F M Keane

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 α6β4 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.

Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network

Background  Several hereditary human diseases are now known to be caused by distinct mutations in genes encoding various desmosome components. Although the effects of some of these mutant genes have been analysed by targeted disruption experiments in mouse models, little is known about the cell and tissue changes in affected human patients.

Increased risk of squamous cell carcinoma in junctional epidermolysis bullosa.

Non‐Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive genodermatosis characterized by skin fragility and blistering. It is usually caused by mutations in the genes encoding the basement membrane proteins laminin 5 or type XVII collagen. Clinically, impaired wound healing and chronic erosions cause major morbidity in affected patients. Previously it was thought that these individuals, unlike patients with dystrophic EB, did not have an increased risk of developing skin cancer. However, we describe three patients with non‐Herlitz JEB (aged 42, 56 and 75 years) who developed cutaneous squamous cell carcinomas (SCCs). The tumours were well‐differentiated in two cases, but one patient had multiple primary SCCs that were either well‐ or moderately differentiated. Most cases of SCC in non‐Herlitz JEB described have occurred in those with laminin 5 defects and on the lower limbs. These clinicopathological observations have important implications for the management of patients with this mechanobullous disorder as well as providing further insight into the biology of skin cancer associated with chronic inflammation and scarring.