Table Of ContentMosaicism in
Human Skin
Understanding Nevi, Nevoid
Skin Disorders, and Cutaneous
Neoplasia
Rudolf Happle
Antonio Torrelo
Second Edition
123
Mosaicism in Human Skin
Colored table by J. Wissmaack, representing “Marie Horstmann, Nevus verrucosus and neuropathic papilloma accord-
ing to Esmarch” originally published in the volume Die Elephantiastischen Formen by F. Esmach and D. Kulenkampff
(auth.), publisher J.F. Richter Verlag, Hamburg, 1885. Figure under Public Domain
Rudolf Happle • Antonio Torrelo
Mosaicism in Human
Skin
Understanding Nevi, Nevoid Skin
Disorders, and Cutaneous Neoplasia
Second Edition
Rudolf Happle Antonio Torrelo
Department of Dermatology Department of Dermatology
Freiburg University Medical Center Hospital Infantil Universitario Niño Jesús
Freiburg, Germany Madrid, Spain
Originally published under: Happle, R. (auth) Mosaicism in Human Skin, Springer-
Verlag Berlin Heidelberg
ISBN 978-3-030-89936-3 ISBN 978-3-030-89937-0 (eBook)
https://doi.org/10.1007/978-3-030-89937-0
© Springer Nature Switzerland AG 2014, 2023
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Preface
This second edition contains many significant changes. First of all, the work
owes its appearance to the steadfast cooperation of two dermatologists from
Freiburg and Madrid, respectively.
During the past years, the molecular revolution in cutaneous biology has
yielded many new discoveries. Therefore, this volume describes several new
categories such as the dichotomy of monoallelic versus biallelic mosaicism;
disseminated mosaicism of biallelic autosomal dominant disorders; isolated
segmental biallelic monoclonal mosaicism; double postzygotic mutations in
cis, involving the gene TEK; and autosomal recessive mosaicism.
In the first edition of this book, one of us wrote: “In the years to come,
further molecular research will show which of the hypotheses presented here
can be corroborated and which of them may turn out to be wrong.” Fortunately,
the number of substantial errors was limited. For example, a conspicuous
case of the so-called X-linked albinism-deafness syndrome was detected to
represent in fact Waardenburg syndrome type 2, thus being an autosomal
dominant trait that has now been moved to the section on “epigenetic mosa-
icism of autosomal genes.”
The first edition contained a short “Note on neoplastic skin lesions.”
This subject was on the borderline to the vast realm of oncology because all
malignant tumors represent mosaics. We had to decide either to expand or
to omit this voluminous subject, and we decided to cut this chapter away.
Many oncological aspects will now be presented in other Chaps. 3 and 10
or elsewhere.
During the preparation of this work, we had lots of fun by learning a great
deal from each other. Of course, we were not always of the same opinion,
which resulted in lively discussions that did not interfere, however, with our
friendship. Presumably, we are so well disposed to each other because we are
born on exactly the same day, albeit with a distance of 25 years.
We want to thank Professor Leena Bruckner-Tuderman and her successor,
Professor Kilian Eyerich who kindly continued to offer to one of us a work-
ing place at the Department of Dermatology in Freiburg. Ms. Juliette
R. Kleemann from Springer Science+Business Media successfully managed
that we could get, and keep, the ultimate deadline to deliver our text in these
cumbersome Corona times, and Mr. Felix Lörch from Springer Heidelberg
performed the steps of the production in an exemplary manner. Last but not
v
vi Preface
least, we should like to thank our wives, Karin in Freiburg and Lourdes in
Madrid, who gave us the time and moral support to fulfill the task of writing
this new edition.
Rudolf Happle Antonio Torrelo
Freiburg, Germany Madrid, Spain
Acknowledgments
The following colleagues or other persons kindly provided photographs or
gave advice how to find cases and references:
David Atherton, London, UK
Jacques Ayer, Geneva, Switzerland
Eulalia Baselga, Barcelona, Spain
Herrmann Blaschko, Oxford, UK
Mario Bittar, Mendoza, Argentina
Ernesto Bonifazi, Bari, Italy
Frédéric Cambazard, St. Etienne, France
Marco Castori, Rome, Italy
WenChieh Chen, Munich, Germany
Hansjörg Cremer, Heilbronn, Germany
Franco Crovato, Genoa, Italy
Hugo Degreef, Leuven, Belgium
Elzo Folkers, Zaandam, The Netherlands
Regina Fölster-Holst, Kiel, Germany
Hansjörg Frei, Zurich, Switzerland
Alejandro García Vargas, Guadalajara, Mexico
Antonia González-Enseñat, Barcelona, Spain
Robert J. Gorlin, Minneapolis, Minnesota, USA
Henning Hamm, Würzburg, Germany
Susanne Happle, Shanghai, China
Adelaide Hebert, Houston, Texas
Helena de las Heras, Madrid, Spain
Susan M. Huson, Manchester, UK
Peter H. Itin, Basel, Switzerland
Marcel Jonkman, Groningen, The Netherlands
Hülya Kayserili, Istanbul, Turkey
Claudia Kluge, Freiburg, Germany
Arne König, Marburg, Germany
Thomas Krieg, Cologne, Germany
Gerhard Kurlemann, Münster, Germany
Michael Landthaler, Regensburg, Germany
Ulrich Langenbeck, Frankfurt, Germany
Eric Legius, Leuven, Belgium
Derek Lim, Birmingham, UK
Gérard Lorette, Tours, France
vii
viii Acknowledgments
Eamonn Maher, Birmingham, UK
Wolfgang Marsch, Halle (Saale), Germany
Silvestre Martínez-García, Málaga, Spain
Beatrice Mintz, Philadelphia, Pennsylvania, USA
Georges Moulin, Lyon, France
Marcel Müller, Freiburg, Germany
Kirsti-Maria Niemi, Helsinki, Finland
Shiro Niiyama, Sagamihara, Japan
Shigeo Nishiyama, Kamakura, Japan
Arnold Oranje, Rotterdam, The Netherlands
Jean-Paul Ortonne, Nice, France
Francis Palisson, Santiago, Chile
Mauro Paradisi, Rome, Italy
Anna M. Pasmooij, Groningen, The Netherlands
Gerd Plewig, Munich, Germany
Howard Pride, Danville, Pennsylvania, USA
Hans-Dieter Rott, Erlangen, Germany
Ramón Ruiz-Maldonado, Mexico City, Mexico
Thomas Ruzicka, Munich, Germany
Aïcha Salhi, Algiers, Algeria
Walter Salzburger, Basel, Switzerland
Silvina Sartori, Santa Fe, Argentina
Maxwell B. Sauder, Ottawa, Canada
Cornelia S. Seitz, Göttingen, Germany
Theo Starink, Amsterdam, The Netherlands
Beat Steinmann, Zurich, Switzerland
Alexander Stella, Vienna, Austria
Alain Taïeb, Bordeaux, France
Iliana Tantcheva-Poor, Cologne, Germany
Mustafa Tekin, Ankara, Turkey
Sigrid Tinschert, Berlin, Germany
Uwe Töllner, Fulda, Germany
Jaime Toribio, Santiago de Compostela, Spain
Adoni Urtizberea, Paris, France
Fereydoun Vakilzadeh, Hildesheim, Germany
Shyam B. Verma, Vadodara, India
Wolf I. Worret, Munich, Germany
Sabine Wever, Basel, Switzerland
Ching-Ying Wu, Kaohsiung, Taiwan
Hitoshi Yaguchi, Tokyo, Japan
Shehu M. Yusuf, Kano, Nigeria
Mónica Zambrano, Quito, Ecuador
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Mosaicism as a Biological Concept . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1 H istorical Beginnings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2 M osaicism in Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.3 M osaicism in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.4 M osaicism in Human Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.5 M osaicism Versus Chimerism . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.6 D oes the Coat of Zebras Reflect Mosaicism? . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3 The Major Categories of Mosaicism . . . . . . . . . . . . . . . . . . . . . . . 11
3.1 N onsegmental Versus Segmental Mosaicism
of Autosomal Dominant Skin Disorders . . . . . . . . . . . . . . . . . 11
3.1.1 Nonsegmental Mosaicism . . . . . . . . . . . . . . . . . . . . . . 11
3.1.2 Segmental Mosaicism . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.2 G enomic Versus Epigenetic Mosaicism . . . . . . . . . . . . . . . . . . 12
3.3 G enomic Mosaicism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.3.1 Genomic Mosaicism of Autosomes . . . . . . . . . . . . . . . 12
3.3.2 Autosomal Recessive Mosaicism . . . . . . . . . . . . . . . . . 22
3.3.3 Didymosis (Twin Spotting) . . . . . . . . . . . . . . . . . . . . . 23
3.3.4 Revertant Mosaicism . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.3.5 Genomic X-Chromosome Mosaicism
in Male Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.3.6 Superimposed Segmental Manifestation
of Polygenic Skin Disorders . . . . . . . . . . . . . . . . . . . . 26
3.4 E pigenetic Mosaicism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.4.1 Epigenetic Mosaicism of Autosomal Genes . . . . . . . . 29
3.4.2 Epigenetic Mosaicism of X Chromosomes . . . . . . . . . 30
3.4.3 X-Linked Genes Escaping Inactivation . . . . . . . . . . . . 32
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4 Relationship Between Hypomorphic Alleles and
Mosaicism of X-Linked or Autosomal Mutations . . . . . . . . . . . . 43
4.1 H ypomorphic Alleles and X-Linked Dominant,
Male-Lethal Cutaneous Syndromes . . . . . . . . . . . . . . . . . . . . . 43
4.2 H ypomorphic Alleles in Autosomal Dominant
Skin Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
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