Epidermolysis Bullosa Simplex, Autosomal Recessive
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA SIMPLEX GENERALIZED OTHERS|
|Synonymous||None (old synonyms may be confusing and should not be used any more)|
|Gene (s)||KRT5 (148040), KRT14 (148066), DST ( 113810)|
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-sydrome. 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 .
Epidermolysis bullosa simplex (EBS) is the most common type of EB. It can be further divided into basal and suprabasal subtypes with generalized and localized phenotypes, involving desmosomal genes, keratin genes, integrins and the plectin gene. EBS-autosomal recessive (EBS-AR) is a rare subtype within the EBS group. EBS-AR is predominantly caused by mutations in the KRT14 gene , but recessive mutations in the KRT5 gene have also been reported . A second autosomal recessive form of EBS, EBS-AR type-2, is caused by mutations in the dystonin (DST) gene [8, 9].
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.
All EBS subtypes are characterized by trauma- or friction- induced skin blistering with either localized or generalized distribution. With only rare exceptions, blisters arise within the basal cell layer of the epidermis. Onset of the disease is usually at birth or shortly after birth, except for localized patients, who often develop blisters not until late childhood or early adulthood. Localized variants can present with a very subtle phenotype and thus may be underdiagnosed. Unless there is a secondary infection, erosions usually heal without scarring, but may leave hyperpigmentation. Additional clinical features like nail dystrophy, nail shedding and alopecia, are usually uncommon within the entire EBS group compared to other forms of EB. Mucosal involvement is rarely seen. High ambient temperatures or sweating (summer) are often aggravating factors .
For EBS-AR, generalized  as well as localized  blistering has been reported. Onset of the disease is usually at birth. Milia are rare but atrophic scarring and dystrophic nails usually occur, along with focal palmoplantar keratoderma. Ichthyotic plaques are seen in rare cases. Extracutaneous involvement is common, including anemia, growth retardation, oral cavity abnormalities and constipation.
EBS-AR is caused by recessive mutations in the keratins KRT14 or KRT5, that are mostly expressed in the basal epidermal layer . It was suggested that the presence of abnormal keratin 5 or 14 proteins leads to dominant forms of EBS, whereas a total absence of these keratins leads to recessive forms .
Genetic testing reveals mutations in the KRT5, KRT14 or DST gene.
Management of all EBS variants starts with prevention of blister formation in everyday life, e.g., by appropriate foot wear and clothing. Large blisters can cause pain and should be opened, in order to release the pressure from surrounding tissue. When the skin at the roof of a blister has been removed, special wound care is necessary, using non adhesive dressings. Prevention of wound infection is paramount. Antibiotics, such as tetracyclines, have been reported to reduce blister formation in some EBS patients .
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