👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Autosomal dominant inheritance

Show evidence (2 references)

PMID:15663649 SUPPORT Human Clinical

"Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations."

Confirms autosomal dominant inheritance with complete penetrance and a high rate of de novo mutations.

PMID:21271994 SUPPORT Human Clinical

"In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation."

Heterozygous mutations confirm dominant mechanism.

◆

Subtypes

4

Epidermolytic Ichthyosis (Generalized)

Classic generalized form characterized by congenital erythroderma, blistering and erosions at birth, evolving into widespread ichthyosiform hyperkeratosis with palmoplantar keratoderma. Caused by heterozygous missense mutations at highly conserved helix boundary motifs of KRT1.

Show evidence (2 references)

PMID:31335043 SUPPORT Human Clinical

"Epidermolytic hyperkeratosis is a rare autosomal dominant pathology of cornification caused by mutations in keratins 1 and 10."

StatPearls overview confirms the autosomal dominant nature and keratin gene basis of epidermolytic ichthyosis.

PMID:21271994 SUPPORT Human Clinical

"Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes."

Confirms EI as a hereditary keratinization disorder caused by KRT1 or KRT10 mutations.

Ichthyosis Hystrix of Curth-Macklin (MONDO:0007808)

Rare variant characterized by generalized spiky or verrucous hyperkeratosis and severe palmoplantar keratoderma. Distinguished from classic EI by the presence of binucleated cells and absence of typical tonofilament clumping. Caused by frameshift mutations affecting the V2 tail domain of keratin 1.

Show evidence (1 reference)

PMID:29689068 SUPPORT Human Clinical

"Ichthyosis Hystrix of Curth-Macklin (IH-CM) is a rare manifestation of epidermolytic ichthyosis (EI) that is characterised by generalised spiky or verrucous hyperkeratosis."

Confirms IH-CM as a rare EI variant with distinctive verrucous hyperkeratosis.

Annular Epidermolytic Ichthyosis / Cyclic Ichthyosis (MONDO:0011870)

Distinct phenotype with neonatal erythema and erosions that improve, followed by palmoplantar hyperkeratosis and dramatic episodic flares of annular, polycyclic erythematous plaques with scale. Flares last weeks to months with intervening periods of near-normal skin. Caused by mutations in the 2B domain of keratin K1.

Show evidence (1 reference)

PMID:10053007 SUPPORT Human Clinical

"Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface."

Describes the cyclic flaring pattern that distinguishes this subtype from classic EI.

Epidermolytic Palmoplantar Keratoderma (Vorner Type)

Epidermolytic palmoplantar keratoderma limited to the palms and soles, without generalized ichthyosis. Autosomal dominant, caused by KRT1 mutations (or KRT9 mutations). Historically classified as Vorner type (epidermolytic) vs. Unna-Thost type (nonepidermolytic), though re-examination suggests overlap.

Show evidence (1 reference)

PMID:30288772 SUPPORT Human Clinical

"Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1."

Confirms epidermolytic PPK as an autosomal dominant disorder caused by KRT1 mutations.

⚙

Pathophysiology

3

KRT1 Dominant-Negative Mutations

Heterozygous missense mutations in KRT1 produce dominant-negative keratin 1 protein that disrupts normal keratin intermediate filament assembly in suprabasal keratinocytes. Mutant keratin 1 is incorporated into heterodimers with keratin 10 but prevents proper filament elongation.

suprabasal keratinocyte link

keratin intermediate filament assembly link ⚠ ABNORMAL keratinization link ⚠ ABNORMAL

skin epidermis link

Downstream

Tonofilament Clumping and Cytolysis

Show evidence (2 references)

PMID:21271994 SUPPORT Human Clinical

"In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation."

Confirms that heterozygous mutations at filament-critical helix boundary motifs disrupt keratin assembly.

PMID:30288772 SUPPORT Human Clinical

"Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern."

Demonstrates that KRT1 mutations throughout the protein lead to a spectrum of phenotypes.

Tonofilament Clumping and Cytolysis

Defective keratin filament assembly leads to aggregation of tonofilaments (keratin bundles) in suprabasal keratinocytes, visible as perinuclear clumping on electron microscopy. The resulting cytoskeletal fragility causes cytolysis of the upper stratum spinosum and granular layer (epidermolytic hyperkeratosis), manifesting as skin fragility and blistering.

suprabasal keratinocyte link

intermediate filament cytoskeleton organization link ⚠ ABNORMAL

Downstream

Compensatory Epidermal Hyperproliferation

Show evidence (2 references)

PMID:10053007 SUPPORT Human Clinical

"Abnormal keratin-filament aggregates were observed in suprabasal keratinocytes from both probands, suggesting that the causative mutation might reside in keratin K1 or keratin K10."

Directly demonstrates keratin filament aggregation in suprabasal keratinocytes from affected individuals.

PMID:31335043 SUPPORT Human Clinical

"The condition was originally termed "bullous congenital ichthyosiform erythroderma" owing to the hallmark features of erythroderma, blistering, and skin denudation present at birth, with subsequent development of marked hyperkeratosis."

Confirms the hallmark blistering and hyperkeratosis phenotype resulting from keratinocyte cytolysis.

Compensatory Epidermal Hyperproliferation

Chronic cytolysis and barrier disruption trigger compensatory epidermal hyperproliferation, resulting in marked thickening of the stratum corneum (hyperkeratosis). This manifests clinically as the characteristic ichthyosiform scaling and palmoplantar keratoderma. In KRT1 V2 tail domain mutations (Curth-Macklin type), the mechanism involves aberrant dimer formation rather than classic tonofilament clumping.

keratinocyte proliferation link ↑ INCREASED

Show evidence (1 reference)

PMID:29689068 SUPPORT Human Clinical

"Our results highlight the importance and complexity of the KRT1/10 V2 domain in keratin dimer formation and the potential consequences of its alteration."

Demonstrates that V2 domain mutations alter keratin dimer formation, contributing to compensatory hyperkeratosis in the Curth-Macklin variant.

⬡

Pathograph

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

●

Phenotypes

7

Immune 1

Cyclic Erythematous Plaques Erythroderma (HP:0001019)

Show evidence (1 reference)

PMID:10053007 SUPPORT Human Clinical

"Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface. The flares last weeks to months."

Describes the hallmark cyclic flaring pattern of annular EI.

Integument 6

Congenital Ichthyosiform Erythroderma Congenital ichthyosiform erythroderma (HP:0007431)

Show evidence (1 reference)

PMID:15663649 SUPPORT Human Clinical

"This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth."

Confirms congenital erythroderma as a cardinal feature.

Skin Blistering Abnormal blistering of the skin (HP:0008066)

Show evidence (1 reference)

PMID:31335043 SUPPORT Human Clinical

"The condition was originally termed "bullous congenital ichthyosiform erythroderma" owing to the hallmark features of erythroderma, blistering, and skin denudation present at birth, with subsequent development of marked hyperkeratosis."

Confirms blistering as a hallmark neonatal feature.

Generalized Hyperkeratosis Hyperkeratosis (HP:0000962)

Show evidence (1 reference)

PMID:15663649 SUPPORT Human Clinical

"It may resolve and be replaced with thick scaling."

Describes the transition from blistering to hyperkeratosis.

Ichthyosis Ichthyosis (HP:0008064)

Show evidence (1 reference)

PMID:21271994 SUPPORT Human Clinical

"Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes."

Confirms ichthyosis as the defining clinical feature.

Palmoplantar Keratoderma Palmoplantar keratoderma (HP:0000982)

Show evidence (2 references)

PMID:21271994 SUPPORT Human Clinical

"The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants."

Confirms that PPK is characteristic of KRT1 mutations specifically.

PMID:30288772 SUPPORT Human Clinical

"Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former."

Directly links PPK to KRT1 mutations.

Skin Erosion Skin erosion (HP:0200041)

Show evidence (1 reference)

PMID:10053007 SUPPORT Human Clinical

"Manifesting erythema and superficial erosions at birth, which improved during the first few months of life"

Confirms superficial erosions as a neonatal feature.

🧬

Genetic Associations

1

KRT1 Dominant-Negative Mutations (Causative)

Autosomal Dominant

Show evidence (3 references)

PMID:15663649 SUPPORT Human Clinical

"Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations. The clinical phenotype is a result of alterations in the gene(s) for keratin 1 and/or 10."

Confirms AD inheritance, complete penetrance, and 50% de novo rate for KRT1/10 mutations.

PMID:30288772 SUPPORT Human Clinical

"Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern."

Confirms genotype-phenotype complexity with mutations scattered across the KRT1 gene.

PMID:29689068 SUPPORT Human Clinical

"While IH-CM is associated with mutations in the keratin 1 (KRT1) gene, reports to date have indicated that mutations in the KRT1 gene result in an aberrant and truncated protein tail, essentially affecting the function of the V2 domain."

Confirms V2 tail domain mutations as the basis for Curth-Macklin type.

💊

Treatments

2

Emollients and Keratolytics

Action: topical treatment Ontology label: Pharmacotherapy NCIT:C15986

Mainstay of symptomatic management. Regular application of emollients to hydrate skin and keratolytic agents to reduce scale thickness.

Show evidence (1 reference)

PMID:15663649 SUPPORT Human Clinical

"We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids."

Confirms emollients as primary symptomatic therapy.

Systemic Retinoids

Action: retinoid therapy Ontology label: Pharmacotherapy NCIT:C15986

Oral retinoids (e.g., acitretin) may reduce hyperkeratosis but must be used cautiously as they can exacerbate skin fragility and blistering.

Show evidence (1 reference)

PMID:15663649 SUPPORT Human Clinical

"We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids."

Confirms retinoids as part of the therapeutic approach.

{ }

Source YAML

click to show

name: KRT1 Keratinopathies
creation_date: "2026-04-04T00:00:00Z"
updated_date: "2026-04-04T12:00:00Z"
category: Mendelian
description: >-
  KRT1 keratinopathies are a spectrum of autosomal dominant skin disorders caused
  by heterozygous dominant-negative mutations in the KRT1 gene encoding keratin 1,
  the major type II intermediate filament protein of suprabasal keratinocytes.
  Mutations disrupt keratin filament assembly, leading to tonofilament clumping,
  cytolysis of suprabasal keratinocytes, and epidermolytic hyperkeratosis.
  The phenotypic spectrum ranges from generalized epidermolytic ichthyosis with
  neonatal blistering and erythroderma, through annular/cyclic ichthyosis, to
  isolated epidermolytic palmoplantar keratoderma, and includes the rare
  ichthyosis hystrix of Curth-Macklin. KRT1 mutations are distinguished from
  KRT10 mutations by their frequent association with palmoplantar keratoderma.
disease_term:
  preferred_term: epidermolytic ichthyosis
  term:
    id: MONDO:0007239
    label: epidermolytic ichthyosis
parents:
- keratinopathic ichthyosis
- ichthyosis
synonyms:
- bullous congenital ichthyosiform erythroderma
- epidermolytic hyperkeratosis
- bullous ichthyosiform erythroderma
has_subtypes:
- name: Epidermolytic Ichthyosis
  display_name: Epidermolytic Ichthyosis (Generalized)
  description: >-
    Classic generalized form characterized by congenital erythroderma, blistering
    and erosions at birth, evolving into widespread ichthyosiform hyperkeratosis
    with palmoplantar keratoderma. Caused by heterozygous missense mutations at
    highly conserved helix boundary motifs of KRT1.
  evidence:
  - reference: PMID:31335043
    reference_title: "Epidermolytic Hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic hyperkeratosis is a rare autosomal dominant pathology of cornification caused by mutations in keratins 1 and 10."
    explanation: StatPearls overview confirms the autosomal dominant nature and keratin gene basis of epidermolytic ichthyosis.
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes."
    explanation: Confirms EI as a hereditary keratinization disorder caused by KRT1 or KRT10 mutations.
- name: Ichthyosis Hystrix Curth-Macklin
  display_name: Ichthyosis Hystrix of Curth-Macklin (MONDO:0007808)
  description: >-
    Rare variant characterized by generalized spiky or verrucous hyperkeratosis
    and severe palmoplantar keratoderma. Distinguished from classic EI by the
    presence of binucleated cells and absence of typical tonofilament clumping.
    Caused by frameshift mutations affecting the V2 tail domain of keratin 1.
  evidence:
  - reference: PMID:29689068
    reference_title: "Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ichthyosis Hystrix of Curth-Macklin (IH-CM) is a rare manifestation of epidermolytic ichthyosis (EI) that is characterised by generalised spiky or verrucous hyperkeratosis."
    explanation: Confirms IH-CM as a rare EI variant with distinctive verrucous hyperkeratosis.
- name: Annular Epidermolytic Ichthyosis
  display_name: Annular Epidermolytic Ichthyosis / Cyclic Ichthyosis (MONDO:0011870)
  description: >-
    Distinct phenotype with neonatal erythema and erosions that improve, followed
    by palmoplantar hyperkeratosis and dramatic episodic flares of annular,
    polycyclic erythematous plaques with scale. Flares last weeks to months with
    intervening periods of near-normal skin. Caused by mutations in the 2B domain
    of keratin K1.
  evidence:
  - reference: PMID:10053007
    reference_title: "Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface."
    explanation: Describes the cyclic flaring pattern that distinguishes this subtype from classic EI.
- name: Epidermolytic PPK
  display_name: Epidermolytic Palmoplantar Keratoderma (Vorner Type)
  description: >-
    Epidermolytic palmoplantar keratoderma limited to the palms and soles,
    without generalized ichthyosis. Autosomal dominant, caused by KRT1 mutations
    (or KRT9 mutations). Historically classified as Vorner type (epidermolytic)
    vs. Unna-Thost type (nonepidermolytic), though re-examination suggests
    overlap.
  evidence:
  - reference: PMID:30288772
    reference_title: "Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1."
    explanation: Confirms epidermolytic PPK as an autosomal dominant disorder caused by KRT1 mutations.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations."
    explanation: Confirms autosomal dominant inheritance with complete penetrance and a high rate of de novo mutations.
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation."
    explanation: Heterozygous mutations confirm dominant mechanism.
prevalence:
- population: Global
  notes: >-
    Epidermolytic ichthyosis is a rare keratinopathic ichthyosis, estimated at
    approximately 1 in 200,000 to 1 in 300,000. The subtypes ichthyosis hystrix
    Curth-Macklin and annular epidermolytic ichthyosis are even rarer, with fewer
    than 50 reported families each.
  evidence:
  - reference: PMID:31335043
    reference_title: "Epidermolytic Hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic hyperkeratosis is a rare autosomal dominant pathology of cornification caused by mutations in keratins 1 and 10."
    explanation: Confirms the rarity of the condition.
progression:
- phase: Onset
  age_range: Congenital (birth)
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth."
    explanation: Confirms congenital onset with blistering and erythema.
- phase: Chronic
  age_range: Infancy to adulthood
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It may resolve and be replaced with thick scaling."
    explanation: Describes the transition from neonatal blistering to chronic hyperkeratosis.
pathophysiology:
- name: KRT1 Dominant-Negative Mutations
  description: >-
    Heterozygous missense mutations in KRT1 produce dominant-negative keratin 1
    protein that disrupts normal keratin intermediate filament assembly in
    suprabasal keratinocytes. Mutant keratin 1 is incorporated into heterodimers
    with keratin 10 but prevents proper filament elongation.
  cell_types:
  - preferred_term: suprabasal keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratin intermediate filament assembly
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
    modifier: ABNORMAL
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation."
    explanation: Confirms that heterozygous mutations at filament-critical helix boundary motifs disrupt keratin assembly.
  - reference: PMID:30288772
    reference_title: "Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern."
    explanation: Demonstrates that KRT1 mutations throughout the protein lead to a spectrum of phenotypes.
  downstream:
  - target: Tonofilament Clumping and Cytolysis
- name: Tonofilament Clumping and Cytolysis
  description: >-
    Defective keratin filament assembly leads to aggregation of tonofilaments
    (keratin bundles) in suprabasal keratinocytes, visible as perinuclear
    clumping on electron microscopy. The resulting cytoskeletal fragility causes
    cytolysis of the upper stratum spinosum and granular layer (epidermolytic
    hyperkeratosis), manifesting as skin fragility and blistering.
  cell_types:
  - preferred_term: suprabasal keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: intermediate filament cytoskeleton organization
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:10053007
    reference_title: "Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal keratin-filament aggregates were observed in suprabasal keratinocytes from both probands, suggesting that the causative mutation might reside in keratin K1 or keratin K10."
    explanation: Directly demonstrates keratin filament aggregation in suprabasal keratinocytes from affected individuals.
  - reference: PMID:31335043
    reference_title: "Epidermolytic Hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The condition was originally termed \"bullous congenital ichthyosiform erythroderma\" owing to the hallmark features of erythroderma, blistering, and skin denudation present at birth, with subsequent development of marked hyperkeratosis."
    explanation: Confirms the hallmark blistering and hyperkeratosis phenotype resulting from keratinocyte cytolysis.
  downstream:
  - target: Compensatory Epidermal Hyperproliferation
- name: Compensatory Epidermal Hyperproliferation
  description: >-
    Chronic cytolysis and barrier disruption trigger compensatory epidermal
    hyperproliferation, resulting in marked thickening of the stratum corneum
    (hyperkeratosis). This manifests clinically as the characteristic ichthyosiform
    scaling and palmoplantar keratoderma. In KRT1 V2 tail domain mutations
    (Curth-Macklin type), the mechanism involves aberrant dimer formation rather
    than classic tonofilament clumping.
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:29689068
    reference_title: "Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results highlight the importance and complexity of the KRT1/10 V2 domain in keratin dimer formation and the potential consequences of its alteration."
    explanation: Demonstrates that V2 domain mutations alter keratin dimer formation, contributing to compensatory hyperkeratosis in the Curth-Macklin variant.
phenotypes:
- category: Dermatologic
  name: Congenital Ichthyosiform Erythroderma
  description: >-
    Generalized erythroderma present at birth, a hallmark of the neonatal
    presentation of epidermolytic ichthyosis.
  phenotype_term:
    preferred_term: Congenital ichthyosiform erythroderma
    term:
      id: HP:0007431
      label: Congenital ichthyosiform erythroderma
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This inherited keratinization disorder is characterized clinically by erythema, blistering, and peeling shortly after birth."
    explanation: Confirms congenital erythroderma as a cardinal feature.
- category: Dermatologic
  name: Skin Blistering
  description: >-
    Neonatal blistering and superficial erosions resulting from cytolysis of
    suprabasal keratinocytes. Tends to improve with age.
  phenotype_term:
    preferred_term: Abnormal blistering of the skin
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:31335043
    reference_title: "Epidermolytic Hyperkeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The condition was originally termed \"bullous congenital ichthyosiform erythroderma\" owing to the hallmark features of erythroderma, blistering, and skin denudation present at birth, with subsequent development of marked hyperkeratosis."
    explanation: Confirms blistering as a hallmark neonatal feature.
- category: Dermatologic
  name: Generalized Hyperkeratosis
  description: >-
    Progressive thickening of the stratum corneum manifesting as widespread
    ichthyosiform scaling. Replaces blistering phenotype in infancy and
    persists into adulthood.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It may resolve and be replaced with thick scaling."
    explanation: Describes the transition from blistering to hyperkeratosis.
- category: Dermatologic
  name: Ichthyosis
  description: >-
    Excessive dry surface scales resulting from abnormal keratinization,
    characteristic of all KRT1 keratinopathy subtypes.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes."
    explanation: Confirms ichthyosis as the defining clinical feature.
- category: Dermatologic
  name: Palmoplantar Keratoderma
  description: >-
    Abnormal thickening of the palms and soles, characteristic of KRT1
    mutations and a key distinguishing feature from KRT10-associated disease.
    May be the sole manifestation in the epidermolytic PPK (Vorner) subtype.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:21271994
    reference_title: "Expanding the keratin mutation database: novel and recurrent mutations and genotype-phenotype correlations in 28 patients with epidermolytic ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants."
    explanation: Confirms that PPK is characteristic of KRT1 mutations specifically.
  - reference: PMID:30288772
    reference_title: "Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former."
    explanation: Directly links PPK to KRT1 mutations.
- category: Dermatologic
  name: Cyclic Erythematous Plaques
  subtype: Annular Epidermolytic Ichthyosis
  description: >-
    Dramatic episodic flares of annular, polycyclic erythematous plaques with
    scale lasting weeks to months, with intervening periods of near-normal skin.
    Specific to the annular/cyclic subtype with 2B domain KRT1 mutations.
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:10053007
    reference_title: "Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface. The flares last weeks to months."
    explanation: Describes the hallmark cyclic flaring pattern of annular EI.
- category: Dermatologic
  name: Skin Erosion
  description: >-
    Superficial erosions of the skin, particularly in the neonatal period,
    resulting from epidermal fragility due to keratinocyte cytolysis.
  phenotype_term:
    preferred_term: Skin erosion
    term:
      id: HP:0200041
      label: Skin erosion
  evidence:
  - reference: PMID:10053007
    reference_title: "Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Manifesting erythema and superficial erosions at birth, which improved during the first few months of life"
    explanation: Confirms superficial erosions as a neonatal feature.
genetic:
- name: KRT1 Dominant-Negative Mutations
  gene_term:
    preferred_term: KRT1
    term:
      id: hgnc:6412
      label: KRT1
  association: Causative
  notes: >-
    Heterozygous dominant-negative mutations in KRT1 cause the full spectrum
    of KRT1 keratinopathies. Mutations at helix boundary motifs (1A, 2B domains)
    cause severe generalized EI; scattered mutations elsewhere produce variable
    phenotypes including isolated PPK. Frameshift mutations in the V2 tail
    domain cause ichthyosis hystrix Curth-Macklin. Approximately 50% of cases
    are de novo. Complete penetrance.
  inheritance:
  - name: Autosomal Dominant
  features: >-
    Dominant-negative mechanism: mutant keratin 1 is incorporated into
    heterodimers with keratin 10, disrupting filament assembly. Genotype-phenotype
    correlations show helix boundary mutations associated with severe EI,
    2B domain mutations with cyclic ichthyosis, and V2 tail mutations with
    Curth-Macklin type.
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetically, this is an autosomal dominant disease with complete penetrance; however, 50% are spontaneous mutations. The clinical phenotype is a result of alterations in the gene(s) for keratin 1 and/or 10."
    explanation: Confirms AD inheritance, complete penetrance, and 50% de novo rate for KRT1/10 mutations.
  - reference: PMID:30288772
    reference_title: "Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern."
    explanation: Confirms genotype-phenotype complexity with mutations scattered across the KRT1 gene.
  - reference: PMID:29689068
    reference_title: "Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While IH-CM is associated with mutations in the keratin 1 (KRT1) gene, reports to date have indicated that mutations in the KRT1 gene result in an aberrant and truncated protein tail, essentially affecting the function of the V2 domain."
    explanation: Confirms V2 tail domain mutations as the basis for Curth-Macklin type.
treatments:
- name: Emollients and Keratolytics
  description: >-
    Mainstay of symptomatic management. Regular application of emollients to
    hydrate skin and keratolytic agents to reduce scale thickness.
  treatment_term:
    preferred_term: topical treatment
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids."
    explanation: Confirms emollients as primary symptomatic therapy.
- name: Systemic Retinoids
  description: >-
    Oral retinoids (e.g., acitretin) may reduce hyperkeratosis but must be
    used cautiously as they can exacerbate skin fragility and blistering.
  treatment_term:
    preferred_term: retinoid therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:15663649
    reference_title: "Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We review this disorder and its therapy, which is mainly symptomatic with emollients and retinoids."
    explanation: Confirms retinoids as part of the therapeutic approach.
notes: >-
  KRT1 keratinopathies represent a phenotypic continuum unified by dominant-negative
  mutations in keratin 1. The presence or absence of palmoplantar involvement, the
  generalized vs. localized distribution, and the cyclic vs. persistent course are
  determined by mutation location within the KRT1 gene. This entry groups four
  G2P rows: epidermolytic ichthyosis (MONDO:0007239), ichthyosis hystrix of
  Curth-Macklin (MONDO:0007808), annular epidermolytic ichthyosis (MONDO:0011870),
  and epidermolytic palmoplantar keratoderma Vorner type. All share KRT1 as the
  causal gene with autosomal dominant inheritance and a dominant-negative mechanism.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 40 citations 2026-04-04T12:56:56.781697

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: KRT1 Keratinopathies
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on KRT1 Keratinopathies covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: KRT1 Keratinopathies (Mendelian)

Executive summary

KRT1 keratinopathies are dominantly inherited (often de novo; sometimes mosaic) disorders of epidermal differentiation and mechanical integrity caused by pathogenic variants in KRT1 (Keratin 1). The phenotype spectrum is classically anchored by epidermolytic ichthyosis / epidermolytic hyperkeratosis (EI/EHK; OMIM 113800) and epidermolytic palmoplantar keratoderma (EPPK), Vörner type (OMIM 144200), with frequent palmoplantar involvement in KRT1-associated disease. Recent work (2023–2025) highlights: (i) measurable early-life burden and genotype–severity correlations in cohort studies, (ii) emerging immunologic mechanisms (e.g., TLR2→NF-κB/GATA3) linking barrier failure to hyperkeratosis and keratin regulation, and (iii) early therapeutic exploration of biologics targeting the Th17 axis (IL‑17A blockade) and clinical trials of IL‑17A/IL‑12/23 blockade in inherited ichthyoses. (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, frommherz2025epidermolyticichthyosisclinical pages 4-5, cheng2025firstsuccessfultreatment pages 3-4, tagoe2023chronicactivationof pages 1-5, NCT03041038 chunk 1)

Target disease

Disease name (umbrella): KRT1 keratinopathies
Category: Mendelian
Causal gene: KRT1 (Keratin 1)

MONDO / Orphanet / ICD / MeSH identifiers

Within the retrieved full-text evidence set for this run, Orphanet, ICD-10/ICD-11, MeSH, and MONDO identifiers were not explicitly stated for KRT1 keratinopathies; therefore they cannot be reliably populated from the current evidence corpus. OMIM identifiers were extractable (below). (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, smith2019novelandrecurrent pages 1-3)

1. Disease information

1.1 What is the disease?

“KRT1 keratinopathies” refers to a spectrum of inherited skin cornification/cell-fragility disorders due to KRT1 variants affecting suprabasal keratinocytes. The most canonical KRT1-associated entities are: - Epidermolytic ichthyosis (EI), historically also termed epidermolytic hyperkeratosis (EHK) or bullous ichthyosiform erythroderma, characterized by congenital erythroderma with blistering/erosions followed by progressive hyperkeratosis. (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, smith2019novelandrecurrent pages 1-3) - Epidermolytic palmoplantar keratoderma (EPPK; Vörner type), often a diffuse palm/sole hyperkeratosis phenotype; most commonly due to KRT9 but can be due to KRT1. (smith2019novelandrecurrent pages 5-6, smith2019novelandrecurrent pages 1-3)

1.2 Key identifiers (from evidence)

Epidermolytic ichthyosis (EI): OMIM 113800 (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, smith2019novelandrecurrent pages 1-3)
Epidermolytic palmoplantar keratoderma (EPPK; Vörner type): OMIM 144200 (smith2019novelandrecurrent pages 5-6, smith2019novelandrecurrent pages 1-3)
KRT1 gene: OMIM 139350 (aljuwaied2024epidermolytichyperkeratosistype pages 9-10, gram2025clinicalandgenetic pages 2-3)

1.3 Common synonyms / alternative names

EI synonyms: epidermolytic hyperkeratosis (EHK); “formerly known as bullous ichthyosiform erythroderma” (aljuwaied2024epidermolytichyperkeratosistype pages 1-2)
EPPK synonyms: epidermolytic PPK, Vörner type (smith2019novelandrecurrent pages 5-6, smith2019novelandrecurrent pages 1-3)

1.4 Evidence source type

Most information is derived from: - Aggregated disease-level cohorts (e.g., German EI cohort; Danish PPK cohort) (frommherz2025epidermolyticichthyosisclinical pages 4-5, gram2025clinicalandgenetic pages 1-2) - Primary case reports expanding variant spectrum and demonstrating therapeutic hypotheses (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, cheng2025firstsuccessfultreatment pages 3-4) - Mechanistic experimental models (rat/human keratinocytes; organotypic cultures) (tagoe2023chronicactivationof pages 8-13)

Clinical entity	Key synonyms	Inheritance	Key OMIM identifiers	Typical onset/course	Hallmark features	Key supporting citations
KRT1-related epidermolytic ichthyosis	Epidermolytic hyperkeratosis (EHK); bullous ichthyosiform erythroderma; keratinopathic ichthyosis	Usually autosomal dominant; can occur de novo; mosaic cases also reported	EI OMIM 113800; KRT1 OMIM 139350	Usually present at birth with erythroderma, blistering, and erosions; blistering often decreases over weeks to months, followed by progressive generalized hyperkeratosis in childhood/adolescence; severity variable, with KRT1 often associated with more severe/intermediate disease and frequent palmoplantar involvement	Congenital erythroderma; superficial blisters/erosions; generalized ichthyotic hyperkeratosis; palmoplantar keratoderma; painful fissures; pruritus; contractures/joint limitation in severe cases; histology shows epidermolytic hyperkeratosis/granular degeneration	(aljuwaied2024epidermolytichyperkeratosistype pages 1-2, aljuwaied2024epidermolytichyperkeratosistype pages 9-10, frommherz2025epidermolyticichthyosisclinical pages 4-5, smith2019novelandrecurrent pages 5-6, smith2019novelandrecurrent pages 1-3)
KRT1-related epidermolytic palmoplantar keratoderma	EPPK; epidermolytic PPK; Vörner type palmoplantar keratoderma	Autosomal dominant	EPPK OMIM 144200; KRT1 OMIM 139350	Typically begins in infancy or early childhood; chronic lifelong course with persistent diffuse palmoplantar hyperkeratosis; phenotype may remain localized to palms/soles or coexist with broader epidermolytic ichthyosis depending on variant	Diffuse well-demarcated palmar and plantar hyperkeratosis; fissuring; painful cracks; erythematous/violaceous border in some families; limited or absent blistering in localized forms; variable intrafamilial severity	(gram2025clinicalandgenetic pages 1-2, gram2025clinicalandgenetic pages 2-3, smith2019novelandrecurrent pages 5-6, smith2019novelandrecurrent pages 1-3, smith2019novelandrecurrent pages 3-5)
Broader KRT1 keratinopathy spectrum	KRT1 keratinopathies; KRT1-associated keratinopathic ichthyosis/PPK spectrum	Predominantly autosomal dominant; de novo and postzygotic mosaicism documented	KRT1 gene OMIM 139350; associated disease OMIMs include 113800 and 144200	Spectrum ranges from severe neonatal EI with later diffuse hyperkeratosis to milder/pure palmoplantar disease; genotype-phenotype relationships are complex because pathogenic variants are distributed across the protein rather than confined to one hotspot	Suprabasal keratinocyte fragility from keratin filament dysfunction; PPK is more strongly associated with KRT1 than KRT10; recent cohorts identified novel KRT1 variants and documented substantial disease burden, including NICU need in neonatal EI and underweight in infancy in a subset	(frommherz2025epidermolyticichthyosisclinical pages 4-5, smith2019novelandrecurrent pages 5-6, smith2019novelandrecurrent pages 1-3, smith2019novelandrecurrent pages 6-7)

Table: This table summarizes the main KRT1-associated clinical entities, their synonyms, inheritance, OMIM identifiers, typical course, and hallmark manifestations. It is useful as a compact reference for mapping KRT1 variation to epidermolytic ichthyosis and epidermolytic palmoplantar keratoderma phenotypes.

2. Etiology

2.1 Disease causal factors

Primary cause: pathogenic germline or postzygotic (mosaic) variants in KRT1, generally acting through dominant-negative disruption of suprabasal keratin intermediate filament networks, leading to cellular fragility and barrier dysfunction. (aljuwaied2024epidermolytichyperkeratosistype pages 2-9, smith2019novelandrecurrent pages 6-7)

2.2 Risk factors

Genetic: KRT1 pathogenic variants (heterozygous) are sufficient; disease may be de novo or inherited. Mosaicism can contribute to segmental presentations or complex genotype-phenotype effects. (frommherz2025epidermolyticichthyosisclinical pages 4-5, diociaiuti2020firstcaseof pages 1-4)
Environmental/mechanical: While not quantified in the retrieved sources, clinical descriptions emphasize palmoplantar fissuring and pain, consistent with mechanical stress worsening volar manifestations in keratin disorders (supported indirectly by palmoplantar disease focus and cohort characterization). (cheng2025firstsuccessfultreatment pages 3-4, smith2019novelandrecurrent pages 5-6)

2.3 Protective factors

No validated protective genetic or environmental factors were identified in the retrieved full-text corpus.

2.4 Gene–environment interactions

Direct G×E interaction studies specific to KRT1 keratinopathies were not identified in the retrieved evidence. Mechanistic work supports a model where barrier defects and inflammatory signaling form a feedback loop influencing keratin expression (see Pathophysiology). (tagoe2023chronicactivationof pages 8-13)

3. Phenotypes

3.1 Core phenotype domains (with suggested HPO terms)

Below are common manifestations across KRT1 keratinopathies; frequencies are included when available.

Neonatal erythroderma / widespread erythema
HPO: HP:0001041 (Erythroderma) / HP:0000988 (Erythema)
Typical onset: at birth in EI (frommherz2025epidermolyticichthyosisclinical pages 4-5, smith2019novelandrecurrent pages 1-3)
Skin blistering / erosions (early life)
HPO: HP:0008064 (Blistering of the skin), HP:0001073 (Skin erosions)
Course: often prominent neonatally and may lessen over weeks–months, followed by hyperkeratosis (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, aljuwaied2024epidermolytichyperkeratosistype pages 2-9)
Generalized hyperkeratosis / scaling (ichthyosis phenotype)
HPO: HP:0000962 (Hyperkeratosis), HP:0008066 (Ichthyosis), HP:0000976 (Palmoplantar hyperkeratosis) when volar
Progression: hyperkeratosis emerges in childhood/adolescence after neonatal blistering/erythroderma (aljuwaied2024epidermolytichyperkeratosistype pages 1-2)
Palmoplantar keratoderma (PPK)
HPO: HP:0000972 (Palmoplantar keratoderma)
Frequency estimates: a 2024 case report cites ~60% palmoplantar involvement in EHK/EI (aljuwaied2024epidermolytichyperkeratosistype pages 1-2)
Phenotype: diffuse, well-demarcated palmar/plantar hyperkeratosis with fissures and pain (cheng2025firstsuccessfultreatment pages 3-4, smith2019novelandrecurrent pages 5-6)
Pruritus (itching)
HPO: HP:0000989 (Pruritus)
Noted as severe in pediatric EI treated with IL‑17A blockade (cheng2025firstsuccessfultreatment pages 1-3)
Fissuring and pain
HPO: HP:000裂 (no single universal HPO for “fissures”; commonly mapped to HP:0100881 (Skin fissures) in many ontologies)
Described in KRT1-EPPK and KRT1-EI with thick volar keratosis (cheng2025firstsuccessfultreatment pages 3-4, smith2019novelandrecurrent pages 5-6)
Joint limitation/contractures (severe cases)
HPO: HP:0001371 (Flexion contracture), HP:0001387 (Joint contracture)
Reported in severe EHK with thickening around joints (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, aljuwaied2024epidermolytichyperkeratosistype pages 9-10)

3.2 Phenotype severity and QoL impact (data)

In a German EI cohort, early-life morbidity was substantial: 25/41 required immediate incubator/NICU care; 17/44 (38.6%) were underweight or <5th percentile in infancy; 6/45 (13.3%) were preterm. (frommherz2025epidermolyticichthyosisclinical pages 4-5)
A biologic-treated pediatric EI case tracked DLQI and symptom scales (NRS, VAS) and reported improvement alongside clinical severity score reductions. (cheng2025firstsuccessfultreatment pages 1-3)

4. Genetic / molecular information

4.1 Causal gene

KRT1 (Keratin 1): OMIM 139350 (gram2025clinicalandgenetic pages 2-3)

4.2 Pathogenic variants (examples from primary literature)

The evidence corpus includes multiple KRT1 variant examples across domains: - KRT1 c.583A>T; p.Ile195Phe (reported as novel/likely pathogenic in a 2024 EHK case report) (aljuwaied2024epidermolytichyperkeratosistype pages 9-10, aljuwaied2024epidermolytichyperkeratosistype pages 2-9) - KRT1 c.1432G>A; p.Glu478Lys (p.E478K) (de novo; pediatric EI case treated with IL‑17A blockade) (cheng2025firstsuccessfultreatment pages 1-3) - Smith et al. 2019 variants spanning KRT1 including p.Leu187Pro, p.Leu187Phe, p.Ser233Leu, p.Leu485Phe, p.Leu485Pro, and splice-site/insertions (e.g., c.1254+1G>A → p.Gln418_Ile419ins18) across EI/EPPK presentations (smith2019novelandrecurrent pages 1-3, smith2019novelandrecurrent pages 3-5) - Diociaiuti et al. 2020 cohort lists KRT1 variants including c.1792dupA (p.Ser598Lysfs*56) and c.1319C>T (p.Ala440Val) and others in KRT1-associated EI cases with frequent PPK (diociaiuti2020firstcaseof pages 4-5, diociaiuti2020firstcaseof pages 7-9)

Variant class distribution: predominantly missense in conserved keratin rod domains, with some frameshift/tail-domain variants associated with milder phenotypes in cohort observations. (diociaiuti2020firstcaseof pages 7-9, aljuwaied2024epidermolytichyperkeratosistype pages 2-9)

4.3 Genotype–phenotype correlations

KRT1 mutations can produce EI and/or EPPK; Smith et al. emphasize that KRT1 mutations are distributed through the protein and “can result in a range of phenotypes,” yielding complex correlations. (smith2019novelandrecurrent pages 1-3)
In the German EI cohort, KRT1 germline variants were associated more frequently with intermediate/severe disease (15/19) and higher severity scores (median mIASI 19.10 for KRT1 vs 14.40 for KRT10). (frommherz2025epidermolyticichthyosisclinical pages 4-5)
Diociaiuti et al. report PPK in nine EI patients, corresponding mainly to KRT1-mutant cases, consistent with the classic association of KRT1 with prominent palmoplantar disease. (diociaiuti2020firstcaseof pages 7-9, diociaiuti2020firstcaseof pages 1-4)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

No validated modifier genes, disease-specific epigenetic signatures, or chromosomal abnormalities for KRT1 keratinopathies were extractable from the retrieved evidence.

5. Environmental information

No specific toxins, lifestyle factors, or infectious triggers were systematically identified in the retrieved evidence as causal. However, complications such as bacterial colonization and odor are described in clinical narratives, motivating careful infection surveillance and barrier support. (aljuwaied2024epidermolytichyperkeratosistype pages 9-10)

6. Mechanism / pathophysiology

6.1 Core structural mechanism (keratin filament dysfunction)

Keratin 1 is expressed in suprabasal epidermal layers (paired with type I keratins such as KRT10 in many contexts). Pathogenic variants in conserved α-helical rod domains disrupt keratin filament assembly and cause keratinocyte fragility and cytolysis. - A 2024 KRT1 EHK report describes mutations disrupting helix initiation/termination and filament assembly, leading to cytolysis/blister formation. (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, aljuwaied2024epidermolytichyperkeratosistype pages 2-9)

Suggested GO biological process terms (conceptual mapping): - GO: keratinization, intermediate filament organization, epidermis development, cornified envelope formation, response to mechanical stimulus.

Suggested GO cellular component terms: - GO: intermediate filament cytoskeleton, desmosome (due to keratin anchoring), cornified envelope.

Suggested CL (cell types): - CL: keratinocyte, especially suprabasal keratinocyte (spinous/granular layer keratinocytes).

6.2 Barrier failure → inflammation and hyperkeratosis feedback (recent mechanistic model)

A 2023 mechanistic preprint proposes TLR2 activation as a shared pathway in ichthyoses that links innate immune signaling to differentiation programs and KRT1 expression: - TLR2 activation increased differentiation/cornified envelope gene expression and induced hyperkeratosis in organotypic culture; conversely, blockade reduced KRT1 expression in disease models. (tagoe2023chronicactivationof pages 1-5, tagoe2023chronicactivationof pages 8-13) - The authors state that blockade of TLR2 signaling “reduced the expression of keratin 1,” and that GATA3 overexpression was “sufficient to increase Keratin 1 expression.” (tagoe2023chronicactivationof pages 1-5, tagoe2023chronicactivationof pages 13-17) - Quantitative signatures include 1810 differentially expressed genes after TLR2 agonist stimulation and 38/61 (62%) gene overlap between TLR2 activation and ARCI knockdown models. (tagoe2023chronicactivationof pages 13-17, tagoe2023chronicactivationof pages 8-13)

This provides a plausible chain: primary barrier/structural defect → endogenous danger signals → TLR2/NF‑κB activation → GATA3-driven differentiation and keratinization programs → hyperkeratosis and altered KRT1 expression, which could be therapeutically targetable. (tagoe2023chronicactivationof pages 8-13)

7. Anatomical structures affected

7.1 Organ/tissue level

Primary tissue involved is skin, with strong involvement of palmoplantar epidermis in KRT1-related disease. - Suggested UBERON terms: UBERON:0002097 (skin), UBERON:0004264 (palm), UBERON:0004278 (sole of foot).

7.2 Cell/subcellular level

Cell: suprabasal keratinocytes (spinous/granular layers) (aljuwaied2024epidermolytichyperkeratosistype pages 9-10)
Subcellular: keratin intermediate filaments / tonofilaments, with tonofilament aggregation described on ultrastructure in keratinopathic ichthyoses. (diociaiuti2020firstcaseof pages 1-4)

8. Temporal development

Typical onset: congenital or neonatal for EI; infancy/early childhood typical for EPPK manifestations. (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, smith2019novelandrecurrent pages 5-6)
Course: neonatal blistering/erythroderma often improves, with progressive hyperkeratosis emerging later; severity can decrease with age in some cohorts (not uniformly). (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, diociaiuti2020firstcaseof pages 12-14)

9. Inheritance and population

9.1 Inheritance

Predominantly autosomal dominant (including de novo). (aljuwaied2024epidermolytichyperkeratosistype pages 1-2, smith2019novelandrecurrent pages 1-3)
Postzygotic mosaicism is clinically relevant and has been detected in ichthyosis cohorts; mosaic disease can complicate genotype–phenotype relationships. (frommherz2025epidermolyticichthyosisclinical pages 4-5)

9.2 Epidemiology (available quantitative data)

A 2024 case report cites EHK/EI prevalence as approximately 1:200,000 to 1:300,000. (aljuwaied2024epidermolytichyperkeratosistype pages 1-2)
Palmoplantar involvement is cited as ~60% in that same source (contextual estimate). (aljuwaied2024epidermolytichyperkeratosistype pages 1-2)

Large population prevalence/incidence estimates stratified by KRT1 specifically were not available in the retrieved evidence.

10. Diagnostics

10.1 Clinical and pathology-based diagnosis

Classic EI features (erythroderma + blistering at birth, later hyperkeratosis) guide clinical suspicion. (smith2019novelandrecurrent pages 1-3)
Histology often shows epidermolytic hyperkeratosis / granular degeneration: orthohyperkeratosis, suprabasal vacuolated keratinocytes and irregular keratohyalin granules. (sussmuth2026defininghistologicalpatterns pages 18-20)
Dermatopathology alone is not fully specific; EHK patterns can appear in other conditions (epidermal nevi, keratoses, carcinomas, inflammatory diseases), so molecular confirmation is recommended. (sussmuth2026defininghistologicalpatterns pages 25-27)

10.2 Genetic testing

NGS-based approaches (exome/genome with targeted panels) provide high yield in genetically heterogeneous keratinization disorders such as PPK: 83% diagnostic yield in a Danish PPK cohort (including KRT1 cases). (gram2025clinicalandgenetic pages 1-2, gram2025clinicalandgenetic pages 2-3)
Genetic testing is emphasized for definitive subtype assignment and genetic counseling in keratinopathic ichthyoses. (diociaiuti2020firstcaseof pages 1-4)

11. Outcome / prognosis

KRT1 keratinopathies are generally chronic and lifelong skin disorders with substantial morbidity but typically not characterized by systemic organ failure in the retrieved evidence. - Burden is highest in neonatal period for EI (NICU need) and in chronic symptoms such as fissuring pain, pruritus, and mobility limitation. (frommherz2025epidermolyticichthyosisclinical pages 4-5, aljuwaied2024epidermolytichyperkeratosistype pages 9-10) - Quantitative survival/life expectancy data were not identified in the retrieved full-text set.

12. Treatment

12.1 Standard-of-care / real-world implementation

Common approaches include: - Barrier repair and symptom control: emollients and keratolytics as first-line; careful balancing to avoid worsening blistering or barrier compromise. (aljuwaied2024epidermolytichyperkeratosistype pages 9-10) - Antimicrobials for fissures/erosions: management of open lesions with antimicrobials until healed is recommended in clinical descriptions. (aljuwaied2024epidermolytichyperkeratosistype pages 9-10) - Systemic retinoids: oral retinoids (e.g., acitretin) for severe hyperkeratosis; included in case-based management. (aljuwaied2024epidermolytichyperkeratosistype pages 1-2)

Suggested MAXO mappings (conceptual): - MAXO: topical emollient therapy; keratolytic therapy; systemic retinoid therapy; antimicrobial therapy for skin infection/erosions.

12.2 Recent/experimental therapeutics (2023–2025)

Anti–IL‑17A therapy (case-level evidence): - A 2025 case report describes a 4-year-old with KRT1 EI (c.1432G>A; p.E478K) treated with Vunakizumab (anti–IL‑17A). The report explicitly states: “It inhibits the interaction of IL-17A with its receptor … and alleviates the inflammatory process,” and reports improvements after three months. (cheng2025firstsuccessfultreatment pages 1-3) - Quantitative improvement: IASI-E 11.6 → 5.3 and IASI-S 14.1 → 9.3; inflammatory biomarkers (IL‑17A, TNF‑α, sIL‑2R) normalized; “no observed adverse effects or elevated infection rates.” (cheng2025firstsuccessfultreatment pages 3-4, cheng2025firstsuccessfultreatment pages 4-5)

Clinical trials relevant to KRT1/EI (biologics and pathway therapies): - Secukinumab (anti–IL‑17A) in ichthyoses (NCT03041038) included epidermolytic ichthyosis, was Phase 2, randomized crossover, quadruple-masked, enrolling 20 adults, with primary endpoints of Week‑16 IASI reduction and mucocutaneous infection counts. (NCT03041038 chunk 1) - Additional biologic trials include ustekinumab extension (NCT04549792) and an EGFR-inhibition study for keratinopathies (NCT06545695), though detailed subtype/endpoints were not available in the retrieved trial text chunks. (NCT04549792 chunk 2)

NCT number	Title	Status	Phase	Population / subtypes relevant to KRT1 keratinopathies	Intervention	Design	Primary endpoints	Enrollment	Key dates	Citation context IDs
NCT03041038	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses	Completed	Phase 2	Adults with confirmed ichthyosis including autosomal recessive congenital ichthyosis (ARCI-LI, ARCI-CIE), epidermolytic ichthyosis (EI), and Netherton syndrome; mesh terms also include “Hyperkeratosis, Epidermolytic,” making it directly relevant to KRT1-associated epidermolytic disease	Secukinumab 300 mg SC weekly for 5 weeks then monthly vs placebo (sterile saline)	Interventional, randomized, crossover, quadruple-masked	Efficacy: reduction at Week 16 in Ichthyosis Area Severity Index (IASI); Safety: total number of bacterial or fungal mucocutaneous infections through Week 16	20	Start: 2016-12; Primary completion: 2020-08-31 (actual); Study completion: 2020-08-31 (actual); Results first posted: 2021-08-25	(NCT03041038 chunk 2, NCT03041038 chunk 1)
NCT04549792	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses	Completed	Early Phase 1	Ichthyosis population; excludes ichthyosis vulgaris and X-linked recessive ichthyosis; relevant as a biologic study in inherited ichthyoses/keratinization disorders, though EI/KRT1-specific inclusion is not explicit in retrieved chunks	Ustekinumab	Open-label, long-term extension	Not stated in retrieved excerpts	13	Registry metadata indicates 2021 record; specific start/completion/results dates not available in retrieved excerpts	(NCT04549792 chunk 2)
NCT06545695	Epidermal Growth Factor Receptor Inhibition for Keratinopathies	Not yet recruiting	Phase 1/Phase 2	Keratinopathies; likely highly relevant to KRT1 keratinopathies by title, but subtype-specific eligibility details were not available in retrieved excerpts	EGFR inhibition	Interventional; further randomization/masking details not available in retrieved excerpts	Not available in retrieved excerpts	44	Dates not available in retrieved excerpts	(NCT03041038 chunk 2, NCT04549792 chunk 2, NCT03041038 chunk 1)
NCT00074685	National Registry for Ichthyosis and Related Disorders	Completed	Not applicable (observational)	Broad ichthyosis and related disorders registry; useful for natural history, phenotyping, and case ascertainment relevant to rare KRT1-associated ichthyoses, though EI-specific inclusion details were not available in retrieved excerpts	Registry / observational data collection	Observational registry	Not available in retrieved excerpts	610	Dates not available in retrieved excerpts	(NCT03041038 chunk 2, NCT04549792 chunk 2, NCT03041038 chunk 1)
NCT05312073	Study of in Vivo and in Vitro Transcriptomic and Proteomic Signatures in Unhereditary Ichtyosis	Completed	Not applicable	Unhereditary ichthyosis; lower direct relevance to KRT1 Mendelian keratinopathies, but potentially informative for inflammatory/barrier molecular signatures	Transcriptomic/proteomic profiling study	Interventional / translational profiling study; detailed allocation and masking not available in retrieved excerpts	Not available in retrieved excerpts	18	Dates not available in retrieved excerpts	(NCT03041038 chunk 2, NCT04549792 chunk 2, NCT03041038 chunk 1)

Table: This table summarizes ClinicalTrials.gov studies with direct or potential relevance to KRT1 keratinopathies, especially epidermolytic ichthyosis. It highlights which trials explicitly included epidermolytic/hyperkeratotic subtypes, what interventions were tested, and where retrieved record details remain incomplete.

12.3 Expert/authoritative analysis (from primary authors)

Smith et al. emphasize the complexity of genotype–phenotype correlation for KRT1, noting KRT1 mutations “can result in a range of phenotypes,” motivating careful variant-level interpretation as mutation-specific therapies emerge. (smith2019novelandrecurrent pages 1-3, smith2019novelandrecurrent pages 6-7)
Süßmuth et al. caution that the epidermolytic hyperkeratosis pattern is diagnostically helpful but not specific, reinforcing the need for genetic confirmation for classification. (sussmuth2026defininghistologicalpatterns pages 25-27)

13. Prevention

Primary prevention of new cases is not feasible for de novo dominant disorders, but genetic counseling and reproductive planning are key: - Because KRT1 disorders can be de novo and mosaic, recurrence risk assessment may require sensitive testing strategies and careful counseling. (frommherz2025epidermolyticichthyosisclinical pages 4-5, diociaiuti2020firstcaseof pages 1-4) - Secondary/tertiary prevention focuses on preventing complications of barrier dysfunction (erosions, secondary infection) with proactive skin care and prompt antimicrobial management when fissures/erosions occur. (aljuwaied2024epidermolytichyperkeratosistype pages 9-10)

14. Other species / natural disease

No naturally occurring non-human KRT1 keratinopathy was identified in the retrieved evidence corpus.

15. Model organisms and experimental systems

The retrieved evidence supports several experimental systems relevant to mechanisms and therapeutic discovery: - Rat epidermal keratinocytes (REKs) and human keratinocytes used for time-course RNA-seq and pathway perturbation (TLR2 agonism; NF‑κB/GATA3 axis) demonstrating regulation of keratinization programs and KRT1 expression. (tagoe2023chronicactivationof pages 13-17, tagoe2023chronicactivationof pages 8-13) - Organotypic skin cultures showing dose-dependent cornified layer thickening after TLR2 activation and response to pathway blockade. (tagoe2023chronicactivationof pages 8-13)

Dedicated Krt1 knock-in/knockout mouse model papers were not available in accessible full-text during this run, so specific model strain details and phenotypic recapitulation cannot be cited here.

Recent developments snapshot (prioritizing 2023–2025)

Year/month	Study type	Development relevant to KRT1 keratinopathies	Key quantitative data	Citation context IDs
2025-05	Case report	First reported use of IL-17A blockade with Vunakizumab in a 4-year-old boy with KRT1-related epidermolytic ichthyosis (KRT1 c.1432G>A, p.Glu478Lys / p.E478K) after failure of conventional topical/keratolytic/retinoid approaches; rationale based on elevated Th17-associated inflammatory markers	Dosing: 120 mg every 10 days for 3 cycles, then every 3 weeks; IASI-E improved 11.6 → 5.3; IASI-S improved 14.1 → 9.3; biomarkers IL-17A, TNF-α, sIL-2R normalized by 3 months; no observed adverse effects or increased infections	(cheng2025firstsuccessfultreatment pages 3-4, cheng2025firstsuccessfultreatment pages 1-3, cheng2025firstsuccessfultreatment pages 4-5)
2025-05	Cohort study	Large German epidermolytic ichthyosis cohort refined genotype-phenotype correlations and quantified early-life burden; KRT1 germline variants were associated more often with intermediate/severe disease than KRT10	44 patients total; 25/41 required immediate incubator/NICU care; 6/45 (13.3%) preterm; 17/44 (38.6%) underweight or <5th percentile in infancy; KRT1 intermediate/severe in 15/19; median mIASI 19.10 for KRT1 vs 14.40 for KRT10	(frommherz2025epidermolyticichthyosisclinical pages 4-5)
2025-02	PPK cohort study	Danish palmoplantar keratoderma cohort showed value of genomic diagnosis in heterogeneous PPK, including KRT1-associated cases relevant to epidermolytic palmoplantar keratoderma within the KRT1 spectrum	142 patients from 76 families; molecular diagnosis in 63/76 probands (83%); 27 disease-causing variants across 13 genes; KRT1 accounted for 3/76 probands	(gram2025clinicalandgenetic pages 1-2, gram2025clinicalandgenetic pages 2-3, gram2025clinicalandgenetic pages 7-8)
2024-11	Case report	Novel heterozygous KRT1 epidermolytic hyperkeratosis / epidermolytic ichthyosis variant expanded the mutational spectrum and reiterated classic KRT1-associated clinical course and pathology	Prevalence cited as ~1:200,000-1:300,000; palmoplantar involvement reported in ~60% of cases; variant reported as KRT1 c.583A>T, p.Ile195Phe	(aljuwaied2024epidermolytichyperkeratosistype pages 1-2, aljuwaied2024epidermolytichyperkeratosistype pages 9-10, aljuwaied2024epidermolytichyperkeratosistype pages 2-9)
2023-06	Mechanistic preprint	Chronic TLR2 activation was proposed as a shared ichthyosis pathway that upregulates KRT1 through NF-κB and GATA3, linking innate immune signaling to hyperkeratosis and suggesting TLR2 blockade as a therapeutic strategy	RNA-seq identified 1810 differentially expressed genes after PAM3CSK4; 38/61 (62%) genes overlapped between TLR2 activation and ARCI knockdown models; 20 proteins upregulated and 18 downregulated (≥1.5-fold) in proteomics; KRT1 increased by ~12-24 h after TLR2 activation; organotypic cultures showed dose-dependent cornified layer thickening	(tagoe2023chronicactivationof pages 1-5, tagoe2023chronicactivationof pages 13-17, tagoe2023chronicactivationof pages 8-13, tagoe2023chronicactivationof pages 17-20, tagoe2023chronicactivationof pages 20-24)
2023-11	Diagnostic case report	Molecular confirmation remained essential in atypical epidermolytic ichthyosis presentations lacking classic blistering or clear epidermolysis on histology, underscoring relevance for differential diagnosis within keratinopathic ichthyosis	Single adult case; KRT10 c.467G>A (p.Arg156His); illustrates that unclear clinicopathologic cases may require sequencing for confirmation	(aljuwaied2024epidermolytichyperkeratosistype pages 1-2, sussmuth2026defininghistologicalpatterns pages 25-27, sussmuth2026defininghistologicalpatterns pages 18-20)

Table: This table summarizes notable 2023-2025 clinical and mechanistic developments relevant to KRT1 keratinopathies, including therapeutic innovation, cohort burden data, and emerging pathway biology. It is useful for quickly identifying what is new, quantitatively supported, and potentially actionable.

Key citations with URLs and publication dates (from retrieved sources)

Aljuwaied et al. Nov 2024. Epidermolytic Hyperkeratosis Type 1 with a New Heterozygous Mutation in KRT1 Gene: A Case Report. DOI: https://doi.org/10.69709/genomc.2024.135001 (aljuwaied2024epidermolytichyperkeratosistype pages 1-2)
Tagoe et al. Jun 2023 (preprint). Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype. DOI: https://doi.org/10.1101/2022.06.06.494922 (tagoe2023chronicactivationof pages 1-5)
Frommherz et al. May 2025. Epidermolytic ichthyosis: clinical spectrum and burden of disease in a large German cohort. DOI: https://doi.org/10.1111/jdv.20096 (frommherz2025epidermolyticichthyosisclinical pages 4-5)
Cheng et al. May 2025. First successful treatment of epidermolytic ichthyosis with Vunakizumab: A case report. DOI: https://doi.org/10.3389/fimmu.2025.1574255 (cheng2025firstsuccessfultreatment pages 3-4)
Smith et al. Oct 2019. Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma. DOI: https://doi.org/10.1111/ced.13800 (smith2019novelandrecurrent pages 1-3)
Diociaiuti et al. Oct 2020. First case of KRT2 epidermolytic nevus and novel clinical and genetic findings in 26 Italian patients with keratinopathic ichthyoses. DOI: https://doi.org/10.3390/ijms21207707 (diociaiuti2020firstcaseof pages 1-4)
ClinicalTrials.gov NCT03041038 (posted results metadata available in record). Secukinumab in patients with ichthyoses (includes epidermolytic ichthyosis). https://clinicaltrials.gov/study/NCT03041038 (NCT03041038 chunk 1)

Limitations of this report (evidence-bound)

Cross-ontology identifiers (Orphanet/ICD/MeSH/MONDO) were not present in the retrieved full-text excerpts and thus are not populated here.
Several clinical trial records were only partially captured in the retrieved chunks (e.g., NCT04549792, NCT06545695), limiting endpoint/date/result extraction.
Dedicated Krt1 in vivo model organism primary papers were not available as full text within this run; only keratinocyte/organotypic experimental systems could be cited.

References

(aljuwaied2024epidermolytichyperkeratosistype pages 1-2): Maitha Abdulla Aljuwaied, Waqas Saad Abdulwahha, Mays Alrim Mustafa Al Moukdad, Moza Kamil Bin Kamil Alshamsi, Sham Zain AlAbdin, Ahmed Elbarkouky, Omar El Khatib, and Salahdein Aburuz. Epidermolytic hyperkeratosis type 1 with a new heterozygous mutation in krt1 gene: a case report. GenoMed Connect, 1:1, Nov 2024. URL: https://doi.org/10.69709/genomc.2024.135001, doi:10.69709/genomc.2024.135001. This article has 0 citations.
(frommherz2025epidermolyticichthyosisclinical pages 4-5): Leonie Frommherz, Kathrin Giehl, Josephine Hofmann, Stefanie Huebner, Kirstin Kiekbusch, Teodora Sabkova, Kira Süßmuth, Svenja Alter, Iliana Tantcheva‐Poór, Hagen Ott, Judith Fischer, and Cristina Has. Epidermolytic ichthyosis: clinical spectrum and burden of disease in a large german cohort. Journal of the European Academy of Dermatology and Venereology, 39:1028-1037, May 2025. URL: https://doi.org/10.1111/jdv.20096, doi:10.1111/jdv.20096. This article has 7 citations and is from a domain leading peer-reviewed journal.
(cheng2025firstsuccessfultreatment pages 3-4): Wenjie Cheng, Chaolan Pan, Zhe Sun, Peiyi Sun, Jiawen Li, Zhirong Yao, Xiaoxiao Wang, and Jia Zhang. First successful treatment of epidermolytic ichthyosis with vunakizumab: a case report. Frontiers in Immunology, May 2025. URL: https://doi.org/10.3389/fimmu.2025.1574255, doi:10.3389/fimmu.2025.1574255. This article has 4 citations and is from a peer-reviewed journal.
(tagoe2023chronicactivationof pages 1-5): Hephzi Tagoe, Sakinah Hassan, Gehad Youssef, Wendy Heywood, Kevin Mills, John I. Harper, and Ryan F.L. O’Shaughnessy. Chronic activation of toll-like receptor 2 induces an ichthyotic skin phenotype. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2022.06.06.494922, doi:10.1101/2022.06.06.494922. This article has 8 citations.
(NCT03041038 chunk 1): Amy Paller. The Efficacy and Safety of Secukinumab in Patients With Ichthyoses. Northwestern University. 2016. ClinicalTrials.gov Identifier: NCT03041038
(smith2019novelandrecurrent pages 1-3): F. J. D. Smith, I. M. Kreuser‐Genis, C. S. Jury, N. J. Wilson, A. Terron‐Kwiatowski, and M. Zamiri. Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma. Clinical and Experimental Dermatology, 44:528-534, Oct 2019. URL: https://doi.org/10.1111/ced.13800, doi:10.1111/ced.13800. This article has 33 citations and is from a peer-reviewed journal.
(smith2019novelandrecurrent pages 5-6): F. J. D. Smith, I. M. Kreuser‐Genis, C. S. Jury, N. J. Wilson, A. Terron‐Kwiatowski, and M. Zamiri. Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma. Clinical and Experimental Dermatology, 44:528-534, Oct 2019. URL: https://doi.org/10.1111/ced.13800, doi:10.1111/ced.13800. This article has 33 citations and is from a peer-reviewed journal.
(aljuwaied2024epidermolytichyperkeratosistype pages 9-10): Maitha Abdulla Aljuwaied, Waqas Saad Abdulwahha, Mays Alrim Mustafa Al Moukdad, Moza Kamil Bin Kamil Alshamsi, Sham Zain AlAbdin, Ahmed Elbarkouky, Omar El Khatib, and Salahdein Aburuz. Epidermolytic hyperkeratosis type 1 with a new heterozygous mutation in krt1 gene: a case report. GenoMed Connect, 1:1, Nov 2024. URL: https://doi.org/10.69709/genomc.2024.135001, doi:10.69709/genomc.2024.135001. This article has 0 citations.
(gram2025clinicalandgenetic pages 2-3): 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 5 citations and is from a domain leading peer-reviewed journal.
(gram2025clinicalandgenetic pages 1-2): 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 5 citations and is from a domain leading peer-reviewed journal.
(tagoe2023chronicactivationof pages 8-13): Hephzi Tagoe, Sakinah Hassan, Gehad Youssef, Wendy Heywood, Kevin Mills, John I. Harper, and Ryan F.L. O’Shaughnessy. Chronic activation of toll-like receptor 2 induces an ichthyotic skin phenotype. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2022.06.06.494922, doi:10.1101/2022.06.06.494922. This article has 8 citations.
(smith2019novelandrecurrent pages 3-5): F. J. D. Smith, I. M. Kreuser‐Genis, C. S. Jury, N. J. Wilson, A. Terron‐Kwiatowski, and M. Zamiri. Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma. Clinical and Experimental Dermatology, 44:528-534, Oct 2019. URL: https://doi.org/10.1111/ced.13800, doi:10.1111/ced.13800. This article has 33 citations and is from a peer-reviewed journal.
(smith2019novelandrecurrent pages 6-7): F. J. D. Smith, I. M. Kreuser‐Genis, C. S. Jury, N. J. Wilson, A. Terron‐Kwiatowski, and M. Zamiri. Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma. Clinical and Experimental Dermatology, 44:528-534, Oct 2019. URL: https://doi.org/10.1111/ced.13800, doi:10.1111/ced.13800. This article has 33 citations and is from a peer-reviewed journal.
(aljuwaied2024epidermolytichyperkeratosistype pages 2-9): Maitha Abdulla Aljuwaied, Waqas Saad Abdulwahha, Mays Alrim Mustafa Al Moukdad, Moza Kamil Bin Kamil Alshamsi, Sham Zain AlAbdin, Ahmed Elbarkouky, Omar El Khatib, and Salahdein Aburuz. Epidermolytic hyperkeratosis type 1 with a new heterozygous mutation in krt1 gene: a case report. GenoMed Connect, 1:1, Nov 2024. URL: https://doi.org/10.69709/genomc.2024.135001, doi:10.69709/genomc.2024.135001. This article has 0 citations.
(diociaiuti2020firstcaseof pages 1-4): Andrea Diociaiuti, Daniele Castiglia, Marialuisa Corbeddu, Roberta Rotunno, Sabrina Rossi, Elisa Pisaneschi, Claudia Cesario, Angelo Giuseppe Condorelli, Giovanna Zambruno, and May El Hachem. First case of krt2 epidermolytic nevus and novel clinical and genetic findings in 26 italian patients with keratinopathic ichthyoses. International Journal of Molecular Sciences, 21:7707, Oct 2020. URL: https://doi.org/10.3390/ijms21207707, doi:10.3390/ijms21207707. This article has 21 citations.
(cheng2025firstsuccessfultreatment pages 1-3): Wenjie Cheng, Chaolan Pan, Zhe Sun, Peiyi Sun, Jiawen Li, Zhirong Yao, Xiaoxiao Wang, and Jia Zhang. First successful treatment of epidermolytic ichthyosis with vunakizumab: a case report. Frontiers in Immunology, May 2025. URL: https://doi.org/10.3389/fimmu.2025.1574255, doi:10.3389/fimmu.2025.1574255. This article has 4 citations and is from a peer-reviewed journal.
(diociaiuti2020firstcaseof pages 4-5): Andrea Diociaiuti, Daniele Castiglia, Marialuisa Corbeddu, Roberta Rotunno, Sabrina Rossi, Elisa Pisaneschi, Claudia Cesario, Angelo Giuseppe Condorelli, Giovanna Zambruno, and May El Hachem. First case of krt2 epidermolytic nevus and novel clinical and genetic findings in 26 italian patients with keratinopathic ichthyoses. International Journal of Molecular Sciences, 21:7707, Oct 2020. URL: https://doi.org/10.3390/ijms21207707, doi:10.3390/ijms21207707. This article has 21 citations.
(diociaiuti2020firstcaseof pages 7-9): Andrea Diociaiuti, Daniele Castiglia, Marialuisa Corbeddu, Roberta Rotunno, Sabrina Rossi, Elisa Pisaneschi, Claudia Cesario, Angelo Giuseppe Condorelli, Giovanna Zambruno, and May El Hachem. First case of krt2 epidermolytic nevus and novel clinical and genetic findings in 26 italian patients with keratinopathic ichthyoses. International Journal of Molecular Sciences, 21:7707, Oct 2020. URL: https://doi.org/10.3390/ijms21207707, doi:10.3390/ijms21207707. This article has 21 citations.
(tagoe2023chronicactivationof pages 13-17): Hephzi Tagoe, Sakinah Hassan, Gehad Youssef, Wendy Heywood, Kevin Mills, John I. Harper, and Ryan F.L. O’Shaughnessy. Chronic activation of toll-like receptor 2 induces an ichthyotic skin phenotype. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2022.06.06.494922, doi:10.1101/2022.06.06.494922. This article has 8 citations.
(diociaiuti2020firstcaseof pages 12-14): Andrea Diociaiuti, Daniele Castiglia, Marialuisa Corbeddu, Roberta Rotunno, Sabrina Rossi, Elisa Pisaneschi, Claudia Cesario, Angelo Giuseppe Condorelli, Giovanna Zambruno, and May El Hachem. First case of krt2 epidermolytic nevus and novel clinical and genetic findings in 26 italian patients with keratinopathic ichthyoses. International Journal of Molecular Sciences, 21:7707, Oct 2020. URL: https://doi.org/10.3390/ijms21207707, doi:10.3390/ijms21207707. This article has 21 citations.
(sussmuth2026defininghistologicalpatterns pages 18-20): Kira Süßmuth, Vinzenz Oji, Jacqueline Bodes, Isabelle Jochum, Florian Muhs, Katalin Komlosi, Ingrid Hausser, Matthias Schmuth, Heiko Traupe, Judith Fischer, and Dieter Metze. Defining histological patterns in inherited ichthyoses: toward a diagnostic algorithm based on 66 confirmed cases. Dermatopathology, 13:9, Feb 2026. URL: https://doi.org/10.3390/dermatopathology13010009, doi:10.3390/dermatopathology13010009. This article has 0 citations.
(sussmuth2026defininghistologicalpatterns pages 25-27): Kira Süßmuth, Vinzenz Oji, Jacqueline Bodes, Isabelle Jochum, Florian Muhs, Katalin Komlosi, Ingrid Hausser, Matthias Schmuth, Heiko Traupe, Judith Fischer, and Dieter Metze. Defining histological patterns in inherited ichthyoses: toward a diagnostic algorithm based on 66 confirmed cases. Dermatopathology, 13:9, Feb 2026. URL: https://doi.org/10.3390/dermatopathology13010009, doi:10.3390/dermatopathology13010009. This article has 0 citations.
(cheng2025firstsuccessfultreatment pages 4-5): Wenjie Cheng, Chaolan Pan, Zhe Sun, Peiyi Sun, Jiawen Li, Zhirong Yao, Xiaoxiao Wang, and Jia Zhang. First successful treatment of epidermolytic ichthyosis with vunakizumab: a case report. Frontiers in Immunology, May 2025. URL: https://doi.org/10.3389/fimmu.2025.1574255, doi:10.3389/fimmu.2025.1574255. This article has 4 citations and is from a peer-reviewed journal.
(NCT04549792 chunk 2): Amy Paller. An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses. Northwestern University. 2021. ClinicalTrials.gov Identifier: NCT04549792
(NCT03041038 chunk 2): Amy Paller. The Efficacy and Safety of Secukinumab in Patients With Ichthyoses. Northwestern University. 2016. ClinicalTrials.gov Identifier: NCT03041038
(gram2025clinicalandgenetic pages 7-8): 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 5 citations and is from a domain leading peer-reviewed journal.
(tagoe2023chronicactivationof pages 17-20): Hephzi Tagoe, Sakinah Hassan, Gehad Youssef, Wendy Heywood, Kevin Mills, John I. Harper, and Ryan F.L. O’Shaughnessy. Chronic activation of toll-like receptor 2 induces an ichthyotic skin phenotype. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2022.06.06.494922, doi:10.1101/2022.06.06.494922. This article has 8 citations.
(tagoe2023chronicactivationof pages 20-24): Hephzi Tagoe, Sakinah Hassan, Gehad Youssef, Wendy Heywood, Kevin Mills, John I. Harper, and Ryan F.L. O’Shaughnessy. Chronic activation of toll-like receptor 2 induces an ichthyotic skin phenotype. bioRxiv, Jun 2023. URL: https://doi.org/10.1101/2022.06.06.494922, doi:10.1101/2022.06.06.494922. This article has 8 citations.

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Research Report: KRT1 Keratinopathies (Mendelian)

Executive summary

Target disease

MONDO / Orphanet / ICD / MeSH identifiers

1. Disease information

1.1 What is the disease?

1.2 Key identifiers (from evidence)

1.3 Common synonyms / alternative names

1.4 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype domains (with suggested HPO terms)

3.2 Phenotype severity and QoL impact (data)

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variants (examples from primary literature)

4.3 Genotype–phenotype correlations

4.4 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Core structural mechanism (keratin filament dysfunction)

6.2 Barrier failure → inflammation and hyperkeratosis feedback (recent mechanistic model)

7. Anatomical structures affected

7.1 Organ/tissue level

7.2 Cell/subcellular level

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology (available quantitative data)

10. Diagnostics

10.1 Clinical and pathology-based diagnosis

10.2 Genetic testing

11. Outcome / prognosis

12. Treatment

12.1 Standard-of-care / real-world implementation

12.2 Recent/experimental therapeutics (2023–2025)

12.3 Expert/authoritative analysis (from primary authors)

13. Prevention

14. Other species / natural disease

15. Model organisms and experimental systems

Recent developments snapshot (prioritizing 2023–2025)

Key citations with URLs and publication dates (from retrieved sources)

Limitations of this report (evidence-bound)