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Inherited palmoplantar keratodermas are individually rare; the prevalence of epidermolytic keratoderma in Northern Ireland was 4.4 per 100,000.9 Autosomal recessive keratodermas may occur with locally high prevalence in sequestered populations or communities amongst whom consanguineous union is common.
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Palmoplantar skin is structurally specialized,10 with absence of hair and increased epidermal thickness and rugosity, features necessary to cope with increased friction and mechanical stress. Dermatoglyphics together with eccrine sweat also enhance grip. Localized palmoplantar hypertrophy (callus) is a physiological response to sustained friction, for example, from ill-fitting footwear or manual work. In the inherited PPKs, excessive epidermal thickening is the result of a broad range of pathogenic pathways.
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Many keratodermas are associated with defects of keratinocyte structure. The major structural component of keratinocytes is the 10-nm (intermediate) filament cytoskeleton. Keratins are a family of rod-like proteins, expressed in pairs in a tissue and differentiation specific manner, which initially dimerize then assemble to form multimeric intermediate filaments.7 Defects in individual keratins affect skin in a distribution corresponding to the expression pattern of the particular keratin.3 Keratin 9 (K9) is specific to palmoplantar skin, although its likely partner in these sites, keratin 1, is also expressed in hair-bearing skin. Other keratins constitutively or facultatively expressed in palmoplantar skin include K6, K16 (also found in mucosa, hair follicles, and nail bed), and K17 (hair follicles and nail bed11). There are multiple K6 isoforms,12,13 and defects in K6a, K6b, and K6c as well as all the other keratins named above can result in keratoderma. The majority of pathogenic mutations in keratins occur in the highly conserved boundary peptides of the α-helical rod domain regions, which are thought vital for end-to-end overlap interactions during the elongation phase of filament assembly....