Clinical Cases in Pigmentary Disorders [1st ed.] 9783030508227, 9783030508234

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Clinical Cases in Pigmentary Disorders [1st ed.]
 9783030508227, 9783030508234

Table of contents :
Front Matter ....Pages i-viii
15-Year-Old Female with Palmar, Periorbital, Oral Mucosal, and Gingival Hyperpigmentation (Mahin Alamgir, Britney N. Wilson, Young Lee, Babar Rao)....Pages 1-4
A 5-Year-Old Boy with White Spots on His Trunk, Acne, and Pink Urine (Mahin Alamgir, Britney N. Wilson, Babar Rao)....Pages 5-8
A 58-Year-Old Male with Bronze Hyperpigmented Skin Over the Nape of the Neck and Extremities (Britney N. Wilson, Mahin Alamgir, Babar Rao)....Pages 9-12
Hypomelanotic Diffuse Macules in a 13 Years Old Boy (Pierangela Rana, Fabio Arcangeli)....Pages 13-15
White Maculo-papular Lesions in a 13-Year-Old Boy (Annalisa Franch, Fabio Arcangeli)....Pages 17-20
A 6-Year-Old Child with Patches of Discoloration (Seyyede Zeinab Azimi, Alireza Firooz)....Pages 21-24
A 23-Year-Old Girl with White Hair from Birth (Seyyede Zeinab Azimi, Alireza Firooz)....Pages 25-28
A Patient with Acrofacial Depigmentation and Chronic Fatigue (Mirna àitum, Vedrana Bulat, Maja Kovačević, Andy Goren)....Pages 29-32
Erythematous Spot in a Young Female Patient with Generalised Hypopigmentation (Mirna àitum, Vedrana Bulat, Maja Kovačević, Andy Goren)....Pages 33-39
Progressive Reticulated Pigmentation of the Folds (Katerina Damevska, Anastasiya Atanasova Chokoeva, Ivana Dohcheva Karajovanov, Anita Najdova)....Pages 41-46
Multiple Café-Au-Lait Macules Since Birth (Xue-Gang Xu, Ya-Xin Guo, Xing-Hua Gao)....Pages 47-52
A Teenager with Sudden and Localized Hair Graying (Özgür Gündüz)....Pages 53-57
A Middle-Aged Female with Hyperpigmentation (Johannes F. Dayrit, Maria Juliet Enriquez-Macarayo, Evangeline B. Handog)....Pages 59-64
Generalized Mottled Hyperpigmentation in a 28-Year-Old Filipino Woman (Johannes F. Dayrit, Maria Juliet Enriquez-Macarayo, Evangeline B. Handog)....Pages 65-69
A Young Man with Pigmentation on the Tongue (Marta Kurzeja, Małgorzata Olszewska, Lidia Rudnicka)....Pages 71-74
Larval Secretions and Dark Facial Spots (Zekayi Kutlubay, N. Deniz Esin, Defne Özkoca, Ümit Türsen, Erdal Polat)....Pages 75-78
Dark Facial Spots and Rash (Lawrence Chukwudi Nwabudike, Alin Laurentiu Tatu)....Pages 79-81
The Dermatologist’s Fingernail (Lawrence Chukwudi Nwabudike, Alin Laurentiu Tatu, Diana Sabina Radaschin, Valeriu Ardeleanu)....Pages 83-87
A Young Female with Hyperpigmentation on Face Showed Few Weeks Before Visit (Sudip Parajuli, Upama Paudel, Anil Kumar Das, Dinesh Binod Pokhrel)....Pages 89-93
A Six-Year Boy with Hypopigmented Lesions on the Neck, Retroauricullary, and on the Lateral Face (Asja Prohic)....Pages 95-97
Homogenous Black Pigmented Lesion of the Fifth Toe (Alin Laurentiu Tatu, Diana Sabina Radaschin, Florin Ciprian Bujoreanu, Lawrence Chukwudi Nwabudike)....Pages 99-102
Piperine Extract and White Patches (Alin Laurentiu Tatu, Bianca Mihaila, Rodica Dinica, Olimpia Dumitriu Buzia, Diana Sabina Radaschin, Lawrence Chukwudi Nwabudike)....Pages 103-107
Repigmentation of Palpebral White Patch (Diana Sabina Radaschin, Alin Laurentiu Tatu, Lawrence Chukwudi Nwabudike, Valeriu Ardeleanu)....Pages 109-113
A Case of Dark Spots in a 57-Year-old Female (Nguyen Van Thuong, Le Huu Doanh, Michael Tirant)....Pages 115-118
A Challenging Variant of Hyperpigmentary Disorders (Nguyen Van Thuong, Le Huu Doanh, Michael Tirant)....Pages 119-121
A Child with Hypopigmented Patches (Le Huu Doanh, Nguyen Van Thuong, Michael Tirant)....Pages 123-126
A Woman with Facial Hypopigmented Macules (Nguyen Van Thuong, Le Huu Doanh, Michael Tirant)....Pages 127-130
A Woman with Progressive Diffuse Symmetric Hyper and Hypopigmentation (Le Huu Doanh, Nguyen Van Thuong, Michael Tirant)....Pages 131-135
A Young Woman with Facial Hyperpigmented Macules (Le Huu Doanh, Nguyen Van Thuong, Michael Tirant)....Pages 137-140
Asymptomatic Hyperpigmentation Without Preceding Inflammation in a Female (Le Huu Doanh, Nguyen Van Thuong, Michael Tirant)....Pages 141-143
Brown Patches in a 51-Year-Old Man (Nguyen Van Thuong, Le Huu Doanh, Michael Tirant)....Pages 145-148
Dyschromatosis in a 23-Year-Old Male (Le Huu Doanh, Nguyen Van Thuong, Michael Tirant)....Pages 149-151
Facial Hypopigmentation in a Vietnamese Woman (Le Huu Doanh, Nguyen Van Thuong, Michael Tirant)....Pages 153-155
An Elderly Masked Man (Yasemin Yuyucu Karabulut, Gözde Arslan, Ahmet Çelik, Ümit Türsen)....Pages 157-161
Hyperpigmented Plaques (Emin Gündüz, Ümit Türsen, Yasemin Yuyucu Karabulut)....Pages 163-167
A Painful White Streak on the Leg (Uwe Wollina)....Pages 169-171
A Pruritic Erythematous Rash After Childbirth (Uwe Wollina)....Pages 173-175
A Reddish-Brownish Pruriginous Plaque on the Trunk (Uwe Wollina)....Pages 177-179
Fever and Generalized Erythema with Multiple Macular Hypopigmentations (Uwe Wollina)....Pages 181-184
Multiple Macular Hypopigmentations on the Lower Legs (Uwe Wollina)....Pages 185-187
Painful Discoloured Great Toe of a Young Man (Uwe Wollina)....Pages 189-191
Reddish Brown Nodules and Plaques in an Elderly Man with Prostate Cancer (Uwe Wollina)....Pages 193-196
Whitish Translucent Papules and Plaques on Fingers and Palms (Uwe Wollina)....Pages 197-200
Yellowish Axillary Hair (Uwe Wollina)....Pages 201-203
Hypopigmented Facial Patches in a 44-Year-Old Female (Fariba Ghalamkarpour, Shirin Zaresharifi, Zahra Asadi-Kani)....Pages 205-209
Back Matter ....Pages 211-213

Citation preview

Clinical Cases in Dermatology Series Editor: Robert A. Norman

Torello Lotti Michael Tirant Davinder Parsad Editors

Clinical Cases in Pigmentary Disorders

Clinical Cases in Dermatology Series Editor Robert A. Norman Tampa, FL, USA

This series of concise practical guides is designed to facilitate the clinical decision-­ making process by reviewing a number of cases and defining the various diagnostic and management decisions open to clinicians. Each title is illustrated and diverse in scope, enabling the reader to obtain relevant clinical information regarding both standard and unusual cases in a rapid, easy to digest format. Each focuses on one disease or patient group, and includes common cases to allow readers to know they are doing things right if they follow the case guidelines. More information about this series at http://www.springer.com/series/10473

Torello Lotti • Michael Tirant • Davinder Parsad Editors

Clinical Cases in Pigmentary Disorders

Editors Torello Lotti Dermatology University of Rome Guglielmo Marconi Rome Italy Davinder Parsad Department of Dermatology Postgraduate Institute of Medical Education and Research Chandigarh India

Michael Tirant Dermatology University of Rome Guglielmo Marconi Rome Italy Department of Dermatology Hanoi Medical University Hanoi Vietnam

Clinical Cases in Dermatology ISBN 978-3-030-50822-7    ISBN 978-3-030-50823-4 (eBook) https://doi.org/10.1007/978-3-030-50823-4 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

1 15-Year-Old Female with Palmar, Periorbital, Oral Mucosal, and Gingival Hyperpigmentation ����������������������������������������������������������    1 Mahin Alamgir, Britney N. Wilson, Young Lee, and Babar Rao 2 A 5-Year-Old Boy with White Spots on His Trunk, Acne, and Pink Urine ����������������������������������������������������������������������������������������    5 Mahin Alamgir, Britney N. Wilson, and Babar Rao 3 A 58-Year-Old Male with Bronze Hyperpigmented Skin Over the Nape of the Neck and Extremities ��������������������������������    9 Britney N. Wilson, Mahin Alamgir, and Babar Rao 4 Hypomelanotic Diffuse Macules in a 13 Years Old Boy ����������������������   13 Pierangela Rana and Fabio Arcangeli 5 White Maculo-papular Lesions in a 13-Year-Old Boy ������������������������   17 Annalisa Franch and Fabio Arcangeli 6 A 6-Year-Old Child with Patches of Discoloration ������������������������������   21 Seyyede Zeinab Azimi and Alireza Firooz 7 A 23-Year-Old Girl with White Hair from Birth����������������������������������   25 Seyyede Zeinab Azimi and Alireza Firooz 8 A Patient with Acrofacial Depigmentation and Chronic Fatigue��������   29 Mirna Šitum, Vedrana Bulat, Maja Kovačević, and Andy Goren 9 Erythematous Spot in a Young Female Patient with Generalised Hypopigmentation�����������������������������������������������������������������������������������   33 Mirna Šitum, Vedrana Bulat, Maja Kovačević, and Andy Goren 10 Progressive Reticulated Pigmentation of the Folds������������������������������   41 Katerina Damevska, Anastasiya Atanasova Chokoeva, Ivana Dohcheva Karajovanov, and Anita Najdova

v

vi

Contents

11 Multiple Café-Au-Lait Macules Since Birth������������������������������������������   47 Xue-Gang Xu, Ya-Xin Guo, and Xing-Hua Gao 12 A Teenager with Sudden and Localized Hair Graying������������������������   53 Özgür Gündüz 13 A Middle-Aged Female with Hyperpigmentation��������������������������������   59 Johannes F. Dayrit, Maria Juliet Enriquez-Macarayo, and Evangeline B. Handog 14 Generalized Mottled Hyperpigmentation in a 28-Year-Old Filipino Woman����������������������������������������������������������   65 Johannes F. Dayrit, Maria Juliet Enriquez-Macarayo, and Evangeline B. Handog 15 A Young Man with Pigmentation on the Tongue����������������������������������   71 Marta Kurzeja, Małgorzata Olszewska, and Lidia Rudnicka 16 Larval Secretions and Dark Facial Spots����������������������������������������������   75 Zekayi Kutlubay, N. Deniz Esin, Defne Özkoca, Ümit Türsen, and Erdal Polat 17 Dark Facial Spots and Rash��������������������������������������������������������������������   79 Lawrence Chukwudi Nwabudike and Alin Laurentiu Tatu 18 The Dermatologist’s Fingernail��������������������������������������������������������������   83 Lawrence Chukwudi Nwabudike, Alin Laurentiu Tatu, Diana Sabina Radaschin, and Valeriu Ardeleanu 19 A Young Female with Hyperpigmentation on Face Showed Few Weeks Before Visit����������������������������������������������������������������������������   89 Sudip Parajuli, Upama Paudel, Anil Kumar Das, and Dinesh Binod Pokhrel 20 A Six-Year Boy with Hypopigmented Lesions on the Neck, Retroauricullary, and on the Lateral Face����������������������   95 Asja Prohic 21 Homogenous Black Pigmented Lesion of the Fifth Toe������������������������   99 Alin Laurentiu Tatu, Diana Sabina Radaschin, Florin Ciprian Bujoreanu, and Lawrence Chukwudi Nwabudike 22 Piperine Extract and White Patches������������������������������������������������������  103 Alin Laurentiu Tatu, Bianca Mihaila, Rodica Dinica, Olimpia Dumitriu Buzia, Diana Sabina Radaschin, and Lawrence Chukwudi Nwabudike 23 Repigmentation of Palpebral White Patch��������������������������������������������  109 Diana Sabina Radaschin, Alin Laurentiu Tatu, Lawrence Chukwudi Nwabudike, and Valeriu Ardeleanu

Contents

vii

24 A Case of Dark Spots in a 57-Year-old Female ������������������������������������  115 Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant 25 A Challenging Variant of Hyperpigmentary Disorders������������������������  119 Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant 26 A Child with Hypopigmented Patches ��������������������������������������������������  123 Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant 27 A Woman with Facial Hypopigmented Macules ����������������������������������  127 Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant 28 A Woman with Progressive Diffuse Symmetric Hyper and Hypopigmentation����������������������������������������������������������������  131 Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant 29 A Young Woman with Facial Hyperpigmented Macules����������������������  137 Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant 30 Asymptomatic Hyperpigmentation Without Preceding Inflammation in a Female ����������������������������������������������������������������������  141 Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant 31 Brown Patches in a 51-Year-Old Man����������������������������������������������������  145 Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant 32 Dyschromatosis in a 23-Year-Old Male��������������������������������������������������  149 Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant 33 Facial Hypopigmentation in a Vietnamese Woman������������������������������  153 Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant 34 An Elderly Masked Man ������������������������������������������������������������������������  157 Yasemin Yuyucu Karabulut, Gözde Arslan, Ahmet Çelik, and Ümit Türsen 35 Hyperpigmented Plaques������������������������������������������������������������������������  163 Emin Gündüz, Ümit Türsen, and Yasemin Yuyucu Karabulut 36 A Painful White Streak on the Leg��������������������������������������������������������  169 Uwe Wollina 37 A Pruritic Erythematous Rash After Childbirth����������������������������������  173 Uwe Wollina 38 A Reddish-Brownish Pruriginous Plaque on the Trunk����������������������  177 Uwe Wollina 39 Fever and Generalized Erythema with Multiple Macular Hypopigmentations������������������������������������������  181 Uwe Wollina

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Contents

40 Multiple Macular Hypopigmentations on the Lower Legs������������������  185 Uwe Wollina 41 Painful Discoloured Great Toe of a Young Man������������������������������������  189 Uwe Wollina 42 Reddish Brown Nodules and Plaques in an Elderly Man with Prostate Cancer����������������������������������������������������������������������  193 Uwe Wollina 43 Whitish Translucent Papules and Plaques on Fingers and Palms������  197 Uwe Wollina 44 Yellowish Axillary Hair����������������������������������������������������������������������������  201 Uwe Wollina 45 Hypopigmented Facial Patches in a 44-Year-Old Female��������������������  205 Fariba Ghalamkarpour, Shirin Zaresharifi, and Zahra Asadi-Kani Index�������������������������������������������������������������������������������������������������������������������� 211

Chapter 1

15-Year-Old Female with Palmar, Periorbital, Oral Mucosal, and Gingival Hyperpigmentation Mahin Alamgir, Britney N. Wilson, Young Lee, and Babar Rao

A 15-year-old Asian female presents to the emergency room due to a 4-month history of increasing fatigue, nausea, and vomiting. She vomited between 3 and 12 times a day and displayed signs of dehydration due to her inability to tolerate oral intake. She also complained of a 12 lb weight loss despite no changes in diet and a sense of lightheadedness when she stands abruptly. She was diagnosed with alopecia areata 2 years ago and was treated with monthly intralesional triamcinolone injections for 3 months. Physical examination of the scalp revealed three well-defined patches of hair loss without scarring. Further examination revealed hyperpigmentation of the area around the eyes, dorsa of the hands, palmar creases, buccal mucosa, oral cavity, and gingiva (Figs. 1.1 and 1.2). The patient reported this hyperpigmentation has worsened over the last year. Her temperature is 99.7 °F, pulse is 89/min, and blood pressure is 101/67 mmHg. Her pregnancy test came back negative, sodium level was 127 mEq/L, potassium was 5.6  mEql/L, thyroid-stimulating hormone was 4.2  μU/mL, AM cortisol was 1 μg/dL. Dermatology was consulted. What’s your diagnosis?

M. Alamgir (*) · B. Rao Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA B. N. Wilson New Jersey Medical School, Newark, NJ, USA Y. Lee Chungnam National University, Daejeon, South Korea © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_1

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Fig. 1.1  Hyperpigmentation of the palms, a common finding in Addison’s disease. Image courtesy of Dr Young Lee and Dr Jeung-Hoon Lee, Professor Emeritus, Chungnam National University, Daejeon, South Korea Fig. 1.2 Hyperpigmentation of the oral mucosa, another characteristic finding of Addison’s disease. Image courtesy of Dr Young Lee and Dr Jeung-Hoon Lee, Professor Emeritus, Chungnam National University, Daejeon, South Korea

Differential Diagnoses 1. Addison’s disease 2. Cushing’s disease 3. Peutz-Jeghers Syndrome

1  15-Year-Old Female with Palmar, Periorbital, Oral Mucosal, and Gingival…

3

Diagnosis Addison disease.

Discussion Addison’s disease is an insidious syndrome resulting from primary adrenocortical insufficiency [1]. In the US, the most common cause of primary adrenocortical insufficiency is autoimmune adrenalitis, which may occur sporadically or as a manifestation of polyglandular autoimmune syndromes such autoimmune thyroiditis and type 2 diabetes mellitus. Infectious adrenalitis due to tuberculosis is the most common cause of primary adrenal insufficiency world-wide, though rare in the US [2]. Other causes of Addison’s disease include adrenal hemorrhage and adrenalectomy. Addison’s disease causes various symptoms including progressive generalized bronze hyperpigmentation, slowly progressive weakness, fatigue, anorexia, nausea, vomiting and diarrhea [1]. Patients can also present with loss of libido as a result of hypoandrogenism. Patients with primary adrenal insufficiency develop hyperkalemia and hyponatremia because mineralocorticoids stimulate sodium reabsorption and potassium excretion; thus a deficiency results in increased excretion of sodium and decreased excretion of potassium. Glucocorticoid deficiency contributes to hypotension as cortisol upregulates α1 receptors in arterioles and increases their sensitivity to norepinephrine and epinephrine. Hyperpigmentation is a result of increased levels of adrenocorticotropic hormone (ACTH), a hormone released from the anterior pituitary. ACTH, γ- and β-lipotropin, β-endorphin, and melanocyte-stimulating hormone (MSH) share a common precursor hormone, pro-opiomelanocortin (POMC) [3]. In primary adrenal insufficiency, POMC production is strongly increased in response to the drop in cortisol levels along with concomitant release of MSH causing bronze hyperpigmentation of the skin and oral mucosa [4]. Diagnosis is based on clinical presentation, laboratory studies, and endocrine evaluation. Morning serum cortisol levels: 12 g/dL were met. He reported an improvement of all symptoms and now receives phlebotomy every 3 months.

Key Points • Primary hereditary hemochromatosis presents as a classic triad of diabetes mellitus, hepatomegaly, and bronze hyperpigmentation, • Hemochromatosis is present in 1–2% of all diabetic patients, and diabetes is often the first clinical manifestation of the disease. • Early recognition and treatment can delay the onset of systemic manifestation such as diabetes, arthralgias, and cirrhosis.

References 1. Salgia RJ, Brown K. Diagnosis and management of hereditary hemochromatosis. Clin Liver Dis. 2015;19(1):187–98. 2. Nicolaidou E, Katsambas AD. Pigmentation disorders: hyperpigmentation and hypopigmentation. Clin Dermatol. 2014;32(1):66–72. 3. Chacon AH, Morrison B, Hu S. Acquired hemochromatosis with pronounced pigment deposition of the upper eyelids. J Clin Aesthet Dermatol. 2013;6(10):44–6. 4. Wolff K, Johnson R, Saavedra AP, Roh EK. Fitzpatrick’s color atlas and synopsis of clinical dermatology, 8e. New York: McGraw-Hill; 2017. 5. Marks JG, Miller JJ. 1—Introduction. In: Marks JG, Miller JJ, editors. Lookingbill and Marks’ principles of dermatology. 6th ed. London: Elsevier; 2019. 6. Barton JC, Corwin QE. Hemochromatosis: genetics, pathophysiology, diagnosis and treatment. Cambridge: Cambridge University Press; 2000. 7. Raju K, Venkataramappa SM. Primary hemochromatosis presenting as type 2 diabetes mellitus: a case report with review of literature. Int J Appl Basic Med Res. 2018;8(1):57–60.

Chapter 4

Hypomelanotic Diffuse Macules in a 13 Years Old Boy Pierangela Rana and Fabio Arcangeli

Mahesh is a 13 year old orphan. His parents died due to AIDS but he is HIV negative. He presents a lot of diffuse hypopigmented large macules (3–12 cm in diameter) with shaded and flat edges. They have increased in number and diameter since 1 year ago, involving his extremities, face, buttocks and back (Fig. 4.1). Based on the case description and the photograph, what is your diagnosis? 1. Vitiligo 2. Leprosy 3. Pityriasis versicolor 4. Tuberous sclerosis 5. Postinflammatory hypopigmentation (e.g. Pityriasis alba) Pin test (to prick the white skin) was positive (it means a decrease sensitivity to pain). There was nodular infiltration along the ulnar nerve at elbow level. Punch biopsy of hypopigmented macule on the trunk shows part of the skin with mild net ridge and sub-epithelial perivascular lymphocytic collections. Histological features indicate a possible diagnosis of indeterminate leprosy.

Diagnosis Indeterminate leprosy

P. Rana Pediatrics, Azienda USL BAT, Barletta Andria Trani, Bari, Italy F. Arcangeli (*) University Unit of Dermatology and Regenerative Medicine, University of Rome Guglielmo Marconi, Rome, Italy © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_4

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Fig. 4.1  Multiple flat hypopigmented lesions on back

Discussion Leprosy or Hansen’s disease is a chronic infection caused by Mycobacterium leprae, which affects the skin and peripheral nerves in various ways and degrees. Mycobacterium leprae is an obligate intracellular bacterium, not particularly pathogenic but very immunogenic, which multiplies slowly, especially in the skin and peripheral nerves. The intensity of the cellular immune responses of the organism determines the clinical presentation of the disease. In individuals who have a vigorous cellular immune response the disease shows only one or few lesions in which the Mycobacterium leprae are very rare, the number of skin lesion is limited and nerve involvement is usually asymmetric (tuberculoid form). In individuals with minimal cellular immune response, the Mycobacterium leprae disseminates to the whole organism. Extensive skin involvement is observed and nerve involvement tends to be symmetrical in distribution (lepromatous form) [1]. Indeterminate form is the most benign form, it can evolve towards one of the two extremities (tuberculoid or lepromatous form), remain stable or heal completely. It manifests itself with the appearance of one or more macular cutaneous lesions, with clear margins, hypochromic and / or erythematous, sometimes with focal hypoesthesia.

4  Hypomelanotic Diffuse Macules in a 13 Years Old Boy

15

Hypomelanotic macules may be the earliest sign of leprosy. The hypopigmented patches of Tuberculoid leprosy are large with raised or infiltrated borders. They are asymmetrically distributed on the extremities, buttocks, back and face. There is often an associated loss of tactile sensations. In Lepromatous leprosy the lesions are usually small and multiple, subtle and quite defined. They favor extremities, face and buttocks and exhibit little or no loss of feeling. In Indeterminate leprosy the macules always have flat and well or ill defined borders. They are asymmetrically distributed, mainly on exposed sites and may be hypoesthetic or anesthetic. These lesions may regress spontaneously or evolve in lepromatous or tuberculoid leprosy. Systemic treatment usually results in repigmentation [2]. Our patient, according to the Multidrug Therapy Plan Recommended by the WHO [3], was treated with Rifampicin 600 mg monthly and Dapson 100 mg daily. Isolation was not necessary because after the treatment has started the patient is no longer contagious. About differential diagnosis we have to consider that: –– Hypomelanotic macules of vitiligo are symmetrically distributed, mainly in the periorificial sites of the face, distal extremities, armpits, elbows and knees. Their borders are well defined and there is no sensitivity alteration. –– Pityriasis versicolor shows little lenticular macules on the trunk, sometimes confluent and always with well defined edges and no hypoesthesia. –– White macules of Tuberous sclerosis are usually small in size, oval or lenticular shaped or shaped like ash leaf. No hypoesthesia was noticed. –– Postinflammatory hypopigmentation presented macules with ill defined borders, variable distribution and shape. Previous inflammatory lesions are always present and, like every other disease described above, lack hypoesthesia.

Key Points –– –– –– ––

Leprosy Hypomelanotic macules Early signs of leprosy Hypoesthesia in leprosy

References 1. Reibel F, Cambau E, Aubry A. Update on epidemiology, diagnosis and treatment of leprosy. Medecine et Maladies. 2015;45(9):383–93. 2. Ferri FF.  Leprosy. Ferri’s clinical advisor 2015, 5 books in 1. Philadelphia, PA.  Elsevier/ Mosby; 2015. 687 3. The World Health Organization. Diagnosis of leprosy. Leprosy elimination. Available at http:// www.who.int/lep/diagnosis/en/. Accessed 15 Apr 2016.

Chapter 5

White Maculo-papular Lesions in a 13-Year-Old Boy Annalisa Franch and Fabio Arcangeli

A 13-year-old boy came for a medical examination because of a few whitish maculo-­ papular lesions on his abdomen (Fig. 5.1). There were approximately ten of these lesions, ranging from 2 to 5 mm wide, and exclusively localized on the abdominal wall. They were ivory white in color, with a smooth surface and a hard consistency. The patient did not show any symptoms, and has always been in good health, with the exception of chickenpox, which he caught and recovered from 8 months before. Based on the case description and the photograph, what is your diagnosis? 1. Chickenpox scarring 2. Lichen sclerosus and atrophicus 3. Something else ? Punch biopsy was performed and histological examination showed epidermal and dermal atrophy with disappearance of the skin appendages.

Diagnosis Localized scleroderma (guttate morphoea) Chickenpox scarring was quite an interesting hypothesis, but there were no topographical correspondence with the former chickenpox lesions. Even Lichen

A. Franch Pediatrics, Azienda USL Alto Adige, Alto Adige, Italy F. Arcangeli (*) University Unit of Dermatology and Regenerative Medicine, University of Rome Guglielmo Marconi, Rome, Italy © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_5

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Fig. 5.1 Whitish maculo-papular lesions on the abdominal wall

Fig. 5.2 Maculo-papular lesion with lilac-ring on the patient’s face

sclerosus et atrophicus could be excluded because it usually shows typical genital area lesions and is itchy. Subsequent blood tests resulted regular and no therapy was performed. After 2½ years, the boy came back because of asthenia and abdominal pain. On that occasion it was noted that abdominal lesions were still present but less defined. A new maculo-papular ivory white lesion, about 5 mm wide, with smooth surface, hard consistency and a violaceous peri-lesional ring (lilac-ring) had appeared on his face. Two other smaller lesions with an hyperpigmented peri-lesional border on the left arm were present (Fig. 5.2). All blood chemistry tests (including CBC, inflammation indexes, ANA, RF, ATA, anti Scl-70, ACA, faecal calprotectin) had normal results. An examination by a surgeon and abdominal US also showed nothing relevant. The subsequent gastroenterological examination and MR enterography did not show any signs of pathological situations.

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Discussion Localized scleroderma constitutes a group of rare diseases characterized by excessive collagen deposition leading to thickening of the dermis, subcutaneous tissues, or both. Its incidence is about 1–3 new cases/year/100,000 subjects in the pediatric age [1]. As shown by extensive evidence, it is likely to have an autoimmune origin. In order to be expressed, it needs a triggering factor in a genetically predisposed individual. In our case, most probably, chickenpox worked as a trigger. Clinically, it is characterized by hardened and thinned areas of skin, variable in size and morphology, with a smooth surface, ivory-white color, hard consistency and a lilac-ring, which is only present in the disease’s active phases. Usually localized scleroderma diagnosis is made on a clinical basis. There are no specific laboratory markers and the histological analysis is reserved for particular cases. There are various different types of localized scleroderma. Plaque morphea is the most benign type, the second most frequent in the pediatric age, mainly localized on the trunk. There are five sub variations, among which is the rare guttate form. In the pediatric age the most frequent and severe is linear scleroderma. Typically localized on the limbs and less frequently on the face, it can lead to reforming and disfiguring outcomes. Generalized morphea, deep morphea and mixed forms are all very rare and very severe forms [2]. The majority of localized scleroderma affects patients, regardless of the severity of the subtype, reaches a complete remission in 5–6 years. One or more disease recurrences are possible and may be complicated by extracutaneous manifestations (25% of patients) or by comorbidity [3]. Our patient had a recurrent episode of illness about 2 years after the first appearance and he suffered a painful gastro-enterical condition, which occurs in about 6% of cases. The blood test negative and the absence of internal organs involvement allowed to exclude systemic sclerosis. The guttate morphea our patient showed did not require any particular therapy, since the tissue damage was minimal. The most severe forms, such as the progressive linear scleroderma (which may involve joint lines or facial features en coup de Sabre) and generalized or deep subtypes, need therapy. In these cases it needs to be as timely and effective as possible, in order to stop the inflammation and stabilize the tissue damage before it becomes irreversibly disabling or disfiguring.

Key Points • Localized scleroderma (guttate morphoea) is a cutaneous inflammatory disease, of a presumably autoimmune origin, which leads to an abnormal fibrosis of the affected area.

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• The tissue damage may also cause heavy sequelae of an aesthetic and functional nature. • Early diagnosis with rapid appropriate treatment, are able to modify the disease’s outcomes.

References 1. Kelsey CE, Torok KS. The Localized Scleroderma Cutaneous Assessment Tool: responsiveness to change in a pediatric clinical population. J Am Acad Dermatol. 2013;69(2):214–20. 2. Zulian F, Vallongo C, Athreya BH, Laxer R, et  al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Reumatology (Oxford). 2006;45:614–20. 3. Martini G, Fadanelli G, Agazzi A, Vittadello F, Meneghel A, Zulian F. Disease course and long-­ term outcome of juvenile localized scleroderma: experience from a single pediatric rheumatology centre and literature review. Autoimmun Rev. 2018;17(7):727–34.

Chapter 6

A 6-Year-Old Child with Patches of Discoloration Seyyede Zeinab Azimi and Alireza Firooz

A 6-year-old boy was brought to our dermatology office for discreet hypopigmentations on his neck and chest area since 1 month ago (Fig.  6.1). The lesions were slightly pruritic. He did not use any medication for it before.

Fig. 6.1  A 6-year-old boy complaining of discoloration in his trunk S. Z. Azimi (*) · A. Firooz Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_6

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Based on the case description and the photograph, what is your diagnosis? • Tinea Versicolor • Tinea Corporis • Guttate Psoriasis • Pityriasis Alba • Erythrasma • Seborrheic Dermatitis • Vitiligo • Confluent and Reticulated Papillomatosis Detailed physical examination revealed hyperpigmented patches on his back as well. His mother was worried if his face would be involved in the future. Wood-­ lamp examination showed orange fluorescence.

Diagnosis Tinea versicolor.

Discussion Tinea versicolor is a common benign fungal infection of the stratum corneum. The fungus results in discolored macules and patches on the trunk and neck. These lesions may be hypopigmented or hyperpigmented [1]. Colors range from white to red to brown. The condition is not contagious [2]. Tinea versicolor is caused by the dimorphic, lipophilic yeast in the genus Malassezia. Malassezia globosa, Malassezia sympodialis, and Malassezia furfur are the major species isolated in tinea versicolor [3]. It is very difficult to culture in a laboratory in a special media of C12- to C14-sized fatty acids. Malassezia is the normal flora of the skin surfaces of many animals, as well as humans [4]. The incidence of tinea versicolor is the same in all races however, the alteration in skin pigmentation is more apparent in darker-skinned individuals. There is no sex dominancy. Tinea versicolor most commonly occurs in persons aged 15–24 years, when the sebaceous glands are further active. It is uncommon before puberty or after age 65 years [5]. Scaling terminates with treatment in a few days, but discoloration may last for weeks to months. The prognosis is excellent [2]. Tinea versicolor mostly involves the trunk, the back, the abdomen, and the proximal extremities.

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The face, the scalp, and the genitalia are not common areas. In fair skin patients, the color of each lesion varies from almost white to reddish-brown or fawn-colored. In darker skin types, varying degrees of either hypopigmentation or hyperpigmentation will be seen. A fine, dustlike scale is sometimes seen. The lesions are more apparent in winter since the lesions fail to tan in the summer. Conversely, the lesions become subtler in winter months as background tan fades. Mostly, the condition is asymptomatic. However, patients sometimes report mild pruritus. Family history is positive in about 20% of patients. These patients present a higher rate of recurrence and longer duration of disease [6]. Tinea versicolor is often diagnosed by the observation of the classic hypopigmented-­to hyperpigmented, centrally coalescing, oval-to-round patches with mild scale. The scale is not always evident and may require scratching or stretching of the skin surface. A dermatoscope is also a useful tool in examining the affected skin [7]. The diagnosis is often clinical. The ultraviolet black light (Wood lamp) demonstrates the coppery-orange fluorescence of tinea versicolor. Potassium hydroxide (KOH) examination confirms the diagnosis which shows spores with short mycelium referred to like the spaghetti and meatballs or the bacon and eggs. The ink blue stain, Parker ink, methylene blue stain, or Swartz-Medrik stain can be added to the KOH preparation for better visualization. Contrast stain of 1% Chicago sky blue 6B and 8% KOH (as the clearing agent) reaches the maximum sensitivity and specificity [8]. Cultures are rarely obtained and special media are needed. Up to now, blood examination revealed no abnormal finding however further assessment is warranted. The organism is localized to the stratum corneum. Malassezia furfur can be identified by hematoxylin and eosin (H&E) alone, while periodic acid-Schiff (PAS) or methenamine silver staining is more confirmatory. Rarely, the organism moves toward the stratum granulosum, and it can even be found inside keratinocytes [9]. The epidermis has mild hyperkeratosis and acanthosis. Mild perivascular infiltrate is present in the dermis. Tinea versicolor is not contagious and does not leave any permanent scar or pigmentary alterations, and any skin color changes resolve in 1–2 months after treatment. Recurrence is frequent, and prophylactic therapy may decrease the rate. Selenium sulfide, zinc-pyrithione, sodium sulfacetamide, ciclopirox olamine, tacrolimus, as well as azole and allylamine antifungals are effective topical agents. Treating with topicals from the neck to the knees is necessary even for the involvement of small areas of skin. Our patient was treated with ketoconazole shampoo and topical clotrimazole for 1 month. Weekly applications of topical agents for the following few months may help prevent a recurrence. Oral therapy with systemic antifungals can be used in companion with topical regimens. Fluconazole and itraconazole are the preferred oral agents [10, 11].

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Key Points Tinea versicolor is a common benign non-contagious fungal infection of the stratum corneum. Recurrence is common. Weekly applications of topical agents for a few months may help prevent a recurrence.

References 1. Prohic A, Jovovic Sadikovic T, Krupalija-Fazlic M, Kuskunovic-Vlahovljak S.  Malassezia species in healthy skin and in dermatological conditions. Int J Dermatol. 2016;55(5):494–504. 2. Carreira A, Ferreira JB, Pereira I, Ferreira J, Filipe P, Ferreira RB, et al. Blad-containing oligomer: a novel fungicide used in crop protection as an alternative treatment for tinea pedis and tinea versicolor. J Med Microbiol. 2018;67(2):198–207. 3. Crespo-Erchiga V, Florencio VD. Malassezia yeasts and pityriasis versicolor. Curr Opin Infect Dis. 2006;19(2):139–47. 4. Prohić A, Jovović Sadiković T, Kuskunović-Vlahovljak S, Baljić R. Distribution of Malassezia species in patients with different dermatological disorders and healthy individuals. Acta Dermatovenerol Croat. 2016;24(4):274–81. 5. Muhammad N, Kamal M, Islam T, Islam N, Shafiquzzaman M. A study to evaluate the efficacy and safety of oral fluconazole in the treatment of tinea versicolor. Mymensingh Med J. 2009;18(1):31–5. 6. He SM, Du WD, Yang S, et al. The genetic epidemiology of tinea versicolor in China. Mycoses. 2008;51(1):55–62. 7. Zhou H, Tang XH, De Han J, Chen MK. Dermoscopy as an ancillary tool for the diagnosis of pityriasis versicolor. J Am Acad Dermatol. 2015;73(6):e205–6. 8. Lim SL, Lim CS.  New contrast stain for the rapid diagnosis of pityriasis versicolor. Arch Dermatol. 2008;144(8):1058–9. 9. Janaki C, Sentamilselvi G, Janaki VR, Boopalraj JM. Unusual observations in the histology of Pityriasis versicolor. Mycopathologia. 1997;139(2):71–4. 10. Gupta AK, Lyons DC. Pityriasis versicolor: an update on pharmacological treatment options. Expert Opin Pharmacother. 2014;15(12):1707–13. 11. Sepaskhah M, Sadat MS, Pakshir K, Bagheri Z. Comparative efficacy of topical application of tacrolimus and clotrimazole in the treatment of pityriasis versicolor: a single blind, randomised clinical trial. Mycoses. 2017;25:338–42.

Chapter 7

A 23-Year-Old Girl with White Hair from Birth Seyyede Zeinab Azimi and Alireza Firooz

A 23-year-old girl came to our dermatology office for her white forelock since her birth seeking for treatment. Her mother had the same presentation (Fig. 7.1).

Fig. 7.1  A 23-year-old girl with white hair from birth

S. Z. Azimi (*) · A. Firooz Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_7

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Based on the case description and the photograph, what is your diagnosis? • Piebaldism • Alezzandrini Syndrome • Waardenburg Syndrome • Albinism • Leprosy • Addison Disease • Systemic Sclerosis • Vogt-Koyanagi-Harada (VKH) Disease

Diagnosis Piebaldism.

Discussion Piebaldism is a rare genetic disorder of melanocyte development identified by a congenital white forelock and multiple symmetrical hypopigmented or depigmented macules. The severity of phenotypes in piebaldism associate with the site of the mutation of the KIT gene. Dominant-negative missense mutations of the intracellular tyrosine kinase domain result in the most severe mutations, while mutations in the amino-terminal extracellular ligand-binding domain result in a mild form. The white hair and patches are absolutely formed at birth and do not usually develop thereafter [1]. Piebaldism is one of the cutaneous signs of Waardenburg syndrome as well. Other signs include heterochromia of the irides, lateral displacement of inner canthi, and deafness [2]. Piebaldism is a benign disorder. However, patients are at risk for actinic complications due to the absence of cutaneous melanocytes. Spontaneous repigmentation is unusual [3]. Patients should know about the genetic basis of the disorder. Also, they should be informed about the importance of the use of sunscreens, sun-protective tools as well as sun avoidance. The use of a camouflage cover-up makes a good appearance.

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The white forelock is apparent in 80–90% of patients. The central frontal scalp is permanently white, mostly in a triangular shape, from birth or as the hairs grow. The eyebrow and eyelash hair may also be involved. Sometimes symmetric white spots on the face, trunk, and extremities may be found. In some patients, white patches of hair may be located other than frontal area. A white forelock may be the only pigmentation change of skin or hair in some patients. Congenital leukoderma should be in mind and evaluation of ocular, auditory, and/or neurologic abnormalities is mandatory [4]. Other conditions that should be considered consist of chemical leukoderma, onchocerciasis, proteus syndrome, pinta, tuberous sclerosis, yaws, and vitiligo [5]. The most frequent features of Waardenburg syndrome are broad nasal root, a first-degree relative, heterochromia irides, skin hypopigmentation, white forelock, intense blue iris, synophrys, premature graying, ptosis of the eyelids, and hypoplasia alae nasi. Poliosis could be the first sign of Waardenburg syndrome [4]. Poliosis may also be seen in patients with tuberous sclerosis, melanoma, those who use medications such as topical prostaglandin analogs and topical chloramphenicol [6]. Genetic analysis can be effectively used for diagnosis.

Medical Care piebaldism is usually considered unresponsive to medical or light treatment. Dermabrasion and thin split-skin grafts with subsequent minigrafting methods were applied. Additional irradiation with ultraviolet A (10  J/cm2) was provided. This combined method led to 95–100% repigmentation of the leukoderma. Autologous punch grafting for repigmentation in piebaldism may be considered in some cases [7]. Autologous cell suspension transplantation using a cell extraction device can be another option. Surgery can be considered for patients with stable vitiligo [8].

Key Points Piebaldism is a rare genetic disorder of melanocyte development identified by a congenital white forelock and multiple symmetrical hypopigmented or depigmented macules. Piebaldism is usually considered unresponsive to medical or light treatment.

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A combination of dermabrasion and thin split-skin grafts with subsequent minigrafting method and additional irradiation with ultraviolet A (10 J/cm2) can be considered a good treatment.

References 1. Spritz RA. Out, damned spot! J Invest Dermatol. 2006;126(5):949–51. 2. Jan IA, Stroedter L, Haq AU, Din ZU. Association of Shah-Waardenburgh syndrome: a review of 6 cases. J Pediatr Surg. 2008;43(4):744–7. 3. Frances L, Betlloch I, Leiva-Salinas M, Silvestre JF. Spontaneous repigmentation in an infant with piebaldism. Int J Dermatol. 2015;54(6):e244–6. 4. Grob A, Grekin S. Piebaldism in children. Cutis. 2016;97(2):90–2. 5. Desch LW.  White forelock could be early sign of tuberous sclerosis. Arch Pediatr Adolesc Med. 1996;150(6):651–2. 6. Sleiman R, Kurban M, Succaria F, Abbas O. Poliosis circumscripta: overview and underlying causes. J Am Acad Dermatol. 2013;69(4):625–33. 7. Garg T, Khaitan BK, Manchanda Y. Autologous punch grafting for repigmentation in piebaldism. J Dermatol. 2003;30(11):849–50. 8. Komen L, Vrijman C, Tjin EP, Krebbers G, de Rie MA, Luiten RM, et  al. Autologous cell suspension transplantation using a cell extraction device in segmental vitiligo and piebaldism patients: a randomized controlled pilot study. J Am Acad Dermatol. 2015;73(1):170–2.

Chapter 8

A Patient with Acrofacial Depigmentation and Chronic Fatigue Mirna Šitum, Vedrana Bulat, Maja Kovačević, and Andy Goren

Tina is a 54-year-old Caucasian woman who has been in our practice for the first time 15 years ago. She has presented with symmetric snow white patches with well-­ demarcated borders on the periorbital area, the dorsa of the hands and feet, trunk, anogenital area, the elbows, knees, axillae, inguinal folds, and forearms 15 years ago. She simultaneously presented with weight gain, listlessness, and general fatigue. We established that she was hypothyroid (confirmed by thyroid function tests). No other family members were affected. These problems were resolved with conventional thyroid replacement therapy. Narrowband UVB phototherapy has been administered to the patient, on several occasions, with partial repigmentation. The disease was in a stabile phase, until 6 months ago (she has not been in our practice for 10 years up to this point). Over the past 6 months she has noticed de novo depigmented areas on her face and dorsa of the hands (Fig. 8.1a–d). About 1 year ago generalized fatigue recurred despite evidence for normal thyroid replacement, and it has significantly impacted her home life and work, with simultaneous complaints of abdominal cramps, bloating, as well as loss of apetite. Tina usually eats a balanced diet and is not a vegetarian. Strict vegeterians can become anemic from a diet-related deficiency of vitamin B12 (cobalamin). The laboratory studies showed haemoglobin level of 7.3 g/dL, serum iron was 33 μg/dL (normal, 60–150), feritin was lower than 5 ng/mL (normal, 35–260), and vitamin B12 was 50 pg/mL (normal, 180–950). Our patient was producing autoantibodies to gastric parietal cell antigens. The patient was treated with daily oral

M. Šitum · V. Bulat (*) · M. Kovačević Department of Dermatology and Venereology, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia e-mail: [email protected] A. Goren Applied Biology, Irvine, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_8

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a

b

c

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Fig. 8.1 (a–d) Lesion borders were convex as if the depigmenting process was invading the surrounded pigmented skin

ferrum carbonate for 6 months and monthly intramuscular injection of vitamin B12 for the next 6 months, with no clinical response. On admission, excisional biopsy of depigmented and clinically uninvolved skin has been performed. Lesional skin biopsy H&E (200x) stain shows total loss of melanocytes of the basal layer of the epidermis. Lesional skin biopsy HMB45 stain shows total loss of melanocytes of the basal layer of the epidermis. Immunohistochemical analysis of the skin corresponded to the absolute type of vitiligo, without DOPA-positive melanocytes. Gastroscopy findings showed atrophic gastric mucosa with a large polypoid mass located in the antrum. Biopsy results of the lesion showed poorly differentiated adenocarcinoma. A high subtotal gastrectomy with gastrojejunostomy, resection of the associated lymph nodes, and omentectomy were performed. Six months after the operation the patient developed partial repigmentation of the skin of the face and dorsa of the hands. Based on the case description and the photograph, what is your diagnosis? 1. nonsegmental vitiligo 2. tinea versicolor 3. pityriasis alba 4. cutaneous T-cell lymphoma of the hypopigmented type 5. piebaldism

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Diagnosis Nonsegmental vitiligo.

Discussion Vitligo is a chronic acquired depigmenting disorder due to loss of epidermal melanocytes. It occurs in about 1–2% of the world’s population, and affects all races and both sexes equally. It represents an autoimmune condition in which the patient’s immune system attacks melanocytes. Nonsegmental vitiligo has been significantly associated with various cutaneous and noncutaneous diseases [1]. At first glance, vitiligo and associated diseases appear to be quite clinically different. However, they have common genetic risk factors, suggesting that they share a similar autoimmune pathogenesis [2]. Various autoimmune diseases are associated, with demonstration of autoantibodies (e.g. antinuclear, antismooth muscle, antiendomysium, antithyroperoxidase and antithyroglobulin antibodies, parietal cell antibodies). Lesions of vitiligo are often symmetric snow white patches with well-demarcated border occurring anywhere, but with the preference for the face, dorsa of the hands and feet, trunk, anogenital areas as well as the elbows, knees, axillae, inguinal folds, and forearms [3]. Acute de novo depigmentations in older patients with chronic stable vitiligo could present first clinical signs of internal neoplasm, and these patients should therefore be subjected to regular oncologic follow-ups. Some authors have hypothesised that temporary autoimmune process is directly linked to gastric adenocarcinoma and as the collateral damage of melanocytes resulting in vitiligo [4]. The evolution of vitiligoassociated neoplasm is less progressive, limited in size with variable and more uncommon localisations and distribution and are of older age of onset compared to vitiligo. The follow-up of the patient for development of further depigmentation of the skin or hair, halo nevi, melanoma, or other carcinoma is needed. Tinea versicolor is a superficial infection of the stratum corneum by the lipophilic fungus of the Malassezia species. Unlike vitiligo, which is characterised by snow white patches of the skin, tinea versicolor is presented with hyperpigmented or hypopigmented patches on the upper back of a young adult with slight scale when scraped [5]. Also, the distribution of skin lesions in tinea versicolor is usually limited to the chest and neck. A potassium hydroxide (KOH) preparation of the scale shows short hyphae and budding cells (“spaghetti and meatballs”). Pityriasis alba is a variant of postinflammatory hypopigmentation. The initial event is a patch of eczema, which may or may not be noticed. The child then presents with multiple, hypopigmented, ill-defined areas on the face and/or arms, unlike in vitiligo, which is presented with well demarcated convex borders of depigmented skin lesions. Often there is a history of atopic dermatitis [3]. The diagnosis of T-cell lymphoma of the hypopigmented type is also worth mentioning here due to the fact that it is presented with hypopigmented, asymptomatic

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maculas and patches which might resemble vitiligo. Biopsy and immunophenotyping need to be performed in order to establish the correct diagnosis. Histologically, biopsy of the hypopigmented lesion shows the infiltrate which is composed of CD8+ cells [3]. Piebaldism (synonym partial albinism) is a rare autosomal dominant depigmentation disorder and, unlike vitiligo, often presents at birth. Piebaldism is due to decreased melanocyte expression of stem cell factor receptor, which is required for normal melanocyte migration to the skin [6]. It is characterised by a white forelock and depigmented patches in mid-frontal areas. Symmetrical distribution of depigmented areas only on ventral skin surfaces (unlike vitiligo, where both dorsal and ventral skin surfaces are affected) with islets of the hyperpigmented macules within the snow white patches (which are also not present in vitiligo) are main clinical features of piebaldism [5]. Patients are otherwise healthy, whereas patients with vitiligo might develop numerous autoimmune diseases which are closely connected to their original condition. Based on the patient’s medical history, clinical picture, and biopsy results, the diagnosis of nonsegmental vitiligo was made. Of note, acute de novo depigmentations in older patients with chronic stable vitiligo could present first clinical signs of internal neoplasm, and these patients should therefore be subjected to regular oncologic follow-ups.

Key Points • Vitligo is a chronic, acquired depigmenting disorder due to loss of epidermal melanocytes. • Lesions of vitiligo are often symmetric snow white patches with well-­demarcated border occurring anywhere, but with the preference for the face, dorsa of the hands and feet, trunk, anogenital areas as well as the elbows, knees, axillae, inguinal folds, and forearms. • Nonsegmental vitiligo is usually associated with various autoimmune diseases.

References 1. Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16:90–100. 2. Lotti T, D’Erme AM. Vitiligo as a systemic disease. Clin Dermatol. 2014;32:430–4. 3. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. Mosby/Elsevier: St. Louis; 2012. 4. Schallreuter KU, Bahadoran P, Picardo M, Slominski A, Elassiuty YE, Kemp EH, et al. Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else. Exp Dermatol. 2008;17:139–60. 5. Paller AS, Mancini AJ. Hurwitz clinical pediatric dermatology. St. Louis: Elsevier; 2016. 6. Caputo R, Tadini G. Atlas of genodermatoses. Taylor and Francis Group: London; 2006.

Chapter 9

Erythematous Spot in a Young Female Patient with Generalised Hypopigmentation Mirna Šitum, Vedrana Bulat, Maja Kovačević, and Andy Goren

Doris is a 5-year-old Caucasian female who lives in the Mediterranean region. She was born with completely translucent irises and non-patterned reduction of pigment in the skin and hair. Her skin, hair, eyelashes and eyebrows have been white since she was born and have not changed with advancing age (Fig. 9.1). The child is displaying normal intelligence and her general physical examination is normal. She has been suffering from photophobia, nystagmus, and reduced visual acuity and she regularly attends ophthalmologic examinations. After sun exposure, she always develops sunburn. Doris was born to parents who have normal hair and eye colour for their ethnic backgrounds. Her younger brother also has normal hair and eye colour. Based on the case description and the photograph, what is your diagnosis? 1. Hermansky-Pudlak syndromes (HPS) 2. Vitiligo 3. Oculocutaneous albinism type 1A (OCA1A) 4. Piebaldism 5. Phenylketonuria Doris was referred to the paediatric dermatology clinic with non-itchy and non-­ tender pinkish-yellow spot on the dorsum of her right hand, which gradually increased in size in 1 year (Fig. 9.2). The dermatoscopic evaluation revealed a nevus with a homogenous yellowish light-brown pattern and central dotted vessels (Fig. 9.3). M. Šitum · V. Bulat (*) · M. Kovačević Department of Dermatology and Venereology, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia e-mail: [email protected] A. Goren Applied Biology, Irvine, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_9

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34 Fig. 9.1  Patient has translucent irises and non-patterned reduction of pigment in the skin and hair. The skin, hair, eyelashes and eyebrows are white, while irises are completely translucent

Fig. 9.2 Pinkish-yellow spot on the dorsum of patient’s hand

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Fig. 9.3  Nevus with a homogenous yellowish light-brown pattern and central dotted vessels at the dermatoscopic evaluation

An excision of the lesion measuring 6 mm in diameter was obtained: the specimen showed fused rete ridges containing junctional nests of nevus cells with a dense lichenoid lymphocytic infiltrate, involving the circumferential margin of the lesion. This finding is consistent in patients with halo nevus.

Diagnosis Oculocutaneous albinism type 1A (OCA1A).

Discussion Albinism (albus meaning white in Latin) comprises a group of rare Mendelian disorders characterised by generalised decrease of pigmentation due to enzyme defects in the melanin biosynthesis within melanocytes of the skin, hair follicles and eyes with an onset at birth [1]. The number and structure of epidermal, ocular and follicular melanocytes are normal, but fail to produce normal amounts of melanin. The two main categories of albinism are oculocutaneous (OCA) and ocular albinism (OA). Seven distinct forms of OCA are inherited in autosomal recessive pattern and caused by mutations in seven different genes. OCA types 1–7 affect the skin, hair follicles, and eyes [2]. The amount of reduction in melanin pigment can vary depending on one’s type of albinism with a wide spectrum of presentations.

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OA primarily affects the retinal pigment epithelium, while skin and hair may appear similar or slightly lighter than that of other family members. Albinism occurs in all racial and ethnic groups throughout the world. In most populations, approximately one in 20,000 people has some type of albinism. OCA type 1A is the most common form in Caucasians [3]. Most children with OCA1A are born to parents who have normal hair and eye colour for their ethnic backgrounds. OCA1A is the most severe form of albinism. Patients with OCA1A have an autosomal recessive inheritance pattern. It is characterised by complete absence of tyrosinase activity due to a mutation of its encoding gene tyrosinase (TYR), which has been mapped at chromosome 11q14–21 [4]. Due to a completely inactive tyrosinase in OCA1A, the melanocytes of the skin, hair, and eyes synthesize neither eumelanin nor pheomelanin throughout the patient’s life. The diagnosis of albinism may be established by its presence at birth. OCA1A characteristic phenotype includes white hair, pinkish skin, and red pupils. The eyelashes and eyebrows are white as well. Irises are completely translucent on slit lamp examination. The auditory evoked response may be abnormal, but without hearing impairment [5]. OCA1A phenotype provides an example of the role of eumelanin in protection against UV radiation. These patients have an extreme cutaneous and ocular sensitivity even when exposed to minimal amounts of UV radiation. Sunburn always develops after sun exposure. The skin does not have the ability to tan. Amelanotic nevi may be present. With age, the hair may develop a slight yellow tint due to denaturation of hair keratins. Ocular abnormalities are most severe with OCA1A. Eye findings include photophobia, nystagmus (which typically develops at 6–8 weeks of age), strabismus, and reduced visual acuity. Reduced visual acuity (1/10 or less with intense photophobia) is most severe in OCA1A, and some patients are legally blind [6]. Patients with albinism have neither mental retardation nor CNS abnormalities.

Diagnosis The diagnosis of OCA1 is established by clinical findings of profound depigmentation of the skin and hair and characteristic ocular findings, but clinical phenotype of different types of OCA is not always distinguishable, making molecular diagnosis essential for genetic counselling [1]. Molecular genetic testing of TYR (encoding tyrosinase) is used infrequently in diagnosis, except to distinguish between types 1A and 1B, as the phenotypes may be nearly identical in the first year of life. A substantial fraction of patients with albinism (approximately 20% of patients investigated) routinely remain molecularly unresolved, because only one mutation is found, or no mutations are found in any of the known genes [7]. About 1  in 70 people have a gene for albinism. Couples whom are each carriers of the recessive albinism gene have a 1 in 4 chance of producing a child with albinism. Over the past decade, the list of genes associated with albinism has expanded, increasing diagnostic complexity [7]. Ophthalmological examination revealed colour vision deficiency, photophobia, strabismus, a slow horizontal nystagmus, reduced visual acuity, and absent pigment in the fundus with a red pupil.

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Differential Diagnosis The majority of disorders associated with cutaneous, ocular, and follicular hypopigmentation have their onset at birth or during infancy. The differential diagnosis includes several rare genodermatoses, such as Hermansky-Pudlak syndrome (HPS), an autosomal recessive disorder characterised primarily by the mutations in one of several genes which interrupts the biogenesis of melanosomes, platelet dense bodies and lysosomes. By comparison, patients with albinism have normal epidermal melanocyte number within the epidermis [4]. Patients with clinical presentation of OCA with additional systemic manifestations such as bleeding diathesis as well as interstitial pulmonary fibrosis and granulomatous colitis would suggest HPS [4]. Occasionally, patients with total body vitiligo and piebaldism may be thought to have OCA, but their epidermis lacks melanocytes. By comparison, the structure of epidermal, ocular and follicular melanocytes are normal in patients with albinism [4]. Vitligo is an acquired depigmenting disorder due to loss of epidermal melanocytes. It occurs in about 1–2% of the world’s population (significantly more frequent than albinism), and affects all races and both sexes equally. A family history is present in about 20–30% of cases and is more commonly seen in patients with younger onset of the disease. It represents an autoimmune condition in which the patient’s immune system attacks the pigment-producing cells—melanocytes. In contrast to that in the patient with albinism, which is immediately present at birth, peak onset of vitiligo is 10–30 years of age. Various autoimmune diseases are associated, with demonstration of autoantibodies [e.g. antinuclear (16.8%), antimicrosomal (25.6%), antismooth muscle (5.5%), antiendomysium (1.8%)]. Lesions of vitiligo are often symmetric snow white patches with well-demarcated border occurring anywhere, but with the preference for the face, dorsa of the hands and feet, trunk, anogenital areas as well as the elbows, knees, axillae, inguinal folds, and forearms. The diagnosis of albinism may be established by the presence at birth and by the facts that normal eye colour is retained in vitiligo (but not in albinism). Vitiligo can also cause partial depigmentation of hair (poliosis), unlike albinism, in wihich the patients have total loss of pigmentation of hair on glabrous skin [6]. Piebaldism (synonym partial albinism) is a rare autosomal dominant depigmentation disorder and similarly to albinism, often presents at birth. Piebaldism is due to decreased melanocyte expression of stem cell factor receptor, which is required for normal melanocyte migration to the skin. Melanocytes migrate during embryologic development in a dorsal-ventral direction, and melanocytes with decreased stem cell factor receptor expression are unable to migrate to ventral skin surfaces, such as the forehead, chin, chest, abdomen, and volar arms and legs. For this reason, depigmented areas are predominantly found on ventral skin surfaces [3]. Piebaldism is characterised by a white forelock and depigmented patches in mid-frontal areas (in OCA1A hair is completely white). Involvement of eyelashes and eyebrows has been described. Symmetrical distribution of depigmented areas on ventral skin surfaces with islets of the hyperpigmented macules within the snow white patches are main clinical features of piebaldism. The presence of white forelock and the pattern

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of depigmentation suggests piebaldism. Patients are otherwise healthy and normal eye colour is retained in piebaldism (but not in OCA1A). Piebaldism with deafness is called Woolf’s syndrome [3]. There are several inherited disorders of amino acid metabolism with related hypopigmentation of skin, hair and eyes with an onset at birth or during infancy such as phenylketonuria, an autosomal recessive disorder in which phenylalanine hydroxylase activity is severely reduced or absent. In contrast to this disorder, patients with albinism have neither mental retardation nor CNS abnormalities [4]. Based on the patient’s medical history and clinical picture, the diagnosis of OCA1A was made. In a proportion of cases of oculocutaneous albinism, though normal melanocytes do not produce melanin, the abnormal melanocytes in naevi can overcome the genetic defect in melanogenesis and produce melanin pigment. The follow-up of the patient for development of nevi, amelanotic melanoma, or other carcinoma is needed.

Treatment There is no specific treatment available for albinism. The parents were instructed to protect Doris from sun exposure (sunscreens, hats, sunglasses, sun-protective clothing, or avoiding sun exposure altogether if possible) in order to avoid cutaneous and ocular photocarcinogenesis, in particular the development of squamous cell carcinomas [6]. The latter are a significant cause of morbidity and mortality, especially in the Mediterranean region (this region is characterised by a very high number of sunny days all year round). The patient should undergo ophthalmologic evaluation early in life, and ophthalmologic follow-up of these patients is mandatory. Nystagmus may ameliorate with age. People with albinism are at risk of social isolation because the condition is often misunderstood. Social stigmatization can occur, especially within communities of colour, where the race or paternity of a person with albinism may be questioned [8]. Patients with OCA have a normal lifespan, as well as normal development, intelligence and fertility [1].

Key Points • Oculocutaneous albinism is a group of rare inherited disorders of pigmentation with absent or deficient biosynthesis of melanin. • OCA1A is the most severe and the most common form of albinism. • OCA1A is characterised by generalised depigmentation of skin, hair and eyes. • The age of onset is at birth.

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References 1. Grønskov K, Ek J, Brondum-Nielsen K.  Oculocutaneous albinism. Orphanet J Rare Dis. 2007;2:43. 2. Grønskov K, Brøndum-Nielsen K, Lorenz B, et al. Clinical utility gene card for: oculocutaneous albinism. Eur J Hum Genet. 2014;22(8) https://doi.org/10.1038/ejhg.2013.307. 3. Caputo R, Tadini G. Atlas of Genodermatoses. London: Taylor and Francis Group; 2006. 4. Paller AS, Mancini AJ.  Hurwitz clinical pediatric dermatology. St. Louis: Mosby/ Elsevier; 2016. 5. de Vijlder HC, de Vijlder JJM, Neumann HAM. Oculocutaneous albinism and skin cancer risk. J Eur Acad Dermatol Venereol. 2013;27:e433–4. 6. Ortonne JP, Passeron T.  Vitiligo and other disorders of hypopigmentation. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed. Edinburgh: Mosby; 2012. p. 1023–48. 7. 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. 8. Maia M, Volpini BMF, Santos GA, et al. Quality of life in patients with oculocutaneous albinism. An Bras Dermatol. 2015;90(4):513–7.

Chapter 10

Progressive Reticulated Pigmentation of the Folds Katerina Damevska, Anastasiya Atanasova Chokoeva, Ivana Dohcheva Karajovanov, and Anita Najdova

A 42-year-old female presented to the clinic with a 10-year history of hyper pigmented lesions distributed on her folds and abdomen. Gradually, the lesions became more dark-colored and pronounced, accompanied with mild itching sensation. Pulmonal sarcoidosis with 5-years of duration was reported from the patient’s medical history, treated with systemic administration of prednisolone. The treatment regimen was discontinued 1 year ago. Her younger sister had similar lesions, restricted to the axillary and groin areas. During the clinical examination, multiple hyper pigmented lesions was observed bilateral in axillar folds and groins, affecting also the lateral part of the abdomen, composed of lentigo-like brown macules and papules, some of them forming a reticular hyperpigmented plaques (Figs. 10.1, 10.2, and 10.3). Few pitted perioral scars were seen on examination. Biopsy for histological evaluation was obtained of abdominal lesion. The histological examination revealed basilar hyperpigmentation predominantly located at the tips of elongated branched (antler-like) rete ridges (Fig. 10.4). Based on the case descriptions and photographs, what is your diagnosis? 1. Cutaneous sarcoidosis 2. Acanthosis nigricans 3. Dowling-Degos Disease 4. Confluent and Reticulated Papillomatosis 5. Reticulate acropigmentation of Kitamura

K. Damevska (*) · I. D. Karajovanov · A. Najdova University Clinic of Dermatology, Ss Cyril and Methodius University, Skopje, Macedonia A. A. Chokoeva “ProArt”-Dermatology and Aesthetic Clinic, Plovdiv, Bulgaria © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_10

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Fig. 10.2  Lesions on left axilla

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10  Progressive Reticulated Pigmentation of the Folds Fig. 10.3 Finely reticulated, hyperpigmented macules in the popliteal fossae

Fig. 10.4 Histological examination revealed irregular rete ridge elongation with a basilar hyperpigmentation on the tips, a mild perivascular lymphocytic infiltrate, and a dermal melanosis with melanin-laden melanophages

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Diagnosis Dowling-Degos Disease.

Discussion Dowling-Degos Disease is a rare reticulated pigmented anomaly, recently considered as autosomal dominant genodermatosis, characterized by reticulate pattern of abnormally hyperpigmentations, usually affecting the body folds and creases. First discovered by Dowling and Freudenthal in 1938, the disease is later described by Degos and Ossipowski in 1954, as Reticulated pigmentary dermatosis of the folds. Most cases are sporadic, but affected families have been also reported, with reported female predominance with 3–5:1 ratio. The onset varies between individuals aged 11–50 years, with an average age of 23 years [1]. The disease is usually presented as typical reticulate pigmentation of the flexures, occurring in adult life, as asymptomatic, symmetrical, progressive, small, round, pigmented macules or papules forming reticulate pattern over axillae, groin, face, neck, arms and trunk, occasionally hyperkeratotic, accompanied by comedo-­like lesions and pitted acneiform scars. Various clinical manifestations have been reported in the literature during decades. Prominent comedones and pitted scars have been recently described by Mohanty et al. [2] as sporadic findings of the disease, occurring without the typical flexural hyperpigmentations. Follicular variant of the disease is considered as extremely rare. Galli-Galli Syndrome have been described as an acantholytic variant of the disease, caused by mutations in keratin 5. In etiologic aspect, Dowling-Degos is considered as autonomic-dominant genodermatosis, caused by a loss-of-function mutation in the non-helical head domain of the keratin 5 gene (KRT5), leading to only one functional copy of KRT5. Mutations in POFUT1, POGLUT1, and PSENEN, which encode protein O-fucosyltransferase 1, protein O-glucosyltransferase 1, and presenilin enhancer protein 2 gene, respectively, have been also implicated in pathogenesis, as POFUT1 and POGLUT1 mutations have been linked to a variant form of the disease which usually involves non-flexural areas, while PSENEN mutations have been associated the variant of coexistence with hidradenitis suppurativa [3]. Furthermore, several reported associations of Dowling-Degos disease and hidradenitis suppurativa are suggestive that although considered primary as pigmentary disorder, Dowling-Degos is closely linked to the wide spectrum of disorder of keratinization. The coexistence of Dowling Degos, acne inversa and follicular cysts is susceptive of common follicular anomaly with a single underlying defect of follicular proliferation [4].

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Dowling Degos has been described in association also with pigmentary disorders of skin folds (Kitamura’s disease), rheumatologic diseases, neutrophilic diseases, as well as cutaneous and other malignancies (squamous cell carcinoma, epidermal cysts, keratoacanthoma), where abnormal epithelial proliferation involving mainly the pilosebaceous apparatus has been recognized as a triggering factor [5]. Histology is essential to diagnosis of Dowling Disease, showing a concentration of melanin at the tips or characteristic thin branch-like patterns of epidermal downgrowth. Differential diagnoses include the wide spectrum of reticulate pigment disorders of the skin, showing similar clinical manifestation, but distributing different genetic anomaly expression as reticulate acropigmentation of Kitamura (location of the pigmented lesions is primarily acral), reticulate acropigmentation of Dohi, Galli-Galli disease, and Haber syndrome. Other disorders of keratinization, acanthosis nigricans, confluent ant reticulated papillomatosis, lentiginosis profuse perigenitoaxillaris has also a similar appearance [2]. In some cases, genetic testing would be helpful to diagnosis, but since it is not a routine practice, it would be hardly applied in every day practice. Although many different treatment regiments have been tried, there is no effective treatment for Dowling-Degos yet. Depigmenting agents such as hydroquinone, as well as systemic and topical retinoids have been implicated as a treatment option, as well as various energy-based devises, especially Erbium YAG and fractional Erbium YAG have been reported as beneficial in treating Dowling-Degos disease [6].

Key Points • Dowling-Degos Disease is autosomal dominant genodermatosis, caused by a loss-of-function mutation in the non-helical head domain of the keratin 5 gene. • The disease is characterized by reticulate pattern of abnormally hyperpigmentations, accompanied by comedo-like lesions and pitted acneiform scars. • Lessions usually affect the body folds and creases. • Most treatments have poor long-term efficacy.

References 1. Tod BM, Steenkamp I, Jordaan HF, Visser WI. Dowling-Degos disease presenting primarily with comedones and atrophic scarring. Dermatopathology (Basel). 2019;6(2):153–6. 2. Mohanty P, Jain S, Mohapatra L, Acharya S. Dowling-Degos disease—a novel presentation of an uncommon disease. Indian Dermatol Online J. 2019;10(5):587–90. 3. Betz RC, Planko L, Eigelshoven S, Hanneken S, Pasternack SM, Bussow H, et al. Loss-of-­ function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet. 2006;78(3):510–9.

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4. Loo WJ, Rytina E, Todd PM. Hidradenitis suppurativa, Dowling-Degos and multiple epidermal cysts: a new follicular occlusion triad. Clin Exp Dermatol. 2004;29:622–4. 5. Choudhary SV, Jain D, Agrawal P, Singh A. Dowling-Degos disease and hidradenitis suppurativa: co occurrence or association? Indian Dermatol Online J. 2013;4(3):191–4. 6. Piccolo V, Corneli P, Russo T, Danielsson M, Zalaudek I, Argenziano G. Classic dowling degos disease: a rare genodermatosis. G Ital Dermatol Venereol. 2019; https://doi.org/10.23736/ S0392-0488.19.06386-7.

Chapter 11

Multiple Café-Au-Lait Macules Since Birth Xue-Gang Xu, Ya-Xin Guo, and Xing-Hua Gao

A 1-year-old boy presented to our department with multiple café-au-lait macules (CALMs) since birth. The parents claimed that the number and size of CALMs gradually increased in the year. On physical examination, there were numerous discrete, well-circumscribed, round or oval, uniformly pigmented macules on the trunk and extremities, ranging in size from 1 mm to greater than 10 cm in the greatest diameter (Fig. 11.1). No other cutaneous anomalies, or other organ abnormalities were identified. No family history of genetic diseases was reported. Based on the case description and the photograph, what is your diagnosis? 1. Café-au-lait macules 2. Neurofibromatosis type 1 3. Legius syndrome 4. McCune-Albright syndrome

Diagnosis Neurofibromatosis type 1.

X.-G. Xu · Y.-X. Guo · X.-H. Gao (*) Department of Dermatology, The First Hospital of China Medical University, Shenyang, China © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_11

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Fig. 11.1 Multiple CALMs on the trunk and extremities

Discussion Genetic testing is required to make a final diagnosis. Upon obtaining written informed consent, peripheral blood samples were obtained from the patient and his parents. By whole exome sequencing, a novel heterozygous variant was identified in NF1 of the boy but not in his parents. Then the diagnosis of neurofibromatosis type 1 (NF1) was determined. Neurofibromatoses are a group of three heterogeneous disorders that include NF1, neurofibromatosis type 2, and schwannomatosis. NF1 is the most common of these three inherited genetic conditions, affecting approximately 1 in 3000 individuals [1, 2]. NF1 is a multisystem disorder in which some features present at birth but most are age-related manifestations. The clinical features of NF1 include neurofibroma, pigmentary abnormalities, low-grade gliomas, skeletal dysplasias, as well as involvements of other organs. NF1 is an autosomal dominant disease with complete penetrance, although approximately half of the affected individuals are sporadic cases caused by a new (or de novo) NF1 gene mutation. All people with a germline NF1 mutation have this disease, however, patients can show extreme variability in their clinical features, even from the same family [1]. In addition to the common generalized NF1, few patients harbor presentations of NF1 that are restricted to one segment of their body. This type is known as “segmental” or mosaic NF1, which probably arises from a somatic mutation in NF1. To date, >3000 different NF1 mutations have been

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identified, however, genetic testing usually does not predict future complications as only few genotype-phenotype correlations have been established [2]. For a patient fulfills clinical diagnostic criteria for NF1, genetic testing is not necessary. Genetic testing can confirm a suspected diagnosis before a clinical diagnosis is determined, differentiate NF1 from other conditions, and assist in genetic counseling and family planning. For sporadic case presenting with only multiple CALMs, genetic testing is usually recommended to assist the diagnosis. Blood sample is usually enough, and testing of affected tissue (melanocytes from CALMs or Schwann cells from neurofibromas) is necessary for patients with somatic mosaicism. A negative genetic testing, with 95% (but not 100%) sensitivity, can’t exclude all patients with NF1. The NF1 gene encodes a protein called neurofibromin, which functions as negative regulators of the Ras proto-oncogene, which controls cell proliferation [1]. Loss of neurofibromin expression, as seen in tumors associated with NF1, is predicted to lead to increased cell growth and survival through aberrantly activation of RAS.  RAS transmits its growth-promoting signal through the AKT-mechanistic target of rapamycin (mTOR) and MEK-extracellular signal-regulated kinase (ERK) effector pathway [2]. Although many clinical features of NF1 are apparent from birth, complete loss of gene function is needed for the formation of tumors. Cells in tumors associated with NF1, such as Schwann cells in neurofibromas, have a mutation of both NF1 alleles: the germ-line mutation and a somatically acquired mutation of the other allele. In a National Institutes of Health consensus development conference regarding NF1, 7 criteria were demarcated (Box 11.1). The clinical presentations of NF1 is characterized by multiple CALMs and neurofibromas. The diagnosis of NF1 in a child is usually first suspected on the presence of CALMs. In general, CALMs in NF1 have uniform and regular borders. Axillary and inguinal freckles, Crowe sign, are small pigmented macules that appear in skinfold regions, typically beginning at about 3–5 years of age. In some cases, there may be similar diffuse freckling all over the body. Additional skin manifestations include juvenile xanthogranulomas and nevus

Box 11.1 Diagnostic Criteria of NF1 Two or more of the following clinical features are required to establish the diagnosis of NF1: • Six or more CALMs of ≥5 mm in diameter before puberty or ≥15 mm in diameter after puberty • Axillary freckling or freckling in inguinal regions • Two or more dermal neurofibromas or one or more plexiform neurofibromas • Two or more Lisch nodules (iris hamartomas) • An optic pathway glioma • A distinctive long bone dysplasia involving the sphenoid wing or thinning of the long bone cortex with or without pseudarthrosis • A first-degree relative with NF1 diagnosed by the above criteria

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Fig. 11.2 Multiple CALMs and neurofibromas on the trunk (arrow: plexiform neurofibroma)

anemicus. There are many other conditions that present with CALMs, including Legius syndrome, piebaldism, Fanconi anemia, tuberous sclerosis, and McCune-­Albright syndrome [3]. One important differential diagnosis of NF1 is Legius syndrome, caused by pathogenic variants in SPRED1, which encodes a protein that also functions within the Ras signaling pathway. People with Legius syndrome have multiple CALMs, intertriginous freckling, learning disabilities, and relative macrocephaly. But other manifestations of NF1, such as neurofibromas or other tumors, ophthalmologic findings, and skeletal manifestations, are not present in patients with Legius syndrome. Various types of neurofibromas are common manifestations of NF1 (Fig. 11.2) [3]. Cutaneous neurofibromas typically emerge in the teenage and increase in numbers with increasing age. Neurofibromas are skin-colored or have a mild purplish coloration and may either be raised above the skin or pucker subcutaneously. They usually first appear on the trunk and then extend to the extremities, neck, and face. Cutaneous neurofibromas are benign tumors, not at risk for malignant transformation, but may have significant impact on quality of life. In a child with NF1, the

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number of CALMs does not predict the severity of neurofibromas and it is not possible to predict future neurofibroma burden. Plexiform neurofibromas are a distinct type of neurofibroma that arise from 1 or multiple nerve trunks or branches, and may transform into malignant peripheral nerve sheath tumors (MPNSTs). Plexiform neurofibromas may have overlying skin manifestations (such as thickened orange-peel overlying skin with a purplish brown coloration), and have an associated hairy patch or region of hyperpigmentation. About 50% of NF1 patients present with plexiform neurofibromas. Symptoms such as pain, rapid growth, or neurologic dysfunction indicate plexiform neurofibromas may transform into MPNSTs. NF1 also has variable presentations of other organs and tissues. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumors (optic pathway gliomas and glioblastoma), peripheral nerve tumors (spinal neurofibromas and MPNSTs), cardiovascular abnormalities, nonnervous-system tumors (higher risk of gastrointestinal stromal tumors, breast cancers, leukemia, lymphoma, etc.), learning disabilities, attention deficits, or social and behavioural problems. NF1 is a lifelong condition and has many of the tumor related complications as mentioned above, ranging from quality-of-life concerns to potentially life-­ threatening complications [3]. Patients with NF1 also may continue to face social and vocational challenges. Medical and psychosocial supports should be continued for all patients. To prompt diagnosis and provide optimum care for patients with NF1, clinicians must be aware of the diverse clinical features of NF1. We advocate a multidisciplinary approach to care, entailing a dedicated team of specialists throughout the lifetime of the patient [1, 3]. The CALMs have no malignant potential. For CALMs that reduce quality of life, individuals can receive dermatological camouflage treatments. Neurofibromas are benign Schwann-cell tumors. Generally, they do not need to be removed by plastic surgeon. Neurofibromas removal should be led by symptoms-such as pain, functional deficits, and findings of a risk-benefit assessment. The mechanisms that underlie various complications of NF1 are gradually coming to light, and this is leading to the development of new approaches to therapy. Preclinical studies and human clinical trials are underway on drugs that target the Ras signaling regulated by the NF1 gene product. For example, selumetinib is confirmed leading to a partial reduction of plexiform neurofibroma tumor volume. We believe the prospect of new treatments will significantly improve quality of life and health of NF1 patients in the years to come.

Key Points • Café-au-lait macules (CALMs) present in many disorders, and neurofibromatosis type 1 is one of the most important differential diagnosis of CALMs. • Neurofibromatosis type 1 is a multiple organ systems disorder, which needs multidisciplinary treatment throughout the lifetime of the patient.

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Conflicts of Interest  None declared.

Funding Sources  This work was supported by the National Key Research and Development Program of China (No. 2016YFC0901504) and the 111 Project (D18011).

References 1. Hirbe AC, Gutmann DH.  Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13(8):834–43. 2. Gutmann DH, Ferner RE, Listernick RH, et al. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017;3:17004. 3. Miller DT, Freedenberg D, Schorry E, et al. Health supervision for children with neurofibromatosis type 1. Pediatrics. 2019;143(5):e20190660.

Chapter 12

A Teenager with Sudden and Localized Hair Graying Özgür Gündüz

A 16-year old boy presented to our clinic with his father, complaining that a patch of his hair has been turned into white in the last 3 months. A white lock of hair was visible on the border between the right parietal and temporal regions (Fig. 12.1a). An underlying flesh-colored asymptomatic papule –11.0 × 7.0  mm in size- was revealed after shaving the white hairs (Fig.  12.1b, c). All the graying hairs were originating from this papule (Fig. 12.2). No other similar areas of white hair follicles were observed in his entire body by routine inspection. A further full mucosal and cutaneous examination with wood lamp did not reveal white macules or patches. The patient had no personal or familial history of autoimmune diseases. His opthalmologic examination was unremarkable and the result of the neurological examination was normal.

a

b

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Fig. 12.1 (a) Patch of white hair on the vertex, (b) underlying flesh-colored, asymptomatic papule revealed by physical examination, (c) a close-up view of the underlying papule after the hair has been shaved

Ö. Gündüz (*) Faculty of Medicine, Department of Dermatology and Venerology, Kırıkkale University, Yahşihan/Kirikkale, Turkey © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_12

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Fig. 12.2  White hairs originating from a structureless papule, as seen on the dermoscope

Based on the case description and the photographs, what is your diagnosis? 1. Sarcoidosis 2. Melanoma 3. Halo Naevus 4. Waardenburg Syndrome 5. Vitiligo An excisional biopsy was performed and histopathological examination showed groups of nevoid cells surrounded and infiltrated by cytotoxic T lymphocytes (Fig. 12.3a–c), indicating the papule as a “halo nevus”. Complete blood count, liver enzymes, blood urea nitrogen, creatinine, thyroid function tests, sedimentation rates were found to be in normal range.

Diagnosis Poliosis due to Halo Nevus.

Discussion Poliosis is defined as a localized patch of white hair. It is an uncommon but easily recognized physical feature. It is foremost known and traditionally called as “White forelock” when the central frontal scalp is involved. Poliosis can occur due to various genetic conditions, such as piebaldism, tuberous sclerosis, Waardenburg syndrome, prolidase deficiency, or it can be acquired (Table  12.1). Many of these genetic conditions may also affect central nervous system and are classified under neurocutaneous syndromes [1]. In these conditions, poliosis is usually observed at

12  A Teenager with Sudden and Localized Hair Graying Fig. 12.3 (a) Nevoid cells marked immunohistochemically with Melan-A (×200) (b) CD8 immunohistochemical staining reveals a lymphocytic infiltrate, largely composed of CD8+ cytotoxic T lymphocytes (c) a dense dermal lymphocytic infiltrate surrounding scarce nevoid cells (H&E, ×200)

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Table 12.1  Some of the genetic and non-genetic conditions seen frequently with poliosis [1] Frequent causes of poliosis Condition Distinguishing features 1. Genetic conditions Tuberous Seizures after birth, hypopigmented (ash-leaf) macules, Shagreen patch after 5 sclerosis years, perinasal angiofibromas (adenoma sebaceum), ungual fibromas later in life Waardenburg White forelock, deafness, poliosis of eyelashes syndrome Piebaldism Congenital white forelock, limited or generalized white patches over the body, Hirschsprung disease or deafness can accompany. 2. Conditions seen with acquired poliosis Halo nevus Typical clinical (ABCDE rule; no asymmetry, regular, distinguishable borders, homogen colored, diameter less than 5 mm, not enlarging) and dermoscopical features (symmetry, no blue-white veil, no pseudopods, no broadnetwork, no peripheral dots and globules) of a melanoctyic nevus Vitiligo Other mucocutaneous areas of pigment loss. Increased visibility of depigmented areas with Wood lamp examination. Loss of pigmentation frequently seen as symmetric white patches on acral sites and face. Other autoimmune disease may accompany (Graves, Pernicious Anemia, Diabetes Mellitus type 1) Melanoma Typical clinical and dermoscopic features of melanoma. Confirmation by biopsy if suspected Medications Imiquimod, Chloramphenicol, Acitretin, Chloroquine, Cetuximab

birth or in childhood. Poliosis may also be observed during the clinical course of various nongenetic, acquired diseases (i.e.,vitiligo, Alezzandrini syndrome, sarcoidosis, melanocytic lesions, melanoma, etc.) after the childhood. Halo nevus (Sutton’s nevus) is typically a melanocytic nevus, encircled with a round white area of depigmentation, the so-called “halo”. Halo nevi can be observed in approximately 5% of white-skinned children [2, 3]. A T-lymphocyte mediated immune reaction is suspected to be the cause of the initial peripheral depigmentation, which is followed by the loss of the color of nevus itself [4]. At the end of this process, the nevus disappears and repigmentation occurs. Halo nevi are usually spotted on the back. Halo nevi incidence is higher in patients with vitiligo and can be the first manifestation of this disease. There are also reports about halo nevi due to melanoma and sarcoidosis. When a halo nevus is observed, a dermoscopical examination should be initially conducted. If no suspicious features for melanoma is observed, then the patient should be examined for vitiligo, one of the frequent causes of halo nevus. Based on the patient’s clinical features, biopsy results and lack of any other systemic findings, the diagnosis of halo nevus was made. After the establishment of diagnosis, the patient was examined again for an overlooked vitilgo, for other accompanying autoimmune diseases, for a possible melanoma and neurocutaneous syndromes. His parents were informed and instructed about the aforementioned diseases. Routine check-ups at 6-month-intervals were planned.

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Key Points • Poliosis is a phenomenon, which occurs due to various genetic and nongenetic conditions. • Poliosis due to genetic conditions is seen at relatively younger ages than acquired poliosis, usually at the birth or during the childhood. • Acquired poliosis may be seen in people with an increased number of nevi. • Acquired poliosis may also be a manifestation of vitiligo and sometimes melanoma.

References 1. Sleinman R, Kurban M, Succaria F, Abbas O. Poliosis circumscripta: overview and underlying causes. J Am Acad Dermatol. 2013;69:625–33. 2. Mooney MA, Barr RJ, Buxton MG. Halo nevus or halo phenomenon? A study of 142 cases. J Cutan Pathol. 1995;22:342–8. 3. Walker S, Lucke TW, Burden AD, Thomson J.  Poliosis circumscripta associated with scalp naevi: a report of four cases. Br J Dermatol. 1999;140(6):1182–4. 4. Zeff RA, Freitag A, Grin CM, Grant-Kels JM. The immune response in halo nevi. J Am Acad Dermatol. 1997;37:620–4.

Chapter 13

A Middle-Aged Female with Hyperpigmentation Johannes F. Dayrit, Maria Juliet Enriquez-Macarayo, and Evangeline B. Handog

A 58-year-old Filipino female consulted at the clinic because of a 1-year duration of hyperpigmented patches on both cheeks. On physical examination, she presented with a symmetrical grayish-black hyperpigmentation on both cheeks, extending to the zygomatic areas, mandible, nostrils, upper lip and eyebrow regions (Fig. 13.1); skin texture was coarse. Closer examination revealed telangiectasias and confetti-­ like depigmentation on both malar areas (Fig. 13.2). Based on the case description and the photographs, what is your diagnosis? 1. Melasma 2. Riehl’s Melanosis 3. Lichen Planus Pigmentosus 4. Exogenous Ochronosis 5. Post-inflammatory Hyperpigmentation For the past 5 years, with the desire to simply improve her facial skin appearance, she has been applying an exfoliant skin lightening solution nightly (containing 2% hydroquinone and 0.025% tretinoin), with daily application of sunscreen. After 4 years of using this regimen, she noted roughness of her facial skin and appearance of hyperpigmentation on areas where the solution was applied. There were no lesions on the sclerae and ears. Urine ferric chloride test was negative.

J. F. Dayrit De La Salle Medical and Health Sciences Institute, Dasmarinas, Cavite, Philippines M. J. Enriquez-Macarayo Angeles University Hospital, Angeles, Philippines E. B. Handog (*) Asian Hospital and Medical Center, Alabang, Muntinlupa, Philippines e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_13

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Fig. 13.1  A 58-year-old female presenting with symmetrical grayish black hyperpigmentation on both cheeks, extending to the zygomatic areas, mandible, nostrils, upper lip and eyebrow regions

Dermoscopy done on the affected left malar area revealed reddish brown clods and wormlike structures obliterating follicular openings; the confetti-like depigmentation showed white clods and areas with pinkish hue (Fig. 13.3). Microscopic examination (H & E) of a 3 mm biopsy specimen taken on the same area of dermoscopic examination, revealed yellowish to reddish-brown material in various shapes and sizes and areas of solar elastosis (Fig. 13.4a, b).

Diagnosis Exogenous Ochronosis.

Discussion Ochronosis is a rare disorder presenting with blue-black or gray-blue deep pigmentation of the skin [1]. Two types exists: Endogenous Ochronosis (alkaptonuria) which is an autosomal recessive metabolic condition due to a deficiency in

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Fig. 13.2 Telangiectasias (red arrow) and confetti-­ like depigmentation (black arrow) on the malar area

homogentisate 1,2-dioxygenase and Exogenous Ochronosis (EO) which is an acquired cosmetically induced pigmentation devoid of systemic symptoms [1–4]. EO’s predisposing factors include unprotected ultraviolet light exposure, prolonged application of chemical agents as hydroquinone (HQ), phenol, resorcinol, mercury, picric acid [1, 4, 5] and intake of antimalarials as hydroxychloroquine [3]. Worsening of the pigmentation with continuous use of the offending agent is a notable clue to EO [6]. It has been hypothesized that chemical agents such as HQ competitively inhibit the enzyme homogentisic oxidase leading to the cutaneous accretion of homogentisic acid and ochronotic pigment in the papillary dermis [2].

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Fig. 13.3 Dermoscopy showing reddish-brown clods (red arrow) and wormlike structures (black arrow) obliterating follicular openings; white areas with pinkish hue (yellow arrow), represent the confetti-like depigmentation

Fig. 13.4 Histology showing yellowish to reddish-brown amorphous material (red arrows) in various shapes and sizes with areas of solar elastosis (black arrow); H& E (a) ×100, (b) ×400

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In the 2011–2018 Philippine Dermatological Society’s Health Information System registry, which catered to 641, 631 consultations among Filipinos, only 127 cases (0.02%) were diagnosed to have exogenous ochronosis, predominantly among females than males (F  =  91.34% versus M  =  8.66%) and highest among the

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41–60 year old age group. It was the fifth most common facial hypermelanosis; the top four being melasma, solar lentigenes, ephelids and erythema dyschromicum perstans [7]. Patients present with asymptomatic deep blue black to gray black macules, mostly on the malar, temples, lower cheeks and even on the posterolateral neck areas. Symmetry may or may not be present. It is more common in darker skin types with no age nor sex predilection. Urine ferric chloride test can be carried out to rule out endogenous ochronosis. Dermoscopy was done in this case and findings were compatible with the established findings for EO [6, 8]. Skin biopsy remains, though, as the gold standard to establish the diagnosis [1, 4]. EO remains to be a very difficult condition to treat with topical options presenting with inconsistent results [6]. Procedural management appears to offer promising outcomes [1, 6]. Use of the offending agent must be ceased immediately and continuous judicious application of broad-spectrum sunscreen is a must, together with other sun avoidance practices. Based on the clinical presentation, dermoscopic findings, biopsy results and affirmed by the patient’s medical history, the diagnosis of exogenous ochronosis was arrived at. This case proves that not all hyperpigmentary disorders seen on the face is melasma. It is important to elicit a complete history, especially that of past medications taken or applied. Dermoscopy has found its place in helping establish the diagnosis. Skin biopsy can always be done when in doubt, as in this case. The patient was advised to discontinue all skin lightening creams and religiously apply sunscreens. Two monthly sessions of combined Er:YAG resurfacing and Q-switched Nd:YAG laser treatments has already resulted to a significant improvement (Fig. 13.5a, b).

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Fig. 13.5 (a) prior to treatment (b) decrease in the pigmentation after the laser treatments (Quantificare standardized 3D medical imaging)

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Key Points • Exogenous ochronosis is an acquired cosmetically induced pigmentation due to deposition of polymerized homogentisic acid in the collagen • It is very vital to elicit a history of a preceding prolonged used of topical medications such as hydroquinone, phenols or resorcinol, exacerbated by unprotected ultraviolet light exposure • Deep grayish-black or blue-black facial hyperpigmentation with confetti-like depigmentation is a useful clue differentiating EO from other facial hyperpigmentary conditions • A high degree of suspicion on the part of the dermatologists, dermoscopy and skin biopsy aid in the final diagnosis

References 1. Le Borgne De Lavillandre J, Lesort C, Martin C, et al. Dermpath and clinic: exogenous ochronosis. Eur J Dermatol. 2019;29(2):239–40. 2. Bhattar PA, Zawar VP, Godse KV, et  al. Exogenous ochronosis. Indian J Dermatol. 2015;60(6):637–43. 3. Tekgoz E, Akincioglu E, Cinar M, Yilmaz S. A case of exogenous ochronosis associated with hydroxychloroquine. Eur J Rheumatol. 2018;5(3):206–8. 4. Rodrigues M, Pandya AG. Hypermelanosis. In: Kang S, Amagai M, Bruckner AL, et al., editors. Fitzpatrick’s Dermatology in General Medicine. 9th ed. New York: McGraw-Hill; 2019. p. 1368. 5. Sanchez-Martinez EV, Garcia-Briz MI, Moneva-Leniz LM, et al. Exogenous ochronosis: the failure of depigmenting creams. Dermatol Online J. 2019;25(4):12. 6. Simmons BJ, Griffith RD, Bray FN, et al. Exogenous ochronosis: a comprehensive review of the diagnosis, epidemiology, causes and treatments. Am J Clin Dermatol. 2015;16:205–12. 7. Philippine Dermatological Society’s Health Information System registry, 2019. 8. Gil I, Segura S, Martínez-Escala E, et al. Dermoscopic and reflectance confocal microscopic features of exogenous ochronosis. Arch Dermatol. 2010;146:1021–5.

Chapter 14

Generalized Mottled Hyperpigmentation in a 28-Year-Old Filipino Woman Johannes F. Dayrit, Maria Juliet Enriquez-Macarayo, and Evangeline B. Handog

A 28-year-old Filipina presented with a 20-year history of multiple hyper- and hypopigmented macules on the face, trunk and extremities. The lesions, noted to be nonpruritic and nontender, simultaneously appeared, initially on the trunk and spread gradually to the upper and lower extremities. Involvement of the face was noted 1 year prior to consult. Previous treatment with topical miconazole and oral itraconazole proved futile. She was also diagnosed clinically as a case of hypopigmented mycosis fungoides in another dermatology clinic, for which she underwent narrow band UVB phototherapy for 20 sessions. The patient was born to non-­ consanguineous parents. Similar skin lesions were also present in her two (maternal) aunts, an uncle and two male cousins (Fig. 14.1). Physical examination revealed multiple, widespread hypopigmented and depigmented macules on the face, trunk and extremities (Fig. 14.2a–c) sparing the palms, soles and the oral mucosa. Based on the case description and photographs, what is your diagnosis? 1. Hypopigmented mycosis fungoides 2. Poikiloderma 3. Scleroderma

J. F. Dayrit De La Salle Medical and Health Sciences Institute, Dasmarinas, Cavite, Philippines M. J. Enriquez-Macarayo Angeles University Hospital, Angeles, Philippines E. B. Handog (*) Asian Hospital and Medical Center, Muntinlupa, Philippines e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_14

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Fig. 14.1  Family pedigree. Proband is a 28-year-old lady. Two maternal aunts, an uncle and two male cousins are also affected. (□) Men. (○) Women. ( ) Affected. ( ) Patient

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Fig. 14.2 (a–c) Generalized macular hyperpigmentation with guttate hypopigmented and depigmented macules on the face, trunk and extremities

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Fig. 14.3 Dermoscopy shows white dots, clods and areas with irregular outline (black arrow) alternating with dark brown dots, clods and areas (red arrow)

4 . Amyloidosis cutis dyschromica 5. Xeroderma pigmentosum Dermoscopy revealed white and brown dots, clods and areas with irregular outline. Few blood vessels were noted (Fig. 14.3). Microscopic examination of a hyperpigmented macule revealed focal thinning of the epidermis and amorphous deposits of globular eosinophilic material in the papillary dermis. Pigment-laden macrophages are also noted (Fig. 14.4).

Diagnosis Amyloidosis cutis dyschromica.

68 Fig. 14.4 Histopathology revealed deposits of eosinophilic, amorphous globular masses in the dermal papillae (black arrow) and pigment-laden macrophages (red arrow), H&E (a) ×100 (b) ×400

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Discussion Amyloidosis cutis dyschromica (ACD) is a rare subtype of primary localized cutaneous amyloidosis characterized by prepubertal onset of alternating hyperpigmented, hypopigmented or depigmented macules, along with amyloid deposition in the papillary dermis. Presently, there are less than 100 cases reported in the English language literature. The condition is more commonly seen in patients with Asian ethnicity [1]. The compound heterozygosity or homozygosity of the transmembrane glycoprotein NMB (GPNMB) truncating alleles is the cause of autosomal recessive ACD. More recently, semidominant GPNMB mutations in a Filipino pedigree have been identified, thereby expanding the inheritance pattern of this disorder [2, 3]. Molecular analysis of the blood sample in our patient revealed homozygous mutation in the GPNMB gene. Immunofluorescence studies showed that GPNMB staining was significantly reduced in the lesional skin of the proband and affected relatives. Sanger-sequencing in available family members showed a semi-dominant pattern of inheritance with heterozygotes displaying milder clinical features of skin dyschromia [2]. Histopathology usually shows foci of amorphous eosinophilic globular masses in the papillary dermis. Congo red stain shows apple-green birefringence under polarized light microscopy. Dermoscopy reveals white spots with ill-defined

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margins and hyperpigmented black dots and clods. There is usually retention of skin markings [4]. Amyloidosis cutis dyschromica may resemble other dermatological conditions such as hypo- and hyperpigmented tinea versicolor, hypopigmented mycosis fungoides and poikiloderma seen in connective tissue diseases such as scleroderma, dermatomyositis and lupus erythematosus. Other rare genodermatoses that should be excluded are dyschromatosis universalis hereditaria, xeroderma pigmentosum and Degos disease. In a review on the management of 48 reported cases of ACD in the literature, topical treatments and oral antioxidants and vitamins have no effect. Acitretin has been reported to improve the dyschromia in a few cases. Spontaneous resolution has not been observed in any of the cases [1]. This case highlights the importance of correlating clinical, dermoscopy and histopathological findings in making a diagnosis of amyloidosis cutis dyschromica. Molecular and genetic studies are often required to validate the diagnosis of this rare genodermatosis.

Key Points • Amyloidosis cutis dyschromica is a genodermatosis and is a form of primary localized cutaneous amyloidosis • Hyperpigmented and hypopigmented or depigmented macules that may be progressive from puberty to adulthood • Onset before puberty • Usually nonpruritic or mildly pruritic • Dermoscopy, skin biopsy, molecular and genetic studies aid in the final diagnosis Physical examination revealed multiple, widespread hypopigmented and depigmented macules on the face, trunk and extremities (Fig. 14.2a–c) sparing the palms, soles and the oral mucosa.

References 1. Mahon C, Oliver F, Purvis D, Agnew K.  Amyloidosis cutis dyschromia in two siblings and review of the epidemiology, clinical features, and management in 48 cases. Australas J Dermatol. 2016;57(4):307–11. 2. Onoufriadis A, Hsu CK, Eide CR, Nanda A, Orchard GE, Tomita K, et  al. Semidominant GPNMB mutations in amyloidosis cutis dyschromica. J Invest Dermatol. 2019;139(12):2550–4. 3. Yang CF, Lin SP, Chiang CP, Wu YH, H’ng WS, Chang CP, et  al. Loss of GPNMB causes autosomal-recessive amyloidosis cutis dyschromica in humans. Am J Hum Genet. 2018;102(2):219–32. 4. Wang L, Jiang X, Zhang N, Liu L, Zhou H, Liu H. Case of amyloidosis cutis dyschromica with dermoscopy 2018. J Dermatol. 2019;46(2):e77–9.

Chapter 15

A Young Man with Pigmentation on the Tongue Marta Kurzeja, Małgorzata Olszewska, and Lidia Rudnicka

Five-year-old boy with a hyperpigmented brownish macules on the tongue was referred by a pediatrician to Department of Dermatology for assessment and treatment. The lesion had first been noticed approximately 6 months earlier, after pneumonia treated with clarithromycin at a dose 250 mg per day for 1 week. The patient do not suffer from any chronic diseases, also family history is not significant. Clinical examination revealed three homogenous, pale brown macules with well-­ defined borders on the right side of the dorsal surface of the tongue and on the root of the tongue (Fig.  15.1a). The lesions were not infiltrated. The rest of the oral mucosa was normal. There were no ocular, skin, or nail hyperpigmentation and the cervical nodes was not enlarged. Findings from the laboratory tests were within reference range. Videodermoscopy of lesions were performed using FotoFinder Medicam 800. Dermoscopic examination of the pigmentation on the tongue revealed homogenous, brownish pattern with dots similar in size and distributed regularly within central part of the lesion (Fig. 15.1b). The clinical and dermoscopic picture of the hyperpigmented macule was stable within the 6 months observation. Based on the case description and the photograph, what is your diagnosis? 1. Drug induced pigmentation 2. Melanocytic macule 3. Physiological pigmentation 4. Addison’s disease

M. Kurzeja (*) · M. Olszewska · L. Rudnicka Department of Dermatology, Warsaw Medical University, Warsaw, Poland e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_15

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Fig. 15.1 (a) 5 year-old boy with homogenous, pale brown macules with well-defined borders on the right side of the dorsal surface of the tongue and on the root of the tongue. (b) Dermoscopy of the tongue showed homogeneous, brownish pattern with dots similar in size and distributed regularly within central part of the lesion

Diagnosis Drug induced pigmentation of the tongue.

Discussion A diagnosis of drug-induced pigmentation of the tongue was made on a basis of medical history, stable clinical as well as dermoscopic picture of the lesions within 6 months observation and the correlation between the appearance of the pigmentation and the introduction of the antibiotics. Oral pigmented lesions are usually a diagnostic dilemma for the clinician. A differential diagnosis is wide and include physiological melanocytic lesions, chemically induced melanosis and pigmentation associated with systemic diseases. Also, taken into consideration are benign and malignant neoplasms of the oral mucosa [1, 2]. Physiological pigmentation are usually seen in African, Asian and Mediterranean populations. It occurs within the first two decades of life. The color ranges from light to dark brown. The attached gingiva is the most common affected site of the oral cavity [3]. Chemically induced melanosis include foreign body exposure, heavy metal intoxication, smoker’s melanosis, amalgam tattoo and drug-induced pigmentation. Introduction of foreign materials for example graphite pencil may result in the color changes of oral the mucosa [1, 2]. Rarely increased level of heavy metals in the blood may also lead to diffuse discoloration of the oral soft tissues [2]. Smoker’s melanosis is a common benign pigmentation of the oral mucosa from cigarette or pipe smoking. It occurs in approximately 25–30% of smokers, most commonly on the anterior attached mandibular gingiva and interdental papillae [1, 4]. Amalgam

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tattoo is one of the most frequent causes of oral hyperpigmentation. It occurs when the restoration fragments enter the oral mucosa [1]. The most common sites of involvement are gingiva and alveolar mucosa. Drug-induced pigmentation is an adverse effect of a number of medications. The most common drug, which induced oral discoloration is minocykline [5, 6]. Oral pigmentation may be also a manifestation of systemic diseases such as Addison’s disease, Laugier-Hunziker syndrome and Peutz-Jeghers syndrome. Addison’s disease is the result of primary adrenocortical insufficiency [1]. Hyperpigmentation of the skin and mucous membranes is an early and highly specific sign of Addison’s disease, occurring in up to 92% of patients [4]. Laugier-­ Hunziker syndrome acquired, idiopathic disease characterized by pigmentation of the oral mucosa, lips and longitudinal melanonychia [3]. Peutz-Jeghers syndrome is rare genetic disorder inherited in an autosomal dominant manner and caused by mutation of the LKB1 gene on chromosome 19. The clinical features include pigmented mucocutaneous macules, most commonly around the lips, intestinal hamartomatous polyposis and an increased risk of cancer in many organs, including the small intestine, colon, stomach, pancreas, breast and genital tract [2]. In the oral cavity we can also observe benign pigmented neoplasms such as nevus, melanocytic macule or melanoacanthoma [1, 2]. Intraoral melanocytic nevi are uncommon, most frequently arise during the third and fourth decades of life and are localized on the hard palate, buccal mucosa, and vermilion border [7]. Melanocytic macule is a more commonly seen benign pigmented lesion. The most frequently it occurs on the lips in young adults or in the oral cavity in forth decade of life [1]. Intraoral melanoacanthoma is unusual begin, rapidly enlarging benign pigmented lesion commonly localized on the buccal mucosa in black females in the third to fourth decades of life [2, 7]. Intraoral melanomas are rare malignant neoplasm, accounting for less than 1% of all oral malignancies, with a higher incidence in Orientals, Hispanics, and Africans. In most of cases oral melanoma occurs in the fourth through seventh decades of life on the hard palate and maxillary gingiva [7]. Drug-induced pigmentation should be always considered in the differential diagnosis of patients with intraoral discoloration. Most common drug-induced pigmentation is flat and can be black, gray, blue or brown. It may be focal, multifocal or diffuse. Hard palate, gingiva and buccal mucosa are the most frequent affected sites of oral cavity. Numerous of medication from a diverse and unrelated groups of systemically administered drugs are associated with oral hyperpigmentation [1, 2, 8]. The most common cause of intraoral pigmentation is minocycline. In almost all cases minocykline induces blue–black discoloration of gnathic bones, without involvement of the oral mucosa. Discoloration of the bones can make the overlying tissue appear bluish. However, pigmentation of oral mucosa, resulting from increased melanin production, has been also rarely reported after minocycline therapy [5, 6]. Other drugs, which may a trigger drug-induced hyperpigmentation are chloroquine, hydroksychlorochine, amiodarone, zidovudine, clofazimine, ketoconazole, phenothiazine, imatinib, golimumab and oral contraceptives [4, 8, 9]. Diagnosis is based on the temporal relationship between intraoral pigmentation with initiation of the drug administration. Drug-induced oral pigmentation most

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commonly disappear within weeks to months after stopping the medication, although sometimes it remains permanent. Re-administration of the drug may cause a relapse or aggravation of oral pigmentation [1]. In doubtful cases biopsy may be necessary, especially when the dermoscopic pattern indicates melanoma or discoloration occurs in the same locations where oral melanoma most often develops. In the histopathology examination either features imitating melanotic macule or fine brown-­yellow granules in lamina propria are visible [4, 8]. In conclusion, pigmentation in oral cavity may be a result of many conditions, ranging from harmless physiological discoloration to malignant tumors. The differential diagnosis of pigmented mucosal lesions may be a diagnostic challenge for clinicians. In many cases the correct diagnosis can be made on the basis of clinical signs, dermoscopy and laboratory tests, biopsy is necessary in doubtful cases.

Key Points • Pigmentation in oral cavity may be a result of many conditions, including physiological melanocytic lesions, chemically induced melanosis, pigmentation associated with systemic diseases, are benign and malignant neoplasms • The most common cause of drug induced intraoral pigmentation is minocycline • Diagnosis is based on the temporal relationship between intraoral pigmentation with initiation of drug administration, only in doubtful cases biopsy is needed

References 1. Eisen D. Disorders of pigmentation in the oral cavity. Clin Dermatol. 2000;18(5):579–87. 2. Kauzman A, Pavone M, Blanas N, Bradley G. Pigmented lesions of the oral cavity: review, differential diagnosis, and case presentations. J Can Dent Assoc. 2004;70(10):682–3. 3. Lambertini M, Patrizi A, Ravaioli GM, Dika E.  Oral pigmentation in physiologic conditions, post-inflammatory affections and systemic diseases. G Ital Dermatol Venereol. 2018;153(5):666–71. 4. Rosebush MS, Briody AN, Cordell KG. Black and Brown: non-neoplastic pigmentation of the oral mucosa. Head Neck Pathol. 2019;13(1):47–55. 5. Tosios KI, Kalogirou EM, Sklavounou A.  Drug-associated hyperpigmentation of the oral mucosa: report of four cases. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(3):e54–66. 6. Filitis DC, Graber EM.  Minocycline-induced hyperpigmentation involving the oral mucosa after short-term minocycline use. Cutis. 2013;92(1):46–8. 7. Lambertini M, Patrizi A, Fanti PA, Melotti B, Caliceti U, Magnoni C, et al. Oral melanoma and other pigmentations: when to biopsy? J Eur Acad Dermatol Venereol. 2018;32(2):209–14. 8. Yuan A, Woo SB. Adverse drug events in the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119(1):35–47. 9. Dika E, Starace M, Lambertini M, Patrizi A, Veronesi G, Alessandrini A, et al. Oral and nail pigmentations: a useful parallelism for the clinician. J Dtsch Dermatol Ges. 2020;18(1):7–14.

Chapter 16

Larval Secretions and Dark Facial Spots Zekayi Kutlubay, N. Deniz Esin, Defne Özkoca, Ümit Türsen, and Erdal Polat

A 31-year old female patient applied to our outpatient clinic with the complaint of darkening on the face and the neck. Her complaint has started six years ago and previously she has visited several dermatology out-patient clinics and has received topical Cligman treatment. She stated that she was precautious about sun protection and used SPF 50 sunscreen frequently. Three years ago, she was treated with a six sessions of chemical peeling; however the cosmetic results were unsatisfying for the patient. Upon dermatological examination, the patient had bilateral light brown patchy hyperpigmentation with irregular borders on the malar eminences, frontal and temporal areas (Fig. 16.1a, b). According to the Fiztpatrick scale, the patient had a skin phototype 3. She had no other medical or surgical diseases and was not using any prescribed drugs. Based on the case description and the photographs, what is your diagnosis? 1. Melasma 2. Post-lesional hyperpigmentation The patient was informed about and her consent was received for larval secretion therapy. Thereafter, 500 Lucilla serciata larvae of the third stage of evolution

Z. Kutlubay (*) · D. Özkoca Cerrahpaşa Medical Faculty, Department of Dermatology, Istanbul University-Cerrahpaşa, Istanbul, Turkey e-mail: [email protected] N. D. Esin Medical Faculty, Department of GETAT, Medipol University, Istanbul, Turkey Ü. Türsen Medical Faculty, Department of Dermatology, Mersin University, Mersin, Turkey E. Polat Cerrahpaşa Medical Faculty, Department of Medical Microbiology, Istanbul University-­Cerrahpaşa, Istanbul, Turkey © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_16

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Fig. 16.1 (a) and (b) Bilateral light brown patchy hyperpigmentation with irregular borders on the malar eminences, frontal and temporal areas

were added to 1 ml of distilled water and were passed through a 450 nm injection filter in order to prevent contamination and to overcome the odour of the larvae [1]. The patient’s face was washed with distilled water using the hydro-waver device. The secretions of the larvae were sprayed to the face of the patient with the oxygen injection spray gun of the device. The complete penetration of the secretions was sustained with the ultrasonic hand-piece of the device. The patient was instructed not to wash her face for 12 h. The treatment routine was applied daily for eight consecutive days. Near-complete clearance of the lesions was achieved at the end of the eighth session. The face of the patient after treatment is seen in Fig. 16.2a, b.

Diagnosis Melasma

Discussion Melasma is a disease that occurs due to the increased accumulation of dermal and epidermal melanin. The disease manifests itself with symmetrical hyperpigmented patches with irregular borders. The patient population consists of mainly females;

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Fig. 16.2 (a) and (b) Near complete clearance of the facial lesions after eight sessions of larval therapy

almost 90%. The most frequent locations of the lesions are the face and the forearms. The disease has an increased prevalence in the Hispanic, Asian and African American populations. The most frequently considered differential diagnosis of the disease is post-lesional hyperpigmentation. Drug induced hyperpigmentation, cutaneous lupus erythematosus, actinic lichen planus, lichen planus pigmentosus, pigmented contact dermatitis (Riehl’s melanosis), exogenous ochronosis, erythema dyschromicum perstans, acquired Hori nevus, poikiloderma of Civatte, erythromelanosis follicularis faciei et colli and mercury deposition are the other diseases that should be considered for the differential diagnosis. Wood-lamp examination is useful for diagnosis and visualisation of the borders of the disease [2]. The treatment of melasma can be divided into three categories. These are: topical depigmenting agents, chemical peels, laser and light devices. Topical depigmenting agents produce the best results in the treatment of moderate-to-severe melasma patients, combination therapies yielding better results in particular. The most commonly used combination therapy is the triple combination therapy (TCT): hydroquinone, tretinoin, and fluocinolone acetonide; which was also used in this patient. Chemical peels and laser and light devices produce less benefit compared to topical depigmenting agents [3]. Larvae therapy has been long used for the treatment of chronic wounds. The larval secretions include protease, collagenase, trypsin, leucine aminopeptidase, carboxypeptidase A and B and elastase. These secretions disturb the differentiation of monocytes into macrophages from the pro-inflammatory to pro-angiogenic

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pathway. Furthermore, these secretions decrease the production of the pro-inflammatory cytokines, namely TNF-alpha, IL-12p40 and macrophage migration inhibiting factor, and increase the production of anti-inflammatory cytokines, namely IL10. These in turn prevent the proliferation of melanocytes and the accumulation of melanin around the keratinocytes [4]. The effect of larval secretions on melanocytes makes larvae therapy a reasonable choice in the treatment of melasma. There are no case reports of the use of larval secretions in the treatment of melasma and thus, this is a unique case.

Key Points • Melasma is a disease that occurs due to the increased accumulation of dermal and epidermal melanin and it manifests itself with symmetrical hyperpigmented patches with irregular borders. • The treatment of melasma are topical depigmenting agents, chemical peels, laser and light devices. • Larval secretions prevent the proliferation of melanocytes and the accumulation of melanin around the keratinocytes and therefore can be used in the treatment of melasma.

References 1. Polat E, Cakan H, Aslan M, Sırekbasan S, Kutlubay Z, Ipek T, et  al. Detection of anti-­ leishmanial effect of the Lucilia sericata larval secretions in vitro and in vivo on Leishmania tropica: first work. Exp Parasitol. 2012;132(2):129–34. 2. Bolognia J, Jorizzo JL, Rapini RP. Dermatology. St Louis: Mosby/Elsevier; 2008. 3. Rivas S, Pandya AG. Treatment of melasma with topical agents, peels and lasers: an evidence-­ based review. Am J Clin Dermatol. 2013;14(5):359–76. 4. Nigam Y, Morgan C. Does maggot therapy promote wound healing? The clinical and cellular evidence. J Eur Acad Dermatol Venereol. 2016;30(5):776–82.

Chapter 17

Dark Facial Spots and Rash Lawrence Chukwudi Nwabudike and Alin Laurentiu Tatu

A 39-year old female with a history of 13 years facial pigmentation, 12 years itchy rash on sun exposure and pimples on face with facial redness. The pigmentation worsened with sun-exposure. There was no history of loss of appetite, weight loss, muscle weakness and fatigue. The patient had received a wide range of topical and systemic therapies, with only temporary relief in many cases. Examination showed hyperpigmented facial macules involving the forehead, cheeks and perioral areas, centrofacial erythema with papules (Fig. 17.1a, b).

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Fig. 17.1 (a and b) Photographs before, showing forehead with marked hyperpigmentation and occacional papules. Lower face with perioral hyperpigmentation, central facial erythema with erythematous papules

L. C. Nwabudike (*) N. Paulescu National Institute of Diabetes, Bucharest, Romania A. L. Tatu Faculty of Medicine and Pharmacy/Clinical Department, Dermatology, Medical and Pharmaceutical Research Unit/Competitive, Interdisciplinary Research Integrated Platform “Dunărea de Jos”, ReForm-UDJG “Dunărea de Jos” University, Galati, Romania Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galati, Romania © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_17

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Based on the case description and the photograph, what is your diagnosis? • Drug-induced hyperpigmentation • Addison’s disease • Post-inflammatory hyperpigmentation • Acne

Diagnosis Melasma, rosacea, photosensitivity rash (possibly solar urticaria).

Discussion Melasma is a common, benign skin disorder characterized by increased pigmentation, especially in sun-exposed areas. It is more frequent in females and there tends to be a familial predisposition. Hormonal factors may play a role. There was no history of recent drug use, which could support a diagnosis of drug-induced hyperpigmentation. Muscle weakness, fatigue and weight loss were not elicited in the history, thus ruling out Addison’s disease. The erythematous rash was centrofacial and often worse with sun exposure, suggesting rosacea, rather than acne. Rosacea is also more common amongst women. The patient was treated with homeopathic Causticum MK potency weekly, photoprotection and bland facial wash. At 2 months, melasma and rosacea improved, but not photosensitivity rash; At 5 months, melasma and rosacea remitted, photosensitivity rash was better; At 11 months photosensitivity rash relapsed with antibiotic therapy for another ailment, rosacea and melasma remained in remission. She returned 2 years later with melasma, rosacea, acne still remitted and photosensitivity had remitted (Fig. 17.2). Homeopathy is a system of treatment, which uses infinitesimal concentrations of medicines to bring about healing. Nanomolecules have been found in homeopathic solutions, which appear to have been generated by the process of producing the homeopathic medicine [1, 2]. It is thought that these nanomolecules may subsequently influence physiological processes in the body. Homeopathy is a holistic therapy, as it works on the entire organism, not simply the physical ailment. For this reason, it was possible for the patients three ailments—melasma, rosacea and photosensitive rash to all respond to one treatment, whereas in conventional medicine, they would have required three different treatments. Homeopathy’s value as a form of integrative (complementary and alternative) medicine has been disputed by some. In themselves, homeopathic principles, especially the principle of “like cures like” have been shown to be compatible with

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Fig. 17.2  Shows clearance of hyperpigmentation, erythema and papules

classical biomedical principles [3] and the argument has been made that a more expanded view be taken, in order to facilitate better understanding of these principles [3]. Homeopathy has been shown to have potential value in the management of a variety of diseases, including long-standing intractable lichen planus [4], severe acne [5] and mycoses fungoides [6].

References 1. Montagner L, Aïssa J, Ferris S, Montagner J-L, Lavallée C. Electromagnetic signals are produced by aqueous nanostructures derived from bacterial DNA sequences. Interdiscip Sci Comput Life Sci. 2009;1:81–90. 2. Chickramane PS, Suresh AK, Bellare RJ, Kane GS.  Extreme homeopathic dilutions retain starting materials: a nanoparticulate perspective. Homeopathy. 2010;99:231–42. 3. Eskinazi D.  Homeopathy re-revisited: is homeopathy compatible with biomedical observations? Arch Intern Med. 1999;159(17):1981–7. https://doi.org/10.1001/archinte.159.17.1981. 4. Nwabudike LC, Miulescu M, Tatu AL. Case series of an alternative therapy for generalised lichen planus: four case studies. Exp Ther Med. 2019;18:943–8. https://doi.org/10.3892/ etm.2019.7677. 5. Nwabudike LC. Case reports of acne and homeopathy. Complement Med Res. 2018;25:52–5. https://doi.org/10.1159/000486309. 6. Nwabudike LC. Homeopathy as therapy for mycosis fungoides: case reports of three patients. Homeopathy. 2019;108(4):277–84. https://doi.org/10.1055/s-0039-1687822.

Chapter 18

The Dermatologist’s Fingernail Lawrence Chukwudi Nwabudike, Alin Laurentiu Tatu, Diana Sabina Radaschin, and Valeriu Ardeleanu

A 54-year old, male dermatologist of African origin developed a pigmented band on his right index finger about 2 months earlier. There had been no history of trauma or drug ingestion. He had had occasional lighter bands on this fingernail and on others, which tended to wax and wane with time. This band was much darker. The patient also had pigmented bands involving several toenails. His self-examination showed a 1–2 mm wide, dark brown to black band, extending from the proximal nail fold to the edge of the right index fingernail (Fig. 18.1). There was no Hutchinson sign. Self-dermoscopy (Fig. 18.2) showed a uniformly coloured band, with no blotches or dots suggestive of haemorrhage. The margins of the band were smooth. No micro-Hutchinson sign was seen. Dermoscopy of the free edge suggested involvement of the ventral nail plate. In order to eliminate subjectivity, the patient also consulted colleagues of his at the next international conference, with a uniform response of a benign lesion.

L. C. Nwabudike (*) N. Paulescu National Institute of Diabetes, Bucharest, Romania A. L. Tatu Faculty of Medicine and Pharmacy/Clinical Department, Dermatology, Medical and Pharmaceutical Research Unit/Competitive, Interdisciplinary Research Integrated Platform “Dunărea de Jos”, ReForm-UDJG “Dunărea de Jos” University, Galati, Romania Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galati, Romania D. S. Radaschin Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galati, Romania Faculty of Medicine and Pharmacy/Clinical Department, Dermatology, “Dunărea de Jos” University, Galati, Romania V. Ardeleanu General Hospital CFR Galați, Surgery Department, Arestetic Clinic Galați, Faculty of Medicine, Ovidius University from Constanța, “Dunărea de Jos” University from Galați, Galati, Romania © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_18

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Fig. 18.2  (Heine Delta 20T): Uniform dark brown to black band, with a width of 1 mm, borders are uniform, white lines are an artefact due to dryness of the nail. No micro-­ Hutchinson sign is visible

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The dermatologist (also an author of this paper), still regularly examines his fingernail and there has been no change in the lesion. Based on the case description and the photograph, what is your diagnosis? 1. Melanonychia striata 2. Subungual haemorrhage 3. Subungual melanoma 4. Linear ungual nevus

Diagnosis Ethnic melanonychia striata.

Discussion Melanonychia is a brown or black discolouration of the nail plate, which is usually seen as a streak along the nail plate, from the proximal to distal portion. Melanonychia striata may be due to increased melanocyte activity or melanocyte hyperplasia in the nail matrix, both resulting in increased deposition of melanin in the nail plate [1]. Causes of increased melanocyte activity include ethnic melanonychia (in dark-­ skinned individuals), pregnancy, chronic local trauma, infections, dermatologic disorders (lichen planus, psoriasis), endocrine disorders, hemochromatosis, porphyria, Peutz-Jeghers syndrome and Laugier-Hunziker syndrome; melanocyte hyperplasia can result from nail matrix melanocytic nevi, nail lentigo and nail matrix/subungual melanoma [1]. Up to 96% of black people over the age of 50 years [2] and 1.4% of Caucasians [3] develop melanonychia striata. There is no sex predilection. Criteria for the diagnosis of nail melanoma include the ABCDEF criteria [4]. These are: • Age—with peak age between fifth to seventh decades, also for African Americans, Asians and Native Americans. • Brown, black band, with band width greater than 3 mm and variegated borders. • Change in morphology of the nail band or lack of change despite adequate treatment.

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• Digit involved. The thumb more than big toe and big toe more than index finger for subungual melanoma. • Extension of black-brown pigment onto the proximal or lateral nail folds (Hutchinson sign). • Family or personal hstory of dysplastic nevus or melanoma. Dermoscopy of the nail shows a grey background with regular, parallel grey or dark brown lines in the case of melanonychia and the pseudo-micro-Hutchinson sign may be visible. Dermoscopy of the free edge of the nail plate showed pigmentation of the dorsal aspect of the nail plate when the proximal nail matrix is involved and pigmentation of the ventral nail plate when the distal nail matrix is involved [5]. Subungual melanoma may show brown background overlaid by longitudinal lines, which are irregular in width, parallelism and in colour, while nail erosion and the micro-Hutchinson sign may be visible [1, 6]. Most dermatologists adopt a wait and see approach, with regular monitoring in order to avoid damage to the nail plate. A biopsy is always warranted when there are warning signs, such as age, single nail occurrence, sudden onset, increased darkening, the presence of the Hutchinson or micro-Hutchinson sign. In this case, the patient’s lesion has remained stable and is still being monitored clinically.

Key Points • Melanonychia striata is a longitudinal darkening of the nail plate, which may be due to increased melanocyte activity or melanocyte hyperplasia. • It is very common in those of African or African American descent, where it may reach 96% prevalence in those over 50 years of age. • The ABCDEF rule is a useful guide to differentiation of subungual melanoma from benign causes of longitudinal melanonychia. • Dermoscopy may be useful in differentiating benign melanonychia from melanoma. • Biopsy may be required in order to confirm the diagnosis.

References 1. Leung AKC, Lam JM, Leong KF, Sergi CM. Melanonychia striata: clarifying behind the black curtain. A review on clinical evaluation and management of the 21st century. Int J Dermatol. 2019;58:1239–45. https://doi.org/10.1111/ijd.14464. 2. Leyden JJ, Spott DA, Goldschmidt H. Diffuse and banded melanin pigmentation in nails. Arch Dermatol. 1972;105(4):548–50. https://doi.org/10.1001/archderm.1972.01620070020007. 3. Duhard E, Calvet C, Mariotte N, Tichet J, Vaillant L. Prevalence of longitudinal melanonychia in the white populationAnnales de Dermatologie et de Venereologie. 1995;122(9):586–90.

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4. Levit EK, Kagen MH, Scher RK, Grossman M, Altman E. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol. 2000 Feb;42(2 Pt 1):269–74. 5. Starace M, Alessandrini A, Brandi N, Piraccini BM. Use of nail dermoscopy in the management of melanonychia: review. Dermatol Pract Concept. 2019;9(1):38–43. https://doi.org/10.5826/ dpc.0901a10. 6. Ronger S, Touzet S, Ligeron C, et al. Dermoscopic examination of nail pigmentation. Arch Dermatol. 2002;138(10):1327–33. https://doi.org/10.1001/archderm.138.10.1327.

Chapter 19

A Young Female with Hyperpigmentation on Face Showed Few Weeks Before Visit Sudip Parajuli, Upama Paudel, Anil Kumar Das, and Dinesh Binod Pokhrel

A 25-year-old female (Fig. 19.1) presented with history of dark pigmented patches on cheeks which had just started few weeks back. There was no history of itching and redness prior to the onset of the skin lesions. There was no history of photosensitivity, joint pains or oral ulcers. She agreed that the pigmentation increased on exposure to sunlight and did not go away even after completely avoiding it. She was annoyed and complained that this pigmentation was ruining her life and hampering her interpersonal relationship because of low self-esteem. On examination, there were well-defined hyper pigmented patches of 2 × 2 cm on both malar area, whole of upper lip and nasal bridge without any surface changes. Based on the case description and the photograph what is your diagnosis? 1. Melasma 2. Pigmented contact dermatitis 3. Lichen planus pigmentosus 4. Post inflammatory hyperpigmentation 5. Acquired bilateral naevus of ota like macules (ABNOM) On further examination, Wood’s lamp examination did not show major changes in pigmentation.

S. Parajuli (*) · U. Paudel · A. K. Das · D. B. Pokhrel Department of Dermatology and Venereology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_19

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Fig. 19.1  A young female with pigmentation on both malar area, upper lip and nasal bridge of face

Diagnosis Melasma.

Discussion Melasma is an acquired condition of hyperpigmentation which usually presents with symmetrical hyperpigmentation on face. There is wide range of prevalence from 1–50% [1]. It is usually a clinical diagnosis with three types of

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presentation-­centrofacial (50–80%), malar and mandibular types. Forehead, nose, and upper lip are involved in centrofacial pattern without involvement of philtrum, cheek and chin [1]. The pigmentation is limited to cheeks in malar pattern while it involves chin and jaw area in mandibular pattern, however, mixed patterns can also be seen in practice. Melasma can also be classified as epidermal, dermal and mixed type. In vivo reflectance confocal microscopy has revealed that distribution of melanophages is heterogenous suggesting that all melasma are mixed type with the dermis often showing solar elastosis and mixed vascularity [2]. Epidermal pigment can be differentiated from dermal type in clinical practice by wood’s lamp examination. Epidermal melasma is darker compared with dermal melasma and accentuates under wood’s light examination. The exact cause of melasma is unknown and is believed to be multifactorial in origin. Visible light and UV exposure has been shown to exacerbate this condition. There are studies which shows a strong relation of genetics as predisposing factor for development of melasma. Hormones in oral contraceptive pills and thyroid disorders are often found to exacerbate melasma. In addition, certain drugs and vitamin B12 deficiencies, inflammation, and reactive oxygen species have been implicated in pathogenesis of Melasma. Recently, melasma has been proposed to be due to complex interaction between epidermal melanocytes, keratinocytes, dermal fibrolasts, mast cells and vascular endothelial cells [2]. Melasma impairs quality of life and is associated with psychiatric disturbances. In one of the study it was seen that the prevalence of anxiety (11.6%) and depression (12.8%) was higher in patients with Melasma [3]. In another study in which Melasma quality of life scale was primary outcome, it was seen that 71% were severely affected by melasma [4]. Pigmented contact dermatitis is one of the differential diagnosis of this condition. It usually presents with reticulate slate grey or brown pigmentation and there may be subtle signs of preceding dermatitis in the form of erythema, edema and pruritus. Face (forehead, zygomatic area and temples) and neck are principally involved but hands, forearm and trunk can also be involved. Patch tests using standard series, cosmetic series and fragrance series might be done in suspected cases of Pigmented contact dermatitis. Lichen planus pigmentosus (LPP) and erythema dyschromicum perstans (EDP) are two different entities which can be easily distinguished from melasma by their characteristic slate grey pigmentation compared with brown/dark brown pigmentation of melsama. LPP presents as diffuse macular hyperpigmentation involving face, neck, upper limbs or more widespread involvement. EDP starts as hyperpigmented macules and patches of variable size with ashy grey to brownblue colour. They have thin erythematous border in early stage which is absent in late stage or heals with hypopigmentation accentuating central hyperpigmentation. There has been a proposal to umbrella term “Lichenoides melanodermatitis” to embrace all the differential diagnoses of pigmentary disorders which comes as a reaction pattern [5]. Post inflammatory hyperpigmentation is more readily distinguished from melasma by history of preceding cutaneous insults like inflammatory dermatoses, photo reactions, contact dermatitis, and infections. Clinically, they present as

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macular hyperpigmentation at the site of inflammation. In general, PIH disappears slowly with time after removal of inciting events. ABNOM consists of blue-brown to slate grey mottled pigmentation on face predominantly affecting malar area without involvement of ocular and oral mucosa. Sun exposure and pregnancy are found to be trigger of this condition. This is a rare condition compared to melasma and we are of opinion that if a patient with melasma on malar area do not respond to usual treatment then a diagnosis has to be revised and the patient should be treated as ABNOM. The results of treatment with lasers (Combination of Pigment removing Q-switched Nd:YAG) are variable in this condition. Melasma is treated with range of topical treatment that includes hydroquinone, Kojic acid, Azelaic acid, and tretinoin with sun protection as central to the management. Kligman’s cream and its modification which consists of combination of hydroquinone, tretinoin and topical steroid offers a rapid clearance of pigmentation. The disadvantages of Kligman’s formula are steroid induced side effects on long run which includes rosacea, hypertrichosis and rebound effects. Epidermal melasma responds very well to topical treatment. The usual practice includes starting hyroquinone 4% or Kligman’s cream at bed time for a minimum period of 2 months and then maintain it with sun protection along with use of alternate lightening agents such as Kojic acid for a long period of time. The patient should be warned of irritating potential of topical agents which includes erythema and burning. Other treatment includes use of oral tranexamic acid in a dose of 250 mg twice a day for a minimum period of two months which is reserved for melasma not responding to topical and mixed type of melasma. Chemical peels, energy based devices like intense pulsed light therapy, QS Nd:YAG can be used for treatment refractory cases but not as first line. Whatever treatment is done the patient must be counseled that the condition might relapse and there is continuous need of therapy in order to maintain the normal colour of skin. Patient has to be counseled that melasma sometimes disappear spontaneously after discontinuation of hormonal influence or careful sun avoidance.

Key Points • Melasma is one of the important cause of facial melanosis in our clinical practice. • The diagnosis is clinical and the lesions presents as hyperpigmented patch with centrofacial or malar or mandibular pattern. • Sun protection remains central to the management followed by use of lightening topical agents such as hydroquinone, Kojic acid, and tretinoin. Tranexamic acid is used orally for refractory cases and for mixed and dermal type of melasma. • Kligman’s cream and modified Kligman’s cream can be used for rapid clearance followed by maintenance with lightening agents (without steroids). • Energy based devices, chemical peels and other newer therapeutic agents can be used after proper counseling and understanding the realistic expectations of the patients.

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References 1. Ogbechie-Godec OA, Elbuluk N, Ronald O. Melasma: an up-to-date comprehensive review. Dermatol Ther (Heidelb). 2017;7:305–18. 2. Sarkar R, Bansal A, Ailawadi P.  Future therapies in Melasma. What lies ahead? Indian J Dermatol Venereol Leprol. 2020;86:8–17. 3. Dabas G, Vinay K, Parsad D, Kumar A, Kumaran MS. Psychological disturbances in patients with pigmentary disorders: a cross-sectional study. J Eur Acad Dermatol Venereol. 2019; https://doi.org/10.1111/jdv.15987. 4. Anderson L, Rodrigues M. Quality of life in a cohort of melasma patients in Australia. Australas J Dermatol. 2019;60(2):160–2. https://doi.org/10.1111/ajd.12969. 5. Heymann WR. The darkness of lichen planus pigmentosus. Dermatology world and insights archives. October 24 2016. Available https://www.aad.org/dw/dw-insights-and-inquiries/ medical-dermatology/the-darkness-of-lichen-planus-pigmentosus.

Chapter 20

A Six-Year Boy with Hypopigmented Lesions on the Neck, Retroauricullary, and on the Lateral Face Asja Prohic

A six-year boy presented to our department with hypopigmented lesions symmetrically distributed on the lateral portion of the neck, retroauricullary, and to a lesser extent on the lateral face (Fig. 20.1). He had a history of slow onset lesions of 6 months, without pruritus. A physical examination showed numerous hypopigmented macules in the aforementioned areas. The fine scales were not evident on the lesions, however, became apparent after gentle scratching. Based on the case description and the photograph, what is your diagnosis? 1. Pityriasis alba 2. Pityriasis versicolor 3. Drug-induced hypopigmentation 4. Eruptive hypomelanosis 5. Postinflammatory hypopigmentation A potassium hydroxide (KOH) direct microscopy of the scales showed the presence of spherical yeast cells and short hyaline hyphae, giving a ‘spaghetti and meatball’ appearance which was typical findings in pityriasis versicolor.

Diagnosis Pityriasis versicolor

A. Prohic (*) Department of Dermatovenerology, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_20

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Fig. 20.1  A six-year boy with hypopigmented lesions on the lateral portion of the neck, retroauricullary, and on the lateral face

Discussion Pityriasis versicolor (PV), or tinea versicolor, is a superficial fungal infection caused by commensal and lipophilic yeasts of the genus Malassezia, formerly known as Pityrosporum. Being lipid-dependend, Malassezia yeasts are found in the highest density in the sebaceous areas of the skin, which provide the source of lipids essential for their growth [1]. Although Malassezia yeasts have been associated with a number of skin conditions, PV is the only skin disease in which Malassezia yeasts in the mycelial phase can be seen under the light microscope. Various endogenous and exogenous factors, such as immunosuppression, hyperhidrosis, diabetes mellitus, use of oils and oily creams, and corticosteroid therapy, lead to the conversion from saprophytic yeast to pathogenic, mycelial form. Yeasts are capable of invading the stratum corneum causing its thickening and disruption, which is clinically evident as the fine scale [2]. Patients with PV can present with symptoms ranging from hypopigmented to hyperpigmented macules or very superficial plaques with fine scales, usually seen on the trunk or the proximal parts of the extremities. Sporadically, more unusual regions of the body such as the face and scalp, arms and legs, even palms and soles can be involved. The face is usually the only site affected by PV in children, especially in tropics where warm and moist climate provide favorable conditions for yeast pathogenicity [3]. Lesions are usually asymptomatic and smaller than trunk lesions. Today the genus Malassezia comprises 17 lipophilic species, of which M. globosa is the most commonly isolated from PV lesions. Higher pathogenicity of M. globosa over other species might be result of its high lipolytic activity in lesional skin of PV [2].

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The role of Malassezia in the etiology of hypopigmentation can be explained by the activity of dicarboxylic acid, especially azelaic acid, produced by Malassezia, which competitively inhibit tyrosinase, the enzyme in melanocytes that is responsible for melanin production. It has also been suggested that the lipoperoxidation process induced by Malassezia may account for the clinical hypopigmented appearance of the skin patches [4]. PV is usually treated with topical antimycotic drugs, including topical ketoconazole and terbinafine. Recurrent and widespread infections may require systemic treatment with different oral antifungals, such as ketoconazole, itraconazole and fluconazole [5].

Key Points • Pityriasis versicolor rarely occurs in children, which is related to the inactivity of the sebaceous glands seen in this period. • Face is usually the most common site involved in children, in contrast to adults. • Affected children often have an atypical presentation: the lesions are usually without evident fine scales and often smaller than those present on the trunk. • Direct microscopy of skin scrapings reveals the clusters of yeast and short hyphae of the causative fungus, confirming the diagnosis of this condition. • Topical antifungal therapy is usually sufficient. Systemic treatment may be needed in recurrent and widespread infections.

References 1. Prohic A, Jovovic Sadikovic T, Krupalija-Fazlic M, Kuskunovic-Vlahovljak S. Malassezia species in healthy skin and in dermatological conditions. Int J Dermatol. 2016;55(5):494–504. 2. Prohic A, Ozegovic L.  Malassezia species isolated from lesional and non-lesional skin in patients with pityriasis versicolor. Mycoses. 2007;50(1):58–63. 3. Jena DK, Sengupta S, Dwari BC, Ram MK. Pityriasis versicolor in the pediatric age group. Indian J Dermatol Venereol Leprol. 2005;71(4):259–61. 4. Gupta D, Thappa DM. The enigma of color in Tinea versicolor. Pigment Int. 2014;1:32–5. 5. Gupta AK, Foley KA.  Antifungal treatment for Pityriasis versicolor. Fungi (Basel). 2015;1(1):13–29.

Chapter 21

Homogenous Black Pigmented Lesion of the Fifth Toe Alin Laurentiu Tatu, Diana Sabina Radaschin, Florin Ciprian Bujoreanu, and Lawrence Chukwudi Nwabudike

We present the case of a 80-year-old female, referred to our service for a single, homogenous, brown-black, well-demarcated, slightly painful lesion, approximately 4  cm in diameter, located on the fifth toe. The lesion was first observed by the patient several days before presentation to the hospital. The patient had a history of hypertension treated with antihypertensives. She reported several episodes of syncope in the 4 days prior to presentation. The physical examination revealed chronic venous insufficiency with tortuous varicose veins, diminished dorsalis pedis pulses and onychodystrophy (Figs. 21.1, 21.2, and 21.3). Based on the case description and the photograph, what is your diagnosis? • Acral melanoma • Acral hematoma • Tissue necrosis

A. L. Tatu (*) Faculty of Medicine and Pharmacy, Clinical Department, Dermatology, Medical and Pharmaceutical Research Unit, Competitive, Interdisciplinary Research Integrated Platform “Dunărea de Jos”, ReForm-UDJG “Dunărea de Jos” University, Galati, Romania Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galati, Romania D. S. Radaschin · F. C. Bujoreanu Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galati, Romania Faculty of Medicine and Pharmacy, Clinical Department, Dermatology, “Dunărea de Jos” University, Galati, Romania L. C. Nwabudike N. Paulescu Institute, Bucharest, Romania © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_21

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Fig. 21.1  Solitary, homogenous, brown-black, well-demarcated, slightly painful lesion, approximately 4 cm in diameter, located on the fifth toe of the left limb

Fig. 21.2 (A) homogenous violaceous-purple pigmentation, (B) pseudoHutchinson sign

B

A

Fig. 21.3  Fading of the initial lesion after 4 days. New lesion developed on the third toe

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Diagnosis Acral hematoma associated with atheroembolism with peripheral vascular disease and the patient was referred to vascular surgery department.

Discussion The difficulty of the differential diagnosis in this clinical case consists of identifying the correct symptoms which could lead to the diagnose of certainty. The first presumed diagnosis, and the most severe and life threating, is acral melanoma. In a pigmented lesion, the role of dermoscopy is crucial. Firstly, the characteristics of any acral melanoma are rapidly observed using a dermoscope. The typical pattern of the pigment distribution in acral lesions is a very important parameter to be aware of. The parallel ridge pattern is highly suggestive for any acral pigmented melanoma [1]. This pattern corresponds to the accumulation of atypical melanocytes in the crista profunda intermedia [2]. In our case, there was a homogenous violaceous-black pigmentation, and no ridge pattern detectable. Secondly, another important aspect in deciding the correct clinical diagnose, is evaluating the nail and nail plate, also using a dermoscope. The periungual pigmentation of the nail fold visible clinically is called Hutchinson’s sign, and the same pigmentation visible only by using the dermoscope is known as microHutchinson sign. These represent important clinical signs in the diagnose of acral melanoma. The possibility that the hyperpigmented lesion would be an acral hematoma was very high. Even though the discoloration of the skin was brown black, and at first sight, the diagnosis was very difficult, the patient had history of sincopal episodes. The fact that the lesions was painful made the diagnose more probably than tissue necrosis due to atheroembolism or thrombangiitis obliternas, even though tissue necrosis may be accompanied by pain in the acut phases. Atherosclerosis is the main cause for atheroembolism. Atheroembolism occurs mostly after surgical interventions such as arteriography. The obstruction of vessels can be observed on any blood vessel, of any size, but regarding the skin necrosis, the obstruction involves small vessels that nourish the skin. Men are usually more affected than women, smoking, high levels of cholesterol (especially low-density lipoprotein), obesity, diabetes or arterial hypertension are important risk factors in the development of the atheromatous disorder. Symptoms associated with atherosclerosis obliterans include intermittent claudication, peripheric cyanosis or livedo vascularis. When affecting the lower limbs, the pulses are diminished, there is an important hair loss on the inferior extremities and gangrene may occur [3]. Thromboangiitis obliterans occurs typically in younger population and is highly associated with smoking. In the course of the disease, the patient can develop intermittent claudication, ischemic ulcers and also gangrene [3].

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Two days following admission, the patient was treated with local and systemic antibiotic therapy. The lesion on the fifth toe showed improvement, with central clearing and the colour shifted from black to violaceous-purple. In time, the patient developed a similar reaction on the third toe, of the same limb. The treatment initiated consisted of anticoagulant therapy and pentoxifylline resulting in improvement of symptoms such as pain relief and central clearing of the affected area.

Key Points • In pigmented lesions the use of dermoscopy is highly needed, sometimes being the most important help for the physician to decide. • Another important aspect when having to deal with pigmented lesions is the follow up period. For our patient, a period of several days revealed the central clearing of the lesion further confirming the diagnosis.

References 1. Soyer HP, Giuseppe A, Hofmann-Wellenhof R, Johr RH. Color atlas of melanocytic lesions of the skin [Internet]. Berlin Heidelberg: Springer; 2007. 2. Saida T, Koga H, Uhara H. Key points in dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol. 2011;38(1):25–34. 3. Wolff K, Johnson RA, Suurmond D, Fitzpatrick TB. Fitzpatrick’s color atlas and synopsis of clinical dermatology. New York: McGraw-Hill Medical Pub. Division; 2005.

Chapter 22

Piperine Extract and White Patches Alin Laurentiu Tatu, Bianca Mihaila, Rodica Dinica, Olimpia Dumitriu Buzia, Diana Sabina Radaschin, and Lawrence Chukwudi Nwabudike

We present the case of a 56 years old female, who referred to our clinic for the presence of 0.5–1 cm, asymptomatic, pale-white plaques, sharply delimited, and multiple milk-white macules, located on the dorsal hands. The lesions developed over a period of 12 months, gradually enlarging. The patient revealed she had multiple summer sun exposures and reported severe erythema and oedema on the presented

A. L. Tatu (*) Faculty of Medicine and Pharmacy, Clinical Department, Dermatology, Medical and Pharmaceutical Research Unit, Competitive, Interdisciplinary Research Integrated Platform “Dunărea de Jos”, ReForm-UDJG “Dunărea de Jos” University, Galați, Romania Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galați, Romania B. Mihaila Pharm SC Ecofarmacia Network SRL, Sibiu, Romania R. Dinica Department of Chemistry, Faculty of Sciences and Environment, ‘Dunărea de Jos’ University of Galați, Galați, Romania Medical and Pharmaceutical Research Unit, Competitive, Interdisciplinary Research Integrated Platform ‘Dunărea de Jos’, Galați, Romania O. D. Buzia Medical and Pharmaceutical Research Unit, Competitive, Interdisciplinary Research Integrated Platform ‘Dunărea de Jos’, Galați, Romania Faculty of Medicine, Department of Pharmacy, Pharmacology Sciences, ‘Dunărea de Jos’ University of Galați, Galați, Romania D. S. Radaschin Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galați, Romania Faculty of Medicine and Pharmacy, Clinical Department, Dermatology, “Dunărea de Jos” University, Galați, Romania L. C. Nwabudike N. Paulescu Institute, Bucharest, Romania © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_22

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a

b

Fig. 22.1 (a) Milky white, sharply demarcated, asymptomatic plaque and multiple white macules on dorsal hand of vitiligo, before treatment. (b) Insular pattern of repigmentation for the vitiligo lesion after 3 weeks of daily treatment with piperine ointment

a

b

c

Fig. 22.2  Insular repigmentation pattern. Dermoscopy images of the vitiligo lesion (a) Initial status, (b) After 3 weeks of piperine treatment, (c) After 12 weeks of piperine extract

lesions. The physical examination revealed no pathologic findings. The patient had no personal history of malignancy but suffered from arterial hypertension, dyslipidaemia receiving chronic treatment with antihypertensives and statin therapy. The topical treatment with high potency steroids was unsuccessful. We initiated topical therapy with piperine extract. The results were observed after 3 weeks of daily applications. The pattern of repigmentation consisted in pigmentation islands (Figs. 22.1a, b and 22.2a, b, c).  ased on the case description and the photograph, what is your diagnosis? B • Pityriasis alba • Pityriasis versicolor • Sutton nevus • Postinflammatory hypomelanosis • Vitiligo

Diagnosis Vitiligo

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Discussion Vitiligo is a chronic, acquired, autoimmune disorder which is associated with genetic and nongenetic factors, characterised by the presence of milky-white macules, sharply defined margins, which can coalescence into forming plaques. It is the most common disorder of depigmentation. Vitiligo lowers significatively the quality of life of the patient and induces an important psychological impact. It affects both females and males in equal proportions [1]. even though, females address more frequently to the dermatologist. It can develop at any age, with peak incidences at 20–30 years old. It does not show racial or ethnic differences. Personal or family medical history often suggest other autoimmune comorbidities. Vitiligo is associated with other autoimmune disorders, especially thyroid diseases such as Hashimoto’s thyroiditis or Grover’s disease but also has been connected to psoriasis, systemic lupus erythematous, type 1 diabetes with adult onset and rheumatoid arthritis. It is important to evaluate the thyroid function and antibodies, requesting hormones levels, serum TSH, antithyroid peroxidase antibodies as well as antithyroglobulin antibodies and antinuclear antibodies in the initial screening of the newly diagnosed vitiligo patient. Nowadays, vitiligo is thought to have multiple systemic implications resulting in a more complex therapeutic management. The destruction of epidermal melanocytes is attributed to various theories. The autoimmune hypothesis or the humoral hypothesis, implies the existence of specific antibodies that target various melanocytic structures resulting in melanocytic apoptosis. The inflammatory infiltrate localised mainly in the margins of active lesions is composed mainly from cytotoxic lymphocytes CD 8+ which contribute to the destruction of melanocytes through granzymes and perforins pathway. The clinical debut is associated with either physical trauma (koebner phenomen), sunburn, pregnancy or psychological stress. These are environment factors that trigger the development of vitiligo. The clinical forms of vitiligo depend on the localisation, the size and the number of depigmented plaques. It is classified into nonsegmental and segmental vitiligo by the Vitiligo Global Consesus Conference in 2012 [2]. The segmental type describes white patches of depigmented lesions unilateral distributed, in a dermatomal manner, affecting only half of the body. The nonsegmental type, the most common form, is divided into several categories depending on the body area affected. It can manifest as a generalised form, with scattered and symmetrical lesions, an acrofacial form which affects the distal parts of the fingers and the face, the universal form refers to a total depigmentation of the body and the mucosal form that involves the mucosal cavities of the body. Vitiligo can alter any body zone but more frequently the lesions are observed on sun exposed areas, periorificial and skin folds. The diagnosis is established clinically in a majority of cases. The histopathological examination describes a loss in

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the epidermal melanocytes and an inflammatory infiltrate composed by mainly lymphocytes localised into the dermis, perivascular and perifollicular. The evolution of this disease is unpredictable. It usually has a chronic development over time, with slowly progressive skin depigmentation. The therapeutical target is focused on repopulating the lesions with viable melanocytes mainly from perilesional or perifollicular sites and ceasing disease activity, lowering the potential of growth of the lesions. Topical therapy includes high potency steroids, calcineurin inhibitors and phototherapy. Phototherapy is considered one of the most effective therapy for vitiligo patients in terms of repigmentation goals and safety use. Phototherapy has immunomodulatory effects lowering cytotoxic T cells activity and increasing the melanocytic proliferation. The systemic medication is preferred to patients with rapid progression of the disease. Oral corticosteroids are preferred in trying to stop the disease activity but not to repigmentate the lesions [3]. In a recent study, it has been observed that patients who were diagnosed with vitiligo and rheumatoid arthritis in treatment with oral janus kinases inhibitors (Tofacitinib) had a better result to UVB exposure compared with patients treated with phototherapy alone [4]. Janus kinases (JAK) are very important in cell communication and transmission of cytokines. The JAK inhibitors represent a new therapeutical perspective in the management of vitiligo. Another therapeutical perspective is represented by alternative medication. A previous study performed by our team highlights the ability of piperine, an alkaloid from Piper Nigrum, to promote melanocytic proliferation in vivo [5]. It has been shown that Piper Nigrum has immunomodulatory effects and anti-inflammatory effects. It can be used alone or combined with travoprost solution. Pigmentation of skin lesions was obtained after 3 weeks of daily application. The adverse effects were rare, erythema being the only symptom related in one patient.

Key Points • Vitiligo represents a chronic, acquired, autoimmune, skin condition which is considered to be the most common cause of depigmentation. • It involves progressive melanocytic destruction causing milky white patches, which can affect individuals at any age. • It is frequently associated with other autoimmune diseases such as thyroiditis, rheumatoid arthritis, systemic lupus erythematous and psoriasis • In a majority of cases the diagnosis is based on clinical appearance • The histopathological examination reveals a decrease in epidermal melanocytic population and inflammatory infiltrate abundant in cytotoxic lymphocytes • The prognostic is unpredictable • The treatment goals are to repopulate the lesions with active melanocytes and to stop the progression of active lesions.

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References 1. Ezzedine K, Eleftheriadou V, Whitton M, van Geel N.  Vitiligo. Lancet (London, England). 2015;386(9988):74–84. 2. Ezzedine K, Lim HW, Suzuki T, Katayama I, Hamzavi I, Lan CCE, et al. Revised classification/ nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res. 2012;25(3):E1–13. 3. Rath N, Kar HK, Sabhnani S. An open labeled, comparative clinical study on efficacy and tolerability of oral minipulse of steroid (OMP) alone, OMP with PUVA and broad/narrow band UVB phototherapy in progressive vitiligo. Indian J Dermatol Venereol Leprol. 2008;74(4):357–60. 4. Gianfaldoni S, Tchernev G, Wollina U, et al. Micro-focused phototherapy associated to Janus kinase inhibitor: a promising valid therapeutic option for patients with localized Vitiligo. Open Access Maced J Med Sci. 2018;6(1):46–8. 5. Mihăilă B, Dinică RM, Tatu AL, Buzia OD. New insights in vitiligo treatments using bioactive compounds from Piper nigrum. Exp Ther Med. 2019;17(2):1039–44.

Chapter 23

Repigmentation of Palpebral White Patch Diana Sabina Radaschin, Alin Laurentiu Tatu, Lawrence Chukwudi Nwabudike, and Valeriu Ardeleanu

We present the case of a 27-year-oldmale, who referred to our clinic for the presence of 0.5–1  cm, asymptomatic, pale-white plaques, sharply delimited, and multiple milk-white macules, located periorbital and on the dorsal hands. The lesions developed over a period of 6 months, gradually enlarging. The patient revealed the debut of the lesions after sun exposure. The physical examination revealed no pathologic findings. The topical treatment with high potency steroids was unsuccessful. We initiated phototherapy using the excimer laser 308 nm one session per week combined with 2 application per week of topical calcineurin inhibitor. The initial test session confirmed a minimal erythematous dose of 150mj. The results were observed after 9 sessions with increasing energy up to 350mj. The pattern of repigmentation consisted in diffuse repigmentation areas (Figs. 23.1 and 23.2). Based on the case description and the photographs, what is your diagnosis? • Pityriasis alba • Pityriasis versicolor • Sutton nevus • Postinflammatory hypomelanosis • Vitiligo

D. S. Radaschin · A. L. Tatu (*) Faculty of Medicine and Pharmacy/Clinical Department, Dermatology, Medical and Pharmaceutical Research Unit/Competitive, “Dunărea de Jos” University, Galati, Romania Infectious Diseases Clinical Hospital “St. Parascheva”, Dermatology, Galati, Romania L. C. Nwabudike N. Paulescu Institute, Bucharest, Romania V. Ardeleanu General Hospital CFR Galați, Surgery Department; Arestetic Clinic, Galați, Faculty of Medicine Ovidius University Constanța, “Dunărea de Jos” University, Galati, Romania © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_23

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Fig. 23.1  The initial lesions, depigmentated white patch, sharply demarcated, periorbital

Fig. 23.2 Repigmentation of the initial lesion, after 9 sessions (once per week) with 308 nm excimer laser and topical calcineurin inhibitor two applications per week

Diagnosis Vitiligo.

Discussion Vitiligo is a chronic, acquired, autoimmune disorder which is associated with genetic and nongenetic factors, characterised by the presence of milky-white macules, sharply defined margins, which can coalescence into forming plaques. It is the most common disorder of depigmentation. Vitiligo lowers significatively the quality of life of the patient and induces an important psychological impact. It affects both females and males in equal proportions [1] even though, females address more frequently to the dermatologist. It can

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develop at any age, with peak incidences at 20 to 30 years old. It does not show racial or ethnic differences. Personal or family medical history often suggest other autoimmune comorbidities. Vitiligo is associated with other autoimmune disorders, especially thyroid diseases such as Hashimoto’s thyroiditis or Grover’s disease but also has been connected to psoriasis, systemic lupus erythematous, type 1 diabetes with adult onset and rheumatoid arthritis. It is important to evaluate the thyroid function and antibodies, requesting hormones levels, serum TSH, antithyroid peroxidase antibodies as well as antithyroglobulin antibodies and antinuclear antibodies in the initial screening of the newly diagnosed vitiligo patient. Nowadays, vitiligo is thought to have multiple systemic implications resulting in a more complex therapeutic management. The destruction of epidermal melanocytes is attributed to various theories. The autoimmune hypothesis or the humoral hypothesis, implies the existence of specific antibodies that target various melanocytic structures resulting in melanocytic apoptosis. The inflammatory infiltrate localised mainly in the margins of active lesions is composed mainly from cytotoxic lymphocytes CD 8+ which contribute to the destruction of melanocytes through granzymes and perforins pathway. The clinical debut is associated with either physical trauma (koebner phenomen), sunburn, pregnancy or psychological stress. These are environment factors that trigger the development of vitiligo. The clinical forms of vitiligo depend on the localisation, the size and the number of depigmented plaques. It is classified into nonsegmental and segmental vitiligo by the Vitiligo Global Consesus Conference in 2012 [2]. The segmental type describes white patches of depigmented lesions unilateral distributed, in a dermatomal manner, affecting only half of the body. The nonsegmental type, the most common form, isdivided intoseveral categories depending on the body area affected. It can manifest as a generalised form, with scattered and symmetrical lesions, an acrofacial form which affects the distal parts of the fingers and the face, the universal form refers to a total depigmentation of the body and the mucosal form that involves the mucosal cavities of the body. Vitiligo can alter any body zone but more frequently the lesions are observed on sun exposed areas, periorificial and skin folds. The diagnosis is established clinically in a majority of cases. The histopathological examination describes a loss in the epidermal melanocytes and an inflammatory infiltrate composed by mainly lymphocytes localised into the dermis, perivascular and perifollicular. The evolution of this disease is unpredictable. It usually has a chronic development over time, with slowly progressive skin depigmentation. The therapeutical target is focused on repopulating the lesions with viable melanocytes mainly from perilesional or perifollicular sites and ceasing disease activity, lowering the potential of growth of the lesions. Topical therapy includes high potency steroids, calcineurin inhibitors and phototherapy. Phototherapy is considered one of the most effective therapy for vitiligo patients in terms of repigmentation goals and safety use. Phototherapy has immunomodulatory effects lowering cytotoxic T cells activity and increasing the melanocytic proliferation. The systemic medication is preferred to

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patients with rapid progression of the disease. Oral corticosteroids are preferred in trying to stop the disease activity but not to repigmentate the lesions [3]. In a recent study, it has been observed that patients who were diagnosed with vitiligo and rheumatoid arthritis in treatment with oral janus kinases inhibitors (Tofacitinib) had a better result to UVB exposure compared with patients treated with phototherapy alone [4]. Janus kinases (JAK) are very important in cell communication and transmition of cytokines. The JAK inhibitors represent a new therapeutical perspective in the management of vitiligo. Phototherapy represents a viable therapeutical approach in vitiligo. The UVB spectrum (broadband UVB 290-320 nm and narrowband UVB 311 nm) reaches the epidermal layer of the skin and manifests its immunospuressive effects. The depletion of cytotoxic lymphocytes and Langerhans cells as well as the promotion of melanocytic proliferation are key factors in the immunomodulatory effects of phototherapy. The pigmentation starts from the active margins of the lesion, especially perifollicular. The side effects associated with the excimer laser are erythema, vesicles or hyperpigmentation. One of the most important advantages in using the 308 nm laser is the limited body area exposed to UVB. The laser can address one single lesion opposed to the classic UVB therapy where the whole body was exposed.

Key Points • Vitiligo represents a chronic, acquired, autoimmune, skin condition which is considered to be the most common cause of depigmentation. • It involves progressive melanocytic destruction causing milky white patches, which can affect individuals at any age. • It is frequently associated with other autoimmune diseases such as thyroiditis, rheumatoid arthritis, systemic lupus erythematous and psoriasis • In a majority of cases the diagnosis is based on clinical appearance • The histopathological examination reveals a decrease in epidermal melanocytic population and inflammatory infiltrate abundant in cytotoxic lymphocytes • The prognostic is unpredictable • The treatment goals are to repopulate the lesions with active melanocytes and to stop the progression of active lesions.

References 1. Ezzedine K, Eleftheriadou V, Whitton M, van Geel N.  Vitiligo. Lancet (London, England). 2015;386(9988):74–84. 2. Ezzedine K, Lim HW, Suzuki T, Katayama I, Hamzavi I, Lan CCE, et al. Revised classification/ nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res. 2012;25(3):E1–13.

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3. Rath N, Kar HK, Sabhnani S. An open labeled, comparative clinical study on efficacy and tolerability of oral minipulse of steroid (OMP) alone, OMP with PUVA and broad/narrow band UVB phototherapy in progressive vitiligo. Indian J Dermatol Venereol Leprol. 2008;74(4):357–60. 4. Gianfaldoni S, Tchernev G, Wollina U, et al. Micro-focused phototherapy associated to Janus Kinase inhibitor: a promising valid therapeutic option for patients with localized Vitiligo. Open Access Maced J Med Sci. 2018;6(1):46–8.

Chapter 24

A Case of Dark Spots in a 57-Year-old Female Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant

A 57-year-old female presented to the hospital with a 6-month history of a dyspigmentation of the skin on her face, neck, back, bilateral arms and legs. The lesion was non-itchy and painless. She denied using any medication within 3 months before the onset of the disease. She is a farmer and often has to be exposed to sunlight. No one in her family had similar lesions (Fig. 24.1). On examination, there was multiple oval blue-violet macules and patches scattered on her forehead, neck, back, upper and lower extremities. The lesion’s surface was scaleless, and the border was unclear with normal skin. Based on the case description and the photographs, what is your diagnosis? 1. Lichen planus pigmentosus. 2. Urticaria pigmentosa. 3. Macular amyloidosis. 4. Ashy dermatosis. Histopathological examination showed mild epidermal atrophy, dense lymphocyte infiltration, melanin incontinence and melanophages in the upper dermis (Figs. 24.2 and 24.3).

Diagnosis Lichen planus pigmentosus.

N. Van Thuong · L. H. Doanh · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_24

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Fig. 24.1  A 57-year-old female presented to the hospital with a 6-month history of an asymptomatic dyspigmentation of the skin on his face, neck, back, bilateral arms and legs Fig. 24.2  H&E (10×) revealed epidermal atrophy, dense lichenoid lymphocytic infiltration in the upper dermis

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Fig. 24.3  H&E (40×) revealed lymphocytic, melanin incontinence with scattered melanophages

Discussion Lichen planus pigmentosus (LPP) is a chronic relapsing dyspigmentation of the skin with onset in the third to fourth decades of life [1]. LPP was first reported in 1974 by Bhutani et al. [2], describing the clinical and histopathological features in a series of 40 patients. LPP manifests as pigmentation without any features of inflammation or preceding raised lesions. Lesions of LPP initially appear as small, ill-defined, oval macules, which later coalesce to form large areas of pigmentation. Pigments may vary from gray to blue, brown, or brownish-black. The face and neck are the most frequent initial sites, followed by the upper extremities [3]. The histopathology of LPP reveals atrophic epidermis with hypergranulosis, band-like lymphocytic infitrate of the upper dermis with colloid body, and marked melanin incontinence with many interstitial and perivascular melanophages [1]. The differiential diagnoses includeds Ashy dermatosis, pigmented contact dermatitis, melasma, acanthosis nigrican, drug-induced pigmentation, postinflammatory pigmentation, macular amylodosis, urticaria pigmentosa. Pigmented plaques tend to persist for months to years. Medium or high potency topical steroid have been commonly used but with many side effects. Topical tacrolimus is considered a reasonable treatment option. A report on the use of low-fluence Q-switched Nd-YAG (1064 nm) in 3 weekly sessions, combined with 0.1% tacrolimus, in linear LPP of the forehead, for a total duration of 4 months showed complete clearance of pigmentation, with no recurrence at 6 months of follow-up [4].

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Key Points • Lichen planus pigmentosus (LPP) is a chronic relapsing dyspigmentation of the skin with onset in the third to fourth decades of life. • Diagnosis is based on clinical and histopathological. • LPP is mainly treated with topical corticosteroid.

References 1. Mathews I, Thappa DM, Singh N, Gochhait D.  Lichen planus pigmentosus: a short review. Pigment Int. 2016;3(1):5. 2. Bhutani LK, Bedi TR, Pandhi RK, Nayak NC.  Lichen planus pigmentosus. Dermatology. 1974;149(1):43–50. 3. Gorouhi F, Davari P, Fazel N (2014) Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis. Sci World J 2014. 4. Kim JE, Won CH, Chang S, Lee MW, Choi JH, Moon KC. Linear lichen planus pigmentosus of the forehead treated by neodymium: yttrium–aluminum–garnet laser and topical tacrolimus. J Dermatol. 2012;39(2):189–91.

Chapter 25

A Challenging Variant of Hyperpigmentary Disorders Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant

A 20-year-old female presented to the clinic because of hyperpigmented macules on the trunk for 1 month, with symmetric distribution and mild pruritus, no lesions on the face, mucosa, limbs and nails. She denied having any erythematous lesions before, her medical history was significant with hepatitis C virus infection for 1 year (Figs. 25.1 and 25.2). Based on the case description and the photographs, what is your diagnosis? 1. Post-inflammatory hyperpigmentation. 2. Allergic contact dermatitis. 3. Lichen planus pigmentosus. 4. Erythema dyschromicum perstans. Histopathology revealed epidermal atrophy, basal layer hyperpigmentation, band-like lichenoid infiltration of lymphocytes with presence of melanophages at the dermis.

Diagnosis Lichen planus pigmentosus.

N. Van Thuong · L. H. Doanh · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_25

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Fig. 25.1  Symmetric hyperpigmented macules on the trunk with reticulated distribution along Blaschko lines Fig. 25.2 Generalized dotted hyperpigmentation with no Wickham’s striae and no telangiectasia

Discussion Lichen planus pigmentosus (LPP) is an uncommon variant of lichen planus, most commonly affected young to middle-aged adults with skin type III–V and female predominance. Typically, LPP presents as irregularly shaped or oval dark brown to gray macules on sun-exposed area or intertriginous zones. In the face, it favors temple and preauricular area while it affects all sides of the neck. Hallmarks of classical lichen planus are almost absent: no significant pruritus, no Wickham’s striae; palms, soles, nails and oral mucosa are usually not involved [1]. Distribution includes symmetric pattern (in majority of cases), linear (along lines of Blaschko), segmental, reticulated and follicular pattern. Etiology is not clear but associated with hepatitis C virus infection, sun exposure and contactants such as mustard oil and nickel [2].

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Histopathology revealed epidermal atrophy, vacuolar degeneration of basal cell layer, with band-like lichenoid infiltration in the dermis, scattered melanophages, pigment incontinence [3]. Thorough history and medical examination, triggering factors and comorbidities identification are required for management. LPP responses partially to topical and oral steroids, as well as other immunodulators. Topical drugs includes medium-high potency topical corticosteroids, tacrolimus, depigmenting agents (hydroquinone, Kojic acid), may or may not be in combination with systemic therapy (oral corticosteroid, dapsone) [2]. Erythema dyschromicum perstans (EDP or ashy dermatosis) and LPP shares multiple similar characteristics both clinically and histopathologically. However, EDP often presents with previous erythematous macules stage and histopathology reveals mild perivascular inflammatory infiltration. Post inflammatory hyperpigmentation develops as previous history of dermatosis subsides. So it can be ruled out in this case. For this clinical case, diagnosis of LPP was confirmed by histopathology and it belongs to linear variant, along Blaschko lines-a rare variant of LPP, etiology may be related to HCV infection.

Key Points • Lichen planus pigmentosus (LPP) is an uncommon variant of lichen planus, most commonly affecting young to middle-aged adults with skin type III–V and female predominance • Diagnosis of LPP especially rare variant can be challenging, so doctors need complete history and examination and order biopsy for further investigation when clinically suspected LPP for prompt management.

References 1. Bolognia Jean, Jorizzo Joseph L, Schaffer Julie V (eds) (2012) Dermatology. Elsevier Saunders. 2. Robles-Méndez JC, Rizo-Frías P, Herz-Ruelas ME, Pandya AG, Ocampo Candiani J. Lichen planus pigmentosus and its variants: review and update. Int J Dermatol. 2017;57(5):505–14. 3. Ghosh A, Coondoo A.  Lichen planus pigmentosus: the controversial consensus. Indian J Dermatol. 2016;61(5):482–6.

Chapter 26

A Child with Hypopigmented Patches Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant

A 7-year-old boy presented with hypopigmented patches on his face 5 months ago. The lesions started as small hypopigmented macules on the cheeks and gradually increased in number and size. The lesions were asymptomatic with no preceding erythema or inflammation, so his mother did not pay much attention. Based on the case description and the photograph, what is your diagnosis? 1. Vitiligo 2. Pityriasis versicolor 3. Pityriasis alba 4. Post-inflammatory hypopigmentation 5. Nevus depigmentosus On physical examination, there were multiple ill-defined, symmetrically distributed hypopigmented macules and patches covered by mild scaling on the face. The lesions accentuated after exposure to sun. There was no fluorescence under Wood’s light. Laboratory examinations, all the routine investigations were within normal limits. Potassium hydroxide (KOH) mount from a hypopigmented lesion was negative. The boy had a history of xerosis for 4 years and his father has a history of atopic dermatitis (Figs. 26.1 and 26.2).

Diagnosis Pityriasis alba.

L. H. Doanh · N. Van Thuong · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_26

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Fig. 26.1  A 7 years old boy presented complaning of the multiple ill-defined, symmetrically distributed hypopigmented macules and patches over the face

Fig. 26.2  Under Wood’s light, there was no fluorescence and hypopigmented patches with indistinct borders

Discussion Pityriasis alba is a common skin disorder mainly affecting the head and neck region of children. The etiology and pathogenesis remain poorly understood but it is considered to be a minor manifestation of atopic dermatitis in many cases. Associated findings in some research include atrophic sebaceous glands, iron-deficiency anemia, and low levels of serum copper [1]. The significance of these findings and their relationship to pityriasis alba is uncertain. The disease is characterized by multiple ill-defined rounds or oval-shaped hypopigmented macules or patches, often with mild scaling and asymptomatic (or

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mildly pruritic). The lesions initially may be mildly erythematous but may unnoticed [2]. They are most commonly located on the face (especially the cheeks), arms, and upper trunk; and they are more noticeable in people with darker skin types [3]. Sun exposure accentuates the lesion. Under Wood’s light, the lesions of pityriasis alba may be accentuated but are non-fluorescent. There are two uncommon variants, a pigmenting and an extensive pityriasis alba. Pigmenting pityriasis alba may be associated with superficial dermatophyte infection. Extensive pityriasis alba is characterized by typical lesions distributed in a generalized fashion, and seen more commonly in adults [4]. The differential diagnosis of pityriasis alba includes post-inflammatory hypopigmentation, pityriasis versicolor, vitiligo, nevus depigmentosus, mycosis fungoides. Post-inflammatory hypopigmentation can be ruled out due to the absence of a preceding dermatitis. Vitiligo is an acquired disease involving multiple genes and nongenetic environmental factors. It is characterized by progressive autoimmune-mediated destruction of epidermal melanocytes [2]. In vitiligo, the contrast between normal and affected skin is greater than that of pityriasis alba and under Wood lamp will fluoresce more brightly and have edges with sharper demarcation. Pityriasis versicolor is a common yeast infection of the skin. The lesions of pityriasis vesicolor are hypopigmented, pink or salmon-colored, or hyperpigmented macules with slight scales, there are mainly located on the trunk. Pityriasis versicolor can be distinguished by KOH mount of the lesion. Yeast cells that resemble spaghetti and meatballs are observed on microscopy [5]. Nevus depigmentosus is an uncommon birthmark characterised by a well-defined pale patch, almost all cases are present before the age of 2 and have well-defined borders [5]. Skin biopsy is usually not necessary, but it can distinguish pityriasis alba from mycosis fungoides [6]. Pityriasis alba is self-limiting and not dangerous but time to resolution may take several months to a few years; although most cases resolve within 1 year. Accepted treatments include emollients and low-potency topical corticosteroids. Treatment with topical calcineurin inhibitors, such as 0.1% tacrolimus ointment and 1% pimecrolimus cream or calcipotriol have also been reported to be effective. Other treatment options, usually reserved for extensive Pityriaisis alba, include psoralen-­ UVA (PUVA) and excimer laser [2, 3]. Key Points • The diagnosis of Pityriasis alba is based on the clinical appearance and distribution of the skin lesions. • The differential diagnosis includes post-inflammatory hypopigmentation, pityriasis vesicolor, vitiligo, nevus depigmentosus, mycosis fungoides. • Self-limiting condition with no reliable treatment.

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References 1. Patel AB, Kubba R, Kubba A.  Clinicopathological correlation of acquired hypopigmentary disorders. Indian J Dermatol Venereol Leprol. 2013;79(3):376–82. 2. Lapeere H, Boone B, De Schepper S, et al. Hypomelanoses and hypermelanoses. In: Goldsmith LA, Katz SI, Gilchrest BA, et al., editors. Fitzpatrick’s dermatology in general medicine, vol. 1. 8th ed. New York: McGraw-Hill Medical; 2012. p. 804. 3. Miazek N, Michalek I, Pawlowska-Kisiel M, Olszewska M, Rudnicka L.  Pityriasis Alba-­ common disease, enigmatic entity: up-to-date review of the literature. Pediatr Dermatol. 2015;32(6):786–91. 4. Fenner J, Silverberg NB.  Skin diseases associated with atopic dermatitis. Clin Dermatol. 2018;36(5):631–40. 5. Bieber T, Bussmann C. Atopic dermatitis. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed. Oxford: Elsevier; 2012. 6. Gameiro A, Gouveia M, Tellechea Ó, Moreno A.  Childhood hypopigmented mycosis fungoides: a commonly delayed diagnosis. BMJ Case Rep. 2014;23 https://doi.org/10.1136/ bcr-2014-208306.

Chapter 27

A Woman with Facial Hypopigmented Macules Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant

A 48-year-old patient presented to our clinic with some hypopigmented taches on her face evolved since 3 months. She reported no functional symptom as well as no exposure to any new substance or new condition recently and she did not have any treatment before. On examination, there were well-defined macules on her face without any scale or telangiectasia. On Wood’s lamp examination of this area, hypopigmented skin has sharper borders under black light and fluoresces bright blue-white. Dermoscopy revealed a pattern of hypopigmentation with perifollicular pigmentation (Fig. 27.1). Based on the case description and the photograph, what is your diagnosis? 1. Pityriasis alba 2. Vitiligo 3. Tinea versicolor 4. Hypopigmented mycosis fungoides (Fig. 27.2)

Diagnosis Vitiligo.

N. Van Thuong · L. H. Doanh · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_27

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Fig. 27.1  Hypopigmented macules on the face of a 48  year-old patient and the lesions under Wood’s lamp examination

Fig. 27.2  Dermoscopy revealed a pattern of hypopigmentation with residual perifollicular pigmentation

Discussion Vitiligo is an acquired chronic hypopigmented disease of the skin resulting from selective destruction of melanocytes. This disease affects approximately 1% of the population worldwide, more noticeable in dark-skinned people. Vitiligo can affect

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people of all age but it is more common in young people, with the average age of onset is 24. Although several theories have been proposed, the pathogenesis of vitiligo remains unclear. It related to both genetic and nongenetic factors. Theories regarding destruction of melanocytes include autoimmune, cytotoxic, oxidant-­ antioxidant, and neural mechanisms. Vitiligo is frequently associated with autoimmune disorders, the most common are thyroid abnormalities. Classically, primary lesions can be described as white, non-scaly macules with well-defined border. The most common involved sites are the face, neck, forearms, feet, dorsal hand, fingers, and scalp. A Wood lamp examination reveals bright blue-white fluorescences, and this may be necessary to see lesions on patients with light skin. Dermoscopy is useful in assessing the stage of evolution and the status of disease activity in vitiligo. The most useful dermoscopic clues are observed in the perifollicular region, since progressive lesions display perifollicular pigmentation while stable lesions display perifolliclar depigmentation. Histopathology is not compulsory a criteria in the diagnosis of vitiligo. It is occasionally helpful for differentiating vitiligo from other hypopigmentary disorders. The histopathology characters of vitiligo are reduction or absence of melanocyte in the lesion, and in early stage, lymphocyte infiltration can be seen. Further testing may be necessary in patients with suggestive signs or symptoms to rule out an underlying condition. Vitiligo may be associated with thyroid disease, diabetes mellitus, pernicious anemia, Addison disease, and alopecia areata. Appropriate tests should be performed only in the presence of signs or symptoms of associated disease. Laboratory work for vitiligo may include the following: • Thyroid panel consisting of thyroid-stimulating hormone (TSH), free triiodothyronine (T3), and free thyroxine (T4) levels • Antinuclear antibody • Antithyroid peroxidase antibody • Complete blood count Pityriasis alba (PA) is a common, benign skin disorder occurring predominantly in children. It is characterized by ill-defined hypopigmented macules and patches (or thin plaques), round or oval, often with mild scaling and sometimes with mild pruritus. They are most commonly located on the face (especially the cheeks), arms, and upper trunk; and they are more noticeable in people with darker skin types. In this case, we can clinically ruled out the diagnosis of PA, since the age of patient and lesion characteristics are not appropriate. Tinea versicolor (TV) is a common superficial cutaneous fungal infection. Affected skin are usually the trunk, the back, the abdomen, and the proximal extremities. The face, the scalp, and the genital region are less common. The diagnosis is usually confirmed by potassium hydroxide (KOH) examination, which demonstrates spores with short mycelium and has been referred to as the “spaghetti and meatballs” sign of tinea versicolor. The ultraviolet black light (Wood’s lamp) can be used to demonstrate the coppery-orange fluorescence of tinea versicolor. However, in some cases, the lesions appear darker than the unaffected skin under the Wood lamp, but they do not fluoresce. In this patient, with location of lesions on

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the face and blue-white fluorescences under Wood lamp, TV is less likely diagnosed. A KOH examination can be performed if available. Hypopigmented mycosis fungoides (HMF) is a rare subtype of mycosis fungoides. Unlike conventional MF, which is most commonly found in the middle-age patients (from 50 to 60 year old), HMF most commonly affects young population with average age of diagnosis at 17  year old. Clinical features of HMF are hypopigmented-­to-achromic macules or plaques, which are mainly distributed on the trunk and proximal extremities, especially the buttocks, as well as the pelvic girdle and the lower limbs. The lesions may be atrophic with telangiectasia. HMF is pathologically characterised with focal parakeratosis, little or no spongiosis, lymphocytic infiltrate in the upper dermis and epidermis. Pautrier microabscesses are seldom described. Key Points • Vitiligo is common in hypopigmented disorders. Clinical history and examination is important in diagnosis. • Wood lamp reveals shaper border lesion with blue-white fluorescences. • Dermoscopy is useful in evaluation of disease activity.

References 1. Rashighi M, Harris JE.  Vitiligo pathogenesis and emerging treatments. Dermatol Clin. 2017;35(2):257–65. 2. Baldini E, Odorisio T, Sorrenti S. Vitiligo and autoimmune thyroid disorders. Front Endocrinol (Lausanne). 2017;8:290. 3. Givler DN, Basit H, Givler A. Pityriasis Alba. Cutis. 2005;76(1):21–4. 4. Gupta AK, Kogan N, Batra R.  Pityriasis versicolor: a review of pharmacological treatment options. Expert Opin Pharmacother. 2005;6(2):165–78. 5. Furlan FC, Sanches JA. Hypopigmented mycosis fungoides: a review of its clinical features and pathophysiology. An Bras Dermatol. 2013;88(6):954–60.

Chapter 28

A Woman with Progressive Diffuse Symmetric Hyper and Hypopigmentation Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant

A 40-year-old woman presented with progressive diffuse symmetric spotted hypopigmentation on non-atrophic hypopigmented macules, that appeared firstly on the face developing over 4 years. The lesion was mild itchy, but no pain. Patient had no history of significant medical problems or disease. She denied using any long-term medications, topical creams, or preparations before the onset of the skin changes (Figs. 28.1 and 28.2).

Fig. 28.1  Generalized mottled hyper- and hypopigmented macules

L. H. Doanh · N. Van Thuong · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_28

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Fig. 28.2  Image of dermoscopy

Based on the case description and the photograph, what is your diagnosis? 1 . Amyloidosis cutis dyschromica 2. Dyschromatosis universalis hereditarian 3. Poikiloderma-like cutaneous amyloidosis 4. Macular amyloidosis 5. Lichen amyloidosis 6. Chronic arsenic toxicity A skin biopsy was performed and histopathology revealed homogenous eosinophilic masses in the papillary dermis and sparse melanophages in the superficial dermis. Congo red stain was positive (Figs. 28.3 and 28.4).

28  A Woman with Progressive Diffuse Symmetric Hyper and Hypopigmentation Fig. 28.3 Histopathology revealed amorphous eosinophilic deposits (amyloid) in the papillary dermis

Fig. 28.4  Congo red stain revealed amyloid deposits in the papillary dermis showing positive staining

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Diagnosis Amyloidosis cutis dyschromica (ACD).

Discussion Primary cutaneous amyloidosis is a group of cutaneous disorders that are characterized by extracellular deposition of amyloid in the skin without systemic involvement. Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis that presents with diffuse hypo and hyperpigmented patches and macules with no or mild itch. Atrophy and blisters are rarely seen. Onset is almost always before puberty, occasionally after puberty. The disease is generally not associated with systemic symptoms. However, there is one case report in which ACD was associated with generalized morphea, and another case report involved two siblings suffering spasticity, motor weakness, and atypical Parkinsonism [1–3]. Histopathological examination reveals local amyloid deposits in the papillary dermis. There is no significant alterations in the reticular dermis. Amyloid stains positive for crystal violet and Congo red. In rare instances, amyloid is not detected with the former stains and immunochemistry for anti-cytokeratin antibodies should be obtained if suspicion remains. This disease has positive staining for CK34βE12 and CK5/6 and faint positivity or absence of staining for AE1/AE3. The pathogenesis is poorly understood but the disease is thought to be caused by an inherited increase in sensitivity to UVB leading to defects in DNA repair [4]. In terms of treatment and outcome, Ozcan et al. used oral acitretin (0.75 mg/kg/ day for 3  months) with significant improvement in hyperpigmentation [5]. In another retrospective study published by Qiao et al., ten patients were treated with oral vitamin E and vitamin C with minimal improvement [6]. Three patients received 20 mg of oral acitretin daily for 3 months. A good response was observed in two of the three patients. Long term follow up of patients treated with acitretin was not published. Key Points • Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis. • This disease is characterized by generalized mottled hyper and hypopigmented macules distributed over the entire body. Amyloid stains positive for crystal violet and Congo red. • The treatment includes actitretin, vitamin E and vitamin C.

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References 1. Vijaikumar M, Thappa DM.  Amyloidosis cutis dyschromica in two siblings. Clin Exp Dermatol. 2001;26:674–6. 2. Morales Callaghan AM, Vila JB, Fraile HA, Romero AM, Garcia GM. Amyloidosis cutis dyschromica in a patient with generalized morphoea. Br J Dermatol. 2004;150:616–7. 3. Fernandes NF, Mercer SE, Kleinerman R, Lebwohl MG, Phelps RG. Amyloidosis cutis dyschromica associated with atypical Parkinsonism, spasticity and motor weakness in a Pakistani female. J Cutan Pathol. 2011;38(10):827–31. 4. Moriwaki S, Nishigori C, Horiguchi Y, Imamura S, Toda K, Takebe H.  Amyloidosis cutis dyschromica. DNA repair reduction in the cellular response to UV light. Arch Dermatol. 1992;128(7):966–70. 5. Ozcan A, Senol M, Aydin NE, Karaca S. Amyloidosis cutis dyschromica: a case treated with acitretin. J Dermatol. 2005;32:474–7. 6. Qiao J, Fang H, Yao H. Amyloidosis cutis dyschromica. Orphanet J Rare Dis. 2012;7:95.

Chapter 29

A Young Woman with Facial Hyperpigmented Macules Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant

A 27-year-old woman presented with hyperpigmented patches on the forehead and bilateral cheeks. The onset was one year ago. Initially, she had erythematous macules then turned spontaneously into hyperpigmented taches. She was diagnosed with allergic contact dermatitites, treated with topical corticosteroid but there was no improvement. She has no specific personal medical history as well as no family history of autoimmune disorders. She is an accountant and a carefully history interrogation revealed no exposure to any new substance or new condition recently. She reported no arthralgia, no fever, no hair loss, no tiredness, no photosensitivity. Physical examination found some hyperpigmented macules and some of them had a atrophy center. On examination with a dermoscope, we observed follicular plugging, telangiectasia, and hyperkeratosis. No fluorescence was observed on Wood's lamp examination of this area. There’s no mucosal lesion (Figs. 29.1 and 29.2). Based on the case description and the photograph, what is your diagnosis? 1. Melasma 2. Pigmented allergic contact dermatitis 3. Discoid lupus erythematosus 4. Lichen Planus Pigmentosus Laboratory bilan revealed a normal CBC, normal erythrocyte sedimentation rate. Results for antinuclear antibody, cardiolipin antibodies, β-2 glycoprotein 1 antibodies, anti-Jo-1, anti-centromere, DNA topoisomerase 1 antibody, rapid plasma reagin, HIV, and urinalysis were all unremarkable. A skin biopsy done on the frontal lesion showed degeneration of the basal layer, and a marked thickening of the basement membrane, follicular plugging, lymphohistiocytic infiltrate surrounding appendages and vessels and deposition of dermal mucin. L. H. Doanh · N. Van Thuong · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_29

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Fig. 29.1  Hyperpigmented macules on the forehead and bilateral cheeks of a young patient. The lesion had slight telangectasia and atrophy

Fig. 29.2  Dermoscopy (×20) showed keratin plugs (blue arrow), perifollicular whitish halo (circle), telangiectasia (black arrow) and “rosettes” sign (square)

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Diagnosis Discoid lupus erythematosus (DLE)

Discussion This patient's cutaneous eruption was dermoscopically and histopathologically consistent with DLE. Although clinical manifestation may not be typical. DLE is a subtype of cutaneous lupus erythematosus, characterised by erythematous to violaceous, scaly macules or plaques with prominent follicular plugging that often results in scarring and atrophy. Lesions in the scalp usually cause cicatricial alopecia. Patients may report mild pruritus or occasional pain within the lesions, but most patients are asymptomatic. Approximately 16% of patients with discoid DLE may develop systemic lupus erythematosus (SLE) involvement within 3 years of diagnosis [1]. Therefore a bilan screening of SLE must be done at the point of diagnosis and regularly repeated in follow-up period. The characteristic histopathologic alterations observed in discoid lupus erythematosus (DLE) include: alteration of the basal cell layer, thickening of the basement membrane, follicular plugging, hyperkeratosis, atrophy of the epidermis, inflammatory cell infiltrate (usually lymphocytic) in a perivascular, periappendageal and a deposit of mucin is seen within the dermis. On dermoscopy, perifollicular whitish halo, follicular keratotic plugs and telangiectasia were the most common criteria. A special sign “rosettes” which varies in size from 0.2–0.5 mm is believed to stem from an optical effect of the polarized light and its interaction with adnexal openings that are narrowed or filled with keratin [2]. Melasma is an acquired hypermelanosis, mostly affect sun-exposed areas. Melasma presents as symmetrically distributed hyperpigmented macules. Areas that receive excessive sun exposure, including the cheeks, the upper lip, the chin, and the forehead, are the most common locations; however, melasma can occasionally occur in other sun-exposed locations [3]. Patients may inquire about progressive hyperpigmentation of the face, which may be temporally related to pregnancy or to the use of oral contraceptive pills. Intense or long term exposure to sunlight worsens the condition. The excess melanin can be visually localized to the epidermis or the dermis by use of a Wood lamp. Epidermal pigment is enhanced during examination with a Wood light, whereas, dermal pigment is not. Pigmented contact dermatitis (also known as Riehls melanosis) is caused by an allergic contact dermatitis to a variety of topical and airborne allergens in a long period of time. Many cases are preceded by mild erythema, edema, and pruritus, followed by a diffuse-to-reticulated pattern of hyperpigmentation. The pigmentation varies, and can be brown, slate-gray, gray-brown, red-brown, or blue-brown.

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The site of pigmented contact dermatitis also depends on the allergen responsible. Pigmented cosmetic dermatitis more commonly involves the face, whereas pigmented contact dermatitis due to textiles more often involves the anterior thighs or the axilla, with sparing of the axillary vault. Lichen planus pigmentosus (LPP) is a photodistributed dyschromia of unknown etiology, described clinically as hyperpigmented gray-blue or brown-black macules in a photodistributed pattern. Lesions of LPP initially appear as small, ill-defined, oval-to-round macules, which later become confluent to form large areas of pigmentation. Pigmentation varies from slate gray to blue to brown to brownish-black; in a single patient, the pigment is generally uniform. The face and neck are the most frequent initial sites, followed by the upper extremities. Co-existent classic lichen planus lesions can be seen in up to 20% of LPP patients [4]. Key Points • Discoid lupus erythematosus (DLE) may be a cause of hyperpigmentation. • A screening of systemic lupus erythematosus must be done for all DLE.

References 1. Goldsmith LA, Katz SI, Gilchrest BA, et  al. Chronic cutaneous lupus erythematosus (discoid lupus erythematosus). In: Fitzpatrick’s dermatology in general medicine, vol. 1. 8th ed. New York: Mc Graw Hill; 2012. p. 996–8. 2. Jha AK, Sonthalia S, và Sarkar R.  Dermoscopy of discoid lupus erythematosus. Indian Dermatol Online J. 2016;7(5):458. 3. Ogbechie-Godec OA, và Elbuluk N. Melasma: an up-to-date comprehensive review. Dermatol Ther. 2017;7(3):305–18. 4. Wolff M, Sabzevari N, Gropper C. A case of Lichen Planus pigmentosus with facial dyspigmentation responsive to combination therapy with chemical peels and topical retinoids. J Clin Aesthetic Dermatol. 2016;9(11):44–50.

Chapter 30

Asymptomatic Hyperpigmentation Without Preceding Inflammation in a Female Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant

A 24-year-old Vietnamese woman presented to the clinic because of hypopigmented lesions on her upper extremities for 2 weeks. She denied any preceding changes such as erythema, blisters or erosion (Fig. 30.1). Based on the case description and photographs, what is your diagnosis? 1. Allergic contact dermatitis 2. Post-inflammatory hypopigmentation 3. Phytophotodermatitis Fig. 30.1  A 24-year-old female with multiple brown pigmented patches on both hands. The pigmentations showed irregular shape with rather sharp borders

L. H. Doanh · N. Van Thuong · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_30

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The patient denied any history of trauma or irritation. In history taking, she returned from a 1-week sea vacation 5 days before the skin lesions appeared. During her trip, she spent approximately 3 h per day on the beach. There was no history of a similar skin rash in the past and she was otherwise systemically well. She had no familial history of similar skin lesion. Besides, she has eaten two limes each day in the recent 2 months to lose weight. On examination, the only abnormalities were restricted to the skin examination. Most of the pigmentation showed irregular shaped, homogeneous, brown colored patches with sharp borders. They were located mostly on the lateral sides of the forearms and the dorsum of hands. On follow-up, the lesions resolved spontaneously without any treatment. There was no recurrence at 3-months’ follow-up.

Diagnosis Phytophotodermatitis-photosensitization from the psoralens found in lime juice

Discussion Phytophotodermatitis is a phototoxic reaction caused by skin contact with plant juices that contain photosensitizing substances such as furocoumarins or psoralens, followed by intense sunlight exposure—particularly ultraviolet A (UVA) radiation (320 nm to 400 nm). Typical manifestations of phytophotodermatitis begins with erythematous swelling at the locations of contact and exposure, and vesicles or blisters can also be present with itching or burning sensation. It usually leaves brown pigmentation on inflamed areas but the pigmentation can disappear without any treatment. This feature play a pivotal role in phytophotodermatitis diagnosis. In a lot of clinical cases, hyperpigmented patches without any preceding erythema or blistering could be the only clinical finding of phytophotodermatitis, depending on the amount of contacting substance, skin color of the affected patient and intensity of photo-exposure. Lime is the most common culprit for asymptomatic hyperpigmentation as clinical feature of phytophotodermatitis. There are other types of plant family that can cause phytophotodermatitis , as shown in Table 30.1 [1]. Table 30.1  Common plants associated with phytophotodermatitis

Plant family Rutaceae Umbelliferae

Common name of plant Lemon, lime, Persian lime, bergamot Celery*, carrots, parsley, parsnip, fennel, dill Moraceae Fig Ranunculaceae Buttercup Cruciferae Mustard

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Until now there have been many reports in which waiters who prepare cocktails with lime, such as mojito, developed spontaneous, usually asymptomatic pigmentation on the dorsum of hands [2]. In most of these asymptomatic pigmentation induced by contact with lime, an interval of 7 to 14 days between exposure and onset of lesion was a common finding. The patient in this report shared several clinical features. She developed spontaneous hyperpigmented patches on the hands, usually the most contact-prone body part. The pigmentations were of homogeneous brown color with distinct borders. Most importantly, the patient travelled to the location with strong sunlight before the onset and she had history of using lime for losing weight 2 months before the trip. Last but not least, the lesions faded away without any treatment. In terms of treatment, no medications are required in most of cases. In some single cases, treatment is aimed at reducing inflammatory response including cool wet dressings, soothing lotions, topical corticosteroids and systemic antipruritic agents. Systemic corticosteroids can be used in severe cases or when lesions are too extensive for topical therapy to be practical or effective. Sunscreen should be used to avoid any further hyperpigmentation when the patient is outside. Use of a bleaching agent such as 4% hydroquinone can be used if skin discoloration is bothersome. Key Points • Lime is the most common culprit for asymptomatic hyperpigmentation as clinical feature of phytophotodermatitis. • No medications are required in most of cases.

References 1. Greenaway C. A tropical skin eruption. Can J Infect Dis. 2002;13(2):82–142. 2. Choi JY. Asymptomatic hyperpigmentation without preceding inflammation as a clinical feature of citrus fruits-induced phytophotodermatitis. Ann Dermatol. 2018;30(1):75–8.

Chapter 31

Brown Patches in a 51-Year-Old Man Nguyen Van Thuong, Le Huu Doanh, and Michael Tirant

A 51-year-old male presented to NHDV with patchy brown spots on his upper cheek. He is a farmer and exposed to a lot of sunshine. He has never had a treatment and seems a little apprehensive during the consultation. He reported that he has previously experienced melasma and his family has a history of the condition-but it quickly went away without any treatment. However, this time he started noticing the discoloration during the previous summer (Fig. 31.1).

Fig. 31.1  A 51 year-old male presented complaining of brown patches on his cheeks. Looking at his skin under a Wood’s light showed clearly hyperpigmented plaque

N. Van Thuong · L. H. Doanh · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_31

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Fig. 31.2  Image shows network brown pigmentation on dermoscopy with ×10 magnification

Based on the case description and the photographs, what is your diagnosis? 1. Melasma 2. Freckle 3. Post-inflammatory hyperpigmentation 4. Allergic contact dermatitis On examination, we found multiples brown, tan patches with ill-defined border on his cheeks and jaws. Looking at his skin under a Wood’s light showed clear hyperpigmented plaques. For differential diagnosis with other hyperpigmentation conditions, dermoscopy was indicated. The result showed network brown pigmentation on dermoscopy with ×10 magnification (Fig. 31.2).

Diagnosis Epidermal melasma

Discussion Melasma is a common pigmentation disorder that causes brown or gray patches to appear on the skin, primarily on the face. According to the American Academy of Dermatology, it is more commonly seen in women, though it still affects approximately 10% of men [1]. The most common area for patches of melasma to appear is the face. Other common locations include the upper lips, bridge of the nose, cheeks, and forehead.

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Potential triggers for melasma include: • Changes in hormones during pregnancy (chloasma), hormone treatment, or while taking birth control pills • Sun exposure • Certain skin care products, if they irritate a person's skin Also, there may be a genetic component to melasma, as people whose close relatives have experienced melasma are more likely to develop it themselves. Diagnosis of melasma is not difficult. A visual examination of the affected area is often enough to diagnose. To rule out specific causes, your doctor might also perform some tests like Wood’s light, dermoscopy and biopsy. Male patients are not as concerned about the appearance of their skin as women are and they will be reluctant to follow a stringent skin care plan. To encourage the greatest degree of treatment adherence, clinicians should take into careful consideration of each patient’s individual needs when creating treatment regimens, as preferences and expectations might differ greatly among men and their female counterparts. Regardless of sex, physicians should counsel all patients regarding protection from sun exposure, with emphasis on optimal and regular application of sunscreen and use of hats and clothing that block the sun. Physicians must be extra attentive to male patients, who have shown to be less successful in adhering to sunscreen application guidelines. There is a paucity of literature on treatment of melasma in men. Most of the guidelines for melasma have been based on studies done predominantly in women. The management recommendations for men are similar to those for women, and there are no separate recommendations for the men. Various treatment options for melasma, include the use of topical and oral depigmenting agents, chemical peels, and surgical modalities, such as dermabrasion and lasers [2–4]. The treatment of melasma is challenging, often unsatisfactory, and needs to be continued indefinitely to avoid recurrence. Further studies on melasma in men belonging to different population groups would go a long way in a better understanding of the differences from their female counterparts [5]. Key Points • Diagnosis of melasma is not difficult to establish. • The treatment of melasma is challenging. • There is a paucity of literature on treatment of melasma in men.

References 1. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB. Melasma: a clinical, light microscopic, ultrastructural, andimmunofluorescence study. J Am Acad Dermatol. 1981;4(6):698–710. 2. Shankar K, et al. Evidence-based treatment for melasma: expert opinion and a review. Dermatol Ther (Heidelb). 2014;4:165–86.

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3. Văn Thường N.  Bệnh rám má, Bệnh học Da liễu tập 1. Nhà xuất bản y học, trang; 2016. p. 143–148 4. Rashmi Sarkar MD, MNAMS. Melasma in men: a review of clinical, etiological, and management issues. J Clin Aesthet Dermatol. 2018;11(2):53–9. 5. Vazquez M, Maldonado H, Benmaman C, et al. Melasma in men (1988). a clinical and histologic study. Int J Dermatol. 27:25–7.

Chapter 32

Dyschromatosis in a 23-Year-Old Male Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant

A 23-year-old man presented with hyper and hypopigmented macules on the dorsal aspects of the extremities that had appeared early since his childhood (Fig. 32.1). On examination, skin lesions were asymptomatic but they became more pronounced (obvious) after exposure to the sun. His development was normal and there was no particular past medical history except for partial color blindness. Regarding family medical history, his grandfather and brother also had the same skin lesion with the similar features. Laboratory examinations including complete blood counts, blood biochemistry and urinalysis revealed no abnormalities (Fig. 32.2).

Fig. 32.1  Hyper and hypopigmentation macules on the dorsal aspect of the hand and fingers

L. H. Doanh · N. Van Thuong · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_32

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Fig. 32.2  Hyper and hypopigmentation macules on the dorsal aspect of the hand and feet

 ased on the case description and the photograph, what is your diagnosis? B 1. Vitiligo 2. Dyschromatosis symmetrica hereditaria 3. Dyschromatic amyloidosis 4. Amyloidosis cutis dyschromica 5. Focal hypopigmentation

Diagnosis Dyschromatosis symmetrica hereditaria

Discussion Dyschromatosis symmetrica hereditaria (DSH), initially known as reticulated acropigmentation of Dohi, was first described by Toyama in 1929 [1]. It is a rare pigmentary genodermatosis that is characterized by the onset of hyper- and hypopigmented macules on the face and dorsal aspects of the extremities in infancy or early childhood [2]. The skin lesions commonly stop spreading before adolescence, and last a lifetime. The pattern of inheritance is basically reported to be autosomal dominant. In several cases, the skin lesions are reported to become more obvious after exposure to sunlight, but there was no evidence of photosensitivity. Apart from the skin lesions, there are no common disorders associated with DSH. DSH was formerly considered to be a Japanese/Korean specific genodermatosis, but a similar

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condition has been reported among Europeans and South Americans [3]. There is currently no diagnostic standard of DSH. Clinically, DSH is characterized by hyperand hypopigmented macules on the dorsum of hands and feet appearing in infancy or early childhood. Pathological findings allow us to assess epidermal melanization but may not show consistent findings due to different sampling or assessment methods. In 2003, in the Chinese and Japanese groups, some researchers have identified pathogenic mutations in the ADAR1 gene. Prior to this, most of our cases were diagnosed with DSH based on clinical features [4]. After 2003, however, the diagnosis is greatly supported by mutation analysis, especially in doubtful cases [5].

Key Points • Dyschromatosis symmetrica hereditaria is a rare pigmentary genodermatosis. • DSH is characterized by hyper- and hypopigmented macules on the dorsum of hands and feet appearing in infancy or early childhood.

References 1. Ostlere LS. Reticulate acropigmentation of Dohi. Clin Exp Dermatol. 1995;20(6):477–9. 2. Hayashi M, Suzuki T. Dyschromatosis symmetrica hereditaria. J Dermatol. 2013;40(5):336–43. 3. Oyama M, Shimizu H, Ohata Y, et  al. Dyschromatosis symmetrica hereditaria (reticulate acropigmentation of Dohi): report of a Japanese family with the condition and a literature review of 185 cases. Br J Dermatol. 1999;140(3):491–6. 4. Peng AC-Y, Chen Y-A, Chao S-C. Dyschromatosis symmetrica hereditaria: a retrospective case series and literature review. Dermatologica Sinica. 2013;31(1):19–24. 5. Miyamura Y, et al. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet. 2003;73(3):693–9.

Chapter 33

Facial Hypopigmentation in a Vietnamese Woman Le Huu Doanh, Nguyen Van Thuong, and Michael Tirant

A 36-year-old Vietnamese woman presented to the clinic because of hypopigmented lesions on her face developed over 1 month. She denied having any pruritus or pain (Fig. 33.1).

Fig. 33.1  A 36-year-old female with well-defined, confetti-like hypopigmented macules on hyperpigmented base

L. H. Doanh · N. Van Thuong · M. Tirant (*) Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_33

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 ased on the case description and the photographs, what is your diagnosis? B 1. Vitiligo 2. Post-inflammatory hypopigmentation 3. Chemical hypomelanosis 4. Morphea 5. Pityriasis alba The patient reported applying Piper betle leaves once daily for 1 month to treat melasma. In the first week, the melasma improved quickly but then relapsed, and she also noticed multiple small white macules on the hyperpigmented base appeared on her cheeks. Wood lamp revealed no blue-white fluorescence; no skin atrophy or telangiectasia was detected on Dermoscopy (Fig. 33.2).

Diagnosis Chemical hypomelanosis following Piper betle.

Fig. 33.2  No fluorescence on Wood lamp

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Discussion Betle chewing used to be a traditional habit in South and Southeast Asia. In this modern life, skin disease following Piper betle is considered to be an old story. It was first described in 1997 by Yang on 137 Taiwanese population. At that time topical dressings with steamed betel leaves was a hot trend to manage hyperpigmented disorders such as melasma, solar lentigines and freckles. The leaves were steamed first, left to cool and then applied on pigmented areas. After a few months, multiple women sought for dermatologists because of leukomelanosis-hypopigmented macules interspersed with hyperpigmented areas [1]. Piper betle leaves extracts, which contains phenolic derivatives (benzene, phenol, catechol, hydroquinone) are well-known of depigmentation effects and they can also cause melanocytotoxicity in vivo. In 1999, 2 years after first description, Liao et al. suggested three stages of this pigmentary disorder. The first stage is bleaching stage, when pre-existing hyperpigmented disorders improve quickly, almost patients are satisfied as their skins were softer, more tender and whitened. The second stage is the mottled hyperpigmentation stage. In this stage, all patients experienced prominent irregular hyperpigmentation. Yang and Liao supposed this phenomenon was post-­ inflammatory hyperpigmentation process. The third stage is the confetti-like depigmentation stage, which gradually developed over the area treated with piper betel leaves, in addition to the mottled hyperpigmentation already present after the second stage. This depigmentation resulted from the leaf extract mentioned above [2]. The mentioned clinical case was in third stage with obvious confetti-like hypopigmentation. Diagnosis was made based on medical history and clinical examination. Wood lamp and Dermoscopy assisted to rule out vitiligo and other inflammatory disorders.

Key Points • The story of Piper betle-induced leukomelanosis is still going on in some rural areas in Vietnam. • Until now, there have been no treatment guidelines were recommended for this disorder. • Management is mainly based on experiences with poor response.

References 1. Yang LJ, Chen DY, Chan HL.  Hyperpigmentation with confetti appearance  – the sequelae of facial application with piper betle leaf: a clinical survey of 137 patients. Dermatol Sin. 1997;15:249–55. 2. Liao YL, Chiang YC, Tsai TF, et  al. Contact leukomelanosis induced by the leaves of piper betle L. (Piperaceae): a clinical and histopathologic survey. J Am Acad Dermatol. 1999;40:583–9.

Chapter 34

An Elderly Masked Man Yasemin Yuyucu Karabulut, Gözde Arslan, Ahmet Çelik, and Ümit Türsen

A 58-year-old male patient was admitted to cardiology clinic with the complaint of color change of his face. On his medical history he had previous myocardial infarction, coronary bypass, ventricular tachycardia. He had left venrticular systolic dysfunction and an intracardiac defibrillator. He did not have any dyspnea and he was Class I symptomatic according to New York Heart Association Classification. He had 35% left ventricular ejection fraction on transtorasic echocardiogram. He was taken amiodarone 400 mg/daily about 5 years, ramipril 2.5 mg/daily, asetil salicylic acid 100 mg/daily, sotalol 160 mg/daily. It was thought that the color change on the face of the patient using amiodarone was related to drug use and directed to dermatology for biopsy. An incisional biopsy was performed by dermatology clinic with the preliminary diagnosis of amiodarone-associated pigmentation. Hyperpigmented skin ellipse with a size of 6 × 2 × 1 mm was sampled (Fig. 34.1).  ased on the case description and the photograph, what is your diagnosis? B –– Addison Disease –– Amiodarone Discoloration –– Cushing Disease –– Porphyria Cutanea Tarda

Y. Y. Karabulut · G. Arslan · A. Çelik Department of Pathology, School of Medicine, Mersin University, Mersin, Turkey Ü. Türsen (*) Department of Dermatology, School of Medicine, Mersin University, Mersin, Turkey © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_34

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Fig. 34.1 Blue–gray discoloration appeared on the face spreading to the neck, particularly on the nose, cheeks and chin

Diagnosis Amiodarone Discoloration In the histological serial sections mild orthokeratosis, follicular plugging and mild epidermal atrophy were observed in the epidermis, and granular accumulations consistent with light brown-yellow lipofuscin pigment were observed in histiocyte cytoplasms, which were accompanied by a few number of lymphocytes perivascular concentrating in the papillary and superficial dermis (Figs. 34.2, 34.3, and 34.4). The diagnosis of pigmentation due to amiodorone effect was confirmed by these histomorphological findings. Patients symptoms disappeared in 15 months after stopping the use of amiodarone (Fig. 34.5).

Discussion Amiodarone is an anti-arrhythmic and coronary vasodilator and associated with a phototoxic/photosensitivity reaction is up to 50% of patients [1, 2]. It has long been known to induce a distinctive blue-gray discoloration of sun-exposed areas, especially the face. Pigmentation is also sometimes seen in the sclera and cornea [3]. Factors affecting the risk of developing pigmentary changes include daily dosage and duration of treatment with a high risk associated with dosages more than 800 mg/day, and the onset of an early photosensitivity on light-exposed areas [4]. The concentration of amiodarone in the fat-associated tissues is up to 500 times the serum concentration and more than 10 times the myocardial concentration. Its

34  An Elderly Masked Man Fig. 34.2 Granular accumulations consistent with light brown-yellow lipofuscin pigment were observed in histiocyte cytoplasms (H&E, ×200)

Fig. 34.3 Concentrating lipofuscin pigment were observed in histiocyte cytoplasms in the superficial dermis (H&E, ×400)

Fig. 34.4 Perivascular concentrating lipofuscin pigment were observed in histiocyte cytoplasms (H&E, ×400)

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Fig. 34.5  The blue–gray discoloration disappeared after stopping the use of amiodarone

half-­life averages 52 days and may exceed 100 days so it takes a long time to pass its effects [5]. The mechanism involved in pigmentation is still hypothetical but it is characterized by the presence of macrophages containing PAS-positive, yellow-brown lipofuscin like granules predominantly located in a perivascular distribution [1]. The deposit of lipofuscin in dermal histiocytes which contain dense bodies of osmiophilic material [4]. Melanin pigmentation of the epidermis isn’t increased; indeed its absence in involved skin has recently been documented [2]. Similar inclusions may be found in the hepatocytes, Kupffer cells, pulmonary macrophages and neutrophil polymorphs. Pigmentation is usually reversible after discontinuation of the medication, but lesions may persist for up to 1 year [4].

Key Points • Amiodarone is an anti-arrhythmic and coronary vasodilator drug. • Granular accumulations consistent with light brown-yellow lipofuscin pigment cause color change of skin.

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References 1. Trimble JW, Mendelson DS, Fetter BF, et al. Cutaneous pigmentation secondary to amiodarone therapy. Arch Dermatol. 1983;119:914–8. 2. Hass N, Schadendorf D. Hypomelanosis due to block of melanosomal maturation in amiodarone induced hyperpigmentation. Arch Dermatol. 2001;137:513–4. 3. Bahadır S, Apaydın R, Cobanoğlu U, et al. Amiodarone pigmentation, eye and thyroid alterations. J Eur Acad Dermatol Venereol. 2000;14:194–5. 4. Dereure O. Drug-induced skin pigmentation epidemiology, diagnosis and treatment. Am J Clin Dermatol. 2001;2:253–62. 5. Kounis NG, et al. Dose-dependent appearance and disappearance of amiodarone-induced skin pigmentation. Clin Cardiol. 1996;19:592–4.

Chapter 35

Hyperpigmented Plaques Emin Gündüz, Ümit Türsen, and Yasemin Yuyucu Karabulut

The patient was hospitalized and followed up in our clinic in terms of systemic steroid treatment during severe episodes. Short term systemic steroids and Colchicine 3  ×  0.5  mg/day were followed up in remission with topical and oral mucosa care treatments. Ophthalmologic examination revealed no pathological findings. Systemic screening was performed in terms of systemic involvement of Behçet’s disease and no systemic involvement was detected except cardiovascular involvement. In remission, the patient was followed up with colchicine 3 × 0.5 mg/ day and nonsteroidal anti-inflammatory drugs. Hyperpigmented, erythematous and atrophic plaques were detected in the thigh and abdominal region in the last 1 year. Subsequently, psoriasiform and hyperpigmented plaques were observed in the lower extremities. Based on the case description and photographs, what is your diagnosis? 1. Psoriasis Vulgaris 2. Mycosis Fungoides 3. Morphea 4. Erythema Nodosum

E. Gündüz · Ü. Türsen (*) Department of Dermatology, Faculty of Medicine, Mersin University, Mersin, Turkey Y. Y. Karabulut Department of Pathology, Faculty of Medicine, Mersin University, Mersin, Turkey © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_35

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Photograph 1.1 and Photograph 1.5 biopsy localization. Two biopsies were taken from the anterior lesions.

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In the specimen taken from the abdominal region (Photograph 1.1), histopathologically, the epidermis showed orthokeratosis, irregular acanthosis and mild spongiosis, and it was noted that lymphocytes showing basilar sequencing in large areas of the dermoepidermal junction could also progress to transepidermal. In the papillary dermis, lymphoid cell infiltration, which is characterized by interstitial dispersion in the fibrotic ground around the vessels and which exhibits signs of atypia characterized by nuclear coarseness and hyperchromasia, has been observed, similar to transepidermal dispersions. It was observed that the lymphoid cells identified in serial sections can also attach to 2 hair follicle epithelium. In the histopathology of psoriasiform and hyperpigmented plaque lesions (Photograph 1.5) in the lower extremities, compact hyperkeratosis, parakeratosis and psoriasiform hyperplasia were observed in the epidermis. It has been observed that lymphocytes showing basilar sequence in the dermoepidermal junction can also progress in transepidermal. Infrequent lymphoid cell infiltration around the thick-­ walled vascular structures in the papillary dermis, perpendicular to the epidermis on the fibrotic floor, was noted. No specific infectious agent was detected with Methenamine Silver. No specific infectious agent was observed with PAS.

Diagnosis Mycosis Fungoides.

Discussion Hyperpigmented papules and plaques may be encountered in many dermatological conditions. Typically, classical Mycosis Fungoides patients progress from the patch stage to the plaque stage and finally to the tumoral stage, and have a long clinical course that lasts years, or even decades. Before definitive diagnosis, non-­specific eczematous or psoriasiform skin lesions are observed in the majority of patients. Early patch stage Mycosis Fungoides typically presents with erythematous, finescaling lesions of varying size, sometimes itchy. Atrophy, hypopigmentation, hyperpigmentation, telangiectasia may be observed in these early lesions. Initial skin lesions tend to be located on the hips, trunk and other covered parts of the extremities [1]. Behçet’s disease is a multi-organ disorder that is more common in countries around the Silk Road, and manifests as mucosal ulcers and skin lesions, and with ocular involvement [2]. It was first described by Hippocrates but was brought to attention in 1937 by Hulusi Behçet, a Turkish dermatologist from Istanbul, who reported three patients with recurrent oral and genital ulceration, hypopyon uveitis, and erythema nodosum [3]. Skin disease occurs in over 75% of patients with Behçet’s disease [4]. Erythema nodosum usually occurs in the lower extremities and is characterized by red, painful nodules 1–5  cm in diameter. They are more

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commonly observed in female patients, and they heal with pigmentation in 1–6 weeks [2]. Acneiform lesions are another common presentation of the disease. Although its appearance is similar to ordinary acne, and it appears on the usual acne sites, such as the face, back, and chest, it also occurs on unusual sites such as the arms and legs [5]. Hyperpigmented postinflammatory macular eruption on the extensor forearms bilaterally after a recent typical Behçet’s disease flare up of papulopustules. İmportantly, inflammatory manifestations of Behçet’s disease can also mimic infections [6]. Malignant lymphoma is rarely associated with Behcet’s disease, as only 12 cases have been reported in the literature, including a case of cutaneous T-cell lymphoma. Through a review of these 12 cases, the age of the patients ranged between 31 and 75 years. There were two cases of T cell lymphoma including a cytotoxic T cell lymphoma, 2 cases of Hodgkin Lymphoma and 7 cases of B cell lymphoma [7]. In one patient with Behçet’s disease, intraepithelial atypical lymphocytes were detected in the oral mucosa. The cells with cerebriform nuclei showed condensed chromatin at the nuclear membranes and rather scanty cytoplasm. Many of these cells were present in association with macrophages [8]. This observation suggests that both cells may play a role in the pathogenic mechanism of Behçet’s syndrome or that they may act in concert. Certainly, too, the occurrence of atypical lymphocytes in the epithelium and their absence in the submucosal layer of early oral Behçet’s lesions are unusual findings for these cells in non-lymphomatous disorders. The atypical lymphocytes with cerebriform nuclei fulfill the criteria [9–11]. The exact pathogenesis of malignant lymphoma arising in the setting of Behçet’s disease is not known, and it remains unclear if it is induced by immunosuppressive therapy. The predisposing role of immunosuppressive therapy, and especially Cyclosporin, has been previously discussed [12]. Based on the patient’s medical history, clinical photographs and biopsy results, the diagnosis of Mycosis Fungoides was made. The patient was instructed topical therapy (topical clobetasole propionate 0.05%, Bexarotene gel, emollients) and phototherapy (narrow-band UVB three times a week). Significant improvement was observed clinically after the current treatment. Key Points • Behçet’s disease is a multi organ disorder. • Cutaneous T cell Lymphoma and associated with Behçet’s disease • Atypical (cerebriform) nuclei.

References 1. Radonich MA, Lazova R, Bolognia J. Cutaneous natural killer/T-cell lymphoma. J Am Acad Dermatol. 2002;46(3):451–6. 2. Rokutanda R, Kishimoto M, Okada M. Update on the diagnosis and management of Behçet’s disease. Open Access Rheumatol. 2015;7:1–8.

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3. Behçet H. Über rezidivierende aphthöse, durch ein Virus verursachte Geschwüre am Mund, am Auge und an den Genitalien. Dermatol Wochenschr. 1937;36:1152–7. 4. Sakane T, Takeno M, Suzuki N, Inaba G.  Behçet’s disease. N Engl J Med. 1999;341(17):1284–91. 5. Hatemi G, Bahar H, Uysal S, et al. The pustular skin lesions in Behcet’s syndrome are not sterile. Ann Rheum Dis. 2004;63(11):1450–2. 6. Sanchez IM, Shinkai K. Atypical Behçet’s disease with endocarditis, pyoderma gangrenosum-­ like ulcers and MRSA positive skin abscesses. JAAD Case Rep. 2018;4(5):449–51. 7. Chelly I, Limaïem F, Mekni A, Bellil S, Bellil K, Ghorbel IB, et  al. Cutaneous gamma-­ delta T-cell lymphoma (CGD-TCL) arising in the setting of Behçet’s disease. Pathologica. 2008;100(3):166–9. 8. Honma T, Saito T, Fujioka Y. Intraepithelial atypical lymphocytes in oral lesions of Behçet’s syndrome. Arch Dermatol. 1981;117:83–5. 9. Lutzner MA, Jordan HW. The ultrastructure of an abnormal cell in Sezary’s syndrome. Blood. 1968;31:719–26. 10. Brownlee TR, Murad TM. Ultrastructure of mycosis fungoides. Cancer. 1970;26:686–98. 11. Meyer CJ, van Leeuwen AW, van der Loo EM, et al. Cerebriform (Sezary-like) mononuclear cells in healthy individuals, a morphologically distinct population of T cells: relationship with mycosis fungoides and Sezary’s syndrome. Virchows Arch B Cell Pathol. 1977;25:95–104. 12. Houman MH, Ben Ghorbel I, B’Chir-Hamzaoui S, Lamloum M, Kchir N, Miled M. Intestinal lymphoma associated with Behçet’s disease. Am Med İnterne. 2001;152:415–8.

Chapter 36

A Painful White Streak on the Leg Uwe Wollina

A 19-year-old woman presented in the emergency room with a painful white streak on her left thigh. She had been cleaning the limestone in the bathroom at home. After finishing the procedure, she noted some burning and stinging pain. Based on the case description and the photograph, what is your diagnosis? 1. Thermal burn. 2. Chemical burn. 3. Mechanical trauma. 4. Insect bite. 5. Herpes zoster.

U. Wollina (*) Department of Dermatology and Allergology, Municipal Hospital of Dresden, Academic Teaching Hospital, Dresden, Germany e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_36

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Upper leg with a trace of formic acid leaving a scar with elevated borders and a whitish central necrosis.

Diagnosis Chemical burn due to skin contact to formic acid.

Discussion The patient had been used concentrated formic acid to remove limestone from the toilet bowl. Some drops of the fluid moistened her trousers, but she did not care immediately. The she experienced stinging and burning pain. When she removed the trousers, she noted an inflammatory streak that developed a centrally depigmented de-epithelized area. In the emergency room, we noted a dry necrotic wound with elevated erythematous borders. This represents a chemical burn grade IIa. We irrigated and cleaned the wound. Thereafter, we applied a topical corticosteroid ointment with topical fusidinic acid to reduce the inflammation and protect against secondary infection. Vaccination against tetanus was controlled. A sterile wound dressing was used to cover the wound. The wound healed leaving a hypertrophic scar. Topical scar management with silicon foils and moisturizers was recommended. Chemical burns are among the most common injuries at the workplace and the household. In a nationwide study from South Korea, the hospital visit incidence was 1.96 per 10,000 person-year in the general population [1]. Skin and eyes are equally affected.

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Chemical burns can be caused by acids and bases. Chemical burns by most acids are self-limiting due to a coagulative necrosis, while burns by bases can go deep into the tissue (colliquative necrosis). The depth of chemical burns is also dependent upon the concentration of the responsible chemical and the thickness of the skin. The necrosis appears whitish in the acute phase but changes its color according to the responsible acid [2]. Formic acid (syn. methanoic acid) is the simplest carboxylic acid. Originally characterized in ants, it is widely distributed in the chemical industry. Formic acid is colorless but has a penetrating odor. The compound is used as antibacterial and preservative agent in agriculture, as a coagulant in rubber production and tanning and finishing of leather and textiles. Formic acid can also be found in cleaning products. In concentrations ≥10%, formic acid is corrosive to the skin. Systemic reactions are rare. A third-degree burn has been observed after treatment of warts with a commercially available 85% solution with or without an occlusive dressing [3, 4]. Key Points • Chemical burns are common injuries to the skin. • They represent emergencies. • Bases and acids can cause chemical burns.

References 1. Koh DH, Lee SG, Kim HC.  Incidence and characteristics of chemical burns. Burns. 2017;43(3):654–64. 2. Wollina U.  Disorders caused by physical and chemical damage. In: Burgdorf W, Plewig G, Wolff HH, Landthaler M, editors. Braun-Falco’s dermatology. 3rd ed. Heidelberg: Springer Medizin Verlag; 2009. p. 598–616. 3. Balagué N, Vostrel P, Beaulieu JY, van Aaken J. Third degree formic acid chemical burn in the treatment of a hand wart: a case report and review of the literature. Springerplus. 2014;3:408. 4. Lux-Battistelli C, Muller C, Moragny J, Henquinet T. Caustic necrosis due to topical formic acid 85% (Objectif ZeroVerrue(®)). Ann Dermatol Venereol. 2016;143(8–9):543–6.

Chapter 37

A Pruritic Erythematous Rash After Childbirth Uwe Wollina

A 31-year-old healthy woman developed an intensely pruritic rash 2 days after her first, uncomplicated childbirth to a little girl. The gynecologist presented her to exclude a drug allergy. The lesion where located on striae distensae gravidarum only. Based on the case description and the photograph, what is your diagnosis? 1. Drug allergy 2. Lichen planus 3. Atopic dermatitis 4. Polymorphic eruption of pregnancy 5. Herpes gestationis

U. Wollina (*) Department of Dermatology and Allergology, Municipal Hospital of Dresden, Academic Teaching Hospital, Dresden, Germany e-mail: [email protected] © Springer Nature Switzerland AG 2020 T. Lotti et al. (eds.), Clinical Cases in Pigmentary Disorders, Clinical Cases in Dermatology, https://doi.org/10.1007/978-3-030-50823-4_37

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The patient presented with urticarial erythematous lesions restricted to striae distensae. The periumbilical region was spared. Excoriations were missing. Laboratory investigation were within the normal range or negative except a slight elevation of liver enzymes (ASAT 1.15  μkat/L, ALAT 0.63  μkat/L—normal range for both: