Genetic Basis of Cutaneous Diseases

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).

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 .