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Olmsted syndrome (OS) is an extremely rare hereditary skin disease, that is usually characterized by mutilating palmoplantar keratoderma (PPK) and periorificial keratotic plaques. The diagnosis of this disease depends primarily on the clinical presentation and OS has to be differentiated from other disorders associated with hyperkeratosis. In recent years, there have been many advances in molecular genetic research on the pathogenesis of the disease. The genes that can cause disease after specific mutations include TRPV3, MBTPS2/S2P and PERP. Therefore, genetic testing has become one of the important methods for the diagnosis of this disease.OS treatment is difficult, and conventional therapy uses topical drugs to soften the cuticle of the skin, or oral Avi A.Excision of palmoplantar keratosis may also be used for constricting rings that severely restrict movement, but they often reoccur after initial improvement. In terms of precision treatment, researchers have tried the small molecule drugs erlotinib and sirolimus and have achieved some results. This paper summarizes the etiology, pathogenesis, clinical manifestations, diagnosis, treatment and prognosis of OS, in order to improve the clinicans' awareness of OS.

Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare genodermatosis characterized by a classic triad of follicular ichthyosis, alopecia, and photophobia. We report a Chinese patient displaying features of IFAP triad along with painful palmoplantar keratoderma, recurrent infections, periorificial keratotic plaques, nail dystrophy, and pachyonychia. Whole‐exome sequencing revealed an intronic variant (NM_015884.3: exon7:c.970+5G>A) in the gene MBTPS2. Sanger sequencing confirmed that the variant segerated with phenotype in the family. Sequencing of cDNAs derived from the patient indicated the variant introduced a new splice donor site, leading to partial skipping of exon 7 (r.951_970del). An in vitro mini‐gene assay also revealed abnormal splicing of exon 7. This study presents a case complicated with X‐linked IFAP syndrome and Olmsted syndrome, and highlights the significance of using validation assays to identify the pathogenicity of intronic variants in MBTPS2. [ABSTRACT FROM AUTHOR]

TRPV3 is a non-selective cation channel that is highly expressed in keratinocytes in the skin. Traditionally, keratinocytes-expressed TRPV3 is involved in multiple physiological and pathological functions of the skin, such as itching, heat pain, and hair development. Although the underlying mechanisms by which TRPV3 functions in vivo remain obscure, recent research studies suggest that several cytokines and EGFR signaling pathways may be involved. However, there have also been other studies with opposite results that question the role of TRPV3 in heat pain. In addition, an increasing number of studies have suggested a novel role of TRPV3 in promoting skin regeneration, indicating that TRPV3 may become a new potential target for regulating skin regeneration. This paper not only reviews the role of keratinocytes-expressed TRPV3 in the physiological and pathological processes of itching, heat pain, hair development, and skin regeneration, but also reviews the relationship between TRPV3 gene mutations and skin diseases such as atopic dermatitis (AD) and Olmsted syndrome (OS). This review will lay a foundation for further developing our understanding of the mechanisms by which TRPV3 is involved in itching, heat pain, and hair development, as well as the treatments for TRPV3-related skin diseases. [ABSTRACT FROM AUTHOR]

Genetic gain-of-function mutations of warm temperature-sensitive transient receptor potential vanilloid 3 (TRPV3) channel cause Olmsted syndrome characterized by severe itching and keratoderma, indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases. However, currently available TRPV3 tool inhibitors are either nonselective or less potent, thus impeding the validation of TRPV3 as therapeutic target. Using whole-cell patch-clamp and single-channel recordings, we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A (IAA) and isochlorogenic acid B (IAB) that selectively inhibit TRPV3 currents with IC50 values of 2.7 ± 1.3 and 0.9 ± 0.3 μmol/L, respectively, and reduce the channel open probability to 3.7 ± 1.2% and 3.2 ± 1.1% from 26.9 ± 5.5%, respectively. In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus. Furthermore, the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol. Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers. Taken together, our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology, but also holds developmental potential for treatment of dermatitis and chronic pruritus.

Olmsted syndrome (OS) is a rare genetic disorder, characterized by painful palmoplantar keratoderma (PPK), periorificial and intertriginous hyperkeratoses, and alopecia. Fewer than 75 cases have been described. Variants in TRPV3 result in constitutive activation of transient receptor potential vanilloid 3, leading to increased epidermal growth factor receptor (EGFR) signaling, palmoplantar epidermal hyperproliferation, and exquisite lesional pain. We describe pre‐school aged twins with OS with partial improvement from oral erlotinib, an EGFR inhibitor, but dramatic reduction of their persistent palmoplantar thickening and pain from adding acitretin. [ABSTRACT FROM AUTHOR]

Background: Olmsted syndrome is a rare and complex skin disorder affecting 46 (published) infants as of 2012. The infants affected in this case were born premature at 28 weeks' gestation. Infants affected by this syndrome demonstrate numerous plaques on several specific areas of the skin. Common treatments include exfoliation in addition to psoriasis treatments. The extremely fragile nature of the premature infants' skin complicates treatment modalities.Clinical Findings: The progression of the infants' dermatologic findings and plaque formation is discussed in this case study.Primary Diagnosis: The primary diagnosis of Olmsted syndrome was made with the assistance of a multidisciplinary team to work through several differential diagnoses presenting with severe forms of palmoplantar keratoderma.Interventions: The management of skin plaques in twin premature infants is presented in this case study. An evidence-based approach, utilizing the model of family-centered care, is presented with multidisciplinary involvement and an outline of the specific plan of care for the extensive skin care regimen used.Outcomes: An interdisciplinary skin care regimen was created to provide consistency in transition from hospital to home. Using a consistent approach, the plaques were able to be softened and many removed. Continual maintenance is required to manage continual buildup of skin plaques.Practice Recommendations: Premature infants are at increased risk for infection due to the immaturity of their skin. The complexity of their skin complicates the ability to recognize and care for rare skin disorders. This case study illuminates the practicality of a consistent and evidence-based approach to a complex and rare skin disorder. [ABSTRACT FROM AUTHOR]

Abstract The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane. The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses. While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX remains obscure. This review presents the biological role of MBTPS2 in development, summarizes its mutations and implicated disorders, and discusses outstanding unanswered questions.

Genetic gain-of-function mutations of warm temperature-sensitive transient receptor potential vanilloid 3 (TRPV3) channel cause Olmsted syndrome characterized by severe itching and keratoderma, indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases. However, currently available TRPV3 tool inhibitors are either nonselective or less potent, thus impeding the validation of TRPV3 as therapeutic target. Using whole-cell patch-clamp and single-channel recordings, we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A (IAA) and isochlorogenic acid B (IAB) that selectively inhibit TRPV3 currents with IC 50 values of 2.7 ± 1.3 and 0.9 ± 0.3 μmol/L, respectively, and reduce the channel open probability to 3.7 ± 1.2% and 3.2 ± 1.1% from 26.9 ± 5.5%, respectively. In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus. Furthermore, the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol. Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers. Taken together, our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology, but also holds developmental potential for treatment of dermatitis and chronic pruritus. Our identification of natural isochlorogenic acids A and B as specific TRPV3 channel inhibitors not only provides molecular tools but also holds therapeutic potential for dermatitis and chronic pruritus. [Display omitted] [ABSTRACT FROM AUTHOR]

Mutations of TRPV3 lead to severe dermal hyperkeratosis in Olmsted syndrome, but whether the mutants are trafficked to the cell membrane or not is controversial. Even less is known about TRPV3 function in intestinal epithelia, although research on ruminants and pigs suggests an involvement in the uptake of NH4+. It was the purpose of this study to measure the permeability of the human homologue (hTRPV3) to NH4+, to localize hTRPV3 in human skin equivalents, and to investigate trafficking of the Olmsted mutant G573S. Immunoblotting and immunostaining verified the successful expression of hTRPV3 in HEK-293 cells and Xenopus oocytes with trafficking to the cell membrane. Human skin equivalents showed distinct staining of the apical membrane of the top layer of keratinocytes with cytosolic staining in the middle layers. Experiments with pH-sensitive microelectrodes on Xenopus oocytes demonstrated that acidification by NH4+ was significantly greater when hTRPV3 was expressed. Single-channel measurements showed larger conductances in overexpressing Xenopus oocytes than in controls. In whole-cell experiments on HEK-293 cells, both enantiomers of menthol stimulated influx of NH4+ in hTRPV3 expressing cells, but not in controls. Expression of the mutant G573S greatly reduced cell viability with partial rescue via ruthenium red. Immunofluorescence confirmed cytosolic expression, with membrane staining observed in a very small number of cells. We suggest that expression of TRPV3 by epithelia may have implications not just for Ca2+ signalling, but also for nitrogen metabolism. Models suggesting how influx of NH4+ via TRPV3 might stimulate skin cornification or intestinal NH4+ transport are discussed. [ABSTRACT FROM AUTHOR]

Mutations of TRPV3 lead to severe dermal hyperkeratosis in Olmsted syndrome, but whether the mutants are trafficked to the cell membrane or not is controversial. Even less is known about TRPV3 function in intestinal epithelia, although research on ruminants and pigs suggests an involvement in the uptake of NH4+. It was the purpose of this study to measure the permeability of the human homologue (hTRPV3) to NH4+, to localize hTRPV3 in human skin equivalents, and to investigate trafficking of the Olmsted mutant G573S. Immunoblotting and immunostaining verified the successful expression of hTRPV3 in HEK-293 cells and Xenopus oocytes with trafficking to the cell membrane. Human skin equivalents showed distinct staining of the apical membrane of the top layer of keratinocytes with cytosolic staining in the middle layers. Experiments with pH-sensitive microelectrodes on Xenopus oocytes demonstrated that acidification by NH4+ was significantly greater when hTRPV3 was expressed. Single-channel measurements showed larger conductances in overexpressing Xenopus oocytes than in controls. In whole-cell experiments on HEK-293 cells, both enantiomers of menthol stimulated influx of NH4+ in hTRPV3 expressing cells, but not in controls. Expression of the mutant G573S greatly reduced cell viability with partial rescue via ruthenium red. Immunofluorescence confirmed cytosolic expression, with membrane staining observed in a very small number of cells. We suggest that expression of TRPV3 by epithelia may have implications not just for Ca2+ signalling, but also for nitrogen metabolism. Models suggesting how influx of NH4+ via TRPV3 might stimulate skin cornification or intestinal NH4+ transport are discussed. [ABSTRACT FROM AUTHOR]

We describe two siblings with diffuse, mutilating palmo-plantar keratoderma suggestive of Olmsted syndrome, with significantly compromised quality of life in the form of inability to walk and grasp objects. This was accompanied by severe pruritus and erythromelalgia-like symptoms. The keratoderma responded to acitretin therapy but there was paradoxical worsening of burning and pruritus which were further disabling. The poor response to medical and phototherapy in relieving these symptoms is described.

Olmsted syndrome is a rare genetic disorder characterized by severe thickening of the palms and soles, often resistant to conventional treatments. We present the case of a patient with Olmsted syndrome with a 16-year follow-up. The patient presented at five years of age with treatment-resistant palmoplantar keratoderma despite three years of dermatological management, leading to complications. Surgical interventions included initial debridement down to the deep dermis, which resulted in recurrence after three months. This was followed by a decision for extensive excision down to the subcutaneous tissue, use of a bilayer wound matrix dressing followed by negative pressure wound therapy, and a thin split-thickness graft, resulting in full resolution. The patient, now a college student, has regained normal daily activities. This case underscores the challenges and highlights a novel surgical approach for managing Olmsted syndrome, demonstrating a 16-year follow-up and aiming to improve patient outcomes in these complex cases., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Khan et al.)

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3 +/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3 +/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None disclosed.

The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane. The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses. While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX remains obscure. This review presents the biological role of MBTPS2 in development, summarizes its mutations and implicated disorders, and discusses outstanding unanswered questions. [ABSTRACT FROM AUTHOR]

We describe two siblings with diffuse, mutilating palmo-plantar keratoderma suggestive of Olmsted syndrome, with significantly compromised quality of life in the form of inability to walk and grasp objects. This was accompanied by severe pruritus and erythromelalgia-like symptoms. The keratoderma responded to acitretin therapy but there was paradoxical worsening of burning and pruritus which were further disabling. The poor response to medical and phototherapy in relieving these symptoms is described. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid-3 (TRPV3) ion channels are prominently expressed in keratinocytes, playing a vital role in skin functions. Honokiol and magnolol (H&M) the primary bioactive constituents in Magnolia officinalis extract, demonstrate anti-inflammatory and skin-protective properties. Nevertheless, the underlying mechanism regarding their effect on Ca2+-permeable ion channels remain unclear. Our purpose in this study is to investigate the effect of H&M on TRPV3 and cytokine release in normal human epidermal keratinocytes (NHEKs), including its gain-of-function (GOF) mutants (G573S and G573C) associated with Olmstead syndrome. We performed whole-cell patch-clamp, fura-2 spectrofluorimetry to investigate channels activity, CCK-8 assay to analyze cell death and enzyme-linked immunosorbent assay to assess the cytokine release from NHEKs. H&M inhibited the TRPV3 current (I TRPV3) and cytosolic calcium increase in NHEKs, HEK293T cells overexpressing hTRPV3 and its GOF mutants. Moreover, the release of pro-inflammatory cytokines (interleukin-6 and -8) from keratinocytes stimulated by TRPV3 agonist was effectively suppressed by H&M. Our findings provide insights into the mechanism underlying the anti-inflammatory effects of H&M, highlighting their potential in treating skin diseases. [Display omitted] • Honokiol and magnolol (H&M) inhibit TRPV3 in human epidermal keratinocytes. • H&M inhibit overactive TRPV3 variants linked with Olmsted syndrome. • H&M suppress IL-6 and IL-8 release through TRPV3 in keratinocytes. • H&M can be potentially used to treat inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Olmsted syndrome (OS) is a rare congenital, mutilating palmoplantar keratoderma first described by Olmsted in 1927. It starts in the neonatal period or in childhood, and has a slow but progressive disabling course. We report the case of a 16-year-old boy who presented with keratoderma of the palm and soles since childhood with lateral supraciliary madarosis and clubbing. The patient was started on oral retinoids and topical keratolytics and had partial improvement in 2 months. Keratoderma of the palms and soles along with lateral supraciliary madarosis and clubbing in our case is a very rare finding, and to the best of our knowledge, has not been reported so far.

Olmsted syndrome is a rare genodermatosis. Palmoplantar keratoderma and periorificial keratodermic plaques are the most important clinical findings. Additional findings associated with a large number of systems may accompany such as teeth, nail deformities, alopecia, mental retardation, and bone–joint anomalies. Therefore, it is difficult to make a differential diagnosis from other palmoplantar keratodermas. It also needs to be differentiated from acrodermatitis enteropathica because of periorificial plaques. The absence of regression in lesions with zinc treatment excludes this disease. We present here an Olmsted syndrome case with essential thrombocytosis for the first time.

Olmsted syndrome (OS) is a rare congenital, sharply circumscribed transgredient palmoplantar keratoderma, first described by Olmsted in 1927, characterized by clinical features such as symmetrical involvement of keratoderma of the palms and soles and the symmetrical hyperkeratotic plaques around the body orifices. Other clinical findings include flexion deformities of the fingers, localized alopecia, leukokeratosis of the tongue, short stature, and laxity of the large joints. It starts in the neonatal period or in childhood. The disease has a slow but progressive and extremely disabling course. Treatment of OS is often based on topical therapy with retinoic acid, corticosteroid, emollients, and keratolytics. We present a case of OS in three siblings, two males and a female, born to nonconsanguineous parents with no family history. They were treated with topical corticosteroids and emollients and showed mild improvement in symptoms.

We report a case of mutilating keratoderma with alopecia and keratoses follicularis spinulosa decalvans (KFSD), which was initially diagnosed as ectodermal dysplasia and Olmsted syndrome but was revisited as a case of X-linked Olmsted (XLO) syndrome. We focus on this uncommon entity (XLO) to highlight the differentials of alopecia with palmoplantar keratoderma.

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. [ABSTRACT FROM AUTHOR]

Olmsted syndrome is a very rare congenital disorder, characterized by palmoplantar keratoderma and periorificial keratotic lesions. Recently, TRPV3 was reported to be a causative gene of Olmsted syndrome. We identified a heterozygous missense mutation of TRPV3, c.1703G>T, p.Gly568Val, in a Japanese patient with Olmsted syndrome. To the best of our knowledge, this is the first report of a Japanese patient with Olmsted syndrome harboring a missense mutation in TRPV3. We conducted in silico analysis of TRPV3 to evaluate whether the p.Gly568Val leads to structural changes in the TRPV3 selectivity filter. The selectivity filter was shown to become dilated and hyperpermeable as a result of genetic mutation (p.Gly573Ser, p.Tr692Gly or p.Gly568Val) as well as after a change in temperature (300 K to 310 K). In silico analysis of TRPV3 could be a useful approach in predicting mutation-induced activated states of ion channels, and thus enrich our understanding of the pathogenesis of Olmsted syndrome. [ABSTRACT FROM AUTHOR]

Background Olmsted syndrome (OS) is a congenital dermatosis characterized by palmoplantar keratoderma and periorificial keratotic plaque. TRPV3 (transient receptor potential vanilloid subtype 3) encodes a thermosensitive Ca 2+ channel and is the causative gene of OS. However, the molecular mechanism that causes the pathological development of OS is unclear. Objective We aimed to investigate the molecular mechanisms underlying OS pathology from the perspective of lipid metabolism. Methods Comprehensive lipidomics and microarray analyses were conducted on tissue samples from a non-lesional skin area of OS model rats ( Ht rats) and from wild type (WT) rats as the control. Results Infiltration of leukocytes such as eosinophils and neutrophils and an increase in the fibrotic region were detected in the unaffected skin area of Ht rats compared with the WT rats. Among about 600 lipid species examined, the levels of 15-lipoxygenase (LOX) metabolites, the precursors of anti-inflammatory and pro-resolving lipid mediators, and dihydroceramides decreased by ≥16-fold in Ht rats compared with WT rats. Consistent with the decreases in the 15-LOX metabolites, expression levels of the genes that encode the 15-LOXs, Alox15 and Alox15b , were largely reduced. Conversely, increased expression levels were detected of Il36b , Ccl20 , Cxcl1 , and Cxcl2 , which encode cytokines/chemokines, and S100a8 and S100a9 , which encode the Ca 2+ binding proteins that are implicated in epidermal proliferation. Conclusion The pro-inflammatory state in the unaffected skin of Ht rats caused by decreases in 15-LOX metabolites and increases in cytokines/chemokines may contribute to the pathogenesis of OS. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist. [ABSTRACT FROM AUTHOR]

Olmsted syndrome is a very rare and severe cicatrizing keratoderma associated with periorificial lesion. Most cases are sporadic but familial occurrence has been also seen. Till now around 73 cases have been reported and none of the reported cases have 4 siblings affected from this disease. We are reporting cases of 4 siblings of age 30 year female, 26 year female, 20 year male and 10 year male who were born to a third degree consangueinous marriage and presented with palmoplantar keratoderma, periorificial hyperkeratosis, flexion deformity, pseudoainhum and contracture of digits. There was no cardiac involvement. Hence, the diagnosis of Olmsted syndrome was made and all four patients were non responsive to treatment which included topical corticosteroid, topical salicylic acid, systemic isotretinoin, systemic acitretin and oral zinc in child. [ABSTRACT FROM AUTHOR]

Olmsted syndrome (OS) is a rare congenital, mutilating palmoplantar keratoderma first described by Olmsted in 1927. It starts in the neonatal period or in childhood, and has a slow but progressive disabling course. We report the case of a 16-year-old boy who presented with keratoderma of the palm and soles since childhood with lateral supraciliary madarosis and clubbing. The patient was started on oral retinoids and topical keratolytics and had partial improvement in 2 months. Keratoderma of the palms and soles along with lateral supraciliary madarosis and clubbing in our case is a very rare finding, and to the best of our knowledge, has not been reported so far. [ABSTRACT FROM AUTHOR]

We report a case of mutilating keratoderma with alopecia and keratoses follicularis spinulosa decalvans (KFSD), which was initially diagnosed as ectodermal dysplasia and Olmsted syndrome but was revisited as a case of X-linked Olmsted (XLO) syndrome. We focus on this uncommon entity (XLO) to highlight the differentials of alopecia with palmoplantar keratoderma. [ABSTRACT FROM AUTHOR]

Olmsted syndrome is an uncommon genetic disorder with symmetrical, diffuse, transgredient, mutilating palmoplantar keratoderma and periorificial hyperkeratosis. Olmsted syndrome in a female patient is particularly rare, and we report two unrelated female patients of Olmsted syndrome, who presented with perioral hyperkeratosis and palmoplantar keratoderma. One of our patients also had woolly hair from birth and flexion contracture of a digit, while the other had pseudoainhum. There was no cardiac involvement. Hence, the diagnosis of Olmsted syndrome was made.

Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. The disease starts usually at birth or in early childhood. About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe. Most of reported OS cases are sporadic, although familial cases with different mode of inheritance were also described. Mutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features. OS has to be differentiated from other severe forms of PPK including Vohwinkel, Clouston, Papillon-Lefèvre or Haim-Munk syndromes, Mal de Meleda, pachyonychia congenita, Tyrosinemia type II and acrodermatitis enteropathica. When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation. However, additional genes remain to be identified. No specific and satisfactory therapy is currently available for OS. Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief. Specific management of pain and itching is important to reduce the morbidity of the disease. The disease is debilitating and progressive keratoderma and auto-amputation of digits can prevent patients from grasping and walking, and confine them to a wheelchair. New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms. The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy. Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. The disease starts usually at birth or in early childhood. About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe. Most of reported OS cases are sporadic, although familial cases with different mode of inheritance were also described. Mutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features. OS has to be differentiated from other severe forms of PPK including Vohwinkel, Clouston, Papillon-Lefevre or Haim-Munk syndromes, Mal de Meleda, pachyonychia congenita, Tyrosinemia type II and acrodermatitis enteropathica. When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation. However, additional genes remain to be identified. No specific and satisfactory therapy is currently available for OS. Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief. Specific management of pain and itching is important to reduce the morbidity of the disease. The disease is debilitating and progressive keratoderma and auto-amputation of digits can prevent patients from grasping and walking, and confine them to a wheelchair. New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms. The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy. [ABSTRACT FROM AUTHOR]

Olmsted syndrome is a rare disorder characterized by the combination of periorificial, keratotic plaques and bilateral palmoplantar keratoderma. New associated features are being reported. Olmsted syndrome is particularly rare in a female patient, and we report such a case in a six year-old Indian girl, who presented with keratoderma of her soles since birth and on her palms since the age of two years along with perioral and perinasal hyperkeratosis. She had sparse, light brown, thin hair. Although the psychomotor development of the child was normal until 18 months of age, the keratoderma plaques had restricted the child′s mobility after that stage.

Olmsted syndrome (OS) is a rare congenital, sharply circumscribed transgredient palmoplantar keratoderma, first described by Olmsted in 1927, characterized by clinical features such as symmetrical involvement of keratoderma of the palms and soles and the symmetrical hyperkeratotic plaques around the body orifices. Other clinical findings include flexion deformities of the fingers, localized alopecia, leukokeratosis of the tongue, short stature, and laxity of the large joints. It starts in the neonatal period or in childhood. The disease has a slow but progressive and extremely disabling course. Treatment of OS is often based on topical therapy with retinoic acid, corticosteroid, emollients, and keratolytics. We present a case of OS in three siblings, two males and a female, born to nonconsanguineous parents with no family history. They were treated with topical corticosteroids and emollients and showed mild improvement in symptoms. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist.

Olmsted syndrome is a very rare and severe cicatrizing keratoderma associated with periorificial lesion. Most cases are sporadic but familial occurrence has been also seen. Till now around 73 cases have been reported and none of the reported cases have 4 siblings affected from this disease. We are reporting cases of 4 siblings of age 30 year female, 26 year female, 20 year male and 10 year male who were born to a third degree consangueinous marriage and presented with palmoplantar keratoderma, periorificial hyperkeratosis, flexion deformity, pseudoainhum and contracture of digits. There was no cardiac involvement. Hence, the diagnosis of Olmsted syndrome was made and all four patients were non responsive to treatment which included topical corticosteroid, topical salicylic acid, systemic isotretinoin, systemic acitretin and oral zinc in child.

Background: Olmsted syndrome is a rare keratinization disorder characterized by a combination of periorificial keratotic plaques and bilateral palmoplantar transgredient keratoderma. Other clinical manifestations include diffuse alopecia, leukokeratosis of the oral mucosa, onychodystrophy, hyperkeratotic linear streaks, follicular hyperkeratosis and constriction of digits. Main observations: We report a case of Olmsted syndrome in a 5-year-old male presented by mutilating palmoplantar keratoderma, perioral keratoses and linear hyperkeratotic lower limb plaques. Conclusions: Olmsted syndrome is a rare genodermatosis with only 43 cases reported so far. We present another case of the disease. [ABSTRACT FROM AUTHOR]

Background: Olmsted syndrome is a rare congenital skin disorder presenting with periorifical hyperkeratotic lesions and mutilating palmoplantar keratoderma, which is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of Olmsted syndrome. Methods: Genetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of Olmsted syndrome. Results: The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation. In depth clinical and immunological analysis found multiple indicators of immune dysregulation, including frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood. Conclusions: These results provide the first comprehensive assessment of the immunological features of Olmsted syndrome. The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome, and have important clinical consequences with regard to the treatment of Olmsted syndrome patients. [ABSTRACT FROM AUTHOR]