Dystrophic Epidermolysis Bullosa

Excerpt

Clinical characteristics: Dystrophic epidermolysis bullosa (DEB) is characterized by skin fragility manifested by blistering and erosions with minimal trauma. Many individuals also have dystrophic or absent nails. DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB).

Clinical findings in severe RDEB include skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring. Blistering and erosions affecting the whole body may be present in the neonatal period. Oral involvement may lead to mouth blistering, fusion of the tongue to the floor of the mouth, and progressive diminution of the size of the oral cavity and mouth opening. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Malnutrition with vitamin and mineral deficiency may lead to growth deficiency in young children. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring results in contractures and pseudosyndactyly. The lifetime risk of aggressive squamous cell carcinoma (SCC) is greater than 90%.

In contrast, the blistering in intermediate RDEB may be localized to hands, feet, knees, and elbows with or without involvement of flexural areas and the trunk, and without severe scarring.

In DDEB, blistering is often mild and limited to hands, feet, knees, and elbows, but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB.

Diagnosis/testing: The diagnosis of DEB is established in a proband with characteristic clinical findings and biallelic COL7A1 pathogenic variants (for RDEB) or a heterozygous pathogenic variant in COL7A1 (for DDEB) identified by molecular genetic testing. Skin biopsy using transmission electron microscopy and/or immunofluorescent antibody/antigen mapping can be considered in those with inconclusive molecular genetic testing or if genetic mutation analysis is not available.

Management: Targeted therapies: Beremagene geperpavec-svdt topical therapy in those with molecularly confirmed DEB (must be applied by a health care provider); prademagene zamikeracel autologous gene-corrected keratinocyte grafts (one-time surgical application per lesion; must be performed through a Zevanskyn™ Qualified Treatment Center); birch triterpenes / birch bark extract topical therapy.

Supportive care: Minimize new blisters with education of caretakers, wrapping and padding extremities, and soft and loose-fitting clothing; vaginal delivery is the preferred method, but in certain circumstances, cesarian delivery may be recommended to prevent trauma of an affected fetus; encourage play that reduces risk of skin trauma; dressing and padding to protect bone prominences; new blisters should be lanced, drained, and in most cases dressed with nonadherent dressings, covered with padding for stability and protection, and secured with an elastic mesh-like wrap for integrity (e.g., burn net). Antibiotics and antiseptics for wound infection; appropriate footwear and physical therapy to preserve ambulation; topical, oral, and psychological therapies for pain and itch; specialized treatment of SCC; good dental care; dilation of esophageal strictures and webs to improve swallowing; management of constipation. Fluid and electrolyte management as needed; nutritional support including feeding gastrostomy tube, vitamin A, zinc, selenium, and carnitine supplementation. Anemia is treated with iron supplements and transfusions as needed. Eye lubricants and protective contact lenses may prevent corneal abrasions. Angiotensin-converting enzyme inhibitors for cardiomyopathy; treatment of urologic and kidney manifestations per urologist and nephrologist. Occupational and physical therapy may help prevent hand and other joint contractures. Surgical release of fingers often needs to be repeated. Calcium and vitamin D supplementation and bisphosphonates as needed for osteoporosis. Estrogen replacement as needed for delayed puberty; suppression of menses can prevent exacerbation of anemia; psychosocial support.

Surveillance: Thorough skin examination at each visit and as recommended by dermatologist; evaluation of crusted, non-healing, and painful lesions as well as those with exuberant scar tissue at least annually beginning at age ten years; biopsies of suspicious lesions for evidence of SCC. Assess oral mucosa, feeding, esophageal involvement, gastrointestinal manifestations, growth, nutrition, hand function, footwear, mobility, and family needs at each visit. Serum vitamin A, selenium, carnitine, zinc, 25-hydroxyvitamin D₃, complete blood count, iron studies, and urinalysis every six to 12 months; ophthalmology examinations as needed; annual echocardiogram to identify dilated cardiomyopathy starting at age two years; annual spine radiographs and DXA scan to assess for osteoporosis starting at age six years or earlier in those with unexplained pain and/or fractures; evaluation of pubertal status at each visit beginning at age ten to 12 years.

Agents/circumstances to avoid: Nasogastric tubes are discouraged because of oral and esophageal fragility; poorly fitting or coarse-textured clothing and footwear; activities/bandages that traumatize the skin.

Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives should be offered to permit early diagnosis and treatment in order to identify those who would benefit from management of trauma to the skin.

Genetic counseling: DEB is inherited in either an autosomal dominant (DDEB) or autosomal recessive (RDEB) manner. Some COL7A1 pathogenic variants are associated with both DDEB and RDEB. Molecular characterization of the COL7A1 pathogenic variants is the only accurate method to determine mode of inheritance and recurrence risk; phenotype severity and skin biopsy findings alone are not sufficient.

DDEB: About 70% of individuals diagnosed with DDEB are reported to have an affected parent. If a parent of a proband with DDEB is affected and/or is known to be heterozygous for the COL7A1 pathogenic variant, the risk to the sibs is 50%. Each child of an individual with DDEB has a 50% chance of inheriting the pathogenic variant. Intrafamilial clinical variability and reduced penetrance have been observed among heterozygous family members.

RDEB: If both parents are known to be heterozygous for a COL7A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs of a proband with RDEB are typically asymptomatic, although some pathogenic variants are associated with both DDEB and RDEB.

Once the COL7A1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.