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.

Pharmacological Inhibition of the Temperature-Sensitive and Ca2+-Permeable Transient Receptor Potential Vanilloid TRPV3 Channel by Natural Forsythoside B Attenuates Pruritus and Cytotoxicity of Keratinocytes

“…Inside-out or whole-cell patch-clamp recordings demonstrate that these TRPV3 mutants are constitutively open, with robust inward currents (Xiao et al, 2008;Lin et al, 2012) and elevation of intracellular Ca 21 that subsequently triggers keratinocyte cell death (Lin et al, 2012). Similar gain-of-function TRPV3 mutations were also reported in studies from other countries, which were performed in patients with OS characterized by dermatitis and severe itching (Duchatelet et al, 2014;Eytan et al, 2014;Kariminejad et al, 2014;Choi et al, 2018). These observations demonstrate that TRPV3 has emerged as a promising therapeutic target, and specific inhibition of overactive TRPV3 may present therapeutic potential for the treatment of chronic pruritus or skin diseases, which is a currently unmet medical need.…”

Pain mechanisms in hereditary palmoplantar keratodermas

“…In a survey of 50 OS case reports, 21 mentioned pain . This pain results in sleep disturbances, mobility difficulties and interference with grasping . Some individuals with OS also experience erythromelalgia, a condition in which the skin becomes intensely red and painful, often in response to warming …”

“…Home remedies, wet soaks, salicylic acid, urea, tar, shale oil, antibacterial treatment, retinoids and corticosteroids have been utilized to treat OS pain . More extreme measures such as complete removal of the affected skin and subsequent skin graft have also been used .…”

“…It remains to be determined whether TRPV3 gain of function leads to OS pain solely by virtue of its effects on keratinocyte biology or whether it also reflects TRPV3 hyperfunction in neurons or other cell types. Additional candidate contributors to pain in OS include Candida and bacterial infections, which are common in the hands and feet of individuals with this disorder, and immunological/inflammatory cell changes …”

“…34,103 Home remedies, wet soaks, salicylic acid, urea, tar, shale oil, antibacterial treatment, retinoids and corticosteroids have been utilized to treat OS pain. 101,104,105 More extreme measures such as complete removal of the affected skin and subsequent skin graft have also been used. 106 Though some individuals have reported initial relief from this procedure, keratoderma often returns in the grafted tissue.…”