α6β4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia

Junctional epidermolysis bullosa with pyloric atresia (JEB-PA) (MIM 226730) is an autosomal recessive disorder resulting from mutations in the genes encoding alpha6 beta4 integrin (ITGA6 and ITGB4). Clinically it is characterized by mucocutaneous fragility and gastrointestinal atresia, which most commonly affects the pylorus, Additional features of JEB-PA include involvement of the urogenital tract, aplasia cutis and failure to thrive. While most affected individuals have a poor prognosis resulting in death in infancy, others have milder clinical features and a better prognosis. We report two previously undescribed homozygous ITGB4 mutations in two unrelated families, which resulted in severe skin blistering, pyloric atresia and lethality in infancy. Delineation of the mutations was used to undertake DNA-based prenatal diagnosis in subsequent pregnancies at risk for recurrence in both families. We review all previously published ITGA6 and ITGB4 mutation reports to help define genotype-phenotype correlation in this rare genodermatosis.