Palmoplantar Keratoderma, Epidermolytic

A number sign (#) is used with this entry because epidermolytic palmoplantar keratoderma is caused by heterozygous mutation in the keratin-9 gene (KRT9; 607606) on chromosome 17q12. A mild form of epidermolytic palmoplantar keratoderma is caused by mutation in the keratin-1 gene (KRT1; 139350) on chromosome 12q.

Description

Palmoplantar keratoderma (PPK) is a common hereditary cutaneous disorder characterized by marked hyperkeratosis on the surface of palms and soles (Hennies et al., 1995). PPK has been classified into diffuse, focal, and punctate forms according to the pattern of hyperkeratosis on the palms and soles (Lucker et al., 1994). Diffuse PPK develops at birth or shortly thereafter and involves the entire palm and sole with a sharp cutoff at an erythematous border; there are no lesions outside the volar skin, and, in particular, no follicular or oral lesions. In contrast, focal PPK is a late-onset form in which focal hyperkeratotic lesions develop in response to mechanical trauma; an important distinguishing feature is the presence of lesions at other body sites, e.g., oral and follicular hyperkeratosis (Stevens et al., 1996). Palmoplantar keratodermas can be further subdivided histologically into epidermolytic and nonepidermolytic PPK (Risk et al., 1994).

Genetic Heterogeneity of Palmoplantar Keratoderma

Nonepidermolytic palmoplantar keratoderma (NEPPK; 600962) is caused by mutation in the KRT1 gene. A focal form of NEPPK (FNEPPK1; 613000) is caused by mutation in the KRT16 gene (148067). Another focal form, FNEPPK2 (616400), is caused by mutation in the TRPV3 gene (607066); mutation in TRPV3 can also cause Olmsted syndrome (OLMS; 614594), a severe mutilating form of PPK. The diffuse Bothnian form of NEPPK (PPKB; 600231) is caused by mutation in the AQP5 gene (600442). The Nagashima type of nonepidermolytic diffuse PPK (PPKN; 615598) is caused by mutation in the SERPINB7 gene (603357).

A generalized form of epidermolytic hyperkeratosis (EHK; 113800), also designated bullous congenital ichthyosiform erythroderma (BCIE), is caused by mutation in the keratin genes KRT1 and KRT10 (148080).

For a discussion of punctate PPK, see 148600; for a discussion of striate PPK, see 148700.

Nomenclature

Vorner (1901) provided an early description of epidermolytic hyperkeratosis limited to the palms and soles, whereas Thost (1880) and Unna (1883) reported what appeared to be a nonepidermolytic 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 several descendants; Lind et al. (1994) stated that the designation 'Unna-Thost' is misleading and should be avoided.

Clinical Features

Localized epidermolytic hyperkeratosis was first described by Vorner (1901). Blasik et al. (1981), Fritsch et al. (1978), and Camisa and Williams (1985) reported affected families. In an affected father and daughter, Moriwaki et al. (1988) noted a decrease in 67-kD keratin (KRT1; 139350) in the involved epidermis and the appearance of 48-kD keratin. Southern blot analysis using 67-kD keratin cDNA showed no abnormality in the gene for 67-kD keratin.

Kanitakis et al. (1987) reported a Greek family with EPPK in which 21 individuals over 6 generations were affected, all of whom developed diffuse PPK before 2 months of age and had no other cutaneous or systemic disease. Kanitakis et al. (1987) reviewed 27 published families or cases of EPPK, which in all instances appeared to be inherited as an autosomal dominant trait. The disease was present at birth or developed during the first weeks of life as a palmoplantar erythema which subsequently became covered with a thick horny layer. The clinical features were almost invariable from one patient to another, with disease involving the entire volar surface and sometimes extending to the lateral aspects of the fingers and toes. The hyperkeratosis was diffuse, thick, and uniform, but in some cases demonstrated deep fissures or pits, and a thin, erythematous rim was sometimes present. In rare cases, small hyperkeratotic plaques were present over the dorsa of the hands. Some patients had hyperhidrosis; palmoplantar blistering was exceptional. Mucous membrane, adnexal, or tooth abnormalities were not present.

Keratosis palmaris et plantaris as described by Thost (1880) and Unna (1883) and later delineated by Greither (1952) is characterized by diffuse hyperkeratosis of the palms and soles which usually becomes evident between the ages of 3 and 12 months. Low serum vitamin A has been found in some cases. Goette (1974) described successful use of topical vitamin A. A PPK family reported by Anderson and Klintworth (1961) had clinodactyly also, possibly as an independent trait (see 148520).

Gamborg Nielsen (1985) did a follow-up study on hereditary palmoplantar keratoderma originally surveyed in the northernmost county of Sweden (Norrbotten) by Bergstrom (1967). Two clinical types were found: a common form with the usual autosomal dominant inheritance and a severe form thought to have autosomal recessive inheritance (see 244850). Mal de Meleda (248300) is a recessive form of keratosis palmoplantaris in which the phenotype includes hyperhidrosis and perioral erythema.

Alsaleh and Teebi (1990) described 2 affected sons of phenotypically normal, consanguineous Arab parents. They presented with patchy eczematous skin lesions followed by palmoplantar keratoderma and raised serum levels of IgE. Nogita et al. (1991) described the disorder in a 32-year-old Japanese man who had knuckle-pad-like lesions over the dorsal aspect of the proximal interphalangeal joints since the age of 3 or 4 months and whose father had had the same skin disease.

Reis et al. (1994) studied multiple unrelated German pedigrees with marked hyperkeratosis restricted to the palms and soles, including the family originally described by Thost (1880) and the family studied by Reis et al. (1992). Histopathologic analysis in at least 1 patient from each family revealed typical signs of epidermolytic hyperkeratosis, consisting of a thickened granular layer with large irregularly shaped keratohyalin granules located in the granular layer of the epidermis and perinuclear vacuolization of the keratinocytes. The thickness of the scales varied among patients between and within families.

Torchard et al. (1994) studied a large 4-generation French kindred with EPPK, originally reported by Blanchet-Bardon et al. (1987). The EPPK lesions in this family appeared on the entire surface of the palms and soles, demarcated from normal skin by a distinct band of erythema, and display the typical histopathologic features of epidermolytic hyperkeratosis resulting from abnormal tonofilament aggregations. Several affected members of this family also developed breast or ovarian cancer.

Hatsell et al. (2001) studied 3 Scottish kindreds segregating autosomal dominant PPK in which affected members displayed palmoplantar hyperkeratosis that varied in severity and had been present since childhood. In the most severely affected cases, there was confluent plantar keratoderma on weight-bearing surfaces, sparing the instep, and normal skin bordering the keratoderma displayed a violaceous erythema. In milder cases, there was patchy plantar keratoderma in weight-bearing areas, resembling focal keratoderma. There was no generalized transgradient keratoderma, but several individuals had developed marked local callosities on dorsal toes or fingers at sites of rubbing. The remaining skin looked entirely normal except for mild hyperkeratosis of the knees in 1 man, and nails, hair, and teeth were normal. Although epidermolysis was not identified by light microscopy in biopsies from 3 patients, electron microscopy revealed that a minority of keratinocytes in the spinous and granular layers appeared to be undergoing cytolysis, with tonofilaments forming tight clumps or aggregates at the cell surface, often adjacent to desmosomes. These changes did not appear to affect clusters of adjacent cells and were thus less disruptive than those typically seen in epidermolytic hyperkeratosis (113800) where blistering is associated with extensive cell lysis.

Kuster et al. (2002) performed a follow-up study of the now 8-generation pedigree with EPPK, originally described by Vorner (1901), involving 32 affected individuals (17 males and 15 females). Examination of an affected 42-year-old man and his affected 15-year-old daughter and 9-year-old son showed the typical diffuse yellow-grayish keratoses over the entire surface of the palms and soles, sharply bordered by red margins; all had clubbing of the nails and knuckle pad-like keratoses on the finger joints with variable expression. The father and son showed slightly increased palmoplantar hidrosis, but this was not observed in the daughter. Mycotic infection of the plantar scales was also found in the father and son. Histopathologic examination confirmed epidermolytic hyperkeratosis.

Unilateral Palmoplantar Verrucous Nevus

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.

Epidermolytic Palmoplantar Keratoderma Associated With Knuckle Pads

Lu et al. (2003) studied a family from Shandong, China, with autosomal dominant EPPK associated with knuckle pads. Both the hyperkeratosis and knuckle pads were friction-related. Lu et al. (2003) stated that aggravation of the hyperkeratosis by friction had not previously been reported. The right hand of each right-handed affected member showed more severe hyperkeratosis than the less frequently used left hand. The knuckle pads on the right hand were likewise more prominent than those on the left hand. Furthermore, the knuckle pad on the more frequently used proximal interphalangeal joint of the index finger was more severely affected than that on the less frequently used interphalangeal joint of the thumb. One patient showed EPPK symptoms approximately 5 months after birth, whereas another showed EPPK symptoms at a little more than 1 year after birth.

Chiu et al. (2007) reported a large 5-generation Taiwanese family with EPPK in which 13 affected members had severe epidermolytic hyperkeratosis, surrounded by a characteristic erythematous border on the palmoplantar surface. In addition, 6 adults among the 13 affected individuals had prominent knuckle pads on the dorsal aspect of the fingers and to a lesser extent the toes. For each right-handed patient, both the hyperkeratosis and knuckle pads were more severe on the right hand than on the left. The age of onset of palmoplantar hyperkeratosis was in the early months of life. Skin biopsies showed the characteristic features of epidermolytic hyperkeratosis.

Codispoti et al. (2009) studied a 4-generation southern Italian family in which 11 of 24 members had EPPK. In all patients, the lesions initially appeared around 2 months of age, presenting a diffuse PPK with a well-demarcated erythematous border; none had any involvement of hair, teeth, or nails. One patient showed hyperkeratotic pad-like plaques on the metacarpophalangeal and proximal interphalangeal joints, which were more severe on the more frequently used right hand. Histologic analysis of a knuckle-pad biopsy showed hyperkeratosis and epidermolysis, with vacuolar degeneration of keratinocytes in the upper spinous and granular layers, pyknotic nuclei, and a thickened granular layer containing an increased number of keratohyalin granules.

Inheritance

Klaus et al. (1970) demonstrated dominant inheritance and male-to-male transmission.

Alsaleh and Teebi (1990) suggested the existence of an autosomal recessive form, but because of the high background frequency of consanguinity in Kuwait where the patients were observed, and because of the possibility of gonadal mosaicism, the evidence for recessive inheritance was not strong in the small family studied by them.

Population Genetics

Covello et al. (1998) found the point prevalence of EPPK in Northern Ireland to be 4.4 per 100,000.

Mapping

In a large family with epidermolytic palmoplantar keratoderma, Reis et al. (1992) mapped the disease locus to 17q11-q23 by linkage analysis using microsatellite DNA polymorphisms; maximum lod score = 6.66 with D17S579 at theta = 0.00. Thus, the disease mutation maps to the same region as the type I (acidic) keratin gene cluster (e.g., 148080). One acidic keratin, keratin-9 (KRT9; 607606), is expressed only in the terminally differentiated epidermis of palms and soles; thus, the KRT9 gene was considered a candidate for the site of the mutation in epidermolytic palmoplantar keratoderma.

In a large 4-generation French kindred with EPPK, originally reported by Blanchet-Bardon et al. (1987), in which 8 of 10 affected females over 40 years of age also developed breast or ovarian cancer, Torchard et al. (1994) obtained a maximum 2-point lod score for EPPK of 6.62 between markers THRA1 and D17S8000 on chromosome 17q21. Linkage between EPPK and breast/ovarian cancer yielded a maximum lod score of 0.92 at theta = 0.08.

Heterogeneity

Hatsell et al. (2001) screened 6 affected individuals from a 6-generation Scottish family segregating a mild form of EPPK in an autosomal dominant fashion and identified a common haplotype for microsatellite markers spanning the type II keratin cluster on chromosome 12q13; no linkage was seen for markers mapping to 17q12-q21.

Molecular Genetics

In 5 unrelated German pedigrees with epidermolytic PPK, including the family originally described by Thost (1880) and the family previously studied by Reis et al. (1992) with linkage to chromosome 17q11-q23, Reis et al. (1994) identified heterozygosity for a missense mutation in the KRT9 gene (R162W; 607606.0001). Two other missense mutations were also detected in 1 EPPK kindred each, N160K (607606.0004) and R162Q (607606.0005), respectively. All 3 mutations involved highly conserved residues in coil 1A of KRT9.

In 4 affected members of a large 4-generation French kindred with EPPK originally reported by Blanchet-Bardon et al. (1987), in which 8 of 10 affected females over 40 years of age also developed breast or ovarian cancer, Torchard et al. (1994) identified a missense mutation in the KRT9 gene (N160Y; 607606.0003). The mutation was not found in unaffected family members or in 20 unrelated controls. Noting that the KRT9 gene is not expressed in the mammary gland, Torchard et al. (1994) stated that the most likely explanation for the association of EPPK with hereditary breast/ovarian cancer syndrome is that the 2 conditions resulted from distinct genetic events on chromosome 17q in linked genes.

Covello et al. (1998) studied 4 Northern Irish EPPK kindreds and identified heterozygosity for missense mutations in exon 1 of KRT9 in all of the families: R162Q and M156T (607606.0010) in 1 family each, and M156V (607606.0006) in 2 families.

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.

In 3 Scottish families with a mild form of EPPK, Hatsell et al. (2001) identified a splice site mutation in the KRT1 gene (139350.0014).

Kuster et al. (2002) analyzed the KRT9 gene in members of the EPPK pedigree originally described by Vorner (1901) and identified heterozygosity for a missense mutation in affected individuals (607606.0013).

In a family from Shandong, China, with autosomal dominant epidermolytic palmoplantar keratoderma associated with knuckle pads, Lu et al. (2003) identified a heterozygous missense mutation in the KRT9 gene (L160F; 607606.0012).

In affected members a 5-generation Taiwanese family with EPPK associated with knuckle pads, Chiu et al. (2007) identified heterozygosity for the common R163W mutation in the KRT9 gene (607606.0001), previously designated R162W.

In a 4-generation southern Italian family in which 11 of 24 members had EPPK, 1 of whom also had knuckle pads, Codispoti et al. (2009) identified heterozygosity for the R163W mutation. Quantitative RT-PCR analysis of a knuckle-pad skin biopsy revealed an almost 90-fold increase in KRT9 expression compared to control.

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 (139350.0004) that Kimonis et al. (1994) found in association with nonepidermolytic PPK (600962) was located in the amino-terminal variable end region, which may be involved in supramolecular interactions of keratin filaments rather than stability.