ORPHA: 2309;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Pachyonychia congenita 3 | 615726 | Autosomal dominant | 3 | KRT6A | 148041 |
A number sign (#) is used with this entry because of evidence that pachyonychia congenita-3 (PC3) is caused by heterozygous mutation in the keratin-6a gene (KRT6A; 148041) on chromosome 12q13.
Pachyonychia congenita (PC) is an autosomal dominant genodermatosis with the main clinical features of hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts. Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011).
For a discussion of genetic heterogeneity of pachyonychia congenita, see 167200.
Historical Classification of Pachyonychia Congenita
Gorlin et al. (1976) suggested that 2 distinct syndromes are subsumed under the designation pachyonychia congenita. PC type 1, the Jadassohn-Lewandowsky type, shows oral leukokeratosis. PC type 2, the Jackson-Lawler type, has natal teeth and epidermoid cysts (cylindromas), but no oral leukoplakia. Corneal dystrophy may be a feature exclusively of the Jackson-Lawler type.
Smith et al. (1998) stated that PC type 2, in contrast to PC type 1, has minimal oral involvement and milder keratoderma, and multiple steatocystomas (184500) is a major clinical feature. Steatocystoma, also known as eruptive vellus cyst, is a cystic hamartoma lined by sebaceous ductal epithelium.
On the basis of a study of 13 patients with PC type 1 or type 2, Terrinoni et al. (2001) concluded that the presence of pilosebaceous cysts following puberty is the best indicator of PC type 2; prepubescent patients are more difficult to classify due to the lack of cysts. Natal teeth are indicative of PC type 2, although their absence does not preclude the PC type 2 diagnosis.
The form of PC caused by mutation in the KRT6A gene, here designated PC3, has also been designated PC-6a (Eliason et al., 2012) and PC-K6a (Shah et al., 2014).
Bowden et al. (1995) identified a Slovenian family in which a grandfather, father, and daughter had pachyonychia congenita of the Jadassohn-Lewandowsky type. The father and daughter had classic changes with thickened nails, palmoplantar keratoderma, and leukokeratosis of the tongue. The grandfather had only minor nail changes and mild keratoderma.
Du et al. (2012) reported a 32-year-old Chinese woman with toenail thickening, plantar hyperkeratosis with fissuring, and mild focal palmar hyperkeratosis but no fingernail changes. She also exhibited oral leukokeratosis, chapped lips, and fissured tongue. Histopathology of the plantar lesion showed hyperkeratosis, acanthosis, and a moderate increase in the granular layer with minimal lymphocytic infiltrate in the upper dermis. Her 7-year-old daughter had focal plantar hyperkeratosis, fissured tongue, and gingivitis, but no nail or hand involvement. Both patients reported hyperhidrosis of the hands and feet.
Goldberg et al. (2020) presented a case series of 9 children with PC3 and symptomatic mucosal involvement. Oral leukokeratosis presented early in the neonatal period. Seven patients had painful feeding as infants; 4 were diagnosed with failure to thrive, 3 of whom required a feeding tube. One patient (case 8) was diagnosed with oral and airway leukokeratosis with severe vocal cord involvement. He died at age 4 as a result of acute laryngitis that led to cardiorespiratory arrest.
Abdollahimajd et al. (2019) reported an 8-year-old girl with PC3 who had painful plantar hyperkeratosis and thickened nails with a progressive course since infancy. She also had follicular hyperkeratosis and buccal leukokeratosis.
Samuelov et al. (2020) analyzed 815 individuals with confirmed keratin mutations registered in the International Pachyonychia Congenita Research Registry to delineate clinical features and phenotype-genotype correlations. Mutations in KRT6A accounted for 41% of all cases. PC3 was associated with oral leukokeratosis, hoarse voice, younger age of onset, and highest number of fingernail and toenail involvement.
Abdollahimajd et al. (2019) treated an 8-year-old girl with PC3 with oral rosuvastatin. After 6 months of treatment, the girl reported a marked decrease in plantar pain. Physical examination revealed partial improvement with fewer scales and fissures. Ultrasound demonstrated a 3.6-mm reduction in plantar callous thickness, a 23.4% decrease.
The transmission pattern of PC3 in the family reported by Bowden et al. (1995) was consistent with autosomal dominant inheritance.
In affected members of a Slovenian family segregating PC3, Bowden et al. (1995) identified heterozygosity for a 3-bp deletion in the KRT6A gene (Asn171del; 148041.0001).
Terrinoni et al. (2001) identified 3 novel mutations (148041.0002-148041.0004) and 2 previously identified mutations (see, e.g., 148041.0001) in the KRT6A gene in patients with pachyonychia congenita.
Smith et al. (2005) identified keratin mutations in 30 probands from the International Pachyonychia Congenita Research Registry, 17 of whom had mutations in the KRT6A gene (see, e.g., 148041.0001 and 148041.0005-148041.0008).
In a 32-year-old Chinese woman with pachyonychia congenita, Du et al. (2012) identified heterozygosity for a splice site mutation in the KRT6A gene (148041.0009). Her 7-year-old daughter, who had only focal plantar hyperkeratosis with no nail or hand involvement, was also heterozygous for the mutation.
Wilson et al. (2014) identified 18 different mutations in KRT6A in 31 families recruited through the International Pachyonychia Congenita Research Registry. The most common mutation was Asn172del, found in 10 families. Four mutations, including a nonsense mutation (E461X; 148041.0010), were novel.
Spaunhurst et al. (2012) studied the clinical characteristics of patients who would previously have been diagnosed with the Jadassohn-Lewandowsky type of PC: 89 with PC3, caused by mutation in KRT6A, and 68 with PC1 (167200), caused by mutation in KRT16 (148070). Patients with PC3 and PC1 were found to have distinct phenotypic differences. Patients with PC3 experienced earlier onset and more extensive nail disease and had a higher prevalence of oral leukokeratosis, hoarse voice, cyst formations and follicular hyperkeratosis compared to patients with PC1. Both groups experienced similar plantar keratoderma and plantar pain. Patients with PC1 more commonly reported palmar keratoderma.
Abdollahimajd, F., Rajabi, F., Shahidi-Dadras, M., Saket, S., Youssefian, L., Vahidnezhad, H., Uitto, J. Pachyonychia congenita: a case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation. Brit. J. Derm. 181: 584-586, 2019. [PubMed: 30307612] [Full Text: https://doi.org/10.1111/bjd.17276]
Bowden, P. E., Haley, J. L., Kansky, A., Rothnagel, J. A., Jones, D. O., Turner, R. J. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nature Genet. 10: 363-365, 1995. [PubMed: 7545493] [Full Text: https://doi.org/10.1038/ng0795-363]
Du, Z.-F., Xu, C.-M., Zhao, Y., Liu, W.-T., Chen, X.-L., Chen, C.-Y., Fang, H., Ke, H.-P., Zhang, X.-N. Two novel de novo mutations of KRT6A and KRT16 genes in two Chinese pachyonychia congenita pedigrees with fissured tongue or diffuse plantar keratoderma. Europ. J. Derm. 22: 476-480, 2012. [PubMed: 22668561] [Full Text: https://doi.org/10.1684/ejd.2012.1773]
Eliason, M. J., Leachman, S. A., Feng, B., Schwartz, M. E., Hansen, C. D. A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita. J. Am. Acad. Derm. 67: 680-686, 2012. [PubMed: 22264670] [Full Text: https://doi.org/10.1016/j.jaad.2011.12.009]
Goldberg, I., Mashiah, J., Kutz, A., Derowe, A., Warshauer, E., Schwartz, M. E., Smith, F., Sprecher, E., Hansen, C. D. Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children. Brit. J. Derm. 182: 708-713, 2020. [PubMed: 31777952] [Full Text: https://doi.org/10.1111/bjd.18742]
Gorlin, R. J., Pindborg, J. J., Cohen, M. M., Jr. Syndromes of the Head and Neck. (2nd ed.) New York: McGraw-Hill (pub.) 1976. Pp. 600-603.
McLean, W. H. I., Hansen, C. D., Eliason, M. J., Smith, F. J. D. The phenotypic and molecular genetic features of pachyonychia congenita. J. Invest. Derm. 131: 1015-1017, 2011. [PubMed: 21430705] [Full Text: https://doi.org/10.1038/jid.2011.59]
Samuelov, L., Smith, F. J. D., Hansen, C. D., Sprecher, E. Revisiting pachyonychia congenita: a case-cohort study of 815 patients. Brit. J. Derm. 182: 738-746, 2020. [PubMed: 31823354] [Full Text: https://doi.org/10.1111/bjd.18794]
Shah, S., Boen, M., Kenner-Bell, B., Schwartz, M., Rademaker, A., Paller, A. S. Pachyonychia congenita in pediatric patients: natural history, features, and impact. JAMA Derm. 150: 146-153, 2014. [PubMed: 24132595] [Full Text: https://doi.org/10.1001/jamadermatol.2013.6448]
Smith, F. J. D., Jonkman, M. F., van Goor, H., Coleman, C. M., Covello, S. P., Uitto, J., McLean, W. H. I. A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum. Molec. Genet. 7: 1143-1148, 1998. [PubMed: 9618173] [Full Text: https://doi.org/10.1093/hmg/7.7.1143]
Smith, F. J. D., Liao, H., Cassidy, A. J., Stewart, A., Hamill, K. J., Wood, P., Joval, I., van Steensel, M. A. M., Bjorck, E., Callif-Daley, F., Pals, G., Collins, P., Leachman, S. A., Munro, C. S., McLean, W. H. I. The genetic basis of pachyonychia congenita. J. Invest. Derm. Symp. Proc. 10: 21-30, 2005. [PubMed: 16250206] [Full Text: https://doi.org/10.1111/j.1087-0024.2005.10204.x]
Spaunhurst, K. M., Hogendorf, A. M., Smith, F. J. D., Lingala, B., Schwartz, M. E., Cywinska-Bernas, A., Zeman, K. J., Tang, J. Y. Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16. Brit. J. Derm. 166: 875-878, 2012. [PubMed: 22098151] [Full Text: https://doi.org/10.1111/j.1365-2133.2011.10745.x]
Sybert, V. P. Genetic Skin Disorders. (2nd ed.) New York: Oxford Univ. Press (pub.) 2010. Pp. 248-253.
Terrinoni, A., Smith, F. J. D., Didona, B., Canzona, F., Paradisi, M., Huber, M., Hohl, D., David, A., Verloes, A., Leigh, I. M., Munro, C. S., Melino, G., McLean, W. H. I. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J. Invest. Derm. 117: 1391-1396, 2001. [PubMed: 11886499] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01565.x]
Wilson, N. J., O'Toole, E. A., Milstone, L. M., Hansen, C. D., Shepherd, A. A., Al-Asadi, E., Schwartz, M. E., McLean, W. H. I., Sprecher, E., Smith, F. J. D. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Brit. J. Derm. 171: 343-355, 2014. [PubMed: 24611874] [Full Text: https://doi.org/10.1111/bjd.12958]