Introduction

In 1987, deletions in the steroid sulfatase gene were found to underlie X-linked recessive ichthyosis . This heralded an era of tremendous progress in the elucidation of the genetic bases of inherited skin disorders, made possible by rapid advances in molecular technology (including the development of next-generation massively parallel sequencing), discovery of candidate genes, utilization of animal models, and sequencing of the human genome, including single nucleotide polymorphisms (SNPs) useful for linkage analysis and homozygosity mapping (see Ch. 54 ) . Better understanding of signaling pathways, molecules involved in cell–cell communication and adhesion, and mechanisms of cutaneous differentiation have also contributed to the momentum.

As a result of this explosion in research, more than 1000 genes were recognized to be responsible for a particular human phenotype by the year 2000, with approximately 300 of these conditions including cutaneous abnormalities ; by 2017, these numbers had increased to nearly 3800 and 1400, respectively . Currently, the molecular genetic bases of the majority of single-gene inherited skin disorders have been established . The emergence of new genomic and proteomic databases has transformed laborious positional cloning approaches and traditional functional studies, circumventing previous obstacles to the study of rare conditions and facilitating identification of candidate genes. For example, microarray (see Ch. 3 )-based SNP genotyping enabled the identification of ABCA12 mutations as the cause of harlequin ichthyosis; although classic linkage analysis was not possible due to the limited size of the pedigrees, homozygosity mapping (utilizing the aforementioned technology) linked this autosomal recessive condition to a region of homozygosity shared by affected individuals from diverse ethnic backgrounds . With whole-exome (the transcribed portion of the genome) and whole-genome sequencing now feasible and relatively affordable, disease-causing genes can potentially be identified without genetic mapping .

In the past, diagnosis of genodermatoses was complicated by the existence of multiple complex classification systems based on various combinations of clinical, histologic, radiographic, and biochemical criteria. Inconsistent nomenclature laden with descriptive terms, eponyms, and synonyms added to the confusion and potential for misdiagnosis . As the genetic bases of genodermatoses have been determined, integration of molecular and clinical data has helped to simplify disease categorization and eliminate redundant terminology. This has been successfully accomplished for disorders such as epidermolysis bullosa (EB) and ichthyoses, but it represents a work in progress, to be continually refined as additional genotype–phenotype correlations are established . In addition, grouping hereditary skin disorders according to their molecular bases ( Table 55.1 ) can supplement traditional morphologic classification, clarifying pathomechanisms and the relationships between conditions.

As the “morbid anatomy of the dermatologic genome” continues to be established, new challenges will arise and additional questions will be answered . Because of the rarity of many genodermatoses, their full clinical spectra have yet to be elucidated. However, with the increasing availability of genetic and biochemical testing ( www.genetests.org ), dermatologists can establish the diagnosis in patients with mild or atypical presentations, thereby expanding the range of phenotypes. Continuing to decipher heritable skin disorders will require close interactions between basic scientists and clinicians . Hopefully, such translational research will continue to lead to better understanding of cutaneous structure and function; insights into the pathogenesis of common multifactorial disorders; and effective therapies as well as diagnostic and prognostic information, improved genetic counseling and DNA-based prenatal/preimplantation testing for patients with genodermatoses.

In this chapter, Tables 55.3 to 55.8 divide selected monogenic skin disorders with a known genetic basis into categories according to their primary clinical features. Groups of monogenic conditions similarly listed in tables elsewhere in the book are noted in Table 55.2 .

Mckusick’s Mendelian Inheritance in MAN

McKusick’s Mendelian Inheritance in Man (MIM) database was first published in 1966 as “Catalogs of Autosomal Dominant, Autosomal Recessive and X-linked Phenotypes”. In the 1994 edition, the subtitle was changed to “A Catalog of Human Genes and Genetic Disorders”, reflecting the progress that had been made in the field. Online MIM (OMIM; https://omim.org/ ) has been widely available on the Internet for over 30 years, providing immediate access to current information on human genes and genetic diseases . This database is updated continuously and can be searched by entering a constellation of clinical features as well as the name of a gene or syndrome.

A particular six-digit number (MIM number) is assigned to each OMIM entry. The first digit of the MIM number indicates the mode of inheritance of the corresponding genetic defect: 1 for autosomal dominant (entries before May 1994); 2 for autosomal recessive (entries before May 1994); 3 for X-linked; 4 for Y-linked; 5 for mitochondrial; and 6 for autosomal dominant or recessive (entries after May 1994). Phenotype entries describe the clinical and biochemical features, inheritance, mapping, and molecular genetics of a given disease or trait; a “#” is used to designate those for which the molecular basis is known. Gene entries are marked by a “*”, while gene plus phenotype entries are indicated with a “+”; both are appended with important disease-causing allelic variants (each of which is given a four-digit extension, beginning with .0001).

Genotype–Phenotype Correlations

Genotype–phenotype correlations in genodermatoses are often complex. Mutations in a single gene can cause more than one clinical disorder, a phenomenon referred to as allelic or clinical heterogeneity (see Table 54.2 ). This can result either from the same mutation occurring in patients with different genetic backgrounds or ages at presentation (e.g. identical PTEN mutations leading to Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome) or from different mutations (e.g. distinct mutations in the gene encoding lamin A/C leading to Hutchinson–Gilford progeria and familial partial lipodystrophy). Mutations that affect different domains of a protein can produce divergent phenotypes; for example, mutations in the sterile alpha motif (SAM) domain of the p63 protein typically cause AEC ( a nkyloblepharon, e ctodermal dysplasia and c left lip/palate) syndrome, while those in the DNA-binding domain give rise to EEC ( e ctrodactyly, e ctodermal dysplasia and c left lip/palate) syndrome. Various mutations in a particular gene can even lead to disorders with different modes of inheritance, such as X-linked dominant incontinentia pigmenti (a male-lethal condition due to a genomic rearrangement resulting in a partial deletion of the n uclear factor-κB e ssential mo dulator [NEMO] gene) and X-linked recessive hypohidrotic ectodermal dysplasia with immunodeficiency (due to milder, “hypomorphic” mutations in the NEMO gene). Conditions found to represent unexpected examples of allelic heterogeneity in the transforming growth factor-β (TGF-β) signaling pathway include mutations in the TGF-β receptor 1 gene ( TGFBR1 ) in Ferguson–Smith multiple self-healing squamous epithelioma (loss-of-function) as well as Loeys–Dietz syndrome (gain-of-function), and fibrillin 1 gene ( FBN1 ) mutations in generalized stiff skin syndrome as well as Marfan syndrome.

The type of mutation can also affect the severity of a genodermatosis. The potentially lethal generalized severe form of junctional EB (JEB, an autosomal recessive disorder) is typically caused by mutations in the LAMB3 gene that lead to a premature termination codon (resulting in a complete absence of the LAMB3 protein), whereas milder forms of JEB are produced by missense or splice-site mutations in the same gene (resulting in a LAMB3 protein with decreased function). In contrast, in autosomal dominant conditions where there is dimerization of the mutated protein product (e.g. the KIT tyrosine kinase receptor that is defective in piebaldism), dominant negative missense mutations often result in more severe disease (via abnormal proteins binding to and disrupting normal proteins) than do mutations that lead to premature termination codons and thereby result in haploinsufficiency (complete loss of half of the proteins).

In other instances, mutations in different genes produce the same clinical disorder; this is referred to as locus or genetic heterogeneity . Locus heterogeneity can occur when mutated proteins serve a similar function (e.g. components of various b iogenesis of l ysosome-related o rganelle c omplexes [BLOCs] in Hermansky–Pudlak syndrome) or interact with one another in a complex (e.g. hamartin and tuberin in tuberous sclerosis), as a ligand and receptor (e.g. endothelin-3 and the endothelin-B receptor in type 4 Waardenburg syndrome), or in a signaling pathway (e.g. various RAS–mitogen-activated protein kinase [MAPK] pathway proteins in cardio-facio-cutaneous syndrome; see below). However, phenotypic differences can arise when these proteins also have distinct functions and/or tissue distributions; for example, the neurologic abnormalities in Griscelli syndrome 1 result from myosin Va expression in neurons, and the immunodeficiency and hemophagocytic syndrome that characterize Griscelli syndrome 2 reflect RAB27A expression in hematopoietic cells.

Molecular Classification of Hereditary Skin Disorders

Molecular classification (see Table 55.1 ) represents a useful approach to the categorization of genodermatoses. Based on the pathogenetic defect rather than the clinical presentation, it can highlight similarities between conditions with seemingly disparate phenotypes (e.g. classic ichthyoses and metabolic disorders such as Gaucher disease, both caused by defects in lipid metabolism) and facilitate better understanding of important cellular pathways (e.g. RAS signaling) and responses to external stimuli (e.g. pyrin/NOD family members that function in innate immunity). Several groups of genodermatoses for which molecular classification has been instructive are discussed below.

Defects in Intercellular Junctions

Mutations in genes encoding components of desmosomes and gap junctions underlie a variety of genodermatoses, several of which have prominent extracutaneous manifestations.

Desmosomal defects

Desmosomes are intercellular junctions that provide mechanical integrity to tissues by anchoring intermediate filaments to the cell surface and mediating strong cell–cell adhesion (see Ch. 56 ). They are particularly important in stratified squamous epithelia and the myocardium, tissues that are subjected to substantial mechanical stress . It is therefore not surprising that impaired keratinization (especially palmoplantar keratoderma), skin fragility, and cardiomyopathy represent features of disorders caused by defects in desmosomal proteins such as desmoplakin, plakoglobin and plakophilin 1 (see Fig. 56.8 and Table 56.5 ). Abnormal hair (oftentimes woolly in nature) can also result from abnormalities in these proteins, and defects in other desmosomal components such as desmoglein 4 and corneodesmosin (which are highly expressed within the hair follicle) can lead to hypotrichosis and (for desmoglein 4) an autosomal recessive form of monilethrix ( Fig. 55.1 ). Additional consequences of desmosomal defects include inflammatory peeling skin (corneodesmosin) and s evere dermatitis, a llergies, and m etabolic wasting (SAM; desmoglein 1, desmoplakin).

Autosomal recessive monilethrix due to desmoglein 4 mutations.

Sparse short hairs, stubble and follicular papules on the scalp. Inset: Trichogram showing alternating elliptical nodes and constrictions.

Connexin defects

Gap junctions are intercellular channels that connect the cytoplasm of neighboring cells, facilitating communication that coordinates cellular growth, differentiation and responses to stimuli as well as tissue morphogenesis and homeostasis (see Ch. 58 ). Transmembrane connexin proteins undergo oligomerization to form the connexons that compose gap junctions. Connexin proteins such as Cx26, Cx30, Cx31, and Cx43 are preferentially expressed in ectoderm-derived epithelia of the inner ear and cornea as well as in the epidermis and its appendages . This accounts for the sensorineural deafness, keratitis, and cutaneous abnormalities ranging from keratoderma to erythrokeratoderma to ectodermal dysplasias affecting the hair and nails that are observed in various connexin disorders (see Table 55.1 ). Several connexins are expressed in lymphatic cells, and mutations in the gene encoding Cx47 cause a hereditary type of lymphedema .

Transmembrane Transporter Defects

Abnormalities in transmembrane transporters underlie a variety of genodermatoses, ranging from occipital horn syndrome and Menkes disease (both due to mutations in the gene encoding the ATP7A copper transporter) to oculocutaneous albinism types 2 and 4 (due to defective transporters on lysosome-related organelles) to metabolic disorders such as acrodermatitis enteropathica, Hartnup disease, and hemochromatosis. This list also includes defects in a fatty acid transporter in ichthyosis prematurity syndrome and an intracellular nucleoside transporter in H syndrome ( Fig. 55.2 ) . Disorders of calcium pumps and ATP-binding cassette (ABC) transporters, which underscore the important roles of transmembrane transporters in cutaneous homeostasis, are discussed below.

H syndrome.

This autosomal recessive disorder due to mutations in the SLC29A3 gene (which encodes a nucleoside transporter) presents with h yperpigmentation, h ypertrichosis, induration and varicose veins in a characteristic distribution pattern on the thighs with sparing of the knees ( A ). Additional features include h allux valgus and flexion contractures of the toes ( B ), h epatosplenomegaly, h eart anomalies, h earing loss, h ypogonadism, low h eight and h yperglycemia/diabetes mellitus.

Calcium pump defects

Darier disease and Hailey–Hailey disease are distinct autosomal dominant disorders that share the histologic feature of epidermal acantholysis leading to suprabasal cleft formation; on an ultrastructural level, this corresponds to disruption of the desmosome–keratin intermediate filament complex. The two conditions also have some clinical similarities, including intertriginous involvement, vesiculobullous lesions (relatively uncommon in Darier disease), nail changes, exacerbation with heat, and frequent superinfections. As a result of these overlapping features, it was initially postulated that Darier disease and Hailey–Hailey disease were allelic disorders caused by defects in a gene encoding a structural component of the epidermis. However, linkage studies mapped Darier disease to chromosome 12 and Hailey–Hailey disease to chromosome 3, and no candidate structural genes were found in these regions.

In 1999, pathogenetic mutations in the ATP2A2 gene, which encodes a sarcoplasmic/endoplasmic reticulum Ca ²⁺ ATPase, were identified in patients with Darier disease. Subsequently, mutations in the ATP2C1 gene on chromosome 3, which encodes a Ca ²⁺ ATPase localized to the Golgi apparatus, were shown to cause Hailey–Hailey disease. Determining the molecular bases of these genodermatoses thus demonstrated the pivotal role of calcium homeostasis in epidermal differentiation and cell–cell adhesion .

ATP-binding cassette transporter defects

Members of the ABC transporter superfamily bind and hydrolyze adenosine triphosphate (ATP) in order to transport various molecules across a cell membrane or into a vesicle. Well-known examples include the cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7; the chloride ion channel that is defective in patients with cystic fibrosis) and the P glycoprotein (ABCB1; an important cellular mechanism of multidrug resistance). Several phenotypically diverse genodermatoses are also caused by mutations in ABC transporters (see Table 55.1 ) .

Because fragmentation and calcification of elastic fibers in the skin, eyes, and cardiovascular system are major features of pseudoxanthoma elasticum (PXE), the latter was initially thought to represent a heritable connective tissue disorder that (presumably) resulted from mutations in a gene encoding an extracellular matrix protein. Surprisingly, PXE was instead found to be caused by mutations in the ABCC6 gene, which encodes an organic acid transporter (based on in vitro studies) that is expressed almost exclusively in the liver and kidneys. Together with evidence that metabolites present in the sera of PXE patients interfere with the normal assembly of elastic fibers in vitro , this suggests that PXE is actually better characterized as a metabolic disorder with secondary connective tissue manifestations.

Biallelic mutations in ABCA12 , which encodes a transporter that secretes lipids into lamellar granules, cause both harlequin ichthyosis and a form of lamellar ichthyosis (see Fig. 56.2 ). Patients with harlequin ichthyosis tend to have nonsense mutations, whereas those with lamellar ichthyosis typically have missense mutations. This represents one of the most clearcut genotype–phenotype correlations observed to date for non-syndromic autosomal recessive ichthyoses. Defective formation of intercellular lipid layers, which are essential for epidermal barrier function, due to genetic defects in lipid metabolism also represents the pathomechanism of an expanding list of other ichthyosiform disorders (see Table 55.1 and Fig. 56.2 ) .

Defects in DNA Repair Genes, Tumor Suppressor Genes and Oncogenes

Hereditary cancer syndromes that affect the skin can be divided into groups based upon whether the associated malignancies are primarily cutaneous (e.g. basal cell nevus syndrome; see Table 55.6 ) or extracutaneous (see Table 55.7 ); individuals in the latter group may have either benign cutaneous neoplasms (e.g. Cowden syndrome) or non-neoplastic skin lesions (e.g. ataxia–telangiectasia) . To complement this clinical approach, molecular classification of such syndromes can help to explain relationships among disorders, understand the disrupted pathway or process, and suggest candidate genes for patients with similar phenotypes for which the underlying molecular defect has not yet been identified. In addition to characterization based on the specific pathomechanism (e.g. RAS–MAPK pathway activation ; see below), hereditary cancer syndromes can be separated into three general categories: (1) defective DNA repair and protection of genomic integrity (“caretaker” genes); (2) defective tumor suppressor (“gatekeeper”) genes; and (3) activated oncogenes.

Table 55.6

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