Epidermolysis Bullosa Recessive Dystrophic, Inversa
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA RECESSIVE DYSTROPHIC, INVERSA|
|Estimated prevalence||< 1/1.000.000|
|Gene (s)||COL7A1 (120120)|
The term epidermolysis bullosa (EB) describes a clinically and genetically heterogeneous spectrum of rare inherited conditions that are characterized by a marked mechanical fragility of epithelial tissues with blistering and erosions occurring after minor trauma. There are four major types of EB: EB simplex (EBS), dystrophic EB (DEB), junctional EB (JEB), and Kindler-syndrome. Except for Kindler-syndrome, each major EB-type is further subclassified . EB is based on mutations involving at least 15 structural genes expressed within the epidermis and the basement membrane zone (BMZ) [2, 3] (Figure 1). Besides the structural genes, MMP1 (collagenase-1) has been identified as a modifier of severity in dystrophic EB [4, 5]. In addition to the skin involvement, many EB forms present as a multisystemic disease associated with numerous extracutaneous manifestations. Secondary complications like chronic inflammation, chronic wound healing and scarring can result in severe impairments like pseudosyndactyly and mitten formation as well as life threatening forms of cancer, like squamous cell carcinoma in DEB .
Dystrophic or dermolytic epidermolysis bullosa (DEB) is characterized by tissue separation within the upper papillary dermis. The cleft formation occurs at the sub-lamina densa level, where collagen VII forms the anchoring fibrils (AF). DEB is divided into two major categories, the dominant (DDEB) and recessive (RDEB) forms, according to the mode of inheritance. Further subclassifications are made by clinical phenotype and severity of disease . RDEB is subdivided into seven subtypes with RDEB severe generalized (RDEB-sev gen) being the most severe form of DEB (Table 1). RDEB-inversa (RDEB-I) is a rare subtype of RDEB, with blistering and skin lesions primarily at intertriginous skin sites . Less than 100 cases of RDEB-I have been reported to date. All forms of DEB are caused by mutations in the COL7A1 gene (3p.21.31).
Table 1: RDEB subtypes.
|RDEB, generalized severe||RDEB-gen sev||COL7A1|
|RDEB, generalized intermediate||RDEB-gen intermediate|
|RDEB, bullous dermolysis of newborn||RDEB-BDN|
Figure 1. Schematic representation of EB-causing components.
© graphic design by R. Hametner
Schematic of the basement membrane zone (BMZ). Intermediate filaments composed of keratin 5 and 14 insert on the keratin (cytoskeletal) linker proteins plectin and BPAG1 (BP230) at the superior aspect of the BMZ. Plectin and BPAG1 interact with transmembrane α6β4 integrin and type XVII collagen (BP180/BPAG2), forming hemidesmosomes that attach basal keratinocytes to the underlying basement membrane. Anchoring filaments reach out below the hemidesmosome and include laminin-332 and laminin-311 that associate with type XVII collagen and α6β4 integrin, but also laminin-511, type IV collagen and nidogen, thereby forming the lamina densa. Anchoring fibrils extend as banded projections from the lamina densa and contain type VII collagen molecules. Type VII collagen triple helices attach the lamina densa to papillary dermis and are critical for the integrity of the epidermal-dermal junction through their ability to bind laminin-332.
In RDEB-I, the disease starts at birth in a generalized fashion. During early childhood, blister formation then shows the tendency to localize at intertriginous skin sites (skin folds), the neck and the lumbosacral area. The oral cavity, esophagus and the lowermost portion of the genitourinary tract are severely affected. Nail dystrophy shows variable severity among patients. Esophageal involvement may result in strictures and impairment of nutrient intake. Lesions of the genitourinary tract may lead to vaginal strictures and impairment of normal sexual function. RDEB-I patients may develop SCCs, but with a much lower cumulative risk, compared to RDEB-gen severe and RDEB-gen intermediate .
More than 600 distinct mutations in the COL7A1 gene have been disclosed in DEB that interfere with the structural and functional integrity of its proteinaceous product, the type VII collagen [7, 8]. The latter polymerizes to form anchoring fibrils (AF) that anchor the epidermal basement membrane with the dermis. Collagen VII in normal tissues is restricted to stratified squamous epithelia, with blistering affecting the skin, mucous membranes and upper third of the esophagus. Secondary systemic manifestations of DEB, such as anemia, renal failure and squamous cell carcinomas are downstream complications due to blood loss, infections and chronic inflammation. In DEB skin, collagen VII is either reduced or absent. Ultrastructurally, electron microscopy reveals paucity, rudimentary structure, or complete lack of AF.
In RDEB, compound heterozygosity for COL7A1 mutations is common. A functionally and/or structurally residual protein expression accounts for a generally milder phenotype . Different mutations and allelic combinations, however, generate a continuum of biological phenotypes. They often are family specific in each individual patient (“private mutations”). This makes phenotype-genotype correlations possible to provide the basis for more accurate genetic counseling and prenatal diagnosis for at-risk families .
Diagnosis by clinical examination can be confirmed by antigen mapping of punch biopsies. Electron microscopy shows cleavage area sub-lamina densa. Genetic testing of the COL7A1 gene confirms the diagnosis on the molecular level.
Currently no causative therapy is available for neither form of DEB and treatment is primarily preventive. In everyday life, blister formation has to be avoided by protective padding of the skin and appropriate clothing. Wound care management is paramount in order to prevent secondary infections and to reduce scarring. Tracheolaryngeal complications (esophageal strictures) can be treated by balloon dilatation. Special diet is always necessary. SCCs are treated surgically.
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