DISEASE CARD

Disease group Keratinization disorder
DISEASE NAME PACHYONYCHIA CONGENITA
Synonymous

Pachyonychia congenita type 1
Pachyonychia congenita type 2
Jadassohn-Lewandowsky syndrome
Jackson-Lawler syndrome

Estimated prevalence Unknown
OMIM 167200, 167210
Inheritance Autosomal dominant
Gene (s) KRT6A (148041), KRT6B (148042),
KRT16 (148067), KRT17 (148069)

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 associated 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 [4], KRT6B [5], KRT16 [5], or KRT17 [3], to be causally involved in the pathomechanism. Therefore, the new nomenclature referes to the affected gene, e.g., a patient with a mutation in KRT6A is now designated as subtype PC-6a [6].

Clinical Description

Onychodystrophy is the most prominent clinical feature observed in both 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 discolored. 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, which may be associated with frictional blisters on the feet especially in hot weather during childhood. Focal palmoplantar keratoderma 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 develop mainly on areas of friction, such as the elbows, knees and waistband. It is more accentuated in patients that crawl on their knees, in order to avoid plantar pain. The follicular keratoses often improve with age [7].

Oral leukokeratoses may be seen on the tongue and oral mucosa, with severe oral lesions sometimes resembling candidiasis. The oral findings are often present soon after birth and may be the first sign of PC [7].

Cysts often develop in PC patients, 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. The cysts 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, 8, 9, 10].

Laryngeal involvement may produce hoarseness, and in infancy occasionally presents as a life-threatening respiratory stridor requiring emergent tracheotomy [7]. In patients in which laryngoscopy has been performed, the larynx demonstrates a white-to-pink thickening or an exophytic mass formation [11, 12, 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 manifestations are primarily found in PC-6b and PC-17 patients. Hair abnormalities 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 suggest 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, ist 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 phenodopy the KRT17 based phenotype, it was suggested that K6b ist he partner of K17 in heterodimer formation and filament assembly.

Nearly all previously reported mutations which cause 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 [7, 8, 9, 10]. Molecular analysis is performed by sequencing KRT6A, KRT6B, KRT16 or KRT17.

Treatment

Emollients and keratolytics may help with keratoderma in milder cases. Regular paring of palmoplantar hyperkeratosis can be locally beneficial. Oral retinoids uptake (acitretin 25-35mg/day) makes the keratin more flexible and less pronounced without complete clearing, but treatment is often unsatisfactory and may be associated with side-effects. Rarely, laryngeal involvement may require assessment and treatment by laryngoscopy and tracheotomy. Antibiotic therapy and surgical excision of infected axillary or pubic cysts may be necessary. Angular chelosis frequently demonstrates secondary yeast infection with may require topical antifungals.

References

1
Müller C. (1904) On the causes of congenital onychogryphosis. Mcn Med Wochenschr 49:2180-2182.

2
Jadassohn J, Lewandowsky F. (1906) [Pachyonychia congenita. Keratosis disseminata circumscripta (follicularis). Tylomata. Leukokeratosis linguae] Urban and Schwarzenberg, pp29–30.

3
Bowden PE, Haley JL, Kansky A, Rothnagel JA, Jones DO, Turner RJ. (1995) Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet 10:363-365. Investig Dermatol Symp Proc 10:3-17.

4
LSmith FJD, Jonkmann MF, van Goor H, Coleman CM, Covello SP, Uitto J, McLean WH. (1998) A mutation in human keratin 6b produces a phenocopy of the K17 disorder pachyonoychia congenita type 2. Hum Molec Genet 7:1143-1148.

5
McLean WHI, Rugg EL, Lunny DP, Morley SM, Lane EB, Swensson O, Dopping-Hepenstal PJ, Griffiths WA, Eady RA, Higgings C, et al. (1995) Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 9:273-278.

6
McLean WHI, Hansen CD, Eliason MJ, Smith FJD. (2011) The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol 131:1015-1017.

7
Leachman SA, Kaspar RL, Fleckman P, Florell SR, Smith FJ, McLean WH, Lunny DP, Milstone LM, van Steensel MA, Munro CS, O'Toole EA, Celebi JT, Kansky A, Lane EB. (2005) Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc 10:3-17.

8
Feinstein A, Friedman J, Schewach-Millet M. (1988) Pachyonychia congenita. J Am Acad Dermatol 19:705–711.

9
Su WP, Chun SI, Hammond DE, Gordon H. (1990) Pachyonychia congenita: A clinical study of 12 cases and review of the literature. Pediatr Dermatol 7:33–38.

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

11
Cohn AM, McFarlane JR, Knox J. (1976) Pachyonychia congenita with involvement of the larynx. Arch Otolaryngol 102:233-235.

12
Benjamin B, Parsons DS, Molloy HF. (1987) Pachyonychia congenita with laryngeal involvement. Int J Pediatr Otorhinolaryngol 13:205–209.

13
Wudy SA, Lenders H, Pirsig W, Mohr W, Teller WM. (1995) Diagnosis and management of laryngeal obstruction in childhood pachyonychia congenita. Int J Pediatr Otorhinolaryngol 31:109–115.

14
Munro CS. (2001) Pachyonychia congenita: Mutations and clinical presentations. Br J Dermtol 144:929-930.

15
Connors JB, Rahil AK, Smith FJD, McLean WHI, Milstone LM. (2001) Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. Br J Dermatol 144:1058–1062.

16
Xiao SX, Feng YG, Ren XR, Tan SS, Li L, Wang JM, Shi YZ. (2004) A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset pachyonychia congenita type 2. J Invest Dermatol 122:892–895.