Epidermal Disorders Epidermolysis Bullosa Simplex

Inheritance: Autosomal dominant (rarely autosomal recessive).

Clinical description: Epidermolysis bullosa simplex (EBS) is part of a heterogeneous group of inherited blistering diseases collectively known as epidermolysis bullosa (EB). All EB subtypes are characterized by the appearance of cutaneous blisters upon exposure of the skin to mechanical trauma (Fig. 2a). The major EB subtypes are defined by the location of blister formation within the skin.[19] In EBS, blisters form within the epidermal basal cells. The age of onset of EBS is variable. Progressive improvement with age is common. Three clinical forms of EBS have been delineated. Blisters occurring exclusively over the feet and hands distinguish the Weber-Cockayne type of EBS. In EBS Koebner type, blistering is generalized. The most severe, fortunately rare, and often life-threatening form of EBS is known as Dowling-Meara EBS and is characterized by skin and mucosal hemorrhagic blisters arranged in small clusters. EBS Dowling-Meara type is occasionally associated with milia formation, nail dystrophy, and severe palmoplantar keratoderma (PPK).

E1 V1 H1 LI L12 L2 H2 V2 E2

E1 V1 H1 LI L12 L2 H2 V2 E2

HEAD CENTRAL ROD TAIL

DOMAIN DOMAIN DOMAIN

Fig. 1 Schematic structure of a prototypic keratin molecule. The central rod domain is divided into four regions, which are separated by three nonhelical short linker sequences and the stutter sequence, where helix polarity is reversed. The rod domain is flanked by the highly conserved HIM and HTM. The head and tail domains consist of extreme end domains (E1, E2), variable domains (V1, V2), and homology domains (H1, H2). In contrast with the central rod domain, head and tail domains greatly vary in structure between different keratin types.

Skin pathology: Blister formation and typical vacuolar changes are seen within the epidermal basal cell layer. Keratin filament clumping is typical of Dowling-Meara cases.

Molecular genetics: Mutations in two keratins specifically expressed in epidermal basal cells, K5 and K14, underlie most cases of EBS.[2,20] The majority of EBS-causing mutations are missense mutations, affecting amino acids located within the rod segment or at its boundaries. The same regions have been shown in many other keratin disorders to carry deleterious mutations,[2] leading to the implementation of a diagnostic strategy based on initial pathological examination of skin tissues, followed by mutation analysis of rod boundaries-encoding regions, and ending with examination of the rest of the keratin gene (Fig. 3). Mutations affecting the end domains of the rod segment have been shown to exert a dominant negative effect, resulting in the synthesis of aberrant keratin proteins with altered three-dimensional structure, which interferes with normal protein functions during KIF assembly. Abnormal KIF affects cell resilience so that on exposure of the skin to friction, the cytoskeleton collapses, leading to cell cytolysis and intraepidermal blistering. Recessive K14 nonsense mutations are considered to be rare except in populations characterized by a high inbreeding coefficient.™ As a rule, recessive mutations as well as dominant mutations located within the conserved helix end motifs are associated with severe phenotypes; missense mutations located outside these regions generally cause milder forms of EBS. The nature of an amino acid substitution, and not only its location, is also a major determinant of phenotype severity.[20]

Mutations in K5 end domains have also been reported. A recurrent mutation, P25L, located in the V1 head domain of K5 has been found to cause a rare subtype of

EBS associated with mottled pigmentation. P25L has been suggested to impair melanin granule aggregation and keratin filament function by interfering with posttransla-tional processing.1-20-1 Mutations in K5 tail domain have been shown to cause dominant EBS, possibly because of abnormal protein folding.[22,23]

Those major advances in our understanding of the molecular basis of EBS and other keratin disorders have led to the development of DNA-based prenatal testing, usually carried out during the first trimester (Fig. 4). Prenatal diagnosis is provided based on previous knowledge of mutation(s) in the family, sequencing of fetal and parental DNA, and confirmation of mutation using ancillary tests such as polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) or allele-specific PCR. A particular problem arises when prenatal diagnosis is requested with no prior knowledge of the mutation. Microscopical examination of fetal skin biopsy, which entails significant risks and is carried out late in pregnancy, has rarely been performed in such cases.

Differential diagnosis: The differential diagnosis of EBS encompasses a large spectrum of inherited blistering conditions, including other EB types[19]; epidermolytic hyperkeratosis (EHK); Kindler syndrome (MIM173650), caused by mutations in kindlin, typically accompanied by pigmentary and atrophic changes affecting sun-exposed skin; ectodermal dysplasia with skin fragility (MIM604536), typified by suprabasal separation and due to plakophilin 1 deficiency; EB with muscular dystrophy (MIM226670), due to mutations in plectin gene; and incontinentia pigmenti (MIM318310), characterized by congenital blisters distributed along the lines of Blashko. In addition, EBS can result from mutations in genes coding for integrinp4, plectin, and collagen XVII, known to be usually involved in the pathogenesis of non-EBS phenotypes.[24-26] EBS should also be distinguished from congenital blistering resulting from infectious, autoimmune, and neoplastic causes.

Management: Patient care involves wound care, including sterile dressings and lancing of blisters to prevent spread; infection control; and nutritional support. Novel therapeutic approaches include the use of biological dressings or skin equivalents, and burgeoning attempts to cure EB through gene therapy.

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