Pain Mechanisms in Hereditary Palmoplantar Keratodermas

R.L. Weinberg; P.A. Coulombe; M. Polydefkis; M.J. Caterina

Disclosures

The British Journal of Dermatology. 2020;182(3):543-551. 

In This Article

Abstract and Introduction

Abstract

Background: Palmoplantar keratodermas (PPKs) are a heterogeneous group of skin disorders characterized by thickening of the epidermis on the palms of the hands and soles of the feet. Individuals with PPKs report varying degrees of palmoplantar pain that can severely affect quality of life.

Objectives: To provide an overview of the scope of pain in hereditary PPKs and highlight candidate mechanisms underlying this pain.

Methods: In this review, we discuss several forms of hereditary PPKs, with a focus on the incidence, nature, candidate underlying mechanisms and treatment of pain in these conditions. We also synthesize this information with current understanding of the mechanisms contributing to pathological pain in other conditions.

Results: Pain is a major problem for many, but not all individuals with hereditary PPK. This pain remains poorly understood, inconsistently reported and inadequately treated. The heterogeneity of pain prevalence and presentations across the many forms of PPK suggests that there may exist corresponding heterogeneity in the cellular and molecular mechanisms that drive and shape PPK-associated pain. Some candidate mechanisms include structural (e.g. fissures and blisters), infectious and immune/inflammatory processes. However, a growing body of evidence also supports the occurrence of localized neuropathic alterations in the affected skin of individuals with PPK, which might contribute to their pain.

Conclusions: Greater understanding of these diverse mechanisms may provide a rational basis for the development of improved and targeted approaches to prevention and treatment of pain in individuals with PPK.

Introduction

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.[1–4] Gain- or loss-of-function mutations in at least 25 genes have been implicated in hereditary PPK,[5] although the total may be substantially higher (https://panelapp.genomicsengland.co.uk/WebServices/list_panels/). Examples include genes encoding ion channels, secreted proteins, adhesion molecules and keratins.[5] Pain can be a prominent symptom of PPK and can significantly impact quality of life. Despite similar histological presentations, some forms of PPK are more consistently associated with pain than others. However, the rarity of PPK makes gathering data on pain prevalence difficult, and pain is not always addressed in case reports. This review focuses on candidate mechanisms underlying pain in PPK (Figure 1) and describes a few PPKs that exemplify the spectrum of pain phenotypes seen in these conditions.

Figure 1.

Potential sources of pain in palmoplantar keratoderma (PPK) skin. (a) Structural lesions seen in some patients with painful PPK. Black fibres represent nociceptors in basal state. Red fibres represent nociceptors sensitized by the injury associated with fissures or blisters. (b) Cell types that might contribute to either the development of pain or touch-evoked allodynia in PPK skin. Arrows represent soluble factors released by the indicated cell types that could sensitize nociceptive neurons. Nociceptive neurons can be sensitized (to augment pain sensation) or injured (i.e. rendered neuropathic) by either extrinsic factors emanating from the indicated cell types or by intrinsic factors such as PPK-associated gene mutations. Sensitized or neuropathic nociceptors in turn sensitize spinal cord and brain circuits, which make inputs from low-threshold mechanoreceptors feel painful. Epi, epidermis; Derm, dermis.

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