Porokeratosis is a rare skin disorder characterized by one or more annular plaques with a surrounding raised horny border that spreads centrifugally. Variants of porokeratosis have been described that differ in morphologic shapes, distribution, and clinical course (Schamroth ... Porokeratosis is a rare skin disorder characterized by one or more annular plaques with a surrounding raised horny border that spreads centrifugally. Variants of porokeratosis have been described that differ in morphologic shapes, distribution, and clinical course (Schamroth et al., 1997). However, as noted by Sybert (2010), the existence of several families with expression of more than one variant of porokeratosis among members, and individuals expressing more than one variant, suggest that the distinctions among these variants may be artificial. Disseminated superficial actinic porokeratosis (DSAP) is the most common subtype of porokeratosis. It is characterized by multiple small, annular, anhidrotic, keratotic lesions that are located predominantly on sun-exposed areas of the skin, such as the face, neck, and distal limbs. The lesions typically begin to develop in adolescence and reach near-complete penetrance by the third or fourth decade of life (summary by Wu et al., 2004 and Zhang et al., 2012). For a discussion of genetic heterogeneity of porokeratosis, see 175800.
Chernosky and Freeman (1967) first suggested the existence of a photosensitive variety of porokeratosis. Lesions, which occur almost only in sun-exposed areas of the skin, develop after age 16 years, with penetrance nearly complete by age 30 or ... Chernosky and Freeman (1967) first suggested the existence of a photosensitive variety of porokeratosis. Lesions, which occur almost only in sun-exposed areas of the skin, develop after age 16 years, with penetrance nearly complete by age 30 or 40. DSAP is much more frequent than porokeratosis of Mibelli (175800) from which it must be distinguished. The histopathologic picture is typical. Ultraviolet radiation provokes typical porokeratotic lesions in DSAP (Chernosky and Anderson, 1969). Linear porokeratosis appears to be a nonhereditary trait (Rahbari et al., 1974), although its occurrence in families with DSAP has been reported (Welton, 1972; Moreland and Wyre, 1981; Commens and Shumack, 1987). Happle (1991) suggested that somatic recombination may explain linear porokeratosis. Somatic crossing-over at an early stage of embryogenesis may involve the DSAP locus, resulting in a precursor cell for a clone growing out in a linear fashion. Homozygosity would explain the observation that the lesions of linear porokeratosis are far more pronounced than those of associated DSAP, as well as the fact that linear porokeratosis occurs sporadically. Disseminated porokeratosis of intensified severity similar to that observed in the linear type would be expected to occur in 25% of the children of parents who are both affected with DSAP. Wu et al. (2004) reported a 5-generation Chinese family from the Anhui province with DSAP. Affected individuals developed cutaneous lesions in their teenage years, with the earliest age of onset at 10 years. The lesions were multiple, small, annular keratotic lesions ranging from 0.1 to 0.2 cm in diameter. They tended to occur on sun-exposed sites, such as the face, neck, and distal limbs. Skin biopsy of 1 patient showed cornoid lamella consisting of a compact column of parakeratotic cells. In affected members of the family reported by Wu et al. (2004), Zhang et al. (2012) identified a heterozygous splice site mutation in the MVK gene (251170.0014). - Clinical Variability Cao et al. (2012) reported a large 6-generation Chinese family with autosomal dominant disseminated superficial porokeratosis. Most had onset of skin lesions between ages 20 and 30 years. The lesions were annular, ranging from 2 to 6 mm in diameter, with brown raised borders and slightly atrophic centers. Histologic studies showed absent granular layers below the parakeratotic column. The lesions were not limited to sun-exposed areas such as the face and limbs, but were also found on nonexposed areas, including the chest and back.
By exome sequencing of 3 members (2 affected and 1 unaffected) of a 4-generation Chinese family with autosomal dominant DSAP, Zhang et al. (2012) identified a heterozygous mutation in the MVK gene (251170.0009). Sanger sequencing confirmed that the ... By exome sequencing of 3 members (2 affected and 1 unaffected) of a 4-generation Chinese family with autosomal dominant DSAP, Zhang et al. (2012) identified a heterozygous mutation in the MVK gene (251170.0009). Sanger sequencing confirmed that the mutation segregated with the disorder in 6 affected individuals. Sequencing of the MVK gene in 57 additional pedigrees and 25 patients with sporadic disease identified 13 additional heterozygous MVK mutations in 22 cases. Overall, 14 mutations (see, e.g., 251170.0009-251170.0010; 251170.0012-251170.0015) were found in 18 (33%) probands with familial DSAP and in 4 (16%) of 25 patients with sporadic occurrence. The mutational spectrum included missense, truncating, and splice site mutations. There was no evidence of secondary somatic MVK mutations within skin lesions of 5 patients. The phenotypic severity was variable, even among those with the same mutation. Two of the mutations, G202R (251170.0010) and 417insC (251170.0012), had previously been identified in patients with hyper-IgD syndrome (260920) and mevalonic aciduria (610377). However, the patients with DSAP1 had no clinical features of either disorder, including normal IgD levels. Although porokeratosis lesions have not been reported in individuals with mevalonic aciduria, some cases with hyper-IgD syndrome can have transient inflammatory skin lesions. In addition, heterozygous parents of patients with recessive MVK mutations do not have features of DSAP1. This clinical diversity suggests the involvement of additional factors, such as environmental exposure, particularly ultraviolet radiation, in disease manifestation. Functional studies in keratinocytes suggested that MVK plays a role in regulating calcium-induced keratinocyte differentiation and may protect keratinocytes from UV radiation-induced apoptosis. Sequencing the MVK gene in 5 individuals with porokeratosis of Mibelli (175800), 2 with linear porokeratosis, and 4 with disseminated superficial porokeratosis found no mutations, suggesting that MVK mutations may be specific for the DSAP subtype of porokeratosis. - Associations Pending Confirmation Zhang et al. (2004) performed genomewide linkage analysis in 3 Chinese families with DSAP and localized the gene to an 8.0-cM region on chromosome 12 that partially overlapped the DSAP1 locus identified by Xia et al. (2000). Screening of 30 candidate genes in this region identified 3 different variants in the SSH1 gene (606778) in 2 families and in 1 nonfamilial case. The SSH1 gene mapped outside of the DSAP1 locus identified by Xia et al. (2000). Two of the SSH1 variants occurred in an alternative isoform (isoform f) of the gene. As SSH1 encodes a phosphatase with a role in actin dynamics, the authors suggested that cytoskeletal disorganization in epidermal cells may be associated with the pathogenesis. In all 17 affected members of a 6-generation Chinese family with DSAP, Zhang et al. (2005) identified a missense mutation in the SART3 gene (V591M; 611684.0001). The mutation was also found in 2 of 7 family members whose phenotypes were uncertain, presumably because they were too young for onset of DSAP1. The mutation was not found in 2 unaffected family members, 5 spouses, or 192 unrelated individuals. Frank et al. (2007, 2007) disputed the findings of Zhang et al. (2004) and Zhang et al. (2005). Frank et al. (2007) found no variation in the SSH1 gene in 5 unrelated Dutch patients with DSAP, and noted that variation in the SSH1 and SART3 genes have not been replicated in additional DSAP families. Frank et al. (2007, 2007) also found inconsistencies in some of the methodology used by the other authors.