Palmoplantar Keratoderma, Nonepidermolytic

A number sign (#) is used with this entry because of evidence that diffuse nonepidermolytic palmoplantar keratoderma (NEPPK) is caused by heterozygous mutation in the KRT1 gene (139350) on chromosome 12q.

A focal form of NEPPK (FNEPPK; 613000) is caused by mutation in the KRT16 gene (148067) on chromosome 17q. The diffuse Bothnian type of NEPPK (PPKB; 600231) is caused by mutation in the AQP5 gene (600442) on chromosome 12q13. The diffuse Nagashima type of NEPPK (PPKN; 615598) is caused by mutation in the SERPINB7 gene (603357) on chromosome 18q21. A form of NEPPK that can be focal or diffuse (PPKNEFD; 615735) is caused by mutation in the KRT6C gene (612315) on chromosome 12q13.

For discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200).

Nomenclature

Vorner (1901) provided an early description of localized epidermolytic hyperkeratosis of the palms and soles, whereas Thost (1880) and Unna (1883) reported what appeared to be a nonepidermolytic diffuse form of palmoplantar keratoderma; the designations 'Vorner' and 'Unna-Thost' thus became eponymous for the epidermolytic and nonepidermolytic forms of the disorder, respectively. However, Kuster and Becker (1992) and Kuster et al. (2002) reinvestigated the Thost kindred and found features of epidermolytic hyperkeratosis in a study of a descendant; Lind et al. (1994) stated that the designation 'Unna-Thost' is misleading and should be avoided.

Clinical Features

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.

Mapping

Kimonis et al. (1994) performed linkage analysis in a 4-generation family segregating autosomal dominant nonepidermolytic PPK and excluded the chromosomal region of the type I keratins; they obtained a maximum multipoint lod score of 3.61 (theta = 0.0) in the type II keratin region on chromosome 12q11-q13 with markers D12S96, D12S103, and D12S90.

In 2 unrelated families from the south of England segregating autosomal dominant diffuse NEPPK, Kelsell et al. (1995) found linkage to chromosome 12q, with a 2-point lod score of 3.83 at D12S368 (theta = 0.0). A crossover event in an affected individual from 1 of the families placed the susceptibility locus centromeric to marker D12S96.

In 3 unrelated families from the south of England with diffuse NEPPK, including 2 families previously reported by Kelsell et al. (1995), Kelsell et al. (1999) performed fine mapping and further analysis of the previously identified crossover event, which placed the disease locus centromeric to D12S803, proximal to the type II keratin gene cluster.

Heterogeneity

Rogaev et al. (1993) analyzed anonymous microsatellite and VNTR markers in a large 5-generation Uzbek family with NEPPK and obtained lod scores greater than 3.00 for markers clustered in the 17q12-q22 interval over a range of assumptions concerning penetrance, disease allele frequency, and marker allele frequencies. Haplotype analysis localized the NEPPK defect to an 8-cM region between THRA1 and D17S806 containing a cluster of keratin genes as well as the retinoic acid receptor alpha gene (RARA; 180240); an informative insertion/deletion polymorphism within the coding sequence of the C-terminal domain of the KRT10 gene (148080) was shown to segregate with the disease (lod score, 8.36 at theta = 0.00).

Molecular Genetics

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.

Genotype/Phenotype Correlations

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.