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Background: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy.Objective: On the basis of preventing the accumulation of toxic metabolites while replenishing essential end-products, we studied the efficacy of topical lovastatin/cholesterol in different variants of porokeratosis.Methods: A series of 5 patients with disseminated superficial actinic porokeratosis (DSAP,n=1), porokeratosis palmaris et plantaris disseminata (PPPD,n=2) and linear porokeratosis (LP,n=2) were enrolled. Patients were genotyped prior to initiation of therapy and then applied topical lovastatin/cholesterol twice daily to a unilateral defined treatment area for up to 3 months. Response was evaluated and patients were photographed every visit.Results: Three patients had MVD mutations and 2 patients had PMVK mutations. Treatment with topical lovastatin/cholesterol (but not cholesterol alone) resulted in near complete clearance of DSAP lesions after 4 weeks of therapy, and moderate improvement of lesions in PPPD and LP. There were no adverse events.Limitations: Case series design with a small number of patients. Conclusion:Topical cholesterol/lovastatin is a safe and effective therapy for porokeratosis that underscores the utility of a pathogenesis-based therapies which replace deficient end-products and prevent accumulation of potentially toxic precursors.

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IMPORTANCE Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. OBJECTIVE To identify genetic mutations associated with linear porokeratosis. DESIGN, SETTING, AND PARTICIPANTS Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. INTERVENTIONS OR EXPOSURES Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. MAIN OUTCOMES AND MEASURES Germline and somatic genomic characteristics of participants with linear porokeratosis. RESULTS Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). CONCLUSIONS AND RELEVANCE Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.

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