Knowledge on rare diseases and orphan drugs

Prevalence of junctional epidermolyis bullosa-pyloric atresia syndrome (JEB-PA) is unknown. More than 100 cases have been reported worldwide.

Skin manifestations include severe blistering, atrophic scarring, and nail dystrophy. Congenital absence of skin (aplasia cutis congenita) is common, and ear anomalies are also relatively common. The manifestations of pyloric atresia include intractable vomiting, abdomen distension, and an absence of stools. Patients present oral cavity involvement and, if they survive, enamel hypoplasia. Other extracutaneous manifestations include involvement of the respiratory, gastrointestinal and genitourinary tracts. In particular, genitourinary malformations and acquired genitourinary abnormalities (polypoid bladder wall lesions, hemorrhagic cystitis, urethral strictures) are relatively frequent and characteristic. Growth delay and anemia, secondary to the extensive cutaneous and mucosal lesions, are common. Polyhydramnios, secondary to pyloric atresia, is usually present in pregnancies with an affected fetus. Some patients with an identical presentation have been found to have intraepidermal rather than intra-lamina lucida blister formation, necessitating their inclusion under the rarer subtypes of EB simplex (EBS; epidermolytic) severe with pyloric atresia rather than under junctional EB. These patients might have mutations in the intracellular domain of integrin beta4, or plectin deficiency.

The condition is caused by biallelic mutations in either of the genes encoding the two subunits of alpha6-beta4 integrin, ITGA6 (2q31.1) and ITGB4 (17q11-qter).

Diagnosis in neonates is suspected based on clinical findings of skin fragility and gastric outlet obstruction demonstrated by X-rays without contrast. In addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone by immunofluorescence antigen mapping and/or transmission electron microscopy, a negative or highly reduced immunofluorescence staining for integrin alpha6beta4 is typical of JEB-PA. Genetic testing should be the gold standard, in order to differentiate from EBS with pyloric atresia, particularly if immunofluorescence mapping and/or transmission electron microscopy are not available/feasible.

The main differential diagnosis is of EBS with pyloric atresia.

Diagnosis may be suspected on ultrasound findings of polyhydramnios, secondary to pyloric atresia, with high levels of alpha-feto-protein (> 20 times normal values). Prenatal diagnosis by genetic testing should be offered to the family.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.

Pyloric atresia must be corrected surgically in the first days of life; without this, the disorder is lethal in the neonatal period. Multidisciplinary management with hospitalization in neonatal intensive care is required. Patients should be monitored and treated for water-electrolyte balance, failure to thrive, anemia, infectious and respiratory complications, etc. Pain management is also extremely important in these patients and often requires opioids. Skin management is based on the avoidance of blistering by meticulous protective padding of the skin, avoidance of trauma in daily life, lancing and draining of new blisters, and prevention of secondary infection by careful wound care.

JEB-PA leads in most cases to early death within the first months of life. Prognosis depends predominantly on the prompt surgical correction of pyloric atresia. Amongst patients in whom this is successful, a minority show mild skin involvement or a gradual improvement of blistering lesions, allowing the recanalized patient to reach a normal life span.

Last update: June 2021 - Expert reviewer(s): Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin* - Dr Gianluca TADINI | ERN-Skin*

* European Reference Network