Ebook Vitiligo and other hypomelanoses of hair and skin: Part 1

Vitiligo and Other
Hypomelanoses of
H air and Skin


TOPICS IN DERMA TOLOGY
Series Editors: John A. Parrish and Thomas B. Fitzpatrick
Harvard Medical School, Boston, Massachusetts

VITILIGO AND OTHER HYPOMELANOSES OF HAIR AND SKIN
Jean-Paul Ortonne, David B. Mosher, and Thomas B. Fitzpatrick


Vitiligo and Other
Hypomelanoses of
Hair and Skin
Jean-Paul Ortonne, M.D.
H6pital Pasteur
Centre Hospitalier Universitaire
Nice, France

David B. Mosher, M.D.
and

Thomas B. Fitzpatrick, M.D.

Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts

PLENUM MEDICAL BOOK COMPANY

New York and London


Library of Congress Cataloging in Publication Data
Ortonne, Jean-Paul, 1943Vitiligo and other hypo melanoses of hair and skin.
(Topics in dermatology)
Includes bilbiographical references and index.
1. Vitiligo. 2. Pigmentation disorders. I. Mosher, David B. II. Fitzpatrick,
Thomas B. III. Title. IV. Series. [DNLM: 1. Pigmentation disorders. 2. Skin
manifestations. WR 265 078v]
RL790.077 1982
616.5 1 5
82-16490
e-ISBN-13: 978-1-4615-9272-3
ISBN-13: 978-1-4615-9274-7
DOl: 10.1 007/978-1-4615-9272-3

© 1983 Plenum Publishing Corporation
Softcover reprint of the hardcover 1st edition

1983

233 Spring Street, New York, N.Y. 10013
Plenum Medical Book Company is an imprint of Plenum Publishing Corporation
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher

Acknowledgments
The authors wish to acknowledge the assistance of the many colleagues who
have inspired and assisted them in this endeavor. Particularly appreciated is
the editorial review of Dr. John A. Parrish and the assistance of Dr. Madhu A.
Pathak particularly in the areas of chemical leukoderma and vitiligo. Diane
Patry assisted with typing and copy preparation. We are particularly indebted
to Pat K. Novak for her tireless diligence as copy editor.

v


Preface
Leukoderma is a generic term for any pigmentary dilution, be it congenital or
acquired, circumscribed or generalized, devoid of or partially lacking in pigmentation. In the approach to the diagnosis of leukoderma, we have generally
first considered the age of onset, whether leukoderma was congenital or acquired, the extent and pattern of involvement, and the degree of pigmentary
dilution. The organization of this monograph reflects this approach. For example, we have separated the section devoted to various disease entities into
diffuse and circumscribed leukoderma and the latter into various etiologies
such as genetic, metabolic, infectious, and endocrinologic.
One of several justifications for this monograph is to present an approach
to the diagnosis of leukoderma, as detailed in Part II. In formulating a guide
for the physician, we have found some limitations to our previous approach;
we therefore offer the following new classification based upon a clinical-pathologic correlation. This could provide the means to describe both the
clinical and pathologic findings in one term.
I. Melanocytopenic leukoderma (reduction or absence of melanocytes)
A. Vitiligo
B. Piebaldism
C. Chemical leukoderma
D. Waardenburg's syndrome

II. Melanopenic leukoderma (reduction or absence of melanin)
A. Albinism
B. White macule of tuberous sclerosis
C. Nevus depigmentosis
In the melanocytopenic leukodermas, melanocytes are absent and the macules are usually pure white. However, in the melanopenic leukodermas, melanocytes are present, but there is a reduction of melanin, due to a defect in
melanosome formation, melanization of melanosomes, melanosome transfer,
or other process, so that mild to very marked pigmentary dilution is apparent.
Differential diagnosis of a melanocytopenic leukoderma that is congenital
and circumscribed would, for example, have to include piebaldism, whereas
if it were acquired and circumscribed, vitiligo and chemical leukoderma would

vii


viii
PREFACE

have to be considered. Per contra, a melanopenic leukoderma that is acquired
and circumscribed would include tinea versicolor, postinfiammatory hypomelanosis, leprosy, sarcoidosis, and idiopathic guttatehypomelanosis. Melanopenic leukoderma that is congenital and circumscribed would include the white
macules in tuberous sclerosis and nevus depigmentosis.
Most of the diffuse hypomelanoses are congenital melanopenic disordersthese include albinism and phenylketonuria. Diffuse hypomelanoses that are
exceptions include vitiligo universalis, which is an acquired melanocytopenia.
While this monograph itself does not embrace the newer terms "melanopenic" and "melanocytopenic," the tables, descriptive paragraphs, clinical photographs, and photomicrographs provide corresponding bases for the new terms
which designate clinical-pathologic findings.
Jean-Paul Ortonne
David B. Mosher
Thomas B. Fitzpatrick


Contents

PART I. SKIN COLOR AND THE MELANIN PIGMENTARY SYSTEM
Melanins ............................................ .
Epidermal Dendritic Cells ............................ .
Origin of Melanocytes ................................ .
Biologic Basis of Melanin Pigmentation ................ .
Race, Light, Age, and Melanocytes ..................... .
Factors Controlling Pigmentation ...................... .
References ........................................... .

1
3
7
9
11
20
22
28

PART II. APPROACH TO THE PROBLEM OF LEUKODERMA . ...... . 37
History .............................................. .
Physical Examination ................................ .
Histology and Electron Microscopy .................... .
Pathogenesis ......................................... .
Reference ............................................ .

40
41
51
54
56

PART III. HYPOMELANOTIC DISORDERS ....................... .

57

Chapter 1. Genetic and Congenital Disorders . ............. .

59

Section 1. Disorders with Features of Oculocutaneous
Albinism ...................................... .

59

Introduction ......................................... .
Tyrosinase-Negative Oculocutaneous Albinism ......... .
Tyrosinase-Positive Oculocutaneous Albinism .......... .
Yellow-Mutant Oculocutaneous Albinism .............. .
Hermansky-Pudlak Syndrome ........................ .
Chediak-Higashi Syndrome ........................... .
Albinism and Immunodeficiency ...................... .
Cross-McKusick-Breen Syndrome .................... .
Oculocutaneous Albinoidism ......................... .
Ocular Albinism ..................................... .

59
65
69
74
75

79
87
88
89
89

ix


x
CONTENTS

Abnormalities of the Optic Pathway in Albinism ........
Other Defects in Albinos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Treatment of Albinism ................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

92
93
93
93
95

Section 2. Disorders with Relative Generalized Decreased
Pigmentation ................................... 102
Copper Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Histidinemia ..........................................
Phenylketonuria ......................................
Disorders of Methionine Metabolism ....................

Tietz Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References ............................................

102
107
109
119

123
123

Section 3. Disorders with Circumscribed Hypomelanosis .... 129
Vitiligo ...............................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Piebaldism ...........................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Waardenburg Syndrome ...............................
References ..........................................
Piebaldism with Deafness (Woolf Syndrome) ............
References ..........................................
Ziprkowski-Margolis Syndrome ........................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tuberous Sclerosis ....................................
References ..........................................
Nevus Depigmentosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References ..........................................
Incontinentia Pigmenti Achromians ....................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Incontinentia Pigmenti ................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

Ataxia-Telangiectasia ..................................
References ..........................................
Xeroderma Pigmentosum ..............................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Neurofibromatosis .....................................
References ..........................................
Dyschromatosis Symmetrica; Dyschromatosis Universalis
Hereditaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Hypopigmented Markings in Dark-Skinned People:
Pigmentary Demarcation Lines . . . . . . . . . . . . . . . . . . . ..
References ..........................................

129
286
310
334
337
364
369
372
373
374
375
396
398
410
411

426

427
432
433
435
435
438
438
440
440
444
444
451


Other Miscellaneous Syndromes ...................... .
Darier-White Disease ............................... .
Autosomal Recessive Deafness Associated with Vitiligo
(Rozycki Syndrome) .............................. .
Focal Dermal Hypoplasia Syndrome ................... .
Hypopigmentation with Punctate Kp.ratosis of the Palms
and Soles ........................................ .
Hypomelanoses in Possible Ectodermal Dysplasia
Syndromes ...................................... .
References ........................................... .

452
452
452
456
456

460
46

Section 4. Disorders Affecting Hair Pigmentation without
Affecting Skin Pigmentation .................... . 461
Premolar Aplasia, Hyperhidrosis, and Canities Prematura
Fanconi Syndrome ................................... .
Rothmund-Thomson Syndrome ....................... .
Dystrophia Myotonica ................................ .
Premature Aging Syndromes .......................... .
Werner Syndrome (Pangeria) ........................ .
Hutchinson-Gilford Syndrome (Progeria) ............ .
Fisch Syndrome ..................................... .
Kappa Chain Deficiency .............................. .
Hereditary Premature Canities ......................... .
Bird-Headed Dwarfism (Seckel Syndrome) ............. .
Treacher Collins Syndrome, Pierre Robin Syndrome,
Hallerman-Streiff Syndrome, Down Syndrome,
Chromosome Five p-Syndrome .................... .
Prolidase Deficiency ................................. .
References ........................................... .

461
461
462
462
462
462
463
464

464
464
465
465
466
466

Chapter 2. Hypomelanoses Associated with Nutritional and
Metabolic Disorders . .......................... . 467

Kwashiorkor ..........................................
Generalized Dyschromia in a Malnourished Infant . . . . . ..
Pigmentary Changes in the Hair of Patients with
Nephrosis, Ulcerative Colitis, or Extensive Resection
of the Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Severe Iron Deficiency ............................... "
Copper Deficiency .....................................
Vitamin B12 Deficiency (Pernicious Anemia) .............
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

467
469
470
470
470
471
471

Chapter 3. Hypomelanosis Associated with Endocrine
Disorders . ..................................... 473

Hyperthyroidism ...................................... 473
Hypopituitarism ...................................... 473

xi

CONTENTS


xii
CONTENTS

Addison Disease ......................................
Cushing Syndrome ....................................
Hypogonadism ........................................
Hypoparathyroidism, Addison Disease, and Chronic
Mucocutaneous Candidiasis ........................
Goiter and Paratertiary Butylphenol Depigmentation .....
References ............................................

473
473
474
474
474
474

Chapter 4. Hypomelanosis Secondary to Irradiation and
Physical Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 475
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 477

Chapter 5. Chemical Hypomelanosis . . . . . . . . . . . . . . . . . . . . . .. 479
Phenolic Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Sulfhydryl Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Cinnamic Aldehyde. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Metals ...............................................
Hydrogen Peroxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Guanonitrofuracin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Mephenesin Carbamate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Triparanol (MER-29) ..................................
Dinitrochlorobenzene (DNCB) . . . . . . . . . . . . . . . . . . . . . . . . ..
Arsenic ..............................................
Nitrogen Mustard and Thiotepa . . . . . . . . . . . . . . . . . . . . . . ..
Corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Butyrophenone .......................................
Chloroquine Diphosphate. . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Eserine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Epinephrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Phototoxic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

482
496
497
497
497
497
498
498
498
499

499
499
500
501
502
502
503
503

Chapter 6. Hypomelanosis Associated with Inflammation ... 509
Eczematous Dermatitis and Atopic Dermatitis ..... . . . . ..
Lupus Erythematosus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Achromic Guttate Parapsoriasis ........................
Psoriasis .............................................
Pityriasis Alba ........................................
References ............................................

509
509
512
513
516
521

Chapter 7. Infectious and Parasitic Hypomelanosis ......... 523
Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
yaws .................................................
Pinta .................................................
Endemic Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Leukoderma in Secondary Syphilis . . . . . . . . . . . . . . . . . . . ..

523
534
536
542
543


Herpes Zoster. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tinea Versicolor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Onchocerciasis ........................................
Post-Kala-Azar Dermatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tuberculosis ..........................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

544
545
555
559
562
563

Chapter 8. Leukoderma Acquisitum Centrifugum: Halo
Nevus and Other Hypomelanoses Associated with
Neoplasms .................................... 567
Halo Nevus .......................................... ,
Halo Phenomena around Lesions Other Than Nevus Cell
Nevus ............................................
Pathogenesis ..........................................
Diagnosis ........................................... "

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

567
595
599
606
607
607

Chapter 9. Miscellaneous Hypomelanoses . . . . . . . . . . . . . . . . .. 613
Sarcoidosis ...........................................
Idiopathic Guttate Hypomelanosis ......................
Macular Tropical Hypochromia ........................
Vogt-Koyanagi-Harada Syndrome ......................
Alezzandrini Syndrome ...............................
Senile Graying of Hair. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Sudden Whitening of Hair . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Alopecia Areata. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Vagabond's Leukomelanoderma ........................
Heterochromia Irides and Horner Syndrome. . . . . . . . . . . ..
Hypomelanosis in Scleroderma. . . . . . . . . . . . . . . . . . . . . . . ..
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

613
619
627
627
641
641

651
656
657
662
663
664

PART IV. LEUKODERMAS WITHOUT HYPOMELANOSIS ........... 673
Nevus Anemicus ......................................
Edema of the Skin ....................................
Anemia ..............................................
References ............................................
INDEX

673
677

677
677

................................. , .................. 679

xiii

CONTENTS


Vitiligo and Other
Hypomelanoses of
Hair and Skin

FIGURE 1. Components of skin color. Any variation in skin color arises from
different ratios of blue, red, brown. and yellow. (From: Quevedo WC Jr: The control
of color in mammals. Am Zool 9:531-540. 1969. Copyright. 1969. American Society
of Zoologists. Used with permission.)


I
Skin Color and the Melanin
Pigmentary System
The skin is a complex organ system endowed with the capacity to undergo a
wide array of color changes. Normal skin color arises from a mixture of red,
blue, yellow, and brown colored pigments (Fig. 1). In normal skin, melanin is
the major pigment or color determinant and imparts a color ranging from a
very light tan to a deep brown or black, depending on the quantity of melanin
in the epidermis. A yellow hue may be imparted by carotenoids, red by oxygenated hemoglobin in the capillaries, and blue by reduced hemoglobin in the
dermal venules and by pigment in the dermis.
Melanin is synthesized by a specialized cell, the melanocyte, which is a
dendritic cell found in the basal layer of the epidermis, though some melanocytes higher in the epidermis and a few in the dermis may be found. The
melanin pigmentary system consists of millions of such melanocytes, each of
which is functionally associated with 36 keratinocytes (Fig. 2); this cluster of
keratinocytes and the associated melanocyte is referred to as the "epidermal
melanin unit" [1-3] which appears to be a structural and functional entity.
Within each functioning melanocyte, melanin is synthesized and packaged in
specialized pigment organelles called "melanosomes." The dendritic processes
of the melanocytes project in between keratinocytes so that a single melanocyte
supplies melanosomes to its group of 36 keratinocytes. These melanosomes
migrate centrifugally along the dendritic processes of the melanocytes and are
then transferred to or captured by keratinocytes. Although the number of active

epidermal melanin units per unit area varies markedly over various regions of
the human skin [4-6], the keratinocyte/melanocyte ratio remains constant [7].
It has been suggested that the epidermal melanin unit is the functional integrator
of the multicellular system of melanin pigmentation in humans and animals
[1].

Although skin color may be conceptually envisioned as an admixture of
the above colors of red, blue, yellow, and brown, normal skin color and racial
differences in skin color are a function of the number, size, and distribution
of the melanin-laden organelles. It is the melanosomes distributed to the keratinocytes that impart skin color. In the absence of disease, the other color

1


2

PART I

FIGURE 2. The epidermal melanin unit. Relationship of basal melanocyte high-level Langerhans
cells and keratinocytes in mammalian epidermis. (From: Quevedo WC Jr: The control of color in
mammals. Am Zo019:531-540. 1969. Copyright. 1969. American Society of Zoologists. Used with
permission.)

contributors have minor or insignificant roles. Hence, in the absence of melanin,
the skin remains essentially white, as in tyrosinase-negative albinism or macules of vitiligo.
Recent evidence that the movement of keratinocytes within the epidermis
is more complex than was originally thought [8] is not inconsistent with the
epidermal melanin unit concept. Keratinocytes do not just divide randomly in
the germinal layer of certain types of human and of mouse epidermis [9-11].
Mitoses may also occur in suprabasilar keratinocytes [12,13]. According to the

epidermal proliferation unit concept, the young basal cells divide and move
peripherally in the epidermis before final division and formation of orderly
columns of cornified cells [13-16]. Each or several epidermal proliferative units
then may be associated with a donor melanocyte.
Study of the melanin-producing mechanism must be approached at five
scientific levels [17]: macromolecular (visual )-the skin viewed as an organ
system; multicellular (histologic)-the epidermal melanin unit; cellular-me-


lanocytes as unicellular secretory glands; subcellular (electron microscopic)the melanosome as a metabolic unit of melanogenesis; and macromolecular
(biochemical)-tyrosinase, the enzyme, and melanoprotein, the end product of
melanogenesis. This chapter touches each of these levels but concentrates on
the cellular, subcellular, and macromolecular aspects.

MELANINS
There are three different melanins-eumelanin, phaeomelanin, and neuromelanin. Eumelanin is the brown-black pigment of skin and hair and most
responsible for skin color. Phaeomelanin is a red-yellow pigment found in
hair in humans. Neuromelanin is present in neurons of the central nervous
system, in adrenal medulla, and in other areas of the chromaffin system.

Eumelanin
Eumelanin is a high-molecular-weight polymer of which the precise molecular structure has yet to be determined, in part because eumelanin is insoluble in most solvents and resists most chemical alterations and degradations.
Observations based on the work of Raper [18] with plant tyrosinases and modified by Mason [19] led to the conclusion that melanin is a polymer of indole5,6-quinone units. Use of labeled precursors, however, showed this to be an
oversimplification [20,21]. Work of Nicolaus and Piatelli [22] with squid melanin showed melanin to be a complex heteropolymer composed of 5,6-dihydroxyindole and 5,6-hydroxyindole-2-carboxylic acid moieties at various oxidative levels. The proportion of various subunits, molecular chain length, and
molecular weight of eumelanin are still unknown. Blois et a1. [23] consider
melanin to be a highly irregular three-dimensional polymer joined by covalent
bonds. Melanin possesses a free radical character [24] related to a semiquinonoid form of 5,6-dihydroxyindole stabilized by resonance throughout the
highly conjugated polymer [23]. Melanin may be able to function as a mild free
radical quencher and may also have some weak acid cation exchange capabilities. Melanin has specific absorption peaks only in the infrared region at 3
and 6 J.L [23], but shows a rather nonspecific wide absorption band from 200

to 2400 nm.
Tyrosine-Melanin Pathway

Melanin is formed by the enzymatic conversion of a colorless, naturally
occurring amino acid tyrosine to a brown polymer (Fig. 3). Many early observations showed tyrosine to be the substrate for melanin synthesis. Early work
was done by Raper [18], who studied the aerobic oxidation of tyrosine and
dopa in the presence of mealworm tyrosinase. Hogeboom and Adams [25]
demonstrated tyrosinase activity in mouse melanoma extracts. Fitzpatrick et
a1. [26] found tyrosinase activity in normal human skin irradiated with ultra-

3

SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM


4
PART!

OM
7
~
at - ....2
COOM

OM

oil/NOt

I'lOOtJC ,

OM

-s - ~~- at - COOM

s - Cllz - f" - ~

NM:z

~~
~ - II~

NM:z

COOM

S - S - CYSTD_

2

- S - cysn:l~

S.I . DIKYDIIOXYlllOOU

FIGURE 3. Metabolic pathway of eumelanin and phaeomelanin biosynthesis. Both begin with
the enzymatic (tyrosinase) conversion of tyrosine to dopa to dopaquinone. (From: Jimbow K et al:
Some aspects of melanin biology: 1950-1975. J Invest Dermoto! 67:72-89, 1976. Copyright, 1976,
The Williams & Wilkins Company. Used with permission.)

violet radiation in vivo. Subsequent studies in which radioactive tyrosinase
was incorporated in vertebrate melanocytes have established that tyrosine is
involved in melanogenesis.
In the classical tyrosine-melanin conversion scheme of Raper and Mason
[18,19), tyrosine in the presence of tyrosinase and molecular oxygen is oxidized
to dopa which in turn is irreversibly oxidized to dopaquinone. In vitro 14C_
labeled dopa [27,28] and tyrosine [29] are incorporated into melanosomes.
Dopaquinone then undergoes spontaneous rapid and irreversible intramolecular change to form 5,6-dihydroxyindole-2-carboxylic acid (leukodopachrome) which is readily and reversibly oxidized to dopachrome. Dopachrome
then is decarboxylated and rearranged to form 5,6-dihydroxyindole, which is
readily oxidized to indole-5,6-quinone. According to the Raper-Mason scheme,
melanin is a homopolymer of covalently bonded indole-5,6-quinone units.
However, experimental results of labeled precursor studies of Swan [20,21]'
Nicolaus and Piatelli [22], and Hempel [30,31] have shown melanin is not such
a simple polymer compound but rather is a complex heteropolymer composed
of intermediates, namely 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-car-


boxylic acid moieties at various oxidative levels; many different indoles combine to form this complex polymer, which becomes protein-bound to form
melanoprotein.
Tyrosinase

Tyrosinase is a specific copper-requiring enzyme responsible for oxidation
of tyrosine to dopa. Although there are champions of a two-enzyme system,
most investigators consider the tyrosine-to-melanin pathway a single enzyme
system. Tyrosinase is present throughout the phylogenetic scale, but different
tyrosinases have different characteristics. Studies using polyacrylamide gel
electrophoresis have separated multiple forms of tyrosinase from a variety of
pigmented mammalian tissues [32-36). Three active tyrosinases have been
found. The two soluble tyrosinases, Tl and Tz, were found to have similar

molecular weights (MW) (66,600 and 56,700) but to have different amino acid
compositions. It is possible that both T 1 and T z are dimers, as a few polypeptides
with tyrosinase activity and a MW of 30,000 were found [34). The third tyrosinase is an insoluble protein. These multiple tyrosinase forms, derived from
mouse melanoma and from hair bulbs, can utilize both tyrosine and dopa in
the initial steps of melanin synthesis [37). Yet Holstein et al. [38) have shown
in electrophoretic studies that mouse melanoma and hair bulb tyrosinase utilize
both tyrosine and dopa. They also showed that all forms of tyrosinase may
convert tyrosine and dopa to melanin in the presence of adequate catalase to
block peroxidase. Hearing [39) and Hearing and Eckel [40) also demonstrated
both substrates were utilized by tyrosinase in mouse melanoma. Jimbow et al.
[41) demonstrated that the (purified, solubilized) melanosomal enzyme(s) released by nonionic detergent BRIJ 35, which is greatly inactivated by trypsin
[39,41]' uses both tyrosine and dopa as substrates to form melanin.
Some controversy remains, however. Edelstein et al. [37) were also unable
to demonstrate tyrosine utilization by the enzyme released by trypsin from
melanosomes of B-16 mouse melanomas. Okun et al. [37,42,43) concluded from
electron microscopic and electrophoretic studies in which they were unable
to demonstrate the tyrosine-melanin reaction with melanosomes and melanocytes, that one enzyme is not responsible for both the conversion of tyrosine
to dopa and of dopa to dopaquinone. Rather, they suggest that a peroxidase
present in melanosomes causes hydroxylation of tyrosine to dopa and that dopa
oxidase converts dopa to dopaquinone. This is the two-step, two-enzyme theory
of conversion of tyrosine to melanin: The question of a "protyrosinase" activated by a specific protease has also been raised [38,44,45). The two-step theory
is not widely accepted because others have not been able to isolate a second
enzyme system. Lerner et al. [46) were unable to separate tyrosinase activity
from dopa oxidase activity reported [25) responsible for activation of the second
step in melanin synthesis. It was found that the so-called dopa activity was,
in fact, tyrosinase activity with such a long induction period that it appeared
to have no relationship to the oxidation of tyrosine. The presence of dopa
shortens the induction period by a logarithmic function of the amount of dopa
added.
For the moment, the balance of evidence favors the single-enzyme hy-

5

SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM


6

PART!

pothesis-that tyrosinase is the only enzyme responsible for catabolism of
tyrosine to melanin.

Phaeomelanin
Phaeomelanins are yellow and red sulfur-containing pigments found in
the hair of mammals. Unlike eumelanin, phaeomelanin is soluble in dilute
alkali. Phaeomelanins, like eumelanin, are derived from tyrosine via dopaquinone. But it is the interaction of cysteine with dopaquinone at this level which
results in phaeomelanin synthesis. With a 1,6 addition of cysteine to dopaquinone, 13-(5-S-cysteinyl-3,4-dehydroxyphenyl)alanine or 2-S-cysteinyldopa
is formed [47,48]. This is further oxidized to form phaeomelanin [49]. A minor
product of the 1,6 addition may be 2-S-cysteinyldopa [50,51]. Sulfhydryl compounds have a role in in vivo synthesis [52]; in fact, under some experimental
conditions, sulfhydryl compounds may induce pigment cells to produce yellow
pigment [53].
The curious genetic control affecting the common pathway of eumelanin
and phaeomelanin synthesis is reflected in the agouti mouse, which has only
a few subapical phaeomelanosomes, the rest being eumelanogenic. The follicular melanocytes initially produce brown-black eumelanin, temporarily switch
to yellow phaeomelanin production, and soon revert to the original eumelanin
synthesis. Guinea pig studies have shown melanosomes in red or yellow follicles to be spherical whereas those of black follicles are ellipsoidal [54].

Various differences in biochemical behavior have been observed between
eumelanin and phaeomelanin. It has been demonstrated that more sulfhydryl
compounds containing glutathione and cysteine are incorporated into phaeomelanogenic melanocytes and phaeomelanin than into eumelanic melanocytes
and eumelanin. In the presence of adequate reduced glutathione in vitro, melanocytes that in vivo synthesize only eumelanin elaborate phaeomelanin. It
has been suggested that the agouti band in the agouti mouse is derived from
cyclically changing patterns of competition by keratinocytes and melanocytes
for substrate common to hair growth and to melanogenesis. So it was suggested
that cyclic changes in the type of melanin synthesized may involve histochemical changes, not genetic intervention [52]. The failure of Knisely et al. [55] to
confirm these findings with yellow (AY/a) specimens in similar conditions and
in cultures of (A/A) agouti skin may relate to such histochemical factors not
extant in these systems. Although cysteine is an established substrate for phaeomelanogenesis, cysteinyldopa, and phaeomelanin may be produced by eumelanogenic melanocytes [56]. Furthermore, it has become clear that there is
a third melanocyte pigment, namely, trichochrome [57], which like eumelanin
and phaeomelanin has dopaquinone as a critical intermediate. The factors that
select one final pathway over another remain unclear.

Neuromelanin
The trigeminal and dorsal root ganglia, substantia nigra, locus caeruleus,
and the pigmented nuclei of the basal ganglia contain cytoplasmic organelles
containing a brown pigment called "neuromelanin." There appear to be important differences between eumelanin and neuromelanin. Since patients with


oculocutaneous albinism have normal amounts of neuromelanin, it seems unlikely that neuromelanin is formed by the action of tyrosinase. There are other
significant differences between melanin and neuromelanin. The pigment particles of the substantia nigra appear to have a higher electron density than
melanosomes, a size range from 0.5 to 2.5 f.L, a single limiting membrane, and
no longitudinal or cross-striations typical of eumelanin melanosomes [58]. The
presence of labeled tyrosine in the area of pigmented granules in neurons has
persuaded investigators that tyrosine must be present. The enzyme catalyzing
the hydroxylation of tyrosine to dopa is probably tyrosine hydroxylase [29],
and not the copper-requiring oxidase tyrosinase. Since tyrosine hydroxylase
catabolizes only CNS tyrosine, CNS abnormalities should not be expected with

disorders of eumelanin synthesis, and disorders of neuromelanin (such as Parkinson disease) would not be expected to have obligate aberrations of cutaneous
eumelanogenesis.

EPIDERMAL DENDRITIC CELLS
The epidermis is populated with three types of identifiable dendritic cells.
These are melanocytes, Langerhans cells, and a-dendritic or indeterminate
cells. The melanocyte and Langerhans cell can be distinguished by their nuclear
characteristics, the presence of specific organelles, and characteristic cytoplasm. The indeterminate cell lacks organelles characteristic of the other two
types of dendritic cells; it is a "ghost cell," one of uncertain lineage.
Nucleus
Cytoplasm
Organelle

Melanocyte
Oval
Granular
Melanosome
(round to oval)

Langerhans cell
Indeterminate cell
Lobulated
Lobulated
Clear
Clear
Langerhans or Birbeck
None
(rod-disc)

Langerhans cells are dendritic cells found in the epidermis and once thought

to be related to melanocytes but demonstrated by Breathnach [59] not to be of
neural crest origin. These cells are characterized by a clear cytoplasm, a lobulated nucleus, absence of desmosomes, and presence of specific organelles
called "Birbeck" or "Langerhans" granules. These granules have a disclike form
and may appear under the electron microscope as rod-like bodies with rounded
ends and a central striated line. Some of these granules have a blown-out
boundary membrane at one end along with an enclosed clear zone; these assume
the general shape of a hand mirror or tennis racket. Langerhans cells arise in
the bone marrow from some precursor of the mononuclear phagocyte system
[59a]; but it does appear to be an immunologically significant cell and not just
a macrophage that has migrated from the dermis to the epidermis. Although
Langerhans cells can phagocytize melanin granules, these cells are not typical
macrophages. To dramatize its possible role in the epidermis, like that of the
osteoblast in bone, Prunieras [60] has suggested calling the Langerhans cell an
"epidermoclast. "
Further more recent evidence has illuminated the role of the Langerhans
cell. Langerhans cells have been shown to have a role in allergic contact reactions in which they lie in close apposition to lymphocytes [61]. The cellular

7

SKIN COLOR AND
THE MELANIN
PIGMENTARY
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8
PART!

membrane has been shown to have Fc receptor sites for IgG, C3, and IgA antigens
[62,63]. It would appear that Langerhans cells are part of the monocyte-macrophage-histiocyte [64] line and have an important role in the afferent

limb of the immune system [65].
The "a-dendritic" or "indeterminate" cell is even more of a mystery. It
resembles a Langerhans cell without Langerhans granules. The origin and role
of this third type of dendritic cell are unknown. It may be a premelanocyte
with induction potential, an effete melanocyte, a displaced dermal phagocyte,
an undifferentiated cell capable of becoming a Langerhans cell or melanocyte,
or some totally unrelated cell. The work of Mishima and Kawasaki [66] and
Mottaz and Zelickson [67], in which for a time, in vitiligo, melanocytes and
indeterminate cell populations seemed inversely related quantitatively, certainly suggests some direct relationship between the a-dendritic cell and the
melanocyte.
Melanocytes are dendritic cells with a granular cytoplasm, an oval nucleus
with a nucleolus, cell-specific organelles called melanosomes, and no desmosomes (Fig. 4).

FIGURE 4.
epidermis.

Electron microscopic view of a melanocyte and surrounding keratinocyte in human


ORIGIN OF MELANOCYTES

9

In mammals and other vertebrates, melanocytes originate from the neural
crest (Fig. 5), and migrate to the skin, eyes, leptomeninges, and inner ear in
early embryonic life (Fig. 6). The neural crest origin of melanocytes was established by Rawles [68,69], who grafted mouse somite tissue together with
overlying ectoderm to chick embryo coelom. When the neural crest or cells
derived therefrom were excluded, no pigment formed in the grafts. However,
with neural crest tissue present, growth of pigmented hairs and differentiation
of melanocytes was observed in host tissue adjacent to the grafts. Neural crest

tissue was clearly essential for pigment cell formation and pigment elaboration.
By cleverly timing the stages at which grafts were obtained, Rawles was able
to plot the migration of melanoblasts from the neural crest. Melanoblasts appeared cranially and moved in a caudal direction along the anteroposterior
axis.
Mintz [70] demonstrated that the skin of mice is colonized by clones of
melanoblasts. Cleaving fertilized mouse ova, placed adjacently in vitro, will
combine to form a single blastocyst which can be returned to the mouse uterus
to develop into a normal mouse. Combination of black and albino cleaving ova
produced a mouse that was variegated in color and often striped. The stripes
tended to be 17 alternating black and white bands on each side, the right side
appearing to be independent of the left. It is as if each region were colonized
by one of 34 melanoblasts divided equally between two longitudinal middorsal
chains (neural crest). Each primary melanoblast must proliferate laterally and
to a much lesser extent longitudinally to give rise to a clone of melanoblasts
which colonize a specific region of the skin.
Undifferentiated melanocyte precursors which initially invade the dermis
and then the epidermis and hair follicles can be found in the human skin by
the eighth week of fetal development. "Premelanin granules" have been found
by light microscopy in the 10th week in a black fetus [71]. The first few epidermal melanocytes are usually present by the 11th fetal week and become
much more numerous during the 12th to 14th weeks.

N!;~L

CR!;ST

M(;LANOBLAS TS

"M!;LANOGONIA"

M~LANO(VH.S

FIGURE 5. Development and migration of melanoblasts. Melanoblasts migrated from the neural
crest in early fetal development and appeared as undifferentiated melanocyte precursors in the
eighth week. Epidermal melanocytes usually first appear in the 11th week.

SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM


10
PART!

8

MISCEllANEOUS
SITES
Mucous mtm brone
Internal ear
Orb ital cavil,
Metenle"

FIGURE 6. The embryonic origin. dispersion. and development of melanocytes in humans. Retinal melanocytes (A); choroidal melanocytes (B). (From: Fitzpatrick TB. Quevedo WC Jr: Albinism.
in The Metabolic Basis of Inherited Disease. 2nd ed. Edited by JB Wyngaarden. DS Fredrickson.
Copyright. 1966. McGraw-Hill Book Company. Used with permission.)

Dermal melanocytes then precede the epidermal ones by about two weeks.
In early fetal development, the density of the skin melanocyte population is
reduced in a cephalocaudal direction corresponding to the anteroposterior wave

of migration observed by Rawles. This gradually disappears with time. The
number of dermal melanocytes decreases with development until only a few
remain after birth (Mongolian spots).
The differentiation of melanoblasts into melanocytes is a function of the
genetic constitution of the melanoblasts and the nature of the environment into
which they migrate. Weiss and Andres [72] injected melanoblasts of young