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Chapter 50. Inherited Palmoplantar Keratodermas

Mozheh Zamiri; Maurice A. M. van Steensel; Colin S. Munro

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Inherited Palmoplantar Keratodermas at a Glance1–8
  • Palmoplantar keratoderma (PPK) is chronic and pathological thickening, predominantly due to hyperkeratosis, of the hairless skin of palms and soles.
  • PPK may be acquired in inflammatory skin diseases such as eczema, psoriasis, and lichen planus, and has been reported as a paraneoplastic phenomenon.
  • Genetically determined PPKs are a heterogeneous group of individually rare disorders inherited by a variety of mechanisms or occurring sporadically.
  • PPK may form part of ectodermal syndromes or be associated with other systemic anomalies. Important associations of specific PPKs include cardiomyopathy, impaired hearing, neuropathy and neurodevelopmental defects, and esophageal cancer.
  • The mechanisms of inherited PPK include altered differentiation arising from defects in synthesis, distribution or function of structural components such as intermediate filaments, desmosomes and gap junction proteins, or altered inflammatory responses.
  • The severity of palmoplantar hyperkeratosis varies from inconvenience to major functional and social disability. Plantar pain in focal keratoderma is one of the most debilitating features, with hyperhidrosis and secondary dermatophyte infection contributing to symptoms.
  • Treatment is unsatisfactory, as it relies largely on physical treatments and appropriate foot care, but oral retinoids are of value in some cases.

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.

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.

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.3 Typically, ...

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