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

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