Punctate Palmoplantar Keratoderma

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Definitions

1

Punctate palmoplantar keratoderma clinical definition

A papular or punctate palmoplantar keratoderma in which affected individuals develop multiple discrete hyperkeratotic lesions on palms and soles.

OTHER

Show evidence (2 references)

PMID:23000146 SUPPORT Human Clinical

"Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles."

This abstract sentence defines the inherited punctate PPK phenotype and inheritance pattern.

PMID:36793812 SUPPORT Human Clinical

"Palmoplantar keratoderma (PPK) is an umbrella term for a group of heterogeneous disorders, acquired or inherited, that are characterized by hyperkeratosis of palmar and/or plantar surfaces."

This case-report abstract supports the broader PPK classification and palmoplantar hyperkeratosis definition.

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Type 1 punctate palmoplantar keratoderma usually segregates as an autosomal dominant trait in families with heterozygous AAGAB loss-of-function variants.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:31526046 SUPPORT Human Clinical

"PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations."

This directly supports autosomal dominant inheritance for AAGAB-associated PPPK1.

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Subtypes

2

Punctate palmoplantar keratoderma type 1A MONDO:0019332

AAGAB-associated punctate palmoplantar keratoderma type 1 with autosomal dominant inheritance and multiple punctate palmoplantar hyperkeratotic lesions.

Punctate palmoplantar keratoderma type 1B

COL14A1-associated punctate palmoplantar keratoderma type 1B has been described in the subtype framework used by current guidelines, but the evidence base is smaller than for AAGAB-associated type 1A.

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Discussions and Knowledge Gaps

2

Does punctate palmoplantar keratoderma type 1 confer an increased risk of malignancy that would justify cancer surveillance, or is the long-proposed association unconfirmed?

CONTROVERSY OPEN controversy_pppk1_malignancy_association

Attached to

pathophysiology#Growth Factor Receptor Signaling Increase

A cancer association has been proposed for decades and some authors recommend malignancy surveillance, with a mechanistic rationale that EGFR and related receptor tyrosine kinase signaling is dysregulated in AAGAB-deficient keratinocytes and is also a feature of neoplasia. Primary family studies did not observe co-segregation of cancer with AAGAB variants, and a PRISMA systematic review of 45 studies covering more than 800 individuals judged the evidence too poor in quality to confirm an association and questioned routine surveillance. The competing published positions leave the clinical counseling question unresolved.

Show evidence (4 references)

PMID:31526046 SUPPORT Human Clinical

"In some families there appears to be an association with cancer."

A Canadian family series reports cancers in some AAGAB-mutation families, representing the position that a malignancy link may exist.

PMID:23743648 PARTIAL Human Clinical

"It is not clear whether there is truly an over-representation of malignancy in PPKP1 cases, and malignant neoplasms were not prevalent in the six kindreds reported here."

A primary AAGAB replication study finds the malignancy over-representation uncertain and not prevalent in its own kindreds.

PMID:23064416 REFUTE Human Clinical

"Although a few cases of cancer were reported in the larger families studied here, we did not observe co-segregation with the p34 mutations and so any causal link remains unproven."

The gene-discovery study found no co-segregation of cancer with AAGAB mutations, arguing against a causal malignancy link.

+ 1 more reference

Why is hyperkeratosis in punctate palmoplantar keratoderma so sharply focal on palmar skin when the causative AAGAB haploinsufficiency is expressed throughout the epidermis, and is a somatic second hit required to trigger each lesion?

KNOWLEDGE GAP OPEN gap_pppk1_focal_distribution_mechanism

Attached to

pathophysiology#Keratinocyte Hyperproliferation

AAGAB loss of function is constitutional and expressed across palmoplantar epidermis, yet lesions arise as discrete punctate foci rather than diffuse keratoderma. A somatic second-hit model has been proposed but was not identified by microdissection and sequencing, leaving the focal patterning mechanism undefined and mechanistically important for understanding p34 control of keratinocyte proliferation.

Show evidence (1 reference)

PMID:23743648 SUPPORT Human Clinical

"the extremely focal distribution of hyperkeratosis on the palmar skin in the disorder is striking. The mechanism(s) responsible for producing this very focal disease on the background of a mutation expressed throughout the palmar skin are likely to be of clinical relevance, but they remain to be defined."

The authors highlight the unexplained focal patterning of lesions despite a constitutional mutation as an open mechanistic question.

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Pathophysiology

3

AAGAB Haploinsufficiency

Heterozygous nonsense, frameshift, splice, or other loss-of-function variants in AAGAB reduce functional p34 dosage in type 1A disease. The p34 protein binds clathrin adaptor complexes, so haploinsufficiency links the inherited variant to abnormal membrane-trafficking biology in keratinocytes.

Keratinocyte CL:0000312

AAGAB hgnc:25662

Clathrin-mediated endocytosis GO:0072583 ↓ DECREASED

Downstream

Growth Factor Receptor Signaling Increase p34 deficiency is proposed to impair endocytic recycling and turnover of receptor tyrosine kinases, increasing EGFR protein abundance and phosphorylation.

Show evidence (3 references)

PMID:23064416 SUPPORT Human Clinical

"In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22."

This establishes heterozygous AAGAB loss-of-function variants as a cause of autosomal dominant punctate PPK.

PMID:23000146 SUPPORT Human Clinical

"AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone."

This connects the causal gene product with membrane-trafficking biology.

PMID:23064416 SUPPORT Human Clinical

"Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology."

Electron microscopy of patient lesional epidermis shows intracellular vesicle abnormalities, directly supporting disturbed membrane-trafficking biology from p34 haploinsufficiency.

Growth Factor Receptor Signaling Increase

Impaired receptor endocytosis and turnover increases growth-factor receptor signaling in keratinocytes. This mechanism is best supported for EGFR in AAGAB-knockdown keratinocyte models, which also show elevated levels of the receptor tyrosine kinase Axl, indicating a broader receptor-tyrosine-kinase turnover defect; together this provides a plausible route from vesicle-traffic dysfunction to epidermal hyperproliferation.

Keratinocyte CL:0000312

Epidermal growth factor receptor signaling pathway GO:0007173 ↑ INCREASED Clathrin-mediated endocytosis GO:0072583 ↓ DECREASED

Downstream

Keratinocyte Hyperproliferation Increased receptor signaling drives increased cell division in keratinocytes and focal lesional epidermal hyperproliferation.

Show evidence (2 references)

PMID:23064416 SUPPORT In Vitro

"We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation."

This abstract sentence states the proposed mechanism linking AAGAB/p34 deficiency to growth-factor signaling and proliferation.

PMID:23743648 SUPPORT In Vitro

"The upregulation of Axl protein expression after small interfering RNA knockdown of AAGAB demonstrates the involvement of p34 in RTK turnover in addition to EGFR."

p34 knockdown also increases the receptor tyrosine kinase Axl, showing the trafficking defect broadens receptor tyrosine kinase signaling beyond EGFR alone.

Keratinocyte Hyperproliferation

Increased keratinocyte proliferation in palmoplantar epidermis produces focal hyperkeratotic papules and plaques. The anatomic restriction to palms and soles is not fully explained, but pressure-bearing and frictional sites are clinically important for lesion coalescence and symptoms.

Keratinocyte CL:0000312

Positive regulation of keratinocyte proliferation GO:0010838 ↑ INCREASED Keratinization GO:0031424 ↑ INCREASED

Skin of palm and sole UBERON:0013776

Downstream

Punctate palmoplantar hyperkeratosis Focal keratinocyte hyperproliferation produces punctate palmoplantar hyperkeratosis.

Palmoplantar keratoderma Hyperproliferative palmoplantar epidermis manifests as palmoplantar keratoderma.

Foot pain from plantar keratoses Hyperkeratotic plantar pressure-site lesions produce foot pain.

Show evidence (2 references)

PMID:23064416 SUPPORT Human Clinical

"Immunohistochemistry showed hyperproliferation within the punctate lesions."

Lesional tissue evidence supports hyperproliferation within punctate lesions.

PMID:23064416 SUPPORT In Vitro

"Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation."

Cell-based knockdown experiments support increased keratinocyte proliferation as a downstream effect of AAGAB deficiency.

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Histopathology

1

Orthokeratotic hyperkeratosis with central epidermal depression

Lesional palmar or plantar skin may show orthokeratosis or compact orthokeratosis, hypergranulosis, and a defined central epidermal or dermal depression, consistent with a focal hyperproliferative hyperkeratosis.

Show evidence (1 reference)

PMID:23064416 SUPPORT Human Clinical

"Histology of lesional palmar epidermis from 3 unrelated kindreds – Families 1, 11 and 15 – all showed very similar findings of a well-defined central epidermal depression associated with hypergranulosis and a prominent layer of overlying orthokeratosis"

This supports the characteristic histopathologic pattern in AAGAB-associated punctate PPK lesions.

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Pathograph

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

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Phenotypes

3

Integument 1

Palmoplantar keratoderma FREQUENT Palmoplantar keratoderma HP:0000982

Show evidence (1 reference)

PMID:34121213 SUPPORT Human Clinical

"Palmoplantar keratoderma (PPK) is a collective term for keratinizing disorders in which the main clinical symptom is hyperkeratosis on the palms and soles."

This guideline abstract supports palmoplantar hyperkeratosis as the defining clinical symptom of PPK.

Other 2

Punctate palmoplantar hyperkeratosis FREQUENT Punctate palmoplantar hyperkeratosis HP:0007530

Show evidence (1 reference)

PMID:31526046 SUPPORT Human Clinical

"Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles."

This directly supports the core punctate palmoplantar hyperkeratosis phenotype.

Foot pain from plantar keratoses Foot pain HP:0025238

Show evidence (1 reference)

PMID:24588319 SUPPORT Human Clinical

"In family 5, PPPK1 developed around the age of 20 years and progressed thereafter in the 68-year-old Danish proband. She presented with severe, very painful punctate palmoplantar keratoderma on the pressure points of her soles."

This case-series text supports painful plantar involvement in severe disease.

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Genetic Associations

3

AAGAB loss-of-function variants (Causative germline variant)

Gene: AAGAB hgnc:25662 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:23064416 SUPPORT Human Clinical

"In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22."

This establishes AAGAB loss-of-function variants as causative in autosomal dominant punctate PPK.

PMID:31526046 SUPPORT Human Clinical

"We have identified 5 heterozygous AAGAB loss of function mutations in 11 families."

This independent Canadian family series supports recurrent heterozygous AAGAB loss-of-function variants.

AAGAB c.370C>T p.Arg124Ter founder variant (Population founder variant)

Gene: AAGAB hgnc:25662 relationship_type: RISK_FACTOR variant_origin: GERMLINE

Show evidence (1 reference)

PMID:38311882 SUPPORT Human Clinical

"This study confirms that the frequently observed variant AAGAB c.370C>T, p.Arg124Ter in punctate PPK among patients in the Region of Southern Denmark is caused by a founder variant."

This supports founder effect status for the recurrent Southern Denmark AAGAB variant.

COL14A1-associated type 1B (Reported genetic association)

Gene: COL14A1 hgnc:2191 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (1 reference)

PMID:36793812 PARTIAL Human Clinical

"In type 1 PPPK, also known as Buschke-Fischer-Brauer disease, loss-of-function mutations in either the AAGAB or the COL14A1 genes have been associated with the disorder."

This supports COL14A1 as a reported association, but this entry treats AAGAB as the stronger established mechanism because the report and primary mechanistic studies center on AAGAB.

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Medical Actions

4

Topical keratolytics and physical debridement

Action: Pharmacotherapy NCIT:C15986

Symptomatic treatment may include topical keratolytics such as urea, salicylic acid, or lactic acid and repeated physical debridement, especially when no reversible underlying acquired etiology is present.

Target Phenotypes: Punctate palmoplantar hyperkeratosis HP:0007530

Show evidence (2 references)

PMID:17298101 PARTIAL Human Clinical

"If no such etiology is evident, then conservative treatment options include topical keratolytics (urea, salicylic acid, lactic acid), repeated physical debridement, topical retinoids, topical psoralen plus UVA, and topical corticosteroids."

This review concerns acquired PPK broadly, so it partially supports conservative symptomatic management options for palmoplantar hyperkeratosis rather than disease-specific efficacy in inherited punctate PPK.

PMID:33765759 PARTIAL Human Clinical

"After treatment with 30% urea plus 10% salicylic acid, the patient experienced an improvement in her condition."

This single AAGAB-associated BFB case supports potential symptomatic improvement with keratolytics but is case-level evidence.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling is appropriate for autosomal dominant families, especially when molecular testing identifies an AAGAB pathogenic variant.

Show evidence (1 reference)

PMID:39630431 SUPPORT Human Clinical

"It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes."

Confirmed molecular diagnosis provides the basis for subtype-specific counseling in affected families.

Systemic retinoids

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172

Oral retinoids such as acitretin have been used as symptomatic therapy for recalcitrant palmoplantar keratoderma, including hereditary punctate forms. The support is partial because the abstract-backed evidence is broader PPK management literature rather than controlled punctate PPK-specific efficacy.

Target Phenotypes: Punctate palmoplantar hyperkeratosis HP:0007530

Show evidence (1 reference)

PMID:17298101 PARTIAL Human Clinical

"Etretinate and acitretin have also shown some success as alternative treatments in recalcitrant cases."

This acquired PPK review supports systemic retinoid use in recalcitrant PPK; it is partial support for hereditary punctate PPK.

KM-001 topical TRPV3 antagonist trial

Action: Pharmacotherapy NCIT:C15986

KM-001 topical 1% cream is an investigational therapy studied in open-label phase I/phase Ib trials for type I punctate palmoplantar keratoderma or pachyonychia congenita; no efficacy result is asserted here from the trial registry summaries.

Target Phenotypes: Punctate palmoplantar hyperkeratosis HP:0007530 Foot pain HP:0025238

Show evidence (2 references)

clinicaltrials:NCT05435638 SUPPORT Human Clinical

"In this phase 1 open label study for patients with type I punctate palmoplantar keratoderma or pachyonychia congenital, 2 arms will be recruited to be treated twice daily, with 1% topical KM-001."

The trial record supports KM-001 as an investigational topical therapy evaluated in type I punctate PPK.

clinicaltrials:NCT05956314 SUPPORT Human Clinical

"This Phase 1b, open-label, single-center, prospective trial will be assessing the safety, tolerability, and efficacy of topical KM-001 1% in patients with PPPK1 or PC diseases."

The trial record supports a second open-label KM-001 study in PPPK1 or pachyonychia congenita.

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Environmental Factors

2

Mechanical pressure and friction

Mechanical pressure and friction are not primary causes of hereditary punctate PPK, but pressure-bearing plantar sites are where lesions commonly become confluent and symptomatic.

Show evidence (1 reference)

PMID:23743648 SUPPORT Human Clinical

"PPKP1 (OMIM ♯148600, Buschke–Fischer–Brauer type) is characterized by the progressive development of discrete areas of hyperkeratosis on the palms and soles, followed by more extensive diffuse hyperkeratosis on the pressure-bearing areas of plantar skin."

This supports pressure-bearing plantar skin as a site of more extensive disease.

Water exposure and skin care context

Water exposure and personal skin-care practices may modulate plantar hyperkeratosis severity in affected individuals, but they are modeled as modifiers rather than primary causes.

Show evidence (2 references)

PMID:23743648 PARTIAL Human Clinical

"There is no apparent genotype–phenotype correlation within this small group of patients, but our clinical observation is that environmental factors and personal skin care regimes affect the degree of plantar hyperkeratosis."

This supports environmental and skin-care context as a modifier of plantar hyperkeratosis severity.

PMID:36793812 SUPPORT Human Clinical

"A typical feature is the worsening of papules after exposure to water"

This describes water exposure as a typical aggravating factor for punctate palmoplantar keratoderma papules.

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Clinical Trials

2

NCT05435638 PHASE_I COMPLETED

Phase I open-label study of topical KM-001 1% in type I punctate palmoplantar keratoderma or pachyonychia congenita, with lesion clearance and pain assessments.

Target Phenotypes: Punctate palmoplantar hyperkeratosis HP:0007530 Foot pain HP:0025238

Show evidence (1 reference)

clinicaltrials:NCT05435638 SUPPORT Human Clinical

"At the in-clinic visits, treatment efficacy (lesion clearance - IGA, CGI-S, PGI-C, PGI-S and VAS pain) will also be assessed."

The registry summary supports the trial endpoints relevant to lesion clearance and pain.

NCT05956314 PHASE_I COMPLETED

Phase Ib open-label study of topical KM-001 1% in PPPK1 or pachyonychia congenita, with safety, tolerability, efficacy, pharmacokinetic, and patient-reported diary assessments.

Target Phenotypes: Punctate palmoplantar hyperkeratosis HP:0007530 Foot pain HP:0025238

Show evidence (1 reference)

clinicaltrials:NCT05956314 SUPPORT Human Clinical

"The patient will complete a patient-reported diary, consisting of treatment compliance and self-assessments for efficacy."

The registry summary supports patient-reported efficacy assessment during the KM-001 trial.

{ }

Source YAML

click to show

name: Punctate Palmoplantar Keratoderma
category: Mendelian
creation_date: "2026-05-10T15:03:46Z"
updated_date: "2026-05-10T15:03:46Z"
synonyms:
- punctate PPK
- punctate keratosis palmoplantaris
- punctate palmoplantar hyperkeratosis
- punctate palmoplantar keratoderma type 1
- Buschke-Fischer-Brauer disease
description: >
  Punctate palmoplantar keratoderma is a rare hereditary palmoplantar
  keratoderma characterized by multiple discrete hyperkeratotic papules or
  plaques on the palms and soles. Type 1 disease is usually autosomal dominant
  and is most strongly associated with heterozygous loss-of-function variants in
  AAGAB, with resulting p34 haploinsufficiency, impaired vesicle trafficking,
  increased growth-factor receptor signaling, keratinocyte hyperproliferation,
  and focal palmoplantar hyperkeratosis. Severity is variable; lesions can
  increase with age, coalesce at pressure-bearing plantar sites, and cause pain
  or functional limitation.
disease_term:
  preferred_term: punctate palmoplantar keratoderma
  term:
    id: MONDO:0017675
    label: punctate palmoplantar keratoderma
parents:
- Hereditary palmoplantar keratoderma
has_subtypes:
- name: Type 1A
  display_name: Punctate palmoplantar keratoderma type 1A
  subtype_term:
    preferred_term: punctate palmoplantar keratoderma type 1
    term:
      id: MONDO:0019332
      label: punctate palmoplantar keratoderma type 1
  description: >
    AAGAB-associated punctate palmoplantar keratoderma type 1 with autosomal
    dominant inheritance and multiple punctate palmoplantar hyperkeratotic
    lesions.
- name: Type 1B
  display_name: Punctate palmoplantar keratoderma type 1B
  description: >
    COL14A1-associated punctate palmoplantar keratoderma type 1B has been
    described in the subtype framework used by current guidelines, but the
    evidence base is smaller than for AAGAB-associated type 1A.
definitions:
- name: Punctate palmoplantar keratoderma clinical definition
  definition_type: OTHER
  description: >
    A papular or punctate palmoplantar keratoderma in which affected individuals
    develop multiple discrete hyperkeratotic lesions on palms and soles.
  evidence:
  - reference: PMID:23000146
    reference_title: "Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles."
    explanation: This abstract sentence defines the inherited punctate PPK phenotype and inheritance pattern.
  - reference: PMID:36793812
    reference_title: "Punctate Palmoplantar Keratoderma: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Palmoplantar keratoderma (PPK) is an umbrella term for a group of heterogeneous disorders, acquired or inherited, that are characterized by hyperkeratosis of palmar and/or plantar surfaces."
    explanation: This case-report abstract supports the broader PPK classification and palmoplantar hyperkeratosis definition.
inheritance:
- name: Autosomal dominant inheritance
  description: >
    Type 1 punctate palmoplantar keratoderma usually segregates as an autosomal
    dominant trait in families with heterozygous AAGAB loss-of-function variants.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:31526046
    reference_title: "AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations."
    explanation: This directly supports autosomal dominant inheritance for AAGAB-associated PPPK1.
prevalence:
- population: General population
  measure_type: POINT_PREVALENCE
  prevalence_class: RARE
  rate_per_100000: 1.17
  percentage: Rare
  notes: >
    Population prevalence is uncertain and the systematic-review evidence base is
    dominated by family reports and case series rather than population-based
    studies. A single literature-derived point estimate of approximately 1.17 per
    100,000 is recorded in rate_per_100000 and should be treated as an
    approximation rather than a measured population rate.
  evidence:
  - reference: PMID:37705065
    reference_title: "Is punctate palmoplantar keratoderma type 1 associated with malignancy? A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 773 studies identified, 45 were included. Most studies were reports on single families (24 of 45 studies) or multiple families (10 of 45 studies)."
    explanation: This supports that available epidemiologic evidence is largely case- and family-report based.
  - reference: PMID:36793812
    reference_title: "Punctate Palmoplantar Keratoderma: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a rare condition, with a prevalence estimated to be 1.17 per 100,000 persons"
    explanation: A single literature-derived estimate places punctate PPK prevalence near 1.17 per 100,000, consistent with a rare disorder while remaining an approximation rather than a population-based measurement.
progression:
- phase: Onset
  age_range: Late childhood to adulthood
  notes: >
    Onset is variable and may occur from late childhood through adulthood,
    depending on family and variant background.
  evidence:
  - reference: PMID:31526046
    reference_title: "AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles."
    explanation: This directly supports the typical onset range and initial clinical morphology.
- phase: Chronic progression
  age_range: Adolescence through adulthood
  notes: >
    Lesions can increase in number and size with advancing age and coalesce at
    pressure points, especially on plantar surfaces.
  evidence:
  - reference: PMID:23743648
    reference_title: "Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PPKP1 (OMIM ♯148600, Buschke–Fischer–Brauer type) is characterized by the progressive development of discrete areas of hyperkeratosis on the palms and soles, followed by more extensive diffuse hyperkeratosis on the pressure-bearing areas of plantar skin."
    explanation: This supports progressive lesion development and plantar pressure-site coalescence.
pathophysiology:
- name: AAGAB Haploinsufficiency
  description: >
    Heterozygous nonsense, frameshift, splice, or other loss-of-function
    variants in AAGAB reduce functional p34 dosage in type 1A disease. The p34
    protein binds clathrin adaptor complexes, so haploinsufficiency links the
    inherited variant to abnormal membrane-trafficking biology in keratinocytes.
  gene:
    preferred_term: AAGAB
    term:
      id: hgnc:25662
      label: AAGAB
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Clathrin-mediated endocytosis
    term:
      id: GO:0072583
      label: clathrin-dependent endocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22."
    explanation: This establishes heterozygous AAGAB loss-of-function variants as a cause of autosomal dominant punctate PPK.
  - reference: PMID:23000146
    reference_title: "Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone."
    explanation: This connects the causal gene product with membrane-trafficking biology.
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology."
    explanation: Electron microscopy of patient lesional epidermis shows intracellular vesicle abnormalities, directly supporting disturbed membrane-trafficking biology from p34 haploinsufficiency.
  downstream:
  - target: Growth Factor Receptor Signaling Increase
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      p34 deficiency is proposed to impair endocytic recycling and turnover of
      receptor tyrosine kinases, increasing EGFR protein abundance and
      phosphorylation.
    evidence:
    - reference: PMID:23064416
      reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation."
      explanation: Keratinocyte knockdown experiments support the link from AAGAB deficiency to increased EGFR abundance and activation.
- name: Growth Factor Receptor Signaling Increase
  description: >
    Impaired receptor endocytosis and turnover increases growth-factor receptor
    signaling in keratinocytes. This mechanism is best supported for EGFR in
    AAGAB-knockdown keratinocyte models, which also show elevated levels of the
    receptor tyrosine kinase Axl, indicating a broader receptor-tyrosine-kinase
    turnover defect; together this provides a plausible route from
    vesicle-traffic dysfunction to epidermal hyperproliferation.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Epidermal growth factor receptor signaling pathway
    term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    modifier: INCREASED
  - preferred_term: Clathrin-mediated endocytosis
    term:
      id: GO:0072583
      label: clathrin-dependent endocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation."
    explanation: This abstract sentence states the proposed mechanism linking AAGAB/p34 deficiency to growth-factor signaling and proliferation.
  - reference: PMID:23743648
    reference_title: "Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The upregulation of Axl protein expression after small interfering RNA knockdown of AAGAB demonstrates the involvement of p34 in RTK turnover in addition to EGFR."
    explanation: p34 knockdown also increases the receptor tyrosine kinase Axl, showing the trafficking defect broadens receptor tyrosine kinase signaling beyond EGFR alone.
  downstream:
  - target: Keratinocyte Hyperproliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Increased receptor signaling drives increased cell division in
      keratinocytes and focal lesional epidermal hyperproliferation.
    evidence:
    - reference: PMID:23064416
      reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation."
      explanation: This supports the growth-factor signaling to keratinocyte-proliferation step in the causal chain.
- name: Keratinocyte Hyperproliferation
  description: >
    Increased keratinocyte proliferation in palmoplantar epidermis produces
    focal hyperkeratotic papules and plaques. The anatomic restriction to palms
    and soles is not fully explained, but pressure-bearing and frictional sites
    are clinically important for lesion coalescence and symptoms.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: Skin of palm and sole
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  biological_processes:
  - preferred_term: Positive regulation of keratinocyte proliferation
    term:
      id: GO:0010838
      label: positive regulation of keratinocyte proliferation
    modifier: INCREASED
  - preferred_term: Keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: INCREASED
  evidence:
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemistry showed hyperproliferation within the punctate lesions."
    explanation: Lesional tissue evidence supports hyperproliferation within punctate lesions.
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation."
    explanation: Cell-based knockdown experiments support increased keratinocyte proliferation as a downstream effect of AAGAB deficiency.
  downstream:
  - target: Punctate palmoplantar hyperkeratosis
    causal_link_type: DIRECT
    description: Focal keratinocyte hyperproliferation produces punctate palmoplantar hyperkeratosis.
  - target: Palmoplantar keratoderma
    causal_link_type: DIRECT
    description: Hyperproliferative palmoplantar epidermis manifests as palmoplantar keratoderma.
  - target: Foot pain from plantar keratoses
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Hyperkeratotic plantar pressure-site lesions produce foot pain.
phenotypes:
- name: Punctate palmoplantar hyperkeratosis
  category: Clinical
  frequency: FREQUENT
  description: >
    Multiple small, discrete hyperkeratotic papules or plaques affect the palms
    and soles.
  phenotype_term:
    preferred_term: Punctate palmoplantar hyperkeratosis
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:31526046
    reference_title: "AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles."
    explanation: This directly supports the core punctate palmoplantar hyperkeratosis phenotype.
- name: Palmoplantar keratoderma
  category: Clinical
  frequency: FREQUENT
  description: >
    Hyperkeratosis is localized to palmar and plantar surfaces, consistent with
    the broader palmoplantar keratoderma phenotype.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:34121213
    reference_title: "Japanese guidelines for the management of palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Palmoplantar keratoderma (PPK) is a collective term for keratinizing disorders in which the main clinical symptom is hyperkeratosis on the palms and soles."
    explanation: This guideline abstract supports palmoplantar hyperkeratosis as the defining clinical symptom of PPK.
- name: Foot pain from plantar keratoses
  category: Clinical
  description: >
    Plantar pressure-site lesions can be painful and may impair standing or
    walking in more severe cases.
  phenotype_term:
    preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: PMID:24588319
    reference_title: "New and recurrent AAGAB mutations in punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family 5, PPPK1 developed around the age of 20 years and progressed thereafter in the 68-year-old Danish proband. She presented with severe, very painful punctate palmoplantar keratoderma on the pressure points of her soles."
    explanation: This case-series text supports painful plantar involvement in severe disease.
histopathology:
- name: Orthokeratotic hyperkeratosis with central epidermal depression
  finding_term:
    preferred_term: Orthokeratotic hyperkeratosis
    term:
      id: NCIT:C35541
      label: Hyperkeratosis
  description: >
    Lesional palmar or plantar skin may show orthokeratosis or compact
    orthokeratosis, hypergranulosis, and a defined central epidermal or dermal
    depression, consistent with a focal hyperproliferative hyperkeratosis.
  diagnostic: true
  evidence:
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology of lesional palmar epidermis from 3 unrelated kindreds – Families 1, 11 and 15 – all showed very similar findings of a well-defined central epidermal depression associated with hypergranulosis and a prominent layer of overlying orthokeratosis"
    explanation: This supports the characteristic histopathologic pattern in AAGAB-associated punctate PPK lesions.
genetic:
- name: AAGAB loss-of-function variants
  association: Causative germline variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: Type 1A
  gene_term:
    preferred_term: AAGAB
    term:
      id: hgnc:25662
      label: AAGAB
  evidence:
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22."
    explanation: This establishes AAGAB loss-of-function variants as causative in autosomal dominant punctate PPK.
  - reference: PMID:31526046
    reference_title: "AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified 5 heterozygous AAGAB loss of function mutations in 11 families."
    explanation: This independent Canadian family series supports recurrent heterozygous AAGAB loss-of-function variants.
- name: AAGAB c.370C>T p.Arg124Ter founder variant
  association: Population founder variant
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  subtype: Type 1A
  gene_term:
    preferred_term: AAGAB
    term:
      id: hgnc:25662
      label: AAGAB
  evidence:
  - reference: PMID:38311882
    reference_title: "Identification of a founder variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate palmoplantar keratoderma in Southern Denmark."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study confirms that the frequently observed variant AAGAB c.370C>T, p.Arg124Ter in punctate PPK among patients in the Region of Southern Denmark is caused by a founder variant."
    explanation: This supports founder effect status for the recurrent Southern Denmark AAGAB variant.
- name: COL14A1-associated type 1B
  association: Reported genetic association
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: Type 1B
  gene_term:
    preferred_term: COL14A1
    term:
      id: hgnc:2191
      label: COL14A1
  evidence:
  - reference: PMID:36793812
    reference_title: "Punctate Palmoplantar Keratoderma: A Case Report."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "In type 1 PPPK, also known as Buschke-Fischer-Brauer disease, loss-of-function mutations in either the AAGAB or the COL14A1 genes have been associated with the disorder."
    explanation: This supports COL14A1 as a reported association, but this entry treats AAGAB as the stronger established mechanism because the report and primary mechanistic studies center on AAGAB.
environmental:
- name: Mechanical pressure and friction
  presence: Exacerbating factor
  description: >
    Mechanical pressure and friction are not primary causes of hereditary
    punctate PPK, but pressure-bearing plantar sites are where lesions commonly
    become confluent and symptomatic.
  evidence:
  - reference: PMID:23743648
    reference_title: "Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PPKP1 (OMIM ♯148600, Buschke–Fischer–Brauer type) is characterized by the progressive development of discrete areas of hyperkeratosis on the palms and soles, followed by more extensive diffuse hyperkeratosis on the pressure-bearing areas of plantar skin."
    explanation: This supports pressure-bearing plantar skin as a site of more extensive disease.
- name: Water exposure and skin care context
  presence: Exacerbating factor
  description: >
    Water exposure and personal skin-care practices may modulate plantar
    hyperkeratosis severity in affected individuals, but they are modeled as
    modifiers rather than primary causes.
  evidence:
  - reference: PMID:23743648
    reference_title: "Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no apparent genotype–phenotype correlation within this small group of patients, but our clinical observation is that environmental factors and personal skin care regimes affect the degree of plantar hyperkeratosis."
    explanation: This supports environmental and skin-care context as a modifier of plantar hyperkeratosis severity.
  - reference: PMID:36793812
    reference_title: "Punctate Palmoplantar Keratoderma: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A typical feature is the worsening of papules after exposure to water"
    explanation: This describes water exposure as a typical aggravating factor for punctate palmoplantar keratoderma papules.
diagnosis:
- name: Clinical morphology and differential diagnosis
  description: >
    Diagnosis is based on punctate palmoplantar hyperkeratotic lesions, family
    history, and exclusion of acquired or infectious mimics when appropriate.
  evidence:
  - reference: PMID:32147745
    reference_title: "Diagnosis and Management of Inherited Palmoplantar Keratodermas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Palmoplantar keratodermas are grouped depending on the morphology of the keratoderma into diffuse, focal/striate or papular/punctate."
    explanation: This supports morphology-based clinical classification, including papular/punctate forms.
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In severely affected cases, where keratoderma resembled plantar warts, presence of human papilloma virus was excluded in the clinical work-up."
    explanation: This supports excluding wart-like mimics in severe plantar disease.
- name: Genetic testing
  description: >
    Molecular testing can confirm AAGAB-associated punctate PPK and helps
    distinguish punctate PPK from other inherited palmoplantar keratoderma
    subtypes with overlapping clinical morphology.
  evidence:
  - reference: PMID:39630431
    reference_title: "Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes."
    explanation: This supports genetic testing as diagnostically useful in palmoplantar keratoderma cohorts.
  - reference: PMID:38311882
    reference_title: "Identification of a founder variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate palmoplantar keratoderma in Southern Denmark."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend testing for the variant as initial screening in our region and potentially for all Danish patients presenting with punctate PPK."
    explanation: This supports targeted founder-variant testing in the Southern Denmark context.
treatments:
- name: Topical keratolytics and physical debridement
  description: >
    Symptomatic treatment may include topical keratolytics such as urea,
    salicylic acid, or lactic acid and repeated physical debridement, especially
    when no reversible underlying acquired etiology is present.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Punctate palmoplantar hyperkeratosis
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:17298101
    reference_title: "Acquired palmoplantar keratoderma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "If no such etiology is evident, then conservative treatment options include topical keratolytics (urea, salicylic acid, lactic acid), repeated physical debridement, topical retinoids, topical psoralen plus UVA, and topical corticosteroids."
    explanation: This review concerns acquired PPK broadly, so it partially supports conservative symptomatic management options for palmoplantar hyperkeratosis rather than disease-specific efficacy in inherited punctate PPK.
  - reference: PMID:33765759
    reference_title: "A novel AAGAB mutation in a Peruvian family with punctate palmoplantar keratoderma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "After treatment with 30% urea plus 10% salicylic acid, the patient experienced an improvement in her condition."
    explanation: This single AAGAB-associated BFB case supports potential symptomatic improvement with keratolytics but is case-level evidence.
- name: Genetic counseling
  description: >
    Genetic counseling is appropriate for autosomal dominant families, especially
    when molecular testing identifies an AAGAB pathogenic variant.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39630431
    reference_title: "Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes."
    explanation: Confirmed molecular diagnosis provides the basis for subtype-specific counseling in affected families.
- name: Systemic retinoids
  description: >
    Oral retinoids such as acitretin have been used as symptomatic therapy for
    recalcitrant palmoplantar keratoderma, including hereditary punctate forms.
    The support is partial because the abstract-backed evidence is broader PPK
    management literature rather than controlled punctate PPK-specific efficacy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
  target_phenotypes:
  - preferred_term: Punctate palmoplantar hyperkeratosis
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:17298101
    reference_title: "Acquired palmoplantar keratoderma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Etretinate and acitretin have also shown some success as alternative treatments in recalcitrant cases."
    explanation: This acquired PPK review supports systemic retinoid use in recalcitrant PPK; it is partial support for hereditary punctate PPK.
- name: KM-001 topical TRPV3 antagonist trial
  description: >
    KM-001 topical 1% cream is an investigational therapy studied in open-label
    phase I/phase Ib trials for type I punctate palmoplantar keratoderma or
    pachyonychia congenita; no efficacy result is asserted here from the trial
    registry summaries.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Punctate palmoplantar hyperkeratosis
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  - preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: clinicaltrials:NCT05435638
    reference_title: "Phase I, Open Label Study Designed to Evaluate the Safety and Efficacy of a 1% Topical Formulation of KM-001 in the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenital Diseases"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this phase 1 open label study for patients with type I punctate palmoplantar keratoderma or pachyonychia congenital, 2 arms will be recruited to be treated twice daily, with 1% topical KM-001."
    explanation: The trial record supports KM-001 as an investigational topical therapy evaluated in type I punctate PPK.
  - reference: clinicaltrials:NCT05956314
    reference_title: "Phase 1b, Open Label Study to Evaluate the Safety, Tolerability, and Efficacy of a 1% Topical Formulation of KM-001 for the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenita"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This Phase 1b, open-label, single-center, prospective trial will be assessing the safety, tolerability, and efficacy of topical KM-001 1% in patients with PPPK1 or PC diseases."
    explanation: The trial record supports a second open-label KM-001 study in PPPK1 or pachyonychia congenita.
clinical_trials:
- name: NCT05435638
  phase: PHASE_I
  status: COMPLETED
  description: >
    Phase I open-label study of topical KM-001 1% in type I punctate
    palmoplantar keratoderma or pachyonychia congenita, with lesion clearance
    and pain assessments.
  target_phenotypes:
  - preferred_term: Punctate palmoplantar hyperkeratosis
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  - preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: clinicaltrials:NCT05435638
    reference_title: "Phase I, Open Label Study Designed to Evaluate the Safety and Efficacy of a 1% Topical Formulation of KM-001 in the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenital Diseases"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the in-clinic visits, treatment efficacy (lesion clearance - IGA, CGI-S, PGI-C, PGI-S and VAS pain) will also be assessed."
    explanation: The registry summary supports the trial endpoints relevant to lesion clearance and pain.
- name: NCT05956314
  phase: PHASE_I
  status: COMPLETED
  description: >
    Phase Ib open-label study of topical KM-001 1% in PPPK1 or pachyonychia
    congenita, with safety, tolerability, efficacy, pharmacokinetic, and
    patient-reported diary assessments.
  target_phenotypes:
  - preferred_term: Punctate palmoplantar hyperkeratosis
    term:
      id: HP:0007530
      label: Punctate palmoplantar hyperkeratosis
  - preferred_term: Foot pain
    term:
      id: HP:0025238
      label: Foot pain
  evidence:
  - reference: clinicaltrials:NCT05956314
    reference_title: "Phase 1b, Open Label Study to Evaluate the Safety, Tolerability, and Efficacy of a 1% Topical Formulation of KM-001 for the Treatment of Type I Punctate Palmoplantar Keratoderma or Pachyonychia Congenita"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient will complete a patient-reported diary, consisting of treatment compliance and self-assessments for efficacy."
    explanation: The registry summary supports patient-reported efficacy assessment during the KM-001 trial.
discussions:
- discussion_id: controversy_pppk1_malignancy_association
  prompt: >-
    Does punctate palmoplantar keratoderma type 1 confer an increased risk of
    malignancy that would justify cancer surveillance, or is the long-proposed
    association unconfirmed?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Growth Factor Receptor Signaling Increase
  rationale: >-
    A cancer association has been proposed for decades and some authors
    recommend malignancy surveillance, with a mechanistic rationale that EGFR
    and related receptor tyrosine kinase signaling is dysregulated in
    AAGAB-deficient keratinocytes and is also a feature of neoplasia. Primary
    family studies did not observe co-segregation of cancer with AAGAB variants,
    and a PRISMA systematic review of 45 studies covering more than 800
    individuals judged the evidence too poor in quality to confirm an
    association and questioned routine surveillance. The competing published
    positions leave the clinical counseling question unresolved.
  evidence:
  - reference: PMID:31526046
    reference_title: "AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In some families there appears to be an association with cancer."
    explanation: A Canadian family series reports cancers in some AAGAB-mutation families, representing the position that a malignancy link may exist.
  - reference: PMID:23743648
    reference_title: "Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "It is not clear whether there is truly an over-representation of malignancy in PPKP1 cases, and malignant neoplasms were not prevalent in the six kindreds reported here."
    explanation: A primary AAGAB replication study finds the malignancy over-representation uncertain and not prevalent in its own kindreds.
  - reference: PMID:23064416
    reference_title: "Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although a few cases of cancer were reported in the larger families studied here, we did not observe co-segregation with the p34 mutations and so any causal link remains unproven."
    explanation: The gene-discovery study found no co-segregation of cancer with AAGAB mutations, arguing against a causal malignancy link.
  - reference: PMID:37705065
    reference_title: "Is punctate palmoplantar keratoderma type 1 associated with malignancy? A systematic review of the literature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "the review did not confirm an association between PPPK1 and malignancy."
    explanation: A systematic review could not confirm a PPPK1-malignancy association and questioned cancer surveillance based on PPPK1 alone.
- discussion_id: gap_pppk1_focal_distribution_mechanism
  prompt: >-
    Why is hyperkeratosis in punctate palmoplantar keratoderma so sharply focal
    on palmar skin when the causative AAGAB haploinsufficiency is expressed
    throughout the epidermis, and is a somatic second hit required to trigger
    each lesion?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Keratinocyte Hyperproliferation
  rationale: >-
    AAGAB loss of function is constitutional and expressed across palmoplantar
    epidermis, yet lesions arise as discrete punctate foci rather than diffuse
    keratoderma. A somatic second-hit model has been proposed but was not
    identified by microdissection and sequencing, leaving the focal patterning
    mechanism undefined and mechanistically important for understanding p34
    control of keratinocyte proliferation.
  evidence:
  - reference: PMID:23743648
    reference_title: "Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the extremely focal distribution of hyperkeratosis on the palmar skin in the disorder is striking. The mechanism(s) responsible for producing this very focal disease on the background of a mutation expressed throughout the palmar skin are likely to be of clinical relevance, but they remain to be defined."
    explanation: The authors highlight the unexplained focal patterning of lesions despite a constitutional mutation as an open mechanistic question.
review_notes: >-
  Falcon research completed on 2026-05-10 using
  research/Punctate_Palmoplantar_Keratoderma-deep-research-falcon.md and its
  citations file. ORPHA:307967 was not cited in evidence because
  `just fetch-reference ORPHA:307967` did not find a supported structured
  reference source.

  COL14A1 is included conservatively as a reported type 1B association with
  PARTIAL support; the strongest primary and mechanistic evidence in the
  Falcon report supports AAGAB-associated type 1A disease.

📚

References & Deep Research

Deep Research

1

Falcon ▸

1. Disease Information

Edison Scientific Literature 35 citations 2026-05-10T11:26:46.388556

1. Disease Information

1.1 Overview and definition (current understanding)

Punctate palmoplantar keratoderma (punctate PPK; PPPK/PPKP) is a rare disorder of keratinization characterized by multiple discrete hyperkeratotic papules/lesions on the palms and soles, often progressive with age and prone to coalescence at pressure-bearing sites. A classic description for type 1 notes “progressive development of discrete areas of hyperkeratosis on the palms and soles, followed by more extensive diffuse hyperkeratosis on the pressure-bearing areas of plantar skin.” (matsuzawa2013heterozygousmutationsin pages 1-2)

1.2 Key identifiers and subtype taxonomy

In the landmark genetics literature, OMIM recognizes three inherited punctate PPK types: - PPKP1 (Buschke–Fischer–Brauer): OMIM #148600 - PPKP2 (porokeratotic type / porokeratosis punctata palmaris et plantaris): OMIM #175860 - PPKP3 (acrokeratoelastoidosis): OMIM #101850 (pohler2012haploinsufficiencyforaagab pages 1-2)

The 2021 Japanese Dermatological Association guidelines further subdivide punctate type 1 into: - Punctate PPK type 1A: AAGAB - Punctate PPK type 1B: COL14A1 (yoneda2021japaneseguidelinesfor pages 4-5)

Orphanet / ICD-10 / ICD-11 / MeSH / MONDO: these identifiers were not explicitly provided in the retrieved excerpts; therefore, they cannot be reliably populated from this evidence set.

1.3 Common synonyms and alternative names

Punctate palmoplantar keratoderma (PPPK)
Punctate PPK / PPKP
Buschke–Fischer–Brauer disease (type 1) (gram2023ispunctatepalmoplantar pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)
Porokeratosis punctata palmaris et plantaris (type 2) (gram2023ispunctatepalmoplantar pages 1-2)
Acrokeratoelastoidosis (type 3) (gram2023ispunctatepalmoplantar pages 1-2)

1.4 Evidence sources (individual vs aggregated)

The evidence base is dominated by families and case reports/series rather than large epidemiologic cohorts. A 2023 systematic review identified 45 included studies, where most were single-family or multi-family reports; it counted 280 index cases and 817 total affected individuals across the literature. The review emphasized limitations of study quality and concluded it could not confirm a malignancy association. (gram2023ispunctatepalmoplantar pages 1-2)

2. Etiology

2.1 Disease causal factors (genetic and mechanistic)

PPPK type 1 (PPKP1/Buschke–Fischer–Brauer) is most strongly associated with heterozygous loss-of-function variants in AAGAB, consistent with haploinsufficiency. (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2014newandrecurrent pages 1-2)

A less frequent genetic association reported for punctate PPK type 1 includes COL14A1, emphasized in guidelines as punctate type 1B and referenced as occurring in Chinese pedigrees. (yoneda2021japaneseguidelinesfor pages 4-5, thomas2020diagnosisandmanagement pages 5-6)

2.2 Risk factors

Genetic risk: - AAGAB heterozygous truncating/splice variants (nonsense/frameshift/splice) are repeatedly observed in pedigrees and case series. Recurrent variants include AAGAB c.370C>T (p.Arg124Ter). (pohler2014newandrecurrent pages 2-3, pohler2014newandrecurrent pages 1-2)

Environmental/occupational modifiers: - Lesions may worsen with water exposure and at pressure/friction sites (knowles2023punctatepalmoplantarkeratoderma pages 4-5, elhaji2020aagabmutationsin pages 1-2). - Lesions can be worse in manual labourers (trauma/friction exposure). (thomas2020diagnosisandmanagement pages 5-6)

Acquired punctate PPK phenocopies: - The 2023 systematic review notes PPK can be hereditary or acquired due to exposures/conditions such as “arsenic exposure, menopause, and paraneoplastic syndromes.” (gram2023ispunctatepalmoplantar pages 1-2)

2.3 Protective factors

No genetic or environmental protective factors were identified in the retrieved sources.

2.4 Gene–environment interaction

Direct GxE interaction studies were not identified in this evidence set; however, multiple sources consistently indicate that mechanical stress/pressure and water exposure can modulate severity in genetically affected individuals (suggesting an interaction between inherited predisposition and local environmental triggers). (thomas2020diagnosisandmanagement pages 5-6, elhaji2020aagabmutationsin pages 1-2)

3. Phenotypes

3.1 Core clinical phenotypes

Morphology: multiple punctate hyperkeratotic papules/lesions on palms and soles, which may coalesce into plaques at pressure-bearing areas. (matsuzawa2013heterozygousmutationsin pages 1-2, pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)

Pain and functional impact: plantar pain can be prominent; a case series highlights plantar pain with functional impact on walking/standing and notes that manual paring and analgesia can help. (zamiri2019painfulpunctatepalmoplantar pages 5-6)

Progression: a large Danish cohort reported progression in 31/42 punctate probands (74%), stability in 8/42 (19%), and improvement in 1/42 (2%). (gram2025clinicalandgenetic pages 3-4)

Distribution: in the Danish cohort, punctate probands had palms and soles involvement in 40/42 (95%). (gram2025clinicalandgenetic pages 3-4)

3.2 Age of onset

Often begins in adolescence/early adulthood, but range is broad. Median onset for punctate PPK in the Danish cohort was 19.0 years (range 5–47). (gram2025clinicalandgenetic pages 3-4)
A pain-focused series reports onsets spanning childhood through later adulthood (e.g., ~8 to 50s). (zamiri2019painfulpunctatepalmoplantar pages 5-6)

3.3 Histopathology

A characteristic lesion histology described in genetic studies includes a central epidermal depression with hypergranulosis and an overlying orthokeratotic layer; immunostaining suggests a hyperproliferative basal compartment. (pohler2012haploinsufficiencyforaagab pages 1-2)

3.4 Suggested HPO terms (examples)

(IDs not provided in evidence; listed as term labels for mapping) - Punctate palmoplantar keratoderma - Palmoplantar hyperkeratosis - Hyperkeratosis - Plantar pain - Progressive skin disease - Verrucous skin lesion / Hyperkeratotic papule

4. Genetic / Molecular Information

4.1 Causal genes

AAGAB (major gene for PPKP1/PPPK1 type 1A) (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)
COL14A1 (reported; emphasized as type 1B in guidelines; rare compared to AAGAB) (yoneda2021japaneseguidelinesfor pages 4-5, thomas2020diagnosisandmanagement pages 5-6)

4.2 Pathogenic variant classes and functional consequences

AAGAB variants reported across studies are predominantly truncating/splice variants consistent with loss of function and haploinsufficiency (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2014newandrecurrent pages 1-2). A 2014 multi-family report noted “27 distinct loss-of-function mutations reported in AAGAB,” illustrating substantial allelic heterogeneity. (pohler2014newandrecurrent pages 2-3)

A large 2019 series lists many AAGAB truncating/splice variants across families and includes both familial and sporadic cases, supporting dominant inheritance and recurrent mutational spectra. (zamiri2019painfulpunctatepalmoplantar pages 5-6)

Founder variant example (recent development): A 2024 Clinical Genetics study demonstrates AAGAB c.370C>T (p.Arg124Ter) is a founder variant in Southern Denmark: shared haplotype 3.0 Mb and an estimated most recent common ancestor 12.1 generations (~339 years; CI 137–568); it recommends initial screening for this variant in the region and potentially all Danish punctate PPK patients. (gram2024identificationofa pages 1-2)

4.3 Modifier genes / epigenetics / chromosomal abnormalities

No validated modifier genes, epigenetic drivers, or chromosomal abnormalities specific to PPPK were identified in the retrieved sources.

5. Environmental Information

5.1 Environmental and lifestyle contributors

Mechanical stress/friction: worse in manual labourers; pressure points are common sites of coalescence. (thomas2020diagnosisandmanagement pages 5-6, pohler2012haploinsufficiencyforaagab pages 1-2)
Water exposure: reported to worsen papules in several reports. (knowles2023punctatepalmoplantarkeratoderma pages 4-5, elhaji2020aagabmutationsin pages 1-2)

5.2 Infectious agents

No infectious triggers were identified as causal in the retrieved evidence.

6. Mechanism / Pathophysiology

6.1 Mechanistic causal chain (AAGAB/PPKP1)

AAGAB encodes p34 (α- and γ-adaptin–binding protein), linked to clathrin adaptor complexes and membrane trafficking. Functional work supports the causal chain: 1) AAGAB loss-of-function → p34 deficiency (haploinsufficiency) (pohler2012haploinsufficiencyforaagab pages 1-2, giehl2012nonsensemutationsin pages 1-2) 2) Disrupted vesicle trafficking/endocytic recycling, with ultrastructural abnormalities in intracellular vesicle biology in lesional epidermis (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2012haploinsufficiencyforaagab pages 4-5) 3) Increased EGFR protein and activation: keratinocyte knockdown leads to markedly increased EGFR protein and phosphorylation, consistent with impaired receptor turnover (pohler2012haploinsufficiencyforaagab pages 4-5) 4) Keratinocyte hyperproliferation: increased cell division in vitro and hyperproliferative lesions in vivo (pohler2012haploinsufficiencyforaagab pages 1-2) 5) Clinical manifestation as focal hyperproliferative hyperkeratosis (punctate lesions) (pohler2012haploinsufficiencyforaagab pages 1-2)

A complementary mechanistic discussion highlights that impaired RTK endocytosis (EGFR/Axl) could sustain growth-factor signaling and drive hyperkeratosis. (matsuzawa2013heterozygousmutationsin pages 4-4)

6.2 Suggested GO biological process / cellular component terms (labels)

Endocytosis; clathrin-mediated endocytosis (pohler2012haploinsufficiencyforaagab pages 4-5)
Vesicle-mediated transport; endosomal recycling (pohler2012haploinsufficiencyforaagab pages 1-2)
EGFR signaling pathway / receptor tyrosine kinase signaling (pohler2012haploinsufficiencyforaagab pages 4-5)
Regulation of keratinocyte proliferation (pohler2012haploinsufficiencyforaagab pages 1-2)

6.3 Suggested CL (cell types)

Keratinocyte; basal keratinocyte (pohler2012haploinsufficiencyforaagab pages 4-5)

6.4 Molecular profiling (transcriptomics/proteomics/metabolomics)

No disease-specific omics profiling studies were identified in the retrieved sources.

7. Anatomical Structures Affected

7.1 Organ/tissue level

Primary sites: palmar and plantar skin (thick glabrous epidermis), frequently both. (gram2025clinicalandgenetic pages 3-4)

7.2 Suggested UBERON terms (labels)

Skin of palm; skin of sole; epidermis

7.3 Subcellular/cellular compartments

Mechanistic evidence implicates vesicular/endocytic compartments (clathrin adaptor-related trafficking and receptor turnover). (pohler2012haploinsufficiencyforaagab pages 4-5)

8. Temporal Development

8.1 Onset

Typically after childhood/adolescence, with broad variability by family and cohort; Danish cohort median 19 years. (gram2025clinicalandgenetic pages 3-4)

8.2 Course

Often chronic and progressive; lesions increase in number and can coalesce over time. (pohler2012haploinsufficiencyforaagab pages 1-2, gram2025clinicalandgenetic pages 3-4)

9. Inheritance and Population

9.1 Inheritance

Type 1 punctate PPK is classically autosomal dominant with variable expressivity; AAGAB variants segregate in pedigrees with multiple affected generations. (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2014newandrecurrent pages 1-2)

9.2 Epidemiology and statistics

Prevalence estimates in a review of inherited PPK: “1 in 100,000” with AD inheritance. (thomas2020diagnosisandmanagement pages 5-6)
A case report cites an estimated prevalence of 1.17 per 100,000. (knowles2023punctatepalmoplantarkeratoderma pages 4-5)

9.3 Founder effects and population distribution (recent)

A 2024 founder study in Southern Denmark supports a founder origin for AAGAB c.370C>T (p.Arg124Ter) with a 3.0 Mb shared haplotype and estimated origin ~339 years; it recommends first-tier screening for this variant in Denmark. (gram2024identificationofa pages 1-2)

10. Diagnostics

10.1 Clinical diagnosis

Key features include punctate hyperkeratotic lesions on palms/soles; guidelines emphasize excluding look-alikes such as callus/clavus and viral warts when diagnosing PPK. (yoneda2021japaneseguidelinesfor pages 9-10)

10.2 Histopathology

Characteristic lesions may show central epidermal depression with orthokeratosis and hypergranulosis, consistent with hyperproliferation. (pohler2012haploinsufficiencyforaagab pages 1-2)

10.3 Genetic testing strategy (expert consensus / implementation)

Guidelines recommend genetic counseling and consent in hereditary PPK (yoneda2021japaneseguidelinesfor pages 10-12).
In Denmark, initial testing for founder AAGAB c.370C>T (p.Arg124Ter) is recommended for regional patients and potentially all Danish punctate PPK patients. (gram2024identificationofa pages 1-2)

10.4 Differential diagnosis

The punctate phenotype should prompt consideration of punctate PPK types 1A/1B/2/3 and related entities (including Cole disease), and recognition that PPK can be acquired (e.g., arsenic exposure or paraneoplastic syndromes). (yoneda2021japaneseguidelinesfor pages 10-12, gram2023ispunctatepalmoplantar pages 1-2)

11. Outcome / Prognosis

PPPK is primarily a chronic morbidity condition with variable severity; pain can be significant and impair ambulation in some patients (zamiri2019painfulpunctatepalmoplantar pages 5-6). No survival/mortality impact was identified in the retrieved sources.

Malignancy association (expert analysis; 2023 systematic review)

A 2023 Orphanet Journal of Rare Diseases systematic review states: “we could not confirm an association between PPPK1 and malignancy” and highlights “a lack of well-designed studies” to conclude cancer risk; it questions whether surveillance should be offered on the basis of existing literature. (gram2023ispunctatepalmoplantar pages 1-2)

12. Treatment

12.1 Standard management (real-world implementation)

Evidence and guidelines emphasize symptomatic management: - Topical keratolytics/emollients: urea and salicylic acid preparations are repeatedly listed. (yoneda2021japaneseguidelinesfor pages 8-9, knowles2023punctatepalmoplantarkeratoderma pages 4-5) - Mechanical debridement/paring/dermabrasion: cone cutters/razors/punches/scissors, and patient self-care. (yoneda2021japaneseguidelinesfor pages 8-9, yoneda2021japaneseguidelinesfor pages 9-10) - Systemic retinoids: guideline synthesis reports acitretin use with reported benefit in case-based evidence (see below). (yoneda2021japaneseguidelinesfor pages 10-12) - Practical measures: comfortable footwear and reducing trauma/friction. (thomas2020diagnosisandmanagement pages 5-6)

12.2 Retinoids (evidence and statistics)

The Japanese guidelines summarize case-based evidence and state that oral retinoids are useful for PPK; they report acitretin was used in 12 cases, with 10/12 showing therapeutic effect, and isotretinoin in 6 cases with variable outcomes and discontinuation for side effects in some cases. (yoneda2021japaneseguidelinesfor pages 10-12)

12.3 Emerging/experimental therapies (2022–2024 developments)

Two completed interventional trials evaluate KM-001 topical 1% cream, described as “a potent and selective TRPV3 antagonist,” in PPPK1 or pachyonychia congenita: - NCT05435638 (ClinicalTrials.gov record dated 2022; Phase 1; COMPLETED; enrollment 14): topical KM-001 1% twice daily for 12 or 16 weeks. (NCT05435638 chunk 1) - NCT05956314 (ClinicalTrials.gov record dated 2023; Phase 1b; COMPLETED; enrollment 18; primary completion Nov 2024; last update Jan 15, 2025): topical KM-001 1% twice daily for 12 or 16 weeks, with pain and clinician/patient global outcomes. (NCT05956314 chunk 1, NCT05956314 chunk 2)

No efficacy results were available in the retrieved trial record excerpts (status only).

12.4 Suggested MAXO terms (labels)

Topical keratolytic therapy (salicylic acid; urea)
Mechanical debridement/paring
Systemic retinoid therapy (acitretin; isotretinoin)
Genetic counseling
Genetic testing
Topical TRPV3 antagonist therapy (KM-001; investigational)

13. Prevention

No disease-specific primary prevention is established for hereditary PPPK. Secondary/tertiary prevention focuses on symptom control and prevention of fissures/pain via keratolytics, debridement, and minimizing mechanical stress. (yoneda2021japaneseguidelinesfor pages 8-9, thomas2020diagnosisandmanagement pages 5-6)

Genetic counseling and cascade testing can be considered for at-risk relatives in hereditary families. (yoneda2021japaneseguidelinesfor pages 10-12)

14. Other Species / Natural Disease

No naturally occurring animal disease analogs were identified in the retrieved sources.

15. Model Organisms

No whole-animal model systems were identified in the retrieved sources. However, mechanistic evidence includes in vitro keratinocyte knockdown experiments (e.g., HaCaT keratinocytes) showing increased proliferation and altered EGFR protein/phosphorylation, supporting cell-based modeling of AAGAB haploinsufficiency. (pohler2012haploinsufficiencyforaagab pages 1-2, pohler2012haploinsufficiencyforaagab pages 4-5)

Subtype summary table

Subtype	Synonyms / nomenclature	OMIM ID	Typical clinical features / onset	Known genes	Inheritance	Key citations (year / URL)
PPKP1 / PPPK1	Punctate palmoplantar keratoderma type 1; Buschke-Fischer-Brauer disease; punctate PPK type 1A and 1B in Japanese guidelines	148600	Progressive discrete hyperkeratotic lesions/papules on palms and soles; often begin in the 1st-2nd decades or after adolescence; lesions increase with age and may coalesce on pressure-bearing plantar skin; type 1A: numerous tiny punctate keratotic papules from childhood-adolescence that can fuse into larger plaques (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)	Type 1A: AAGAB (major established cause); Type 1B: COL14A1 (reported in Chinese family/families; much rarer) (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5, gram2023ispunctatepalmoplantar pages 1-2)	Autosomal dominant (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)	Pohler et al. 2012, https://doi.org/10.1038/ng.2444; Matsuzawa et al. 2013, https://doi.org/10.1038/jid.2013.243; Yoneda et al. 2021, https://doi.org/10.1111/1346-8138.15850; Gram et al. 2023, https://doi.org/10.1186/s13023-023-02862-8 (pohler2012haploinsufficiencyforaagab pages 1-2, matsuzawa2013heterozygousmutationsin pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5, gram2023ispunctatepalmoplantar pages 1-2)
PPKP1A	Punctate PPK type 1A; Buschke-Fischer-Brauer type	148600	Numerous tiny punctate keratotic papules on palmoplantar skin from childhood to adolescence; lesions gradually increase and may fuse into larger hyperkeratotic lesions (yoneda2021japaneseguidelinesfor pages 4-5)	AAGAB (yoneda2021japaneseguidelinesfor pages 4-5, pohler2012haploinsufficiencyforaagab pages 1-2)	Autosomal dominant (yoneda2021japaneseguidelinesfor pages 4-5)	Yoneda et al. 2021, https://doi.org/10.1111/1346-8138.15850; Pohler et al. 2012, https://doi.org/10.1038/ng.2444 (yoneda2021japaneseguidelinesfor pages 4-5, pohler2012haploinsufficiencyforaagab pages 1-2)
PPKP1B	Punctate PPK type 1B	Not specified in provided sources	Included by Japanese guidelines as a punctate PPK subtype; detailed phenotype not expanded in retrieved excerpts beyond punctate palmoplantar hyperkeratosis classification (yoneda2021japaneseguidelinesfor pages 4-5)	COL14A1 (yoneda2021japaneseguidelinesfor pages 4-5, gram2023ispunctatepalmoplantar pages 1-2)	Autosomal dominant (yoneda2021japaneseguidelinesfor pages 4-5)	Yoneda et al. 2021, https://doi.org/10.1111/1346-8138.15850; Gram et al. 2023, https://doi.org/10.1186/s13023-023-02862-8 (yoneda2021japaneseguidelinesfor pages 4-5, gram2023ispunctatepalmoplantar pages 1-2)
PPKP2	Porokeratotic type; porokeratosis punctata palmaris et plantaris; punctate PPK type 2	175860	Tiny punctate keratotic lesions appearing around puberty; histopathology characterized by a coronoid lamella-like column of parakeratotic cells (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)	Unknown in provided sources (yoneda2021japaneseguidelinesfor pages 4-5)	Autosomal dominant (yoneda2021japaneseguidelinesfor pages 4-5)	Pohler et al. 2012, https://doi.org/10.1038/ng.2444; Yoneda et al. 2021, https://doi.org/10.1111/1346-8138.15850; Gram et al. 2023, https://doi.org/10.1186/s13023-023-02862-8 (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5, gram2023ispunctatepalmoplantar pages 1-2)
PPKP3	Acrokeratoelastoidosis; punctate PPK type 3	101850	Small keratotic papules appearing after adolescence on the marginal edges of palmar and plantar surfaces (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5)	Unknown in provided sources (yoneda2021japaneseguidelinesfor pages 4-5)	Autosomal dominant (yoneda2021japaneseguidelinesfor pages 4-5)	Pohler et al. 2012, https://doi.org/10.1038/ng.2444; Yoneda et al. 2021, https://doi.org/10.1111/1346-8138.15850; Gram et al. 2023, https://doi.org/10.1186/s13023-023-02862-8 (pohler2012haploinsufficiencyforaagab pages 1-2, yoneda2021japaneseguidelinesfor pages 4-5, gram2023ispunctatepalmoplantar pages 1-2)

Table: This table summarizes the punctate palmoplantar keratoderma subtype framework used in the retrieved sources, including OMIM identifiers, clinical patterns, inheritance, and the distinction between type 1A (AAGAB) and type 1B (COL14A1). It is useful for quickly aligning historical subtype names with current gene-based understanding.

Visual evidence (figures)

Pedigrees/clinical images/histology and an AAGAB mutation schematic (including the panel describing mutation locations relative to functional domains) were retrieved from a multi-family PPPK1 mutation report. (pohler2014newandrecurrent media e8a4666c, pohler2014newandrecurrent media f62067ed, pohler2014newandrecurrent media 7e640702)

Notes on gaps and limitations

1) This run’s retrieved excerpts did not explicitly contain Orphanet/ICD/MeSH/MONDO identifiers; these should be added by querying OMIM/Orphanet/MONDO directly if required for KB completeness. 2) Some gene claims (e.g., COL14A1 as type 1B) are supported here through guideline and review-level evidence but not by direct full-text extraction of the original COL14A1 pedigree paper in this run. 3) ClinicalTrials.gov entries show completed studies of KM-001, but trial results were not present in the retrieved record chunks.

References

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(elhaji2020aagabmutationsin pages 1-2): Youssef Elhaji, Cherise Hedlin, Anu Nath, Emma L. Price, Christopher Gallant, Stacey Northgrave, and Peter R. Hull. Aagab mutations in 18 canadian families with punctate palmoplantar keratoderma and a possible link to cancer. Journal of Cutaneous Medicine and Surgery, 24:28-32, Jan 2020. URL: https://doi.org/10.1177/1203475419878161, doi:10.1177/1203475419878161. This article has 15 citations and is from a peer-reviewed journal.
(zamiri2019painfulpunctatepalmoplantar pages 5-6): M. Zamiri, Neil J. Wilson, A. Mackenzie, G. Sobey, C. Leitch, and F.J.D. Smith. Painful punctate palmoplantar keratoderma due to heterozygous mutations in aagab. British Journal of Dermatology, 180:1250-1251, Feb 2019. URL: https://doi.org/10.1111/bjd.17442, doi:10.1111/bjd.17442. This article has 7 citations and is from a highest quality peer-reviewed journal.
(gram2025clinicalandgenetic pages 3-4): Stine Bjørn Gram, Klaus Brusgaard, Ulrikke Lei, Mette Sommerlund, Gabrielle Randskov Vinding, Sondre Olai Kjellevold Sleire, Alex Hørby Christensen, Sanne Pedersen Fast, Rasmus Bach, Anette Bygum, and Lilian Bomme Ousager. Clinical and genetic findings in patients with palmoplantar keratoderma. JAMA Dermatology, 161:157, Feb 2025. URL: https://doi.org/10.1001/jamadermatol.2024.4824, doi:10.1001/jamadermatol.2024.4824. This article has 6 citations and is from a domain leading peer-reviewed journal.
(gram2024identificationofa pages 1-2): Stine Bjørn Gram, Anne Sofie Fredberg Jørgensen, Anette Bygum, Klaus Brusgaard, and Lilian Bomme Ousager. Identification of a founder variant aagab c.370c>t, p.arg124ter in patients with punctate palmoplantar keratoderma in southern denmark. Clinical Genetics, 105:561-566, Feb 2024. URL: https://doi.org/10.1111/cge.14486, doi:10.1111/cge.14486. This article has 1 citations and is from a peer-reviewed journal.
(giehl2012nonsensemutationsin pages 1-2): Kathrin A. Giehl, Gertrud N. Eckstein, Sandra M. Pasternack, Silke Praetzel-Wunder, Thomas Ruzicka, Peter Lichtner, Kerstin Seidl, Mike Rogers, Elisabeth Graf, Lutz Langbein, Markus Braun-Falco, Regina C. Betz, and Tim M. Strom. Nonsense mutations in aagab cause punctate palmoplantar keratoderma type buschke-fischer-brauer. American journal of human genetics, 91 4:754-9, Oct 2012. URL: https://doi.org/10.1016/j.ajhg.2012.08.024, doi:10.1016/j.ajhg.2012.08.024. This article has 98 citations and is from a highest quality peer-reviewed journal.
(pohler2012haploinsufficiencyforaagab pages 4-5): Elizabeth Pohler, Ons Mamai, Jennifer Hirst, Mozheh Zamiri, Helen Horn, Toshifumi Nomura, Alan D Irvine, Benvon Moran, Neil J Wilson, Frances J D Smith, Christabelle S M Goh, Aileen Sandilands, Christian Cole, Geoffrey J Barton, Alan T Evans, Hiroshi Shimizu, Masashi Akiyama, Mitsuhiro Suehiro, Izumi Konohana, Mohammad Shboul, Sebastien Teissier, Lobna Boussofara, Mohamed Denguezli, Ali Saad, Moez Gribaa, Patricia J Dopping-Hepenstal, John A McGrath, Sara J Brown, David R Goudie, Bruno Reversade, Colin S Munro, and W H Irwin McLean. Haploinsufficiency for aagab causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nature Genetics, 44:1272-1276, Oct 2012. URL: https://doi.org/10.1038/ng.2444, doi:10.1038/ng.2444. This article has 114 citations and is from a highest quality peer-reviewed journal.
(matsuzawa2013heterozygousmutationsin pages 4-4): Takamitsu Matsuzawa, T. Kawamura, Y. Ogawa, Masaaki Takahashi, R. Aoki, Kohji Moriishi, Yoshio Koyanagi, Hiroyuki Gatanaga, A. Blauvelt, and Shinji Shimada. Heterozygous mutations in aagab cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. Journal of Investigative Dermatology, 133:2805-2808, Dec 2013. URL: https://doi.org/10.1038/jid.2013.243, doi:10.1038/jid.2013.243. This article has 23 citations and is from a highest quality peer-reviewed journal.
(yoneda2021japaneseguidelinesfor pages 9-10): Kozo Yoneda, Akiharu Kubo, Toshifumi Nomura, Akemi Ishida‐Yamamoto, Yasushi Suga, Masashi Akiyama, Nobuo Kanazawa, and Takashi Hashimoto. Japanese guidelines for the management of palmoplantar keratoderma. The Journal of Dermatology, Jun 2021. URL: https://doi.org/10.1111/1346-8138.15850, doi:10.1111/1346-8138.15850. This article has 10 citations.
(yoneda2021japaneseguidelinesfor pages 10-12): Kozo Yoneda, Akiharu Kubo, Toshifumi Nomura, Akemi Ishida‐Yamamoto, Yasushi Suga, Masashi Akiyama, Nobuo Kanazawa, and Takashi Hashimoto. Japanese guidelines for the management of palmoplantar keratoderma. The Journal of Dermatology, Jun 2021. URL: https://doi.org/10.1111/1346-8138.15850, doi:10.1111/1346-8138.15850. This article has 10 citations.
(yoneda2021japaneseguidelinesfor pages 8-9): Kozo Yoneda, Akiharu Kubo, Toshifumi Nomura, Akemi Ishida‐Yamamoto, Yasushi Suga, Masashi Akiyama, Nobuo Kanazawa, and Takashi Hashimoto. Japanese guidelines for the management of palmoplantar keratoderma. The Journal of Dermatology, Jun 2021. URL: https://doi.org/10.1111/1346-8138.15850, doi:10.1111/1346-8138.15850. This article has 10 citations.
(NCT05435638 chunk 1): Study Designed to Evaluate Safety and Efficacy of 1% Topical Formulation of KM-001 on Type 1 Punctate Palmoplantar Keratoderma or Pachyonychia Congenita Diseases. Kamari Pharma Ltd. 2022. ClinicalTrials.gov Identifier: NCT05435638
(NCT05956314 chunk 1): Assessment of KM-001 - Safety, Tolerability, and Efficacy in Patients With PPPK1 or PC. Kamari Pharma Ltd. 2023. ClinicalTrials.gov Identifier: NCT05956314
(NCT05956314 chunk 2): Assessment of KM-001 - Safety, Tolerability, and Efficacy in Patients With PPPK1 or PC. Kamari Pharma Ltd. 2023. ClinicalTrials.gov Identifier: NCT05956314
(pohler2014newandrecurrent media e8a4666c): Elizabeth Pohler, M. Huber, S. E. Boonen, M. Zamiri, M. Zamiri, P. A. Gregersen, Mette Sommerlund, Mette Ramsing, Daniel Hohl, W. McLean, and F. Smith. New and recurrent aagab mutations in punctate palmoplantar keratoderma. The British Journal of Dermatology, 171:433-436, Aug 2014. URL: https://doi.org/10.1111/bjd.12927, doi:10.1111/bjd.12927. This article has 10 citations.
(pohler2014newandrecurrent media f62067ed): Elizabeth Pohler, M. Huber, S. E. Boonen, M. Zamiri, M. Zamiri, P. A. Gregersen, Mette Sommerlund, Mette Ramsing, Daniel Hohl, W. McLean, and F. Smith. New and recurrent aagab mutations in punctate palmoplantar keratoderma. The British Journal of Dermatology, 171:433-436, Aug 2014. URL: https://doi.org/10.1111/bjd.12927, doi:10.1111/bjd.12927. This article has 10 citations.
(pohler2014newandrecurrent media 7e640702): Elizabeth Pohler, M. Huber, S. E. Boonen, M. Zamiri, M. Zamiri, P. A. Gregersen, Mette Sommerlund, Mette Ramsing, Daniel Hohl, W. McLean, and F. Smith. New and recurrent aagab mutations in punctate palmoplantar keratoderma. The British Journal of Dermatology, 171:433-436, Aug 2014. URL: https://doi.org/10.1111/bjd.12927, doi:10.1111/bjd.12927. This article has 10 citations.

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OpenScientist Report

Definitions

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Clinical Trials

Source YAML

References & Deep Research

Deep Research

1. Disease Information

1.1 Overview and definition (current understanding)

1.2 Key identifiers and subtype taxonomy

1.3 Common synonyms and alternative names

1.4 Evidence sources (individual vs aggregated)

2. Etiology

2.1 Disease causal factors (genetic and mechanistic)

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interaction

3. Phenotypes

3.1 Core clinical phenotypes

3.2 Age of onset

3.3 Histopathology

3.4 Suggested HPO terms (examples)

4. Genetic / Molecular Information

4.1 Causal genes

4.2 Pathogenic variant classes and functional consequences

4.3 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental Information

5.1 Environmental and lifestyle contributors

5.2 Infectious agents

6. Mechanism / Pathophysiology

6.1 Mechanistic causal chain (AAGAB/PPKP1)

6.2 Suggested GO biological process / cellular component terms (labels)

6.3 Suggested CL (cell types)

6.4 Molecular profiling (transcriptomics/proteomics/metabolomics)

7. Anatomical Structures Affected

7.1 Organ/tissue level

7.2 Suggested UBERON terms (labels)

7.3 Subcellular/cellular compartments

8. Temporal Development

8.1 Onset

8.2 Course

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology and statistics

9.3 Founder effects and population distribution (recent)

10. Diagnostics

10.1 Clinical diagnosis

10.2 Histopathology

10.3 Genetic testing strategy (expert consensus / implementation)

10.4 Differential diagnosis

11. Outcome / Prognosis

Malignancy association (expert analysis; 2023 systematic review)

12. Treatment

12.1 Standard management (real-world implementation)

12.2 Retinoids (evidence and statistics)

12.3 Emerging/experimental therapies (2022–2024 developments)

12.4 Suggested MAXO terms (labels)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Subtype summary table

Visual evidence (figures)

Notes on gaps and limitations