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Keratoderma Hereditarium Mutilans

Mendelian MONDO:0007422 Hereditary Palmoplantar Keratoderma Connexin Disorders

Keratoderma hereditarium mutilans, also known as Vohwinkel syndrome, is a rare autosomal dominant genodermatosis characterized by diffuse palmoplantar keratoderma with a distinctive honeycomb pattern, pseudoainhum (constricting bands around digits leading to autoamputation), and sensorineural hearing loss. The classic form is caused by mutations in the GJB2 gene encoding connexin 26. The ichthyotic variant (Camisa syndrome) is caused by mutations in the LOR gene encoding loricrin.

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Mappings
0
Definitions
0
Inheritance
5
Pathophysiology
0
Histopathology
8
Phenotypes
2
Genes
5
Treatments
2
Subtypes
0
Differentials
0
Datasets
0
Trials
◆

Subtypes

2
Classic Vohwinkel Syndrome
The classic form caused by GJB2 mutations, featuring the complete triad of palmoplantar keratoderma, pseudoainhum, and sensorineural hearing loss.
Show evidence (1 reference)
PMID:10369869 SUPPORT
"VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation, distinctive starfish-like acral keratoses and moderate degrees of deafness. "
This landmark paper identified the D66H mutation in GJB2 as causative for classic Vohwinkel syndrome with the characteristic triad.
Loricrin Keratoderma (Variant Vohwinkel Syndrome)
A variant form caused by LOR gene mutations, featuring keratoderma and pseudoainhum but with ichthyosis instead of hearing loss. Also known as Camisa variant.
Show evidence (2 references)
PMID:9326398 SUPPORT
"Vohwinkel's keratoderma is thus clinically and genetically heterogeneous. Only the variant with ichthyosis appears to be due to loricrin mutation. "
This paper established that loricrin mutations cause the ichthyotic variant without hearing loss.
PMID:12072018 SUPPORT
"Functional studies in transgenic mice have shown that the accumulation of mutant loricrin in the nucleus appears to interfere with the later stages of epidermal differentiation, thereby explaining the clinical manifestations of ichthyosis, keratoderma and pseudoainhum. "
Confirms loricrin mutations underlie the ichthyotic variant of Vohwinkel syndrome.
⚙

Pathophysiology

5
Gap Junction Dysfunction
Mutations in GJB2 disrupt connexin 26 function, impairing gap junction-mediated intercellular communication in the epidermis and cochlea. The D66H mutation occurs at a highly conserved residue in the first extracellular domain and may interfere with connexon assembly, docking, or gating properties. This leads to defective ion homeostasis and impaired cellular coordination during differentiation.
Keratinocyte link
Gap junction assembly link Cell-cell signaling link
Skin of palm and sole link
Show evidence (2 references)
PMID:10369869 SUPPORT
"This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction. "
Describes the molecular mechanism of GJB2 D66H mutation disrupting gap junction function.
PMID:14681042 SUPPORT Model Organism
"Expression of the transgene resulted in a loss of Cx26 and Cx30 at intercellular junctions of epidermal keratinocytes and accumulation of these connexins in the cytoplasm. "
Transgenic mouse model demonstrates that D66H mutation causes loss of connexins at cell junctions.
Abnormal Epidermal Differentiation
Defective gap junction signaling leads to hyperproliferation and abnormal keratinization of palmoplantar epidermis, resulting in the characteristic thickened honeycomb-patterned skin. The mutation impairs epidermal differentiation as well as inner ear function.
Keratinocyte link
Keratinocyte differentiation link
Show evidence (2 references)
PMID:10369869 SUPPORT
"Our results provide evidence that a specific mutation in Cx26 can impair epidermal differentiation, as well as inner ear function. "
Establishes that GJB2 mutations affect both epidermal and cochlear function.
PMID:14681042 SUPPORT Model Organism
"Following birth, the transgenic mice developed keratoderma similar to that of human carriers of Cx26 (D66H). "
Transgenic mice expressing mutant Cx26 develop keratoderma like human patients.
Mutant Loricrin Nuclear Accumulation
In the ichthyotic variant, mutant loricrin is mislocalized to the nuclei of granular layer keratinocytes and fails to incorporate into the cornified cell envelope. The frameshift mutation creates an abnormal C-terminal peptide containing nuclear localization signals, causing aberrant nuclear translocation and interference with late stages of epidermal differentiation.
Keratinocyte link
Cornified envelope assembly link Keratinocyte differentiation link
Show evidence (3 references)
PMID:11121146 SUPPORT
"Mutant loricrin, as a dominant negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes. "
Describes the mechanism by which mutant loricrin causes disease through nuclear interference.
PMID:9326398 SUPPORT
"a G insertion producing a frameshift after codon 231 and an abnormal C-terminal peptide lacking residues necessary for cross-linking. "
Identifies the specific mutation and its effect on loricrin protein structure.
PMID:11038186 SUPPORT Model Organism
"Immunofluorescence and immunoelectron microscopy showed the mutant loricrin protein in the nucleus and cytoplasm of epidermal keratinocytes, but did not detect the protein in the cornified cell envelope. "
Transgenic mouse studies confirm nuclear mislocalization of mutant loricrin.
Digital Constriction and Autoamputation
Fibrous bands encircle digits (pseudoainhum), progressively constricting and potentially leading to spontaneous amputation. The pathogenesis involves aberrant keratinization and tissue remodeling secondary to keratinocyte dysfunction.
Show evidence (1 reference)
PMID:10369869 SUPPORT
"VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation "
Describes the progression from constricting bands to autoamputation.
Cochlear Dysfunction
Connexin 26 is essential for potassium recycling in the cochlea. Its dysfunction disrupts the endocochlear potential required for auditory transduction, causing sensorineural hearing loss. This phenotype is specific to GJB2 mutations and is absent in the loricrin-associated variant.
Cochlea link
Show evidence (2 references)
PMID:10369869 SUPPORT
"Mutations in the connexin26 (Cx26) gene (GJB2) at 13q11-q13 are a major cause of autosomal recessive hearing loss (DFNB1), but have also been reported in autosomal dominant deafness (DFNA3). "
Establishes the role of GJB2 in both skin and hearing phenotypes.
PMID:9326398 SUPPORT
"In our second family (VK2), affected members had sensorineural deafness but not ichthyosis. "
Confirms that deafness segregates with connexin mutations, not loricrin mutations.
⬡

Causal Graph

graph LR
    Gap_Junction_Dysfunction["Gap Junction Dysfunction"]
    Mutant_Loricrin_Nuclear_Accumulation["Mutant Loricrin Nuclear Accumulation"]
    Abnormal_Epidermal_Differentiation["Abnormal Epidermal Differentiation"]
    Cochlear_Dysfunction["Cochlear Dysfunction"]
    Digital_Constriction_and_Autoamputation["Digital Constriction and Autoamputation"]

    Gap_Junction_Dysfunction --> Abnormal_Epidermal_Differentiation
    Gap_Junction_Dysfunction --> Cochlear_Dysfunction
    Abnormal_Epidermal_Differentiation --> Digital_Constriction_and_Autoamputation
    Mutant_Loricrin_Nuclear_Accumulation --> Digital_Constriction_and_Autoamputation

    style Gap_Junction_Dysfunction fill:#dbeafe
    style Mutant_Loricrin_Nuclear_Accumulation fill:#dbeafe
    style Abnormal_Epidermal_Differentiation fill:#dbeafe
    style Cochlear_Dysfunction fill:#dbeafe
    style Digital_Constriction_and_Autoamputation fill:#dbeafe
●

Phenotypes

8
Ear(1) Integument(6) Limbs(1)
Ear 1
Sensorineural Hearing Loss FREQUENT Sensorineural hearing impairment (HP:0000407)
Show evidence (2 references)
PMID:10369869 SUPPORT
"A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families. "
Sensorineural deafness is part of the classic Vohwinkel phenotype.
PMID:20031451 SUPPORT
"Vohwinkel Syndrome (VS) is a type of diffuse hereditary palmoplantar keratodermas (DHPPK) accompanied by skeletal dimorphisms and sensorineural deafness. "
Confirms sensorineural deafness as a component of the syndrome.
Integument 6
Palmoplantar Keratoderma VERY_FREQUENT Palmoplantar keratoderma (HP:0000982)
Show evidence (1 reference)
PMID:10369869 SUPPORT
"VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation "
Honeycomb keratoderma is a defining feature of the syndrome.
Honeycomb Palmoplantar Hyperkeratosis VERY_FREQUENT Honeycomb palmoplantar hyperkeratosis (HP:0007465)
Show evidence (1 reference)
PMID:10369869 SUPPORT
"VS is characterized by papular and honeycomb keratoderma "
Honeycomb pattern is characteristic of the syndrome.
Starfish-Shaped Hyperkeratoses FREQUENT Hyperkeratosis (HP:0000962)
Show evidence (1 reference)
PMID:10369869 SUPPORT
"distinctive starfish-like acral keratoses "
Starfish-like acral keratoses are a characteristic feature.
Knuckle Pads FREQUENT Knuckle pad (HP:0032541)
Show evidence (2 references)
PMID:6237617 SUPPORT
"keratotic structures taking the shape of a starfish and/or knuckle pads on the dorsal surfaces of the hands "
Describes starfish-shaped keratoses and knuckle pads as characteristic features.
PMID:30335335 SUPPORT
"The classic Vohwinkel syndrome is a hereditary PPK associated with "starfish" keratoses on the knuckles "
StatPearls review confirms starfish keratoses on knuckles are part of classic syndrome.
Ichthyosis VERY_FREQUENT Ichthyosis (HP:0008064)
Show evidence (2 references)
PMID:9326398 SUPPORT
"Our first family (VK1) also had ichthyosis but not deafness. "
Ichthyosis is present in the loricrin variant but not classic form.
PMID:11038186 SUPPORT Model Organism
"At birth, transgenic mice (ML.VS) exhibited erythrokeratoderma with an epidermal barrier dysfunction. 4 d after birth, high-expressing transgenic animals showed a generalized scaling of the skin "
Transgenic mice with mutant loricrin develop ichthyosis-like scaling.
Alopecia OCCASIONAL Alopecia (HP:0001596)
Limbs 1
Pseudoainhum VERY_FREQUENT Autoamputation of digits (HP:0007460)
Show evidence (2 references)
PMID:10369869 SUPPORT
"constrictions of digits leading to autoamputation "
Pseudoainhum with potential autoamputation is a key feature.
PMID:12072018 SUPPORT
"the clinical manifestations of ichthyosis, keratoderma and pseudoainhum "
Pseudoainhum is a feature of both genetic forms.
🧬

Genetic Associations

2
GJB2 (Causative)
Show evidence (2 references)
PMID:10369869 SUPPORT
"All 10 affected members were heterozygous for a non-conservative mutation, D66H, in Cx26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a common mutation in classical VS. "
Identifies D66H as a common mutation in classic Vohwinkel syndrome across multiple families.
PMID:20031451 SUPPORT
"Genetic study showed a nucleotide change (c.196G>C) in exon 1 of GJB2 gene, producing a missense mutation, D66H. "
Confirms the specific nucleotide change causing the D66H mutation.
LOR (Causative)
Show evidence (2 references)
PMID:9326398 SUPPORT
"a G insertion producing a frameshift after codon 231 and an abnormal C-terminal peptide lacking residues necessary for cross-linking. "
Identifies the specific loricrin mutation causing the ichthyotic variant.
PMID:12072018 SUPPORT
"identified a recurrent insertion mutation in the loricrin gene resulting in a mutant polypeptide with an unusual C terminus. "
Confirms the recurrent nature of loricrin insertion mutations.
💊

Treatments

5
Keratolytic Therapy
Topical agents containing salicylic acid or urea to soften and reduce hyperkeratotic skin lesions on palms and soles.
Emollients
Regular application of moisturizers to maintain skin hydration and reduce cracking and discomfort.
Retinoids
Oral retinoids (isotretinoin, acitretin) may help control hyperkeratosis and can prevent digital constrictions in some patients. Relapse typically occurs upon discontinuation of treatment.
Show evidence (1 reference)
PMID:6237617 SUPPORT
"One of the patients was successfully treated with isotretinoin, 0.6 mg/kg/day orally. "
First report of successful isotretinoin treatment for the ichthyotic variant of Vohwinkel syndrome.
Surgical Intervention
Surgical release of constricting bands may be necessary to prevent autoamputation of digits; in severe cases, amputation may be required.
Hearing Aids and Cochlear Implants
Audiological management for sensorineural hearing loss, including hearing aids for mild-moderate loss and cochlear implants for profound loss. Applicable only to classic GJB2-associated form.
{ }

Source YAML

click to show 
name: Keratoderma Hereditarium Mutilans
creation_date: '2026-02-06T03:39:54Z'
updated_date: '2026-02-17T21:53:14Z'
description: >
  Keratoderma hereditarium mutilans, also known as Vohwinkel syndrome, is a rare
  autosomal dominant genodermatosis characterized by diffuse palmoplantar keratoderma
  with a distinctive honeycomb pattern, pseudoainhum (constricting bands around digits
  leading to autoamputation), and sensorineural hearing loss. The classic form is
  caused
  by mutations in the GJB2 gene encoding connexin 26. The ichthyotic variant (Camisa
  syndrome) is caused by mutations in the LOR gene encoding loricrin.
category: Mendelian
disease_term:
  preferred_term: keratoderma hereditarium mutilans
  term:
    id: MONDO:0007422
    label: keratoderma hereditarium mutilans
parents:
- Hereditary Palmoplantar Keratoderma
- Connexin Disorders
has_subtypes:
- name: Classic Vohwinkel Syndrome
  description: >
    The classic form caused by GJB2 mutations, featuring the complete triad of
    palmoplantar keratoderma, pseudoainhum, and sensorineural hearing loss.
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      VS is characterized by papular and honeycomb keratoderma associated with
      constrictions of digits leading to autoamputation, distinctive starfish-like
      acral keratoses and moderate degrees of deafness.
    explanation: This landmark paper identified the D66H mutation in GJB2 as
      causative for classic Vohwinkel syndrome with the characteristic triad.
- name: Loricrin Keratoderma (Variant Vohwinkel Syndrome)
  description: >
    A variant form caused by LOR gene mutations, featuring keratoderma and pseudoainhum
    but with ichthyosis instead of hearing loss. Also known as Camisa variant.
  evidence:
  - reference: PMID:9326398
    supports: SUPPORT
    snippet: >
      Vohwinkel's keratoderma is thus clinically and genetically heterogeneous. Only
      the variant with ichthyosis appears to be due to loricrin mutation.
    explanation: This paper established that loricrin mutations cause the
      ichthyotic variant without hearing loss.
  - reference: PMID:12072018
    supports: SUPPORT
    snippet: >
      Functional studies in transgenic mice have shown that the accumulation of mutant
      loricrin in the nucleus appears to interfere with the later stages of epidermal
      differentiation, thereby explaining the clinical manifestations of ichthyosis,
      keratoderma and pseudoainhum.
    explanation: Confirms loricrin mutations underlie the ichthyotic variant of
      Vohwinkel syndrome.
pathophysiology:
- name: Gap Junction Dysfunction
  description: >
    Mutations in GJB2 disrupt connexin 26 function, impairing gap junction-mediated
    intercellular communication in the epidermis and cochlea. The D66H mutation occurs
    at a highly conserved residue in the first extracellular domain and may interfere
    with connexon assembly, docking, or gating properties. This leads to defective
    ion homeostasis and impaired cellular coordination during differentiation.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Gap junction assembly
    term:
      id: GO:0016264
      label: gap junction assembly
  - preferred_term: Cell-cell signaling
    term:
      id: GO:0007267
      label: cell-cell signaling
  locations:
  - preferred_term: Skin of palm and sole
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  downstream:
  - target: Abnormal Epidermal Differentiation
    description: >
      Impaired gap junction communication disrupts calcium signaling and
      intercellular coordination required for normal keratinocyte differentiation.
    evidence:
    - reference: PMID:10369869
      supports: SUPPORT
      snippet: >
        Our results provide evidence that a specific mutation in Cx26 can impair
        epidermal differentiation, as well as inner ear function.
      explanation: Demonstrates that GJB2 mutations lead to impaired epidermal
        differentiation.
  - target: Cochlear Dysfunction
    description: >
      Connexin 26 dysfunction in the inner ear disrupts potassium recycling
      and the endocochlear potential required for hearing.
    evidence:
    - reference: PMID:10369869
      supports: SUPPORT
      snippet: >
        Mutations in the connexin26 (Cx26) gene (GJB2) at 13q11-q13 are a major cause
        of autosomal recessive hearing loss (DFNB1), but have also been reported in
        autosomal dominant deafness (DFNA3).
      explanation: Establishes the causal link between GJB2 mutations and
        hearing loss.
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      This mutation occurs at a highly conserved residue in the first extracellular
      domain of the Cx26 molecule, and may exert its effects by interfering with
      assembly into connexons, docking with adjacent cells or gating properties of
      the gap junction.
    explanation: Describes the molecular mechanism of GJB2 D66H mutation
      disrupting gap junction function.
  - reference: PMID:14681042
    supports: SUPPORT
    snippet: >
      Expression of the transgene resulted in a loss of Cx26 and Cx30 at intercellular
      junctions of epidermal keratinocytes and accumulation of these connexins in
      the
      cytoplasm.
    explanation: Transgenic mouse model demonstrates that D66H mutation causes
      loss of connexins at cell junctions.
    evidence_source: MODEL_ORGANISM
- name: Abnormal Epidermal Differentiation
  description: >
    Defective gap junction signaling leads to hyperproliferation and abnormal
    keratinization of palmoplantar epidermis, resulting in the characteristic
    thickened honeycomb-patterned skin. The mutation impairs epidermal differentiation
    as well as inner ear function.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  downstream:
  - target: Digital Constriction and Autoamputation
    description: >
      Chronic aberrant keratinization leads to formation of fibrous constricting
      bands around digits that progressively tighten and may cause autoamputation.
    evidence:
    - reference: PMID:10369869
      supports: SUPPORT
      snippet: >
        VS is characterized by papular and honeycomb keratoderma associated with
        constrictions of digits leading to autoamputation
      explanation: Links the keratoderma phenotype to digital constriction and
        autoamputation.
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      Our results provide evidence that a specific mutation in Cx26 can impair
      epidermal differentiation, as well as inner ear function.
    explanation: Establishes that GJB2 mutations affect both epidermal and
      cochlear function.
  - reference: PMID:14681042
    supports: SUPPORT
    snippet: >
      Following birth, the transgenic mice developed keratoderma similar to that of
      human carriers of Cx26 (D66H).
    explanation: Transgenic mice expressing mutant Cx26 develop keratoderma like
      human patients.
    evidence_source: MODEL_ORGANISM
- name: Mutant Loricrin Nuclear Accumulation
  description: >
    In the ichthyotic variant, mutant loricrin is mislocalized to the nuclei of
    granular layer keratinocytes and fails to incorporate into the cornified cell
    envelope. The frameshift mutation creates an abnormal C-terminal peptide containing
    nuclear localization signals, causing aberrant nuclear translocation and interference
    with late stages of epidermal differentiation.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Cornified envelope assembly
    term:
      id: GO:1903575
      label: cornified envelope assembly
  - preferred_term: Keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  downstream:
  - target: Digital Constriction and Autoamputation
    description: >
      Nuclear interference with keratinocyte differentiation leads to
      defective cornification and formation of constricting bands.
    evidence:
    - reference: PMID:12072018
      supports: SUPPORT
      snippet: >
        the accumulation of mutant loricrin in the nucleus appears to interfere
        with the later stages of epidermal differentiation, thereby explaining
        the clinical manifestations of ichthyosis, keratoderma and pseudoainhum.
      explanation: Establishes the mechanistic link between loricrin nuclear
        accumulation and pseudoainhum.
  evidence:
  - reference: PMID:11121146
    supports: SUPPORT
    snippet: >
      Mutant loricrin, as a dominant negative disrupter, is not likely to affect
      cornified cell envelope crosslinking directly, but seems to interfere with
      nuclear/nucleolar functions of differentiating keratinocytes.
    explanation: Describes the mechanism by which mutant loricrin causes disease
      through nuclear interference.
  - reference: PMID:9326398
    supports: SUPPORT
    snippet: >
      a G insertion producing a frameshift after codon 231 and an abnormal C-terminal
      peptide lacking residues necessary for cross-linking.
    explanation: Identifies the specific mutation and its effect on loricrin
      protein structure.
  - reference: PMID:11038186
    supports: SUPPORT
    snippet: >
      Immunofluorescence and immunoelectron microscopy showed the mutant loricrin
      protein in the nucleus and cytoplasm of epidermal keratinocytes, but did not
      detect the protein in the cornified cell envelope.
    explanation: Transgenic mouse studies confirm nuclear mislocalization of
      mutant loricrin.
    evidence_source: MODEL_ORGANISM
- name: Digital Constriction and Autoamputation
  description: >
    Fibrous bands encircle digits (pseudoainhum), progressively constricting and
    potentially leading to spontaneous amputation. The pathogenesis involves aberrant
    keratinization and tissue remodeling secondary to keratinocyte dysfunction.
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      VS is characterized by papular and honeycomb keratoderma associated with
      constrictions of digits leading to autoamputation
    explanation: Describes the progression from constricting bands to
      autoamputation.
- name: Cochlear Dysfunction
  description: >
    Connexin 26 is essential for potassium recycling in the cochlea. Its dysfunction
    disrupts the endocochlear potential required for auditory transduction, causing
    sensorineural hearing loss. This phenotype is specific to GJB2 mutations and
    is absent in the loricrin-associated variant.
  locations:
  - preferred_term: Cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      Mutations in the connexin26 (Cx26) gene (GJB2) at 13q11-q13 are a major cause
      of autosomal recessive hearing loss (DFNB1), but have also been reported in
      autosomal dominant deafness (DFNA3).
    explanation: Establishes the role of GJB2 in both skin and hearing
      phenotypes.
  - reference: PMID:9326398
    supports: SUPPORT
    snippet: >
      In our second family (VK2), affected members had sensorineural deafness but
      not ichthyosis.
    explanation: Confirms that deafness segregates with connexin mutations, not
      loricrin mutations.
phenotypes:
- name: Palmoplantar Keratoderma
  description: >
    Diffuse thickening of the skin on palms and soles with a characteristic
    honeycomb or starfish pattern, typically appearing in infancy or early childhood.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      VS is characterized by papular and honeycomb keratoderma associated with
      constrictions of digits leading to autoamputation
    explanation: Honeycomb keratoderma is a defining feature of the syndrome.
- name: Honeycomb Palmoplantar Hyperkeratosis
  description: >
    The characteristic honeycomb pattern of hyperkeratosis on palms and soles,
    a hallmark feature of both GJB2 and LOR forms.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Honeycomb palmoplantar hyperkeratosis
    term:
      id: HP:0007465
      label: Honeycomb palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      VS is characterized by papular and honeycomb keratoderma
    explanation: Honeycomb pattern is characteristic of the syndrome.
- name: Pseudoainhum
  description: >
    Constricting fibrous bands around digits, particularly affecting the fifth toe
    and other fingers, which may progress to autoamputation.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Autoamputation of digits
    term:
      id: HP:0007460
      label: Autoamputation of digits
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      constrictions of digits leading to autoamputation
    explanation: Pseudoainhum with potential autoamputation is a key feature.
  - reference: PMID:12072018
    supports: SUPPORT
    snippet: >
      the clinical manifestations of ichthyosis, keratoderma and pseudoainhum
    explanation: Pseudoainhum is a feature of both genetic forms.
- name: Sensorineural Hearing Loss
  description: >
    Bilateral, progressive hearing impairment ranging from mild to profound,
    typically presenting in early childhood. Present in classic GJB2-associated
    form but absent in loricrin-associated variant.
  frequency: FREQUENT
  subtype: Classic Vohwinkel Syndrome
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      A missense mutation in connexin26, D66H, causes mutilating keratoderma with
      sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.
    explanation: Sensorineural deafness is part of the classic Vohwinkel
      phenotype.
  - reference: PMID:20031451
    supports: SUPPORT
    snippet: >
      Vohwinkel Syndrome (VS) is a type of diffuse hereditary palmoplantar
      keratodermas (DHPPK) accompanied by skeletal dimorphisms and sensorineural
      deafness.
    explanation: Confirms sensorineural deafness as a component of the syndrome.
- name: Starfish-Shaped Hyperkeratoses
  description: >
    Distinctive star-shaped keratotic lesions on the dorsal surfaces of hands,
    feet, elbows, and knees.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      distinctive starfish-like acral keratoses
    explanation: Starfish-like acral keratoses are a characteristic feature.
- name: Knuckle Pads
  description: >
    Thickened skin over the knuckles (interphalangeal joints), presenting
    as keratotic structures on the dorsal surfaces of the hands, often with
    a starfish-like appearance.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Knuckle pad
    term:
      id: HP:0032541
      label: Knuckle pad
  evidence:
  - reference: PMID:6237617
    supports: SUPPORT
    snippet: >
      keratotic structures taking the shape of a starfish and/or knuckle pads
      on the dorsal surfaces of the hands
    explanation: Describes starfish-shaped keratoses and knuckle pads as
      characteristic features.
  - reference: PMID:30335335
    supports: SUPPORT
    snippet: >
      The classic Vohwinkel syndrome is a hereditary PPK associated with
      "starfish" keratoses on the knuckles
    explanation: StatPearls review confirms starfish keratoses on knuckles are
      part of classic syndrome.
- name: Ichthyosis
  description: >
    Generalized scaling of the skin, characteristic of the loricrin-associated
    (Camisa) variant but absent in classic GJB2-associated form.
  frequency: VERY_FREQUENT
  subtype: Loricrin Keratoderma (Variant Vohwinkel Syndrome)
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:9326398
    supports: SUPPORT
    snippet: >
      Our first family (VK1) also had ichthyosis but not deafness.
    explanation: Ichthyosis is present in the loricrin variant but not classic
      form.
  - reference: PMID:11038186
    supports: SUPPORT
    snippet: >
      At birth, transgenic mice (ML.VS) exhibited erythrokeratoderma with an epidermal
      barrier dysfunction. 4 d after birth, high-expressing transgenic animals showed
      a generalized scaling of the skin
    explanation: Transgenic mice with mutant loricrin develop ichthyosis-like
      scaling.
    evidence_source: MODEL_ORGANISM
- name: Alopecia
  description: >
    Sparse hair or patchy hair loss, particularly affecting eyebrows and eyelashes
    in some patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
genetic:
- name: GJB2
  gene_term:
    preferred_term: GJB2
    term:
      id: hgnc:4284
      label: GJB2
  association: Causative
  notes: >
    Autosomal dominant. The D66H mutation (c.196G>C) in exon 1 is the most common
    pathogenic variant causing classic Vohwinkel syndrome. The mutation occurs at
    a highly conserved residue in the first extracellular domain of connexin 26.
  variants:
  - name: D66H
    description: >
      Missense mutation (c.196G>C) causing substitution of aspartate to histidine
      at position 66 in the first extracellular domain. Most common mutation in
      classic Vohwinkel syndrome.
  evidence:
  - reference: PMID:10369869
    supports: SUPPORT
    snippet: >
      All 10 affected members were heterozygous for a non-conservative mutation,
      D66H, in Cx26. The same mutation was found subsequently in affected individuals
      from two unrelated Spanish and Italian pedigrees segregating VS, suggesting
      that D66H in Cx26 is a common mutation in classical VS.
    explanation: Identifies D66H as a common mutation in classic Vohwinkel
      syndrome across multiple families.
  - reference: PMID:20031451
    supports: SUPPORT
    snippet: >
      Genetic study showed a nucleotide change (c.196G>C) in exon 1 of GJB2 gene,
      producing a missense mutation, D66H.
    explanation: Confirms the specific nucleotide change causing the D66H
      mutation.
- name: LOR
  gene_term:
    preferred_term: LOR
    term:
      id: hgnc:6663
      label: LOR
  association: Causative
  notes: >
    Autosomal dominant. Frameshift mutations (commonly 730insG) cause the ichthyotic
    variant (Camisa syndrome). The mutation produces an abnormal C-terminal peptide
    with nuclear localization signals.
  variants:
  - name: 730insG
    description: >
      Recurrent insertion mutation causing frameshift after codon 231, producing
      an abnormal C-terminal peptide that mislocalizes to the nucleus.
  evidence:
  - reference: PMID:9326398
    supports: SUPPORT
    snippet: >
      a G insertion producing a frameshift after codon 231 and an abnormal C-terminal
      peptide lacking residues necessary for cross-linking.
    explanation: Identifies the specific loricrin mutation causing the
      ichthyotic variant.
  - reference: PMID:12072018
    supports: SUPPORT
    snippet: >
      identified a recurrent insertion mutation in the loricrin gene resulting in
      a mutant polypeptide with an unusual C terminus.
    explanation: Confirms the recurrent nature of loricrin insertion mutations.
treatments:
- name: Keratolytic Therapy
  description: >
    Topical agents containing salicylic acid or urea to soften and reduce
    hyperkeratotic skin lesions on palms and soles.
- name: Emollients
  description: >
    Regular application of moisturizers to maintain skin hydration and
    reduce cracking and discomfort.
- name: Retinoids
  description: >
    Oral retinoids (isotretinoin, acitretin) may help control hyperkeratosis
    and can prevent digital constrictions in some patients. Relapse typically
    occurs upon discontinuation of treatment.
  evidence:
  - reference: PMID:6237617
    supports: SUPPORT
    snippet: >
      One of the patients was successfully treated with isotretinoin, 0.6 mg/kg/day
      orally.
    explanation: First report of successful isotretinoin treatment for the
      ichthyotic variant of Vohwinkel syndrome.
- name: Surgical Intervention
  description: >
    Surgical release of constricting bands may be necessary to prevent
    autoamputation of digits; in severe cases, amputation may be required.
- name: Hearing Aids and Cochlear Implants
  description: >
    Audiological management for sensorineural hearing loss, including
    hearing aids for mild-moderate loss and cochlear implants for profound loss.
    Applicable only to classic GJB2-associated form.
datasets:
references:
- reference: DOI:10.1016/j.yadr.2007.07.011
  title: 'Ichthyosis Update: Towards a Function-Driven Model of Pathogenesis of the
    Disorders of Cornification and the Role of Corneocyte Proteins in These Disorders'
  findings: []
- reference: DOI:10.1093/hmg/8.7.1237
  title: A missense mutation in connexin26, D66H, causes mutilating keratoderma
    with sensorineural deafness (Vohwinkel's syndrome) in three unrelated
    families
  findings: []
- reference: DOI:10.1177/2050313x231204197
  title: 'Palmoplantar keratoderma, pseudo-ainhum and knuckle pads in an African patient:
    A case report'
  findings: []
- reference: DOI:10.3390/biology10010059
  title: 'Connexins and the Epithelial Tissue Barrier: A Focus on Connexin 26'
  findings: []