BIOCHEMICAL, MOLECULAR AND ULTRASTRUCTURAL HETEROGENEITY IN SEVERE MUTILATING RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA

Patients with severe mutilating recessive dystrophic epidermolysis bul losa (REBD-M) present with a rather uniform clinical picture of extens ive mucocutaneous blistering, scarring and severe synechias of the fin gers and toes. Since molecular heterogeneity commonly underlies clinic ally homogeneous connective tissue disorders and to further increase o ur understanding of the pathobiology and biochemistry of the skin in R EBD-M patients, the same five patients were investigated with respect to the ultrastructure of anchoring fibrils (AF), presence of collagen VII, the major AF protein, and expression of neutral matrix metallopro teases (MMP) and their inhibitors. Intact, clinically uninvolved skin from three patients had neither AF nor collagen VII, but surprisingly, the skin from two REBD-M patients revealed ultrastructurally normal A F and stained positive with antibodies to collagen VII. One of the two AF/collagen VII positive patients exhibited some normal AF, but most of the fibrils revealed breaks and disintegration of the outer segment with some of only half the normal length. The unaffected skin of this patient revealed an elevated level of MMP activity. The other patient had a normal pattern of AF in uninvolved skin, but no AF in blistered areas. Like one of the AF/collagen VII negative patients, this AF/col lagen VII positive patient had a MMP activity corresponding to control s In non-blistered skin, while in blistered skin a significant elevati on of MMP activity was seen. Our results support the hypothesis that R EBD-M comprises an ultrastructurally and biochemically heterogeneous g roup of blistering disorders. The presence or absence of AF in clinica lly intact skin does not correlate with the severity of the phenotype REBD-M patients. Furthermore, while increased MMP activity might play a pathogenetic role in some patients, no evidence for such a relation could be found in others.