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

Preferred synonyms

“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

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.

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

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

4.2 Pathogenic variant

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

5. Environmental and lifestyle information

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

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

6.4 Molecular profiling and advanced technologies

7. Anatomical structures affected

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

8. Temporal development

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

9. Inheritance and population

9.1 Inheritance

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

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

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

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]

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

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.

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

15. Model organisms and experimental systems

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.

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.

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.