Palmoplantar Keratoderma-Deafness Syndrome: Research Report

Verification status. I ran two searches. The evidence base is the OMIM, GeneReviews, Bedoukian 2021 and PMC pages those searches returned, plus a PubMed E-utilities query. I did not open full texts. PMIDs that I did not retrieve are marked [PMID not verified]. Run just fetch-reference on them and quote snippets from the cached files. Do not copy snippets or CURIEs from this report. Every HP, GO, CL, UBERON, NCIT and CHEBI suggestion below is a lead from memory and must be looked up before binding. I have included no CURIEs for that reason.

Scope. I did not confirm that MONDO:0007852 is the right ID for this concept. Check it with runoak before using it. The OMIM entry is #148350 (autosomal dominant, GJB2). A mitochondrial form is associated with MT-TS1 and sits partly in the separate OMIM mitochondrial-deafness entries. See the lump/split note at the end.

1. Disease Information

• Overview. PPK with deafness is an autosomal dominant condition with sensorineural hearing loss and progressive hyperkeratosis of the palms and soles (OMIM #148350). The hearing loss is slowly progressive and high-frequency.
• Identifiers.
• OMIM #148350.
• MGI/Disease Ontology DOID:0111505 (MGI).
• GenCC curates GJB2 against OMIM:148350 (GenCC).
• Not verified: Orphanet, ICD and MeSH IDs.
• Synonyms. "Keratoderma, palmoplantar, with deafness" is the OMIM title. The related term "Bart-Pumphrey syndrome" is not the same entity. It is a GJB2-associated condition with knuckle pads and leukonychia, and I did not verify it.
• Data source. The data are aggregated disease-level and case-report resources, not EHR-derived.

2. Etiology

• Causes. The condition can be caused by mutation in GJB2 (connexin 26) or in the mitochondrial MT-TS1 gene (OMIM, above).
• Genetic risk factors.
• GJB2 mutations are confined to a narrow spectrum. The affected codons are 59, 73 and 75 (OMIM, above).
• Known variants: p.Gly59Ser (c.175G>A, also reported in a de novo Vohwinkel case, PMC11745274), p.Arg75Gln/Trp, and p.Asp50Asn (reported in KID syndrome, PMC3750395).
• A GJB2 frameshift plus a novel missense variant gave a variable PPK-with-deafness phenotype (Bedoukian 2021, Mol Genet Genomic Med).
• Environmental and protective factors. None are established. Aminoglycoside exposure is a recognized modifier for MT-TS1 and mtDNA hearing loss in general, but I did not verify it for this entity.
• Gene-environment interaction. None documented here.

3. Phenotypes

Frequencies were not retrieved. Suggested HPO terms are to be looked up, not recalled.

Onset, severity and quality-of-life data were not retrieved.

4. Genetic/Molecular Information

• GJB2 (HGNC symbol GJB2). The CURIE is to be looked up, in lowercase hgnc: form. Inheritance is autosomal dominant. Variants are missense at codons 59, 73 and 75. The functional consequence is generally described as a dominant-negative or gain-of-function effect on connexin 26 hemichannels or gap junctions. I did not verify this here.
• MT-TS1 m.7445A>G (mitochondrial tRNA-Ser(UCN)).
• Many relatives in one family had PPK plus deafness with m.7445A>G (OMIM, above).
• In vitro studies indicate an endonucleolytic processing defect, caused by a non-cleavable C at the processing junction (GeneReviews NBK1422).
• A Portuguese family with deafness and PPK carried A7445G (ResearchGate listing). [PMID not verified]
• Modifier genes, epigenetics, chromosomal abnormalities. None documented in what I retrieved.

5. Environmental Information

Nothing disease-specific was found. No infectious agents are implicated.

6. Mechanism / Pathophysiology (causal chains)

GJB2 form 1. A dominant missense variant (codon 59, 73 or 75) alters connexin 26. The change in channel behavior is inferred and not demonstrated here. 2. This leads to disrupted gap-junction or hemichannel function in the cochlea and epidermis. 3. In the cochlea, disrupted potassium and metabolite recycling leads to progressive hair-cell and supporting-cell dysfunction. This step is inferred. 4. The result is slowly progressive high-frequency sensorineural hearing loss. 5. In the epidermis, impaired keratinocyte differentiation and barrier function leads to progressive palmoplantar hyperkeratosis. Palms and soles are affected because GJB2 is highly expressed there. This is inferred.

MT-TS1 form 1. m.7445A>G places a non-cleavable C at the tRNA processing junction. 2. This results in an endonucleolytic processing defect in the mitochondrial tRNA-Ser(UCN) transcript. 3. This is inferred to impair mitochondrial translation and lower oxidative phosphorylation capacity in high-energy tissues. The cochlea is the best-documented target. 4. The result is childhood-onset sensorineural hearing loss. 5. Why only some families develop PPK is unexplained. It may reflect heteroplasmy or nuclear modifiers (speculative).

Candidate GO and CL concepts to look up: gap junction, connexin complex, mitochondrial tRNA processing, keratinocyte differentiation, inner ear hair cell, keratinocyte.

7. Anatomical Structures Affected

• Organs. Skin of the palms and soles (epidermis) and the inner ear (cochlea).
• Cells. Keratinocytes and cochlear hair cells or supporting cells.
• Subcellular. Plasma membrane gap junctions (GJB2) and mitochondria (MT-TS1).
• Lateralization. Bilateral, though I did not verify this.

8. Temporal Development

• Hearing loss is slowly progressive.
• PPK is progressive.
• Detailed natural-history data were not retrieved.

9. Inheritance and Population

• GJB2 form: autosomal dominant. Mitochondrial form: maternal inheritance.
• Prevalence, penetrance and founder data were not retrieved. The disorder is rare.
• The Cameroonian KID cases and the Portuguese mtDNA family show that both forms occur in different populations.

10. Diagnostics

• Approach. Audiometry plus dermatological examination, followed by genetic testing.
• Genetic testing. Sequence GJB2 first. Then test mtDNA MT-TS1, including m.7445A>G, which is offered as a clinical test (Saint Francis lab listing). Hearing-loss gene panels also cover both.
• Differential. Vohwinkel syndrome, KID syndrome and Bart-Pumphrey syndrome (all GJB2-related), and other PPK syndromes. I did not verify distinguishing features beyond this.

11. Outcome/Prognosis

No survival or quality-of-life data were retrieved. The hearing loss is progressive.

12. Treatment

I found no disease-specific trials. Management is supportive:

• Hearing. Hearing aids and, if needed, cochlear implantation. In dismech, bind the surgical action rather than the device term, per CLAUDE.md.
• Skin. Keratolytics and emollients. Oral retinoids are sometimes used for PPK. I did not verify this for this entity.
• Aminoglycosides. Avoid them in the mitochondrial form. This is a standard precaution for mtDNA hearing loss and is not verified for this entity.
• Counseling. Genetic counseling.
• NCIT terms need lookup. Candidates are the generic supportive-care and surgical-procedure terms already listed in CLAUDE.md.

13. Prevention

Genetic counseling with maternal-lineage counseling for the mitochondrial form. No primary prevention exists.

14. Other Species / Natural Disease

Not evaluated. Check OMIA before asserting any naturally occurring animal disease.

15. Model Organisms

Not evaluated. Mouse Gjb2 models exist, but I did not verify any that reproduce this dominant PPK-with-deafness phenotype. Check MGI.

Curation Notes (lump/split)

• GJB2 variants span several allelic syndromes. Vohwinkel, KID, Bart-Pumphrey and PPK-with-deafness are all linked to GJB2, and the case reports above show phenotypic overlap. Apply the CLAUDE.md lump/split rules. A possible outcome is a Grouping of GJB2 keratoderma-deafness syndromes, with PPK-deafness as its own entry.
• The mitochondrial form may need its own entry. It differs on inheritance and mechanism, which meets the two-axis promotion rule. Alternatively, record it as a has_subtypes row with a pointer.
• Remaining work.
• Fetch the primary literature for the classic GJB2 PPK-deafness reports, the Portuguese m.7445A>G family paper and the GeneReviews chapter.
• Resolve the MONDO ID.
• Fill the missing sections (frequencies, epidemiology, models) before drafting the entry.

Sources

• OMIM #148350
• GeneReviews: Nonsyndromic Hearing Loss and Deafness, Mitochondrial (NBK1422)
• Bedoukian et al. 2021, Mol Genet Genomic Med
• Vohwinkel syndrome with de novo GJB2 p.Gly59Ser (PMC11745274)
• GJB2 p.Asp50Asn in KID syndrome (PMC3750395)
• GenCC GJB2–OMIM:148350 submission
• MGI disease page for 148350
• Portuguese A7445G family (ResearchGate)
• PubMed query for "palmoplantar keratoderma deafness GJB2": 52 hits, 20 returned, including PMIDs 40667477, 35938034, 34916582, 33443819 and 31408183. I did not open or verify them.

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:0007852 (2 mentions) - the report calls it "if available"; MONDO calls it palmoplantar keratoderma-deafness syndrome

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: OMIM.

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

All extracted references resolved successfully.