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Arch Dermatol Res (2008) 300:211 214 DOI 10.1007/s00403-008-0840-7 CASE STUDY Recurrent mutation in keratin 17 in a large family with pachyonychia congenita type 2 Carol Oh Adib Brad Jones Haihui Liao Frances J. D. Smith Rustum Solomon Conleth A. Egan Sancy Leachman Received: 3 November 2007 / Revised: 28 December 2007 / Accepted: 13 February 2008 / Published online: 18 March 2008 Springer-Verlag 2008 Introduction Pachyonychia congenita (PC) is a rare autosomal dominant syndrome associated with a constellation of physical Wndings of variable penetrance. It is subdivided into two major groups, termed PC1 (Jadassohn and Lewandowski) and PC2 (Jackson and Lawler). The term pachyonychia congenita was coined in a 1906 article by Jadassohn and Lewandowski of a patient with nail dystrophy, plantar keratoderma, oral leukokeratosis and abnormal skin keratinisation [12]. In 1951, Jackson and Lawler described PC2, in which three generations of a family demonstrated skin cysts and natal teeth in addition to nail dystrophy, palmoplantar keratoderma, palmoplantar hyperhidrosis and follicular keratosis [11]. It is now recognized that both types of pachyonychia congenita are disorders of keratin genes involving K6a or K16 in PC1 and K6b or K17 in PC2 [3, 16, 21, 23]. The diagnosis of pachyonychia congenita may at times be diycult as it shares several features in common with various disorders of ectodermal dysplasia, such as C. Oh Adib (&) B. Jones C. A. Egan Department of Dermatology, Our Lady of Lourdes Hospital, Drogheda, Ireland e-mail: caroloh@bigpond.net.au H. Liao F. J. D. Smith Epithelial Genetics Group, Human Genetics Unit, Pathology and Neuroscience, University of Dundee, Ninewells Hospital, Dundee, UK R. Solomon Department of Pathology, Our Lady of Lourdes Hospital, Drogheda, Ireland S. Leachman Department of Dermatology, University of Utah, Salt Lake City, Utah, USA Clouston syndrome, which has been misdiagnosed as pachyonychia congenita [27]. Indeed, most clinical features of PC have been based primarily on a compilation of case reports and small case series of PC patients that have not been mutation tested. In order to avoid future diagnostic confusion, correlation of accurate phenotype with genotype is imperative in distinguishing future cases of pachyonychia congenita from other disorders. This report contributes a careful, comprehensive assessment of the clinical and pathological features of PC in a genotypically dewned K17 mutation carrier and family members. Case report We report a case of pachyonychia congenita type 2 (Jackson- Lawler) in a father and daughter, within a large family pedigree (Fig. 1). The proband, a 19-year old female, presented with nail dystrophy of all Wngernails and toenails from early childhood (Fig. 2a). There was subungual hyperkeratosis of Wngernails with yellow grey discolouration. The thumb, index, middle Wngers and all toenails were most severely avected. Further examination revealed multiple skin-coloured cysts scattered over trunk and limbs, being most pronounced in the axillae and groin, Wrst appearing in puberty. They varied in size from 0.5 to 2 cm; they sometimes became inxamed and ruptured. Other features of pachyonychia congenita were noted: focal palmoplantar hyperkeratosis, follicular keratosis and sparse but protuberant eyebrows. The 46-year old father of the proband revealed more severe signs of pachyonychia congenita. He reported a similar timeline sequence of events, with nail dystrophy in early childhood and cysts appearing at puberty. All Wngernails and toenails were markedly thickened (Fig. 2b). Cysts were present on the trunk and limbs (Fig. 3), once again
212 Arch Dermatol Res (2008) 300:211 214 Fig. 1 Pedigree of pachyonychia congenita type 2. Squares indicate males, and circles, females. Blackened symbols are avected individuals. The proband is indicated by a slash. The asterisks indicate individuals born with natal teeth Fig. 2 a Dystrophy of all toenails with subungual hyperkeratosis in the daughter b Marked dystrophy avecting all toenails in the father being most prominent in the axillae. In addition, he had oral leukokeratosis (unlike the daughter), protuberant eyebrows and focal palmoplantar keratoderma with occasional blistering of the soles. Both father and daughter experienced palmoplantar hyperhidrosis, with maceration in summer months. Neither father nor daughter was born with natal or pre-natal teeth. There was a strong family history over four generations, of nail dystrophy, palmoplantar keratoderma, and cysts, with two of the XX avected family members being born with natal teeth. Natal teeth were not consistently present, nor was oral leukokeratosis in this family. There was no skeletal abnormality, ocular abnormality, deafness, learning disability or major medical problems identiwed in the extended pedigree to suggest other diagnoses of ectodermal dysplasia; there was no evidence of laryngeal oedema or respiratory stridor being reported. Excisional biopsies were taken from axillary and truncal cysts from the 19-year old female. Histological examination of both specimens revealed similar features of a cyst wall comprising two to three layers of epithelial cells. Embedded within the cyst walls were Xattened sebaceous gland lobules. No granular layer was noted, and in some areas, a homogenous horny layer protruded into the lumen. These features were consistent with a steatocystoma. A blood sample and buccal swab was sent for genotyping and DNA was isolated using a standard procedure, with informed consent and appropriate ethical approval. K6b and K17 genes were ampliwed by long-range PCR, using primers speciwc to the respective functional genes to avoid ampliwcation of additional K6 genes or K17 pseudogenes. The primer pairs and conditions were as reported previously [22]. PCR products were puriwed for sequencing using QIA quick PCR puriwcation kit (Qiagen, Crawley, UK) and sequenced using internal primers. Sequencing ladders were analyzed on an ABI 377 or 3100 automated DNA sequencers, according to manufacturer s instructions. Genetic testing revealed a mutation, p.m88t (c.263t > C), in keratin 17, reported in two previous cases [4, 18]. Discussion Fig. 3 Multiple trunkal cysts in the father, increasing in number with age The main features of pachyonychia congenita (PC) in general, are nail dystrophy, palmoplantar hyperkeratosis and hyperhidrosis with or without bullae, oral leukokeratosis and follicular keratosis [7]. In diverentiating PC1 from PC2, the best indicator of PC2 is the presence of steatocystomas, and sometimes natal teeth and pili torti or protuberant eyebrows [23]. In PC2, nail dystrophy usually presents in early childhood, followed by skin cysts at puberty, although sebaceous cysts have been reported at the age of one [5, 8]. The unifying features, almost always present in both PC1 and PC2, are pachyonychia (thickening of the
Arch Dermatol Res (2008) 300:211 214 213 nail), and painful plantar keratoderma [13]. Pachyonychia may be due to thickening of the nail plate, the hyponychium or nail bed [1]. Several less established features have also been described: angular cheilosis and exophytic lesions in the posterior commissure of the larynx causing hoarseness [2, 13]. The occurrence of hidradenitis suppurativa in PC2 may be explained by a keratin mutation involving pilosebaceous glands leading to apocrine occlusion [24]. Rare signs (and possibly incorrectly associated with PC) are corneal dyskeratosis, cataracts, mental retardation and alopecia [7], none of which were seen in this pedigree. Late onset PC or pachyonychia congenita tarda describes nail dystrophy and palmoplantar keratoderma arising in the third and fourth decades [10, 14]. Our case demonstrated typical features of PC2 in the absence of ocular and skeletal abnormalities, deafness and mental retardation, excluding disorders of ectodermal dysplasia, occasionally be confused with PC [27]. We were able to conwrm the PC2 phenotype by genotyping; it is important to do this, as not only does it add to our database of mutations causing PC2, but it also prevents confusion of PC2 from other disorders with overlapping signs of nail dystrophy and keratoderma. The abnormalities in PC are attributable to mutations in the keratin genes. It is known that K6a or K16 mutations lead to the PC1 phenotype, whereas K6b or K17 mutations cause the PC2 phenotype [3, 16, 21, 23]. The distribution of K17 in pilosebaceous and glandular structures may account for cyst formation and protuberant eyebrows in PC2 [25, 26]. Oral epithelia predominantly express K6a and K16, therefore oral leukokeratosis is predominantly a type 1 feature; the expression of all four keratins in the nail explains why this is common to both types of PC [15]. Despite having complete penetrance, the expressivity of PC2 is variable and often age-dependent. There also appears to be genetic heterogeneity between and within families in the histology of cyst type: epidermoid cysts, eruptive vellus hair cysts and steatocysts [4, 27]. Similar to our case, a K17 mutation (M88T) was found in two other families with clinical features of PC2 [22, 27]. Mutations in K17 can cause either PC2, or a phenotype resembling familial steatocystoma multiplex with little or no nail changes [6, 9, 19]. Mutations in K16 causing PC1 also demonstrate phenotypic variation depending on environmental factors, such trauma in aggravating plantar hyperkeratosis [20]. Occasionally, phenotypic features overlap beyond typical PC1 and PC2 boundaries, as reported by Ward et al. [28] in which a PC1 patient developed steatocysts. Research of the literature brings to awareness that there is great variation or heterogeneity in the phenotype of PC2, being dependent upon environmental and genetic factors and the underlying mutation [17]. The variation in phenotype presents diyculty in classifying signs as belonging to, or separate from the syndrome. This is highlighted by the variety of cyst types found in PC, varying even amongst individuals bearing the same genetic mutation. This case report is valuable in providing an accurate account of the positive features of PC2 conwrmed by genotyping. Only by reporting accurate cases with both complete phenotype and genotype, can a good meta-analysis ever be performed for such a rare disorder. Acknowledgments We would like to thank PC Project and DEBRA UK. Support for genetic testing and phenotypic characterization was obtained through PC Project, a U.S. 501(c)(3) public charity founded to develop a cure for pachyonychia congenita. The Epithelial Genetics Group is supported by the Pachyonychia Congenita Project (FJDS) and DEBRA UK. References 1. Achten G, Wanet-Rouard J (1970) Pachyonychia. Br J Dermatol 83:56 62 2. Benjamin B, Parsons DS, Molloy HF (1987) Pachyonychia congenita with laryngeal involvement. Int J Pediatr Otorhinolaryngol 13:205 209 3. Bowden PE, Haley JL, Kansky A et al (1995) Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet 10:363 365 4. Celebi JT, Tanzi EL, Yao YJ et al (1999) IdentiWcation of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. J Invest Dermatol 113:848 850 5. Clementi M, Cardin de Stefani E, Dei Rossi C et al (1986) Pachyonychia congenita Jackson-Lawler type: a distinct malformation syndrome. Br J Dermatol 114:367 370 6. Covello SP, Smith FJD, Sillevis Smitt JH et al (1998) Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Br J Dermatol 139:475 480 7. Feinstein A, Friedman J, Schewach-Miller M (1988) Pachyonychia congenita. J Am Acad Dermatol 19:705 711 8. Feng YG, Xiao SX, Ren XR et al (2003) Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts. Br J Dermatol 148:452 455 9. Giustini S, Amorosi B, Canci C et al (1998) Pachyonychia congenita with steatocystoma multiplex. A report of two cases and a discussion of the classiwcation. Eur J Dermatol 8:158 160 10. Hannaford R, Stapleton K (2000) Pachyonychia congenita tarda. Australas J Dermatol 41:175 177 11. Jackson ADM, Lawler SD (1951) Pachyonychia congenita: a report of six cases in one family. Ann Eugen 16:141 146 12. Jadassohn J, Lewandowski F (1906) Pachyonychia congenita. Keratosis disseminata circumscripts (follicularis). Tylomata. Leukokeratosis linguae. In: Neisser A, Jacobi E (eds) Konographia dermatologica, vol. 1. Urban and Schwarzenberg, Berlin, pp 29 31 13. Leachman SA, Kaspar RL, Fleckman P et al (2005) Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc 10:3 17 14. Lucker GPH, Steijlen PM (1995) Pachyonychia congenita tarda. Clin Exp Dermatol 20:226 229 15. McGowan KM, Coulombe PA (2000) Keratin 17 expression in the hard epithelial context of the hair and nail, and its relevance for the pachyonychia congenita phenotype. J Invest Dermatol 114:1104 1107 16. McLean WHI, Rugg EL, Lunny DP et al (1995) Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 9:273 278
214 Arch Dermatol Res (2008) 300:211 214 17. Munro CS (2001) Pachyonychia congenita: mutations and clinical presentations. Br J Dermatol 144:929 930 18. Oh SW, Kim MY, Lee JS et al (2006) Keratin 17 mutation in pachyonychia congenital type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity. J Invest Dermatol 3:161 164 19. Smith FJD, Corden LD, Rugg EL et al (1997) Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J Invest Dermatol 108:220 223 20. Smith FJD, Fisher MP, Healy E et al (2000) Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp Dermatol 9:170 177 21. Smith FJD, Jonkman MF, van Goor H et al (1998) A mutation in human keratin K6b produces a phenocopy of the K17 disorder pschyonychia congenita type 2. Hum Mol Genet 7:1143 1148 22. Smith FG, Liao H, Cassidy AJ et al (2005) The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc 10:21 30 23. Terrinoni A, Smith FJD, Didona B et al (2001) Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J Invest Dermatol 117:1391 1396 24. Todd P, Garioch J, Rademaker M et al (1990) Pachyonychia congenita complicated by hidradenitis suppurativa: a family study. Br J Dermatol 23:663 666 25. Troyanovsky SM, Guelstein VI, Tchipysheva TA et al (1989) Patterns of expression of keratin 17 in human epithelia: dependency on cell position. J Cell Sci 93:419 426 26. Troyanovsky SM, Leube RE, Franke WW (1992) Characterization of the human gene encoding cytokeratin 17 and its expression pattern. Eur J Cell Biol 59:127 137 27. Van Steensel MA, Jonkman MF, Van Geel M et al (2003) Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol 121:1035 1038 28. Ward KM, Cook-Bolden FE, Christiano AM et al (2003) IdentiWcation of a recurrent mutation in keratin 6a in a patient with overlapping clinical features of pachyonychia congenita types 1 and 2. Clin Exp Dermatol 28:434 436