Porokeratosis 7, Multiple Types

A number sign (#) is used with this entry because of evidence that multiple types of porokeratosis (POROK7) are caused by heterozygous mutation in the MVD gene (603236) on chromosome 16q24.

Description

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), several families with expression of more than one variant of porokeratosis among members, and individuals expressing more than one variant, have been reported, suggesting that the distinctions among these variants may be artificial.

Mutations in the MVD gene have been found to cause multiple types of porokeratosis, which have been described as disseminated superficial actinic porokeratosis (DSAP), nonactinic disseminated superficial porokeratosis (DSP), solar facial porokeratosis, linear porokeratosis, and hyperkeratotic porokeratosis.

The preferred title of this entry was formerly 'Porokeratosis 7, Disseminated Superficial Actinic Type; POROK7.'

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.

Clinical Features

Luan et al. (2011) reported a 4-generation Chinese family from the Anhui province with disseminated superficial actinic porokeratosis. The average age at onset was 28 years, but the earliest onset was at age 16. The skin lesions were small, conically shaped papules, 1 to 3 mm in diameter, that enlarged centrifugally over months or years, leaving a central atrophic area and a well-defined irregular keratotic rim. Most lesions were on the extremities, especially distally on the extensor and lateral surfaces. The face, neck, and trunk were also affected, but the palms, soles, and oral mucosal surfaces were spared. The lesions become more prominent with sunlight exposure. There was intrafamilial variation in the number of lesions and severity of disease. The proband, who had DSAP, also developed linear atrophic plaques along the left side of her leg after left foot trauma as a teen. Histologic specimens of both DSAP and the linear lesions from the proband showed an invagination of the epidermis containing a column of parakeratotic cells overlying an absent granular layer. There was no malignant transformation in the linear lesion. None of the other affected family members had linear lesions.

Mapping

By genomewide linkage analysis of a 4-generation Chinese family with DSAP, Luan et al. (2011) identified a locus, which they termed DSAP4, on chromosome 16q24.1-q24.3 (maximum lod score of 3.73 at D16S3074). The candidate interval was 17.4 cM between D16S3091 and D16S413. Molecular analysis excluded pathogenic mutations in the ATP2C2 gene (613082).

Molecular Genetics

In the 4-generation Chinese family with DSAP mapping to chromosome 16q24.1-q24.3, previously studied by Luan et al. (2011), Zhang et al. (2015) sequenced the candidate gene MVD and identified a missense mutation (F249S; 603236.0001) that segregated fully with disease in the family. Subsequent analysis of 12 isoprenoid genes in 134 Chinese probands with porokeratosis revealed 13 MVD mutations in 62 patients. The mutations segregated completely with disease in all families for which DNA was available, including three 3-generation pedigrees. Zhang et al. (2015) noted that 50 of the 62 patients carried either the F249S mutation or an N292S mutation (603236.0002), thus accounting for 81% of porokeratosis patients with mutations in MVD. In 1 proband, 2 MVD missense mutations were detected, P101R and R228Q; the authors stated that this compound heterozygous patient had late-onset porokeratosis at age 50 years, and that his daughter, who carried only the R228Q mutation, had no lesions at age 30 years. Although 56 probands exhibited DSAP and/or nonactinic DSP, other porokeratosis subtypes were represented, including solar facial porokeratosis in 6, linear porokeratosis in 3, and hyperkeratotic porokeratosis in 1. Zhang et al. (2015) observed that even within families, affected individuals carrying the same mutation showed different clinical manifestations and varying degrees of severity. All examined lesional tissue showed cornoid lamella, a histologic hallmark of porokeratosis with vertical columns of parakeratosis overlying an area of hypogranulosis with dyskeratotic cells.

Nomenclature

In OMIM, the designation DSAP4 had been used for a porokeratosis locus on chromosome 18p11.3; the designation for the form on 18p11 has been changed to POROK6 (612353).