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 ... 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.
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. ... 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 type 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.