Epidermolysis bullosa simplex associated with muscular dystrophy: Phenotype-genotype correlations and review of the literature

Background: Epidermolysis bullosa simplex associated with muscular dystroph y (EBS-MD; OMIM# 226670) is an autosomal recessive disorder caused by genet ic defects in the plectin gene. Because EBS-MD is relatively rare, and gene defects have been elucidated only in a limited number of patients, the pre cise phenotype-genotype correlations have not yet been fully elucidated. Objective: The purpose of this study was to define clinical features of EBS -MD and to clarify its phenotype-genotype correlations. Methods: Clinical, ultrastructural, immunohistochemical, and molecular feat ures of 4 unrelated Japanese patients with EBS-MD were recorded. In additio n, 6 cases with defined plectin gene mutations reported in the literature w ere reviewed. Results: In skin of the EBS-MD patients, the blister formation always occur s just above the hemidesmosomes, and expression of plectin is absent or mar kedly reduced in all cases examined. All 10 patients, including 6 cases in the literature, showed generalized blistering at birth or soon thereafter, and experienced nail deformities. In addition, decayed teeth (5 cases), ure thral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respi ratory complications (2), alopecia (1), and laryngeal webs (1) were present . All 8 patients who were older than 9 years demonstrated considerable musc le weakness, and the majority of them ended up being wheelchair bound. Amon g the 10 patients, 7 were products of consanguineous marriage, 9 have prema ture termination codon (PTC) mutations in both alleles of the plectin gene, and 7 cases were homozygous for the mutation. One patient who is homozygou s for a 2719de19 in-frame deletion mutation that resulted in elimination of 3 amino acids, QEA, could still walk at the age of 46 and showed milder cl inical severity Conclusion: EBS-MD reveals clinical features not only characteristic of EBS and MD, but also other manifestations including urethral, dental, and resp iratory complications. The majority of patients are products of consanguine ous marriage and have homozygous plectin gene mutations. Whereas patients w ith PTC mutations in both alleles typically showed severe clinical features of EBS-MB and ended up being wheelchair bound, a homozygous patient for an in-frame deletion mutation showed positive, yet attenuated plectin express ion and milder clinical phenotype. Thus plectin immunofluorescence, combine d with identification of the underlying plectin mutations, is of value in p redicting the severity of the muscle involvement that occurs later in life of patients with EBS-MD.