Clinical and Pathological Features of Pachyonychia Congenita

Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah 84112-5550, USA.
Journal of Investigative Dermatology Symposium Proceedings (Impact Factor: 3.73). 11/2005; 10(1):3-17. DOI: 10.1111/j.1087-0024.2005.10202.x
Source: PubMed


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.

40 Reads
  • Source
    • "Pachyonychia congenita is characterized by hypertrophic nail dystrophy and associated ectodermal features with subdivisions that have been suggested based on the clinical features [4] "
    [Show abstract] [Hide abstract]
    ABSTRACT: A 5-year-old female, known case of pachyonychia congenita, presented with diffuse hair loss; remaining hairs were easily plucked kinky hairs. Hair samples from patient were investigated using a light microscope. The hairs of the patients were mainly anagen hairs and unlike normal plucked anagen hairs, showed keratinization and cornification of their hair bulbs. No specific hair shaft abnormality was found.
    09/2012; 850658(2). DOI:10.1155/2012/850658
  • Source
    • "To our surprise, deletion of Krt16 produced spontaneously arising PPK-like lesions in mice, suggesting that PPK pathogenesis in PC is more complex than previously appreciated and may represent, at least in part, a loss of function phenotype. Almost all human PC patients harboring KRT16 mutations report PPK (Leachman et a, 2005, Liao et al, 2007, Fu et al, 2011). However, many mutations in KRT16 only elicit milder overall PC phenotypes, often diagnosed as FPPK because of the limited and at times absent nail involvement (Liao et al, 2007; Shamsher et al, 1995; Smith et al, 2000; Smith et al, 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Keratin 16 (KRT16 in human, Krt16 in mouse), a type I intermediate filament protein, is constitutively expressed in epithelial appendages and is induced in the epidermis upon wounding and other stressors. Mutations altering the coding sequence of KRT16 cause pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by hypertrophic nail dystrophy, oral leukokeratosis, and palmoplantar keratoderma (PPK). PPK associated with PC is extremely painful and compromises patient mobility, making it the most debilitating PC symptom. In this study, we show that, although inherited in a recessive manner, the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16(-/-) front and hind paws, which severely compromise the animals' ability to walk. Our findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms.
    Journal of Investigative Dermatology 02/2012; 132(5):1384-91. DOI:10.1038/jid.2012.6 · 7.22 Impact Factor
  • Source
    • "The phenotypic and mutational spectrum found in PC is reported by Wilson et al., 2011. For PC patients, the most painful, disabling feature is focal plantar keratoderma (Leachman et al., 2005; Liao et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pachyonychia congenita (PC) is a keratinizing disorder predominantly caused by mutations in keratin 6a (K6a) (∼50% of cases) or K6b, K16, or K17. One means of treating PC is identification of small-molecule inhibitors of PC-related keratins. Here, we cloned the human K6a promoter, and using a cell-based reporter gene assay, a chemical library was screened for K6a inhibitors. One compound, compactin, the precursor of all cholesterol-lowering statins, was of particular interest. We found that, surprisingly, simvastatin and other statins inhibit K6a promoter activity and K6a protein expression. Further investigation showed that this effect works through cholesterol/mevalonate pathway inhibition rather than an off-target effect. Inhibition of both basal and IFN-γ-inducible K6a expression by statins was demonstrated. Both these K6a inhibitory effects were found to be mediated by Stat1 transcription factor, but only the IFN-γ-inducible promoter activity was controlled via the Stat/JAK pathway. The repressive effect of statins was found to be mediated by the isoprenoid pathway downstream of mevalonate (the intermediate following 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) but upstream of cholesterol, specifically the geranylgeranylation pathway. These data set the scene for further unraveling signaling pathways that control the K6a promoter, as well as facilitating clinical trials for statins in PC patients.
    Journal of Investigative Dermatology 03/2011; 131(5):1045-52. DOI:10.1038/jid.2011.41 · 7.22 Impact Factor
Show more