👪

Inheritance

2

Autosomal dominant (GJB2) HP:0000006

GJB2-related disease segregates as an autosomal dominant trait.

autosomal dominant inheritance

Show evidence (1 reference)

PMID:10633135 SUPPORT Human Clinical

"We report a missense mutation in the connexin 26 gene (GJB2) in a family with an autosomal dominant syndrome of hearing loss and hyperkeratosis"

Establishes autosomal dominant segregation of the GJB2 form.

Mitochondrial (MT-TS1) HP:0001427

The MT-TS1 m.7445A>G form is maternally inherited through mtDNA.

mitochondrial inheritance

Show evidence (1 reference)

PMID:11069477 SUPPORT Human Clinical

"The combination was shown to be associated with the A7445G point mutation in the mitochondrial genome (mtDNA)."

Associates the keratoderma-deafness combination with an mtDNA variant.

◆

Subtypes

2

GJB2-related (autosomal dominant)

GJB2 hgnc:4284

The main form, caused by heterozygous dominant-negative GJB2 missense variants; keratoderma penetrance varies by allele, notably for R75 alleles.

Mitochondrial (MT-TS1 m.7445A>G)

MT-TS1 hgnc:7497

A maternally inherited non-epidermolytic keratoderma with sensorineural deafness associated with the mitochondrial tRNA-Ser(UCN) variant m.7445A>G, with incomplete penetrance of both features.

⚙

Pathophysiology

5

Dominant-Negative GJB2 Missense Variant

A heterozygous GJB2 missense variant (G59A, R75W/R75Q, H73R, deletion of E42) produces a connexin 26 subunit that cannot form functional gap junction channels and interferes with wild-type subunits.

GJB2 hgnc:4284

gap junction channel activity GO:0005243 ↓ DECREASED

Downstream

Loss of Connexin 26 Gap Junction Coupling Mutant subunits suppress the channel activity and trafficking of co-expressed wild-type connexin 26.

Trans-Dominant Inhibition of Epidermal Connexin 43 Skin-associated mutant subunits interact directly with wild-type connexin 43 and inhibit its channels, in parallel with (not downstream of) the loss of connexin 26 coupling; deafness-only mutants suppress connexin 26 but spare connexin 43.

Show evidence (2 references)

PMID:10633135 SUPPORT Human Clinical

"We report a missense mutation in the connexin 26 gene (GJB2) in a family with an autosomal dominant syndrome of hearing loss and hyperkeratosis"

Identifies a GJB2 missense variant as the cause in a dominant pedigree.

PMID:41516362 SUPPORT REVIEW SYNTHESIS Human Clinical

"A subset of GJB2 missense variants cause autosomal dominant HL through dominant-negative or gain-of-function mechanisms"

Places dominant GJB2 missense variants in a dominant-negative mechanism.

Loss of Connexin 26 Gap Junction Coupling

Gap junctional intercellular communication through connexin 26 channels is lost, both because mutant subunits are non-functional and because they impair trafficking of wild-type connexin 26 to the plasma membrane.

gap junction-mediated intercellular transport GO:1990349 ↓ DECREASED

Animal models

CX26 R75W transgenic mouse treated with AAV base editing Mouse rescues AAV-delivered adenine base editing of R75W restores gap junction plaques in cochlear supporting cells, a preclinical correction of the lesion.

Downstream

Impaired Potassium Recycling by Organ of Corti Supporting Cells In the cochlea, loss of supporting-cell gap junction coupling impairs potassium handling around the sensory hair cells; inferred from the R75W dominant-negative mouse.

Show evidence (2 references)

PMID:17993581 SUPPORT In Vitro

"the mutant has a dominant negative effect on connexin trafficking"

H73R impairs trafficking of co-expressed wild-type connexin 26, a second route to lost coupling.

PMID:21040787 SUPPORT INDIRECT In Vitro

"dominant-negative effects of these Cx26 mutants likely contribute to the pathogenesis of hearing loss"

Cell-based coupling assays tie the dominant-negative loss of connexin 26 function to hearing loss.

Trans-Dominant Inhibition of Epidermal Connexin 43

Mutant connexin 26 subunits interact with connexin 43 in keratinocytes and suppress its channel function. This is proposed as the principal reason dominant GJB2 variants produce a skin phenotype.

keratinocyte CL:0000312

GJA1 hgnc:4274

connexin 43 gap junction channel activity GO:0005243 ↓ DECREASED

palmoplantar skin UBERON:0013776

Downstream

Palmoplantar keratoderma Disturbed epidermal gap junction communication is thought to perturb keratinocyte growth and differentiation and so produce palmoplantar hyperkeratosis; the intermediate steps are not established.

Show evidence (2 references)

PMID:11493646 SUPPORT INDIRECT In Vitro

"the principal mechanism for manifestation of dominant GJB2 mutations in the skin is their dominant interference with the function of wtCx43"

The authors' proposed model, built on the oocyte data, naming connexin 43 interference as the principal skin mechanism.

PMID:11493646 SUPPORT Human Clinical

"Cx26 and Cx43 focally colocalize at gap junctional plaques in affected skin tissue of two carriers of DeltaE42"

Patient skin shows the two connexins colocalized, consistent with a direct interaction in vivo.

Impaired Potassium Recycling by Organ of Corti Supporting Cells

Supporting cells of the organ of Corti fail to clear potassium from the cortilymph around the sensory hair cells. In the dominant-negative mouse the endolymph potential stays normal, so the defect is local to the organ of Corti rather than to endolymph generation; the authors extend this to humans only as probable.

organ of Corti supporting cell CL:0002490

potassium ion transmembrane transport GO:0071805 ↓ DECREASED

organ of Corti UBERON:0002227

Downstream

Organ of Corti Degeneration Disturbed cortilymph homeostasis degrades the organ of Corti.

Show evidence (1 reference)

PMID:12700168 SUPPORT INDIRECT Model Organism

"the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular space surrounding the sensory hair cells, due to impaired K(+) transport by supporting cells, resulting in degradation of the organ of Corti"

In R75W transgenic mice, impaired supporting-cell potassium transport degrades the organ of Corti.

Organ of Corti Degeneration

Supporting cells deform, the tunnel of Corti fails to form, and sensory hair cells degenerate.

auditory hair cell CL:0000202

organ of Corti UBERON:0002227

Animal models

R75W dominant-negative Gjb2 transgenic mouse Mouse recapitulates Reproduces supporting-cell deformity, failure of the tunnel of Corti and hair-cell degeneration with severe to profound deafness.

Downstream

Sensorineural hearing loss Loss of sensory hair cells produces sensorineural hearing loss.

Show evidence (1 reference)

PMID:12700168 SUPPORT INDIRECT Model Organism

"two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells"

The R75W dominant-negative mouse shows organ of Corti degeneration with deafness.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

2

Ear 1

Sensorineural hearing loss Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:10633135 SUPPORT Human Clinical

"The affected family members have high frequency, slowly progressive, bilateral, sensorineural hearing loss and palmoplantar hyperkeratosis"

Documents bilateral progressive sensorineural hearing loss.

PMID:20890442 SUPPORT Human Clinical

"The patient and a number of her maternal family members also had congenital hearing loss"

Documents congenital-onset hearing loss with R75W.

Integument 1

Palmoplantar keratoderma HP:0000982

Show evidence (4 references)

PMID:10633135 SUPPORT Human Clinical

"The affected family members have high frequency, slowly progressive, bilateral, sensorineural hearing loss and palmoplantar hyperkeratosis"

Documents palmoplantar hyperkeratosis in affected family members.

PMID:41516362 SUPPORT REVIEW SYNTHESIS Human Clinical

"variants impair gap junction formation and cause severe prelingual HL with variably penetrant Palmoplantar Keratoderma"

Records allele-dependent, variable penetrance of the keratoderma.

PMID:17993581 SUPPORT Human Clinical

"causing a syndrome of focal palmoplantar keratoderma with severe progressive sensorineural hearing impairment"

Documents the focal form of the keratoderma (H73R).

+ 1 more reference

🧬

Genetic Associations

2

GJB2 (Heterozygous dominant-negative missense variants in connexin 26.)

Gene: GJB2 hgnc:4284 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:40059830 SUPPORT BACKGROUND Human Clinical

"Dominant-negative mutations of GJB2, such as R75W, cause syndromic hearing loss and palmoplantar keratoderma"

States the causal role of dominant-negative GJB2 variants.

PMID:9856479 SUPPORT Human Clinical

"We have observed a similar phenotype in an Egyptian family that segregated with a heterozygous missense mutation of GJB2, leading to a non-conservative amino acid substitution (R75W)"

Family segregation of a heterozygous GJB2 variant with the phenotype.

MT-TS1 (The mitochondrial tRNA-Ser(UCN) variant m.7445A>G, reported with incomplete penetrance. The keratoderma association rests on few pedigrees, so its strength is not established and it is not graded CAUSATIVE here.)

Gene: MT-TS1 hgnc:7497 relationship_type: UNKNOWN

Show evidence (2 references)

PMID:11069477 SUPPORT Human Clinical

"This mutation is responsible for a subtype of NEPPK which is so far the only mtDNA mutation-associated keratoderma."

Assigns the keratoderma-deafness subtype to the mtDNA variant.

PMID:11069477 SUPPORT Human Clinical

"The penetrance of both features was incomplete"

Records incomplete penetrance in the reported pedigree.

💊

Medical Actions

1

Cochlear implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Cochlear implantation with hearing rehabilitation restores auditory input. The disease-specific evidence is a single R75W case report; the rationale that GJB2 pathology spares the cochlear neurons the implant stimulates comes from nonsyndromic GJB2 deafness.

Mechanism Target:

BYPASSES Organ of Corti Degeneration — The implant stimulates spiral ganglion neurons directly, bypassing the degenerated organ of Corti.

Show evidence (1 reference)

PMID:41516362 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"with preserved cochlear neurons that support excellent cochlear implant (CI) outcomes"

Said of recessive GJB2 (DFNB1) deafness: the cochlear neurons the implant stimulates are preserved, the basis for bypassing the organ of Corti.

Show evidence (1 reference)

PMID:20890442 SUPPORT Human Clinical

"Cochlear implantation was done to modify hearing loss of the patient and further hearing rehabilitation had been provided by the hearing support service team in hospital"

Cochlear implantation was used in an R75W palmoplantar keratoderma-deafness patient.

🔬

Diagnosis

1

GJB2 sequencing

Congenital or progressive hearing loss with palmoplantar keratoderma in an autosomal dominant pedigree prompts GJB2 sequencing; mtDNA testing for m.7445A>G applies to maternally inherited families.

Show evidence (1 reference)

PMID:20890442 SUPPORT Human Clinical

"led us to test for a mutation in the GJB2 gene in both patients"

The dominant keratoderma-deafness combination led to GJB2 testing.

🐁

Animal Models

2

R75W dominant-negative Gjb2 transgenic mouse

Species

Mouse

Genotype

Transgenic expression of human connexin 26 R75W

Publication

PMID:12700168

Pathograph links

Organ of Corti Degeneration recapitulates fidelity: moderate observes: tissue Reproduces supporting-cell deformity, failure of the tunnel of Corti and hair-cell degeneration with severe to profound deafness.

Limitations: The mouse is a model of the cochlear arm only; it is described as non-syndromic, so it does not model the keratoderma. Transgene overexpression does not reproduce the human heterozygous dosage, and the potassium mechanism is the authors' inference (endocochlear potential was normal).

Show evidence (1 reference)

PMID:12700168 SUPPORT Model Organism

"two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells"

The model reproduces organ of Corti degeneration and deafness.

CX26 R75W transgenic mouse treated with AAV base editing

Species

Mouse

Genotype

CX26 R75W transgenic, treated with AAV-delivered adenine base editor

Publication

PMID:40059830

Pathograph links

Loss of Connexin 26 Gap Junction Coupling rescues fidelity: moderate observes: cellular AAV-delivered adenine base editing of R75W restores gap junction plaques in cochlear supporting cells, a preclinical correction of the lesion.

Limitations: The quoted result is restored gap junction plaque structure, not shown here to restore coupling or hearing; preclinical, untested in humans, and does not address the skin.

Show evidence (1 reference)

PMID:40059830 SUPPORT Model Organism

"AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells"

Base editing rescues the junction defect in the R75W mouse.

{ }

Source YAML

click to show

name: Palmoplantar Keratoderma-Deafness Syndrome
creation_date: "2026-10-01T23:39:00Z"
category: Mendelian
description: >-
  Palmoplantar keratoderma-deafness syndrome combines focal or diffuse
  palmoplantar keratoderma with sensorineural hearing loss. Its main form is
  autosomal dominant and caused by heterozygous GJB2 missense variants (for
  example G59A, R75W/R75Q, H73R and deletion of E42) that encode
  dominant-negative connexin 26: the mutant subunits form no functional channels
  and suppress co-expressed wild-type connexin 26. The disease then branches by
  tissue. In the epidermis, the skin-associated mutants tested in vitro
  (deletion of E42, D66H, R75W) also trans-dominantly inhibit connexin 43, the
  proposed reason some dominant GJB2 alleles cause deafness alone and others
  cause deafness with keratoderma. In the
  cochlea, loss of gap junction coupling impairs potassium handling by organ of
  Corti supporting cells, leading to supporting-cell deformity and hair-cell
  degeneration (a cochlear mechanism inferred from a dominant-negative mouse
  model). A rarer maternally inherited form is associated with the
  mitochondrial MT-TS1 variant m.7445A>G and is not explained by connexin 26.
disease_term:
  preferred_term: palmoplantar keratoderma-deafness syndrome
  term:
    id: MONDO:0007852
    label: palmoplantar keratoderma-deafness syndrome
synonyms:
- palmoplantar keratoderma with deafness
- keratoderma, palmoplantar, with deafness
- palmoplantar keratoderma-hearing loss syndrome
- palmoplantar keratoderma and sensorineural deafness
- PPK-deafness syndrome
parents:
- Genodermatosis
notes: >-
  The connexin 26 pathograph below is scoped to the GJB2 subtype. The
  mitochondrial MT-TS1 m.7445A>G form shares the clinical picture but not the
  mechanism (immunolabelling showed normal connexin 26 expression in its
  proband), so it is recorded as a subtype and a genetic entry rather than
  forced through the gap junction chain; its own mechanism (a mitochondrial
  tRNA processing defect) is not modelled here. GJB2 also causes the allelic
  dominant skin-and-deafness disorders curated separately as
  Keratitis-Ichthyosis-Deafness_Syndrome (MONDO:0007850) and
  Keratoderma_Hereditarium_Mutilans (Vohwinkel, MONDO:0007422); MONDO and
  Orphanet place this entity on a clinical spectrum with them. No GeneReviews
  chapter covers this disease (just check-genereviews --online, NO_CHAPTER; the
  GJB2 nonsyndromic deafness chapter is a different disease). No treatment for
  the keratoderma itself is sourced: the acitretin reports found concern KID and
  Vohwinkel syndromes, not this entity, and were not carried over.
has_subtypes:
- name: GJB2
  display_name: GJB2-related (autosomal dominant)
  description: >-
    The main form, caused by heterozygous dominant-negative GJB2 missense
    variants; keratoderma penetrance varies by allele, notably for R75 alleles.
  genes:
  - preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
- name: MT-TS1
  display_name: Mitochondrial (MT-TS1 m.7445A>G)
  description: >-
    A maternally inherited non-epidermolytic keratoderma with sensorineural
    deafness associated with the mitochondrial tRNA-Ser(UCN) variant
    m.7445A>G, with incomplete penetrance of both features.
  genes:
  - preferred_term: MT-TS1
    term:
      id: hgnc:7497
      label: MT-TS1
inheritance:
- name: Autosomal dominant (GJB2)
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: GJB2-related disease segregates as an autosomal dominant trait.
  evidence:
  - reference: PMID:10633135
    reference_title: A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a missense mutation in the connexin 26 gene (GJB2) in a family
      with an autosomal dominant syndrome of hearing loss and hyperkeratosis
    explanation: Establishes autosomal dominant segregation of the GJB2 form.
- name: Mitochondrial (MT-TS1)
  inheritance_term:
    preferred_term: mitochondrial inheritance
    term:
      id: HP:0001427
      label: Mitochondrial inheritance
  description: The MT-TS1 m.7445A>G form is maternally inherited through mtDNA.
  evidence:
  - reference: PMID:11069477
    reference_title: Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combination was shown to be associated with the A7445G point mutation
      in the mitochondrial genome (mtDNA).
    explanation: Associates the keratoderma-deafness combination with an mtDNA variant.
pathophysiology:
- name: Dominant-Negative GJB2 Missense Variant
  biological_scale: MOLECULAR
  subtypes:
  - GJB2
  description: >-
    A heterozygous GJB2 missense variant (G59A, R75W/R75Q, H73R, deletion of
    E42) produces a connexin 26 subunit that cannot form functional gap junction
    channels and interferes with wild-type subunits.
  genes:
  - preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
  molecular_functions:
  - preferred_term: gap junction channel activity
    term:
      id: GO:0005243
      label: gap junction channel activity
    modifier: DECREASED
  downstream:
  - target: Loss of Connexin 26 Gap Junction Coupling
    causal_link_type: DIRECT
    description: >-
      Mutant subunits suppress the channel activity and trafficking of
      co-expressed wild-type connexin 26.
    evidence:
    - reference: PMID:9856479
      reference_title: Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Not only was R75W alone incapable of inducing electrical conductance
        between adjacent cells, but it almost completely suppressed the activity
        of co-expressed wildtype protein
      explanation: >-
        R75W abolishes its own channel function and dominantly suppresses
        wild-type connexin 26 in paired oocytes.
  - target: Trans-Dominant Inhibition of Epidermal Connexin 43
    causal_link_type: DIRECT
    description: >-
      Skin-associated mutant subunits interact directly with wild-type
      connexin 43 and inhibit its channels, in parallel with (not downstream
      of) the loss of connexin 26 coupling; deafness-only mutants suppress
      connexin 26 but spare connexin 43.
    evidence:
    - reference: PMID:11493646
      reference_title: "trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        only those Cx26 mutants associated with a skin phenotype also
        significantly (P<0.05) inhibited intercellular conductance of
        co-expressed wtCx43, indicating a direct interaction of mutant Cx26
        units with wtCx43
      explanation: >-
        In paired Xenopus oocytes every mutant suppressed wild-type connexin
        26, but only the skin-associated ones also inhibited connexin 43, which
        the authors attribute to direct binding by the mutant subunit; an in
        vitro result for three alleles.
  evidence:
  - reference: PMID:10633135
    reference_title: A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a missense mutation in the connexin 26 gene (GJB2) in a family
      with an autosomal dominant syndrome of hearing loss and hyperkeratosis
    explanation: Identifies a GJB2 missense variant as the cause in a dominant pedigree.
  - reference: PMID:41516362
    reference_title: "GJB2-Related Hearing Loss: Genotype-Phenotype Correlations, Natural History, and Emerging Therapeutic Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A subset of GJB2 missense variants cause autosomal dominant HL through
      dominant-negative or gain-of-function mechanisms
    explanation: Places dominant GJB2 missense variants in a dominant-negative mechanism.
- name: Loss of Connexin 26 Gap Junction Coupling
  biological_scale: CELLULAR
  subtypes:
  - GJB2
  description: >-
    Gap junctional intercellular communication through connexin 26 channels is
    lost, both because mutant subunits are non-functional and because they
    impair trafficking of wild-type connexin 26 to the plasma membrane.
  biological_processes:
  - preferred_term: gap junction-mediated intercellular transport
    term:
      id: GO:1990349
      label: gap junction-mediated intercellular transport
    modifier: DECREASED
  downstream:
  - target: Impaired Potassium Recycling by Organ of Corti Supporting Cells
    causal_link_type: DIRECT
    description: >-
      In the cochlea, loss of supporting-cell gap junction coupling impairs
      potassium handling around the sensory hair cells; inferred from the R75W
      dominant-negative mouse.
    evidence:
    - reference: PMID:12700168
      reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular
        space surrounding the sensory hair cells, due to impaired K(+) transport by
        supporting cells, resulting in degradation of the organ of Corti
      explanation: >-
        The authors attribute the cochlear defect to impaired supporting-cell
        potassium transport in the dominant-negative mouse.
  evidence:
  - reference: PMID:17993581
    reference_title: A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the mutant has a dominant negative effect on connexin trafficking
    explanation: >-
      H73R impairs trafficking of co-expressed wild-type connexin 26, a second
      route to lost coupling.
  - reference: PMID:21040787
    reference_title: Dominant Cx26 mutants associated with hearing loss have dominant-negative effects on wild type Cx26.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      dominant-negative effects of these Cx26 mutants likely contribute to the
      pathogenesis of hearing loss
    explanation: >-
      Cell-based coupling assays tie the dominant-negative loss of connexin 26
      function to hearing loss.
- name: Trans-Dominant Inhibition of Epidermal Connexin 43
  biological_scale: CELLULAR
  subtypes:
  - GJB2
  description: >-
    Mutant connexin 26 subunits interact with connexin 43 in keratinocytes and
    suppress its channel function. This is proposed as the principal reason
    dominant GJB2 variants produce a skin phenotype.
  genes:
  - preferred_term: GJA1
    term:
      id: hgnc:4274
      label: GJA1
  molecular_functions:
  - preferred_term: connexin 43 gap junction channel activity
    term:
      id: GO:0005243
      label: gap junction channel activity
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: palmoplantar skin
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  downstream:
  - target: Palmoplantar keratoderma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disturbed epidermal gap junction communication is thought to perturb
      keratinocyte growth and differentiation and so produce palmoplantar
      hyperkeratosis; the intermediate steps are not established.
    evidence:
    - reference: PMID:17993581
      reference_title: A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: >-
        In the skin, several connexins are expressed and are involved in the
        regulation of epidermal growth and differentiation
      explanation: >-
        Background plausibility only: connexins take part in regulating
        epidermal growth and differentiation; the quote does not itself link
        connexin 43 inhibition to hyperkeratosis.
  evidence:
  - reference: PMID:11493646
    reference_title: "trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      the principal mechanism for manifestation of dominant GJB2 mutations in the
      skin is their dominant interference with the function of wtCx43
    explanation: >-
      The authors' proposed model, built on the oocyte data, naming connexin 43
      interference as the principal skin mechanism.
  - reference: PMID:11493646
    reference_title: "trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cx26 and Cx43 focally colocalize at gap junctional plaques in affected skin
      tissue of two carriers of DeltaE42
    explanation: >-
      Patient skin shows the two connexins colocalized, consistent with a direct
      interaction in vivo.
- name: Impaired Potassium Recycling by Organ of Corti Supporting Cells
  biological_scale: CELLULAR
  subtypes:
  - GJB2
  description: >-
    Supporting cells of the organ of Corti fail to clear potassium from the
    cortilymph around the sensory hair cells. In the dominant-negative mouse the
    endolymph potential stays normal, so the defect is local to the organ of
    Corti rather than to endolymph generation; the authors extend this to humans
    only as probable.
  cell_types:
  - preferred_term: organ of Corti supporting cell
    term:
      id: CL:0002490
      label: organ of Corti supporting cell
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  locations:
  - preferred_term: organ of Corti
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  downstream:
  - target: Organ of Corti Degeneration
    causal_link_type: DIRECT
    description: Disturbed cortilymph homeostasis degrades the organ of Corti.
    evidence:
    - reference: PMID:12700168
      reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular
        space surrounding the sensory hair cells, due to impaired K(+) transport by
        supporting cells, resulting in degradation of the organ of Corti
      explanation: >-
        Impaired potassium transport is followed by degradation of the organ of
        Corti in the mouse.
  evidence:
  - reference: PMID:12700168
    reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular
      space surrounding the sensory hair cells, due to impaired K(+) transport by
      supporting cells, resulting in degradation of the organ of Corti
    explanation: >-
      In R75W transgenic mice, impaired supporting-cell potassium transport
      degrades the organ of Corti.
- name: Organ of Corti Degeneration
  biological_scale: TISSUE
  subtypes:
  - GJB2
  description: >-
    Supporting cells deform, the tunnel of Corti fails to form, and sensory hair
    cells degenerate.
  cell_types:
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  locations:
  - preferred_term: organ of Corti
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  downstream:
  - target: Sensorineural hearing loss
    causal_link_type: DIRECT
    description: Loss of sensory hair cells produces sensorineural hearing loss.
    evidence:
    - reference: PMID:12700168
      reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        two lines of transgenic mice that showed severe to profound hearing loss,
        deformity of supporting cells, failure in the formation of the tunnel of
        Corti and degeneration of sensory hair cells
      explanation: Hair-cell degeneration accompanies severe to profound deafness in the mouse.
  evidence:
  - reference: PMID:12700168
    reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      two lines of transgenic mice that showed severe to profound hearing loss,
      deformity of supporting cells, failure in the formation of the tunnel of
      Corti and degeneration of sensory hair cells
    explanation: >-
      The R75W dominant-negative mouse shows organ of Corti degeneration with
      deafness.
phenotypes:
- category: Cutaneous
  name: Palmoplantar keratoderma
  description: >-
    Focal (for example H73R) or diffuse (for example R75W) hyperkeratosis of the
    palms and soles; penetrance varies by allele.
  phenotype_term:
    preferred_term: palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:10633135
    reference_title: A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected family members have high frequency, slowly progressive,
      bilateral, sensorineural hearing loss and palmoplantar hyperkeratosis
    explanation: Documents palmoplantar hyperkeratosis in affected family members.
  - reference: PMID:41516362
    reference_title: "GJB2-Related Hearing Loss: Genotype-Phenotype Correlations, Natural History, and Emerging Therapeutic Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      variants impair gap junction formation and cause severe prelingual HL with
      variably penetrant Palmoplantar Keratoderma
    explanation: Records allele-dependent, variable penetrance of the keratoderma.
  - reference: PMID:17993581
    reference_title: A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      causing a syndrome of focal palmoplantar keratoderma with severe
      progressive sensorineural hearing impairment
    explanation: Documents the focal form of the keratoderma (H73R).
  - reference: PMID:20890442
    reference_title: Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of Connexin 26.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented to our clinic with diffuse hyperkeratosis of the palms and soles
    explanation: Documents the diffuse form of the keratoderma (R75W).
- category: Auditory
  name: Sensorineural hearing loss
  description: >-
    Bilateral sensorineural hearing loss whose severity depends on the allele:
    high-frequency and slowly progressive with G59A, severe congenital or
    prelingual with R75W/R75Q.
  phenotype_term:
    preferred_term: sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:10633135
    reference_title: A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected family members have high frequency, slowly progressive,
      bilateral, sensorineural hearing loss and palmoplantar hyperkeratosis
    explanation: Documents bilateral progressive sensorineural hearing loss.
  - reference: PMID:20890442
    reference_title: Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of Connexin 26.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient and a number of her maternal family members also had
      congenital hearing loss
    explanation: Documents congenital-onset hearing loss with R75W.
genetic:
- name: GJB2
  subtype: GJB2
  gene_term:
    preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
  relationship_type: CAUSATIVE
  association: >-
    Heterozygous dominant-negative missense variants in connexin 26.
  evidence:
  - reference: PMID:40059830
    reference_title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Dominant-negative mutations of GJB2, such as R75W, cause syndromic hearing
      loss and palmoplantar keratoderma
    explanation: States the causal role of dominant-negative GJB2 variants.
  - reference: PMID:9856479
    reference_title: Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have observed a similar phenotype in an Egyptian family that segregated
      with a heterozygous missense mutation of GJB2, leading to a
      non-conservative amino acid substitution (R75W)
    explanation: Family segregation of a heterozygous GJB2 variant with the phenotype.
- name: MT-TS1
  subtype: MT-TS1
  gene_term:
    preferred_term: MT-TS1
    term:
      id: hgnc:7497
      label: MT-TS1
  relationship_type: UNKNOWN
  association: >-
    The mitochondrial tRNA-Ser(UCN) variant m.7445A>G, reported with incomplete
    penetrance. The keratoderma association rests on few pedigrees, so its
    strength is not established and it is not graded CAUSATIVE here.
  evidence:
  - reference: PMID:11069477
    reference_title: Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation is responsible for a subtype of NEPPK which is so far the
      only mtDNA mutation-associated keratoderma.
    explanation: Assigns the keratoderma-deafness subtype to the mtDNA variant.
  - reference: PMID:11069477
    reference_title: Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The penetrance of both features was incomplete
    explanation: Records incomplete penetrance in the reported pedigree.
treatments:
- name: Cochlear implantation
  description: >-
    Cochlear implantation with hearing rehabilitation restores auditory input.
    The disease-specific evidence is a single R75W case report; the rationale
    that GJB2 pathology spares the cochlear neurons the implant stimulates comes
    from nonsyndromic GJB2 deafness.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_mechanisms:
  - target: Organ of Corti Degeneration
    treatment_effect: BYPASSES
    description: >-
      The implant stimulates spiral ganglion neurons directly, bypassing the
      degenerated organ of Corti.
    evidence:
    - reference: PMID:41516362
      reference_title: "GJB2-Related Hearing Loss: Genotype-Phenotype Correlations, Natural History, and Emerging Therapeutic Strategies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        with preserved cochlear neurons that support excellent cochlear implant
        (CI) outcomes
      explanation: >-
        Said of recessive GJB2 (DFNB1) deafness: the cochlear neurons the implant
        stimulates are preserved, the basis for bypassing the organ of Corti.
  evidence:
  - reference: PMID:20890442
    reference_title: Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of Connexin 26.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cochlear implantation was done to modify hearing loss of the patient and
      further hearing rehabilitation had been provided by the hearing support
      service team in hospital
    explanation: Cochlear implantation was used in an R75W palmoplantar keratoderma-deafness patient.
diagnosis:
- name: GJB2 sequencing
  description: >-
    Congenital or progressive hearing loss with palmoplantar keratoderma in an
    autosomal dominant pedigree prompts GJB2 sequencing; mtDNA testing for
    m.7445A>G applies to maternally inherited families.
  evidence:
  - reference: PMID:20890442
    reference_title: Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of Connexin 26.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      led us to test for a mutation in the GJB2 gene in both patients
    explanation: The dominant keratoderma-deafness combination led to GJB2 testing.
animal_models:
- name: R75W dominant-negative Gjb2 transgenic mouse
  species: Mouse
  genotype: Transgenic expression of human connexin 26 R75W
  publication: PMID:12700168
  modeled_mechanisms:
  - target: Organ of Corti Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces supporting-cell deformity, failure of the tunnel of Corti and
      hair-cell degeneration with severe to profound deafness.
    limitations: >-
      The mouse is a model of the cochlear arm only; it is described as
      non-syndromic, so it does not model the keratoderma. Transgene
      overexpression does not reproduce the human heterozygous dosage, and the
      potassium mechanism is the authors' inference (endocochlear potential
      was normal).
    evidence:
    - reference: PMID:12700168
      reference_title: Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        two lines of transgenic mice that showed severe to profound hearing loss,
        deformity of supporting cells, failure in the formation of the tunnel of
        Corti and degeneration of sensory hair cells
      explanation: The model reproduces organ of Corti degeneration and deafness.
- name: CX26 R75W transgenic mouse treated with AAV base editing
  species: Mouse
  genotype: CX26 R75W transgenic, treated with AAV-delivered adenine base editor
  publication: PMID:40059830
  modeled_mechanisms:
  - target: Loss of Connexin 26 Gap Junction Coupling
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      AAV-delivered adenine base editing of R75W restores gap junction plaques in
      cochlear supporting cells, a preclinical correction of the lesion.
    limitations: >-
      The quoted result is restored gap junction plaque structure, not shown
      here to restore coupling or hearing; preclinical, untested in humans, and
      does not address the skin.
    evidence:
    - reference: PMID:40059830
      reference_title: AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        AAV-mediated base editing also restored the fragmented GJPs to orderly
        outlines in cochlear supporting cells
      explanation: Base editing rescues the junction defect in the R75W mouse.

📚

References & Deep Research

Deep Research

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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: Palmoplantar Keratoderma-Deafness Syndrome · 2026-10-01T23:46:27Z · View source

Created the entry for MONDO:0007852 (OMIM:148350, Orphanet:2202). Deep research was requested from falcon (the curate default) via the documented --fallback path; no falcon key was available, so claude_code produced the report and its frontmatter records fell_back/requested_provider. The report was thin (2 web searches); its term and reference validation sections were re-run after a transient OLS timeout (3/3 references resolved, none off topic). All evidence was sourced independently from PubMed: the G59A defining pedigree (PMID:10633135), R75W oocyte dominant-negative study (PMID:9856479), Cx43 trans-dominant study with patient-skin colocalization (PMID:11493646), H73R trafficking study (PMID:17993581), HeLa dominant-negative study (PMID:21040787), R75W transgenic mouse (PMID:12700168), AAV base-editing rescue (PMID:40059830), 2026 GJB2 review (PMID:41516362), Korean R75W family with cochlear implantation (PMID:20890442), and the mitochondrial m.7445A>G pedigree (PMID:11069477). Lump/split: the pathograph is scoped to the GJB2 subtype; the MT-TS1 m.7445A>G form is a has_subtypes row and genetic entry (relationship_type UNKNOWN, single-pedigree basis) because its proband had normal connexin 26 and its mechanism is unrelated. Keratoderma therapy was deliberately left unsourced: the acitretin reports found concern KID and Vohwinkel syndromes. GeneReviews: NO_CHAPTER (checked online with synonyms). A pre-PR red-team subagent pass found no blocking issues and its important findings were fixed before commit: edge evidence moved onto the edges it supports (the potassium and organ-of-Corti edges now carry the mouse quote; the oocyte-based skin edge is graded INDIRECT; the Cx43 hypothesis quote marked as the authors' model and paired with the patient-skin colocalization result), MT-TS1 downgraded from CAUSATIVE, the base-editing rescue moved to its own animal-model record limited to plaque morphology, and the cochlear-implant rationale re-sourced and qualified with the device term. Validation: validate-disorders, 31/31 snippets, terms, qualifier terms (online), entity refs, causal targets, enum, duplicate keys, coarse phenotypes and snippet grading all pass; 2/2 phenotypes connected; GJB2 and GJA1 grounded.

Claude Code ▸

Palmoplantar Keratoderma-Deafness Syndrome: Research Report

claude-haiku-4-5-20251001, claude-sonnet-5-5 9 citations 2026-10-01T23:21:05.757011

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.

Phenotype	Notes	HPO term to look up
Palmoplantar keratoderma	Progressive. Mitochondrial form is described as scaling, hyperkeratosis and a honeycomb appearance of palms, soles and heels (GeneReviews NBK1422).	"Palmoplantar keratoderma"
Sensorineural hearing impairment	Slowly progressive, high-frequency. MT-TS1 variants are usually childhood-onset.	"Sensorineural hearing impairment"
Variable additional features	Reported with GJB2 variants, including KID-spectrum overlap (see lump/split below).	Look up only if sourced

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.

Outcome	Count
Terms checked	3
Resolved	2
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

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

MONDO: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.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	2
Off topic	0

All extracted references resolved successfully.

Palmoplantar Keratoderma-Deafness Syndrome

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Palmoplantar Keratoderma-Deafness Syndrome: Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology (causal chains)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Curation Notes (lump/split)

Sources

Term Validation

Terms the report names something else

Prefixes with no resolver

Reference Validation