Alternative titles; symbols
ORPHA: 448264; DO: 0111709;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.2 | Palmoplantar keratoderma, nonepidermolytic, focal | 613000 | Autosomal dominant | 3 | KRT16 | 148067 |
A number sign (#) is used with this entry because of evidence that focal nonepidermolytic palmoplantar keratoderma-1 (FNEPPK1) is caused by heterozygous mutation in the KRT16 gene (148067) on chromosome 17q21.
Another focal form of NEPPK1, FNEPPK2 (616400), is caused by heterozygous mutation in the TRPV3 gene (607066). Focal forms of PPK associated with esophageal carcinoma (TOC; 148500) and with gingival hyperplasia (148730) have been described.
For a discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200).
Focal nonepidermolytic palmoplantar keratoderma-1 (FNEPPK1) is an autosomal dominant skin disorder characterized by large, hard, compact, painful masses of keratin that develop at sites of recurrent friction, principally on the feet, though also on the palms and other sites, without evidence of epidermolysis (summary by Kelsell et al., 1995).
Stevens et al. (1994) studied one 2-generation and two 3-generation families in which focal NEPPK segregated as an autosomal dominant with an age of onset of 6 to 7 years. Affected individuals developed large, hard, compact painful masses of keratin at sites of recurrent friction on the feet and hands. Blistering occurred in hot weather upon walking approximately 1 mile. The onychocorenal band was widened with multiple splinter hemorrhages, keratosis pilaris was seen on the arms and legs, and a whitish opalescence over the hard palate, buccal mucosa, and glans penis of circumcised males.
Kelsell et al. (1995) reported a large 4-generation Caucasian pedigree segregating autosomal dominant focal NEPPK associated with orogenital hyperkeratosis. Patients presented at 6 to 7 years of age with development of large, hard, compact painful masses of keratin, particularly on the soles and other areas of repeated mechanical trauma. Skin biopsies from 2 affected individuals confirmed the nonepidermolytic pattern of PPK.
Smith et al. (2000) examined 6 affected members from a 3-generation family with mild FNEPPK, in which the keratoderma was confined to the weight-bearing areas of the soles, with no evidence of palmar keratoderma, nail changes, or oral leukokeratosis. Histologic analysis of a plantar skin biopsy showed no signs of epidermolysis, consistent with the diagnosis of FNEPPK.
Terrinoni et al. (2000) described a patient with a localized thickening of the skin in parts of the right palm and the right sole, following the Blaschko lines. Light microscopy showed hyperkeratosis, vacuolar degeneration of keratinocytes in the upper spinosum and granular layer, pyknotic nuclei, and a thickened granular layer containing an increased number of keratohyaline granules. Histologic findings were consistent with the diagnosis of disease similar to localized palmoplantar epidermolytic hyperkeratosis, or focal EPPK, and ultrastructural analysis suggested a keratin defect. The authors proposed that this clinical entity be referred to as 'unilateral palmoplantar verrucous nevus,' rather than localized or focal epidermolytic palmoplantar keratoderma, as the lesions are present only on one side of the body and follow the lines of Blaschko. This patient was found to have somatic mosaicism for a mutation in the KRT16 gene (see MOLECULAR GENETICS).
The transmission pattern of FNEPPK1 in the families reported by Shamsher et al. (1995) was consistent with autosomal dominant inheritance.
In a multigenerational family with autosomal dominant focal NEPPK, Stevens et al. (1994) performed segregation analysis using markers flanking the keratin gene clusters at chromosomes 12q and 17q; they excluded linkage to chromosome 12q, but obtained a Z-score of 3.2 (theta = 0.0) on chromosome 17q12-q21.
In a large, 4-generation Caucasian pedigree with focal NEPPK, Kelsell et al. (1995) excluded linkage to markers on chromosome 12q11-q12, but obtained a lod score of 3.25 on chromosome 17q12-q21 with 3-point analysis involving a microsatellite marker within intron 4 of the KRT9 gene (607606) and D17S855 (theta = 0.0).
In 2 families with identical clinical phenotypes of focal NEPPK with follicular and orogenital hyperkeratosis, 1 of which was the large multigenerational family with linkage to chromosome 17q12-q21 previously studied by Stevens et al. (1994), Shamsher et al. (1995) sequenced the KRT16 gene and identified heterozygosity for 2 different missense mutations in affected individuals (148067.0002 and 148067.0003, respectively). The mutations were not found in unaffected family members or in 30 unrelated controls. Shamsher et al. (1995) noted that the manifestations of focal NEPPK are very similar to those of pachyonychia congenita, with the only significant difference being the extent of nail involvement; see, e.g., pachyonychia congenita-1 (PC1; 167200), in which mutation in the KRT16 gene has also been found (148067.0001).
McLean (1997) noted that the 2 families studied by Shamsher et al. (1995) had mild nail changes similar to those that occur in a much more severe form in pachyonychia congenita, and concluded that expression of nail dystrophy in addition to palmoplantar keratoderma is not dependent on the specific mutation, as this has been found to vary greatly within large families. Because of the marked phenotypic variability observed in all keratin diseases, even among persons with the same mutation, McLean (1997) suggested that there are probably modifier genes and/or environmental influences yet to be defined.
In a 3-generation family with mild FNEPPK, Smith et al. (2000) identified a complex deletion (148067.0011) in the KRT16 gene. The authors noted that the deletion, which removes a keratin-16 helix termination motif (HTM), unexpectedly resulted in a relatively mild phenotype. In vitro studies suggested that loss of the HTM sequence may render the mutant protein less capable of contributing to filament assembly and thus decrease its dominant-negative effect.
In a patient with unilateral palmoplantar verrucous nevus, Terrinoni et al. (2000) reported somatic mosaicism for a 12-bp deletion in the KRT16 gene in a biopsy from lesional epidermis.
Lessard and Coulombe (2012) generated Krt16 -/- mice and observed failure to thrive and increased postnatal mortality, with more than 30% of mice dying within 24 hours of birth and over 60% before weaning age. The survivors continued to grow and gained weight but remained smaller and lighter than their littermate controls. Hyperplastic lesions on the dorsal midline posterior tongue were observed in all mutant mice by postnatal day 3 (P3). Surviving mice no longer had visible lesions, but tongue architecture showed thickened epithelium and loss of normal filiform papillae; the authors suggested that the oral lesions might be painful and affect feeding behavior. Starting at 4 to 6 weeks of age, Krt16 -/- mice developed prominent hyperkeratotic calluses of both the front and hind paws, particularly in areas of high physical impact, consistent with the KRT16-associated focal PPK observed in humans. Adult mutant mice were significantly less active than control animals, which the authors hypothesized was the result of substantial discomfort due to the palmoplantar lesions. Reduced filaggrin expression in established front paw calluses was observed, indicating focal loss of barrier protection. In contrast to human disease, nail morphology was not affected in Krt16 -/- mice.
Kelsell, D. P., Stevens, H. P., Ratnavel, R., Bryant, S. P., Bishop, D. T., Leigh, I. M., Spurr, N. K. Genetic linkage studies in non-epidermolytic palmoplantar keratoderma: evidence for heterogeneity. Hum. Molec. Genet. 4: 1021-1025, 1995. [PubMed: 7544664] [Full Text: https://doi.org/10.1093/hmg/4.6.1021]
Lessard, J. C., Coulombe, P. A. Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders. J. Invest. Derm. 132: 1384-1391, 2012. [PubMed: 22336941] [Full Text: https://doi.org/10.1038/jid.2012.6]
McLean, W. H. I. Personal Communication. Philadelphia, Pa. 2/26/1997.
Shamsher, M. K., Navsaria, H. A., Stevens, H. P., Ratnavel, R. C., Purkis, P. E., Kelsell, D. P., McLean, W. H. I., Cook, L. J., Griffiths, W. A. D., Geschmeissner, S., Spurr, N., Leigh, I. M. Novel mutations in keratin 16 gene underly focal nonepidermolytic palmoplantar keratoderma (NEPPK) in two families. Hum. Molec. Genet. 4: 1875-1881, 1995. [PubMed: 8595410] [Full Text: https://doi.org/10.1093/hmg/4.10.1875]
Smith, F. J. D., Fisher, M. P., Healy, E., Rees, J. L., Bonifas, J. M., Epstein, E. H., Jr., Tan, E. M. L., Uitto, J., McLean, W. H. I. Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp. Derm. 9: 170-177, 2000. [PubMed: 10839714] [Full Text: https://doi.org/10.1034/j.1600-0625.2000.009003170.x]
Stevens, H. P., Kelsell, D. P., Spurr, N. K., Bishop, D. T., Purkis, P. E., Griffiths, W. A. D., Rustin, M. H. A., Leigh, I. M. Keratin staining and linkage of non-epidermolytic focal palmoplantar keratodermas (PPK) to 17q. (Abstract) Brit. J. Derm. 131: 425 only, 1994.
Terrinoni, A., Puddu, P., Didona, B., De Laurenzi, V., Candi, E., Smith, F. J. D., McLean, W. H. I., Melino, G. A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus. J. Invest. Derm. 114: 1136-1140, 2000. [PubMed: 10844556] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00983.x]