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Classifications

Harrison's Part

Channelopathy

🔗

Mappings

MONDO

MONDO:0100296 Olmsted syndrome 1

The entry denotes exactly the MONDO class: Olmsted syndrome in which the cause is a variation in TRPV3 (OMIM:614594). The parent MONDO:0031421 Olmsted syndrome also covers the MBTPS2 (X-linked) and PERP (Olmsted syndrome 2) forms, which this entry excludes.

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Inheritance

2

Autosomal dominant inheritance HP:0000006

Most cases are sporadic and carry a de novo heterozygous TRPV3 missense variant; familial transmission in an autosomal dominant pattern is also reported, including a three-generation family with a mild, partly nonpenetrant phenotype.

Autosomal dominant inheritance

Show evidence (5 references)

PMID:22405088 SUPPORT Human clinical

"Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS."

Trio exome sequencing established the de novo heterozygous origin of the first TRPV3 variant.

PMID:24758389 SUPPORT BACKGROUND Human clinical

"Recently, pathogenic heterozygous mutations in TRPV3 were identified, with most cases showing de novo dominant inheritance."

Summarises that heterozygous TRPV3 variants act dominantly and are mostly de novo.

PMID:24452206 SUPPORT BACKGROUND Human clinical

"Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS."

Records the autosomal dominant pattern of TRPV3 disease, including one familial case, and separates it from the X-linked MBTPS2 form.

+ 2 more references

Autosomal recessive inheritance HP:0000007

Rare families carry biallelic TRPV3 variants with recessive transmission. The primary report is Duchatelet et al. 2014 (PMID:24606194, a letter without an abstract, listed under references); the claim is cited through the review.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

The review records both dominant and recessive TRPV3-related Olmsted syndrome.

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Discussions and Knowledge Gaps

4

Do Olmsted syndrome TRPV3 variants injure keratinocytes through impaired channel trafficking and lysosomal dysfunction in addition to plasma-membrane calcium overload?

EMERGING HYPOTHESIS OPEN os1_lysosomal_trafficking_hypothesis

Attached to

pathophysiology#Keratinocyte Calcium Overload pathophysiology#Keratinocyte Apoptosis

In heterologous expression, G573A/S/C and W692G variants are largely retained in the endoplasmic reticulum, reduce surface delivery of other membrane proteins, impair cell adhesion and reduce lysosome number, and G568C/G568D variants leak calcium from lysosomes and disturb lysosomal pH. These findings come from transfected non-keratinocyte cell lines and have not been confirmed in patient keratinocytes or skin.

Posed by dismech curation Posed 2026-10-13T00:00:00Z

Show evidence (2 references)

PMID:27754757 SUPPORT In vitro / ex vivo

"Our qualitative and quantitative data suggests that these naturally occurring TRPV3 mutants are mainly restricted in the ER."

ER retention of the Olmsted syndrome variants in expression systems.

PMID:36063600 SUPPORT In vitro / ex vivo

"We demonstrate that OS-mutants cause defective pH-maintenance at the lysosomes."

Lysosomal pH defect caused by two Olmsted syndrome variants.

Can direct pharmacological inhibition of TRPV3 treat Olmsted syndrome 1, as an alternative or adjunct to EGFR inhibition?

KNOWLEDGE GAP OPEN os1_trpv3_antagonist_gap

Attached to

pathophysiology#TRPV3 Gain-of-Function Channel Activation treatments#Erlotinib clinical_trials#NCT07090889

Erlotinib acts one step downstream of the lesion, on EGFR transactivation, and does not address channel-driven calcium overload or keratinocyte itch signalling directly; a TRPV3 antagonist would target the initiating event. No result of TRPV3 antagonism in a patient has been published; a phase 1 study of the oral TRPV3 inhibitor KM-023 (NCT07090889) with an open-label Olmsted syndrome cohort is recruiting.

Posed by dismech curation Posed 2026-10-13T00:00:00Z

Show evidence (2 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy."

The review proposes TRPV3 antagonism as the targeted strategy.

PMID:22405088 SUPPORT Human clinical

"Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders."

The gene-discovery study proposes TRPV3 as a therapeutic target.

What is the channel-level mechanism of the rare recessive TRPV3 families, and does it differ from the dominant gain-of-function variants?

KNOWLEDGE GAP OPEN os1_recessive_mechanism_gap

Attached to

inheritance#Autosomal recessive inheritance pathophysiology#TRPV3 Gain-of-Function Channel Activation

Dominant disease is explained by constitutively open heteromeric channels, but a recessive mode implies that one wild-type allele suffices to prevent disease, which the simple gain-of-function model does not predict. The recessive report (PMID:24606194) is a letter without an abstract, so the recessive claim is carried by the review only.

Posed by dismech curation Posed 2026-10-13T00:00:00Z

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

The review attributes gain of function to the dominant variants and names recessive forms without a mechanism, which is the gap.

Is immune dysregulation (hyper-IgE, eosinophilia, recurrent skin infection) a primary consequence of TRPV3 gain of function, or secondary to barrier failure and infection of the keratotic skin?

EMERGING HYPOTHESIS OPEN os1_immune_dysregulation_hypothesis

Attached to

pathophysiology#Cutaneous Inflammation with Mast Cell Infiltration phenotypes#Increased circulating IgE concentration phenotypes#Eosinophilia phenotypes#Recurrent skin infections

A single profiled G573A patient had hyper-IgE, persistent eosinophilia, elevated circulating follicular helper T cells and frequent dermal infections. TRPV3 is also expressed by Langerhans cells, so a primary immunological contribution cannot be excluded, but barrier failure in fissured keratotic skin would produce the same picture secondarily. No cohort has been immunophenotyped.

Posed by dismech curation Posed 2026-10-13T00:00:00Z

Show evidence (1 reference)

PMID:23692804 SUPPORT Human clinical

"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."

The authors' own statement of the open question.

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Pathophysiology

8

TRPV3 Gain-of-Function Channel Activation

Mechanism confidence: Established

Missense variants in TRPV3 lock the thermosensitive, calcium-permeable cation channel into a constitutively open state. Expressed in HEK293 cells, Olmsted syndrome variants conduct much larger inward currents than wild-type channel, with elevated basal open probability and increased voltage sensitivity; the magnitude of the gain of function tracks clinical severity.

keratinocyte CL:0000312

TRPV3 hgnc:18084

Genetic context TRPV3 hgnc:18084 allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Heterozygous, mostly de novo, germline missense variants; the channel is constitutively active rather than merely more active, so the variant consequence is recorded as GAIN_OF_FUNCTION.

TRPV3 calcium-permeable cation channel activity GO:0005262 ⇑ GAIN OF FUNCTION

Downstream

Keratinocyte Calcium Overload A constitutively open calcium-permeable channel in the keratinocyte plasma membrane admits unregulated calcium influx.

Show evidence (3 references)

PMID:22405088 SUPPORT In vitro / ex vivo

"In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants."

Patch-clamp recordings of the G573S, G573C and W692G channels show constitutive activation.

PMID:32795529 SUPPORT In vitro / ex vivo

"These variant TRPV3 channels, in either homomeric or heteromeric form, exhibited differentially elevated basal open probability, increased voltage sensitivity, and cytotoxicity."

Seven expressed variants show graded gain of channel function, including when co-assembled with wild-type subunits as in heterozygous patients.

PMID:32795529 SUPPORT BACKGROUND Human clinical

"We have previously shown that gain-of-function variations in transient receptor potential vanilloid-3 (TRPV3) underlay Olmsted syndrome, a rare hyperkeratotic skin channelopathy."

States the gain-of-function mechanism and frames the disease as a skin channelopathy.

Keratinocyte Calcium Overload

Mechanism confidence: Established

Unregulated calcium entry through constitutively active TRPV3 disturbs keratinocyte calcium homeostasis. TRPV3 is one of the principal calcium entry pathways of keratinocytes, and Olmsted syndrome variants are cytotoxic when expressed; some variants also act as calcium-leaky channels at lysosomes and disturb lysosomal pH and number.

keratinocyte CL:0000312

calcium ion transmembrane transport into keratinocytes GO:0070588 ↑ INCREASED keratinocyte calcium ion homeostasis GO:0055074 ↕ DYSREGULATED

Downstream

Keratinocyte Apoptosis Calcium overload through the constitutively open channel is cytotoxic to the cells expressing it.

EGFR-mTOR Signaling Hyperactivation in Epidermis TRPV3 forms a signalling complex with TGF-alpha/EGFR in keratinocytes, and TRPV3 channel activity stimulates TGF-alpha release, so constitutive channel activity transactivates EGFR.

Keratinocyte-Driven Itch Signaling Keratinocyte TRPV3 couples to protease-activated receptor 2 signalling and to nerve growth factor release, through which hyperactive channel activity is transmitted to pruriceptive sensory neurons.

Show evidence (2 references)

PMID:27754757 SUPPORT In vitro / ex vivo

"TRPV3 is one of the key ion channel involved in Ca2+-signaling in keratinocyte and thus involved in skin-related functions."

Places TRPV3 as a principal calcium-signalling channel of keratinocytes, the cell in which the gain-of-function variants act.

PMID:36063600 SUPPORT In vitro / ex vivo

"We propose that G568C and G568D mutants most-likely act as Ca2+-leaky channels from lysosomes with different abilities."

Two Olmsted syndrome variants also leak calcium from intracellular stores, extending the calcium-handling defect beyond the plasma membrane.

Keratinocyte Apoptosis

Mechanism confidence: Provisional

Olmsted syndrome TRPV3 variants are cytotoxic to the cells expressing them, and elevated keratinocyte apoptosis was proposed by the gene-discovery study as the proximate cause of the hyperkeratosis. The channel's partial retention in the endoplasmic reticulum, reduced cell adhesion and lysosomal abnormalities observed in expression systems may contribute.

keratinocyte CL:0000312

keratinocyte apoptotic process GO:0097283 ↑ INCREASED

Downstream

Epidermal Hyperproliferation and Hyperkeratosis Elevated keratinocyte apoptosis was proposed to drive compensatory epidermal turnover and hyperkeratosis.

Show evidence (2 references)

PMID:22405088 SUPPORT INDIRECT In vitro / ex vivo

"These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals."

The authors propose keratinocyte apoptosis as the link between constitutive channel activity and hyperkeratosis; the sentence is hypothesis rather than measurement, hence the provisional confidence.

PMID:26902751 SUPPORT In vitro / ex vivo

"Additionally, a functional assay indicated that the Met672Ile mutation imposed a more significant induction of apoptosis on HaCaT cells compared with that of the wild type."

A patient variant increases apoptosis when expressed in HaCaT keratinocytes, a measurement of the process in a keratinocyte line.

EGFR-mTOR Signaling Hyperactivation in Epidermis

Mechanism confidence: Established

Keratinocyte TRPV3 is physically complexed with TGF-alpha/EGFR and its activity stimulates TGF-alpha release, so a constitutively active channel transactivates EGFR. Lesional epidermis from patients shows increased phosphorylated EGFR and phosphorylated ribosomal protein S6, indicating activation of both EGFR and the downstream mTOR cascade. Excess TGF-alpha/EGFR signalling in skin is known to produce hairless phenotypes.

keratinocyte CL:0000312

epidermal growth factor receptor signaling pathway GO:0007173 ↑ INCREASED

skin epidermis UBERON:0001003

Animal models

Trpv3 knockout mouse Mouse perturbs Removal of TRPV3 phenocopies reduced TGF-alpha/EGFR signalling in hair, the opposite direction to the disease.

Downstream

Epidermal Hyperproliferation and Hyperkeratosis EGFR signalling drives keratinocyte proliferation; its inhibition with erlotinib resolves the keratoderma, which is the strongest evidence that this signalling sustains the hyperkeratosis.

Hair Follicle Dysfunction Excess TGF-alpha/EGFR activity produces hairless phenotypes in mice, and TRPV3 controls hair morphogenesis through this complex.

Show evidence (2 references)

PMID:20403327 SUPPORT In vitro / ex vivo

"Here we show that keratinocyte TRPV3, a member of the transient receptor potential (TRP) family of Ca(2+)-permeant channels, forms a signaling complex with TGF-alpha/EGFR."

Biochemical demonstration of the TRPV3-TGF-alpha/EGFR complex in keratinocytes.

PMID:31895414 SUPPORT Human clinical

"Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation."

Direct evidence of EGFR and mTOR pathway activation in patient lesional epidermis.

Epidermal Hyperproliferation and Hyperkeratosis

Mechanism confidence: Established

Sustained EGFR signalling and keratinocyte turnover produce thickened, hyperproliferative epidermis with massive orthokeratotic hyperkeratosis, most severely over the palms and soles and around body orifices. The resulting keratoderma is transgredient, progressive and painful; its circumferential extension around digits forms constricting bands.

keratinocyte CL:0000312

keratinocyte proliferation GO:0043616 ↑ INCREASED keratinization GO:0031424 ↑ INCREASED

skin epidermis UBERON:0001003

Downstream

Palmoplantar keratoderma Palmoplantar hyperkeratosis is the direct clinical expression of the epidermal process.

Periorificial keratotic plaques The same hyperkeratotic process around the mouth, nose, eyes, anus and genitalia.

Nail dystrophy Nail abnormalities accompany the keratoderma; the nail unit is a keratinizing epithelium.

Pseudoainhum Circumferential hyperkeratosis around digits forms constricting bands.

Pain Thick, fissuring plantar and palmar keratoderma is painful and limits walking and grasping.

Limitation of joint mobility Hyperkeratosis over the digits and joints restricts joint movement.

Oral leukokeratosis Leukokeratosis of the oral mucosa is a keratinizing lesion of the same disordered epithelium.

Recurrent skin infections Fissured, hyperkeratotic skin is the site of the recurrent bacterial and candidal infections.

Show evidence (2 references)

PMID:36709954 SUPPORT BACKGROUND Human clinical

"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."

Names palmoplantar epidermal hyperproliferation as the tissue consequence of channel activation.

PMID:22405088 SUPPORT Human clinical

"Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders."

The gene-discovery study attributes the keratinization defect to TRPV3.

Hair Follicle Dysfunction

Mechanism confidence: Established

TRPV3 is expressed in hair follicles and controls hair morphogenesis through its complex with TGF-alpha/EGFR. The patient G573S and G573C substitutions arose spontaneously in the DS-Nh mouse and WBN/Kob-Ht rat and cause dominant hairlessness, and most patients have alopecia.

hair follicle morphogenesis GO:0031069 ⚠ ABNORMAL hair cycle GO:0042633 ⚠ ABNORMAL

hair follicle UBERON:0002073

Animal models

DS-Nh mouse (spontaneous Trpv3 Gly573Ser) Mouse recapitulates The patient G573S variant causes dominant hairlessness.

Downstream

Alopecia Defective hair growth from constitutively active follicular TRPV3 presents as alopecia.

Show evidence (2 references)

PMID:16858425 SUPPORT Model organism

"An amino-acid substitution at the same position in one gene was detected in DS-Nh mice and WBN/Kob-Ht rats: Gly573 to Ser (Nh mutation) or Gly573 to Cys (Ht mutation), located in the transient receptor potential (TRP) cation channel subfamily V member 3 (TRPV3) gene."

The same Gly573 substitutions later found in patients cause dominant hairlessness in two rodent species.

PMID:22405088 SUPPORT Human clinical

"Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord."

TRPV3 is expressed in the hair follicle, the site of this process.

Cutaneous Inflammation with Mast Cell Infiltration

Mechanism confidence: Established

Constitutively active TRPV3 in keratinocytes promotes skin inflammation. Rodents carrying the Gly573 substitutions develop spontaneous allergic dermatitis with increased lesional mast cells, and transgenic expression of TRPV3(Gly573Ser) alone is sufficient to produce dermatitis. Patients show acute inflammatory flares with vasodilatation, redness and burning pain of the extremities.

keratinocyte CL:0000312 mast cell CL:0000097

inflammatory response GO:0006954 ↑ INCREASED

skin of body UBERON:0002097

Animal models

DS-Nh mouse (spontaneous Trpv3 Gly573Ser) Mouse recapitulates Spontaneous dermatitis with increased lesional mast cells.

TRPV3(Gly573Ser) transgenic mouse Mouse recapitulates Dermatitis develops in transgenic but not wild-type littermates under the same conditions.

Trpv3 G573S mouse on 129S1/SvImJ background (pathogen-free) Mouse fails to recapitulate No dermatitis develops under S. aureus-free conditions despite the same gain-of-function allele.

Downstream

Erythromelalgia Acute inflammatory flares of the extremities with vasodilatation, redness and burning pain present as erythromelalgia.

Pain Inflammatory flares contribute burning pain in addition to the mechanical pain of the keratoderma.

Show evidence (3 references)

PMID:16858425 SUPPORT Model organism

"Histopathological analyses revealed that mast cells in skin lesions were increased in both rodents compared to their age-matched parent strains, and that this may partially be due to hairlessness and dermatitis."

Increased lesional mast cells in both TRPV3-mutant rodent strains.

PMID:18754035 SUPPORT Model organism

"These transgenic mice spontaneously developed dermatitis, whereas wild-type mice did not display this phenotype when maintained under the same conditions."

Transgenic TRPV3(Gly573Ser) is sufficient to cause dermatitis, isolating the channel variant as the cause.

PMID:24452206 SUPPORT Human clinical

"Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia."

Inflammatory flares in a patient with a de novo L673F variant.

Keratinocyte-Driven Itch Signaling

Mechanism confidence: Provisional

Hyperactive keratinocyte TRPV3 transmits itch to sensory neurons. The channel is required for protease-activated receptor 2-evoked neuronal activation and scratching, and the Gly573Ser variant raises the keratinocyte nerve growth factor response to heat; DS-Nh mice carrying the variant scratch spontaneously even without dermatitis. The output is conditional: the same Gly573Ser variant on a 129S1/SvImJ background under Staphylococcus aureus-free housing produces no spontaneous itch, reduced pruritogen-evoked scratching and epidermal sensory hypoinnervation, so hyperactive TRPV3 does not cause itch unconditionally.

keratinocyte CL:0000312

Animal models

DS-Nh mouse (spontaneous Trpv3 Gly573Ser) Mouse recapitulates Mice carrying the Nh variant scratch spontaneously, independently of dermatitis.

TRPV3(Gly573Ser) transgenic mouse Mouse measures Keratinocyte nerve growth factor response to heat is raised by the variant.

Trpv3 G573S mouse on 129S1/SvImJ background (pathogen-free) Mouse fails to recapitulate No spontaneous itch, and pruritogen-evoked scratching is reduced rather than increased.

Downstream

Pruritus Keratinocyte-to-neuron itch signalling driven by the hyperactive channel is the proposed basis of the severe pruritus.

Show evidence (3 references)

PMID:18754035 SUPPORT Model organism

"A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat."

The patient variant increases keratinocyte NGF release in response to warmth, a pruritogenic output.

PMID:18754035 SUPPORT Model organism

"Interestingly, C57BL-Nh mice developed spontaneous scratching behavior, separately from the development of dermatitis."

Scratching occurs independently of dermatitis, pointing to itch generated by the channel variant itself.

PMID:32004565 SUPPORT BACKGROUND Human clinical

"TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome, which is associated with severe pruritus."

Background statement linking the human gain-of-function variants to severe pruritus, which the study then models.

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Pathograph

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Phenotypes

19

Blood 2

Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:23692804 SUPPORT Human clinical

"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."

Hyper-IgE production in the single profiled patient.

Eosinophilia Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:23692804 SUPPORT Human clinical

"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."

Persistent eosinophilia in the profiled patient, with the authors' caution that its role may be primary or secondary.

Eye 1

Corneal abnormality OCCASIONAL Abnormal cornea morphology HP:0000481

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."

Corneal involvement listed among associated features without further specification.

Head and Neck 1

Oral leukokeratosis OCCASIONAL Oral leukoplakia HP:0002745

The review names "leukokeratosis" without a site; the case literature places it in the oral mucosa, so it is bound to the HPO oral leukoplakia term. HPO has no leukokeratosis term (OLS search "oral leukokeratosis", ontology=hp, returns only HP:0002745).

Show evidence (2 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."

Leukokeratosis among the frequently associated features.

PMID:39926429 SUPPORT BACKGROUND Human clinical

"Uncommon cutaneous manifestations such as nail dystrophy, leukokeratosis of the oral mucosa, and hyperhidrosis or hypohidrosis of the palmoplantar region may also be observed in association with OS"

Names the oral mucosa as the site of the leukokeratosis.

Immune 1

Recurrent skin infections FREQUENT HP:0001581

Show evidence (3 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."

Recurrent infections among the frequently associated features.

PMID:23692804 SUPPORT BACKGROUND Human clinical

"A review of published cases noted the common concordance of recurrent bacterial and candida infections in keratotic areas"

Localises the recurrent infections to the keratotic skin, which is the basis for binding the skin-infection term.

PMID:23692804 SUPPORT Human clinical

"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."

Frequent dermal infections in a TRPV3 G573A patient.

Integument 8

Palmoplantar keratoderma OBLIGATE HP:0000982

Course: PROGRESSIVE

Show evidence (3 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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 defining feature across the reported case series.

PMID:22405088 SUPPORT Human clinical

"Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching."

Palmoplantar keratoderma in all TRPV3-mutant individuals of the discovery cohort.

PMID:35789571 SUPPORT Human clinical

"Subsequently, he experienced several episodes of recurring painful plaques on his feet that occurred following trauma"

In a milder, later-onset case the plantar plaques arose at sites of trauma, showing that mechanical injury can provoke the keratoderma at pressure-bearing skin.

Periorificial keratotic plaques VERY_FREQUENT Periorificial hyperkeratosis HP:0034521

Show evidence (2 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques."

Periorificial plaques are one of the diagnostic triad.

PMID:36709954 SUPPORT BACKGROUND Human clinical

"Olmsted syndrome (OS) is a rare genetic disorder, characterized by painful palmoplantar keratoderma (PPK), periorificial and intertriginous hyperkeratoses, and alopecia."

Names periorificial and intertriginous hyperkeratoses among the characteristic features.

Alopecia VERY_FREQUENT HP:0001596

Show evidence (2 references)

PMID:22405088 SUPPORT Human clinical

"Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching."

Alopecia in most cases of the TRPV3 discovery cohort.

PMID:24758389 SUPPORT Human clinical

"He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits."

Diffuse alopecia in a TRPV3-confirmed patient.

Nail dystrophy FREQUENT HP:0008404

Show evidence (2 references)

PMID:39469632 SUPPORT BACKGROUND Human clinical

"Olmsted syndrome (OS) is a rare congenital skin disorder, typically characterized by symmetrical, severe palmoplantar and periorificial keratoderma, often accompanied by alopecia, and onychodystrophy, with varying degrees of pruritus and pain."

Onychodystrophy among the typical accompanying features.

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."

Nail abnormalities are frequently associated.

Pruritus VERY_FREQUENT HP:0000989

Show evidence (2 references)

PMID:22405088 SUPPORT Human clinical

"Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching."

Severe itching is a defining feature in the TRPV3 cohort.

PMID:31895414 SUPPORT Human clinical

"All 4 patients had sustained improvements in pruritus and pain."

Pruritus was a treatment-tracked symptom in all four patients.

Palmoplantar hyperhidrosis OCCASIONAL HP:0007410

Show evidence (1 reference)

PMID:39926429 SUPPORT BACKGROUND Human clinical

"Uncommon cutaneous manifestations such as nail dystrophy, leukokeratosis of the oral mucosa, and hyperhidrosis or hypohidrosis of the palmoplantar region may also be observed in association with OS"

Palmoplantar hyperhidrosis listed among uncommon associated manifestations.

Hypohidrosis OCCASIONAL HP:0000966

Show evidence (1 reference)

PMID:39926429 SUPPORT BACKGROUND Human clinical

"Uncommon cutaneous manifestations such as nail dystrophy, leukokeratosis of the oral mucosa, and hyperhidrosis or hypohidrosis of the palmoplantar region may also be observed in association with OS"

Palmoplantar hypohidrosis listed among uncommon associated manifestations.

Squamous cell carcinoma of the skin HP:0006739

Not wired to a mechanism node: the single case report does not establish whether the carcinoma arose from chronic hyperproliferation, from the TGF-alpha/EGFR excess, or by chance, and no study has tested this.

Show evidence (2 references)

PMID:39469632 SUPPORT Human clinical

"The patient presented with disabling, bilateral palmoplantar keratoderma, and subsequently developed squamous cell carcinoma on the right sole."

Plantar squamous cell carcinoma in a TRPV3 V306M patient.

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"OS patients may have a higher susceptibility to develop malignant tumors in keratotic areas such as verrucous carcinoma (a squamous cell carcinoma) and its variant epithelioma cuniculatum located on the sole of the foot, and malignant melanoma"

The review's statement of malignancy risk in keratotic skin; it covers Olmsted syndrome of all genetic forms, not the TRPV3 form alone.

Limbs 1

Autoamputation of digits OCCASIONAL HP:0007460

Show evidence (2 references)

PMID:24758389 SUPPORT Human clinical

"He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits."

Autoamputation of two digits in a TRPV3-confirmed boy.

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Autoamputation as a recognised complication.

Musculoskeletal 1

Limitation of joint mobility FREQUENT HP:0001376

Show evidence (1 reference)

PMID:31895432 SUPPORT Human clinical

"Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis."

Joint restriction from hyperkeratosis in two of three patients.

Prenatal and Birth 1

Pseudoainhum FREQUENT Digital constriction ring HP:0010491

Sequelae: Autoamputation of digits

Show evidence (2 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques."

Pseudoainhum is part of the suggestive triad.

PMID:24758389 SUPPORT Human clinical

"Constriction of digits, onychodystrophy and pruritus may also occur."

Digital constriction among the associated features.

Constitutional 2

Pain VERY_FREQUENT HP:0012531

Sequelae: Growth delay

Show evidence (2 references)

PMID:31895432 SUPPORT Human clinical

"The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."

Intolerable pain in all three TRPV3-confirmed patients.

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Pain and itching are variable but can be severe."

Pain is variable but can be severe across reported cases.

Erythromelalgia OCCASIONAL HP:0032147

Show evidence (2 references)

PMID:24452206 SUPPORT Human clinical

"Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia."

Erythromelalgia in a de novo L673F patient.

PMID:31895432 SUPPORT Human clinical

"The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."

Erythromelalgia in all three patients of the erlotinib series.

Growth 1

Growth delay OCCASIONAL HP:0001510

Show evidence (1 reference)

PMID:31895432 SUPPORT Human clinical

"The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."

Severe growth delay in all three patients before treatment.

🧬

Genetic Associations

1

TRPV3

Gene: TRPV3 hgnc:18084 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:22405088 SUPPORT Human clinical

"Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each)."

Independent affected individuals carried TRPV3 missense variants, establishing TRPV3 as the causal gene.

PMID:22405088 SUPPORT Human clinical

"Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord."

Gene product identity and expression in the affected tissues.

PMID:32795529 SUPPORT Human clinical

"We identified five previously unreported TRPV3 variations (R416Q, R416W, L655P, W692S, and L694P) and three recurrent variations (G568D, G568V, and L673F) in nine unrelated patients."

Expands the TRPV3 variant spectrum across nine unrelated patients.

+ 1 more reference

Variants (7)

p.Gly573Ser (G573S) Pathogenic

single nucleotide variant

The first and most recurrent Olmsted syndrome variant, identified de novo in the index trio and in three further patients; the same substitution occurs spontaneously in the hairless DS-Nh mouse.

Show evidence (1 reference)

PMID:22405088 SUPPORT Human clinical

"Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS."

Discovery of the recurrent G573S variant.

p.Trp692Gly (W692G) and p.Trp692Cys (W692C) Pathogenic

single nucleotide variant

Substitutions of Trp692 in the TRP domain, each identified as a de novo heterozygous variant in a patient with the classic mutilating phenotype.

Show evidence (1 reference)

PMID:24758389 SUPPORT Human clinical

"TRPV3 was sequenced and a new de novo heterozygous missense mutation, c.2076G>C (p.Trp692Cys), was identified."

Reports the de novo W692C variant in a boy with mutilating keratoderma, alopecia and pseudoainhum.

p.Leu673Phe (L673F) Pathogenic

single nucleotide variant

A recurrent S4-S5 linker variant associated with severe disease and erythromelalgia-like inflammatory flares.

Show evidence (1 reference)

PMID:24452206 SUPPORT Human clinical

"Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging."

First report of the de novo L673F variant.

p.Val306Met (V306M) Likely pathogenic

single nucleotide variant

An atypical variant in exon 8 reported in an adult with mutilating keratoderma who developed plantar squamous cell carcinoma.

Show evidence (1 reference)

PMID:39469632 SUPPORT Human clinical

"Genetic analysis identified a novel heterozygous p.Val306Met missense mutation in the exon 8 of TRPV3."

Reports the heterozygous V306M variant; functional characterisation was not reported, hence likely pathogenic rather than pathogenic.

p.Gly573Ala (G573A) Likely pathogenic

single nucleotide variant

A third substitution of the Gly573 hotspot, found in a patient whose immunological work-up showed hyper-IgE, eosinophilia and frequent skin infections.

Show evidence (1 reference)

PMID:23692804 SUPPORT Human clinical

"The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation."

Reports the G573A variant at the recurrent Gly573 position; no electrophysiology was reported, hence likely pathogenic.

p.Met672Ile (M672I) Likely pathogenic

single nucleotide variant

A familial variant segregating through three generations with a mild, partly nonpenetrant, atypical phenotype (sclerodactyly-like fingers in the proband, focal plantar plaques in the grandfather); it increases apoptosis of HaCaT keratinocytes but less than the classic hotspot variants.

Show evidence (2 references)

PMID:26902751 SUPPORT Human clinical

"However, TRPV3 sequencing results revealed an identical heterozygous mutation c.2016G > A in the proband, his mother and his maternal grandfather"

Segregation of the c.2016G>A (p.Met672Ile) variant with disease in the family.

PMID:26902751 SUPPORT In vitro / ex vivo

"Additionally, a functional assay indicated that the Met672Ile mutation imposed a more significant induction of apoptosis on HaCaT cells compared with that of the wild type."

Functional support in a keratinocyte line, consistent with the cytotoxic gain of function of other variants.

p.Leu655Pro (L655P) Likely pathogenic

single nucleotide variant

A heterozygous variant in exon 15 found in a patient with classic Olmsted syndrome and in his father, treated with erlotinib. The source abstract calls c.1964T>C a frameshift mutation, but a single-nucleotide substitution producing p.Leu655Pro is a missense change, as the article title states; the same residue was reported as L655P in the genotype-phenotype series.

Show evidence (1 reference)

PMID:39926429 SUPPORT Human clinical

"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."

Reports the heterozygous L655P variant in the patient and his father; the quoted sentence misnames the substitution as a frameshift.

💊

Medical Actions

5

Erlotinib

Action: Pharmacotherapy NCIT:C15986

Agent: erlotinib CHEBI:114785

Platform: Small molecule

Oral EGFR tyrosine kinase inhibitor, used at doses below oncology dosing (2 mg/kg/day in the paediatric series), which produced disappearance of hyperkeratosis and pain within three months in TRPV3-confirmed patients, sustained over twelve months, with remission of anorexia, insomnia and catch-up growth; adverse effects were mild to moderate. It is the first mechanism-directed therapy, with consistent responses in uncontrolled case series.

Mechanism Target:

INHIBITS EGFR-mTOR Signaling Hyperactivation in Epidermis — Blocks the EGFR transactivated by hyperactive TRPV3.

Show evidence (1 reference)

PMID:31895432 SUPPORT Human clinical

"Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention."

The authors frame the response as a consequence of blocking EGFR transactivation.

Target Phenotypes: Palmoplantar keratoderma HP:0000982 Pain HP:0012531

Show evidence (7 references)

PMID:31895432 SUPPORT Human clinical

"Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared."

Primary response in three TRPV3-confirmed patients.

PMID:31895432 SUPPORT Human clinical

"The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted."

Dosing and tolerability.

PMID:31895414 SUPPORT Human clinical

"Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores."

Independent series confirming near-complete resolution of keratoderma on erlotinib monotherapy.

+ 4 more references

Sirolimus

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Platform: Small molecule

Oral mTOR inhibitor (0.8 mg/m2 twice daily to a trough of 10-15 ng/mL), which improved erythema and periorificial hyperkeratosis in two children before they were switched to erlotinib for the palmoplantar keratoderma.

Mechanism Target:

INHIBITS EGFR-mTOR Signaling Hyperactivation in Epidermis — Inhibits the mTOR arm downstream of EGFR, shown activated in lesional epidermis.

Show evidence (1 reference)

PMID:31895414 SUPPORT Human clinical

"Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation."

The activated mTOR signalling that sirolimus was given to inhibit.

Target Phenotypes: Periorificial keratotic plaques HP:0034521

Show evidence (2 references)

PMID:31895414 SUPPORT Human clinical

"Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward."

Sirolimus response in two children.

PMID:31895414 SUPPORT Human clinical

"Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL."

Dosing used.

Systemic retinoids (acitretin)

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172

Platform: Small molecule

Oral retinoids reduce hyperkeratosis but give only partial, temporary relief as monotherapy; acitretin added to erlotinib produced a dramatic reduction of residual palmoplantar thickening and pain in twins.

Mechanism Target:

MODULATES Epidermal Hyperproliferation and Hyperkeratosis — Retinoids normalise keratinocyte differentiation and reduce hyperkeratosis without acting on the channel or EGFR.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."

Retinoids are listed as treatments of the hyperkeratosis itself.

Show evidence (2 references)

PMID:36709954 SUPPORT Human clinical

"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."

Acitretin added to erlotinib.

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."

Retinoids as symptomatic therapy with partial, temporary benefit.

Topical emollients and keratolytics

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Emollients, keratolytics and topical corticosteroids are symptomatic measures for the hyperkeratosis and offer only temporary partial relief.

Mechanism Target:

MODULATES Epidermal Hyperproliferation and Hyperkeratosis — Softens and removes hyperkeratotic scale without altering the underlying process.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."

Emollients and keratolytics are listed as symptomatic treatments of the hyperkeratosis.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."

Symptomatic topical therapies and their limited benefit.

Pain and pruritus management

Action: Supportive care for pain and pruritus Ontology label: Supportive Care NCIT:C15747

Platform: Other

Specific management of pain and itch is a central part of care and reduces morbidity; before erlotinib, pain was often refractory to multiple analgesics.

Target Phenotypes: Pain HP:0012531 Pruritus HP:0000989

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Specific management of pain and itching is important to reduce the morbidity of the disease."

Review recommendation on symptom management.

🔬

Diagnosis

2

Clinical diagnosis on the keratoderma-periorificial plaque pattern

Diagnosis rests on the combination of severe, mutilating palmoplantar keratoderma with periorificial keratotic plaques, usually with alopecia and pseudoainhum; incomplete or atypical presentations make clinical diagnosis difficult.

Clinical diagnosis NCIT:C15607

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Review statement of the clinical diagnostic basis.

TRPV3 sequencing

Sequencing of TRPV3 (and MBTPS2 for the X-linked form) confirms the diagnosis and distinguishes the genetic forms; exome sequencing identified the original variants.

TRPV3 gene sequencing NCIT:C15709

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation."

Genetic testing for TRPV3 and MBTPS2 is the confirmatory step.

📈

Progression

1

Onset in infancy or early childhood

Keratoderma usually begins at birth or in the first years of life and progresses thereafter; later-onset adult presentations have been reported with milder variants.

Show evidence (2 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"The disease starts usually at birth or in early childhood."

Review statement of the usual age of onset.

PMID:31895432 SUPPORT Human clinical

"Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment."

States that the keratoderma begins in infancy and is progressive.

📊

Prevalence

1

Published literature, all genetic forms of Olmsted syndrome

Cases/families reported in the literature Ultra-rare

No population-based prevalence estimate exists. The 2015 review counted about 73 reported cases of Olmsted syndrome of all genetic forms (TRPV3, MBTPS2 and molecularly unconfirmed), so the TRPV3-specific count is smaller than this figure.

Show evidence (2 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"About 73 cases have been reported worldwide."

The systematic literature review gives the total number of Olmsted syndrome cases reported up to December 2014, establishing the disease as ultra-rare.

PMID:24452206 SUPPORT BACKGROUND Human clinical

"Approximately 50 cases have been reported, with the molecular basis described in only 9."

An earlier count of reported cases, with the number that were molecularly confirmed; both figures place the disease in the ultra-rare band.

⚖️

Clinical Burden

High

Progressive keratoderma, pseudoainhum with autoamputation and intractable pain can prevent grasping and walking and confine patients to a wheelchair; erlotinib-treated patients had been wheelchair-bound with growth delay, anorexia, insomnia and depression before treatment.

Show evidence (2 references)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Review statement of the functional burden.

PMID:31895432 SUPPORT Human clinical

"Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis."

Two of three TRPV3-confirmed patients were wheelchair-bound before erlotinib.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Olmsted Syndrome 1:

Olmsted syndrome, X-linked (MBTPS2) Not Yet Curated MONDO:0010486

Distinguishing Features

X-linked recessive inheritance in males with a hemizygous MBTPS2 variant; overlapping keratoderma phenotype but a different gene and mechanism (regulated intramembrane proteolysis), so it is excluded from this entry.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form."

The X-linked form is caused by MBTPS2 rather than TRPV3.

Keratoderma hereditarium mutilans (Vohwinkel syndrome) MONDO:0007422

Distinguishing Features

Honeycomb keratoderma with pseudoainhum and starfish-shaped acral keratoses, usually with sensorineural deafness (GJB2) or ichthyosis (LOR); lacks the periorificial plaques of Olmsted syndrome.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Vohwinkel syndrome is listed first among the mutilating keratoderma differentials.

Clouston syndrome MONDO:0007510

Distinguishing Features

Hidrotic ectodermal dysplasia (GJB6) with nail dystrophy, hypotrichosis and keratoderma but without periorificial plaques or pseudoainhum.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Listed differential.

Papillon-Lefevre syndrome MONDO:0009490

Distinguishing Features

Transgredient keratoderma with early-onset periodontitis and tooth loss (CTSC); no periorificial plaques.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Listed differential.

Pachyonychia congenita MONDO:0016471

Distinguishing Features

Focal painful plantar keratoderma with hypertrophic nail dystrophy and oral leukokeratosis (keratin 6/16/17 variants); keratoderma is focal rather than diffuse and transgredient.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Listed differential.

Tyrosinemia type II MONDO:0010160

Distinguishing Features

Painful focal palmoplantar keratoses with pseudodendritic corneal erosions and elevated plasma tyrosine (TAT deficiency).

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Listed differential.

Acrodermatitis enteropathica MONDO:0008713

Distinguishing Features

Periorificial and acral dermatitis with alopecia and diarrhoea from zinc deficiency (SLC39A4); low serum zinc and response to zinc supplementation distinguish it.

Show evidence (1 reference)

PMID:25886873 SUPPORT REVIEW SYNTHESIS Human clinical

"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."

Listed differential; the periorificial distribution overlaps most closely.

🔬

Clinical Trials

1

NCT07090889 PHASE_I RECRUITING

First-in-human phase 1a/1b study of KM-023, an oral TRPV3 inhibitor: single and multiple ascending doses with a food-effect arm in healthy volunteers, followed by a 12-week open-label cohort of Olmsted syndrome patients assessing safety, pharmacokinetics, drug penetration into skin layers and keratoderma efficacy. No results are available.

Target Phenotypes: Palmoplantar keratoderma HP:0000982

Show evidence (2 references)

clinicaltrials:NCT07090889 SUPPORT Other

"Finally, the efficacy of KM-023 will be investigated in Olmsted Syndrome patients."

Registry summary stating the efficacy objective in Olmsted syndrome patients.

clinicaltrials:NCT07090889 SUPPORT Other

"In the second part of the trial, Olmsted Syndrome patients will take KM-023 twice daily, for a duration of 12 weeks."

Design of the patient cohort.

🐁

Animal Models

4

DS-Nh mouse (spontaneous Trpv3 Gly573Ser)

Spontaneous hairless mutant carrying the same Gly573Ser substitution found in patients. Develops dominant hairlessness, spontaneous allergic and pruritic dermatitis with increased lesional mast cells, and scratching behaviour; it does not develop palmoplantar keratoderma.

Species

Mouse

Genotype

Trpv3 Gly573Ser (Nh), heterozygous, autosomal dominant

Background

DS

Genes

TRPV3 hgnc:18084

Publication

PMID:16858425

Pathograph links

Hair Follicle Dysfunction recapitulates fidelity: moderate observes: tissue The patient G573S variant causes dominant hairlessness.

Limitations: Rodent hairlessness is complete, whereas human alopecia is variable; the mouse lacks the palmoplantar and periorificial keratoderma that define the human disease.

Readouts

Hair coat

Direction: ABOLISHED

Interpretation: Spontaneous hairlessness inherited with the Trpv3 variant.

Show evidence (1 reference)

PMID:16858425 SUPPORT Model organism

"DS-Nh mice and WBN/Kob-Ht rats are spontaneous hairless mutant rodent strains."

The hairless phenotype of the strains.

Show evidence (1 reference)

PMID:16858425 SUPPORT Model organism

"We concluded that TRPV3 was the gene responsible for Nh and Ht mutations, and that mutation in TRPV3 possibly correlated with increased mast cell numbers."

Genetic identification of Trpv3 as the hairless gene.

Cutaneous Inflammation with Mast Cell Infiltration recapitulates fidelity: moderate observes: tissue Spontaneous dermatitis with increased lesional mast cells.

Limitations: The rodent dermatitis is allergic in character and depends on housing conditions and genetic background: the same variant re-derived on 129S1/SvImJ and kept Staphylococcus aureus-free develops no dermatitis (PMID:35058747). Its relation to the inflammatory flares of patients is inferred.

Readouts

Lesional mast cell count

Direction: INCREASED

Interpretation: Increased mast cells in dermatitis lesions versus parental strains.

Show evidence (1 reference)

PMID:16858425 SUPPORT Model organism

"Histopathological analyses revealed that mast cells in skin lesions were increased in both rodents compared to their age-matched parent strains, and that this may partially be due to hairlessness and dermatitis."

Histological measurement of mast cells.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"DS-Nh mice also develop allergic and pruritic dermatitis."

The dermatitis phenotype of the strain.

Keratinocyte-Driven Itch Signaling recapitulates fidelity: moderate observes: organism Mice carrying the Nh variant scratch spontaneously, independently of dermatitis.

Limitations: Scratching behaviour is an organism-level proxy for itch; the keratinocyte signalling step is inferred rather than measured in this strain.

Divergences from the human mechanism

proxy quantity qualifying

The readout is scratching bouts, standing in for keratinocyte-to-neuron itch signalling, which is the quantity the node describes.

Readouts

Spontaneous scratching behaviour

Direction: INCREASED

Interpretation: Scratching develops separately from dermatitis in C57BL-Nh mice.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"Interestingly, C57BL-Nh mice developed spontaneous scratching behavior, separately from the development of dermatitis."

Behavioural measurement of itch.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"We propose that TRPV3(Gly573Ser) is a cause of pruritus and/or dermatitis associated with scratching, and suggest that TRPV3 may represent a therapeutic target in pruritic dermatitis."

The authors attribute pruritus to the variant.

The WBN/Kob-Ht rat carries the paralogous Gly573Cys substitution (the patient G573C variant) with the same hairless and dermatitis phenotype (PMID:16858425); it is recorded here rather than as a separate model because the same publication characterises both strains together.

Show evidence (1 reference)

PMID:16858425 SUPPORT Model organism

"An amino-acid substitution at the same position in one gene was detected in DS-Nh mice and WBN/Kob-Ht rats: Gly573 to Ser (Nh mutation) or Gly573 to Cys (Ht mutation), located in the transient receptor potential (TRP) cation channel subfamily V member 3 (TRPV3) gene."

Identity of the model's causal variant.

TRPV3(Gly573Ser) transgenic mouse

Transgenic expression of the patient Gly573Ser variant from a TRPV3 promoter fragment; the mice spontaneously develop dermatitis, isolating the variant channel as sufficient cause, and show an increased keratinocyte nerve growth factor response to heat.

Species

Mouse

Genotype

Transgenic TRPV3 Gly573Ser under a putative TRPV3 promoter

Genes

TRPV3 hgnc:18084

Publication

PMID:18754035

Pathograph links

Cutaneous Inflammation with Mast Cell Infiltration recapitulates fidelity: moderate observes: tissue Dermatitis develops in transgenic but not wild-type littermates under the same conditions.

Limitations: Transgene copy number and expression level are not those of a heterozygous germline allele, and the mice do not develop keratoderma.

Readouts

Spontaneous dermatitis

Direction: INCREASED

Interpretation: Dermatitis in transgenic mice, absent in wild type.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"These transgenic mice spontaneously developed dermatitis, whereas wild-type mice did not display this phenotype when maintained under the same conditions."

The dermatitis readout.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"Here, we constructed TRPV3(Gly573Ser) transgenic mice, with a putative promoter sequence in the 5' region of TRPV3, to investigate the involvement of TRPV3 in the development of specific types of dermatitis."

Construction and purpose of the model.

Keratinocyte-Driven Itch Signaling measures fidelity: moderate observes: cellular Keratinocyte nerve growth factor response to heat is raised by the variant.

Readouts

Nerve growth factor response to heat

Direction: INCREASED

Interpretation: A pruritogenic keratinocyte output is increased by the patient variant.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat."

The NGF readout.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat."

The transgenic line is informative for this node because the patient variant raises the keratinocyte nerve growth factor output that drives pruriceptive signalling.

Show evidence (1 reference)

PMID:18754035 SUPPORT Model organism

"Here, we constructed TRPV3(Gly573Ser) transgenic mice, with a putative promoter sequence in the 5' region of TRPV3, to investigate the involvement of TRPV3 in the development of specific types of dermatitis."

Construction of the model.

Trpv3 G573S mouse on 129S1/SvImJ background (pathogen-free)

The Gly573Ser allele re-derived on a 129S1/SvImJ background and housed free of Staphylococcus aureus. Unlike DS-Nh mice, these animals develop neither dermatitis nor spontaneous scratching; pruritogen-evoked scratching, cold perception and acute mechanical pain are reduced, and the epidermis is hypoinnervated. The model shows that the dermatitis and itch of the variant depend on genetic background and skin microbiome.

Species

Mouse

Genotype

Trpv3 G573S gain-of-function point mutation, re-derived and backcrossed onto 129S1/SvImJ

Background

129S1/SvImJ

Genes

TRPV3 hgnc:18084

Publication

PMID:35058747

Pathograph links

Cutaneous Inflammation with Mast Cell Infiltration fails to recapitulate fidelity: low observes: tissue No dermatitis develops under S. aureus-free conditions despite the same gain-of-function allele.

Limitations: The negative result is conditional on pathogen-free housing and the 129S1/SvImJ background; it does not show that the allele cannot cause inflammation, only that it does not do so alone.

Divergences from the human mechanism

boundary omission qualifying

Staphylococcus aureus colonisation, on which the DS-Nh dermatitis depends, is excluded by the housing conditions, so a trigger that patients' skin carries is outside the model.

Readouts

Spontaneous dermatitis

Direction: UNCHANGED

Interpretation: No dermatitis in mutants or littermates under pathogen-free housing.

Show evidence (1 reference)

PMID:35058747 SUPPORT Model organism

"In our experiments, Trpv3G573S mutants were raised in S. aureus-free environment, and we did not observe any dermatitis or spontaneous scratching in the Trpv3G573S mutants (Figure 5A)."

The dermatitis observation.

Show evidence (1 reference)

PMID:35058747 SUPPORT Model organism

"We fail to observe any spontaneous itch responses and/or dermatitis in Trpv3 G573S mutants under specific pathogen (Staphylococcus aureus)-free conditions."

The negative dermatitis result that makes this model informative for the conditionality of the inflammation node.

Keratinocyte-Driven Itch Signaling fails to recapitulate fidelity: low observes: organism No spontaneous itch, and pruritogen-evoked scratching is reduced rather than increased.

Limitations: Scratching behaviour is an organism-level proxy; the reduced pruritogen-evoked scratching is attributed by the authors to epidermal sensory hypoinnervation, a developmental consequence of the hyperactive channel that patients have not been examined for.

Divergences from the human mechanism

proxy quantity qualifying

Scratching bouts and epidermal nerve fibre density stand in for the keratinocyte-to-neuron signalling the node describes.

Readouts

Spontaneous scratching behaviour

Direction: UNCHANGED

Interpretation: No spontaneous scratching under pathogen-free housing.

Show evidence (1 reference)

PMID:35058747 SUPPORT Model organism

"We fail to observe any spontaneous itch responses and/or dermatitis in Trpv3 G573S mutants under specific pathogen (Staphylococcus aureus)-free conditions."

The spontaneous itch observation.

Pruritogen-evoked scratching

Direction: DECREASED

Interpretation: Scratching in response to pruritogens is markedly reduced in mutants.

Show evidence (1 reference)

PMID:35058747 SUPPORT Model organism

"However, we find that the scratching events in response to various pruritogens are dramatically decreased in Trpv3 G573S mice in comparison to wild-type littermates."

The evoked-itch measurement.

Epidermal sensory innervation

Direction: DECREASED

Interpretation: Epidermal sensory hypoinnervation, proposed by the authors to underlie the reduced itch and pain responses.

Show evidence (1 reference)

PMID:35058747 SUPPORT Model organism

"Interestingly, we observe sensory hypoinnervation of the epidermis in Trpv3 G573S mutants, which might contribute to the deficits in acute mechanical pain, cool, cold, and itch sensations."

The innervation measurement and the authors' interpretation.

Show evidence (1 reference)

PMID:35058747 SUPPORT Model organism

"We re-derived the Trpv3G573S mutants using 129S1/SvlmJ eggs; the animals obtained were then backcrossed to 129S1/SvlmJ background for six-eight generations."

Establishes the model as the patient-hotspot allele on a defined background, which is what makes the negative itch result informative for this node.

Show evidence (1 reference)

PMID:35058747 SUPPORT Model organism

"We re-derived the Trpv3G573S mutants using 129S1/SvlmJ eggs; the animals obtained were then backcrossed to 129S1/SvlmJ background for six-eight generations."

Derivation and background of the model.

Trpv3 knockout mouse

Loss-of-function model, the inverse of the human lesion: Trpv3-null mice have wavy hair and curly whiskers, the phenotype of TGF-alpha and EGFR loss-of-function mutants, and defective skin-barrier cornification. It establishes the TRPV3-TGF-alpha/EGFR axis that the gain-of-function variants overdrive.

Species

Mouse

Genotype

Trpv3 null (loss of function)

Genes

TRPV3 hgnc:18084

Publication

PMID:20403327

Pathograph links

EGFR-mTOR Signaling Hyperactivation in Epidermis perturbs fidelity: low observes: tissue Removal of TRPV3 phenocopies reduced TGF-alpha/EGFR signalling in hair, the opposite direction to the disease.

Limitations: An inverse (loss-of-function) model; it demonstrates that TRPV3 sits in the EGFR axis but does not reproduce the hyperactivation of the disease.

Divergences from the human mechanism

cause unrepresented qualifying

The model deletes the channel; the disease has a constitutively active one. The axis is shared, the direction of perturbation is not.

Readouts

Hair coat morphology

Direction: ALTERED

Interpretation: Wavy hair and curly whiskers, the signature of reduced TGF-alpha/EGFR signalling.

Show evidence (1 reference)

PMID:20403327 SUPPORT Model organism

"Unexpectedly, we found that mice lacking the Trpv3 gene also exhibit wavy hair coat and curly whiskers."

The hair readout of the knockout.

Show evidence (1 reference)

PMID:20403327 SUPPORT In vitro / ex vivo

"Here we show that keratinocyte TRPV3, a member of the transient receptor potential (TRP) family of Ca(2+)-permeant channels, forms a signaling complex with TGF-alpha/EGFR."

The knockout study established the complex this node describes.

Show evidence (1 reference)

PMID:20403327 SUPPORT Model organism

"Unexpectedly, we found that mice lacking the Trpv3 gene also exhibit wavy hair coat and curly whiskers."

The knockout phenotype that identified the EGFR-axis relationship.

{ }

Source YAML

click to show

name: Olmsted Syndrome 1
creation_date: '2026-10-13T08:45:00Z'
description: >-
  Olmsted syndrome 1 is the TRPV3-associated form of Olmsted syndrome, a rare
  keratinizing genodermatosis defined by bilateral, mutilating, transgredient
  palmoplantar keratoderma and periorificial keratotic plaques, typically with
  alopecia, nail dystrophy, severe pruritus and pain, and constricting digital
  bands (pseudoainhum) that can progress to autoamputation. Heterozygous missense
  variants in TRPV3, most often arising de novo, produce a constitutively open
  thermosensitive calcium-permeable cation channel in keratinocytes; rare families
  carry biallelic TRPV3 variants. Channel gain of function drives keratinocyte
  calcium overload, cytotoxicity, EGFR and mTOR pathway activation, epidermal
  hyperproliferation with hyperkeratosis, cutaneous inflammation and itch. The
  EGFR inhibitor erlotinib has produced clinical remission of the keratoderma and
  pain in treated patients. The X-linked MBTPS2 form (Olmsted syndrome, X-linked)
  and the PERP form (Olmsted syndrome 2) have different causal genes and
  mechanisms and are not covered by this entry.
category: Mendelian
disease_term:
  preferred_term: Olmsted syndrome 1
  term:
    id: MONDO:0100296
    label: Olmsted syndrome 1
synonyms:
- Olmsted syndrome
- OS
- palmoplantar keratoderma, mutilating, with periorificial keratotic plaques 1
- TRPV3-related Olmsted syndrome
- mutilating palmoplantar keratoderma with periorificial keratotic plaques
parents:
- Olmsted Syndrome
- Hereditary Palmoplantar Keratoderma
- Channelopathies
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100296
      label: Olmsted syndrome 1
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The entry denotes exactly the MONDO class: Olmsted syndrome in which the
      cause is a variation in TRPV3 (OMIM:614594). The parent MONDO:0031421
      Olmsted syndrome also covers the MBTPS2 (X-linked) and PERP (Olmsted
      syndrome 2) forms, which this entry excludes.
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
    notes: >-
      A keratinizing genodermatosis presenting with palmoplantar keratoderma and
      periorificial keratotic plaques; managed by dermatology.
    evidence:
    - reference: PMID:39469632
      reference_title: "Case report: Novel p.Val306Met missense mutation in TRPV3 in a case of Olmsted syndrome accompanied by squamous cell carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Olmsted syndrome (OS) is a rare congenital skin disorder, typically characterized by symmetrical, severe palmoplantar and periorificial keratoderma, often accompanied by alopecia, and onychodystrophy, with varying degrees of pruritus and pain."
      explanation: The disease is a skin disorder defined by cutaneous keratinization, hair and nail features, which places it in the dermatology chapter.
  channelopathy_category:
    classification_value: epithelial channelopathy
    notes: >-
      TRPV3 is a calcium-permeable cation channel expressed in epidermal
      keratinocytes, an epithelial cell type, and the disease arises from its
      constitutive activation. ChannelopathyOrganSystemEnum has no skin-specific
      value; of the four values, epithelial channelopathy is the one that names
      the affected tissue type rather than an unaffected organ system.
    evidence:
    - reference: PMID:32795529
      reference_title: "Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "We have previously shown that gain-of-function variations in transient receptor potential vanilloid-3 (TRPV3) underlay Olmsted syndrome, a rare hyperkeratotic skin channelopathy."
      explanation: The disease is described as a skin channelopathy.
prevalence:
- population: Published literature, all genetic forms of Olmsted syndrome
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists. The 2015 review counted
    about 73 reported cases of Olmsted syndrome of all genetic forms (TRPV3,
    MBTPS2 and molecularly unconfirmed), so the TRPV3-specific count is smaller
    than this figure.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "About 73 cases have been reported worldwide."
    explanation: >-
      The systematic literature review gives the total number of Olmsted
      syndrome cases reported up to December 2014, establishing the disease as
      ultra-rare.
  - reference: PMID:24452206
    reference_title: "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Approximately 50 cases have been reported, with the molecular basis described in only 9."
    explanation: >-
      An earlier count of reported cases, with the number that were molecularly
      confirmed; both figures place the disease in the ultra-rare band.
progression:
- phase: Onset in infancy or early childhood
  notes: >-
    Keratoderma usually begins at birth or in the first years of life and
    progresses thereafter; later-onset adult presentations have been reported
    with milder variants.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The disease starts usually at birth or in early childhood."
    explanation: Review statement of the usual age of onset.
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment."
    explanation: States that the keratoderma begins in infancy and is progressive.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Progressive keratoderma, pseudoainhum with autoamputation and intractable
    pain can prevent grasping and walking and confine patients to a wheelchair;
    erlotinib-treated patients had been wheelchair-bound with growth delay,
    anorexia, insomnia and depression before treatment.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Review statement of the functional burden.
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis."
    explanation: Two of three TRPV3-confirmed patients were wheelchair-bound before erlotinib.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most cases are sporadic and carry a de novo heterozygous TRPV3 missense
    variant; familial transmission in an autosomal dominant pattern is also
    reported, including a three-generation family with a mild, partly
    nonpenetrant phenotype.
  evidence:
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS."
    explanation: Trio exome sequencing established the de novo heterozygous origin of the first TRPV3 variant.
  - reference: PMID:24758389
    reference_title: "Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Recently, pathogenic heterozygous mutations in TRPV3 were identified, with most cases showing de novo dominant inheritance."
    explanation: Summarises that heterozygous TRPV3 variants act dominantly and are mostly de novo.
  - reference: PMID:24452206
    reference_title: "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS."
    explanation: Records the autosomal dominant pattern of TRPV3 disease, including one familial case, and separates it from the X-linked MBTPS2 form.
  - reference: PMID:26902751
    reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, TRPV3 sequencing results revealed an identical heterozygous mutation c.2016G > A in the proband, his mother and his maternal grandfather"
    explanation: Vertical transmission of a heterozygous TRPV3 variant through three generations, the autosomal dominant familial pattern.
  - reference: PMID:26902751
    reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation we described was detected in a familial pedigree that presented with minor symptoms and whose clinical traits were partly nonpenetrant."
    explanation: Reduced penetrance and mild expression in this dominant family.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Rare families carry biallelic TRPV3 variants with recessive transmission.
    The primary report is Duchatelet et al. 2014 (PMID:24606194, a letter
    without an abstract, listed under references); the claim is cited through
    the review.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: The review records both dominant and recessive TRPV3-related Olmsted syndrome.
genetic:
- name: TRPV3
  gene_term:
    preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    Heterozygous missense variants in TRPV3, encoding the transient receptor
    potential vanilloid 3 cation channel expressed in keratinocytes and hair
    follicles, cause Olmsted syndrome 1. Recurrent variants cluster at Gly573
    (G573S, G573C), Gly568 (G568D, G568V), Leu673 (L673F) and Trp692 (W692G,
    W692C, W692S); variants in the S4-S5 linker and TRP domain produce the
    strongest channel gain of function and the severest phenotypes, whereas
    other positions (for example R416Q) give milder disease. Most variants arise
    de novo. No ClinGen gene-disease validity assertion for TRPV3 was found in
    the committed ClinGen validity export (cache/clingen/gene_validity.csv), so
    no gene_disease_validity tier is recorded.
  evidence:
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each)."
    explanation: Independent affected individuals carried TRPV3 missense variants, establishing TRPV3 as the causal gene.
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord."
    explanation: Gene product identity and expression in the affected tissues.
  - reference: PMID:32795529
    reference_title: "Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified five previously unreported TRPV3 variations (R416Q, R416W, L655P, W692S, and L694P) and three recurrent variations (G568D, G568V, and L673F) in nine unrelated patients."
    explanation: Expands the TRPV3 variant spectrum across nine unrelated patients.
  - reference: PMID:32795529
    reference_title: "Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional changes were particularly pronounced in variants corresponding to severer Olmsted syndrome (e.g., L673F and W692S) but not in mild Olmsted syndrome variants (e.g., R416Q)."
    explanation: Electrophysiology of expressed variants ties the degree of channel dysfunction to clinical severity.
  variants:
  - name: p.Gly573Ser (G573S)
    description: >-
      The first and most recurrent Olmsted syndrome variant, identified de novo
      in the index trio and in three further patients; the same substitution
      occurs spontaneously in the hairless DS-Nh mouse.
    clinical_significance: PATHOGENIC
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:22405088
      reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS."
      explanation: Discovery of the recurrent G573S variant.
  - name: p.Trp692Gly (W692G) and p.Trp692Cys (W692C)
    description: >-
      Substitutions of Trp692 in the TRP domain, each identified as a de novo
      heterozygous variant in a patient with the classic mutilating phenotype.
    clinical_significance: PATHOGENIC
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:24758389
      reference_title: "Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TRPV3 was sequenced and a new de novo heterozygous missense mutation, c.2076G>C (p.Trp692Cys), was identified."
      explanation: Reports the de novo W692C variant in a boy with mutilating keratoderma, alopecia and pseudoainhum.
  - name: p.Leu673Phe (L673F)
    description: >-
      A recurrent S4-S5 linker variant associated with severe disease and
      erythromelalgia-like inflammatory flares.
    clinical_significance: PATHOGENIC
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:24452206
      reference_title: "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging."
      explanation: First report of the de novo L673F variant.
  - name: p.Val306Met (V306M)
    description: >-
      An atypical variant in exon 8 reported in an adult with mutilating
      keratoderma who developed plantar squamous cell carcinoma.
    clinical_significance: LIKELY_PATHOGENIC
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:39469632
      reference_title: "Case report: Novel p.Val306Met missense mutation in TRPV3 in a case of Olmsted syndrome accompanied by squamous cell carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis identified a novel heterozygous p.Val306Met missense mutation in the exon 8 of TRPV3."
      explanation: Reports the heterozygous V306M variant; functional characterisation was not reported, hence likely pathogenic rather than pathogenic.
  - name: p.Gly573Ala (G573A)
    description: >-
      A third substitution of the Gly573 hotspot, found in a patient whose
      immunological work-up showed hyper-IgE, eosinophilia and frequent skin
      infections.
    clinical_significance: LIKELY_PATHOGENIC
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:23692804
      reference_title: "Olmsted syndrome: exploration of the immunological phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation."
      explanation: Reports the G573A variant at the recurrent Gly573 position; no electrophysiology was reported, hence likely pathogenic.
  - name: p.Met672Ile (M672I)
    description: >-
      A familial variant segregating through three generations with a mild,
      partly nonpenetrant, atypical phenotype (sclerodactyly-like fingers in
      the proband, focal plantar plaques in the grandfather); it increases
      apoptosis of HaCaT keratinocytes but less than the classic hotspot
      variants.
    clinical_significance: LIKELY_PATHOGENIC
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:26902751
      reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, TRPV3 sequencing results revealed an identical heterozygous mutation c.2016G > A in the proband, his mother and his maternal grandfather"
      explanation: Segregation of the c.2016G>A (p.Met672Ile) variant with disease in the family.
    - reference: PMID:26902751
      reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Additionally, a functional assay indicated that the Met672Ile mutation imposed a more significant induction of apoptosis on HaCaT cells compared with that of the wild type."
      explanation: Functional support in a keratinocyte line, consistent with the cytotoxic gain of function of other variants.
  - name: p.Leu655Pro (L655P)
    description: >-
      A heterozygous variant in exon 15 found in a patient with classic
      Olmsted syndrome and in his father, treated with erlotinib. The source
      abstract calls c.1964T>C a frameshift mutation, but a single-nucleotide
      substitution producing p.Leu655Pro is a missense change, as the article
      title states; the same residue was reported as L655P in the
      genotype-phenotype series.
    clinical_significance: LIKELY_PATHOGENIC
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:39926429
      reference_title: "Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: Reports the heterozygous L655P variant in the patient and his father; the quoted sentence misnames the substitution as a frameshift.
pathophysiology:
- name: TRPV3 Gain-of-Function Channel Activation
  description: >-
    Missense variants in TRPV3 lock the thermosensitive, calcium-permeable
    cation channel into a constitutively open state. Expressed in HEK293 cells,
    Olmsted syndrome variants conduct much larger inward currents than wild-type
    channel, with elevated basal open probability and increased voltage
    sensitivity; the magnitude of the gain of function tracks clinical severity.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genetic_context:
    gene:
      preferred_term: TRPV3
      term:
        id: hgnc:18084
        label: TRPV3
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous, mostly de novo, germline missense variants; the channel is
      constitutively active rather than merely more active, so the variant
      consequence is recorded as GAIN_OF_FUNCTION.
  genes:
  - preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: TRPV3 calcium-permeable cation channel activity
    term:
      id: GO:0005262
      label: calcium channel activity
    modifier: GAIN_OF_FUNCTION
    description: >-
      The variant channel opens constitutively, outside its normal temperature
      and ligand gating, which is a qualitative loss of regulatory constraint
      rather than a quantitative increase in a regulated activity.
  evidence:
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants."
    explanation: Patch-clamp recordings of the G573S, G573C and W692G channels show constitutive activation.
  - reference: PMID:32795529
    reference_title: "Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These variant TRPV3 channels, in either homomeric or heteromeric form, exhibited differentially elevated basal open probability, increased voltage sensitivity, and cytotoxicity."
    explanation: Seven expressed variants show graded gain of channel function, including when co-assembled with wild-type subunits as in heterozygous patients.
  - reference: PMID:32795529
    reference_title: "Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "We have previously shown that gain-of-function variations in transient receptor potential vanilloid-3 (TRPV3) underlay Olmsted syndrome, a rare hyperkeratotic skin channelopathy."
    explanation: States the gain-of-function mechanism and frames the disease as a skin channelopathy.
  downstream:
  - target: Keratinocyte Calcium Overload
    causal_link_type: DIRECT
    description: >-
      A constitutively open calcium-permeable channel in the keratinocyte
      plasma membrane admits unregulated calcium influx.
    evidence:
    - reference: PMID:18754035
      reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We reported that the Gly573Ser substitution in transient receptor potential vanilloid 3 (TRPV3) led to increased ion channel activity in keratinocytes and caused spontaneous hairlessness in DS-Nh mice."
      explanation: The same substitution found in patients increases channel activity in keratinocytes of the DS-Nh mouse.
- name: Keratinocyte Calcium Overload
  description: >-
    Unregulated calcium entry through constitutively active TRPV3 disturbs
    keratinocyte calcium homeostasis. TRPV3 is one of the principal calcium
    entry pathways of keratinocytes, and Olmsted syndrome variants are
    cytotoxic when expressed; some variants also act as calcium-leaky channels
    at lysosomes and disturb lysosomal pH and number.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: calcium ion transmembrane transport into keratinocytes
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  - preferred_term: keratinocyte calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:27754757
    reference_title: "TRPV3 mutants causing Olmsted Syndrome induce impaired cell adhesion and nonfunctional lysosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TRPV3 is one of the key ion channel involved in Ca2+-signaling in keratinocyte and thus involved in skin-related functions."
    explanation: Places TRPV3 as a principal calcium-signalling channel of keratinocytes, the cell in which the gain-of-function variants act.
  - reference: PMID:36063600
    reference_title: "Olmsted syndrome causing point mutants of TRPV3 (G568C and G568D) show defects in intracellular Ca(2+)-mobilization and induce lysosomal defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We propose that G568C and G568D mutants most-likely act as Ca2+-leaky channels from lysosomes with different abilities."
    explanation: Two Olmsted syndrome variants also leak calcium from intracellular stores, extending the calcium-handling defect beyond the plasma membrane.
  downstream:
  - target: Keratinocyte Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Calcium overload through the constitutively open channel is cytotoxic to
      the cells expressing it.
    evidence:
    - reference: PMID:32795529
      reference_title: "Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These variant TRPV3 channels, in either homomeric or heteromeric form, exhibited differentially elevated basal open probability, increased voltage sensitivity, and cytotoxicity."
      explanation: Cytotoxicity of the expressed variant channels scales with their gain of function.
  - target: EGFR-mTOR Signaling Hyperactivation in Epidermis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      TRPV3 forms a signalling complex with TGF-alpha/EGFR in keratinocytes, and
      TRPV3 channel activity stimulates TGF-alpha release, so constitutive
      channel activity transactivates EGFR.
    evidence:
    - reference: PMID:20403327
      reference_title: "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-alpha release."
      explanation: Establishes the feed-forward loop in keratinocytes by which TRPV3 activity drives release of the EGFR ligand TGF-alpha.
    - reference: PMID:31895432
      reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation."
      explanation: The clinical series' background statement summarises the animal-model and keratinocyte-line evidence for the TRPV3-to-EGFR transactivation link that motivated erlotinib treatment; the sentence describes model evidence, not a human observation.
  - target: Keratinocyte-Driven Itch Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Keratinocyte TRPV3 couples to protease-activated receptor 2 signalling
      and to nerve growth factor release, through which hyperactive channel
      activity is transmitted to pruriceptive sensory neurons.
    evidence:
    - reference: PMID:32004565
      reference_title: "PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that keratinocytes lacking TRPV3 impair the function of protease-activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists."
      explanation: Loss of keratinocyte TRPV3 reduces PAR2-evoked neuronal activation and scratching; the inverse model system supports TRPV3 as a keratinocyte-to-neuron itch relay.
- name: Keratinocyte Apoptosis
  description: >-
    Olmsted syndrome TRPV3 variants are cytotoxic to the cells expressing them,
    and elevated keratinocyte apoptosis was proposed by the gene-discovery study
    as the proximate cause of the hyperkeratosis. The channel's partial
    retention in the endoplasmic reticulum, reduced cell adhesion and lysosomal
    abnormalities observed in expression systems may contribute.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte apoptotic process
    term:
      id: GO:0097283
      label: keratinocyte apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals."
    explanation: The authors propose keratinocyte apoptosis as the link between constitutive channel activity and hyperkeratosis; the sentence is hypothesis rather than measurement, hence the provisional confidence.
  - reference: PMID:26902751
    reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, a functional assay indicated that the Met672Ile mutation imposed a more significant induction of apoptosis on HaCaT cells compared with that of the wild type."
    explanation: A patient variant increases apoptosis when expressed in HaCaT keratinocytes, a measurement of the process in a keratinocyte line.
  downstream:
  - target: Epidermal Hyperproliferation and Hyperkeratosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Elevated keratinocyte apoptosis was proposed to drive compensatory
      epidermal turnover and hyperkeratosis.
    evidence:
    - reference: PMID:22405088
      reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals."
      explanation: The proposed causal sequence from apoptosis to hyperkeratosis.
- name: EGFR-mTOR Signaling Hyperactivation in Epidermis
  description: >-
    Keratinocyte TRPV3 is physically complexed with TGF-alpha/EGFR and its
    activity stimulates TGF-alpha release, so a constitutively active channel
    transactivates EGFR. Lesional epidermis from patients shows increased
    phosphorylated EGFR and phosphorylated ribosomal protein S6, indicating
    activation of both EGFR and the downstream mTOR cascade. Excess TGF-alpha/EGFR
    signalling in skin is known to produce hairless phenotypes.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: epidermal growth factor receptor signaling pathway
    term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    modifier: INCREASED
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:20403327
    reference_title: "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that keratinocyte TRPV3, a member of the transient receptor potential (TRP) family of Ca(2+)-permeant channels, forms a signaling complex with TGF-alpha/EGFR."
    explanation: Biochemical demonstration of the TRPV3-TGF-alpha/EGFR complex in keratinocytes.
  - reference: PMID:31895414
    reference_title: "Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation."
    explanation: Direct evidence of EGFR and mTOR pathway activation in patient lesional epidermis.
  downstream:
  - target: Epidermal Hyperproliferation and Hyperkeratosis
    causal_link_type: DIRECT
    description: >-
      EGFR signalling drives keratinocyte proliferation; its inhibition with
      erlotinib resolves the keratoderma, which is the strongest evidence that
      this signalling sustains the hyperkeratosis.
    evidence:
    - reference: PMID:36709954
      reference_title: "Two for two: Dual therapy with erlotinib and acitretin for twins with severe keratoderma in Olmsted syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "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."
      explanation: States the causal sequence from EGFR signalling to palmoplantar epidermal hyperproliferation.
    - reference: PMID:31895432
      reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared."
      explanation: Therapeutic EGFR blockade reverses the hyperkeratosis, supporting the edge by intervention.
  - target: Hair Follicle Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Excess TGF-alpha/EGFR activity produces hairless phenotypes in mice, and
      TRPV3 controls hair morphogenesis through this complex.
    evidence:
    - reference: PMID:20403327
      reference_title: "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Conversely, excessive activities of TGF-alpha/EGFR result in hairless phenotypes and skin cancers."
      explanation: Background statement, from the mouse literature, that excess EGFR activity causes hair loss.
- name: Epidermal Hyperproliferation and Hyperkeratosis
  description: >-
    Sustained EGFR signalling and keratinocyte turnover produce thickened,
    hyperproliferative epidermis with massive orthokeratotic hyperkeratosis,
    most severely over the palms and soles and around body orifices. The
    resulting keratoderma is transgredient, progressive and painful; its
    circumferential extension around digits forms constricting bands.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: INCREASED
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:36709954
    reference_title: "Two for two: Dual therapy with erlotinib and acitretin for twins with severe keratoderma in Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "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."
    explanation: Names palmoplantar epidermal hyperproliferation as the tissue consequence of channel activation.
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders."
    explanation: The gene-discovery study attributes the keratinization defect to TRPV3.
  downstream:
  - target: Palmoplantar keratoderma
    causal_link_type: DIRECT
    description: Palmoplantar hyperkeratosis is the direct clinical expression of the epidermal process.
    evidence:
    - reference: PMID:31895432
      reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."
      explanation: TRPV3-confirmed patients with severe palmoplantar hyperkeratosis.
  - target: Periorificial keratotic plaques
    causal_link_type: DIRECT
    description: The same hyperkeratotic process around the mouth, nose, eyes, anus and genitalia.
    evidence:
    - reference: PMID:36709954
      reference_title: "Two for two: Dual therapy with erlotinib and acitretin for twins with severe keratoderma in Olmsted syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Olmsted syndrome (OS) is a rare genetic disorder, characterized by painful palmoplantar keratoderma (PPK), periorificial and intertriginous hyperkeratoses, and alopecia."
      explanation: Periorificial lesions are described as hyperkeratoses, the same tissue process as the keratoderma.
  - target: Nail dystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Nail abnormalities accompany the keratoderma; the nail unit is a keratinizing epithelium.
    evidence:
    - reference: PMID:39469632
      reference_title: "Case report: Novel p.Val306Met missense mutation in TRPV3 in a case of Olmsted syndrome accompanied by squamous cell carcinoma."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Olmsted syndrome (OS) is a rare congenital skin disorder, typically characterized by symmetrical, severe palmoplantar and periorificial keratoderma, often accompanied by alopecia, and onychodystrophy, with varying degrees of pruritus and pain."
      explanation: Onychodystrophy accompanies the keratoderma; no study has examined the nail unit mechanism directly.
  - target: Pseudoainhum
    causal_link_type: DIRECT
    description: Circumferential hyperkeratosis around digits forms constricting bands.
    evidence:
    - reference: PMID:24758389
      reference_title: "Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits."
      explanation: Constriction bands arising within mutilating keratoderma.
  - target: Pain
    causal_link_type: DIRECT
    description: Thick, fissuring plantar and palmar keratoderma is painful and limits walking and grasping.
    evidence:
    - reference: PMID:31895432
      reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment."
      explanation: Pain is attributed to the keratoderma itself.
  - target: Limitation of joint mobility
    causal_link_type: DIRECT
    description: Hyperkeratosis over the digits and joints restricts joint movement.
    evidence:
    - reference: PMID:31895432
      reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis."
      explanation: Joint restriction is attributed directly to the hyperkeratosis.
  - target: Oral leukokeratosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Leukokeratosis of the oral mucosa is a keratinizing lesion of the same disordered epithelium.
    evidence:
    - reference: PMID:39926429
      reference_title: "Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Uncommon cutaneous manifestations such as nail dystrophy, leukokeratosis of the oral mucosa, and hyperhidrosis or hypohidrosis of the palmoplantar region may also be observed in association with OS"
      explanation: Oral leukokeratosis is reported as a cutaneous manifestation of the keratinizing disorder; the mucosal mechanism has not been studied.
  - target: Recurrent skin infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Fissured, hyperkeratotic skin is the site of the recurrent bacterial and candidal infections.
    evidence:
    - reference: PMID:23692804
      reference_title: "Olmsted syndrome: exploration of the immunological phenotype."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "A review of published cases noted the common concordance of recurrent bacterial and candida infections in keratotic areas"
      explanation: Infections localise to the keratotic skin, so the keratoderma is the proximate cause; whether an intrinsic immune defect contributes is an open question recorded in discussions.
- name: Hair Follicle Dysfunction
  description: >-
    TRPV3 is expressed in hair follicles and controls hair morphogenesis through
    its complex with TGF-alpha/EGFR. The patient G573S and G573C substitutions
    arose spontaneously in the DS-Nh mouse and WBN/Kob-Ht rat and cause
    dominant hairlessness, and most patients have alopecia.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: hair follicle morphogenesis
    term:
      id: GO:0031069
      label: hair follicle morphogenesis
    modifier: ABNORMAL
  - preferred_term: hair cycle
    term:
      id: GO:0042633
      label: hair cycle
    modifier: ABNORMAL
  locations:
  - preferred_term: hair follicle
    term:
      id: UBERON:0002073
      label: hair follicle
  evidence:
  - reference: PMID:16858425
    reference_title: "Association of a mutation in TRPV3 with defective hair growth in rodents."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "An amino-acid substitution at the same position in one gene was detected in DS-Nh mice and WBN/Kob-Ht rats: Gly573 to Ser (Nh mutation) or Gly573 to Cys (Ht mutation), located in the transient receptor potential (TRP) cation channel subfamily V member 3 (TRPV3) gene."
    explanation: The same Gly573 substitutions later found in patients cause dominant hairlessness in two rodent species.
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord."
    explanation: TRPV3 is expressed in the hair follicle, the site of this process.
  downstream:
  - target: Alopecia
    causal_link_type: DIRECT
    description: Defective hair growth from constitutively active follicular TRPV3 presents as alopecia.
    evidence:
    - reference: PMID:22405088
      reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching."
      explanation: Alopecia in most TRPV3 patients.
- name: Cutaneous Inflammation with Mast Cell Infiltration
  description: >-
    Constitutively active TRPV3 in keratinocytes promotes skin inflammation.
    Rodents carrying the Gly573 substitutions develop spontaneous allergic
    dermatitis with increased lesional mast cells, and transgenic expression of
    TRPV3(Gly573Ser) alone is sufficient to produce dermatitis. Patients show
    acute inflammatory flares with vasodilatation, redness and burning pain of
    the extremities.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: PMID:16858425
    reference_title: "Association of a mutation in TRPV3 with defective hair growth in rodents."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Histopathological analyses revealed that mast cells in skin lesions were increased in both rodents compared to their age-matched parent strains, and that this may partially be due to hairlessness and dermatitis."
    explanation: Increased lesional mast cells in both TRPV3-mutant rodent strains.
  - reference: PMID:18754035
    reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These transgenic mice spontaneously developed dermatitis, whereas wild-type mice did not display this phenotype when maintained under the same conditions."
    explanation: Transgenic TRPV3(Gly573Ser) is sufficient to cause dermatitis, isolating the channel variant as the cause.
  - reference: PMID:24452206
    reference_title: "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia."
    explanation: Inflammatory flares in a patient with a de novo L673F variant.
  downstream:
  - target: Erythromelalgia
    causal_link_type: DIRECT
    description: Acute inflammatory flares of the extremities with vasodilatation, redness and burning pain present as erythromelalgia.
    evidence:
    - reference: PMID:24452206
      reference_title: "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia."
      explanation: The erythromelalgia is described as flares of inflammation.
  - target: Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Inflammatory flares contribute burning pain in addition to the mechanical pain of the keratoderma.
    evidence:
    - reference: PMID:24452206
      reference_title: "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia."
      explanation: Burning pain occurs within the inflammatory flares.
- name: Keratinocyte-Driven Itch Signaling
  description: >-
    Hyperactive keratinocyte TRPV3 transmits itch to sensory neurons. The
    channel is required for protease-activated receptor 2-evoked neuronal
    activation and scratching, and the Gly573Ser variant raises the keratinocyte
    nerve growth factor response to heat; DS-Nh mice carrying the variant
    scratch spontaneously even without dermatitis. The output is conditional:
    the same Gly573Ser variant on a 129S1/SvImJ background under Staphylococcus
    aureus-free housing produces no spontaneous itch, reduced pruritogen-evoked
    scratching and epidermal sensory hypoinnervation, so hyperactive TRPV3 does
    not cause itch unconditionally.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:18754035
    reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat."
    explanation: The patient variant increases keratinocyte NGF release in response to warmth, a pruritogenic output.
  - reference: PMID:18754035
    reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, C57BL-Nh mice developed spontaneous scratching behavior, separately from the development of dermatitis."
    explanation: Scratching occurs independently of dermatitis, pointing to itch generated by the channel variant itself.
  - reference: PMID:32004565
    reference_title: "PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome, which is associated with severe pruritus."
    explanation: Background statement linking the human gain-of-function variants to severe pruritus, which the study then models.
  downstream:
  - target: Pruritus
    causal_link_type: DIRECT
    description: Keratinocyte-to-neuron itch signalling driven by the hyperactive channel is the proposed basis of the severe pruritus.
    evidence:
    - reference: PMID:18754035
      reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We propose that TRPV3(Gly573Ser) is a cause of pruritus and/or dermatitis associated with scratching, and suggest that TRPV3 may represent a therapeutic target in pruritic dermatitis."
      explanation: Mouse evidence that the patient variant causes pruritus; human support for the phenotype itself is on the phenotype node.
    - reference: PMID:35058747
      reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
      supports: REFUTE
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We fail to observe any spontaneous itch responses and/or dermatitis in Trpv3 G573S mutants under specific pathogen (Staphylococcus aureus)-free conditions."
      explanation: The same variant on another background and without S. aureus produces no spontaneous itch, so the variant alone does not account for pruritus in the mouse; the edge is kept because patients are not pathogen-free and the human phenotype is consistent.
phenotypes:
- category: Dermatologic
  name: Palmoplantar keratoderma
  description: >-
    Bilateral, diffuse, mutilating and transgredient palmoplantar keratoderma
    beginning in infancy or early childhood and progressing over time; the
    defining feature of the syndrome.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Mutilating transgredient palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: The defining feature across the reported case series.
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching."
    explanation: Palmoplantar keratoderma in all TRPV3-mutant individuals of the discovery cohort.
  - reference: PMID:35789571
    reference_title: "Treatment of TRPV3 mutation-associated Olmsted syndrome with erlotinib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequently, he experienced several episodes of recurring painful plaques on his feet that occurred following trauma"
    explanation: In a milder, later-onset case the plantar plaques arose at sites of trauma, showing that mechanical injury can provoke the keratoderma at pressure-bearing skin.
- category: Dermatologic
  name: Periorificial keratotic plaques
  description: >-
    Hyperkeratotic, often erythematous plaques around the mouth, nostrils, eyes,
    ears, anus and genitalia, and in intertriginous areas; the second cardinal
    feature. Absent in some atypical TRPV3 cases, including the de novo L673F
    patient with erythromelalgia (PMID:24452206), so the feature is very
    frequent rather than obligate.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Periorificial keratotic plaques
    term:
      id: HP:0034521
      label: Periorificial hyperkeratosis
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques."
    explanation: Periorificial plaques are one of the diagnostic triad.
  - reference: PMID:36709954
    reference_title: "Two for two: Dual therapy with erlotinib and acitretin for twins with severe keratoderma in Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Olmsted syndrome (OS) is a rare genetic disorder, characterized by painful palmoplantar keratoderma (PPK), periorificial and intertriginous hyperkeratoses, and alopecia."
    explanation: Names periorificial and intertriginous hyperkeratoses among the characteristic features.
- category: Dermatologic
  name: Pseudoainhum
  description: >-
    Constricting hyperkeratotic bands encircling the digits, which can
    progress to autoamputation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pseudoainhum (digital constriction bands)
    term:
      id: HP:0010491
      label: Digital constriction ring
  sequelae:
  - target: Autoamputation of digits
    causal_link_type: DIRECT
    description: Progressive constriction by the bands leads to loss of digits.
    evidence:
    - reference: PMID:24758389
      reference_title: "Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits."
      explanation: Pseudoainhum leading to autoamputation in a TRPV3 W692C patient.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques."
    explanation: Pseudoainhum is part of the suggestive triad.
  - reference: PMID:24758389
    reference_title: "Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Constriction of digits, onychodystrophy and pruritus may also occur."
    explanation: Digital constriction among the associated features.
- category: Musculoskeletal
  name: Autoamputation of digits
  description: Spontaneous loss of digits following progressive pseudoainhum.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autoamputation of digits
    term:
      id: HP:0007460
      label: Autoamputation of digits
  evidence:
  - reference: PMID:24758389
    reference_title: "Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits."
    explanation: Autoamputation of two digits in a TRPV3-confirmed boy.
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Autoamputation as a recognised complication.
- category: Dermatologic
  name: Alopecia
  description: >-
    Diffuse alopecia of the scalp, and often of eyebrows and eyelashes, present
    in most TRPV3 patients.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Diffuse alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching."
    explanation: Alopecia in most cases of the TRPV3 discovery cohort.
  - reference: PMID:24758389
    reference_title: "Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits."
    explanation: Diffuse alopecia in a TRPV3-confirmed patient.
- category: Dermatologic
  name: Nail dystrophy
  description: Onychodystrophy accompanies the keratoderma in many patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Onychodystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:39469632
    reference_title: "Case report: Novel p.Val306Met missense mutation in TRPV3 in a case of Olmsted syndrome accompanied by squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Olmsted syndrome (OS) is a rare congenital skin disorder, typically characterized by symmetrical, severe palmoplantar and periorificial keratoderma, often accompanied by alopecia, and onychodystrophy, with varying degrees of pruritus and pain."
    explanation: Onychodystrophy among the typical accompanying features.
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."
    explanation: Nail abnormalities are frequently associated.
- category: Dermatologic
  name: Pruritus
  description: Severe, often intractable itch, present from early childhood.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Severe pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching."
    explanation: Severe itching is a defining feature in the TRPV3 cohort.
  - reference: PMID:31895414
    reference_title: "Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 4 patients had sustained improvements in pruritus and pain."
    explanation: Pruritus was a treatment-tracked symptom in all four patients.
- category: Clinical
  name: Pain
  description: >-
    Intense, often intolerable pain of the keratotic palms and soles, with
    burning pain during inflammatory flares; a major driver of disability.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Palmoplantar pain
    term:
      id: HP:0012531
      label: Pain
  sequelae:
  - target: Growth delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Growth delay with anorexia and insomnia accompanied intractable pain in
      the erlotinib series and remitted with it; the intermediates (anorexia,
      sleep loss, immobility) are described but not measured.
    evidence:
    - reference: PMID:31895432
      reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."
      explanation: Growth delay, anorexia and insomnia co-occurred with intolerable pain and progressed together; the direction of the link is inferred from their joint remission on erlotinib.
  evidence:
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."
    explanation: Intolerable pain in all three TRPV3-confirmed patients.
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pain and itching are variable but can be severe."
    explanation: Pain is variable but can be severe across reported cases.
- category: Dermatologic
  name: Erythromelalgia
  description: >-
    Episodic flares of redness, warmth and burning pain of the extremities,
    reported in several TRPV3 patients, including those with L673F.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Erythromelalgia
    term:
      id: HP:0032147
      label: Erythromelalgia
  evidence:
  - reference: PMID:24452206
    reference_title: "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia."
    explanation: Erythromelalgia in a de novo L673F patient.
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."
    explanation: Erythromelalgia in all three patients of the erlotinib series.
- category: Dermatologic
  name: Oral leukokeratosis
  description: White keratotic thickening of the oral mucosa, a frequently associated feature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Oral leukokeratosis
    term:
      id: HP:0002745
      label: Oral leukoplakia
  notes: >-
    The review names "leukokeratosis" without a site; the case literature
    places it in the oral mucosa, so it is bound to the HPO oral leukoplakia
    term. HPO has no leukokeratosis term (OLS search "oral leukokeratosis",
    ontology=hp, returns only HP:0002745).
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."
    explanation: Leukokeratosis among the frequently associated features.
  - reference: PMID:39926429
    reference_title: "Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Uncommon cutaneous manifestations such as nail dystrophy, leukokeratosis of the oral mucosa, and hyperhidrosis or hypohidrosis of the palmoplantar region may also be observed in association with OS"
    explanation: Names the oral mucosa as the site of the leukokeratosis.
- category: Ophthalmologic
  name: Corneal abnormality
  description: Corneal involvement is reported among associated features; the review does not specify the lesion.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Corneal abnormality
    term:
      id: HP:0000481
      label: Abnormal cornea morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."
    explanation: Corneal involvement listed among associated features without further specification.
- category: Immunologic
  name: Recurrent skin infections
  description: >-
    Recurrent bacterial and candidal infections of the keratotic skin are
    frequently reported; the sources describe infections of the keratotic
    areas rather than systemic infection.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent infections of keratotic skin
    term:
      id: HP:0001581
      label: Recurrent skin infections
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections."
    explanation: Recurrent infections among the frequently associated features.
  - reference: PMID:23692804
    reference_title: "Olmsted syndrome: exploration of the immunological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "A review of published cases noted the common concordance of recurrent bacterial and candida infections in keratotic areas"
    explanation: Localises the recurrent infections to the keratotic skin, which is the basis for binding the skin-infection term.
  - reference: PMID:23692804
    reference_title: "Olmsted syndrome: exploration of the immunological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Frequent dermal infections in a TRPV3 G573A patient.
- category: Immunologic
  name: Increased circulating IgE concentration
  description: >-
    Hyper-IgE with elevated circulating follicular helper T cells was found on
    immunological profiling of a single TRPV3 G573A patient; it is not an
    established feature of the disease and its frequency is unknown.
  phenotype_term:
    preferred_term: Hyper-IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:23692804
    reference_title: "Olmsted syndrome: exploration of the immunological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Hyper-IgE production in the single profiled patient.
- category: Hematologic
  name: Eosinophilia
  description: >-
    Persistent peripheral eosinophilia in the same single TRPV3 G573A patient;
    frequency unknown.
  phenotype_term:
    preferred_term: Persistent peripheral eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:23692804
    reference_title: "Olmsted syndrome: exploration of the immunological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Persistent eosinophilia in the profiled patient, with the authors' caution that its role may be primary or secondary.
- category: Dermatologic
  name: Palmoplantar hyperhidrosis
  description: Hyperhidrosis of the palmoplantar region is an uncommon associated feature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Palmoplantar hyperhidrosis
    term:
      id: HP:0007410
      label: Palmoplantar hyperhidrosis
  evidence:
  - reference: PMID:39926429
    reference_title: "Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Uncommon cutaneous manifestations such as nail dystrophy, leukokeratosis of the oral mucosa, and hyperhidrosis or hypohidrosis of the palmoplantar region may also be observed in association with OS"
    explanation: Palmoplantar hyperhidrosis listed among uncommon associated manifestations.
- category: Dermatologic
  name: Hypohidrosis
  description: Hypohidrosis of the palmoplantar region is reported as an uncommon associated feature, in other patients than those with hyperhidrosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Palmoplantar hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
  evidence:
  - reference: PMID:39926429
    reference_title: "Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Uncommon cutaneous manifestations such as nail dystrophy, leukokeratosis of the oral mucosa, and hyperhidrosis or hypohidrosis of the palmoplantar region may also be observed in association with OS"
    explanation: Palmoplantar hypohidrosis listed among uncommon associated manifestations.
- category: Musculoskeletal
  name: Limitation of joint mobility
  description: Hyperkeratosis over the digits and joints restricts movement and, with pain, can prevent walking.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint restriction from hyperkeratosis
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis."
    explanation: Joint restriction from hyperkeratosis in two of three patients.
- category: Growth
  name: Growth delay
  description: >-
    Severe growth delay with anorexia and insomnia accompanied intractable pain
    in the erlotinib-treated adolescents and improved as pain remitted.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies."
    explanation: Severe growth delay in all three patients before treatment.
- category: Oncologic
  name: Squamous cell carcinoma of the skin
  description: >-
    Cutaneous squamous cell carcinoma arising in long-standing plantar
    keratoderma has been reported in a single adult with a V306M variant, and
    the 2015 review of Olmsted syndrome of all genetic forms records a higher
    susceptibility to malignant tumours, verrucous carcinoma among them, in
    keratotic areas; frequency is not estimable from the literature.
  phenotype_term:
    preferred_term: Plantar squamous cell carcinoma
    term:
      id: HP:0006739
      label: Squamous cell carcinoma of the skin
  notes: >-
    Not wired to a mechanism node: the single case report does not establish
    whether the carcinoma arose from chronic hyperproliferation, from the
    TGF-alpha/EGFR excess, or by chance, and no study has tested this.
  evidence:
  - reference: PMID:39469632
    reference_title: "Case report: Novel p.Val306Met missense mutation in TRPV3 in a case of Olmsted syndrome accompanied by squamous cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with disabling, bilateral palmoplantar keratoderma, and subsequently developed squamous cell carcinoma on the right sole."
    explanation: Plantar squamous cell carcinoma in a TRPV3 V306M patient.
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "OS patients may have a higher susceptibility to develop malignant tumors in keratotic areas such as verrucous carcinoma (a squamous cell carcinoma) and its variant epithelioma cuniculatum located on the sole of the foot, and malignant melanoma"
    explanation: >-
      The review's statement of malignancy risk in keratotic skin; it covers
      Olmsted syndrome of all genetic forms, not the TRPV3 form alone.
diagnosis:
- name: Clinical diagnosis on the keratoderma-periorificial plaque pattern
  description: >-
    Diagnosis rests on the combination of severe, mutilating palmoplantar
    keratoderma with periorificial keratotic plaques, usually with alopecia and
    pseudoainhum; incomplete or atypical presentations make clinical diagnosis
    difficult.
  diagnosis_term:
    preferred_term: Clinical diagnosis
    term:
      id: NCIT:C15607
      label: Clinical Diagnosis
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Review statement of the clinical diagnostic basis.
- name: TRPV3 sequencing
  description: >-
    Sequencing of TRPV3 (and MBTPS2 for the X-linked form) confirms the
    diagnosis and distinguishes the genetic forms; exome sequencing identified
    the original variants.
  diagnosis_term:
    preferred_term: TRPV3 gene sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation."
    explanation: Genetic testing for TRPV3 and MBTPS2 is the confirmatory step.
differential_diagnoses:
- name: Olmsted syndrome, X-linked (MBTPS2)
  disease_term:
    preferred_term: Olmsted syndrome, X-linked
    term:
      id: MONDO:0010486
      label: Olmsted syndrome, X-linked
  distinguishing_features:
  - >-
    X-linked recessive inheritance in males with a hemizygous MBTPS2 variant;
    overlapping keratoderma phenotype but a different gene and mechanism
    (regulated intramembrane proteolysis), so it is excluded from this entry.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form."
    explanation: The X-linked form is caused by MBTPS2 rather than TRPV3.
- name: Keratoderma hereditarium mutilans (Vohwinkel syndrome)
  disease_term:
    preferred_term: keratoderma hereditarium mutilans
    term:
      id: MONDO:0007422
      label: keratoderma hereditarium mutilans
  distinguishing_features:
  - >-
    Honeycomb keratoderma with pseudoainhum and starfish-shaped acral keratoses,
    usually with sensorineural deafness (GJB2) or ichthyosis (LOR); lacks the
    periorificial plaques of Olmsted syndrome.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Vohwinkel syndrome is listed first among the mutilating keratoderma differentials.
- name: Clouston syndrome
  disease_term:
    preferred_term: Clouston syndrome
    term:
      id: MONDO:0007510
      label: Clouston syndrome
  distinguishing_features:
  - Hidrotic ectodermal dysplasia (GJB6) with nail dystrophy, hypotrichosis and keratoderma but without periorificial plaques or pseudoainhum.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Listed differential.
- name: Papillon-Lefevre syndrome
  disease_term:
    preferred_term: Papillon-Lefevre disease
    term:
      id: MONDO:0009490
      label: Papillon-Lefevre disease
  distinguishing_features:
  - Transgredient keratoderma with early-onset periodontitis and tooth loss (CTSC); no periorificial plaques.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Listed differential.
- name: Pachyonychia congenita
  disease_term:
    preferred_term: pachyonychia congenita
    term:
      id: MONDO:0016471
      label: pachyonychia congenita
  distinguishing_features:
  - Focal painful plantar keratoderma with hypertrophic nail dystrophy and oral leukokeratosis (keratin 6/16/17 variants); keratoderma is focal rather than diffuse and transgredient.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Listed differential.
- name: Tyrosinemia type II
  disease_term:
    preferred_term: tyrosinemia type II
    term:
      id: MONDO:0010160
      label: tyrosinemia type II
  distinguishing_features:
  - Painful focal palmoplantar keratoses with pseudodendritic corneal erosions and elevated plasma tyrosine (TAT deficiency).
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Listed differential.
- name: Acrodermatitis enteropathica
  disease_term:
    preferred_term: acrodermatitis enteropathica
    term:
      id: MONDO:0008713
      label: acrodermatitis enteropathica
  distinguishing_features:
  - Periorificial and acral dermatitis with alopecia and diarrhoea from zinc deficiency (SLC39A4); low serum zinc and response to zinc supplementation distinguish it.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: Listed differential; the periorificial distribution overlaps most closely.
treatments:
- name: Erlotinib
  description: >-
    Oral EGFR tyrosine kinase inhibitor, used at doses below oncology dosing
    (2 mg/kg/day in the paediatric series), which produced disappearance of
    hyperkeratosis and pain within three months in TRPV3-confirmed patients,
    sustained over twelve months, with remission of anorexia, insomnia and
    catch-up growth; adverse effects were mild to moderate. It is the first
    mechanism-directed therapy, with consistent responses in uncontrolled case
    series.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: erlotinib
      term:
        id: CHEBI:114785
        label: erlotinib
  target_mechanisms:
  - target: EGFR-mTOR Signaling Hyperactivation in Epidermis
    treatment_effect: INHIBITS
    description: Blocks the EGFR transactivated by hyperactive TRPV3.
    evidence:
    - reference: PMID:31895432
      reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention."
      explanation: The authors frame the response as a consequence of blocking EGFR transactivation.
  target_phenotypes:
  - preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  - preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared."
    explanation: Primary response in three TRPV3-confirmed patients.
  - reference: PMID:31895432
    reference_title: "Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted."
    explanation: Dosing and tolerability.
  - reference: PMID:31895414
    reference_title: "Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores."
    explanation: Independent series confirming near-complete resolution of keratoderma on erlotinib monotherapy.
  - reference: PMID:31895414
    reference_title: "Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d."
    explanation: Paediatric dose used.
  - reference: PMID:36709954
    reference_title: "Two for two: Dual therapy with erlotinib and acitretin for twins with severe keratoderma in Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Response to erlotinib can be partial, and in these twins was completed by adding acitretin.
  - reference: PMID:35789571
    reference_title: "Treatment of TRPV3 mutation-associated Olmsted syndrome with erlotinib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He tolerated the medication well aside from nausea that was controlled with ondansetron, and his pain nearly resolved, with only intermittent flares."
    explanation: A fourth independent TRPV3 patient, treated with erlotinib 50 then 75 mg daily alongside acitretin, with near-resolution of pain.
  - reference: PMID:39926429
    reference_title: "Erlotinib therapy for Olmsted syndrome with p.L655P missense mutation in the TRPV3 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "After 3 months of treatment, most plantar lesions resolved, and the pain experienced was mildly alleviated."
    explanation: >-
      In the L655P patient erlotinib 75 mg daily was given together with oral
      acitretin, so the resolution of most plantar lesions within three months
      cannot be attributed to erlotinib alone; the pain effect was smaller.
- name: Sirolimus
  description: >-
    Oral mTOR inhibitor (0.8 mg/m2 twice daily to a trough of 10-15 ng/mL),
    which improved erythema and periorificial hyperkeratosis in two children
    before they were switched to erlotinib for the palmoplantar keratoderma.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: EGFR-mTOR Signaling Hyperactivation in Epidermis
    treatment_effect: INHIBITS
    description: Inhibits the mTOR arm downstream of EGFR, shown activated in lesional epidermis.
    evidence:
    - reference: PMID:31895414
      reference_title: "Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation."
      explanation: The activated mTOR signalling that sirolimus was given to inhibit.
  target_phenotypes:
  - preferred_term: Periorificial keratotic plaques
    term:
      id: HP:0034521
      label: Periorificial hyperkeratosis
  evidence:
  - reference: PMID:31895414
    reference_title: "Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward."
    explanation: Sirolimus response in two children.
  - reference: PMID:31895414
    reference_title: "Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL."
    explanation: Dosing used.
- name: Systemic retinoids (acitretin)
  description: >-
    Oral retinoids reduce hyperkeratosis but give only partial, temporary relief
    as monotherapy; acitretin added to erlotinib produced a dramatic reduction
    of residual palmoplantar thickening and pain in twins.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_mechanisms:
  - target: Epidermal Hyperproliferation and Hyperkeratosis
    treatment_effect: MODULATES
    description: Retinoids normalise keratinocyte differentiation and reduce hyperkeratosis without acting on the channel or EGFR.
    evidence:
    - reference: PMID:25886873
      reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."
      explanation: Retinoids are listed as treatments of the hyperkeratosis itself.
  evidence:
  - reference: PMID:36709954
    reference_title: "Two for two: Dual therapy with erlotinib and acitretin for twins with severe keratoderma in Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Acitretin added to erlotinib.
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."
    explanation: Retinoids as symptomatic therapy with partial, temporary benefit.
- name: Topical emollients and keratolytics
  description: >-
    Emollients, keratolytics and topical corticosteroids are symptomatic
    measures for the hyperkeratosis and offer only temporary partial relief.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Epidermal Hyperproliferation and Hyperkeratosis
    treatment_effect: MODULATES
    description: Softens and removes hyperkeratotic scale without altering the underlying process.
    evidence:
    - reference: PMID:25886873
      reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."
      explanation: Emollients and keratolytics are listed as symptomatic treatments of the hyperkeratosis.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief."
    explanation: Symptomatic topical therapies and their limited benefit.
- name: Pain and pruritus management
  description: >-
    Specific management of pain and itch is a central part of care and reduces
    morbidity; before erlotinib, pain was often refractory to multiple analgesics.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive care for pain and pruritus
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Specific management of pain and itching is important to reduce the morbidity of the disease."
    explanation: Review recommendation on symptom management.
animal_models:
- name: DS-Nh mouse (spontaneous Trpv3 Gly573Ser)
  species: Mouse
  genotype: Trpv3 Gly573Ser (Nh), heterozygous, autosomal dominant
  background: DS
  genes:
  - preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  publication: PMID:16858425
  description: >-
    Spontaneous hairless mutant carrying the same Gly573Ser substitution found
    in patients. Develops dominant hairlessness, spontaneous allergic and
    pruritic dermatitis with increased lesional mast cells, and scratching
    behaviour; it does not develop palmoplantar keratoderma.
  modeled_mechanisms:
  - target: Hair Follicle Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The patient G573S variant causes dominant hairlessness.
    limitations: >-
      Rodent hairlessness is complete, whereas human alopecia is variable; the
      mouse lacks the palmoplantar and periorificial keratoderma that define the
      human disease.
    readouts:
    - name: Hair coat
      target: Hair Follicle Dysfunction
      direction: ABOLISHED
      interpretation: Spontaneous hairlessness inherited with the Trpv3 variant.
      evidence:
      - reference: PMID:16858425
        reference_title: "Association of a mutation in TRPV3 with defective hair growth in rodents."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "DS-Nh mice and WBN/Kob-Ht rats are spontaneous hairless mutant rodent strains."
        explanation: The hairless phenotype of the strains.
    evidence:
    - reference: PMID:16858425
      reference_title: "Association of a mutation in TRPV3 with defective hair growth in rodents."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We concluded that TRPV3 was the gene responsible for Nh and Ht mutations, and that mutation in TRPV3 possibly correlated with increased mast cell numbers."
      explanation: Genetic identification of Trpv3 as the hairless gene.
  - target: Cutaneous Inflammation with Mast Cell Infiltration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Spontaneous dermatitis with increased lesional mast cells.
    limitations: >-
      The rodent dermatitis is allergic in character and depends on housing
      conditions and genetic background: the same variant re-derived on
      129S1/SvImJ and kept Staphylococcus aureus-free develops no dermatitis
      (PMID:35058747). Its relation to the inflammatory flares of patients is
      inferred.
    readouts:
    - name: Lesional mast cell count
      target: Cutaneous Inflammation with Mast Cell Infiltration
      direction: INCREASED
      interpretation: Increased mast cells in dermatitis lesions versus parental strains.
      evidence:
      - reference: PMID:16858425
        reference_title: "Association of a mutation in TRPV3 with defective hair growth in rodents."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Histopathological analyses revealed that mast cells in skin lesions were increased in both rodents compared to their age-matched parent strains, and that this may partially be due to hairlessness and dermatitis."
        explanation: Histological measurement of mast cells.
    evidence:
    - reference: PMID:18754035
      reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "DS-Nh mice also develop allergic and pruritic dermatitis."
      explanation: The dermatitis phenotype of the strain.
  - target: Keratinocyte-Driven Itch Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Mice carrying the Nh variant scratch spontaneously, independently of dermatitis.
    limitations: >-
      Scratching behaviour is an organism-level proxy for itch; the keratinocyte
      signalling step is inferred rather than measured in this strain.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The readout is scratching bouts, standing in for keratinocyte-to-neuron
        itch signalling, which is the quantity the node describes.
    readouts:
    - name: Spontaneous scratching behaviour
      target: Keratinocyte-Driven Itch Signaling
      direction: INCREASED
      interpretation: Scratching develops separately from dermatitis in C57BL-Nh mice.
      evidence:
      - reference: PMID:18754035
        reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, C57BL-Nh mice developed spontaneous scratching behavior, separately from the development of dermatitis."
        explanation: Behavioural measurement of itch.
    evidence:
    - reference: PMID:18754035
      reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We propose that TRPV3(Gly573Ser) is a cause of pruritus and/or dermatitis associated with scratching, and suggest that TRPV3 may represent a therapeutic target in pruritic dermatitis."
      explanation: The authors attribute pruritus to the variant.
  evidence:
  - reference: PMID:16858425
    reference_title: "Association of a mutation in TRPV3 with defective hair growth in rodents."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "An amino-acid substitution at the same position in one gene was detected in DS-Nh mice and WBN/Kob-Ht rats: Gly573 to Ser (Nh mutation) or Gly573 to Cys (Ht mutation), located in the transient receptor potential (TRP) cation channel subfamily V member 3 (TRPV3) gene."
    explanation: Identity of the model's causal variant.
  notes: >-
    The WBN/Kob-Ht rat carries the paralogous Gly573Cys substitution (the
    patient G573C variant) with the same hairless and dermatitis phenotype
    (PMID:16858425); it is recorded here rather than as a separate model
    because the same publication characterises both strains together.
- name: TRPV3(Gly573Ser) transgenic mouse
  species: Mouse
  genotype: Transgenic TRPV3 Gly573Ser under a putative TRPV3 promoter
  genes:
  - preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  publication: PMID:18754035
  description: >-
    Transgenic expression of the patient Gly573Ser variant from a TRPV3
    promoter fragment; the mice spontaneously develop dermatitis, isolating the
    variant channel as sufficient cause, and show an increased keratinocyte
    nerve growth factor response to heat.
  evidence:
  - reference: PMID:18754035
    reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we constructed TRPV3(Gly573Ser) transgenic mice, with a putative promoter sequence in the 5' region of TRPV3, to investigate the involvement of TRPV3 in the development of specific types of dermatitis."
    explanation: Construction of the model.
  modeled_mechanisms:
  - target: Cutaneous Inflammation with Mast Cell Infiltration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Dermatitis develops in transgenic but not wild-type littermates under the same conditions.
    limitations: >-
      Transgene copy number and expression level are not those of a heterozygous
      germline allele, and the mice do not develop keratoderma.
    readouts:
    - name: Spontaneous dermatitis
      target: Cutaneous Inflammation with Mast Cell Infiltration
      direction: INCREASED
      interpretation: Dermatitis in transgenic mice, absent in wild type.
      evidence:
      - reference: PMID:18754035
        reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "These transgenic mice spontaneously developed dermatitis, whereas wild-type mice did not display this phenotype when maintained under the same conditions."
        explanation: The dermatitis readout.
    evidence:
    - reference: PMID:18754035
      reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we constructed TRPV3(Gly573Ser) transgenic mice, with a putative promoter sequence in the 5' region of TRPV3, to investigate the involvement of TRPV3 in the development of specific types of dermatitis."
      explanation: Construction and purpose of the model.
  - target: Keratinocyte-Driven Itch Signaling
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Keratinocyte nerve growth factor response to heat is raised by the variant.
    readouts:
    - name: Nerve growth factor response to heat
      target: Keratinocyte-Driven Itch Signaling
      direction: INCREASED
      interpretation: A pruritogenic keratinocyte output is increased by the patient variant.
      evidence:
      - reference: PMID:18754035
        reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat."
        explanation: The NGF readout.
    evidence:
    - reference: PMID:18754035
      reference_title: "Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A physiological study revealed that TRPV3(Gly573Ser) induced a higher nerve growth factor response to heat."
      explanation: The transgenic line is informative for this node because the patient variant raises the keratinocyte nerve growth factor output that drives pruriceptive signalling.
- name: Trpv3 G573S mouse on 129S1/SvImJ background (pathogen-free)
  species: Mouse
  genotype: Trpv3 G573S gain-of-function point mutation, re-derived and backcrossed onto 129S1/SvImJ
  background: 129S1/SvImJ
  genes:
  - preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  publication: PMID:35058747
  description: >-
    The Gly573Ser allele re-derived on a 129S1/SvImJ background and housed
    free of Staphylococcus aureus. Unlike DS-Nh mice, these animals develop
    neither dermatitis nor spontaneous scratching; pruritogen-evoked
    scratching, cold perception and acute mechanical pain are reduced, and the
    epidermis is hypoinnervated. The model shows that the dermatitis and itch
    of the variant depend on genetic background and skin microbiome.
  evidence:
  - reference: PMID:35058747
    reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We re-derived the Trpv3G573S mutants using 129S1/SvlmJ eggs; the animals obtained were then backcrossed to 129S1/SvlmJ background for six-eight generations."
    explanation: Derivation and background of the model.
  modeled_mechanisms:
  - target: Cutaneous Inflammation with Mast Cell Infiltration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: No dermatitis develops under S. aureus-free conditions despite the same gain-of-function allele.
    limitations: >-
      The negative result is conditional on pathogen-free housing and the
      129S1/SvImJ background; it does not show that the allele cannot cause
      inflammation, only that it does not do so alone.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Staphylococcus aureus colonisation, on which the DS-Nh dermatitis
        depends, is excluded by the housing conditions, so a trigger that
        patients' skin carries is outside the model.
      evidence:
      - reference: PMID:35058747
        reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In our experiments, Trpv3G573S mutants were raised in S. aureus-free environment, and we did not observe any dermatitis or spontaneous scratching in the Trpv3G573S mutants (Figure 5A)."
        explanation: States the pathogen-free housing that places the S. aureus trigger outside the model's boundary.
    readouts:
    - name: Spontaneous dermatitis
      target: Cutaneous Inflammation with Mast Cell Infiltration
      direction: UNCHANGED
      interpretation: No dermatitis in mutants or littermates under pathogen-free housing.
      evidence:
      - reference: PMID:35058747
        reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In our experiments, Trpv3G573S mutants were raised in S. aureus-free environment, and we did not observe any dermatitis or spontaneous scratching in the Trpv3G573S mutants (Figure 5A)."
        explanation: The dermatitis observation.
    evidence:
    - reference: PMID:35058747
      reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We fail to observe any spontaneous itch responses and/or dermatitis in Trpv3 G573S mutants under specific pathogen (Staphylococcus aureus)-free conditions."
      explanation: The negative dermatitis result that makes this model informative for the conditionality of the inflammation node.
  - target: Keratinocyte-Driven Itch Signaling
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: No spontaneous itch, and pruritogen-evoked scratching is reduced rather than increased.
    limitations: >-
      Scratching behaviour is an organism-level proxy; the reduced
      pruritogen-evoked scratching is attributed by the authors to epidermal
      sensory hypoinnervation, a developmental consequence of the hyperactive
      channel that patients have not been examined for.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Scratching bouts and epidermal nerve fibre density stand in for the
        keratinocyte-to-neuron signalling the node describes.
    readouts:
    - name: Spontaneous scratching behaviour
      target: Keratinocyte-Driven Itch Signaling
      direction: UNCHANGED
      interpretation: No spontaneous scratching under pathogen-free housing.
      evidence:
      - reference: PMID:35058747
        reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We fail to observe any spontaneous itch responses and/or dermatitis in Trpv3 G573S mutants under specific pathogen (Staphylococcus aureus)-free conditions."
        explanation: The spontaneous itch observation.
    - name: Pruritogen-evoked scratching
      target: Keratinocyte-Driven Itch Signaling
      direction: DECREASED
      interpretation: Scratching in response to pruritogens is markedly reduced in mutants.
      evidence:
      - reference: PMID:35058747
        reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, we find that the scratching events in response to various pruritogens are dramatically decreased in Trpv3 G573S mice in comparison to wild-type littermates."
        explanation: The evoked-itch measurement.
    - name: Epidermal sensory innervation
      target: Keratinocyte-Driven Itch Signaling
      direction: DECREASED
      interpretation: Epidermal sensory hypoinnervation, proposed by the authors to underlie the reduced itch and pain responses.
      evidence:
      - reference: PMID:35058747
        reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, we observe sensory hypoinnervation of the epidermis in Trpv3 G573S mutants, which might contribute to the deficits in acute mechanical pain, cool, cold, and itch sensations."
        explanation: The innervation measurement and the authors' interpretation.
    evidence:
    - reference: PMID:35058747
      reference_title: "Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We re-derived the Trpv3G573S mutants using 129S1/SvlmJ eggs; the animals obtained were then backcrossed to 129S1/SvlmJ background for six-eight generations."
      explanation: Establishes the model as the patient-hotspot allele on a defined background, which is what makes the negative itch result informative for this node.
- name: Trpv3 knockout mouse
  species: Mouse
  genotype: Trpv3 null (loss of function)
  genes:
  - preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  publication: PMID:20403327
  description: >-
    Loss-of-function model, the inverse of the human lesion: Trpv3-null mice
    have wavy hair and curly whiskers, the phenotype of TGF-alpha and EGFR
    loss-of-function mutants, and defective skin-barrier cornification. It
    establishes the TRPV3-TGF-alpha/EGFR axis that the gain-of-function
    variants overdrive.
  evidence:
  - reference: PMID:20403327
    reference_title: "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unexpectedly, we found that mice lacking the Trpv3 gene also exhibit wavy hair coat and curly whiskers."
    explanation: The knockout phenotype that identified the EGFR-axis relationship.
  modeled_mechanisms:
  - target: EGFR-mTOR Signaling Hyperactivation in Epidermis
    relationship: PERTURBS
    fidelity: LOW
    model_scale: TISSUE
    description: Removal of TRPV3 phenocopies reduced TGF-alpha/EGFR signalling in hair, the opposite direction to the disease.
    limitations: >-
      An inverse (loss-of-function) model; it demonstrates that TRPV3 sits in
      the EGFR axis but does not reproduce the hyperactivation of the disease.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The model deletes the channel; the disease has a constitutively active
        one. The axis is shared, the direction of perturbation is not.
    readouts:
    - name: Hair coat morphology
      target: EGFR-mTOR Signaling Hyperactivation in Epidermis
      direction: ALTERED
      interpretation: Wavy hair and curly whiskers, the signature of reduced TGF-alpha/EGFR signalling.
      evidence:
      - reference: PMID:20403327
        reference_title: "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Unexpectedly, we found that mice lacking the Trpv3 gene also exhibit wavy hair coat and curly whiskers."
        explanation: The hair readout of the knockout.
    evidence:
    - reference: PMID:20403327
      reference_title: "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here we show that keratinocyte TRPV3, a member of the transient receptor potential (TRP) family of Ca(2+)-permeant channels, forms a signaling complex with TGF-alpha/EGFR."
      explanation: The knockout study established the complex this node describes.
clinical_trials:
- name: NCT07090889
  phase: PHASE_I
  status: RECRUITING
  description: >-
    First-in-human phase 1a/1b study of KM-023, an oral TRPV3 inhibitor:
    single and multiple ascending doses with a food-effect arm in healthy
    volunteers, followed by a 12-week open-label cohort of Olmsted syndrome
    patients assessing safety, pharmacokinetics, drug penetration into skin
    layers and keratoderma efficacy. No results are available.
  notes: >-
    The registry eligibility criteria require a confirmed TRPV3 or PERP
    variant with visible palmoplantar keratoderma, so the patient cohort may
    include PERP-related Olmsted syndrome 2 as well as this disease. Phase and
    status are as recorded on ClinicalTrials.gov on 2026-10-13.
  target_phenotypes:
  - preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: clinicaltrials:NCT07090889
    reference_title: "A Combined Single and Multiple Ascending Dose Phase 1a/1b, Double-blind, Placebo-Controlled, and Food-effect Study to Evaluate the Safety and Pharmacokinetics of Oral KM-023 in Healthy Participants. Followed by a 3-month Open Label Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Oral KM-023 in Olmsted Syndrome Patients"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Finally, the efficacy of KM-023 will be investigated in Olmsted Syndrome patients."
    explanation: Registry summary stating the efficacy objective in Olmsted syndrome patients.
  - reference: clinicaltrials:NCT07090889
    reference_title: "A Combined Single and Multiple Ascending Dose Phase 1a/1b, Double-blind, Placebo-Controlled, and Food-effect Study to Evaluate the Safety and Pharmacokinetics of Oral KM-023 in Healthy Participants. Followed by a 3-month Open Label Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Oral KM-023 in Olmsted Syndrome Patients"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the second part of the trial, Olmsted Syndrome patients will take KM-023 twice daily, for a duration of 12 weeks."
    explanation: Design of the patient cohort.
discussions:
- discussion_id: os1_lysosomal_trafficking_hypothesis
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    Do Olmsted syndrome TRPV3 variants injure keratinocytes through impaired
    channel trafficking and lysosomal dysfunction in addition to plasma-membrane
    calcium overload?
  attaches_to:
  - pathophysiology#Keratinocyte Calcium Overload
  - pathophysiology#Keratinocyte Apoptosis
  rationale: >-
    In heterologous expression, G573A/S/C and W692G variants are largely
    retained in the endoplasmic reticulum, reduce surface delivery of other
    membrane proteins, impair cell adhesion and reduce lysosome number, and
    G568C/G568D variants leak calcium from lysosomes and disturb lysosomal pH.
    These findings come from transfected non-keratinocyte cell lines and have
    not been confirmed in patient keratinocytes or skin.
  evidence:
  - reference: PMID:27754757
    reference_title: "TRPV3 mutants causing Olmsted Syndrome induce impaired cell adhesion and nonfunctional lysosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our qualitative and quantitative data suggests that these naturally occurring TRPV3 mutants are mainly restricted in the ER."
    explanation: ER retention of the Olmsted syndrome variants in expression systems.
  - reference: PMID:36063600
    reference_title: "Olmsted syndrome causing point mutants of TRPV3 (G568C and G568D) show defects in intracellular Ca(2+)-mobilization and induce lysosomal defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that OS-mutants cause defective pH-maintenance at the lysosomes."
    explanation: Lysosomal pH defect caused by two Olmsted syndrome variants.
  posed_by: dismech curation
  posed_date: "2026-10-13T00:00:00Z"
- discussion_id: os1_trpv3_antagonist_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Can direct pharmacological inhibition of TRPV3 treat Olmsted syndrome 1, as
    an alternative or adjunct to EGFR inhibition?
  attaches_to:
  - pathophysiology#TRPV3 Gain-of-Function Channel Activation
  - treatments#Erlotinib
  - clinical_trials#NCT07090889
  rationale: >-
    Erlotinib acts one step downstream of the lesion, on EGFR transactivation,
    and does not address channel-driven calcium overload or keratinocyte itch
    signalling directly; a TRPV3 antagonist would target the initiating event.
    No result of TRPV3 antagonism in a patient has been published; a phase 1
    study of the oral TRPV3 inhibitor KM-023 (NCT07090889) with an open-label
    Olmsted syndrome cohort is recruiting.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy."
    explanation: The review proposes TRPV3 antagonism as the targeted strategy.
  - reference: PMID:22405088
    reference_title: "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders."
    explanation: The gene-discovery study proposes TRPV3 as a therapeutic target.
  posed_by: dismech curation
  posed_date: "2026-10-13T00:00:00Z"
- discussion_id: os1_recessive_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the channel-level mechanism of the rare recessive TRPV3 families,
    and does it differ from the dominant gain-of-function variants?
  attaches_to:
  - inheritance#Autosomal recessive inheritance
  - pathophysiology#TRPV3 Gain-of-Function Channel Activation
  rationale: >-
    Dominant disease is explained by constitutively open heteromeric channels,
    but a recessive mode implies that one wild-type allele suffices to prevent
    disease, which the simple gain-of-function model does not predict. The
    recessive report (PMID:24606194) is a letter without an abstract, so the
    recessive claim is carried by the review only.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: The review attributes gain of function to the dominant variants and names recessive forms without a mechanism, which is the gap.
  posed_by: dismech curation
  posed_date: "2026-10-13T00:00:00Z"
- discussion_id: os1_immune_dysregulation_hypothesis
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    Is immune dysregulation (hyper-IgE, eosinophilia, recurrent skin infection)
    a primary consequence of TRPV3 gain of function, or secondary to barrier
    failure and infection of the keratotic skin?
  attaches_to:
  - pathophysiology#Cutaneous Inflammation with Mast Cell Infiltration
  - phenotypes#Increased circulating IgE concentration
  - phenotypes#Eosinophilia
  - phenotypes#Recurrent skin infections
  rationale: >-
    A single profiled G573A patient had hyper-IgE, persistent eosinophilia,
    elevated circulating follicular helper T cells and frequent dermal
    infections. TRPV3 is also expressed by Langerhans cells, so a primary
    immunological contribution cannot be excluded, but barrier failure in
    fissured keratotic skin would produce the same picture secondarily. No
    cohort has been immunophenotyped.
  evidence:
  - reference: PMID:23692804
    reference_title: "Olmsted syndrome: exploration of the immunological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: The authors' own statement of the open question.
  posed_by: dismech curation
  posed_date: "2026-10-13T00:00:00Z"
references:
- reference: PMID:25886873
  title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
- reference: PMID:24606194
  title: "Olmsted syndrome with erythromelalgia caused by recessive transient receptor potential vanilloid 3 mutations."
notes: >-
  No GeneReviews chapter covers Olmsted syndrome (the committed Bookshelf index
  and a PubMed "Olmsted syndrome[TI] AND genereviews[book]" search both return
  nothing), so the 2015 Orphanet Journal of Rare Diseases review (PMID:25886873)
  is the phenotype baseline. The Orphanet record (ORPHA:659) covers Olmsted
  syndrome of all genetic forms rather than the TRPV3 form, so its phenotype
  and epidemiology rows describe the parent concept. Disease occurrence and the
  inheritance patterns are likewise stated for Olmsted syndrome as a whole in
  the sources; the case counts therefore include MBTPS2 and molecularly
  unconfirmed cases.

📚

References & Deep Research

References

2

PMID:25886873

Olmsted syndrome: clinical, molecular and therapeutic aspects.

No top-level findings curated for this source.

PMID:24606194

Olmsted syndrome with erythromelalgia caused by recessive transient receptor potential vanilloid 3 mutations.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Olmsted Syndrome 1 · 2026-10-22T21:24:09Z · View source

De novo curation of Olmsted syndrome 1 (MONDO:0100296), the TRPV3 gain-of-function form of Olmsted syndrome, from the Falcon deep-research report (research/Olmsted_Syndrome_1-deep-research-falcon.md) and the primary literature it surfaced; the X-linked MBTPS2 and PERP forms are excluded. Causal chain: TRPV3 constitutive channel activation -> keratinocyte calcium overload -> apoptosis, EGFR/mTOR hyperactivation and itch signalling -> epidermal hyperproliferation/hyperkeratosis, hair follicle dysfunction and cutaneous inflammation -> the mutilating palmoplantar keratoderma, periorificial plaques, pseudoainhum, alopecia, pain, pruritus and erythromelalgia phenotypes. Inheritance bound to HP:0000006 and HP:0000007 (rare recessive families); seven TRPV3 variants recorded; erlotinib, sirolimus, acitretin and supportive care as treatments with target_mechanisms; DS-Nh, TRPV3(G573S) transgenic, pathogen-free 129S1 G573S and Trpv3 knockout mice as animal_models with modeled_mechanisms, including the FAILS_TO_RECAPITULATE finding on the pathogen-free G573S line. No GeneReviews chapter exists (just check-genereviews: NO_CHAPTER); no ClinGen TRPV3 assertion in the committed export; ORPHA:659 is the parent concept and not cited. Validated with just validate, validate-terms, count-verified-snippets (159/159), validate-disorders, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-coarse-phenotypes, check-enum-values, check-block-scalar-comments, validate-stubs, compliance (99.1% weighted), check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-retired-support-prose, check-reference-titles, check-case-collisions and check_gene_activity_grounding --against-ref origin/main (TRPV3 is grounded on GO:0005262 at the channel-activation node).

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 44 citations 2026-10-13T09:09:01.627649

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Olmsted Syndrome 1
MONDO ID: MONDO:0100296 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Olmsted Syndrome 1 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Olmsted syndrome 1: disease-characteristics research report

Scope and evidence standard. Olmsted syndrome 1 (OS1) here means TRPV3-associated Olmsted syndrome, not every condition described clinically as “Olmsted syndrome.” The literature often pools TRPV3 disease with genetically distinct MBTPS2- and PERP-associated disease; pooled frequencies must not be assigned to OS1. Evidence below distinguishes human observations, cell experiments, animal models, and registered trials. DOI links are provided when available; PMIDs were not consistently present in the retrieved records and are not guessed. Suggested ontology labels are candidates for knowledge-base curation, not assertions that an unverified accession has been confirmed. (duchatelet2015olmstedsyndromeclinical pages 2-4, kalinovskii2023trpv3ionchannel pages 13-14, duchatelet2015olmstedsyndromeclinical pages 5-7)

1. Disease information and identifiers

OS1 is an exceptionally rare Mendelian disorder of epidermal keratinization, classically involving bilateral, progressively thickening, sometimes mutilating palmoplantar keratoderma (PPK) and keratotic plaques around body openings. Hair loss, nail changes, painful fissures, and itch may accompany it; a genetically established TRPV3 case need not have every classical feature. The 2012 gene-discovery abstract describes OS as “a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching.” (lin2012exomesequencingreveals pages 1-2, guo2023novelinsightsinto pages 6-8)

Disease: OMIM #614594, cited for TRPV3-associated OS; causal gene TRPV3, OMIM 607066. The supplied MONDO identifier is MONDO:0100296; its exact cross-reference to the OS1 subtype was not independently established in the retrieved literature and should be checked before database import. ORPHA:659 labels the broader Olmsted syndrome phenotype, rather than an independently verified TRPV3-only subtype. An older review also lists OMIM #300918 for a separate X-linked form. The review’s alternative labels include “mutilating palmoplantar keratoderma with periorificial keratotic plaques” and “palmoplantar and periorificial keratoderma.” (duchatelet2015olmstedsyndromeclinical pages 2-4, hao2024casereportnovel pages 1-2, lin2012exomesequencingreveals pages 1-2)
ICD-10/ICD-11 and MeSH: an OS1-specific code or descriptor was not verified; do not substitute a generic keratoderma code as though subtype-specific. The cited information is aggregated publications, experimental studies, and trial registries, not an individual electronic-health-record extract. (duchatelet2015olmstedsyndromeclinical pages 2-4, lin2012exomesequencingreveals pages 1-2)

Core sources: Lin et al., American Journal of Human Genetics, 9 March 2012, https://doi.org/10.1016/j.ajhg.2012.02.006; Duchatelet and Hovnanian, Orphanet Journal of Rare Diseases, 2015, https://doi.org/10.1186/s13023-015-0246-5. (lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 1-2)

2. Etiology, susceptibility, protection, and gene–environment interaction

Primary cause: germline pathogenic variants affecting the Ca²⁺-permeable, warm-responsive TRPV3 cation channel. Well-characterized dominant missense substitutions increase basal channel activity; pathogenic disease can also result from biallelic TRPV3 variants. Some apparently sporadic cases are de novo; multigenerational pedigrees establish dominant transmission. The initial six-person study found p.Gly573Ser in four patients, p.Gly573Cys in one, and p.Trp692Gly in one; tested variants were absent from 216 ancestry-matched controls. This small control set does not establish a current gnomAD allele frequency. (lin2012exomesequencingreveals pages 2-4, lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 5-7)

Environmental causal risk: no toxin, diet, infection, occupation, smoking behavior, or lifestyle exposure is established as an initiating cause of OS1. Pressure and friction localize or worsen thickened plantar skin, and warmth can provoke burning pain in some cases; these are manifestations or modifiers, not demonstrated primary causes. The relevant gene–environment result is experimental, not human epidemiology: mutant DS-Nh mice develop spontaneous dermatitis under certain Staphylococcus aureus and genetic-background conditions but not reliably under pathogen-free conditions. Skin infection in a person with OS1 can consequently be a complication without being the genetic disease’s cause. (duchatelet2015olmstedsyndromeclinical pages 4-5, fatima2022abnormalsomatosensorybehaviors pages 1-2, dansoabeam2013olmstedsyndromeexploration pages 1-3)

Protection and modification: no replicated protective allele, protective lifestyle exposure, or named modifier gene has been validated for OS1. Variable manifestations among relatives carrying the same variant make genetic background and environmental modification plausible, but neither a human modifying locus nor quantitative gene–environment interaction has been demonstrated. Avoid interpreting an unaffected relative or unconfirmed variant as proof of incomplete penetrance. (duchatelet2015olmstedsyndromeclinical pages 5-7, ni2016anovelmutation pages 3-4, zhang2025erlotinibtherapyfor pages 2-4)

3. Phenotypes and quality-of-life consequences

The following are suggested HPO concept labels; accession numbers and OS1-wide frequencies should be verified against HPO before import. The only directly countable genotype-specific series below comprised six selected TRPV3-positive patients, not a representative cohort. (lin2012exomesequencingreveals pages 1-2)

Phenotype type and suggested HPO concept	Onset, severity, course and available frequency	Functional impact / evidence
Sign: palmoplantar keratoderma; hyperkeratosis; painful skin fissures	Usually infancy; may progress from focal pressure-site plaques to diffuse, thick, transgredient lesions. 6/6 in Lin’s selected series. Severe or mutilating disease is possible.	Walking, hand use, and footwear can become difficult. (lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 4-5)
Sign: periorificial hyperkeratosis/keratotic plaques	Often early childhood; 6/6 in the original classical series, but absent in documented atypical genetically investigated cases. Sites include mouth, nostrils, ears, eyes, umbilicus, genital and anal regions.	Pain, inflammation, appearance, and secondary infection; absence does not exclude OS1. (lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 4-5, hao2024casereportnovel pages 2-5)
Sign: pseudoainhum, digit constriction, flexion contracture, spontaneous digit amputation	Later consequence of progressive keratoderma; variable, not obligatory.	Loss of grasp, mobility and, exceptionally, digits; radiographic osteolysis and deformity can coexist. (duchatelet2015olmstedsyndromeclinical pages 4-5, hao2024casereportnovel pages 1-2)
Sign: alopecia/hypotrichosis; nail dystrophy	Variable childhood manifestations; some hair abnormality in 6/6 in the original series, ranging from alopecia universalis to sparse curly hair; normal hair occurs in other reports.	Appearance and psychosocial effects; nail damage and periungual infection may impair dexterity. (lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 4-5)
Symptoms: pruritus; palmoplantar pain; burning pain/erythromelalgia	Episodic or persistent, severity variable. 6/6 reported severe lesional itch in Lin’s selected series. In a mixed-genotype, historical OS review, approximately 50% had painful PPK and 16% had reported itch; these are not OS1 frequencies and inconsistent reporting limits interpretation. Heat-associated flares are uncommon.	Sleep disruption, inability to walk or grasp, reduced participation in sport and daily activity. (lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 4-5, zhang2025erlotinibtherapyfor pages 2-4)
Other signs: leukokeratosis, corneal disease, sweating abnormalities, recurrent skin infections, growth delay	Inconsistently reported; individual onset and OS1-specific percentages unavailable.	Corneal disease can threaten vision; recurrent infection increases treatment burden. (duchatelet2015olmstedsyndromeclinical pages 4-5, duchatelet2015olmstedsyndromeclinical pages 5-7, dansoabeam2013olmstedsyndromeexploration pages 1-3)
Laboratory finding: high IgE and eosinophilia	Demonstrated in one TRPV3 p.Gly573Ala patient; not an established diagnostic biomarker.	Suggests clinically relevant inflammatory assessment where indicated, not routine expectation of immunodeficiency. (dansoabeam2013olmstedsyndromeexploration pages 1-3)

No validated OS1-specific EQ-5D, SF-36, PROMIS, or per-phenotype quality-of-life distribution was identified. Reported pain, itch, insomnia, walking limitation and digit loss provide qualitative evidence of potentially severe disability; avoid manufacturing numerical scores. (duchatelet2015olmstedsyndromeclinical pages 4-5, duchatelet2015olmstedsyndromeclinical pages 7-8)

4. Genetics and molecular annotation

TRPV3 is the defining gene for this entry; a human study locates it at 17p13 and gives OMIM 607066. Its product is a tetramer-forming, six-transmembrane nonselective cation channel. Altered gating near the S4–S5 linker or post-S6 TRP region is established for some substitutions, but do not assume that every reported variant has experimentally proven gain of function. Confirm the current HGNC identifier, reference transcript, and residue numbering before importing genomic HGVS strings. (lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 5-7, lin2012exomesequencingreveals pages 4-6)

Strong functional examples: heterozygous c.1717G>A, p.Gly573Ser; c.1717G>T, p.Gly573Cys; c.2074T>G, p.Trp692Gly. All three had constitutive currents in transfected-cell experiments. Human lesional skin and cultured mutant-expressing cells additionally exhibited increased apoptosis/cell death. (lin2012exomesequencingreveals pages 2-4, lin2012exomesequencingreveals pages 1-2, lin2012exomesequencingreveals pages 4-6)
Other reported genotypes: p.Gly573Ala; familial p.Met672Ile; milder familial p.Gln580Pro; homozygous p.Trp521Ser; and two affected brothers with compound-heterozygous p.Gly568Cys and splice-associated p.Gln216_Gly262del. This illustrates recessive as well as dominant TRPV3 disease; molecular functionality and penetrance vary by allele. (dansoabeam2013olmstedsyndromeexploration pages 1-3, duchatelet2015olmstedsyndromeclinical pages 5-7, ni2016anovelmutation pages 3-4)
Important 2024–2025 qualification: a 2024 single-patient report describes c.916G>A, p.Val306Met and plantar squamous-cell carcinoma; pathogenicity predictions conflict and the authors specifically request electrophysiological confirmation. A January 2025 familial report describes c.1964T>C, p.Leu655Pro (p.L655P). Because this substitution changes one amino acid rather than the reading frame, it is a missense variant, despite contradictory “frameshift” wording in that article. Neither case report by itself supplies a verified ACMG/AMP classification or population-database allele frequency. (hao2024casereportnovel pages 2-5, zhang2025erlotinibtherapyfor pages 2-4, zhang2025erlotinibtherapyfor pages 1-2)
Separate disease genes: X-linked MBTPS2 and autosomal PERP can cause Olmsted-like/Olmsted syndrome but should not be annotated as causal genes for molecularly defined TRPV3-OS1. KRT1, GJB2, LOR, SLURP1, and CTSC chiefly inform overlapping disorders and differential testing. No OS1-specific causal aneuploidy or recurrent translocation, established modifier gene, reproducible methylation signature, founder allele, or protective variant was identified. (kalinovskii2023trpv3ionchannel pages 13-14, duchatelet2015olmstedsyndromeclinical pages 7-8, hao2024casereportnovel pages 2-5)

Variant-origin guidance: inherited or de novo germline TRPV3 variants underlie this Mendelian entry; no evidence retrieved establishes a recurrent causative somatic OS1 mutation. Assign pathogenic/likely pathogenic/VUS status only after variant-specific ClinVar/ClinGen and ACMG assessment, including segregation and functional data; do not convert a case-report author’s conjecture or an in-silico score into a database classification. (lin2012exomesequencingreveals pages 2-4, hao2024casereportnovel pages 2-5)

5. Environmental information

There is no established initiating infectious agent, occupational toxin, radiation exposure, or dietary/lifestyle cause of OS1. Secondary bacterial or candidal infection occurs in abnormal keratotic skin; in the DS-Nh mouse, S. aureus exposure changes the expression of dermatitis and itch. Pressure-bearing skin is prominently affected, and some patients report heat-provoked erythromelalgia; neither observation demonstrates preventability of a germline TRPV3 mutation by exposure avoidance. No zoonotic transmission is relevant. (duchatelet2015olmstedsyndromeclinical pages 5-7, fatima2022abnormalsomatosensorybehaviors pages 1-2, duchatelet2015olmstedsyndromeclinical pages 4-5)

6. Mechanism and pathophysiology

Ordered causal chain; evidence levels indicated.

Germline activating TRPV3 variants lead to abnormally active channel gating; for p.Gly573Ser, p.Gly573Cys and p.Trp692Gly, increased basal currents were demonstrated in vitro. (lin2012exomesequencingreveals pages 2-4)
Excess channel activity leads to abnormal keratinocyte cation/Ca²⁺ signaling; enhanced conductance is demonstrated, while its precise magnitude and spatiotemporal distribution in each patient’s living epidermis are inferred. (lin2012exomesequencingreveals pages 2-4, duchatelet2015olmstedsyndromeclinical pages 7-8)
Altered channel signaling leads to a disturbed balance of epidermal proliferation, terminal differentiation and cell survival. Increased apoptosis is demonstrated in mutant-expressing cells and selected human lesions; exactly how apoptosis produces chronic hyperkeratosis remains inferred. (lin2012exomesequencingreveals pages 2-4, lin2012exomesequencingreveals pages 4-6, duchatelet2015olmstedsyndromeclinical pages 7-8)
Branch A—experimental cell trafficking: some mutant TRPV3 proteins lead to reduced surface localization, altered ER/Golgi distribution, poorer cell adhesion and defective lysosomal labeling/movement in engineered HaCaT keratinocytes. A contribution of these abnormalities to human OS1 lesion formation is inferred, not established for every allele. (yadav2017trpv3mutantscausing pages 1-4, yadav2017trpv3mutantscausing pages 4-6)
Branch B—skin signaling and inflammation: TRPV3 activity can lead to TGF-α/EGFR-linked epidermal signaling and inflammatory mediator release in non-OS1 experimental systems. Its precise position upstream of human OS1 keratoderma, any MAPK/mTOR involvement, and the fraction of patients with intrinsic immune dysregulation remain inferred; a single human patient had IgE/eosinophil abnormalities. (duchatelet2015olmstedsyndromeclinical pages 7-8, dansoabeam2013olmstedsyndromeexploration pages 1-3, zhang2025erlotinibtherapyfor pages 4-6)
Branch C—hair and sensation: abnormal follicular TRPV3 activity leads to impaired hair growth in experimental systems and is consistent with human hypotrichosis/alopecia. Abnormal epidermal innervation and inflammatory signaling may lead to itch, burning or pain; the precise human neural mechanism is not demonstrated, and one mutant-mouse strain instead showed reduced responses to several pruritogens. (guo2023novelinsightsinto pages 6-8, fatima2022abnormalsomatosensorybehaviors pages 1-2, lin2012exomesequencingreveals pages 1-2)
Downstream barrier damage and prolonged hyperkeratosis lead to fissures, infection susceptibility and constriction bands; progressive constriction can result in contractures and auto-amputation. A carcinoma association is reported, but a direct mutation-to-cancer causal sequence or risk magnitude is unproven. (duchatelet2015olmstedsyndromeclinical pages 4-5, hao2024casereportnovel pages 1-2)

Cell types and suggested ontology concepts: epidermal keratinocyte and hair-follicle keratinocyte are the primary cellular candidates (CL: keratinocyte, verify precise IDs); sensory neuron, mast cell, eosinophil, T lymphocyte, and Langerhans cell are implicated variably, often by inference rather than demonstrated primary injury. Candidate GO biological processes are calcium-ion transmembrane transport, regulation of epidermal-cell differentiation, keratinocyte proliferation, apoptotic process, epidermis development, cell adhesion, inflammatory response, and sensory perception of itch/pain. Candidate GO cellular components include plasma membrane/ion-channel complex, endoplasmic reticulum, Golgi apparatus, lysosome, and nucleus-associated ER membrane. The lysosomal result is an engineered-cell observation, not proof that OS1 is clinically a generalized lysosomal storage disorder. (yadav2017trpv3mutantscausing pages 1-4, yadav2017trpv3mutantscausing pages 4-6, dansoabeam2013olmstedsyndromeexploration pages 1-3, guo2023novelinsightsinto pages 3-4)

Molecular profiling and technology: a small p.Gln580Pro-associated investigation reported reduced differentiation, gap-junction, tight-junction and desmosome-associated expression, with increased proliferation/cell-death-associated proteins; it is not a validated diagnostic multi-omic signature. No OS1-specific reproducible metabolomic, lipidomic, epigenomic, single-cell or spatial-transcriptomic signature or therapeutic CRISPR screen was established by the retrieved evidence. EGFR-directed treatment offers clinical pathway support but does not alone prove the full proposed pathway. (duchatelet2015olmstedsyndromeclinical pages 7-8, zhang2025erlotinibtherapyfor pages 4-6)

7. Anatomical structures affected

Primary: palmar and plantar epidermis, often bilaterally; periorificial facial and anogenital epidermis; hair follicles and nails. Secondary/variable: hand and foot digits, underlying phalanges and joints, oral mucosa, corneal surface, cutaneous sensory nerve endings, and infected keratotic skin. Candidate UBERON labels for mapping include skin of palm, skin of sole, epidermis, hair follicle, nail, digit, cornea, and oral mucosa; exact accession IDs should be checked. Hands and feet are classically bilateral, whereas degree of severity and complications, including a reported right-sole carcinoma, can be asymmetric. CL labels: keratinocyte and sensory neuron; infiltrating mast cell and leukocyte where biopsy demonstrates them. GO cellular components: plasma membrane, ER, Golgi and lysosome as above. (lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 4-5, hao2024casereportnovel pages 1-2, yadav2017trpv3mutantscausing pages 4-6)

8. Temporal development

Classical disease begins at birth, during infancy, or in early childhood, sometimes becoming especially evident when walking or grasping begins. In Lin’s six-person TRPV3 series, all six developed symptoms in the first year. The usual untreated course is chronic, slowly progressive, with focal lesions potentially extending and thickening; the tempo and eventual severity vary considerably. An atypical familial patient described in 2025 reported approximately eight years of symptoms at age 31, so childhood onset is not an absolute diagnostic requirement. Pain or erythromelalgia can flare with warmth; sustained spontaneous remission rates have not been measured. No formal validated staging system, progression-rate estimate, or defined molecular critical window exists. Early control of keratoderma, fissures and contracture risk is clinically rational, but disease-modifying prevention of future digit loss has not been proven. (duchatelet2015olmstedsyndromeclinical pages 2-4, lin2012exomesequencingreveals pages 1-2, duchatelet2015olmstedsyndromeclinical pages 4-5, zhang2025erlotinibtherapyfor pages 2-4)

9. Inheritance and population

Dominant OS1 often reflects a de novo heterozygous activating variant, although affected parents and children establish familial autosomal-dominant disease. Rare homozygous and compound-heterozygous autosomal-recessive TRPV3 genotypes are reported. The dominant transmission risk for a heterozygous affected parent is 50% per pregnancy, conditional on that allele being pathogenic; for two carriers of a confirmed recessive genotype, conventional Mendelian recurrence risk is 25%. These are genetic-counseling calculations, not observed OS1 penetrance estimates. Penetrance, germline-mosaicism frequency, carrier frequency, founder effects, anticipation, and reliable genotype-stratified sex ratio remain unknown. Consanguinity may matter in a particular recessive pedigree but is not a prerequisite. (duchatelet2015olmstedsyndromeclinical pages 5-7, lin2012exomesequencingreveals pages 2-4, ni2016anovelmutation pages 3-4)

The 2015 review found 73 reported patients in 59 publications through 1 December 2014, including molecularly different and untyped forms; it conjectured overall prevalence below one per million and described approximately 63% male among published cases. Neither figure is a measured OS1-specific prevalence or sex ratio. Incidence per 100,000 person-years, population age distribution, and ethnic/geographic enrichment cannot be reliably quantified. Case reports encompass several backgrounds and imply worldwide occurrence, not a proven regional prevalence difference. (duchatelet2015olmstedsyndromeclinical pages 2-4, duchatelet2015olmstedsyndromeclinical pages 1-2, duchatelet2015olmstedsyndromeclinical pages 5-7)

10. Diagnostics

Clinical assessment: inspect both palms and soles for progressive thick plaques and fissures, assess periorificial sites, hair and nails, painful or constricted digits, gait, infection and vision. Because genetically established OS1 can be atypical, the classical skin combination is suggestive rather than a rigid requirement. Skin biopsy may show psoriasiform epidermal hyperplasia, acanthosis, ortho-/parakeratosis, and inflammatory infiltrates; these changes are nonspecific. Radiographs are useful for contractures, osteolysis or suspected bony involvement, not for identifying the causal allele. Suspicious enlarging, bleeding or ulcerated lesions require biopsy to exclude cancer. (duchatelet2015olmstedsyndromeclinical pages 7-8, lin2012exomesequencingreveals pages 2-4, hao2024casereportnovel pages 1-2, zhang2025erlotinibtherapyfor pages 2-4)

Molecular confirmation: sequence TRPV3 using a suitable keratoderma/genodermatosis panel or single-gene assay when the phenotype is characteristic; family segregation and variant interpretation are essential. Trio whole-exome sequencing established the original de novo variant and is useful when phenotype or inheritance is unclear; exome or genome analysis may help if panel testing is unrevealing, including evaluation of other Olmsted-like genes. Seek orthogonal confirmation as appropriate and consider biallelic/splice variants. Routine karyotyping, CMA, FISH, mitochondrial DNA and repeat-expansion assays are not primary tests for molecularly typical OS1. No validated disease-specific serum enzyme, circulating protein, imaging biomarker, RNA-seq, proteomic, metabolomic, methylation or liquid-biopsy diagnostic assay was found. Measure serum zinc when acrodermatitis enteropathica is plausible rather than treating zinc as an OS1 biomarker. (lin2012exomesequencingreveals pages 1-2, lin2012exomesequencingreveals pages 2-4, duchatelet2015olmstedsyndromeclinical pages 5-7, duchatelet2015olmstedsyndromeclinical pages 7-8)

Differential: GJB2/LOR-associated Vohwinkel syndrome; SLURP1-associated mal de Meleda; GJB6-associated Clouston syndrome; CTSC-associated Papillon–Lefèvre/Haim–Munk syndromes; keratin-associated pachyonychia congenita; TAT-related tyrosinemia II; zinc-transport-related acrodermatitis enteropathica; Huriez-like disease; and MBTPS2/PERP Olmsted-like conditions. Periorificial plaques, family segregation, associated findings, and targeted molecular testing help discriminate them. No evidence supports a universal population or newborn OS1 screening program; offer targeted family testing when an informative familial allele is established. (duchatelet2015olmstedsyndromeclinical pages 7-8, kalinovskii2023trpv3ionchannel pages 13-14, hao2024casereportnovel pages 2-5)

11. Outcomes and prognosis

Severe PPK can impair walking and grasping, lead to flexion contractures and, in advanced cases, spontaneous digit loss; itch and pain may cause insomnia. Corneal disease can impair sight. Secondary infection is a recognized complication. Published cases associate longstanding keratotic skin with squamous-cell carcinoma and, occasionally, melanoma, but there is no robust OS1-specific absolute cancer risk or screening interval. A 2024 patient with a novel, not functionally confirmed TRPV3 p.Val306Met variant developed biopsy-confirmed plantar squamous-cell carcinoma requiring foot amputation; this is a serious observed event, not proof of a variant-specific oncogenic mechanism. Historical authors reported no established reduction in life expectancy, which should not be construed as a measured normal survival curve. OS1-specific mortality, five-/ten-year survival, validated prognosis models, biomarker-based risk stratification and long-term treatment durability are unavailable. (duchatelet2015olmstedsyndromeclinical pages 7-8, duchatelet2015olmstedsyndromeclinical pages 4-5, hao2024casereportnovel pages 1-2, hao2024casereportnovel pages 2-5)

12. Treatment and real-world implementation

Evidence-graded care sequence: confirm genotype and assess pain, mobility, fissures, infection, eye disease and suspicious skin lesions; begin individualized barrier and symptomatic treatment; consider specialist-supervised systemic treatment for disabling disease; record pain, mobility, lesion area/thickness and adverse effects over time. There is no large OS1 randomized efficacy trial in the retrieved material. NCIT suggestions below are intervention-class labels, not verified NCIT accessions. (duchatelet2015olmstedsyndromeclinical pages 8-9, duchatelet2015olmstedsyndromeclinical pages 7-8, NCT07090889 chunk 1)

Supportive dermatologic care — NCIT concepts: emollient therapy, keratolytic therapy, wound care, physical/occupational therapy. Moisturizers and protective skin care, carefully selected urea or salicylic-acid keratolytics, fissure care, footwear adaptation, and indicated management of documented bacterial/fungal infection may relieve symptoms. Historical outcomes range from poor to moderate; none reliably corrects the mutation. Candidate ChEBI labels: urea and salicylic acid; verify accession IDs before annotation. (duchatelet2015olmstedsyndromeclinical pages 8-9, lin2012exomesequencingreveals pages 1-2)
Systemic retinoids — NCIT concept: retinoid therapy. Acitretin or historical etretinate may reduce thickness and itch, but recurrence or incomplete relief is common and safety monitoring is necessary. In the 2012 original series, three treated patients improved in skin lesions and itching after four weeks, while hair improvement remained limited after one year. In a 2024 case, acitretin 10 mg three times daily, topical tretinoin and moisturizers produced moderate improvement after six months; later carcinoma arose despite intermittent management. These uncontrolled observations are not a validated response rate. Candidate ChEBI labels: acitretin, tretinoin. (lin2012exomesequencingreveals pages 1-2, hao2024casereportnovel pages 1-2, duchatelet2015olmstedsyndromeclinical pages 8-9)
EGFR inhibition — NCIT concept: EGFR inhibitor therapy; agent erlotinib. A published 2020 three-patient report describes erlotinib for TRPV3-associated OS (Greco et al., JAMA Dermatology, https://doi.org/10.1001/jamadermatol.2019.4126); a separate 2020 publication examines EGFR and mTOR pathway targeting (https://doi.org/10.1001/jamadermatol.2019.4141). A 2023 twin case report describes combined erlotinib and acitretin (https://doi.org/10.1111/pde.15264). These publications were identified bibliographically or through subsequent papers; their full primary outcome and safety data were not retrieved here, so no pooled effect is calculated. (zhang2025erlotinibtherapyfor pages 6-7, zhang2025erlotinibtherapyfor pages 6-6)
Detailed 2025 real-world example: a patient and his father carried heterozygous TRPV3 p.Leu655Pro; the symptomatic patient received erlotinib 75 mg/day together with oral acitretin. Plantar lesions improved by three months and only mild residual change was described at five months; mild gastric discomfort and transient forearm burning were recorded. Combination treatment and lack of a control prevent attribution of benefit or toxicity solely to erlotinib. For a separate 2024 patient, painful disabling PPK improved only moderately under retinoid-based care and subsequent SCC required surgery. (zhang2025erlotinibtherapyfor pages 2-4, hao2024casereportnovel pages 1-2)
Investigational direct TRPV3 blockade — NCIT concept: investigational TRPV3 inhibitor. NCT07090889, first posted 29 July 2025, started 8 July 2025, registers oral KM-023 phase 1 testing in healthy volunteers followed by an approximately 12-week open-label cohort of up to eight Olmsted patients, measuring safety, pharmacokinetics, plantar-callus dimensions and lesion scores. Its eligibility accepts TRPV3 or PERP, so even a future combined result would require genotype separation for OS1. The estimated 64 total participants are mainly healthy volunteers, not 64 OS1 cases; no efficacy or adverse-event outcome was available in the retrieved registry. Registry: https://clinicaltrials.gov/study/NCT07090889. Separate topical KM-001 studies NCT05435638 and NCT05956314 enrolled punctate PPK or pachyonychia congenita, not OS1; their results cannot be relabeled as OS1 treatment success. (NCT07090889 chunk 1, NCT07090889 chunk 2, NCT05435638 chunk 1, NCT05956314 chunk 1)
Other measures: analgesia, topical lidocaine, selected neuropathic-pain agents and itch management may be needed; surgical debulking or grafting has often been followed by recurrent keratosis. Biopsy and oncologic excision are indicated for suspected cancer. No disease-correcting gene therapy, RNA therapy, cell therapy, immunotherapy, established pharmacogenomic dosing rule or approved OS1-specific precision intervention was verified. A trial registry discussing erlotinib for other keratinopathies, NCT06545695, excludes TRPV3-OS1 under its listed entry criteria and must not be presented as an OS1 trial. (duchatelet2015olmstedsyndromeclinical pages 8-9, hao2024casereportnovel pages 1-2, NCT06545695 chunk 1)

Recent evidence at a glance: the table juxtaposes primary observations and trial design while flagging where molecular attribution or therapeutic efficacy remains uncertain. (lin2012exomesequencingreveals pages 1-2, hao2024casereportnovel pages 1-2, NCT07090889 chunk 1)

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. (lin2012exomesequencingreveals pages 2-4, lin2012exomesequencingreveals pages 1-2, lin2012exomesequencingreveals pages 4-6)	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. (dansoabeam2013olmstedsyndromeexploration pages 1-3)	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. (fatima2022abnormalsomatosensorybehaviors pages 1-2, fatima2022abnormalsomatosensorybehaviors pages 2-3)	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. (hao2024casereportnovel pages 1-2, hao2024casereportnovel pages 2-5)	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. (zhang2025erlotinibtherapyfor pages 1-2, zhang2025erlotinibtherapyfor pages 2-4, zhang2025erlotinibtherapyfor pages 4-6)	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. (NCT07090889 chunk 1, NCT07090889 chunk 2)	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.

13. Prevention

Primary: no vaccine, diet, environmental intervention, or prophylactic medication prevents a confirmed germline OS1 variant. Genetic counseling permits family-specific assessment of dominant versus recessive recurrence risk and, where appropriate and desired, discussion of cascade testing, prenatal testing and preimplantation testing after a familial pathogenic allele is validated. These are reproductive options, not treatment or prevention of disease in someone carrying the variant. (duchatelet2015olmstedsyndromeclinical pages 7-8, duchatelet2015olmstedsyndromeclinical pages 5-7)

Secondary/tertiary: recognize childhood lesions promptly, address fissures and pain, protect function, manage infections, monitor progressive digit constriction, and assess visual complaints. Persistently bleeding, ulcerated, enlarging or morphologically changing keratotic lesions warrant prompt dermatologic evaluation and biopsy, given reported cancers, although no evidence-based OS1 surveillance interval is known. Population-wide newborn screening, prophylactic antibiotics, or preventive EGFR inhibition is not established. (duchatelet2015olmstedsyndromeclinical pages 4-5, hao2024casereportnovel pages 1-2, duchatelet2015olmstedsyndromeclinical pages 7-8)

14. Other species and naturally occurring disease

Orthologous Trpv3 mutations occur in mouse (Mus musculus, NCBI Taxon:10090) and rat (Rattus norvegicus, NCBI Taxon:10116). Naturally occurring DS-Nh mice carry p.Gly573Ser and WBN/Kob-Ht rats p.Gly573Cys at the homologous residue. Both can exhibit hairlessness and dermatitis, providing comparative evidence of conserved channel biology. They are not evidence that the complete human OS1 disorder naturally occurs in those species: the original human report notes rodent facial dermatitis and whole-body hairlessness without paw keratosis. Species-specific ortholog NCBI Gene IDs and breed VBO identifiers were not verified; DS-Nh and WBN/Kob-Ht are laboratory strains, not demonstrated companion-animal disease breeds. OS1 is inherited, not zoonotic or cross-species transmissible. (lin2012exomesequencingreveals pages 4-6, guo2023novelinsightsinto pages 3-4, fatima2022abnormalsomatosensorybehaviors pages 1-2)

15. Model organisms and research uses

Spontaneous genetic models: DS-Nh Trpv3^G573S mice and WBN/Kob-Ht Trpv3^G573C rats model channel hyperactivity, hair abnormalities, itch and inflammation. A separately constructed G573S transgenic mouse has also been reported. Their major limitation is incomplete recreation of mutilating human palmoplantar disease. (lin2012exomesequencingreveals pages 4-6, guo2023novelinsightsinto pages 3-4)
Background/microbiome experiment: a backcrossed 129S1/SvlmJ Trpv3^G573S mouse under S. aureus-free housing did not show spontaneous dermatitis or itch; it exhibited epidermal sensory hypoinnervation and diminished responses to cold, mechanical pain and several pruritogens. Thus a model’s apparent antipruritic or pro-pruritic phenotype cannot be generalized without specifying genetic background, microbiological conditions and assay. Fatima et al., 4 January 2022, https://doi.org/10.3389/fnmol.2021.790435. (fatima2022abnormalsomatosensorybehaviors pages 1-2, fatima2022abnormalsomatosensorybehaviors pages 2-3)
Human cell models: mutant-expressing HEK293 cells establish channel-gating differences; HaCaT keratinocytes transfected with selected alleles show variant-dependent viability/apoptosis, ER-associated trafficking, adhesion and lysosomal phenotypes. These are mechanistic tests and compound-screening platforms, not fully differentiated human soles or clinical efficacy models. Original reports: Lin et al., 2012, https://doi.org/10.1016/j.ajhg.2012.02.006; Ni et al., 2016, https://doi.org/10.1038/srep21815; Yadav and Goswami, 2017, https://doi.org/10.1080/19336950.2016.1249076. No validated OS1 patient-derived organoid, iPSC system, or verified MGI model accession was established here. (lin2012exomesequencingreveals pages 2-4, ni2016anovelmutation pages 3-4, yadav2017trpv3mutantscausing pages 1-4)

Verbatim, traceable abstract excerpts

Human genetics / functional expression, 2012: “In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants.” The same abstract calls the apoptosis-to-hyperkeratosis connection something that the mutations “might” cause, distinguishing measurement from inference. https://doi.org/10.1016/j.ajhg.2012.02.006. (lin2012exomesequencingreveals pages 1-2)
Human immune case, 2013: “The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome.” One patient, not an established universal OS1 biomarker. https://doi.org/10.1186/1750-1172-8-79. (dansoabeam2013olmstedsyndromeexploration pages 1-3)
Recent clinical surveillance, 2024: “The patient presented with disabling, bilateral palmoplantar keratoderma, and subsequently developed squamous cell carcinoma on the right sole.” This describes an event; the authors explicitly state additional experiments are needed to establish how p.Val306Met affects the channel. https://doi.org/10.3389/fonc.2024.1420555. (hao2024casereportnovel pages 1-2, hao2024casereportnovel pages 2-5)

Knowledge-base import cautions: Preserve OS1 versus broad-OS denominators, label hypothesized edges in the causal chain, capture variant-specific evidence instead of assigning gain of function to every case allele, record the 2025 p.Leu655Pro missense/“frameshift” reporting inconsistency, and keep trial enrollment separate from treatment response. Ontology accession numbers, HGNC accession, gnomAD frequencies, ClinVar classifications and PMIDs should be independently verified before structured import where not explicitly supported above. (duchatelet2015olmstedsyndromeclinical pages 1-2, hao2024casereportnovel pages 2-5, zhang2025erlotinibtherapyfor pages 2-4, NCT07090889 chunk 1)

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(dansoabeam2013olmstedsyndromeexploration pages 1-3): Dina Danso-Abeam, Jianguo Zhang, James Dooley, Kim A Staats, Lien Van Eyck, Thomas Van Brussel, Shari Zaman, Esther Hauben, Marc Van de Velde, Marie-Anne Morren, Marleen Renard, Christel Van Geet, Heidi Schaballie, Diether Lambrechts, Jinsheng Tao, Dean Franckaert, Stephanie Humblet-Baron, Isabelle Meyts, and Adrian Liston. Olmsted syndrome: exploration of the immunological phenotype. Orphanet Journal of Rare Diseases, 8:79-79, May 2013. URL: https://doi.org/10.1186/1750-1172-8-79, doi:10.1186/1750-1172-8-79. This article has 69 citations and is from a peer-reviewed journal.
(ni2016anovelmutation pages 3-4): Cheng Ni, Ming Yan, Jia Zhang, Ruhong Cheng, Jianying Liang, Dan Deng, Zhen Wang, Ming Li, and Zhirong Yao. A novel mutation in trpv3 gene causes atypical familial olmsted syndrome. Scientific Reports, Feb 2016. URL: https://doi.org/10.1038/srep21815, doi:10.1038/srep21815. This article has 54 citations and is from a peer-reviewed journal.
(zhang2025erlotinibtherapyfor pages 2-4): Jia Zhang, MengYue Guo, DongYang Yuan, JinYang Wei, and Hongzhou Cui. Erlotinib therapy for olmsted syndrome with p.l655p missense mutation in the trpv3 gene: a case report. Frontiers in Medicine, Jan 2025. URL: https://doi.org/10.3389/fmed.2025.1512673, doi:10.3389/fmed.2025.1512673. This article has 3 citations.
(hao2024casereportnovel pages 2-5): Yangyang Hao, Rong Wu, Xi Chen, Yunjia Shen, Mengwei Chou, and Jianqiang Yang. Case report: novel p.val306met missense mutation in trpv3 in a case of olmsted syndrome accompanied by squamous cell carcinoma. Frontiers in Oncology, Oct 2024. URL: https://doi.org/10.3389/fonc.2024.1420555, doi:10.3389/fonc.2024.1420555. This article has 0 citations.
(duchatelet2015olmstedsyndromeclinical pages 7-8): Sabine Duchatelet and Alain Hovnanian. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet Journal of Rare Diseases, Mar 2015. URL: https://doi.org/10.1186/s13023-015-0246-5, doi:10.1186/s13023-015-0246-5. This article has 130 citations and is from a peer-reviewed journal.
(lin2012exomesequencingreveals pages 4-6): Zhimiao Lin, Quan Chen, Mingyang Lee, Xu Cao, Jie Zhang, Donglai Ma, Long Chen, Xiaoping Hu, Huijun Wang, Xiaowen Wang, Peng Zhang, Xuanzhu Liu, Liping Guan, Yiquan Tang, Haizhen Yang, Ping Tu, Dingfang Bu, Xuejun Zhu, KeWei Wang, Ruoyu Li, and Yong Yang. Exome sequencing reveals mutations in trpv3 as a cause of olmsted syndrome. American journal of human genetics, 90 3:558-64, Mar 2012. URL: https://doi.org/10.1016/j.ajhg.2012.02.006, doi:10.1016/j.ajhg.2012.02.006. This article has 270 citations and is from a highest quality peer-reviewed journal.
(zhang2025erlotinibtherapyfor pages 1-2): Jia Zhang, MengYue Guo, DongYang Yuan, JinYang Wei, and Hongzhou Cui. Erlotinib therapy for olmsted syndrome with p.l655p missense mutation in the trpv3 gene: a case report. Frontiers in Medicine, Jan 2025. URL: https://doi.org/10.3389/fmed.2025.1512673, doi:10.3389/fmed.2025.1512673. This article has 3 citations.
(yadav2017trpv3mutantscausing pages 1-4): Manoj Yadav and Chandan Goswami. Trpv3 mutants causing olmsted syndrome induce impaired cell adhesion and nonfunctional lysosomes. Channels, 11:196-208, Feb 2017. URL: https://doi.org/10.1080/19336950.2016.1249076, doi:10.1080/19336950.2016.1249076. This article has 37 citations and is from a peer-reviewed journal.
(yadav2017trpv3mutantscausing pages 4-6): Manoj Yadav and Chandan Goswami. Trpv3 mutants causing olmsted syndrome induce impaired cell adhesion and nonfunctional lysosomes. Channels, 11:196-208, Feb 2017. URL: https://doi.org/10.1080/19336950.2016.1249076, doi:10.1080/19336950.2016.1249076. This article has 37 citations and is from a peer-reviewed journal.
(zhang2025erlotinibtherapyfor pages 4-6): Jia Zhang, MengYue Guo, DongYang Yuan, JinYang Wei, and Hongzhou Cui. Erlotinib therapy for olmsted syndrome with p.l655p missense mutation in the trpv3 gene: a case report. Frontiers in Medicine, Jan 2025. URL: https://doi.org/10.3389/fmed.2025.1512673, doi:10.3389/fmed.2025.1512673. This article has 3 citations.
(guo2023novelinsightsinto pages 3-4): Yaotao Guo, Yajuan Song, Wei Liu, Tong Wang, Xianjie I. Ma, and Zhou Yu. Novel insights into the role of keratinocytes-expressed trpv3 in the skin. Biomolecules, 13:513, Mar 2023. URL: https://doi.org/10.3390/biom13030513, doi:10.3390/biom13030513. This article has 37 citations.
(duchatelet2015olmstedsyndromeclinical pages 8-9): Sabine Duchatelet and Alain Hovnanian. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet Journal of Rare Diseases, Mar 2015. URL: https://doi.org/10.1186/s13023-015-0246-5, doi:10.1186/s13023-015-0246-5. This article has 130 citations and is from a peer-reviewed journal.
(NCT07090889 chunk 1): Study of KM-023 in Healthy Volunteers and Patients With Olmsted Syndrome.. Orvida Pharma (formerly Kamari Pharma). 2025. ClinicalTrials.gov Identifier: NCT07090889
(zhang2025erlotinibtherapyfor pages 6-7): Jia Zhang, MengYue Guo, DongYang Yuan, JinYang Wei, and Hongzhou Cui. Erlotinib therapy for olmsted syndrome with p.l655p missense mutation in the trpv3 gene: a case report. Frontiers in Medicine, Jan 2025. URL: https://doi.org/10.3389/fmed.2025.1512673, doi:10.3389/fmed.2025.1512673. This article has 3 citations.
(zhang2025erlotinibtherapyfor pages 6-6): Jia Zhang, MengYue Guo, DongYang Yuan, JinYang Wei, and Hongzhou Cui. Erlotinib therapy for olmsted syndrome with p.l655p missense mutation in the trpv3 gene: a case report. Frontiers in Medicine, Jan 2025. URL: https://doi.org/10.3389/fmed.2025.1512673, doi:10.3389/fmed.2025.1512673. This article has 3 citations.
(NCT07090889 chunk 2): Study of KM-023 in Healthy Volunteers and Patients With Olmsted Syndrome.. Orvida Pharma (formerly Kamari Pharma). 2025. ClinicalTrials.gov Identifier: NCT07090889
(NCT05435638 chunk 1): Study Designed to Evaluate Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases. Orvida Pharma (formerly Kamari Pharma). 2022. ClinicalTrials.gov Identifier: NCT05435638
(NCT05956314 chunk 1): Assessment of KM-001 - Safety, Tolerability, and Efficacy in Patients With PPPK1 or PC. Orvida Pharma (formerly Kamari Pharma). 2023. ClinicalTrials.gov Identifier: NCT05956314
(NCT06545695 chunk 1): Amy Paller. Epidermal Growth Factor Receptor Inhibition for Keratinopathies. Northwestern University. 2027. ClinicalTrials.gov Identifier: NCT06545695
(fatima2022abnormalsomatosensorybehaviors pages 2-3): Mahar Fatima, Hannah Slade, Lorraine R Horwitz, Angela Shi, Jingyi Liu, Delaney McKinstry, Troy Villani, Haoxing Xu, and Bo Duan. Abnormal somatosensory behaviors associated with a gain-of-function mutation in trpv3 channels. Frontiers in Molecular Neuroscience, Jan 2022. URL: https://doi.org/10.3389/fnmol.2021.790435, doi:10.3389/fnmol.2021.790435. This article has 11 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	13
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	4
Resolved	1
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0100296 (2 mentions) - the report calls it "if available"; MONDO calls it Olmsted syndrome 1

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Taxon.

Ask OpenScientist

OpenScientist Report

Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Clinical Trials

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Olmsted syndrome 1: disease-characteristics research report

1. Disease information and identifiers

2. Etiology, susceptibility, protection, and gene–environment interaction

3. Phenotypes and quality-of-life consequences

4. Genetics and molecular annotation

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcomes and prognosis

12. Treatment and real-world implementation

13. Prevention

14. Other species and naturally occurring disease

15. Model organisms and research uses

Verbatim, traceable abstract excerpts

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Prefixes with no resolver