Hereditary palmoplantar keratodermas. Part I. Non‐syndromic palmoplantar keratodermas: classification, clinical and genetic features

Abstract

The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the epidermis of palms and soles and includes genetic as well as acquired conditions. We review the nosology of hereditary PPKs that comprise an increasing number of entities with different prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be divided into the following: (i) non-syndromic, isolated PPKs, which are characterized by a unique or predominant palmoplantar involvement; (ii) non-syndromic PPKs with additional distinctive cutaneous and adnexal manifestations, here named complex PPKs; (iii) syndromic PPKs, in which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis of the different hereditary PPKs is based mainly on clinical history and features combined with histopathological findings. In recent years, the exponentially increasing use of next-generation sequencing technologies has led to the identification of several novel disease genes, and thus substantially contributed to elucidate the molecular basis of such a heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where other well-defined genetic diseases, which may present PPK among their phenotypic manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are summarized.

Loss‐of‐function mutation in DSG1 underlies focal palmoplantar keratoderma

“…Based on the distribution pattern of hyperkeratotic lesions, PPKs are clinically classified into four types: diffuse, striate, focal and punctate. 1,2 To date, more than 20 genes have been reported to be responsible for PPKs. 1,2 Although the majority of reported heterozygous loss-of-function mutations in the gene encoding desmoglein 1 (DSG1), a key molecule for epidermal adhesion and differentiation, are associated with striate PPK, 3 a very limited number of studies have suggested that dominant DSG1 mutations also cause non-striate PPK.…”

Pain mechanisms in hereditary palmoplantar keratodermas

“…Palmoplantar keratodermas (PPKs) are rare skin disorders characterized by profound thickening of the skin, particularly on the palms of the hands and the soles of the feet, as a result of hyperkeratosis. PPKs can be acquired through malnutrition, inflammatory disease, paraneoplastic effects or chemical exposure, but are most commonly inherited . Gain‐ or loss‐of‐function mutations in at least 25 genes have been implicated in hereditary PPK, although the total may be substantially higher (https://panelapp.genomicsengland.co.uk/WebServices/list_panels/).…”

Alitretinoin in punctate palmoplantar keratoderma

“…D ear E ditor , Palmoplantar keratoderma punctata type 1 (PPKP1) (MIM 148600), also known as the Buschke–Fischer–Brauer type, is a hereditary disorder of keratinization, characterized by multiple hyperkeratotic papules with central indentation irregularly distributed on the palms and soles . The lesions gradually progress in size and number with age and can be painful during ambulation.…”

“…To date, there are no standardized treatments established for PPKP1 . Adequate therapies for the treatment of this disorder are necessary as palmar and plantar skin play critical functional and social roles.…”