👪

Inheritance

1

Autosomal Recessive HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:24671081 SUPPORT Human Clinical

"We describe two large consanguineous families with autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy and with no mutations in any known culprit gene."

The founding families show autosomal recessive transmission of the hair-keratoderma phenotype.

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Discussions and Knowledge Gaps

2

Why does KANK2 p.Ala670Val cause woolly hair and keratoderma, while other recessive KANK2 variants are reported with nephrotic syndrome and no skin phenotype?

KNOWLEDGE GAP OPEN ppkwh_kank2_allele_specificity

Attached to

pathophysiology#KANK2 Loss of Coactivator Sequestration

The nephrotic-syndrome KANK2 variants were tested and did not disrupt the interaction with NCOA3 (SRC-3), whereas the skin variant is proposed to act through SRC sequestration. Whether the two phenotypes reflect separate functions of KANK2 is untested, and only one skin allele is known.

Show evidence (1 reference)

PMID:25961457 SUPPORT In Vitro

"None of the KANK2 mutations identified in individuals with NS abrogated the interaction with NCOA3 (Supplemental Figure 9)."

Shows that the nephrotic-syndrome KANK2 alleles leave the coactivator interaction intact, which distinguishes them mechanistically from the keratoderma allele.

Are sensorineural hearing loss and maculopathy part of KANK2-related woolly hair-palmoplantar keratoderma syndrome?

KNOWLEDGE GAP OPEN ppkwh_unconfirmed_extracutaneous_features

Attached to

phenotypes#

A single type IV case with these findings was diagnosed clinically and the report does not state that KANK2 was tested, so a separate disorder cannot be excluded.

Show evidence (1 reference)

PMID:41818120 SUPPORT Human Clinical

"Here we report a 25-year-old woman with woolly hair, palmoplantar keratoderma without any cardiac morbidity. However, she had sensorineural hearing loss and maculopathy."

Single case report of the extracutaneous findings in a clinically labelled type IV patient.

⚙

Pathophysiology

3

KANK2 Loss of Coactivator Sequestration

The homozygous KANK2 p.Ala670Val missense variant alters SIP, an ankyrin-repeat protein that normally sequesters steroid receptor coactivators (SRCs) in the cytoplasm and so restrains transcriptional activation by steroid receptors, including the vitamin D receptor. The variant is predicted to abolish this sequestering ability; the precise molecular defect has not been demonstrated biochemically.

KANK2 hgnc:29300

protein sequestering activity GO:0140311 ↓ DECREASED

Downstream

Nuclear Accumulation of SRC-2 and SRC-3 in Epidermal Basal Cells Loss of cytoplasmic retention by mutant SIP allows SRC-2 and SRC-3 to accumulate in the nucleus of basal keratinocytes.

Show evidence (3 references)

PMID:24671081 SUPPORT Human Clinical

"Using whole-exome sequencing, we identified a homozygous missense c.2009C>T mutation in KANK2 in the patients (p.Ala670Val)."

Identifies the initiating lesion, a homozygous KANK2 missense variant in affected family members.

PMID:24671081 SUPPORT BACKGROUND In Vitro

"KANK2 encodes the steroid receptor coactivator (SRC)-interacting protein (SIP), an ankyrin repeat containing protein, which sequesters SRCs in the cytoplasm and controls transcription activation of steroid receptors, among others, also of the vitamin D receptor (VDR)."

States the normal cytoplasmic-sequestering function of SIP that the variant disrupts; this is the paper's summary of prior cell-based work, not its own result.

PMID:24671081 SUPPORT INDIRECT Computational

"The mutation in KANK2 is predicted to abolish the sequestering abilities of SIP."

Loss of sequestering function is a prediction for the A670V variant, not a direct biochemical measurement; the downstream cellular findings are the experimental support.

Nuclear Accumulation of SRC-2 and SRC-3 in Epidermal Basal Cells

In patient epidermis the steroid receptor coactivators SRC-2 (NCOA2) and SRC-3 (NCOA3), coactivators of the vitamin D receptor that take part in epidermal differentiation, are nuclear in basal cells rather than cytoplasmic.

basal cell of epidermis CL:0002187

protein localization to nucleus GO:0034504 ↑ INCREASED

Downstream

Increased Vitamin D Receptor Transactivation in Keratinocytes Nuclear SRC-2 and SRC-3 act as VDR coactivators, so their nuclear availability increases vitamin D-induced VDR transcriptional activation.

Show evidence (1 reference)

PMID:24671081 SUPPORT Human Clinical

"Furthermore, SRC-2 and SRC-3, coactivators of VDR and important components of epidermal differentiation, are localised to the nucleus of epidermal basal cells in patients, in contrast to the cytoplasmic distribution in the heterozygous control."

Direct observation of nuclear SRC-2/SRC-3 in patient basal epidermal cells.

Increased Vitamin D Receptor Transactivation in Keratinocytes

Cultured patient keratinocytes show increased vitamin D-induced transactivation, indicating enhanced VDR-dependent transcription. The VDR target genes responsible for the skin and hair phenotype have not been identified.

keratinocyte CL:0000312

vitamin D receptor signaling pathway GO:0070561 ↑ INCREASED

Downstream

Palmoplantar Keratoderma Dysregulated VDR-dependent epidermal transcription is proposed to underlie the palmoplantar hyperkeratosis; the intermediate differentiation targets are not known.

Woolly Hair Altered VDR signalling is proposed to affect hair-shaft formation; hair-follicle cells were not examined directly.

Show evidence (1 reference)

PMID:24671081 SUPPORT In Vitro

"Indeed, vitamin D-induced transactivation was increased in patient's keratinocytes."

Measured in cultured keratinocytes from a patient.

⬡

Pathograph

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Phenotypes

3

Integument 2

Palmoplantar Keratoderma VERY_FREQUENT HP:0000982

Onset: INFANTILE

Show evidence (3 references)

PMID:24671081 SUPPORT Human Clinical

"We describe two large consanguineous families with autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy and with no mutations in any known culprit gene."

Palmoplantar keratoderma is a defining feature of the affected members of the founding families.

PMID:35283492 SUPPORT REVIEW SYNTHESIS Human Clinical

"All 7 patients were young, had striate PPK and occasional pseudoanhium of fifth toe."

Summary of the founding KANK2 families (seven patients), recording that the keratoderma was striate in all of them.

PMID:35283492 SUPPORT INDIRECT Human Clinical

"abnormal hair texture since birth and thickening over the palms and soles since 6 months of age"

Supports infantile onset of the keratoderma, but in a single patient diagnosed clinically; KANK2 testing was not performed.

Woolly Hair VERY_FREQUENT HP:0002224

Onset: CONGENITAL

Show evidence (2 references)

PMID:24671081 SUPPORT Human Clinical

"We describe two large consanguineous families with autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy and with no mutations in any known culprit gene."

Woolly hair is the second defining feature in the founding families.

PMID:35283492 SUPPORT INDIRECT Human Clinical

"abnormal hair texture since birth and thickening over the palms and soles since 6 months of age"

Supports congenital onset of the hair abnormality, in a single clinically diagnosed patient without KANK2 testing.

Other 1

Pseudoainhum of the Fifth Toe OCCASIONAL

Left unbound. OLS search of HP for "pseudoainhum" returns only HP:0009775 Amniotic constriction ring, which carries Pseudoainhum as a synonym but sits under HP:0011409 Abnormal placental membrane morphology; "digital constriction" returns its child HP:0010491 Digital constriction ring, under the same parent. Both assert an amniotic origin that a keratoderma-associated constricting band does not have.

Show evidence (1 reference)

PMID:35283492 SUPPORT REVIEW SYNTHESIS Human Clinical

"All 7 patients were young, had striate PPK and occasional pseudoanhium of fifth toe."

Secondary summary of the founding KANK2 families reporting occasional fifth-toe pseudoainhum; the primary report's abstract does not mention it.

🧬

Genetic Associations

1

KANK2 (Causative)

Gene: KANK2 hgnc:29300 relationship_type: CAUSATIVE

Autosomal Recessive

Show evidence (1 reference)

PMID:24671081 SUPPORT Human Clinical

"Using whole-exome sequencing, we identified a homozygous missense c.2009C>T mutation in KANK2 in the patients (p.Ala670Val)."

Establishes KANK2 as the causal gene in the founding families.

Variants (1)

KANK2 c.2009C>T (p.Ala670Val)

Gene: KANK2 hgnc:29300 missense variant

Homozygous missense variant identified by whole-exome sequencing in the affected members of two consanguineous families; predicted to abolish SRC sequestration by SIP.

Show evidence (1 reference)

PMID:24671081 SUPPORT Human Clinical

"Using whole-exome sequencing, we identified a homozygous missense c.2009C>T mutation in KANK2 in the patients (p.Ala670Val)."

Reports the variant and its homozygous state in patients.

💊

Medical Actions

1

Oral Acitretin with Topical Keratolytics

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172

Platform: Small molecule

Systemic retinoid therapy (acitretin 25 mg daily) combined with topical keratolytics, with liver function and lipid monitoring, was followed by marked improvement of the keratoderma within two months in one clinically diagnosed type IV patient. No KANK2-specific or controlled treatment data exist.

Mechanism Target:

Palmoplantar Keratoderma

Show evidence (1 reference)

PMID:35283492 SUPPORT INDIRECT Human Clinical

"Remarkable improvement in palmoplantar keratoderma was noticed within 2 months of oral acitretin therapy."

Single-patient response to acitretin plus topical keratolytics. The patient was diagnosed clinically; KANK2 testing could not be done, so the response is not genotype-confirmed.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Wooly Hair-Palmoplantar Keratoderma Syndrome:

Naxos disease MONDO:0011017

Overlapping Features JUP-related desmosomal syndrome with the same woolly hair and palmoplantar keratoderma plus arrhythmogenic right ventricular cardiomyopathy; cardiac evaluation and sequencing distinguish it.

Show evidence (1 reference)

PMID:24671081 SUPPORT Human Clinical

"The combination of palmoplantar keratoderma and woolly hair is uncommon and reported as part of Naxos and Carvajal syndromes, both caused by mutations in desmosomal proteins and associated with cardiomyopathy."

Names Naxos disease as the desmosomal, cardiomyopathy-associated mimic.

Carvajal syndrome MONDO:0011581

Overlapping Features DSP-related desmosomal syndrome with woolly hair, striate palmoplantar keratoderma and predominantly left-ventricular cardiomyopathy.

Show evidence (1 reference)

PMID:24671081 SUPPORT Human Clinical

"The combination of palmoplantar keratoderma and woolly hair is uncommon and reported as part of Naxos and Carvajal syndromes, both caused by mutations in desmosomal proteins and associated with cardiomyopathy."

Names Carvajal syndrome as the other desmosomal, cardiomyopathy-associated mimic.

{ }

Source YAML

click to show

name: Wooly Hair-Palmoplantar Keratoderma Syndrome
creation_date: "2026-10-11T00:00:00Z"
category: Mendelian
description: >-
  Wooly hair-palmoplantar keratoderma syndrome (keratoderma with woolly hair
  type IV, PPKWH) is an autosomal recessive ectodermal disorder in which woolly
  scalp hair is combined with palmoplantar keratoderma, without the
  cardiomyopathy that defines the clinically overlapping desmosomal syndromes
  (Naxos disease, JUP; Carvajal syndrome, DSP). It was defined in two
  consanguineous families homozygous for the KANK2 missense variant
  c.2009C>T (p.Ala670Val). KANK2 encodes the steroid receptor
  coactivator-interacting protein (SIP), which holds steroid receptor
  coactivators in the cytoplasm; in patients, SRC-2 and SRC-3 are nuclear in
  basal epidermal cells and vitamin D receptor transactivation is increased in
  keratinocytes, making this a non-desmosomal cause of the hair-keratoderma
  combination.
disease_term:
  preferred_term: wooly hair-palmoplantar keratoderma syndrome
  term:
    id: MONDO:0014492
    label: wooly hair-palmoplantar keratoderma syndrome
synonyms:
- palmoplantar keratoderma and woolly hair
- PPKWH
- KWWH type IV
- keratoderma with woolly hair type IV
- keratoderma with wooly hair type IV
- woolly hair-palmoplantar hyperkeratosis syndrome
- wooly hair-palmoplantar hyperkeratosis syndrome
- type 4 woolly hair-palmoplantar keratoderma syndrome
parents:
- palmoplantar keratoderma
notes: >-
  No GeneReviews chapter covers this disease (checked with just
  check-genereviews --online against the entry name and synonyms). The
  molecularly confirmed literature is a single report of two consanguineous
  families (PMID:24671081). Later case reports labelled type IV
  (PMID:35283492, PMID:41818120) made the diagnosis clinically, without KANK2
  testing, so features first described in those cases (finger contractures,
  thickened nails, sensorineural hearing loss, maculopathy) are not recorded
  as phenotypes of this entry. The Orphanet record (ORPHA:420686) also lists
  leukonychia and sparse hair; it could not be cited because the Orphanet
  structured cache was not available to this curation.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two large consanguineous families with autosomal-recessive
      palmoplantar keratoderma and woolly hair, without cardiomyopathy and with
      no mutations in any known culprit gene.
    explanation: >-
      The founding families show autosomal recessive transmission of the
      hair-keratoderma phenotype.
pathophysiology:
- name: KANK2 Loss of Coactivator Sequestration
  description: >-
    The homozygous KANK2 p.Ala670Val missense variant alters SIP, an
    ankyrin-repeat protein that normally sequesters steroid receptor
    coactivators (SRCs) in the cytoplasm and so restrains transcriptional
    activation by steroid receptors, including the vitamin D receptor. The
    variant is predicted to abolish this sequestering ability; the precise
    molecular defect has not been demonstrated biochemically.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KANK2
    term:
      id: hgnc:29300
      label: KANK2
  molecular_functions:
  - preferred_term: protein sequestering activity
    term:
      id: GO:0140311
      label: protein sequestering activity
    modifier: DECREASED
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing, we identified a homozygous missense
      c.2009C>T mutation in KANK2 in the patients (p.Ala670Val).
    explanation: >-
      Identifies the initiating lesion, a homozygous KANK2 missense variant in
      affected family members.
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: IN_VITRO
    snippet: >-
      KANK2 encodes the steroid receptor coactivator (SRC)-interacting protein
      (SIP), an ankyrin repeat containing protein, which sequesters SRCs in the
      cytoplasm and controls transcription activation of steroid receptors,
      among others, also of the vitamin D receptor (VDR).
    explanation: >-
      States the normal cytoplasmic-sequestering function of SIP that the
      variant disrupts; this is the paper's summary of prior cell-based work,
      not its own result.
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The mutation in KANK2 is predicted to abolish the sequestering abilities
      of SIP.
    explanation: >-
      Loss of sequestering function is a prediction for the A670V variant, not
      a direct biochemical measurement; the downstream cellular findings are
      the experimental support.
  downstream:
  - target: Nuclear Accumulation of SRC-2 and SRC-3 in Epidermal Basal Cells
    causal_link_type: DIRECT
    description: >-
      Loss of cytoplasmic retention by mutant SIP allows SRC-2 and SRC-3 to
      accumulate in the nucleus of basal keratinocytes.
    evidence:
    - reference: PMID:24671081
      reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Furthermore, SRC-2 and SRC-3, coactivators of VDR and important
        components of epidermal differentiation, are localised to the nucleus of
        epidermal basal cells in patients, in contrast to the cytoplasmic
        distribution in the heterozygous control.
      explanation: >-
        Homozygous patients show nuclear SRC-2/SRC-3 where a heterozygous
        control retains them in the cytoplasm, consistent with lost
        sequestration by the mutant protein.
- name: Nuclear Accumulation of SRC-2 and SRC-3 in Epidermal Basal Cells
  description: >-
    In patient epidermis the steroid receptor coactivators SRC-2 (NCOA2) and
    SRC-3 (NCOA3), coactivators of the vitamin D receptor that take part in
    epidermal differentiation, are nuclear in basal cells rather than
    cytoplasmic.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: basal cell of epidermis
    term:
      id: CL:0002187
      label: basal cell of epidermis
  biological_processes:
  - preferred_term: protein localization to nucleus
    term:
      id: GO:0034504
      label: protein localization to nucleus
    modifier: INCREASED
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, SRC-2 and SRC-3, coactivators of VDR and important
      components of epidermal differentiation, are localised to the nucleus of
      epidermal basal cells in patients, in contrast to the cytoplasmic
      distribution in the heterozygous control.
    explanation: >-
      Direct observation of nuclear SRC-2/SRC-3 in patient basal epidermal
      cells.
  downstream:
  - target: Increased Vitamin D Receptor Transactivation in Keratinocytes
    causal_link_type: DIRECT
    description: >-
      Nuclear SRC-2 and SRC-3 act as VDR coactivators, so their nuclear
      availability increases vitamin D-induced VDR transcriptional activation.
    evidence:
    - reference: PMID:24671081
      reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Indeed, vitamin D-induced transactivation was increased in patient's
        keratinocytes.
      explanation: >-
        The paper presents increased VDR transactivation as the expected
        consequence of lost coactivator sequestration ("Indeed"); the link
        between the two observations is inferred from their co-occurrence in
        patient cells rather than shown by a rescue or knockdown experiment.
- name: Increased Vitamin D Receptor Transactivation in Keratinocytes
  description: >-
    Cultured patient keratinocytes show increased vitamin D-induced
    transactivation, indicating enhanced VDR-dependent transcription. The VDR
    target genes responsible for the skin and hair phenotype have not been
    identified.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: vitamin D receptor signaling pathway
    term:
      id: GO:0070561
      label: vitamin D receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Indeed, vitamin D-induced transactivation was increased in patient's
      keratinocytes.
    explanation: >-
      Measured in cultured keratinocytes from a patient.
  downstream:
  - target: Palmoplantar Keratoderma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysregulated VDR-dependent epidermal transcription is proposed to
      underlie the palmoplantar hyperkeratosis; the intermediate
      differentiation targets are not known.
    evidence:
    - reference: PMID:24671081
      reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These findings provide evidence that keratoderma and woolly hair can be
        caused by a non-desmosomal mechanism and further underline the
        importance of VDR for normal hair and skin phenotypes.
      explanation: >-
        The authors attribute the keratoderma to the VDR-coactivator mechanism;
        the step from increased VDR transactivation to hyperkeratosis is their
        interpretation rather than a demonstrated causal experiment.
  - target: Woolly Hair
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered VDR signalling is proposed to affect hair-shaft formation;
      hair-follicle cells were not examined directly.
    evidence:
    - reference: PMID:24671081
      reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These findings provide evidence that keratoderma and woolly hair can be
        caused by a non-desmosomal mechanism and further underline the
        importance of VDR for normal hair and skin phenotypes.
      explanation: >-
        The authors link the hair phenotype to VDR dysregulation by inference;
        no follicular cell assay was reported.
phenotypes:
- name: Palmoplantar Keratoderma
  category: Dermatological
  description: >-
    Thickening of the palmar and plantar skin, described as striate in the
    founding families. In a later, genetically unconfirmed type IV case it was
    diffuse with transgrediens and began at about 6 months of age.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Striate palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two large consanguineous families with autosomal-recessive
      palmoplantar keratoderma and woolly hair, without cardiomyopathy and with
      no mutations in any known culprit gene.
    explanation: >-
      Palmoplantar keratoderma is a defining feature of the affected members
      of the founding families.
  - reference: PMID:35283492
    reference_title: "Type 4 Woolly Hair-Palmoplantar Keratoderma Syndrome: A Rare Entity."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 7 patients were young, had striate PPK and occasional pseudoanhium of
      fifth toe.
    explanation: >-
      Summary of the founding KANK2 families (seven patients), recording that
      the keratoderma was striate in all of them.
  - reference: PMID:35283492
    reference_title: "Type 4 Woolly Hair-Palmoplantar Keratoderma Syndrome: A Rare Entity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal hair texture since birth and thickening over the palms and soles
      since 6 months of age
    explanation: >-
      Supports infantile onset of the keratoderma, but in a single patient
      diagnosed clinically; KANK2 testing was not performed.
- name: Woolly Hair
  category: Dermatological
  description: >-
    Tightly curled, woolly scalp hair, present from birth in the reported
    type IV case.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Woolly hair
    term:
      id: HP:0002224
      label: Woolly hair
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two large consanguineous families with autosomal-recessive
      palmoplantar keratoderma and woolly hair, without cardiomyopathy and with
      no mutations in any known culprit gene.
    explanation: >-
      Woolly hair is the second defining feature in the founding families.
  - reference: PMID:35283492
    reference_title: "Type 4 Woolly Hair-Palmoplantar Keratoderma Syndrome: A Rare Entity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal hair texture since birth and thickening over the palms and soles
      since 6 months of age
    explanation: >-
      Supports congenital onset of the hair abnormality, in a single clinically
      diagnosed patient without KANK2 testing.
- name: Pseudoainhum of the Fifth Toe
  category: Dermatological
  description: >-
    Occasional constricting band of the fifth toe (pseudoainhum) in the founding
    families, a recognised complication of hereditary keratoderma.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pseudoainhum of the fifth toe
  notes: >-
    Left unbound. OLS search of HP for "pseudoainhum" returns only HP:0009775
    Amniotic constriction ring, which carries Pseudoainhum as a synonym but sits
    under HP:0011409 Abnormal placental membrane morphology; "digital
    constriction" returns its child HP:0010491 Digital constriction ring, under
    the same parent. Both assert an amniotic origin that a keratoderma-associated
    constricting band does not have.
  evidence:
  - reference: PMID:35283492
    reference_title: "Type 4 Woolly Hair-Palmoplantar Keratoderma Syndrome: A Rare Entity."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 7 patients were young, had striate PPK and occasional pseudoanhium of
      fifth toe.
    explanation: >-
      Secondary summary of the founding KANK2 families reporting occasional
      fifth-toe pseudoainhum; the primary report's abstract does not mention
      it.
genetic:
- name: KANK2
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KANK2
    term:
      id: hgnc:29300
      label: KANK2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    KANK2 encodes SIP (steroid receptor coactivator-interacting protein). The
    only allele molecularly linked to this disease is homozygous p.Ala670Val.
    Other recessive KANK2 variants were found in families with nephrotic
    syndrome (PMID:25961457) and are a separate phenotype; no ClinGen
    gene-disease validity assertion for KANK2 and this disease is cached.
  variants:
  - name: KANK2 c.2009C>T (p.Ala670Val)
    description: >-
      Homozygous missense variant identified by whole-exome sequencing in the
      affected members of two consanguineous families; predicted to abolish
      SRC sequestration by SIP.
    gene:
      preferred_term: KANK2
      term:
        id: hgnc:29300
        label: KANK2
    type: missense variant
    evidence:
    - reference: PMID:24671081
      reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Using whole-exome sequencing, we identified a homozygous missense
        c.2009C>T mutation in KANK2 in the patients (p.Ala670Val).
      explanation: >-
        Reports the variant and its homozygous state in patients.
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing, we identified a homozygous missense
      c.2009C>T mutation in KANK2 in the patients (p.Ala670Val).
    explanation: >-
      Establishes KANK2 as the causal gene in the founding families.
treatments:
- name: Oral Acitretin with Topical Keratolytics
  description: >-
    Systemic retinoid therapy (acitretin 25 mg daily) combined with topical
    keratolytics, with liver function and lipid monitoring, was followed by
    marked improvement of the keratoderma within two months in one clinically
    diagnosed type IV patient. No KANK2-specific or controlled treatment data
    exist.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_mechanisms:
  - target: Palmoplantar Keratoderma
  evidence:
  - reference: PMID:35283492
    reference_title: "Type 4 Woolly Hair-Palmoplantar Keratoderma Syndrome: A Rare Entity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Remarkable improvement in palmoplantar keratoderma was noticed within 2
      months of oral acitretin therapy.
    explanation: >-
      Single-patient response to acitretin plus topical keratolytics. The
      patient was diagnosed clinically; KANK2 testing could not be done, so the
      response is not genotype-confirmed.
differential_diagnoses:
- name: Naxos disease
  disease_term:
    preferred_term: Naxos disease
    term:
      id: MONDO:0011017
      label: Naxos disease
  description: >-
    JUP-related desmosomal syndrome with the same woolly hair and palmoplantar
    keratoderma plus arrhythmogenic right ventricular cardiomyopathy; cardiac
    evaluation and sequencing distinguish it.
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combination of palmoplantar keratoderma and woolly hair is uncommon
      and reported as part of Naxos and Carvajal syndromes, both caused by
      mutations in desmosomal proteins and associated with cardiomyopathy.
    explanation: >-
      Names Naxos disease as the desmosomal, cardiomyopathy-associated mimic.
- name: Carvajal syndrome
  disease_term:
    preferred_term: Carvajal syndrome
    term:
      id: MONDO:0011581
      label: arrhythmogenic cardiomyopathy with wooly hair and keratoderma
  description: >-
    DSP-related desmosomal syndrome with woolly hair, striate palmoplantar
    keratoderma and predominantly left-ventricular cardiomyopathy.
  evidence:
  - reference: PMID:24671081
    reference_title: "Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combination of palmoplantar keratoderma and woolly hair is uncommon
      and reported as part of Naxos and Carvajal syndromes, both caused by
      mutations in desmosomal proteins and associated with cardiomyopathy.
    explanation: >-
      Names Carvajal syndrome as the other desmosomal, cardiomyopathy-associated
      mimic.
discussions:
- discussion_id: ppkwh_kank2_allele_specificity
  prompt: >-
    Why does KANK2 p.Ala670Val cause woolly hair and keratoderma, while other
    recessive KANK2 variants are reported with nephrotic syndrome and no skin
    phenotype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#KANK2 Loss of Coactivator Sequestration
  rationale: >-
    The nephrotic-syndrome KANK2 variants were tested and did not disrupt the
    interaction with NCOA3 (SRC-3), whereas the skin variant is proposed to act
    through SRC sequestration. Whether the two phenotypes reflect separate
    functions of KANK2 is untested, and only one skin allele is known.
  evidence:
  - reference: PMID:25961457
    reference_title: "KANK deficiency leads to podocyte dysfunction and nephrotic syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      None of the KANK2 mutations identified in individuals with NS abrogated
      the interaction with NCOA3 (Supplemental Figure 9).
    explanation: >-
      Shows that the nephrotic-syndrome KANK2 alleles leave the
      coactivator interaction intact, which distinguishes them mechanistically
      from the keratoderma allele.
- discussion_id: ppkwh_unconfirmed_extracutaneous_features
  prompt: >-
    Are sensorineural hearing loss and maculopathy part of KANK2-related
    woolly hair-palmoplantar keratoderma syndrome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#
  rationale: >-
    A single type IV case with these findings was diagnosed clinically and the
    report does not state that KANK2 was tested, so a separate disorder cannot
    be excluded.
  evidence:
  - reference: PMID:41818120
    reference_title: "Type 4 Woolly Hair-palmoplantar Keratoderma Syndrome with a Novel Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a 25-year-old woman with woolly hair, palmoplantar
      keratoderma without any cardiac morbidity. However, she had sensorineural
      hearing loss and maculopathy.
    explanation: >-
      Single case report of the extracutaneous findings in a clinically
      labelled type IV patient.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Wooly Hair-Palmoplantar Keratoderma Syndrome · 2026-10-11T20:24:30Z · View source

New entry for KANK2-related woolly hair-palmoplantar keratoderma syndrome (MONDO:0014492, keratoderma with woolly hair type IV). The deep-research source was a single Perplexity report (research/Wooly_Hair-Palmoplantar_Keratoderma_Syndrome-deep-research-perplexity.md); just preflight-dr returned PASS (KANK2 mentioned 43 times, MONDO OMIM 616099), and its reference validation resolved 16/16 references. The report's acitretin CURIE (CHEBI:50173) was not used; acitretin is CHEBI:50172. just check-genereviews --online found no GeneReviews chapter. The molecular evidence rests on one report of two consanguineous families (PMID:24671081): homozygous KANK2 c.2009C>T p.Ala670Val, nuclear SRC-2/SRC-3 in patient basal epidermal cells, and increased vitamin D-induced transactivation in patient keratinocytes. The pathophysiology is a three-node chain (loss of SIP coactivator sequestration -> nuclear SRC-2/SRC-3 -> increased VDR transactivation) with inferential (directness INDIRECT) edges to palmoplantar keratoderma and woolly hair. Pseudoainhum of the fifth toe is recorded from a secondary summary and left without an HPO binding, because the only HPO term carrying the synonym is under amniotic/placental abnormality; it is not wired to a mechanism. Acitretin is recorded from a single clinically diagnosed, KANK2-untested case (PMID:35283492). Features reported only in genetically unconfirmed cases (finger contractures, nail thickening, hearing loss, maculopathy) were not added as phenotypes; the last two are a KNOWLEDGE_GAP discussion, as is the allele-specificity question raised by nephrotic-syndrome KANK2 variants (PMID:25961457). Orphanet ORPHA:420686 could not be cited because the Orphadata cache is absent locally. Validation: just validate, validate-terms and validate-disorders pass; 23/23 snippets verified.

Perplexity ▸

Woolly hair–palmoplantar keratoderma syndrome: disease-characteristics report

sonar-deep-research 54 citations 2026-10-11T20:08:30.995569

Woolly hair–palmoplantar keratoderma syndrome: disease-characteristics report

Disease identity and scope. MONDO:0014492 refers specifically to KANK2-associated palmoplantar keratoderma and woolly hair (PPKWH), also called keratoderma with woolly hair type IV. Its characteristic combination is sparse or woolly hair, childhood-onset palmoplantar keratoderma, and nail changes without the cardiomyopathy characteristic of the clinically overlapping Naxos and Carvajal syndromes. That distinction is important both for knowledge-base annotation and for the initial assessment of a person whose genetic diagnosis is not yet known. [46][47][53][141]

Evidence boundary. The central human genetic and mechanistic evidence is a 2014 investigation of two consanguineous families, subsequently described as comprising seven affected people. Later reports diagnosed type IV clinically but did not establish a new, molecularly confirmed KANK2 series. Thus, percentages calculated from published cases would misleadingly imply a representative cohort. Evidence below is labeled as human clinical, patient-cell, other-gene/model, or inference where that distinction matters. [31][93][79]

1. Disease information and identifiers

Identifier or name	Value and interpretation
Disease name and MONDO	Woolly hair–palmoplantar keratoderma syndrome; MONDO:0014492. [46]
OMIM	616099, Palmoplantar keratoderma and woolly hair; PPKWH. The KANK2 gene, separately, is OMIM 614610. [46][34]
Orphanet	ORPHA:420686. [47]
ICD-10	Q82.8, an Orphanet-listed, nonspecific congenital skin-malformation code—not a uniquely identifying code for this genotype. [47]
ICD-11; disease-specific MeSH	A distinct identifier was not verified. PubMed indexes the founding article under broader terms including Keratoderma, Palmoplantar and Hair Diseases. [31]
Other identifiers	MedGen C4015202; an alternative MedGen concept, C4706686, and SNOMED CT 764108000 are also associated with the type-IV description. [46][172]
Synonyms	Palmoplantar keratoderma and woolly hair; PPKWH; woolly hair-palmoplantar hyperkeratosis syndrome; keratoderma with woolly hair type IV; KWWH type IV. The 2025 classification also calls it KANK2-pEDD, meaning a KANK2-associated palmoplantar epidermal differentiation disorder. [47][61]
Evidence provenance	Aggregated disease-level resources, anchored principally in published family examinations, sequencing, patient keratinocyte assays, and individual case reports—not an EHR-derived incidence or outcomes dataset. [31][47][93]

Orphanet describes the syndrome as “a very rare, hereditary epidermal disorder” in which palmoplantar keratoderma “progressively worsens with age” and cardiomyopathy is “notably absent.” [47]

2. Etiology, risks, protection, and gene–environment interaction

The demonstrated cause is an inherited, biallelic KANK2 missense variant, c.2009C>T, p.(Ala670Val), identified by whole-exome sequencing in affected members of the two founding families. KANK2 encodes steroid receptor coactivator–interacting protein (SIP), which regulates the localization and transcriptional activity of nuclear-receptor coactivators. This is a non-desmosomal cause of the hair–keratoderma combination; JUP, DSP, and DSC2 belong primarily in the differential diagnosis, not as established causes of MONDO:0014492. [53][51]

Genetic risk is chiefly inheriting two disease-associated alleles; parental consanguinity can increase the chance of homozygosity for a rare familial allele. Six unaffected parents in the founding-family assessment were reported as heterozygous. No validated susceptibility locus, severity-modifier allele, protective allele, or population carrier frequency was established for this syndrome. The clinically reported families originated near Jerusalem, but that observation does not establish an ethnic-specific risk or a quantified founder effect. [79][95][53]

Environmental causation and protection: no toxin, diet, infection, occupation, smoking exposure, or protective lifestyle practice has been shown to cause or prevent the KANK2 disorder. Because palmoplantar skin bears mechanical load, friction may reasonably aggravate existing keratoderma; this is a care-related inference, not a demonstrated KANK2 gene–environment interaction. In the founding experiments, vitamin D was an assay stimulus revealing increased receptor-mediated transcription—not evidence that vitamin D exposure causes disease or that supplementation treats it. [53][44]

3. Phenotypes and functioning

The table separates reported manifestations from features of a clinically suspected but genetically unconfirmed case. “Not quantified” means that neither a valid disease-wide percentage nor a standardized quality-of-life score is available. HPO identifiers are suggested phenotype annotations, not assertions of HPO-curated frequencies. [47][53][93]

Phenotype and type	Onset, course, severity, and frequency	Function or quality-of-life impact; suggested HPO
Palmoplantar keratoderma—physical sign: typically striate on palms, with marked plantar involvement	Early childhood; progressively thickens; variable extent. A later clinically diagnosed case reported onset at 6 months and unusually diffuse disease. Cardinal feature in the genetically studied families; no population percentage. [47][93][61]	Thick plantar skin may impede comfortable walking or hand use; individual disability scores are unavailable. HP:0000982 (palmoplantar keratoderma). [177][93]
Woolly, tightly curled scalp hair—physical sign	Usually apparent from birth; texture and prominence vary, so “woolly” should not be forced as 100% of molecularly affected individuals. HP:0002224. [53][47][198]	Visible hair difference may affect well-being, but syndrome-specific patient-reported measures are unavailable. [47]
Sparse scalp and body hair, including eyebrows or eyelashes—physical signs	Congenital or early-life hair abnormality; degree varies; frequency not quantified. HP:0002209 (sparse scalp hair); use a more specific eyebrow/eyelash term only when documented. [47][282]	Possible cosmetic and psychosocial burden; not measured for this cohort. [47]
Leukonychia—nail sign	Reported fingernail whitening; precise onset, penetrance, and severity unavailable. HP:0001820. [47][279]	Functional impairment not established. [47]
Follicular keratoses or papules—skin sign	Reported as a clinical clue, including on extremities and cheeks; frequency and timing unknown. HP:0007502 (follicular hyperkeratosis) when histologically or clinically appropriate. [95][61][369]	Discomfort or appearance-related impact is plausible, not quantified. [61]
Fifth-toe pseudoainhum—constricting-band sign	Occasionally reported; age and risk of digit loss in molecularly confirmed PPKWH are unknown. Record the observed digital constriction precisely rather than assigning an unverified HPO code. [47][93]	Potentially important for toe function and early assessment; disease-specific outcome data are absent. [47]
Severe finger contractures; thickened nails—additional signs in one case	Observed in a 35-year-old clinically diagnosed, unsequenced man with diffuse keratoderma. Do not treat these as established frequencies or genotype-specific manifestations. [93]	Contractures directly limited joint movement in that patient; no cohort-level measure. [93]
Sensorineural hearing loss and maculopathy—provisional findings	A 2026 report describes these in one 25-year-old woman labeled type IV. Its abstract does not report KANK2 confirmation; a causal association remains unproven. [391]	Hearing and visual consequences require their own evaluation; do not yet populate them as established KANK2-PPKWH phenotypes. [391]

Negative clinical feature: absence of cardiomyopathy is part of the currently described KANK2 phenotype, not a test that safely identifies the gene before sequencing. The small number of observed patients cannot establish lifetime cardiac risk as exactly zero. [53][47][141]

4. Genetic and molecular information

Item	Knowledge-base-ready finding and evidence limit
Established syndrome-associated gene	*KANK2; HGNC:29300, NCBI Gene:25959, chromosome 19p13.2, gene OMIM 614610. The disease association has limited/supportive, rather than uniformly definitive, submitted GenCC assessments*; Genomics England retains a low-evidence panel classification. [235][57][79]
Principal reported allele	KANK2 c.2009C>T, p.(Ala670Val): inherited germline, homozygous missense allele segregating with the syndrome in the founding families. Patient-cell experiments support altered function, but a single paper’s designation of it as causal should not be misrepresented as an independently verified, current ClinVar ACMG/AMP “pathogenic” classification. [53][79]
Population frequency and variant classification	A reliable *allele-specific gnomAD frequency, rsID, and current ClinVar assertion for this exact KANK2* allele were not verified. Do not substitute the identically written PIDD1 c.2009C>T, p.Ala670Val ClinVar record: it is a different gene**. [205][53]
Functional direction	Evidence supports impaired cytoplasmic sequestration of SRC-2/NCOA2 and SRC-3/NCOA3, with increased vitamin-D-stimulated transcription in patient keratinocytes. A specific downstream epidermal target gene and the full molecular route to hair-shaft shape remain unresolved; calling the allele a universal KANK2 null would go beyond the experiments. [53][68]
Protein-structure resource	PDB 6TMD is an experimentally solved, 1.50-Å crystal structure of the human A670V ankyrin-repeat fragment, released 2020-12-16. It is structural evidence, not a measured clinical penetrance or treatment response. [250]
Other alleles and phenotypes	Biallelic alterations of *KANK2* have separately been implicated in nephrotic syndrome 16. Those renal findings must not automatically be added as manifestations of the p.Ala670Val hair–skin syndrome. [112][57]
Modifiers, epigenetics, chromosomal abnormalities	No validated modifier gene, disease-specific DNA-methylation or chromatin signature, recurrent causative chromosomal rearrangement, anticipation mechanism, or germline-mosaicism estimate was identified for MONDO:0014492. The established lesion is a single-nucleotide variant, not an aneuploidy. [53][79]

5. Environmental and infectious information

No infectious agent or transmissible process is implicated. There is no established disease-specific toxic, radiation, pollution, occupational, dietary, alcohol, or smoking etiology. Mechanical skin care can matter after disease develops, but should not be coded as a proven initiating exposure. The available family and keratinocyte evidence supports a Mendelian condition, rather than an acquired keratoderma. [53][47][44]

6. Mechanism and pathophysiology

Ordered causal chain

Inherited homozygous KANK2 p.Ala670Val leads to altered function of the SIP/KANK2 ankyrin-repeat protein; the genotype and patient-cell effects are demonstrated, while the precise molecular binding defect is inferred. [53][250]
Altered SIP regulation leads to less effective cytoplasmic retention of the steroid-receptor coactivators SRC-2/NCOA2 and SRC-3/NCOA3: their nuclear localization in patient basal epidermal cells, versus cytoplasmic localization in a heterozygous control, was observed. [53]
Increased nuclear coactivator availability results in increased vitamin-D-induced receptor transactivation in patient keratinocytes, as experimentally measured. This places altered coactivator localization upstream of the measured transcriptional output. [53]
Altered epidermal transcription and differentiation is inferred to lead to excessive palmoplantar cornification and altered follicular/hair growth, resulting in keratoderma, woolly or sparse hair, and associated nail findings. The individual transcriptional targets and the route to each anatomical feature have not been demonstrated. [53][68]
Branch—other KANK2 dysfunction, not established as this syndrome’s causal route: KANK2 deficiency leads to altered podocyte RHOA signaling and filtration defects in experimental systems. This explains why KANK2 can also be associated with a separate nephrotic phenotype; it does not demonstrate that the skin-associated A670V allele causes nephrosis. [112][216]

Pathway and cell annotation. The best-supported syndrome-specific pathway is nuclear-receptor coactivation, including vitamin D receptor signaling—suggested GO:0070561—in epidermal keratinocytes, particularly CL:0002187 basal epidermal cells; broader CL:0000312 denotes keratinocytes. Cytoplasm-to-nucleus redistribution is directly relevant; a desmosomal structural defect, Wnt/MAPK/mTOR activation, mitochondrial metabolic lesion, primary immunodeficiency, and systemic inflammatory mechanism have not been demonstrated for this genotype. The A670V protein structure is available, but no disease-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or CRISPR-screen signature was established. [53][129][220][230][250]

Cross-phenotype caution: research in other cells shows KANK2 interactions with focal-adhesion/cytoskeletal machinery, and podocyte knockdown alters RHOA activity. These are useful functional hypotheses, not proof that those pathways drive A670V keratoderma. [112][106]

Exact founding-abstract evidence (human patient-cell study; PMID: 24671081): “Indeed, vitamin D-induced transactivation was increased in patient's keratinocytes.” The authors also report that SRC-2 and SRC-3 “are localised to the nucleus of epidermal basal cells in patients, in contrast to the cytoplasmic distribution in the heterozygous control.” Published online 26 March 2014; DOI 10.1136/jmedgenet-2014-102346; URL: https://pubmed.ncbi.nlm.nih.gov/24671081/. [31]

7. Anatomy and localization

Level	Affected site or compartment; suggested ontology
Organ and system	Primarily skin and hair, within the integumentary system; nails are also affected. No confirmed primary cardiac involvement in molecularly described PPKWH. [47][53]
Palm and sole	Epidermis (UBERON:0001003) of palmar skin (UBERON:0001514) and plantar skin (UBERON:0001516); a combined palm/sole site can use UBERON:0013776. Plantar involvement may be more severe. [47][222][304]
Follicle and cells	Scalp hair follicle, UBERON:0002074; epidermal keratinocyte, CL:0000312, and basal cell of epidermis, CL:0002187. Hair-follicle involvement is clinically evident, whereas the reported coactivator-localization assay specifically examined basal epidermal cells. [222][230][53]
Subcellular	Cytoplasm and nucleus, the experimentally compared coactivator locations. Assign specific GO cellular-component accessions only after ontology validation; mitochondria, ER, and lysosomes are not implicated by the patient assay. [53]
Laterality	Generally described as palmoplantar involvement rather than a defined unilateral lesion; a numerical bilateral-versus-asymmetric frequency is unavailable. Fifth-toe pseudoainhum can be recorded by its actual side for each patient. [47][93]

8. Temporal development

Hair texture is generally abnormal at birth; keratoderma emerges in infancy or early childhood and may increase with age. One clinically diagnosed adult recalled palmoplantar thickening from six months; Orphanet lists neonatal, infancy, and childhood onset. The disorder is chronic, not an acute infection or relapsing-remitting episode. Published evidence does not support a formal early/intermediate/end-stage system, a measured progression rate, or predictable spontaneous remission. The useful intervention window is early recognition of hair plus keratoderma—both to address progressive skin thickening and, before molecular clarification, to investigate possible cardiac syndromes. [47][93][141]

9. Inheritance and population

Orphanet estimates prevalence at fewer than 1 per 1,000,000 people—equivalently fewer than 0.1 per 100,000—rather than a measured point prevalence. Incidence per 100,000 per year is unavailable. Reported inheritance is autosomal recessive. Consanguinity characterized the two original Arab families; a separate clinically diagnosed case had non-consanguineous parents, but lacked KANK2 testing. No reliable sex ratio, age distribution, allele-specific geographic distribution, population carrier frequency, lifetime penetrance, or expressivity percentage exists. There is no evidence for genetic anticipation. For two confirmed carrier parents, standard autosomal-recessive segregation implies a 25% affected-child probability per pregnancy, assuming both carry disease-causing alleles. [47][53][79][93]

Do not transfer population statistics from Naxos disease—including estimates from Greek islands—to this distinct, non-cardiomyopathic KANK2 condition. [28][47]

10. Diagnosis and differential diagnosis

Clinical entry point: examine hair texture and density, distribution of palmar versus plantar thickening, nails, follicular papules, and toe constrictions; document pedigree and age at onset. Before the genotype is established, obtain cardiac evaluation, including ECG and echocardiography, because phenotypically similar desmosomal disorders can develop cardiomyopathy. These tests were normal in the founding description and in a later clinically diagnosed case; a normal examination alone does not establish a KANK2 diagnosis. [53][93][141]

Molecular strategy: a hereditary palmoplantar-keratoderma or cardiocutaneous panel including KANK2, JUP, DSP, and *DSC2 is a practical first approach. If a familial KANK2 allele is known, targeted testing and segregation analysis are appropriate. WES found the founding allele; WES or WGS can help when a panel is negative or features are atypical. NCBI GTR lists KANK2 coding-region sequencing. Chromosomal microarray, karyotype, FISH, mitochondrial sequencing, and repeat-expansion assays are not routine tests for this established single-gene phenotype*, absent a separate indication. No validated blood metabolite, enzyme assay, circulating biomarker, RNA-sequencing test, proteomic assay, epigenomic test, or liquid biopsy diagnoses it. [53][54][404][61]

A biopsy may show nonepidermolytic hyperkeratosis and acanthosis but is not molecularly diagnostic. The unsequenced adult case showed hyperkeratosis, parakeratosis, hypergranulosis, and epidermal hyperplasia without epidermolysis. [61][93]

Differential	Crucial distinction or test
Naxos disease—JUP	Similar hair and keratoderma with arrhythmogenic, predominantly right-ventricular cardiomyopathy; assess heart and sequence the relevant gene. [18][51]
Carvajal syndrome—DSP	Similar ectodermal signs with potentially serious left-ventricular or dilated cardiomyopathy, often developing in childhood. [17][50]
DSC2-associated cardiocutaneous disease	Keratoderma/hair findings can overlap, with arrhythmogenic cardiomyopathy; use a multigene assessment rather than appearance alone. [51]
Other inherited palmoplantar keratodermas, including DSG1- or KRT1-associated disease	Skin distribution, nails, other organ findings, inheritance, and sequencing help separate them. A Danish cohort published online 4 December 2024 identified a genetic diagnosis in 63/76 families (83%), but *reported no KANK2* diagnosis; its yield is not a PPKWH-specific diagnostic sensitivity. PMID 39630431**; https://jamanetwork.com/journals/jamadermatology/fullarticle/2826499. [264][308][320]

11. Outcomes and prognosis

The described KANK2 syndrome lacks the documented cardiomyopathy burden of Naxos and Carvajal syndromes. Nevertheless, five- or ten-year survival, life expectancy, syndrome-specific mortality, disability rates, and EQ-5D/SF-36/PROMIS scores have not been measured. The principal documented burden is chronic, potentially progressive keratoderma with hair/nail changes; occasional constricting toes warrant attention. A 35-year-old clinically diagnosed but unsequenced man had marked finger contractures, demonstrating a possible functional concern without establishing its frequency in confirmed KANK2 disease. Neither a validated prognostic molecular marker nor a genotype-based prediction model exists. [47][93][53]

Important renal distinction: KANK2 is also a nephrotic-syndrome gene, but available evidence does not establish proteinuria or renal failure as an expected complication of the founding p.Ala670Val PPKWH phenotype. [112][216]

12. Treatment and implementation

There is no established curative or KANK2-targeted treatment. Treatment is directed at keratoderma, function, and correctly identifying any patient who instead has a cardiomyopathy-associated genotype. A clinical report documented improvement after combined topical keratolytics and oral acitretin, but did not genotype its patient; it cannot supply a KANK2-specific response rate. [93][44][141]

Intervention and suggested annotation	Use, evidence, outcomes, and cautions
Emollients and topical keratolytics; suggested chemicals urea CHEBI:16199, salicylic acid CHEBI:16914	Symptomatic softening and reduction of hyperkeratosis, based largely on broader inherited-keratoderma management. The clinically diagnosed adult received topical keratolytics alongside acitretin, so their separate effect cannot be estimated. No KANK2-specific NCIt intervention code was verified. [44][93][326][330]
Careful mechanical reduction of callus, footwear or pressure accommodation, and functional support	Practical measures for symptomatic keratoderma; tailor podiatry or hand therapy to pain, gait, or contractures. This is supportive extrapolation, not a syndrome-specific trial result. [44][93]
Oral acitretin, a systemic retinoid; CHEBI:50173, NCIT:C985	In one unsequenced 35-year-old, 25 mg daily plus topical keratolytics produced reported “remarkable improvement” within two months. This is one combined-treatment observation, not a response percentage. The authors monitored liver function and lipid profile; systemic-retinoid reproductive and other safety precautions require specialist review. [93][324]
Assessment of a toe constriction, with procedural referral if threatening function	Pseudoainhum was reported, but no KANK2-specific surgical outcome or preferred procedure was established. [47][93]
Gene, cell, RNA, immunologic, or pathway-targeted therapy	No established treatment, response rate, KANK2-PPKWH-specific NCT trial identifier, or validated genotype-guided drug regimen was identified. Increased vitamin-D-stimulated transcription does not justify vitamin D or VDR-targeted treatment. [53][61]

Exact case-report text (human clinical, genetically unconfirmed; PMID: 35283492): “Remarkable improvement in palmoplantar keratoderma was noticed within 2 months of oral acitretin therapy.” The publication is a letter without an abstract, so this is an article-text quotation, not an abstract quotation. Indian Journal of Dermatology, 2021, 66:693–695; DOI 10.4103/ijd.IJD_107_21; URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC8906310/. [93]

13. Prevention and counseling

Primary prevention of the mutation itself is not achievable through vaccination, diet, or exposure avoidance; the condition is not infectious. Genetic counseling can explain recessive recurrence risk and offer testing of relatives for a known familial variant, carrier testing, and, where appropriate and desired, reproductive options including prenatal or preimplantation testing. These are family-planning measures, not treatment of an affected child. [47][53][61]

Secondary prevention is timely recognition of congenital unusual hair followed by evolving palmoplantar thickening, molecular clarification, and initial cardiac assessment while Naxos/Carvajal-type disease remains possible. No established population newborn-screening program for this syndrome was identified. Tertiary prevention focuses on skin comfort and mobility, inspection of constricting bands, and care of any clinically present fissures or complications; no syndrome-specific prophylactic medication is established. [141][47][44]

14. Other species and natural disease

Species or comparative finding	Relevance and limit
*Human, Homo sapiens* (NCBI Taxon:9606)**	The naturally occurring, genetically studied disease is human KANK2-associated PPKWH. [53]
*Dog, Canis lupus familiaris* (NCBI Taxon:9615)**	OMIA records woolly hair as an animal trait, but this is *not evidence of a naturally occurring canine KANK2* palmoplantar-keratoderma syndrome**; no qualifying breed/VBO identifier was established. [382]
Other animal species	Kank2 orthologs enable mechanistic comparisons, but no verified spontaneous animal case recapitulating this specific combined human skin-and-hair syndrome was identified. It is not zoonotic. [112][294]

15. Model organisms and research applications

Model or resource	What it demonstrates; what it does not recapitulate
Patient-derived human keratinocytes and epidermal biopsy	Most directly relevant disease model: increased vitamin-D-induced transactivation and altered SRC-2/SRC-3 localization in A670V-associated disease. These are functional findings in patient material, but do not identify all downstream target genes. PMID 24671081. [53]
Purified human A670V protein fragment; PDB 6TMD	X-ray structure of mutant KANK2 ankyrin repeats at 1.50 Å supports structural investigation; a purified fragment does not reproduce hair-follicle development or a whole patient’s disease. [250]
*Zebrafish, Danio rerio* (NCBI Taxon:7955), kank2 NCBI Gene:571549**	Experimental knockdown produced proteinuria and podocyte foot-process effacement, modeling a renal KANK-deficiency phenotype, not demonstrated woolly hair plus keratoderma. PMID 25961457; published 2015; https://pubmed.ncbi.nlm.nih.gov/25961457/. [112][242]
Cultured podocytes and Drosophila nephrocytes	Knockdown experiments support conserved renal-cell functions and altered RHOA-associated behavior; they are not validated models of the A670V epidermal syndrome. PMID 25961457. [112]
*Mouse, Mus musculus* (NCBI Taxon:10090), Kank2 NCBI Gene:235041; MGI:2384568**	Ortholog and knockout resources exist, including an available knockout strain, but a verified A670V knock-in reproducing both human hair and palmoplantar findings was not identified. A general knockout must not be described as a phenotypically validated PPKWH model. [294][296][297]

Evidence assessment for database ingestion

The highest-confidence entry is the specific combination MONDO:0014492 → autosomal-recessive KANK2 → reported homozygous p.Ala670Val → hair, keratoderma, nail findings → altered SRC localization and vitamin-D-induced keratinocyte transactivation. Code the last step from transcriptional dysregulation to particular hair and skin structures as mechanistic inference. Keep cardiomyopathy-associated JUP/DSP/DSC2 disorders, other-KANK2-allele nephrotic syndrome, and the unconfirmed 2026 hearing/retinal findings distinct from the established disease phenotype. [53][57][68][112][391]

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	16
On topic	10
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	28
Resolved	18
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	10

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Gene, Taxon, MGI.

18 of 28 terms resolved to a current term; the rest could not be looked up either way.

Wooly Hair-Palmoplantar Keratoderma Syndrome

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Woolly hair–palmoplantar keratoderma syndrome: disease-characteristics report

1. Disease information and identifiers

2. Etiology, risks, protection, and gene–environment interaction

3. Phenotypes and functioning

4. Genetic and molecular information

5. Environmental and infectious information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomy and localization

8. Temporal development

9. Inheritance and population

10. Diagnosis and differential diagnosis

11. Outcomes and prognosis

12. Treatment and implementation

13. Prevention and counseling

14. Other species and natural disease

15. Model organisms and research applications

Evidence assessment for database ingestion

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