin. References 1 Block L. Medicated topicals. In: Gennaro AR, Popovich NG, Der Marderosian AH et al. (eds) Remington. The Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott Williams and Wilkins, 2000. 2 Polano MK, Ponec M. Bioavailability and effects of various vehicles on percutaneous absorption. In: Mauvais-Jarvis P, Vickers CFH, Wepierre J (eds) Percutaneous Absorption of Steroids. London: Academic Press, 1980.

Transdermal therapeutic systems Transdermal therapeutic systems (TTSs) deliver drugs through the skin to elicit systemic therapeutic effects. This dosage form usually consists of a multilayer patch containing a reservoir of highly soluble drug, an insoluble outer covering and a rate-controlling microporous polymeric membrane. The microporous membrane side of the patch is held against the skin by adhesive, allowing the drug direct contact with the skin. The membrane controls the rate at which drug is delivered to the skin and therefore the rate of absorption. The benefit of these systems is that they may allow for long-term administration of drug, while avoiding the potential difficulties of other administration routes [1]. Only certain drugs, however, are suitable for transdermal delivery. The drug must penetrate the skin at adequate rates so that the rate-limiting step is supply of drug from the system and not the ability of the skin to transport drug. This allows drug input to be constant in all patients despite variations in skin permeability. Usually, agents effective at a parenteral dose of 2 mg per day or less are ideal for transdermal delivery. The less potent the drug, the higher its skin permeability must be to achieve a therapeutic response through a reasonable area of skin [2,3]. Currently available TTSs include scopolamine, nitroglycerin, nicotine, clonidine and 17-β-oestradiol for use in

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Box 181.2 Advantages of transdermal therapeutic systems over traditional topical dosage forms • Avoids the need for intravenous therapy, which is both inconvenient and risky • Avoids oral therapy, which is sometimes associated with variable absorption and metabolism • Permits the use of drugs with a short half-life • Avoids hepatic first-pass effect and allows lower daily dosage of drug • Permits reversibility of drug delivery by removal of the system from the skin • Provides a simplified drug regimen • Decreases the chance of over- or underdosing

the treatment of motion sickness, angina pectoris, smoking cessation, hypertension and hormone replacement respectively. TTSs for paediatric use are in development, as evidenced by preliminary studies using theophylline for the treatment of apnoea in premature infants, showing positive results [4–6]. There are several advantages to using TTSs. Some authors have noted that transdermal delivery approaches zero-order drug kinetics, which is similar to the administration of a continuous intravenous infusion, and thereby provides some distinct advantages over traditional topical dosage forms as shown in Box 181.2. References 1 Nahata MC, Taketomo C. Pediatrics. In: DiPiro JT, Talbert RL, Yee GC et al. (eds) Pharmacotherapy. A Pathophysiologic Approach, 6th edn. New York: McGraw-Hill, 2005. 2 Ghadially R, Shear NH. Topical therapy and percutaneous absorption. In: Yaffe SJ, Aranda JV (eds) Paediatric Pharmacology. Therapeutic Principles in Practice, 2nd edn. Philadelphia: W.B. Saunders, 1992. 3 Surber C, Smith EW, Schwarb FP. Drug concentration in the skin. In: Bronaugh RL, Maibach HI (eds) Percutaneous Absorption, 3rd edn. New York: Marcel Dekker, 1999. 4 Rutter N. Clinical consequences of an immature barrier. Semin Neonatol 2000;5:281–7. 5 West DP, Worobec S, Solomon LM. Pharmacology and toxicology of infant skin. J Invest Dermatol 1981;76:147–50. 6 Micali G, Bhatt RH, Distefano G et al. Evaluation of transdermal theophylline pharmacokinetics in neonates. Pharmacotherapy 1993;13:386–90.

Skin metabolism of drugs Not only may drugs penetrate the skin unchanged, but they may also be metabolized in the skin or interact with receptors present on or in epidermal cells. Enzyme systems responsible for drug metabolism in skin resemble those of the liver. This system is membrane bound and requires NADPH and oxygen for catalytic activity, as well as exhibiting a pH optimum [1].

Oxidative reactions that occur in skin include alcohol oxidation, hydroxylation of aliphatic and alicyclic carbon atoms, oxidation of aromatic rings, deamination and dealkylation. Steroid hormones, oestradiol, oestriol, as well as glucocorticoids, prostaglandins, retinoids, benzoyl peroxide, aldrin, anthralin, 5-fluorouracil, nitroglycerin, theophylline and propranolol are among those drugs that have been demonstrated to undergo significant skin metabolism [2]. There is little information on conjugation reactions in skin but methylation, sulphate conjugation and glucuronide formation have been demonstrated [2]. The skin is also involved in metabolic activation of carcinogens such as benzopyrene by oxidation of aromatic rings [3]. References 1 Ghadially R, Shear NH. Topical therapy and percutaneous absorption. In: Yaffe SJ, Aranda JV (eds) Paediatric Pharmacology. Therapeutic Principles in Practice, 2nd edn. Philadelphia: W.B. Saunders, 1992. 2 Bronaugh RL, Kraeling MEK, Yourick JJ et al. Cutaneous metabolism during in vitro percutaneous absorption. In: Bronaugh RL, Maibach HI (eds) Percutaneous Absorption, 3rd edn. New York: Marcel Dekker, 1999. 3 Kapitulunik J, Levin W, Conney AH et al. Benzoα-pyrene-7,8dihydrodiol is more carcinogenic than benzo(α)-pyrene in newborn mice. Nature 1977;266:378–80.

Vehicles Emollients Emollients are bland, fatty or oleaginous substances that hydrate and soften the skin. They are occlusive to varying degrees and this results in decreased TEWL. In the majority of cases emollients contain lipids, such as liquid paraffin or soya oil. The use of emollients is indicated in scaly dermatoses and for routine cleansing of skin in children with dry skin or inflammatory conditions. Moreover, emollients are an essential part of the treatment of atopic dermatitis, and are used as first-line therapy for the management of mild disease [1,2]. Emollients should be applied once or twice daily to xerotic skin, and especially immediately after bathing for optimal occlusion of hydrated stratum corneum [2,3]. Petrolatum is probably the most occlusive and therefore the best emollient available. Unfortunately, it is not well accepted by patients because of its greasiness and staining properties [4]. Also, extensive use on the body of a petroleum-based emollient can lead to overheating and secondary infection, especially in children with atopic dermatitis. Emollients can also be used as bath additives, as bathing in water alone dries the skin. Studies have shown that oil-in-water emollients enhance the skin barrier function in both healthy and diseased skin [2]. The application of

Principles of Paediatric Dermatological Therapy

vegetable or mineral oils during or after bathing reduces the TEWL, thus having a moisturizing effect. For this reason, bath oils are particularly useful in children with atopic dermatitis. Bath oils also keep the skin clean and free from debris (crusts and scales). Moreover, in these children the use of over-the-counter soaps should be avoided, as they are alkaline and may contain perfumes or fragrances that may irritate the skin. Ceramide-based emollients have been advocated for treatment of atopic dermatitis by blocking TEWL. These are thought to improve symptoms by restoring skin barrier function to the epidermis. Studies have demonstrated improvement in symptoms when used as adjunctive therapy with topical corticosteroids or topical immunomodulating agents [2,5].

Protectants These are used to protect the skin against inflammation due to irritating chemicals (e.g. in napkin dermatitis) or repeated trauma or friction. Zinc oxide (1–25%) is one of the most widely used and clinically accepted skin protectants, and is mildly astringent and antiseptic as well [6]. It is available as a paste, ointment or lotion. Other protective preparations contain water-repellent substances such as dimethicone or other silicones. References 1 Breternitz M, Kowatzki D, Langenauer M, Elsner P, Fluhr JW. Placebocontrolled, double-blind, randomized, prospective study of a glycerolbased emollient on eczematous skin in atopic dermatitis: biophysical and clinical evaluation. Skin Pharmacol Physiol 2008;21(1):39–45. 2 Simpson EL. Atopic dermatitis: a review of topical treatment options. Curr Med Res Opin 2010;26(3):633–40. 3 Saeki H, Furue M, Furukawa F et al. Guidelines for management of atopic dermatitis. J Dermatol 2009;36(10):563–77. 4 Lane AT, Drost SS. Effects of repeated application of emollient cream to premature neonates’ skin. Pediatrics 1993;92:415–19. 5 Chamlin SL, Kao J, Frieden IL et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002;47:198–208. 6 Knutson K, Pershing LK. Topical drugs. In: Gennaro AR, Popovich NG, Der Marderosian AH et al. (eds) Remington. The Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott, Williams and Wilkins, 2000.

Topical dermatological therapeutic agents Local anaesthetics Topical anaesthetic creams and gels containing lidocaine (sometimes combined with prilocaine) or amethocaine are used for decreasing the pain of numerous clinical procedures such as venepuncture, intravenous cannulation, peripherally inserted central catheters, lumbar puncture and circumcision [1].

181.7

The most widely used local anesthetic for injection is lidocaine hydrochloride 1%. It is useful for procedures including circumcision, lumbar puncture and chest tube insertion. When lidocaine injection is used, strategies should be implemented to reduce the pain associated with administration, including preadminstration of topical anesthetics [1]. The combination of lidocaine and prilocaine (EMLA) has been substantiated as safe for use in neonates if used no more than once per day and not over a widespread area of application [2]. It is particularly useful in preventing pain in superficial procedures in children, specifically curettage of molluscum contagiosum [3]. Although methaemoglobin levels are increased with just 1 g applied to the foreskin in neonates prior to circumcision, levels do not normally exceed therapeutic range and there is no evidence of adverse clinical symptomatology [4]. Although side-effects of EMLA are usually mild, application of an excessive amount to a compromised cutaneous barrier can cause systemic toxicity [3]. Eutectic mixtures of lidocaine without prilocaine have also been made available recently and carry little risk of methaemoglobinaemia as well as more rapid local anaesthesia.

Antibacterials Bacterial skin infections in paediatric patients can often be treated with topical antibacterials. However, their use is limited because of the risks of promoting bacterial resistance and of sensitization reactions.

Fusidic acid Topical fusidic acid is a compound with an acceptable safety profile that is primarily used for staphylococcal skin infections. It has been found to be of particular use in the treatment of impetigo. Fusidic acid is available as a cream, making it a clinically and bacteriologically effective treatment for impetigo [5]. Sensitization due to fusidic acid has increased significantly in the past decade. However, development of resistance to fusidic acid can apparently be minimized by restricting therapy to no more than 14 days at a time [5].

Metronidazole Topical metronidazole gel (0.75%) is an active and safe compound for the treatment of the inflammatory lesions of rosacea [6]. Its mechanism of action is not fully understood. It has shown positive results in the treatment of perioral dermatitis in children [7].

Mupirocin Mupirocin is a topical antibiotic that is produced by Pseudomonas fluorescens. Few local side-effects result from the use of mupirocin, and there is little systemic absorption. It is effective for skin infections, particularly those

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resulting from Gram-positive organisms [6]. Unlike other topical antibiotics, it is effective for the treatment of impetigo caused by Staphylococcus aureus, Streptococcus pyogenes and other strains. Several reports of randomized clinical trials have maintained that mupirocin is as effective as systemic erythromycin for treatment of impetigo in children and fewer adverse reactions are exhibited. Mupirocin is not available as a systemic drug and for that reason is a frequently used topical antibiotic; however, resistant strains of Staph. aureus are now being recognized and caution must prevail to protect the valuable role of this topical antibiotic. Thus, to avoid resistance, mupirocin should not be used for longer than 10 days [6].

Silver nitrate An alternative therapeutic approach is the use of topical silver nitrate in paediatric patients. A 40% silver nitrate paste has been shown to be highly effective in treating molluscum contagiosum in a series of paediatric patients, with minimal side-effects and no scarring [8].

relatively safe for use in children with regard to potential systemic toxicity, these agents, particularly ethylenediamine derivatives, are not commonly used by dermatologists owing to the relatively high risk of allergic contact sensitization [10].

Antiseptics Chlorhexidine Chlorhexidine gluconate may be used safely for infant and paediatric bathing in order to reduce the number of Gram-negative and Gram-positive organisms present on the skin surface. The active agent is bactericidal on contact and binds with skin proteins to leave a skin residue. In the newborn nursery, the frequency of bathing may vary according to the presence of outbreaks of staphylococcal infections. Most of the chlorhexidinecontaining products contain isopropyl alcohol in order to facilitate absorption [11]. This is an important consideration if used in premature infants in whom increased percutaneous absorption may enhance the potential for toxicity [12].

Antifungals Topical antifungals are safely used for the treatment of superficial fungal infections of the skin and mucosae in children. They are not usually effective as monotherapy for mycoses of the nails and hair or for the treatment of deep mycoses. A plethora of topical agents is currently available. The preferred formulation for delivery of a topical antifungal into epidermis is usually a cream or solution. Ointments may be messy and may be too occlusive for macerated or fissured intertriginous lesions but may be useful in very thickened, hyperkeratotic lesions. The use of antifungal powders, whether applied by shake containers or aerosols, is largely confined to the feet and moist lesions of the groin and other intertriginous areas, being less efficient than other dosage forms for drug delivery into the epidermis. Although approved formulations, topical solutions for application to fungal nails represent a marginally effective dosage form. Most currently available topical antifungals are imidazole or triazole structures, such as clotrimazole, econazole, miconazole and oxiconazole. There is evidence showing the safety and effectiveness of topical miconazole nitrate in the treatment of napkin dermatitis [9]. Non-imidazole compounds include ciclopiroxolamine, haloprogin, tolnaftate, naftifine and terbinafine. In general, topical antifungals are safe for use in children with regard to potential systemic toxicity, and allergic contact sensitization rarely occurs.

Povidone–iodine Povidone–iodine is one of the most commonly used antiseptics and is used in concentrations up to 10% in various dosage forms. It is active against Gram-positive and Gram-negative organisms and yeast. Owing to potential toxic systemic effects and skin necrosis, iodine-containing antiseptics in neonates and young children should be very selectively used and with extra caution [11–15].

Others Other skin antiseptics used in children include cetrimide [16,17] and hydrogen peroxide [18,19]. The use of hexachlorophene has been abandoned due to the high risk of percutaneous toxicity (see Chapter 3).

Antivirals Although not as efficacious as systemic treatment approaches to most viral eruptions, topical antivirals such as aciclovir and idoxuridine are occasionally useful at selected anatomical sites (e.g. eyes) for the treatment of herpes simplex virus (HSV) infections in children.

Aciclovir Aciclovir is available as a topical cream as well as an ophthalmic formulation and may be effective if used early and frequently applied [20–22]. These topical agents rarely produce systemic side-effects in children.

Idoxuridine

Antihistamines Topical antihistamines are typically antipruritic and may have some degree of local anaesthetic activity. Although

Idoxuridine is used as an ophthalmic ointment [23] and has treatment recommendations that are similar to aciclovir.

Principles of Paediatric Dermatological Therapy

Antiparasitics Lindane Antiparasitic preparations are usually indicated for the treatment of scabies and pediculosis. Although efficacious, lindane (γ-benzene hexachloride), available in several dosage forms, is potentially neurotoxic to children. Neurotoxicity in children suggests an increased systemic absorption due to their relatively large surface area compared to body mass [24]. Its use during pregnancy is contraindicated for this reason [25]. Lindane is no longer available in several countries for clinical use. Seizures, dizziness, nervous system damage, gastrointestinal side-effects, hormone disruption and death have been reported in children when lindane was overused or inappropriately dosed [24]. In countries where it is still allowed, current recommendations usually stipulate that it be used for second-line treatment when safer treatments have failed. It is recommended that only enough lindane be prescribed for a single dosage in order to avoid overuse. Although toxicity from a single proper application of lindane is not typical, accidental ingestion or industrial exposure may cause dizziness, seizures, nervous system damage, gastrointestinal side-effects, hormone disruption and anaemia [24].

181.9

[37], crotamiton, monosulfiram 25% in a lotion diluted with 2–3 parts of water and malathion 0.5%, which is available in an aqueous base (marketed as Derbac-M® in the UK).

Astringents Astringents are substances that inhibit cutaneous or mucocutaneous oozing, discharge and bleeding upon application to the affected area by providing a protein coagulant effect. When applied as a wet dressing or compress, astringents cool and dry the skin through evaporation. These agents typically produce vasoconstriction, reduce cutaneous blood flow and cleanse the skin of exudate, crust and debris. Astringents must be properly diluted to avoid irritant contact dermatitis, particularly in children.

Aluminium acetate Aluminium acetate solution, 0.13–0.5% final concentration, is recognized as safe and effective for use in children as a compress or wet dressing [38]. It is used as an astringent for the treatment of minor skin irritations. It is commercially available as tablets and powders for dilution and is typically known as modified Burrow’s solution.

Permethrin

Potassium permanganate

Topical permethrin, in various dosage forms, is safe and effective for both scabies [26–28] and pediculosis [29–31] in infants and children. During application, particular attention should be paid to areas that are most often involved. To maximize exposure of mites to the drug, it is generally recommended that the cream be applied in the evening and left on overnight. Contraindications for its use include pregnancy and infants of less than 2 months of age [32].

Potassium permanganate crystals are usually administered either as a wet compress in a dilution of 10 mL of 1% solution diluted to 1 litre or added to a bath for further dilution to allow soaking [39]. The concentrated solution is highly irritating, and dilution before contact is essential to avoid the risk of a chemical burn [40,41].

Benzyl benzoate Benzyl benzoate is available in topical formulations for use in the treatment of scabies in infants, young children and pregnant or nursing mothers [33–35]. It is viewed as relatively safe for use in this population with rarely reported systemic side-effect issues.

Ivermectin Extemporaneously prepared topical ivermectin has found use as a treatment for scabies in children. Cure rates have been reported to be high and with long-term effectiveness. The systemic drug is already widely used in the treatment of topical diseases in children and the topical version appears to be well tolerated in this population [36,37].

Others Other antiparasitic preparations used in children include carbaryl, as a relatively low-risk treatment for head lice

Skin test antigens Candida albicans and mumps skin test antigens An approach to wart treatment in children includes intralesional injection of Candida albicans antigen or mumps skin test antigen injected locally into the base of the wart [42,43]. The mechanism of action is probably related to stimulation of a delayed-type hypersensitivity reaction in the patient, which destroys the wart as immune response develops. An anti-HPV immunity is presumably generated that allows for long-term remission. Side-effects of this therapy, including itching at the injection site and postinjection flu-like symptoms, have been mild and selflimited [44].

Coal tar and anthralin Coal tar is a complex mixture of organic compounds, rich in polycyclic hydrocarbons, which is produced by the distillation of coal. Little is known about its exact mechanism of action. However, there are several possible effects, including inhibition of DNA synthesis [45]. Coal tar may be used in different concentrations alone, in an ointment

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or paste base or included with other substances such as salicylic acid, hydrocortisone or zinc oxide. Scalp preparations and shampoos are also available. The main use of coal tar is for the treatment of plaque psoriasis, scalp psoriasis, atopic dermatitis and seborrhoeic dermatitis and in general, it is quite effective and considered relatively safe for use in childhood [45]. Until recently, its use has been limited due to cosmetic unacceptability by the patient, as coal tar is capable of staining and has a detectable odour. Improved formulations are available, rendering the use of coal tar more acceptable to children than in the past. Anthralin (dithranol) is a synthetic anthraquinone that is structurally related to acridine, a component of crude coal tar. The most common childhood clinical indication for anthralin is psoriasis [46]. It is an effective treatment for childhood psoriasis with a safety margin for shortterm use [47]. It is additionally utilized as a topical therapy for alopecia areata in children [48]. It is a primary irritant and should not be applied to normal skin, the face, genitalia or areas of acute inflammation. It also stains clothing and skin [47]. Anthralin dosing is often titrated to response and tolerance and is therefore used at various concentrations. Short contact (application for 30–60 min daily, then removed with mineral oil) is often effective and represents a more practical approach for children.

Corticosteroids The usefulness of topical steroids is a direct result of their anti-inflammatory properties. Although most marketed topical steroid preparations have not been tested in children and their use in children has been derived by inference from adult studies (see Table 181.1), children often require shorter treatment duration and a lower potency steroid [49]. Although topical steroids are very effective in controlling acute and chronic inflammatory dermatoses, they are not necessarily disease-modifying agents [50]. Therefore, upon stopping topical steroid therapy, the dermatosis may often recur, particularly as an acute rebound flare. Local side-effects, although not life-threatening, are more common than systemic side-effects, often insidious in their onset and frequently troublesome. Potential sideeffects associated with topical corticosteroids include striae, petechiae, telangiectasia, atrophy and acne or rosacea [49,51]. In general, these side-effects are correlated with the length of use and potency of the corticosteroid [51]. The choice of topical corticosteroid depends on the age of the patient, severity of the disease, and the area of the body being treated. In childhood, except for very high potency, topical steroids may be used safely on non-extensive body surface areas for short, intermittent periods of time on unoc-

Table 181.1 Topical corticosteroids in controlled trials that included paediatric subjects Drug name and strength

Clinical potency (United States Pharmacopeia)

Alclometasone dipropionate cream 0.05% Desonide cream 0.05% Hydrocortisone ointment 1% Clobetasone butyrate cream 0.05% Diflucortolone valerate cream 0.1% Fluocinolone acetonide cream 0.025% Fluticasone propionate cream 0.05% Hydrocortisone butyrate cream 0.01% Mometasone furoate cream 0.1% Halcinonide cream 0.1% Betametasone dipropionate cream 0.05% Halobetasol propionate cream 0.05% Halobetasol propionate ointment 0.05%

Low Low Low Medium Medium Medium Medium Medium Medium High Very high Very high Very high

Reproduced with permission from Hepburn D, Yohn JJ, Weston WL. Topical steroid treatment in infants, children, and adolescents. In: Schachner LA (ed) Advances in Dermatology. St Louis, MO: Mosby Year Book, 1994.

cluded skin. Avoidance of occluded steroids in the paediatric population is imperative, as significant skin atrophy is sometimes irreversible and can develop within 7 days of superpotent topical steroid application (e.g. clobetasol propionate), and as early as 2 weeks without occlusion [52]. As occlusion raises the concentration of the topically applied steroid in the upper layers of the stratum corneum to a relatively high level, steroid may be detected in the stratum corneum for many days or even a few weeks after the initial application to the skin [52]. Other common complications seen with occlusion of topical steroids include miliaria and overgrowth of skin yeast and bacteria [53]. Based on these considerations, it is advisable to follow some general guidelines when treating children with topical steroids. 1 Choose the steroid potency according to the anatomical area requiring treatment. In infants, excessive skin folding may be seen and this may result, if treating these areas topically, in a natural occlusive phenomenon. In skinfold areas, as well as the napkin area that is virtually under airtight occlusion, the use of lowpotency steroids is recommended. Treatment of intertriginous areas, such as axillae, groin or breasts where the skin is thin, moist and to some degree occluded, also requires particular caution. On the trunk and extremities, moderate potency steroids can be used more safely. 2 Limit applications to up to twice per day and limit duration of therapy (e.g. 14 days).

Principles of Paediatric Dermatological Therapy Table 181.2 United States Pharmacopeia steroid potency listing Steroid potency

Use

Restrictions

Low potency

Chronic application

May be used on the face and intertriginous areas, with occlusion, and in infants and young children

Medium potency

Moderate inflammatory dermatoses

May be used on the face and intertriginous areas for a limited duration

High potency

Severe inflammatory dermatoses (intermediate duration or for longer if the skin is thickened)

May be used on the face and intertriginous areas for short treatment duration

Very high potency

Thick, chronic lesions

For short duration of therapy and on small surfaces; not to be used with occlusive dressings; high likelihood of skin atrophy

Reproduced with permission from Corticosteroids (Topical). In: Drug Information for the Health Care Professional. USPDI, 23rd edn. Thomson Micromedex, 2003.

3 Avoid use of superpotent steroids. 4 If the child does not respond to therapy, do not continue and consider alternative therapies. Topical steroids are categorized by the USP (United States Pharmacopeia) into four groups with respect to clinical potency (Table 181.2). Topical corticosteroids are most effective in higher doses for 1–2 weeks. Lowerpotency corticosteroids are recommended for infants with mild disease, while medium-potency agents are recommended for moderate to severe disease and are limited to 5–10-day treatments. Superpotent agents should not be used in children under 12 years of age and are limited to 1–2 week use [51]. The protracted use of topical steroids may also be associated with significant systemic side-effects. With regard to systemic side-effects, infants and toddlers are at high risk as they have a greater surface– bodyweight ratio [54] and they may be less able to metabolize potent glucocorticoids adequately. Systemic side-effects from topical steroids include hypothalamic– pituitary–adrenal axis suppression, failure to thrive, overt Cushing syndrome, glaucoma and benign cephalic hypertension [49]. Factors that may influence the risk of systemic sideeffects include the amount of drug applied, extent of skin surface treated, frequency of application, length of treatment and potency/use of occlusion.

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Intralesional steroids in paediatric patients are selectively used, as the side-effects are potentially more serious.

Immune response modifiers Cytokine inhibition Topical calcineurin inhibitors such as tacrolimus and pimecrolimus offer significant and targeted therapeutic alternatives for the treatment of atopic dermatitis [55]. Systemic tacrolimus is used as an immunosuppressant in transplant medicine. Topical tacrolimus and pimecrolimus cause inhibition of interleukin 2 (IL-2) and T-cell-derived cytokines (tissue necrosis factor alpha (TNF-α) and other interleukins), known inflammatory mediators in the pathogenesis of atopic dermatitis [56,57]. Tacrolimus ointment can be effective against atopic dermatitis that is difficult to treat with topical steroids [58]. Multiple studies have demonstrated the efficacy and relative safety of these compounds for alleviating the signs and symptoms of atopic dermatitis; 0.03% tacrolimus (Protopic) and pimecrolimus (Elidel) are licensed for use in children over 2 years of age. They provide an alternative treatment for those children with moderate to severe atopic dermatitis requiring regular potent steroids and are particularly useful on the face instead of topical steroids [58]. There are theoretical concerns about the risk of malignancy, in particular lymphoma. The evidence is based on animal studies at systemic doses but only minimal blood levels are achieved when applied topically in the clinical situation. It is therefore important to advise the family that the child should be protected from sun exposure if using these topical medications, and for these preparations not to be prescribed to children who are immunosuppressed. Since 2006, the topical calcineurin inhibitors (tacrolimus and pimecrolimus) have had a boxed warning that highlights the possible increased risk of skin cancer and lymphoma. The label clarified that these drugs are indicated as second-line therapy for short-term treatment of atopic dermatitis in patients who do not respond adequately to topical corticosteroids. According to the latest knowledge, there is no scientific evidence of an increased risk for malignancy due to a topical treatment with calcineurin inhibitors. However, caution prevails. Long-term safety data and studies of a sufficient number of patients using these drugs are necessary to exclude enhanced risk [59]. Long-term studies have shown a low risk of side-effects and no loss of effectiveness in treating atopic dermatitis [59]. However, the use of topical tacrolimus for skin conditions other than licensed indications should be consid-

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ered with caution and with monitoring of blood levels [60]. Side-effects other than local irritation (pruritus and warmth or transient skin burning sensation) for the first several days of treatment are rare [61].

Cytokine upregulation Imiquimod is an immune response modifier that is approved for the topical treatment of anogenital warts in patients 12 years and older [62]. Its mechanism of action includes stimulation of the local immune response by promoting cytokine upregulation (TNF-α, IL-1, IL-6, IL-8 and interferons), all capable of stimulating a cytotoxic reaction towards HPV infection. Good results with imiquimod treatment have been reported in some studies for the treatment of long-lasting cutaneous warts and molluscum contagiosum in children although one large multicentre study sponsored by the manufacturer showed that the clinical benefit of imiquimod for molluscum was not superior to placebo. An advantage in children is the convenience of a home-based therapy without the pain often associated with other therapies. Overall, imiquimod cream is well tolerated, and the most common adverse reactions include erythema, burning, itching, erosion and tenderness, frequently localized to the application site [63]. Topical imiquimod is also used in the treatment of recurrent and resistant periungual and common warts in children [64,65]. Sinecatechins are derived from green tea, and these extracts have been shown to have activity against external genital warts (EGW). The exact mechanism, however, remains unknown. As a topical agent, a commercially available preparation that has been approved for use against EGW sinecatechins appears to be well tolerated and associated with a decreased rate of wart recurrence.

Insect repellents An effective insect repellent for use on skin in children should be non-toxic, non-irritant, non-allergic, harmless to clothing, odourless and easy to apply, and should offer protection for several hours in variable weather conditions.

Diethyltoluamide Diethyltoluamide (DEET) is the most universally accepted repellent for skin application to date. Product forms include aerosols, pump sprays, lotion creams, liquids, roll-on sticks and impregnated towelettes, in various concentrations [66]. The American Academy of Pediatrics Committee on Environmental Health recommends that only children older than 2 months be exposed to DEET products, and the recommended concentration range is10–30%. DEET is broadly effective against mosquitoes, ticks and other arthropods when used on the skin [67]. DEET should be used cautiously as cases of systemic

toxicity have been reported following topical use. Reported reactions include hypotension, seizures, respiratory distress and death. Conclusions show a low overall risk of toxicity and lack of a dose-dependent relationship between exposure and the severity of neurological manifestations.

Oil of citronella Oil of citronella, mixed with inert ingredients, is also used as a topical repellent in children over 2 years of age. It is rarely cited as a cause of systemic toxicity or allergic contact sensitization [68].

Picaridin Picaridin is a commonly used active ingredient in Europe, Australia and more recently the United States, and is becoming increasingly popular because of its relatively low toxicity, comparable efficacy and customer approval. Picaridin is odourless, does not feel sticky or greasy on application, will not damage fabrics and is less likely to irritate the skin. In Europe, concentrations of up to 20% have been shown to be protective for up to 8–10 hours. Picaridin is not recommended for use in children younger than 2 years of age. Although picaridin seems to have similar efficacy to DEET, there are limited data to date supporting the assumption [67].

Human skin substitutes Treatment of full-thickness burn injury consists of excision of the affected area with donor skin grafted onto the wound. If there is not sufficient skin available, the wound may be covered until sufficient skin is available. Unfortunately, for extensive full-thickness burn injuries, sufficient skin is often not readily available, so alternative therapies are desirable [69]. One possible alternative is the use of human skin substitutes (HSSs), which may be made by various processes including cultured autologous keratinocytes. HSSs have been used in combination with artificial bilayer (dermis and epidermis) temporary skin substitutes with nearly equivalent results to skin grafting. Immediately after excision of the full-thickness burn, the artificial skin is placed to minimize fluid loss and infection. HSSs are useful not only in the treatment of full-thickness burn excision, but also for grafting after removal of giant naevi in children [70,71]. Some difficulties have arisen with the use of HSSs. Compared with the use of an autograft, HSSs seem to require a longer period of time for the graft to take. Occasionally, there may be subsequent depigmentation of the affected area, or wrinkling of the grafted HSS over the scar. In general, however, scarring from these grafts usually appears to be minimal with nearly normal pigmentation [72].

Principles of Paediatric Dermatological Therapy

Keratolytics These substances are used to reduce or promote exfoliation of hyperkeratotic skin. Topical salicylic acid dissolves the intercellular matrix and thereby softens hyperkeratotic areas by enhancing the shedding of scales [73]. Salicylic acid is available in various dosage forms such as gels, ointments, creams, transdermal patches or adhesive plasters, in concentrations of up to 70%. Salicylic acid preparations to extensive areas of skin, particularly in children, should be used with great caution as they may induce systemic toxicity (see Chapter 3).

Potassium hydroxide Potassium hydroxide (KOH) has been shown to be effective in treating the lesions of molluscum contagiosum when applied in an aqueous solution to the affected areas. Potassium hydroxide is an alkali known to dissolve keratin when applied topically to skin [74]. It can also act as a concentration-dependent irritant to the skin. Sideeffects are usually limited to a stinging sensation at application sites. Some children may demonstrate transient hyper- and/or hypopigmentation in the treated areas [74]. However, KOH is a safe, inexpensive and noninvasive alternative for the treatment of molluscum contagiosum in children.

Retinoids Tazarotene Tazarotene is a topical acetylenic retinoid that normalizes keratinization of the follicular epithelium. It is currently used for the treatment of acne and psoriasis and has been reported to produce a clinical improvement in the treatment of childhood Darier disease [75] and is also commonly employed for the topical management of various autosomal recessive congenital ichthyoses.

Squaric acid dibutylester A useful treatment for warts is squaric acid dibutylester (SADBE) immunotherapy. Although not commercially available, SADBE is an extemporaneously compounded topical sensitizing agent with some long-term safety data for use in children. Topical SADBE generates an anti-HPV response via cell-mediated immune reactivity, which provides long-term remission. Side-effects are usually local application site reactions (erythema, burning and pruritus), which are reversible. A major benefit of SADBE is that application is painless and it is easy to use, both of obvious benefit in treating the paediatric population [76,77].

Cantheridin Cantharidin, derived from blister beetle extract, is a common modality in the treatment of molluscum contagiosum amongst paediatric dermatologists. Cantharidin

181.13

is a topical treatment that produces a small intraepidermal blister that heals without scarring. Side-effects are common and include discomfort/pain, severe blisters, irritation or inflammation, hypo- and hyperpigmentation, infection, scarring and itching [78].

Trichloroacetic acid Although cantharidin is an effective treatment for molluscum contagiosum, treatment of facial lesions is not recommended with this agent. Trichloroacetic acid is a safe and effective agent most commonly used in the treatment of verrucae. Topical trichloroacetic acid is an effective treatment of facial molluscum contagiosum that erodes the skin and is generally not absorbed systemically. Patients describe only a mild stinging sensation and the agent is generally well tolerated [79].

Sunscreens Most sunscreen ingredients are considered safe for use in children over 6 months old. Although infants under 6 months of age should not be exposed to prolonged direct sunlight, a physical blocking agent such as micronized zinc oxide is considered safe for use in selected patients [80]. Sunscreen products are arbitrarily divided into UVA blockers, active in the range 320–400 nm, and UVB blockers, active in the range 290–320 nm [81]. The current method of rating sunscreen effectiveness is the sun protection factor (SPF) number. SPF represents a multiple of the amount of time it takes for skin to turn red – the minimal erythema dose (MED). Hence, an SPF of 15 should allow an individual to be exposed to sun 15 times longer before turning red. This method, however, is representative of UVB (290–320 nm) activity, which is more responsible for erythema. UVA has some erythogenic potential in the lower wavelengths (320–340 nm) but, otherwise, erythema is a poor indicator of UVA activity. Most currently available sunscreen formulations aim for coverage of both UVB and UVA spectra. UVA protection in addition to UVB is advertised as ‘full-spectrum’ sun protection [81]. Products may be categorized as chemical sunscreens and/or physical blockers. Chemical sunscreens such as octocrylene and oxybenzone have some UVA activity in the 320–340 nm range. Avobenzone, benzopheonomes and dicamphor sulphonic acid are effective in most of the UVA range [81]. Methoxyphenyltriazene is a new sunscreen in Europe with a broadspectrum filter that stabilizes avobenzone-containing sunscreens and offers excellent broad-spectrum protection [81]. The physical blockers zinc oxide and titanium dioxide are effective in both the UVB and UVA ranges [82]. Some compounds are effective in both ranges; the usual formulations aim to cover most of both and are termed ‘broad-spectrum’ blockers. The efficiency of each agent is

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related to the spectrum of wavelengths absorbed, amount of product applied (2 mg/cm2 recommended), time for which sunscreen dries prior to UV exposure (15 minutes recommended) and the resistance to washing off during swimming or sweating [81,83].

Vitamin D3 analogues Various vitamin D3 analogues are currently available for topical use, including calcitriol, calcipotriol (calcipotriene in the USA) and tacalcitol. Calcipotriol is a vitamin D3 analogue that has a high binding affinity to cellular receptors for the biologically active form of vitamin D3 (1,25-dihydroxy-vitamin D3) (calcitriol). Receptors for calcitriol have been demonstrated in various cells, including keratinocytes and fibroblasts. These analogues produce dose-dependent inhibition of proliferation and stimulation of terminal differentiation in cultured human keratinocytes [84]. Unlike calcitriol, however, calcipotriol and tacalcitol present a lower risk of inducing calcium-related side-effects. Favourable results in the treatment of psoriasis in children have been reported with calcitriol [85,86], whereas calcipotriol has been shown to be effective for congenital ichthyoses [84] and on localized linear scleroderma and morphoea [87,88]. A less proven use for topical calcipotriol is in the treatment of vitiligo in children [89], especially if used in combination with sunlight therapy [90,91]. A long-term study (106 weeks) in child patients with psoriasis who were treated with topical calcipotriol showed significant improvement in psoriasis assessment severity index (PASI) scores compared with baseline. In this study values of 1,25-dihydroxyvitamin D3 were decreased and 50% of patients had levels below the normal range. Therefore, monitoring of vitamin D metabolites is suggested for chronic paediatric vitamin D3 analogue topical therapy [92]. References 1 Lehr VT, Taddio A. Topical anesthesia in neonates: clinical practices and practical considerations. Semin Perinatol 2007;31(5):323–9. 2 Essink-Tjebbes CM, Hekster YA, Liem KD et al. Topical use of local anesthetics in neonates. Pharm World Sci 1999;21:173–6. 3 Raso SM, Fernandez JB, Beobide EA, Landaluce AF. Methemoglobinemia and CNS toxicity after topical application of EMLA to a 4-yearold girl with molluscum contagiosum. Pediatr Dermatol 2006; 23(6):592–3. 4 Law RM, Halpern S, Martins RF et al. Measurement of methemoglobin after EMLA analgesia for newborn circumcision. Biol Neonate 1996;70:213–17. 5 Schofer H. Evaluation of imiquimod for the therapy of external genital and anal warts in comparison with destructive therapies. Br J Dermatol 2007;157(Suppl 2):52–5. 6 Gelmetti C. Local antibiotics in dermatology. Dermatol Ther 2008;21:187–95. 7 Miller SR, Shalita AR. Topical metronidazole gel (0.75%) for the treatment of perioral dermatitis in children. J Am Acad Dermatol 1994;31:847–8.

8 Niizeki K, Hashimoto K. Treatment of molluscum contagiosum with silver nitrate paste. Pediatr Dermatol 1999;16:395–7. 9 Eichenfield LF, Bogen ML. Absorption and efficacy of miconazole nitrate 0.25% ointment in infants with diaper dermatitis. J Drugs Dermatol 2007;6(5):522–6. 10 Rietschel RL, Fowler JF Jr. Antihistamine dermatitis. In: Rietschel RL, Fowler JF Jr (eds) Fisher ’s Contact Dermatitis, 5th edn. Philadelphia: Lippincott, Williams and Wilkins, 2001. 11 Metry WD, Hebert AA. Topical therapies and medications in the pediatric patient. Pediatr Clin North Am 2000;47:867–76. 12 Malathi I, Millar MR, Leening JP et al. Skin disinfection in preterm infants. Arch Dis Child 1993;69:312–16. 13 Pyati SM, Ramamurthy RS, Krauss MT et al. Absorption of iodine in the neonate following topical use of povidone iodine. J Pediatr 1977;91:825–8. 14 Parravincini E, Fontana C, Giuseppe L et al. Iodine, thyroid function, and very low birth weight infants. Pediatrics 1996;98: 730–4. 15 Reuss ML, Paneth N, Pinto-Martin JA et al. The relation of transient hypothroxinemia in preterm infants to neurologic development at two years of age. N Engl J Med 1996;334:821–58. 16 Langford JH, Artemi P, Benrimoj SI. Topical antimicrobial prophylaxis in minor wounds. Ann Pharmacother 1997;31:559–63. 17 Lee JY, Wang BJ. Contact dermatitis caused by cetrimide in antiseptics. Contact Dermatol 1995;33:168–71. 18 Christensen OB, Anehus S. Hydrogen peroxide cream: an alternative to topical antibiotics in the treatment of impetigo contagiosa. Acta Dermatol Venereol 1994;74:460–2. 19 Davies MR, Rode H, Cywes S et al. Burn wound management. Prog Pediatr Surg 1981;14:33–61. 20 Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis 2002;186:S40–6. 21 Spruance SL, Nett R, Marbury T et al. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother 2002;46:2238–43. 22 Power WJ, Hillery MP, Benedict-Smith A et al. Acyclovir ointment plus topical betamethasone or placebo in first episode disciform keratitis. Br J Ophthalmol 1992;76:711–13. 23 McCulley JP, Binder PS, Kaufman HE et al. A double-blind, multicenter clinical trial of acyclovir vs idoxuridine for treatment of epithelial herpes simplex keratitis. Ophthalmology 1982;89: 1195–200. 24 Bhalla M, Thami GP. Reversible neurotoxicity after an overdose of topical lindane in an infant. Pediatr Dermatol 2004;21(5):597–9. 25 Solomon LM, Fharner L, West DP. Gamma benzene hexachloride toxicity. Arch Dermatol 1977;113:353–7. 26 Hamm H, Beiteke U, Höger PH et al. Treatment of scabies with 5% permethrin cream: results of a German multicenter study. J Dtsch Dermatol Ges 2006;4(5):407–13. 27 Quarterman MJ, Lesher JL Jr. Neonatal scabies treated with permethrin 5% cream. Pediatr Dermatol 1994;11:264–6. 28 Paller AS. Scabies in infants and small children. Semin Dermatol 1993;12:3–8. 29 Chouela E, Abeldano A, Cirigliano M et al. Head louse infestations: epidemiologic survey and treatment evaluation in Argentinian school-children. Int J Dermatol 1997;36:819–25. 30 Klaus S, Shvil Y, Mumcuoglu KY. Generalized infestation of a 31/2-year-old girl with the pubic louse. Pediatr Dermatol 1994;11:26–8. 31 Haustein UF. Pyrethrin and pyrethroid (permethrin) in the treatment of scabies and pediculosis. Hautarzt 1991;42:9–15. 32 Metry WD, Hebert AA. Topical therapies and medications in the pediatric patient. Pediatr Clin North Am 2000;47:867–76.

Principles of Paediatric Dermatological Therapy 33 Elgart ML. Cost–benefit analysis of ivermectin, permethrin and benzyl benzoate in the management of infantile and childhood scabies. Expert Opin Pharmacother 2003;4:1521–4. 34 Folster-Holst R, Rufli T, Christophers E. Treatment of scabies with special consideration of the approach in infancy, pregnancy and while nursing. Hautarzt 2000;51:7–13. 35 Haustein UF, Hlawa B. Treatment of scabies with permethrin versus lindane and benzyl benzoate. Acta Dermatol Venereol 1989;69: 348–51. 36 Victoria J, Trujillo R. Topical ivermectin: a new successful treatment for scabies. Pediatr Dermatol 2001;18:63–5. 37 Buffet M, Dupin N. Current treatments for scabies. Fundam Clin Pharmacol 2003;17:217–25. 38 Food and Drug Administration. Skin protectant drug products for over-the-counter human use. Subpart A – astringent drug products. 21 CFR, 347.1. Federal Register 1994;59:28768. 39 Gelmetti C. Skin cleansing in children. J Eur Acad Dermatol Venereol 2001;15:12–15. 40 Henderson J, Anderson WD, Jaward WA. Potassium permanganate due to a dispensing error. Burns 2003;29:401–2. 41 Baron S, Moss C. Caustic burn caused by potassium permanganate. Arch Dis Child 2003;88:96. 42 Johnson SM, Roberson PK, Horn TD. Intralesional injection of mumps or candida skin test antigens: a novel immunotherapy for warts. Arch Dermatol 2001;137:451–5. 43 Clifton MM, Johnson SM, Roberson PK et al. Immunotherapy for recalcitrant warts in children using intralesional mumps or Candida antigens. Pediatr Dermatol 2003;20:268–71. 44 Bacelieri R, Johnson SM. Cutaneous warts: an evidence-based approach to therapy. Am Fam Physician 2005;72(4):647–52. 45 Paghdal KV, Schwartz RA. Topical tar: back to the future. J Am Acad Dermatol 2009;61(2):294–302. 46 Rogers M. Childhood psoriasis. Curr Opin Pediatr 2002;14:404–9. 47 De Jager ME, de Jong EM, van de Kerkhof PC, Seyger MM. Efficacy and safety of treatments for childhood psoriasis: a systematic literature review. J Am Acad Dermatol 2010;62:1013–30. 48 Garg S, Messenger AG. Alopecia areata: evidence-based treatments. Semin Cutan Med Surg 2009;28(1):15–18. 49 Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician 2009;79(2):135–40. 50 Christophers E. Thoughts on the use of topical corticosteroids. In: Christophers E, Schopf E, Kligman AM et al. (eds) Topical Corticosteroid Therapy: A Novel Approach to Safer Drugs. New York: Raven Press, 1988. 51 Simpson EL. Atopic dermatitis: a review of topical treatment options. Curr Med Res Opin 2010;26(3):633–40. 52 Katz HI, Prawer SE, Mooney JJ et al. Preatrophy: covert sign of thinned skin. J Am Acad Dermatol 1989;20:731–5. 53 Sterry W. Therapy with topical corticosteroids. Arch Dermatol Res 1992;284:S27–9. 54 West DP, Worobec S, Solomon LM. Pharmacology and toxicology of infant skin. J Invest Dermatol 1981;76:147–50. 55 Ashcroft DM, Dimmock P, Garside R, Stein K, Williams HC. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ 2005;330(7490):516. 56 Kang S, Lucky AW, Pariser D et al. Tacrolimus Ointment Study Group. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001;44:S58–64. 57 Kapp A, Papp K, Bingham A et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a non-steroid anti inflammatory drug. J Allergy Clin Immunol 2002;110:277–84. 58 Saeki H, Furue M, Furukawa F et al. Guidelines for management of atopic dermatitis. J Dermatol 2009;36(10):563–77.

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59 Thaci D, Salgo R. Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies. Clin Dermatol 2010;28(1):52–6. 60 Allen DM, Esterly NB. Significant absorption of tacrolimus after topical application in a patient with lamellar ichthyosis. Arch Dermatol 2002;138:1259–60. 61 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. 62 Diamantis ML, Bartlett BL, Tyring SK. Safety, efficacy and recurrence rates of imiquimod cream 5% for treatment of anogenital warts. Skin Therapy Lett 2009;14(5):1–3, 5. 63 Campaner AB, Santos RE, Galvao MA, Beznos GW, Aoki T. Effectiveness of imiquimod 5% cream for treatment of extensive anogenital warts in a seven-year-old child. Pediatr Infect Dis J 2007;26(3): 265–6. 64 Grussendorf-Conen EI, Jacobs S. Efficacy of imiquimod 5% cream in the treatment of recalcitrant warts in children. Pediatr Dermatol 2002;19:263–6. 65 Schofer H. Evaluation of imiquimod for the therapy of external genital and anal warts in comparison with destructive therapies. Br J Dermatol 2007;157(Suppl 2):52–5. 66 Veltri JC, Osimitz TG, Bradford DC et al. Retrospective analysis of calls to poison control centers resulting from exposure to the insect repellent N,N-diethyl-M-toluamide (DEET) from 1985–1989. J Toxicol Clin Toxicol 1994;32:1–16. 67 Katz TM, Miller JH, Hebert AA. Insect repellents: historical perspectives and new developments. J Am Acad Dermatol 2008;58(5): 865–71. 68 Rietschel RL, Fowler JF Jr. Appendix. In: Rietschel RL, Fowler JF Jr (eds) Fisher ’s Contact Dermatitis, 5th edn. Philadelphia: Lippincott, Williams and Wilkins, 2001. 69 Fitton AR, Drew P, Dickson WA. The use of a bilaminate artificial skin substitute (Integra) in acute resurfacing of burns: an early experience. Br J Plastic Surg 2001;54:208–12. 70 Suzuki S, Kawai K, Ashoori F et al. Long-term follow-up study of artificial dermis composed of outer silicone layer and inner collagen sponge. Br J Plastic Surg 2000;53:659–66. 71 Earle SA, Marshall DM. Management of giant congenital nevi with artificial skin substitutes in children. J Craniofac Surg 2005; 16(5):904–7. 72 Gohari S, Gambla C, Healey M et al. Evaluation of tissue-engineered skin (human skin substitute) and secondary intention healing in the treatment of full thickness wounds after Mohs micrographic or excisional surgery. Dermatol Surg 2002;28:1107–14. 73 Loden M, Bostrom P, Kneczke M. Distribution and keratolytic effect of salicylic acid and urea in human skin. Skin Pharmacol 1995;8:173–8. 74 Short KA, Fuller LC, Higgins EM. Double-blind, randomized, placebo-controlled trial of the use of topical 10% potassium hydroxide solution in the treatment of molluscum contagiosum. Pediatr Dermatol 2006;23(3):279–81. 75 Brazzelli V, Prestinari F, Barbagallo T, Vassallo C, Agozzino M, Borroni G. Linear Darier ’s disease successfully treated with 0.1% tazarotene gel ‘short-contact’ therapy. Eur J Dermatol 2006;16(1): 59–61. 76 Silverberg NB, Lim JK, Paller AS et al. Squaric acid immunotherapy for warts in children. J Am Acad Dermatol 2000;42: 803–8. 77 Micali G, Nasca MR, Tedeschi A et al. Use of squaric acid dibutylesther for percutaneous warts in children. Pediatr Dermatol 2000;17:315–18. 78 Coloe J, Morrell DS. Cantharidin use among pediatric dermatologists in the treatment of molluscum contagiosum. Pediatr Dermatol 2009;26(4):405–8.

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79 Bard S, Shiman MI, Bellman B, Connelly EA. Treatment of facial molluscum contagiosum with trichloroacetic acid. Pediatr Dermatol 2009;26(4):425–6. 80 Friedlander J, Lowe NJ. Sunscreens. In: Arndt KA, Robinson JK, LeBoit PE (eds) Cutaneous Medicine and Surgery. Philadelphia: W.B. Saunders, 1996, pp.751–7. 81 MacNeal RJ, Dinulos JG. Update on sun protection and tanning in children. Curr Opin Pediatr 2007;19(4):425–9. 82 Mitchnick MA, Fairhurst D, Pinnell SR. Microfine zinc oxide (Z-cote) as a photostable UVA/UVB sunblock agent. J Am Acad Dermatol 1999;40:85–90. 83 Kim SM, Oh BH, Lee YW, Choe YB, Ahn KJ. The relation between the amount of sunscreen applied and the sun protection factor in Asian skin. J Am Acad Dermatol 2010;62(2):218–22. 84 Lucker GPH, van de Kerkhof PCM, van Dijk MR et al. Effect of topical calcipotriol on congenital ichthyoses. Br J Dermatol 1994;131:546–50. 85 Kircik L. Efficacy and safety of topical calcitriol 3 microg/g ointment, a new topical therapy for chronic plaque psoriasis. J Drugs Dermatol 2009;8(8 Suppl):s9–16. 86 Lebwohl M, Ortonne JP, Andres P, Briantais P. Calcitriol ointment 3 microg/g is safe and effective over 52 weeks for the treatment of mild to moderate plaque psoriasis. Cutis 2009;83(4):205–12. 87 Cunningham BB, Landells IDR, Langman C et al. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol 1998; 39:211–15. 88 Kreuter A, Gambichler T, Avermaete A et al. Combined treatment with calcipotriol ointment and low-dose ultraviolet A1 phototherapy in childhood morphea. Pediatr Dermatol 2001;18:241–5. 89 Gargoom AM, Duweb GA, Elzorghany AH, Benghazil M, Bugrein OO. Calcipotriol in the treatment of childhood vitiligo. Int J Clin Pharmacol Res 2004;24(1):11–14. 90 Ameen M, Exarchou V, Chu AC. Topical calcipotriol as monotherapy and in combination with psoralen plus ultraviolet A in the treatment of vitiligo. Br J Dermatol 2001;145:476–9. 91 Whitton ME, Ashcroft DM, Gonzalez U. Therapeutic interventions for vitiligo. J Am Acad Dermatol 2008;59(4):713–17. 92 Park SB, Suh DH, Youn JI. A pilot study to assess the safety and efficacy of topical calcipotriol treatment in childhood psoriasis. Pediatr Dermatol 1999;16:321–5.

Systemic therapeutic agents Antibacterials Some antibiotics present problems when used in infancy and childhood and are probably best avoided, especially when suitable safer alternatives are available. Systemic tetracycline and its derivatives may be incorporated into developing teeth and bone, and may cause permanent discoloration as a result of fetal or childhood exposure [1]. Systemic antibiotics for paediatric use in dermatology include penicillin, dicloxacillin, amoxicillin, cephalexin, azithromycin and others [2].

Antifungals The use of systemic antifungals for superficial dermatophytosis in children should be limited to those fungal infections that are refractory to topical agents or where topical treatment is not sufficient to eradicate the infection. Typical conditions that need systemic treatment include tinea capitis, mucocutaneous candidiasis, ony-

chomycoses, systemic infections in severely ill or immunocompromised patients and deep mycoses. There are numerous systemic agents available, although not all are recommended for paediatric use. Griseofulvin, a firstgeneration compound, is used in children for tinea capitis. Griseofulvin is one of only two US Food and Drug Administration-approved drugs for the treatment of tinea capitis. Terbinafine has also received an indication for the treatment of tinea capitis in children and is available both in tablet form and as granules. Other antifungal agents, such as itraconazole, have more consistent absorption rates and longer periods of retention in infected tissues than griseofulvin [3]. Itraconazole, terbinafine and fluconazole have been shown to be relatively safe and effective treatments in children with tinea capitis [4,5]. These systemic antifungals avoid gastrointestinal side-effects due to griseofulvin [6]. The use of ketoconazole should be reserved owing to its relative toxicity.

Antihistamines H1-blocking antihistamines antagonize the peripheral action of histamine and are particularly valuable in treating histamine-dominant disorders such as urticaria, angio-oedema and insect bites. Those antihistamines with a significant sedative effect (diphenhydramine and promethazine) may be used to promote sleep, especially in sleep-disrupted children [7]. New-generation antihistamines may cause less sedation (citerizine, loratidine, fexofenadine) but have less affinity to H1-receptor sites. Levocetirizine, a second-generation antihistamine, has a twofold higher affinity for H1receptors than cetirizine [8]. H2 antihistamines (such as cimetidine and ranitidine) are generally indicated for the control of gastric acid secretions, and can be useful to protect vulnerable patients against gastric complications from protracted systemic corticosteroid therapy. Various authors have shown that cimetidine may provide an antipruritic activity and may enhance cell-mediated immunity [9]. Cimetidine has also been utilized in the treatment of common variable immunodeficiency [10,11], hypergammaglobulin E [12] and to reverse the cutaneous anergy associated with Crohn disease. Other dermatological conditions, often appearing in childhood, which may be responsive to cimetidine include mucocutaneous candidiasis [13], herpes zoster and a variety of HPV infections, ranging from plane warts to common warts and/or plantar warts [9,14]. Ranitidine, when used with an H1-blocking antihistamine, is a useful adjunctive treatment for severe/ symptomatic mastocytosis in infants (see Chapter 75).

Antivirals Aciclovir and derivatives such as valaciclovir and famciclovir work by inhibition of DNA viral synthesis and have

Principles of Paediatric Dermatological Therapy

been widely used for the treatment of HSV1 and HSV2 infections in children. Its mode of action involves activation by thymidine kinase and subsequent inhibition of viral polymerase. In children, oral aciclovir is particularly indicated for severe herpetic gingivostomatitis and for severe genital HSV infections in adolescents. Intravenous administration is required for eczema herpeticum and for HSV infections in immunocompromised children. Although aciclovir is more active against HSV infections, it can also be used for varicella and herpes zoster infections. In both conditions, parenteral administration of the drug is recommended for severe cases, especially in immunocompromised children and infected neonates. In one study, oral aciclovir for varicella in children was beneficial and well tolerated but only when administered within 2 h of the onset of the eruption. A vaccine for varicella is now available [15].

Biological agents Tumour necrosis factor α (TNF-α), a proinflammatory cytokine, has been found to be increased within inflamed skin. Because of this finding, studies have been undertaken to determine whether an anti- TNF-α antibody (infliximab) is useful for treatment of inflammatory skin diseases, particularly psoriasis [16]. Preliminary reports on biological agents in the paediatric population have been noted as promising for the dermatological manifestations of Crohn disease, Behçet disease and graft-versus-host disease [16–18]. Recent data suggest that etanercept, a soluble TNF receptor fusion protein, significantly reduces disease severity in children and adolescents with moderate-tosevere plaque psoriasis. In a 48-week study conducted by Paller et al., children and adolescents received weekly treatment with 0.8 mg/kg etanercept. Reductions in disease severity were seen as early as week 2 of weekly treatment. Longer term data are needed to fully assess the safety of etanercept in the paediatric population [19].

Chemotherapeutic agents Vinblastine and etoposide (a derivative of podophyllotoxin) are very potent agents that can cause severe sideeffects in children and should be used selectively. Both drugs have been reported to provide positive outcomes in children with multisystem Langerhans cell histiocytosis [20,21]. They appear to be equivalent in terms of response time and long-term remission of disease. Unfortunately, these agents can cause significant toxicity such as leucopenia, and long-term sequelae, including diabetes insipidus [20]. Vincristine has proved to be an effective treatment for Kasabach–Merritt syndrome, which is administered through a central (Hickman) line, given as a once-weekly dose (Chapter 112).

181.17

Colchicine Colchicine has been used when dapsone has failed in the treatment of linear immunoglobulin A (IgA) bullous dermatosis. It is reported to be relatively safe for use in children in low doses [22]. It has been used for the treatment of certain types of vasculitis (see Chapter 163).

Corticosteroids The use of systemic corticosteroids in children is usually limited to certain severe dermatological disorders; among these are severe erythema multiforme, lupus erythematosus, bullous dermatoses, such as bullous dermatosis of childhood, pemphigus, pemphigoid and drug-induced toxic epidermal necrolysis. Systemic steroids are also used for the treatment of shock in acute allergic reactions such as anaphylactic shock, angioneurotic oedema, multiple bee or wasp stings, poisonous bites and allergic contact dermatitis. Other indications include complicated haemangiomas and neonatal haemangiomatosis [23]. Oral steroids are not recommended for the routine treatment of psoriasis and atopic dermatitis, although occasionally this may be necessary for severe refractory atopic dermatitis for a limited period in combination with a steroid-sparing agent, such as ciclosporin or azathioprine (see Chapter 30).

Ciclosporin Ciclosporin, a potent immunosuppressant that requires careful consideration of risk versus benefit, has been found to be of use in treating disorders such as severe psoriasis [24] and atopic dermatitis (see Chapters 30, 82). Use of immonsuppressants, including ciclosporin, is generally limited to a 6-month period. Usage for longer periods has been observed to be safe in rheumatoid arthritis patients on etanercept. However, use for more than 1 year has not been well assessed in paediatric patients [25].

Essential fatty acids Essential fatty acids (EFAs) are those acids that cannot be synthesized by humans and must therefore be a part of the diet. Major essential fatty acids found in humans are linoleic acid and its products, γ-linoleic acid and arachidonic acid. Deficiency of EFA in the diet leads to a scaly dermatitis and impaired skin barrier function [26,27]. Oral intake may cause clinical improvement in the skin of patients with atopic dermatitis [28]. The eicopentaenoic acids (EPAs) are polyunsaturated fatty acids found in large quantities in fish oils. Long-term administration of fish oil, rich in omega-3 fatty acids, may modify the severity of psoriasis and enhance the efficacy of co-administered conventional psoriatic therapy. Oral and intravenous supplementations of omega-3 and omega-6 fatty acids have been found effective in adult

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psoriatic patients [25]. EPAs have also been proposed as a supplementary treatment in patients who are receiving ciclosporin for psoriasis and other dermatoses because of their possible renal protective effects [29].

Immunoglobulins Intravenous immunoglobulin (IVIG) has been used successfully to treat Kawasaki’s disease (see Chapter 168) and toxic epidermal necrolysis (TEN) (see Chapter 78). IVIG may also be a useful treatment modality for children with intractable atopic dermatitis although the data for this indication are quite limited [30].

Interferons Paediatric patients with haemangiomas have been successfully treated with subcutaneous injections of INF-α 2a and b [31,32]; however, it is now recognized that there is a long-term risk of neurological complications such as irreversible spastic diplegia when the medication is used in infants. Interferon may also be effective in severe, intractable atopic dermatitis (see Chapter 30).

Retinoids Retinoids for systemic administration in dermatology currently include isotretinoin and acitretin. They have profound effects on cell differentiation and may play a role in chemoprevention [33]. Isotretinoin (13-cis-retinoic acid) is very effective in the treatment of severe, recalcitrant, nodulocystic acne. It decreases the size of sebaceous glands and alters keratinization of the glandular acroinfundibulum. It also inhibits the release of arachidonic acid by macrophages, thus contributing to an anti-inflammatory effect [33]. Remissions following therapy are, in the majority of cases, definitive. Other dermatological conditions for which isotretinoin may be effective include various ichthyoses and Darier disease [34]. Isotretinoin may be useful in the prevention of malignant skin tumours in individuals who are predisposed to skin cancers, including those previously exposed to arsenic insecticides, patients with naevoid basal cell carcinoma syndrome or with xeroderma pigmentosum [35,36]. Isotretinoin is associated with a variety of skin and mucosal side-effects such as xerosis, cheilitis, conjunctival irritation, skin fragility and hair loss. Other side-effects include headache from pseudo-tumour cerebri, papilloedema, nausea, vomiting, visual disturbances and arthralgia, usually as a result of hyperostoses and tendinous calcifications. Premature epiphyseal closure and pathological fractures have been observed in long-term therapy patients. Hypertriglyceridaemia develops in approximately 25% of patients under treatment and is usually reversible. The risk of teratogenicity is an extremely important factor to consider when prescribing systemic isotretinoin

[34]. Pregnancy is an absolute contraindication and women should not become pregnant for at least 1 month after the drug has been discontinued. Some women have taken the drug during pregnancy, and several infants with multiple major anomalies have been born. A specific syndrome that includes CNS, ear and great vessel abnormalities, along with hypoplasia of the thymus and parathyroid gland, has been described. Acitretin is a retinoid that has replaced etretinate and has a terminal elimination half-life of about 55–60 h. When taken with alcohol, acitretin can be reverse metabolized to the parent compound etretinate, which is then stored and eliminated over a prolonged period of time [33,37]. Acitretin is an effective treatment for severe psoriasis, because of its effect on epidermal differentiation and keratinization. Because of long-term storage and biological activity, the use of acitretin for psoriasis in children should be undertaken with careful consideration of risk versus benefit. Beside psoriasis, a wide variety of disorders of keratinization are reported to be responsive to acitretin: erythrokeratoderma variabilis [38], Papillon– Lefevre syndrome [39], epidermal naevus syndrome [40] and keratitis–ichthyosis–deafness syndrome (KID) syndrome [41]. Darier disease, lamellar ichthyosis and nonbullous ichthyosiform erythroderma are responsive to both acitretin and isotretinoin. For these conditions, chronic therapy is usually necessary, as remissions following discontinuation of treatment have not been reported. Successful outcomes in cases of harlequin fetus treated with acitretin have also been reported [42]. Acitretin toxicity is similar to that of isotretinoin with regard to mucocutaneous signs, hyperlipidaemia and abnormal liver function tests. Some patients on long-term therapy may develop tendinous and ligamentous calcifications and hyperostoses as may be seen with chronic high-dose vitamin A. Acitretin is also teratogenic, so contraception should be used during treatment and for 2 years after treatment has stopped because of long half-life and tissue storage [33].

Propranolol Infantile haemangioma, characterized by growth related to cellular hyperplasia, is the most common vascular tumour. They are clinically heterogeneous in size, location, risk of complications and rate of proliferation. The major goals of management are to prevent or reverse any threat to life or function and to prevent permanent disfigurement. Propranolol, a non-selective β-blocker traditionally used in the treatment of hypertension, was first observed to inhibit the growth phase of a proliferation infantile haemangioma in a 4-month-old infant. Sans et al. found that propranolol administered orally at 2–3 mg/kg per day had a rapid therapeutic effect, with colour changes

Principles of Paediatric Dermatological Therapy

and softening of the lesion within the first hours of treatment. The effect was sustained for several weeks and resulted in considerable shortening of the natural course of the infantile haemangioma [43]. Most common serious adverse effects are bradycardia and hypotension [44]. Although propranolol may represent an effective and possibly safer therapeutic option for infantile haemangiomas, β-blockers should be used with caution for this indication until there is further understanding of the mechanism of action and optimal dosing. References 1 Ayangeo L, Sheridan PJ. Minocycline-induced staining of torus palatinus and alveolar bone. J Periodontol 2003;74:669–71. 2 Mirensky Y, Parish LC, Witkowsky JA. Recent advances in antimicrobial therapy of bacterial infections of the skin. In: Dahl MV, Lynch PJ (eds) Current Opinion in Dermatology, 2nd edn. Philadelphia: Current Science, 1995. 3 Ginter-Hanselmayer G, Smolle J, Gupta A. Itraconazole in the treatment of tinea capitis caused by Microsporum canis: experience in a large cohort. Pediatr Dermatol 2004;21(4):499–502. 4 Koumantaki E, Georgala S, Rallis E et al. Microsporum canis tinea capitis in an 8-month-old infant successfully treated with 2 weekly pulses of oral itraconazole. Pediatr Dermatol 2001;18:60–2. 5 Gupta AK, Ginter G. Itraconazole is effective in the treatment of tinea capitis caused by Microsporum canis. Pediatr Dermatol 2001;18: 519–22. 6 Gupta AK, Adam P, Dlova N et al. Therapeutic options for the treatment of tinea capitis caused by Trichophyton species: griseofulvin versus the new oral antifungal agents, terbinafine, itraconazole and fluconazole. Pediatr Dermatol 2001;18:433–8. 7 Adair RH, Bauchner H. Sleep problems in childhood. Curr Probl Pediatr 1993;23; 147–70. 8 Singh-Franco D, Ghin HL, Robles GI, Borja-Hart N, Perez A. Levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children. Clin Ther 2009;31(8): 1664–87. 9 Choi YS, Hann SK, Park Y-K. The effect of cimetidine on verruca plana juvenilis: clinical trials in six patients. J Dermatol 1993;20: 497–500. 10 Wershil DK, Mekery VA, Galli SJ. Cimetidine and common variable hypogammaglobulinemia. N Engl J Med 1985;313:264–6. 11 White WB, Ballow M. Modulation of suppressor-cell activity by cimetidine in patients with common variable hypogammaglobulinemia. N Engl J Med 1985;312:198–202. 12 Simon GL, Miller HG, Scott SJ. Cimetidine in the treatment of hyperimmunoglobulinemia E with impaired chemotaxis. J Infect Dis 1983;147:1121–2. 13 Jorizzo JL, Sams WM, Jegasothy BV et al. Cimetidine as an immunomodulator: chronic mucocutaneous candidiasis as a model. Ann Intern Med 1980;92:192–5. 14 Gooptu C, Higgins CR, James MP. Treatment of viral warts with cimetidine: an open-label study. Clin Exp Dermatol 2000;25(3): 183–5. 15 DiNicola AF. Varicella vaccine guidelines. Pediatrics 1995;96: 375–6. 16 Kugathasan S, Miranda A, Nocton J et al. Dermatologic manifestations of Crohn’s disease in children: response to infliximab. J Pediatr Gastroenterol Nutr 2003;34:150–4. 17 Saulsbury FT, Mann JA. Treatment with infliximab for a child with Behçet’s disease. Arthritis Rheum 2003;49:599–600.

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18 Sleight BS, Chan KW, Braun TM, Serrano A, Gilman AL. Infliximab for GVHD therapy in children. Bone Marrow Transplant 2007;40(5):473–80. 19 Paller AS, Siegfried EC, Langley RG et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008;358(3):241–51. 20 Gadner H, Grois N, Arico M et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr 2001; 138:728–34. 21 Grifo AH. Langerhans cell histiocytosis in children. J Pediatr Oncol Nurs 2009;26(1):41–7. 22 Ang P, Tay Y. Treatment of linear IgA bullous dermatosis of childhood with colchicine. Pediatr Dermatol 1999;16:50–2. 23 Pope E, Krafchik BR, Macarthur C et al. Oral versus high-dose pulse corticosteroids for problematic infantile hemangiomas: a randomized, controlled trial. Pediatrics 2007;119(6):e1239–47. 24 Pereira TM, Vieira AP, Fernandes JC, Sousa-Basto A. Cyclosporin A treatment in severe childhood psoriasis. J Eur Acad Dermatol Venereol 2006;20(6):651–6. 25 Silverberg NB. Pediatric psoriasis: an update. Ther Clin Risk Manag 2009;5:849–56. 26 Skolnik P, Eaglstein WH, Ziboh VA. Human essential fatty acid deficiency. Arch Dermatol 1977;113:939–41. 27 Tolesson A, Frithz A, Berg A et al. Essential fatty acid in infantile seborrheic dermatitis. J Am Acad Dermatol 1993;28: 957–61. 28 Van Gool CJ, Thijs C, Henquet CJ et al. Gamma-linolenic acid supplementation for prophylaxis of atopic dermatitis: a randomized controlled trial in infants at high familial risk. Am J Clin Nutr 2003;77:493–51. 29 Elzinga L, Kelley VE, Houghton DC et al. Modification of experimental nephrotoxicity with fish oil as the vehicle for cyclosporine. Transplant 1987;43:271–5. 30 Ricci G, Dondi A, Patrizi A, Masi M. Systemic therapy of atopic dermatitis in children. Drugs 2009;69(3):297–306. 31 Tryfonas GI, Tsikopoulos G, Liasidou E et al. Conservative treatment of hemangiomas in infants and childhood with interferon-alpha 2a. Pediatr Surg Int 1998;13:590–3. 32 Garmendia G, Miranda M, Borroso S et al. Regression of infancy hemangiomas with recombinant IFN-alpha 2b. J Interfer Cytok Res 2001;21:31–8. 33 Di Giovanna JJ. Systemic retinoid therapy. Dermatol Clin 2001; 19:161–78. 34 American Academy of Pediatrics Committee on Drugs. Retinoid therapy for severe dermatological disorders. Pediatrics 1992;90: 119–20. 35 Kraemer KH, di Giovanna JJ, Moshell AN et al. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1998;318:1633–7. 36 Pack JL, di Giovanna JJ, Sarnoff DS et al. Treatment and prevention of basal cell carcinoma with oral isotretinoin. J Am Acad Dermatol 1998;19:176–85. 37 Berbis P. Acitretin. Ann Dermatol Venereol 2001;128:737–45. 38 Graham-Brown RA, Chave TA. Acitretin for erythrokeratodermia variabilis in a 9-year-old girl. Pediatr Dermatol 2002;19: 510–12. 39 Al-Khenaizan S. Papillon–Lefevre syndrome: the response to acitretin. Int J Dermatol 2002;41:938–41. 40 Pandhi D, Reddy BS. A rare association of epidermal nevus syndrome and ainhum-like digital constriction. Pediatr Dermatol 2002;19: 349–52. 41 Sahoo B, Handa S, Kaur I et al. KID syndrome: response to acitretin. J Dermatol 2002;29:499–502. 42 Singh S, Bhura M, Maheshwari A et al. Successful treatment of harlequin ichthyosis with acitretin. Int J Dermatol 2001;40:472–3.

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43 Sans V, Dumas de la Roque E, Berge J et al. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics 2009;124(3): e423–31. 44 Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendations. Pediatr Dermatol 2009;26(5):610–14.

Conclusion Principles of paediatric dermatological therapy evolve from many considerations. Paediatric skin serves as an

accessible target organ for drug activity in numerous conditions. Drug targeting to skin in the paediatric population also minimizes the risk of systemic toxicity in this group of patients. Contrary to this, the skin may also serve as a preferred route for delivery of a systemic drug. As the skin provides a rate-limiting effect upon the transit of active pharmacological agents, the state of the skin barrier, as determined by the nature of the skin condition as well as gestational and postnatal age, is an important factor in therapeutic decision making, especially in neonates and young children.

182.1

C H A P T E R 182

The Use of Emerging Biological Treatments in Children Polly Livermore & Clarissa Pilkington Paediatric Rheumatology, Great Ormond Street Hospital for Children NHS Trust, London, UK

Introduction, 182.1

Cell-targeted biologicals, 182.10

Summary, 182.14

Anticytokine therapies, 182.1

Introduction Historically, physicians have treated the symptoms of disease, however with increasing technology and knowledge, biological agents are used in the current times to target the root cause of diseases and thus not only treat the symptoms but with the aim of re-educating the immune system and putting diseases into remission. In the last few years this shift in treatment has grown from a new understanding of the immunopathophysiological basis of the underlying disease conditions, allowing the development of newer technologies that use organisms to create new drugs. Biological agents are thus defined as ‘A substance that is made from a living organism or its products and is used in the prevention, diagnosis, or treatment of diseases. Biological drugs include antibodies, interleukins, and vaccines’ [1]. Currently there are limited data on biological agents being used for paediatric dermatological conditions. This is due to lack of multicentre, randomized, placebocontrolled studies, but also more importantly to the majority of dermatological conditions in children being treated topically, rather than submitting the whole body, including vital organs, to the exposure of powerful chemicals. Psoriasis, however, is one exception and biological therapies are indicated if more conventional therapies have failed. Closely related to dermatological diseases, with overlap into this area, are the rheumatological conditions where these treatments are slowly becoming familiar practice. This chapter will present each therapy using the knowledge gained from paediatric rheumatological conditions, and discuss in turn the differential diagnoses that may benefit from such therapies.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

The tumour necrosis factor α (TNF-α) therapies are used most frequently and are presented first. The structure, pharmacokinetics, dosage, efficacy and side-effects will all be described and supported by current literature where appropriate. At the end of this section, the most important issues related to their use in paediatric patients, such as how to encourage compliance of painful injections, or how to instill realistic hopes and expectations, will be discussed. The extended family of biological therapies such as anakinra, tocilizumab and rituximab will then be covered. Reference 1 National Cancer Institute. www.cancer.gov/dictionary.

Anticytokine therapies Tumour necrosis factor α Tumour necrosis factor is one of the main cytokines involved in stimulating the inflammatory process. TNF receptors are the body’s natural way of controlling excess TNF. However, in many autoimmune conditions, such naturally occurring TNF receptors cannot adequately regulate TNF activity, leading to an imbalance. It is thought that TNF-α resides at the apex of an inflammatory cytokine cascade that is responsible for the pathophysiology of some autoimmune conditions. TNF-α can be produced by numerous cell types, but in inflammatory conditions is usually produced by activated macrophages. TNF-α may contribute to the pathogenesis of inflammatory conditions inducing other proinflammatory cytokines (e.g. interleukin 1 (IL-1), IL-6) and chemokines (e.g. IL-8); by enhancing leukocyte migration, by increasing endothelial layer permeability and adhesion molecule expression; and by improving the function and induction

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of synthesis of acute-phase reactants and other proteins [1]. It was proved in animal studies initially that the inhibition of TNF-α with soluble TNF receptor constructs ameliorated the signs of inflammation and prevented joint damage and destruction [2]. With tools from molecular biology, different compounds have been created, all of which bind strongly to TNF-α and inhibit its proinflammatory activities. Etanercept is a fusion protein made up of two recombinant p75 TNF receptors fused with the Fc portion of a human immunoglobulin 1 (IgG-1). Infliximab and adalimumab are both monoclonal antibodies; the first is a chimeric molecule (composed of the variable region of a murine antibody grafted to the constant region of a human antibody); the second is a human-derived antibody [3].

Etanercept Structure Etanercept is a human TNF receptor p75–Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary mammalian expression system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand-binding domain of a human TNF receptor 2 (TNF-R2/p75) to the Fc domain of human IgG-1. This Fc component contains the hinge, CH2 and CH3 regions but not the CH1 region of IgG-1 [4]. The resultant molecule binds both TNF-α and LT-β (lymphotoxin β, previously termed TNF-β) with high affinity and specificity.

Pharmacokinetics Etanercept is slowly absorbed from the site of subcutaneous injection, reaching a maximum concentration approximately 48 h after a single dose. With twice weekly doses it is anticipated that steady-state concentrations are approximately twice as high as those observed after single doses. Etanercept is cleared slowly from the body, with a half-life of approximately 70 h. There is no apparent pharmacokinetic difference between males and females; the presence of renal or hepatic impairment should not require a change in dosage. Methotrexate has no effect on the pharmacokinetics of etanercept [4]. In a polyarticular juvenile idiopathic arthritis (JIA) trial with etanercept, 69 patients were administered 0.4 mg etanercept/kg twice weekly for 3 months. Serum concentration profiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 years of age) had reduced clearance (increased clearance when normalized by weight) compared with older children (12 years) and adults. Simulation of dosing suggests that while older children (10–17 years) will have serum levels close to those seen in adults, younger children will have appreciably lower levels [4–6].

Drug dose Juvenile idiopathic arthritis In JIA (age 4 years and above, although it has FDA (Food and Drug Administration) approval from 2 years and above in the United States) 0.4 mg/kg (up to a maximum of 25 mg per dose) is given twice weekly as a subcutaneous injection with an interval of 3–4 days between doses. Whilst the license is for twice weekly etanercept in paediatrics, many physicians find that once weekly (at 0.8 mg/kg per dose) is as efficacious. In patients who are well controlled on twice weekly doses, the move to once weekly often improves patient and family satisfaction [5].

Paediatric plaque psoriasis In paediatric plaque psoriasis (age 8 years and above) 0.8 mg/kg (up to a maximum of 50 mg per dose) is given once weekly for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks. If retreatment with etanercept is indicated, the above guidance on treatment duration should be followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

Efficacy Juvenile idiopathic arthritis Etanercept was the first TNF-α antagonist to be approved for use in treating JIA in 1999, and has recently received FDA approval for treating children as young as 2 years old with severe polyarticular JIA. The one and only randomized controlled trial of etanercept for the treatment of refractory polyarticular JIA enrolled 69 patients in a multicenter, placebo-controlled trial employing a drug withdrawal design, followed by an open-label extension phase. Patients were aged 4–17 years with moderately to severely active polyarticular JIA refractory to or intolerant of methotrexate. Patients were randomized to placebo or active drug after an initial 3-month treatment with etanercept. The results showed that patients randomized to continue drug therapy had a significant longer median time to disease flare than those randomized to placebo [5]. The open-label extension phase results were published recently providing information on 318 patient years of etanercept therapy, including up to 8 years of continuous therapy for some. Whilst the results of the 11 patients who continued etanercept therapy for 8 years were impressive, only 20 out of the initial 69 patients continued into the open-label extension trial. Eleven of the patients who failed to respond during the initial phase and a further 38 withdrew for a variety of reasons including lack of efficacy, adverse events, physician decision or patient refusal [6]. Registries aim to capture information about all patients receiving the same drug or type of drug; this often includes age, sex, drug doses, other medications and side-

The Use of Emerging Biological Treatments in Children

effects experienced. The initial data of 322 patients with JIA and 12 with non-JIA rheumatic diseases were published from the German and Austrian JIA/etanercept registry in 2004. Of 592 patient treatment years there were 69 reports of adverse events in 56 patients and treatment was discontinued in only 53 JIA patients, in 25 because of lack of efficacy [7]. More recently, the German registry set up in 2001 presented data on a total of 722 patients with JIA. Data were examined on those available at 12 months and they found 81% of those on etanercept and methotrexate met the criteria for a 30% improvement and 70% of those on etanercept alone [8]. Similar results have been observed in the Dutch registry of 146 JIA/etanercept patients, although the response waned after 2 years of treatment. This could be explained by a high percentage of patients with systemic-onset JIA, who have been shown to respond less well than patients with other subtypes of JIA [9–11].

Psoriasis A group of 211 paediatric patients aged 4–17years old with moderate to severe plaque psoriasis (as defined by a static physicians global assessment (sPGA) score of ≥3, involving ≥10% of the body surface area, and PASI ≥12) were enrolled into a randomized, double-blind, placebocontrolled study. The primary endpoint was 75% or greater improvement from baseline in the psoriasis areaand-severity index (PASI 75) at week 12. Secondary endpoints included PASI 50, PASI 90, a physician’s global assessment of clear or almost clear of disease, and safety assessments. Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy. Patients received etanercept 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomized to etanercept had positive efficacy responses (e.g. PASI 75) than those randomized to placebo (57% and 11%, respectively). After the initial phase, all patients received etanercept 0.8 mg/kg (up to 50 mg) once weekly for a further 24 weeks and the results were similar to those seen in the initial phase. At week 36, 138 patients underwent a second randomisation to placebo or etanercept to investigate the effects of withdrawal and retreatment. At week 48, response was lost by 29 of the 69 patients assigned to placebo. Four serious adverse events (three infections) occurred in three patients during treatment with openlabel extension; all resolved without sequelae [12]. Uveitis Chronic uveitis occurs in up to 30% of children with JIA, especially in those with oligoarticular forms, below the age of 7 years old, of female gender and with antinuclear antibody (ANA) positivity. As Schmeling and Horneff discuss, TNF-α has been implicated in the pathogenesis

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of uveitis and has been extensively studied in animal models [13]. The question as to whether etanercept is good for uveitis has been researched for many years now. In 2001, Reiff et al. suggested that etanercept has a beneficial effect on treatment-resistant uveitis as observed in their cohort of 10 paediatric patients with uveitis (seven due to JIA) in a prospective study over 3 months [14]. In a retrospective study, 229 questionnaires were returned out of 310 sent to paediatric rheumatologists enquiring about uveitis and etanercept administration. Thirty-one patients had a history of uveitis (13.5%) before etanercept addition. Upon starting etanercept, 32 courses of uveitis occurred in 19 patients and in two further patients (1%) in whom uveitis occurred for the first time. The study concluded that during treatment with etanercept there were both relapses and first occurrences of uveitis, and that the frequency and severity of flares was not influenced by etanercept [13]. A more recent study compared 24 patients with JIA taking etanercept and 21 taking infliximab. Of these 45 patients, uveitis improved in 14 (31%), no change was observed in 14 (31%), and the activity of uveitis increased in 17 (38%). However, inflammatory activity improved more frequently in those taking infliximab than etanercept. Uveitis developed for the first time in four patients taking etanercept and one taking infliximab. In conclusion, uveitis improved in one-third of patients on antiTNF treatment and infliximab may be more effective than etanercept [15]. It is only fair to say that case reports have been published postulating whether etanercept could in fact cause uveitis in patients rather than affecting the natural progression of the disease itself [16,17]. However, so far these remain only as case reports and until the data from the registries are published, this question can not be answered.

Orphan diseases Anti-TNF agents as a whole have been used in a variety of autoimmune conditions, including juvenile-onset spondyloarthropathies [17–20], TRAPS (TNF receptor superfamily 1A-associated periodic fever syndrome) [21,22], chronic recurrent multifocal osteomyelitis [23], Behcet disease [24–26], inflammatory myopathies [27–29] and various types of vasculitis [30–33]. Whilst etanercept is not licensed for such conditions, physicians will try these medications in an acutely unwell child who has failed conventional treatment, producing interesting results that are published as case reports.

Contraindications • Patients who are hypersensitive to the active substance. • Patients with sepsis. • Patients with active infections.

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• Premature babies or neonates as the solvent contains benzyl alcohol. • Must not be administered with abatacept, anakinra and other anti-TNFs. Live vaccines should not be given with etanercept, and adolescents should use contraception whilst taking the drug.

Side-effects Injection site reactions Compared to placebo, patients with rheumatic diseases treated with etanercept had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately 3–5 days. No treatment was given for the majority of injection site reactions, and those who were given treatment received topical preparations such as corticosteroids or oral antihistamines. Additionally, some patients developed recall injection site reactions characterized by a skin reaction at the most recent site of injection along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment [4].

Infections and general side-effects The types of infections seen in clinical trials in JIA patients aged 2–18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae, appendicitis, gastroenteritis, oesophagitis/gastritis, group A streptococcal septic shock, and soft tissue and postoperative wound infection. Severe non-infectious adverse events reported included depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis and type I diabetes mellitus [4]. In one study in children with JIA arthritis aged 4–17 years, 43 of 69 (62%) children experienced an infection while receiving etanercept during 3 months of the study (part 1 open label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types and proportion of adverse events in JIA patients were similar to those seen in trials of etanercept in adult patients with rheumatoid arthritis, and the majority were mild. Several generalized adverse events were reported more commonly in 69 JIA patients receiving 3 months of Enbrel compared to 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 events per patient year), abdominal pain (19%, 0.74 events per patient year) and vomiting (13%, 0.74 events per patient year) [4].

In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with etanercept developed injection site reactions compared with 3.4% of placebo-treated patients during the first 12 weeks of treatment [4].

Malignancies Malignancies have been reported whilst patients have been receiving anti-TNF agents [4]; 48 reported cases of paediatric malignancies over an 8-year period (2001–2008) have been investigated by the FDA, from all over the globe. The highest number of one type of cancer to occur were 10 anti-TNF-associated hepatosplenic T-cell lymphomas reported in juvenile inflammatory bowel disease patients. There were seven non-Hodgkin lymphomas, six Hodgkin lymphomas and six leukaemias; the rest were a variety of single cases of cancers. Patient treatment years were estimated to be 22,645 treatment years for infliximab for patients aged 0–16 years and for etanercept to be 26,800 treatment years for patients aged 0–17 years. Twenty-one of the malignancies were reported in children with Crohn disease, 15 in children with JIA and four in ulcerative colitis. It is currently unclear whether this risk of malignancy is increased in children with JIA as there are no data for JIA children on alternative treatments, unlike the data from adults that indicate an increased risk of lymphoma in patients with rheumatoid arthritis [34]. Tuberculosis One of the major concerns with TNF-α blockers is their potentially pro-infective action. The reactivation of tuberculosis has become less of a concern with careful screening and prophylaxis before starting therapy. However there are two case reports in the literature of two systemic patients dying whilst on anti-TNF – one on infliximab and the other receiving etanercept [35].

Infliximab Structure Infliximab is a chimeric human–murine IgG-1 monoclonal antibody produced by recombinant DNA technology. After reconstitution each millilitre contains 10 mg of infliximab [36]. Infliximab binds with high affinity to both soluble and transmembrane forms of TNF-α but not to lymphotoxin α (TNF-ß). Infliximab inhibits the functional activity of TNF-α in a wide variety of in vitro bioassays. Infliximab prevented disease in transgenic mice that developed polyarthritis as a result of constitutive expression of human TNF-α and, when administered after disease onset, it allowed eroded joints to heal. In vivo, infliximab rapidly forms stable complexes with human TNF-α, a process that parallels the loss of TNF-α bioactivity [36].

The Use of Emerging Biological Treatments in Children

Pharmacokinetics Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of infliximab yielded dose-proportional increases in the maximum serum concentration (Cmax) and area under the concentration–time curve (AUC). The volume of distribution at steady state (median Vd of 3.0–4.1 L) was not dependent on the administered dose and indicated that infliximab is predominantly distributed within the vascular compartment. No time dependency of the pharmacokinetics was observed. The elimination pathways for infliximab have not been characterized. Unchanged infliximab was not detected in urine. No major age- or weight-related differences in clearance or volume of distribution were observed in rheumatoid arthritis patients. The pharmacokinetics of infliximab in elderly patients has not been studied, and studies have not been performed in patients with liver or renal disease [36]. In combination therapy with methotrexate, serum infliximab concentrations tend to be slightly higher than when administered alone [1]. Overall, serum levels in paediatric patients with Crohn disease (53 patients aged 6–17 years; 8 patients aged 6–10 years) were similar to those in adult Crohn disease. The median terminal half-life for the 5 mg/kg dose in paediatric patients with Crohn disease is 10.9 days [36].

Drug dose • Adult rheumatoid arthritis: the dose is 3 mg/kg IV given as an intravenous infusion over a 2 h period followed by an additional 3 mg/kg infusion at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter [36]. When administered in conjunction with methotrexate there is an enhanced clinical response and also a decrease in its immunogenicity [1]. • Adult psoriatic arthritis: the dose is 5 mg/kg given as an intravenous infusion over a 2 h period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter [36]. • Adult psoriasis: the dose is 5 mg/kg given as an intravenous infusion over a 2 h period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after four doses), no additional treatment with infliximab should be given [36]. • Crohn disease (6–17 years): the dose is 5 mg/kg given as an intravenous infusion over a 2 h period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval may be sufficient. Available data do not support further infliximab treatment in paediatric

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patients not responding within the first 10 weeks of treatment [36]. Infliximab has not been studied in patients with Crohn disease aged less than 6 years. Due to insufficient data on safety and efficacy, infliximab is not recommended for use in any other paediatric indication [36].

Efficacy Whilst other areas of the discussion on infliximab have been extrapolated from adult evidence, this section will only detail paediatric studies to provide a concise report.

Paediatric Crohn disease (6–17 years) In the REACH study, 112 patients (aged 6–17 years, median age 13.0 years) with moderate to severe active Crohn disease (median paediatric Crohn disease activity index of 40) and an inadequate response to conventional therapies received 5 mg/kg infliximab at weeks 0, 2 and 6. All patients were required to be on a stable dose of 6 mercaptopurine, azathioprine (AZA) or methotrexate (MTX) (35% were also receiving corticosteroids at baseline). Patients assessed by the investigator to be in clinical response at week 10 were randomized and received 5 mg/kg infliximab at either 8 weeks or 12 weeks as a maintenance treatment regimen. If response was lost during maintenance treatment, crossing over to a higher dose (10 mg/kg) and/or shorter dosing interval (q8 weeks) was allowed. Thirty-two evaluable paediatric patients crossed over (nine subjects in the q8 week and 23 subjects in the q12 week maintenance groups). Twentyfour of these patients (75.0%) regained clinical response after crossing over. The proportion of subjects in clinical response at week 10 was 88.4% (99/112). The proportion of subjects achieving clinical remission at week 10 was 58.9% (66/112). At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52) than the q12 week maintenance treatment group (35.3%, 18/51; P = 0.013). At week 54, the figures were 55.8% (29/52) and 23.5% (12/51) in the q8 week and q12 week maintenance groups, respectively (P 30% in no more than one of the six criteria. After 32 weeks or at disease flare, patients were eligible to enrol into the open-label extension phase. Amongst those who responded at week 16 (n = 144), the paediatric ACR 30/50/70/90 responses were maintained for up to 2 years in the open-label extension phase in patients who received adalimumab throughout the study. Overall responses were generally better and fewer patients developed antibodies when treated with a combination of adalimumab and MTX compared to adalimumab alone. Taking these results into consideration, adalimumab is recommended for use in combination with MTX and for use as monotherapy in patients for whom MTX use is not appropriate [46]. Papers have been published using adalimumab in those with poly-JIA who have failed to respond to one or both other anti-TNF agents, with good results [47,48]. Whilst adalimumab has been reported in a variety of paediatric diseases, most of the literature highlights the positive effect adalimumab has on juvenile uveitis [49–52].

Side-effects Injection reactions and infections The most frequently reported adverse events from a randomized, double-blind, stratified, placebo-controlled, multicentre, medication-withdrawal study, after adjustment according to extent of exposure, were infections and injection site reactions. These events were considered mild to moderate. Serious adverse events considered pos-

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sibly related to the study drug by the investigators occurred in 14 patients: six during the open-label lead-in phase, one during the double-blind phase and seven during the open-label extension phase. Of these, seven were serious infections (one case each of bronchopneumonia, herpes simplex virus infection, pharyngitis, pneumonia and unspecified viral infection, and two cases of herpes zoster). Nine patients during the open-label leadin phase, no patients during the double-blind phase, and three patients during the open-label extension phase discontinued treatment because of adverse events. No deaths, malignant conditions, opportunistic infections, cases of tuberculosis, demyelinating diseases or lupuslike reactions were reported during this study [46].

Immunogenicity Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodies and the occurrence of adverse events. In patients with polyarticular JIA, adalimumab antibodies were identified in 27/171 subjects (15.8%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when adalimumab was used as an add-on to methotrexate [45]. Other concerns Malignancies remain a concern as with the other two antiTNF agents. Whilst there are less data available about malignancies in juvenile rheumatology or dermatology patients, these concerns must be taken seriously and the data will emerge as the registries publish their findings.

Other considerations with anti-TNF-α As these therapies earn themselves a space on the pharmacy shelves, the paediatrician has many issues to contemplate. In the United Kingdom, the National Institute of Clinical Excellence (NICE) has issued guidance on administering etanercept to young people [53]. Whilst this makes some of the processes easier, it has made some of the prescribing issues more complicated. For example, currently when any physician (according to NICE this should be a paediatric rheumatologist) would like to commence an anti-TNF drug, he needs to ask the child’s local Primary Care Trust (PCT) if they would be willing to carry the cost of the therapy. If it has NICE approval then this often happens without too many problems. However, if the patient falls outside the guidance windows (for example a 3-year-old with JIA who needs etanercept (the license is for 4–17years), or a child who needs adalimumab for uveitis) then the Hospital Trust often has to plead the case. Whilst this discussion occurs

between the PCT and local Trust, the child, young person and family are often left waiting and hoping for their new therapy: this can be an agonizing and distressing wait for a child with a disease flare. As these therapies are still deemed ‘new’, many parents have concerns about consenting for their children. Unlike in adult care, where the majority of adults make their own decisions and take their own responsibility, often parents find it much harder to speak for their child. This is continually made harder by new revelations, such as the media hype over malignancies and anti-TNF therapies. Whilst in the UK there is an etanercept registry, this is still only a couple of years old, and is collecting anonymous data on children and young people receiving etanercept. The appreciation of paediatric-specific issues must not be taken lightly. For example, although not necessarily a concern for the adult, live vaccines (such as MMR, BCG, chickenpox) should not be given to people receiving antiTNF agents. Children should have their chickenpox antibody titres recorded before commencing therapy to determine their antibody status and, if negative, the family should be educated on the avoidance of peers who have chickenpox, when and how to get a zoster immune globulin (ZIG) injection to provide short-term cover and, even if chickenpox does develop, that they should contact their local physician for aciclovir treatment and stop antiTNF drugs until the spots have crusted. As these therapies are either given subcutaneously or intravenously; the needle phobic child can pose a problem to the healthcare professional and child’s family. Good education at a developmentally appropriate level, with good support, the intervention of a psychologist or play worker, local anaesthetic agents and distraction or guided imagery may help. Side-effects experienced by young people, such as the pain on administering adalimumab, must be handled appropriately and the young person listened to and ways to minimize their discomfort discussed. Whilst it is acknowledged that these therapies often work better if given concurrently with methotrexate, a vast number of children and young people cannot physically or emotionally tolerate methotrexate due to its associated feelings of nausea, vomiting and general feelings of ill health. Before the physician even broaches the thought of a new drug with these children, adolescents and their families, he must gain the trust of the family and highlight how different drugs make different people feel differently. Just because these young people have ‘failed’ one therapy, it does not mean this new drug will not work for them, or even have the same unpleasant side-effects. On the other hand, an important role of the physician and multi-professional team is the balance between realistic hope and excessive faith in a new wonder drug [54]. From work undertaken with adults, it

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has been found that unrealistic expectations from sources such as the media and internet cause unnecessary angst in patients on anti-TNF [55]. This is the same in young people, although their expectations are confounded by their own developmental stages, hopes and expectations; if these therapies do not work, then how do we support the child, young person and family [56]? The threshold for switching from one anti-TNF agent to another is different for every physician in the country, as is the question about when is the best time to stop these therapies if a child’s disease is in remission on treatment. Only with time and evidence from personal experience and from the registries can we answer these questions in the future. References 1 Cassidy JT, Petty RE. Textbook of Rheumatology, 8th edn. New York: Saunders Elsevier, 2008. 2 Seymour HE, Worsley A, Smith JM, Thomas SH. Anti-TNF agents for rheumatoid arthritis. Br J Clin Pharmacol 2001;51(3):201–8. 3 Magnani A, Palmisani E, Sala I et al. Review for the generalist: update on biologic therapies for paediatric rheumatic diseases. http:// www.pedrheumonlinejournal.org/july - august05/Biologics.htm , 2005. 4 Anon. Enbrel 25mg powder and solvent for solution for injection: Summary of Product Characteristics. Wyeth, UK, 2009. 5 Horneff G, Ebert A, Fitter S et al. Safety and efficacy of once weekly etanercept 0.8 mg/kg in a multicentre 12 week trial in active polyarticular course juvenile idiopathic arthritis. Rheumatology (Oxf) 2009;48(8):916–19. 6 Lovell DJ, Giannini EH, Reiff A et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000;342(11): 763–9. 7 Horneff G, Schmeling H, Biedermann T et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis 2004;63(12):1638–44. 8 Horneff G, De Bock F, Foeldvari I et al. Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry. Ann Rheum Dis 2009;68(4):519–25. 9 Lovell DJ, Reiff A, Ilowite NT et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum 2008;58(5):1496–504. 10 Quartier P, Taupin P, Bourdeaut F et al. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum 2003;48(4):1093–101. 11 Hayward K, Wallace CA. Recent developments in anti-rheumatic drugs in pediatrics: treatment of juvenile idiopathic arthritis. Arthritis Res Ther 2009;11(1):216. 12 Paller AS, Siegfried EC, Langley RG et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008;358(3):241–51. 13 Schmeling H, Horneff G. Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology (Oxf) 2005;44(8): 1008–11. 14 Reiff A, Takei S, Sadeghi S et al. Etanercept therapy in children with treatment-resistant uveitis. Arthritis Rheum 2001;44(6): 1411–15. 15 Tynjala P, Lindahl P, Honkanen V, Lahdenne P, Kotaniemi K. Infliximab and etanercept in the treatment of chronic uveitis associated

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with refractory juvenile idiopathic arthritis. Ann Rheum Dis 2007;66(4):548–50. Reddy AR, Backhouse OC. Does etanercept induce uveitis? Br J Ophthalmol 2003;87(7):925. Monnet D, Moachon L, Dougados M, Brezin AP. Severe uveitis in an HLA-B27-positive patient with ankylosing spondylitis. Nat Clin Pract Rheumatol 2006;2(7):393–7. Henrickson M, Reiff A. Prolonged efficacy of etanercept in refractory enthesitis-related arthritis. J Rheumatol 2004;31(10):2055–61. Homeff G, Burgos-Vargas R. TNF-alpha antagonists for the treatment of juvenile-onset spondyloarthritides. Clin Exp Rheumatol 2002;20(6 Suppl 28):S137–42. Tse SM, Burgos-Vargas R, Laxer RM. Anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondylarthropathy. Arthritis Rheum 2005;52(7):2103–8. Takada K, Aksentijevich I, Mahadevan V, Dean JA, Kelley RI, Kastner DL. Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum 2003;48(9):2645–51. Grateau G. Clinical and genetic aspects of the hereditary periodic fever syndromes. Rheumatology (Oxf) 2004;43(4):410–15. Aktay Ayaz N, Topaloglu R, Ozaltin F, Cagler Tuncali M, Bakkaloglu A. A case of chronic recurrent multifocal osteomyelitis successfully treated with etanercept. Paediatr Rheumatol Online J 2008. http:// www.ped-rheum.com/content/6/S1/P191/abstract 6[1], P191. Sfikakos PP. Behcet’s disease: a new target for anti-tumour necrosis factor treatment. Ann Rheum Dis 2002;61(Suppl 2):ii51–3. Estrach C, Mpofu S, Moots RJ. Behcet’s syndrome: response to infliximab after failure of etanercept. Rheumatology (Oxf) 2002;41(10): 1213–14. Melikoglu M, Fresko I, Mat C et al. Short-term trial of etanercept in Behcet’s disease: a double blind, placebo controlled study. J Rheumatol 2005;32(1):98–105. Amarillo CKS. Etanercept is effective in the treatment of polymyositis/ dermatomyositis which is refractory to conventional therapy including steroids and other disease modifying agents. Arthritis Rheum 2000;43:S193. Pachman L, Niewold T, Shrestha S, Morgan G, Sullivan C. TNFalpha levels and IFNalpha activity in children with juvenile dermatomyositis (JDM) are associated and modified by etanercept. Clin Immunol 2009;131(Suppl 1):S158. Hengstman GJ, van den Hoogen FH, van Engelen BG. Treatment of dermatomyositis and polymyositis with anti-tumor necrosis factoralpha: long-term follow-up. Eur Neurol 2004;52(1):61–3. Tan AL, Holdsworth J, Pease C, Emery P, McGonagle D. Successful treatment of resistant giant cell arteritis with etanercept. Ann Rheum Dis 2003;62(4):373–4. Wegener Granulomatosis Etanercept Research Group. Etanercept plus standard therapy for Wegener ’s granulomatosis. N Engl J Med 2005;352(4):351–61. Arbach O, Gross WL, Gause A. Treatment of refractory Churg–Strauss syndrome (CSS) by TNF-alpha blockade. Immunobiology 2002;206(5): 496–501. Wagner AD, Andresen J, Jendro MC, Hulsemann JL, Zeidler H. Sustained response to tumor necrosis factor alpha-blocking agents in two patients with SAPHO syndrome. Arthritis Rheum 2002;46(7):1965–8. Woodcock J. Letter from Janet Woodcock, Director, Center for Drug Evaluation and Research to Dr Randy Cron, Birmingham, Alabama on behalf of the Pediatric Rheumatology Medical Listserver. Personal communication, 2010. Gerloni V, Pontikaki I, Gattinara M, Fantini F. Focus on adverse events of tumour necrosis factor alpha blockade in juvenile idiopathic arthritis in an open monocentric long-term prospective study of 163 patients. Ann Rheum Dis 2008;67(8):1145–52.

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36 Anon. Remicade 100mg powder for concentration for solution for infusion: Summary of Product Characteristics. Schering-Plough Ltd, USA, 2010. 37 Ruperto N, Lovell DJ, Cuttica R et al. A randomized, placebocontrolled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2007;56(9):3096–106. 38 Richards JC, Tay-Kearney ML, Murray K, Manners P. Infliximab for juvenile idiopathic arthritis-associated uveitis. Clin Experiment Ophthalmol 2005;33(5):461–8. 39 Sharma SM, Ramanan AV, Riley P, Dick AD. Use of infliximab in juvenile onset rheumatological disease-associated refractory uveitis: efficacy in joint and ocular disease. Ann Rheum Dis 2007;66(6): 840–1. 40 Bracaglia C, Buonuomo PS, Caminiti S, Insalaco A, Campana A, Cortis E. Infliximab to treat chronic uveitis in juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2008. http://www.pedrheum.com/content/6/S1/P47 6[S1], P47. 41 Riley P, McCann LJ, Maillard SM, Woo P, Murray KJ, Pilkington CA. Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology (Oxf) 2008;47(6): 877–80. 42 Famsworth NN, George SJ, Hsu S. Successful use of infliximab following a failed course of etanercept in a pediatric patient. Dermatol Online J 2005. http://dermatology-s10.cdlib.org/113/case_reports/ infliximab/hsu.html 11[3], 11. 43 Menter MA, Cush JM. Successful treatment of pediatric psoriasis with infliximab. Pediatr Dermatol 2004;21(1):87–8. 44 Carrasco R, Smith JA, Lovell D. Biologic agents for the treatment of juvenile rheumatoid arthritis: current status. Paediatr Drugs 2004;6(3):137–46. 45 Anon. Humira pen and syringe: Summary of Product Characteristics. Abbott Laboratories Ltd, UK, 2010. 46 Lovell DJ, Ruperto N, Goodman S et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med 2008;359(8):810–20. 47 Katsicas MM, Russo RA. Use of adalimumab in patients with juvenile idiopathic arthritis refractory to etanercept and/or infliximab. Clin Rheumatol 2009;28(8):985–8. 48 Trachana M, Pratsidou-Gertsi P, Kanakoudi-Tsakalidou F, Diafa C, Padralos G, Badouraki M. The use of etanercept and adalimumab in the management of JIA: a 5 year follow up study. Pediatr Rheumatol Online J 2008. http://www.ped-rheum.com/content/6/S1/P93 6[Suppl.1], P.93. 49 Biester S, Deuter C, Michels H et al. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 2007;91(3):319–24. 50 Mansour AM. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 2007;91(3):274–6. 51 Tynjala P, Kotaniemi K, Lindahl P et al. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology (Oxf) 2008;47(3):339–44. 52 Rudwaleit M, Rodevand E, Holck P et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis 2009;68(5):696–701. 53 Anon. Etanercept for the treatment of juvenile idiopathic arthritis. TA35. London: National Institute of Clinical Excellence (NICE), 2002. 54 Wilkinson N, Jackson G, Gardner-Medwin J. Biologic therapies for juvenile arthritis. Arch Dis Child 2003;88(3):186–91. 55 Marshall NJ, Wilson G, Lapworth K, Kay LJ. Patients’ perceptions of treatment with anti-TNF therapy for rheumatoid arthritis: a qualitative study. Rheumatology (Oxf) 2004;43(8):1034–8. 56 Livermore PA, Wedderburn LR, Woo P. An in-depth analysis of young people’s experience of their juvenile idiopathic arthritis (JIA) once receiving etanercept. J Adv Nurs. In press.

Cell-targeted biologicals Targeting B-cells Rituximab Structure Rituximab is a monoclonal antibody composed of a chimeric IgG-1 antibody that binds to CD20. CD20 is a receptor found on B-cells from the late pre-B-cell (i.e. not stem cells) to the terminal plasma differentiation cell. It is not found on mature antibody-secreting plasma cells, and therefore it is uncommon for circulating immunoglobulin levels to fall below normal [1]. The ligand for the CD20 receptor is unknown, but treatment with rituximab depletes B-cells by causing B-cell lysis. This occurs through antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity and pro-apoptotic signals [2]. Apart from depletion of circulating B-cells, there may be effects on other populations of immune cells, such as autoreactive T effector cells [3], which play a part in rituximab’s effectiveness. Rituximab was first used in the treatment of B-cell lymphomas, and then in autoimmune disorders thought to be driven by the production of autoantibodies. Rituximab is now approved in the USA and Europe for the treatment of adult rheumatoid arthritis that has failed anti-TNF treatment. Rituximab has been used in systemic lupus erythematosus in adults [4] and in children [5], though there have been no clinical trials in children. Rituximab has also been used in autoimmune thrombocytopenia, haemolytic anaemia, anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis and some autoimmune neuropathies. Case reports of the use of rituximab in dermatological diseases include its use in pemphigus vulgaris, paraneoplastic pemphigus, primary cutaneous B-cell lymphoma, dermatomyositis and chronic graft versus host disease [6]. In some of these conditions, the rationale was to deplete pathogenic autoantibodies such as in pemphigus [7,8], whereas in other conditions without a clear-cut autoantibody role, such as dermatomyositis [9], the effect of the rituximab may be through its effect on other immunoregulatory pathways. In all these conditions, randomized controlled clinical trials are essential in both children and adults to ascertain the effectiveness of the rituximab treatment. Currently there is a phase II/III trial ongoing in adult and paediatric inflammatory myopathies.

Pharmacokinetics Rituximab is cleared in a highly variable manner, with wide variations in serum levels after treatment [10]. The depletion of B-cells is variable between patients, as is the time to B-cell repopulation. The return of B-cells may herald a disease relapse, though this is not always the case [11]. In patients who do not respond to rituximab, a

The Use of Emerging Biological Treatments in Children

second course may be effective, especially if they had high levels of B-cells prior to rituximab infusion [12].

Drug dose There have been many dosing regimens used in the treatment of different diseases, as well as in different reports from the same disease. Clinical trials are needed to find the optimum regimen, and this may vary with disease. Rituximab is given as an intravenous infusion at doses varying between a single infusion of 375 mg/m2 to 1000 mg total dose, to repeated infusions at weekly intervals (for 4–8 weeks, 250–500 mg/m2), to two doses a fortnight apart (from 500 mg/m2 to 1000 mg total dose) [13]. Some of these regimens use concomitant immunosuppression such as IV cyclophosphamide or IV corticosteroid. The later helps prevent some of the common side-effects such as infusion reactions. The regimen used for oncological treatment has been standardized at 375 mg/m2 at weekly intervals for 4 weeks. The treatment regimen for rheumatoid arthritis and systemic lupus erythematosus tends to be two infusions, 2 weeks apart, of 500 mg/m2.

Efficacy Most of the evidence for efficacy comes from case-based reports for dermatological conditions. A multicentre study of 21 patients with severe pemphigus (corticosteroid refractory or corticosteroid dependent) were given 4-weekly infusions of 375 mg/m2 of rituximab. Eighteen of 21 patients (86%; 95% confidence interval, 64–97%) had a complete remission at 3 months, but disease relapsed in nine patients after a mean of 18.9 ± 7.9 months [8]. There have been randomized, placebo-controlled trials in patients with rheumatoid arthritis and systemic lupus erythematosus. The REFLEX trial for rheumatoid arthritis [14] demonstrated an improvement at 24 weeks in patients on rituximab and methotrexate (n = 311) who had failed one anti-TNF compared with placebo and methotrexate (n = 209). Patients assigned to placebo and rituximab had active, longstanding rheumatoid arthritis. Improvement was seen in the arthritis (ACR and European League Against Rheumatism [EULAR] response) of patients in the rituximab group, as well as improvements in fatigue, disability and health-related quality of life. Rituximab depleted peripheral CD20+ B-cells, but the mean immunoglobulin levels (IgG, IgM and IgA) remained within normal ranges [14]. In the SUNRISE trial, patients who had failed anti-TNF for rheumatoid arthritis were randomized to retreatment at 24 weeks with a course of rituximab (n = 318) or placebo (n = 157). Relative to baseline, patients who took rituximab during retreatment had significantly improved efficacy at week 48 compared to patients who took a placebo during retreatment [15]. A recent update on clinical trials

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in systemic lupus erythematosus reported a disappointing lack of significant efficacy in the LUNAR and EXPLORER phase II/III trials in non-renal lupus [4]; however other B-cell-depletion therapies look promising, and trials are ongoing.

Side-effects Studies in children on the safety of rituximab have been reported for patients with systemic lupus erythematosus [16]. There were few adverse events reported in 19 patients with organ- or life-threatening lupus given rituximab. Five cases developed herpes zoster and other adverse events were respiratory tract infections, but there was no placebo group for comparison. In the study of pemphigus patients receiving rituximab, serious side-effects were seen but there was no placebo group for comparison. The adverse events seen were pyelonephritis (n = 1, 12 months after rituximab treatment) and septicaemia (n = 1, 18 months after rituximab; the patient died). These patients had normal IgG levels but a profound decrease in the number of circulating B-lymphocytes. In the REFLEX trial for rheumatoid arthritis, most adverse events occurred with the first rituximab infusion and were of mild to moderate severity. The rate of serious infections was 5.2 per 100 patient years in the rituximab group and 3.7 per 100 patient years in the placebo group. In the SUNRISE trial, the rate of adverse events was similar in the rituximab and placebo groups. The use of rituximab has shown that it is safe in many conditions, but it can have potentially serious side-effects, which may occur at different rates in different diseases. Long-term surveillance of patients in these cohorts is needed to clarify this.

Targeting co-stimulatory molecules for T-cell activation Abatacept Structure Abatacept is a selective co-stimulation modulator that blocks T-cell activation. It achieves this by blocking the second signal required for T-cell activation, which is an antigen-independent process. The first signal that is needed for T-cell activation is the presentation of an antigen within the major histocompatibility complex (MHC) on the surface of an antigen-presenting cell (APC) such as a macrophage or a dendritic cell. The antigen+MHC binds to the T-cell receptor (TCR) on the T-lymphocyte to activate the T-cell. This needs to be accompanied by a second signal of ligands (CD80/86) on the surface of the APC binding to the CD28 molecule on the T-cell surface. This ligand–receptor complex activates the CD28 molecule, which initiates T-cell proliferation through increased cytokine expression. As CD28 molecules are constitu-

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tively expressed on naive and activated T-cells, they enhance the T-cell response. However, activated T-cells start to express a CD28 homologue: CTLA-4 (cytotoxic T-lymphocyte antigen 4). CTLA-4 competes with CD28 to bind to the APC ligand (CD80/86), but has far greater avidity than CD28 does. CTLA-4 bound to the APC ligand halts T-cell activation and proliferation, allowing the dampening down of the immune response back to a steady state. CTLA-4 may be important in downregulating autoreactive T-cells and potentially destructive peripheral T-cell responses. Abatacept is a CTLA-4 molecule fused with the Fc portion of IgG-1. This prolongs its half-life and prevents complement fixation. Abatacept blocks the CD28 second signal and so down-regulates T-cell proliferation. It has been used in conditions where overproduction of T-cells is thought to be part of the pathogenic process.

Drug dose Abatacept is given as an infusion every 4 weeks at 10 mg/ kg. In a dose-response phase I trial, abatacept showed linear pharmacokinetics between 1 and 20 mg/kg with a half-life of 12–14 days in healthy volunteers and rheumatoid arthritis patients [17]. This is the dosing regimen that has been used in both adult and paediatric clinical trials.

Efficacy In adult rheumatoid arthritis clinical trials, abatacept has been shown to be effective in patients who had an inadequate response to methotrexate [18–20] or an inadequate response to anti-TNF [21,22] and, in patients with early arthritis, appeared to prevent progression to rheumatoid arthritis in some patients [23]. Using abatacept in combination with etanercept did not increase efficacy and increased side-effects [24]. In paediatric clinical trials, abatacept has been shown to be effective in patients with JIA, both for their arthritis [25] and their uveitis [26]. The first trial was a randomized, double-blind, placebo-controlled, withdrawal trial. The trial enrolled 190 patients into an open-label 4-month treatment phase (170 completed this) and then randomized responders to either a treatment (n = 60) or placebo (n = 62) arm for a further 6 months. The time to flare was taken as the outcome measure: the median time to flare in the placebo group was 6 months, and there were insufficient events in the abatacept group to give a median time to flare. The trial patients (n = 153) then entered a long-term extension study [26] and, at 21 months, 90% had achieved an improvement (ACR Pedi 30) with 39% achieving remission (ACR Pedi 100) on medication. An open-label, 26-week, phase I, dose-escalation study of abatacept in 43 patients with stable psoriasis vulgaris achieved a 50% improvement in 46% of the patients. The greatest effect was seen in the higher doses [27]. In

patients who improved, there was a decrease in T-cells and dendritic cells within psoriatic plaques [28].

Side-effects In the adult clinical trials, the reported side-effects were similar in the abatacept and placebo groups. For instance, in one trial, with 433 patients in the abatacept group and 219 patients in the placebo group, the reported adverse events were 87.3% versus 84%, and included infusion reactions (8.8% vs. 4.1%) but with a higher incidence of infections in the abatacept group at 1 year [18]. In a Cochrane review of abatacept trials in rheumatoid arthritis [20], seven trials with 2908 patients were reviewed; abatacept seemed to be safe, although serious infections were more common at 1 year. When abatacept and etanercept were given concomitantly, there were more serious adverse events with no significant increase in efficacy. The only randomized, placebo-controlled trial in children reported no tuberculosis and no malignancies but three subjects (of 153 in the long-term extension phase) developed pneumonia and one developed multiple sclerosis [29].

Alefacept Structure Alefacept blocks co-stimulation by blocking the binding of CD2 on memory T-cells with LFA-3 (lymphocyte function-associated antigen 3) on APCs such as dendritic cells. As alefacept causes apoptosis of memory T-cells, monitoring of CD4+ lymphocytes needs to be undertaken during treatment. Alefacept has been approved for use in moderate to severe plaque psoriasis since 2003.

Drug dose Alefacept is used as an intramuscular injection at 15 mg once a week for a 12-week cycle. It can also be given intravenously at 7.5 mg once a week for 12 weeks. Retreatment cycles can be given 12 weeks later.

Efficacy Alefacept was the earliest biological agent to be approved for psoriasis and has one of the lowest efficacies when compared to other biological agents such as infliximab [30]. The efficacy of alefacept for achieving PASI 75 has been around 30%: 28% for patients on 7.5 mg IV versus 8% on placebo [31], and 30% on 7.5 mg IV or 15 mg IM [32]. Those patients who achieved a PASI 75 maintained an improvement throughout follow-up [33]. Alefacept tends to be given in combination with other psoriasis therapies, and may allow for dose reduction or discontinuation of concomitant therapies [34].

Side-effects In an analysis of 13 clinical trials [35], alefacept was used to treat 1869 patients aged 15–84 years with psoriasis in

The Use of Emerging Biological Treatments in Children

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six multicentred, randomized, controlled trials and five multicentred, open-label trials. The most commonly reported adverse events were headache (0–14%), nasopharyngitis (8–25%), upper respiratory tract infections (0–12%), influenza (0–8%) and pruritus (0–7%). The incidence of infections was not related to the CD4+ T-cell count. Discontinuation of treatment due to adverse events was not increased by repeated courses of alefacept: adverse events (0–5%), serious adverse events (0–5%), serious infections (0–1%) and malignancies (0–5%). No opportunistic infections were seen.

ustekinumab at week 12, and 48.9% of these achieved PASI 75 at 12 weeks.

Ustekinumab Structure

Efalizumab

Ustekinumab is a fully humanized anti-IL-12/IL-23p40 monoclonal antibody, which prevents IL-12 and IL-23p40 from binding to their receptors on T-cells. IL-12 and IL-23 are produced by antigen-presenting cells, and promote Th1 responses by increasing cell-mediated immunity.

Drug dose Ustekinumab is licensed to be given as an infusion at weeks 0 and 4 and then 12 weekly, at a dose of 45 mg, or if over 100 kg at 90 mg. The 90 mg dose appears to be only slightly more effective than the 45 mg dose, and partial responders may benefit from reducing the dosing interval to 8 weekly. If there is no response by 28 weeks, discontinuation of therapy should be considered.

Efficacy The Phoenix trials (randomized, placebo controlled trials) used either 45 or 90 mg at weeks 0 and 4 and then 12 weekly. In the Phoenix 1 trial [36], 766 patients with moderate to severe psoriasis were randomized to receive ustekinumab at 45 mg (n = 255) or 90 mg (n = 256) or placebo (n = 255) at weeks 0 and 4 and then 12 weekly. The placebo group crossed over to receive ustekinumab at week 12. PASI 75 was achieved at 12 weeks by 171/255 (67.1%) in the 45 mg group, 170/256 (66.4%) in the 90 mg group and 8/255 (3.1%) in the placebo group. Long-term response was assessed at 40 weeks in 150 patients from the 45 mg group and 172 patients from the 90 mg group. These long-term responders were randomly assigned to either continue their maintenance dose (n = 162) or to withdrawal (n = 160); the PASI 75 response was better maintained at 1 year in the ustekinumab group. In a trial comparing ustekinumab and etanercept [37], 903 patients were randomly assigned to ustekinumab 45 or 90 mg or to etanercept 50 mg twice weekly. At 12 weeks, there was 75% improvement in the PASI in 67.5% of the 45 mg ustekinumab group, in 73.8% of the 90 mg group and in 56.8% of the etanercept group. The patients who did not respond to etanercept were crossed over to

Side-effects In the Phoenix 2 trial [38], 1230 patients with moderate to severe psoriasis were randomized to receive ustekinumab at 45 mg (n = 409) or 90 mg (n = 411) or placebo (n = 410), at weeks 0 and 4 and then 12 weekly. Adverse events were seen in 217 (53.1%), 197 (47.9%) and 204 (49.8%), respectively, and serious adverse events were seen in 8 (2%), 5 (1.2%) and 8 (2%), respectively.

Efalizumab was approved for the treatment of moderate to severe plaque psoriasis. Efalizumab binds to CD11a, which is a subunit of a T-cell surface molecule called LFA1. This prevents LFA-1 binding to ICAM-1 (intracellular adhesion molecule 1) and activation of the T-cell. Efalizumab was pulled from the market in April 2009 due to progressive multifocal leukoencephalopathy (PML) developing in some patients. PML is a progressive, often fatal, infection of the central nervous system by the human JC polyomavirus. The virus primarily affects oligodendrocytes, leading to demyelination in multiple areas. Symptoms include dementia, ataxia and focal neurological abnormalities such as visual disturbances, and leads to a vegetative state within months. PML is seen in impaired immunity where CD4+ T-cells are reduced, such as in AIDS, or the use of immunosuppressive therapy such as efalizumab. PML has also been reported with rituximab, but this is used in patients with B-cell disorders that themselves predispose PML [39]. References 1 Cambridge G, Leandro MJ, Edwards JC et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 2003;48(8):2146–54. 2 Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005;8:140–74. 3 Liossis SN, Sfikakis PP. Rituximab-induced B cell depletion in autoimmune diseases: potential effects on T cells. Clin Immunol 2008;127(3):280–5. 4 Looney RJ. B cell-targeted therapies for systemic lupus erythematosus: an update on clinical trial data. Drugs 2010;70(5):529–40. 5 Marks SD, Patey S, Brogan PA et al. B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 2005;52(10):3168–74. 6 Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2). J Am Acad Dermatol 2007;56(1):e55–e79. 7 Salopek TG, Logsetty S, Tredget EE. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol 2002;47(5):785–8. 8 Joly P, Mouquet H, Roujeau JC et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007;357(6):545–52.

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9 Rios FR, Callejas Rubio JL, Sanchez CD, Saez Moreno JA, Ortego CN. Rituximab in the treatment of dermatomyositis and other inflammatory myopathies. A report of 4 cases and review of the literature. Clin Exp Rheumatol 2009;27(6):1009–16. 10 Thurlings RM, Teng O, Vos K et al. Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2010;69(2):409–12. 11 Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006;54(2): 613–20. 12 Vital EM, Dass S, Rawstron AC et al. Management of non-response to rituximab in rheumatoid arthritis: Predictors and outcome of retreatment. Arthritis Rheum 2010;62(5):1273–9. 13 Nagel A, Hertl M, Eming R. B-cell-directed therapy for inflammatory skin diseases. J Invest Dermatol 2009;129(2):289–301. 14 Cohen SB, Emery P, Greenwald MW et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54(9):2793–806. 15 Mease PJ, Cohen S, Gaylis NB et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE Trial. J Rheumatol 2010;37(5):917–27. 16 Podolskaya A, Stadermann M, Pilkington C, Marks SD, Tullus K. B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch Dis Child 2008;93(5):401–6. 17 Ma Y, Lin BR, Lin B et al. Pharmacokinetics of CTLA4Ig fusion protein in healthy volunteers and patients with rheumatoid arthritis. Acta Pharmacol Sin 2009;30(3):364–71. 18 Kremer JM, Genant HK, Moreland LW et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144(12):865–76. 19 Russell AS, Wallenstein GV, Li T et al. Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment. Ann Rheum Dis 2007;66(2):189–94. 20 Maxwell LJ, Singh JA. Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol 2010;37(2):234–45. 21 Genovese MC, Schiff M, Luggen M et al. Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann Rheum Dis 2008;67(4):547–54. 22 Sherrer Y. Abatacept in biologic-naive patients and TNF inadequate responders: clinical data in focus. Curr Med Res Opin 2008;24(8): 2283–94. 23 Emery P, Durez P, Dougados M et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis 2010;69(3): 510–16. 24 Weinblatt M, Schiff M, Goldman A et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis 2007;66(2):228–34. 25 Ruperto N, Lovell DJ, Quartier P et al. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebocontrolled withdrawal trial. Lancet 2008;372(9636):383–91. 26 Zulian F, Balzarin M, Falcini F et al. Abatacept for severe antiTNFalpha refractory juvenile idiopathic arthritis-related uveitis. Arthritis Care Res (Hoboken) 2010;62(2):821–5.

27 Abrams JR, Lebwohl MG, Guzzo CA et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999;103(9):1243–52. 28 Abrams JR, Kelley SL, Hayes E et al. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J Exp Med 2000;192(5):681–94. 29 Ruperto N, Lovell DJ, Quartier P et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum 2010;62(6):1792–802. 30 Brimhall AK, King LN, Licciardone JC, Jacobe H, Menter A. Safety and efficacy of alefacept, efalizumab, etanercept and infliximab in treating moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. Br J Dermatol 2008;159(2):274–85. 31 Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47(6): 821–33. 32 Frampton J, Wagstaff A. Alefacept. Am J Clin Dermatol 2003;4(4):277–86. 33 Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003;139(6):719–27. 34 Searles G, Bissonnette R, Landells I, Shear NH, Papp K, Lui H. Patterns of combination therapy with alefacept for the treatment of psoriasis in Canada in the AWARE study. J Cutan Med Surg 2009;13(Suppl 3):S131–8. 35 Goffe B, Papp K, Gratton D et al. An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy. Clin Ther 2005;27(12):1912–21. 36 Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX 1). Lancet 2008;371(9625): 1665–74. 37 Griffiths CE, Strober BE, van de KP et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010;362(2):118–28. 38 Papp KA, Langley RG, Lebwohl M et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371(9625):1675–84. 39 Carson KR, Focosi D, Major EO et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 2009;10(8):816–24.

Summary The biologicals are powerful new drug treatments that can be very effective at controlling chronic inflammatory conditions, improving the quality of life for the affected child and their family. They need to be monitored for side-effects, both during treatment and long term. Registries will be an important source of these data. The expec-

The Use of Emerging Biological Treatments in Children

tations of patients and parents starting these drugs need to be taken into consideration. More clinical trials are needed in the paediatric age range to establish the pharmacokinetic and side-effect profile of these treatments in children, which are often different from those in adults,

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and in differing diseases as these may alter the outcome. Trials are also needed for comparison of effectiveness of these drugs in order to allow a more streamlined therapeutic protocol that is evidence based, and may save time and money.

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C H A P T E R 183

Hypersensitivity Reactions to Drugs Hagen Ott Department of Pediatric Dermatology, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany

Urticarial eruptions, 183.2

Bullous drug eruptions, 183.9

Exanthematous drug eruptions, 183.4

Fixed drug eruptions, 183.11

Diagnostic approach to drug hypersensitivity reactions, 183.12

Pustular eruptions, 183.7

Definition. As defined by the World Health Organization (WHO), adverse drug reactions (ADRs) represent any noxious, unintended and undesired effect of a drug that occurs at doses used for prevention, diagnosis or treatment or for the modification of physiological functions [1]. Adverse drug reactions are often classified as type A (augmented) reactions, which represent predictable sideeffects caused by the drug’s pharmacological action, and type B (bizarre) reactions, which are unpredictable due to the patient’s pharmacogenomic predisposition (idiosyncrasy) or drug hypersensitivity [2]. Drug hypersensitivity, which accounts for about 20% of all ADRs, is subdivided into non-immunological ADRs, designated as drug intolerances, and immune-mediated side-effects, termed drug allergy [3]. Adhering to the Gell and Coombs classification of immunological hypersensitivity, drug allergies can manifest as IgE-dependent immediate reactions (type I), IgG- and/or IgM-mediated cytotoxic reactions (type II), immune complex reactions (type III) and cellular reactions (type IV). According to a recent proposal by Pichler and co-workers, drug-induced type IV hypersensitivity can further be categorized into reactions with the predominant activation and recruitment of monocytes/macrophages (type IVa), eosinophils (type IVb), T-cells (type IVc) and neutrophils (type IVd) [4]. Epidemiology. In the course of the last decade, information regarding the incidence of ADRs in children has steadily increased. In a first landmark meta-analysis, Impicciatore and co-workers found that the overall incidence of ADRs in hospitalized children was 9.5% and that 2.1% of all paediatric hospital admissions were due to

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

ADRs of varying severity. In contrast, the meta-analytic weighted average for ADRs in paediatric outpatients was only 1.5%, with a higher incidence of side-effects occurring in infants and toddlers as compared to schoolchildren and adolescents [5]. In one of the largest prospective studies to date, Menniti-Ippolito and co-workers analysed ADRs occurring in 24,000 ambulatory paediatric patients over a oneyear period. The authors calculated an overall incidence of 15.1 ADRs per 1000 patients and reported that, besides gastrointestinal complaints (39%), cutaneous side-effects were most frequently encountered (36%). In this context, beta-lactam antibiotics, especially cephalosporins, and macrolide antibiotics, particularly azithromycin, were shown to be the most relevant culprit drugs [6]. This is in line with the results of another large-scale outpatient study including nearly 6000 children, of whom 7.3% developed a skin rash under antibiotic treatment. Interestingly, the rate of skin rashes varied according to the applied substance: cutaneous symptoms were observed in 12.3%, 7.4%, 8.5% and 2.6% of children receiving cefaclor, penicillins, sulphonamides or other cephalosporins, respectively [7]. These data are consistent with a recent retrospective cohort study that also demonstrated that ADR severity obviously depended on the drug class: antibiotics such as penicillins, cephalosporins and glycopeptides induced mild to moderate reactions in the majority of patients, whereas antineoplastic agents were more commonly associated with severe ADRs [8,9]. Taken together, cutaneous drug reactions represent a major paediatric health problem frequently encountered in daily clinical practice. However, recent reports have highlighted that self- or parent-reported drug hypersensitivity is diagnostically confirmed in fewer than 10% of cases [10,11]. Thus, a thorough dermatological and allergological evaluation is warranted in every child with

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suspected drug hypersensitivity, particularly in order to avert patient and parental anxiety leading to unnecessary avoidance of the incriminated substances. Clinical manifestations. As a great imitator of disease, drug hypersensitivity may elicit hepatic (hepatitis, druginduced liver injury), renal (interstitial nephritis, glomerulonephritis), pulmonary (pneumonitis, eosinophilic pneumonia) or haematological (haemolytic anaemia, thrombocytopenia, granulocytopenia) dysfunction as well as systemic anaphylaxis [12]. However, the skin represents the most frequent target organ of drug hypersensitivity, displaying a vast array of possible clinical signs and symptoms. For didactical reasons, these can be classified into mostly immunoglobulin-mediated urticarial rashes and cellmediated pustular, exanthematous or bullous reactions as well as fixed drug eruptions [12]. Finally, many other skin, nail and hair disorders can occur after drug intake, but do not represent genuine hypersensitivity reactions and are therefore discussed in detail elsewhere in this textbook.

Urticarial eruptions Urticaria and angioedema Urticaria is characterized by the sudden appearance of pruritic papules and wheals of varying size with adjacent erythema that may coalesce into linear, polycyclic or serpiginous plaques (Fig. 183.1). Urticarial skin lesions are

Fig. 183.1 Acute urticaria appearing about 30 minutes after drug intake on the fifth day of treatment with clarithromycin.

usually migratory and transient, last a maximum of 24 hours and may be accompanied by angioedema. By definition, urticaria is regarded as acute if present for less than 6 weeks, and as chronic if persisting for more than 6 weeks (also see Chapter 74) [13]. It is widely accepted that up to 25% of all persons experience at least one episode of urticaria during their lifetime and that infections represent the most frequent underlying cause in childhood. Moreover, urticaria and/ or angioedema may be the presenting signs in more than 80% of paediatric patients suffering from anaphylaxis [14,15]. However, the exact incidence of drug-related urticaria, which is mostly of the acute type in children and adolescents, remains to be determined. Nevertheless, urticaria is regarded as the second most common drug eruption, accounting for an estimated 15–20% of all cutaneous drug reactions [16]. Pathophysiologically, drug-induced urticaria most often corresponds to an immediate (type I) hypersensitivity reaction. In sensitized patients, mast cells (MC) carry drug-specific IgE antibodies (sIgE) bound to the highaffinity IgE receptor (IgεRI) on their surface. Usually within minutes to 2 hours after oral intake, the culprit drug cross-links sIgE molecules, thus inducing MC mediator release. In childhood, drugs most frequently involved in immediate-type drug allergy are beta-lactam antibiotics (penicillin, amoxicillin, cephalosporins), sulphonamides and myorelaxants [17,18]. Intriguingly, acute drug-induced urticaria may also be due to non-immunological intolerance reactions. Most importantly, non-steroidal anti-inflammatory drugs (NSAIDs), a pharmacologically heterogeneous group of cyclo-oxygenase inhibitors, are known to skew arachidonic acid metabolism towards the 5-lipoxygenase pathway, thus enhancing the synthesis of proinflammatory cysteinyl leukotrienes. As a clinical consequence, 0.5–4% of children treated with NSAIDs such as ibuprofen, diclofenac or paracetamol (acetominophen) may develop acute urticaria within minutes to a maximum of 24 hours after drug ingestion. Concurrent facial angioedema manifests in an age-dependent manner: in fewer than 5% of infants and toddlers, but in up to 20% of adolescents and young adults with NSAID intolerance, acute urticaria is accompanied by facial oedema. It is also noteworthy that more than 80% of intolerant children will cross-react upon challenge with another NSAID [19–22]. Besides discontinuing exposure to the suspected trigger, systemic antihistamines represent the mainstay of treatment of acute drug-induced urticaria. Second-generation H1-antagonists such as cetirizine, loratadine or ketotifen should be preferentially used in order to avoid ADRs that are frequently associated with first-generation antihistamines, particularly drowsiness. In contrast, it is still a matter of debate whether so-called third-generation

Hypersensitivity Reactions to Drugs

H1-antihistamines such as desloratadine, levocetirizine or fexofenadine are more efficacious in the therapy of acute urticaria than their predecessors. Non-responsive patients may benefit from short-term systemic glucocorticoid therapy, for example methylprednisolone 1 mg/kg/day over 3 days, although the efficacy of this treatment modality remains to be verified in controlled clinical trials [13,23].

Serum sickness-like reactions Serum sickness-like reactions (SSLRs) may occur during the first course of treatment with the culprit agent and usually arise within 1 to 3 weeks after drug initiation. Typical symptoms comprise low-grade fever, arthralgia and an urticarial, sometimes morbilliform, scarlatiniform or polymorphous rash that is often only mildly pruritic and self-limited. Lymphadenopathy and eosinophilia may also be present; however, in contrast to true serum sickness, characteristic laboratory changes, vasculitis or renal involvement are not regularly encountered [24]. Epidemiological data on SSLRs are still very scarce, but this hypersensitivity reaction is known to mostly affect infants and children. Accordingly, the estimated pooled incidence of cefaclor-related SSLRs has been calculated in the range 0.02–0.2% per drug course in paediatric patients. Moreover, epidemiological investigations suggest that the risk of SSLR is greater under treatment with cefaclor than with any other antibiotic therapy, including further cephalosporins. A retrospective cohort study disclosed that the relative risk of SSLRs for cefaclor compared with amoxicillin was 19 : 1. Furthermore, the WHO database for international drug monitoring registered 722 reports of SSLRs to cefaclor compared with only 34 for amoxicillin and 12 for cephalexin [25,26]. Hence, even if prospective controlled trials are lacking, cefaclor can be regarded as the principal eliciting drug in SSLRs. This is also corroborated by a considerable number of case reports and case series published during the last two decades [27–30]. Other drugs that have been implicated in causing SSLRs include biological agents (efalizumab [31], omalizumab [32], rituximab [33], infliximab [34]), antibiotics (cefuroxim [35], cefazolin [36], meropenem [37], minocycline [38], ciprofloxacin [39], rifampicin [40]), antimycotics (griseofulvin [41], itraconazole [42]) and other agents such as bupropion [43], clopidogrel [44], fluoxetine [45], Nacetylcysteine [46] or streptokinase [47] . In vitro parameters that are characteristically altered in true type III serum sickness such as immune complexes, hypocomplementaemia or albuminuria are not regularly observed in SSLRs. This clearly implies that serum sickness reactions and SSLRs are clinically similar disorders, but arise due to distinct hypersensitivity mechanisms. More than 15 years ago, Kearns and co-workers postu-

183.3

lated that a reactive cefaclor metabolite may be generated in genetically susceptible hosts, and bind with tissue proteins to elicit an inflammatory response manifesting as SSLR. However, this pathogenetic model still awaits clinical and experimental corroboration [48]. As the underlying cause of SSLRs remains unknown, its treatment is purely symptomatic, mainly consisting of discontinuation of the offending agent, antihistamines in case of urticaria, and NSAIDs for patients with arthralgia and/or arthritis. As in drug-induced urticaria, it is still unclear whether a short course of systemic glucocorticoids is a viable treatment option in SSLR patients with persisting symptoms despite antihistamine therapy. However, in a retrospective study of 31 children presenting to the emergency department for cefaclor-induced SSLR, a combination of oral prednisone and an antihistamine was found to be the preferred medication prescribed by the majority of treating paediatricians [49]. References 1 WHO. International drug monitoring: the role of national centres. Report of a WHO meeting. World Health Org Tech Rep Ser 1972;498:1–25. 2 Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM (ed.) Textbook of Adverse Drug Reactions. Oxford: Oxford University Press, 1977; 10. 3 Johansson SG, Bieber T, Dahl R et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004;113:832–6. 4 Pichler WJ, Adam J, Daubner B, Gentinetta T, Keller M, Yerly D. Drug hypersensitivity reactions: pathomechanism and clinical symptoms. Med Clin North Am 2010;94:645–64, xv. 5 Impicciatore P, Choonara I, Clarkson A, Provasi D, Pandolfini C, Bonati M. Incidence of adverse drug reactions in paediatric in/outpatients: a systematic review and meta-analysis of prospective studies. Br J Clin Pharmacol 2001;52:77–83. 6 Menniti-Ippolito G, Raschetti R, Da CR, Giaquinto C, Cantarutti L. Active monitoring of adverse drug reactions in children. Italian Paediatric Pharmacosurveillance Multicenter Group. Lancet 2000;355:1613–14. 7 Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes in children: a survey in a private practice setting, Arch Dermatol 2000;136: 849–54. 8 Bourgeois FT, Mandl KD, Valim C, Shannon MW. Pediatric adverse drug events in the outpatient setting: an 11-year national analysis. Pediatrics 2009;124:e744–e750. 9 Clavenna A, Bonati M. Adverse drug reactions in childhood: a review of prospective studies and safety alerts, Arch Dis Child 2009;94:724–8. 10 Rebelo GE, Fonseca J, Araujo L, Demoly P. Drug allergy claims in children: from self-reporting to confirmed diagnosis. Clin Exp Allergy 2008;38:191–8. 11 Lange L, Koningsbruggen SV, Rietschel E. Questionnaire-based survey of lifetime-prevalence and character of allergic drug reactions in German children. Pediatr Allergy Immunol 2008;19:634–8. 12 Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol 2010;125:S126–S137. 13 Zuberbier T, Asero R, Bindslev-Jensen C et al. EAACI/GA(2)LEN/ EDF/WAO guideline: definition, classification and diagnosis of urticaria, Allergy 2009;64:1417–26.

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14 Mehl A, Wahn U, Niggemann B. Anaphylactic reactions in children – a questionnaire-based survey in Germany. Allergy 2005;60: 1440–5. 15 de Silva IL, Mehr SS, Tey D, Tang ML. Paediatric anaphylaxis: a 5 year retrospective review, Allergy 2008;63:1071–6. 16 Tan EK, Grattan CE. Drug-induced urticaria. Expert Opin Drug Saf 2004;3:471–84. 17 Shin HT, Chang MW. Drug eruptions in children. Curr Probl Pediatr 2001;31:207–34. 18 Segal AR, Doherty KM, Leggott J, Zlotoff B. Cutaneous reactions to drugs in children. Pediatrics 2007;120:e1082–e1096. 19 Sanchez-Borges M. NSAID hypersensitivity (respiratory, cutaneous, and generalized anaphylactic symptoms). Med Clin North Am 2010;94:853–64, xiii. 20 Sanchez-Borges M, Capriles-Behrens E, Caballero-Fonseca F. Hypersensitivity to non-steroidal anti-inflammatory drugs in childhood. Pediatr Allergy Immunol 2004;15:376–80. 21 Kidon MI, Kang LW, Chin CW, Hoon LS, Hugo VB. Nonsteroidal anti-inflammatory drug hypersensitivity in preschool children. Allergy Asthma Clin Immunol 2007;3:114–22. 22 Kidon MI, Kang LW, Chin CW et al. Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children. Pediatrics 2005;116:e675–e680. 23 Del CA, Sastre J, Montoro J et al. Use of antihistamines in pediatrics, J Investig Allergol Clin Immunol 2007;17(Suppl. 2):28–40. 24 Shah KN, Honig PJ, Yan AC. “Urticaria multiforme”: a case series and review of acute annular urticarial hypersensitivity syndromes in children, Pediatrics 2007;119:e1177–e1183. 25 Heckbert SR, Stryker WS, Coltin KL, Manson JE, Platt R. Serum sickness in children after antibiotic exposure: estimates of occurrence and morbidity in a health maintenance organization population. Am J Epidemiol 1990;132:336–42. 26 Stricker BH, Tijssen JG. Serum sickness-like reactions to cefaclor. J Clin Epidemiol 1992;45:1177–84. 27 Sanklecha MU. Cefaclor induced serum sickness like reaction. Indian J Pediatr 2002;69:921. 28 Isaacs D. Serum sickness-like reaction to cefaclor. J Paediatr Child Health 2001;37:298–9. 29 Parra FM, Igea JM, Martin JA, Alonso MD, Lezaun A, Sainz T. Serum sickness-like syndrome associated with cefaclor therapy. Allergy 1992;47:439–40. 30 Hebert AA, Sigman ES, Levy ML. Serum sickness-like reactions from cefaclor in children. J Am Acad Dermatol 1991;25:805–8. 31 Shraf-Benson S, Wall GC, Veach LA. Serum sickness-like reaction associated with efalizumab. Ann Pharmacother 2009;43:383–6. 32 Pilette C, Coppens N, Houssiau FA, Rodenstein DO. Severe serum sickness-like syndrome after omalizumab therapy for asthma. J Allergy Clin Immunol 2007;120:972–3. 33 Finger E, Scheinberg M. Development of serum sickness-like symptoms after rituximab infusion in two patients with severe hypergammaglobulinemia. J Clin Rheumatol 2007;13:94–5. 34 Gamarra RM, McGraw SD, Drelichman VS, Maas LC. Serum sicknesslike reactions in patients receiving intravenous infliximab. J Emerg Med 2006;30:41–4. 35 Baniasadi S, Fahimi F, Mansouri D. Serum sickness-like reaction associated with cefuroxime and ceftriaxone. Ann Pharmacother 2007; 41:1318–19. 36 Brucculeri M, Charlton M, Serur D. Serum sickness-like reaction associated with cefazolin. BMC Clin Pharmacol 2006;6:3. 37 Ralph ED, John M, Rieder MJ, Bombassaro AM. Serum sickness-like reaction possibly associated with meropenem use. Clin Infect Dis 2003;36:E149–E151. 38 Landau M, Shachar E, Brenner S. Minocycline-induced serum sickness-like reaction. J Eur Acad Dermatol Venereol 2000;14:67–8.

39 Guharoy SR. Serum sickness secondary to ciprofloxacin use. Vet Hum Toxicol 1994;36:540–1. 40 Parra FM, Perez Elias MJ, Cuevas M, Ferreira A. Serum sickness-like illness associated with rifampicin. Ann Allergy 1994;73:123–5. 41 Colton RL, Amir J, Mimouni M, Zeharia A. Serum sickness-like reaction associated with griseofulvin. Ann Pharmacother 2004;38: 609–11. 42 Park H, Knowles S, Shear NH. Serum sickness-like reaction to itraconazole. Ann Pharmacother 1998;32:1249. 43 Waibel KH, Katial RK. Serum sickness-like reaction and bupropion. J Am Acad Child Adolesc Psychiatry 2004;43:509. 44 Phillips EJ, Knowles SR, Shear NH. Serum sickness-like reaction associated with clopidogrel. Br J Clin Pharmacol 2003;56:583. 45 Shapiro LE, Knowles SR, Shear NH. Fluoxetine-induced serum sickness-like reaction. Ann Pharmacother 1997;31:927. 46 Mohammed S, Jamal AZ, Robison LR. Serum sickness-like illness associated with N-acetylcysteine therapy. Ann Pharmacother 1994; 28:285. 47 Schweitzer DH, van der Wall EE, Bosker HA, Scheffer E, Macfarlane JD. Serum-sickness-like illness as a complication after streptokinase therapy for acute myocardial infarction. Cardiology 1991;78:68–71. 48 Kearns GL, Wheeler JG, Childress SH, Letzig LG. Serum sickness-like reactions to cefaclor: role of hepatic metabolism and individual susceptibility. J Pediatr 1994;125:805–11. 49 Joubert GI, Hadad K, Matsui D, Gloor J, Rieder MJ. Selection of treatment of cefaclor-associated urticarial, serum sickness-like reactions and erythema multiforme by emergency pediatricians: lack of a uniform standard of care, Can J Clin Pharmacol 1999;6:197–201.

Exanthematous drug eruptions Maculopapular exanthems Maculopapular exanthems (MPEs) represent the most common adverse drug reactions affecting the skin. Historical and more recent cohort studies have shown that they account for 35–90% of all cutaneous ADRs, depending on the investigated populations of varying age, with different underlying diseases in variable clinical settings [1–4]. Literally all xenobiotic therapeutic agents may cause MPE, and the majority of licensed drugs induce exanthematous rashes in 1% or more of treated patients. In children, beta-lactam antibiotics (penicillins, cefaclor, other cephalosporins, sulfamethoxazole) and aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine) most frequently elicit MPE, whereas other culprit drugs such as macrolide antibiotics, thiazide diuretics, NSAIDs or benzodiazepines are less frequently encountered [5]. Although its complex pathophysiology remains to be fully elucidated, drug-induced MPE is generally considered to be a non-immediate, T-cell-mediated hypersensitivity reaction of type IVc according to the modified Gell and Coombs classification. Briefly, highly activated, drugspecific CD4+ and CD8+ T-cells infiltrate the cutis accompanied by eosinophils and macrophages as well as different dendritic cell subpopulations. Allergen-specific T-cells synthesize and liberate cytotoxic granule proteins

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183.5

such as perforin and granzyme B, thus causing keratinocyte damage, which manifests as vacuolar damage upon histology. Moreover, T-cells and other leucocytes as well as resident skin cells release a heterogeneous profile of cytokines and chemokines that, terminally, enhance inflammatory processes and contribute to the recruitment of eosinophils, which are often, but not always, detectable upon lesional skin biopsy [5,6]. Maculopapular exanthem typically occurs within the second week after start of treatment, but may also first appear one or two days after the end of drug therapy (‘eruption of the ninth day’). In contrast, sensitized individuals may reveal a faster disease onset, developing skin symptoms within the first day of drug re-exposure. Characteristic cutaneous features consist of symmetrically distributed, erythematous, sometimes salmon-coloured macules and papules that usually coalesce into a morbilliform (Fig. 183.2), scarlatiniform or rubelliform rash. However, MPEs are clinically heterogeneous, sometimes manifesting as annular, urticarial, purpuric or serpiginous eruptions (Fig. 183.3). Therefore the differential diagnosis of drug-induced exanthemas is broad including, among others, viral infections (Epstein–Barr virus, parvovirus B19, human herpesvirus (HHV) 6, adenovirus, etc.), bacterial infections (Streptococcus pyogenes, Treponema pallidum, etc.), systemic juvenile arthritis (Still disease), Kawasaki syndrome, graft-versus-host-disease (GvHD) and erythema multiforme. In general, MPEs spare the palmoplantar region and mucous membranes,

are only moderately pruritic and usually not associated with high-grade fever or general malaise [7]. Uncomplicated exanthematous rashes resolve spontaneously without sequelae within a few days after drug withdrawal. Hence, systemic glucocorticoid treatment (e.g. methylprednisolone 1 mg/kg/day over 3–5 days) can usually be reserved for children with marked pruritus. Yet, blister formation, evolving erythroderma, mucous membrane involvement, atypical target lesions and the involvement of other organ systems have to be regarded as signs of impending serious drug rashes that should prompt immediate hospital admission for further diagnostic workup and intensified treatment under close medical supervision (see below).

Fig. 183.2 Morbilliform maculopapular exanthem occurring after five days of treatment with amoxicillin.

Fig. 183.3 Atypical, erythema infectiosum-like drug rash first observed after four days of oral amoxicillin treatment.

DRESS syndrome: drug rash with eosinophilia and systemic symptoms DRESS syndrome, also called drug-induced or anticonvulsant hypersensitivity syndrome (DIHS/AHS), represents a rare but acute and potentially fatal multisystem drug reaction. Basically, it is characterized by the clinical tetrad of fever, maculopapular rash, lymphadenopathy and internal organ involvement. Most strikingly, the onset of DRESS may be delayed for more than 3 weeks after initial drug exposure whereas symptoms regularly persist for longer than 2 weeks after discontinuation of the causative agent [8].

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The exact incidence of DRESS is unknown, but it is thought to occur in approximately 1 : 1000 to 1 : 10,000 of exposures to aromatic anticonvulsants [9]. In children and adolescents, the drugs most frequently implicated are the aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbital, oxcarbazepine) and lamotrigine [10,11], but other agents have also been described as causes of paediatric DRESS, i.e. allopurinol [12], vancomycin [13], minocycline [13], sulfasalazine [14], aspirin [15], nevirapine [16] and dapsone [17]. Interestingly, amoxicillin has been shown to elicit flare-ups in adolescents with DRESS syndrome previously induced by other drugs [18]. The first non-specific clinical signs are a fever in excess of 38.5°C and malaise, which may precede cutaneous and internal symptoms by several days. Approximately 85% of all patients then develop a rash; this has recently been shown to occur in up to 100% of paediatric patients with anticonvulsant-induced DRESS syndrome [10,19]. Cutaneous eruptions may be polymorphous and vary during the clinical course. Initially, starting in the facial region and spreading craniocaudally, non-specific maculopapular and often morbilliform rashes are observed, which later become infiltrated showing a follicular accentuation [20,21]. In children, cutaneous symptoms may evolve into erythroderma, vesiculobullous lesions, targetoid or even blistering eruptions in 44%, 16%, 13% and 9% of patients, respectively. While mucosal lesions such as cheilitis, conjunctivitis and pharyngitis appear in about 50% of children and are usually discrete, up to 70% of children reveal massive facial oedema (Fig. 183.4), sometimes with a

Fig. 183.4 Marked facial oedema and malaise in a child with DRESS syndrome. Courtesy of Dr Lars Lange, Department of Pediatric Allergology and Pulmonology, Marienhospital, Bonn, Germany.

characteristic periorbital accentuation. Nearly 90% of patients will develop some degree of lymphadenopathy at a minimum of two sites, with enlarged (>2 cm) lymph nodes particularly in the cervical region, but general lymphadenopathy can also be observed [10]. In a sizeable number of patients, internal organ involvement may be delayed by 1–4 weeks after the onset of skin symptoms. Whereas some individuals suffer from only mild systemic symptoms, others may be afflicted with severe multiorgan failure accounting for a mortality of 10% in adult patients with DRESS syndrome [22]. Most commonly observed, hepatic dysfunction may range from an isolated elevation of serum liver enzymes to acute hepatitis and hepatic necrosis with terminal liver failure [23–25]. Acute kidney injury is the second most commonly observed internal manifestation of DRESS syndrome. Affected patients reveal isolated haematuria or interstitial nephritis, but may also develop acute renal failure requiring transient dialysis [26–28]. Other less common, but clinically relevant systemic reactions involve the central nervous system (encephalitis, aseptic meningitis), the bronchopulmonary system (pneumonitis, respiratory distress syndrome), myocarditis, transient thyroiditis, colitis and pancreatitis [20]. Haematological abnormalities include peripheral leucocytosis (>11 × 109/L), atypical lymphocytosis (>5%) and eosinophilia (>1.5 × 109/L) occurring in more than 70% of patients within the first 2–3 weeks of DRESS manifestation. Further non-specific changes detected in peripheral blood are neutropenia, agranulocytosis and thrombocytopenia [8]. The pathogenesis of DRESS syndrome has not been fully elucidated. However, the currently most widely accepted pathogenetic model postulates that, in a first step, genetically predisposed individuals metabolize the culprit drug into a reactive compound that cannot be detoxified due to genetically determined abnormalities within the required enzyme systems. As a consequence, the bioactivated drug metabolite irreversibly modifies cellular proteins, which then serve as targets for an immune-mediated type IVb hypersensitivity reaction orchestrated by activated T-cells secreting large amounts of interleukin-5 and interferon-γ. Finally, this massive drug-induced immune stimulation may lead to reactivation of latent lymphotropic viruses, particularly HHV-6, which could be responsible for the markedly chronic course in patients with DRESS syndrome [6]. In the management of DRESS syndrome, prompt withdrawal of the offending drug is imperative, especially in order to avoid ongoing toxic metabolite accumulation. Whether systemic glucocorticoids have a beneficial effect is still a matter of controversy, mainly because while clinical improvement has been documented in patients, corticosteroids may also promote deleterious viral reactivation.

Hypersensitivity Reactions to Drugs

Likewise, the clinical benefit of N-acetylcysteine and intravenous immunoglobulins, which have both been successfully used in single cases of DRESS syndrome, remains unclear [29,30]. Due to this lack of valid data, a specific medical therapy for acute DRESS syndrome currently cannot be definitively recommended. References 1 Borch JE, Andersen KE, Bindslev-Jensen C. Cutaneous adverse drug reactions seen at a university hospital department of dermatology. Acta Derm Venereol 2006;86:523–7. 2 Fiszenson-Albala F, Auzerie V, Mahe E et al. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol 2003;149:1018–22. 3 Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions: clinical pattern and causative agents – a 6 year series from Chandigarh, India. J Postgrad Med 2001;47:95–9. 4 Hunziker T, Kunzi UP, Braunschweig S, Zehnder D, Hoigne R. Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey, Allergy 1997;52:388–93. 5 Yawalkar N. Maculopapular drug eruptions. In: Pichler WJ (ed.) Drug Hypersensitivity. Basel: Karger, 2007; 242–51. 6 Hausmann O, Schnyder B, Pichler WJ. Drug hypersensitivity reactions involving skin. In: Uetrecht J (ed.) Handbook of Experimental Pharmacology. Berlin, Heidelberg: Springer, 2010; 30–52. 7 Segal AR, Doherty KM, Leggott J, Zlotoff B. Cutaneous reactions to drugs in children. Pediatrics 2007;120:e1082–e1096. 8 Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007;156:1083–4. 9 Ben mM, Leclerc-Mercier S, Blanche P et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore) 2009;88:131–40. 10 Newell BD, Moinfar M, Mancini AJ, Nopper AJ. Retrospective analysis of 32 pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS). Pediatr Dermatol 2009;26:536–46. 11 D’Orazio JL. Oxcarbazepine-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Clin Toxicol (Phila) 2008;46:1093–4. 12 Dewan AK, Quinonez RA. Allopurinol-induced DRESS syndrome in an adolescent patient. Pediatr Dermatol 2010;27:270–3. 13 Vinson AE, Dufort EM, Willis MD, Eberson CP, Harwell JI. Drug rash, eosinophilia, and systemic symptoms syndrome: Two pediatric cases demonstrating the range of severity in presentation – A case of vancomycin-induced drug hypersensitivity mimicking toxic shock syndrome and a milder case induced by minocycline. Pediatr Crit Care Med 2010;11:e38–e43. 14 Rosenbaum J, Alex G, Roberts H, Orchard D. Drug rash with eosinophilia and systemic symptoms secondary to sulfasalazine. J Paediatr Child Health 2010;46:193–6. 15 Kawakami T, Fujita A, Takeuchi S, Muto S, Soma Y. Drug-induced hypersensitivity syndrome: drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome induced by aspirin treatment of Kawasaki disease. J Am Acad Dermatol 2009;60:146–9. 16 Santos RP, Ramilo O, Barton T. Nevirapine-associated rash with eosinophilia and systemic symptoms in a child with human immunodeficiency virus infection. Pediatr Infect Dis J 2007;26: 1053–6. 17 Sheen YS, Chu CY, Wang SH, Tsai TF. Dapsone hypersensitivity syndrome in non-leprosy patients: a retrospective study of its incidence in a tertiary referral center in Taiwan. J Dermatolog Treat 2009;20: 340–3.

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18 Mardivirin L, Valeyrie-Allanore L, Branlant-Redon E et al. Amoxicillininduced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro. Eur J Dermatol 2010;20:68–73. 19 Kardaun SH, Sidoroff A, Valeyrie-Allanore L et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007;156:609–11. 20 Mockenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009;7:142–60. 21 Mansur AT, Pekcan YS, Goktay F. Anticonvulsant hypersensitivity syndrome: clinical and laboratory features. Int J Dermatol 2008;47:1184–9. 22 Eshki M, Allanore L, Musette P et al. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure. Arch Dermatol 2009;145: 67–72. 23 Kano Y, Ishida T, Hirahara K, Shiohara T. Visceral involvements and long-term sequelae in drug-induced hypersensitivity syndrome. Med Clin North Am 2010;94:743–59, xi. 24 Lens S, Crespo G, Carrion JA, Miquel R, Navasa M. Severe acute hepatitis in the dress syndrome: Report of two cases. Ann Hepatol 2010;9:198–201. 25 Mennicke M, Zawodniak A, Keller M et al. Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation. Am J Transplant 2009;9: 2197–202. 26 Fujita Y, Hasegawa M, Nabeshima K et al. Acute kidney injury caused by zonisamide-induced hypersensitivity syndrome. Intern Med 2010;49:409–13. 27 Savard S, Desmeules S, Riopel J, Agharazii M. Linezolid-associated acute interstitial nephritis and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Am J Kidney Dis 2009;54:e17–e20. 28 Zuliani E, Zwahlen H, Gilliet F, Marone C. Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment. Clin Nephrol 2005;64:155–8. 29 Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update. Dermatology 2003;206:353–6. 30 Cumbo-Nacheli G, Weinberger J, Alkhalil M, Thati N, Baptist AP. Anticonvulsant hypersensitivity syndrome: is there a role for immunomodulation? Epilepsia 2008;49:2108–12.

Pustular eruptions Acute generalized exanthematous pustulosis Acute generalized exanthematous pustulosis (AGEP) is considered a serious pustular drug hypersensitivity reaction occurring with an incidence of up to five cases per million per year in the general population [1]. Although rare in paediatric patients, it has been observed in children treated with aminopenicillins [2], cefixime [3], clindamycin [3], paracetamol [4], bufexamac [5] and cytarabine [6]. In rare cases, AGEP has also been described to appear in the course of viral (e.g. parvovirus B19 [7], coxsackievirus [8], cytomegalovirus [9]) and bacterial (e.g. Chlamydia pneumoniae [10], Mycoplasma pneumoniae

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[11]) infections. However, infectious agents could not be verified as independent risk factors by multivariate calculations of the corresponding odds ratios in the largest investigation to date including 97 adult cases of AGEP and 1009 controls [12]. Whether these results are transferable to the paediatric population remains unclear until similar case-control studies have been performed in children and adolescents. Acute generalized exanthematous pustulosis usually has a fast onset during the first week, sometimes even the first day, of treatment. Initially, the typical skin rash consists of an erythematous oedema with a certain flexural predilection, which is subsequently covered by hundreds to thousands of non-follicular, often coalescing, sterile pustules. Virtually all affected patients develop fever, and the majority reveal peripheral leucocytosis with a neutrophil count exceeding 7000/μL [1]. At this stage, the main differential diagnoses include pustulosis subcornealis (Sneddon–Wilkinson) and pustular psoriasis. A minority of patients, however, may display additional cutaneous lesions such as facial oedema, atypical target lesions, blisters or mucosal erosions. Hence, in very rare instances, children may also present with a clinical overlap of AGEP and toxic epidermal necrolysis or DRESS syndrome, respectively [2,13. In these cases, skin biopsy is warranted to demonstrate the characteristic intraepidermal or subcorneal pustules with papillary oedema and mixed perivascular infiltrates, with or without eosinophils (Fig. 183.5). Drug-specific, HLA-expressing CD4+ and CD8+ T-cells are thought to play a central role in the pathogenesis of AGEP, which can therefore be regarded as a type IVd drug hypersensitivity reaction. Upon stimulation with the culprit drug, allergen-specific T-cells migrate into the epidermis, where they kill keratinocytes and induce vesicle formation. In a second step, T-cells synthesize and secrete significant amounts of the chemoattractant cytokines IL-8 (CXCL-8) and granulocyte-macrophage colonystimulating factor (GM-CSF), thus recruiting large

Fig. 183.5 Subcorneal pustule with papillary oedema and mixed perivascular infiltrates with scattered eosinophils. Courtesy of Dr Mossaad Megahed, Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.

quantities of neutrophils, which are responsible for intraepidermal pustule formation [14]. Controlled trials evaluating different treatment modalities in patients with AGEP do not exist, probably because AGEP is usually self-limited, healing after 2 weeks with fine desquamation and without scarring. Nevertheless, empirical therapy should consist of immediate drug withdrawal in all patients, and judicious use of prednisolone in severe cases at a dose of 1–2 mg/kg/day until resolution of the eruption. However, a recent retrospective investigation in 16 AGEP patients, of whom four were children, found no difference regarding the course and duration of AGEP between patients treated with intravenous hydrocortisone, oral prednisolone or topical agents alone [15]. References 1 Halevy S. Acute generalized exanthematous pustulosis, Curr Opin Allergy Clin Immunol 2009;9:322–8. 2 Riten K, Shahina Q, Jeannette J, Palma-Diaz MF. A severe case of acute generalized exanthematous pustulosis (AGEP) in a child after the administration of amoxicillin-clavulanic acid: brief report. Pediatr Dermatol 2009;26:623–5. 3 Ozmen S, Misirlioglu ED, Gurkan A, Arda N, Bostanci I. Is acute generalized exanthematous pustulosis an uncommon condition in childhood? Allergy 2010 Nov;65(11):1490–2. 4 Sezer E, Sezer T, Koseoglu D, Filiz NO. Acute generalized exanthematous pustulosis in a child. Pediatr Dermatol 2007;24:93–5. 5 Belhadjali H, Ghannouchi N, Njim L et al. Acute generalized exanthematous pustulosis induced by bufexamac in an atopic girl. Contact Dermatitis 2008;58:247–8. 6 Chiu A, Kohler S, McGuire J, Kimball AB. Cytarabine-induced acute generalized exanthematous pustulosis. J Am Acad Dermatol 2002;47:633–5. 7 Ofuji S, Yamamoto O. Acute generalized exanthematous pustulosis associated with a human parvovirus B19 infection. J Dermatol 2007;34:121–3. 8 Feio AB, Apetato M, Costa MM, Sa J, Alcantara J. [Acute generalized exanthematous pustulosis due to Coxsackie B4 virus]. Acta Med. Port 1997;10:487–91. 9 Haro-Gabaldon V, Sanchez-Sanchez-Vizcaino J, Ruiz-Avila P, Gutierrez-Fernandez J, Linares J, Naranjo-Sintes R. Acute generalized exanthematous pustulosis with cytomegalovirus infection. Int J Dermatol 1996;35:735–7. 10 Manzano S, Guggisberg D, Hammann C, Laubscher B. [Acute generalized exanthematous pustulosis: first case associated with a Chlamydia pneumoniae infection]. Arch Pediatr 2006;13:1230–2. 11 Lim CS, Lim SL. Acute generalized exanthematous pustulosis associated with asymptomatic Mycoplasma pneumoniae infection. Arch Dermatol 2009;145:848–9. 12 Sidoroff A, Dunant A, Viboud C et al. Risk factors for acute generalized exanthematous pustulosis (AGEP) – results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157: 989–96. 13 Son CH, Lee CU, Roh MS, Lee SK, Kim KH, Yang DK. Acute generalized exanthematous pustulosis as a manifestation of carbamazepine hypersensitivity syndrome. J Investig Allergol Clin Immunol 2008; 18:461–4. 14 Hausmann O, Schnyder B, Pichler WJ. Drug hypersensitivity reactions involving skin. In: Uetrecht J (ed.) Handbook of Experimental Pharmacology. Berlin, Heidelberg: Springer, 2010; 30–52.

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15 Chang SL, Huang YH, Yang CH, Hu S, Hong HS. Clinical manifestations and characteristics of patients with acute generalized exanthematous pustulosis in Asia. Acta Derm Venereol 2008;88:363–5.

Bullous drug eruptions Stevens–Johnson syndrome, toxic epidermal necrolysis Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent clinical variants of the same severe bullous drug reaction occurring with an incidence of one to two cases per million per year in the general population [1]. As both entities are also thoroughly discussed in Chapter 78 of this textbook, the current section will focus on key clinical points only. Stevens–Johnson syndrome and TEN are differentiated quantitatively, depending on the extent of total body surface area (TBSA) involvement. By definition, SJS covers less than 10% and TEN more than 30% TBSA, whereas disease courses affecting 10–30% TBSA are designated as SJS/TEN overlap. This distinction is crucial, because it is directly related to the patient’s prognosis. Toxic epidermal necrolysis is associated with a mortality of 25–50% whereas mortality rates in patients with SJS vary from 1% to 5%, primarily depending on concurrent comorbidities [2,3]. In a widely noted recent publication, Levi and coworkers presented the results of a pooled analysis of medications as risk factors for the development of SJS/ TEN in 80 paediatric patients (90%) of patients suffering from full-blown SJS/TEN. Nearly 75% of affected children and adults will have eye involvement

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at some disease stage. Early ocular symptoms include conjunctivitis, foreign body sensation and photophobia. Up to 40% of TEN survivors suffer from long-term ocular disorders such as xerophthalmia (59% of cases), subconjunctival fibrous scarring (33%), corneal epithelial erosions (29%), trichiasis (16%), symblepharon (14%) or even visual loss (8%) [12]. Besides ophthalmological complications, strictures of the anogenital mucosa may be associated with dysuria and painful defecation. Perhaps even more importantly, pulmonary mucosal damage leads to bronchial epithelium sloughing and severe respiratory symptoms including acute respiratory distress syndrome in up to 30% of patients [13]. Other acute visceral manifestations of SJS/ TEN include sometimes severe colitis, hepatitis and nephritis. Most importantly, bacterial sepsis is observed at an incidence of about 15.5/1000 patient days and is often due to bloodstream infection with Staphylococcus aureus, Pseudomonas aeruginosa or Enterobacteriaceae organisms [14]. In an effort to predict mortality with only a few, easily obtainable clinical parameters, Bastuji-Garin and coworkers established a clinical score (SCORTEN) applicable to adult patients. SCORTEN comprises seven criteria found to be independent predictors of outcome: • age >40 years • TBSA involvement >10% • serum urea >28 mg/dL • glucose level >252 mg/dL • bicarbonate level 120 beats per minute • presence of visceral or haematological malignancies. Obviously, due to its age dependency, this score is not transferable to affected children and a modified scoring system to be used in paediatric SJS/TEN has not yet been developed [15,16]. If suspicion of SJS/TEN arises, the incriminated drug and, if possible, all other non-vitally indicated medications should be discontinued. Furthermore, the patient is best admitted to an intensive care unit for continuous monitoring, interdisciplinary supportive care and specific therapy. Interestingly, retrospective, uncontrolled data suggest that treatment in a burns care centre, which provides advanced treatment facilities (quarantine unit, air-fluidized beds), may not only shorten the overall length of hospital stay, but could also reduce the risk of systemic infections and, consequently, infection-related mortality. As in the treatment of critically ill burns patients, supportive therapy of SJS/TEN primarily consists of intravenous rehydration, total parenteral nutrition, maintenance of acid–base and electrolyte homeostasis as well as treatment of blood glucose and serum protein imbalances. In contrast, prophylactic antibiotic therapy

is not recommended, but can be initiated upon positive blood cultures and further clinical signs of systemic infection [1,17]. It is generally accepted that wound care represents the mainstay of SJS/TEN management [13,18–21]. While some centres prefer a minimally invasive approach, others favour stringent operative wound debridement consisting of the complete removal of exfoliated skin areas. In both cases, at least partial restoration of the epidermal barrier function should be undertaken by coverage of the denuded dermis with different biological materials. In this regard, commercially available temporary skin coverings (e.g. Biobrane™, Smith & Nephew, Hull, UK) and nanocrystalline silver dressings (e.g. Acticoat™, Smith & Nephew, Hull, UK) have been successfully used, although their clinical benefit has not yet been evaluated in controlled trials [1,13]. Furthermore, it is generally agreed that early ophthalmological consultations are pivotal in treating acute lesions and preventing the previously mentioned longterm complications. Topical treatment includes lubricants, antibiotics and glucocorticoids as well as the frequent release of symblephara. More recently, the sutureless transplantation of cryopreserved amniotic membrane to the ocular surface during the acute phase of SJS/TEN has yielded promising results, but needs further evaluation before its routine application in daily clinical practice [22]. Many uncontrolled, mostly retrospective trials have yielded conflicting results assessing the benefit of systemic treatment with several immunosuppressant and/ or immunomodulatory agents [glucocorticoids, intravenous immunoglobulins (IVIG), cyclophosphamide, ciclosporin A, TNF-α antagonists, plasmapheresis) [2]. In a recent milestone paper, Schneck and co-workers studied the effect of systemic treatments on the mortality of SJS/ TEN in a large population of adult patients. In summary, the authors found that glucocorticoids positively affected the outcome of SJS/TEN if given in moderate to high doses (100–500 mg) for a short time at disease onset, whereas this could not be demonstrated for IVIG therapy [23]. Likewise, Koh and Tay recently performed a stateof-the-art review concerning childhood SJS/TEN and found that an evidence-based recommendation in favour of or against either systemic glucocorticoid therapy or IVIG treatment is currently impossible [24]. References 1 Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal necrolysis (Lyell’s disease). Burns 2010;36:152–63. 2 Mockenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009;7:142–60. 3 Harr T, French LE. Severe cutaneous adverse reactions: acute generalized exanthematous pustulosis, toxic epidermal necrolysis and Stevens–Johnson syndrome. Med Clin North Am 2010;94:727–42, x.

Hypersensitivity Reactions to Drugs 4 Levi N, Bastuji-Garin S, Mockenhaupt M et al. Medications as risk factors of Stevens–Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics 2009;123:e297–e304. 5 Birch J, Chamlin S, Duerst R, Jacobsohn D. Mycoplasma pneumoniae and atypical Stevens–Johnson syndrome in a hematopoietic stem cell transplant recipient. Pediatr Blood Cancer 2008;50:1278–9. 6 Fournier S, Bastuji-Garin S, Mentec H, Revuz J, Roujeau JC. Toxic epidermal necrolysis associated with Mycoplasma pneumoniae infection. Eur J Clin Microbiol Infect Dis 1995;14:558–9. 7 Ball R, Ball LK, Wise RP, Braun MM, Beeler JA, Salive ME. Stevens– Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system. Pediatr Infect Dis J 2001;20:219–23. 8 Arvidson J, Kildal M, Linde T, Gedeborg R. Toxic epidermal necrolysis and hemolytic uremic syndrome after allogeneic stem-cell transplantation. Pediatr Transplant 2007;11:689–93. 9 Takeda H, Mitsuhashi Y, Kondo S, Kato Y, Tajima K. Toxic epidermal necrolysis possibly linked to hyperacute graft-versus-host disease after allogeneic bone marrow transplantation. J Dermatol 1997;24: 635–41. 10 Hemmige V, Jenkins E, Lee JU, Arora VM. Toxic epidermal necrolysis (TEN) associated with herbal medication use in a patient with systemic lupus erythematosus. J Hosp Med 2010 Oct;5(8):491–3. 11 Horne NS, Narayan AR, Young RM, Frieri M. Toxic epidermal necrolysis in systemic lupus erythematosus. Autoimmun Rev 2006;5: 160–4. 12 Gueudry J, Roujeau JC, Binaghi M, Soubrane G, Muraine M. Risk factors for the development of ocular complications of Stevens– Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2009;145:157–62. 13 Struck MF, Hilbert P, Mockenhaupt M, Reichelt B, Steen M. Severe cutaneous adverse reactions: emergency approach to non-burn epidermolytic syndromes. Intensive Care Med 2010;36:22–32. 14 de Prost N, Ingen-Housz-Oro S, Duong T et al. Bacteremia in Stevens– Johnson syndrome and toxic epidermal necrolysis: epidemiology, risk factors, and predictive value of skin cultures. Medicine (Baltimore) 2010;89:28–36. 15 Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149–53. 16 Guegan S, Bastuji-Garin S, Poszepczynska-Guigne E, Roujeau JC, Revuz J. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol 2006;126:272–6. 17 Shiga S, Cartotto R. What are the fluid requirements in toxic epidermal necrolysis? J Burn Care Res 2010;31:100–4. 18 Paquet P, Pierard GE. New insights in toxic epidermal necrolysis (Lyell’s syndrome): clinical considerations, pathobiology and targeted treatments revisited. Drug Safety 2010;33:189–212. 19 Sotozono C, Ueta M, Kinoshita S. Systemic and local management at the onset of Stevens–Johnson syndrome and toxic epidermal necrolysis with ocular complications. Am J Ophthalmol 2010; 149:354. 20 Hanken I, Schimmer M, Sander CA. Basic measures and systemic medical treatment of patients with toxic epidermal necrolysis. J Dtsch Dermatol Ges 2010;8:341–6. 21 Koh MJ, Tay YK. Stevens–Johnson syndrome and toxic epidermal necrolysis in Asian children. J Am Acad Dermatol 2010;62:54–60. 22 Shay E, Khadem JJ, Tseng SC. Efficacy and limitation of sutureless amniotic membrane transplantation for acute toxic epidermal necrolysis. Cornea 2010;29:359–61. 23 Schneck J, Fagot JP, Sekula P et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008 Jan;58(1):33–40.

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24 Koh MJ, Tay YK. An update on Stevens–Johnson syndrome and toxic epidermal necrolysis in children. Curr Opin Pediatr 2009; 21:505–10.

Fixed drug eruptions Fixed drug eruptions (FDE) are characterized by mucocutaneous lesions that recur at exactly the same site upon readministration of the causative medication. Depending on the studied populations, FDEs are the second to third most common drug eruptions in children and adolescents, occurring in about 10% of cases [1,2]. In the paediatric age group, drugs that have been associated with FDE are antihistamines (dimenhydrinate [3], hydroxyzine [4], loratadine [5]), antibiotics (amoxicillin [6], teicoplanin [7], vancomycin [8], co-trimoxazole [9], tetracycline [4], metronidazole [4]), NSAIDs (paracetamol [10], ibuprofen [11], nimesulide [12], naproxen [13], metamizol [14]), anticonvulsants (phenytoin, phenobarbital [4,15]) and other agents (methylphenidate [4], pseudoephedrine [16]). Interestingly, FDEs have also been described in patients who had not received any medication before the onset of eruptions. Although this phenomenon has not been systematically investigated, these non-specific exacerbations might be attributable to exogenous, non-pharmacological triggers such as UV radiation [17]. The lesions of FDE appear as solitary, pruritic, wellcircumscribed, erythematous, sometimes bullous macules and plaques that spontaneously heal with a characteristic, dusky brown hyperpigmentation upon drug discontinuation. After retreatment with the culprit drug, a flare-up reaction is usually observed within 1–8 hours. Yet, previously involved sites do not always exacerbate, which is probably due to a refractory period of variable duration. Similarly, some patients remain free of symptoms despite ongoing administration of the causative agent, which might be interpreted as a certain desensitization achieved by continued allergen exposure [18]. The sites of predilection include the lips, trunk, legs, arms and genitals, which are often affected particularly in male adolescents [4]. Interestingly, generalized bullous fixed drug eruption (GBFDE), a widespread bullous variant mimicking ‘mild’ SJS/TEN in adult patients, has not been described in children so far [19]. Although the exact immunological mechanisms of FDE remain unknown, evidence has accumulated that skinresident CD8+ effector/memory T-cells play a pivotal pathogenetic role. Upon drug administration, these T-cells are stimulated to release proinflammatory cytokines, particularly interferon-γ and tumour necrosis factor-α, which contribute to further cell recruitment (e.g. CD4+ T-cells, regulatory T-cells) and keratinocyte damage,

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which may be enhanced by perforin- and/or FAS ligandmediated cytolysis [17,18]. Histology reveals hydropic degeneration of the basal layer, which results in pigmentary incontinence. Individual dyskeratotic cells may be found in the epidermis, whereas the dermis demonstrates oedema and superficial or deep perivascular lymphohistiocytic infiltrate with scattered eosinophils. Subepidermal bullae may also be present [20]. References 1 Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions: clinical pattern and causative agents – a 6-year series from Chandigarh, India. J Postgrad Med 2001;47:95–9. 2 Sharma VK, Dhar S. Clinical pattern of cutaneous drug eruption among children and adolescents in north India. Pediatr Dermatol 1995;12:178–83. 3 Rodriguez-Jimenez B, Dominguez-Ortega J, Gonzalez-Garcia JM, Kindelan-Recarte C. Dimenhydrinate-induced fixed drug eruption in a patient who tolerated other antihistamines. J Investig Allergol Clin Immunol 2009;19:334–5. 4 Nussinovitch M, Prais D, Ben-Amitai D, Amir J, Volovitz B. Fixed drug eruption in the genital area in 15 boys. Pediatr Dermatol 2002;19:216–19. 5 Pionetti CH, Kien MC, Alonso A. Fixed drug eruption due to loratadine. Allergol Immunopathol (Madr) 2003;31:291–3. 6 Dhar S, Kanwar AJ. Fixed drug eruption on the tongue of a 4-year-old boy. Pediatr Dermatol 1995;12:51–2. 7 Duong T, Hamel D, Benlahrech S et al. First fixed drug eruption due to teicoplanin with a peri-oral distribution. J Eur Acad Dermatol Venereol 2009;23:1107. 8 Gilmore ES, Friedman JS, Morrell DS. Extensive fixed drug eruption secondary to vancomycin. Pediatr Dermatol 2004;21:600–2. 9 Morelli JG, Tay YK, Rogers M, Halbert A, Krafchik B, Weston WL. Fixed drug eruptions in children. J Pediatr 1999;134:365–7. 10 Ayala F, Nino M, Ayala F, Balato N. Bullous fixed drug eruption induced by paracetamol: report of a case. Dermatitis 2006; 17:160. 11 Sanchez-Borges M, Capriles-Hulett A, Caballero-Fonseca F. Risk of skin reactions when using ibuprofen-based medicines. Expert Opin Drug Safety 2005;4:837–48. 12 Sarkar R, Kaur C, Kanwar AJ. Extensive fixed drug eruption to nimesulide with cross-sensitivity to sulfonamides in a child. Pediatr Dermatol 2002;19:553–4. 13 Li H, Wiederkehr M, Rao B et al. Peculiar unilateral fixed drug eruption of the breast. Int J Dermatol 2002;41:96–8. 14 Ozkaya-Bayazit E. Topical provocation in fixed drug eruption due to metamizol and naproxen. Clin Exp Dermatol 2004;29:419–22. 15 Scheinfeld N. Impact of phenytoin therapy on the skin and skin disease. Expert Opin Drug Safety 2004;3:655–65. 16 Hindioglu U, Sahin S. Nonpigmenting solitary fixed drug eruption caused by pseudoephedrine hydrochloride. J Am Acad Dermatol 1998;38:499–500. 17 Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 2009;9:316–21. 18 Shiohara T, Mizukawa Y, Teraki Y. Pathophysiology of fixed drug eruption: the role of skin-resident T cells. Curr Opin Allergy Clin Immunol 2002;2:317–23. 19 Mockenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009;7:142–60. 20 Ozkaya E. Fixed drug eruption: state of the art. J Dtsch Dermatol Ges 2008;6:181–8.

Diagnostic approach to drug hypersensitivity reactions The diagnostic workup of suspected drug hypersensitivity reactions in children and adolescents requires fundamental knowledge of the underlying pharmacological and immunological pathomechanisms. With this in mind, further diagnostic steps are taken depending on the individual patient’s age, the severity of the drug reaction, the incriminated trigger(s) and the availability of potential alternative medications. As validated test methods have been established for only a limited number of drug classes, patients with a history of complicated drug hypersensitivity should be evaluated in specialized centres disposing of sufficient experience in the field of drug allergy, especially with regard to drug provocation testing. Irrespective of the underlying type of drug hypersensitivity, a thorough medical history is the indispensable prerequisite for a targeted allergological workup. It should be acquired using a standardized template, such as the Questionnaire on Drug Hypersensitivity of the European Network for Drug Allergy (ENDA), which captures the following and other important anamnestic data [1]: • list of all drugs including over-the-counter substances and natural remedies; • time of onset (e.g. first day of treatment, 2 days after end of therapy); • time interval between intake and onset of first symptoms (e.g. after 30 minutes, after 24 hours); • previous clinical documentation (e.g. anaesthesia/ emergency protocols, allergy pass); • description of cutaneous reaction (e.g. urticaria, maculopapular exanthem, erythroderma); • extracutaneous reactions (e.g. dyspnoea, cardiocirculatory dysregulation, liver involvement); • clinical course of skin reaction (e.g. persistence under treatment with alternative medication); • allergic reaction or tolerance after re-exposure; • previous diagnostic results (e.g. skin test, specific IgE, provocation tests). The ENDA questionnaire has been published in English, French, Spanish, German and seven other European languages and is available for free download from the homepage of EAACI – the European Academy of Allergy and Clinical Immunology (http://www.eaaci. net/sections-a-igs/ig-on-drug-allergy/resources/669demoly-enda-questionnaires-for-drug-allergy-ig).

Immediate drug hypersensitivity reactions If an immediate (type I) drug allergy is suspected, the detection of allergen-specific IgE antibodies can be achieved by a limited number of in vitro (fluorescence

Hypersensitivity Reactions to Drugs

enzyme immunoassay, basophil activation test) and in vivo (skin prick, drug provocation) diagnostic tests.

Skin tests Due to a rapidly declining diagnostic sensitivity, skin tests should be performed within 6 months after the drug reaction, but not within the first 4 weeks as this might be a phase of relative refractoriness. Of note, skin prick and intradermal tests may elicit severe immediate allergic reactions themselves. Thus, high-risk patients such as infants and toddlers with drug-induced anaphylaxis should only be tested in centres of paediatric allergology that provide adequate emergency facilities [2]. Skin prick testing is performed with a soluble preparation of the incriminated drug and potentially crossallergenic compounds. If the test substances are known to cause non-specific histamine liberation (e.g. opioid analgesics, muscle relaxants, narcotic agents), or if the patient has suffered severe drug-induced anaphylaxis, sequentially titrated skin tests with ascending allergen concentrations are recommendable. Intradermal tests can be performed in individual cases to enhance diagnostic sensitivity, but only if prior skin prick testing has yielded negative results [3]. In order to avoid false negative results, non-irritative but still immunogenic test concentrations should be applied. Unfortunately, these have only been defined for beta-lactam antibiotics and some non-beta-lactam antibiotics so far [4,5]. If a beta-lactam allergy is suspected, the EAACI recommends further diagnostic steps including skin prick and intradermal tests with the following haptens: penicilloyl-polylysine (PPL), ‘minor determinant mixture’ (MDM), amoxicillin, ampicillin and cephalosporins such as cefaclor and cefuroxime. Clinically validated MDM- and PPL-preparations have been temporarily unobtainable, but are now commercially available again (www.diater.com) [6–9]. Even if the corresponding test performance parameters have not been fully elucidated, positive prick or intradermal tests are strong indicators of an immediate drug allergy. Accordingly, positive prick tests were observed in up to 70% of paediatric patients with cephalosporin allergy [10]. Likewise, negative skin test results clearly lower the probability of IgE-mediated drug allergy, but cannot rule it out completely due to negative predictive values of maximally 90% [11].

In vitro tests Immunological laboratory investigations represent a valuable supplemental tool for drug allergy diagnosis. Drug-specific IgE antibodies can be detected in serum probes of affected patients using highly standardized fluorescence enzyme immunoassays (e.g. ImmunoCAP™, Phadia, Freiburg, Germany). However, only a very limited

183.13

number of test substances are currently available for serological IgE detection, mainly penicillins and cephalosporins. Moreover, recent studies of children and adults with beta-lactam allergy have revealed a limited test sensitivity ranging from only 40% to 75%, whereas test specificity was excellent reaching 80% up to 100% [12–14].

Drug provocation tests As the current diagnostic gold standard, double-blind placebo-controlled drug challenges (DBPCDC) are performed in children and adolescents with suspected drug allergy under the following indications: • to exclude or verify drug allergy in patients with negative results of previous skin and laboratory tests; • to exclude or verify cross-reactivity against a chemically related alternative medication, e.g. cephalosporins in patients with penicillin allergy; • to exclude or verify cross-reactivity against a chemically non-related alternative medication, which is only performed in patients with suspected ‘multiple drug allergy syndrome’. Patients with a history of severe anaphylaxis should not undergo provocation tests with the culprit drug. Similarly, non-IgE-mediated, potentially severe reactions such as SSLRs and serious comorbidities represent absolute contraindications. Depending on the severity of the initial drug reaction, provocation tests can be performed in an ambulatory or in-hospital setting. Beginning with a low initial dose (e.g. 1 : 100 dilution) the incriminated substance is usually applied in increasing doses (1 : 10, 1 : 1) at 30 min intervals until first allergic symptoms arise or until the therapeutic end dose is tolerated without any complications. In case of a positive provocation, the patient should be provided with an allergy pass containing information on the culprit drug and possible cross-allergens as well as on the tested and tolerated alternative medications [15].

Non-immediate drug hypersensitivity reactions As previously mentioned, non-immediate (type IV) drug hypersensitivity reactions, particularly MPEs, are frequently suspected in children and adolescents with erythematous rashes. However, recent reports have highlighted that these eruptions correspond to nonimmediate drug allergy in fewer than 10% of cases. Thus, a thorough allergological workup is warranted in every child with presumed drug hypersensitivity, particularly in order to avert unnecessary avoidance of the incriminated substance.

Skin tests Currently, epicutaneous patch tests are frequently used to diagnose cell-mediated drug hypersensitivity in children.

183.14

Chapter 183

In contrast, intradermal tests with late readings after 48 to 72 hours are less readily performed due to their painfulness and the elevated risk of locally irritative or even systemic allergic reactions. While petrolatum is used as vehicle in the majority of cases, other substances are diluted in distilled water (e.g. heparin) or ethanol (e.g. betamethasone). Substances of high clinical relevance in the paediatric age group (e.g. beta-lactams, macrolides, clindamycin, phenytoin, carbamazepine) are usually dissolved at 10% in petrolatum, whereas other drugs are tested at higher (e.g. famciclovir 30%, isoniazid 50%, omeprazole 30%) or at lower concentrations (e.g. codeine 1%, diclofenac 1%, metamizole 1%, vancomycin 0.005%). Due to an obvious lack of controlled trials, the clinical usefulness of patch tests in children with drug hypersensitivity remains to be determined [16]. First paediatric studies suggested a very low diagnostic sensitivity of maximally 10%, while test specificity was not investigated at all [17]. Likewise, the negative predictive value of drug patch tests, which was previously thought to be very high (>90%), has been questioned by a recent publication [18]. Therefore, further studies are required before the clinical significance of patch testing in children with drug hypersensitivity can be conclusively determined.

In vitro tests In contrast to the diagnosis of immediate allergic drug reactions, standardized laboratory tests for further assessment of cell-mediated drug allergies are currently not available. Only the lymphocyte transformation test (LTT) has been successfully used to verify specific T-cell responses to betalactam antibiotics, anticonvulsants and sulphonamides in selected patients. However, the LTT is still poorly standardized and its application is still limited to children with severe cutaneous drug reactions in whom in vivo skin or provocation tests are contraindicated [19,20].

Provocation tests Considering the low sensitivity of the previously mentioned skin tests, DBPCDC remains the diagnostic gold standard in non-immediate drug allergic reactions, too [21]. Yet, patients with a history of severe drug reactions, particularly SJS/TEN and DRESS, are usually not advised to undergo re-exposure for safety reasons. In contrast to immediate reactions, provocation tests can usually be performed in an ambulatory or day hospital setting. Beginning with a maximum dilution of 1 : 100 the culprit drug is also applied in increasing doses (1 : 10, 1 : 1) at 30 min intervals until first allergic symptoms arise or until the therapeutic end dose is tolerated without any complications. The pathomechanisms under-

lying non-immediate drug reactions and recently published results of a clinical pilot study imply that the diagnostic sensitivity of oral provocation tests may be enhanced by continued drug application for a further 3–5 days [18]. References 1 Wedi B. Fragebogen Medikamentenüberempfindlichkeit. Allergo Journal 2005;8:613–16. 2 Bagg A, Chacko T, Lockey R. Reactions to prick and intradermal skin tests. Ann Allergy Asthma Immunol 2009;102:400–2. 3 Brockow K, Romano A. Skin tests in the diagnosis of drug hypersensitivity reactions. Curr Pharm Des 2008;14:2778–91. 4 Blanca M, Romano A, Torres MJ et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009;64:183–93. 5 Schnyder B. Hauttestungen bei Medikamentenallergien. Allergologie 2009;9:302–9. 6 Torres MJ, Blanca M. Importance of skin testing with major and minor determinants of benzylpenicillin in the diagnosis of allergy to betalactams. Statement from the European Network for Drug Allergy concerning AllergoPen withdrawal. Allergy 2006;61:910–11. 7 Blanca M, Romano A, Torres MJ et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009;64:183–93. 8 Romano A, Viola M, Bousquet PJ et al. A comparison of the performance of two penicillin reagent kits in the diagnosis of beta-lactam hypersensitivity. Allergy 2007;62:53–8. 9 Romano A, Gueant-Rodriguez RM et al. Diagnosing immediate reactions to cephalosporins, Clin Exp Allergy 2005;35:1234–42. 10 Romano A, Gaeta F, Valluzzi RL, Alonzi C, Viola M, Bousquet PJ. Diagnosing hypersensitivity reactions to cephalosporins in children. Pediatrics 2008;122:521–7. 11 Blanca M, Romano A, Torres MJ et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009;64:183–93. 12 Fontaine C, Mayorga C, Bousquet PJ et al. Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy. Allergy 2007;62:47–52. 13 Fernandez TD, Torres MJ, Blanca-Lopez N et al. Negativization rates of IgE radioimmunoassay and basophil activation test in immediate reactions to penicillins. Allergy 2009;64:242–8. 14 Blanca M, Mayorga C, Torres MJ et al. Clinical evaluation of Pharmacia CAP System RAST FEIA amoxicilloyl and benzylpenicilloyl in patients with penicillin allergy. Allergy 2001;56:862–70. 15 Aberer W, Bircher A, Romano A et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003;58:854–63. 16 Friedmann PS, Ardern-Jones M. Patch testing in drug allergy. Curr Opin Allergy Clin Immunol 2010 Aug;10(4):291–6. 17 Romano A, Gaeta F, Valluzzi RL, Alonzi C, Viola M, Bousquet PJ. Diagnosing hypersensitivity reactions to cephalosporins in children. Pediatrics 2008;122:521–7. 18 Blanca-Lopez N, Zapatero L, Alonso E et al. Skin testing and drug provocation in the diagnosis of nonimmediate reactions to aminopenicillins in children. Allergy 2009;64:229–33. 19 Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy 2004;59:809–20. 20 Kano Y, Hirahara K, Mitsuyama Y, Takahashi R, Shiohara T. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy 2007;62:1439–44. 21 Demoly P, Romano A, Botelho C et al. Determining the negative predictive value of provocation tests with beta-lactams. Allergy 2010;65:327–32.

184.1

C H A P T E R 184

Poisoning and Paediatric Skin Giuseppe Micali1, Stephanie A. St Pierre2, Erika E. Reid3 & Dennis P. West3 1

Dermatology Clinic, University of Catania, Catania, Italy Cook County Hospital, Chicago, IL USA 3 Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA 2

Introduction, 184.1 Toxicology and organ systems, 184.1

Percutaneous absorption and systemic toxicity, 184.2

inhalation and injection of some

Paediatric skin absorption, 184.2

Therapeutic agents, 184.3

Fundamentals of percutaneous

Compounds used for non-therapeutic

absorption, 184.2

Cutaneous symptoms following ingestion, toxicants, 184.14 Conclusion, 184.15

purposes, 184.13

Introduction Myriad substances capable of causing serious poisoning in humans after dermal exposure continue to be discovered and reported. These substances include organic and inorganic chemicals, originating as both natural and synthetic materials. Poisoning is often classified according to the type of toxicity produced. Furthermore, this toxicity may be produced in a variety of ways. Either the chemical may have a direct toxic effect or it may be inherently toxic at a given dose without undergoing biotransformation. In addition, it may act through interference with metabolic processes or it may undergo conversion to a toxic metabolite [1]. In the majority of cases, poisoning is associated with acute exposure to a toxicant. Conversely, chronic poisoning is usually related to an accumulation of the toxic agent in the body, often resulting in organ damage [1]. Fatal, or near-fatal, outcomes have resulted after accidental, as well as intentional, dermal exposure. Systemic poisoning related to percutaneous absorption of some substances (i.e. mercury) is well documented [2]. In the paediatric population two major causes of nondermal poisoning are recognized: accidental ingestion of a poison in preschool children and, in adolescents, intentional ingestion of an overdose of a much narrower range of agents, most commonly a drug [2]. Poisoning from dermal exposure is relatively uncommon in the paediatric population [1]. Although systemic poisoning by percutaneous absorption is conspicuously less frequent, fatal or near-fatal outHarper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

comes have occurred [3,4]. Alternatively, toxicity after ingestion, inhalation or injection of a drug may manifest with cutaneous symptoms. For substances or drugs causing cutaneous reactions through an immunological mechanism please refer to Chapter 183. References 1 Temple AR, Mancini RE. Management of poisoning. In: Yaffe SJ (ed) Paediatric Pharmacology. Therapeutic Principles in Practice, 2nd edn. Philadelphia: W. B. Saunders, 1992. 2 Vale JA, Meredith TJ. Poisoning. In: Barltrop D, Brueton MJ (eds) Paediatric Therapeutics. Principles and Practice. Oxford: ButterworthHeinemann, 1991. 3 Marzulli FN, Maibach HI. Dermatotoxicology, 5th edn. Washington, DC: Taylor and Francis, 1996. 4 Arena JM, Drew R. Poisoning: Toxicology,Symptoms,Treatment, 5th edn. Springfield, IL: Charles C. Thomas, 1986.

Toxicology and organ systems Toxicants vary in terms of route of entry as well as rate and extent of absorption. The most frequent mode of entry is via the percutaneous, gastrointestinal and/or respiratory route [1]. In general, the respiratory system offers the most rapid route of entry and dermal entry the least rapid, although this depends on both drug concentration and surface area of epithelium involved [1]. Depending on whether the toxicant is a gas, liquid or solid, the importance of a particular route may be inconsequential or of key importance. Once the drug or chemical enters the system, it is transported and usually undergoes biotransformation. A nearly optimal transport system is provided by the circulatory system because it can easily distribute water-soluble as well as lipid-soluble compounds via an aqueous medium or via carrier

184.2

Chapter 184

proteins. Proteins may serve to bind toxicants for release at some tissue distant from the site of entry. Such transport may carry a toxicant to a site of toxic action, to a site of metabolism, to a site of storage or to organs of elimination. These concurrent events result in a dynamic flux that makes the study of poisoning quite complex [1]. Reference 1 Guthrie FE, Hodgson E. Absorption and distribution of toxicants. In: Hodgson E, Levi PE, (eds) A Textbook of Modern Toxicology, 2nd edn. Stamford, CT: Appleton and Lange, 1997.

Paediatric skin absorption Human stratum corneum (SC) is physically and chemically organized to prevent excessive water loss and to restrict movement of selected molecules into the system [1]. Nonetheless, it is permeable to a number of toxicants in solid, liquid or gaseous phases. Skin not only serves as a passive barrier to diffusion but also accommodates metabolism of topically applied substances before entry to the systemic circulation. Epidermis accounts for a major portion of skin biotransformation, although total skin metabolic activity is relatively low when compared to some other organ systems [2]. Full-term infants have a fully mature SC and epidermis which, similar to adults, possesses excellent barrier properties. By contrast, an infant who is born prematurely may have a poorly developed and poorly functioning SC. Although rapid postnatal maturation of the epidermis occurs over the first 2–3 weeks of age [3], a preterm infant’s skin provides inadequate barrier effect in this early neonatal period [4] and this results in significantly enhanced percutaneous absorption [5]. Moreover, since the ratio of surface area to bodyweight for a newborn may be three times that of an adult, given an equal area of application of drug to newborn skin and adult skin, the proportion systemically absorbed per kilogram of bodyweight is significantly more in the infant [6]. References 1 Micali G, Lacarrubba F, Bongu A, West DP. The skin barrier. In: Freinkel RK, Woodley DT (eds) The Biology of the Skin. New York: Parthenon, 2001. 2 Guthrie FE, Hodgson E. Absorption and distribution of toxicants. In: Hodgson E, Levi PA (eds) A Textbook of Modern Toxicology, 2nd edn. New York: McGraw-Hill Professional, 1997. 3 Evans NJ, Rutter N. Development of the epidermis in the newborn. Biol Neonate 1986;49:74–80. 4 Harpin VA, Rutter N. Barrier properties of the newborn infant’s skin. J Pediatr 1983;102:419–25. 5 Kalia VN, Nonato LB, Lund CH, Guy RH. Development of skin barrier function in premature infants. J Invest Dermatol 1998;111:320–6. 6 Freeman S, Maibach HI. Systemic toxicity in man secondary to percutaneous absorption. In: Marks R, Plewig G (eds) The Environmental Threat to the Skin. London: Martin Dunitz, 1992.

Fundamentals of percutaneous absorption For percutaneous absorption to occur, a topically administered drug must diffuse through the SC and be absorbed into the inner epidermis and dermis. The drug must be in solution and penetrate readily through the SC. Transport of molecules across the SC is generally considered to be passive and is expressed by Fick’s first law: J = (D·K·δC)/L, in which J is flux, K the SC/vehicle partition coefficient, D the diffusion coefficient in the SC, δC the concentration difference across the membrane, and L the length of diffusion pathway of the SC [1,2]. Many drugs for topical skin use are capable of producing systemic side-effects, the occurrence and severity of which depend largely on: physical and chemical properties of the drug, such as molecular weight and size, water and oil solubility; chemical and physical properties of the vehicle; drug concentration in the vehicle; thickness of the SC; temperature, humidity, occlusion and presence of skin diseases or damages [3–8]. (See also Chapter 181) References 1 Micali G, Lacarrubba F, Bongu A, West DP. The skin barrier. In: Freinkel RK, Woodley DT (eds) The Biology of the Skin. New York: Parthenon, 2001. 2 Morimoto Y, Sugibayashi K, Natsume H. The transdermal drug delivery system and transcutaneous absorption. Acta Dermatol Venereol 1994;185(suppl):15–17. 3 Micali G, Distefano G. Percutaneous absorption in neonates: a review. G Int Dermatol Pediatr (Italy) 1989;1:31–8. 4 Rasmussen JE. Percutaneous absorption in children. In: Dobson RL (ed) Year Book of Dermatology. Chicago: Year Book Medical, 1979. 5 Delgado-Charro MB, Guy RH. Percutaneous penetration and transdermal drug delivery. Dermatol Found 1998;32:1–12. 6 Held E, Sveinsdottir S, Agner T. Effect of long-term use of moisturizers on skin hydration, barrier function and susceptibility to irritants. Acta Dermatol Venereol 1999;79:49–51. 7 Zettersen EM, Man MQ, Sato J et al. Recessive x-linked ichthyosis: role of cholesterol-sulfate accumulation in the barrier abnormality. J Invest Dermatol 1998;111:784–90. 8 Schafer P, Bewick-Sonntag C, Capri MG, Berardesca E. Physiological changes in skin barrier function in relation to occlusion level, exposure time and climatic conditions. Skin Pharmacol Appl Skin Physiol 2002;15:7–19.

Percutaneous absorption and systemic toxicity Several commonly used drugs and chemicals have been reported as the cause of systemic toxicity following percutaneous absorption in neonates and infants. There are also a growing number of reports of less commonly encountered drugs with percutaneous toxicity in infants

Poisoning and Paediatric Skin

[1]. The likelihood of a substance resulting in systemic toxicity by percutaneous absorption depends upon two unrelated factors. First is the ability to transit the SC epidermal cells and epidermal-dermal membrane. Initial entry also includes follicular and sweat duct transport with subsequent movement into the circulation. There are a number of toxicants, especially lipophilic substances, such as organophosphate insecticides and polychlorinated biphenyls, that penetrate the skin quite readily [2]. A second property involved is the ability to injure a particular target site after being transported there in the same or in a biotransformed state [3–7]. Systemic toxicity following dermal delivery may be associated with therapeutic agents intended for topical application to human skin as well as with compounds not intended for topical application (Box 184.1).

184.3

References 1 West DP, Worobec S, Solomon LM. Pharmacology and toxicity of infant skin. J Invest Dermatol 1981;76:147–50. 2 Emmett EA. Toxic responses of the skin. In: Klaassen CD (ed) Casarett and Doull’s Toxicology. The Basic Science of Poisons, 6th edn. New York: McGraw-Hill, 2001. 3 Birmingham DJ. Cutaneous absorption and systemic toxicity. In: Drill VA, Lazar P (eds) Cutaneous Toxicity. New York: Raven Press, 1984. 4 Arena JM, Drew R. Poisoning: Toxicology,Symptoms,Treatment, 5th edn. Springfield, IL: Charles C. Thomas, 1986. 5 Goldsmith LA. Physiology, Biochemistry, and Molecular Biology of the Skin, 2nd edn. New York: Oxford University Press, 1991. 6 Blank IH, Scheuplein RJ. The epidermal barrier. In: Rook A (ed) Progress in the Biological Sciences in Relation to Dermatology 2. Cambridge: Cambridge University Press, 1964. 7 Schaefer H, Redelmeier TE (eds). Skin Barrier: Principles of Percutaneous Absorption. Basel: Karger Publishing, 1996.

Therapeutic agents Alcohols Box 184.1 Selected agents associated with systemic toxicity following percutaneous absorption Therapeutic agents Alcohols • Ethanol • Isopropanol • Methanol Amitraz Anaesthetics, local • Benzocaine • Cocaine • Lidocaine • Lidocaine/prilocaine combination Antihistamines • Diphenhydramine hydrochloride • Diphenylpyraline hydrochloride • Doxepin • Promethazine Boric acid Camphor Cerium nitrate Chlorhexidine Clonidine Corticosteroids Diethyltoluamide Epinephrine Eucalyptus oil Hexachlorophene Iodine • Iodine, povidone-iodine Lactic acid Lindane Mafenide

Malathion Mercurials Neomycin Nicotine Oestrogens Opioid Phenol • Phenol • Castellani’s solution Podophyllin resin Pyrethrin Salicylic acid and salicylates Resorcinol Silver nitrate Tars Warfarin Non-therapeutic agents Acetylcholinesterase inhibitor • (anticholinesterase) insecticides • Organophosphates • Carbamates Aniline dye Arsenic Carbon tetrachloride Henna Naphthalene Potassium dichromate

Alcohol is a commonly used topical antiseptic in newborn nurseries, especially for procedures such as venepuncture, arterial cannulation and spinal tap. It usually evaporates from the skin, but several cases of percutaneous absorption have been reported.

Ethanol The cases of 28 children of both sexes, ranging in age from 3 months to 1 year, and presenting with alcohol intoxication from percutaneous absorption were reported [1]. Poisoning occurred in Argentina where it was a popular procedure to apply alcohol-soaked cloths to the abdomen of babies as a home remedy for the treatment of disturbances of the gastrointestinal tract such as cramps, pain, vomiting and diarrhoea or because of crying, excitability and irritability. Alcohol-soaked cloths had been applied on the babies’ abdomens under rubber pants, and the number of applications varied from one to three; it was estimated that each application contained approximately 40 mL of 70% ethanol. Medical consultation took place from 1 to 23 hours after application. Alcoholic breath and abdominal erythema were valuable clues to the diagnosis. All 28 children showed some degree of CNS depression, 24 showed miosis, 15 hypoglycaemia, five convulsions, five respiratory depression and two died. Eleven children had blood alcohol levels of 0.6–1.49 g%. Of the two who died, one was autopsied: the findings were consistent with ethanol intoxication. Several other reported cases of alcohol intoxication following percutaneous absorption exist in the literature. One such case report involves a preterm infant treated with local application of ethanol-soaked compresses on the legs to relieve puncture haematomas [2]. In another

184.4

Chapter 184

case, a 27-week gestational age preterm infant developed extensive haemorrhagic skin necrosis on the back and buttocks after umbilical arterial catheterization; the skin was cleaned with methylated spirits [3]. A report of alcohol intoxication also exists for a 2-year-old child treated with alcohol-soaked bandages applied to damaged skin [4].

thetic before an upper gastrointestinal endoscopy [16,17]. A 17 year old treated with one spray of topical benzocaine 20% prior to bronchoscopy developed cyanosis and dyspnea [18]. Furthermore, gel-type benzocaine was found to cause methaemoglobinaemia in a 6-year-old boy treated with 7.5% benzocaine gel to a single painful tooth on one occasion [19].

Isopropanol

Cocaine

Isopropanol is a clear, colourless, volatile alcohol usually sold as a 70% rubbing alcohol solution for disinfection. Toxicity consisting of mental status changes, ketosis and metabolic acidosis from topical absorption has been reported in children sponge-bathed with isopropanol for fever reduction [5,6]. Furthermore, a case has been reported of a 2-year-old boy who developed coffeeground emesis during emergency department evaluation for lethargy and fever. Medical history revealed an isopropanol rubdown for fever reduction. Blood isopropanol concentrations and acetone metabolite were elevated [7].

There are reports of hypertension and seizures after application of a solution of tetracaine 0.5%, adrenaline 0.05% and cocaine 11.8% (TAC) to burns or mucous membranes of children, raising concern for potential toxicity during routine use [20–22]. Documentation of cocaine serum levels in 75% of 77 children 15 minutes after application of TAC has raised additional concerns [23]. There is a report in the literature of a 7-month-old child who died after 10 mL of TAC was applied to a lip laceration [24]. A report of a 5-month-old infant who became diaphoretic, tachycardic and hypertensive after receiving intranasal cocaine before laryngoscopy suggests that the maximum dose of 1 mg/kg in children has not been well validated [25].

Methanol Methanol, if ingested, is rapidly absorbed from the gastrointestinal tract, causing severe systemic effects. However, poisoning may also occur from skin absorption or inhalation of methanol [8]. An 8-month-old child died from methanol toxicity after application of olive oil and warm methanol compresses on the chest for the treatment of a common cold [9].

Amitraz Amitraz is an amidine mainly used in veterinary medicine for the treatment of demodicosis and other ectoparasitic infestations. In the rural Black Sea region, 43 children were reported with amitraz intoxication, 14 of whom had dermal exposure. The most common systemic side-effect with dermal toxicity was CNS depression [10]. In Turkey, seven patients between 2 and 6 years of age were reported to have amitraz poisoning. One of these cases was due to dermal exposure. Unconsciousness was the most common initial symptom, followed by dizziness and vomiting within the first 30–150 minutes [11].

Anaesthetics, local Benzocaine Benzocaine is a local anaesthetic commonly used topically for pain relief. Topical application of benzocaine to the skin and mucous membranes of infants is reported to produce methaemoglobinaemia [12–15]. A 2-year-old child developed severe methaemoglobinaemia after topical application of 3% benzocaine to a large area of skin that had lost its integrity, as did a 3-year-old boy following one spray of topical 20% benzocaine anaes-

Lidocaine Systemic toxicity from viscous lidocaine applied to the oral cavity has been reported in at least two children [26,27]. Clinical signs are those of CNS stimulation followed by depression and later inhibition of cardiovascular function. In one child, the mother had been applying lidocaine hydrochloride 2% solution to the infant’s gums with her finger 5–6 times daily for 1 week; the child experienced two generalized seizures within 1 hour. The other child had a seizure after receiving 22 mg/kg oral viscous lidocaine for stomatitis herpetica over a 24-hour period. In this case, however, ingestion and absorption from the gastrointestinal tract may have contributed to the clinical picture. It has been suggested that for paediatric patients, viscous lidocaine should be applied with an oral swab to individual lesions, thus limiting buccal absorption by decreasing the surface area exposed to lidocaine [26]. Use of both excessive and appropriate amounts of combination lidocaine and prilocaine (EMLA) creams has resulted in methaemoglobinaemia in children under 3 years of age [28–30]. A 28-day-old premature infant born at 36 and 5/7 gestation developed methaemoglobinaemia after EMLA was applied to the lower back in preparation for lumbar puncture [30]. One case involved a 21-monthold girl anaesthetized with EMLA prior to curettage of molluscum contagiosum who experienced subsequent seizures and respiratory depression. The child’s lidocaine level was 2.5 μg/mL (drawn 4 hours after EMLA application) [31].

Poisoning and Paediatric Skin

Antihistamines Diphenhydramine hydrochloride Diphenhydramine hydrochloride is an antihistamine available in many topical forms used to relieve itching. Diphenhydramine toxicity was described in a 4-year-old boy who developed hyperactivity, irregular eye movements, hallucinations, disorientation, ataxia, tongue rolling and combative behaviour after topical application of 90 mL Caladryl lotion (1% diphenhydramine, 2% alcohol, 2% menthol by volume) for severe pruritus presumably associated with a varicella infection [32]. A 19-month-old child treated for varicella with diphenhydramine syrup, colloidal oatmeal baths, acetaminophen and frequent applications of Caladryl lotion presented with dilated pupils, ataxia, urinary retention and facial grimacing. Her diphenhydramine serum level was found to be 1948 ng/mL [33]. An 8-year-old boy who also had varicella, treated with excessive topical Caladryl lotion and Benadryl spray, subsequently developed acute-onset mental confusion and hallucinations [34].

184.5

further application, 1 day later, all symptoms spontaneously disappeared. Known symptoms of promethazine toxicity include delirium, tachycardia and hypotension [38].

Boric acid Boric acid, usually up to 10% concentration, is present in talcum powders, ointments and solutions. There are several reports of boric acid toxicity occurring in premature or newborn infants after topical application in talcum powders and solutions for the treatment of dermatitis (diaper rash) and burns [39–43]. A usual course of events was that, after a few days, patients developed nausea, vomiting, diarrhoea, an erythrodermic rash, CNS irritability and, in severe cases, renal failure and shock, often leading to death [39,40,44–46]. Extensive desquamation occurred 1–2 days after the onset of rash [47]. Because concentrated boric acid is rarely available for topical application today, these cases are of historical interest only [47].

Diphenylpyraline hydrochloride

Camphor

Diphenylpyraline hydrochloride has been used topically for the treatment of eczematous and other pruritic dermatoses. Its use caused symptomatic psychosis in 12 patients, nine of whom were children. Active drug applied ranged from 225 to 1350 mg. Symptoms included psychomotor restlessness, disorientation and optic and acoustic hallucinations. After discontinuation of therapy, all symptoms disappeared within 4 days [35].

Camphor is used as an antiseptic and rubefacient. In cold remedies, it is used either by application to the chest or via a vaporizer. It is also used as a topical analgesic for ‘fever blisters’ and cold sores [48]. FDA regulations prohibit products containing more than 11% camphor concentration, and recommend use of alternative products that do not contain camphor, given the potential toxicity if ingested [49]. Although the majority of reported cases are due to oral ingestion, a case report suggests possible dermal absorption and intoxication in a 7-year-old boy. He had normal growth and development until the age of 15 months when he developed serious alteration in cerebral function after crawling through spirits-of-camphor spilled by a sibling [48]. One year later, a brief major motor seizure occurred after inhalation of a camphorated vaporizer preparation. Further, a 9-month-old infant had evidence of poisoning after being treated with a camphorated dressing applied to a burn. The infant had a camphor blood level of 2.6 mg/L and seizure activity occurred [50]. A 3-yearold Hispanic girl with history of epilepsy experienced a tonic-clonic seizure after a camphor ointment was rubbed over her upper chest, forehead and back every hour for 10 hours in an attempt to relieve her cold symptoms. The mother had also been using camphor-containing products in a vaporizer, in a bowl with water under the crib, hanging camphor tablets around the crib, and leaving crushed tablets around the house to ward off cockroaches [51]. Another child treated for flatulence with a camphorcontaining solution on the abdomen presented with severe status epilepticus [52].

Doxepin Topical doxepin cream is indicated for treatment of pruritus associated with eczematous skin changes. Usually, systemic side-effects after topical application are limited to CNS side-effects such as drowsiness, but more severe adverse reactions have been reported in children who were treated over a large surface area with topical doxepin. Paediatric cases of doxepin toxicity have occurred subsequent to dermal exposure to this tricyclic compound [36,37]. Symptoms included difficulty to arouse and responsiveness only to noxious stimuli. Application to non-intact skin barrier and application of a large quantity of the compound to extensive body surface areas probably contributed to systemic toxicity [36,37].

Promethazine Promethazine is used to treat allergy symptoms, nausea and vomiting after surgery and to prevent motion sickness. A 16-month-old boy weighing 11.5 kg, who suffered with generalized eczema, awoke with abnormal behaviour, loss of balance, inability to focus, irritability, drowsiness and failure to recognize his mother a few hours after promethazine 2% cream was applied to the skin. With no

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Chapter 184

Cerium nitrate

Diethyltoluamide

Cerium nitrate is used in combination with silver sulphadiazine to treat severe burns. A 16-year-old girl experienced extensive burns over 95% of her body. After 6 days of use of cerium nitrate–silver sulphadiazine cream with daily dressing changes, she developed a bluish hue in healthy areas of the skin. Methaemoglobinaemia levels were found to be 31.8% [53].

Diethyltoluamide (DEET) has been used as an insect repellent for nearly five decades. Although it has an overall low incidence of toxic effects, prolonged use and use of high concentrations in children have been discouraged because of reports of toxic encephalopathy, seizures and death [61–70]. Although not confirmed as attributed to DEET, a death did occur in a a 6-year-old girl after only 10 applications of a 15% DEET preparation [70].

Chlorhexidine Chlorhexidine, an antimicrobial skin cleanser, was detected in low levels in the serum of preterm and term neonates with intact skin, who were bathed by standard methods. No clinical toxic effects were seen [54]. Chlorinated hydrocarbons are neurotoxic chemicals (cytotoxic to nerve cells) producing characteristic signs of CNS toxicity if given acutely in a sufficiently high dose. Chlorhexidine, however, seems to be well tolerated and is suitable to reduce umbilical cord-related infections in the neonatal period [55].

Eucalyptus oil Eucalyptus oil is commonly used to treat colds or as an insect repellant. A 6-year-old girl with a history of urticaria presented with slurred speech, ataxia and muscle weakness that progressed to unconsciousness following widespread application of a home remedy containing eucalyptus oil. Following removal of the topical preparation, her symptoms resolved within 6 hours, with no long-term sequelae [71].

Hexachlorophene Clonidine Clonidine is a direct-acting α2-adrenergic agonist used for an increasingly wide variety of conditions. Transdermal clonidine toxicity occurred in two boys using the patch for treatment of attention deficit hyperactivity disorder. A 15 year old developed drowsiness, hypotension and bradycardia after the integrity of his clonidine patch was disrupted. A 6 year old developed altered mental status and, on ECG, sinus arrhythmia with ST-T wave elevation in the precordial leads was evident. It was determined that the toxicity was due to his clonidine patch being placed over an abraded, itchy area. When the patient scratched the pruritic area, this upset the integrity of the patch and caused increased absorption of clonidine in the area of disrupted skin [56]. Two infants less than 9 months old were reported to experience bradycardia and lethargy due to clonidine toxicity. One of the infants ingested the patch while the other had oral exposure [57].

Corticosteroids Systemic effects resulting from percutaneous absorption of corticosteroids have been frequently reported, especially with respect to high-potency corticosteroids. However, 1% hydrocortisone ointment was reported to cause Cushing syndrome in an 11-year-old boy with Netherton syndrome, a congenital disease of decreased skin barrier function, after application to his entire body for more than 1 year [58]. Chronic suppression of adrenal axis function and impairment of growth hormone are risk factors in infants treated with chronic topical corticosteroids that possess significant corticosteroid activity [59,60].

Hexachlorophene was widely used in nurseries for the prevention of Staphylococcus aureus infection. In 1972 in France, as a result of the accidental addition of 6.3% of hexachlorophene to batches of baby talcum powder, 204 babies fell ill and 36 died from respiratory arrest [72–74]. Two brothers with congenital ichthyosis died after bathing with detergents containing hexachlorophene. Other cases of hexachlorophene myelinopathy caused by percutaneous absorption in premature infants have been reported [75–77]. Among affected infants, common factors were: presence of skin rashes or wounds, prematurity with low birthweight and repeated exposure to hexachlorophene [78–80]. Factors contributing to hexachlorophene toxicity in infants include a greater number of exposures to the drug, increased drug concentration, absence of adequate rinsing, presence of large areas of abraded skin, hepatic, biliary or renal disease and low birthweight. UV lights help to dechlorinate (detoxify) hexachlorophene and exert a protective effect, although it is best to avoid hexachlorophene in young children and infants. General suggestions for use of topical hexachlorophene include: limit exposure to 1–2 baths with accurate thorough rinsing; do not use in infants under 1200 g or under 35 weeks of age or on large areas of abraded skin, or in those with hepatic damage [81].

Iodine Iodine may also produce toxicity after dermal delivery. In 30 neonates admitted to an intensive care unit, who repeatedly received skin detergents with iodine antiseptic, five were found to have iodine goitre and hypothyroidism [82]. Povidone-iodine is a water-soluble iodine

Poisoning and Paediatric Skin

complex, which retains the broad-range microbicidal activity of iodine without the undesirable effects of iodine tincture. Systemic toxicity may occur when it is used on large areas of burned (non-intact) skin or on neonates [83]. Another case of povidone-iodine toxicity was reported in a 34-day-old premature infant born at 25 weeks’ gestation, after topical treatment for a scalp lesion. Topical povidone-iodine was applied three times a day for 20 days to an area with significant loss of skin and subcutaneous tissue. Thyroid-stimulating hormone and free T4 levels were elevated, leading to a laboratory diagnosis of hypothyroidism. Thyroid abnormalities resolved with thyroid hormone replacement and discontinuation of the povidone-iodine treatment [84].

Lactic acid A 21-month-old child developed irritability, agitation, muscle contractions, ataxia, fever and diarrhoea over a period of 1 week after being treated for congenital lamellar ichthyosis with a topical lactic acid 5% and propylene glycol 20% cream once weekly for a period of months. She was also treated with a glycerin-containing cream for 2 weeks as well as a 12% glycolic acid cream twice daily for 2 weeks. These were applied in excess of the amount prescribed. Blood gas showed metabolic acidosis with an anion gap of 24. Lactic acid level was elevated at 9.39 mmol/L (normal: 0.66–1.88) [85].

Lindane Lindane is the γ isomer of benzene hexachloride. Topical 1% lotion normally used for the treatment of scabies may cause significant CNS toxicity in infants and children [85–91]. A premature, malnourished infant had one application of lindane over the entire body with subsequent soap and water bath. Two days later the infant showed a marked mental and motor deficit. Serum lindane level 46 hours after application was 0.10 μg/mL(0.005 μg/mL is the mean level after treatment in infants and children) [91]. The risk of toxicity is significantly reduced when lindane is used according to directions [92]. In many countries its use in children is now completely discouraged; for scabies, permethrin ointment should be used instead.

Mafenide Mafenide acetate is a topical sulphonamide, used for the treatment of burns. Methaemoglobinaemia was detected after percutaneous absorption of mafenide over large surface areas in two children [93].

Malathion A single topical application of 0.5% malathion represents a relatively safe treatment approach to infestation [94]. However, use of the compound in higher topical concen-

184.7

trations and in the environment as a pesticide invokes a higher level of risk [95]. Four children developed systemic toxicity, including hyperglycaemia in all children and comatose status in one child, following hair washing with a solution containing 50% malathion in xylene, for the treatment of head lice [96].

Mercurials The use of mercury in medicine is becoming less common. However, attention should be paid to the possibility of mercurial poisoning, as mercury is still present in several products for human use. Patients and parents are often unaware of possible risk because product labelling may not indicate the possible hazards with use of the product. Although there are considerable absorption differences among various topical mercurial compounds, all mercurial preparations have potential risk and may be capable of producing systemic poisoning after dermal use. Some mercury compounds may be readily absorbed through skin; absorption of ammoniated mercury chloride in psoriatic patients has been demonstrated [97]. There have been some cases [98,99] of children who died following the treatment of omphalocoeles with merbromin (an organic mercurial antiseptic). Poisoning of a nursing infant has followed the use of perchloride of mercury lotion for cracked nipples [100]. Repeated cutaneous application of yellow mercuric oxide ointment for infected eczema resulted in mercury poisoning in a 4-month-old infant. Toxic levels of mercury were measured in blood, urine, cerebrospinal fluid and tissues [101]. Systemic absorption has also been observed following absorption through the oral mucosa of phenylmercury borate-containing mouthwashes from which mercury is absorbed and causes acrodynia in small children [102]. In view of the risks of topically induced systemic sideeffects as well as contact allergic reactions to mercurials, justification for continued clinical use of some of these drugs seems lacking.

Neomycin A triple antibiotic spray containing polymyxin, bacitracin and neomycin, used in neonatal intensive care, has been implicated in percutaneous toxicity. A 26-week gestational age infant received repeated and long-term topical triple antibiotic dosing and developed severe nerve deafness. The phenomenon was secondary to skin absorption of the ingredient neomycin, the most ototoxic aminoglycoside [103]. Absorption of neomycin may be increased if associated with dimethylsulphoxide. In a young girl with chronic dermatomyositis, approximately 30% of the body surface was treated with an ointment containing 1% neomycin and 11% dimethylsulphoxide for a 2-month period.

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Vertigo, nystagmus and complete loss of hearing occurred [104]. Given the fact that neomycin is also known as a potent contact allergen and a high percentage of cutaneous bacteria are neomycin resistant, this antibiotic can simply be considered obsolete.

Nicotine Acute overdose of nicotine is highly toxic. Poisoning secondary to dermal absorption of nicotine has been described following accidental application of a nicotine patch [105,106]. Symptoms reported included cutaneous rash, vomiting, diarrhoea and hypotension as well as lethargy, irritability, headache, fussiness and fatigue. Nicotine poisoning secondary to dermal absorption from a traditional remedy has also been described. An 8-year-old boy with moderate eczema developed symptoms consistent with nicotine poisoning within 30 minutes of topical application of a traditional remedy published in a book from Bangladesh. Further investigations confirmed the presence of tobacco leaves in the composition of the compound. Blood samples taken 12 hours after application of the remedy demonstrated acute nicotine poisoning [107]. Ingestion of nicotine patches with systemic toxicity has been reported [105].

Oestrogens Topical application of oestrogen-containing preparations may lead to absorption of hormones with systemic oestrogenic effects. Pseudo-precocious puberty in female infants and feminization in males resulted from 2–10 times daily topical applications of an ointment containing oestrogens for a period of 2–18 months for treatment or prevention of ammoniacal dermatitis. These oestrogens were absorbed systemically, producing not only local effects (pigmentation and pubic hair) but also distant effects such as areolar pigmentation and mammary enlargement or gynaecomastia. Female infants developed vaginal discharge and bleeding [108]. A report of four African-American girls aged 14 months to 93 months who were using oestrogen or placentacontaining hair products described breast and pubic hair development within 2–24 months of initial use of product. Discontinuing use of the hair products resulted in regression of the breasts and pubic hair [109]. The development of gynaecomastia in prepubertal boys has been described in association with indirect exposure to their mothers’ oestrogen creams and as related to oestrogen-containing ointments and hair creams [110–113].

Opioids There was a reported paediatric death due to opioid toxicity after a caregiver applied three fentanyl patches to a 4-year-old child in an attempt to alleviate the child’s pain

[57]. A 6-year-old girl developed altered mental status after her grandfather placed a transdermal fentanyl patch over a painful abrasion she developed after falling off a swingset. She recovered with administration of naloxone [114]. Another case involved an 8-month-old girl napping next to her grandmother. The infant became unresponsive and had a questionable seizure. Upon questioning, it was discovered the grandmother had been wearing a fentanyl patch that approximated the child’s skin during the nap. The child recovered at the hospital with naloxone [115].

Phenol Phenol can be applied as a local anaesthetic (0.5–2.0%) or as one component of multi-ingredient antifungals, such as Castellani’s paint (4.4% phenol). Moderate to severe toxicity has been reported after the application of 2–4% phenol in infants [116]. Use of a 2% phenol solution on an umbilical stump in a 1-day-old child produced circulatory collapse and death within 11 hours [117]. Another child similarly treated developed severe methaemoglobinaemia that required exchange blood transfusion [117]. Castellani’s solution (or paint) is an old remedy mainly used for the local treatment of fungal skin infections. It contains boric acid, fuchsin, resorcinol, water, phenol, acetone and spirit (see also boric acid, resorcinol, and alcohols). The application of Castellani’s solution to napkin eruptions and other areas where absorption is rapid may cause serious complications, as reported in a 6-month-old boy who became cyanotic with 41% methaemoglobin after two applications of Castellani’s solution on the napkin area [118]. Another case is described of a 6-week-old infant who, some hours after the application of Castellani’s paint to the entire body surface except the face for the treatment of a severe seborrhoeic eczema, became drowsy and had shallow breathing and blue urine [119]. Sixteen infants with the same dermatosis were painted twice daily for 48 hours in the napkin area and skinfolds, and phenol was detected in the urine of four of them [119]. An 11-year-old boy with xeroderma pigmentosum developed multifocal ventricular arrhythmias after undergoing phenol peeling of the face for premalignant skin lesions using a solution of 3 mL 88% phenol diluted with 2 mL distilled water and 8 drops liquid soap [120].

Podophyllin resin Podophyllin resin is a powerful skin irritant widely used in the local treatment of condylomata acuminata. Absorption of the resin may lead to severe systemic symptoms, particularly in children. A 16-year-old girl who developed major neurological complications as well as haematological and hepatic toxicity, and became comatose after

Poisoning and Paediatric Skin

one application of a 20% podophyllin tincture for vulvar warts, has been reported [121]. After 4 months the patient was still suffering from peripheral neuropathy. Another case includes a 15-year-old female who developed dizziness, nausea, vomiting and right-sided abdominal pain a few hours after application of 20% podophyllin tincture on vulvar warts [122]. The treatment was repeated the next morning and afternoon. The following morning the patient had tachycardia, fever and tachypnoea. She developed granulocytopenia and thrombocytopenia and was precomatose. The patient subsequently improved and was discharged 4 weeks after the initial application.

Pyrethrin Topical pyrethrins are commonly used in the treatment of pediculosis and scabies. Typically, their use does not result in adverse effects. One case report describes a 2-year-old otherwise healthy girl treated for head lice three times over 12 days using over-the-counter topical pyrethrin products containing 0.33% pyrethrum extract. Two days after the last treatment, the patient’s parents noted the onset of stuttering and increased clumsiness in the child. The symptoms resolved over the following weeks. Of note, the patient’s mother, who was breastfeeding the child, also had used the same treatment regimen containing pyrethrin and was asymptomatic [123].

Resorcinol Resorcinol, used for its keratolytic properties in various products, is a constituent of the antifungal Castellani’s solution. It has also been used in the treatment of leg ulcers [124]. One report included seven cases of acute poisoning causing five deaths in babies as a consequence of topical resorcinol application [125]. Another reported case included an infant treated with a 12.5% resorcinol ointment applied to the napkin area, causing cyanosis, a maculopapular eruption, haemolytic anaemia and methaemoglobinaemia [125].

Salicylic acid and salicylates Salicylate poisoning in young children is often more serious than in older children and adults because younger children might be more prone to the early development of metabolic acidosis [126] or perhaps just because of their larger body surface/weight ratio. Although ingestion of aspirin tablets is the most frequent cause of salicylate poisoning, percutaneous absorption of salicylic acid or methylsalicylate may result in significant systemic toxicity. Thirteen fatal cases following percutaneous salicylate intoxication have been reported, where 10 were in children less than 3 years of age [127]. Symptoms were those of salicylism. Children with lamellar ichthyosis have been described as developing salicylate intoxication after application of

184.9

salicylate ointment (10%) [128,129]. A newborn ‘collodion baby’ developed salicylate poisoning after treatment with topical 20% salicylate in petrolatum applied twice daily over the whole body [130]. In neonates, infants and children, salicylate intoxication may also occur inadvertently through placental transfer [131,132], breast milk [133] or by application of teething gels to the gums [134]. A 9-year-old child developed abdominal pain, nausea, constipation, mildly impaired mental performance and weakness which began within several days of initiating a topical salicylic acid 15% patch treatment (3.75 mg, 6 mm) for a plantar wart. Work-up was negative and a salicylate level was not drawn. The patch was ultimately removed, and upon rechallenge, the symptoms returned. After definitive removal, symptoms resolved completely within 2 weeks [135].

Silver nitrate Fatal methaemoglobinaemia in a 3-year-old girl, who was treated with silver nitrate solution for burns involving 82% of the body surface, has been described [136]. In children, another potential major complication following the extensive use of topical silver nitrate is electrolyte disturbance.

Tacrolimus Tacrolimus is an immunosuppressive drug used in a topical preparation in the treatment of severe atopic dermatitis, after bone marrow transplants, and for vitiligo. Toxic tacrolimus levels were reported in an 11-month-old boy with graft-versus-host disease who received two applications of topical tacrolimus to the upper extremities. Serum levels reached 23.4 ng/mL and rapidly decreased following discontinuation, with no subsequent adverse effects observed [137]. Three children with Netherton’s syndrome aged 3, 5 and 14 using topical tacrolimus 0.1% experienced significant absorption of the drug that was within or above the range used in organ transplant recipients. None of the patients experienced any adverse effects [138]. In three girls with Netherton syndrome ages 4, 8 and 8 years old, tachyphylaxis became evident in conjunction with low but detectable serum levels of tacrolimus [139].

Tars Tars have been used medicinally for a variety of purposes including for their analgesic, antimicrobial and antidandruff properties. A case of methaemoglobinaemia occurred in a 3-month-old infant with severe atopic eczema following application of an ointment containing 2.5% crude coal tar and 5% benzocaine (see also local anaesthetics) to about half the body surface for 5 days [140]. On the fifth day the infant suddenly became critically ill, cyanotic and anoxic.

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Warfarin The risk of transcutaneous intoxication by warfarin in infants has rarely been reported [141,142]. In Vietnam, the application to 741 infants of a talcum powder accidentally contaminated with the anticoagulant warfarin caused an epidemic of haemorrhagic disorders that was fatal to 177 babies [143]. References 1 Gimenez ER, Vallejo NE, Izurieta EM et al. Acute alcoholic intoxication by the percutaneous route. Clinical and experimental study. Arch Argent Pediatr 1968;66:121–35. 2 Castot A, Garnier R, Lanfranchi C et al. Effects systémiques indesiderables des médicaments appliqu sur la peau, chez l’enfant. A propos de quelques observations. Therapie 1980;35:423–32. 3 Harpin VA, Rutter N. Percutaneous alcohol absorption and skin necrosis in a preterm infant. Arch Dis Child 1982;57:477–9. 4 Puschel K. Percutaneous alcohol intoxication. Eur J Pediatr 1981;136:317–18. 5 McFadden SW, Haddow JE. Coma produced by topical application of isopropanol. Pediatrics 1969;43:622–3. 6 Vivier PM, Lewander WJ, Martin HF et al. Isopropyl alcohol intoxication in a neonate through chronic dermal exposure: a complication of culturally-based umbilical care practice. Pediatr Emerg Care 1994;10:91–3. 7 Dyer S, Mycyk MB, Arens RW et al. Hemorrhagic gastritis from topical isopropanol exposure. Ann Pharmacother 2002;36:1733–5. 8 Litovitz T. The alcohols: ethanol, methanol, isopropanol, ethylene glycol. Pediatr Clin North Am 1986;33:311–23. 9 Kahn A, Blum D. Methyl alcohol poisoning in an 8-month-old boy: an unusual route of intoxication. J Pediatr 1979;94:841–3. 10 Kalyoncu M, Dilber E, Okten A. Amitraz intoxication in children in the rural Black Sea region: analysis of forty three patients. Human Exper Toxicol 2002;21:269–72. 11 Agin H, Calkavur S, Uzun H, Bak M. Amitraz poisoning: clinical and laboratory findings. Indian Pediatr 2004;41(5):482–6. 12 Haggerty RJ. Blue baby due to methemoglobinemia. N Engl J Med 1962;267:1303. 13 Meynadier J, Peyron JL. Resorption transcutanèe des medicaments. Rev Pract 1982;32:2685–6, 2686–91. 14 Steinberg JB, Zepernick RG. Methemoglobinemia during anesthesia. J Pediatr 1962;61:885–6. 15 Olson ML, McEvoy GK. Methemoglobinemia induced by local anesthetics. Am J Hosp Pharm 1981;38:89–93. 16 Eldadah M, Fitzgerald M. Methemoglobinemia due to skin application of benzocaine. Clin Pediatr (Phila) 1993;32(11):687–8. 17 Dahshan A, Donovan GK. Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: a case report and review of the literature. Pediatrics. 2006;117:e806–9. 18 So TY, Farrington E. Topical benzocaine-induced methemoglobinemia in the pediatric population. J Pediatr Health Care 2008;22:335–9. 19 Chung NY, Batra R, Itzkevitch M, Boruchov D, Baldauf M. Severe methemoglobinemia linked to gel-type topical benzocaine use: a case report. J Emerg Med 2010;38(5):601–6. 20 Bonadio WA. TAC: a review. Pediatr Emerg Care 1989;5:128–30. 21 Wehner D, Hamilton GC. Seizures following topical application of local anesthetics to burn patients. Ann Emerg Med 1984;13: 456–8. 22 Daya MR, Burton BT, Schleiss MR et al. Recurrent seizure following mucosal application of TAC. Ann Emerg Med 1988;17:646–8. 23 Terndrup TE, Walls HC, Mariani PJ, Gavula DP, Madden CM, Cantor RM. Plasma cocaine and tetracaine levels following applica-

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tion of topical anesthesia in children. Ann Emerg Med 1992;21:162–6. Dailey RH. Fatality secondary to misuse of TAC solution. Ann Emerg Med 1988;17:159–60. Rezvani M, Hartfield D. Cocaine toxicity after laryngoscopy in an infant. Can J Clin Pharmacol 2006;13(2):e232–5. Giard MJ, Uden DL, Whitelock DJ et al. Seizures induced by oral viscous lidocaine. Clin Pharm 1983;2:110. Mofenson HC, Caraccio TR, Miller H et al. Lidocaine toxicity from topical mucosal application. Clin Pediatr 1983;22:190–2. Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol 2001;44(suppl):399–400. Rincon E, Baker RL, Iglesias AJ, Duarte AM. CNS toxicity after topical application of EMLA cream on a toddler with molluscum contagiosum. Pediatr Emerg Care 2000;16:252–4. Shachor-Meyouhas Y, Galbraith R, Shavit I. Application of topical analgesia in triage: a potential for harm. J Emerg Med 2008;35:39–41. Parker JF, Vats A, Bauer G. EMLA toxicity after application for allergy skin testing. Pediatrics 2004;113:410–11. Patranella P. Diphenhydramine toxicity due to topical application of Caladryl. Clin Pediatr 1986:25:163. McGann KP, Pribanich S, Graham JA, Browning DG. Diphenhydramine toxicity in a child with varicella. A case report. J Fam Pract 1992;35(2):210, 213–14. Bernhardt DT. Topical diphenhydramine toxicity. Wis Med J 1991;90(8):469–71. Camman R, Hennecke H, Beier R. Symptomatische Psychosen nack Kolton-Gelee-Applikation. Psychiatr Neurol Med Psychol 1971;23:426–31. Zell-Kanter M, Toerne TS, Spiegel K, Negrusz A. Doxepin toxicity in a child following topical administration. Ann Pharmacother 2000;34:328–9. Vo MY, Williamsen AR, Wassermann GS et al. Toxic reaction from topically applied doxepin in a child with eczema. Arch Dermatol 1995;131:1467–8. Page CB, Duffull SB, Whyte IM, Isbister GK. Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. QJM 2009;102(2):123–31. Ducey J, Williams DB. Transcutaneous absorption of boric acid. J Pediatr 1953;43:644–51. Brooke C, Boggs T. Boric-acid poisoning: report of a case and review of the literature. Am J Dis Child 1951;82:465–72. Baker DH, Wilson RE. The lethality of boric acid in the treatment of burns. JAMA 1963;186:1169–70. Goldbloom RB, Goldbloom A. Boric acid poisoning – report of four cases and a review of 109 cases from the world literature. J Pediatr 1953;43:631–43. Skipworth GB, Goldstain N, McBride WP. Boric acid intoxication from “medicated talcum powder”. Arch Dermatol 1967;95 :83–6. Rubenstein AD, Musher DM. Epidemic boric acid poisoning simulating staphylococcal toxic epidermal necrolysis of the newborn infant: Ritter ’s disease. J Pediatr 1970;77:884–7. Fisher R, Freimuth HC, O’Conner KAO. Boron absorption from borated talc. JAMA 1955;157:503–5. Valdes-Dapena MA, Arey JB. Boric acid poisoning. Three fatal cases with pancreatic inclusions and a review of the literature. J Pediatr 1962;61:531–46. Siegel E, Wason S. Boric acid toxicity. Pediatr Clin North Am 1986;33:363–7. Skoglund RR, Ware LL, Schanberger JE. Prolonged seizures due to contact and inhalation exposure to camphor. A case report. Clin Pediatr 1977;16:901–2.

Poisoning and Paediatric Skin 49 Committee on Drugs, American Academy of Pediatrics. Camphor revisited: focus on toxicity. Pediatrics 1994;94(1):127–8. 50 Joly C, Bouillie C, Hummel M. Intoxication aigue par le camphre administré par voie externe chez un nourrison. Ann Pediatr (Paris) 1980;27:395–6. 51 Khine H, Weiss D, Graber N, Hoffman RS, Esteban-Cruciani N, Avner JR. A cluster of children with seizures caused by camphor poisoning. Pediatrics 2009;123(5):1269–72. 52 Guilbert J, Flamant C, Hallalel F, Doummar D, Frata A, Renolleau S. Anti-flatulence treatment and status epilepticus: a case of camphor intoxication. Emerg Med J 2007;24(12):859–60. 53 Attof R, Magnin C, Bertin-Maghit M, Olivier L, Tissot S, Petit P. Methemoglobinemia by cerium nitrate poisoning. Burns 2006;32(8):1060–1. 54 Cowen J, Ellis SH, McAinsh J. Absorption of chlorhexidine from the intact skin of newborn infants. Arch Dis Child 1979;54:379–83. 55 Sankar MJ, Paul VK, Kapil A et al. Does skin cleansing with chlorhexidine affect skin condition, temperature and colonization in hospitalized preterm low birth weight infants? A randomized clinical trial. J Perinatol 2009;29:795–801. 56 Broderick-Cantwell JJ. Case study: accidental clonidine patch overdose in attention-deficit/hyperactivity disorder patients. J Am Acad Child Adolesc Psychiatry 1999;38(1):95–8. 57 Parekh D, Miller MA, Borys D, Patel PR, Levsky ME. Transdermal patch medication delivery systems and pediatric poisonings, 2002– 2006. Clin Pediatr (Phila) 2008;47:659–63. 58 Halverstam CP, Vachharajani A, Mallory SB. Cushing syndrome from percutaneous absorption of 1% hydrocortisone ointment in Netherton syndrome. Pediatr Dermatol 2007;24(1):42–5. 59 Munro DD. The effect of percutaneously absorbed steroids in hypothalamic-pituitary-adrenal function after intensive use in patients. Br J Dermatol 1976;94(suppl):67–76. 60 Borzyskowski M, Grant DB, Wells RS. Cushing’s syndrome induced by topical steroids used for the treatment of non-bullous ichthyosiform erythroderma. Clin Exp Dermatol 1976;1:337–42. 61 Edwards DL, Johnson CE. Insect-repellent-induced toxic encephalopathy in a child. Clin Pharm 1987;6:496–8. 62 Grybowksy J, Weinstein D, Ordway NK. Toxic encephalopathy apparently related to the use of an insect repellent. N Engl J Med 1961;264:289–91. 63 Heick HMC, Shipman RT, Norman MG et al. Reye-like syndrome associated with use of insect repellent in a presumed heterozygote for ornithine carbamoyl transferase deficiency. J Pediatr 1980;97:471–3. 64 De Garbino JP, Laborde A. Toxicity of an insect repellent: N-Ndiethyltoluamide. Vet Hum Toxicol 1983;25:422–3. 65 Roland EH, Jan JE, Rigg JM. Toxic encephalopathy in a child after brief exposure to insect repellents. Can Med Assoc J 1985;132:155–6. 66 Zadicoff CM. Toxic encephalopathy associated with use of insect repellent. J Pediatr 1979;95:140–2. 67 Orasky S, Roseman B, Fish D et al. Seizures temporally associated with use of DEET insect repellent – New York and Connecticut. MMWR 1989;38:678–80. 68 Osimitz TG, Murphy JV. Neurological effects associated with use of the insect repellent N,N-diethyl-m-toluamide (DEET). J Toxicol Clin Toxicol 1997;35:435–41. 69 Lipscomb JW, Kramer JE, Leikin JB. Seizure following brief exposure to the insect repellent N,N-diethyl-m-toluamide. Ann Emerg Med 1992;21:315–17. 70 Briassoulis G, Narlioglou M, Hatzis T. Toxic encephalopathy associated with use of DEET insect repellents: a case analysis of its toxicity in children. Hum Exp Toxicol 2001;20:8–14. 71 Darben T, Cominos B, Lee CT. Topical eucalyptus oil poisoning. Australas J Dermatol 1998;39:265–7.

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72 Pines WI. Hexachlorophene was too potent and too dangerous to be used as it once was? FDA Consumer 1972;6:24. 73 Anonymous. Hexachlorophene today. Lancet 1982;i:87–8. 74 Martin-Bouyer G, Lebreton R, Toga M et al. Outbreak of accidental hexachlorophene poisoning in France. Lancet 1982;i:91–5. 75 Shuman RM, Leech RW, Alvord EC Jr. Neurotoxicity of hexachlorophene in humans II. A clinicopathological study of 46 premature infants. Arch Neurol 1975;32:320–5. 76 Goutieres F, Arcardi J. Accidental percutaneous hexachlorophene intoxication in children. BMJ 1977;2:663–5. 77 Curley A, Hawk RE, Kimbrough RD et al. Dermal absorption of hexachlorophane in infants. Lancet 1971;ii:296–7. 78 Powell H, Swarmer O, Gluck L et al. Hexachlorophene myelinopathy in premature infants. J Pediatr 1973;82:976–81. 79 Menni S, Piccinno R. Cloro e cute infantile. G Ital Dermatol Venereol 1994;129:471–6. 80 Goldstein GS. Hexachlorophene poisoning. Lancet 1982;i:500. 81 Tryala EE, Hillman LS, Hillman RE et al. Clinical pharmacology of hexachlorophene in newborn infants. J Pediatr 1977;91:481–6. 82 Chabrolle JP, Rossier A. Goitre and hypothyroidism in the newborn after cutaneous absorption of iodine. Arch Dis Child 1978;53:495–8. 83 Eichenfield LF, Hardaway CA. Neonatal dermatology. Curr Opin Pediatr 1999;11(5):471–4. 84 Khashu M, Chessex P, Chanoine JP. Iodine overload and severe hypothyroidism in a premature neonate. J Pediatr Surg 2005;40:E1–4. 85 Ramírez ME, Youseef WF, Romero RG et al. Acute percutaneous lactic acid poisoning in a child. Pediatr Dermatol 2006;23:282–5. 86 Ginsburg CM, Lowry W, Reisch JS. Absorption of lindane (gamma benzene hexachloride) in infants and children. J Pediatr 1977;91:998–1000. 87 US Food and Drug Administration. FDA Public Health Advisory: Safety of Topical Lindane Products for the Treatment of Scabies and Lice. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/ucm110845.htm (accessed July 2010). 88 Lee B, Groth P. Scabies: transcutaneous poisoning during treatment. Pediatrics 1977;59:643. 89 Matsuoka LY. Convulsions following application of gamma benzene hexachloride. J Am Acad Dermatol 1981;5:98–9. 90 Bhalla M, Thami GP. Reversible neurotoxicity after an overdose of topical lindane in an infant. Pediatr Dermatol 2004;21:597–9. 91 Pramanik AK, Hansen RC. Transcutaneous gamma benzene hexachloride absorption and toxicity in infants and children. Arch Dermatol 1979;115:1224–5. 92 Solomon LM, Fahrner L, West DP. Gamma benzene hexachloride toxicity. A review. Arch Dermatol 1977;113:353–7. 93 Ohlgisser M, Adler M, Ben-Dov D et al. Methemoglobinaemia induced by mafenide acetate in children. A report of two cases. Br J Anaesth 1978;50:299–301. 94 Meinking TL, Vicaria M, Eyerdam DH et al. A randomized, investigator-blinded, time-ranging study of the comparative efficacy of 0.5% malathion gel versus Ovide Lotion (0.5% malathion) or Nix crème rinse (1% permethrin) used as labeled, for the treatment of head lice. Pediatr Dermatol 2007;24:405–11. 95 Harnly M, McLaughlin R, Bradman A, Anderson M, Gunier R. Correlating agricultural use of organophosphates with outdoor air concentrations: a particular concern for children. Environ Health Perspect 2005;113:1184–9. 96 Ramu A, Slonim EA, Eyal F. Hyperglycemia in acute malathion poisoning. Isr J Med Sci 1973;9:631–4. 97 Bork K, Morsches B, Holzmann H. Zum Problem der QuecksilberResorption aus weisser Präzipatatsalbe. Arch Dermatol Forsch 1973;248:137–43.

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98 Stanley-Brown EG, Frank JE. Mercury poisoning from application to omphalocele. JAMA 1971;216:2144–5. 99 Clark JA, Kasselberg AG, Glick AD et al. Mercury poisoning from merbromin (mercurochrome) therapy of omphalocele. Clin Pediatr 1982;21:445–7. 100 Hunt GM. Mercury poisoning in infancy. BMJ 1966;i:1482. 101 De Bont B, Lauwerys R, Govaerts H, Moulin D. Yellow mercuric oxide ointment and mercury intoxication. Eur J Pediatr 1986;145:217–18. 102 Schaad UB, Kehrer BH. Phenylhydrargyrum boricum in glycerin (Glycero-Merfen) in young children: undesirable mercury resorption in mouth mucosa even when free of lesions. Schweiz Med Wochenschr 1983;113:148–50. 103 Morrel P, Hey E, Mackee IW et al. Deafness in preterm baby associated with topical antibiotic spray containing neomycin. Lancet 1985;i:1167–8. 104 Herd JK, Cramer A, Hoak FC et al. Ototoxicity of topical neomycin augmented by dimethyl sulfoxide. Pediatrics 1967;40:905–7. 105 Woolf A, Burkhart K, Caraccio T et al. Childhood poisoning involving transdermal nicotine patches. Pediatrics 1997;99:e4. 106 Wain AA, Martin J. Can transdermal nicotine patch cause acute intoxication in a child? A case report and review of literature. Ulster Med J 2004;73:65–6. 107 Davies P, Levy S, Pahari A et al. Acute nicotine poisoning associated with a traditional remedy for eczema. Arch Dis Child 2001;85:500–2. 108 Beas F, Vargas L, Spada RP et al. Pseudoprecocious puberty in infants caused by a dermal ointment containing estrogens. J Pediatr 1969;75:127–30. 109 Tiwary CM. Premature sexual development in children following the use of estrogen- or placenta-containing hair products. Clin Pediatr (Phila) 1998;37(12):733–9. 110 Felner EI, White PC. Prepubertal gynecomastia: indirect exposure to estrogen cream. Pediatrics 2000;105:E55. 111 Halpérin DS, Sizonenko PC. Prepubertal gynecomastia following topical inunction of estrogen containing ointment. Helv Paediatr Acta 1983;38:361–6. 112 Edidin DV, Levitsky LL. Prepubertal gynecomastia associated with estrogen-containing hair cream. Am J Dis Child 1982;136: 587–8. 113 Zimmerman PA, Francis GL, Poth M. Hormone-containing cosmetics may cause signs of early sexual development. Mil Med 1995;160:628–30. 114 Meyer D, Tobias JD. Adverse effects following the inadvertent administration of opioids to infants and children. Clin Pediatr (Phila) 2005;44:499–503. 115 Behrman A, Goertemoeller S. A sticky situation: toxicity of clonidine and fentanyl transdermal patches in pediatrics. J Emerg Nurs 2007;33:290–3. 116 Department of Health and Human Services Agency for Toxic Substances and Disease Registry. Medical Management Guidelines for Phenol. www.atsdr.cdc.gov/mhmi/mmg115.html (accessed July 2010). 117 Von Hinkel GK, Kitzell HW. Phenolvergiftungen bei Neugeborenen durch kutane Resorption. Dtsch Gesundh-Wes 1968; 23:240. 118 Lundell E, Nordman R. A case of infantile poisoning by topical application of Castellani’s solution. Ann Clin Res 1973;5:404–6. 119 Rogers SCF, Burrows D, Neill D. Percutaneous absorption of phenol and methyl alcohol in Magenta Paint B.P.C. Br J Dermatol 1978;98:559–60.

120 Unlü RE, Alagöz MS, Uysal AC et al. Phenol intoxication in a child. J Craniofac Surg 2004;15(6):1010–13. 121 Slater GE, Rumack BH, Peterson RG. Podophyllum poisoning. Systemic toxicity following cutaneous application. Obstet Gynecol 1978;52:94–6. 122 Stoehr GP, Peterson AL, Taylor WJ. Systemic complications of local podophyllin therapy. Ann Intern Med 1978;89:362–3. 123 Hammond K, Leikin JB. Topical pyrethrin toxicity leading to acuteonset stuttering in a toddler. Am J Ther 2008;15:323–4. 124 Freeman S, Maibach HI. Systemic toxicity in man secondary to percutaneos absorption. In: Marks R, Plewig G (eds) The Environmental Threat to the Skin. London: Martin Dunitz, 1991. 125 Cunningham AA. Resorcin poisoning. Arch Dis Child 1956;31:173–6. 126 Winters RW, White JS, Hughes MC et al. Disturbances of acid–base equilibrium in salicylate intoxication. Pediatrics 1959;23: 260–85. 127 Van Weiss JF, Lever WF. Percutaneous salicylic acid intoxication in psoriasis. Arch Dermatol 1964;90:614–19. 128 Abdel-Magid EH, el Awad Ahmed FR. Salicylate intoxication in an infant with ichthyosis transmitted through skin ointment – a case report. Pediatrics 1994;94:939–40. 129 Chiaretti A, Schembri Wismayer D, Tortorolo L, Piastra M, Polidori G. Salicylate intoxication using a skin ointment. Acta Paediatr 1997;86:330–1. 130 Yamamura S, Kinoshita Y, Kitamura N et al. Neonatal salicylate poisoning during the treatment of a collodion baby. Clin Pediatr 2002;41:451–2. 131 Ahlfors CE, Shwer ML, Ford KB. Bilirubin–albumin binding in neonatal salicylate intoxication. Dev Pharmacol Ther 1982;4: 47–60. 132 Lynd PA, Andreasen AC, Wyatt RJ. Intrauterine salicylate intoxication in a newborn. Clin Pediatr 1976;15:912–13. 133 Clarke JH, Wilson WG. A 16-day-old breast-fed infant with metabolic acidosis caused by salicylate. Clin Pediatr 1981;20:53–4. 134 Paynter AS, Alexander FW. Salicylate intoxication caused by teething ointment. Lancet 1979;ii:1132. 135 Loraschi A, Marelli R, Crema F, Lecchini S, Cosentino M. An unusual systemic reaction associated with topical salicylic acid in a paediatric patient. Br J Clin Pharmacol 2008;66:152–3. 136 Ternberg JL, Luce E. Methemoglobinemia: a complication of the silver nitrate treatment of burns. Surgery 1968;63:328–30. 137 Prot-Labarthe S, Therrien R, Champagne MA, Duval M, Joubert C. Toxic serum levels of tacrolimus after topical administration in an infant with severe cutaneous graft-versus-host disease. Bone Marrow Transplant 2007;40:295–6. 138 Allen A, Siegfried E, Silverman R et al. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 2001;137:747–50. 139 Shah KN, Yan AC. Low but detectable serum levels of tacrolimus seen with the use of very dilute, extemporaneously compounded formulations of tacrolimus ointment in the treatment of patients with Netherton syndrome. Arch Dermatol 2006;142:1362–3. 140 Goluboff N, MacFadyen DJ. Methemoglobinemia in an infant associated with application of a tar-benzocaine ointment. J Pediatr 1955;47:222–6. 141 Green P. Haemorrhagic diathesis attributed to “warfarin” poisoning. Can Med Assoc J 1955;72:769–70. 142 Fristedt B, Sterner N. Warfarin intoxication from percutaneous absorption. Arch Environ Health 1965;11:205–8. 143 Martin-Bouyer G, Linh PD, Tuan LC et al. Epidemic of haemorrhagic disease in Vietnamese infants caused by warfarin-contaminated talcs. Lancet 1983;i:230–2.

Poisoning and Paediatric Skin

Compounds used for non-therapeutic purposes Acetylcholinesterase inhibitor (anticholinesterase) insecticides Accidental poisoning by acetylcholinesterase inhibitor (anticholinesterase) insecticides such as the organophosphates and carbamates remains an important public health problem in regions where these agents are in common usage. A report from South Africa describes 54 children suffering from severe poisoning after anticholinesterase insecticide exposure. The route of contamination was documented in 40 children. Enteral exposure was observed in 27 cases compared to eight from transcutaneous exposure. Five children had mixed exposure. No significant differences were detected in terms of the incidence of presenting clinical features such as seizures, cardiac arrhythmias or respiratory failure. Duration of ventilation, duration of hospital stay and mortality were uninfluenced by the route of exposure. Four children died. Mortality was associated with the presence of cardiac arrhythmia and respiratory failure [1]. One 4-year-old boy in Italy developed central pontine myelinolysis after his father sprayed a dilution of carbamate pesticide carbaryl on the guard dog as well as in a garden where the child spent time. Symptoms included ataxia, confusion, external ocular nerve palsies, miosis, excessive salivation and tearing. Dyspnoea and headache occurred later in his course. Carbaryl was identified in the blood and urine, but the method of exposure was not identified by the authors. Interestingly, serum sodium levels remained within normal limits during his hospital stay [2].

Aniline dye Percutaneous toxicity has been reported with aniline dye used to mark diapers. Cyanosis in infants of 3–64 days of age was attributed to absorption of aniline dye from the diaper in the occluded buttock area [3]. Another report described 12 children in Mumbai aged 4–13 years who developed shortness of breath, drowsiness and cyanosis after participating in the Holi festival, a celebration involving the throwing of coloured powders or waters on one another. One patient required intubation and mechanical ventilation. All children had acquired methaemoglobinaemia, presumed to be secondary to colours contaminated with aniline dye [4].

Arsenic A case series describes seven people in Iran who were inadvertently exposed to a solution of 30% arsenic in isopropyl alcohol. As prescribed by a dermatologist, the patients used the solution over the entire body on one occasion to treat scabies. Three of the seven were chil-

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dren: two of these were 5 years old and the third was a 16 year old. The children experienced symptoms including itching, bullae, vomiting and seizures. The 16 year old experienced tachycardia, hypotension, oliguria and respiratory distress, and ultimately died. A stock solution at the pharmacy thought to be benzoyl benzoate was tested and was found to be 30% arsenic [5].

Carbon tetrachloride Fatal poisoning has occurred in a child after liberal use of this solvent was used to remove adhesive plaster [6].

Henna Henna may be used in traditional ceremonies, as a cosmetic agent or for analgesic, anti-inflammatory or antipyretic effects. One case series described four children under the age of 4 with glucose-6-phosphate dehydrogenase (G6PD) deficiency who developed a haemolytic anaemia after their parents applied topical henna. The amount of henna applied ranged from a small area such as the palms and soles to application over the entire body. Symptoms included pallor, jaundice, red urine, vomiting, seizures and death [7]. Other similar cases of haemolytic anaemia in children with G6PD deficiency as old as 11 years of age have been described [8–10].

Naphthalene Naphthalene is commonly found in moth repellent products such as mothballs, flakes and crystals in 100% concentration. It is well absorbed following oral, dermal and inhalation exposure. Multiple cases of severe toxicity and death by dermal exposure have been documented in infants [11,12]. An impressive case is that of a 6-day-old female exposed for 3 days to diapers and blankets that had been stored in naphthalene and subsequently rinsed in water. Naphthalene’s insolubility probably precluded its removal by water. Daily baby oil rubdowns could have facilitated the dermal absorption of naphthalene, which is lipophilic. Jaundice, cyanosis and a loud flow murmur developed 2 days later. She died after 4 days. Postmortem examination showed extramedullary haematopoiesis in the heart, liver, spleen and adrenals. There were gross and microscopically evident haemoglobin deposits in the renal tubules [13]. In those reports involving both inhalation and dermal absorption, it is not clear whether one route exclusively could have contributed to the development of toxicity [13].

Paraquat Paraquat is a defoliant and contact herbicide. If ingested, paraquat is, in the majority of cases, lethal. Systemic toxicity from percutaneous absorption has also been described

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in adults, but rarely in children [14]. It may be seen also in adolescents as an occupational illness [15]. Symptoms of toxicity from cutaneous exposure to highly concentrated material include skin necrosis as well as CNS and pulmonary symptoms.

Potassium dichromate Six days after insertion of a nasal foreign body, progressive occurrence of diarrhoea, vomiting, nasal obstruction, acute renal failure, pancreatitis, hepatitis and drowsiness justified hospitalization of a 3-year-old girl. Past history revealed that the child had accidentally inserted a crystal into her nose. Acute potassium dichromate poisoning was confirmed by high plasma chromium level and by spectrophotometric analysis of the crystal [16]. References 1 Verhulst L, Waggie Z, Hatherill M et al. Presentation and outcome of severe anticholinesterase insecticide poisoning. Arch Dis Child 2002;86:352–5. 2 Santinelli R, Tolone C, d’Avanzo A, del Giudice EM, Perrone L, d’Avanzo M. Pontine myelinolysis in a child with carbamate poisoning. Clin Toxicol (Phila) 2006;44:327–8. 3 Kagan BM, Mirman B, Kalvin J et al. Cyanosis in premature infants due to aniline dye intoxication. J Pediatr 1949;34:574–8. 4 Mauskar A, Karande S, Kulkarni M. Acquired methemoglobinemia due to contaminated colours: a preventable disaster. J Trop Pediatr 2009;55:139–40. 5 Majid Cheraghali A, Haghqoo S, Shalviri G, Shariati YR, Ghassemi M, Khosravi S. Fatalities following skin exposure to arsenic. Clin Toxicol (Phila) 2007;45:965–7. 6 Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services, Public Health Service. Toxicological Profile for Carbon Tetrachloride. www.atsdr.cdc.gov/ toxprofiles/phs30.html (accessed July 2010). 7 Raupp P, Hassan JA, Varughese M et al. Henna causes life threatening haemolysis in glucose-6-phosphate dehydrogenase deficiency. Arch Dis Child 2001;85:411–12. 8 Katar S, Devecioglu C, Ozbek MN, Ecer S. Henna causes lifethreatening hyperbilirubinaemia in glucose-6-phosphate dehydrogenase deficiency. Clin Exp Dermatol 2007;32:235–6. 9 Kök AN, Ertekin MV, Ertekin V, Avci B. Henna (Lawsonia inermis Linn.) induced haemolytic anaemia in siblings. Int J Clin Pract 2004;58:530–2. 10 Devecio lu C, Katar S, Do ru O, Ta MA. Henna-induced hemolytic anemia and acute renal failure. Turk J Pediatr 2001;43:65–6. 11 Dawson JP, Thayer WW, Desforges JF. Acute hemolytic anemia in the newborn infant due to naphthalene poisoning. Report of two cases with investigation into the mechanism of the disease. Blood 1958;13:1113–25. 12 Schafer WB. Acute hemolytic anemia related to naphthalene. Report of a case in a newborn infant. Pediatrics 1951;7:172–4. 13 Siegel E, Wason S. Mothball toxicity. Pediatr Clin North Am 1986;33:369–74. 14 Roth B, Bulla M, von Lilien T, Statz A, Okonek S. Clinical findings and treatment of paraquat poisoning in childhood. Monatsschr Kinderheilk 1983;131:458–63. 15 Weinbaum Z, Samuels SJ, Schenker MB. Risk factors for occupational illnesses associated with the use of paraquat (1,1′-dimethyl-4,4′bipyridylium dichloride) in California. Arch Environ Health 1995;50:341–8.

16 André N, Paut O, Arditti J et al. Intoxication grave au dichromate de potassium après introduction nasale accidentelle. Arch Pèdiatr (Paris) 1998;5:145–8.

Cutaneous symptoms following ingestion, inhalation and injection of some toxicants Systemic poisoning by ingestion, inhalation or injection of some toxicants (see Box 184.2) may produce cutaneous symptoms. However, the reports in infants are very few.

Dioxins After an accident in a chemical plant in Seveso, Italy, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) spread over a populated area. The entire population, including children, was affected and contamination took place not only through direct exposure but also through inhalation and ingestion of contaminated foods, especially fruits and vegetables. Dermatological manifestations were recognized as early lesions and late lesions. Early lesions appeared within a few hours or a few days after the accident and were ascribed to direct cutaneous exposure to the toxic cloud or to contaminated soil. Late lesions were represented by an acneiform eruption (chloracne), which appeared some 30–60 days after the accident. Lesions were considered to have resulted from both direct exposure to TCDD and from inhalation or intake of contaminated foods. Most patients were children aged 2–10 years or adolescents. Comedo-like and cystic lesions character-

Box 184.2 Selected agents associated with cutaneous toxicity following systemic exposure in children Chemotherapeutic agents Alkylating agents • Cyclophosphamide • Decarbazine • Nitrosoureas Antibiotics • Adriamycin • Daunomycin • Actinomycin D • Bleomycin Antimetabolites • Methotrexate • 5-Fluorouracil • Cytarabine • Dioxins Hexachlorobenzene Pentachlorophenol Thallium

Poisoning and Paediatric Skin

ized the eruption; the malar area was most frequently affected, while the centrofacial region was consistently spared, as reported in other chloracne cases [1,2]. Severe cutaneous manifestations were detected in eight children, all of whom had shown early lesions. All of them showed diffuse follicular hyperkeratosis associated with comedones on the limbs. In three of these children, granuloma annulare or erythema elevatum diutinum-like lesions occurred on the palms, and two sisters had comedones and cysts of the axillae. Sequelae at follow-up consisted of cicatricial atrophy [3–5].

Hexachlorobenzene Ingestion of hexachlorobenzene, a fungicide added to wheat seedlings, was the cause of porphyria involving more than 4000 people in Eastern Turkey from 1956 to 1961 [6]. Initial symptoms mentioned by most subjects were weakness, loss of appetite, photosensitivity and development of erythema, which occurred principally on the sun-exposed areas of the skin but was often generalized with accompanying pruritus. Hyperpigmentation was maximal in exposed areas of the skin, but in most subjects the entire integument became darker. Hypertrichosis occurred principally on the forehead, cheeks, arms and legs and it was sufficiently distinctive in the age group of 5–15 years that the children were described as ‘monkey children’. Development of bullae, often up to 5 cm in size, occurred frequently, healing with severe mutilating scars. During the early period of active porphyria, those affected were irritable with colic and experienced loss of appetite, weakness and red or brown urine (porphyrinuria). Most patients were between the ages of 6 and 15 years. In some villages almost all children under the age of 2 years who had been breastfed by mothers who had eaten the contaminated wheat died of the condition known as pembe yara, which included symptoms of weakness, convulsions and localized cutaneous annular erythema.

Pentachlorophenol In 1987, a family of nine members (father, mother and seven children: boys aged 12, 8 and 4 years and girls aged 11, 9 and 3 years, and a 2-month-old infant), with intoxication by a chlorinated compound, was described [7]. The intoxication arose from ingestion of an edible oil, which had been stored in a plastic container where, presumably, it had become contaminated with hexachlorobenzene, pentachlorophenol and a mixture of chlorinated dibenzop-dioxins and chlorinated dibenzofurans. Cutaneous manifestations in the father and the four eldest children were comedones, papules, cysts and milia on the forehead, cheeks, neck, thorax, shoulders, back, buttocks, abdomen, genitals and, in two girls, on the earlobes. The father and the two eldest sons also had hypertrichosis,

184.15

hyperpigmentation of the skin, follicular hyperkeratosis and increased cutaneous fragility. The mother and the three youngest children, including the newborn baby, only had discrete papules on the cheeks. Cutaneous lesions were preceded by systemic symptoms. An outbreak of illness occurred among 20 infants in a newborn nursery and was characterized by sweating, fever, tachycardia, tachypnea, hepatomegaly and acidosis. Nine infants became very ill and two died. The epidemiological study revealed that the illness was caused by percutaneous absorption of pentachlorophenol, which was being used as an antimicrobial neutralizing agent in the terminal diaper rinse [8].

Thallium Thallium poisoning following ingestion may produce serious symptoms. With regard to skin, hair loss was consistently present [9–12]. References 1 Tindall JP. Chloracne and chloracnegens. J Am Acad Dermatol 1985;13:539–58. 2 Taylor JS. Environmental chloracne: update and overview. Ann NY Acad Sci 1979;320:295–307. 3 Caputo R, Monti M, Ermacora E et al. Cutaneous manifestations of tetrachlorobenzo-p-dioxin in children and adolescents. Follow-up 10 years after the Seveso, Italy, accident. J Am Acad Dermatol 1988;19:812–19. 4 Caputo R. Cutaneous manifestations of tetrachlorobenzo-p-dioxin in children and adolescents. In: Marks R, Plewig G (eds) The Environmental Threat to the Skin. London: Martin Dunitz, 1991. 5 Moccarelli P, Marocchi A, Brambilla P. Clinical laboratory manifestations of exposure to dioxin in children. A six-year study effects of an environmental disaster near Seveso, Italy. JAMA 1986;256:2687–95. 6 Cripps DJ, Gocmen A, Peters HA. Porfiria Turcica. Twenty years after hexachlorobenzene intoxication. Arch Dermatol 1980;116:46–50. 7 Rodriguez-Pichardo A, Camacho F. Chloracne as a consequence of a family accident with chlorinated dioxins. J Am Acad Dermatol 1990;22:1121. 8 Armstrong RW, Eichner ER, Klein DE et al. Pentachlorophenol poisoning in a nursery for newborn infants. II. Epidemiologic and toxicologic studies. J Pediatr 1969;75:317–25. 9 Heyl T, Barlow RJ. Thallium poisoning: a dermatological perspective. Br J Dermatol 1989;121:787–92. 10 Grossman H. Thallotoxicosis. Pediatrics 1955;16:865–72. 11 Niehues R, Horstkotte, Klein RM et al. Repeated ingestion with suicidal intent of potentially lethal amounts of thallium. Deutsch Med Wochenschr 1995;120:403–8. 12 Centers for Disease Control and Prevention. Thallium poisoning from eating contaminated cake – Iraq, 2008. MMWR 2008;57:1015–18.

Conclusion Although skin clearly functions as a protective barrier, substances are capable of transiting human skin and may over-ride the barrier effect to produce systemic poisoning. Alternatively, agents administered systemically may produce cutaneous toxicity.

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Chapter 184

An inadequate skin barrier, as may be found in premature infants, may be responsible for enhanced percutaneous absorption of potential toxins [1]. Although the skin barrier may be fully functional in term and older paediatric patients, this population has higher skin surface to bodyweight ratio compared to adults and is therefore a more vulnerable population for poisoning through the skin. Even though an argument could be made that percutaneous absorption through infants’ and children’s skin might be used to advantage in topical transdermal drug delivery, the risk of poisoning through the skin in this

population remains of paramount concern [2]. As this chapter illustrates, poisoning and the skin remain an important issue in paediatric patients who may be inadvertently exposed to myriad agents not intended to cause harm. References 1 Nonato LB, Kalia YN, Naik A et al. The development of skin barrier function in the neonate. In: Bronaugh RL, Maibach HI (eds) Percutaneous Absorption: Drugs, Cosmetics, Mechanisms, Methodology, 3rd edn. New York: Marcel Dekker, 1999. 2 West DP, Worobec S, Solomon LM. Pharmacology and toxicology of infant skin. J Invest Dermatol 1981;76:147–50.

185.1

C H A P T E R 185

Dermoscopy of Melanocytic Lesions in the Paediatric Population Jennifer L. DeFazio1, Ralph P. Braun2 & Ashfaq A. Marghoob1 1

Department of Dermatology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Dermatology Clinic, University Hospital Zürich, Zürich, Switzerland

2

Introduction, 185.1

Halo naevi, 185.12

Spitz naevi, 185.16

Congenital melanocytic naevi, 185.5

Differentiating benign naevi from

Conclusion, 185.21

Acquired melanocytic naevi (common and

melanoma, 185.12

dysplastic), 185.9

Introduction Melanocytic neoplasms comprise one of the most common tumours encountered in the skin of children. Some of these neoplasms are evident at birth while many others develop, become visible and/or change during life’s most biologically dynamic growth periods, namely infancy into childhood and childhood into adolescence. Although the vast majority of pigmented skin lesions in children are benign and of no consequence, some may herald a phenotype with an increased predisposition towards melanoma, others may be potential precursors to melanoma, while a few will unfortunately be malignant. The challenge for clinicians is to distinguish between these melanocytic lesions so as to appropriately direct prevention education and targeted screening to populations that will derive the most benefit from such efforts, while at the same time correctly differentiating benign naevi from melanoma. This challenge is compounded by the fact that many melanocytic naevi in childhood and adolescence are new and evolving lesions that have not yet undergone senescence. Although the presence of a new melanocytic lesion or a change within a pre-existing melanocytic lesion may be a sensitive and specific sign for melanoma in older adults, this is not true in children. Thus, the clinician evaluating melanocytic lesions in children needs not only to be aware of the primary static morphology patterns of benign naevi, but also needs to know the normal dynamic morphology of changing naevi. This knowledge may help them identify outlier lesions that do not conform

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

to benign naevus patterns or growth characteristics, thereby indirectly helping them to isolate potential malignant lesions. Patient history of symptoms, analytical analysis of the lesion, differential recognition and comparative recognition may all play a role in improving diagnostic accuracy [1]. Although the patient’s history is very important, this is often not easily obtainable in a reliable fashion from young children. Hence, thorough cutaneous examination with attention to primary morphology becomes critically important, as it is often the only information available for rendering a diagnosis. Unfortunately, relying purely upon the primary clinical morphology has proven to be a challenge since melanomas arising in children often do not manifest a clinically ominous appearance (i.e. lack the ABCD features). However, the use of dermoscopy can aid in the evaluation of skin lesions by allowing the physician to assess both the surface macroscopic and subsurface microscopic primary morphology of skin lesions. By analysing a lesion’s dermoscopic colours, structures and patterns, the clinician can enhance their diagnostic accuracy. This in turn will lead to the timely biopsy of potentially fatal cutaneous malignancies, while at the same time decreasing the unnecessary removal of many clinically atypical but benign naevi. Dermoscopy is a non-invasive, in vivo technique that allows the clinician to visualize colours and structures located at the epidermis, dermoepidermal (DE) junction and upper dermis that are otherwise not routinely visible to the unaided eye. This technique affords the dermatologist an additional tool in his or her armamentarium to more accurately evaluate and diagnose skin lesions. Multiple studies have documented the ability of dermoscopy to improve the clinician’s sensitivity, specificity and

185.2

Chapter 185

diagnostic accuracy [2–5]. Two types of dermoscopes are available, one utilizing standard light-emitting diode (LED) illumination (non-polarized dermoscopy) and the other utilizing cross-polarized LED light (polarized dermoscopy). The non-polarized dermatoscope utilizes standard LED illumination, requiring a liquid interface and direct contact between the glass plate of the dermatoscope and the lesion. The most commonly used liquids applied to the skin are isopropyl alcohol, ultrasound gel or mineral oil. In contrast, the polarized dermatoscope

does not require a liquid interface nor does it require direct skin contact as the cross-polarized light minimizes light reflectance from the cutaneous surface, allowing visualization of light reflected from deeper tissue [6,7]. In the paediatric examination, non-contact dermoscopy is often better tolerated and less traumatizing given that the instrument does not touch the patient. The presence or absence of specific dermoscopic structures and their distribution can assist in correctly classifying most skin lesions (Table 185.1). Many of the colours

Table 185.1 Dermoscopic structures and their histopathological correlations Dermoscopic structures

Definition

Histopathological correlation

Pigment network (reticulation)

Grid-like network consisting of pigmented ‘lines’ and hypopigmented ‘holes’

The lines of the network are due to melanin in keratinocytes and/or melanocytes along the epidermal rete ridges. The holes of the network correspond to the suprapapillary plate

Pseudo-network

In facial lesions, diffuse pigmentation interrupted by non-pigmented follicular openings, appearing similar to a network

Pigment in the epidermis or dermis interrupted by follicular and adnexal openings of the face

Negative network

The ‘negative’ of the pigment network, consisting of hypopigmented lines making up the grid, and dark areas filling up the ‘holes’. Sometimes the negative network resembles multiple, clustered, elongated, irregular globules, each of which is surrounded by hypopigmentation

It is believed to represent thin elongated rete ridges and large tubular melanocytic nests within a widened papillary dermis. However, it may also represent bridging of rete ridges

Structureless (homogeneous) areas

Areas devoid of dermoscopic structures but without signs of regression. These areas can be hypopigmented, but they cannot be depigmented. If the area is uniformly dark, it is referred to as a ‘blotch’ (see below). If the area is depigmented then it is referred to as a scar-like area or regression structure (see below)

Structureless hypopigmented areas are due to decreased melanin concentration or simply the fact that the areas are devoid of discernible structures. Structureless hyperpigmented areas are known as blotches and they correspond to the presence of melanin in all layers of the skin

Dots

Small, round structures that are less than 0.1 mm in diameter. They may be black, brown, grey or bluish in colour

Aggregates of melanocytes or melanin granules. Black dots represent pigment in the upper epidermis or stratum corneum. Brown dots represent pigment at the dermoepidermal junction. Grey-blue dots represent pigment in the papillary dermis

Peppering or granularity

Tiny, blue-grey granules

Melanin deposited as intracellular (mostly within melanophages) or extracellular particles in the upper dermis

Globules

Round to oval structures that may be brown, black, bluish or red in colour. They differ from dots by having a diameter greater than 0.1 mm

Nests of melanocytes in the dermis or along the DE junction. Brown globules represent naevomelanocytic nests in the upper dermis. Bluish globules represent naevomelanocytic nests in the deeper dermis. The bluish hue is due to the Tyndall effect. Black globules are due to heavily melanized naevomelanocytic nests in the upper dermis

Dermoscopy of Melanocytic Lesions

185.3

Table 185.1 Continued Dermoscopic structures

Definition

Histopathological correlation

Streaks (pseudo-pods, radial streaming)

Radially arranged, projections of dark pigment (brown to black) at the periphery of the lesion. These projections emanate from the main tumour body and extend away from the main tumour body towards uninvolved skin

Confluent junctional nests of melanocytes at the periphery of the lesion. They usually reflect radial growth of the lesion

Blotches

Dark brown to black, usually homogeneous areas of pigment that obscure the ability to see any underlying structures

Aggregates of melanin in the stratum corneum, epidermis and upper dermis

Regression structures. Also known as blue-white veil over flat areas or blue-white structure over flat areas or scar-like depigmentation

White, scar-like depigmentation, which is lighter than the surrounding skin and appears shiny white under polarized dermoscopy. It is frequently associated with a blue-white veil with adjacent blue-grey areas or peppering

Scar-like changes including fibrotic papillary dermis, lymphocytic infiltrates and/or variable numbers of melanophages

Blue-white veil over raised areas. Also known as blue-white structures over raised areas

Irregular, confluent blue pigmentation with an overlying white ‘ground glass’ haze

Aggregation of heavily pigmented cells in the dermis in combination with compact orthokeratosis of the stratum corneum

Vascular pattern

The morphology of blood vessels in melanocytic lesions includes comma vessels, dotted vessels, linear vessels, serpentine vessels, corkscrew or torturous vessels, and polymorphous vessels. In addition, the milky red area (also known as the pink veil) is also considered to be a vascular structure

The blood vessels may represent tumour neoangiogenesis or may simply represent normal dilated blood vessels in the papillary dermis. The milky red area reflects an increased vascular volume

Milia-like cysts

Round whitish or yellowish structures that shine brightly (like ‘stars in the sky’) under non-polarized dermoscopy

Intraepidermal keratin cysts

Comedo-like openings

‘Blackhead’-like plugs on the surface of the lesion

Concave clefts in the surface of the epidermis, often filled with keratin

Fingerprint-like structures

Thin light brown parallel running lines

Probably represent thin, elongated pigmented epidermal rete ridges

Ridges and fissures. Also known as gyri and sulci

An undulating and thickened epidermal surface creates gyri (ridges) and sulci (fissures). This often gives the lesion a cerebriform appearance

Wedge-shaped clefts of the surface of the epidermis often filled with keratin (fissures)

Moth-eaten border

Concave invaginations of the lesion border

Not available

Leaf-like areas

Brown to grey-blue discrete bulbous structures that form a pattern resembling a leaf

Irregular shaped tumour islands of pigmented basal cell carcinoma

Spoke-wheel-like structures

Well-circumscribed brown to grey-blue-brown radial projections meeting at a darker central hub

Tumour nests of basal cell carcinoma radiating from the follicular epithelium

Large blue-grey ovoid nests

Large, well-circumscribed bluish areas that are larger than globules

Large round to oval tumour nests of basal cell carcinoma in the dermis

Multiple blue-grey globules

Non-aggregated round well-circumscribed structures which, in the absence of a pigment network, suggest basal cell carcinoma

Small tumour nests of basal cell carcinoma in the dermis

Lacunae

Red, maroon or black lagoons

Dilated vascular spaces

Parallel patterns

On acral areas, parallel rows of pigmentation following the furrows (naevi) or ridges (melanoma) of the dermatoglyphics

Pigmented melanocytes in the furrows (crista limitants) or ridges (crista intermedia) of acral skin

Chrysalis

Bright white linear orthogonal lines that are seen only with polarized dermoscopy

Collagen in the dermis

185.4

Chapter 185

and structures seen on dermoscopy have been correlated with histopathological findings, supporting the role of dermoscopy as a bridge between gross clinical inspection and histopathological analysis [8–10] (see Table 185.1). Since visualizing lesions with a dermoscope poses neither physical discomfort nor emotional stress, it serves as the ideal looking glass to examine paediatric skin lesions. Its use, in turn, can help the clinician identify subtle clinical clues, confirm naked-eye clinical diagnoses and assist in monitoring lesions [11,12]. Needless to say, diagnostic precision is not only crucial for the proper management of the patient but it also helps in allaying the anxieties of parents, especially when the decision to perform a surgical procedure is contemplated. Dermoscopy helps in the evaluation of neoplasms (benign and malignant), inflammatory conditions such as psoriasis, infections such as molluscum and warts, infestations such as scabies and lice, just to mention a few. This chapter will focus on the key dermoscopic features of melanocytic lesions commonly encountered in the paedi-

atric population including congenital melanocytic naevi, acquired naevi, halo naevi and Spitz naevi. In addition, the dermoscopic features of melanoma will be discussed. Furthermore, this chapter will focus on lesions located on the torso and extremities. It will not discuss the dermoscopic features of lesions located on the palms, soles, nails or face. Before discussing the dermoscopic features of melanocytic lesions, it is important to first decide whether the lesion under investigation is melanocytic or nonmelanocytic in origin. The two-step dermoscopy algorithm was created to help in this endeavour (Fig. 185.1). The first step requires that the observer decide if the lesion is melanocytic or not. If the lesion is considered to be of melanocytic origin then one proceeds to the second step. In the second step the observer decides whether the melanocytic lesion is benign and can be monitored or is suspect enough to warrant a biopsy. For a lesion to be considered melanocytic, it has to have any of the following structures: network, streaks, aggregated globules,

Melanocytic lesion Level 1

Step 2

Nevus

Melanoma

Level 2

Basal cell carcinoma

Level 3

Seborrhoeic keratosis

Level 4

Angioma angiokeratoma

Level 5

Dermatofibroma

Level 6

Vascular structures in non-melanocytic tumours = keratinizing tumour, SCC, clear cell acanthoma, sebaceous hyperplasia

Level 7

Level 8

Fig. 185.1 Schematic of the two-step dermoscopy algorithm. Reproduced from Handbook of Dermoscopy with permission from Informa.

Dermoscopy of Melanocytic Lesions

homogeneous blue colour (blue naevus), parallel pattern (palms and soles) or pseudo-network (face) (Fig. 185.1, level 1). If the lesion has none of these structures and none of the structures commonly seen in non-melanocytic tumours (Fig. 185.1, levels 2–6) then it is also considered to be of melanoctyic origin (Fig. 185.1, levels 7–8). It is important to recognize that many featureless lesions can be correctly diagnosed based on their vascular structures (Fig. 185.1, levels 6–7). Furthermore, it is important to remember that a completely structureless lesion (Fig. 185.1, level 8) is considered to be of melanocytic origin. References 1 Marghoob AA, Scope A. The complexity of diagnosing melanoma. J Invest Dermatol 2009;129(1):11–13. 2 Binder M, Puespoeck-Schwarz M, Steiner A et al. Epiluminescence microscopy of small pigmented skin lesions: short-term formal training improves the diagnostic performance of dermatologists. J Am Acad Dermatol 1997;36:197–202. 3 Paganelli G, Soyer HP, Argenziano G et al. Diagnosis of pigmented skin lesions by dermoscopy: web-based training improves diagnostic performance of non-experts. Br J Dermatol 2003;148:698–702. 4 Kittler H, Pehamberger H, Wolff K, Binder M. Diagnostic accuracy of dermoscopy. Lancet 2002;3:159–65. 5 Bafounta ML, Beauchet A, Aegerter P, Saiag P. Is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? Results of a meta-analysis using techniques adapted to the evaluation of diagnostic tests. Arch Dermatol 2001;137(10):1361–3. 6 Pan Y, Gareau DS, Scope A, Rajadhyaksha M, Mullani NA, Marghoob AA. Polarized and nonpolarized dermoscopy: the explanation for the observed differences. Arch Dermatol 2008;144(6):828–9. 7 Benvenuto-Andrade C, Dusza SW, Agero AL et al. Differences between polarized light dermoscopy and immersion contact dermoscopy for the evaluation of skin lesions. Arch Dermatol 2007;143(3):329–38. 8 Yadav S, Vossaert KA, Kopf AW, Silverman M, Grin-Jorgensen C. Histopathologic correlates of structures seen on dermoscopy (epiluminescence microscopy). Am J Dermatopathol 1993;15(4):297–305. 9 Rezze GG, Scramim AP, Neves RI, Landman G. Structural correlations between dermoscopic features of cutaneous melanomas and histopathology using transverse sections. Am J Dermatopathol 2006;28(1):13–20. 10 Massi D, de Giorgi V, Soyer HP. Histopathologic correlates of dermoscopic criteria. Dermatol Clin 2001;19(2):259–68. 11 Menzies SW, Gutenev A, Avramidis M, Batrac A, McCarthy WH. Short-term digital surface microscopic monitoring of atypical or changing melanocytic lesions. Arch Dermatol 2001;137(12):1583–9. 12 Benvenuto C, Marghoob AA. Ten reasons why dermoscopy is beneficial for the evaluation of skin lesions. Expert Rev Dermatol 2006;1(3):1–6.

Congenital melanocytic naevi The presence of congenital melanocytic naevi (CMN) is determined in utero. Depending on a multitude of factors including timing of proliferation, senescence, melanin synthesis and melanin transfer, these naevi may be visible at birth or become apparent months to years thereafter.

185.5

The aforementioned factors probably also exert an influence on the clinical morphology manifested by the CMN. Although the majority of senescent CMN will not change significantly over time, some may develop focal changes, the most feared of which is the development of melanoma. The most widely used classification of CMN divides lesions into three categories based on size: small (95% clearance was achieved.

188.6

Chapter 188

(a)

(b)

Fig. 188.6 Port wine stain on the arm and hand: pre-laser treatment (left) and after six laser treatments using the pulsed dye laser over a period of 4 years (right). (Last three treatments with the Perfecta V beam, Candela.)

For everyone in the laser room it is mandatory for the eyes to be protected with suitable goggles. If the PWS is around the eye, the patient requires a laser eye shield, which is an opaque contact lens, inserted on to the eye prior to treatment. Once the child is anaesthetized it is also an opportune time to have the eyes formally examined by an ophthalmologist to exclude glaucoma and choroidal angiomas. Analgesia is given during the general anaesthetic to minimize discomfort on waking. This includes intravenous paracetamol, and diclofenac or codeine phosphate suppository. If large areas are being treated or if the site is in a painful area, such as the perineum, fentanyl can be used as an adjunct to other analgesics, given intravenously a few minutes before the child wakes up from the anaesthetic, at a dose of 1–2 μg/kg. Treatment with the short pulsed laser causes the skin to become immediately purpuric, an effect which usually takes 5–10 days to subside. With the longer pulse width lasers there is less bruising. Cooling the skin reduces the risk of postoperative complications. This is administered in conjunction with the laser treatment, by either an attached cooling device and/or a cool air machine. Immediately after laser treatment it is advisable to apply a cold compress over the treated area. If postoperative swelling is a potential cause for concern (e.g. the neck, eyes or lips), then a single dose of dexa-

methasone can be given during the procedure intravenously at a dose of 0.125–0.25 mg/kg [10]. In some cases, oral dexamethasone is given 6–8 hourly postoperatively for the first 24 h if significant swelling is expected. Postoperative skin care is very important and includes adequate analgesia and the regular application of a moisturizing cream. Blistering is uncommon and ideally should not occur. If blisters appear then we would advocate the application of an antiseptic or antibacterial cream for 5 days to minimize the risk of secondary infection. Patient selection is an important factor in relation to skin type and colour [11]. Pale skin may hyperpigment, whereas those with racially dark skin can hypopigment. This effect is also dependent on sun exposure posttreatment. Sun protection is essential. As treatment may take several years it is advisable for the child and the parents to use a high factor sunblock daily. This is particularly relevant in the summer and while on holiday in sunny climates. A sunblock cream should be continued for at least 1 year after completion of laser treatment. Atrophic or hypertrophic scarring following laser treatment with the PDL is rare, the frequency being 0.1% [12]. This can be minimized if the procedure is performed to the highest standard and if postoperative skin care is meticulous.

Laser Treatment for Cutaneous Vascular Anomalies References 1 Pratt AG. Birthmarks in infants. Arch Dermatol Syphilol 1953;67:302–5. 2 Jacobs AH, Walton RG. The incidence of birthmarks in the neonates. Pediatrics 1976;58:218–22. 3 Mulliken JB, Young AE. Vascular Birthmarks: Haemangiomas and Malformations. Philadelphia: W.B. Saunders, 1988:179–95. 4 Renfro L, Geronemus R. Anatomical differences of port wine stains in response to treatment with the pulsed dye laser. Arch Dermatol 1993:28:182–8. 5 Lanigan SW. Port wine stains on the lower limb: response to pulsed dye laser therapy. Clin Exp Dermatol 1996;21:88–92. 6 Syed S, Linward J, Kennedy H et al. Ten years’ experience of laser treatment for vascular birthmarks in children. 15th International Society for the Study of Vascular Anomalies (ISSVA), New Zealand, 2004, T8: 39 (abstract). 7 Heger M, Beek JF, Moldovan NI et al. Towards optimization of selective photothermolysis: prothromic pharmaceutical agents as potential adjuvants in laser treatment of port wine stains – a theoretical study. Thromb Haemost 2005;93:242–56. 8 Harper JI, Syed S, Linward L. Refractory port wine stains: improved response to higher fluence and longer pulsed width. 15th International Society for the Study of Vascular Anomalies (ISSVA), New Zealand, 2004, T9: 39 (abstract). 9 Huikeshoven M, Koster PH, de Borgie CA et al. Redarkening of portwine stains 10 years after pulsed-dye-laser treatment. N Engl J Med 2007;356:1235–40. 10 Neonatal and Paediatrics Pharmacists Group, Royal College of Paediatrics and Child Health. Medicines in children. 2003: 181. 11 Fitzpatrick TB. Soleil et peau. J Med Esthet 1975;2:33034. 12 Seukeran DC, Collins P, Sheehan-Dare RA. Adverse reactions following pulsed tunable dye laser treatment of port-wine stains in 701 patients. Br J Dermatol 1997;136:725–9.

(a)

188.7

Treatment of haemangiomas Haemangiomas are common, affecting 1 in 10 children, and most are uncomplicated, resolving spontaneously in 3–5 years. Indications for laser treatment of haemangiomas are as follows.

Early lesions that potentially may cause a problem Most haemangiomas are not evident at birth but appear within the first few weeks of life and then increase in size. At the earliest stage when the lesions are less than 1.5 mm in thickness, laser treatment could be considered in an attempt to reduce the proliferative growth phase (Fig. 188.7). Garden et al. [1] showed in their prospective study that PDL therapy could prevent enlargement and promote involution of capillary haemangiomas with minimal adverse effects. They stated that therapy should be initiated as early as possible, when the lesions are relatively flat, for optimal results. This was further supported by Barlow et al. [2] and Hohenleutner and Landthaler [3], showing that early proliferating haemangiomas respond well to PDL therapy. However, Batta et al. [4] disputed this in a randomized controlled study of early uncomplicated childhood haemangiomas. Our own results at Great Ormond Street Hospital have been variable, with some lesions showing a favourable response, whereas others have continued to enlarge with the focus of growth

(b)

Fig. 188.7 (a) A girl aged 32 days with an extensive, rapidly growing haemangioma on the right side of the face with almost complete closure of the right eye and ulceration of the upper lip (before treatment). (b) Two weeks after one laser treatment and starting oral steroids. The eye is now open and the ulceration of the lip is healing, with improved feeding and significant reduction in pain.

188.8

Chapter 188

seemingly occurring from the deeper component. The advent of propranolol therapy for infantile haemangiomas [5] has changed our clinical practice and reduced the need for laser treatment of early haemangiomas.

Ulcerated haemangiomas The main indication for laser treatment of haemangiomas, in our experience, is the treatment of ulceration that has failed to respond to conservative management (Fig. 188.8). Ulceration is a common complication of any haemangioma, but occurs more frequently at certain sites. The factors that lead to ulceration are multiple and include rapid growth of the lesions causing localized areas of infarction; trauma, especially from scratching and contact with irritant body fluids, such as with peri-oral and genital lesions. Ulcerated haemangiomas frequently become secondarily infected. Initial conservative treatment is daily nursing care, which can usually be carried out by the parents, and involves bathing the area with an antiseptic or astringent solution, applying a non-adhesive dressing and covering with a dry dressing. At present, at Great Ormond Street Hospital, we use dilute potassium permanganate solution for cleansing, Mepitel®, Sorbisan® and gauze pads held in place with Micropore tape or a tubular bandage, depending on the site. In addition to the change of dressings it is essential to ensure that the child has adequate analgesia and, if necessary, appropriate antibiotics. If after a period of 1–2 weeks there is no improvement, and especially if the child is in a great deal of discomfort, laser treatment should be considered. PDL treatment has been shown to be an effective treatment in promoting the healing of these ulcers and also producing rapid pain relief [6–10]. Our own experience has shown this to be a very effective treatment but it does require good nursing care postoperatively and we usually keep the child in hospital for 3 days to ensure that the nursing care is supervised and that the parents are given appropriate instruction on dressing changes at home. We are fortunate in having clinical nurse specialists who liaise with the family when the child is discharged home. In our series at Great Ormond Street Hospital we have treated more then 300 patients with ulcerated haemangiomas. The most common organisms cultured from ulcerated haemangiomas were Pseudomonas (30%) and S. aureus (19%). Treatment with propranolol for these children showed a very good response for superficial haemangiomas but in our published series of 30 children we noted that for deep ulcerations it can make the ulceration worse as seen in two of our cases [5]. These two children then had successful laser treatment to enhance healing.

Post-involution telangiectasia Most haemangiomas regress almost completely, leaving behind a mark that may not be cosmetically acceptable.

(a)

(b)

(c) Fig. 188.8 (a) Large ulcerated haemangioma on the forearm that had failed to heal after several weeks of conservative treatment, including appropriate antibiotics and dressings (before treatment). (b) Same patient 4 weeks after laser treatment. (c) Same patient 18 months after laser treatment.

Some may leave superficial telangiectasia, which at certain sites, especially on the face, require laser treatment. The results are usually excellent and treatment should be considered at any age, but ideally from 4 to 10 years old.

Laser Treatment for Cutaneous Vascular Anomalies References 1 Garden JM, Bakers AD, Paller AS. Treatment of cutaneous haemangioma by the flashlamp-pumped dye laser: prospective analysis. J Pediatr 1992;120:555–60. 2 Barlow RJ, Walker NPJ, Morley AC. Treatment of haemangiomas with 585-nm pulsed dye laser. Br J Dermatol 1996;134:700–4. 3 Hohenleutner U, Landthaler M. Laser treatment of childhood haemangioma: progress or not? Lancet 2002;360:502–3. 4 Batta K, Goodyear HM, Moss C et al. Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a one year analysis. Lancet 2002;360:521–7. 5 Manunza F, Syed S, Laguda B et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Br J Dermatol 2010;162:466–8. 6 Syed S. Treatment of ulcerated haemangiomas. Laser Meeting, Institute of Child Health, London, May 2000 (abstract). 7 Lacour M, Syed S, Linward J et al. Role of the pulsed dye laser in the management of ulcerated capillary haemangiomas. Arch Dis Child 1996;74:161–3. 8 Kim HJ, Colombo M, Frieden IJ. Ulcerated haemangiomas: clinical characteristics and response to therapy. J Am Acad Dermatol 2001;44:962–72. 9 Bruckner A, Frieden IJ. Haemangiomas of infancy. J Am Acad Dermatol 2003;48:477–93. 10 Morelli J, Tan O, Weston W. Treatment of ulcerated haemangiomas with the pulsed tunable dye laser. Am J Dis Child 1991;145:1062–4.

188.9

but are often seen in children on the cheeks (Fig. 188.9) and dorsum of the hands. Frequently, they are multiple. Most telangiectasias are isolated skin lesions with no associated disorder. Another type is matt telangiectasia, which can be seen in connective tissue disorders, in particular systemic sclerosis. Telangiectasias are also a feature of certain genetic disorders, namely essential telangiectasia, the more common autosomal dominant disorder, and Osler– Weber–Rendu syndrome, in which there are mucosal lesions with a risk of gastrointestinal bleeding. Another genetic disorder in which laser treatment is beneficial is Rothmund–Thomson syndrome. Most small superficial telangiectasia respond extremely well to the vascular PDL and most disappear completely with one or two treatments. Large vessel telangiectasias, such as those that develop on the alar sulci, may need the long pulse duration lasers [1]. Leg telangiectasias may respond well to short PDL, but venulectasias, which are relatively deep in the dermis, have wider diameters and tend to be under greater hydrostatic pressure, and therefore sclerotherapy is considered to be a more effective treatment.

Treatment of telangiectasia These are superficial blood vessels, the most common type being the spider naevus. They can occur on any site

(a)

Reference 1 Hsia J, Lowery JA, Zelickson B. Treatment of leg telangiectasia using a long-pulse dye laser at 595 nm. Laser Surg Med 1997;20:1–5.

(b)

Fig. 188.9 (a) Telangiectasia on the cheek (before treatment). (b) Same patient: removal of telangiectasia after one laser treatment.

188.10

Chapter 188

Treatment of cutis marmorata telangiectatica congenita

Treatment of inflammatory epidermal naevi

Cutis marmorata telangiectatica congenita (CMTC) is a developmental vascular disorder present from birth and characterized by a purplish reticulate and mottled discoloration of the skin. It can involve circumscribed segments of the skin but is usually widespread. The lesions of CMTC may be associated with other medical problems, namely ulceration and localized lipoatrophy at the sites of vascular discoloration, as well as other developmental abnormalities such as macrocephaly and hemihypertrophy. Pulsed dye laser therapy for this condition shows a variable response, but is often disappointing. However, if small papular lesions are noticed within the CMTC then it is worth treating, as these usually disappear after a couple of treatments reducing the risk of bleeding and increasing in size. The skin lesions have a tendency to fade and become less conspicuous with age. Often it remains most noticeable on the legs.

Inflammatory linear verrucous epidermal naevus (ILVEN) can occur in childhood, often under the age of 1 year, and usually persists but can, rarely, resolve spontaneously. The lesions tend to be pruritic and are often cosmetically unacceptable. Pulsed dye laser treatment can improve these lesions by reducing and sometimes removing the erythematous component [1,2].

Treatment of angioma serpigiosum

Other indications for vascular laser treatment

This is a rare disorder affecting the small vessels of the upper dermis and is characterized clinically by minute red or purple puncta. It usually starts in childhood and is seen mainly in female patients. Typically, the lesions appear on the lower limbs and buttocks and are unilateral and asymptomatic [1]. They respond well to PDL therapy but this does not have any effect on the progression of the condition and new lesions can continue to appear [2]. References 1 Katta R, Wagner A. Angioma serpiginosum with extensive cutaneous involvement. J Am Acad Dermatol 2000;42:384–5. 2 Long CC, Lanigan SW. Treatment of angioma serpiginosum using pulsed dye laser. Br J Dermatol 1997;136:631–2.

Treatment of the skin lesions in Goltz syndrome This condition is also known as focal dermal hypoplasia (see Chapter 133) [1]. It is inherited as an X-linked dominant trait. The skin features present as striate, atrophic and lipomatous lesions that are present from birth. Telangiectasia and hyperpigmentation and/or hypopigmentation can be associated with these lesions. Treatment with the PDL removes the telangiectasia and can improve the cosmetic appearance, especially on the face. Reference 1 Goltz RW, Peterson WC, Gorlin RJ et al. Focal dermal hypoplasia. Arch Dermatol 1962; 86: 708–17.

References 1 Alster TS. Inflammatory linear verrucous epidermal naevus: successful treatment with the 585 nm flashlamp pulsed dye laser. J Am Acad Dermatol 1994;31:513–14. 2 Sidwell R, Syed S, Harper JI. Pulsed dye laser treatment for inflammatory linear verrucous epidermal naevus. Br J Dermatol 2001;144:1267–9.

Hypertrophic, keloid and acne scars These can be improved by PDL treatment, reducing the erythema, some flattening of the scar and in many cases cessation of the itch which is often the major problem, especially the vertical cardiothoracic scars over the sternum [1–3]. The results are variable.

Chronic inflammatory skin conditions: psoriasis and eczema This is an exciting new dimension for PDL treatment. There is evidence that psoriasis lesions can be cleared following treatment with the vascular PDL [4–8]. An immunohistochemical study carried out to evaluate the role of the superficial capillary bed in the pathogenesis of psoriasis [6] demonstrated that selective photothermolysis following PDL therapy resulted in: (i) a significant reduction in endothelial cell proliferation; and (ii) a significant reduction of the CD4+ and CD8+ T-cell infiltrate in the superficial papillary dermis. In this study it was also found that there was a corresponding reduction of the epidermal thickness, thus showing an association between epidermal hyperplasia and dermal angiogenesis. At Great Ormond Street Hospital we studied the effects of the vascular PDL on discoid areas of eczema with a similar positive result (Fig. 188.10) [9,10]. Thus, the PDL may offer another option for treatment of difficult refractory localized areas of psoriasis and eczema.

Laser Treatment for Cutaneous Vascular Anomalies

(a)

188.11

(b)

Fig. 188.10 Eczema has a predilection to port wine stains perhaps because of the increased vascularity (Sidwell et al. [9]) (left side is before treatment). After laser treatment and successful removal of the port wine stain, there is no further recurrence of eczema at that site (right).

References 1 Kono T, Ercocen AR, Nakazawa H et al. The flashlamp pumped pulsed dye laser (585 nm) treatment of hypertrophic scars in Asians. Ann Plast Surg 2003;51:366–71. 2 Alster TS, Taviji EL. Hypertrophic scars and keloids: etiology and management. Am J Clin Dermatol 2003;4:235–43. 3 Patel N, Clement M. Selective non-ablasive treatment of acne scarring with 585-nm flashed pumped dye laser. Dermatol Surg 2002;28:942–5. 4 Krueger JG. The immunological basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002;46:1–23. 5 Macdonald Hull S, Goodfield M, Wood EJ et al. Active and inactive edges of psoriatic plaques: identification by tracings and investigation by laser Doppler flowmetry and immunocyto-chemical technique. J Invest Dermatol 1989;92:782–5.

6 Hern S, Allen MH, Sousa AR et al. Immunohistochemical evaluation of psoriatic plaques following selective photothermolysis of the superficial capillaries. Br J Dermatol 2001;145:45–53. 7 Katugampola GA, Rees AM, Lanigan SW. Laser treatment of psoriasis. Br J Dermatol 1995;133:909–13. 8 Zelickson BD, Mehregan DA, Wendelschfer-Crabb G et al. Clinical and histological evaluation of psoriatic plaques treated with flashlamp pulsed dye laser. J Am Acad Dermatol 1996;35:64–8. 9 Sidwell R, Syed S, Harper JI. Port wine stains and eczema. Br J Dermatol 2001;144:1269–70. 10 Syed S, Weibel L, Kennedy H, Harper JI. A pilot study showing pulsed-dye laser treatment improves localized areas of chronic atopic dermatitis. Clin Exp Dermatol 2008;33(3):243–8.

189.1

C H A P T E R 189

The Use of Resurfacing, Pigment and Depilation Lasers in Children Andrew C. Krakowski1 & Lawrence F. Eichenfield2 1

Department of Dermatology, University of California, San Diego, CA, USA San Diego Medical School, University of California; Rady Children’s Hospital, San Diego, CA, USA

2

Introduction, 189.1

Depilation, 189.3

Warts (verrucae vulgaris), 189.7

Practical considerations when utilizing

Pigmented lesions, 189.4

Other lesions, 189.8

lasers in children, 189.1

Introduction Lasers are an important modality for treating a broad set of paediatric skin conditions. With the introduction of relatively specific laser targeting of tissues, based on the principle of selective photothermolysis, lasers have become standard therapy for a variety of vascular and pigmented lesions. With continued technological developments, lasers are now utilized for a large set of other conditions as well, including hair disorders, nonpigmented birthmarks and acquired lesions, scars, and inflammatory skin diseases. Lasers are not only useful for treating the physical aspects of certain skin conditions. Laser surgery can improve a patient’s overall quality of life on a psychosocial level, helping to increase self-esteem that may improve performance and strengthen peer integration skills. Laser surgery can also help alleviate feelings of anxiety, guilt and vulnerability among caregivers. This chapter starts with a general discussion of practical considerations important in paediatric laser therapy, followed by discussion of conditions for which lasers are commonly utilized for the purposes of resurfacing, pigmentary issues and depilation, rather than by specific laser technology. Vascular lesion lasers are discussed in Chapter 188.

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Practical considerations when utilizing lasers in children General laser safety All personnel using or working around lasers must be aware of the regulations applicable to safe laser treatment. The two most common causes of laser-related accidents are fires and eye injuries; safety must be a top priority with laser use in a paediatric population. Access to the laser treatment area should be limited to essential personnel only. All participants in the laser treatment process, including patient family members, should wear properly fitted, wavelength-appropriate safety eyewear. Patients must utilize eye protection, which may include standard goggles or metal corneal shields. Opaque covers should be placed over all windows. Operating room staff should ensure that all flammable materials (hair, masks, gauze, cannulas, airways, etc.) and flammable gases (oxygen, nitrous oxide, etc.) commonly used in general anesthesia are appropriately shielded from the laser [1]. Flammable agents should not be used to clean the skin, and it is wise to protect untreated surrounding zones of skin with wet gauze. Lasers should always be placed in ‘stand-by’ mode when not in active use.

Preoperative management Laser surgery may often require multiple treatment sessions, and laser care plans are helpful, delineating the expected number and frequency of laser treatments over time and establishing what are the reasonable expectations of successful therapy. The costs of therapy may be considerable, so insurance coverage and expected out-ofpocket expenses may need to be considered in the decision making. A discussion of planned methods of pain

189.2

Chapter 189

management, the laser procedure itself, and an acknowledgement of potential risks and complications are appropriate in advance of the procedure. Ideally, legal minors should be able to offer their assent to laser procedures. Baseline photographs can be very useful to assess clinical response over time, and review of ‘before-and-after ’ photographs may help to establish a reasonable level of patient and caregiver expectation. Patients and caregivers should be instructed that sunburn and suntan may absorb laser light and make treatments less effective and lead to increased risk of postinflammatory pigment changes. Patients should, therefore, avoid direct sun exposure to the area to be treated for several weeks prior to procedures. Likewise, unless otherwise medically indicated, aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen should be avoided prior to treatment in order to avoid excessive bruising.

Perioperative management The type of laser being used is a key factor in pain management. For example, the sensation that results from using a device like the flashlamp-pumped pulsed dye laser has been described as feeling ‘like a rubber band being snapped against the skin’ and it is not uncommon for tingling or burning sensations to persist for up to several hours after treatment. While many adults may be able to tolerate even moderately large laser procedures without anaesthesia, paediatric patients may require more complicated pre- and postoperative preparations. This is particularly important in conditions where multiple treatments are necessary since the paediatric patient’s level of comfort depends not only on pain management at a specific moment in time but also on how noxious stimuli (either real or perceived) are managed as a cumulative experience of each preceding visit. The adage that ‘you never get a second chance to make a first impression’ certainly applies to paediatric laser surgery. Consequently, the spectrum of laser surgery pain control ranges from nothing at all via topical anaesthetics, local intradermal injections, localized nerve blocks and light sedation to general anaesthesia. For topical anaesthesia, the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine in a ratio of 1:1 by weight (EMLA Cream, AstraZeneca, Wilmington, DE) may be applied to intact skin under an occlusive dressing for at least 1 hour; maximum dermal analgesia is achieved at 2–3 hours and persists for 1–2 hours after removal. Onset of action is much faster (5–10 minutes) when applied to oral or genital mucosa. Dermal application of the cream may cause a transient, local blanching followed by a transient, local erythema. The patient should be supplied with dressings such as Tegaderm for purposes of occlusion and specific instructions on how to utilize this medi-

cine safely. EMLA contains prilocaine, which has been associated with methaemoglobinaemia in children. Alternatively, liposomal lidocaine 4% cream (LMX, formerly known as Ela-Max, Ferndale Laboratories, Ferndale, MI) does not need to be applied under occlusion to be effective. It has been shown to be as effective as EMLA cream with a fast onset of action and excellent safety profile. Refer to Chapter 190 for more information on paediatric anaesthesia. In those cases where topical anaesthesia does not provide the safe co-operation of the patient, the paediatric laser surgeon must consider other options. Topical anaesthetics may be used in conjunction with oral analgesics. Intradermal 1% lidocaine solution can effectively reduce or eliminate pain on a local basis. While some pain and anxiety are associated with the injection itself, the anaesthetic procedure makes the laser treatments much more tolerable for most patients. General anaesthesia must be considered when immobility is required for safety purposes or when large lesions covering multiple dermatomes are being treated. General anaesthesia allows for the treatment of large areas during one session and is extremely helpful when patient immobilization is demanded and cannot be obtained in the normal office setting. For obvious reasons, general anaesthesia on children should only be administered by paediatrics-trained physicians in an environment with quick and easy access to the monitoring equipment and support systems to handle the rare but deadly serious emergencies that can arise [2].

Postoperative management Depending on the laser and technique used, treated skin may be overly sensitive to the sun, and patients should avoid direct sun exposure for several months; a sunscreen that protects against both UVB and UVA with an SPF 30 or greater is recommended. Likewise, a purplish discoloration may appear at the treatment site with lasers used for treating vascular, pigmentary or hair disorders and occurs immediately after treatment. This discoloration may persist for 7–10 days but should fade to red and, subsequently, to normal skin colour over the course of several weeks. Crusting is common in the first several days and may last up to 2 weeks. There is always the possibility of temporary hypo- or hyperpigmentation of the skin that may last for several months. Caregivers should be forewarned of these skin changes in order to avoid unnecessary anxiety and ill will. References 1 Waldorf HA, Kauvar ANB, Geronemus RG, Leffell DJ. Remote fire with pulsed dye laser: risk and prevention. J Am Acad Dermatol 1996;34:503–6. 2 Chapas AM, Geronemus RG. Our approach to pediatric dermatology laser surgery. Lasers Surg Med 2005;37:255–63.

The Use of Resurfacing, Pigment and Depilation Lasers in Children

Depilation Hirsutism and hypertrichosis Hirsutism is excessive androgen-dependent growth of terminal hair. It may arise secondary to endocrinopathies, such as polycystic ovarian syndrome (PCOS), from physiological variants of hair growth with normal hormonal status, or idiopathically. Generalized hypertrichosis, which is not androgen dependent, can be congenital (e.g. hypertrichosis lanuginosa, Ambras syndrome, Cornelia de Lange syndrome, etc.) or acquired (e.g. secondary to phenytoin or ciclosporin administration). Local hypertrichosis may frequently occur within melanocytic naevi, Becker naevi, other hamartomas, in association with pilonidal cysts, or it may be idiopathic. Familial, ethnic/racial variations and cultural expectations play a role in the presentation of hypertrichosis. In addition, hair-bearing skin surfaces in non-hair bearing skin regions secondary to plastic reconstruction may benefit from hair removal lasers (Fig. 189.1). Current laser technologies for depilation are primarily based upon mechanisms of selective photothermolysis [1]. By targeting and heating melanin-rich structures in the hair follicle, it is possible to affect the stem cells of the bulge and/or the matrix cells of the bulb. The goal is to maximize the ratio of bulb/bulge damage to epidermal heating. Individuals with dark hair and pale skin are optimal responders; conversely, patients with grey or blond hair tend to respond less well because there may be insufficient melanin to absorb laser energy. A variety of techniques may improve treatment response, including varying pulse durations, wavelengths, and application of epidermal cooling. The safety and tolerability of laser hair removal in children remain less well characterized in the literature and are extrapolated from experience in adults. In adults, laser hair removal is an established treatment for hyper-

189.3

trichosis that is safe, well tolerated and may be associated with improvement in quality of life. One meta-analysis showed that laser hair removal may be more effective short term than shaving, waxing, electrolysis and epilation [2]. A broad set of lasers and light sources have been utilized for hair removal in adults, while the specific paediatric literature remains limited. In general, the long-pulsed ruby (694 nm), long-pulsed alexandrite (755 nm) and diode (800–810 nm) lasers have been used with Fitzpatrick skin types II–IV with appropriate surface cooling. The long-pulsed alexandrite with cryogen cooling at fluences of 16–32 J/cm2 and long-pulsed alexandrite with continuous chilled-air cooling at fluences of 16–27 J/cm2 have both been used in paediatric patients with lighter skin. YAG lasers are ideal for treating dark skin or hair that is very thick and black. The long-pulsed Nd:YAG (1064 nm) with a chilled contact sapphire tip at fluences of 20–35 J/cm2 or a long-pulsed Nd:YAG with cryogen cooling air fluences of 16–26 J/cm2 have been used to successfully treat children with Fitzpatrick skin types IV–VI [3]. Intense pulsed light (IPL) has also been used. Patients should be warned that high-power, highenergy treatments may cause transient crusting of the skin. Long-term complications include paradoxical laserinduced hair growth, pain, scarring and postinflammatory pigment changes (especially in patients with darker skin types), though the incidence of these side-effects remains low. Normal hair regrowth occurs quite commonly and should be anticipated; 4–6 treatments per year is usually sufficient to effectively control hair growth in the majority of patients. Even without retreatments, hair regrowth is often less dense (i.e. returning individual hairs are thinner), and it may take several years before hair regrowth fully returns to its previous state. Unlike most adults, younger children may not be able to tolerate hair laser treatment without anaesthesia, and special care

Fig. 189.1 Adolescent female with hirsutism associated with hyperandrogenism and polycystic ovary disease before therapy and 4 months after four long-pulsed alexandrite laser procedures.

189.4

Chapter 189

with pain relief is encouraged. General anaesthesia is appropriate for younger children with extensive treatment areas. The administration of long-acting local anaesthetic nerve blocks after treatment may also be helpful in the recovery phase. The speed and effectiveness of treatment vary with the machine, the patient’s adherence to surgical pre- and postoperative protocols, and the experience of the laser surgeon. Overall, depilation by laser is well tolerated in children if administered appropriately.

Pseudo-folliculitis barbae Numerous laser technologies have been used to treat pseudo-folliculitis barbae (PFB), a chronic inflammatory disease of hair-bearing areas induced by plucking or shaving of curved hairs. In this condition, the sharpened hair remnants may penetrate the skin and incite a foreign body reaction that can lead to formation of papules, papulopustules and, rarely, hypertrophic scars and keloids. Postinflammatory hyperpigmentation is a common sequela. Much of the reported use of lasers as therapy for PFB comes from dermatological surgeons treating the condition in the US military. The 810 nm diode, long-pulsed Nd:YAG and long-pulsed alexandrite lasers have been utilized for this purpose. The long-pulsed Nd:YAG (40– 100 J/cm2 fluences) remains the modality of choice for Fitzpatrick skin types IV, V and VI [4]. References 1 Anderson RR, Parrish LA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983;220: 224–7. 2 Haedersdal M, Wulf HC. Evidence based review of hair removal using lasers and light sources. J Eur Acad Dermatol Venerol 2006;20: 9–20. 3 Rajpar SF, Hague JS, Abdullah A, Lanigan SW. 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(6):684–7. 4 Ross E, Cooke L, Timko A, Overstreet KA, Graham BS, Barnette DJ. Treatment of pseudofolliculitis barbae in skin types IV, V, and VI with a long-pulsed neodymium:yttrium aluminum garnet laser. J Am Acad Dermatol 2002;47:263–70.

Pigmented lesions [1] Melanin, the main chromophore of the epidermis, possesses a wide absorption spectrum that slowly decreases from the ultraviolet to the near-infrared. This makes it well suited for treatment by a number of highly selective Q-switched lasers, such as the Q-switched frequencydoubled Nd:YAG (532 nm), Q-switched ruby (694 nm), Q-switched alexandrite (755 nm) and Q-switched Nd:YAG (1064 nm). Less pigment-selective lasers, such as the long-

pulsed ruby (694 nm), variable-pulsed diode (800–810 nm) and long-pulsed Nd:YAG lasers, are particularly useful for targeting larger pigmented structures. Ablative lasers, such as the carbon dioxide (10,600 nm) and erbium:YAG (2940 nm) lasers, are not pigment specific and have been used to remove superficial pigmented lesions via nonspecific destruction.

Naevus of Ota and naevus of Ito Naevus of Ota, involving areas of the face supplied by the first and second divisions of the trigeminal nerve, and naevus of Ito (naevus fuscocoeruleus acromiodeltoideus), usually presenting on the neck, shoulder or upper arm, are anatomic-specific presentations of the same underlying condition. They consist, histologically, of elongated dendritic melanocytes scattered among collagen bundles in the upper portion of the dermis. Unlike dermal melanocytosis, these lesions do not disappear spontaneously. In fact, darkening of lesions has been noted during and after puberty. These disorders are almost always benign, though rare transformation to malignant melanoma has been reported in naevus of Ota, most frequently among white patients. Because several studies suggest that treatment of children for these lesions produces complete clearance faster than treatment of similar lesions in adults, many paediatric laser surgeons advocate early intervention [2]. The concentration of pigment in naevus of Ota and Ito is reduced as compared to lentigines or café-au-lait macules. Consequently, it is difficult for these pigmented dermal lesions to become heated enough using longpulsed technologies such that sufficient pigment reduction can be achieved. Short pulses of Q-switched technologies, however, are capable of delivering the energy required for selective heating of these lesions. Q-switched lasers utilize high energy delivered in short pulses, allowing significant fragmentation of pigment; they are standardly utilized for naevus of Ota and Ito. Several specific lasers have been utilized to treat these lesions, including the Q-switched ruby, alexandrite and Nd:YAG lasers [3]. The Q-switched Nd:YAG (1064 nm) laser is particularly useful for lesions on darker skin types (Figs 189.2, 189.3). In patients with lighter skin types, the Q-switched ruby laser (1–7 treatments at fluences of 9–10 J/cm2 with 5 mm spot size) has been demonstrated to be a very safe and effective treatment modality [4]. The risk of postinflammatory pigment change should be addressed, and the need for multiple treatment sessions should be anticipated. Lesions that involve the periorbital areas and those of a predominantly blue-green colour (reflecting a greater depth than the predominantly brown lesions) tend to require more treatment sessions. Acquired dermal melanocytosis (aka Hori naevus) is less amenable to laser treatment than true naevi of Ota and Ito. In adults,

The Use of Resurfacing, Pigment and Depilation Lasers in Children

189.5

Fig. 189.2 Naevus of Ota. Typical blue-grey appearance prior to a series of treatments with a Q-switched Nd:YAG laser.

Fig. 189.3 Naevus of Ota. Intraoperative image showing punctate petechiae immediately after laser treatment.

initial topical bleaching with tretinoin 0.1% and hydroquinone 5% ointment containing 7% lactic acid has been used to help reduce epidermal melanin prior to laser surgery. This has not been fully investigated in the paediatric age group.

Café-au-lait macules Café-au-lait macules are superficial, discrete, homogenously coloured, light tan to dark brown macules or patches, which develop in childhood and can increase with age. While single lesions are common in healthy people, multiple café-au-lait macules may be associated with systemic conditions (e.g. neurofibromatosis, McCune–Albright, Bloom, Silver–Russell, Watson, and

Westerhof syndromes). These lesions have no reported tendency toward malignant transformation, so treatment usually focuses on minimizing deformity. Several lasers have been reported to lighten café-au-lait macules with variable responses. ‘Long-pulsed’ lasers (i.e. on the order of milliseconds) mostly in the visible light spectrum have been used with some reported success. Intense pulsed light devices and long-pulsed alexandrite, diode and KTP lasers have also been used to gently heat static epidermal pigmented lesions. These lasers possess an excellent safety profile, but multiple treatment sessions are usually required and complete clearance does not always occur. Treatment with a Q-switched ruby or Q-switched alexandrite works well in patients with lighter skin types (Fitzpatrick I–IV); whitening at the lowest fluences is a clinical sign of effective treatment. Other options include the 510 pigmented dye laser, frequency-doubled Nd:YAG (532 nm) laser, especially in darker skin types, Er:YAG resurfacing, and the carbon dioxide (CO2) laser used at low power. Café-au-lait macules may recur after laser therapy and in some cases, hyperpigmentation – occasionally permanent – may occur in treated areas. Other studies have reported clearing without recurrence with various laser technologies. Most follow-up studies to date have demonstrated that recurrence of pigmentation may occur and multiple treatments are to be expected.

Dermal melanocytosis (Mongolian spots) These deep brown to bluish-grey macules or patches typically occur in the lumbosacral areas, buttocks and, less commonly, the lower limbs, flanks and shoulders of otherwise normal infants. Their distinctive slate blue to blueblack colour is a result of the Tyndall effect, a phenomenon

189.6

Chapter 189

of light scattering in the skin. Light rays with long wavelengths (e.g. red, orange and yellow) are less scattered after striking melanin and pass through the skin relatively free from disruption. Colours with shorter wavelengths (e.g. blue, purple and violet), however, strike melanin and scatter back to the skin’s surface, creating the slate grey colour characteristic of these lesions. Dermal melanocytosis is very common in Asian, African-American, Hispanic and Native American newborns. The condition is almost always present at birth and tends to fade during the first several years of life, though lesions have rarely been known to persist into adulthood. Treatment is usually unnecessary; however, good results have been obtained using the Q-switched ruby and Q-switched Nd:YAG lasers [5]. Postinflammatory pigmentation change is a concern.

Becker naevus (pigmented hairy epidermal naevus) The Becker naevus is characterized by the presence of a sharply demarcated, irregularly bordered, light or dark brown patch with hypertrichosis, usually on the shoulder. It primarily manifests in young men with onset of puberty. Though malignant transformation is not thought to occur, Becker naevus can cause significant cosmetic concerns for affected patients, most of whom are adolescents already overly concerned with body image. Multiple lasers have been used to treat these lesions, with mixed results. While pigment-specific Q-switched alexandrite, Nd:YAG and ruby lasers possess an excellent safety and tolerability profile, persistence and recurrence are common problems. Repigmentation in these cases is thought to be related to the persistence of deep hair follicle melanocytes that remain unchanged after Q-switched treatments. For this reason, long-pulsed ruby (694 nm) and long-pulsed alexandrite (755 nm) lasers have gained consideration for their ability to decrease both pigmentation and hair density. The extended pulse duration (3 ms) of the long-pulsed alexandrite, for example, more thoroughly heats the pigmented follicle, damages deep hair follicle melanocytes and, theoretically, reduces the likelihood of long-term repigmentation. Other lasers, such as the 2940 nm erbium:YAG laser, have been used to target tissue water in order to remove the entire epidermis and varying thicknesses of the dermis. Post-treatment erythema, oedema, burning and crusting have been known to occur, along with pigmentary changes, herpes simplex infection, milia formation and scarring. Fractional resurfacing lasers, such as the 1550 nm wavelength erbium-doped fibre laser (6–10 mJ; multiple treatment sessions), may be a promising new treatment modality for Becker naevus [6]. Because surrounding skin is effectively spared, epidermal repair is fairly quick between treatment sessions and with poten-

tially fewer adverse events than traditional ablative laser techniques. Of note, the hypertrichosis associated with Becker naevus has not been reported to improve with current fractional resurfacing techniques. Consequently, optimal treatment may require the combination of multiple lasers.

Lentigines These small, flat, circular or oval, discrete brown lesions range in size from 1 to 15 mm in diameter. They reflect an increase in the number of melanocytes at the dermoepidermal junction without formation of nests, and they may involve any cutaneous surface, including the conjunctiva and oral mucosa in a scattered distribution. They may be present at birth or acquired and can suggest the presence of an underlying disorder such as Peutz–Jeghers syndrome, multiple lentiginosis/LEOPARD syndrome and Carney complex. Lentigines are themselves entirely benign; however, patients may seek treatment to minimize deformity or improve cosmesis. Q-switched 532 nm, ruby and alexandrite lasers have all been used with good success. The long-pulsed 532 nm (KTP), IPL, 810 nm diode and long-pulsed alexandrite have also been used. The CO2 or erbium:YAG lasers are options for resurfacing after non-selective epidermal destruction.

Linear verrucous epidermal naevi Linear verrucous epidermal naevi, with their tendency to thicken over time, can pose significant concerns to patients. These lesions may tend to respond well to ablation by carbon dioxide and erbium:YAG (2940 nm) lasers; only a limited number of passes is required before the lesion separates from the dermis. The residual wound usually heals well, though long-term follow-up is limited in the literature. Risks include hypertrophic scarring and recurrence. Inflammatory linear verrucous epidermal naevi (ILVEN), more specifically, have been treated using the 585 nm flashlamp-pumped pulsed dye laser in a paediatric population. While the exact mechanism of action is unknown, the pulsed dye laser is known to destroy capillaries, which may inhibit the release of inflammatory mediators [7]. The carbon dioxide laser has also been to treat ILVEN in at least one case report [8].

Congenital melanocytic naevi Laser technologies have been attempted as an alternative means of removing as many melanocytes as possible and reducing the risk for malignant transformation. The possibility that thermally damaged residual naevus cells may persist in remodelled dermal connective tissue (i.e. scar tissue) remains the focus of much debate. The decision to use laser as a treatment for congenital naevi is based on a number of factors which include, but are not limited to, the

The Use of Resurfacing, Pigment and Depilation Lasers in Children

following: the size of the lesion; the location of the lesion; the ability to follow it clinically; the lesion’s known histology and malignant potential; the surgeon’s experience; the risk of general anaesthesia; the patient’s family history of melanoma; and the wishes of the patient and caregivers. One treatment strategy for the consideration of laser surgery for congenital melanocytic lesions is as follows. If a congenital naevus is located in an area that lends itself to a technically simple and cosmetically acceptable excision, then surgery remains the ‘gold standard’. If a lesion cannot be excised, due to either technical or cosmetic constraints, then laser becomes a potential treatment modality; numerous lesions or lesions covering large surface areas over multiple cosmetic units are good examples. The balance of utility of laser treatment versus unknown effects on the course of residual naevomelanocytes should be considered and discussed with patients. Use of the normal-mode ruby laser and the Q-switched ruby laser, both used separately and in conjunction with one another, has been reported [9]. Likewise, good clinical outcomes using non-selective CO2 have also been reported. Long-term studies (>10 years) of malignant potential in lesions treated with energy remain a priority for paediatric laser surgeons.

Tattoos Estimates of tattoo prevalence are as high as 25% of all US adults and they are increasingly common in adolescents. Dissatisfaction is a common problem leading individuals to request laser tattoo removal. Proceed cautiously with laser removal as the FDA does not regulate tattoos, so it is not always clear exactly what materials are being targeted. Likewise, the high energies pulsed by Q-switched lasers (of the order of 109 Watts/cm2) interact with the pigmented materials and may alter them chemically, physically or thermally. While the mechanism of tattoo removal is not entirely understood, it is believed to be related to selective photothermolysis and subsequent fragmentation, cavitation stem effect and inflammatory reactions. Q-switched lasers, like the Q-switched ruby, alexandrite, Nd:YAG and frequency-doubled Nd:YAG (532 nm), are the workhorses. These lasers produce very high powers in short pulses (1–10 nanoseconds) with good thermal confinement, leading to safe and effective tattoo removal. As certain tattoo pigments are well known to darken (e.g. beiges and ‘flesh’-coloured pigments), a test treatment is suggested, and absorption spectra analysis may help guide specific therapy. Postinflammatory pigment change is always a concern. Of note, the lasing of tattoo pigment may result in pathogenic tissue spatter, and Q-switched lasers are all potent retinal hazards. Additionally, patients have been known to spike fevers after laser tattoo removal treat-

189.7

ment, and cases of systemic allergic reactions to sensitizing tattoo material have been reported [10].

Minocycline-induced hyperpigmentation The Q-switched ruby (694 nm), alexandrite (755 nm) and Nd:YAG (1064 nm) lasers have been reported to successfully treat the blue-black hyperpigmentation associated with oral minocycline use [11]. References 1 Hague JS, Lanigan SW. Laser treatment of pigmented lesions in clinical practice: a retrospective case series and patient satisfaction survey. Clin Exp Dermatol 2008;33:139–41. 2 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(5):391–5. 3 Wang HW, Liu YH, Zang GK et al. Analysis of 602 Chinese cases of nevus of ota and the treatment results by Q-switched alexandrite laser. Dermatol Surg 2007;33:455–60. 4 Geronemus RG. Q-switched ruby laser therapy of nevus of Ota. Arch Dermatol 1992;128(12):1618–22. 5 Kagami S, Asahina A, Watanabe R et al. Laser treatment of 26 Japanese patients with Mongolian spots. Dermatol Surg 2008;34: 1689–94. 6 Glaich AS, Goldberg LH, Dai T et al. Fractional resurfacing: a new therapeutic modality for Becker ’s nevus. Arch Dermatol 2007;143: 1488–90. 7 Sidwell RU, Syed S, Harper JI. Pulsed dye laser for inflammatory linear verrucous epidermal nevus. Br J Dermatol 2001;144:1267–9. 8 Ulkur E, Celikoz B, Yuksel F, Karagoz H. Carbon dioxide laser therapy for an inflammatory linear verrucous epidermal nevus: a case report. Aesthet Plast Surg 2004;28:428–30. 9 Waldorf HA, Kauvar AN, Geronemus RG. Treatment of small and medium congenital nevi with the Q-switched ruby laser. Arch Dermatol 1996;132(3):301–4. 10 Ashinoff R, Levine VJ, Soter NA. Allergic reactions to tattoo pigment after laser treatment. Dermatol Surg 1995;4:291–4. 11 Tsao H, Busam K, Barnhill RL et al. Treatment of minocycline-induced hyperpigmentation with the Q-switched ruby laser. Arch Dermatol 1996;132:1250–1.

Warts (verrucae vulgaris) It is common for children to have one or more warts during childhood. Many treatments have been used for viral warts, but cure rates vary widely depending on the subtypes of warts, the skill and training of the physicians providing treatments, and the chosen treatment modality [1]. Traditional management methods include cryotherapy, intralesional injection of antigens, topical immune response modifier, topical immunotherapy with contact sensitizer, curettage, antimitotic agents, photodynamic therapy and oral cimetidine. A single ideal treatment remains to be determined. Some children, for example those immunosuppressed after organ transplantation or chemotherapy or those with a congenital immune deficiency disorder, can

189.8

Chapter 189

develop huge numbers of large warts that are recalcitrant to traditional treatment modalities. For this population, laser surgery with a pulsed dye laser (PDL) or carbon dioxide laser may be an appropriate alternative. Safety, tolerability and cost-effectiveness (potentially fewer number of treatment sessions with laser surgery compared to other modalities) must also be considered. Multiple investigations have studied PDL treatment for viral warts, and this treatment has been reported to be safe and tolerable. Studies on the efficacy of PDL are mixed at best. In one randomized controlled trial, PDL efficacy was equivalent to cryosurgery; however, other reported cure rates have ranged from 0% to 100% [2]. This wide range may result from differences in the techniques of PDL treatment and variations in the characteristics of treated warts. It may also be a referral bias (i.e. the laser surgeon may be managing the most treatment-resistant cases). Although the mechanism of action for PDL treatment for viral warts is not known, it is thought that this method of laser surgery primarily targets the superficial dilated capillaries in warts. Through selective photothermolysis of oxyhaemoglobin within the microvasculature, the wart’s blood supply may be specifically destroyed. For this reason, paring down the hyperkeratotic surface of warts to the extent that blood vessels are seen, without causing bleeding, may aid PDL treatment. Additionally, cells infected with the human papilloma virus are heat sensitive, and it has been postulated that the damage of virally infected keratinocytes by PDL may contribute to the destructive process. Multiple stacked pulses using 7 mm spot, 12 joules/cm2, 1.5 ms is a good starting point, but multiple sessions are required. Likewise, plantar and palmar warts typically require a more aggressive approach. The carbon dioxide and Er:YAG lasers are capable of precision ablation, and the size of the treatment footprint can be varied for small lesions [3]. Consequently, viral papillomas may be removed with a thin, highly focused beam of short pulses of continuous wave treatment. Although laser ablation achieves good cure rates, recurrences are common. Many patients require multiple treatments, and management of immunocompromised or immunodeficient children may be extremely challenging. In general, greater success is achieved with facial warts than with hand or plantar warts; plantar warts contain the highest concentration of viral particles. Two techniques can help improve ablative laser results. First, large lesions should have their hyperkeratotic surfaces pared down to a level where bleeding starts to occur before using the laser. This saves time because plantar tissue has relatively low water content, making it more difficult to remove with the carbon dioxide and Er:YAG lasers. Second, a perilesional border of 1–5 mm of normal skin should be vaporized along with the primary lesion; because wart virus can be found in normal perilesional

epidermis up to 1 cm from lesions, ablating a border may help to decrease recurrence. Several safety considerations must be borne in mind when treating viral warts with the carbon dioxide and Er:YAG lasers. When these lasers are passed across the shaved wart several times, a cleavage plane may develop at the epidermal junction. In the case of periungal warts, care must be taken to preserve the growing nailbed. Likewise, the plume of smoke generated by tissue ablation requires the use of a high-pressure smoke evacuation system. It is also important to wear fine-particle filtration masks during treatment. While natural transmission of human papilloma virus is unlikely, intact viral DNA has been detected in the plume. The motto ‘Better safe than sorry!’ should be employed when lasing warts and other potentially infectious agents. Although laser ablation is capable of achieving good cure rates, recurrences in a paediatric population are common and many patients require multiple treatments. Likewise, the treatment is expensive. For these reasons, laser treatment of warts is generally reserved for recalcitrant cases only. References 1 Park HS, Choi WS. Pulsed dye laser treatment for viral warts: a study of 120 patients. J Dermatol 2008;35:491–8. 2 Robson KJ, Cunningham NM, Kruzan KL et al. Pulsed-dye laser versus conventional therapy in the treatment of warts: a prospective randomized trial. J Am Acad Dermatol 2000;43:275–80. 3 Serour F, Somekh E. Successful treatment of recalcitrant warts in pediatric patients with carbon dioxide laser. Pediatr Surg 2003;13: 219–23.

Other lesions Acanthosis nigricans Several cases of treatment-resistant acanthosis nigricans responding to laser therapy have been reported, though paediatric data are lacking. Long-pulsed alexandrite (5 ms) and continuous-wave carbon dioxide laser (three sessions at 4–6-week intervals) have been used with clinically significant results [1,2].

Acne scarring Numerous medical and procedural interventions have been proposed for the treatment and resolution of acne scaring. The condition, however, remains difficult to treat and may be associated with an under-reported and underappreciated degree of psychosocial co-morbidities [3]. Most of the literature for treating acne scars with lasers comes directly from experience within the adult patient population, though there is an increasing literature to support treatment within paediatrics. Ablative laser

The Use of Resurfacing, Pigment and Depilation Lasers in Children

resurfacing for acne scarring has yielded the most reported and lasting results. Continuous or pulsed carbon dioxide (10,600 nm) lasers and Er:YAG lasers have been used to ablate the entire epidermis with superficial papillary dermis, resulting in prolonged recovery periods of up to 6 months duration. Other adverse effects have included a prolonged erythema, as well as significant risk of hyperpigmentation and permanent hypopigmentation (particularly in darker skin types). Scarring from the procedure itself is also a risk. Ablative ‘fractional’ resurfacing has provided improved cosmesis with a more rapid postoperative recovery time and markedly reduced incidences of adverse effects. Post-treatment care should consist of semi-occlusive dressings or non-comedogenic moisturizers; occlusive ointments such as petrolatum jelly should be avoided in order to reduce acne flares. Additionally, the use of daily UVA and UVB sunscreen with a minimum sun protection factor (SPF) 30 may help to minimize the risk of postinflammatory pigment changes.

189.9

growth factor (TGF)-β1, which has been shown to promote fibrosis formation, and increased levels of bFGF, which has been shown to promote tightly organized collagen bundles. These findings may help explain the seemingly beneficial effects of laser resurfacing on keloids at a cellular level, though future studies are necessary to elucidate this point more completely. Likewise, laser produces minimal damage to the adjoining tissue, and there is minimal pain in the immediate period after surgery. Reepithelialization, however, may take longer than with conventional surgical excision. When the current evidence is considered in total, carbon dioxide and resurfacing lasers can be used to debulk large keloids, especially when used as one of a number of concurrent treatment techniques. Lesions should be expected to recur, but laser treatment may delay this happening. The Nd:YAG and 585–595 nm flashlamp-pumped pulsed dye lasers are also effective with excellent safety profiles.

Neurofibroma Burns and burn scars Use of the carbon dioxide laser to remove burn slough in thermally injured children is not a well-established technique, though preliminary research by the authors suggests that there will be a role for it. Blood loss is always a major concern in burn surgery, and laser ablation has the benefit of sealing small blood vessels as it cuts. The bed that is left behind will accept a skin graft, and the rates of postoperative infection tend to be less. The carbon dioxide laser can, however, be slow and cumbersome to use over large areas. Pulsed dye laser at 585–595 has been utilized to miminize erythema and, to a degree, hypertrophy associated with burn scars. Fractionated carbon dioxide ablative lasers also appear useful, with evolving medical literature of use.

Hypertrophic scars and keloids The pulsed dye laser (585–595 nm) has been used to improve scar erythema and hypertrophy. The fractional carbon dioxide (CO2) and Er:YAG (1550 nm) lasers have also been utilized for scar revision, with an expanding literature to support their use [4]. Keloids remain a difficult challenge for clinicians because of recurrence, which varies based on age and ethnicity/race. Numerous therapies have been incorporated into the management strategy for keloids and include cryotherapy, compression, surgical excision, steroids, radiation, lasers, silicone gel sheets, interferon, antineoplastic agents and retinoids. Laser surgery for keloids offers several potential advantages over other treatment modalities. Biological studies have suggested that use of the carbon dioxide and Er:YAG lasers could be linked to decreased levels of transforming

Carbon dioxide laser has been used to remove cutaneous neurofibromas. Scarring, burns and pigment changes are possible side-effects.

Naevus sebaceus (sebaceous naevus) Several light-based technologies have been used as an alternative to surgical excision for the treatment of naevus sebaceus. Carbon dioxide laser vaporization has been reported in the literature, as has photodynamic therapy with topical δ-aminolaevulinic acid.

Mastocytoma/urticaria pigmentosa Several reports of laser treatment for mastocytomas exist in the paediatric literature. The 585 nm pulsed dye laser has been reported to be effective in reducing the severity of weal formation and improving cosmesis. Likewise, the frequency-doubled Q-switched Nd:YAG laser has been utilized to reduce the overall number of lesions in urticaria pigmentosa, but recurrence is common.

Molluscum contagiosum As with warts, molluscum contagiosum has been treated using pulsed dye laser; clearance rates vary widely and multiple treatments are usually required.

Keratosis pilaris Paediatric cases of laser therapy for keratosis pilaris are limited. Published reports suggest that multiple treatments should be anticipated, and local pain is the most common side-effect. Pulsed dye laser and KTP (532 nm) lasers have been utilized for reducing erythema associated with keratosis pilaris atrophicans and keratosis pilaris rubra.

189.10

Chapter 189

Striae These common lesions may pose significant psychosocial concern to affected patients. The 585 nm flashlamppumped pulsed dye laser may help to lighten the pink to violaceous colour of newer striae; treatment should be avoided in darker skin types or used only with extreme caution. Repigmentation of atrophic lesions has been temporarily achieved using the 308 nm xenon chloride excimer laser. Non-ablative lasers have been investigated for their role in stimulating production of dermal collagen and elastin, which may help with older, more atrophic lesions. Current paediatric literature remains limited.

Vitiligo Vitiligo is a psychologically and socially distressing condition in which localized areas are devoid of melanocytes; affected patients present with depigmented macules and patches in an often symmetrically distributed presentation. Management of vitiligo can be notoriously challenging. Phototherapy can be extremely helpful, with UVB, narrow-band UVB (311–313 nm) and UVA (with and without psoralen) as the modalities that have been used effectively. The monochromatic 308 nm excimer laser has recently been approved as a therapy for vitiligo; it may

have the advantage of being able to treat large areas within a short time period. Areas of the body like the face and neck seem to respond better than bony prominences and extremities. Excimer laser may be used in conjunction with other topical therapies [5]. For those patients with widespread disease (>50% body surface area), the possibility of whole-body depigmentation may be an option. Topical 4-methoxyphenol and multiple treatments with the Q-switched ruby laser have achieved total depigmentation [6]. References 1 Rosenback A, Ram R. Treatment of acanthosis nigricans of the axillae using a long-pulsed (5-msec) alexandrite laser. Dermatol Surg 2004;30: 1158–60. 2 Bredlich R, Krahn G, Kunzi-Rapp K, Wortmann S, Peter RU. Continuous-wave carbon dioxide laser therapy of pseudo-acanthosis nigricans. Br J Dermatol 1998;139:937–8. 3 Cotterill JA, Cunliffe WJ. Suicide in dermatologic patients. Lasers Surg Med 2008;40:381–6. 4 Tierney E, Mahmoud B, Srivastava D et al. Treatment of surgical scars with nonablative fractional laser versus pulsed dye laser: a randomized controlled trial. Dermatol Surg 2009;35:1172–80. 5 Hadi S, Tinio P, Al-Ghaithi K et al. Treatment of vitiligo using the 308nm excimer laser. Photomed Laser Surg 2006;24:354–7. 6 Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol 2000;42:760–9.

190.1

C H A P T E R 190

Sedation and Anaesthesia Yuin-Chew Chan1 & Lawrence F. Eichenfield2 1

Dermatology Associates, Gleneagles Medical Centre, Singapore Pediatric and Adolescent Dermatology, Rady Children’s Hospital; San Diego School of Medicine, University of California, San Diego, CA, USA

2

Pain perception, 190.1

Topical anaesthetics, 190.3

Pharmacological agents, 190.7

Local anaesthetics, 190.1

Perioperative analgesics, 190.6

Other techniques, 190.10

Techniques to decrease the pain of

Sedation, 190.6

injection, 190.3

A sound knowledge of anaesthetic options for paediatric patients reduces the anxiety and pain associated with dermatological procedures for both children and their care-givers [1,2].

Pain perception Children of all ages, including infants, perceive and remember pain. Multiple factors influence a child’s response to pain during a surgical procedure. These include the type of painful stimulus, psychosocial factors, previous medical experiences and painful events in the past [3]. Previously, procedural pain control in young children was not given serious attention because of the misconception that their neuronal pain pathways were undeveloped. However, we now recognize that even neonates are able to experience pain. Moreover, intensely painful physical experiences in children can have long-term physiological and psychological ramifications. Therefore, the management of acute pain is essential [4–6]. The age of the child is a significant factor that determines the intensity of the experienced pain, as well as the anticipation of pain. Infants and young children often have a disproportionate fear of pain compared to older children and adults. This is due to anatomical (e.g. larger surface area for stimulation of sensory neurones) and neurophysiological (e.g. non-functional descending noradrenergic fibres at the spinal level) differences and

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

because infants and young children may fail to fully comprehend the indication or necessity of the procedure. They are also more likely to have needle phobia and stranger anxiety. The child’s anxiety may also be influenced by parental fear, so it is important to alleviate the apprehension of both the child and his parents, for instance by providing fun activities or having an aquarium in the waiting area. References 1 Chen BK, Eichenfield LF. Pediatric anesthesia in dermatologic surgery: when hand-holding is not enough. Dermatol Surg 2001;27:1010–18. 2 Yeo LF, Eichenfield LF, Chan YC. Skin surgery in children: local anaesthesia and sedation techniques. Expert Opin Pharmacother 2007;8: 317–27. 3 Cunningham BB, Eichenfield LF. Decreasing the pain of procedures in children. Curr Prob Dermatol 1999;ii:1–36. 4 Anand KJS, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321. 5 Walco GA, Cassidy RC, Schechter NL. Pain, hurt and harm. The ethics of pain control in infants and children. N Engl J Med 1994;331: 541–4. 6 Larsson BA. Pain management in neonates. Acta Paediatr 1999;88: 1301–10.

Local anaesthetics History The first topical anaesthetic was probably cocaine, the numbing qualities of which were noted in Peru some centuries ago. The first medical use described was in 1884 by Carl Koller, as a topical ophthalmic anaesthetic [1]. The first synthetic anaesthetic was procaine, an ester anaesthetic, which was developed in 1905. Lidocaine (also known as lignocaine), the first synthetic amide anaesthetic, was created in 1943 [2].

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Chapter 190

Mechanism of action Sensory nerve conduction is mediated by the opening of voltage-gated sodium channels. When sufficient intracellular influx of sodium occurs, an action potential is propagated. Local anaesthetics inhibit the voltagegated sodium channels in the neuronal cell membrane: this increases the threshold of excitatory potential and prevents the transmission of the noxious stimuli. The specific site of action of local anaesthetics is the intracellular portion of the sodium channel. Local anaesthetics can be combined with vasoconstrictors, such as adrenaline, to provide improved haemostasis, reduce systemic toxicity and increase the duration of anaesthesia.

Classification of local anaesthetics Local anaesthetics are weak bases that typically consist of three important components: an aromatic ring, an ester or amide linkage and a tertiary amine. The aromatic ring determines potency as lipid solubility allows it to permeate the neuronal membrane. The latter two parts are responsible for protein binding and hence duration of anaesthesia. Local anaesthetics are classified as either amide or ester based (Table 190.1). The ester-based anaesthetics include procaine cocaine, chloroprocaine and benzocaine. They are metabolized by plasma cholinesterase and other non-specific esterases. The amide-based anaesthetics include lidocaine, bupivacaine, prilocaine, mepivacaine, levobupivacaine and ropivacaine. These are primarily metabolized in the liver via microsomal enzymes. Variations exist in properties affecting lipophilic status, pKa and protein binding influence potency, speed of onset and duration of action, as well as potential toxicity [3].

Lidocaine Lidocaine is usually administered as a 0.5–2% (5–20 mg/ mL) solution. The maximum recommended dose in

patients 4 years of age and above is 4.5 mg/kg, which is equivalent to a maximum volume of 0.45 mL of 1% lidocaine per kilogram of body weight [4]. The addition of adrenaline counteracts the natural vasodilatory effect of lidocaine and hence decreases the rate of lidocaine absorption, increases its duration of action and reduces the risk of systemic toxicity. As an added benefit, the localized vasoconstriction induced by adrenaline also decreases the amount of intraoperative bleeding during surgical excision. We recommend a maximum adrenaline dosage equivalence of 0.01 mg/mL (concentration of 1 : 100,000). The maximum recommended dose of lidocaine combined with adrenaline is 6 mg/kg, equivalent to a maximum volume of 0.6 mL per kilogram of body weight. For an average newborn weighing 4 kg, the maximum volume of lidocaine combined with adrenaline is only 2.4 mL. It is not advisable to use adrenaline in procedures involving end-arterial structures, e.g. distal digits, penis or pinna of the ear, as there is a risk of vasoconstriction of the distal end arteries and subsequent cutaneous necrosis. A disadvantage of lidocaine as a local anaesthetic is the pain associated with its injection. The addition of 8.4% sodium bicarbonate (1 mmol/mL) to 1% lidocaine (with or without adrenaline) in a ratio of 1 : 10 has been shown to decrease pain without significant alteration of onset, extent or duration of anaesthesia [5]. The increase in the pH of the mixture, as well as faster nerve penetration as a result of an increase in the proportion of the uncharged and more lipophilic form of the amide molecule, may explain the reduction in pain. Lidocaine is more soluble and has a longer shelf-life at acid pH. After the addition of bicarbonate as a buffer, the mixture should be refrigerated, as the initial concentration of lidocaine falls to 66% after 4 weeks at room temperature. Refrigeration at a temperature of 0–4°C maintains lidocaine at 94.5% of its initial concentration after 4 weeks [6]. The average duration of anaesthesia with plain lidocaine is 40–60 min, and

Table 190.1 Properties of selected local anaesthetics Local anaesthetic

Onset of action (min)

Duration of action (h) With adrenaline

Maximum dose Without adrenaline

With adrenaline

Without adrenaline

Amides Lidocaine 2 1.0–6.5 Bupivacaine 5 4.0–8.0 Others: prilocaine, mepivacaine, levobupivacaine, ropivacaine

0.5–2.0 2.0–4.0

6 mg/kg 3 mg/kg

4.5 mg/kg 2 mg/kg

Esters Procaine 6–10 Tetracaine Slow Others: cocaine, benzocaine, chloroprocaine

0.25–0.5 2.0–4.0

1 g in adults Unknown

0.5–1.5 4.0–8.0

Sedation and Anaesthesia

is decreased to 30 min with the addition of sodium bicarbonate [7]. For extended procedures, the addition of adrenaline to lidocaine is recommended.

Adverse effects Local adverse effects related to the injection include pain, haematoma or ecchymosis, nerve damage and vasovagal syncope. Ester anaesthetics are more likely than amide anaesthetics to cause allergic reactions. Allergic reactions to ester anaesthetics are related to their metabolism to paraaminobenzoic acid, a potential allergen. True allergic reactions to lidocaine and other amide anaesthetics are rare, making up less than 1% of adverse reactions [3]. Cross-reactivity of allergic reactions between the amide and ester anaesthetic classes is rare. Injection into a highly vascularized area, accidental intravascular injection or overdosage results in high, possibly toxic, systemic concentrations which may cause adverse central nervous system (CNS) and cardiovascular effects. Initially, stimulation of the nervous system occurs, causing perioral tingling and numbness, anxiety, apprehension, restlessness, nervousness, disorientation, confusion, dizziness, blurring of vision, twitching, shivering or seizures. At greater doses, neurodepression can occur, resulting in unconsciousness, respiratory depression or coma. Cardiovascular toxicity is generally noted after CNS symptoms have developed [8]. Effects include prolonged electrocardiographic intervals, bradycardia, hypotension, decreased myocardial contractility and cardiac arrest. Bupivacaine is especially associated with cardiac toxicity: an increase in PR interval and major widening of QRS usually precede arrhythmias (ventricular tachycardia, rarely torsades de pointe). References 1 Calverley RK, Scheller MS. Anesthesia as a specialty: past, present and future. In: Barash PG, Cullen BF, Stoelting RK, eds. Clinical Anesthesia, 2nd edn. Philadelphia: JB Lippincott, 1992:3–33. 2 Grekin RC, Auletta MJ. Local anesthesia in dermatology surgery. J Am Acad Dermatol 1988;19:599–614. 3 Norris RL. Local anesthetics. Emerg Med Clin North Am 1992;10:707–18. 4 McEvoy GK, Snow EK, Kester L et al. AHFS Drug Information 2006. Authority of the Board of American Society of Health-System Pharmacists, Bethesda, MD, 2006:3201–5, 3198–200. 5 Christoph RA, Buchanan L, Begalid K et al. Pain reduction in local anesthetic administration through pH buffering. Ann Emerg Med 1988;17:117–20. 6 Larson PO, Ragi G, Swandby M et al. Stability of buffered lidocaine and adrenaline used for local anesthesia. J Dermatol Surg Oncol 1991;17:411–14. 7 Holmes SG. Choosing a local anesthetic. Dermatol Clin 1994;12:817–23. 8 Grekin RC, Auletta MJ. Local anesthesia in dermatology surgery. J Am Acad Dermatol 1988;19:599–614.

190.3

Techniques to decrease the pain of injection There are several techniques that may be employed to decrease the pain of lidocaine infiltration [1]. Prior treatment of the injection site with topical anaesthetics such as EMLA cream or liposomal lidocaine (LMX cream), pH buffering of the anaesthetic solution, using small gauge needles (e.g. 30 gauge), warming of the anaesthetic to body temperature, cooling the injection site with ice or ethyl chloride spray, and a slow injection rate minimize the pain of the injection. Counter-stimulation techniques, such as pinching or rubbing of the injection site prior to infiltration, may reduce the pain of injection by activating substance-P fibres in the skin [2].

Topical anaesthetics In order to gain access to the sensory nerve endings, cutaneous analgesics must diffuse through the stratum corneum, which is the major barrier preventing local anaesthetics from penetrating the deeper tissue layers [3]. None of the topical agents to date, even when used under occlusion, produces reliable anaesthesia of the palms and soles. Topical anaesthetics are convenient, cost-effective and associated with few adverse effects. Novel anaesthetic formulations and transdermal delivery systems are promising and may result in even more effective and safer topical analgesia in the future [4].

Eutectic mixture of local anaesthetics (EMLA) EMLA cream is a mixture of 2.5% lidocaine and 2.5% prilocaine. EMLA melts at a lower temperature than lidocaine or prilocaine alone, resulting in a stable cream at room temperature. It has been shown in numerous clinical trials to be safe and efficacious for needlestick, venepuncture, intravenous catheterization, lumbar puncture, debridement of ulcers, ablative treatment of molluscum contagiosum, laser treatment on skin and genital mucosa, and other superficial skin surgery [5]. EMLA cream alone does not appear to provide sufficient analgesia for deep biopsies or scalpel excision of skin. Standard usage requires application of the product on the skin surface with an occlusive wrap, such as Tegaderm or Cellophane wrap, for 60–120 min. Patch preparations may allow easier application with equivalent efficacy [6]. The maximum recommended doses for EMLA on intact healthy skin in children are shown in Table 190.2. The depth and degree of analgesia is related to the duration of application. The maximum depth of analgesia is 5 mm. Mucous membranes, genital skin and diseased skin with

190.4

Chapter 190

Table 190.2 Recommended eutectic mixture of local anaesthetics dosing on intact and healthy skin in children Age/body weight

Maximum dose (g)

Maximum application area (cm2)

Maximum application time (h)

0–3 months old or 5 kg 1–6 years old and >10 kg 7–12 years old and >20 kg

1 2 10 20

10 20 100 200

1 4 4 4

Table 190.3 Recommended application times for EMLA cream in selected procedures Indication

Application time (min)

Molluscum contagiosum

30–60 (15 in children with atopic dermatitis) 60 5–15 60 30 60

Skin biopsy (pretreatment) Condylomata acuminata Port wine stain (pulsed-dye laser) Leg ulcers (debridement) Vaccination Adapted from Kearns et al. 2003 [31].

an impaired skin barrier function absorb more rapidly, allowing for shorter application times (5–40 min). The recommended application times for EMLA cream in selected procedures are shown in Table 190.3. EMLA commonly causes blanching or erythema at the site of application. It may occasionally cause transient, local irritation, swelling, purpura or pruritus. Periorbital application should be avoided as corneal ulceration and irritation are possible adverse effects [7]. Methaemoglobinaemia due to the prilocaine component, a potentially life-threatening complication, has been reported, mainly in neonates and infants less than 3 months of age as their methaemoglobin reductase pathway is immature [8]. However, two reports attributed methaemoglobinaemia in a 3-year-old toddler to the excessive use of EMLA and in a 7-month-old infant to prolonged use while receiving inhaled nitric oxide [9,10]. Use of medications associated with methaemoglobinaemia (including sulphonamides, dapsone, benzocaine and chloroquine) may increase the risk of EMLA-associated methaemoglobinaemia in infants. CNS toxicity has been reported after excessive application of EMLA over an extensive area [11].

Liposomal lidocaine Liposomal lidocaine (LMX) is a topical anaesthetic that is encapsulated in a phospholipid-based carrier. Liposomal

vehicles facilitate and improve diffusion of the local anaesthetic through the dermis. In a systematic review, topical liposomal anaesthetics were found to be effective prior to dermal instrumentation [12]. Liposomeencapsulated lidocaine is commercially available in both 4% and 5% preparations. In comparative clinical trials, LMX (applied for 30 min) and EMLA (applied for 60 min) were equally effective in reducing the pain associated with venepuncture and intravenous catheter insertion in children [13,14]. The faster onset of anaesthesia with LMX is an advantage in paediatric clinical practice. In studies carried out in adults, LMX has been shown to produce a longer duration of analgesia as the phospholipid carrier serves to maintain a longer localization of the anaesthetic [15–17]. There have been no reports of serious adverse effects with the use of LMX. However, LMX should not be applied for more than 2 h in order to avoid excessive systemic levels of lidocaine. In children weighing less then 20 kg, LMX should not be applied to a surface area greater then 100 cm2 [18]. The absence of prilocaine prevents the risk of methaemoglobinaemia.

Lidocaine ointment and spray These lidocaine formulations work well as local anaesthetics when they are applied to mucosal surfaces such as those of the oropharynx, nose, vagina and cervix. However, they are not effective when applied to intact skin, as the lidocaine molecule is too big to penetrate the stratum corneum. Hence, EMLA cream has been found to be significantly more effective than 40% lidocaine ointment, even though the concentration of lidocaine in the latter formulation is many times greater [19].

Tetracaine formulations Tetracaine is used in multiagent formulations for the repair of dermal lacerations. The first such agent, tetracaine/adrenaline/cocaine (TAC), was introduced in 1980. In recent years, other tetracaine-containing topical anaesthetics, such as lidocaine/adrenaline/tetracaine, have replaced TAC due to the potential of cocaine to produce adverse effects [20]. Both tetracaine and liposomal tetracaine have been found to provide equivalent, if not greater, efficacy than EMLA for instrumentation of intact skin [21,22].

Lidocaine/tetracaine patch A lidocaine/tetracaine patch is a topical agent that consists of a eutectic formulation of 70 mg lidocaine and 70 mg tetracaine and uses an oxygen-activated heating element to enhance delivery of the local anesthetic. The temperature of the patch increases once removed from the package, which subsequently warms the underlying skin after application. In one study it provided appropriate analgesia after 20 min of application for venepuncture

Sedation and Anaesthesia

in children; only transient and minor side-effects, such as erythema and oedema, were noted [23].

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is a known sensitizer, allergic contact dermatitis seldom occurs when it is used preoperatively, presumably because of lack of prior exposure and sensitization.

Subcutaneous infusion anaesthesia In the tumescent technique used for subcutaneous infusion anaesthesia, large volumes of highly diluted local anaesthetics, e.g. ropivacaine or prilocaine, are instilled into the subcutaneous layer by infusion pumps [24,25]. This provides profound perioperative anaesthesia owing to slow absorption from the relatively avascular subcutaneous fat. It also provides hydrodissection of the skin from underlying vessels and nerves, facilitating surgery. However, further studies need to be done to evaluate the feasibility of this technique in paediatric dermatological surgery [26].

Iontophoresis devices Iontophoresis devices have been advocated for needleless delivery of local anaesthetics. A low-voltage direct current is applied to skin immersed in a local anaesthetic solution or placed under an anaesthetic-impregnated patch, facilitating transfer across the stratum corneum. Lidocaine iontophoresis has a rapid onset of anaesthesia (within 10 min) and appears to be as efficacious as EMLA cream and local lidocaine injection in providing pain relief for intravenous cannulation in children [27–30]. A study conducted in children 5–15 years of age found that the subjects tolerated iontophoresis well and systemic levels of lignocaine were low [31]. A prospective trial, evaluating lignocaine iontophoresis in 60 children undergoing shave biopsy, curettage, injection and punch biopsy, revealed that most of the subjects did not require any supplemental anaesthesia. No significant adverse events were reported [32].

Needle-free injection devices Needle-free injection devices use high gas pressure to accelerate fine drug particles to supersonic speed and deliver them into the skin. Several clinical trials studying paediatric patients demonstrated the clinical efficacy of needle-free injections [33–35]. However, another study showed that a needle-free injection device is not completely painless or cost-effective [36].

Topical anaesthesia for mucosal surfaces Topical Cetacaine (benzocaine 14%, tetracaine 2%), benzocaine, viscous lidocaine, liposomal lidocaine and EMLA are effective topical agents for inducing mucosal anaesthesia. Anaesthetic effect is almost immediate upon application. These agents are useful for decreasing the pain of intralesional lidocaine injection, but are insufficient for scalpel surgery when used alone. In infants, the use of Cetacaine and benzocaine should be avoided because of the risk of methaemoglobinaemia [37]. While benzocaine

References 1 Eichenfield LF, Weilepp A. Pain control in pediatric procedures. Curr Opin Dermatol 1997;4:151–61. 2 Barnhill BJ, Holbert MD, Jackson NM, Erickson RS. Using pressure to decrease the pain of intramuscular injections. J Pain Symptom Manage 1996;12:52–8. 3 Friedman PM, Mafong EA, Friedman ES, Geronmus RG. Topical anesthetics update: EMLA and beyond. Dermatol Surg 2001;27:1019–26. 4 Houck CS, Sethna NF. Transdermal analgesia with local anesthetics in children: review, update and future directions. Expert Rev Neurother 2005;5:625–34. 5 Garjraj NM, Pennant JH, Watcha MR. Eutectic mixture of local anesthetics (EMLA). Anesth Analg 1994;78:574–83. 6 Chang PC, O’Connor G, Rogers PJC et al. A multicentre randomized study of single-unit dose package of EMLA patch vs. EMLA cream 5% for venepuncture in children. Can J Anesth 1994;41:59–63. 7 McKinlay JR, Hofmeister E, Ross EV. EMLA cream-induced eye injury. Arch Dermatol 1999;135:855–6. 8 Jakobson B, Nilsson A. Methaemoglobinemia in children treated with prilocaine–lidocaine cream and trimethoprim–suphamethoxazole. A case report. Acta Anaesth Scand 1985;29:453–5. 9 Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol 2001;44:399–400. 10 Sinisterra S, Miravet E, Alfonso I et al. Methemoglobinemia in an infant receiving nitric oxide after the use of eutectic mixture of local anesthetic. J Pediatr 2002;141:285–6. 11 Rincon E, Baker RL, Iglesias AJ et al. CNS toxicity after topical application of EMLA cream on a toddler with molluscum contagiosum. Pediatr Emerg Care 2000;16:252–4. 12 Eidelman A, Weiss JM, Lau J, Carr DB. Topical anesthetics for dermal instrumentation: a systematic review of randomized, controlled trials. Ann Emerg Med 2005;46:343–51 13 Eichenfield LF, Funk A, Fallon-Friedlander S et al. A clinical study to evaluate the efficacy of ELA-Max (4% liposomal lidocaine) as compared with eutectic mixture of local anesthetics cream for pain reduction of venepuncture in children. Pediatrics 2002;109:1093–9. 14 Kleiber C, Sorenson M, Whiteside K et al. Topical anesthetics for intravenous insertion in children: a randomized equivalency study. Pediatrics 2002;110:758–61. 15 Bucalo BD, Mirikitani EJ, Moy RL. Comparison of skin anesthetic effect of liposomal lidocaine, nonliposomal lidocaine, and EMLA using 30-minute application time. Dermatol Surg 1998;24:537–41. 16 el-Ridy MS, Khalil RM. Free versus liposome-encapsulated lignocaine hydrochloride topical applications. Pharmazie 1999;54:682–4. 17 Friedman PM, Fogelman JP, Nouri K et al. Comparative study of the efficacy of four topical anesthetics. Dermatol Surg 1999;25: 950–4. 18 Friedman PM, Mafong EA, Friedman ES, Geronmus RG. Topical anesthetics update: EMLA and beyond. Dermatol Surg 2001;27:1019–26. 19 Hernandez E, Gonzalez S, Gonzalez E. Evaluation of topical anesthetics by laser-induced sensation: comparison of EMLA 5% cream and 40% lidocaine in an acid mantle ointment. Lasers Surg Med 1998;23:167–71. 20 Bush S. Is cocaine needed in topical anaesthesia? Emerg Med J 2002;19:418–22. 21 Carceles MD, Alonso JM, Garcia-Munoz M et al. Amethocaine– lidocaine cream, a new topical formulation for preventing

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22

23

24

25

26

27

28

29

30

31

32

33

34

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venepuncture-induced pain in children. Reg Anesth Pain Med 2002;27:289–95. Eidelman A, Weiss JM, Lau J, Carr DB. Topical anesthetics for dermal instrumentation: a systematic review of randomized, controlled trials. Ann Emerg Med 2005;46:343–51. Sethna NF, Verghese ST, Hannallah RS, Solodiuk JC, Zurakowski D, Berde CB. A randomized controlled trial to evaluate S-Caine patch for reducing pain associated with vascular access in children. Anesthesiology 2005;102:403–8. Moehrle M, Breuninger H. Dermatosurgery using subcutaneous infusion anesthesia with prilocaine and ropivacaine in children. Pediatr Dermatol 2001;18:469–72. Breuninger H, Nogova L, Hobbach PS, Schimek F. Ropivacaine, an advantageous anesthetic for subcutaneous infusion anesthesia. Hautarzt 2000;51:759–62. Dohil MA, Eichenfield LF. Subcutaneous infusion anesthesia for dermatologic surgery in children: are we ready? Pediatr Dermatol 2001;18:532–3. Zempsky WT, Anand KJ, Sullivan KM et al. Lidocaine iontophoresis for topical anesthesia before intravenous line placement in children. J Pediatr 1998;132:1061–3. Galinkin JL, Rose JB, Harris K et al. Lidocaine iontophoresis versus eutectic mixture of local anesthetics (EMLA) for IV placement in children. Anesth Analg 2002;94:1484–8. Kim MK, Kini NM, Troshynski TJ et al. A randomized clinical trial of dermal anesthesia by iontophoresis for peripheral intravenous catheter placement in children. Ann Emerg Med 1999;33:395–9. Sherwin J, Awad IT, Sadler PJ et al. Analgesia during radial artery cannulation. Comparison of the effects of lidocaine applied by local injection iontophoresis. Anaesthesia 2003;58:474–6. Kearns GL, Heacook J, Daly SJ, Singh H, Alander SW, Qu S. Percutaneous lidocaine administration via a new iontophoresis system in children: tolerability and absence of systemic bioavailability. Pediatrics 2003;112:578–82. Zempsky WT, Parkinson TM: Lidocaine iontophoresis for topical anesthesia before dermatologic procedures in children: a randomized controlled trial. Pediatr Dermatol 2003;20:364–8. Wolf AR, Stoddart PA, Murphy PJ et al. Rapid skin anaesthesia using high velocity lignocaine particles: a prospective placebo controlled trial. Arch Dis Child 2002;86:309–12. Munshi AK, Hegde A, Bashir N. Clinical evaluation of the efficacy of anesthesia and patient preference using the needle-less jet syringe in pediatric dental practice. J Clin Pediatr Dent 2001;25:131–6. Zempsky WT, Bean-Lijewski J, Kauffman RE et al. Needle-free powder lidocaine delivery system provides rapid effective analgesia for venipuncture or cannulation pain in children: randomized, double-blind Comparison of Venipuncture and Venous Cannulation

Pain after Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment Trial. Pediatrics 2008;121(5):979–87. 36 Lysakowski C, Dumont L, Tramer MR, Tassonyi E. A needle-free jetinjection system with lidocaine for peripheral intravenous cannula insertion: a randomized controlled trial with cost-effectiveness analysis. Anesth Analg 2003;96:215–19. 37 Nguyen ST, Cabrales RE, Bashour CA et al. Benzocaine-induced methemoglobinemia. Anesth Analg 2000;90:369–71.

Perioperative analgesics Adjuvant agents can be used to provide perioperative analgesia for paediatric patients. The use of acetaminophen alone (15–20 mg/kg orally or 20 mg/kg per rectum) or with codeine may be useful for perioperative pain. An added benefit of codeine is its mild to moderate sedative effect, which is particularly useful in young children. Non-steroidal anti-inflammatory agents such as ibuprofen and ketorolac may also be used, although their effects on platelet function and haemostasis should be considered.

Sedation Sedation should be considered as a continuum within which a patient may drift from a state of consciousness to deep sedation and on to general anaesthesia. This continuum can be extremely variable and depends on individual response, age, health status and drug combinations used (Table 190.4). Definitions relevant to sedation as proposed by the American Society of Anesthesiologists are listed below: • Minimal sedation (‘anxiolysis’): A drug-induced state during which patients respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected.

Table 190.4 Continuum of depth of sedation Minimal sedation (anxiolysis)

Moderate sedation (conscious sedation)

Deep sedation/analgesia

General anaesthesia

Responsiveness

Normal response to verbal stimulation

Purposeful* response to verbal or tactile stimulation

Purposeful* response after repeated or painful stimulation

Unarousable, even with painful stimulus

Airway

Unaffected

No intervention required

Intervention may be required

Intervention often required

Spontaneous ventilation

Unaffected

Adequate

May be inadequate

Frequently inadequate

Cardiovascular function

Unaffected

Usually maintained

Usually maintained

May be impaired

* Reflex withdrawal from a painful stimulus is not considered a purposeful response.

Sedation and Anaesthesia

• Moderate sedation (‘conscious sedation’): A drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. Reflex withdrawal from a painful stimulus is not considered a purposeful response. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained. • Deep sedation/analgesia: A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. The ability to independently maintain ventilatory function maybe impaired. Patients may require assistance in maintaining a patent airway and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained. Reflex withdrawal from a painful stimulus is not considered a purposeful response. • Anaesthesia: A drug-induced loss of consciousness during which patients are not arousable, even by painful stimulation. The ability to independently maintain ventilatory function is often impaired. Patients often require assistance in maintaining a patent airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or druginduced depression of neuromuscular function. Cardiovascular function may be impaired. Doctors should be aware of national and regional guidelines for the use of sedation in children in both the office and hospital setting. These guidelines may dictate the appropriate level of monitoring, equipment required, implementation of sedation protocols and staff training [1,2]. In general, deep sedation and general anaesthesia for dermatological procedures in children are most safely performed with the assistance of an anaesthetist. Conscious and deep sedation may be safely performed in an ambulatory setting if the facility and staff are appropriately equipped and trained. Selecting an appropriate sedative technique requires preoperative assessment of the child’s medical status, the degree of pain expected during the procedure, the duration of the procedure, the need or absence of need for the child to be motionless, the expertise of the practitioner performing the sedation, the facility resources for monitoring the patient and responding to adverse events, and knowledge of minimal levels of monitoring and personnel required for the level of sedation used [3]. Preoperative assessment must include the general health of the child, with the awareness that underlying systemic diseases may greatly increase the risk of adverse events. As protective airway reflexes may be compromised to varying degrees depending upon the type and dosage of sedative agents used, as well as the patient’s baseline medical condition, adequate ‘nil by

190.7

mouth’ status should be ensured for elective sedative procedures. Monitoring may include the use of a pulse oximeter, which continuously measures heart rate and arterial oxygen saturation using a spectrophotometric technique. References 1 American Academy on Pediatrics; American Academy on Pediatric Dentistry. Guideline for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatr Dent 2008/2009;30(Suppl 7):143–59. 2 Hackel A, Badgwell JM, Binding RR et al. Guidelines for the pediatric perioperative anesthesia environment. American Academy of Pediatrics. Section on Anesthesiology. Pediatrics 1999;103:512–15. 3 Litman RS. Recent trends in the management of pain during medical procedures in children. Pediatr Ann 1995;24:158–63.

Pharmacological agents There is a broad array of medications that can be used as sedative, hypnotic, analgesic and anaesthetic agents. Analgesia refers to the relief of pain, amnesia to lack of memory, hypnosis to lack of consciousness and sedation to a decrease in consciousness. Anxiolytic agents decrease anxiety but have no analgesic effects. Local, topical or regional anaesthesia, together with sedatives that can induce amnesia, may produce the desired effect of a painless or minimally painful experience not remembered by the patient.

Benzodiazepines Benzodiazepines are sedative agents with potent anxiolytic effects but no analgesic properties. Diazepam may be administered via oral, sublingual, rectal and intravenous routes. The intramuscular route is not recommended, as absorption is slow and erratic. For infants 1–6 months old, the dose is 0.05–0.1 mg/kg intravenously; oral dosing is not recommended. For children more than 6 months old, the dose is 0.1–0.2 mg/kg intravenously or 0.4 mg/kg orally. The maximum doses are 10 mg intravenously and 20 mg orally. The onset of action is 1–3 min after intravenous administration and 30–60 min after oral administration. However, its duration of action is rather unpredictable owing to the presence of active metabolites, often lasting for 2–4 h. Prolonged sedation is not uncommon. Intravenous diazepam is painful at the injection site owing to the presence of propylene glycol in the formulation. This, as well as its longer and more unpredictable duration of action, makes it less popular than midazolam for intravenous use in children. Midazolam is a short-acting benzodiazepine that is useful for perioperative sedation in children. After intravenous adminstration, the medication acts rapidly (1–5 min) and has a short duration of action (less than 2 h).

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Chapter 190

It has an excellent safety profile. Routes of administration include intravenous, oral, intramuscular and rectal. Intravenous dosing is 0.02–0.1 mg/kg, not exceeding 5 mg. Intranasal and oral routes require higher dosing owing to variable absorption: oral and nasal dosing is 0.2–0.5 mg/ kg, up to 15 mg. Midazolam has potent anxiolytic effects and the anterograde amnesic effect is profound, making the agent useful for repetitive procedures (e.g. pulsed-dye laser treatment). Premedication with oral midazolam significantly reduces the pain of intravenous catheter insertion [1]. The addition of an analgesic agent, such as acetaminophen/codeine or fentanyl, may be reasonable, although the combination increases the risks of respiratory depression [2]. Pulsed oximetry monitoring is recommended as higher doses of midazolam are associated with transient drops in transcutaneous oxygen saturation. Flumazenil is the specific antagonist for benzodiazepines, and may reverse the depressant effects in a dosedependent fashion. Incremental doses of 0.01 mg/kg can be administered intravenously over 15 s. Doses may be repeated every 60 s as needed to a maximum of four additional doses (0.05 mg/kg, maximum dose 1 mg). Routine postoperative use of flumazenil in the setting of midazolam sedation appears to be safe, but more studies need to be done to assess its cost-effectiveness [3].

unpleasant dreams and emergence reactions. It is contraindicated in paediatric patients with active upper or lower airway disease, head injury, epilepsy or acute eye globe injury.

Opiates Opiates are primarily used for analgesia, often as adjuncts to sedative agents. Morphine, meperidine and fentanyl are potent analgesics. Fentanyl, a synthetic opiate agonist, has a rapid onset (within 5 min) and relatively short duration of action (30–60 min) when given intravenously (1–3 μg/kg), allowing titration of medication for pain relief with less risk of prolonged respiratory depression and hypotension. Fentanyl lozenges have been utilized for paediatric procedures, but studies to date report conflicting results with regard to its efficacy as a premedication [5–7]. Codeine may be useful peri- and postoperatively for procedure-related pain. Side-effects common to this class of drugs include respiratory and cardiovascular depression, nausea and vomiting [8]. Naloxone is the antidote for opiate overdosage. Incremental doses of 0.01 mg/kg can be administered intravenously and may be repeated every 2–3 min as needed. Patients who receive naloxone should be observed for at least 1 h to detect recurrence of sedation.

Chloral hydrate Barbiturates Barbiturates are potent sedative agents with amnesic effects. These medications are non-specific CNS depressants and have more profound respiratory and cardiovascular depressant effects than benzodiazepines. Pentobarbital may be used orally, or less commonly per rectum or via intramuscular injection (1.5–6 mg/kg, maximum dose 100 mg), with an onset of action within 30 min and duration of action lasting 6 h. Barbiturates have no analgesic effect. Their use in paediatric procedures has decreased greatly as a result of the better safety profile of benzodiazepines.

Chloral hydrate is a sedative agent that has been used in children for several decades. Doses of 50–75 mg/kg (up to 100 mg/kg) are administered orally. Chloral hydrate has a slow onset (30–60 min) and induces sleep lasting 4–8 h, with amnesic effect. It requires prolonged monitoring both during and at the conclusion of a procedure. It lacks analgesic properties. Common adverse effects include nausea, vomiting and diarrhoea. Several deaths have been reported from chloral hydrate use, most commonly from overdosage or its use in children with underlying cardiac or systemic disease. It has been reported to cause liver tumours, but there is no evidence that children receiving sedative dosages are at risk for this [9].

Ketamine Ketamine is an anaesthetic agent that may be given via the intramuscular or intravenous routes. It produces profound sedation, amnesia and analgesia, and induces a ‘trance-like’ state (‘dissociative anaesthesia’). Onset is rapid: 1 min for the intravenous route (0.5 mg with an infusion of 0.01–0.2 mg/kg/min) and 5 min for the intramuscular route (0.5–1 mg/kg). Duration of sedation is quite variable, usually less than 90 min, but may be longer in some individuals [4]. It should be used together with an anti-sialagogue agent (e.g. atropine) at a dose of 0.01– 0.02 mg/kg to attenuate the increase in salivary secretions. Postoperative nausea and prolonged unarousability are problems associated with its use. Ketamine may cause

Propofol Propofol is an intravenous anaesthetic that provides rapid onset of sedation; it is an aqueous formulation that appears milky in colour. The agent has an almost immediate onset of sedation after bolus dosing of 0.4–1.0 mg/kg followed by continuous infusion of 30–50 μg/kg/min. Propofol produces relatively limited haemodynamic instability and has a short duration of action, allowing a ‘clean head wake-up’ without the nausea or hangover effect that is commonly associated with traditional gas anaesthetics. Antiemetic properties have also been observed. The agent is safe for outpatient surgery even in children under 2 years of age, and has no known cumula-

Sedation and Anaesthesia

tive hazardous physical effects. Propofol does not have profound analgesic qualities and concurrent analgesics for painful procedures are appropriate. In a study of propofol anaesthesia in 48 children undergoing outpatient pulsed-dye laser treatment, 62% were calm and pain-free upon awakening. The mean recovery time was 25 min, and none of the patients experienced emesis [10]. Propofol induction and halothane maintenance was shown to be associated with a lower incidence of adverse events during induction, postoperative nausea and vomiting, and postoperative delirium compared with sevoflurane anaesthesia [11]. Respiratory depression is dose dependent, and hypoxia and apnoea are not uncommon, thus limiting its use to well-equipped facilities with staff who are proficient in critical airway and ventilatory management.

Nitrous oxide Nitrous oxide (N2O) is a gas anaesthetic that has analgesic effects and rapidly induces a sedated, dissociative state with a euphoric feeling and profound amnesic effect. When used alone, 35–50% N2O has analgesic properties with minimal respiratory and cardiovascular effects [12,13]. It is commonly administered with other agents to achieve general anaesthesia. There is an extensive history of its use in paediatric procedures. N2O use requires extensive training and/or credentialling of personnel, a fail-safe system for oxygen/gas delivery to prevent anoxia, a scavenger device to eliminate gas traces and continuous oximetry monitoring. Concerns have been raised about possible teratogenicity and spontaneous abortions from N2O gas [14]. Nitrous oxide is a weak teratogen in rats that are exposed to it at high concentrations for long periods of time [15,16]. Large survey studies that evaluated outcomes in women who had anaesthesia, including nitrous oxide, for surgery during pregnancy suggested no increase in congenital anomalies, but rather an increase in the risk for abortions and low birthweight neonates [17,18]. This increased risk was attributed to the requirement for surgery and not the anaesthesia. Despite the lack of clinical evidence, delaying the use of nitrous oxide in pregnant teenagers until the second trimester may reduce the risks for teratogenicity and spontaneous abortion.

General gas anaesthesia The use of general gas anaesthesia is appropriate for painful but essential surgical procedures in children which cannot be safely or effectively performed with the use of local anaesthetics and sedative agents. The decision to utilize general anaesthesia has to be individualized and depends on the age and underlying health of the patient, the extent and location of the planned procedure and the need for a motionless patient, as well as on the medical

190.9

and personnel resources available to induce and administer anaesthetic agents appropriately, including monitoring and ensuring safe postoperative recovery. Recommended preoperative fasting intervals for infant formula vary from 4 to 8 h. In healthy infants, formula may be consumed up to 4 h before surgery without any increase in gastric volume compared with infants who have not consumed formula 8 h before surgery [19]. A variety of anaesthetic gases are commonly used, including halothane, isoflurane, sevofluorane and N2O. The risks of general anaesthesia are dependent upon a variety of factors, including the age of the patient and underlying systemic conditions [20]. An increased risk of complications is associated with the use of general anaesthesia in the first year of life, with an even greater risk assigned to the first month of life [21–23]. Children, especially infants, may be better served by paediatric anaesthetists who have considerable experience in working with this patient population [24].

Laryngeal masks Induction of anaesthesia with inhalational gases (halothane, isoflurane, desflurane, sevoflurane) is done with mask inhalation, followed by endotracheal visualization and intubation. Laryngeal masks are devices that allow placement of a hypopharyngeal airway, without the need for visualization or intubation of the trachea. After initial facemask induction of anaesthesia, the device – a deflated ‘mask-on-a-stick’ – is placed in the mouth and pushed towards and below the epiglottis superior to the vocal cords. It is then inflated using a syringe (similar to a Foley catheter) and the breathing loop is connected to the exposed end. Both the effort of breathing by the patient and the procedural workload required of the anaesthetist associated with the insertion of the laryngeal mask compare favourably with endotracheal intubation [25,26]. The use of this device has gained widespread acceptance in paediatric surgical patients in whom there is no ‘critical airway’, and has been used successfully for dermatological and laser surgery in children. References 1 McErlean M, Bartfield JM, Karunakar TA et al. Midazolam syrup as a premedication to reduce the discomfort associated with pediatric intravenous catheter insertion. J Pediatr 2003;142:429–30. 2 Yaster M, Nichols DG, Desphande JK et al. Midazolam-fentanyl intravenous sedation in children: case report of respiratory arrest. Pediatrics 1990;86:463–7. 3 Shannon M, Albers G, Burkhart K et al. Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. The Flumazenil Pediatric Study Group. J Pediatr 1997;131:582–6. 4 Green SM, Nakamura R, Johnson NE. Ketamine sedation for pediatric procedures. Part 1. A prospective series. Ann Emerg Med 1990;19:1024–32. 5 Ashburn MA, Streisand JB, Tarver SD et al. Oral transmucosal fentanyl citrate for premedication in paediatric outpatients. Can J Anaesth 1990;37:857–66.

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Chapter 190

6 Howell TK, Smith S, Rushman SC et al. A comparison of oral transmucosal fentanyl and oral midazolam for premedication in children. Anaesthesia 2002;57:798–805. 7 Klein EJ, Diekema DS, Paris CA et al. A randomized, clinical trial of oral midazolam plus placebo versus oral midazolam plus oral transmucosal fentanyl for sedation during laceration repair. Pediatrics 2002;109:894–7. 8 Litman RS. Recent trends in the management of pain during medical procedures in children. Pediatr Ann 1990;24:158–63. 9 American Academy of Pediatrics Committee on Drugs and Committee on Environmental Health. Use of chloral hydrate for sedation in children. Pediatrics 1993;94:471–3. 10 Vischoff D, Charest J. Propofol for pulsed dye laser treatments in pediatric outpatients. Can J Anesth 1994;41:728–32. 11 Moore JK, Moore EW, Elliott RA et al. Propofol and halothane versus sevoflurane in paediatric day-case surgery: induction and recovery characteristics. Br J Anaesth 2003;90:461–6. 12 American Academy of Pediatrics. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 1992;89:1110–15. 13 Litman RS, Berkowitz RJ, Ward DS. Levels of consciousness and ventilatory parameters in young children during sedation with oral midazolam and nitrous oxide. Arch Pediatr Adolesc Med 1996;150:671–5. 14 Rowland AS, Baird DD, Weinberg CR et al. Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992;327:993–7. 15 Keeling PA, Rocke DA, Nunn JF et al. Folinic acid protection against nitrous oxide teratogenicity in the rat. Br J Anaesth 1986;58:528–34. 16 Fujinaga M, Baden JM, Yhap EO et al. Reproductive and teratogenic effects of nitrous oxide, isoflurane, and their combination in SpragueDawley rats. Anesthesiology 1987;67:960–4. 17 Mazze RI, Kallen B. Reproductive outcome after anesthesia and operation during pregnancy. A registry study of 5405 cases. Am J Obstet Gynecol 1989;161:1178–85. 18 Mazze RI, Kallen B. Appendectomy during pregnancy. A Swedish registry study of 778 cases. Obstet Gynecol 1991;77:835–40. 19 Cook-Sather SD, Harris KA, Chiavacci R et al. A liberalized fasting guideline for formula-fed infants does not increase average gastric fluid volume before elective surgery. Anesth Analg 2003;96:965–9. 20 Cohen MM, Cameron CB, Duncan PG. Pediatric anesthesia morbidity and mortality in the perioperative period. Anesth Analg 1990;70:160–7. 21 Tiret L, Nivoche Y, Hatton F et al. Complications related to anaesthesia in infants and children. A prospective survey of 40240 anaesthetics. Br J Anaesth 1988;61:263–9. 22 Holzman RS. Morbidity and mortality in pediatric anesthesia. Pediatr Clin North Am 1994;41:239–56. 23 Cohen MM, Cameron CB, Duncan PG. Pediatric anesthesia morbidity and mortality in the perioperative period. Anesth Analg 1990;70:160–7. 24 Keenan RL, Shapiro JH, Dawson K. Frequency of anesthetic cardiac arrests in infants: effect of pediatric anesthesiologists. J Clin Anesth 1991;3:433–7. 25 Faberowski LW, Banner MJ. The imposed work of breathing is less with the laryngeal mask airway compared with endotracheal tubes. Anesth Analg 1999;89:644–6. 26 Weinger MB, Vredenburgh AG, Schumann CM et al. Quantitative description of the workload associated with airway management procedures. J Clin Anesth 2000;47:315–18.

Other techniques Hypnosis Hypnosis may be effective in decreasing the pain and anxiety of surgical procedures in older children. A variety of techniques, for example visual imagery, are used for distraction and to reduce awareness and perception of pain. Hypnosis has been useful for treatment of chronic pain as well as for acute management of painful injuries and procedures.

Other techniques These include the use of illustrated procedure books and dolls to display the planned procedure, concealment of the needle, draping of the surgical tray and constructing a curtain which obscures the procedure from the patient’s field of view. For infants, cuddling, swaddling or using a pacifier may be soothing. In neonates, feeding a mixture of sucrose and water has been found to be as effective as EMLA cream for pain relief during venepuncture [1,2]. Distraction techniques involving visual imagery or deep breathing may be useful. In the older child, singing, storytelling and lively background music may be helpful [3,4]. For office procedures, allowing the child to choose a movie and watching it on a portable DVD player during the surgical procedure is an excellent distraction technique. Parents should be strongly discouraged from threatening to punish a child for not co-operating. The parent should be the key emotional support for the child during the procedure and should have both hands free and be fully focused on soothing the child. The doctor should have adequate assistance in restricting the child and should not ask the parents to fulfil this role. The use of positive reinforcement and reward is another key tool. Gifts of stickers, toys and sweets ensure that the child leaves feeling that he or she has done a great job, regardless of how difficult the procedure had been. References 1 Gradin M, Eriksson M, Holmqvist G et al. Pain reduction at venipuncture in newborns: oral glucose compared with local anesthetic cream. Pediatrics 2002;110:1053–7. 2 Abad F, Diaz-Gomez NM, Domenech E et al. Oral sucrose compares favourably with lidocaine–prilocaine cream for pain relief during venepuncture in neonates. Acta Paediatr 2001;90:160–5. 3 Rothman KF. Pain management for dermatologic procedures in children. Adv Dermatol 1995;10:287–308. 4 Eichenfield LF, Weilepp A. Pain control in pediatric procedures. Curr Opin Dermatol 1997;4:157–61.

191.1

C H A P T E R 191

Treatment of Congenital Melanocytic Naevi Neta Adler1 & Bruce S. Bauer2 1

Department of Plastic and Reconstructive Surgery, Hadassah Medical Center, Hebrew University School of Medicine, Jerusalem, Israel NorthShore University HealthSystem, Highland Park Hospital, Chicago, IL, USA

2

Introduction, 191.1

Partial thickness excision, 191.2

Indications for treatment, 191.1

Serial excision, 191.2

Timing of treatment, 191.2

Tissue expansion, 191.2

Introduction Congenital naevi present in approximately 1% of the births [1]; those that are larger (20 cm or greater) occur in approximately 1 in 20,000 births [2]. Giant lesions (>50 cm) are even less common [3]. While most surgeons are familiar with treating the small and intermediate size naevi, it is difficult to gain enough experience when approaching more extensive lesions. Many strategies have been tried for the removal and reconstruction of large and giant naevi. Serial excision can often debulk these massive lesions but rarely remove them completely. Excision and split thickness skin graft has generally poor functional and aesthetic outcomes. Dermabrasion, curettage, chemical peel and laser treatment all have problems with recurrence because these modalities eliminate only the superficial portion of the naevus while the cells of congenital pigmented naevi can usually be found as deep as the subcutaneous fat and sometimes even in deeper structures [4]. There is also difficulty following the lesions for malignant transformation because of resulting scarring. The long-term effects of laser treatment on the remaining naevus cells remain to be determined. Juvenile skin although elastic does not have the laxity of an adult skin and local flaps used in adults are often difficult in children. When direct excision and primary closure are not a possibility, then tissue expansion is the ‘workhorse’ treatment modality for many medium to large naevi. Facial naevi that cross multiple aesthetic units as well as those involving the periorbital area may require expansion in combination with full thickness skin graft Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Regional consideration in paediatric tissue expansion, 191.3 Conclusions, 191.8

(expanded or non-expanded). Finally, some unique cases may benefit from a free flap and tissue expansion as an adjunct procedure to close the donor site. References 1 Walton RG, Jacobs AH, Cox AJ. Pigmented lesions in newborn infants. Br J Dermatol 1976;95:389–96. 2 Castilla EE, da Graça Dutra M, Orioli-Parreiras IM. Epidemiology of congenital pigmented naevi: I. Incidence rates and relative frequencies. Br J Dermatol 1981;104:307–15. 3 Marghoob AA, Kopf AW, Bittencourt FV. Moles present at birth: their medical significance. Skin Cancer Foundation J 1999;36:95–8. 4 Arneja JS, Gosain AK. Giant congenital melanocytic nevi. Plast Reconstr Surg 2007;120:26e–40e.

Indications for treatment The appropriate treatment of large and giant naevi is controversial. Although the risk of malignant transformation in congenital pigmented naevi is well established [1–4], many feel that the risk of developing melanoma is too low to warrant the unsightly scars or grafts that may follow treatment. There is no evidence in the literature that demonstrates decrease in occurrence of melanoma after excision of large congenital melanocytic lesion. Furthermore, these patients have increased risk of extracutaneous melanoma [5,6]. Others feel that, in the presence of neurocutaneous melanosis, the greatest risk lies within the central nervous system, so the excision of the cutaneous lesion can only have limited benefits. However, the appearance of these lesions clearly produces a stigma with significant psychological implications. The challenge for the surgeon involved in treating these often complex lesions is to develop treatment modalities that do not only accomplish the excision of all or most of the naevus but also lead to an optimal aesthetic and functional outcome.

191.2

Chapter 191

References 1 Marghoob AA, Kopf AW, Bittencourt FV. Moles present at birth: their medical significance. Skin Cancer Foundation J 1999;36:95–8. 2 Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol 1979;1:123–30. 3 Watt AJ, Kotsis SV, Chung KC. Risk of melanoma arising in large melanocytic nevi: a systematic review. Plast Reconstr Surg 2004;113: 1968–74. 4 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;132:170–5. 5 Bittencourt FV, Marghoob AA, Kopf AW et al. Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 2000;106:736–41. 6 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;132:170–5.

Timing of treatment The life time risk of malignant melanoma for small and medium congenital pigmented naevi is reported to be 0–4.9% [1]. However, because the risk of melanoma is nearly nil prior to puberty for small naevi [2,3], one may comfortably wait until the child may be old enough to excise the lesion under local anaesthesia. If the lesion is located in an area where the excision and reconstruction may not likely be accomplished under local anaesthesia or where there may be possibility of a better final scar with earlier excision, then early excision under general anaesthesia may be warranted. Certainly, many naevi positioned in prominent parts of the face may present as a significant source of peer ridicule starting quite early in the school years and delaying the excision in an effort to avoid a general anaesthetic is not in the child’s best interests. The authors advocate treatment of large and giant naevi by 6 months of age in most cases. Although many of the tissue expansion procedures used in the treatment of large naevi can be applied to older children and adults, the intolerance for repeated procedures and the decreased elasticity of the skin may make the excision of extensive lesions impractical in older patients. Also, for larger naevi the greatest risk for malignancy is in the first few years [4,5]. References 1 Tromberg J, Bauer B, Benvenuto-Andrade C et al. Congenital melanocytic nevi needing treatment. Dermatol Ther 2005;18:136–50. 2 Chun K, Vázquez M, Sánchez JL. Malignant melanoma in children. Int J Dermatol 1993;32:41–3. 3 Rhodes AR, Melski JW. Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 1982;100:219–24. 4 Kaplan EN. The risk of malignancy in large congenital nevi. Plast Reconstr Surg 1974;53:421–8. 5 Trozak DJ, Rowland WD, Hu F. Metastatic malignant melanoma in prepubertal children. Pediatrics 1975;55:191–204.

Partial thickness excision Partial thickness excision of large and giant naevi has taken the form of early dermabrasion, curettage, laser or, more recently, excision leaving the underlying subcutaneous fat in place to minimize contour deformities and covering this with a dermal collagen substructure and very thin, split thickness skin graft or even culture skin. These latter approachs have been particularly applied to the extremities where techniques such as expansion are not as readily applied. The potential downside of each of these approaches is that while the surface naevus population may be reduced, the deeper naevus cells will frequently ‘bleed through’ over time leaving an even more significant deformity at an age where complete excision may no longer be an option. Circumferential grafting of the extremities with these approaches can still also result in significant late functional disturbance.

Serial excision Serial excision is the excision of a lesion in more than one stage. The inherent viscoelastic properties of skin are used, allowing the skin to stretch over time. These techniques enable wound closure to be accomplished with a shorter scar than if the original lesion was elliptically excised in a single stage and to reorient the scar closer to the relaxed skin lines. This technique can be applied to small or medium naevi, depending on the location of the naevus and the laxity of the local skin.

Tissue expansion Several types of tissue expanders exist based on shape, size and type of filling valve. The shape that the authors most commonly use in treatment of congenital naevi is rectangular (Fig. 191.1). Expander volumes have a wide range and vary according to the anatomical site. Saline is delivered in a controlled fashion via the valve port which is located at some distance from the expander, overlying firm tissue. While integrated ports have been used by some surgeons, we use remote ports in all cases with no ports externalized, despite the fact that the parents typically carry out the expander injections. Because the skin overlying the port can be readily anesthetized with a topical anaesthetic, we do see not benefit of externalizing the ports. Consideration for the incisions, expander placement, flap movement in relation to the defect and postoperative scars take preoperative planning and discussion with the patient and family. In regards to donor site, colour, texture and contour of the recipient site must be matched to maximize aesthetic and functional outcome. The donor site tissue must be free of infection, or have

Treatment of Congenital Melanocytic Naevi

191.3

than two decades has demonstrated that expanded transposition and rotation flaps may frequently be preferable. It provides greater versatility in flap design and range [1,2]. References 1 Bauer BS, Margulis A. The expanded transposition flap: shifting paradigms based on experience gained from two decades of pediatric tissue expansion. Plast Reconstr Surg 2004;114:98–106. 2 Joss GS, Zoltie N, Chapman P. Tissue expansion technique and the transposition flap. Br J Plast Surg 1990;43:328–33.

Regional consideration in paediatric tissue expansion Fig. 191.1 Experience has show that standard rectangular expanders in different volumes can be used in most cases.

stable scars, to minimize the risk of expander failure or extrusion. Careful selection of expander size is also imperative in areas with thin donor skin, in order to avoid expander folds or prominence which can create areas of excessive pressure and skin compromise. In the majority of the cases, the expanders are placed through an incision within the border of the lesion. In other cases such as unstable scar, vascular tumour and craniofacial deformities, the incisions are planned outside of the border of defect or on occasion at a distant site. A pocket is dissected to allow placement of the expander with placement of the port in a separate pocket over a region with firm skeletal support for ease of outpatient filling. Partial fill of the expander (10–20% of the listed volume) assures the expander is properly positioned without firm surface folds that can cause pressure against the flap. Closed suction drains are placed for a few days (3–10 days) to control the potential dead space from wide undermining. Serial injections are started 7–10 days post insertion provided the skin flaps are in excellent condition and continue on a weekly basis for about 10–12 weeks. Most pediatric patients go on a home expansion protocol with injections performed by the parents under the direction of our nursing staff and surgeons. If another set of expanders is needed to fully excise the lesion (serial expansion) we usually wait 4–6 months. A broad-spectrum antibiotic is started upon surgery and is continued until the drains are removed. By maintaining a low threshold for placing the patient back on antibiotic in the presence of suspected incipient infection, most infections can be controlled before loss of the expander. The design of an expanded flap is of major importance. While the early dogma of tissue expansion emphasized designing advancement flaps only, experience over more

The optimal choice of treatment still varies by body region and we discuss the most pertinent issues and considerations necessary for successful tissue expansion in each body region.

Scalp The expander is placed in a pocket dissected subgaleal but staying above the periosteum. Flaps are designed with consideration of the major blood supplies to the scalp (superficial temporal, postauricular, occipital vessels and contribution from supraorbital vessels). Port placement in the preauricular area has produced the least migration. The expanders used in scalp reconstruction are usually of 250 or 500 mL volume. Giant naevi might require serial expansion with a larger expander placed after each stage to distribute expansile forces evenly over the hair follicles. As previous studies have shown, tissue expansion itself does not induce proliferation of hair follicles but can more than double the size of the scalp without visible decrease in hair density [1]. Despite former thoughts that expansion may affect cranial vault morphology, it usually self-corrects within 3–4 months [2,3]. The use of expanded transposition flaps versus simple advancement flap design has greatly reduced the number of serial expansion required and has resulted in improved reconstruction of hair direction and hairline (Fig. 191.2).

Face and neck Large and giant naevi of the face are the most visible of these lesions and also represent the area where unsightly scarring is most readily visible; consequently, the planning and execution of the reconstructive plan must be very detailed. A description of all the nuances of treatment of facial naevi is beyond the scope of this chapter. What follows is the summary of the highlights. To achieve an optimal aesthetic and functional result in the facial and cervical regions, one must adhere to the subunit principle. This dictates incision placement so the

191.4

Chapter 191

(a) (b)

(c)

(d)

Fig. 191.2 (a) Giant congenital naevus covering the right scalp, upper ear, forehead and cheek. Expanded flaps are used to reconstruct the forehead and scalp. The surgeon must not overextend the flap but rather repeat expansion if needed. (b) Three months after one set of expansion. Increasing use of transposition flaps allows for better reconstruction of temporal hairline. (c,d) Final result 8 months after additional serial excision of the naevus in the right temple and cheek. The upper ear was reconstructed with postauricular flap and full thickness skin grafting of the upper periauricular surface was performed to avoid hair growth in this non-hair-bearing area. The patient may need some minor scar revision in the future.

final result has the scar hidden in a natural crease (e.g. nasolabial fold). Undue tension on facial structures (brow, eyelid, mouth) can cause disfigurement such as brow asymmetry or ptosis, anterior hairline asymmetry, lower lid and oral drooping, especially when using cervical skin flaps cephalad to the cervicomandibular angle. Neale et al. [4] report 10% lower eyelid ectropion rate and >10% lower lip deformity in this context. Judicious flap design and the use of expanded transposition and rotation flaps, use of multiple expanders and overexpansion are recommended to further minimize these complications (Fig. 191.3). For periorbital reconstruction, expanded full thickness skin grafts can also achieve better functional and aesthetic results than split thickness skin graft, using the benefits of expansion to eliminate size of the graft as a limitation in choice of this option. Pre-expansion of a donor site will allow a single, large, full thickness skin graft to be harvested for reconstruction of the eyelids, canthus and the region between eyelid and brow, without the multiple ‘seams’ that follow use of multiple smaller grafts. Where previously we carried the single graft onto the nasal dorsum when the naevus involve the periorbital area and

nose, we now use flaps from expanded forehead for that coverage (often combined with excision of naevus of the forehead). The supraclavicular area is the ideal donor site for grafts to be placed on the face because of excellent colour and texture match. Part of the expansion provides for the graft tissue with the remainder used for primary closure of the donor site. Donor-site expansion also allows harvest of free flaps from distant sites to cover complete cheek or forehead aesthetic units when regional tissue is not available. The eyebrow may be reconstructed at the same time as the eyelid, treated after the adjacent forehead or eyelid naevus is excised, and reconstructed, or left unresected as an important aesthetic landmark. When the eyebrow is heavily involved with the naevus, it is our current practice to leave a small portion of the naevus unexcised, to mimic the normal eyebrow. If the naevus is darkly pigmented in a fair-skinned child, the residual lesion may be lightened through laser treatment at a later time. However, the long-term effectiveness of this approach has not yet been established. The residual brow naevus is closely followed, and if changes suspicious for malignant transformation arise, the lesion is excised and reconstructed with

Treatment of Congenital Melanocytic Naevi

(a)

(b)

191.5

(c)

Fig. 191.3 (a) Patient with naevus of the cheek, part of the lower eyelid and side of the nose. (b) Reconstruction was carried out with two sets of cheek–neck expansion. Transverse movement of expanded cheek flap minimizes risk of canthal and lid distortion. The lower eyelid and nose were reconstructed with full thickness skin graft taken from the supraclavicular area. Now the authors would probably reconstruct the nose with the expanded flap and the eyelid with full thickness skin graft as a separate unit. (c) Final result 6 months postoperative.

temporal scalp flap based on a branch of superficial temporal artery. If the temporal scalp is minimally involved with naevus and there is a plan for simultaneous expansion of the temporal scalp, an island flap can be planned from the area of maximally expanded flap, with the effect that the hair density is lessened in expansion, and the resultant reconstructed brow will likewise not be too dense. However, for patients where the temporal scalp is involved with naevus, reconstruction with micrografts or strip grafts may become necessary. These are decisions that may not be possible to make until the late teens or adult years.

Trunk The most common location of giant naevi was found to be over the posterior trunk, often extending anteriorly in a dermatomal distribution. Tissue expansion can be very effective on the anterior trunk, provided that the lesion is confined either to the lower abdomen or central abdomen and that there is sufficient uninvolved skin above, or above and below the naevus to expand. Expansion must be avoided in or around the area of the breast bud in females and lesions of the breast should be left until after breast development. Flaps below the chest should be designed as transposition or rotation flaps rather than direct advancement to avoid pulling down of the areola– nipple complex. The use of expanded transposition flaps has enabled excision of naevi of the upper back and buttock and/or perineal region, where previously it was thought that

only skin grafting was possible. Tissue expanders in the 500–750 mL range are used most commonly in infants and young children. Serial expansion with careful planning has made possible the excision of progressively larger naevi of the back and buttocks with excellent outcomes (Fig. 191.4). In patients with giant naevi involving the entire or near entire back, flanks and abdomen, and with markedly variegated naevus architecture or colour, one may decide to excise the greater part of the naevus of the back alone, and cover this with split thickness (non-meshed) skin grafts. Some literature suggests that this is the area at greatest risk of degeneration, and when colour, texture or character of the naevus makes follow-up difficult excision may be warranted to ‘simplify’ follow-up. We still recognize that split thickness skin grafts elsewhere on the trunk and extremities may be associated with significant deformity and potential functional disturbance during growth, so recommend against grafting elsewhere. The back is the only area where split thickness skin grafting may provide a reasonable aesthetic result as long as the graft is not meshed.

Extremities Tissue expansion of the extremities has been viewed classically as of limited value and is associated with higher risk of complications [5,6]. The geometry of the extremity, as well as the limited flexibility of the skin (particularly in the lower extremity) makes regional expansion of limited use.

191.6

Chapter 191

(a)

(b)

(d)

(c)

(e)

(f)

Fig. 191.4 (a,b) Naevus of the right abdomen, flank and back. (c) First expansion at age 6 months of the lower abdomen and back. The naevus was partially excised and reconstructed with the expanded transposition flaps. (d) Six months later the patient had a second expansion of the abdomen and back. (e) Final result after third expansion cycle, excision of the remaining naevus at the lower chest with expanded flap reconstruction. The reconstruction plan has to take into consideration avoiding any distortion of the developing breast area. (e) Final result postoperative, back view. (f) Final result postoperative, front view.

In the past decade, the authors have begun to find a way around these limitations [7]. Large expanded transposition flaps from the scapular region are used to cover the upper arm and shoulder. For circumferential naevi from the elbow to the wrist, expansion of the flank creates a large pedicled flap through which the forearm can be placed during vascularization of the flap from the recipient bed. After 3 weeks the pedicle is divided (Fig. 191.5). Expanded full thickness skin grafts have been used effectively for the dorsum of the hand with excellent aesthetic outcome. Although pedicled flaps are not readily available for coverage of more extensive lesions of the arm, thigh or leg, the authors have had success with expanded free flaps from the abdomen and scapular region. These procedures have been used only in very carefully selected cases, and the optimum timing of these complex reconstructive procedures is still under consideration.

Satellite naevi Satellite naevi may appear anywhere over the course of the first few years of life, and their number seems to correlate directly with the likelihood of neurocutaneous melanosis [8]. They may vary in size from small to medium lesions. To date, no case of melanoma has been reported arising in a satellite naevus [9]. With this in mind, it is generally agreed that the primary reason for excision of satellite naevi is an aesthetic one. A significant benefit may also result from excising multiple satellite naevi on the face before the child enters his or her school years. In addition, some of the larger satellites on the extremities may be excised in infancy and early childhood (simultaneously with other procedures on the major lesion) by relatively simple serial excision techniques, where if left to later childhood and adolescence the reduced flexibility of the surrounding tissues may no longer allow excision without expansion or grafting.

Treatment of Congenital Melanocytic Naevi

(a)

(b)

(d)

191.7

(c)

(e)

Fig. 191.5 (a) Naevus of the upper extremity from the shoulder to the wrist, circumferential. (b) Expansion of the flank and groin in preparation for pedicled flap. (c) The upper extremity was attached to the flank after partial excision of the naevus and elevation of the expanded flank flap. The pedicle of the flap was divided 2–3 weeks later. (d) Six months later the back was expanded in preparation for reconstruction of the shoulder and upper arm area with transposition flap from the back. (e) Eight months later after further excision of the remaining sling of naevus at the wrist area and primary closure. Complete excision will require one more step of excision and primary closure at the wrist.

References 1 MacLennan SE, Corcoran JF, Neale HW. Tissue expansion in head and neck burn reconstruction. Clin Plast Surg 2000;27:121–32. 2 Colonna M, Cavallini M, De Angelis A et al. The effects of scalp expansion on the cranial bone: a clinical, histological, and instrumental study. Ann Plast Surg 1996;36:255–60. 3 Moelleken BR, Mathes SJ, Cann CE et al. Long-term effects of tissue expansion on cranial and skeletal bone development in neonatal min-

iature swine: clinical findings and histomorphometric correlates. Plast Reconstr Surg 1990;86:825–34. 4 Neale HW, Kurtzman LC, Goh KB et al. Tissue expanders in the lower face and anterior neck in pediatric burn patients: limitations and pitfalls. Plast Reconstr Surg 1993;91:624–31. 5 Pandya AN, Vadodaria S, Coleman DJ. Tissue expansion in the limbs: a comparative analysis of limb and non-limb sites. Br J Plast Surg 2002;55:302–6.

191.8

Chapter 191

6 Casanova D, Bali D, Bardot J et al. Tissue expansion of the lower limb: complications in a cohort of 103 cases. Br J Plast Surg 2001;54: 310–16. 7 Margulis A, Bauer BS, Fine NA. Large and giant congenital pigmented nevi of the upper extremity: an algorithm to surgical management. Ann Plast Surg 2004;521:158–67. 8 Marghoob AA, Dusza SW, Oliveria SO et al. Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients with large congenital melanocytic nevi. Arch Dermatol 2004;140:171–5. 9 DeDavid M, Orlow SJ, Provost N et al. A study of large congenital melanocytic nevi and associated malignant melanomas: review of cases in the New York University Registry and the world literature. J Am Acad Dermatol 1997;36:409–16.

Conclusions Although the exact risk of malignant degeneration of large and giant congenital naevi has yet to be determined,

the psychological impact on these children and their families justify excision and reconstruction, provided that they can be accomplished with an optimal aesthetic and functional outcome. The ability to present organized discussion of current views of malignant change to parents, patients (when old enough) and other allied healthcare workers is critical. Experience with a large population of children with large and giant congenital melanocytic naevi has demonstrated that thoughtful application of the full spectrum of reconstructive options, heavily weighted toward the use of tissue expansion (as well as expanded pedicled and free flaps) can result in total or near total excision of many of these extensive naevi with predictably good outcomes.

192.1

C H A P T E R 192

Nursing Care of Paediatric Skin Jane White1, Jane Linward1, Jacqueline Denyer2 & Bisola Laguda3 1

Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Trust, London, UK Epidermolysis Bullosa Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK 3 Paediatric Dermatology, Chelsea and Westminster Hospital, London, UK 2

Neonate, 192.1

Infections and infestations, 192.4

Intensive care, 192.13

Eczema, 192.4

Vascular birthmarks, 192.7

Summary, 192.19

Psoriasis, 192.4

Systemic treatment, 192.10

The nursing care of many skin conditions is an essential part of the management of children with various dermatological conditions. This varies from providing advice and guidance to parents in the clinic, through monitoring of children on systemic medication, to the treatment of children with more serious skin conditions in hospital. At Great Ormond Street Hospital for Children (GOSH), we have a dedicated dermatology ward with a team of specialist nurses. It would be impossible to cover all aspects of nursing care, but in this section of the book we have included guidelines for the nursing care of selected conditions used by our department, which we hope will be of practical value to nurses, paediatricians and dermatologists. The skin care regimens that are listed should be viewed as personal practice and we appreciate that there are many different approaches to treatment. It may well be that our suggestions could be improved and we are willing to update our ideas. Nevertheless, the purpose of this section is to provide a basic plan of management that can be used by other nurses/doctors.

Neonate Collodion baby Management of the baby born with a collodion membrane is detailed in Chapter 121. The nursing aspects are listed in Table 192.1. The outlook for these children is usually very good. The majority evolve into having various types of inherited ichthyosis, but in approximately 10% the skin can subsequently look normal or mildly dry and scaly. The mortality for this condition is low, but requires appropriate neonatal skin care. Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

Harlequin ichthyosis This is the rarest and most severe form of ichthyosis with a high mortality in the neonatal period mainly due to sepsis, respiratory failure and electrolyte imbalances. Harlequin ichthyosis is described in detail in Chapter 12. The nursing management is along similar lines to looking after a collodion baby (Table 192.1), with more of an emphasis on eye care because of the severe ectropion and respiratory problems as a result of restricted chest movement. The majority of babies now survive as a result of intensive nursing and medical care and the early administration of the oral retinoid, acetretin (Neotigason®). An oil-based liquid formulation can be made, which has a short half-life and needs to be kept in the dark. This can be given initially through the nasogastric tube. These children will have a lifelong severe ichthyosiform erythroderma.

The newborn with epidermolysis bullosa These babies have fragile skin and are prone to blistering and wounds. In many of those severely affected, extensive wounds resulting from intrauterine movements and birth trauma are present at delivery. Recognition of this condition is of primary importance so that these babies can be handled with care and the appropriate measures taken to look after their skin. Management is by assessment and guidance from a specialized multidisciplinary team. An outreach service is available in the UK by Clinical Nurse Specialists to avoid the transportation of vulnerable neonates. Epidermolysis bullosa comprises a group of genetic disorders with a number of different subtypes that vary in severity. The most severe forms are dystrophic epidermolysis bullosa and junctional epidermolysis bullosa (see Chapter 118). Nursing care for the newborn suspected of having epidermolysis bullosa is summarized in Table 192.2.

192.2

Chapter 192

Table 192.1 Nursing care of the collodion baby and harlequin ichthyosis Action

Rationale

Initial assessment Nose, throat and skin swabs for MC&S

To exclude secondary infection

MRSA screen

To ensure early detection, increased susceptibility due to poor skin integrity and hospitalization

Baseline temperature, pulse, respiratory rate and blood pressure, increase frequency as indicated

To obtain the normal range and detect deterioration of condition

Length and weight

To assess fluid loss, monitor weight gain and calculate drug doses

Assess skin and record in the nursing notes

To assess extent of condition and monitor progress

Skin treatment Strict hourly application of 50 : 50 white soft paraffin/liquid paraffin

To reduce fluid loss, increase mobility and comfort and prevent fissures

When condition allows, daily baths with an oily emollient

To cleanse and increase hydration of the skin

Use a soap substitute, such as aqueous cream or emulsifying ointment

Normal soap too astringent

Eyes: 4-hourly eye care with saline; apply eye ointment/emollient eye drops as prescribed by the ophthalmologist

To prevent dryness and infection in the presence of ectropion

For severe ectropion, especially in babies with harlequin ichthyosis in whom the eyes are usually closed, apply drops/ointment to eyelids only

To prevent damage to the mucosal lining of the eyelids

Mouth: 2-hourly mouth care if limited oral intake and marked eclabium

To prevent dry, cracked and sore lips and mouth

Pressure areas, nurse on infant pressure-relieving mattress, turn regularly and monitor pressure areas

To relieve pressure to the skin and alleviate pain from fissured areas

Fluid and electrolyte balance Meticulous fluid balance monitoring is essential

Poor skin integrity can lead to increased fluid, electrolyte and protein loss, leading to dehydration, hypoglycaemia and renal failure

Nutrition Initiate enteral feeding as soon as possible

To ensure optimum intake, leading to adequate hydration and weight gain and increased wound healing

A Haberman feeder, with a specially designed teat, helps to maximize oral feeding

Allows for decreased sucking caused by eclabium

If a nasogastric tube is required, secure with a tubular bandage, such as Tubifast®

Adhesive tape may damage skin and is difficult to secure due to greasy emollients

Involve dietitian for assessment and guidance, encourage breastfeeding where possible

To ensure optimum dietary intake and promote maternal/baby bonding

General measures Nurse in a humidified incubator

To introduce moisture and maintain body temperature

Incubator temperature should be kept comparatively low

Absence of sweating and use of greasy emollients will inhibit heat loss

Avoid venepuncture and intravenous access, if possible

To minimize risk of secondary bacterial sepsis

Ensure adequate analgesia is administered when indicated

To ensure baby is comfortable and rested

Minimal handling

To prevent pain and damage to the skin

Nurse under strict protective precautions

To minimize risk of secondary infection

Observe digits closely

Constricting bands can cause ischaemia

Monitor respiratory effort closely, mainly relevant to babies with harlequin ichthyosis

Respiratory difficulties may result from restriction of chest movement and blockage of nasal passages

Ensure routine newborn checks are made, e.g. Guthrie’s test and maternal postnatal checks

To avoid omissions due to baby’s complications

Encourage parental contact; handling baby on infant mattress may make this easier

To promote bonding; baby may be difficult to handle owing to greasy emollients

Give practical and emotional support to the family Discharge planning Set up mechanism for rapid access to medical treatment

Children can rapidly become unwell due to dehydration and sepsis

Teach carers the emollient therapy to be continued at home and any additional care the baby may require

To sustain recovery

Make adequate follow-up arrangements

To monitor progress and discuss further management and prognosis

Set up local community nurse support

To ensure adequate support and assistance for the family after discharge from hospital

MC&S, microscopy, culture and antibiotic sensitivity; MRSA, methicillin-resistant Staphylococcus aureus.

Nursing Care of Paediatric Skin

192.3

Table 192.2 Immediate nursing care of the newborn with epidermolysis bullosa Action

Rationale

Remove cord clamp and replace with ligature Nurse in cot/bassinette unless incubator required for reasons such as prematurity

To avoid trauma to the surrounding skin To avoid additional blistering from heat and humidity within incubator

Skin treatment Lance all blisters with a sterile needle Leave the roof on the blister Dust area with cornflour

To prevent blisters from enlarging To protect the underlying skin To dry the blisters and limit their spread

Wound management* Ensure adequate analgesia given prior to dressing changes Apply a non-adherent primary dressing such as soft silicone or lipidocolloid Cover primary dressing with soft silicone foam and antimicrobial agent Dress fingers and toes individually Secure with tubular bandage

To avoid trauma to the wound and surrounding skin and to encourage healing To provide padding to avoid trauma, to absorb exudate and avoid critical colonization To avoid digital fusion To avoid using adhesive tape that will tear the skin

Fixation of cannulae If IV cannula required secure with soft silicone rather than adhesive based tape Removal of adhesive products Use silicone medical adhesive remover spray to dissolve adhesive

To ensure skin integrity on removal To avoid skin stripping

Nappy area Cleanse skin with 50% liquid paraffin, 50% white soft paraffin Cover open or blistered areas with hydrogel-impregnated gauze dressing Line disposable nappy with soft liner

To avoid friction To assist healing and avoid contamination To prevent edges of nappy from rubbing the skin

Feeding Use Haberman feeder if not breastfed Apply teething gel to teat Protect lips with petroleum jelly Avoid nasogastric tube if possible If essential, use tube suitable for long-term feeding and secure with Mepiform® (Mölnlycke)

To To To To To

avoid further mucosal blistering from traditional teats reduce pain from oral lesions and allow infant to suck avoid the teat sticking to the lips and tearing the skin avoid damage to mucosa minimize mucosal and skin damage

Handling Lift on soft pad; use a roll-and-lift technique Avoid bathing until intrauterine and birth damage have healed

Shearing forces from traditional handling can result in skin loss When naked, the infant will kick legs together and remove skin from healing areas

Clothing Dress in front-fastening baby suit; turn clothing inside out

To protect skin; to prevent seams from rubbing

* When recommended products are not available, use a non-adherent dressing but apply 50% liquid paraffin/50% white soft paraffin over the dressing to reduce adhesion and minimize skin damage.

192.4

Chapter 192

Eczema ‘Wet wrap’ dressings ‘Wet wrap’ dressings are used to treat children with severe generalized eczema that has not responded to firstline therapy (see Chapter 30). Various techniques have been described. At GOSH we use two methods: one is used exclusively in hospital for the treatment of an acute exacerbation of eczema (Table 192.3) and the other has been adapted mainly for use at home (Table 192.4). Wet dressings are widely used at home, especially in the UK. Sometimes they are used without topical steroids but with simple emollients applied directly to the skin. Whichever method is used, the effect of wet dressings can be very dramatic; it can make the child feel more comfortable with a reduction in itching and an improved sleep pattern. Wet dressings are undoubtedly a valuable tool for the treatment of children with severe generalized eczema; however, use at home requires good compliance and must be carefully monitored. It has been recommended by the National Patient Safety Agency (NPSA) that information is given to families about the potential fire hazard associated with paraffin-based skin products on clothing and dressings near an open flame (NPSA 2007, Rapid Response Report 4, 26th Nov 2007).

Paste bandages The use of paste bandages is of particular value for the treatment of intensely itchy and lichenified eczema on the arms or legs where scratching is causing excessive skin damage. They are ideal for localized areas, such as the wrists or lower legs/ankles. At GOSH we have traditionally used zinc oxide-impregnated bandages covered with Coban®, which is a dry, elasticated self-adhesive strapping. This can be left on for up to 5 days. Coban® is not advisable if there is a known latex allergy .The method of application is detailed in Table 192.5.

Psoriasis Dithranol preparations Dithranol is a time-honoured treatment for plaque psoriasis (Chapter 82). Traditionally, it has been used as an inpatient treatment incorporated at varying strengths (usually 0.05–2%) in Lassar ’s paste (zinc and salicylic acid paste BP). It is left on for a defined period of time, dependent on the thickness of the psoriasis, the individual skin sensitivity and age of the child, usually from 30 min to 2 h. It must be explained to the family that dithranol produces a temporary brownish-purple staining of the skin and may ‘burn’ the normal surrounding skin if this is not protected. ‘Short-contact’ therapy can be undertaken by the patient as a day-attender at hospital. For children therapy

should be supervised in a hospital unit by nurses who are experienced in applying dithranol preparations. In certain situations when parents are taught the treatment regimen it can be carried out at home with caution. Other formulations available include Dithrocream® 0.1–2%. The nursing procedure is detailed in Table 192.6.

Scalp treatment A traditional treatment for scalp psoriasis is the use of Cocois® (coal tar solution 12%, salicylic acid 2%, precipitated sulphur 4%, in a coconut oil emollient base). This is massaged into the scalp, left on for a defined period of time and then washed off with a prescribed shampoo, usually one containing coal tar (Table 192.7). As the scalp improves, the duration of treatment and frequency can be reduced. At home it may be more practical to apply the scalp ointment at teatime, when the child returns home from school, leave it on for 2–4 h and wash off prior to going to bed.

Infections and infestations Care of the dermatology inpatient with MRSA The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the hospital setting as well as the community remains a concern. This is part of a much wider problem of antibiotic resistance. The carriage of MRSA is particularly relevant to children with chronic skin disease. In the community, skin colonization is not as much of an issue as it is in a hospital environment, where it can be transmitted to other patients, some of whom would be at risk because of immunosuppression. Often these strains are resistant to most common antibiotics, which can include fucidic acid (Fucidin®) and mupirocin (Bactroban®). The treatment of MRSA infection is usually with intravenous antibiotics, such as teicoplanin and vancomycin. Newer drugs now available include linezolid, daptomycin and tigecycline. There are strict infection control measures to prevent cross-infection within the hospital setting (Table 192.8).

Staphylococcal scalded skin syndrome Certain strains of S. aureus produce toxins, which can cause widespread skin peeling (Chapter 54). The source of infection is often the nasopharynx, umbilicus, skin wound, blood or as a result of breastfeeding. The symptoms develop within a few hours to a few days. The upper part of the epidermis peels off like wet tissue paper. Affected children can be very unwell and require highdependency nursing care (Table 192.9). Treatment includes intravenous fluids, antibiotics and adequate analgesia.

Nursing Care of Paediatric Skin

192.5

Table 192.3 Wet dressings for inpatient treatment using Tubegauz® (Fig. 192.1a–d) Action

Rationale

Initial assessment on admission Nose, throat and skin swabs for MC&S MRSA screen if previous hospitalization and/or recurrent antibiotic therapy Baseline temperature, pulse, respiratory rate and blood pressure, increase frequency as indicated Length and weight Assess skin and record findings

To detect secondary infection To ensure early detection, increased susceptibility owing to these factors To obtain baseline values To monitor growth and calculate drug doses To assess severity of eczema and monitor progress with treatment

Treatment procedure Cut appropriately sized pieces of the cotton tubular bandage (Tubegauz®) for the arms, legs and trunk Soak the individual pieces of Tubegauz® (suit 1) in the steroid cream* (not water) Put on the first layer of ‘wet’ Tubegauz®; tie the arm and leg pieces to the trunk Then apply the second ‘dry’ suit over the top of the wet layer, securing the arm and leg pieces to the trunk section Keep hands covered; if the child is a thumb-sucker a small hole can be cut in the bandage

The technique involves two layers of bandaging To produce the first ‘wet’ layer This enables all affected areas on the limbs and trunk to be covered by a dressing impregnated with a weak steroid cream This completes the dressing To minimize damage from scratching

Treatment regimen Dressings are changed twice daily by the nursing staff usually for 3 days Apply separate topical preparation to face and neck as prescribed

There is usually a rapid improvement, and in most cases >90% clearance of eczema in this period of time Areas not covered by the wet dressings

Treatment immediately after the application of wet dressings The child is kept in hospital for a further 1–2 days and the residual or recurrent areas of eczema are treated with an appropriate topical steroid ointment† (without the use of dressings) once or twice daily, as needed The use of a moisturizing agent at other times during the day to all areas of dry skin (2–3 times daily)

Treatment during this time is then continued after discharge from hospital at home; it allows for the skin condition to stabilize To maintain the integrity of the skin barrier

General measures Twice-daily cool baths with an oily bath emollient Use a soap substitute, such as aqueous cream or emulsifying ointment to wash If there is any suspicion of secondary bacterial infection, oral antibiotics should be prescribed‡ A sedative antihistamine is also helpful in this situation and should be given as prescribed Loose cotton pyjamas should be worn over wet dressings

To cleanse and hydrate the skin Normal soap too drying and can irritate the skin Skin infection may be responsible for the exacerbation of eczema To help settle the child To prevent child becoming cold

Discharge planning Educate caregivers on treatment and management at home, support with written instructions Liaise with GP and community paediatric nursing team as appropriate Outpatient follow-up appointment within 2–3 weeks

Essential so that the control of eczema is maintained To ensure child and caregiver are supported locally To closely monitor progress and review long-term treatment plan

MC&S, microscopy, culture and antibiotic sensitivity; MRSA, methicillin-resistant Staphylococcus aureus. * Currently we use: for babies under 1 year, 0.5% hydrocortisone cream, and for children over 1 year, betamethasone valerate 0.01% cream (Betnovate® diluted 1 : 10). Both hydrocortisone and Betnovate® can be diluted with either aqueous or cetomacrogol cream. † Currently we use: for babies under 1 year, 1% hydrocortisone ointment; for children over 1 year, betamethasone valerate 0.025% ointment (Betnovate-RD®). ‡ If there is overt impetiginization then wet dressings should be delayed until 48–72 h after commencing antibiotics and when appropriate treatment has been confirmed from the skin swab results. If eczema herpeticum is suspected then this is an absolute contraindication to the use of wet dressings.

192.6

Chapter 192

(a)

(b)

(c)

(d)

Fig. 192.1 (a–d) Wet dressings for inpatient treatment using Tubegauz®. Table 192.4 Wet dressings more suitable for use at home using Tubifast® Action

Rationale

Treatment procedure Apply the weak topical steroid ointment, beclomethasone dipropionate 0.0025% substitute only to the affected areas, including the face Apply 50 : 50 white soft paraffin/liquid paraffin liberally to the unaffected areas Apply a suit of Tubifast® bandages (one wet layer and one dry layer). Tubifast has a tighter fit than Tubegauz®. The wet layer uses water and needs to be kept damp using a sponge or spray Then apply the second ‘dry’ suit over the top of the wet layer, securing the arm and leg pieces to the trunk section

To reduce inflammation As a moisturizing agent and to maintain the integrity of the skin barrier To reduce itching and prevent damage from scratching, as well as maintaining an appropriate skin temperature This completes the dressing

Treatment regimen For use in hospital, dressings are changed twice daily for 3–5 days Continue nightly wet wraps at home for 6–8 weeks gradually reducing frequency after this period if effective

This will produce a significant improvement, sufficient for the child to be discharged Stopping wet wraps abruptly can induce a flare of eczema

The initial assessment on admission, general measures and discharge planning are similar to those described with the other method (see Table 192.3). A set of Tubifast® garments (Medlock Medical) includes long-sleeved vests, tights/leggings, mittens and socks, in different sizes, which makes it much easier for the family, and they can be washed and reused.

Nursing Care of Paediatric Skin

192.7

Table 192.5 The application of Ichthopaste and Coban® bandages (Fig. 192.2a–d) Action

Rationale

Preparation Explain the procedure to patient and caregiver including why it is indicated; use photographs and a doll if appropriate Ensure the topical treatments are prescribed on the patient’s prescription chart Assemble and prepare the following: Ichthopaste roll, Coban® bandage, emollient/topical treatment to be applied to the skin, round-ended scissors Select appropriate distraction toys for the child as he/she will be required to sit still during the treatment

To alleviate anxiety, determine the level of cooperation and ensure that informed consent to treatment is given To adhere to the medication policy

To avoid boredom and anxiety during treatment

Administration Apply the emollient/topical therapy to the affected area

To reduce inflammation and maximize comfort

Legs and feet Wind the Ichthopaste bandage around the foot, overlapping one-half of the width of the bandage; bandage the ankle separately in the same fashion; work up the leg, occasionally reversing the direction of winding in order to make a pleat

This allows for shrinkage and maximum mobility; pleating and overlapping prevents a tourniquet effect from occurring

Arms and hands Using approximately 15-cm lengths, cover the palms and backs of hands; fingers can be bandaged separately as required; work up the arms, winding the Ichthopaste bandage around the arm, occasionally reversing the direction in order to make a pleat Coban® bandage Wind the Coban® bandage around the limb, leaving a small section of Ichthopaste showing at both ends Release most of the tension from the bandage during use

As with the legs and feet

To secure the underlying Ichthopaste bandage and protect clothing

General measures Usually left in situ for 12–48 h, but can be left for longer For home use: ensure that the caregiver is competent in application following demonstration Support with written instructions; advise that treatment may stain clothing/bedding

Scabies Scabies is a highly contagious mite infestation transmitted by close physical contact. All members of the family and close contacts should be treated simultaneously. Written instructions given to the family increase the likelihood of the correct procedure being followed (Table 192.10). There are a number of different topically applied treatments that can be used, which include: permethrin 5% cream (Lyclear®) and malathion 0.5% in an aqueous base (Derbac-M®). For more details see Chapter 72.

To prevent constriction To ensure correct application To support verbal instructions

Vascular birthmarks Skin care after laser therapy for port-wine stains Laser treatment for port-wine stains is described in detail in Chapter 188. Meticulous attention to skin care after laser treatment is essential and minimizes the risk of scarring and postoperative pigmentary changes (Table 192.11).

192.8

Chapter 192

(a)

(b) (d)

(c) Fig. 192.2 (a–d) The application of Ichthopaste and Coban® bandages.

Nursing aspects of haemangiomas Haemangiomas are common birthmarks and the majority do not require any intervention. However, if medical treatment is needed, propranolol is now increasingly used in preference to oral steroids and requires nursing input for safe monitoring .The main medical complica-

tion of haemangiomas is bleeding from trauma. In certain situations they can become necrotic on the surface and ulcerate, which may be slow to heal and give rise to local problems depending on the site. Haemangiomas are discussed in detail in Chapter 113. Nursing aspects of non-ulcerated and ulcerated

Nursing Care of Paediatric Skin Table 192.6 The application of dithranol preparations Action

Rationale

Preparation To alleviate anxiety, determine the level of cooperation and ensure informed consent to treatment

Ensure that the treatments are prescribed on the patient’s prescription chart and check each preparation

To adhere to the medication policy and ensure correct strength is used

Assemble and prepare the following: disposable gloves (for the nurse), dithranol preparation, white soft paraffin, talcum powder, arachis oil*, bath emollient, moisturizer, orange sticks and spatula, gauze squares, old pyjamas/gown or Tubegauze suit Can be a lengthy treatment; need to prevent boredom and anxiety

Apply white soft paraffin to all areas of healthy skin surrounding the psoriasis plaques

To prevent the dithranol burning healthy skin

Use either an orange stick or spatula (depending on size of plaque) to apply the dithranol preparation to the areas of psoriasis

To ensure the dithranol is applied carefully and accurately

Check the time of application

To ensure the dithranol is left on for the correct amount of time

Dress the patient in old pyjamas/ gown or Tubegauze suit

Action

Rationale

Assess the patient’s scalp psoriasis and record extent and severity

To monitor effectiveness of therapy

Explain the procedure to the child and caregiver, including why it is indicated; use photographs if appropriate

To alleviate anxiety, determine the level of cooperation and ensure informed consent to treatment is given

Ensure the treatments are prescribed on the patient’s prescription chart and check against the preparations

To adhere to the medications policy and ensure that the correct treatments are administered

Assemble and prepare the following equipment: disposable gloves, plastic comb, scalp ointment, shampoo

Administration

Dust treated skin with talcum powder

Table 192.7 The application of scalp preparations for psoriasis

Preparation

Explain the procedure to patient and caregiver, including why it is indicated; use photographs if appropriate

Select appropriate distraction toys for the child as he/she will be required to sit still during the treatment

192.9

To help keep the dithranol preparation in situ and prevent smearing Dithranol will stain all contacts

Removal After the allocated time, remove the dithranol using gauze squares and arachis oil (or olive oil in cases of peanut allergy) Follow with a bath using an oily bath emollient Use a soap substitute to cleanse the skin, such as aqueous cream or emulsifying ointment * Olive oil can be used in cases of nut allergy.

Select appropriate distraction tools for the child, as he/she will be required to sit still during the treatment

To prevent boredom and anxiety

Administration The scalp ointment should be applied in a methodical manner by parting the hair in sections; part the hair with a comb and apply a smear of the ointment along the parting; use the comb to gently encourage any scale to lift from the scalp; reapply the ointment to the thickened encrusted areas; part the hair, 1 cm from the treated area and repeat until the whole scalp is treated

This technique ensures adequate coverage of the whole scalp

Leave in situ for the required time; a shower cap/scarf may be used

The longer it is left on, the more effective it is, ideally overnight

If left overnight, pillow cases should be covered

The treatment may stain pillow cases

After the allocated time, wash the hair with the prescribed shampoo

To remove the loosened scale/ crust

Comb the hair against its natural fall

To gently lift any remaining scale, being careful not to pull out any scalp hairs

Additional points Carers should be involved in the treatment

In order to continue the treatment at home as necessary

Review the scalp with each treatment

To monitor effectiveness

192.10

Chapter 192

Table 192.8 Care of the dermatology inpatient with methicillin-resistant Streptococcus aureus (MRSA) infection Action

Rationale

Environment Nurse in an isolation cubicle with an infection precautions sign clearly visible Keep the door closed at all times Remove excess equipment from the cubicle before the patient is isolated When bathing is required, if possible limit use of bathroom to MRSA patient only or clean thoroughly following each use Ensure the bath is rinsed thoroughly after cleaning The isolation room should be cleaned regularly during use and surfaces should be kept clean and dry

To prevent transmission of MRSA to others and to alert those entering the cubicle MRSA can be airborne To prevent unnecessary items being contaminated To prevent cross-infection To prevent skin irritation to next patient Reduces the risk of contamination

Staff/visitors Ensure MRSA status is recorded confidentially in all of the patient’s relevant medical and nursing documentation Limit the number of staff/visitors entering the cubicle at the same time Prior to entry into isolation cubicle: wear plastic apron; wash hands; wear disposable gloves; collect all equipment required Prior to exiting isolation cubicle: remove plastic apron and gloves; wash hands Involve play specialist for activities

Essential information Reduces the risk of cross-infection To protect clothing and to prevent cross-infection

Child will be bored in cubicle; no access to playroom

Skin care In cases of colonization only, normal skin care regime should continue When attending to wound/skin care, hands should be washed before and after; and gloves should be worn Equipment Where possible, allocate equipment for sole patient use Equipment should be kept clean and dry Do not take into the cubicle unnecessary equipment, including pens, notes and personal stethoscopes Clean/disinfect all equipment before removing from the room

Reduces the risk of cross-infection Less likely to become contaminated To avoid unnecessary contamination To prevent cross-infection

General measures Give practical and reassuring support to the family After discharge from hospital Thorough cleaning of the cubicle according to a strict hospital protocol

haemangiomas are detailed in Tables 192.12 and 192.13 respectively. Ulcerated haemangiomas occur most commonly in the nappy area and around the mouth. They may easily become secondarily infected and can be difficult to heal. The child may be distressed, feed poorly and fail to thrive. First-line treatment is conservative daily nursing care. If this fails after a period of 1–2 weeks then laser treatment should be considered.

Acknowledging the stigma of MRSA status, and parental concerns

Systemic treatment Methylprednisolone Intravenous bolus infusions of methylprednisolone are used to treat a number of severe inflammatory conditions, including: connective tissue disorders, such as systemic lupus erythematosus, dermatomyositis and mixed connective tissue disease (Chapter 175); graft-versus-host disease (Chapter 178); vasculitis (Chapters 160, 163, 167)

Nursing Care of Paediatric Skin

192.11

Table 192.9 Nursing care of staphylococcal scalded skin syndrome Action

Rationale

On admission Nose, throat and skin swabs for culture and antibiotic sensitivities, including a specific request for an MRSA screen Baseline temperature, pulse, respiratory rate and blood pressure, increase frequency as indicated Height and weight Assess skin and record

For early detection of infection To obtain the normal range and detect deterioration of condition To assess fluid loss, monitor weight loss and calculate drug doses To assess extent of condition and monitor progress

Skin care Daily bathing/washes; dependent on mobility and fragility of the skin Use an oily emollient in the water Use a soap substitute such as aqueous cream or emulsifying ointment Dress denuded areas with Vaseline Gauze® soaked liberally in a 50 : 50 mixture of white soft paraffin/liquid paraffin. These are changed every 12–24 h Secure with a loose Tubegauz® suit Apply the 50 : 50 paraffin mix to all exposed areas, in particular the face and napkin area As the dressings dry out, reapply the 50 : 50 paraffin mix to the Vaseline Gauze® Eyes: at least 4-hourly eye care in the acute period; apply eye ointment/ drops as prescribed Mouth: 2-hourly mouth care if limited oral intake and in the presence of mucosal and lip involvement Pressure areas: nurse on a pressure-relieving mattress, monitor pressure areas and position patient appropriately

To clean the skin To prevent dryness Normal soap too astringent For comfort, to promote healing and to protect denuded areas from infection and further trauma To keep dressings in situ To protect these areas and prevent further trauma To maximize effectiveness of dressings To prevent damage, infection and long-term complications To prevent and/or improve mucosal and lip involvement To relieve pressure on the skin and alleviate pain

Fluid and electrolyte balance Administer IV replacement fluid as prescribed Secure cannula with non-adhesive tape/dressing and bandage well Careful fluid balance monitoring essential Consider urinary catheter for painful micturition and/or urine retention

To correct fluid, electrolyte and protein loss and prevent dehydration, renal failure and shock Adhesive tapes/band-aid plasters will damage fragile skin To ensure correct fluid balance and to observe for urinary retention To normalize urine output and reduce pain on micturition

Nutrition Encourage/initiate enteral feeding If a nasogastric tube is required, secure with a tubular bandage or non-adhesive tape Involve dietitian for assessment and guidance

To prevent weight loss, protein loss and promote wound healing Adhesive tape will damage fragile skin To ensure optimum dietary intake

Pain relief Ensure adequate analgesia is administered; consider IV analgesics with extensive skin involvement

To ensure child is pain free; extensive skin loss causes high levels of pain that may be difficult to control with oral analgesics alone

General measures Minimal handling Provide constant environmental temperature where possible (30–32°C is optimum) Monitor core temperature closely Nurse under strict infectious and protective precautions in a cubicle Give practical and emotional support to the child and family

To prevent pain and damage to the skin Temperature regulation is compromised due to extensive skin loss Skin temperature is unreliable; at risk of hypothermia because of excess heat loss To protect against further sepsis Child and family may experience high levels of distress

Discharge planning Teach the parents/carer the skin care regimen to be continued at home

To sustain recovery

192.12

Chapter 192

Table 192.10 Treatment of scabies Action

Rationale

Pretreatment Contact tracing should include all close/prolonged skin-to-skin contacts of the last 6 weeks even if asymptomatic

Clinical manifestations may not appear for at least 1 month after initial infestation

Ensure that treatments are coordinated to treat all contacts on the same day or avoid interaction until treatment is administered

In order to avoid reinfection

Application Always read the advice leaflet before applying the treatment

In order to apply the treatment correctly; preparations may vary

Ensure that the skin is kept cool and dry

Increased absorption can occur when the skin is damp

Do not bathe before applying the cream

Hot baths can increase absorption of the cream into the bloodstream

The cream or lotion should be applied to the entire body surface area

Missing areas will prevent complete eradication

Apply particularly thoroughly to behind the ears, axillae, external genitalia, inner thighs, backs of knees and under the nails Always treat the face and scalp in infants, young children and the immunocompromised

The head and face are commonly affected within these groups

Avoid application around the eyes and mucous membranes

Will be an irritant

The treatment should be left in situ for 8–12 h or overnight

In order to allow time for the cream/lotion to penetrate the burrows and skin

Mittens should be used on the hands of thumb-sucking infants and toddlers

To avoid ingestion and removal of the treatment

Gloves should be worn when applied by an unaffected person

To avoid further cases of infection

If hands are washed during treatment, more cream should be applied

Otherwise hands will be left untreated

After the allocated time the application should be washed off with cool, plain water Post-treatment A normal bath should follow treatment

Mites can continue to live for 72 h following separation from skin

All clothes and any items worn next to the skin should be turned inside out and washed using a hot wash cycle; any items that cannot be laundered should be stored away for at least 3 days Additional points Patients should be advised that itching may continue for at least 2 weeks and that scabietic nodules can take several months to resolve

As mites die they release allergen that can cause pruritus; avoid unnecessary retreatments, which can cause a contact irritant dermatitis

Antihistamines, emollients and/or topical steroid preparations can be considered

To alleviate symptoms

Observe for secondary bacterial infection

Can occur due to broken skin and scratching

Patients must be given full written and verbal instructions on treatment guidelines

In order to achieve optimal treatment and compliance

Always provide reassurance and practical and emotional support

To alleviate anxiety and minimize distress

If infestations occur within the hospital setting, involve the infection control team

To avoid further transmission

Nursing Care of Paediatric Skin

192.13

Table 192.11 Skin care after laser therapy Action

Rationale

Immediately after laser treatment Any discomfort can be relieved with the use of ice packs

Laser treatment produces local heat in the skin at the point of treatment; ice cools the area and makes the skin feel more comfortable

Give the child analgesia if needed. This is usually done during the procedure either by intramuscular injection or by suppository if the child is having a general anaesthetic

To ensure that there is no pain postoperatively

After discharge from hospital A moisturizing cream should be applied to the treated area at least four times daily; post-laser treatment skin tends to be dry and may feel itchy

To prevent trauma from rubbing or scratching to the laser-treated area, which could result in scarring

Avoid soap, shampoo or bubble bath for 3 weeks post-laser treatment

These will dry the area and may cause further scratching

No swimming in chlorinated water for 3 weeks

Chlorine dries the skin and may cause itching

Table 192.12 Nursing aspects of non-ulcerated haemangiomas Action

Rationale

Cut fingernails – nails need to be cut twice weekly and the edges buffed

To prevent trauma from scratching

Apply a thin layer of moisturizing ointment (such as Vaseline®) over the surface of the haemangioma at least once daily

The overlying skin is often dry

Application of a tubular bandage (Tubifast®) for large haemangiomas on the chest or arms, in the form of a vest or sleeve

To protect and prevent trauma from scratching or when picking up the child

Apply firm pressure for 5 min without release if the haemangioma bleeds

To stop bleeding

Reapply pressure and seek medical advice, if bleeding persists after 5 min of pressure

May require surgical intervention

Use Vaseline® on the dummy (pacifier) and teat, for haemangiomas around the mouth or on the lips. Apply Vaseline® around the nipple if the baby is breastfed

To lubricate and prevent any trauma to the haemangioma

and morphoea (Chapter 173). It is usually used to treat the acute phase of the illness and the child is then established on maintenance treatment, the nature of which depends on the diagnosis, but often this would include oral prednisolone at least initially. Traditionally methylprednisolone is given as daily infusions for three consecutive days and then repeated one week later (Table 192.14). This regimen can be varied according to clinical circumstances. The dose used by our department at GOSH is 30 mg/ kg or 0.5 g if the bodyweight exceeds 15 kg, given over 2 h in 30 mL of normal saline (0.9%).

systemic therapy, and nurse-led monitoring clinics are a valuable and cost-effective resource. Successful monitoring is dependent on commitment, monitoring for adverse effects, patient education and support. Examples of drugs requiring monitoring are listed in Table 192.15. Systemic therapy should be monitored according to published guidelines or as recommended by the pharmaceutical company. What needs to be done will vary according to the specific medication and condition, but some basic principles of management are listed in Table 192.16.

Systemic drug therapy monitoring

Intensive care

There has been an increase in the use of systemic drug therapy for widespread and incapacitating dermatological disease. Dermatology nurses have an increasingly important role in the monitoring of patients undergoing

Toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is characterized by extensive areas of skin loss and necrosis, usually the

192.14

Chapter 192

Table 192.13 Nursing aspects of ulcerated haemangiomas Action

Rationale

Preparation Assemble and prepare the following: sterile dressing pack; extra gauze swabs; Mepitel® dressing; Sorbsan® (alginate) dressing; potassium permanganate crystals/solution; Tegaderm®, bandage or Tubifast® Method Take a wound swab for microbiology

To identify any infection

Analgesia: 30–45 min prior to dressing

Pain relief enables the dressing to be performed with least possible stress to the child

Prepare a solution of dilute potassium permanganate using sterile water or cooled boiled water (pink not purple)

To clean the ulcer

Remove any dressing on child; if it is adherent, irrigate with the cleansing solution Allow the haemangioma to dry naturally or use a hair dryer on a cool setting at arm’s length; do not wipe or pat dry

A dry wound is less likely to become infected

Apply the Mepitel® dressing to the ulcerated area; if an antibiotic or antiseptic ointment has been prescribed then this should be applied to the dressing (not directly on the ulcer) before it is put in place

Mepitel® is a non-adherent perforated dressing that allows exudate to soak through

Over the Mepitel® place the Sorbsan® dressing, then the gauze swabs, held in place with an adhesive film dressing (Tegaderm®), bandage or tubular dressing (Tubifast®), whichever is appropriate for the affected site

To provide padding and a secure dressing

Dressings should be changed once or twice daily

The frequency depends on various factors, which include: infection, site and extent/depth of ulceration

Support Make arrangements for the dressings to be applied at home by either the parents or paediatric community nurses

It is best if the parents can apply the dressings at home they but may need some supervision initially

Review the child weekly initially

Close monitoring needed

Give the parents/carer written information on haemangiomas, a contact telephone number of the clinical nurse specialist at the hospital and the website of the Birthmark Support Group

Information and support are an essential part of management

Nursing Care of Paediatric Skin

192.15

Table 192.14 The administration of intravenous methylprednisolone Action

Rationale

Preparation Ensure child and family are fully informed of reason for treatment, administration and possible side-effects

To ensure that informed consent is given to treatment and that child and family are fully prepared

Obtain baseline temperature, pulse, respiratory rate and blood pressure; discuss with medical staff if vital signs are outside the normal range

To ensure child is fit for treatment and to obtain baseline in order to monitor side-effects

Record blood pressure cuff size on vital signs chart

To prevent variations in future recordings

Obtain baseline urinalysis; discuss with medical staff if any abnormalities, in particular evidence of glycosuria

Treatment can cause glycosuria

Negotiate when to commence infusion with child and family

To fit in with the child’s routine

Administration Check dose and route of administration according to IV guidelines

In order to give treatment safely

Administer the infusion over at least 2 h

To minimize side-effects

Ensure that the child stays in bed and is occupied with quiet activities throughout the infusion

To minimize side-effects and prevent boredom/anxiety

Monitor temperature, pulse, respiratory rate and blood pressure every 15 min for the first hour and then every 30 min

To ensure early detection of changes to vital signs

Observe for side-effects such as: hypotension, hypertension, tachycardia, blurred vision, flushing, sweating, headaches, metallic taste in mouth and mood changes; discuss any occurrence with medical staff

For early detection and to alleviate symptoms; to discuss action

After completion, monitor temperature, pulse, respiratory rate and blood pressure at 2 h, 4 h and then 4-hourly until next infusion

Methylprednisolone may continue to affect vital signs despite completion of infusion

Discuss any significant changes in vital signs with medical staff immediately

To discuss action

Post-infusion Check urinalysis daily and prior to discharge

To detect glycosuria

Ensure cannula is flushed with heparin 10 units/mL

To keep cannula patent

On discharge Ensure vital signs and urinalysis are within normal limits

To ensure that child is fit for discharge

Ensure oral prednisolone is started/restarted if prescribed

To avoid omission/confusion

Give contact numbers and procedure for parents to follow should the child become unwell at home

In case of emergency

Ensure child has follow-up clinic appointment date/admission date for next pulse

To ensure adequate follow-up/continuation of treatment

192.16

Chapter 192

Table 192.15 Examples of drugs that require monitoring Drug

Indication

Essential monitoring requirements

Prednisolone

Severe atopic dermatitis, bullous dermatoses, connective tissue disorders, vasculitis

BP, weight, growth ,urine dipstick for glucose Baseline electrolytes, varicella antibodies

Ciclosporin

Severe atopic dermatitis, psoriasis

BP, weight, height, surface area, full blood count, urea and electrolytes, liver function tests, varicella antibodies, GFR within 6 months

Azathioprine

Severe atopic dermatitis/ steroid-sparing drug

Weight, thiopurine methyltransferase (TPMT) prior to starting, full blood count, urea and electrolytes, liver function tests including ALT, varicella antibodies

Acitretin

Severe forms of ichthyosis/other disorders of keratinization, psoriasis

Weight, growth, full blood count, urea and electrolytes, liver function tests, fasting cholesterol and triglyceride, targeted X-ray investigation as required, dexa-scan yearly

Methotrexate

Psoriasis, morphoea

Weight, height, surface area, full blood count, urea and electrolytes, liver function tests including ALT, varicella antibodies

Propranolol

Haemangioma

BP, weight, full blood count, urea and electrolytes, glucose, thyroid function tests, baseline abdominal ultrasound and echocardiogram

Roaccutane®

Acne

Weight, growth, full blood count, urea and electrolytes, liver function tests, fasting cholesterol and triglyceride Pre-treatment pregnancy test if female of child-bearing age, monthly HCG and five weeks after stopping treatment

Thalidomide

Behçet disease, vasculitis

Baseline and 6-monthly nerve conduction studies, effective contraception, registry

Biologics (administer according to manufacturer’s guidelines)

Psoriasis

PASI/DLQ1, assesment for latent TB including chest X-ray, full blood count, urea and electrolytes, liver function tests, hepatitis B, C, HIV (in those at risk), varicella antibodies, cardiac and neurological assessments

Sulfapyridine/dapsone

Bullous dermatoses

Weight, full blood count, urea and electrolytes, liver function tests

Hydroxychloroquine

Systemic lupus erythematosus

Renal and liver function at baseline, enquire about visual impairment

ALT, alanine transaminase; BP, blood pressure; DLQI, Dermatology Life Quality Index; GFR, glomerular filtration rate; HCG, human chorionic gonadotropin; PASI, Psoriasis Area and Severity Index.

Nursing Care of Paediatric Skin

192.17

Table 192.16 Systemic drug therapy monitoring Action

Rationale

Prior to treatment Carry out baseline blood tests, urinalysis and vital sign monitoring as required Measure weight and surface area

To ensure that the child is suitable for treatment and to provide a baseline prior to treatment

Check chickenpox (varicella) status if applicable

Relevant to immunosuppressive treatments

Ensure that the patient and/or carer is fully informed about the treatment, including indication for use, side-effects, complications and monitoring required

To ensure informed consent is given to treatment

Give written information about the treatment, allow time for this to be read and allocate time for questions

To ensure patient/carer is fully informed and is given time to contemplate treatment

Ensure written/verbal consent is obtained as required

To record consent for treatment

Provide a booklet for the carer in order to have a written hand-held record; this should include: contact telephone numbers; details of medication, i.e. name of drug, dose, frequency, mode of administration, date of commencement; monitoring required; baseline vital signs and blood tests; steroid card if applicable

To ensure appropriate monitoring is carried out and recorded

Ensure carer is competent in handling and administering medication correctly; discuss appropriate handling in those who are/may become pregnant where relevant

To ensure medication is handled and administered safely

On commencement of treatment Ensure that GP, referring physician and any other relevant healthcare professionals are informed of treatment in writing

To initiate good communication

Ensure that system is in place for relevant monitoring to be carried out

For safe monitoring

Record blood results, urinalysis and blood pressure as applicable in patient’s hand-held record

Baseline data are required to observe for any changes

Ensure that an appropriate healthcare professional is allocated to check blood results as a routine during treatment

For safe monitoring

Troubleshooting In event of the following: medication is vomited shortly after administration; the child has vomiting and/or diarrhoea and may not be absorbing medication; a dose is forgotten

Carers need instruction on what action to take if this occurs

Ensure that carer is advised not to stop treatment; if any adverse effects are noted they should seek help from relevant healthcare professional

Stopping treatment abruptly may be detrimental

Follow-up Ensure that the family/patient has a follow-up appointment

Patient must be followed up on a regular basis

Give adequate supplies of the medication and instructions on how to obtain repeat prescription

To continue supply

Advise carer to ensure they do not run out of the medication

This may be detrimental

Advise carer to bring hand-held record to all appointments

For monitoring and communication

192.18

Chapter 192

Table 192.17 Nursing care of toxic epidermal necrolysis Action

Rationale

On admission Take nose, throat and skin swabs for culture and antibiotic sensitivities, including a specific request for an MRSA screen

For detection of bacterial colonization/infection

Record baseline temperature, pulse, respiratory rate and blood pressure, increase frequency as indicated

To obtain baseline data

Height and weight

To assess fluid loss, monitor weight loss and calculate drug doses

Assess skin and record

To assess extent of condition and monitor progress

Skin care Daily bathing/washes; dependent on mobility and fragility of the skin

To clean the skin

Use an oily emollient in the water

To prevent dryness and maintain the integrity of the skin barrier

Use a soap substitute such as aqueous cream or emulsifying ointment

Normal soap too astringent

Dress denuded areas with Vaseline Gauze® soaked liberally in a 50 : 50 mixture of white soft paraffin/liquid paraffin

For comfort, to promote healing and to protect denuded areas from infection and further trauma

Secure with Tubegauz® suit

To keep dressings in situ

Apply the 50 : 50 paraffin mix to all exposed areas, in particular the face and nappy area

To protect these areas and prevent further trauma

Reapply 50 : 50 paraffin mix to the Vaseline Gauze®, if the dressings dry out

To maximize effectiveness of dressings

Eyes: at least 4-hourly eye care in the acute period; apply eye ointment/drops as prescribed

To prevent damage, infection and long-term complications

Mouth: 2-hourly mouth care if limited oral intake and in the presence of mucosal and lip involvement

To prevent and/or improve mucosal and lip involvement

Pressure areas, nurse on a pressure-relieving mattress, monitor pressure areas and position patient appropriately

To relieve pressure on the skin and alleviate pain

Fluid and electrolyte balance Administer IV replacement fluid as prescribed

To correct fluid, electrolyte and protein loss and prevent dehydration, renal failure and shock

Secure cannula with non-adhesive tape/dressing and bandage well

Adhesive tapes/band-aid plasters will damage fragile skin

Monitor fluid balance carefully especially with genital/urethral involvement

To ensure correct fluid balance and to observe for urinary retention

Consider urinary catheter for painful micturition and/or urine retention

To normalize urine output and reduce pain on micturition

Nutrition Encourage/initiate enteral feeding

To prevent weight loss, protein loss and promote wound healing

Secure nasogastric tube, if required, with a tubular bandage or non-adhesive tape

Adhesive tape will damage fragile skin

Involve dietitian for assessment and guidance

To ensure optimum dietary intake

Pain relief Ensure adequate analgesia is administered; will need IV morphine with extensive skin involvement

To ensure child is pain free; extensive skin loss causes high levels of pain that may be difficult to control with oral analgesics alone

Consider ventilation with sedation for severely affected patients

In order to promote comfort, alleviate anxiety and to allow for optimum skin and mucosal nursing care

General measures Minimal handling

To prevent pain and damage to the skin

Provide constant environmental temperature where possible (30–32°C is optimum)

Temperature regulation is compromised due to extensive skin loss

Monitor core temperature closely

Skin temperature is unreliable; at risk of hypothermia because of excess heat loss

Nurse under strict protective precautions in a cubicle

To avoid secondary infection and sepsis

Position the patient carefully in bed and involve the assistance of a physiotherapist

To administer passive exercises and prevent contractures developing

Give practical and emotional support to the child and family

Child and family may experience high levels of distress

Discharge planning Teach the parents/carer the skin care regimen to be continued at home

To sustain recovery

Ensure ophthalmology follow-up is organized

To check for ophthalmic complications

Assess need for psychological support follow-up

The severity of the illness and hospitalization will have a psychological long-term impact on the child and family

Nursing Care of Paediatric Skin

result of a drug reaction (Chapter 183) and also seen as a manifestation of severe acute graft-versus-host disease (GVHD) (Chapter 178). These children are very ill and require high-dependency care in an intensive care unit. The nursing management is detailed in Table 192.17.

Summary Nurses play a vital role in the management of children with skin disease. This is particularly relevant to those

192.19

with more severe disease requiring either admission to hospital or regular outpatient attendance. The scope of involvement in patient care of the clinical nurse specialist continues to develop; in the UK, the clinical nurse specialist role now includes nurse-led clinics and nurse prescribing and is recognized as an expert nursing resource. The British Dermatological Nursing Group (BDNG) is an affiliated group of the British Association of Dermatologists and is at the forefront of dermatological nursing development, encompassing research and evidencebased practice.

1

Index

Note: page numbers in italics refer to figures; those in bold to tables or boxed material. abacavir, hypersensitivity 52.5 abatacept 182.11–182.12 juvenile idiopathic arthritis 175.4, 182.12 psoriasis 82.5, 182.12 ABCA12 gene mutations 121.25, 121.33–121.34 collodion baby 12.1 harlequin ichthyosis 13.1–13.3, 13.2, 121.28 pathology 121.32 phenotypes 121.34 ABCC6 gene mutations 95.7, 144.2 R114X 144.6 ABC transporter A12 121.28, 121.34 gene mutations see ABCA12 gene mutations ABC transporters 121.28 ABDH5 (CGI-58) gene mutations 11.5, 121.53 abdominal injuries, non-accidental 154.4, 154.8 abdominal pain Henoch–Schönlein purpura 160.4, 160.6 hereditary angioedema 177.18 juvenile dermatomyositis 175.11 polyarteritis nodosa 167.10 abscesses acne 79.6 hyper-IgE syndromes 177.22, 177.22 immunodeficiency syndromes 177.2–177.3 intraoral 147.17, 147.18 metastatic subcutaneous tuberculous 57.3 neonatal 9.3 Absidia corymbifera 63.22 Absidia ramosa 63.22 absorption, percutaneous 184.2–184.3 factors affecting 181.2, 181.2–181.5 MEDOC 121.63 preterm and term neonates 3.3, 3.4 systemic toxicity due to 184.2–184.14, 184.3 neonates 5.7, 17.7–17.8 non-therapeutic agents 184.13–184.14 therapeutic agents 184.3–184.10 see also topical therapy Acanthamoeba infections, HIV-infected children 52.4 acantholytic and dyskeratotic epidermal naevus 110.12–110.13 acanthosis nigricans (AN) autosomal dominant 115.20 clinical features 172.18, 172.18 insulin resistance-associated 172.18 laser treatment 189.8 accessory tragi 10.2–10.3, 10.3 acetaminophen 190.6 acetazolamide-induced hypertrichosis 148.30 acetylcholine blanch response, atopic dermatitis 25.1

acetylcholinesterase inhibitor insecticides 184.13 α-N-acetylgalactosaminidase deficiency 169.10 Acharia stimulea 73.4 achondroplasia and severe combined immunodeficiency 127.3 achondroplasia–hypochondroplasia 139.3 Achorion schoenleinii see Trichophyton schoenleinii achromic naevus see naevus depigmentosus aciclovir 181.16–181.17 eczema herpeticum 33.3 erythema multiforme 78.7 herpes zoster 49.14 HSV infections 48.6, 48.7, 64.8, 147.5, 153.20, 153.22 resistance 48.6, 147.5, 147.5 topical 48.7, 181.8 varicella 49.13, 64.7 warts 47.9 acid-fast bacilli (AFB) leprosy 70.4, 70.4 morphological index (MI) 70.4 numbers per smear (BI) 70.4 acid sphingomyelinase 27.4, 27.5 atopic dermatitis 27.11 acitretin 181.18 adverse effects 121.67–121.68, 181.18 generalized pustular psoriasis in neonates/ infants 11.3 harlequin ichthyosis 13.5, 192.1 lichen planus 85.10 MEDOC 121.67 monitoring therapy 192.16 pityriasis rubra pilaris 83.6 porokeratosis 126.4–126.5 psoriasis 82.4 Ackerman syndrome 127.4 acne (vulgaris) 79.1–79.21 aetiology and pathogenesis 79.2–79.5, 79.3 Becker naevus 104.13 bodybuilding 79.16, 79.16 burden of disease 179.2–179.3 clinical features 79.6, 79.6–79.7 comedonal 79.6, 79.6, 79.7 differential diagnosis 79.21 cosmetic 79.19 cystic fibrosis 170.3, 170.4 cysts 79.6 differential diagnosis 79.21, 79.21 endocrine disorders with insulin resistance 79.16, 79.16–79.17 epidemiology 79.1 excoriated see acne excoriée des jeunes filles genetics 79.1–79.2 infantile 79.15, 79.15 inflammatory 79.6 differential diagnosis 79.21

mechanical 79.19 neonatal 8.5, 8.7, 79.14–79.15, 79.15 differential diagnosis 79.21 papulopustular 79.6, 79.6, 79.7 pathology 79.5–79.6 pigmentary changes 104.5 postinflammatory lesions 79.6 primary non-inflammatory lesions 79.5 prognosis 79.7 radiation 79.19 scarring 79.6, 79.7 laser therapy 188.10, 189.8–189.9 treatment 79.10 striae development and 146.2 treatment 79.7, 79.7–79.10 non-pharmacological 79.10 oral agents 79.8–79.10 topical therapy 79.7–79.8 variants 79.14–79.21 acne conglobata 79.6–79.7, 79.7 infantum 79.15, 79.15 prognosis 79.7 treatment 79.7 acne excoriée des jeunes filles (excoriated acne) 79.21, 180.3, 180.10 acne fulminans 79.6, 79.17, 79.17 acneiform eruptions Cushing disease 172.7 drug-induced 79.19–79.20, 79.20 acneiform naevus linear 110.6 unilateral 79.17–79.19, 79.18 acne inversa see hidradenitis suppurativa Acne-QoL 179.3 acne venenata 79.19 acne vermoulante see atrophoderma vermiculata acne vulgaris see acne acoustic neuromas see vestibular schwannomas acquired immunodeficiency syndrome (AIDS) see HIV infection/AIDS acral enlargement syndrome 172.18 acral hypermobility, Rothmund–Thomson syndrome 136.3, 136.3 acral keratoderma 120.25 acral keratoses, PTEN hamartoma-tumour syndrome 137.18, 137.19 acral peeling skin syndrome (APSS) 121.23 Acremonium 63.4 acrocephalopolysyndactyly type II 141.10 acrocephalosyndactyly see Apert syndrome acrochordon 10.17 acrodental dysostosis of Weyer 127.63, 127.79 acrodermatitis chronica atrophicans (ACA) 59.1 aetiology 59.3 clinical features 59.5–59.6, 59.6 diagnosis 59.7–59.8

Harper’s Textbook of Pediatric Dermatology, 3rd edition. Edited by A. Irvine, P. Hoeger and A. Yan. © 2011 Blackwell Publishing Ltd.

2

Index

acrodermatitis chronica atrophicans (ACA) (cont.) differential diagnosis 16.6, 59.6 prognosis 59.9 treatment 59.8–59.9, 59.9 acrodermatitis enteropathica 169.15 clinical features 65.8, 65.8, 169.15 genetics 115.26 hair loss 148.20–148.21 HIV infection 52.5 napkin area 20.11–20.12 acrodermatitis enteropathica-like skin lesions methylmalonic acidaemia 20.11–20.12, 169.8 propionic acidaemia 169.7, 169.7 acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome 127.5, 127.79 acrodynia, mercury intoxication 148.18–148.19 acrogeria 134.7–134.8 acrokeratoelastoidosis (AKE) 120.23 acrokeratosis paraneoplastica 137.2 acrokeratosis verruciformis Darier disease 125.2, 125.2 of Hopf 125.1 acromegaly 172.24–172.25 acne 79.16 acromelanosis 104.9 acrometageria 134.7–134.8 acromial dimples, chromosome disorders 116.11 acropigmentation 104.9 acropustulosis, infantile see infantile acropustulosis acrorenal field defect, ectodermal dysplasia, lipoatrophic diabetes (AREDYLD) syndrome 127.4–127.5 acrylate gelling material (AGM)-containing napkins 21.1–21.2, 21.3 ACTH see adrenocorticotropic hormone Actiform Cool® dressings, epidermolysis bullosa simplex 118.8 actinic keratoses, xeroderma pigmentosum 135.10–135.11 actinic lichen nitidus 85.15–85.16 actinic lichen planus 85.6 actinic porokeratosis, disseminated superficial see disseminated superficial actinic porokeratosis actinic prurigo (AP) 106.4–106.6 clinical features 106.4, 106.4–106.5, 106.5 differential diagnosis 106.3, 106.5, 106.5 treatment 106.5–106.6 Actinomadura madurae 63.4 Actinomadura pelletieri 63.4 Actinomyces 63.26 Actinomyces israelii 63.26 Actinomycetales 63.26–63.28 actinomycosis 63.26–63.27 abdominopelvic 63.26 cervicofacial 63.26 disseminated 63.26 pulmonary 63.26 actinomycotic mycetoma (chronic cutaneous nocardiosis) 63.4, 63.27 clinical features 63.5, 63.5 treatment 63.6, 63.28 acute generalized exanthematous pustulosis (AGEP) 183.7–183.9 clinical features 87.5, 183.8 drugs associated with 87.5, 183.7 histopathology 183.8, 183.8 acute granulocytic leukaemia 99.14–99.15 acute haemorrhagic oedema (AHO) in infancy 161.1–161.4 aetiology and pathogenesis 161.1 clinical features 161.2, 161.2–161.4, 161.3 differential diagnosis 161.4 Henoch–Schönlein purpura and 161.1, 161.3–161.4, 161.4 pathology 161.1–161.2 prognosis 161.4 treatment 161.4

acute intermittent porphyria (AIP) 107.4, 115.26 clinical features 107.13 porphyrin profile 107.5 treatment 107.15 acute lymphoblastic leukaemia (ALL) 99.13 leukaemia cutis 99.14, 99.15 acute monocytic leukaemia (AMoL) 99.14, 99.14 congenital 99.16, 99.16 acute myeloid leukaemia (AML) 99.13 congenital 99.16, 99.16 diagnosis 99.16 gingival swelling 147.21, 147.21 leukaemia cutis 99.13–99.14, 99.14, 99.15 acute myelomonocytic leukaemia (AMMoL) 99.14 congenital 99.16 acute ulcerative gingivitis (AUG) 147.7 acycloguanosine see aciclovir ADA gene 177.30 adalimumab 182.6–182.8 juvenile idiopathic arthritis 175.4, 182.6–182.7 pharmacokinetics 182.6–182.7 psoriasis 82.5 side-effects 182.7–182.8 Adams–Oliver syndrome 10.19, 10.20, 112.19 ADAMTS2 gene mutations 142.3 adapalene, acne 79.7–79.8 addiction, UV light 108.9 Addison disease 172.9–172.10 clinical features 172.9, 172.10 hyperpigmentation 104.7–104.8, 172.9, 172.10 oral hyperpigmentation 147.16 adelmidrol, atopic dermatitis 25.10 adeno-associated virus (AAV) vectors, gene therapy 140.3, 140.4–140.5 adenoma sebaceum see facial angiofibromatosis, tuberous sclerosis adenosine deaminase (ADA) deficiency 177.30, 177.30, 177.32 adenosine monophosphate-activated protein kinase (AMPK) 137.8, 137.16 adenovirus vectors, gene therapy 140.3, 140.4 adherens junctions 91.1, 91.2 adhesins, Staphylococcus aureus 26.1–26.2 adhesiotherapy see occlusotherapy adhesive tapes dystrophic epidermolysis bullosa 118.18, 118.25 epidermolysis bullosa simplex 118.8–118.9 neonatal skin damage 5.4–5.5, 17.10, 17.10 adipose tissue (fat) brown 141.3 development 2.21 disorders 141.1–141.9 dysregulation, Proteus syndrome 111.4 neonatal 7.1 adipose triglyceride lipase (ATGL) 121.53 adnexal disorders 94.1–94.13 inflammatory 94.1–94.4 neoplastic see adnexal tumours adnexal polyp of neonatal skin 6.11–6.12 adnexal tumours 94.4–94.13 apocrine differentiation 94.6–94.9 eccrine differentiation 94.9–94.12 follicular differentiation 94.4–94.6 sebaceous differentiation 94.12–94.13 adolescents acne vulgaris 179.2–179.3 atopic dermatitis 34.6, 179.2 herpes genitalis 48.4 seborrhoeic dermatitis 41.1–41.5 surgical treatment 186.1 see also puberty adrenal gland disorders 172.7–172.10 adrenal hyperplasia congenital see congenital adrenal hyperplasia nodular 172.7 adrenal hypoplasia 172.9 adrenaline see epinephrine

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

adrenal tumours glucocorticoid-producing 172.7 oestrogen-producing 172.16, 172.16 virilizing 172.14, 172.15 adrenarche 172.11 premature 172.12, 172.13 adrenoceptors, reactivity in atopic dermatitis 25.1–25.2 adrenocorticotropic hormone (ACTH) deficiency 172.9 ectopic production 162.7 excess states 104.7–104.8, 172.7–172.8 failure of responsiveness 172.9 familial unresponsiveness syndrome 104.8 plasma 172.8, 172.10 testing, hyperandrogenaemia 172.15 adrenoleucodystrophy 172.9, 172.10 Siemerling–Creutzfeldt form 104.8 ADULT syndrome 127.5, 127.79 adult T-cell leukaemia/lymphoma (ATL) 53.4, 102.6 adverse drug reactions (ADRs) 183.1 cystic fibrosis 170.3, 170.4 epidemiology 183.1–183.2 erythema multiforme 78.2 gingival hyperplasia 147.20, 147.20 hyperpigmentation 104.4–104.5, 104.8 hypertrichosis 148.30, 148.30 melasma 104.6 neonatal erythroderma 11.8 oral hyperpigmentation 147.16 oral ulceration 147.9 pemphigus vulgaris 91.3 Stevens–Johnson syndrome 78.1, 78.2, 78.2 telogen effluvium 148.20, 148.20 toxic epidermal necrolysis 78.1, 78.2, 78.2 vesiculobullous 87.5, 87.5 see also drug eruptions; drug hypersensitivity reactions AEC syndrome see ankyloblepharon–ectodermal dysplasia–clefting syndrome Aedes aegypti, leprosy transmission 70.2 aeroallergens 32.1, 32.2 atopic eczema and 24.8, 32.1–32.9 epidemiological evidence 32.3 historical context 32.2–32.3 management approaches 32.7, 32.7–32.9, 32.8 role in disease flares 32.5–32.6 specific allergens 32.6–32.7 minimizing exposure 32.8 pathophysiology of sensitization 32.3–32.4, 32.4 properties promoting sensitization 32.6 skin as route of sensitization 32.4–32.5, 32.5 specific immunotherapy 32.8–32.9 timing of sensitization 32.3 urticarial reactions 74.4–74.5 aeroallergies, atopic eczema and 32.1–32.9 aerodigestive tract, HPV infections 47.6 Afipia felis 58.5 afloqualone 104.12 African histoplasmosis 63.16–63.17 African tick bite fever (ATBF) 61.2, 61.5–61.6, 61.10 agammaglobulinaemia 177.27 autosomal dominant 177.25 autosomal recessive 177.25 with dwarfism and ectodermal dysplasia 127.3 X-linked see X-linked agammaglobulinaemia age gestational see gestational age laser treatment of vascular anomalies 188.3, 188.4 percutaneous drug absorption and 181.2–181.3 surgery and 186.1, 187.1 AGEP see acute generalized exanthematous pustulosis agminate naevus 109.17 AGPAT2 gene mutations 141.18

Index AICDA gene mutations 177.26 AIDS see HIV infection/AIDS AIRE gene 149.1, 172.28, 177.13 air pollution, atopic dermatitis and 22.11–22.12 airway involvement see respiratory tract involvement AK2 gene 177.30 alastrim 51.3 Al Awadi–Raas–Rothschild syndrome 10.8 albendazole, cutaneous larva migrans 68.4 albinism ocular 138.8 type 1, Nettleship–Falls type 121.11, 121.13 oculocutaneous (OCA) 138.7–138.8 clinical features 138.5, 138.7 differential diagnosis 105.6, 138.8 gene therapy approach 140.11–140.12 genetic basis 115.25, 138.2, 138.7–138.8 prenatal diagnosis 2.15, 2.36, 139.3 tumour susceptibility 137.2 patient advocacy groups 179.7 albopapuloid lesions, dystrophic epidermolysis bullosa 118.13 Albright hereditary osteodystrophy (AHO) 95.11–95.12 cutaneous ossification 95.9–95.10, 95.11 differential diagnosis 95.11, 95.12 oral pigmentation 147.16 progressive osseous heteroplasia overlap 95.10, 95.11 pseudo-hypoparathyroidism 172.26–172.27 alcohol intoxication 184.3–184.4 Alcyonidium gelatinosum 73.9 ALDH3A2 (FALDH) gene mutations 11.10, 121.34, 121.47 alefacept 82.5, 182.12–182.13 Aleppo button 67.1 alexandrite lasers hair removal 189.3, 189.4 other lesions 189.8 pigmented lesions 189.4, 189.5, 189.6 Alezzandrini syndrome 105.6 alfacalcidol, Albright hereditary osteodystrophy 95.12 ALK-1 gene 112.5 alkaptonuria 115.26, 169.4, 169.6 alleles 115.2 hypomorphic 115.6–115.7 loss see loss of heterozygosity allergen(s) atopic dermatitis 24.7–24.8, 30.3, 30.3, 30.10 avoidance, atopic dermatitis 30.3, 30.8–30.9 defined 32.1 see also aeroallergens; contact allergens; food allergens allergen sensitization atopic dermatitis 22.10–22.11 air pollution and 22.12 food allergens 31.1–31.2 pathophysiology 32.3–32.4 timing 32.3 contact dermatitis 44.1, 44.2 cystic fibrosis 170.3 fetal period 22.7–22.8 skin as route of 31.2–31.3, 32.4–32.5, 32.5 allergic contact dermatitis (ACD) 44.1–44.12 allergens see contact allergens atopic dermatitis with 30.3, 30.3, 30.10, 44.1 clinical features 44.2–44.4, 44.5 differential diagnosis atopic dermatitis 28.10 child abuse 154.10 juvenile plantar dermatosis 43.1–43.2 phytophotodermatitis 45.10, 45.10 epidemiology 44.2, 44.3–44.4 napkin area 19.3, 20.2, 20.4 patch testing 44.4–44.8 pathogenesis 44.1–44.2 patient education and treatment 44.8 plants/plant products 44.4, 44.11, 44.11–44.12, 45.5, 45.5–45.7

allergic gingivostomatitis 147.15 allergic march see atopic march allergic salute 10.6 ‘allergic (atopic) shiners’ 28.5, 104.6 allergies drug 183.1 see also drug hypersensitivity reactions eosinophilic pustular folliculitis 36.3 food see food allergies insulin 172.22, 172.23 meningococcal disease 55.12 Netherton syndrome 124.5 plants/plant products 45.3–45.7 alligator boy 12.1 allopurinol, adverse reactions 78.2 all-trans-retinoic acid see tretinoin allylamine antifungals 62.15 alopecia 148.1 androgenetic (AGA) 79.16, 148.21–148.22 atrichia with papular lesions 127.87 biotin deficiency 148.21, 169.9 Clouston syndrome 127.90, 127.90 diffuse (global) 148.4, 148.4, 148.5–148.6 ‘en coup de sabre’ morphoea 173.5, 173.6 focal 148.4, 148.4, 148.22–148.23 familial 148.23 non-scarring 148.23 scarring 148.22, 148.22–148.23 ichthyosis follicularis with atrichia and photophobia 121.55–121.56 KID syndrome 122.2, 127.91 non-scarring 148.4, 148.4 focal 148.23 occipital, normal infants 148.1, 148.2 pressure 148.23 progeria 134.2, 134.2 propionic acidaemia 169.7, 169.7 pure hair-nail ectodermal dysplasia 127.96 scarring (cicatricial) 148.4, 148.4 congenital erosive and vesicular dermatosis 16.4, 16.5 focal 148.22, 148.22–148.23 newborn infants in incubators 5.4 patient advocacy groups 179.7 tissue expansion 187.26, 187.27 tinea capitis 62.6, 62.7 traumatic inflicted 154.7 triangular 148.23, 148.23 universal/near total, in infancy 148.6, 148.7–148.9 see also hair loss alopecia–anosmia–deafness–hypogonadism 127.5 alopecia areata (AA) 149.1–149.7 anagen effluvium 148.18 associations 149.4 circumscripta 149.1, 149.3 clinical features 149.2–149.4, 149.3 course and prognosis 149.3, 149.3–149.4 differential diagnosis 149.4 epidemiology 149.1 genetics 149.1–149.2 histopathology 149.4 ophiasis type 149.2–149.3, 149.5 pathogenesis 149.2 patient advocacy groups 179.7 pattern of hair loss 148.4 totalis (AAT) 149.1, 149.2, 149.3 treatment 149.4, 149.5, 149.6 treatment 149.4, 149.4–149.6 twenty-nail dystrophy 150.5 universalis (AAU) 149.1, 149.2, 149.3 treatment 149.4, 149.5 alopecia congenita with keratosis palmoplantaris 127.50 alopecia, keratosis pilaris, cataracts and psoriasis 148.7 alopecia–onychodysplasia–hypohidrosis 127.6 alopecia–onychodysplasia–hypohidrosis– deafness 127.6

3

alopecia universalis congenita (ALUNC) (generalized atrichia) 127.87, 148.6 clinical features 127.7, 127.87 pathogenesis 115.24, 127.83 alopecia universalis–onychodystrophy–total vitiligo 127.7 ALOX12B gene mutations autosomal recessive congenital ichthyosis 121.34–121.35 collodion baby 12.1, 121.30 ALOXE3 gene mutations autosomal recessive congenital ichthyosis 121.34–121.35 collodion baby 12.1, 121.30 α-fetoprotein amniotic fluid, cystic hygroma 114.16 maternal serum, aplasia cutis congenita 10.20 α-hydroxy acids, ichthyoses/MEDOC 121.66 Alström syndrome 141.9–141.10, 172.19 Alternaria 63.7–63.8 alternariosis 63.8 alternative therapies see complementary and alternative therapies aluminium, allergy 44.9 aluminium acetate 181.9 aluminium chloride hexahydrate, epidermolysis bullosa simplex 118.8 ALUNC see alopecia universalis congenita alveolar soft part sarcoma 99.6 Alves syndrome 127.9 amalgam tattoos 147.14 amastia 10.8 Amblyomma americanum 59.11 amblyopia, infantile haemangioma 113.8–113.9 Ambras syndrome 116.16, 148.29 amelo-cerebrohypohidrotic syndrome 127.7 amelo-onychohypohidrotic dysplasia 127.7 American Academy of Pediatrics (AAD) 1.3 American histoplasmosis see histoplasmosis American Rheumatology Association (ARA), systemic lupus erythematosus criteria 175.5, 175.5 amethocaine, topical 181.7 laser treatment 188.3 amikacin, nocardiosis 63.28 amino acid formula (AAF) 31.12, 31.16 aminoacidopathies 169.1–169.6 amino acid transport defects, inherited 169.9–169.10 aminoglycosides, topical, Hailey–Hailey disease 91.10 5-aminolaevulinate dehydratase (ALAD) 107.2–107.4 deficiency porphyria (ADP) 107.3–107.4 clinical features 107.13 porphyrin profile 107.5 treatment 107.15 gene 107.3, 107.3 5-aminolaevulinate synthase (ALAS) 107.1–107.2 genes 107.2, 107.3, 107.3 5-aminolaevulinic acid (ALA) 107.1 accumulation 107.4, 107.5, 107.6 Gorlin syndrome 132.15–132.16 neurotoxicity 107.7 Amish brittle hair syndrome 148.11 amitraz intoxication 184.4 amitriptyline, epidermolysis bullosa 118.8, 118.25–118.26 Ammi majus 45.8, 45.8 ammonia, in napkin dermatitis 18.1, 19.2, 20.1 ammoniacal dermatitis 18.1, 19.2 ammoniacal ulcers see Jacquet dermatitis ammonium lactate, newborn skin care 5.6 amniocentesis DNA-based prenatal diagnosis 139.3–139.4 indications 17.2 skin injuries 17.2 timing 2.3, 2.3

4

Index

amniotic (constriction) bands 10.20–10.21 congenital erosive and vesicular dermatosis and 16.1 congenital lymphoedema 114.11 amniotic fluid, fetal wound healing and 17.2 amorolfine 62.15 dermatophytoses 62.16 onychomycosis 62.17 amoxicillin bacterial vaginitis 153.23 induced pemphigus foliaceus 91.6 Lyme borreliosis 59.9 rash induced by 183.5 amphotericin B candidosis 62.24 coccidioidomycosis 63.14 leishmaniasis 67.13 penicilliosis 63.19 sporotrichosis 63.19 ampicillin eruption, infectious mononucleosis 49.15 amputations meningococcal disease 55.11, 55.12 purpura fulminans 162.11, 162.13 amyloid 159.1 keratinocyte-derived (AK) 159.1 pathology 159.2 amyloid A (AA) protein 159.1 amyloid light chain (AL) protein 159.1 amyloidosis 159.1–159.5 aetiology 159.1–159.2 bullous 159.3–159.4 classification 159.1, 159.2 clinical features 159.2–159.4 cutaneous 159.2–159.4, 159.3 aetiology 159.1–159.2 classification 159.2 MEN 2A 159.1, 159.3, 172.30 primary localized (PLCA) 159.1, 159.2, 159.2–159.4 secondary 159.4 differential diagnosis 159.4–159.5 diffuse biphasic 159.3 familial primary cutaneous (FPCA) autosomal dominant 138.3, 138.9, 159.3 Sipple syndrome (MEN 2A) association 159.1, 159.3 friction 104.7, 159.2 genodermatosis-associated 159.4 juvenile idiopathic arthritis 175.3 lichen 104.12, 159.1 clinical features 159.2, 159.3 differential diagnosis 159.4 familial cutaneous 159.1 pigmentary changes 104.7, 104.12 treatment 159.5 macular 159.2 clinical features 159.2, 159.3 differential diagnosis 159.4 hyperpigmentation 104.7 neurotrophic 159.4 pathology 159.2 poikiloderma-like 159.3 prognosis 159.4 systemic 159.2, 159.4 treatment 159.5 X-linked cutaneous see Partington syndrome amyloidosis dyschromica cutis 104.12 anabolic steroid abuse, acne 79.16, 79.16 Anacardiaceae 45.5, 45.5 anaemia dystrophic epidermolysis bullosa 118.16, 118.26 Fanconi see Fanconi anaemia junctional epidermolysis bullosa 118.31 anaesthesia 190.1–190.10 defined 190.6, 190.7 dystrophic epidermolysis bullosa 118.25 general gas 190.9 laryngeal masks 190.9 laser treatment 188.2–188.3, 189.2

mastocytosis 75.12 subcutaneous infusion 190.5 for surgical procedures 186.1 see also local anaesthetics; topical anaesthetics anaesthetic agents 190.7–190.9 anagen 148.1–148.2, 148.3 bulbs 148.5, 148.5 hair loss 148.18–148.20 loose hairs 148.5, 148.5 anagen effluvium 148.18, 148.18–148.19 anakinra juvenile idiopathic arthritis 175.3 periodic fever (autoinflammatory) syndromes 74.13, 79.17, 176.2, 176.3 Wegener granulomatosis 167.6 analgesia 190.6, 190.7 see also pain management analgesics 190.7–190.9 laser treatment 188.6 perioperative 190.6 anaphylaxis arthropod bites 71.5 clinical features 74.11 drugs 74.3, 74.4 foods 31.5–31.6, 74.4 hymenopterid stings 73.2–73.3 mastocytosis 75.12 treatment 74.12–74.13 anaplasmosis (Anaplasma phagocytophilium infections) 59.10, 61.3 anaplastic large-cell lymphoma (ALCL) primary cutaneous (C-ALCL) 99.22, 99.22, 102.6–102.7, 102.7 systemic (S-ALCL) 99.22, 102.6 ANCA see antineutrophil cytoplasmic antibodies anchoring fibrils, development 2.7–2.8, 2.20 anchoring filaments 91.14, 91.14 development 2.7–2.8, 2.20 ancient history 1.1 Ancylostoma braziliense 68.1 Ancylostoma caninum 68.1 androgen(s) 17α-alkylated, hereditary angioedema 177.18–177.19 abuse, acne 79.1, 79.16, 79.16 acne pathogenesis 79.2–79.3, 79.3 autonomous secretion, precocious puberty 172.12 deficiency 172.11 excess see hyperandrogenaemia androgenetic alopecia (AGA) 79.16, 148.21–148.22 androgen receptors acne pathogenesis 79.3, 79.3 Becker naevi 110.15 gene (AR) polymorphisms, acne 79.1–79.2, 79.3 anetoderma (macular atrophy) 145.11–145.14 aetiology 145.11–145.13 classification 145.11 clinical features 145.13, 145.13–145.14 differential diagnosis 133.7, 145.14, 145.14 histopathology 145.13 perifollicular 145.12 of prematurity 17.9, 145.13 primary 145.11–145.12, 145.12, 145.13, 145.13 secondary 145.12–145.13 treatment 145.14 aneuploidy 116.3–116.4 aneurysms, Kawasaki disease 168.7, 168.7–168.8, 168.9, 168.10 angel kiss 112.15 Angelman syndrome 116.5, 116.11, 141.9 angioblastoma of Nakagawa see tufted angioma angiocentric T-cell lymphoma of childhood 77.14 angiodyskinesia syndrome 166.3 angioedema 74.1 clinical features 74.2, 74.11 differential diagnosis 74.11 drug-induced 183.2–183.3 food allergies 31.5, 31.6, 45.4, 74.4

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

hereditary see hereditary angioedema idiopathic 74.10 plants/plant products 45.3–45.4, 45.4 treatment 74.12–74.13 angiofibromas Birt–Hogg–Dubé syndrome 137.8 facial, MEN 1 172.30 tuberous sclerosis 129.6–129.7 see also facial angiofibromatosis, tuberous sclerosis angiogenesis, wound healing 17.1 angioid streaks, pseudo-xanthoma elasticum 144.5, 144.5 angiokeratoma(s) localized 112.20 syndromic 112.20, 169.10, 169.11 angiokeratoma corporis circumscriptum see Fabry disease angiokeratoma corporis diffusum 112.20, 169.10 angiolymphoid hyperplasia with eosinophilia (ALHE) 98.1–98.2, 98.2 angioma, tufted see tufted angioma angioma serpiginosum of Hutchinson 112.20 laser treatment 188.10 with oesophageal papillomatosis 133.7 angiomatosis, cutaneovisceral see lymphangioendotheliomatosis, multifocal angiomyolipomas 141.4 renal, tuberous sclerosis 129.9, 129.11 angio-oedema see angioedema angiosarcoma 99.6 lymphoedema 114.13 angiotensin-converting enzyme (ACE), serum 158.4 angora hair naevus syndrome 110.15 angular cheilitis, oral candidosis with 62.21 angular stomatitis 147.12–147.13, 147.13 anhidrotic ectodermal dysplasia see hypohidrotic ectodermal dysplasia aniline dye poisoning 5.7, 17.7, 184.13 ankyloblepharon–ectodermal dysplasia–clefting (AEC) syndrome (Hay–Wells syndrome) 127.74–127.77 clinical features 127.7–127.8, 127.76–127.77, 127.77 differential diagnosis 127.77 molecular pathogenesis 115.23, 127.74 neonatal erythroderma 11.5, 127.76, 127.76 pathology 127.74–127.75 treatment 127.77 ankyloblepharon filiforme adnatum 127.77, 127.77 ankyloglossia 147.22 annular erythema of infancy 36.10, 76.2, 76.6–76.7 clinical features 76.6, 76.7 neutrophilic figurate variant 76.6 annular erythemas 76.1–76.8, 76.2, 76.2 annular lichen planus 85.6–85.7, 85.7 annular lipoatrophy of the ankles 77.10 anogenital granulomatosis 114.19, 151.23 anogenital warts see condyloma acuminata anonychia 115.24, 150.8 with bizarre flexural pigmentation 127.8 anonychia–onychodystrophy with brachydactyly type b and ectrodactyly 127.8 anorexia nervosa carotenaemia 171.2, 171.4 cutaneous signs 65.9, 65.9 Anthozoa, stinging 73.7–73.8, 73.8 anthralin (dithranol) 181.9–181.10 alopecia areata 149.6 psoriasis 82.2, 82.2 nursing care 192.4, 192.9 short-contact therapy 82.2, 192.4 anthrax, cutaneous 87.5, 87.8 anti-5-hydroxytryptamine (5-HT)4 antibodies, neonatal lupus erythematosus 14.4 antiandrogens, acne 79.9–79.10 antibacterials see antibiotics

Index antibiotics acne 79.8–79.9, 79.17 acute infectious purpura fulminans 162.10 adverse reactions cystic fibrosis patients 170.3, 170.4 fixed drug eruptions 183.11 maculopapular exanthems 183.4, 183.5 red man syndrome 11.8 serum sickness-like reactions 183.3 atopic dermatitis 26.3–26.4, 30.5 Chlamydia infections 153.16 endemic treponematoses 60.7 gonorrhoea 153.11–153.12 infectious mononucleosis 49.15, 49.15 linear IgA disease of childhood 89.10–89.11 Lyme borreliosis 59.7, 59.8–59.9, 59.9 meningococcal infection 55.9 napkin dermatitis 21.4 Neisseria meningitidis carriers 55.13 nocardiosis 63.28 perioral dermatitis 38.3 psoriasis 82.4 Rocky Mountain spotted fever 61.4 skin prick and intradermal tests 183.13 streptococcal vulvitis/balanitis 151.9 systemic 181.16 topical 181.6–181.7 acne 79.8 atopic dermatitis 26.3–26.4, 30.5 burn wounds 187.18 dystrophic epidermolysis bullosa 118.19–118.20 epidermolysis bullosa simplex 118.7 sensitization to 44.10 triggering linear IgA disease of childhood 89.3 anti-C1q antibodies 163.1–163.2, 163.5 anticardiolipin antibodies postvaricella purpura fulminans 162.5 systemic lupus erythematosus 175.7 anticentromere antibodies (ACA) morphoea 173.7 systemic sclerosis 174.3, 174.4 anticholinesterase insecticides 184.13 anticipation, genetic 115.5 anticoagulants Behçet disease 167.17 see also heparin; warfarin anticonvulsant hypersensitivity syndrome (AHS) see DRESS syndrome anticonvulsants see antiepileptic drugs antiendomysial antibodies 90.3 antiepileptic drugs (anticonvulsants) hypersensitivity reactions 183.4, 183.6, 183.11 tuberous sclerosis 129.10–129.11 anti-fibrillarin antibodies, systemic sclerosis 174.4 antifibrinolytic agents, hereditary angioedema 177.18 antifungal agents aspergillosis 63.21 atopic dermatitis 26.7–26.8 blastomycosis 63.10 candidiasis 62.23–62.24 chromomycosis 63.7 chronic mucocutaneous candidiasis 177.14 coccidioidomycosis 63.14 cryptococcosis 63.3 dermatophytoses 62.14–62.15 fusariosis 63.22 infantile seborrhoeic dermatitis 35.6–35.7 mycetoma 63.6 napkin dermatitis 21.4 paracoccidioidomycosis 63.12 phaeohyphomycosis 63.8 pityriasis versicolor 62.28 seborrhoeic dermatitis 41.4 serum sickness-like reactions 183.3 systemic 181.16 topical 181.8

antihistamines atopic dermatitis 25.9, 30.5 drug-induced urticaria 183.2–183.3 eosinophilic pustular folliculitis 36.5 hypersensitivity reactions to 44.10, 183.11 immediate hypersensitivity reactions 45.4 mastocytosis 75.11 solar urticaria 106.7 systemic 181.16 topical 181.8 toxic effects 184.5 urticaria 74.12, 74.12 see also H2-receptor antagonists antihistone antibodies (AHA), morphoea 173.7 anti-laminin-332 antibodies pemphigoid 91.15, 91.18 prenatal diagnostic testing 139.8 anti-La/SSB antibodies disease associations 14.3 maternofetal transfer 14.3 neonatal lupus erythematosus 14.3–14.4, 14.9 antimalarials granuloma annulare 93.8 sarcoidosis 158.5 anti-matrilin I antibodies, relapsing polychondritis 167.20 antimicrobial agents see antibiotics antimicrobial peptides (AMPs) acne vulgaris 79.5 atopic dermatitis 24.6–24.7, 26.3 drugs acting on 25.10–25.11 eczema herpeticum 33.1 anti-mitochondrial M2 antibodies, systemic sclerosis 174.4 antimitotics, warts 47.8–47.9 antimonial compounds, leishmaniasis 67.12–67.13 antineutrophil cytoplasmic antibodies (ANCA) 167.1 microscopic polyangiitis 167.8 polyarteritis nodosa 167.10 relapsing polychondritis 167.20 Wegener granulomatosis 167.1, 167.2, 167.2 disease monitoring 167.5–167.6, 167.6 antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) 167.1–167.14 renal-limited 167.8 antinuclear antibodies (ANA) juvenile idiopathic arthritis 175.3 morphoea 173.7 relapsing polychondritis 167.20 vitiligo 105.5 antioxidants ataxia telangiectasia 177.5 photoprotective effects 108.11 sunburn palliation 108.7 in sunscreens 108.13–108.14 antiparasitics, topical 181.9 antiphospholipid antibodies, neuropsychiatric systemic lupus erythematosus 175.7 antiphospholipid antibody syndrome anetoderma 145.12–145.13 purpura fulminans 162.4, 162.6, 162.6–162.7, 162.12 treatment 162.12 anti-PM-Scl antibodies, systemic sclerosis 174.4 antiproliferative agents, warts 47.8–47.9 antiretroviral agents HIV infection 52.5 hypersensitivity reactions 52.4–52.5 anti-RNA polymerase I and II antibodies, systemic sclerosis 174.4 anti-RNP antibodies disease associations 14.3 neonatal lupus erythematosus 14.3, 14.9 anti-Ro/SSA antibodies disease associations 14.3 follow-up of mothers with 14.10–14.11

5

maternofetal transfer 14.3 neonatal lupus erythematosus 14.1, 14.3–14.4, 14.9 antisense oligonucleotides (AON) 140.14 antisense therapies 139.2, 140.6 antiseptics 181.8 newborn skin care 5.1–5.2, 5.7 skin decontamination in premature infants 5.4 transcutaneous absorption in newborn 5.7, 5.7 antistreptolysin O (ASO) test 54.2 antithrombin therapy, acute infectious purpura fulminans 162.11 anti-thymocyte globulin (ATG) 178.8 antithyroid drugs 172.6 anti-To or Th antibodies, systemic sclerosis 174.4 anti-topoisomerase I (Scl 70) antibodies morphoea 173.7 systemic sclerosis 174.4 anti-topoisomerase IIα antibodies, morphoea 173.8 α1-antitrypsin deficiency panniculitis 77.11–77.12 antituberculous drugs atypical mycobacterial infections 57.7, 57.8, 57.9, 57.10 tuberculosis 57.4–57.5 anti-type II collagen antibodies 167.20 anti-U1 RNP antibodies, systemic sclerosis 174.4 antiviral agents eczema herpeticum 33.3 HSV infections 48.6–48.7, 153.20 molluscum contagiosum 46.6 systemic 181.16–181.17 topical 181.8 varicella 49.13 warts 47.9 ants, venomous 73.2–73.3, 73.3 anxiety, lichen simplex chronicus 42.1 anxiolysis 190.6, 190.6 aortic thrombosis, neonates 17.6 AP1S1 gene mutations 121.50–121.51 AP1S2 gene mutations 121.51 AP3B1 gene mutations 138.6 APACHE syndrome 112.13 APC gene mutations 137.11 APECED see autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy Apert syndrome, acne 79.17–79.19, 79.18 aphthosis, complex 151.13 aphthous ulcers genital 151.13, 151.13–151.14 recurrent oral see recurrent aphthous stomatitis apids, stinging 73.2–73.3 aplasia cutis congenita (ACC) (congenital absence of skin) 10.18–10.20 alopecia 148.22, 148.23 chromosome disorders 116.10 clinical features 10.18–10.20, 10.20 dystrophic epidermolysis bullosa 118.12, 118.12 focal dermal hypoplasia 133.1, 133.4 Frieden’s classification 10.19 lumbosacral region 10.17 membranous 10.18, 10.20 non-membranous 10.18, 10.20 vs. congenital erosive and vesicular dermatosis 16.6 aplastic anaemia, gingival enlargement 147.20, 147.20 Apligraf®, dystrophic epidermolysis bullosa 118.21 apocrine hidrocystoma 94.6–94.7 Schöpf–Schulz–Passarge syndrome 127.86 apocrine miliaria see Fox–Fordyce disease apocrine naevus 94.9 apocrine sweat glands, development 2.38 apolipoprotein A-I, acne 79.1 apolipoprotein E (apoE) 140.17 aponeurotic fibroma, calcifying 97.13 apoptosis, periderm cells 2.25–2.26 appendages, skin see skin appendages

6

Index

aquagenic palmar hyperwrinkling, transient 170.3, 170.4 aquagenic urticaria 74.6 Aquaphor®, premature infants 5.5 aqueous cream BP, atopic dermatitis 27.16 Araçatuba virus 51.20 arachnidism 73.5–73.6 arachnodactyly congenital contractural (CCA) 115.23, 145.5, 145.7 Marfan syndrome 145.5, 145.5 ARCI see autosomal recessive congenital ichthyoses AREDYLD syndrome 127.4–127.5 Argasid ticks 71.6–71.7, 71.7 AR gene polymorphisms, acne 79.1–79.2, 79.3 arginine catabolic mobile element (ACME) 54.2 arginosuccinic aciduria 148.10 argyria 104.5 armadillo proteins 127.97 ARPC3 gene 126.1 arrhythmogenic right ventricular cardiomyopathy (ARVC) 127.99, 148.16 arsenic intoxication 184.13 hair loss 148.19 pigmentary changes 104.5, 104.12 ARS gene mutations 120.4–120.5 artemis deficiency 11.8, 177.31 arterial catheterization, complications in neonates 17.6–17.7, 17.7 arterial malformations (AM) 112.1 arteriography, arteriovenous malformations 112.3 arteriovenous fistula (AVF) 112.1 arteriovenous malformations (AVM) 112.1–112.6 clinical features 112.1–112.2, 112.2 differential diagnosis 112.3 histopathology 4.4, 112.1 inherited 112.5–112.6 localized or extensive 112.1–112.4 prognosis 112.3 syndromic 112.4–112.5 treatment 112.3–112.4 arthralgia/arthritis Behçet disease 167.16, 167.17 Blau syndrome 158.9, 158.9 cystic fibrosis 170.2 erythema infectiosum 49.6 familial/paediatric granulomatous see Blau syndrome gonococcal 153.10–153.11 Henoch–Schönlein purpura 160.3–160.4, 160.6 juvenile idiopathic see juvenile idiopathic arthritis Kawasaki disease 168.5 Lyme borreliosis see Lyme arthritis multicentric reticulohistiocytosis 103.12 psoriasis see psoriatic arthritis relapsing polychondritis 167.19 rubella 49.4 smallpox 51.5 systemic sclerosis 174.10 arthrochalasia multiplex congenita see Ehlers–Danlos syndrome (EDS), arthrochalasia-type Arthroderma benhamiae 62.3, 62.4 clinical features of infections 62.6 arthrogryposis and ectodermal dysplasia 127.9 restrictive dermopathy 15.2, 15.2 arthropod(s) biting behaviour 71.7 feeding on blood 71.1–71.2 noxious and venomous 73.1–73.7 see also insect(s); tick(s) arthropod bites 71.1–71.8, 73.1 anaphylactiform reactions 71.5 clinical features 71.6, 71.6–71.7, 71.7 differential diagnosis 71.8 immunopathology 71.3, 71.3–71.5, 71.4, 71.5 prognosis 71.7–71.8

reactions 71.2–71.3 treatment 71.8 vesiculobullous lesions 87.9 see also insect bites; mite bites; spider bites; tick bites arylsulphatase E (ARSE) gene defects, recessive X-linked ichthyosis with 121.11, 121.12 Asboe–Hansen sign 87.2, 91.3 ascorbic acid deficiency 65.6 aseptic meningitis syndrome (AMS), vaccinia immune globulin therapy 51.14 ash leaf spots see hypopigmented (hypomelanotic) macules ashy dermatosis, HIV infection 52.5 aspergillosis 63.20–63.21 chronic granulomatous disease 64.5, 64.6 clinical features 63.20, 63.20 congenital 8.5, 8.6, 8.7 immunocompromised children 63.20, 63.20, 64.10 oral ulceration 147.6, 147.6–147.7 pathology 63.21, 63.21 Aspergillus 63.4, 63.20, 63.21 Aspergillus flavus 63.20 Aspergillus fumigatus 63.20 Aspergillus niger 63.20 Aspergillus terreus 63.20 aspirin erythromelalgia 166.3 Kawasaki disease 168.9 tufted angioma 113.24 urticarial reactions 74.4 Wegener granulomatosis 167.6 association studies, atopic eczema 23.3, 23.3, 23.6–23.7 asthma aeroallergen sensitization 32.4, 32.5 atopic dermatitis and 22.11, 23.1 food-allergy and 31.2, 31.8–31.9 immunology 24.1 astringents 181.9 astrocytomas, giant cell, tuberous sclerosis 129.11 asymmetrical periflexural exanthem of childhood 49.19–49.20, 49.20 3A syndrome 172.9 ataxia telangiectasia (AT) 177.1–177.5, 177.2 cancer susceptibility 137.3, 177.4 chromosome instability 116.7, 177.4 clinical features 177.3, 177.3–177.4, 177.4 differential diagnosis 128.8, 177.5 pathogenesis and genetics 115.27, 177.3 prognosis 177.5 telangiectases 112.19–112.20, 116.12, 116.12, 177.3, 177.3–177.4 treatment 177.5 ataxia telangiectasia-like disorder 177.5 ATGL/PNPLA2 gene mutations 121.53 athelia 10.8 athlete’s foot see tinea pedis ATM gene mutations heterozygous, cancer risk 112.20, 177.4 homozygous, ataxia telangiectasia 112.19, 112.20, 177.3 ATM protein 135.23, 177.3 atopic dermatitis (AD) 32.1 acute lesions 24.3–24.4, 28.4, 28.5 aeroallergies and 24.8, 32.1–32.9 age of onset 22.5 allergic contact dermatitis with 30.3, 30.3, 30.10, 44.1 allergic sensitization and 22.10–22.11 anatomical distribution 28.1–28.3, 28.2, 28.3 factors influencing 27.7, 27.7–27.8, 27.14 animal models 23.4 breastfeeding and 22.9 burden of disease 179.2 childhood, distribution 28.1–28.3, 28.2, 28.3 chronic lesions 24.3, 24.4, 28.4, 28.5 clinical features 28.1–28.10, 28.8–28.9

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

associated physical signs 28.4–28.6, 28.5, 28.6 configuration 28.4 dark skin types 28.6, 28.7 distribution 28.1–28.3, 28.2, 28.3 morphology 28.4, 28.5 specific subtypes 28.6–28.8, 28.8 cost 22.4 definition binary vs. continuous 28.13 challenges 23.1–23.2 incident cases 28.13 key requirements 28.14, 28.14–28.15, 28.15 in population surveys 22.1–22.2, 22.2, 22.3 progressive nosology 28.13–28.14 diagnostic criteria 28.1, 28.10–28.19 clinical settings 28.12–28.13 epidemiological studies 22.2, 22.2, 22.3 low disease prevalence and 28.12, 28.12 purpose 28.12–28.13 relevance of topic 28.10–28.11 validation studies 28.15–28.19 differential diagnosis 28.9, 28.10 infantile seborrhoeic dermatitis 28.10, 35.5 nummular dermatitis 28.10, 40.2 diffuse dry type 28.8 environmental factors in development 23.2, 27.14–27.16 environmental risk factors 22.8–22.12 epidemiology 22.1–22.15 descriptive 22.4–22.7 disease definition for 22.1–22.2, 22.2, 22.3 reasons for studying 22.1 ethnic group studies 22.6 examination 30.2 extrinsic 24.1, 28.11 sensitization to microbial antigens 26.6–26.7 family size and 22.6 fetal predictors 22.8–22.9 with filaggrin mutations see under FLG gene mutations filaggrin role in pathogenesis 23.11, 23.11 food-allergic sensitization 31.1–31.3 food allergies see under food allergies gender differences 22.5 genetics 22.8, 23.1–23.17 candidate gene studies 23.7–23.14, 23.9–23.10 methodological approaches 23.2–23.4 parent of origin effects 23.2 pathophysiological model 23.11, 23.11 twin studies 23.2 whole-genome association studies 23.6–23.7 whole-genome linkage studies 23.5 genital area 151.2, 151.2–151.3 geographical variation 22.6–22.7 gut microflora and 22.9 hapten-induced murine (mAD) 27.11 head and neck type 26.6, 26.6 histopathology of skin reactions 24.3 history taking, clinical 30.1–30.2, 30.2 HIV infection 52.4 hygiene hypothesis 22.6, 22.10 immunizations 30.2 immunology 24.1–24.9, 24.2 adaptive skin responses 24.3–24.5, 24.4 clinical implications 24.8–24.9 disease triggers 24.6–24.8 innate responses 24.6–24.7, 24.7 notable cells 24.4–24.5 skin reaction patterns 24.3 systemic responses 24.1–24.2, 24.2 immunopharmacological mechanisms 25.1–25.13 cell regulatory abnormalities 25.6–25.9 cytokines 25.5–25.6 impaired β-adrenoceptor reactivity 25.1–25.2 inflammatory mediators 25.2–25.5 therapeutic implications 25.9–25.13

Index impetiginized 26.1, 26.3, 28.8 incidence 22.4 infant feeding and 22.9–22.10 infantile differential diagnosis 28.10, 35.5 distribution 28.1, 28.2 infections 22.10, 24.6–24.7 intrinsic see atopiform dermatitis investigations 30.2–30.3 irritant contact dermatitis and 30.10 irritants and washing 22.10 Kawasaki disease precipitating 168.5 lichen simplex chronicus 28.3, 42.2 lichen striatus with 86.2, 86.3, 86.3 linear 86.5 Malassezia and see under Malassezia management 30.1–30.11, 30.4 microbiology 26.1–26.9 migrant studies 22.6 molluscum contagiosum with 28.8–28.9, 28.9, 46.1 morbidity 22.4 nail involvement 150.4 napkin area 20.2, 20.8 natural history 22.5–22.6 neonatal 11.2–11.3 nomenclature 23.1–23.2, 28.11, 28.11 non-atopic see atopiform dermatitis with null filaggrin mutations 28.8 nummular or discoid 28.8, 28.8, 40.1 outside-inside-outside model 25.10, 27.1 patch testing 44.8 periorbital pigmentation 28.5, 104.6 pets and 22.10 pigmentation changes 28.5, 28.6, 28.6, 104.1, 104.5 pityriasis alba 28.6, 28.7, 37.1, 37.2 post-pubertal 28.3, 28.3 prevalence 22.4, 22.5 prevention 22.14 psychoneuroimmunology 34.3–34.4 psychosocial aspects 34.1–34.6 assessment 34.4, 34.4 clinical utility 34.5–34.6, 34.6 impact on family 34.2–34.3 interactions with disease 34.1–34.2 treatment approaches 30.9, 34.4–34.5 quality of life assessment 29.9–29.16, 179.2 dermatology-specific measures 29.11 disease-specific measures 29.11–29.13 generic measures 29.10 impact on family 29.13–29.14 types of measures available 29.10 using proxies 29.9 utility measures 29.14 validity and reliability 29.9–29.10 risk factors 22.8–22.12 seborrhoeic dermatitis and 35.1–35.2, 35.2 secular trends 22.7 severity aeroallergen load and 32.6 distribution 22.4 food allergy and 31.8, 31.14 quality of life correlations 29.11 severity scoring 29.1–29.9 additional measures 29.7 choice of measure 29.1 clinical signs 29.2–29.5 diagnostic criteria and 28.12 disease extent 29.5–29.6 global measures 29.6–29.7 lack of standardization 29.7 patient symptoms 29.6 validity and reliability 29.1–29.2, 29.2 skin barrier dysfunction 24.5, 25.10, 27.1, 27.9–27.18, 27.15 smallpox vaccination 24.7, 28.8, 30.2, 51.12–51.13 social class gradient 22.6, 22.6 SPINK5 gene polymorphisms 23.10, 23.11, 27.11, 27.18, 124.2

Staphylococcus aureus see under Staphylococcus aureus subacute lesions 28.4, 28.5 Sutton’s summer prurigo 42.6 treatment 30.3–30.11 adjunctive measures 30.8–30.9 aeroallergen-specific immunotherapy 32.8–32.9 assessing compliance 30.9 dietary restrictions 30.9, 31.11–31.17, 31.14 education and general advice 30.3–30.4 immunopharmacologically targeted 25.9–25.11 initial 30.4–30.8 poor response to initial 30.9–30.10 psychological approaches 30.9, 34.4–34.5 systemic 30.10–30.11 trigger factors 30.3 UK diagnostic criteria 22.2, 22.2, 22.3 vitiligo with 105.4 Wiskott–Aldrich syndrome 177.33, 177.33 Atopic Dermatitis Quickscore (ADQ) 29.5 atopic ‘dirty neck’ 28.5, 28.6, 104.9 atopic eczema see atopic dermatitis atopic eczema/dermatitis syndrome (AEDS) see atopic dermatitis atopic (allergic) march 22.10–22.11, 23.1, 24.1, 31.1, 32.2 food-allergic sensitization and 31.1–31.2 interventions to prevent 32.8 skin barrier disruption 27.12, 27.18 ‘atopic (allergic) shiners’ 28.5, 104.6 atopiform dermatitis (intrinsic atopic dermatitis; non-atopic eczema) 22.11, 24.1, 32.1 clinical features 28.6, 28.18–28.19 nomenclature 28.11, 28.19 sensitization to microbial antigens 26.3, 26.6–26.7 atopy 32.1 defined 23.1 immunology 24.1 impaired β-adrenoceptor reactivity 25.1–25.2 inheritance 31.9 lichen striatus 86.2, 86.3 Netherton syndrome 124.5 pityriasis rosea and 84.2 pompholyx and 39.1 atopy patch test (APT) aeroallergens 32.5–32.6, 32.7–32.8 food allergens 31.10 ATP2A2 gene mutations 110.12, 125.1 ATP2C1 gene 91.10, 110.13 ATP6V0A2 gene mutations 134.13, 134.14 ATP7A gene mutations 134.14, 143.1, 148.10 ATP-binding cassette transporters see ABC transporters Atrax funnel web spiders 73.5 atraxotoxin 73.5 ATR gene product 135.23 atrichia, generalized see alopecia universalis congenita atrichia with papular lesions (APL) 127.87, 148.6 clinical features 127.9, 127.87, 148.7 pathogenesis 127.83 atrophic lesions focal dermal hypoplasia 133.1, 133.4 incontinentia pigmenti 130.3, 130.4 see also skin atrophy atrophic lichen planus 85.7 atrophoderma(s) 145.16–145.21 associated with other syndromes 145.18–145.19 follicular see follicular atrophoderma of Moulin, linear 145.17 atrophoderma of Pasini and Pierini (APP) 145.16–145.17 clinical features 104.5, 145.16–145.17, 145.17 differential diagnosis 145.17 vs. morphoea 145.16, 145.17, 145.17 atrophoderma reticulata see atrophoderma vermiculata

7

atrophoderma vermiculata (AV) 145.17–145.18 clinical features 123.2–123.3 inheritance 123.1 atrophy, skin see skin atrophy attachment relationships, atopic dermatitis 34.2 attention deficit hyperactivity disorder (ADHD) atopic dermatitis and 179.2 neurofibromatosis 1 128.6 recessive X-linked ichthyosis 121.12 attention-seeking behaviour atopic dermatitis 30.9 genital complaints 151.24 atypical mole syndrome (AMS) 109.18–109.22, 109.19 aetiology 109.18–109.19 cancer risk 109.20–109.21, 137.3 clinical features 109.20, 109.20 management 109.21–109.22 scoring system 109.18, 109.19 atypical (dysplastic) naevi 109.18–109.22 clinical features 109.19 pathology 4.2, 109.19–109.20, 109.20 Auchmeromyia luteola 69.1 Auspitz’s sign 80.1 autism recessive X-linked ichthyosis with 121.11, 121.12 self-injurious behaviour 180.6 tuberous sclerosis 129.5 autoallergens, atopic dermatitis 24.8, 31.3 autoantibodies lichen planus pemphigoides 85.7–85.8 maternofetal transfer 14.3 microscopic polyangiitis 167.8 morphoea 173.7–173.8 neonatal lupus erythematosus 14.3 pemphigus 91.1–91.2 placental transfer 14.3 relapsing polychondritis 167.20 systemic lupus erythematosus 175.5 systemic sclerosis 174.3, 174.4 Wegener granulomatosis 167.1, 167.2 see also specific antibodies autoimmune disease alopecia areata associations 149.4 anetoderma 145.12–145.13 complement deficiencies 177.19–177.20, 177.20 dermatitis herpetiformis and 90.3, 90.5 graft-versus-host disease with 178.8 hyperpigmentation 104.8–104.9 lichen planus and 85.1, 85.1 lichen sclerosus association 152.5 linear IgA disease and 89.3 morphoea association 173.7 neonatal lupus erythematosus and 14.10 pityriasis rubra pilaris 83.1 subepidermal blistering 91.13 urticaria 74.8 vitiligo associations 105.4–105.5 autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED) 127.9–127.10 alopecia areata 149.1 chronic mucocutaneous candidiasis 62.22, 177.13 clinical features 177.15 endocrine disorders 172.28, 172.28 genetics and pathogenesis 115.28, 177.13 skin infections 64.2, 64.3 autoimmune polyendocrinopathy syndrome, type 1 see autoimmune polyendocrinopathy-candidiasisectodermal dystrophy autoinflammatory syndromes see periodic fever syndromes autoinoculation HPV infections 47.2, 47.3 tuberculosis 57.3 Automeris io 73.4 autonomic fibres, embryonic-fetal transition 2.17

8

Index

autonomic (dys)function atopic dermatitis 25.2 Ehlers–Danlos syndrome 142.7 autoreactivity, IgE-mediated, atopic dermatitis 26.7 autosomal dominant polycystic kidney disease (ADPKD) 129.1, 129.9 autosomal dominant skin disorders 115.2, 115.2 gene therapy 140.9, 140.9, 140.13 inheritance 115.1, 115.2–115.3 segmental forms 115.15, 115.15, 115.16 autosomal mutations genomic mosaicism of lethal 115.14, 115.14 genomic mosaicism of non-lethal 115.14 autosomal recessive congenital ichthyoses (ARCI) 121.2, 121.24–121.38 ABCA12-deficient 121.25, 121.33–121.34 see also ABCA12 gene mutations clinical subtypes 121.25, 121.25, 121.26, 121.27 collodion baby 12.1–12.2 CYP4F2-deficient 121.26, 121.34 differential diagnosis 121.36–121.38 harlequin ichthyosis see harlequin ichthyosis ichthyin-deficient 121.26, 121.34 clinical features 121.34, 121.35 pathology 121.32 lamellar ichthyosis/congenital ichthyosiform erythroderma (LI/CIE) phenotype 121.31–121.32 see also congenital ichthyosiform erythroderma; lamellar ichthyosis lipoxygenase-deficient 121.34–121.36, 121.36 molecular classification 121.25–121.28, 121.32–121.36 TG1-deficient 121.25, 121.32–121.33 genetics and pathogenesis 121.33 pathology 121.32 phenotype 121.27, 121.28, 121.33 see also TGM1 gene mutations autosomal recessive skin disorders 115.3, 115.3 gene therapy 140.9, 140.9 revertant mosaicism 115.17–115.18 Avenzoar 1.1 Avicenna 1.1 avobenzone 108.13, 181.13 axial transposition flaps 186.5 axillary freckling 128.3, 128.3 azathioprine atopic dermatitis 30.10 monitoring therapy 192.16 pemphigus vulgaris 91.4 polyarteritis nodosa 167.11 psoriasis 82.2 systemic lupus erythematosus 175.8 Wegener granulomatosis 167.6 azelaic acid, acne 79.8 azithromycin acne 79.8–79.9 Chlamydia infections 153.16, 153.22 Lyme borreliosis 59.9 azole antifungals 62.14–62.15 B4GALT7 gene mutations 134.17, 142.3 babesiosis 59.10 baby powders napkin dermatitis 21.4 newborn skin care 5.8 baby wipes, napkin area care 21.1 bacillary angiomatosis 58.1–58.4 AIDS/HIV infection 52.2, 58.1, 58.2 cutaneous 58.2–58.3, 58.3 extracutaneous 58.3 pathology 58.2, 58.2 bacillary peliosis hepatis 58.3 bacillary splenitis 58.3 bacille Calmette–Guérin (BCG) vaccination complications 57.3 disseminated disease 57.3, 64.2 neonates 17.11 primary immunodeficiencies 64.2, 64.5

cutaneous response 57.3 leprosy prophylaxis 70.10 site, changes in Kawasaki disease 168.5 bacteraemia, Bartonella infections 58.3 bacteria nummular dermatitis pathogenesis 40.1 urticaria causation 74.3 bacterial artificial chromosomes (BACs) 116.3, 140.5 bacterial infections acute infectious purpura fulminans 162.2–162.5, 162.3 arthropod bites 71.5 atopic dermatitis 28.8, 28.8, 30.5 pathogenic role 24.6–24.7 congenital 8.4–8.5, 8.6 diabetes mellitus 172.21 dystrophic epidermolysis bullosa 118.19– 118.20, 118.20 eczema herpeticum 33.2 genital area 151.8–151.10 HIV infection 52.1–52.2 neonatal 9.1–9.4 oral ulceration/stomatitis 147.7 postinfectious purpura fulminans 162.3, 162.5 primary immunodeficiencies 64.2, 64.2–64.3, 64.4–64.5 secondary immunodeficiencies 64.9 severe ichthyoses 121.64 skin grafts 187.12–187.13 smallpox vaccination site 51.10, 51.11, 51.11–51.12 staphylococcal and streptococcal 54.3–54.7 vesiculobullous lesions 87.4, 87.4–87.5, 87.8 vulvovaginitis 152.2 see also specific infections bacterial vaginitis (BV) 153.22–153.23 Bacterium ammoniagenes 18.1, 19.2 Bairnsdale ulcer 57.7 Baisch syndrome 127.10 balanitis lichen sclerosus 152.5 neonatal 9.3 streptococcal 151.8–151.9, 151.9 balanoposthitis 9.3 balneo-phototherapy, warts 47.10 balsam of Peru allergy 44.3, 44.4, 44.9–44.10 bamboo hair see trichorrhexis invaginata band of Unna 70.3–70.4 Bannayan–Riley–Ruvalcaba syndrome (BRRS) 137.17–137.20 differential diagnosis 111.8, 128.8, 137.19–137.20 genital area 151.5 lipomatosis 141.7 pathogenesis 115.27, 137.17 tumour susceptibility 137.6, 137.19 vascular anomalies 112.17–112.18, 137.17 see also PTEN hamartoma tumour syndrome Bannayan–Zonana syndrome see Bannayan– Riley–Ruvalcaba syndrome barbiturates 190.8 Bardet–Biedl syndrome 141.9 barrier, skin see skin barrier Bartonella bacilliformis 58.1–58.2, 58.8 identification 58.9 Bartonella claridgeiae 58.5 Bartonella elizabethae 58.1 Bartonella henselae bacillary angiomatosis 58.1, 58.2 cat scratch disease 58.5 identification 58.3–58.4, 58.7 Bartonella infections 58.1–58.10 fever with bacteraemia 58.3 hepatic and splenic involvement 58.3 see also bacillary angiomatosis; bartonellosis; cat scratch disease Bartonella quintana 58.1 identification 58.3–58.4 Bartonella rochalimae 58.8 Bartonella vinsonii 58.1

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bartonellosis 58.1–58.2, 58.8–58.10 clinical features 58.9, 58.9, 58.10 pathology 58.8, 58.8 vs. bacillary angiomatosis 58.4 Bart–Pumphry syndrome 120.21–120.22, 122.1, 127.92 clinical features 120.22, 122.2 knuckle pads 96.1 molecular pathology 120.21 Bart syndrome 16.6 basal cell carcinoma (BCC) 99.1–99.2 arising in naevus sebaceous 110.4 Bazex–Dupré–Christol syndrome 137.1 calcification 95.7 clinical features 99.2, 99.2 Gorlin syndrome 99.1, 132.1 clinical features 132.8–132.9 pathogenesis 132.2 pathology 132.4 risk factors 132.4, 132.12–132.13 surveillance 132.14 treatment 132.14–132.16 hereditary skin disorders with proneness to 137.2, 137.3 naevoid (NBCCs) 132.4, 132.8–132.9 xeroderma pigmentosum 99.1, 99.2, 135.8, 135.8 basal cell naevus syndrome see Gorlin syndrome basal cells embryonic epidermis 2.4, 2.5 embryonic-fetal transition 2.13, 2.13, 2.14 fetal 2.19, 2.20 periderm origins 2.24 basal lamina, embryonic skin 2.7, 2.7 basal layer (stratum basale) 27.1, 27.2 keratins 117.2, 117.2 basal layer to surface length ratio, neonates 3.5–3.6 basaloid follicular hamartomas, naevoid 110.6–110.7 Basan syndrome 10.21, 127.3 base excision repair (BER) 135.1–135.2 basement membrane zone (BMZ) antibodies, childhood linear IgA disease 89.1, 89.2 distribution of target antigen 89.5 immunofluorescence studies 89.4–89.5, 89.5 nature of 89.6 ultrastructural localization of antigen 89.5–89.6 antigens in pemphigoid 91.14, 91.14–91.15 structure 91.14, 91.14 basidiobolomycosis 63.23–63.24 Basidiobolus ranarum 63.23 Bateman, Thomas 1.1, 1.2 bath additives, emollient 181.6–181.7 bathing atopic dermatitis 27.16, 30.4–30.5 genital dermatitis 151.3 newborn infants 5.1–5.2 bathing suit ichthyosis 121.27, 121.33 bathing suit pattern, pityriasis rosea 84.2 bathing trunk naevi 109.5, 109.5 see also congenital melanocytic naevi (CMN), giant Bazex–Dupré–Christol syndrome (BDCS) 137.1–137.2, 137.2 clinical features 137.1, 137.7 differential diagnosis 132.13, 137.1–137.2 follicular atrophoderma 137.1, 137.7, 145.18 BCC see basal cell carcinoma B-cell lymphoma, cutaneous see cutaneous B-cell lymphoma B-cells, biologicals targeting 182.10–182.11 BCG vaccination see bacille Calmette–Guérin (BCG) vaccination Bcl-2, mastocytosis 75.5 BCMO1 gene mutations 171.2 Bean syndrome see blue rubber bleb naevus syndrome Beare–Stevenson syndrome 115.23

Index Beau’s lines 150.1 becaplermin, infantile haemangiomas 113.7–113.8 Becker naevus 104.9–104.10, 104.13 hypertrichosis 104.13, 148.32, 148.32–148.33 laser treatment 104.13, 189.5 Becker naevus syndrome 104.13, 110.15 Beckwith–Wiedemann syndrome (BWS) 137.4, 137.7–137.8 macroglossia 147.22, 147.22 bed bugs (Cimex spp.) 71.1, 73.3–73.4 bite reactions 71.2–71.3 biting behaviour 71.7 diagnostic criteria 71.6, 71.7, 73.3–73.4 management 73.4 bee stings 73.2–73.3 behavioural changes child sexual abuse 155.2 photoprotective 108.17, 108.18 behavioural interventions atopic dermatitis 34.5 self-mutilation 180.11 behavioural problems skin lesions due to 180.1–180.14 tuberous sclerosis 129.5 Behçet disease (BD) 167.14–167.19 aetiology and pathogenesis 167.14–167.15 clinical features 167.15, 167.15–167.16 cutaneous lesions 77.3, 77.4, 167.16, 167.16 diagnostic criteria 167.15, 167.15 genital lesions 151.23, 167.15 oral lesions 147.3, 167.15, 167.15 pathology 167.15 prognosis 167.18 treatment 167.16–167.18, 167.17 Beighton scoring system, joint hypermobility 142.5, 142.6 bejel see syphilis, endemic benign cephalic histiocytosis (BCH) 103.10, 103.10, 103.13, 103.13–103.14 benzalkonium chloride allergy 44.4 benzathine penicillin 153.7 benzethonium chloride, newborn skin care 5.6 benzoates, hypersensitivity to 157.4, 157.5 benzocaine topical use 190.5 toxicity 5.7, 184.4 benzodiazepines 190.7–190.8 benzoic acid, percutaneous absorption 181.2–181.3 benzoyl peroxide acne 79.8 allergy 44.3 benzydamine hydrochloride mouthwashes or sprays 147.3, 147.4 benzyl alcohol, head lice 72.13 benzyl benzoate 72.6–72.7, 181.9 benzylpenicillin, Lyme borreliosis 59.9 Berardinelli–Seip congenital lipoatrophy 115.28, 141.18 Berliner’s sign 49.8 Berlin syndrome 134.18–134.19 Berloque dermatitis see phytophotodermatitis β2-adrenoceptor agonists, atopic dermatitis 25.10 β-adrenoceptors, reactivity in atopy 25.1–25.2, 25.7 β-carotene 171.1 content of foods 171.3 erythropoietic protoporphyria 107.14 excessive dietary intake 171.1, 171.4 excessively high levels see carotenaemia inborn errors of metabolism 171.2–171.3, 171.4, 171.4, 171.5–171.6 metabolism 171.1, 171.2 normal serum levels 171.2 photoprotective effects 108.11 β-catenin 127.83, 127.84 β-glucocerebrosidase 27.4, 27.5 atopic dermatitis 27.11 betaine, homocystinuria 169.5 betamethasone, alopecia areata 149.5

bevacizumab 99.9 BHD (FLCN) gene mutations 137.8 biliary dyskinesia, carotenaemia 171.3 binding injuries, abusive 154.4, 154.4 Biobrane dressings, burn wounds 187.17–187.18, 187.18–187.19 biofeedback, atopic dermatitis 34.5 biolistic delivery, therapeutic genes 140.6 biological agents 181.17, 182.1–182.15 anticytokine 182.1–182.10 cell-targeted 182.10–182.14 juvenile idiopathic arthritis 175.3, 175.4 monitoring therapy 192.16 pityriasis rubra pilaris 83.7 psoriasis 82.5–82.6 relapsing polychondritis 167.20 safety 82.5–82.6 serum sickness-like reactions 183.3 Wegener granulomatosis 167.6 see also specific agents biological weapons, vesiculobullous reactions 87.5, 87.5 biopsy, skin see skin biopsy biopsychosocial theory 179.5–179.6 biopterin synthesis, defective 169.3, 169.4 bioterrorism, use of smallpox 51.14–51.15 biotin 65.6 deficiency 65.6 hair loss 148.21, 148.21 hyperpigmentation 104.8 -responsive multiple carboxylase deficiency 20.11 treatment 65.6 biotinidase deficiency 169.9 holocarboxylase synthetase deficiency 11.11 biotinidase deficiency 115.26, 148.21, 169.9 bipolar affective disorder, Darier disease and 125.3 Bipolaris 63.7–63.8 Birbeck granules 103.5, 103.6 birch pollen allergy 32.7 birthmarks genital area 151.5–151.8 see also vascular malformations Birt–Hogg–Dubé syndrome (BHDS) 137.4, 137.8, 137.8–137.9 bitemporal aplasia cutis see focal facial dermal dysplasia bitemporal forceps marks syndrome see focal facial dermal dysplasia bites arthropod see arthropod bites; insect bites; spider bites human 154.4, 154.4–154.5 snake 73.10, 162.4, 162.7 B–K mole syndrome see atypical mole syndrome black dot hairs 149.2 black flies (Simulium) 71.2 bite pathology 71.5 biting behaviour 71.7 Brazilian pemphigus and 91.6–91.7 blackheads (open comedones) 79.5, 79.6 black piedra 62.32, 62.32 black widow spider (Latrodectus mactans) 73.5, 73.5 bladder diverticulae cutis laxa 143.3 Ehlers–Danlos syndrome 142.6–142.7 blanching phenomenon, cutaneous neuroblastoma 99.11, 99.11 blaschkitis (Blaschko dermatitis) 86.1 vs. lichen striatus 86.5 Blaschko linear acquired inflammatory skin eruption (BLAISE) see lichen striatus Blaschko’s lines 115.9, 115.9 acneiform naevus 79.18 broad bands 115.10, 115.11 diseases following 86.1–86.2 embryological origin 86.1, 115.10, 115.10 epidermal naevi 110.1 hair follicle naevus 94.6

head and neck 115.10, 115.10 incontinentia pigmenti 130.1 lichen striatus 86.1 linear granuloma annulare 93.6 linear lichen planus 85.7 linear morphoea 173.2, 173.4–173.5 linear psoriasis 80.6 narrow bands 115.10, 115.11 pigmentary mosaicism/hypomelanosis of Ito 131.1 blastic NK-cell lymphoma 99.25, 102.16 Blastomyces dermatitidis 63.9 blastomycosis 63.9–63.10 keloidal see lobomycosis South American see paracoccidioidomycosis blastomycosis-like pyoderma 54.6 Blau syndrome/early-onset sarcoidosis 158.1, 158.6–158.10 clinical features 158.8, 158.8–158.9, 158.9 pathogenesis 115.28, 158.7, 158.7–158.8 vs. classic sarcoidosis 158.2 bleeding see haemorrhage/bleeding bleomycin-induced hyperpigmentation 104.4, 104.9 blepharitis dystrophic epidermolysis bullosa 118.16 seborrhoeic 41.3, 41.4 blepharocheilodontic syndrome 127.10 blepharophimosis, ptosis and epicanthus inversus (BPES) 116.15, 116.15 blindness leprosy 70.11–70.12 measles 49.2 smallpox 51.5 blistering disorders see vesiculobullous disorders/lesions blistering distal dactylitis (BDD) 54.7 blisters/blistering age of onset 87.5–87.6 bullous pemphigoid 91.15, 91.15–91.16, 91.16 clinical features 87.1–87.2 congenital erosive and vesicular dermatosis 16.4 distribution 87.7–87.10 dystrophic epidermolysis bullosa 118.11– 118.12, 118.12 epidermolysis bullosa simplex 118.4–118.6, 118.5, 118.6 management 118.7, 118.7 epidermolytic ichthyosis 121.17 family history 87.6, 87.6–87.7 friction 87.2, 87.9 generalized 87.7, 87.7–87.8 genital 87.10, 151.12–151.16 incontinentia pigmenti 130.2, 130.2 intraepidermal 87.2, 87.2, 87.3 Kindler syndrome 119.1–119.2 linear IgA disease of childhood 89.1 localized 87.8, 87.8–87.9 localized vulvar pemphigoid 91.17, 91.17 mucosal surfaces 87.9, 87.9–87.10 neonates 87.6, 87.6 ocular 87.10 oral 87.2, 87.10 pemphigoid gestationis in newborn 91.20 pemphigus foliaceus 91.5 pemphigus vulgaris 91.3 physical causes 87.9 subcorneal 87.2, 87.2, 87.3 subepidermal 87.2, 87.2, 87.3 sucking, neonates 87.6 superficial epidermolytic ichthyosis 121.21 systemic illness with 87.4–87.5 terminology 87.1 see also bullae; vesiculobullous disorders/ lesions BLM complex 136.6 BLM gene 116.7, 136.6 BLNK gene mutations 177.25 Bloch–Sulzberger syndrome see incontinentia pigmenti

9

10

Index

BLOC lysosomal complexes 138.6 blood-feeding arthropods 71.1–71.2 blood transfusions, epidermolysis bullosa 118.26 blood vessels, skin embryonic-fetal transition 2.16–2.18, 2.17 embryonic skin 2.9, 2.11 fetal skin 2.23 prominent, chromosome disorders 116.13 skin flap design 187.21 Bloom syndrome 136.5–136.7 café-au-lait spots 116.12 clinical features 136.6 differential diagnosis 136.6 hypertrichosis 116.16 pathogenesis 115.27, 116.6–116.7, 136.5–136.6 tumour susceptibility 136.6, 137.4 Blount disease 141.10 blueberry muffin syndrome causes 8.2 congenital infections 8.1, 9.6, 49.16 congenital leukaemia 99.16 blue/black macular pigmented lesions 109.22–109.23 blue naevus 109.23–109.24, 109.24 cellular 109.23–109.24 histopathology 4.2 blue napkin syndrome 169.6 blue rubber bleb angiomatosis 115.26 blue rubber bleb naevus syndrome (of Bean) 112.10–112.11 clinical features 112.10, 112.10 histopathology 4.4, 112.10 blue sclerae, osteogenesis imperfecta 145.9 blunt trauma, non-accidental 154.4 Bockhart’s impetigo 54.4–54.5 bodybuilding acne 79.16, 79.16 body louse (Pediculus humanus) 72.9, 72.9, 72.10 clinical features of infestation 72.10–72.11, 72.11 treatment of infestations 72.13 body rocking 180.3, 180.3 Bohn nodules (cysts) 6.11, 147.10 boils (furuncles) 54.5 bone cysts, intraoral 147.19–147.20 bone marrow failure dyskeratosis congenita 136.9, 136.10 Fanconi anaemia 136.12 leukaemia 99.13 bone marrow mast cells, in mastocytosis 75.6–75.8, 75.7 bone marrow transplantation see haematopoietic stem cell transplantation bone pain, epidermolysis bullosa 118.22 Bonnet–Dechaume–Blanc syndrome 112.4 bony swellings, intraoral 147.19–147.20 Book dysplasia 127.10 boric acid toxicity 184.5 hair loss 148.18 newborn infants 5.7 Bork syndrome 127.62 Borrelia afzelii 59.3, 59.5 Borrelia burgdorferi 59.1 atrophoderma of Pasini and Pierini 145.16 congenital infection 8.6, 59.7 detection methods 59.7–59.8 Jessner’s lymphocytic infiltrate 101.1 lichen sclerosus and 59.6, 152.5 morphoea and 59.6, 173.1 pathogenic genospecies 59.3 transmission by ticks 59.1–59.4 see also Lyme borreliosis Borrelia garinii 59.3, 59.5 borrelial lymphocytoma 59.1 clinical features 59.5, 59.5 Jessner’s lymphocytic infiltrate and 101.1 treatment 59.8–59.9, 59.9 Borrelia valaisiana 59.3 bot fly cattle 69.2–69.3 horse 69.2–69.3

human 69.1–69.2 sheep nasal 69.3 botryomycosis 54.6 Bourneville disease see tuberous sclerosis complex boutonneuse fever (Rickettsia conorii) 61.2, 61.5, 61.5–61.6 Bowenoid papulosis 47.5 box jellyfish (Chironex fleckeri) 73.7, 73.8, 73.9 BP180 see bullous pemphigoid antigen of 180 kDa BP230 see bullous pemphigoid antigen of 230 kDa BPF resin allergy 44.10 brachial artery catheterization, complications in neonates 17.7 Brachmann-de Lange syndrome see Cornelia de Lange syndrome brachymetapody–anodontia–hypotrichosis– albinoidism 127.10 bradykinin 177.17 BRAF mutations 109.3, 109.12 branchial arch abnormalities 10.2–10.5, 10.7 branchial cysts 10.4–10.5 branchial fistulae 10.4–10.5 branchial sinuses 10.4–10.5 branchio-otic (BO) syndrome 10.4 branchio-oto-renal (BOR) syndrome 10.4, 10.6–10.7 Brauer syndrome 127.28, 145.18 Brazilian pemphigus (fogo selvagem) 91.2, 91.6–91.8 clinical features 91.7, 91.7 treatment 91.7–91.8 breast(s) abscess, neonatal 9.3 accessory (supernumerary) 10.8 developmental abnormalities 10.7–10.8 incontinentia pigmenti 130.4–130.5, 130.5 breastfed infants, atopic dermatitis 22.9 food allergies 31.7–31.8 maternal dietary restrictions 31.12, 31.16 breast milk, atopic dermatitis and 27.14 breech delivery, iatrogenic injuries 17.4 Brégeat syndrome 112.4 Brill–Zinsser disease 61.2, 61.7 British Contact Dermatitis Society (BCDS) 44.6–44.7, 44.8 British Dermatological Nursing Group (BDNG) 192.19 brittle hair, trichothiodystrophy 135.19, 135.20 brittle hair, impaired intelligence, decreased fertility and short stature (BIDS) 148.11 bronchogenic cysts, cutaneous 10.5–10.6 bronze baby syndrome 17.11, 104.9 Brooke–Spiegler syndrome (BSS) 137.9–137.10 associated malignancies 137.3, 137.10 pathogenesis 127.68, 137.9 brown fat 141.3 brown recluse spider (Loxosceles reclusa) 73.5, 73.5, 73.6 bruising accidental 154.3, 154.3 child abuse 154.3, 154.3, 154.3–154.4, 154.4 differential diagnosis 154.4, 154.10–154.12 excessive Ehlers–Danlos syndrome 142.8, 142.14 Marfan syndrome 145.6 iatrogenic neonatal 17.3–17.4 see also ecchymoses Brunzell syndrome 141.18 Bruton disease see X-linked agammaglobulinaemia BTK gene mutations 177.25 bubble bath products, newborn infants 5.2, 5.6 buckle injuries, abusive 154.4 buffalopox 51.2, 51.20 bulbous hair pegs 2.36, 2.37 bulimia cutaneous signs 65.9, 65.9 knuckle pad-like lesions 96.1

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

bullae 87.1, 87.2 acute graft-versus-host disease 178.5 arthropod bites 71.4, 71.4 bullous pemphigoid 91.15, 91.15, 91.16 clinical assessment 87.1–87.2 linear IgA disease of childhood 89.7, 89.7 see also blisters/blistering; vesiculobullous disorders/lesions bullous congenital ichthyosiform erythroderma of Brocq see epidermolytic ichthyosis bullous dermolysis of the newborn 115.22, 118.14 bullous drug eruptions 87.5, 183.9–183.11 bullous impetigo see impetigo, bullous bullous lichen planus 85.7–85.8 bullous pemphigoid (BP) 91.13, 91.13, 91.15–91.17 clinical features 91.15, 91.15–91.16, 91.16 differential diagnosis 91.16–91.17 epidermolysis bullosa acquisita 91.24 pompholyx 39.3 pathology 91.15, 91.15 of pregnancy see pemphigoid gestationis prognosis 91.16 treatment 91.17 vulva 151.12, 151.12 bullous pemphigoid antigen of 180 kDa (BP180) 91.14, 91.14 BPAG2 (COL17A1) gene mutations 118.30 bullous pemphigoid 91.14, 91.15 lichen planus pemphigoides 85.7 linear IgA disease 89.3, 89.6 localized vulvar pemphigoid 91.15, 91.17 mucous membrane pemphigoid 91.18 pemphigoid gestationis in the newborn 91.19–91.20 bullous pemphigoid antigen of 230 kDa (BP230) 91.14, 91.14 bullous pemphigoid 91.14 localized vulvar pemphigoid 91.15, 91.17 pemphigoid gestationis in newborn 91.19–91.20 ‘bullous pemphigoid of childhood’ 89.2 bullous rashes, newborn infants 8.1 bumble bees 73.2 Bunostomum phlebotomum 68.1 bupivacaine 190.2, 190.3 burden of paediatric skin disease 179.1–179.6 acne vulgaris 179.2–179.3 atopic dermatitis 179.2 biopsychosocial theory 179.5 congenital malformations 179.3 coping strategies 179.6 definitions 179.1 infantile haemangiomas 179.3 measures 179.1–179.2 secondary impact 179.5 Bureau–Barrière–Thomas disease 120.25 Burkitt’s lymphoma 147.19 burning bush (Dictamnus albus) 45.10, 45.10 burns/scalds blistering 87.9 chemical see chemical burns child abuse 154.5, 154.5–154.7, 154.6, 154.7 differential diagnosis 154.7, 154.10–154.12 suspicious features 154.5 cigarette see cigarette burns contact, inflicted 154.5, 154.6 cultured keratinocyte grafts 187.14 deep partial thickness 187.16, 187.17 full-thickness 187.16–187.17, 187.17 human skin substitutes 181.12 hypertrophic scarring 187.3–187.5, 187.8 immersion accidental 154.6 forced 154.5, 154.5, 154.5–154.6, 154.6 laser therapy 189.9 napkin area 20.12 self-inflicted 180.9, 180.10 splash and spill 154.6 superficial partial thickness 187.16, 187.16

Index transillumination devices 17.10 wound management 187.16–187.18, 187.17, 187.18–187.19 Burow’s triangle 187.21, 187.22 Buruli ulcer 57.7–57.8 vs. tropical ulcer 66.4 Buschke–OIlendorff syndrome (BOS) 116.13, 145.1–145.4 aetiology and pathogenesis 115.27, 145.1–145.2 clinical features 116.14, 116.15, 145.2, 145.2–145.3 differential diagnosis 145.3, 145.3 pathology 145.2 butcher’s wart 47.5 buttonholing signs 128.3 para-tertiary butyl phenol formaldehyde (BPF) allergy 44.10 C1 inhibitor (C1 INH) 177.17 deficiency 74.2, 74.8, 177.17, 177.20 serum 177.18 treatment 177.18 see also hereditary angioedema C1q deficiency 177.17, 177.19, 177.20 C1r deficiency 177.17, 177.19, 177.20 C1s deficiency 177.17, 177.19, 177.20 C2 deficiency 175.5, 177.17, 177.19, 177.20 C3 deficiency 177.19, 177.20 C3 nephritic factor (C3NeF) 141.15–141.16, 172.19 C4 deficiency 175.5, 177.17, 177.19, 177.20 serum 177.18 C5 deficiency 177.19, 177.20 C5 dysfunction 177.19, 177.20 C6 deficiency 175.5, 177.19, 177.20 C7 deficiency 175.5, 177.19, 177.20 C8α deficiency 177.19, 177.20 C8β deficiency 177.19, 177.20 C9 deficiency 177.19, 177.20 cachexia, Cockayne syndrome 135.15, 135.16, 135.17 cactus spine injuries 45.1 cadherins, desmosomal 127.97 caesarean section, iatrogenic injuries 17.5 café-au-lait macules (CALMs) 109.10–109.11 associated syndromes 109.10, 109.12, 128.7–128.8, 128.8 chromosome disorders 116.12 clinical features 109.2, 109.10 Fanconi anaemia 116.12, 136.11 Gorlin syndrome 132.13 histopathology 128.6 laser treatment 189.5 neurofibromatosis 1 109.10, 128.1–128.3, 128.2, 128.3 neurofibromatosis 2 128.12 pathogenesis 128.7 Proteus syndrome 111.4 segmental neurofibromatosis 1 128.11 vs. congenital melanocytic naevi 109.1 CAGE questionnaire, tanning-modified 108.9 caida de mollera 154.12 Caladryl lotion, toxicity 184.5 calcification cutaneous 95.2–95.9 benign nodular 95.8–95.9 causes (classification) 95.2, 95.2 differential diagnosis 144.7 dystrophic 95.5–95.7 iatrogenic 95.9, 95.9 idiopathic 95.3–95.5 metastatic 95.8–95.9 pseudo-hypoparathyroidism 172.26, 172.26 pseudo-xanthoma elasticum 95.7, 144.2, 144.3 see also calcinosis cutis ectopic Gorlin syndrome 132.9–132.10, 132.10 pseudo-xanthoma elasticum 144.6–144.7

calcifying aponeurotic fibroma 97.13 calcifying epithelioma of Malherbe see pilomatricoma calcifying fibrous pseudo-tumour 97.7 calcifying panniculitis 77.12, 95.6–95.7 calcineurin inhibitors, topical 181.11–181.12 alopecia areata 149.6 atopic dermatitis 25.11–25.12, 30.7–30.8 eosinophilic pustular folliculitis 36.5 lichen sclerosus 152.7 lichen simplex chronicus 42.2–42.3 mode of action 25.11, 25.11 Netherton syndrome 124.7 perioral dermatitis 38.3 pityriasis alba 37.2 psoriasis 82.3 safety 30.8 seborrhoeic dermatitis 41.4 vitiligo 105.6 see also pimecrolimus; tacrolimus calcinosis circumscripta 95.6 calcinosis cutis 95.2 dermatomyositis 95.5–95.6, 95.6, 175.11, 175.12 iatrogenic 95.9, 95.9 infantile, of heel 95.7 milia-like Down syndrome 95.4, 116.11 idiopathic 95.3–95.4 tumoral see tumoral calcinosis see also calcification, cutaneous calcinosis of scrotum/vulva, idiopathic 95.3, 151.22 calcinosis universalis 95.6 calciphylaxis 77.12, 95.8–95.9 calcipotriene see calcipotriol calcipotriol 181.14 ichthyoses/MEDOC 121.66–121.67 prurigo nodularis 42.5 psoriasis 82.2, 82.2–82.3 vitiligo 105.7 calcitonin 95.2 calcitonin gene-related product (CGRP)-positive nerve fibres 2.9–2.11, 2.17 calcitriol Albright hereditary osteodystrophy 95.12 topical 82.3, 181.14 calcium (Ca2+) aberrant deposition in skin 95.2–95.12 atopic dermatitis pathogenesis 27.6, 27.16 dietary intake, pseudo-xanthoma elasticum 144.8 endocrine regulation 95.1–95.2 epidermal gradient 27.2, 27.5 skin barrier regulation 27.5–27.6 solutions, iatrogenic calcinosis cutis 95.9, 95.9 supplements, Albright hereditary osteodystrophy 95.12 calcium channel deficiency 177.31 calcofluor white stain dermatophytes 62.11 pityriasis versicolor 62.28, 62.28 California flea rickettsiosis 61.2, 61.10 Calliphora 69.3, 69.4 Callitroga americana 69.3 Callitroga hominivorax 69.3 callosities, hereditary painful 120.17 Camarena syndrome 127.11 Camisa palmoplantar keratoderma see loricrin keratoderma Campath 1H 178.5, 178.8 camphor poisoning 184.5 camptodactyly, Blau syndrome 158.9, 158.9 Campylobacter skin infections 64.4 Canada, paediatric dermatology 1.3 canakinumab, juvenile idiopathic arthritis 175.3 Canale–Smith syndrome 177.8 cancer anti-TNF drug-treated patients 182.4, 182.6, 182.8 ataxia telangiectasia 137.3, 177.4 Bloom syndrome 136.6

11

cartilage–hair hypoplasia syndrome 137.3, 177.6 dyskeratosis congenita 136.9, 137.3 eosinophilic cellulitis with 36.9 eosinophilic fasciitis with 36.11 erythema gyratum repens 76.4 Fanconi anaemia 136.12 genital 151.20 hereditary skin disorders predisposing to 115.27, 137.1–137.20, 137.3–137.6 lichen planus pemphigoides 85.8 linear IgA disease and 89.8 loss of heterozygosity 115.15 multistep theory 135.2 oral ulceration 147.7 paraneoplastic pemphigus 91.9 Rothmund–Thomson syndrome 136.3–136.4, 137.3 skin infections complicating 64.7 xeroderma pigmentosum 135.9, 137.3 see also malignant skin tumours Candida granuloma 62.22, 62.22, 177.15 identification 62.23, 62.23 infections see candidiasis median rhomboid glossitis 147.24 pathogenic species 62.19 sources 62.19–62.20 urticarial reactions 74.3 Candida albicans 62.19 acute infectious purpura fulminans 162.3 carriage rates 62.20 granuloma gluteale infantum 20.4 id reactions see id reactions intertrigo 20.3, 54.7 napkin dermatitis 20.8–20.9 Candida antigen immunotherapy 181.9 molluscum contagiosum 46.5 Candida dubliniensis 62.19, 62.20 Candida glabrata 62.19 candidal leucoplakia 62.21, 147.13 candidate gene studies 23.3 atopic dermatitis 23.7–23.14, 23.9–23.10 candidiasis (candidosis; Candida infections) 62.19–62.25 aetiology and pathogenesis 62.20–62.21, 147.11 chronic localized 177.15 chronic mucocutaneous see chronic mucocutaneous candidiasis clinical features 62.21–62.23 collodion baby 12.3 congenital cutaneous 8.5, 8.6, 9.4, 62.21–62.22 anogenital region 20.5–20.6 diagnostic testing 11.11–11.13 differential diagnosis 62.23, 88.3 neonatal erythroderma 11.7 treatment 62.24 diabetes mellitus 172.21 diagnosis 62.23 differential diagnosis 62.23 endocrinopathy with see autoimmune polyendocrinopathy-candidiasisectodermal dystrophy familial chronic nail 177.15 genital area 151.11 historical context 62.19 HIV infection 52.2 immunosuppressed children 64.10 mucocutaneous, with thymoma (Good syndrome) 64.3 napkin area see napkin dermatitis, candidal neonatal 9.4 disseminated disease 9.4 superficial disease 9.4 use of emollients and 5.5 oral 62.20–62.21, 147.11–147.13 acute erythematous atrophic 62.21 acute pseudo-membranous (thrush) 62.20, 62.21, 147.11–147.12, 147.12 angular stomatitis 147.12–147.13, 147.13

12

Index

candidiasis (candidosis; Candida infections) (cont.) chronic atrophic (chronic denture stomatitis) 147.12 chronic erythematous 62.21, 147.12 chronic hyperplastic 62.21, 147.13 HIV infection 52.2, 62.20 treatment 62.24 pathology 62.21 primary immunodeficiencies 64.3, 64.5, 64.6 prognosis 62.23 treatment 62.23–62.24 vulvovaginal 152.2 Candidide, infantile 9.4 candidosis see candidiasis Cantagalo virus 51.20 cantharidin 181.13 molluscum contagiosum 46.5 warts 47.8 Cantu syndrome see onychotrichodysplasia and neutropenia cao giao (coin rubbing) 154.11–154.12 hCAP18 see LL-37 capillaries embryonic-fetal transition 2.17, 2.17 embryonic skin 2.9, 2.11 capillary haemangiomas see haemangiomas, superficial capillary malformation-arteriovenous malformation (CM-AVM) 112.5–112.6, 112.6, 115.26 capillary malformations (CMs) (port-wine stains) 112.14–112.18 clinical features 112.14, 112.14 differential diagnosis 112.15 intraoral 147.14, 147.15 Klippel–Trenaunay syndrome 112.16 laser treatment 112.15, 188.4–188.6 skin care after 188.6, 192.7, 192.13 localized or extensive (port-wine stain) 112.14–112.15 occult spinal dysraphism 112.18 pathology 4.5, 112.14 prognosis 112.14 Sturge–Weber syndrome 112.15 syndromic 112.15–112.18 treatment 112.15 CAPS see cryopirin-associated periodic syndromes capsaicin, topical, prurigo nodularis 42.5 capsaicinoids 45.2 caput succedaneum 17.3–17.4 carbamates contact allergy 44.4, 44.10 toxicity 184.13 carbamazepine, Stevens–Johnson syndrome/ toxic epidermal necrolysis 78.2, 78.5 carbaryl 181.9 lice 72.12 toxicity 184.13 carbon baby syndrome 104.9 carbon dioxide (CO2) laser congenital melanocytic naevi 189.7 infantile haemangiomas 113.18 other lesions 189.8, 189.9 pigmented lesions 189.4, 189.5, 189.6 warts 189.8 carbon tetrachloride poisoning 184.13 carbuncles 54.5 carcinoembryonic antigen (CEA) 2.30, 2.31 CARD4 (NOD1) gene, atopic dermatitis 23.9, 23.13 CARD9 gene mutations 177.13 CARD15 gene see NOD2 gene cardiac disease dystrophic epidermolysis bullosa 118.16 juvenile dermatomyositis 175.11 Kawasaki disease 168.6–168.8, 168.7 neonatal lupus erythematosus 14.4, 14.6–14.7 systemic sclerosis 174.8–174.10, 174.9 vaccinia vaccination and 51.13–51.14

cardiac failure hepatic haemangiomas 113.21, 113.21 infantile haemangioma 113.9 cardiac fibromas, Gorlin syndrome 132.10–132.11 cardiac rhabdomyomas, tuberous sclerosis 129.8, 129.8–129.9 cardiac valvular abnormalities Ehlers–Danlos syndrome 142.6 Marfan syndrome 145.6 pseudo-xanthoma elasticum 144.6, 144.7 Cardiff Acne Disability Index 179.3 cardiofaciocutaneous syndrome (CFC) 127.11–127.12 differential diagnosis 121.9–121.10 keratosis pilaris atrophicans 123.2 tumour susceptibility 137.6 cardiomyopathy Carvajal syndrome 127.99 Naxos syndrome 127.99 neonatal lupus erythematosus 14.4, 14.7 cardiovascular disease Behçet disease 167.16, 167.17 Ehlers–Danlos syndrome 142.6 Kawasaki disease 168.6–168.7, 168.9, 168.10 Marfan syndrome 145.6, 145.6 progeria 134.2–134.3 pseudo-xanthoma elasticum 144.6, 144.7 Sweet syndrome 156.3 Wegener granulomatosis 167.4 Carey syndrome 127.12 Carney complex 172.30–172.31 congenital melanocytic naevi 109.1–109.2 Cushing syndrome 172.7 genetics 109.2, 115.27 lentigines 109.12 L-carnitine supplements 169.8 carotenaemia 104.8, 171.1–171.6 aetiology and pathogenesis 171.1–171.3 clinical features 171.4, 171.4–171.5 dietary 171.1, 171.4 differential diagnosis 171.5, 171.5 hyperlipidaemias 171.1–171.2, 171.4–171.5 metabolic 171.2–171.3, 171.4, 171.4, 171.5–171.6 pathology 171.3–171.4 prognosis 171.5 treatment 171.5–171.6 carotene 65.4 content of foods 171.3 see also β-carotene carotenoderma 65.5 carotenoid 15,15’-mono-oxygenase (CMO) 171.1, 171.2, 171.2 gene mutations 171.2 carotenoids 171.1 Carpenter syndrome 141.10 Carrión disease see bartonellosis cartilage–hair hypoplasia syndrome (CHH) 177.6 cancer susceptibility 137.3, 177.6 clinical features 127.12, 177.2, 177.6 cartilagenous rests of the neck, congenital (wattles) 10.2, 10.3, 10.3 Carvajal syndrome (Carvajal–Huerta syndrome) 127.99 clinical features 127.13 genetic basis 115.20, 120.15–120.16 woolly hair 148.16 Casal’s necklace 104.8 CASP8 gene 177.8 CASP10 gene 177.8 Castellani’s solution (or paint) 184.8 Castleman disease, paraneoplastic pemphigus 91.9 catagen 148.2, 148.3 cataract–alopecia–sclerodactyly syndrome 127.13 cataract, hypertrichosis, mental retardation (CAHMR) syndrome 127.13 cataracts neurofibromatosis 2 128.13 Rothmund–Thomson syndrome 136.3

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

β-catenin 127.83, 127.84 caterpillars, noxious 73.4 catfish 73.9 cat flea (Ctenocephalides felis) 71.1 bites 71.5, 71.6, 71.6 murine typhus transmission 61.8 see also flea bites cathelicidins atopic dermatitis 24.7, 25.10–25.11 eczema herpeticum 33.1 cathepsin C (CTSC) 120.13 cathepsin D 27.4 cathepsin L2 27.4 cats, aeroallergens 32.2 avoidance strategies 32.8 cat scratch disease 58.5–58.7 clinical features 58.6, 58.6 vs. bacillary angiomatosis 58.1, 58.2 cattlepox 51.2, 51.20 CAV1 gene mutations 141.18 cavernous haemangiomas see haemangiomas, deep cayenne pepper spots, Schamberg disease 165.2, 165.3 CCBE1 gene 114.9 CD1a expression, Langerhans cells 2.15 CD2, mast cells in mastocytosis 75.6, 75.8 CD3 genes 177.31 CD4+/CD56+ haematodermic neoplasm 99.25, 102.16 CD4+ lymphocytopenia, idiopathic 64.3 CD4+ T helper cells graft-versus-host disease 178.2, 178.4 lichen planus 85.2 sarcoidosis 158.2 see also Th1 cells; Th2 cells CD8A gene 177.31 CD8+ cytotoxic T cells graft-versus-host disease 178.2, 178.4, 178.4 lichen planus 85.2 CD8 deficiency 177.31 CD18 177.28 CD19 gene mutations 177.25 CD20 182.10 CD25, mast cells in mastocytosis 75.6, 75.8 CD28 182.11–182.12 CD30+ lymphoproliferative disorders, primary cutaneous 99.22–99.23, 102.6–102.9 CD40 gene mutations 177.26 CD40LG gene mutations 177.26 CD45 deficiency 177.31 CD79A gene mutations 177.25 CD79B gene mutations 177.25 CD117 see kit protein CDH3 gene mutations 127.100 CDKN1B gene mutations 172.29 CDKN1C gene mutations 137.7 CDKN2A gene 109.21, 109.25 testing 109.21–109.22 cDNA transfer, gene therapy 140.10–140.11 CDSN gene mutations 127.100 CEBPE gene 177.11 CEDNIK syndrome 120.15, 121.51 clinical features 120.15, 121.51 molecular pathology 115.20, 120.15, 121.51 cefaclor, serum sickness-like reaction 183.3 cefotaxime gonococcal infections 153.12 Lyme borreliosis 59.9 ceftriaxone gonococcal infections 153.12, 153.22 Lyme borreliosis 59.9 cefuroxime axetil, Lyme borreliosis 59.9 ceiling effects, quality of life measures 29.10 cell adhesion molecules (CAMs) embryonic skin 2.8 hair follicle development 2.34 cell-mediated immunity (CMI) granuloma annulare 93.3 leprosy 70.2–70.3 see also T-cells

Index cell therapy 140.16–140.17 dystrophic epidermolysis bullosa 118.21 cellular proliferative nodules 4.2 cellulitis 54.5–54.6 bullous 87.8 eosinophilic 36.9–36.11 HIV infection 52.2 lymphoedematous areas 114.11, 114.13 neonatal 9.3 perianal see perianal streptococcal dermatitis variola vaccination 51.10, 51.11–51.12 centipede bites 73.6, 73.7 Centre de Référence National des Maladies Génétiques à Expression Cutanée (MAGEC) 11.4 centromeric repulsion 116.13, 116.13 Centruroides scorpions 73.6 cephalhaematoma 17.4, 17.4 cephalocoele 10.12, 10.13 cephalosporins gonorrhoea 153.12 Lyme borreliosis 59.9 ceramidase 27.4, 27.4 inherited deficiency 169.12–169.13 ceramides 27.2–27.3 insufficiency in atopic dermatitis 27.10 cerebral cavernous malformations, hereditary (CCM) 112.11–112.12 cerebral developmental venous anomaly (DVA) 112.9–112.10 cerebral dysgenesis, neuropathy, ichthyosis and palmoplantar keratoderma syndrome see CEDNIK syndrome cerebral heterotopia, nasal 10.14–10.15 cerebral palsy, congenital erosive and vesicular dermatosis 16.5 cerebro-oculo-facio-skeletal (COFS) syndrome 135.6, 135.7, 135.21–135.22 cerebrotendinous xanthomatosis 115.26 cerium nitrate poisoning 184.6 Cernunnos syndrome 177.31 cervical cancer, HPV vaccination 47.9 cervical cleft, congenital midline 10.5 cervical intraepithelial neoplasia (CIN) 47.6 cervical lymphadenitis atypical mycobacterial infections 57.5–57.6, 57.9, 57.9 tuberculous 57.3 cervical lymphadenopathy, Kawasaki disease 168.4, 168.4 cervicitis Chlamydia 153.13 differential diagnosis 153.11 gonococcal 153.10, 153.12 Cetacaine, topical 190.5 cetearyl alcohol allergy 44.11 cetrimide 181.8 cetuximab acneiform eruption induced by 79.20 squamous cell carcinoma 99.3 CEVD see congenital erosive and vesicular dermatosis CGI-58 (ABDH5) gene mutations 11.5, 121.53 Chanarin–Dorfman syndrome see neutral lipid storage disease with ichthyosis chancre 153.3 chancroid 155.4 CHARGE syndrome 151.16 CHD7 gene mutations 151.16 Chédiak–Higashi syndrome (CHS) 177.6–177.9, 177.8 clinical features 138.7, 177.2, 177.6–177.7 differential diagnosis 177.7, 177.7–177.8 pathogenesis and genetics 115.25, 138.7, 177.6 pigmentary changes 138.2, 138.7, 177.6 prognosis 177.7 treatment 177.8 cheek biting 180.3 cheilitis actinic prurigo 106.4, 106.5 angular, oral candidosis with 62.21

atopic dermatitis 28.3, 28.4 exfoliating, with perlèche 28.3 granulomatous see orofacial granulomatosis lip-lick 28.3 see also perioral dermatitis cheiropompholyx 39.1 chemical burns extravasation injuries 17.8, 17.8 non-accidental 154.5 saline flush-out technique 17.9, 17.9 chemical depilatories 148.33 chemical injury atopic dermatitis 24.5 plants 45.2, 45.2–45.3 chemical irritants, napkin dermatitis 19.2 chemotherapeutic agents 181.17 ataxia telangiectasia 177.5 choriocarcinoma 99.13 congenital/infantile fibrosarcoma 99.8 hair loss 148.18 Hodgkin disease 99.19 hyperpigmentation induced by 104.4–104.5, 104.8, 104.9 Langerhans cell histiocytosis 103.5–103.6 melanoma 109.27 neuroblastoma 99.12 oral ulceration caused by 147.9 solitary fibrous tumour/haemangiopericytoma 99.9 squamous cell carcinoma 99.3 topical, molluscum contagiosum 46.5 chequerboard pattern, pigmentary mosaicism 115.10, 115.11 chest drains, neonatal skin damage 17.6 chewing pads 96.1 Cheyletiella mites 71.4–71.5, 71.7 chickenpox see varicella chiggers see trombiculid mites chignon, vacuum extraction 17.4, 17.5 chilblain lupus 115.28 child abuse 154.1–154.12, 155.1–155.7 bite marks 154.4, 154.4–154.5 bruises 154.3, 154.3, 154.3–154.4, 154.4 burns/scalds 154.5, 154.5–154.7, 154.6, 154.7 conditions mimicking 154.9, 154.9–154.12 confidentiality 155.7 documentation 154.2 emotional 154.9 epidemiology 154.1, 155.1 fabricated/induced illness 154.8, 154.8–154.9 management 154.2–154.3, 155.4–155.7 multidisciplinary investigation 155.6–155.7 napkin dermatitis 20.12 neglect see neglect oral injuries 147.4, 154.7 perpetrators 154.1 physical 154.2–154.8 definition 154.2, 154.2 epidemiology 154.1, 155.1 injury patterns 154.3–154.8 risk factors 154.2, 154.2 red flags in history 154.2, 154.2 reporting suspected 155.4–155.6 risk factors 154.1, 154.1, 155.1 sexual see sexual abuse Childhood Atopic Dermatitis Impact Scale (CADIS) 29.14, 179.2 childhood cancer syndrome see constitutional mismatch repair deficiency syndrome child protection services 155.6–155.7 Children’s Dermatology Life Quality Index (CDLQI) 29.11, 29.12, 29.13, 179.1–179.2 Children’s Life Quality Index (CLQI) 29.10 CHILD syndrome 110.18, 121.55 clinical features 110.18, 115.13, 121.44 genetics 110.18, 115.20 histopathology 110.18 pathogenesis 115.12–115.13, 115.13, 121.54–121.55 treatment 110.18

13

Chilopoda (centipedes) 73.6, 73.7 chimeraplasts 140.11–140.12 CHIME syndrome see Zunich neuroectodermal syndrome Chinese medicine, traditional, atopic dermatitis 30.11 Chironex fleckeri (box jellyfish) 73.7, 73.9 Chlamydia trachomatis (CT) infections 153.13–153.17 clinical features 153.14–153.15 diagnosis 153.15–153.16, 153.22 infantile 153.14, 153.16 neonatal conjunctivitis 153.13, 153.14, 153.16 older children 153.14, 153.16 pneumonia 153.13, 153.14, 153.16 sexual abuse 153.14–153.15, 155.4 treatment 153.16, 153.22 chloasma 104.7 chloracne 79.19, 184.14–184.15 chloral hydrate 190.8 chlorambucil, granuloma annulare 93.8 chloramphenicol bartonellosis 58.10 Rocky Mountain spotted fever 61.4 spotted fever group rickettsial infections 61.6 typhus group rickettsial infections 61.8, 61.10 chlorazole black E stain 62.11 chlorhexidine gluconate 181.8 mouthwashes or sprays 147.3, 147.8–147.9 toxicity 184.6 chlorofluorocarbons (CFCs) 108.3, 108.17 chloroma (granulocytic sarcoma) 99.13, 99.14–99.15, 99.15 chloroquine hyperpigmentation induced by 104.4 porphyria cutanea tarda 107.14 sarcoidosis 158.5 cholecalciferol 108.5 cholestasis–lymphoedema syndrome 114.8 cholestatic hepatitis, neonatal lupus erythematosus 14.4, 14.7, 14.10 cholesterol biosynthesis disorders 121.54–121.55 serum, effects of retinoids 121.67–121.68 stratum corneum 27.2–27.3 cholesterol esters, stratum corneum 27.2–27.3 cholesterol sulphate 121.13 cholinergic urticaria 74.5, 74.5–74.6 chondrodysplasia punctata (CDP) 121.53 rhizomelic (RCDP) 121.48, 121.49 clinical features 121.43 X-linked dominant (type 2) see Conradi– Hünermann–Happle syndrome X-linked recessive 121.11, 121.12 chondroectodermal dysplasia see Ellis–van Creveld syndrome chondroid syringomas, calcification 95.7 chordee 151.16 chorioamnionitis, candidal 11.7 choriocarcinoma 99.12–99.13 non-gestational ovarian (NGCO) 99.12 chorionic villus sampling (CVS) 17.2–17.3, 17.3 DNA-based prenatal diagnosis 139.2, 139.2–139.3 infantile haemangiomas and 17.3, 113.4–113.5 practical aspects 139.6 timing 2.3, 2.3 choristomas, naevus sebaceous 110.5, 110.5 Christ–Siemens–Touraine syndrome see under hypohidrotic ectodermal dysplasia chromate sensitivity 44.9 chromomycosis (chromoblastomycosis) 63.6–63.7 chromophores 108.4–108.5 chromosomal abnormalities 116.3–116.7 acute myeloid leukaemia 99.16 ataxia telangiectasia 116.7, 177.4 Bloom syndrome 116.6–116.7, 136.5–136.6 congenital/infantile fibrosarcoma 97.15, 99.8 cutaneous T-cell lymphoma 99.21 dermatofibrosarcoma protuberans 97.14, 99.7 Fanconi anaemia 116.6, 136.11

14

Index

chromosomal abnormalities (cont.) haemangiopericytoma 99.9 lipomatous tumours 141.2, 141.3 mastocytosis 75.5 melanoma 185.20 pigmentary mosaicism/hypomelanosis of Ito 131.1–131.2 Rothmund–Thomson syndrome 136.1–136.2 Spitz naevi 185.20 chromosomal disorders 116.1–116.19 skin abnormalities 116.7–116.17 testing for 116.1–116.3 chromosome(s) methods of analysis 116.1–116.3 painting (spectral karyotyping) 116.2 chromosome 1q21, atopic dermatitis 23.5, 27.9 chromosome 3p24, atopic dermatitis 23.5 chromosome 5q23–31, atopic dermatitis 23.12 chromosome 11 open reading frame 30 (C11orf30), atopic dermatitis 23.6 chromosome breakage disorders 116.6–116.7 chromosome deletions see deletions chromosome inversions 116.4–116.5 chromosome translocations see translocations, chromosome chronic active hepatitis (CAH), lichen planus association 85.2, 85.3 chronic bullous disease of childhood (CBDC) see linear IgA disease (LAD), childhood chronic granulomatous disease (CGD) 177.9–177.13 clinical features 177.2, 177.9–177.10 differential diagnosis 177.10 pathogenesis 177.9 skin infections 64.2, 64.5–64.6, 177.9 treatment 177.12 chronic infantile neurological cutaneous articular syndrome (CINCA) see NOMID/CINCA syndrome chronic mucocutaneous candidiasis (CMC) 62.22–62.23, 147.11, 177.2–177.3, 177.13–177.16 clinical features 62.22, 62.22, 177.13, 177.13–177.14 differential diagnosis 177.14 familial 62.22, 177.15 idiopathic 62.23 keratitis-associated 177.15 late-onset 177.15 nail lesions 62.22, 62.22, 177.13, 177.14 oral lesions 62.22, 147.13 pathogenesis 177.13 primary immunodeficiencies 64.2, 64.3 treatment 62.24, 177.14 variants 177.15 see also autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy chronic myelocytic leukaemia, juvenile 99.13 leukaemia cutis 99.14, 99.15 chronic skin disease, burden of see burden of paediatric skin disease chrysalis babies 12.3, 13.5 chrysalis-like structures, Spitz naevi 185.17, 185.18, 185.19 chrysiasis 104.5 Chrysomyia bezziana 69.3 CHS1 gene mutations 138.7 Churg–Strauss syndrome 36.10 chylous reflux 114.17 CIAS1 gene 74.9, 74.13, 176.2 cicatricial alopecia see alopecia, scarring cicatricial pemphigoid see mucous membrane pemphigoid ciclopiroxalamine, dermatophytoses 62.16 ciclopirox nail lacquer 62.17 ciclosporin 181.17 atopic dermatitis 30.10–30.11 Behçet disease 167.17, 167.17 dystrophic epidermolysis bullosa 118.20 graft-versus-host disease 178.8, 178.9 granuloma annulare 93.8

hypertrichosis induced by 148.30, 148.32 monitoring therapy 192.16 pemphigus vulgaris 91.4 psoriasis 82.2, 82.4 cidofovir HSV infections 48.7 molluscum contagiosum 46.6 monkeypox 51.19 smallpox 51.8 vaccinia vaccination complications 51.14 warts 47.9 cigarette burns 154.6, 154.7 differential diagnosis 154.7 lumbosacral scar-like defects resembling 10.17 CIITA gene 177.31 cimetidine 181.16 linear IgA disease of childhood 89.10 warts 47.9 Cimex hemipterus 73.3 Cimex lectularis 71.1, 73.3 see also bed bugs CINCA syndrome see NOMID/CINCA syndrome cinnamaldehyde/cinnamic aldehyde hypersensitivity 44.4, 157.4, 157.5 ciprofloxacin bartonellosis 58.10 gonococcal infections 153.22 induced photosensitivity, cystic fibrosis 170.3 circumcision and infections 9.3 phimosis 151.18, 152.8 citronella, oil of 181.12 citrullinaemia 148.10 Civatte bodies 85.3 Cladophilaphora 63.8 Cladosporium carrionii 63.6 cladrabine, aggressive systemic mastocytosis 75.12 CLAPO syndrome 112.18 clarithromycin acne 79.8–79.9, 79.17 atypical mycobacterial infections 57.7, 57.8, 57.9, 57.10 Chlamydia infections 153.16, 153.22 leprosy 70.10 claudin-1 121.57, 121.58 CLDN1 gene mutations 121.57 clefting, ectropion and conical teeth syndrome 127.10 cleft lip/palate AEC/Rapp–Hodgkin syndrome 127.75, 127.77 EEC syndrome 127.78 focal dermal hypoplasia 133.3 surgical repair 187.23, 187.25 cleft lip/palate–ectodermal dysplasia syndrome (CLEPD1) 127.13, 127.100 Clericuzio-type poikiloderma with neutropenia 115.28, 127.52 clindamycin, topical, acne 79.8 clitoris agenesis 151.16 hair tourniquet 151.20 pseudocyst, lichen sclerosus 152.6 clobetasol alopecia areata 149.5 infantile haemangioma 113.17 lichen sclerosus 152.7 clofazimine granulomatous cheilitis 114.19 leprosy 70.9, 70.9, 70.12 clomipramine, nail biting 180.11 clonidine toxicity 184.6 clothing epidermolysis bullosa 118.17, 118.19 genital dermatitis 151.3 sun protection 108.16, 108.16–108.17 clothing louse see body louse clotrimazole, dermatophytoses 62.16–62.17

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

clotting disorders see coagulopathies Clouston syndrome (hidrotic ectodermal dysplasia) 120.21–120.22, 127.89–127.91 clinical features 120.22, 127.33, 127.90, 127.90–127.91 molecular pathology 115.23, 127.89 oral lesions 147.10 vs. KID syndrome 120.22, 122.2 CLOVE syndrome (CLOVES) 111.1, 114.10 epidermal naevi 110.13 lipomas 141.7 vascular malformations 112.18 Clutton’s joints 153.5 CMA1 gene, atopic dermatitis 23.9, 23.12–23.13 CMO1 gene mutations 171.2 CMV see cytomegalovirus cnidarian stings 73.7–73.8, 73.9 coagulopathies acute infectious purpura fulminans 162.2–162.5 Kasabach–Merritt phenomenon 113.25–113.26 management options 55.11 meningococcal disease 55.2, 55.3, 55.3–55.5, 55.4 vs. child abuse 154.10–154.11 see also localized intravascular coagulation coal tar 181.9–181.10 atopic dermatitis 30.8 napkin dermatitis 21.4 newborn skin care 5.6 psoriasis 82.2, 82.2 toxicity 184.9 cobalt allergy 44.3, 44.4 Coban® bandages, eczema 192.4, 192.7, 192.8 Cobb syndrome 112.5 cobras, spitting 73.10 cocaine maternal use 7.1 topical anaesthesia 190.1 toxicity 184.4 Coccidioides immitis 63.13, 63.14 Coccidioides posadasii 63.13 coccidioidomycosis 63.13–63.14 primary cutaneous 63.14 primary pulmonary 63.13 systemic or disseminated 63.13, 63.13 Cochin Jewish disorder see Haim–Munk syndrome cockade pattern see target-like lesions Cockayne syndrome (CS) 135.6, 135.14–135.18 clinical categories 135.16 clinical features 135.7, 135.14–135.16, 135.15 complementation groups 135.18 diagnostic tests 135.17 differential diagnosis 135.17 epidemiology 135.14 histopathology 135.16–135.17 molecular basis 115.28, 135.4, 135.18 patient support groups 135.24 premature ageing 134.5 treatment 135.17–135.18 see also xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex Cocois®, scalp psoriasis 192.4, 192.9 codeine 190.6, 190.8 coeliac disease see gluten-sensitive enteropathy Coffin–Siris syndrome 127.14 cognitive–behavioural therapy (CBT), atopic dermatitis 34.5 Cohen syndrome 141.10 coin rubbing (cao giao) 154.11–154.12 COL1A1 gene mutations 142.2–142.3, 145.9 COL1A1–PDGFB gene fusions 97.14, 99.7 COL1A2 gene mutations 142.2–142.3, 142.6, 145.9 COL3A1 gene mutations 142.2 COL5A1 gene mutations 142.2 COL5A2 gene mutations 142.2 COL7A1 gene exon skipping 140.15 mutations 118.11, 139.10 therapeutic transfer 140.5, 140.6, 140.10–140.11

Index COL17A1 gene mutations 118.30 trans-splicing 140.15 colchicine 181.17 Behçet disease 167.16, 167.17, 167.17 familial Mediterranean fever 176.2, 176.3 linear IgA disease of childhood 89.10, 89.11 cold creams 181.4 cold-induced autoinflammatory syndrome 1 gene see CIAS1 gene cold panniculitis 77.6–77.7, 77.7 cold sores see herpes labialis cold urticaria 74.5, 74.5 diagnosis 74.12 familial see familial cold urticaria colitis dystrophic epidermolysis bullosa 118.15 indeterminate 157.1 Kindler syndrome 119.2 see also ulcerative colitis collagen 145.9 deposition, systemic sclerosis 174.4–174.5, 174.5 diabetes-related changes 172.20 fibrils embryonic-fetal transition 2.16 embryonic skin 2.7, 2.8 fetal 2.20 production, keloids and hypertrophic scars 187.5 type I Ehlers–Danlos syndrome 142.2–142.3 embryonic skin 2.8, 2.9 osteogenesis imperfecta 145.9 type II 145.9 oral therapy, relapsing polychondritis 167.20 type III Ehlers–Danlos syndrome 142.2 embryonic skin 2.8, 2.9 type IV 145.9 prenatal diagnostic testing 139.8 type V Ehlers–Danlos syndrome 142.2 embryonic skin 2.8, 2.9 type VI, embryonic skin 2.8, 2.9 type VII 118.11, 145.9 embryonic-fetal transition 2.16 embryonic skin 2.7–2.8 prenatal diagnostic testing 139.8 substitution therapy 140.17 type XVII see bullous pemphigoid antigen of 180 kDa collagenomas 116.14 collodion baby 12.1–12.3, 121.30–121.31 acral self-healing 12.1–12.2, 121.33 aetiology 12.1–12.2, 121.30 clinical features 12.2, 12.2–12.3, 12.3, 121.30, 121.30 complications and prognosis 12.3 differential diagnosis 12.3, 13.5 MEDOC 121.5 neonatal erythroderma 11.4, 11.4 nursing care 192.1, 192.2 pathology 12.2 segmental 121.30, 121.31 self-healing 12.1–12.2, 121.30, 121.33 treatment 12.3–12.4, 121.30–121.31 collodion membrane clinical features 12.2, 12.2–12.3, 12.3 complications 12.3 pathology 12.2 colloid bodies 85.3 colobomas, naevus sebaceous 110.5, 110.5 colophony allergy 44.3, 44.10, 44.10 colorectal carcinoma, Gardner syndrome 137.12 coma blisters 87.9 comedo(nes) clinical features 79.6, 79.6 closed 79.5 fistulated 79.6

formation (comedogenesis) 79.3–79.5 inflammatory response 79.5–79.6 open 79.5, 79.6 pathology 79.5–79.6 comedo naevus (follicular naevus) 110.5–110.6, 110.6 Comel–Netherton syndrome see Netherton syndrome commissural lip pits 10.6–10.7 common variable immunodeficiency (CVID) 177.2, 177.25, 177.27 clinical features 177.27, 177.27 skin infections 64.2, 64.4–64.5, 177.27, 177.27 compact mesenchyme 2.8–2.9 comparative genomic hybridization (CGH) array (aCGH) 116.2–116.3 Spitz naevus vs. melanoma 185.18–185.20 compartment syndrome meningococcal septicaemia 55.6, 55.8 purpura fulminans 162.8, 162.10 surgical intervention 55.11, 55.12, 162.12– 162.13, 162.13 complementary and alternative therapies psoriasis 82.6 warts 47.10 complementary DNA (cDNA) transfer, gene therapy 140.10–140.11 complement deficiencies 177.16–177.21, 177.20 clinical features 177.19–177.20 mucocutaneous findings 177.2 neonatal lupus erythematosus 14.8, 14.9 pathogenesis 177.19 systemic lupus erythematosus 175.5, 177.19, 177.20 treatment 177.20–177.21 urticaria 74.2, 74.8 complement system 177.16, 177.16 compliance, atopic dermatitis 30.9–30.10 Compositae contact allergy 44.11, 44.11, 45.5–45.7 oral exposure and 44.2 compound heterozygosity 115.5 compound naevus 4.2 deep penetrating 4.2 compression garments, lymphoedema 114.12 computed tomography (CT) arteriovenous malformations 112.2 infantile haemangioma 113.11 Proteus syndrome 111.7 Sturge–Weber syndrome 112.16 tuberous sclerosis 129.3, 129.3, 129.11 venous malformations 112.9 conductive deafness, with ptosis and skeletal anomalies 127.13 condyloma acuminata (anogenital warts) 47.6–47.7, 153.17–153.18 clinical features 153.17, 153.17–153.18, 155.3 giant 47.6 HIV infection 52.4 sexual abuse implications 153.17, 155.3 treatment 153.18, 153.22 condyloma lata anogenital region 20.7 endemic syphilis 60.5 secondary syphilis 153.3 cone shells 73.8 confetti lesions, tuberous sclerosis 104.2 confluent and reticulated papillomatosis of Gougerot and Carteaud 104.9 congenital absence of skin see aplasia cutis congenita congenital adrenal hyperplasia 172.14, 172.15 acne 79.16–79.17 Addison disease 172.9 clinical features 172.14 hyperpigmentation 104.8 precocious puberty 172.11, 172.12 vulval abnormalities 151.16 congenital ectodermal dysplasia of the face see focal facial dermal dysplasia

15

congenital erosive and vesicular dermatosis (CEVD) 16.1–16.7 clinical features 16.1–16.5, 16.2–16.3, 16.4, 16.5 differential diagnosis 16.5–16.6 pathogenesis 16.1 pathology 16.1 prognosis 16.5 treatment 16.6–16.7 congenital erythropoietic porphyria (CEP) 107.4, 115.26 clinical features 107.8, 107.11, 107.11–107.12, 107.12 incidence 107.8 pathogenesis 107.7 porphyrin profile 107.5 prenatal diagnosis 139.3 treatment 107.14 congenital ichthyosiform erythroderma (CIE) (non-bullous) 121.25, 121.31–121.32 clinical features 121.26, 121.31–121.32, 121.34, 121.35 collodion baby 11.4, 11.4, 12.1 differential diagnosis 83.6, 121.36–121.38 genetic basis 115.20, 115.24, 121.25–121.26, 121.32–121.36 management 121.38, 121.65, 121.67 neonatal erythroderma 11.4, 11.4 pathology 121.32 see also autosomal recessive congenital ichthyoses congenital infections 8.1–8.7 bacterial 8.4–8.5, 8.6 diagnostic work-up 8.1, 8.2 fungal 8.5, 8.6 protozoal 8.5, 8.6 viral 8.3, 8.3, 8.4 congenital insensitivity to pain with anhidrosis (CIPA) 115.28, 127.15 congenital lipomatous overgrowth, vascular malformations and epidermal naevi see CLOVE syndrome congenital malformations, burden of disease 179.3 congenital melanocytic naevi (CMN) 109.1–109.8 aetiology and pathogenesis 109.1–109.2, 185.9 clinical features 109.2, 109.3–109.5, 109.4, 109.5 dermoscopy see under dermoscopy differential diagnosis 109.1, 109.2 frequency 109.1, 109.2 genetic counselling 109.8 giant (GCMN) and large 109.5, 185.5, 187.26–187.30 clinical features 109.5, 109.5, 187.26, 187.28 complications 109.5–109.7, 109.6 histology 185.28, 187.28 indications for treatment 191.1–191.2 management 109.8, 187.28–187.30, 191.1–191.8 melanoma risk 109.7, 109.25, 187.26 partial thickness excision 109.8, 186.6–186.7, 191.2 serial excision 187.10, 187.30, 191.2 timing of treatment 191.2 tissue expansion 187.30, 187.31, 191.2–191.6, 191.4, 191.5, 191.6, 191.7 giant cerebriform 109.5 hairy 109.4, 109.4, 148.31, 148.31 laser treatment 109.8, 189.6–189.7 medium 185.5 melanoma arising in 109.7, 109.7, 109.25, 109.25 dermoscopic evaluation 185.5–185.9 histopathology 109.3 pathology 4.1–4.2, 4.2, 109.2–109.3, 109.3 satellite naevi 109.5–109.6, 109.6, 187.26 treatment 191.6 small 109.5, 185.5 treatment 109.7–109.8, 191.1–191.8 congenital reticular ichthyosiform erythroderma see ichthyosis en confettis

16

Index

congenital self-healing reticulohistiocytosis (CSHRH) 103.2–103.3, 103.4, 103.4–103.5 congenital smooth muscle hamartoma (CSMH) 10.11, 148.31, 148.31 Congo floor maggot 69.1 conidiobolomycosis 63.23–63.24 Conidiobolus coronatus 63.23 conjunctival injection, Kawasaki disease 168.3–168.4, 168.4 conjunctivitis see gonococcal conjunctivitis; neonatal conjunctivitis connective tissue diseases dystrophic calcification 95.5–95.6 eosinophilic fasciitis 36.11 hereditary 115.23 oral lesions 147.9 panniculitis 77.10–77.11 see also specific diseases connective tissue naevus histopathology 4.7–4.8 of proteoglycan type (CNTP) 110.7 Proteus syndrome 111.3–111.4, 111.4 connexin(s) 122.1, 127.88–127.89, 127.89 defects see gap junction protein defects connexin 26 (Cx26) mutations 122.7, 127.89 connexin 30.3 (Cx30.3) mutations 122.7, 122.9, 127.89 connexin 31 (Cx31) mutations 122.7 connexin 43 (Cx43) mutations 127.89 Conradi–Hünermann–Happle syndrome (X-linked dominant chondrodysplasia punctata; CDPX2) 121.53–121.55 clinical features 121.43, 121.53–121.54 diagnosis 121.55 differential diagnosis 130.6 follicular atrophoderma 145.18 genetics 115.20, 121.54 histology 121.54 neonatal erythroderma 11.5 pathogenesis 121.54–121.55 prenatal diagnosis 139.3 segmental collodion membranes 121.30, 121.31 constipation, dystrophic epidermolysis bullosa 118.15, 118.24–118.25 constitutional mismatch repair deficiency syndrome (CMRDS) 137.14–137.15 differential diagnosis 128.8, 137.15 tumour susceptibility 137.5, 137.15 contact allergens important paediatric 44.8–44.12 lichenoid reactions 85.9 pompholyx 39.1 standard series, for patch testing 44.6–44.7, 44.7–44.8 urticarial reactions 74.4–74.5 contact dermatitis allergic see allergic contact dermatitis atopic dermatitis with 30.10 genital region 151.2, 151.3 irritant see irritant contact dermatitis lichen striatus 86.2, 86.2 pigmentation changes after 104.5 vesiculobullous lesions 87.9 vs. infantile seborrhoeic dermatitis 35.6 vs. nummular dermatitis 40.2 contact sensitivity sunscreens 108.15 UV-induced suppression 108.8 contact sensitizers alopecia areata 149.5–149.6 warts 47.9, 150.3 contact urticaria, sunscreens 108.15 contagious pustular dermatitis see orf contiguous gene syndromes (CGS) 115.6, 116.4 recessive X-linked ichthyosis 121.11, 121.12–121.13 continuous positive airways pressure (CPAP), nasal damage 17.6 contraception, isotretinoin-treated females 79.9

contractures dystrophic epidermolysis bullosa 118.11, 118.12, 118.21–118.22 severe MEDOC phenotypes 121.64–121.65 Cook syndrome 127.15 coping strategies 179.6 copper 65.7 deficiency 65.7, 65.7, 148.10 coproporphyria, hereditary see hereditary coproporphyria coproporphyrin 107.5 coproporphyrinogen oxidase (CPO) 107.6 deficiency 107.6 gene 107.3, 107.6 COPS syndrome 95.7 corals 73.7–73.8 Cordylobia anthrophaga 69.1–69.2 corneal dystrophy, keratosis follicularis spinulosa decalvans 123.3, 123.3 corneal opacities, recessive X-linked ichthyosis 121.12 Cornelia de Lange syndrome 115.24, 148.29 corneocytes 27.1–27.3, 27.2 shedding see desquamation site-specific size variations 27.8 corneodermato-osseous syndrome 127.15 corneodesmosin (CDSN) 27.3 atopic dermatitis 27.9 gene mutations 127.100 hydrolysis, in desquamation 27.3–27.4 corneodesmosomes 27.2, 27.3, 27.10 inherited disorders 121.4 proteolytic breakdown 27.3–27.4 cornification 27.1, 27.6 Mendelian disorders of see Mendelian disorders of cornification cornified envelope (CE) 117.2 atopic dermatitis 27.9–27.10, 27.10 fetal development 2.19–2.20, 2.21 inherited disorders affecting 121.3–121.4 periderm cells 2.24, 2.26 proteins 27.1–27.2 periderm cells 2.24, 2.26 structure 27.1–27.3, 27.2 transglutaminase 1 function 121.33 cornoid lamella, porokeratosis 126.1, 126.2 cornstarch powder (cornflour) epidermolysis bullosa simplex 118.7, 118.8 napkin dermatitis 21.4 CORO1A gene 177.30 coronary artery aneurysms, Kawasaki disease 168.7, 168.7–168.8, 168.9, 168.10 coronary artery disease, pseudo-xanthoma elasticum 144.6, 144.7 coronin 1A deficiency 177.30 corps ronds and grains 125.1 corticosteroids 181.17 adverse effects 113.15–113.17, 172.7 alopecia areata 149.4–149.5 amyloidosis 159.5 anti-Ro/SSA-positive pregnant women 14.10 atopic dermatitis 30.10 Behçet disease 167.16, 167.17, 167.17 Brazilian pemphigus 91.7–91.8 bullous pemphigoid 91.17 drug hypersensitivity reactions 183.3, 183.5, 183.8 dystrophic epidermolysis bullosa 118.20–118.21 epidermolysis bullosa acquisita 91.24 epidermolysis bullosa simplex 118.8 erythema multiforme 78.7 graft-versus-host disease 178.8, 178.9 Henoch–Schönlein purpura 160.6 hepatic haemangiomas 113.21, 113.22 hypereosinophilic syndrome 36.7–36.8 infantile haemangiomas 113.15–113.17, 113.16 inflammatory linear verrucous epidermal naevus 110.18 intra-articular, juvenile idiopathic arthritis 175.4

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

intralesional 181.11 granuloma annulare 93.8, 93.9 granulomatous cheilitis 114.19 hypertrophic scars 187.5 infantile haemangioma 113.17 keloids 187.5, 187.6 lichen simplex chronicus 42.2 Jessner’s lymphocytic infiltrate 101.3 junctional epidermolysis bullosa 118.33 juvenile dermatomyositis 175.12 juvenile idiopathic arthritis 175.2 Kasabach–Merritt phenomenon 113.26 Kawasaki disease 168.9 Langerhans cell histiocytosis 103.5–103.6 lepra reactions 70.12 lichen planus 85.10, 150.6 meningococcal disease 55.11 morphoea 173.9 mucous membrane pemphigoid 91.19 neonatal subcutaneous fat necrosis 7.3 pemphigus foliaceous 91.6 pemphigus vulgaris 91.4 polyarteritis nodosa 167.11 post-steroid panniculitis 77.7–77.8 relapsing polychondritis 167.20 sarcoidosis 158.5 Stevens–Johnson syndrome/toxic epidermal necrolysis 78.6, 78.7, 183.10 striae related to 146.2 Sweet syndrome 156.4 systemic lupus erythematosus 175.8 systemic sclerosis 174.11 topical see topical corticosteroids tuberous sclerosis 129.10–129.11 urticaria 74.12–74.13 urticarial vasculitis 163.5 vitiligo 105.7 cortisol deficiency 172.9–172.10 excess 172.7–172.8 Corynebacterium, pitted keratolysis 56.1 Corynebacterium afermentans 56.3 Corynebacterium minutissimum 56.3 cosmetic camouflage, vitiligo 105.8 cosmetic products acne induced by 79.19 baby skin care 5.5–5.8 Costello syndrome 134.16, 137.6 co-stimulatory molecules, biologicals targeting 182.11–182.13 co-trimoxazole see trimethoprim-sulphamethoxazole coumarin drugs purpura fulminans complicating 162.4, 162.6 see also warfarin Cowden’s naevus, linear 110.13 Cowden syndrome 137.17–137.20 clinical features 112.17–112.18, 137.17–137.19 diagnostic criteria 137.19, 137.19 differential diagnosis 132.13, 137.19–137.20 lipomatosis 141.7 oral lesions 147.17 pathogenesis 115.27, 137.17 tumour susceptibility 137.6, 137.19 see also PTEN hamartoma tumour syndrome cowpox 51.2, 51.15–51.17 clinical features 51.16, 51.16–51.17, 51.17 diagnosis 51.2, 51.17 protection against smallpox 51.8 cow’s milk allergy 31.6 atopic eczema 31.3–31.4 dietary restrictions 31.12, 31.15–31.16, 31.17 symptoms 31.6, 31.6–31.7 urticaria 74.2, 74.3 coxsackie viruses congenital infection 8.3, 8.4 hand-foot-and-mouth disease 49.9, 49.10 herpangina 49.11 neonatal infections 9.6 crab louse see pubic louse cradle cap 11.2, 35.2

Index clinical features 35.3, 35.3–35.4 prognosis 35.5 treatment 35.6 see also seborrhoeic dermatitis, infantile cranial dysraphism, cutaneous signs 10.12–10.13, 10.13 cranial fasciitis 97.8 cranio-ectodermal syndrome 127.16 craniofacial anomalies AEC/Rapp–Hodgkin syndrome 127.75, 127.77 EEC syndrome 127.78 Gorlin syndrome 132.5–132.7, 132.6, 132.7 hypohidrotic ectodermal dysplasia 127.70, 127.70 psychosocial issues 179.3 see also facial features craniosynostosis, Proteus syndrome 111.5 C-reactive protein (CRP) Kawasaki disease 168.6, 168.6, 168.9 morphoea 173.7 urticaria 74.12 creams 181.4 creeping eruptions 68.1 causes 68.3, 69.2 dermal myiasis 69.2–69.3 see also cutaneous larva migrans Creseis acicula 73.8 CREST syndrome see systemic sclerosis (SSc), limited cutaneous cri-du-chat syndrome 116.15–116.16 crinkled mouse 127.66, 127.67 Crohn disease 157.1–157.3 aetiology and pathogenesis 157.1, 158.7, 158.8 clinical features 157.1–157.2 genital area 151.23 linear IgA disease and 89.3 metastatic 20.9, 20.10, 151.23, 157.2 oral 147.8, 157.1–157.2, 157.2, 157.2 orofacial granulomatosis 114.18, 151.23 perianal 157.2 treatment 157.2, 157.4–157.5, 182.5 Cronkhite–Canada syndrome 127.52 Cross–McKusick–Breen syndrome 138.6–138.7 Crosti–Gianotti syndrome see Gianotti–Crosti syndrome crotamiton 181.9 scabies 72.6 Crowe’s sign 128.3 Crow–Fukase syndrome see POEMS syndrome CRTAP gene mutations 145.9 crusts, vesiculobullous disease 87.1 cryopirin-associated periodic syndromes (CAPS) 176.2, 176.3 treatment 74.13, 176.2 urticarial lesions 74.9, 163.5 cryosurgery 186.2 cryotherapy cutaneous larva migrans 68.4 granuloma annulare 93.8 molluscum contagiosum 46.4 porokeratosis 126.4 warts 47.8 cryptococcosis 63.2–63.3 HIV-related 52.2, 63.2, 63.3 Cryptococcus neoformans 63.2 CSA gene defects 135.6 function 135.3, 135.4, 135.18 CSB gene defects 135.6, 135.21 function 135.3, 135.4, 135.18, 135.24 CSF3R gene 177.10 Ctenocephalides felis see cat flea CTLA-4 182.12 CT scanning see computed tomography Culicoides (biting midges) 71.2, 71.7 cupping 154.12 curettage 186.2 giant congenital naevi 109.8, 186.6, 186.7, 187.28–187.30, 187.29, 187.30

molluscum contagiosum 46.4 warts 47.8 curly hair–acral keratoderma–caries syndrome (CHACS) 120.26 curly hair–ankyloblepharon–nail dysplasia syndrome (CHANDS) 127.17 Curry–Hall syndrome see Weyer acrofacial dysostosis Curvularia 63.4, 63.8 Cushing disease 172.7–172.9 clinical features 172.7, 172.8 hyperpigmentation 104.8, 162.7 Cushing syndrome 172.7–172.9 striae 146.2, 172.7, 172.8 cutaneous B-cell lymphoma (CBCL) 99.25–99.27, 102.14–102.15 clinical features 99.25, 99.25–99.26, 99.26 epidemiology 102.2 pathology 99.26 cutaneous larva migrans (CLM) 68.1–68.4 clinical features 68.2, 68.2–68.3, 68.3 diagnosis 68.3, 68.3 cutaneous T-cell and NK-cell lymphomas 99.19–99.25, 102.2–102.10 cutaneous T-cell lymphoma (CTCL) 99.19–99.25, 102.2–102.10 differential diagnosis 77.15 epidemiology 102.1 peripheral, unspecified 99.25 primary and secondary 99.19 see also mycosis fungoides; other specific types cuticle, nail 150.1 Cutimed Sorbact® dressings 118.20 cutis aplasia see aplasia cutis congenita cutis gyrata syndrome 115.23 cutis hypoplasia, chromosome disorders 116.10 cutis laxa 134.12, 143.1–143.4 acquired forms 143.1, 143.3–143.4 aetiology 143.1 autosomal dominant 115.23, 143.1, 143.2 autosomal recessive 143.1, 143.2–143.3 type I 143.1, 143.2–143.3 type II (with mental retardation) 134.12–134.14, 143.3 type III (DeBarsy syndrome) 134.6–134.7, 143.3 clinical features 143.2, 143.2–143.4 differential diagnosis 143.4 inherited forms 143.1, 143.2–143.3 marfanoid type 115.23 pathology 143.1–143.2 postinflammatory elastolysis and see postinflammatory elastolysis and cutis laxa transient neonatal 143.4 treatment 143.4 X-linked (occipital horn syndrome) 134.14, 142.1 aetiology 143.1 clinical features 143.3 differential diagnosis 142.8 cutis marmorata chromosome disorders 116.8–116.9, 116.9 neonatal lupus erythematosus 14.4, 14.5–14.6 cutis marmorata and macrocephaly 112.19 cutis marmorata telangiectatica congenita (CMTC) 112.19 laser treatment 188.10 vs. harlequin colour change 6.3, 6.3 cutis tricolor 115.16 cutis verticis gyrata (CVG) 10.1–10.2 cutting 180.9 CXCR4 gene mutations 47.2, 177.26 cyanocobalamin see vitamin B12 CYB gene mutations 177.9 cyclic AMP (cAMP), atopic dermatitis 25.6–25.8, 25.7, 25.10 cyclobutane pyrimidine dimers (CPD) 108.7, 135.2 cyclophosphamide infantile haemangiomas 113.18 juvenile dermatomyositis 175.12

17

mucous membrane pemphigoid 91.19 pemphigus vulgaris 91.4 polyarteritis nodosa 167.11 systemic lupus erythematosus 175.8 Wegener granulomatosis 167.6 CYGB gene mutations 120.17 CYLD gene mutations 127.68, 137.9 cylindrocarcinoma 137.10 cylindromas, genetic predisposition to 137.9, 137.10 cylindromatosis, familial (FC) 137.9–137.10 associated malignancies 137.3, 137.10 pathogenesis 115.27, 127.68, 137.9 Cynergy Multiplex laser system® 188.3, 188.3 Cynergy Nd:Yag laser® 188.3 Cynergy PDL laser® 188.3 cyproterone acetate, acne 79.9–79.10 Cyrano nose 113.9, 113.9 cystathionine β-synthase (CBS) deficiency 169.5, 169.5 cystatin A protease inhibitor 27.4, 27.11 cystatin protease inhibitors 27.4 cysteine, erythropoietic protoporphyria 107.14 cysticercosis, dystrophic calcification 95.7 cystic eyelids–palmoplantar keratosis– hypodontia–hypotrichosis see Schöpf–Schulz–Passarge syndrome cystic fibrosis 170.1–170.4 aetiology and pathogenesis 170.1 clinical features 170.1–170.3 cutaneous features 20.11, 170.2, 170.2–170.3, 170.3 diagnosis 170.4 salivary gland enlargement 147.22 treatment 170.4 cystic hygroma see lymphatic malformations (LM), macrocystic cysts defined 92.1 dermoid see dermoid cysts differential diagnosis 92.1–92.9, 92.2 epidermal 92.5–92.6 eruptive vellus hair 92.6–92.7, 92.7 trichilemmal 92.5–92.6 see also lumps, cutaneous cytochrome P450 4F2 (CYP4F2) (FLJ39501) gene mutations 12.1, 121.26, 121.34 cytogenetic techniques 116.1–116.3 cytokeratins 127.95 ectodermal dysplasias related to 127.95–127.97 see also keratin(s) cytokines acne vulgaris 79.5 atopic dermatitis 24.3–24.4, 25.5–25.6 candidate gene studies 23.12 Henoch–Schönlein purpura 160.2 lichen planus 85.2 morphoea 173.2 superantigen-mediated release 54.1 systemic sclerosis 174.5 cytomegalovirus (CMV) 49.16–49.17 identification 49.17 infectious mononucleosis 49.15 cytomegalovirus (CMV) infections 49.16–49.17 congenital/neonatal 8.4, 9.5–9.6, 49.16 HIV infection 49.16–49.17, 52.3 oral ulceration 147.6 pemphigus foliaceus with 91.6 cytophagic histiocytic panniculitis 77.13–77.14 cytotoxic agents see chemotherapeutic agents cytotoxic T cells see CD8+ cytotoxic T cells D2-40 immunostaining 4.5, 4.5, 4.6 Dabska tumour 99.10 dacarbazine, melanoma 109.27 dactylitis, blistering distal 39.3 dandruff 41.2, 41.3 treatment 41.4 dapsone acne 79.8 bullous pemphigoid 91.17

18

Index

dapsone (cont.) dermatitis herpetiformis 90.5–90.6 eosinophilic pustular folliculitis 36.5 epidermolysis bullosa acquisita 91.24 erythema elevatum diutinum 164.2 granuloma annulare 93.8 Henoch–Schönlein purpura 160.6 IgA pemphigus 91.10 infantile acropustulosis 88.3 leprosy 70.9, 70.9 linear IgA disease of childhood 89.10 monitoring therapy 192.16 pemphigus vulgaris 91.4 prurigo pigmentosa 42.7 darbepoietin α, epidermolysis bullosa 118.26 Darier disease 125.1–125.4 aetiology and pathogenesis 115.21, 125.1 associated conditions 125.3 clinical features 125.1–125.3, 125.2, 125.3 complications 125.3 dermal ridge abnormalities 10.22 differential diagnosis 91.10, 125.3 localized (epidermal naevus – Darier type) 110.12–110.13, 125.1, 125.3 oral lesions 125.3, 147.10 pathology 125.1, 125.2 prognosis 125.3 treatment 125.3–125.4 Darier–Gottron syndrome see progressive symmetric erythrokeratoderma Darier–Roussy sarcoidosis 158.4 Darier’s sign, mastocytosis 75.11, 75.11 Darier–White disease see Darier disease dark-skin types atopic dermatitis 28.6, 28.7 severity scoring 29.2 oral pigmentation 147.15 reaction to sun exposure 108.12, 108.12 transient neonatal pustular melanosis 6.8, 6.9 vitamin D synthesis 108.6 dasatinib, mastocytosis 75.12 day-care centres, napkin dermatitis prevention 21.2 DCLRE1C gene 177.31 DDB1 135.13 DDB1 gene defects 135.6 DDB2 135.13 DDB2 gene defects 135.6 DDB proteins 135.3 D-dimers, venous malformations 112.8, 112.9 deafness Cockayne syndrome 135.16 conductive, with ptosis and skeletal anomalies 127.13 congenital syphilis 153.5 KID syndrome 122.2, 127.92 palmoplantar keratoderma with see palmoplantar keratoderma (PPK)deafness syndromes severe MEDOC phenotypes 121.65 deafness and onychodystrophy (DOOR syndrome) 127.17, 150.8 deafness and onychodystrophy (Robinson syndrome) 127.17 DeBarsy syndrome 134.6–134.7, 143.3 decorin 134.5 dectin-1 177.13 deep penetrating naevus 4.2 DEET see diethyltoluamide defensins (human (β)-defensins; HBDs) acne vulgaris 79.5 atopic dermatitis 24.7, 25.10–25.11, 26.3 erythema toxicum neonatorum 6.6 degloving injuries, dystrophic epidermolysis bullosa 118.14 Degos disease see erythrokeratoderma en cocardes dehydration MEDOC 121.63 Netherton syndrome 124.6

dehydroepiandrosterone sulphate (DHEAS) acne neonatorum 79.15 acne pathogenesis 79.2, 79.3 elevated serum levels acne 79.16, 79.17 androgen excess states 172.15 19 DEJ-1, embryonic skin 2.7–2.8 delayed hypersensitivity allergic contact dermatitis 44.1, 45.5–45.7 drugs 183.13–183.14 insect bites 71.3, 71.3–71.4 deletions (genetic) 115.6, 116.4 1p36 116.12 1q syndrome 116.14 2q37 116.8 3q23 116.15, 116.15 3q27 syndrome 116.10 4q 116.11 4q34 116.16, 116.16, 116.17, 116.17 5p syndrome see cri-du-chat syndrome 6q16–q21 116.17 6q syndrome 116.9, 116.14 7q 116.9 8q22–24 116.16 12q microdeletion see Buschke–Ollendorff syndrome 16q 116.14 17q21 116.15 18p syndrome 116.11, 116.12 18q syndrome 116.8, 116.11 22q11 microdeletion see DiGeorge syndrome methods of detection 116.2 Xp (del Xp) 116.8, 121.11, 121.12–121.13 Xp22.32 116.9 Delhi boil 67.1 dematiaceous fungi, mycoses due to 63.6–63.8 Demodex brevis 72.14, 72.15 Demodex folliculitis (demodicidosis) 72.14–72.16 clinical features 72.15, 72.15 diagnosis 72.15, 72.15–72.16 differential diagnosis 72.15–72.16 HIV infection 52.4 pathology 72.15, 72.15 treatment 72.16 vs. perioral dermatitis 38.3 Demodex folliculorum 72.14, 72.15 dendritic cells (DC) allergen sensitization 31.3, 32.3–32.4, 32.4 allergic contact dermatitis 44.1 atopic dermatitis 24.4, 25.5 genetically engineered 140.17 interstitial 103.1 Dendrocnide 45.3, 45.3 Dendy, Walter C. 1.1, 1.2 Dennie–Morgan lines (infraorbital folds) 28.5, 28.5, 28.15 dental abnormalities AEC/Rapp–Hodgkin syndrome 127.75, 127.76 congenital erythropoietic porphyria 107.11 congenital syphilis 153.5 dyskeratosis congenita 136.8 dystrophic epidermolysis bullosa 118.15, 118.26 EEC syndrome 127.78 Ehlers–Danlos syndrome 142.8, 142.14, 142.14 focal dermal hypoplasia 133.2, 133.3 hypohidrotic ectodermal dysplasia 127.68–127.69, 127.69 incontinentia pigmenti 130.4, 130.4 odonto-onychodermal dysplasia 127.84–127.85 Schöpf–Schulz–Passarge syndrome 127.86 dental abscesses 147.17, 147.18 dental care ectodermal dysplasias 127.103, 127.104 epidermolysis bullosa 118.26, 118.32 focal dermal hypoplasia 133.8 dental pits, tuberous sclerosis 129.7 dentition normal development 127.104 see also teeth

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

dento-oculocutaneous syndrome 127.4 denture stomatitis, chronic 147.12 depigmentation chromosome disorders 116.11 remaining skin, in vitiligo 105.8 vitiligo 105.2, 105.2, 105.3 see also hypopigmentation depilation lasers 148.33, 189.3–189.4 depilatories, chemical 148.33 depression, atopic dermatitis 34.2 dermabrasion 186.2 giant congenital naevi 109.8 dermal erythropoiesis 8.1, 8.2 see also blueberry muffin syndrome dermal hypoplasia focal see focal dermal hypoplasia Proteus syndrome 111.4 dermal malignant tumours 99.4–99.10 dermal melanocytosis acquired 189.4–189.5 congenital see Mongolian spots dermal naevi see intradermal naevi dermal nodules, histopathology 4.3–4.4 dermal papilla, development 2.37 dermal ridges absent, onychodystrophy and palmoplantar anhidrosis see Basan syndrome aplasia 10.21 dissociation 10.22 hypoplasia 10.21–10.22 of-the-end pattern 10.22 punctate interruptions 10.22 see also dermatoglyphs dermal sinuses cranial dysraphism 10.16 hypertrichosis 148.32 spinal dysraphism 10.17 Dermanyssus mites 71.4–71.5, 71.7, 71.7 dermatitis see eczema dermatitis artefacta 154.11, 180.3 dermatitis artefacta syndrome 180.7 Dermatitis Family Impact (DFI) score 29.11, 29.13, 29.13–29.14, 179.2 dermatitis herpetiformis (DH) 90.1–90.6, 91.13 aetiology 90.1–90.3, 90.2 associated diseases 90.4–90.5 clinical features 90.4, 90.4 differential diagnosis 90.5 infantile acropustulosis 88.3 linear IgA disease of childhood 89.1, 89.2, 89.4 pompholyx 39.3 histopathology 90.3, 90.3–90.4 oral lesions 147.9 prognosis 90.5 treatment 90.5–90.6 dermatitis para-artefacta syndrome 180.7 dermatitis verrucosa 63.6 Dermatobium hominis 69.1–69.2, 69.3 dermatochalasis see cutis laxa dermatofibroma (fibrous histiocytoma) 92.4–92.5 clinical features 92.5, 92.5 histopathology 4.3 dermatofibrosarcoma protuberans (DFSP) 99.7 giant cell fibroblastoma and 97.13–97.14 pathology 4.3, 99.7 dermatoglyphs (fingerprints) congenital abnormalities 10.21–10.22 development 2.29, 2.31, 2.31, 2.32 see also dermal ridges dermatographism 74.5 transient neonatal 6.3, 6.3 white, atopic dermatitis 25.1, 28.5–28.6, 28.6 dermatome excision of skin lesions 186.2 split-thickness skin grafts 186.5, 187.13, 187.13 dermatomegaly see cutis laxa dermatomyositis, juvenile see juvenile dermatomyositis dermatopathia pigmentosa reticularis 117.3–117.4, 127.97

Index clinical features 117.3–117.4, 127.17 genetics 115.25, 138.3 reticulate hyperpigmentation 127.97, 138.9–138.11 dermatopathology, role of histopathology 4.1–4.8 Dermatophagoides see housedust mites dermatophytes anthrophilic 62.2–62.4, 62.3 culture 62.11–62.13, 62.13 ecological groups 62.2, 62.3 geophilic 62.2, 62.3 id reactions see id reactions microscopy 62.11, 62.12 molecular diagnostics 62.13–62.14 new and old species concepts 62.2, 62.13 zoophilic 62.2, 62.3, 62.4, 62.4 see also individual species dermatophytic pseudomycetoma 63.25 dermatophytoses 62.1–62.19 clinical features 62.5–62.11 deep 63.25–63.26 diabetes mellitus 172.21 diagnosis 62.11–62.14 differential diagnosis 62.14 epidemiology 62.2–62.4 HIV infection 52.2, 52.2 ichthyoses 121.32, 121.64 pathogenesis 62.4–62.5 pathology 62.5 transmission/source of infection 62.4 treatment 62.14–62.17 see also specific diseases dermis embryonic 2.4, 2.4, 2.8, 2.8 embryonic-fetal transition 2.16, 2.17 fetal 2.21, 2.22, 2.22 neonatal 3.5–3.6 dermoepidermal junction (DEJ) embryonic 2.4, 2.4, 2.5, 2.7, 2.7–2.8 embryonic-fetal transition 2.16, 2.16 fetal 2.20 major structural proteins 118.3 dermographism see dermatographism dermoid cysts 92.6 clinical features 92.6, 92.6 congenital inclusion 10.15, 10.15–10.16 cranial dysraphism 10.12–10.13 occult spinal dysraphism 10.17 sublingual 147.23 dermoid sinus cyst, nasal 10.15 dermo-odonto-dysplasia 127.18 dermoscopy 109.1, 185.1–185.21 acquired melanocytic naevi 109.13, 109.14, 185.9–185.12 benign patterns 185.9, 185.9–185.11, 185.10, 185.11, 185.12 melanoma risk factors 185.11–185.12 senescence 185.10, 185.11 congenital melanocytic naevi 109.5, 185.5–185.9 diffuse brown pigmentation pattern 185.8, 185.8, 185.8 globular pattern 185.7, 185.8, 185.8 multicomponent pattern 185.8, 185.8, 185.8 reticular pattern 185.6, 185.8, 185.8 reticuloglobular pattern 185.8, 185.8, 185.8 structures 185.5–185.7, 185.6, 185.6, 185.7, 185.7 halo naevi 185.12, 185.13 histopathological correlates 185.2–185.3, 185.2–185.4 melanoma diagnosis 185.12–185.16, 185.14, 185.15, 185.16 molluscum contagiosum 46.4 non-polarized 185.2 polarized 185.2 porokeratosis 126.3 Spitz naevi 109.15, 185.16–185.21 atypical pattern 185.17–185.20, 185.19, 185.20 changes over time 185.20, 185.20–185.21

globular pattern 185.17, 185.19 homogeneous pattern 185.17, 185.19 negative network pattern 185.16–185.17, 185.18 network pattern 185.16, 185.18 patterns 185.16–185.18, 185.17 starburst pattern 109.15, 109.16, 185.16, 185.17, 185.18 two-step algorithm 185.4, 185.4–185.5 dermotrichic syndrome 127.18 DeSanctis–Cacchione syndrome 135.9, 135.11 desmocollin (DSC) 27.1, 127.97 hydrolysis, in desquamation 27.3–27.4 IgA autoantibodies 91.9 desmocollin 3 (DSC3) gene mutations 127.100 desmoglein (DSG) 27.1, 127.97 hydrolysis, in desquamation 27.3–27.4 desmoglein-1 (DSG1) 91.1, 91.2 autoantibodies 91.1, 91.5, 91.6 gene mutations 120.15–120.16, 127.100 staphylococcal scalded skin syndrome 54.8 desmoglein-3 91.1, 91.2 autoantibodies 91.1–91.2 pemphigus neonatorum 91.8 desmoglein-4 (DSG4) gene mutations 127.96, 127.100, 148.15 desmoid-type fibromatosis, infantile 97.8–97.9 desmoplakin 27.1, 127.97, 127.98, 127.99 gene mutations see DSP gene mutations desmoplastic trichoepithelioma (DTE) 94.5–94.6 desmosomes 91.1, 91.2, 127.97–127.98 embryonic epidermis 2.4, 2.5 inherited disorders 121.4, 125.1, 127.97– 127.100, 127.98 stratum corneum 27.3 stratum spinosum 27.1, 27.2 desogestrel, acne 79.9–79.10 desquamation 27.3–27.4, 27.10 atopic dermatitis 27.11 in different body sites 27.8 graft-versus-host disease 178.5, 178.6 Kawasaki disease 168.3, 168.3 neonatal 6.2, 6.2 recessive X-linked ichthyosis 121.13 regulation 27.4, 27.5 detergents atopic dermatitis and 24.5, 27.15–27.16 effect on barrier function 27.6, 27.7 newborn infants 5.6, 5.6–5.7 developing countries, atopic dermatitis 22.6–22.7 development, skin 2.1–2.41 embryonic-fetal transition 2.12–2.18 embryonic period 2.4–2.11 features unique to humans 2.23–2.39 fetal period 2.19–2.23 importance of studying 2.1–2.2 methods of studying 2.2 regionalization 2.27, 2.27 time scale 2.2–2.3, 2.3 developmental abnormalities 10.1–10.22 developmental venous anomaly (DVA) 112.9–112.10 dexametasone anti-Ro/SSA-positive pregnant women 14.10 post-laser treatment 188.6 suppression test 172.15 diabetes insipidus, Langerhans cell histiocytosis 103.3, 103.4, 103.6 diabetes mellitus 172.20–172.24 carotenaemia 171.1–171.2, 171.4–171.5 cutaneous manifestations 172.20, 172.20–172.23 cystic fibrosis 170.2 familial partial lipodystrophy 141.15 granuloma annulare and 93.2 insulin lipoatrophy 141.13 localized fat hypertrophy 141.4 pathogenesis 172.20 diabetic dermopathy 172.22 diabetic microangiopathy 172.20 diabetic neuropathy 172.20

19

diapers see napkin(s) diarrhoea, napkin dermatitis due to 19.1–19.2 diastematomyelia 10.16, 10.17, 148.31 diazepam 190.7 diazoxide-induced hypertrichosis 148.30 diclofenac topical gel, porokeratosis 126.4 Dictamnus albus 45.10, 45.10 didymosis (twin spotting) 115.15–115.17 examples 115.16, 115.17, 115.17 mechanism 115.15–115.16, 115.16 didymosis aplasticosebacea 110.5 didymosis vascularis 115.16 Dieffenbachia 45.2, 45.2 dietary management acne 79.10 atopic dermatitis 30.9, 31.11–31.17, 31.14 dystrophic epidermolysis bullosa 118.23 hyperlipidaemias 169.14–169.15 metabolic carotenaemia 171.4–171.5 Netherton syndrome 124.6 organic acidurias 169.6, 169.8 orofacial granulomatosis 157.5 phenylketonuria 169.4, 169.4 Refsum disease 121.50 tyrosinaemia type II 169.5 N,’N-diethyl-3-methylbenzamide see diethyltoluamide diethyltoluamide (DEET) 71.8, 73.1, 181.12 toxic effects 184.6 differentiation, epidermal see epidermal differentiation diffuse large B-cell lymphoma, primary cutaneous (PCDLBCL) 99.27, 102.15 DiGeorge syndrome 177.21 hypoparathyroidism 172.25 mucocutaneous findings 177.2 neonatal erythroderma 11.10 skin infections 64.2, 64.3 digital fibromatosis 97.11, 97.11–97.12, 97.12 digits constrictions, severe MEDOC 121.64–121.65 eccrine sweat gland development 2.29–2.31, 2.31, 2.32 fusion, dystrophic epidermolysis bullosa 118.14, 118.14, 118.21–118.22 surgery 187.18–187.19, 187.20 infarctions, systemic lupus erythematosus 175.6, 175.6 nail development 2.28–2.29, 2.29, 2.30 dihydrorhodamine 123 assay 177.10 dihydrotestosterone (DHT), acne pathogenesis 79.3, 79.3, 79.4 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) 95.1–95.2, 108.5 dimethyl sulphoxide (DMSO) examination of dermatophytes 62.11 topical, amyloidosis 159.5 dimeticone, lice 72.13 dimorphic fungi, mycoses due to 63.8–63.20 dimples 10.6 acromial, chromosome disorders 116.11 occult spinal dysraphism 10.17 dimple sign, dermatofibroma 92.5 dinitrochlorobenzene (DNCB) alopecia areata 149.5 UV-induced suppression of contact sensitivity 108.8 warts 47.9 diode lasers, pigmented lesions 189.5 dioxin poisoning 184.14–184.15 chloracne 79.19, 184.14–184.15 hyperpigmentation 104.8 diphencyprone see diphenylcyclopropenone diphenhydramine hydrochloride toxicity 184.5 diphenylcyclopropenone (DPCP) alopecia areata 149.5–149.6 dyschromia induced by 104.12 warts 47.9, 150.3 diphenylhydantoin, Fabry disease 169.11 diphenylpyraline hydrochloride toxicity 184.5 Diplopoda 73.7

20

Index

discoid dermatitis see nummular dermatitis disinfection neonatal intensive care unit (NICU) 5.3 skin puncture sites in premature infants 5.4 disomy functional 131.1, 131.2 uniparental see uniparental disomy disperse blue allergy 44.4 disseminated superficial actinic porokeratosis (DSAP) 126.2 genetics 126.1, 126.2 management 126.3–126.5 disseminated superficial porokeratosis (DSP) 126.1, 126.2 distichiasis, lymphoedema–distichiasis syndrome 114.6, 114.7 distraction techniques, pain management 190.10 dithranol see anthralin diuretics, lymphoedema 114.12 Divry–van Bogaert syndrome 112.20 DKC1 gene 136.8 DLX3 gene 127.79 DNA fetal see fetal DNA gene therapy strategies targeting 140.10–140.12 naked, cutaneous delivery 140.6, 140.7 DNA-based prenatal diagnosis 139.2–139.6, 139.3, 139.11 DNA damage nucleotide excision repair pathway 135.2–135.5, 135.3 recognition 135.3–135.4 senescence-associated 135.23 ultraviolet (UV)-induced 108.4, 135.2 DNA mismatch repair (MMR) 135.1, 135.2 see also constitutional mismatch repair deficiency syndrome DNA polymerase δ 135.5 DNA polymerase ε 135.1, 135.5, 135.14 DNA repair 135.1–135.2 defects basal cell carcinoma 99.1 disorders caused by 135.2–135.24 Rothmund–Thomson syndrome 136.1 see also nucleotide excision repair (NER)-defective syndromes direct reversion 135.1 excision repair 135.1–135.2 see also DNA mismatch repair; nucleotide excision repair mitochondrial 135.23–135.24 senescence and 135.23 translesional synthesis 135.1 DNA vaccines 140.17 DNA variants of unknown significance (VUS) 116.3 DNMT3B gene mutations 177.26 DOCK8 gene mutations 64.3, 177.22 dogfish, spiny 73.9 Dogger Bank itch 73.9 dogs aeroallergens 32.2 avoidance strategies 32.8 hookworms 68.1, 68.4 dolichostenomelia see marfanoid habitus dominant skin disorders see autosomal dominant skin disorders domperidone, dystrophic epidermolysis bullosa 118.24 DOOR syndrome (deafness and onychodystrophy) 127.17, 150.8 DOPA 138.1 Doppler sonography, infantile haemangioma 113.11 double-blind placebo-controlled drug challenges (DBPCDC) 183.13, 183.14 double-blind placebo-controlled food challenges (DBPCFC) 31.4, 31.7, 31.10

Dowling–Degos disease 117.4, 127.95 genetics 138.3 hyperpigmentation 138.10, 138.11 downless mouse 127.66, 127.66–127.67 Down syndrome (trisomy 21) collagenomas 116.14 cutis marmorata 116.8 diagnosis 116.4 diffuse depigmentation 116.11 dry skin 116.8 elastosis perforans serpiginosa 116.11 eosinophils 36.1 hair abnormalities 116.14, 116.15 hyperkeratosis and keratosis pilaris 116.11 ichthyosis 116.8 milia-like calcinosis cutis 95.4, 116.11 pityriasis rubra pilaris 83.5 premature skin wrinkling 116.9 prenatal diagnosis 114.20 syringomas 94.9, 116.13 doxepin cream lichen simplex chronicus 42.3 toxicity 184.5 doxycycline acne 79.8 Chlamydia infections 153.16 Lyme borreliosis 59.9, 59.9 post-tick bite prophylaxis 59.10 Rocky Mountain spotted fever 61.4 scrub typhus 61.10 spotted fever group rickettsial infections 61.6 dressings burn wounds 187.17–187.18, 187.18–187.19 dystrophic epidermolysis bullosa 118.18, 118.18–118.19 epidermolysis bullosa simplex 118.8 junctional epidermolysis bullosa 118.32 semi-permeable, premature infants 5.4 skin grafts 187.13 ulcerated haemangiomas 188.8 see also occlusive dressings; wet wrap dressings DRESS syndrome 183.5–183.7 clinical features 183.6, 183.6 HIV-related 52.4–52.5 vs. infectious mononucleosis 49.15 drooling dermatitis 27.14–27.15 drospirenone, acne 79.9–79.10 drug(s) adverse reactions see adverse drug reactions metabolism in skin 181.6 neonatal injuries 17.7–17.8 percutaneous absorption see absorption, percutaneous transdermal delivery 181.5–181.6, 181.6 triggering linear IgA disease of childhood 89.3 drug allergies 183.1 see also drug hypersensitivity reactions drug eruptions 183.2–183.12 acneiform 79.19–79.20, 79.20 bullous 87.5, 183.9–183.11 exanthematous 183.4–183.7, 183.5 fixed see fixed drug eruptions HIV infection 52.4–52.5 hyperpigmentation 104.5 lichenoid see lichenoid drug eruptions pustular 183.7–183.9 urticarial 74.3–74.4, 183.2–183.4 vs. measles 49.3 drug hypersensitivity reactions 183.1–183.14 antiretroviral agents 52.4–52.5 clinical manifestations 183.2 cutis laxa 143.1, 143.3 diagnostic approach 183.12–183.14 epidemiology 183.1–183.2 immediate 183.12–183.13 non-immediate 183.13–183.14 see also drug eruptions drug-induced hypersensitivity syndrome (DIHS) see DRESS syndrome drug intolerances 183.1

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

drug provocation tests 183.13, 183.14 drug rash with eosinophilia and systemic symptoms see DRESS syndrome drug therapy principles 181.1–181.20 systemic see systemic drug therapy topical see topical therapy dry skin (xerosis) atopic dermatitis 28.6, 28.7, 30.4–30.5 chromosomal disorders 116.8 nummular dermatitis and 40.1 DSC3 gene mutations 127.100 DSG1 gene mutations 120.15–120.16, 127.100 DSG4 gene mutations 127.96, 127.100, 148.15 DSP gene mutations 118.9, 120.15–120.16, 127.98, 127.99, 148.16 DTNBP1 gene mutations 138.6 Dubowitz syndrome 127.19 duct tape occlusion molluscum contagiosum 46.5 warts 47.8 dumb cane (Dieffenbachia) 45.2, 45.2 dummies (pacifiers), atopic dermatitis and 27.14, 27.15 Duncan syndrome 177.8 duplications (genetic) 116.4 dup 1q syndrome 116.9 Dupuytren’s contracture 97.9 dwarfism, cerebral atrophy and keratosis pilaris 148.8 dysautonomia Ehlers–Danlos syndrome 142.7 familial, type II 127.15 dyschromatoses, inherited 138.3, 138.11–138.12 dyschromatosis symmetrica hereditaria 115.25, 138.3, 138.11–138.12 dyschromatosis universalis hereditaria 138.3, 138.12 dyschromia acquired cutaneous 104.12 see also pigmentary changes dyshidrosis/dyshidrotic eczema see pompholyx dyskeratosis acantholytic, differential diagnosis 125.3 Darier disease 125.1, 125.2 hereditary benign intraepithelial 115.20, 147.11 papular acantholytic, of the vulva 151.7 dyskeratosis congenita 136.7–136.11 autosomal dominant (Scoggins) 127.20–127.21, 136.7 autosomal recessive 127.21, 136.7 cancer susceptibility 136.9, 137.3 clinical features 136.8, 136.8–136.9, 136.9, 138.10 differential diagnosis 136.9 oral lesions 136.9, 147.11 pathogenesis 136.8, 138.3 pathology 136.8 premature ageing 134.5 prognosis 136.9 reticulate hyperpigmentation 136.8, 136.8, 136.9, 138.9, 138.10 treatment 136.9–136.10 X-linked 115.20, 127.19–127.20, 136.7 dyskeratosis follicularis see Darier disease dyskerin 136.8 dysphagia, dystrophic epidermolysis bullosa 118.14–118.15, 118.22–118.24 dyspigmentation see pigmentary changes dysplastic naevi see atypical naevi dysplastic naevus syndrome see atypical mole syndrome dystopia canthorum, Waardenburg syndrome 138.5, 138.6 dystrophic epidermolysis bullosa (DEB) 118.1, 118.10–118.26 aetiology and pathogenesis 118.10–118.11 cell therapy 140.16–140.17 cleavage plane 118.2 clinical features 118.11–118.16 differential diagnosis 91.23–91.24, 118.16

Index generalisata (Pasini) 115.22 generalisata mutilans (Hallopeau–Siemens) 115.22 generalisata non-mutilans 115.22 gene therapy 118.21, 140.5, 140.6, 140.9, 140.10–140.11, 140.15 inversa 115.22 localisata 115.22 localisata (Cockayne–Touraine) 115.22 molecular pathology 118.3 nail changes 150.8–150.9, 150.9 neonatalis (bullous dermolysis of newborn) 115.22, 118.14 pathology 118.11 patient advocacy groups 179.7 praetibialis 115.22 preimplantation genetic diagnosis 139.10 prenatal diagnosis 139.3, 139.7, 139.7–139.8, 139.9 prevention and treatment of complications 118.21–118.26 prognosis 118.16 protein therapy 140.17 skin care 118.17, 118.17–118.19, 118.18 skin grafting 187.18–187.19, 187.20 treatment 118.17–118.26 ears, external accessory tragi 10.2–10.3, 10.3 atopic dermatitis 28.3, 28.4 cleaning, newborn infants 5.2 hairy 115.4, 115.24, 148.30 juvenile spring eruption 106.9, 106.9–106.10 relapsing polychondritis 167.19, 167.20 severe MEDOC phenotypes 121.65 Wegener granulomatosis 167.3 eating disorders 65.9, 65.9–65.10 EBP gene mutations 11.5, 121.54 ecallantide 177.18 ecchymoses Henoch–Schönlein purpura 160.3, 160.3 lichen sclerosus 152.6, 152.6 see also bruising; purpura eccrine naevus 94.12, 110.7 mucinous 94.11, 94.12, 110.7 porokeratotic 110.11, 110.11–110.12 eccrine poroma 94.10–94.11, 94.11 eccrine sweat glands formation on digits 2.29–2.31, 2.31, 2.32 formation on general body surface 2.31–2.33 eccrine syringofibroadenoma, Schöpf–Schulz– Passarge syndrome 127.85, 127.86 Echinoidea 73.8 echocardiography Kawasaki disease 168.8 tuberous sclerosis 129.8, 129.8, 129.10 echovirus infections 49.8, 49.20 neonatal 8.4, 9.6 eclabion (eclabium) collodion baby 12.2, 121.30 harlequin ichthyosis 13.3 management 121.65 ECM1 gene mutations 97.20 econazole, dermatophytoses 62.17 ecthyma 54.4 HIV infection 52.2 vs. tropical ulcer 66.4 ecthyma contagiosum see orf ecthyma gangrenosum, immunocompromised children 64.4, 64.9 ectodermal defect with skeletal abnormalities 127.21 ectodermal dysplasia (ED) 127.1–127.104, 127.3–127.64 with adrenal cyst 127.23 Christ–Siemens–Touraine type see hypohidrotic ectodermal dysplasia (HED), X-linked classification 127.2 collodion baby 121.30 definition 127.1–127.2

with distinctive facies and preaxial polydactyly 127.23 with ectrodactyly and macular dystrophy (EEM syndrome) 127.24, 127.100 of face, congenital see focal facial dermal dysplasia gap junction protein defects 127.88–127.95 genetics 115.23 hair loss 148.3, 148.6 hidrotic (ED2) see Clouston syndrome hidrotic, Christianson–Fourie type 127.33 hypohidrotic (HED) see hypohidrotic ectodermal dysplasia management 127.103–27.104 Margarita Island type 115.23, 127.43 molecular insights 127.2 nail abnormalities 150.9 with natal teeth (Turnpenny type) 127.22 neonatal erythroderma 11.5 and neurosensory deafness 127.22 with palatal paralysis 127.22 patient advocacy groups 179.7 pure hair-nail type 117.7, 127.24, 127.96 with severe mental retardation 127.22 with severe mental retardation and syndactyly 127.23 structural/adhesive molecule mutations 127.95–127.103 sweat gland abnormalities 2.33 Swiss-type 127.3 with syndactyly 127.23 TNF-like/NF-κB signalling pathway mutations 127.65–127.73, 127.66 TP63-related phenotypes 127.73–127.79 transcription factor/homeobox gene defects 127.73–127.83 vs. trichothiodystrophy 135.20 Wnt-β-catenin pathway defects 127.83–127.88 ectodermal dysplasia–skin fragility syndrome 118.9, 127.98 clinical features 127.44 genetic basis 115.23 preimplantation genetic diagnosis 139.10 ectodysplasin-A (EDA) 127.66, 127.67 replacement therapy 127.71 ectodysplasin-A receptor (EDAR) 127.66, 127.67 ectopia lentis congenital dominant 145.4, 145.5 Marfan syndrome 145.6 ectrodactyly 127.78, 127.78 ectrodactyly–ectodermal dysplasia-clefting syndrome (EEC) 127.77–127.79 molecular pathogenesis 127.74 prenatal diagnosis 139.3, 139.4 type 1 (EEC1) 127.25 type 3 (EEC3) 115.23, 127.24 without cleft lip/palate 127.25 ectropion collodion baby 12.2, 121.30 harlequin ichthyosis 121.28, 121.29–121.30 management 121.65 eczema atopic see atopic dermatitis chromosome disorders 116.8 definition 23.1–23.2 food allergy and 31.1–31.18 see also under food allergies genital area 151.2–151.3 hyper-IgE syndromes 177.23 immunodeficiency syndromes 177.2–177.3 impetiginized 26.1, 26.3, 28.8 laser treatment 188.10, 188.11 non-atopic see atopiform dermatitis nursing care 192.4, 192.5, 192.6, 192.6, 192.8 patient advocacy groups 179.7 seborrhoeic pattern of infantile 35.1 vulval 151.2, 151.3, 152.2–152.3 Wiskott–Aldrich syndrome 177.33, 177.33 World Allergy Organization (WAO) nomenclature 28.11, 28.11

21

Eczema Area and Severity Index (EASI) 29.3–29.5, 29.5 self-assessed (SA-EASI) 29.5 eczema herpeticum 28.8, 33.1–33.4 aetiology 24.7, 33.1–33.2 clinical features 28.9, 33.2, 33.2, 33.3 definition 33.1 diagnostic testing 30.3 differential diagnosis 33.2–33.3, 51.6, 51.7 prognosis 33.3–33.4 treatment and prevention 30.5–30.6, 33.3 eczema-like purpura of Doucas and Kapetanakis 165.5 eczema vaccinatum (EV) 24.7, 51.11, 51.12–51.13 clinical features 28.8, 28.8, 51.12 vaccinia immune globulin treatment 51.14 EDA1 gene mutations 127.66, 127.66 EDAR 127.66, 127.67 EDARADD gene mutations 127.66, 127.67 EDAR-associated death domain protein (EDARADD) 127.67, 127.67 EDAR gene mutations 127.66, 127.66–127.67 edema see oedema EDN3 gene mutations 138.6 EDNRB gene mutations 138.6 education family and child, atopic dermatitis 30.3–30.4, 34.5 public, Lyme borreliosis 59.10 Edwardsiella lineate 73.8 Edwards’ syndrome (trisomy 18) 116.8–116.9, 116.16 EEC syndrome see ectrodactyly–ectodermal dysplasia-clefting syndrome EEM syndrome (ectodermal dysplasia with ectrodactyly and macular dystrophy) 127.24, 127.100 efalizumab 182.13 pityriasis rubra pilaris 83.7 psoriasis 82.5 egg allergy (hen’s) 31.6 dietary restrictions 31.12, 31.15–31.16, 31.17 history taking 31.8 Ehlers–Danlos-like syndrome 134.17 Ehlers–Danlos syndrome (EDS) 115.23, 142.1–142.14 aetiology and pathogenesis 142.2–142.3 arthrochalasia-type (types VIIA and VIIB) 142.4, 142.12–142.13 aetiology 142.2–142.3 clinical features 142.5, 142.12–142.13, 142.13 differential diagnosis 142.8 investigations 142.8 classic (types I and II) 142.4, 142.11 aetiology 142.2 clinical features 142.3–142.8, 142.4, 142.5, 142.6, 142.7 dermatosparaxis-type (type VIIC) 142.4, 142.13 aetiology 142.3 investigations 142.9 differential diagnosis 142.8 dystrophic calcification 95.7 fibronectin-deficient (type X) 142.3, 142.4, 142.14 hypermobility-type (type III) 142.2, 142.4, 142.12 investigations 142.8–142.9 kyphoscoliosis-type (type VI) 142.4, 142.12 aetiology 142.2 clinical features 142.5, 142.7, 142.12, 142.13 investigations 142.8 patient advocacy groups 179.7 periodontitis-type (type VIII) 142.4 aetiology 142.3 clinical features 142.8, 142.14, 142.14 prenatal diagnosis 139.3 progeroid (Kresse syndrome) 134.17–134.18, 142.4 aetiology 134.17, 142.3 clinical features 134.17–134.18, 142.14

22

Index

Ehlers–Danlos syndrome (EDS) (cont.) spondylocheiro dysplastic-type (SCD-EDS) 142.2, 142.12 tenascin-X deficient 142.3, 142.4, 142.9, 142.14 treatment 142.9 type IX see cutis laxa, X-linked vascular (type IV) 142.4, 142.12 aetiology 142.2 clinical features 142.3, 142.6, 142.7, 142.8, 142.12 investigations 142.8 life-threatening complications 142.6, 142.9, 142.12 Villefranche classification 142.1–142.2, 142.4 X-linked (type V) 142.2, 142.4, 142.12 ehrlichiosis, monocytic 61.3 eicosanoids, atopic dermatitis 25.3, 25.9–25.10 eicosapentaenoic acids (EPAs) 25.9–25.10, 181.17–181.18 Eker rat 129.2–129.3 ELA2 gene 177.10 elastic fibres 143.1 abnormalities anetoderma 145.11, 145.13 cutis laxa 143.1–143.2 granuloma annulare 93.3, 93.4 pseudo-xanthoma elasticum 144.2, 144.3, 144.3 embryonic skin 2.9, 2.10 fetal 2.21 elastin embryonic skin 2.9 fetal skin 2.21 gene mutations 143.1 elastolysis acquired 143.3 focal, anetoderma 145.11 generalized 143.1 see also cutis laxa; postinflammatory elastolysis and cutis laxa elastoma, juvenile 145.1 Busche–Ollendorff syndrome 145.2, 145.2 differential diagnosis 145.3 familial 145.1 elastorrhexis, papular 145.3 elastosis, linear focal (LFE) 146.3 elastosis perforans serpiginosa (EPS) 116.11 Ehlers–Danlos syndrome 142.3 pseudo-xanthoma elasticum 144.5 Elattoproteus syndrome 111.5 elbows, congenital hair on 148.30 electrocoagulation 186.2 electrode placement sites, calcinosis cutis 95.9 electrolysis, for hair removal 148.33 electrolyte imbalances, MEDOC 121.63 electromagnetic spectrum 108.1–108.2, 108.2 electron microscopy, poxviruses 51.1, 51.2 electrosurgery, molluscum contagiosum 46.5 Elejalde syndrome 138.7, 177.7 ‘Elephant Man’ 111.1 elimination diets adverse effects 31.12–31.13 atopic eczema 31.11–31.17, 31.14 elliptical incisions, planning 187.2 Ellis–van Creveld syndrome (EvC) 127.26, 127.79 Elschnig syndrome 127.10 Emberger syndrome 114.9 embolization arterial, arteriovenous malformations 112.3–112.4 infantile haemangiomas 113.18 embryogenesis of skin 2.1–2.41 embryonic-fetal transition mucoid quality of skin 2.12, 2.13 skin development 2.12–2.18 embryonic period of development 2.2, 2.3 embryonic skin 2.4–2.11 EMLA cream 181.7, 190.3–190.4 doses and application times 190.4 laser treatment 188.2–188.3, 189.2 toxicity 184.4

emollients 181.6–181.7 atopic dermatitis 27.15, 30.4–30.5 Darier disease 125.4 ichthyoses/MEDOC 121.10–121.11, 121.38, 121.65 Netherton syndrome 124.6–124.7 newborn infants 5.7–5.8 pityriasis rubra pilaris 83.6 premature infants 5.5 emotional abuse 154.9 EMSY protein 23.6 emulsions 181.4 enamel paint appearance, kwashiorkor 65.2, 65.3 encephalitis herpes 48.5 measles 49.2 postvaccinia 51.11, 51.13 smallpox 51.5 tick-borne (TBE) 59.10 encephalocoele 10.12–10.13 encephalocraniocutaneous lipomatosis (ECCL) 111.8, 141.6 encephalomyelitis, Lyme neuroborreliosis 59.6 ‘en coup de sabre’ morphoea 173.5, 173.5–173.6, 173.6 endocarditis, Erysipelothrix rhusiopathiae 56.6 endocrine disorders cutaneous manifestations 172.1–172.31 cystic fibrosis 170.2 epidermal naevi with 110.19–110.20 hyperpigmentation 104.7–104.8 insulin resistance and acne 79.16, 79.16–79.17 Langerhans cell histiocytosis 103.3 urticaria 74.8 endoglin 112.5 endothelial cells infantile haemangiomas 113.3 systemic sclerosis pathogenesis 174.5 endothelial dysfunction, meningococcal disease 55.3, 55.3 endotoxin 55.2–55.3, 162.2 endotracheal intubation, dystrophic epidermolysis bullosa 118.25 endotracheal tubes, neonatal skin damage 17.6, 17.10 endovascular papillary angioendothelioma, malignant 99.10 enteral feeding Crohn disease 157.2 dystrophic epidermolysis bullosa 118.23, 118.24, 118.24 Enterobius vermicularis (threadworms) 151.10, 152.3 diagnosis 152.4, 152.4 enteroviral infections 49.9–49.11 neonates 9.6 non-specific eruptions 49.19 enterovirus 71 infections 49.9, 49.10, 49.11 enthesitis-related arthritis 175.2, 175.3–175.4 entomophtoromycosis 63.23–63.24 eosinophil cationic protein (ECP) 36.9 eosinophilia 36.1–36.2 angiolymphoid hyperplasia with 98.1–98.2 atopic dermatitis 24.1 bullous pemphigoid 91.16 clonal 36.6 congenital 36.1 cutaneous larva migrans 68.3 erythema toxicum neonatorum 6.5 familial or hereditary 36.1 idiopathic 36.7 infantile 36.2 infantile acropustulosis 88.2 neonatal 36.1 older children 36.2 Omenn syndrome 11.9 primary 36.6–36.7 reactive 36.7 secondary 36.6 eosinophilic cellulitis 36.9–36.11 eosinophilic fasciitis 36.11–36.12

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

eosinophilic folliculitis, necrotizing 36.5 eosinophilic granuloma (EG) 103.1–103.2, 103.3–103.4 see also Langerhans cell histiocytosis eosinophilic panniculitis 36.12–36.13, 77.1 eosinophilic pustular folliculitis (eosinophilic pustulosis) adult 36.2, 36.5 infancy and childhood 36.2–36.6 clinical features 36.3–36.5, 36.4 differential diagnosis 6.7, 36.5, 88.3 histopathology 36.3, 36.3 treatment 36.5 eosinophilic spongiosis, pemphigus vulgaris 91.3 eosinophils 36.1 atopic dermatitis 24.1, 24.3 eotaxin atopic dermatitis 25.5 eosinophilic pustular folliculitis 36.2 ephelides see freckles epidermal appendages see skin appendages epidermal cells appendage development 2.28, 2.28 hair follicle development 2.34, 2.35 nail development 2.30 sweat gland development 2.29–2.31 epidermal cysts 92.5–92.6 calcification 95.7 epidermal differentiation 27.1–27.3, 27.2 disturbances in atopic dermatitis 27.9–27.10, 27.10 modulators, ichthyoses/MEDOC 121.66–121.67 regulation 27.5–27.7 terminal 27.1, 27.6 epidermal differentiation complex (EDC) genes, atopic dermatitis 27.9 epidermal growth factor receptor-inhibitors, acneiform eruption induced by 79.19–79.20 epidermal growth factor receptors (EGFR) acne pathogenesis 79.4, 79.4 embryonic-fetal transition 2.14, 2.14 epidermal hyperkeratosis see epidermolytic ichthyosis epidermal malignant tumours 99.1–99.4 epidermal naevi (EN) 110.1–110.20 aetiology 110.1–110.2 alopecia 148.23 Darier type (EN-D) 110.12–110.13, 125.1, 125.3 dyskeratotic and acantholytic 110.12–110.13 endocrine abnormalities and 110.19–110.20 epidermolytic hyperkeratotic type (EN-EHK) 110.12, 110.12, 117.4, 117.5, 121.19 genital area 151.5–151.6, 151.6, 151.7 Hailey–Hailey type 110.13 inflammatory 110.16–110.18, 188.10 inflammatory linear verrucous see inflammatory linear verrucous epidermal naevus keratinocytic see keratinocytic epidermal naevi keratitis, ichthyosis, deafness (KID) type 110.13 linear, histopathology 4.7–4.8, 4.8 linear verrucous, laser therapy 189.6 non-organoid 110.8–110.15 organoid 110.2, 110.3–110.7 pigmented hairy see Becker naevus Proteus syndrome 110.13, 111.3, 111.4 systematized 110.9 vascular anomalies and 110.20 see also specific types epidermal naevus syndrome 110.1 aetiology 110.1–110.2 congenital melanocytic naevi 109.2 epidermal ridges primary, development 2.29, 2.31, 2.32 secondary, development 2.31, 2.31, 2.32 see also dermatoglyphs

Index epidermis differentiation see epidermal differentiation embryonic 2.4, 2.4–2.7, 2.5, 2.6 embryonic-fetal transition 2.13, 2.13–2.16 fetal 2.19–2.20, 2.22, 2.23 neonatal 3.2–3.5, 3.3 skin barrier see skin barrier stem cells 140.1–140.2 stratification, development 2.13, 2.13–2.14, 2.19 structure 27.1–27.3 UV radiation-induced thickening 108.7–108.8 epidermodysplasia verruciformis (EV) 137.10–137.11 associated malignancies 137.2, 137.10, 137.11 clinical features 47.4, 47.5, 137.11 pathogenesis 47.2, 47.5, 137.10–137.11 epidermoid carcinoma see squamous cell carcinoma epidermoid cysts acne 79.6 Gardner syndrome 137.11 genital area 151.21 Gorlin syndrome 132.7 occult spinal dysraphism 10.17 epidermolysis bullosa (EB) cleavage planes 118.2 dystrophic see dystrophic epidermolysis bullosa hereditary 115.22, 118.1, 118.1–118.34 cancer susceptibility 137.2 cell therapy 140.16–140.17 classification 118.1, 118.3 diagnosis 118.1–118.2 differential diagnosis 87.6–87.7 gene therapy 140.9, 140.9–140.10 preimplantation genetic diagnosis 139.10–139.11 prenatal diagnosis 139.3, 139.7, 139.7–139.8, 139.8, 139.9, 139.12 inversa 118.14 mixed see Kindler syndrome nail changes 150.8–150.9, 150.9 nursing care of newborn 192.1, 192.3 oral lesions 147.9 patient advocacy groups 179.7 pretibial 118.13 pruriginosa 118.13 skin grafting 118.21–118.22, 118.22, 118.33, 187.18–187.19, 187.20 superficialis 118.9 vs. epidermolytic ichthyosis 121.20 see also specific types epidermolysis bullosa acquisita 91.13, 91.22–91.24 aetiology and pathogenesis 91.22 clinical features 91.23, 91.23 IgA-mediated 89.1 pathology 91.22–91.23, 91.23 epidermolysis bullosa simplex (EBS) 117.3, 118.1, 118.4–118.9, 127.95 aetiology and pathogenesis 118.4 autosomal recessive 118.4, 118.9 cleavage plane 118.2 clinical features 118.4–118.7 differential diagnosis 118.7 Dowling–Meara (EBS-DM) 115.22, 118.4, 118.7 clinical features 118.5–118.7, 118.6 management 118.8–118.9 periderm cells 2.27 prenatal diagnosis 139.3 generalisata 115.22 generalized, other (Köbner) 115.22, 118.4, 118.5 gene therapy 140.9, 140.10, 140.15 genetic basis 115.22, 118.3 lethal acantholytic 115.22, 118.9, 127.99 localized (Weber–Cockayne) 115.22, 118.4, 118.7 clinical features 118.4–118.5, 118.5 with mottled pigmentation 115.22, 118.9 with muscular dystrophy 115.22, 118.9

Ogna type 115.22, 118.4, 118.9 pathology 118.4 prenatal diagnosis 139.9 prognosis 118.7 rarer types 118.9 reticulated hyperpigmentation 104.10 treatment 118.7, 118.7–118.9 variants 118.4 vesiculobullous lesions 87.7 epidermolytic hyperkeratosis (EHK) 117.4 epidermolytic ichthyosis 117.5, 121.17, 121.19 gene therapy 140.9, 140.9 periderm cells 2.27 superficial epidermolytic ichthyosis 117.6, 121.22 see also epidermolytic ichthyosis epidermolytic ichthyosis (EI) (bullous congenital ichthyosiform erythroderma of Brocq; BCIE) 117.4–117.6, 121.17–121.21 annular variant (cyclic ichthyosis with) 121.19 clinical features 117.5, 121.17–121.19, 121.18, 121.19 differential diagnosis 121.20–121.21, 121.37 management 121.21, 121.22, 121.64, 121.67 neonatal erythroderma 11.4–11.5 offspring of parents with epidermal naevi 110.2, 110.12 pathogenesis 115.20, 121.19–121.20 pathology 4.7, 117.5, 121.19 prenatal diagnosis 121.21, 139.3 vesiculobullous lesions 87.7 epidermolytic ichthyosis of Siemens see superficial epidermolytic ichthyosis epidermolytic toxins, staphylococcal see exfoliative toxins (ETs), staphylococcal Epidermophyton, culture 62.12–62.13, 62.13 Epidermophyton floccosum 62.2, 62.3 clinical features of infection 62.6, 62.9 epidermotropism, mycosis fungoides 102.3–102.4 epididymitis differential diagnosis 153.11 gonococcal 153.10 epigenetic inheritance 115.7 epilepsy, tuberous sclerosis 129.4, 129.10–129.11 epilepsy and yellow teeth syndrome 127.7 epiloia see tuberous sclerosis complex epinephrine (adrenaline) insect sting anaphylaxis 73.2–73.3 with local anaesthetics 190.2 urticaria 74.12 EpiPen® 73.3 epiphyseodesis Klippel–Trenaunay syndrome 112.17 Parkes Weber syndrome 112.4 Epipremnum aureum 45.2 epithelial cells hair follicle development 2.36 wound healing 17.1 epithelioid cell granuloma, tuberculoid leprosy 70.3, 70.3 epithelioid haemangioma see angiolymphoid hyperplasia with eosinophilia epithelioid sarcoma 99.6 epithelioma adenoides cysticum of Brooke see multiple familial trichoepitheliomas Epstein–Barr virus (EBV) acute genital ulcers 151.13 extranodal NK/T-cell lymphoma 99.23–99.24 Gianotti–Crosti syndrome 50.1–50.2 Hodgkin disease 99.17 hydroa vacciniforme and 106.8 hydroa vacciniforme-like cutaneous T-cell lymphoma 99.24, 99.25 identification 49.16 infectious mononucleosis 49.14–49.16, 147.6 subcutaneous panniculitis-like T-cell lymphoma 77.14 Epstein pearls 6.11, 147.10 epulis (epulides) 147.18, 147.18 congenital granular, of newborn 147.17 giant cell 147.18, 147.18

23

equestrian panniculitis 77.7 erbium-doped fibre lasers, Becker naevus 189.6 erbium:YAG (Er:YAG) lasers pigmented lesions 189.4, 189.5, 189.6 scarring 189.9 warts 189.8 ERCC1 gene mutations 135.6, 135.13, 135.22 ERCC1 protein 135.4, 135.13 ERCC2 gene mutations 148.12 ERCC6 gene see CSB gene ERCC8 gene see CSA gene Erdheim–Chester disease (ECD) 103.11, 103.13, 103.14 ergocalciferol 108.5 erlotinib-induced acneiform eruption 79.20 erosions AEC syndrome 127.76, 127.76 dystrophic epidermolysis bullosa 118.12, 118.13 epidermolytic ichthyosis 121.17, 121.21 oral mucosal 89.10 periorificial 89.10 porphyria cutanea tarda 107.8, 107.8–107.9 vesiculobullous disease 87.1, 87.2 eruption cysts 147.17 eruptive macular pigmentation, idiopathic 104.5 eruptive pseudoangiomatosis 49.20 eruptive vellus hair cysts 92.6–92.7, 92.7 erysipelas 54.6 differential diagnosis 49.6, 56.6 lymphoedematous limbs 114.11 erysipeloid 56.4–56.6, 56.5 Erysipelothrix rhusiopathiae 56.4, 56.5–56.6 erythema Kawasaki disease 168.2, 168.2, 168.3, 168.3 sunburn 108.6, 108.6 erythema ab igne 104.9 erythema annulare centrifugum 76.1–76.3, 76.2 clinical features 76.1–76.2, 76.3 erythema chronicum migrans (ECM) 59.1 vs. erysipeloid 56.6 see also erythema migrans erythema dyschromicum perstans HIV infection 52.5 hyperpigmentation 104.5, 104.6, 104.6 erythema elevatum diutinum (EED) 164.1–164.2 erythema gyratum atrophicans transiens neonatale 76.2, 76.7–76.8 erythema gyratum repens 76.1, 76.2, 76.4 erythrokeratodermia variabilis Cram–Mevorah 122.9, 122.9–122.10 erythema induratum of Bazin 77.16 erythema infectiosum 49.5–49.7 clinical features 49.5–49.6, 49.6 differential diagnosis 49.3, 49.6 see also parvovirus B19 erythema marginatum 76.2, 76.4–76.5 clinical features 76.5, 76.5 erythema migrans (EM) 59.4–59.5, 76.6 clinical features 59.4, 59.4–59.5, 76.2 diagnosis 59.7–59.8 differential diagnosis 59.5 prognosis 59.9 tongue (geographical tongue) 147.23, 147.24–147.25 treatment 59.8–59.9, 59.9 erythema multiforme (EM) 78.1–78.8 bullous 78.2 classification 78.1, 78.2 clinical features 78.3–78.4, 78.4 differential diagnosis 78.4 drugs associated with 78.2, 78.2, 87.5 epidemiology 78.1–78.2 genital area 151.14, 151.14–151.15 major 78.3 vaccinia vaccination 51.11, 51.13 vs. smallpox 51.6 management 78.6–78.8 minor 78.3 vaccinia vaccination 51.11, 51.13 oral lesions 147.9

24

Index

erythema multiforme (EM) (cont.) orf 51.21 pathogenesis 78.2–78.3 terminology 78.1 urticaria resembling 74.10, 74.10, 74.11 variant of polymorphic light eruption 106.1 vesiculobullous lesions 87.5 erythema neonatorum (allergicum) see erythema toxicum neonatorum erythema nodosum 77.2–77.5 aetiology 77.2–77.3, 77.3 clinical features 77.3, 77.4 differential diagnosis 77.4 epidemiology 77.2 histopathology 77.3–77.4 investigations 77.4, 77.4 pathogenesis 77.3 plantar see palmoplantar hidradenitis sarcoidosis 158.4 treatment 77.4 tuberculosis 57.3–57.4, 57.4, 77.2 erythema nodosum leprosum (ENL) 70.11, 77.2 treatment 70.12 erythema streptogenes see pityriasis alba erythematosquamous skin diseases, neonatal 11.2–11.4 erythema toxicum neonatorum (ETN) 6.4–6.8 aetiology 6.5–6.6 clinical features 6.4, 6.6, 6.6–6.7, 6.7 differential diagnosis 6.4, 6.7, 87.6, 88.2–88.3 pathology 6.6 transient pustular melanosis with 6.8, 6.9 erythrasma 56.3, 56.3–56.4 erythrocyte sedimentation rate (ESR) Kawasaki disease 168.6, 168.6, 168.9 urticaria 74.12 erythroderma congenital ichthyosiform erythroderma 121.26, 121.31 in infancy, histopathology 4.7 lamellar ichthyosis 121.28 neonatal see neonates, erythroderma Sézary syndrome 99.21 see also ichthyosiform erythroderma erythroderma progressiva symmetrica see progressive symmetric erythrokeratoderma erythrodermia desquamativa Leiner see Leiner disease erythrodontia 107.11 erythrokeratoderma(s) 122.1–122.14, 122.3–122.5 atypical ichthyosiform see keratitis-ichthyosisdeafness (KID) syndrome progressive symmetric see progressive symmetric erythrokeratoderma erythrokeratoderma (or genodermatose) en cocardes 122.3, 122.10 erythrokeratoderma with ataxia (EKA) 122.3, 122.14 erythrokeratodermia variabilis (EKV) 122.1, 122.3, 122.7–122.10 Cram–Mevorah (with erythema gyratum repens) 122.3, 122.9, 122.9–122.10 differential diagnosis 83.6, 122.7–122.8 Mendes da Costa 122.7–122.9 clinical features 122.7, 122.8 pathogenesis 115.20, 122.7 erythromelalgia 166.1–166.3 clinical features 166.2, 166.2–166.3 primary 166.1–166.3 secondary 166.1 erythromycin acne 79.8–79.9 bacillary angiomatosis 58.4 bullous pemphigoid 91.17 Chlamydia infections 153.16, 153.22 perioral dermatitis 38.3 pityriasis rosea 84.4 erythropoiesis, dermal 8.1, 8.2 erythropoietic porphyria, congenital see congenital erythropoietic porphyria

erythropoietic protoporphyria (EEP) 115.26 aetiology 107.6–107.7 clinical features 107.8, 107.9–107.11, 107.10 differential diagnosis 107.13 hypertrichosis 148.29 incidence 107.8 non-cutaneous manifestations 107.11 pathogenesis 107.7 pathology 107.7–107.8 porphyrin profile 107.5 treatment 107.14–107.15 erythropoietin, epidermolysis bullosa 118.26 eschar cowpox 51.16, 51.16 mite or tick bites 71.5, 71.5 rickettsial spotted fevers 61.5, 61.5 scrub typhus 61.9, 61.9 Esciichthys vipera 73.9 espundia 67.8 essential fatty acids (EFAs) 181.17–181.18 deficiency 65.4, 148.21, 181.17 estimated gestational age (EGA) 2.2, 2.3, 2.3 etanercept 181.17, 182.2–182.4 adverse effects 82.5–82.6, 182.4 contraindications 182.3–182.4 juvenile idiopathic arthritis 175.4, 182.2–182.3, 182.4 periodic fever syndromes 176.2, 176.3 pharmacokinetics 182.2 pityriasis rubra pilaris 83.7 psoriasis 82.2, 82.5, 182.2, 182.3 uveitis 182.3 ethambutol atypical mycobacterial infections 57.7, 57.8, 57.9 tuberculosis 57.4–57.5 ethanol intoxication 184.3–184.4 ethical issues, prenatal diagnosis 139.12 ethnic healing methods, marks inflicted by 154.11–154.12 ethylenediamine, contact allergy 44.10 etoposide 181.17 etretinate adverse effects 121.67–121.68 dyskeratosis congenita 136.10 Gorlin syndrome 132.15 granuloma annulare 93.8 harlequin ichthyosis 13.4, 13.4 IgA pemphigus 91.10 lichen planus 85.10 MEDOC 121.67 porokeratosis 126.4–126.5 psoriasis 82.4 ETV6–NTRK3 gene fusion 97.15, 99.8 eucalyptus oil, toxicity 184.6 Euphorbia 45.2, 45.2 Europe, paediatric dermatology in 1.4–1.5 European Academy of Dermatology and Venereology, atopic dermatitis guidance 30.1 European Journal of Pediatric Dermatology 1.5 European League against Rheumatism (EULAR) Behçet disease treatment 167.17, 167.18 Henoch–Schönlein purpura diagnosis 160.1 European Network for Drug Allergy (ENDA) questionnaire 183.12 European Society for Pediatric Dermatology (ESPD) 1.3, 1.5 European standard series of contact allergens 44.6–44.7, 44.7 eutectic mixture of local anaesthetics see EMLA cream EVC genes 127.79 evening primrose oil, atopic dermatitis 25.9–25.10 EVER1 (TMC6) gene 47.5, 137.10–137.11 EVER2 (TMC8) gene 47.5, 137.10–137.11 Ewing’s sarcoma 99.6 exanthema subitum 49.7–49.8

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

exanthems classic infectious 49.1 drug eruptions 183.4–183.7, 183.5 viral 49.1–49.20 exclamation mark hairs 149.2 excoriations, self-inflicted 180.9 exercise associated urticaria 74.6 induced urticarial vasculitis 163.2 lymphoedema 114.12 exfoliative dermatitis, atopic dermatitis 28.9 exfoliative (or epidermolytic) toxins (ETs), staphylococcal 27.7, 54.2 bullous impetigo 54.4 scalded skin syndrome 9.2, 11.6, 54.8 exogen 148.2 exon skipping 140.14, 140.15 Exophiala 63.7–63.8 Exophiala jeanselmei 63.4 expression quantitative trait loci (eQTL) mapping 23.4 EXT1 gene 127.79 extensively hydrolysed formula (EHF) 31.12, 31.16 extracellular matrix (ECM) deposition, systemic sclerosis 174.4 extracorporeal photopheresis (ECP), graftversus-host disease 178.9 extranodal NK/T-cell lymphoma, nasal type 99.23, 102.10 skin involvement 99.23, 99.24 variants 77.14, 99.24 extravasation injuries management 17.9, 17.9 neonates 17.8, 17.8–17.9, 17.9 extremities see limbs eyebrows reconstruction, giant congenital naevi 191.4–191.5 surgical scar placement 187.3 thinning, atopic dermatitis 28.5, 28.6 eye care harlequin ichthyosis 192.1, 192.2 staphylococcal scalded skin syndrome 192.11 toxic epidermal necrolysis 78.6–78.7, 192.18 eyelashes congenital trichomegaly 148.31 drug-induced hypertrichosis 148.32 pubic lice infestation 72.11, 72.11, 72.13 eyelids cysts, Schöpf–Schulz–Passarge syndrome 127.85–127.86 dermatitis 44.4, 44.5 reconstruction, giant congenital naevi 191.4 eye manifestations see ophthalmological manifestations eye protection, laser treatment 188.6, 189.1 F12 gene mutations 177.17 fabricated/induced illness see factitious disorder by proxy fabrics, photoprotective 108.16, 108.16 Fabry disease 112.20, 169.10–169.11 differential diagnosis 166.3, 169.11 genetics 115.26 face aesthetic units 186.3, 187.2–187.3, 187.5 oedema, DRESS syndrome 183.6, 183.6 skin tension lines 187.2, 187.3 surgical scar placement 186.2, 186.2, 187.2–187.3 tissue expansion 191.3–191.5, 191.5 facemasks, skin damage 17.6 facial angiofibromatosis, tuberous sclerosis (adenoma sebaceum) 129.2, 129.5, 129.5 erythema preceding 129.3 historical description 129.1 management 129.11–129.12 facial dermal dysplasia, focal see focal facial dermal dysplasia

Index facial dermatitis contact allergy 44.4 patch testing 44.5, 44.8 facial features ataxia telangiectasia 177.4 atopic dermatitis 28.1, 28.2 focal dermal hypoplasia 133.2, 133.3, 133.3 Gorlin syndrome 132.5–132.7, 132.6, 132.7 homocystinuria 169.5, 169.5 HSV infection 48.5 hyper-IgE syndromes 177.23 hypohidrotic ectodermal dysplasia 127.70, 127.70 miliary osteoma cutis 95.12 progeria 134.2, 134.2 Proteus syndrome 111.6 psoriasis 80.4 rhabdomyosarcoma 99.5, 99.5 tinea 62.7, 62.8 facial hemiatrophy ‘en coup de sabre’ morphoea 173.5, 173.5, 173.6 Parry–Romberg syndrome 173.6 facial nerve (VII) palsy granulomatous cheilitis 114.18, 114.19 Lyme borreliosis 59.6, 59.9, 59.9 facies leontina 70.6 factitious disorder by proxy (fabricated illness) 154.8–154.9, 180.13 alerting features 154.8 terminology 180.1, 180.2 factitious disorders 180.1, 180.12–180.13 differential diagnosis 180.8 panniculitis 77.12–77.13 terminology 180.1, 180.2 factor VIII gene therapy 140.17 factor V Leiden, meningococcal disease 55.6 factor D deficiency 177.19, 177.20 factor H deficiency 177.20 factor I deficiency 177.20 faecal impaction, dystrophic epidermolysis bullosa 118.24–118.25 faeces contamination, day-care centres 21.2 napkin dermatitis 19.1–19.2 failure to thrive junctional epidermolysis bullosa 118.31 Netherton syndrome 124.6 see also growth failure FALDH (ALDH3A2) gene mutations 11.10, 121.34, 121.47 falx cerebri calcification, Gorlin syndrome 132.9–132.10, 132.10, 132.11 famciclovir 181.16–181.17 herpes zoster 49.14 HSV infections 48.6–48.7 varicella 49.13 familial adenomatous polyposis (FAP) 137.11 familial atypical multiple mole–melanoma (FAMMM) syndrome see atypical mole syndrome familial cold urticaria (familial cold autoinflammatory syndrome; FCAS) 176.2, 176.3 genetics 115.24–115.26, 115.28 urticarial lesions 74.9, 163.5 familial dysautonomia, type II 127.15 familial Hibernian fever 74.9, 176.2 familial hypercholesterolaemia (FH) 169.13 clinical features 169.14, 169.14 treatment 169.14–169.15 familial Mediterranean fever (FMF) 176.1–176.2, 176.3 amyloidosis 159.4 Henoch–Schönlein purpura and 160.1 treatment 159.5, 176.2 vs. erythema nodosum 77.4 familial partial lipodystrophy (FPLD) 115.28, 141.14–141.15 familial tumoral calcinosis (FTC) 95.4–95.5 hyperphosphataemic 95.4 normophosphataemic 95.4

family atopic dermatitis 34.6 impact of disease 34.2–34.3 measuring impact on 29.13–29.14 psychosocial assessment 34.4, 34.4 burden of chronic skin disease 179.1–179.6 education, atopic dermatitis 30.3–30.4, 34.5 see also parents Family Dermatology Life Quality Index (FDLQI) 179.2 FANC genes 136.11 Fanconi anaemia (Fanconi pancytopenia) 136.11–136.12 clinical features 116.12, 136.11, 138.9 pathogenesis 116.6, 136.11, 138.3 tumour susceptibility 136.12, 137.4 Fannia 69.3 Farber lipogranulomatosis 169.12–169.13 farnesyltransferase inhibitors (FTI), restrictive dermopathy 15.3 fascial dystrophy, congenital 97.1, 97.20–97.21 fasciitis cranial 97.8 eosinophilic 36.11–36.12 nodular 97.7–97.8 proliferative 97.7 fasciocutaneous flaps 186.5 fasciotomies, purpura fulminans 162.13, 162.13 FasL, Stevens–Johnson syndrome/toxic epidermal necrolysis 78.2–78.3 FATP4 gene mutations 121.32, 121.36 fat tissue see adipose tissue fatty acids affecting skin barrier function 27.6–27.7 atopic dermatitis 27.10–27.11 essential see essential fatty acids free (FFA) generation 27.4, 27.10 normal infants 27.13, 27.14 infantile seborrhoeic dermatitis 35.2 stratum corneum 27.2–27.3 see also omega-6 unsaturated fatty acids fatty acid transport proteins (FATPs) 121.36 fatty alcohol–nicotinamide–adenine dinucleotide reductase (FAO) enzyme complex 121.34, 121.47 fatty aldehyde dehydrogenase (FALDH) 11.10, 121.42, 121.47 faun tail 10.17, 148.31–148.32, 148.32 favus 62.1, 62.5 clinical features 62.6, 62.8 FBN1 gene mutations 145.4, 145.5 FBN2 gene mutations 145.4, 145.5 FcεRI (high-affinity IgE receptor), atopic dermatitis 24.4, 25.5, 31.3 febrile seizures, roseola infantum 49.8 feet see foot felon 48.3 Felty syndrome 147.9 fentanyl analgesia 188.6, 190.8 poisoning 184.8 Ferguson–Smith syndrome 137.2 fermitin family homologue 1 (FERMT1) 118.34, 119.1 FERMT1 (KIND1) gene mutations 118.34, 119.1 FERMT3 gene mutations 177.11, 177.28–177.29 ferricytochrome c reduction assay 177.10 ferritin, serum 103.18 ferrochetalase 107.6–107.7 defective 107.6–107.7, 107.9–107.10 gene 107.3, 107.6, 107.7 fetal DNA invasive sampling methods 139.2–139.4 in maternal blood, genetic testing 139.11 fetal period of development 2.2, 2.3 fetal scalp blood sampling 17.3, 17.4 electrodes 17.3, 17.3

25

fetal skin 2.19–2.23 first trimester 2.19 regional variations 2.27, 2.27 second trimester 2.19–2.21 third trimester 2.22–2.23 wound healing 3.6, 17.2 fetal skin biopsy 17.3 indications 139.8–139.9 inherited skin disorders 139.6–139.9, 139.7, 139.8 timing 2.3, 2.3, 139.7 fetus iatrogenic injuries 17.2–17.3 monitoring, intrapartum 17.3 sensitization to allergens 22.8–22.9 fever juvenile idiopathic arthritis 175.2 Kawasaki disease 168.2, 168.6 measles 49.1, 49.2 roseola infantum 49.7 smallpox 51.5 see also periodic fever syndromes fexofenadine, atopic dermatitis 25.9 FGF23 gene mutations 95.4 FGFR1 gene rearrangements 36.6 FGFR2 gene mutations 79.17–79.19 mosaic 110.6 FGFR3 gene mutations, mosaic 110.8, 110.10, 115.20 FGFR5 gene mutations 110.15 FH gene mutations 137.13, 137.14 fibrillin 145.5 disorders 145.4, 145.5, 145.7 embryonic skin 2.9, 2.10 striae pathogenesis 146.2 β-fibrilloses see amyloidosis fibrinogen, Staphylococcus aureus binding 26.2 fibrinolytic pathway dysfunction, meningococcal disease 55.3, 55.3–55.5, 55.4 fibroblast growth factor 23 (FGF23) 110.19–110.20 fibroblast growth factor receptor-2 (FGFR2), acne 79.2, 79.4, 79.4, 79.5 fibroblast growth factors (FGFs), acne 79.4, 79.4 fibroblastoma, giant cell 97.13–97.14 fibroblasts allogenic injection therapy 140.16 genetically engineered, therapeutic use 140.17 morphoea pathogenesis 173.2 systemic sclerosis pathogenesis 174.4, 174.5 therapeutic gene transfer 140.6 wound healing 17.1 fibrodysplasia ossificans progressive (FOP) 95.9–95.10, 95.11 fibroepithelial polyps/nodules, oral 147.18, 147.18 fibrofolliculomas, Birt–Hogg–Dubé syndrome 137.8 fibrolipomatous hamartoma, precalcaneal congenital see precalcaneal congenital fibrolipomatous hamartoma fibromas Birt–Hogg–Dubé syndrome 137.8 calcifying aponeurotic 97.13 cardiac, Gorlin syndrome 132.10–132.11 Gardner syndrome 137.12 intraoral, tuberous sclerosis 129.7, 129.8 juvenile active ossifying 147.20 periungual see periungual fibromas fibromatoses 97.1, 97.2–97.16 classification 97.1, 97.1 digital (inclusion body) 97.11, 97.11–97.12, 97.12 gingival 97.10–97.11, 127.29, 147.20, 147.20 infantile (desmoid-type) 97.8–97.9, 147.19 plantar–palmar (superficial) 97.9–97.10 subcutaneous pseudo-sarcomatous see nodular fasciitis terminology 97.1–97.2 fibromatosis colli 97.4–97.5 fibronectin, Staphylococcus aureus binding 26.2

26

Index

fibrosarcoma, congenital/infantile 97.14–97.16, 99.8 clinical features 97.15, 97.15, 99.8 inflammatory 97.15 pathology 97.15, 97.15, 99.8 vs. infantile fibromatosis 97.9 fibrous dysplasia, oral 147.19 fibrous hamartoma of infancy 97.5–97.6 clinical features 97.5–97.6, 97.6 genital area 151.21 pathology 97.5, 97.5, 97.6 fibrous histiocytoma see dermatofibroma fibrous hyperplasia of labum majus, prepubertal unilateral 151.21 fibrous pseudo-tumour, calcifying 97.7 Fibulila 73.9 fibulin gene mutations 143.1, 143.2 Fick’s first law 184.2 fiddler’s neck 79.19 fifth digit syndrome 127.14 fifth disease see erythema infectiosum fig (Ficus carica) 45.10, 45.10 filaggrin 27.1–27.2, 27.10, 121.9 deficiency atopic dermatitis 23.11, 23.11, 27.9–27.10 ichthyosis vulgaris 121.9 degradation 23.7, 23.8, 27.4 expression and function 23.7–23.8, 23.8 gene mutations see FLG gene mutations filariasis 114.11 filum terminale, tight 10.16 finasteride, androgenetic alopecia 148.22 fingerprints see dermatoglyphs finger-sucking 180.2–180.3, 180.3, 180.3 Finkelstein disease see acute haemorrhagic oedema (AHO) in infancy Finlay–Marks syndrome 127.55 Finn® chambers, patch testing 44.5 FIP1L1-PDGFRA gene fusion 36.6 fire ants 73.2, 73.3 fire corals 73.7 FIRST 13.6 first trimester 2.2, 2.3 skin development 2.4–2.19 Fischer syndrome (Fischer–Volavsek syndrome) 127.26 fish allergies 31.6 venomous 73.7, 73.9 fish oil 181.17–181.18 atopic dermatitis 25.9–25.10 fish tank granuloma 57.6–57.7 fixed drug eruptions (FDE) 183.11–183.12 blistering 87.5, 87.9 drugs associated with 87.5, 183.11 genital area 151.14, 151.14, 152.2 hyperpigmentation 104.5 flag sign, kwashiorkor 65.3, 65.3, 148.21 flaky tail mouse 121.7, 121.9 Flamazine, burn wounds 187.18 flaps see skin flaps FLCN (BHD) gene mutations 137.8 flea bites differential diagnosis 71.8 identification 71.6, 71.6 immunopathology 71.3–71.4 sensitivity to 71.2 toxic reactions 71.5 flea-borne typhus 61.2, 61.8 fleas 71.1, 71.2 biting behaviour 71.6, 71.6, 71.7 control measures 71.8, 73.1 transmission of rickettsias 61.8, 61.10 flesh flies 69.3 Flexispira skin infections 64.4 flexural dermatitis atopic dermatitis 28.1–28.3, 28.3 diagnosis 28.17–28.18, 28.18 flexural psoriasis 80.4, 80.4 flexural sparing

ichthyosis vulgaris 121.8, 121.8, 121.9 recessive X-linked ichthyosis 121.10, 121.11 FLG gene mutations allergen sensitization 32.4–32.5 allergic contact dermatitis 44.1–44.2 atopic dermatitis 22.8, 22.11, 23.8–23.10, 23.9, 25.10, 27.9 food allergies and 31.2–31.3 pathophysiological model 23.11, 23.11 phenotype 28.8 skin barrier dysfunction 24.5 skin surface pH and 27.18 Staphylococcus aureus adhesion and 26.2 ichthyosis vulgaris 23.8, 121.4, 121.9 Flinders Island spotted fever 61.2 FLJ39501 (CYP4F2) mutations 12.1, 121.26, 121.34 floor effects, quality of life measures 29.10 FLT4 gene 114.4 fluconazole 62.15, 181.16 congenital cutaneous candidiasis 11.7 dermatophytoses 62.16 onychomycosis 62.17 fludrocortisone 172.10 fluid imbalances, MEDOC 121.63 flumazenil 190.8 fluorescence in situ hybridization (FISH) 116.2, 116.4 fluorescence microlymphography 114.3 fluoroquinolones, leprosy 70.9–70.10 5-fluorouracil (5-FU), topical Gorlin syndrome 132.14 porokeratosis 126.4 fluoxetine, trichotillomania 180.11 flushing, transient neonatal 6.3 fluticasone propionate, atopic dermatitis 30.7 FMR1 gene 116.8 foam dressings, epidermolysis bullosa simplex 118.8 foam vehicles 181.4 focal acral hyperkeratosis (FAH) 120.25 focal dermal hypoplasia (FDH) (Goltz syndrome) 133.1–133.8 atrophoderma 145.18 clinical features 127.27, 127.87, 133.1–133.4, 133.2, 133.3 definition 127.87 differential diagnosis 16.5, 130.6, 131.5, 133.7 genetics 115.28, 133.5, 133.6 histopathology 133.4–133.5 incidence 133.1 pathogenesis 127.83, 133.5–133.7 treatment 133.7–133.8, 188.10 focal epithelial hyperplasia 47.6, 47.6, 147.19 focal facial dermal dysplasia (FFDD) 145.18–145.19 type I (Brauer syndrome) 127.28, 145.18 type II 127.28, 145.18 type III 145.19 fogo selvagem see Brazilian pemphigus folate deficiency 65.6, 104.8 follicle-centre lymphoma, primary cutaneous (PCFCL) 99.26–99.27, 102.14–102.15 follicular atrophoderma 145.18 Bazex–Dupré–Christol syndrome 137.1, 137.7, 145.18 X-linked chondrodysplasia punctata 145.18 follicular hyperkeratosis, with scalp alopecia 148.7–148.9 follicular mucinosis, mycosis fungoidesassociated 102.5 follicular naevus (naevus comedonicus) 110.5–110.6, 110.6 follicular occlusion tetrad 79.7 folliculin 137.8, 137.8 folliculin interacting proteins (FNIP) 137.8, 137.8 folliculitis bacterial 54.4–54.5 genital area 151.9–151.10, 151.10 Demodex see Demodex folliculitis

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

eosinophilic pustular see eosinophilic pustular folliculitis HIV infection 52.2 hookworm 68.2 Malassezia (Pityrosporum) 41.3, 62.28, 62.28–62.29 necrotizing eosinophilic 36.5 tufted 148.18, 148.18 folliculitis ulerythema reticulata see atrophoderma vermiculata folliculitis ulerythematosa see atrophoderma vermiculata Fonsecaea compactum 63.6 Fonsecaea pedrosoi 63.6 food additives, urticarial reactions 74.4 food allergens common 31.6, 31.6 dietary restriction 31.13–31.17 sensitization allergic march and 31.1–31.2 skin barrier disruption and 27.14–27.15, 31.2–31.3 food allergies allergic (IgE-mediated) 31.5, 31.5–31.6 allergic (atopic) march and 31.1–31.2 atopic dermatitis 24.7–24.8, 31.1–31.18, 31.4 neonates 11.3 phenotypes 31.5, 31.5–31.7 diagnosis 31.7–31.11 allergy-specific tests 31.8, 31.9, 31.9–31.10 history taking 31.7–31.9 oral food challenge tests 31.10, 31.10–31.11 elimination diets 31.11–31.17 Netherton syndrome 124.5 non-allergic (non-IgE) hypersensitivity 31.5, 31.5, 31.6 orofacial granulomatosis 157.4, 157.5 urticaria and angio-oedema 31.5, 31.6, 45.4, 74.4 food challenge testing double-blind placebo-controlled (DBPCFC) 31.4, 31.7, 31.10 oral (OFC) 31.10, 31.10–31.11, 31.14 food intolerance 31.5 foot athlete’s see tinea pedis Gorlin syndrome 132.7–132.8 Kawasaki disease 168.2–168.3, 168.3 sole of see soles of feet foot eczema allergic contact 44.4, 44.5 patch testing 44.8 footwear allergic reactions 44.4, 44.5, 44.9, 44.10 epidermolysis bullosa 118.8, 118.19 occlusive, juvenile plantar dermatosis 43.1 forceps deliveries 17.4 Fordyce’s spots or granules 147.10 forehead plaques, tuberous sclerosis 129.5, 129.5, 129.12 foreign bodies penile urethra 151.20 vaginal 151.19–151.20, 152.2 forkhead box N1 deficiency 177.31 formaldehyde contact allergy 44.4, 44.11 warts 47.9 formylglycine-generating enzyme (FGE) 121.14 foscarnet, HSV infections 48.7 founding effect 115.6 FOXC2 gene 114.6 Fox–Fordyce disease (FFD) 94.3–94.4, 94.4 FOXN1 gene 177.31 FOXP3 gene mutations 177.28 fractional photothermolysis, striae 146.4 fractures, child abuse 154.8 fragile X syndrome 116.8, 116.9 fragility, skin see skin fragility fragrance hypersensitivity 44.3–44.4, 44.9–44.10 framboesia tropica see yaws Francois dyscephalic syndrome 127.31

Index freckles 108.7, 108.7 freckles (ephelides) excessive, chromosome disorders 116.12 neurofibromatosis 1 128.3, 128.3 segmental neurofibromatosis 1 128.11, 128.11 free vascularized tissue transplants (free flaps) 186.5, 187.21 frenulum, torn 154.7 fresh frozen plasma (FFP) acute infectious purpura fulminans 162.10–162.11 hereditary angioedema 177.18 meningococcal disease 55.11 postinfectious purpura fulminans 162.12 Friar Tuck sign 180.5, 180.5 frictional lichenoid dermatitis 28.10 friction amyloidosis 104.7 friction blisters 87.2, 87.9 friction-related napkin dermatitis 19.2 Fried tooth and nail syndrome 127.28 Frizzled protein 127.83, 127.84 frontonasal dysplasia and dilated Virchow– Robin spaces 127.56 fruit allergy 31.17, 32.7 fucosidosis 115.26, 169.11 FUCT1 gene mutations 177.11, 177.28 fumagoid bodies 63.7 fumarate hydratase (FH) gene mutations 137.13, 137.14 fumaric acid esters, granuloma annulare 93.8 fungal infections atopic dermatitis 24.7 congenital 8.5, 8.6 diabetes mellitus 172.21 genital 151.11 HIV infection 52.2, 52.2 neonatal 9.4–9.5 oral 147.6–147.7 primary immunodeficiencies 64.2, 64.3, 64.5, 64.6 secondary immunodeficiencies 64.10 subcutaneous 63.1 superficial 62.1–62.34, 62.2 systemic 63.1 vesiculobullous lesions 87.4, 87.4 vulvovaginitis 152.2 see also mycoses fungi aeroallergens 32.2 causing urticaria 74.3 funnel web spiders (Atrax) 73.5 furuncles 54.5 furunculosis 54.5 fusariosis 63.21–63.22 Fusarium 63.4, 63.21 fusidic acid 26.4, 181.7 Fusobacterium ulcerans 66.1, 66.2 Futcher lines (pigmentary demarcation lines) 104.9 G6PC3 gene 177.10 gabapentin, erythromelalgia 166.3 GABEB see generalized atrophic benign epidermolysis bullosa gadding 71.3 galactosyltransferase I deficiency 134.17, 142.3 Galen 1.1 Galli–Galli disease 117.4 GALNT3 gene mutations 95.4 ganciclovir, CMV infections 9.6, 49.17 gangosa 60.4 gangrene iatrogenic neonatal 17.6, 17.7, 17.7 meningococcal septicaemia 55.6, 55.8 management 55.11–55.12 purpura fulminans 162.8, 162.10 Rocky Mountain spotted fever 61.1–61.2, 61.3 gap junction protein defects (connexin defects) 122.2, 127.89 ectodermal dysplasias 127.88–127.95 erythrokeratodermas 122.1–122.10

palmoplantar keratoderma-deafness syndromes 120.21–120.22 gap junctions 122.1, 127.88–127.89, 127.89 GAPO 134.15 Garcia–Hafner–Happle syndrome (mosaic FGFR3 gene mutations) 110.8, 110.10, 115.20 Gardner fibroma 4.3, 4.4 Gardner syndrome 137.11–137.12 clinical features 137.11–137.12, 137.12 desmoid fibromatosis 97.9 intraoral bony swellings 147.19 lipomas 141.7 pathogenesis 115.27, 137.11 tumour susceptibility 137.4, 137.11, 137.12 Garin–Bujadoux–Bannwarth (GBB) syndrome 59.6 garment naevi 109.5, 109.5, 187.26, 187.26 see also congenital melanocytic naevi (CMN), giant GARP gene, atopic dermatitis 23.6 Gasterophilus 69.2–69.3 gastrointestinal diseases hypertrichosis 148.30 oral ulceration 147.7–147.8 gastrointestinal manifestations Behçet disease 167.16, 167.17 cystic fibrosis 170.1 dystrophic epidermolysis bullosa 118.14–118.15, 118.15 food allergies 31.5, 31.6, 31.8 graft-versus-host disease 178.5–178.6, 178.8 Henoch–Schönlein purpura 160.4, 160.5, 160.6 hereditary angioedema 177.18 junctional epidermolysis bullosa 118.31 juvenile dermatomyositis 175.11 Kawasaki disease 168.5 Kindler syndrome 119.2–119.3 mastocytosis 75.10 MEN 2b 172.30 murine typhus 61.8 Proteus syndrome 111.6 Rocky Mountain spotted fever 61.3 systemic sclerosis 174.7, 174.8 tuberous sclerosis 129.9 Wegener granulomatosis 167.5, 167.5 gastrointestinal microflora, atopic dermatitis and 22.9 gastro-oesophageal reflux, dystrophic epidermolysis bullosa 118.15, 118.24 gastrostomy feeding, dystrophic epidermolysis bullosa 118.24, 118.24 Gaucher disease collodion baby 121.30 type 1 104.8 type 2 (infantile) 121.44 GD2 monoclonal antibodies, neuroblastoma 99.12 gels 181.4 gene(s) deletions 115.6 incomplete penetrance 115.2–115.3 mutations see mutations pleiotropism 115.3 variable expression 115.2–115.3 gene editing 140.11–140.12, 140.12 gene gun approach 140.6 gene knockdown 140.13–140.15 gene locus transfer 140.11 generalized atrophic benign epidermolysis bullosa (GABEB) 118.31 gene therapy 140.9, 140.15 genetics 115.22 generalized eruptive histiocytosis (GEH) 103.10, 103.13, 103.14 generalized essential telangiectasia (GET) 112.18 generalized lymphatic dysplasia 114.9, 114.9 generalized multisegmental lymphatic dysplasia 114.9 gene therapy 139.1–139.2, 140.1–140.22 applications 140.9, 140.9–140.10 cell level strategies 140.16–140.17

27

chronic granulomatous disease 177.12 delivery methods 140.2–140.9, 140.3 ex vivo approach 140.6 in vivo approach 140.6–140.7 non-viral 140.5–140.6 viral vectors 140.2–140.5, 140.3 DNA level strategies 140.10–140.12 dystrophic epidermolysis bullosa 118.21, 140.5, 140.6, 140.9, 140.10–140.11, 140.15 erythromelalgia 166.3 Fanconi anaemia 136.12 junctional epidermolysis bullosa 139.2, 140.9, 140.10, 140.11, 140.15 leucocyte adhesion deficiency 177.29 Netherton syndrome 124.7 pachyonychia congenita 117.8, 139.2, 140.9, 140.10, 140.13 porphyrias 107.14–107.15 protein level strategies 140.17–140.18 RNA level strategies 140.12–140.15 severe combined immunodeficiency 177.32 systemic protein delivery 140.16–140.17 target cells 140.1–140.2 target tissue 140.1 genetic disorders associated with urticaria 74.7, 74.8–74.9 with childhood-onset obesity 141.9–141–10 genetic heterogeneity 115.6, 115.26–115.29 genetic immunization 140.17 genetics impact of/on paediatric dermatology 115.1–115.2 molecular 139.1–139.2 principles of 115.2–115.7 genetic skin disorders 115.1 gene therapy 140.9, 140.9–140.10 MIM numbers 115.19–115.26 molecular biology and mapping 115.19–115.29 pigmentation 115.25, 138.1–138.12, 138.2–138.3 predisposing to malignancy 115.27, 137.1–137.20 extracutaneous malignancies 137.4–137.6 mucocutaneous and extracutaneous malignancies 137.3 mucocutaneous malignancies 137.2 preimplantation genetic diagnosis (PGD) 139.9–139.11, 139.10 prenatal diagnosis 139.1–139.12 see also genodermatoses; inheritance; Mendelian skin disorders; specific disorders genetic testing, molecular ectodermal dysplasias 127.103–27.104 ichthyoses 121.6 prenatal diagnosis 139.2–139.6 genital disease/area 151.1–151.25 anatomical abnormalities 151.16–151.19 birthmarks 151.5–151.8 blisters/vesiculobullous lesions 87.10, 151.12–151.16 foreign bodies 151.19–151.20 HSV infections see herpes genitalis inflammatory dermatoses 151.2–151.5 lesions mimicking sexual abuse 155.4, 155.5, 155.6 linear IgA disease of childhood 89.7, 89.7 lymphoedema 114.19 neoplasia 151.20–151.22 non-sexually acquired infections 151.8–151.12 porokeratosis 126.3, 126.4 psychological aspects 151.24–151.25 sexually transmitted diseases 153.1–153.23 signs of systemic disease 151.23 warts see condyloma acuminata; warts, external genital see also napkin area; penis; perianal area; perineum; scrotum; vulva genital injuries accidental trauma 155.5 indicating sexual abuse 155.2, 155.2–155.3 non-accidental 154.3, 154.4, 154.5, 154.5–154.6

28

Index

genital ulcers 151.12–151.16 aphthous 151.13, 151.13–151.14 Behçet disease 151.23, 167.15 HSV infections 153.20 non-sexually acquired acute 151.13 vs. sexual abuse 155.5, 155.6 genitourinary manifestations dystrophic epidermolysis bullosa 118.16 EEC syndrome 127.78 Ehlers–Danlos syndrome 142.6–142.7 juvenile dermatomyositis 175.11 Proteus syndrome 111.6 genodermatose (or erythrokeratoderma) en cocardes 122.3, 122.10 genodermatoses amyloidosis associated with 159.4 autosomal dominant 115.2, 115.2 defined 115.1 gene and cell therapy 140.9, 140.9–140.22 molecular genetics 139.1–139.2 neonatal erythroderma 11.4–11.5 vesiculobullous lesions 87.6–87.7 see also genetic skin disorders; inheritance; Mendelian skin disorders genome-wide association studies (GWAS) alopecia areata 149.2 atopic dermatitis 23.6–23.7, 23.17 genomic imprinting see imprinting, genomic genomic locus transfer 140.11 gentamicin sulphate allergy 44.3 German measles see rubella germ cell tumours 99.12–99.13 germicidal radiation 108.3 geroderma osteodysplastica 134.15 gestational age estimated (EGA) 2.2, 2.3, 2.3 percutaneous drug absorption and 181.2–181.3 transepidermal water loss and 3.2, 3.3 GFI1 gene 177.10 Gianotti–Crosti syndrome 50.1–50.5 clinical features 50.2, 50.2–50.4, 50.3 diagnostic criteria 50.3 differential diagnosis 50.4, 50.4 HIV infection 52.4 pathogenesis 50.1–50.2 pathology 50.2 prognosis 50.4 treatment 50.4–50.5 giant axon neuropathy with curly hair 115.24 giant cell astrocytomas, tuberous sclerosis 129.11 giant cell epulis/granuloma 147.18, 147.18 giant cell fibroblastoma 97.13–97.14 giant congenital naevi see congenital melanocytic naevi (CMN), giant giant Russian hogweed (Heracleum mantegazzianum) 45.8, 45.9 gigantism 172.24–172.25 Gilchrist disease see blastomycosis Gilles de la Tourette syndrome 180.3–180.4, 180.10 gingival cysts of infancy 147.10 gingival fibromatosis, hereditary 97.10–97.11, 147.20 clinical features 97.10, 127.29, 147.20 hypertrichosis 148.29 gingival hyperplasia (or hypertrophy) drug-induced 147.20, 147.20 hereditary see gingival fibromatosis, hereditary juvenile hyalinosis 97.18, 97.18 gingival swelling, generalized 147.20–147.22 gingivitis 147.15, 147.15 acute ulcerative (AUG) 147.7 Kindler syndrome 119.2 gingivostomatitis allergic 147.15 herpetic see herpes gingivostomatitis GJA1 gene mutations 120.22, 127.89, 127.92–127.93 GJB2 mutations 120.21 cutaneous mosaicism 110.13 KID syndrome 122.2

palmoplantar keratoderma-deafness syndromes 120.21–120.22 Vohwinkel syndrome 127.92 GJB3 gene mutations 122.7, 127.89 GJB4 gene mutations 122.7, 122.9 GJB6 gene mutations 120.21–120.22, 122.2, 127.89 Gleevec see imatinib mesylate Gleich syndrome 74.7 gliadin 90.3 glioma nasal 10.14–10.15 optic pathway 128.5–128.6 Gli protein 132.3 Global Alliance to Improve Outcomes in Acne 79.7, 79.7 global genome repair (GGR) 135.3, 135.3 globules congenital melanocytic naevi 185.6, 185.6, 185.6–185.7, 185.7 histopathological correlate 185.2 glomangiomas see glomuvenous malformations glomangiomatosis 115.27 glomangiomyoma 92.8 glomerulonephritis acquired partial lipoatrophy and 141.15 acute poststreptococcal 54.2, 54.4 microscopic polyangiitis 167.8 urticarial vasculitis 163.2 Wegener granulomatosis 167.2–167.3, 167.4, 167.6 glomulin mutations 92.8, 112.11 glomus tumours 92.8 subungual, neurofibromatosis 1 128.4 glomuvenous malformations (GVM) (glomangiomas) 92.8 autosomal dominant 112.11 clinical features 92.8, 92.8, 112.10, 112.11 pathology 4.4, 4.5, 112.11 Glossina (tsetse flies) 71.7 glossitis 147.23–147.25 benign migratory (erythema migrans) 147.23, 147.24–147.25 infections 147.24 median rhomboid 147.23–147.24, 147.24 nutritional deficiencies 147.24 glucocorticoid-induced TNFR-related ligand (GITRL) 24.6 glucocorticoids see corticosteroids glucose-6-phosphate deficiency, rickettsial diseases 61.3, 61.6, 61.7 glucose transporter protein 1 (GLUT1), infantile haemangioma 4.5, 113.2, 113.3 glucosylceramide sphingomyelin deacylase 27.10 glutaraldehyde epidermolysis bullosa simplex 118.8 warts 47.9 glutathione peroxidase 65.8 gluten-free diet dermatitis herpetiformis 90.6 linear IgA disease of childhood 89.9 gluten-sensitive enteropathy (GSE) (coeliac disease) dermatitis herpetiformis 90.1, 90.2, 90.3, 90.4–90.5 linear IgA disease of childhood and 89.2, 89.3 oral ulceration 147.7 glycerin, newborn skin care 5.6 glyceryl aminobenzoate (glyceryl PABA) 108.15 glycogen embryonic-fetal transition 2.14 embryonic skin 2.4, 2.5 fetal skin 2.19, 2.21 glycolic acid, topical, striae 146.4 glycosylation defects, cutis laxa 143.1 GM1 gangliosidosis 169.12 GNAS gene mutations cutaneous ossification 95.10, 95.11, 95.12 pigmented macules 109.10 pseudo-hypoparathyroidism 172.26

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

Gobello syndrome 110.15 goitre 172.5 gold allergy 44.4 Goldenhar syndrome 10.2–10.3 gold salts chrysiasis induced by 104.5 contact allergy 44.4 pemphigus vulgaris 91.4 Goltz–Gorlin syndrome see focal dermal hypoplasia Goltz syndrome see focal dermal hypoplasia gonadal mosaicism 115.6, 115.6 tuberous sclerosis 129.3–129.4 gonadotropin deficiency 172.24 gonadotropin-releasing hormone agonists 172.12 gondou 60.4 gonococcal arthritis 153.10–153.11 gonococcal conjunctivitis neonatal (ophthalmia neonatorum) 153.8, 153.9–153.10 diagnosis 153.11, 153.22 prophylaxis 153.12 treatment 153.12, 153.22 older children 153.10 gonococcal infection, disseminated (DGI) 153.9, 153.10–153.11 treatment 153.12 gonorrhoea 153.8–153.13 aetiology and pathogenesis 153.9 clinical features 153.9–153.11 diagnosis 153.11, 153.22 differential diagnosis 153.11 history 153.8–153.9 pathology 153.9 perinatally acquired 8.6, 153.9–153.10 prognosis 153.11 treatment 153.11–153.12, 153.22 Good syndrome 64.3 Gorham–Stout syndrome (Gorham disease) 112.13, 114.17 Gorlin–Chaudhry–Moss syndrome 127.29 Gorlin’s sign 142.8 Gorlin syndrome (naevoid basal cell carcinoma syndrome) 132.1–132.16 aetiology and pathogenesis 115.15, 115.27, 132.1–132.4 basal cell carcinomas see under basal cell carcinoma clinical features 132.4–132.11, 132.5 diagnosis 132.11–132.12 diagnostic criteria 132.12, 132.12 differential diagnosis 132.13, 137.1 malignancies 132.8–132.9, 132.10, 132.11, 137.3 pathology 132.4 patient advocacy groups 179.7 prevalence 132.1–132.2 prognosis 132.12–132.13 surveillance and prophylaxis 132.13–132.14 treatment 132.14–132.16 Gottron’s sign (papules) juvenile dermatomyositis 175.10, 175.10 vs. knuckle pads 96.2, 96.3 Gottron syndrome see progressive symmetric erythrokeratoderma graft-versus-host disease (GVHD) 178.1–178.12 acute (aGVHD) 178.5–178.6, 178.6 pathogenesis 178.2–178.3 treatment 178.8 at-risk clinical situations 178.1 chronic 178.6–178.8, 178.7 pathogenesis 178.3 treatment 178.8–178.9 clinical features 178.5–178.8 clinical grading 178.6 differential diagnosis 178.8 experimental animal models 178.1–178.2 graft-versus-leukaemia (GVL) effect 178.11 histopathology 178.3, 178.3, 178.3–178.4, 178.4 immunopathology 178.4, 178.4–178.5, 178.5 lichenoid 85.8–85.9, 85.10 maternal 178.1

Index neonatal erythroderma 11.9–11.10 oral lesions 147.8, 147.8, 178.7 prevention 178.8 risk factors 178.6 severe combined immunodeficiency 177.30, 177.32 transfusion 178.1 treatment 178.8–178.9 graft-versus-host reaction (GVHR) 178.1 erythema toxicum neonatorum 6.5–6.6 graft-versus-leukaemia (GVL) effect 178.11 grain itch mites 71.5, 71.7 Gram-negative septicaemia, neonatal 8.6 Gram stain, congenital vesicular lesions 8.2 granular cell layer see stratum granulosum granular cell tumours 92.8–92.9 genital area 151.20 granular nerve cell sheath tumours (GNCST) 92.9 granulation tissue development 17.1 junctional epidermolysis bullosa 118.31, 118.32 granulocyte colony-stimulating factor (G-CSF), dyskeratosis congenita 136.10 granulocyte macrophage colony-stimulating factor (GM-CSF) atopic dermatitis 24.2, 24.3, 24.4 Fanconi anaemia 136.12 granulocytes, wound healing 17.1 granulocytic sarcomas 99.13, 99.14–99.15, 99.15 granuloma(s) ataxia telangiectasia 177.4, 177.4 Candida 62.22, 62.22, 177.15 chronic granulomatous disease 177.9, 177.10 eosinophilic see eosinophilic granuloma immunodeficiency syndromes 177.2–177.3 leprosy 70.3, 70.3–70.4, 70.4 mycotic 63.25 pyogenic see pyogenic granuloma swimming pool/fish tank 57.6–57.7 granuloma annulare (GA) 93.1–93.9 aetiology 93.1–93.2 clinical features 93.5–93.7 differential diagnosis 93.7–93.9 disease associations 93.2 generalized 93.6 histopathology 4.3 imaging 93.7 linear 93.6 localized 93.5, 93.5–93.6, 93.6 palisading pattern 93.3, 93.4 papular umbilicated 93.7, 93.7 pathogenesis 93.2–93.3 pathology 93.3–93.5 perforating 93.4, 93.4, 93.5, 93.7 prevalence 93.5 prognosis 93.7 sarcoidal pattern 93.3–93.4, 93.4 subcutaneous 93.4, 93.6, 93.6–93.7 treatment 93.8, 93.9 granuloma gluteale infantum 20.3–20.4, 20.4, 21.2, 152.3 granuloma multiforme 70.8 granulomatosis anogenital 114.19, 151.23 juvenile systemic see Blau syndrome orofacial see orofacial granulomatosis Wegener 167.1–167.8 granulomatous cheilitis see orofacial granulomatosis granulomatous slack skin (GSS) 102.5–102.6 graphite tattoos 147.14 Graves disease 172.5–172.6 graying of hair see greying of hair great toenails congenital malalignment 150.2, 150.2 ingrown 150.2–150.3 green tea (extracts) 181.12 photoprotective effects 108.7 warts 47.10 green tumours see granulocytic sarcomas

Grenz zone 70.3–70.4 greying of hair ataxia telangiectasia 177.4 chromosome disorders 116.15–116.16 overnight, in adults 149.3 vitiligo 105.3, 105.5 see also white forelock grief reaction, parental 179.5 Griscelli syndrome (Griscelli-Prunieras syndrome) 138.2, 138.7 lymphoproliferation 177.8 pathogenesis 115.25, 138.7 vs. Chédiak–Higashi syndrome 177.7, 177.7–177.8 griseofulvin 62.14, 181.16 dermatophytoses 62.15, 62.16, 62.17 group A streptococcus (GAS) (Streptococcus pyogenes) 54.1–54.2 blistering distal dactylitis 54.7 cellulitis 54.5–54.6 congenital infections 8.5, 8.6 ecthyma 54.4 epidemiology 54.3 erysipelas 54.6 erythema marginatum 76.4–76.5 exotoxins 54.1–54.2, 54.3 impetigo 54.4 infantile haemangiomas 113.8 intertrigo 54.7 invasive disease 54.1, 54.3 M protein types 54.1–54.2, 54.10 necrotizing fasciitis 54.6–54.7 perianal streptococcal dermatitis 20.6, 54.7 recurrent toxin-mediated perineal erythema 54.11 scarlet fever 54.10 skin grafts 187.13 streptococcal toxic shock syndrome 54.10 group B streptococcus, perinatal infection 8.6 growth androgen excess states 172.14 hypogonadism 172.11 precocious puberty 172.12 growth factor receptors developing hair follicles 2.34 embryonic skin 2.6, 2.8 growth factors, embryonic skin 2.8 growth failure Brazilian pemphigus 91.7 Cockayne syndrome 135.16 dystrophic epidermolysis bullosa 118.16 hypopituitarism 172.24 ichthyoses 121.32, 121.63 Netherton syndrome 124.6 progeria 134.2 see also short stature growth hormone (GH) acne pathogenesis 79.2, 79.3 deficiency 172.24 excess 172.24–172.25 treatment, organic acidurias 169.8 growth retardation–alopecia–pseudo-anodontia– optic atrophy (GAPO) 127.30 Guarnieri’s bodies 51.7 Günther disease see congenital erythropoietic porphyria gut microflora, atopic dermatitis and 22.9 gypsy moth caterpillar 73.4 H1-receptor antagonists see antihistamines H2-receptor antagonists 181.16 mastocytosis 75.11 see also cimetidine habits, physiological 180.1, 180.2–180.6, 180.3 haem, biosynthetic pathway 107.1–107.7, 107.2, 107.3 haemangio-endothelioma, kaposiform see kaposiform haemangio-endothelioma haemangiomas congenital 113.22–113.23 histopathology 4.5, 113.23

29

non-involuting (NICH) 113.23, 113.23 rapidly involuting (RICH) 113.22–113.23 deep (cavernous) 113.1, 113.3, 113.4 vulval 152.3 hepatic see hepatic haemangiomas infantile (IH) 113.1–113.18 aetiology and pathogenesis 113.1–113.2 alarming 113.15, 113.15 associations 113.11–113.13 burden of disease 179.3 chorionic villus sampling and 17.3, 113.4–113.5 clinical features 113.3–113.5, 113.4, 113.5 complications 113.6–113.9 differential diagnosis 112.3, 112.3, 113.10, 154.10, 154.11 epidemiology 113.4–113.5 hepatic see hepatic haemangiomas histopathology 4.5, 113.3 imaging studies 113.11 infection 113.7, 113.8 involution 113.5, 113.5, 113.6 laser treatment 113.18, 188.7–188.8 localized 113.1 lower body, and structural malformations 113.13, 113.13, 113.14 multifocal 113.20, 113.20–113.21, 113.21 nursing care 192.8–192.10, 192.13, 192.14 occult spinal dysraphism 10.17, 113.13 oral 147.14, 147.14–147.15 precursor lesions 113.3, 113.4, 113.5 prognosis 113.6 segmental 113.1, 113.5 surgical treatment 113.18, 186.7, 186.7 treatment 113.14–113.18 ulceration 113.6–113.8, 113.7, 113.8, 188.8, 188.8 mixed 113.1, 113.3, 113.4 sinusoidal 112.13 superficial (capillary or strawberry) 113.1 chromosome disorders 116.13 clinical features 113.3, 113.4 thyroid disease and 113.22 haemangiomatosis benign neonatal 113.20 cutaneous and visceral 113.20, 113.20–113.22, 113.21 disseminated (diffuse; multiple) neonatal 113.10, 113.20 haemangiopericytoma (HPC) 99.8–99.9, 99.9 haem arginate 107.15 haemarthrosis, venous malformations 112.9 haematinic deficiencies glossitis 147.24 oral ulceration 147.1, 147.7 haematodermic neoplasm (HDN), CD4+/CD56+ 99.25, 102.16 haematological disorders, oral ulceration 147.7, 147.7 haematological features dyskeratosis congenita 136.9 eosinophilic fasciitis 36.11 Fanconi anaemia 136.11–136.12 Langerhans cell histiocytosis 103.3 neonatal lupus erythematosus 14.4, 14.7, 14.10 haematological neoplasm, precursor 99.25, 102.16 haematopoietic stem cell transplantation (HCT; SCT) Chédiak–Higashi syndrome 177.8 chronic granulomatous disease 177.12 dyskeratosis congenita 136.10 dystrophic epidermolysis bullosa 140.16–140.17 Fanconi anaemia 136.12 genodermatoses 140.16–140.17 graft-versus-host disease 178.1, 178.2 clinical features 178.5–178.8 incidence 178.5 pathogenesis 178.2 prevention 178.8

30

Index

haematopoietic stem cell transplantation (HCT; SCT) (cont.) leucocyte adhesion deficiency 177.29 porphyrias 107.14 severe combined immunodeficiency 177.32 skin infections after 64.7, 64.8 Wiskott–Aldrich syndrome 177.34 haemin 107.15 haemochromatosis 104.8, 115.26 haemoglobinopathies, parvovirus B19 infection 49.6 haemolysins, staphylococcal, atopic dermatitis 26.2, 26.3 haemolytic anaemia, Kasabach–Merritt phenomenon 113.25 haemophagocytic lymphohistiocytosis (HLH) 103.1, 103.17–103.19 Chédiak–Higashi syndrome 177.6 diagnostic criteria 103.18, 103.18 familial (FHLH) 103.17–103.19, 177.8 haemophagocytic syndrome cytophagic histiocytic panniculitis 77.13 subcutaneous panniculitis-like T-cell lymphoma 77.15, 102.10 haemophilia A, gene therapy 140.17 Haemophilus ducreyi 155.4 Haemophilus influenzae, purpura fulminans 162.2, 162.3 haemorrhage/bleeding arteriovenous malformations 112.2 Ehlers–Danlos syndrome 142.8 hereditary haemorrhagic telangiectasia 112.5 infantile haemangiomas 113.8 pseudo-xanthoma elasticum 144.6 tuberous sclerosis 129.9 haemorrhagic oedema of infancy see acute haemorrhagic oedema (AHO) in infancy Hailey–Hailey disease (HHD) 91.10, 115.21 clinical features 87.7, 91.10 differential diagnosis 91.10, 125.3 localized 110.13 Haim–Munk syndrome 120.12–120.13, 127.30 hair abnormal shedding, testing for 148.4–148.5 acquired progressive kinking 148.17 bamboo see trichorrhexis invaginata beading monilethrix 117.7, 117.8, 148.14, 148.14 pseudomonilethrix 148.15, 148.15 black dot 149.2 breakage 148.10–148.14 brittle, trichothiodystrophy 135.19, 135.20 coarse, chromosome disorders 116.14–116.15 development in utero 2.38, 2.38, 148.1, 148.2 excessive see hypertrichosis exclamation mark 149.2 fine, chromosome disorders 116.14 greying see greying of hair growth 148.1–148.2 abnormal cycling 148.18–148.21 abnormal initiation 148.5–148.6 assessment 148.4 cycle 148.1–148.2, 148.3 lanugo see lanugo hair localized tufts 148.17–148.18 microscopic examination 148.5, 148.5 miniaturization 148.21–148.22 removal methods 148.33, 189.3–189.4 shaft abnormalities see hair shaft abnormalities sparse scalp, chromosome disorders 116.15 spiky, chromosome disorder 116.15 tiger-tail 135.19, 135.20 unruly acquired localized 148.17 hair shaft abnormalities with 148.15–148.18 loose anagen syndrome with 148.19, 148.19 woolly see woolly hair hair abnormalities AEC/Rapp–Hodgkin syndrome 127.75, 127.76 Bazex–Dupré–Christol syndrome 137.1, 137.7 chromosome disorders 116.14–116.16

Clouston syndrome 127.90 dyskeratosis congenita 136.8–136.9 EEC syndrome 127.78 focal dermal hypoplasia 133.3 hypohidrotic ectodermal dysplasia 127.68, 127.69 hypothyroidism 172.3 incontinentia pigmenti 130.4 Menkes syndrome 65.7, 65.7, 148.10, 148.10 Netherton syndrome 124.4, 124.4–124.5, 148.12, 148.13 odonto-onychodermal dysplasia 127.84 protein-energy malnutrition 65.2–65.3, 65.3, 148.19, 148.20 Rothmund–Thomson syndrome 136.2, 136.2–136.3 Schöpf–Schulz–Passarge syndrome 127.86 trichothiodystrophy 135.19, 135.20, 148.12, 148.12 HAIR–AN syndrome 172.17, 172.18 acne 79.16 hair canals 2.38, 2.39 hair collar sign 148.31 aplasia cutis congenita 10.18 cranial dysraphism 10.13, 10.13 hair disorders 148.1–148.33 hereditary 115.24 hair dye allergy 44.11 hair follicle(s) bulge region 148.2, 148.3 compound 148.17–148.18 development 2.28, 2.28, 2.33–2.39, 148.1, 148.2 stages 2.33–2.34, 2.34 fetus 2.21, 2.22 hyperkeratinization, acne 79.3–79.5 lichen planus involvement see lichen planopilaris loss of immune privilege, alopecia areata 149.2 matrix, development 2.35, 2.36 miniaturization 148.21–148.22 penetration of drugs 181.3 stem cells 2.36–2.38 hair follicle naevus 94.6 hair germs 2.34–2.35, 2.35, 2.37 Hairless (HR) gene mutations 127.83, 127.87, 148.6 hair loss 148.1, 148.3–148.23 diffuse (global) 148.4, 148.4 evaluation 148.3–148.5 microscopic examination 148.5, 148.5 physical examination 148.3–148.5 focal 148.4, 148.4 normal childhood 148.1–148.2, 148.2 trichotillomania 180.5, 180.5 types 148.5–148.23 see also alopecia; atrichia; hypotrichosis hair pegs 2.35, 2.35–2.36, 2.36 bulbous 2.36, 2.37 hair prostheses 149.6 hair pull test 148.4–148.5, 148.19, 148.20 hair reduction, permanent 148.33 hair shaft abnormalities 148.6–148.18 diagnosis 148.5 with hair breakage 148.10–148.15 with unruly hair 148.15–148.18 hair tourniquet 151.20 hair tract 2.35, 2.36 hair window test 148.4 hairy leucoplakia, oral 52.3, 147.13 hairy naevi, congenital 109.4, 109.4, 148.31, 148.31 hairy pinnae of ear 115.4, 115.24 Hallerman–Streiff syndrome 127.31 Haloclava producta 73.8 halo naevus 109.24 clinical features 109.24, 109.24 dermoscopy 185.12, 185.13 vitiligo and 105.4, 105.5 halothane anaesthesia 190.9 hamartin 129.1, 129.3

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

hand(s) congenital erythropoietic porphyria 107.11, 107.12 Darier disease 125.2 dystrophic epidermolysis bullosa 118.14, 118.14, 118.21–118.22 skin grafting 187.18–187.19, 187.20 Gorlin syndrome 132.7–132.8 HSV infections 48.3, 48.3–48.4, 48.4 Kawasaki disease 168.2, 168.2–168.3, 168.3 hand dermatitis acute and recurrent vesicular 39.1 atopic dermatitis 28.3, 28.3 contact allergy 44.4 patch testing 44.5 pathogenesis 44.1–44.2 hand-foot-and-mouth disease (HFMD) 49.9–49.11 clinical features 49.10, 49.10 differential diagnosis 39.3, 49.9 oral lesions 147.6 vesiculobullous lesions 87.8 Hand–Schüller–Christian disease 103.1–103.2, 103.4 handwashing neonatal intensive care unit (NICU) 5.3 obsessive 180.3, 180.8 Hansen disease see leprosy Hapalochlaena maculosa 73.8 Happle–Tinschert syndrome 145.18 haptens 44.1 hard water see under water harlequin baby 13.1 harlequin colour change (HCC), neonatal 6.2–6.3, 6.3 harlequin fetus see harlequin ichthyosis harlequin ichthyosis (HI) 13.1–13.6, 121.28–121.30 aetiology 13.1–13.3, 115.20, 121.28–121.29, 121.34 clinical features 13.3, 13.3–13.5, 121.28, 121.29 differential diagnosis 13.5 management 13.5–13.6, 121.29–121.30, 121.65, 121.66 mouse model 13.1–13.3, 13.2 nursing care 192.1, 192.2 pathology 2.39, 13.3 prenatal diagnosis 13.5, 139.3 Hartnup disease 65.5, 169.9–169.10 clinical features 65.6, 169.9–169.10 Hashimoto–Pritzker disease see congenital self-healing reticulohistiocytosis Hashimoto thyroiditis 172.5, 172.6 hats, photoprotection 108.17 Hawaiian garlands 45.8 HAX1 gene 177.10 Hayden syndrome 127.32 Hay–Wells syndrome see ankyloblepharon– ectodermal dysplasia–clefting (AEC) syndrome headache, systemic lupus erythematosus 175.7 head banging 180.3, 180.3 head louse (Pediculus capitis) 72.9, 72.10 clinical features of infestation 72.10, 72.11 differential diagnosis 72.12 patient advocacy group 179.7 prevention and control 72.13–72.14 treatment of infestations 72.12, 72.13 see also nits head size and shape, Gorlin syndrome 132.5 head trauma, intentional (IHT) 154.7 healing see wound healing health-related quality of life (HRQoL) 29.9 see also quality of life hearing loss see deafness heart block, congenital complete 14.1, 14.4, 14.6–14.7 investigations 14.8 prevention and management 14.9–14.10 heat intolerance hypohidrotic ectodermal dysplasia 127.69 lamellar ichthyosis 121.32

Index heat loss neonates 3.6 prevention, premature infants 5.4 heat urticaria 74.5 heavy metals see metals Heck disease 47.6, 47.6, 147.19 HED see hypohidrotic ectodermal dysplasia Hedera helix (ivy) 45.7, 45.7 hedgehog signalling pathway 121.54, 132.2, 132.3 inhibitors, Gorlin syndrome 132.16 heelprick marks, neonates 17.10–17.11 Heerfordt syndrome 158.4 Heimler syndrome 127.57 Helicobacter skin infections 64.4 helminth parasites, fetal immune responses 22.8–22.9 helper T cells see CD4+ T helper cells hemidesmosomes 91.14, 91.14 embryonic skin 2.7–2.8 fetal skin 2.20 hemihyperplasia with multiple lipomas 111.8 Hemileuca caterpillars 73.4 hemiparesis, tuberous sclerosis 129.5 Hemiptera 73.3 hemizygosity 115.3 henna products contact allergy 44.11 toxicity 184.13 Hennekam syndrome 114.9, 114.9 Henoch–Schönlein purpura (HSP) 160.1–160.6 acute haemorrhagic oedema of infancy and 161.1, 161.3–161.4, 161.4 aetiology and pathogenesis 160.1–160.2 clinical features 160.2–160.4, 160.3 complications 160.2 differential diagnosis 160.5, 163.5 epidemiology 160.1 histology 160.4–160.5, 160.5 investigations 160.4–160.5 purpura fulminans 162.4, 162.6–162.7 treatment 160.5–160.6 vs. child abuse 154.11, 154.11 heparin in meningococcal disease 55.11 in purpura fulminans 162.11, 162.12 purpura fulminans complicating 162.4, 162.7 hepatic disease see liver disease hepatic haemangiomas 113.21, 113.21–113.22 embolization 113.18 thyroid disease and 113.22 hepatitis B 153.18–153.19 Gianotti–Crosti syndrome 50.1–50.2, 50.3 prognosis and treatment 153.19 urticaria 74.3 vaccination 153.19 Gianotti–Crosti syndrome prevention 50.4–50.5 lichen planus association 85.3 hepatitis B virus (HBV) 153.18–153.19 detection 153.19 Gianotti–Crosti syndrome 50.4 hepatitis C virus (HCV), lichen planus association 85.2–85.3 hepatoerythropoietic porphyria (HEP) aetiology 107.5 clinical features 107.8, 107.12–107.13 incidence 107.8 pathogenesis 107.7 porphyrin profile 107.5 treatment 107.14 hepoxilin pathway 121.25 Heracleum mantegazzianum 45.8, 45.9 herald patch, pityriasis rosea 84.1, 84.2, 84.2 herbal remedies, atopic dermatitis 30.11 hereditary angioedema (HAE) 74.1, 74.8, 177.17–177.19 clinical features 74.8, 74.8, 177.17–177.18 differential diagnosis 177.18 genetics 115.2, 115.26

pathogenesis 74.2, 177.17 treatment 74.13, 177.18–177.19 hereditary benign intraepithelial dyskeratosis 115.20, 147.11 hereditary benign telangiectasia (HBT) 112.18 hereditary cancer syndromes 115.27, 137.1– 137.20, 137.2–137.6 hereditary coproporphyria (HCP) 107.6, 115.26 clinical features 107.8, 107.13 porphyrin profile 107.5 treatment 107.15 hereditary haemorrhagic telangiectasia (HHT) 112.5, 115.26, 147.16 hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome 137.13–137.14 clinical features 137.13, 137.13–137.14 pathogenesis 115.27, 137.13 tumour susceptibility 137.4, 137.13–137.14 hereditary mucoepithelial dysplasia 127.32, 147.15 hereditary non-polyposis colorectal cancer (HNPCC) syndrome 137.14 hereditary sensory and autonomic neuropathy, type IV 127.15 hereditary skin disorders see genetic skin disorders hereditary symmetrical aplastic naevi of temples see focal facial dermal dysplasia Hermansky–Pudlak syndrome 138.2, 138.6–138.7 differential diagnosis 138.6–138.7, 177.8 pathogenesis 115.25, 138.6 Hernandez syndrome 134.17 herpangina 49.11 differential diagnosis 49.10, 49.11 oral lesions 147.6 herpes encephalitis 48.5 herpes genitalis (genital herpes) 48.4, 153.19–153.20 diagnosis and treatment 153.20, 153.22 sexual abuse implications 48.4, 153.19–153.20, 155.3 herpes gestationis see pemphigoid gestationis herpes gingivostomatitis (orolabial herpes infections) 48.2–48.3, 147.4–147.5 aciclovir-resistant 147.5, 147.5 HIV-infected children 52.2 primary 48.2–48.3, 147.4–147.5 clinical features 48.2, 48.3, 147.4, 147.4 differential diagnosis 48.3, 147.4 treatment 48.6, 147.5 recurrent 48.3, 147.5, 147.5 treatment 48.7 see also herpes labialis herpes gladiatorum 48.5 herpes keratitis 48.5 herpes labialis (cold sores) 48.3, 147.5, 147.5 see also herpes gingivostomatitis herpes simplex virus (HSV) 48.1 aciclovir resistance 48.6, 147.5 amplicons, gene therapy 140.3, 140.5 Behçet disease pathogenesis 167.14 detection methods 48.2 transmission 153.19–153.20 type 1 (HSV-1) 48.1 genital infections 48.4 gingivostomatitis 48.2, 48.3 type 2 (HSV-2) 48.1 genital infections 48.4 typing 48.2 vaccines 48.7 herpes simplex virus (HSV) infections 48.1–48.7 aetiology 48.1 atopic dermatitis acute disseminated see eczema herpeticum immune responses 24.7, 33.1 recurrent 33.4 clinical features 48.2–48.6 congenital 8.3, 8.3, 8.4 cutaneous 48.2–48.5, 48.5 diagnosis 48.2 disseminated 48.5

31

dystrophic calcification 95.7 erythema multiforme 78.2, 78.3, 78.7 face 48.5 genital see herpes genitalis hand lesions 48.3, 48.3–48.4, 48.4 HIV-infected children 52.2 ichthyoses 121.64 immunocompromised children 48.5–48.6, 64.3, 64.7–64.8 immunology 48.2 napkin area infection 20.12, 20.12 neonatally acquired 9.5, 153.20 orolabial see herpes gingivostomatitis pathology 48.1–48.2 pinna 48.5, 48.5 prevention 48.7 primary 48.1, 48.2 clinical features 48.2–48.3, 48.4 treatment 48.6–48.7 recurrent 48.2 atopic dermatitis 33.4 clinical features 48.3, 48.4 treatment 48.7 treatment 48.6–48.7 vesiculobullous lesions 87.8 herpes zoster (shingles) 49.13–49.14 clinical features 49.14, 49.14 HIV-infected children 52.3, 52.3 immunocompromised children 49.14, 64.7 oral lesions 147.6 vesiculobullous lesions 87.8 herpetic paronychia 48.3 herpetic whitlow 48.3, 48.3–48.4 Hertoghe’s sign 28.5, 28.6 heterochromia irides, Waardenburg syndrome 138.5, 138.6 heteroinoculation, HPV infections 47.2–47.3 heterozygosity 115.2 compound 115.5 loss of see loss of heterozygosity hexachlorobenzene poisoning 184.15 hexachlorophene poisoning 5.7, 17.7–17.8, 184.6 hHb3 (KRT83) gene mutations 117.7, 127.96 hHb6 (KRT86) gene mutations 117.7, 127.96 hibernoma 141.3–141.4 hidradenitis, palmoplantar see palmoplantar hidradenitis hidradenitis suppurativa (HS) (acne inversa) 79.20, 94.2–94.3 clinical features 79.20, 79.20, 94.2, 94.2 genital area 151.14 management 79.20, 94.3 patient advocacy group 179.7 hidrocystoma, apocrine 94.6–94.7 HID syndrome see hystrix-like ichthyosis with deafness (HID) syndrome highly active antiretroviral therapy (HAART) 52.5 hypersensitivity reactions 52.4–52.5 Hippocrates 1.1 Hirschsprung disease 138.6 hirsutism acne 79.16 laser treatment 189.3, 189.3–189.4 histamine atopic dermatitis 25.2, 25.3–25.4, 25.9 food allergies 31.4 non-specific release 74.4 urticaria 74.1, 74.2 see also antihistamines histidase 27.4 histiocytes CD14+/CD14- 103.1 granuloma annulare 93.3 histiocytosis 103.1–103.19 atypical self-healing 6.7 benign cephalic (BCH) 103.10, 103.10, 103.13, 103.13–103.14 cellular origin 103.1 classification 103.2

32

Index

histiocytosis (cont.) generalized eruptive (GEH) 103.10, 103.13, 103.14 indeterminate cell (ICH) 103.11, 103.13, 103.14 Langerhans cell see Langerhans cell histiocytosis non-Langerhans cell 103.1, 103.8–103.17 classification 103.9, 103.9 clinical features 103.9–103.12 evaluation 103.12–103.13 pathology 103.13, 103.13–103.14 predominantly dendritic cell line (JXG family) 103.9, 103.9–103.11 predominantly macrophage cell line (non-JXG family) 103.9, 103.12 treatment 103.14 unclassified 103.12 progressive nodular (PNH) 103.10–103.11, 103.13 histiocytosis X see Langerhans cell histiocytosis histogenesis, skin 2.2, 2.3 histopathology 4.1–4.8 dermal nodules 4.3–4.4 inflammatory dermatoses 4.6–4.7 pigmented lesions 4.1–4.3 vascular lesions 4.4–4.6 Histoplasma capsulatum 63.14–63.16 Histoplasma capsulatum var. duboisii 63.16–63.17 histoplasmosis 63.14–63.16 acute pulmonary 63.15 African 63.16–63.17 chronic pulmonary 63.15 disseminated 63.15, 63.16 HIV-related 52.2, 63.15 oral lesions 147.7 primary cutaneous 63.15 history of paediatric dermatology 1.1–1.5 hives see urticaria HIV infection/AIDS 52.1–52.5 acute seroconversion illness 52.1 atypical mycobacterial infections 52.2, 57.5, 57.9 bacillary angiomatosis 52.2, 58.1, 58.2 clinical features 52.1–52.5 congenital 8.4 cryptococcosis 52.2, 63.2, 63.3 cutaneous manifestations 52.1–52.5 cytomegalovirus infections 49.16–49.17, 52.3 differential diagnosis 52.5 endemic treponematoses 60.7 eosinophilic pustular folliculitis 36.2, 36.5 epidemiology 52.1 histoplasmosis 52.2, 63.15 hyperpigmentation 104.8 hypertrichosis 148.32 lipodystrophy 52.5, 141.16 malignant skin tumours 52.5, 99.1 molluscum contagiosum 46.1, 52.3, 52.3 napkin dermatitis 20.7, 52.2 oral candidiasis 52.2, 62.20 oral ulceration 147.6 pityriasis rubra pilaris 52.5, 83.5 postexposure prophylaxis 153.21 prognosis 52.5 salivary gland enlargement 147.21 scabies 52.4, 72.5 seborrhoeic dermatitis 41.1, 41.3, 41.4–41.5, 52.4 sexual transmission 153.20–153.21 treatment 52.5, 153.21 tuberculosis 57.1 see also human immunodeficiency virus HLA associations actinic prurigo 106.4 alopecia areata 149.1 Behçet disease 167.14 dermatitis herpetiformis 90.3 granuloma annulare 93.1 Henoch–Schönlein purpura 160.1 juvenile dermatomyositis 175.10 juvenile idiopathic arthritis 175.1

lichen planus 85.1–85.2, 85.2 linear IgA disease of childhood 89.2, 89.6, 89.8 psoriasis 81.1–81.2 sarcoidosis 158.2 Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap 78.2 systemic lupus erythematosus 175.6 systemic sclerosis 174.2, 174.3 HLA-DR embryonic epidermis 2.6–2.7, 2.7 embryonic-fetal transition 2.15 graft-versus-host disease 178.2, 178.4–178.5, 178.5 HLA-DR3, leprosy susceptibility 70.3 HLA molecules, graft-versus-host disease 178.2 HMB-45 immunostaining 2.6, 2.6, 2.15 Hodgkin and Reed–Sternberg cells (HRS) 99.17, 99.18–99.19 Hodgkin disease 99.17–99.19, 99.18 Hoffmann–Zurhelle syndrome 133.7 holocarboxylase synthetase deficiency 148.21 neonatal erythroderma 11.10–11.11 holoclones 140.2 holster sign, allergic contact napkin dermatitis 20.2, 20.4 homeobox genes causing ectodermal dysplasias 127.73–127.83 fetal skin fibroblasts 3.6 homeopathic treatment, warts 47.10 home remedies, napkin dermatitis 21.4 homocystinuria 169.5, 169.5 homogentisic acid oxidase deficiency 169.6 homozygosity 115.3 honey, epidermolysis bullosa 118.20 honey bees 73.2 honeycomb atrophy see atrophoderma vermiculata hookworms 68.1 Hôpital des Enfants Malades 1.2 HOPP syndrome see hypotrichosis–osteolysis– periodontitis–palmoplantar keratoderma syndrome Hori naevus 189.4–189.5 hornets 73.2 Hornstein–Birt–Hogg–Dubé syndrome 115.27 horse flies (Tabanus spp.) 71.2 biting behaviour 71.7 secondary infection of bites 71.5 Hortaea werneckii 62.32–62.33 hot water immersion accidental 154.6 forced 154.5, 154.5, 154.5–154.6, 154.6 see also burns/scalds housedust mites (HDM) 32.2, 32.6–32.7 atopic dermatitis evolution 24.8 avoidance 30.9, 32.8 environmental load and eczema severity 32.6 specific immunotherapy 32.8 Howel–Evans syndrome (tylosis with oesophageal carcinoma) 120.17–120.18 clinical features 120.17–120.18, 120.18 genetics 115.21 oral lesions 147.10 tumour susceptibility 120.17–120.18, 137.4 Hoyeraal–Hreidarsson syndrome 136.7, 136.9 genetic basis 136.8 treatment 136.10 HPS gene mutations 138.6 HPV see human papillomaviruses HRAS gene mutations 134.16 HRNR gene, atopic dermatitis 23.6 HSV see herpes simplex virus H syndrome 115.28, 148.29 HTLV-1 see human T-lymphotrophic virus type 1 human bite marks 154.4, 154.4–154.5 human chorionic gonadotrophin (hCG), choriocarcinoma 99.12, 99.13 human flea (Pulex irritans) 71.1, 71.2, 71.6 human herpesvirus-6 (HHV-6) 49.12 pityriasis rosea 84.1–84.2 roseola infantum 49.7

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

human herpesvirus-7 (HHV-7) 49.12 pityriasis rosea 84.1–84.2 roseola infantum 49.7 human herpesvirus-8 (HHV-8) 49.17–49.18 angiolymphoid hyperplasia with eosinophilia 98.1 human herpesvirus (HHV) infections 49.12–49.19 human immunodeficiency virus (HIV) 52.1 criteria for testing in children 153.21 infection see HIV infection/AIDS human papillomaviruses (HPV) 47.1, 47.2, 153.17 classification 47.1 E5 protein 137.11 genotyping 47.7–47.8 immunity 47.1–47.2 infecting naevus sebaceous 110.4–110.5 role in non-wart skin conditions 47.3 types in relation to lesions 47.3–47.7 vaccines 47.9 human papillomavirus (HPV) infections 47.1–47.11 aerodigestive tract 47.6, 47.6 anogenital see condyloma acuminata clinical features 47.3–47.7 congenital 8.4 cutaneous 47.3–47.5, 47.4, 47.5 differential diagnosis 47.7 epidemiology 47.1–47.2 epidermodysplasia verruciformis 137.10 genital 47.6, 47.6–47.7, 47.7 histology 47.7 HIV infection 52.4, 52.4 immunocompromised children 64.3, 64.7 intraoral 147.18–147.19 mode of transmission 47.2–47.3 neoplasia associated with 47.6, 47.7 subclinical and latent 47.2 treatment 47.8–47.11 see also warts human skin substitutes (HSS) 140.16, 181.12 epidermolysis bullosa 118.21, 140.16 human tail 10.17 human T-lymphotrophic virus type 1 (HTLV-1) 53.1–53.4, 102.6 epidemiology 53.1 skin manifestations see infective dermatitis human T-lymphotrophic virus type 1 (HTLV-1)associated myelopathy (HAM) 53.4 humectants, ichthyoses/MEDOC 121.66 humidity, ambient, preterm infants 3.2 humoral immunity leprosy 70.3 primary deficiency disorders 64.4–64.5, 177.24–177.27, 177.25–177.26 Hunter syndrome (mucopolysaccharidosis II) 169.11, 169.11, 169.12 prenatal diagnosis 139.3 Huriez syndrome 120.8, 120.8–120.9 tumour susceptibility 137.3 Hurler–Scheie syndromes 169.11, 169.12 Hurler syndrome 169.11, 169.11–169.12 hypertrichosis 148.29 Hurwitz, Sidney 1.3, 1.5 Hutchinson–Gilford syndrome (progeria) 134.1–134.3 aetiology 115.28, 134.1 clinical features 134.2, 134.2 Hutchinson’s sign 49.14 Hutchinson’s teeth 153.5 Hutchinson’s triad, congenital syphilis 153.5 hyalinoses 97.1, 97.16–97.20 infantile systemic 97.16–97.17 juvenile 97.17, 97.17–97.19, 97.18 terminology 97.2 hyalinosis cutis et mucosae 97.19–97.20 hyalohyphomycosis 63.21–63.22 hyaluronic acid-rich proteoglycan matrix, embryonic skin 2.8, 2.10 hyaluronidase, extravasation injuries 17.9, 17.9

Index hydatid disease, dystrophic calcification 95.7 hydration, stratum corneum see stratum corneum (SC), hydration hydroa vacciniforme (HV) 106.8–106.9 clinical features 106.8, 106.8, 106.9 differential diagnosis 106.3 hydroa vacciniforme-like cutaneous T-cell lymphoma (CTCL) 77.14, 99.24–99.25, 102.10 clinical features 99.24, 99.25, 102.10 hydrocephalus congenital melanocytic naevi with 109.6 neonatal lupus erythematosus 14.7 hydrocoele, congenital 151.16 hydrocortisone Addison disease 172.10 Henoch–Schönlein purpura 160.6 topical atopic dermatitis 30.6, 30.7 napkin dermatitis 21.4 hydrogel dressings, epidermolysis bullosa simplex 118.8 hydrogen peroxide cream dystrophic epidermolysis bullosa 118.20 epidermolysis bullosa simplex 118.7 hydroquinone, melasma 104.7 hydroxychloroquine hyperpigmentation induced by 104.4 Jessner’s lymphocytic infiltrate 101.3 monitoring therapy 192.16 sarcoidosis 158.5 hydroxymethylglutaryl (HMG) CoA reductase inhibitors 169.15 Hydrozoa 73.7 hygiene hypothesis 22.6, 22.10 Hylesia moths 73.4 hymen imperforate 151.16 injuries, sexual abuse 155.2, 155.2 hymenopterids, venomous 73.2–73.3 hyperactivity, tuberous sclerosis 129.5 hyperandrogenaemia (HA) (androgen excess) 172.14–172.16 acne 79.16–79.17 clinical features 172.14, 172.15 hair loss 148.21–148.22 insulin resistance 172.14, 172.15, 172.18 hyperandrogenism, insulin resistance and acanthosis nigricans syndrome see HAIR–AN syndrome hypercalcaemia metastatic calcification 95.8 neonatal subcutaneous fat necrosis 7.3, 77.8, 77.9 hypercholesterolaemia, familial (FH) see familial hypercholesterolaemia hypercortisolism 172.7–172.8 hypereosinophilic disorders 36.1–36.13 hypereosinophilic syndrome (HES), idiopathic 36.2, 36.6–36.9 differential diagnosis 36.7, 36.10 hyperextensible skin chromosome disorders 116.9 Ehlers–Danlos syndrome 142.3, 142.5 Marfan syndrome 145.6 pseudo-xanthoma elasticum 144.4 hyperglycaemia, diabetes mellitus 172.20 hyperhidrosis mal de Meleda 120.5 pitted keratolysis 56.1 hyperhomocystinaemia 169.5 hyperimmunoglobulin D syndrome (HIDS) 176.2, 176.3 urticarial lesions 74.9, 163.5 hyperimmunoglobulin E syndromes (HIES) 177.21–177.24 autosomal recessive (AR-HIES) 177.22, 177.23 classic (autosomal dominant) 177.22 clinical features 177.22, 177.22–177.23 differential diagnosis 28.10, 177.23 mucocutaneous findings 177.2

pathogenesis 177.22 skin infections 64.2, 64.3, 177.22, 177.22 treatment 177.23–177.24 hyperimmunoglobulin M syndromes (HIMS) 177.24, 177.26 mucocutaneous findings 177.2, 177.24, 177.27 hyperinsulinaemia 172.17, 172.18 see also insulin resistance hyperkeratosis chromosome disorders 116.11 epidermolytic see epidermolytic hyperkeratosis epidermolytic ichthyosis 117.5, 121.18, 121.21 erythrokeratodermia variabilis 122.7, 122.8 focal acral (FAH) 120.25 ichthyosis bullosa of Siemens 117.6 keratinocytic epidermal naevi 110.9 KID syndrome 122.2, 122.6 lamellar ichthyosis/congenital ichthyosiform erythroderma 121.31–121.32 mal de Meleda 120.5 Norwegian scabies 72.4–72.5 Rothmund–Thomson syndrome 136.2, 136.2 Sjögren–Larsson syndrome 121.42, 121.46 hyperkeratotic cutaneous capillary–venous malformation (HCCVM) 112.12 hyperlinear palms and soles atopic dermatitis 28.6, 28.7 ichthyosis vulgaris 121.8, 121.8 hyperlipoproteinaemias/hyperlipidaemias 169.13–169.15 carotenaemia 171.1–171.2, 171.4–171.5 classification 169.13, 169.14 clinical features 169.14, 169.14 hypermelanosis linear and whorled naevoid see linear and whorled naevoid hypermelanosis phylloid 115.10 see also melanosis hypernatraemia MEDOC 121.63 Netherton syndrome 124.6 hyperostoses, Proteus syndrome 111.5 hyperparathyroidism 172.27–172.28 primary 95.8 secondary 95.8, 95.9 hyperphenylalaninaemia (HPA) 169.1–169.4 hyperpigmentation 104.4–104.10 Addison disease 104.7–104.8, 172.9, 172.10 atopic dermatitis 28.5, 28.6, 28.6, 104.5 autoimmune disease 104.8–104.9 Brazilian pemphigus 91.7 chromosome disorders 116.11–116.12 circumscribed 104.4–104.7 Cushing disease 104.8, 162.7 diffuse 104.7–104.9, 138.9 drug-induced 104.4–104.5, 104.8, 147.16 endocrine and metabolic disorders 104.7–104.8 familial progressive 104.9, 138.3, 138.9 flagellate 104.9 infective causes 104.4 inflammatory disorders 104.4, 104.5 inherited disorders 138.3, 138.9–138.11 lichen planus 85.5, 85.5, 104.5, 104.6 lichen simplex chronicus 42.1, 42.2, 104.5 linear 104.9, 138.9 minocycline-induced see under minocycline neurofibromatosis 1 128.4, 128.4 nutritional abnormalities 104.8 obesity 65.10 oral 147.15–147.16 perifollicular, congenital melanocytic naevi 185.7, 185.7 periorbital 104.6 phytophotodermatoses 45.8, 45.9, 45.11 pigmentary mosaicism 131.3, 131.3 postinflammatory 104.4, 104.5 protein-energy malnutrition 65.2, 65.2, 65.3, 104.8 Proteus syndrome 111.4 prurigo pigmentosa 42.7 reticulated see reticulate hyperpigmentation

33

segmental neurofibromatosis 1 128.11, 128.11 serpentine supravenous 104.9 tinea nigra 62.33, 62.33 transient localized neonatal 6.3–6.4, 6.4 xeroderma pigmentosum 135.8, 135.8 see also pigmentary changes hypersensitivity reactions see allergies hypertension congenital adrenal hyperplasia 172.14 pseudo-xanthoma elasticum 144.6 hyperthermia, congenital erosive and vesicular dermatosis 16.4 hyperthyroidism 172.5–172.7 hyperpigmentation 104.8 neonatal 172.5 hypertrichosis 148.1, 148.28–148.33 Becker naevus 104.13, 148.32, 148.32–148.33 chromosome disorders 116.16 congenital melanocytic naevi 185.6, 185.7, 185.7 eyelashes 148.32 generalized 148.28–148.30 acquired 148.30 congenital 148.29 and dental defects 127.33 hereditary 148.28–148.30 laser treatment 148.33, 189.3, 189.3–189.4 localized 148.30–148.33 acquired 148.32–148.33 congenital 148.30–148.32, 148.31 lumbosacral (faun tail) 10.17, 148.31–148.32, 148.32 midback 148.32 naevoid 148.31 porphyria 107.9, 107.9, 107.11, 148.29–148.30 treatment 148.33 hypertrichosis lanuginosa, congenital 148.28–148.29, 148.29 hypertrichosis terminalis, generalized, with or without gingival hyperplasia 127.29 hypertrichosis universalis congenita 116.16, 148.29 hypertrophic scars 187.3–187.7 aetiology 187.3–187.5 clinical features 187.3, 187.8 laser treatment 188.10, 189.9 skin graft donor site 187.13, 187.14 treatment 187.5–187.7 hyphomycoses 63.20–63.22 hypnotherapy/hypnosis atopic dermatitis 34.5 pain and anxiety 190.10 warts 47.10 hypnotic agents 190.7–190.9 hypocomplementaemic urticarial vasculitis syndrome 163.1, 163.4, 163.5 Hypoderma 69.2–69.3 hypodermis embryonic-fetal transition 2.17–2.18 fetal skin 2.21 hypodontia, X-linked 127.64, 127.66 hypogammaglobulinaemia of infancy, transient 177.26 hypogonadism 172.10–172.11 hypohidrosis Huriez syndrome 120.9 hypohidrotic ectodermal dysplasia 127.68 KID syndrome 127.91 lamellar ichthyosis 121.32 hypohidrotic ectodermal dysplasia (HED) 127.68–127.72 with acanthosis nigricans 127.41 autosomal dominant (EDA3) 127.68–127.71 clinical features 127.35, 127.68–127.70 pathogenesis 127.66, 127.66–127.67 autosomal dominant with T-cell immunodeficiency 127.66, 127.71–127.72 autosomal recessive 127.68–127.71 clinical features 127.35, 127.68–127.70 pathogenesis 127.66, 127.66–127.67

34

Index

hypohidrotic ectodermal dysplasia (HED) (cont.) with deafness 127.36 with hypothyroidism and agenesis of corpus callosum 127.38 with hypothyroidism and ciliary dyskinesia (HEDH syndrome) 127.36–127.37 with immunodeficiency (EDA-ID) 127.71, 177.24, 177.26 clinical features 127.35, 127.71 genetics and pathogenesis 115.23, 127.66, 127.67 with immunodeficiency osteopetrosis and lymphoedema (OL-EDA-ID syndrome) 114.8, 127.71 clinical features 127.36 genetics and pathogenesis 127.66, 127.67 prenatal diagnosis 114.20 universal/near total alopecia 148.6 X-linked (ED1) (Christ–Siemens–Touraine) 127.68–127.71 clinical features 116.10, 127.34, 127.68– 127.70, 127.69, 127.70 neonatal desquamation 6.2 pathogenesis 115.23, 116.9–116.10, 127.66, 127.66 pathology 127.68, 127.68 sweat testing 115.13–115.14, 115.14 hypomastia 10.8 hypomelanosis, phylloid 115.10, 115.11 hypomelanosis of Ito (HI) 115.14, 131.1–131.5 clinical features 131.3, 131.3–131.4 diagnosis 131.4–131.5 differential diagnosis 104.3, 116.11, 131.5, 131.5 histopathology 131.3 pathogenesis and genetics 131.1–131.2 treatment 131.5 hypomelanotic macules see hypopigmented macules hypomorphic alleles 115.6–115.7 hyponychium 150.1 hypoparathyroidism 172.25 hypopigmentation 104.1–104.3 bullous pemphigoid 91.15 chromosome disorders 116.11 Darier disease 125.2, 125.3 inflammatory or infectious diseases 104.1 inherited disorders 104.1, 138.2, 138.4–138.9 lichen striatus 86.4, 86.4 mycosis fungoides 99.21, 102.2–102.3, 102.3 nutritional disorders 104.1–104.2 perifollicular, congenital melanocytic naevi 185.6, 185.7, 185.7 pigmentary mosaicism 131.3, 131.3 pityriasis alba 37.1–37.2, 37.2, 104.1 postinflammatory 104.1 Proteus syndrome 111.4 xeroderma pigmentosum 135.8, 135.8 see also depigmentation; pigmentary changes hypopigmented (hypomelanotic) macules differential diagnosis 104.2, 104.3 tuberous sclerosis 104.2, 104.3, 129.6, 129.6, 129.7 hypopituitarism 172.24 hypoplastic lesions, Proteus syndrome 111.5 hypospadias 151.16 hypothalamo-pituitary-adrenal (HPA) axis, atopic dermatitis 34.3–34.4 hypothermia, neonatal subcutaneous fat necrosis and 7.1 hypothyroidism 172.1–172.5 acquired 172.1, 172.2–172.3 carotenaemia 171.2, 171.5 congenital 172.1–172.2, 172.2, 172.3 transient 172.1, 172.3 hepatic haemangiomas and 113.22 neonatal lupus erythematosus and 14.8 precocious puberty 172.11 hypotrichosis 148.6 Bazex–Dupré–Christol syndrome 137.1, 137.7 with juvenile macular dystrophy (HJMD) 115.24, 127.14, 127.100

localized autosomal recessive (LAH) 148.6 type 1 (LAH1) 127.42, 127.100 type 2 (LAH2) 127.42, 127.100 type 3 (LAH3) 127.43, 127.100 Marie–Unna 148.16–148.17 clinical features 148.8, 148.17, 148.17 genetics 115.24 and recurrent skin vesicles 127.38, 127.100 hypotrichosis–deafness 120.21 hypotrichosis–lymphoedema–telangiectasia 114.8 hypotrichosis–osteolysis–periodontitis– palmoplantar keratoderma syndrome (HOPP) 120.20–120.21, 127.38 hypotrichosis simplex (of the scalp) 127.100, 148.6 clinical features 127.38, 127.100 genetics 115.24 hypoxia inducible factor (HIF) 137.13 hystrix-like ichthyosis with deafness (HID) syndrome 120.21, 122.1, 122.2, 127.40 iatrogenic disorders blistering 87.9 hypopigmentation 104.1 neonates 17.1–17.5 oral ulceration 147.9 panniculitis 77.12–77.13 see also adverse drug reactions iatrogenic transmission, HPV infections 47.3 IBIDS syndrome 121.59, 148.11 see also trichothiodystrophy IB proteins 127.65 ibuprofen adverse reactions 78.2 -impregnated dressings, epidermolysis bullosa 118.25 icatibant 177.18 ice cube test, cold urticaria 74.5, 74.12 Ichthopaste and Coban® bandages, eczema 192.7, 192.8 ichthyin 12.1, 121.26, 121.34 deficiency see under autosomal recessive congenital ichthyoses gene (NIPAL4) mutations 121.34, 122.11–122.12 ichthymol, atopic dermatitis 30.8 ichthyoses 121.1–121.72 acquired, causes 121.50 autosomal dominant congenital see keratodermic ichthyoses autosomal recessive congenital (ARCI) see autosomal recessive congenital ichthyoses bathing suit 121.27, 121.33 chromosomal disorders 116.8, 116.9 common, and related syndromes 121.2, 121.7–121.17 epidermolytic see epidermolytic ichthyosis erythrodermic, collodion baby 12.1, 12.2 harlequin see harlequin ichthyosis keratinopathic 121.17 keratodermic 121.2, 121.17–121.24 neonatal erythroderma 11.4–11.5 pathogenic mechanisms 121.3–121.4 patient advocacy groups 13.6, 121.63, 179.7 recessive X-linked see recessive X-linked ichthyosis ichthyosiform erythroderma bullous congenital see epidermolytic ichthyosis congenital reticular see ichthyosis en confettis Netherton syndrome 124.3, 124.3–124.4 non-bullous congenital see congenital ichthyosiform erythroderma ichthyosis bullosa of Siemens see superficial epidermolytic ichthyosis ichthyosis congenita 121.32 type I see harlequin ichthyosis type II see lamellar ichthyosis type III 121.32 type IV 121.32 see also autosomal recessive congenital ichthyoses

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

ichthyosis en confettis (congenital reticular ichthyosiform erythroderma; ichthyosis variegata) 121.38 clinical features 121.38, 121.39 genetic basis 115.20, 117.6 ichthyosis-follicular atrophoderma-hypotrichosis 115.20 ichthyosis follicularis 123.1, 148.7 ichthyosis follicularis with atrichia and photophobia (IFAP) 121.55–121.56, 127.38 clinical features 121.45 genetics 115.21 ichthyosis and hypotrichosis, autosomal recessive (ARIH) 121.56–121.57 ichthyosis-hypotrichosis-sclerosing cholangitis syndrome (IHSC) syndrome 115.21, 121.57, 121.57–121.58 ichthyosis hystrix 110.9, 110.20, 121.23 of Curth–Macklin (IHCM) 121.23 differential diagnosis 121.20–121.21 genetic basis 115.20, 121.23 of Rheydt 122.1 ichthyosis linearis circumflexa (ILC) 124.1 clinical features 122.5, 124.3, 124.3–124.4 trichorrhexis invaginata 148.13, 148.13 see also Netherton syndrome ichthyosis nigricans 121.11 ichthyosis prematurity syndrome (IPS) 121.36 clinical features 121.36, 121.37 genetics 115.20 ichthyosis variegata see ichthyosis en confettis ichthyosis vulgaris (IV) 121.7–121.11 clinical features 121.7–121.8, 121.8 differential diagnosis 121.9–121.10, 121.10, 121.10 epidemiology 121.7 genetics and pathogenesis 23.8, 115.20, 121.9 management 121.10–121.11 pathology 121.8–121.9 ICOS gene mutations 177.25 idiopathic hypereosinophilic syndrome see hypereosinophilic syndrome (HES), idiopathic idoxuridine, topical 181.8 HSV infections 48.7 orf 51.23 id reactions infantile seborrhoeic dermatitis 35.3 nickel contact allergy 44.9 pompholyx 39.1 IFAP syndrome see ichthyosis follicularis with atrichia and photophobia IFNGR1 gene mutations 177.11 IFNGR2 gene mutations 177.11 IgA see immunoglobulin A IgE see immunoglobulin E IGHM gene mutations 177.25 IGLL1 gene mutations 177.25 IKBA gene mutations 177.26 IkBα gene mutations 127.66 IKBKG gene mutations see NEMO/IKKγ gene mutations IKK (IκB kinase) 127.65, 127.67 IKKγ gene mutations see NEMO/IKKγ gene mutations IL2RA gene mutations 177.8 IL2RG gene mutations 177.30 IL4 gene, atopic dermatitis 23.12 IL4RA gene, atopic dermatitis 23.9, 23.12 IL7R gene 177.30 IL12B gene mutations 177.11 IL12RB1 gene mutations 177.11 IL13 gene, atopic dermatitis 23.9, 23.12 ILVEN see inflammatory linear verrucous epidermal naevus imatinib mesylate dermatofibrosarcoma protuberans 99.7 hypereosinophilic syndrome 36.8 mastocytosis 75.12 morphoea 173.9–173.10

Index imiquimod cream 181.12 condyloma acuminata 153.18 Gorlin syndrome 132.14 granuloma annulare 93.8 infantile haemangioma 113.18 molluscum contagiosum 46.5 porokeratosis 126.4 warts 47.9 immediate (type I) hypersensitivity drugs 183.12–183.13 insect bites 71.4 plants/plant products 45.3–45.4, 45.4 immune complexes dermatitis herpetiformis 90.3 granuloma annulare 93.2–93.3 immune response modifiers 181.11–181.12 molluscum contagiosum 46.5 psoriasis 82.3 vitiligo 105.6 warts 47.9 immune restoration disease (IRIS) 52.5 immune system effects of UV radiation 108.8 role of lymphatic system 114.2 immunization, genetic 140.17 immunocompromised children aspergillosis 63.20, 63.20, 64.10 atypical mycobacterial infections 57.8, 57.9, 57.10, 64.2, 64.9 blastomycosis-like pyoderma 54.6 cellulitis 54.5–54.6 crusted (Norwegian) scabies 72.4 cryptococcosis 63.2 cutaneous infections 64.1–64.10 cytomegalovirus infections 49.16–49.17 herpes zoster 49.14, 64.7 HPV infections 64.3, 64.7 HSV infections 48.5–48.6, 64.3, 64.7–64.8 aciclovir-resistant 147.5, 147.5 human herpesvirus-8 infections 49.17, 49.18 molluscum contagiosum 46.1, 46.2, 64.3, 151.11 opportunistic mycoses 63.1 porokeratosis 126.1 trichosporosis 63.3, 63.4 varicella 49.13, 64.7 immunodeficiency, centromeric instability and facial anomalies (ICF) syndromes 177.26 immunodeficiency disorders 177.1–177.34 combined (CIDs) 64.2–64.3 see also severe combined immunodeficiency lymphoproliferative 177.8 neonatal erythroderma 11.8–11.10 phagocytic defects 64.5–64.6, 177.10–177.11 pityriasis rubra pilaris 83.1 predominantly humoral 64.4–64.5, 177.24–177.27, 177.25–177.26 primary (PID) 177.1–177.34 histopathology 4.7 mucocutaneous features 177.1, 177.2–177.3 skin infections 64.1–64.6, 64.2 secondary 64.6, 64.6–64.10 immunodeficiency with lymphoproliferation 177.8 immunofluorescence (IF) bullous pemphigoid 91.15, 91.15, 91.16 dermatitis herpetiformis 90.2, 90.2, 90.3–90.4 epidermolysis bullosa acquisita 91.22–91.23, 91.23 lichen planus 85.3 linear IgA disease of childhood 89.4–89.5, 89.5 localized vulvar pemphigoid 91.17 mucous membrane pemphigoid 91.18 pemphigus 91.3, 91.3, 91.5, 91.8 urticarial vasculitis 163.3 Wegener granulomatosis 167.1, 167.2 immunoglobulin(s) deficiencies Netherton syndrome 124.5 primary 64.4–64.5, 177.24–177.28, 177.25–177.26

intravenous therapy see intravenous immunoglobulin immunoglobulin A (IgA) dermatitis herpetiformis 90.1–90.2, 90.2, 90.3 Henoch–Schönlein purpura 160.1–160.2 linear disease of childhood see linear IgA disease (LAD), childhood selective deficiency 177.2, 177.24, 177.25 immunoglobulin A (IgA)-epidermolysis bullosa 91.13 immunoglobulin A pemphigus 91.9–91.10 intraepidermal neutrophilic IgA dermatosis (IEN) 91.2, 91.9 subcorneal pustular dermatosis (SPD) 91.2, 91.9 immunoglobulin E (IgE) atopic dermatitis 24.1, 24.4 aeroallergen-exacerbated 32.3, 32.7–32.8 cytokines regulating 25.5, 25.8 IgE-mediated autoreactivity 26.7 Malassezia and 26.5–26.6 neonates 11.2–11.3 superantigen-specific 24.6, 26.3 drug hypersensitivity reactions 183.13 food allergy 31.5, 31.5–31.6, 31.9–31.10 high-affinity receptor see FcεRI hyper-IgE syndromes 177.23 neonates with elevated serum levels 11.13 Netherton syndrome 11.5 Omenn syndrome 11.9 urticaria 74.2 immunoglobulin M (IgM) deficiency 177.2, 177.26 immunohistochemistry, prenatal diagnosis 139.7–139.8, 139.8 immunological abnormalities hypohidrotic ectodermal dysplasia with immunodeficiency 127.71 Netherton syndrome 124.5–124.6 immunoregulatory genes, atopic dermatitis 23.12 immunosuppression, UV-induced 108.8 immunosuppressive therapy pemphigus vulgaris 91.4–91.5 relapsing polychondritis 167.20 systemic sclerosis 174.10–174.11 see also azathioprine; ciclosporin; cyclophosphamide; methotrexate; other specific agents immunotherapy leprosy 70.10 molluscum contagiosum 46.5 neuroblastoma 99.12 specific (SIT), atopic eczema 32.8 topical alopecia areata 149.5–149.6 warts 47.9, 150.3, 181.9 impetiginized eczema 26.1, 26.3, 28.8 impetigo 54.3–54.4 arthropod bites 71.5 Bockhart’s 54.4–54.5 bullous 54.4, 54.8 napkin area 20.2, 20.6, 20.6 neonatal 9.2, 9.2–9.3 vs. inflicted burns 154.7, 154.11 complications 54.4 differential diagnosis infantile acropustulosis 88.2 leishmaniasis 67.11–67.12, 67.12 nummular dermatitis 40.2 genital area 151.9–151.10 HIV infection 52.2 neonatal 9.2, 9.2–9.3 non-bullous (impetigo contagiosa) 54.4 napkin area 20.6 pigmentation changes after 104.5 treatment 54.4 impetigo furfuracea see pityriasis alba imprinting, genomic 115.5, 116.5 atopic eczema 23.2 loss of, Beckwith–Wiedemann syndrome 137.7 pigmentary mosaicism 131.2

35

inborn errors of metabolism see metabolic disorders, inherited inclusion body fibromatosis 97.11, 97.11–97.12, 97.12 incontinentia pigmenti (IP) 130.1–130.6 aetiology 115.25, 127.66, 127.67, 130.1–130.2, 138.3 clinical features 127.38–127.39, 130.2–130.5 cutaneous features/stages 130.2, 130.2–130.3, 130.3, 138.9 differential diagnosis 6.7, 16.5, 130.5–130.6, 131.5, 133.7 pathology 130.2 patient advocacy group 179.7 treatment 130.6 vesiculobullous lesions 87.7 incontinentia pigmenti achromians see hypomelanosis of Ito incubators, neonatal intensive care unit 5.4 indeterminate cell histiocytosis (ICH) 103.11, 103.13, 103.14 indoor air pollution, atopic dermatitis and 22.12 infant(s) acute haemorrhagic oedema (AHO) of skin 161.1–161.4 dystrophic epidermolysis bullosa 118.18–118.19 pedal papules 7.4–7.5 skin anatomy 3.1 skin care 5.5–5.8 sunscreen recommendations 108.15 surgical treatment 186.1 infant feeding atopic dermatitis and 22.9–22.10 dystrophic epidermolysis bullosa 118.22, 118.22–118.24 food allergies and 31.7–31.8 infantile acropustulosis (IA) 88.1–88.3 clinical features 87.9, 88.1, 88.2 differential diagnosis 88.2–88.3 erythema toxicum neonatorum 6.7, 88.2–88.3 pompholyx 39.3, 88.2 scabies 72.7, 72.8, 88.2 infantile (desmoid-type) fibromatosis 97.8–97.9 infantile fibrosarcoma 97.14–97.16, 97.15 infantile haemangiomas see haemangiomas, infantile infantile perineal (perianal) protrusion 10.10, 151.18, 151.18 infantile seborrhoeic dermatitis see seborrhoeic dermatitis, infantile infantile spasms, tuberous sclerosis 129.4, 129.5, 129.10–129.11 infantile systemic hyalinosis 97.16–97.17 Infants’ Dermatitis Quality of Life Index (IDQOL) 29.11–29.13, 29.13, 179.2 infarctions digital, systemic lupus erythematosus 175.6, 175.6 polyarteritis nodosa 167.9, 167.9 infection control, at day-care centres 21.2 infections anetoderma aetiology 145.12 Chédiak–Higashi syndrome 177.6 complement deficiencies 177.19, 177.20 cutaneous see skin infections dystrophic calcification after 95.7 erythema nodosum aetiology 77.2, 77.3 etanercept-treated patients 182.4 Henoch–Schönlein purpura aetiology 160.2 hypohidrotic ectodermal dysplasia with immunodeficiency 127.71 infliximab-treated patients 182.6 insulin injection site 172.23 juvenile dermatomyositis pathogenesis 175.10 lichen striatus aetiology 86.2 morphoea aetiology 173.1 nails 150.3 Netherton syndrome 124.5–124.6 oral ulceration/stomatitis 147.4–147.7

36

Index

infections (cont.) pityriasis rubra pilaris aetiology 83.1–83.2 polyarteritis nodosa aetiology 167.9 psoriasis pathogenesis 81.2 sarcoidosis aetiology 158.2 sexually transmitted 153.1–153.23 tongue involvement 147.24 urticaria aetiology 74.2–74.3 UV-induced susceptibility 108.8 vulvovaginitis 152.2 Wiskott–Aldrich syndrome 177.33 infectious mononucleosis (IM) 49.14–49.16 clinical features 49.15, 49.15 cytomegalovirus (CMV) 49.15 oral lesions 147.6 infective dermatitis (ID) (HTLV-1 infection) 53.1–53.4 clinical features 53.1, 53.3, 53.4 diagnosis 53.1–53.4, 53.2 differential diagnosis 28.9, 53.4 pathophysiology 53.1, 53.2 infective panniculitis 77.12 inflammation acne vulgaris 79.5, 79.6 wound healing 17.1 inflammatory bowel disease (IBD) 157.1 isotretinoin and 79.9 linear IgA disease and 89.3 see also Crohn disease; ulcerative colitis inflammatory lesions, focal dermal hypoplasia 133.1, 133.5 inflammatory linear verrucous epidermal naevus (ILVEN) 110.16–110.18 clinical features 110.16, 110.17 differential diagnosis 110.17, 110.17–110.18, 154.10 genital area 151.5–151.6 laser treatment 188.10, 189.6 management 110.18 inflammatory mediators, in atopic dermatitis 25.2–25.5 drugs acting on 25.9–25.10 intradermal effects 25.3–25.4 in vitro studies 25.2–25.3 in vivo measurement 25.3 inflammatory skin diseases adnexa 94.1–94.4 genital region 151.2–151.5 histopathology 4.6–4.7 HIV infection 52.4–52.5 hyperpigmentation 104.4, 104.5 hypopigmentation 104.1 laser treatment 188.10 napkin area 20.7–20.10 patient advocacy group 179.7 vesiculobullous lesions 87.5, 87.8 infliximab 181.17, 182.4–182.6 Crohn disease 182.5 doses 182.5 efficacy 182.5–182.6 juvenile idiopathic arthritis 175.4, 182.5–182.6 Kawasaki disease 168.9 pharmacokinetics 182.5 pityriasis rubra pilaris 83.7 psoriasis 82.5, 182.5 side-effects 182.6 infraorbital folds, atopic dermatitis 28.5, 28.5, 28.15 infrared-A, water-filtered (wIRA) 47.9 infrared radiation 108.2, 108.2, 108.2 ingrown nails 150.2–150.3 inhalant allergens see aeroallergens inheritance autosomal dominant 115.1, 115.2–115.3 autosomal recessive 115.3, 115.3 epigenetic 115.7 Mendelian 115.2–115.4 exceptions and variations 115.4–115.7 mitochondrial 115.5 paradominant 115.5–115.6, 115.6 polygenic 115.1, 115.7

semi-dominant 115.5 X-linked 115.3, 115.3–115.4, 115.4 Y-linked 115.4, 115.4 inherited skin disorders see genetic skin disorders INI1/SMARCB1 gene 128.14 ink spot lentigo 109.11, 109.11 innate immunity receptor genes, atopic dermatitis 23.13–23.14 inner root sheath, development 2.36, 2.37, 2.38 inosine pranobex, warts 47.9 insect(s) biting behaviour 71.7 feeding on blood 71.1–71.2 noxious and venomous 73.1–73.4 stings, vesiculobullous lesions 87.9 see also arthropod(s); specific types insect bites 71.1–71.8, 73.1, 73.3–73.4 diagnostic features 71.6, 71.6–71.7, 71.7, 73.1 differential diagnosis 28.10, 71.8 immunopathology 71.3, 71.3–71.5, 71.4, 71.5 pigmentation changes after 104.5 prognosis 71.7–71.8 reactions 71.2–71.3 treatment 71.8, 73.1 vesiculobullous lesions 87.9 see also flea bites insecticide-impregnated mosquito nets 71.3 insecticides bed bugs 73.4 poisoning 184.13 insect repellents 71.8, 73.1, 181.12 INSR gene mutations 141.17 insulin acne pathogenesis 79.2–79.3, 79.3, 79.4 adverse reactions to therapy 172.22–172.23 allergies 172.22, 172.23 deficiency 172.20 injection sites infections 172.23 localized fat hypertrophy 141.4, 172.22, 172.22–172.23 local side-effects 172.22–172.23 lipoatrophy 141.13, 172.23, 172.23 insulin-like growth factor-1 (IGF-1) acne pathogenesis 79.2–79.3, 79.3, 79.4, 79.4 treatment, acne complicating 79.16 insulin-like growth factor-1 receptor (IGF1R), acne pathogenesis 79.2, 79.4, 79.4 insulin-like growth factor-2 (IGF-2) gene 137.7 insulin receptors acne pathogenesis 79.2, 79.3 antibodies 172.17, 172.17 gene mutations 141.17–141.18 primary defects 172.17, 172.17 insulin resistance (IR) 172.17–172.20 acne 79.2, 79.3, 79.3 associated conditions 172.17 clinical features 172.18, 172.18–172.19 diabetes mellitus 172.20 endocrine disorders and acne 79.16, 79.16–79.17 hair loss 148.21–148.22 hyperandrogenaemia (HA) 172.14, 172.15, 172.18 monitoring 79.17 treatment 172.19 type A 172.17, 172.18 type B 172.17, 172.19 insulin-sensitizing agents, acne 79.10 integrin α6β4 antibodies 91.18 intensive care neonatal see neonatal intensive care toxic epidermal necrolysis 192.13–192.19, 192.18 interferon-α 181.18 aggressive systemic mastocytosis 75.12 angiolymphoid hyperplasia with eosinophilia 98.2 induced hypertrichosis 148.32

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

infantile haemangioma 113.17–113.18 Kasabach–Merritt phenomenon 113.26 neurological complications 113.17–113.18 polyarteritis nodosa 167.11–167.12 solitary fibrous tumour/haemangiopericytoma 99.9 tufted angioma 113.24 warts 47.9 interferon-β1, intralesional, granuloma annulare 93.8 interferon-γ (IFN-γ) atopic dermatitis pathogenesis 24.2, 24.4, 25.5 inherited defects 177.11 lichen planus pathogenesis 85.2 therapy chronic granulomatous disease 177.12 granuloma annulare 93.8 hyper-IgE syndrome 177.24 interferon-gamma release assays (IGRA) 57.4, 57.6 interleukin-1 (IL-1) acne 79.2, 79.4, 79.4 atopic dermatitis 24.3 Blau syndrome 158.7 interleukin-2 (IL-2) receptors, atopic dermatitis 25.5, 33.1 interleukin-4 (IL-4), atopic dermatitis 25.5 increased production 24.2, 24.3–24.4, 25.5 regulatory factors 25.8 Staphylococcus aureus interaction 24.6, 24.7 interleukin-5 (IL-5) atopic dermatitis 24.1, 24.2, 24.3–24.4, 25.5 hypereosinophilic disorders 36.7, 36.9 interleukin-7 receptor (IL7R) deficiency 11.8, 177.30 interleukin-8 (IL-8) acne vulgaris 79.5 atopic dermatitis 24.3, 26.3 interleukin-10 (IL-10), atopic dermatitis 24.7, 25.5 interleukin-12 (IL-12) atopic dermatitis 24.4 inherited defects 177.11 interleukin-13 (IL-13), atopic dermatitis 24.1, 24.2, 24.3–24.4, 24.7, 25.5 interleukin-16 (IL-16), atopic dermatitis 25.5 interleukin-17 (IL-17), atopic dermatitis 24.4 interleukin-31 (IL-31), atopic dermatitis 24.4 intermediate filaments (IF) 117.1, 117.2, 127.95 epidermal basement membrane zone 91.14, 91.14 see also keratin intermediate filaments intermediate-layer cells embryonic-fetal transition 2.13, 2.13, 2.14 fetal period 2.19, 2.20, 2.20 internal transcribed spacer (ITS) sequencing, dermatophytes 62.13–62.14 International League of Associations for Rheumatology (ILAR), juvenile idiopathic arthritis classification 175.1, 175.2 International Society of Pediatric Dermatology 1.2 International Study of Asthma and Allergies in Childhood (ISAAC) 28.17–28.18, 28.18 International Symposium of Paediatric Dermatology, first (1972) 1.2, 1.2, 1.4 intertrigo napkin dermatitis 20.2, 20.2–20.3 obesity 65.10 seborrhoeic 41.3 secondary Candida infection 20.3, 54.7 streptococcal 20.6, 20.6, 54.7 vs. infantile seborrhoeic dermatitis 35.6 intoxication see poisoning intracytoplasmic sperm injection (ICSI) 139.10 intradermal (or dermal) naevi acquired 4.2, 4.2, 109.13, 109.13, 109.14 congenital 109.2, 109.3 intradermal testing drug hypersensitivity 183.13, 183.14 plant/plant products 45.4

Index Intrasite Conformable® dressings, epidermolysis bullosa 118.8, 118.32 intrauterine infections, neonatal scarring lesions 16.6 intravascular large B-cell lymphoma 99.27, 102.15 intravenous immunoglobulin (IVIG) 181.18 hyper-IgE syndrome 177.24 Kawasaki disease 168.8–168.9 neonatal lupus erythematosus prophylaxis 14.10 pemphigus vulgaris 91.5 Stevens–Johnson syndrome/toxic epidermal necrolysis 78.7 inversions, chromosome 116.4–116.5 involucrin atopic dermatitis 27.9 periderm cells 2.24, 2.26 iodine toxicity 17.7, 184.6–184.7 Io moth caterpillar 73.4 ionizing radiation 108.2, 108.2 iontophoresis epidermolysis bullosa simplex 118.8 local anaesthetics 190.5 IPEX syndrome 177.2, 177.28 IRAK4 deficiency 177.2, 177.11, 177.23 IRAK gene mutations 127.66 IRF6 gene mutations 10.7 iris heterochromia, neuroblastoma 99.11 iron deficiency, dystrophic epidermolysis bullosa 118.16, 118.26 supplements, epidermolysis bullosa 118.26 irritant contact dermatitis (ICD) allergic contact dermatitis and 44.1 differential diagnosis 28.10, 44.4 genital region 151.2, 151.3 irritants atopic dermatitis and 22.10 napkin dermatitis 19.2 plant 45.1–45.3, 45.2 vulvovaginitis 152.3 irritation, sunscreen-induced 108.16 ISAAC (International Study of Asthma and Allergies in Childhood) 28.17–28.18, 28.18 ischaemia, critical limb management 162.12–162.14 purpura fulminans 162.8, 162.10 isocoproporphyrin 107.5, 107.6 isoflurane 190.9 Iso–Kikuchi syndrome 150.8, 150.8 isoleucine supplements 169.7, 169.8 isoniazid 57.4 isopropanol toxicity 184.4 isopropyl alcohol toxicity to newborn 5.7, 17.7 umbilicus care 5.2 isotretinoin (Roaccutane®) 181.18 acne 79.9, 79.10, 79.17 cystic fibrosis patients 170.4 adverse effects 79.9, 121.67–121.68, 181.18 Gorlin syndrome 132.15 granuloma annulare 93.8 MEDOC 121.67 monitoring therapy 192.16 perioral dermatitis 38.3 pityriasis rubra pilaris 83.6 prurigo pigmentosa 42.7 teratogenicity 79.9, 181.18 topical, acne 79.7–79.8 xeroderma pigmentosum 135.11 itching see pruritus itching powder 45.1–45.2 itching purpura 165.5 itch–scratch cycle, atopic dermatitis disease evolution 24.6 interventions 30.5, 30.9, 34.5 ITGA6 gene mutations 118.30 ITGB2 gene mutations 177.11, 177.28 ITGB4 gene mutations 117.3, 118.30 Itin syndrome 148.11

Ito disease see hypomelanosis of Ito; pigmentary mosaicism Ito lines (pigmentary demarcation lines) 104.9 ITPKC gene polymorphism 168.2, 168.5 itraconazole 62.15, 181.16 atopic dermatitis 26.7–26.8 chronic granulomatous disease 177.12 dermatophytoses 62.16 onychomycosis 62.17 sporotrichosis 63.19 ivermectin 181.9 cutaneous larva migrans 68.4 lice 72.12 scabies 72.7 ivy (Hedera helix) 45.7, 45.7 Ixodes pacificus 59.1 Ixodes persulcatus 59.1, 59.3 Ixodes ricinus lifecycle 59.2, 59.2 transmission of Lyme borreliosis 59.1, 59.2–59.3 Ixodes scapularis 59.1, 59.3 Ixodid ticks bites 59.3–59.4, 71.4–71.5 biting behaviour 59.2, 71.7 infections transmitted 59.10 lifecycle 59.2, 59.2 Lyme disease transmission 59.1–59.3 Rocky Mountain fever transmission 61.1 Jackson–Lawler syndrome (PC-2) 127.96 clinical features 120.20, 127.50 molecular pathogenesis 115.24, 120.19 Jacquet dermatitis 20.2, 20.4, 21.2, 152.3, 152.3 Jadassohn–Lewandowsky syndrome (PC-1) 127.96 clinical features 120.20, 127.49 molecular pathogenesis 115.24, 120.19 pathology 120.19–120.20 JAK3 deficiency 177.30, 177.30 Janus kinases (JAKs) 177.22 Japan, paediatric dermatology in 1.4 Japanese lacquer tree 45.5, 45.6 Japanese Society for Pediatric Dermatology 1.3, 1.4 Japanese spotted fever (Rickettsia japonica) 61.2, 61.5–61.6 jaw cysts, Gorlin syndrome 132.7, 132.7 histopathology 132.4 surveillance 132.14 treatment 132.16 jellyfish stings 73.7, 73.8 Jenner, Edward 51.8 Jessner’s lymphocytic infiltrate (JLI) 101.1–101.3 clinical features 101.1–101.2, 101.2 histopathology 101.1, 101.2 Job syndrome 177.22 Johanson–Blizzard syndrome 127.39, 127.68 Johnson neuroectodermal syndrome 127.5 joint hypermobility Beighton scoring system 142.5, 142.6 Ehlers–Danlos syndrome 142.5, 142.6, 142.7, 142.9, 142.12 Marfan syndrome 145.5–145.6 Rothmund–Thomson syndrome 136.3, 136.3 joint mobility, limited, diabetes mellitus 172.21, 172.21 joint pain/inflammation see arthralgia/arthritis Jorgenson syndrome 127.35 Journal of Pediatric Dermatology 1.3 journals, paediatric dermatology 1.3 juglone 45.2 junctional epidermolysis bullosa (JEB) 118.1, 118.29–118.33 aetiology and pathogenesis 118.30 cleavage plane 118.2 clinical features 118.30–118.32, 118.32 gene therapy 139.2, 140.9, 140.10, 140.11, 140.15 Herlitz 115.22, 118.30–118.31, 118.31, 118.32 localisata 115.22

37

molecular pathology 118.3 nail abnormalities 118.31, 150.9 non-Herlitz 118.30, 118.31, 118.32, 118.32 pathology 118.30 preimplantation genetic diagnosis 139.10–139.11 prenatal diagnosis 139.3, 139.4, 139.7, 139.7–139.8, 139.8, 139.9 prognosis 118.32 protein therapy 140.17 with pyloric atresia (JEB-PA) 115.22, 118.30, 118.31–118.32 revertant mosaicism 115.17 treatment 118.32–118.33 see also generalized atrophic benign epidermolysis bullosa junctional naevi acquired 4.2, 109.13, 109.13 congenital 4.2, 109.3 JUP gene mutations 127.99 juvenile chronic arthritis see juvenile idiopathic arthritis juvenile dermatomyositis (JDM) 175.9–175.12 calcinosis 95.5–95.6, 95.6, 175.11, 175.12 clinical features 175.10, 175.10–175.11 diagnostic criteria 175.10 differential diagnosis 175.10 hypertrichosis 148.30 panniculitis 77.10 juvenile hyalinosis 97.17–97.19, 97.18 clinical features 97.18, 97.18–97.19 pathology 97.17, 97.17–97.18, 97.18 juvenile idiopathic arthritis (JIA) 175.1–175.5 classification 175.1, 175.2 clinical features 175.2–175.4, 175.3 differential diagnosis 175.2 pathogenesis 175.1–175.2 systemic (sJIA) 175.2, 175.2–175.3 treatment 175.2–175.3, 175.4 abatacept 175.4, 182.12 adalimumab 175.4, 182.6–182.7 etanercept 175.4, 182.2–182.3, 182.4 infliximab 175.4, 182.5–182.6 urticaria 74.7, 74.7 juvenile macular dystrophy hypotrichosis with 115.24, 127.14, 127.100 Sjögren–Larsson syndrome 121.47 juvenile myelomonocytic leukaemia 128.4 juvenile plantar dermatosis (JPD) 43.1–43.2, 43.2 juvenile polyposis-haemorrhagic telangiectasia (JP-HT) 112.5 juvenile rheumatoid arthritis see juvenile idiopathic arthritis juvenile spring eruption (JSE) 106.9, 106.9–106.10 juvenile systemic granulomatosis see Blau syndrome juvenile temporal arteritis (JTA) 36.7 juvenile xanthogranuloma (JXG) adult form (AXG) 103.10, 103.13, 103.14 clinical features 103.9, 103.9–103.10 neurofibromatosis 1 association 128.4 pathology 4.3, 103.13, 103.13 systemic 103.11 Kabuki make-up syndrome, dermatoglyphic patterns 10.22 KAL1 gene defects, recessive X-linked ichthyosis with 121.11, 121.12 kala-azar see visceral leishmaniasis kallikrein-related peptidases (KLK) 27.3–27.4, 27.5 atopic dermatitis 27.11 in different body sites 27.8 Netherton syndrome and 121.58, 124.2 skin barrier homeostasis 27.6 Kallman syndrome, recessive X-linked ichthyosis 121.11, 121.12 Kamino bodies 109.15, 109.15

38

Index

kaposiform haemangio-endothelioma (KHE) 113.24 histopathology 4.5, 4.6, 113.24 Kasabach–Merritt phenomenon 113.24–113.26 Kaposi sarcoma (KS) 49.17–49.18 AIDS-related 52.1, 52.5 intraoral 147.15 lymphatic origin 114.21 lymphoedema 114.13 vs. bacillary angiomatosis 58.4 Kaposi’s varicelliform eruption see eczema herpeticum karyotypic chromosome analysis 116.1–116.2 Kasabach–Merritt phenomenon (KMP) 113.24–113.26 clinical features 113.25, 113.25 differential diagnosis 112.9, 113.25–113.26 management 113.26 Kathon CG allergy 44.3 Kawasaki, Tomisaku 1.3 Kawasaki disease (KD) 168.1–168.10 aetiology and pathogenesis 168.1–168.2 cardiovascular and other complications 168.6–168.8, 168.7, 168.9, 168.10 clinical features 168.2, 168.2–168.5, 168.3, 168.4 diagnosis 168.2, 168.2–168.5 differential diagnosis 168.5–168.6 measles 49.3 papular-purpuric gloves and socks syndrome 49.9 toxic shock syndrome 54.9 epidemiology 168.1 incomplete (atypical) 168.6, 168.6 laboratory findings 168.6 management 168.8–168.10 pathology 168.8, 168.9 perineal eruption 20.9–20.10, 168.3 polyarteritis nodosa and 167.8 prognosis 168.10 KCNQ1OT1 gene 137.7 keloidal blastomycosis see lobomycosis keloids 187.3–187.7 acne conglobata 79.7 aetiology 187.3–187.5 chromosome disorders 116.10–116.11 clinical features 187.3, 187.8 laser treatment 188.10, 189.9 treatment 187.5–187.7 keratin(s) 117.1–117.2, 117.2, 127.95 acidic 117.1 basic/neutral 117.1 developing hair follicles 2.35, 2.36, 2.38, 2.38 differentiation-specific expression 117.2, 117.2, 127.95 embryonic-fetal transition 2.13–2.14, 2.14 embryonic skin 2.4, 2.5, 2.7 hard 117.1 heptad motif 117.1, 121.19–121.20 periderm 2.24 soft 117.1 structure 117.1, 117.2, 121.19–121.20 tissue-specific distribution 127.95 keratin 1 (K1) 117.2 embryonic-fetal transition 2.13–2.14, 2.14 mosaic defects 110.12, 117.4–117.6 mutations see KRT1 gene mutations keratin 2 (KRT2) gene mutations 117.4–117.6, 121.22 keratin 4 (KRT4) gene mutations 117.6–117.7 keratin 5 (K5) 127.95 deficiency 117.3 embryonic epidermis 2.4 embryonic-fetal transition 2.13–2.14 gene mutations see KRT5 gene mutations haploinsufficiency 117.4 keratin 6 gene mutations see KRT6 gene mutations keratin 8 (K8) 127.95 embryonic epidermis 2.4, 2.7 gene mutations (KRT8) 117.8 keratin 9 120.3

keratin 10 (K10) embryonic epidermis 2.7 embryonic-fetal transition 2.13–2.14, 2.14 mosaic defects 110.2, 110.12, 117.4 mutations see KRT10 gene mutations keratin 13 (KRT13) gene mutations 117.6–117.7 keratin 14 (K14) 127.95 deficiency 117.3 embryonic epidermis 2.4 embryonic-fetal transition 2.13–2.14 gene mutations see KRT14 gene mutations haploinsufficiency 117.4 keratin 16 (KRT16) gene mutations 120.19, 127.96 keratin 18 (K18) 127.95 embryonic epidermis 2.4, 2.7 embryonic-fetal transition 2.16 keratin 18, gene mutations (KRT18) 117.8 keratin 19 (K19), embryonic epidermis 2.4 keratin 20 (K20), embryonic epidermis 2.7 keratin disorders 117.3, 117.3–117.8 ectodermal dysplasias 127.95–127.97 keratinopathic ichthyoses 121.17 pathogenic mechanisms 117.2, 121.3–121.4, 121.19–121.20 keratin intermediate filaments (KIF) 117.1, 121.20 embryonic 2.4, 2.5 epidermolytic ichthyosis 121.20 fetal 2.19, 2.20 network 117.1, 117.2 keratinization 117.1 developing skin 2.27–2.28 follicular, fetal skin 2.28, 2.38, 2.39 hereditary disorders of 115.20–115.21 interfollicular, fetal skin 2.19–2.20, 2.21, 2.28 keratinocytes atopic dermatitis 24.4, 26.2 cultured, skin grafting 140.16, 187.14–187.15, 187.15 differentiation-specific expression of keratins 117.2, 117.2 embryonic 2.4 embryonic-fetal transition 2.13, 2.13–2.14 epidermal structure 27.1–27.3, 27.2 fetal 2.19–2.20 as gene therapy target 140.1–140.2 genetically engineered, therapies using 140.17–140.18 melanosome transfer 138.1 necrosis, graft-versus-host disease 178.3, 178.3, 178.4 sunburn-damaged 108.6 terminal differentiation 27.1, 27.6 therapeutic gene transfer 140.6 vitiligo 105.1 keratinocytic epidermal naevi 110.8–110.11 associated syndromes 110.10–110.11, 110.20 clinical features 110.8, 110.8–110.10, 110.9, 110.10 keratinopathic ichthyoses 121.17 keratitis herpes 48.5 interstitial, congenital syphilis 153.5 smallpox 51.5 keratitis-ichthyosis-deafness (KID) syndrome 122.1–122.7, 122.4, 127.40, 127.91–127.92 cancer susceptibility 137.2 clinical features 121.45, 122.2–122.6, 122.6, 127.91–127.92 differential diagnosis 122.6–122.7, 127.92 genetic basis 115.21, 120.21, 122.2, 122.2, 127.89 hair loss 122.2, 127.91, 148.8 management 121.64, 127.92 naevus 110.13 keratoacanthomas 47.5 keratoderma(s) 120.1–120.26 acral 120.25 palmoplantar see palmoplantar keratoderma use of term 120.1

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

keratodermic ichthyoses 121.2, 121.17–121.24 keratohyalin granules developing eccrine sweat glands 2.31, 2.33 fetal epidermis 2.20, 2.21 ichthyosis vulgaris 121.9 profilaggrin 23.7, 23.8 stratum granulosum 27.1, 27.2 keratolytics 181.13 ichthyoses/MEDOC 121.63, 121.66 molluscum contagiosum 46.5 warts 47.8 keratolytic winter erythema 122.3 keratosis, traumatic/frictional 147.11 keratosis follicularis see Darier disease keratosis follicularis spinulosa decalvans (KFSD) 123.1 aetiology and pathogenesis 123.1 alopecia 148.7, 148.22–148.23 clinical features 123.3, 123.3, 123.4 differential diagnosis 121.56 keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK syndrome) 120.7, 120.7–120.8 keratosis palmaris et plantaris with oesophageal carcinoma see Howel–Evans syndrome keratosis palmoplantaris areata et striata (striate palmoplantar keratoderma) 120.15–120.16 clinical features 120.16, 120.16 molecular pathology 115.21, 120.15–120.16 type I 120.15, 127.40, 127.100 type II 120.15–120.16, 127.40, 127.99 type III 120.16, 127.40, 127.97 see also Carvajal syndrome keratosis palmoplantaris nummularis 120.17 keratosis palmoplantaris papillomatosa et verrucosa Jakac–Wolf 120.25–120.26 keratosis palmoplantaris punctata 120.23, 120.24 keratosis palmoplantaris striata see keratosis palmoplantaris areata et striata keratosis palmoplantaris with periodontopathia see Papillon–Lefèvre syndrome keratosis palmoplantaris with periodontopathia and onychogryphosis see Haim–Munk syndrome keratosis pilaris 123.1–123.4 associated disorders and syndromes 123.2, 123.2 chromosome disorders 116.11 clinical features 123.2, 123.2 differential diagnosis 123.4 ichthyosis vulgaris 121.8 prognosis 123.4 treatment 123.4, 189.9 keratosis pilaris atrophicans 123.1, 148.22–148.23 associated disorders and syndromes 123.1, 123.2, 123.2 clinical features 123.2, 123.2–123.3, 123.3 differential diagnosis 16.6, 123.4 treatment 123.4 keratosis pilaris atrophicans faciei (ulerythema ophryogenes) 123.1 clinical features 123.2, 123.2–123.3 keratosis pilaris atrophicus 123.1 keratosis pilaris rubra faciei 123.2 keratosis (lichen) spinulosa, keratosis pilaris 123.2 kerion hair loss 148.23 tinea capitis 62.6, 62.8 ketamine 190.8 ketoconazole 181.16 atopic dermatitis 26.7 shampoo 41.4, 62.15 ketotic hyperglycinaemia syndromes 169.7 ketotifen, mastocytosis 75.12 Ki-67, pilomatrix carcinoma 99.4 kidney malformations, Gorlin syndrome 132.11 KID syndrome see keratitis-ichthyosis-deafness (KID) syndrome Kimura disease 98.1, 98.2 Kindler syndrome 118.34, 119.1–119.3

Index clinical features 119.1–119.2, 119.2 diagnostic criteria 119.2 differential diagnosis 119.2, 136.4, 136.4 genetic basis 115.22, 118.3, 118.34, 119.1 loss of dermatoglyphics 10.21 treatment 119.2–119.3 vesiculobullous lesions 87.7 Kindler–Weary syndrome 119.2 kindlins 119.1 kinking of hair, acquired progressive 148.17 kinky hair disease see Menkes syndrome Kirghizian dermato-osteolysis 127.41 KIT (c-kit) gene mutations mastocytosis 75.3–75.5, 75.5, 104.6 other diseases 75.4 piebaldism 138.4–138.5 therapies targeting 75.12 KIT ligand (KITLG) gene polymorphism 138.5 c-KIT protein 75.3–75.4, 75.4, 138.5 mastocytosis pathogenesis 75.4, 75.5 kiwi allergy 31.6 Klein–Waardenburg syndrome 138.6 KL gene mutations 95.4 KLICK syndrome 120.7, 120.7–120.8 Kligman’s solution 104.7 Klinefelter syndrome 116.10 incontinentia pigmenti 130.1, 130.2 vascular abnormalities 116.13 XXYY variant see XXYY syndrome Klippel–Trenaunay syndrome (KTS) 112.16–112.17 differential diagnosis 111.8, 112.17 epidermal naevi with 110.20 genital area 151.6–151.7 lymphatic disorders 114.10 patient advocacy group 179.7 KLK see kallikrein-related peptidases knuckle pads 96.1–96.3 clinical features 96.2, 96.2 differential diagnosis 96.2, 96.3 familial 96.1, 96.2, 96.2 pathology 96.1, 96.2 Koebner phenomenon atopic dermatitis 28.4 lichen nitidus (LN) 85.15, 85.16 lichen planus 85.4, 85.4 napkin dermatitis 20.9 plane warts 47.4, 47.4 pseudo-xanthoma elasticum 144.4–144.5 psoriasis 80.4–80.5, 80.5 vitiligo 105.4 Koenen’s tumours see periungual fibromas, tuberous sclerosis KOH see potassium hydroxide Kohlschutter–Tonz syndrome 127.7 koilonychia, transitory 150.2 Koplik’s spots 147.11 differential diagnosis 49.3 erythema infectiosum 49.5 measles 49.2, 49.2 kRAS gene 114.8 Kresse syndrome see Ehlers–Danlos syndrome (EDS), progeroid KRIT1 mutations 112.11–112.12 KRT gene mutations 117.3, 117.3–117.8 KRT1 gene mutations epidermolytic ichthyosis 11.4, 117.4–117.6, 121.17 pathogenesis 121.19–121.20 phenotype 117.5, 121.18, 121.19, 121.20 ichthyosis hystrix of Curth–Macklin 121.21, 121.23 keratosis palmoplantaris striata 120.16 mosaic, epidermolytic epidermal naevi 110.12, 117.4–117.6, 121.19 KRT2 gene mutations 117.4–117.6, 121.22 KRT4 gene mutations 117.6–117.7 KRT5 gene mutations Dowling–Degos disease 117.4, 127.95, 138.11 epidermolysis bullosa simplex 117.3, 118.4, 118.9, 127.95

KRT6 gene mutations 120.19, 127.96 gene knockdown approach 140.13 KRT8 gene mutations 117.8 KRT9 gene mutations 120.3 KRT10 gene mutations epidermolytic ichthyosis 11.4, 117.4–117.6, 121.17 pathogenesis 121.19–121.20 phenotype 121.18, 121.19, 121.20 retinoid therapy 121.21, 121.22 mosaic, epidermolytic epidermal naevi 110.2, 110.12, 117.4, 121.19 KRT13 gene mutations 117.6–117.7 KRT14 gene mutations epidermolysis bullosa simplex 118.4, 118.9, 127.95 Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis 117.3–117.4, 127.97, 138.9–138.11 KRT16 gene mutations 120.19, 127.96 KRT17 gene mutations 120.19, 127.96 KRT18 gene mutations 117.8 KRT75 gene polymorphism 117.7–117.8 KRT81 gene mutations 117.7 KRT83 (hHb3) gene mutations 117.7, 127.96 KRT85 (KRTHB5) gene mutations 117.7, 127.96 KRT86 (hHb6) gene mutations 117.7, 127.96 KTP lasers, pigmented lesions 189.5 kwashiorkor 65.1 cutaneous manifestations 65.2, 65.2–65.3, 65.3 hair abnormalities 65.2–65.3, 65.3, 148.20, 148.21 pigmentation changes 104.1, 104.8 kyphoscoliosis, Ehlers–Danlos syndrome 142.12, 142.13 labial fusion/adhesions 151.17, 151.17 differential diagnosis 151.17, 155.5 lichen sclerosus 152.6 labia majora 152.1 prepubertal unilateral fibrous hyperplasia 151.21 labia minora 152.1 agenesis 151.16 hypertrophy 151.16, 151.16 labour, fetal injuries during 17.3–17.5 α-lactalbumin/oleic acid, topical 47.9 lactic acid toxicity 184.7 LAD285 89.6 Lag monoclonal antibody 103.5 lagophthalmos, cicatricial, lamellar ichthyosis 121.32 LAMA3 gene mutations 118.30, 139.10–139.11 LAMB3 gene mutations 118.30 preimplantation genetic testing 139.10–139.11 therapy 139.2, 140.10, 140.11 LAMB acronym see Carney complex LAMC2 gene mutations 118.30 lamellar bodies (or granules) (LB) 27.1, 27.2, 27.2–27.3 atopic dermatitis 27.11 fetal skin 2.20, 2.21 inherited disorders 121.3 regulation of secretion 27.6 lamellar ichthyosis (LI) 121.25, 121.31–121.32 autosomal dominant 121.38 clinical features 121.25, 121.27, 121.31–121.32 collodion baby 12.1, 12.3 differential diagnosis 121.36–121.38 gene therapy 140.9 genetic basis 115.20, 115.24, 121.25–121.26, 121.32–121.36 management 121.38, 121.65, 121.67 pathology 121.32 prenatal diagnosis 139.3, 139.4 see also autosomal recessive congenital ichthyoses lamin A deficiency 15.1 gene mutations see LMNA gene mutations

39

lamina densa, embryonic skin 2.7, 2.7 laminin 5/epiligrin/kalinin embryonic skin 2.7–2.8 substitution therapy 140.17 laminin-332 118.30 see also anti-laminin-332 antibodies laminin γ1 chain antibodies 91.15 laminopathies 15.1, 134.1, 141.14 lamins 134.1 Langer–Giedion syndrome (trichorhinophalangeal syndrome type II) 127.61, 127.80–127.81 with facial hypertrichosis 116.16 molecular pathology 127.79 Langerhans cell histiocytosis (LCH) 103.1–103.8 classification 103.2–103.3 clinical features 103.3, 103.3–103.5 congenital 8.1, 8.2 disseminated, with haematological dysfunction (DLCH) 103.2, 103.4, 103.4 evaluation 103.5 genital area 151.20 napkin area 20.10–20.11, 20.11 oral involvement 147.19 pathogenesis 103.2 pathology 103.5, 103.5, 103.6 prognosis 103.6 progressive multifocal chronic (PMC-LCH) 103.2–103.3, 103.4 treatment 103.5–103.6 vs. infantile seborrhoeic dermatitis 35.3, 35.6 Langerhans cells (LC) atopic dermatitis 24.4, 25.5, 31.3 embryonic 2.6–2.7, 2.7 embryonic-fetal transition 2.15, 2.15 fetal 2.20 graft-versus-host disease 178.4, 178.5 langerin 103.4, 103.5 Langer’s lines 187.2, 187.3 lanolin allergy 44.3, 44.4, 44.11 premature neonate skin care 5.5 lansoprazole, dystrophic epidermolysis bullosa 118.24 lanugo hair 148.1 development 2.36, 2.37, 2.38, 2.38 diazoxide-induced growth 148.30 persistent excess 148.28–148.29 La (SSB) ribonucleoprotein 14.3 see also anti-La/SSB antibodies larva currens 68.3 larva migrans, cutaneous see cutaneous larva migrans laryngeal involvement epidermolysis bullosa simplex 118.7, 118.9 hereditary angioedema 177.18 junctional epidermolysis bullosa 118.30, 118.31, 118.33 see also respiratory tract involvement laryngeal masks 190.9 laryngo-onychocutaneous (LOC) syndrome 118.30, 118.32 laser Doppler flowmetry (LDF), morphoea 173.8 lasers history 188.1 safe use 189.1 vascular 188.1–188.3, 188.2 development 188.1 mechanism of action 188.1–188.2 newer generation 188.3, 188.3 vascular pulsed-dye 188.2–188.3 laser treatment 189.1–189.10 ablative 186.2 acanthosis nigricans 189.8 acne scarring 188.10, 189.8–189.9 anaesthesia 188.2–188.3, 189.2 angioma serpiginosum 188.10 Becker naevus 104.13, 189.5 burns and burn scars 189.9 capillary malformations (port-wine stains) 112.15, 188.4–188.6

40

Index

laser treatment (cont.) procedure 188.3, 188.4, 188.4–188.6 results 188.4, 188.5, 188.6 chronic inflammatory skin conditions 188.10, 188.11 congenital melanocytic naevi 109.8, 189.6–189.7 cutis marmorata telangiectatica congenita 188.10 eczema 188.10, 188.11 facial angiofibromatosis 129.12 focal dermal hypoplasia (Goltz syndrome) 133.7–133.8, 188.10 hair removal 148.33, 189.3–189.4 hypertrophic and keloid scars 188.10, 189.9 infantile haemangiomas 113.18, 188.7–188.8 early proliferative stage 188.7, 188.7–188.8 post-involution telangiectasia 188.8 ulcerated lesions 188.8, 188.8 inflammatory epidermal naevi 188.10 keratosis pilaris 189.9 lymphatic malformations 112.14 mastocytoma 189.9 melasma 104.7 molluscum contagiosum 46.5, 189.9 naevus sebaceus 189.9 neurofibromas 189.9 perioperative management 189.2 pigmented lesions 189.4–189.7 porokeratosis 126.5 postoperative management 189.2 preoperative management 189.1–189.2 psoriasis 82.6, 188.10 sarcoidosis 158.5 striae 146.4, 189.10 telangiectasia 188.9, 188.9 vascular lesions 188.1–188.11 vitiligo 105.7, 189.10 warts 47.8, 189.7–189.8 Lassar’s paste 192.4 latex allergy 45.4, 74.4–74.5 Latin America, paediatric dermatology 1.3, 1.4 Latin American Society for Pediatric Dermatology (SLADP) 1.4 Latrodectus (widow spiders) 73.5, 73.5–73.6 Laurence–Moon–Bardet–Biedel syndrome 172.19 Lawrence syndrome 141.19 laxity, skin see skin laxity learning disabilities (mental retardation) autosomal recessive cutis laxa type II 134.13, 143.3 Cockayne syndrome 135.16 Gorlin syndrome 132.5 incontinentia pigmenti 130.5 mucopolysaccharidoses 169.12 neurofibromatosis 1 128.6 self-injurious behaviour 180.6 self-mutilation 180.10 Sjögren–Larsson syndrome 121.46 tuberous sclerosis 129.1, 129.4–129.5 X-linked 121.11, 121.12–121.13, 141.10 Ledderhose disease 97.9 left ventricular cardiomyopathy 127.99 Legius syndrome (NF1-like syndrome) 115.25, 128.7–128.8, 128.8 Leiner disease (Leiner–Moussous syndrome) 11.1, 35.4, 35.6, 124.6 Leiner phenotype 177.19, 177.20 leiomyomas cutaneous 137.13, 137.13 genital area 151.20 uterine 137.13 leiomyomatosis cutaneous 115.27 with renal cancer see hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome leiomyosarcomas 99.6 hereditary leiomyomatosis and renal cell cancer syndrome 137.13 HIV-related 52.5

Leishman–Donovan bodies 67.1 see also Leishmania, amastigotes Leishmania 67.2–67.3, 67.3 amastigotes 67.1, 67.2, 67.3 biopsy 67.4, 67.4, 67.6, 67.7 smears 67.10, 67.11 Leishmania subgenus 67.2, 67.3 promastigotes 67.2, 67.3 taxonomic classification 67.2, 67.3 Viannia subgenus 67.2, 67.3, 67.4–67.5, 67.7 Leishmania aethiopica 67.3, 67.7, 67.8 Leishmania amazonensis 67.3, 67.8, 67.9, 67.10 Leishmania braziliensis 67.2, 67.3 clinical features 67.6, 67.7–67.8 histopathology 67.4, 67.7 Leishmania chagasi 67.2, 67.3, 67.6, 67.9 Leishmania donovani 67.8, 67.9, 67.10 Leishmania guyanensis 67.7–67.8 Leishmania infantum 67.2, 67.3, 67.9 Leishmania major 67.4, 67.7, 67.10 Leishmania mexicana 67.3, 67.7, 67.8 pathology 67.4, 67.4 Leishmania panamensis 67.5, 67.7, 67.7–67.8 leishmaniasis 67.1–67.13 aetiology 67.2–67.3 clinical features 67.5 cutaneous (CL) 67.1, 67.5–67.9 diagnosis 67.10–67.11, 67.11 differential diagnosis 67.11–67.12, 67.12 diffuse (cutaneous) (DL; DCL) 67.8, 67.8 history 67.1–67.2 treatment 67.12–67.13 disease control 67.10 localized cutaneous (LCL) 67.5–67.7 clinical features 67.5, 67.5–67.7, 67.6, 67.7 diagnosis 67.10–67.11 differential diagnosis 67.11–67.12, 67.12 prognosis 67.13 treatment 67.12–67.13 vs. tropical ulcer 66.4 mucocutaneous (MCL) see mucocutaneous leishmaniasis New World 67.1, 67.2 Old World 67.1, 67.2 pathology 67.3–67.5, 67.4 post-kala-azar dermal (PKDL) 67.9–67.10 prognosis 67.13 recidivans (lupoid) 67.8, 67.8–67.9 treatment 67.12–67.13 Leishmania test 67.11, 67.11 Leishmania tropica 67.1, 67.4, 67.7, 67.8 leishmaniomas 67.9 leishmanization 67.10 LEKT1 27.4, 27.5 atopic dermatitis pathogenesis 27.11 gene see SPINK5 gene immunohistochemistry 124.6, 124.7 Netherton syndrome pathogenesis 11.5, 121.58, 124.1–124.2 LEKTI-2 27.4 Lelis syndrome 127.41 LEMD3 gene 116.13, 145.1, 145.2 Lenaerts’ syndrome 134.12 lenalidomide, Behçet disease 167.17 lentigines 109.11–109.12 associated syndromes 109.12 clinical features 109.11, 109.11 ink spot 109.11, 109.11 laser treatment 189.6 solar 108.7, 108.7 lentiginosis neonatorum 6.9 lentigo simplex, Peutz–Jeghers syndrome 137.16, 137.16 lentivirus vectors, gene therapy 140.3, 140.4 Lenz–Majewski syndrome 134.10–134.11 LEOPARD syndrome 109.12, 115.25, 128.8 tumour susceptibility 137.6 lepra bonita 70.7 lepra cells 70.4, 70.4 lepra reactions

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

treatment 70.12 type 1 70.10–70.11 type 2 70.11 LEPRE1 gene mutations 145.9 leprechaunism 141.17–141.18, 172.18 lepromin test 70.2 leprosy 70.1–70.12 aetiology and pathogenesis 70.1–70.2 borderline 70.6 histopathology 70.3 immune response 70.2 borderline lepromatous (BL) 70.6 borderline tuberculoid (BT) 70.5, 70.5–70.6, 70.6 classification 70.8–70.9 clinical features 70.4–70.7 complications 70.10–70.12 deformities and disabilities 70.12 diagnosis 70.7–70.8 differential diagnosis 70.8 dimorphous 70.6 epidemiology 70.1 eye complications 70.11–70.12 histoid 70.7 histopathology 70.3–70.4 immunology 70.2–70.3 immunoprophylaxis 70.10 immunotherapy 70.10 indeterminate 70.6–70.7, 70.7 histopathology 70.3 immune response 70.2 vs. pityriasis alba 37.2, 70.8 lepromatous (LL) 70.6 histopathology 70.3–70.4 immune response 70.2–70.3 Lucio 70.7, 70.11 mid-borderline (BB) 70.6 multibacillary (MB) 70.2, 70.8–70.9, 70.9 multidrug therapy (MDT) 70.9, 70.9 paucibacillary (PB) 70.2, 70.8–70.9, 70.9 prognosis 70.8 pure neural 70.7 reactions 70.10–70.11 spectrum 70.4, 70.4 treatment 70.9–70.10 tuberculoid (TT) 70.4–70.5, 70.5 histopathology 70.3, 70.3 immune response 70.2 vaccination 70.10 WHO strategy for 2006–2010 70.12 see also Mycobacterium leprae leptomeningeal melanocytosis 109.7, 109.25, 109.25 Leptophaeria 63.4 Leptopsylla segnis (mouse flea) 61.8 Leptotrobidium 61.9 see also trombiculid mites Lesch–Nyhan syndrome 180.10 Lestringant syndrome 115.20 Letterer–Siwe disease 103.1–103.2, 103.4, 103.4 leucocyte adhesion deficiency (LAD) 177.2, 177.11, 177.28–177.29 leucocytoclastic vasculitis see vasculitis, leucocytoclastic leucoderma, postinflammatory 104.1 leucoderma syphiliticum 104.12 leuconychia, punctate 150.3–150.4, 150.4 leucoplakia dyskeratosis congenita 136.9, 136.10 oral see oral leucoplakia leukaemia 99.13–99.17 aspergillosis 63.20, 63.20, 63.21 clinical features 99.13–99.16 congenital 99.16, 99.16, 99.17 diagnosis 99.16 differential diagnosis 99.16 gingival swelling 147.21, 147.21 graft-versus-leukaemia (GVL) effect 178.11 infantile eosinophilia 36.2 juvenile myelomonocytic 128.4 non-specific lesions 99.13, 99.15

Index primary extramedullary 99.13, 99.15 treatment 99.16–99.17 urticaria 74.8 see also specific types leukaemia cutis 99.13–99.15 aleukaemic 99.15 clinical features 99.14, 99.14–99.15, 99.15 congenital 99.16, 99.16 diagnosis 99.16 leukaemids 99.13, 99.15 leukotriene B4, atopic dermatitis 25.3 leukotriene C4, atopic dermatitis 25.3, 25.4 leukotriene receptor antagonists, urticaria 74.13 levamisole, warts 47.9 Levin syndrome I 127.16 levocetirizine 181.16 Lhermitte–Duclos disease 137.19 lice diseases transmitted by 72.9 epidemic typhus transmission 61.7 feeding behaviour 71.7, 72.10 infestations 72.9–72.14 aetiology and pathogenesis 72.9–72.10 clinical features 72.10–72.11 diagnosis 72.12 differential diagnosis 72.12 pathology 72.10 patient advocacy group 179.7 prevention and control 72.13–72.14 treatment 72.12–72.13 see also body louse; head louse; pubic louse lichen amyloidosis see amyloidosis, lichen lichen aureus 165.4 lichenification, Sjögren–Larsson syndrome 121.42, 121.46 lichen nitidus (LN) 85.15–85.16 actinic 85.15–85.16 clinical features 85.15, 85.15–85.16, 85.16 differential diagnosis 85.16, 86.5 pathology 85.15, 85.15 lichenoid drug eruptions (LDE) 85.8 differential diagnosis 85.10 drugs associated with 85.8, 85.9 histopathology 85.3 oral lesions 147.8 lichenoid lesions/reactions 85.1, 85.8–85.9 differential diagnosis 85.9–85.10 graft-versus-host disease 85.8–85.9, 85.10, 178.7, 178.7 lichenoid purpura 165.5 lichen planopilaris (LPP) 85.5–85.6 pathology 85.3 lichen planus (LP) 85.1–85.10 actinic 85.6 acute (exanthematous; eruptive) 85.7 aetiology and pathogenesis 85.1–85.3 annular 85.6–85.7, 85.7 associated diseases 85.1, 85.1 atrophic 85.7 bullous 85.7–85.8 clinical features 85.3–85.9, 85.4, 85.5 clinical variants 85.6–85.8 differential diagnosis 85.9–85.10, 86.5 familial 85.4 follicular see lichen planopilaris hyperpigmentation 85.5, 85.5, 104.5, 104.6 hypertrophic 85.6 incidence 85.3–85.4 inverse 85.4, 85.7 linear 85.7 lupus erythematosus overlap 85.8 nails 85.5, 85.5, 150.6, 150.6 oral 85.6, 85.10, 147.8, 147.8–147.9 pathology 85.3, 85.3 trachyonychia 150.5, 150.6 treatment 85.10 vulval 152.2 lichen planus pemphigoides 85.7–85.8 lichen planus pigmentosus 85.7 lichen purpuricus 165.4

lichen sclerosus 152.2, 152.5–152.8 aetiology and pathogenesis 59.6, 152.5 bullous 91.18 clinical features 152.5, 152.5–152.6, 152.6 complications 152.6 differential diagnosis 152.6–152.7, 152.7 lichen planus 85.10 sexual abuse 155.5, 155.6 infantile perineal protrusion 10.10 pathology 152.5, 152.5 phimosis 151.18 prognosis 152.6 treatment 152.7–152.8 lichen sclerosus et atrophicus see lichen sclerosus lichen simplex chronicus (LSC) 42.1–42.3 atopic dermatitis 28.3, 42.2 clinical features 42.1, 42.2 hyperpigmentation 41.2, 42.2, 104.5 lichen (keratosis) spinulosa, keratosis pilaris 123.2 lichen striatus 86.1–86.6 aetiology and pathogenesis 86.1–86.2, 86.2 clinical features 86.3, 86.3–86.5, 86.4, 86.5 differential diagnosis 85.9–85.10, 86.5, 86.5, 131.5 familial 86.2 nail 86.5, 150.6–150.7 pathology 86.2–86.3, 86.3 prognosis 86.5 treatment 86.6 lidocaine 190.2–190.3 injections 181.7 laser treatment 189.2 reducing pain of 190.2, 190.3 liposomal (LMX) 190.4 ointment and spray 190.4 properties 190.2 topical 181.7, 190.4–190.5 infantile haemangiomas 113.8 laser treatment 189.2 see also EMLA cream toxicity 184.4 lidocaine/tetracaine patch 190.4–190.5 LIG4 syndrome 177.31 ligatures, self-applied 180.9, 180.10 lignocaine see lidocaine lilac ring, morphoea 173.3, 173.4 Limberg flaps 187.21–187.23, 187.25 limb–mammary syndrome (LMS) 127.41, 127.79 limbs atopic dermatitis 28.1–28.3, 28.2, 28.3 tissue expansion 191.5–191.6, 191.7 lindane 181.9 lice 72.12 resistance, head lice 72.13 scabies 72.6 toxicity 5.7, 72.6, 72.12, 181.9, 184.7 linear and whorled naevoid hypermelanosis (LWNH) 131.1–131.5 clinical features 131.3, 131.3–131.4, 138.9 diagnosis 131.4–131.5 differential diagnosis 104.10, 131.5, 131.5 histopathology 131.3 pathogenesis and genetics 131.1–131.2, 138.3 treatment 131.5 linear atrophoderma of Moulin 145.17 linear eruptions, mimicking child abuse 154.9, 154.10 linear focal elastosis (LFE) 146.3 linear hyperpigmentation 104.9, 138.9 linear IgA associated bullous disease in children 89.1–89.11 linear IgA disease (LAD), childhood (chronic bullous disease of childhood; CBDC) 89.1–89.11, 91.13 aetiology 89.2 clinical features 89.6–89.8, 89.7, 89.8 differential diagnosis 89.9, 89.9, 91.24 epidemiology 89.3, 89.4 molecular biology 89.6 oral lesions 147.9

41

pathology 89.3–89.6, 89.4, 89.5 precipitating factors 89.2–89.3 prognosis 89.8–89.9 treatment 89.9–89.11, 89.10 linear morphoea see morphoea, linear linear porokeratosis clinical features 126.2, 126.3 differential diagnosis 86.5 management 126.4, 126.5 risk factors 126.1 linear streaks, Proteus syndrome 111.4 linear verrucous epidermal naevus inflammatory see inflammatory linear verrucous epidermal naevus laser therapy 189.6 lingual thyroid 147.23 lingual tonsil 147.23 linkage analysis 23.2 atopic dermatitis 23.5 prenatal diagnosis 139.6 linkage disequilibrium (LD) 23.3 linoleic acid infantile seborrhoeic dermatitis 35.2 normal infants 27.14 skin barrier function and 27.7, 27.10–27.11, 27.16 Linuche unguiculata 73.8 lip(s) atopic dermatitis 28.3, 28.4 Kawasaki disease 168.4, 168.4 pits, congenital 10.6–10.7 LIPH gene mutations 127.100 lipid lamellae atopic dermatitis 27.10 stratum corneum 27.2–27.3 lipids inborn errors of metabolism 121.3 plasma effects of retinoids 121.67–121.68 in psoriasis 80.6–80.7 skin surface, seborrhoeic dermatitis 41.2 stratum corneum 27.10 alterations in atopic dermatitis 27.10–27.11 barrier-repair medications 121.65–121.66 normal infants 27.14 origins 3.2, 27.2–27.3 vernix caseosa 3.1, 3.1–3.2 see also fatty acids lip-lick cheilitis, secondary 28.3 lip-licking/biting 180.3, 180.9, 180.10 lipoatrophic panniculitis, idiopathic 77.10 lipoatrophy 141.10–141.19, 141.11 acquired generalized 141.19 acquired localized 141.11, 141.11, 141.11–141.14 acquired partial (APL) 141.15–141.16 acral 141.12, 141.13 of the ankles 77.10, 141.12 annular 141.12 Berardinelli–Seip congenital 115.28, 141.18 centrifugal 141.11–141.12 cephalothoracic 141.8–141.9 chromosome disorders 116.9 classification 141.11 congenital total 172.18 insulin 141.13, 172.23, 172.23 lupus panniculitis 77.10 naevoid disorders with 141.12 partial 172.18–172.19 premature ageing syndromes with 134.5–134.12 semi-circular 141.12 lipoblastoma 141.3 lipoblastomatosis 141.3 lipodystrophy 141.1 familial partial (FPLD) 115.28, 141.14–141.15 in HIV-infected patients 52.5, 141.16 lipogranulomatosis subcutanea 77.1 lipohypertrophic disorders 141.1–141.10, 141.2 lipohypertrophy, insulin therapy-related localized 141.4, 172.22, 172.22–172.23

42

Index

lipoid proteinosis 97.19–97.20 lipoma fetal (hibernoma) 141.3–141.4 genital area 151.21 infantile 141.3 lumbosacral 10.16–10.17, 141.2–141.3 midline 148.32 solitary 141.2–141.3 variants 141.4 lipomatosis benign cervical (multiple symmetric) 141.8–141.9 encephalocraniocutaneous 111.8, 141.6 inherited 141.6–141.7 multiple 141.1–141.2 segmental, of Touraine and Renault 141.1 lipomatous lesions focal dermal hypoplasia 133.1, 133.3, 133.4 Proteus syndrome 111.4, 111.4 lipomyelocoele 10.16 lipomyelomeningocoele 10.16–10.17 lipopolysaccharide (LPS), Neisseria meningitidis 55.1, 55.5 lipoprotein lipase (LPL) deficiency 169.13, 169.14, 169.15 liposarcoma 99.6 liposomes, cutaneous gene delivery 140.7 liposuction, Proteus syndrome 111.8 lipoteichoic acid (LTA), atopic dermatitis 26.2, 26.3 12(R)-lipoxygenase, epidermal 121.25, 121.35–121.36 lipoxygenase-3, epidermal 121.25, 121.35–121.36 lipoxygenases 12.1 Lipschutz ulcer 151.13 liquor carbonis detergens (LCD), psoriasis 82.2 Lisch nodules 128.5 listeriosis (Listeria monocytogenes) congenital (early-onset) infection 8.6, 52.2 late-onset infection 9.3–9.4 lithium gluconate, topical 41.4 lithium succinate ointment 41.4 livedo reticularis chromosome disorders 116.13 neonatal lupus erythematosus 14.5, 14.5–14.6 polyarteritis nodosa 77.6, 77.6, 167.9, 167.9 liver biopsy, fetal 17.3 liver disease erythropoietic protoporphyria 107.11, 107.14 Gianotti–Crosti syndrome 50.4 graft-versus-host disease 178.6, 178.8 hyperpigmentation 104.8 lichen planus association 85.2–85.3 neonatal lupus erythematosus 14.4, 14.7, 14.10 liver transplantation calcinosis cutis after 95.9 erythropoietic protoporphyria 107.11 liver X receptor (LXR) 121.54 LKB1 (STK11) gene mutations 137.16 LL-37 (hCAP18) atopic dermatitis 25.11, 26.3 erythema toxicum neonatorum 6.6 LMNA gene mutations 134.1 familial partial lipodystrophy 141.14 Hutchinson–Gilford syndrome 134.1 mandibuloacral dysplasia 134.8, 141.15 restrictive dermopathy 15.1, 15.3 Loboa loboi 63.24, 63.25 lobomycosis 63.24–63.25 lobster claw deformity, focal dermal hypoplasia 133.2, 133.3 lobucavir, HSV infections 48.7 local anaesthetics 181.7, 190.1–190.3 adverse effects 190.3 classification 190.2, 190.2 iontophoresis 190.5 laser treatment 188.2–188.3, 188.3, 189.2 mechanism of action 190.2 needle-free injection devices 190.5 subcutaneous infusion 190.5

toxicity 184.4, 190.3 see also lidocaine; topical anaesthetics localized autosomal recessive hypotrichosis see hypotrichosis, localized autosomal recessive localized intravascular coagulation (LIC) differential diagnosis 112.9, 113.25–113.26 Klippel–Trenaunay syndrome 112.16 venous malformation-associated 112.8–112.9 localized scleroderma severity index (LoSSI) 173.8 Loeys–Dietz syndrome 142.2, 142.8 Löfgren syndrome 158.4 Lone Star tick 59.11 lonomism (Lonomia envenomation) 73.4 loop marks, abusive 154.3–154.4 loose anagen syndrome (LAS) 148.19–148.20 diagnosis 148.5, 148.5, 148.19–148.20 phenotypes 148.19, 148.19 LOR gene mutations 120.6, 122.12 loricrin 120.6 atopic dermatitis 27.9 loricrin keratoderma (Camisa palmoplantar keratoderma) 120.6–120.7, 122.4, 122.12–122.13 clinical features 120.6, 120.6, 121.44, 122.13, 122.13 differential diagnosis 120.7, 121.38, 122.13 pathogenesis 115.21, 120.6, 122.12 loss of heterozygosity (LOH) 115.14–115.15 didymosis 115.15 segmental forms of autosomal dominant skin disorders 115.15, 115.15 lotions 181.4 Louis–Bar syndrome see ataxia telangiectasia louse see lice louse-borne typhus 61.2, 61.6–61.8 lower-lip pits, congenital 10.7 Loxosceles spiders 73.5, 73.5 LRP5/6 127.83, 127.84 LRRC8A gene mutations 177.25 LRRC32 gene, atopic dermatitis 23.6 Lucilia 69.3 Lucilia serpiginosa 69.3 Lucio leprosy 70.7, 70.11 Lucio’s phenomenon 70.11 treatment 70.12 lumps, cutaneous 92.1–92.9, 92.2 colour 92.1, 92.3 itchy 92.1, 92.4 surface appearance 92.1, 92.3 tender/painful 92.1, 92.4 texture 92.1, 92.4 see also cysts; nodules lung involvement see pulmonary involvement lunula 150.1 lupus dermatitis, neonatal 14.4, 14.5, 14.5 lupus erythematosus (LE) anetoderma 145.12–145.13 chronic granulomatous disease 177.9–177.10 differential diagnosis 105.6, 106.3 dystrophic calcification 95.6 immunodeficiency syndromes 177.2–177.3 lichen planus overlap 85.8 neonatal see neonatal lupus erythematosus oral lesions 147.13 patient advocacy group 179.7 pigmentation changes 104.5 profundus 77.10 subtypes 14.1 systemic see systemic lupus erythematosus lupus miliaris disseminatus faciei (LMDF) 38.3 lupus nephritis 175.7, 175.7–175.8 lupus panniculitis 77.10 lupus pernio 158.1, 158.3–158.4 lupus vulgaris 57.3 vs. leishmaniasis 67.12 Lutzomyia sand flies 58.8, 67.3 Lutz–Splendore–Almeida disease see paracoccidioidomycosis Lyell syndrome see toxic epidermal necrolysis

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

Lymantria dispar 73.4 Lyme arthritis 59.1, 59.7 diagnosis 59.7–59.8 treatment 59.8–59.9, 59.9 Lyme borreliosis (Lyme disease) 59.1–59.11 aetiopathogenesis 59.3–59.4 associated infections 59.10–59.11 chronic 59.10 clinical features 59.4, 59.4–59.7, 59.5, 59.6, 76.6 cutaneous features see erythema migrans diagnosis 59.7–59.8 epidemiology and ecology 59.1–59.3 musculoskeletal manifestations 59.7 nervous system manifestations see neuroborreliosis in pregnancy 8.6, 59.7 prevention 59.10 prognosis 59.9–59.10 skin manifestations 59.4–59.6 treatment 59.8–59.9 lymphadenopathy atopic dermatitis 30.2 cat scratch disease 58.5, 58.6, 58.6 chronic granulomatous disease 177.10 Gianotti–Crosti syndrome 50.3 Kawasaki disease 168.4, 168.4 leishmaniasis 67.6, 67.7 sinus histiocytosis with massive (SHML) 103.12, 103.13, 103.14 lymphadenosis benigna cutis see borrelial lymphocytoma lymphangiectasia 114.11, 114.15 lymphangio-endothelioma, benign 112.13, 114.20–114.21 lymphangio-endotheliomatosis, multifocal 113.20, 113.27 lymphangiogenesis 114.1–114.2 lymphangiography contrast 114.3 indirect 114.3 isotope see lymphoscintigraphy lymphangioma acquired, lymphoedema 114.11 acquired progressive (benign lymphangioendothelioma) 112.13, 114.20–114.21 congenital 114.15 genital area 151.6, 151.7 intraoral 147.17 lymphangioma circumscriptum see lymphatic malformations (LM), microcystic lymphangiomatosis, diffuse 114.17 lymphangiosarcoma 114.13 lymphangitis acute 114.19 smallpox vaccination site 51.9, 51.10 lymphatic aplasia 114.4 lymphatic disorders 114.1–114.21 antenatal presentation and diagnosis 114.20 investigations 114.2–114.3 later onset 114.18–114.19 see also lymphoedema lymphatic dysplasia generalized 114.9, 114.9 generalized multisegmental 114.9 lymphatic endothelial cells (LECs) 114.1 lymphatic hyperplasia 114.4 lymphatic hypoplasia 114.4 lymphatic malformations (LM) 112.12–112.14, 114.15–114.17 clinical features 112.12, 112.12 genital area 151.6, 151.7 macrocystic (cystic hygroma) 112.12, 114.15–114.16 clinical features 112.12, 112.12, 114.15, 114.16 differential diagnosis 112.13, 114.16 treatment 112.13, 114.16 microcystic 112.12, 114.16–114.17 clinical features 112.12, 114.16–114.17, 114.17 differential diagnosis 112.13 pathology 4.4, 4.4–4.5, 112.12

Index lymphatic system 114.1–114.3 development 114.1–114.2 function 114.2 lymphatic tumours 114.20–114.21 lymphatic vessels, structure 114.2 lymphocyte transformation test (LTT) drug hypersensitivity 183.14 leprosy 70.2–70.3 lymphocytic infiltrate, Jessner’s see Jessner’s lymphocytic infiltrate lymphocytic interstitial pneumonitis (LIP) 52.1 lymphocytic vasculitis see vasculitis, lymphohistocytic/lymphocytic lymphocytoma, borrelial see borrelial lymphocytoma lymphoedema 114.1, 114.4–114.13 anogenital 114.19 chromosome disorders 116.9 complications 114.13 congenital multisegmental 114.9–114.11 diagnosis 114.11 investigations 114.2–114.3 with overgrowth, vascular or cutaneous manifestations 114.9–114.11 primary 114.4–114.11, 115.26 congenital onset see Milroy disease later onset (Meige disease) 114.5–114.6, 114.6 phenotypic classification 114.4, 114.5 syndromic 114.7–114.11 secondary 114.11 treatment 114.12–114.13 lymphoedema congenita 114.4 lymphoedema–distichiasis (LD) syndrome 114.6–114.7, 114.7 genetics 114.6, 115.26 prenatal diagnosis 114.20 lymphoedema–myelodysplasia 114.9 lymphoedema praecox 114.4, 114.6 lymphoedema tarda 114.4 lymphoepithelial kazal-type 5 serine protease inhibitor see LEKT1 lymphogranuloma venereum 155.4 see also Chlamydia trachomatis (CT) infections lymphohistiocytosis, haemophagocytic see haemophagocytic lymphohistiocytosis lymphohistocytic vasculitis see vasculitis, lymphohistocytic/lymphocytic lymphoid structures, malignant tumours of 99.13–99.27 lymphoma anti-TNF treated patients 182.4 cutaneous 99.17–99.27, 102.1–102.17 diagnostic approach 102.17 eosinophilia 36.7 epidemiology 102.1–102.2 Hodgkin see Hodgkin disease lymphomatoid papulosis developing into 102.9 non-Hodgkin see non-Hodgkin lymphoma pityriasis lichenoides and 100.1 primary 99.19, 102.1 subcutaneous panniculitis-like T-cell see subcutaneous panniculitis-like T-cell lymphoma urticaria 74.8 WHO/EORTC classification 99.19, 99.20, 102.1, 102.1 see also cutaneous B-cell lymphoma; cutaneous T-cell lymphoma genital area 151.20 oral 147.19 patient advocacy groups 179.7 Wiskott–Aldrich syndrome 177.33–177.34 see also specific types lymphomatoid papulosis (LyP) 99.22–99.23, 102.8–102.9 clinical features 99.22, 99.22–99.23, 102.8, 102.8 histopathology 99.23, 102.8, 102.8–102.9 immunophenotype 102.9 pityriasis lichenoides and 100.1, 100.3

lymphoproliferative disease inherited immunodysregulatory disorders 177.8 linear IgA disease and 89.3, 89.8 lymphoproliferative syndrome autoimmune 177.8 autosomal recessive EBV-associated 177.8 X-linked 177.8 lymphoscintigraphy 114.2–114.3 lymphoedema–distichiasis syndrome 114.7, 114.7 lymphotactin, neuroblastoma 99.12 Lynch syndrome 137.14 lyonization see X-inactivation lysosomal storage diseases 169.10–169.13 LYST gene mutations 138.7, 177.6, 177.8 lysyl hydroxylase 142.2 LYVE-1 114.1 macrocephaly, Gorlin syndrome 132.5 macrocephaly, alopecia, cutis laxa and scoliosis (MACS syndrome) 134.14–134.15 macrogingiva and giant fibroadenomas, congenital 148.29 macroglossia 147.22, 147.22 hypothyroidism 172.2, 172.2, 172.3 macrolide antibiotics, acne 79.8–79.9 macrophage activation syndrome 175.2–175.3 macrophages 103.1 atopic dermatitis 24.3 wound healing 17.1 macrotragus 10.3 maculae ceruleae 72.11, 72.12 macular amyloidosis see amyloidosis, macular macular atrophy see anetoderma macular dystrophy, juvenile see juvenile macular dystrophy macules chromosome disorders 116.10 Schamberg disease 165.2, 165.2 maculopapular exanthems (MPES), druginduced 183.4–183.5, 183.5 madarosis, leprosy 70.6, 70.7 Madelung disease 141.8–141.9 Madura foot see mycetoma Madurella 63.4 Madurella mycetomatis 63.4 maduromycosis see mycetoma mafenide toxicity 184.7 Maffucci syndrome 112.11, 114.17 differential diagnosis 111.8 tumour susceptibility 137.5 maggot infestations see myiasis MAGIC syndrome 147.3, 167.20 magnetic resonance angiography (MRA) arteriovenous malformations 112.3 infantile haemangioma 113.11 magnetic resonance imaging (MRI) arteriovenous malformations 112.3 congenital melanocytic naevi 109.7 infantile haemangioma 113.11 juvenile dermatomyositis 175.11, 175.11 lymphatic disorders 114.3 morphoea 173.8 Proteus syndrome 111.7 Sturge–Weber syndrome 112.16 systemic lupus erythematosus 175.7 tuberous sclerosis 129.3, 129.4, 129.11 venous malformations 112.9 Majocchi disease 165.4–165.5 major histocompatibility complex (MHC) associations see HLA associations class I deficiency 177.31 class II deficiency 177.31 malabsorption cystic fibrosis 170.1 Netherton syndrome 124.6 oral lesions 147.1, 147.7, 147.24 malar rash, systemic lupus erythematosus 175.6, 175.6

43

Malassezia (Pityrosporum) associated diseases 62.25–62.31 atopic dermatitis 22.10, 24.7, 26.5–26.9 allergic sensitization 26.5–26.6, 62.29 antifungal therapy and 26.7–26.8 clinical significance 26.6–26.7 colonization 62.26 folliculitis 41.3, 62.28, 62.28–62.29 fungaemia and invasive infection 9.5, 62.29–62.30 identification 62.27–62.28 neonatal cephalic pustulosis 8.5, 8.6, 9.4–9.5, 62.29 clinical features 8.7, 9.4–9.5, 9.5 treatment 9.5 pityriasis versicolor 62.25–62.27 seborrhoeic dermatitis 62.29 of adolescence 41.1–41.2 infantile 35.2–35.3, 62.29 Malassezia furfur 62.25–62.26, 62.29–62.30 Malassezia globosa 62.26, 62.27 Malassezia pachydermatis 62.29–62.30 Malassezia restricta 62.26 Malassezia sympodialis 62.26 malathion 181.9 lice 72.12 resistance, head lice 72.13 toxicity 184.7 mal de Meleda 120.4–120.5 clinical features 120.5, 120.5, 122.5 molecular pathology 115.21, 120.4–120.5 Maldonado, Ramon Ruiz 1.3, 1.4 malignant disease see cancer malignant endovascular papillary angioendothelioma 99.10 malignant peripheral nerve sheath tumours (MPNST) 128.4 malignant skin tumours (skin cancer) 99.1–99.27 AIDS-related 52.5, 99.1 dermal 99.4–99.10 epidermal 99.1–99.4 hereditary skin disorders with proneness to 115.27, 137.2, 137.3 HPV infections and 47.5, 47.7 lichen sclerosus 152.6 lymphoedematous areas 114.13 lymphoid structures 99.13–99.27 neural crest and germ cell origin 99.10–99.13 porokeratosis 126.1, 126.4–126.5 Rothmund–Thomson syndrome 136.3–136.4 tanning bed use and 108.4 UV-induced 108.8–108.9 xeroderma pigmentosum 135.6, 135.8, 135.8, 135.11 see also specific types malingering 180.7 malnutrition dystrophic epidermolysis bullosa 118.16 protein-energy see protein-energy malnutrition skin manifestations 65.1–65.9 see also nutritional deficiencies malodour epidermolytic ichthyosis 121.19 mal de Meleda 120.5 pitted keratolysis 56.1 tropical ulcers 66.2, 66.3 Malpuech–Michels–Mingarelli–Carnevale (3MC) syndrome 10.9 mammalian target of rapamycin (mTOR) inhibitors tuberous sclerosis 129.12 see also rapamycin signalling pathway Birt–Hogg–Dubé syndrome 137.8, 137.8 cancer-prone genodermatoses 137.8 Peutz–Jeghers syndrome 137.16 PTEN hamartoma-tumour syndromes 137.17, 141.6–141.7 tuberous sclerosis 129.3 mandibuloacral dysplasia (MAD) 134.8–134.9, 141.15

44

Index

manganese superoxide dismutase (MnSOD), autoreactivity in atopic dermatitis 26.7 mannose-binding lectin (MBL) deficiency 177.17, 177.19–177.20, 177.20 manual lymphatic drainage therapy (MLD) 114.12 MAPBP1P gene 177.11 maple syrup urine disease 11.11, 20.11–20.12 maquas 154.11 marasmus 65.1 cutaneous manifestations 65.2, 65.2 hair abnormalities 65.2, 148.20, 148.21 marfanoid ageing syndrome 134.18 marfanoid-craniosynostosis syndrome (Shprintzen–Goldberg) 145.4, 145.5, 145.7 marfanoid habitus (dolichostenomelia) 145.4 Marfan syndrome 145.5 MEN 2b 172.29–172.30 other causes 145.4, 145.7 Marfan syndrome (MFS) 145.4, 145.4–145.8 aetiology 115.23, 145.5 clinical features 145.5, 145.5–145.6, 145.7 diagnosis 145.6–145.7, 145.6–145.7 management 145.7 striae 145.6, 146.1 marginal zone B-cell lymphoma, primary cutaneous (PCMZL) 99.26, 102.14 Marie–Unna hypotrichosis 115.24, 148.8, 148.16–148.17, 148.17 marimastat, arteriovenous malformations 112.3 marine envenomations 73.7–73.9 Marinesco–Sjögren syndrome 148.11 marker chromosome 22 syndrome 116.13, 116.13, 116.14 Maroteaux–Lamy syndrome 169.11, 169.12 Marshall syndrome (acquired cutis laxa) see postinflammatory elastolysis and cutis laxa Marshall syndrome (hereditary) 127.43 ‘mask of pregnancy’ 104.6 MASP-2 deficiency 177.20 massage, lymphoedema 114.12 mast cell(s) (MC) 75.3 apoptosis, mastocytosis 75.5 atopic dermatitis 24.3 atypias, mastocytosis 75.7, 75.7–75.8 degranulators 75.6 growth factors, mastocytosis 75.5 infantile haemangiomas 113.3 infiltrates, mastocytosis 75.6–75.7, 75.7 diagnostic criteria 75.1, 75.1–75.2, 75.7, 75.11 mediators 75.6, 75.6 phenotype in mastocytosis 75.5–75.6, 75.8 mast cell chymase, atopic dermatitis 23.9, 23.12–23.13 mast cell leukaemia (MCL) 75.2, 75.2–75.3 clinical features 75.10 diagnosis 75.7 mast cell sarcoma (MCS) 75.2, 75.3 Master disease 59.11 mastocytoma 75.2 clinical features 75.8, 75.8 extracutaneous 75.2 laser treatment 189.9 prognosis 75.10 mastocytosis 75.1–75.12 aetiology and pathogenesis 75.3, 75.3–75.6 aggressive systemic (ASM) 75.2, 75.3, 75.12 aleukaemic subvariant 75.2 anaesthesia in 75.12 classification 75.1–75.3, 75.2 clinical features 75.8–75.10 cutaneous (CM) 75.1, 75.2, 75.3 clinical features 75.8–75.9 diagnosis 75.11, 75.11 differential diagnosis 75.11 diffuse cutaneous 75.2 clinical features 75.8–75.9, 75.9, 75.10 neonatal erythroderma 11.5 prognosis 75.10 urticaria 74.7

indolent systemic (ISM) 75.2, 75.2–75.3 maculopapular cutaneous (urticaria pigmentosa) 75.2 clinical features 75.8, 75.9 differential diagnosis 128.8, 154.11 laser treatment 189.9 prognosis 75.10 pathology 75.6–75.8 patient advocacy group 179.7 pigmentation changes 104.6 plus gastrointestinal stromal tumours 137.4 prognosis 75.10–75.11 smouldering systemic (SSM) 75.3 systemic (SM) 75.1–75.3 with associated clonal haematological non-mast cell lineage disease (AHNMD) 75.2, 75.2–75.3 bone marrow mast cells 75.7, 75.7–75.8 clinical features 75.8, 75.10 diagnostic criteria 75.1, 75.1–75.2, 75.11 treatment 75.12 treatment 75.11–75.12 masturbation 151.24, 155.2 materia alba, gingival 147.11 matriptase 121.56–121.57 matrix metalloproteinases (MMPs), acne vulgaris 79.5 maturation, developing skin 2.2–2.3, 2.3 premature infants 5.3 Mauserung (moulting effect) epidermolytic ichthyosis 121.18 superficial epidermolytic ichthyosis 117.6, 121.21, 121.22 maxacalcitol, warts 47.8–47.9 maxadilan 67.3 Max-Joseph spaces, lichen planus 85.3 MBL2 gene polymorphisms 177.17 MBTPS2 gene mutations 121.56 McCune–Albright syndrome genetic basis 115.25 pigmentary mosaicism 115.10, 115.14 pigmented macules 109.10, 128.8 precocious puberty 172.11, 172.12 McGrath syndrome see ectodermal dysplasia– skin fragility syndrome measles 49.1–49.3 atypical and modified 49.2 clinical features 49.1–49.2, 49.2 complications 49.2 HIV-infected children 52.3 Koplik’s spots 49.2, 49.3, 147.11 vaccination 49.3 measles virus 49.1 mebendazole 151.10 mecA gene 54.2 mechanical injury atopic dermatitis 24.5 plants 45.1–45.2, 45.2 mechanobullous genodermatoses 87.6, 87.6–87.7 median raphe cysts (and canals) of penis (and scrotum) 10.9, 151.18, 151.18, 151.19 Mediterranean fever, familial see familial Mediterranean fever MEDNIK syndrome 121.50–121.51 differential diagnosis 120.15, 121.51 genetic basis 115.21 MEDOC see Mendelian disorders of cornification medroxyprogesterone acetate 172.12 medulloblastoma, Gorlin syndrome 132.10, 132.14 Mees’ lines 148.19 Meesmann corneal dystrophy 117.8 MEFV gene mutations 160.1, 167.14, 176.1 Megalopyge caterpillars 73.4 megalymphatics 114.4 meganucleases 140.11, 140.12 Megarbane–Loiselet neonatal progeroid syndrome 134.9–134.10 meglumine antimoniate, leishmaniasis 67.12–67.13 meibomian cysts, Gorlin syndrome 132.7

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

Meige disease 114.5–114.6, 114.6 melanin absorption of radiation 108.5 synthesis 138.1 developing hair follicle 2.36 hereditary disorders 138.7–138.8 onset in fetus 2.15 UV radiation-induced changes 108.7 melanoblasts, pattern of migration 185.8–185.9 melanocytes developing hair follicle 2.36, 2.36 embryonic epidermis 2.6, 2.6 embryonic-fetal transition 2.15, 2.15 hereditary disorders of ontogenesis 138.4–138.6 loss, in vitiligo 105.1–105.2 melanin synthesis 138.1 migration to epidermis 138.1, 138.4 transplantation, vitiligo 105.7–105.8 melanocytic naevi 109.1–109.24 acquired (benign) 109.12–109.14 aetiology 109.12–109.13 clinical features 109.13, 109.13–109.14 dermoscopy 109.13, 109.14, 185.9–185.12 management 109.14 pathology 4.2, 4.2, 109.13 atypical (dysplastic) see atypical naevi chromosome disorders 116.12 congenital see congenital melanocytic naevi dermoscopy 185.1–185.21 genital area 151.5, 151.5 nail matrix 150.7, 150.7 oral 147.14 see also pigmented lesions melanocytosis acquired dermal 189.4–189.5 congenital dermal see Mongolian spots leptomeningeal 109.7, 109.25, 109.25 melanoleucoderma 127.44 melanoma 109.24–109.27 aetiology 108.8–108.9, 109.25, 109.25–109.26 amelanotic 185.13 arising in congenital naevi see under congenital melanocytic naevi arising in naevus of Ota 109.23 arising in naevus spilus 109.17, 109.18 atypical mole syndrome 109.20–109.21 early detection 109.21 clinical features 109.26, 109.26–109.27 dermoscopic features 185.12–185.16, 185.14, 185.15, 185.16 familial 109.21, 109.25 genital area 151.5, 151.20 hereditary skin disorders with proneness to 137.2, 137.3 incidence 109.24–109.25 neonatal/congenital 109.25–109.26 ocular 109.21, 109.26 pathology 109.26, 109.26 prevention 109.27 prognosis 109.27 treatment 109.27 vs. atypical Spitz naevi 109.17, 109.26, 185.18–185.20 xeroderma pigmentosum 109.25, 135.8 melanonychia, longitudinal 150.7, 150.7 melanophilin 138.1, 138.7 melanosis Becker see Becker naevus familial diffuse (or universal) 104.9 neurocutaneous 109.6 transient neonatal pustular see transient neonatal pustular melanosis universal acquired 104.9 see also hypermelanosis melanosomes 138.1 embryonic-fetal transition 2.15, 2.15 fetal 2.20 inherited disorders of biogenesis and transfer 138.6–138.7 transfer to keratinocytes 138.1, 138.4

Index melanotic neuroectodermal tumour of infancy 147.14 melasma 104.6–104.7 Melkersson–Rosenthal syndrome 114.18, 114.19, 157.3 melorheostosis 145.2 membrane attack complex (MAC) deficiencies 177.19, 177.20 membrane-bound transcription factor protease, site 2 (MBTPS2) 121.56 membrane cofactor protein deficiency 177.20 MEN see multiple endocrine neoplasia MEN1 gene mutations 172.29 menarche 172.11 premature 172.12 Mendelian disorders of cornification (MEDOC) 121.1–121.9 classification 121.1 diagnostic approaches 121.4–121.6 erythrokeratodermas 122.1–122.14, 122.3–122.5 genetic bases 121.2 ichthyoses 121.1–121.72 keratodermas 120.1–120.26 management 121.64 complications 121.63–121.65 epidermal differentiation modulators 121.66–121.67 systemic retinoids 121.67–121.69 topical therapies 121.65–121.66 neonatal presentations 121.5 pathogenic mechanisms 121.3–121.4 syndromic 121.2, 121.42–121.66, 121.43–121.46 Mendelian inheritance 115.2–115.4 exceptions and variations 115.4–115.7 Mendelian skin disorders 115.19–115.29 benign tumours 115.27 connective tissue disorders 115.23 cutaneous cancer proneness 115.27 ectodermal dysplasias 115.23 epidermolysis bullosa 115.22 extracutaneous cancer proneness 115.27 genetic heterogeneity 115.26–115.29 hair and nail disorders 115.24 keratinization disorders 115.20–115.21 metabolic disorders 115.26 MIM numbers 115.19–115.26 novel nosological categories 115.29 other autosomal 115.28 other X-linked 115.28 pigmentation disorders 115.25 vascular lesions 115.26 see also genetic skin disorders; genodermatoses Mendes da Costa disease see erythrokeratodermia variabilis (EKV), Mendes da Costa Mendes da Costa–van der Valk syndrome 148.6 menin 172.29 meningeal melanocytosis see leptomeningeal melanocytosis meningiomas 128.13 neurofibromatosis 2 128.12 primary cutaneous 148.31 meningitis, meningococcal 55.6 meningitis belt, African 55.1–55.2 meningococcaemia, chronic 55.12–55.13 meningococcal infection 55.1–55.13 clinical features 55.6–55.7 complement deficiencies 177.19, 177.20 epidemiology 55.1–55.2 laboratory diagnosis 55.9 prevention 55.13 see also Neisseria meningitidis meningococcal septicaemia, acute allergic complications 55.12 clinical features 55.6, 55.6–55.7, 55.7, 55.8, 55.9 differential diagnosis 55.7–55.9, 55.11 management 55.9–55.12, 55.10, 162.10–162.14 mortality 55.2 outcome of skin disease 55.12 pathophysiology 55.2, 55.2–55.6, 55.3, 55.4 purpura fulminans 162.2, 162.3

clinical features 55.6, 55.7, 55.8, 162.2, 162.2 pathology 162.7, 162.7 pathophysiology 162.2–162.5 prognosis 162.8 treatment 160.10–162.14, 160.13 meningococcus see Neisseria meningitidis meningocoele cranial 10.12–10.13 rudimentary (atretic, sequestrated) 10.13, 10.13–10.14 spinal 10.16 meningoencephalitis, Lyme neuroborreliosis 59.6 meningoencephalocoele 10.12 Menkes syndrome 65.7, 65.7 clinical features 65.7, 65.7, 148.10, 148.10 genetic basis 115.26 pili torti 65.7 trichorrhexis nodosa 148.10 mental retardation see learning disabilities Mepilex® dressings dystrophic epidermolysis bullosa 118.18, 118.18 epidermolysis bullosa simplex 118.8 Mepitel® dressings burn wounds 187.17 epidermolysis bullosa 118.18, 118.32 mercapto chemicals, allergy 44.3, 44.10 Mercuriali, Geronimo 1.1 mercurials allergy 44.3, 44.9 poisoning 184.7 mercury intoxication 184.7 hair loss 148.18–148.19 newborn infants 5.7 Merkel cells eccrine sweat gland development and 2.30, 2.31 embryonic 2.7 embryonic-fetal transition 2.15–2.16, 2.16 fetal 2.20 hair follicle development and 2.34–2.35, 2.37–2.38 Merlin 128.13–128.14 Merrick, Joseph Carey 111.1 mesenchymal cells appendage development 2.28, 2.28 hair follicle development 2.34, 2.35, 2.36 nail development 2.30 sweat gland development 2.29 mesenchyme, compact 2.8–2.9 mesenteric cysts, Gorlin syndrome 132.11 mesoectodermal dysplasia see Ellis–van Creveld syndrome mesomelic dwarfism–skeletal abnormalities– ectodermal dysplasia 127.45 Mesopotamia, ancient 1.1 metabolic disorders hyperpigmentation 104.7–104.8 inherited 115.26, 169.1–169.15 autosomal dominant inheritance 115.2, 115.2 classification 169.1 neonatal erythroderma 11.10–11.11 skin symptoms 169.2–169.3 napkin dermatitis 20.11–20.12 urticaria 74.9 metabolism of drugs, cutaneous 181.6 metageria 134.7, 134.8 metals causing hair loss 148.18–148.19 hyperpigmentation induced by 104.5, 104.8 lichenoid reactions 85.9 metaphyseal chondrodysplasia, McKusick type 127.12 Méténier’s sign 142.7 metformin 79.10, 172.19 methaemoglobinaemia EMLA cream-induced 190.4 intoxications causing 184.4, 184.6, 184.7, 184.9 newborn infants 5.7, 17.7

45

methanol intoxication 184.4 methicillin-resistant Staphylococcus aureus (MRSA) 54.2–54.3 atopic dermatitis 26.3 community-associated (CA-MRSA) 54.2–54.3 epidemiology 54.3 epidermolysis bullosa 118.19–118.20 furunculosis 54.5 hospital-associated (HA-MRSA) 54.2 nursing care 192.4, 192.10 USA200 strain 54.2 methotrexate atopic dermatitis 30.11 juvenile dermatomyositis 175.12 monitoring therapy 192.16 morphoea 173.9 pemphigus vulgaris 91.4 pityriasis rubra pilaris 83.6–83.7 psoriasis 82.2, 82.4 sarcoidosis 158.5 systemic sclerosis 174.11 Wegener granulomatosis 167.6 methoxyphenyltriazene 181.13 methylchloroisothiazolinone/ methylisothiazolinone (MCI/MI) allergy 44.11 methylene blue 5.7 methylmalonic acidaemia 169.8 acrodermatitis enteropathica-like lesions 20.11–20.12, 169.8 clinical features 169.8, 169.8, 169.9 neonatal erythroderma 11.11 methylprednisolone administration 192.10–192.13, 192.15 alopecia areata 149.5 juvenile dermatomyositis 175.12 Kawasaki disease 168.9 morphoea 173.9 pemphigus vulgaris 91.4 Stevens–Johnson syndrome/toxic epidermal necrolysis 78.6, 78.7 metronidazole acute ulcerative gingivitis 147.7 bacterial vaginitis 153.23 perioral dermatitis 38.3 propionic acidaemia 169.8 topical 181.7 Trichomonas vaginalis infection 153.22, 153.22 tropical ulcer 66.5 mexilitene, erythromelalgia 166.3 Meyerson phenomenon 112.14 Meyerson’s naevus 109.24 MHC see major histocompatibility complex MICA gene 149.1, 167.14 Michelin tyre syndrome 10.11, 148.31 miconazole atopic dermatitis 26.7 dermatophytoses 62.17 oral candidosis 62.24 microarray studies, chromosome disorders 116.2–116.3 microcephaly–lymphoedema–chorioretinal dysplasia 114.8 Micrococcus sedentarius, pitted keratolysis 56.1 microcomedo formation 79.3–79.5 histopathology 79.5 see also comedo microfilaments embryonic dermoepidermal junction 2.7, 2.7 epidermal basement membrane 91.14 microglossia 147.22 Micronia prolifera 73.8–73.9 micronychia 150.8 microorganisms atopic dermatitis 26.1–26.9 napkin dermatitis 18.1, 19.2–19.3 neonatal skin 5.1–5.2, 5.2 see also bacteria; fungi microphthalmia-associated transcription factor (MITF) 138.6

46

Index

microphthalmia with linear skin defects (MLS) 133.7 microsatellite markers, atopic dermatitis 23.5 microscopic polyangiitis (MPA) 167.8 Microsporum clinical features of infection 62.6 culture 62.12–62.13, 62.13 Microsporum audouinii 62.1 clinical features of infection 62.6, 62.6 deep mycoses 63.25 disease pathogenesis 62.5 epidemiology 62.3, 62.3, 62.4 Microsporum canis 62.3, 62.4 clinical features of infection 62.6, 62.7, 62.8, 62.8–62.9 deep mycoses 63.25 identification 62.12, 62.13, 62.14 treatment 62.15, 62.16 Microsporum ferrugineum 62.2–62.3, 62.3 clinical features of infection 62.6 deep mycoses 63.25 identification 62.13, 62.14 Microsporum fulvum 62.3 Microsporum gypseum 62.3, 62.6 Microsporum langeronii 63.25 Microsporum nanum 62.3 microstomia, dystrophic epidermolysis bullosa 118.15, 118.15, 118.23 microvilli embryonic epidermis 2.4, 2.5, 2.6 embryonic-fetal transition epidermis 2.14, 2.14 MIDAS syndrome 115.4, 115.28 midazolam 118.25, 190.7–190.8 midges 71.2 biting (Culicoides) 71.2, 71.7 midline cervical cleft, congenital 10.5 midline sinus of upper lip 10.7 Miescher cheilitis see orofacial granulomatosis Mikaelian syndrome 127.22 Mikulicz ulcers 147.2 milia 6.11, 6.11 Bazex–Dupré–Christol syndrome 137.1 dystrophic epidermolysis bullosa 118.11, 118.12, 118.12 epidermolysis bullosa acquisita 91.23, 91.23 epidermolysis bullosa simplex 118.6 Gorlin syndrome 132.7 vesiculobullous disease 87.1, 87.2 milia-like calcinosis cutis Down syndrome 95.4, 116.11 idiopathic 95.3–95.4 milia-like cysts, congenital melanocytic naevi 185.6, 185.7, 185.7 miliaria 6.9–6.11 apocrine see Fox–Fordyce disease generalized blistering 87.7–87.8 napkin area 20.9 miliaria crystallina (sudamina) 6.10, 87.7–87.8 napkin area 20.9 miliaria profunda 6.10, 87.8 miliaria pustulosa 6.10, 87.8 miliaria rubra (prickly heat) 6.10, 6.10, 87.8 chromosome disorders 116.10 napkin area 20.9 milk allergy see cow’s milk allergy consumption, acne and 79.1, 79.10 milk–alkali syndrome 95.8 milk-crust 35.2 see also cradle cap milker’s nodules 51.2, 51.24 diagnosis 51.1, 51.24 Millard technique, cleft lip repair 187.23, 187.25 millipedes, venomous 73.7 Milroy disease (congenital familial primary lymphoedema) 114.4–114.5, 114.6 antenatal diagnosis 114.20 genetics 114.4, 115.26 miltefosine, leishmaniasis 67.13 MIM numbers 115.19–115.26 mineral deficiencies 65.7–65.9

mineral oil preparation, scabies 72.5 mineral oils infantile seborrhoeic dermatitis 35.6 scabies 72.5 minocycline acne 79.8 -induced hyperpigmentation 104.4, 104.5, 104.8 laser therapy 189.7 leprosy 70.9, 70.10 prurigo pigmentosa 42.7 sarcoidosis 158.5 minor histocompatibility antigens (mHAs) 178.2 minoxidil induced hypertrichosis 148.30, 148.30 topical therapy 148.22, 149.6 mite bites 73.1 diagnostic criteria 71.7, 71.7, 73.1 management 73.1 reactions 71.4–71.5, 71.5 mites housedust see housedust mites scrub typhus transmission 61.9 MITF gene mutations 138.6 mitochondrial DNA repair 135.23–135.24 mitochondrial inheritance 115.5 mitral valve prolapse (MVP), Ehlers–Danlos syndrome 142.6 Mitsuda reaction 70.2 mixed immunobullous disease of childhood 89.1, 89.9 MLH1 gene mutations 137.14–137.15 MLPH gene mutations 138.7, 177.7–177.8 moccasin lesion, Proteus syndrome 111.3–111.4, 111.4 Mohr syndrome 147.23 moisturizing agents, atopic dermatitis 30.4–30.5 mokihana 45.8 molecular biology 115.19–115.29 molecular genetics 139.1–139.2 molluscoid pseudo-tumours, Ehlers–Danlos syndrome 142.3, 142.6 molluscs, venomous 73.8 molluscum contagiosum 46.1–46.6 aetiology 46.1 atopic dermatitis with 28.8–28.9, 28.9, 46.1 clinical features 46.2–46.4, 46.3 congenital or neonatal 8.3, 8.4 diagnosis 46.4, 46.4 differential diagnosis 46.4, 155.5 epidemiology 46.1 genital area 151.10, 151.10–151.11 HIV-related 46.1, 52.3, 52.3 immunocompromised children 46.1, 46.2, 64.3, 151.11 laser treatment 46.5, 189.9 oral 147.19 pathology 46.2, 46.2 treatment 46.4–46.6 molluscum contagiosum viruses (MCV) 46.1, 151.10 geographical distribution of subtypes 46.1 immune response 46.2 molluscum fibrosum pendulum, tuberous sclerosis 129.7 Moloney murine leukaemia virus (MoMuLV) 140.2 Mongolian spots 109.22, 109.23 differential diagnosis 154.10, 154.10 laser treatment 189.5–189.6 monilethrix 117.7, 127.95–127.96, 148.14–148.15 beaded hair 117.7, 117.8, 148.14, 148.14 clinical features 127.45, 148.9, 148.14, 148.15 genetic basis 115.24, 117.7, 127.96 keratosis pilaris 123.2 monkeypox 51.2, 51.18–51.19 clinical features 51.18, 51.19, 51.19 vesiculobullous lesions 87.5, 87.5 monoblastic sarcoma 99.13 monocyte chemotactic protein 4, atopic dermatitis 25.5

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

monocytes 103.1 atopic dermatitis 24.2 wound healing 17.1 monocytic ehrlichiosis 61.3 monogenic skin disorders see Mendelian skin disorders monosomy 116.3 monosulfiram 181.9 monounsaturated fatty acids (MUSFA), atopic dermatitis 27.10–27.11 montelukast, urticaria 74.13 Montenegro skin test 67.2, 67.13 Moraceae 45.10 Morgan–Dennie lines (infraorbital folds) 28.5, 28.5, 28.15 morphoea 173.1–173.10 aetiology and pathogenesis 173.1–173.2 associated conditions 173.7 Borrelia burgdorferi and 59.6, 173.1 circumscribed (or plaque) 173.3, 173.3, 173.4, 173.4 classification 173.3, 173.3 clinical features 173.3–173.7, 173.4 course and prognosis 173.3–173.4 deep, subcutaneous (profunda) 173.4 differential diagnosis 173.9 disabling pansclerotic 173.3, 173.6–173.7 epidemiology 173.1 generalized 173.3, 173.6 guttate 173.4 histopathology 4.8, 173.2–173.3 hyperpigmentation 104.5 laboratory tests 173.7–173.8 linear 173.3, 173.3, 173.4–173.6 head (‘en coup de sabre’) 173.5, 173.5–173.6, 173.6 pathogenesis 173.2 trunk and limbs 173.4–173.5, 173.5 mixed 173.3, 173.7 monitoring and imaging 173.8 treatment 173.9–173.10 vs. atrophoderma of Pasisni and Pierini 145.16, 145.17, 145.17 morpholine antifungals 62.15 Morquio syndrome 169.11, 169.12 mosaicism 115.9–115.18 chromosomal 116.6 cutaneous 110.1–110.2 epidermal naevi 110.1–110.2 extracutaneous 110.1–110.2 functional 115.12 autosomal mutations 115.12 X-linked male-lethal mutations 115.12, 115.12–115.13, 115.13 X-linked non-lethal mutations 115.13– 115.14, 115.14 genomic 115.12 autosomal lethal mutations 115.14, 115.14 autosomal non-lethal mutations 115.14–115.15 gonadal 115.6, 115.6 tuberous sclerosis 129.3–129.4 lethal and non-lethal mutations 115.12 loss of heterozygosity 115.14–115.15 mechanisms 110.2, 115.12–115.18 pigmentary see pigmentary mosaicism pigmentary patterns 115.9–115.12, 115.11 Blaschko’s lines 115.10, 115.11 chequerboard 115.10, 115.11 patchy without midline separation 115.10–115.12 phylloid 115.10, 115.11 Proteus syndrome 111.1 revertant 115.17–115.18 see also Blaschko’s lines mosquitoes biting behaviour 71.6, 71.7 immunopathology of bites 71.3–71.4 leprosy transmission 70.2 repellents 73.1 sensitivity to bites 71.3

Index mosquito nets, insecticide-impregnated 71.3 mother–child relationship, atopic dermatitis 34.2 moths, noxious 73.4 motretinide, acne 79.7–79.8 moulds 32.2, 32.8 moulting effect see Mauserung mouse flea (Leptopsylla segnis) 61.8 mouth disorders 147.1–147.25 red and pigmented lesions 147.14–147.17 sore 147.1–147.10 swellings/lumps 147.17–147.22 ulcers see oral ulceration white patches see oral leucoplakia moxibustion 154.11 MPO gene 177.11 M protein, group A streptococcus 54.1–54.2 MRI see magnetic resonance imaging MRSA see methicillin-resistant Staphylococcus aureus MSH2 gene mutations 137.14–137.15 MSH5 gene mutations 177.25 MSH6 gene mutations 137.14–137.15 MSX1 gene 127.79 mTOR see mammalian target of rapamycin Mucha–Habermann disease 100.1 mucinous eccrine naevus 94.12, 110.7 mucinous naevus 110.7 Muckle–Wells syndrome 176.2, 176.3 amyloidosis 159.4 genetics 115.26, 115.28 urticarial lesions 74.9, 163.5 mucocoele, salivary gland 147.21, 147.21 mucocutaneous leishmaniasis (MCL) 67.7–67.8 clinical features 67.6, 67.7–67.8 history 67.1 pathology 67.5 prognosis 67.13 treatment 67.12–67.13 mucocutaneous lymph node syndrome see Kawasaki disease mucoepithelial dysplasia, hereditary 127.32, 147.15 mucopolysaccharides, pseudo-xanthoma elasticum 144.2–144.3 mucopolysaccharidoses (MPS) 169.11, 169.11–169.12 type IH (Hurler) 148.29, 169.11, 169.11–169.12 type II (Hunter) 139.3, 169.11, 169.11, 169.12 mucormycosis 63.22–63.23, 147.7 diabetes mellitus 172.21 Mucor pusillus 63.22 mucosal involvement linear IgA disease of childhood 89.7, 89.7 pseudo-xanthoma elasticum 144.5, 144.5 systemic lupus erythematosus 175.6 vesiculobullous disorders 87.9, 87.9–87.10 see also oral manifestations mucosal melanotic macules, Peutz–Jeghers syndrome 137.16, 137.16 mucosal neuromas, MEN 2b 172.29, 172.29 mucositis-deafness 120.21 mucous membrane pemphigoid (MMP) 91.13, 91.13, 91.18–91.19 aetiology and pathogenesis 91.15, 91.18 clinical features 91.18–91.19, 91.19 differential diagnosis 91.19, 91.24 with IgA antibodies 89.1, 89.9 prognosis 91.19 treatment 91.19 vulva 91.19, 151.12–151.13 Muir–Torre syndrome (MTS) 137.14–137.15 pathogenesis 115.27, 137.14–137.15 tumour susceptibility 137.4, 137.14, 137.15 multicentric reticulohistiocytosis (MRH) 103.12, 103.13, 103.14 multifactorial traits 115.7 multiorgan failure, meningococcal septicaemia 55.7, 55.9 multiple carboxylase deficiency

biotin-responsive 20.11 hair loss 148.21, 148.21 vs. infantile seborrhoeic dermatitis 35.6 multiple endocrine neoplasia (MEN) 172.29, 172.29–172.30 type 1 (MEN 1) 115.27, 137.5, 172.29, 172.30 type 2A (MEN 2A) (Sipple syndrome) 115.27, 172.29 cutaneous amyloidosis 159.1, 159.3, 172.30 tumour susceptibility 137.5 type 2B (MEN2B) 137.5, 172.29–172.30 type 4 (type X) 172.29 multiple familial trichoepitheliomas (MFT) 137.9–137.10 associated malignancies 137.3, 137.10 clinical features 137.10, 137.10 pathogenesis 115.27, 127.68, 137.9 multiple hamartoma syndrome see Cowden syndrome multiple lentigines syndrome see LEOPARD syndrome multiple self-healing squamous epitheliomas 137.2 multiple sulphatase deficiency (MSD) 121.14, 121.44 Mulvihill–Smith syndrome 134.11–134.12 mumps 147.21 mumps skin test antigen, wart treatment 181.9 MUNC 13-4 103.17 Munchhausen syndrome see factitious disorders Munchhausen syndrome by proxy (MSBP) see factitious disorder by proxy Munro microabscesses 80.1 mupirocin ointment 181.7–181.8 folliculitis 54.5 infected atopic dermatitis 26.4 Murray–Puretic–Drescher syndrome see juvenile hyalinosis Musca 69.3, 69.4 Muscina stabulans 69.4 muscle paresis/paralysis, leprosy 70.5–70.6 musculocutaneous flaps 186.5 musculoskeletal manifestations Ehlers–Danlos syndrome 142.5–142.6, 142.7 juvenile dermatomyositis 175.11, 175.11 Lyme borreliosis 59.7 Marfan syndrome 145.5, 145.5–145.6, 145.6 neurofibromatosis 1 128.4–128.5 pigmentary mosaicism 131.4, 131.4 Proteus syndrome 111.5, 111.5 systemic lupus erythematosus 175.6 systemic sclerosis 174.10 yaws 60.3, 60.4, 60.4 see also skeletal manifestations mustard gas 87.5, 87.9 mutational analysis, prenatal diagnosis 139.6 mutations lethal and non-lethal 115.12 point 115.6 MVK gene mutations 176.2 mycetoma (Madura foot) 63.4–63.6 actinomycotic see actinomycotic mycetoma clinical features 63.5, 63.5 eumycotic 63.4, 63.5, 63.6 c-myc gene 110.3 MYCN gene 99.10 mycobacteria 57.1 atypical (non-tuberculous; NTM) 57.1, 57.5–57.10 identification 57.6 Runyon classification 57.1, 57.2 see also individual species mycobacterial infections 57.1–57.10 non-tuberculous (atypical) 57.5–57.10 immunocompromised children 57.8, 57.9, 57.10, 64.2, 64.9 primary immunodeficiencies 64.2, 64.2 see also leprosy; tuberculosis Mycobacterium avium-intracellulare complex (MAIC) 57.1, 57.8–57.9

47

clinical features 57.9, 57.9 HIV infection 52.2, 57.5, 57.9 Mycobacterium chelonae 57.9–57.10 Mycobacterium fortuitum 57.9, 57.10 Mycobacterium kansasii 57.6, 57.8 Mycobacterium leprae 70.1–70.2 immune responses 70.2–70.3 phenolic glycolipid I (PGL-I) 70.3 see also leprosy Mycobacterium malmoense 57.6 Mycobacterium marinum HIV infection 52.2 infections 57.6–57.7 Mycobacterium scrofulaceum 57.8 Mycobacterium tuberculosis 57.4 see also tuberculosis Mycobacterium ulcerans 57.7–57.8 geographical distribution 57.6, 57.7 transmission 45.1, 57.7 Mycobacterium vaccae therapy, atopic dermatitis 30.11 Mycobacterium xenopi 57.6 mycophenolate mofetil (MMF) atopic dermatitis 30.11 pemphigus vulgaris 91.4 systemic lupus erythematosus 175.8 Wegener granulomatosis 167.6 Mycoplasma hominis, congenital infection 8.6 Mycoplasma pneumoniae congenital infection 8.6 erythema multiforme 78.2, 78.3 mycoses cryptococci 63.2–63.6 deep 63.1–63.26 oral lesions 147.6, 147.6–147.7 dematiaceous fungi 63.6–63.8 dimorphic fungi 63.8–63.20 opportunistic 63.1 see also fungal infections mycosis fungoides (MF) 99.20–99.21, 102.2–102.6 clinical features 99.20–99.21, 102.2–102.3 differential diagnosis 4.7, 102.3 folliculotropic 99.21, 102.5 genetic features 102.4 histopathology 99.21, 102.3–102.4, 102.4 hypopigmented 99.21, 102.2–102.3, 102.3 immunophenotype 102.4 patch (erythematous; premycotic) stage 99.20, 99.20, 102.2, 102.3 pityriasis lichenoides-like 99.21 plaque (mycotic) stage 99.20, 102.2 prognosis and predictive factors 102.4–102.5 treatment 99.21, 102.5 tumour stage 99.20, 99.20–99.21, 99.21, 102.2 variants and subtypes 99.21, 102.5–102.6 mycotic granuloma 63.25 mycotic hypothesis, infantile seborrhoeic dermatitis 35.2–35.3 MYD88 gene 177.11 myelocystocoele 10.16 myeloid cell tumour, extramedullary 99.13 myeloid sarcoma 99.13 myeloperoxidase deficiency 177.11 myeloproliferative disorders, chronic eosinophilic 36.6 myiasis 69.1–69.4 aural 69.3 body cavity 69.3–69.4 cutaneous 69.1 dermal 69.2–69.3 genitourinary 69.3–69.4 intestinal 69.4 nasal 69.3 ocular 69.3 subcutaneous 69.1–69.2, 69.2 wound 69.3 MYO5A gene mutations 138.7, 177.7 myocardial infarction Kawasaki disease 168.8, 168.10 pseudo-xanthoma elasticum 144.6

48

Index

myocarditis Kawasaki disease 168.7 neonatal lupus erythematosus 14.4, 14.7 myofibroblasts, systemic sclerosis 174.5 myofibroma/myofibromatosis 97.2–97.3 clinical features 97.3 histopathology 4.3, 97.2, 97.2–97.3 spontaneous regression 97.3, 97.4 myopathy neutral lipid storage disease with ichthyosis 121.52 systemic sclerosis 174.10 myosin Va 138.1, 138.7 myrmecia 47.4 myxoedema hypothyroidism 172.2, 172.2, 172.3 pretibial 172.5–172.6 myxomas, Carney complex 172.30 nadifloxacin, topical, acne 79.8 NADPH oxidase deficiency 177.9 Naegeli–Franceschetti–Jadassohn syndrome (NFJS) 117.3–117.4, 127.97 clinical features 117.3, 127.45 genetic basis 115.25, 117.4, 127.97, 138.3 hyperpigmentation 117.4, 127.97, 138.9–138.11, 138.10 naevogenesis, theories of 185.9 naevoid basal cell carcinoma (NBCC) 132.4, 132.8–132.9 naevoid basal cell carcinoma (NBCC) syndrome see Gorlin syndrome naevoid basaloid follicular hamartomas 110.6–110.7 naevoid hypertrichosis 148.31 naevus (naevi) achromic see naevus depigmentosus apocrine 94.9 connective tissue see connective tissue naevus deep penetrating 4.2 dermal see intradermal naevi eccrine 94.12, 110.7 epidermal see epidermal naevi Gorlin syndrome 132.8, 132.8 hair follicle 94.6 junctional see junctional naevi lipoatrophy associated with 141.12 melanocytic see melanocytic naevi nail matrix 150.7, 150.7 patient advocacy group 179.7 straight hair 148.17 woolly hair 110.9–110.10, 110.10, 148.17, 148.17 see also specific types naevus anaemicus 112.14 naevus comedonicus (follicular naevus) 110.5–110.6, 110.6 naevus depigmentosus (ND) 104.2–104.3 differential diagnosis 104.3, 105.5, 131.5 treatment 104.3, 131.5 naevus elasticus 145.1 naevus flammeus neonatorum 112.15 chromosome disorders 116.12–116.13 naevus lipomatosus, lumbosacral area 10.17, 10.18 naevus lipomatosus cutaneous superficialis 133.7 naevus of Ito 109.22–109.23 laser treatment 189.4–189.5 naevus of Ota 109.22–109.23 laser treatment 189.4–189.5, 189.5 naevus of Starink 110.12–110.13 naevus sebaceous (NS) 110.3–110.5 associated syndromes 110.5, 110.5 clinical features 110.3, 110.3–110.4, 110.4 hypophosphataemic rickets and 110.19–110.20 management 110.5, 189.9 Proteus syndrome 111.4 secondary neoplasms 110.4, 110.4–110.5 naevus sebaceous syndrome 110.5, 111.8 naevus spilus (speckled lentiginous naevus) 109.17–109.18

clinical features 109.17–109.18, 109.18 phacomatosis pigmentokeratotica 110.13–110.14, 110.14 naevus trichilemmocysticus 110.6 naevus unius lateris 110.9 naftifine 62.15 Nagashima disease 104.10 Naga sore see tropical ulcer Nagayama’s spots 49.7 nail(s) anatomy and physiology 150.1 bifid/split 116.16–116.17 broad 116.16–116.17 development 2.28–2.29, 2.29, 2.30 dysplastic, chromosome disorders 116.16, 116.17 familial chronic candidiasis 177.15 fungal infections see onychomycosis growth 150.1 herringbone (chevron) 150.3 hypoplasia 116.16, 150.8 ingrown 150.2–150.3 keratinization 2.28 lichen planus 85.5, 85.5, 150.6, 150.6 lichen striatus 86.5, 150.6–150.7 newborn infants 150.1 pitting, psoriasis 80.5, 80.5, 150.5 psoriasis 80.2, 80.5, 80.5, 150.4–150.5 volar 116.17 white spots 150.3–150.4, 150.4 nail abnormalities AEC/Rapp–Hodgkin syndrome 127.75, 127.76 chromosome disorders 116.16–116.17 chronic mucocutaneous candidiasis 62.22, 62.22, 177.13, 177.14 Clouston syndrome 127.90, 127.90 Darier disease 125.2, 125.2 dystrophic epidermolysis bullosa 118.14, 118.22 EEC syndrome 127.78 epidermolysis bullosa simplex 118.6, 118.6 focal dermal hypoplasia 133.3, 133.4 graft-versus-host disease 178.7 hypohidrotic ectodermal dysplasia 127.69 junctional epidermolysis bullosa 118.31, 150.9 odonto-onychodermal dysplasia 120.11, 127.85 pachyonychia congenita 120.20, 120.20, 150.9 pure hair-nail ectodermal dysplasia 127.96 Schöpf–Schulz–Passarge syndrome 127.86 nail bed 150.1 splinter haemorrhages, psoriasis 150.5 nail biting (onychophagia) 150.3, 180.3–180.4, 180.4 by age group 180.3 treatment 180.11 nail care atopic dermatitis 30.5 newborn infants 5.2 nail disorders 150.1–150.9 common 150.2–150.6 hereditary 115.24 uncommon 150.6–150.9 nail dystrophy alopecia areata 149.3 dyskeratosis congenita 136.8, 138.10 dystrophic epidermolysis bullosa 150.8–150.9, 150.9 habits causing 180.4, 180.4 incontinentia pigmenti 130.3–130.4, 130.4 lamellar ichthyosis/congenital ichthyosiform erythroderma 121.31 twenty-nail see twenty-nail dystrophy nailfolds 150.1 capillary changes, prescleroderma 174.5, 174.6 congenital hypertrophy of lateral 150.2 nail matrix 150.1 naevi 150.7, 150.7 nail–patella syndrome 115.24, 150.8, 150.8 nail plate 150.1

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

Naja nigricollis 73.10 naloxone 190.8 NALP1 gene 105.1 NAME syndrome see Carney complex nanoparticles 108.13 naphthalene poisoning 184.13 naphthaquinones, plant-derived 45.2 napkin(s) absorbency of used 21.1–21.2 acrylate gelling material (AGM)-containing 21.1–21.2, 21.3 changing 5.2, 21.1 disposable 21.1–21.2 vs. washable cloth 19.1, 21.2, 21.2–21.3 zinc oxide/petrolatum-containing 21.2 role in napkin dermatitis 19.1 washable cloth 21.1 napkin area care 21.1–21.3 dermatophytoses 62.9 psoriasis 20.8, 20.8, 80.2, 151.4 varicella 20.12, 151.11, 151.11 see also genital disease/area; perianal area napkin dermatitis 5.2–5.3, 18.1, 20.1–20.12, 20.2 allergic 19.3, 20.2, 20.4 atopic 20.2, 20.8 bullous impetigo 20.2, 20.6, 20.6 candidal 20.2, 20.5–20.6, 62.21, 151.11 clinical features 20.5, 20.5, 62.21 history 18.1 HIV infection 52.2 irritant contact dermatitis with 20.8–20.9 pathogenesis 19.2–19.3 psoriasiform skin reaction 20.5, 20.5 treatment 21.4, 62.24 causative factors 18.1, 18.1, 19.1–19.3 contact 20.1–20.4 definition 18.1 differential diagnosis 20.1–20.12, 20.3 history 18.1 in HIV infection 20.7, 52.2 infectious 20.5–20.7 inflammatory conditions 20.7–20.10 intertrigo 20.2, 20.2–20.3 irritant contact (primary) 20.1–20.2, 20.2 clinical features 20.1–20.2, 20.3 secondary infections 20.8–20.9 Jacquet type see Jacquet dermatitis lichen striatus and 86.2, 86.2 management 21.1–21.5 metabolic conditions 20.11–20.12 mixed 20.8–20.9 neoplastic 20.10–20.11 prevention 5.3, 5.8, 21.1–21.3 seborrhoeic 20.2, 20.7–20.8, 20.8, 35.4, 35.4 tide water mark type 20.1–20.2, 20.3 treatment 21.3–21.5, 21.4 complications 21.5 W-shaped 19.2 ‘napkin psoriasis’ 20.5 nappes claires, neonatal pityriasis rubra pilaris 11.3, 11.4 nappies see napkin(s) nappy rash see napkin dermatitis nasal chondritis relapsing polychondritis 167.19 Wegener granulomatosis 167.3, 167.3 nasal glioma (nasal cerebral heterotopia) 10.14–10.15 nasal secretions, atopic dermatitis and 27.14 nasal tip, infantile haemangioma 113.9, 113.9 nasal type extranodal NK/T-cell lymphoma 99.23, 102.10 skin involvement 99.23, 99.24 variants 77.14, 99.24 nasogastric feeding dystrophic epidermolysis bullosa 118.23 epidermolysis bullosa simplex 118.8–118.9 nasopharyngeal chlamydial infections 153.14 National Institute for Health and Clinical Excellence (NICE)

Index anti-TNF-α therapy 182.8 atopic dermatitis guideline 30.1, 30.6, 31.12, 31.12 natural killer (NK)-cell lymphoma, blastic 99.25, 102.16 natural killer (NK) cells alopecia areata 149.1, 149.2 atopic dermatitis 33.1 natural killer (NK)/T-cell lymphoma, extranodal, nasal type see nasal type extranodal NK/T-cell lymphoma natural moisturizing factor (NMF) 27.2, 27.4, 27.10 atopic dermatitis 27.9–27.10, 27.10 infants 27.13–27.14 production from filaggrin 23.7–23.8, 23.8 Nav1.7 channels 166.1 Navajo poikiloderma (Clericuzio-type poikiloderma with neutropenia) 115.28, 127.52 Naxos disease 127.46, 127.99 genetic basis 115.21 woolly hair 148.16 Naxos-like syndrome 127.99, 148.16 NCF gene mutations 177.9 Nd:YAG lasers hair removal 189.3, 189.4 pigmented lesions 189.4, 189.5, 189.6, 189.7 tattoo removal 189.7 neck congenital cartilagenous rests (wattles) 10.2, 10.3 congenital midline cleft 10.5 signs in atopic dermatitis 28.5, 28.6, 104.9 tissue expansion 191.3–191.5, 191.5 necklace of Venus 104.12 necrobiosis, granuloma annulare 93.3, 93.4 necrobiosis lipoidica diabeticorum (NLD) 172.22, 172.22 necrobiotic xanthogranuloma (NXG) 103.12, 103.14 necrosis/necrotic lesions iatrogenic neonatal 17.6, 17.7 pityriasis lichenoides 100.2, 100.2 see also subcutaneous fat necrosis (SFN), neonatal necrotizing eosinophilic folliculitis 36.5 necrotizing fasciitis (NF) 54.1, 54.6–54.7 immunocompromised children 64.9 nectin 1 127.100 needle-free injections, local anaesthetics 190.5 needle marks, neonates 17.10 neglect 154.9 incidence/prevalence 154.1, 155.1 medical 154.9 reporting 155.4–155.6 see also child abuse Neisseria gonorrhoeae (gonococcus) 153.8 diagnostic tests 153.11 see also gonorrhoea Neisseria infections, complement deficiencies 177.19, 177.20 Neisseria meningitidis (meningococcus) 55.1 antibiotic resistance 55.9 carriage 55.1 diagnostic methods 55.9 eradication 55.13 pathogenic role in disease 55.5, 55.5 vaccines 55.13 see also meningococcal infection Nelson syndrome 104.8 NEMO 127.65, 127.67, 130.2 NEMO/IKKγ gene mutations 115.2, 127.66, 127.67 hypohidrotic ectodermal dysplasia with immunodeficiency 115.6–115.7, 127.71, 177.26 hypohidrotic ectodermal dysplasia with immunodeficiency osteopetrosis and lymphoedema 114.8, 127.71 incontinentia pigmenti 130.2

neodymium:YAG lasers see Nd:YAG lasers Neofibularia nolitangere 73.9 neomycin allergy 44.3, 44.4, 44.10 toxicity 5.7, 17.7, 184.7–184.8 neonatal conjunctivitis chlamydial 153.13, 153.14 diagnosis 153.15, 153.22 treatment 153.16, 153.22 differential diagnosis 153.11 gonococcal see gonococcal conjunctivitis, neonatal neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome 115.21, 121.57, 121.57–121.58 neonatal intensive care collodion baby 12.3 harlequin ichthyosis 13.5–13.6 iatrogenic skin disorders 17.6–17.11 monitoring-related problems 17.9–17.10 neonatal intensive care unit (NICU) handwashing 5.3 skin care of premature infants 5.3–5.5 neonatal lupus erythematosus (NLE) 14.1–14.11, 175.9 aetiology and pathogenesis 14.3–14.4 cardiac features 14.4, 14.6–14.7 investigation 14.8 management 14.9–14.10 clinical features 14.4, 14.4–14.7 cutaneous features 14.4, 14.4–14.6, 14.5, 14.6, 14.7 differential diagnosis 14.7, 76.6–76.7, 112.19 histology 14.8, 14.8–14.9 management 14.9 definition 14.1 education, follow-up and prognosis 14.10–14.11 epidemiology 14.1, 14.2 haematological features 14.4, 14.7 management 14.10 hepatic features 14.4, 14.7, 14.10 historical perspective 14.1 investigations 14.7–14.9, 14.8 management 14.9, 14.9–14.10 neurological disease 14.7 research registry 14.1 serology 14.1, 14.9 neonatal-onset multisystem inflammatory disease (NOMID) see NOMID/CINCA syndrome neonates acne 8.5, 8.7, 79.14–79.15, 79.15 adnexal polyp 6.11–6.12 bullous dermolysis 115.22, 118.14 dermis 3.5–3.6 desquamation 6.2, 6.2 dystrophic epidermolysis bullosa 118.12, 118.12 skin care 118.17, 118.17–118.18 eosinophilia 36.1 epidermis 3.2–3.5, 3.3 erythroderma 11.1–11.13 adverse drug reactions 11.8 AEC syndrome 11.5, 127.76, 127.76 cutaneous disorders 11.1–11.6 diagnostic work-up 11.11–11.13, 11.12 differential diagnosis 11.1–11.13, 11.2, 35.6 immunological disorders 11.8–11.10 inborn errors of metabolism 11.10–11.11 infections and toxicities 11.6–11.7 MEDOC 121.5 Netherton syndrome 11.5, 124.3, 124.3 seborrhoeic dermatitis 11.2, 11.2, 35.4, 35.5 harlequin colour change 6.2–6.3, 6.3 hyperpigmentation 104.9 iatrogenic disorders 17.1–17.11 antenatal/intrapartum 17.1–17.5 postnatal 17.6–17.11 infections acquired 9.1–9.7, 9.2

49

congenital 8.1–8.7 erythroderma 11.6–11.7 ingrown fingernails 150.3 junctional epidermolysis bullosa 118.30– 118.31, 118.31 Malassezia cephalic pustulosis see under Malassezia MEDOC 121.5 melanoma 109.25–109.26 microbial colonization of skin 5.1–5.2, 5.2 milia 6.11, 6.11 miliaria 6.9–6.11 nails 150.1 nursing care 192.1, 192.2, 192.3 pemphigus 91.2, 91.8, 91.9 percutaneous absorption 184.2 topical therapies 3.3, 181.2–181.3 toxic risks 3.4, 5.7, 5.7 percutaneous respiration 3.6 perianal dermatitis 6.11 pustular eruptions 8.1, 9.1, 9.2 scar formation 17.1–17.2 sebaceous gland activity 3.6 skin anatomy 3.1, 3.3 skin care 5.1–5.8 at birth/in maternity hospital 5.1–5.2 over-the-counter products 5.5–5.8 skin physiology 3.1–3.6 skin roughness 3.3, 3.4 skin surface pH 3.3, 3.4–3.5 sterile transient papulopustular eruptions 6.4, 6.4–6.9 stratum corneum hydration 3.3, 3.4, 27.13 subcutaneous tissue disorders 7.1–7.5 surgical treatment 186.1 thermoregulation 3.6 transepidermal water loss 3.2–3.4, 3.3, 27.12–27.13 transient dermatoses 6.1, 6.1–6.12 transient localized hyperpigmentation 6.3–6.4, 6.4 transient pustular melanosis see transient neonatal pustular melanosis vernix caseosa see vernix caseosa vesiculobullous lesions 87.6, 87.6–87.7 wound healing 3.6 see also preterm infants neoplasia see tumour(s) neoprene allergy 44.10 Neotestudina rosatii 63.4 nephrotic syndrome carotenaemia 171.2, 171.5 purpura fulminans 162.4, 162.6 nerve fibres embryonic-fetal transition 2.16, 2.17, 2.18 embryonic skin 2.9–2.11, 2.10, 2.11 growth into skin grafts 187.12, 187.12 role of Merkel cells in development 2.16 nerve growth factor (NGF) embryonic skin 2.8 mastocytosis pathogenesis 75.5 production by Merkel cells 2.7, 2.16 nerve growth factor receptor (NGFR) embryonic skin 2.8 p75 developing hair follicles 2.34, 2.35 embryonic-fetal transition 2.17 embryonic skin 2.10, 2.11 Netherton-Comèl syndrome see Netherton syndrome Netherton syndrome 121.58, 124.1–124.8 aetiology and pathogenesis 115.21, 121.4, 124.1–124.2 clinical features 121.45, 121.58, 124.3, 124.3–124.6, 124.4 diagnostic testing 11.13, 124.6, 124.7 differential diagnosis 121.36 hair abnormalities 124.4, 124.4–124.5, 148.12, 148.13 neonatal erythroderma 11.5, 124.3, 124.3 pathology 4.7, 124.2–124.3

50

Index

Netherton syndrome (cont.) prenatal diagnosis 124.7, 139.3 prognosis 124.7–124.8 skin barrier dysfunction 27.11, 121.63, 124.2, 124.3 treatment 121.63, 124.6–124.7 nettles, stinging 45.3, 45.3 netuvidine, HSV infections 48.7 Network for Ichthyoses and Related Keratinization Disorders (NIRK) 11.4 Neu–Laxova syndrome 121.38, 121.45 neural cell adhesion molecule (NCAM) 2.8, 2.34 neural crest-derived malignant tumours 99.10–99.12 neural tube defects cranial, cutaneous signs 10.12–10.13, 10.13 spinal occult, cutaneous signs 10.16–10.18 neural tumours histopathology 4.3, 4.3 neurofibromatosis 2 128.12, 128.12–128.13 neurilemmomas see schwannomas neurinomas see schwannomas neuroblastoma 99.10–.99.12 clinical features 99.10–99.11, 99.11 familial 99.10 racoon eyes 99.11, 154.11 neuroborreliosis 59.6 aetiology 59.3 diagnosis 59.7, 59.8 prognosis 59.9 treatment 59.9, 59.9 neurocutaneous melanosis 109.6 neuroendocrine tumours, genital area 151.20 neurofibromas cutaneous 128.3, 128.3 genital 151.20 histopathology 128.6 laser therapy 189.9 neurofibromatosis 1 128.3–128.4 pathogenesis 128.7 plexiform (PNFs) 128.4, 128.4, 128.6, 128.11 segmental neurofibromatosis 1 128.11 subcutaneous 128.3–128.4 neurofibromatoses 128.1–128.14, 128.2 patient advocacy group 179.7 neurofibromatosis type 1 (NF1) 128.1–128.10, 128.2 associated malignancies 128.3–128.4, 128.5, 137.3 café-au-lait macules 109.10, 128.1–128.3, 128.2 dermatological features 128.1–128.4, 128.2, 128.3, 128.4 diagnostic criteria 128.1, 128.2 differential diagnosis 111.8, 128.7–128.8, 128.8, 137.15 epidemiology 128.1 genetics and pathogenesis 115.27, 128.6–128.7 genetic testing 128.8 genital involvement 151.21 management 128.8–128.9 non-dermatological features 128.4–128.6, 128.5 oral involvement 147.17 pathology 128.6 segmental/mosaic 128.10–128.12, 128.11 neurofibromatosis type 1 (NF1)-like cutaneous lesions 128.13 neurofibromatosis type 1 (NF1)-like syndrome (Legius syndrome) 115.25, 128.7–128.8, 128.8 neurofibromatosis type 2 (NF2) 128.2, 128.12–128.14 dermatological features 128.12, 128.12–128.13 differential diagnosis 128.8, 128.14 genetics and pathogenesis 115.27, 128.13–128.14 NIH diagnostic criteria 128.12 plaques 128.12, 128.12 neurofibromin 128.7 neurolemmomas, genital 151.20 neuroligin 4 (NLGN4) gene defects 121.11, 121.13

neurological disorders cutis verticis gyrata 10.1 seborrhoeic dermatitis 41.2 vs. leprosy 70.8 neurological manifestations ataxia telangiectasia 177.4 Behçet disease 167.16, 167.17 Chédiak–Higashi syndrome 177.7 Cobb syndrome 112.5 Cockayne syndrome 135.14, 135.15, 135.16 congenital melanocytic naevi 109.6–109.7 Ehlers–Danlos syndrome 142.7 epidemic typhus 61.7 epidermal naevi 110.5, 110.10, 110.20 erythrokeratoderma with ataxia 122.14 focal dermal hypoplasia 133.4 Gorlin syndrome 132.10 incontinentia pigmenti 130.5 juvenile dermatomyositis 175.11 Lyme borreliosis see neuroborreliosis neonatal lupus erythematosus 14.7 Parry–Romberg syndrome 173.6 PHACE syndrome 113.11 phacomatosis pigmentokeratotica 110.14 phenylketonuria/hyperphenylalaninaemia 169.3 pigmentary mosaicism 131.3–131.4, 131.4 Proteus syndrome 111.6 PTEN hamartoma-tumour syndrome 137.19 Rocky Mountain spotted fever 61.3 Sjögren–Larsson syndrome 121.42–121.47 Sturge–Weber syndrome 112.15–112.16 systemic lupus erythematosus 175.6–175.7, 175.7 tuberous sclerosis 129.4–129.5, 129.11 Wegener granulomatosis 167.4, 167.4 xeroderma pigmentosum 135.7, 135.9 neuromas see schwannomas neuronal ceroid lipofuscinosis infantile (INCL) 139.3 late-infantile (LINCL) 139.3 neuropathic vulval pain 151.24 neuropeptide Y (NPY), embryonic-fetal transition 2.17 neurosarcoidosis 158.4 neurosurgery, tuberous sclerosis 129.11 neurosyphilis 153.5 neutral lipid storage disease (NLSD) 121.52 neutral lipid storage disease with ichthyosis (NLSDI) (Chanarin–Dorfman syndrome) 121.52–121.53 clinical features 11.5, 121.44, 121.52 differential diagnosis 121.37 genetics 115.20, 121.53 neutral lipid storage disease with myopathy (NLSDM) 121.52 neutropenia cyclic 177.10 oral ulceration 147.7, 147.7 severe congenital 177.10 X-linked 177.10 neutrophilic dermatosis acute febrile see Sweet syndrome of the hands 156.1–156.3 nevirapine hypersensitivity 52.4–52.5 nevus see naevus newborn infants see neonates NF1 see neurofibromatosis type 1 NF1 gene 128.7, 128.11, 141.6 NF2 see neurofibromatosis type 2 NF2 gene 128.13–128.14 NF-κB see nuclear factor-κB NFKB1A gene mutations 177.26 NHEJ1 syndrome 177.31 NHP2 gene 136.8 niacin (nicotinamide; niacinamide) deficiency 65.5, 65.5 treatment granuloma annulare 93.8 Hartnup disease 169.10 pellagra 65.5

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

NICE see National Institute for Health and Clinical Excellence nickel allergy contact dermatitis 44.8–44.9 atopic dermatitis and 30.10 clinical features 44.4, 44.5, 44.9 epidemiology 44.2, 44.3–44.4 pathogenesis 44.1–44.2 lichen striatus 86.2 pompholyx 39.1, 39.3 nicotinamide see niacin nicotine poisoning 184.8 Nijmegen breakage syndrome 177.5 Nikolsky sign 87.2 pemphigus vulgaris 91.3 staphylococcal scalded skin syndrome 11.6, 54.9 Stevens–Johnson syndrome/toxic epidermal necrolysis 183.9 NIPAL4 (ichthyin) gene mutations 121.34, 122.11–122.12 NIPBL gene mutations 148.29 nipples atopic dermatitis 28.3, 28.4 developmental abnormalities 10.7–10.8 supernumerary 10.7, 10.7–10.8 nitric oxide (NO) eosinophilic pustular folliculitis 36.3 topical therapy, molluscum contagiosum 46.6 nitric oxide synthase inducible (iNOS), atopic dermatitis 26.3 neuronal (nNOS), eosinophilic pustular folliculitis 36.3 nitroblue tetrazolium (NBT) reduction assay 177.10 nitroprusside, erythromelalgia 166.3 nitrous oxide (N2O) 190.9 nits 72.10, 72.10, 72.11 differential diagnosis 72.12 removal of dead 72.13 treatment 72.12, 72.13 see also head louse NK cells see natural killer (NK) cells NKG2D receptor 149.2 NLRP3 74.9, 176.2 NMDA-type glutamate receptors 27.6–27.7 Nocardia 63.4 Nocardia asteroides 63.27 Nocardia brasiliensis 63.4, 63.5, 63.27, 63.27 Nocardia caviae 63.27 Nocardia farcinica 63.27 nocardiosis 63.27–63.28 acute primary cutaneous 63.28 chronic cutaneous see actinomycotic mycetoma pulmonary 63.27, 63.27 NOD1 (CARD4) gene, atopic dermatitis 23.9, 23.13 NOD2 gene atopic dermatitis 23.13 Blau syndrome 158.7–158.8 Crohn disease 157.1, 158.8 NOD2 protein 158.7, 158.7–158.8 nodular fasciitis 97.7–97.8 nodular proliferative neurocristic hamartoma 109.3 nodular tuberculid 77.16 nodular vasculitis 77.16 nodules cellular proliferative 4.2 defined 92.1 dermal, histopathology 4.3–4.4 differential diagnosis 92.1–92.9, 92.2 polyarteritis nodosa 167.9, 167.9, 167.10 subcutaneous, chromosome disorders 116.13, 116.14 subepidermal calcified 95.3, 95.3 see also lumps, cutaneous NOMID/CINCA syndrome 176.2, 176.3 urticarial lesions 8.1, 74.9, 163.5 non-accidental injury 154.1–154.12 see also child abuse

Index non-bullous congenital ichthyosiform erythroderma see congenital ichthyosiform erythroderma non-Hodgkin lymphoma (NHL) 99.19–99.27 non-B-non-T (null) cell type 99.25–99.26 see also cutaneous B-cell lymphoma; cutaneous T-cell lymphoma non-ketotic hyperglycinaemia 20.11–20.12 non-Langerhans cell histiocytosis see under histiocytosis non-steroidal anti-inflammatory drugs (NSAIDs) eosinophilic pustular folliculitis 36.5 Henoch–Schönlein purpura 160.6 hypersensitivity reactions to 74.4, 183.2, 183.11 perioperative analgesia 190.6 sunburn 108.6–108.7 Noonan syndrome associated malignancies 137.6 cutis verticis gyrata 10.1 genetics 115.28 keratosis pilaris atrophicans faciei 123.2 lymphatic disorders 114.8 prenatal diagnosis 114.20 NOP10 gene 136.8 noradrenaline, responses in atopic dermatitis 25.1, 25.2 North American blastomycosis 63.9–63.10 North American Contact Dermatitis Group (NACDG) 44.6–44.7, 44.7, 44.9 North Asian tick typhus (Rickettsia sibirica) 61.2, 61.5–61.6 Norwegian scabies see scabies, crusted nose actinic prurigo 106.4, 106.5 atopic dermatitis 28.3, 28.4 congenital inclusion dermoid cysts 10.15 congenital midline masses 10.14, 10.14 dermoid sinus cyst 10.15 surgical scar placement 187.3, 187.6, 187.7 notalgia paraesthetica 104.7 Notch protein 127.83 Nottingham Eczema Severity Score (NESS) 29.5, 29.10 NRAS gene mutations 109.3, 177.8 NSAIDs see non-steroidal anti-inflammatory drugs NSDHL gene mutations 110.18, 121.54, 121.55 NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione) 169.4, 169.6 nuchal translucency, fetal 114.20, 116.9 nuclear factor-κB (NF-κB) 127.65 Hodgkin disease 99.17 signalling pathway (and defects) 127.65– 127.68, 127.67 Blau syndrome 158.7, 158.8 Crohn disease 158.8 ectodermal dysplasias 127.66, 127.68–127.73, 130.2 nucleotide excision repair (NER) 135.1–135.2 cellular capacity testing 135.10 global genome repair (GGR) 135.3, 135.3 pathway 135.2–135.5, 135.3 senescence and 135.23 transcription coupled repair (TCR) 135.3, 135.3–135.4 nucleotide excision repair (NER)-defective syndromes 135.5–135.24, 135.6 clinical features 135.7 genotype-phenotype interactions 135.4, 135.4, 135.5 heterozygous carriers 135.23 new therapeutic strategies 135.24 pathogenesis 135.2–135.5, 135.3 patient support groups 135.24 see also Cockayne syndrome; trichothiodystrophy; xeroderma pigmentosum nummular (discoid) atopic dermatitis 28.8, 28.8, 40.1 nummular (discoid) dermatitis 40.1–40.3

clinical features 40.1–40.2, 40.2 differential diagnosis 28.10, 40.2, 40.2 treatment 26.3–26.4 nursing care 192.1–192.19 collodion baby 12.3–12.4, 192.1, 192.2 eczema 192.4, 192.5–192.6, 192.6, 192.8 epidermolysis bullosa in newborn 192.1, 192.3 harlequin ichthyosis 192.1, 192.2 infections and infestations 192.4–192.7, 192.10–192.12 neonatal conditions 192.1 psoriasis 192.4, 192.9 systemic drug therapy 192.10–192.13, 192.15–192.17 toxic epidermal necrolysis 192.13–192.19, 192.18 vascular birthmarks 192.7–192.10, 192.13, 192.14 see also skin care nut allergy 31.6, 31.15, 31.17 nutrition acne risk and 79.1 dystrophic epidermolysis bullosa 118.22, 118.22–118.24 see also dietary management nutritional deficiencies dystrophic epidermolysis bullosa 118.16 eczematous patients on elimination diets 31.12–31.13 glossitis 147.24 hair loss 148.20, 148.20–148.21 HIV-related eruptions resembling 52.5 skin manifestations 65.1–65.9 tropical ulcers and 66.2 see also malabsorption; malnutrition nutritional disorders 65.1–65.10 hyperpigmentation 104.8 hypopigmentation 104.1–104.2 nutritional support dystrophic epidermolysis bullosa 118.23, 118.24, 118.24 Netherton syndrome 124.6 severe ichthyoses 121.29, 121.63 Stevens–Johnson syndrome/toxic epidermal necrolysis 78.6 nystatin, candidosis 62.24 OA1 gene defects 121.11, 121.13 obesity 65.9–65.10, 141.10 Cushing disease 172.7, 172.8 cutaneous signs 65.9, 65.10 genetic disorders with childhood-onset 141.9–141–10 insulin resistance 172.17, 172.18 striae 65.10, 146.1 obsessive–compulsive disorders 180.8 obstetric complications, Ehlers–Danlos syndrome 142.8 OCA2 gene mutations 138.8 occipital horn syndrome see cutis laxa, X-linked occlusive dressings (wraps) atopic dermatitis 30.7 lichen simplex chronicus 42.2 percutaneous drug absorption and 181.4 see also wet wrap dressings occlusotherapy (duct tape occlusion) molluscum contagiosum 46.5 warts 47.8 octopus, blue-ringed 73.8 ocular albinism see albinism, ocular ocular manifestations see ophthalmological manifestations oculo-auriculo-vertebral syndrome 10.2–10.3 oculocutaneous albinism see albinism, oculocutaneous oculodentodigital dysplasia (ODDD) (oculodento-osseous dysplasia) 127.92–127.93 autosomal dominant 127.46 autosomal recessive 127.47 palmoplantar keratoderma 120.22

51

oculoglandular syndrome, Parinaud 58.5, 58.6 oculo-osteocutaneous syndrome 127.10 oculotrichodysplasia 127.47 odontogenic cysts 147.19 odontogenic keratocysts, Gorlin syndrome see jaw cysts, Gorlin syndrome odontomicronychial dysplasia 127.48 odonto-onychodermal dysplasia (OODD) 120.10–120.11, 127.83–127.85 clinical features 120.10–120.11, 120.11, 127.48, 127.84–127.85 molecular pathology 120.10, 127.83 odonto-onycho-hypohidrotic dysplasia with midline scalp defect 127.23 odontotrichomelic syndrome 127.58 odour see malodour oedema acute haemorrhagic oedema of infancy 161.3 acute scrotal 151.22, 151.22 facial, DRESS syndrome 183.6, 183.6 hands and feet, Kawasaki disease 168.2–168.3, 168.3 juvenile dermatomyositis 175.11 lymphoedema 114.11 pitting, vs. sclerema neonatorum 7.4 Rocky Mountain spotted fever 61.2–61.3, 61.3 sunburn 108.6 oesophageal carcinoma, keratosis palmaris et plantaris with see Howel–Evans syndrome oesophageal strictures, dystrophic epidermolysis bullosa 118.15, 118.23–118.24 oestriol, unconjugated (uE3), maternal blood 121.12 oestrogen deficiency 172.11 excess 172.16, 172.16–172.17 precocious puberty 172.11 topical therapy labial fusion 151.17 systemic toxicity 184.8 Oestrus ovis 69.3 ofloxacin, leprosy 70.9 oil-in-water emulsions 181.4 infantile seborrhoeic dermatitis 35.6 oil of bergamot 45.10 oil of citronella 181.12 ointments 181.4 oleic acid, skin barrier disruption 27.6–27.7, 27.11, 27.16 oligoarrays 116.3 oligoarthritis 175.2, 175.3 extended 175.3 persistent 175.3 oligonucleotides, cutaneous gene transfer 140.5–140.6 olive oil, skin barrier disruption 27.6, 27.7, 27.16 Ollier disease 112.11 Olmsted syndrome 120.12 omalizumab, hyper-IgE syndrome 177.24 omega-3 unsaturated fatty acids 181.17–181.18 omega-6 unsaturated fatty acids (ω-6 USFA) 181.17–181.18 atopic dermatitis 27.10–27.11 skin barrier function 27.6–27.7 see also linoleic acid Omenn syndrome clinical features 177.30 histopathology 4.7 neonatal erythroderma 11.8–11.9, 11.9 pathogenesis 115.28, 177.31 omphalitis neonatorum 9.3 omphalomesenteric duct completely patent 10.9 partially patent 10.9 onchocerciasis dermatitis 28.10 dystrophic calcification 95.7 vs. leprosy 70.8 Online Mendelian Inheritance in Man (OMIM) 115.19–115.24 onychia, candidal 62.21, 62.24

52

Index

Onychocola 63.8 onycholysis nail psoriasis 150.5 parakeratosis pustulosa 150.4, 150.4 onychomycosis candidal 62.21, 62.24 dematiaceous fungi 63.8 dermatophyte 62.10–62.11, 62.11 differential diagnosis 62.14 treatment 62.17 distal and lateral 62.10 endonyx 62.11 proximal subungual 62.10, 62.11 superficial white 62.10 total dystrophic 62.11 see also onychomycosis onychophagia see nail biting onychotillomania 150.3, 180.3, 180.4 onychotrichodysplasia and neutropenia 127.48, 148.8 onychotrichodysplasia, neutropenia and mental retardation (ONMR) 148.11 ophthalmia neonatorum 153.8, 153.13 see also gonococcal conjunctivitis, neonatal; neonatal conjunctivitis ophthalmia nodosa 73.4 ophthalmological manifestations ataxia telangiectasia 177.3, 177.3 atopic dermatitis 28.5, 28.5 Behçet disease 167.16, 167.17, 167.17 Blau syndrome 158.9 Cockayne syndrome 135.16 congenital erythropoietic porphyria 107.12 dystrophic epidermolysis bullosa 118.15– 118.16, 118.26 Ehlers–Danlos syndrome 142.7–142.8, 142.12 focal dermal hypoplasia 133.2, 133.4 Gorlin syndrome 132.7 herpes zoster 49.14 hyperthyroidism 172.5, 172.6 ichthyosis follicularis with atrichia and photophobia 121.56 IgA mucous membrane pemphigoid 89.9 incontinentia pigmenti 130.5 infantile haemangiomas 113.8–113.9 juvenile xanthogranuloma 103.10 Kawasaki disease 168.3–168.4, 168.4 KID syndrome 122.2–122.6, 127.92 lamellar ichthyosis 121.32 leprosy 70.11–70.12 linear IgA disease of childhood 89.7, 89.8 linear morphoea 173.6 Marfan syndrome 145.6, 145.6 measles 49.2 mucous membrane pemphigoid 91.18–91.19, 91.19 naevus sebaceous 110.5, 110.5 neurofibromatosis 1 128.5–128.6 neurofibromatosis 2 128.13 oculocutaneous albinism 138.7 phacomatosis pigmentokeratotica 110.14 porphyria cutanea tarda 107.9 Proteus syndrome 111.6 pseudo-xanthoma elasticum 144.5, 144.5– 144.6, 144.7 psoriasis 80.6 Refsum disease 121.48 sarcoidosis 158.4 severe MEDOC phenotypes 121.65 Sjögren–Larsson syndrome 121.47 smallpox 51.5 smallpox vaccination 51.11, 51.12, 51.12 toxic epidermal necrolysis 183.9–183.10 tyrosinaemia type II 169.4 vesiculobullous disorders 87.10 Wegener granulomatosis 167.4–167.5, 167.5 xeroderma pigmentosum 135.8, 135.9 ophthalmomyiasis 69.3 opioids/opiates analgesics 190.8 intoxication 184.8

opportunistic infections 63.26–63.28 HIV infection 52.1 mycoses 63.1 optic pathway gliomas 128.5–128.6 ORAI1 gene 177.31 oral carcinoma 147.7 oral contraceptives acne 79.9–79.10 Darier disease 125.4 melasma 104.6 oestrogen excess 172.16 oral leucoplakia (white patches) 147.10–147.14 acquired persistent 147.13 acquired transient 147.11–147.13 candidal leucoplakia 62.21, 147.13 congenital 147.10–147.11 definition 147.10 dyskeratosis congenita 136.9, 136.10, 147.11 hairy leucoplakia 52.3, 147.13 with normal anatomy 147.10 of unknown cause 147.13, 147.13 oral manifestations Behçet disease 147.3, 167.15, 167.15 candidiasis see under candidiasis child abuse 147.4, 154.7 chronic mucocutaneous candidiasis 62.22, 147.13 Crohn disease 147.8, 157.1–157.2, 157.2, 157.2 Darier disease 125.3, 147.10 dermatological disorders 147.8–147.9 dystrophic epidermolysis bullosa 118.15, 118.15, 118.23 Ehlers–Danlos syndrome 142.8, 142.14, 142.14 focal epithelial hyperplasia 47.6, 47.6 graft-versus-host disease 147.8, 147.8, 178.7 junctional epidermolysis bullosa 118.31 Kawasaki disease 168.4, 168.4 Kindler syndrome 119.2 leukaemia cutis 99.14 lichen planus 85.6, 85.10, 147.8, 147.8–147.9 linear IgA disease of childhood 89.7, 89.7, 147.9 mucous membrane pemphigoid 91.18 paracoccidioidomycosis 63.11 pemphigus vulgaris 91.3, 91.3 Proteus syndrome 111.6 pseudo-xanthoma elasticum 144.5, 144.5 venous malformations 112.8, 112.8 vesiculobullous disorders 87.10, 147.9 vitiligo 105.3–105.4 oral mucosal diseases 147.1–147.22 oral ulceration 147.1–147.10 Behçet syndrome 147.3 iatrogenic 147.9 infectious causes 147.4–147.7 MAGIC syndrome 147.3 neoplasia-associated 147.7 recurrent aphthous see recurrent aphthous stomatitis systemic diseases causing 147.7–147.9 traumatic 147.3–147.4 see also stomatitis orf 51.2, 51.20–51.23 clinical features 51.21, 51.21, 51.21–51.22, 51.22 diagnosis 51.1, 51.22–51.23 giant 51.22, 51.22 treatment 51.23, 51.23 organic acidurias 169.6–169.9 organogenesis 2.3, 2.4 organophosphate poisoning 184.13 oriental sore 67.1 Orientia tsutsugamushi 61.1, 61.2, 61.9–61.10 ornithine transcarbamylase deficiency 20.11–20.12 Ornithonyssus mites 71.4–71.5 orofacial granulomatosis (OFG) 114.18–114.19, 147.8, 157.3–157.4 aetiology 114.18, 157.4 anogenital granulomatosis and 151.23 clinical features 114.18–114.19, 114.19, 157.2, 157.3, 157.3–157.4, 157.4 treatment 114.19, 157.4–157.5

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

orofaciodigital (OFD) syndrome type I 127.49, 148.6 type II 147.23 Oroya fever 58.1–58.2, 58.8, 58.9 orthopaedic manifestations see musculoskeletal manifestations orthopaedic surgery, Proteus syndrome 111.7–111.8 orthopoxviruses 51.1, 51.2, 51.3–51.20 Osler–Weber–Rendu disease see hereditary haemorrhagic telangiectasia osseous heteroplasia, progressive see progressive osseous heteroplasia ossification, cutaneous 95.2, 95.9–95.12 mechanisms 95.10 primary disorders 95.9–95.12, 95.11 pseudo-hypoparathyroidism 172.26 tumours 95.7 ossifying fibroma, juvenile active 147.20 osteoarthritis, Ehlers–Danlos syndrome 142.5 osteogenesis imperfecta (OI) 145.8–145.11 classification 145.9, 145.10 clinical features 145.9, 145.9, 145.10 osteoma cutis (OC) miliary, of the face 95.12 plate-like 95.9–95.10, 95.12 osteomas Gardner syndrome 137.12 primary 95.12 osteomyelitis jaw 147.20 smallpox 51.5 osteopathia striata, focal dermal hypoplasia 133.2–133.3 osteopenia, hyper-IgE syndromes 177.23 osteoperiostitis endemic syphilis 60.5 yaws 60.3, 60.4 osteopetrosis, lymphoedema, ectodermal dysplasia anhidrotic and immunodeficiency (OL-EDA-ID) syndrome see hypohidrotic ectodermal dysplasia (HED), with immunodeficiency osteopetrosis and lymphoedema osteopoikilosis (OPK) 145.1 Busche–Ollendorff syndrome 116.13, 116.15, 145.2 pathology 145.2 osteoporosis epidermolysis bullosa 118.22 familial 127.66 osteosarcoma, Rothmund–Thomson syndrome 136.3, 136.4 otitis externa, patch testing 44.8 Oudtshoorn disease 122.3 outer root sheath, development 2.37 ovarian choriocarcinoma, non-gestational (NGCO) 99.12 ovarian fibromas, Gorlin syndrome 132.11 overgrowth Beckwith–Wiedemann syndrome 137.7 capillary malformations 112.14 Klippel–Trenaunay syndrome 112.16–112.17 lymphoedema with 114.9–114.11 Parkes Weber syndrome 112.4 Proteus syndrome 111.4–111.5, 111.5 overweight children, psoriasis risk 81.2 owl’s eye appearance, neonatal lupus erythematosus 14.6, 14.6 oxalate crystals, plant-derived 45.2 ozone layer 108.3, 108.17–108.18 P1-derived artificial chromosomes (PAC) 140.5 P2RY5 gene mutations 127.100, 148.16 p14 deficiency 177.11 p53 gene 127.73–127.74 sun-damaged skin 108.8–108.9 p63 gene see TP63 (p63) gene p73 gene 127.73–127.74 PABA (para-aminobenzoic acid) 108.12, 108.15 pachydermodactyly 96.2

Index pachyonychia congenita (PC) 120.19–120.20, 127.96 autosomal recessive 127.50, 127.96 clinical features 120.20, 120.20 gene-based therapy 117.8, 139.2, 140.9, 140.10, 140.13 hair abnormalities 148.9 nail abnormalities 120.20, 120.20, 150.9 oral lesions 147.10–147.11 patient advocacy group 179.7 type 1 see Jadassohn–Lewandowsky syndrome type 2 see Jackson–Lawler syndrome pacifiers see dummies paediatric condition falsification 180.13 paediatric dermatology in Europe 1.4–1.5 future 1.5 global establishment 1.2–1.3 history and development 1.1–1.5 in Japan 1.4 in Latin America 1.4 in North America 1.3–1.4 training 1.3 Paediatric Rheumatology European Society (PReS), Henoch–Schönlein purpura diagnosis 160.1 pagetoid reticulosis 99.21, 102.5 PAHX gene mutations 121.48, 121.49 pain congenital insensitivity to, with anhidrosis (CIPA) 115.28, 127.15 erythromelalgia 166.2 perception 190.1 pain management 190.1–190.10 epidermolysis bullosa 118.25–118.26 laser procedures 188.6 non-pharmacological techniques 190.10 perioperative analgesia 190.6 pharmacological agents 190.7–190.9 sedation 190.6–190.7 see also anaesthesia; local anaesthetics; topical anaesthetics Pallister–Killian syndrome 116.11–116.12, 116.12 palm(s) congenital syphilis 153.4 Ehlers–Danlos syndrome 142.3, 142.6 erythema, Kawasaki disease 168.2, 168.2 hyperlinear see hyperlinear palms and soles pompholyx see pompholyx transient aquagenic hyperwrinkling 170.3, 170.4 palmar pits Darier disease 125.2 differential diagnosis 132.13 Gorlin syndrome 132.4, 132.7–132.8, 132.8 palmoplantar anhidrosis, absence of dermal ridge patterns, onychodystrophy and see Basan syndrome palmoplantar hidradenitis (PH) 77.3, 94.1–94.2 clinical features 94.1 differential diagnosis 39.3, 94.1–94.2 palmoplantar keratoderma (PPK) 117.6, 120.1–120.26 AEC syndrome 127.76 with alopecia 127.50 with arrhythmogenic right ventricular cardiomyopathy and woolly hair see Naxos disease classification 120.1–120.3, 120.2 Clouston syndrome 127.90, 127.91 with clubbing of fingers and toes and skeletal deformity 120.25 cum degeneratione granulosa Vörner 120.3–120.4, 120.4 diffuse hereditary with associated features 120.6–120.15 without associated features 120.3–120.6 epidermolysis bullosa simplex 118.6 epidermolytic (Vörner–Thost) 115.21 epidermolytic ichthyosis 121.18–121.19 erythrokeratodermia variabilis 122.7

focal hereditary with associated features 120.17–120.22 without associated features 120.15–120.17 focal non-epidermolytic 127.96 ichthyin-deficient ARCI 121.34, 121.35 with left ventricular cardiomyopathy and woolly hair see Carvajal syndrome mutilating with ichthyosis (of Camisa) see loricrin keratoderma with periorificial keratotic plaques (Olmsted syndrome) 120.11–120.12 of Vohwinkel see Vohwinkel syndrome odonto-onychodermal dysplasia 120.11, 127.85 with oesophageal cancer see Howel–Evans syndrome papular hereditary, without associated features 120.23–120.25 pathogenic mechanisms 121.4 with periodontitis see Papillon–Lefèvre syndrome pityriasis rubra pilaris 83.3, 83.4, 83.5 progrediens et transgrediens 122.5 Schöpf–Schulz–Passarge syndrome 127.86 with scleroatrophy see Huriez syndrome with squamous cell carcinoma of skin and sex reversal 120.9–120.10, 137.2 striate see keratosis palmoplantaris areata et striata of uncertain identity 120.25–120.26 palmoplantar keratoderma (PPK)-deafness syndromes 120.21, 120.21–120.22, 127.50 clinical features 120.22, 120.22 molecular pathology 115.21 palmoplantar keratoses, PTEN hamartomatumour syndrome 137.19 pancreatic panniculitis 77.11 panhypogammaglobulinaemia, primary 177.24–177.27 panniculitis 77.1–77.16 α1-antitrypsin deficiency 77.11–77.12 calcifying 77.12, 95.6–95.7 classification 77.1, 77.2 cold 77.6–77.7, 77.7 connective tissue diseases 77.10–77.11 cytophagic histiocytic 77.13–77.14 dermatomyositis 77.10 eosinophilic 36.12–36.13, 77.1 equestrian 77.7 factitial 77.12–77.13 iatrogenic 77.12–77.13 idiopathic lipoatrophic 77.10 idiopathic nodular 77.1 infective 77.12 lipophagic, of childhood 77.10 lupus 77.10 oedematous scarring vasculitic 77.14 pancreatic 77.11 popsicle 77.7 post-steroid 77.7–77.8 traumatic 77.12–77.13 see also erythema nodosum Panton-Valentine leukocidin (PVL) 54.2 PAPA syndrome 79.17 papillary tip microabscesses, dermatitis herpetiformis 90.3, 90.3 papillomas focal dermal hypoplasia 133.2, 133.5, 133.7–133.8 juvenile respiratory tract 153.18 oral 147.18–147.19 see also warts Papillon–Leage and Psaume syndrome 127.49 Papillon–Lefèvre syndrome 120.12–120.13 clinical features 120.13, 120.14, 127.51 molecular pathology 115.21, 120.13 Papio cynocephalus 60.2 papular acantholytic dyskeratosis of the vulva 151.7 papular acrodermatitis of childhood see Gianotti–Crosti syndrome

53

papular elastorrhexis 145.3 papular-purpuric gloves and socks syndrome (PPGSS) 39.3, 49.8–49.9 papular urticaria (PU) 71.1–71.8 see also insect bites papules acne 79.6, 79.6 chromosome disorders 116.10 Darier disease 125.2, 125.2 lichen planus 85.4, 85.4 pearly penile 151.16–151.17 pityriasis lichenoides 100.2, 100.2 papulonecrotic tuberculids 57.3 papulopustular eruptions, sterile transient neonatal 6.4, 6.4–6.9 PAR2 see protease-activated receptor 2 para-aminobenzoic acid (PABA) 108.12, 108.15 parabens, allergy 44.11 paracetamol (acetaminophen) 190.6 Paracoccidioides brasiliensis 63.10, 63.12 paracoccidioidomycosis 63.10–63.13 acute juvenile 63.10, 63.11 chronic adult 63.10–63.11, 63.11, 63.12 paradominance 115.5–115.6, 115.6 paradominant inheritance 115.17, 115.17 parakeratosis pustulosa 150.4, 150.4 paraneoplastic pemphigus 91.2, 91.8–91.9 parangi see yaws paraphenylenediamine (PPD) allergy 44.2, 44.3, 44.11 parapoxviruses 51.1, 51.2, 51.20–51.24 identification 51.1, 51.2 paraquat poisoning 184.13–184.14 parasitic infestations dystrophic calcification 95.7 fetal immune responses 22.8–22.9 genital area 151.10 HIV-infected children 52.4 neonatal 8.5, 8.6, 9.6–9.7 urticaria 74.3 parathyroid gland disorders 172.25–172.28 parathyroid hormone (PTH) 95.1 resistance 172.26 parathyroid hormone-related peptide (PTHrP) 95.1 parathyroid hyperplasia 172.27 parathyroid tumours 172.27 paravaccinia see milker’s nodules parechoviruses, neonatal infections 9.6 parenteral nutrition, total (TPN), extravasation injuries 17.8, 17.8, 17.9 parents assessing child’s quality of life 29.9 burden of chronic skin disease 179.1–179.6 risk factors for child abuse 154.2, 154.2 see also family Parents’ Index of Quality of Life in Atopic Dermatitis (PIQoL-AD) 29.14, 179.2 Parinaud oculoglandular syndrome 58.5, 58.6 Parkes Weber syndrome 112.4, 114.10 differential diagnosis 111.8 paronychia acute 150.3 candidal 62.21, 62.24 herpetic 48.3 paroxysmal extreme pain disorder (PEPD), neonates 6.2, 6.3 Parrot sign, ichthyosis vulgaris 121.8 Parry–Romberg syndrome 173.3, 173.6 patient advocacy group 179.7 Partington syndrome (X-linked reticulate pigmentary disorder) 138.3, 138.11 aetiology 159.1–159.2 amyloid deposits 159.4 functional mosaicism 115.13 parvovirus B19 aplastic crisis 49.6 congenital infection 8.4, 49.6 erythema infectiosum 49.5–49.6 papular-purpuric gloves and socks syndrome 49.8, 49.9

54

Index

parvovirus (cont.) vs. rubella 49.4 see also erythema infectiosum paste bandages, eczema 192.4, 192.7, 192.8 Pastia’s lines 54.10 Patau syndrome 116.10 patched see PTCH patch testing aimed 44.8 allergic contact dermatitis 44.4–44.8 drug hypersensitivity 183.13–183.14 lichenoid lesions 85.9 plant/plant products 45.4 recording of results 44.8, 44.8, 44.8 standard series of allergens 44.6–44.7, 44.7–44.8 techniques 44.5–44.8, 44.7 see also atopy patch test patchy pityriasiform lichenoid eczema 28.8 pathogen-associated molecular patterns (PAMPs) 23.13 pathomimicry see factitious disorders patient advocacy groups 179.6, 179.7 Patient-Oriented Eczema Measure (POEM) 29.6 patients, paediatric burden of skin disease 179.1–179.6 education, atopic dermatitis 30.3–30.4, 34.5 pattern recognition receptors (PRRs) 23.13 Patterson syndrome 104.9 Pautrier microabscesses 99.21, 102.4, 102.4 PAX3–FKHR gene fusion 99.4–99.5 PAX3 gene mutations 138.6 PAX7–FKHR gene fusion 99.5 P-cadherin embryonic-fetal transition 2.14 gene mutations 127.100 PDGFB–COL1A1 gene fusion 97.14, 99.7 PDGFRA gene rearrangements 36.6 PDGFRB gene rearrangements 36.6 peanut allergy 31.6, 45.4 dietary restrictions 31.15, 31.15–31.16 pearly penile papules 151.16–151.17 pedal papules of infancy 7.4–7.5, 10.10–10.11 painful piezogenic 7.4–7.5 Pediatric Dermatology 1.5 pediculocides 72.12–72.13 pediculosis see lice, infestations pediculosis capitis 72.10, 72.11 see also head louse pediculosis corporis 72.10–72.11, 72.11 see also body louse pediculosis pubis 72.11, 72.11, 72.12 see also pubic louse Pediculus humanus capitis see head louse Pediculus humanus humanus see body louse peeling skin syndromes (PSS) 121.23 pefloxacin, leprosy 70.9 Pelea anisata 45.8 peliosis hepatis, bacillary 58.3 pellagra 65.5, 65.5 hyperpigmentation 104.8 pelvic inflammatory disease (PID) 153.10, 153.11 PELVIS syndrome 113.13 pemphigoid 91.13, 91.13–91.20 aetiology and pathogenesis 91.14, 91.14–91.15 bullous see bullous pemphigoid cicatricial see mucous membrane pemphigoid localized juvenile vulvar see vulvar pemphigoid, localized juvenile mucous membrane see mucous membrane pemphigoid patient advocacy group 179.7 pemphigoid (herpes) gestationis 91.14 in newborn 16.6, 87.7, 91.13, 91.19–91.20 pathogenesis 91.15 pemphigoid nodularis 91.15–91.16 pemphigus 91.1–91.10 aetiology and pathogenesis 91.1–91.2 antigens 91.1–91.2, 91.2, 91.2 Brazilian endemic see Brazilian pemphigus

chronic benign familial see Hailey–Hailey disease IgA 91.2, 91.9–91.10 paraneoplastic 91.2, 91.8–91.9 patient advocacy group 179.7 types 91.1, 91.2 pemphigus acutus neonatorum see staphylococcal scalded skin syndrome pemphigus erythematosus 91.2, 91.8 pemphigus foliaceous 91.5–91.6 Brazilian endemic see Brazilian pemphigus clinical features 91.5–91.6, 91.6 differential diagnosis 91.6 history 91.1 neonatal 16.6, 87.7, 91.8 non-endemic 91.2 pathogenesis 91.1–91.2 treatment 91.6 pemphigus neonatorum 91.2, 91.8 pemphigus vegetans 91.2, 91.5 clinical features 91.5, 91.5 pemphigus vulgaris 91.2, 91.3–91.5 clinical features 91.3, 91.3 differential diagnosis 91.4 drug-induced 91.3 history 91.1 neonatal 16.6, 87.7, 91.2, 91.8, 91.9 pathogenesis 91.1–91.2 pathology 91.3, 91.3 treatment 91.4–91.5 penciclovir cream, HSV infections 48.7 penetrance, incomplete 115.2–115.3 penicillamine fetal exposure, transient neonatal cutis laxa 143.4 pseudo-xanthoma elasticum-like lesions 144.7 systemic sclerosis 174.11 penicillin actinomycosis 63.27 allergy 74.4 endemic treponematoses 60.7 meningococcal infection 55.9 syphilis 153.7, 153.7 tropical ulcer 66.5 penicillin-binding protein 54.2 penicilliosis 63.19–63.20 Penicillium marneffei 63.19 penile urethra, foreign bodies 151.20 penis anatomical abnormalities 151.16 fixed drug eruptions 151.14, 151.14 hair tourniquet 151.20 median raphe cysts and canals 10.9, 151.18, 151.18 neoplasia 151.20–151.21 pearly papules 151.16–151.17 warts 47.7, 47.8 pentachlorophenol toxicity 5.7, 184.15 pentobarbital 190.8 pentoxifylline angiolymphoid hyperplasia with eosinophilia 98.2 granuloma annulare 93.8 sarcoidosis 158.5 Penttinen progeroid disorder 134.10 peptidase deficiency 115.26 peptidoglycan (PGN), atopic dermatitis 26.2, 26.3 peptidylarginine deiminase (PAD 1 and 3) 23.7, 23.8 peptidyl-deiminase 27.2 percutaneous absorption see absorption, percutaneous Perfecta V beam laser 188.3, 188.4 perforin mutations 103.17–103.18 perianal area Crohn disease 157.2 lichen sclerosus 152.6, 152.6 melanocytic naevi 151.5 neonatal dermatitis 6.11

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

pseudo-verrucous papules and nodules 20.9, 20.9, 21.2 see also genital disease/area; napkin dermatitis; perineum perianal (perineal) protrusion, infantile 10.10, 151.18, 151.18 perianal streptococcal dermatitis (PSD) 20.6, 54.7, 151.8, 155.5 pericarditis, vaccinia vaccination 51.13–51.14 periderm 2.23–2.27, 17.2 collodion baby 12.1, 12.2 embryo 2.4, 2.4, 2.5, 2.6 embryonic-fetal transition 2.14, 2.14 fetal 2.20, 2.20, 2.21 keratins 2.24 origin 2.24 regional variations 2.26–2.27 regression 2.24, 2.25 periderm cells changes during skin development 2.24, 2.25 embryonic 2.4, 2.5, 2.6 embryonic-fetal transition 2.13, 2.13, 2.14 fetal 2.20 function 2.26 perifollicular fibromas, Birt–Hogg–Dubé syndrome 137.8 perifollicular macular atrophy 145.12 perilipin 121.53 perineal hygiene, girls 152.1, 152.4 perineal (perianal) protrusion, infantile 10.10, 151.18, 151.18 perineum Kawasaki disease 20.9–20.10, 168.3 median raphe cysts 151.18, 151.19 recurrent toxin-mediated erythema (RPE) 54.11, 151.9 see also genital disease/area; perianal area periocular signs, atopic dermatitis 28.5, 28.5, 28.6 periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) 74.7–74.8, 176.2–176.4, 176.3 periodic fever syndromes (autoinflammatory syndromes) 176.1–176.4, 176.3 acne 79.17 Behçet disease status 167.14–167.15 urticarial lesions 74.9, 163.5 see also specific syndromes perioral dermatitis 38.1–38.3 atopic dermatitis with 30.10 clinical features 38.1–38.2, 38.2 with extrafacial genital manifestations 20.9, 20.10 granulomatous form 38.1, 38.2, 38.2, 38.3 histopathology 38.1, 38.2 treatment 38.3, 38.3 see also cheilitis periorbital erythema, neonatal lupus erythematosus 14.6, 14.6 periorbital hyperpigmentation 104.6 periorbital pigmentation, atopic dermatitis 28.5, 104.6 peripheral nerves, leprosy 70.5, 70.5–70.6, 70.7 peripheral neuro-epithelioma 99.6 periungual fibromas 150.7 tuberous sclerosis 129.6–129.7, 129.7, 129.12, 150.7 periungual warts 47.4, 47.5, 150.3 Perlman, Henry Harris 1.3 permethrin 181.9 Demodex folliculitis 72.16 as insect repellent 73.1 lice 72.12 resistance, head lice 72.13 scabies 72.6 perniola syndrome 148.8 peroxisomal disorders 121.49–121.50 peroxisome proliferator-activated receptor-α (PPAR-α) skin barrier development 3.2, 27.13 skin barrier homeostasis 27.7

Index petechiae Schamberg disease 165.2, 165.3 Wiskott–Aldrich syndrome 177.33, 177.33 petechial rash meningococcal disease 55.6, 55.7 Rocky Mountain spotted fever 61.1, 61.2, 61.3 petrolatum 181.6 head lice 72.13 pets, household aeroallergens 32.2 avoidance strategies 32.8 atopic dermatitis and 22.10, 30.9 Peutz–Jeghers syndrome (PJS) 137.16 clinical features 109.12, 137.16, 137.16 oral pigmentation 147.14 pathogenesis 115.27, 137.16 tumour susceptibility 137.5, 137.16 PEX7 gene mutations 121.48, 121.49 PFAPA see periodic fever, aphthous stomatitis, pharyngitis and adenitis P gene 131.2 pH skin surface changes after birth 27.13 in different body sites 27.8 neonates 3.4, 3.4–3.5 stratum corneum 27.2, 27.4, 27.4–27.5 atopic dermatitis 27.11 vaginal 152.1, 153.23 PHACE syndrome 113.11–113.13 clinical features 113.11–113.13, 113.13 diagnostic criteria 113.12 hypothyroidism 113.22 patient advocacy group 179.7 propranolol therapy 113.17 phacomatosis cesioflammea 115.16 phacomatosis pigmentokeratotica 110.13–110.15 clinical features 110.14, 110.14 didymosis 115.16, 115.17 vitamin D-resistant rickets 110.14, 110.19 phacomatosis pigmentovascularis (PPV) 109.22, 112.18 didymosis 115.16, 115.17 variants 112.18, 112.18 phacomatosis spilorosea 115.16, 115.17 Phaeoannellomyces werneckii 63.7–63.8 phaeohyphomycosis 63.7–63.8 phage φC31 140.6, 140.10 phagocytic defects, primary 64.5–64.6, 177.10–177.11 pharyngitis gonococcal 153.10 herpes gingivostomatitis 48.2 PHC syndrome 127.10 phenol poisoning 184.8 phenothrin, lice 72.12 phenotypic reversion, pigmentary mosaicism 131.2 L-phenylalanine plus UVA therapy, vitiligo 105.7 phenylephrine, percutaneous absorption 3.3, 181.2 phenylketonuria (PKU) 169.1–169.4 clinical features 169.3 ‘malignant’ 169.3 screening and treatment 169.4, 169.4 tetrahydrobiopterin (BH4)-dependent 169.4 phenylmercuric acetate allergy 44.3 phenytoin dystrophic epidermolysis bullosa 118.20 induced gingival hyperplasia 147.20, 147.20 induced hypertrichosis 148.30 Phialophora 63.7–63.8 Phialophora verrucosa 63.4, 63.6 φC31 phage 140.6, 140.10 phimosis 151.17–151.18 lichen sclerosus 152.5, 152.8 phlebectasia, generalized 112.19 phlebitis, arthropod bites 71.5 phlebography, venous malformations 112.9 phleboliths 112.8 phlebotomine sandflies

bartonellosis 58.8 bite reactions 71.5, 71.5 biting behaviour 71.7 control measures 67.10 leishmaniasis 67.1, 67.2–67.3, 67.3 phlebotomy, porphyria cutanea tarda 107.14 Phoneutria spiders 73.5 phorbol esters, plant-derived 45.2 Phormia 69.3 phosphate, regulation 95.1–95.2 phosphatonins 95.2 phosphodiesterase, atopic dermatitis 25.7, 25.7–25.8 phosphodiesterase inhibitors, atopic dermatitis 25.10 phosphoinositide 3-kinase (PI3K)/Akt pathway, acne 79.2, 79.3, 79.3 phosphoinositide system, atopic dermatitis 25.8 phospholipase A2, secretory (sPLA2) 27.4, 27.4 atopic dermatitis 27.10 barrier development after birth 27.13 phospholipase C, atopic dermatitis 25.8 phospholipids, atopic dermatitis 27.10 photoageing 108.8, 108.9 photoallergic reactions, blistering 87.5, 87.9 photobiology 108.1, 108.4–108.9 photocarcinogenesis 108.8–108.9 photochemotherapy (PUVA) alopecia areata 149.6 atopic dermatitis 30.11 graft-versus-host disease 178.9 induced hypertrichosis 148.30 morphoea 173.9 psoriasis 82.3 Schamberg disease 165.3 UV light exposure 108.4 vitiligo 105.7 photocontact dermatitis, sunscreens 108.15 photodermatoses, idiopathic 106.1–106.10, 106.2 photodynamic therapy (PDT) Gorlin syndrome 132.15–132.16 porokeratosis 126.5 warts 47.9 Photofrin®, Gorlin syndrome 132.15 photoleucomelanodermatitis of Kobori 104.12 photolyase 135.1, 135.24 photoprotection 108.1, 108.11–108.18 actinic prurigo 106.5 after laser treatment 188.6, 189.2 atypical mole syndrome 109.21 endogenous 108.11–108.12 exogenous 108.12–108.18 Gorlin syndrome 132.14 melanoma prevention 109.27 melasma 104.7 neonatal lupus erythematosus 14.9, 14.10 personal behavioural changes 108.17, 108.18 polymorphic light eruption 106.3 porphyrias 107.13–107.14 protective wear 108.16, 108.16–108.17 solar urticaria 106.7 structural and environmental changes 108.17–108.18 UV Index 108.17, 108.17 vitiligo 105.8 xeroderma pigmentosum 135.10 see also sunscreens photosensitivity Cockayne syndrome 135.14, 135.16 drug-induced, cystic fibrosis 170.3, 170.4 Kindler syndrome 119.1, 119.2 porphyrias 107.10, 107.10 trichothiodystrophy 135.20, 148.12 xeroderma pigmentosum 135.8, 135.9–135.10 photosensitivity disorders blistering 87.9 idiopathic 106.1–106.10, 106.2 phototherapy acne 79.10 atopic dermatitis 30.11 bronze baby syndrome 104.9

55

complications 17.11 erythropoietic protoporphyria 107.14 granuloma annulare 93.8 mastocytosis 75.12 morphoea 173.9 pityriasis rubra pilaris 83.2, 83.7 polymorphic light eruption 106.3 psoriasis 82.3 UV light exposure 108.4 vitiligo 105.7 see also photochemotherapy; ultraviolet B (UVB) therapy phototoxic reactions blistering 87.5, 87.9 plants 45.8–45.11 porphyrin-induced 107.7, 107.8 phrynoderma 123.3 Phthirus pubis see pubic louse phycomycosis 63.22–63.24, 147.7 phylloid hypermelanosis 115.10 phylloid hypomelanosis 115.10, 115.11 phylloid pattern, pigmentary mosaicism 115.10, 115.11 Physalia physalis 73.7 physical abuse see child abuse, physical physiotherapy/physical therapy dystrophic epidermolysis bullosa 118.22 Ehlers–Danlos syndrome 142.9 juvenile dermatomyositis 175.12 juvenile idiopathic arthritis 175.4 lymphoedema 114.12 morphoea 173.10 phytanic acid 121.48–121.49 phytanic acid storage disease see Refsum disease, classic adult phytanoyl-CoA 2-hydroxylase (PhyH) 121.48 phytodermatoses 45.1–45.11 allergic 45.3–45.7 classification 45.1, 45.2 irritant 45.1–45.3 phototoxic 45.8–45.11 phytophotodermatitis 45.8–45.11 clinical features 45.8, 45.9, 87.9 linear hyperpigmentation 104.9 risk activities 45.8, 45.9 vs. allergic contact dermatitis 45.10, 45.10 vs. child abuse 154.10 PIBIDS 135.19, 148.11 picaridin 73.1, 181.12 picker’s nodule see prurigo nodularis piebaldism 138.2, 138.4–138.5 clinical features 138.4, 138.5 differential diagnosis 105.5, 138.5 genetic basis 115.25, 138.4–138.5 piedra 62.31–62.32 black 62.32, 62.32 white 62.31, 62.32 Piedraia hortae 62.32 piercing 180.8 piezogenic papules, pedal 7.4–7.5 Ehlers–Danlos syndrome 142.3 pigmentary changes (dyspigmentation) AEC syndrome 127.76–127.77 Chédiak–Higashi syndrome 138.7, 177.6 chromosome disorders with 116.11–116.12 Fanconi anaemia 136.11 focal dermal hypoplasia 133.1, 133.3 graft-versus-host disease 178.7 mosaic, archetypical patterns 115.9–115.12, 115.11 neonatal lupus erythematosus 14.4, 14.6 pigmentary mosaicism 131.3, 131.3 pinta 60.5, 60.5, 104.4 pityriasis versicolor 62.27, 62.27, 104.1, 104.4 postinfectious 104.1, 104.4 Proteus syndrome 111.4 see also hyperpigmentation; hypopigmentation pigmentary demarcation lines 104.9 pigmentary mosaicism (PM) 131.1–131.5 clinical features 131.3, 131.3–131.4, 131.4 diagnosis 131.4–131.5

56

Index

pigmentary mosaicism (PM) (cont.) differential diagnosis 131.5, 131.5 histopathology 131.3 pathogenesis and genetics 131.1–131.2 treatment 131.5 see also hypomelanosis of Ito pigmentation acquired disorders 104.1–104.13 congenital melanocytic naevi 109.3, 109.4 diffuse background, congenital melanocytic naevi 185.6, 185.7, 185.7 epidermolysis bullosa simplex with mottled 118.9 inherited disorders 115.25, 138.1–138.12, 138.2–138.3 normal process 138.1, 138.4 oral mucosa 147.15 teeth 147.16, 147.16, 147.16 UV radiation-induced 108.7 see also hyperpigmentation; hypopigmentation pigmented hairy epidermal naevus see Becker naevus pigmented lesions benign 104.13 blue/black macular 109.22–109.23 dermoscopy 185.1–185.21 histopathology 4.1–4.3 incontinentia pigmenti 130.3, 130.3 laser treatment 189.4–189.7 nails 150.7, 150.7 oral 147.14–147.17 see also melanocytic naevi pigmented macules Peutz–Jeghers syndrome 109.12, 137.16, 137.16 PTEN hamartoma tumour syndrome 137.19 pigmented naevi chromosome disorders 116.12 dystrophic epidermolysis bullosa 118.13 oral 147.14 pigmented purpuras (pigmented purpuric eruptions) 165.1–165.6 pigmented purpuric lichenoid dermatosis (PPLD) of Gougerot and Blum 165.5 pigmented spindle cell naevus of Reed 109.15, 109.16, 185.16 see also Spitz naevus PIK3CA mutations, mosaic 110.8, 110.10 pilar cysts see trichilemmal cysts pili annulati 148.16 pili bifurcati, mosaic trisomy 8 116.15 pili incarnati 117.7–117.8 pili multigemini 148.17 pili torti 148.13–148.14, 148.14 associated syndromes 148.14, 148.14 and developmental delay 127.51 Netherton syndrome 124.4, 124.5 and onychodysplasia 127.51 and onychodysplasia (Beare type) 127.51 pili trianguli et canaliculi 148.16 pilodental dysplasia with refractive errors 127.51 pilomatricoma (pilomatrixoma) 92.1–92.4 clinical features 92.1–92.2, 92.3 dystrophic calcification 95.7 histopathology 4.3, 4.3 pilomatrix carcinoma 92.3, 99.4 pilonidal sinuses 10.17 pilosebaceous apparatus development 2.33–2.39 see also hair follicle(s) pimecrolimus 181.11–181.12 atopic dermatitis 25.11–25.12, 30.7–30.8 eczema herpeticum and 33.3 mode of action 25.11, 25.11 perioral dermatitis 38.3 pityriasis alba 37.2 vitiligo 105.6 pinch marks, abusive 154.4 pinnae see ears, external pinta 60.1–60.7 aetiology 60.1, 60.2, 60.2 clinical features 60.5, 60.5, 60.5

differential diagnosis 60.5–60.6, 60.6 distribution 60.2 dyspigmentation 60.5, 60.5, 104.4 laboratory tests 60.6, 60.6 pathology 60.3 prognosis 60.7 treatment 60.7 pintids 60.5 pinworms (threadworms) 151.10, 152.3, 152.4, 152.4 pitted keratolysis 56.1–56.2, 56.2 pityriasis alba 37.1–37.2 atopic dermatitis 28.6, 28.7, 37.1, 37.2 differential diagnosis 37.2, 70.8, 105.5 extensive 37.2 hypopigmentation 37.1–37.2, 37.2, 104.1 treatment 37.2 pityriasis amiantacea 148.23 pityriasis lichenoides (PL) 100.1–100.3 clinical features 100.2, 100.2–100.3 pathology 4.6–4.7, 4.7, 100.1–100.2, 100.2 pityriasis lichenoides chronica (PLC) 100.1, 100.3 histopathology 100.2 hypopigmentation 104.1 pityriasis lichenoides et varioliformis acuta (PLEVA) 100.1, 100.3 differential diagnosis 100.3 histopathology 100.2 pityriasis rosea 84.1–84.4 clinical features 84.2, 84.2–84.3, 84.3 gigantea 84.3 papular 84.3 pigmentation changes 104.5 pityriasis rubra pilaris (PRP) 83.1–83.7 aetiology and pathogenesis 83.1–83.2 associated diseases 83.5 classification 83.2, 83.2–83.3, 83.3 clinical features 83.3–83.5 clinical types 83.3–83.5 differential diagnosis 83.6, 83.6 epidemiology 83.1 hereditary 122.5 histopathology 83.2 HIV-associated 52.5, 83.5 neonatal 11.3, 11.4 patient advocacy group 179.7 prognosis 83.6 ‘sandal’ 83.3 treatment 83.6–83.7 type I and II (adult) 83.3 type III (classic juvenile) 83.3, 83.3–83.4, 83.4 type IV (localized juvenile) 83.5, 83.5 type V (atypical juvenile) 83.5, 83.5 pityriasis sicca faciei see pityriasis alba pityriasis simplex see pityriasis alba pityriasis versicolor 62.25–62.28 aetiology and pathogenesis 62.26–62.27 clinical features 62.27, 62.27 diagnosis 62.27–62.28, 62.28 neonatal 9.5 pathology 62.27 pigmentary changes 62.27, 62.27, 104.1, 104.4 treatment 62.28 vs. vitilogo 105.5 Pityrosporum see Malassezia PKC412, mastocytosis 75.12 PKP1 gene mutations 118.9, 127.98, 139.10 placenta steroid sulphatase deficiency 121.12 transfer of autoantibodies 14.3 plakins 127.97 plakoglobin 27.1, 127.99 plakophilin 1 27.1, 127.98 plantar dermatosis, juvenile (JPD) 43.1–43.2, 43.2 plantar nodules, bilateral congenital adipose see precalcaneal congenital fibrolipomatous hamartoma plantar–palmar fibromatosis 97.9–97.10 plantar pits, Gorlin syndrome 132.4, 132.7–132.8 plantar warts 47.4

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

plants/plant products allergic contact dermatitis 44.4, 44.11, 44.11–44.12, 45.5, 45.5–45.7 cutaneous reactions see phytodermatoses identification 45.1 irritant reactions 45.1–45.3 urticaria and angio-oedema 45.3–45.4, 45.4 plasmablastic lymphoma 99.27 plasmacytoid monocytes, Jessner’s lymphocytic infiltrate 101.1, 101.2 plasma exchange pemphigus vulgaris 91.5 polyarteritis nodosa 167.11 Wegener granulomatosis 167.6 plasmid DNA gene delivery 140.5–140.6 in vivo transfer methods 140.6–140.7 plasminogen activator inhibitor 1 (PAI-1), purpura fulminans 162.5 plastic surgery 187.1–187.32 age considerations 187.1 methods of wound cover 187.10–187.30 reconstructive ladder 187.1, 187.2 scar placement 187.2–187.3, 187.3, 187.4, 187.5, 187.6, 187.7 scar revision 187.7–187.9, 187.9 skin closure and suture technique 187.2 wound healing 187.1–187.2 platelet-activating factor (PAF), atopic dermatitis 25.4 platelet-derived growth factor (PDGF) AA, embryonic skin 2.6, 2.8 BB, embryonic skin 2.8 mastocytosis pathogenesis 75.5 platelet-derived growth factor receptor-α (PDGFR-α), embryonic skin 2.6, 2.8 platelet-derived growth factor receptor-β (PDGFR-β), embryonic skin 2.8 plate-like osteoma cutis (OC) 95.9–95.10, 95.12 PLEC1 gene mutations 117.3, 118.9, 118.30 trans-splicing 140.15 plectin/HD1 91.14, 91.14 antibodies 91.15 pleiotropism 115.3 pleuromutilin, infected atopic dermatitis 26.4 PLOD1 gene mutations 142.2 PMS2 gene mutations 137.14 Pneumocystis jiroveci pneumonia 52.1, 113.16–113.17 pneumonia infantile chlamydial 153.13, 153.14, 153.16 varicella 49.13 pneumothorax, iatrogenic skin damage 17.6 PNP gene 177.30 podophyllotoxin/podophyllin resin molluscum contagiosum 46.5 toxicity 184.8–184.9 warts 47.9 podopompholyx 39.1 POEMS syndrome hypertrichosis 148.30 pigmentation changes 104.8–104.9 poikiloderma differential diagnosis 136.9 dyskeratosis congenita 136.8 hereditary acrokeratotic 119.2 Kindler syndrome 119.1, 119.2 mycosis fungoides 102.2–102.3, 102.3 with neutropenia, Clericuzio type 115.28, 127.52 Rothmund–Thomson syndrome 136.2, 136.2 xeroderma pigmentosum 135.8, 135.8 poikiloderma congenitale 16.5–16.6 point mutations 115.6 poisoning 184.1–184.16 cutaneous symptoms of systemic 184.14, 184.14–184.15 paediatric skin absorption 184.2–184.14 non-therapeutic agents 184.3, 184.13–184.14 therapeutic agents 184.3, 184.3–184.12

Index purpura fulminans 162.4 toxicology 184.1–184.2 poison ivy (Toxicodendron radicans) 44.12, 45.5, 45.6 control measures 45.7 vesiculobullous lesions 87.9 poison oak 44.12, 45.5 Poland syndrome 10.8 police, investigation of child abuse 155.7 poliomyelitis 49.9 poliosis tuberous sclerosis 129.6, 129.7 vitiligo 105.3, 105.3 Waardenburg syndrome 138.5 pollen allergy 32.6, 32.7 management 32.8 Pollitt syndrome 127.62, 148.11 polyarteritis nodosa (PAN) 167.8–167.13 aetiology and pathogenesis 167.9 clinical features 167.9–167.10, 167.10, 167.10, 167.11 criteria for classification 167.9 cutaneous 77.5–77.6, 77.6, 167.9, 167.9–167.10, 167.10, 167.11 investigations 167.10, 167.12 microscopic see microscopic polyangiitis pathology 167.9, 167.11 prognosis 167.12–167.13 purpura fulminans 162.4, 162.6–162.7 treatment 167.11–167.12 polyarthritis 175.2 rheumatoid factor negative 175.3 rheumatoid factor positive 175.3 polycystic kidney disease autosomal dominant (ADPKD) 129.1, 129.9 tuberous sclerosis 129.4, 129.9 polycystic ovary syndrome (PCOS) acne 79.16 hair loss 148.21–148.22 treatment 79.10, 189.3, 189.3 polydactyly 150.8 polygenic inheritance 115.1, 115.7 polygenic skin disorders, segmental involvement 115.15, 115.16 polyglandular autoimmune syndromes (PGAS) 172.28, 172.28 type 1 see autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy polymastia 10.8 PolyMem® dressings, epidermolysis bullosa 118.20 polymerase chain reaction (PCR) congenital vesicular lesions 8.2 dermatophytes 62.13, 62.14 Lyme borreliosis 59.7–59.8 Mycobacterium tuberculosis 57.4 polymorphic eruptions, Henoch–Schönlein purpura 160.3, 160.3 polymorphic light eruption (PLE) 106.1–106.3 clinical features 106.1–106.2, 106.2 differential diagnosis 106.3, 106.5, 106.5 erythema multiforme (EM) variant 106.1 Kawasaki disease 168.3, 168.3 pigmentation changes 104.5 pinpoint 85.16 treatment 106.3 polymorphous light eruption see polymorphic light eruption polyposis, skin pigmentation, alopecia and fingernail changes 127.52 polythelia (supernumerary nipples) 10.7, 10.7–10.8 pompholyx 39.1–39.4 clinical features 39.2, 39.2–39.3, 39.3 differential diagnosis 39.3, 88.2 vesiculobullous lesions 87.9 popliteal pterygium syndrome 10.7, 115.28 popsicle panniculitis 77.7 PORCN gene 127.83, 133.5, 133.6, 133.7 Porcupine protein 133.5

porokeratosis 126.1–126.5 clinical variants 126.1–126.3 diagnosis 126.3 genital 126.3, 126.4 histology 126.1, 126.2 malignant degeneration 126.1, 126.4–126.5, 137.2 management 126.3–126.5 punctate 126.3 with pustules 126.2 risk factors 126.1 porokeratosis of Chernosky see disseminated superficial actinic porokeratosis porokeratosis of Mantoux 132.13 porokeratosis of Mibelli (PM) 126.1–126.2, 126.4 porokeratosis palmaris et plantaris disseminata (PPPD) 126.2–126.3 genetics 126.1, 126.3 management 126.4–126.5 porokeratosis ptchyotropica 126.3 porokeratosis punctata palmaris et plantaris see keratosis palmoplantaris punctata porokeratotic adnexal ostial naevus 110.12 porokeratotic eccrine naevi (PEN) 110.11, 110.11–110.12 porokeratotic eccrine ostial and dermal duct naevi (PEODDN) 110.12, 110.20 poroma, eccrine 94.10–94.11, 94.11 porphobilinogen (PBG) 107.1 accumulation 107.4, 107.5, 107.6 neurotoxicity 107.7 synthesis 107.2–107.3 porphobilinogen deaminase (PBGD) 107.4 deficiency 107.4 gene 107.3, 107.4 porphyria(s) 107.1–107.15 acute 107.1, 107.2, 107.5 aetiology 107.2 clinical features 107.13 pathogenesis 107.7 treatment 107.15 aetiology 107.1–107.7 classification 107.1, 107.2 clinical features 107.8–107.13 cutaneous 107.1, 107.2, 107.5 acute cutaneous syndrome 107.8 clinical features 107.8–107.13 pathogenesis 107.7 subacute cutaneous syndrome 107.8 treatment 107.13–107.15 differential diagnosis 107.13 history 107.1, 107.3 homozygous 107.11–107.13 hypertrichosis 107.9, 107.9, 107.11, 148.29–148.30 incidence 107.8 mixed 107.1, 107.2, 107.5 aetiology 107.2 clinical features 107.13 pathogenesis 107.7 treatment 107.15 pathogenesis 107.7 pathology 107.7–107.8 tooth pigmentation 147.16 treatment 107.13–107.15 porphyria cutanea tarda (PCT) aetiology 107.5–107.6 clinical features 107.8, 107.8, 107.8–107.9, 107.9 differential diagnosis 107.13 genetics 115.2, 115.26 hyperpigmentation 104.8 hypertrichosis 107.9, 107.9, 148.29 incidence 107.8 pathogenesis 107.7 pathology 107.7 porphyrin profile 107.5 treatment 107.14 types 107.5, 107.5 porphyria variegata (PV) aetiology 107.6, 115.26 clinical features 107.8, 107.13

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hypertrichosis 148.29–148.30 porphyrin profile 107.5 treatment 107.15 porphyrins 107.1 mechanism of phototoxicity 107.7 profiles of childhood porphyrias 107.5 structure 107.3 synonyms 107.3 Portuguese man-of-war 73.7 port-wine stain see capillary malformations port-wine stain, venous malformations and limb hypotrophy 112.17 positron emission tomography (PET), Sturge– Weber syndrome 112.16 posterior tibial artery catheterization, complications in neonates 17.7 postherpetic neuralgia 49.14 posthitis 9.3 postinflammatory elastolysis and cutis laxa (PECL) (Marshall syndrome) 143.3–143.4, 145.14 after Sweet syndrome 77.11, 156.3, 156.4 post-kala-azar dermal leishmaniasis (PKDL) 67.9–67.10 post-Lyme syndrome 59.9–59.10 post-steroid panniculitis 77.7–77.8 poststreptococcal glomerulonephritis, acute 54.2, 54.4 postvaccinia encephalomyelitis (or encephalitis) (PVEM) 51.11, 51.13 postvaccinia encephalopathy (PVE) 51.13 potassium dichromate poisoning 184.14 potassium hydroxide (KOH) diagnostic preparations candidal napkin dermatitis 20.5 candidiasis 62.23, 62.23 congenital vesicular lesions 8.2 dermatophytoses 62.11, 62.12 molluscum contagiosum 46.4, 46.4 pityriasis versicolor 62.27–62.28 scabies 72.5 Scytalidium 62.34, 62.34 topical therapy 46.5, 181.13 potassium iodide (KI) granuloma annulare 93.8 patch test, dermatitis herpetiformis 90.4 sporotrichosis 63.19 potassium permanganate 181.9 povidone-iodine 181.8 toxicity 5.7, 184.6–184.7 powders see baby powders; cornstarch powder poxviruses 51.1–51.25 capsule (C) form 51.2 mulberry (M) form 51.2 zoonotic 51.1, 51.2 PPD see paraphenylenediamine P protein 138.8 Prader–Willi syndrome (PWS) 116.5, 116.11 insulin resistance 172.19 obesity 141.9 self-mutilation 180.10 preauricular cysts and sinuses 10.3–10.4, 10.4 preauricular skin tags, chromosome disorders 116.13, 116.13 precalcaneal congenital fibrolipomatous hamartoma (PCFH) (pedal papules of infancy) 7.4–7.5, 10.10–10.11 precocious puberty 172.11–172.12 central, with epidermal naevi 110.20 clinical features 172.12, 172.13 precursor haematological neoplasm 99.25, 102.16 prednisolone/prednisone acne fulminans 79.17 alopecia areata 149.5 aphthous genital ulcers 151.14 atopic dermatitis 30.10 bullous pemphigoid 91.17 epidermolysis bullosa acquisita 91.24 graft-versus-host disease 178.9 infantile haemangiomas 113.15, 113.16 lepra reactions 70.12

58

Index

prednisolone/prednisone (cont.) linear IgA disease of childhood 89.10 monitoring therapy 192.16 morphoea 173.9 pemphigus foliaceous 91.6 pemphigus vulgaris 91.4 sarcoidosis 158.5 Sweet syndrome 156.4 pregnancy complications Ehlers–Danlos syndrome 142.8 pseudo-xanthoma elasticum 144.7–144.8 iatrogenic injuries to newborn 17.2–17.3 linear IgA disease 89.8–89.9 Lyme borreliosis 8.6, 59.7 melasma 104.6 sexually transmitted diseases 153.1 striae 146.1 preimplantation genetic diagnosis (PGD) 139.1, 139.9–139.11, 139.10 preimplantation genetic haplotyping (PGH) 139.1, 139.11 premature ageing ataxia telangiectasia 177.4 Cockayne syndrome 134.5, 135.15, 135.16 premature ageing syndromes 134.1–134.19 apparent 134.18–134.19 with skin atrophy/lipoatrophy 134.5–134.12 with skin laxity 134.12–134.18 true 134.1–134.5 pre-mRNA trans-splicing (PTM) molecule 140.14, 140.15 prenatal diagnosis 139.1–139.12 aneuploidies 116.4 DNA-based 139.2–139.6, 139.4 development 139.2–139.6 disorders suitable for 139.3, 139.4 fetal DNA in maternal blood 139.11 practical aspects 139.6 ethical issues 139.12 fetal skin biopsy 139.6–139.9, 139.7, 139.8 FISH 116.2 iatrogenic injuries 17.2–17.3 lymphatic disorders 114.20 non-invasive 139.11–139.12 timing of different methods 2.3, 2.3 prepubertal unilateral fibrous hyperplasia of labium majus 151.21 prepubertal vulval fibroma 151.21 prescleroderma 174.2 clinical features 174.5, 174.6 preservatives, allergy 44.10–44.11 pressure alopecia 148.23 pressure garments, hypertrophic scars 187.5, 187.8 preterm infants 2.22–2.23 barrier function of skin 2.23, 3.1, 3.2–3.4 bathing or washing 5.2 congenital cutaneous candidiasis 11.7 congenital erosive and vesicular dermatosis 16.1, 16.5 iatrogenic skin disorders 17.6–17.11 monitoring-related problems 17.9–17.10 napkin dermatitis 21.2 percutaneous absorption 184.2 topical therapies 3.3, 181.2–181.3 toxicity 3.4, 17.7–17.8 percutaneous respiration 3.6 perianal dermatitis 6.11 pH of skin surface 3.5 restrictive dermopathy 15.2 sclerema neonatorum 7.4, 77.9 skin anatomy 3.1, 3.3 skin breakdown 5.4 skin care 5.3–5.5 thermoregulation 3.6 transepidermal water loss 2.23, 3.2–3.4, 3.3, 5.4, 181.2 pretibial myxoedema 172.5–172.6 PRF1 gene mutations 103.17–103.18, 177.8 prickly heat see miliaria rubra

primary cutaneous anaplastic large-cell lymphoma (C-ALCL) 99.22, 102.6–102.7 clinical features 99.22, 102.6, 102.7 histopathology 102.6, 102.7 primary cutaneous CD30+ lymphoproliferative disorders 99.22–99.23, 102.6–102.9 primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) 102.15 leg type 99.27, 102.15 other 99.27 primary cutaneous follicle-centre lymphoma (PCFCL) 99.26–99.27, 102.14–102.15 primary cutaneous lymphoma 99.19, 99.20, 102.1 primary cutaneous marginal zone B-cell lymphoma (PCMZL) 99.26, 102.14 primary cutaneous peripheral T-cell lymphoma, unspecified 99.25 primary localized cutaneous amyloidosis (PLCA) 159.1, 159.2, 159.2–159.4 primin 45.5 primitive neuroectodermal tumour (PNET), Gorlin syndrome 132.10, 132.14 Primula obconica 45.5, 45.6 Pringle disease see tuberous sclerosis complex PRKAR1A gene defects 109.2 PRKDC deficiency 177.31 probiotics, atopic dermatitis 30.11 procaine 190.2 procaine penicillin 153.7, 153.7 procollagen type I carboxyterminal propeptide (P1cp), morphoea 173.8 proctitis, gonococcal 153.10, 153.12 profilaggrin 23.7, 23.8, 121.9 gene mutations see FLG gene mutations see also filaggrin progeria see Hutchinson–Gilford syndrome progressive multifocal leukoencephalopathy (PML) 182.13 progressive nodular histiocytosis (PNH) 103.10–103.11, 103.13 progressive osseous heteroplasia (POH) 95.10–95.11 Albright hereditary osteodystrophy (AHO) overlap 95.10–95.11, 95.11 clinical features 95.10, 95.10, 95.11 plate-like osteoma cutis 95.12 pseudo-hypoparathyroidism (PHP) overlap 95.10–95.11, 95.11 progressive pigmented dermatosis see Schamberg disease progressive symmetric erythrokeratoderma (PSEK) 122.4, 122.10–122.12 clinical features 122.11, 122.12 differential diagnosis 83.6, 122.12 pathogenesis 115.20, 122.11–122.12 prolidase deficiency 177.23 proliferating cell nuclear antigen (PCNA) 135.5 promethazine toxicity 184.5 properdin deficiency 177.19 Propionibacterium acnes antibiotic resistance 79.8 role in acne 79.5, 79.6 treatments targeting 79.8 propionic acidaemia 169.6–169.8 clinical features 169.7, 169.7 propofol 190.8–190.9 propolis allergy 44.3 propranolol 181.18–181.19 erythromelalgia 166.3 infantile haemangioma 113.17, 188.8 monitoring therapy 192.16 proptosis, Wegener granulomatosis 167.5, 167.5 propylene glycol contact allergy 44.11 newborn skin care 5.6 PROQOLID database 29.10 prosector’s wart 57.2–57.3 prostacyclin therapy meningococcal disease 55.11 purpura fulminans 162.11, 162.12

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

prostaglandin analogues atopic dermatitis 25.10 hypertrichosis induced by 148.32 prostaglandin E1, atopic dermatitis 25.7 prostaglandin E2, atopic dermatitis 25.3, 25.7 protease-activated receptor 2 (PAR2) 27.6, 27.6 atopic dermatitis 27.11 protease inhibitors atopic dermatitis 27.11 dystrophic epidermolysis bullosa 118.20 stratum corneum 27.4 proteases exogenous, degrading skin barrier 27.6, 27.7 stratum corneum atopic dermatitis 27.11 desquamation 27.3–27.4, 27.5 skin barrier function 27.6, 27.8 protectants, skin 181.7 newborn infants 5.8 see also skin barrier products protein-based therapies 140.17–140.18 epidermolysis bullosa 118.21 protein C acquired deficiency due to drugs or specific diseases, purpura fulminans 162.4, 162.6 postvaricella purpura fulminans 162.5 purpura fulminans pathogenesis 162.1 concentrates, acute infectious purpura fulminans 162.11 congenital deficiency 115.26 prognosis 162.10 purpura fulminans 162.1, 162.3, 162.5–162.6 meningococcal sepsis 55.3 purpura fulminans pathogenesis 162.2–162.5 recombinant activated 55.11, 162.11 protein-energy malnutrition 65.1–65.4 aetiology 65.1–65.2 cutaneous manifestations 65.2, 65.2–65.3, 65.3 hair abnormalities 65.2–65.3, 65.3, 148.19, 148.20 see also kwashiorkor; marasmus protein gene product 9.5 (PGP 9.5) embryonic-fetal transition 2.17, 2.18 embryonic skin 2.9, 2.10 protein S acquired deficiency due to drugs or specific diseases, purpura fulminans 162.4, 162.6 postvaricella purpura fulminans 162.5, 162.6 purpura fulminans pathogenesis 162.1 congenital deficiency 115.26 prognosis 162.10 purpura fulminans 162.1, 162.3, 162.5–162.6 purpura fulminans pathogenesis 162.2–162.5 proteoglycan-rich matrix embryonic skin 2.8, 2.10 fetal skin 2.21 Proteus-like syndrome 111.1–111.3, 114.10, 137.20 see also PTEN hamartoma tumour syndrome Proteus syndrome 111.1–111.8 aetiology and pathogenesis 111.1–111.3 Biesecker diagnostic criteria 111.1, 111.2 clinical features 111.3, 111.3–111.6, 111.4, 111.5 differential diagnosis 111.8 encephalocraniocutaneous lipomatosis and 141.6 epidermal naevus 110.13, 111.3, 111.4 facial phenotype with seizures and mental deficiency 111.6 lipomas 141.7 lymphatic disorders 114.10 management 111.7–111.8 natural history 111.7 pathology 111.3 proposed classification 111.1, 111.2 protoporphyrin 107.5, 107.6, 107.7 protoporphyrinogen oxidase (PPO) 107.6 defective 107.6 gene 107.3, 107.6 protozoal infections, congenital 8.5, 8.6

Index PROX-1 114.1, 114.2 PRPRC gene 177.31 prurigo 42.3–42.8 Sutton’s summer 42.6–42.7 prurigo nodularis 42.3–42.5, 42.4 prurigo pigmentosa 42.7 pruritus atopic dermatitis management strategies 30.5 pathogenesis 24.3, 24.4 severity scoring 29.6 cutaneous larva migrans 68.2 Darier disease 125.2, 125.4 dystrophic epidermolysis bullosa 118.12, 118.21 genital region 151.2, 151.3 hypertrophic scars 187.5 lichen planus 85.5 lichen simplex chronicus 42.1 louse infestations 72.10–72.11 Netherton syndrome 124.4 prurigo nodularis 42.3–42.4 seborrhoeic dermatitis 35.4–35.5 Sjögren–Larsson syndrome 121.42, 121.46 vulval 151.2 see also itch–scratch cycle; scratching pruritus pigmentosa 104.10 psammoma bodies 95.7 Pseudallescheria boydii 63.4 pseudo-acromegaly 172.18 pseudo-ceramides, atopic dermatitis 25.10 pseudocowpox see milker’s nodules pseudo-Darier’s sign 148.31 pseudo-dominance 115.5 pseudo-folliculitis barbae 117.7–117.8, 127.95 laser treatment 189.4 pseudo-Hutchinson’s sign 150.7 pseudohypoaldosteronism, type I 6.10 pseudo-hypoparathyroidism (PHP) 172.26–172.27 Albright hereditary osteodystrophy 95.11–95.12, 172.26 clinical features 172.26, 172.26, 172.27 progressive osseous heteroplasia 95.10, 95.11 pseudo-Kaposi sarcomatous changes, arteriovenous malformations 112.2 Pseudomonas aeruginosa botryomycosis 54.6 HIV infection 52.2 immunocompromised children 64.2–64.3 skin graft infections 187.13 Pseudomonas infections collodion baby 12.3 immunocompromised children 64.9 pseudomonilethrix 148.15, 148.15 pseudomycetoma, dermatophytic 63.25 pseudo-paralysis of Parrot 153.5 pseudo-pelade of Brocq, lichen planopilaris 85.6 pseudo-porphyria 107.13 pseudo-pseudo-hypoparathyroidism (PPHP) 172.26–172.27 pseudo-rheumatoid nodule see granuloma annulare (GA), subcutaneous pseudo-verrucous papules and nodules, perianal 20.9, 20.9, 21.2 pseudo-xanthoma elasticum (PXE) 144.1–144.8 aetiology and pathogenesis 115.23, 144.1–144.2 calcification 95.7, 144.2, 144.3, 144.6–144.7 clinical features 144.3–144.7, 144.4, 144.5 differential diagnosis 144.7 localized acquired cutaneous 144.5 pathology 144.2–144.3, 144.3 patient advocacy group 179.7 perforating 144.5 prevalence 144.1 treatment 144.7–144.8 variants 144.5 psoralens, phytophotodermatitis 45.8, 45.10 psoralens with ultraviolet A (PUVA) therapy see photochemotherapy

psoriasiform lesions candidal napkin dermatitis 20.5, 20.5 Kawasaki disease 168.5 psoriasis 80.1–80.7 clinical features 80.1–80.6, 80.2 congenital/neonatal 11.3, 80.6 differential diagnosis 80.7 infantile acropustulosis 88.3 lichen sclerosus 152.6, 152.7 pityriasis rubra pilaris 83.6, 83.6 epidemiology 80.1, 80.2 erythrodermic pustular 80.4 facial involvement 80.4 flexural 80.4, 80.4 generalized pustular (GPP) 11.3, 80.6 genetic factors 81.1–81.2 genital area 151.3–151.4, 151.4 guttate 80.3, 80.3 HIV infection 52.4 infantile 11.3, 11.3 Koebner phenomenon 80.4–80.5, 80.5 lichen striatus with 86.3, 86.3 linear 80.6 mechanism 115.15 vs. inflammatory linear verrucous epidermal naevus 110.17, 110.17 nails 80.2, 80.5, 80.5, 150.4–150.5 ‘napkin’ 20.5 in napkin area 20.8, 20.8, 80.2, 151.4 napkin dermatitis triggering 20.9 nursing care 192.4, 192.9 oral lesions 147.13 pathogenesis 81.1–81.2 pathology 80.1 patient advocacy group 179.7 pigmentation changes 104.5 plaque 80.2, 80.3, 80.3–80.4, 80.4 plasma lipids 80.6–80.7 prognosis 80.7 provoking/exacerbating factors 81.2 rare clinical presentations 80.6 scalp 80.1, 80.2 nursing care 192.4, 192.9 seborrhoeic dermatitis and 35.1–35.2, 35.2, 35.5–35.6, 41.4 treatment 82.1–82.6, 82.2 abatacept 82.5, 182.12 alefacept 82.5, 182.12–182.13 biological agents 82.5–82.6 etanercept 82.5, 182.2, 182.3 infliximab 82.5, 182.5 laser therapy 82.6, 188.10 systemic 82.4–82.6 topical 82.1–82.3 ustekinumab 182.12 psoriatic arthritis 80.5–80.6, 175.2, 175.4 infliximab therapy 182.5 PSORS loci 81.1, 81.2 Psychoda 69.4 psychodermatology 180.1–180.14 psychological disorders acne excoriée des jeunes filles 79.21 cutis verticis gyrata 10.1 genital disease 151.24–151.25 lichen simplex chronicus 42.1 prurigo nodularis 42.4 self-mutilation 180.7 skin disorders due to 180.1–180.14 systemic lupus erythematosus 175.7 warts 47.10 psychological treatment atopic dermatitis 30.9, 34.4–34.5 lichen simplex chronicus 42.3 self-mutilation 180.11 warts 47.10 psychoneuroimmunology, atopic dermatitis 34.3–34.4 psychosocial issues acne 179.2–179.3 atopic dermatitis 34.1–34.6, 179.2 congenital malformations 179.3

59

congenital melanocytic naevi 109.6 Darier disease 125.3–125.4 ectodermal dysplasias 127.103 genital disease 151.24–151.25 infantile haemangiomas 179.3 measures 179.2 Proteus syndrome 111.7 severe ichthyoses 121.65 vitiligo 105.3 see also burden of paediatric skin disease PTCH gene mutations 99.1, 132.2–132.4 somatic mosaicism 132.2, 132.13 testing for 132.12 PTCH protein 132.2, 132.2, 132.3 PTEN gene mutations 137.17 indications for testing 137.19 linear Cowden’s naevus 110.13 Proteus-like syndromes 111.1–111.3, 114.10 PTEN hamartoma tumour syndrome (PHTS) 137.17–137.20 associated malignancies 137.6, 137.19 clinical features 137.17–137.19, 137.18 differential diagnosis 137.19–137.20 genital area 151.5 lipomatosis 141.6–141.7 pathogenesis 115.27, 137.17 treatment 137.20 vascular anomalies 112.17–112.18, 137.17, 137.18 PTEN protein 137.8 pterygium, xeroderma pigmentosum 135.8, 135.9 PTPN11 gene 109.12, 114.8 PTPN22 gene 149.2 PTSTPIP gene 79.17 puberty delayed 172.11 naevus sebaceous changes 110.4, 110.4 precocious see precocious puberty surgical treatment 186.1 see also adolescents pubic louse (Phthirus pubis) 72.9, 72.9–72.10 clinical features of infestation 72.11, 72.11, 72.12 treatment of infestations 72.13 Pulex irritans (human flea) 71.1, 71.2, 71.6 pulmonary hypertension, systemic sclerosis 174.8, 174.9 pulmonary involvement Birt–Hogg–Dubé syndrome 137.9 cystic fibrosis 170.2 hereditary haemorrhagic telangiectasia 112.5 juvenile dermatomyositis 175.11 Langerhans cell histiocytosis 103.3 Proteus syndrome 111.6 sarcoidosis 158.4 systemic sclerosis 174.7–174.8, 174.9 tuberous sclerosis 129.9 urticarial vasculitis 163.2 Wegener granulomatosis 167.3, 167.4 see also respiratory tract involvement pulsed-dye lasers (PDL) 188.1 angiolymphoid hyperplasia with eosinophilia 98.2 angioma serpiginosum 188.10 chronic inflammatory skin conditions 188.10, 188.11 cutis marmorata telangiectatica congenita 188.10 Goltz syndrome 188.10 granuloma annulare 93.8 infantile haemangiomas 113.7, 113.18, 188.7–188.8 inflammatory epidermal naevi 188.10 pigmented lesions 189.4, 189.5, 189.6 port-wine stains 188.4–188.6 scarring 188.10, 189.9 striae 189.10 telangiectasia 188.9 vascular 188.2–188.3

60

Index

pulsed-dye lasers (PDL) (cont.) adverse effects 188.3 mechanism of action 188.2–188.3 newer generation 188.3, 188.3 warts 189.8 punch biopsy 4.1 punctate porokeratosis 126.3 purine nucleoside phosphorylase (PNP) deficiency 177.30 purpura acute haemorrhagic oedema of infancy 161.2, 161.2, 161.3 Henoch–Schönlein purpura 160.2–160.3, 160.3 HIV-infected children 52.5 itching 165.5 meningococcal septicaemia 55.6, 55.7 management 55.11–55.12 pigmented 165.1–165.6 self-inflicted 180.10 see also ecchymoses purpura annularis telangiectoides 165.4–165.5 purpura fulminans 162.1–162.14 acquired protein C and S deficiency 162.1, 162.4, 162.6 acute infectious 162.2–162.5, 162.3 clinical features 162.2, 162.2 pathogenesis 162.2–162.5 prognosis 162.8 treatment 162.10–162.14, 162.13 aetiology and pathogenesis 162.1–162.7, 162.3–162.4 antiphospholipid syndrome 162.4, 162.6–162.7, 162.12 bites or envenomation 162.4, 162.7 classification 162.1–162.7, 162.3–162.4 clinical features 162.8, 162.9, 162.10, 162.11 congenital protein C and S deficiency 162.1, 162.3, 162.5–162.6 prognosis 162.10 differential diagnosis 55.9, 55.11, 162.14 meningococcal disease see under meningococcal septicaemia, acute pathology 162.7, 162.7 platelet-mediated 162.4, 162.7 postinfectious 162.3, 162.5, 162.6 clinical features 162.2, 162.9, 162.10, 162.11 prognosis 162.8 treatment 162.12 prognosis 162.8–162.10 treatment 162.10–162.14 vasculitic disorders 162.4, 162.12 purpuric pigmented lichenoid dermatitis 165.5 pustular drug eruptions 183.7–183.9 pustular folliculitis, eosinophilic see eosinophilic pustular folliculitis pustular melanosis, transient neonatal see transient neonatal pustular melanosis pustules acne 79.6, 79.6 neonatal 8.1, 9.1, 9.2 spongiform, of Kogoj 80.1 vesiculobullous disease 87.1, 87.2 pustulosis acute generalized exanthematous see acute generalized exanthematous pustulosis eosinophilic see eosinophilic pustular folliculitis neonatal cephalic see under Malassezia putsi fly 69.1–69.2 PUVA therapy see photochemotherapy PVRL1 gene mutations 127.100 Pyemotes mites 71.5 pyoderma gangrenosum, HIV-infected children 52.5 pyodermas 54.3–54.7 epidemiology 54.3 pathophysiology 54.1–54.3 pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome 79.17 pyogenic granuloma 92.7

clinical features 92.7, 92.7 histopathology 4.5 oral 147.18 pyogenic infections, primary immunodeficiencies 64.2–64.3, 64.4 pyostomatitis vegetans 157.2 pyrantel pamoate 151.10 pyrazinamide, tuberculosis 57.4 Pyrenochaeta mackinnonii 63.4 Pyrenochaeta romeroi 63.4 pyrethrins lice 72.12 toxicity 184.9 pyrethroids, lice 72.12 pyridoxine (vitamin B6) deficiency 65.5 treatment, homocystinuria 169.5 pyrimidine-6,4-pyrimidone photoproducts 135.2 pyrin 176.1 pyrrolidone carboxylic acid (PCA) 23.7, 23.8 Q-switched lasers pigmented lesions 189.4, 189.5, 189.6, 189.7 tattoo removal 189.7 quality of life (QoL) acne 179.3 atopic dermatitis 34.3 measurement 29.9–29.16, 179.2 defined 29.9, 179.1 health-related (HRQoL) 29.9 measures 179.1–179.2 quantitative trait loci (eQTL) mapping 23.4 quaternium allergy 44.4, 44.11 Queensland tick typhus (Rickettsia australis) 61.2, 61.5–61.6 Quincke’s oedema see hereditary angioedema RAB27A gene mutations 138.7, 177.7, 177.8 Rab27a protein 138.1 Rabson–Mendenhall syndrome 141.17–141.18, 172.18 Rac2 deficiency 177.11 RAC2 gene mutations 177.11 racoon eyes, neuroblastoma 99.11, 154.11 racoon sign, neonatal lupus erythematosus 14.6, 14.6 radial artery sampling, complications in neonates 17.7 radial ray defects, Rothmund–Thomson syndrome 136.3 radiation hypersensitivity, Gorlin syndrome 132.4 ionizing 108.2, 108.2 radiation acne 79.19 radiation chimera 178.2 radiation therapy ataxia telangiectasia 177.5 dermatofibrosarcoma protuberans 99.7 Gorlin syndrome 132.14–132.15, 132.15 hair loss 148.18 Hodgkin disease 99.19 keloids 187.5–187.6 mucositis complicating 147.9 neuroblastoma 99.12 xeroderma pigmentosum 135.11 radiculopathy, Lyme neuroborreliosis 59.6 radiographs, plain Busche–Ollendorff syndrome 116.15, 145.2 Gorlin syndrome 132.9, 132.9–132.10, 132.10, 132.11, 132.12 venous malformations 112.9, 112.9 radish (Raphanus niger) 45.4 RAF1 gene 109.12 RAG1/RAG2 gene mutations 11.8, 177.31 Rajka & Langeland atopic dermatitis severity scoring system 29.5 Ramichloridium 63.8 ranitidine 181.16 RANTES, atopic dermatitis 24.4, 25.5 RANTES gene, atopic dermatitis 23.9, 23.12 ranula 147.21, 147.22

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

rapamycin Peutz–Jeghers syndrome mouse model 137.16 PTEN hamartoma-tumour syndrome 137.20 squamous cell carcinoma 99.3 tuberous sclerosis 129.12 Raphanus niger (radish) 45.4 Rapp–Hodgkin syndrome 127.74 clinical features 127.53, 127.75 genetic basis 115.23 see also ankyloblepharon–ectodermal dysplasia–clefting syndrome RASA1 mutations 112.4, 112.6 RASGRP2 gene mutations 177.28 rashes cystic fibrosis 170.2, 170.2, 170.3, 170.3 dermatitis herpetiformis 90.4, 90.4 erythema infectiosum 49.5, 49.6 fabricated 154.9 graft-versus-host disease 178.5, 178.6 infectious mononucleosis 49.15, 49.15 juvenile dermatomyositis 175.10, 175.10 juvenile idiopathic arthritis 175.2, 175.3 measles 49.2, 49.2 meningococcal septicaemia 55.6, 55.6, 55.12 papular-purpuric gloves and socks syndrome 49.8 rickettsial spotted fevers 61.5, 61.5 Rocky Mountain spotted fever 61.1, 61.2 roseola infantum 49.8 rubella 49.4, 49.4 syphilis 153.3, 153.4, 153.4 systemic lupus erythematosus 175.6, 175.6 typhus group rickettsial diseases 61.7, 61.8, 61.9 varicella 49.12, 49.12 rat flea (Xenopsylla cheopis) 61.8 rattlesnakes 73.10 Raynaud phenomenon differential diagnosis 174.2 Kawasaki disease 168.5 systemic sclerosis 174.2, 174.3, 174.11 razor bumps 117.7–117.8 REACH study 182.5, 182.6 recessive skin disorders see autosomal recessive skin disorders recessive X-linked ichthyosis (RXLI) (steroid sulphatase deficiency) 121.11–121.14 clinical features 116.8, 116.9, 121.10, 121.11–121.12 contiguous gene syndromes 121.11, 121.12–121.13 diagnosis 121.14 differential diagnosis 121.9, 121.10, 121.13– 121.14, 121.37 gene therapy 140.9 pathogenesis 115.21, 121.13 treatment 121.14 reconstructive ladder 187.1, 187.2 reconstructive surgery see plastic surgery RECQL4 gene mutations 136.1, 136.3 RECQL (BLM) gene mutations 116.7, 136.6 RecQ proteins 136.1, 136.6 rectal infections chlamydial 153.14, 153.15 gonococcal 153.10 recurrent aphthous stomatitis (RAS) 147.1–147.3 clinical features 147.2, 147.2, 147.2 differential diagnosis 147.2 herpetiform 147.2 major 147.2, 147.2 minor 147.2 treatment 147.2–147.3 recurrent respiratory papillomatosis (RRP) 47.6 recurrent toxin-mediated (perineal) erythema (RPE) 54.11, 151.9 red man syndrome, neonatal 11.8 red moss dermatitis 73.9 5α-reductase, acne 79.3 Reed naevus 109.15, 109.16, 185.16 see also Spitz naevus Reed–Sternberg cells 99.17

Index Reed syndrome see hereditary leiomyomatosis and renal cell cancer syndrome reflectance confocal microscopy (RCM), molluscum contagiosum 46.4 reflex sympathetic dystrophy 166.3 Refsum disease classic adult (ARD) 121.48–121.50 clinical features 121.43, 121.48, 121.49 genetics 115.21, 121.48–121.50 infantile form 121.48, 121.49 regulatory T cells, atopic dermatitis 24.5 relapsing polychondritis (RP) 167.19–167.21 clinical features 167.19, 167.19–167.20, 167.20 diagnostic criteria 167.19 reliability (repeatability) atopic dermatitis diagnostic criteria 28.14 atopic dermatitis scoring indices 29.1–29.2, 29.2 quality of life measures 29.9–29.10 Rel proteins 127.65 renal carcinoma Birt–Hogg–Dubé syndrome 137.9 hereditary leiomyomatosis and renal cell cancer syndrome 137.13–137.14 tuberous sclerosis 129.9 renal disease bullous pemphigoid with 91.16 calciphylaxis/metastatic calcification 77.12, 95.8 DRESS syndrome 183.6 dystrophic epidermolysis bullosa 118.16 Henoch–Schönlein purpura 160.4, 160.6 polyarteritis nodosa 167.9, 167.10, 167.12 Sweet syndrome 156.3 systemic lupus erythematosus 175.7, 175.7–175.8 systemic sclerosis 174.10 tuberous sclerosis 129.9, 129.11 urticarial vasculitis 163.2 Wegener granulomatosis 167.4, 167.6 see also glomerulonephritis renal failure, chronic hyperpigmentation 104.8 microscopic polyangiitis 167.8 oral leucoplakia 147.13 tuberous sclerosis 129.9 renal transplant recipients, skin infections 64.7 Rendu–Osler–Weber disease 112.5, 115.26 repeatability see reliability replication factor C (RFC) 135.5 replication protein A (RPA) 135.3, 135.4, 136.6 Research Registry for Neonatal Lupus (RRNL) 14.1 resorcinol toxicity 5.7, 184.9 respiration, percutaneous 3.6 respiratory insufficiency/failure harlequin ichthyosis 13.4–13.5 restrictive dermopathy 15.2, 15.3 respiratory papillomatosis, recurrent (RRP) 47.6 respiratory support, neonatal, skin complications 17.6 respiratory symptoms food allergies 31.5, 31.6 Langerhans cell histiocytosis 103.3 respiratory tract infections ataxia telangiectasia 177.4 Chlamydia trachomatis 153.13 HPV 47.6 hyper-IgE syndromes 177.22 non-specific viral eruptions 49.19 triggering polyarteritis nodosa 77.5–77.6 triggering Schönlein–Henoch purpura 160.2 triggering urticaria 74.2 see also aspergillosis; pneumonia respiratory tract involvement cystic fibrosis 170.2 infantile haemangioma 113.9 mucous membrane pemphigoid 91.19 paraneoplastic pemphigus 91.9 relapsing polychondritis 167.19, 167.20–167.21

Wegener granulomatosis 167.3, 167.3, 167.5 see also laryngeal involvement; pulmonary involvement restrictive dermopathy 15.1–15.3, 115.23 clinical features 15.2, 15.2–15.3, 15.3 differential diagnosis 12.3, 15.3 retention hyperkeratosis, recessive X-linked ichthyosis 121.13 RET gene mutations 159.1, 172.29 reticular dysgenesis 177.30 reticular lamina, embryonic skin 2.8 reticular network congenital melanocytic naevi 185.5–185.6, 185.6, 185.6 histopathological correlate 185.2 reticulate acropigmentation of Kitamura 117.4, 138.3, 138.11 reticulate hyperpigmentation dermatopathia pigmentosa reticularis 127.97, 138.9–138.11 differential diagnosis 104.9–104.10, 127.97 dyskeratosis congenita 136.8, 136.8, 138.9, 138.10 inherited causes 138.9–138.11 Naegeli-Franceschetti-Jadassohn syndrome 117.4, 127.97, 138.9–138.11, 138.10 in zosteriform distribution see linear and whorled naevoid hypermelanosis reticulate pigmentary disorder, X-linked see Partington syndrome reticulin antibodies, dermatitis herpetiformis 90.2–90.3 reticulohistiocytoma (RH) 103.12, 103.13 reticulohistiocytosis congenital self-healing (CSHRH) 103.2–103.3, 103.4, 103.4–103.5 multicentric (MRH) 103.12, 103.13, 103.14 retinaldehyde reductase 171.1, 171.2 retinal lesions, incontinentia pigmenti 130.5 retinal phacomas (astrocytomas), tuberous sclerosis 129.7–129.8, 129.8 retinal pigment epithelium, congenital hypertrophy (CHRPE) 137.12 retinitis pigmentosa, Refsum disease 121.48 retinoblastoma, familial 109.25 13-cis-retinoic acid see isotretinoin all-trans-retinoic acid see tretinoin retinoic acid embryopathy 121.68 retinoic acid metabolism blocking agents (RAMBAs) 121.68 retinoids 181.18 adverse effects 121.67–121.68, 181.18 Darier disease 125.4 dystrophic epidermolysis bullosa 118.20 epidermolytic ichthyosis 121.21, 121.22 erythrokeratodermia variabilis 122.8–122.9 Gorlin syndrome 132.15 harlequin ichthyosis 121.29 ichthyoses/MEDOC 121.67–121.69 monitoring and follow-up 121.68–121.69 Netherton syndrome 124.7 palmoplantar keratodermas 120.4 pityriasis rubra pilaris 83.6 porokeratosis 126.4–126.5 psoriasis 82.2, 82.4 teratogenicity 79.9, 121.68, 181.18 topical 181.13 acne 79.7–79.8 Darier disease 125.4 Gorlin syndrome 132.15 ichthyoses/MEDOC 121.66 porokeratosis 126.4 warts 47.8 see also specific agents retinol see vitamin A retinol-binding protein 4 (RBP4) deficiency 171.3, 171.4 retinol-binding protein 4 (RBP4) gene mutations 171.3 retrotransposons 115.7, 115.12

61

retroviral vectors, gene therapy 140.2–140.4, 140.3 Reye syndrome, varicella 49.12–49.13 RFX5 gene 177.31 RFXANK gene 177.31 RFXAP gene 177.31 rhabdomyomas, cardiac, tuberous sclerosis 129.8, 129.8–129.9, 129.10 rhabdomyomatous mesenchymal hamartoma (RMH) 10.11–10.12 rhabdomyosarcoma (RMS) 99.4–99.6 alveolar 99.4–99.5 botryoid 99.5, 99.5 clinical features 99.5, 99.5 congenital alveolar 99.5 embryonal 99.5 genital area 151.20 pathology 99.5, 99.5 prognosis 99.6, 99.6 rhagades, atopic dermatitis 28.3, 28.4 Rhazes 1.1 rheumatic fever 54.2 erythema marginatum 76.4–76.5 Jones’ criteria 76.5 rheumatoid arthritis abatacept 182.12 infliximab 182.5 juvenile see juvenile idiopathic arthritis rituximab 182.11 rheumatoid factor morphoea 173.7–173.8 -positive polyarthritis 175.3 rheumatoid nodule, benign see granuloma annulare (GA), subcutaneous Rhinocladiella aquaspersa 63.6 rhinoentomophtoromycosis 63.23–63.24 Rhinoestrus purpureus 69.3 rhinoplasty, open tip 187.3, 187.7 rhinosporidiosis 63.24 Rhinosporidium seeberi 63.24 Rhizopus arrhizus 63.22 Rhizopus microsporus 63.22 Rhizopus oryzae 63.22 Rhodoid naevus syndrome see capillary malformation-arteriovenous malformation rhomboid flaps 186.5, 187.21–187.23, 187.25 Rhus dermatitis 44.12, 45.5, 45.6 rib anomalies, Gorlin syndrome 132.7, 132.9, 132.9 riboflavin deficiency 65.5 ribonuclear protein (RNP) 14.3 ribozyme-mediated gene knockdown 140.13–140.15 ribozyme-mediated trans-splicing 140.15 Richner–Hanhart disease see tyrosinaemia, type II rickets 108.5 vitamin D-dependent, atrichia 148.6 vitamin D-resistant see vitamin D-resistant rickets Rickettsia 61.1, 61.2 Rickettsia africae 61.2, 61.5–61.6, 61.10 Rickettsia akari 61.4–61.5 Rickettsia australis 61.2, 61.5–61.6 Rickettsia conorii (boutonneuse fever) 61.2, 61.5, 61.5–61.6 Rickettsia felis 61.2, 61.8, 61.10 Rickettsia honei 61.2 Rickettsia japonica 61.2, 61.5–61.6 rickettsial infections 61.1–61.10, 61.2 recently described 61.10 spotted fever group 61.4–61.6 typhus group 61.6–61.10 see also Rocky Mountain spotted fever rickettsial pox 61.4–61.5 Rickettsia mongolotimonae infection 61.2, 61.5–61.6 Rickettsia parkerii infection 61.2, 61.5–61.6 Rickettsia prowazeckii 61.1, 61.2, 61.7–61.8 Rickettsia rickettsii 61.1, 61.2 Rickettsia sibirica 61.2, 61.5–61.6 Rickettsia slovaca 61.2, 61.5–61.6, 61.10

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Index

Rickettsia typhi 61.1, 61.2, 61.8 RIDDLE syndrome 177.5 Rieger syndrome 10.9 rifampicin atypical mycobacterial infections 57.7, 57.8, 57.9 bartonellosis 58.10 leprosy 70.9, 70.9 tuberculosis 57.4 right ventricular cardiomyopathy 127.99 Riley–Smith syndrome see Bannayan–Riley–Ruvalcaba syndrome ring vaccination, smallpox 51.7 ringworm see dermatophytoses Ritter disease see staphylococcal scalded skin syndrome rituximab 182.10–182.11 pemphigus foliaceous 91.6 pemphigus vulgaris 91.5 systemic lupus erythematosus 175.8 urticarial vasculitis 163.5 Wegener granulomatosis 167.6 RMRP gene mutations 177.6 RNA-based therapeutic approaches 139.2, 140.6, 140.12–140.15, 140.14 RNA/DNA oligonucleotides (RDO) 140.11–140.12 RNA interference (RNAi) 117.8, 139.2, 140.13, 140.14 RNA polymerase II 135.3–135.4 RNP (ribonuclear protein) 14.3 Ro 20-1724 phosphodiesterase inhibitor, atopic dermatitis 25.8 Roaccutane® see isotretinoin Robert syndrome 116.13, 116.13 Robinow syndrome 10.9 Robinson syndrome 127.17 Rocky Mountain spotted fever (RMSF) 61.1–61.4, 61.2 clinical features 61.1–61.3, 61.2, 61.3 diagnosis 61.3–61.4 differential diagnosis 49.3, 49.9, 61.3 pathology 61.1, 61.2 prognosis 61.3 treatment 61.4 Rogers’ syndrome 116.10 Rombo syndrome 132.13 differential diagnosis 137.1–137.2 Ro (SSA) ribonucleoprotein 14.3 see also anti-Ro/SSA antibodies rosacea steroid 38.1 vs. perioral dermatitis 38.1, 38.3 Rosai–Dorfman disease, cutaneous (CRDD) 103.12 roseola infantum 49.7–49.8 roseola vaccinatum 51.11 rosin allergy see colophony allergy Rosselli–Gulienetti syndrome 127.53, 148.4 Rothmann–Makai syndrome 77.1 Rothmund–Thomson syndrome (RTS) 136.1–136.5 associated malignancies 136.3–136.4, 137.3 clinical features 127.54, 136.2–136.4, 136.3, 136.4 differential diagnosis 133.7 dystrophic calcification 95.7 pathogenesis 115.28, 136.1–136.2 premature ageing 134.5 roxithromycin, acne 79.8–79.9 RSPO1 gene 120.8, 120.9 R-Spondins 120.8, 120.9 rubber chemicals contact allergy 44.4, 44.10 type 1 hypersensitivity 45.4 rubella 49.4–49.5 clinical features 49.4, 49.4 congenital 8.1, 8.4, 49.4, 49.5 differential diagnosis 49.4, 49.6 vaccination 49.5

rubeola see measles Rubinstein–Taybi syndrome, keloids 116.11 ruby lasers hair removal 189.3 pigmented lesions 189.4, 189.5, 189.6, 189.7 rue (Ruta spp.) 45.10, 45.10, 45.11 rule of nines, atopic dermatitis severity scoring 29.6 runt disease 178.2 Russell’s sign 65.9 Russian gadfly 69.3 Rutaceae 45.10 Ruta spp. see rue Ruvulcaba–Myhre–Smith syndrome see Bannayan–Riley–Ruvalcaba syndrome S100 proteins, atopic dermatitis 27.9 Sabina syndrome 127.55, 148.11 see also trichothiodystrophy Sabra dermatitis 45.1 sabre tibia 60.4, 60.4 SACRAL syndrome 113.13 saddle nose deformity, Wegener granulomatosis 167.3, 167.3 S-adenosyl-L-methionine (SAM), porphyria cutanea tarda 107.14 Sagartia rosea 73.9 Salamon syndrome 127.64 salbutamol, atopic dermatitis 25.10 salicylate poisoning 184.9 salicylic acid, topical 181.13 acne 79.8 ichthyoses 121.63, 121.66 molluscum contagiosum 46.5 porokeratosis 126.4 toxicity 5.7, 184.9 warts 47.8 saline flush-out technique, extravasation injuries 17.9, 17.9 saliva, atopic dermatitis and 27.14 salivary gland swellings 147.21, 147.21–147.22 tumours 147.19 salmon patch 112.15 salpingitis 153.11 gonococcal 153.10 salting of skin (Turkish remedy) 154.12 SAMD9 gene mutations 95.4 sandflies see phlebotomine sandflies sand pit vulvitis 152.2–152.3 sandwich sign, dermatophytosis 62.5 Sanfilippo syndrome (mucopolysaccharidosis III) 169.11, 169.12 San Joaquin Valley fever see coccidioidomycosis sapienic acid 79.5 sarco-endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) 125.1 sarcoidosis 158.1–158.10 angiolupoid 158.3 classic 158.1–158.6 clinical features 158.3, 158.3–158.4 Darier–Roussy 158.4 differential diagnosis 158.5 early-onset see Blau syndrome laboratory findings 158.4 metastatic calcification 95.8 pathogenesis 158.1–158.3 pathology 158.3 prognosis 158.4 salivary gland enlargement 147.22 treatment 158.5 vs. Blau syndrome 158.2 sarcomas oral facial 147.19 soft tissue 99.4–99.10 see also specific types Sarcophaga 69.4 Sarcoptes scabiei var. hominis 72.1–72.2, 72.2 see also scabies SART3 gene 126.1, 126.3 SASSAD index 29.5

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

satellite cell necrosis, graft-versus-host disease 178.3, 178.4 satellite naevi congenital melanocytic naevi 109.5–109.6, 109.6, 187.26 treatment 191.6 SBDS gene 177.11 scabies 72.1–72.9 aetiology and pathogenesis 72.1–72.2 atopic dermatitis with 30.2 clinical features 72.2–72.5, 72.3, 72.4 crusted (Norwegian) 52.4, 72.4–72.5 clinical features 72.4, 72.4–72.5, 72.5 differential diagnosis 72.5 pathogenesis 72.2 pathology 72.2 diagnosis 72.5, 72.5–72.6 differential diagnosis 72.5–72.6 atopic dermatitis 28.10 infantile acropustulosis 72.7, 72.8, 88.2 genital area 151.10, 151.10 HIV infection 52.4, 72.5 infantile acropustulosis and 88.1 napkin area 20.6–20.7 neonatal 8.5, 8.6, 9.6–9.7, 72.4 clinical features 8.7, 9.7 erythroderma 11.7 treatment 9.7 nodular 72.4, 72.4, 72.7 nursing care 192.7, 192.12 pathology 72.2, 72.2 prognosis 72.7–72.8 treatment 72.6–72.7 vesiculobullous lesions 87.8 scalds see burns/scalds scales/scaling congenital ichthyosiform erythroderma 121.26, 121.31 ichthyosis vulgaris 121.8 lamellar ichthyosis 121.25, 121.31 neonatal, MEDOC 121.5 recessive X-linked ichthyosis 121.10, 121.11 vesiculobullous disease 87.1 scalp abrasions, vacuum extraction 17.4, 17.5 AEC/Rapp–Hodgkin syndrome 127.75, 127.76, 127.76 aplasia cutis congenita 10.18–10.20, 10.19, 10.20 atopic dermatitis 28.1, 28.2 eosinophilic pustular folliculitis 36.4, 36.4 infantile seborrhoeic dermatitis 35.3, 35.3–35.4, 35.4 lichen planopilaris 85.5–85.6 neonatal iatrogenic injuries 17.3, 17.3, 17.4 psoriasis 80.1, 80.2 nursing care 192.4, 192.9 ringworm see tinea capitis seborrhoeic dermatitis see dandruff surgical scar placement 187.3 tissue expansion 187.26, 187.27, 191.3, 191.4 washing, neonates 5.2 scalp–ear–nipple syndrome 127.55 SCALP syndrome 10.19, 110.5 scarlet fever 54.10–54.11 pathogenesis 54.1–54.2 raspberry tongue 147.24 vs. erythema infectiosum 49.6 scars/scarring 187.3–187.9 acne see acne, scarring after laser treatment 188.6 alopecia see alopecia, scarring congenital erosive and vesicular dermatosis 16.1–16.4, 16.5 congenital erythropoietic porphyria 107.11, 107.11 congenital lumbosacral 10.17 development 17.1–17.2, 186.3 dystrophic epidermolysis bullosa 118.11, 118.11, 118.12 Ehlers–Danlos syndrome 142.3, 142.5

Index epidermolysis bullosa acquisita 91.23, 91.23 erythropoietic protoporphyria 107.10, 107.10 extravasation injuries 17.8, 17.9 hypertrophic see hypertrophic scars infantile haemangiomas 113.6 keloidal see keloids laser treatment 188.10, 189.8–189.9 leishmaniasis 67.7, 67.7 lichen sclerosus 152.6 Marfan syndrome 145.6 neonates differential diagnosis 16.6 iatrogenic 17.6, 17.9–17.11, 17.10, 17.11 problematic 187.3–187.9 purpura fulminans 162.8, 162.11 smallpox 51.4 surgical neonates 17.11, 17.11 placement 186.2, 186.2, 186.3, 187.2–187.3, 187.3, 187.4 surgical revision 187.7–187.9, 187.9 vaccination site 17.11, 51.9, 51.10 vesiculobullous disease 87.1 SCC see squamous cell carcinoma Scedosporium prolificans 63.8 Schamberg disease 165.1–165.3 clinical features 165.2, 165.2–165.3, 165.3 segmental 165.2, 165.3 Schefflera actinophylla 45.2 Schimmelpenning–Feuerstein–Mims syndrome 110.5 Schindler disease 169.10 Schinzel–Giedion midface retraction syndrome 127.55–127.56 Schinzel syndrome 127.62 Schönlein–Henoch purpura see Henoch– Schönlein purpura school-aged children, atopic dermatitis 34.2, 34.6 schools, head lice programs 72.13–72.14 Schöpf–Schulz–Passarge syndrome 127.85–127.86 clinical features 127.56, 127.86, 148.9 odonto-onycho-dermal dysplasia and 120.10, 127.83, 127.86 schwannomas genital 151.20–151.21 pathology 128.13 peripheral nerve 128.12–128.13 vestibular 128.12, 128.13 schwannomatosis 128.2, 128.14 schwannomin 128.13–128.14 SCID see severe combined immunodeficiency sclerema neonatorum (SN) 7.4, 77.9 treatment 7.3, 77.9 vs. subcutaneous fat necrosis 7.1, 7.3, 7.4 sclerodactyly congenital erythropoietic porphyria 107.11, 107.12 palmoplantar keratoderma with scleroatrophy 120.8–120.9 scleroderma 174.1 differential diagnosis 174.2 graft-versus-host disease 178.7, 178.7–178.8 localized see morphoea systemic see systemic sclerosis scleromalacia perforans 107.12 scleromyositis 174.7 see also systemic sclerosis (SSc), limited Scleroplus 1d laser 188.3 sclerotherapy, percutaneous cystic hygroma 114.16 venous malformations 112.10 SCN9A gene mutations 6.2, 166.1–166.2 scoliosis, neurofibromatosis 1 128.5 SCORAD index 29.2, 29.3, 29.4 modified (SCORAD-D) 29.13–29.14 Patient-Oriented (PO-SCORAD) 29.2, 29.5 SCORMA index 75.10 scorpion stings 73.6 SCORTEN score 78.5–78.6, 78.6, 183.10

scratching atopic dermatitis 30.5 pathogenic role 24.5, 24.6 psychological aspects 34.1–34.2 lichen simplex chronicus 42.1 prurigo nodularis 42.3–42.4 see also itch–scratch cycle scratch testing, plant/plant products 45.4 screw worms 69.3 scrofuloderma 57.3 vs. leishmaniasis 67.12 scrotum acute oedema 151.22, 151.22 disorders 151.22 fixed drug eruptions 151.14 hair growth in infants 148.32 idiopathic calcinosis 95.3, 151.22 lymphangioma 151.6 median raphe cysts 151.18 neoplasia 151.20–151.21 scrub typhus 61.2, 61.9, 61.9–61.10 scrum pox 48.5 scutula 62.6 SCYL1BP1 gene 134.15 Scytalidium dimidiatum 62.33–62.34 Scytalidium hyalinum 62.33, 62.34 Scytalidium infections 62.33, 62.33–62.34, 62.34 sea anemones 73.7–73.8, 73.8 sea bather’s eruption 73.8 sealpox 51.2, 51.24 sea-urchins 73.8, 73.9 sebaceous glands activity in neonates 3.6 development 2.36, 2.37 regulation of lipogenesis, in acne 79.2–79.3 sebaceous hyperplasia 94.12–94.13 premature (PSH) 94.13 sebaceous naevus see naevus sebaceous sebaceous naevus syndrome 110.5, 111.8 sebopsoriasis 35.1, 41.4 seborrhiasis 41.4 seborrhoea 35.1 seborrhoeic blepharitis 41.3, 41.4 seborrhoeic dermatitis of adolescence 41.1–41.5 clinical features 41.2, 41.2–41.4, 41.3 differential diagnosis 41.4 pathogenesis 41.1–41.2 pathology 41.2 prognosis 41.4 treatment 41.4–41.5 adult-type 28.10, 35.1 AIDS-related 41.1, 41.3, 41.4–41.5, 52.4 congenital 35.3 infantile (ISD) 35.1–35.7 bipolar 35.4, 35.4, 35.7 clinical features 35.3, 35.3–35.5, 35.4, 35.5 concepts of 35.1–35.2, 35.2 differential diagnosis 35.5–35.6 erythroderma 11.2, 11.2, 35.4, 35.5 histopathology 35.3 Malassezia (Pityrosporum) yeasts 35.2–35.3, 62.29 napkin area 20.2, 20.7–20.8, 20.8, 35.4, 35.4 pathogenesis 35.2–35.3 prevalence 35.1 prognosis 35.5 treatment 5.2, 35.6–35.7 vs. atopic dermatitis 28.10, 35.5 Malassezia (Pityrosporum) yeasts 41.1–41.2, 62.29 seborrhoeic pattern of infantile eczema 35.1 sebum, hormonal regulation of secretion 79.2–79.3 secondary disease 178.2 second trimester 2.2, 2.3 skin development 2.19–2.21 sedation 190.6–190.7 deep 190.6, 190.7 minimal 190.6, 190.6

63

moderate (conscious) 190.6, 190.7 pharmacological agents 190.7–190.9 segmental involvement autosomal dominant skin disorders 115.15, 115.15, 115.16 polygenic skin disorders 115.15, 115.16 seipin gene mutations 141.18 seizures incontinentia pigmenti 130.5 tuberous sclerosis 129.4, 129.10–129.11 selenium 65.8 deficiency 65.8, 104.1 selenium sulphide shampoo excessive absorption 65.8 seborrhoeic dermatitis 41.4 tinea capitis 62.15, 62.16 self-esteem 179.2 atopic dermatitis 34.2 self-inactivating (SIN) vectors 140.3–140.4 self-injurious behaviour (SIB) 180.6 self-mutilation 180.1, 180.6–180.12 classification 180.6–180.7 clinical features 180.8–180.10, 180.9 compulsive 180.8 differential diagnosis 180.8, 180.11 factitious disorder 180.13 history 180.2 impulsive 180.8 major 180.10 pathology 180.10 prognosis 180.10–180.11 stereotypic 180.10 superficial 180.7–180.10 treatment 180.11 sella turcica bridging, Gorlin syndrome 132.10, 132.11 semi-dominant inheritance 115.5 Sener syndrome 127.56 senescence, DNA repair capacity and 135.23 Sensenbrenner syndrome 127.16 sensorineural hearing loss, enamel hypoplasia and nail defects 127.57 sensory loss, leprosy 70.4–70.5, 70.6 sentinel node biopsy, melanoma 109.27 sepsis collodion baby 12.3 purpura fulminans 162.2–162.5 see also bacterial infections; infections septicaemia Gram-negative, neonatal 8.6 premature infant 5.3 see also meningococcal septicaemia, acute serine leucoprotease inhibitor (SLPI) 27.4 serine protease inhibitors of Kazal type (SPINK) 27.4 see also LEKT1; SPINK5 gene serine protease-PAR2 pathway atopic dermatitis 27.11 skin barrier homeostasis 27.6, 27.6 serine proteases atopic dermatitis 27.11 desquamation 27.3–27.4, 27.5 skin barrier homeostasis 27.6 serine-threonine kinase 11 (STK11) 137.8, 137.16 SERPING1 gene mutations 177.17 serum amyloid A (SAA) protein 159.1 serum sickness 74.5, 163.5 serum sickness-like reactions (SSLRs) 74.1, 74.10 differential diagnosis 163.5 drug-induced 183.3 Servelle–Martorell syndrome 112.17 sesame allergy 31.6, 31.16 sesquiterpene lactones, allergy 44.11, 45.5–45.6 Setleis syndrome 127.28, 145.19 seventh nerve palsy see facial nerve palsy severe combined immunodeficiency (SCID) 177.29–177.32 achondroplasia with 127.3 clinical features 177.30–177.32 differential diagnosis 177.32 mucocutaneous findings 177.2

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Index

severe combined immunodeficiency (SCID) (cont.) neonatal graft-versus-host disease 11.9–11.10 pathogenesis 177.30–177.31 prognosis 177.32 skin infections 64.2, 64.2–64.3 treatment 177.32 X-linked 177.30, 177.30 sevoflurane 190.9 sex hormones, disorders 172.10–172.17 sex linked traits 115.3 sex reversal, palmoplantar keratoderma with squamous cell carcinoma of skin and 120.9–120.10 sexual abuse 155.1–155.7 anogenital warts 153.17, 155.3 attributing vulval conditions to 151.24–151.25 bacterial vaginitis 153.22 chancroid 155.4 chlamydial infections 153.14–153.15, 155.4 definition 155.2 differential diagnosis 155.4, 155.5, 155.6 epidemiology 154.1, 155.1 general clinical indicators 155.2 genital herpes 48.4, 153.19–153.20, 155.3 genital injuries 155.2, 155.2–155.3 genital warts 47.7, 47.11 gonorrhoea 153.9, 153.11 hepatitis B 153.19 HIV infection 153.20–153.21 management 155.4–155.7 risk factors 155.1 self-mutilation and 180.7 sexually transmitted diseases 153.1, 153.2, 153.22, 155.3–155.4 skin manifestations 155.2–155.4 syphilis 153.3, 155.3 Trichomonas vaginalis infection 153.21 vulvovaginitis 152.3 sexually transmitted diseases (STDs) 153.1–153.23 diagnosis and treatment 153.22 modes of transmission 153.1 policy on childhood 153.1–153.2, 153.2 sexual abuse implications 153.1, 153.2, 153.22, 155.3–155.4 vulvovaginitis 152.2 sexual transmission HPV infections 47.3 molluscum contagiosum 46.1 Sézary syndrome (SS) 99.20, 99.21–99.22, 102.6 SH2D1A gene mutations 177.8 Shabbir syndrome 118.30, 118.32 shagreen patches, tuberous sclerosis 129.5, 129.5–129.6 Shah–Waardenburg syndrome 138.2, 138.6 shampoo ketoconazole 41.4, 62.15 newborn infants 5.2, 5.6–5.7 selenium sulphide see selenium sulphide shampoo sheep maggot 69.3 shellfish allergy 31.6 shelterin complex gene mutations 136.8 shingles see herpes zoster shock acute infectious purpura fulminans 162.2 meningococcal 55.7, 55.9 shoes see footwear short anagen syndrome 148.20 short-interfering RNAs (siRNA) 140.13, 140.14 see also RNA interference short-limb skeletal dysplasia with severe combined immunodeficiency (SCID) 127.3 short stature atopic dermatitis 30.2 recessive X-linked ichthyosis with 121.11, 121.12 Werner syndrome 134.4 see also growth failure

SHOX gene defects, recessive X-linked ichthyosis with 121.11, 121.12 Shprintzen–Goldberg syndrome (marfanoidcraniosynostosis syndrome) 145.4, 145.5, 145.7 Shulman syndrome 36.11–36.12 Shwachman–Bodian–Diamond syndrome (SBDS) 177.11 sialadenitis, chronic recurrent 147.21 sialidosis, prenatal diagnosis 139.3 sickle cell anaemia, leg ulcers 66.4 sideroblastic anaemia 107.2 Siemerling–Creutzfeldt disease 104.8 silencing RNAs see short-interfering RNAs silicone gel, hypertrophic scars 187.5, 187.8 silicone medical adhesive removers (SMAR) 118.18 silky down 10.17 silver-impregnated dressings, dystrophic epidermolysis bullosa 118.20 silver nitrate 181.8 toxicity 184.9 Silver–Russell syndrome, café-au-lait spots 116.12 silver sulphadiazine burn wounds 187.18 dystrophic epidermolysis bullosa 118.20 Simulium black flies 71.2 bite reactions 71.5 biting behaviour 71.7 sinecatechins, polyphenol 47.9, 181.12 single gene skin disorders see Mendelian skin disorders single nucleotide polymorphisms (SNPs) 23.3 atopic dermatitis 23.6 single photon emission computed tomography (SPECT) Sturge–Weber syndrome 112.16 systemic lupus erythematosus 175.7 sinus histiocytosis with massive lymphadenopathy (SHML) 103.12, 103.13, 103.14 sinus tracts, acne 79.6 Sipple syndrome see multiple endocrine neoplasia (MEN), type 2A sirolimus, tuberous sclerosis 129.12 sister chromatid exchange (SCE), Bloom syndrome 136.5, 136.6 Sistrunk’s operation 10.5 Six Area, Six Sign Atopic Dermatitis (SASSAD) index 29.5 sixth disease 49.7–49.8 Sjögren–Larsson syndrome (SLS) 121.42–121.48 clinical features 121.42–121.47, 121.43, 121.46 diagnosis 121.47 differential diagnosis 121.37–121.38 genetics and pathogenesis 115.21, 121.47 histology 121.47 neonatal erythroderma 11.10 prenatal diagnosis 121.47, 139.3 treatment 121.47–121.48 Sjögren syndrome, graft-versus-host disease 178.8 Sjögren syndrome antigen A (Ro) 14.3 see also anti-Ro/SSA antibodies Sjögren syndrome antigen B (La) 14.3 see also anti-La/SSB antibodies skeletal anomalies–ectodermal dysplasia–growth and mental retardation 127.57 skeletal manifestations CHILD syndrome 121.55 congenital erythropoietic porphyria 107.12 congenital syphilis 153.4–153.5, 153.5 Conradi-Hünermann-Happle syndrome 121.53–121–54 eosinophilic granuloma 103.3–103.4 Fanconi anaemia 136.11 focal dermal hypoplasia 133.2, 133.2–133.3 Gorlin syndrome 132.9, 132.9 hyper-IgE syndromes 177.23 Langerhans cell histiocytosis 103.3–103.4

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

mastocytosis 75.10 naevus sebaceous 110.5 neurofibromatosis 1 128.4–128.5 osteogenesis imperfecta 145.9, 145.10 Refsum disease 121.48 restrictive dermopathy 15.2, 15.3 Rothmund–Thomson syndrome 136.3, 136.3 tuberous sclerosis 129.9 skin absorption via see absorption, percutaneous breakdown, preterm infants 5.4 drug metabolism 181.6 embryogenesis 2.1–2.41 fetal see fetal skin roughness, neonates 3.4, 3.5 tension lines 187.1, 187.2 thickening, UV-induced 108.7–108.8 skin appendages development 2.14, 2.22, 2.28, 2.28–2.39 topical drug penetration 181.3 see also adnexal disorders; hair follicle(s); nail(s); sebaceous glands; sweat glands skin application food test (SAFT) 45.4 skin atrophy dystrophic epidermolysis bullosa 118.11, 118.12–118.13 junctional epidermolysis bullosa 118.31 Kindler syndrome 119.2 premature ageing syndromes with 134.5–134.12 see also atrophic lesions; atrophoderma(s); lipoatrophy skin barrier 27.1–27.9 brick wall analogy 27.3, 27.3 development from birth atopic dermatitis 27.14, 27.15 normal 27.12–27.14 filaggrin functions 23.7–23.8, 23.8 homeostasis 27.5–27.9 inherited disorders affecting 121.3–121.4 neonates 3.2–3.4, 3.3, 27.12–27.13 penetration by drugs 181.1–181.2 premature infants 2.23, 3.1 regulation of structure and function 27.5–27.7, 27.6 reserve hypothesis 27.7, 27.7–27.8 stratum corneum pH and 27.5 structure 27.1–27.3, 27.2, 27.10 variations in structure and function 27.7–27.8 skin barrier dysfunction allergic contact dermatitis 44.1 atopic dermatitis 24.5, 27.1, 27.9–27.18, 27.10 aeroallergen sensitization 32.4–32.5 altered lipid metabolism 27.10–27.11 barrier development and 27.14, 27.15 candidate gene studies 23.7–23.11 clinical implications 27.14–27.16, 27.15 disturbed skin differentiation 27.9–27.10, 27.10 drugs acting on 25.10 elevated stratum corneum pH 27.11 stratum corneum protease activity 27.11 atopic march 27.12, 27.18 food allergies 27.14–27.15, 31.2–31.3 ichthyoses 121.4 infantile seborrhoeic dermatitis 35.2 MEDOC 121.63 Netherton syndrome 27.11, 121.63, 124.2, 124.3 skin barrier products napkin area care 21.4 neonatal units 5.4, 17.10 see also protectants, skin skin barrier-repair medications atopic dermatitis 25.10 ichthyoses/MEDOC 121.65–121.66 skin bio-equivalents, artificial see human skin substitutes skin biopsy cutaneous lymphoma 102.17 epidermolysis bullosa 118.1–118.2 fetal see fetal skin biopsy

Index histopathological examination 4.1–4.8 normal looking 4.7–4.8 reasons for 4.1 skin cancer see malignant skin tumours skin care dystrophic epidermolysis bullosa 118.17–118.19 infants 5.5–5.8 lymphoedema 114.12 newborn baby 5.1–5.8 post-laser treatment 188.6, 192.7, 192.13 premature infant 5.3–5.5 see also nursing care skin cleansing agents newborn infants 5.2, 5.6, 5.6 see also detergents; soaps skin colour congenital hypothyroidism 172.2 reaction to sun exposure and 108.12, 108.12 see also dark-skin types; pigmentation; skin phototypes skin-derived antileucoprotease (SKALP) 27.4 skin dimples see dimples skin-equivalent grafting 140.16 skin flaps 186.5, 187.21–187.23 axial pattern 186.5, 187.21 cleft lip repair 187.23, 187.25 fasciocutaneous 186.5 free 186.5, 187.21 local 187.21–187.23 musculocutaneous 186.5 random pattern 186.5, 186.5, 187.21 rectangular advancement 187.21, 187.22 rhomboid 186.5, 187.21–187.23, 187.25 rotation 187.21, 187.24 transposition 186.5, 186.5, 187.21, 187.24 V-Y advancement 187.21, 187.22, 187.23 skin fragility dystrophic epidermolysis bullosa 118.12– 118.13, 118.19 Ehlers–Danlos syndrome 142.3, 142.5 Kindler syndrome 119.1–119.2, 119.2 skin fragility–ectodermal dysplasia syndrome see ectodermal dysplasia–skin fragility syndrome skin fragility–woolly hair syndrome 127.57, 127.99 skin grafts 186.3–186.5, 187.10–187.19 artificial skin substitutes 118.21, 140.16, 181.12 biology 187.11–187.12, 187.12 burn wounds 187.16–187.18 clinical applications 187.16–187.19 contracture 187.12 cultured keratinocytes 140.16, 187.14–187.15, 187.15 donor sites 187.13, 187.14 epidermolysis bullosa 118.21–118.22, 118.22, 118.33, 187.18–187.19, 187.20 full-thickness (FTG) 186.3–186.5, 186.4, 187.10, 187.11 harvesting 187.13 vs. split-thickness 186.5, 187.11 history 187.10–187.11 naevus depigmentosus 104.3, 131.5 purpura fulminans 162.13 split-thickness (SSG) 186.3–186.5, 186.4, 187.10, 187.11 Chinese method of expansion 187.14 harvesting 187.13, 187.13 mesh expansion 187.13–187.14, 187.14 storage 187.11 vs. full-thickness 186.5, 187.11 surgical technique 187.12–187.13, 187.13 vacuum-assisted closure therapy 187.13 skin hyperextensibility see hyperextensible skin skin infections atopic dermatitis 28.8, 28.8–28.9 diagnosis 30.2 management 30.5–30.6, 30.10 pathogenesis 22.10, 24.6–24.7 Chédiak–Higashi syndrome 177.6

chronic granulomatous disease 64.2, 64.5–64.6, 177.9 collodion baby 12.3, 121.31 common variable immunodeficiency 64.2, 64.4–64.5, 177.27, 177.27 cutaneous larva migrans 68.3, 68.3, 68.4 Darier disease 125.3 diabetes mellitus 172.20–172.21 epidermolytic ichthyosis 121.21, 121.64 hyper-IgE syndromes 64.2, 64.3, 177.22, 177.22 ichthyoses/MEDOC 121.64 immunocompromised children 64.1–64.10 infantile haemangiomas 113.7, 113.8 leucocyte adhesion deficiency 177.29 lymphoedematous areas 114.11, 114.12–114.13 napkin dermatitis 20.5–20.7, 20.8–20.9 neonatal see neonates, infections Netherton syndrome 124.5–124.6 nursing care 192.4–192.7 pigmentation changes after 104.1, 104.4 scabies 72.3–72.4 smallpox vaccination site 51.10, 51.11, 51.11–51.12 vesiculobullous lesions 87.4, 87.4–87.5, 87.8–87.9 see also bacterial infections; fungal infections; parasitic infestations; viral infections; specific infections skin laxity differential diagnosis 143.4 premature ageing syndromes with 134.12–134.18 pseudo-xanthoma elasticum 144.4, 144.4 see also cutis laxa skin pathergy test, Behçet disease 167.16 skin phototypes 108.12, 108.12 sunscreen recommendations 108.15 see also dark-skin types skin prick tests (SPT) aeroallergens 32.7–32.8 drug hypersensitivity 183.13 food allergens 31.8, 31.9, 31.9 plant allergens 45.4, 45.4 skin scrapings, dermatophytoses 62.11 skin substitutes, human see human skin substitutes skin surface pH see pH, skin surface probes, neonatal intensive care 17.9 skin tags chromosome disorders 116.13, 116.13 Gorlin syndrome 132.7 tuberous sclerosis 129.7 skin test antigens, therapeutic use 181.9 skin tests drug hypersensitivity 183.13–183.14 see also intradermal testing; patch testing; skin prick tests skin tumours adnexal 94.4–94.13 associated amyloidosis 159.4 calcification and ossification 95.7 chromosome disorders 116.13–116.14 differential diagnosis 92.1–92.9 hereditary skin disorders with benign 115.27 malignant see malignant skin tumours Schöpf–Schulz–Passarge syndrome 127.86 surgery 186.2 skin wrinkling see wrinkling, skin slapping injuries, abusive 154.3, 154.4 SLC29A3 gene mutations 148.29 SLC35C1 (FUCT1) gene 177.11, 177.28 SLC39A13 gene mutations 142.2 SLC45A2 gene mutations 138.8 SLE see systemic lupus erythematosus sleep disturbance, atopic dermatitis 29.6, 179.2 SLUG gene mutations 138.6 SLURP-1 protein 120.4–120.5 SMAD4 gene 112.5 small hairpin RNA (shRNA) 140.14

65

smallpox (variola) 51.1, 51.3–51.8 aetiology 51.3 as bioterrorist weapon 51.14–51.15 classification of clinical types 51.4, 51.4 clinical features 51.3–51.5, 51.6 confluent subtype 51.4, 51.6 differential diagnosis 51.5–51.7 discrete form 51.4, 51.5 eradication 51.3 flat type 51.4, 51.4 haemorrhagic type 51.4, 51.4 historical aspects 51.3 immune response 51.10 investigations 51.7 modified type 51.4, 51.4, 51.5 ordinary 51.4, 51.4, 51.5, 51.6 pathology 51.7 semi-confluent subtype 51.4 treatment 51.7–51.8 vesiculobullous lesions 87.5, 87.5 virus 51.3, 51.7 smallpox vaccination 51.8–51.15 atopic dermatitis 24.7, 28.8, 30.2, 51.12–51.13 bioterrorism incidents 51.14–51.15 complications 51.10–51.14, 51.11 treatment 51.14 vaccinia immune globulin therapy 51.14 contraindications 51.14 history 51.8 immune response 51.10 postexposure 51.7 procedures 51.8–51.10, 51.9 site reactions 51.9, 51.10 smallpox after 51.5 SMARCB1/INI1 gene 128.14 Smith–Lemli–Opitz syndrome (SLOS) 121.54 prenatal diagnosis 139.3 smoking acne and 79.10 acne inversa and 79.20, 79.20 passive, atopic dermatitis and 22.11–22.12, 30.9 xeroderma pigmentosum 135.9 Smoothened gene 99.1 smooth muscle hamartoma acquired 10.11 congenital (CSMH) 10.11, 148.31, 148.31 smooth muscle tumours, HIV-related 52.5 SMO (smoothened) protein 132.2, 132.3 snake bites 73.10 purpura fulminans 162.4, 162.7 SNAP29 120.15, 121.51 Sneddon syndrome 112.20 soaps atopic dermatitis and 24.5, 27.15–27.16 effect on barrier function 27.6, 27.7 newborn infants 5.2, 5.6, 5.6 Society for Pediatric Dermatology (SPD) 1.3 socks, epidermolysis bullosa 118.8, 118.19 sodium lauryl sulphate (SLS), atopic dermatitis and 27.16 sodium–proton exchanger-1 (NHE1) 27.4, 27.13 sodium pyrrolidone carboxylic acid (NaPCA) 27.2 sodium stibogluconate, leishmaniasis 67.12–67.13 soft skin, fragile X syndrome 116.8 soft-tissue sarcomas 99.4–99.10 SOLAMEN syndrome 137.6, 141.7 see also PTEN hamartoma tumour syndrome solar lentigines 108.7, 108.7 solar radiation properties 108.1–108.2, 108.2 UV light 108.3–108.4 see also sun exposure; ultraviolet (UV) radiation solar urticaria (SU) 74.6 clinical features 106.6–106.7, 106.7 differential diagnosis 106.3, 106.7 idiopathic 106.6–106.7 phototesting 106.7, 106.7

66

Index

Solenopsis invicta 73.2 Solenopsis richteri 73.2 soles of feet congenital syphilis 153.4, 153.4 cystic warts 47.5 erythema, Kawasaki disease 168.2, 168.3 juvenile plantar dermatosis 43.1, 43.2 pompholyx see pompholyx solitary fibrous tumour (SFT) 99.8–99.9, 99.9 Soliva pterosperma 45.2 Sonic Hedgehog (SHH) 132.2, 132.3 sorivudine, HSV infections 48.7 SOS1 gene 114.8 South American blastomycosis see paracoccidioidomycosis Southern tick-associated rash illness (STARI) 59.11 SOX2 gene 116.10 SOX10 gene mutations 138.6 SOX18 114.2 soya allergy 31.6 soya formula 31.16 sparfloxacin, leprosy 70.9 spasticity, Sjögren–Larsson syndrome 121.42 specific granule deficiency 177.11 speckled lentiginous naevi see naevus spilus spectinomycin, gonorrhoea 153.12 spectral karyotyping (SKY) 116.2 sphenoid wing dysplasia, neurofibromatosis 1 128.4, 128.5 spheroids, Ehlers–Danlos syndrome 142.3 spichthyin (Spict) 121.34 spider bites 73.5–73.6 purpura fulminans 162.4, 162.7 spider naevus laser treatment 188.9 see also telangiectasia spinal dysraphism occult cutaneous signs 10.16–10.18, 10.17 lumbosacral haemangiomas 10.17, 113.13 lumbosacral hair growth 10.17, 148.31– 148.32, 148.32 lumbosacral lipomas 10.16–10.17, 141.2–141.3 midline capillary malformations 112.18 open 10.16 spindle cell lesions, benign 97.1–97.21 SPINK5 gene 27.4, 124.1 atopic dermatitis 23.10, 23.11, 27.11, 27.18, 124.2 gene therapy 124.7 Netherton syndrome 11.5, 121.58, 124.1–124.2, 148.13 SPINK9 gene 27.4 spinosad 72.13 spinous cells, fetal skin 2.20, 2.21 spiradenocarcinoma 137.10 spiroadenomas 137.9, 137.10 spirochaetes, tropical ulcer 66.2 spironolactone, hyperandrogenism 148.22 Spitzenpigment 104.9 Spitz naevus 109.14–109.17 atypical dermoscopic patterns 185.17–185.18, 185.19, 185.20 vs. melanoma 109.17, 109.26, 185.18–185.20 clinical features 109.15, 109.16 dermoscopy see under dermoscopy histopathology 4.2, 109.15, 109.15 malignant or metastasizing 109.16 management 109.17 prognosis 109.15–109.17 Splendore–Hoeppli phenomenon, hypereosinophilic syndrome 36.7 splenitis, bacillary 58.3 spliceosome-mediated RNA trans-splicing (SMaRT) 140.15 splinter haemorrhages, nail psoriasis 150.5 splints, dystrophic epidermolysis bullosa 118.21

split hand-foot malformation (SHFM), non-syndromic 127.57, 127.79 sponge diver’s sickness 73.9 sponges, stinging 73.8–73.9 Sporothrix schenckii 63.17 sporotrichosis 63.17–63.19 disseminated 63.18 fixed cutaneous 63.18, 63.18 HIV-related 52.2 lymphocutaneous 63.18, 63.18 multifocal (disseminated) cutaneous 63.18 vs. leishmaniasis 67.12, 67.12 spotty skin pigmentation, Carney complex 109.1–109.2, 109.12 SPRED1 gene mutations 128.8 Sprengel deformity, Gorlin syndrome 132.6, 132.7 spring eruption, juvenile (JSE) 106.9, 106.9–106.10 SPTL 1b laser 188.3 Squalus acanthias 73.9 squamous cell carcinoma (SCC) 99.3 chronic tropical ulcers 66.4, 66.5 Clouston syndrome 127.91 dystrophic epidermolysis bullosa 118.13, 118.16, 118.19 epidermodysplasia verruciformis 137.10, 137.11 hereditary skin disorders with proneness to 137.2, 137.3 KID syndrome 127.92 lichen sclerosus 152.6 Netherton syndrome 124.4 palmoplantar keratoderma and sex reversal with 120.9–120.10 palmoplantar keratoderma with scleroatrophy 120.9 xeroderma pigmentosum 135.8, 135.8 squamous cell papillomas intraoral 147.18–147.19 see also warts squamous epitheliomas, multiple self-healing 137.2 squaric acid dibutyl ester (SADBE) 181.13 alopecia areata 149.5–149.6 warts 47.9, 150.3 SRY gene 115.4 SSH1 gene 126.1, 126.3 ST14 gene mutations 121.56 stable flies (Stomoxys) 71.7 staphylococcal α-toxin, atopic dermatitis pathogenesis 24.6 staphylococcal cassette chromosome mec (SCCmec) 54.2 staphylococcal enterotoxin B (SEB), atopic dermatitis pathogenesis 24.6, 26.2 staphylococcal ETs see exfoliative toxins (ETs), staphylococcal staphylococcal infections chronic granulomatous disease 177.9 complicating napkin dermatitis 20.9 epidemiology 54.3 genital area 151.9, 151.9–151.10 HIV infection 52.2 HTLV-1-related 53.1 hyper-IgE syndromes 177.22, 177.22 immunodeficiency syndromes 177.2–177.3 localized cutaneous 54.3–54.7 napkin area 20.6, 20.6 neonatal 9.1–9.3 pathophysiology 54.2–54.3 primary immunodeficiencies 64.2–64.3, 64.4 toxin-mediated disease 54.8–54.11 see also Staphylococcus aureus staphylococcal protein A, atopic dermatitis pathogenesis 24.6, 26.2, 26.3 staphylococcal scalded skin syndrome (SSSS) 54.2, 54.8–54.9 genital area 151.10 localized (bullous impetigo) 54.4, 54.8

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

neonatal 8.5, 9.2–9.3, 11.6–11.7, 11.7 nursing care 192.4, 192.11 staphylococcal toxic shock syndrome (TSS) 54.2, 54.9 staphylococci 54.2–54.3 Staphylococcus aureus acute infectious purpura fulminans 162.2, 162.3 atopic dermatitis 24.6–24.7, 26.1–26.5, 27.14 clinical infection 28.8 mechanisms of adherence 26.1–26.2 skin colonization 22.10, 26.1 skin defence and 26.3 therapeutic strategies 26.3, 26.3–26.4, 30.5 virulence factors 24.6, 26.2–26.3 blastomycosis-like pyoderma 54.6 blistering distal dactylitis 54.7 botryomycosis 54.6 cellulitis 54.5–54.6 congenital infections 8.5, 8.6 epidemiology of infections 54.3 folliculitis 54.4–54.5 furunculosis 54.5 genital area infections 151.2, 151.3 HIV infection 52.2 impetigo 20.6, 54.4 methicillin-resistant see methicillin-resistant Staphylococcus aureus neonatal impetigo 9.2–9.3 neonatal infections 9.1–9.3 neonatal pustular eruptions 9.1 neonatal skin 5.1–5.2 paronychia 150.3 pathogenesis of disease 54.2–54.3 primary immunodeficiencies 64.2–64.3, 64.4 recurrent toxin-mediated perineal erythema 54.11 toxic shock syndrome 54.9 see also staphylococcal infections Staphylococcus epidermidis (coagulase-negative staphylococci) neonatal skin 5.1 premature infants 5.3, 5.5 residence in follicles 79.5 staphylogenic Lyell syndrome see staphylococcal scalded skin syndrome STAT1 gene mutations 177.11 STAT3 gene mutations 177.22 statins 169.15 STAT proteins 177.22 steatocystoma multiplex 115.27, 127.96 stem cell factor (SCF; kit ligand) 75.3–75.4, 75.4 mastocytosis pathogenesis 75.4, 75.5 stem cells epidermal 140.1–140.2 follicular 2.36–2.38 stem cell transplantation, haematopoietic see haematopoietic stem cell transplantation Stemmer’s sign 114.11 stereotypic self-mutilation 180.10 sternocleidomastoid tumour see fibromatosis colli steroid rosacea 38.1 steroids see corticosteroids steroid sulphatase (STS) 121.13 deficiency see recessive X-linked ichthyosis sterol response element-binding protein-1 (SREBP-1) 79.2–79.3 Ster-Zac powder 17.7–17.8 Stevens–Johnson syndrome (SJS) 78.1–78.8, 183.9–183.11 classification 78.1, 78.2 clinical features 78.4, 78.4–78.5, 183.9, 183.9–183.10 drugs associated with 78.2, 78.2, 183.9 epidemiology 78.1–78.2 HIV-related 52.4 management 78.6–78.8, 183.10 neonatal/early infantile 11.8 orf 51.21–51.22 pathogenesis 78.2–78.3

Index terminology 78.1 vaccinia vaccination 51.11, 51.13 vesiculobullous lesions 87.5 Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap 78.5–78.6, 183.9 classification 78.1, 78.2 drugs associated with 78.2, 78.2 management 78.6–78.8 STI571 see imatinib mesylate stiff baby syndrome see restrictive dermopathy stiff man syndrome 97.21 stiff skin syndrome 97.1, 97.20–97.21 stillbirths, congenital syphilis 153.4 Still disease see juvenile idiopathic arthritis STIM1 gene 177.31 stingrays 73.7, 73.9 STK11 gene mutations 109.12, 137.16 stomatitis 147.1–147.10 angular 147.12–147.13, 147.13 aphthous see recurrent aphthous stomatitis chronic denture 147.12 infectious causes 147.4–147.7 pemphigus vulgaris 91.3, 91.3 see also oral ulceration Stomoxys (stable flies) 71.7 stork bite 112.15 straight hair naevus 148.17 stratum basale see basal layer stratum corneum (SC) barrier function 27.3, 27.3 damage, drug penetration and 181.3 fetal skin 2.20 filaggrin function 23.7, 23.8 hydration drug penetration effects 181.3 excessive, napkin area 19.2 neonates 3.4, 3.5, 27.13 postnatal changes 27.13 inherited disorders affecting 121.3–121.4 lipids see under lipids penetration by drugs/chemicals 181.1–181.2, 184.2 see also absorption, percutaneous pH gradient 27.2, 27.4, 27.4–27.5 atopic dermatitis 27.11 premature infants 2.23 proteases see under proteases structure 27.1–27.3, 27.2 thickness neonates 3.1, 3.4 site-specific variations 27.7–27.8 UV-induced increase 108.7–108.8 stratum corneum L-like enzyme 27.4 stratum granulosum (granular cell layer) 27.1, 27.2 fetal 2.20, 2.21 filaggrin function 23.7, 23.8 stratum spinosum 27.1, 27.2 keratins 117.2, 117.2 streptococcal infections acute infectious purpura fulminans 162.2, 162.3 atopic dermatitis 28.8 cutaneous polyarteritis nodosa 77.5–77.6 epidemiology 54.3 erythema nodosum 77.2 genital area 151.8–151.9, 151.9 guttate psoriasis 80.3, 82.4 HTLV-1-related 53.1 localized cutaneous 54.3–54.7 neonatal 9.3 pathophysiology 54.1–54.2 perianal dermatitis (PSD) 20.6, 54.7, 151.8, 155.5 postinfectious purpura fulminans 162.3, 162.5 skin grafts 187.13 toxin-mediated disease 54.8–54.11 vaginitis 152.2 streptococcal intertrigo 54.7 napkin area 20.6, 20.6

streptococcal pyrogenic exotoxin-A (SPE-A) 54.3, 54.10 streptococcal pyrogenic exotoxins (SPEs) 54.1–54.2, 54.10, 54.11 streptococcal toxic shock syndrome (STSS) 54.1, 54.10 streptococci 54.1–54.2 group A β-haemolytic (GAS) see group A streptococcus superantigens 54.1 Streptococcus, Behçet disease pathogenesis 167.14 Streptococcus pneumoniae complement deficiencies 177.19, 177.20 septicaemia 55.11 purpura fulminans 162.2, 162.3 Streptococcus pyogenes see group A streptococcus streptolysin O 54.2, 54.10 Streptomyces somaliensis 63.4 streptomycin atypical mycobacterial infections 57.8 induced hypertrichosis 148.30 tropical ulcer 66.5 stress atopic dermatitis and 30.3, 34.1–34.2, 34.3–34.4 pompholyx and 39.1 stretch marks see striae striae (striae distensae; SD) 146.1–146.4 aetiology and pathogenesis 146.1–146.2 clinical features 146.3 corticosteroid-related 146.2 Cushing disease/syndrome 146.2, 172.7, 172.8 differential diagnosis 146.3, 154.10 familial 146.1 Marfan syndrome 145.6, 146.1 obesity 65.10, 146.1 pathology 146.2–146.3 treatment 146.3–146.4, 189.10 striae albae (SA) 146.2, 146.3 striae gravidarum (SG) 146.1 striae nigrae (SN) 146.3 striae rubrae (SR) 146.2, 146.3 striated muscle hamartoma 10.11–10.12 striate lesions, focal dermal hypoplasia 133.1, 133.3, 133.4 string of pearls sign 89.7, 89.7 Strongyloides stercoralis 68.3 STS gene 121.11, 121.12 stun gun injuries, abusive 154.6–154.7 Sturge–Weber syndrome (SWS) 112.15–112.16 oral involvement 147.14, 147.15 patient advocacy group 179.7 STX11 gene mutations 103.17–103.18, 177.8 subacute sclerosing panencephalitis 49.2 subaponeurotic haemorrhage 17.4 subcorneal pustular dermatosis, vs. infantile acropustulosis 88.3 subcutaneous fat necrosis (SFN), neonatal 7.1–7.5, 77.8–77.9 clinical features 7.1–7.2, 7.2, 77.8, 77.8 pathology 7.1, 7.2, 77.8 subcutaneous infusion anaesthesia 190.5 subcutaneous nodules, chromosome disorders 116.13, 116.14 subcutaneous panniculitis-like T-cell lymphoma (SPTL) 77.14–77.16, 99.23, 102.9–102.10 clinical features 77.14, 77.14–77.15, 99.23, 99.23, 102.9 cytophagic histiocytic panniculitis and 77.13 subcutaneous tissue embryo 2.4, 2.4 embryonic-fetal transition 2.16, 2.17, 2.17–2.18 fetal 2.21, 2.22 neonatal disorders 7.1–7.5 surgical excision 186.3 see also adipose tissue subependymal nodules, tuberous sclerosis 129.3, 129.3, 129.11 subepidermal calcified nodule 95.3, 95.3 substance abuse, parental 154.2 subungual exostosis 150.7, 150.7 subungual hyperkeratosis, psoriasis 150.5

67

subungual warts 47.4, 150.3 sucking blisters 87.6 sudden infant death syndrome (SIDS), nappy cleaning chemicals and 21.3 suffocation, forced 154.8 Sugio–Kajii syndrome see trichorhinophalangeal syndrome (TRPS), type III suicidal behaviour 180.8 sulphamethoxazole-trimethoprim see trimethoprim-sulphamethoxazole sulphamethoxypyridazine, linear IgA disease of childhood 89.10 sulphapyridine bullous pemphigoid 91.17 dermatitis herpetiformis 90.5–90.6 epidermolysis bullosa acquisita 91.24 linear IgA disease of childhood 89.10 monitoring therapy 192.16 sulphur-deficient brittle hair syndrome see trichothiodystrophy sulphur granules, actinomycosis 63.26 sulphur ointment, scabies 72.6 SUMF1 gene mutations 121.14 summer camps 179.6 sunburn 108.6, 108.6–108.7 carcinogenic effects 108.8–108.9 palliation 108.6–108.7 xeroderma pigmentosum 135.8 sunburn cells 108.6 sun exposure acquired melanocytic naevi and 109.12 actinic prurigo 106.4 childhood 108.1 erythropoietic protoporphyria 107.10 hydroa vacciniforme 106.8 Jessner’s lymphocytic infiltrate 101.1 pityriasis lichenoides 100.3 polymorphic light eruption 106.1–106.2, 106.3 solar urticaria 106.6–106.7 squamous cell carcinoma 99.3 vitamin D synthesis 108.6 xeroderma pigmentosum 135.8, 135.8 see also ultraviolet (UV) radiation sun protection see photoprotection sun protection factor (SPF) 108.14, 181.13 sunscreens 108.12–108.16, 181.13–181.14 adverse effects 108.15–108.16 efficacy 108.14 inorganic 108.12–108.13, 108.13 organic 108.13, 108.13–108.14 porphyrias 107.14 recommended usage 108.14–108.15 substantivity 108.14 vitiligo 105.8 superantigens staphylococcal, atopic dermatitis 24.6, 26.2–26.3 streptococcal 54.1 superficial epidermolytic ichthyosis (SEI) (ichthyosis bullosa of Siemens) 117.4– 117.6, 121.21–121.23 clinical features 117.6, 121.21, 121.22 differential diagnosis 121.20, 121.22–121.23 genetic basis 115.20, 121.22–121.23 superoxide dismutase 108.11 support groups, patient 179.6, 179.7 Suprasorb X® dressings, epidermolysis bullosa simplex 118.8 supraspinous fossae 10.6 surfactants, atopic dermatitis and 27.16 surfer’s knots 96.1 surgery 186.1–186.7, 187.1–187.32 age considerations 186.1, 187.1 anaesthesia 186.1, 190.1–190.10 arteriovenous malformations 112.3, 112.4 basal cell carcinoma 99.2 calcifying aponeurotic fibroma 97.13 calcifying fibrous pseudo-tumour 97.7 congenital/infantile fibrosarcoma 97.16, 99.8 congenital melanocytic naevi 109.8, 186.6, 186.6–186.7, 187.28–187.30, 187.29, 187.30

68

Index

surgery (cont.) Dabska tumour 99.10 dermatofibrosarcoma protuberans 99.7 digital fibromatosis 97.12 dystrophic epidermolysis bullosa 118.21–118.22 fibrous hamartomas of infancy 97.6 giant cell fibroblastoma 97.14 gingival fibromatosis 97.11 indications 186.2 infantile desmoid-type fibromatosis 97.9 infantile haemangiomas 113.18, 186.7, 186.7 Klippel–Trenaunay syndrome 112.17 lichen sclerosus 152.7–152.8 lymphatic malformations 112.13–112.14 lymphoedema 114.12–114.13 melanoma 109.27 meningococcal disease 55.11–55.12, 55.12 morphoea 173.10 naevus sebaceous 110.5 neuroblastoma 99.12 palmar-plantar fibromatosis 97.10 pilomatrix carcinoma 99.4 plastic see plastic surgery porokeratosis 126.4 Proteus syndrome 111.7–111.8 purpura fulminans 162.12–162.14, 162.13 rhabdomyosarcoma 99.6 scar placement and alignment 186.2, 186.2, 186.3, 187.2–187.3, 187.3, 187.4 scar revision 187.7–187.9, 187.9 skin lesion removal 186.2–186.3 full-thickness 186.2, 186.2–186.3 partial-thickness 186.2 subcutaneous tissue 186.3 solitary fibrous tumour/haemangiopericytoma 99.9 Spitz naevus 109.17 warts 47.8 surgical wound closure 186.3–186.6, 187.10–187.30 complex combined techniques 187.23 delayed 187.10 flaps 186.5, 186.5, 187.21–187.23 larger defects 187.23–187.30 primary 186.3, 186.4, 187.10 principles 187.2 secondary 187.10 serial excision 187.10, 187.10 skin grafts 186.3–186.5, 187.10–187.19 tissue expansion 186.5–186.6, 186.6 vacuum-assisted closure therapy 187.13 Sutton’s summer prurigo 42.6–42.7 Sutton’s ulcers 147.2, 151.13 sweat glands AEC syndrome 127.76 development 2.28, 2.29–2.33, 2.38 EEC syndrome 127.78 fetus 2.21, 2.22 hypohidrotic ectodermal dysplasia 127.69 odonto-onychodermal dysplasia 127.85 sweating diminished see hypohidrosis effects in atopic dermatitis 25.2–25.3 neonates 3.6 premature infants 2.23, 3.6 sweat testing cystic fibrosis 170.4 X-linked hypohidrotic ectodermal dysplasia 115.13–115.14, 115.14 Sweet syndrome (SS) 156.1–156.4 aetiology and pathogenesis 156.1 α1-antitrypsin deficiency with 77.11 associated diseases 156.2, 156.3 clinical features 156.1–156.3, 156.2 diagnostic criteria 156.3, 156.3 differential diagnosis 156.4 histopathology 156.3 laboratory tests 156.3–156.4 malignancy-associated 156.3, 156.4

prognosis 156.4 treatment 156.4 swimming atopic dermatitis 30.3 genital dermatitis 151.3 swimming pool granuloma 57.6–57.7 Swiss cheese lesions, borderline leprosy 70.6 symblepharon, mucous membrane pemphigoid 91.19, 91.19 sympathetic nervous system, atopic dermatitis 25.2, 34.3–34.4 syndets, newborn skin care 5.6 syndrome of inappropriate antidiuretic hormone secretion (SIADH) 110.20 synovial sarcoma 99.6 synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome 79.17 syphilis 153.2–153.8 acquired 153.2 clinical features 60.5, 153.2–153.3 diagnosis 153.5–153.6, 153.6 differential diagnosis 153.6–153.7 prognosis 153.6 sexual abuse implications 153.3, 155.3 treatment 153.7, 153.7 anetodermic lesions 145.12 congenital 153.2, 153.3–153.5 anogenital region 20.7 clinical features 8.4, 8.5, 8.6, 153.4, 153.4 diagnosis 153.5–153.6, 153.6 differential diagnosis 153.6–153.7 late onset 153.3, 153.5 prognosis 153.6 treatment 153.7, 153.7 endemic 60.1–60.7 aetiology 60.1, 60.2, 60.2 clinical features 60.5, 60.5 differential diagnosis 60.5–60.6, 60.6 distribution 60.2 laboratory tests 60.6, 60.6 pathology 60.3 prognosis 60.7 treatment 60.7 history 153.2 latent 153.3 pathology 153.2 pigmentary changes 104.4, 104.12 primary 153.3 secondary 153.3 syringocystadenoma papilliferum (SP) 94.7–94.8, 94.8 naevus sebaceous 110.4, 110.4 syringoma 94.9–94.10, 94.10 chondroid, calcification 95.7 chromosome disorders 116.13 genital area 151.20 systemic drug therapy 181.1, 181.16–181.19 monitoring 192.13, 192.16, 192.17 nursing care 192.10–192.13, 192.15 systemic lupus erythematosus (SLE) 175.5–175.9 bullous 91.13, 91.24 classification criteria 175.5, 175.5 clinical features 175.6, 175.6, 175.6–175.8 complement deficiencies 175.5, 177.19, 177.20 neonatal see neonatal lupus erythematosus neuropsychiatric (NP-SLE) 175.6–175.7, 175.7 pathogenesis 175.5–175.6 purpura fulminans 162.6, 162.6–162.7, 162.12 urticarial vasculitis and 163.1–163.2, 163.5 systemic sclerosis (SSc) 174.1–174.11 aetiology and pathogenesis 174.1–174.5, 174.5 autoantibodies 174.3, 174.4 calcinosis cutis 95.6 classification criteria 174.7, 174.7 clinical features 174.5–174.10 differential diagnosis 105.6, 174.10 diffuse cutaneous (dcSSc) 174.1, 174.2 clinical features 174.6, 174.6, 174.7 early and late stages 174.3 limited 174.2, 174.7 limited cutaneous (lcSSc) 174.1, 174.2

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

clinical features 174.6–174.7 early and late stages 174.3 pigmentation changes 104.8 sine scleroderma 174.2 treatment 174.10–174.11 T4 endonuclease V, xeroderma pigmentosum 135.11, 135.24 Tabanus see horse flies tabby mouse 127.66, 127.66 tacalcitol, topical 181.14 tache noir 61.5, 61.5 tacrolimus 181.11–181.12 alopecia areata 149.6 atopic dermatitis 25.11–25.12, 30.7–30.8 Behçet disease 167.17 eczema herpeticum and 33.1, 33.3 graft-versus-host disease 178.9 granuloma annulare 93.8 mode of action 25.11, 25.11 Netherton syndrome 124.7 perioral dermatitis 38.3 pityriasis alba 37.2 psoriasis 82.3 toxicity 184.9 vitiligo 105.6 tags, skin see skin tags tail, human 10.17 talcum powder, napkin area care 21.4 tale of a nail sign 116.16, 116.17 Tamayo, Lourdes 1.3, 1.4 tanapoxvirus 51.2, 51.24–51.25 clinical features 51.24, 51.24–51.25, 51.25 tanning 108.7 addiction 108.9 tanning agents, phototoxic reactions 45.10 tanning beds 108.4 TAP deficiency 177.3 TAP genes 177.31 tapir’s nose 67.8 tar see coal tar tarantulas 73.5 target lesions erythema multiforme 78.3–78.4, 78.4 Stevens–Johnson syndrome/toxic epidermal necrolysis 183.9, 183.9 target-like lesions (cockades) acute haemorrhagic oedema in infancy 161.2, 161.3 Henoch–Schönlein purpura 160.3, 160.3 urticaria 74.10, 74.10 TAT gene mutations 120.19 tattoos 180.8 amalgam and graphite, oral mucosa 147.14 laser removal 189.7 vitiligo therapy 105.8 taurodontia, absent teeth and sparse hair 127.58 Tay syndrome 148.11 see also trichothiodystrophy tazarotene 181.13 acne 79.7–79.8 TBX1 gene 177.21 T-cell lymphoma, cutaneous see cutaneous T-cell lymphoma T-cell nuclear factor (TCNF) 53.1 T-cells activation by superantigens 54.1 allergic contact dermatitis 44.1 alopecia areata 149.2, 149.4 atopic dermatitis 24.3, 24.4, 24.5, 25.5, 26.2 granuloma annulare 93.3 Jessner’s lymphocytic infiltrate 101.1 lichen planus 85.2 see also CD4+ T helper cells; CD8+ cytotoxic T cells; cell-mediated immunity TCR deficiencies 177.31 tea tree oil cutaneous reactions 45.7 seborrhoeic dermatitis 41.4 warts 47.10

Index Tedania ignis 73.8–73.9 teenagers see adolescents teeth natal 134.5 normal development 127.104 pigmentation 147.16, 147.16, 147.16 see also dental abnormalities telangiectasia 112.18–112.20 acquired naevoid 112.19 ataxia telangiectasia 112.19–112.20, 116.12, 116.12, 177.3, 177.3–177.4 chromosome disorders 116.12 generalized essential (GET) 112.18 hereditary benign (HBT) 112.18 hereditary haemorrhagic (HHT) 112.5, 115.26, 147.16 laser treatment 188.9, 188.9 localized vascular malformations 112.18–112.19 macularis eruptiva 112.19 neonatal lupus erythematosus 14.4, 14.5, 112.19 post-involution haemangiomas 188.8 syndromic 112.19–112.20 unilateral naevoid (UNT) 112.18 xeroderma pigmentosum 135.8, 135.8 telogen 148.2, 148.3 bulbs 148.5, 148.5 loss 148.20–148.21 telogen effluvium 148.20, 148.20–148.21 telomerase complex gene mutations 136.8 TEL–TRKC (ETV6–NTRK3) gene fusion 97.15, 99.8 temozolamide, solitary fibrous tumour/ haemangiopericytoma 99.9 temperature induced urticaria 74.5, 74.5 napkin area 19.2 regulation see thermoregulation temporal arteritis, juvenile (JTA) 36.7 tenascin (tenascin-X) deficiency 142.3, 142.9 hair follicle development 2.34, 2.35 teratogenicity, retinoids 79.9, 121.68, 181.18 terbinafine 62.15, 181.16 dermatophytoses 62.15, 62.16, 62.17 TERC gene mutations 136.8, 136.9 TERT gene mutations 136.8, 136.9 testicular feminization syndrome 172.16–172.17 testicular maldescent, recessive X-linked ichthyosis 121.12 testitoxicosis, familial 172.12 testolactone 172.12 testosterone acne pathogenesis 79.3, 79.3 plasma 172.14–172.15 see also androgen(s) tethered spinal cord 10.17, 113.13 tetracaine 190.2 formulations 190.4–190.5 tetracaine/adrenaline/cocaine (TAC) 190.4 tetracyclines acne 79.8 dystrophic epidermolysis bullosa 118.20 hyperpigmentation induced by 104.4, 104.5, 104.8 mouthwash 147.3 perioral dermatitis 38.3 Rocky Mountain spotted fever 61.4 spotted fever group rickettsial infections 61.6 typhus group rickettsial infections 61.8, 61.10 tetrahydrobiopterin (BH4) 169.4 tetramelic deficiencies, ectodermal dysplasia, deformed ears and other abnormalities 127.58 tetrasomy 8p, mosaic 116.15 tetrasomy 12p, mosaic see Pallister–Killian syndrome TEWL see transepidermal water loss textbooks, paediatric dermatology 1.3 TG1 see transglutaminase 1

TGF-β see transforming growth factor-β TGFBR gene mutations 142.8 TGM1 gene mutations 121.33 collodion baby 12.1–12.2, 121.30 phenotypes 121.25, 121.27, 121.28, 121.33 prenatal diagnosis 139.4 TGM5 gene mutations 121.23 Th1 (type 1 T helper) cells atopic dermatitis 24.3–24.4, 24.5, 31.3 graft-versus-host disease 178.2 sarcoidosis 158.2 Th2 (type 2 T helper) cells aeroallergen sensitization 32.3–32.4, 32.4 atopic dermatitis 22.9, 24.1, 24.2, 24.3–24.4, 24.5, 25.5 innate immune responses and 24.7 skin barrier dysfunction and 24.5 Staphylococcus aureus and 24.6, 24.7 food allergen sensitization 31.3 morphoea 173.2 Th17 (type 17 T helper) cells, atopic dermatitis 24.4, 24.5 thalidomide actinic prurigo 106.6 Behçet disease 167.16 Jessner’s lymphocytic infiltrate 101.3 lepra reactions 70.12 monitoring therapy 192.16 prurigo nodularis 42.5 thallium poisoning 148.19, 184.15 thanatophoric dysplasia, prenatal diagnosis 139.3 Thanos syndrome 111.5 thelarche 172.11 premature 172.11, 172.12, 172.13 Theonella mirabilis 73.9 theophylline, atopic dermatitis 25.10 thermal injuries 187.16 see also burns/scalds thermal relaxation time (TRT) 188.3 thermography, morphoea monitoring 173.5, 173.8 thermoregulation hypohidrotic ectodermal dysplasia 127.69 neonates 3.6 severe MEDOC 121.64 thiabendazole, cutaneous larva migrans 68.4 Thibierge–Weissenbach syndrome 95.6 thimble jellyfish 73.8 thimerosal (thiomersal) allergy 44.3–44.4, 44.9 thin skin, chromosome disorders 116.9 thiopurine methyltransferase (TPMT) activity 30.10, 91.4 third trimester 2.2–2.3, 2.3 skin development 2.22–2.23 thiuram mix allergy 44.3, 44.10 thorns, penetrating injuries 45.1 threadworms (pinworms) 151.10, 152.3, 152.4, 152.4 3A syndrome 172.9 3MC (Malpuech–Michels–Mingarelli–Carnevale) syndrome 10.9 Three Item Severity (TIS) score 29.5 thrombocytopenia Kasabach–Merritt phenomenon 113.25 multifocal lymphangio-endotheliomatosis 113.27 neonatal lupus erythematosus 14.4, 14.7, 14.10 oral purpura 147.16, 147.16 Wiskott–Aldrich syndrome 177.34 thrombocytosis, Kawasaki disease 168.6, 168.6 thrombomodulin, meningococcal disease 55.3, 55.4 thrombophlebitis, superficial 77.6 thrombosis purpura fulminans 162.1, 162.2, 162.5, 162.7, 162.7 venous malformations 112.8–112.9 thrombotic thrombocytopenic purpura, familial 115.28

69

thrush (acute pseudo-membranous candidosis), oral 62.19, 62.21, 147.11–147.12, 147.12 thumb deformity and alopecia 127.59 polydactyly 150.8 thumb sign, Marfan syndrome 145.7, 145.7 thumb-sucking 180.2–180.3, 180.3, 180.11 thymic stromal lymphopoietin (TSLP) 27.6 atopic dermatitis 24.4, 27.11 thymopentin, atopic dermatitis 30.11 thymostimulin (TP-1), atopic dermatitis 30.11 thyroglossal duct cysts 10.5 thyroid (gland) aplasia or hypoplasia 172.1 lingual 147.23 thyroid acropathy 172.6 thyroid disease cutaneous manifestations 172.1–172.7 haemangiomas and 113.22 Langerhans cell histiocytosis 103.3 see also hyperthyroidism; hypothyroidism thyroiditis Hashimoto 172.5, 172.6 vitiligo association 105.4–105.5 thyroid ophthalmopathy 172.5, 172.6 thyrotropin, serum 172.3 thyroxine therapy 172.3 tick(s) biting behaviour 71.6–71.7, 71.7 infections transmitted 59.10–59.11 removal of attached 59.10 transmission of rickettsias 61.1, 61.2, 61.5, 61.10 transmitting Lyme borreliosis 59.1–59.3 tick bites 71.4–71.5, 71.5 antibiotic prophylaxis 59.10 Lyme borreliosis 59.1, 59.3–59.4, 76.6 systemic complications 71.8 tick-borne encephalitis (TBE) 59.10 tick-borne lymphadenopathy (Rickettsia slovaca) 61.2, 61.5–61.6, 61.10 tick typhus North Asian (Rickettsia sibirica) 61.2, 61.5–61.6 Queensland (Rickettsia australis) 61.2, 61.5–61.6 tics, habit 180.3–180.4 TIE2/TEK gene mutations 112.8, 112.11 Tietz syndrome 115.25, 138.6 tiger-tail hair 135.19, 135.20 tinea capitis clinical features 62.5–62.7, 62.6, 62.7, 62.8 differential diagnosis 62.14, 149.4 ectothrix infections 62.5, 62.6 large-spored 62.6 small-spored 62.6 endothrix infections 62.5, 62.6 epidemiology 62.2–62.4 geography of dermatophytes causing 62.7, 62.8 HIV infection 52.2, 52.2 lamellar ichthyosis/congenital ichthyosiform erythroderma 121.32, 121.64 neonatal 8.5, 8.6 pathogenesis 62.5 transmission 62.4 treatment 62.15 tinea corporis clinical features 62.8, 62.8–62.9 differential diagnosis 40.2, 62.14 treatment 62.16 tinea cruris 62.9, 151.11 differential diagnosis 62.14 treatment 62.16 Tinea faciei, clinical features 62.7, 62.8 tinea imbricata 62.2, 62.9, 62.9 tinea incognito 62.9 tinea manuum 62.10, 62.14 tinea nigra 62.32–62.33, 62.33 tinea pedis 62.9–62.10 clinical features 62.9, 62.9, 62.10 differential diagnosis 62.14 incidence 62.9–62.10

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Index

tinea pedis (cont.) lymphoedema 114.13 transmission 62.4 treatment 62.16–62.17 tinea unguium 62.10–62.11 differential diagnosis 62.14 treatment 62.17 see also onychomycosis tinea versicolor see pityriasis versicolor TINF2 gene 136.8 tin protoporphyrin 107.15 tissue expansion 186.5–186.6, 187.23–187.26 biomechanics 187.26 clinical applications 186.6, 187.26, 187.27 giant congenital naevi 187.30, 187.31, 191.2–191.6 choice of expander 191.2–191.3, 191.3 extremities 191.5–191.6, 191.7 face and neck 191.3–191.5, 191.5 procedure 191.3 scalp 191.3, 191.4 trunk 191.5, 191.6 tissue inhibitor of metalloproteinase 1 (TIMP-1), serum 36.11 tissue plasminogen activator (tPA) meningococcal disease 55.11, 162.11–162.12 postinfectious purpura fulminans 162.12 tissue transplants, free vascularized (free flaps) 186.5, 187.21 titanium dioxide 108.12, 108.15–108.16, 181.13 TLR2 gene, atopic dermatitis 23.13 TLR3 gene 177.11 TLR9 gene, atopic dermatitis 23.9, 23.13, 23.14 TMC6 (EVER1) gene 47.5, 137.10–137.11 TMC8 (EVER2) gene 47.5, 137.10–137.11 TNF-α see tumour necrosis factor-α TNF gene 167.14 TNFR-associated factor (TRAF) 127.67 TNFRSF1A gene mutations 74.9, 176.2 TNFRSF6 gene 177.8 TNFRSF13B gene mutations 177.25 TNFR superfamily member 19 (TNFRSF19) 127.68 TNFSF6 gene 177.8 TNX gene mutations 142.2, 142.3 toadfish 73.9 tocilizumab, juvenile idiopathic arthritis 175.3 toenails congenital malalignment of big 150.2, 150.2 ingrown 150.2–150.3 toll-like receptors (TLRs) 26.3 acne vulgaris 79.5 inherited signalling defects 177.11 tongue acquired lesions 147.23–147.25 congenital/developmental lesions 147.22–147.23 discoloration 147.25 furred 147.25 geographical 147.23, 147.24–147.25 hairy 147.25, 147.25 lesions 147.22–147.25 localized enlargement 147.25 raspberry 147.24 scrotal/fissured 114.18, 114.19, 147.22–147.23, 147.23 strawberry 147.24 swollen 147.23 unilateral atrophy, morphoea 173.6, 173.6 tongue tie 147.22 tonsil, lingual 147.23 tonsillitis, herpes gingivostomatitis 48.2 tooth and nail syndrome see Witkop syndrome topical anaesthetics 181.7, 190.3–190.5 allergic reactions to 44.10 laser treatment 188.2–188.3, 189.2 mucosal surfaces 190.5 topical corticosteroids 181.10, 181.10–181.11 absorption 82.1–82.2 factors affecting 181.4 neonates 5.7

alopecia areata 149.4–149.5 atopic dermatitis 30.6, 30.6–30.7, 30.7 eczema herpeticum and 33.1, 33.3 polythene occlusion 30.7 severity scoring 29.7 side effects 30.6 clinical potency 181.10, 181.11, 181.11 Darier disease 125.4 dystrophic epidermolysis bullosa 118.21 eosinophilic pustular folliculitis 36.5 finger-tip units 30.7 graft-versus-host disease 178.9 granuloma annulare 93.8, 93.9 infantile acropustulosis 88.3 infantile haemangioma 113.17 infantile seborrhoeic dermatitis 35.6 lichen planus 85.10, 147.8 lichen sclerosus 152.7 lichen simplex chronicus 42.2 mastocytosis 75.12 napkin dermatitis 21.4 orofacial granulomatosis 157.5 pemphigus vulgaris 91.4 pompholyx 39.3–39.4 psoriasis 82.1–82.2, 82.2 recurrent aphthous ulceration 147.3 seborrhoeic dermatitis 41.4 side-effects 181.10, 181.11, 184.6 contact allergy 30.10, 44.10 perioral dermatitis 38.1, 38.3 striae 146.2 sunburn 108.6–108.7 vitiligo 105.6 vulval dermatitis 151.3 topical therapy 181.1–181.16 allergic reactions 30.10, 44.10–44.11 barrier properties of skin 181.1–181.2 factors affecting drug penetration 181.2, 181.2–181.5 anatomical site 181.3 appendages 181.3 damage to stratum corneum 181.3 hydration of stratum corneum 181.3 solute 181.3–181.4 technique of application 181.4 vehicle 181.4 gene therapy 140.7 skin metabolism of drugs 181.6 systemic delivery of drugs via 181.5 therapeutic agents 181.7–181.16 transdermal therapeutic systems 181.5–181.6, 181.6 vehicles 181.6–181.7 see also absorption, percutaneous TORCH serology 8.1 tori, intraoral 147.19 torticollis, fibromatosis colli 97.5 total parenteral nutrition (TPN), extravasation injuries 17.8, 17.8, 17.9 Touraine lentiginosis 109.12 Touraine polyfibromatosis 96.1 toxicants, exposure to see poisoning toxic epidermal necrolysis (TEN) 78.1–78.8, 183.9–183.11 acute graft-versus-host disease 178.5 classification 78.1, 78.2 clinical features 78.5, 78.5–78.6, 183.9, 183.9–183.10 drugs associated with 78.2, 78.2, 87.5, 183.9 epidemiology 78.1–78.2 genital area 151.13–151.14 intensive care 192.13–192.19 management 78.6–78.8, 183.10 neonatal/early infantile 11.8 pathogenesis 78.2–78.3 SCORTEN score 78.5–78.6, 78.6, 183.10 terminology 78.1 vesiculobullous lesions 87.5, 87.8 vs. staphylococcal scalded skin syndrome 54.9 see also Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

toxic erythema, neonatal see erythema toxicum neonatorum Toxicodendron (Rhus) dermatitis 44.12, 45.5, 45.6 Toxicodendron radicans see poison ivy toxic oil syndrome 104.9 toxicology 184.1–184.2 toxic shock syndrome (TSS) 54.9–54.10 clinical features 54.9 HIV infection 52.2 menstrual 54.9 neonatal 8.5 non-menstrual 54.9 staphylococcal 54.2, 54.9 streptococcal 54.1, 54.10 toxic shock syndrome toxin-1 (TSST-1) 54.9, 54.11 toxin-mediated (perineal) erythema, recurrent (RPE) 54.11 toxin-mediated syndromes 54.8–54.11 epidemiology 54.3 pathophysiology 54.1–54.3 Toxocara infections 36.10 Toxoplasma gondii, congenital 8.6 TP53 gene see p53 gene TP63 (p63) gene 127.73–127.74 HSV infections 48.2 mutations, ectodermal dysplasias 11.5, 127.73–127.79, 148.17 somatic mosaicism 131.2 trace elements 65.7 deficiencies 65.7–65.9 tracheostomy, junctional epidermolysis bullosa 118.33 trachyonychia see twenty-nail dystrophy traditional Chinese medicine, atopic dermatitis 30.11 TRAF6 127.67, 127.68 TRAF6 gene mutations 127.66 tragi, accessory 10.2–10.3, 10.3 training, paediatric dermatology 1.3 transcription coupled repair (TCR) 135.3, 135.3–135.4 transcription factor IIH (TFIIH) 135.3, 135.4, 135.21 transcription factors, defects causing ectodermal dysplasias 127.73–127.83 transcutaneous absorption see absorption, percutaneous transcutaneous monitoring, neonatal intensive care 5.4, 17.9–17.10 transdermal therapeutic systems (TTSs) 181.5–181.6, 181.6 transepidermal water loss (TEWL) collodion baby 121.30 infantile seborrhoeic dermatitis 35.2 as measure of barrier function 27.8, 181.2 neonates 3.2–3.4, 27.12–27.13 premature infants 2.23, 3.2–3.4, 3.3, 5.4, 181.2 transforming growth factor-β (TGF-β) Henoch–Schönlein purpura 160.2 Marfan syndrome pathogenesis 145.5 morphoea pathogenesis 173.2 problem scars 187.6–187.7 transglutaminase(s) 121.33 transglutaminase 1 (TG1) 12.1, 121.33 atopic dermatitis 27.9 deficiency see autosomal recessive congenital ichthyoses (ARCI), TG1-deficient gene mutations see TGM1 gene mutations periderm cells 2.24, 2.26 transglutaminase 5 (TG5) 121.23 transient hypogammaglobulinaemia of infancy 177.26 transient neonatal dermatoses, common 6.1, 6.1–6.12 transient neonatal pustular melanosis (TPM) 6.4, 6.8–6.9 clinical features 6.8–6.9, 6.9 differential diagnosis 6.4, 6.7, 88.3 transillumination burns, neonates 17.10

Index translesional synthesis 135.1 defects 135.14 translocations, chromosome 116.5 ataxia telangiectasia 116.7, 177.4 balanced 116.5 dermatofibrosarcoma protuberans 97.14, 99.7 methods of detection 116.2, 116.5 rhabdomyosarcoma 99.4–99.5 unbalanced 116.5 transplant recipients cytomegalovirus infections 49.17 skin infections 64.7, 64.8, 64.9, 64.10 transport defects, inherited 169.9–169.10 transposable elements (transposons) 115.7, 115.12, 131.2 gene delivery 140.6 trans-splicing strategy 140.14, 140.15 transthyretin 159.1 trans-urocanic acid (tUCA) 27.2 transverse nasal line 10.6 TRAPS (tumour necrosis factor receptorassociated periodic syndromes) 74.9, 176.2, 176.3 trauma dystrophic calcification after 95.7 dystrophic epidermolysis bullosa 118.19 granuloma annulare and 93.1 indicating sexual abuse 155.2, 155.2–155.3 knuckle pads due to 96.1 lymphoedema complicating 114.11 oral keratosis 147.11 oral ulceration 147.3–147.4 palmoplantar hidradenitis and 94.1 pigmentary changes after 104.1, 104.4 triggering morphoea 173.1 tropical ulcers 66.2 traumatic panniculitis 77.12–77.13 tree nut allergy 31.6, 31.15, 31.17 Treponema diagnostic tests 60.6, 60.6 tropical ulcer 66.2 Treponema carateum 60.1, 60.2 treponemal serology tests 60.6, 60.6, 153.6 Treponema pallidum 153.2 detection 153.4, 153.6, 154.5 infection see syphilis serological tests 153.6 Treponema pallidum ssp. endemicum (T. endemicum) 60.2 Treponema pallidum ssp. pertenue (T. pertenue) 60.2 experimental studies 60.7 pathology 60.2, 60.2–60.3 treponematoses, endemic 60.1–60.7 see also pinta; syphilis, endemic; yaws tretinoin (all-trans-retinoic acid) acne 79.7–79.8 Gorlin syndrome 132.14 striae 146.3–146.4 triamcinolone intralesional alopecia areata 149.4–149.5 infantile haemangioma 113.17 keloids 187.5 lichen simplex chronicus 42.2 orofacial granulomatosis 157.5 intramuscular, nail lichen planus 150.6 triatomine bugs 71.6, 71.7 triazole antifungals 62.15 trichilemmal cyst naevus 110.6 trichilemmal cysts (pilar cysts) 92.5–92.6 calcification 95.7 trichilemmomas, PTEN hamartoma-tumour syndrome 137.17–137.19, 137.18 trichloroacetic acid (TCA) 146.4, 181.13 trichobezoars 180.5 trichoblastoma 110.4 trichodental dysplasia 127.59 trichodento-osseous (TDO) syndrome 127.79–127.80 clinical features 127.59, 127.80 genetic basis 115.24, 127.79

trichodiscomas, Birt–Hogg–Dubé syndrome 137.8 trichoepitheliomas desmoplastic 94.5–94.6 genetic predisposition to 137.9, 137.10 genital area 151.20 multiple familial see multiple familial trichoepitheliomas trichofolliculoma 94.4–94.5 tricho-hepatic-enteric syndrome 177.8 trichomatricoma see pilomatricoma trichomegaly of eyelashes, congenital 148.31 Trichomonas vaginalis (TV) infection 153.21– 153.22, 153.22 tricho-oculodermovertebral syndrome 127.9 tricho-odonto-onychial dysplasia 127.60 tricho-odonto-onychial dysplasia (with amastia) 127.59 tricho-odonto-onycho-dermal syndrome 127.60 tricho-onycho-dental (TOD) dysplasia 127.60 trichophagia 180.5 Trichophyton, culture 62.12–62.13, 62.13 Trichophyton concentricum 62.2, 62.3 clinical features of infection 62.6, 62.9 Trichophyton equinum 62.3, 62.4 identification 62.13, 62.14 Trichophyton erinacei 62.3 Trichophyton interdigitale 62.2, 62.3, 62.4 clinical features of infection 62.6, 62.8, 62.9, 62.9, 62.10, 62.11 identification 62.13, 62.14 Trichophyton mentagrophytes 62.3, 62.4 clinical features of infections 62.6, 62.7 deep mycoses 63.25 identification 62.13, 62.14 new species concept 62.2, 62.13 primary immunodeficiencies 64.5 Trichophyton rubrum 62.2, 62.3 African population 62.3, 62.4, 62.11, 62.14 clinical features of infection 62.6, 62.9, 62.10, 62.10, 62.11 deep mycoses 63.25 neonatal infection 8.6 Trichophyton schoenleinii 62.1, 62.3, 62.3 clinical features of infection 62.6, 62.10 deep mycoses 63.25 disease pathogenesis 62.5 identification 62.12, 62.14 Trichophyton simii 62.3, 62.4 Trichophyton tonsurans 62.3, 62.3–62.4 clinical features of infection 62.5–62.6, 62.7, 62.8, 62.9, 62.10 disease pathogenesis 62.5 identification 62.12, 62.13, 62.14 transmission 62.4 treatment 62.15, 62.16 Trichophyton verrucosum 62.3, 62.4 clinical features of infections 62.6 microscopy 62.12 Trichophyton violaceum 62.3, 62.3, 62.3–62.4 clinical features of infections 62.6, 62.7, 62.10 deep mycoses 63.25 trichopoliodystrophy see Menkes syndrome trichorhinophalangeal syndrome (TRPS) 127.79 type I 115.24, 127.61, 127.79, 127.80–127.81 type II see Langer–Giedion syndrome type III 127.61, 127.79, 127.80–127.81 trichorrhexis invaginata (bamboo hair) 148.12, 148.12–148.13 diagnosis 124.6 Netherton syndrome 124.1, 124.4, 124.4–124.5, 148.12, 148.13 trichorrhexis nodosa 148.10, 148.10 Netherton syndrome 124.4, 124.5 syndrome (Pollitt syndrome) 127.62, 148.11 trichoschisis 148.10, 148.10–148.12 Trichosporon (Trichosporon beigelii) trichosporosis 63.3–63.4 white piedra 62.32 trichosporosis 63.3–63.4

71

trichothiodystrophy (TTD) 121.58–121.59, 135.18–135.21 associated syndromes 135.19, 148.11, 148.12 clinical features 121.46, 135.7, 135.19, 135.19–135.20 differential diagnosis 121.37, 135.20–135.21 genetic classification 135.21 hair abnormalities 135.19, 135.20, 148.12, 148.12 laboratory tests 135.21 non-photosensitive 115.24, 135.6, 135.21, 148.12 pathogenesis 115.24, 135.4, 135.5, 148.12 photosensitive 115.24, 135.6, 135.21, 148.11, 148.12 treatment 135.21 trichoschisis 148.12 trichothiodystrophy-neurocutaneous syndrome 127.62 trichotillomania 180.3, 180.4–180.6 clinical features 180.5, 180.5 differential diagnosis 149.4, 180.5 history 180.2 obsessive 180.8 treatment 180.5–180.6, 180.11 triclosan, newborn infants 5.6 triglycerides, serum, effects of retinoids 121.67–121.68 triglyceride storage disease see neutral lipid storage disease trimethoprim-sulphamethoxazole (TMP-SMX; co-trimoxazole) chronic granulomatous disease 177.12 HIV-related hypersensitivity 52.4 mycetoma 63.6 nocardiosis 63.28 Wegener granulomatosis 167.6 trioxilins 121.26, 121.34 trisomies 116.3–116.4 trisomy 8, mosaic 116.15, 116.15 trisomy 12, mosaic 116.12 trisomy 13 (Patau syndrome) 116.10 trisomy 14, mosaic 116.12 trisomy 18 (Edwards’ syndrome) 116.8–116.9, 116.16 trisomy 21 see Down syndrome trombiculid mites bite reactions 71.4–71.5 biting behaviour 71.7, 71.7 scrub typhus transmission 61.9 tropical spastic paraparesis (TSP) 53.4 tropical ulcer 66.1–66.5 acute 66.2–66.3, 66.3 aetiopathogenesis 66.2, 66.2 chronic 66.3, 66.3, 66.5 clinical features 66.2–66.3, 66.3 differential diagnosis 66.4, 66.4 tropical warble fly 69.1–69.2 TRPS see trichorhinophalangeal syndrome TRPS1 gene 127.79 True Test®, patch testing 44.5 trunk atopic dermatitis 28.1, 28.2 tissue expansion 191.5, 191.6 TSC1 gene 129.1, 129.3, 129.4 TSC2 gene 129.1, 129.2–129.3, 129.4 tsetse flies 71.7 T-shirt-and-shorts pattern, pityriasis rosea 84.2 TTD-A gene defects 135.6, 135.21, 148.12 TTD-A protein 135.3, 135.4 TTDN1 gene mutations 135.5, 135.6, 135.21 Tubegauz® wet dressings, eczema 192.5, 192.6 tuberculids, papulonecrotic 57.3 tuberculosis congenital 8.5, 8.6 cutaneous 57.2–57.5 diagnosis 57.4 endogenous source 57.2, 57.3 haematogenous source 57.2, 57.3 inoculation, exogenous source 57.2–57.3 treatment 57.4–57.5

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Index

tuberculosis (cont.) erythema induratum of Bazin 77.16 erythema nodosum 57.3–57.4, 57.4, 77.2 fish 57.7 genital area 151.11 global epidemiology 57.1 oroficial 57.3 TNF-α blocker therapy and 182.4 warty 57.3 tuberculosis cutis verrucosa 57.3 tuberculous abscesses, metastatic subcutaneous 57.3 tuberin 129.1, 129.3, 137.8 tuberous sclerosis complex (TSC) 129.1–129.12 aetiology and pathogenesis 129.1–129.3 associated malignancies 137.5 clinical features 129.4–129.9 course and prognosis 129.10 diagnostic criteria 129.2, 129.10 genetics 115.27, 129.1, 129.3–129.4 hypomelanotic macules 104.2, 104.3, 129.6, 129.6, 129.7 oral lesions 147.17 patient advocacy groups 129.12, 179.7 periungual fibromas 129.6–129.7, 129.7, 129.12, 150.7 prenatal diagnosis 129.10 prevalence 129.1 treatment 129.10–129.12 vs. vitiligo 105.5 tubers historical description 129.1, 129.2 neuroimaging 129.3, 129.3, 129.4 Tubifast® wet dressings, eczema 192.6 tufted angioma (TA) 113.23–113.24 clinical features 113.23, 113.24 differential diagnosis 112.15, 113.24 histopathology 4.5, 4.5, 113.23 Kasabach–Merritt phenomenon 113.24–113.26 tufted folliculitis 148.18, 148.18 tumbu fly 69.1–69.2 tumoral calcinosis 95.4, 95.4–95.5 familial (FTC) 95.4–95.5 secondary or uraemic 95.8 tumour(s) biopsy, fetal 17.3 genitalia 151.20–151.21 Proteus syndrome 111.5–111.6, 111.6 skin see malignant skin tumours; skin tumours see also cancer tumour necrosis factor-α (TNF-α) 181.17, 182.1–182.2 atopic dermatitis 24.3, 25.5 graft-versus-host disease 178.2 tumour necrosis factor-α (TNF-α) blockers 181.17, 182.1–182.10 juvenile dermatomyositis 175.12 juvenile idiopathic arthritis 175.4 other considerations 182.8 periodic fever (autoinflammatory) syndromes 176.2, 176.3 psoriasis 82.5 safety 82.5–82.6 Wegener granulomatosis 167.6 see also adalimumab; etanercept; infliximab tumour necrosis factor-like/NF-κB signalling pathway 127.65–127.68, 127.67 mutations 127.65–127.73, 127.66 tumour necrosis factor receptor-associated periodic syndromes (TRAPS) 74.9, 176.2, 176.3 tumour necrosis factor type 2 (TNF-2) allele, linear IgA disease of childhood 89.6 Tuomaala syndrome 127.10 turban tumours 137.10 Turcot syndrome 109.10 Turner syndrome antenatal diagnosis 114.20 benign melanocytic naevi 109.13, 116.12 café-au-lait spots 116.12 cutis verticis gyrata 10.1, 10.2

eczema 116.8 hypertrichosis 116.16 keloid scar formation 116.10–116.11 lymphatic disorders 114.7–114.8, 114.15, 116.9 twenty-nail dystrophy (TND) (trachyonychia) 150.5, 150.5–150.6 idiopathic 150.5 lichen planus 85.5, 85.5, 150.5, 150.6 twin spotting see didymosis twin studies 115.7 TYK2 gene mutations 177.11, 177.22 tylosis see Howel–Evans syndrome Tyndall effect 109.22, 189.5–189.6 typhus 61.2, 61.6–61.10 epidemic (louse-borne) 61.2, 61.6–61.8 murine (flea-borne) 61.2, 61.8 scrub 61.2, 61.9, 61.9–61.10 sylvatic 61.2, 61.7 TYR gene mutations 138.7–138.8 tyrosinaemia 169.4–169.5 type I (hepatorenal) 169.4 type II (oculocutaneous) 115.26, 169.4–169.5 palmoplantar keratoderma 120.19 prenatal diagnosis 139.3 tyrosinase 138.1, 138.7 tyrosine kinase inhibitors (TKI) dermatofibrosarcoma protuberans 99.7 hypereosinophilic syndrome 36.8 keratinocytic epidermal naevi 110.10 mastocytosis 75.12 TYRP1 gene mutations 138.8 Tzanck smear 8.2 UBR1 gene mutations 127.68 ULBP genes 149.2 ulcerative colitis 157.1 bullous pemphigoid with 91.16 linear IgA disease and 89.3 oral lesions 147.8 ulcers/ulceration bacterial, vs. leishmaniasis 67.11–67.12, 67.12 chromosome disorders 116.10 dystrophic epidermolysis bullosa 118.12 genital see genital ulcers immunodeficiency syndromes 177.2–177.3 infantile haemangiomas 113.6–113.8, 113.7, 113.8, 188.8, 188.8 junctional epidermolysis bullosa 118.31, 118.32 juvenile dermatomyositis 175.11 oral see oral ulceration subcutaneous fat necrosis 7.1, 7.2 tropical 66.1–66.5 vesiculobullous disease 87.1, 87.2 ulcus vulvae acutum 151.13 ulerythema ophryogenes see keratosis pilaris atrophicans faciei ulnar mammary syndrome (of Pallister) 127.62 ultrasonography antenatal diagnosis 114.20 arteriovenous malformations 112.2 infantile haemangioma 113.11 morphoea 173.8 venous malformations 112.9 ultraviolet A (UVA) 108.2, 108.3 cutaneous effects 108.4–108.5, 108.6, 108.7, 108.8 polymorphic light eruption 106.2 protection in sunscreens 108.13, 108.13, 181.13 provocation testing actinic prurigo 106.5, 106.5 solar urticaria 106.7, 106.7 psoralen photosensitization 45.8 sun protection factor 108.14 ultraviolet A (UVA) therapy psoralens with see photochemotherapy UVA1, morphoea 173.9 ultraviolet B (UVB) 108.2, 108.3 cutaneous effects 108.4–108.5, 108.6, 108.7, 108.8 protection in sunscreens 108.13, 108.13, 181.13 sun protection factor 108.14

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

ultraviolet B (UVB) therapy actinic prurigo 106.5–106.6 alopecia areata 149.6 narrowband (NB-UVB) (TL-01) atopic dermatitis 30.11 polymorphic light eruption 106.3 psoriasis 82.3 vitiligo 105.7 psoriasis 82.2, 82.3 vitiligo 105.7 ultraviolet C (UVC) 108.2, 108.3 ultraviolet-damaged DNA-binding protein (UV-DDB) 135.3 ultraviolet protection factor (UPF) 108.16–108.17 ultraviolet (UV) radiation 108.1, 108.2, 108.2–108.9 acquired melanocytic naevi and 109.12 addiction 108.9 artificial sources 108.4 basal cell carcinoma risk 99.1 cutaneous defences 108.11–108.12 cutaneous effects 108.4–108.9 early 108.5–108.8 late 108.8–108.9 optical properties 108.4, 108.4–108.5 DNA damage 108.4, 135.2 neonatal lupus erythematosus and 14.4, 14.6 properties 108.2, 108.2–108.3 protection from exposure see photoprotection sensitivity Cockayne syndrome 135.17 Gorlin syndrome 132.4 see also photosensitivity solar radiation 108.3–108.4 sources 108.3–108.4 vitamin D synthesis 108.6 see also sun exposure Umbelliferae 45.10, 45.11 umbilical arterial catheterization, complications 17.6, 17.7 umbilical polyp 10.9 umbilical sinus 10.9 umbilicus cleansing 5.2 developmental abnormalities 10.8–10.9 infections (omphalitis) 9.3 UNC13D gene mutations 177.8 UNC13D mutations 103.17–103.18 UNC93B1 gene 177.11 Uncinaria stenocephala 68.1 uncombable hair, retinal pigmentary dystrophy, dental anomalies and brachydactyly 127.62 uncombable hair syndrome 148.15, 148.15–148.16 UNG gene mutations 177.26 ungual fibromas, tuberous sclerosis 129.6–129.7, 129.7, 129.12 uniparental disomy 115.5, 115.5, 116.5–116.6 DNA-based prenatal diagnosis and 139.6 United States (USA), paediatric dermatology 1.3 unruly hair see hair, unruly urachal cyst 10.9 urachus, patent 10.9 Urbach–Wiethe syndrome 97.19–97.20 urea-containing products ichthyoses/MEDOC 121.66 toxicity to newborn 5.7 urethral prolapse 155.5, 155.6 urethritis Chlamydia 153.13 differential diagnosis 153.11 gonococcal 153.10 Urgotul® dressings, epidermolysis bullosa 118.18, 118.32 urine, napkin dermatitis 19.2 urocanic acid (UCA) 23.7, 23.8 trans-urocanic acid (tUCA) 27.2 uroporphyrin 107.5, 107.7 uroporphyrinogen decarboxylase (UROD) 107.4–107.6

Index deficiency 107.5–107.6 gene 107.3, 107.5, 107.12–107.13 uroporphyrinogen III synthase (UROS) 107.4 deficiency 107.4 gene 107.3, 107.4 urticaria 74.1–74.13 acute 74.11 aetiology 74.2–74.6, 74.3 aquagenic 74.6 cholinergic 74.5, 74.5–74.6 chronic 74.11, 74.12 clinical features 74.1, 74.2, 74.10–74.11 cockade pattern 74.10, 74.10 cold see cold urticaria contact, sunscreens 108.15 cystic fibrosis 170.3 differential diagnosis 74.11, 74.11, 163.4 drug-induced 74.3–74.4, 183.2, 183.2–183.3 exercise-associated 74.6 food allergies 31.5, 31.6, 45.4, 74.4 genetic disorders associated with 74.7, 74.8–74.9 heat 74.5 idiopathic 74.10–74.13 newborn infants 8.1 papular (PU) 71.1–71.8 pathogenesis 74.1–74.2 physical 74.5–74.6 genetic 74.8–74.9 plants/plant products 45.3–45.4, 45.4 pressure-induced 74.6 prognosis 74.11 solar see solar urticaria systemic disease associated 74.7, 74.7–74.8 treatment 74.11–74.13, 74.12 vibratory 74.6 see also anaphylaxis; angioedema Urticaria 45.3, 45.3 urticarial vasculitis 163.1–163.5 aetiology and pathogenesis 163.1–163.2, 163.2 clinical features 163.2, 163.2, 163.3 diagnosis 163.4, 163.4 differential diagnosis 163.4–163.5 epidemiology 163.1 histopathology 4.6, 4.6, 4.7, 163.2–163.4, 163.3 hypocomplementaemic 163.1, 163.4, 163.5 immunohistopathology 163.4 treatment 163.5 urticaria multiforme 74.10, 163.4–163.5 urticaria neonatorum see erythema toxicum neonatorum urticaria pigmentosa see mastocytosis, maculopapular cutaneous urushiols 45.5, 45.7 ustekinumab 182.13 uta 67.1, 67.7 uterine leiomyomas (fibroids) 137.13 utility measures, atopic dermatitis 29.14 UV see ultraviolet uveitis Blau syndrome 158.9 etanercept therapy 182.3 juvenile idiopathic arthritis 175.3 Kawasaki disease 168.3–168.4, 168.4 sarcoidosis 158.4 uveoparotid fever 158.4 UV Index (UVI) 108.17, 108.17 vaccination atopic dermatitis 30.2 bullous pemphigoid after 91.16 complications in neonates 17.11 genetic skin diseases 140.17 historical aspects 51.8 local, warts 47.9 morphoea development and 173.1 tuberous sclerosis 129.11 urticarial reactions 74.5 vaccinia 51.8–51.15 autoinoculation 51.11, 51.12, 51.12 contact (accidental) 51.11, 51.12, 51.12, 51.13

fetal 51.13 gangrenosum (VG) 51.13 generalized (GV) 51.11, 51.13 progressive (PV) (vaccinia necrosum; VN) 51.11, 51.13, 51.13 vaccinia immune globulin (VIG) cowpox 51.17 monkeypox 51.19 smallpox 51.8 smallpox vaccination complications 51.14 vaccinia virus (VACV) 51.8 immune response 24.7, 51.10 recombinant 51.10 vaccination see smallpox vaccination vacuum-assisted closure (VAC) therapy 187.13 vacuum extractors, neonatal injuries 17.4, 17.5 vacuum ultraviolet (UV) light 108.2, 108.2 vagina 152.1 chlamydial infections 153.14, 153.15 foreign bodies 151.19–151.20, 152.2 rhabdomyosarcoma 99.5, 99.5 sampling methods 152.3–152.4 vaginal bleeding, prepubertal child 151.20 vaginal discharge foreign bodies 151.20 gonorrhoea 153.10 investigations 152.3 normal variant 151.24 vulvovaginitis with 152.1–152.2, 152.3 vaginal intraepithelial neoplasia (VaIN) 47.6 vaginitis 152.1 bacterial (BV) 153.22–153.23 see also vulvovaginitis valaciclovir 181.16–181.17 herpes zoster 49.14 HSV infections 48.6–48.7, 153.20, 153.22 varicella 49.13 validity atopic dermatitis diagnostic criteria 28.14 atopic dermatitis severity scales 29.1–29.2, 29.2 quality of life measures 29.9–29.10 vancomycin, red man syndrome 11.8 van der Woude syndrome 10.7, 115.28 vanishing bone disease 112.13, 114.17 vanishing creams 181.4 van Lohuizen syndrome 112.19 variably charged X (VCX3A) gene defects 121.11, 121.12–121.13 variants of unknown significance (VUS), DNA 116.3 varicella (chickenpox) 49.12–49.13 anetoderma 145.12, 145.13, 145.13 clinical features 49.12, 49.12–49.13 congenital 8.3, 8.3, 8.4, 49.13 neonatal scarring lesions 16.6 differential diagnosis 49.10, 49.13 genital area 151.11, 151.11 HIV-infected children 52.2–52.3, 52.3 immunocompromised children 49.13, 64.7 napkin area 20.12, 151.11, 151.11 neonatal 9.6 oral lesions 147.6 postinfectious purpura fulminans 162.3, 162.5 clinical features 162.2, 162.9, 162.10, 162.11 pathogenesis 162.5, 162.6 treatment 162.12 vaccination 49.13, 49.14 varicella-zoster immunoglobulin (VZIG) 9.6 varicella-zoster virus (VZV) 49.12 identification 49.13, 49.14 reactivation, herpes zoster 49.13 varicella-zoster virus (VZV) infections HIV-infected children 52.2–52.3, 52.3 ichthyoses 121.64 immunocompromised children 64.7 varicose ulcer 66.4 varicose veins, chromosome disorders 116.13 variola major see smallpox variola minor (alastrim) 51.3 variola sine eruptione 51.4, 51.4 variolation 51.8

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vascular abnormalities chromosome disorders 116.12–116.13 surgical treatment 186.7, 186.7 systemic sclerosis 174.5 vascular anomalies classification 112.1, 112.2, 113.1, 113.2 hereditary 115.26 histopathology 4.4–4.6 laser treatment 188.1–188.11 occult spinal dysraphism 10.17 patient advocacy group 179.7 see also vascular malformations; vascular tumours vascular endothelial growth factor-C (VEGF-C) 114.1, 114.2 vascular endothelial growth factor-D (VEGF-D) 114.1, 114.2 vascular endothelial growth factor receptor 3 (VEGFR3) 114.1–114.2 vascular malformations 112.1–112.20 classification 112.1, 112.2 complex combined 4.5, 114.16 epidermal naevi and 110.20 fast-flow 112.1–112.6 genital area 151.6, 151.6–151.7, 151.7 histopathology 4.4–4.5 nursing care 192.7–192.10, 192.13, 192.14 oral 147.14–147.15 patient advocacy group 179.7 Proteus syndrome 111.4 slow-flow 112.7–112.20 see also specific types vascular malformations–dysregulated growth syndromes aetiology and pathogenesis 111.1–111.3 classification 111.1, 111.2 see also CLOVE syndrome; Proteus syndrome vascular sclerosis, multifocal 104.9 vascular tumours 113.1–113.27 classification 112.1, 112.2, 113.2 histopathology 4.5 Kasabach–Merritt phenomenon 113.24–113.26 multifocal 113.20 vasculature, cutaneous see blood vessels, skin vasculitides, systemic antineutrophil cytoplasmic antibody (ANCA)-associated (AAV) 167.1–167.14 purpura fulminans 162.4, 162.6–162.7, 162.12 vasculitis Behçet disease 167.15 cystic fibrosis 170.3, 170.4 granuloma annulare 93.4 histopathology 4.6, 4.6–4.7, 4.7 immunodeficiency syndromes 177.2–177.3 Kawasaki disease 168.8 leucocytoclastic 4.6 acute haemorrhagic oedema of infancy 161.1–161.2 Henoch–Schönlein purpura 160.5, 160.5 HIV-infected children 52.5 urticarial vasculitis 163.2–163.3, 163.3 lymphohistocytic/lymphocytic acute haemorrhagic oedema of infancy 161.1, 161.2 epidemic typhus 61.7 pigmented purpuras 165.2 pityriasis lichenoides 4.6–4.7, 4.7 Rocky Mountain spotted fever 61.1, 61.2 meningococcal disease 55.12 nodular 77.16 Sweet syndrome 156.1, 156.3 systemic lupus erythematosus 175.6, 175.6 urticarial see urticarial vasculitis Wegener granulomatosis 167.2 V Beam Perfecta® laser 188.3, 188.3 VCX3A gene defects 121.11, 121.12–121.13 vegetable oils infantile seborrhoeic dermatitis 35.6 premature neonate skin care 5.5 skin barrier function and 27.16 VEGFR3 gene 114.4

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Index

vehicles 181.6–181.7 contact allergy to 44.11 drug penetration through skin and 181.4 Veldt sore 66.4 vellus hair cysts, eruptive 92.6–92.7, 92.7 Venereal Disease Research Laboratory (VDRL) test 153.4, 153.6 venous malformations (VMs) 112.7–112.12 clinical features 112.8, 112.8–112.9 differential diagnosis 112.9–112.10 familial multiple cutaneous and mucosal (VMCM) 112.7, 112.11, 115.26 genital area 151.6, 151.6 histopathology 4.4, 4.4, 112.7–112.8 inherited 112.11–112.12 intraoral 147.14–147.15 localized or extensive 112.7–112.11 prognosis 112.9 radiological imaging 112.9, 112.9 syndromic 112.11 treatment 112.10 venous ulcers, chromosome disorders 116.10 ventouse, neonatal injuries 17.4, 17.5 verapamil, dystrophic epidermolysis bullosa 118.23 ver du cayor 69.1–69.2 ver macaque 69.1–69.2 vernix caseosa 3.1–3.2 composition 3.1, 3.1–3.2 excessive, MEDOC 121.5 removal at birth 5.1 verrucae see warts verrucous lesions, incontinentia pigmenti 130.2–130.3, 130.3 verruga peruana 58.2, 58.8 clinical features 58.9, 58.9, 58.10 differential diagnosis 58.9–58.10 see also bartonellosis vertebral anomalies, Gorlin syndrome 132.9, 132.9 vertical transmission HIV infection 52.1 HPV infections 47.3 vesicles 87.1, 87.2 clinical assessment 87.1–87.2 vesicular eczema of palms and soles see pompholyx vesiculobullous disorders/lesions 87.1–87.10 age of onset 87.5–87.6 autoimmune 87.8 cleavage planes 87.1–87.2, 87.3 clinical features 87.1–87.2 congenital erythropoietic porphyria 107.11 cutaneous larva migrans 68.3, 68.3 dermatitis herpetiformis 90.4 diagnostic algorithm 87.2–87.4, 87.3, 87.3 drug reactions 87.5, 87.5 family history 87.6, 87.6–87.7 genital area 151.12–151.16 investigations 87.4 napkin dermatitis 20.3, 20.12 neonates 87.6, 87.6–87.7 oral lesions 87.10, 147.9 porphyria cutanea tarda 107.8, 107.8–107.9 purpura fulminans 162.8, 162.9 subepidermal autoimmune diseases 91.13 systemic illness with 87.4–87.5 terminology 87.1, 87.2 vs. child abuse 154.11 vulva 152.2 vesiculopustular lesions congenital 8.1, 8.2 scabies in infants 72.4, 72.4, 72.7 vesiculous stomatitis virus (VSV-G) 140.2–140.3 vespids 73.2 vestibular schwannomas 128.12, 128.13 vestibule, vaginal 152.1 vigabatrin, tuberous sclerosis 129.10 vinblastine 98.2, 181.17 vincristine 181.17

infantile haemangiomas 113.18 Kasabach–Merritt phenomenon 113.26 viral exanthems 49.1–49.20 classic 49.1–49.8 hyperpigmentation 104.5 neonates 9.6 non-specific 49.19 other well-recognized 49.8–49.18 uncertain aetiology 49.19–49.20 viral infections atopic dermatitis 24.7, 28.8–28.9 congenital 8.3, 8.3, 8.4 genital 151.10–151.11 Gianotti–Crosti syndrome 50.1–50.2 HIV-infected children 52.2–52.4 lichen striatus and 86.2 neonatal 9.5–9.6 oral 147.4–147.6 postinfectious purpura fulminans 162.3, 162.5 primary immunodeficiencies 64.2, 64.3 secondary immunodeficiencies 64.7–64.8 severe ichthyoses 121.64 vesiculobullous lesions 87.4, 87.4–87.5, 87.8 vulvovaginitis 152.2 Virchow cells 70.4, 70.4 virilization, scrotal hair in infants 148.32 viruses causing urticaria 74.3 pityriasis lichenoides and 100.1 triggering graft-versus-host disease 178.3 virus vectors self-inactivating (SIN) 140.3–140.4 skin gene therapy 140.2–140.5, 140.3 visceral leishmaniasis (VL) (kala-azar) 67.9–67.10 congenital 67.9 diagnosis 67.11 differential diagnosis 67.12 history 67.1, 67.2 post-kalazar-dermal leishmaniasis 67.9–67.10 prognosis 67.13 treatment 67.12–67.13 visible light 108.2, 108.2 visual impairment see blindness vitamin A 65.4, 171.1 deficiency 65.4–65.5, 171.4 measles and 49.2 phrynoderma 123.3 excess 65.5 ichthyoses/MEDOC 121.66 metabolism 171.1, 171.2 inherited defects 171.2–171.3 pityriasis rubra pilaris and 83.1 normal serum levels 171.2 supplementation 65.5 measles 49.3 metabolic carotenaemia 171.5 see also β-carotene vitamin B2 deficiency 65.5 vitamin B3 see niacin vitamin B6 see pyridoxine vitamin B12 (cyanocobalamin) 65.6 deficiency 65.6 hyperpigmentation 104.8 sore tongue 147.24 vitamin C deficiency 65.6 vitamin D 108.5–108.6 calcium metabolism 95.1–95.2 deficiency 108.5 avoidance 109.21 excess 95.8, 108.5–108.6 ichthyoses/MEDOC 121.66–121.67 supplementation 108.5–108.6 synthesis 108.6 vitamin D2 (ergocalciferol) 108.5 vitamin D3 (cholecalciferol) 108.5 vitamin D analogues 181.14 Albright hereditary osteodystrophy 95.12 porokeratosis 126.4 prurigo nodularis 42.5 psoriasis 82.2–82.3 warts 47.8–47.9

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

vitamin D-dependent rickets, atrichia 148.6 vitamin deficiencies 65.4–65.7 hyperpigmentation 104.8 vitamin D receptor mutations 148.6 vitamin D-resistant rickets hypophosphataemic, epidermal naevi with 110.19–110.20 phacomatosis pigmentokeratotica 110.14, 110.19 vitamin H see biotin vitamin K, pseudo-xanthoma elasticum 144.2, 144.8 vitamin PP see niacin vitamin supplements dystrophic epidermolysis bullosa 118.23 pseudo-xanthoma elasticum 144.8 vitelline cyst 10.9 vitiligo 105.1–105.8 aetiology and pathogenesis 105.1 associated autoimmune diseases 105.4–105.5 associated skin conditions 105.4 classification and distribution 105.3–105.5 clinical features 105.2, 105.2–105.3, 105.3, 105.4 congenital 105.2 differential diagnosis 105.5–105.6 epidemiology 105.2 familial background 105.5 Koebner phenomenon 105.4 laser treatment 105.7, 189.10 lichen sclerosus and 152.6–152.7, 152.7 non-segmental 105.1, 105.3–105.4 pathology 105.1–105.2 patient advocacy groups 179.7 prognosis 105.6 psychological effects 105.3 segmental 105.1, 105.3, 105.5 differential diagnosis 104.3, 131.5 pathophysiology 105.1 treatment 105.6–105.8 trichrome 105.2 Vogt–Koyanagi–Harada syndrome 105.6 Vohwinkel-like palmoplantar keratodermadeafness 120.21, 127.92 Vohwinkel syndrome 120.21–120.22, 122.4, 127.92 differential diagnosis 120.7, 122.13 molecular pathology 115.21, 120.21, 120.21–120.22 Voigt lines 104.9 volar pads, development 2.29, 2.30 von Hippel–Lindau disease 137.5 voriconazole, fusariosis 63.22 vulva anatomical abnormalities 151.16, 151.16 anatomy and physiology 152.1 bullous pemphigoid 151.12, 151.12 dermatitis 151.2, 151.3, 152.2–152.3 epidermal naevi 151.5–151.6, 151.6 fixed drug eruptions 151.14 idiopathic calcinosis 95.3 lichen sclerosus 152.5–152.6, 152.6 mucous membrane pemphigoid 91.19, 151.12–151.13 neoplasia 151.20–151.21 neuropathic pain 151.24 papular acantholytic dyskeratosis 151.7 vascular malformations 151.6, 151.6–151.7, 151.7 vulval disease 151.1 differentiation from sexual abuse 151.24–151.25 psychological aspects 151.24 see also genital disease/area vulval fibroma, prepubertal 151.21 vulval intraepithelial neoplasia (VIN) 47.6, 151.20 vulvar pemphigoid, localized juvenile 91.13, 91.13–91.14, 91.17–91.18 autoantibodies 91.15, 91.17 clinical features 91.17, 91.17

Index vulvitis 152.2–152.3 see also vulvovaginitis vulvovaginal warts 47.6, 47.6 vulvovaginitis 152.1–152.4 aetiology and pathogenesis 152.1–152.3 candidal 152.2 clinical features 152.3 diagnosis 152.3–152.4 differential diagnosis 153.11, 155.5 gonorrhoea 153.10, 153.12 infectious causes 152.2 streptococcal 151.8–151.9 treatment 152.4 Trichomonas vaginalis 153.21 with vaginal discharge 152.1–152.2 Waardenburg–Shah syndrome 138.2, 138.6 Waardenburg syndrome (WS) 138.2, 138.5–138.6 clinical features 138.5, 138.5–138.6 genetic basis 115.25, 138.6 Walbaum–Dehane–Schlemmer syndrome 127.63 Wangiella 63.8 warble fly 69.2–69.3 warfarin dystrophic calcification 95.6 transcutaneous intoxication 184.10 warts (verrucae) 47.1 affecting naevus sebaceous 110.4–110.5 anogenital see condyloma acuminata butcher’s 47.5 categories 47.3 common (verrucae vulgaris) clinical features 47.3–47.4, 47.4 management 47.11 prevalence 47.1 cystic 47.5 deep plantar (myrmecia) 47.4 differential diagnosis 47.7 doughnut/ring 47.5, 47.5 epidermodysplasia verruciformis 47.5 external genital (EGW) clinical features 47.6, 47.6–47.7, 47.7 management 47.11 transmission 47.3 filiform/digitate 47.4 histology 47.7 HIV infection 52.4, 52.4 immunity 47.1–47.2 immunocompromised children 64.7 immunodeficiency syndromes 177.2–177.3 laser treatment 47.8, 189.7–189.8 mosaic 47.4, 47.5 penile 47.7, 47.8 perioral 147.19 periungual 47.4, 47.5, 150.3 plane/flat (verruca plana) 47.4, 47.4 prevalence 47.1 ‘prosector’s’ 57.2–57.3 punctate 47.4 regression 47.2 subungual 47.4, 150.3 treatment 47.8–47.11, 47.10, 181.9 vulvovaginal 47.6, 47.6 see also human papillomavirus (HPV) infections warts, hypogammaglobulinaemia, infections, myelokathexis syndrome see WHIM syndrome washing atopic dermatitis 27.16, 30.4–30.5 newborn infant 5.1–5.2 washing powders, atopic dermatitis and 30.3 WASP gene 177.10, 177.33 wasps 73.2 water hardness, atopic dermatitis and 22.7, 22.12, 27.6, 27.16 transepidermal loss see transepidermal water loss water-filtered infrared-A (wIRA) irradiation, warts 47.9

water-in-oil emulsions 181.4 infantile seborrhoeic dermatitis 35.6 Watson syndrome 109.10, 128.8 wattles 10.2, 10.3, 10.3 wax tree 45.5 Weber–Christian disease 77.1, 77.13 weever fish, lesser 73.9 Wegener granulomatosis (WG) 167.1–167.8 aetiology and pathogenesis 167.2 clinical features 167.3, 167.3–167.6, 167.4, 167.5, 167.5 diagnostic criteria 167.1 pathology 167.2–167.3, 167.3 prognosis 167.6 treatment 167.6 Weil–Felix test 61.10 Wells syndrome 36.9–36.11 Werner syndrome 134.3–134.4 aetiology 115.28, 134.4 associated malignancies 137.5 dystrophic calcification 95.7 West, Charles 1.1–1.2 Weston, William 1.3 wet-combing method, head lice 72.13 wet wrap dressings atopic dermatitis/eczema 30.8, 192.4, 192.5, 192.6, 192.6 pompholyx 39.4 Weyer acrofacial dysostosis 127.63, 127.79 wheat allergy 31.6 atopic eczema 31.3, 31.4 dietary restriction 31.17 WHIM syndrome 177.3, 177.26 skin infections 64.2 warts 47.2 white footprints in the snow appearance, lichen planopilaris 85.6 white forelock piebaldism 138.4 Waardenburg syndrome 138.6 whiteheads 79.5 white patches, oral see oral leucoplakia white piedra 62.31, 62.32 white sponge ‘naevus’ of Cannon (white sponge hyperplasia of mucosa) 117.6–117.7, 147.10 clinical features 117.7, 147.10 molecular basis 115.21, 127.95 whitlow, herpetic 48.3, 48.3–48.4 WHN gene 177.31 Wickham’s striae 85.1, 85.4, 85.4 widow spiders (Latrodectus) 73.5, 73.5–73.6 Wiedemann–Rautenstrauch syndrome 134.5–134.6 WILD syndrome 114.10–114.11 Willan, Robert 1.1 William syndrome 116.16 Wilson disease 65.7 Wilson–Turner syndrome 141.10 Winchester syndrome 148.31 Winer’s nodular calcinosis 95.3, 95.3 winged helix nude deficiency 177.31 Wiskott–Aldrich syndrome (WAS) 177.32–177.34 associated malignancies 137.5 clinical features 177.3, 177.33, 177.33–177.34 differential diagnosis 28.10, 177.34 neonatal erythroderma 11.10 pathogenesis 115.28, 177.33 skin infections 64.2 treatment 177.34 Witkop syndrome 127.63, 127.79 WNT4 gene mutations 120.9 WNT10A gene mutations 120.10, 127.83 Wnt-β-catenin pathway defects ectodermal dysplasias 127.83–127.88, 127.84 focal dermal hypoplasia 127.87, 133.5 odonto-onychodermal dysplasia 120.10, 127.83–127.85 palmoplantar hyperkeratosis with squamous cell carcinoma and sex reversal 120.9

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Wohlfahrtia 69.3–69.4 Wohlfahrtia magnifica 69.3 Wohlfahrtia vigil 69.3 Wolf–Hirschorn syndrome 116.10, 116.10 Wood’s light, erythrasma 56.3 woolly hair 148.16 associated syndromes 148.16 autosomal recessive 127.63, 148.16 chromosome disorders 116.15 hypotrichosis, everted lower lip and outstanding ears 127.64 naevus 110.9–110.10, 110.10, 148.17, 148.17 World Allergy Organization (WAO), classification of atopic dermatitis 28.11, 28.11 World Congresses of Pediatric Dermatology 1.2–1.3, 1.3 World Health Organization (WHO) leprosy 70.1, 70.9, 70.9 leprosy strategy 70.12 sunscreen recommendations 108.14 World Health Organization (WHO)-EORTC, cutaneous lymphoma classification 99.19, 99.20, 102.1, 102.1 wound contraction 187.2 myiasis 69.3 remodelling 17.1–17.2, 187.2 tensile strength 187.2 wound closure, surgical see surgical wound closure wound dressings see dressings wound healing 17.1–17.2, 187.1–187.2 burn wounds 187.16 delayed primary 187.10 fetal skin 3.6, 17.2 neonates 3.6 partial-thickness skin excision 186.2 primary 186.3, 187.2, 187.10 secondary 186.3, 187.2, 187.10 W-plasty, scar revision 187.9, 187.9 wrinkling, skin excessive/premature chromosome disorders 116.9 differential diagnosis 134.14 in water, cystic fibrosis 170.2–170.3 wrinkly skin syndrome 134.14 wrist sign, Marfan syndrome 145.7 WRN gene 134.4 WT1 gene testing, infantile eosinophilia 36.2 Wuchereria bancroftii 114.11 Wyburn–Mason syndrome 112.4 xanthelasma 169.14, 169.14 xanthodermia 171.1 xanthogranuloma adult (AXG) 103.10, 103.13, 103.14 juvenile see juvenile xanthogranuloma necrobiotic (NXG) 103.12, 103.14 xanthoma disseminatum (XD) 103.11, 103.13, 103.14 xanthomas diabetes mellitus 172.21 hyperlipoproteinaemias 169.13, 169.14, 169.14 verrucous, CHILD syndrome 110.18 X-autosome translocations 130.5–130.6 XEDAR 127.66, 127.68 xenon chloride excimer laser, 308-nm, vitiligo 105.7 Xenopsylla cheopis (rat flea) 61.8 xeroderma pigmentosum (XP) 135.5–135.14, 135.6 associated malignancies 135.8, 135.9, 137.3 basal cell carcinoma 99.1, 99.2, 135.8, 135.8 clinical features 135.7, 135.8, 135.8–135.9 complementation groups 135.6–135.7, 135.11, 135.11–135.14 A (XPA) 135.4, 135.11–135.12 B (XPB) 115.24, 135.12 C (XPC) 135.3, 135.4, 135.12 D (XPD) 135.12–135.13

76

Index

xeroderma pigmentosum (XP) (cont.) E (XPE) 135.4, 135.13 F (XPF) 135.13 G (XPG) 135.5, 135.13 differential diagnosis 135.9–135.10, 135.10 epidemiology 135.7–135.8 gene therapy 140.11 genotype-phenotype interactions 135.4 heterozygotes 135.23 histopathology 135.9 history 135.5–135.7 laboratory tests 135.10 melanoma 109.25, 135.8 with neurological symptoms 135.6, 135.7, 135.9, 135.11 pathogenesis 115.27, 135.2–135.5, 135.3 patient advocacy groups 135.24, 179.7 prenatal diagnosis 139.3 skin cancers 135.6, 135.8, 135.8, 135.11 treatment 135.10–135.11, 135.24 xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex 135.6, 135.18 clinical features 135.7, 135.15, 135.18 molecular basis 135.12, 135.13, 135.18 xeroderma pigmentosum/trichothiodystrophy (XP/TTD) complex 135.6, 135.21 xeroderma pigmentosum variant (XPV) 135.1, 135.11, 135.13–135.14 xeroderma–talipes–enamel defect (XTE syndrome) 127.64 xerosis see dry skin XIAP gene mutations 177.8 X-inactivation (lyonization) 115.3–115.4 CHILD syndrome 115.13, 115.13 Conradi-Hünermann-Happle syndrome (CDPX2) 121.55 escape from 115.4 focal dermal hypoplasia 133.5 pigmentary mosaicism 131.1, 131.2 X-linked male-lethal mutations 115.12, 115.12 X-linked agammaglobulinaemia (XLA) 177.25, 177.27 mucocutaneous findings 177.3 skin infections 64.2, 64.4 X-linked ectodysplasin-A2 receptor (XEDAR) 127.66, 127.68 X-linked recessive ichthyosis see recessive X-linked ichthyosis X-linked skin diseases 115.3, 115.3–115.4 fetal sexing 139.11 functional mosaicism male-lethal mutations 115.12, 115.12–115.13, 115.13 non-lethal mutations 115.13–115.14, 115.14

inheritance 115.4, 115.4 preimplantation sex typing 139.10 XPA gene defects 135.4, 135.6, 135.11–135.12 XPA protein 135.3, 135.4, 135.11–135.12 XPB gene defects 135.4, 135.6 trichothiodystrophy 135.21, 148.12 xeroderma pigmentosum 135.12 xeroderma pigmentosum/Cockayne syndrome complex 135.18 XPB protein 135.3, 135.4, 135.12 XPC gene defects 135.6, 135.12 editing, zinc finger nucleases 140.11 heterozygous carriers 135.23 XPC protein 135.3, 135.3, 135.12 XPD gene defects 135.4, 135.6 cerebro-oculo-facio-skeletal syndrome 135.21–135.22 trichothiodystrophy 135.21, 148.12 xeroderma pigmentosum 135.12–135.13, 135.21 xeroderma pigmentosum/Cockayne syndrome 135.18 XPD protein 135.3, 135.4, 135.12–135.13 XPE gene 135.13 XPE protein 135.3, 135.13 XPF gene defects 135.6 XPF protein 135.3, 135.4–135.5, 135.13 XPG gene defects 135.6 cerebro-oculo-facio-skeletal syndrome 135.21–135.22 xeroderma pigmentosum 135.13 xeroderma pigmentosum/Cockayne syndrome 135.18 XPG protein 135.3, 135.4–135.5, 135.13 X-rays, diagnostic see radiographs, plain X-ray therapy see radiation therapy XTE syndrome 127.64 XXY syndrome 116.15 XXYY syndrome 116.9, 116.10, 116.12 vascular abnormalities 116.13 yaws 60.1–60.7 aetiology 60.1, 60.2, 60.2 clinical features 60.3, 60.3–60.4, 60.4, 60.5 crab 60.3 differential diagnosis 60.5–60.6, 60.6, 66.4, 67.12 distribution 60.1–60.2 laboratory tests 60.6, 60.6 pathology 60.2, 60.2–60.3 prognosis 60.7 treatment 60.7

Volume 1, pp. 1.1–114.21; Volume 2, pp. 115.1–192.19

yeast infections neonatal 9.4–9.5 see also candidiasis; Malassezia yellow-jackets 73.2 yellow nail syndrome 114.11 Yemenite deaf–blind hypopigmentation syndrome 115.25 Yersinia pseudotuberculosis 147.24 Y-linked inheritance 115.4, 115.4 Young–Simpson syndrome 172.2 zafirlukast, urticaria 74.13 Zanier–Roubicek syndrome 127.64 ZAP-70 deficiency 177.31 zileuton granuloma annulare 93.8 Sjögren–Larsson syndrome 121.48 Zimmerman–Laband syndrome 148.29 zinc 65.8 deficiency 65.8 acrodermatitis enteropathica 65.8, 65.8, 169.15 cystic fibrosis 170.2 genital lesions 151.23 hair loss 148.20–148.21 napkin dermatitis 20.11 tropical ulcers 66.2 treatment, acrodermatitis enteropathica 65.8, 169.15 zinc and salicylic acid paste 192.4 zinc finger nucleases/metanucleases (ZFN) 140.11, 140.12 zinc oxide skin protectant 181.7 sunscreens 108.12, 108.15–108.16, 181.13 zinc sulphate, warts 47.9 zinc transporter 1 (ZnT1) 137.11 Zinsser–Cole–Engman syndrome see dyskeratosis congenita, X-linked Zlotogora–Ogur syndrome 127.13 ZMPSTE24 gene mutations mandibuloacral dysplasia 134.8, 134.9, 141.15 restrictive dermopathy 15.1, 15.3 zoster sine herpete 49.14 Z-plasty, scar revision 187.9, 187.9 Zunich neuroectodermal syndrome (Zunich– Kaye syndrome; CHIME syndrome) 121.45, 121.51–121.52 zygomycosis 63.22–63.24, 147.7