DISEASE CARD

Definition

Pachyonychia congenita (PC) (Greek: thick nails from birth) is a rare, autosomal dominant keratinization disorder, first described in the early nineteen hundreds.^{1, 2} It is characterized by hypertrophic nail dystrophy and ectodermal features. Historically, two subtypes have been distinguished, PC type 1 (Jadassohn-Lewandowski syndrome) and PC type 2 (Jackson-Lawler syndrome). Molecular analysis revealed mutations in one of the four keratin genes KRT6A, KRT6B, KRT16, or KRT17, to be pathogenic. The new nomenclature is linked to the affected gene, e.g., a patient with a mutation in KRT6A is now designated as subtype PC-6a.^3-6

Clinical Description

Onychodystrophy is the most prominent clinical feature observed in all PC variants, and consists of three abnormal findings: 1) hyperkeratosis of the nail bed; 2) thickening of the nail plate; 3) distortion or curvature of the nail plate. Hyperkeratosis of the nail bed generally appears in the first year or two of life. The nails are sometimes discoloured. Nail dystrophy often results in reduced fine motor skills (e.g., opening drinking cans). Nail loss and regrowth can be associated with infection^.7

All PC variants show focal palmoplantar keratoderma (PPK), which may be associated with frictional blisters on the feet especially in hot weather. The PPK is non-erythematous, usually more severe on the plantar surface, and may result in severe pain when walking. The keratoderma do not extend to the dorsal aspects of hand and feet.⁷

Follicular keratoses develops mainly on areas of friction, such as the elbows, knees and waistband. They show a tendency to improve with age.⁷

Oral leukokeratosis may be seen on the tongue and oral mucosa. Severe oral lesions sometimes resemble candidiasis. The oral findings are often present soon after birth and may be the first sign of PC.⁷

Cysts develop in PC patients rather frequently, including epidermal inclusion cysts, and pilosebaceous cysts, such as steatocystomas and vellus hair cysts. Epidermal inclusion cysts are variable in size and severity. The cysts have a punctum and contain a “cheesy” keratinous material, they can become painful, inflamed and infected. Pilosebaceous cysts are round to oval, flesh-colored to yellow papules without a visible punctum. They are located on the face, upper trunk and arms. PC-6b and PC-17 subtypes usually develop all types of cysts, whereas PC-6a and PC-16 subtypes do not develop steatocystomas or vellus hair cysts.^7-10

Laryngeal involvement may produce hoarseness, and in infancy occasionally presents as a life-threatening respiratory stridor requiring emergent tracheostomy. In patients in which laryngoscopy has been performed, the larynx demonstrates a white-to-pink thickening or an exophytic mass formation.^11-13

Some PC patients present with teeth at birth or during the first month of life. These teeth usually develop in the frontal position, they are soft, friable and prone to caries. They are usually lost within the first few months of life. These teeth are replaced by normal permanent teeth during childhood.⁷

Hair abnormalities are primarily found in PC-6b and PC-17 patients and include thickened or coarse hair that is sometimes brittle or curly. Pili torti (twisted hair) have been reported in association with PC-6b and PC-17.¹⁴

Pathogenesis

Tonofilament aggregates, seen on electron microscopy, point towards an intermediate filament disorder. The clinical phenotypes are associated with mutations in KRT6A, KRT6B, KRT16 and KRT17, with distribution of lesions corresponding to the expression patterns of these genes. Keratin 17, for example, is constitutively expressed in the pilosebaceous unit and basal appendage keratinocytes, with lesser basal expression in palmoplantar skin and a number of other minor epithelial populations. It is not expressed in mucosae. Since mutations in the KRT6B gene were found to phenocopy the KRT17 based phenotype, it was suggested that K6b is the partner of K17 in heterodimer formation and filament assembly.

Nearly all previously reported mutations underlying PC have affected one of the highly conserved peptide sequences at either end of the helical rod domain, the helix initiation motive (HIM) and the helix termination motive (HTM), respectively. Mutations in these motifs are highly disruptive to intermediate filament assembly. It has been speculated that mutations in the HTM could be more pathogenic in the larynx and that mutations in the HIM are more pathogenic in the hair.⁷ Furthermore, the non-HIM/HTM mutations may be associated with a late onset (PC tarda).^{15, 16} Identical mutations may produce distinct effects in different individuals, thus phenotype and severity depend on genetic background and environmental factors as well as the underlying mutation.

Diagnosis

The diagnosis of PC is primarily based on clinical assessment of the nail dystrophy, focal palmoplantar hyperkeratosis, and any other associated ectodermal features. Histopathology of palmoplantar epidermis shows gross hyperkeratosis with alternating ortho and parakeratosis. Acanthosis is present with patchy hypergranulosis. There is no gross epidermolysis. Natal or prenatal teeth indicate for PC-6b or PC-17, but the absence of this clinical feature does not automatically indicate a PC-6a or PC-16 subtpye. PC-6b and PC-17 patients usually develop all types of cysts, whereas PC-6a or PC-16 patients do not develop steatocystomas or vellus hair cysts. Molecular analysis is performed by sequencing KRT6A, KRT6B, KRT16 or KRT17.

Treatment

Emollients and keratolytics as well as mechanical debridement may help to treat keratoderma in milder cases. Treatment with oral retinoids is often unsatisfactory. Antibiotic therapy and surgical excision of infected axillary or pubic cysts may be necessary. Angular cheilosis frequently demonstrates secondary yeast infection, which may require topical antifungals.

References

^{1. Müller C. On the causes of congenital onychogryphosis. Münch Med Wochenschr. 1904;49:2180-2182.}

^{2. Jadassohn J, Lewandowsky F. Pachyonychia congenita, keratosis disseminata circumscripta (foliculosis): tylomata; leukokeratosis linguae. Ikonographica Dermatologica, Baltimore: Urbanand Schwarzenburg. 1906;629.}

^{3. Bowden PE, Haley JL, Kansky A, Rothnagel JA, Jones DO, Turner RJ. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet. 1995;10(3):363-365.}

^{4. Smith FJ, Jonkman MF, van Goor H, et al. A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum Mol Genet. 1998;7(7):1143-1148.}

^{5. McLean W, Rugg E, Lunny D, et al. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. 1995;9(3):273-278.}

^{6. McLean WI, Hansen CD, Eliason MJ, Smith FJ. The phenotypic and molecular genetic features of pachyonychia congenita. Journal of investigative dermatology. 2011;131(5):1015-1017.}

^{7. Leachman SA, Kaspar RL, Fleckman P, et al., editors. Clinical and pathological features of pachyonychia congenita. Journal of Investigative Dermatology Symposium Proceedings; 2005: Elsevier.}

^{8. Feinstein A, Friedman J, Schewach-Millet M. Pachyonychia congenita. J Am Acad Dermatol. 1988;19(4):705-711.}

^{9. Su WD, Chun SI, Hammond DE, Gordon H. Pachyonychia congenita: a clinical study of 12 cases and review of the literature. Pediatr Dermatol. 1990;7(1):33-38.}

^{10. Moon SE, Lee YS, Youn JI. Eruptive vellus hair cyst and steatocystoma multiplex in a patient with pachyonychia congenita. J Am Acad Dermatol. 1994;30(2):275-276.}

^{11. Cohn AM, McFarlane JR, Knox J. Pachyonychia congenita with involvement of the larynx. Archives of Otolaryngology. 1976;102(4):233-235.}

^{12. Benjamin B, Krisons DS, Molloy H. Pachyonychia congenita with laryngeal involvement. International journal of pediatric otorhinolaryngology. 1987;13(2):205-209.}

^{13. Wudy S, Lenders H, Pirsig W, Mohr W, Teller W. Diagnosis and management of laryngeal obstruction in childhood pachyonychia congenita. International journal of pediatric otorhinolaryngology. 1995;31(1):109-115.}

^{14. Munro C. editorial comment Pachyonychia congenita: mutations and clinical presentations. British Journal of Dermatology. 2001;144:929ą930.}

^{15. Connors J, Rahil A, Smith F, McLean W, Milstone L. Delayed‐onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. British Journal of Dermatology. 2001;144(5):1058-1062.}

^{16. Xiao S-X, Feng Y-G, Ren X-R, et al. A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset pachyonychia congenita type 2. Journal of investigative dermatology. 2004;122(4):892-895.}