Isolated Focal Non-epidermolytic Palmoplantar Keratoderma

Mendelian MONDO:0014622 Pathograph 19 Show in embeddings browser Focal palmoplantar keratoderma Hereditary palmoplantar keratoderma

Isolated focal non-epidermolytic palmoplantar keratoderma (FNEPPK2, OMIM 616400) is a very rare autosomal dominant keratinization disorder in which hyperkeratotic plaques form on limited areas of the palms and soles, without the periorificial plaques, alopecia and mutilating keratoderma of Olmsted syndrome. It is caused by heterozygous gain-of-function missense variants in TRPV3, a warmth-sensitive calcium-permeable cation channel of keratinocytes. The defining family is a Chinese father and son carrying TRPV3 p.Gln580Pro, whose lesional skin showed reduced keratinocyte differentiation and junctional proteins with increased proliferation and cell-death proteins. The disease lies at the mild end of the TRPV3 gain-of-function spectrum whose severe end is Olmsted syndrome 1.

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1
Inheritance
8
Pathophys.
8
Phenotypes
19
Pathograph
1
Genes
1
Variants
1
Medical Actions
2
Differentials
2
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
The defining TRPV3 p.Gln580Pro family shows transmission of a heterozygous variant from an affected father to an affected son, consistent with autosomal dominant inheritance.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:25886873 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"2 (father and son) | Male | TRPV3 p.Gln580Pro"
Row of the review's case table for He et al. (the defining family): two affected males, father and son, carrying TRPV3 p.Gln580Pro. Vertical father-to-son transmission of a heterozygous variant supports autosomal dominant inheritance; the inheritance mode itself is inferred from the pedigree shape rather than stated in the row.
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Pathophysiology

8
TRPV3 Gain-of-Function Channel Activation
Heterozygous missense variants in TRPV3, of which p.Gln580Pro in the S4-S5 linker is the defining allele, increase channel activity. Mutant channels expressed in HEK293 cells carry much larger inward currents than wild type, attributed to constitutive opening.
TRPV3 hgnc:18084 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRPV3 (hgnc:18084). hgnc:18084 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context TRPV3 hgnc:18084 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TRPV3 (hgnc:18084). hgnc:18084 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
calcium channel activity GO:0005262 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased calcium channel activity (GO:0005262). GO:0005262 is a molecular function from the Gene Ontology.
Downstream
Keratinocyte Calcium Overload
Cutaneous Nociceptive Sensitization
Show evidence (2 references)
PMID:25886873 SUPPORT REVIEW SYNTHESIS In Vitro
"Functional studies of four TRPV3 mutations (p.Gly573Ser, p.Gly573Cys, p.Trp692Gly and p.Gln580Pro) using patch clamp analysis on transfected HEK293 cells expressing TRPV3 mutants were performed"
The review places p.Gln580Pro among the TRPV3 alleles characterized by patch clamp in transfected HEK293 cells, which is the functional basis for calling it gain of function.
PMID:25886873 SUPPORT REVIEW SYNTHESIS In Vitro
"These studies have shown that these mutations lead to much larger inward currents probably because of the constitutive opening of the mutants"
States the electrophysiological result for the group of alleles that includes p.Gln580Pro: larger inward currents from constitutively open channels.
Keratinocyte Calcium Overload
Constitutively open mutant TRPV3 channels allow excess calcium entry into keratinocytes, raising intracellular calcium.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
calcium ion transmembrane transport GO:0070588 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology.
Downstream
Keratinocyte Proliferation-Differentiation Imbalance
TRPV3-Linked EGFR Pathway Activation
Keratinocyte Apoptosis
Show evidence (1 reference)
PMID:42725047 SUPPORT BACKGROUND Other
"Pathogenic gain-of-function mutations in TRPV3 result in constitutive channel activation and excessive Ca2+ influx."
General statement, made in the discussion of a TRPV3 focal plantar case, that gain-of-function TRPV3 variants cause excessive calcium influx.
TRPV3-Linked EGFR Pathway Activation
TRPV3 activity is coupled to epidermal growth factor receptor signaling in keratinocytes; persistent TRPV3 activation is reported to stimulate EGFR-related pathways that add to epidermal thickening. Not yet shown directly for p.Gln580Pro.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
epidermal growth factor receptor signaling pathway GO:0007173 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased epidermal growth factor receptor signaling pathway (GO:0007173). GO:0007173 is a biological process from the Gene Ontology.
Downstream
Palmoplantar Epidermal Hyperkeratosis
Show evidence (1 reference)
PMID:31895432 SUPPORT INDIRECT BACKGROUND Other
"In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation."
Background statement, drawn from animal and keratinocyte cell-line work, that TRPV3 signaling transactivates EGFR. Graded OTHER because the one sentence summarizes both model-organism and in vitro sources.
Keratinocyte Proliferation-Differentiation Imbalance
In lesional skin from p.Gln580Pro carriers, transcriptomic and proteomic profiling showed reduced keratinocyte differentiation proteins and increased proliferation proteins, leaving the epidermis immature and hyperproliferative.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
keratinocyte differentiation GO:0030216 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased keratinocyte differentiation (GO:0030216). GO:0030216 is a biological process from the Gene Ontology. keratinocyte proliferation GO:0043616 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased keratinocyte proliferation (GO:0043616). GO:0043616 is a biological process from the Gene Ontology.
Downstream
Palmoplantar Epidermal Hyperkeratosis
Impaired Keratinocyte Cell Adhesion
Show evidence (2 references)
PMID:25886873 SUPPORT REVIEW SYNTHESIS Human Clinical
"Transcriptomic and proteomic investigation in patients with the p.Gln580Pro mutation, leading only to focal PPK, showed decreased expression of proteins involved in keratinocyte differentiation, in gap junction, tight junction and desmosome formation, but increased expression of proteins..."
Review summary of the patient-tissue omics in the defining p.Gln580Pro family (He et al.): differentiation proteins down, proliferation proteins up.
PMID:39748945 SUPPORT REVIEW SYNTHESIS Human Clinical
"In 2015, transcriptomic and proteomic studies on skin lesions and non-lesions of OS patients carrying the p.Gln580Pro mutation revealed downregulation of proteins involved in keratinocyte differentiation and cell-cell connections, while proteins related to keratinocyte proliferation and cell..."
A second review summary of the same patient-tissue study. Not independent of the item above: both restate He et al. 2015, whose own letter has no quotable abstract.
Impaired Keratinocyte Cell Adhesion
Lesional p.Gln580Pro skin shows reduced expression of gap junction, tight junction and desmosome proteins, which the source interprets as compromised keratinocyte cell adhesion.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
cell-cell adhesion GO:0098609 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell-cell adhesion (GO:0098609). GO:0098609 is a biological process from the Gene Ontology.
Downstream
Suprabasal Keratinocyte Disadhesion
Show evidence (1 reference)
PMID:25886873 SUPPORT REVIEW SYNTHESIS Human Clinical
"Thus, the TRPV3 p.Gln580Pro gain-of-function mutation disrupts the balance between keratinocyte proliferation and differentiation, and compromises cell adhesion."
Review conclusion from the p.Gln580Pro patient-tissue omics that cell adhesion is compromised.
Keratinocyte Apoptosis
Mutant TRPV3 increases keratinocyte apoptosis. In HaCaT keratinocytes, p.Gln580Pro raised the apoptotic fraction only slightly, less than the severe Olmsted alleles p.Gly573Cys and p.Trp692Gly, matching its milder clinical phenotype.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
keratinocyte apoptotic process GO:0097283 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased keratinocyte apoptotic process (GO:0097283). GO:0097283 is a biological process from the Gene Ontology.
Downstream
Palmoplantar Epidermal Hyperkeratosis
Show evidence (2 references)
PMID:26902751 SUPPORT PRIMARY RESULT In Vitro
"Flow cytometry analysis further demonstrated G573C, W692G more remarkably increased the number of the apoptosis cells, whereas Q580P slightly enhanced the rate of apoptosis."
Direct in vitro measurement that p.Gln580Pro modestly increases apoptosis of transfected HaCaT keratinocytes.
PMID:26902751 SUPPORT PRIMARY RESULT In Vitro
"The cytotoxicity exerted by G573C and W692G were more obvious, while the cytotoxicity imposed by M672I and Q580P were milder."
CCK8 viability assay in HaCaT cells showing milder cytotoxicity of p.Gln580Pro than of severe Olmsted alleles.
Palmoplantar Epidermal Hyperkeratosis
The combined effect of an immature, over-proliferating epidermis with altered cell death and adhesion is thickening of the cornified and spinous layers of palmar and plantar skin, which appears clinically as focal hyperkeratotic plaques.
keratinization GO:0031424 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased keratinization (GO:0031424). GO:0031424 is a biological process from the Gene Ontology.
palmar and plantar skin UBERON:0013776 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in palmar and plantar skin, annotated with skin of palmar/plantar part of autopod (UBERON:0013776). UBERON:0013776 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Focal Palmoplantar Hyperkeratosis
Focal Plantar Hyperkeratosis
Hyperkeratosis on Biopsy
Epidermal Acanthosis
Hypogranulosis
Rete Ridge Elongation
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"Histopathologic examination reveals prominent hyperkeratosis, thickened stratum spinosum with reduced stratum granulosum, disadhesion of cells in the suprabasal layers, elongation of rete ridges, and sparse lymphocyte infiltration in the dermis."
Orphanet histopathology for the disease records prominent hyperkeratosis and a thickened spinous layer.
Cutaneous Nociceptive Sensitization
Proposed mechanism for pain: TRPV3 is expressed in nociceptive neurons, and over-activation in skin may raise local inflammatory cytokines that act on sensory nerves. This is a hypothesis stated for Olmsted syndrome and has not been tested in FNEPPK2.
Downstream
Activity-Related Plantar Pain
Show evidence (1 reference)
PMID:25886873 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Of note, TRPV3 is expressed in nociceptive neurons."
Places TRPV3 in nociceptive neurons, the substrate for the proposed pain mechanism.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Isolated Focal Non-epidermolytic Palmoplantar Keratoderma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Integument 7
Focal Palmoplantar Hyperkeratosis Patchy palmoplantar hyperkeratosis HP:0005588 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal palmoplantar hyperkeratosis, annotated with Patchy palmoplantar hyperkeratosis (HP:0005588). HP:0005588 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:448264 SUPPORT Other
"A rare hereditary palmoplantar keratoderma characterized by focal hyperkeratotic lesions on the palms and soles."
Orphanet definition names focal palmoplantar hyperkeratotic lesions as the characteristic feature.
PMID:25886873 SUPPORT REVIEW SYNTHESIS Human Clinical
"Transcriptomic and proteomic investigation in patients with the p.Gln580Pro mutation, leading only to focal PPK"
States that the p.Gln580Pro allele produces only focal palmoplantar keratoderma.
Focal Plantar Hyperkeratosis HP:0007556 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal plantar hyperkeratosis, annotated with Plantar hyperkeratosis (HP:0007556). HP:0007556 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26902751 SUPPORT REVIEW SYNTHESIS Human Clinical
"China | male | Focal plantar keratoderma | + | c. 1739 A > C/Wild type"
Literature-review table row for a p.Gln580Pro (c.1739A>C) carrier from the defining Chinese family; the table carries two identical rows, one per affected male.
PMID:42725047 SUPPORT PRIMARY RESULT Human Clinical
"Physical examination revealed scattered hyperkeratosis plaques confined to the soles, predominantly affecting weight-bearing areas."
Single case with heterozygous TRPV3 p.Gly568Asp and isolated focal plantar disease. The authors label the case TRPV3-related Olmsted spectrum, but the reported phenotype (soles only, no periorificial plaques or alopecia) is the isolated focal phenotype.
Hyperkeratosis on Biopsy HP:0000962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent hyperkeratosis, annotated with Hyperkeratosis (HP:0000962). HP:0000962 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"Histopathologic examination reveals prominent hyperkeratosis"
Orphanet histopathology lists prominent hyperkeratosis.
Epidermal Acanthosis HP:0025092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thickened stratum spinosum, annotated with Epidermal acanthosis (HP:0025092). HP:0025092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"thickened stratum spinosum with reduced stratum granulosum"
Orphanet histopathology lists a thickened stratum spinosum.
Hypogranulosis HP:0025816 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced stratum granulosum, annotated with Hypogranulosis (HP:0025816). HP:0025816 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"thickened stratum spinosum with reduced stratum granulosum"
Orphanet histopathology lists a reduced stratum granulosum.
Suprabasal Keratinocyte Disadhesion Acantholysis HP:0100792 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Suprabasal keratinocyte disadhesion, annotated with Acantholysis (HP:0100792). HP:0100792 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"disadhesion of cells in the suprabasal layers"
Orphanet histopathology lists suprabasal cell disadhesion, which matches the HPO definition of acantholysis as loss of cohesion between keratinocytes.
Rete Ridge Elongation HP:0034768 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elongation of rete ridges, annotated with Rete ridge elongation (HP:0034768). HP:0034768 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"elongation of rete ridges, and sparse lymphocyte infiltration in the dermis"
Orphanet histopathology lists elongation of rete ridges.
Constitutional 1
🧬

Genetic Associations

1
TRPV3 (Causative germline gain-of-function variant)
Gene: TRPV3 hgnc:18084 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRPV3 (hgnc:18084). hgnc:18084 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
ORPHA:448264 SUPPORT Other
"TRPV3 | transient receptor potential cation channel subfamily V member 3 | hgnc:18084 | Disease-causing germline mutation(s) (gain of function) in"
Orphanet gene-disease row naming TRPV3 gain-of-function germline variants as disease-causing.
PMID:26902751 SUPPORT BACKGROUND Human Clinical
"However, a milder phenotype, reported in another Chinese family, was resulted from p.Gln580Pro mutation."
Restates the defining family report, in which TRPV3 p.Gln580Pro causes a mild phenotype.
Variants (1)
TRPV3 c.1739A>C p.(Gln580Pro) Pathogenic
Heterozygous missense variant in the S4-S5 linker, reported in a Chinese father and son with focal palmoplantar keratoderma. Functionally a gain-of-function allele, but milder in apoptosis and predicted-stability assays than the Olmsted alleles.
Functional effects
Gain of function - increased TRPV3 channel activity
Predicted to stabilize the protein, unlike the destabilizing severe Olmsted alleles, which the authors relate to its mild phenotype.
Show evidence (2 references)
PMID:26902751 SUPPORT REVIEW SYNTHESIS Human Clinical
"China | male | Focal plantar keratoderma | + | c. 1739 A > C/Wild type"
Gives the c.1739A>C genotype, heterozygous with a wild-type allele, in the focal plantar keratoderma family.
PMID:26902751 SUPPORT PRIMARY RESULT Computational
"The only positive value was due to the Gln580Pro mutation (Table 2), which resulted in a relatively stable protein structure and caused the mildest phenotypic appearance."
In silico stability prediction separating p.Gln580Pro from the destabilizing severe alleles.
💊

Medical Actions

1
Topical Keratolytics and Retinoids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: acitretin CHEBI:50172 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses acitretin (CHEBI:50172). CHEBI:50172 is a therapeutic agent from Chemical Entities of Biological Interest. tretinoin CHEBI:15367 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tretinoin, annotated with all-trans-retinoic acid (CHEBI:15367). CHEBI:15367 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Conventional symptomatic therapy for keratoderma. No treatment study exists for FNEPPK2. In the one isolated focal TRPV3 case with reported treatment (p.Gly568Asp), topical tretinoin, topical corticosteroid, keratolytics and oral acitretin did not help. Erlotinib has been used in severe TRPV3-related Olmsted syndrome (PMID:31895432) but not in this disease.
Target Phenotypes: Focal plantar hyperkeratosis HP:0007556 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Focal plantar hyperkeratosis, annotated with Plantar hyperkeratosis (HP:0007556). HP:0007556 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42725047 REFUTE PRIMARY RESULT Human Clinical
"The patient did not respond to topical treatment, including 0.1% tretinoin ointment and mometasone furoate ointment."
Single-case non-response to topical retinoid and corticosteroid in isolated focal plantar TRPV3 disease.
PMID:42725047 REFUTE PRIMARY RESULT Human Clinical
"Localized PPK phenotype causes by TRPV3 mutation is refractory to multiple conventional treatments, including topical keratolytics and oral acitretin."
The authors' statement, from their case, that localized TRPV3 keratoderma did not respond to keratolytics or oral acitretin.
📊

Prevalence

1
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet point-prevalence class <1 / 1,000,000, sourced by Orphanet to the single defining family report (PMID:25285920). Orphanet's concept ORPHA:448264 also lists KRT16 as a disease gene, so the class covers both TRPV3- and KRT16-related isolated focal NEPPK.
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25285920"
Orphanet epidemiology row giving the point-prevalence class.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Isolated Focal Non-epidermolytic Palmoplantar Keratoderma:

Olmsted syndrome 1 Not Yet Curated MONDO:0100296
Overlapping Features Allelic TRPV3 gain-of-function disease at the severe end of the spectrum. Distinguished by mutilating, progressive keratoderma and periorificial keratotic plaques, which are absent in FNEPPK2.
Distinguishing Features
  • Bilateral mutilating palmoplantar keratoderma with periorificial keratotic plaques indicates Olmsted syndrome.
  • Isolated focal plaques without periorificial plaques or alopecia fit FNEPPK2.
Show evidence (1 reference)
PMID:25886873 SUPPORT REVIEW SYNTHESIS Human Clinical
"Initially, the hallmarks for the diagnosis of OS are bilateral mutilating palmoplantar keratoderma (Figure 1A) associated with periorificial keratotic plaques"
Gives the Olmsted syndrome hallmarks that separate it from isolated focal disease.
Palmoplantar keratoderma, nonepidermolytic, focal 1 Not Yet Curated MONDO:0013073
Overlapping Features KRT16-related focal NEPPK (FNEPPK1, OMIM 613000). Clinically overlapping; Orphanet groups both genes under ORPHA:448264, and molecular testing separates them.
Distinguishing Features
  • A pathogenic KRT16 variant indicates FNEPPK1; a TRPV3 gain-of-function variant indicates FNEPPK2.
Show evidence (1 reference)
ORPHA:448264 SUPPORT Other
"KRT16 | keratin 16 | hgnc:6423 | Disease-causing germline mutation(s) in"
Orphanet lists KRT16 as a second disease gene for the same clinical concept, so KRT16 disease is the main genetic differential.
{ }

Source YAML

click to show 
name: Isolated Focal Non-epidermolytic Palmoplantar Keratoderma
creation_date: "2026-10-15T14:36:39Z"
category: Mendelian
synonyms:
- palmoplantar keratoderma, nonepidermolytic, focal type 2
- palmoplantar keratoderma, nonepidermolytic, focal 2
- FNEPPK2
description: >-
  Isolated focal non-epidermolytic palmoplantar keratoderma (FNEPPK2, OMIM
  616400) is a very rare autosomal dominant keratinization disorder in which
  hyperkeratotic plaques form on limited areas of the palms and soles, without
  the periorificial plaques, alopecia and mutilating keratoderma of Olmsted
  syndrome. It is caused by heterozygous gain-of-function missense variants in
  TRPV3, a warmth-sensitive calcium-permeable cation channel of keratinocytes.
  The defining family is a Chinese father and son carrying TRPV3 p.Gln580Pro,
  whose lesional skin showed reduced keratinocyte differentiation and
  junctional proteins with increased proliferation and cell-death proteins. The
  disease lies at the mild end of the TRPV3 gain-of-function spectrum whose
  severe end is Olmsted syndrome 1.
disease_term:
  preferred_term: isolated focal non-epidermolytic palmoplantar keratoderma
  term:
    id: MONDO:0014622
    label: isolated focal non-epidermolytic palmoplantar keratoderma
parents:
- Focal palmoplantar keratoderma
- Hereditary palmoplantar keratoderma
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The defining TRPV3 p.Gln580Pro family shows transmission of a heterozygous
    variant from an affected father to an affected son, consistent with
    autosomal dominant inheritance.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "2 (father and son) | Male | TRPV3 p.Gln580Pro"
    explanation: >-
      Row of the review's case table for He et al. (the defining family): two
      affected males, father and son, carrying TRPV3 p.Gln580Pro. Vertical
      father-to-son transmission of a heterozygous variant supports autosomal
      dominant inheritance; the inheritance mode itself is inferred from the
      pedigree shape rather than stated in the row.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet point-prevalence class <1 / 1,000,000, sourced by Orphanet to the
    single defining family report (PMID:25285920). Orphanet's concept
    ORPHA:448264 also lists KRT16 as a disease gene, so the class covers both
    TRPV3- and KRT16-related isolated focal NEPPK.
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:25285920"
    explanation: Orphanet epidemiology row giving the point-prevalence class.
pathophysiology:
- name: TRPV3 Gain-of-Function Channel Activation
  description: >-
    Heterozygous missense variants in TRPV3, of which p.Gln580Pro in the
    S4-S5 linker is the defining allele, increase channel activity. Mutant
    channels expressed in HEK293 cells carry much larger inward currents than
    wild type, attributed to constitutive opening.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  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
  molecular_functions:
  - preferred_term: calcium channel activity
    term:
      id: GO:0005262
      label: calcium channel activity
    modifier: INCREASED
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Functional studies of four TRPV3 mutations (p.Gly573Ser, p.Gly573Cys, p.Trp692Gly and p.Gln580Pro) using patch clamp analysis on transfected HEK293 cells expressing TRPV3 mutants were performed"
    explanation: >-
      The review places p.Gln580Pro among the TRPV3 alleles characterized by
      patch clamp in transfected HEK293 cells, which is the functional basis for
      calling it gain of function.
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "These studies have shown that these mutations lead to much larger inward currents probably because of the constitutive opening of the mutants"
    explanation: >-
      States the electrophysiological result for the group of alleles that
      includes p.Gln580Pro: larger inward currents from constitutively open
      channels.
  downstream:
  - target: Keratinocyte Calcium Overload
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25886873
      reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "Thus, these mutations are gain-of-function mutations and result in elevated intracellular Ca2+ inducing increased apoptosis, suggesting that enhanced cell-death could drive OS"
      explanation: >-
        Links the gain-of-function TRPV3 alleles (including p.Gln580Pro in the
        preceding sentence) to elevated intracellular calcium.
  - target: Cutaneous Nociceptive Sensitization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25886873
      reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Thus, it is also likely that TRPV3 over-activation leads to local overproduction of inflammatory cytokines which could affect the somatosensory system, leading to a peripheral neuropathic pain."
      explanation: >-
        A hypothesis stated for TRPV3 over-activation in Olmsted syndrome, not
        a result in FNEPPK2. It is the only sourced proposal for how a
        hyperactive keratinocyte channel produces pain.
- name: Keratinocyte Calcium Overload
  description: >-
    Constitutively open mutant TRPV3 channels allow excess calcium entry into
    keratinocytes, raising intracellular calcium.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  evidence:
  - reference: PMID:42725047
    reference_title: "Palmoplantar Keratoderma: A Mechanism-Based Disease Classification."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Pathogenic gain-of-function mutations in TRPV3 result in constitutive channel activation and excessive Ca2+ influx."
    explanation: >-
      General statement, made in the discussion of a TRPV3 focal plantar case,
      that gain-of-function TRPV3 variants cause excessive calcium influx.
  downstream:
  - target: Keratinocyte Proliferation-Differentiation Imbalance
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42725047
      reference_title: "Palmoplantar Keratoderma: A Mechanism-Based Disease Classification."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "The elevation of intracellular calcium disrupts normal keratinocyte proliferation and differentiation pathways, and promotes inflammatory signaling within the skin."
      explanation: States the step from raised intracellular calcium to disrupted keratinocyte proliferation and differentiation.
  - target: TRPV3-Linked EGFR Pathway Activation
    causal_link_type: DIRECT
  - target: Keratinocyte Apoptosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39748945
      reference_title: "Pathogenesis and management of TRPV3-related Olmsted syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "In 2012, Lin et al. (2012) found that gain-of-function mutations in TRPV3 (p.Gly573Cys, p.Gly573Ser, and p.Trp692Gly) lead to sustained channel opening, continuous influx of Ca2+ into cells, causing calcium overload and inducing increased apoptosis of keratinocytes, which may result in the hyperkeratosis observed in OS."
      explanation: >-
        Describes calcium overload inducing keratinocyte apoptosis for three
        Olmsted alleles; applied here to p.Gln580Pro by inference, since the
        same review reports p.Gln580Pro also induces apoptosis in HaCaT cells.
- name: TRPV3-Linked EGFR Pathway Activation
  description: >-
    TRPV3 activity is coupled to epidermal growth factor receptor signaling in
    keratinocytes; persistent TRPV3 activation is reported to stimulate
    EGFR-related pathways that add to epidermal thickening. Not yet shown
    directly for p.Gln580Pro.
  biological_scale: CELLULAR
  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
  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: OTHER
    quote_role: BACKGROUND
    snippet: "In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation."
    explanation: >-
      Background statement, drawn from animal and keratinocyte cell-line work,
      that TRPV3 signaling transactivates EGFR. Graded OTHER because the one
      sentence summarizes both model-organism and in vitro sources.
  downstream:
  - target: Palmoplantar Epidermal Hyperkeratosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42725047
      reference_title: "Palmoplantar Keratoderma: A Mechanism-Based Disease Classification."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "Persistent activation of TRPV3 has also been shown to stimulate epidermal growth factor receptor-related pathways, further contributing to abnormal epidermal thickening."
      explanation: Links TRPV3-driven EGFR pathway activity to epidermal thickening.
- name: Keratinocyte Proliferation-Differentiation Imbalance
  description: >-
    In lesional skin from p.Gln580Pro carriers, transcriptomic and proteomic
    profiling showed reduced keratinocyte differentiation proteins and
    increased proliferation proteins, leaving the epidermis immature and
    hyperproliferative.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: DECREASED
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Transcriptomic and proteomic investigation in patients with the p.Gln580Pro mutation, leading only to focal PPK, showed decreased expression of proteins involved in keratinocyte differentiation, in gap junction, tight junction and desmosome formation, but increased expression of proteins involved in keratinocyte proliferation and cell death"
    explanation: >-
      Review summary of the patient-tissue omics in the defining p.Gln580Pro
      family (He et al.): differentiation proteins down, proliferation proteins
      up.
  - reference: PMID:39748945
    reference_title: "Pathogenesis and management of TRPV3-related Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In 2015, transcriptomic and proteomic studies on skin lesions and non-lesions of OS patients carrying the p.Gln580Pro mutation revealed downregulation of proteins involved in keratinocyte differentiation and cell-cell connections, while proteins related to keratinocyte proliferation and cell death were upregulated"
    explanation: >-
      A second review summary of the same patient-tissue study. Not independent
      of the item above: both restate He et al. 2015, whose own letter has no
      quotable abstract.
  downstream:
  - target: Palmoplantar Epidermal Hyperkeratosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39748945
      reference_title: "Pathogenesis and management of TRPV3-related Olmsted syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Consequently, the involved region remains immature and continues to proliferate inappropriately. This excessive epithelial proliferation can lead to hyperkeratosis."
      explanation: >-
        Review reasoning from Olmsted syndrome histology (persistent basal
        keratins, raised Ki-67) that an immature, over-proliferating epidermis
        produces hyperkeratosis.
  - target: Impaired Keratinocyte Cell Adhesion
    causal_link_type: DIRECT
- name: Impaired Keratinocyte Cell Adhesion
  description: >-
    Lesional p.Gln580Pro skin shows reduced expression of gap junction, tight
    junction and desmosome proteins, which the source interprets as
    compromised keratinocyte cell adhesion.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: DECREASED
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Thus, the TRPV3 p.Gln580Pro gain-of-function mutation disrupts the balance between keratinocyte proliferation and differentiation, and compromises cell adhesion."
    explanation: Review conclusion from the p.Gln580Pro patient-tissue omics that cell adhesion is compromised.
  downstream:
  - target: Suprabasal Keratinocyte Disadhesion
    causal_link_type: DIRECT
- name: Keratinocyte Apoptosis
  description: >-
    Mutant TRPV3 increases keratinocyte apoptosis. In HaCaT keratinocytes,
    p.Gln580Pro raised the apoptotic fraction only slightly, less than the
    severe Olmsted alleles p.Gly573Cys and p.Trp692Gly, matching its milder
    clinical phenotype.
  biological_scale: CELLULAR
  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:26902751
    reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Flow cytometry analysis further demonstrated G573C, W692G more remarkably increased the number of the apoptosis cells, whereas Q580P slightly enhanced the rate of apoptosis."
    explanation: Direct in vitro measurement that p.Gln580Pro modestly increases apoptosis of transfected HaCaT keratinocytes.
  - reference: PMID:26902751
    reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The cytotoxicity exerted by G573C and W692G were more obvious, while the cytotoxicity imposed by M672I and Q580P were milder."
    explanation: CCK8 viability assay in HaCaT cells showing milder cytotoxicity of p.Gln580Pro than of severe Olmsted alleles.
  downstream:
  - target: Palmoplantar Epidermal Hyperkeratosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Palmoplantar Epidermal Hyperkeratosis
  description: >-
    The combined effect of an immature, over-proliferating epidermis with
    altered cell death and adhesion is thickening of the cornified and spinous
    layers of palmar and plantar skin, which appears clinically as focal
    hyperkeratotic plaques.
  biological_scale: TISSUE
  locations:
  - preferred_term: palmar and plantar skin
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: INCREASED
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Histopathologic examination reveals prominent hyperkeratosis, thickened stratum spinosum with reduced stratum granulosum, disadhesion of cells in the suprabasal layers, elongation of rete ridges, and sparse lymphocyte infiltration in the dermis."
    explanation: Orphanet histopathology for the disease records prominent hyperkeratosis and a thickened spinous layer.
  downstream:
  - target: Focal Palmoplantar Hyperkeratosis
    causal_link_type: DIRECT
  - target: Focal Plantar Hyperkeratosis
    causal_link_type: DIRECT
  - target: Hyperkeratosis on Biopsy
    causal_link_type: DIRECT
  - target: Epidermal Acanthosis
    causal_link_type: DIRECT
  - target: Hypogranulosis
    causal_link_type: DIRECT
  - target: Rete Ridge Elongation
    causal_link_type: DIRECT
- name: Cutaneous Nociceptive Sensitization
  description: >-
    Proposed mechanism for pain: TRPV3 is expressed in nociceptive neurons, and
    over-activation in skin may raise local inflammatory cytokines that act on
    sensory nerves. This is a hypothesis stated for Olmsted syndrome and has not
    been tested in FNEPPK2.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Of note, TRPV3 is expressed in nociceptive neurons."
    explanation: Places TRPV3 in nociceptive neurons, the substrate for the proposed pain mechanism.
  downstream:
  - target: Activity-Related Plantar Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Focal Palmoplantar Hyperkeratosis
  category: Clinical
  description: >-
    Hyperkeratotic plaques limited to circumscribed areas of the palms and
    soles rather than diffuse involvement; the defining feature of the
    disease.
  phenotype_term:
    preferred_term: Focal palmoplantar hyperkeratosis
    term:
      id: HP:0005588
      label: Patchy palmoplantar hyperkeratosis
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare hereditary palmoplantar keratoderma characterized by focal hyperkeratotic lesions on the palms and soles."
    explanation: Orphanet definition names focal palmoplantar hyperkeratotic lesions as the characteristic feature.
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Transcriptomic and proteomic investigation in patients with the p.Gln580Pro mutation, leading only to focal PPK"
    explanation: States that the p.Gln580Pro allele produces only focal palmoplantar keratoderma.
- name: Focal Plantar Hyperkeratosis
  category: Clinical
  description: >-
    Both p.Gln580Pro carriers are tabulated as having focal plantar
    keratoderma. A child with a different heterozygous TRPV3 variant
    (p.Gly568Asp) had scattered plaques confined to the soles, mainly over
    weight-bearing areas, without periorificial plaques or alopecia.
  phenotype_term:
    preferred_term: Focal plantar hyperkeratosis
    term:
      id: HP:0007556
      label: Plantar hyperkeratosis
  evidence:
  - reference: PMID:26902751
    reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "China | male | Focal plantar keratoderma | + | c. 1739 A > C/Wild type"
    explanation: >-
      Literature-review table row for a p.Gln580Pro (c.1739A>C) carrier from the
      defining Chinese family; the table carries two identical rows, one per
      affected male.
  - reference: PMID:42725047
    reference_title: "Palmoplantar Keratoderma: A Mechanism-Based Disease Classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Physical examination revealed scattered hyperkeratosis plaques confined to the soles, predominantly affecting weight-bearing areas."
    explanation: >-
      Single case with heterozygous TRPV3 p.Gly568Asp and isolated focal plantar
      disease. The authors label the case TRPV3-related Olmsted spectrum, but the
      reported phenotype (soles only, no periorificial plaques or alopecia) is
      the isolated focal phenotype.
- name: Hyperkeratosis on Biopsy
  category: Histological
  description: Prominent hyperkeratosis of the cornified layer on skin biopsy.
  phenotype_term:
    preferred_term: Prominent hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Histopathologic examination reveals prominent hyperkeratosis"
    explanation: Orphanet histopathology lists prominent hyperkeratosis.
- name: Epidermal Acanthosis
  category: Histological
  description: Thickened stratum spinosum on skin biopsy.
  phenotype_term:
    preferred_term: Thickened stratum spinosum
    term:
      id: HP:0025092
      label: Epidermal acanthosis
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "thickened stratum spinosum with reduced stratum granulosum"
    explanation: Orphanet histopathology lists a thickened stratum spinosum.
- name: Hypogranulosis
  category: Histological
  description: Reduced stratum granulosum on skin biopsy.
  phenotype_term:
    preferred_term: Reduced stratum granulosum
    term:
      id: HP:0025816
      label: Hypogranulosis
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "thickened stratum spinosum with reduced stratum granulosum"
    explanation: Orphanet histopathology lists a reduced stratum granulosum.
- name: Suprabasal Keratinocyte Disadhesion
  category: Histological
  description: >-
    Loss of cohesion between keratinocytes in the suprabasal layers on skin
    biopsy.
  phenotype_term:
    preferred_term: Suprabasal keratinocyte disadhesion
    term:
      id: HP:0100792
      label: Acantholysis
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "disadhesion of cells in the suprabasal layers"
    explanation: >-
      Orphanet histopathology lists suprabasal cell disadhesion, which matches
      the HPO definition of acantholysis as loss of cohesion between
      keratinocytes.
- name: Rete Ridge Elongation
  category: Histological
  description: Elongated rete ridges on skin biopsy.
  phenotype_term:
    preferred_term: Elongation of rete ridges
    term:
      id: HP:0034768
      label: Rete ridge elongation
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "elongation of rete ridges, and sparse lymphocyte infiltration in the dermis"
    explanation: Orphanet histopathology lists elongation of rete ridges.
- name: Activity-Related Plantar Pain
  category: Clinical
  description: >-
    Pain in the plantar lesions after physical activity. The 2020 report
    titled "Mutation in TRPV3 causes painful focal plantar keratoderma"
    (PMID:32314439) describes painful disease but has no quotable text; the
    quoted case carries TRPV3 p.Gly568Asp.
  phenotype_term:
    preferred_term: Plantar pain after physical activity
    term:
      id: HP:6001399
      label: Plantar pain
  evidence:
  - reference: PMID:42725047
    reference_title: "Palmoplantar Keratoderma: A Mechanism-Based Disease Classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient reported occasional pain after physical activity."
    explanation: Pain after activity in the child with isolated focal plantar TRPV3 disease (p.Gly568Asp).
genetic:
- name: TRPV3
  association: Causative germline gain-of-function variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TRPV3 | transient receptor potential cation channel subfamily V member 3 | hgnc:18084 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet gene-disease row naming TRPV3 gain-of-function germline variants as disease-causing.
  - reference: PMID:26902751
    reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "However, a milder phenotype, reported in another Chinese family, was resulted from p.Gln580Pro mutation."
    explanation: Restates the defining family report, in which TRPV3 p.Gln580Pro causes a mild phenotype.
  notes: >-
    No ClinGen gene-disease validity record for TRPV3 was found in
    cache/clingen/gene_validity.csv, so no validity tier is recorded. Orphanet's
    ORPHA:448264 also lists KRT16, but KRT16-related focal NEPPK is the separate
    MONDO:0013073 (FNEPPK1) and is not curated here.
  variants:
  - name: TRPV3 c.1739A>C p.(Gln580Pro)
    description: >-
      Heterozygous missense variant in the S4-S5 linker, reported in a Chinese
      father and son with focal palmoplantar keratoderma. Functionally a
      gain-of-function allele, but milder in apoptosis and predicted-stability
      assays than the Olmsted alleles.
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: Gain of function - increased TRPV3 channel activity
      description: >-
        Predicted to stabilize the protein, unlike the destabilizing severe
        Olmsted alleles, which the authors relate to its mild phenotype.
    evidence:
    - reference: PMID:26902751
      reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "China | male | Focal plantar keratoderma | + | c. 1739 A > C/Wild type"
      explanation: Gives the c.1739A>C genotype, heterozygous with a wild-type allele, in the focal plantar keratoderma family.
    - reference: PMID:26902751
      reference_title: "A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      snippet: "The only positive value was due to the Gln580Pro mutation (Table 2), which resulted in a relatively stable protein structure and caused the mildest phenotypic appearance."
      explanation: In silico stability prediction separating p.Gln580Pro from the destabilizing severe alleles.
treatments:
- name: Topical Keratolytics and Retinoids
  description: >-
    Conventional symptomatic therapy for keratoderma. No treatment study exists
    for FNEPPK2. In the one isolated focal TRPV3 case with reported treatment
    (p.Gly568Asp), topical tretinoin, topical corticosteroid, keratolytics and
    oral acitretin did not help. Erlotinib has been used in severe TRPV3-related
    Olmsted syndrome (PMID:31895432) but not in this disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
    - preferred_term: tretinoin
      term:
        id: CHEBI:15367
        label: all-trans-retinoic acid
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Focal plantar hyperkeratosis
    term:
      id: HP:0007556
      label: Plantar hyperkeratosis
  evidence:
  - reference: PMID:42725047
    reference_title: "Palmoplantar Keratoderma: A Mechanism-Based Disease Classification."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The patient did not respond to topical treatment, including 0.1% tretinoin ointment and mometasone furoate ointment."
    explanation: Single-case non-response to topical retinoid and corticosteroid in isolated focal plantar TRPV3 disease.
  - reference: PMID:42725047
    reference_title: "Palmoplantar Keratoderma: A Mechanism-Based Disease Classification."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Localized PPK phenotype causes by TRPV3 mutation is refractory to multiple conventional treatments, including topical keratolytics and oral acitretin."
    explanation: The authors' statement, from their case, that localized TRPV3 keratoderma did not respond to keratolytics or oral acitretin.
differential_diagnoses:
- name: Olmsted syndrome 1
  disease_term:
    preferred_term: Olmsted syndrome 1
    term:
      id: MONDO:0100296
      label: Olmsted syndrome 1
  description: >-
    Allelic TRPV3 gain-of-function disease at the severe end of the spectrum.
    Distinguished by mutilating, progressive keratoderma and periorificial
    keratotic plaques, which are absent in FNEPPK2.
  distinguishing_features:
  - Bilateral mutilating palmoplantar keratoderma with periorificial keratotic plaques indicates Olmsted syndrome.
  - Isolated focal plaques without periorificial plaques or alopecia fit FNEPPK2.
  evidence:
  - reference: PMID:25886873
    reference_title: "Olmsted syndrome: clinical, molecular and therapeutic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Initially, the hallmarks for the diagnosis of OS are bilateral mutilating palmoplantar keratoderma (Figure 1A) associated with periorificial keratotic plaques"
    explanation: Gives the Olmsted syndrome hallmarks that separate it from isolated focal disease.
- name: Palmoplantar keratoderma, nonepidermolytic, focal 1
  disease_term:
    preferred_term: palmoplantar keratoderma, nonepidermolytic, focal 1
    term:
      id: MONDO:0013073
      label: palmoplantar keratoderma, nonepidermolytic, focal 1
  description: >-
    KRT16-related focal NEPPK (FNEPPK1, OMIM 613000). Clinically overlapping;
    Orphanet groups both genes under ORPHA:448264, and molecular testing
    separates them.
  distinguishing_features:
  - A pathogenic KRT16 variant indicates FNEPPK1; a TRPV3 gain-of-function variant indicates FNEPPK2.
  evidence:
  - reference: ORPHA:448264
    reference_title: "Isolated focal non-epidermolytic palmoplantar keratoderma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRT16 | keratin 16 | hgnc:6423 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists KRT16 as a second disease gene for the same clinical concept, so KRT16 disease is the main genetic differential.
references:
- reference: PMID:25285920
  title: A gain-of-function mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family.
- reference: PMID:32314439
  title: Mutation in TRPV3 causes painful focal plantar keratoderma.
notes: >-
  The two papers that report this disease directly, He et al. 2015
  (PMID:25285920, the defining p.Gln580Pro family) and Peters et al. 2020
  (PMID:32314439), are letters with no abstract, and two fetches of each
  returned no quotable text (content_type unavailable). They are listed under
  references but not cited as evidence. Claims about the defining family are
  taken from reviews that summarize it (PMID:25886873, PMID:39748945) and from
  the case table in PMID:26902751, so those items are not independent of one
  another. The only other quotable isolated focal TRPV3 case found
  (PMID:42725047, p.Gly568Asp) is labelled by its authors as TRPV3-related
  Olmsted spectrum disease.
📚

References & Deep Research

References

2
PMID:25285920
A gain-of-function mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family.
No top-level findings curated for this source.
PMID:32314439
Mutation in TRPV3 causes painful focal plantar keratoderma.
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: Isolated_Focal_Non-epidermolytic_Palmoplantar_Keratoderma · 2026-10-15T15:12:41Z · View source

New entry for MONDO:0014622 (FNEPPK2, OMIM 616400), TRPV3 gain-of-function. Deep research: Perplexity report research/Isolated_Focal_Non-epidermolytic_Palmoplantar_Keratoderma-deep-research-perplexity.md; just preflight-dr returned PASS (TRPV3 mentioned 63 times). The report's term validation flagged UBERON:0001514 and UBERON:0001516 as aorta terms, not palmar/plantar skin; neither was used, and the tissue node binds UBERON:0013776 instead. Its one off-topic reference (DOI:10.1111/ddg.150_12930, the German version of a PPK review) was not used. The two disease-specific papers, He et al. 2015 (PMID:25285920) and Peters et al. 2020 (PMID:32314439), are letters with no abstract; each was fetched twice (second time with --force) and stayed content_type unavailable. They are listed under references but not cited. Evidence about the defining p.Gln580Pro family therefore comes from the Duchatelet and Hovnanian Olmsted review (PMID:25886873), a 2024 Olmsted review (PMID:39748945) and the case table and HaCaT assays of Ni et al. 2016 (PMID:26902751). Orphanet ORPHA:448264 supplies the definition, histopathology, prevalence class and gene rows; the Orphanet concept also lists KRT16, which MONDO splits off as MONDO:0013073 (FNEPPK1), recorded here as a differential. An additional isolated focal plantar TRPV3 p.Gly568Asp case (PMID:42725047), labelled Olmsted spectrum by its authors, supports plantar distribution, activity-related pain and non-response to keratolytics, tretinoin and acitretin (REFUTE evidence on the treatment). Pathophysiology chain: TRPV3 gain-of-function channel activation -> keratinocyte calcium overload -> proliferation-differentiation imbalance, EGFR pathway activation and keratinocyte apoptosis -> palmoplantar epidermal hyperkeratosis -> clinical and histological phenotypes; impaired cell adhesion -> suprabasal disadhesion; a hypothesised nociceptive branch -> plantar pain. All 8 phenotypes are causally connected. Validation: just validate, just validate-terms, just count-verified-snippets (37/37), just validate-disorders (pass), and the offline gates (duplicate keys, entity refs, causal targets, qualifier terms, coarse phenotypes, snippet length, title snippets, snippet grading, folded hyphens, block scalar comments, enum values) all pass. No GeneReviews chapter (check-genereviews NO_CHAPTER with synonyms present). No ClinGen validity record for TRPV3 in cache/clingen.

Perplexity ▸
Isolated Focal Non-epidermolytic Palmoplantar Keratoderma
sonar-deep-research 51 citations 2026-10-15T14:41:33.604565

Isolated Focal Non-epidermolytic Palmoplantar Keratoderma

Disease-knowledge-base research report — evidence reviewed through 15 October 2026

Executive summary and scope clarification

Isolated focal non-epidermolytic palmoplantar keratoderma corresponding specifically to MONDO:0014622 is FNEPPK2, OMIM 616400, an extremely rare autosomal-dominant disorder caused by activating germline variants in TRPV3. It produces localized hyperkeratotic plaques on palmoplantar pressure/friction sites without histologic epidermolysis or the extensive periorificial, hair, nail, and mutilating manifestations of classic Olmsted syndrome. The defining report identified heterozygous TRPV3 NM_145068.4:c.1739A>C, p.(Gln580Pro), rs786205869 in a Chinese father and son; the variant arose de novo in the father and was inherited by his son. Functional assays showed increased intracellular Ca²⁺, supporting gain of function (GOF) (PMID: 25285920). [79][106]

A terminology warning is essential:

  • MONDO:0014622 / OMIM 616400 / FNEPPK2 denotes the TRPV3-related condition requested here. [18][20]
  • OMIM 613000 / FNEPPK1 is a clinically overlapping but distinct KRT16-related disorder. [21]
  • OMIM 615735 is focal-or-diffuse non-epidermolytic PPK with plantar blistering due chiefly to KRT6C. [10][17]
  • Clinical literature sometimes uses “focal non-epidermolytic PPK” for this broader phenotype group, including KRT16, KRT6C, DSG1, and TRPV3. Those data should not automatically be assigned to MONDO:0014622. [50][424]

Evidence for the precise MONDO entity remains sparse: the canonical disease–gene assignment rests principally on one father–son family, supplemented by a 2020 report titled “Mutation in TRPV3 causes painful focal plantar keratoderma” (PMID: 32314439) whose PubMed record has no abstract. [83][121]

1. Disease information

1.1 Definition

Isolated FNEPPK2 is a hereditary keratinization disorder characterized by focal, patchy hyperkeratosis of the palms and soles, rather than uniform involvement of the entire palmoplantar surface. “Non-epidermolytic” means that biopsy does not show the keratinocyte cytolysis and tonofilament clumping typical of epidermolytic PPK. Orphanet describes it as “a rare hereditary palmoplantar keratoderma characterized by focal hyperkeratotic lesions on the palms and soles.” [16]

The canonical TRPV3 family had focal PPK “with no other abnormalities,” distinguishing the mild isolated phenotype from classic TRPV3-related Olmsted syndrome. [79]

1.2 Identifiers and synonyms

Resource Identifier/name Notes and URL
MONDO MONDO:0014622 Isolated focal non-epidermolytic palmoplantar keratoderma; https://monarchinitiative.org/MONDO:0014622 [20]
OMIM 616400 Palmoplantar keratoderma, nonepidermolytic, focal 2; FNEPPK2; https://omim.org/entry/616400 [118]
Orphanet ORPHA:448264 https://www.orpha.net/en/disease/detail/448264 [16]
Disease Ontology DOID:0111711 Listed in OMIM clinical synopsis. [227]
MedGen C4225339, UID 895056 https://www.ncbi.nlm.nih.gov/medgen/895056 [18]
MeSH D007645, Keratoderma, Palmoplantar Broad parent descriptor; no dedicated focal-TRPV3 MeSH term. [212]
SNOMED CT 706885006, palmoplantar keratoderma Broad clinical concept; a dedicated FNEPPK2 code was not identified. [406]
ICD-10 Q82.8, other specified congenital malformations of skin Common umbrella code for hereditary PPK; not specific to FNEPPK2. [216][217]
ICD-11 EC20.3Z, other specified hereditary palmoplantar keratoderma Best-fitting umbrella category; no uniquely indexed FNEPPK2 code was identified. [216]

Preferred synonyms

Synonym Scope
Palmoplantar keratoderma, nonepidermolytic, focal 2 Exact OMIM phenotype
FNEPPK2 Exact abbreviation
Isolated focal non-epidermolytic palmoplantar keratoderma Orphanet/MONDO preferred label
Focal non-epidermolytic palmoplantar keratoderma due to TRPV3 Unambiguous descriptive label
Focal plantar keratoderma due to TRPV3 Used in later clinical literature, but may describe a narrower plantar-only presentation

“Hereditary painful callosities,” “keratosis palmoplantaris nummularis,” and generic “focal PPK” may instead refer to KRT6C- or KRT16-related disease and should not be treated as exact synonyms without molecular confirmation. [424]

1.3 Evidence provenance

The entry is based on:

  1. Individual-level human case data: principally a Chinese father and son, with segregation, biopsy, omics, and in-vitro functional studies (PMID 25285920).
  2. A later individual case report: PMID 32314439.
  3. Aggregated disease-level resources: OMIM, Orphanet, MONDO, MedGen, ClinVar and expert gene panels.

It is not based on population EHR aggregation or a disease registry.

2. Etiology

2.1 Causal factor

The established cause is a heterozygous germline activating missense variant in TRPV3. In the defining family, p.Gln580Pro arose de novo in the father and was transmitted to his affected son, demonstrating vertical autosomal-dominant transmission. Transfected HEK293T cells expressing mutant TRPV3 had increased intracellular Ca²⁺ relative to wild type. [46][93]

TRPV3 encodes a warmth-sensitive, Ca²⁺-permeable, nonselective cation channel expressed especially in keratinocytes. It forms a fourfold-symmetric tetramer, with each subunit containing six transmembrane helices. [369][370]

2.2 Risk and protective factors

Factor class Current evidence
Causal genetic factor Heterozygous GOF TRPV3 variant; strongest exact-disease evidence is p.Gln580Pro.
Family history An affected parent confers a theoretical 50% transmission probability for each pregnancy, assuming heterozygosity and full germline representation.
De novo occurrence Demonstrated in the father of the canonical family. [83]
Mechanical pressure/friction Likely determines lesion localization and severity; focal PPK generally arises over mechanically stressed pressure points. [409][424]
Warmth Biologically plausible symptom modifier because TRPV3 is warmth-activated, but disease-specific quantitative exposure data are unavailable. [64][404]
Age/sex/ethnicity No validated susceptibility effect. Two affected males in one Chinese family cannot establish male predominance or an ethnic association.
Toxins, smoking, alcohol, diet, occupation No evidence that these cause the Mendelian disorder. High-friction occupations may aggravate established lesions.
Infectious agents None are causal. Fissures may permit secondary bacterial or fungal infection.
Protective genetic variants/modifiers None established.
Protective environmental factors No controlled evidence; reducing repetitive pressure/friction is rational symptomatic prevention, not prevention of the genotype.

2.3 Gene–environment interaction

The best-supported model is that constitutive genetically enhanced TRPV3 activity creates a susceptible epidermis, while repetitive pressure, friction, weight bearing, and possibly warmth amplify local calcium signaling, keratinocyte turnover, pain, and callus formation. The localization mechanism is biologically plausible but has not been experimentally demonstrated specifically for p.Gln580Pro.

There are no published FNEPPK2 GWAS, formal interaction analyses, susceptibility loci, or validated modifier genes.

3. Phenotypes

Because the defining family contains only two affected individuals, percentages would be misleading. “2/2” below describes that family, not a population frequency.

Phenotype Type and characteristics Frequency/evidence Suggested HPO
Focal/patchy palmoplantar hyperkeratosis Physical sign; localized plaques on palms and soles rather than diffuse disease; chronic Defining feature, 2/2 canonical cases HP:0007497 focal friction-related palmoplantar hyperkeratosis; HP:0000982 palmoplantar keratoderma [406][409]
Non-epidermolytic PPK Histopathologic sign; absence of epidermolytic degeneration Defining diagnostic qualifier HP:0007404 nonepidermolytic palmoplantar hyperkeratosis [405]
Prominent hyperkeratosis/acanthosis Biopsy sign: thick stratum corneum and stratum spinosum Reported in defining disease description HP:0000962 hyperkeratosis; HP:0032243 acanthosis, if supported locally
Reduced stratum granulosum Histologic abnormality Reported No precise widely used HPO term; encode as pathology text
Suprabasal cell disadhesion Histologic sign Reported HP:0008066 abnormal blistering of skin only if clinically present; otherwise textual annotation
Elongated rete ridges Histologic sign Reported No specific HPO term
Sparse dermal lymphocytes Histologic/laboratory pathology finding Reported No specific disease-level HPO term
Palmoplantar pain Symptom, especially in the 2020 “painful focal plantar” report; potentially pressure- or warmth-provoked Not quantified for canonical family HP:0012531 pain; consider HP:0025538 plantar pain
Fissuring Physical manifestation common to focal PPK, potentially painful and infection-prone Not established in every FNEPPK2 patient HP:0010646 skin fissures
Erythromelalgia-like warmth/pain Possible allelic TRPV3 manifestation, better documented in atypical Olmsted phenotypes Not part of the defining isolated family HP:0032147 erythromelalgia
Absence of major extracutaneous abnormalities Negative phenotype: no classic periorificial plaques, alopecia, mutilation, or major nail changes in the defining family 2/2 defining cases Record as explicit negative HPO annotations

Orphanet’s disease-level pathology includes “prominent hyperkeratosis, thickened stratum spinosum with reduced stratum granulosum, disadhesion of cells in the suprabasal layers, elongation of rete ridges, and sparse lymphocyte infiltration in the dermis.” [47]

Onset, severity, and progression

  • The exact age at onset for both defining patients was not available in the PubMed record, which has no abstract.
  • The father retained only focal PPK at age 37, supporting a relatively mild, non-mutilating course for p.Gln580Pro. [139]
  • Focal hereditary PPK as a broader category usually begins in childhood and may become painful after mechanical stress, but this must be tagged as phenotype-group evidence, not exact-disease frequency. [50]
  • A 2020 report establishes that some TRPV3-related focal plantar disease is painful (PMID 32314439), but its publicly accessible record does not disclose the exact variant or complete clinical course. [121][196]

Quality-of-life impact

No FNEPPK2-specific validated DLQI, EQ-5D, SF-36, or PROMIS study exists. Expected burden includes pain on walking, reduced mobility, difficulty standing or working, impaired grip if palms are affected, shoe intolerance, and time spent on debridement and topical treatment.

For context only, a mixed palmoplantar-dermatosis study reported mean DLQI 8.53 and CDLQI 8.28 in its PPK subgroup, but this is not an FNEPPK2-specific estimate. [326]

4. Genetic and molecular information

4.1 Causal gene

Item Annotation
Gene TRPV3, transient receptor potential cation channel subfamily V member 3
HGNC HGNC:18084
NCBI Gene 162514
Ensembl ENSG00000167723
UniProt Q8NET8
OMIM gene 607066
Location 17p13.2; GRCh38 chr17:3,510,502–3,557,812
Protein Ca²⁺-permeable nonselective cation channel; homotetramer with six transmembrane helices per monomer
Primary cell expression Epidermal and follicular keratinocytes; lower-level expression in sensory and other tissues

Identifiers and chromosomal localization are supported by NCBI/Alliance/UniProt-linked resources. [362][365][374]

4.2 Pathogenic variant

Variant field p.Gln580Pro
Transcript NM_145068.4
HGVS coding c.1739A>C
Protein p.(Gln580Pro), Q580P
dbSNP rs786205869
Genomic description in original report GRCh37 chr17:3,427,496 T>G, reflecting the reverse-strand orientation
Exon/domain Exon 13; cytosolic S4–S5 linker
Variant class Missense SNV
Origin Germline; de novo in father, inherited by son
Inheritance Autosomal dominant
Functional consequence Gain of function, increased intracellular Ca²⁺
ClinVar status Reported as pathogenic in current aggregated variant resources
OMIM allelic variant 607066.0005
Population frequency No credible common-population frequency was identified; the rarity, de novo observation, segregation and functional effect support pathogenicity. A current exact gnomAD count should be rechecked before production ingestion.
Evidence level Limited human case count but supportive segregation, de novo occurrence, functional assay, transcriptomics, proteomics and immunohistochemistry

The variant lies at a conserved residue in the linker between transmembrane segments S4 and S5, a region central to channel gating. [93][113]

4.3 Other variants and allelic disorders

Other activating TRPV3 variants—such as p.Gly573Cys, p.Gly573Ser, p.Trp692Gly, p.Leu673Phe and others—usually produce Olmsted syndrome or an Olmsted-like phenotype, not necessarily isolated FNEPPK2. Severe variants are associated with mutilating PPK, periorificial plaques, alopecia, warmth-induced pain and pruritus. p.Gln580Pro has a comparatively mild focal phenotype. [167][180]

Accordingly, a laboratory finding of a different TRPV3 variant should be interpreted against the complete allelic spectrum rather than automatically assigned to MONDO:0014622.

4.4 Modifier, epigenetic and chromosomal findings

Category Finding
Modifier genes None validated for FNEPPK2
Epigenetic signature None reported
DNA methylation/histone changes No disease-specific studies
Copy-number/structural variants None established
Aneuploidy/translocation/inversion Not implicated
Somatic mosaicism Not reported for TRPV3-FNEPPK2; somatic mosaicism is described in some KRT16 disorders but is a different entity
Anticipation Not reported and not expected for a missense channelopathy

5. Environmental and lifestyle information

Domain Assessment
Mechanical exposure Pressure, friction, prolonged walking, standing, and repetitive hand use are expected to aggravate localization and pain.
Temperature Warmth is a plausible trigger because TRPV3 activation begins in the innocuous-warm range; disease-specific challenge studies are lacking. [64][440]
Humidity/sweating May promote maceration, fissuring or secondary infection, but no FNEPPK2-specific evidence exists.
Smoking/alcohol/diet/exercise No causal associations. Exercise can mechanically aggravate plantar disease.
Occupational factors Manual labor, prolonged standing and restrictive footwear may worsen manifestations but do not cause the Mendelian disorder.
Toxins/radiation/pollution Not implicated.
Infectious agents No initiating pathogen. Bacteria or fungi may secondarily colonize fissures.
Drugs No drug is known to induce inherited FNEPPK2; acquired drug-induced PPK is a differential diagnosis.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

  1. Heterozygous germline TRPV3 p.Gln580Pro alters the S4–S5 channel-gating linker, which leads to increased channel activity.
  2. Increased TRPV3 activity leads to excessive Ca²⁺ influx and elevated intracellular Ca²⁺ in epidermal keratinocytes, demonstrated in mutant-transfected HEK293T cells.
  3. Abnormal Ca²⁺ signaling leads to dysregulation of keratinocyte proliferation, terminal differentiation and survival, supported by lesional transcriptomic/proteomic data and keratin-marker immunohistochemistry.
  4. Dysregulated differentiation leads to persistence/expansion of KRT14-positive basal-like cells and reduced KRT10-positive differentiated suprabasal cells.
  5. The differentiation imbalance leads to reduced expression of proteins involved in terminal differentiation, tight junctions, gap junctions and desmosomes, while proliferation- and cell-death-associated proteins increase.
  6. Impaired differentiation and intercellular adhesion lead to acanthosis, suprabasal disadhesion, altered granular-layer development and excessive cornified material.
  7. Excess cornification leads to focal hyperkeratotic palmoplantar plaques.
  8. Mechanical load at palmar/plantar pressure points likely amplifies local injury and repair signaling, resulting in focal distribution—this localization step is inferred rather than directly demonstrated for p.Gln580Pro.
  9. Branch—pain: hyperkeratosis/fissuring plus keratinocyte release of ATP, inflammatory mediators and neuroactive substances may activate cutaneous nociceptive pathways, leading to pressure- or warmth-provoked pain; this branch is supported by broader TRPV3 evidence but not fully demonstrated in FNEPPK2.
  10. Branch—inflammation: cell stress/death and barrier disruption may produce sparse dermal lymphocytic inflammation; marked systemic immune activation is not a defining feature.

The original primary report concluded from functional and omics findings that p.Gln580Pro disrupts the balance between keratinocyte proliferation and differentiation (PMID 25285920). [162]

6.2 Molecular and cellular detail

Normal TRPV3 participates in epidermal calcium signaling and can form a functional complex with TGF-α/EGFR. Activation influences EGFR signaling and calcium-dependent transglutaminase activity, thereby coordinating proliferation, terminal differentiation, cornified-envelope formation and barrier repair. [142][275]

In the p.Gln580Pro lesions:

  • differentiation and cell-junction proteins were reduced;
  • proliferation and cell-death proteins were increased;
  • KRT14 staining extended through a broader basal layer;
  • KRT10 staining was weaker in the spinous layer. [137][138]

Potential downstream pathways supported principally by broader TRPV3 studies include:

  • Ca²⁺/calmodulin and CaMKII signaling;
  • TGF-α/ADAM17/EGFR signaling;
  • PI3K–AKT and NF-κB signaling;
  • calcium-dependent transglutaminase-1 activity;
  • ATP-mediated signaling to sensory neurons;
  • apoptosis and inflammatory mediator release.

EGFR/mTORC2/NF-κB involvement is best regarded as broader hyperactive-TRPV3 biology, not yet directly established in p.Gln580Pro FNEPPK2. [61]

6.3 Suggested GO and Cell Ontology annotations

Biological entity/process Suggested ontology term
Keratinocyte CL:0000312
Epidermal keratinocyte CL:4052061
Suprabasal keratinocyte CL:4033013 [442]
Calcium channel activity GO:0005262
Ion channel activity GO:0005216
Plasma membrane GO:0005886
Integral component of plasma membrane GO:0005887
Calcium-ion transport GO:0006816
Response to temperature stimulus GO:0009266
Keratinocyte differentiation GO:0030216
Positive regulation of keratinocyte differentiation GO:0045618
Cell population proliferation GO:0008283
Apoptotic process GO:0006915
Cell–cell adhesion GO:0098609
Desmosome GO:0030057
Tight junction GO:0070160
Cornification GO:0070268
Epidermis development GO:0008544

Core TRPV3 annotations include calcium-channel activity and localization to plasma membrane/lysosome. [437][438]

6.4 Molecular profiling and advanced technologies

Modality Disease-specific evidence
Transcriptomics Performed in the defining study; altered keratinocyte proliferation/differentiation transcriptional programs
Proteomics Performed; reduced differentiation/junction proteins and increased proliferation/cell-death proteins
Immunohistochemistry Broader KRT14-positive layer and weaker KRT10 expression
Metabolomics/lipidomics No FNEPPK2-specific data
Single-cell RNA sequencing No disease-specific study
Spatial transcriptomics None
Patient-derived organoids/iPSCs None reported
CRISPR/RNAi screens None specific to FNEPPK2
Structural biology General TRPV3 cryo-EM structures exist; a recent structure database lists human TRPV3-Q580P, but this is not yet a clinical diagnostic assay. [113]

7. Anatomical structures affected

Level Affected structure Suggested ontology
Organ Skin UBERON:0002097
Primary site Palmar and plantar skin UBERON:0013776, skin of palmar/plantar part of autopod
Palm Palmar skin UBERON:0001514
Sole Plantar skin UBERON:0001516
Tissue Keratinized stratified squamous epithelium/epidermis UBERON:0001003, epidermis
Epidermal layers Basal, spinous, granular and cornified layers Textual or layer-specific UBERON terms
Main cell Keratinocyte CL:0000312
Secondary cells Sparse dermal lymphocytes; sensory nerve endings potentially involved in pain CL:0000542 lymphocyte; nociceptor annotations where demonstrated
Subcellular Plasma membrane TRPV3 channel GO:0005886
Secondary subcellular systems Cell junctions/desmosomes/tight junctions GO:0030057; GO:0070160
Lateralization Generally bilateral/symmetric is expected for inherited PPK, but exact lateralization frequency is unavailable

There is no established internal-organ involvement in isolated FNEPPK2.

8. Temporal development

Feature Current understanding
Onset Exact onset in the canonical patients is not stated in the accessible PubMed record. Broader hereditary focal PPK commonly begins in infancy or childhood.
Pattern Chronic and insidious rather than acute
Early stage Localized thickening at pressure/friction sites
Intermediate stage Increasing compact hyperkeratosis, potentially pain or fissuring
Advanced stage Persistent painful plaques may impair walking or grip; mutilation is not characteristic of the defining p.Gln580Pro phenotype
Progression Mild/slow or mechanically fluctuating; father remained focal at age 37 [139]
Duration Presumed lifelong
Remission No spontaneous-remission data; symptomatic reduction requires ongoing treatment
Critical periods Early pressure management may reduce secondary callus, pain and fissures, but no formally validated window exists

No accepted staging system or longitudinal natural-history cohort exists.

9. Inheritance and population

9.1 Inheritance

Characteristic Assessment
Mode Autosomal dominant, monoallelic
Recurrence risk 50% for offspring of a heterozygous affected person
De novo risk Demonstrated; p.Gln580Pro arose de novo in the father
Penetrance Both known carriers in the defining family were affected, but the sample is insufficient to establish complete penetrance
Expressivity Likely variable across TRPV3 alleles; p.Gln580Pro is mild compared with classic Olmsted variants
Anticipation Not reported
Germline mosaicism Not reported; low residual recurrence risk after an apparently de novo case cannot be excluded
Consanguinity Not relevant to the canonical dominant family
Founder effect None established
Carrier frequency Unknown; for a dominant disorder, “carrier” generally means an at-risk heterozygous individual

9.2 Epidemiology

No defensible prevalence or incidence estimate exists for the exact MONDO entity. Orphanet labels it rare but does not provide a numeric estimate. [376]

The defining OMIM evidence originally involved one Chinese family with two affected males. Consequently:

  • prevalence per 100,000: unknown;
  • annual incidence: unknown;
  • sex ratio: unknown;
  • geographic or ethnic enrichment: not established;
  • age distribution: unknown.

Precise prevalence estimates are generally unavailable for hereditary PPKs and mild cases may be underdiagnosed. [383]

For context, a 2024 Danish PPK cohort included 142 participants from 76 families and achieved a molecular diagnosis in 63/76 families (83%), but it did not identify TRPV3 among the reported causal genes and therefore supplies diagnostic-context—not FNEPPK2 prevalence—data. The cohort was 63% female, with median age 52 years, range 18–92 (published online 4 December 2024; DOI 10.1001/jamadermatol.2024.4824). [331][332]

10. Diagnostics

10.1 Recommended workflow

  1. Clinical morphology: document focal versus diffuse or punctate lesions; palmar/plantar distribution; pressure dependence; pain, blistering and fissures.
  2. History: childhood onset, affected relatives, de novo presentation, occupational friction, medication exposure, infection and systemic symptoms.
  3. Examine extracutaneous sites: nails, hair, teeth, oral/periorificial mucosa, joints, hearing, heart and esophagus to detect syndromic mimics.
  4. Exclude acquired causes: fungal microscopy/culture, patch testing when dermatitis is suspected, and selected laboratory studies guided by history.
  5. Skin biopsy: confirm non-epidermolytic hyperkeratosis and assess acanthosis, granular-layer changes and cell adhesion.
  6. Molecular testing: sequence a multigene hereditary PPK panel including TRPV3, KRT16, KRT6C, KRT6A, KRT6B, KRT17, DSG1, DSP, KRT1, KRT9, AAGAB and other phenotype-relevant genes.
  7. Segregation and variant interpretation: confirm candidate variants by orthogonal testing and test parents/affected relatives.
  8. WES/WGS: use when panel testing is negative, the phenotype is atypical, or structural/noncoding variants are suspected.

Histopathology and molecular testing are recommended because clinically similar PPKs can have different molecular causes. [421] A recent cohort used WES or WGS with an in-silico PPK panel, plus targeted Sanger testing, and achieved an 83% family-level diagnostic yield across PPKs. [425]

10.2 Test utility

Test Utility in FNEPPK2
Targeted TRPV3 sequencing Appropriate when focal PPK is isolated and TRPV3 channelopathy is strongly suspected
Multigene PPK panel Preferred first-line molecular test because of major phenotypic overlap
WES Useful after negative panel testing or for atypical disease
WGS Useful for unresolved cases, CNVs, noncoding variants and research discovery
CMA Low expected yield for an isolated single-gene phenotype; consider only with developmental anomalies
Karyotype/FISH Not routinely indicated
Mitochondrial testing Not indicated
Repeat-expansion testing Not indicated
RNA sequencing Research/variant-resolution tool; not routine
Proteomics/metabolomics/liquid biopsy No diagnostic role
Imaging/electrophysiology Not routine unless symptoms suggest another disorder

10.3 Histopathology

Expected findings are:

  • prominent hyperkeratosis;
  • thickened spinous layer/acanthosis;
  • reduced granular layer;
  • suprabasal disadhesion;
  • elongated rete ridges;
  • sparse dermal lymphocytes;
  • absence of classic epidermolytic degeneration. [47]

10.4 Differential diagnosis

Differential Distinguishing features
KRT16-FNEPPK1, OMIM 613000 Focal painful callosities at friction sites; may include follicular/orogenital keratosis; keratin structural defect rather than ion channel GOF
KRT6C-PPK, OMIM 615735 Plantar-predominant focal/diffuse disease, painful blistering, minimal nail changes [17]
Pachyonychia congenita Thickened/dystrophic nails, plantar pain, oral leukokeratosis; genes KRT6A/B/C, KRT16, KRT17
Olmsted syndrome Severe progressive/mutilating PPK, periorificial plaques, alopecia, nail abnormalities, pseudoainhum, warmth-induced pain/pruritus
Striate PPK Linear palmar keratosis along flexor surfaces; DSG1, DSP or KRT1
Punctate PPK Numerous small discrete “raindrop” keratoses; frequently AAGAB
Epidermolytic PPK Diffuse sharply demarcated PPK with epidermolytic histology; often KRT9 or KRT1
Tylosis with esophageal cancer Focal PPK plus oral/esophageal leukokeratosis and high esophageal SCC risk; RHBDF2
Acquired calluses/corns Direct mechanical relationship, no Mendelian segregation, normal intervening skin
Tinea manuum/pedis Positive fungal microscopy/culture
Palmoplantar psoriasis/eczema Erythema, inflammation, scale, pruritus; biopsy/clinical course differs
Acquired paraneoplastic/drug-related PPK Adult onset and temporal relationship to malignancy or medication

10.5 Screening

  • No population or newborn screening is recommended.
  • Cascade testing is appropriate after identifying a familial pathogenic variant.
  • Predictive testing of asymptomatic relatives should follow genetic counseling.
  • Prenatal diagnosis and preimplantation genetic testing are technically possible once the familial variant is known.

11. Outcome and prognosis

Outcome domain Assessment
Survival Expected to be normal for isolated FNEPPK2
Life expectancy No evidence of reduction
Disease-specific mortality None reported
Malignancy risk No established increased risk for isolated TRPV3-FNEPPK2; do not extrapolate the esophageal-cancer risk of RHBDF2 tylosis
Chronic morbidity Painful calluses, fissures, difficulty walking/standing, impaired hand function, footwear limitations
Complications Secondary bacterial/fungal infection through fissures; altered gait and activity avoidance
Recovery Genetic predisposition is lifelong; lesions can improve symptomatically but recurrence is expected
Prognostic factors Mechanical load, lesion thickness, fissuring, pain and exact TRPV3 allele
Molecular prognostic biomarkers None validated

The hereditary PPK treatment review concluded that hPPK is generally not life-threatening but can impair mobility and cause discomfort or intractable pain; evidence is dominated by case reports and small heterogeneous series rather than randomized trials. [318]

12. Treatment

12.1 Current standard care

No treatment is approved specifically for MONDO:0014622, and no curative therapy exists for hereditary PPK. [301]

Treatment/intervention Use and evidence Important adverse effects/limitations Suggested NCIT annotation
Emollients/occlusive moisturizers First-line softening of compact keratin Temporary effect; frequent application Emollient Preparation
Urea Topical humectant/keratolytic, commonly 10–40% depending on tolerance Burning on fissured skin Urea; Keratolytic Agent
Salicylic acid Keratolytic, often around 5–10%; DermNet gives 6% as an example Irritation; systemic salicylate risk if extensive/occluded, especially in children Salicylic Acid
Lactic acid/ammonium lactate Keratolytic and moisturizer Stinging/irritation Lactic Acid
Propylene glycol under occlusion Softens hyperkeratosis Irritant/contact dermatitis Propylene Glycol
Mechanical paring/debridement Reduces plaque thickness and focal pressure Cuts, bleeding, infection if excessive Debridement
Pressure redistribution Cushioned footwear, orthotics, gloves, activity modification Does not change molecular disease Orthotic Device; Supportive Care
Topical retinoid May reduce limited hyperkeratosis Irritation; avoid during pregnancy Retinoid
Calcipotriol Occasionally used empirically Irritation; limited evidence Calcipotriol
Oral acitretin/isotretinoin For severe refractory hyperkeratosis; responses vary Teratogenicity, dryness, hyperlipidemia, hepatotoxicity; may increase fragility and pain Acitretin; Isotretinoin
Antibiotic/antifungal therapy Only for documented secondary infection Organism/drug-specific adverse effects Anti-Infective Agent
Analgesia Individualized for painful lesions Does not treat hyperkeratosis Analgesic Agent
Surgery/excision/grafting Rare, last-resort intervention Recurrence, scarring and inconsistent outcomes Surgical Procedure; Skin Grafting

Mechanical debridement and topical urea, salicylic acid or lactic acid are standard first-line measures. Oral retinoids may improve hyperkeratosis, but increased skin fragility can limit their use. [305] Topical treatment must generally be continued because it reduces manifestations rather than curing the disorder. [310]

12.2 Mechanism-targeted and experimental therapy

EGFR inhibition

In three patients with severe TRPV3-related Olmsted syndrome—not isolated FNEPPK2—erlotinib produced disappearance of hyperkeratosis and pain within three months, sustained during continued treatment. This supports the relevance of TRPV3–EGFR coupling but remains off-label and potentially disproportionate for mild focal disease (PMCID PMC6990711). [201]

Erlotinib can cause acneiform rash, diarrhea, paronychia, hepatic toxicity and rare interstitial lung disease; specialist risk–benefit review is essential.

Direct TRPV3 inhibitors

Topical KM-001, a TRPV3 inhibitor, has been studied in pachyonychia congenita and punctate PPK1—not FNEPPK2—in phase 1 studies NCT05435638 and NCT05956314. Company-reported 2024 results described improvement in at least one prespecified parameter in 88% of eight UK completers and 86% of seven Israeli completers, with only mild treatment-emergent events; these small, open-label results cannot establish efficacy in TRPV3-FNEPPK2. [289][297]

As of the review date:

  • no interventional trial was identified as specifically enrolling MONDO:0014622; [291]
  • oral selective TRPV3 inhibitors are under development for Olmsted syndrome and severe keratodermas;
  • no gene, RNA or cell therapy has reached clinical testing for FNEPPK2.

12.3 Practical algorithm

  1. Reduce friction/pressure and optimize footwear.
  2. Daily emollient plus urea, lactic acid or cautious salicylic acid.
  3. Regular professional or carefully supervised paring.
  4. Treat fissures and confirmed infection.
  5. Add topical retinoid or calcipotriol for refractory limited plaques.
  6. Consider low-dose systemic retinoid only for substantial disability.
  7. For severe molecularly confirmed TRPV3 disease, discuss specialist access to trials or exceptional targeted therapy; erlotinib evidence comes from severe Olmsted syndrome, not isolated FNEPPK2.

No FNEPPK2-specific pharmacogenomic guidance exists.

13. Prevention

Prevention level Intervention
Primary prevention The genotype cannot be prevented after conception. Reproductive options include donor gametes, prenatal testing and preimplantation genetic testing for a known familial variant.
Secondary prevention Early dermatologic and genetic evaluation of symptomatic relatives; cascade variant testing
Tertiary prevention Reduce friction/pressure, maintain skin hydration, pare thick keratin safely, treat fissures early, and monitor for secondary infection
Behavioral Cushioned shoes, moisture-wicking socks, gloves for repetitive manual work, gradual activity adjustment
Environmental Avoid poorly fitting footwear and repetitive high-pressure tasks where feasible
Counseling Explain autosomal-dominant 50% transmission risk, possibility of de novo occurrence, uncertain penetrance estimates and allelic overlap with Olmsted syndrome
Immunization/prophylaxis No disease-specific vaccine or prophylactic medication
Public health No population screening program is justified by present evidence

14. Other species and naturally occurring disease

No natural animal disorder caused by the exact human TRPV3 p.Gln580Pro variant has been established. The best natural comparative disease is KRT16-related FNEPPK1 in dogs, which models a related but molecularly distinct human focal PPK.

Species/model Gene and variant Phenotype and relevance Limitations
Dog, Canis lupus familiaris; NCBI Taxon 9615; Dogue de Bordeaux Canine KRT16, NCBI Gene 490978; c.[1147_1148delinsCGGA;1165del], p.(Val383ArgfsTer11); OMIA:002088-9615 Painful focal non-epidermolytic footpad hyperkeratosis, fissures, infection and lameness; natural large-animal model of human FNEPPK1; PMID 25521457 Autosomal recessive in dogs and KRT16-based, whereas human MONDO:0014622 is dominant TRPV3-GOF disease [256][257]
DS-Nh mouse, Mus musculus; Taxon 10090 Trpv3 p.Gly573Ser GOF Constitutive channel activity, hyperkeratosis, thickened epidermal layers, abnormal hair and dermatitis; models hyperactive TRPV3 biology Does not reproduce isolated palmoplantar localization; mice lack human-like palms/soles [271][274]
WBN/Kob-Ht rat, Rattus norvegicus; Taxon 10116 Trpv3 p.Gly573Cys GOF Hairlessness and dermatitis-like disease Not a focal PPK model [271]
Trpv3-knockout mouse Loss of function Defective terminal differentiation, reduced cornified-envelope density and impaired barrier Opposite direction of effect from p.Gln580Pro GOF, useful mainly for normal gene function [278][281]

There is no zoonotic potential or cross-species transmission; these are inherited, noninfectious disorders.

15. Model organisms and experimental systems

Model type Model Findings/applications Principal limitation
Human clinical p.Gln580Pro father and son Defines genotype–phenotype relationship and mild focal presentation Only two canonical affected people
Heterologous cellular HEK293T cells expressing wild-type or Q580P TRPV3 Mutant increased intracellular Ca²⁺, establishing GOF Non-keratinocyte cell line
Human tissue Lesional/nonlesional skin transcriptomics, proteomics and IHC Differentiation/junction proteins down; proliferation/cell-death proteins up; KRT14 expanded and KRT10 reduced Tiny sample size and no independent cohort
Spontaneous GOF mouse DS-Nh Trpv3 G573S Channel hyperactivity, epidermal hyperplasia, hyperkeratosis, itch/dermatitis and altered sensory behavior Allele and tissue distribution differ from FNEPPK2
Spontaneous GOF rat WBN/Kob-Ht G573C Confirms conserved GOF effect Hair/dermatitis-dominant phenotype
Knockout mouse Trpv3−/− Establishes requirement for terminal differentiation and barrier formation Models loss rather than gain of function
Natural canine model Recessive KRT16 Dogue de Bordeaux Footpad hyperkeratosis and fissuring closely mimic focal mechanical disease Different gene and inheritance
Structural model Cryo-EM/biophysical TRPV3 systems Channel gating, S4–S5 linker function and antagonist design Structural effects do not alone predict human severity
Future model Patient-derived keratinocytes, organotypic palmoplantar epidermis or CRISPR Q580P knock-in Could test pressure, temperature, EGFR and direct TRPV3 inhibitors No validated FNEPPK2-specific platform yet reported

Suggested resources are MGI (MGI:2181407 for mouse Trpv3), IMSR for mouse strains, OMIA for the canine disorder, and NCBI Gene/Alliance for orthology. MGI currently links Trpv3 to human FNEPPK2 but does not list a mouse model that precisely reproduces the human focal phenotype. [58]

Recent developments and current expert interpretation

2023–2024 developments

  1. A 2023 review emphasized that TRPV3 is a nonselective cation channel highly expressed in keratinocytes and specifically noted that p.Gln580Pro produces much milder focal PPK than the severe Olmsted variants (published 10 March 2023). [67][167]
  2. A 2023 ion-channel/pain review connected TRPV3 variants to painful neuropathic and erythromelalgia-like phenotypes, supporting neurocutaneous mechanisms but not providing FNEPPK2-specific prevalence data. [192]
  3. A July 2024 review highlighted the reciprocal positive-feedback relationship between TRPV3 calcium signaling and TGF-α/EGFR pathways. [71]
  4. A December 2024 review of TRPV3-related Olmsted syndrome summarized genotype–phenotype correlations and the p.Gln580Pro omics findings. It reported that variants with stronger gating effects generally produce more severe keratinization than p.Gln580Pro. [63][180]
  5. The 2024 Danish PPK cohort demonstrated the practical value of deep phenotyping plus WES/WGS panels, with an 83% family-level diagnostic yield, although no TRPV3 diagnosis was reported. [331]

Expert synthesis

Current evidence supports treating MONDO:0014622 as the mild focal end of the TRPV3 gain-of-function channelopathy spectrum, while keeping it distinct from classic Olmsted syndrome for clinical coding. The strongest mechanistic evidence is the combination of:

  • de novo occurrence and parent-to-child segregation;
  • increased mutant-channel calcium activity;
  • altered lesional differentiation and junctional programs;
  • concordant histology and keratin-marker abnormalities.

The principal uncertainties are the very small number of molecularly characterized patients, unknown penetrance and epidemiology, absence of prospective natural-history data, and lack of treatment trials specific to FNEPPK2.

Primary evidence quotations

The two principal disease-specific publications are letters with no PubMed abstract, so an exact abstract quotation is not available. Their titles provide the most direct author-level statements:

  • He et al., J Invest Dermatol, epub 6 October 2014; print March 2015, PMID 25285920, DOI 10.1038/jid.2014.429: “A gain-of-function mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family.” [79]
  • Peters et al., J Eur Acad Dermatol Venereol, first published 20 April 2020, PMID 32314439, DOI 10.1111/jdv.16498: “Mutation in TRPV3 causes painful focal plantar keratoderma.” [121][390]

A review-level treatment summary states: “No specific or curative therapy exists for hereditary palmoplantar keratoderma” and notes potentially profound quality-of-life impairment, pain and functional limitation. [301]

Knowledge-base curation recommendations

  1. Use MONDO:0014622 → OMIM:616400 → ORPHA:448264 → TRPV3 as the primary mapping.
  2. Store p.Gln580Pro as the canonical disease variant:
  3. NM_145068.4:c.1739A>C;
  4. NP_659529.1:p.(Gln580Pro), subject to transcript verification;
  5. rs786205869;
  6. germline, heterozygous, autosomal dominant, GOF.
  7. Do not merge OMIM 613000/KRT16 or OMIM 615735/KRT6C into this entry; represent them as differential/phenotypically related diseases.
  8. Record HP:0007497 as the most specific core phenotype and HP:0007404 as the non-epidermolytic qualifier.
  9. Represent pressure/friction aggravation, pain, fissures and childhood onset as lower-confidence or broader-focal-PPK annotations unless supported in an individual FNEPPK2 case.
  10. Tag mechanistic assertions by evidence:
  11. human case tissue: transcriptomics/proteomics/IHC;
  12. in vitro: mutant HEK293T calcium assay;
  13. model organism: GOF mouse/rat and KO mouse;
  14. inferred: mechanical localization, nociceptive ATP signaling and detailed EGFR downstream branches.
  15. Mark prevalence, incidence, sex ratio, carrier frequency, validated penetrance, protective factors, epigenetic signatures and prognostic biomarkers as unknown/not available.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 10
On topic 2
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • DOI:10.1111/ddg.150_12930 (1 mention) - Keratosis palmoplantaris: klinische und genetische Aspekte
  • shared terms: ppk

Weighed against this report's own most characteristic terms: trpv3, focal, fneppk2, ppk, pain, variant, gln580pro, disease, pressure, phenotype, isolated, olmsted, gene, palmoplantar, painful, disorder, hyperkeratosis, keratinocyte, mondo, plantar.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 41
Resolved 35
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 5
Terms whose name was checked 22
Terms named correctly 14
Terms named as a different term 5
Terms whose name is worth a second look 3

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:0014622 (12 mentions) - the report calls it "MONDO"; MONDO calls it isolated focal non-epidermolytic palmoplantar keratoderma
  • DOID:0111711 (1 mention) - the report calls it "Disease Ontology"; DOID calls it focal nonepidermolytic palmoplantar keratoderma 2
  • GO:0005887 (1 mention) - the report calls it "Integral component of plasma membrane"; GO calls it GO_0005887
  • UBERON:0001514 (1 mention) - the report calls it "Palmar skin"; UBERON calls it descending aorta
  • UBERON:0001516 (1 mention) - the report calls it "Plantar skin"; UBERON calls it abdominal aorta

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005887 (GO_0005887) (1 mention) - replaced by GO:0005886

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0005216 (1 mention) - the report calls it "Ion channel activity"; GO calls it monoatomic ion channel activity, and lists "ion channel activity" among its other names
  • GO:0005886 (2 mentions) - the report calls it "Plasma membrane", "Plasma membrane TRPV3 channel"; GO calls it plasma membrane
  • UBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0005886 - called "Plasma membrane", "Plasma membrane TRPV3 channel"

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, OMIA, MGI, OMIM.