Diffuse Nonepidermolytic Palmoplantar Keratoderma

Mendelian MONDO:0010962 Pathograph 9 Diffuse palmoplantar keratoderma Autosomal dominant disease

Diffuse nonepidermolytic palmoplantar keratoderma is a rare autosomal dominant isolated palmoplantar keratoderma caused by germline KRT1 variants. Affected individuals develop diffuse, sharply demarcated hyperkeratosis of the palms and soles without the epidermolysis that characterizes epidermolytic keratinopathies. Associated findings include dry skin, umbilical or areolar hyperkeratosis, knuckle pad-like lesions, hyperhidrosis, nail changes, and recurrent fungal infection or onychomycosis. Histology shows orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild superficial dermal lymphocytic inflammation without epidermolysis.

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1
Mappings
1
Definitions
1
Inheritance
3
Pathophys.
1
Histopath.
15
Phenotypes
9
Pathograph
1
Genes
2
Treatments
5
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0010962 diffuse nonepidermolytic palmoplantar keratoderma
skos:exactMatch Orphanet ORPHA:530838
Orphanet ORPHA:530838 lists MONDO:0010962 as an exact cross-reference for KRT1-related diffuse nonepidermolytic keratoderma.
📘

Definitions

1
Orphanet KRT1-related diffuse nonepidermolytic keratoderma definition
A rare genetic isolated diffuse palmoplantar keratoderma with diffuse, well-demarcated hyperkeratosis of the palms and soles, additional cutaneous/nail findings, and nonepidermolytic histology.
OTHER
Show evidence (2 references)
ORPHA:530838 SUPPORT Other
"A rare, genetic, isolated diffuse palmoplantar keratoderma characterized by diffuse, mild to thick, finely demarcated hyperkeratosis of palms and soles."
Orphanet defines the disorder as a rare isolated diffuse palmoplantar keratoderma.
PMID:30452289 SUPPORT Human Clinical
"pedigree with diffuse nonepidermolytic palmoplantar keratoderma (NEPPK)."
The clinical pedigree report uses the same diffuse NEPPK disease label.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Diffuse nonepidermolytic palmoplantar keratoderma is inherited in an autosomal dominant pattern.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:530838 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance.
PMID:7531539 SUPPORT Human Clinical
"An autosomal dominant form of diffuse non-epidermolytic palmoplantar keratoderma"
The northern Sweden linkage study describes the disease as autosomal dominant.
⚙

Pathophysiology

3
KRT1 germline keratin 1 defect
Disease-causing germline KRT1 variants alter keratin 1, a type II keratin expressed in suprabasal epidermal keratinocytes. In diffuse NEPPK pedigrees, KRT1 variation segregates with diffuse palmoplantar keratoderma and points to a keratin filament defect distinct from KRT9-related epidermolytic PPK.
suprabasal keratinocyte link
intermediate filament organization link ⚠ ABNORMAL
Downstream
Nonepidermolytic palmoplantar keratinization disturbance KRT1 variation disrupts the keratinocyte cytoskeletal program that supports palmoplantar epidermal differentiation.
Show evidence (2 references)
ORPHA:530838 SUPPORT Other
"KRT1 | keratin 1 | hgnc:6412 | Disease-causing germline mutation(s) in"
Orphanet's gene row anchors the upstream disease mechanism to KRT1.
PMID:30452289 SUPPORT Human Clinical
"sequencing of relevant potential causative genes, including KRT1, KRT6C, KRT10, KRT16, AQP5, and SERPINB7, was performed."
The clinical genetic study evaluated keratinization genes and identified KRT1 variation in the affected pedigree.
Nonepidermolytic palmoplantar keratinization disturbance
The KRT1-related keratinocyte defect produces abnormal palmoplantar keratinization and diffuse hyperkeratosis while preserving nonepidermolytic histology. This separates the entity from epidermolytic palmoplantar keratoderma and supports the diffuse palmoplantar hyperkeratosis phenotype.
palmoplantar keratinocyte link
keratinization link ⚠ ABNORMAL keratinocyte differentiation link ⚠ ABNORMAL
Downstream
Diffuse palmoplantar hyperkeratosis Abnormal palmoplantar keratinization directly produces diffuse thickening of the palms and soles.
Nonepidermolytic palmoplantar hyperkeratosis The hyperkeratosis occurs without epidermolysis on histology.
Palmoplantar scaling skin Disordered cornification contributes to palmoplantar scaling.
Show evidence (2 references)
ORPHA:530838 SUPPORT Other
"diffuse, mild to thick, finely demarcated hyperkeratosis of palms and soles"
Orphanet defines the disease by diffuse palmoplantar hyperkeratosis.
PMID:7531539 SUPPORT Human Clinical
"frequently complicated by fungal infections"
The historical linkage cohort supports fungal infection as a recurring complication of the diffuse nonepidermolytic PPK phenotype.
Orthokeratotic hyperkeratosis without epidermolysis
Lesional skin biopsy shows orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild upper-dermal lymphocytic infiltrates without epidermolysis, matching the nonepidermolytic clinical designation.
keratinocyte link
cornification link ⚠ ABNORMAL
Downstream
Nonepidermolytic palmoplantar hyperkeratosis Nonepidermolytic histology distinguishes the hyperkeratosis from epidermolytic keratinopathies.
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"Histological examination of lesions reveals orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild lymphocyte infiltrations in the upper dermis with no evidence of epidermolysis."
Orphanet's histology statement supports a nonepidermolytic microscopic pattern.
✶

Histopathology

1
Orthokeratotic hyperkeratosis without epidermolysis
Microscopic lesions show orthokeratotic hyperkeratosis with acanthosis, hypergranulosis, mild superficial dermal lymphocytic infiltrates, and no evidence of epidermolysis.
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild lymphocyte infiltrations in the upper dermis with no evidence of epidermolysis."
Orphanet lists the characteristic histopathologic findings.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Diffuse Nonepidermolytic Palmoplantar Keratoderma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Cardiovascular 1
Erythema FREQUENT Erythema (HP:0010783)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0010783 | Erythema | Frequent (79-30%)"
Orphanet lists erythema as frequent.
Immune 1
Atopic dermatitis OCCASIONAL Atopic dermatitis (HP:0001047)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0001047 | Atopic dermatitis | Occasional (29-5%)"
Orphanet lists atopic dermatitis as occasional.
Integument 3
Dry skin FREQUENT Dry skin (HP:0000958)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0000958 | Dry skin | Frequent (79-30%)"
Orphanet lists dry skin as frequent.
Knuckle pad OCCASIONAL Knuckle pad (HP:0032541)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0032541 | Knuckle pad | Occasional (29-5%)"
Orphanet lists knuckle pad as occasional.
Scaling skin OCCASIONAL Scaling skin (HP:0040189)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0040189 | Scaling skin | Occasional (29-5%)"
Orphanet lists scaling skin as occasional.
Other 10
Nonepidermolytic palmoplantar hyperkeratosis OBLIGATE Nonepidermolytic palmoplantar hyperkeratosis (HP:0007404)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0007404 | Nonepidermolytic palmoplantar keratoderma | Obligate (100%)"
Orphanet lists nonepidermolytic palmoplantar keratoderma as obligate.
Diffuse palmoplantar hyperkeratosis VERY_FREQUENT Diffuse palmoplantar hyperkeratosis (HP:0007447)
Show evidence (2 references)
ORPHA:530838 SUPPORT Other
"HP:0007447 | Diffuse palmoplantar kyperkeratosis | Very frequent (99-80%)"
Orphanet lists diffuse palmoplantar hyperkeratosis as very frequent.
PMID:30452289 SUPPORT Human Clinical
"Histological findings, clinical features, and medical history were in accordance with the diagnosis of diffuse NEPPK."
The clinical pedigree report supports the diffuse NEPPK diagnosis in affected individuals.
Abnormal umbilicus morphology FREQUENT Abnormal umbilicus morphology (HP:0001551)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0001551 | Abnormal umbilicus morphology | Frequent (79-30%)"
Orphanet lists abnormal umbilicus morphology as frequent.
Concave nail OCCASIONAL Concave nail (HP:0001598)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0001598 | Concave nail | Occasional (29-5%)"
Orphanet lists concave nail as occasional.
Thickened Achilles tendon OCCASIONAL Thickened Achilles tendon (HP:0004690)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0004690 | Thickened Achilles tendon | Occasional (29-5%)"
Orphanet lists thickened Achilles tendon as occasional.
Decreased movement range in interphalangeal joints OCCASIONAL Decreased movement range in interphalangeal joints (HP:0006203)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0006203 | Decreased movement range in interphalangeal joints | Occasional (29-5%)"
Orphanet lists decreased movement range in interphalangeal joints as occasional.
Palmoplantar blistering OCCASIONAL Palmoplantar blistering (HP:0007446)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0007446 | Palmoplantar blistering | Occasional (29-5%)"
Orphanet lists palmoplantar blistering as occasional.
Onychomycosis FREQUENT Onychomycosis (HP:0012203)
Show evidence (2 references)
ORPHA:530838 SUPPORT Other
"HP:0012203 | Onychomycosis | Frequent (79-30%)"
Orphanet lists onychomycosis as frequent.
PMID:7531539 SUPPORT Human Clinical
"frequently complicated by fungal infections"
The northern Sweden cohort describes fungal infections as frequent complications of diffuse non-epidermolytic PPK.
Palmoplantar scaling skin OCCASIONAL Palmoplantar scaling skin (HP:0025524)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0025524 | Palmoplantar scaling skin | Occasional (29-5%)"
Orphanet lists palmoplantar scaling skin as occasional.
Tendon thickening OCCASIONAL Tendon thickening (HP:0032523)
Show evidence (1 reference)
ORPHA:530838 SUPPORT Other
"HP:0032523 | Tendon thickening | Occasional (29-5%)"
Orphanet lists tendon thickening as occasional.
🧬

Genetic Associations

1
KRT1 germline pathogenic variants (Causative germline variant)
Show evidence (3 references)
ORPHA:530838 SUPPORT Other
"KRT1 | keratin 1 | hgnc:6412 | Disease-causing germline mutation(s) in"
Orphanet identifies KRT1 germline mutations as disease-causing for this disorder.
PMID:30452289 SUPPORT Human Clinical
"We identified a novel splice-site mutation"
The affected pedigree report identifies a KRT1 splice-site mutation segregating with NEPPK.
PMID:30452289 SUPPORT Human Clinical
"in all individuals with NEPPK in the pedigree."
The variant was found in affected individuals in the clinical pedigree.
💊

Treatments

2
Topical emollient and keratolytic symptom therapy
Action: application of emollient to skin MAXO:0000996
Topical emollients, keratolytics, topical retinoids, and topical steroids are used symptomatically to soften hyperkeratosis, reduce scale, and relieve pain or functional impairment. These treatments are not curative.
Mechanism Target:
MODULATES Nonepidermolytic palmoplantar keratinization disturbance — Topical therapy acts downstream by reducing the symptomatic cornified burden.
Target Phenotypes: Diffuse palmoplantar hyperkeratosis ↗ Palmoplantar scaling skin ↗
Show evidence (1 reference)
PMID:32307694 SUPPORT Human Clinical
"Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms."
The hereditary PPK treatment review supports topical symptom-directed therapy.
Oral retinoid therapy
Action: Pharmacotherapy NCIT:C15986
Agent: retinoid ↗
Oral retinoids are a systemic option for severe hereditary palmoplantar keratoderma, but benefit varies by PPK subtype and tolerability can limit use.
Mechanism Target:
MODULATES Nonepidermolytic palmoplantar keratinization disturbance — Retinoids modulate keratinocyte differentiation and cornification.
Target Phenotypes: Diffuse palmoplantar hyperkeratosis ↗
Show evidence (1 reference)
PMID:32307694 SUPPORT Human Clinical
"Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance."
The hereditary PPK treatment review supports oral retinoids as a systemic treatment option with variable efficacy and tolerance.
{ }

Source YAML

click to show 
name: Diffuse Nonepidermolytic Palmoplantar Keratoderma
category: Mendelian
creation_date: "2026-05-09T17:03:34Z"
updated_date: "2026-05-09T17:03:34Z"
synonyms:
- KRT1-related diffuse nonepidermolytic keratoderma
- KRT1-related diffuse NEPPK
- Diffuse nonepidermolytic palmoplantar keratoderma
- Non-epidermolytic palmoplantar keratoderma
- NEPPK
- Diffuse palmoplantar keratoderma, Bothnian type
- Thost-Unna palmoplantar keratoderma
- Unna-Thost palmoplantar keratoderma
description: >
  Diffuse nonepidermolytic palmoplantar keratoderma is a rare autosomal
  dominant isolated palmoplantar keratoderma caused by germline KRT1 variants.
  Affected individuals develop diffuse, sharply demarcated hyperkeratosis of
  the palms and soles without the epidermolysis that characterizes epidermolytic
  keratinopathies. Associated findings include dry skin, umbilical or areolar
  hyperkeratosis, knuckle pad-like lesions, hyperhidrosis, nail changes, and
  recurrent fungal infection or onychomycosis. Histology shows orthokeratotic
  hyperkeratosis, acanthosis, hypergranulosis, and mild superficial dermal
  lymphocytic inflammation without epidermolysis.
disease_term:
  preferred_term: diffuse nonepidermolytic palmoplantar keratoderma
  term:
    id: MONDO:0010962
    label: diffuse nonepidermolytic palmoplantar keratoderma
parents:
- Diffuse palmoplantar keratoderma
- Autosomal dominant disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010962
      label: diffuse nonepidermolytic palmoplantar keratoderma
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:530838
    mapping_justification: >
      Orphanet ORPHA:530838 lists MONDO:0010962 as an exact cross-reference
      for KRT1-related diffuse nonepidermolytic keratoderma.
external_assertions:
- name: Orphanet KRT1-related diffuse nonepidermolytic keratoderma record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:530838
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=530838
  description: >
    Orphanet's ORPHA:530838 structured record provides the disease definition,
    autosomal dominant inheritance, KRT1 disease-gene assertion, worldwide
    prevalence class, HPO phenotype rows, and exact MONDO and OMIM cross-
    references used in this entry.
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0010962 | Exact"
    explanation: Orphanet maps ORPHA:530838 exactly to the MONDO identifier used by this entry.
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:600962 | Exact"
    explanation: Orphanet lists OMIM:600962 as an exact external cross-reference.
- name: Orphanet Thost-Unna palmoplantar keratoderma historical record
  source: Orphanet
  assertion_type: sparse_historical_disease_record
  external_id: ORPHA:496
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=496
  description: >
    ORPHA:496 is a sparse Orphanet historical record for Thost-Unna
    palmoplantar keratoderma. It is retained here only as a synonym/history
    signal and is not used as the phenotype or gene-evidence source.
  evidence:
  - reference: ORPHA:496
    reference_title: Thost-Unna palmoplantar keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thost-Unna palmoplantar keratoderma"
    explanation: The sparse Orphanet record supports Thost-Unna palmoplantar keratoderma as a historical label.
definitions:
- name: Orphanet KRT1-related diffuse nonepidermolytic keratoderma definition
  definition_type: OTHER
  description: >
    A rare genetic isolated diffuse palmoplantar keratoderma with diffuse,
    well-demarcated hyperkeratosis of the palms and soles, additional
    cutaneous/nail findings, and nonepidermolytic histology.
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, genetic, isolated diffuse palmoplantar keratoderma characterized by diffuse, mild to thick, finely demarcated hyperkeratosis of palms and soles."
    explanation: Orphanet defines the disorder as a rare isolated diffuse palmoplantar keratoderma.
  - reference: PMID:30452289
    reference_title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pedigree with diffuse nonepidermolytic palmoplantar keratoderma (NEPPK)."
    explanation: The clinical pedigree report uses the same diffuse NEPPK disease label.
inheritance:
- name: Autosomal dominant inheritance
  description: Diffuse nonepidermolytic palmoplantar keratoderma is inherited in an autosomal dominant pattern.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance.
  - reference: PMID:7531539
    reference_title: The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An autosomal dominant form of diffuse non-epidermolytic palmoplantar keratoderma"
    explanation: The northern Sweden linkage study describes the disease as autosomal dominant.
prevalence:
- population: Worldwide
  percentage: Unknown
  notes: >
    Orphanet lists worldwide point prevalence as unknown. The northern Sweden
    linkage cohort represents a regional founder context and is not used as a
    global prevalence estimate.
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | PMID:30452289"
    explanation: Orphanet records unknown worldwide point prevalence.
  - reference: PMID:7531539
    reference_title: The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "encountered in northern Sweden with a prevalence of 0.3-0.55%."
    explanation: The linkage paper documents a high regional prevalence in northern Sweden, consistent with founder enrichment rather than worldwide prevalence.
progression:
- phase: Onset
  age_range: Infancy to childhood
  notes: Orphanet lists both infancy and childhood onset.
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet lists infancy as an onset category.
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet lists childhood as an onset category.
- phase: Chronic palmoplantar keratoderma
  age_range: Childhood through adulthood
  notes: >
    The disorder is modeled as a chronic inherited keratinization disorder with
    persistent palmoplantar hyperkeratosis and variable associated cutaneous
    complications.
  evidence:
  - reference: PMID:7531539
    reference_title: The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary palmoplantar keratoderma is characterized by hyperkeratosis of the skin of palms and soles."
    explanation: The linkage study supports chronic palmoplantar hyperkeratosis as the core inherited disease manifestation.
genetic:
- name: KRT1 germline pathogenic variants
  association: Causative germline variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: KRT1
    term:
      id: hgnc:6412
      label: KRT1
  features: >
    Germline pathogenic KRT1 variants, including splice-site variants, cause
    diffuse NEPPK in affected pedigrees. ORPHA:530838 records KRT1 as the
    disease-causing germline gene.
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRT1 | keratin 1 | hgnc:6412 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies KRT1 germline mutations as disease-causing for this disorder.
  - reference: PMID:30452289
    reference_title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel splice-site mutation"
    explanation: The affected pedigree report identifies a KRT1 splice-site mutation segregating with NEPPK.
  - reference: PMID:30452289
    reference_title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in all individuals with NEPPK in the pedigree."
    explanation: The variant was found in affected individuals in the clinical pedigree.
pathophysiology:
- name: KRT1 germline keratin 1 defect
  description: >
    Disease-causing germline KRT1 variants alter keratin 1, a type II keratin
    expressed in suprabasal epidermal keratinocytes. In diffuse NEPPK pedigrees,
    KRT1 variation segregates with diffuse palmoplantar keratoderma and points
    to a keratin filament defect distinct from KRT9-related epidermolytic PPK.
  gene:
    preferred_term: KRT1
    term:
      id: hgnc:6412
      label: KRT1
  cell_types:
  - preferred_term: suprabasal keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: intermediate filament organization
    term:
      id: GO:0045109
      label: intermediate filament organization
    modifier: ABNORMAL
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KRT1 | keratin 1 | hgnc:6412 | Disease-causing germline mutation(s) in"
    explanation: Orphanet's gene row anchors the upstream disease mechanism to KRT1.
  - reference: PMID:30452289
    reference_title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sequencing of relevant potential causative genes, including KRT1, KRT6C, KRT10, KRT16, AQP5, and SERPINB7, was performed."
    explanation: The clinical genetic study evaluated keratinization genes and identified KRT1 variation in the affected pedigree.
  downstream:
  - target: Nonepidermolytic palmoplantar keratinization disturbance
    causal_link_type: DIRECT
    description: >
      KRT1 variation disrupts the keratinocyte cytoskeletal program that
      supports palmoplantar epidermal differentiation.
    evidence:
    - reference: PMID:30452289
      reference_title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diffuse NEPPK is a relatively rare subtype of palmoplantar keratoderma."
      explanation: The KRT1 pedigree paper connects KRT1 variation to diffuse NEPPK as a palmoplantar keratoderma subtype.
- name: Nonepidermolytic palmoplantar keratinization disturbance
  description: >
    The KRT1-related keratinocyte defect produces abnormal palmoplantar
    keratinization and diffuse hyperkeratosis while preserving nonepidermolytic
    histology. This separates the entity from epidermolytic palmoplantar
    keratoderma and supports the diffuse palmoplantar hyperkeratosis phenotype.
  cell_types:
  - preferred_term: palmoplantar keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: ABNORMAL
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "diffuse, mild to thick, finely demarcated hyperkeratosis of palms and soles"
    explanation: Orphanet defines the disease by diffuse palmoplantar hyperkeratosis.
  - reference: PMID:7531539
    reference_title: The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "frequently complicated by fungal infections"
    explanation: The historical linkage cohort supports fungal infection as a recurring complication of the diffuse nonepidermolytic PPK phenotype.
  downstream:
  - target: Diffuse palmoplantar hyperkeratosis
    causal_link_type: DIRECT
    description: >
      Abnormal palmoplantar keratinization directly produces diffuse thickening
      of the palms and soles.
  - target: Nonepidermolytic palmoplantar hyperkeratosis
    causal_link_type: DIRECT
    description: >
      The hyperkeratosis occurs without epidermolysis on histology.
  - target: Palmoplantar scaling skin
    causal_link_type: DIRECT
    description: >
      Disordered cornification contributes to palmoplantar scaling.
- name: Orthokeratotic hyperkeratosis without epidermolysis
  description: >
    Lesional skin biopsy shows orthokeratotic hyperkeratosis, acanthosis,
    hypergranulosis, and mild upper-dermal lymphocytic infiltrates without
    epidermolysis, matching the nonepidermolytic clinical designation.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: cornification
    term:
      id: GO:0070268
      label: cornification
    modifier: ABNORMAL
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Histological examination of lesions reveals orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild lymphocyte infiltrations in the upper dermis with no evidence of epidermolysis."
    explanation: Orphanet's histology statement supports a nonepidermolytic microscopic pattern.
  downstream:
  - target: Nonepidermolytic palmoplantar hyperkeratosis
    causal_link_type: DIRECT
    description: >
      Nonepidermolytic histology distinguishes the hyperkeratosis from
      epidermolytic keratinopathies.
histopathology:
- name: Orthokeratotic hyperkeratosis without epidermolysis
  description: >
    Microscopic lesions show orthokeratotic hyperkeratosis with acanthosis,
    hypergranulosis, mild superficial dermal lymphocytic infiltrates, and no
    evidence of epidermolysis.
  diagnostic: true
  finding_term:
    preferred_term: orthokeratotic hyperkeratosis
    term:
      id: NCIT:C35541
      label: Hyperkeratosis
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild lymphocyte infiltrations in the upper dermis with no evidence of epidermolysis."
    explanation: Orphanet lists the characteristic histopathologic findings.
phenotypes:
- name: Nonepidermolytic palmoplantar hyperkeratosis
  frequency: OBLIGATE
  diagnostic: true
  description: Diffuse palmoplantar hyperkeratosis lacks histologic epidermolysis.
  phenotype_term:
    preferred_term: Nonepidermolytic palmoplantar hyperkeratosis
    term:
      id: HP:0007404
      label: Nonepidermolytic palmoplantar hyperkeratosis
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007404 | Nonepidermolytic palmoplantar keratoderma | Obligate (100%)"
    explanation: Orphanet lists nonepidermolytic palmoplantar keratoderma as obligate.
- name: Diffuse palmoplantar hyperkeratosis
  frequency: VERY_FREQUENT
  diagnostic: true
  description: Diffuse mild to thick, finely demarcated hyperkeratosis affects the palms and soles.
  phenotype_term:
    preferred_term: Diffuse palmoplantar hyperkeratosis
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007447 | Diffuse palmoplantar kyperkeratosis | Very frequent (99-80%)"
    explanation: Orphanet lists diffuse palmoplantar hyperkeratosis as very frequent.
  - reference: PMID:30452289
    reference_title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological findings, clinical features, and medical history were in accordance with the diagnosis of diffuse NEPPK."
    explanation: The clinical pedigree report supports the diffuse NEPPK diagnosis in affected individuals.
- name: Dry skin
  frequency: FREQUENT
  description: Diffuse dry skin is a frequent associated cutaneous feature.
  phenotype_term:
    preferred_term: Dry skin
    term:
      id: HP:0000958
      label: Dry skin
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000958 | Dry skin | Frequent (79-30%)"
    explanation: Orphanet lists dry skin as frequent.
- name: Atopic dermatitis
  frequency: OCCASIONAL
  description: Atopic dermatitis is an occasional associated feature.
  phenotype_term:
    preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001047 | Atopic dermatitis | Occasional (29-5%)"
    explanation: Orphanet lists atopic dermatitis as occasional.
- name: Abnormal umbilicus morphology
  frequency: FREQUENT
  description: Umbilical hyperkeratosis or abnormal umbilical morphology is frequent.
  phenotype_term:
    preferred_term: Abnormal umbilicus morphology
    term:
      id: HP:0001551
      label: Abnormal umbilicus morphology
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001551 | Abnormal umbilicus morphology | Frequent (79-30%)"
    explanation: Orphanet lists abnormal umbilicus morphology as frequent.
- name: Concave nail
  frequency: OCCASIONAL
  description: Concave nails are occasional.
  phenotype_term:
    preferred_term: Concave nail
    term:
      id: HP:0001598
      label: Concave nail
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001598 | Concave nail | Occasional (29-5%)"
    explanation: Orphanet lists concave nail as occasional.
- name: Thickened Achilles tendon
  frequency: OCCASIONAL
  description: Thickening of the Achilles tendon is occasional.
  phenotype_term:
    preferred_term: Thickened Achilles tendon
    term:
      id: HP:0004690
      label: Thickened Achilles tendon
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004690 | Thickened Achilles tendon | Occasional (29-5%)"
    explanation: Orphanet lists thickened Achilles tendon as occasional.
- name: Decreased movement range in interphalangeal joints
  frequency: OCCASIONAL
  description: Restricted interphalangeal joint motion is occasional.
  phenotype_term:
    preferred_term: Decreased movement range in interphalangeal joints
    term:
      id: HP:0006203
      label: Decreased movement range in interphalangeal joints
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006203 | Decreased movement range in interphalangeal joints | Occasional (29-5%)"
    explanation: Orphanet lists decreased movement range in interphalangeal joints as occasional.
- name: Palmoplantar blistering
  frequency: OCCASIONAL
  description: Blistering of palms and soles can occur occasionally.
  phenotype_term:
    preferred_term: Palmoplantar blistering
    term:
      id: HP:0007446
      label: Palmoplantar blistering
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007446 | Palmoplantar blistering | Occasional (29-5%)"
    explanation: Orphanet lists palmoplantar blistering as occasional.
- name: Erythema
  frequency: FREQUENT
  description: Erythema is frequent.
  phenotype_term:
    preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010783 | Erythema | Frequent (79-30%)"
    explanation: Orphanet lists erythema as frequent.
- name: Onychomycosis
  frequency: FREQUENT
  description: Fungal nail infection is a frequent complication.
  phenotype_term:
    preferred_term: Onychomycosis
    term:
      id: HP:0012203
      label: Onychomycosis
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012203 | Onychomycosis | Frequent (79-30%)"
    explanation: Orphanet lists onychomycosis as frequent.
  - reference: PMID:7531539
    reference_title: The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "frequently complicated by fungal infections"
    explanation: The northern Sweden cohort describes fungal infections as frequent complications of diffuse non-epidermolytic PPK.
- name: Palmoplantar scaling skin
  frequency: OCCASIONAL
  description: Scaling of palmar and plantar skin can occur occasionally.
  phenotype_term:
    preferred_term: Palmoplantar scaling skin
    term:
      id: HP:0025524
      label: Palmoplantar scaling skin
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025524 | Palmoplantar scaling skin | Occasional (29-5%)"
    explanation: Orphanet lists palmoplantar scaling skin as occasional.
- name: Tendon thickening
  frequency: OCCASIONAL
  description: Tendon thickening is occasional.
  phenotype_term:
    preferred_term: Tendon thickening
    term:
      id: HP:0032523
      label: Tendon thickening
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0032523 | Tendon thickening | Occasional (29-5%)"
    explanation: Orphanet lists tendon thickening as occasional.
- name: Knuckle pad
  frequency: OCCASIONAL
  description: Knuckle pad-like keratoses on the fingers are occasional.
  phenotype_term:
    preferred_term: Knuckle pad
    term:
      id: HP:0032541
      label: Knuckle pad
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0032541 | Knuckle pad | Occasional (29-5%)"
    explanation: Orphanet lists knuckle pad as occasional.
- name: Scaling skin
  frequency: OCCASIONAL
  description: Scaling outside the palmoplantar distribution can occur occasionally.
  phenotype_term:
    preferred_term: Scaling skin
    term:
      id: HP:0040189
      label: Scaling skin
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040189 | Scaling skin | Occasional (29-5%)"
    explanation: Orphanet lists scaling skin as occasional.
diagnosis:
- name: Clinical dermatologic and histologic diagnosis
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >
    Diagnosis is supported by the characteristic diffuse palmoplantar
    hyperkeratosis phenotype and lesional histology showing nonepidermolytic
    orthokeratotic hyperkeratosis.
  results: Diffuse palmoplantar hyperkeratosis without epidermolysis supports the diagnosis.
  evidence:
  - reference: ORPHA:530838
    reference_title: KRT1-related diffuse nonepidermolytic keratoderma (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Histological examination of lesions reveals orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild lymphocyte infiltrations in the upper dermis with no evidence of epidermolysis."
    explanation: Orphanet describes the diagnostic histologic pattern.
- name: KRT1 molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >
    Sequencing of KRT1 and other palmoplantar keratoderma genes can identify a
    causative germline KRT1 variant in a compatible clinical pedigree.
  results: A pathogenic germline KRT1 variant supports molecular diagnosis.
  evidence:
  - reference: PMID:30452289
    reference_title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation detection via polymerase chain reaction and Sanger sequencing of relevant potential causative genes"
    explanation: The pedigree study used molecular sequencing to identify the causative variant.
treatments:
- name: Topical emollient and keratolytic symptom therapy
  description: >
    Topical emollients, keratolytics, topical retinoids, and topical steroids
    are used symptomatically to soften hyperkeratosis, reduce scale, and relieve
    pain or functional impairment. These treatments are not curative.
  treatment_term:
    preferred_term: application of emollient to skin
    term:
      id: MAXO:0000996
      label: application of emollient to skin
  target_mechanisms:
  - target: Nonepidermolytic palmoplantar keratinization disturbance
    treatment_effect: MODULATES
    description: Topical therapy acts downstream by reducing the symptomatic cornified burden.
  target_phenotypes:
  - preferred_term: Diffuse palmoplantar hyperkeratosis
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
  - preferred_term: Palmoplantar scaling skin
    term:
      id: HP:0025524
      label: Palmoplantar scaling skin
  evidence:
  - reference: PMID:32307694
    reference_title: "Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms."
    explanation: The hereditary PPK treatment review supports topical symptom-directed therapy.
- name: Oral retinoid therapy
  description: >
    Oral retinoids are a systemic option for severe hereditary palmoplantar
    keratoderma, but benefit varies by PPK subtype and tolerability can limit
    use.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: retinoid
      term:
        id: CHEBI:26537
        label: retinoid
  target_mechanisms:
  - target: Nonepidermolytic palmoplantar keratinization disturbance
    treatment_effect: MODULATES
    description: Retinoids modulate keratinocyte differentiation and cornification.
  target_phenotypes:
  - preferred_term: Diffuse palmoplantar hyperkeratosis
    term:
      id: HP:0007447
      label: Diffuse palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:32307694
    reference_title: "Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance."
    explanation: The hereditary PPK treatment review supports oral retinoids as a systemic treatment option with variable efficacy and tolerance.
references:
- reference: ORPHA:530838
  title: KRT1-related diffuse nonepidermolytic keratoderma
  found_in:
  - Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma-deep-research-fallback.md
- reference: ORPHA:496
  title: Thost-Unna palmoplantar keratoderma
  found_in:
  - Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma-deep-research-fallback.md
- reference: PMID:30452289
  title: Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
  found_in:
  - Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma-deep-research-fallback.md
- reference: PMID:7531539
  title: The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.
  found_in:
  - Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma-deep-research-fallback.md
- reference: PMID:32307694
  title: "Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature."
  found_in:
  - Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma-deep-research-fallback.md
clinical_trials: []
datasets: []
notes: >-
  ORPHA:530838 is the primary structured record for KRT1-related diffuse
  nonepidermolytic keratoderma. ORPHA:496 is sparse and is used only to retain
  the historical Thost-Unna palmoplantar keratoderma naming context. This entry
  is separate from the broader KRT1 keratinopathy entry, which focuses on
  epidermolytic ichthyosis and epidermolytic PPK spectrum disease.
📚

References & Deep Research

References

5
ORPHA:530838
KRT1-related diffuse nonepidermolytic keratoderma
No top-level findings curated for this source.
ORPHA:496
Thost-Unna palmoplantar keratoderma
No top-level findings curated for this source.
PMID:30452289
Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.
No top-level findings curated for this source.
PMID:7531539
The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.
No top-level findings curated for this source.
PMID:32307694
Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature.
No top-level findings curated for this source.

Deep Research

1
Diffuse Nonepidermolytic Palmoplantar Keratoderma Research Fallback ▸

Diffuse Nonepidermolytic Palmoplantar Keratoderma Research Fallback

Deep-research provider attempts were bounded and did not produce usable output:

  • just research-disorder falcon Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma was stopped after extended silence; the wrapper returned exit code 124 after the provider process was terminated.
  • just research-disorder openai Diffuse_Nonepidermolytic_Palmoplantar_Keratoderma was stopped after extended silence; the wrapper returned exit code 124 after the provider process was terminated.

Local curation proceeded from generated Orphanet and PubMed caches:

  • ORPHA:530838: primary structured record for KRT1-related diffuse nonepidermolytic keratoderma, including definition, autosomal dominant inheritance, KRT1 gene association, epidemiology, exact MONDO/OMIM mappings, and 15 HPO phenotype rows.
  • ORPHA:496: sparse historical Thost-Unna palmoplantar keratoderma record, used only as a naming-history signal.
  • PMID:30452289: KRT1 splice-site mutation in a large Han Chinese diffuse NEPPK pedigree.
  • PMID:7531539: autosomal dominant diffuse non-epidermolytic palmoplantar keratoderma in northern Sweden, regional prevalence, fungal infections, and chromosome 12q11-q13 linkage.
  • PMID:32307694: hereditary palmoplantar keratoderma treatment review supporting topical symptom therapy and oral retinoids.

Scope note: no provider-generated synthesis was used. The YAML claims are limited to snippets available in the cached Orphanet/PubMed references listed above.