Expanding the Phenotypic Spectrum of Olmsted Syndrome

TO THE EDITOR Palmoplantar keratodermas (PPKs) are a group of genetically heterogeneous genodermatoses. Recently mutations in TRPV3 were identified as a cause of the rare form of PPK, Olmsted syndrome (OS; OMIM 614594; Lai-Cheong et al., 2012Lai-Cheong J.E. Sethuraman G. Ramam M. et al.Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome.Br J Dermatol. 2012; 167: 440-442Crossref PubMed Scopus (61) Google Scholar; Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar; Danso-Abeam et al., 2013Danso-Abeam D. Zhang J. Dooley J. et al.Olmsted syndrome: exploration of the immunological phenotype.Orphanet J Rare Dis. 2013; 8: 79Crossref PubMed Scopus (38) Google Scholar; Kariminejad et al., 2014Kariminejad A. Barzegar M. Abdollahimajd F. et al.Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3.Clin Exp Dermatol. 2014; 39: 492-495Crossref PubMed Scopus (13) Google Scholar; Duchatelet et al., 2014Duchatelet S. Pruvost S. de Veer S. et al.A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia.JAMA Dermatol. 2014; 150: 303-306Crossref PubMed Scopus (37) Google Scholar). OS was first reported in 1927 in an Italian American boy with painful palmoplantar keratoderma, deep fissures, pseudoainhum, curved thickened nails, and periorificial hyperkeratosis with fissuring (Olmsted, 1927Olmsted H.C. Keratodermia palmaris et plantaris congenitalis: report of a case showing associated lesions of unusual location.Am J Dis Child. 1927; 33: 757-764Crossref Google Scholar). About 50 clinical cases of OS have been described, and all generally exhibit the features described by Olmsted as well as some additional features (Mevorah et al., 2005Mevorah B. Goldberg I. Sprecher E. et al.Olmsted syndrome: mutilating palmoplantar keratoderma with periorificial keratotic plaques.J Am Acad Dermatol. 2005; 53: S266-S272Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). In this study, we report the case of six families, referred to the Pachyonychia Congenita Project for the evaluation of painful plantar keratoderma, but lacking pseudoainhum or significant periorificial keratoderma. In each case, after no mutations were identified in the PC-associated keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17, and in some cases, after other candidate genes including GJB6, DSP, DSG1, KRT5, and KRT14 had been screened, we identified heterozygous missense mutations in TRPV3, thus greatly expanding the phenotypic spectrum of OS. Samples were obtained with written, informed patient consent and ethical approval by a Western Institutional Review Board that complies with principles of the Helsinki Accord. An 18-year-old girl of European ancestry from Family 1 initially noted focal callus formation on the soles at age 4. Severe, painful plantar keratoderma now necessitates periodic use of a wheelchair. She has mild keratoderma on the hands, thin nail plates with koilonychia, and fine slow-growing hair. She has no periorificial keratoderma (Figure 1a, b, c,Supplementary Figure S1 online and Supplementary Table S1 online). A likely diagnosis was PC, but no causative mutations were identified in the PC-related keratin genes nor in other candidate genes. Therefore, a whole-exome sequencing approach was performed (Supplementary Methods online), and data were analyzed for sequence variants in known keratoderma genes. A heterozygous missense mutation, p.Gly573Cys; c,1717G>T, was identified in TRPV3 and confirmed by Sanger sequencing (Supplementary Methods online) but was not present in her unaffected parents or brother. This mutation has been reported in a sporadic case of Olmsted syndrome (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). TRPV3 was considered a candidate gene for five additional families in which no mutations were identified in the PC-associated keratin genes or in other candidate genes. Exons and intron/exon boundaries of TRPV3 were amplified by PCR for Sanger sequencing (Supplementary Methods online). A 7-year-old Brazilian girl in Family 2 presented with easily peeling hyperkeratosis on her toes and feet at about 18 months of age, and these have evolved into painful, focal hyperkeratosis. She has erythema and hyperkeratosis of the distal fingers and subungual hyperkeratosis. She has had transient periorificial hyperkeratosis and her nail plates are normal (Figure 1d, e, f,Table 1, Supplementary Figure S1 online). A previously unreported heterozygous missense mutation, p.Gly568Val; c.1703G>T, was identified (Supplementary Figure S2 online); this mutation was not detected in either of her unaffected parents. Amino acid, p.Gly568 is highly conserved across several species. This mutation is not in the dbSNP database or the NHLBI Exome Variant Server (http://evs.gs.washington.edu/EVS/).Table 1Clinical findings in patients with mutations in TRPV3ReportInheritanceTRPV3 mutationPlantar keratodermaPalmar keratodermaPseudoainhumPeriorificial keratodermaHairOlmsted's patientDiffuse-SDiffuse-SPresentPresentDryLin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google ScholarADp.Gly573Ser (4)1Individual families.M(1)2Individuals.; Mod(1); S(2)M(1)2Individuals.; Mod(1); S(2)PresentM(1)2Individuals.; Mod(1); S(2)Alopecia - M(1); Mod (1); S (2)Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google ScholarADp.Gly573Cys (1)MMAbsentMAlopecia - MLin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google ScholarADp.Trp692Gly (1)ModModPresentModAlopecia - MLai-Cheong et al., 2012Lai-Cheong J.E. Sethuraman G. Ramam M. et al.Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome.Br J Dermatol. 2012; 167: 440-442Crossref PubMed Scopus (61) Google ScholarADp.Gly573Ser (1)Diffuse-SDiffuse-SPresentMFine-dryDanso-Abeam et al., 2013Danso-Abeam D. Zhang J. Dooley J. et al.Olmsted syndrome: exploration of the immunological phenotype.Orphanet J Rare Dis. 2013; 8: 79Crossref PubMed Scopus (38) Google ScholarADp.Gly573Ala (1)Diffuse-SDiffuse-SAbsentSAlopecia-SDuchatelet et al., 2014Duchatelet S. Pruvost S. de Veer S. et al.A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia.JAMA Dermatol. 2014; 150: 303-306Crossref PubMed Scopus (37) Google ScholarADp.Leu673Phe (1)Diffuse-SDiffuse-SAbsentAbsentFine, dryDuchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google ScholarARp.Gly568Cys; p.Gln216_Gly262del (1)Diffuse-S (1); Focal-Mod(1)NRAbsentAbsentFine-dryEytan et al., 2014Eytan O. Fuchs-Telem D. Mevorach B. et al.Olmsted syndrome caused by a homozygous recessive mutation in TRPV3.J Invest Dermatol. 2014; 136: 1752-1754Abstract Full Text Full Text PDF Scopus (35) Google ScholarARp.Trp521Ser (1)Diffuse-SDiffuse-SAbsentPresentSparseKariminejad et al., 2014Kariminejad A. Barzegar M. Abdollahimajd F. et al.Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3.Clin Exp Dermatol. 2014; 39: 492-495Crossref PubMed Scopus (13) Google ScholarADp.Trp692Cys (1)Diffuse-SDiffuse-SPresentPresent (Mod)Sparse; fragileHe et al., 2015He Y. Zeng K. Zhang X. et al.A Gain of Function Mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family.J Invest Dermatol. 2015; 135: 907-909Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarADp.Gln580Pro (1)2Individuals.Focal-ModFocal-ModAbsentAbsentNormalFamily 1ADp.Gly573Cys (1)Focal-SFocal-MAbsentAbsentFineFamily 2ADp.Gly568Val (1)Focal-ModFocal-MAbsentMNormalFamily 3ADp.Gly568Asp (2)2Individuals.Focal-ModMAbsentMFineFamily 4ADp.Gly568Asp (1)Focal-ModFocal-MAbsentNRNormalFamily 5ADp.Gly573Ser (1)Focal-ModM/transientAbsentM/transientFragile, sparseFamily 6ADp.Gly573Ser (1)Focal-ModMAbsentAbsentNormalReportFollicular keratosisErythemaHyperhidrosisNailsLesional itchLesional painLeukokeratosisOlmsted's patientNRLesion border; dorsal handsHandsThickenedNRPresentNRLin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google ScholarScalpLesion borderNRNRS (4)2Individuals.PresentNRLin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google ScholarScalpLesion borderNRNRSPresentNRLin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google ScholarNRLesion borderNRNRSPresentNRLai-Cheong et al., 2012Lai-Cheong J.E. Sethuraman G. Ramam M. et al.Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome.Br J Dermatol. 2012; 167: 440-442Crossref PubMed Scopus (61) Google ScholarNRNRNRDystrophyNo“Functional impairment”NRDanso-Abeam et al., 2013Danso-Abeam D. Zhang J. Dooley J. et al.Olmsted syndrome: exploration of the immunological phenotype.Orphanet J Rare Dis. 2013; 8: 79Crossref PubMed Scopus (38) Google ScholarNRLesion borderNRDystrophySSNRDuchatelet et al., 2014Duchatelet S. Pruvost S. de Veer S. et al.A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia.JAMA Dermatol. 2014; 150: 303-306Crossref PubMed Scopus (37) Google ScholarNRErythromelalgiaPresentThin, brittleSSNRDuchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google ScholarMErythromelalgiaPresentNormalSSNREytan et al., 2014Eytan O. Fuchs-Telem D. Mevorach B. et al.Olmsted syndrome caused by a homozygous recessive mutation in TRPV3.J Invest Dermatol. 2014; 136: 1752-1754Abstract Full Text Full Text PDF Scopus (35) Google ScholarNRDiffuse, palms and solesNRNRPresentPresentPresentKariminejad et al., 2014Kariminejad A. Barzegar M. Abdollahimajd F. et al.Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3.Clin Exp Dermatol. 2014; 39: 492-495Crossref PubMed Scopus (13) Google ScholarNRNRNRDystrophic/absentSSNRHe et al., 2015He Y. Zeng K. Zhang X. et al.A Gain of Function Mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family.J Invest Dermatol. 2015; 135: 907-909Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarNRNRNRNRNRNRNRFamily 1MLesion borderHands and feetKoilonychia; thin platesAbsentSAbsentFamily 2AbsentLesion border; distal digits (hands)FeetNormalAbsentSAbsentFamily 3MLesion borderFeetKoilonychia; thin plates; onychoschiziaSSPresentFamily 4NRLesion borderNROnychoschiziaNRSAbsentFamily 5MLesion border; dorsal feetFeetKoilonychia; thin plates; onychoschiziaAbsentSAbsentFamily 6NRLesion borderNoNormalNRSAbsentAbbreviations: M, mild; Mod, moderate; NR, not reported; S, severe.1 Individual families.2 Individuals. Open table in a new tab Abbreviations: M, mild; Mod, moderate; NR, not reported; S, severe. The proband from Family 3, a 38-year-old European female, developed calluses on her feet at the age of 8–9 years. She now has severe plantar pain and difficulty in walking (Figure 1g, h, i, Table 1,Supplementary Figure S1 online). She has thin nail plates with koilonychia. Her father, two paternal uncles and grandmother were similarly affected showing autosomal dominant inheritance of the disorder. A previously unreported heterozygous missense mutation, p.Gly568Asp;c.1703G>A (Supplementary Figure S2 online), was identified in the proband and in one affected paternal uncle; it was not present in an unaffected paternal uncle nor in her mother, (her father is deceased). This mutation is not listed in dbSNP or the NHLBI Exome Variant Server. Interestingly, we found the same mutation, p.Gly568Asp, in Family 4 from South America. The first sign of a skin abnormality in the 25-year-old proband was peeling skin on her feet at age 4 years. Painful, focal keratoses formed on her feet and to a lesser extent on her hands. She has mild periungual hyperkeratosis on her fingers and toes, onychoschizia and longitudinal overcurvature of several toenails. She has no periorificial hyperkeratosis, and her hair is normal (Table 1). No clinical information or DNA samples were available from her parents or from other family members. A 55-year-old man of European ancestry from Family 5 presented with painful calluses on the soles of his feet. Focal hyperkeratoses with thin surrounding rim of erythema started on his heels as a child when he started to walk and spread to the soles of his feet. He has thin nail plates with koilonychia and sparse, fragile hair. He develops severe hyperhidrosis accompanied by burning pain in the feet and bright erythema on the dorsal hands and feet in response to extremes of temperature. He has no palmar hyperkeratosis, but has had transient perioral and periauricular hyperkeratosis (Figure 1j, k, l, Table 1,Supplementary Figure S1 online). He believes that etretinate and acitretin have significantly improved his quality of life. His father was also affected. A heterozygous missense mutation, p.Gly573Ser; c.1717G>A, the most commonly reported mutation to date in TRPV3, was identified in this individual. Mutation p.Gly573Ser, was also found in a 7-year-old girl of European ancestry (Family 6), who developed thickening of the skin on her heels at about 4 years of age (Table 1). She has severe plantar pain and now uses crutches to aid her mobility. Her parents are unaffected. The genetic basis of autosomal dominant OS was recently elucidated (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar) when heterozygous missense mutation, p.Gly573Ser, was identified in TRPV3 in a Chinese family. Mutations in TRPV3 were subsequently identified in five additional Chinese families. All developed symptoms before 1 year of age, had varying severity of palmoplantar hyperkeratosis, periorificial hyperkeratosis, alopecia, and severe lesional pain and itch. All but one had constricting digital bands. Several heterozygous mutations have been reported at codons 573; p.Gly573Ser (Lai-Cheong et al., 2012Lai-Cheong J.E. Sethuraman G. Ramam M. et al.Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome.Br J Dermatol. 2012; 167: 440-442Crossref PubMed Scopus (61) Google Scholar), p.Gly573Ala (Danso-Abeam et al., 2013Danso-Abeam D. Zhang J. Dooley J. et al.Olmsted syndrome: exploration of the immunological phenotype.Orphanet J Rare Dis. 2013; 8: 79Crossref PubMed Scopus (38) Google Scholar), and p.Gly573Cys (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar) and two mutations at codons 692; p.Trp692Gly (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar) and p.Trp692Cys (Kariminejad et al., 2014Kariminejad A. Barzegar M. Abdollahimajd F. et al.Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3.Clin Exp Dermatol. 2014; 39: 492-495Crossref PubMed Scopus (13) Google Scholar). The heterozygous missense mutation p.Leu673Phe was found in a patient with OS and erythromelalgia (Duchatelet et al., 2014Duchatelet S. Pruvost S. de Veer S. et al.A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia.JAMA Dermatol. 2014; 150: 303-306Crossref PubMed Scopus (37) Google Scholar). Homozygous missense and compound heterozygous mutations in TRPV3 have been shown to result in recessive OS with (Duchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google Scholar) or without erythromelalgia (Eytan et al., 2014Eytan O. Fuchs-Telem D. Mevorach B. et al.Olmsted syndrome caused by a homozygous recessive mutation in TRPV3.J Invest Dermatol. 2014; 136: 1752-1754Abstract Full Text Full Text PDF Scopus (35) Google Scholar). Recently, the heterozygous missense mutation p.Gln580Pro was identified in a family with focal palmoplantar keratoderma (He et al., 2015He Y. Zeng K. Zhang X. et al.A Gain of Function Mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family.J Invest Dermatol. 2015; 135: 907-909Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar), more reminiscent of the cases described here. TRPV3 belongs to the family of transient receptor potential (TRP) cation channels and is widely expressed in keratinocytes and hair follicles (Peier et al., 2002Peier A.M. Reeve A.J. Andersson D.A. et al.A heat-sensitive TRP channel expressed in keratinocytes.Science. 2002; 296: 2046-2049Crossref PubMed Scopus (726) Google ScholarNilius et al., 2013Nilius B. Biro T. Owsianik G. TRPV3: time to decipher a poorly understood family member!.J Physiol. 2013; 592: 295-304Crossref PubMed Scopus (93) Google Scholar) as well as in other tissues including the brain, spinal cord, sensory neurons, and the cornea. Mutations in TRPV3 causing autosomal dominant OS were shown to be gain-of-function mutations resulting in increased TRPV3 activity (Lin et al., 2012Lin Z. Chen Q. Lee M. et al.Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.Am J Hum Genet. 2012; 90: 558-564Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). In this study, two, to our knowledge previously unreported, mutations were identified at codon 568. Interestingly another amino acid substitution at this position, p.Gly568Cys, was recently reported in combination with a splice site mutation, exhibiting autosomal recessive inheritance in this case (Duchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google Scholar). TRPV3 forms a tetrameric complex, each subunit consists of six transmembrane domains (S1–S6) and a cytoplasmic amino and carboxy termini (Supplementary Figure S2 online). p.Gly568 is within the linker region between S4 and S5, near the boundary of S4. It is predicted that substitution of this glycine is less damaging than substitutions further within the S4–S5 linker such as p.Gly573 (Duchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google Scholar). In silico prediction tools (PolyPhen and Mutation Taster) predict all three variants at codon 568, p.Gly568Asp, p.Gly568Val (this study), and p.Gly568Cys (Duchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google Scholar) to be damaging. In our families, no other mutations were identified in TRPV3, and in Family 2, the parents were wild-type for p.Gly568 indicating a de novo mutation, p.Gly568Val, in the proband. Mutation p.Gly568Asp was shown to be dominantly inherited in Family 3; the mutation was identified in the proband and an affected paternal uncle (affected father is deceased). However, in the family reported with p.Gly568Cys in combination with a splice site mutation (Duchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google Scholar) the unaffected father was heterozygous for p.Gly568Cys and the clinical phenotype of the two affected brothers was significantly different. Overall, these findings suggest that environmental factors/modifier genes may also be involved in determining the phenotypic variability. TRPV3 is involved in many cellular and physiological processes. Recently, Cheng et al., 2010Cheng X. Jin J. Hu L. et al.TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.Cell. 2010; 141: 331-343Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar) demonstrated the important role of TRPV3 in regulating EGFR signaling in hair and skin barrier function using a TRPV3 knockout mouse model that developed a wavy hair coat and curly whiskers in addition to a red, dry scaly skin at birth, reminiscent of mice with a defective skin barrier. Although reported as a thermosensitive cation channel, activated at 30–33 °C, this thermosensory role is unclear (Nilius and Biro, 2013Nilius B. Biro T. TRPV3: a 'more than skinny' channel.Exp Dermatol. 2013; 22: 447-452Crossref PubMed Scopus (58) Google Scholar). Interestingly, coexistence of erythromelalgia with OS has been reported (Duchatelet et al., 2014Duchatelet S. Guibbal L. de Veer S. et al.Olmsted syndrome with erythromelalgia caused by recessive TRPV3 mutations.Br J Dermatol. 2014; 171: 675-678Crossref PubMed Scopus (23) Google Scholar, Duchatelet et al., 2014Duchatelet S. Pruvost S. de Veer S. et al.A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia.JAMA Dermatol. 2014; 150: 303-306Crossref PubMed Scopus (37) Google Scholar), and one of our patients has findings compatible with erythromelalgia. Many OS patients report hyperhidrosis (including four of ours). In this study, heterozygous missense mutations were identified in TRPV3 in six families, (two previously unreported and two recurrent mutations) with painful, palmoplantar keratoderma. were as severe as OS (Table 1). The cases we have described the phenotypic spectrum of Olmsted syndrome caused by mutations in Mutations in TRPV3 be considered as a cause of painful in the of periorificial hyperkeratosis and pseudoainhum as described by In and to painful caused by mutations in genes other than TRPV3 not be referred to as Olmsted The no of all the patients and families involved in this and and for also and Sprecher for and and to of Project for all her with data and are by from the Pachyonychia Congenita Project and The for and at the of is by a to Supplementary is to the online of the at at with Supplementary