Junctional epidermolysis bullosa (ORPHA:305)
A group of inherited epidermolysis bullosa characterized by involvement of the skin and mucous membranes, and is defined by the formation of blistering lesions between the epidermis and the dermis at the lamina lucida level of the cutaneous basement membrane zone and by healing of lesions with atrophy and/or exuberant granulation tissue formation.
Epidemiology
Junctional epidermolysis bullosa (JEB) is the less common, but frequently early lethal form of EB. Point prevalence is generally below 1/1,000,000 worldwide except in the Netherlands where it is estimated at 1/475,000. Prevalence at birth ranges from 1/110,000-455,000 worldwide.
Clinical description
Onset is usually at birth with the exception of late-onset JEB. Several JEB subtypes have been described based on clinical features. All subtypes are characterized by the presence of enamel hypoplasia manifesting as localized or more extensive thimble-like pitting of some or all of the tooth surfaces. Blistering is usually associated with atrophic scarring or with exuberant granulation tissue formation and nail dystrophy. Additional skin findings may include congenital aplasia cutis and progressive hair loss. Mucosal involvement is constant, although of variable severity, and can affect the gastrointestinal, respiratory and genitourinary tracts and the eyes. Pyloric atresia is the hallmark of the JEB with pyloric atresia subtype. JEB is divided in the following subtypes: severe JEB, intermediate JEB, localized JEB, JEB with pyloric atresia (JEB-PA), JEB inversa, late-onset JEB, laryngo-onycho-cutaneous syndrome (LOC) syndrome and JEB with interstitial lung disease and nephrotic syndrome.
Etiology
JEB is caused by mutations in various genes, including COL17A1 (10q25.1), ITGA6 (2q31.1), ITGB4 (17q25.1), LAMA3 (18q11.2), LAMB3 (1q32.2), LAMC2 (1q25.3) and ITGA3 (17q21.33).
Diagnostic methods
Diagnosis is based on determination of the level within which blisters develop on skin biopsy samples following minor traction to the skin. The recommended techniques are immunofluorescence antigen mapping and transmission electron microscopy. In JEB, the blister cleavage plane is localized within the lamina lucida of the cutaneous basement membrane zone. Subtypes are then defined on the basis of immunofluorescence and electron microscopic findings, and clinical presentation. Genetic testing should be always performed, as it is necessary for antenatal diagnosis.
Differential diagnosis
Diagnosis is usually straightforward with little need for extensive differential diagnosis. However, in the neonatal period, in utero Herpes simplex infection may need to be considered, especially if there is no family history of blistering disease or if the clinical findings are very atypical for EB. The differential diagnosis in neonates may include inherited or acquired skin disorders with a similar presentation.
Antenatal diagnosis
Prenatal diagnosis should always be offered to families at risk of having a child with severe JEB.
Genetic counseling
Inheritance is autosomal recessive. Parents of a child with JEB are obligate carriers of the pathogenic variants. For each pregnancy of the parents, the risk of having an affected child is 25%.
Management and treatment
Patients affected by most JEB forms require hospitalization in neonatal intensive care because of the severity skin lesions and extracutaneous manifestations, and 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. Subsequently, patient management should involve a multidisciplinary team, to ensure coordinated care. 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.
Prognosis
Patients with JEB, particularly those with severe subtypes (severe JEB, JEB-PA and JEB with interstitial lung disease and nephrotic syndrome) are at major risk of death during the first few years of life.

                            Last update: 
                            May 2021


                            - Expert reviewer(s): 
                            Pr Cristina HAS | ERN-Skin*


                                * European Reference Network