ORPHA: 2309;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Pachyonychia congenita 4 | 615728 | Autosomal dominant | 3 | KRT6B | 148042 |
A number sign (#) is used with this entry because of evidence that pachyonychia congenita-4 (PC4) is caused by heterozygous mutation in the KRT6B gene (148042) 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 KRT6B gene, here designated PC4, has also been designated PC-6b (Eliason et al., 2012) and PC-K6b (Shah et al., 2014).
Smith et al. (1998) reported a 5-generation Dutch family segregating autosomal dominant pachyonychia congenita, which was described as the Jackson-Lawler type. Hypertrophic nail dystrophy affected all fingernails and toenails, and focal palmoplantar keratoderma occurred on the pressure points of the feet. Steatocystomas were widespread in postpubescent affected individuals. Mild lingual hyperkeratosis was present on the margins of the tongue.
Guo et al. (2014) reported a 9-year-old Chinese girl who presented at age 6 years with thickened fingernails and toenails. Physical examination showed hyperkeratotic nails. Steatocystoma multiplex, palmoplantar keratoderma, and natal teeth were not present.
The transmission pattern of PC4 in the family reported by Smith et al. (1998) was consistent with autosomal dominant inheritance.
In affected members of a family segregating pachyonychia congenita of the Jackson-Lawler type, Smith et al. (1998) identified heterozygosity for a missense mutation in the KRT6B gene (E472K; 148042.0001).
In 2 families (families 29 and 30) segregating pachyonychia congenita, Smith et al. (2005) identified heterozygosity for the same E472K mutation in the KRT6B gene that had been identified in a Dutch family by Smith et al. (1998). Haplotype analysis showed that family 29 had an independent occurrence of the mutation; haplotype analysis was not possible in family 30 because of lack of samples, but the family was not of Dutch ancestry.
In 9 of 84 families with pachyonychia congenita recruited through the International Pachyonychia Congenita Research Registry, Wilson et al. (2014) identified heterozygous mutations in the KRT6B gene, including 1 novel mutation (L469R; 148042.0002). The authors noted that the analogous mutation had been reported in the KRT6A gene (148041.0004).
In a 9-year-old Chinese girl with delayed onset of PC4, Guo et al. (2014) identified a heterozygous missense mutation (G499S; 148042.0003) in the KRT6B gene.
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 (148041) and KRT16 (148067) were the most common (41% and 31%, respectively). Mutations in KRT6B accounted for 9% of PC patients. Young age at diagnosis or involvement of a high number of fingernails and toenails was significantly associated with PC3 (615726). Plantar keratoderma was seen in all PC patients; however, palmar keratoderma was most common in PC1 (167200). Oral leukokeratosis, nursing difficulties, hoarseness, and ear pain/ear wax were significantly associated with PC3. Cysts and natal teeth were most commonly seen in PC2 (167210). Natal teeth were not reported in either PC1 or PC4. Lack of fingernail involvement was most commonly seen in PC1 and PC4. Samuelov et al. (2020) determined that 55% of PC4 patients with no fingernail involvement had the E472K mutation.
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]
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.
Guo, K., Xiao, S., Geng, S., Feng, Y., Zhang, D., Zhou, P., Zhang, Y. Delayed-onset pachyonychia congenita caused by a novel mutation in the V2 domain of keratin 6b. (Letter) J. Derm. 41: 108-109, 2014. [PubMed: 24354895] [Full Text: https://doi.org/10.1111/1346-8138.12349]
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]
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]