Epidermolysis Bullosa Simplex, with Mottled Pigmentation
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION|
|Synonymous||None (old synonyms may be confusing and should not be used any more)|
|Gene (s)||KRT5 (148040)|
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 with mottled pigmentation is a rare subtype within the EBS group. It is characterized by generalized blistering and mottled or reticulate brown pigmentation, caused by mutations in KRT5 [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 with mottled pigmentation is characterized by congenital mottled appearance of the skin. Blistering is similar to EBS-generalized intermediateand mostly affects the limbs and the trunk. Blistering is often accompanied by mild nail dystrophy and focal palmoplantar keratoderma. Milia are rarely seen. Onset of the disease is usually at birth or during infancy.
EBS with mottled pigmentation is caused by dominant negative mutations in the KRT5 gene, that is 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, as seen in EBS-generalized severe, 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 [8, 9, 10]. EBS with mottled pigmentaion is strongly associated with a missense mutation (p.P25L) affecting the KRT5 head domain . This aberration is suggested to impair melanin granule aggregation and keratin filament function by interfering with post-translational processing. Other data, however, suggest the same phenotype to result from other mutations in KRT5 and KRT14 or unrelated genes like plectin .
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 blister formation predominantly on the trunk and limbs, and a mottled or reticulate brown pigmentation. 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 the KRT5 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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