Knowledge on rare diseases and orphan drugs

The reported prevalence at birth varies between populations, from to 1/333,000 in the United States to 1/77,000 in Europe.

Blisters develop spontaneously or after the mildest trauma at birth or during the neonatal period and affect all of the body (with predilection for skin over bony prominences) with extensive involvement of the oral and gastrointestinal mucosa. Congenital skin ulceration with extensive denudation of a body area may be present. Lesions heal with retracting scars and milia. Epidermolysis bullosa (EB) nevi may occur. Excessive scarring can lead to adhesion of fingers and toes resulting to pseudosyndactyly, and to joint contractures that further cause disabling hand and foot deformities (''mitten deformities''). Scarring alopecia of the scalp and permanent loss of nail plates are also observed. Eye involvement is frequent and includes blepharitis, loss of eyelashes, ectropion, symblepharon, and corneal blisters that can lead to loss of vision. Chewing and swallowing difficulties are due to ankyloglossia, obliteration of the oral vestibules and progressive microstomia. Dental caries are numerous. Esophageal stricture is frequent and results in severe dysphagia. Anal and perianal erosions cause major pain during defecation and foster constipation. Extensive gastrointestinal involvement in combination with a hypercatabolic state due to permanent wounding, infection and inflammation, induce a state of chronic malnutrition which contributes to growth retardation, delayed puberty, osteopenia and osteoporosis. Urethral strictures may occur. Refractory anemia, iron deficiency and hypoalbuminemia are also observed. Nearly all patients develop at least one aggressive squamous cell carcinoma (SCC), typically during the third-fourth decade of life.

The disease is caused by homozygous or compound heterozygous biallelic nonsense mutations in COL7A1 (3p21.31) that usually result in premature termination codons leading to a lack of functional collagen VII, the main constituent of anchoring fibrils that anchor the basement membrane to the dermis.

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 EB. 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.

Antenatal diagnosis is always recommended to parents having a child with severe RDEB. The disease-causing pathogenic variants should be disclosed before.

The pattern of inheritance 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.

Protective padding of the skin reduces the blistering and careful wound care helps in preventing secondary infections. Treatment of pain and itch is highly warranted but partly limited in effectiveness. Regular follow-up at an EB-experienced dentist is recommended. Physiotherapy and occupational therapy are necessary to delay gradual loss of mobility and autonomy. Hand and foot deformities can be treated by surgery. Follow-up by a dietitian is essential and gastrostomy feeding may be necessary. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. Transfusions, iron supplementation, and erythropoietin administration improve anemia and iron deficiency. Vitamin D supplementation may be indicated to prevent osteoporosis. Regular follow-up is necessary for the surveillance of SCC. Psychological support should be offered.

Life expectancy is significantly reduced, mostly due to the development of aggressive SCC with frequent metastases. By the age of 55, the cumulative risk for developing SCC and death is greater than 90% and about 80%, respectively. Other complications that affect prognosis include chronic renal failure, and more rarely, multifactorial cardiomyopathy.

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

* European Reference Network