Clinical and Pathological Features of Pachyonychia Congenita

Abstract

Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.

Keratin 16 regulates innate immunity in response to epidermal barrier breach

“…Inherited dominant mutations in KRT6, KRT16, and KRT17 are causative for pachyonychia congenita (PC), a clinically heterogeneous disorder characterized by dystrophic nails and hyperkeratotic lesions in glabrous skin and oral epithelia (13). In mice, loss of Krt16, but not Krt6a/b or Krt17, results in prominent, chronic lesions on front and hind paws that closely resemble palmoplantar keratoderma (PPK) in PC patients (14).…”

Hedgehog Signaling, Keratin 6 Induction, and Sebaceous Gland Morphogenesis

“…In addition to better mouse models, however, resolution of this issue awaits a better understanding of cellular homeostasis in mature SGs. As a side note, the frequent occurrence of steatocystoma lesions and, though in a rare manner, of premature tooth eruption 19,20 lends further credence to the notion that K6 protein(s) (and their partners) may fulfill roles other than structural support in epithelia. In this vein, the positive role of K17 16 and other skin keratins 87 toward the regulation of protein synthesis could be enhanced by mutations in K6 isoforms, and/or in K17.…”

“…3,7,18 A puzzling element that is frequently (Ͼ50%) associated with mutations in K6a, K6b and K17 is the development of epithelial cysts, generally, at the time of puberty. 19,20 Other than steatocystoma multiplex, a "pure" glandular disorder, epidermal inclusion cysts are seen in type 1 and type 2 pachyonychia congenita, while vellus hair cysts and steatocystomas are additionally seen in type 2 pachyonychia congenita. 20 The content of these cysts bear a resemblance to sebaceous glands (SGs); in the case of steatocystoma multiplex they are believed, in fact, to originate from SG ducts.…”

“…19,20 Other than steatocystoma multiplex, a "pure" glandular disorder, epidermal inclusion cysts are seen in type 1 and type 2 pachyonychia congenita, while vellus hair cysts and steatocystomas are additionally seen in type 2 pachyonychia congenita. 20 The content of these cysts bear a resemblance to sebaceous glands (SGs); in the case of steatocystoma multiplex they are believed, in fact, to originate from SG ducts. 20 -22 There is no molecular rationale, at present, for the development and proliferation of cysts in the skin of individuals bearing mutations in those keratin genes.…”

siRNA silencing of keratinocyte-specific GFP expression in a transgenic mouse skin model

“…Pachyonychia congenita is an autosomal dominant disorder caused by mutations (often single-nt changes) in the KRT6, KRT16 and KRT17 genes, resulting in thickened dystrophic nails, leukokeratosis and hyperkeratosis with painful blistering. 12,13 The outcome of the clinical trial included improvement at the site of siRNA treatment, but not the paired control injection site on the opposite foot receiving vehicle alone. Importantly, no adverse events were observed.…”