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Olmsted Syndrome Caused by a Heterozygous p.Gly568Val Missense Mutation in TRPV3 Gene.

ABSTRACT: Olmsted syndrome (OS) is a rare congenital skin disorder characterized by severe palmoplantar and periorificial keratoderma, alopecia, onychodystrophy, and severe pruritus. Recently, pathogenic 'gain-of-function' mutations of the transient receptor potential vanilloid 3 gene (TRPV3), which encodes a cation channel involved in keratinocyte differentiation and proliferation, hair growth, inflammation, pain and pruritus, have been identified to cause OS. Due to the rarity, the pattern of inheritance of OS is still unclear. We report a case of OS in a 3-year-old Korean girl and its underlying gene mutation. The patient presented with a disabling, bilateral palmoplantar keratoderma with onychodystrophy. She also exhibited pruritic eczematous skin lesions around her eyes, ears and gluteal fold. Genetic analysis identified a heterozygous p.Gly568Val missense mutation in the exon 13 of TRPV3. To our knowledge, this is the first case of OS in the Korean population showing a missense mutation p.Gly573Ser.

SUBMITTER: Choi JY

PROVIDER: S-EPMC5823840 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Olmsted Syndrome Caused by a Heterozygous p.Gly568Val Missense Mutation in TRPV3 Gene.

Choi Ji Young JY Kim Song Ee SE Lee Sang Eun SE Kim Soo Chan SC

Yonsei medical journal 20180301 2

Olmsted syndrome (OS) is a rare congenital skin disorder characterized by severe palmoplantar and periorificial keratoderma, alopecia, onychodystrophy, and severe pruritus. Recently, pathogenic 'gain-of-function' mutations of the transient receptor potential vanilloid 3 gene (TRPV3), which encodes a cation channel involved in keratinocyte differentiation and proliferation, hair growth, inflammation, pain and pruritus, have been identified to cause OS. Due to the rarity, the pattern of inheritanc ...[more]

PMID: 29436206

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Project description:ImportanceOlmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment. It is most often caused by mutations in the transient receptor potential vanilloid 3 (TRPV3) gene. In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation.ObjectiveTo examine the possibility of blocking EGFR transactivation with the inhibitor erlotinib hydrochloride to treat PPK in patients with Olmsted syndrome due to TRPV3 mutations.Design, setting, and participantsIn this case series, 3 patients from 2 unrelated families who had TRPV3-mutation-associated PPK were treated with erlotinib from May 5, 2018, through May 13, 2019.Main outcomes and measuresClinical follow-up included evaluation of PPK progression, pain and interventions for pain, as well as erlotinib dose adjustment based on treatment effect, plasma levels, and tolerance.ResultsThe 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies. Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis. All patients experienced depression and did not engage in social activities. Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared. All patients were able to touch the ground with their feet, wear shoes, and walk. Anorexia and insomnia remitted and paralleled improved growth. In addition, the patients resumed social activities. These improvements were sustained across 12 months of treatment and follow-up. The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted.Conclusions and relevanceThe findings of this study report improvement of PPK in patients with Olmsted syndrome caused by TRPV3 mutations when treated with erlotinib. Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention.

Dataset Information

Olmsted Syndrome Caused by a Heterozygous p.Gly568Val Missense Mutation in TRPV3 Gene.

Publications

Olmsted Syndrome Caused by a Heterozygous p.Gly568Val Missense Mutation in TRPV3 Gene.

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