Knowledge on rare diseases and orphan drugs

Less than 100 cases of recessive dystrophic epidermolysis bullosa inversa (RDEB-I) have been reported to date; it is probably underreported.

The disease manifests at birth or shortly thereafter with generalized blistering and superficial erosions of intermediate severity that heal with atrophic scarring and milia formation. From adolescence to early adulthood, blistering tends to localize to folds, particularly axillae, groin, perianal area and natal cleft. Women may present with marked vulvovaginal and inframammary skin blistering. Other predilection sites include the base of the neck, the uppermost back, and the lumbosacral area. Nail dystrophy is typical but of variable severity. Mucosal lesions with blistering and scarring in the mouth are characteristic and can lead to microglossia (loss of lingual papillae and fusion of the tongue to the mouth floor) and ankyloglossia (obliteration of the oral vestibules and progressive restriction of oral aperture). Esophageal involvement is often severe and is associated with a risk of esophageal stricture that can impair intake of nutrients. Lesions of the lowermost portion of the genitourinary tract are also common and may lead to the development of vaginal strictures that may impair normal sexual function. Other less common extracutaneous features include external auditory canal stenosis or complete occlusion with varying degrees of hearing loss; corneal erosions, and anemia. Growth delay is rare. Patients may develop squamous cell carcinomas, with a cumulative risk reaching 23% by age 50 which is much lower than in either of the two generalized forms of RDEB (severe RDEB and intermediate RDEB).

The disease is caused by mutations in the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function or reduced amounts of collagen VII. This impairs collagen VII assembly into anchoring fibrils which anchor the basement membrane to the underlying dermis. This in turn causes reduced skin resistance to minor trauma. Compound heterozygosity for a loss-of-function COL7A1 mutation in combination with a missense mutation is prototypic. Specific glycine and arginine substitutions are implicated to affect the thermostability of type VII and cause this phenotype.

Diagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples showing a cleavage plane located below the lamina densa of the cutaneous basement membrane zone. Genetic testing confirms the diagnosis.

The differential diagnosis includes other forms of epidermolysis bullosa. In the neonatal period also herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, and staphylococcal scalded skin syndrome may need to be considered.

Genetic prenatal diagnosis may be considered where the mutations have previously been identified in and affected sibling.

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.

Treatment is symptomatic and includes wound management, treatment of pain and pruritus, nutritional supply, and regular examinations of skin and visible mucous membranes to screen for skin cancer.

Prognosis is generally good.

Last update: May 2021 - Expert reviewer(s): Pr Martin LAIMER | ERN-Skin*

* European Reference Network