RARE DISEASE
Mutilating palmoplantar keratoderma with periorificial keratotic plaques
Mutilating palmoplantar keratoderma with periorificial keratotic plaques
Mutilating palmoplantar keratoderma with periorificial keratotic plaques
Synonyms: Mutilating palmoplantar hyperkeratosis with periorificial keratotic plaques, Olmsted syndrome, Palmoplantar and periorificial keratoderma
Synonyms: Mutilating palmoplantar hyperkeratosis with periorificial keratotic plaques, Olmsted syndrome, Palmoplantar and periorificial keratoderma
Synonyms: Mutilating palmoplantar hyperkeratosis with periorificial keratotic plaques, Olmsted syndrome, Palmoplantar and periorificial keratoderma
Drug discovery
5
drugs
With orphan designations
Overview
Mutilating palmoplantar keratoderma with periorificial keratotic plaques (Olmsted syndrome) is an ultra-rare genodermatosis characterized by bilateral transgredient palmoplantar hyperkeratosis, periorificial plaques, and digital constrictions leading to spontaneous amputation. Autosomal dominant or X-linked inheritance is linked to TRPV3 or MBTPS2 mutations. Onset occurs in infancy/early childhood, with complications including severe infections, mobility limitations, and squamous cell carcinoma risk [1][2][4][15].
Therapies
Categories: rare genetic diseases, rare skin diseases
Research Papers
55 drug discovery papers about Mutilating palmoplantar keratoderma with periorificial keratotic plaques, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
55 drug discovery papers about Mutilating palmoplantar keratoderma with periorificial keratotic plaques, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2024-09-01 | Cutting Through Complexity: Surgical Management of Severe Palmoplantar Keratoderma.
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.
2016-02-01 | Using a Distant Abdominal Skin Flap to Treat Digital Constriction Bands
In this study, a Vohwinkel syndrome case is presented where in 5th digit constriction bands in the right hand were reconstructed using a distant abdominal skin flap. Vohwinkel syndrome, or keratoderma hereditarium mutilans, is a rare, autosomal dominant genetic skin condition that causes palmoplantar hyperkeratosis and constricts finger and/or toe bands. In a typical manifestation, the finger and toe constriction bands lead to progressive strangulation and autoamputation, which requires immediate clinical treatment. Topical keratolytics and systemic retinoids have been used to treat hyperkeratosis but without consistent results. Only 1 effective approach for autoamputation has been accepted, reconstructive surgery. Applying a distant abdominal skin flap produced satisfying postoperative effects at the 18-month follow-up.
2008-03-01 | Palmoplantar Keratoderma and Skin Grafting: Postsurgical Long‐term Follow‐up of Two Cases with Olmsted Syndrome
Abstract: Olmsted syndrome is a rare congenital mutilating palmoplantar keratoderma associated with periorificial keratotic plaques. Treatment options include topical keratolytics, systemic retinoids, and debulking procedures. Full‐thickness excision of hyperkeratotic plaques followed by skin grafting has been reported in the medical literature, although long‐term results have not been evaluated. We present two cases of Olmsted syndrome with severe palmoplantar keratoderma treated with excision and skin grafting, along with long‐term clinical results 11 years (patient 1) and 6 years (patient 2) following the initial surgery.
1990-02-01 | Mutilating palmoplantar keratoderma with periorificial keratotic plaques (Olmsted's syndrome)
We report the case of a boy, now aged 4 years, with a progressive, painful and disabling palmoplantar keratoderma, associated with well-defined hyperkeratotic plaques around the mouth and nostrils. His mother has an identical palmoplantar keratoderma. The palmoplantar keratoderma failed to improve with etretinate, but considerable benefit resulted from full-thickness excision of the skin of both palms, followed by skin grafting. We believe that he has a distinctive but extremely rare form of hereditary palmoplantar keratoderma, first described by Olmsted.
small molecules
2026-09-11 | Palmoplantar Keratoderma: A Mechanism-Based Disease Classification.
Palmoplantar keratoderma (PPK) represents a diagnostically challenging group of genodermatoses due to its extensive genetic heterogeneity. Although multiple causative genes have been identified, the clinical utility of these discoveries remains limited, because few studies directly compare how distinct molecular mechanisms translate into divergent clinical phenotypes. We describe and analyze three paradigmatic PPK cases with genetically confirmed diagnoses involving SERPINB7-related Nagashima-type PPK, TRPV3-related Olmsted spectrum disorder, and KRT1-associated PPK. Clinical features, disease severity, and genetic mutations were systematically compared. These observations generated a novel classification framework and were then integrated with a comprehensive review of contemporary literature to contextualize and support the comparative findings. Three patients with palmoplantar keratoderma (PPK) harboring distinct pathogenic variants were analyzed and comparatively evaluated. Despite overlapping clinical features, these cases corresponded to three distinct pathogenic mechanisms: defective barrier homeostasis, overactive signaling, and structural collapse. A mechanism-based classification framework was established accordingly. Through comprehensive literature review, 56 PPK-associated genes were identified, the majority of which could be systematically assigned to the three mechanistic categories based on their primary molecular functions. This study highlights that clinically overlapping PPK phenotypes arise from distinct molecular mechanisms. Our mechanism-based classification provides a framework linking genotype to pathogenesis, which may improve diagnostic precision, support the development of mechanism-targeted therapeutic strategies, and thereby advancing personalized management in hereditary PPK.
2025-08-27 | Treatment of Olmsted Syndrome With Erlotinib
The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2025-02-10 | Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report.
Olmsted syndrome (OS) is a rare disorder characterized by a mutilating palmoplantar keratoderma and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. Recently, transient receptor potential vanilloid 3 (TRPV3) mutations associated with autosomal dominant or recessive OS have been reported. Here we describe a classically OS case with definitive diagnosis of OS based on clinical features and a genetic assay. Genetic analysis revealed heterozygous variants in the TRPV3 gene using whole-exome sequencing of case-parents' trios. This mutation was not identified in his mother. Notably, a previously unreported heterozygous frameshift mutation, c.1964 T > C (p.L655P), was identified in exon 15 of the TRPV3 gene in this patient and his father. Additionally, the patient was effectively managed with oral erlotinib at a daily dose of 75 mg. After 3 months of treatment, most plantar lesions resolved, and the pain experienced was mildly alleviated. No significant adverse effects were observed in this case during treatment. In addition, we review the OS literature regarding TRPV3 gene mutations.
2025-02-06 | TRPV3 Mutation-Associated Olmsted Syndrome in a Hispanic Patient: Response to Erlotinib and Review of Literature.
Olmsted syndrome (OS) is a rare genetic condition characterized by severe palmoplantar and periorificial keratoderma, often linked to TRPV3 gene mutations. This case report describes a 23-month-old Hispanic boy with TRPV3-associated OS who initially showed limited improvement with acitretin but experienced substantial recovery with the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. A review of the literature indicates that erlotinib has shown efficacy in other cases of OS, making it a promising therapeutic option. This report underscores erlotinib's potential to effectively manage TRPV3 mutation-associated OS, especially when traditional treatments fail.
2024-12-25 | Atypical presentation of TRPV3 variant: Cerebral palsy and intellectual disability without dermatologic features of olmsted syndrome
To the Editor: Olmsted syndrome (OS) is a rare genodermatosis, with limited cases reported globally, primarily characterized by progressive palmoplantar keratoderma and keratotic plaques, and is linked to mutations in the TRPV3 gene on chromosome 17p13.2.1,2 We read with great interest the case report by Frantz et al, which describes a mild presentation of OS due to a loss-of-function mutation in the TRPV3 gene (transient receptor potential vanilloid-3).3 Their patient exhibited dermatologic features, including nonpruritic hyperkeratotic palms and soles with scarring alopecia. Here, we report a 17-year-old male of Asian descent, with cerebral palsy and intellectual disability, but without any dermatologic features typically associated with OS, despite carrying a TRPV3 variant (Fig 1). He was referred for psychiatric evaluation due to academic decline, impulsivity, and emotional dysregulation. A physical exam demonstrated no evidence of palmoplantar keratoderma, periorificial plaques, or any other skin lesions. Cognitive testing revealed an FSIQ of 69 (95% confidence interval, 65-76), indicating intellectual disability. Genome-wide oligonucleotide array-based comparative genomic hybridization analysis, performed using the Human Genome CGH Microarray kit, identified an intragenic deletion of approximately 13 kilobases (kb) in the TRPV3 gene at cytogenetic band 17p13.2. The deleted genomic segment included exons 3-8 of the TRPV3 gene (arr[GRCh38] 17p13.2(3532389_3545489)×1). Since parental genetic data were unavailable, it remains unclear whether this variant was inherited or de novo.
gene therapies
2025-04-02 | Papillomavirus-like particles as vectors for ex vivo gene therapy of the skin.
Ex vivo gene delivery to the skin utilizing retroviral vectors has been demonstrated to be a viable clinical option for replacement of defective genes. However, because these vectors integrate their cargo into the genome, safety issues arise when utilizing them to deliver gene-editing nucleases. Here, we explored the use of Papillomavirus, a non-integrating viral vector, for ex vivo skin gene editing, exploiting its natural tropism for basal keratinocytes. We demonstrated that Papillomavirus-like particles (PVLPs) can deliver a variety of DNA constructs encoding fluorophores, Cre recombinase, calcium indicators, Cas9, and short hairpin RNA (shRNA) to keratinocytes, offering advantages over other viral vectors such as adeno-associated virus (AAV) and Lentivirus. We further showed that PVLPs can be used for gene therapy for Olmsted syndrome, a genetic skin disease caused by a gain-of-function mutation in the Trpv3 gene. Specifically, PVLP-delivered SaCas9 and shRNA effectively disrupted the Trpv3 gene or reduced its expression, leading to decreased TRPV3 activity and mitigating the hyperactivity associated with Olmsted syndrome. Skin equivalents generated from PVLP-treated keratinocytes exhibited complete transduction, and PVLP-shRNA treatment significantly reduced hyperkeratosis in skin equivalents from mice bearing the Olmsted syndrome mutation. These findings highlight PVLP as a promising tool for ex vivo skin gene therapy.
cell therapies
2024-09-01 | Cutting Through Complexity: Surgical Management of Severe Palmoplantar Keratoderma.
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.
2016-02-01 | Using a Distant Abdominal Skin Flap to Treat Digital Constriction Bands
In this study, a Vohwinkel syndrome case is presented where in 5th digit constriction bands in the right hand were reconstructed using a distant abdominal skin flap. Vohwinkel syndrome, or keratoderma hereditarium mutilans, is a rare, autosomal dominant genetic skin condition that causes palmoplantar hyperkeratosis and constricts finger and/or toe bands. In a typical manifestation, the finger and toe constriction bands lead to progressive strangulation and autoamputation, which requires immediate clinical treatment. Topical keratolytics and systemic retinoids have been used to treat hyperkeratosis but without consistent results. Only 1 effective approach for autoamputation has been accepted, reconstructive surgery. Applying a distant abdominal skin flap produced satisfying postoperative effects at the 18-month follow-up.
2008-03-01 | Palmoplantar Keratoderma and Skin Grafting: Postsurgical Long‐term Follow‐up of Two Cases with Olmsted Syndrome
Abstract: Olmsted syndrome is a rare congenital mutilating palmoplantar keratoderma associated with periorificial keratotic plaques. Treatment options include topical keratolytics, systemic retinoids, and debulking procedures. Full‐thickness excision of hyperkeratotic plaques followed by skin grafting has been reported in the medical literature, although long‐term results have not been evaluated. We present two cases of Olmsted syndrome with severe palmoplantar keratoderma treated with excision and skin grafting, along with long‐term clinical results 11 years (patient 1) and 6 years (patient 2) following the initial surgery.
1990-02-01 | Mutilating palmoplantar keratoderma with periorificial keratotic plaques (Olmsted's syndrome)
We report the case of a boy, now aged 4 years, with a progressive, painful and disabling palmoplantar keratoderma, associated with well-defined hyperkeratotic plaques around the mouth and nostrils. His mother has an identical palmoplantar keratoderma. The palmoplantar keratoderma failed to improve with etretinate, but considerable benefit resulted from full-thickness excision of the skin of both palms, followed by skin grafting. We believe that he has a distinctive but extremely rare form of hereditary palmoplantar keratoderma, first described by Olmsted.
small molecules
2026-09-11 | Palmoplantar Keratoderma: A Mechanism-Based Disease Classification.
Palmoplantar keratoderma (PPK) represents a diagnostically challenging group of genodermatoses due to its extensive genetic heterogeneity. Although multiple causative genes have been identified, the clinical utility of these discoveries remains limited, because few studies directly compare how distinct molecular mechanisms translate into divergent clinical phenotypes. We describe and analyze three paradigmatic PPK cases with genetically confirmed diagnoses involving SERPINB7-related Nagashima-type PPK, TRPV3-related Olmsted spectrum disorder, and KRT1-associated PPK. Clinical features, disease severity, and genetic mutations were systematically compared. These observations generated a novel classification framework and were then integrated with a comprehensive review of contemporary literature to contextualize and support the comparative findings. Three patients with palmoplantar keratoderma (PPK) harboring distinct pathogenic variants were analyzed and comparatively evaluated. Despite overlapping clinical features, these cases corresponded to three distinct pathogenic mechanisms: defective barrier homeostasis, overactive signaling, and structural collapse. A mechanism-based classification framework was established accordingly. Through comprehensive literature review, 56 PPK-associated genes were identified, the majority of which could be systematically assigned to the three mechanistic categories based on their primary molecular functions. This study highlights that clinically overlapping PPK phenotypes arise from distinct molecular mechanisms. Our mechanism-based classification provides a framework linking genotype to pathogenesis, which may improve diagnostic precision, support the development of mechanism-targeted therapeutic strategies, and thereby advancing personalized management in hereditary PPK.
2025-08-27 | Treatment of Olmsted Syndrome With Erlotinib
The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2025-02-10 | Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report.
Olmsted syndrome (OS) is a rare disorder characterized by a mutilating palmoplantar keratoderma and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. Recently, transient receptor potential vanilloid 3 (TRPV3) mutations associated with autosomal dominant or recessive OS have been reported. Here we describe a classically OS case with definitive diagnosis of OS based on clinical features and a genetic assay. Genetic analysis revealed heterozygous variants in the TRPV3 gene using whole-exome sequencing of case-parents' trios. This mutation was not identified in his mother. Notably, a previously unreported heterozygous frameshift mutation, c.1964 T > C (p.L655P), was identified in exon 15 of the TRPV3 gene in this patient and his father. Additionally, the patient was effectively managed with oral erlotinib at a daily dose of 75 mg. After 3 months of treatment, most plantar lesions resolved, and the pain experienced was mildly alleviated. No significant adverse effects were observed in this case during treatment. In addition, we review the OS literature regarding TRPV3 gene mutations.
2025-02-06 | TRPV3 Mutation-Associated Olmsted Syndrome in a Hispanic Patient: Response to Erlotinib and Review of Literature.
Olmsted syndrome (OS) is a rare genetic condition characterized by severe palmoplantar and periorificial keratoderma, often linked to TRPV3 gene mutations. This case report describes a 23-month-old Hispanic boy with TRPV3-associated OS who initially showed limited improvement with acitretin but experienced substantial recovery with the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. A review of the literature indicates that erlotinib has shown efficacy in other cases of OS, making it a promising therapeutic option. This report underscores erlotinib's potential to effectively manage TRPV3 mutation-associated OS, especially when traditional treatments fail.
2024-12-25 | Atypical presentation of TRPV3 variant: Cerebral palsy and intellectual disability without dermatologic features of olmsted syndrome
To the Editor: Olmsted syndrome (OS) is a rare genodermatosis, with limited cases reported globally, primarily characterized by progressive palmoplantar keratoderma and keratotic plaques, and is linked to mutations in the TRPV3 gene on chromosome 17p13.2.1,2 We read with great interest the case report by Frantz et al, which describes a mild presentation of OS due to a loss-of-function mutation in the TRPV3 gene (transient receptor potential vanilloid-3).3 Their patient exhibited dermatologic features, including nonpruritic hyperkeratotic palms and soles with scarring alopecia. Here, we report a 17-year-old male of Asian descent, with cerebral palsy and intellectual disability, but without any dermatologic features typically associated with OS, despite carrying a TRPV3 variant (Fig 1). He was referred for psychiatric evaluation due to academic decline, impulsivity, and emotional dysregulation. A physical exam demonstrated no evidence of palmoplantar keratoderma, periorificial plaques, or any other skin lesions. Cognitive testing revealed an FSIQ of 69 (95% confidence interval, 65-76), indicating intellectual disability. Genome-wide oligonucleotide array-based comparative genomic hybridization analysis, performed using the Human Genome CGH Microarray kit, identified an intragenic deletion of approximately 13 kilobases (kb) in the TRPV3 gene at cytogenetic band 17p13.2. The deleted genomic segment included exons 3-8 of the TRPV3 gene (arr[GRCh38] 17p13.2(3532389_3545489)×1). Since parental genetic data were unavailable, it remains unclear whether this variant was inherited or de novo.
gene therapies
2025-04-02 | Papillomavirus-like particles as vectors for ex vivo gene therapy of the skin.
Ex vivo gene delivery to the skin utilizing retroviral vectors has been demonstrated to be a viable clinical option for replacement of defective genes. However, because these vectors integrate their cargo into the genome, safety issues arise when utilizing them to deliver gene-editing nucleases. Here, we explored the use of Papillomavirus, a non-integrating viral vector, for ex vivo skin gene editing, exploiting its natural tropism for basal keratinocytes. We demonstrated that Papillomavirus-like particles (PVLPs) can deliver a variety of DNA constructs encoding fluorophores, Cre recombinase, calcium indicators, Cas9, and short hairpin RNA (shRNA) to keratinocytes, offering advantages over other viral vectors such as adeno-associated virus (AAV) and Lentivirus. We further showed that PVLPs can be used for gene therapy for Olmsted syndrome, a genetic skin disease caused by a gain-of-function mutation in the Trpv3 gene. Specifically, PVLP-delivered SaCas9 and shRNA effectively disrupted the Trpv3 gene or reduced its expression, leading to decreased TRPV3 activity and mitigating the hyperactivity associated with Olmsted syndrome. Skin equivalents generated from PVLP-treated keratinocytes exhibited complete transduction, and PVLP-shRNA treatment significantly reduced hyperkeratosis in skin equivalents from mice bearing the Olmsted syndrome mutation. These findings highlight PVLP as a promising tool for ex vivo skin gene therapy.
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Drug Discovery Landscape
5 orphan drug designations for Mutilating palmoplantar keratoderma with periorificial keratotic plaques.
5 orphan drug designations for Mutilating palmoplantar keratoderma with periorificial keratotic plaques.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
(R)-(3-(2'-cyclopropyl-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)pyrrolidin-1-yl)(5-hydroxy-6-methylpyridin-2-yl)methanone | small molecules | EMA | — | FGK Representative Service GmbH |
(R)-(3-(2'-cyclopropyl-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)pyrrolidin-1-yl)(5-hydroxy-6-methylpyridin-2-yl)methanone | small molecules | FDA | Orvida Pharma Ltd. | |
(R)-(3-(2'-cyclopropyl-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl) pyrrolidin-1-yl)(5-fluoropyridin-2-yl)methanone | small molecules | EMA | — | Granzer Regulatory Consulting & Services GmbH |
(R)-(3-(2'-cyclopropyl-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl) pyrrolidin-1-yl)(5-fluoropyridin-2-yl)methanone | small molecules | FDA | Orvida Pharma Ltd. | |
Erlotinib | small molecules | EMA | Imagine Institut Des Maladies Genetiques Necker Enfants Malades |
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