Cancer Health Center

continued...

Dystrophic epidermolysis bullosa

Approximately 95% of individuals with the heritable disorder dystrophic epidermolysis bullosa (DEB) have a detectable germline mutation in the gene COL7A1. This gene, which is located at 3p21.3, is expressed in the basal keratinocytes of the epidermis and encodes for type VII collagen. This collagen forms a part of the fibrils that anchor the basement membrane to the dermis, thereby providing structural stability and resistance to mild skin trauma.[93] The lack of type VII collagen results in generalized blistering, often starting from birth, and is associated with skin atrophy and scarring.[93]

There are two recessively inherited subtypes of DEB: severe-generalized (HDEB-sev gen; previously named Hallopeau-Siemens type) and generalized-other (HDEB-O; previously named non-Hallopeau-Siemens type); and a dominantly inherited form, dominant dystrophic epidermolysis bullosa (DDEB). The clinical manifestations demonstrate a continuum of severity that complicates definitive diagnosis, especially early in life. The severe generalized subtype, associated with formation of pseudosyndactyly (a mitten-like deformity secondary to fusion of interdigital webbing) in early childhood, carries a SCC risk of up to 85% by the age of 45.[94,95] These cancers arise in nonhealing wounds and usually metastasize to cause death within 5 years of the diagnosis of SCC.[96] In one case series, SCC was the leading cause of death for the 15 patients with the severe generalized subtype.[97] Early mortality also has been observed in this disorder, with a mortality rate of up to 40% by the age of 30.[98] Extracutaneous manifestations of HDEB-severe generalized include short stature, anemia, strictures of the gastrointestinal and genitourinary tracts, and corneal scarring that may result in blindness.

Diagnosis of epidermolysis bullosa may be accomplished by immunofluorescence or electron microscopy. A list of recommended diagnostic antibodies and their suppliers is available at the website of the Dystrophic EB Research Association. Mutation testing is generally used for prenatal diagnosis rather than for the primary diagnosis of epidermolysis bullosa.[99,100]

The rate of de novo mutation for DDEB is approximately 30%; maternal germline mosaicism has also been reported.[101,102] Glycine substitutions in exons 73 to 75 are the most common mutations in DDEB. G2034R and G2043R account for half of these mutations. Less frequently, splice junction mutations and substitutions of glycine and other amino acids may cause the dominant form of dystrophic epidermolysis bullosa. In contrast, more than 400 mutations have been described for the two types of recessive epidermolysis bullosa. The recessive form of the disease is caused primarily by null mutations, although amino acid substitutions, splice junction mutations, and missense mutations have also been reported. In-frame exon skipping may generate a partially functional protein in recessive disease. A founder mutation, c.6527insC (p.R525X), has been observed in 27 of 49 Spanish individuals with recessive DEB.[103] Genotype-phenotype correlations suggest an inverse correlation between the amount of functional protein and severity.