Rogaev et al. (1993) studied a large 5-generation Uzbek pedigree segregating autosomal dominant nonepidermolytic palmoplantar keratoderma. Affected individuals had thick, white, smooth skin that desquamated in large flakes on the palmar surfaces of the hands and the soles ... Rogaev et al. (1993) studied a large 5-generation Uzbek pedigree segregating autosomal dominant nonepidermolytic palmoplantar keratoderma. Affected individuals had thick, white, smooth skin that desquamated in large flakes on the palmar surfaces of the hands and the soles of the feet. Skin creases displayed deep fissures, nails were often stubby with numerous hangnails, and the skin over the joint surfaces of the hands and feet was thickened, red, and edematous with poor elasticity. The skin on the backs of the hands, tops of the feet, and in the interdigital spaces was reddened and wrinkled, with very fine desquamation. Blistering, either spontaneously or in response to mild mechanical or thermal stress, was not a feature of the disease in this pedigree, and skin in other parts of the body was unaffected. Skin biopsies from affected individuals lacked cytolysis and abnormal keratohyalin granules and were thus consistent with nonepidermolytic hyperkeratosis. Kimonis et al. (1994) examined 6 affected and 1 unaffected member across 3 generations of a family segregating autosomal dominant nonepidermolytic palmoplantar keratoderma. In adults the disease manifested as moderate to severe thickening of the skin on palms and soles, with extension of hyperkeratosis along the Achilles tendon of the foot and occasionally the extensor tendon of the great toe. However, involvement stopped abruptly at the wrist flexure and at the border of the dorsal aspect of the hands and feet, with an erythematous halo separating hyperkeratotic from normal-appearing skin. There were discrete hyperkeratotic pads over several knuckles of the hands, and some adult patients experienced mild limitation of extension of the digits; nails showed a slight beaking (concave) deformity. Three of the 4 adult patients examined had dermatophyte infection of the toenails and feet, and 2 had involvement of the palms. Hyperkeratosis of the umbilicus and nipple areolae were present, as well as very mild thickening and dryness of the knees and elbows. The 2 affected children who were examined had presented at birth with mild thickening of the palms and soles; both had generalized dryness with fine, powdery scale, and hyperkeratosis of the areolae and umbilicus. Biopsy of affected palms and elbow showed hyperkeratosis of the stratum corneum with no evidence of epidermolysis; on electron microscopy, cells of the granular and spinous layers did not show the aggregated tonofilaments or large keratohyalin granules characteristic of epidermolytic hyperkeratosis. Kimonis et al. (1994) stated that the NEPPK in this family was consistent with that described previously by Thost (1880) and Unna (1883). Lind et al. (1994) described an autosomal dominant form of NEPPK with a high prevalence in northern Sweden (see Bothnian-type PPK, 600231). Kelsell et al. (1999) studied 3 families from the south of England with nonepidermolytic PPK that was present at birth: affected individuals had diffuse smooth waxy thickening of the entire palmoplantar surface including the non-weight-bearing digits, and secondary fungal infection was a common clinical problem leading to desquamation of the palms and soles. Two of the families had previously been reported by Kelsell et al. (1995), and skin biopsies from 2 affected individuals from each family confirmed the nonepidermolytic pattern of PPK. Terron-Kwiatkowski et al. (2002) reported 2 families with PPK. In the first family, a single affected girl who was born to unaffected parents had symmetric diffuse PPK at birth, but no history of skin fragility or blistering even in the neonatal period. At 8 years of age, she was noted to have diffuse PPK with some superficial scale as well as fine scaling over the lateral and anterior neck, lower back, external ears, and axillae. In the second family, an affected father and daughter each had mild diffuse PPK at birth with no history of neonatal fragility or blistering. The 34-year-old father had persistent mild diffuse PPK and mild flexural-limited scaling; the daughter had similarly mild disease with involvement limited to the palms and soles, popliteal fossae, and axillae.
Both epidermolytic and nonepidermolytic forms of palmoplantar keratoderma have been observed with various mutations in the KRT1 gene (139350). Kimonis et al. (1994) suggested that the specific region of the keratin protein affected by mutation might be a ... Both epidermolytic and nonepidermolytic forms of palmoplantar keratoderma have been observed with various mutations in the KRT1 gene (139350). Kimonis et al. (1994) suggested that the specific region of the keratin protein affected by mutation might be a major determining factor in the different clinical and histologic consequences. Mutations of the KRT1 and KRT9 genes that are associated with the epidermolytic form of PPK affect the central regions of the protein that are important for filament assembly and stability, and for that reason lead to cellular degeneration or disruption. On the other hand, the mutation of the KRT1 gene that Kimonis et al. (1994) found in association with PPK was located in the amino-terminal variable end region, which may be involved in supramolecular interactions of keratin filaments rather than stability.
In a 4-generation family with nonepidermolytic PPK mapping to chromosome 12q11-q13, Kimonis et al. (1994) identified a missense mutation in the KRT1 gene (K73I; 139350.0004) that segregated completely with the disease and was not found in 50 unrelated ... In a 4-generation family with nonepidermolytic PPK mapping to chromosome 12q11-q13, Kimonis et al. (1994) identified a missense mutation in the KRT1 gene (K73I; 139350.0004) that segregated completely with the disease and was not found in 50 unrelated controls. In 2 families with mild PPK, Terron-Kwiatkowski et al. (2002) identified a splice site mutation (139350.0010) and a deletion (139350.0011) in the KRT1 gene, respectively. - Heterogeneity In 3 affected and 3 unaffected members of a large 5-generation Uzbek pedigree with NEPPK mapping to chromosome 17q12-q22, Rogaev et al. (1993) analyzed exon 1 of the KRT10 gene (in which mutations had been found in patients with generalized epidermolytic hyperkeratosis; see 113800) but found no mutations.