Mosaicism in Human Skin: Understanding Nevi, Nevoid Skin Disorders, and Cutaneous Neoplasia

Description

This second edition offers a fully revised and updated work on a rapidly growing field of knowledge, and was prepared by two experts whose goal was to explain the molecular basis of mosaic skin disorders in a language that is accessible for practicing physicians and medical students alike. It presents a timely and comprehensive overview of the strikingly manifold patterns and peculiarities of mosaic skin disorders in a straightforward, reader-friendly way that will help physicians to further improve genetic counseling and treatment outcomes. The first two parts of the book are devoted to the mechanisms and patterns of cutaneous mosaicism, and include an explanation of genomic and epigenetic mosaicism and a description of the archetypical segmental patterns including the lines of Blaschko and the flag-like, phylloid and lateralization pattern, the non-segmental pattern of large congenital melanocytic nevi, and the sash-like arrangement as noted in a particular type of cutis tricolor. The concept of lethal mutations surviving as mosaics has now been confirmed by molecular analysis in many sporadically occurring phenotypes. The difference between monoallelic and biallelic traits has deepened our understanding of hereditary mosaics, especially of multiple benign skin tumors. Moreover, recognition of the fundamental difference between the simple segmental and the superimposed types of mosaicism is important for the purpose of genetic counseling. In the third part, the various mosaic skin disorders are examined in depth, including nevi, didymotic disorders, other binary genodermatoses, mosaic manifestations of autosomal skin disorders, and nevoid skin disorders such as phenotypes reflecting functional X-chromosome mosaicism or a superimposed mosaic manifestation of common skin diseases with a polygenic background. Reader-friendly and clearly structured, Mosaicism in Human Skin will appeal to both experienced dermatologists and residents in training, as well as to medical geneticists and pediatricians.   Preface Acknowledgments Contents 1: Introduction 2: Mosaicism as a Biological Concept 2.1 Historical Beginnings 2.2 Mosaicism in Plants 2.3 Mosaicism in Animals 2.4 Mosaicism in Human Skin 2.5 Mosaicism Versus Chimerism 2.6 Does the Coat of Zebras Reflect Mosaicism? References 3: The Major Categories of Mosaicism 3.1 Nonsegmental Versus Segmental Mosaicism of Autosomal Dominant Skin Disorders 3.1.1 Nonsegmental Mosaicism 3.1.2 Segmental Mosaicism 3.2 Genomic Versus Epigenetic Mosaicism 3.3 Genomic Mosaicism 3.3.1 Genomic Mosaicism of Autosomes 3.3.1.1 Mosaicism Caused by Loss of Heterozygosity 3.3.1.2 Genomic Mosaicism of Lethal Autosomal Mutations Mosaicism Caused by Lethal Cytogenetic Abnormalities Mosaicism Caused by Lethal Molecular Defects 3.3.1.3 Genomic Mosaicism of Nonlethal Autosomal Mutations Simple Segmental Mosaicism of Autosomal Dominant Disorders Superimposed Mosaicism of Autosomal Dominant Disorders Monoallelic Versus Biallelic Mosaicism Disseminated Mosaicism of Biallelic Autosomal Dominant Disorders Isolated Segmental Biallelic Monoclonal Mosaicism Blue Rubber Bleb Angiomatosis (“Blue Rubber Bleb Nevus Syndrome”): A Unique Type of Postzygotic Mosaicism 3.3.2 Autosomal Recessive Mosaicism 3.3.3 Didymosis (Twin Spotting) 3.3.4 Revertant Mosaicism 3.3.5 Genomic X-Chromosome Mosaicism in Male Patients 3.3.6 Superimposed Segmental Manifestation of Polygenic Skin Disorders 3.4 Epigenetic Mosaicism 3.4.1 Epigenetic Mosaicism of Autosomal Genes 3.4.2 Epigenetic Mosaicism of X Chromosomes 3.4.2.1 Functional X-Chromosome Mosaicism in Female Patients 3.4.2.2 Why Do Women Live Longer? 3.4.2.3 Functional X-Chromosome Mosaicism in Male Patients 3.4.3 X-Linked Genes Escaping Inactivation References 4: Relationship Between Hypomorphic Alleles and Mosaicism of X-Linked or Autosomal Mutations 4.1 Hypomorphic Alleles and X-Linked Dominant, Male-Lethal Cutaneous Syndromes 4.2 Hypomorphic Alleles in Autosomal Dominant Skin Disorders References 5: The Archetypical Patterns of Segmental Cutaneous Mosaicism 5.1 Lines of Blaschko 5.1.1 Lines of Blaschko, Narrow Bands 5.1.2 Lines of Blaschko, Broad Bands 5.1.3 Analogy of Blaschko’s Lines in Other Organs 5.1.4 Blaschko’s Lines in Animals 5.1.5 Analogy of Blaschko’s Lines in the Murine Brain 5.2 Flag-like Pattern 5.3 Phylloid Pattern 5.4 Lateralization Pattern References 6: Less Well-Defined or So Far Unclassifiable Patterns 6.1 Oblique Pattern (Sash-Like Pattern) 6.2 Pallister-Killian Pattern 6.3 Midfacial Pattern References 7: Nevi 7.1 The Theory of Lethal Genes Surviving by Mosaicism 7.2 Pigmentary Nevi 7.2.1 Melanocytic Nevi 7.2.1.1 Common Small Melanocytic Nevus 7.2.1.2 Common “Atypical” Melanocytic Nevi 7.2.1.3 Large Congenital Melanocytic Nevus 7.2.1.4 Spitz Nevus 7.2.1.5 Cellular Blue Nevus 7.2.1.6 Papular Nevus Spilus 7.2.1.7 Macular Nevus Spilus 7.2.1.8 Linear Lentiginous Nevus 7.2.1.9 Nevus Cesius (Segmental Dermal Melanocytosis) 7.2.2 Other Nevi Reflecting Pigmentary Mosaicism 7.2.2.1 Linear Hypomelanosis in Narrow Bands (Pigmentary Mosaicism of the Ito Type) 7.2.2.2 Linear Hypermelanosis in Narrow Bands 7.2.2.3 Linear Hypermelanosis in Broad Bands 7.2.2.4 Flag-Like Hypomelanosis 7.2.2.5 Flag-Like Hypermelanosis 7.2.2.6 Flag-Like Lentiginosis (Including “Partial Unilateral Lentiginosis” [PUL]) 7.2.2.7 Phylloid Hypomelanosis 7.2.2.8 Phylloid Hypermelanosis 7.2.2.9 Hypermelanocytic Guttate and Macular Segmental Hypomelanosis 7.3 Epidermal Nevi 7.3.1 Keratinocytic Nevi 7.3.1.1 Common Keratinocytic Nevi of the Soft Type, Including Seborrheic Keratoses Seborrheic Keratoses Are Acquired Keratinocytic Nevi An Early Postzygotic FGFR3 Mutation Causes a Distinct Neurocutaneous Syndrome Early Postzygotic PIK3CA Mutations Cause CLOVES Syndrome 7.3.1.2 Common Keratinocytic Nevi of the Hard, Verrucous Type 7.3.1.3 SASKIA (Segmentally Arranged Seborrheic Keratoses with Impending Atypia) Nevus: A New Skin Disorder? 7.3.1.4 Linear PTEN Nevus (Linear Cowden Nevus Included) 7.3.1.5 Epidermal Nevus of the Proteus Type 7.3.1.6 Hystrix-Like Epidermal Nevus of NEVADA Syndrome 7.3.1.7 Keratinopathic Epidermal Nevus 7.3.1.8 Inflammatory Linear Verrucous Epidermal Nevus (ILVEN) 7.3.1.9 CHILD Nevus 7.3.1.10 Nevus Corniculatus 7.3.1.11 Nevus Kerinokeratoticus 7.3.1.12 Papular Epidermal Nevus with “Skyline” Basal Cell Layer (PENS) 7.3.1.13 Other Keratinocytic Nevi 7.3.2 Organoid Epidermal Nevi 7.3.2.1 Nevus Sebaceus Nevus Marginatus: A Peculiar Variant of Nevus Sebaceus 7.3.2.2 Nevus Comedonicus 7.3.2.3 Linear Epidermolytic Comedones 7.3.2.4 Angora Hair Nevus and Schauder Syndrome 7.3.2.5 Becker Nevus and Becker Nevus Syndrome 7.3.2.6 Porokeratotic Eccrine Nevus: A Mosaic Manifestation of KID Syndrome 7.3.2.7 Eccrine Nevus of the Castori Type 7.3.2.8 Nevus Trichilemmocysticus 7.3.2.9 Acne Nevus of Munro 7.3.2.10 Linear Follicular Mucinous Nevus 7.3.2.11 Linear Pigmented Follicular Nevus 7.4 Vascular Nevi 7.4.1 Capillary Nevi 7.4.1.1 Nevus Flammeus of Sturge-Weber Syndrome The End of the Trigeminal Concept of Facial Nevi Flammei 7.4.1.2 Nevus Flammeus of Klippel-Trenaunay Syndrome 7.4.1.3 Sturge-Weber Syndrome Versus Klippel-Trenaunay Syndrome 7.4.1.4 Port-Wine Nevus of the Proteus Type 7.4.1.5 Port-Wine Nevus of the CLOVES Type 7.4.1.6 Nevus Roseus 7.4.1.7 Rhodoid Nevus: A Specific Name for an Otherwise Nameless Capillary Malformation 7.4.1.8 Cutis Marmorata Telangiectatica Congenita (CMTC) 7.4.1.9 Reticular Capillary Nevus: A Hallmark of Megalencephaly-Reticular Capillary Nevus Syndrome (“Macrocephaly-Capillary Malformation Syndrome”) 7.4.1.10 Telangiectatic Nevus with Underlying and Surrounding Dilated Veins 7.4.1.11 Angiokeratoma Circumscriptum 7.4.1.12 Segmentally Arranged Angioma Serpiginosum 7.4.1.13 Nevus Anemicus 7.4.1.14 Nevus Vascularis Mixtus 7.4.2 Venous Nevi 7.4.2.1 Large Venous Nevus 7.4.2.2 Small Venous Nevi (“Hereditary Cutaneomucosal Venous Malformations”) 7.4.2.3 Venous Nevus of the Servelle-Martorell Type 7.5 Connective Tissue Nevi 7.5.1 Collagen Nevi of Tuberous Sclerosis Complex 7.5.2 Linear Collagen Nevus 7.5.3 Elastin-Rich Nevus 7.5.4 Segmental Manifestation of Ehlers-Danlos Syndromes 7.6 Fatty Tissue Nevi 7.6.1 Nevus Lipomatosus Superficialis 7.6.2 Nevus Psiloliparus 7.7 Hairless Nevus of Oculoectodermal Syndrome References 8: Didymotic Skin Disorders 8.1 Allelic Didymosis 8.1.1 Cutis Tricolor 8.1.1.1 Ruggieri-Happle Syndrome 8.1.1.2 Cutis Tricolor Parvimaculata 8.1.1.3 Cutis Tricolor of the Blaschko-Linear Type 8.1.2 Didymosis in Keratinopathic Ichthyosis of Brocq 8.1.3 Didymosis in Darier Disease 8.2 A Note on the Theoretical Concept of Nonallelic Didymosis References 9: Other Binary Genodermatoses, in Which Didymosis Is Excluded or Questionable 9.1 Phacomatosis Spilosebacea (Aka Phacomatosis Pigmentokeratotica) 9.2 Paired Occurrence of Nevus Sebaceus and Melorheostosis 9.3 Paired Occurrence of Nevus Sebaceus and Aplasia Cutis Congenita 9.4 Paired Occurrence of Nevus Psiloliparus and Aplasia Cutis Congenita 9.5 Paired Occurrence of Capillary Nevi 9.5.1 Paired Nevus Flammeus and Nevus Anemicus 9.5.2 Nevus Vascularis Mixtus 9.6 The Group of Phacomatosis Pigmentovascularis 9.6.1 Phacomatosis Cesioflammea 9.6.2 Phacomatosis Spilorosea 9.6.3 Phacomatosis Melanorosea 9.6.4 Phacomatosis Cesiomarmorata 9.7 Melorheostosis Coexisting with Arteriovenous Malformation as a Possible Binary Skin Disorder References 10: Mosaic Manifestation of Autosomal Dominant Skin Disorders 10.1 Hereditary Multiple Skin Tumors 10.1.1 Trichoepithelioma 10.1.2 Trichodiscoma 10.1.3 Pilomatricoma 10.1.4 Basaloid Follicular Hamartoma 10.1.5 Perifollicular Fibroma (Fibrofolliculoma): A Hallmark of Hornstein-Knickenberg Syndrome (Illegitimately Called Birt-Hogg-Dubé Syndrome) 10.1.5.1 Segmental mosaicism in nonsyndromic perifollicular fibromas 10.1.5.2 Superimposed Mosaicism in Hornstein-Knickenberg Syndrome 10.1.6 Syringoma 10.1.7 Spiradenoma 10.1.8 Eccrine Poroma 10.1.9 Cylindromatosis 10.1.10 Glomangiomatosis 10.1.10.1 Superimposed Mosaicism Involving Internal Organs 10.1.10.2 Practical Aspects 10.1.11 Lipomatosis 10.1.12 Neurofibromatosis 1 10.1.12.1 Simple Mosaicism in NF1 10.1.12.2 Superimposed Mosaicism in NF1 10.1.12.3 Extracutaneous Superimposed Mosaicism 10.1.12.4 The Issue of “Genetic Transmission of Segmental NF1” 10.1.12.5 Genetic Counseling in Cases of Segmental NF1 10.1.12.6 Other Practical Aspects 10.1.13 Neurofibromatosis 2 10.1.14 Schwannomatosis 10.1.15 Legius Syndrome 10.1.16 Leiomyomatosis 10.1.16.1 Familial Occurrence of Superimposed Mosaicism 10.1.17 Gorlin Syndrome 10.1.17.1 Simple Segmental Involvement 10.1.17.2 Superimposed Mosaic Involvement 10.1.18 Hereditary Nonsyndromic Multiple Basal Cell Carcinoma 10.1.19 PTEN Hamartoma Syndrome (Cowden Disease Included) 10.1.19.1 Cowden Variant of PTEN Hamartoma Syndrome 10.1.19.2 Bannayan-Riley-Ruvalcaba Variant of PTEN Hamartoma Syndrome 10.1.19.3 “Lhermitte-Duclos Variant” of PTEN Hamartoma Syndrome 10.1.19.4 Superimposed Mosaicism in PTEN Hamartoma Syndrome 10.1.20 Cutaneous Mastocytosis 10.2 Disorders of Keratinization 10.2.1 Keratinopathic Ichthyosis of Brocq 10.2.2 Keratinopathic Ichthyosis of Siemens (Aka Superficial Epidermolytic Ichthyosis) 10.2.2.1 Papular Epidermal Nevus with “Skyline” Basal Cell Layer (PENS) 10.2.3 Darier Disease 10.2.4 Hailey-Hailey Disease 10.2.5 Dowling-Degos Disease, Including the Galli-Galli Variant 10.2.6 Acanthosis Nigricans 10.2.7 KID Syndrome 10.2.8 Autosomal Dominant Dyskeratosis Congenita 10.2.9 Pachyonychia Congenita 10.2.10 Porokeratosis of the DSAP Subtype 10.2.10.1 Practical Aspect 10.2.11 Porokeratosis of the Mibelli Subtype in Plaques 10.2.11.1 Familial Occurrence of Superimposed Mosaicism in the Mibelli Subtype 10.2.12 Porokeratosis Palmaris, Plantaris et Disseminata Subtype 10.2.13 Superimposed Mosaicism in Unclassifiable Subtypes of Porokeratosis 10.2.14 Costello Syndrome 10.2.15 Acrokeratoelastoidosis 10.3 Disorders of Connective Tissue or Bones 10.3.1 Tuberous Sclerosis Complex 10.3.1.1 Simple Segmental TSC 10.3.1.2 Superimposed Mosaicism in TSC 10.3.1.3 Cases of Unclassifiable Mosaic TSC 10.3.1.4 Genetic Counseling 10.3.2 Buschke-Ollendorff Syndrome 10.3.2.1 Superimposed Mosaic Skin Lesions 10.3.2.2 Familial Occurrence of Superimposed Mosaicism 10.3.2.3 Superimposed Mosaic Involvement of Bones 10.3.3 Ehlers-Danlos Syndromes 10.3.4 Marfan Syndrome 10.3.5 Albright’s Hereditary Osteodystrophy 10.3.6 Hereditary Osteomatosis Cutis 10.3.6.1 A Note on “Progressive Osseous Heteroplasia” 10.3.7 Zimmermann-Laband Syndrome 10.3.8 Brachman de Lange Syndrome (Cornelia de Lange Syndrome) 10.4 Vascular Disorders 10.4.1 Hereditary Hemorrhagic Telangiectasia (Osler-Rendu-Weber Disease) 10.4.2 Rhodoid Nevus Syndrome (“Capillary Malformation-Arteriovenous Malformation”) 10.5 Blistering Skin Disorders 10.5.1 Autosomal Dominant Dystrophic Epidermolysis Bullosa 10.5.2 Transient Superficial Acantholysis Arranged Along Blaschko’s Lines in a Newborn References 11: Revertant Mosaicism 11.1 Revertant Mosaicism Is a Frequent Phenomenon 11.2 Revertant Mosaicism in Autosomal Dominant Skin Disorders 11.3 Revertant Mosaicism in Autosomal Recessive Skin Disorders References 12: Nevoid Skin Disorders 12.1 Cutaneous Lesions Reflecting Functional X-Chromosome Mosaicism 12.1.1 X-Linked Dominant, Male-Lethal Traits 12.1.1.1 Incontinentia Pigmenti 12.1.1.2 Focal Dermal Hypoplasia 12.1.1.3 Conradi-Hünermann-Happle Syndrome 12.1.1.4 MIDAS Syndrome 12.1.1.5 Oral-Facial-Digital Syndrome Type 1 12.1.1.6 Terminal Osseous Dysplasia with Pigmentary Defects (TODPD) 12.1.1.7 Aicardi Syndrome 12.1.2 X-Linked Dominant, Nonlethal Traits 12.1.2.1 Christ-Siemens-Touraine Syndrome 12.1.2.2 X-Linked Dyskeratosis Congenita 12.1.2.3 Menkes Syndrome 12.1.2.4 IFAP Syndrome 12.1.2.5 Reticulate Pigmentary Disorder of Partington 12.1.2.6 X-Linked Dominant Hypertrichosis 12.2 Congenital Autosomal Disorders Representing Non-nevi 12.2.1 Benign Skin Tumors Reflecting Lethal Autosomal Mutations Surviving by Mosaicism 12.2.1.1 Syringocystadenoma Papilliferum 12.2.1.2 Maffucci Syndrome 12.2.1.3 Happle-Tinschert Syndrome 12.2.2 Hemihyperplasia with Multiple Lipomas: Probably a Mild Phenotype Within PROS 12.2.3 Other Autosomal Non-nevi 12.2.3.1 Salmon Patch (“Unna’s Nevus,” “Median Nevus Flammeus,” “Nevus Simplex”) 12.2.3.2 White Sponge Hyperplasia of the Mucosa (“White Sponge Nevus”) 12.2.3.3 “Basal Cell Nevus” 12.2.3.4 “Blue Rubber Bleb Nevus” 12.3 Nevoid Arrangement of Acquired Skin Disorders 12.3.1 Lichen Striatus 12.3.2 “Blaschkitis”: No Entity, but an Umbrella Term Including the Linear Manifestation of Various Acquired Inflammatory Skin Disorders 12.3.3 Purpuric Pigmented Dermatoses, Including Lichen Aureus 12.3.4 Linear Grover Disease 12.3.5 Linear Juvenile Xanthogranuloma 12.3.6 Linear Atrophoderma of Moulin 12.3.7 Superimposed Segmental Manifestation of Common Polygenic Skin Disorders 12.3.7.1 Acquired Inflammatory Disorders Psoriasis Vulgaris Psoriasis Pustulosa Atopic Dermatitis Chronic Prurigo Lichen Planus Lichen Planopilaris Lichen Nitidus Acne Vulgaris Cutaneous Lupus Erythematosus Discoid Lupus Erythematosus Lupus Erythematosus Profundus Subacute Cutaneous Lupus Erythematosus Practical Aspects Systemic Lupus Erythematosus Dermatomyositis Pemphigus Vulgaris Bullous Pemphigoid Graft-Versus-Host Disease Morphea Granuloma Annulare Erythema Multiforme Common Drug Eruption Fixed Drug Eruption Superimposed Lateralized Exanthem of Childhood Leprosy 12.3.7.2 Linear Mycosis Fungoides 12.3.7.3 Vitiligo 12.3.7.4 Cherry Angiomas References Glossary Index