Severe generalized junctional epidermolysis bullosa (ORPHA:79404)
A severe form of junctional epidermolysis bullosa (JEB) characterized by blisters and extensive erosions, localized to the skin and mucous membranes.
Epidemiology
Prevalence at birth is estimated to range between 1/200,000-2,500,000 worldwide. According to data from U.S. and Italian EB registries, about 20% of patients with JEB have the severe type.
Clinical description
The extreme severity of this condition is apparent at birth. Bullae present spontaneously even with a gentle touch, with an onset within the first several months to one to two years of life. After the eruption, blisters lose their roof and remain visible as erosions that do not heal. Exuberant granulation tissue is a characteristic manifestation which arises on such eroded epithelium and may involve the skin (around nail folds, in a mask-like distribution on the face, and at sites of friction, such as shoulders and buttocks), and the upper airways. Involvement of mucous membranes may affect the entire gastrointestinal (GI) tract, genitourinary tract, and respiratory tract to the bronchioles. However, the most significant and frequent mucosal lesions are those in the upper part of the GI and respiratory tracts. The extensive erosions and ulcerations of the oral mucosa severely hamper feeding, and involvement of the laryngotracheal mucosa, manifesting as hoarseness, dyspnea and stridor, may lead to acute respiratory failure requiring tracheostomy. Other consistent features include nail anomalies with paronychia, several degrees of onychodystrophy and nail shedding. Dental abnormalities, when survival enables their observation, include regularly marked hypoplasia or complete absence of enamel. Frequent ocular lesions comprise corneal blisters, erosions and scarring, and ectropion formation. Failure to thrive is an almost constant finding, and multifactorial anemia is also common.
Etiology
Severe JEB is caused by mutations in one of the three laminin-332 coding genes: LAMA3 (18q11.2), LAMB3 (1q32) and LAMC2 (1q25-q31). In most cases, null mutations are found on both alleles of the causative gene.
Diagnostic methods
In addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone, a negative immunofluorescence staining for laminin-332 is typical of severe JEB. However, in rare cases the staining is strongly reduced and thus does not enable differentiation of severe JEB from intermediate JEB. In these cases, genetic testing, showing null mutations in one of the three genes encoding laminin-332, is necessary to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes other types epidermolysis bullosa, in particular congenital autoimmune bullous diseases.
Antenatal diagnosis
Prenatal diagnosis should always be recommended and diseases-causing pathogenic variants should be disclosed in advance.
Genetic counseling
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.
Management and treatment
The approach is multidisciplinary with neonatal pathology units for severely affected patients, antibiotics for pulmonary infections, local antisepsis for slow-healing lesions and advanced dressing for the treatment of ulcers. Nutritional support is mandatory.
Prognosis
Prognosis is poor and the most severe JEB patients die in the first few years of life, with the major causes of death being failure to thrive, respiratory failure, sepsis, and pneumonia. Some rare patients with generalized cutaneous and internal disease reach the age of 10-15 years. In addition, squamous cell carcinomas may arise in a minority of severe JEB patients (4.5% according to data from the U.S. National EB Registry).

                            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