Hair Disorders: Diagnosis and Management (Series in Dermatological Treatment) 2021031153, 2021031154, 9781138611900, 9781032115108, 1138611905

Table of contents :
Cover
Half Title
Series Page
Title Page
Copyright Page
Contents
Contributors
1. Alopecia Areata
2. Male Androgenetic Alopecia
3. Female Androgenic Alopecia
4. Telogen Effluvium
5. Anagen Effluvium
6. Tinea Capitis
7. Trichotillomania
8. Traction Alopecia
9. Alopecia in Newborns, Infants, and Children
10. Lichen Planopilaris
11. Frontal Fibrosing Alopecia
12. Discoid Lupus Erythematosus
13. Fibrosing Alopecia in a Pattern Distribution
14. Central Centrifugal Cicatricial Alopecia
15. Folliculitis Decalvans
16. Dissecting Cellulitis
17. Acne Keloidalis Nuchae
18. Pseudopelade of Brocq
19. Other Causes of Scarring Alopecia
20. Hypertrichosis
21. Hirsutism
22. Hair Shaft Disorders
23. Disorders of Hair Pigmentation
24. Hair in Genetic Diseases
25. Hair in Dermatologic Disease
26. Hair in Systemic Disease
27. Scalp Infections and Infestations
28. Hair Cosmetic Problems
Index

Citation preview

Hair Disorders

Series in Dermatological Treatment About the Series

Published in association with the Journal of Dermatological Treatment, the Series in Dermatological Treatment keeps readers up to date with the latest clinical therapies to improve problems with the skin, hair, and nails. Each volume in the series is prepared separately and typically focuses on a topical theme. Volumes are published on an occasional basis, depending on the emergence of new developments.

Atlas of Genital Dermoscopy Giuseppe Micali and Francesco Lacarrubba Hair Disorders: Diagnosis and Management Alexander C. Katoulis, Dimitrios Ioannides, and Dimitris Rigopoulos Techniques in the Evaluation and Management of Hair Disease Rubina Alves and Juan Grimalt Retinoids in Dermatology Ayse Serap Karadag, Berna Aksoy, and Lawrence Charles Parish Facial Skin Disorders Ronald Marks Dermatologic Reactions to Cancer Therapies Gabriella Fabbrocini, Mario E. Lacouture, and Antonella Tosti Acne Scars: Classification and Treatment, Second Edition Antonella Tosti, Maria Pia De Padova, Gabriella Fabbrocini, and Kenneth Beer Phototherapy Treatment Protocols, Third Edition Steven R. Feldman and Michael D. Zanolli Dermatoscopy in Clinical Practice: Beyond Pigmented Lesions, Second Edition Giuseppe Micali and Francesco Lacarrubba Nail Surgery Bertrand Richert, Niton Di Chiacchio, and Eckart Haneke Abdominal Stomas and Their Skin Disorders, Second Edition Callum C. Lyon and Amanda Smith Textbook of Atopic Dermatitis Sakari Reitamo, Thomas A. Luger, and Martin Steinhoff For more information about this series please visit: https://www.crcpress.com/Series-in-Dermatological-Treatment/book-series/ CRCSERDERTRE

Hair Disorders Diagnosis and Management

Edited by Alexander C. Katoulis, MD, MSc, PhD Professor of Dermatology & Venereology Head of the Second Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School at “Attikon” University General Hospital, Athens, Greece

Dimitrios Ioannides, MD, PhD Professor of Dermatology & Venereology Head of the First Department of Dermatology Aristotle University of Thessaloniki at the Hospital for Skin and Venereal Diseases,Thessaloniki, Greece

Dimitris Rigopoulos, MD, PhD Professor of Dermatology & Venereology National and Kapodistrian University of Athens Director of “Andreas Syggros” Hospital for Skin and Venereal Diseases Athens, Greece

First edition published 2022 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN © 2022 Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Names: Katoulis, Alexander C., editor. | Ioannides, Dimitrios, editor. | Rigopoulos, Dimitris, editor. Title: Hair disorders : diagnosis and management / edited by Alexander C. Katoulis, Dimitrios Ioannides, Dimitris Rigopoulos. Other titles: Series in dermatological treatment. Description: First edition. | Boca Raton : CRC Press, 2021. | Series: Series in dermatological treatment | Includes bibliographical references and index. | Summary: “A comprehensive resource for the practicing dermatologist on how to diagnose and manage the range of hair disorders in patients. Extensive illustration accompanies each condition and shows the results of the latest diagnostic tools, including dermoscopy”–Provided by publisher. Identifiers: LCCN 2021031153 (print) | LCCN 2021031154 (ebook) | ISBN 9781138611900 (hardback) | ISBN 9781032115108 (paperback) | ISBN 9780429465154 (ebook) Subjects: MESH: Hair Diseases–diagnosis | Hair Diseases–therapy Classification: LCC RL151 (print) | LCC RL151 (ebook) | NLM WR 450 | DDC 616.5/46–dc23 LC record available at https://lccn.loc.gov/2021031153 LC ebook record available at https://lccn.loc.gov/2021031154

ISBN: 978-1-138-61190-0 (hbk) ISBN: 978-1-032-11510-8 (pbk) ISBN: 978-0-429-46515-4 (ebk) DOI: 10.1201/9780429465154 Typeset in Times New Roman by KnowledgeWorks Global Ltd.

Contents Contributors....................................................................................................................................................................................vii

1. Alopecia Areata........................................................................................................................................................................ 1 Andrew G. Messenger 2. Male Androgenetic Alopecia................................................................................................................................................. 15 Ralph M. Trüeb 3. Female Androgenic Alopecia................................................................................................................................................ 24 Demetrios Ioannides, Ilias Papadimitriou, and Efstratios Vakirlis 4. Telogen Effluvium.................................................................................................................................................................. 33 Aurora Alessandrini, Michela Starace, and Bianca Maria Piraccini 5. Anagen Effluvium.................................................................................................................................................................. 39 Vasiliki Chasapi 6. Tinea Capitis........................................................................................................................................................................... 49 Ricardo Romiti and Alessandra Anzai 7. Trichotillomania..................................................................................................................................................................... 57 Francesco Lacarrubba, Anna Elisa Verzì, and Giuseppe Micali 8. Traction Alopecia................................................................................................................................................................... 62 Raimonds Karls 9. Alopecia in Newborns, Infants, and Children..................................................................................................................... 68 Deniz Seçkin 10. Lichen Planopilaris................................................................................................................................................................ 80 Marcela Farid, Alessandra Nahas, and Antonella Tosti 11. Frontal Fibrosing Alopecia................................................................................................................................................... 85 Alexander C. Katoulis, Konstantina Diamanti, Evangelia Bozi, Georgia Pappa, and Sofia Georgala 12. Discoid Lupus Erythematosus.............................................................................................................................................. 93 Ilias Papadimitriou, Efstratios Vakirlis, and Dimitrios Ioannides 13. Fibrosing Alopecia in a Pattern Distribution...................................................................................................................... 96 Alexander C. Katoulis, Efthymia Soura, Konstantina Diamanti, and Evangelia Bozi 14. Central Centrifugal Cicatricial Alopecia.......................................................................................................................... 100 Joohee Han and Maria K. Hordinsky 15. Folliculitis Decalvans........................................................................................................................................................... 107 Anna Waśkiel-Burnat, Lidia Rudnicka, Małgorzata Olszewska, Adriana Rakowska, and Joanna Czuwara 16. Dissecting Cellulitis...............................................................................................................................................................110 Michela Starace, Aurora Alessandrini, and Bianca Maria Piraccini

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17. Acne Keloidalis Nuchae........................................................................................................................................................117 Mariya Miteva and Samar Sabiq 18. Pseudopelade of Brocq......................................................................................................................................................... 121 Adriana Rakowska and Joanna Czuwara 19. Other Causes of Scarring Alopecia.................................................................................................................................... 124 Carmen Gloria Gonzàlez, Vincenzo Piccolo, Teresa Russo, Michela Starace, and Giuseppe Argenziano 20. Hypertrichosis...................................................................................................................................................................... 129 Diana Morales Robles, Mariana Saldaña, Rosalia del Carmen Velez-Muñiz, Maria Abril Martinez Velasco, and Daniel Asz-Sigall 21. Hirsutism............................................................................................................................................................................... 146 Sergio Enrique Leal-Osuna, Jessica Gonzalez Gutierrez, Karla Iñigo Gomez, Pamela Orozco Olguin, Melanie Marmolejo Chavira, Angelica Flores Vidal, and Daniel Asz-Sigall 22. Hair Shaft Disorders............................................................................................................................................................ 160 Bengisu Orzalan, Lilian Mathias Delorenze, Michela Starace, Teresa Russo, Giuseppe Argenziano, and Vincenzo Piccolo 23. Disorders of Hair Pigmentation...........................................................................................................................................175 Nina L. Tamashunas and Wilma F. Bergfeld 24. Hair in Genetic Diseases...................................................................................................................................................... 187 Helena E. Fryssira-Kanioura 25. Hair in Dermatologic Disease............................................................................................................................................. 194 Gabriella Fabbrocini, Maria Carmela Annunziata, Mariateresa Cantelli, and Angela Patrì 26. Hair in Systemic Disease..................................................................................................................................................... 204 A. Tülin Güleç 27. Scalp Infections and Infestations.........................................................................................................................................217 Stamatis Gregoriou, Theodora Tsironi, Eftychia Platsidaki, and Dimitris Rigopoulos 28. Hair Cosmetic Problems...................................................................................................................................................... 225 Zoe Diana Draelos Index............................................................................................................................................................................................. 229

Contributors Aurora Alessandrini Department of Specialized Experimental and Diagnostic Medicine Division of Dermatology University of Bologna Bologna, Italy Maria Carmela Annunziata Department of Clinical Medicine and Surgery University of Naples Federico II Naples, Italy Alessandra Anzai Department of Dermatology Universidade de São Paulo Faculdade de Medicina São Paulo, Brazil

Melanie Marmolejo Chavira Dermatologist Clinica Dermalomas Mexico City, Mexico Joanna Czuwara Department of Dermatology Medical University of Warsaw Warsaw, Poland Lilian Mathias Delorenze Hospital Universitário Antonio Pedro Dermatology Department Fluminense Federal University Rio de Janeiro, Brazil

Giuseppe Argenziano Dermatology Unit Second University of Naples Naples, Italy

Konstantina Diamanti Dermatologist-Venereologist, Academic Scholar Second Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School “Attikon” General University Hospital Athens, Greece

Daniel Asz-Sigall Dermato-oncology and Trichology Clinic National University of Mexico Mexico City, Mexico

Zoe Diana Draelos Dermatology Consulting Services, PLLC High Point, North Carolina

Wilma F. Bergfeld Department of Dermatology Cleveland Clinic Foundation Cleveland, Ohio

Gabriella Fabbrocini Department of Clinical Medicine and Surgery University of Naples Federico II Naples, Italy

Evangelia Bozi Dermatologist-Venereologist Second Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School “Attikon” General University Hospital Athens, Greece

Marcela Farid Dermatology Division, Department of Medical Clinics University Hospital Ribeirão Preto Medical School University of São Paulo Ribeirão Preto, Brazil

Mariateresa Cantelli Department of Clinical Medicine and Surgery University of Naples Federico II Naples, Italy Vasiliki Chasapi Andreas Syggros Hospital of Cutaneous & Venereal Diseases Athens, Greece

Helena E. Fryssira-Kanioura Clinical Medical Genetics Medical School National and Kapodistrian University of Athens Athens, Greece Sofia Georgala Professor Emeritus National and Kapodistrian University of Athens Medical School Athens, Greece

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viii Karla Iñigo Gomez Dermato-oncologist Clínica Dermalomas Mexico City, Mexico Carmen Gloria Gonzàlez Clínica Dávila Santiago, Chile Stamatis Gregoriou 1st Department of Dermatology-Venereology University of Athens Medical School Athens, Greece Ayşe Tülin Güleç Department of Dermatology Baskent University Ankara, Turkey Jessica Gonzalez Gutierrez Dermato-oncologist Hospital Angeles Puebla Puebla, Mexico Joohee Han Department of Dermatology University of Minnesota Medical School Minneapolis, Minnesota Maria K. Hordinsky Department of Dermatology University of Minnesota Medical School Minneapolis, Minnesota Demetrios Ioannides Professor of Dermatology and Venereology First Department of Dermatology and Venereology Aristotle University of Thessaloniki Hospital for Skin and Venereal Diseases Thessaloniki, Greece Alexander C. Katoulis Professor of Dermatology and Venereology Second Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School “Attikon” General University Hospital Athens, Greece Raimonds Karls Dermatology Clinic of Health Centre 4 Riga, Latvia Francesco Lacarrubba Dermatology Clinic University of Catania Catania, Italy Sergio Enrique Leal-Osuna Dermatology Department Hospital Español Mexico City, Mexico

Contributors Andrew G Messenger Honorary Professor of Dermatology Department of Infection, Immunity and Cardiovascular Disease University of Sheffield Sheffield, United Kingdom Giuseppe Micali Dermatology Clinic University of Catania Catania, Italy Mariya Miteva Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, Florida Alessandra Nahas Nahas Clinique São Paulo, Brazil Małgorzata Olszewska Department of Dermatology Medical University of Warsaw Warsaw, Poland Pamela Orozco Olguin Dermato-oncologist Clínica Dermalomas Mexico City, Mexico Bengisu Orzalan Kırklareli State Hospital Dermatology and Venereology Clinic Kırklareli, Turkey Ilias Papadimitriou 1st Department of Dermatology-Venereology Aristotle University Medical School Thessaloniki, Greece Georgia Pappa Physician, Clinical Research Associate Second Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School “Attikon” General University Hospital Athens, Greece Vincenzo Piccolo Dermatology Unit Second University of Naples Naples, Italy Bianca Maria Piraccini Department of Specialized Experimental and Diagnostic Medicine Division of Dermatology University of Bologna Bologna, Italy

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Contributors Eftychia Platsidaki 1st Department of Dermatology-Venereology University of Athens Medical School Athens, Greece Adriana Rakowska Department of Dermatology Medical University of Warsaw Warsaw, Poland Dimitris Rigopoulos Professor of Dermatology and Venereology First Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School “Andreas Syggros” Hospital Athens, Greece Diana Morales Robles Dermato-oncologist Clínica Dermalomas Mexico City, Mexico Ricardo Romiti Department of Dermatology Universidade de São Paulo Faculdade de Medicina São Paulo, Brazil Lidia Rudnicka Department of Dermatology Medical University of Warsaw Warsaw, Poland Teresa Russo Dermatology Unit Second University of Naples Naples, Italy Samar Sabiq Consultant in Dermatology and Hair Disorders King Abdullah Medical Complex Jeddah, Saudi Arabia Mariana Saldaña Dermato-oncologist Clínica Dermalomas Mexico City, Mexico Deniz Seçkin Department of Dermatology Başkent University Faculty of Medicine Ankara, Turkey Efthymia Soura Dermatologist – Venereologist, Academic Scholar First Department of Dermatology and Venereology National and Kapodistrian University of Athens Medical School “Andreas Syggros” Hospital Athens, Greece

Michela Starace Department of Specialized Experimental and Diagnostic Medicine Division of Dermatology University of Bologna Bologna, Italy Nina L. Tamashunas Case Western Reserve University School of Medicine and Department of Dermatology Cleveland Clinic Foundation Cleveland, Ohio Antonella Tosti Department of Dermatology and Cutaneous Surgery University of Miami-Miller School of Medicine Miami, Florida Ralph M. Trüeb Professor of Dermatology University of Zurich and Center for Dermatology and Hair Diseases Wallisellen, Switzerland Theodora Tsironi 1st Department of Dermatology-Venereology University of Athens Medical School Athens, Greece Efstratios Vakirlis 1st Department of Dermatology-Venereology Aristotle University Medical School Thessaloniki, Greece María Abril Martínez Velasco Dermato-oncology and Trichology Clinic National University of Mexico Mexico City, Mexico Rosalía del Carmen Vélez Muñiz Dermatologist Clínica Dermalomas Mexico City, Mexico Anna Elisa Verzì Dermatology Clinic University of Catania Catania, Italy Angelica Flores Vidal Dermato-oncologist Clínica Dermalomas Mexico City, Mexico Anna Waśkiel-Burnat Department of Dermatology Medical University of Warsaw Warsaw, Poland

1 Alopecia Areata Andrew G. Messenger

Introduction Alopecia areata is a chronic inflammatory disease that causes non-scarring hair loss. The severity ranges from small patches of hair loss, which often recover spontaneously, to complete loss of hair where the prognosis for recovery is poor. The nails may also be affected. Current evidence indicates that alopecia areata is caused by a T-cell–mediated autoimmune mechanism occurring in genetically predisposed individuals. Environmental factors may be responsible for triggering the disease. The Latin term “alopecia” is derived from the Ancient Greek word ἀλωπεκία, meaning fox-mange, from ἀλώπηξ (fox). The first description of alopecia areata is generally attributed to the Roman physician Celsus (ca BC 25–AD 50) [1]. Under the heading “areae,” he described two types of hair loss: the first, known as “alopecia” which “… spreads in no certain form. It is found in the hair of the head, and in the beard.” The second type, called “ophiasis,” “… begins at the hinder part of the head … it creeps with two heads to the ears…” The term “alopecia areata” was first used by Sauvages in 1763 (cited by Hebra and Kaposi [2]). In the English literature, Robert Willan described alopecia areata under the title “porrigo decalvans,” illustrated in Plate XL of Thomas Bateman’s 1819 Atlas (Figure 1.1). The first detailed account in more recent times was by Hebra and Kaposi [2] and many aspects of their description of the clinical features, the natural history and the response to treatment could appear in a modern textbook. Early ideas about the etiology were numerous and included infectious, metabolic, vascular, neuropathic and trophoneurotic theories. The current view, that alopecia areata is an autoimmune disease, was first suggested by Rothman in a discussion of a paper presented by Van Scott [3] although an association with thyroid disease and vitiligo had been recognized from the early years of the twentieth century [4].

Epidemiology Incidence and Prevalence In a population study in Minnesota, USA, the incidence rate of alopecia areata was 20.2 per 100,000 patient years with a projected lifetime risk of 1.7% [5]. A more recent study in the same population found slightly higher rates of incidence (21.3 per 100,000 patient years) and lifetime risk (2.1%) [6]. A

DOI: 10.1201/9780429465154-1

questionnaire-based study from France in 20,000 adults with an age distribution similar to that of the population reported a point prevalence for alopecia areata of 1.04% [7]. As far as is known, alopecia areata occurs in all ethnic groups. Several large case series of alopecia areata have been reported from Europe [8], North America [9, 10] and Asia [11, 12], but these have generally been drawn from hospital clinic attenders. In the US Nurses’ Health Studies, self-reported alopecia areata was more common in black and Hispanic women than in white women [13]. In the Global Burden of Disease Study, WHO estimated the disability-adjusted life years (DALYs) for alopecia areata at 1,332,800. This compares with DALYs for psoriasis at 1,050,660 and for diabetes mellitus at 46,857,100 [14].

Age The onset of alopecia areata may occur at any age. However, in most affected individuals the first episode occurs before the age of 40, with the peak age of onset between the 2nd and 4th decades.

Sex Data from population studies have given conflicting results on the sex-specific frequency rates of alopecia areata. The American studies reported the frequency of alopecia areata is the same in both sexes [5, 6], whereas in the study from France the prevalence in women was twice that in men [7].

Clinical Features The characteristic initial lesion of alopecia areata is a circumscribed, hairless smooth patch. The skin within the bald patch appears normal or slightly reddened (Figure 1.2). Short, easily extractable broken hairs, known as exclamation mark hairs, are often seen at the margins of the bald patches during active phases of the disease. The subsequent progress is unpredictable; the initial patch may regrow hair within a few months, or further patches may appear after varying intervals. A succession of discrete patches may coalesce to give large areas of hair loss (Figure 1.3a and 1.3b). In some cases, this progresses to total loss of scalp hair (alopecia totalis) or loss of all hair on the body (alopecia universalis) (Figure 1.4). The initial hair loss is occasionally diffuse

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FIGURE 1.1  Alopecia areata under the title “porrigo decalvans,” illustrated in Plate XL of Thomas Bateman’s 1819 Atlas. (From Messenger AG, Sinclair RD, Farrant P, de Berker DAR. Acquired disorders of hair. In: Rook’s Textbook of Dermatology, eds Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D, 2016, 9th Edition, John Wiley & Sons Ltd., Chichester, with permission.)

without the development of discrete bald areas. Regrowth is often at first fine and non-pigmented, but usually the hairs gradually resume their normal caliber and color. Regrowth in one region of the scalp may occur while the alopecia is extending in others.

FIGURE 1.3  (a) Multiple hairless patches of alopecia areata. (By courtesy of Prof. Alexander C. Katoulis.) (b) Multiple coalescing patches of alopecia areata. (By courtesy of Prof. Alexander C. Katoulis.)

FIGURE 1.2  Solitary, hairless patch of circumscribed alopecia areata. (By courtesy of Prof. Alexander C. Katoulis.)

FIGURE 1.4  Alopecia areata universalis. (By courtesy of Prof. Alexander C. Katoulis.)

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Alopecia Areata

FIGURE 1.5  Alopecia areata of the beard. (By courtesy of Prof. Alexander C. Katoulis.)

The scalp is the first affected site in most cases, but any hairbearing skin can be affected. In dark-haired men, patches in the beard are conspicuous (Figure 1.5) and in such individuals are often the first to be noticed. The eyebrows and eyelashes are lost in many cases of alopecia areata and may be the only sites affected. The extension of alopecia along the back of the scalp is known as ophiasis (Figure 1.6).

FIGURE 1.7  (a) Dermoscopic image of alopecia areata showing yellow dots, black dots, exclamation hair and coudability hair. (b) Dermoscopic image of alopecia areata showing yellow dots, black dots, broken hair, and white unaffected hair. (By courtesy of Prof. Alexander C. Katoulis.)

Dermoscopy Dermoscopy (Figure 1.7a and 1.7b) can be helpful in confirming a diagnosis of alopecia areata. In a review of the published literature, the reported features and their frequencies were yellow dots (6–100% of patients), short vellus hairs (34–100%), black dots (also known as cadaverized hairs, 0–84%), broken hairs (0–71%) and exclamation mark hairs (12–71%) [15]. None is absolutely specific for alopecia areata and their significance needs to be interpreted in the context of the gross clinical features.

Sparing of White Hairs

FIGURE 1.6  Ophiasis.

In patients with gray hair, which is an admixture of pigmented and non-pigmented hair, the disease process appears preferentially to affect pigmented hair, so that non-pigmented or white hair is spared (Figure 1.8). This may result in a dramatic change in hair color if the alopecia progresses rapidly, and is probably the explanation for historical accounts of people “going white overnight.” Sparing of white hair is a relative

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FIGURE 1.8  The characteristic sparing of white hair in alopecia areata. (By courtesy of Prof. Alexander C. Katoulis.)

phenomenon and white hairs, although less susceptible to the disease, are not immune. During the regrowth phase, hairs may be non- or hypopigmented but hair pigmentation usually recovers completely. In cases where regrowing hairs remain non-pigmented, the possibility of concurrent vitiligo should be considered.

Nail Dystrophy Alopecia areata may also involve the nails. Published frequencies vary widely [16], possibly reflecting differences in casemix as nail disease is more common in the context of severe hair loss. Alopecia areata typically causes fine stippled pitting of the nails. Some cases show less well-defined roughening of the nail plate (trachyonychia) or a non-specific atrophic dystrophy (Figure 1.9). Less common features include red spotting of the lunula and longitudinal splitting of the nail plate. For some

Hair Disorders

FIGURE 1.10  Diffuse form of alopecia areata. (By courtesy of Prof. Alexander C. Katoulis.)

patients, severe nail dystrophy is the most troublesome aspect of the disease as it interferes with manual activities.

Diffuse Alopecia Areata Alopecia areata occasionally presents in a diffuse fashion rather than forming well-defined patches of hair loss (Figure 1.10). The onset is typically acute with a large increase in hair shedding and a diffuse, though not necessarily uniform, reduction in hair density. Hair may be lost from other sites such as the eyebrows and limbs. A pull test is usually strongly positive. Dermoscopy shows features of alopecia areata including yellow dots, exclamation mark hairs and cadaverized hairs. The term acute diffuse and total alopecia has been used to describe a form of rapidly progressive diffuse alopecia areata that affects young adult women, that usually recovers spontaneously within 6 months and has a good prognosis. Most cases have been reported from East Asian countries [17–19]. The histology shows typical features of alopecia areata including peribulbar inflammation.

Alopecia Areata Incognita

FIGURE 1.9  Trachyonychia in a patient with alopecia areata. (By courtesy of Prof. Alexander C. Katoulis.)

This entity was first described by Rebora in 1987 [20]. Most cases are adult women who present with a rapid onset of increased hair shedding resembling acute telogen effluvium. There is no rarefaction of scalp hair unless the shedding persists and only a small proportion of cases (1–2%) develop small patches of hair loss. Only scalp hair is affected. A pull test is strongly positive showing telogen roots; dystrophic forms are rare. Histology shows follicular miniaturization and an increase in telogen follicles [21]. Subtle peribulbar lymphocytic inflammation is seen in a small proportion of cases. The status of alopecia areata incognita is uncertain, in particular whether it truly represents a form of alopecia areata. Yellow dots are a consistent feature on dermoscopy but yellow dots may also be seen in other conditions, including female pattern hair loss [22]. Confusingly the term has also been applied to diffuse alopecia areata [23].

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Alopecia Areata

Differential Diagnosis In children the main sources of difficulty are tinea capitis and trichotillomania. Tinea capitis should always be considered in children presenting with patchy hair loss. There is usually evidence of scalp inflammation but this may be limited to mild scaling. The hair loss in trichotillomania may be asymmetrical or occur in artificial shapes. Broken hairs are usually present across the areas of hair loss, giving a bristly texture and, unlike exclamation mark hairs, are firmly anchored in the scalp. In most cases, the true diagnosis will become evident with time; a biopsy is useful when doubt remains. Occasionally, the early stages of scarring alopecia can resemble alopecia areata. The diffuse form of alopecia areata is perhaps the most difficult to identify. A history of previous episodes of hair loss, nail dystrophy and the usually rapid progression may provide clues, but other causes of diffuse hair loss may need to be excluded. Pattern hair loss and telogen effluvium are the main differential but lack the broken hairs, black dots and exclamation mark hairs seen on dermoscopy of alopecia areata. Secondary syphilis and lupus erythematosus can cause both patchy and diffuse hair loss.

Classification of Severity Alopecia areata is conventionally classified as patchy, alopecia totalis and alopecia universalis. In addition to these simple criteria, a more detailed classification should include the disease duration and, with regard to patchy alopecia, the extent of the hair loss. Description of the pattern should include the presence of ophiasis, the involvement of sites on the trunk and limbs and the presence of nail disease. A number of scoring systems have been devised of which the Severity of Alopecia Tool (SALT) is the most widely used and is applicable to clinical practice [24]. The impact of alopecia areata on patient quality of life can be assessed using a variety of instruments, both disease-specific and non-specific. The Dermatology Life Quality Instrument (DLQI) is straightforward and most dermatologists are familiar with its use although other more disease-specific methods have been devised [25].

Associated Diseases/Comorbidities Autoimmune Disease Numerous studies have shown an increased risk of other autoimmune diseases in patients with alopecia areata [14]. There is variation between studies in the level of risk for individual diseases, but the overall theme is fairly constant. In the largest study of its type, incorporating 4334 patients with alopecia areata and over 700,000 controls, Chu and colleagues reported significant associations with vitiligo, thyroid disease, lupus erythematosus, psoriasis and rheumatoid arthritis [26]. The frequency of Type 1 diabetes mellitus is not increased in patients with alopecia areata but is more common than expected in their relatives, suggesting a protective effect of the diabetes genotype [27, 28].

Atopic Disease Atopic disease is also more common than expected in alopecia areata and is associated with earlier onset and more severe forms of hair loss [14, 26]. Atopic dermatitis in a Korean population was significantly more common in patients with earlyonset alopecia areata, whereas thyroid disease was the most common in late-onset disease [29].

Down’s Syndrome In two studies on institutionalized subjects with Down’s syndrome, alopecia areata was diagnosed in 60 out of 1000 (6%) cases in the first [30] and in 19 out of 214 (8.9%) in the second [31], frequencies well in excess of that expected in the population at large. Other autoimmune diseases are also common in Down’s syndrome.

Autoimmune Polyendocrinopathy Syndrome Type 1 Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1) is a genetic disease due to mutations in the autoimmune regular gene (AIRE) at chromosome 21q22. AIRE protein is expressed in the thymus and is involved in the deletion of self-recognizing T cells. The cardinal features of APS-1 are Addison’s disease, hypoparathyroidism and chronic mucocutaneous candidiasis but other autoimmune diseases are also common and alopecia areata occurs in about 50% of cases [32]. This association has led to the idea that AIRE dysfunction could be involved in the pathogenesis of sporadic alopecia areata.

Quality of Life and Mental Health Disorders Impairment in quality of life in people suffering from alopecia areata has been reported by many studies [33, 34]. Adverse effects on mental health, vitality, social functioning and emotions are common themes. Women appear more likely to suffer reduced quality of life than men but the evidence for a contribution of other factors, such as disease duration and severity of hair loss, is conflicting. It is important to recognize the serious impact that alopecia areata can have on quality of life. On the other hand, not all patients with alopecia areata experience a reduction in quality of life due to their disease—57% in one study [35]—and recruitment into quality of life studies may be biased toward those more adversely affected. The prevalence of psychiatric disorders, particularly depression and anxiety, appears greater in patients with alopecia areata than in the general population [14]. In a questionnairebased study, 8.8% of respondents with alopecia areata were diagnosed as suffering from depression and 18.2% from anxiety, compared with previously published data reporting frequencies of 1.3–1.5% for depression and 2.5% for anxiety in the general population [36]. In a large study from Taiwan using information from a national database depression (2.9%) and anxiety (5%) and were significantly more common in those with alopecia areata compared to controls (depression 2.2%; anxiety 3.3%). Depression was more common in those with early onset alopecia (40 years). In about half of

6

Hair Disorders

those with alopecia areata psychiatric disease preceded the hair loss [37].

Pathophysiology There is abundant evidence that alopecia areata is an autoimmune disease [38]: • There is an increased frequency of other autoimmune diseases in patients with alopecia areata. • There is an increased frequency of organ-specific autoantibodies in patients with alopecia areata. Serum antibodies to hair follicle tissue also occur with increased frequency in alopecia areata although these antibodies appear not to bind to hair follicles in vivo and their pathogenetic significance is not known. • The pathology is characterized by infiltration of hair bulbs by activated T-lymphocytes. • In animal models of alopecia areata, depletion of CD4 and CD8 T cells results in hair regrowth [39]. • Hair regrows in human alopecic skin when transplanted onto immunodeficient mice [40]. • T cells isolated from scalps of patients with alopecia areata and cultured with hair follicle homogenates induced both hair loss and the pathologic findings of alopecia areata when injected into autologous scalp grafted onto immunodeficient mice, indicating the hair follicle lesion is mediated by T cells [41]. Passive transfer of patient serum in the same model failed to induce hair loss [42]. • Alopecia areata shares genetic associations with several autoimmune diseases, particularly with genes of the Major Histocompatibility Complex (MHC).

Immunopathology Certain tissues, including the central nervous system, the eyes, testis and placenta, have immune privilege, meaning they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response. Antigens within immune privileged sites interact with T cells to induce tolerance rather than rejection. In 1971, Billingham and Silvers proposed that the hair follicle is also an immune privileged site [43]. In experiments on guinea pigs, they found that pigmented hairs survived in skin grafts taken from black donor animals transplanted onto immunologically incompatible white-skinned recipients. Further experimental evidence for hair follicle immune privilege came from a study that demonstrated the induction of hair growth in a human female recipient by implantation into her skin of dermal sheath from a male donor [44]. The induced hair follicle was not rejected despite the presence of Y chromosome in the dermal compartment, confirming its donor derivation. The breakdown of this immune-privileged status is thought to underlie the immune-mediated assault on the hair follicle in

alopecia areata [45–47]. There is very low or absent expression of MHC Class I proteins (HLA-A, B, C) in the lower part of normal follicular epithelium making the follicle vulnerable to attack by natural killer (NK) cells as NK cells are primed to eliminate MHC Class I—negative cells. Hair follicles appear to protect from this process by downregulating the expression of ligands, such as MICA (MHC Class I polypeptide-related sequence A), that stimulate the activation of NK-cell receptors, and by secreting molecules that inhibit NK-cell and T-cell activation [48]. The failure of immune privilege in alopecia areata is associated with increased expression of MICA and MHC Class I, the local release of immune activating cytokines, notably interferon-γ and IL-15, and an influx of T cells, NK cells and dendritic cells, culminating in a CD8+ cell attack on the follicle. Experiments in the CH3/HeJ mouse model of alopecia areata indicate that CD8+NKG2D+ cells are responsible for causing the follicular lesion [49]. The same study showed that cytokine signaling via the activating JAK-STAT pathway in target immune cells plays an important role the immunopathology of alopecia areata and this has been exploited by the use of drugs that inhibit Janus Kinase (JAK) enzymes in its treatment [47, 49]. It is not fully clear whether this sequence of events in and around the hair follicle is initiated by a peripheral fault residing in the follicle’s ability to maintain immune privilege or by more central dysregulation of the immune system [50]. Gilhar and colleagues showed that an alopecic lesion could be induced in normal hair follicles transplanted onto immunodeficient mice following injection into the transplanted skin of peripheral blood mononuclear cells (PBMC) from healthy donors enriched for cells showing expression of NKG2D and CD56, suggesting primacy of immune dysregulation [51]. However, there must still be a mechanism to explain targeting of the hair follicle.

Genetics The importance of genetic factors in alopecia areata is apparent from the high frequency of a positive family history [52]. In most reports, this ranges from 10% to 20% of cases, but mild cases can be overlooked or concealed and the true figure may be greater. The lifetime risk of alopecia areata in the children of a proband is around 6% [53, 54]. A family history of alopecia areata is more common in those with disease onset before the age of 30 years [55]. There are several reports of alopecia areata in twins [56–58]. Two studies found a concordance rate of 55% and 42% for alopecia among monozygotic twins with 0% and 10% concordance respectively among the dizygotic pairs [59, 60].

Gene Associations Case control studies have identified associations between alopecia areata and a variety of genes involved in regulating immune and inflammatory responses [61]. The strongest associations to date have been with genes of the MHC, particularly the Class II alleles HLA-DQB1*0301 and HLADRB1*1104 [62, 63]. An association has also been reported with AIRE gene haplotypes, suggesting a defect in the

7

Alopecia Areata induction of immune tolerance [64]. The AIRE locus is on the long arm of chromosome 21 within the Down’s critical region, and thymic AIRE expression is reduced in Down’s syndrome despite the presence of an extra copy of AIRE [65]. Genome-wide association studies (GWAS) have confirmed the strong association with HLA-DR and also identified several other genomic regions associated with alopecia areata [66]. These include genes controlling activation and proliferation of T regulatory lymphocytes and some genes expressed in the hair follicle. There is a strong association with genes within the ULBP cluster coding for activating ligands of the NKG2D receptor, supporting a role for NK and certain CD8+ T cells in the pathogenesis of the disease. Some of the risk loci identified for alopecia areata are shared by other immune-mediated diseases including Graves’ disease, inflammatory bowel disease, coeliac disease, vitiligo, rheumatoid arthritis, systemic lupus erythematosus and psoriasis.

Environmental Factors The idea that alopecia areata is triggered by infection, either directly or as a consequence of a remote “focus of infection,” has a long history. It was predominant until well into the twentieth century and sporadic reports connecting alopecia areata with infective agents continue to appear. The “external” factor most frequently implicated in triggering alopecia areata is psychological stress [67–69]. The published evidence is conflicting, with some studies failing to show any relationship between stressful events and onset of hair loss [70, 71]. One case-controlled study found a significantly increased history of childhood and lifetime traumatic events, both physical and emotional, in adults with alopecia areata [72]. The association between atopic disease and alopecia areata is well-established but our understanding of its pathobiological significance is limited. Li and colleagues have suggested that dust mite allergy has a role in early-onset alopecia areata [73] and seasonal relapse of alopecia areata following allergic rhinitis has been reported [74]. Several cross-sectional studies have reported an increased frequency of vitamin D deficiency in alopecia areata compared to unaffected controls. Vitamin D may have immunomodulatory functions and low levels of vitamin D have been reported in other autoimmune diseases [75]. However, one large prospective study found no association between the incidence of alopecia areata and predicted vitamin D levels suggesting that deficiency may be a consequence rather than a cause [76]. Some small uncontrolled case series have reported a response to topical calciprotriol in patchy alopecia areata [75]; no trials of oral vitamin D supplementation have yet been reported. Deficiencies of other micronutrients that have been linked to alopecia areata include zinc, iron and folate. However, the studies are small and results are conflicting to the extent that no firm conclusion as to their significance can be drawn [77]. Despite the uncertain nature of some of the evidence, it is entirely possible that environmental factors are responsible for triggering alopecia areata in some patients. If so, it seems likely that a diversity of factors can operate in this way.

Pathology Anagen follicles at the margins of expanding patches of alopecia areata characteristically show a perifollicular and intrafollicular inflammatory cell infiltrate, concentrated in and around the hair bulb (Figure 1.11). The inflammatory infiltrate is composed mainly of activated T-lymphocytes, with a preponderance of CD4 cells, and an admixture of macrophages, Langerhans cells and cells expressing NK-cell markers [48, 78, 79]. In contrast to the inflammatory scarring alopecias, little or none of the inflammatory infiltrate is seen around the isthmus of the hair follicle, the site of hair follicle stem cells [80]. This may explain why follicles are not destroyed in alopecia areata. Lymphocytic infiltration of the dermal papilla and bulbar epithelium may be accompanied by increased expression of MHC Class I and II antigens and of intercellular adhesion molecule-1 (ICAM-1) [81–83]. Normal numbers of follicles are found in established bald patches and in alopecia universalis. Both anagen and telogen follicles are found in these sites, with a higher proportion in telogen than in normal scalp. Follicles are smaller than normal and anagen follicles do not develop beyond the Anagen 3–4 stage, when the hair shaft starts to form [3]. The inflammatory infiltrate tends to be less pronounced than in early lesions and is associated mainly with anagen follicles. Alopecia areata causes a disturbance in the normal dynamics of the hair cycle. Anagen follicles are precipitated into telogen. This may occur as a centrifugal wave, reminiscent of a molt wave [19]. Follicles are able to re-enter anagen but, while the disease is active, are unable to progress beyond the Anagen 3–4 stage (3). It has been suggested that they then return prematurely to telogen and that these truncated cycles continue until disease activity wanes [84]. Cells of several different types and differentiation pathways are found in the hair bulb, but which of these is the

FIGURE 1.11  Peribulbar chronic inflammatory cell infiltrate predominantly composed of lymphocytes (swarm of bees). A few histiocytes and rare eosinophils are also noted. On the left, there is separate perivascular chronic inflammation, HE × 400. (By courtesy of Dr Eleni Ieremia.)

8

Hair Disorders

primary focus of the pathology is unknown. Epithelial cells in the hair bulb matrix undergoing early cortical differentiation may show vacuolar degeneration [85, 86] and are also the predominant cell type showing aberrant MHC expression. The pigmentary features of alopecia areata have also raised the possibility that alopecia areata is primarily a disease of hair bulb melanocytes. A study using in vitro T-cell activation methodology to search for autoantigens identified a stronger response to hair follicle trichohyalin and tyrosinase-related protein 2 in PBMC from patients with alopecia areata than from healthy controls [87]. Significantly, the interruption of anagen in established alopecia areata at the III/IV stage of development coincides with the early signs of hair cortex differentiation and melanization.

Disease Course and Prognosis Alopecia areata does not destroy hair follicles, and the potential for regrowth of hair is retained for many years and is possibly lifelong. In some patients, patches of hair loss occur at infrequent intervals interspersed with long periods of normal hair growth. In others, alopecia areata is more persistent, so that new patches of hair loss continue to develop at the same time as regrowth occurs elsewhere. In a relatively small proportion of patients, hair loss progresses to involve all of the scalp (alopecia totalis) or the entire skin surface (alopecia universalis); in these cases, spontaneous recovery is the exception rather than the rule. Data from secondary and tertiary referral centers indicate that 34–50% of patients will recover within 1 year, although almost all will experience more than one episode of the disease, and 14–25% progress to alopecia totalis or alopecia universalis, from which full recovery is unusual (less than 10%) [8, 9, 88]. One study from Japan reported that spontaneous remission within 1 year occurred in 80% of patients with a small number of circumscribed patches of hair loss [11]. The prognosis is less favorable when onset occurs during childhood [68, 88] and in ophiasis [68].

Investigations In most cases, alopecia areata can be diagnosed clinically and investigations are usually not needed. If there is diagnostic uncertainty, a biopsy may be necessary although the histological features may be subtle and require a pathologist experienced in the interpretation of hair pathology. Situations where a biopsy can be helpful include diffuse alopecia and possible early scarring alopecia. In selected case, other diagnostic tests may include: • Fungal culture • Serology for lupus erythematosus • Syphilis serology Unless relevant symptoms and signs are present, it is debatable whether routine “one-off” screening for other autoimmune diseases is appropriate as the risk is small and lifelong.

Management General Principles of Management A number of treatments can induce hair growth in alopecia areata, but none has been shown to alter the course of the disease. Few treatments have been subjected to randomized controlled trials and there are few published data on longterm outcomes. These difficulties mean that counseling of the patient and, where relevant, of their family, are of paramount importance. This should include discussion of the nature of the disease and its natural history, the treatments available and their chances of success. Assessment of the psychosocial impact of the disease is an important part of the consultation. Some patients have great difficulty coping with alopecia areata and require considerable support. Sources of support may include the physician, specialist nurses, other patients, formal patient support groups and, in some circumstances, professional counseling services. Most patients presenting to clinicians want to receive treatment although, after counseling, some will prefer to leave their alopecia untreated. Spontaneous remission occurs in up to 80% of patients with limited patchy hair loss of short duration (less than 1 year) [11]. Such patients may be managed by reassurance alone, with advice that regrowth cannot be expected within 3 months of the development of any individual patch. The prognosis in long-standing extensive alopecia is less favorable. However, all treatments have a significant failure rate in this group and some patients prefer not to be treated, other than by cosmetic measures, such as wearing a wig, if appropriate.

Limited Patchy Alopecia A potent topical steroid (e.g., clobetasol), delivered in lotion, foam or shampoo formulation, may hasten recovery of hair growth in mild degrees of alopecia areata [89, 90]. Treatment should be continued for at least 3 months. Folliculitis is an occasional complication. Topical steroids are ineffective in alopecia totalis/universalis. Intralesional steroid is generally the most effective local treatment in limited patchy alopecia areata although the formal evidence base is of low quality [91]. One study reported complete regrowth in 63% of patients at 4 months [92] and, in a second, 82% showed more than 50% regrowth at 12 weeks [93]. A depot steroid is administered by fine needle injection into the upper subcutis, or using a needleless device. Triamcinolone acetonide 5–10 mg/mL is the most widely used agent although a small study comparing different steroid concentrations found that 2.5 mg/mL was as effective as higher concentrations [94]. Multiple injections are usually needed. There is no set upper dose but most practitioners limit the total dose of triamcinolone to 20 mg. Local atrophy is a common side effect but this recovers within a few months. Intralesional steroid will not prevent the development of alopecia at other sites and is not suitable for patients with rapidly progressive alopecia or alopecia totalis/universalis. The use of dithranol (anthralin) to induce an irritant dermatitis was first proposed in 1979. Early studies failed to show a

Alopecia Areata consistent response. However, recent case series using more aggressive treatment regimens have suggested that dithranol can promote worthwhile regrowth in some patients [95, 96]. Limiting factors include coping with a sore scalp, discoloration of the hair and staining of fabrics. Topical minoxidil has been widely used but the evidence for efficacy is poor [97].

Extensive and Rapidly Progressive Alopecia Areata There is little consensus among dermatologists on the place of systemic steroids in treating alopecia areata, except a general acceptance that a worthwhile response in alopecia totalis/ universalis is very unlikely. Long-term daily treatment with systemic corticosteroids will produce some regrowth of hair in some patients with chronic patchy disease. One small, partly controlled study reported that 30–47% of patients treated with a 6-week tapering course of oral prednisolone (starting at 40 mg/day) showed more than 25% hair regrowth [98]. There are several case series reporting a favorable response to high-dose pulsed corticosteroid treatment using different oral and intravenous regimens [99–101]. In the only controlled trial, patients receiving prednisolone 200 mg once a week for 3 months showed better hair regrowth at 6 months than those taking placebo [102], but this was not statistically significant [103]. In most patients, continued treatment is needed to maintain hair growth. In the author’s opinion relatively short courses of systemic steroids may have a place in managing exacerbations or rapidly progressive alopecia areata but the risks of long-term treatment in chronic disease outweigh the benefits.

Extensive Patchy Alopecia/AT/AU Since its introduction in the early 1980s, contact immunotherapy has been the most effective and best-documented treatment for extensive alopecia areata. Although the cost of contact immunotherapy in terms of materials is relatively low, the high costs associated with specialist clinical staff administering the treatment and patient travel, and its non-licensed status, have limited its widespread use and, in some countries, it has been largely replaced by JAK inhibitors, a trend that is likely to spread. The patient is sensitized to a potent skin allergen by application to a small area on the scalp and the same allergen is then applied to the scalp, usually at weekly intervals, in a concentration sufficient to induce a mild contact dermatitis. The allergens that have been used in the treatment of alopecia areata include dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE) and diphenylcyclopropenone (DPCP). Most centers now use DPCP [104]. In an analysis of 45 published studies comprising 2227 patients, albeit most of low quality, 56% of those with patchy alopecia and 29% of those with alopecia totalis/universalis had major hair regrowth with contact immunotherapy [105]. Adverse prognostic features included SALT scores greater than 50, atopic disease, nail involvement and disease duration greater than 1 year. Almost half of all patients relapsed following treatment; the relapse rate was lower in those receiving maintenance treatment (38%) than in those not receiving

9 maintenance (49%). Although its nature precludes blinded controlled trials, the validity of contact immunotherapy is supported by studies showing ipsilateral hair regrowth when only one-half of the scalp is treated. Most practitioners discontinue treatment after 6 months if no response is obtained, although one study from Canada reported better results with more prolonged treatment [106]. Two case report series of contact immunotherapy in children with alopecia areata reported response rates of 33% [107] and 32% [108]. A third study found a similar short-term response in children with severe alopecia areata, but less than 10% experienced sustained benefit [109]. Most patients will develop occipital and/or cervical lymphadenopathy during contact immunotherapy. This is usually temporary but may persist throughout the treatment period. Severe dermatitis is the most common adverse event, but the risk can be minimized by careful titration of the concentration. Uncommon adverse effects include urticaria and vitiligo. Cosmetically disabling pigmentary complications, both hyperand hypopigmentation (including vitiligo), may occur if contact immunotherapy is used in patients with pigmented skin. Contact immunotherapy has been in use for over 30 years and no long-term side effects have been reported. Sensitization of health professionals involved in delivering contact immunotherapy (doctors, nurses, pharmacy technicians) is a significant problem and they must take care to avoid skin contact with the allergen. The mode of action of contact immunotherapy is unknown. Happle [110] suggested that the contact allergen competes for CD4 cells, attracting them away from the perifollicular region (“antigenic competition”). Other suggested mechanisms include the non-specific stimulation of a local T-suppressorcell response [82] and increased expression of TGF-β in the skin, which acts to suppress the immune response [111]. Some clinicians use systemic immunosuppressive drugs (ciclosporin, azathioprine and methotrexate) in severe alopecia areata, either stand-alone or as steroid-sparing agents. A systematic review of case series concluded that ciclosporin is more effective, and the relapse rate is lower, when used in combination with systemic steroids [112] but it is less clear whether ciclosporin is effective when used alone. In the only randomized controlled trial of ciclosporin in moderate-tosevere alopecia areata those receiving ciclosporin showed a greater improvement than the placebo group but this was not statistically significant [113]. Positive results have been reported for azathioprine in a few small case series [114] but there are no controlled studies. Methotrexate has probably been the most widely used drug in this category, first reported by Joly in 2006 [115]. Several case series have since been published. A critical review in 2018 concluded there was insufficient evidence to conclude whether methotrexate is useful for maintaining regrowth in extensive alopecia areata although there was some evidence to suggest that hair regrowth may be induced by methotrexate when used in combination with systemic corticosteroids [116]. Nevertheless, methotrexate is a relatively safe drug, most dermatologists are experienced in its use and, despite the rather weak evidence base, it is worthy of consideration in certain cases.

10

Janus Kinase Inhibitors Many cytokines activate immune cells via the JAK-STAT signaling pathway. Drugs that inhibit JAK prevent the development of hair loss, and reverse it, in a mouse model of alopecia areata [49]. The oral administration of the JAK inhibitors, ruxolitinib [49], tofacitinib [117] and baracitinib [118], also promotes hair regrowth in patients with alopecia areata. The outcome of formal controlled trials is awaited, but a review of published case reports and case series concluded that about 45% of patients experienced a good response to treatment with JAK inhibitors and 21% a partial response [119]. Preliminary evidence indicates that continued treatment is needed to maintain the response. JAK inhibitors are immunosuppressive but reported side effects (in alopecia areata) appear minimal with upper respiratory infections the most common complaint.

Others Platelet-Rich Plasma (PRP): In a randomized controlled trial in limited patchy alopecia areata Trink and colleagues reported that PRP was more effective than intralesional corticosteroid at stimulating hair regrowth and produced more lasting remissions [120]. A later trial supported the idea that PRP is at least as effective as intralesional corticosteroid in limited patchy disease, although the overall numbers treated are quite small. One case series found that that PRP did not produce sustained benefit in severe (>50%) alopecia areata [121]. Phototherapy: The use of various forms of phototherapy in alopecia areata has a long history. These have included UVB, UVA, photochemotherapy (PUVA) and photodynamic therapy (PDT). UVB and PDT do not work. The evidence for PUVA is slightly stronger but there are no controlled trials [121]. Both topical psoralens with local UVA to the scalp and systemic psoralens with whole body irradiation have been used. In the author’s experience, PUVA can stimulate hair regrowth but continued treatment is needed to maintain it, leading to unacceptably high cumulative doses of UVA. Laser Therapy: Several small controlled trials and case series in patchy alopecia areata have reported hair regrowth following treatment with a 308-nm excimer laser [121]. Overall, about 50% of patches appear to respond. However, there is little or no published information on relapse rates and the treatment regimens are arduous (e.g., twice weekly for 12 weeks).

Children with Alopecia Areata Alopecia areata presents a particular therapeutic challenge in children as the treatment options are more limited, compounded by the often, severe nature of the disease in this age group. Intralesional injections are rarely tolerated by young children and there is a reluctance to use systemic drugs such as corticosteroids or immunosuppressives. Possible options include topical corticosteroids, topical minoxidil and anthralin, but these are unlikely to help in extensive alopecia areata. Very young children are often oblivious of their hair loss, and it is the parents who are more likely to need support, but older children may struggle to cope—teasing and bullying at school

Hair Disorders are common problems, for example. Patient support groups or charities aimed at helping those with visible skin disorders can provide invaluable advice for patients and their families; occasionally input from a pediatric clinical psychologist is needed.

Non-Medical Treatments Women with extensive alopecia will usually benefit from wearing a wig, hairpiece or bandana. A few brave patients prefer not to conceal their lack of hair. Men tend to shave their heads although some opt for a wig. The use of semi-permanent tattooing can be helpful to disguise loss of eyebrows.

Conclusions Much progress has been made in recent years toward understanding the etiology and pathogenesis of alopecia areata, knowledge that is being translated into new and better treatments. Nevertheless, for a significant number of people with alopecia areata treatment is not effective and here the clinician has an important pastoral role in helping patients to cope with their hair loss and to lead as normal a life as possible. Resources British Association of Dermatologists Guidelines for the Management of Alopecia Areata http://www.bad.org.uk/library-media%5Cdocuments%5CAlopecia_ areata_guidelines_2012.pdf Alopecia UK: http://www.alopeciaonline.org.uk National Alopecia Areata Foundation: http://www.naaf.org British Association of Dermatologists Patient Information: https:// www.bad.org.uk/shared/get-file.ashx?id=68&itemtype= document

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d­ iabetes in relatives of patients with alopecia areata (AA). Am J Med Genet. 1994;51(3):234–9. 28. Noso S, Park C, Babaya N, Hiromine Y, Harada T, Ito H, et al. Organ specificity in autoimmune diseases: thyroid and islet autoimmunity in alopecia areata. J Clin Endocrinol Metab. 2015;100(5):1976–83. 29. Lee NR, Kim B-K, Yoon NY, Lee S-Y, Ahn S-Y, Lee W-S. Differences in comorbidity profiles between early-onset and late-onset alopecia areata patients: a retrospective study of 871 Korean patients. Ann Dermatol. 2014;26(6):722–6. 30. du Vivier A, Munro DD. Alopecia areata, autoimmunity and Down’s syndrome. Br Med J. 1975;i:191–2. 31. Carter DM, Jegasothy BV. Alopecia areata and Down syndrome. Arch Dermatol. 1976;112:1397–9. 32. Vogel A, Strassburg CP, Obermayer-Straub P, Brabant G, Manns MP. The genetic background of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and its autoimmune disease components. J Mol Med (Berl). 2002; 80(4):201–11. 33. Rencz F, Gulacsi L, Pentek M, Wikonkal N, Baji P, Brodszky V. Alopecia areata and health-related quality of life: a systematic review and meta-analysis. Br J Dermatol. 2016;175(3):561–71. 34. Liu LY, King BA, Craiglow BG. Health-related quality of life (HRQoL) among patients with alopecia areata (AA): A systematic review. J Am Acad Dermatol. 2016;75(4):806–12, e3. 35. Shi Q, Duvic M, Osei JS, Hordinsky MK, Norris DA, Price VH, et al. Health-Related Quality of Life (HRQoL) in alopecia areata patients—a secondary analysis of the National Alopecia Areata Registry Data. J Investig Dermatol Symp Proc. 2013;16(1):S49–50. 36. Koo JY, Shellow WV, Hallman CP, Edwards JE. Alopecia areata and increased prevalence of psychiatric disorders. Int J Dermatol. 1994;33(12):849–50. 37. Chu SY, Chen YJ, Tseng WC, Lin MW, Chen TJ, Hwang CY, et al. Psychiatric comorbidities in patients with alopecia areata in Taiwan: a case-control study. Br J Dermatol. 2012;166(3):525–31. 38. Kalish RS, Gilhar A. Alopecia areata: autoimmunity–the evidence is compelling. J Investig Dermatol Symp Proc. 2003;8(2):164–7. 39. McElwee KJ, Yu M, Park SW, Ross EK, Finner A, Shapiro J. What can we learn from animal models of Alopecia areata? Dermatology. 2005;211(1):47–53. 40. Gilhar A, Krueger GG. Hair growth in scalp grafts from patients with alopecia areata and alopecia universalis grafted onto nude mice. Arch Dermatol. 1987;123(1):44–50. 41. Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS. Autoimmune hair loss (alopecia areata) transferred by T  lymphocytes to human scalp explants on SCID mice. J Clin Invest. 1998;101(1):62–7. 42. 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(2):166–71. 43. Billingham RE, Silvers WK. A biologist’s reflections on dermatology. J Invest Dermatol. 1971;57(4):227–40. 44. Reynolds AJ, Lawrence C, Cserhalmi-Friedman PB, Christiano AM, Jahoda CA. Trans-gender induction of hair follicles. Nature. 1999;402(6757):33–4.

12 45. Paus R, Slominski A, Czarnetzki BM. Is alopecia areata an autoimmune-response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb? Yale J Biol Med. 1993;66(6):541–54. 46. Christoph T, Muller-Rover S, Audring H, Tobin DJ, Hermes B, Cotsarelis G, et al. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol. 2000;142(5):862–73. 47. Pratt CH, King LE, Messenger AG, Christiano AM, Sundberg JP. Alopecia areata. Nat Rev Dis Primers. 2017;3:17011. 48. Ito T, Ito N, Saatoff M, Hashizume H, Fukamizu H, Nickoloff BJ, et al. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J Invest Dermatol. 2008;128(5):1196–206. 49. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043–9. 50. Rajabi F, Drake LA, Senna MM, Rezaei N. Alopecia areata: a review of disease pathogenesis. Br J Dermatol. 2018;179(5):1033–48. 51. Gilhar A, Keren A, Shemer A, d’Ovidio R, Ullmann Y, Paus R. Autoimmune disease induction in a healthy human organ: a humanized mouse model of alopecia areata. J Invest Dermatol. 2013;133(3):844–7. 52. McDonagh AJG, Messenger AG. The pathogenesis of alopecia areata. Dermatol Clin. 1996;14:661–70. 53. van der Steen P, Traupe H, Happle R, Boezeman J, Strater R, Hamm H. The genetic risk for alopecia areata in first degree relatives of severely affected patients. An estimate. Acta Derm Venereol. 1992;72(5):373–5. 54. Blaumeiser B, van der Goot I, Fimmers R, Hanneken S, Ritzmann S, Seymons K, et al. Familial aggregation of alopecia areata. J Am Acad Dermatol. 2006;54(4):627–32. 55. Colombe BW, Price VH, Khoury EL, Garovoy MR, Lou CD. HLA class II antigen associations help to define two types of alopecia areata. J Am Acad Dermatol. 1995; 33(5 Pt 1):757–64. 56. Omens DV, Omens HD. Alopecia areata in twins. Arch Dermatol. 1946;53:193. 57. Hendren OS. Identical alopecia areata in identical twins. Arch Dermatol. 1949;60:793–5. 58. Weidmann AI, Ziion LS, Mamelok AE. Alopecia areata occurring simultaneously in identical twins. Arch Dermatol. 1956;74:424–6. 59. Jackow C, Puffer N, Hordinsky M, Nelson J, Tarrand J, Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment? J Am Acad Dermatol. 1998;38(3):418–25. 60. Rodriguez TA, Fernandes KE, Dresser KL, Duvic M. Concordance rate of alopecia areata in identical twins supports both genetic and environmental factors. J Am Acad Dermatol. 2010;62(3):525–7. 61. Gilhar A, Paus R, Kalish RS. Lymphocytes, neuropeptides, and genes involved in alopecia areata. J Clin Invest. 2007;117(8):2019–27. 62. Colombe BW, Lou CD, Price VH. The genetic basis of alopecia areata: HLA associations with patchy alopecia areata versus alopecia totalis and alopecia universalis. J Investig Dermatol Symp Proc. 1999;4(3):216–9.

Hair Disorders 63. de Andrade M, Jackow CM, Dahm N, Hordinsky M, Reveille JD, Duvic M. Alopecia areata in families: association with the HLA locus. J Investig Dermatol Symp Proc. 1999;4(3):220–3. 64. Wengraf DA, McDonagh AJ, Lovewell TR, Vasilopoulos Y, Macdonald-Hull SP, Cork MJ, et al. Genetic analysis of autoimmune regulator haplotypes in alopecia areata. Tissue Antigens. 2008;71(3):206–12. 65. Gimenez-Barcons M, Casteras A, Armengol Mdel P, Porta E, Correa PA, Marin A, et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol. 2014;193(8):3872–9. 66. Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010;466(7302):113–7. 67. Greenberg SI. Alopecia areata: a psychiatric survey. Arch Dermatol. 1955;72:454–7. 68. De Waard-van der Spek FB, Oranje AP, De Raeymaecker DM, Peereboom-Wynia JD. Juvenile versus maturity-onset alopecia areata—a comparative retrospective clinical study. Clin Exp Dermatol. 1989;14(6):429–33. 69. Gupta MA, Gupta AK, Watteel GN. Stress and alopecia areata: a psychodermatologic study. Acta Derm Venereol. 1997;77(4):296–8. 70. MacAlpine I. Is alopecia areata psychosomatic? Br J Dermatol. 1958;70:117–31. 71. van der Steen P, Boezeman J, Duller P, Happle R. Can alopecia areata be triggered by emotional stress? An uncontrolled evaluation of 178 patients with extensive hair loss. Acta Derm Venereol. 1992;72(4):279–80. 72. Willemsen R, Vanderlinden J, Roseeuw D, Haentjens P. Increased history of childhood and lifetime traumatic events among adults with alopecia areata. J Am Acad Dermatol. 2009;60(3):388–93. 73. Li SF, Zhang XT, Qi SL, Ye YT, Cao H, Yang YQ, et al. Allergy to dust mites may contribute to early onset and severity of alopecia areata. Clin Exp Dermatol. 2015;40(2): 171–6. 74. Crosby DL, Gammon WR. Seasonal alopecia areata with atopy. J Am Acad Dermatol. 1989;21(4 Pt 1):806–7. 75. Lin X, Meng X, Song Z. Vitamin D and alopecia areata: possible roles in pathogenesis and potential implications for therapy. Am J Transl Res. 2019;11(9):5285–300. 76. Thompson JM, Li T, Park MK, Qureshi AA, Cho E. Estimated serum vitamin D status, vitamin D intake, and risk of incident alopecia areata among US women. Arch Dermatol Res. 2016;308(9):671–6. 77. Thompson JM, Mirza MA, Park MK, Qureshi AA, Cho E. The role of micronutrients in alopecia areata: a review. Am J Clin Dermatol. 2017;18(5):663–79. 78. Perret C, Wiesner-Menzel L, Happle R. Immunohisto­ chemical analysis of T-cell subsets in the peribulbar and intrabulbar infiltrates of alopecia areata. Acta Derm Venereol. 1984;64(1):26–30. 79. Wiesner-Menzel L, Happle R. Intrabulbar and peribulbar accumulation of dendritic OKT 6-positive cells in alopecia areata. Arch Dermatol Res. 1984;276(5):333–4.

Alopecia Areata 80. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61(7):1329–37. 81. Messenger AG, Bleehen SS. Expression of HLA-DR by anagen hair follicles in alopecia areata. J Invest Dermatol. 1985;85(6):569–72. 82. Bröcker EB, Echternacht-Happle K, Hamm H, Happle R. Abnormal expression of class I and class II major histocompatibility antigens in alopecia areata: modulation by topical immunotherapy. J Invest Dermatol. 1987;88(5): 564–8. 83. McDonagh AJG, Snowden JA, Stierle C, Elliott K, Messenger AG. HLA and ICAM-1 expression in alopecia areata in vivo and in vitro: the role of cytokines. Br J Dermatol. 1993;129(3):250–6. 84. Messenger AG, Slater DN, Bleehen SS. Alopecia areata: alterations in the hair growth cycle and correlation with the follicular pathology. Br J Dermatol. 1986;114(3):337–47. 85. Thies W. Vergleichende histologische Untersuchungen bei Alopecia areata und narbig-atrophisierenden. Arch Klin Exp Dermatol. 1966;227:541–9. 86. Messenger AG, Bleehen SS. Alopecia areata: light and electron microscopic pathology of the regrowing white hair. Br J Dermatol. 1984;110(2):155–62. 87. Wang EHC, Yu M, Breitkopf T, Akhoundsadegh N, Wang X, Shi FT, et al. Identification of autoantigen epitopes in alopecia areata. J Invest Dermatol. 2016;136(8):1617–26. 88. Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long term follow-up study of 191 patients. J Am Acad Dermatol. 2006;55(3):438–41. 89. Charuwichitratana S, Wattanakrai P, Tanrattanakorn S. Randomized double-blind placebo-controlled trial in the treatment of alopecia areata with 0.25% desoximetasone cream. Arch Dermatol. 2000;136(10):1276–7. 90. 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(10):1243–7. 91. Kassim JM, Shipman AR, Szczecinska W, Siah TW, Lam M, Chalmers J, et al. How effective is intralesional injection of triamcinolone acetonide compared with topical treatments in inducing and maintaining hair growth in patients with alopecia areata? A critically appraised topic. Br J Dermatol. 2014;170(4):766–71. 92. Kubeyinje EP. Intralesional triamcinolone acetonide in alopecia areata amongst 62 Saudi Arabs. East Afr Med J. 1994;71(10):674–5. 93. 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(11):748–53. 94. Chu TW, AlJasser M, Alharbi A, Abahussein O, McElwee K, Shapiro J. Benefit of different concentrations of intralesional triamcinolone acetonide in alopecia areata: an intrasubject pilot study. J Am Acad Dermatol. 2015;73(2): 338–40. 95. Ngwanya MR, Gray NA, Gumedze F, Ndyenga A, Khumalo NP. Higher concentrations of dithranol appear to induce hair growth even in severe alopecia areata. Dermatol Ther. 2017;30(4):e12500.

13 96. Daunton A, Harries M. Efficacy of topical dithranol (Dithrocream(R)) in the treatment of alopecia areata: a retrospective case series. Br J Dermatol. 2019;180(5):1246–7. 97. Messenger AG, McKillop J, Farrant P, McDonagh AJ, Sladden M. British Association of Dermatologists’ guidelines for the management of alopecia areata 2012. Br J Dermatol. 2012;166(5):916–26. 98. Olsen EA, Carson SC, Turney EA. Systemic steroids with or without 2% topical minoxidil in the treatment of alopecia areata. Arch Dermatol. 1992;128(11):1467–73. 99. Sharma VK. Pulsed administration of corticosteroids in the treatment of alopecia areata. Int J Dermatol. 1996; 35(2):133–6. 100. Friedli A, Labarthe MP, Engelhardt E, Feldmann R, Salomon D, Saurat JH. Pulse methylprednisolone therapy for severe alopecia areata: an open prospective study of 45 patients. J Am Acad Dermatol. 1998;39(4 Pt 1):597–602. 101. Nakajima T, Inui S, Itami S. Pulse corticosteroid therapy for alopecia areata: study of 139 patients. Dermatology. 2007;215(4):320–4. 102. Kar BR, Handa S, Dogra S, Kumar B. Placebo-controlled oral pulse prednisolone therapy in alopecia areata. J Am Acad Dermatol. 2005;52(2):287–90. 103. Sladden MJ, Hutchinson PE. Is oral pulsed prednisolone useful in alopecia areata? Critical appraisal of a randomized trial. J Am Acad Dermatol. 2005;53(6):1100–1. 104. Happle R, Hausen BM, Wiesner-Menzel L. Diphencyprone in the treatment of alopecia areata. Acta Derm Venereol. 1983;63(1):49–52. 105. Lee S, Kim BJ, Lee YB, Lee WS. Hair regrowth outcomes of contact immunotherapy for patients with alopecia areata: a systematic review and meta-analysis. JAMA Dermatol. 2018;154(10):1145–51. 106. Wiseman MC, Shapiro J, MacDonald N, Lui H. Predictive model for immunotherapy of alopecia areata with diphencyprone. Arch Dermatol. 2001;137:1063–8. 107. MacDonald Hull S, Pepall L, Cunliffe WJ. Alopecia areata in children: response to treatment with diphencyprone. Br J Dermatol. 1991;125(2):164–8. 108. Schuttelaar ML, Hamstra JJ, Plinck EP, Peereboom-Wynia JD, Vuzevski VD, Mulder PG, et al. Alopecia areata in children: treatment with diphencyprone. Br J Dermatol. 1996;135(4):581–5. 109. Tosti A, Guidetti MS, Bardazzi F, Misciali C. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis. J Am Acad Dermatol. 1996;35(2 Pt 1):199–201. 110. Happle R. Antigenic competition as a therapeutic concept for alopecia areata. Arch Dermatol Res. 1980;267(1):109–14. 111. Hoffmann R, Wenzel E, Huth A, van der Steen P, Schaufele M, Konig A, et al. Growth factor mRNA levels in alopecia areata before and after treatment with the contact allergen diphenylcyclopropenone. Acta Derm Venereol. 1996;76(1):17–20. 112. Nowaczyk J, Makowska K, Rakowska A, Sikora M, Rudnicka L. Cyclosporine with and without systemic corticosteroids in treatment of alopecia areata: a systematic review. Dermatol Ther (Heidelb). 2020;10(3):387–99. 113. Lai VWY, Chen G, Gin D, Sinclair R. Cyclosporine for moderate-to-severe alopecia areata: a double-blind,

14 randomized, placebo-controlled clinical trial of efficacy and safety. J Am Acad Dermatol. 2019;81(3):694–701. 114. Farshi S, Mansouri P, Safar F, Khiabanloo SR. Could azathioprine be considered as a therapeutic alternative in the treatment of alopecia areata? A pilot study. Int J Dermatol. 2010;49(10):1188–93. 115. Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis. J Am Acad Dermatol. 2006;55(4):632–6. 116. Browne R, Stewart L, Williams HC. Is methotrexate an effective and safe treatment for maintaining hair regrowth in people with alopecia totalis? A critically appraised topic. Br J Dermatol. 2018;179(3):609–14. 117. Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients. J Am Acad Dermatol. 2017;76(1):22–8.

Hair Disorders 118. Jabbari A, Dai Z, Xing L, Cerise JE, Ramot Y, Berkun Y, et al. Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib. EBioMedicine. 2015;2(4): 351–5. 119. Phan K, Sebaratnam DF. JAK inhibitors for alopecia areata: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2019;33(5):850–6. 120. Trink A, Sorbellini E, Bezzola P, Rodella L, Rezzani R, Ramot Y, et al. A randomized, double-blind, placebo- and active-controlled, half-head study to evaluate the effects of platelet-rich plasma on alopecia areata. Br J Dermatol. 2013;169(3):690–4. 121. Marchitto MC, Qureshi A, Marks D, Awosika O, RengifoPardo M, Ehrlich A. Emerging nonsteroid-based procedural therapies for alopecia areata: a systematic review. Dermatol Surg. 2019;45(12):1484–506.

2 Male Androgenetic Alopecia Ralph M. Trüeb

Epidemiology and Clinical Presentation Androgenetic alopecia is the single most frequent cause of hair loss in both sexes. It is understood to represent a hereditary and androgen dependent, progressive thinning of the scalp hair that follows a defined pattern with significant differences between the sexes with respect to frequency, age of onset, and pattern of hair loss. While male pattern androgenetic alopecia is characterized by its typical bitemporal recession of hair and balding vertex, the female pattern is set apart by its diffuse thinning of the crown with an intact frontal hairline. Nevertheless, 4% of males may present with the female pattern of androgenetic alopecia [1]. Androgenetic alopecia affects approximately 50% of men by the age of 50 years and up to 70% of all males in later life [2]. First signs may occur during adolescence [3], leading to an age-dependent progressive, usually non-scarring patterned alopecia. Androgenetic alopecia that is clinically evident between the ages of 10 and 20 is called premature alopecia. Before puberty, it presents in both sexes exclusively with the female pattern [4], indicating pathogenic factors beyond androgen metabolism. Due to the frequency and an often significant impairment of life quality perceived by affected individuals, hair loss cures have been experimented on for ages. In a community-based survey of men conducted in Switzerland in 1998 to characterize the significance of scalp hair and self-perception of hair loss, and to evaluate treatment of hair loss, of 508 men aged 15–74 years (27% age 15–27 years, 41% age 30–49 years, and 32% age 50–74 years), 43% reported hair loss. Of these, 26% admitted to the use of hair-growth promoting agents, while 31% rejected use of hair-growth promoting agents because of no need, and 27% because they didn’t believe that they worked [5]. What is remarkable about the history of hair-loss solutions is that despite the more recent genuine advances in effective medical treatments, hair cosmetics, and surgical procedures, phony remedies continue to be marketed today with success. For prevention or treatment of hair loss, herbal solutions, oils, lotions, and vitamins have been advanced with questionable results. With the advance of medical technologies, ultraviolet light-emitting lamps, electrical-scalp simulators, and vacuum-cap machines have all been alleged to help stimulate the follicles to grow hair. Despite their claims, most lack

DOI: 10.1201/9780429465154-2

scientifically measurable efficacy in preventing hair loss or promoting hair growth.

Management Prerequisites for a successful management of hair loss are twofold: on the psychological and on the technical level. These require on the part of the attending physician a genuine interest in the patient’ complaint on the emotional level, and a genuine interest in the problem of hair loss on the scientific level [6]. On the psychological level, for a successful encounter at an office visit, one must be sure that the patient’s key concerns have been directly and specifically solicited and addressed: acknowledge the patient’s perspective on the hair loss problem, explore patient’s expectations from treatment, and educate patients into the basics of hair growth. Physicians should recognize that alopecia goes well beyond the simple physical aspects of hair loss. One must recognize the psychological impact of hair loss. Patients’ psychological reactions to hair loss are less related to physicians’ ratings than to patients’ own perceptions. Some patients have difficulties adjusting to hair loss. The best way to alleviate the emotional distress is to eliminate the hair disorder that is causing it. In other words, the intensity of the distress that the patient feels should be part of the clinician’s formula in deciding how aggressively to treat the hair disease. For example, a decision to use or not to use topical minoxidil or oral finasteride in a patient with a borderline clinical state of androgenetic alopecia, or to recommend or not to recommend hair surgery, may hinge on the amount of distress the patient feels from the alopecia. Finally, Maffei et al. [7] found the prevalence of personality disorders in subjects with androgenetic alopecia to be significantly higher than in the general population, and found the existence of three distinct personality profiles: suspicious, with grandiose sense of self-importance, obsessive, and socially withdrawn; impulsive, identity disordered, and socially maladjusted; or dramatic, emotional, and dependent. The psychological effects of hair loss may be hard to differentiate clinically from pre-existing psychopathology. Nevertheless, patients with personality disorders tend to experience more distress from hair loss than non-disordered patients, since these individuals lack a secure sense of self and effective coping skills. Ultimately, patients with personality

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Hair Disorders

  FIGURE 2.1  Successful treatment of premature alopecia in a 15-year-old boy (a) before and (b) after 6 months with 2% minoxidil solution b.i.d.

disorders tend to be more difficult to handle with respect to treatment of hair loss. Patient compliance issues are a problem in patients with paranoid, avoidant, or passive-aggressive (negativistic) personality disorders. Nocebo reactions are more frequent in patients with paranoid, passive-aggressive (negativistic), or histrionic personality disorders. Finally, overvalued ideas are typical for patients with histrionic or narcissistic personality disorders. On the technical level, prerequisites for success are: a specific diagnosis, a profound understanding of the underlying pathophysiology, the best available evidence gained from the scientific method for clinical decision making, and regular follow-up of the patient combining standardized global photographic assessments and epiluminescence microscopic photography with or without computer-assisted image analysis. The diagnosis and treatment of male pattern androgenetic alopecia are relatively straightforward and easy [8], with 5% topical minoxidil b.i.d. and 1 mg oral finasteride in men having excellent evidence levels (either randomized, double-blind, comparative clinical studies of high-quality, e.g., sample size calculation, flow chart of patient inclusion, ITT-analysis, sufficient size, or meta-analysis, which includes at least one randomized double-blind, comparative clinical studies of high-quality) for their therapeutic use [9]. Minoxidil promotes hair growth through increasing the duration of anagen. It causes hair follicles at rest to grow, and enlarges suboptimal follicles. Minoxidil was serendipitously discovered to be a hair growth promoting agent, when patient taking the compound orally for treatment of arterial hypertension, developed generalized hypertrichosis [10]. In an analysis of clinical trial data in 636 males, a therapeutic benefit of topical minoxidil solution was compared to age, duration

of balding, and diameter of balding vertex area [11]: age was found to be the denominator for predicting treatment success. The younger subjects experienced better efficacy than the older subjects (Figure 2.1), although clear treatment effects were noted also in the older age group that had still retained some hair (Figure 2.2). There was an inverse relationship between effect and duration of balding. Males with duration of balding 21 years. The diameter of vertex balding in men showed an inverse relationship with efficacy of minoxidil. Males with 15 cm. Finally, duration of hair loss less than 1 year compared to more than 10 years at onset of treatment resulted in a significantly more effective treatment with respect to stabilization of alopecia and new hair growth. van der Donk et al. [12] conducted a prospective study of the psychological changes in men who received either topical minoxidil solution or placebo, and found favorable changes in psychological adjustment and self-image among responders to topical minoxidil solution compared to placebo recipients, but only in the group aged above 35 years. In a study of 1495 men aged 20–40 years who suffered from androgenetic alopecia and were subjected to treatment with 5% topical minoxidil solution in the setting of two private dermatological practices, Mapar and Omidian [13] found that almost all the patients gradually avoided continuing the treatment. Only in a few patients was the cessation of medication due to adverse effects. The causes of discontinuation in the majority of patients were the low effect of medication and an aversion to this topical treatment method. The authors concluded that the insignificant cosmetic effect of minoxidil solution caused discontinuity of treatment among almost all patients.

17

Male Androgenetic Alopecia

  FIGURE 2.2  Successful treatment of senescent alopecia in a 70-year-old man (a) before and (b) after 6 months with 5% minoxidil solution b.i.d.

Therefore, treatment of male androgenetic alopecia in the 18 to 20–35 to 40 years age group with oral finasteride would seem to be more reliable than topical minoxidil. Finasteride is a competitive inhibitor of type 2 5α-reductase and inhibits the conversion of testosterone to dihydrotestosterone (DHT). The rationale for the use of finasteride to treat male androgenetic alopecia is based on the absence of androgenetic alopecia in men with congenital deficiency of type 2 5α-reductase, and the presence of increased 5α-reductase activity and DHT levels in balding scalp [14]. In 2002, the Finasteride Male Pattern Hair Loss Study Group conducted a clinical study over a 5-year-period on male androgenetic alopecia in patients aged 18–41 years with 1 mg oral finasteride daily. The hair counts increased in 48% of patients at 1 year and in 66% at 2 years. After 5 years of treatment, hair count remained similar to the 1-year level, but patients showed significant improvement in their gross hair appearance using global photography. It was suggested that the maximal number of hairs is obtained by the end of 1 year oral finasteride treatment, and further improvement results from increase in hair length, diameter, and pigmentation. Kaufman et al. showed that finasteride 1 mg/day over 5 years resulted in marked and sustained reduction of further development of male androgenetic alopecia. Therefore, 1 mg oral finasteride daily may be recommended to improve or to prevent progression of androgenetic alopecia in male patients [15]. In order to ascertain whether treatment with 1 mg oral finasteride can improve the quality of life of male patients with androgenetic alopecia, Yamazaki et al. [16] performed a study on Japanese males aged 19–76 years (average, 33.8) who answered Visual Analogue Scale (VAS), Dermatology Life Quality Index (DLQI), WHO/QOL-26, and State-Trait Anxiety Inventory (STAI) questionnaires before and after

administration of oral finasteride for 6 months. The changes in these indices before and after treatment were statistically analyzed, and the improved values of the indices in the high treatment responders (excellent or good) and the low treatment responders (moderate or no change) from baseline were compared. There was a statistical difference in the VAS and DLQI indices before and after administration of oral finasteride, while no significant change was found for the WHO/QOL-26 and STAI indices. Interestingly, comparison of high and low responders failed to reveal any statistical difference in the improvement of VAS and DLQI scores. The authors concluded that oral finasteride improves the quality of life of men treating androgenetic alopecia, and VAS and DLQI are useful for the evaluation of patients’ quality of life. However, oral finasteride failed to improve the patients’ anxiety, nor did its efficacy correlate with the level of reported anxiety. More recent studies demonstrated superiority of 0.5 mg oral dutasteride versus 1 mg oral finasteride in the treatment of male androgenetic alopecia (Figure 2.3). Dutasteride is a dual inhibitor of 5α-reductase isotypes 1 and 2 (used for treatment of benign prostatic hyperplasia) and therefore capable of decreasing DHT levels to a greater extent than finasteride. A study performed by Gubelin Harcha et al. [17] demonstrated efficacy and safety of 0.5 mg dutasteride in increasing hair growth and restoration in men with androgenetic alopecia, while being well-tolerated. In another study performed by Jung et al. [18], 0.5 mg dutasteride/day also proved to be effective in men with androgenetic alopecia recalcitrant to finasteride. The plasma half-life time of dutasteride (3–5 weeks) is significantly longer than that of finasteride (age-dependent, from 5 to 8 hours). With respect to possible sexual adverse effects related to therapeutic 5α-reductase inhibition (decreased libido and erectile dysfunction), it may therefore be advisable to start

18

Hair Disorders

 

FIGURE 2.3  Successful treatment of male androgenetic alopecia in a 28-year-old male with 5α-reductase inhibitors: (a) before and (b) after 6 months treatment with 1 mg oral finasteride, (c) further improvement 3 months after switch to 0.5 mg oral dutasteride.

patients on oral finasteride, and only if results are unsatisfactory at 6 months and tolerance is good, to switch from finasteride to dutasteride. The limited success rate of treatment of androgenetic alopecia with topical minoxidil or modulators of androgen metabolism, such as oral finasteride or dutasteride, means that further pathogenic pathways must be taken into account [19]. Both the vasorelaxant and hair growth-promoting effect of minoxidil is due to the actions of its sulphated metabolite, minoxidil sulphate. Minoxidil is sulphated by a group of enzymes known as sulfotransferases, some of which are

expressed in the hair follicle with wide inter-individual variations in the level of enzyme activity. Recent studies have proposed that enzymatic assay of sulfotransferase activity in plucked hair follicles may predict response to topical minoxidil in the treatment of androgenetic alopecia. A subsequent analysis confirmed the clinical utility and validity of a sulfotransferase enzyme test in successfully ruling out 95.9% of non-responders to topical minoxidil for the treatment of androgenetic alopecia [20]. Alternatively, topical minoxidil can be substituted with a minoxidil sulphate solution [21], or oral minoxidil in a dosage of 1.25 mg daily may be given [22].

Male Androgenetic Alopecia Both, in the human liver and in the hair follicle, sulfotransferase activity is significantly inhibited by salicylic acid [23]. The implication of a microscopic follicular inflammation in the pathogenesis of androgenetic alopecia has emerged from several independent studies: an early study referred to an inflammatory infiltrate of activated T cells and macrophages in the upper third of the hair follicles, associated with an enlargement of the follicular dermal sheath composed of collagen bundles (perifollicular fibrosis), in regions of actively progressing alopecia [24]. Horizontal section studies of scalp biopsies indicated that the perifollicular fibrosis is generally mild, consisting of loose, concentric layers of collagen that must be distinguished from cicatricial alopecia. The significance of follicular microinflammation and fibrosis in androgenetic alopecia has remained controversial. Nevertheless, morphometric studies in male patients with androgenetic alopecia treated with topical minoxidil showed that 55% of those with microinflammation had regrowth in response to treatment, in comparison to 77% in those patients without inflammation and fibrosis [25]. An important question is how the inflammatory reaction pattern is generated around the individual hair follicle. Inflammation is regarded a multistep process which may start from a primary event. The observation of a perifollicular infiltrate in the upper follicle near the infundibulum suggests that the primary causal event for the triggering of inflammation might occur near the infundibulum. On the basis of this localization and the microbial colonization of the follicular infundibulum with Propionibacterium spp., Staphylococcus spp., Malassezia spp., or other members of the transient flora, one could speculate that microbial toxins or antigens could be involved in the generation of the inflammatory response. The production of porphyrins by Propionibacterium spp. in the pilosebaceous duct has also been considered to be a possible cofactor of this initial pro-inflammatory stress. Alternatively, keratinocytes themselves may respond to chemical stress from irritants, pollutants, and UV irradiation, by producing radical oxygen species and nitric oxide, and by releasing intracellularly stored IL-1α. This pro-inflammatory cytokine by itself has been shown to inhibit the growth of isolated hair follicles in culture. Moreover, adjacent keratinocytes, which express receptors for IL-1, start to engage the transcription of IL-1 responsive genes: mRNA coding for IL-1β, TNFα, and IL-1α, and for specific chemokine genes, such as IL-8, and monocyte chemoattractant protein-1 (MCP-1) and MCP-3, themselves mediators for the recruitment of neutrophils and macrophages, have been shown to be upregulated in the epithelial compartment of the human hair follicle. Besides, adjacent fibroblasts are also fully equipped to respond to such a pro-inflammatory signal. The upregulation of adhesion molecules for blood-borne cells in the capillary endothelia, together with the chemokine gradient, drive the transendothelial migration of inflammatory cells, which include neutrophils through the action of IL-8, T cells and Langerhans cells at least in part through the action of MCP-1. After processing of localized antigen, Langerhans cells, or alternatively keratinocytes, which may also have antigen presenting capabilities, could then present antigen to newly infiltrating T-lymphocytes and induce T-cell proliferation. The antigens are selectively destroyed by infiltrating macrophages,

19 or natural killer cells. On the occasion that the causal agents persist, sustained inflammation is the result, together with connective tissue remodeling, where collagenases, such as matrix metalloproteinase (also transcriptionally driven by proinflammatory cytokines) play an active role. Collagenases are suspected to contribute to the tissue changes in perifollicular fibrosis [26]. So far, the inflammatory component has not been included in treatment protocols for androgenetic alopecia. PiérardFranchimont et al. [27] hypothesized on a microbial-driven inflammatory reaction abutting on the hair follicles and conducted a study to compare the effect of 2% ketoconazole shampoo to that of an unmedicated shampoo used in combination with or without 2% minoxidil therapy. They found that hair density and size and proportion of anagen follicles were improved almost similarly by both ketoconazole and minoxidil regimens, and concluded that there may be a significant action of ketoconazole upon the course of androgenic alopecia and that Malassezia spp. may play a role in the inflammatory reaction. Later, Berger et al. [28] performed a 6-month, randomized, investigator-blinded, parallel-group clinical study with healthy men between the ages of 18 and 49 years exhibiting Hamilton-Norwood type III vertex or type IV baldness to assess the hair growth benefits of a 1% pyrithione zinc shampoo. The efficacy of a 1% pyrithione zinc shampoo (used daily) was compared with that of 5% minoxidil topical solution (applied twice daily), a placebo shampoo, and a combination of the 1% pyrithione zinc shampoo and the 5% minoxidil topical solution. Hair count results showed a significant net increase in total visible hair counts for the 1% pyrithione zinc shampoo, the 5% minoxidil topical solution, and the combination treatment groups relative to the placebo shampoo after 9 weeks of treatment. The relative increase in hair count for the 1% pyrithione zinc shampoo was slightly less than half that for the minoxidil topical solution. However, no advantage was seen in using both the 5% minoxidil topical solution and the 1% pyrithione zinc shampoo. In the original description of fibrosing alopecia in a pattern distribution, patients displayed progressive scarring alopecia in a pattern distribution [29]. Close clinical examination reveals obliteration of follicular orifices, perifollicular erythema, and follicular keratosis limited to the area of androgenetic hair loss. Histological findings of androgenetic alopecia, i.e., increased numbers of miniaturized hair follicles with underlying fibrous streamers, are evident in the majority of patients, and associated with a perifollicular lymphocytic infiltrate. A pattern of follicular interface dermatitis targeting the upper follicle is found in early lesions, whereas perifollicular lamellar fibrosis and the presence of selectively fibrosed follicular tracts characterize late lesions. Eventually, Olsen [30] acknowledged the existence of cicatricial pattern hair loss. For successful management of male androgenetic alopecia one must remain open-minded for the possibility of a multitude of cause-relationships underlying hair loss, and accordingly for the potential of combination treatments. It is important to manage male androgenetic alopecia strategically with the variety of current therapeutic options depending on the individual’s needs. Ultimately, combination treatments

20

Hair Disorders

  FIGURE 2.4  Successful treatment with combination therapy with 1 mg oral finasteride and 5% topical minoxidil solution b.i.d.: (a) before and (b) after 24 months treatment.

substantial improvement and give satisfactory results, as long as the patient has a realistic expectation regarding the treatment results [32]. Hair-line design, evaluation of the donor and recipient areas as well as the discussion of graft numbers are basic parts of the hair transplant consultation. There are two donor hair harvesting techniques that are performed under local anesthesia: in one technique, a strip of scalp skin is taken from the occipital area, which then is divided into mini- or

with topical minoxidil, oral finasteride, surgery, and appropriate scalp care, including anti-inflammatory agents, may act synergistic (Figures 2.4–2.6). The scientific rationale for such an approach is given, but again there is a need for clinical studies to establish increase in efficacy of combination regimens and adjuvant treatments [31]. In patients with advanced hair loss, autologous hair transplantation represents the only treatment that can produce

  FIGURE 2.5  Successful treatment of male androgenetic alopecia in a 29-year-old man (a) after autologous hair transplantation and (b) 6 months of added 1 mg oral finasteride.

21

Male Androgenetic Alopecia

  FIGURE 2.6  Successful treatment of male androgenetic alopecia with evidence of follicular inflammation and fibrosis in a 30-year-old man with 1 mg oral finasteride and 100 mg oral doxycycline in combination with a topical compound of 3% minoxidil and 0.2% triamcinolone acetonide and witch hazel-based shampoo. (a) Before and (b) after 9 months.

micro-grafts, each containing 1–4 hairs. The grafts are then planted into tiny slits in the desired recipient area. The other technique is follicular unit extraction (FUE): multiple follicles are harvested with small 1 mm punches and planted in the target area, avoiding the occipital linear scar of the strip technique. However, FUE is more labor intensive and therefore usually more expensive. A natural looking result can be achieved with both procedures. One or two sessions usually provide a good coverage of a balding recipient area. Final results are usually seen 6–8 months after the surgery. Ultimately, the influence of the prescribing physician should be kept in mind, since inspiring confidence versus skepticism and fear clearly impacts the outcome of treatment. Treatment success relies on patient compliance that, on its part, relies on comprehension of treatment benefit, confidence, and motivation. A positive physician-patient relationship and regular ­follow-up visits (at 3, 6, 12, and 24 months; Figure 2.1), including standardized photographic assessments, are the most important factors in determining the degree of patient compliance. The overall goal is to gain short-term compliance as a prerequisite to long-term adherence to treatment. Recommendations for improvement of patient compliance are summarized in Table 2.1. More recently, the post-finasteride syndrome (PFS) has been claimed to occur in men who have taken oral finasteride to treat hair loss or benign prostatic hyperplasia [33]. While the incidence of persistent sexual, mental, and physical side effects despite quitting finasteride is unknown, and the condition is not recognized by the scientific community, individuals who suffer from PFS do present with very distinctive and homogenous symptoms. The concept has emerged from reports of non-dermatologists, neuroendocrinological research, case reports and uncontrolled studies. These have been scrutinized

by hair experts who found that persistent sexual side effects were only documented in low-quality studies with a strong bias selection, and a significant nocebo effect [34]. Others totally dispute the credibility of the PFS [35]. In any case, the PFS is a problem that has to be dealt with. Low quality studies neither confirm nor refute the condition as a valid nosologic entity. Therefore, it is as inappropriate to dismiss the condition, as it would be to demonize finasteride for treatment of male pattern hair loss. Whether the PFS represents a nocebo reaction, specifically an induced delusional disorder on the background of a histrionic personality disorder [36], or a real drug-related adverse event is irrelevant, while the best way to alleviate the TABLE 2.1 Recommendations for Improvement of Patient Compliance • Only recommend treatments that are effective in circumstances when they are required • Prescribe the minimum number of different medications, e.g., combining active ingredients into a single compound • Simplify dosage regimen by selecting different treatment or using a preparation that needs fewer doses during the day • Select treatments with lower levels of side effects or fewer concerns for long-term risks • Discuss possible side effects, and whether it is important to continue medication regardless of those effects • Advice on minimizing or coping with side effects • Regular follow-up for reassurance on drug safety and treatment benefits • Develop trust so patients don’t fear embarrassment or anger if unable to take a particular drug, allowing the doctor to propose a more acceptable alternative Source: From Trüeb RM, Lee W-S. Male Alopecia. Guide to Successful Management. Springer International Publishing Switzerland (2014).

22 TABLE 2.2 Recommendations for Prescription of Oral Finasteride in Treatment of Male Androgenetic Alopecia • Efficacy and safety of oral finasteride for treatment of male androgenetic alopecia in men aged 18 through 40 with mild to moderate androgenetic alopecia (Hamilton-Norwood IIv-V) has been demonstrated 24 • Refrain from prescribing oral finasteride to a patient with a personal history of depression, histrionic personality disorder, sexual dysfunction, or fertility problems • When fertility is an issue, may consider performing a sperm count before and during treatment with oral finasteride (respective commercial kits have become available) • In any case of adverse effects, immediately stop oral finasteride treatment • In all men 45 and over, perform PSA before, after starting therapy with oral finasteride, and thereafter on twice yearly basis. The level should drop by ca. 50% upon initiation of therapy. In case of increase >0.4 ng/mL per year, refer to urologist to check prostate condition • For men who choose regular prostate-cancer screening, the use of oral finasteride meaningfully reduces the risk of prostate cancer Source: Modified from Trüeb RM, Lee W-S. Male Alopecia. Guide to Successful Management. Springer International Publishing Switzerland (2014).

emotional distress related to hair loss is to effectively treat the condition causing the problem. It is not sufficient to only discuss the plausibility of the PFS. There is a need for practical recommendations to include such important issues as: patient selection and risk assessment, appropriate patient information, how to react in case of drug-related adverse events, issues of fertility and malignancy, management of the PFS, and alternatives, specifically the use of topical finasteride [37]. Up-to-date there is no predictive factors for the risk of development of the PFS, and there is no known treatment for the

Hair Disorders disorder. Preliminary recommendations for the prescription of oral finasteride in the treatment of male androgenetic alopecia are summarized in Table 2.2. Finally, topical finasteride has emerged in a concentration of 0.25% in combination with 5% minoxidil b.i.d. as an effective alternative (Figure 2.7) [38]. As a basic principle, the doctor’s choice has to be consistent with the patient’s philosophy of living. This particularly pertains to the prescription of oral finasteride or dutasteride for treatment of male pattern hair loss, where a choice must be made for long-term systemic medication with known (sexual side-effects, gynecomastia, fertility issues) and unknown risks (post-finasteride syndrome, breast cancer) for treatment of a basically cosmetic condition.

REFERENCES





1. Trüeb RM. Female pattern baldness in men. J Am Acad Dermatol 1993;29:782–3. 2. Norwood OT. Male-pattern baldness: classification and incidence. South Med J 1975;68:1359–70. 3. Price VH. Androgenetic alopecia in adolescents. Cutis 2003 Feb;71(2):115–21. 4. Griggs J, Burroway B, Tosti A. Pediatric androgenetic alopecia: a review. J Am Acad Dermatol 2019 Aug 12;S0190–9622(19):32565–4. 5. Trüeb RM, de Viragh PA, and Swiss Trichology Study Group. Status of scalp hair and therapy of alopecia in men in Switzerland. Praxis (Bern 1994) 2001;90:241–8. 6. Trüeb RM. The difficult hair loss patient: a particular challenge. Int J Trichoology 2013;5:110–11. 7. Maffei C, Fossati A, Rinaldi F, Riva E. Personality disorders and psychopathologic symptoms in patients with androgenetic alopecia. Arch Dermatol 1994;130(7):868–7.

  FIGURE 2.7  Successful treatment of male androgenetic alopecia in a 45-year-old man with a topical solution of 5% minoxidil and 0.25% finasteride b.i.d. (a) Before and (b) after 6 months.

Male Androgenetic Alopecia

























8. Blume-Peytavi U, Blumeyer A, Tosti A, Finner A, Marmol V, Trakatelli M, Reygagne P, Messenger A, European Consensus Group. S1 guideline for diagnostic evaluation in androgenetic alopecia in men, women and adolescents. Br J Dermatol 2011 Jan;164(1):5–15. 9. Blumeyer A, Tosti A, Messenger A, Reygagne P, Del Marmol V, Spuls PI, Trakatelli M, Finner A, Kiesewetter F, Trüeb R, Rzany B, Blume-Peytavi U. European Dermatology Forum (EDF). Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. J Dtsch Dermatol 2011;Ges;9 (Suppl 6):S1–57. 10. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol 2004;150:186–94. 11. Rundegren J. Pattern alopecia: what clinical features determine the response to topical minoxidil treatment? IHRS2004 abstract B2.4, JDDG 2004;2:500. 12. van der Donk J, Passchier J, Dutree-Meulenberg RO, Stolz E, Verhage F. Psychologic characteristics of men with alopecia androgenetica and their modification. Int J Dermatol 1991;30:22–8. 13. Mapar MA, Omidian M. Is topical minoxidil solution effective on androgenetic alopecia in routine daily practice? J Dermatol Treat 2007;18(5):268–70. 14. Kaufman KD. Androgen metabolism as it affects hair growth in androgenetic alopecia. Dermatol Clinics 1996;14:697–711. 15. Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R, Bergfeld W, Price VH, Van Neste D, Roberts JL, Hordinsky M, Shapiro J, Binkowitz B, Gormley GJ. Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol 1998;39:578–89. 16. Yamazaki M, Miyakura T, Uchiyama M, Hobo A, Irisawa R, Tsuboi R. Oral finasteride improved the quality of life of androgenetic alopecia patients. J Dermatol 2011;38:773–7. 17. Gubelin Harcha W, Barboza Martínez J, Tsai TF, Katsuoka K, Kawashima M, Tsuboi R, Barnes A, Ferron-Brady G, Chetty D. A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. J Am Acad Dermatol 2014;70(3):489–98. 18. Jung JY, Yeon JH, Choi JW, Kwon SH, Kim BJ, Youn SW, Park KC, Huh CH. Effect of dutasteride 0.5 mg/d in men with androgenetic alopecia recalcitrant to finasteride. Int J Dermatol 2014;53(11):1351–7. 19. Trüeb RM. Molecular mechanisms of androgenetic alopecia. Exp Gerontol 2002;37:981–90. 20. Goren A, Castano JA, McCoy J, Bermudez F, Lotti T. Novel enzymatic assay predicts minoxidil response in the treatment of androgenetic alopecia. Dermatol Ther 2014;27(3):171–3. 21. Dias PCR, Miot HA, Trüeb RM, Ramos PM. Use of minoxidil sulfate versus minoxidil base in androgenetic alopecia treatment: friend or foe? Skin Appendage Disord 2018 Oct;4(4):349–350. 22. Ramos PM, Sinclair RD, Kasprzak M, Miot HA. Minoxidil 1 mg oral versus minoxidil 5% topical solution for the treatment of female-pattern hair loss: a randomized clinical trial. J Am Acad Dermatol 2020 Jan;82(1):252–3.

23 23. Goren A, Sharma A, Dhurat R, J Shapiro J, Sinclair R, Situm M, Kovacevic M, Lukinovic Skudar V, Goldust M, Lotti T, McCoy J. Low-dose daily aspirin reduces topical minoxidil efficacy in androgenetic alopecia patients. Dermatol Ther 2018 Nov;31(6):e12741. 24. Jaworsky C, Kligman AM, Murphy GF. Characterisation of inflammatory infiltrates in male pattern alopecia: implication for pathogenesis. Br J Dermatol 1992;127:239–46. 25. Whiting DA. Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia. J Am Acad Dermatol 1993;28:755–63. 26. Mahé YF, Michelet JF, Billoni N, Jarrousse F, Buan B, Commo S, Seint-Leger D, Bernard BA. Androgenetic alopecia and microinflammation. Int J Dermatol 2000;39:576–84. 27. Piérard-Franchimont C, De Doncker P, Cauwenbergh G, Piérard GE. Ketoconazole shampoo: effect of long-term use in androgenic alopecia. Dermatology 1998;196:474–7. 28. Berger RS, Fu JL, Smiles KA, Turner CB, Schnell BM, Werchowski KM, Lammers KM. The effects of minoxidil, 1% pyrithione zinc and a combination of both on hair density: a randomized controlled trial. Br J Dermatol 2003;149:354–62. 29. Zinkernagel MS, Trüeb RM. Fibrosing alopecia in a pattern distribution. Patterned lichen planopilaris or androgenetic alopecia with a lichenoid tissue reaction pattern? Arch Dermatol 2000;136:205–211. 30. Olsen EA. Female pattern hair loss and its relationship to permanent/cicatricial alopecia: a new perspective. J Investig Dermatol Symp Proc 2005;10:217–21. 31. Rajput RJ. Controversy: is there a role for adjuvants in the management of male pattern hair loss? J Cutan Aesthet Surg 2010 May-Aug; 3(2): 82–6. 32. Bunagan MJ, Banka N, Shapiro J. Hair transplantation update: procedural techniques, innovations, and applications. Dermatol Clin 2013;31:141–53. 33. Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML. Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med 2011;8(3): 872–84. 34. Fertig R, Shapiro J, Bergfeld W, Tosti A. Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome. Skin Appendage Disord 2017;2(3–4):120–9. 35. Grimalt R. Post-finasteride syndrome (CS2-3). 10th World Congress for Hair Research Kyoto, Japan, October 31– November 3, 2017. 36. Trüeb RM, Régnier A, Dutra Rezende H, Gavazzoni Dias MFR. Post-finasteride syndrome: an induced delusional disorder with the potential of a mass psychogenic illness? Skin Appendage Disord 2019 Aug;5(5):320–6. 37. Rezende HD, Dias MFRG, Trüeb RM. A Comment on the post-finasteride syndrome. Int J Trichology 2018 Nov-Dec;10(6):255–61. 38. Suchonwanit P, Srisuwanwattana P, Chalermroj N, Khunkhet S. A randomized, double-blind controlled study of the efficacy and safety of topical solution of 0.25% finasteride admixed with 3% minoxidil vs. 3% minoxidil solution in the treatment of male androgenetic alopecia. J Eur Acad Dermatol Venereol 2018 Dec;32(12):2257–63.

3 Female Androgenic Alopecia Demetrios Ioannides, Ilias Papadimitriou, and Efstratios Vakirlis

Introduction: Epidemiology Female pattern androgenic alopecia (FAGA) is a non-scarring alopecia that mostly affects post-menopausal women; in such cases, reduced hair density occurs, over the crown and frontal scalp, while the front hairline is mainly unaffected. The disease may initiate in puberty, however, it more commonly affects women of higher age. In Caucasian women, the prevalence during the third to fourth decade is 3–12%, while in the fifth decade increases to 14–28% to reach a peak of 29–59% in women older than 70 years.1,2 The term “female pattern hair loss” (FPHL) was used in the past to describe the disease, but recently it has been clarified that this term refers to all the alopecias presenting a FAGA distribution.3 FAGA is a chronic disease, typically realized by the patient years after its commencement. The gradual thinning and disappearing of hair becomes evident only when a great portion of the scalp has been affected. Occasional or continuous hair shedding may, in some cases, be indicative of the early stages of FAGA. The rise of the disease may precede menarche or present a late onset during the post-menopausal age.2,4–6 The clinical presentation is characterized by the miniaturization and rarefaction of hair over the mid-frontal scalp that may spare the frontal hairline without any signs of inflammation or scarring. Sometimes the clinical presentation is similar to the male pattern of androgenic alopecia, accompanied either with increased temporal involvement or not, with vertex rarefaction. Hair-loss is evident even in the early stages being particularly visible when the patient’s hairstyle parts the hair along the midline. Accordingly, a “Christmas tree” pattern, having its base at the front, develops in the frontal hairline2,7 (Figure 3.1). The first classification system for the clinical assessment of FAGA was proposed by Ludwig in 1977, and is still in use. His scale consists of three stages: stage I is characterized by perceivable mild thinning of the hair over the anterior part of the crown with a wide midline part, while the front hairline remains unaffected; in stage II hair recession on the crown, frontal, and vertex region becomes evident; in stage III the severe decrease in hair density over the crown and the diffuse rarefaction produces an AGA-like image, that is, mostly encountered in post-menopausal women (Figure 3.2a–3.2e). Nevertheless, many alternative scales were introduced since then;8 for example, recently, a new five-point scale has been

24

introduced, based on the extend of hair loss in the midline part.9,10 The psychological impact of FAGA to the social life of women is more prominent, in comparison to men suffering with AGA, since hair and hairstyle for women is a sign of femininity and beauty.11 Several surveys indicate close correlation between hair-loss and sleep disorders, lower self-esteem and poor body-image.12

Pathogenesis – Genetics The pathogenesis of FAGA is multi-factorial. FAGA – as in the case of AGA – is characterized by the shortening of the anagen phase, and the miniaturization and transformation of terminal hair to vellus hair.13–15 This leads to an increased number of hair being in the telogen phase, and a decreased number to the anagen, respectively; as a result, hair shedding and low hair coverage occur. While in male androgenic alopecia (MAGA) androgens have a main role in the path of follicle miniaturization, in FAGA this is less clear. Nevertheless, circulating and topically synthesized estrogen and androgen levels are able to influence the hair follicles in FAGA.16 In MAGA, the enzyme 5α-reductase type II transforms, inside the hair follicle, free testosterone into dihydrotestosterone (DHT). DHT-binding hair follicles present androgen receptors (AR)17; the higher the affinity that DHT presents for the AR, the more important the role in MAGA.18 It has been demonstrated that women with FAGA present no evidence of clinical or biochemical hyperandrogenism, hence, rendering the role of androgens controversial.19,20 In particular, comparisons between the levels of circulating testosterone of women with FAGA and those of control samples present no variations.21 A certain case of a female patient with FAGA, presenting complete androgen insensitivity syndrome, suggests that androgens may act with unknown mechanisms.22 Levels of 5α-reductase in susceptible hair follicles with FAGA remain low, while aromatase, which competes for the same substance, but converts testosterone to estradiol, records higher values.23 Estrogens play an unclear role in FAGA. On the one hand, estrogens may inhibit 5α-reductase and improve hair loss.24 This condition is confirmed by the increased prevalence of the disease in postmenopausal females and women treated with

DOI: 10.1201/9780429465154-3

25

Female Androgenic Alopecia

FAGA include insulin resistance, microvascular insufficiency, and inflammatory abnormalities.30 Recently, the genetic predisposition and the polygenic inheritance, attributed to a combination of mutations have been confirmed.31 The proposed theory dictates that variations of the X-linked AR gene, which is a nuclear transcription factor, consists of CAG repetitions that affect its transcriptional activity.32 It has been proposed that the number of CAG repetitions affects the probability to develop FAGA. In line with this theory, the Hair Genetic Test measures the length of CAG repetitions in the AR test, and results of short repetitions are linked with a significant risk of developing FAGA.33

Diagnosis

FIGURE 3.1  Christmas tree hair loss pattern.

aromatase inhibitor; both conditions having low estrogen levels and induced hair loss.16,25,26 Moreover, elevated estrogen levels during pregnancy result in the prolongation of the anagen phase of the hair follicle, and the sudden loss of estrogens, post-partum, is believed to trigger the telogen gravidarium.27 Topical estrogen lotions have been used with controversial results.28 On the other hand, the higher estrogen levels, attributed to an aromatase gene variant, have been associated with the development of FAGA.29 Other parameters that may trigger

The diagnosis of FAGA is clinical; it is based on the typical clinical picture, the personal and family medical history, and it is also accompanied with physical examination and hair evaluation methods. When signs of the characteristic clinical pattern are absent, non-invasive hair evaluation methods, such as pull test, trichoscopy, trichogram, and laboratory tests or invasive technics, like skin biopsy, may be employed.34 The hair-pull test evaluates the number of shedding telogen hair via gently pulling. In the early stages of FAGA, hair-pull test results may be positive.35 The hallmark for the diagnosis of FAGA is provided by the findings of trichoscopy. Anisotrichosis is characterized by hair shafts miniaturization to a percentage of greater than 20%, which is more apparent at the central hair part area36–39 (Figure 3.3). Rakowska et al. proposed three major and three

FIGURE 3.2  (a) Ludwig I. Perceivable mild thinning of hair over the anterior part of the crown, (b) Ludwig II. Decreased hair density over frontal and vertex region, (c) and (d) Ludwig III. Severe decrease in hair density and prominent diffuse rarefaction, (e) increased temporal involvement.

26

Hair Disorders

FIGURE 3.3  (a) and (b) Trichoscopy of a central hair part reveals anisotrichosis, more than 10% of thin hairs, single-hair pilosebaceous units, vellus hairs and peripilar signs (perifollicular discoloration).

minor criteria for the diagnosis of FAGA (Table 3.1).40 The presence of two major criteria alone, or one major in combination with two minor, secures the diagnosis of FAGA with a specificity of 98%. Likewise, the peripilar sign, that corresponds to perifollicular inflammation, is also suggestive of FAGA (Figure 3.2a and 3.2b).41 Videodermoscopy provides higher magnification than hand-held dermoscopy, while it also enables storage of retrieved images. With the support of appropriate software, monitoring of the hair density under treatment can also be performed. When applying trichogram, abnormal anagen/telogen hair ratios were observed to a percentage of 62% and 84.2% of the early and advanced cases respectively.42 In difficult cases, namely when other types of alopecia cannot be excluded, scalp biopsy may be performed. It is advised to conduct a 4-mm punch at the vertex of the scalp since hair miniaturization may be normal at bitemporal region. Both vertical as well as horizontal sections must be evaluated.43,44 Terminal/vellus-like hair ratios below 3:1 are considered as diagnostic for FAGA, as opposed to normal ratios of 7:1.45 TABLE 3.1 Fulfillment of Two Major Criteria or One Major and Two Minor Criteria is Required to Diagnose FAGA Based on Trichoscopy Major Criteria

Minor Criteria

More than four yellow dots in four images at a 70-fold magnification in the frontal area Lower average hair thickness in the frontal area in comparison with the occiput (calculated from not less than 50 hairs from each area) More the 10% of thin hairs (below 0.03 mm) in the frontal area

Ratio of single-hair unit percentage, frontal area to occiput >2:1 Ratio of number of vellus hairs, frontal area to occiput >1.5:1 Ratio of hair follicles with perifollicular discoloration, frontal area to occiput >3:1

Source: Data from Rakowska A et al. Int J Trichology. 2009;1(2):123.

Other histopathological features are the increased number of follicular streamers, and the mild perifollicular inflammation with fibrosis of the upper portion of the hair follicle.43,46 In the majority of the cases, there is no underlying hormonal abnormality; hence, additional laboratory tests are needed, such as thyroid function, iron and zinc levels, as well as prolactine. When the clinical presentation suggests androgen excess – hirsutism, severe acne or menstrual abnormalities – the hormonal activity must be evaluated.21,47

Differential Diagnosis The differential diagnosis of FAGA includes: Chronic tellogen effluvium, post-partum hair loss, diffuse alopecia areata, trichotillomania, frontal fibrosing alopecia, and other hair loss conditions caused by hypothyroidism and iron deficiency.

Treatment FAGA is a chronic disease and poses only cosmetic concerns. It’s significantly negative psychological impact on women’s everyday life is indicative of longstanding treatment. At the same time, the expectations of the treatment must be realistic, the aim being to reduce hair loss and promote hair growth to a certain extent. Various treatment approaches are available nowadays, but with uncertain efficacy. It is clear though that early initiation of therapy as well as the simultaneous application of different treatment combinations may prove efficient.

Pharmacological Treatments • Oral minoxidil Oral minoxidil, a medication originally prescribed for the treatment of hypertension, has made a comeback in being used as treatment for hair loss. In order

27

Female Androgenic Alopecia to avoid potential side effects often occurring–low blood pressure, increased heart rate, dizziness etc.– low doses have been administered (0.25  mg/day), which show increased hair density after 6 months of treatment and good tolerability.48 • Topical minoxidil The application of 1 mL of topical minoxidil (2%) twice per day is currently the only treatment approved by FDA for females above 18 years of age with FAGA.49 The aforementioned treatment demonstrated a noticeable efficacy according to a Cochrane systematic review.50 Even though the detailed function of minoxidil is not fully comprehended, it nevertheless induces hair growth via extending the anagen phase and by shortening the telogen. This mechanism occurs possibly due to the vasodilatatory, proliferative, andiandrogenic, and anti-inflammatory effects of minoxidil.51,52 Other researchers state that minoxidil acts as a biological response-modifier by turning testosterone into less active androgens.53 Minoxidil is available both in a solution form (2% and 5%) and as a foam spray for the treatment of FAGA. The efficacy and safety of minoxidil in hair loss have been confirmed via several randomized placebo-controlled studies.54–57 The topical application of 5% minoxidil, twice per day, has been proven as more effective compared to that of 2%, but it has been associated with increased local side effects – facial hypertrichosis, contact dermatitis with pruritus and irritation; the latter may be avoided by using foam spray products.58,59 • Antiandrogen Therapies (systemic) These systemic therapies are divided into two main categories: Peripheral antiandrogens and androgen receptor antagonists. 1. Peripheral antiandrogens a. Finasteride Finasteride inhibits the 5α-reductase type II, an enzyme that converts the free testosterone to DHT. It is FDA approved for the treatment of MAGA in doses of 1 mg per day. This treatment decreases hair loss progression in males with mild to moderate AGA disease above 18-year-old49,58; however, in cases of postmenopausal women with FAGA, it provided no beneficial effects when compared to placebo treatments applied for a period of 1 year.60 Nevertheless, studies regarding the use of finasteride by premenopausal women suggested that higher doses (2.5–5 mg/ day) may potentially be necessary to treat FAGA.61–63 Finasteride is contraindicated for women being in a reproductive age due to the risk of developing feminization, in male fetuses, and liver abnormalities. Finasteride 0.05% in topical gel has been promising for the treatment of pattern hair loss.64

b. Dutasteride Dutasteride inhibits both 5α-reductase type I and II, but it is currently not approved by the FDA for the treatment of AGA and FAGA. It has been used successfully in males with AGA, at a dose of 2.5 mg/day, reducing the serum DHT by more than 90%, while it has been also promising for treating FAGA, in doses ranging from 0.25–0.5  mg/day, with no occurring side effects.65,66 Meso­ therapy with dutasteride has also been proven helpful for augmenting hair growth in women treated for 18 weeks67; however, as in the case of finasteride, its administration should be avoided to women in childbearing age or to those with an abnormal liver function. 2. Androgen receptor antagonists a. Spironolactone Spironolactone, although it is not FDA approved for FAGA treatment, it is often used for such purpose as well as for hirsutism and acne. It acts via reducing testosterone levels, but it can also block the AR in tissues.68 Treatment should start in low doses of 50 mg/ day and gradually increase in 100–200 mg/day. When combined with 5% minoxidil, it yields better results.69 Spironolactone is adviced not to be used during pregnancy since it can promote hypertension, nausea, and menorrhagia. b. Cyprotenone acetate Cyprotenone is an antagonist of DHT for AR in tissues and also inhibits the secretion of gonadotropin hormone. The usage of cyprotenone in FAGA alone (in doses of 25–50 mg/ day on the first 10 days of the menstrual cycle) or in combination with ethinyl-estradiol or spinololactone, has demonstrated good results especially in cases of hyperandrogenism.50,70 c. Flutamide Flutamide is a non-steroidal antiandrogen, effective in the treatment of FAGA, providing long-term remission. It inhibits the androgens from binding with their receptors and it is used in yearly reducing doses of 250, 125, and 62.5 mg/day. However, the liver function has to be monitored since Flutamide may cause dose-dependent liver dysfunction.71 • Topical estrogens (fulvestrant, alfatradiol) The efficacy of topical estrogens has not been supported by sufficient evidence yet.13,72 • Topical prostaglandin analogs The usage of prostaglandin (latanoprost, travoprost, and bimatoprost), for the treatment of glaucoma, produced eyelash growth as a side effect; since then, bimatoprost has been used for eyelash hypotrichosis as an FDA approved treatment.73 Further

28

Hair Disorders studies are needed to clarify their obscure contribution in hair growth in FAGA and AGA.74 • Topical ketoconazole Topical ketoconazole shampoo stimulates hair growth by depressing androgen pathways, hence, providing valid results, especially when combined with systemic finasteride.75,76

Surgical Treatment: Hair Transplant Surgery Transplantation of hair follicles, taken from the occipital area (donor area) and placed in the recipient area, is based on the fact that occipital follicles lack androgen-sensitive receptors. These invasive methods, namely the FUE (follicular unit extraction) and the FUT (follicular unit transplantation), consist of the extraction of androgen resisting hair follicles and their transplantation to the recipient area by using hand held, motorized, and robotic devices. The two techniques share the implantation method, while the extraction of the hair follicles is totally different. With the FUT an elliptical strip in the donor area is performed and the harvesting of the hair follicles is accomplished with the help of microscopes. This provides excellent results in terms of excising healthy hair follicles, while the defect is closed with the help of the trichophytic technique leaving a minimal linear scar that is difficult to distinguish. With this method, a large number of follicles can be obtained, while future hair transplant operations can be performed, in the same patient, by excising the old linear scar together with the new strip. With the FUE method, micro punches are used in order to excise the intact hair follicle at once. With this technique, a large number of small circular scars is created, while the possibility of injuring the grafts while excising is greater. Moreover, in order to achieve large numbers of grafts, the harvesting area is expanded beyond the occipital region to the temporal zone, while the shaving of these zones is mandatory. The transplanted hair follicles will create new hair in a period of 3–6 months.77,78 The choice of technique will be made on behalf of the surgeon, following careful evaluation of the patient’s clinical aspect.

Light Therapy Light sources of different wavelengths are currently used for the treatment of FAGA, but the exact details of their mechanism are not yet known. Low-level-laser-light (LLLL) therapy, is presumed to be able to promote vasodilatation, activate dormant hair follicles and increase the production of adenosine triphosphate.79 Nowadays, many light sources for home use and special laser medical devices exist, emitting light at wavelengths ranging from 630 to 670 nm; for example, the HairMax laser comb was approved by the FDA, for the treatment of FAGA, in 2011. With regard to the latter, clinical data has shown significantly better results in hair density compared to the control group, when used 3 times per week for a total period of 8–16 weeks.80 Other medical devices used for the treatment of hair loss include CO2 laser, erbium-glass laser, and thulium laser. These devices emit light in different wavelengths and many different protocols are currently used.

Regarding the 1550 nm erbium-glass laser, low energy settings should be favored, as well as long intervals in between treatments, because of the possibility of developing perifollicular fibrosis and hair shaft breakage.81 The 1927 nm thulium laser should be used in low energy settings, once per week. In order to obtain optimal results and maintain hair growth, continuous application must be granted.81 The 10,600 nm CO2 laser should be used in higher energy settings, but with the limitation of no more than 22 sessions applied. The high energy settings are associated with better results in terms of hair growth, but the pain can be intolerable for the patient. Topical application of anesthetics can partially resolve this side effect.

CG210TM CG210 is a botanical hair lotion that has been proven safe and efficient when applied to males and females with AGA and FAGA respectively.82 It acts via normalizing the apoptotic pathway of the hair follicle. This is achieved via three mechanisms: The regulation of apoptosis through the level normalization of anti-apoptotic Bcl-2 protein; the reduction of the inflammation; and the increase in collagen of the hair.

Microneedling Microneedling is a minimally invasive technique that utilizes multiple fine needles in order to penetrate through the epidermis to the deeper stratus of the skin. This method creates micro-inflammation within the papillary dermis and at the same time, releases multiple growing factors that activate the hair bulge. A number of different devices exist, consisting of manual pens and rollers, automatic pens and devices with adjustable needle depth and rate of vibrations. Some devices are equipped with radio frequencies, in order to increase the micro-inflammation with thermal injury. Microneedling has demonstrated a great value in the treatment of hair loss especially when used with topical treatments, such as minoxidil, PRP, or topical peripheral antiadrogens.83–85

Platelet-Rich Plasma Therapy Platelet-rich plasma therapy (PRP) is a concentrate of platelets and plasma taken from the patient’s blood. When injected in the patient, it releases many growth factors and cytokines which may promote hair growth. The research data seems promising, especially when combined with microneedling,86 while this technique can be used in combination to hair transplantation.78 The expected results thought should be limited as they result inferior in terms of total number of hair count and terminal hairs, in comparison with minoxidil.87

Nutritional Supplementation Many vitamins, minerals, and antioxidants, such as biotin, zinc, magnesium, coper, selenium, cysteine methionine, arginine, glutamine, tyrosine, iron, B-complex vitamins, and

Female Androgenic Alopecia vitamins A, C, and E88,89 saw palmetto, green tea extract, etc, are commonly used in order to promote hair-growth, but due to the lack of randomized controlled trials their beneficial effect on FAGA cannot be thoroughly justified.90,91

Cosmetic Concealment Keratin fibers, as well as topical sprays and powders are used to camouflage hair loss affected areas.92 Scalp micro-pigmentation is a new technique in which little dots are tattooed on the scalp to assimilate real grown hair. In more severe cases, hair extensions and hair pieces may be used so as to decrease psychological distress.

Emerging Therapies In order to validate the increased efficacy of various combination regimes, a significant amount of clinical research is necessary. For example, botulinum toxin (150 units) injections have been recently used by several researchers indicating that improving hair-growth may be achieved via increasing blood flow in the hair follicle.93 Valproic acid, a widely used anti-convulsant, seems to be a potential treatment option for androgenic alopecia.94 Roxythromycin (RXM) is a macrolide antibiotic that can increase hair elongation and inhibits catagen-like changes induced in vitro with IFN-γ. Topical 5% RXM solution has demonstrated signs of hair growth in approximately 50% of individuals with AGA, yet their effectiveness on FAGA remains to be proven.95 Clascoterone is a topical anti-androgen medication, primarily used for moderate to severe acne, and lately is under evaluation for AGA and FAGA. Clascoterone is a selective androgen receptor antagonist without systemic absorption when applied topically on the skin. Currently, different topical applied concentrations are under investigation for achieving the major therapeutic outcome.96,97 Setipiprant is a drug developed for the treatment of asthma and is currently under investigation for the treatment of AGA.98 Setipiprant is a D2 prostaglandin receptor antagonist. It is thought that the miniaturization of the hair follicle, the sebaceous gland hyperplasia and the alopecia might be induced by high levels of PGD2. In the future, whether trials for the use of Setipiprant in FAGA will be performed, still remains to be seen. Janus Kinase (JAK) inhibitors, when administrated systemically, shown no effect in AGA, but recently the topical application of these drugs are under investigation for AGA.99 JAK inhibitors seem to promote the hair follicle cycle and to initiate hair growth even on dormant–in telogen fase–hair follicles in human with AGA.100 More studies must be carried out in the future, in order to confirm the efficacy and the safety for the treatment of FAGA.

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29 for American Society for Dermatologic Surgery [et al]. 2001;27(1):53–54. 2. Olsen EA. Female pattern hair loss. In: Whitting DA, Blume-Peytavi U, Tosti A, Trüeb RM, eds. Hair growth and disorders. Berlin, Heidelberg: Springer Berlin Heidelberg; 2008:172–183. 3. Ioannides D, Lazaridou E. Female pattern hair loss. In: Ioannides D, Tosti A, eds. Alopecias-practical evaluation and management. Vol. 47. Basel: Karger Medical and Scientific Publishers; 2015:45–54. 4. Dinh QQ, Sinclair R. Female pattern hair loss: current treatment concepts. Clin Interv Aging. 2007;2(2):189–199. 5. Olsen EA. Female pattern hair loss. J Am Acad Dermatol. 2001;45(3):S70–S80. 6. Trüeb RM. Diffuse hair loss. In: Hair growth and disorders. Berlin: Springer; 2008:259–272. 7. Blume-Peytavi U, Blumeyer A, Tosti A, et al. S1 guideline for diagnostic evaluation in androgenetic alopecia in men, women and adolescents. Br J Dermatol. 2011;164(1):5–15. 8. Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol. 1977;97(3):247–254. 9. Collins FE, Biondo S, Sinclair RD. Bad hair day: a guide to female hair loss. New York City: Thomas C Lothian Pty Ltd; 2005. 10. Yip L, Sinclair RD. Antiandrogen therapy for androgenetic alopecia. Exp Rev Dermatol. 2006;1(2):261–269. 11. Cash TF, Price VH, Savin RC. Psychological effects of androgenetic alopecia on women: comparisons with balding men and with female control subjects. J Am Acad Dermatol. 1993;29(4):568–575. 12. Cash TF. The psychology of hair loss and its implications for patient care. Clindermatol. 2001;19(2):161–166. 13. Levy LL, Emer JJ. Female pattern alopecia: current perspectives. Int J Women’s Health. 2013;5:541. 14. Messenger A, Sinclair R. Follicular miniaturization in female pattern hair loss: clinicopathological correlations. Br J Dermatol. 2006;155(5):926–930. 15. Randall VA. Androgens and hair growth. Dermatol Therapy. 2008;21(5):314–328. 16. Yip L, Rufaut N, Sinclair R. Role of genetics and sex steroid hormones in male androgenetic alopecia and female pattern hair loss: an update of what we now know. Australas J Dermatol. 2011;52(2):81–88. 17. Deplewski D, Rosenfield RL. Role of hormones in pilosebaceous unit development. Endocrine Rev. 2000;21(4): 363–392. 18. Grino PB, Griffin JE, Wilson JD. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology. 1990; 126(2):1165–1172. 19. Rushton D, Ramsay I, James K, Norris M, Gilkes J. Biochemical and trichological characterization of diffuse alopecia in women. Br J Dermatol. 1990;123(2):187–197. 20. Schmidt J, Lindmaier A, Trenz A, Schurz B, Spona J. Hormone studies in females with androgenic hairloss. Gynecol Ostet Invest 1991;31(4):235–239. 21. Futterweit W, Dunaif A, Yeh H-C, Kingsley P. The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia. J Am Acad Dermatol 1988; 19(5):831–836.

30 22. Cousen P, Messenger A. Female pattern hair loss in complete androgen insensitivity syndrome. Br J Dermatol 2010; 162(5):1135–1137. 23. Sawaya ME, Price VH. Different levels of 5α-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol. 1997;109(3):296–300. 24. Niiyama S, Happle R, Hoffmann R. Influence of estrogens on the androgen metabolism in different subunits of human hair follicles. EJD. 2001;11(3):195–198. 25. Conrad F, Paus R. Estrogens and the hair follicle: Östrogene und der Haarfollikel. JDDG: J Dtsch Dermatolo Ges. 2004;2(6):412–423. 26. Mirmirani P. Hormonal changes in menopause: do they contribute to a ‘midlife hair crisis’ in women? Br J Dermatol 2011;165:7–11. 27. Muallem MM, Rubeiz NG. Physiological and biological skin changes in pregnancy. Clin Dermatol 2006;24(2):80–83. 28. Georgala S, Katoulis A, Georgala C, Moussatou V, Bozi E, Stavrianeas N. Topical estrogen therapy for androgenetic alopecia in menopausal females. Dermatology. 2004; 208(2):178–179. 29. Yip L, Zaloumis S, Irwin D, et al. Gene-wide association study between the aromatase gene (CYP19A1) and female pattern hair loss. Br J Dermatol. 2009;161(2):289–294. 30. Mesinkovska NA, Bergfeld WF. Hair: What is New in Diagnosis and Management?: Female Pattern Hair Loss Update: Diagnosis and Treatment. Dermatol Clin. 2013; 31(1):119–127. 31. Ellis JA, Harrap SB. The genetics of androgenetic alopecia. Clin Dermatol. 2001;19(2):149–154. 32. Yamazaki M, Sato A, Toyoshima Ke, et al. Polymorphic CAG repeat numbers in the androgen receptor gene of female pattern hair loss patients. J Dermatol. 2011;38(7): 680–684. 33. Schweiger ES, Boychenko O, Bernstein RM. Update on the pathogenesis, genetics and medical treatment of patterned hair loss. J Drugs Dermatol: JDD. 2010;9(11):1412–1419. 34. Singal A, Sonthalia S, Verma P. Female pattern hair loss. Indian J Dermatol Venereol Leprol. 2013;79(5):626. 35. Piraccini BM. Evaluation of Hair Loss. In: D. Ioannides AT, ed. Alopecias-practical evaluation and management. Vol. 47. Basel: Karger Publishers; 2015:10–20. 36. De Lacharrière O, Deloche C, Misciali C, et al. Hair diameter diversity: a clinical sign reflecting the follicle miniaturization. Arch Dermatol. 2001;137(5):641–646. 37. Tosti A, Iorizzo M, Piraccini B. Androgenetic alopecia in children: report of 20 cases. Br J Dermatol. 2005; 152(3):556–559. 38. Sewell LD, Elston DM, Dorion RP. “Anisotrichosis”: A novel term to describe pattern alopecia. J Am Acad Dermatol. 2007;56(5):856. 39. Inui S, Nakajima T, Itami S. Scalp dermoscopy of androgenetic alopecia in Asian people. J Dermatol. 2009;36(2): 82–85. 40. Rakowska A, Slowinska M, Kowalska-Oledzka E, Olszewska M, Rudnicka L. Dermoscopy in female androgenic alopecia: method standardization and diagnostic criteria. Int J Trichology. 2009;1(2):123.

Hair Disorders 41. Deloche C, De Lacharrière O, Misciali C, et al. Histological features of peripilar signs associated with androgenetic alopecia. Arch Dermatol Res. 2004;295(10):422–428. 42. Galliker NA, Trüeb RM. Value of trichoscopy versus trichogram for diagnosis of female androgenetic alopecia. Int J Trichology. 2012;4(1):19. 43. Vujovic A, Del Marmol V. The female pattern hair loss: review of etiopathogenesis and diagnosis. Bio Med Res Int. 2014;2014. 44. Whiting DA. Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia. J Am Acad Dermatol. 1993;28(5): 755–763. 45. Whiting D. The value of horizontal sections of scalp biopsies. J Cutan Aging Cosmet Dermatol. 1990;1(33):165–173. 46. Horenstein MG, Jacob JS. Follicular streamers (stelae) in scarring and non-scarring alopecia. J Cutan Pathol. 2008;35(12):1115–1120. 47. Sinclair RD, Dawber RP. Androgenetic alopecia in men and women. Clin Dermatol. 2001;19(2):167–178. 48. Jimenez-Cauhe J, Saceda-Corralo D, Rodrigues-Barata R, et al. Effectiveness and safety of low-dose oral minoxidil in male androgenetic alopecia. J Am Acad Dermatol. 2019;81(2):648–649. 49. Kanti V, Messenger A, Dobos G, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men–short version. J Eur Acad Dermatol. 2018;32(1):11–22. 50. Rogers NE, Avram MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol. 2008; 59(4):547–566. 51. Messenger A, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004;150(2):186–194. 52. Haber RS. Pharmacologic management of pattern hair loss. Facial Plast Surg Clin. 2004;12(2):181–189. 53. WHITING DA, Jacobson C. Treatment of female androgenetic alopecia with minoxidil 2%. Int J Dermatol. 1992;31(11):800–804. 54. Jacobs JP, Szpunar CA, Warner ML. Use of topical minoxidil therapy for androgenetic alopecia in women. Int J Dermatol. 1993;32(10):758–762. 55. Tsuboi R, Tanaka T, Nishikawa T, et al. A randomized, placebo-controlled trial of 1% topical minoxidil solution in the treatment of androgenetic alopecia in Japanese women. Eur J Dermatol. 2007;17(1):37–44. 56. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007;57(5):767–774. 57. Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004;50(4):541–553. 58. Blume-Peytavi U, Hillmann K, Dietz E, Canfield D, Bartels NG. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol. 2011;65(6):1126–1134. e1122.

Female Androgenic Alopecia 59. Leyden J, Dunlap F, Miller B, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol. 1999;40(6):930–937. 60. Price VH, Roberts JL, Hordinsky M, et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol. 2000;43(5):768–776. 61. Shum KW, Cullen DR, Messenger AG. Hair loss in women with hyperandrogenism: four cases responding to finasteride. J Am Acad Dermatol. 2002;47(5):733–739. 62. Yeon J, Jung J, Choi J, et al. 5 mg/day finasteride treatment for normoandrogenic Asian women with female pattern hair loss. J Euro Acad Dermatol. 2011;25(2):211–214. 63. Iorizzo M, Vincenzi C, Voudouris S, Piraccini BM, Tosti A. Finasteride treatment of female pattern hair loss. Arch Dermatol. 2006;142(3):298–302. 64. Hajheydari Z, Akbari J, Saeedi M, Shokoohi L. Comparing the therapeutic effects of finasteride gel and tablet in treatment of the androgenetic alopecia. Indian J Dermatol Venereol Leprol. 2009;75(1):47. 65. Olsen EA, Hordinsky M, Whiting D, et al. The importance of dual 5α-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-­ controlled study of dutasteride versus finasteride. J Am Acad Dermatol. 2006;55(6):1014–1023. 66. Olszewska M, Rudnicka L. Effective treatment of female androgenic alopecia with dutasteride. J Drugs Dermatol JDD. 2005;4(5):637–640. 67. Moftah N, Moftah N, Abd-Elaziz G, et al. Mesotherapy using dutasteride-containing preparation in treatment of female pattern hair loss: photographic, morphometric and ultrustructural evaluation. J Euro Acad Dermatol. 2013; 27(6):686–693. 68. Martínez FMC. Hair loss in women. In: Handbook of Hair in Health and Disease. Berlin: Springer; 2012:70–97. 69. Hoedemaker C, Van Egmond S, Sinclair R. Treatment of female pattern hair loss with a combination of spironolactone and minoxidil. Australas J Dermatol. 2007;48(1): 43–45. 70. Sinclair R, Wewerinke M, Jolley D. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol. 2005;152(3):466–473. 71. Paradisi R, Porcu E, Fabbri R, Seracchioli R, Battaglia C, Venturoli S. Prospective cohort study on the effects and tolerability of flutamide in patients with female pattern hair loss. Ann Pharmacother. 2011;45(4):469–475. 72. Gassmueller J, Hoffmann R, Webster A. Topical fulvestrant solution has no effect on male and postmenopausal female androgenetic alopecia: results from two randomized, proof-of-concept studies. Br J Dermatol. 2008;158(1): 109–115. 73. Cohen JL. Enhancing the growth of natural eyelashes: the mechanism of bimatoprost-induced eyelash growth. Dermatol Surg. 2010;36(9):1361–1371. 74. Blume-Peytavi U, Lönnfors S, Hillmann K, Bartels NG. A randomized double-blind placebo-controlled pilot study to assess the efficacy of a 24-week topical treatment by latanoprost 0.1% on hair growth and pigmentation in healthy volunteers with androgenetic alopecia. J Am Acad Dermatol. 2012;66(5):794–800.

31 75. Perez BH. Ketocazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men. Med Hypotheses. 2004;62(1):112–115. 76. McElwee KJ, Shapiro J. Promising therapies for treating and/or preventing androgenic alopecia. Skin Therapy Lett. 2012;17(6):1–4. 77. Unger WP, Unger RH. Hair transplanting: an important but often forgotten treatment for female pattern hair loss. J Am Acad Dermatol. 2003;49(5):853–860. 78. Rose PT. The latest innovations in hair transplantation. Facial Plast Surg. 2011;27(04):366–377. 79. Oron U, Ilic S, De Taboada L, Streeter J. Ga-As (808 nm) laser irradiation enhances ATP production in human neuronal cells in culture. Photomed Laser Surg. 2007;25(3): 180–182. 80. Leavitt M, Charles G, Heyman E, Michaels D. HairMax LaserComb® laser phototherapy device in the treatment of male androgenetic alopecia. Clin Drug Investig. 2009; 29(5):283–292. 81. Fayne R, Sanchez N, Tosti A. Laser and light-based therapies in the treatment of hair loss. In: Hair and scalp treatments. Berlin: Springer; 2020:47–63. 82. Cucé LC, Rodrigues CJ, Patriota RCR. Cellium® GC: evaluation of a new natural active ingredient in 210 mg/mL topical solution, through scalp biopsy. Surg Cosmet Dermatol. 2011;3:123–128. 83. Farid CI, Abdelmaksoud RA. Platelet-rich plasma microneedling versus 5% topical minoxidil in the treatment of patterned hair loss. Journal of the Egyptian Women’s Dermatologic Society. 2016;13(1):29–36. 84. Jha AK, Vinay K, Zeeshan M, Roy PK, Chaudhary R, Priya A. Platelet-rich plasma and microneedling improves hair growth in patients of androgenetic alopecia when used as an adjuvant to minoxidil. J Cosmet Dermatol. 2019; 18(5):1330–1335. 85. Shah KB, Shah AN, Solanki RB, Raval RC. A comparative study of microneedling with platelet-rich plasma plus topical minoxidil (5%) and topical minoxidil (5%) alone in androgenetic alopecia. Int J Trichology. 2017;9(1):14. 86. Vincenzi C, Marisaldi B, Tosti A. Regenerative Treatments: Microneedling and PRP. In: Tosti A, Asz-Sigall D, Pirmez R, eds. Hair and Scalp Treatments: A Practical Guide. Cham: Springer International Publishing; 2020:35–46. 87. Bruce AJ, Pincelli TP, Heckman MG, et al. A Randomized, Controlled Pilot Trial Comparing Platelet-Rich Plasma to Topical Minoxidil Foam for Treatment of Androgenic Alopecia in Women. Dermatol Surg 9000; Publish Ahead of Print. 88. Haneke E, Baran R. Micronutrients for hair and nails. In: Nutrition for Healthy Skin. Berlin: Springer; 2010:149–163. 89. Saini R, Badole SL, Zanwar AA. Arginine Derived Nitric Oxide: Key to Healthy Skin. In: Bioactive Dietary Factors and Plant Extracts in Dermatology. Berlin: Springer; 2013: 73–82. 90. Finner AM. Nutrition and hair: deficiencies and supplements. Dermatol Clin. 2013;31(1):167–172. 91. Rajput RJ. Controversy: is there a role for adjuvants in the management of male pattern hair loss? J Cutan Aesthetic Surg 2010;3(2):82.

32 92. Draelos ZD. Shampoos, conditioners, and camouflage techniques. Dermatol Clin. 2013;31(1):173–178. 93. Freund BJ, Schwartz M. Treatment of male pattern baldness with botulinum toxin: a pilot study. Plast Reconstr Surg. 2010;126(5):246e–248e. 94. Jo SJ, Shin H, Park YW, et al. Topical valproic acid increases the hair count in male patients with androgenetic alopecia: a randomized, comparative, clinical feasibility study using phototrichogram analysis. J Dermatol. 2014;41(4):285–291. 95. Ito T, Fukamizu H, Ito N, et al. Roxithromycin antagonizes catagen induction in murine and human hair follicles: implication of topical roxithromycin as hair restoration reagent. Arch Dermatol Res. 2009;301(5):347. 96. Longo LM. High Concentration Formulation. In: Google Patents; 2019.

Hair Disorders 97. Marks DH, Prasad S, De Souza B, Burns LJ, Senna MM. Topical Antiandrogen Therapies for Androgenetic Alopecia and Acne Vulgaris. Am J Clinl Dermatol. 2019:1–10. 98. Garza LA, Liu Y, Yang Z, et al. Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med. 2012;4(126): 126ra134–126ra134. 99. Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients. J Am Acad Dermatol. 2017;76(1):22–28. 100. Harel S, Higgins CA, Cerise JE, et al. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015;1(9):e1500973.

4 Telogen Effluvium Aurora Alessandrini, Michela Starace, and Bianca Maria Piraccini

Introduction The term telogen effluvium (TE), coined by Kligman in 1961 (1), defines a diffuse and profuse loss of hair in telogen phase. It is the most common cause of diffuse hair loss in young females. Normal hair cycle results in replacement of every hair on the scalp every 3–5 years (2). Hair remains anchored to the follicle throughout the telogen phase and is shed only when the follicle starts its growth phase again and produces a new hair. Hair loss becomes evident about 3 months after the event causing telogen effluvium. An accurate clinical history allows in many cases identifying the event triggering the disease. Patients affected by telogen effluvium, as well as by androgenetic alopecia, may complain of psychological distress, as hair is very important in the communication of beauty, attractiveness, and self-esteem. A wide variety of potential triggers have been implicated in the pathogenesis of telogen effluvium, like endocrine, nutritional, and autoimmune disorders: in females TE is often due to sideropenic anemia or iron deficiency without anemia, but a post-partum alopecia can be also described. Diagnosis includes history of the hair loss, pull test, trichoscopy and, in doubtful cases, scalp biopsy. The disease is usually self-limiting, and therapies include cosmetic or medical ones.

Etiology and Pathogenesis Telogen effluvium may affect both sexes, but it occurs more frequently in adult females. The exact prevalence of telogen effluvium is not known, but it is considered to be quite common. Patients complain of increased hair loss either upon washing or during the day. The number of fallen hair ranges from 100 to 600 daily. It’s a reactive process, triggered mainly by metabolic stress, hormonal changes, or medications. The most common causes include systemic diseases, menopause, pregnancy, crush diets, post-operative stress, thyroid disorders, anemia, iron deficiency, and infections. Telogen effluvium is defined as a non-scarring, diffuse, hair loss that occurs around 3 months after a triggering event and lasting for about 6 months. In TE, hair loss is usually less than 50% of the scalp hair (3).

DOI: 10.1201/9780429465154-4

Kligman (1) hypothesized that whatever is the cause of hair loss, the follicle tends to be in the form of premature termination of anagen; later the follicle precipitates into catagen and goes into resting stage mimicking telogen (4). Hair cycle is composed by sequential phases of growth and rest called anagen (active hair growth), catagen (involution), and telogen phase (resting). The anagen phase may last for about 2–8 years, the catagen phase lasts for 4–6 weeks, and the telogen phase lasts for 2–3 months. The exogen phase of hair follicle (the release of telogen hair) coincides with the end of telogen phase (5). In the normal scalp, 90–95% of the hair follicles are in the anagen phase and 5–10% in the telogen phase, with a hair shedding of about 100–150 hair daily. Only a few follicles will be in the transitional or catagen phase. This cycle can be altered by many factors and a large number of hair follicles stop growing prematurely and starts entering the telogen phase simultaneously. After about 2–3 months of initial insult there is excessive hair shedding. The causes of TE are listed in Table 4.1. The diagnosis of telogen effluvium indicates an increased loss of hair, acute or chronic, which can be the consequence of five different pathogenetic mechanisms, according to Headington’s classification (6): 1. Premature interruption of the follicular cycle with abrupt passage of the follicle from the growth phase (anagen) to the phase of rest (telogen). It is the most common form and is the cause of factors that interfere with the mitotic activity of keratinocytes of the follicle matrix. The entry into telogen allows the follicle to overcome the insult without being damaged. Hair loss becomes evident about 3 months after the follicle enters the rest phase because the hair remains normally anchored to the follicle for the duration of the telogen and is eliminated only when the follicle resumes its growth activity and produces a new hair. 2. Synchronization of the follicular cycle by extension of the anagen. This page achieves conditions that prolong the duration of anagen by preventing the physiological entry into the rest phase of the follicle. Telogen effluvium appears when conditions that prolonged the anagen disappear and all follicles in prolonged anagen enter at the same time. This is the

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TABLE 4.1 Principal Causes of Telogen Effluvium Post-partum effluvium Major surgery Hemorrhage Weight loss Febrile illness Drugs Thyroid dysfunction Renal/hepatic disfunction Malnutrition

telogen effluvium after pregnancy or after termination of the contraceptive pill. 3. Synchronization of the follicular cycle for decreased duration of the anagen. The shortening of the anagen phase means that the follicular cycle is much shorter and that the number of follicles that goes into rest phase has increased compared to the norm. 4. Early teloptosis. The hair detaches from the follicle before the end of the telogen phase. It is a typical consequence of the use of topical products containing keratolytics for the treatment of hyperkeratotic scalp diseases such as seborrheic dermatitis and psoriasis. The dissolution of the keratin determines the removal of the scales but also melts the keratin binding that allows the attachment of the root in telogen to the hair follicle. 5. Delayed teloptosis. The hair is retained in the follicle beyond the end of the telogen phase. Recently, Rebora (7) has proposed a newer classification with three types of telogen effluvium and a new variety of TE. In particular conditions, different mechanisms may overlap.

Type 1: Premature Teloptosis It may correspond to Headington’s immediate telogen release. The hair detaches from the follicle before the end of the telogen phase. It is a typical consequence of the use of topical products containing keratolytics for the treatment of scalp scaling diseases, such as scalp psoriasis and seborrheic dermatitis. The dissolution of keratin causes the removal of the scales and also dissolves the keratin bond (cadherine), which allows the attachment of the root in telogen to the hair follicle. In this type of TE, proteolysis plays a pathogenetic role, in particular any factor, exogenous or endogenous, capable of breaking down cadherins.

Type 2: Collective Teloptosis It may correspond to Headington’s delayed anagen and telogen releases. It’s determined by conditions that cause synchronization of the follicular cycle. These conditions prolong the duration of the anagen by preventing the follicle from returning to the resting phase. Telogen

effluvium appears when the conditions that prolong the anagen are minor and all prolonged anagen follicles come to rest at the same time. Examples of this type are the postpartum TE, TE from interruption of the contraceptive pill, and TE from interruption of minoxidil or finasteride.

Type 3: Premature Entry into the Telogen Phase In this type of TE, which may correspond to Headington’s immediate anagen release, the anagen phase is interrupted prematurely and the hairs accelerate their process to telogen, in which they remain for 3 months before eventually being dislodged. Examples of this type are drug-induced TE, TE due to dietary deficiencies and “autoimmune TE,” which is often associated with other autoimmune diseases, like Hashimoto’s thyroiditis.

Clinical Classification The diagnosis of telogen effluvium includes two separate entities, distinguished in acute and chronic, with different causes, onset, symptoms, and outcome (8).

Acute TE Acute TE results from noxious events that precipitate the entry of a large number of follicles into their resting phase (telogen). Possible causes include systemic diseases, drugs, fever, stress, weight loss, delivery, iron deficiency, and inflammatory scalp disorders. Although a large number of drugs have been occasionally reported to produce TE, only for a few drugs the relation has been proven (9) and severity of hair loss depends on the drug, its dosage and patient’s susceptibility (Table 4.2). Hair loss starts approximately 3 months after the causative event, corresponding to the duration of the telogen phase. Hair loss may be very severe with a daily shedding of 100 to 200 hairs and this worries the patient even if about 50% of hairs should be lost before noticing an evident reduction of the hair density. The pull test is positive, with more than 10 telogen hair roots extracted on the same day of shampooing. Management include research of possible causes, though a careful clinical history and laboratory investigations, including: complete blood cell count, ferritin, TSH, fT3, fT4, and folic acid. Acute telogen effluvium usually undergoes spontaneous resolution after removal of the cause.

TABLE 4.2 Drugs Inducing Telogen Effluvium Oral retinoids Oral contraceptive Anticonvulsants Antithyroid drugs Beta blockers Hypolipidemic drugs Amphetamine

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  FIGURE 4.1  Clinical presentation of telogen effluvium in the anterior area (a) and temporal area (b).

Chronic TE Chronic TE is characterized by increased hair shedding lasting for more than six months. This condition mostly affects middle aged women and frequently remains unexplained since the patient doesn’t remember the causative factor. The daily shedding is mild (usually less than 100 hairs daily), but the patients are very distressed and complain of progressive temporal thinning and decreased hair mass. Scalp pain (trichodynia) is frequently reported (10). The clinical examination and trichoscopy only show that the hair of the temporal region is thinner and shorter, and pull test is normal or slightly positive (Figure 4.1). Chronic telogen effluvium usually onsets acutely and lasts long with periodic relapses and remissions. Temporary benefit may sometimes be achieved with a short course of topical steroids. Elongation of the hair cycle, with a longer anagen phase, can be promoted by cosmetic lotions that combine the effects of increasing hair follicle vascularization with activation of hair growth.

Comorbidity and Trigger Factors Sometimes telogen effluvium is associated to paresthesia on the scalp with painful sensation (trichodynia) (11). In more details, the term describes a diffuse or localized sensation of pain, tenderness, or burning that may be spontaneous or triggered by hair movement and is thought to be a sing of mild scalp inflammation associated with hair loss. This symptom seems to be related to the release of substance P and is also present in androgenetic alopecia and alopecia areata (12). Common triggering events are acute febrile illness, severe infection, major surgery, severe trauma, postpartum hormonal changes, hypothyroidism, discontinuing estrogen-containing medication, rapid weight loss, low protein intake, heavy metal ingestion, and iron deficiency. Many medications have been linked to telogen effluvium, but the most common are betablockers, retinoids (including excess vitamin A), anticoagulants, as shown in Table 4.2.

Diagnosis The physical examination can be normal, and it is important to be guided by the symptoms that the patient referred together with physical and instrumental exams. A complete battery of laboratory tests should be performed, which includes complete blood count, urine analysis, serum ferritin and T3, T4, thyroid stimulating hormone (TSH) (13).

Pull Test The pull test allows evaluating the phase in which the hair is located at the time of fall. Simple to perform, allows an immediate assessment of the phase. Using the thumb and index exert a pull, slight but steady, of a tuft of 60 hair at 2 cm from the scalp and evaluate the type of the root and the number of hairs that are extracted. The test is usually performed in 4–6 areas of the head: the frontal, parietal and occipital part of the scalp, and usually detaches some roots in telogen. Normally the pull test extracts hairs in the telogen phase and the number is the equivalent of the daily fall, that is, about 50–70 hairs/day, and became 100–150 during the washing. It is considered pathological, the extraction of more than 6 hairs in telogen phase, from 4 to 5 days after the last washing. It is important to remember that the result of the pull test can be influenced by many external factors, such as the frequency of brushing, the distance from the last wash and on the traction force of the physician. The numbers of hair that are extracted with the pull are reduced by shampooing, brushing, and combing.

Trichoscopy Dermoscopy, even more videodermatoscopy (VDS), is useful in the evaluation of the physiology and pathology of the hair and scalp (trichoscopy). The technique has been applied to the scalp, in order to study its skin, vessels, and hair shaft and allow a non-invasive diagnosis avoiding the biopsy. Magnification ranges from 20× to 70×.

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FIGURE 4.2  Trichoscopic findings in telogen effluvium: presence of short regrowing hair are predominant.

There are no specific trichoscopy findings in telogen effluvium. However, the presence of upright regrowing hairs and predominance of hair follicle openings with only one emerging hair shaft may be indicative of telogen effluvium in the absence of features characteristic for other causes of hair loss (Figure 4.2). According to Rudnicka et al. (14) telogen effluvium can be defined a diagnosis of exclusion.

Pathology Vertical and horizontal sectioning of scalp biopsy should be evaluated. The number and density of hair follicles is usually normal, but there is an increased percentage of the hair follicles that are in the catagen or the telogen phase. If 25% of the follicles are in telogen phase, the diagnosis of telogen effluvium is confirmed. The percentage of telogen hair should not typically be higher than 50% (15). FIGURE 4.3  Clinical (a) and trichoscopic picture (b) of androgenetic alopecia.

Differential Diagnosis There are other causes of diffuse hair loss, which include mainly androgenetic alopecia, diffuse alopecia areata (DAA), and alopecia areata incognita (AAI). Androgenetic alopecia (AGA) is the most common cause of non-scarring alopecia, characterized by a progressive miniaturization of hair follicles usually occurring in a pattern distribution (Figure 4.3). Pull test can be positive with telogen roots if a telogen effluvium is also associated. Trichoscopy is diagnostic, and there are specific signs that can be detected (16). 1. Reduced hair thickness with the presence of • Increased number of hair with a diameter less than 0.03 mm due to hair miniaturization, especially evident in the frontal area. The presence of more than 10X of thin hair, below than 0.03 mm, in the frontal area is considered a major diagnostic criterion of androgenetic alopecia. • Anisotrichosis: A variation of the diameter that affects more than 20% of the hair of the

androgen-dependent regions is considered a major diagnostic criterion of androgenetic alopecia. 2. Reduced number of hair with presence of yellow dots in androgen-dependent areas that correspond to empty follicles or they contain completely miniaturized hairs. In the frontal area, the presence of more than four yellow dots in four images at 70-times magnification is a major diagnostic criterion of AGA. 3. Reduced number of hair per pilosebaceous unit. Alopecia areata (AA) can be characterized by a diffuse hair loss, rather than typical bald patches. The two most common variants of non-patchy AA are AAI and DAA. First described by Rebora in 1987 (17), alopecia areata incognita is more common (about 86%) among young females, especially between 20 and 40 years old. Clinically, they are characterized by a widespread and severe hair loss, which develops rapidly in a few weeks in AAI, while diffuse alopecia areata can however appear over a prolong time. Currently, there are no studies that describe DAA and AAI in standardized way and, therefore, these clinical variants of AA are often not recognized.

37

Telogen Effluvium

FIGURE 4.4  Clinical (a) and trichoscopic picture (b) of alopecia areata incognita with yellow dots with short regrowing hairs.

The role of trichoscopy in alopecia areata incognita has been described for the first time by Tosti et al. (18), who have documented the presence of diffuse yellow dots in 95% of patients. Another typical trichoscopic feature of AAI is the presence of short regrowing hair (0.2–0.4 mm) (Figure 4.4). Finally in a small percentage of cases, we found the presence of exclamation point hair, black dots, and dystrophic hair, confirming AAI as a variant of classical alopecia areata. According to Inui et al. (19), the trichoscopic combination of yellow dots and/or short hairs in regrowth has a diagnostic sensitivity for AAI of 96%. The characteristic trichoscopic features of DAA include instead the presence of black dots and diffuse yellow dots, with an amount proportional to the severity of the disease; in this case, black dots are the result of an acute damage to the follicles, not grouped to oval areas but widespread and expanded to the whole scalp (Figure 4.5). The distinction between the two entities is not always easy, therefore, in the majority of cases a scalp biopsy is required to confirm the diagnosis.

FIGURE 4.5  Clinical (a) and trichoscopic picture (b) of diffuse alopecia areata with empty yellow dots, black dots, and dystrophic hairs.

Treatment The most important aspect in the management of TE is counseling the patient about the natural history and the benign course of the disease. Drugs like beta-blockers, retinoids, anticoagulants, or antithyroid drugs need to be substitute if possible and endocrine disorders like thyroid dysfunction should be treated. Nutritional deficiencies should also be corrected. Acute telogen effluvium usually undergoes spontaneous resolution and if the causative event is identified by history and has been adequately treated, there is no further treatment required. Chronic telogen effluvium does not tend to improve or regress and it’s characterized by periodic relapses and remissions. In some cases, it can be addressed to drugs which cannot be withdrawn, or to systemic diseases. In other patients the cause remains unknown. Treatment include oral intake of nutritional containing iron, vitamins and amino acids necessary for hair follicle growth

38

Hair Disorders

activity and the topical application of cosmetic lotions specifically formulated for blocking acute hair shedding. The research in the hair follicle biology has discovered several molecules that are expressed differently in the phases of the hair cycle, indicating a promoting or inhibitory activity on hair growth (20). Factors known to promote hair growth contained in cosmetic lotions that are effective in acute telogen effluvium include insulin-like growth factor-1 (IGF-1), noggin protein, fibroblast growth factor (FGF), and vascular endothelia growth factor (VEGF). Topical minoxidil has not been proven to promote recovery of hair in telogen effluvium, but it has theoretical benefit in prolonging anagen phase (21). Adjuvant and newer modalities of treatment include physical therapies such as microneedling (22) that can have a role, especially when cosmetic procedures do not give enough results, because it induces a rapid arresting of the hair loss.



REFERENCES











1. Kligman AM. Pathologic dynamics of human hair loss. Telogen effluvium. Arch Dermatol. 1961; 83: 175. 2. Habif TP. Hair diseases. In: Habif TP, editor. Clinical Dermatology: A Colour Guide to Diagnosis and Therapy, 3rd edn. St. Louis: Mosby; 1996. pp. 739–47. 3. Trueb RM. Diffuse hair loss. In: Blume-Peytavi U, Tosti A, Whiting DA, Trueb R, editors. Hair Growth and Disorders, 1st edn. Berlin: Springer; 2008. pp. 259–72. 4. Messenger AG, Berker DA, Sinclair RD. Disorders of hair. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s Text Book of Dermatology, 8th edn. Oxford: Blackwell Publishing; 2010. pp. 66.1–66.100. 5. Malkud S. Telogen effluvium: a review. J Clin Diagn Res. 2015 Sep; 9(9): WE01–3. 6. Headington JT: Telogen effluvium: new concepts and review. Arch Dermatol. 1993;129: 356–63. 7. Rebora A. Proposing a simpler classification of telogen effluvium. Skin Appendage Disord. 2016 Sep; 2(1–2): 35–38. 8. Piraccini BM, Iorizzo M, Rech G, Tosti A. Drug-induced hair disorders. Curr Drug Saf. 2006;1:301–5.

















9. Piraccini BM, Starace M, Alessandrini A. Hair changes due to drugs. In: Alopecia (Miteva M), 1st edn. Elsevier, 2018; 245–58. 10. Baldari M, Montinari M, Guarrera M, Rebora A. Trichodynia is a distinguishing symptom of telogen effluvium. J Eur Acad Dermatol Venereol. 2009 Jun;23(6): 733–4. 11. Rebora A. Trychodynia. Dermatology, 1996;192:292–293. 12. Rebora A. Trichodynia: a review of the literature. Int J Dermatol. 2016 Apr; 55(4): 382–4. 13. Shrivastava SB. Diffuse hair loss in adult female: approach to diagnosis and management. Indian J Dermatol Venereol Leprol. 2009; 75: 20–31. 14. Rudnicka L, Olszewska M, Rakowska A, Slowinska M. Trichoscopy update 2011. J Dermatol Case Rep. 2011 Dec 12 ;5(4): 82. 15. Hughes EC, Gossman WG. Telogen Effluvium. 2019 May 15. StatPearls [Internet]. Treasure Island (FL). StatPearls Publishing; 2019 Jan. 16. Rakowska A, Slowinska M, Kowalska-Oledzka E, Olszewska M, Rudnicka L. Dermoscopy in female androgenic alopecia: method standardization and diagnostic criteria. Int J Trichology. 2009 Jul; 1(2): 123–30. 17. Rebora A. Alopecia areata incognita: a hypothesis. Dermatologica. 1987; 174: 214–8. 18. Tosti A, Whiting D, Iorizzo M, et al. The role of scalp dermoscopy in the diagnosis of alopecia areata incognita. J Am Acad Dermatol. 2008 Jul; 59(1): 64–7. 19. Inui S, Nakajima T, Itami S. Significance of dermoscopy in acute diffuse and total alopecia of the female scalp: review of twenty cases. Dermatology. 2008; 217(4): 333–36. 20. Paus R. Frontiers in the (neuro-)endocrine controls of hair growth. J Investig Dermatol Symp Proc. 2007 Dec; 12(2): 20–2. 21. Buhl AE. Minoxidil’s action in hair follicles. J Invest Dermatol. 1991; 96: 73–4S). 22. Starace M, Alessandrini A, Brandi N, Piraccini BM. Preliminary results of the use of scalp microneedling in different types of alopecia. J Cosmet Dermatol. 2019 Jun; 19(3): 646–650.

5 Anagen Effluvium Vasiliki Chasapi

Introduction: Definition Anagen effluvium is a type of non-scarring alopecia with abrupt diffuse hair loss due to a direct action of an agent, which impairs or interrupts the metabolic or mitotic activity of the hair follicles in the anagen phase of the hair cycle.1 This results in varying degrees of hair follicle dystrophy. As 80–90% of scalp hair follicles are normally in the anagen phase, the majority of hairs are affected.1 In this condition, anagen hairs are frequently broken off rather than shed and because of this, the term “anagen effluvium” looks like misleading. Anagen effluvium is separated in two forms: the dystrophic anagen effluvium and the loose anagen syndrome.2 The most common cause of the anagen effluvium is chemotherapy. Other causative agents are radiation, several drugs, toxic chemicals, and inflammatory disorders.3–6 Generally, anagen effluvium is reversible and hair regrowth is observed 2–3 months after cessation of the insult. Rarely, alopecia is permanent.1 Hair loss can be devastating to patient’s self-esteem, self-image and overall quality of life. In these circumstances additionally to treatment, a psychosomatic approach and the provision of medical aesthetic, as well as tips for styling, have great importance in the management.

Epidemiology Anagen effluvium affects equally men and women worldwide. It has not regional predilection.

Etiology Chemotherapy and the radiation on the head and neck are most commonly implicated in the induction of anagen effluvium.7,8 The incidence of anagen effluvium after chemotherapy is about 65%.9 It is most commonly associated with mitotic inhibitors, antimetabolites, and alkylating agents.3,4,7,8,10,11 Other causes of anagen effluvium are medications such as levodopa, cyclosporine, isoniazid, colchicine, bismuth, allopurinol, tamoxifen, and bromocriptine.1,3,9 Exposure to toxic agents and heavy metals including boric acid, mercury, thallium, copper, cadmium, arsenic, and gold can lead to anagen effluvium.12–15

DOI: 10.1201/9780429465154-5

Inflammatory conditions and systemic disorders that result in peribulbar inflammation such as secondary syphilis, systemic lupus erythematosus, alopecia areata, and mycosis fungoides can also act as triggers for anagen effluvium.3,6,12,16 Diet very low in proteins (e.g., Kwashiorkor) may lead to anagen effluvium.17 Pemphigus vulgaris (PV) has also been shown to cause anagen effluvium due to desmosomal proteins expression in the epithelium of the hair follicle.5

Pathogenesis Vital for the accurate diagnosis of hair-associated diseases is an essential understanding of the normal hair cycle. On a normal scalp there are approximately 100,000–150,000 hair follicles. Each individual hair follicle has its own hair cycle, which consists of three distinct and concurrent phases, anagen, catagen, and telogen corresponding to growth, involution, and resting stages.18 During the anagen stage hair is growing and its duration mainly determines the ultimate length of the hair. The matrix cells in the hair bulb undergoes mitotic activities and differentiation resulting in hair growth, genetically determined. Anagen phase lasts between 2 and 6 years with an average of 3 years, in a normal human scalp.12 At any given time approximately 85% of the hair follicles on the scalp are in the anagen stage (Figure 5.1a and 5.1b).18,19 The catagen phase is an intermediate transitional stage with short duration between anagen and telogen phase. In this degradation stage, hair follicle shrinks due to apoptosis. As a result, complete involution occurs in the lower two thirds of the follicle, causing the hair shaft to be pushed upward (Figure 5.2). This phase lasts about 2 weeks and approximately 1–3% of all scalp hairs are in this stage at any time. Catagen phase is followed by the telogen or resting phase in which the keratinization of the proximal hair shaft leads to the formation of a club-shaped structure (club hair) (Figure 5.3). The duration of the telogen stage is approximately 3 months and 6–15% of the hair follicles remain in this phase at any given time. The final process during the telogen stage, named exogen, is characterized by the release of the hair from the follicle. Kenogen is the lag stage between teloptosis (telogen hair falls out) and the initiation of a new hair growth, in anagen phase of the next hair cycle.19,20 The activity of the hair follicles is not synchronous throughout the scalp. Approximately 80–150 hairs are shed daily, which number depends on age and season. Normally

39

40

Hair Disorders

  FIGURE 5.1  Hair in anagen phase. (a) Pyramidal root and (b) rectangular root.

those hairs are telogen hairs.19 Multiple factors such as genetics, immune system, hormones, systemic illness, weight loss, as well as any drug intake, have been implicated in the development and the cycling of the hair follicle and in some cases may cause hair follicle destruction.

Hair Cycle in the Anagen Effluvium

characterized by major proliferative activity for the development of the hair shaft. Any agent or severe event such as medications, toxin exposure, or inflammation, which induces an abrupt interruption of this mitotic activity, can result in abnormal keratinization and weakening of the growing proximal portion of the hair shaft that causes Pohl-Pinkus constrictions and hair fiber breakage. Thus, when the narrow areas rise to the surface of the skin, the hair shaft breaks off (Figure 5.4a and 5.4b). In case of bulb insult, complete hair loss occurs.1–3,20

As it is described above in the anagen phase takes place the epithelial proliferation where the bulb matrix cells are

FIGURE 5.2  Hair in catagen phase.

FIGURE 5.3  Hair in telogen phase.

41

Anagen Effluvium

  FIGURE 5.4  (a) Narrowed portion of the hair shaft and (b) fractured hair.

Hair shedding usually presents within 1–3 weeks after the causative event. As 80–90% of scalp hairs are in the anagen stage and it is too long, a large number of hairs are affected and that’s why hair loss is very extensive leading to alopecia, which is intensely apparent. Additionally, depending on the agent, the dose and the duration of exposure, terminal hairs at other sites such as beard, eyelashes, eyebrows, axillary, and pubic regions can also be affected to a variable degree.7,8 In anagen effluvium, hair loss is generally completely reversible due to induction hair follicle growth from the unaffected stem cells of the bulge. The hair matrix initiates its activity and hair follicle resumes normal cycling within several weeks from cessation of the causative event. Full hair regrowth commonly takes place within 3–6 months.1,3 However, changes in hair color texture, thickness, and waviness, following regrowth are usually described.4,8,21,22

Differential Diagnosis The differential diagnosis can be mainly included telogen effluvium (Table 5.1), as well as trichotillomania, androgenetic alopecia, alopecia areata, and other causes of non-cicatricial alopecia. A thorough clinical history and physical examination are essential for any patient complains of increased hair shedding, in order to associate with the temporal correlation of agents that trigger hair loss and potential underlying systemic diseases. Complete and detailed dermatologic, systemic, and family history of the patients should be elicited to exclude other causes of hair loss such as anemia, malnutrition, metabolic or endocrine disorders, connective tissue and autoimmune diseases, infections, and neoplasms.

Evaluation Clinical Findings Anagen effluvium starts within days of initiating insult. The degree of hair loss differs among patients and is related to the causative specific event. In case of full hair loss, it is completed in 2–3 months after the attack. Anagen effluvium is not a cicatricial alopecia that’s why there are no signs of inflammation or scarring like erythema, pigmentation, and scaling. In some cases, coexistence of telogen and anagen effluvium can lead to full baldness. On the physical examination the narrow or tapered broken part of the hair shaft can be seen with the naked eye, but trichoscopy is more revealing. Associated symptoms are typically absent. If symptoms have been reported, should be related to the cause, such as features from the exposure to toxins or metal poisoning.

There are several tests which may help to confirm the diagnosis of anagen effluvium. The hair pull test (where 80–100 TABLE 5.1 Differential Diagnosis between Anagen Effluvium and Telogen Effluvium Clinical Findings

Anagen Effluvium

Telogen Effluvium

Initiation of shedding after attack Percentage of hair loss Type of hair loss

1–3 weeks

2–3 months

80–95% Anagen hairs (pigmented, dystrophic, or dysplastic bulb) Narrowed or fractured

25–60% Telogen hairs (club white bulb)

Hair shaft

Normal

42 strands of hair are grasped firmly between the thumb and forefinger, and gently pulled in three separate areas of the scalp) is strongly positive and can suggest a diagnosis of anagen effluvium if more than 80% of hairs are released. Anagen and telogen hairs may be easily recognized with the naked eye. However, on any doubt, the conduct of a trichogram followed by light microscopy of roots and hair shafts can identify the type of hair, as well as hair shaft abnormalities.23 Normally anagen hairs have pyramidal or rectangular root enclosed by intact inner- and outer-root sheaths, without angulation >20%, or deformities. The matrix of the hair root appears darkly pigmented (Figure 5.1a and 5.1b). In non-cicatricial alopecia, normal anagen hairs can be never easily plucked. It may occur occasionally in the active stage of scarring alopecia. Telogen hairs are characterized by club-shaped roots with sheaths at the level of the bulb only (Figure 5.3). The trichogram in anagen effluvium indicates a great percentage of anagen dystrophic or dysplastic hairs (>80%) and tapered fracture of the hair shafts. The dysplastic hairs have narrowed bulb (V sign) without sheaths and with angulation of more than 20° and soft or deformed contours of the root and/or shaft (Figure 5.5). The dystrophic hairs have similar characteristics to the dysplastic but with a pointed bulb (! sign) (Figure 5.6).24 In loose anagen syndrome, absence of the outer-root sheath is observed. Dysplastic and dystrophic hairs are revealed most commonly in drugs induced anagen effluvium. As the diagnosis can be based on the history and physical exam, a biopsy rarely is needed. In difficult to identify cases, a biopsy could be useful to distinguish mainly telogen effluvium

Hair Disorders

FIGURE 5.6  Dystrophic hair.

and secondly other types of alopecia. A 4-mm punch biopsy is preferred by dermatopathologists.25–27

Histopathology In anagen effluvium, histopathologic evaluation of the sample indicates predominance of the anagen follicles with a normal anagen to telogen ratio and little to no catagen follicles. In addition, dermal inflammation is minimal to absent.21

Chemotherapy-Induced Alopecia

FIGURE 5.5  Dysplastic hair.

Chemotherapy-induced alopecia (CIA) is a well-known and common side effect of antineoplastic drugs. Τhe anticipated hair loss can be extremely distressing. CIA begins within days of initiating treatment, followed by complete hair loss around the second cycle (4–8 week following induction of therapy). The cytotoxic medications used in chemotherapy target rapidly dividing cells. Unfortunately, hair follicles are innocent bystanders and unintended targets. It has been demonstrated that P53 plays an important role in hair follicle apoptosis and recent studies have shown that Fas and C-Kit do play a role, but the exact molecular pathway is not yet fully understood.28 CIA results from the abrupt cessation of the mitotic activity of the hair follicle due to direct toxic attack to the rapidly dividing bulb matrix cells. Because of the affected dividing hair follicles are in the anagen phase, the term used to describe CIA, is anagen effluvium. While yet CIA has been traditionally classified in acute diffuse hair loss caused by anagen effluvium, more recently it has been considered, that the hair

43

Anagen Effluvium TABLE 5.2 Anticancer Therapies That Can Cause Anagen Effluvium Cytotoxic agents

Radiotherapy Immunotherapies

Targeted therapies

• Alkylating agents (busulfan, cyclophosphamide, and etoposide) • Topoisomerase inhibitors (doxorubicin, daunorubicin, idarubicin, teniposide, topotecan, and irinotecan) • Anti-microtubule agents (paclitaxel, docetaxel, vincristine, and vinblastine) • Methotrexate, bleomycin, 5-fluorouracil, and hydroxyurea • • • • • •

Anti CTLA-4 Anti PD1 Anti PD-L1 EGFR inhibitors EGFR/PDGFR/KIT inhibitors BRAF inhibitors

Stem cell transplantation Vismodegib

FIGURE 5.7  (a) Anagen effluvium post chemotherapy and (b) trichoscopy (fractured hairs post chemotherapy).

follicle can react to the same attack (which is able to stop mitosis) with both shedding patterns, dystrophic anagen effluvium and telogen effluvium.29 The degree of hair loss is related to the dose schedule, the rate and the route of delivery and synchronization of hair cycle.29,30 Hair loss typically is initially presented at the crown of the head, followed by the temporal region. Hair loss may be patchy or diffuse depending on which individual follicles are in anagen phase. In many cases broken hairs can be seen at the surface of the scalp with the naked eye, which become more apparent by trichoscopy (Figure 5.7a and 5.7b). Additionally, if CIA is given at high doses for a long time and with multiple exposures, can also affect to a variable degree hairs at other sites, like eyebrows, eyelashes, beard, and axillary and pubic regions.28 The incidence of anagen effluvium due to chemotherapy is approximately 65%.9 All cytotoxic chemotherapeutic medications have been implicated. However, anagen effluvium most

commonly associated with differences in frequency between the four major classes of anticancer drugs: more than 80% for anti-microtubule agents (e.g., paclitaxel), 60–100% for topoisomerase inhibitors (e.g., doxorubicin), 10–50% for antimetabolites (e.g., 5-fluorouracil plus leucovorin), and more than 60% for alkylating agents (e.g., cyclophosphamide) (Table 5.2).9,31 Hair loss is more severe and it is seen more frequently with combination chemotherapy, than with a single agent.4,9 Anagen effluvium after chemotherapy is usually reversible with hair regrowth taking place within 3–6 months after the cessation of treatment. Changes in hair color, texture, thickness, and waviness have been commonly observed up to 60% of patients but the alterations are generally temporary.22 Nevertheless, permanent diffuse hair loss is well-known to occur with busulfan chemotherapy and following bone marrow transplantation in up to 50% of patients. It was firstly observed with the combination of busulfan and cyclophosphamide. Additionally, it has been related to risk factors such as chronic graft versus host reaction, previous exposure to X-ray and age of patients. Scalp biopsies of these patients demonstrate decreased follicles density without inflammation or fibrosis. It may be a consequence of stem cells destruction or acute damage of matrix keratinocytes.21,32–34 Doxorubicin also leads to total alopecia in most patients receiving this medication.34 Newer anticancer agents have been involved in hair loss (Table 5.2). Diffuse, reversible alopecia has been observed in 50% of patients receiving tyrosine kinase inhibitors like sorafenib or sunitinib.35,36 Grade II hair loss or non-scarring universal alopecia similar to alopecia universalis can be seen in 65% of patients treated with vismodegib, an inhibitor of the sonic hedgehog signaling, that is indicated for the treatment of advanced basal cell carcinoma.37 Non-scarring alopecia and hair curling can also be observed in patients receiving Raf inhibitors Dabrafenib, or Vemurafenib.37 Small molecule inhibitors of the epidermal growth factor receptor (EGFR) and the monoclonal antibodies targeting the

44 EGFR, such as cetuximab can cause a confluence of cutaneous reactions named with the acronym PRIDE: Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching and Dryness due to EGFR inhibitors.38,39 CIA has a significant impact on the quality of life of patients, affecting negatively the individual perception of appearance, body image and self-esteem. According to a study, 47% of female patients stated that hair loss was the most traumatic experience of chemotherapy and 8% declined treatment due to fear of hair loss.40,41

Radiation Radiation for the treatment of brain tumors may lead to diffuse anagen effluvium or cicatricial alopecia. Most patients are not completely bald as hair follicles in the telogen phase at the time of treatment escape destruction. Hair regrowth after radiation therapy occurs depended on type, depth, and dosefractionation. Permanent alopecia occurs due to irreversible destruction of the hair follicle stem cells with doses >30 Gy of deep X-rays, or >50 Gy of soft X-rays.1,8

Fluoroscopy Rarely the use of fluoroscopy during interventional procedures, such as neurointervention has been related to radiation dermatitis and alopecia in exposed areas named “square alopecia” due to their geometric shapes. This is usually considered as alopecia areata. It most commonly affects the retroauricular area, when the highest doses of radiation frequently target this region. The severity depends on the dose, the total time of the procedure, the interval between exposures, the size of the irradiated area and the individual characteristics of the patient (age, smoking, tissue oxygenation, capillary density, and genetic factors).28

Thallium Thallium is a chemical element whose use has been banned in the United States in 1972 due to environmental concerns and extremely high toxicity. Nevertheless, cases of accidental or of occupational exposure, as well as intentional poisoning are reported all over the world. Gastrointestinal symptoms, polyneuropathy, hair loss and the presence of Mees’ lines are the main manifestations after poisoning. Hair loss is caused by binding thallium to the sulfydryl group of hair keratins, which interrupts the formation of the hair shaft. Anagen effluvium occurs 2–3 weeks after toxic thallium exposure or less common over a shorter period of about 7 days.15,42,43

Hair Disorders consumption of polluted water/seafood, exposure to mercury containing antiseptics or fungicides as well as through chronic industrial exposure. Besides hair loss, toxic mercury levels can cause symptoms such as, fatigue, memory loss, irritability, depression, insomnia, tremors, and recurrent infections.13,43,44

Boric Acid Boric acid, a weak acid of boron is found in insecticides, flame retardants, antiseptics, and food preservatives. Boric acid intoxication can lead to anagen effluvium and other signs and symptoms like fever, stiffness, altered mental status, hemorrhagic diathesis, diffuse erythematous skin and bilateral palmar erythema.7,14,43

Arsenic Arsenic is a metalloid occurring in soil, seafood, and water, used by industry in pesticides, animal food additives, as well as metal alloys. Its association with hair loss is not fully confirmed. However, an observational study has indicated that alopecia occurs in 13% of patients consuming water containing ≥56 μg/L of this metalloid. Chronic arsenicosis has also been reported to cause xerostomia, xerophthalmia, conjunctivitis, dental caries, pyogenic skin lesions, palmar-plantar hyperkeratosis, as well as chronic alopecia universalis.2,45

Selenium Although selenium does not belong in metals, its intoxication, can lead to similar symptoms with them, like hair loss and Mees’ lines. These manifestations of selenosis are due to substitution of sulfur with selenium in the keratin proteins, which results in loss of disulfide bridges and abnormal hair growth, as well as nail protein structureless. Other symptoms include diarrhea, fatigue, myalgia, nail changes, and neurological problems.46

Colchicine Colchicine belongs to alkaloids and it is used for the treatment of various diseases such as Behçet’s disease, gout, amyloidosis, and familial Mediterranean fever. Colchicine arrests microtubule polymerization and results in interruption of cells mitosis and disruption of transport systems. As hair follicles are characterized by high cell turnover rate, they are dramatically affected.47

Mercury

Hypervitaminosis A

Mercury is another heavy metal involved in hair loss. As thallium, mercury induces anagen effluvium by binding to the sulfydryl group of keratins in hair. Mercury intoxication is due to

Retinoids are known to cause significant hair loss due to decrease of the anagen phase. In addition, hair loss is also frequently seen in patients taking high doses of supplements

Anagen Effluvium

45

containing vitamin A (RDA >4,000 IU for women and >5,000 IU for men). This effect may be potentiated by concurrent administration of vitamin E. Interestingly, vitamin A deficiency can also result in alopecia.48

MT-45 MT-45, a synthetic analgesic opioid has been reported to cause hair loss. Other symptoms are hair depigmentation, folliculitis, as well as Mees’ lines.49

Alopecia Areata Alopecia areata (AA) commonly causes dystrophic anagen effluvium in healthy individuals. AA reflects the importance of hair cycle disturbances in hair loss. The immune attack results in inflammatory cell infiltrate against the anagen hair bulbs which leads to a significant hair cycle disturbance and rapid shedding of the insufficiently anchored, improperly formed hair shafts (Figure 5.8a and 5.8b). AA incognita can also be appeared with dystrophic anagen effluvium that in some cases is considered as telogen effluvium.6

Pemphigus Vulgaris It has been shown that pemphigus autoantibodies target hair follicles due to the overexpression of the desmosomal proteins in the follicular epithelium. As a result a normal anagen effluvium occurs, which may be caused by a subclinical involvement of the hair follicle. Τhis represents a Nikolsky sign of the scalp inducing hairs shedding with their outer-root sheath from the lesional and perilesional areas.5

Loose Anagen Hair Syndrome Loose anagen hair syndrome (LAHS) is presented with hairs easily pulled without pain from the scalp. It appears rarely, sporadically or as inherited in autosomal dominant pattern disorder with incomplete penetrance. LAHS mainly occurs in children with light blond hairs and with a female to male ratio 6:1 (rarely can affect children with dark hair and adults as well). LAHS can be associated with other syndromes, such as Noonan’s syndrome and hypohidrotic ectodermal dysplasia. It is indicated that LAHS is characterized by the abnormal and premature keratinization of the inner-root sheath, intercellular edema of Huxley cells and dyskeratotic changes in Henle cells, which leads to clefts between the inner and outer root sheath and the hair shaft. Some cases have been described hereditary keratin defects, which lead to impaired adhesion of the cuticle of the inner root sheath to the opposed companion layer (K6HF Mutation of Keratin).50

FIGURE 5.8  (a) Diffuse alopecia areata and (b) dystrophic hair in acute diffuse alopecia areata.

Clinically LAHS appears as frequent shedding with diffuse thinning, hairless patches with irregular shape and sparse hair that does not grow long (Figure 5.9). Hair pull test is strongly positive, pointing out the diagnosis, if about >10% of the grasped scalp hair are removed using gentle traction. LAHS similarly to telogen effluvium leads to greater amounts of hairs that are pulled out. LAHS can be confirmed with microscopy examination by trichogram, where can be seen a predominance (>50%) of loose anagen hairs. On light microscopy the bulb is often misshapen, with a ruffled cuticle and inner and external root sheaths are absent (Figure 5.10a and 5.10b). LAHS is often self-limited and most cases improve in adolescence or adulthood. Nevertheless, in patients with severe disease topical minoxidil may be used as it can be beneficial, resulting in prolongation of the anagen phase. Additionally,

46

Hair Disorders

FIGURE 5.9  Loose anagen hair syndrome.

gentle hair care to minimizing hair trauma, avoiding removal of poorly anchored hairs is recommended.51

Treatment Anagen effluvium is usually reversible with regrowth within 4–12 weeks after cessation of the trigger agent. Anagen effluvium related to chemotherapy can affect the patient emotionally and psychologically very seriously. That’s why the management should be focused on the discussion of the anticipated hair loss and patients be assured that these hair changes are temporary. If it is needed, psychological counseling support should be provided. Generally, it is essential patients be advised to avoid physical or chemical trauma to the hair (e.g., hot appliances, bleaching, or coloring). In addition, patients should be encouraged to plan appropriate camouflaging techniques for head covering (hair piece/wig, powder, crayon, and micropigmentation) that can make them as comfortable as possible with their appearance and protect the scalp from cold and sun exposure. The cornerstone of the management is the shortening of time, within patient suffers from alopecia. Strategies for CIA can be classified into preventive and therapeutic processes. Unfortunately, until today no treatment has been demonstrated to be effective in preventing or stopping hair loss. However, it has been shown that patients using topical minoxidil 2% solution or low dose oral minoxidil showed up hair regrowth approximately 50 days sooner than those receiving placebo.52,53 The use of a scalp tourniquet within anticancer therapy has been reported to result in the limitation of drug delivery to the hair follicles.54 Another process that has been proposed to reduce hair loss in CIA, specifically with taxanes or anthracyclines, is scalp cooling, inducing hypothermia to a scalp temperature of fewer than 24°C during chemotherapy.54–59 It is important to emphasize that if there is a risk for scalp or

FIGURE 5.10  (a, b) Dystrophic hairs in loose anagen hair syndrome.

brain metastasis, this method should not be applied to let the drug penetration. Contraindications to scalp cooling include hematological malignancies, cancer of the head and neck, skin cancer, central nervous malignancies, small carcinoma of the lung, as well as cold trigger diseases, cold sensitivity and pediatric patients.60,61 Experimental approaches have been reported for the development of agents that may prevent CIA. They include drug-specific antibodies; hair growth cycle modifiers, like cyclosporine, AS101 and minoxidil; cytokines and growth factors, such as ImuVert, epidermal growth factor and keratinocyte growth factor; antioxidants, like N-acetylcysteine; apoptosis inhibitors, such as anti-death rFNK protein; cell

Anagen Effluvium cycle and proliferation modifiers as well as cyclin-dependent kinase 2 (CDK2) inhibitors.54,62 For radiotherapy-induced alopecia daily topical minoxidil solution 5% is indicated. If radiation dermatitis is present topical corticosteroids should be used. Topical minoxidil 5% solution can be applied daily for 6 months for anagen effluvium post therapy with EGFR, PDGFR, BRAF inhibitors, and vismodegib. For alopecia attributed to immunotherapies (CTLA-4, PD1, and PDL-1) as well as to stem cell transplant, high potency topical corticosteroids and/or topical minoxidil solution 5% daily should be used.63 For alopecia of eyebrows and eyelashes following chemotherapy can be improved with topical bimatoprost solution 0.03%.64

REFERENCES

















1. Trueb R.M. Diffuse hair loss. In: Blume-Peytavi U., Tosti A., Whiting D.A., Trueb R.M. (eds.) Hair Growth and Disorders. Berlin: Springer 2008; pp. 259–72. 2. Paus R., Olsen E.A., Messenger A.G. Hair growth disorders. In: Wolff K., Goldsmith L.A., Katz S.I., Gilchrest B.A., Zller A.S., Leffell D.J. (eds.) Fitzpatrick’s Dermatology in General Medicine, 7th ed., vol. 2. New York: McGraw-Hill 2008; pp. 753–77. 3. Sperling L.C. Hair and systemic disease. Dermatol Clin 2001; 19: 711–26. 4. Tosti A., Pazzaglia M. Drug reactions affecting hair: Diagnosis. Dermatol Clin 2007; 25: 223–31. 5. Delmonte S., Semino M.T., Parodi A., Rebora A. Normal anagen effluvium: A sign of pemphigus vulgaris. Br J Dermatol 2000; 142: 1244–45. 6. Quercetani R., Rebora A.E., Fedi M.C., Carelli G., Mei S., Chelli A., et al. Patients with profuse hair shedding may reveal anagen hair dystrophy: A diagnostic clue of alopecia areata incognita. J Euro Acad Dermatol Venerel 2011; 25: 808–10. 7. Sinclair R., Grossman K.L., Kvedar J.C. Anagen hair loss. In: Olsen E.A. (ed.) Disorders of Hair Growth: Diagnosis and Treatment. New York: McGraw-Hill 2002; p. 275. 8. Trueb R. Chemotherapy-induced Hair Loss. Skin Therapy Lett 2010; 15: 5–7. 9. Trueb R.M. Chemotherapy-induced alopecia. Semin Cutan Med Surg 2009; 28 (1): 11–4. 10. Freites-Martinez A., Shapir J., Goldfarb S., Nangia J., Jimenez JJ, Paus R., Lacouture ME. CME Part 1: Hair disorders in cancer patients. J Am Acad Dermatol 2018; 80 (5): 1179–96. 11. Bidwal S.G., Mehta R.D. Cutaneous Adverse Reactions of Chemotherapy in Cancer Patients: A Clinicoepidemiological Study. Indian J Dermatol 2018; 63(1): 41–6. 12. Saleh D., Cook C. Anagen Effluvium. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing: 2019 Jan. 13. Elhassani S.B. The many faces of methyl mercury poisoning. J Toxicol Clin Toxicol 1982; 19: 875–906. 14. Stein K.M., Odom R.B., Justice G.R., Martin G.C. Toxic alopecia from ingestion of boric acids. Arch Dermatol 1973; 108: 95–7. 15. Bank W.J., Pleasure D.E., Suzuki K., Nigro M., Katz R. Thallium poisoning. Arch Neurol 1972; 26: 456–64.

47 16. Phillips G., Slomiany P., Allison R. Hair loss: Common causes and treatment. Am Fam Physician 2017; 96(6): 371–8. 17. Dawber R., Van Neste D. Hair and Scalp Disorders. 2nd edition. New York, NY: Taylor & Francis Group 2004; pp. 130–2. 18. Kligman A.M. The human hair cycle. J Invest Dermatol 1959; 33: 307–16. 19. Paus R., Cotsarellis G. The biology of hair follicles. N Engl J Med 1999; 341(7): 491–7. 20. Vogt A., McElvee K., Blume-Peytavi U. Biology of the hair follicle. In: Blume-Peytavi U., Tosti A., Whiting D., Trueb R. (eds). Textbook on Hair – From Basic Science to Clinical Application. Berlin: Springer Verlang 2008; pp. 1–22. 21. Vowels M., Chan L.L., Giri N., Russell S., Lam-Po-Tang R. Factors affecting hair regrowth after bone marrow transplantation. Bone Marrow Transplant 1993; 12: 347–50. 22. Yun S.J., Kim S.J. Hair loss pattern due to chemotherapyinduced anagen effluvium: A cross-sectional observation. Dermatology 2007; 215(1): 36–40. 23. Camacho F. Diagnosis in trichology. In: Camacho F., Montagna W. (eds). Trichology, Madrid: Aula Medica 1997; pp. 97–112. 24. Peereboom-Wynia J.P.R. Trichogram. In: Camacho F., Montagna W. (eds). Trichology, Madrid: Aula Medica 1997; pp. 113–7. 25. Hillmann K., Blume-Peytavi U. Diagnosis of hair disorders. Semin Cutane Med Surg 2009; 28: 33–8. 26. Tosti A., Gray J. Assessment of hair and scalp disorders. J Investig Dermatol Symp Proc 2007; 12: 23–7. 27. Blume-Peytavy U., Vogt A. Current standards in the diagnostics and therapy of hair diseases – hair consultation. J Dtsch Dermatol Ges 2011; 9: 394–410. 28. Lesiak K., Bartlett J.R., Frieling G.W. Drug-induced alopecia. In: Hall, J.C., Hall B.J. (eds.) Cutaneous Drug Eruptions: Diagnosis, Histopathology and Therapy, London: Springer Verlag 2015; pp. 215–27. 29. Trueb R.M. Chemotherapy-induced anagen effluvium: Diffuse or patterned? Dermatology 2007; 215: 1–2. 30. Selleri S., Arnaboldi F., Vizzotto L., et al. Epitheliummesenchyme compartment interaction and oncosis on chemotherapy-induced hair damage. Lab Invest 2004; 84(11): 1404–17. 31. Espinosa E., Zamora P., Feliu J., et al. Classification of anticancer drugs – a new system based on therapeutic targets. Cancer Treat Rev 2003; 29(6): 515–23. 32. Baker B., Wilson C., Davis A., et al. Busulphan/cyclophosphamide conditioning for bone marrow transplantation may lead to failure of hair regrowth. Bone Marrow Transplant 1991; 7: 43–7. 33. Tosti A, Piraccini B.M., Vincenzi C., et al. Permanent alopecia after busulfan chemotherapy. Br J Dermatol 2005; 152(5): 1056–8. 34. Tallon B., Blanchard E., Goldberg L.J. Permanent chemotherapy-induced alopecia: Case report and review of the literature. J Am Acad Dermatol 2010; 63: 333–6. 35. Autier J., Escudier B., Wechsler J., Spatz A., Robert C. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol 2008; 144: 886–92.

48 36. Robert C., Mateus C., Spatz A., Wechsler J., Escudier B. Dermatologic symptoms associated with the multikinase inhibitor sorafenib. J Am Acad Dermatol 2009; 60: 299–305. 37. O’ Brayan K.W., Ratner D. The role of targeted molecular inhibitors in the management of advanced nonmelanoma skin cancer. Semin Cutan Med Surg 2011; 30: 57–61. 38. Donovan J.C., Ghazarian D.M., Shaw J.C. Scarring alopecia associated with use of the epidermal growth factor receptor inhibitor gefitinib. Arch Dermatol 2008; 144: 1524–5. 39. Graves J.E., Jones B.F., Lind A.C., Heffernan M.P. Nonscarring inflammatory alopecia associated with the epidermal growth factor receptor inhibitor gefitinib. J Am Acad Dermatol 2006; 55: 349–53. 40. McGarvey E.L., Baum L.D., Pinkerton R.C., Rogers L.M. Psychological sequelae and alopecia among women with cancer. Cancer Pract 2001; 9: 283–9. 41. Munstedt K., Manthey N., Sachsse S., Vahrson H. Changes in self-concept and body image during alopecia induced cancer chemotherapy. Support Care Cancer 1997; 5: 139–43. 42. Lu C.I., Huang C.C., Change Y.C., Tsai Y.T., Kuo H.C., Chuang Y.H., Shih T.S. Short-term thallium intoxication: Dermatological fingings correlated with thallium concentration. Arch Dermatol 2007; 143: 93–8. 43. Kanwar A.J., Narang T. Anagen effluvium. Indian J Dermatol Venereol Leprol 2013; 79: 604–12. 44. Neustadt J., Pieczenik S. Toxic-metal contamination: mercury. Integr Med 2007; 6: 36–7. 45. Ghosh A. Evaluation of chronic arsenic poisoning due to consumption of contaminated ground water in West Bengal, India. Int J Prev Med 2013; 4: 976–9. 46. Aldosary B.M., Sutter M.E., Schwartz M., Morgan B.W. Case series of selenium toxicity from a nutritional supplement. Clin Toxicol (Phila) 2012; 50: 57–64. 47. Combalia A., Balku-Pique C., Fortea A., Ferrando J. Anagen effluvium following acute colchicine poisoning. Int J Trichology 2016; 8: 171–2. 48. Sommer A., Vyas K.S. A global clinical view on vitamin A and carotenoids. Am J Clin Nutr 2012; 96: 12045–65. 49. Helander A., Bradley M., Hasselblad A., Norlen L., Vassilaki I., Backberg M., Lapins J. Acute skin and hair symptoms followed by severe, delayed eye complications in subjects using the synthetic opioid MT-45. Br J Dermatol 2017; 176: 1021–7. 50. Chapalain V., Winter H., Langbein L., Le Roy J.M., Labrèze C., Nicolic M., et al. Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. Arch Dermatol 2002; 138: 501–6.

Hair Disorders 51. Cantatore-Francis J.L., Orlow S.J. Practical guidelines for evaluation of loose anagen hair syndrome. Arch Dermatol 2009; 145: 1123–8. 52. Duvic M., Lemak N.A., Valero V., Hymes S.R., Farmer K.L., Hortobagyi G.N., et al. A randomized trial of minoxidil in chemotherapy-induced alopecia. J Am Acad Dermatol 1996; 35: 74–8. 53. Yang X., Thai K.E. Treatment of permanent chemotherapyinduced alopecia with low dose oral minoxidil. Astralas J Dermatol 2016; 57: e130–2. 54. Wang J., Lu Z., Au J.L. Protection against chemotherapyinduced alopecia. Pharm Res 2006; 23: 2505–14. 55. Giaccone G., Di Giulio F., Morandini M.P., Calciati A. Scalp hypothermia in the prevention of doxorubicin-induced hair loss. Cancer Nurs 1988; 11: 170–3. 56. Martin M., de la Torre-Montero J.C., Lopez-Tarruella S., et al. Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence characteristics, and prevention with scalp cooling. Breast Cancer Res Treat 2018; 171: 627–34. 57. Nangia J., Wang T., Osborne C., et al. Effect of a scalp cooling device on alopecia in women undergoing chemotherapy for breast cancer: the SCALP randomized clinical trial. JAMA 2017; 317: 596–605. 58. Forsberg S.A. Scalp cooling therapy and cytotoxic treatment. Lancet 2001; 357: 1134. 59. Shah W., Wikramanayake T.C., DelCanto G.M., et al. Scalp hypothermia as a preventative measure for chemotherapyinduced alopecia: a review of controlled clinical trials. J Eur Acad Dermatol Venereol 2018; 32: 720–34. 60. Grevelman E.G., Breed W.P. Prevention of chemotherapyinduced hair loss by scalp cooling. Ann Oncol 2005; 16: 352–8. 61. Rugo H.S., Melin S.A., Voigt J. Scalp cooling with adjuvant/­ neoadjuvant chemotherapy for breast cancer and the risk of scalp metastases: systematic review and meta-­analysis. Breast Cancer Res Treat 2017; 163: 199–205. 62. Nakashima-Kamimura N., Nishimaki K., Mori T., et al. Prevention of chemotherapy-induced alopecia by the antideath FNK protein. Life Sci 2008; 82: 218–25. 63. Freites-Martinez A., Shapiro J., et al. Hair disorders in patients with cancer. J Am Acad Dermatol 2019; 80: 1179–96. 64. Ahluwalia G.S. Safety and efficacy of bimatoprost solution 0.03% topical application in patients with chemotherapyinduced eyelash loss. J Invest Dermatol Symp Proc 2013; 16: S73–S76.

6 Tinea Capitis Ricardo Romiti and Alessandra Anzai

Introduction Tinea capitis (TC) is a common fungal infection of the scalp and hair shaft caused by dermatophytes—fungi that invade the stratum corneum and use keratin as a nutrient source. TC involves primary the scalp but may also involve the beard, eyelashes, and eyebrows. It is a common infection especially in children between 3 and 8 years of age, commonly in the 5th and 6th year of both genders (1). TC is considered rare in adults. When observed in adults, the subjects of this kind of infection are usually postmenopausal women. TC is also more common in immunocompromized patients and in patients under immunosuppressive therapy (2, 3). Age of predilection is believed to result from the fungistatic properties of fatty acids of short- and medium-chains in post-pubertal sebum and the presence of Pityrosporum orbiculare (Pityrosporum ovale), which is part of normal flora in adults (4). The pathogens of TC belong to only two genera: Trichophyton and Microsporum. They are present worldwide but there is a great variation in the epidemiology according to the geographic region and season. Species that naturally occur in the soil and occasionally infect humans are called geophilic; species that parasitize animals and rarely infect humans are named zoophilic; and species that preferably parasitize humans are called anthropophilic. Historically, TC was described in two forms: microsporic— when the agent was zoophilic or geophilic, and trichophytic—when caused by anthropophilic dermatophytes. This classification was based on the assumption that fungi are welladapted to the human host, as anthropophilic fungi, cause a widespread infection with multiple lesions, minor inflammation, and non-adapted fungi, as zoophilic or geophilic fungi, produce single lesions with a high inflammatory response. Over the time, this concept is being discarded because of the poor correlation of the clinical picture and causative agent in different studies (5, 6). Regarding types of hair shaft invasion, TC is classified in three types: • Ectothrix: The spores cover the surface of the hair shaft. The ectothrix is related to Microsporum species, but Trichophyton verrucosum can also be the causative agent (Figure 6.1).

DOI: 10.1201/9780429465154-6

• Endothrix: The hyphae form arthrospores and are within the hair shaft. The endothrix type of infection may be caused by Trichophyton tonsurans, Trichophyton soudanense and members of the Tricho­ phyton rubrum of African origin group, Trichophyton violaceum, or Trichophyton rubrum (Figure 6.2). • Favus: Hyphae form large clusters at the base of hairs at the scalp surface forming crusts with depressed centers and raised edges, called scutula. Air spaces in the hair shafts are characteristic. Favus is usually a chronic infection with evolution to scarring alopecia. The favic type of infection is caused by the anthropophilic dermatophyte Trichophyton schoenleinii and is very rare nowadays due to improvements in living conditions and hygiene. It is restricted to endemic areas in Asia and Africa (7, 8).

Epidemiology TC etiological agents undergo variations over time and geographical regions and can reflect changes by migration or immigration. In the United States, Canada, Mexico, and Central America Trichophyton tonsurans is the most common cause of TC (9, 10). Predisposing factors include large family size, crowded living conditions, and low-­ socioeconomic status. Microsporum canis, a zoophilic dermatophyte, is still the most common reported causative agent of TC in Europe, especially in Central and Southern Europe. Nevertheless, there is a recent increase of anthrophilic TC cases mostly in urban areas in Europe. The largest overall increase of anthropophilic dermatophytes has been noted with Trichophyton tonsurans mainly in the United Kingdom and with Trichophyton soudanense and Microsporum audouinii in France and is possibly linked to immigration from African countries (11, 12). In Africa, Trichophyton violaceum, Trichophyton schoenleinii, and Microsporum canis are the most commonly isolated species whereas Trichophyton violaceum and Microsporum canis are prevalent agents in Asia (13–15). In Brazil, Microsporum canis is the main agent in South and Southeast regions followed by Trichophyton tonsurans, while Trichophyton tonsurans is more common in the North and Northeast regions (16).

49

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Hair Disorders

FIGURE 6.3  Multiple areas of alopecia, scaling, and lymphadenopathy.

FIGURE 6.1  Ectothrix type of invasion: Direct microscopy, (a) 40x and (b) 100x.

Clinical Features Clinical diagnosis of TC can be challenging, as symptoms vary from minimal pruritus with little hair loss to severe inflammatory lesions with crusts, edema, and pus discharge. The clinical aspect depends on the causative organism, type of hair invasion, level of host resistance and degree of inflammatory host response (17). Lesions can be single or multiple with variable sizes. Scaling may be minimal or severe and hairs can break at different lengths. Lesions can be associated with pruritus and lymphadenopathy (Figure 6.3). Trichophyton tonsurans and Trichophyton violaceum, tend to cause the “black-dot ringworm,” which is characterized by

FIGURE 6.2  Endothrix type of invasion: Direct microscopy, 100x.

infected hairs that break off at the follicular orifice resulting in a “black dot” aspect at the scalp (Figure 6.4). When a hypersensitivity reaction to fungi occurs, formation of a kerion may result, presenting as an inflammatory scalp mass caused by severe inflammatory signs with pain, pustules, and crusts, often resembling an abscess (Figure 6.5). A kerion may result in permanent scarring hair loss. Rarely, inflammatory TC can develop grains, characterizing a mycetoma (18).

FIGURE 6.4  “Black-dot ringworm”; the infected hairs break off at the scalp surface.

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Tinea Capitis

and more rarely with TC. Clinically, they can be eczematous patches or plaques and papules, observed before or after the initiation of treatment (Figures 6.6 and 6.7). Recognition of this Id reaction is important so that dermatophytids can be distinguished from drug reactions and the decision can be made whether to continue or to stop the systemic antifungal treatment (20–23). An angioedema-like reaction and erythema nodosum secondary to TC have also been reported (24).

Differential Diagnosis

FIGURE 6.5  Kerion: Boggy inflammation of scalp resembling an abscess.

Secondary bacterial infection is considered rare. When present, it is usually present under crusts covering the inflammatory mass and removal of these is an important part of ­management (19). Blue-green fluorescence under filtered ultraviolet or Wood’s light is characteristically present in most ectothrix infections caused by Microsporum species. TC can be associated with Id reactions. Dermatophytids represent a systemic disseminated eczematous eruption secondary to an inflammatory dermatophyte infection. Dermatophytids have been commonly described in association with tinea pedis

Differential diagnosis of TC includes diseases associated with hair loss and with inflammatory signs at different stages. In children, the main differential diagnosis are localized or patchy alopecias, such as alopecia areata and trichotillomania. Both conditions present with broken shafts and can occasionally present with erythema. Other conditions that mimic TC such as seborrhea, contact eczema, and psoriasis may lead to misdiagnosis and mistreatments (25) (Figure 6.8). In adults, diagnosis of TC can be delayed because of a low index of suspicion. Common conditions such as seborrheic dermatitis or psoriasis can present with similar features as TC (26). Discoid lupus erythematosus, lichen planus and other causes of scarring alopecia may sometimes be considered in the differential diagnosis (27). In the presence of pustules and intense inflammatory signs (Figure 6.9), TC can mimic bacterial folliculitis and acne keloidalis (27, 28). When the scarring process becomes chronic and leads to fibrosis, TC can be similar to tufted hair folliculitis or folliculitis decalvans (28, 29) and central centrifugal cicatricial alopecia (30). Other reports described TC patients with fluctuant, alopecic nodules, and plaques with minimal scaling mimicking dissecting cellulitis (29, 31–37).

  FIGURE 6.6  Same patient presenting (a) scalp TC and (b) eczematous patches on the body.

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Hair Disorders

FIGURE 6.9  Scalp TC with pustules and erythema mimicking bacterial folliculitis.

Trichoscopy

FIGURE 6.7  Same patient presenting (a) scalp TC and (b) dermatophytids papules over the trunk.

FIGURE 6.8  Scalp TC with scaling and erythema with minimal alopecia mimicking psoriasis.

The use of a dermoscope, or epiluminescence microscopy, to examine the scalp and hairs has increased the clinician’s diagnostic accuracy when evaluating cases of localized and diffuse hair loss. The dermoscope is a handheld instrument with a transilluminating light source and standard magnifying optics that facilitates visualization of subsurface skin structures that are not visible to the naked eye. Specific trichoscopic signs of TC were described in the literature and represent dystrophic hair shafts in specific shapes. Comma-shaped hairs are characterized by a sharp slanting end, homogeneous thickness, and pigmentation of the hair shaft (Figure 6.10). Corkscrew hairs show exaggerated coiled appearance of the hair shaft (38). Bar code-like hairs also called Morse code-like hairs are characterized by irregular white bands that reproduce the picture of interrupted hairs (Figure 6.11). When they bend at these narrowed paler parts of the infected hair shafts, they are named zigzag hairs, which suggest its structural weakness (Figure 6.12) (39, 40). In a prospective, multicenter study, patients with presumed TC were examined with trichoscopy and the results were compared with mycological culture. The trichoscopy assessment’s sensitivity (95% confidence interval) was 94% (88%; 100%): specificity was 83% (72%; 94%), the positive predictive value was 92%, and the negative predictive value was 86%. Comma hairs, corkscrew hairs, zigzag hairs, Morse code-like hairs and whitish sheath were significantly more frequent in patients with a positive mycological culture (p < 0.0001) (41). Trichoscopy in TC is a very useful diagnostic tool since it is quick, reliable, inexpensive, and noninvasive. Dermoscopes equipped with ultraviolet light can perform as a miniature and portable Wood’s lamp device, and allow detection of fluorescence from each single hair shaft, instead of a patch of fluorescence as in the traditional UV lamp (42). Some publications also demonstrated that the specific markers of TC disappear after successful treatment (43). Therefore, trichoscopy can also be helpful for follow-up studies (44–46).

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Tinea Capitis

  FIGURE 6.10  Scalp TC (a) showing comma and corkscrew hairs with pustules and (b) erythema on trichoscopy.

Laboratory Diagnosis Diagnosis of TC must be confirmed by fungi identification since treatment may be prolonged and carries potential side effects. Direct exam with potassium hydroxide of affected hairs and/or scales obtained by scraping or brushing is a quick and inexpensive test, but requires technical expertise. In addition, in patients with early or inflammatory tinea capitis the direct exam can be false negative. Fungal culture is considered the gold standard diagnostic test. Different sampling

methods were described in the attempt to increase sensitivity and acceptability to children: scraping of scalp, brush method (47), moistened cotton gauze swab (48), or cytobrush (49). Cultures can also be false negative depending on viability of fungal elements, inadequacy in sampling, or use of antifungal agents. In kerions, culture is often negative. Besides, confirmatory cultures may require a 3- to 4-week of incubation period. In selected cases, biopsy for histology examination can be necessary.

  FIGURE 6.11  Scalp TC (a) showing comma and (b) corkscrew hairs on trichoscopy.

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Hair Disorders

  FIGURE 6.12  Scalp TC (a) showing bar-code-like hairs and (b) zigzag hairs on trichoscopy.

New methods as PCR-based detection/identification of species are not universally available but potentially offer a significant advance in the speed and accuracy of diagnosis (50).

culture results can delay treatment initiation and may further increase contacts contamination. Therefore, it is acceptable to start therapy if the clinical picture is strongly suggestive. Drug

Treatment Aims of treatment are eradication of the causative organism, resulting in both a clinical and mycological cure, alleviation of symptoms, prevention of scarring, and reduction of transmission (51). TC requires systemic therapy because topical antifungals cannot effectively penetrate the hair shaft so as to exterminate the fungi reservoir (52). In the late 1950s, griseofulvin became the gold standard for systemic therapy of TC. It is active against dermatophytes and has a long-term safety profile. The main disadvantage of griseofulvin is the long duration of treatment required which may lead to reduced compliance and a higher level of adverse events. The newer oral antifungal agents, including terbinafine, itraconazole, and fluconazole, require a much shorter duration of treatment (53). Oral ketoconazole is not recommended for treatment of TC because of the risk of hepatotoxicity and lack of superiority to griseofulvin in controlled studies. British guidelines recommend using either griseofulvin for 6–8 weeks, or terbinafine for 2–4 weeks, and to consider switching to an alternative drug if no clinical improvement is seen after the recommended treatment duration (51). A recent meta-analysis of controlled trials concluded that among the different antifungal therapies described in the literature, Griseofulvin more effectively treated Microsporum infections; terbinafine and itraconazole more effectively cured Trichophyton infections (54). Therefore, it is important to determine the causative agent to achieve the best treatment response. If cultures come out negative, empiric treatment should be guided by the most frequent etiological agent in the population of interest. In high-risk populations, awaiting

Griseofulvin

Itraconazole

Terbinafine

Agent

Microsporum sp.

Microsporum sp.

Trichophyton sp.

Dose

1 g/day in children >50 kg, or 15–20 mg/kg/day single or divided doses for if 20%, peripilar sign, and yellow dots.39

Laboratory Investigation Endocrine evaluation for hyperandrogenism is recommended in all girls, and in boys with diffuse or FPHL and/or abnormal pubertal development.45 AGA can be the only dermatologic manifestation of PCOS.45 Although a case series found no abnormal testosterone levels or precocious puberty in prebupertal children with AGA, endocrine evaluation is still recommended.47

Histopathology Normal hair density, reduced terminal follicles and increased intermediate and vellus-like follicles with a terminal/vellus ratio 1 year (10). Liver and kidney function and blood pressure must be monitored. Mycophenolate mofetil is usually well-tolerated by patients with fewer adverse effects compared with other immunomodulators. Various case series have shown clinical improvement in LPP after short courses (typically 2–8 months). The suggested dosage for LPP treatment is 500 mg twice a day for 4 weeks and then 1 g twice a day for 5–6 months. Liver function test and blood count should be monitored before starting the medication and during therapy.

Other Treatments Agents that have proven to be efficient in cutaneous lichen planus, such as systemic retinoids and griseofulvin, have been used for LPP with little success. Although acitretin might be considered a first-line agent for cutaneous lichen planus, similar studies have not been performed on LPP. Griseofulvin was effective for symptomatic relief in some case series, but did not seem to halt progression of alopecia. The tetracycline family of antibiotics (especially doxycycline and minocycline) is frequently utilized for LPP because of its favorable side-effects profile, despite the fact that there is low evidence in its efficacy (11). Topical minoxidil can be combined to recruit and prolong the life of anagen hairs and to assist in any concomitant pattern hair loss (4). Both minoxidil 2% and 5% can be used. Tacrolimus can also be used, it can be compounded to obtain at 0.1–0.3% lotion/solution (10). Low-dose naltrexone has demonstrated efficacy in the adjuvant treatment of multiple autoimmune disorders (i.e., Crohn’s disease and multiple sclerosis). This medication provided benefit in LPP in a small case series, including reduction in symptoms of pruritus, clinical evidence of inflammation of the scalp and disease progression. The dosage often used is 1.5–4.0 mg/day. It is well-tolerated and cost-effective (16). Pioglitazone (hypoglycemic drug, 15–30 mg/day) has been reported to have some efficacy in LPP, due to the fact that this medication is an agonist of PPARγ, the same that is deficient in LPP (17). The highest dose seems to be more effective. Relapse usually occurs with discontinuation, but some patients experienced a prolonged remission. There are safety concerns regarding pioglitazone, including increased risk of cancer (bladder, pancreatic and prostate) and heart failure. These adverse events are associated with long-term use (>1 year), cumulative doses and individual susceptibility (10). Thalidomide may have a beneficial effect on the control of LPP. However, it is scarcely utilized because of its side effects. Hair transplantation is not recommended as it might worsen or even trigger the disease (18). Camouflage methods are good options to reduce contrast between hair and visible scalp or cover bare areas, such as

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different hairstyles, light hair color, make-up matching one’s hair color, hats, scarves, scalp micropigmentation, hairpieces, volumizer and hair extension. Care must be taken not to add traction.

REFERENCES











1. Galvan SV, Corralo DS, et al. Frequency of types of alopecia at twenty-two specialist hair clinics: A multicenter study. Skin Appendage Disord 2019; 5: 309–15. 2. Bakhshoudeh B, Salehi M, Sadeghi R, et al. Therapeutic updates on lichen planopilaris and frontal fibrosing alopecia: A systematic review. Rev Clin Med 2018; 5(3): 76–94. 3. Kang H, Alzolibani AA, Otberg N et al. Lichen planopilaris. Dermatol Ther 2008; 21(4): 249–56. 4. Fertig RM, Hu S, Maddy AJ, et al. Medical comorbidities in patients with lichen planopilaris, a retrospective casecontrol study. Int J Dermatol 2018; 57: 804–9. 5. Azzawi S, Penzi LR, Senna MM. Immune privilege collapse and clopecia development: Is stress a factor? Skin Appendage Disord 2018; 4: 236–44. 6. Lyakhovitsky A, Amichai B, Sizopoulou C, et al. A case series of 46 patients with lichen planopilaris: Demographics, clinical evaluation, and treatment experience. J Dermatolog Treat 2015; 26: 275–9. 7. Miteva M, Tosti A. Hair and scalp dermatoscopy. J Am Acad Dermatol 2012 Nov; 67(5): 1040–8. 8. Ocampo JO, Tosti A. Trichoscopy of dark scalp. Skin Appendage Disord 2018; 5: 1–8. 9. Miteva M, Tosti A. Dermoscopy guided scalp biopsy in cicatricial alopecia. J Eur Acad Dermatol Venereol 2013 Oct; 27(10):1299–303.

10. Bolduc C, Sperling LC, Shapiro J. Primary cicatricial alopecia: Lymphocytic primary cicatricial alopecias, including chronic cutaneous lúpus erythematosus, lichen planopilaris, frontal fibrosing alopecia, and Graham-Little syndrome. J Am Acad Dermatol 2016; 75(6): 1081–99. 11. Sperling LC, Nguyen JV. Commentary: treatment of lichen planopilaris. J Am Acad Dermatol 2010; 62(3): 398–401. 12. Miteva M, Tosti A. Pathologic diagnosis of central centrifugal cicatricial alopecia on horizontal sections. Am J Dermatopathol 2014 Nov; 36(11): 859–64. 13. Herskovitz I, Miteva M. Central centrifugal cicatricial alopecia: challenges and solutions. Clin, Cosm Invest Dermatol 2016; 9: 175–81. 14. Sehgal VN, Bajaj P. Lichen planopilaris. Int J Dermatol 2001; 40: 516–7. 15. Lajevardi V, Mahmoudi H, Moghanlou S, et al. Assessing the correlation between trichoscopic features in lichen planopilaris and lichen planopilaris activity index. Australas J Dermatol 2019; 60: 214–18. 16. Lauren C, Strazzulla BA, Lorena A, et al. Novel treatment using low-dose naltrexone for lichen planopilaris. J Drugs Dermatol 2017; 16(11): 1140–42. 17. Tziotzios C, Brier T, Lee JYW, et al. Lichen planus and lichenoid dermatoses. J Am Acad Dermatol 2018; 79(5): 807–17. 18. Chiang YZ, Tosti A, Chaudhry IH, et al. Lichen planopilaris following hair transplantation and face-lift surgery. Br J Dermatol 2012 Mar; 166(3): 666–70.

11 Frontal Fibrosing Alopecia Alexander C. Katoulis, Konstantina Diamanti, Evangelia Bozi, Georgia Pappa, and Sofia Georgala

Definition Frontal fibrosing alopecia (FFA) is a primary lymphocytic cicatricial alopecia with a distinctive clinical pattern of progressive frontotemporal hairline recession and eyebrow loss. First described by Kossard in 1994, it was thought to be a variant of lichen planopilaris (LPP).1

Epidemiology Although most patients with FFA are postmenopausal women (83% in the largest published series) ranging between 55 and 70 years of age, the condition has also been observed in premenopausal women and rarely men.2,3 African-Americans4 and Asians5 are affected less than Caucasians. Family history is present in 8% of patients.2 Currently, there is no epidemiological data on the incidence and prevalence of FFA in the general population. However, several reports indicate an epidemic increase in the number of patients with the disease (as opposed to the stably low incidence of LPP.6 Interestingly, in just two decades since it was described, FFA has been considered as the most common clinical presentation of primary scarring alopecia. Although increased awareness of the disease might be an explanation, it is difficult to believe that FFA went unrecognized for years. Therefore, various environmental or lifestyle factors have been investigated as trigger factors for FFA.7

Etiology and Pathogenesis The exact pathogenesis of FFA remains to be elucidated. An autoimmune reaction targeting follicular antigens has been implicated, involving also immune privilege collapse, and resulting in irreversible alopecia. This Th1-biased CD8+ T-cell activation is centered at the infundibulum and the bulge, which is home to epithelial hair follicle stem cells.8,9 Peroxisome proliferator-activated receptor gamma (PPARγ) deficiency is also hypothesized to enable the inflammatory process to attack the stem cells.10 PPARγ has a strong antifibrotic activity and its decline could correlate with the fibrogenic inflammatory process of FFA. Based on the predominance of postmenopausal women; typical localization on the frontal scalp; increased incidence of

DOI: 10.1201/9780429465154-11

early or iatrogenic menopause; and clinical improvement seen with anti-androgens, an androgen-dependent etiology has been proposed for FFA.2,11,12 It has been suggested that FFA and androgenetic alopecia (AGA) may be pathogenetically related, with FFA constituting the transitioning of AGA toward a cicatricial alopecia,12,13 as it has already been assumed for fibrosing alopecia in a pattern distribution (FAPD).13,14 In a cohort of 35 females with FFA, 57% had also AGA and in 11% FFA, AGA and FAPD coexisted, suggesting that these entities belong to the same nosological spectrum.15 On the other hand, FFA also affects androgen-­independent hairs, such as the eyebrows, and hormone replacement therapy has failed to show any protective effect or efficacy as treatment.1 Therefore, the exact role of hormones still remains unclear. The pathogenesis of FFA also includes a genetic component, as evidenced by frequent familial segregation.16 In fact, a possible autosomal dominant inheritance with incomplete penetrance has been suggested.17 Additionally, four genomic loci have been identified, at which genetic variation is robustly associated with FFA risk. Their biological impact indicates that the disease is a complex immune-inflammatory trait underpinned by risk alleles in MHC Class I molecule-­ mediated antigen processing and T-cell function.18 An increase in transcripts encoding components of the interferon-γ (IFN-γ) pathway in affected scalp tissue has also been observed, suggesting that agents such as Janus kinase (JAK) inhibitors may be efficacious for FFA.18 Increased scalp sweating has been reported in some patients, and although it is difficult to state if the two conditions are really associated, further investigation should be conducted on neurogenic inflammation. It is not yet clear if the inflammatory process in FFA may induce a sweating reflex or modulate the sweat secretion, or, conversely, if it is the increased sweating in the forehead and frontal hairline that triggers and maintains the hair follicle inflammation.19 Finally, environmental factors are under evaluation as possible triggers for FFA development.7 Recently, a doubled incidence of use of facial sunscreens in FFA patients compared to controls has been reported.20 It was speculated that the trigger for FFA might not be a specific ingredient, such as the UV filters, but rather their retention within the hair follicle once applied to the skin, probably due to local low sebum production. This prolonged retention could trigger an immunological response against vellus and epidermal antigens.21 Although the methodology which led to the association between FFA and the use of sunscreens was heavily criticized,22 a recent study

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Hair Disorders

  FIGURE 11.1  (a, b) FFA in a 64-year-old postmenopausal woman with recession of the frontal, temporal and parietal hairline. Some lonely hairs on the cicatricial skin are present. There is associated partial eyebrow loss (note the use of eyebrow pencil).

again confirmed an increased sunscreen use in FFA patients.23 On the other hand, an association of prominent solar elastosis with destruction of sebaceous glands in the affected eyebrows of patients with FFA has been observed, suggesting that actinic damage and permanent hair loss may be pathogenetically related.24 Consequently, the role of sunscreens in FFA remains controversial.

Clinical Presentation FFA is characterized clinically by slowly progressive bandlike recession of the frontotemporal and parietal hairline. This cicatricial hairline transitions into actinically damaged skin of the forehead. The affected skin is slightly atrophic, devoid of follicular ostia, smooth, and lighter than the chronically sun-exposed forehead skin1,12 (Figure 11.1). Less frequently, the entire fringe of the scalp, including the retro-auricular or occipital region, may be affected.2 Moreno-Arrones et al. described three clinical patterns of hair loss, i.e. linear, diffuse, and pseudo-fringe.25 The linear pattern is a band of uniform frontal hairline recession in the absence of loss of hair density behind the hairline. The diffuse pattern is the same as linear, but with at least a 50% decrease in hair density behind the hairline, and a compatible trichoscopic picture of FFA in the central scalp. The pseudo-fringe pattern is characterized by the presence of some retained hair along the hairline, especially in the temporal area, ahead of the alopecic skin (pseudofringe sign).26 Vellus hair is totally absent in all three types and12 together with the isolated “lonely” hairs,27 have been reported as typical for FFA. Partial or complete eyebrow hair loss, occasionally with perifollicular and interfollicular erythema, is seen in 50–95% of patients and is another common diagnostic feature.2,3,12,24 Characteristically, eyebrow loss begins at the lateral third of the brow and may progress to total eyebrow loss. It can either precede or follow the onset of hair loss, but it could also be the sole presentation of the disease, sometimes leading to a misdiagnosis of alopecia areata or senile eyebrow loss.28 Eyebrow pencils and eyebrow tattooing are often used to cover hair loss

(Figures 11.1 and 11.2). Moreover, body hair loss is observed in 27–77% of FFA patients, before or after scalp hair loss, usually affecting the axillae, the pubic area, and the upper or lower limbs.2,29,30 This suggests that the process of permanent hair follicle loss is rather generalized than localized to the frontal scalp and the eyebrows.30 It is interesting to note that both eyebrow and body hair involvement clinically appear to be non-inflammatory and non-scarring, as opposed to the scalp, although their histologic examination shows the features of FFA.30,31 Body hair loss can be difficult to distinguish from physiologic changes occurring after menopause and patients never report it themselves, but biopsy specimens confirm the diagnosis of FFA. The beard is affected in half of the male patients.2 Less frequently, sideburns or eyelash loss (14%) may occur.2 Small flesh-colored facial papules (14–37%) on the temples, cheeks, and chin2,3 (Figure 11.2), as well as perifollicular

FIGURE 11.2  FFA in a 67-year-old postmenopausal woman. Facial flesh-colored papules are a common clinical feature of FFA (white arrows). Tattooing has been used to cover the total eyebrow loss.

87

Frontal Fibrosing Alopecia erythema (follicular red dots), sometimes with follicular keratosis, in the glabellar, forehead, eyebrow, or cheek regions,32,33 are also observed. These reflect vellus follicle destruction by the typical FFA inflammatory infiltrate.33,34 Moreover, diffuse erythema of the face and neck may be present, sometimes with a reticular pattern, owing to follicular and interfollicular lichenoid infiltrate.32 This may cause a burning sensation and it is sometimes misdiagnosed as rosacea. Coexistence of lichen planus pigmentosus (LPPigm) with FFA is quite common in patients with dark phototype (55%), and it is often misdiagnosed as melasma.35,36 LPPigm is an uncommon macular variant of lichen planus occurring either as diffuse or reticulated macules on sun-exposed areas and in flexures. Additionally, pigmented macules are frequently localized along the scalp hairline in FFA and may be a sign of pigmentary incontinence due to interface dermatitis.32 Finally, the depression of frontal veins observed has been justified as a consequence of the overlying atrophic skin tissue.37 Overall, FFA is typically disfiguring, and is associated with marked psychological impact and significant loss of quality of life.38 Assessing duration of FFA is challenging. The insidious onset, the slow progression, the misinterpretation of hair loss as sign of aging, makes it difficult for the patient to identify the time of the disease onset and delays medical consultation. FFA is usually asymptomatic. Nevertheless, during the active phases of the disease, some patients complain of pruritus and/or trichodynia,2 while affected hair follicles may show signs of local inflammation, such as perifollicular erythema and hyperkeratosis.1 The course of FFA is chronic and unpredictable. The average rate of frontal hair loss in untreated patients is 0.95–1.08 cm/ year.2,39 Factors associated with a severe disease course are a diffuse pattern of FFA, loss of eyelashes, presence of facial papules, and body hair involvement.2,25 In a large series, the majority of patients, even with long-standing disease, presented with mild FFA (frontotemporal hairline recession of less than 3 cm), indicating a spontaneous remission at some point.2 Other authors, however, believe that FFA does not

spontaneously resolve, therefore, early recognition and treatment are crucial for halting the disease progression.40

Diagnosis and Differential Diagnosis Clinical features of FFA are generally very suggestive, but trichoscopy is a valid aid in doubtful cases/limited disease, or when the eyebrows are the sole localization of the disease.41 Histopathology can also aid in the differential diagnosis in the early stages or in uncommon areas of involvement. More specifically, trichoscopy in FFA shows reduced/ absent follicular openings and minor perifollicular scaling or erythema in the scalp area (Figure 11.3). Perifollicular erythema may be an index of disease activity and is often accompanied by pruritus. An independent marker of disease severity is the presence of cicatricial white patches.42 Absence of vellus hairs is diagnostic and allows differentiation of FFA from AGA. In contrast to LPP, in which the background may be milky red in the early fibrotic phase of the disease, the background is ivory white to an ivory beige in patients with FFA.43 Trichoscopy of the eyebrows shows multiple empty follicles; they appear as regularly distributed red dots in the early phase of the disease and change their color to more grayish over time (Figure 11.4). The presence of empty follicular openings and vellus hairs may be considered as favorable prognostic factors for eyebrow regrowth. On the contrary, dystrophic hairs, eyebrow regrowth in distinct directions, and whitish areas with absence of follicular openings may be considered negative prognostic factors.41 All these dermoscopic findings can help distinguish FFA from traction alopecia (hair casts, pinpoint white dots, broken and miniaturized hairs), alopecia areata (presence of follicular ostia, yellow and black dots, exclamation mark hairs, tapered hairs), and androgenetic alopecia (vellus hairs, peripilar sign, and hair diameter diversity >20%).44 The histopathologic features in FFA are similar to those found in LPP. In early stages, a lichenoid inflammatory lymphocytic infiltrate involving the isthmus and infundibulum of

  FIGURE 11.3  (a, b) Trichoscopy of the receding hairline in FFA shows loss of follicular orifices, as well as perifollicular erythema and minor perifollicular scaling on some of the remaining follicles.

88

Hair Disorders hypothyroidism in patients with FFA (15%), including thyroid screening in their initial work-up is suggested by some authors.2,49 Once the diagnosis is made, the severity of FFA can then be evaluated, using appropriate scoring systems. Frontal Fibrosing Alopecia Severity Index (FFASI), was introduced in 2016, while50 Frontal Fibrosing Alopecia Severity Score (FFASS) was proposed in 2017.51 Although they both have some limitations, the development of a validated scoring system is an important step toward a standardized and objective method for assessing severity of FFA and response to treatment. As alluded to earlier, the differential diagnosis of FFA mainly includes traction alopecia,52 AGA, and alopecia areata. Dermoscopy can assist in the correct identification of the disease.

FIGURE 11.4  Empty reddish follicular openings in the eyebrow area of a patient with FFA. The reddish dots tend to get more grayish over time.

the hair follicles and mild perifollicular lamellar fibrosis are present. Later stages are instead characterized by more severe perifollicular concentric fibrosis, with reduced follicular density until scar tissue replaces the pilosebaceous units. In general, the lichenoid tissue reaction is milder in FFA than in LPP, the interfollicular epidermis is always spared in FFA in contrast to LPP, and the more prominent eosinophilic necrosis of cells of the hair follicle outer root sheath (apoptosis) is another distinctive characteristic of scalp FFA.45 It has also been reported that, in FFA, inflammation and fibrosis may extend below the isthmus in comparison with LPP.46 Eyebrow and peripheral body hair loss present with histopathological features similar to those found in scalp alopecia.30 Nevertheless, in a recent case series, Katoulis et al. found sebaceous gland preservation in the affected eyebrows in 38% among 33 FFA patients, as opposed to the total absence of sebaceous glands in the affected scalp of all patients.24 This finding could be the pathological correlate for the reported reversibility of eyebrow loss in FFA. It may, therefore, be postulated that the scarring potential in the eyebrows might be lower, compared to that in the frontal scalp. According to the authors, and considering the suggested involvement of androgens in FFA pathogenesis, this difference could be attributed to the fact that eyebrows are not an androgen-dependent region. Direct immunofluorescence is non informative in FFA.47 Recently, a list of major and minor criteria has been proposed for the diagnosis of FFA.48 Two major criteria or one major criterion and two minor criteria are required to diagnose the disease. Major criteria include cicatricial alopecia of the frontal/temporal/frontotemporal scalp on examination (in the absence of follicular keratotic papules on the body) and diffuse bilateral eyebrow alopecia. Minor criteria include typical trichoscopic features, histopathologic features of cicatricial alopecia in the LPP/FFA pattern, involvement (hair loss or perifollicular erythema) of additional FFA sites (occipital hair, facial hair, sideburns, body hair), and presence of non-inflammatory facial papules. There are no laboratory specific tests that are useful for the diagnosis of FFA. However, due to the significant prevalence of

FFA and LPP: Variant or Distinct Entity? Despite the clinical differences between FFA and LPP, their histopathology is similar. This has encouraged the still controversial concept of FFA being a variant of LPP.1 On the other hand, many authorities believe that FFA is a distinct entity.2,13,15,45,53 Firstly, there is no reported correlation of FFA with HLA-DR1, as in classical lichen planus and its variant Graham-Little-Piccardi-Lassueur syndrome.54 Moreover, FFA affects predominantly women; in the largest published series, female to male (F:M) ratio has been estimated at 32:12, whereas the equivalent ratio in LPP ranges from 1.8:1 to 4.9:1.55 Cutaneous and/or mucosal involvement by lichen planus is far more frequently seen in association with LPP (28–50%)56 than with FFA (1.6–9.9%).2,39 Loss of facial and body hair concomitantly with LPP is reported in 7–10%.55,56 On the other hand, loss of eyebrows has been reported in 50–95% of FFA patients,2,3,12,24 and loss of body hair in around 27–77%.2,29,30 Unlike typical LPP, hair loss from eyebrows and body in FFA is, most often, clinically non-inflammatory.30 Classical diffuse LPP elsewhere on the scalp has been reported in association with FFA in 35 days in adults or >40 days

Hot or cold intolerance, tremors, brittle hair, telogen hair loss, dry skin, enlarged thyroid gland, and exophthalmos should raise “de suspicion” of a thyroid disease.

Weight gain, hypertension, moon facies, central obesity, acne, striae, proximal muscle weakness, thin skin, easy bruising, and buffalo hump were some of the signs and symptoms of this syndrome.

Signs of Metabolic Syndrome or Insulin Resistance Acanthosis nigricans and obesity can accompany hirsutism in patients with a metabolic cause.

151

Hirsutism

Symptoms and Signs of Hyperprolactinemia These include amenorrhea and spontaneous or expressible galactorrhea.

Signs of Acromegaly Coarse facial features and large hands are greatly associated to acromegaly.

a mild elevation in the DHEAS and total testosterone levels, 17-hydroxyprogesterone should be performed to exclude late-onset CAH. The 17-Hydroxyprogesterone is a specific marker for CAH and it should be requested in cases of a positive family history or highly clinical suspicious, even if total testosterone and CFT are normal. Some authors suggest it should be routinely performed on all women with hyperandrogenic hirsutism.39

Additional Tests

Laboratory Investigation The most important goal is to identify underlying etiology (Table 21.1 and Figure 21.4). The initial tests should include:

Hyperandrogenism Markers a. Total testosterone level (by mass spectrometry coupled with liquid chromatography assays) during early follicular phase of the menstrual cycle, by morning. Serum testosterone level >200 ng/dL is highly suggestive of an adrenal or ovarian tumor, DHEAS level must be measured in these cases to differentiate between adrenal and ovarian etiology. Normal or mildly elevated total testosterone (>50 ng/dL) suggests PCOS, usually with an increased ratio LH:FSH = 1:3 and the ultrasound findings, although the utility of LH:FSH levels, are controversial.41 There are some patients with PCOS and normal levels of total testosterone (non-hyperandrogenic PCOS), in these cases the diagnosis is done with 2 of 3 signs: amenorrhea, LH:FSH = 1:3 and ovaric ultrasound findings.42–44 b. Sex hormone binding globulin (SHBG) level for calculating the Free Androgen Index (FAI): FAI = (Total testosterone level/SHBG) * 100 c. Albumin levels to measure the Calculated free testosterone (CTF). The recommended formula for this is the Vermeulen equation45 that is available in many medical online calculators. Al Kindi et al. recommend measuring SHBG and albumin levels for the initial hyperandrogenism evaluation and calculating the FAI and CTF.42 Hahn et al. found a significant correlation between CTF, FAI, total testosterone and hirsutism scores, ovarian volume and follicular count.43 These three markers are good indicators for hyperandrogenism with a higher sensitivity (71.4–75.9%) and specificity (83.3–85.2%) than total testosterone or free testosterone alone.42 A reduced SHBG value is also associated with IR and an increased risk of developing type 2 diabetes.34

Adrenal Etiology Markers Serum dehydroepiandrosterone sulfate should be measured in women with hyperandrogenic hirsutism. An adrenal source should be suspected with levels >700 mg/dL. When there is

In cases of amenorrhea, thyroid function tests, prolactin, and Human Chorionic Gonadotropin (hCG) levels should be obtained. A 24-hour urine cortisol test is recommended in cases where Cushing syndrome is suspected.44,46 Testing androstenedione is not recommended for routine screening because is rarely elevated in hyperandrogenism.16 If PCOS is suspected, the addition of androstenedione to DHEA-S may increase sensitivity by 10%.47

Imaging Transvaginal ultrasound in suspected cases of PCOS can confirm diagnosis. The findings include follicle number per ovary of ≥20. An ovarian volume >10 mL with transabdominal ultrasound can also confirm the diagnosis. When an adrenal or ovarian neoplasm is suspected, magnetic resonance imaging or computed tomography is helpful to identify the lesions. When there is hyperprolactinemia >100 ng/mL, cranial magnetic resonance imaging is suggested for pituitary tumors.44,48–59

Differential Diagnosis Hirsutism must be distinguished from hypertrichosis, which is characterized by increased hair growth in a generalized nonsexual distribution and is independent of androgens; it usually presents as generalized or localized growth of vellus type hair over the body. Carcinoid tumors, choriocarcinoma and metastatic lung carcinoma can also cause hirsutism by producing ectopic hormones. Most drugs cause hypertrichosis rather than hirsutism.31

Prognosis The prognosis of the disease depends on the etiological agent and its appropriate treatment.

Treatment Hirsutism is generally best managed using a three-pronged approach that includes: (1) mechanical removal of excess hair, (2) suppression of ovarian androgen production (most often with a combination of oral contraceptive [OC] pill), and (3) anti-androgen medication.60,61

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TABLE 21.1 Summary of Findings in Hirsutism37–59 Laboratory Testing Hirsutism Cause

Clinical History

Physical Examination

T

DHEAS

LH/FSH

17-OHP

Cortisol

Pr

Additional Testing

PCOS

Oligomenorrhea, amenorrhea, infertility. metabolic syndrome

N to ↑

N to ↑

N to >3:1

N

N

N to ↑

Impaired glucose tolerance, hyperlipidemia, ↓SHBG Pelvic ultrasound

CAH (late onset)

Oligomenorrhea, primary amenorrhea Ethnic background Family history Menstrual irregularities, metabolic syndrome, fatigue, mood and sleep disturbance, recurrent opportunistic cutaneous infections

Seborrhea Acne Alopecia Acanthosis nigricans Obesity Acne Hirsutism Premature pubarche

N to ↑

N to ↑

N/N

↑

N to ↑

N

Acne, alopecia, thin skin, easy bruising, striae, hyperpigmentation, Cutaneous infections (fungal), proximal muscle weakness, hypertension, fat redistribution, central obesity Goiter, exophthalmos, brittle hair, tremors, diffuse scalp hair thinning Spontaneous or expressible galactorrhea

N to ↑

N to ↑

N/N

N

↑

N

N

N

N/N

N

N

N to ↑

ACTH stimulation test Genotyping of CYP21A2 (21-hydroxylase deficiency, most common) 24-hour urine cortisol, overnight dexamethasone suppression test Evening ACTH level, CRH stimulation test, potassium level (↓), lipid panel, glucose tolerance test, fasting blood glucose Thyroid function tests

N to ↑

N to ↑

N/N

N

N

Cranial MRI

Large hands, coarse facies, acanthosis nigricans, hyperhidrosis Signs of virilization Abdominal or pelvic palpable mass

N to ↑

N

N/N

N

N

↑ >100 ng/mL suggests prolactinoma N to ↑

↑↑↑ 200 ng/dL (adrenal) N

N ↑ >700 mcg/mL

N/N N/N

N N

N N to ↑

N N

Androstenedione >100 ng/dL Transvaginal ultrasound CT/MRI abdomen or pelvis

N

N/N

N

N

N

Exclusion

N to ↑ * valproic acid ↑ *progestins ↑

N

N/N

N

N

N

Laboratory test

Cushing’s disease

Change in weight Heat or cold intolerance

Hyperprolactinemia

Amenorrhea

Acromegaly

Headache, visual disturbance

Neoplasia

Older age Sudden onset, rapid progression of hirsutism

Idiopathic

Regular ovulation No associated risk factors History of drug intake

Medications

Mild hirsutism (F–G score 8–15) Hirsutism

IGF-1 levels Cranial MRI

Abbreviations:  ↑ = raised; 17-OPH = 17-Hydroxyprogesterone, DHEAS = Dehydroepiandrosterone sulfate, FSH = Follicle stimulating hormone, LH = Luteinizing hormone, N = Normal, Pr = Prolactine, T = Testosteroe.

Hair Disorders

Thyroid

153

Hirsutism

HIRSUTISM

Lab tests for all patients between the first 5 days of menses, by morning. No hormone intake 6 weeks before testing: Special considerations besides initial evaluation

1) Total testosterone 2) SHBG 3) Albumin (Measure the Free calculated testosterone (FCT) and Free androgen index (FAI)

HIRSUTISM + AMENORRHEA - Thyroid function tests Normal results IDIOPATHIC HIRSUTISM

Androgen levels (Total testosterone, FCT or FAI)

- β-HCG

suggests pregnancy luteoma

- Normal androgen levels, LH:FSH = 1:3 and ovaric ultrasound findings suggests non hyperandrogenic PCOS

HIRSUTISM + ACROMEGALY SIGNS IGF-1 levels Cranial MRI

- Prolactin ≥100 ng/ml high probability of pituitary adenoma ≤100 ng/ml other causes

Total testosterone ≥200 ng/dl Suspect adrenal etiology (includes adrenal tumor) or ovarian tumor

DHEA-S

DHEA-S ≥700 μg/ml Suggest adrenal etiology: - 17 –OH progesterone for Congenital Adrenal Hyperplasia - ACTH, CRH stimulation test and 24-hour urine cortisol, K+ for Cushing syndrome - Abdominal CT-Scan or ultrasound for adrenal tumor

Total testosterone ≤200 ng/dl

Suspect PCOS Androstenedione and LH:FSH 1:3 (utility is controversial) SHBG Impaired glucose tolerance Hiperlipidemia Pelvic ultrasound

DHEA-S ≤700 μg/ml - Pelvic CT-Scan or ultrasound to confirm or exclude ovarian tumor - 17 –OH progesterone for late onset CAH

FIGURE 21.4  Evaluation of hirsutism. ACTH = adrenocorticotropic hormone, CRH = corticotropin-releasing hormone, DHEA-S = ­dehydroepiandrosterone-sulfate, FAI = free androgen index, FCT = free calculated testosterone, IGF-1 = insulin-like growth factor 1, LH:FSH = luteinizing hormone:follicle stimulating hormone, PCOS = polycystic ovary syndrome, SHBG = sex hormone binding globulin, β-HCG = human chorionic gonadotropin, 17-OH progesterone = 17-hydroxyprogesterone.

Initial response to treatment generally takes 4–6 months. Treatment for hirsutism can provide cosmetic and psychologic benefits. Women’s rating of their hirsutism often is worse than their physicians’ rating. The stigma associated with hirsutism can lead to depression and affect quality of life.62 After ruling out other treatable causes, the most effective therapy for hirsutism usually involves a combination of modalities, including physical hair removal techniques, topical agents, and medical therapies with a multidisciplinary team. (Tables 21.2 and 21.3, Figure 21.5) Medical therapy involves androgen suppression or antiandrogens and is most useful for hyperandrogenic hirsutism,

but it may also be used in idiopathic hirsutism. Given the lifespan of terminal hair, at least 6 months of medical therapy are required before slower and finer regrowth of hair is noted.63 Hair growth tends to recur after cessation of medical therapy. Concomitant physical hair removal may be used for temporary results and may also hasten the effects of medical therapy. Both laser hair removal and electrolysis can produce permanent hair reduction, although periodic retreatment may be required. Hirsutism usually entails chronic treatment with medications requiring several months of use before any clinically significant decrease in hirsutism is observed.64–75

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Hair Disorders

TABLE 21.2 Mechanical Methods of Hair Removal Method Shaving

Bleaching

Chemical depilation

Plucking

Waxing

Threading

Electrolysis/thermolysis

Laser/light sources (DiodeIPL)

Advantages

Disadvantage

Temporary Hair Reduction Fast, inexpensive Less acceptable to women Easily available Early “stubble” during initial days Can be done at home following shaving Fast, inexpensive Can cause severe skin irritation Easily available Allergy possible Can be done at home Unsuitable for dark skin Good for moustache Easily available Can cause skin irritation Can be done at home Pain-free Easily available Can cause ingrown hairs, folliculitis, and Can be done at home scarring Good for individual long hairs Easily available May cause skin irritation, especially on Can be done at home the face Can be used for larger areas Thermal burns/folliculitis possible Can be done at home Requires skill Mainly used for face Permanent Hair Reduction All hair and skin types Operator-dependent Moderate price Painful Good for small areas Time-consuming, targets one hair follicle Impractical for large areas Dispigmentation/scaring possible Good for all skin types Painful, operator-dependent Most clinically effective Time-consuming, usually 6 treatments and Can be used for larger areas maintenance therapy

Cost

Effect

+

5–10 days

+

Temporary

+

10–15 days

+

Temporary

+

4–6 weeks

++

4–6 weeks

+++

Permanent

+++

Permanent

Source: Modified from Liu et al.34

Physical Hair Removal Treatment Various physical methods of hair removal can be used safely and effectively (see Table 21.2). The choice is dictated by cost and the woman’s tolerance of the various regimens rather than by efficacy.76,77 Bleaching with 6% hydrogen peroxide or with a 20% ammonia solution is a popular method, shaving, and chemical depilatories are inexpensive and painless but entirely cosmetic in nature, with no change in the underlying hair or follicle. Plucking, waxing, threading, and laser hair removal may be more uncomfortable or costly but may eventually reduce regrowth of hair, especially if combined with concomitant medical therapy. Both laser devices and electrolysis have been shown to result in long-term hair reduction. Women with darker skin benefit from Nd:Yag and diode-based lasers for optimal safety. For larger surface areas, laser hair removal is far more practical than electrolysis.77,78

Medical Therapy Topical Therapy The current topical treatments for hirsutism, and especially for facial hair, area based on spironolactone, or its metabolite canrenone, and Eflornithine.79

Eflornithine hydrochloride cream at concentration between 13.9% and 15%, an ornithine decarboxylase inhibitor, has been shown to reduce facial hirsutism over placebo after 8 weeks of use. Two randomized, double-blind studies involving 594 women treated for 24 weeks found a significant reduction of unwanted facial hair in women. Treatment is meant to be used indefinitely because hair growth recurs after cessation of therapy. Eflornithine may also be used as an adjuvant to laser to improve results and prevent hair regrowth. A thin layer should be applied twice daily. Side effects of eflornithine include local irritation, pruritus, and stinging.79–83

Oral Contraceptive (OC) In the absence of contraindications to combined hormonal contraceptives (CHC), these are the first-line therapy to suppress gonadotropins, decrease ovarian androgen production, and augment hepatic production of SHBG, thus decreasing free testosterone levels.84 Multiple studies have shown the benefit of CHC in hirsutism. Oral CHC with non-androgenic (e.g., desogestrel or norgestimate) or anti-androgenic progestins (e.g., cyproterone acetate or drospirenone) may have more benefit.85,86 OC should not be used in women who have IR, thrombophlebitis, cerebrovascular disease, coronary occlusion, abnormal vaginal bleeding, impaired liver function, migraine, smokers aged over 35 years, or individuals with increased risk of breast cancer.87,88

155

Hirsutism TABLE 21.3 Medical Therapy for Hirsutism Treatment Eflornithine hydrochloride

Oral Contraceptive (OC) Combined Hormonal Contraceptives (CHC)

Anti-androgens Spironolactone

Cyproterone Acetate (CPA)

Metformin

Finasteride

Flutamide

Usage

Side Effects/Adverse Effects

Topical Therapy For facial hirsutism Local irritation, pruritus, acne, erythema, burning Thin layer applied twice daily Oral Therapy First line agents Breakthrough bleeding, amenorrhea Oral, vaginal ring, and Nausea, transdermal patch Headache formulations Breast tenderness Venous thromboembolism (rare) 100–200 mg once daily Transient diuresis Can be combined with CHC Fatigue Monitor electrolytes 3 months Headache after starting and annually Gastric upset Breast tenderness Risk of pseudo-hermaphroditism in male fetuses 2 mg combined with ethinyl Irregular menses, breakthrough bleeding, estradiol 0.035 mg (Diane 35) amenorrhea, Nausea, bloating, Headache Breast tenderness Venous thromboembolism Decreased libido Liver toxicity 500–1000 mg twice daily Gastrointestinal upset Useful for treating polycystic Is not effective for idiopathic hirsutism ovary syndrome 2.5–5 mg once daily Minimal Can be combined with CHC Feminization of a male fetus if taken during pregnancy Hepatotoxicity 250–500 mg once daily Hepatotoxicity (monitor serum transaminase levels Can be combined with CHC before treatment, monthly x4 months then annually) Hot flashes, decreased libido, diarrhea Feminization of a male fetus if taken during pregnancy

Source: Modified from Liu et al.34

FIGURE 21.5  Hirsutism treatment.

FDA Pregnancy Category C

X

D

X

B

X

X

156

Anti-androgens Anti-androgens prevent androgen activity at target tissues and are especially useful for idiopathic hirsutism.89–103 These can be divided in two groups: 1. Androgen receptor antagonists, such as Cyproterone Acetate (CPA), Spironolactone, Drospirenone, Flu­ tamide, Dinogest, Bicalutamide, Cimetidine, Isotret­ inoin, and Ketokonazole 2. 5-α reductase inhibitors, such as finasteride and dutasteride For moderate and severe hirsutism, the addition of anti-androgens can enhance the effect of CHC. As added benefit, CHC provides contraception required when using potentially teratogenic anti-androgen therapies.89

Spironolactone Spironolactone is an aldosterone antagonist (pregnancy category C), which also has antiandrogenic effects and decrease levels of total testosterone. Spironolactone competes for the androgen receptor in skin fibroblasts and produces limited suppression of gonadal and adrenal androgen biosynthesis. This drug can be used alone in doses of 50–200 mg daily for at least 6 months, or in combination with CHC. There is a dose-related increase in irregular menses, controlled by concomitant administration of CHC. The regimen starts with a low dose of 50 mg/day, which is sufficient in adrenal SAHA, and the dose is increased monthly by increments of 50 mg to a final dose of 200 mg/day. This regimen reduces the diameter of the facial vellus hair in 83% of patients. Side effects are presented in 75–91% of cases, such as transient diuresis, fatigue, headache, gastric upset, and breast tenderness, that can be minimized by gradual dose increases. Periodic assessment of serum electrolytes to detect electrolyte imbalance should be done at appropriate intervals (3 months after starting and annually thereafter), particularly in women with significant renal or hepatic impairment. There is a theoretical risk of feminizing a male fetus, if pregnancy occurs while the woman is taking this medication.90,91,94

Cyproterone Acetate Cyproterone acetate (CPA) is a progestational agent that inhibits gonadotropin release, thereby decreasing androgen production, and binds competitively to androgen receptors. The recommended dose is 50–100 mg/day from the 5th to the 15th days of the menstrual cycle, for a 6-month period. When a maintenance regimen is required, 2 mg/day may be administered for day 1 to day 21 of the cycle followed by a week without treatment. For mild hirsutism, it is most conveniently administered as a combined pill of ethinyl-estradiol and CPA (35 mg ethinyl estradiol/2 mg CPA), which is effective in controlling acne and hirsutism alone or in combination with spironolactone 100 mg daily. Side effects include loss of libido, mood swings, fatigue, mastodynia, hypertension, irregular

Hair Disorders menstrual bleeding, nausea, depression, and weight gain. CPA is absolutely contraindicated in patients with liver disease.92,93

Finasteride Finasteride is considered to be a potent nonsteroidal antiandrogen that acts by inhibiting the type 2 isoenzyme of 5α reductase, thereby blocking conversion of testosterone to 5α DHT and is very useful in the treatment of idiopathic hirsutism. It is considered to be an effective antiandrogen for women (to reduce hirsutism and female alopecia) and in men (to treat benign prostatic hypertrophy an alopecia). Following 3–6 months of treatment at a dose of 5 mg/day or 7.5 mg/day, significant reduction in 5α DHT levels in serum and follicles were observed, making finasteride useful in both FAGA and hirsutism. It should not be used in women at risk of pregnancy due to its significant teratogenic potential.90,93,95,96,102,103

Flutamide Flutamide is the first non-steroidal anti-androgen available that is devoid of any other hormonal activity. (pregnancy category D). Doses of 250–500 mg daily, alone, or in combination with CHC, appear equally or more effective compared with other anti-androgens; however, the risk of hepatotoxicity, especially at higher doses, and the costs limit its use. Side effects include hot flashes, decreased libido, and diarrhea. Flutamide monitoring includes serum transaminase levels before initiating treatment, monthly for the first 4 months of therapy, and annually thereafter. It is contraindicated in patients with elevated transaminase levels that are twice than the upper normal limit.90,94,95,97

Additional Therapies Glucocorticoids can be used to suppress the adrenal androgen production and may be used in CAH. The proposed dosage regimens are: 1. Prednisone for 6 months: 7.5 mg/day for 2 months, followed by 5 mg/day for 2 months, and 2.5 mg/day for other 2 months. 2. Dexamethasone 0.5 mg/day for 3 months followed by every third day for other 3 months. 3. Dexamethasone for 1 year: 6 months of 0.5 mg/day and 6 months of 0.5 mg every third day, this regimen has less recurrence rate. 4. Deflazacort 30 mg/day for 1 month with a maintenance dose of 6 mg/day up to 2 years. Deflazacort has less risk of side effects. These glucocorticoid regimens reduce levels of DHEA-S, 4 androstenedione and testosterone.91 Gonadotropin-releasing hormone analogues can induce a medical oophorectomy to treat the refractory hirsutism secondary to ovarian hyperandrogenism. However, because the hypoestrogenic side effects, need to combine with an OC pill

157

Hirsutism or estrogen/progestin add-back therapy. Most studies did not find a benefit to the addition of gonadotropin-releasing hormone analog therapy over CHC.98 Insulin sensitizers such as metformin or thiazolidinediones may improve several clinical parameters in PCOS patients. There is insufficient evidence to determine the effectiveness of this approach for hirsutism. Medroxyprogesterone acetate (MPA) has been recommended for using in women with contraindications to estrogencontaining therapies (i.e., CHC). Although short courses of oral MPA can induce a withdrawal bleed in women with PCOS, there is no evidence for long-term therapy. Subcutaneous MPA was studied over 26 weeks, with a decreasing in the SHBG levels (P = 0.002), but no significant decrease in total testosterone or free testosterone was found. In addition, significant weight gain was observed (P = 0.02). There is insufficient evidence to recommend this treatment for hyperandrogenism.99



Recommendations



1. The most effective therapy for hirsutism is the combination of physical hair removal techniques and medical therapies. At least 6 months of medical therapy are required to see a significant improvement in hirsutism (II-2). 2. Only laser hair removal and electrolysis produce permanent hair reduction, and hair growth tends to recur after stopping medical therapy (II-2). 3. All patients experiencing hirsutism who desire treatment should be offered combined hormonal contraceptive therapy as first-line therapy, provided they have no contraindications (I-A). 4. Mechanical hair removal and/or topical therapy can be offered as first-line therapy or as an adjuvant to medical therapy (I-A). 5. Depending on a woman’s goals of treatment, antiandrogens should be considered for moderate to severe hirsutism or to ensure an optimal response in milder hirsutism (I-A). 6. Anti-androgens can be used in conjunction with combined hormonal contraceptive therapy to enhance treatment efficacy (I-A). 7. If a woman on anti-androgen therapy wishes to conceive, anti-androgen therapy should be stopped prior to discontinuing the use of contraception to prevent the potential feminization of a male fetus if pregnancy were to occur (III-B).

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22 Hair Shaft Disorders Bengisu Orzalan, Lilian Mathias Delorenze, Michela Starace, Teresa Russo, Giuseppe Argenziano, and Vincenzo Piccolo

Introduction Hair shaft disorders are a large group of congenital and acquired alterations of the hair shaft. Genetic background and exogenous factors cause and maintain the condition. Some of the hair shaft disorders are characterized by fragility, while the others affect the texture and appearance without causing hair breakage.

Hair Shaft Disorders with Fragility Trichorrhexis Nodosa Trichorrhexis nodosa (TN) is the most common defect of the hair shaft that presents sparse, brittle hair with increased fragility. It might be an important diagnostic clue for metabolic disorders and ectodermal genodermotosis [1, 2].

Epidemiology Trichorrhexis nodosa can either be acquired or inherited. Although acquired TN is suggested to be more common in the young, black female population due to hair weathering procedures, but prevalence data are lacking [3]. Congenital TN may be present at birth, or it may occur within the first 2 months associated to an underlying disorder. It may also appear at the age of 2 years or later [4].

Etiology and Pathophysiology Acquired TN is the more common and is caused by mechanical, chemical, and thermal injury [5]. The primary mechanism is presumably loss of cuticular layer due to damage in the cuticular cells and intercellular substance of hair shaft. After that, the cortical fibers separate and spray out causing minute nodular concentrations [6]. Acquired TN has been divided into three groups based on localized, proximal, or distal location. Pruritic dermatoses of scalp and trichotillomania can also result in localized TN related to scratching and pulling of hair [7, 8]. Chemical traumas including hair dying, bleaching, salt water, and shampooing may cause acquired TN due to harm in the keratin’s cysteine disulfide bonds and fatty acid layer [5]. Trichorrhexis nodosa induced by hair transplantation has been

160

also described [9]. Besides, malnutrition [10], especially zinc, biotin, and iron deficiency or endocrinopathy such as hypothyroidism [11] can also cause acquired TN. The primary congenital TN occurs most often related to associated disorders [12]. Pollitt syndrome, a variant of trichothiodystrophy without photosensitivity, is characterized by congenital TN [13]. TN can also occur as a part of the trichohepatoenteric syndrome (THES) [14]. Although TN primarily occurs in normal hairs when there is a sufficient degree of trauma, it is also seen with other hereditary structural abnormalities such as monilethrix, trichorrhexis invaginata (bamboo hair), pili torti, and pseudomonilethrix which cause weakening of hair shaft in distinctive patterns of defects [12, 15, 16]. Argininosuccinic aciduria (ASA) is an autosomal recessive disorder characterized by the deficiency of argininosuccinase in the urea cycle. As a result of this lack, low serum arginine levels are detected [4]. Hair usually contains 10.5% arginine by weight. The deficiency in arginine causes fragile hair, and approximately half of ASA patients exhibit TN [17]. Citrullinemia is another metabolic disorder caused by the deficiency of argininosuccinic acid synthetase which leads lack of citrulline in hair medulla and internal root sheath. TN, atrophic hair bulbs and sometimes pili torti are seen as a result of the impaired formation of hair [18]. Menkes disease is characterized by pili torti as well as TN and neurological dysfunction. The defect in copper transport causes the disability of enzymes involved in keratin formation. In Netherton syndrome, congenital ichthyosiform erythroderma can be accompanied by the TN related to specific hair-shaft abnormality known as trichorrhexis invaginata [6, 15]. Other associations have also been reported in ectodermal dysplasias, cognitive deficits, and Kabuki syndrome [19].

Clinical Presentation Congenital TN becomes apparent in the first year. Normal hair starts to break at different lengths, even provoking a partial alopecia can occur in time. The hair seems sparse and brittle (Figure 22.1); an inability to grow long hair becomes evident in time. It also affects eyebrows, eyelashes, beard, moustache, axillary, and pubic hairs. Usually, other symptoms of the related disorder accompany hair dysplasia such as lethargy, growth abnormality, convulsions, mental and motor deficits, photosensitivity, and nail and skin changes [4, 15].

DOI: 10.1201/9780429465154-22

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Hair Shaft Disorders

FIGURE 22.1  Congenital trichorrhexis nodosa.

Trichorrhexis nodosa is acquired as a result of extreme or continuous physical and chemical damage to the hair shaft. It is more common in tightly curled hair types, and patients describe rough, dry, and easily breakable hair. It may affect not only the scalp but also other areas of the body such as beard, moustache, and pubic area. Alopecia observed only in the congenital form is rarely seen in acquired TN, but an inability to grow hair induces the patient to seek medical consultation [6]. Three different types of acquired TN have been identified: proximal trichorrhexis nodosa, distal trichorrhexis nodosa, and circumscribed trichorrhexis nodosa [20]. Firmly attached, whitish nodular thickening of hair and broken bluntended shortened hairs of irrational lengths may present on macroscopic examination [1].

Dermoscopy Magnification effects the dermoscopic examination findings. Low magnification may not be indicative for TN diagnose but it shows hair fibrils bending sharply with rounded borders. Multiple nodular thickenings may not so visible if they are not heavily pigmented and these whitish areas may resemble gaps along the hair shaft in trichoscopy with immersion fluid (Figure 22.2). At the level of these nodules, hair easily breaks and leaves slightly thickened, rounded hair shaft end. Sometimes with dry trichoscopy splitting fibers show whitish contours. Higher magnifications demonstrate the image of TN more clearly. The breakage areas with numerous fibers may resemble two brooms or brushes aligned in opposition at high magnification [21, 22]

FIGURE 22.2  (a–c) Multiple nodular thickenings may resemble gaps along the hair shaft in trichoscopy with immersion fluid.

[21]. Seborrheic dermatitis, trichomycosis, trichotillomania may cause TN due to mechanic trauma [8]. TN resulted in partial alopecia can be misdiagnosed as alopecia areata [20].

Diagnosis and Differential Diagnosis

Prognosis and Treatment

Light microscopy shows tiny nodules along the hair shaft where the cuticle cells are absent, and hair splits longitudinally. Eventually, the hair snaps off at these points giving a brushlike appearance at the distal end. Dermoscopy and electron microscopy are also utilized effectively for the diagnose [23]. Other structural anomalies with increased fragility of hair such as monilethrix, trichorrhexis invaginata should be taken into consideration as they may coexist or mimic each other

Hair is a non-living tissue; therefore minimalizing the further damage helps for repair but a total response is not possible. Improving hair care with proper cleansing and conditioning is likely to lessen the degree of hair fragility. Application of a water-based leave-in conditioner is advised after shampooing the hair. Oil or a thick occlusive moisturizer such as coconut oil, jojoba oil, mineral oil, olive oil, or petrolatum can also help to strengthen the hair formation [24].

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Hair Disorders

Monilethrix Monilethrix, also known as “beaded hair,” “necklace hair,” or “nodosa hair,” is a rare, non-syndromic structural disorder of the hair. It is characterized by short and fragile hair, which consists of nodes and internodes resembling a pearl necklace. The term monilethrix derives from monile (Latin) means necklace and the thrix (Greek) means hair [15, 25].

Epidemiology Monilethrix generally shows an autosomal dominant inheritance with a wide range of expressivity while some autosomal recessive cases have also been reported. There is no particular race or gender detected in the literature [18].

Etiology and Pathophysiology Monilethrix has been associated with autosomal dominant mutations in KRT81, KRT83, and KRT86 which encode for the type II hair keratins Hb1, Hb3, and Hb6 causing impaired keratin production. The defect is located on chromosome 12q11q13. Whereas desmoglein 4 gene, a novel member of cadherin family mutation has been described in an autosomal recessive trait [26].

Clinical Presentation Clinical expression changes widely. Beaded, very short, and fragile hairs often accompanied by perifollicular papules and erythema present the characteristic features of the disease. Hair fibrils break down easily leaving a stubble-like appearance, especially in the occipital region because of the friction (Figure 22.3). The onset is mainly seen on the scalp within the first month. As the lanugo hair is replaced by abnormal structural hair emerging from keratotic papules, the clinic of the patient may exhibit hypotrichosis, patchy alopecia, total alopecia, or even cicatricial alopecia. The scalp can be affected in circumscribed or widespread appearance. In severe cases, the eyelashes, eyebrows, pubic, axillary, and limb hair get involved [27]. Keratosis pilaris and koilonychia are commonly associated with monilethrix although it can be an isolated defect [28].

FIGURE 22.4  Monilethrix under high magnification videodermatoscopy.

Holt oram syndrome is characterized by limb defects and cardiovascular anomaly has been reported with monilethrix [29].

Dermoscopy Hair shaft can be examined excellently through high magnification videodermatoscope. It is characterized by the presence of elliptical nodes and periodic constrictions on the hair shaft, resulting in hair fragility at those points (Figure 22.4). The diameter of the hair varies due to nodes with a standard hair thickness and atrophic constrictions regularly disctributed with no medulla. This finding has also been described as “regularly bended ribbon sign” [21]. The narrow internodal sections without hair medulla create weak points where hair breaks down quickly. Lanugo hair may show the abnormality as well. Besides, perifollicular scaling and keratotic follicular plugs may be noticed in dry trichoscopy while the big yellow dots represent the horny hair follicles in trichoscopy with the immersion fluid [30]. Lately, monilethrix clinically shows hair thinning resembling androgenetic alopecia has been reported [31].

Diagnosis and Differential Diagnosis Light polarizing microscopic examination demonstrates beaded hair; elliptical, fusiform, or spindle-shaped nodes about 0.5–1 mm apart which are separated by cracked, narrow intermittent constructions. Scanning electron microscopy reveals typically thinner internodes with longitudinal ridging and absent cuticular scales with normal-hair-size nodal areas [12]. Pili torti, TN, and pseudomonilethrix should be considered as a differential diagnosis. Evaluating the hair in prominent areas such as the occipital region or neck can provide more evidence for monilethrix. Pseudomonilethrix can mimic monilethrix by similar beading along the shaft however the beads are flattened parts of a fiber with an oval or circular cross section in an irregular appearance. Moreover, pseudomonilethrix usually occurs as a result of trauma without a cuticular defect [1, 30].

Prognosis and Treatment

FIGURE 22.3  Monilethrix.

While it may regress during puberty and pregnancy, the complete resolution is very rare. The avoidance of trauma is the most effective method of managing this anomaly. Congenitally

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Hair Shaft Disorders abnormal hair tend to have an increased susceptibility to weathering and cosmetic damage (e.g., sunlight exposure, dyeing, bleaching, perming, and curling), which can prevent hair from growing to its maximum length [12]. No definitive therapy is recognized, but there are reports that describe the improvement during treatment with acitretin [32] and etretinate [33]. Topical minoxidil 2% also leads to an increase of hair shaft [34].

Trichorrhexis Invaginata Definition Trichorrhexis invaginata (TI) is also known as “bamboo hair” characterized with multiple knots and hair fragility. It may be isolated but more commonly occurs as a part of Netherton syndrome [15].

Epidemiology Although true incidence of the disease is not known, Netherton syndrome is inherited in an autosomal-recessive model, and the literature suggests that it affects one in 100,000–200,000 in birth; predominantly in the female gender [35].

Etiology and Pathophysiology The genetic mutation of SPINK5 gene localized on 5q31-32 leads to the defective products of serine protease inhibitor Kazal-type 5 protein (LEKTI) [36]. The mutation of LEKTI causes a boost of skin proteolytic activity and scaling with an impaired skin barrier function [37]. Hair keratinization defect, particularly incomplete sulfhydryl conversion into sulfhydryl bridges causes weakness in the cortical regions. A transient keratinization defect in the inner root sheath results in invagination of the normally keratinized distal portion into the impaired keratinized proximal portion giving a distinctive appearance of a “ball in a cup” [38].

FIGURE 22.5  Trichorrhexis invaginata.

neurological deficits, mental and growth deficiency, recurrent infections, angioedema, urticaria, allergic rhinitis, intermittent aminoaciduria, hypereosinophilia, hypergammaglobulinemia, or hypogammaglobulinemia [39, 44, 45].

Dermoscopy At first sight, trichoscopy reveals irregularly distributed multiple knots where the shaft appears as a bamboo cane (Figure 22.5). High magnification demonstrates the pathognomic model of ball-in-cup as distal part of hair shaft invaginates to the proximal part of the shaft (Figure 22.6). As a result of increased fragility, distal portion of the hair splits off and proximal part shows golf pole aspect (golf-tee-hair). The broken hair fibril with a bulging end has been described as a “matchstick” sign. The frequency of abnormal hairs especially bamboo hair and golf-tee-hairs are found to be more in eyebrows in Netherton syndrome patients [41, 43].

Diagnosis and Differential Diagnosis

Clinical Presentation

Light microscopy reveals different configurations. The typical one is bamboo hair with ball-in-a cup appearance. Golf-tee

It mainly affects scalp, but it’s also seen in eyelashes, eyebrows, as well as secondary sexual hairs. The hair becomes fragile, short, and dull. The clinic spectrum varies from sparse hair to alopecia especially in severe cases. While scalp may improve in time, the eyebrows examination reveals bamboo nodes along the shaft [39–42]. Netherton syndrome is an autosomal disease typically associated with TI, atopy, and ichthyosis. TI is the specific hair alteration to diagnose patients with ichthyosis as Netherton syndrome. Different degrees of erythroderma with a collodion membrane may be rarely present at birth. Most commonly migratory serpiginous circinate plaques of scaly erythema with a double-edged scale at the advancing borders follow the clinic change [1, 43]. Sometimes concomitant features suggestive for atopic dermatitis or severe eczema with diffuse xerosis and lichenification at flexural folds may lead a misdiagnose. Metabolic imbalances and infections may increase the fatal risk in newborns. The condition may be accompanied by

FIGURE 22.6  Trichorrhexis invaginata under high magnification.

164 hair and tulip-like degeneration (a deep invagination and the hair breaks down before reaching the normal length) and matchstick sign are other characteristic findings of TI. Electron microscopy reveals similar findings [15, 46]. A single TI hair is sufficient to diagnose the Netherton syndrome; however, it is not easy to find this characteristic hair shaft anomaly. Numerous hair fibrils of scalp and eyelashes should be examined. Besides as it becomes more prominent over the years, sometimes the abnormality cannot be detected during the first months of life [42]. Although TI is a pathognomic component of Netherton syndrome, other genodermatosis should be taken into consideration. The histological examination can help to distinguish the disease from the other congenital erythroderma conditions such as generalized seborrheic dermatitis, erythrodermic and pustular psoriasis, congenital non-bullous ichthyosiform erythroderma staphylococcal scalded skin syndrome (SSSS) [1].

Prognosis and Treatment There is no particular treatment for the Netherton syndrome. The newborn may die because of severe infections within the first 6 months [45, 47]. Topical treatments should be used with caution due to excessive systemic absorption. It is essential to restrict the treating body surface preferably with hydrophobic creams with a low dose of urea and lactate. Overdose use of an ointment containing urea, NaCl, and lactate daily has been reported to cause exfoliative erythroderma and hypernatremic dehydration. Topical tacrolimus can cause toxicity, and it is reported to have minimal effect [39]. Topical pimecrolimus has been reported to be more effective and safe [48]. Narrowband ultraviolet [43] and systemic retinoid may improve the keratinization and TI in specific cases [48].

Pili Torti Definition Pili torti are a rare, congenital, or acquired condition in which the hair fiber is flattened at irregular intervals and twisted 180 degrees on the long axis. Terminologically pili means hair and torti is twisted in Latin. The hairs become fragile, dry, lusterless, and brittle [49].

Epidemiology Pili torti may be isolated and few of these abnormal hairs can be found on the normal scalp while the pubic and axillary hairs can be normally distorted. The dysplasia can be found as early onset, late onset, pili torti associated with syndromes and acquired pili torti [50].

Etiology and Pathophysiology Pathophysiologically, defective variations of the inner sheath may lead to twisting and uneven molding. Recently, it has been suggested that these alterations may occur as a result of increased reactive oxygen species in the condition of

Hair Disorders mitochondrial dysfunction and it is described in Björnstad syndrome [10]. The hereditary form of pili torti is usually autosomal dominant but may be autosomal recessive or sporadic [18]. Classic form is typically seen in early life and may improve by age [51]. Late onset cases in puberty accompanied by mental retardation have also been reported [52]. It is necessary to evaluate the child for possible neurologic deficits and ectodermal disorders such as ectodermal dysplasia-syndactyly syndrome type 1 [53], Rapp-Hodgkin syndrome [54], and trichodysplasia-xeroderma syndrome [55]. Björnstad syndrome is genetically attributed to missense and nonsense mutations in the BCS1L gene on chromosome 2q34-36 [16] and Crandall syndrome which resembles Björnstad syndrome, accompanied by hypogonadism has been described with pili torti [56]. Both syndromes are characterized with different severity of hearing loss that found to be correlated with intensity of hair dysplasia [18]. In addition, Menkes disease [57], occipital horn syndrome (mild form of Menkes disease) [10], Bazex syndrome [50], Hypotrichosis type 6 [58], trichothiodystrophy, citrullinemia [59], Conradi-Hünermann-Happle syndrome [50], and biotin deficiency can be accompanied by pili torti. Acquired pili torti are described in cicatricial alopecia, especially in lichen planopilaris, cutaneous lupus erythematosus but lately two cases with chronic graft-vs-host disease [60] and one case of pili torti after Erlotinib treatment has been observed due to perfollicular fibrosis of the scalp [61]. Oral retinoid treatment [62], anorexia nervosa [10] are also reported to be associated.

Clinical Presentation Pili torti clinically present as sparse, blond, lusterless hair bending at a variety of angles and intervals causing irregular reflection under the light (Figure 22.7). Patchy alopecia and coarse stubbles resembling steel wool are seen. Although it typically involves the occipital and temporal region, eyebrows and eyelashes may be affected [63].

Dermoscopy Dry trichoscopy at high magnification shows clearly the twists of hair shafts along the long axis through an angle of 180 degrees while low magnification may demonstrate the hairs slightly bent at different angles and intervals (Figure 22.8) [30].

Diagnosis and Differential Diagnosis Under light microscopy pili torti hair seems twisted like a corkscrew. Monilethrix, pili trianguli et canaliculi, pili annulati should be taken into consideration when it comes to differential diagnosis. In pili torti hair shift in and out of focus as the lens traverses its length while in monilethrix the wide nodes and narrow internodes remain in the same plane of focus. Kidney-shaped hairs in cross sections and longitudinal grooves are characteristics for pili trianguli et canaliculi. Pili annulati shows light and dark banding without twisting under light microscopy. Woolly hair can also accompany pili torti  [1].

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Hair Shaft Disorders

  FIGURE 22.7  Pili torti, a) Middle-aged woman with reduced density of hair at vertex and b) Lateral view of the same patient.

Prognosis and Treatment There is no certain way to treat pili torti and often it is related to managing the underlying disorder. In Menkes disease, copper therapy may improve the condition. A 2-month-old baby with Menkes disease was reported to darken his hair after subcutaneous copper histidine administration. However other morphologic features did not change in that case [64]. Biotin supplementation of 30–100 µg/day can be a promising treatment for pili torti in deficient patients [12].

Trichothiodystrophy Trichothiodystrophy (TTD) is characterized by sulfur-deficient brittle hair as a result of different autosomal recessive neuroectodermal disorders [65].

Epidemiology Trichothiodystrophy is a rare condition. The inheritance trait can be either autosomal recessive or X-linked dominant. The incidence of photosensitive form of TTD is reported to be at 1.2 per million [66].

Etiology and Pathophysiology The clinical phenotype varies due to different mutations and the expression of the mutated allele [67]. Mainly it has been

separated as photosensitive and non-photosensitive forms. DNA repair mutations such as ERCC2 (TTD1), ERCC3 (TTD2), and GTF2H5 (TTD3) lead to photosensitive TDD [68, 69]. These genes encode proteins of transcription/repair factor IIH (TFIIH); a transcriptional factor participates in nucleotide excision repair pathway (NER). NER pathway eliminates damaged DNA caused by oxidative stress and UV light [70]. TTD, Xeroderma pigmentosum (XP), and Cockayne syndrome share variant mutations of ERCC2. Although an increased risk for skin cancer is characteristic for XP, TTD is not found to be related to skin neoplasms [71]. MPLKIP mutations have been reported to be responsible for the nonphotosensitive form of the disease [69].

Clinical Presentation Hair characteristically becomes short, brittle, and lusterless with a deficiency in sulfur or cystine content. The scalp may seem sparse, or alopecia can occur. It also affects eyebrows, eyelashes, and body hair. The disease may be mild with only hair involvement as well as mortal during the neonatal period due to sepsis and developmental defects. More than half of the patients display mental deficits, growth retardation, short stature, ichthyosis, and abnormal features at birth [72]. Brittle hair with intellectual impairment, decreased fertility, ichthyosis, and short stature describe BI(D)S and IBI(D)S variants. Photosensitivity often accompanies the symptoms, resulting in the acronym PIBIDS [73]. Cutaneous symptoms also include eczema, dry skin, and erythroderma. Nails may become short and spoon-shaped. Ocular and dental abnormalities are associated with the disease [72].

Dermoscopy

FIGURE 22.8  Pili torti under low magnification.

Tiger tail pattern cannot be detected by trichoscopy but a nonhomogeneous reflection and slightly weaving contours resembling “grains of sand” appearance, have been identified. Still, a confirmation by light microscopy is needed. Trichoschisis, a keen, clean crosscut fracture has been described mostly related to TDD [12, 21, 74].

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Hair Disorders

Diagnosis and Differential Diagnosis Trichothiodystrophy has a broad clinical spectrum including several subtypes. Hair abnormality is pathognomic for the disease. Tiger tail pattern is a combination of diagonal bright and dark bands is typically detected under polarized light. The absence of tiger tail pattern does not exclude the diagnosis. Scanning electron microscopy reveals longitudinal crests and cuticle deficits [72]. Molecular genetic evaluation is often performed to confirm the diagnosis [73]. Differential diagnosis includes Xeroderma pigmentosum, Cockayne syndrome which shares some distinctive features of TDD like photosensitivity. Collodion baby, erythrodermic ichthyosis, and progeroid syndrome also should be taken into consideration. Hair dysplasia with the tiger-tail pattern, trichoschisis, and sulfur deficiency are common findings to differentiate TDD from other diseases [75].

FIGURE 22.9  Pili annulati.

to be a single gene defect located on chromosome 12q24.33 [77]. Sporadic pili annulati forms are also reported. The pathogenesis is not fully explained. Underlying keratin defect [78], matrix formation abnormality [79] are suggested to be potential reasons. It may also be a result of a pathologic signaling and formation of basement membrane components in the hair follicle [80].

Prognosis and Treatment The deficits do not disappear by the age. There is no promising treatment described for the pathology besides the prognosis is very poor. It has been suggested the patients show photosensitivity should prevent from UV radiation exposure [75].

Clinical Presentation Patients with pili annulati often present spangled and shiny hair with striped or silvery beads (Figure 22.9). Scalp involvement is particular, but beard, axillary, and pubic hair can be affected. The phenotype is variable; it is more visible on white or blond hair with naked eye and not every hair shows abnormality. Variability along the hair shaft has also been described [81]. Typically pili annulati are not an anomaly with increased fragility, but the hair may become sensitive to weathering due to air-filled cavities inside the shaft [82]. It can be coincidentally associated with alopecia areata [83], TN [84], hypotrichosis [85], and woolly hair [86].

Hair Shaft Disorders without Fragility Pili Annulati Definition Pili annulati are a hair shaft disorder without fragility typically presenting with spangled-speckled hair due to alternating dark and light bands along the shaft [76].

Epidemiology The onset can be early in infancy or childhood or it may present during adulthood [1].

Dermoscopy Dermoscopy reveals intermittent, cloudy, subtle, short bright bands caused by air-filled cavities within the shaft (Figure 22.10). They involve between half or all of the width of a hair shaft and the bands usually disappear at the distally. TN can be noticed secondary to weathering [21, 30, 82]. Thick hair shafts with

Etiology and Pathophysiology Autosomal dominant inheritance trait with a reduced penetrance and variable expression has been described. It is likely

  FIGURE 22.10  (a, b) Pili annulati under dermoscopy.

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Hair Shaft Disorders intermittent medulla might lead to a misdiagnose as pili annulati in a normal individual [87]. Pseudopili annulati shows twisted hairs without white bands under dermoscopy [21].

Diagnosis Differential Diagnosis On standard light microscopy, these abnormal air spaces cause a dark reflection. Cross-sections of hair also reveal multiple cavities within the cortex [88]. Scanning electron microscopy and transmission electron microscopy shows periodically occuring air-filled areas in the cortex of the hair and longitudinal curtain-like folds [87, 89]. Pseudopili annulati occur as a result of periodic and sometimes partial twisting of normal hair. It may mimic pili annulati due to optical illusion. Light microscopy can easily differentiate this condition. Under dermoscopy, pseudopili annulati does not reveal the pathognomic white bands. Pili annulati differs from trichothiodystrophy; pili annulati shows parallel banding while trichothiodystrophy reveals intermittent bright and dark bands perpendicularly organized to the long axis of hair shaft [81, 90].

Prognosis and Treatment There is no specific treatment for this benign condition. General advice is to protect the hair from damage with a gentle hair care. There is one case with pili annulati and alopecia areata has been reported to have a total improve after application of topical minoxidil solution 2% twice daily for 2 months [83].

Pili Bifurcati

thin, and short and hypopigmentation can be noticed. It can affect scalp, eyelashes, and eyebrows with normal hair formation or hair with other dysplasias such as monilethrix, pili canaliculi [91]. There are some associations described with mosaic trisomy 8 [92], pseudomonilethrix type II, cognitive impairments [93], juvenile cataract [92], protein deficiency, ulcerative colitis, and extensive bowel resection [94].

Dermoscopy There is no specific information with dermoscopic examination [30].

Diagnosis and Differential Diagnosis Trichogram reveals dystrophic anagen hair with thinner hair shafts. Hypopigmentation and telogen effluvium can accompany the typical findings [95]. Light microscopy examination demonstrates typical bifurcation of the hair fiber along the length [96]. Partial bending of hair with a deep groove producing two splits circumscribed by an unsteady cuticle become visible under scanning electron microscopy. Empty spaces in both cortical and medullary sheets can be noticed on crosssection [96]. Differential diagnosis includes acquired splitting of hair shafts, pili gemini and pili multigemini. Acquired splitting of hair shaft shows bifurcation of the hair fibril, but it is important that two branches cannot produce complete cuticles. Pili gemini is a condition in which hair follicle produces two hair shafts emerging through the same pilary canal. When the papilla tip splits into several parts, more than two hair shafts emerge; this situation defines pili multigemini. They occur during anagen phase like pili bifurcati, but the branches do not fuse again [1, 91, 96].

Definition Pili bifurcati are a rare hair shaft anomaly characterized by intermittent ramification of the hair shaft. Segmental duplication produces two parallel branches which fuse together again further up to the shaft. As a characteristic feature, each branch is covered with its own cuticle [91].

Prognosis and Treatment

Epidemiology

Wolly Hair

The exact prevalence is not clear. There are single cases reported in the literature [1].

Definition

Treatment is often not necessary, but a patient with pili bifurcati (PB) and pseudomonilethrix type II showed improvement after daily application of topical 2% minoxidil 1 mL for 3 months [93].

Woolly hair (WH) represents a group of congenital hair shaft abnormalities characterized by kinky, tightly coiled hair [97].

Etiology and Pathophysiology Pili bifurcati are often inherited as autosomal dominant trait. It is caused by a non-permanent duplication of matrix-papilla tip. During the anagen phase normal single tipped papilla transforms to double tip and then back again to single tip at irregular intervals. This change produces bifurcated hair shafts which are parallel to each other with separate cuticles at different diameters [91].

Clinical Presentation It usually presents with diffuse hypotrichosis which is more prominent as alopecia in some regions. The hairs seem fragile,

Epidemiology Prevalence is unknown.

Etiology and Pathophysiology Woolly hair can be seen in syndromic or non-syndromic forms. Non-syndromic WH can be inherited in either autosomal-dominant or autosomal-recessive trait [98]. Mutations in the lysophosphatidic acid receptor 6 (LPAR6), lipase member H (LIPH), and KRT25 genes are mostly responsible for the autosomal recessive WH. The LIPH gene expresses a

168 membrane-associated phosphatidic acid-selective phospholipase A1a, which produces lysophosphatidic acid from phosphatidic acid and takes a vital role for the inner root sheet development of hair. Homozygotes of c.736T>A are common genotype [99, 100]. KRT74 [101], KRT71 keratin genes [102], and recently a missense mutation in KRT25 [103] have also been identified for autosomal dominant WH/hypotrichosis. Syndromic forms of WH are thought to be caused by variations in hair desmosomal junction. Naxos syndrome with desmoplakin mutation, Carvajal syndrome with plakoglobin mutation are accompanied by WH [104]. Woolly hair nevus seems to be the result of somatic heterozygous mutations in harvey rat sarcoma oncogene (HRAS) a crucial regulator in the mitogen-activated protein kinase (MAPK) pathway [105]. The etiology of diffuse partial WH is unknown, but an underlying keratin disorder was reported in the literature [106].

Clinical Presentation Woolly hair describes the typical texture of black people; however, it is a rare condition for non-black individuals. The clinic is characterized by short, tightly coiled/curled kinky hair on the scalp. Hair shafts are generally flattened, ovoid, and irregular with some twists (Figure 22.11). Hypotrichosis may develop. The manifestation of the disease may vary in a wide spectrum [107]. In the autosomal dominant type, diffuse involvement of the scalp with a variable degree of curling is present. The onset is usually during infancy. The autosomal recessive form starts from the birth with tightly coiled texture in white or blond color throughout the scalp. Alternatively, a localized form of the disease can be seen as WH nevus in an association with epidermal nevi and ocular involvement. The hair seems lighter and smaller in diameter in a well-demarcated region. Pili annulati and TN can be seen in all forms

Hair Disorders but it is more often with WH nevus. Woolly hair nevus syndrome is also a localized type of disease, potentially involving extracutaneous structures such as bone with capillary anomaly [86, 98]. A diffuse partial form characterized by typical WH features interspersed with normal hair involving 20–30% of hairs on the scalp. The patient may complain thinning of hair starting in childhood or adult period [106]. Syndromic WH is associated with Noonan syndrome [95], Naxos disease, Carvajal syndrome [108], and cardiofaciocutaneous syndrome [109]. Keratosis pilaris [110], ichthyosis [111], osteoma cutis [112] also have been reported with WH.

Dermoscopy Trichoscopy reveals typical fine wavy hair resembling a crawling snake with broken hair fibrils (Figure 22.12). Pili annulati, dark and light banding alteration of hair; TN may also be seen [21, 30].

Diagnosis and Differential Diagnosis Optical microscopy demonstrates ovoid or elliptical hair crosssections, 180 degrees axial twisting with a smaller diameter than healthy hair. Anagen: telogen ratio is normal. Weathering, TN, or loss of cuticles may be seen [1]. Electron microscopy shows cuticle variations with straight, oval hair shafts, and reduced in diameter [86]. Woolly hair can present with a variety of clinical severity. History and physical examination can help to make the right diagnosis, but genetic tests are necessary to confirm the condition [98]. First, it should be checked whether the disease is localized or diffuse. The localized form is usually due to WH naevus which is a benign condition accompanied by epidermal nevus in almost half patients [86]. Sometimes, ocular

  FIGURE 22.11  (a, b) Woolly hair.

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Hair Shaft Disorders

Pili Trianguli et Canaliculi Pili trianguli et canaliculi or “Uncombable hair syndrome” (UHS) is a structural anomaly of the hair shaft also named as “Cheveux incoiffables” and “Spun-glass hair” [116].

Epidemiology The exact prevalence of UHS is unknown [117].

Etiology and Pathophysiology

FIGURE 22.12  Woolly hair under dermoscopy.

anomaly can occur such as persistent pupillary membrane or localized loss of retinal pigment; therefore ophthalmological examination may be needed [113]. Woolly hair naevus syndrome can extend to the underlying muscle and bone. Neurological, cardiac or renal abnormalities may coexist with the condition  [114]. When the onset is early (infancy or childhood) with a diffuse phenotype, it may be isolated or syndromic with some other findings. The triad of WH, striate palmoplantar keratoderma and fatal cardiomyopathy should be kept in mind. Palms and soles should be checked for keratoderma. If keratoderma is detected, the patient should be evaluated for fatal cardiomyopathy [98]. Naxos disease is a rare syndrome associated with WH. Woolly hair usually presents since birth; palmoplantar keratoderma occurs in the first year. Right ventricular cardiomyopathy clinically may show ventricular tachycardia or sudden death after adolescence period. Carvajal syndrome resembles Naxos disease with generalized WH, palmoplantar keratoderma, and early manifestation of dilated cardiomyopathy [108]. Noonan syndrome and Cardiofaciocutaneous syndrome characteristically show facial dysmorphism with WH and keratosis pilaris [109]. Besides syndromic diarrhea, patients exhibit neonatal skin and inflammatory disease accompanied by facial dysmorphism and immune deficiency in addition to WH. When there is no suspected finding for syndromic type, family history and physical examination of the members are needed to exclude autosomal recessive or dominant forms. Woolly hair may present with different severity due to genetic variations in the same family. For recessive type LIPH or LPAR6 should be checked while the dominant one is usually related to mutations in KRT71 or KRT74 with a milder presentation. Confirmation can be done with genetic laboratory tests such as exome sequencing [98].

Occurrence of uncombable hair is often sporadic but autosomal dominant or recessive inheritance patterns are also reported. Genes implicated in the autosomal recessive variants include PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin), encoding for proteins which give shape and mechanical strength to the hair shaft. It has been suggested that impaired interaction between the structural elements leads to defective keratinization of the inner root sheath. Inner root sheath displays a crucial role in the final shape of the hair shaft and surface construction [118, 119]. However, the genetic background of autosomal dominant inheritance is not clear yet. In the majority of the cases, UHS is an isolated condition of the hair [120].

Clinical Presentation Uncombable hair syndrome is characterized by spun-glass appearance with dry, frizzy, lighter in color, and progressively unruly hair (Figure 22.13). Generally, the hair is projected outward and resisted to lay flat. It usually becomes evident during infancy, rarely in the adolescence period, and improves by age. It is not associated with hair fragility or loss, but hair growth decreases to a slower rate. It involves particularly the scalp sparing the rest of the body hair. Typically most of the scalp hair (over 50%) is found to be affected [118, 121, 122].

Prognosis and Treatment There is no definitive treatment, but in some patients, hair may become less curly in adulthood. Non-ablative functional lasers improved the healthy hair growth in three adult men with autosomal recessive woolly hair [115].

FIGURE 22.13  Uncombable hair.

170

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FIGURE 22.14  Uncombable hair under dermoscopy.

Dermoscopy Dermoscopy reveals triangular or reniform hair shafts with a longitudinal groove or flattening in the middle (Figure 22.14); growing toward multiple directions [123, 124].







Diagnosis nd Differential Diagnosis The light microscopic examination may not be helpful to detect the abnormality. Scanning electron microscopy has been the gold standard to confirm the diagnosis. It demonstrates the pathognomic “pili trianguli et canaliculi” appearance. A triangular, reniform, or heart shape with longitudinal grooves and flattening of the hair surfaces are observed on cross-sectioning [118, 121]. Lately, histopathologic examination of the hair cross-section, which can display the typical longitudinal depression of the hair shaft as well as the triangulated appearance, is suggested to perform for the diagnosis [125]. Pili torti, progeria, WH, monilethrix, trichothiodystrophy, loose anagen hair syndrome, and acquired progressive kinking of the hair should be taken into consideration as the differential diagnosis. Marie Unna hereditary hypotrichosis, anhidrotic ectodermal dysplasia, retinopathy pigmentosa, juvenile cataract, and polydactyly, Hutchinson Gilford progeria may accompany UHS findings [118]. Lately, neurofibromatosis type 1 [126] and phalango-epiphyseal dysplasia [127] reported with UHS.

Prognosis and Treatment















The condition improves with age. There is no promising treatment [98].

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173 107. P. Pavone, R. Falsaperla, M. Barbagallo, A. Polizzi, A. D. Praticò, and M. Ruggieri, “Clinical spectrum of woolly hair: Indications for cerebral involvement,” Ital. J. Pediatr., vol. 43, no. 1, p. 99, December 2017. 108. A. Baykan et al., “Different clinical presentations of Naxos disease and Carvajal syndrome: Case series from a single tertiary center and review of the literature,” Anatol. J. Cardiol., vol. 15, no. 5, pp. 404–8, May 2015. 109. G. Weiss, Y. Confino, A. Shemer, and H. Trau, “Cutaneous manifestations in the cardiofaciocutaneous syndrome, a variant of the classical Noonan syndrome. Report of a case and review of the literature,” J. Eur. Acad. Dermatology Venereol., vol. 18, no. 3, pp. 324–7, May 2004. 110. A. J. Chien, M. C. Valentine, and V. P. Sybert, “Hereditary woolly hair and keratosis pilaris,” J. Am. Acad. Dermatol., vol. 54, no. 2, pp. S35–S39, February 2006. 111. U. Tursen, T. I. Kaya, G. Ikizoglu, M. Aktekin, and N. Aras, “Genetic syndrome with ichthyosis: Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and woolly hair; second report,” Br. J. Dermatol., vol. 147, no. 3, pp. 604–6, September 2002. 112. M. Ruggieri, V. Pavone, P. Smilari, R. Rizzo, and G. Sorge, “Primary osteoma cutis—multiple café-au-lait spots and woolly hair anomaly,” Pediatr. Radiol., vol. 25, no. 1, pp. 34–6, 1995. 113. K. U. Jacobsen and M. Lowes, “Woolly hair naevus with ocular involvement. Report of a case.,” Dermatologica, vol. 151, no. 4, pp. 249–52, 1975. 114. S. A. al-Harmozi, S. F. Mahmoud, and G. C. Ejeckam, “Woolly hair nevus syndrome,” J. Am. Acad. Dermatol., vol. 27, no. 2 Pt 1, pp. 259–60, August 1992. 115. S. Cho, M. J. Choi, Z. Zheng, B. Goo, D.-Y. Kim, and S. Bin Cho, “Clinical effects of non-ablative and ablative fractional lasers on various hair disorders: A case series of 17 patients,” J. Cosmet. Laser Ther., vol. 15, no. 2, pp. 74–9, April 2013. 116. P. Calderon, N. Otberg, and J. Shapiro, “Uncombable hair syndrome,” J. Am. Acad. Dermatol., vol. 61, no. 3, pp. 512– 5, September 2009. 117. H. F. Anderson, C. L. Lonergan, H. S. Qureshi, and K. M. Cordoro, “Uncombable hair syndrome,” Cutis, vol. 82, no. 1, pp. 20, 31–2, July 2008. 118. C. Rieubland, P. A. de Viragh, and M.-C. Addor, “Uncombable hair syndrome: A clinical report,” Eur. J. Med. Genet., vol. 50, no. 4, pp. 309–14, July 2007. 119. F. B. Ü. Basmanav et al., “Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome,” Am. J. Hum. Genet., vol. 99, no. 6, pp. 1292–304, December 2016. 120. A. A. Hebert, J. Charrow, N. B. Esterly, D. F. Fretzin, J. M. Opitz, and J. F. Reynolds, “Uncombable hair (pili trianguli et Canaliculi): Evidence for dominant inheritance with complete penetrance based on scanning electron microscopy,” Am. J. Med. Genet., vol. 28, no. 1, pp. 185–93, September 1987. 121. J. Hicks, D. W. Metry, and J. Barrish, “Uncombable hair (cheveux incoiffables, pili trianguli et canaliculi) syndrome: Brief review and role of scanning electron microscopy in diagnosis—–PubMed—NCBI,” Ultrastruct Pathol., vol. 25, no. 2, pp. 99–103, 2001.

174 122. A. G. Laungani, J. McDonnell, W. F. Bergfeld, and J. T. McMahon, “What is your diagnosis? Uncombable hair syndrome (pili trianguli et canaliculi),” Cutis, vol. 79, no. 4, pp. 272, 291–2, April 2007. 123. A. Kiliç, D. Oğuz, A. Can, H. Akil, and O. Gürbüz Köz, “A case of uncombable hair syndrome: Light microscopy, trichoscopy and scanning electron microscopy,” Acta Dermatovenerol. Croat., vol. 21, no. 3, pp. 209–11, 2013. 124. A. A. Navarini, F. Kaufmann, A. Kaech, R. M. Trüeb, and L.  Weibel, “Picture of the month—quiz case,” Arch. Pediatr. Adolesc. Med., vol. 164, no. 12, pp. 1165–6, December 2010.

Hair Disorders 125. V. Piccolo, A. Cirocco, T. Russo, B. M. Piraccini, M. Starace, and A. Ronchi, “Hair cross-sectioning in uncombable hair syndrome: An easy tool for complex diagnosis—– PubMed—NCBI,” J Am Acad Dermatol., vol. Oct;79, no. 4, pp. e63–e64, 2018. 126. D. Schena, L. Germi, M. R. Zamperetti, F. Darra, S. Giacopuzzi, and G. Girolomoni, “Uncombable hair syndrome, mental retardation, single palmar crease and arched palate in a patient with neurofibromatosis Type I,” Pediatr. Dermatol., vol. 24, no. 5, pp. E73–E75, September 2007. 127. T. M. Fritz and R. M. Trüeb, “Uncombable hair syndrome with angel-shaped phalango—epiphyseal dysplasia,” Pediatr. Dermatol., vol. 17, no. 1, pp. 21–4.

23 Disorders of Hair Pigmentation Nina L. Tamashunas and Wilma F. Bergfeld

Hair Pigmentation

Pigmentation and the Hair Cycle

Pigmentation of the hair fiber is a result of interactions between dermal papilla fibroblasts, matrix keratinocytes, and follicular melanocytes (1). Within follicular melanocytes, melanin pigment is synthesized in cytoplasmic, lysosomallike organelles, or melanosomes, and subsequently transferred to primarily cortical keratinocytes and to medullary keratinocytes to a lesser degree. Melanogenesis for the hair shaft occurs in the hair bulb, where the density of follicular melanocytes to keratinocytes is 1:5 overall and 1:1 in the basal epithelial layer adjacent to the papilla (2). Melanotic 3,4-­ dihydroxyphenylalanine (dopa)-positive melanocytes reside in the basal layer of the infundibulum and near the upper dermal papilla (Figure 23.1). Amelanotic dopa-negative melanocytes have been identified in the outer root sheath of the middle and lower portions of the hair follicle, proximal matrix, and within the periphery of the bulb (3). Discrete, heterogeneous melanocyte populations are located in specific areas throughout the hair follicle, each with a distinguishing protein expression profile. Reservoirs of melanocytic stem cells, which are embryologically derived from neural crest cells that migrate during the first trimester, can be found within base of the hair follicle (2). These cells lack the ability to produce melanin, but are able to proliferate and regenerate to maintain pools of melanoblasts and product progeny that develop into differentiated melanocytes. Hair pigmentation is influenced by the ratio, number, and types of melanin granules found in the cortex of the hair fiber (4). Black-brown eumelanin and yellow-red pheomelanin are the two types of melanin found in mammalian hair. To produce both types of melanin, tyrosine is converted to dopa and subsequently dopaquinone via tyrosinase (Figure 23.2). Dopaquinone then undergoes a series of oxidation-reduction reactions to form either 1) eumelanin, which is under further enzymatic control with tyrosinase, TRP-1 and TRP-2, and 2) pheomelanin. The type of melanin produced correlates with the structure of the melanosome. Eumelanosomes have a fibrillar matrix and elliptical shape, in contrast to pheomelanosomes, which have a vesiculoglobular matrix and usually spherical shape (3). Melanosomes are also categorized by stage depending on whether they are immature and unmelanized (stages I and II) or mature and melanized (stages III and IV) (5).

Unlike ongoing pigmentation in the epidermis, active hair pigmentation is tightly coupled with the hair cycle and only occurs during the anagen, the hair growth stage (1). Researchers commonly use black C57BL/6 mice as a model of hair pigmentation due to their short anagen phase, exclusive production of eumelanin, and synchronous growth pattern (2). At the beginning of anagen, immature melanocytes or melanoblasts, located in the upper, outer root sheath increase in volume and proliferate (6–8). As anagen continues, melanocyte dendrites mature, the Golgi and rough endoplasmic reticulum develop, melanosomes increase in number and size, and melanosomes are transported to keratinocytes (3, 9). Tyrosinase mRNA and protein levels and enzymatic activity parallels the development of melanocytes and melanogenesis during anagen (10, 11). Similarly, levels of inhibitors of pigment production, including 6BH4 and thioredoxin, decrease during mid-anagen to promote melanogenesis (9). The functional pigmentary unit of the hair fiber becomes fully operational during anagen IV. Toward the end of anagen, melanocyte dendrites regress and melanogenesis ceases. Highly active melanocytes are no longer detectable by morphology during catagen. Cessation of melanogenesis may be due to termination of stimulating signaling or emergence of inhibitory signaling (2, 3). During the catagen phase of the hair cycle, well-differentiated melanocytes undergo apoptosis, while less-differentiated melanocytes survive (6, 12). Proliferation of keratinocytes continues, so the proximal portion of the hair shaft lacks melanin (3).

DOI: 10.1201/9780429465154-23

Migration and Differentiation of Follicular Melanocytes Melanocytes, derived from neural crest precursors, migrate to the dermis during embryogenesis. While it remains unclear exactly how certain neural crest cells are committed to become melanocytes, several regulatory factors including microphthalmia – associated transcription factor (MITF), SOX10, Pax3, KIT, fibroblast growth factor-2, and endothelin 3 have been implicated (9, 13). For example, endothelin 3 seems to influence early differentiation prior to entrance into the epidermis but does not play a role in proliferation melanocytes in

175

176

Hair Disorders

Epi-Mc

IF-Mc SG

D

APM

ORS-AMc

B-MMc DP MX B-AMc

FIGURE 23.1  Structure of the hair follicle and location of melanocytes. Epi-Mc = epidermal melanocytes, IF-Mc = infundibular melanocytes, ORS-Mc = outer root sheath melanocytes, B-MMc = bulbar melanogenic melanocytes, B-AMc = bulbar amelanotic melanocytes. (Adapted from refs. [3, 9]).

the epidermis (14). Of note, receptor tyrosine kinase KIT and its associated ligand, stem cell factor (SCF), are critical for the migration, and differentiation of melanocytes of the hair follicle. Melanocytes that express KIT migrate to SCF-rich follicular epithelium, affecting which area of the hair follicle (i.e., hair bulb, outer root sheath) the melanocyte will eventually reside (9).

Hair Color A single melanocyte is able to contain both eumelanosomes and pheomelanosomes, but each melanosome is committed to a single melanogenetic pathway (15, 16). In general, black, brown, and blonde hair contains relatively low, constant levels of pheomelanin with varying amounts of eumelanin, while red hair contains a larger amount of pheomelanin with comparable

amounts of eumelanin (17). Hair follicles that are black contain the most eumelanosomes with substantial amounts of eumelanin. Hair follicles that are brown contain smaller eumelansomes with moderate amounts of melanin. Hair follicles that are blonde contain melanosomes that are poorly melanized with small amounts of eumelanin, so the matrix is often the only part that is visible. In addition to absolute and relative amounts of eumelanin and pheomelanin, hair color is influenced by the melanosome, as its size and shape can influence the way light is scattered (18).

Red Hair Red hair phenotypes are associated with pale skin, tendency to burn rather than tan, and increased risk for development of nonmelanoma and melanoma skin cancer (19). In 1995, polymorphisms in the MC1R gene, which produces the

177

Disorders of Hair Pigmentation Tyrosinase COOH

O

NH2

HO

O2

COOH

Tyrosine

Cysteine

NH2

O

Dopaquinone (DQ)

Tyrosinase

HO

COOH

O2 HO

HO

COOH

COOH

NH2

HO

N H

HO

Dopa

HO N2H

5

1

COOH NH2

2-S-Cysteinyldopa (2SCD)

Dopa O

COOH

Dopachrome Dopachrome tautomerase (Tyrp 2)

N2H

HOOC N2H

NH2

O HOOC

S O

+

S

CD-quinones

CO2

HO

:

S

HO

5-S-Cysteinyldopa (5SCD) DQ

COOH

N+ H

N 2H

+

HO

O O

S

HOOC

HOOC

Cyclodopa

–

NH2

COOH NH2

O

HO COOH

N H

HO

HO

5,6-Dihydroxyindole (DHI)

DQ

O2

N H

5,6-Dihydroxyindole-2carboxylic acid (DHICA)

HO N (HOOC)

S

S N

+

HO

COOH NH2

1,4-Benzothiazine Intermediates

O2

(O)

Tyrp1 (DHICA oxidase) or Tyrosinase

Dopa

(HOOC)

COOH NH2

Pheomelanin

Eumelanin

FIGURE 23.2  Synthesis of eumelanin and pheomelanin. (Adapted from ref. [17].)

melanocortin 1 receptor, were first identified (20). The melanocortin 1 receptor binds α-melanocyte-stimulating hormone (α-MSH), stimulating eumelanin production by melanosome via cAMP signaling and activation of melanogenic transcription factor MITF. Polymorphisms and frame shift mutations in MC1R result in diminished functioning of the melanocortin 1 receptor and, ultimately, altered ratios of eumelanin synthesis to pheomelanin synthesis. Heterozygotes for MC1R polymorphisms synthesis lower amounts of eumelanin and higher amounts of pheomelanin compared to wild-type genotypes, while homozygotes for MC1R polymorphisms synthesis even smaller amounts eumelanin and larger amounts of pheomelanin, which are relatively similar in concentration (17). This relationship indicates a dosage effect. Additionally, polymorphisms in the ASIP gene have been implicated in red hair color in the Icelander and Dutch population (21). ASIP encodes a paracrine signaling protein that competitively inhibits α-MSH bindings to melanocortin 1 receptor. Polymorphisms in other pigmentary genes may have additive effects that alter red hair color (17).

Blonde Hair Blonde hair contains approximately 21% of the eumelanin found within black hair with a relative eumelanin content of 82% (compared to 96% in black hair) (17). Hence, blonde hair is a product of eumelanin dilution rather than significant pheomelanin contribution (17). Blonde hair may have a yellowish tint due to the smaller molecular size of eumelanin polymers, as supported by its increased solubility in alkali environments (22). Little is known about the genetic underpinning of blonde hair, though polymorphisms in genes ASIP, TPCN2, TYRP1, SLC24A4, and MC1R have been implicated in Northern and Central European populations (21, 23).

Brown and Black Hair Interactions between several functional genes likely cause dark hair pigmentation. Polymorphisms in the genes HERC2, OCA2, TYR, EXOC2, IRF4, SLC45A2, and MC1R have been associated with black or brown hair (18, 23). While epidermal keratinocytes completely degrade melanin, cortical

178 keratinocytes minimally digest melanin transferred from melanocytes, which explains why individuals with fair skin may have dark or black hair (3).

Gray Hair Melanocytes in the hair follicle are more sensitive to influences of aging compared to melanocytes located in the epidermis, which may be due to their discontinuous activity (3, 24). Follicular melanocytes have tremendous melanogenetic capacity early in life, as a relatively limited number of melanocytes are able to pigment hair of 1.5 meters or more in length (24). As we age, follicular melanocytic activity dwindles leading to depigmentation of individual hairs; this results in a mixture of white and pigmented hair. Onset of graying appears to be hereditary with an average age of onset in the late-forties (25). For White, Asian, and Black individuals, the average ages of onset are mid-thirties, late-thirties, and mid-forties, respectively (3, 24). Premature graying of the hair occurs before 20 years of age for White individuals, before 25 years of age for Asian individuals, and before 30 years of age for Black individuals (24). Additionally, approximately 50% of people have 50% gray hair by the age of 50 (3). Originally, “gray hair” was thought to be misleading, as hair seemed to be a mixture of white (depigmented) hair and darker (pigmented) hair rather than a hypo-pigmented intermediate. However, age-related reductions in melanogenesis in the hair bulb can occur as gradual loss of pigment over multiple hair cycles (pigmented hair becoming progressively white), gradual loss of pigment within a single hair cycle (change in pigmentation within a single hair fiber), or

Hair Disorders sudden loss of melanogenesis between hair cycles (pigmented hair fiber followed by white hair fiber). True gray hair with reduced, but identifiable, tyrosinase activity has been identified. The exact mechanism that causes aging of the hair follicle is poorly understood. One well-supported component is a significant reduction in melanogenesis in the bulb of anagen hair follicles. Additionally, there seems to be an inadequacy in the transfer of melanosomes to keratinocytes (24). This is evidenced by the presence of melanocytes with a moderate number of melanosomes in close proximity to keratinocytes lacking melanin granules. This could be due to defective melanosomal transfer or melanin incontinence secondary to melanocyte degeneration (24). Ultrastructural analysis reveals changes indicative of reduced melanocytic activity, including less and smaller melanosomes, fewer supporting organelles (i.e., Golgi), packaging of melanosomes within auto-phagolysosomes, and an increased vacuolization (24, 26). In time, the hair bulb lacks any melanogenic melanocytes. Senescence and cell death are the most likely mechanisms of melanocyte loss, but other factors including reactive oxygen species – induced stress, nuclear DNA alterations, and alterations in responsiveness to mitogens and growth factors may play a role in hair graying (24).

Disorders of Hair Pigmentation Disorders that cause hypopigmentation or depigmentation of the hair typically have diffuse effects from birth (i.e., oculocutaneous albinism) or cause poliosis circumscripta due to genetic diseases or acquired conditions (Figure 23.3). Poliosis

FIGURE 23.3  Congenital and acquired conditions with hair hypopigmentation. (See further ref [27].)

179

Disorders of Hair Pigmentation

sub-Saharan Africa (30, 31). Oculocutaneous albinism type 1 (OCA1) and OCA2 are the two most common forms of albinism in the United States.

Etiology – Pathogenesis Oculocutaneous albinisim is caused by mutations in genes necessary for melanogenesis, resulting in reduced pigmentation of the skin, hair, and eyes. The amount of epidermal and follicular melanocytes is maintained in OCA, but the ability to produce pigment is variably impaired depending on the genetic mutation (Table 23.2). Syndromic diseases with albinism as a component are due to dysfunction of melanosomes and melanosome-related organelles such as platelet-dense bodies and lysosomes in Hermansky-Pudlak syndrome and ChediakHigashi syndrome. It is theorized that melanin, in addition to pigmentation, influences in migration of retinal structures to the ganglion cells of the retina, which may contribute to the visual disturbances seen in some of these patients.

Clinical Presentation There is wide phenotypic variability among individuals affected by OCA. Hair, skin, and eye pigmentation and ocular manifestation severity differs between specific types of OCA and may or may not change as the individual develops (Table 23.2). FIGURE 23.4  A case of poliosis circumscripta multiplex in a 15-yearold male, representing foci of poliosis associated with halo nevi of the scalp. (By courtesy of Alexander C. Katoulis.)

Skin and Hair

circumscripta, classically known as “white forelock,” is a discrete patch of hypopigmented hair fibers that can involve any hair-ridden area of the body (Figure 23.4). Histologically, areas of poliosis demonstrate absent or reduced amount of melanin and/or number of melanocytes in the hair bulb (27). The following sections focus on oculocutaneous albinism and vitiligo, but other disorders with hair hypopigmentation are summarized in Table 23.1 (see also Figure 23.5).

Exact color of hair and skin is influenced both by OCA type and ethnicity. Individuals who have the ability to make some melanin may develop a tan, actinic keratoses, and solar lentigines in sun-exposed areas. Lack of melanin puts individuals with OCA at risk for complications related to deleterious effects of ultraviolet light; people with OCA are at an increased risk for early-onset and aggressive cutaneous cancer, most commonly squamous cell carcinoma though basal cell carcinoma and melanoma can also occur (32–34). Skin cancers are most likely to occur on the head and neck (32, 33).

Oculocutaneous Albinism (OCA)

Ocular Manifestations

Oculocutaneous albinisim (OCA) is a group of autosomal recessive genetic diseases in which melanocytes lack the ability, to varying degrees, to produce melanin due to inborn errors in metabolism. Affected individuals are typically born with a generalized reduction in pigmentation of the skin, eyes, or hair.

Ocular findings of OCA include reduced iris pigmentation with colors including blue, green, gray, and light brown; photosensitivity; nystagmus; iris transillumination; prominent red reflex; strabismus; foveal hypoplasia; and delayed maturation of or reduced visual acuity. These findings are similar across OCA type but may vary in degree of severity.

Epidemiology

Diagnosis

Oculocutaneous albinisim, which affects people of all races, affects approximately one in 20,000 people globally with geographical variability. The prevalence in the United States is one in 16,000 people with a slightly higher prevalence among Black individuals compared to White individuals (28, 29). Oculocutaneous albinism type 2 (OCA2) is the most common form of albinism globally with a high prevalence in

Oculocutaneous albinisim may be diagnosed prenatally. Fetal cells obtained via amniocentesis can be analyzed with hybridization of fetal genomic tyrosinase or polymerase chain reaction amplification of the target gene (35). This is superior to electron microscopic examination of fetal skin biopsies because it can be performed at 14 weeks gestation, rather than 20 weeks, and is less invasive (35, 36).

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Hair Disorders

TABLE 23.1 Genetic Conditions Involving Hypopigmentation of Hair Condition

Inheritance

Gene

Encoding Function

HPS-1 HPS-4

AR AR

HPS1 HPS4

Melanosome and lysosome-like vesicle formation

HPS-2

AR

AP3B1

Melanosome and lysosome-like vesicle formation

HPS-3 HPS-5 HPS-6

AR AR AR

HPS3 HPS5 HPS6

Melanosome and lysosome-like vesicle formation

HPS-7 HPS-8

AR AR

DTNBP1 BLOC1S

Melanosome and lysosome-like vesicle formation

AR

CHS1 (LYST)

Melanosome and lysosome-like vesicle formation

GS1

AR

MYO5A

Mature melanosome transfer in melanocytes

GS2

AR

RAB27A

GS3 Tietz syndrome

AR AD

MLPH MITF

Melanoblast migration

Vici syndrome

AR

EPG5

Autophagy regulator

Hermansky-Pudlak syndrome (HPS)

Chediak-Higashi syndrome

Griscelli syndrome (GS)

Clinical Manifestations • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

• • • • • • • • • • • • • • •

Waardenburg syndrome (WS)

WS1

AD

PAX3

Melanoblast migration

• • • •

Cutaneous albinism Nystagmus Decreased visual acuity Iris transillumination Fundus hypopigmentation Prolonged bleeding Granulomatous colitis Pulmonary fibrosis Cutaneous albinism Decreased visual acuity Nystagmus Prolonged bleeding Neutropenia Recurrent infections Conductive hearing loss Cutaneous albinism Decreased visual acuity Nystagmus Mild extra-ocular symptoms Cutaneous albinism Decreased visual acuity Nystagmus Bleeding tendency Silvery sheen to the hair and skin Decreased iris pigmentation Photosensitivity Strabismus Nystagmus Severe immunodeficiency Pancytopenia Bleeding Bruising Hepatosplenomegaly Neurological disorders Pigmentary dilution of skin and hair Ocular albinism Neurological manifestations (developmental motor delay, intellectual disability, hypotonia) Pigmentary dilution of skin and hair Immune defects Hemophagocytic syndrome Pigmentary dilution of skin and hair Generalized hypopigmentation Deafness Oculocutaneous hypopigmentation (uniformly light hair) Corpus callosum agenesis Profound developmental delays Failure to thrive Combined immunodeficiency Progressive microcephaly Cardiomyopathy Cataracts Other organ involvement including lungs, kidneys, thyroid, muscles, and liver Congenital white patches of skin and hair Heterochromia irides Dystopia canthorum Congenital deafness

181

Disorders of Hair Pigmentation TABLE 23.1  (Continued) Genetic Conditions Involving Hypopigmentation of Hair Condition

Piebaldism

Inheritance

Gene

Encoding Function

WS2

AD, AR

MITF, SOX10

Melanoblast migration

WS3

AD, AR

PAX3

Melanoblast migration

WS4

AD

SOX10, EDN3, EDNRB KIT, SCF, SLUG

Melanoblast migration

AD

Melanoblast migration

Clinical Manifestations • • • • • • • • •

Congenital white patches in skin and hair Heterochromia irides Congenital deafness Features of WS1 Limb anomalies Congenital white patches in hair and skin Hirschsprung disease White forelock White, depigmented areas of the skin

Source: See further ref. [71]. Abbreviations:  AR = autosomal recessive, AD = autosomal dominant.

Postnatally, clinical diagnosis can be made based on physical and ophthalmologic evaluation. Distinguishing between types of OCA may be difficult due to overlapping phenotypes (37). Genetic testing including multigene panels or genome sequencing may be helpful in making a specific diagnosis.

Histopathology Histologic examination of skin from patients with OCA1 and OCA2 demonstrate melanocytes as clear suprabasal cells with normal structure but lacking melanin on silver stains (38). Postmortem examination of a 20-week fetus with OCA1 showed stages I and II melanosomes without melanin but lack of stages III and IV melanosomes, which are normally present by week 7 (39). In OCA2, keratinocytes with melanocytes up can be identified, but stages IV melanocytes are rarely present (40).

Management The mainstay of OCA management includes strict photoprotection (i.e., using topical sunscreens, wearing protective clothing, seeking shade, avoiding peak sunlight hours, and

tanning beds) to reduce the risk of cutaneous cancer. For ocular manifestations, refractive lenses may improve visual acuity and sunglasses may help with photophobia. Patients should follow-up yearly with a physician to assess for precancerous or cancerous cutaneous lesions and ophthalmologist for eye exams (41). Needless to say, it is also important to attend to the psychosocial aspect of albinism, focusing on patient education and resources or support groups.

Vitiligo Vitiligo is a relatively common acquired chronic disorder of depigmentation due to loss of melanocytes. Well-demarcated, hypopigmented macules and patches that may be localized or generalized with or without poliosis of hair and/or eyelashes are clinical hallmarks of the disorder (Figure 23.6). A number of clinical subtypes have been described based on lesioned distribution. Vitiligo can be quite striking, especially for individuals with darker skin, having a large impact on quality of life and potentially contributing to psychosocial vulnerabilities including isolation, impaired self-esteem, and stigmatization (42–44).

Epidemiology Vitiligo, the most common depigmenting disorder, has an estimated prevalence of 0.5–1% in most populations worldwide (45). Vitiligo affects men and women equally, though girls and women are more likely to seek treatment (46). Prevalence rates do not seem to differ according to skin type or race (47). Almost 50% of patients present prior to age 20 and nearly 70–80% present before 30 years of age (46).

Etiology – Pathogenesis

FIGURE 23.5  A 5-year-old girl with skin and hair hypopigmentation, physical and psychomotor retardation, acquired microcephaly, and history of recurrent infections, in the context of Griscelli syndrome. (By courtesy of Alexander C. Katoulis.)

Though there are multiple theories about its pathogenesis, the precise etiology of vitiligo is unknown. The autoimmune theory has the most supportive evidence, but it does not fully explain the phenotypic variability of the condition. As such, the convergence theory for vitiligo purports that stress, accumulation of toxic compounds, altered cellular environments, infection, autoimmunity, and impaired melanocytic migration

182

Hair Disorders

TABLE 23.2 Oculocutaneous Albinism and Related Conditions (37, 41, 72, 73) Condition

Gene

Locus

Encoding Function

Clinical Manifestations

Comments

OCA1A

TYR

11q14-11q21

Tyrosinase, which catalyzes the first few steps of melanogenesis

• Pinkish skin • White hair at birth which can become yellow with age (keratin denaturation) • White lashes • Blue-grey irides • Prominent red reflex • Poor visual acuity • Strabismus, which can be exacerbated by bright lights • Lack of pigmented lesion development • White hair at birth that can change to blonde and even light brown through adolescence and adulthood • Blue eyes • Less severe ocular findings compared to OCA1A • Ability to acquire pigmentation (tan, freckles, nevi) with sun exposure • Hair white, golden blonde, reddish blonde, or brown at birth that can deepen with age • Creamy, white skin • Pigmented birthmarks • Ability to acquire pigmentation • Reduction of red reflex with pigment acquisition • Less severe photophobia and nystagmus Ethnic background may ultimately determine phenotypic outcome • Red hair • Reddish brown skin (xanthism) • Ocular manifestation not always detectable Similar phenotypically to OCA2

Absent tyrosine activity with no melanin production

OCA1B

OCA2

OCA2 (formerly P gene)

15q11.2-15q12

Melanosomal membrane protein

OCA3

TYRP1

9p23

Stabilizes tyrosinase and regulates eumelanin production

OCA4

SLC45A2

5p13.2

OCA5

Unknown

4q24

Membrane transport protein Unknown

OCA6

SLC24A5

15q21.1

Melanosome maturation

OCA7

C10orf11

10q22.2-10q22.3

Melanocyte differentiation

• • • • • • •

Golden hair White skin Similar ocular manifestations to OCA1 Golden to brown hair White skin Brown irides Reduced visual acuity less severe than OCA1 • Blonde to dark brown hair • Nystagmus • Iris transillumination

Reduced tyrosinase activity with varying amounts of melanin Increased prevalence in Amish communities

Includes individuals formerly known as brown OCA (brown hair; brown, hazel or blue eyes; light-brown skin with the ability to tan) who have lighter features compared to parents and siblings Common in sub-Saharan Africa Previously called red or rufous OCA Common in Africa Common in Japan Described in a single Pakistani family Described in a Chinese family

Decreased in families of the Faroe Islands

Abbreviation:  OCA = oculocutaneous albinism.

and/or proliferation all individually contribute to the pathogenesis of vitiligo to varying degrees (48). While the hair follicle is generally considered to be an immunologically privileged site, loss of melanocytes within the hair follicle results in hair depigmentation.

Autoimmune Theory Vitiligo is associated with a number of autoimmune conditions, including alopecia areata, autoimmune thyroid diseases

(i.e., Hashimoto’s thyroiditis), and Addison’s disease, and can coexist with other autoimmune conditions in approximately 20% of Caucasian patients (46, 49). Autoantibodies, including ones targeting tyrosinase, can be identified in approximately 10% of patients, though it is unclear whether these actually induce destruction of melanocytes. CD4+ T-lymphocytes, CD8+ T-lymphocytes, and regulating T-lymphocytes (TREGs) have been implicated in the pathogenesis of vitiligo: CD4+ and CD8+ cells have been seen at the dermal–epidermal junction of lesions and a reduction in TREGs in peripheral blood and

183

Disorders of Hair Pigmentation

surrounded by normal skin. Preceding triggers for the onset of vitiligo include pregnancy, sunburns and skin trauma, and/ or emotional stress. It frequently affects the face, dorsal hands, nipples, axillae, sacrum, umbilicus, and inguinal regions (56). A family history of vitiligo and/or premature hair graying is commonly identified among individuals with early-onset vitiligo prior to the age of 12 (57). Leukotrichia and poliosis are associated with vitiligo. Leukotrichia represents the whitening of hair associated with a depigmented patch, whereas poliosis refers to a collection of white hairs that may or may not be associated with a vitiligo patch. Leukotrichia is reported in 9–48.4% of patients with vitiligo (58). Early leukotrichia is considered a hallmark of the segmental variant, which typically is unilateral and progresses and stabilizes quickly (59).

Management

FIGURE 23.6  A young female with vitiligo exhibiting a unilateral, dermatomal distribution, associated with poliosis of the scalp and leukotrichia of the eyelid. (By courtesy of Alexander C. Katoulis.)

TREG dysfunction may permit greater damage to melanocytes (50). This autoimmune response is likely Th-1-mediated, with key cytokines of tumor necrosis factor-α, interferon-γ, and IL-17 (50).

Adhesion Defect Theory Gauthier et al. purposed the “melanocytorrhagy theory,” postulating detachment and elimination of melanocytes following minor mechanical injury led to depigmentation in vitiligo (51). It was further hypothesized that cutaneous injury could activate memory T cells or dendritic cells to detect autoantigens (52). Likewise, Koebner phenomenon occurs in 21–62% of vitiligo patients (53). Adhesion proteins, including tenascin and discoidin domain receptor 1, have been studied in the context of vitiligo to understand how they may reduce melanocyte adhesion (50).

Biochemical Theory It has been postulated that imbalances in redox status may contribute to melanocytic destruction, causing hypopigmented lesions (50). Patient with vitiligo have higher levels of hydrogen peroxide and lower levels of glutathione and catalase (54, 55). Additionally, alterations in the biosynthesis of tetrahydrobiopterin and catecholamine’s have been implicated in this theory (46, 50).

Clinical Presentation Classically, vitiligo presents as discrete, uniformly depigmented macules and patches without signs of inflammation

Leukotrichia is difficult to treat and is considered an unfavorable sign that confers a poorer prognosis with limited repigmentation potential due to dwindling melanocyte reservoirs (60). Leukotrichia may not improve even after repigmentation of a vitiliginous macule or patch. A study assessing the use of excimer laser therapy for vitiligo found that leukotrichia was associated with lower repigmentation rates with both segmental and non-segmental vitiligo. Patients with leukotrichia showed poorer response rates and worse average repigmentation grades compared to those without leukotrichia, suggesting the presence of leukotrichia can act as a predictor to response to treatment (61). Surgical treatment options for follicular depigmentation including follicular unit transplants; tissue grafts as punch, split thickness, or suction-blister grafts; and transplantation of epidermal suspensions. The occipital scalp is commonly used as a donor site. A case series of eight patients treated by dermabrasion and thin split-thickness skin grafting found that repigmentation occurred in all areas, with the earliest and best response (70–95%) in the eyebrows (62). Similar results were found with noncultured cellular grafting (63). It was hypothesized that migration of melanocytes from the epidermis to the hair follicle allowed for repigmentation of the hair. Arrunetegui et al. observed that melanocytes from the hair bulb are able to migrate and repigment hypopigmented lesions, acting as a melanocyte reservoir (64). Assessment of 25 patients with stable, refractory vitiligo were treated with mini-punch grafting and follicular transplantation found that 72% of mini-punch grafting and 68% of follicle transplants demonstrated repigmentation at 6 months (65). Another study comparing punch grafts and follicular hair transplants found that punch grafts were associated with a higher percentage of improvement in vitiligo and shorter time to repigmentation compared to follicular transplants, but had a 90% complication rate of cobblestoning appearance (66). Thaker et al. studied 50 patients with segmental/stabilized vitiligo treated with hair follicle transplantation found an excellent response rate of 61.9%, fair response rate of 25.4%, and poor response rate of 12.7%. Additionally, 11 out of 46 patients with leukotrichia exhibited repigmentation of previously depigmented hairs (67).

184 Follicular unit transplantation has also been explored in the context of eyelash leukotrichia. Follicular unit transplantation using hair from the temporal scalp in 15 patients yielded good to excellent responses in 13 patients (86.67%), fair response in 1 patient (6.66%), and poor response in 1 patient (6.66%) (68). A study assessing autologous noncultured epidermal suspension transplantation found that leukotrichia was improved in 88.1% of treated lesions without significant adverse effects (69). Vinay et al. also found that optimal repigmentation in autologous noncultured outer root sheath hair follicle cell suspension was impacted by the number of melanocytes and hair follicle stem cells in suspension. Additionally, number of stem cells and lack of dermal inflammation were positive predictors of optimal repigmentation (70). Follicular hair transplants have excellent cosmetic results and good color matching, but are labor-intensive. On the other hand, punch grafting can provide larger coverage and is easier to perform, but is less amendable to small areas with specific contours (i.e., eyebrows) and may have more cobblestoning, which may be minimized with smaller punches.

Concluding Remarks Significant research efforts over the past few decades have helped elucidate the physiologic process of hair pigmentation and its complex intrinsic and extrinsic regulation. Though some of their roles are currently undetermined, many genes have been implicated in these intricate processes. Rare genetic conditions with aberrations in hair pigmentation such as melanosome formation or melanoblast migration can be associated with nondermatologic findings including ocular, hematologic, and neurologic manifestations. Currently, treatment of hair hypopigmentation or depigmentation is limited to cosmetic aids such as hair dye and surgical treatments including hair transplantation. Overall, disorder of hair pigmentation can have significant impacts on quality of life and self-esteem.

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Hair Disorders eyelash leucotrichia. J Cutan Aesthet Surg. 2016;9(2): 97–100. 69. Holla AP, Sahni K, Kumar R, Kanwar A, Mehta S, Parsad D. Repigmentation of leukotrichia due to retrograde migration of melanocytes after noncultured epidermal suspension transplantation. Dermatol Surg. 2014;40(2): 169–75. 70. Vinay K, Dogra S, Parsad D, Kanwar AJ, Kumar R, Minz RW, et al. Clinical and treatment characteristics determining therapeutic outcome in patients undergoing autologous non-cultured outer root sheath hair follicle cell suspension for treatment of stable vitiligo. J Eur Acad Dermatol Venereol. 2015;29(1):31–7. 71. Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: Lessons learned from the biology of melanocytes. Exp Dermatol. 2009;18(9):741–9. 72. Lyons CJ, Lambert SR. Taylor and Hoyt’s Pediatric Ophthalmology and Strabismus. 5th ed. Atlanta: Elsevier Health Sciences; 2016. 73. Oculocutaneous Albinism: National Organization for Rare Disorders; 2015 [Available from: https://rarediseases.org/ rare-diseases/oculocutaneous-albinism/.

24 Hair in Genetic Diseases Helena E. Fryssira-Kanioura

In the past 10 years, since the completion of the Human Genome Project, we have seen major advances in the ability to read human genomic DNA and detect variation. The era of Next Generation Sequencing (NGS) is one of the recent advances in genomics. It has contributed greatly to the detection of variation underling many rare genetic disorders and has been employed as a diagnostic tool in Medicine, specifically in cases of an unknown phenotype. Even though, many cases still remain unsolved. Human hair is a key phenotypic indicator of possible underlying metabolic or genetic disorder. Genetic factors are likely to play a major role in the appearance of the clinical symptoms. Genetic hair disorders can cause hypertrichosis or severe alopecia in both adults and children and may occasionally present as part of a multisystem syndrome. Facial dysmorphism plays an important role in the clinical diagnosis of genetic conditions since it often presents as a preliminary clue before clinical examination and molecular genotyping are undertaken. The diagnosis of these genetic disorders is important not only for the initiation of probable therapy but also for the detection of other associated ectodermal anomalies and for appropriate genetic counseling of the family. Cantu syndrome (CS) (OMIM #239850) or hypertrichotic osteochondrodysplasia, first described by Cantu et al. [1]. Cantu syndrome is a rare autosomal dominant disorder characterized by generalized congenital hypertrichosis, neonatal macrosomia, distinctive coarse face, cardiomegaly, and occasionally skeletal abnormalities (Figure 24.1). The facial appearance resembles acromegaloid syndromes or storage disorders [2–4]. Dysmorphic facial features are observed in every CS patient and are usually evident at birth. In younger patients, features include a low frontal hairline, epicanthal folds, flat nasal bridge, anteverted nares, long philtrum, macroglossia, prominent mouth, and thick lips. Important is the fact that CS has been considered as a new member of potassium channelopathies [3]. This syndrome has been attributed to mutated ABCC9 or KCNJ8 genes as the underlying causes. They are both located in the 12p12.1 gene cluster and encode the SUR2 and Kir6.1 subunits of ATPdependent potassium channels (K ATP channel) [3]. Two more entities with overlapping clinical features have also been described: Acromegaloid facial appearance syndrome (AFA; OMIM 102150) and hypertrichosis with acromegaloid facial features (HAFF; OMIM 135400) [5, 6]. The atypical and clinically distinct conditions of AFA and HAFF may belong to the milder end of the ABCC9 phenotype

DOI: 10.1201/9780429465154-24

spectrum [5, 7]. In suspected AFA and HAFF syndromes, even if they cannot be clearly distinguished clinically from CS, mutation analysis of the ABCC9 gene should be carried out to confirm the diagnosis as similar mutations can give rise to dissimilar phenotypes [5, 8]. Most of the patients with CS have a history of early motor and language developmental delays as well as attention problems. Cantú syndrome retains normal and independent intellectual function by adulthood [9]. Various neurologic manifestations, particularly cerebrovascular findings including dilated and tortuous cerebral vessels, white matter changes and persistent fetal circulation are associated with Cantu. Involvement of the KATP SUR2/Kir6.1 subtype potentially plays an important role in the neurologic manifestations of this syndrome. Neurological abnormalities are also seen in Coffin-Siris syndrome (CSS) which is a rare, clinically heterogeneous disorder often considered as a cognitive/developmental delay and 5th finger/nail hypoplasia abnormality [10]. To assist in clarifying the diagnosis, it has been proposed an algorithm with minimal clinical criteria for the diagnosis of CSS. These criteria include: Some degree of developmental delay, hirsutism, coarse facial features, and hypoplastic terminal phalanges of nails of the 5thdigit of the hands or feet [11]. Hypertrichosis/hirsutism particularly over the back is seen frequently in literature cases (93%). Microcephaly, thick eyebrows and long eyelashes are also frequent findings along with thick lips, and this comprise the ‘‘classical/Type A’’ CSS subtype as previously described. Paradoxically, sparse hair to the temporal and frontal areas of the scalp is also a common finding. The degree of developmental delay found in patients with CSS ranges from moderate to severe. Additional features but not crucial for the diagnosis are endocrine and growth abnormalities, gastrointestinal, hearing loss, and vision anomalies [12]. In contrary to the Cantu and Coffin Siris syndrome hair either does not grow or is sparse in trichorhinophalangeal syndrome (TRPS) which is an autosomal dominant condition and one of the most characteristic disorders in this group. There are three distinct subtypes of TRPS: TRPS type I, TRPS type II, and TRPS type III [13]. Features common to all three subtypes include craniofacial and skeletal malformations [14]. Facial anomalies are: Sparse, slowly growing scalp hair, laterally sparse eyebrows, a bulbous tip of the nose, and relative deficiency of the alae nasi

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  FIGURE 24.1  Generalized hypertrichosis of the (a) lower and (b) upper limbs. (From ref. [4] with permission.)

(pear-shaped) and protruding ears (Figure 24.2). Examination of the fingers is valuable because of a slight deviation at the proximal interphalangeal joint. Examination of the parents may signal the diagnosis. Systemic manifestations may also be present, such as congenital heart defects and renal anomalies [15]. Linear growth is decreased in almost all TRPS patients, both prenatally and postnatally. It is postulated that nonsense mutations are usually responsible for the TRPS type I phenotype, while missense mutations cause the TRPS type III phenotype [16]. Langer–Giedion syndrome (LGS) or TRPS type II is a contiguous gene syndrome on 8q24.1, involving loss of functional copies of the TRPS1 and EXT1 genes, resulting in the additional finding of multiple cartilaginous exostoses and mild

intellectual impairment [14]. TRPS1 gene is a transcription factor that regulates proliferation and apoptosis of chondrocyte through Stat3 signaling [17]. TRPS1 gene deficiency has been postulated to impair chondrocyte differentiation in the growth plate and epithelial/mesenchymal cell-cell interactions in developing hair follicles [18]. Moreover, patients with this syndrome may have growth hormone deficiency since this transcription factor has been found to be expressed in the pituitary and hypothalamus [19]. The Multiple Hereditary Exostoses (MHE) is a genetically heterogeneous disorder which can be caused by mutations in the EXT1, EXT2 or EXT3 gene [20]. Another genetic syndrome with hair abnormalities is Noonan syndrome (NS). Noonan syndrome is an autosomal dominant, multisystem disorder characterized by dysmorphic

FIGURE 24.2  Dysmorphic features in a LGS patient. (a) bulbous tip of the nose, a long and flat philtrum, and a thin upper lip vermilion, (b) large laterally protruding ears and a depressed and broad nasal bridge, and (c) pre-axial polydactyly. (From ref. [13] with permission.)

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FIGURE 24.3  (a, b) A child with Noonan syndrome (NS) with sparse slow-growing hair since birth.

features, short stature, cardiac and brain anomalies, predisposition to certain malignancies, and developmental delay. The presence of a cardiac murmur or echocardiographic evidence of hypertrophic cardiomyopathy and sparse brittle hair growth is strongly suggestive of Noonan-like syndrome with loose anagen hair (NS/LAH) (Figure 24.3). Affected children have short stature and growth hormone deficiency. In addition, they have distinctive hyperactive behavior, cognitive defects, hoarse or hypernasal voice, and darkly pigmented skin with sometimes eczema or ichtyosis. The hair is sparse, thin, slowly growing, and easily pulled out [21, 22]. The SHOC2 mutation is responsible for the presence of NS/LAH. NS/LAH is part of the NS group which are clinically related disorders caused by mutations in genes encoding molecules in the RAS/MAPK pathway, which is vital for cell differentiation and proliferation [23]. The SHOC2 mutation encodes a scaffold protein that is localized aberrantly in the cell membrane after stimulation with epidermal growth factor (EGFR) leading to increased MAPK activation. This likely causes a disruption in the proliferation, survival, or differentiation of epithelial stem cells residing in the hair follicle during anagen phase, resulting in LAH [22]. The hairs are predominantly in anagen phase and are easily sparse, and slow growing. The diagnosis can be confirmed by microscopic examination of extracted hair [24]. The diagnosis of hair abnormalities in genetic disorders is important not only for the initiation of proper therapy but also for the detection of other associated ectodermal anomalies and for appropriate genetic counseling. Affected children and their parents are usually psychologically impacted by such conditions. Ectodermal dysplasias (HED) including a big group of disorders, frequently involve poor hair growth, alopecia or thin, wiry hair, and several of these syndromes can be transmitted from generation to generation [10]. The most common type is the X-linked hypohidrotic ectodermal dysplasia (XLHED) which is associated with poor sweating. The affected boys can present in infancy unexplained high fevers. Patients with HED exhibit a typical facies with prominent forehead, thick lips,

and a flattened nasal bridge. Scalp hair is thin, sparse, slowgrowing, and lightly pigmented, though secondary sexual hair can be normal [25]. Clinical signs are less obvious in carrier female. Sparse hair, absent teeth, and deficient eyebrows and eyelashes are good indicators of other affected family members. Approximately one-third of cases are inherited in either an autosomal recessive or autosomal dominant pattern, of which males and females are affected equally [26]. Genetic testing for mutations in the EDAR, EDARADD, and WNT10A genes can be done to confirm diagnosis. 90% of cases are caused by mutations in the EDA1, EDAR, EDARADD, or WNT10A genes [27]. These genes encode for proteins used in the tumor necrosis factor α (TNFα) signaling pathway [28]. These mutations disrupt communication between surface epithelial cells and the underlying mesenchyme during embryonic development and result in poor hair growth. It is now a reality the therapeutic approach of XLHED. This could be done through the intra-amniotic delivery of a fusion protein that substitutes the function of the abnormal EDA protein [29]. Hidrotic ectodermal dysplasia (Clouston syndrome) is a rare autosomal dominant disorder characterized by nail thickening/shortening, palmoplantar keratoderma, and short-thin sparse hair. It is caused by different missense mutations in the gap junction β6 gene (GJB6), which encodes for connexin-30 [30]. Unlike hypohidrotic ectodermal dysplasia, patients with Clouston syndrome have the ability to sweat and have normal dentition. Clouston syndrome should be suspected in patients with nail dystrophy, generalized hypotrichosis, and palmoplantar hyperkeratosis starting early in life (1stmonth of life) [31]. This diagnosis can be confirmed by genetic analysis. The best initial genetic test is targeted analysis for the four known GJB6 pathogenic variants, and if initial testing is inconclusive, sequence analysis can be done [30]. The E.E.C. syndrome (Ectrodactyly-Ectodermal DysplasiaClefting) is a rare form of ectodermal dysplasia that is inherited in an autosomal dominant manner [32]. The incidence of the E.E.C. syndrome is 1.5/100 million of population. The

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FIGURE 24.4  (a) The E.E.C. syndrome, ectrodactyly of the foot and (b) clefting and ectrodactyly of the hand.

 

  FIGURE 24.5  (a) AEC syndrome ankyloblepharon, (b) cleft palate, (c) triangular face with small narrow chin, short philtrum, thin upper lip, and (d) sparse eyebrows and hair.

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Hair in Genetic Diseases symptoms vary from mild to severe and include: Ectrodactyly or split hand/foot malformation, abnormalities of the hair (sparse and coarse) and cleft lip/palate (Figure 24.4). Also, abnormalities of the eyes and urinary tract may occur [33]. Affected individuals with the same disease may not have all the symptoms due to the fact that E.E.C. syndrome shows reduced penetrance and variable expressivity [34]. In 90% of patients with E.E.C. syndrome, the basic defect is a mutation identified in the TP63 gene and are classified as having E.E.C. syndrome type 3. In 10% of affected the mutation is located on the long arm of chromosome 7 and are classified as E.E.C. syndrome type 1 [35]. The p63 protein plays an important role in early development of the ectoderm. Prenatal diagnosis for pregnancies at risk can be offered if the mutation in the family is known. Treatment varies according to the signs and symptoms present in the affected individual by various specialists [36, 37]. Another syndrome in the ectodermal dysplasia group is the AEC syndrome characterized by ankyloblepharon (partial or complete fusion of the eyelids), ectodermal defects, and cleft lip/palate (Figure 24.5). The AEC or Rapp-Hodgkin/HayWells syndrome is distinguished from the E.E.C. syndrome by the absence of ankyloblepharon [38]. The AEC or Rapp– Hodgkin/Hay-Wells once thought to be separate disorders, the two diseases are now considered to be varying presentations of the same genetic disease as both sharing the same mutation [39]. AEC syndrome is due to a mutation in the TP63 gene, a transcription factor, coding for the p63 protein, which is involved in epidermal differentiation [40]. The disease has an autosomal dominant pattern of inheritance, though approximately 70% of mutations are de novo. Additional symptoms of the AEC syndrome include dental hypoplasia, nail dysplasia, decreased sweating, and skin erosions of the scalp of varying severity, leading often to scarring alopecia and hypotrichosis particularly in the neonate [41]. Virtually 100% of newborns with AEC syndrome have skin erosions of the scalp of varying severity, with severe erosions leading to scarring alopecia and hypotrichosis. In a review of 72 cases of Rapp–Hodgkin syndrome, 82% of cases exhibited hair described as dry, wiry, and sparse; 36% showed pili torti et canaliculi, 24% had hypopigmented hair, 21% had scalp dermatitis, and 18% had a prominent forehead or high frontal hairline [42]. Scalp hair loss frequently begins at puberty and continues through the 20s and 30s, and often leads to almost complete hair loss. Absence or thinning of eyebrows and eyelashes is common, and body hair is usually sparse. The severity of Rapp–Hodgkin syndrome varies and can manifest with different degrees of hair symptoms. The diagnosis can be suspected due to the characteristic clinical features and can be confirmed by sequence analysis of the TP63 gene [43]. The cranioectodermal dysplasia (CED) or Sensenbrenner syndrome is one of the ciliopathies, is a multisystem disorder with significant involvement of the skeleton (narrow thorax, short proximal upper and lower limbs, and brachydactyly), ectodermal anomalies (hypodontia, sparse hair, and abnormal nails), growth retardation, and characteristic facial feature (frontal bossing, low set simple ears, telecanthus/epicanthus, and full cheeks) (Figure 24.6). Dolichocephaly due to sagittal craniosynostosis distinguishes CED from other ciliopathies.

FIGURE 24.6  (a and b) A child with cranioectodermal dysplasia (CED). Short stature, acromesomelic dysplasia, sparse hair, and dolichocephaly.

Retinal dystrophy, hepatic fibrosis, and occasionally brain malformations are often observed. From the kidneys nephronophthisis leads to renal failure a major cause of morbidity and mortality in infancy or childhood. The diagnosis of CED is confirmed in 40% of patients by identification of biallelic pathogenic variants in one of the following four genes: WDR10, WDR35, WDR19 and C14orf179 [44, 45]. The development of omics (eg. genomics, proteomics, etc.) era ushered an increase of knowledges that continue to change our understanding of health and disease. Conditions previously thought to be unrelated can result from allelic mutations that lead to markedly different clinical phenotypes (e.g. TP63 associated syndromes). Prior to the molecular era, the way for classifying Ectodermal dysplasias was phenotype and mode of inheritance. More recent classification include a variety of molecular data that help in understanding the relationship of the underlying molecular defect, protein alteration, and resulting phenotype [43]. Classification systems for ectodermal dysplasias (EDs) have been proposed based on the underlying functional defect such as identification of new genes and genetic alterations or structural protein. With the therapeutic management of XLHED now a reality, through the intra-amniotic delivery of a fusion protein, the need to establish the correct diagnosis of the various cases of EDs has never been greater [29].

REFERENCES



1. Cantu JM, Garcia-Cruz D, Sanchez-Corona J, et al. A distinct osteochondrodysplasia with hypertrichosis-individualization of a probable autosomal recessive entity. Hum Genet. 1982;60:36–41. 2. Harakalova M, van Harssel JJ, Terhal PA, et al. Dominant missense mutations in ABCC9 cause Cantu syndrome. Nat Genet. 2012;44(7):793–6.

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3. van Bon BW, Gilissen C, Grange DK, et al. Cantu syndrome is caused by mutations in ABCC9. Am J Hum Genet. 2012;90(6):1094–101. 4. Fryssira H, Psoni S, Amenta S, et al. Cantu Syndrome Associated with Ovarian Agenesis. Mol Syndromol. 2017;8(4):206–10. 5. Czeschik JC, Voigt C, Goecke TO, et al. Wide clinical variability in conditions with coarse facial features and hypertrichosis caused by mutations in ABCC9. Am J Med Genet A. 2013;161A(2):295–300. 6. Dallapiccola B, Zelante L, Accadia L, et al. Acromegaloid facial appearance (AFA) syndrome: Report of a second family. J Med Genet. 1992;29(6):419–22. 7. Kini U, Clayton-Smith J, Acromegaloid facial appearance syndrome. Clin Dysmorphol. 2004;13(4):251–3. 8. Afifi HH, Abdel-Hamid MS, Eid MM, et al. De novo mutationin ABCC9 causes hypertrichosis acromegaloid facial features disorder. Pediatr Dermatol. 2016; 33(2):e109–113. 9. Leon Guerrero CR, Pathak S, Grange DK, et al. Neurologic and neuroimaging manifestations of Cantú syndrome. Neurology. 2016;87(3):270–6. 10. Ahmed A, Almohanna H, Griggs J, et al. Genetic hair disorder: A review. Dermatol Ther (Heidlb). 2019;9(3):421–48. 11. Fleck BJ, Pandya A, Vanner L, et al. Coffin–Siris syndrome: Review and presentation of new cases from a questionnaire study. Am J Med Genet. 2001; 99(1):1–7. 12. Schrier AS, Bodurtha NJ, Burton B, et al. The Coffin-Siris Syndrome: A proposed diagnostic approach and assessment of 15 overlapping cases. Am J Med Genet Part A. 2012;158A(8):1–12. 13. Selenti N, Tzetis M, Braoudaki M, et al. An interstitial deletion at 8q23.1-q24.12 associated with Langer-Giedion syndrome/­ Trichorhinophalangeal syndrome (TRPS) type II and Cornelia de Lange syndrome 4. Mol Cytogenet. 2015;8:64. 14. Maas SM, Shaw AC, Bikker H, et al. Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. Eur J Med Genet. 2015;58(5):279–92. 15. Vaccaro M, Guarneri F, Barbuzza O, et al. A familial case of Trichorhinophalangeal syndrome type I. Pediatr Dermatol. 2009;26(2):171–5. 16. Piccione M, Niceta M, Antona V, et al. Identification of two new mutations in TRPS 1gene leading to the tricho-rhinophalangeal syndrome type I and III. Am J Med Genet Part A. 2009;149A(8):1837–41. 17. Suemoto H, Muragaki Y, Nishioka K, et al. Trichorhi­ nophalangeal syndrome typeI regulates proliferation and apoptosis of chondrocytes through Stat3 signaling. Dev Biol. 2007;312(2):572–81. 18. Nishioka K, Itoh S, Suemoto H, et al. Trichorhinophalangeal syndrome type I deficiency enlarges the proliferative zone of growth plate cartilage by upregulation of Pthrp. Bone. 2008;43(1):64–71. 19. Correa FA, Franca MM, Fang Q, et al. Growth hormone deficiency with advanced bone age: Phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing. Arch Endocrinol Metabolism. 2017;61(6):633–6. 20. D’Arienzo A, Andreani L, Sacchetti F, et al. Hereditary multiple exostoses: Current insights. Orthop Res Rev. 2019; 11:199–211. 21. Gripp KW, Zand DJ, Demmer L, et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome

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with loose anagen hair: Structural brain anomalies and myelofibrosis. Am J Med Genet. 2013;161A(10):2420–30. 22. Cordeddu V, Di Schiavi E, Pennacchio LA, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022–1026. 23. Tafazoli A, Eshraghi P, Koleti ZK, et al. Noonan ­syndrome – A new survey. Arch Med Sci. 2017;13(1):215–22. 24. Dhurat RP, Deshpande DJ. Loose anagen hair syndrome. Int J Trichology. 2010; 2(2):96–100. 25. Wright JT, Grange DK, Fete M. Hypohidrotic Ectodermal Dysplasia. [Updated 2017 Jun 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle: University of Washington; 2003:1993–2018. 26. Fete TJ, Grange DK. Ectodermal dysplasias. In: Hand JL, Corona R, editors. UpToDate, Waltham, MA: Waltham Scientific Publications; 2018. 27. Cluzeau C, Hadj-Rabia S, Jambou M, et al. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat. 2011;32(1):70–72. 28. Trzeciak WH, Koczorowski R. Molecular basis of hypohidrotic ectodermal dysplasia: An update. J Appl Genet. 2016;57(1):51–61. 29. Schneider H, Faschingbauer F, Schuepbach-Mallepell S, et al. Prenatal correction of X-linked hypohidrotic ectodermal dysplasia. N Engl J Med. 2018; 378(17):1604–10. 30. Lamartine J, Munhoz Essenfelder G, Kibar Z, et al. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nat Genet. 2000;26(2):142–4. 31. Der Kaloustian VM. Hidrotic ectodermal dysplasia 2. [Updated 2015 Jan 22]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle: University of Washington; 2005:1993–2018. 32. Rüdiger RA, Haase W, Passarge E. Association of ectrodactyly, ectodermal dysplasia, and cleft lip-palate: The EEC Syndrome. Am J Dis Child. 1970;120(2):160–3. 33. Dhar RS, Bora A. Ectrodactyly ectodermal dysplasia-cleft lip and palate syndrome. J Indian Soc Pedod Prev Dent. 2014;32(4):346–9. 34. Marwaha M, Nanda KDS. Ectrodactyly, ectodermal dysplasia, cleft lip, and palate (EEC syndrome). Contemp Clin Dent. 2012;3(2):205–8. 35. Sutton VR, van Bokhoven, H. TP63-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. University of Washington, Seattle: GeneReviews. 2019. 36. Samra RK, Bhide SV, Goyal, C, et al. Tooth supported overdenture: A concept overshadowed but not yet forgotten! J Oral Res Rev. 2015;7(1):16–21. 37. Elhamouly Υ, Dowidar ΚΜ. Dental management of a child with ectrodactyly ectodermal dysplasia cleft lip/palate syndrome: A case report. Spec Care Dentist. 2019; 39(2):236–40. 38. Kannu P, Savarirayan R, Ozoemena L, et al. Rapp-Hodgkin ectodermal dysplasia syndrome: The clinical and molecular overlap with Hay–Wells syndrome. Am J Med Genet Part A. 2006;140A(8):887–891. 39. Clements SE, Techanukul T, Holden ST, et al. Rapp– Hodgkin and Hay–Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder. Br J Dermatol. 2010;163(3):624–9.

Hair in Genetic Diseases 40. Zarnegar BJ, Webster DE, Lopez-Pajares V, et al. Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63. Am J Hum Genet. 2012;91(3):435–43. 41. Sutton VR, van Bokhoven H. TP63-related disorders. [Updated 2015 Aug 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle: University of Washington; 2010:1993–2018. 42. Park S-W, Yong SL, Martinka M, et al. Rapp-Hodgkin syndrome: A review of the aspects of hair and hair color. J Am Acad Dermatol. 2005;53(4):729–35.

193 43. Wright JT, Morris C, Clements SE, et al. Classifying ectodermal dysplasias: Incorporating the molecular basis and pathways (Workshop II). Am J Med Genet A. 2009;149A(9):2062–7. 44. Handa A, Voss U, Hammarsjö A, Grigelioniene et al. Skeletal ciliopathies: A pattern recognition approach. Jpn J Radiol. 2020; doi:10.1007/s11604-020-00920-w. 45. Antony D, Nampoory N, Bacchelli C, et al. Exome sequencing for the differential diagnosis of ciliary chondrodysplasias: Example of a WDR35 mutation case and review of the literature. Eur J Med Genet. 2017;60(12): 658–66.

25 Hair in Dermatologic Disease Gabriella Fabbrocini, Maria Carmela Annunziata, Mariateresa Cantelli, and Angela Patrì

Introduction The hair and the scalp may be affected by several diseases with varying manifestations. Scalp psoriasis and seborrheic eczema represent the most frequent diseases. Sharply demarcated erythemato-squamous plaques across the natural hairline in psoriasis are opposed to blurred dark-red erythema and yellowish, greasy scales in seborrheic eczema. Whereas with the latter diffuse alopecia may frequently be found, hair loss is less commonly seen in psoriasis and may also be related to therapeutic agents. Dermatomyositis is an autoimmune disease whose symptoms can be cutaneous, muscular, or systemic. Scalp involvement and non-scarring alopecia are common. Caused by the bacteria Treponema pallidum, syphilis can be divided into different phases: primary, secondary, tertiary, and latent. Syphilitic alopecia is a less common manifestation of secondary syphilis. Pityriasis rubra pilaris is an inflammatory papulosquamous skin disorder, categorized into five types. Type II is characterized by ichthyosiform lesions in association with alopecia and eczema. Scleroderma is a rare connective tissue disease divided into systemic sclerosis and localized scleroderma or morphea. Morphea can result in secondary scarring alopecia. Clinical evaluation as well as trichoscopy, laboratory findings, and skin biopsy help clinicians to distinguish among such diseases in order to administer an early and appropriate therapy.

Seborrheic Dermatitis Definition Seborrheic dermatitis (SD) is a chronic relapsing inflammatory skin disorder with a predilection for areas rich in sebaceous glands, namely scalp, nasolabial folds, ears, eyebrows, and chest.1

Epidemiology The prevalence of SD is about 3%, and young men are affected more frequently than women.2 Scalp is one of the commonest sites involved, and if dandruff is included as having SD, its incidence has been found to be 10.16–11.6% and as high as 20–50% in some studies.3–5

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Etiology and Pathogenesis SD etiology is not completely known, but it seems that skin colonization with harmless yeast called Malassezia is implicated.2 M. restricta and M. globosa appear to be the most commonly isolated species in SD patients.2 However, the degree of colonization with the fungus in individuals with SD is not different from the normal population.6,7 Several lines of evidence demonstrate that, besides the pathogenic role of Mallassezia, the host’s immune responses to Malassezia or its byproducts appear to have a causal link to the development and maintenance of SD. Malassezia, by its lipase activity, can hydrolyze human sebum triglycerides and release some metabolites that can disrupt epidermal barrier function and activate inflammatory responses.2 Thus, it has been hypothesized that three major factors, Malassezia proliferation, increased sebum production, and individual predisposition, are involved in the development of SD.8,9

Clinical Presentation Manifestation of SD varies from mild to severe.10 Dandruff is the mildest and most common form that is restricted to the scalp, with fine white or greasy scales without significant erythema or irritation.2 Moderate SD displays erythema, scales, and crusts, while severe SD shows greasy and yellowish scales, as well as erythematous plaques with diffuse borders. The plaques’ size varies from small to large and can be solitary or multiple; also, several plaques may become confluent. The subjective complaint is mostly pruritus.1,11–13 Although hair loss is not usually associated with SD, in chronic cases, there may be temporary hair loss, with increased telogen shedding, that is reversible when the inflammation has been suppressed.14 Some authors, however, describe the socalled “seborrhoeic folliculitis” in a group of patients manifesting low-grade SD with an associated diffuse folliculitis, leading to progressive, diffuse and inexorable, if unrecognized, cicatricial alopecia.15 Moreover, follicular involvement of SD with histological evidence of diffuse, progressive cicatricial alopecia has been reported in the context of severe inflammation with HIV antiretroviral therapy.16–18

Dermoscopy Common trichoscopic findings of SD are arborizing vessels, glomerular vessels, twisted red loops, comma vessels,

DOI: 10.1201/9780429465154-25

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FIGURE 25.1  Trichoscopy of scalp seborrheic dermatitis. (a) Yellowish scales and perifollicular white scales in a mild form. (b) Abundant, yellowish, adherent scales, and structureless red areas in a severe form.

yellowish scales, perifollicular white scale, structureless red areas, honeycomb pigment, perifollicular pigmentation, yellow dots, and brown dots (Figure 25.1).19,20 Kibar et al. also demonstrated that signet ring vessel and hidden hair were specific signs for both SD and psoriasis. These two signs, however, are more commonly found in psoriasis.20

Histopathology Epidermal changes in scalp SD include follicular plugging, mounds of parakeratosis with neutrophils, dilation of infundibulum, shoulder parakeratosis, spongiosis, prominent lymphocytic exocytosis, and thinning of suprapapillary plates.16,18 At the dermal level, edema of the papillary layer, extravasated erythrocytes, tortuous blood vessels nearly touching the epidermis, and inflammatory cell infiltration can be found.16,18 However, among these, the histological features most suggestive for SD are follicular plugging, shoulder parakeratosis, and prominent lymphocytic exocytosis.16,18

Treatment For mild forms, a topical approach is recommended starting with ketoconazole or ciclopirox, or alternatively selenium sulfide/zinc pyrithione, or keratolytic shampoos.21 Non-steroidal and anti-inflammatory with antifungal properties (AIAFp) shampoo (e.g., piroctoneolamine/bisabolol/glycyrrhetic acid/ lactoferrin) may represent a viable option. In case of failure, a 4-week course with a weak-to-moderately potent corticosteroid followed by its gradual discontinuation has to be considered.21 For moderate-to-severe forms, a combination of antifungal or AIAFp shampoo with topical corticosteroids is recommended.21–24 In the case of more resistant SD, systemic antifungals may be used.25,26 For long-term maintenance, antifungal, AIAFp, or other shampoos active on SD may be used once or twice weekly.27–29

Psoriasis Definition

Diagnosis – Differential Diagnosis In most cases, SD is diagnosed without the need for special tools.1 However, scalp SD is sometimes difficult to be differentiated from other skin disorders such as Tinea capitis. In such cases, microscopic and cultural assessments are necessary to detect any fungal infection. The differential diagnosis between psoriasis and SD can be challenging when both conditions are localized to the scalp without the involvement of other skin sites.16 Trichoscopy and histopathology can help clinicians to make the correct diagnosis. Furthermore, the two conditions can occasionally coexist.16

Prognosis Prognosis for SD is good. It may recur after treatment but it does not cause any serious or life-threatening problem.

Psoriasis is a chronic, immune-mediated, inflammatory disease.30 There are five subtypes of psoriasis: vulgaris (plaque), guttate, pustular, inverse, and erythrodermic. The most common variation is plaque psoriasis, which affects approximately 85–90% of the patients.31 Scalp is a typical localization and psoriasis can be also a cause of secondary cicatricial alopecia.32,33

Epidemiology The prevalence of psoriasis is 2–3%. Disease onset may occur at any age, including childhood, with two peak age ranges, 16–22 and 57–60 years.34 Scalp psoriasis is commonly the initial presentation, and almost 80% of patients will eventually experience it.32 A secondary cicatricial alopecia can be a complication whose true incidence is not known, but appropriate control of psoriasis inflammation is important in order to avoid progression to scarring alopecia.33

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Etiology and Pathogenesis Psoriasis is mediated by crosstalk between epidermal keratinocytes, dermal vascular cells, and immunocytes such as antigen-presenting cells (APCs) and T cells. Increased proliferation of keratinocytes and endothelial cells in conjunction with APC/T cell/monocyte/macrophage inflammation leads to the epidermal and vascular hyperplasia that is characteristic of lesional psoriatic skin. Despite the identification of numerous susceptibility loci, no single genetic determinant has been identified as responsible for the induction of psoriasis.31 Psoriatic lesions on the scalp can result in alopecia, whose pathogenesis remains to be determined.35 Alopecia could be a result of telogen effluvium secondary from an inflammatory process or mechanical changes due to friction.36,37 Another possible explanation is that normal hair growth may be disturbed by thick adherent scales causing the inability of the hair shafts to grow normally.36 Recently, it has been reported that hair loss in psoriatic skin may result from abnormal sebaceous gland function.38 Furthermore, alopecia may be also related to the topical or systemic therapies used to treat psoriasis or to associated autoimmune conditions.37

Clinical Presentation Typical scalp psoriasis shows well-demarcated erythematous plaques covered by silver-colored scales affecting various percentages of the scalp.20,33,39 It was once believed that alopecia was not a presentation of scalp psoriasis, but it is now widely accepted that psoriatic alopecia exists. Hair loss is not restricted only to erythrodermic and generalized pustular psoriasis, but also seen in individuals with plaque-type psoriasis.40 Three types of psoriatic alopecia have been described: psoriatic alopecia confined to lesional skin, acute hair fall associated with telogen effluvium, and psoriatic destructive or scarring alopecia.41 Psoriatic alopecia confined to lesional skin, which is the most common type, is characterized by nonscarring alopecia, finer hairs, and an increased number of dystrophic bulbs on silvery plaques. The second type, acute hair fall associated with telogen effluvium, is usually found in individuals suffering from severe psoriasis. In these two forms, the complete hair regrowth is observed after inflammation ceases.33 Psoriatic scarring alopecia, the third type, is the least frequent form.37,41 A history of severe psoriasis, long-standing scalp involvement, immunosuppression, some genetic variants, and probably, staphylococcal infection are predisposing factors in developing follicular fibrosis.42 Interestingly, patients with psoriasis have an OR of 2.5 for developing alopecia areata.43 Susceptibility loci to alopecia areata occur on chromosomes 16 and 18 in regions previously implicated in psoriasis.44

Dermoscopy Dermoscopic evaluation of scalp psoriasis shows decreased hair density, increased vellus hairs, diffuse white scales, signet ring vessels, structureless red areas, and hidden hairs (Figure  25.2).20,42 The vascular pattern displays red dots and globules, twisted red loops, and glomerular vessels.45–47

FIGURE 25.2  Diffuse white scales and structureless red areas in a mild form of psoriasis.

Histopathology The classical histological manifestations include acanthosis, due to keratinocytes’ accelerated movement through the epidermis, hyperkeratosis, parakeratosis, elongation of epidermal rete ridges, increase in the number and size of dermal blood vessels and an increased inflammatory cell infiltrate consisting mostly of neutrophils in the stratum corneum and epidermis (Munro’s microabscesses and Kogoj pustules), significant mononuclear infiltrates in the epidermis as well as leukocyte infiltration (mostly T cells and dendritic cells [DCs]) into the dermis.31 The histopathologic features of psoriatic alopecia include follicular hyperkeratosis, increased number of telogen hairs, perifollicular lymphohistiocytic cell infiltrate around the isthmus and infundibular region.36 The sebaceous glands are decreased in size and number.42 However, the sebaceous gland atrophy can also be found in scalp psoriasis without alopecia.34,42 In psoriatic scarring alopecia, the follicular units are reduced in number and replaced by fibrotic tracts. Sebaceous glands are decreased in size and number, or even absent.32,33,35,37,42,48

Diagnosis – Differential Diagnosis Diagnosis of psoriatic alopecia can be established mainly based on characteristic clinical features. Runne et al.,36 however, found that 66% of affected individuals have never had psoriasis before, and up to 36% experienced only scalp involvement without other manifestations. Therefore, trichoscopic and histopathologic examination can be performed in order to confirm the diagnosis as well as to exclude other causes of alopecia, such as severe SD and chronic cutaneous lupus erythematosus.42

Prognosis Although rarely fatal, a high proportion of psoriatic patients report severe skin discomfort, sleep disturbance, psychological

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Hair in Dermatologic Disease distress, and reduced quality of life (QoL) due to their psoriasis.30 Even though the prognosis of psoriatic alopecia is generally favorable, it can occasionally lead to permanent hair loss.36 Thus, early recognition of the potential for permanent alopecia together with appropriate treatment are truly important in order to minimize the chance of developing irreversible scarring alopecia.

Treatment In reference to scalp psoriasis, no specific treatment for psoriatic alopecia has been reported in the literature. However, topical corticosteroid is a mainstay of treatment as it can inhibit epidermal proliferation, decrease inflammation, and modulate immune functions.49 In patients with thick adherent scales or pityriasis amiantacea, topical keratolytics such as salicylic acid should be given as the first step in order to remove thick scales.50 Calcipotriol–betamethasone dipropionate is well-tolerated and more effective than either of its individual components. Localized phototherapy is better than generalized phototherapy on hair-bearing areas. Methotrexate, cyclosporine, fumaric acid esters, and acitretin are well-recognized agents, but no published randomized controlled trials evaluating these agents specifically in scalp psoriasis exist. Biologics and new small-molecule agents show excellent effects on scalp psoriasis, but the high cost of these treatments means they may be limited to use in extensive scalp psoriasis.51

Clinical Presentation The cutaneous manifestations of DM are the most important aspects of this disease, and their correct evaluation is important for early diagnosis. The hallmark dermatologic findings are Gottron’s papules and heliotrope eruptions, but their presence and severity can vary greatly and do not always correlate with other systemic symptoms.55 Scalp DM (SDM) presents as a treatment-resistant disease, predominantly in women. SDM shows diffuse erythematous and scaly plaques in addition to scalp poikiloderma and non-scarring alopecia.

Dermoscopy Common dermoscopic findings are enlarged tortuous capillaries, peripilar casts, tufting with three or more hair shafts emerging together, and interfollicular scales (Figure 25.3). Other findings include bushy capillaries (similar to those observed in the proximal nail fold), interfollicular pigmentation, and perifollicular pigmentation.40,54

Laboratory Investigation High serum levels of muscular enzyme such as serum creatine kinase, which is released during muscle damage, and nonspecific inflammatory biomarkers such as erythrocyte sedimentation rate and C-reactive protein may be elevated during the

Dermatomyositis Definition Dermatomyositis (DM) is an autoimmune disease whose symptoms can be cutaneous, muscular, or systemic.52 Scalp involvement and non-scarring alopecia are common.46,53

Epidemiology DM has an incidence of 2–9 cases per million individuals, is 2–3 times more common among females, and can affect adults and children.54 The frequency of scalp involvement varies from 28 to 82% and is often encountered as part of a DM flare. Although symptomatic, only 30–40% of patients note clinically significant associated alopecia. In addition, scalp DM seems to have a low association with paraneoplastic DM.53

Etiology and Pathogenesis The cause of DM is unknown. However, factors such as genetic, immunologic, infectious, and environmental have all been considered as part of the cause of DM. Much of the literature demonstrates type 1 interferons and/or antibody and complement mediated damage to myofibrils and capillaries.55 Thus, the main pathogenic mechanism is considered to be microangiopathy affecting skin and muscle.55,56

FIGURE 25.3  Dermatomyositis’ trichoscopic features include enlarged tortuous capillaries, peripilar casts, tufting with three or more hair shafts emerging together and interfollicular scales.

198 acute phase of the DM disease process.57 Autoantibodies, such as the anti-Mi-2 antibodies and anti-tRNA synthetase, have been shown to be closely associated with dermatomyositis.58,59

Histopathology DM shows dilated capillaries and diffuses mucin deposition, followed by interface dermatitis. Partial or segmental thickening of the basement membrane, hyperkeratosis, atrophic epidermis, and acrosyringeal hypergranulosis with hyperkeratosis are very common findings. Scalp involvement in dermatomyositis shows a non-scarring pattern with preserved follicular architecture, intact or slightly atrophic sebaceous glands, and decreased follicular density.54

Diagnosis – Differential Diagnosis The diagnosis of DM is mainly based on the diagnostic criteria proposed by Bohan and Peter in 1975: (i) asymmetrical progressive muscle weakness in the lower and upper limbs, with or without dysphagia or dyspnea; (ii) myositis confirmed by muscle biopsy; (iii) increased serum creatine kinase levels; (iv) abnormal EMG manifesting as primary muscle injury; and (v) characteristic skin lesions.60 A nail-fold capillaroscopic (NFC) test may be used to assists with the diagnosis.58 The gold standard of the imaging study of muscle is the use of magnetic resonance imaging (MRI).58 The use of contrastinduced ultrasound may be a useful tool in detecting muscle lesion and other complications such as fibrosis or cystic hematomas.58–61 Scalp dermatomyositis can also appear similar to cutaneous findings seen in psoriasis and SD. However, the vascular patterns are very different. In psoriasis, vessels appear as red dots at low magnification and as twisted loops at high magnification. Moreover, psoriasis does not exhibit the poikilodermatous changes typically present in dermatomyositis.55 In SD, vessels have an arborizing pattern similar to that seen in the normal scalp, but are increased in number. Patients with SDM may also present tufts of 2 or 3 hairs emerging together and surrounded by peripilar casts, as seen in lichen planopilaris or another scarring alopecia.54

Prognosis Prior to the use of steroids, the prognosis of patients with DM was poor. The morbidity due to DM is widespread and has increased over the years. Only 20–40% of patients achieve remission, whereas 60–80% of patients with DM experience polycyclic or chronic continuous course of the disease. The overall mortality ratio is threefold higher in patients with DM versus the general population.58 The severity of the rash will vary from Gottron’s papules to a generalized erythroderma. Among the causes of death in this population, the most common are infection, respiratory failure, cardiovascular disease, and malignancies.55 Among all adult DM patients, 10–25% develop DM as a paraneoplastic syndrome, which may be associated with various malignancies.61

Hair Disorders

Treatment DM remains challenging to treat. The mainstay of therapy is the administration of steroids.58 In situations where prednisone cannot be used, second-line agents such as methotrexate and azathioprine will be appropriate.55,56,58 Rituximab, intravenous immunoglobulin (IVIG), and other biologics are useful in patients who developed resistance to therapy.58 Antipruritics, topical steroids, hydroxychloroquine, and steroids may be employed to treat superficial skin disease.58 No standard therapeutic agents have been used successfully to treat SDM.53

Syphilis Definition Syphilis is a sexually transmitted infection caused by the bacteria Treponema pallidum. Its course can be divided into different phases: primary (symptoms appear 10–90 days after exposure), secondary (symptoms appear 2 weeks to 6 months after exposure), tertiary (1–46 years after exposure), and latent (no symptoms). It is transmitted through direct contact with the infected mucosal lesion.62 Syphilitic alopecia (SA) is a less common manifestation of secondary syphilis.63

Epidemiology Incidence rates of syphilis have increased substantially around the world, mostly affecting men who have sex with men and people infected with HIV.62 The World Health Organization estimates that 10–12 million new infections of syphilis occur every year.64 Syphilis rates have risen 300% since 2000 in many Western countries.62 Alopecia is an uncommon clinical manifestation of secondary syphilis, ranging from 2.9 to 7%.65

Etiology – Pathogenesis Syphilis is caused by Treponema pallidum which can be spread by sexual contact, blood transfusion, and vertical transmission.64 The precise pathogenesis for SA still has to be ascertained. However, it is regarded as an aspecific immune response to the spirochete antigens in hair follicles.66

Clinical Presentation The manifestation of syphilis varies according to the clinical phase. Classically a solitary, painless, indurated ulcer at the site of inoculation can be found during primary syphilis, while a diffuse, symmetric, maculopapular, possibly pruritic rash as well as a rash on the palms or soles are common during the secondary phase.62 Without treatment, 14–40% of patients progress to tertiary disease—irreversible damage to any organ—within 1–46 years. The damage is primarily neurologic, cardiovascular, or gummatous (necrotic granulomatous lesions pathognomonic of tertiary syphilis).62 Two basic patterns of SA have been described, symptomatic and essential. The first type presents with either a

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Hair in Dermatologic Disease patchy or diffuse scalp alopecia associated with typical skin lesions of secondary syphilis. The “moth-eaten” pattern is the most common type of scalp alopecia and is considered to be a patognomonic manifestation of secondary syphilis.65–67 Essential alopecia is extremely rare and presents as a unique clinical presentation of the disease. It appears as a non-scarring hair loss, miming telogen effluvium and alopecia areata.65 It can occasionally affect hair-bearing areas other than the scalp.68,69

Dermoscopy At trichoscopy, decreased hair density, hair shaft variability, yellow dots, broken hairs, and zigzag hairs can be found.65

Laboratory Investigation The positive result of Treponema pallidum hemagglutination assay (TPHA) test and of rapid plasma reagin (RPR) allows the diagnosis.66

Histopathology Histological examination of SA shows decreased hair density, irregular hair shafts, and normal terminal/vellus ratio with moderate peri-infundibular inflammatory lymphocytic infiltrate and hypoplastic sebaceous glands.65

Diagnosis – Differential Diagnosis Clinical, trichoscopic, and histopathological evaluations may help distinguishing SA from other causes of hair loss, especially when typical skin lesions of syphilis are absent.65

Prognosis Syphilis remains a major cause of morbidity and mortality in the world despite the availability of effective treatment.64 The SA typically resolves with routine antibiotic therapy in 8–12 weeks.66,70

Treatment Primary, secondary, and early latent disease. First-line treatment: benzathine penicillin G 2.4 × 106 units, single intramuscular dose, or doxycycline 100 mg, taken orally twice daily for 14 days. Late latent disease. First-line treatment: benzathine penicillin G 2.4 × 106 units, intramuscular dose once weekly for 3 weeks, or doxycycline 100 mg, taken orally twice daily for 28 days.62,66

Scleroderma – Morphea Definition Scleroderma is a rare connective tissue disease that is manifested by cutaneous sclerosis and variable systemic involvement. Two

categories of scleroderma are known: systemic sclerosis (SSc), characterized by cutaneous sclerosis and visceral involvement, and localized scleroderma (LoS) or morphea, which is confined to the skin and/or underlying tissues.71 Morphea can result in secondary scarring alopecia.72

Epidemiology LoS is a rare disease with an incidence of around 0.3–3 cases per 100,000 inhabitants/year.73 It is more common in Caucasian women, with a ratio of 2–4 women to 1 man. Prevalence is similar in children and adults.71,73

Etiology – Pathogenesis There are references that indicate that LoS and SSc are triggered by viral or bacterial infections, such as by B. Burgdorferi.74 Other studies deny this association.75 Vascular abnormalities have also been reported.76 Although developmental origins have been hypothesized, evidence points to LoS as a systemic autoimmune disorder, as there is a strong correlation to family history of autoimmune disease, the presence of shared HLA types with rheumatoid arthritis, high frequency of autoantibodies, and elevated circulating chemokines and cytokines associated with T-helper cell, IFNγ, and other inflammatory pathways.77

Clinical Presentation Morphea is characterized by skin thickening with increased quantities of collagen in the indurative lesion.71 This entity is subdivided into linear scleroderma, plaque morphea, deep morphea, bullous morphea, and generalized morphea.71 Linear scleroderma is characterized by one or more linear streaks of cutaneous induration that may involve dermis, subcutaneous tissue, muscle and underlying bone. Approximately 67% of patients with linear scleroderma are diagnosed before age 18 years.73 It is usually a single, unilateral lesion of linear distribution and involves the extremities, face, or scalp. Lesions often follow Blaschko’s lines.71 When located on the scalp, it causes an alopecia plaque of linear distribution. The plaque is often atrophic and slightly depressed, and its skin is smooth, shiny, hard, and sometimes pigmented. It is usually unilateral, affecting the parietal region, and it tends to deform the bone. It may extend to the malar and nasal regions and to the upper lip.71 Parry-Romberg Syndrome or Progressive facial hemiatrophy (PFH) is rare disorder of unknown origin, characterized by unilateral atrophy of the skin, subcutaneous tissue, muscle, and underlying bony structures, most commonly affecting dermatomes of one or multiple branches of the trigeminal nerve. Atrophy may be preceded by cutaneous induration and discoloration of the affected skin, such as depigmentation or hyperpigmentation and cicatricial alopecia may be observed in affected areas of the scalp. In most cases, skin inflammation, induration, and adherence are absent or minimal.78 PFH may be clinically very similar to LSsc, and they may coexist in about 20–37% of patients.79 However, the PFH presents skin sclerosis at any of its stages.71 Some authors have described patients with

200 LoS converting with time into PFH.74 Many authors consider LoS and PFH to be the spectrum of the same disease.80

Dermoscopy The most specific dermoscopic feature of morphea consists of whitish fibrotic beams, which are frequently crossed by linear branching vessels; pigment network-like structures are also often evident, while ‘‘comedo-like openings’’ and whitish patches are less commonly seen.19 When scalp is affected, trichoscopy shows pili torti, black dots, and broken hairs, correlated with the presence of perifollicular fibrosis. This fibrosis may distort the hair shaft inducing the formation of pili torti that may easily break, leaving black dots or broken hairs. The progressive sclerosis causes scarring alopecia that is confirmed by the lack of follicular openings in dermoscopy.81

Laboratory Investigation Unlike SSc, whose diffuse (anti-Scl-70 or antitopoisomerase­1 antibodies) and limited (anti-centromere antibodies) forms are frequently characterized by highly specific antibodies, there are no characteristic serologic parameters in LoS. Apart from basic laboratory tests (count blood cells with differential, clinical chemistry, antinuclear antibodies), special lab tests should only be performed if SSc is suspected or to be ruled out (in this case including anti-Scl-70 or anti-­ centromere antibodies).82

Histopathology Histopathological characteristics correlate with the clinical state of morphea. Evaluation of early active morphea reveals a perivascular infiltrate composed of lymphocytes and plasmacells, possibly accompanied by eosinophils and macrophages. Evaluation of sclerotic skin demonstrates thickened and homogenized collagen bundles at the papillary and reticular dermis. The abundant collagen bundles enclose eccrine glands and few dermal blood vessels with fibrotic walls and narrow lumina may be observed as sclerosis progresses. Subcutaneous infiltration and sclerosis reflect deeper involvement.83

Diagnosis – Differential Diagnosis The diagnosis is clinical. Histopathological evaluation of skin biopsies and laboratory tests are not necessary in the majority of morphea cases.83 Given the various disease phases and clinical manifestations, there is a wide variety of possible differential diagnoses to be taken into account. In the early inflammatory phase of morphea, other diagnoses to consider include early-stage extragenital lichen sclerosus, erythema migrans, cutaneous mastocytosis, granuloma annulare, radiation dermatitis, mycosis fungoides, and also drug reactions. Long-standing morphea requires consideration of acrodermatitis chronica atrophicans as well as lipodystrophy, lichen sclerosus, and scarring.82

Hair Disorders

Prognosis Without treatment, the natural history of the LoS is to cause local atrophy and, in some cases and depending on the clinical form, deep involvement of the underlying muscle, bone, and central nervous system with eventually additional morbidity.81

Treatment The management of LoS is still unsatisfactory and there are very few randomized and controlled therapeutic studies.80 Some therapeutic options are proposed for the treatment of LoS: D-penicillamine, topical or oral vitamin D, psoralen-UVA photochemotherapy, phenytoin, corticosteroids, methotrexate, cyclosporine, and interferon.84 Several options are available for the topical treatment, which should be limited to more superficial and limited forms of morphea, such as plaque morphea. In the initial, more inflammatory phase, the use of high-potency topical corticosteroids is recommended. However, no study has demonstrated the real efficacy of this treatment.71

Pityriasis Rubra Pilaris Definition Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous skin disorder, categorized into five types: (I) classic adult type; (II) atypical adult type; (III) classic juvenile type; (IV) circumscribed juvenile type; and (V) atypical juvenile type.85 More recently, HIV-associated PRP was categorized as a separate type (VI).86 Scalp often results involved in the disease and, especially in the type II of PRP, alopecia can occur.87

Epidemiology PRP is considered a rare disease, with an estimated incidence of 1 in 400,000, yet the precise prevalence is unknown.88 Two peaks of onset have been identified: one during the first decade of life and a second one in the sixth and seventh decade of life,88 with no gender predilection.87

Etiology – Pathogenesis The pathogenesis is still unclear: it has been hypothesized that PRP is induced by an abnormal immune response toward different antigenic stimuli such as infections, trauma, and malignancy.87 Most of the cases are sporadic, but familial forms of the disease have been described, in particular, linked to mutations in the gene CARD.87

Clinical Presentation PRP is characterized by a small follicular papule with a central keratotic plug, coalescing scaly yellow pink patches, and by palmoplantar keratoderma. Lesions are symmetrical and diffuse and appear first on the extensor surfaces of the extremities, shoulders, and buttocks, usually spreading caudally with

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Hair in Dermatologic Disease possible development of erythroderma.85,87,88 The scalp can be involved with the onset of hyperkeratosis and itch. The atypical adult type II, developed by 5% of the patients, has a chronic course up to 20 years. It is characterized by ichthyosiform lesions, especially on the legs, in association with alopecia and areas of eczema.87

Dermoscopy Dermoscopy of classical PRP papules may show round/oval yellowish areas surrounded by vessels of mixed morphology, namely linear and dotted. Additionally, central keratin plugs may also be observed.19 Dermoscopy of erythrodermic PRP typically displays peculiar orange blotches and islands of nonerythematous (spared) skin displaying reticular vessels; additional features include diffuse whitish scaling and scattered dotted vessels over a reddish background.19

Histopathology Histopathology reveals psoriasiform dermatitis with irregular hyperkeratosis and alternating vertical and horizontal ortho- and parakeratosis, referred to as the “checkerboard pattern.” Acantholysis and focal acantholytic dyskeratosis within the epidermis have been described, features which have been suggested to be helpful in distinguishing PRP from psoriasis.88

Diagnosis – Differential Diagnosis The diagnosis is primarily clinical. However, especially when PRP is in the erythroderma state, it is rather difficult to establish a clear-cut clinical diagnosis, and it can be misdiagnosed as psoriasis, follicular eczema, follicular ichthyosis, generalized hypersensitivity reaction, T-cell lymphoma, and lichen planopilaris. Differential diagnosis with psoriatic erythroderma can be made if typical roundish areas of normal skin, the island of sparing, can be identified.87

Prognosis Even if PRP is considered a self-limiting condition, with symptoms subsiding within a 2–3 year timeframe, it can have a severe impact on patients’ quality of life, especially in the chronic and refractory forms.85,88

Treatment PRP remains an extremely challenging disease to treat. Topical treatments include corticosteroids, calcipotriol, tazarotene, emollients. Systemic treatments include as first-line treatment isotretinoin, acitretin, while second-line treatments are methotrexate, acitretin + narrowband-UVB, acitretin + UVA, acitretin + PUVA, cyclosporine. For refractory forms, anti-TNF-α, IL-23, and IL-17 inhibitors and apremilast can be considered.87,88

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1. Widaty S, Pusponegoro EH, Rahmayunita G, et al. Applicability of trichoscopy in scalp seborrheic dermatitis. Int J Trichology. 2019;11(2):43–8. 2. Sobhan M, Gholampoor G, Firozian F. Comparison of efficacy and safety of atorvastatin 5% lotion and betamethasone 0.1% lotion in the treatment of scalp seborrheic dermatitis. Clin Cosmet Investig Dermatol. 2019;12:267–75. 3. Suchonwanit P, Triyangkulsri K, Ploydaeng M, et al. Assessing biophysical and physiological profiles of scalp seborrheic dermatitis in the Thai population. Biomed Res Int. 2019;2019:5128376. 4. De AvelarBreunig J, de Almeida Jr HL, Duquia R, et al. Scalp seborrheic dermatitis: prevalence and associated factors in male adolescents. Intl J Dermatol. 2012;51(1):46–9. 5. Misery L, Rahhali N, Duhamel A, et al. Epidemiology of dandruff, scalp pruritus and associated symptoms. Acta Derm Venereol. 2013;93(1):80–1. 6. Pechère M, Krischer J, Remondat C, et al. Malassezia spp carriage in patients with seborrheic dermatitis. J Dermatol. 1999;26(9):558–61. 7. Falk MHS, Linder MT, 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. 8. Meray Y, Gençalp D, Güran M. Putting it all together to understand the role of Malassezia spp. in dandruff etiology. Mycopathologia. 2018;183(6):893–903. 9. Saxena R, Mittal P, Clavaud C, et al. Comparison of healthy and dandruff scalp microbiome reveals the role of commensals in scalp health. Front Cell Infect Microbiol. 2018;8:346. 10. Burns T, Breathnach S, Cox N, et al. Rook’s Textbook of Dermatology, 8th edn. Oxford: Blackwell, 2010;29–30. 11. Borda LJ, Wikramanayake TC. Seborrheic dermatitis and dandruff: a comprehensive review. J Clin Investig Dermatol. 2015;3:1–22. 12. Cheong WK, Yeung CK, Torsekar RG, et al. Treatment of seborrhoeic dermatitis in Asia: a consensus guide. Skin Appendage Disord. 2016;1:187–96. 13. Berk T, Scheinfeld N. Seborrheic dermatitis. P T. 2010; 35:348–52. 14. Piérard-Franchimont C, Xhauflaire-Uhoda E, Piérard GE. Revisiting dandruff. Int J Cosmet. Sci. 2006;28:311–18. 15. Pitney L, Weedon D, Pitney M. Is seborrhoeic dermatitis associated with a diffuse, low-grade folliculitis and progressive cicatricial alopecia? Australas J Dermatol. 2016; 57(3):e105–7. 16. Park JH, Park YJ, Kim SK. Histopathological differential diagnosis of psoriasis and seborrheic dermatitis of the Scalp. Ann Dermatol. 2016;28(4):427–32. 17. Braun-Falco O, Heilgemeir GP, Lincke-Plewig H. Histological differential diagnosis of psoriasis vulgaris and seborrheic eczema of the scalp. Hautarzt. 1979;30:478–83. 18. Lever WF, Elder DE. Lever’s histopathology of the skin. 10th ed. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins, 2009:181. 19. Errichetti E, Stinco G. Dermoscopy in general d­ ermatology: a practical overview. Dermatol Ther. 2016;6:471–507. 20. Kibar M, Aktan Ş, Bilgin M. Dermoscopic findings in scalp psoriasis and seborrheic dermatitis; two new signs;

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signet ring vessel and hidden hair. Indian J Dermatol. 2015;60(1):41–5. 21. Kastarinen H, Oksanen T, Okokon EO, et al. Topical antiinflammatory agents for seborrhoeic dermatitis of the face or scalp. Cochrane Database Syst Rev. 2014;5:CD009446. 22. Ramirez RG, Dorton D. Double-blind placebo-controlled multicentre study of fluocinolone acetonide shampoo (FS shampoo) in scalp seborrhoeic dermatitis. J Dermatol Treat. 1993;4:135–7. 23. Reygagne P, Poncet M, Sidou F, et al. Clobetasol propionate shampoo 0.05% in the treatment of seborrheic dermatitis of the scalp: results of a pilot study. Cutis. 2007;79:397–403. 24. Ortonne JP, Nikkels AF, Reich K, et al. Efficacious and safe management of moderate to severe scalp seborrhoeic dermatitis using clobetasol propionate shampoo 0.05% combined with ketoconazole shampoo 2%: a randomized, controlled study. Br J Dermatol. 2011;165:171–6. 25. Hald M, Arendrup MC, Svejgaard EL, et al. Evidencebased Danish guidelines for the treatment of Malasseziarelated skin diseases. Acta Derm Venereol. 2015;95:12–9. 26. Gupta AK, Richardson M, Paquet M. Systematic review of oral treatments for seborrheic dermatitis. J Eur Acad Dermatol Venereol. 2014;28:16–26. 27. Kastarinen H, Okokon EO, Verbeek JH. Topical antiinflammatory agents for seborrheic dermatitis of the face or scalp: summary of a Cochrane review. JAMA Dermatol. 2015;151(2):221–2. 28. Shuster S, Meynadier J, Kerl H. Treatment and prophylaxis of seborrheic dermatitis of the scalp with antipityrosporal 1% ciclopirox shampoo. Arch Dermatol. 2005;141(1): 47–52. 29. Yap FB. The role of combination calcipotriol plus betamethasone dipropionate gel in the treatment of moderateto-severe scalp seborrhoeic dermatitis. Sultan Qaboos Univ Med J. 2018;18(4):e520–e523. 30. Patruno C, Napolitano M, Balato N, et al. Psoriasis and skin pain: instrumental and biological evaluations. Acta Derm Venereol. 2015;95(4):432–8. 31. Ayala-Fontánez N, Soler DC, McCormick TS. Current knowledge on psoriasis and autoimmune diseases. Psoriasis. 2016;6:7–32. 32. Wright AL, Messenger AG. Scarring alopecia in psoriasis. Acta Derm Venereol. 1990;70:156–9. 33. Almeida MC, Romiti R, Doche I, et al. Psoriatic scarring alopecia. An Bras Dermatol. 2013;88:29–31. 34. Napolitano M, Balato N, Ayala F, et al. Psoriasis in elderly and non-elderly population: clinical and molecular features. G Ital Dermatol Venereol. 2016;151(6):587–95. 35. Bardazzi F, Fanti PA, Orlandi C, et al. Psoriatic scarring alopecia: observations in four patients. Int J Dermatol. 1999;38:765–8. 36. Runne U, Kroneisen-Wiersma P. Psoriatic alopecia: acute and chronic hair loss in 47 patients with scalp psoriasis. Dermatology. 1992;185:82–7. 37. George SM, Taylor MR, Farrant PB. Psoriatic alopecia. Clin Exp Dermatol. 2015;40:717–21. 38. Rittie L, Tejasvi T, Harms PW, et al. Sebaceous gland atrophy in psoriasis: an explanation for psoriatic alopecia? J Invest Dermatol. 2016;136:1792–1800. 39. De Arruda LH, De Moraes AP. The impact of psoriasis on quality of life. Br J Dermatol. 2001;144:33–6.

Hair Disorders 40. Van De Kerkhof PC, Chang A. Scarring alopecia and psoriasis. Br J Dermatol. 1992;126:524–525. 41. Shuster S. Psoriatic alopecia. Br J Dermatol. 1972;87:73–7. 42. Iamsumang W, Sriphojanart T, Suchonwanit P. Psoriatic alopecia in a patient with systemic lupus erythematosus. Case Rep Dermatol. 2017;9(1):51–9. 43. Wu JJ, Nguyen TU, Poon KY, et al. The association of psoriasis with autoimmune diseases. J Am Acad Dermatol. 2012;67:924–30. 44. Martinez-Mir A, Zlotogorski A, Gordon D, et al. Genome­ wide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am J Hum Genet. 2007;80:316–28. 45. Kim GW, Jung HJ, Ko HC, et al. Dermoscopy can be useful in differentiating scalp psoriasis from seborrhoeic dermatitis. Br J Dermatol. 2011;164:652–6. 46. Miteva M, Tosti A. Hair and scalp dermatoscopy. J Am Acad Dermatol. 2012;67(5):1040–8. 47. Ross EK, Vincenzi C, Tosti A. Videodermatoscopy in the evaluation of hair and scalp disorders. J Am Acad Dermatol 2006;55:799–806. 48. Silva CY, Brown KL, Kurban AK, et al. Psoriatic alopecia fact or fiction? A clinic histopathologic reappraisal. Indian J Dermatol Venereol Leprol. 2012;78:611–9. 49. Papp K, Berth-Jones J, Kragballe K, et al. Scalp psoriasis: a review of current topical treatment options. J Eur Acad Dermatol Venereol. 2007;21:1151–60. 50. Van Der Vleuten CJ, Van De Kerkhof PC. Management of scalp psoriasis: guidelines for corticosteroid use in combination treatment. Drugs. 2001;61:1593–8. 51. Wang TS, Tsai TF. Managing scalp psoriasis: An evidencebased review. Am J Clin Dermatol. 2017;18(1):17–43. 52. Muro Y, Sugiura K, Akiyama M. Cutaneous manifestations in dermatomyositis: key clinical and serological features-a comprehensive review. Clin Rev Allergy Immunol. 2016;51(3):293–302. 53. Tilstra JS, Prevost N, Khera P, et al. Scalp dermatomyositis revisited. Arch Dermatol. 2009;145(9):1062–3. 54. Jasso-Olivares JC, Tosti A, Miteva M. Clinical and dermoscopic features of the scalp in 31 patients with dermatomyositis. Skin Appendage Disord. 2017;3(3):119–24. 55. Chen KL, Zeidi M, Werth VP. Recent Advances in pharmacological treatments of adult dermatomyositis. Curr Rheumatol Rep. 2019;21(10):53. 56. Wang S, Keaton R, Kendrick Z. Severe cutaneous findings in a woman with dermatomyositis. Clin Pract Cases Emerg Med. 2019;3(3):222–5. 57. Iaccarino L, Ghirardello A, Bettio S, et al. The clinical features, diagnosis and classification of dermatomyositis. J Autoimmun. 2014;48–49:122–7. 58. Okogbaa J, Batiste L. Dermatomyositis: an acute flare and current treatments. Clin Med Insights Case Rep. 2019;12:1179547619855370. 59. Gupta A, Arora P, Gautam RK. Coexistence of dermatomyositis and alopecia areata: insight into pathogenesis. Indian Dermatol Online J. 2018;9(3):199–201. 60. Zhang X, Wang Y, Ma G, et al. Dermatomyositis as a symptom of primary lung cancer: a case report and review of the literature. Oncol Lett. 2016;11:3413–6. 61. Zhang T, Wu Q, Qin S, et al. Lung cancer with dermatomyositis as the initial diagnosis: a case report. Mol Clin Oncol. 2019;11(1):59–62.

Hair in Dermatologic Disease 62. O’Byrne P, MacPherson P. Syphilis. BMJ. 2019;365:l4159. 63. Chiu HH, Wu CS. Alopecia syphilitica. Indian J Sex Transm Dis AIDS. 2017;38(2):192–3. 64. Yideg Yitbarek G, Ayele BA. Prevalence of syphilis among pregnant women attending antenatal care clinic, Sede Muja district, south Gondar, northwest Ethiopia. J Pregnancy. 2019;2019:1584527. 65. Doche I, Hordinsky MK, Valente NYS, et al. Syphilitic alopecia: case reports and trichoscopic findings. Skin Appendage Disord. 2017;3(4):222–4. 66. Dai S, Wang H, Lin Z. Moth-eaten alopecia in secondary syphilis. Int J Infect Dis. 2019;82:6. 67. Costa MC, Peres AS, Queiróz AJR, et al. Nonspecific diffuse alopecia as a single manifestation of syphilis infection: clinical and trichoscopic features. Int J Dermatol. 2018;57(5):593–5. 68. Vafaie J, Weinberg JM, Smith B, et al. Alopecia in association with sexually transmitted disease: a review. Cutis. 2005;76:361–6. 69. Cuozzo DW, Benson PM, Sperling LC, et al. Essential syphilitic alopecia revisited. J Am Acad Dermatol. 1995;32:840–3. 70. Piraccini BM, Broccoli A, Starace M, et al. Hair and scalp manifestations in secondary syphilis: epidemiology, clinical features and trichoscopy. Dermatology. 2015;231:171–6. 71. Careta M F, Romiti R. Localized scleroderma: clinical spectrum and therapeutic update. An Bras Dermatol. 2015;90(1):62–73. 72. Montoya CL, Calvache N. Linear morphea alopecia: new trichoscopy findings. Int J Trichology. 2017;9(2):92–3. 73. Peterson LS, Nelson AM, Su WP, et al. The epidemiology of morphea (localized scleroderma) in Olmstead Country 1960–1993. J Rheumatol. 1997;24:73–80. 74. Blaszczyk M, Janniger CK, Jablonska S. Childhood scleroderma and its peculiarities. Cutis. 1996;58:141–4,148–52. 75. Sommer A, Gambichler T, Bacharach-Buhles M, et al. Clinical and serological characteristics of progressive facial hemiatrophy: a case series of 12 patients. J Am Acad Dermatol. 2006;54:227. 76. Woolfenden AR, Tong DC, Norbash AM, et al. Progressive facial hemiatrophy: abnormality of intracranial vasculature. Neurology. 1998;50:1915–7.

203 77. Torok KS, Li SC, Jacobe HM, et al. Immunopathogenesis of pediatric localized scleroderma. Front Immunol. 2019;10:908. 78. Jablonska S, Blaszczyk M, Rosinska D. Progressive facial hemiatrophy and scleroderma en coup de sabre: clinical presentation and course as related to the onset in early childhood and young adults. Arch Argent Dermatol. 1998;48: 125–8. 79. DeFelipe J, Segura T, Arellano JI, et al. Neuropathological findings in a patient with epilepsy and the Parry-Romberg syndrome. Epilepsia. 2001;42:1198–203. 80. Gambichler T, Kreuter A, Hoffmann K, et al. Bilateral linear scleroderma “en coup de sabre” associated with facial atrophy and neurological complications. BMC Dermatol. 2001;1:9. 81. Saceda-Corralo D, Tosti A. Trichoscopic features of linear morphea on the scalp. Skin Appendage Disord. 2018; 4(1):31–3. 82. Kreuter A, Krieg T, Worm M, et al. German guidelines for the diagnosis and therapy of localized scleroderma. J Dtsch Dermatol Ges. 2016;14(2):199–216. 83. Mertens JS, Seyger MMB, Thurlings RM, et al. Morphea and Eosinophilic Fasciitis: an update. Am J Clin Dermatol. 2017;18(4):491–512. 84. Hulshof MM, Bouwes Bavinck JN, Bergman W, et al. Double-blind, placebo-controlled study of oral calcitriol for treatment of localized and systemic scleroderma. J Am Acad Dermatol. 2000;43:1017–23. 85. Griffiths WA. Pityriasis rubra pilaris. Clin Exp Dermatol. 1980;5:105–12. 86. Misery I, Faure M, Claidy A. Pityriasis rubra pilaris and human immunodeficiency virus infection - type 6 pityriasis rubra pilaris? Br J Dermatol. 1996;135:1008–9. 87. Moretta G, De Luca EV, Di Stefani A. Management of refractory pityriasis rubra pilaris: challenges and solutions. Clin Cosmet Investig Dermatol. 2017;10:451–7. 88. Ross NA, Chung HJ, Li Q, Andrews JP, et al. Epidemiologic, clinicopathologic, diagnostic and management challenges of Pityriasis Rubra Pilaris: a case series of 100 patients. JAMA Dermatol. 2016;152(6):670–5.

26 Hair in Systemic Disease A. Tülin Güleç

Introduction Hair and scalp involvement can be appreciated in several systemic diseases. Among these, lupus erythematosus takes the first place displaying various kinds of alopecia, either scarring or non-scarring. Dermatomyositis is another autoimmune disease with a frequent occurrence of scalp disease which is mostly associated with persistent severe pruritus and burning sensation. Regarding scleroderma, one of its localized subtypes, namely linear scleroderma en coup de saber is the one causing secondary scarring alopecia in patients with scalp lesions. Cutaneous manifestations are quite common in sarcoidosis that is a multisystemic granulomatous disease, yet hair and scalp involvement is not a usual finding. Nevertheless, it can be the presenting sign of the disease and can be an important clue to reveal the underlying systemic disease. This chapter chiefly discusses the clinical, trichoscopic, and histopathologic features of these four diseases. Current treatment modalities are also provided.

Lupus Erythematosus Definition Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease with a variety of clinical and serologic findings. Hair and scalp involvement is quite frequent among its cutaneous manifestations, which are the second most common clinical feature following joint disease.1–4

Epidemiology Hair loss is a usual finding affecting a majority of the patients (17.3–82.5%) with lupus erythematosus (LE) during their disease course.2–4 Non-scarring alopecia is included in the latest classification system for the disease by Systemic Lupus International Collaborating Clinics (SLICC) due to its high specificity to SLE. It is described as diffuse thinning or hair fragility with visible broken hairs, in the absence of other causes such as iron deficiency, drugs, alopecia areata (AA), and androgenetic alopecia (AGA).5

Etiology – Pathogenesis It has not been clarified yet. However, a complex interaction of host and environmental factors in genetically susceptible 204

people has been proposed. Ultraviolet radiation (UV) and koebnerization play a role in the development of some cutaneous lesions.6 Yet, triggers causing different types of alopecia in these patients are not well-known.7

Clinical Presentation Patients with LE manifests several different types of alopecia that can be generally divided into two groups; LE specific and LE nonspecific ones. The specific types exhibit characteristic LE features in histology, whereas nonspecific ones like telogen effluvium (TE), anagen effluvium (AE), and AA do not.8 LE specific hair loss is further classified into two groups as scarring and non-scarring alopecia. Discoid lupus erythematosus (DLE) and classic lupus panniculitis/profundus of the scalp (LPS) are the scarring alopecias. Non-scarring alopecias include diffuse non-scarring alopecia, a patchy non-scarring alopecia, lupus hair, and linear and annular lupus panniculitis of the scalp (LALPS) (Table 26.1).8

Lupus Erythematosus Specific Scarring Alopecias Discoid Lupus Erythematosus (DLE) Definition DLE is one of the cutaneous diagnostic items listed in the SLICC criteria, and it is the most common type of scarring alopecia in LE.5

Epidemiology DLE is the most frequent form of chronic cutaneous LE, and it occurs primarily on the head and neck area (90%). More than half of the patients (60%) also suffer from scalp disease,8 while some of them (11–20%) have only scalp involvement.4 It has a strong predominance of females (2–3 times) at the ages of 20–40 years.9,10

Etiology – Pathogenesis Host factors determined with genetic predisposition and triggering environmental factors like UV and koebnerization are proposed mechanisms.6,7 DOI: 10.1201/9780429465154-26

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TABLE 26.1 Different Types of Alopecias Observed in Lupus Erythematosus8  I. LE specific alopecias A. Scarring alopecias a. Discoid lupus erythematosus b. Classic lupus panniculitis/profundus B. Non-scarring alopecias a. Diffuse non-scarring alopecia in SLE b. Patchy non-scarring alopecia in SLE c. Lupus hair d. Linear and annular lupus panniculitis of the scalp II. LE non-specific alopecias a. Telogen effluvium b. Anagen effluvium c. Alopecia areata Abbreviations:  LE, lupus erythematosus; SLE, systemic lupus erythematosus.

Clinical Presentation Patients usually present with patchy hair loss of well-demarcated, erythematous, scaly, solitary, or multiple alopecic plaques with atrophy and follicular plugging (Figure 26.1a). Vertex area is the most common site of involvement. Early lesions cause non-scarring alopecia yet progress to scarring patches in time, with associated dyspigmentation. Patients can be asymptomatic or experience pruritus, tenderness, burning, or stinging. A positive pull test for anagen hairs at sites of the lesions is a sign of disease activity.4,8,11,12

Dermoscopy Large keratotic yellow dots, follicular red dots, blue-grey dots in a speckled pattern, interfollicular and perifollicular scaling, and brown scattered pigmentation are the features of active scalp disease (Figures 26.1b and 26.1c). Pink-white appearance lacking follicular openings and fibrotic white dots are observed in longstanding cases. The characteristic vascular feature is thick arborizing vessels.13–17

Laboratory Investigation Antinuclear antibody (ANA) positivity is noted in 15–42% of the patients with scalp DLE.10,11

Histopathology Basal vacuolization of the epidermis and follicular epithelium, perieccrine and perivascular lymphocytic infiltration, and dermal mucin deposition are observed in the early stage of the disease. Follicular plugging and epidermal atrophy emerge, resulting in pigment incontinence and lamellar fibrosis in advanced cases.8,11,12,18 On direct immunofluorescence (DIF), granular deposits of immunoglobulin (Ig)G, IgM, and complement (C)3 at the dermoepidermal junction (DEJ) are noted in 80% of the patients.8,11,12

Diagnosis/Differential Diagnosis DLE of the scalp shares features with other scarring alopecias like lichen planopilaris, central centrifugal cicatricial alopecia, and morphea. Trichoscopic examination and trichoscopy guided

FIGURE 26.1  Discoid lupus erythematosus. (a) Solitary, well-defined, irregularly shaped erythematous plaque with patchy adherent scales on the right parietotemporal area. (b) Trichoscopic features displaying brown scattered pigmentation (red arrows), large keratotic yellow dots (blue arrows), and pink-white appearance (yellow circle) (original magnification; x30). (c) Blue-grey dots in a speckled pattern (blue arrows), perifollicular scaling (red arrow), and interfollicular scaling (green arrow) (original magnification; x30).

two 4-mm scalp biopsy specimens for vertical and horizontal sectioning are needed for the precise diagnosis. Furthermore, extra scalp involvement of possible concomitant cutaneous disease and/or signs of SLE should be searched for.8,11,12,19

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Prognosis

Dermoscopy

Hair loss becomes permanent in advanced disease, and recurrences are possible. There is a risk of progression to SLE in some of the patients (5–15%), especially within 1–3 years after the diagnosis.20 Among SLE patients, 11–18% of them have reported to be associated with DLE.21

Trichoscopic features include large yellow dots, black dots, short vellus hairs, thick arborizing vessels, and diffuse erythema on the interfollicular areas.8

Treatment Prompt diagnosis and appropriate therapeutic intervention in early stages of the disease can reverse hair loss, providing hair regrowth. Photoprotection is needed as it is well-known that UV radiation exacerbates cutaneous lesions, so most probably scalp lesions as well. Sunscreen creams and protecting clothing like sun hats should be strongly recommended. In addition, cessation of smoking could probably be useful for scalp DLE as well, similar to extra scalp cutaneous involvement.22 Highpotency topical and/or intralesional corticosteroids and topical calcineurin inhibitors are first-line treatment options for localized disease. Longstanding DLE lesions that are not responsive to topical corticosteroids or calcineurin inhibitors may show improvement after intralesional corticosteroid injections. Cases refractory to topical agents with extensive involvement or rapidly progressing require systemic treatment, namely immunosuppressant and immunomodulating medications. Antimalarial agents such as hydroxychloroquine (HCQ) and chloroquine are the first-line systemic treatment options. HCQ is preferred over chloroquine since it carries a lower risk of retinal toxicity, which is rare, but there is an increased risk with higher cumulative doses of both drugs. Other treatment modalities with varying efficacy include methotrexate, topical and systemic retinoids, dapsone, thalidomide, cyclophosphamide, azathioprine, mycophenolate mofetil, and intravenous immunoglobulin.12,22,23

Laboratory Investigation Positive ANA with variable titers has been reported (85–95%).26

Histopathology A lobular panniculitis having a heavy lymphocytic infiltrate extending from the reticular dermis into the subcutaneous fat that has widespread hyaline necrosis is observed. There can also be reactive follicles with germinal centers. Majority of the lesions are positive on DIF, with granular deposition of IgG and C3 at the DEJ or perivascular area.24,26

Diagnosis/Differential Diagnosis Subcutaneous panniculitis-like T-cell lymphoma can involve the scalp as well, and it has a significant risk of morbidity and mortality. Therefore, it should be ruled out first by histopathologic examination.27 Other diseases included in differential diagnoses are traumatic panniculitis, panniculitis associated with morphea, and dermatomyositis.8

Prognosis Associated SLE has been reported in 10–50% of the cases with classic LPS.26,28

Treatment Classic Lupus Panniculitis/Lupus Profundus of Scalp (LPS) Definition Lupus panniculitis (LP) is characterized by chronic inflammation of subcutaneous tissue due to LE. If it is associated with an overlying DLE lesion, as occurred in one-third of the patients, it is named as lupus profundus.24 There is an unusual variant of LPS named as LALPS which generally causes reversible alopecia.25

Epidemiology LP is a rare type of chronic LE (2–3%), presenting with tender, firm, erythematous plaques or nodules located on the face, extremities, and breasts of young women, in particular. Scalp involvement leading to scarring alopecia is reported in 16.4% of the cases.26

Clinical Presentation Patients present with patchy hair loss over the tender, indurated, erythematous plaques. There can be overlying skin changes of accompanying DLE.26

Antimalarials, namely HCQ and chloroquine, are the drugs of choice, yet the addition of systemic corticosteroids, methotrexate, or dapsone should be considered in patients with systemic disease or refractory to treatment. Relapse is common after discontinuance of treatment.28,29

Lupus Erythematosus Specific Non-Scarring Alopecias Diffuse Non-Scarring Alopecia Definition It is the most common type of alopecia in SLE, yet frequently misdiagnosed as other causes of diffuse alopecia such as TE and AA. It occurs especially during the disease flare-ups, yet still be evident at a milder degree in remission periods. Nevertheless, severe alopecia involving more than 50% of the scalp is accepted as a sign of disease acitivity.2,3,30

Epidemiology It has been reported in 59–65% of the patients with SLE.2,7

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Etiology – Pathogenesis

Etiology – Pathogenesis

Diffuse hair thinning has been proposed to be a direct result of SLE activity on the scalp, particularly in severe cases with more than 50% hair loss.3

It almost always occurs during active SLE.8,31

Clinical Presentation

Patients present with oval or irregularly shaped, one or more alopecic patches of partial hair loss. Mild erythema and sometimes white or yellow scales are also detected (Figure  26.2a). Complete hair loss in the involved area is unusual (50), TE is unlikely, yet histopathologic confirmation is required for definitive diagnosis. Androgenetic alopecia, and diffuse alopecia areata should also be in the differential diagnosis list. Treatment of SLE flare-up or discontinuing the offending drug reverses the excess hair shedding of TE.7,30

Histopathology

Anagen Effluvium

LALPS represents lobular lymphocytic panniculitis with mucin deposition (65%), hyaline fat degeneration (60%), basal

Anagen effluvium has been seen in more than 60% of patients who had given cyclophosphamide to treat an SLE

210 exacerbation.38 Furthermore, severe disease flare-ups have also been reported to cause this severe alopecia ending up with the loss of almost all the scalp hair.7

Alopecia Areata (AA) Earlier studies have reported that there is an increased risk of AA in patients with LE. However, subsequent reports have proved that this unusual coexistence is a coincidental finding, and most probably previously reported AA cases had been confused with patchy, non-scarring alopecia of SLE.7,31

Others; Hair Shaft Changes in LE SLE can cause changes in hair quality without any hair loss. In a study about the hair diameter in SLE patients, it was shown that the mean hair diameter in SLE patients was noted significantly lower than healthy controls. However, there was no difference between SLE patients using different therapeutic agents, implying that drugs were not responsible for the reduction of hair diameter.39 Altered pigmentation of hair shafts is also common in SLE patients.30 An antimalarial agent, chloroquine, can cause hair shaft hypopigmentation or greyness of scalp hair, eyelashes, eyebrows, and beard, especially in patients with blonde or reddish hair. Moreover, this hair lightening caused by chloroquine was even reported to revert back to normal after switching to hydroxychloroquine.40

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1. Cervera R, Khamashta MA, Font J et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic lupus erythematosus. Medicine (Baltimore) 1993; 72: 113–24. 2. Yun SJ, Lee JW, Yoon HJ et al. Cross-sectional study of hair loss patterns in 122 Korean systemic lupus erythematosus patients: a frequent finding of non-scarring patch alopecia. J Dermatol 2007; 34: 451–5. 3. Gong Y, Ye Y, Zhao Y et al. Severe diffuse non-scarring hair loss in systemic lupus erythematosus-clinical and histopathological analysis of four cases. J Eur Acad Dermatol Venereol 2013; 27: 651–4. 4. Moghadam-Kia S, Franks AG Jr. Autoimmune disease and hair loss. Dermatol Clin 2013; 31: 75–91. 5. Petri M, Orbai AM, Alarcón GS et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677–86. 6. Achtman JC, Werth VP. Pathophysiology of cutaneous lupus erythematosus. Arthritis Res Ther 2015; 17: 182. 7. Chanprapaph K, Udompanich S, Visessiri Y et al. Nonscarring alopecia in systemic lupus erythematosus: a crosssectional study with trichoscopic, histopathological and immunopathological analyses. J Am Acad Dermatol 2019; 81: 1319–29.

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8. Udompanich S, Chanprapaph K, Suchonwanit P. Hair and scalp changes in cutaneous and systemic lupus erythematosus. Am J Clin Dermatol 2018; 19: 679–94. 9. Wilson CL, Burge SM, Dean D, Dawber RP. Scarring alopecia in discoid lupus erythematosus. Br J Dermatol 1992; 126: 307–14. 10. Tan E, Martinka M, Ball N, Shapiro J. Primary cicatricial alopecias: clinicopathology of 112 cases. J Am Acad Dermatol 2004; 50: 25–32. 11. Fabbri P, Amato L, Chiarini C et al. Scarring alopecia in discoid lupus erythematosus: a clinical, histopathologic and immunopathologic study. Lupus 2004; 13: 455–62. 12. Hordinsky M. Cicatricial alopecia: discoid lupus erythematosus. Dermatol Ther 2008; 21: 245–8. 13. Karadag Köse Ö, Güleç AT. Evaluation of a handheld dermatoscope in clinical diagnosis of primary cicatricial alopecias. Dermatol Ther (Heidelb) 2019; 9: 525–35. 14. Rakowska A, Slowinska M, Kowalska-Oledzka E et al. Trichoscopy of cicatricial alopecia. J Drugs Dermatol 2012; 11: 753–8. 15. Abedini R, Kamyab Hesari K, Daneshpazhooh M et al. Validity of trichoscopy in the diagnosis of primary cicatricial alopecias. Int J Dermatol 2016; 55: 1106–14. 16. Ankad BS, Beergouder SL, Moodalgiri VM. Lichen planopilaris versus discoid lupus erythematosus: a trichoscopic perspective. Int J Trichology 2013; 5: 204–7. 17. Duque Estrada B, Tamler C, Sodre CT et al. Dermoscopy patterns of cicatricial alopecia resulting from discoid lupus erythematosus and lichen planopilaris. An Bras Dermatol 2010; 85: 179–83. 18. Chung HJ, Goldberg LJ. Histologic features of chronic cutaneous lupus erythematosus of the scalp using horizontal sectioning: Emphasis on follicular findings. J Am Acad Dermatol 2017; 77: 349–55. 19. Concha JSS, Werth VP. Alopecias in lupus erythematosus. Lupus Sci Med 2018; 5: e000291. 20. Grönhagen CM, Fored CM, Granath F, Nyberg F. Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden. Br J Dermatol 2011; 164: 1335–41. 21. Merola JF, Prystowsky SD, Iversen C et al. Association of discoid lupus erythematosus with other clinical manifestations among patients with systemic lupus erythematosus. J Am Acad Dermatol 2013; 69: 19–24. 22. Garza-Mayers AC, McClurkin M, Smith GP. Review of treatment for discoid lupus erythematosus. Dermatol Ther 2016; 29: 274–83. 23. Tenti S, Fabbroni M, Mancini V et al. Intravenous Immunoglobulins as a new opportunity to treat discoid lupus erythematosus: A case report and review of the literature. Autoimmun Rev 2018; 17: 791–5. 24. Fraga J, García-Díez A. Lupus erythematosus panniculitis. Dermatol Clin 2008; 26: 453–63. 25. Lueangarun S, Subpayasarn U, Tempark T. Distinctive lupus panniculitis of scalp with linear alopecia along Blaschko’s lines: a review of the literature. Int J Dermatol 2019; 58: 144–50. 26. Arai S, Katsuoka K. Clinical entity of lupus erythematosus panniculitis/lupus erythematosus profundus. Autoimmun Rev 2009; 8: 449–52.

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Hair in Systemic Disease 27. LeBlanc RE, Tavallaee M, Kim YH, Kim J. Useful parameters for distinguishing subcutaneous panniculitis-like T-cell lymphoma from lupus erythematosus panniculitis. Am J Surg Pathol 2016; 40: 745–54. 28. Ng PP, Tan SH, Tan T. Lupus erythematosus panniculitis: a clinicopathologic study. Int J Dermatol 2002; 41: 488–90. 29. Park HS, Choi JW, Kim BK, Cho KH. Lupus erythematosus panniculitis: clinicopathological, immunophenotypic, and molecular studies. Am J Dermatopathol 2010; 32: 24–30. 30. Trüeb RM. Involvement of scalp and nails in lupus erythematosus. Lupus 2010; 19: 1078–86. 31. Ye Y, Zhao Y, Gong Yet al. Non-scarring patchy alopecia in patients with systemic lupus erythematosus differs from that of alopecia areata. Lupus 2013; 22: 1439–45. 32. Piraccini BM, Broccoli A, Starace M et al. Hair and scalp manifestations in secondary syphilis: epidemiology, clinical features and trichoscopy. Dermatology 2015; 231: 171–6. 33. Trüeb RM, El Shabrawi-Caelen L, Kempf W. Cutaneous lupus erythematosus presenting as frontal fibrosing alopecia: report of 2 patients. Skin Appendage Disord 2017; 3: 205–10. 34. Alarcon-Segovia D, Cetina JA. Lupus hair. Am J Med Sci 1974; 267: 241–2. 35. Chen YA, Hsu CK, Lee JY, Yang CC. Linear lupus panniculitis of the scalp presenting as alopecia along Blaschko’s lines: a distinct variant of lupus panniculitis in East Asians? J Dermatol 2012; 39: 385–8. 36. Miteva M, Tosti A. Hair and scalp dermatoscopy. J Am Acad Dermatol 2012; 67: 1040–8. 37. Karadağ Köse Ö, Güleç AT. Clinical evaluation of alopecias using a handheld dermatoscope. J Am Acad Dermatol 2012; 67: 206–14. 38. Trüeb RM. Chemotherapy-induced alopecia. Semin Cutan Med Surg 2009; 28: 11–4. 39. Seyahi E, Seyahi N, Fresko I et al. Hair diameter in systemic lupus erythematosus. Lupus 2006; 15: 282–4. 40. Marriott P, Borrie PF. Pigmentary changes following chloroquine. Proc R Soc Med 1975; 68: 535–6.

most probably due to its underdiagnosis till recent years.3–7 It has been mostly reported in adult-onset classic DM and amyopathic/hypomyopathic DM,5 yet rarely noted in juvenile cases as well.6 There is a low association between SDM and paraneoplastic DM.5

Etiology – Pathogenesis The exact pathogenesis of SDM has not been clarified yet. However, a recent case report proposed that scalp pruritus in DM could be due to small-fiber neuropathy. A confocal image of immunostained scalp skin biopsies showed decreased density and formed complex tufts of epidermal nerves, which could explain the mechanism of pruritus in these patients.8

Clinical Presentation The usual clinical appearance is diffuse erythema (100%) and/ or poikiloderma (51%) (Figure 26.4) of the scalp frequently in company with scaling (83%) (Figure 26.5),7 and sometimes associated with diffuse non-scarring alopecia (33–87.5%).4,5,7 Severe, recalcitrant pruritus or burning of the scalp is the drastic symptom of the disease that often aggravates with a DM flare-up.7

Dermoscopy Enlarged capillaries are seen on the scalp in most of the patients (71.4%) regardless of the clinical evidence of scalp involvement. They can be bushy-like in appearance, similar

Dermatomyositis Definition Dermatomyositis (DM) is a systemic autoimmune connective tissue disease characterized by idiopathic inflammatory myopathy associated with cutaneous findings including Gottron’s papules, heliotrope rash, erythema, and/or poikiloderma in sun-exposed areas.1 Involvement of the scalp is quite common in DM, even sometimes being the presenting manifestation of the disease.2

Epidemiology DM predominantly affects females compared to males (2:1), and has an incidence of 2–9 cases per million individuals.3 It has a bimodal incidence (juvenile- and adult-onset) but can be observed in any age group.1 Scalp dermatomyositis (SDM) has a relatively high frequency (25–82%), albeit it has still not been well-characterized,

FIGURE 26.4  Dermatomyositis of the scalp. Diffuse poikiloderma and non-scarring alopecia of the scalp. (Courtesy of Prof Dr Can Baykal.)

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Hair Disorders dermal mucin and telangiectasia are characteristic findings. On horizontal sections, decreased hair counts are noted, which is compatible with a diagnosis of chronic telogen effluvium.11 Immunofluorescence microscopy frequently reveals the deposition of immunoglobulins and complement (C) at the dermoepidermal junction. C5 to C9 found in superficial perivascular area are accepted as a diagnostic finding of DM.12

Diagnosis/Differential Diagnosis Scaly erythematous plaques of the scalp may be the initial presentation of DM and can easily be misdiagnosed as psoriasis or seborrheic dermatitis.4 Therefore, in case of diffuse scaly erythematous or violaceous scalp lesions together with severe pruritus and/or burning, a rush diagnosis should be avoided, and SDM should be kept in mind. FIGURE 26.5  Dermatomyositis of the scalp. Diffuse erythema and scaling of the scalp extending to face and neck. (Courtesy of Prof Dr Soner Uzun.)

to the nail fold vessels of these patients. Perifollicular scaling, sometimes surrounding 2–3 hairs emerging from the same follicle, just like in scarring alopecias, can be observed in nonscarring alopecia of DM (57%) (Figure 26.6). Interfollicular scaling can also be noted (50%).7,9

Laboratory Investigation Melanoma differentiation-associated gene 5 (MDA5) is an autoantigen identified in a subset of patients with DM who exhibits unique clinical features, including increased risk of more diffuse and pronounced non-scarring alopecia.10

Histopathology SDM demonstrates hyperkeratotic and atrophic epidermis, basal cell hydropic degeneration, and focal pigmentary incontinence, while follicular architecture is preserved. Excess

Prognosis Conventional therapies do not provide recovery in most of the cases. Furthermore, there is a high recurrence risk after cessation of the treatment.13 Current literature do not present accurate information regarding the course of scalp involvement.

Treatment Treatment for cutaneous DM may include photoprotection, topical or intralesional corticosteroids, calcineurin inhibitors, and/or systemic therapies such as hydroxychloroquine, methotrexate or mycophenolate mofetil with limited efficacy. Nevertheless, SDM presents as a treatment-resistant disease to almost all above mentioned therapeutic agents.13 Recently, a case with refractory SDM who improved significantly with PRP injections of the scalp has been reported.14

REFERENCES









FIGURE 26.6  Trichoscopic features displaying enlarged, tortuous cap­ illaries (blue arrows) and perifollicular scaling (red arrows) (original magnification; x30).



1. Sontheimer RD. Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects. Dermatol Clin 2002; 20: 387–408. 2. Moghadam-Kia S, Franks AG Jr. Autoimmune disease and hair loss. Dermatol Clin 2013; 31: 75–91. 3. Irazoque-Palazuelos F, Barragán-Navarro Y. Epidemiology, etiology and classification. Reumatol Clin 2009; 5 Suppl 3: 2–5. 4. Kasteler JS, Callen JP. Scalp involvement in dermatomyositis. Often overlooked or misdiagnosed. JAMA 1994; 272: 1939–41. 5. Tilstra JS, Prevost N, Khera P, English JC 3rd. Scalp dermatomyositis revisted. Arch Dermatol 2009; 145: 1062–3. 6. Peloro TM, Miller OF 3rd, Hahn TF, Newman ED. Juvenile dermatomyositis: a retrospective review of a 30-year experience. J Am Acad Dermatol 2001; 45: 28–34. 7. Jasso-Olivares JC, Tosti A, Miteva M et al. Clinical and dermoscopic features of the scalp in 31 patients with dermatomyositis. Skin Appendage Disord 2017; 3: 119–24. 8. Hurliman E, Groth D, Wendelschafer-Crabb G et al. Smallfibre neuropathy in a patient with dermatomyositis and severe scalp pruritus. Br J Dermatol 2017; 176: 209–11.

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9. Miteva M, Tosti A. Hair and scalp dermatoscopy. J Am Acad Dermatol 2012; 67: 1040–8. 10. Kurtzman DJB, Vleugels RA. Anti-melanoma differentiation-­ associated gene 5 (MDA5) dermatomyositis: A concise review with an emphasis on distinctive clinical features. J Am Acad Dermatol 2018; 78: 776–85. 11. Jasso-Olivares J, Diaz-Gonzalez JM, Miteva M. Horizontal and vertical sections of scalp biopsy specimens from dermatomyositis patients with scalp involvement. J Am Acad Dermatol 2018; 78: 1178–84. 12. Magro CM, Crowson AN. The immunofluorescent profile of dermatomyositis: a comparative study with lupus erythematosus. J Cutan Pathol 1997; 24: 543–52. 13. Jorizzo JL. Dermatomyositis: practical aspects. Arch Dermatol 2002; 138: 114–6. 14. Hosking AM, Juhász M, Ekelem C et al. Improvement in scalp dermatomyositis with platelet-rich plasma. JOJ Dermatol & Cosmet 2018; 1: 1–4

Scleroderma Definition Scleroderma is a rare inflammatory connective tissue disorder characterized by sclerosis of the skin and underlying tissues with variable systemic involvement. It has systemic and localized subtypes (morphea). Linear scleroderma en coup de saber (LSCS) is a form of morphea that typically affects the forehead and/or the scalp leading to secondary scarring alopecia.1,2

Epidemiology One-third of the cases with LSCS arise in childhood, and the mean age of onset is 6.4–8.7 years. There is a strong female predominance (70–80%).3–6

Etiology – Pathogenesis The hypotheses for the pathogenesis of scleroderma are diverse including abnormal immunologic processes such as cytokine and chemokine dysregulation, abnormal T-cell signaling, B cell dysfunction, and injury due to autoantibodies to endothelial cells.7

Clinical Presentation Scalp lesions of LSCS present with linear atrophic plaques of alopecia (Figures 26.7a and 26.7b) frequently associated with depression on the midline or paramedian forehead (Figure  26.7c). Thinning or depression of the underlying skull can occur.8 Rarely ulcerative plaques can arise as well (Figure 26.8). Apart from scalp, LSCS can cause alopecia of the eyebrows or eyelashes as well.9

Dermoscopy There are a few reports regarding the dermoscopic features of LSCS. First one reported pinpoint white dots with the loss of

FIGURE 26.7  Linear scleroderma en coupe de saber. (a) Linear atrophic alopecic plaque on the left frontoparietal scalp. (b) Linear atrophic alopecic plaque on the left parietal and occipital area following the same line of the frontal lesion. (c) En coupe de saber on the left paramedian forehead.

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FIGURE 26.8  Linear scleroderma en coupe de saber. Ulceration and hemorrhagic crust on a white sclerotic linear plaque of alopecia on the right parietotemporal area. (Courtesy of Prof. Dr. Can Baykal.)

follicular openings, peripilar casts, pili torti, and short regrowing hairs.10 Another one representing 2 cases demonstrated loss of follicular openings on a whitish skin surface, black dots, broken hairs, and pili torti in a diffuse distribution in addition to short thick linear vessels and branching tortuous vessels on the periphery of the lesions (Figures 26.9a and 26.9b).11

Laboratory Investigation ANA positivity can be detected in about half of the juvenile cases.12,13

Histopathology Histopathologic findings can vary depending on the stage of the disease. In early disease, a superficial and deep perivascular intense inflammatory infiltrate composed of lymphocytes, histiocytes, and variable numbers of plasma cells is observed. The increased amount of abnormal collagen in the reticular dermis extending into the subcutaneous fat cause marked compression to pilosebaceous units and eccrine sweat glands ending up with their loss in advanced cases.14

Diagnosis/Differential Diagnosis The diagnosis is usually made clinically yet needs to be confirmed by a skin biopsy. An ophthalmologic and neurologic examination should be performed to rule out ocular and central nervous system involvement. Other localized scarring alopecias such as discoid lupus erythematosus, lichen planopilaris, and non-scarring ones like alopecia areata, trichotillomania should be differentiated.1–3,15

Prognosis LSCS cause local atrophy and depression, and secondary scarring alopecia on the scalp. In some cases, deep involvement of

FIGURE 26.9  Trichoscopic features of linear scleroderma en coupe de saber. (a) Pili torti (blue arrows) and loss of follicular openings on a pinkwhite appearance (original magnification; x20). (b) Short, thick, tortous, and branching vessels (blue arrows) (original magnification; x20).

the underlying muscle, bone, and central nervous system also occurs, leading to neurological and ocular complications. The disease can be active for years or reactive after a long period of remission.1–3,15

Treatment First-line therapy for localized disease is intralesional injections of triamcinolone acetonide (10 mg/mL), and topical mid- to ultra-potent corticosteroids. Alternatively, topical tacrolimus under occlusion may be tried as well. Second-line options include imiquimod and vitamin D analogs. For extensive lesions, phototherapy (UVA or UVB), systemic steroids, and/or methotrexate are recommended. Nevertheless, no current treatment modalities are adequately evidence-based to conclude that they alter the natural course of the disease.1,15,16

REFERENCES

1. Bielsa Marsol I. Update on the classification and treatment of localized scleroderma. Actas Dermosifiliogr 2013; 104: 654–66.

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2. Fett N, Werth VP. Update on morphea: part I. Epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol 2011; 64: 217–28. 3. 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. 4. Leitenberger J, Cayce R, Haley R et al. Distinct autoimmune syndromes in morphea. Arch Dermatol 2009;145: 545–50. 5. Weibel L, Harper JI. Linear morphea follows Blaschko’s lines. Br J Dermatol 2008; 159: 175–81. 6. Zulian F, Athreya B, Laxer R et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology 2006; 45: 614–20. 7. Gilliam AC. Scleroderma. Curr Dir Autoimmun 2008; 10: 258–79. 8. Weibel L, Laguda B, Atherton D et al. Misdiagnosis and delay in referral of children with localized scleroderma. Br J Dermatol 2011; 165: 1308–13. 9. Mears KA, Servat JJ, Black EH. Linear scleroderma en coup de sabre affecting the upper eyelid and lashes. Graefes Arch Clin Exp Ophthalmol 2012; 250: 1097–9. 10. Montoya CL, Calvache N. Linear morphea alopecia: new trichoscopy findings. Int J Trichology 2017; 9: 92–3. 11. Saceda-Corralo D, Tosti A. Trichoscopic features of linear morphea on the scalp. Skin Appendage Disord 2018; 4: 31–3. 12. Scalapino K, Arkaschaisri T, Lucas M, et al. Childhood onset systemic sclerosis: classification, clinical and serologic features, and survival in comparison with adult onset disease. J Rheumatol 2006; 33: 1004–13. 13. Martini G, Foeldvari I, Russo R et al. Systemic sclerosis in childhood. Clinical and immunologic features of 153 patients in an international database. Arthritis Rheum 2006; 54: 3971–8. 14. Pierre-Louis M, Sperling LC, Wilke MS, Hordinsky MK. Distinctive histopathologic findings in linear morphea (en coup de sabre) alopecia. J Cutan Pathol 2013; 40: 580–4. 15. Li SC. Scleroderma in children and adolescents: localized scleroderma and systemic sclerosis. Pediatr Clin North Am 2018; 65: 757–81. 16. Adrovic A, Sahin S, Barut K, Kasapcopur O. Juvenile scleroderma-what has changed in the meantime? Curr Rheumatol Rev 2018; 14: 219–25.

Sarcoidosis Definition Sarcoidosis is an idiopathic multisystemic granulomatous disease with a diverse range of cutaneous manifestations arising in 20–35% of the patients. However, scalp involvement in sarcoidosis is an unusual situation, reported in only 55 cases till now.1,2 Nevertheless, scalp lesions can be the presenting feature of the disease.2

Epidemiology Sarcoidosis occurs all over the world, with a peak onset between the ages of 20 and 40 years. Its incidence is 10–70/100,000

with the highest occurrence in patients of color.3,4 The prevalence of scalp lesions, alopecia, in particular, appears to be highest in African–American women between the ages of 23 and 78.5

Etiology – Pathogenesis An unknown antigen has been proposed to induce a chronic granulomatous immune reaction in several organs including skin and hair follicles.6

Clinical Presentation Scalp lesions display polymorphic manifestations namely orange-brown or erythematous papules, atrophic, indurated, sometimes scaly plaques, annular lesions, or nodules.2,7–9 These lesions can be associated with localized or diffuse hair loss, which is usually secondary scarring alopecia, yet may be rarely non-scarring as well. Scarring alopecia presents as atropic, scaly or ulcerative areas.7,10,11 There are a few cases reported with non-scarring sarcoidal alopecia involving only extremites.12

Dermoscopy Dermoscopic features of sarcoidal alopecia include perifollicular or follicular orange spots together with prominent telangiectases, in addition to dystrophic hairs and perifollicular scaling.13

Laboratory Investigation There is a high possibility of associated systemic disease.14,15 Therefore, a detailed investigation including chest X-ray, ophthalmologic examination, electrocardiogram, serum angiotensin converting enzyme, and calcium levels should be performed.15

Histopathology The histologic features consist of sarcoidal noncaseating granulomatous inflammation in the dermis. The granulomata are usually circumscribed and composed of epithelioid histiocytes and multinucleated giant cells. Giant cells of both foreign body and Langhans’ types are common.16 Destruction of hair follicles and fibrosis may be seen depending on the stage of sarcoidal alopecia.7,17

Diagnosis/Differential Diagnosis The differential diagnosis includes other causes of scarring alopecia namely discoid lupus erythematosus, lichen planopilaris, necrobiosis lipoidica, morphea, central centrifugal cicatricial alopecia, or alopecia neoplastica.5,11,13,17,18 Scaly annular lesions can resemble tinea capitis as well.2 The diagnosis is established by the presence of noncaseating granulomas on biopsy with appropriate clinical findings.16

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Prognosis Sarcoidosis of the scalp may be the presenting manifestation of the disease, yet it is very seldom that it stays as a single site of involvement. Patients usually have other cutaneous lesions elsewhere and carry a high risk of systemic disease, particularly thoracic involvement.2,7 Since there is a limited number of reported cases regarding scalp sarcoidosis, the natural course of the disease is not well-known.

Treatment Therapeutic options of the scalp sarcoidosis are not satisfactory. Intralesional corticosteroids, oral corticosteroids, immunosuppressive agents such as azathioprine, and antimalarials like hydroxychloroquine have been used with poor response rates.7 Combination of antimalarial drugs (hydroxychloroquine plus quinacrine or chloroquine plus quinacrine) has been suggested helpful after a single-agent antimalarial therapy has failed.17

REFERENCES







1. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Eng J Med 1997; 336: 1224–34. 2. Knight L, Ngwanya M. Sarcoidosis of the scalp: the largest single-instutional case series. Int J Dermatol 2019; 58: e149–51. 3. Ungprasert P, Crowson CS, Matteson EL. Epidemiology and clinical characteristics of sarcoidosis: an update from a population-based cohort study from Olmsted County, Minnesota. Reumatismo 2017; 69: 16–22. 4. Cozier YC, Berman JS, Palmer JR et al. Sarcoidosis in black women in the United States: data from the black women’s health study. Chest 2011; 139: 144–50. 5. House NS, Welsh JP, English JC 3rd. Sarcoidosis-induced alopecia. Dermatol Online J 2012; 18: 4.

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6. Bargagli E, Prasse A. Sarcoidosis: a review for the internist. Intern Emerg Med 2018; 13: 325–31. 7. Katta R, Nelson B, Chen D, Roenigk H. Sarcoidosis of the scalp: a case series and review of the literature. J Am Acad Dermatol 2000; 42: 690–2. 8. Bhushan P, Thatte SS, Singh A. Key messages from a rare case of annular sarcoidosis of scalp. Indian Dermatol Online J 2016; 7: 192–4. 9. Paolino G, Panetta C, Didona D et al. Atrophic and annular scarring alopecia of the scalp as a finding in underlying systemic sarcoidosis. Acta Dermatovenerol Croat 2017; 25: 298–9. 10. Ghosh A, Sengupta S, Coondoo A, Gharami RC. Single lesion of sarcoidosis presenting as cicatricial alopecia: a rare report from India. Int J Trichology 2014; 6: 63–6. 11. Frieder J, Kivelevitch D, Menter A. Symptomatic hypercalcemia and scarring alopecia aspresenting features of sarcoidosis. Proc (Bayl Univ Med Cent) 2018; 31: 224–6. 12. Dan L, Relic J. Sarcoidosis presenting as non-scarring nonscalp alopecia. Australas J Dermatol 2016; 57: e112–3. 13. Torres F, Tosti A, Misciali C, Lorenzi S. Trichoscopy as a clue to the diagnosis of scalp sarcoidosis. Int J Dermatol 2011; 50: 358–61. 14. La Placa M, Vincenzi C, Misciali C, Tosti A. Scalp sarcoidosis with systemic involvement. J Am Acad Dermatol 2008; 59: S126–7. 15. Cheraghi N, Robinson A, O’Donnell P, Belazarian L. Scalp sarcoidosis: a sign of systemic sarcoidosis. Dermatol Online J 2014; 20: pii: doj_21767. 16. Ball NJ, Kho GT, Martinka M. The histologic spectrum of cutaneous sarcoidosis: a study of twenty-eight cases. J Cutan Pathol 2004; 31: 160–8. 17. Henderson CL, Lafleur L, Sontheimer RD. Sarcoidal alopecia as a mimic of discoid lupus erythematosus. J Am Acad Dermatol 2008; 59: 143–5. 18. Tsai CF, Lee HC, Chu CY. Sarcoidal alopecia mimicking discoid lupus erythematosus: Report of a case and review of the literature. Dermatologica Sinica 2014; 32: 43–6.

27 Scalp Infections and Infestations Stamatis Gregoriou, Theodora Tsironi, Eftychia Platsidaki, and Dimitris Rigopoulos

Superficial Folliculitis of the Scalp

Folliculitis Decalvans

Superficial folliculitis of the scalp is an inflammatory disorder of the superficial part of the scalp hair follicles. It can be infectious (bacterial, viral, fungal, parasitic) or noninfectious (chemical irritation, physical injury) etiology. Staphylococcus aureus is the most common cause among the infectious causes.1 Factors that predispose to infectious folliculitis include hyperhidrosis, maceration, friction, obesity, inappropriate use of topical corticosteroids, exposure to oils and tars, diabetes mellitus, and immunosuppression.2 Patients typically present with multiple small dome-shaped follicular papules or pustules on an erythematous base (Figure 27.1). Lesions are often pruritic and slightly tender and heal without scar formation. Diagnosis of scalp folliculitis is usually based on clinical presentation, and historical information alone, and laboratory tests are not needed. In ambiguous or resistant cases, Gram stain and cultures of pustules in order to reveal the causative agent are performed together with antibiotic susceptibility testing. Potassium hydroxide examination of the hair and surrounding scale, fungal culture, or both are performed to exclude infection by a dermatophyte in suspicious or resistant cases. Skin biopsy is rarely needed.3 Histopathology typically shows follicular infiltration of neutrophils with variable admix of lymphocytes and macrophages depending on chronicity of the folliculitis.4 Regarding treatment, mild staphylococcal folliculitis may respond to antibacterial washes that contain chlorhexidine or triclosan. Further, topical antibiotics such as mupirocin, fusidic acid, erythromycin, or clindamycin may be used for 7–10 days.3,5 Topical retapamulin for 5 days may also be effective.6 In more severe cases, systemic antistaphylococcal antibiotics are indicated. Because S. aureus may be penicillin-­resistant, dicloxacillin (250–500 mg four times a day) or cephalexin (250–500 mg four times a day) for 7–10 days are the first choices of therapy.1 For methicillin-resistant organisms (MRSA) patient should be treated for 7–10 days with oral clindamycin (300–450 mg three times a day) or trimethoprim-­sulfamethoxazole (1 or 2 DS tablets twice daily) or doxycycline (100 mg twice daily).3,7,8 In recurrent and recalcitrant folliculitis, mupirocin ointment in the nasal vestibule twice a day for 5 days is recommended for nasal decolonization since auto-inoculation in asymptomatic carriers has been described.9

Folliculitis decalvans (FD) is a rare progressive purulent destructive folliculitis that usually occurs on the scalp and results in scarring alopecia. It is classified as a primary neutrophilic cicatricial alopecia.10 Although its pathogenesis is not entirely clear, it is widely accepted that it may reflect an abnormal response to bacteria, particularly S. aureus. FD usually occurs in young and middle-aged adults of both sexes, with a slight male preponderance.11 The initial lesions are painful follicular pustules typically on the crown that coalesce, progress in depth, become crusted, and eventually resolve with scarring, leaving round to irregularly shaped alopecic patches. When the disease is active, the patches gradually expand centrifugally, with new follicular pustules forming at the advancing margins.12 A characteristic feature is that multiple hairs5–15 emerge from a common dilated follicular orifice. This is called “tufting” or “polytrichia” and looks similar to doll’s hair or bristle tufts of a toothbrush.13 The disease may remain limited to a small circumscribed area of the scalp or may involve many scalp areas over time causing severe scarring. Very rarely, it may affect other hairbearing areas including the beard, inner thighs, pubic, and axillary areas.14,15 The most characteristic dermoscopic findings of FD are the presence of hair tufts, perifollicular erythema, and follicular hyperkeratosis.16 Histopathologically, early lesions show perifollicular neutrophilic infiltration that affects the upper part of the follicle. Later on, as the follicle ruptures, the infiltrate becomes mixed with neutrophils, lymphocytes, histiocytes, and plasma cells. In end-stage lesions, follicular and adventitial dermal fibrosis is seen.15 The diagnosis of FD is made using a combination of the clinical, dermoscopic, and histologic findings. The differential diagnosis of FD depends on the clinical features present at the time of evaluation. In the very early stages, when pustules predominate and scarring starts to develop, it should be distinguished from superficial bacterial folliculitis. When scarring is more evident and many pustules are present, dissecting cellulitis of the scalp, acne keloidalis nuchae, erosive pustular dermatosis of the scalp have to be excluded. Inflammatory tinea capitis that may result in secondary alopecia should also be included in the differential diagnosis. End-stage lesions with advanced scarring can resemble pseudopelade of Brocq,

DOI: 10.1201/9780429465154-27

217

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Hair Disorders

Tinea Capitis

FIGURE 27.1  Superficial folliculitis due to Staphylococcus aureus.

central centrifugal cicatricial alopecia, lichen planopilaris, and discoid lupus erythematosus.12,17 The treatment of this chronic relapsing disease is long and difficult. Once scarring has developed, regrowth of hair cannot be expected. The aim of therapy is to stop the inflammatory process and prevent scarring. There are no randomized controlled trials that support the best treatment option. Consequently, the treatment of FD is mainly based on expert’s opinion and small case series studies.11,18 Since S. aureus and other bacteria seem to play an important role in the pathogenesis of FD, systemic antibiotics are the mainstay of the treatment. Their effectiveness is not only due to their anti-microbial effect but also due to the antiinflammatory properties that some of them have. Cultures of the pustules and susceptibility testing may aid in the treatment selection. The most frequently used antibiotics are oral tetracyclines (doxycycline or minocycline 50–100 mg twice daily for 8–12 weeks) or, in more severe cases, the combination of oral clindamycin (300 mg twice daily) and rifampicin (300 mg twice daily) for 10 weeks. Oral azithromycin (500  mg three times weekly for 3 months) can be used as an alternative in case the above-mentioned antibiotics are ineffective or cause serious side effects. Topical antibiotics as well as oral, intralesional, or topical steroids can be used as adjunctive therapy.11,12,18 Oral isotretinoin (≥0.4 mg/kg/day for more than 3 months) has been proven to be a good treatment alternative.19 Furthermore, tumor necrosis factor inhibitors (infliximab and adalimumab) and photodynamic therapy have been tried in the treatment of FD in selected patients with promising results.18,20

Tinea capitis (TC) is the most common dermatophytosis in children and rarely occurs in adults.21 Its incidence is highest amongst pre-pubertal children aged 3–7 years and is reported more in boys than in girls.22 It is an infection of the skin and scalp hairs caused by dermatophyte fungi divided into anthropophilic and zoophilic; species of genera Trichophyton and Microsporum.23 It is spread through direct transmission via contact with an infested person or stray cats, dogs, and rabbits, which are the most important dermatophyte carriers or indirectly via fomites.24 The spores are long-lived and can infect another individual month later. TC is classified into ectothrix and endothrix types.25 The ectothrix type is caused by Trichophyton verrucosum, Trichophyton mentagrophytes, and all Microsporum species. The hair shaft is invaded at the level of mid-follicle resulting in hair loss with hair shafts breaking 2–3 mm above the scalp level. Endothrix invasion is usually associated with Trichophyton tonsurans and Trichophyton violaceum. Fungi grow only within the hair shaft; the hair becomes very fragile and breaks the surface of the scalp giving a “black dot” appearance. The clinical manifestations of tinea capitis include areas of alopecia, usually round-shaped and with variable scaling and itch. In the case of Microsporum sp, lesions are few in number and can reach large diameters (Figure 27.2). On the other hand, in the case of Trichophyton sp, lesions are multiple and smaller in size.26 Kerion is a severe inflammatory type of tinea capitis usually caused by a T-cell–mediated hypersensitivity reaction against dermatophytes (Figure 27.3).27 Clinically, it presents with painful scaly plaques and intense topical inflammation along with edema, purulent discharge, and regional lymphadenopathy. It is often misdiagnosed as bacterial abscesses. However, hairs plucked from a kerion are painless and alopecia is not present in patients with bacterial infections constituting keys for the differential diagnosis. Pustules may develop representing the inflammatory response to the fungus itself

FIGURE 27.2  A large lesion in a patient with Tinea capitis due to Microsporum sp.

Scalp Infections and Infestations

FIGURE 27.3  Kerion evolving to cicatricial alopecia.

rather than a secondary bacterial infection. Kerion may evolve to cicatricial alopecia if not treated promptly. The development of a secondary rash, usually small follicular papules in other areas of the body such as the trunk or limb, known as id reaction, is sometimes seen in patients with Kerion.28 As it is not an allergic reaction, it should not lead to discontinuation of antifungal treatment. Id reaction can rarely manifest as erythema nodosum. Favus is the most severe form of tinea capitis and nowadays is seen rarely. It is caused by the dermatophyte Trichophyton schoenleinii and its classical picture is characterized by masses resembling yellow, cup-shaped crusts with a central hair, accompanied with an unpleasant odor like rat urine smell.29 If not treated properly, it can leave scarring alopecia. Predisposing factors for dermatophyte infections include a warm and moist environment, atopic diathesis, presence of immunodeficiency diseases, as well as prolonged use of topical corticosteroids and broad-spectrum antibiotics.30 The diagnosis of TC is often delayed. Differential diagnosis includes seborrheic dermatitis, bacterial cellulitis, trichotillomania, and alopecia areata.25 Discoid lupus erythematosus and lichen planus may occasionally have to be considered. TC can be diagnosed with a high index of clinical suspicion. It should always be excluded in a child presenting with alopecia associated with scaling, erythema, or pustules, especially when a history of contact with animals is reported.31 In addition, a possible diagnosis of TC should be considered in adults

219 who are not responding to treatment for seborrheic dermatitis or psoriasis.32 A Wood’s lamp examination demonstrates bright green florescence with Microsporum species caused by the destruction of the cuticle of the hair. Nevertheless, a negative examination does not exclude the diagnosis of TC as endothrix organisms do not fluoresce.31 Mycology remains the gold standard for diagnostic confirmation therefore, fungal cultures should be performed in all suspected cases. Potassium hydroxide [KOH] microscopy examination precedes the culture. Specimens are obtained by using a blunt scalpel if there is scalp scaling and by plucking hair from the periphery. Falsenegative results are observed in cases of abuse of antifungal agents by the patients, delay in the delivery of the collected samples to the laboratory, and the start of culture procedure.33 Trichoscopy is a simple, fast, and inexpensive method for diagnosing and monitoring TC. Comma and corkscrew appearance, V-shaped hair, scales, and follicular keratosis as well as crusts and follicular pustules are seen in tinea capitis.34 Finally, erythema can be present. Skin biopsy can be performed, including PAS or GMS staining in case, the fungus is not readily apparent on hematoxylin and eosin stains.35 Due to poor penetration of the hair follicle, topical antifungal therapy is considered ineffective and should only be used as an adjunct to oral therapy. Empirical systemic therapy should be started if clinical suspicion is high, even when culture results are not available. First-line treatment includes griseofulvin, azoles (itraconazole, fluconazole, ketoconazole) and allylamines (terbinafine). Terbinafine is an allylamine that acts on the cell membrane and is fungicidal, itraconazole exhibits both fungistatic and fungicidal activity, blocking the synthesis of ergosterol, and griseofulvin is a fungistatic drug that inhibits nucleic acid synthesis, arrests cell division at metaphase, and impairs synthesis of the cell wall. Side-effects include diarrhea, nausea, vomiting, and elevated liver enzymes, which are mild and reversible. Griseofulvin (10–25 mg/kg/day) is recommended to be administered for 6–8 weeks, terbinafine (10–20 kg: 62.5 mg/day; 20–40 kg: 125 mg/day; >40 kg: 250 mg/day) for 4 weeks and itraconazole (5 mg/kg/day) for 4–6 weeks.36,37 If there is no clinical improvement after this treatment duration, switching to an alternative treatment should be considered. While laboratory monitoring for griseofulvin is unnecessary when terbinafine or itraconazole is used for more than 4 weeks, baseline evaluation of liver function and full blood counts are recommended.38 Selenium sulfide, zinc pyrithione, povidone–iodine, or ketoconazole shampoos are recommended to be applied to scalp and hair for 5 minutes twice weekly for 2–4 weeks helping to prevent spread in the early phases of therapy. In children with extensive kerions, it is recommended to remove the crusts before initiation of systemic antifungal treatment. Early short course of oral corticosteroids (1 mg/kg/day) being tapered to withdraw in 10 days may be used in severe cases of kerion in order to reduce the inflammation.39 Following up patients include clinical and mycological examinations, which should be performed at intervals of 2–4 weeks. The treatment should be stopped after the culture becomes negative or when clinically hair regrowth is noted.24 Some infection control measures are advised. Bed linen, towels and hats should not be shared. Keeping children out of

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school after starting therapy is controversial. It is suggested that children should, for practical reasons, be allowed back to school or daycare once treatment has been initiated with oral and topical agents.37

Syphilitic Alopecia Syphilitic alopecia may present with other mucocutaneous symptoms of secondary syphilis or be its only presenting feature. Its diagnosis should always be kept in mind, especially in sexually active patients.40 The immune response to Treponema pallidum, or its presence, is related to this non-scarring alopecia.41 The pattern of hair loss can be moth-eaten, diffuse, or both. The “moth-eaten” type is the most common one and is characteristic of secondary syphilis. Differential diagnosis includes trichotillomania, tinea capitis, alopecia areata, and systemic lupus.42 Positive serological tests and empty follicles and broken hairs are seen on trichoscopy lead to the correct diagnosis.41 Syphilitic alopecia is treated with single intramuscular injections of benzathine penicillin (2.4 million units) and usually resolves within 3 months of treatment.43

Pediculosis Capitis Pediculosis capitis is a very common infestation caused by the head louse (Pediculus humanus capitis). It has a worldwide distribution and affects individuals of all ages and socioeconomic classes.44 It is more common among children between 3 and 11 years of age and in girls. It is rare in African Americans, probably due to the twisted nature and the width of their hair shaft.45 The adult head louse is an 1–3 mm long grayish arthropod. It has three pairs of clawed legs. It moves only by crawling; it cannot hop or fly since it is wingless. The life span of the adult female louse is about 30 days. During this time, it produces 5–10 eggs (nits) per day and “glues” them at the base of the hair shafts close to the scalp, where the temperature is optimal for incubation. The eggs are oval and 0.8 mm long. Initially they are translucent; after 8 days they hatch and become white and more visible. The released nymphs require 9–12 days to mature and reach the adult stage. The hatched empty egg shells remain in place moving away from the scalp as the hair grows.46 Head lice are obligate human parasites feeding every few hours by sucking blood while simultaneously they inject saliva. Without blood meals, they can survive for up to 2–3 days off the host.47 Transmission in most cases occurs by direct head-to-head contact with an already infested person. Indirect transmission via fomites (such as brushes, combs, hair accessories, bedding, helmets, and headgear) may also happen but more rarely.48 Pruritus is the most common symptom of head lice infestation and it occurs as a result of sensitization to components of the lice saliva. When a person is infested for the first time, it may take 4–6 weeks until pruritus is evident, but in repeat infestations, pruritus appears within the first 24–48 hours. However, some individuals remain asymptomatic.49

FIGURE 27.4  Nits in a patient with pediculosis.

In clinical examination, in addition to lice and nits (Figure  27.4), excoriations, erythema, and scaling may be seen on the scalp, neck, and postauricular skin (Figure 27.5). Posterior cervical lymphadenopathy with intense local pruritus is also a common finding. In heavy infestation cases with severe scratching, secondary staphylococcal infection may occur. The diagnosis of head lice infestation is made clinically and is confirmed by finding at least one live louse on the scalp or hair of a person.49 However, this may be difficult only via visual inspection of the scalp because lice avoid light and crawl quickly. Finding live lice is better achieved by combing wet or dry hair with a fine-toothed nit comb (teeth of comb 0.2 mm apart).50 Nits are more easily seen than lice, but the presence of nits alone does not confirm the active disease. If they are within 0.65 cm of the scalp, an active infestation is more likely.51 The diagnosis of lice can sometimes be confirmed with the use of a dermatoscope,52 a magnifying lens or a microscope. Furthermore, Wood’s lamp examination of the infested area shows yellow-green fluorescence of lice and nits. Nits may be confused with dandruff, hair spray droplets, and hair casts. These particles are easily moved along the hair shaft in contrast with nits which are firmly attached to the hair shafts.53 Treatment for pediculosis capitis is recommended for individuals with an active infestation.49 Scientifically proven

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of action. The safety and easy availability of pyrethroids and malathion have led to their widespread use as first-line drugs. Recently, a large number of studies from several countries have shown resistance to these agents.58,59 In such cases, benzyl alcohol, spinosad, topical ivermectin, and lately dimethicone are effective alternative therapies.49,60 In topical therapy-resistant cases, oral ivermectin is a treatment option.61 It is noteworthy that psychically acting pediculicides (e.g. benzyl alcohol and dimethicone) cannot cause resistance development due to their mode of action. Depending on each drug’s mode of action, each pediculicide may be solely pediculicidal or both pediculicidal and ovicidal. Since no pediculicide is 100% ovicidal, a second treatment 7–10 days after the initial treatment can increase the probability of nit eradication.49 In addition to the index case, all close contacts should be examined and treated concurrently if found infested. Washing clothing and bed linen used by the infested person during the 2 days prior to therapy in hot water and drying the items on a high-heat dryer cycle is prudent. Temperatures should reach >50°C. Items that cannot be washed may be dry-cleaned or stored in a sealed plastic bag for 2 weeks (e.g. stuffed animals). Vacuuming of furniture and carpeting on which the infested person sat or laid down has also been suggested, even if the risk of transmission from these sites is low. Spraying the home with a pediculicide is not recommended.62

FIGURE 27.5  Erythema and crusting in pediculosis.

Scabies

treatment options for head lice include wet combing and other nonchemical methods, topical pediculicides, and oral therapy. Among the nonchemical treatments for head lice, the one most extensively studied is wet combing. It can be used for patients who are too young for pediculicide treatment or who desire to avoid pediculicide therapy. The hair should be wet, with an added lubricant such as hair conditioner and combing is performed with a fine-toothed comb.54 The procedure should be repeated once every 3–4 days for several weeks and should be continued for 2 weeks after any session in which an adult louse is found. While wet combing can be used as an adjuvant to topical insecticidal therapy, is not by itself sufficient in most situations.46 Other physical methods such as hot air treatments and varying occlusive methods (e.g., with plant-derived oils) have not been studied extensively and seem to have limited efficacy in lice treatment.55,56 Further, the old-time classic approach of shaving one’s head can be traumatic psychologically for both boys and girls. Pediculicides remain the most effective treatment for head lice. The choice of a specific pediculicide should be based on patient age, safety, side effects, ease of use, and efficacy (Table  27.1). In addition, since there is marked geographical variability in the prevalence of pediculicide resistance, the selection of a topical pediculicide should involve consideration of local resistance patterns.57 Multiple topical agents have been developed to date with neurotoxic or physical (i.e. suffocation of the louse) mode

Scabies is a contagious and pruritic infestation of the skin associated with Sarcoptes scabiei var. hominis. Finger webs, wrists, axillary folds, abdomen, buttocks, inframammary folds, and male genitalia are usually affected.63 Scalp often is involved in infants and very young children. Scalp involvement is rarely seen in adults, usually in the setting of immunosuppression and connective tissue disease, the so-called crusted or “Norwegian” scabies.64 However, immunosuppression is not always needed for scalp scabies. Clinically scabies involving the scalp mimic seborrhoeic dermatitis.65 Pruritus is the hallmark of the disease. Its pathognomonic sign is the burrow; a short, wavy, scaly, grey line on the skin surface, whereas other non-specific lesions may be present, such as papules, vesicles, and excoriations.66 A KOH smear from the scalp offers a simple and reliable technique for diagnosis. Especially in the case of crusted scabies, due to the large numbers of mites being present, using skin scraping is easier to achieve diagnosis than in classic scabies. The dermoscopic findings “triangle sign,” which represents the “head” portion of the mite, and “the delta wing jet with contrail” sign, corresponding to the head of the mite and the trailing burrow, is used to confirm the diagnosis.67 As the hair-bearing areas of the scalp are rarely considered to be a site of scabies infestations among adult patients, topical treatments are not applied to this area leading to treatment failures.68 Treatment is similar to that of classic scabies, including available topical scabicidal agents such as benzyl benzoate, permethrin, crotamiton, and sulfur.64 Nevertheless, crust and scale removal are considered necessary for the topical treatment

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TABLE 27.1 Different Agents Used for Pediculosis Capitis Treatment Drug

Mode of Action

Age Group

Regimen

Side Effects/Precautions

Resistance

Pyrethrins with piperonyl butoxide Permethrin (1% and 5%)

Neurotoxin; pediculicidal

≥2 years

≥2 months

Skin irritation; avoid in patients with chrysanthemum or ragweed allergy; safe in pregnancy Skin irritation; category B for pregnancy

Common

Neurotoxin; pediculicidal

Malathion (0.5% lotion or gel)

Neurotoxin; both pediculicidal and ovicidal

≥6 years; contraindicated in