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Review
. 2020 Mar;182(3):564-573.
doi: 10.1111/bjd.18033. Epub 2019 Jul 24.

Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment

Affiliations
Review

Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment

A G Zieman et al. Br J Dermatol. 2020 Mar.

Abstract

Background: Pachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm-derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy and very painful palmoplantar keratoderma (PPK). PC dramatically impacts quality of life although it does not affect lifespan. PC can arise from mutations in any of the wound-repair-associated keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. There is no cure for this condition, and current treatment options for PC symptoms are limited and palliative in nature.

Objectives: This review focuses on recent progress made towards understanding the pathophysiology of PPK lesions, the most prevalent and debilitating of all PC symptoms.

Methods: We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK.

Results: There are three main stages of progression of PPK-like lesions in Krt16 null mice. Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression. At the time of PPK onset, there is elevated oxidative stress and hypoactive Keap1-Nrf2 signalling. During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis.

Conclusions: The progress made suggests new avenues to explore for the treatment of PC-based PPK and deepens our understanding of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16 and KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts and oral leukokeratosis. The study of PC pathophysiology is made challenging because of its low incidence and high complexity. There is no cure or effective treatment for PC. What does this study add? This text reviews recent progress made when studying the pathophysiology of PPK associated with PC. This recent progress points to new possibilities for devising effective therapeutics that may complement current palliative strategies.

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Conflict of interest statement

Conflict of interest disclosures: None declared.

Figures

Figure 1:
Figure 1:
Palmoplantar keratoderma, a genetically heterogeneous disorder. (A) Photograph of PC-based PPK lesions from an individual with a KRT16 L124R mutation. Source: Pachyonychia Congenita Project (www.pachyonychia.org). (B) Table summarizing the diversity of genes which, when mutated, can elicit a PPK clinical presentation. Various clinical subtypes of PPK are accounted for. Additional references for table are 18,89–111. (C) Schematic of select mutations in keratin 16 (K16) protein that are causative for PC, focal non-epidermolytic PPK (FNEPPK), or both PC and FNEPPK. K16 exhibits the tripartite domain structure shared by all IF proteins, with a N-terminal “head” domain, central α-helical “rod” domain, and C-terminal “tail” domain. The central rod domain is comprised of heptad repeat-containing α-helical coils (1A, 1B, Coil 2) separated by non-heptad repeat linkers (L1 and L12). Many attributes of the central rod domain (see red bars) are highly conserved and represent a signature element among IF proteins. Representative mutations that are causative for FNEPPK are in blue text, mutations causative for PC are in gold text, and mutations that are causative for both FNEPPK and PC are in purple text.
Figure 2:
Figure 2:
Development of PPK-like lesions in Krt16 null footpad skin proceeds in three stages: Pre-PPK (at 2 weeks of age), Onset of PPK (at 4 weeks), and Active-PPK (at 8 weeks). (A) Representative histology of Krt16 null footpad skin at 2-, 4-, and 8-weeks of age. At 2 weeks, the epidermis shows a normal thickness and overall architecture but, upon closer inspection, alterations including the abnormal appearance of the granular layer, crowding of basal keratinocytes, and a decreased nuclear aspect ratio of basal keratinocytes can be seen. At 4 weeks, prior to macroscopic appearance of lesions, mild epidermal thickening is observed. By 8 weeks, there is dramatic thickening of the living epidermis and the stratum corneum, infiltration of immune cells, and limited suprabasal cell lysis. Dotted line is epidermal/dermal junction. Derm = dermis. Epi = epidermis, SC = stratum corneum. Scale bar = 100 μm. Images acquired using a Zeiss microscope with Apotome attachment and processed using Zen 2.3 software. (B) Summary of key molecular changes that occur at 2-, 4-, and 8-weeks of age in Krt16 null footpad skin. (C) Potential therapeutic interventions for each stage of lesion development (see refs. 35,37,39,77). SF = sulforaphane. DPN = Diarylpropionitrile.
Figure 3:
Figure 3:
Correlation of transcriptional changes between Krt16 null footpad lesions and human PC-based PPK lesions. (A-B) Correlation coefficients (R) calculated from pairwise comparisons of microarray data from Krt16 null footpad lesions and human PC-based PPK lesions resulting from mutations in KRT6 (A) or KRT16 (B). (C) Correlation coefficients calculated from pairwise comparisons between individual cases of PC-based PPK with either KRT6 or KRT16 mutations. A R value of −1 would convey perfect negative correlation, whereas a R value of 1 conveys perfect correlation between samples. P values for each correlation are denoted in purple text underneath the corresponding R values. Figure adapted from Zieman et al. (2019).

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