15 March 2005

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2386 East Heritage Way, Suite B, Salt Lake City, Utah 84109 USA Phone +1-877-628-7300 • Email—[email protected] www.pachyonychia.org Eur J Pediatr DOI 10.1007/s00431-008-0908-6

SHORT REPORT

Pachyonychia congenita type 2, N92S mutation of 17 : clinical features, mutation analysis and pathological view

Ozgur Cogulu & Huseyin Onay & Ayca Aykut & Neil J. Wilson & Frances J. D. Smith & Tugrul Dereli & Ferda Ozkinay

Received: 16 September 2008 /Accepted: 9 December 2008 # Springer-Verlag 2008

Abstract Pachyonychia congenita (PC) type 2 is a rare Introduction inherited genetic disease characterized by hypertrophic nail dystrophy, palmoplantar hyperkeratosis and multiple piloseba- Pachyonychia congenita (PC) is a very rare autosomal ceous cysts. In some cases, natal teeth and hair abnormalities dominant genetic disease mainly characterized by nail may be present. It is caused by mutations in or its dystrophy and palmoplantar keratoderma. It is caused by expression partner . Here, an N92S (p.Asn92Ser) the mutations in one of four keratin [4, 8]. Clinically, germline keratin 17 gene mutation in a pachyonychia PC is subdivided into two types; PC-1 and PC-2. PC-2 is congenita type 2 female patient is presented. The pedigree characterized by multiple pilosebaceous cysts which nor- includes the 15 members of a family who showed a severe mally develop during puberty, and sometimes natal teeth expression of the phenotype for six generations with a similar and hair abnormalities in addition to the characteristic clinical picture consisting of sebaceous cysts, nail dystrophy, findings such as palmoplantar hyperkeratosis and nail hyperkeratosis, hair abnormalities, natal teeth, hoarseness and dystrophy. While mutations in (KRT16) or hyperhydrosis. In conclusion, we emphasize the importance of (KRT6a) are associated with type 1, mutations diagnosing and managing pachyonychia congenita in child- in keratin 17 (KRT17) or keratin 6b (KRT6b) are associated hood for the assistance of affected children and for the with type 2. KRT17 is expressed in the nail bed, sebaceous development of potential therapies. glands, hair follicles and other epidermal appendages [10]; and the pathophysiology of the disorder is explained by the Keywords Pachyonychia congenita . Genetic testing . structural failure of the keratin. consist of an alpha- Phenotype helical rod domain with four helical segments (1A, 1B, 2A, 2B). To date, almost all mutations in PC have been reported within the highly conserved helix boundary domains at O. Cogulu (*) : A. Aykut : F. Ozkinay Department of Pediatrics, Ege University, Faculty of Medicine, either end of the alpha-helical rod domain of keratin [3]. 35100 Bornova, Izmir, Turkey Here, we describe a patient with PC-2 presenting the features e-mail: [email protected] of the disease which has been transmitted for six generations (Fig. 1). We discuss the importance of recognizing the H. Onay Medical Genetics, Ege University, Faculty of Medicine, features of PC patients and summarize the progress of this 35100 Bornova, Turkey rare disease throughout the childhood and adulthood.

N. J. Wilson : F. J. D. Smith Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, Case report University of Dundee, Dundee DD1 5EH, UK The proband was a 3-year-old female who was referred to the outpatient clinic for evaluation of a thickened nail T. Dereli Dermatology, Ege University, Faculty of Medicine, (Fig. 2). She had natal teeth at birth and was noticed to have 35100 Izmir, Turkey hoarseness at 1 month, dry and sparse hair and nail Eur J Pediatr

Fig. 1 Pedigree analysis of the family

discoloration at 2–3 months. She developed thickened and Discussion discoloured nails of all her fingernails and toenails in the first year of her life. Plantar skin became hyperkeratotic and To date, approximately 30 mutations in KRT17 have been thickened gradually after she was able to walk. She presented reported and all except one have been located in the helix with pinhead-sized yellowish sebaceous lesions at birth, initiation motif domain [8, 9]. The discussion about PC can followed by cystic nodules in the head and face at the end of mainly be summarized in three points which are (1) first year. Hyperhydrosis was reported on her palms and soles. variable age of onset of the features in the different family Physical examination showed sparse, dry and unruly hair, members and between the families, (2) majority of very small, soft yellowish sebaceous lesions and cysts on her mutations have been reported in the helix boundary face, trunk and knees, thickened nails on all of her fingers and domains, (3) genotype–phenotype correlation. The existence toes, palmar and plantar hyperkeratosis and hyperhydrosis. of this mutation in this family is particularly important from There was no lesion in the mucous membranes. She started to two aspects; firstly in defining the functionally critical regions complain of splitting of the nails and pain at age 2.5 years. of the keratin rod domain as suggested by Smith et al. [7], Light microscopy of plantar epidermis from the father showed secondly in bringing new insights into the genotype– plantar epidermal compact hyperkeratosis. Biopsy specimens phenotype correlation. It is known that the beginning of the of steatocysts revealed sebaceous glands within the cyst wall helix 1A and the end of the helix 2B are highly conserved in with collapsed empty cysts surrounded by squamous cells, sequence between keratins. Those regions also play the most epithelium with reflective hyaline cuticle and oval perinuclear critical role for the assembly of keratin dimers [4]. The inclusions in stratum spinosum (Fig. 3). Mutation analysis family members showed a very similar phenotype; therefore, revealed the substitution of asparagine by serine at codon 92 it may be speculated that the p.Asn92Ser mutation may have (p.Asn92Ser) located in the 1A domain of the K17 as caused a basic change in keratin assembly to form the pathological cause of the disorder in this family. All intermediate filaments. The severity of the clinical picture affected members of the family reported a similar history in the family which consists of almost all findings of PC-2 including hoarseness. Figure 2 summarises the views of the also support this hypothesis. The features such as hair proband’s and her father’s features. abnormalities, hoarseness, natal teeth and sebaceous cysts in Eur J Pediatr

a bc

d e f

g

Fig. 2 The views of (a–c) hairs and cysts, (d–g) nails and keratoderma both in the index patient and her father

PC-2 can show variable expression both between and within second decade [1, 6]. In the family presented, sebaceous members of PC families. In our family, the development and cysts developed early in the first year of life in almost all progress of the clinical picture of PC did not vary between members of the family with very mild changes. Hoarseness affected members. Although hair abnormalities such as pili is a rare finding in PC-2. In this family, it is defined in all torti, unruly hair, and hoarseness (some PC-1 suffer from members who also present another rare finding which is hoarseness) are rarely seen in PC-2, the affected members of natal teeth. Therefore, the relation between the occurrence of the presented family consistently showed these unusual natal teeth and laryngeal abnormality may need to be findings. Pilosebaceous cysts which have been reported to evaluated by further reports. The possible development of be indispensable in the diagnosis of PC-2 usually appear at the clinical features of the proband over time can be puberty [6]. It is speculated that the androgenic stimulation observed in Fig. 2 including both the views of the proband of the sebaceous gland, enviromental factors and the and father. characteristics of the mutation may be associated with the The correlation between clinical syndrome and the pair onset of sebaceous cysts [2]. However, there can be of genes involved has been reported to be highly consistent variability in development of cysts for example there are [5]. There may also be modifier genes which promote or reports of patients with the same mutation, p.Met88Thr, delay the onset of symptoms. Nevertheless, the presented where the onset of sebaceous cysts has been in the first year family shows an example of a clear correlation between the of life and in another in which cysts did not occur until the phenotype and genotype. Eur J Pediatr

Fig. 3 Pathological examina- tion of biopsy sample from the father. a Compact hyperkerato- sis, b collapsed empty cyst surrounded by squamous cell and sebaceous glands within the cyst wall, c the epithelium with reflective hyaline cuticle, d perinuclear inclusions in stratum spinosum

ab

cd

Acknowledgements FJDS and NJW are supported by grants from 4. McLean WH, Rugg EL, Lunny DP et al (1995) Keratin 16 and the Pachyonychia Congenita Project (http://www.pachyonychia.org) keratin 17 mutations cause pachyonychia congenita. Nat Genet and The Dystrophic Epidermolysis Bullosa Research Association UK. 9:273–278 We thank Dr Sancy A Leachman, University of Utah, Utah, USA, as 5. Munro CS (2001) Pachyonychia congenita: mutations and clinical PC Project consulting physician. We would like to thank to Ege presentations. Br J Dermatol 144:929–930 University Research and Education Center for providing financial 6. Oh SW, Kim MY, Lee JS, Kim SC (2006) Keratin 17 mutation in support. pachyonychia congenita type 2 patient with early onset steatocys- The authors declare that they have no conflict of interest. toma multiplex and Hutchinson-like tooth deformity. J Dermatol 33:161–164 7. Smith FJ, Coleman CM, Bayoumy NM et al (2001) Novel keratin References 17 mutations in pachyonychia congenita type 2. J Invest Dermatol 116:806–808 8. Smith FJ, Liao H, Cassidy AJ et al (2005) The genetic basis of 1. Celebi JT, Tanzi EL, Yao YJ et al (1999) Mutation report: pachyonychia congenita. J Investig Dermatol Symp Proc 10:21– identification of a germline mutation in keratin 17 in a family with 30 pachyonychia congenita type 2. J Invest Dermatol 113:848–850 9. Szeverenyi I, Cassidy AJ, Chung CW et al (2008) The Human 2. Feng YG, Xiao SX, Ren XR et al (2003) Keratin 17 mutation in Database: comprehensive information on a pachyonychia congenita type 2 with early onset sebaceous cysts. gene family involved in many human diseases. Hum Mutat Br J Dermatol 148:452–455 29:351–360 3. Liao H, Sayers JM et al (2007) A spectrum of mutations in 10. Troyanovsky SM, Guelstein VI, Tchipysheva TA et al (1989) keratins K6a, K16 and K17 causing pachyonychia congenita. J Patterns of expression of keratin 17 in human epithelia: Dermatol Sci 48:199–205 dependency on cell position. J Cell Sci 93(Pt 3):419–426