This is a heterogeneous group of inherited disorders characterized by extreme skin fragility and recurrent blisters. Classification is based upon the level at which blistering occurs. Superficial blistering occurs in epidermolysis bullosa simplex, with breakdown occurring in the basal cells. This type is often inherited as an autosomal dominant trait and is clinically mild, without scarring, and mucous membranes are spared. Nails may be mildly involved.
The autosomal dominant Dowling–Meera form of epidermolysis bullosa simplex can be severe in infancy; the histology of this type is characteristic and can be detected in fetal skin biopsies. In junctional epidermolysis bullosa, the split occurs in the lamina lucida, causing extensive blistering on the skin and mucosal surfaces. Severe scarring may occur. There are several clinical types of junctional epidermolysis bullosa, all inherited as autosomal recessive traits. Germline mutations in several keratin genes have been found to underlie the different forms of epidermolysis bullosa, the type of mutation correlating with phenotype (Jonkman et al. 2003; Porter and Lane 2003; Uitto et al. 2002; Lin and Carter 1989; Korge and Kreig 1996). In dystrophic epidermolysis bullosa, blistering occurs in the dermis.
Dominant and recessive forms are described, but the severe forms are usually recessively inherited. Bullae develop, particularly on the extremities, leading to severe mitten-like scarring and deformity (mutilans). Gastrointestinal involvement is common, leading to esophageal strictures, erosions, and webs, and life-threatening hemorrhage may occur. Chronic anemia and hypoalbuminemia occur. Dental enamel is defective, and there may be laryngeal involvement.
In epidermolysis bullosa, squamous cell carcinoma may develop in the scars, but this tendency is much more marked in the dystrophic type. These carcinomas may occur at multiple sites, mainly on the limbs (Mallipeddi 2002; Tomita et al. 2003). They arise in young individuals (75 % develop in the 20–40-year age group) and are characteristically well or moderately well differentiated, but aggressive in behavior and metastasize readily (Goldberg et al. 1988). The carcinomas may develop on mucosal surfaces, including esophagus, stomach, bronchus, bladder, and tongue (Tidman 1990). Basal cell carcinomas may also develop in epidermolysis bullosa scars.
Simplex forms of epidermolysis bullosa are caused by mutations in the genes for the basal epidermal keratins K5 and K14 (Coulombe et al. 1991), and K1 and K10 mutations occur in epidermolytic ichthyosis. Dystrophic epidermolysis bullosa results from mutations in the anchoring fibril collagen gene COL7A, whereas the junctional form is due to mutations in laminin 5 (Eady and Dunnill 1994). Families with autosomal dominant epidermolysis bullosa simplex have shown linkage to the K14 gene and others to the K5 gene. Mutations in the K14 gene have been demonstrated in affected individuals (Bonifas et al. 1991), and a mutation in type VII collagen has been demonstrated in a family with dystrophic epidermolysis bullosa (Bale and DiGiovanna 1997). The genes in which mutations cause epidermolysis bullosa generally encode proteins in or around the hemidesmosome, the sited anchorage of the basal cell to the cell membrane, and the severity of disease determined by the functional position of the affected protein (Fuchs 1996).
These genes include KRT5, KRT14, PLEC1, DST, ITGB4, ITGA6, COL17A1, LAMA3, LAMB3, LAMC2, and COL7A1. Germline mutations in two adjacent genes (EVER1 and EVER2) have been detected in individuals with this condition (Ramoz et al. 2002; Tate et al. 2004; Majewski and Jablonska 2004).