ORPHA: 402003; DO: 0111710;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Palmoplantar keratoderma, nonepidermolytic, focal or diffuse | 615735 | Autosomal dominant | 3 | KRT6C | 612315 |
A number sign (#) is used with this entry because of evidence that focal or diffuse nonepidermolytic palmoplantar keratoderma (PPKNEFD) is caused by heterozygous mutation in the KRT6C gene (612315) on chromosome 12q13.
Focal or diffuse nonepidermolytic palmoplantar keratoderma (PPKNEFD) is an autosomal dominant skin disorder in which hyperkeratotic plaques form on palms and soles. Palms may be less affected than soles, with mild nail changes present in some patients. Plaques and blistering may result in severe pain (summary by Wilson et al., 2010).
Wilson et al. (2010) described 3 families with focal palmoplantar keratoderma (PPKF). The first family (family 1) involved a father and son with PPKF who both exhibited plantar blistering; neither showed nail changes. In family 2 there were 6 affected individuals over 4 generations who showed minor nail changes, particularly nail hypertrophy of the fifth toe only, but no other ectodermal features. Family 3 consisted of 9 affected individuals over 4 generations; the proband experienced blistering in the summer months and had subtle leukokeratosis along the buccal bite line as well as occasional nail splinter hemorrhages. Although all affected individuals had relatively mild, site-restricted keratoderma and very minor or absent nail changes, they all experienced a significant amount of pain or discomfort, requiring secondary medical care. Bowden (2010) noted close similarities between the phenotype in these patients and that of patients with hereditary painful callosities (114140).
Akasaka et al. (2011) reported a Japanese family in which a 26-year-old man had diffuse hyperkeratosis of the soles of the feet that had developed at around 5 years of age, as well as small hyperkeratotic plaques on his hands that were believed to be related to mechanical stress due to his occupation as an ironworker. His son exhibited focal hyperkeratotic plaques of the feet with blister formation that developed at age 4 years, but did not show any hand lesions. The proband's 36-year-old sister also had focal hyperkeratotic plaques of the plantar surface, present since childhood, some of which were associated with clavus formation and were painful on walking. Her hands were uninvolved. All 3 affected individuals had hyperhidrosis of the soles, but nails were normal. The proband and his sister stated that their father also developed many calluses on the soles of his feet. Biopsy of the proband's soles showed nonepidermolytic orthohyperkeratosis and acanthosis of the epidermis. A clinical diagnosis of nonepidermolytic focal and diffuse PPK was made.
Kubo et al. (2013) studied a 4-generation Japanese family segregating autosomal dominant focal plantar keratoderma. The proband was a 26-year-old man who developed thickened skin on the soles of his feet at 10 years of age. He had focal hyperkeratotic plaques, some of which caused severe pain while walking. His palms were not affected, the nails of his hands and feet appeared normal, and no oral leukokeratosis was observed. Histologic examination of affected plantar skin showed severe hyperkeratosis and some heterogeneity in the eosin staining of the keratinocyte cytoplasm. His 8-year-old daughter had slight focal hyperkeratosis on her soles, which was first noted at 5 years of age and had recently become painful. Her palms and the nails of her hands and feet were not affected. The proband's sister, mother, maternal aunt and uncle, and maternal grandmother were also affected but declined examination.
The transmission pattern of PPKNEFD in the families reported by Wilson et al. (2010) was consistent with autosomal dominant inheritance.
In two 4-generation families segregating autosomal dominant focal palmoplantar keratoderma, Wilson et al. (2010) analyzed microsatellite markers and excluded the type I keratin locus on chromosome 17; however, markers within the type II keratin locus on chromosome 12 were consistent with linkage.
In two 4-generation families with focal palmoplantar keratoderma mapping to chromosome 12q13 as well as a father and son with PPKF, Wilson et al. (2010) excluded mutations in the KRT6A (148041) and KRT6B (148042) genes, and identified heterozygous mutations in the KRT6C gene (612315) in all 3 families: the father and son (family 1) and affected members of family 2 had an in-frame 3-bp deletion (612315.0001), whereas affected members of family 3 had an in-frame 27-bp deletion (612315.0002). Both mutations segregated fully with disease in each family; however, the 3-bp deletion was also present in 3 of 335 population controls. Wilson et al. (2010) suggested that KRT6C mutations might be a common genetic predisposing factor for plantar callus formation, which may be relatively mild and not always come to clinical attention.
In 3 affected members of a Japanese family with focal or diffuse keratoderma in a primarily plantar distribution, who were negative for mutation in the KRT6A, KRT6B, KRT16 (148067), or KRT17 (148069) genes, Akasaka et al. (2011) identified a heterozygous missense mutation in the KRT6C gene (E472K; 612315.0003).
In a father and daughter with focal plantar keratoderma, Kubo et al. (2013) sequenced the candidate gene KRT6C and identified heterozygosity for the E472K mutation, which was not present in an unaffected son. Transfection studies in HaCaT cells showed collapse of the keratin filament network in a dose-dependent manner, suggesting that the mutation has a dominant-negative effect on keratin filament network formation.
Akasaka, E., Nakano, H., Nakano, A., Toyomaki, Y., Takiyoshi, N., Rokunohe, D., Nishikawa, Y., Korekawa, A., Matsuzaki, Y., Mitsuhashi, Y., Sawamura, D. Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation. Brit. J. Derm. 165: 1290-1292, 2011. [PubMed: 21801157] [Full Text: https://doi.org/10.1111/j.1365-2133.2011.10552.x]
Bowden, P. E. Mutations in a keratin 6 isomer (K6c) cause a type of focal palmoplantar keratoderma. J. Invest. Derm. 130: 336-338, 2010. [PubMed: 20081885] [Full Text: https://doi.org/10.1038/jid.2009.395]
Kubo, A., Oura, Y., Hirano, T., Aoyama, Y., Sato, S., Nakamura, K., Takae, Y., Amagai, M. Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma. J. Derm. 40: 553-557, 2013. [PubMed: 23662636] [Full Text: https://doi.org/10.1111/1346-8138.12185]
Wilson, N. J., Messenger, A. G., Leachman, S. A., O'Toole, E. A., Lane, E. B., McLean, W. H. I., Smith, F. J. D. Keratin K6c mutations cause focal palmoplantar keratoderma. J. Invest. Derm. 130: 425-429, 2010. [PubMed: 19609311] [Full Text: https://doi.org/10.1038/jid.2009.215]