| Evidence/source date | Key observation | Inference/limitation |
|---|---|---|
| **Human genetics and functional study — Lin et al., 9 Mar 2012; n=6** | All six patients had first-year onset. Heterozygous TRPV3 missense variants were p.Gly573Ser in 4/6, p.Gly573Cys in 1/6, and p.Trp692Gly in 1/6; variants were de novo where parental samples permitted assessment and were absent from 216 ancestry-matched controls. Mutant-transfected HEK293 cells showed constitutive currents; mutant cells and lesional keratinocytes showed increased death or apoptosis. (pqac-00000042, pqac-00000043, pqac-00000066) | **Strong OS1 gene–disease and gain-of-function evidence**, but based on a small, selected series. HEK293 cells are not native epidermis, and the proposed progression from apoptosis to hyperkeratosis was not fully demonstrated. No population penetrance estimate follows from n=6. |
| **Human immune case — Danso-Abeam et al., 2013; n=1** | A patient carrying TRPV3 c.1718G>C (p.Gly573Ala) had recurrent skin infections, inflammatory lesional infiltrates, hyper-IgE, persistent eosinophilia, and increased circulating follicular T cells. (pqac-00000012) | **Suggestive immune involvement only.** A single uncontrolled case cannot determine whether the abnormalities were primary effects of TRPV3 dysfunction, secondary to barrier failure or infection, or individual-specific. |
| **Genetic mouse study — Fatima et al., 4 Jan 2022** | Trpv3 p.Gly573Ser mice showed no spontaneous itch or dermatitis under *Staphylococcus aureus*-free conditions. Earlier DS-Nh phenotypes depended on *S. aureus* and genetic background; the tested 129S1/SvlmJ mutants instead had reduced pruritogen-evoked scratching, epidermal sensory hypoinnervation, and reduced cold and mechanical-pain responses. (pqac-00000011, pqac-00000048, pqac-00000054) | **Strong evidence for a model-specific gene–microbiome and genetic-background interaction**, but not proof of an equivalent interaction in human OS1. The model incompletely reproduces human mutilating palmoplantar keratoderma and cannot independently predict treatment efficacy. |
| **Human case — Hao et al., 14 Oct 2024; n=1** | Severe bilateral mutilating keratoderma preceded well-differentiated squamous-cell carcinoma of the sole requiring foot amputation. A heterozygous TRPV3 c.916G>A (p.Val306Met) missense variant was reported; computational predictions conflicted, and electrophysiologic validation was not performed. (pqac-00000015, pqac-00000028, pqac-00000038, pqac-00000039) | **Compelling malignancy event but uncertain molecular attribution.** The case supports surveillance of chronic ulcerated or changing lesions, but it neither establishes p.Val306Met as pathogenic nor quantifies OS1-associated cancer risk. |
| **Human treatment case — Zhang et al., 24 Jan 2025; n=1 treated** | Familial heterozygous TRPV3 c.1964T>C (p.Leu655Pro; p.L655P) was associated with focal keratoderma. The patient received **erlotinib plus oral acitretin**; plantar lesions and pain improved over 3–5 months, with mild stomach discomfort and transient forearm burning reported. (pqac-00000016, pqac-00000029, pqac-00000050) | **Very-low-certainty therapeutic evidence:** an uncontrolled single case, combination therapy, no standardized endpoint, and short follow-up prevent attribution to erlotinib or calculation of a response rate. Because c.1964T>C produces an amino-acid substitution, p.L655P is a **missense**, not frameshift, variant despite contradictory wording in the report. |
| **Registered Phase 1 trial — NCT07090889; started 8 Jul 2025, completion estimated 21 Nov 2026** | Oral KM-023 is being evaluated in healthy volunteers and an open-label 12-week disease cohort of up to eight patients. Efficacy endpoints include plantar-callus thickness and size and Investigator Global Assessment. Eligibility accepts confirmed **TRPV3 or PERP** variants. No efficacy outcomes are available. (pqac-00000000, pqac-00000001) | **Prospective but not OS1-specific:** PERP-associated disease is molecularly distinct from TRPV3-associated OS1. Estimated enrollment is not an outcome, and the small open-label cohort will provide only preliminary safety, pharmacokinetic, and efficacy evidence rather than a validated response rate. |


*Table: Evidence-graded comparison of pivotal human, experimental, and trial records relevant to TRPV3-associated Olmsted syndrome 1. It distinguishes established findings from single-case inference, model limitations, variant uncertainty, and a trial that also enrolls non-OS1 disease.*