PMVK-related disseminated superficial and scrotal porokeratosis

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Porokeratosis is a rare keratinisation disorder with an expansive spectrum of genetic mutations involving the mevalonate pathway. A nonsense variant c.412C>T (p.Arg138*) in PMVK (Phosphomevalonate kinase) enzyme has previously been described in only two Chinese families, both exhibiting a phenotype of disseminated superficial porokeratosis with genital involvement. Herein, we report the first genetically confirmed case of PMVK-related porokeratosis from India, presenting with a similar phenotype.

A 20-year-old Indian man presented with multiple persistent non-pruritic skin lesions for approximately 10-15 years. Examination revealed a few skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks [Figures 1a and b]. Dermoscopy revealed a central brown structureless area with a white double-marginated keratin rim (Tram track appearance).

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Figure 1a:

Multiple skin-coloured annular papules over the scrotum.

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Figure 1b:

Dorsum of the foot showing an annular plaque with central clearing and a peripheral hyperpigmented keratotic ridge.

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Histopathological examination of the plaque over the foot showed characteristic features consistent with porokeratosis, including hyperkeratosis, focal parakeratotic columns invaginating into the epidermis, and underlying thinning of the granular layer. No atypia or malignancy was observed [Figure 2].

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Figure 2:

Histopathological examination revealing classic cornoid lamella: A column of parakeratosis (black arrow head) overlying a focal epidermal invagination with underlying hypogranulosis (Haematoxylin & eosin, 200x).

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The patient reported a significant family history with the presence of similar lesions in his brother and paternal grandfather. Whole exome sequencing identified a pathogenic heterozygous nonsense mutation in exon 4 of the PMVK gene; NM_006556.4: c.412C>T (p.Arg138*). The variant was classified as pathogenic based on American College of Medical Genetics and Genomics (ACMG) guidelines. The patient refused Sanger sequencing of his family members. He was started on topical retinoids to which he responded partially.

Familial porokeratosis, as well as most of sporadic cases, are now understood to be caused by mevalonate pathway defects, most commonly due to MVD gene (Mevalonate decarboxylase) and MVK gene (Mevalonate kinase) mutations, and less frequently due to PMVK gene (Phosphomevalonate kinase) and FDPS (Farnesyl diphosphate synthase enzyme) gene mutations. Mevalonate pathway mutations result in impaired formation of essential cholesterol and other isoprenoid-derived lipids. Lesions harboring mutations in MVD and FDPS genes are usually smaller, homogenous, and more superficial than those carrying mutations in MVK and PMVK genes. MVK mutations show the widest range of phenotypes, but giant plaque-like porokeratosis is unique to MVK mutations. Genital porokeratosis and porokeratoma are uniquely associated with PMVK.¹ Some cases of porokeratosis are due to non-mevalonate pathway genes, including the SLC17A9 gene, which is a nucleoside transmembrane protein transporter, and SART3, which regulates cell proliferation.² It is postulated that the 2^nd hit heterozygous mutation results in a localised loss of function in these enzymes, causing abnormal differentiation and parakeratosis.³

Our patient had a nonsense variant (c.412C>T) in the PMVK gene, which has previously been reported in two Chinese families with a similar disseminated superficial porokeratosis phenotype with annular plaques over the hands, neck, and legs, as well as the presence of scrotal porokeratosis [Supplementary Table].⁴ To the best of our knowledge, this is the first genetically confirmed case of PMVK-related disseminated superficial porokeratosis reported from India.