Palmoplantar Keratoderma I, Striate, Focal, Or Diffuse

A number sign (#) is used with this entry because keratosis palmoplantaris striata I (PPKS1) is caused by heterozygous mutation in the DSG1 gene (125670) on chromosome 18q12.

Description

Striate palmoplantar keratoderma belongs to a group of skin diseases in which there is thickening of the skin on the palms and soles. The striate form is characterized by longitudinal hyperkeratotic lesions extending the length of each finger to the palm, and hyperkeratotic lesions are restricted to regions of the body where pressure and abrasion are greatest (summary by Hunt et al., 2001). Patients with diffuse or focal forms of keratoderma associated with mutation in the DSG1 gene have also been reported (Keren et al., 2005; Milingou et al., 2006).

Genetic Heterogeneity of Keratosis Palmoplantaris Striata

Type II PPKS (PPKS2; 612908) is caused by mutation in the DSP gene (125647) on chromosome 6.

Type III PPKS (PPKS3; 607654) is caused by mutation in the keratin-1 gene (KRT1; 139350) on chromosome 12q.

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

Nitoiu et al. (2014) reviewed desmosome biology in cardiocutaneous syndromes and inherited skin disease, including discussion of the involvement of the DSG1 and DSP genes.

Clinical Features

The lesions of the hands consist of a streak of hyperkeratosis running the length of each finger and onto the palm. Bologna (1966) reported a 4-generation kindred in which involvement of males predominated in a striking manner. This disorder is also referred to as the Brunauer-Fohs-Siemens type of palmoplantar keratoderma.

Hennies et al. (1995) described a German kindred with a striated form of palmoplantar keratoderma. Affected members of this family showed marked hyperkeratosis resembling that found in cases of epidermolytic (144200) and nonepidermolytic (600962) palmoplantar keratoderma.

Wan et al. (2004) analyzed affected skin from a patient with PPKS who was previously studied by Hunt et al. (2001) and shown to have a Y365X mutation in the DSG1 gene (see MOLECULAR GENETICS). In affected palmar skin, the stratum corneum was approximately 5 times as thick as the underlying epidermis. Desmosomes were smaller than normal and reduced in number. The most striking and consistent finding was the lack of a clearly defined midline in the extracellular core domain, a key structural component of normal desmosomes. Immunofluorescence analysis showed very weak staining of all desmogleins, whereas desmoplakin staining was mostly unchanged. Plakophilin expression was very weak and aberrantly distributed throughout the spinous layer, and plakoglobin staining was almost absent. Staining for desmocollins showed a marked reduction and disrupted staining pattern compared to normal skin. Analysis of keratin expression and organization showed that K5 (148040) and K10 (148080) were severely reduced, whereas K14 (148066) was present in the basal as well as suprabasal epidermal layers. In addition, staining of hyperproliferation-related K16 (148067) was observed throughout the epidermis. Wan et al. (2004) concluded that mutations in DSG causing PPKS1 may be associated with perturbations in epidermal differentiation accompanied by a marked disruption of several components of the epidermal scaffold, including desmosomes and the keratin intermediate filament network.

Keren et al. (2005) studied a 50-year-old man of Jewish Yemenite origin, who from 3 years of age had thickening of the skin of the palms and soles accompanied by painful fissures. He had 5 daughters, 3 of whom displayed a milder form of keratoderma, mainly evident on the soles. His maternal grandfather, but not his mother, was reported to have been similarly affected. On examination, he had diffuse hyperkeratosis and fissuring on the volar surface of the hands and digits and over the weight-bearing areas of the soles and toes. Mild onycholysis was also present, with yellowish discoloration of most nails. Hair, teeth, mucosae, and nonpalmoplantar skin were normal. Histologic examination of a palmar skin biopsy showed papillomatosis and marked orthohyperkeratosis in the epidermis, with widening of intercellular spaces and disadhesion of keratinocytes in the upper spinous and granular cell layers.

Milingou et al. (2006) reported a father and 2 daughters from a consanguineous Libyan family with a focal, nonstriated form of palmoplantar keratoderma. The proband was a 12-year-old girl who had progressive thickening of her soles from 5 years of age. Examination revealed thick, yellow, and fissured focal areas of keratosis on sites of pressure of the soles and toes. Her toenails were relatively small, slightly ridged, and partially white. Her palms also showed focal areas of slight keratosis on pressure sites. There were slightly hyperkeratotic plaques with follicular keratoses on her knees and on the anterolateral aspect of her ankles. Smooth circumscribed keratoses were observed over the dorsa of some proximal and distal interphalangeal joints of her fingers and toes. The angles of her mouth also showed slight hyperkeratosis. Her 39-year-old father and 6-year-old sister had similar but less pronounced hyperkeratotic lesions on pressure points of the soles, whereas the remainder of the physical examination was unremarkable. Light microscopy of a plantar skin biopsy from the proband showed marked hyperkeratosis, acanthosis, and papillomatosis; there were no epidermolytic changes.

Hershkovitz et al. (2008) studied 3 families with striate palmoplantar keratoderma, including 1 of Jewish Sephardic descent and 2 of Jewish Ashkenazi origin. All 9 patients displayed focal areas of hyperkeratosis, involving palms, soles, and the palmar surface of the fingers. Marked intrafamilial variation was noted. In all cases, histologic examination of palmoplantar skin biopsies revealed orthohyperkeratosis, papillomatosis, widening of the intercellular spaces, and separation of keratinocytes in the upper spinous and granular cell layers.

Dua-Awereh et al. (2009) analyzed 5 Pakistani families segregating autosomal dominant PPKS. All affected individuals had hyperkeratosis of the palms, predominantly on the creases, with linear hyperkeratosis along the flexor aspects of the fingers. Focal hyperkeratosis was seen on the plantar surface of the toes as well as the balls and heels of the feet. The phenotype was more pronounced in areas that undergo frequent mechanical stress. None of the affected individuals had woolly hair, and none of the families had a history of cardiomyopathy, early sudden death, or cancer.

Zamiri et al. (2009) studied a 3-generation Scottish family with the striate form of palmoplantar keratoderma. The proband was a 40-year-old man who had painful thickening of the skin on the palms and soles as well as hyperhidrosis and intermittent associated blistering since childhood. Examination showed linear hyperkeratosis of the volar aspect of the fingers, more extensive focal plantar hyperkeratosis, and mild hyperkeratosis of the knees. His father, paternal uncle, and 8-year-old daughter were similarly affected. Light microscopy of the affected plantar epidermis showed acanthosis with mild spongiosis and intracellular vacuolation, thickened granular layer with hyperkeratosis, mild upper dermal perivascular chronic inflammatory cell infiltrate, and suprabasal cell-cell separation. Electron microscopy revealed normal keratin intermediate filaments but separation of keratinocytes in the spinous layer.

Diagnosis

Bergman et al. (2010) analyzed biopsies from 4 patients with DSG1 mutations, including the patient with diffuse PPK originally reported by Keren et al. (2005) and the 3 patients with PPKS previously studied by Hershkovitz et al. (2008), comparing them to biopsies from 4 patients with palmoplantar keratoderma and mutations in the SLURP1 gene (606119; see Mal de Meleda, 248300), 1 patient with pachyonychia congenita-2 (167210) and a mutation in KRT17 (148069), and 1 patient with focal palmoplantar keratoderma (FNEPPK; 613000) and a mutation in KRT16 (148067). The distinguishing histopathologic features of the cases with mutations in DSG1 included varying degrees of widening of the intercellular spaces and partial disadhesion of keratinocytes in the mid and upper epidermal spinous cell layers, often extending to the granular cell layer. These findings were not observed in any of the other 6 PPK cases; Bergman et al. (2010) concluded that widening of intercellular spaces and disadhesion of epidermal keratinocytes might serve as histologic clues to PPKs caused by DSG1 mutations.

Mapping

In a German kindred with PPKS, Hennies et al. (1995) found linkage of the disorder to markers on chromosome 18q12 with a maximum 2-point lod score of 3.30 at theta = 0.00 for D18S536. A cluster of genes for desmosomal cadherins, desmogleins (DSG1, 125670; DSG2, 125671; DSG3, 169615), and desmocollins (DSC1, 125643 and DSC3, 125645) have been mapped to the same region, making them good candidates for this form of PPK.

In a family of Jewish Yemenite origin segregating autosomal dominant diffuse palmoplantar keratoderma, Keren et al. (2005) used microsatellite markers spanning the 3 known PPKS-associated genes to establish the haplotypes of 4 affected and 3 unaffected family members. All affected individuals shared a common 11.4-Mb segment between markers D18S877 and D18S535 on chromosome 18q12.1, encompassing the DSG1 locus.

By haplotype analysis in a family of Jewish Sephardic descent with PPKS, Hershkovitz et al. (2008) excluded linkage to the KRT1 and DSP loci; the analysis was, however, compatible with linkage to DSG1. Haplotype analysis in another PPKS family, of Jewish Ashkenazi origin, revealed an 8.2-Mb segment common to all patients, between markers D18S877 and D18S1102, an interval encompassing the DSG1 gene.

Molecular Genetics

In a Dutch family with striate palmoplantar keratoderma, Rickman et al. (1999) identified a heterozygous splicing mutation in the gene encoding desmoglein (125670.0001).

In 5 unrelated patients with PPKS, including an affected member of the German kindred originally studied by Hennies et al. (1995), Hunt et al. (2001) analyzed the DSG1 gene and identified heterozygous truncating mutations in all of them (see, e.g., 125670.0002-125670.0004). The preponderance of PPKS mutations in the DSG1 gene rather than in another desmosomal cadherin suggested that desmoglein-1 is a key protein in desmosome structure and function in the epidermis, and that PPKS provides a very sensitive measure of correct desmosome function.

In a family of Jewish Yemenite origin with autosomal dominant diffuse PPK mapping to 18q12, Keren et al. (2005) analyzed the DSG1 gene and identified a heterozygous nonsense mutation (R26X; 125670.0004) that segregated completely with the disease. The same mutation had previously been detected in a sporadic patient with striate PPK (Hunt et al., 2001).

In a father and 2 daughters with a focal, nonstriated form of palmoplantar keratoderma from a consanguineous Libyan family, Milingou et al. (2006) identified heterozygosity for a frameshift mutation in the DSG1 gene (125670.0005) that was not found in unaffected family members or in 50 unrelated controls. The authors noted that the phenotype in this family extended the spectrum of clinical features associated with genetic defects in DSG1.

Hershkovitz et al. (2008) sequenced the DSG1 gene in 3 families with PPKS, including 1 of Jewish Sephardic descent and 2 of Jewish Ashkenazi origin, and identified 3 different heterozygous truncating mutations (see, e.g., 125670.0006) that segregated with disease in each family, respectively. Direct sequencing of cDNA derived from affected skin failed to reveal a pathogenic mutation, suggesting that PPKS results from haploinsufficiency for DSG1.