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At a glance

A form of junctional epidermolysis bullosa (EB) associated with pyloric atresia that often results in death within the first year of life.

Synonyms

Epidermolysis Bullosa Lethalis with Pyloric Atresia; Aplasia Cutis Congenita with Gastrointestinal Atresia; Junctional Epidermolysis Bullosa with Pyloric Atresia; Junctional Epidermolysis Bullosa with Pyloric Atresia and Aplasia Cutis Congenita.

History

The disease bears the name of Rivka Carmi, an Israeli pediatrician and geneticist, who, together with her colleagues, described this disorder in 1982 in two children (a boy and a girl) of consanguineous parents. Both had extensive areas of ☞Aplasia Cutis Congenita (large areas of symmetrically absent skin on the limbs, face, and neck regions), but only one had pyloric atresia. However, the disease has been presented in 1967 by the British pathologists L. Margaret Swinburne and H.G. Kohler at the thirteenth annual meeting of the Paediatric Pathology Society in Leeds, UK.

Incidence

Unknown, but around 100 cases have been reported. Junctional EB (without pyloric stenosis) accounts for approximately 1% of all EB cases.

Genetic inheritance

Autosomal recessive. The vast majority (approximately 80%) of cases are caused by mutations in the Integrin-Alpha-6 (ITGA6) gene located on chromosome 2q31.1. About 5% are caused by mutations in the Integrin-Beta-4 (ITGB4) gene, which has been mapped to chromosome 17q25.1. The proteins encoded by the ITGA6 and ITGB4 genes form a heterodimer cellular adhesion molecule known as α6β4 integrin that is predominantly expressed at the basal surface adjacent to the basement membrane of epithelial cells where it is involved in the formation of hemidesmosomes. These stable adhesions are critical for securing cells to the surrounding adhesion molecules and thus the integrity of epithelial monolayers. In addition, α6β4 integrin stimulates cell migration and controls the invasion and survival of epithelial cells by activating signaling pathways. The remaining 15% of cases are caused by mutations in the Plectin (PLEC) gene located on chromosome 8q24.3. Plectin is abundant in the basal layer of epidermal cells (keratinocytes) where it is a component of both, hemidesmosomes and desmosomes. Plectin is also expressed in striated muscles, gastrointestinal epithelia, and many other tissues.

Pathophysiology

In junctional EB, blister formation in the plane of the lamina lucida results in separation of the epidermis from the basal lamina. The hemidesmosomes in the lamina lucida of these patients are often significantly reduced in quantity and quality (structural anomalies). The bullae per se often heal without significant superficial scarring; however, erosions provide an easy entry portal for bacteria, which trigger inflammation and marked fibrosis and may lead to infections with sepsis. The sequence of events is initiated by separation of the epidermis or intestinal mucosal layers from the basal lamina. The resulting inflammatory reaction triggers substantial fibrosis involving the deep layers of the tissues and leading to damage ...

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