Epidermolysis Bullosa Recessive Dystrophic, severe generalized
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA RECESSIVE DYSTROPHIC, SEVERE, GENERALIZED|
|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) . All forms of DEB are caused by mutations in the COL7A1 gene (3p.21.31).
Table 1: RDEB subtypes.
|RDEB, generalized severe||RDEB-sev gen||COL7A1|
|RDEB, generalized intermediate||RDEB-gen intermediate|
|RDEB, bullous dermolysis of newborn||RDEB-BDN|
Figure1.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
RDEB-sev gen is the most severe subtype of DEB. Blistering of an extremely fragile skin starts at birth, both spontaneously and secondary to often minor mechanical forces. Large lesions typically arise on trauma-exposed sites or over bony prominences and heal with scarring and hypo- or hyperpigmentation. Milia, i.e. keratin-filled cysts resulting from keratin that has become trapped under the epidermis, are pathognomonic. Likewise, repeated blistering with excessive scarring of hands and feet is common, resulting in mitten deformities with complete fusion of all of the individual digits to a keratinaceous cocoon-like, scarred mass (pseudosyndaktyly), contractures and – subsequently – muscle atrophy, bone absorption and progressive disablement including wheelchair dependency .
Oral, genitourinary, anal and ocular mucous membranes are also affected with erosions and scarring. Perianal disease leads to painful stools and constipation [7, 8, 9]. Dystrophic teeth, restricted mouth opening and tongue mobility due to scarring promote severe caries, and, together with esophageal strictures and protein-losing enteropathy lead to reduced food intake and nutritional deficiencies. The risk for early development of highly aggressive squamous cell carcinomas (SCC) is dramatically increased and requires rigorous monitoring .
Involvement of the nail apparatus causes peri- or subungual blistering, hemorrhages and nail bed hyperkeratosis with onycholysis, onychomadesis, nail dystrophy and loss .
EB nevi are a frequent phenomenon especially in RDEB-sev gen [12,13]. They develop most commonly as acquired melanocytic nevi in infancy or adolescence, beginning as flat, black to brown pigmented lesions, which later, while acquiring dermal components, lose their pigment. EB nevi typically arise in sites of previous bullae or erosions, often with a darker rim at the confines of the preceding vesiculation. They frequently manifest with clinical, histological and dermoscopic features highly suggestive of melanoma which may be attributable to histoarchitectural changes in the background of a micromilieu of chronic skin wounding and regeneration . Malignant transformation of these moles, however, has fortunately hitherto not been reported [12,13].
Skin-derived squamous cell carcinoma (SCC) is a very common complication of particularly RDEB-sev gen . Tumors arise most commonly at sites of chronic wounding, regeneration or scarring, and as early as within the second decade of life - with further increasing frequency thereafter. This is complicated by a very aggressive course and extremely high rates of metastasis as well as recurrence. Referring to statistics provided by the U.S. National EB Registry, metastatic SCC is the primary cause of death in RDEB, occurring in the majority of patients with RDEB-sev gen . The cumulative risk of developing SCC and subsequent death in patients with RDEB-sev gen at age 55 is greater than 90% and 78%, respectively. Although data suggest repetitive tissue stress and remodeling, growth activation of keratinocytes, polymorphisms of matrix metalloproteinases and reduced activity of natural killer cells to promote malignant transformation either as a predisposing micro-environment or a distinct pathology, the exact pathogenic pathways involved in tumorigenicity hitherto remain largely unknown .
Extracutaneous involvement.Reflecting many biochemical and ultrastructural similarities shared with the skin, virtually any other organ lined or covered by epithelium may be affected by the pathogenic consequences operative in EB [7, 8, 9]. Blister formation, chronic non-healing wounds and scarring in extracutaneous tissues either primarily or secondarily result in significant morbidity and mortality. Time of onset and severity of extracutaneous complications vary considerably between the different DEB subtypes, and especially those patients suffering from RDEB-sev gen are most commonly and prominently affected by multi-systemic disease.
Extracutaneous involvement in RDEB includes:
* Oral cavity (e.g. microstomia, ankyloglossia, secondary tooth injury by excessive caries and premature loss).
* External eye (e.g. photophobia, corneal ulcerations; corneal pannus formation, limbal broadening; ectropion, symblephara and
* Gastrointestinal tract (e.g. esophageal webbing, stenoses and strictures, hernia, abnormal peristalsis, dysphagia, malabsorption
with nutritional compromise and growth retardation).
* Genitourinary tract (e.g. stenoses with dysuria, hypospadias, epispadias, glomerulonephritis, hydronephrosis, chronic renal
* Musculoskeletal system (e.g. acral deformities, muscular dystrophy, osteopenia and osteoporosis).
* The heart (e.g. cardiomyophathy due to malnutrition and micronutrient deficiency, chronic anemia, transfusion-associated iron
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 [16, 17]. 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 .
In RDEB- sev gen, mutations that result in premature termination codons (PTC) in both alleles (i.e. nonsense mutations or deletion, insertion and splice site mutations with frame shift of translation) result in nonsense mediated mRNA decay or residual expression of truncated polypeptides that are degraded within the cell . This leads to completely absent collagen type VII expression and total loss of AF, clinically manifesting with severe mutilating scarring and blistering.
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. Hand and foot deformities have to be treated surgically. SCCs are also treated surgically.
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