Severe Generalized Recessive Dystrophic Epidermolysis Bullosa

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

COL7A1, MMP1, GRIP1, MMP7, THBS1, TP53, ATN1, DCN, MSC, CD44, POSTN, ABCB5, PIK3CG, PLK1, UPF1, SERPINA13P, TAGLN, TGFB1, TGM2, PRSS55, CRISP2, VEGFA, XPC, PIK3CB, SPZ1, KLF4, SLCO1B3, PIK3CD, ACTB, PIK3CA, MMP13, AKT1, APOB, BMP1, BMP4, CAT, CD68, CDKN2A, COCH, HBEGF, EGF, FCGRT, FN1, HMGB1, IGFBP3, IL1A, ITGB1, SMAD3, MMP3, JAG1, MIR145

Drugs

Allantoin, Allogeneic adipose-derived adult mesenchymal stem cells contained in a fibrin-based bioengineered dermis, Allogeneic human dermal fibroblasts

Allantoin, Allogeneic adipose-derived adult mesenchymal stem cells contained in a fibrin-based bioengineered dermis, Allogeneic human dermal fibroblasts, Allogeneic skin-derived ABCB5-positive mesenchymal stem cells, Angiotensin (1-7), Antisense oligonucleotide targeting exon 73 in the COL7A1 gene, Autologous genetically modified human dermal fibroblasts, Autologous skin equivalent graft composed of keratinocytes and fibroblasts genetically corrected by CRISPR/Cas9-mediated excision of mutation-carrying COL7A1 exon 80, Bilayer engineered skin composed of keratinocytes (patient autologous) and fibroblasts (donor allogeneic) in a plasma matrix, Diacerein, Dry extract from Betulae cortex (birch bark), Ex-vivo-expanded autologous fibroblasts transduced with lentiviral vector containing the COL7A1 gene, Ex-vivo-expanded autologous keratinocytes transduced with retroviral vector containing the COL7A1 gene, Expanded Allogeneic Human Dermal Fibroblasts In Hypothermosol(R)-Frs, Human dermal fibroblasts cultured on a bioresorbable polyglactin mesh, Losartan, Recombinant human alpha 1 chain homotrimer of type VII collagen, Recombinant human collagen alpha-1 (VII) chain homo-trimer (rC7), Skin equivalent graft genetically corrected with a COL7A1-encoding SIN retroviral vector, ex-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced with a COL7A1-encoding retroviral vector

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Severe generalized recessive dystrophic epidermolysis bullosa (RDEB-sev gen) is the most severe subtype of dystrophic epidermolysis bullosa (DEB, see this term), formerly known as the Hallopeau-Siemens type, and is characterized by generalized cutaneous and mucosal blistering and scarring associated with severe deformities and major extracutaneous involvement.

Epidemiology

The reported prevalence varies between populations, from 1/1,250,000 inhabitants in Scotland to 1/2,381,000 inhabitants in the Unites States.

Clinical description

Blisters develop at birth or during the neonatal period and affect all the body as well as the oral and gastrointestinal mucosa. Healing of lesions occurs with retracting scars or milia. 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. In the oral cavity, fusion of the tongue to the mouth floor (ankyloglossia), obliteration of the oral vestibules and progressive restriction of oral aperture (microstomia) cause difficulties in chewing and swallowing. Dental caries are numerous. Esophageal stricture is frequent and result in severe dysphagia. Anal and perianal erosions cause major pain during defecation and therefore self-induced constipation. Oral, esophageal, and anal involvement induce a state of chronic malnutrition which contributes to growth retardation typical of the disease, delayed puberty, osteopenia and osteoporosis. Refractory anemia, iron deficiency and hypoalbuminemia are also observed. Nearly all patients develop at least one aggressive squamous cell carcinoma (SCC; see this term), more often during the third-fourth decade of life.

Etiology

The disease is caused by null mutations within the type VII collagen gene (COL7A1) that usually lead to a lack of functional collagen VII, the main constituent of anchoring fibrils that anchor the basement membrane to the dermis.

Diagnostic methods

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.

Differential 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 (see these terms) may need to be considered.

Antenatal diagnosis

DNA-based prenatal diagnosis is possible for at risk pregnancies.

Genetic counseling

Transmission is autosomal recessive.

Management and treatment

Protective padding of the skin reduces the blistering and careful wound care helps in preventing secondary infections. Hand and foot deformities can be treated by surgery. Due to recurrence, regular physiotherapy is necessary to maintain intraoperative results, but additional treatments are always required. Follow-up by a dietitian is essential and gastrostomy feeding may be necessary in patients unable to maintain adequate nutrition. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. Transfusions, iron supplementation, and erythropoietin administration improve anemia and iron deficiency. A regular follow-up is necessary for the surveillance of SCC, whose treatment is surgical.

Prognosis

Life expectancy is significantly reduced, mostly due to the development of aggressive SCC with frequent metastases. Mortality from metastatic SCC within five years of the time of diagnosis of the first SCC is of 87% by age 45. Other complications that affect the prognosis include chronic renal failure, and more rarely, dilated cardiomyopathy.