The PigmentarySystem: Physiologyand PathophysiologyEdited by

James J. NordlundDermatologist and Professor Emeritus, Group Health Associates, Cincinnati, OH, USA

Raymond E. BoissyProfessor of Dermatology and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Vincent J. HearingChief, Pigment Cell Biology Section, Laboratory of Cell Biology, National Institutes of Health, Bethesda, MD, USA

Richard A. KingDirector, Genetics Division, Department of Medicine, Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA

William S. OettingAssociate Professor, Genetics Division, Department of MedicineInstitute of Human Genetics, University of Minnesota, Minneapolis, MN, USA

Jean-Paul OrtonneProfessor of Dermatology and Chairman, Department of Dermatology, University of Nice-Sophia Antipolis,Nice, France

SECOND EDITION

The Pigmentary System:Physiology and Pathophysiology

A

B

C

D

E

F

G

H

I

A: These two individuals illustrate the wide range of skin and hair color. [Marianne Greenwood (right) graciously shared the photographs(from her book Varför Gra.ter Puman?) that compose this frontispiece.] B: Classical Celtic women with blue eyes and red hair. C: TypicalScandinavian with blue eyes. D: Native American. E: A Peruvian girl. F: Himalayan woman and child. G: A Venezuelan woman. H: Twoteenagers from New Guinea. I: Man from the New Hebrides Islands. See Chapter 27 for further information.

The PigmentarySystem: Physiologyand PathophysiologyEdited by

James J. NordlundDermatologist and Professor Emeritus, Group Health Associates, Cincinnati, OH, USA

Raymond E. BoissyProfessor of Dermatology and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Vincent J. HearingChief, Pigment Cell Biology Section, Laboratory of Cell Biology, National Institutes of Health, Bethesda, MD, USA

Richard A. KingDirector, Genetics Division, Department of Medicine, Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA

William S. OettingAssociate Professor, Genetics Division, Department of MedicineInstitute of Human Genetics, University of Minnesota, Minneapolis, MN, USA

Jean-Paul OrtonneProfessor of Dermatology and Chairman, Department of Dermatology, University of Nice-Sophia Antipolis,Nice, France

SECOND EDITION

© 2006 Blackwell Publishing LtdBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

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First published 1998 by Oxford University PressSecond edition 20061 2006

Library of Congress Cataloging-in-Publication Data

The pigmentary system : physiology and pathophysiology / edited byJames J. Nordlund . . . [et al.]. —2nd ed.

p. ; cm.Includes bibliographical references and index.1. Pigmentation disorders. 2. Melanocytes. I. Nordlund, James J.[DNLM: 1. Pigmentation Disorders–physiopathology. 2. Melanocytes.

3. Pigmentation–physiology. WR 265 P6309 2006]RL790.P53 2006616.5¢5–dc22

2005030369

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15 Chemistry of Melanins, 282Shosuke Ito & Kazumasa Wakamatsu

16 The Physical Properties of Melanins, 311Tadeusz Sarna & Harold A. Swartz

17 Photobiology of Melanins, 342Antony R. Young

18 Toxicological Aspects of Melanin and Melanogenesis, 354

Edward J. Land, Christopher A. Ramsden, & Patrick A. Riley

19 Regulation of Pigment Type Switching by Agouti,Melanocortin Signaling, Attractin, and Mahoganoid,395

Gregory S. Barsh20 Human Pigmentation: Its Regulation by Ultraviolet

Light and by Endocrine, Paracrine, and AutocrineFactors, 410

Zalfa Abdel-Malek & Ana Luisa Kadekaro21 Paracrine Interactions of Melanocytes in Pigmentary

Disorders, 421Genji Imokawa

22 Growth Factor Receptors and Signal TransductionRegulating the Proliferation and Differentiation ofMelanocytes, 445

Ruth Halaban & Gisela Moellmann23 Aging and Senescence of Melanocytes, 464

Debdutta Bandyopadhyay & Estela E. Medrano24 The Genetics of Melanoma, 472

Vanessa C. Gray-Schopfer & Dorothy C. Bennett25 The Transformed Phenotype of Melanocytes, 489

Dong Fang & Meenhard Herlyn

Part II: The Pathophysiology of Pigmentary DisordersSection 3: An Overview of Human Skin Color and its Disorders, 497

26 A More Precise Lexicon for Pigmentation, Pigmentary Disorders, and “Chromatic” Abnormalities,499

James J. Nordlund, Tania Cestari, Pearl Grimes, Henry Chan, & Jean-Paul Ortonne

27 The Normal Color of Human Skin, 504James J. Nordlund & Jean-Paul Ortonne

28 Mechanisms that Cause Abnormal Skin Color, 521

Jean-Paul Ortonne & James J. Nordlund

Contributors, xForeword, xvPreface, xviiAcknowledgements, xviiiFrontispiece can be found between pages ii and iii

Part I: The Physiology of the Pigmentary SystemSection 1: Historical and Comparative Perspectives ofthe Pigmentary System, 3

1 A History of the Science of Pigmentation, 5Sidney N. Klaus

2 Comparative Anatomy and Physiology of Pigment Cellsin Nonmammalian Tissues, 11

Joseph T. Bagnara & Jiro Matsumoto

Section 2: The Science of Pigmentation, 613 General Biology of Mammalian Pigmentation, 63

Walter C. Quevedo Jr. & Thomas J. Holstein4 Extracutaneous Melanocytes, 91

Raymond E. Boissy & Thomas J. Hornyak5 Regulation of Melanoblast Migration and

Differentiation, 108David M. Parichy, Mark V. Reedy, & Carol A. Erickson

6 Melanoblast Development and Associated Disorders, 140

Richard A. Spritz7 Biogenesis of Melanosomes, 155

Raymond E. Boissy, Marjan Huizing, & William A. Gahl

8 Melanosome Trafficking and Transfer, 171Glynis A. Scott

9 Melanosome Processing in Keratinocytes, 181H. Randolph Byers

10 The Regulation of Melanin Formation, 191Vincent J. Hearing

11 The Tyrosinase Gene Family, 213William S. Oetting & Vijayasaradhi Setaluri

12 Molecular Regulation of Melanin Formation:Melanosome Transporter Proteins, 230

Murray H. Brilliant13 Transcriptional Regulation of Melanocyte Function, 242

Kazuhisa Takeda & Shigeki Shibahara14 Enzymology of Melanin Formation, 261

Francisco Solano & José C. García-Borrón

v

Contents

CONTENTS

Bird-Headed Dwarfism (Seckel Syndrome), 657Stan P. Hill

Down Syndrome, 658Rosemary Geary

Fisch Syndrome, 659Stan P. Hill

Premature Canities, 659James J. Nordlund

Mandibulofacial Dysostosis (Treacher CollinsSyndrome), 660

Rosemary GearyMyotonic Dystrophy, 660

Peggy TongPHC Syndrome (Böök Syndrome), 661

Stan P. HillPierre Robin Syndrome, 661

James J. NordlundProlidase Deficiency, 662

Pranav B. Sheth34 Metabolic, Nutritional, and Endocrine Disorders, 664

Metabolic and Nutritional Hypomelanoses, 664Peter S. Friedmann

Hypomelanosis Associated with Endocrine Disorders,667

Peter S. Friedmann35 Chemical, Pharmacologic, and Physical Agents Causing

Hypomelanoses, 669Chemical and Pharmacologic Agents CausingHypomelanoses, 669

Stefania Briganti, Monica Ottaviani, & Mauro Picardo

Physical Agents Causing Hypomelanoses, 683Jean-Philippe Lacour

36 Infectious Hypomelanoses, 686Jean-Philippe Lacour

37 Inflammatory Hypomelanoses, 699Jean-Philippe Lacour

38 Hypomelanoses Associated with MelanocyticNeoplasia, 705

Lieve Brochez, Barbara Boone, & Jean-Marie Naeyaert

39 Miscellaneous Hypomelanoses: Depigmentation, 725Alezzandrini Syndrome, 725

Wiete Westerhof, David Njoo, & Henk E. MenkeIdiopathic Guttate Hypomelanosis, 726

Wiete Westerhof, David Njoo, & Henk E. MenkeLeukoderma Punctata, 729

Wiete Westerhof, David Njoo, & Henk E. MenkeLichen Sclerosus et Atrophicus, 731

Philippe BahadoranVagabond Leukomelanoderma, 732

Wiete Westerhof, David Njoo, & Henk E. MenkeVogt–Koyanagi–Harada Syndrome, 734

Wiete Westerhof, David Njoo, & Henk E. MenkeWesterhof Syndrome, 741

Wiete Westerhof, David Njoo, & Henk E. Menke

Section 4: Disorders of Hypopigmentation,Depigmentation and Hypochromia, 539

29 Genetic Hypomelanoses: Disorders Characterized byCongenital White Spotting —Piebaldism, WaardenburgSyndrome, and Related Genetic Disorders ofMelanocyte Development —Clinical Aspects, 541

Richard A. Spritz30 Genetic Hypomelanoses: Acquired Depigmentation, 551

Rozycki Syndrome, 551Jean L. Bolognia

Vitiligo Vulgaris, 551James J. Nordlund, Jean-Paul Ortonne, & I. Caroline Le Poole

31 Genetic Hypomelanoses: GeneralizedHypopigmentation, 599

Oculocutaneous Albinism, 599Richard A. King & William S. Oetting

Albinoid Disorders, 613Philippe Bahadoran & Jean-Paul Ortonne

Ataxia Telangiectasia, 621Anne-Sophie Gadenne

Hallerman–Streiff Syndrome, 623James J. Nordlund

Histidinemia, 623Marnie D. Titsch

Homocystinuria, 625Allan D. Mineroff

Oculocerebral Syndrome with Hypopigmentation, 626

Jean L. BologniaTietz Syndrome, 630

Jean-Paul OrtonneKappa-Chain Deficiency, 631

Jean-Paul OrtonneMenkes’ Kinky Hair Syndrome, 631

Tanusin PloysangamPhenylketonuria, 634

Allan D. Mineroff32 Genetic Hypomelanoses: Localized

Hypopigmentation, 636“Hypomelanosis of Ito” and Mosaicism, 636

Wolfgang Küster & Rudolf HappleFocal Dermal Hypoplasia, 645

James J. NordlundHypomelanosis with Punctate Keratosis of the Palmsand Soles, 646

Jean L. BologniaDarier–White Disease (Keratosis Follicularis;124200), 647

Jean L. BologniaNevus Depigmentosus, 649

Stella D. CalobrisiTuberous Sclerosis Complex, 652

Pranav B. Sheth33 Genetic Hypomelanoses: Disorders Characterized by

Hypopigmentation of Hair, 657

vi

Hereditary Sclerosing Poikiloderma, 795Eulalia Baselga & Nancy Burton Esterly

Mendes Da Costa Disease, 796Eulalia Baselga & Nancy Burton Esterly

Naegeli–Franceschetti–Jadassohn Syndrome, 798Eulalia Baselga & Nancy Burton Esterly

Reticulated Acropigmentation of Dohi(Dyschromatosis Symmetrica Hereditaria), 799

Eulalia Baselga & Nancy Burton EsterlyReticulate Acropigmentation of Kitamura, 802

Eulalia Baselga & Nancy Burton EsterlyRothmund–Thomson Syndrome, 804

Eulalia Baselga & Nancy Burton Esterly45 Genetic Epidermal Syndromes with Café-au-lait

Macules, 809Familial Multiple Café-au-lait Spots, 809

Nancy Burton EsterlyNeurofibromatosis, 809

Nancy Burton Esterly, Eulalia Baselga, & Sheila S. Galbraith

Neurofibromatosis 1 with Noonan Syndrome, 816

Nancy Burton EsterlyMcCune–Albright Syndrome, 817

Sheila S. Galbraith & Nancy Burton EsterlySegmental Neurofibromatosis, 819

Nancy Burton Esterly & Eulalia BaselgaSilver–Russell Syndrome, 820

Nancy Burton Esterly, Eulalia Baselga, & Sheila S. Galbraith

Watson Syndrome, 823Nancy Burton Esterly

46 Genetic Epidermal Pigmentation with Lentigines, 824

Lentigo Simplex, 824Mary K. Cullen

Lentigo Senilis et Actinicus, 829Mary K. Cullen

Centrofacial Lentiginosis, 837Mary K. Cullen

LEOPARD Syndrome, 842Mary K. Cullen

Carney Complex, 851Mary K. Cullen

Other Lentiginoses, 863Mary K. Cullen

47 Genetic Epidermal Syndromes: LocalizedHyperpigmentation, 873

Anonychia with Flexural Pigmentation, 873Nancy Burton Esterly, Eulalia Baselga, & Beth A. Drolet

Incontinentia Pigmenti, 873Sheila S. Galbraith & Nancy Burton Esterly

Periorbital Hyperpigmentation, 879Nancy Burton Esterly, Eulalia Baselga, & Beth A. Drolet

40 Miscellaneous Hypomelanoses: Hypopigmentation, 745Disseminated Hypopigmented Keratoses, 745

Wiete Westerhof, David Njoo, & Henk E. MenkeHypermelanocytic Punctata et GuttataHypomelanosis, 746

Wiete Westerhof, David Njoo, & Henk E. MenkeProgressive Macular Hypomelanosis, 748

Henk E. Menke, Germaine Relyveld, David Njoo, & Wiete Westerhof

Sarcoidosis, 751Wiete Westerhof, David Njoo, & Henk E. Menke

41 Miscellaneous Hypomelanoses: Extracutaneous Loss ofPigmentation, 754

Alopecia Areata, 754Wiete Westerhof

Heterochromia Irides, 756Wiete Westerhof, David Njoo, & Henk E. Menke

Senile Canities, 760Wiete Westerhof, David Njoo, & Henk E. Menke

Sudden Whitening of Hair, 764Wiete Westerhof, David Njoo, & Henk E. Menke

42 Hypochromia without Hypomelanosis, 767Jean-Philippe Lacour

Section 5: Disorders of Hyperpigmentation andHyperchromia, 769

43 Genetic Epidermal Syndromes: Disorders Characterizedby Generalized Hyperpigmentation, 771

Adrenoleukodystrophy, 771Sheila S. Galbraith & Nancy Burton Esterly

Familial Progressive Hyperpigmentation, 774Nancy Burton Esterly, Eulalia Baselga, Beth A. Drolet,Susan Bayliss Mallory, & Sharon A. Foley

Fanconi Anemia, 776Sheila S. Galbraith & Nancy Burton Esterly

Gaucher Disease, 778Sheila S. Galbraith & Nancy Burton Esterly

44 Genetic Epidermal Syndromes: Disorders Characterizedby Reticulated Hyperpigmentation, 780

Berlin Syndrome, 780Eulalia Baselga & Nancy Burton Esterly

Cantu Syndrome, 781Eulalia Baselga & Nancy Burton Esterly

Kindler Syndrome, 781Eulalia Baselga & Nancy Burton Esterly

Dermatopathia Pigmentosa Reticularis, 784Eulalia Baselga & Nancy Burton Esterly

Dyschromatosis Universalis Hereditaria, 786Eulalia Baselga & Nancy Burton Esterly

Epidermolysis Bullosa with Mottled Pigmentation, 788

Eulalia Baselga & Nancy Burton EsterlyFamilial Mandibuloacral Dysplasia, 790

Eulalia Baselga & Nancy Burton EsterlyHereditary Acrokeratotic Poikiloderma, 792

Eulalia Baselga & Nancy Burton Esterly

vii

CONTENTS

CONTENTS

Erythema Dyschromicum Perstans, 933Norman Levine & Cynthia Burk

Erythromelanosis Follicularis Faciei et Colli, 935Norman Levine & Cynthia Burk

Erythrose Péribuccale Pigmentaire of Brocq, 937Norman Levine & Cynthia Burk

Extracutaneous Neuroendocrine Melanoderma, 938Norman Levine & Cynthia Burk

Felty Syndrome and Rheumatoid Arthritis, 939Norman Levine & Cynthia Burk

Hyperpigmentation Associated with HumanImmunodeficiency Virus (HIV) Infection, 941

Philippe BahadoranMelanoacanthoma, 946

Norman Levine & Cynthia BurkPhytophotodermatitis, 948

Norman Levine & Cynthia BurkPolyneuropathy, Organomegaly, Endocrinopathy, M Protein, and Skin Changes: POEMS Syndrome, 951

James J. NordlundUrticaria Pigmentosum and Mastocytosis, 954

James J. NordlundPoikiloderma of Civatte, 959

Vlada Groysman & Norman LevineRiehl’s Melanosis, 961

Scott Bangert & Norman LevineAtrophoderma of Pasini et Pierini, 963

James J. Nordlund, Norman Levine, Charles S. Fulk, & Randi Rubenzik

Hyperpigmentation Associated with Scleromyxedemaand Gammopathy, 965

Kazunori Urabe, Juichiro Nakayama, & Yoshiaki HoriIchthyosis Nigricans, Keratoses, and EpidermalHyperplasia, 965

James J. NordlundMorphea and Scleroderma, 967

James J. NordlundPigmentary Changes Associated with AddisonDisease, 969

Cindy L. Lamerson & James J. NordlundPigmentary Changes Associated with CutaneousLymphomas, 972

Debra L. Breneman51 Hypermelanosis Associated with Gastrointestinal

Disorders, 979Porphyria Cutanea Tarda, 979

Eun Ji Kwon & Victoria P. WerthCronkhite–Canada Syndrome, 983

Eun Ji Kwon, James J. Nordlund, & Victoria P. Werth

Hemochromatosis and Hemosiderosis, 986Joerg Albrecht & Victoria P. Werth

Primary Biliary Cirrhosis, 992Joerg Albrecht & Victoria P. Werth

Inflammatory Bowel Disease and Pigmentation, 995Joerg Albrecht & Victoria P. Werth

Pigmentary Demarcation Lines, 880Sheila S. Galbraith & Nancy Burton Esterly

Dowling–Degos Disease, 882Sheila S. Galbraith & Nancy Burton Esterly

48 Genetic Epidermal Syndromes: Disorders of Aging, 884Acrogeria, 884

Nancy Burton Esterly, Eulalia Baselga, Peter M. H. Chan, & Beth A. Drolet

Metageria, 886Nancy Burton Esterly, Eulalia Baselga, Peter M. H. Chan, & Beth A. Drolet

Progeria, 886Nancy Burton Esterly, Eulalia Baselga, Peter M. H. Chan, & Beth A. Drolet

Xeroderma Pigmentosum, 889Anita P. Sheth, Nancy Burton Esterly, Eulalia Baselga, Peter M. H. Chan, & Beth A. Drolet

Werner Syndrome, 894Nancy Burton Esterly, Eulalia Baselga, Peter M. H. Chan, Beth A. Drolet, & Cindy L. Lamerson

49 Congenital Epidermal Hypermelanoses, 898Dyskeratosis Congenita, 898

Susan Bayliss Mallory, Peggy L. Chern, & Sharon A. Foley

Ectodermal Dysplasias, 901Susan Bayliss Mallory, Peggy L. Chern, & Sharon A. Foley

Transient Neonatal Pustular Melanosis, 905Susan Bayliss Mallory, Peggy L. Chern, & Sharon A. Foley

Universal Acquired Melanosis, 906Susan Bayliss Mallory, Peggy L. Chern, & Sharon A. Foley

50 Acquired Epidermal Hypermelanoses, 907Acanthosis Nigricans, 907

Norman Levine & Cynthia BurkAcromelanosis Progressiva, 914

Norman Levine & Cynthia BurkBecker Nevus, 915

Norman Levine & Cynthia BurkCafé-au-lait Spots, 917

Norman Levine & Cynthia BurkCarcinoid Syndrome, 919

Norman Levine & Cynthia BurkConfluent and Reticulated Papillomatosis, 922

Norman Levine & Cynthia BurkCutaneous Amyloidosis, 924

Norman Levine & Cynthia BurkDermatosis Papulosa Nigra, 928

Norman Levine & Cynthia BurkEphelides (Freckles), 929

Norman Levine & Cynthia BurkErythema ab Igne, 931

Norman Levine & Cynthia Burk

viii

56 Pigmentary Abnormalities and Discolorations of theMucous Membranes, 1069

John C. Maize, Jr. & John C. Maize, Sr.

Section 7: Benign Neoplasms of Melanocytes, 109157 Common Benign Neoplasms of Melanocytes, 1093

Pigmented Spindle Cell Nevi, 1093Julie V. Schaffer & Jean L. Bolognia

Speckled Lentiginous Nevus (Nevus Spilus), 1098Julie V. Schaffer & Jean L. Bolognia

Melanocytic (Nevocellular) Nevi and Their Biology,1112

Julie V. Schaffer & Jean L. Bolognia58 Rare Benign Neoplasms of Melanocytes, 1148

Nevus Aversion Phenomenon, 1148James J. Nordlund

Melanotic Neuroectodermal Tumor of Infancy, 1148Julie V. Schaffer & Jean L. Bolognia

Pilar Neurocristic Hamartoma, 1157Julie V. Schaffer & Jean L. Bolognia

Section 8: Treatment of Pigmentary Disorders, 116359 Topical Treatment of Pigmentary Disorders, 1165

Rebat M. Halder & James J. Nordlund60 Chemophototherapy of Pigmentary Disorders, 1175

Rebat M. Halder & James J. Nordlund61 UVB Therapy for Pigmentary Disorders, 1183

Thierry Passeron & Jean-Paul Ortonne62 Sunscreens and Cosmetics, 1188

James J. Nordlund & Rebat M. Halder63 Surgical Treatments of Pigmentary Disorders, 1191

Rebat M. Halder & James J. Nordlund64 Laser Treatment of Pigmentary Disorders, 1198

Rebat M. Halder, Lori M. Hobbs, & James J. Nordlund

Index, 1205Plate section can be found between pages 494 and 495

Pellagra, 995Eun Ji Kwon & Victoria P. Werth

Peutz–Jeghers Syndrome, 999Nancy Burton Esterly, Eulalia Baselga, & Beth A. Drolet

52 Acquired and Congenital Dermal Hypermelanosis, 1003Sacral Spot of Infancy, 1003

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImNevus of Ota, 1006

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImNevus of Ito, 1012

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImPhakomatosis Pigmentovascularis, 1013

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImOther Congenital Dermal Melanocytosis, 1015

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImAcquired Dermal Melanocytosis, 1016

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImCarleton–Biggs Syndrome, 1017

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImAcquired Bilateral Nevus of Ota-like Macules(ABNOM), 1017

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImBlue Macules Associated with Progressive SystemicSclerosis, 1018

Sang Ju Lee, Seung Kyung-Hann, & Sungbin Im53 Mixed Epidermal and Dermal Hypermelanoses and

Hyperchromias, 1020Melasma, 1020

Sang Ju Lee, Seung Kyung-Hann, & Sungbin ImMelanosis from Melanoma, 1023

Sang Ju Lee, Seung Kyung-Hann, & Sungbin Im54 Drug-induced or -related Pigmentation, 1026

Peter A. Lio & Arthur J. Sober

Section 6: Disorders of Pigmentation of the Nails andMucous Membranes, 1055

55 The Melanocyte System of the Nail and its Disorders,1057

Robert Baran, Christophe Perrin, Luc Thomas, & Ralph Braun

ix

CONTENTS

Raymond E. Boissy PhDProfessor of Dermatology and Cell Biology, Department ofDermatology, University of Cincinnati College of Medicine,Cincinnati, OH, USA

Jean L. Bolognia MDProfessor of Dermatology, Department of Dermatology, YaleUniversity School of Medicine, New Haven, CT, USA

Barbara Boone MDResident in Dermatology, Universitair Ziekenhuis Ghent, Ghent,Belgium

Ralph P. Braun MDAssistant Professor, Pigmented Skin Lesion Unit, Department ofDermatology, University Hospital, Geneva, Switzerland

Debra L. Breneman MDAssociate Professor of Dermatology, University of Cincinnati,Cincinnati, OH, USA

Stefania Briganti PhDSan Gallicano Dermatological Institute, Rome, Italy

Murray H. Brilliant PhDLindholm Professor of Genetics, Department of Pediatrics,University of Arizona College of Medicine, Tucson, AZ, USA

Lieve Brochez MD PhDProfessor of Dermatology, Department of Dermatology, UniversityHospital of Ghent, Ghent, Belgium

Cynthia J. Burk MDSection of Dermatology, University of Arizona Health SciencesCenter, Tucson, AZ, USA

Stella D. Calobrisi MDMedical Director, The Dermatology Clinic, Boca Raton, FL, USA

Tania Cestari MD PhDAssociate Professor of Dermatology, Department of Dermatology,University of Rio Grande do Sul, Hospital de Clínicas de PortoAlegre, Brazil

Zalfa Abdel-Malek PhDResearch Professor of Dermatology, Department of Dermatology,University of Cincinnati College of Medicine, Cincinnati, OH, USA

Joerg Albrecht MDDepartment of Dermatology, University of Pennsylvania,Philadelphia, PA, USA

Mayra Alvarez-Franco (deceased)Formerly of the Departments of Dermatology and Pathology, YaleUniversity School of Medicine, New Haven, CT, USA

Joseph T. Bagnara PhDProfessor Emeritus, Department Cell Biology and Anatomy,University of Arizona College of Medicine, Tucson, AZ, USA

Philippe Bahadoran MD PhDAssistant Professor of Medicine, Service de Dermatologie, Hôpital l’Archet, Nice, France

Debdutta Bandyopadhyay PhDInstructor of Dermatology, Huffington Center on Aging, BaylorCollege of Medicine, Houston, TX, USA

Scott D. Bangert MDBanner Good Samaritan Hospital, Department of MedicalEducation, Phoenix, AZ, USA

Robert Baran MDHead of Nail Disease Center, Cannes, France

Gregory S. Barsh MD PhDProfessor of Genetics and Pediatrics, Beckman Center for Molecularand Genetic Medicine, Stanford University School of Medicine,Stanford, CA, USA

Eulalia Baselga MDConsultant in Pediatric Dermatology, Hospital de la Santa Creu ISant Pau, Barcelona, Spain

Dorothy C. Bennett MA PhDProfessor of Cell Biology, St George’s Hospital, University ofLondon, London, UK

x

Contributors

José C. García-Borrón PhDProfessor of Biochemistry and Molecular Biology, School ofMedicine, University of Murcia, Murcia, Spain

Rosemary J. Geary MDPresident, East Valley Dermatology Center, Chandler, AZ, USA

Vanessa C. Gray-Schopfer PhDSignal Transduction Team, Cellular and Molecular Biology Section,Institute of Cancer Research, London, UK

Pearl E. Grimes MDVitiligo and Pigmentation Institute of Southern California, DavidGeffen School of Medicine, University of California at Los Angeles,Los Angeles, CA, USA

Vlada Groysman MDSection of Dermatology, University of Arizona Health SciencesCenter, Tucson, AZ, USA

Ruth Halaban PhDSenior Research Scientist, Department of Dermatology, YaleUniversity School of Medicine, New Haven, CT, USA

Rebat M. Halder MDProfessor and Chairman, Department of Dermatology, HowardUniversity, Washington, DC, USA

Seung-Kyung Hann MD PhDDirector, Korea Institute of Vitiligo Research, Yongsan-Gu, Seoul,Korea

Rudolf Happle MDProfessor of Dermatology, Department of Dermatology, Philipp’sUniversity of Marburg, Marburg, Germany

Vincent J. Hearing PhDChief, Pigment Cell Biology Section, Laboratory of Cell Biology,National Institutes of Health, Bethesda, MD, USA

Meenhard Herlyn DVM, DScProfessor and Chair of Program of Molecular and CellularOncogenesis, The Wistar Institute, Philadelphia, PA, USA

Stan P. Hill MDDenver, CO, USA

Lori M. Hobbs MDAssistant Professor, Department of Dermatology, HowardUniversity, Washington, DC, USA

Thomas J. Holstein PhDProfessor Emeritus, Roger Williams University, Bristol, RI, USA

Yoshiaki Hori MD PhD (deceased)Formerly Honorary Professor, Department of Dermatology, KyushuUniversity, Fukuoka, Japan

Henry H. L. Chan MBBS MSc (Clin Derm) MD FRCPFRCP(Ed) FRCP(Glasg) FHKCP FHKAM (Med)Specialist in Dermatology and Honorary Clinical AssociateProfessor, University of Hong Kong and Chinese University ofHong Kong, Hong Kong

Peter Man Hon Chan MDClinical Research Fellow, University of Minnesota, Eagan, MN,USA

Peggy L. Chern MDDepartment of Dermatology, University of Iowa Hospitals andClinics, Iowa City, IA, USA

Mary K. Cullen MDDepartment of Cell Biology and Physiology, Clinical Instructor,Washington University School of Medicine, St Louis, MO, USA

Beth A. Drolet MDDepartment of Dermatology, The Medical College of Wisconsin,Milwaukee, WI, USA

Carol A. Erickson PhDProfessor of Molecular Cellular Biology, University of California atDavis, Davis, CA, USA

Nancy B. Esterly MDProfessor of Dermatology and Pediatrics, Department ofDermatology, The Medical College of Wisconsin, Milwaukee, WI, USA

Dong Fang MD PhDStaff Scientist, The Wistar Institute, Philadelphia, PA, USA

Sharon A. Foley MDDepartment of Dermatology, Washington University School ofMedicine, St Louis, MO, USA

Peter S. Friedmann MD FRCP FMedSciProfessor of Dermatology and Head of Division,Dermatopharmacology Unit, Southampton General Hospital,Southampton, UK

Charles S. Fulk MD FACPDepartment of Pathology, Vanderbilt University, Nashville, TN,USA

Anne-Sophie J. Gadenne MDDepartment of Dermatology, University of Cincinnati College ofMedicine, Cincinnati, OH, USA

William A. Gahl MD PhDClinical Director, National Human Genome Research Institute,National Institutes of Health, Bethesda, MD, USA

Sheila S. Galbraith MDAssistant Professor of Dermatology, Dermatology Department,Medical College of Wisconsin, Milwaukee, WI, USA

xi

CONTRIBUTORS

CONTRIBUTORS

I. Caroline Le Poole PhDLoyola University Medical CenterDepartment of Pathology, Cancer Center, Maywood, IL, USA

Norman Levine MDProfessor of Medicine, Section of Dermatology, University ofArizona College of Medicine, Tucson, AZ, USA

Peter A. Lio MDInstructor in Dermatology, Beth Israel Deaconess Medical Center,Boston, MA, USA

John C. Maize Sr MDMedical Director, DermPath Diagnostics, Maize Center forDermatopathology, Mt Pleasant, SC, USA

John C. Maize Jr MDDermPath Diagnostics, Maize Center for Dermatopathology, Mt Pleasant, Clinical Assistant Professor of Dermatology, MedicalUniversity of South Carolina, SC, USA

Susan Bayliss Mallory MD FAAD FAAPProfessor of Internal Medicine (Dermatology) and Pediatrics,Division of Dermatology, Washington University School ofMedicine, St Louis, MO, USA

Jiro Matsumoto PhDEmeritus Professor, Department of Biology, Keio University,Kohoku-ku, Yokohama, Japan

Estela E. Medrano PhDProfessor of Molecular and Cellular Biology and Dermatology,Huffington Center on Aging, Baylor College of Medicine, Houston,TX, USA

Henk E. Menke MD PhDDermatologist, Department of Dermatology, Sint FranciscusGasthuis, Rotterdam, The Netherlands

Allan D. Mineroff MDLansdale, PA, USA

Gisela E. Moellmann PhDProfessor Emeritus, Yale University School of Medicine, NewHaven, CT, USA

Jean-Marie Naeyaert MD PhDProfessor of Dermatology and Head, Department of Dermatology,University Hospital of Ghent, Ghent, Belgium

Juichiro Nakayama MD PhDDepartment of Dermatology, School of Medicine, Fukuoka University, Fukuoka, Japan

Marcelius Davy Njoo MD PhDStreekzierenhuis Middentwente, Hengelo, The Netherlands

Thomas J. Hornyak MD PhDDermatology Branch, National Cancer Institute, National Institutesof Health, Bethesda, MD, USA

Marjan Huizing PhDHead, Cell Biology of Metabolic Disorders Unit, Medical GeneticsBranch, National Human Genome Research Institute, NationalInstitutes of Health, Bethesda, MD, USA

Sungbin Im MD PhDDirector, Kangnam Wootaeha Skin and Esthetic Clinic, Yeoksam-Dong, Kangnam-Gu, Seoul, Korea

Genji Imokawa PhDDirector, Skin-Bio Assess Institute, Utsunomiya, Tochigi, Japan

Shosuke Ito PhDProfessor of Chemistry, Department of Chemistry, Fujita HealthUniversity School of Health Sciences, Toyoake, Aichi, Japan

Ana Luisa Kadekaro PhDResearch Instructor of Dermatology, University of CincinnatiCollege of Medicine, Cincinnati, OH, USA

Richard A. King MD PhDDirector, Genetics Division, Department of Medicine and AssociateDirector, Institute of Human Genetics, University of Minnesota,Minneapolis, MN, USA

Sidney N. Klaus MDProfessor of Dermatology, Dartmouth-Hitchcock Medical Center,Lebanon, NH, USA

Wolfgang Küster MDProfessor and Chief of Dermatology, TOMESA Clinic, Departmentof Dermatology, Bad Salzschlirf, Germany

Eun Ji Kwon BScDepartment of Dermatology, University of Pennsylvania,Philadelphia, PA, USA

Jean-Philippe Lacour MDService de Dermatologie, Hôpital Archet 2, Nice, France

Cindy L. Lamerson MDClinical Assistant Professor, University of Nevada, Reno, NV, USA

Edward J. Land BSc PhDHonorary Professor, Lennard-Jones Laboratories, School ofGeographical and Physical Sciences, Keele University, Keele, UK

Sang Ju Lee MD PhDDirector, Yonsei Star Skin and Laser Clinic, Chancheon-Dong,Seodaemun-Gu, Seoul, Korea

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Patrick A. Riley MBBS PhD DSc FRCPath CBiol FIBiol FLSProfessor Emeritus of Cell Biology and Director, TotteridgeInstitute for Advanced Studies, London, UK

Randi E. Rubenzik MD FAADSun City West, AZ, USA

Tadeusz Sarna PhD DScProfessor of Biophysics, Department of Biophysics, Faculty ofBiotechnology, Jagiellonian University, Krakow, Poland

Julie V. Schaffer MDAssistant Professor of Dermatology and Pediatrics, New YorkUniversity School of Medicine, New York, NY

Glynis A. Scott MDAssociate Professor of Dermatology and Pathology, Department ofDermatology, University of Rochester School of Medicine,Rochester, NY, USA

Vijayasaradhi Setaluri PhDAssociate Professor of Dermatology, University of Wisconsin Schoolof Medicine and Public Health, Madison, WI, USA

Anita P. Sheth MDDepartment of Dermatology, University of Cincinnati College ofMedicine, Cincinnati, OH, USA

Pranav B. Sheth MDAssistant Professor, Department of Dermatology, University ofCincinnati, Cincinnati, OH, USA

Shigeki Shibahara MD PhDProfessor, Department of Molecular Biology and AppliedPhysiology, Tohoku University School of Medicine, Aoba-ku,Sendai, Miyagi, Japan

Arthur J. Sober MDProfessor of Dermatology, Harvard Medical School, MassachusettsGeneral Hospital, Boston, MA, USA

Francisco Solano PhDProfessor of Biochemistry and Molecular Biology, School ofMedicine, University of Murcia, Spain

Richard A. Spritz, MDProfessor and Director, Human Medical Genetics Program,University of Colorado Health Sciences Center at Fitzsimons,Aurora, CO, USA

Harold M. Swartz MD PhDProfessor of Radiology, Dartmouth Medical School, Hanover, NH,USA

Kazuhisa Takeda MD PhDAssistant Professor of Molecular Biology, Department of MolecularBiology and Applied Physiology, Tohoku University School ofMedicine, Aoba-ku, Sendai, Miyagi, Japan

James J. Nordlund MDDermatologist and Professor Emeritus, Group Health Associates,Cincinnati, OH, USA

William S. Oetting PhDAssociate Professor, Genetics Division,Department of Medicine, Institute of Human Genetics, Universityof Minnesota, Minneapolis, MN, USA

Jean-Paul Ortonne MDProfessor of Dermatology and Chairman, Department ofDermatology, University of Nice-Sophia Antipolis, Nice, France

Monica Ottaviani PhDSan Gallicano Dermatological Institute, Rome, Italy

David M. Parichy PhDAssistant Professor, Department of Biology, University ofWashington, Seattle, WA, USA

Thierry Passeron MDClinical Assistant in Medicine, Nice, France

Christophe Perrin MDLaboratoire d’Anatomie Pathologique, Hôpital L. Pasteur, Nice,France

Mauro Picardo MDSan Gallicano Dermatological Institute, Rome, Italy

Tanusin Ploysangam MD PhDDirector, Institute of Beauty and Health Science, and Director,Belage Skin Care and Cosmetic Center, Nunthawan Prachacheun,Bangtalad, Nonthaburi, Thailand

Walter C. Quevedo Jr PhDEmeritus Professor of Biology, Department of Molecular and CellBiology and Biochemistry, Brown University, Providence, RI, USA

Christopher A. Ramsden BSc PhD DSc Cchem FRSCProfessor of Organic Chemistry, Lennard-Jones Laboratories,School of Geographical and Physical Sciences, Keele University,Keele, UK

H. Randolph Byers MD PhDProfessor of Dermatology, Boston University School of Medicine,Boston, MA, USA

Mark V. Reedy PhDAssistant Professor of Biology, Creighton University, Omaha, NE,USA

Germaine N. Relyveld MDDepartment of Dermatology, Academic Medical Center,Amsterdam, The Netherlands

xiii

CONTRIBUTORS

CONTRIBUTORS

Victoria P. Werth MDProfessor of Dermatology and Chief, VA Dermatology, Departmentof Dermatology, University of Pennsylvania, Philadelphia, PA, USA

Wiete Westerhof MD PhDAssistant Professor of Dermatology, Netherlands Institute forPigment Disorders and Department of Dermatology, AcademicMedical Center, University of Amsterdam, Amsterdam, The Netherlands

Antony R. Young PhDProfessor of Experimental Photobiology, King’s College Londonand St John’s Institute of Dermatology, St Thomas’ Hospital,London, UK

Luc Thomas MD PhDProfessor and Chairman, Department of Dermatology, Lyon 1University, Hotel Dieu, Lyon, France

Marnie D. Titsch MDDermatology Specialist, Oyster Point Dermatology Inc., NewportNews, VA, USA

Peggy Tong MDDermatology Associates, Milwaukee, WI, USA

Kazunori Urabe MD PhDAssociate Professor, Department of Dermatology, Graduate Schoolof Medical Science, Kyushu University, Fukuoka, Japan

Kazumasa Wakamatsu PhDProfessor, Fujita Health University School of Health Sciences,Toyoake, Aichi, Japan

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ests and expertise. Animal pigment has long been known tofunction protectively in some animals as well as decorativelyin others. Pigment can provide camouflage for some and flam-boyant advertisement for others.

The embryonic origin of skin pigment cells, the neural crest,suggests that pigment cells share common traits with a widevariety of nerve cells. And yet, like all stem cells, neural crestcells can differentiate along a multitude of pathways, perhapsto become a sensory neuron or to become a melanocyte. Thesehighly motile embryonic cells, even after settling down anddifferentiating, still retain a remarkable capacity for furthermotion and differentiation or reversion. Witness the havocthat can ensue if melanocytes become cancerous and migrateto all parts of the body to form tumors.

The first edition of The Pigmentary System was un-questionably the definitive text of its time. The editors, whoare themselves pre-eminent in this field, have worked with theauthors to provide significant revisions to nearly every chapter,and a new chapter on melanocytes as malignant cells has beenadded. Virtually any topic related to pigmentary systems canbe found in this single source, from animal chromatophoresto human pigmentary disorders, from basic cell biology toclinical studies and results.

Congratulations to the editors and to those researchers whoare actively engaged in helping us better understand the com-plexities of this fascinating system!

Sally Frost Mason PhDPurdue UniversityWest Lafayette, IN, USA

In this second edition of The Pigmentary System: Physiologyand Pathophysiology, the editors have expanded upon thedynamic field of pigment cell biology to reflect not only therapidly moving pace of developments in this broad field butalso the explosive growth of research and development acrossthe basic life sciences. We have all benefited enormously fromthe recent growth in the research budgets of agencies such asthe National Institutes of Health (NIH), and these benefitstranscend beyond grant recipients to citizens who benefit frombetter treatments or management protocols for diseases thatin the past were nearly always seriously debilitating. Neverbefore have advances come so rapidly or with so muchpromise for improving the human condition. These improve-ments come as a result of better understanding of all aspectsof the composition and function of living cells. From the molecules that direct activity to those that confer shape andphenotype, we know more today about the basic buildingblocks of living matter than at any time previously in ourhistory.

Perhaps even more astounding is the pace at which discov-eries in the life sciences continue to be made. In recent yearswe have experienced near-exponential growth in the quantityand quality of information available across all sectors of thelife sciences. There is little doubt that as we move toward theend of the first decade of the twenty-first century we will haveanswers to many questions, some of which we never imaginedbeing able to ask.

The pigmentary system, as a model system for studyingbasic questions about differentiating stem cells, has providedample opportunities for study across a broad range of inter-

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Foreword

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ongoing scientific work related to pigmentation is an indica-tor of the importance of melanocytes. It also is a clue thatmelanocytes, melanotropins and related cells and factors arenot just a mechanism for sun protection. It is obvious andcertain that melanocytes and melanin are protective againstsunlight. But the role of melanin in the eyes and ears is morethan just sun protection. Melanocytes are involved in manyprocesses within the epidermis. Melanotropins have effects onvirtually every organ system in the body and control inflam-mation, appetite, some functions within the nervous system,and other critical functions. The pigmentary system, includingmelanin, melanocytes and melanotropins, is best described asa modulator that helps the body adapt to the environmentalchanges related to seasonal fluctuations in sunlight, tempera-ture, and humidity.

We hope that scientists, clinicians, students, and residentsfind this book useful in their studies on skin color,melanocytes, and melanin, and that it expands their perspec-tive and view about the pigmentary system as a modulator,not just a method of sun protection.

James J. Nordlund Raymond E. Boissy Vincent J. Hearing Richard A. KingWilliam S. OettingJean-Paul Ortonne

This second edition of The Pigmentary System: Physiologyand Pathophysiology presents the latest information about thebiology of melanocytes and their disorders. The first sectionis dedicated to the science of pigmentation and has been com-pletely rewritten, not just updated. The chapters have beenreorganized to provide the most current and comprehensivereview of the science of pigmentation. New chapters have beenadded and some old chapters in the first edition have beendeleted. All of these were chapters on methodology that wererapidly outdated after publication. Some information and dataremain constant and are unchanged in this edition. Othertopics are entirely new or significantly enlarged since publica-tion of the previous edition.

Part II on the pathophysiology of pigmentary disorders ismostly updated. New chapters have been included. A lexiconon proper terminology for description of skin color has been included as the first chapter in this section. Unless thescientific and clinical communities use the same termin-ology to describe and identify scientific or clinical topics, there will be confusion about the nature and treatment of pigmentary or dyschromic disorders. We hope that this lexicon becomes standard in the dermatological and scientificcommunities.

The comments that we made in the preface to the firstedition are still very relevant. A few are worth repeating. Thisbook is intended to be a reference book for both the scientificand the clinical communities. The fact that there is so much

Preface

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The editors wish to acknowledge the very gracious and generous support of the following companies. Without their support, thisproject would not have been possible.

Galderma International, Paris, FranceProctor and Gamble, Cincinnati, OH, USACombe Inc., White Plains, NY, USA

Acknowledgments

The Physiology of the Pigmentary SystemI

Historical and ComparativePerspectives of the Pigmentary System1

A History of the Science of PigmentationSidney N. Klaus

1

5

Introduction

In Europe, prior to the seventeenth century, notions about the origin of human skin color were based largely on mythsand fanciful stories passed down from the ancient world. Thestories focused on providing explanations for the blackness ofAfricans. Europeans with an ethnocentric perspective thoughtthat it was necessary to justify the darkness of outsiders ratherthan to explain their own paleness. In Europe, two theoriesabout the origin of Africans’ color predominated. The firstproposed that the black hue of African skin was a consequenceof the intense sunlight and heat to which Africans wereexposed. The second idea proposed that African color was aresult of divine intervention, a concept that stemmed from thewell-known passage in Genesis describing Noah’s curse onHam and his progeny.

Such traditional views of skin color were questioned duringthe Age of Discovery. Explorers were returning home fromremote regions of the globe and bringing with them descrip-tions of black-, yellow-, or red-hued peoples. The array ofcolors fascinated scientists and excited them to investigatehow these skin colors originated.

During the sixteenth century, the scientific community pre-pared for this task. Scientists learned new techniques of humandissection and new methods of chemical analysis. Moreimportantly, they adopted a new philosophical approach forthe study of natural phenomena. Rather than analysis of phe-nomenon based on a priori assumptions, they based theiranalyses on firsthand observations and experimentation. Bythe seventeenth century, anatomists and physicians had begunto collect objective data about skin color. For the next twocenturies, so many important observations had been collectedabout the seat of skin color and the causes of its diversity that,as one researcher boasted, “a good sized volume was scarcelylarge enough to contain them.”

The furious pace of forward progress was slowed somewhatin the early part of the nineteenth century when skin color sci-entists in both Europe and America were drawn into acrimo-nious debates over social issues, especially slavery and theplace of “peoples of color” in the family of man. By the endof the century, the slavery issue had been settled, and the dis-covery of the cell and improved methods for the microscopicexamination of the skin had stimulated the discipline to setoff in new directions.

In retrospect, it is clear that the science of skin color hadcompleted its early phase of development by the 1840s. Withthe discovery of the cellular nature of the epidermis, the“modern” phase of skin color science had begun (Meirowsky,1940). This chapter briefly summarizes the first 250 years ofthe earlier phases of pigment research, from its birth in the1600s to its “coming of age” in the 1840s. A history of themodern era, from the 1840s to the present, may be found inreviews by Becker (1959) and Nordlund et al. (1989).

Early Anatomic Discoveries

To the ancient Greeks and Romans who were acquainted withthe peoples of Ethiopia, the black color of the Africans wasregarded as their most characteristic and most curious feature.Greek and Roman scientists were not equipped to investigatethe causes of dark complexions in a meaningful way. Theyunderstood little about dissection of individual tissues andwere unable to sort out the anatomic details related to theskin. They regarded the skin as an amorphous membranemade from the congealing of “moist exhalations” driven tothe surface of the body by internal heat. They believed thatthe color of skin was imposed either from outside by the sunor by some inner humor. These notions about skin color per-sisted through the Middle Ages and into the Renaissance. In1543, Vesalius succeeded in splitting the skin into two layersby applying a burning candle to the abdomen of a livingsubject. He did not examine the skin layers for their contentof color. It was not until 75 years later that the first “scien-tific” study of skin color was performed.

In 1618, Jean Riolan the younger, a Parisian anatomist, wasthe first person to make a detailed analysis of skin color. Heused a technique similar to that of Vesalius to separate the skinof a black subject into two layers. But he used a vesicant ratherthan a flame to produce a blister and carefully examined thetwo layers for their color and texture. He found that, whilethe top of the blister (the cuticle) was pigmented, the base (thecutis) remained white. “Color . . .” he announced “. . . lay inthe outer layer, and did not go so deep as the true skin”(Riolan, 1618).

To Riolan, this finding reinforced the idea that heat and sun-light were the ultimate causes of blackness. Riolan reasonedthat, if the sun caused skin darkening, it was expected that theouter cuticle would be darker than the inner cutis.

CHAPTER 1

planted out of Africa, retain still the complexion of their Prog-enitors” (Boyle, 1664).

Malpighi’s Innovation:the Rete Mucosum

Riolan’s contention that the cuticle was the seat of color hadbeen in place for less than a century when it was supersededby an entirely different notion proposed by the Italiananatomist, Marcello Malpighi. In 1667, Malpighi stated thatthe seat of color was not the cuticle. Rather, he proclaimedthat color was located in a separate layer of the skin sandwiched between the cuticle and the cutis. He named thislayer the rete mucosum. The discovery of rete came about in the following way. In 1665, Malpighi had been searchingfor the structures that mediated the sensation of taste, and hesucceeded in finding large papillae just below the surface ofthe tongue. Turning to the skin to see if he could find similarstructures that mediated touch, he found that he was unableto separate the skin’s layers properly by boiling, the methodthat he had used previously. He was forced to use putre-faction, an old dissection technique in which the separation ofparts is enhanced by allowing a small piece of tissue to decom-pose partially. Using this method, he prepared skin fromcadavers and found that he could easily lift the cuticle fromthe cutis. By this method, he was able to identify the dermalpapillae. However, he also found a mucoid material drapedover the papillae, which he regarded as a protective covering.The material had a netlike appearance when seen from above, so he called it the rete mucosum. Malpighi’s experi-ments were not directed at discovering the proximate cause of skin color. However, in one experiment in which he used skin from an Ethiopian cadaver, he noted that the mucoidmaterial was tinged black. On the basis of this finding, he later wrote “It is certain that the cutis (of the Ethiopian) iswhite, as is the cuticula too; hence all their blackness arisesfrom the underlying mucous and netlike body” (Malpighi,1665).

Malpighi did not follow up on his discovery of the “seat ofcolor” but the putrefaction technique he used allowed thelayers of the skin to be separated gently. The method producedreliable results, and other investigators soon expanded onMalpighi’s finding. In 1677, three years after Malpighi pub-lished his findings, Johann Pechlin, a Dutch anatomist, usedMalpighi’s method of dissection to make a thorough study ofEthiopian skin. In one experiment, after he lifted off thecuticle, he scraped away the black mucous and reapplied thescarf to the cutis. He reported that “. . . a whiteness came forthimmediately of the sort seen often enough in Europe. In truththe surface of the skin was scarcely unattractive.” Pechlin wasconcerned that his results obtained using cadaver skin mightnot be the same had he studied living skin. To his dismay, hewas unable to convince living subjects to cooperate in hisexperiments “. . . because of I don’t know what sort of evil onthe part of the Negroes” (Pechlin, 1677).

A few years later, Alexander Read, an anatomist workingin London, repeated Riolan’s experiments and found the sameresults. However, Read offered a different interpretation. Theskin pigment, he concluded, was not caused by singeing thebody’s surface. He concluded rather that skin color wasderived from the body’s inner humors. As they escapedthrough the skin, some of the elements became attached to thesurface and dried, thus producing the pigment. Negroes, heargued, had darker skin because they had larger pores thanwhites, a morphologic variation allowing greater volumes oftheir humors to escape leaving behind larger amounts of black“remnants” of the humors (Read, 1642).

Perhaps the most detailed analysis of skin color in the sev-enteenth century was carried out by the distinguished writerand physician, Sir Thomas Browne. Browne had listened care-fully to the accounts of explorers who had found variouslycolored races, and he concluded from these accounts that colordid not arise from the influence of climate. “If the fervor ofthe Sun were the cause of the Negroes’ complexion, . . .” hewrote, “. . . it is reasonable to assume that inhabitants of thesame latitude, subjected unto the same vicinity of the Sun,partake of the same hue and complexion, which they do not.”In addition, he noted that Africans who had been transplantedinto “. . . cold and phlegmatic habitations . . .” had not turnedwhite, but “. . . continued their hue, both in themselves andtheir generations.” He rejected the idea that skin blacknesswas acquired from a “. . . power of imagination . . .” or from “. . . anointing with bacon and fat substances.” Instead,he thought that the tincture of the skin was based on an inborntrait, a trait that was passed from father to son by the sperm.

Browne was not an armchair scientist. His diary records theoutline of numerous experiments he carried out to determinefor himself the seat of color. For example, he set out to makea “. . . blistering plaster in a negroes skinne and trie if the nextskin will bee white . . .” and to see whether a “. . . vesicationwill do anything upon a dead cold body.” He even urged hisson Edward, a medical student, to carry out additional studies.He wrote to him asking that he “. . . separate the skin of a black person with boiling water and take notice of the cuticula and cutis and observe how the scarres become whiteror less blacke than any other parts.” He also urged him to “. . . touche the skin with aqua fortis and see how it will alterthe colour.” Unfortunately, Browne did not record the resultsof these experiments (Keynes, 1964).

Another seventeenth century polymath, Robert Boyle,devoted a chapter of his book Experiments and Considera-tions Touching Colours to what he called “the Cause of theBlackness of those many nations which by one common Name we are wont to call Negroes.” He examined the variouscauses proposed at that time and denied that either Noah’scurse on Ham or “heat alone” could produce a true blackness. Instead, he focused on principles of inheritance,concluding that the “Principal Cause of the Blackness ofNegroes is some Peculiar and Seminal Impression.” As evidence, he reported that “the off-spring of Negroes, trans-

6

that he had examined cadavers of Africans and observed that“the bile is black, and the blackness of the skin is in propor-tion to the blackness of the bile.”

Later in the century, another investigator attempted toprove that the pigment of Africans was derived from bile.Samuel Stanhope Smith, a professor of moral theology at theCollege of New Jersey, had learned from an American col-league that bile exposed to the sun and air changed its colorto black. Smith hypothesized that, in southern climates, thesecretion of bile was augmented and, when the bile reachedthe skin, it became “. . . more languid and almost fixed.” In the skin, the aqueous parts of the bile easily escape throughthe pores of the skin by perspiration, while the more denseportion remained in a glutinous state within the rete. There,it received the repeated radiation from the sun and atmosphereand turned black. Smith believed that a cold environmentwould reverse the process of darkening and render the com-plexion “. . . clear and florid.” According to Smith, if Africansmoved to temperate climates from Africa “. . . they wouldsoon lose their imposed color and become the color of Europeans” (Smith, 1788).

Johann Friedrich Blumenbach, the German ethnologist, alsoproposed that bile was the coloring agent of the skin. He had learned that bile was made of a mixture of carbon andhydrogen. He suggested that, as the bile reached the skin, thehydrogen it contained became more volatile than the carbonand combined with atmospheric oxygen. This reaction leftbehind a black carbon residue that became embedded in the Malpighian mucous and caused the skin to darken (Blumenbach, 1865).

Another “chemical” theory was advanced by the youngHumphrey Davy in 1799. Davy thought that light had a greataffinity for oxygen and could extract it from other com-pounds. Davy had evidence that the mucous material of therete was made of a colorless mixture of carbon, nitrogen, andoxygen. He proposed that sunlight extracted the oxygen fromthis mixture and left behind a black material made of carbonand nitrogen. To Davy, this explained differences in skin huesfound throughout the world. “In northern latitudes, where theinhabitants are less exposed to light, the rete continues tocontain its full proportion of oxygen, and the inhabitants arelighter in color. In the torrid zone, on the other hand, wherethe sun was especially intense, larger quantities of oxygenwould be removed, and the blackness peculiar to the negroeswill be found.” Davy had no direct proof that light could sub-tract oxygen from the skin, but he did cite other chemicalexperiments to support his claim. He reported that, when acompound that binds oxygen, such as sulfur of potash, isapplied to the skin of a white person, the skin blackens. Whena compound that gives off oxygen, such as muriatic acid, isapplied to the skin of a Negro, it lightens (Davy, 1799).

An even more imaginative notion about the nature of skincolor was suggested by Immanuel Kant. Kant based his theoryon the well-known capacity of phlogiston to turn blood ablack color. Phlogiston was an imaginary element consideredto be the essential principle of combustion. It was said to be

A few years later, the Dutch microscopist Antoni vanLeeuwenhoek, in a letter to the Royal Society of London,reported on his observations made using his microscope of theskin of a black Moorish girl. “I took from several parts of thearms the outer skin with a fine little instrument and found thatit consisted of little scales. Putting these scales before mymicroscope I found them to be not as transparent as those ofmy skin.” Van Leeuwenhoek concluded that the black colorof the skin was the result of the black scales, and that “thelittle vessels which form the scales of the Moors” may possi-bly develop a slightly darker color (Collected Letters of Antonivan Leeuwenhoek, 1683–1684; see Schierbeek, 1952).

If one follows Malpighi’s directions for uncovering the rete,as the cuticle is lifted off one observes tiny mucoid threadsbridging the angle between the two layers. William Hunterdescribed them as “. . . an infinite number of filaments, as fineas the most delicate threads of a spider’s web, that passbetween the cutis and the more external integuments”(Hunter, 1764). According to some anatomists, the threadswere tiny vessels. This idea led some of the more inventiveinvestigators to propose that the coloring matter in Africans’skin was not the mucous material itself but was a black fluidcontained within the web of small vessels. One contemporaryobserver wrote “. . . between the outward and inner skin ofthe corpse can be found a kind of vascular plexus, spread overthe whole body like a web or net, which was fill’d with a Juiceas black as Ink” (Marana, 1801).

It became something of a challenge to prove unequivocallythat these filaments were in fact “vessels.” In anatomic labo-ratories, the identification of small vessels in anatomic prepa-rations relied on their visualization after they had beeninjected with colored glue or isinglass. Only a few investiga-tors were skilled enough to inject these “. . . most delicatethreads.” One anatomist who was given credit for the firstdemonstration of this vascular network was WilliamBaynham, an American who had moved to London in 1769.Although Baynham never published his findings, he placed hisspecimens on exhibition in John Hunter’s anatomic museum.Not all Baynham’s colleagues were convinced by his discov-ery. William Cruickshank made a careful study of Baynham’spreparations and later wrote that he was “. . . not perfectlysatisfied” with them. He concluded that Baynham had notinjected the vessels of the rete, but rather a series of vesselsthat lay between the rete and the cutis (Cruickshank, 1795).

In the eighteenth century, the attention of researchers beganto move from the anatomy of the rete to the “nature” of thecoloring matter itself. Early attempts to collect and analyzematerial from the rete were not productive. Alexis Littre, aFrench surgeon, soaked pieces of skin from a Negro cadaverfor a week either in warm water or in spirits of wine but wasunable to extract any of the coloring matter (Littre, 1720).

A few years later, another French scientist, Pierre Barrere,in an essay submitted to the Academy of Bordeaux in 1741,denied Malpighi’s claim that the pigment of Africans’ skinarose from the “corps reticulaire.” It is evident, he wrote, thecoloring matter in the skin of Africans was bile. He reported

7

A HISTORY OF THE SCIENCE OF PIGMENTATION

CHAPTER 1

Bolstering the polygenist cause was the English anatomist,John Gordon. Gordon claimed that whites, unlike blacks, hadno rete mucosum. “I have satisfied myself by many dissectionthat in the Negro there is a Black membrane interposedbetween the epidermis and true skin upon which their darkcolor entirely depends . . . But after the strictest examination Ihave not been able to find any light colored rete mucosum inthe inhabitants of Great Britain, nor in those of other nationsresembling them in color” (Gordon, 1815).

Several anatomists disagreed. Richard Harlan, a young lec-turer in anatomy from Philadelphia, wrote that “. . . the exis-tence of the rete mucosum in the white race, so frequentlydenied, has been demonstrated occasionally in the Europeanby skilful anatomists and if not deceived I myself have dis-covered it several times in a living European subject, by raisingthe epidermis with a blister, especially upon the back of thehands and the neck” (Harlan, 1835).

Charles Caldwell, who had moved from Philadelphia to become a professor in a medical college in Lexington, Kentucky, reported that he too found the rete in both races,although the structures were not identical in appearance. “Therete mucosum in blacks is comparatively thick, while in theCaucasian, the rete is present but it is much thinner.” In spiteof this similarity, however, Caldwell concluded that Negroesand Caucasians were sufficiently distinct to be called separatebiological species (Caldwell, 1830).

Experiments of Nature

In addition to the work carried out by anatomists and chemistsin dissecting rooms and laboratories, many physicians madeimportant contributions to the fund of information about skincolor through reporting and analyzing patients with clinicalproblems. John Josselyn, a physician from England who wasvisiting the Massachusetts Bay Colony in 1675, was one ofthe first physicians to advance the science of skin color byusing observations based on a clinical case. While in Boston,Josselyn had been called upon to lance a “corruption” in thepalm of a “Moor.” Later, he described his findings. “After Ilanced it, I perceived that the Moor had one skin more thanEnglishmen, deeper in colour than our European veins, andupon it rests the epidermis” (Josselyn, 1675).

Samuel Marcy, a physician from rural New Jersey, reportedthe case of an albino girl. After providing a full account of herfamily history, including the fact that she had two albinosisters, he went on to consider the cause of the disorder. “Themother accounts for the appearance of the child by attribut-ing it to a severe fright she receive by the falling down of anold white mare she was driving,” wrote Marcy. “Although Iwas unwilling to admit at first that the Great Creator ever lefthis work in so loose a manner, that the imagination of themother should alter or determine form or color of her chil-dren, the birth of two other albino children go further tostrengthen the doctrine that the mind of the mother may affectthe fetus in utero” (Marcy, 1839).

released from the body through the lungs as part of the meta-bolic process. Kant believed that, in regions of the globe wherethe atmosphere was heavily phlogisticated, such as the coastof Africa, it would be impossible to eliminate all the body’sphlogiston by breathing. Kant proposed that the excess phlo-giston would travel through the circulation and, on reachingthe skin, it would precipitate in the ends of the small cuta-neous vessels and turn the skin black (Lovejoy, 1959).

Claude Le Cat, a French physician, claimed that the sourceof Africans’ blackness was neither bile nor blood. He said thatthe black mucous, which he called ethiops, was found only inAfricans and that it was secreted directly into the skin throughthe tips of the cutaneous nerves (Le Cat, 1765).

Although most early scientists believed that skin pigmentwas derived from some “internal” source such as bile orblood, a few investigators decided that the coloring matter wasproduced by glands within the skin itself. The earliest versionof this hypothesis was offered by an English anatomist,Edward Tyson. He proposed that the black colour in Negroes’skins came from glands that were full of a “black liquor.” Hesuggested that the climate might alter the glands so that “. . .they might separate from the mass of blood a differing humorfrom White, and by this means give a different hue to theinhabitants” (Montagu, 1943).

Two French researchers, G. H. Breschet and Roussel deVauzeme, reported that they had found a “. . . chromatogen-ous apparatus . . .” in the cutis which secreted the blackmucous. They said that the mucous was deposited on thesurface of the dermal papillae through short, excretory ductsemanating from glandular parenchyma located in the cutis(Plumbe, 1837).

Another French investigator, M. Gaultier, also argued thatthe coloring matter was secreted within the skin but not fromglands. The pigment of the skin, he said, was produced insteadfrom hair bulbs. Gaultier’s claim was based on the results ofan experiment he carried out on a living subject. He burnedthe skin of a Negro and then closely observed the pattern of repigmentation during the healing process. According toGaultier, the pigment appeared first around the “pores”through which the hairs exited and only later did it radiateout to cover the entire area of the burn (Prichard, 1813).

Differences Between Blacks and Whites

As a more complete picture of skin color began to emerge bythe end of the eighteenth century, political and social forcesrequired the disciplines of anatomy and biology to take on asocial dimension. Advocates of black slavery argued thatAfricans were not the “brothers” of Europeans but ratherwere the product of a separate creation. Skin color, the mostobvious marker of racial identity, was forced to the center ofthe debate over the unity of mankind. The polygenists beganlooking for “significant” anatomic differences between blacksand whites to prove they were separate species. Monogenistsbegan looking for evidence of similarities.

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