Epidermolysis bullosa is a group of inherited disorders of the epithelial basement membrane zone that manifest with blistering of the skin and mucous membranes after minor trauma. The disease appears to be one of the most frequent monogenic causes of infant mortality among Arabs. The disease is traditionally classified into three groups according to the level of cleavage within the skin: Epidermolysis bullosa simplex results from separation of the skin above the basement membrane, junctional epidermolysis bullosa is caused by blister formation within the basement membrane, and in the dystrophic form of epidermolysis bullosa, blisters appear below the basement membrane. To date, all cases of junctional epidermolysis bullosa have been shown to be transmitted in an autosomal recessive fashion.
Clinical and genetic heterogeneity are characteristic of junctional epidermolysis bullosa. Two major clinical variants of this epidermolysis bullosa subtype have been described: the moderately severe non-Herlitz junctional epidermolysis bullosa characterized by localized to generalized blistering, nail dystrophy, scarring alopecia, and mucosal involvement; and the Herlitz type of junctional epidermolysis bullosa, associated with extensive skin and mucosal blistering, nail dystrophy, exuberant granulation tissue, enamel defects, and a high perinatal mortality resulting from overwhelming infections and respiratory complications.
The junctional epidermolysis bullosa subtype, generalized atrophic benign epidermolysis bullosa, is characterized by life-long blistering, resulting in cutaneous atrophy, diffuse scarring alopecia, pigmentary changes, and nail and tooth abnormalities.
The genetic basis of all major clinical variants of epidermolysis bullosa has been delineated. Specific mutations have been demonstrated in 10 different genes expressed within the dermoepidermal adhesion zone, with at least six different genes being involved in the pathogenesis of junctional epidermolysis bullosa. Herlitz junctional epidermolysis bullosa has been shown to be associated with mutations in one of the 3 laminin-5 genes (LAMB3, LAMA3, LAMC2), resulting in premature termination of protein translation, or reduced levels of mRNA transcripts resulting from non-sense-mediated mRNA decay. Non-Herlitz junctional epidermolysis bullosa cases have also been assigned to mutations within the laminin-5 genes.
The current mutation detection strategy followed in the United States and Europe entails analysis of patient samples for the recurrent mutations in LAMB3 followed by sequential screening of LAMB3, LAMC2, and finally LAMA3.
The observation of reduced type XVII collagen/bullous pemphigoid antigen 2 expression in the skin of generalized atrophic benign epidermolysis bullosa patients led to the identification of causative mutations within the gene encoding this protein. Other clinical cases of generalized atrophic benign epidermolysis bullosa were shown to be caused by mutations affecting laminin-5-encoding genes.
A survey performed by Bastaki et al. (1992) between 1985 and 1989 reported the overall incidence of genodermatosis in Kuwait Maternity Hospital to be 0.26 per 1000 livebirths. More specifically, the incidence of epidermolysis bullosa was 0.04 per 1000 livebirths in Kuwait during the over-mentioned period of five years.
Ayoub et al. (2005) identified two newborns with a lethal form of EBJ-Herlitz. The female newborns descended from two unrelated 1st degree consanguineous marriages. The Immunohistology of frozen skin samples revealed an extremely reduced immunoreactivity for the alpha3 laminin-5 subunit.
bullosa herlitz type and who was born to consanguineous parents, Mazzucchelli et al. (2011) found a novel homozygous nonsense mutation in the LAMA3 gene (p.Y955X). The neonate developed blistering of the skin immediately after birth. Electron microscopy of a cutaneous biopsy showed skin cleavage within the lamina lucida and immunoepitope mapping revealed a complete absence of laminin 332 expression. The neonate died at 3 months of age due to sepsis.
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