DeCure for Epidermolytic palmoplantar keratoderma, 1
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for epidermolytic palmoplantar keratoderma, 1 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleEpidermolytic palmoplantar keratoderma, 1 maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for epidermolytic palmoplantar keratoderma, 1 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
keratin 1 (KRT1) — KRT1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet bogdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6UUI · 2.069 Å · ligand octyl beta-D-glucopyranoside (BOG). Experimental structure, not a prediction.
What the evidence adds up to
Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant disorder of keratinization. A 2002 study of five members of a Jewish family found the mutation in exon 1 of the keratin 9 gene, in codon 160. A 2003 report of the first Swedish family with EPPK identified a de novo mutation in KRT9; the authors note that all mutations reported to date, with one exception, are located in the keratin 9 gene on chromosome 17, and the position most frequently mutated is the arginine codon at position 162 in exon 1. A 2013 review states that the three major patterns of palmoplantar keratoderma are diffuse, focal and punctate.
A 2021 systematic review of drug-induced palmoplantar keratoderma included 247 patients (mean age 57.0 years; 60.3% male where sex was reported). PPK most frequently developed after treatment with BRAF inhibitors (73.7%, 182/247), BRAF inhibitors combined with MEK1/2 inhibitors (15.4%, 38/247), tyrosine kinase inhibitors (3.2%, 8/247), or chemotherapy (2.4%, 6/247). The mean latency between starting the drug and onset of PPK was 7.6 months (range 0.25–90 months). Improvement was reported in 24 cases: 50% achieved complete resolution and 50% partial resolution. All patients who achieved complete resolution stopped the suspected drug, with a mean resolution period of 2.4 months (range 2 weeks–6 months). The most common treatments for PPK were keratolytic treatments (n=10) and topical corticosteroids (n=4). This review does not address EPPK specifically; it covers acquired, drug-induced PPK.
A 2024 case report describes a five-year-old girl with severe palmoplantar keratoderma resistant to medical management, who was wheelchair-bound with repeated hospital admissions for sepsis. She was managed with excision of keratoderma from the feet down to subcutaneous tissue, Integra placement with negative pressure wound therapy, and thin split-thickness skin grafts. A similar procedure was performed on the hands. After 16 years, the patient is a college student who walks with stability, can take notes and type, and has almost full range of motion in her fingers. The authors note that based on a PubMed search of 265 articles, this surgical approach with 16-year follow-up data has not been reported before.
What is still missing: no clinical trial has tested any drug specifically for EPPK; the genetic basis is well described but no targeted therapy has been developed; the surgical approach described is a single case with no replication; patient stratification by mutation type has not been attempted in a treatment study; funding for a trial in this rare disease is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Dermatology · 1991 · 8 citations
Mal de Meleda‐like Palmoplantar Keratoderma
AbstractA 38-year-old Japanese man was seen for severe palmoplantar keratoderma, extending to the dorsal aspects with red rims. He had had spontaneous amputations of the toes and surgical amputation of the right lower leg because of squamous cell carcinoma of the right sole. The clinical symptoms suggested those of mal de Meleda, except for the absence of consanguinity and of granular layers in the epidermis. The keratoderma improved with oral etretinate treatment.
Journal of Cutaneous Medicine and Surgery · 2021 · 7 citations · open access
Drugs Associated With the Development of Palmoplantar Keratoderma: A Systematic Review
AbstractBackground Palmoplantar keratoderma (PPK) are a heterogenous group of hereditary and acquired disorders that are characterized by excessive epidermal thickening of the palms and/or soles. PPK has been described as a rare adverse event for some medications. The aim of this systematic review was to summarize outcomes in PPK associated with various medications. This data will assist dermatologists and other healthcare providers treating patients with drug-induced PPK. Methods EMBASE and MEDLINE databases were searched in accordance with PRISMA guidelines using the keyword “palmoplantar keratoderma.” 40 studies met the inclusion criteria. Results A total of 247 patients (mean age: 57.0 years) were included in the analysis. Among patients whose sex was reported, 60.3% ( n = 35/58) were male. PPK most frequently developed after treatment with BRAF inhibitors (73.7%, n = 182/247), BRAF inhibitors combined with MEK1/2 inhibitors (15.4%, n = 38/247), tyrosine kinase inhibitors (TKIs) (3.2%, n = 8/247), or chemotherapy (2.4%, n = 6/247). The mean latency period between initiation of the drug and onset of PPK was 7.6 months (range: 0.25-90 months). Improvement of PPK was reported in 24 cases, with 50% ( n = 12/24) achieving complete resolution and 50% ( n = 12/24) achieving partial resolution. All patients who achieved complete resolution stopped the suspected drug, with a mean resolution period of 2.4 months (range: 2 weeks-6 months). The most common treatments for PPK were keratolytic treatments ( n = 10) and topical corticosteroids ( n = 4). Conclusions PPK was most frequently associated with targeted kinase inhibitors, specifically BRAF, MEK1/2, and tyrosine kinase inhibitors.
A de Novo Mutation in the Keratin 9 Gene in a Family with Epidermolytic Palmoplantar Keratoderma from Northern Sweden
AbstractSir,Palmoplantar keratodermas (PPKs) constitute a hetero-geneous group of skin disorders with the distinctivetrait of hyperkeratosis of palmoplantar skin. Thedisorders are classified clinically by the morphologyand distribution of the hyperkeratosis, the presence ofassociated cutaneous and non-cutaneous features andby the mode of transmission (1, 2).Familial diffuse epidermolytic PPK (EPPK) is themost studied keratoderma and is characterized bygranular and vacuolar degeneration of the cells of thespinous and granular layer. All mutations reported todate, with one exception, are locatedinthekeratin9gene(KRT9)onchromosome17(1,3). The majority of KRT9mutations reported are missense mutations in exon 1of the KRT9 gene, but there are reports of a stopcodon mutation in exon 1 (4) and of a 3 base pairinsertion in exon 6 (5). The position most frequentlyreported to be mutated in KRT9 is the arginine codonat position 162 in exon 1. In addition to KRT9 mutations,there is a recent study revealing a splice site mutationin the KRT1 gene as the cause of mild EPPK (6).The KRT9 gene appears to be the only keratin genewhose expression is restricted to palmoplantar epider-mis (7, 8). Consequently, individuals that carry amutation in the keratin 9 gene only display the effect ofthe mutation in the palmoplantar skin.Here we report the first observation of a Swedishfamily with EPPK and the attribution of the disorder toa de novo mutation in KRT9.MATERIALS AND METHODS
Eponyms in the dermatology literature linked to Palmo-Plantar Keratoderma
AbstractPalmoplantar keratodermas (PPKs) represent a diverse group of hereditary and acquired disorders characterized by hyperkeratosis of the skin on the palms and soles The three major patterns of involvement are diffuse, focal and punctate. There are clinical distinguishing features for each disease in this group, for example, transmigration to areas beyond the palmoplantar skin. Also the extent of associated systemic symptoms if present help in characterization of each type.
Journal of the European Academy of Dermatology and Venereology · 2002 · 3 citations
Keratin‐9 gene mutation in a family with epidermolytic palmoplantar keratoderma
AbstractBACKGROUND: Epidermolytic palmoplantar keratoderma is an autosomal dominant inherited disorder of keratinization. METHODS: We studied five members of a Jewish family with epidermolytic palmoplantar keratoderma. Genomic DNA was extracted from leucocytes, and exon 1 of the keratin 9 gene was amplified using polymerase chain reaction techniques. RESULTS: The mutation was found in exon 1 of the keratin 9 gene in codon 160. CONCLUSIONS: Like most of the other families with clinical features of epidermolytic palmoplantar keratoderma the mutation is found in exon 1 of the keratin 9 gene.
Underline Science Inc. · 2024 · 0 citations · open access
Cutting Through Complexity: Surgical Management of a Severe Palmoplantar Keratoderma
AbstractBackground Palmoplantar keratoderma is a rare condition characterized by progressive thickening of the skin on the palms and soles of the feet. In severe cases, it can lead to complications such as sepsis and lifelong disabilities. Traditionally, it has been managed medically with emollients, keratolytics, vitamin supplementation, and surgically with debridement, often leading to recurrence. We present this clinical vignette to highlight the management of severe palmoplantar keratoderma through a nuanced approach involving tissue excision down to the subcutaneous level. To our knowledge, based on a PubMed search using 'Keratoderma, Palmoplantar, Diffuse' [Mesh] and reviewing 265 articles, this approach has not been reported before with 16-year follow-up data. Methods The patient presented as a five-year-old girl with severe palmoplantar keratoderma, resistant to medical management. She had been wheelchair-bound with repeated hospital admissions for sepsis. She was initially managed with episodic deep debridement, which offered temporary relief followed by rapid recurrence. After obtaining informed consent, the decision was made to excise the keratoderma from her feet, removing the dermis and subcutaneous tissue. After excision, Integra was placed with negative pressure wound therapy (NPWT), followed by a second layer of Integra with NPWT. Final coverage was achieved with a thin split-thickness graft. For the hands, a similar procedure was performed with excision down to the palmar fascia, extending to the subcutaneous tissue of the fingers, which were pinned straight to reduce the possibility of contracture. After negative pressure wound therapy and granulation, a thin split-thickness skin graft was placed. After 6 months of walking as a middle school student, there was a breakdown of the heel to the plantar fascia, which was managed using a rectus free flap for heel reconstruction, followed by a conventional split-thickness skin graft. The flap subsequently shrank, with no recurrence. Results After 16 years, the patient is now a college student who walks with stability in her hands and feet. She can take notes, type, and has almost a full range of motion in her fingers. The patient reports that she is able to lead a normal and productive life. Conclusion Our case report highlights a novel surgical approach that can potentially be used for the treatment of severe palmoplantar keratoderma. It also underscores the challenges of managing this rare and severe condition with conventional treatments and emphasizes the need for innovative surgical solutions for its management.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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