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DOI 10.1007/s00431-008-0908-6 SHORT REPORT Pachyonychia congenita type 2, N92S mutation of keratin 17 gene: 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 inherited genetic disease characterized by hypertrophic nail dystrophy, palmoplantar hyperkeratosis and multiple pilosebaceous cysts. In some cases, natal teeth and hair abnormalities may be present. It is caused by mutations in keratin 17 or its expression partner keratin 6b. Here, an N92S (p.asn92ser) germline keratin 17 gene mutation in a pachyonychia congenita type 2 female patient is presented. The pedigree includes the 15 members of a family who showed a severe expression of the phenotype for six generations with a similar clinical picture consisting of sebaceous cysts, nail dystrophy, hyperkeratosis, hair abnormalities, natal teeth, hoarseness and hyperhydrosis. In conclusion, we emphasize the importance of diagnosing and managing pachyonychia congenita in childhood for the assistance of affected children and for the development of potential therapies. Keywords Pachyonychia congenita. Genetic testing. Phenotype O. Cogulu (*) : A. Aykut : F. Ozkinay Department of Pediatrics, Ege University, Faculty of Medicine, 35100 Bornova, Izmir, Turkey e-mail: ozgur.cogulu@ege.edu.tr H. Onay Medical Genetics, Ege University, Faculty of Medicine, 35100 Bornova, Turkey N. J. Wilson : F. J. D. Smith Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK T. Dereli Dermatology, Ege University, Faculty of Medicine, 35100 Izmir, Turkey Introduction Pachyonychia congenita (PC) is a very rare autosomal dominant genetic disease mainly characterized by nail dystrophy and palmoplantar keratoderma. It is caused by the mutations in one of four keratin genes [4, 8]. Clinically, PC is subdivided into two types; PC-1 and PC-2. PC-2 is characterized by multiple pilosebaceous cysts which normally develop during puberty, and sometimes natal teeth and hair abnormalities in addition to the characteristic findings such as palmoplantar hyperkeratosis and nail dystrophy. While mutations in keratin 16 (KRT16) or keratin 6a (KRT6a) are associated with type 1, mutations in keratin 17 (KRT17) or keratin 6b (KRT6b) are associated with type 2. KRT17 is expressed in the nail bed, sebaceous glands, hair follicles and other epidermal appendages [10]; and the pathophysiology of the disorder is explained by the structural failure of the keratin. Keratins consist of an alphahelical 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 either end of the alpha-helical rod domain of keratin [3]. Here, we describe a patient with PC-2 presenting the features of the disease which has been transmitted for six generations (Fig. 1). We discuss the importance of recognizing the features of PC patients and summarize the progress of this rare disease throughout the childhood and adulthood. Case report The proband was a 3-year-old female who was referred to the outpatient clinic for evaluation of a thickened nail (Fig. 2). She had natal teeth at birth and was noticed to have hoarseness at 1 month, dry and sparse hair and nail
Fig. 1 Pedigree analysis of the family discoloration at 2 3 months. She developed thickened and discoloured nails of all her fingernails and toenails in the first year of her life. Plantar skin became hyperkeratotic and thickened gradually after she was able to walk. She presented with pinhead-sized yellowish sebaceous lesions at birth, followed by cystic nodules in the head and face at the end of first year. Hyperhydrosis was reported on her palms and soles. Physical examination showed sparse, dry and unruly hair, very small, soft yellowish sebaceous lesions and cysts on her face, trunk and knees, thickened nails on all of her fingers and toes, palmar and plantar hyperkeratosis and hyperhydrosis. There was no lesion in the mucous membranes. She started to complain of splitting of the nails and pain at age 2.5 years. Light microscopy of plantar epidermis from the father showed plantar epidermal compact hyperkeratosis. Biopsy specimens of steatocysts revealed sebaceous glands within the cyst wall with collapsed empty cysts surrounded by squamous cells, epithelium with reflective hyaline cuticle and oval perinuclear inclusions in stratum spinosum (Fig. 3). Mutation analysis revealed the substitution of asparagine by serine at codon 92 (p.asn92ser) located in the 1A domain of the K17 protein as the pathological cause of the disorder in this family. All affected members of the family reported a similar history including hoarseness. Figure 2 summarises the views of the proband s and her father s features. Discussion To date, approximately 30 mutations in KRT17 have been reported and all except one have been located in the helix initiation motif domain [8, 9]. The discussion about PC can mainly be summarized in three points which are (1) variable age of onset of the features in the different family members and between the families, (2) majority of mutations have been reported in the helix boundary domains, (3) genotype phenotype correlation. The existence of this mutation in this family is particularly important from two aspects; firstly in defining the functionally critical regions of the keratin rod domain as suggested by Smith et al. [7], secondly in bringing new insights into the genotype phenotype correlation. It is known that the beginning of the helix 1A and the end of the helix 2B are highly conserved in sequence between keratins. Those regions also play the most critical role for the assembly of keratin dimers [4]. The family members showed a very similar phenotype; therefore, it may be speculated that the p.asn92ser mutation may have caused a basic change in keratin assembly to form intermediate filaments. The severity of the clinical picture in the family which consists of almost all findings of PC-2 also support this hypothesis. The features such as hair abnormalities, hoarseness, natal teeth and sebaceous cysts in
a b c 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 members of PC families. In our family, the development and progress of the clinical picture of PC did not vary between affected members. Although hair abnormalities such as pili torti, unruly hair, and hoarseness (some PC-1 suffer from hoarseness) are rarely seen in PC-2, the affected members of the presented family consistently showed these unusual findings. Pilosebaceous cysts which have been reported to be indispensable in the diagnosis of PC-2 usually appear at puberty [6]. It is speculated that the androgenic stimulation of the sebaceous gland, enviromental factors and the characteristics of the mutation may be associated with the onset of sebaceous cysts [2]. However, there can be variability in development of cysts for example there are reports of patients with the same mutation, p.met88thr, where the onset of sebaceous cysts has been in the first year of life and in another in which cysts did not occur until the second decade [1, 6]. In the family presented, sebaceous cysts developed early in the first year of life in almost all members of the family with very mild changes. Hoarseness is a rare finding in PC-2. In this family, it is defined in all members who also present another rare finding which is natal teeth. Therefore, the relation between the occurrence of natal teeth and laryngeal abnormality may need to be evaluated by further reports. The possible development of the clinical features of the proband over time can be observed in Fig. 2 including both the views of the proband and father. The correlation between clinical syndrome and the pair of genes involved has been reported to be highly consistent [5]. There may also be modifier genes which promote or delay the onset of symptoms. Nevertheless, the presented family shows an example of a clear correlation between the phenotype and genotype.
Fig. 3 Pathological examination of biopsy sample from the father. a Compact hyperkeratosis, 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 a b c d Acknowledgements FJDS and NJW are supported by grants from the Pachyonychia Congenita Project (http://www.pachyonychia.org) and The Dystrophic Epidermolysis Bullosa Research Association UK. We thank Dr Sancy A Leachman, University of Utah, Utah, USA, as PC Project consulting physician. We would like to thank to Ege University Research and Education Center for providing financial support. The authors declare that they have no conflict of interest. References 1. Celebi JT, Tanzi EL, Yao YJ et al (1999) Mutation report: identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. J Invest Dermatol 113:848 850 2. 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 3. Liao H, Sayers JM et al (2007) A spectrum of mutations in keratins K6a, K16 and K17 causing pachyonychia congenita. J Dermatol Sci 48:199 205 4. McLean WH, Rugg EL, Lunny DP et al (1995) Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 9:273 278 5. Munro CS (2001) Pachyonychia congenita: mutations and clinical presentations. Br J Dermatol 144:929 930 6. Oh SW, Kim MY, Lee JS, Kim SC (2006) Keratin 17 mutation in pachyonychia congenita type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity. J Dermatol 33:161 164 7. Smith FJ, Coleman CM, Bayoumy NM et al (2001) Novel keratin 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 pachyonychia congenita. J Investig Dermatol Symp Proc 10:21 30 9. Szeverenyi I, Cassidy AJ, Chung CW et al (2008) The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat 29:351 360 10. 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(Pt 3):419 426