Epidermolysis Bullosa Simplex, generalized severe
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED SEVERE (formerly: EBS-Dowling Meara)|
|Synonymous||None (old synonyms may be confusing and should not be used any more)|
|Gene (s)||KRT5 (148040), KRT14 (148066)|
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. Within the EBS group, EBS-generalized severe is one of the most severe subtypes. It is a phenotypically generalized form of a basal subtype, caused by mutations in KRT5 or KRT14 [1, 2].
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 .
EBS-generalized severe is a generalized form of EBS with blister formation on the entire skin surface. It is frequently associated with marked morbidity and in rare cases may result in death during infancy . Small blisters or intact vesicles appear in a grouped or arc-like configuration. This appearance is similar to herpes-simplex like lesions, which explains the originally term “EB-herpetiformis” . Although EBS-generlaized severe is one of the more severe forms within the EBS group, it is most severe during childhood and ameliorates with adulthood. By late childhood, many EBS-generalized severe patients develop hyperkeratosis on the palms and soles which may resolve partially with mid- to late adulthood. A tracheolaryngeal compromise is the only extracutaneous complication in EBS, and is only seen in rare cases of EBS-generalized severe [8, 9].
EBS-generalized severe is usually caused by dominant negative missense muations in KRT5 and KRT14 genes that are mostly expressed in the basal epidermal layer . Phenotype-genotype analysis revealed that mutations affecting conserved areas at the N-terminal and C-terminal regions of the central alpha-helical rod domain of keratin molecules are usually associated with a more severe clinical phenotype, due to impairment of keratin filament assembly and disruption of the intermediate filament cytoskeleton upon trauma. Mutations affecting less conserved areas, like the head or tail domain commonly cause a milder phenotype, although many exceptions from this rule have also been reported [10, 11, 12]. Disease severity is further influenced by homozygosity (severe manifestations) or heterozygosity (milder manifestations) of the genetic defect as well as the kind of point mutation.
Ultrastructural findings in EBS-generalized severe are cell vacuolization, keratin filament clumping, cytolysis and blister formation . In in vitro experiments, the involvement of IL-1 β-induced stress pathways has been shown recently , as well as an overexpression of chemokines and matrix degrading enzymes . Phenotypic improvement with age in some EBS variants has been described. Possible mechanisms are compensatory overexpression of keratins such as KRT15, somatic genetic events (revertant mosaicism) , and the influence of silent sequence alterations on phenotypic manifestations of the EBS causing mutations .
Clinically, patients show generalized, herpetiform blister formation. Skin biopsies, taken from the leading edge of a fresh blister, can be analyzed immunohistochemically or using electron microscopy and show splitting within or just above the basal cell layer. Genetic testing reveals mutations in KRT5 or KRT14 genes.
Management of EBS-generalized severe starts with prevention of blister formation in everyday life by appropriate foot wear and clothing. Large blisters, especially on the soles, 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 . Treatment with botulinum toxin during summer season also showed ameliorating effects, due to reduction of hyperhidrosis . Keratinolytics can be applied to treat palmoplantar keratoderma. The anti-inflammatory drug Diacerein has been tested in a pilot study with EBS-generalized severe patients and showed promising effects .
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