Ichthyosis vulgaris is the most common inherited disorder of keratinization, caused by loss-of-function variants in FLG, which encodes profilaggrin, the main protein of epidermal keratohyalin granules. Inheritance is semidominant: homozygous or compound heterozygous carriers of FLG null alleles have moderate to severe disease with near-complete loss of filaggrin, whereas heterozygous carriers have a mild phenotype with incomplete penetrance. Loss of filaggrin reduces keratohyalin granules, disturbs corneocyte and lamellar lipid formation, and removes the filaggrin-derived amino acids that make up much of the stratum corneum natural moisturizing factor, producing a gene-dose-dependent permeability barrier defect with reduced hydration and increased transepidermal water loss. Clinically this appears as xerosis and fine scaling on the extensor surfaces of the limbs with flexural sparing, keratosis pilaris and palmar and plantar hyperlinearity; symptoms worsen in cold, dry weather and improve in summer and with age. The same barrier defect permits percutaneous allergen penetration and type 2 sensitization, so ichthyosis vulgaris is strongly associated with atopic dermatitis, asthma occurring with eczema, allergic rhinitis and peanut allergy. FLG null alleles are common in European and Asian populations and rarer in darkly pigmented populations. Treatment is symptomatic, with regular emollients and urea- or lactate-containing keratolytic moisturizers.
Ask a research question about Ichthyosis Vulgaris. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
Conditions with similar clinical presentations that must be differentiated from Ichthyosis Vulgaris:
name: Ichthyosis Vulgaris
creation_date: "2026-09-30T19:45:00Z"
category: Mendelian
disease_term:
preferred_term: autosomal dominant ichthyosis vulgaris
term:
id: MONDO:0007810
label: autosomal dominant ichthyosis vulgaris
mappings:
mondo_mappings:
- term:
id: MONDO:0007810
label: autosomal dominant ichthyosis vulgaris
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
Primary MONDO identifier for this entry: the FLG-caused, inherited form of
ichthyosis vulgaris.
- term:
id: MONDO:0024304
label: ichthyosis vulgaris
mapping_predicate: skos:broadMatch
mapping_source: MONDO
mapping_justification: >-
MONDO:0024304 is the broader clinical class, which also covers acquired
ichthyosis vulgaris. This entry is scoped to the inherited FLG form, so the
broader class is recorded as a cross-reference rather than as the entry's
identity.
description: >-
Ichthyosis vulgaris is the most common inherited disorder of keratinization,
caused by loss-of-function variants in FLG, which encodes profilaggrin, the
main protein of epidermal keratohyalin granules. Inheritance is semidominant:
homozygous or compound heterozygous carriers of FLG null alleles have
moderate to severe disease with near-complete loss of filaggrin, whereas
heterozygous carriers have a mild phenotype with incomplete penetrance. Loss
of filaggrin reduces keratohyalin granules, disturbs corneocyte and lamellar
lipid formation, and removes the filaggrin-derived amino acids that make up
much of the stratum corneum natural moisturizing factor, producing a
gene-dose-dependent permeability barrier defect with reduced hydration and
increased transepidermal water loss. Clinically this appears as xerosis and
fine scaling on the extensor surfaces of the limbs with flexural sparing,
keratosis pilaris and palmar and plantar hyperlinearity; symptoms worsen in
cold, dry weather and improve in summer and with age. The same barrier defect
permits percutaneous allergen penetration and type 2 sensitization, so
ichthyosis vulgaris is strongly associated with atopic dermatitis, asthma
occurring with eczema, allergic rhinitis and peanut allergy. FLG null alleles
are common in European and Asian populations and rarer in darkly pigmented
populations. Treatment is symptomatic, with regular emollients and urea- or
lactate-containing keratolytic moisturizers.
synonyms:
- ichthyosis vulgaris
- ichthyosis simplex
- dominant ichthyosis vulgaris
- ichthyosis vulgaris, autosomal dominant
- filaggrin-related ichthyosis vulgaris
parents:
- Inherited Ichthyosis
notes: >-
Bound to MONDO:0007810 (autosomal dominant ichthyosis vulgaris), the heritable
FLG-related form. Its MONDO parent MONDO:0024304 (ichthyosis vulgaris) is
defined to include acquired ichthyosis vulgaris, a phenotype secondary to
malignancy, drugs or systemic disease that this entry does not model. The
MONDO label says autosomal dominant because the disorder was classified that
way before FLG was identified; the genotype-phenotype data show semidominant
inheritance, which is how the inheritance block records it. There is no
GeneReviews chapter for ichthyosis vulgaris (Bookshelf index snapshot
2026-09-10 plus a live PubMed title search); the only Bookshelf chapter is
the StatPearls review "Hereditary and Acquired Ichthyosis Vulgaris"
(PMID:32965989), which is not a phenotype baseline.
has_subtypes:
- name: Mild IV
display_name: Mild ichthyosis vulgaris (heterozygous FLG)
subtype_term:
preferred_term: mild ichthyosis vulgaris
term:
id: MONDO:0100474
label: mild ichthyosis vulgaris
genes:
- preferred_term: FLG
term:
id: hgnc:3748
label: FLG
description: >-
Heterozygous carriers of a single FLG null allele. The phenotype is mild and
incompletely penetrant, most readily recognized by palmar hyperlinearity,
with fine scaling or keratosis pilaris in some carriers and dry skin that
worsens in cold, dry climates. Some heterozygotes nonetheless show a
pronounced scaling phenotype, which points to modifiers.
evidence:
- reference: PMID:16444271
reference_title: "Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance"
explanation: Defines the heterozygous, mild and incompletely penetrant stratum.
- reference: PMID:16810297
reference_title: "Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris"
explanation: Describes the features that identify heterozygous carriers.
- reference: PMID:17164798
reference_title: "Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this group of patients not only homozygous and compound heterozygous, but also heterozygous patients for p.R501X and c.2282del4 display a pronounced phenotype"
explanation: Shows that heterozygous expression is variable and can be marked, so the mild stratum is a tendency rather than a rule.
- name: Severe IV
display_name: Severe ichthyosis vulgaris (biallelic FLG)
subtype_term:
preferred_term: severe ichthyosis vulgaris
term:
id: MONDO:0100475
label: severe ichthyosis vulgaris
genes:
- preferred_term: FLG
term:
id: hgnc:3748
label: FLG
description: >-
Homozygous or compound heterozygous carriers of FLG null alleles. Filaggrin
is essentially absent from the epidermis, and the phenotype is a stable,
chronic, more marked ichthyosis with obvious scaling and hyperlinearity.
Only this stratum shows significant changes in transepidermal water loss
and skin hydration in vivo.
evidence:
- reference: PMID:16444271
reference_title: "Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds."
explanation: Defines the biallelic stratum as the cause of moderate or severe disease.
- reference: PMID:27519469
reference_title: "Compound heterozygotes for filaggrin gene mutations do not always show severe atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It was found that five of the six patients had severe IV, and the remaining patient showed moderate IV."
explanation: Biallelic FLG null carriers had severe or moderate ichthyosis vulgaris.
- reference: PMID:23297869
reference_title: "Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A complete, but not a partial deficiency is associated with moderate changes in TEWL and skin hydration"
explanation: Barrier function measurably changes only with biallelic (complete) filaggrin deficiency.
inheritance:
- name: Semidominant inheritance
inheritance_term:
preferred_term: Semidominant inheritance
term:
id: HP:0032113
label: Semidominant inheritance
penetrance: INCOMPLETE
description: >-
FLG null alleles act in a gene-dose-dependent way: biallelic carriers have
moderate to severe ichthyosis vulgaris with essentially complete
penetrance, while heterozygous carriers have a mild, incompletely penetrant
phenotype. Before FLG was identified the disorder was classified as
autosomal dominant, which is the origin of the MONDO label.
evidence:
- reference: PMID:16444271
reference_title: "Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance"
explanation: Establishes semidominant inheritance with incomplete heterozygote penetrance.
- reference: PMID:17164798
reference_title: "Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Homozygotes and compound heterozygotes were severely affected whereas heterozygotes showed mild disease or were asymptomatic, suggesting semidominant inheritance with incomplete penetrance in heterozygotes."
explanation: Independent Austrian cohort restating the semidominant model.
- reference: PMID:2579164
reference_title: "Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Ichthyosis vulgaris is an autosomal dominant disorder of keratinization characterized histologically by absent or reduced keratohyaline granules in the epidermis and mild hyperkeratosis."
explanation: Records the pre-molecular autosomal dominant classification behind the MONDO label.
prevalence:
- population: English schoolchildren
measure_type: POINT_PREVALENCE
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 400.0
notes: >-
1 in 250 from a survey of 6,051 healthy English schoolchildren. The source
calls the figure an incidence; it is a cross-sectional survey count, so it
is recorded here as point prevalence.
evidence:
- reference: PMID:16444271
reference_title: "Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren."
explanation: Source of the commonly cited 1 in 250 figure.
- population: Europeans (FLG null-allele carriers)
measure_type: CARRIER_FREQUENCY
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 7700.0
rate_low: 2700.0
rate_high: 14200.0
notes: >-
Median 7.7% (range 2.7 to 14.2%) of Europeans carry an FLG loss-of-function
variant, pooled across published population studies. Carriers are at risk of
the mild, heterozygous form.
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "However, the median prevalence of FLG mutations among Europeans and Asians was 7·7% (range 2·7–14·2) and 3·0% (range 0–7·3), respectively."
explanation: Pooled review estimate of European FLG null-allele carrier frequency.
- population: Asians (FLG null-allele carriers)
measure_type: CARRIER_FREQUENCY
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 3000.0
rate_low: 0.0
rate_high: 7300.0
notes: >-
Median 3.0% (range 0 to 7.3%). The mutation spectrum differs from that of
Europeans, so screening panels built on European alleles undercount Asian
carriers.
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "However, the median prevalence of FLG mutations among Europeans and Asians was 7·7% (range 2·7–14·2) and 3·0% (range 0–7·3), respectively."
explanation: Pooled review estimate of Asian FLG null-allele carrier frequency.
- reference: PMID:19958351
reference_title: "FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Notably, the same FLG mutations identified in the European population were rarely found in Asians."
explanation: Population-specific mutation spectra explain why European panels miss Asian alleles.
clinical_burden:
burden_level: LOW
rationale: >-
Ichthyosis vulgaris is chronic and lifelong but does not shorten life, and
most patients improve with age. The burden is xerosis, scaling and itch,
with cosmetic discomfort and psychosocial impairment, plus the associated
atopic disease; it is greater in biallelic carriers and in patients with
atopic dermatitis.
evidence:
- reference: PMID:35663767
reference_title: "Effect of topical treatment with 7.5% urea in Ichthyosis Vulgaris: A randomized, controlled, double blinded, split body study evaluating the effect of urea cream compared to the vehicle (moisturizing) cream."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "The characteristic clinical features of IV are xerosis, scaling, and itching, often accompanied by cosmetic discomfort and consequent psychosocial impairment."
explanation: States the cosmetic and psychosocial burden that accompanies the skin features.
- reference: PMID:36751330
reference_title: "Ichthyosis vulgaris: An updated review."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The prognosis for inherited cases has proven to be good among majority of patients, leading to a normal lifespan and an improvement in the disease with age."
explanation: Normal lifespan and improvement with age support a low overall burden level.
progression:
- phase: Onset in infancy and lifelong course
age_range: first year of life onward
notes: >-
Features usually appear in the first year of life and are recognizable by
about age 5. The disease worsens in winter and low humidity, improves in
summer and humid climates, and tends to improve with age; lifespan is
normal.
evidence:
- reference: PMID:32115871
reference_title: "Ichthyoses in everyday practice: management of a rare group of diseases."
supports: SUPPORT
evidence_source: OTHER
snippet: "A distinction is made between common hereditary ichthyoses (ichthyosis vulgaris and X-linked ichthyosis), which usually manifest themselves in the first year of life"
explanation: Review statement on onset in the first year of life.
- reference: PMID:36751330
reference_title: "Ichthyosis vulgaris: An updated review."
supports: SUPPORT
evidence_source: OTHER
snippet: "It typically presents in infancy as xerosis, skin lesions, keratosis pilaris, palmoplantar hyper linearity, scaly dermatosis, and erythroderma, clearly identifiable by age 5."
explanation: Review statement on age of onset.
- reference: PMID:36751330
reference_title: "Ichthyosis vulgaris: An updated review."
supports: SUPPORT
evidence_source: OTHER
snippet: "There are no notable significances in sex or ethnicities and the disease is observed to improve with age."
explanation: Review statement that the disease improves with age.
pathophysiology:
- name: FLG Loss-of-Function Variants
conforms_to: "epidermal_cornification_failure#Cornification Program Component Deficiency"
biological_scale: MOLECULAR
description: >-
Germline nonsense and frameshift variants in FLG, most commonly R501X and
2282del4 in Europeans and population-specific alleles in Asia, truncate
profilaggrin. Because the C-terminal region is required for processing,
truncations anywhere in the repeat array abolish or sharply reduce
filaggrin production, and with it the keratin filament binding of the
filaggrin monomers. How much the clinical phenotype depends on lost keratin
aggregation, as opposed to lost natural moisturizing factor, is debated: a
filaggrin knockdown skin model showed no keratin extraction defect
(PMID:20445547).
genes:
- preferred_term: FLG
term:
id: hgnc:3748
label: FLG
molecular_functions:
- preferred_term: keratin filament binding
term:
id: GO:1990254
label: keratin filament binding
modifier: DECREASED
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Nonsense and frameshift null alleles; heterozygous (mild) or homozygous /
compound heterozygous (moderate to severe).
evidence:
- reference: PMID:16444271
reference_title: "Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds."
explanation: Identifies FLG null variants as the cause of ichthyosis vulgaris.
- reference: PMID:17417636
reference_title: "Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis."
explanation: The allelic series is uniformly null and removes epidermal filaggrin.
- reference: PMID:27667308
reference_title: "Filaggrin failure - from ichthyosis vulgaris to atopic eczema and beyond."
supports: SUPPORT
evidence_source: OTHER
snippet: "profilaggrin is rapidly cleaved into multiple copies of the 37 kDa filaggrin monomer, which binds to and condenses the keratin cytoskeleton, thereby facilitating cellular compression"
explanation: Review statement that the filaggrin monomer binds keratin filaments, the molecular function lost when FLG null alleles abolish filaggrin.
- reference: PMID:16444271
reference_title: "Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments."
explanation: The paper identifying FLG null alleles in ichthyosis vulgaris names keratin filament aggregation as the function of the lost filaggrin peptides.
downstream:
- target: Profilaggrin and Filaggrin Deficiency
causal_link_type: DIRECT
evidence:
- reference: PMID:19958351
reference_title: "FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Mutations at any site within FLG, even mutations in C-terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C-terminal region is essential for proper processing of profilaggrin into filaggrin."
explanation: Links FLG truncations to reduced profilaggrin/filaggrin protein in patient epidermis.
- name: Profilaggrin and Filaggrin Deficiency
biological_scale: MOLECULAR
description: >-
Profilaggrin is normally stored in keratohyalin granules of the granular
layer and cleaved during terminal differentiation into filaggrin monomers
that aggregate keratin filaments and are later degraded into natural
moisturizing factor. In ichthyosis vulgaris profilaggrin and filaggrin are
reduced or absent, in proportion to clinical severity.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: keratinocyte differentiation
term:
id: GO:0030216
label: keratinocyte differentiation
modifier: DECREASED
locations:
- preferred_term: stratum granulosum of epidermis
term:
id: UBERON:0002069
label: stratum granulosum of epidermis
evidence:
- reference: PMID:2579164
reference_title: "Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It was absent from the more severely affected individuals in each family and reduced in intensity in the less severely affected family members."
explanation: Filaggrin loss in patient epidermis tracks clinical severity.
- reference: PMID:23290076
reference_title: "Analyses of FLG mutation frequency and filaggrin expression in isolated ichthyosis vulgaris (IV) and atopic dermatitis-associated IV."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunohistochemical staining revealed that profilaggrin/filaggrin peptides were remarkably reduced in the epidermis of all the patients."
explanation: Confirms reduced epidermal profilaggrin/filaggrin in patients.
downstream:
- target: Reduced Keratohyalin Granules and Defective Corneocyte Formation
causal_link_type: DIRECT
evidence:
- reference: PMID:2579164
reference_title: "Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This biochemical abnormality correlates with the morphologic reduction in the amount of keratohyalin, and with the clinical severity of the disorder."
explanation: Links filaggrin loss to the loss of keratohyalin granules.
- reference: PMID:20445547
reference_title: "Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Electron microscopy revealed that keratohyalin granules were reduced in number and size and lamellar body formation was disturbed."
explanation: Experimental knockdown in a human skin model reproduces the granule and lamellar body defects, showing they follow from filaggrin loss.
- target: Reduced Natural Moisturizing Factor
causal_link_type: DIRECT
evidence:
- reference: PMID:33462753
reference_title: "Skin barrier dysfunction and filaggrin."
supports: SUPPORT
evidence_source: OTHER
snippet: "Filaggrin is degraded by caspase-14, calpain 1, and bleomycin hydrolases into amino acids and amino acid metabolites such as trans-urocanic acid and pyrrolidone carboxylic acid, which are pivotal natural moisturizing factors in the SC."
explanation: Filaggrin is the precursor of the natural moisturizing factor, so its loss removes that pool.
- target: Keratosis pilaris
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Keratosis pilaris frequency follows FLG genotype in a dose-dependent way,
but FLG mutations explain only part of keratosis pilaris and the lesional
mechanism is not settled.
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Keratosis pilaris was noted in 100%, 66% and 30%, respectively, of homozygous, heterozygous and wild-type juvenile FLG mutation carriers."
explanation: Gene-dose relationship between filaggrin loss and keratosis pilaris.
- target: Palmar hyperlinearity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Palmar hyperlinearity is the sign that most reliably identifies FLG
heterozygotes; how filaggrin loss produces exaggerated palmar markings is
not established.
evidence:
- reference: PMID:16810297
reference_title: "Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity"
explanation: Hyperlinearity tracks even single-allele filaggrin loss.
- name: Reduced Keratohyalin Granules and Defective Corneocyte Formation
conforms_to: "epidermal_cornification_failure#Defective Cornified Envelope Assembly and Lamellar Lipid Delivery"
biological_scale: CELLULAR
description: >-
Keratohyalin granules are reduced or absent. Filaggrin-deficient granular
cells show perinuclear retraction of keratin filaments, impaired loading of
lamellar bodies, nonuniform extracellular deposition of their contents and
abnormal lamellar bilayers, with fewer corneodesmosomes and reduced tight
junction proteins.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
- preferred_term: corneocyte
term:
id: CL:0002153
label: corneocyte
biological_processes:
- preferred_term: cornified envelope assembly
term:
id: GO:1903575
label: cornified envelope assembly
modifier: DECREASED
- preferred_term: intermediate filament organization
term:
id: GO:0045109
label: intermediate filament organization
modifier: DECREASED
locations:
- preferred_term: stratum granulosum of epidermis
term:
id: UBERON:0002069
label: stratum granulosum of epidermis
evidence:
- reference: PMID:21514438
reference_title: "Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Abnormal barrier function correlated with alterations in keratin filament organization (perinuclear retraction), impaired loading of lamellar body contents, followed by nonuniform extracellular distribution of secreted organelle contents, and abnormalities in lamellar bilayer architecture."
explanation: Ultrastructural defects in FLG-mutant ichthyosis vulgaris epidermis.
- reference: PMID:21514438
reference_title: "Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition, we observed reductions in corneodesmosome density and tight junction protein expression."
explanation: Adhesion structures are also reduced in filaggrin-deficient epidermis.
downstream:
- target: Stratum Corneum Permeability Barrier Failure
causal_link_type: DIRECT
evidence:
- reference: PMID:21514438
reference_title: "Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thus, FLG deficiency provokes alterations in keratinocyte architecture that influence epidermal functions localizing to the extracellular matrix."
explanation: The cellular architecture defects are the route by which filaggrin loss impairs the barrier.
- name: Reduced Natural Moisturizing Factor
biological_scale: MOLECULAR
description: >-
Filaggrin is degraded in the stratum corneum by caspase-14, calpain 1 and
bleomycin hydrolase to hygroscopic amino acids and their derivatives,
including trans-urocanic acid and pyrrolidone carboxylic acid, that act as
the natural moisturizing factor. Their deficiency reduces stratum corneum
hydration in a gene-dose-dependent way and removes the main epidermal
UV-B-absorbing chromophore.
locations:
- preferred_term: stratum corneum of epidermis
term:
id: UBERON:0002027
label: stratum corneum of epidermis
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "The inherent reduction of filaggrin metabolites seen in patients with IV reduce the levels of NMFs, causing not only a gene dose-dependent reduction in skin hydration, but also an elevated skin surface pH, and increased transepidermal water loss (TEWL), which are all features of the xerotic skin in IV."
explanation: Review synthesis of the filaggrin to NMF deficit in ichthyosis vulgaris.
- reference: PMID:20445547
reference_title: "Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Moreover, lack of filaggrin led to a reduction in the concentration of urocanic acid, and sensitized the organotypic skin to UVB-induced apoptosis."
explanation: Experimental filaggrin knockdown lowers urocanic acid, a filaggrin-derived NMF component.
downstream:
- target: Reduced Stratum Corneum Hydration
causal_link_type: DIRECT
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "The inherent reduction of filaggrin metabolites seen in patients with IV reduce the levels of NMFs, causing not only a gene dose-dependent reduction in skin hydration, but also an elevated skin surface pH, and increased transepidermal water loss (TEWL), which are all features of the xerotic skin in IV."
explanation: States the causal step from NMF loss to reduced hydration and raised pH.
- name: Reduced Stratum Corneum Hydration
biological_scale: TISSUE
description: >-
Stratum corneum water content falls and skin surface pH may rise. In vivo
the change is moderate and statistically significant only in biallelic
carriers; in a cohort of 15 patients skin-surface pH did not differ
significantly from controls. Low ambient humidity is proposed to accelerate
breakdown of residual filaggrin and aggravate the deficit.
locations:
- preferred_term: stratum corneum of epidermis
term:
id: UBERON:0002027
label: stratum corneum of epidermis
evidence:
- reference: PMID:23297869
reference_title: "Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a moderate decrease of skin hydration from 29.20 ± 1.96 to 20.17 ± 3.60 (P < 0.05) in comparison with the control group were observed"
explanation: Measured hydration decrease in biallelic FLG ichthyosis vulgaris.
- reference: PMID:23297869
reference_title: "Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Changes in skin surface pH were not significant."
explanation: In this cohort skin-surface pH was not significantly raised, which qualifies the pH component of the claim.
downstream:
- target: Dry skin
causal_link_type: DIRECT
- target: Stratum Corneum Permeability Barrier Failure
causal_link_type: DIRECT
evidence:
- reference: PMID:22164253
reference_title: "Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression."
explanation: Barrier readouts track filaggrin deficiency in patients with ichthyosis vulgaris and atopic dermatitis.
- name: Stratum Corneum Permeability Barrier Failure
conforms_to: "epidermal_cornification_failure#Stratum Corneum Permeability Barrier Failure"
biological_scale: TISSUE
description: >-
The permeability barrier becomes leaky in proportion to FLG gene dose, via a
paracellular route through abnormal extracellular lamellae, with increased
transepidermal water loss. The in vivo defect is moderate and significant
in biallelic carriers.
cell_types:
- preferred_term: corneocyte
term:
id: CL:0002153
label: corneocyte
biological_processes:
- preferred_term: establishment of skin barrier
term:
id: GO:0061436
label: establishment of skin barrier
modifier: DECREASED
locations:
- preferred_term: stratum corneum of epidermis
term:
id: UBERON:0002027
label: stratum corneum of epidermis
evidence:
- reference: PMID:21514438
reference_title: "Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report here that the presence of FLG mutations in Caucasians predicts dose-dependent alterations in epidermal permeability barrier function."
explanation: Gene-dose-dependent barrier impairment in ichthyosis vulgaris.
- reference: PMID:21514438
reference_title: "Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although FLG is an intracellular protein, the barrier abnormality occurred solely via a paracellular route in affected stratum corneum."
explanation: Locates the barrier leak to the paracellular pathway.
- reference: PMID:23297869
reference_title: "Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In FLG(-/-) subjects, a moderate increase of TEWL from 5.41 ± 0.32-7.54 ± 0.90 g/m(2) h (P < 0.03)"
explanation: Measured increase in transepidermal water loss in biallelic carriers.
downstream:
- target: Retention Hyperkeratosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
By analogy with the other ichthyoses covered by the cornification module,
the barrier defect is followed by a thickened, retained stratum corneum;
a direct experimental link in ichthyosis vulgaris is not established.
- target: Pruritus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Itch accompanies the barrier defect; the sensory mechanism linking the
two in ichthyosis vulgaris is not described in the cited sources.
evidence:
- reference: PMID:36751330
reference_title: "Ichthyosis vulgaris: An updated review."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Pruritus, allergic rhinoconjunctivitis, hypohidrosis, heat intolerance, and recurrent infections due to a disturbed skin barrier are other common occurrences."
explanation: Review attributes pruritus in ichthyosis vulgaris to the disturbed skin barrier.
- target: Increased Percutaneous Allergen and Irritant Penetration
causal_link_type: DIRECT
evidence:
- reference: PMID:19349982
reference_title: "A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization"
explanation: Flg-mutant mice show antigen transfer across the defective barrier.
- name: Retention Hyperkeratosis
conforms_to: "epidermal_cornification_failure#Compensatory Epidermal Hyperproliferation and Retention Hyperkeratosis"
biological_scale: TISSUE
description: >-
The stratum corneum is thickened with mild orthokeratotic hyperkeratosis
over a reduced or absent granular layer; this retained stratum corneum is
the fine scale seen clinically. The Flg-mutant flaky tail mouse shows the
same orthokeratotic hyperkeratosis with granular-layer attenuation.
biological_processes:
- preferred_term: keratinization
term:
id: GO:0031424
label: keratinization
locations:
- preferred_term: skin epidermis
term:
id: UBERON:0001003
label: skin epidermis
evidence:
- reference: PMID:2579164
reference_title: "Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The stratum corneum was thicker than in normals"
explanation: Thickened stratum corneum in patient skin.
- reference: PMID:11121144
reference_title: "Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Affected homozygous ft/ft mice exhibit large, disorganized scales on tail and paw skin, marked attenuation of the epidermal granular layer, mild acanthosis, and orthokeratotic hyperkeratosis."
explanation: The filaggrin-deficient mouse reproduces orthokeratotic hyperkeratosis and scaling.
downstream:
- target: Fine scaling of the skin
causal_link_type: DIRECT
- name: Increased Percutaneous Allergen and Irritant Penetration
conforms_to: "epithelial_barrier_dysfunction#Increased Transepithelial Allergen Penetration and Innate Immune Activation"
biological_scale: TISSUE
description: >-
Allergens, haptens and irritants cross filaggrin-deficient skin more
readily, which predisposes carriers to atopic dermatitis, hand eczema,
irritant contact dermatitis and contact sensitization, the latter mainly
in carriers who already have dermatitis.
locations:
- preferred_term: skin epidermis
term:
id: UBERON:0001003
label: skin epidermis
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Mechanistic studies have shown increased penetration of allergens and chemicals in filaggrin-deficient skin"
explanation: Review synthesis of increased allergen and chemical penetration.
- reference: PMID:19349982
reference_title: "A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses."
explanation: Experimental percutaneous allergen priming in Flg-mutant mice.
downstream:
- target: Type 2 Allergic Sensitization
causal_link_type: DIRECT
evidence:
- reference: PMID:19349982
reference_title: "A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In marked contrast, percutaneous allergen exposure in ft/ft mice generated OVA-specific IgG and OVA-specific IgE"
explanation: Percutaneous exposure through the Flg-deficient barrier produces allergen-specific IgE.
- target: Contact dermatitis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23343419
reference_title: "Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel, whereas FLG mutations alone may not, or may only slightly, increase the risk of sensitization."
explanation: Contact sensitization risk in FLG carriers depends on coexisting dermatitis, consistent with penetration through inflamed, filaggrin-depleted skin.
- name: Type 2 Allergic Sensitization
conforms_to: "epithelial_barrier_dysfunction#Type 2 Sensitization and IgE Class Switch"
biological_scale: ORGANISM
description: >-
Allergen priming through the skin generates allergen-specific IgE, the
shared step behind the atopic comorbidities of ichthyosis vulgaris. In the
mouse model the response is mixed Th1/Th2.
biological_processes:
- preferred_term: type 2 immune response
term:
id: GO:0042092
label: type 2 immune response
modifier: INCREASED
- preferred_term: isotype switching to IgE isotypes
term:
id: GO:0048289
label: isotype switching to IgE isotypes
modifier: INCREASED
evidence:
- reference: PMID:19349982
reference_title: "A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In marked contrast, percutaneous allergen exposure in ft/ft mice generated OVA-specific IgG and OVA-specific IgE"
explanation: Allergen-specific IgE after cutaneous exposure in Flg-mutant mice.
- reference: PMID:21377035
reference_title: "Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease."
explanation: Human IgE-mediated sensitization associated with FLG null alleles.
downstream:
- target: Atopic dermatitis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Asthma
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Allergic rhinitis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Peanut allergy
causal_link_type: DIRECT
phenotypes:
- name: Dry skin
category: Dermatologic
description: >-
Xerosis, intermittent or persistent, more severe in winter and in dry
climates.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Xerosis
term:
id: HP:0000958
label: Dry skin
temporality: CHRONIC
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Ichthyosis vulgaris is caused by loss-of-function mutations in the filaggrin gene (FLG) and is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders."
explanation: Xerosis is a defining clinical feature.
- reference: PMID:29050444
reference_title: "Treatment of ichthyosis vulgaris with a urea-based emulsion: videodermatoscopy and confocal microscopy evaluation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ichthyosis vulgaris is a common disorder of keratinization caused by mutations in the filaggrin gene and clinically characterized by variable degree of xerosis."
explanation: Xerosis is the core clinical sign, of variable degree.
- name: Fine scaling of the skin
category: Dermatologic
description: >-
Fine, powdery and sometimes coarse polygonal scale on the extensor surfaces
of the limbs (lower legs especially in adults), scalp, central face and
trunk, with sparing of the more hydrated axillae and antecubital and
popliteal fossae.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Fine scaling of the skin
term:
id: HP:0040189
label: Scaling skin
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Individuals intermittently or persistently suffer from xerosis, which manifests itself as fine (powdery) and sometimes even coarse (polygonal) scaling of the extensor surfaces of the extremities, the scalp, central part of the face and the trunk"
explanation: Describes the scale type and distribution.
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "The extensor surfaces of the lower limbs are more often affected in adults than in children,58 while the more hydrated axillae, antecubital and popliteal fossae are rarely involved."
explanation: Flexural sparing and lower-limb predominance in adults.
- reference: PMID:16810297
reference_title: "Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris."
explanation: Fine scale on the limbs is a main characteristic.
- name: Keratosis pilaris
category: Dermatologic
description: >-
Keratotic papules at follicular orifices. Frequency follows FLG gene dose;
FLG mutations account for only a minority of keratosis pilaris overall.
frequency: FREQUENT
phenotype_term:
preferred_term: Keratosis pilaris
term:
id: HP:0032152
label: Keratosis pilaris
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Keratosis pilaris was noted in 100%, 66% and 30%, respectively, of homozygous, heterozygous and wild-type juvenile FLG mutation carriers."
explanation: Gene-dose frequency of keratosis pilaris.
- reference: PMID:25660180
reference_title: "Sebaceous gland, hair shaft, and epidermal barrier abnormalities in keratosis pilaris with and without filaggrin deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thirty-five percent of KP patients displayed filaggrin mutations, demonstrating that filaggrin mutations only partially account for the KP phenotype."
explanation: Keratosis pilaris is associated with, but not specific to, FLG mutations.
- name: Palmar hyperlinearity
category: Dermatologic
description: >-
Exaggerated palmar (and plantar) skin markings. It is the most useful
clinical sign of FLG heterozygosity, but as a screening test its presence
is only moderately predictive of an FLG null genotype, while its absence
largely excludes one.
frequency: FREQUENT
phenotype_term:
preferred_term: Palmar hyperlinearity
term:
id: HP:0033252
label: Palmar hyperlinearity
evidence:
- reference: PMID:16810297
reference_title: "Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity"
explanation: Palmar hyperlinearity identifies FLG heterozygotes.
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Palmar and plantar hyperlinearity, defined as exaggerated skin markings (dermatoglyphics), and keratosis pilaris, defined by keratotic elevations around hair follicle orifices, are frequently observed in individuals with IV"
explanation: Palmar and plantar hyperlinearity are frequent in ichthyosis vulgaris.
- reference: PMID:34608691
reference_title: "Clinical examination for hyperlinear palms to determine filaggrin genotype: A diagnostic test accuracy study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The presence of HLP is not a reliable sign to detect FLG mutations, but the absence of HLP excludes FLG null genotype with a reasonable degree of certainty."
explanation: Diagnostic accuracy of hyperlinear palms for FLG genotype in 3656 children.
- name: Pruritus
category: Dermatologic
description: Itch accompanies the dry, scaling skin.
phenotype_term:
preferred_term: Pruritus
term:
id: HP:0000989
label: Pruritus
evidence:
- reference: PMID:35663767
reference_title: "Effect of topical treatment with 7.5% urea in Ichthyosis Vulgaris: A randomized, controlled, double blinded, split body study evaluating the effect of urea cream compared to the vehicle (moisturizing) cream."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ichthyosis Vulgaris (IV) is a common genetic skin disease, characterized by dry, scaling skin and itch."
explanation: Itch is part of the clinical picture.
- name: Atopic dermatitis
category: Immunologic
description: >-
Roughly 37 to 50% of people with ichthyosis vulgaris have atopic eczema.
FLG null alleles are the strongest known genetic risk factor for atopic
dermatitis, with several-fold risk in heterozygotes and very high risk in
homozygotes; not every biallelic carrier develops it.
frequency: FREQUENT
phenotype_term:
preferred_term: Atopic dermatitis
term:
id: HP:0001047
label: Atopic dermatitis
evidence:
- reference: PMID:36159354
reference_title: "A Case of Ichthyosis Vulgaris and the Use of 70% Glycolic Acid Chemical Peels for Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Approximately 37-50% of people affected have associated atopic eczema and a similar proportion have atopic relatives."
explanation: Frequency of atopic eczema among people with ichthyosis vulgaris, stated as background in a case report.
- reference: PMID:17417636
reference_title: "Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136))"
explanation: Gene-dose risk of moderate-to-severe childhood eczema in FLG null carriers.
- reference: PMID:16550169
reference_title: "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This work establishes a key role for impaired skin barrier function"
explanation: Places the filaggrin barrier defect upstream of atopic dermatitis.
- reference: PMID:27519469
reference_title: "Compound heterozygotes for filaggrin gene mutations do not always show severe atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results suggest that individuals with bi-allelic FLG mutations do not always have severe AD and confirm that not all individuals with bi-allelic FLG mutations have AD."
explanation: Atopic dermatitis is not an obligate consequence even of biallelic FLG loss.
- name: Asthma
category: Respiratory
description: >-
FLG null alleles raise the risk of asthma, but the association is with
asthma in the context of eczema rather than asthma alone.
phenotype_term:
preferred_term: Asthma
term:
id: HP:0002099
label: Asthma
evidence:
- reference: PMID:19501237
reference_title: "Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FLG mutations are also significantly associated with asthma (OR, 1.48; 95% CI, 1.32-1.66). However, although strong effects for the compound phenotype asthma plus eczema (OR, 3.29; 95% CI, 2.84-3.82) were observed, there appears to be no association with asthma in the absence of eczema."
explanation: Meta-analysis quantifying asthma risk and its dependence on eczema.
- name: Allergic rhinitis
category: Respiratory
description: Allergic rhinitis (hay fever) is part of the associated atopic diathesis.
phenotype_term:
preferred_term: Allergic rhinitis
term:
id: HP:0003193
label: Allergic rhinitis
evidence:
- reference: PMID:22158554
reference_title: "One remarkable molecule: filaggrin."
supports: SUPPORT
evidence_source: OTHER
snippet: "Subsequent investigations of the role of FLG-null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis, and peanut allergy."
explanation: Review summarizing the association of FLG null alleles with allergic rhinitis.
- reference: PMID:36751330
reference_title: "Ichthyosis vulgaris: An updated review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Ichthyosis vulgaris has a strong association with atopic disorders such as atopic dermatitis, allergic rhinitis (hay fever), and asthma."
explanation: Review lists allergic rhinitis among the associated atopic disorders.
- name: Peanut allergy
category: Immunologic
description: >-
FLG null alleles are a risk factor for IgE-mediated peanut allergy,
independently of coexisting atopic dermatitis.
phenotype_term:
preferred_term: Peanut allergy
term:
id: HP:0500093
label: Food allergy
evidence:
- reference: PMID:21377035
reference_title: "Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge-positive patients (P = 3.0 × 10(-6); odds ratio, 5.3; 95% CI, 2.8-10.2)"
explanation: Case-control association of FLG null alleles with challenge-proven peanut allergy.
- reference: PMID:21377035
reference_title: "Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis."
explanation: The association is not solely mediated through eczema.
- name: Contact dermatitis
category: Dermatologic
description: >-
FLG mutation carriers have more hand eczema, irritant contact dermatitis and
nickel sensitization; hand eczema in carriers has a dorsal distribution with
palmar hyperlinearity and fissures, and FLG null alleles are associated
with persistent rather than incident hand eczema.
phenotype_term:
preferred_term: Irritant contact dermatitis and hand eczema
term:
id: HP:0032282
label: Contact dermatitis
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "epidemiological studies have found higher levels of hand eczema, irritant contact dermatitis, nickel sensitization and serum vitamin D levels"
explanation: Epidemiological association of FLG mutations with irritant contact dermatitis and hand eczema.
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand eczema in FLG mutation carriers displays a distinct phenotype characterized by its dorsal localization, palmar hyperlinearity and skin fissures."
explanation: Describes the hand eczema phenotype in carriers.
- reference: PMID:26872425
reference_title: "Predictive factors of self-reported hand eczema in adult Danes: a population-based cohort study with 5-year follow-up."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "While filaggrin gene (FLG) null mutations were not associated with incident hand eczema, a statistically significant association was observed with persistent hand eczema (OR 3·1, 95% CI 1·8-5·2)."
explanation: Population cohort association of FLG null alleles with persistent hand eczema.
histopathology:
- name: Reduced or absent granular layer
description: >-
The granular layer is thin or absent, with reduced or absent keratohyalin
granules on electron microscopy in proportion to filaggrin loss and clinical
severity, beneath mild hyperkeratosis. An absent or reduced granular layer
helps separate ichthyosis vulgaris from other non-syndromic ichthyoses,
although acquired ichthyosis shows similar histology.
diagnostic: true
evidence:
- reference: PMID:2579164
reference_title: "Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Electron microscopic studies showed that keratohyaline granules were absent in 3 severely affected individuals, and reduced in number in the others."
explanation: Ultrastructural hallmark of ichthyosis vulgaris.
- reference: PMID:38841231
reference_title: "Clinico-Epidemiologic Profile of Non-Syndromic Congenital Ichthyosis - A Retrospective Chart Review of 107 Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "histological differences including an absent or reduced granular layer in ichthyosis vulgaris can help differentiate among the clinical phenotypes of inherited non-syndromic ichthyosis"
explanation: Diagnostic value of the granular-layer finding among inherited ichthyoses.
- reference: PMID:36159354
reference_title: "A Case of Ichthyosis Vulgaris and the Use of 70% Glycolic Acid Chemical Peels for Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of ichthyosis vulgaris was confirmed by histopathological findings of hyperkeratosis and an absent granular layer."
explanation: Case in which the histologic pattern confirmed the diagnosis.
diagnosis:
- name: Clinical evaluation with histology and FLG genotyping
description: >-
Diagnosis is usually clinical, from xerosis, fine extensor scaling with
flexural sparing, keratosis pilaris, palmar hyperlinearity, atopy and family
history. Histology, electron microscopy and molecular testing of FLG
confirm it; screening panels must include population-specific alleles.
evidence:
- reference: PMID:32115871
reference_title: "Ichthyoses in everyday practice: management of a rare group of diseases."
supports: SUPPORT
evidence_source: OTHER
snippet: "The diagnosis is usually based on clinical evaluation. Molecular genetic testing as well as histological and electron microscopic studies may aid in confirming the diagnosis."
explanation: Review statement of the diagnostic approach to the ichthyoses, including ichthyosis vulgaris.
differential_diagnoses:
- name: X-linked ichthyosis
disease_term:
preferred_term: X-linked ichthyosis
term:
id: MONDO:0010622
label: recessive X-linked ichthyosis
description: >-
The other common hereditary ichthyosis, also presenting in the first year
of life; caused by steroid sulfatase (STS) deficiency and inherited as an
X-linked recessive trait.
distinguishing_features:
- X-linked inheritance affecting males, with STS deletion or steroid sulfatase deficiency.
- Ichthyosis vulgaris shows a reduced or absent granular layer and FLG null alleles.
evidence:
- reference: PMID:36159354
reference_title: "A Case of Ichthyosis Vulgaris and the Use of 70% Glycolic Acid Chemical Peels for Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the differential diagnoses of X-linked recessive ichthyosis, pityriasis rubra pilaris, and xerotic dermatitis were entertained"
explanation: Lists X-linked recessive ichthyosis as a differential diagnosis.
- name: Acquired ichthyosis
disease_term:
preferred_term: acquired ichthyosis
term:
id: MONDO:0018683
label: acquired ichthyosis
description: >-
Scaling resembling ichthyosis vulgaris but with no family history of
ichthyosis or atopy, often transient, and sometimes a sign of malignancy,
autoimmune or metabolic disease, or a drug effect.
distinguishing_features:
- Absence of a family history of ichthyosis or atopic disease.
- Adult onset in association with an underlying condition or medication.
evidence:
- reference: PMID:36165597
reference_title: "Acquired ichthyosis, asteatotic dermatitis or xerosis? An update on pathoetiology and drug-induced associations."
supports: SUPPORT
evidence_source: OTHER
snippet: "Acquired ichthyosis (AI) is a relatively rare cutaneous entity characterized by transient, generalized scaling and pruritus in the absence of family history of ichthyosis or atopic disease."
explanation: Defines the distinguishing clinical context of acquired ichthyosis.
- reference: PMID:36165597
reference_title: "Acquired ichthyosis, asteatotic dermatitis or xerosis? An update on pathoetiology and drug-induced associations."
supports: SUPPORT
evidence_source: OTHER
snippet: "Histopathology of AI is similar to that found in IV."
explanation: Histology does not separate acquired from hereditary ichthyosis vulgaris.
genetic:
- name: FLG
gene_term:
preferred_term: FLG
term:
id: hgnc:3748
label: FLG
association: Causative
relationship_type: CAUSATIVE
notes: >-
Common European alleles are R501X and 2282del4, carried on conserved
ancestral haplotypes; Asian populations carry largely different alleles,
and FLG null alleles are less often found in African American patients.
No ClinGen gene-disease validity record for FLG and ichthyosis vulgaris is
cached in this repository, so no validity tier is recorded. A proportion of
clinically diagnosed ichthyosis vulgaris, especially with atopic dermatitis,
carries no detectable FLG mutation.
case_fractions:
- population: Chinese isolated ichthyosis vulgaris
case_fraction_percent: 74.0
notes: >-
Full FLG sequencing; 43% in ichthyosis vulgaris associated with atopic
dermatitis in the same study.
evidence:
- reference: PMID:23290076
reference_title: "Analyses of FLG mutation frequency and filaggrin expression in isolated ichthyosis vulgaris (IV) and atopic dermatitis-associated IV."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The percentage of mutations in the FLG gene was 74% and 43% in patients with isolated IV and patients with AD-associated IV, respectively."
explanation: FLG mutation yield in isolated and AD-associated ichthyosis vulgaris.
- population: Austrian patients with marked generalized scaling
case_fraction_percent: 71.4
cohort_size: 21
notes: 15 of 21 patients carried p.R501X or c.2282del4, the only alleles screened.
evidence:
- reference: PMID:17164798
reference_title: "Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report the presence of FLG mutations in 15 out of 21 IV patients with a marked generalized scaling phenotype"
explanation: Mutation yield for the two common European alleles.
evidence:
- reference: PMID:16444271
reference_title: "Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds."
explanation: Original identification of FLG as the ichthyosis vulgaris gene.
- reference: PMID:17417636
reference_title: "Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show here that these common European mutations are ancestral variants carried on conserved haplotypes."
explanation: Common European alleles are ancestral.
- reference: PMID:19958351
reference_title: "FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Notably, the same FLG mutations identified in the European population were rarely found in Asians."
explanation: Population-specific mutation spectra.
- reference: PMID:24920311
reference_title: "Filaggrin gene mutations in African Americans with both ichthyosis vulgaris and atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the African American children with both AD and IV, 22.2% were heterozygous for filaggrin null mutations."
explanation: Lower FLG mutation yield in African American patients.
- name: STS
gene_term:
preferred_term: STS
term:
id: hgnc:11425
label: STS
association: Phenotype modifier
relationship_type: MODIFIER
notes: >-
Reported in a single Chinese family: carriers of both an STS deletion and
FLG c.3321delA had more severe ichthyosis than relatives carrying the FLG
variant alone. STS deficiency on its own causes X-linked ichthyosis.
evidence:
- reference: PMID:30021537
reference_title: "Exacerbation of ichthyosis vulgaris phenotype by co-inheritance of STS and FLG mutations in a Chinese family with ichthyosis: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients carried both mutations presented more severe symptom, while those only carried FLG c.3321delA mutation showed slight or normal phenotype."
explanation: Co-inheritance of an STS deletion worsened the FLG-related phenotype in one family.
environmental:
- name: Low ambient humidity and cold season
description: >-
Dry air in winter aggravates ichthyosis vulgaris, and most patients improve
in summer or humid climates. Low humidity is thought to accelerate breakdown
of residual filaggrin in heterozygous carriers.
exposure_term:
preferred_term: low ambient humidity
term:
id: ECTO:0010007
label: exposure to humidity
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Skin symptoms improve as environmental humidity increases; in fact, 80% of patients with IV report improvement during the summer."
explanation: Seasonal and humidity dependence of symptoms.
influences_mechanisms:
- target: Reduced Stratum Corneum Hydration
environmental_effect: EXACERBATES
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Low humidity drives deimination and breakdown of filaggrin; in patients
with little residual filaggrin this is proposed to deepen the hydration
deficit. In reconstructed epidermis with normal filaggrin, dry conditions
instead raised NMF, so the worsening in patients is inferred rather than
directly measured.
evidence:
- reference: PMID:23301728
reference_title: "Ichthyosis vulgaris: the filaggrin mutation disease."
supports: SUPPORT
evidence_source: OTHER
snippet: "Accordingly, IV is typically present, and more severe, during the winter in temperate climates when a drop in humidity may result in further hydrolysis of residual filaggrin (in heterozygous carriers) into its constituent amino acids and their deiminated carboxylic acid derivatives."
explanation: Review states the proposed mechanism by which low humidity worsens disease.
- reference: PMID:28242341
reference_title: "Lowering relative humidity level increases epidermal protein deimination and drives human filaggrin breakdown."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Partial inhibition of PADs with Cl-amidine reversed the effect of dryness on filaggrin breakdown."
explanation: Shows experimentally that dryness drives PAD-dependent filaggrin breakdown in reconstructed human epidermis.
treatments:
- name: Topical urea
description: >-
Urea-containing creams (typically 7.5 to 10%) are a long-standing first-line
keratolytic moisturizer. In a randomized split-body trial, 7.5% urea was
superior to a plain moisturizer on the more keratotic legs but not on the
arms.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: urea
term:
id: CHEBI:16199
label: urea
target_phenotypes:
- preferred_term: Fine scaling of the skin
term:
id: HP:0040189
label: Scaling skin
- preferred_term: Xerosis
term:
id: HP:0000958
label: Dry skin
target_mechanisms:
- target: Reduced Stratum Corneum Hydration
evidence:
- reference: PMID:35663767
reference_title: "Effect of topical treatment with 7.5% urea in Ichthyosis Vulgaris: A randomized, controlled, double blinded, split body study evaluating the effect of urea cream compared to the vehicle (moisturizing) cream."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "On the legs, however, the urea treated areas had a significantly higher decrease in SRRC score (0.7 points [95% CI: 1.1-0.3, p < 0.005]) and increase in hydration (32.1 μS [95% CI: 10.9-53.2, p < 0.006])."
explanation: Randomized split-body evidence for urea on the legs.
- reference: PMID:35663767
reference_title: "Effect of topical treatment with 7.5% urea in Ichthyosis Vulgaris: A randomized, controlled, double blinded, split body study evaluating the effect of urea cream compared to the vehicle (moisturizing) cream."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "On the arms, no significant differences between the two treatments were found."
explanation: Urea was no better than a plain moisturizer on the less keratotic arms.
- reference: PMID:29050444
reference_title: "Treatment of ichthyosis vulgaris with a urea-based emulsion: videodermatoscopy and confocal microscopy evaluation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At the end of treatment the tested urea-based emulsion resulted in a significant clinical improvement of xerosis in all patients."
explanation: Small open series with a 10% urea, ceramide and NMF emulsion.
- name: Regular emollient therapy
description: >-
Regular moisturizers improve dryness and reduce transepidermal water loss,
with the largest effect in biallelic FLG carriers, but do not normalize the
epidermal gene expression profile. Rigorous hydration of the skin several
times a day is the mainstay of ichthyosis care.
therapeutic_modality: OTHER
treatment_term:
preferred_term: supportive care with emollients
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Xerosis
term:
id: HP:0000958
label: Dry skin
target_mechanisms:
- target: Stratum Corneum Permeability Barrier Failure
evidence:
- reference: PMID:24330146
reference_title: "Moisturizing treatment of patients with atopic dermatitis and ichthyosis vulgaris improves dry skin, but has a modest effect on gene expression regardless of FLG genotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Moisturizing treatment improves dry skin and certain aspects of abnormal skin barrier function, especially in patients with AD/IV and dual FLG mutations, but does not normalize the epidermal gene expression profile."
explanation: Emollients improve dryness and barrier readouts, most in biallelic carriers.
- reference: PMID:35663767
reference_title: "Effect of topical treatment with 7.5% urea in Ichthyosis Vulgaris: A randomized, controlled, double blinded, split body study evaluating the effect of urea cream compared to the vehicle (moisturizing) cream."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Skin hydration improved significantly with both urea and moisturising treatment."
explanation: Plain moisturizer also improved hydration in the randomized trial.
- reference: PMID:32115871
reference_title: "Ichthyoses in everyday practice: management of a rare group of diseases."
supports: SUPPORT
evidence_source: OTHER
snippet: "Rigorous hydration of the skin (several times a day) and balneotherapy are the mainstay of ichthyosis treatment."
explanation: Review recommendation for the ichthyoses as a group, including ichthyosis vulgaris.
- name: Ammonium lactate lotion
description: >-
Ammonium lactate 12% lotion, combined with a lipid-based repair cream, is
used for scaling and dryness; lactate is a component of the natural
moisturizing factor. Support is a review-level recommendation rather than a
controlled trial in ichthyosis vulgaris.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ammonium lactate
term:
id: CHEBI:749313
label: ammonium lactate
target_phenotypes:
- preferred_term: Fine scaling of the skin
term:
id: HP:0040189
label: Scaling skin
evidence:
- reference: PMID:36751330
reference_title: "Ichthyosis vulgaris: An updated review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Urea-based creams are highly therapeutic, whereas ammonium lactate 12% lotion with a physiological lipid-based repair cream can help with scaling and dryness."
explanation: Review recommendation for ammonium lactate in ichthyosis vulgaris.
animal_models:
- name: Flaky tail mouse (Flg 5303delA homozygous)
species: Mouse
genotype: Flg ft/ft (5303delA frameshift), homozygous
description: >-
Spontaneous recessive mouse mutant lacking processed filaggrin and F-type
keratohyalin granules, with dry flaky skin, orthokeratotic hyperkeratosis
and enhanced percutaneous allergen priming.
publication: PMID:19349982
notes: >-
The flaky tail line arose on a background carrying the recessive matted
(ma) hair mutation and has been maintained on a mixed strain, so not every
phenotype of the line can be attributed to Flg alone.
modeled_mechanisms:
- target: Profilaggrin and Filaggrin Deficiency
relationship: RECAPITULATES
fidelity: MODERATE
description: ft/ft mice express an abnormal, unprocessed profilaggrin and lack filaggrin.
limitations: >-
Mouse Flg frameshift on a mixed background that also carries the matted
mutation; the mouse is homozygous, so it models biallelic rather than
heterozygous disease.
evidence:
- reference: PMID:11121144
reference_title: "Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mutant mice lacked the large, irregular F-type keratohyalin granules that contain profilaggrin, and filaggrin was absent from the cornified layers of ft/ft epidermis."
explanation: Reproduces the human filaggrin and keratohyalin deficiency.
- target: Increased Percutaneous Allergen and Irritant Penetration
relationship: RECAPITULATES
fidelity: MODERATE
description: Topical allergen produces cutaneous inflammation and allergen-specific antibodies.
limitations: >-
Ovalbumin sensitization in mice; the antibody response is mixed Th1/Th2
rather than purely type 2, and the background matted mutation is a
potential confounder.
evidence:
- reference: PMID:19349982
reference_title: "A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses."
explanation: Direct experimental test of percutaneous priming through a Flg-deficient barrier.
evidence:
- reference: PMID:19349982
reference_title: "A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft)."
explanation: Identifies the Flg frameshift in flaky tail mice.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Ichthyosis Vulgaris · 2026-09-30T20:23:26Z · View source
New entry for FLG-related ichthyosis vulgaris bound to MONDO:0007810, curated from the claimed stub (stub deleted). Subtypes Mild IV (MONDO:0100474, heterozygous FLG) and Severe IV (MONDO:0100475, biallelic FLG) follow the semidominant gene-dose model; inheritance bound to HP:0032113 Semidominant inheritance. Pathophysiology is a causal chain: FLG null variants -> profilaggrin/filaggrin deficiency -> reduced keratohyalin granules and defective corneocyte formation, and reduced natural moisturizing factor -> reduced stratum corneum hydration -> permeability barrier failure -> retention hyperkeratosis (fine scaling) and percutaneous allergen penetration -> type 2 sensitization -> atopic dermatitis, asthma, allergic rhinitis, peanut allergy. Nodes conform to epidermal_cornification_failure (four nodes) and epithelial_barrier_dysfunction (two nodes). Environmental low humidity is linked as EXACERBATES. STS recorded as a MODIFIER from a single family report. Flaky tail mouse recorded under animal_models with the matted background caveat. No ClinGen FLG validity record is cached, so no gene_disease_validity. Deep research: OpenScientist report research/Ichthyosis_Vulgaris-deep-research-openscientist.md completed; its validation sections were missing from the generated report and were retro-fitted with just validate-research-reference (32/32 references resolved, 2/2 quotes found, 0 off topic) and just validate-research-terms (1 unresolved CURIE, NCIT:C177, and several mislabelled NCIT/HP suggestions; none of the report's suggested CURIEs were used). just preflight-dr MONDO:0007810 returned PASS (FLG mentioned 74 times; OMIM 146700 matches). Report citations used: 22158554, 27519469, 30021537, 33462753, 28242341, 38841231, 34608691, 23343419, 26872425, 32115871, 36159354, 36165597, 19349982, 23301728; the rest came from PubMed searches. Kezic 2008 (PMID:18305568, NMF reduction) has no abstract in PubMed and was not cited. just check-genereviews --online reports NO_CHAPTER; only a StatPearls chapter exists. Validation: just validate, validate-terms, count-verified-snippets (97/97), check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes, snippet-length/title/grading/folded-hyphen/environmental gates and validate-disorders all pass. Pruritus remains causally unconnected because no source states its mechanism in ichthyosis vulgaris. Follow-up for scripts/check_gene_activity_grounding.py: the FLG Loss-of-Function Variants node now binds GO:1990254 keratin filament binding (modifier DECREASED, label verified in OLS), supported by PMID:27667308 and PMID:16444271 node evidence; the node description records the knockdown-model caveat (PMID:20445547) on how much lost keratin aggregation contributes to the phenotype. Snippets now 99/99 verified. Review round 1 (PR #13289): the cited references_cache/PMID_27667308.md had not been committed and is now tracked; every cited reference has a tracked cache file. quote_role BACKGROUND added to PMID:2579164 (autosomal dominant framing), PMID:16444271 (1 in 250 figure) and PMID:36159354 (37 to 50% atopic eczema); PMID:19958351, a review, is now graded OTHER with quote_role REVIEW_SYNTHESIS on all three items. Pruritus is connected from Stratum Corneum Permeability Barrier Failure, quoting the review PMID:36751330 that attributes pruritus to the disturbed skin barrier; no cached source links it to reduced hydration specifically. A clinical_burden block (LOW) cites PMID:35663767 and PMID:36751330. The keratohyalin/corneocyte node stays bundled because it mirrors the module node it conforms to. Systemic acitretin (PMID:32115871 concerns severe ichthyoses as a group) and the single-case glycolic acid peel (PMID:36159354) were not added. Snippets 102/102 verified.
Disease: Ichthyosis Vulgaris MONDO ID: MONDO:0007810 · OMIM: 146700 · Category: Mendelian (autosomal semidominant) Report type: Disease knowledge-base entry compiled from primary literature and aggregated disease-level resources
Ichthyosis vulgaris (IV) is the most common inherited disorder of keratinization in humans and is caused by loss-of-function (null) mutations in the filaggrin gene (FLG) on chromosome 1q21.3 within the epidermal differentiation complex. The disease was molecularly defined in 2006, when FLG null mutations — most notably the two European founder alleles R501X (a nonsense mutation) and 2282del4 (a frameshift) — were shown to cause IV and simultaneously to constitute the strongest known genetic risk factor for atopic dermatitis (AD). Inheritance is autosomal semidominant (hemidominant): heterozygotes have mild disease and biallelic carriers have substantially more severe disease, establishing a clear gene-dosage relationship.
Mechanistically, filaggrin (filament-aggregating protein) performs two jobs that are both lost when FLG is truncated: (1) it aggregates keratin intermediate filaments so that keratinocytes collapse into flattened corneocytes forming a competent cornified layer, and (2) after proteolysis by caspase-14, calpain-1 and bleomycin hydrolase it yields hygroscopic amino-acid metabolites — trans-urocanic acid and pyrrolidone carboxylic acid — that make up the stratum corneum's natural moisturizing factor (NMF). Loss of these functions produces the clinical picture of xerosis, fine scaling with flexural sparing, keratosis pilaris, and palmoplantar hyperlinearity, with a histologic hallmark of a reduced or absent granular layer. The very same barrier defect that scales the skin also lets allergens penetrate, mechanistically linking IV to the "atopic march" (AD → food allergy → asthma/rhinitis) and to irritant and allergic contact sensitization.
IV is a chronic, lifelong, non-life-threatening condition that typically manifests within the first year of life, tends to improve in humid climates and worsen in dry winter air, and often improves with age. There is no cure; management is entirely symptomatic — rigorous skin hydration, emollients, and keratolytics (urea, alpha/beta-hydroxy acids, salicylic/lactic acid), with systemic acitretin reserved for severe cases. The flaky-tail mouse (Flg 5303delA) is the canonical model, and filaggrin-dependent barrier biology is conserved in dogs, supporting comparative and translational study. This report synthesizes twelve confirmed findings across all 15 template sections with primary-literature citations.
Ichthyosis vulgaris is caused by loss-of-function mutations in the filaggrin gene (FLG). Two null mutations, R501X and 2282del4, were identified as causative for IV in 15 affected European families, and the mode of inheritance was determined to be semidominant (PMID: 17573887). The 2006 discovery that FLG null mutations cause IV — described as "the most common disorder of keratinization" — and are "also a strong genetic risk factor for atopic eczema" reframed both diseases as filaggrin-barrier disorders (PMID: 22158554). Key identifiers: OMIM #146700 (IV), FLG OMIM #135940 (gene), MONDO:0007810, HGNC gene symbol FLG, locus 1q21.3 (epidermal differentiation complex).
"Two loss-of-function mutations in the filaggrin (FLG) gene, R501X and 2282del4, were identified as causative for ichthyosis vulgaris in 15 affected European families, and the mode of inheritance was found to be semidominant." — PMID: 17573887
IV shows autosomal hemidominant (semidominant) inheritance, and patients carrying bi-allelic FLG mutations tend to have severe phenotypes (PMID: 27519469). In a cohort of 6 biallelic carriers, 5/6 had severe IV and 1/6 moderate IV. Disease expression is further tuned by modifier genes: co-inheritance of a steroid sulfatase (STS) deletion — the cause of X-linked ichthyosis — with an FLG mutation exacerbated the IV phenotype in a Chinese family (PMID: 30021537). This illustrates both gene-dosage effects at the FLG locus and cross-locus modification of severity.
"IV shows autosomal hemidominant (semidominant) inheritance, and patients with bi-allelic FLG mutations tend to have severe IV phenotypes." — PMID: 27519469
FLG null mutations are observed in approximately 7.7% of Europeans and 3.0% of Asians but appear infrequent in darker-skinned populations (PMID: 23301728). Several low-frequency FLG null alleles occur in Europeans and Asians with a cumulative frequency of ~9% in Europe (PMID: 19349982). Approximately 40 distinct loss-of-function FLG mutations have been identified in patients with IV and/or AD across Europe and Asia, with population-specific mutation spectra (e.g., R501X and 2282del4 dominate in Europeans, whereas different recurrent alleles predominate in Asian populations) (PMID: 21173567).
| Population | FLG null carrier frequency | Notes |
|---|---|---|
| European | ~7.7% (cumulative ~9%) | R501X, 2282del4 founder alleles |
| Asian | ~3.0% | Distinct population-specific alleles |
| Darker-skinned populations | Infrequent | Fewer recurrent LOF alleles reported |
"FLG mutations are observed in approximately 7·7% of Europeans and 3·0% of Asians, but appear to be infrequent in darker-skinned populations." — PMID: 23301728
Filaggrin aggregates keratin filaments, forming a keratin network that binds cornified envelopes and collapses keratinocytes into flattened corneocytes (PMID: 33462753). Filaggrin is then degraded by caspase-14, calpain-1, and bleomycin hydrolase into amino acids and metabolites — trans-urocanic acid and pyrrolidone carboxylic acid — that are pivotal natural moisturizing factors in the stratum corneum (PMID: 33462753). Environmental humidity modulates this: lowering relative humidity increases PAD (peptidyl-arginine deiminase)-mediated filaggrin deimination and breakdown, and partial PAD inhibition with Cl-amidine reversed the dryness effect (PMID: 28242341) — providing a molecular explanation for the characteristic winter worsening of IV.
"Filaggrin is degraded by caspase-14, calpain 1, and bleomycin hydrolases into amino acids and amino acid metabolites such as trans-urocanic acid and pyrrolidone carboxylic acid, which are pivotal natural moisturizing factors in the SC." — PMID: 33462753
IV is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders (PMID: 23301728). The scaling characteristically spares the flexures and predominates on the extensor surfaces. Histology shows an absent or reduced granular layer (hypogranulosis with retention hyperkeratosis) — a feature that helps differentiate IV among non-syndromic ichthyoses (PMID: 38841231). Palmar hyperlinearity has moderate diagnostic value for FLG genotype (sensitivity 46–72%, specificity 60–89% across pediatric cohorts; PMID: 34608691). Vitamin D deficiency is highly prevalent even in milder congenital ichthyosis phenotypes (PMID: 38841231).
Suggested HPO terms: HP:0000958 (Dry skin/xerosis), HP:0100792 (Ichthyosis/scaling), HP:0032152 (Keratosis pilaris), HP:0007598 (Palmoplantar hyperlinearity), HP:0008064 (Ichthyosis), HP:0100512 (Vitamin D deficiency). UBERON: UBERON:0002097 (skin of body), UBERON:0001003 (epidermis), UBERON:0002027 (stratum corneum region). CL: CL:0000312 (keratinocyte), CL:0002187 (basal cell of epidermis), corneocyte.
"is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders." — PMID: 23301728
FLG null mutations that cause IV are major genetic predisposing factors for atopic dermatitis and are associated with atopic asthma, allergic rhinitis, and peanut allergy (PMID: 21576945, PMID: 22158554). In the flaky-tail mouse (Flg 5303delA) and engineered FLG-deficient mice, topical allergen application produces enhanced cutaneous allergen priming and allergen-specific antibody responses (PMID: 19349982), directly validating the "filaggrin hypothesis" that a defective barrier permits percutaneous antigen transfer. "Reduced FLG expression compromises epidermal barrier function and is associated with atopic dermatitis, allergy, and asthma" (PMID: 33894197).
"topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses." — PMID: 19349982
Rigorous skin hydration (several times daily) and balneotherapy are the mainstay of ichthyosis treatment; systemic acitretin is reserved for severe disease on a case-by-case basis (PMID: 32115871). Ichthyoses "remain incurable" but "can be managed well with symptomatic treatment" (PMID: 32115871). Topical keratolytics (urea, alpha/beta-hydroxy acids, salicylic acid, lactic acid), retinoids and corticosteroids are used; a 70% glycolic acid chemical peel was ~90% efficacious in reducing hyperkeratinization as an adjunct (PMID: 36159354). Gene therapy for genodermatoses is emerging but current management "remains largely palliative" (PMID: 42707485).
Suggested NCIT terms: NCIT:C1516 (Emollient agent), NCIT:C29736 (Urea), NCIT:C1214 (Salicylic acid), NCIT:C1878 (Acitretin), NCIT:C177 (Retinoid).
"Rigorous hydration of the skin (several times a day) and balneotherapy are the mainstay of ichthyosis treatment." — PMID: 32115871
Diagnosis is usually based on clinical evaluation, with molecular genetic testing, histology and electron microscopy aiding confirmation, and family-tree mapping being useful (PMID: 32115871). IV and X-linked ichthyosis (STS deficiency) are the two common ichthyoses, both usually manifesting in the first year of life. Differential diagnoses include X-linked recessive ichthyosis, pityriasis rubra pilaris, and xerotic/asteatotic dermatitis (PMID: 36159354). Acquired ichthyosis is histologically similar to IV but lacks a family/atopy history and may signal underlying malignancy or metabolic disease (PMID: 36165597). Upfront whole-genome sequencing is increasingly used for primary atopic/barrier disorders (PMID: 39381601).
"The diagnosis is usually based on clinical evaluation. Molecular genetic testing as well as histological and electron microscopic studies may aid in confirming the diagnosis." — PMID: 32115871
Common hereditary ichthyoses (IV and X-linked) usually manifest within the first year of life (PMID: 32115871). In a survey of 222 adults with congenital ichthyosis (IV n=86), the ichthyoses had a lifelong impact on quality of life (PMID: 42001132). Across pediatric chronic skin disorders including congenital ichthyosis, elevated rates of anxiety, depression, stigma and emotional distress were consistently reported, affecting emotional functioning, peer relationships, school participation and sleep (PMID: 42490938). Approximately 37–50% of IV patients have associated atopic eczema (PMID: 36159354).
"the ichthyoses have a lifelong impact on quality of life." — PMID: 42001132
The spontaneous flaky-tail mouse carries a Flg 1-bp deletion (5303delA) analogous to human FLG mutations and is a validated model of filaggrin deficiency, showing a barrier defect and enhanced percutaneous allergen priming (PMID: 19349982). Engineered FLG-deficient mice show a low threshold for cutaneous allergen sensitization but no spontaneous dermatitis or atopy (PMID: 33894197) — capturing the barrier/sensitization axis but not spontaneous inflammation. In dogs, filaggrin and filaggrin-2 expression is reduced in atopic versus healthy skin (PMID: 40042058), indicating conserved filaggrin-dependent barrier biology across mammals.
Suggested NCBI Taxon terms: Mus musculus (10090), Canis lupus familiaris (9615). Orthologous gene: mouse Flg.
"we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft)." — PMID: 19349982
Heterozygous FLG carriers have increased risk of atopic, irritant, and allergic (nickel) dermatitis. Critically, among individuals with dermatitis and frequent hand eczema, FLG mutations were strongly associated with contact sensitization to allergens other than nickel (OR 5.71, 95% CI 1.31–24.94), but no association was found in participants without dermatitis (PMID: 23343419). R501X was significantly associated with polysensitivity (≥3 contact allergies) (PMID: 30868611), and FLG null mutations were associated with persistent hand eczema (OR 3.1, 95% CI 1.8–5.2) (PMID: 26872425). The FLG risk is thus conditional on inflammation/exposure — the defining signature of a gene–environment interaction.
"In participants without dermatitis, no association was found between contact sensitization and FLG mutations." — PMID: 23343419
FLG and other skin-barrier gene mutations, together with Langerhans cells, type-2 innate lymphoid cells (ILC2s), IL-33 and TSLP, have important roles in allergic sensitization through the skin, supporting the dual-allergen-exposure hypothesis — epicutaneous allergen exposure drives food allergy while oral exposure promotes tolerance (PMID: 32249942). The atopic march is proposed to reflect an epithelial barrier defect self-sustained by secondary allergenic sensitization, explaining progression from AD to allergic asthma; early emollient therapy is proposed to prevent AD in high-risk children (PMID: 29676818).
"the atopic march could correspond to an epithelial dysfunction, self-sustained by a secondary allergenic sensitization, explaining the transition from AD to allergic asthma." — PMID: 29676818
IV is the most common inherited disorder of keratinization, a scaly-skin disease presenting as generalized dryness and fine, flaky scaling that spares the flexures. Identifiers: MONDO:0007810; OMIM #146700; ORPHA:454 (ichthyosis vulgaris); ICD-10 Q80.0; ICD-11 EC20.0; MeSH D016112 (Ichthyosis Vulgaris); gene FLG (OMIM #135940, HGNC:3748). Synonyms: ichthyosis simplex, filaggrin-deficiency ichthyosis, autosomal-dominant ichthyosis vulgaris, "fish-scale disease" (common). Information here is derived predominantly from aggregated disease-level resources (OMIM, Orphanet) and cohort/case-series primary literature rather than patient-level EHR data.
Primary cause: monogenic/genetic — loss-of-function FLG null mutations (Findings 1–3). Genetic risk factors: heterozygous or biallelic FLG null alleles (R501X, 2282del4 in Europeans; ~40 population-specific LOF alleles overall). Modifier genes: STS (steroid sulfatase) deletion co-inheritance worsens phenotype (Finding 2). Environmental risk factors: low ambient humidity / dry cold climate exacerbates disease via enhanced filaggrin deimination and breakdown (Finding 4); irritant and allergen exposures precipitate dermatitis in carriers (Finding 11). Protective factors: humid, warm environments reduce scaling; regular emollient use restores barrier function (supportive, Findings 7, 12). No specific protective genetic allele is established. Gene–environment interaction: FLG-conferred sensitization risk is conditional on skin inflammation/exposure (Finding 11); epicutaneous allergen exposure through a barrier-defective epidermis drives sensitization whereas oral exposure promotes tolerance (Finding 12).
| Phenotype | Type | Onset | Severity/Frequency | HPO |
|---|---|---|---|---|
| Xerosis (dry skin) | Physical sign | Infancy/childhood | Near-universal; variable | HP:0000958 |
| Fine scaling, flexural sparing | Physical sign | First year of life | Core feature | HP:0008064 / HP:0100792 |
| Keratosis pilaris | Physical sign | Childhood | Common | HP:0032152 |
| Palmar/plantar hyperlinearity | Physical sign | Childhood | Sens 46–72% for FLG | HP:0007598 |
| Reduced/absent granular layer | Lab/histology | Congenital | Diagnostic hallmark | — |
| Associated atopic eczema | Clinical | Childhood | ~37–50% | HP:0000964 |
| Vitamin D deficiency | Lab abnormality | Any | Highly prevalent | HP:0100512 |
Onset is typically within the first year of life (Finding 9); severity ranges mild→severe scaling with biallelic carriers more severe (Finding 2); course is chronic, often improving with age and in humid climates, worsening in winter (Finding 4). Quality-of-life impact: lifelong QoL burden with elevated anxiety, depression, stigma, and sleep/school disruption (Finding 9).
Causal gene: FLG (filaggrin), 1q21.3, epidermal differentiation complex; OMIM #135940; HGNC:3748. Variant types: predominantly nonsense (R501X) and frameshift (2282del4) truncating mutations; ~40 distinct LOF alleles reported (Finding 3). Classification: R501X and 2282del4 are established pathogenic per ACMG (null variants in a gene where LOF is the mechanism). Allele frequency: cumulative ~9% in Europe; carrier ~7.7% Europeans, ~3.0% Asians (Finding 3). Origin: germline. Functional consequence: loss of function with a semidominant gene-dosage effect (Findings 1–2). Modifier genes: STS (Finding 2). Epigenetics: nanopore sequencing has enabled allelic phasing and methylation profiling of FLG in IV/AD (PMID: 38336337); disease-specific methylation signatures are not established. Chromosomal abnormalities: not a feature of isolated IV (STS deletion is relevant only as a co-inherited modifier).
Environmental factors: low relative humidity increases filaggrin deimination/breakdown and lowers stratum corneum pH, worsening the barrier (Finding 4). Lifestyle: frequent long hot baths, harsh soaps, and low-humidity heating aggravate xerosis; occupational wet-work/irritant exposure precipitates hand eczema in FLG carriers (Finding 11). Infectious agents: none cause IV; however, barrier breakdown predisposes to secondary skin infection and colonization (general principle). IV is not an infectious disease.
Ordered causal chain (initiating lesion → clinical manifestation):
Molecular pathways / processes: epidermal terminal differentiation and cornification; keratin filament aggregation; NMF biogenesis; Th2 allergic sensitization (IL-33/TSLP/ILC2). Enzymes: caspase-14, calpain-1, bleomycin hydrolase (filaggrin catabolism); PAD1/PAD (deimination). Suggested GO terms: GO:0031424 (keratinization), GO:0018149 (peptide cross-linking), GO:0008544 (epidermis development), GO:0030216 (keratinocyte differentiation). Suggested CL terms: CL:0000312 (keratinocyte), corneocyte, CL:0000453 (Langerhans cell). Subcellular: keratohyalin granules (their loss is the histologic "reduced granular layer"); cytoskeleton (keratin intermediate filaments). Transcriptomics: RNA-seq of nonlesional skin shows modest differential expression in IV relative to healthy donors, far fewer changes than in AD, and xenobiotic/lipid-metabolism gene upregulation is AD-specific, not seen in IV (PMID: 28899689) — indicating IV is a barrier-structural disease without the prominent inflammatory transcriptome of AD.
Primary organ: skin (UBERON:0002097), specifically the epidermis (UBERON:0001003) and stratum corneum (UBERON:0002027). Tissue: keratinizing stratified squamous epithelium. Cells: keratinocytes/corneocytes (CL:0000312); the granular layer is deficient. Subcellular: keratohyalin granules (GO cellular component: cornified envelope; keratin filament). Localization: generalized, extensor-predominant with flexural sparing; palms and soles show hyperlinearity; bilateral and symmetric distribution. Secondary involvement: eyes/systemic atopy via the atopic march (asthma — respiratory system; allergic rhinitis).
Onset: congenital/infantile — usually within the first year of life (Finding 9); insidious/chronic onset. Progression: generally stable to slowly improving with age; fluctuating/episodic with seasonal (winter) worsening (Finding 4). Duration: chronic, lifelong (Finding 9). Remission: no true remission; symptomatic improvement with emollients and in humid conditions. Critical period: infancy/early childhood is the window during which barrier-directed emollient therapy may modify atopic-march trajectory (Finding 12).
Inheritance: autosomal semidominant (hemidominant) — heterozygotes mild, biallelic carriers severe (Findings 1–2). Penetrance: incomplete/variable; expressivity: variable and gene-dosage dependent. Epidemiology: among the most common genetic skin disorders; population carrier frequencies ~7.7% (European) and ~3.0% (Asian) for FLG null alleles (Finding 3); commonly cited clinical IV prevalence estimates range roughly 1 in 80 to 1 in 250 in populations of European descent (from aggregated resources; exact figure varies by ascertainment). Founder effects: R501X and 2282del4 are European founder alleles; distinct recurrent alleles in Asian populations (Finding 3). Affected populations: higher in European and Asian ancestry, infrequent in darker-skinned populations. Sex ratio: approximately equal (autosomal). Consanguinity: increases likelihood of biallelic (severe) disease.
Diagnosis is clinical, supported by histopathology (hyperkeratosis with reduced/absent granular layer), electron microscopy, and molecular FLG genotyping (Finding 8). Genetic testing: targeted FLG single-gene/panel testing; WES/WGS increasingly used upfront for primary atopic/barrier disorders (PMID: 39381601); nanopore sequencing resolves FLG allelic phasing, intragenic CNVs, and methylation (PMID: 38336337). Biomarker: reduced stratum-corneum NMF; palmar hyperlinearity as a clinical proxy for FLG genotype (Finding 5). Differential diagnosis: X-linked recessive ichthyosis (STS deficiency), pityriasis rubra pilaris, acquired ichthyosis, asteatotic/xerotic dermatitis (Finding 8). Screening: cascade family testing feasible; no routine population newborn screening.
IV is non-life-threatening with normal life expectancy; there is no disease-specific mortality. Morbidity is driven by chronic xerosis/scaling, pruritus, keratosis pilaris, secondary atopic disease, and psychosocial burden (Finding 9). Complications: atopic dermatitis (~37–50%), asthma/rhinitis/food allergy via the atopic march, persistent hand eczema and contact sensitization in carriers (Findings 6, 11, 12), and secondary skin infection. Prognostic factors: genotype (biallelic → more severe), ancestry, and environmental humidity. Recovery: symptoms are controllable but not curable; often milder in adulthood.
Pharmacotherapy / supportive: emollients and rigorous hydration (first-line), keratolytics (urea, alpha/beta-hydroxy acids, lactic/salicylic acid), topical retinoids/corticosteroids, and systemic acitretin for severe disease (Finding 7). Adjunctive 70% glycolic acid peel (~90% efficacy for hyperkeratosis; Finding 7). Barrier-repair ceramide/NMF-replenishing moisturizers target the specific molecular deficit (PMID: 23757122). Advanced/experimental: gene therapy for genodermatoses is in development but management remains largely palliative (PMID: 42707485). Personalized/preventive: early emollient therapy in high-risk infants may attenuate the atopic march (Finding 12). NCIT: emollient (C1516), urea (C29736), salicylic acid (C1214), acitretin (C1878).
No primary prevention of IV exists (monogenic). Secondary/tertiary prevention focuses on barrier maintenance: consistent emollient use, humidification, avoidance of harsh soaps/irritants, and — in FLG carriers — occupational skin protection to prevent hand eczema (Finding 11). Early-life emollient therapy is a proposed strategy to prevent AD and interrupt the atopic march in high-risk children (Finding 12). Genetic counseling and reproductive options are relevant for families, especially with biallelic/severe disease (PMID: 42272196). Prenatal/preimplantation testing is feasible where a familial FLG genotype is known.
Filaggrin-dependent barrier biology is conserved in mammals. In dogs (Canis lupus familiaris, NCBI Taxon 9615), filaggrin and filaggrin-2 expression is reduced in atopic skin (PMID: 40042058; PMID: 39811760), making canine atopic dermatitis a natural comparative model of filaggrin barrier dysfunction. No IV-equivalent scaling disease with an FLG null etiology is canonically catalogued in companion animals, but the conserved barrier mechanism is of veterinary relevance. Zoonotic potential: none (non-infectious).
Mouse (Mus musculus, NCBI Taxon 10090): the spontaneous flaky-tail mutant carries Flg 5303delA, analogous to human FLG mutations, and recapitulates barrier defect + enhanced percutaneous allergen priming (PMID: 19349982). Engineered FLG-deficient mice show a low threshold for cutaneous allergen sensitization but no spontaneous dermatitis/atopy (PMID: 33894197) — a key limitation (models the barrier/sensitization axis, not spontaneous inflammation). In vitro: canine primary epidermal organoids and reconstructed epidermis reproduce barrier defects after proinflammatory/allergic cytokine exposure (PMID: 41260506; PMID: 39811760). Applications: studying barrier physiology, allergen penetration, atopic-march initiation, and candidate therapeutics. Resources: MGI (mouse Flg).
FLG null mutation (R501X / 2282del4; 1q21.3)
│ (loss of function; semidominant, gene-dosage)
▼
↓ / absent filaggrin protein in stratum granulosum
│
┌──────────┴───────────────────────────┐
▼ ▼
Failed keratin-filament No filaggrin proteolysis
aggregation (caspase-14, calpain-1,
→ defective corneocytes / bleomycin hydrolase)
reduced granular layer → loss of NMF (trans-UCA, PCA)
│ │
└──────────────┬─────────────────────────┘
▼
Impaired stratum-corneum barrier + ↓ hydration
│
┌────────────┼──────────────────────────┐
▼ ▼ ▼
XEROSIS, Winter worsening Percutaneous
SCALING, (low humidity → allergen entry
KERATOSIS ↑PAD deimination, → Langerhans/ILC2,
PILARIS, ↓SC pH) IL-33/TSLP, Th2
PALMAR │
HYPERLINE- ▼
ARITY ATOPIC MARCH: AD →
(IV phenotype) food allergy, asthma,
rhinitis; contact
sensitization*
*conditional on inflammation/exposure
The unifying interpretation is that a single structural deficiency — loss of filaggrin — produces two coupled outputs: (1) a structural/hydration failure that generates the visible IV phenotype, and (2) a permeability failure that opens an epicutaneous route for allergic sensitization. The first output is constitutive; the second is conditional, requiring environmental allergen/irritant exposure and inflammation (Findings 11–12). This explains why IV and atopic disease co-segregate yet are dissociable, why biallelic carriers are more severely affected (dose-dependent protein loss, Finding 2), and why the disease fluctuates with ambient humidity (Finding 4). Therapeutically, it explains why barrier restoration (emollients, NMF/ceramide replacement, keratolysis) is both the mainstay symptomatic treatment and a rational preventive strategy against the atopic march.
| PMID | Finding(s) supported | Contribution |
|---|---|---|
| 17573887 | F1, F2 | R501X/2282del4 causal; semidominant inheritance |
| 22158554 | F1, F6 | FLG LOF causes IV, "most common disorder of keratinization" |
| 27519469 | F2 | Biallelic FLG → severe IV; gene dosage |
| 30021537 | F2 | STS modifier exacerbates IV |
| 23301728 | F3, F5 | Ancestry-specific FLG frequencies; core clinical features |
| 19349982 | F3, F6, F10 | European cumulative freq ~9%; flaky-tail mouse; allergen priming |
| 21173567 | F3 | ~40 population-specific LOF alleles |
| 33462753 | F4 | Filaggrin keratin aggregation + NMF catabolism enzymes |
| 28242341 | F4 | Low humidity → filaggrin deimination/breakdown |
| 38841231 | F5 | Reduced/absent granular layer histologic hallmark |
| 34608691 | F5 | Palmar hyperlinearity diagnostic accuracy for FLG |
| 33894197 | F6, F10 | FLG loss compromises barrier; FLG-deficient mouse phenotype |
| 21576945 | F6 | Filaggrin hypothesis; AD/asthma association |
| 32115871 | F7, F8, F9 | Hydration/acitretin mainstay; clinical diagnosis; first-year onset |
| 36159354 | F7, F8, F9 | Glycolic acid peel ~90%; differentials; ~37–50% eczema |
| 42707485 | F7 | Gene therapy emerging; management "largely palliative" |
| 36165597 | F8 | Acquired ichthyosis mimics IV histologically |
| 39381601 | F8 | Upfront WGS for primary atopic/barrier disorders |
| 42001132 | F9 | Lifelong QoL impact (n=86 IV) |
| 42490938 | F9 | Psychosocial burden in pediatric skin disease |
| 40042058 | F10 | Reduced filaggrin in canine atopic skin |
| 23343419 | F11 | GxE: FLG sensitization conditional on dermatitis (OR 5.71) |
| 30868611 | F11 | R501X → polysensitivity |
| 26872425 | F11 | FLG null → persistent hand eczema (OR 3.1) |
| 32249942 | F12 | Dual-allergen hypothesis; FLG/Langerhans/ILC2/IL-33/TSLP |
| 29676818 | F12 | Atopic march = self-sustained epithelial dysfunction |
| 28899689 | §6 | IV has fewer transcriptomic changes than AD |
| 38336337 | §4, §10 | Nanopore FLG phasing/CNV/methylation |
Note on evidence quality: Causality, mechanism, and genetics are supported by strong human genetic and biochemical evidence plus mouse-model validation. Epidemiology figures are ancestry-specific and derive from carrier-frequency and cohort studies. Treatment evidence is largely observational/case-series (no cure); gene therapy is preclinical/early. One citation (PMID 33894197) was flagged as a title-based mismatch in the knowledge state but its barrier/atopy content aligns with Findings 6 and 10.
Ichthyosis vulgaris (MONDO:0007810; OMIM 146700) is the most common inherited disorder of keratinization, caused by autosomal semidominant loss-of-function (null) mutations in the filaggrin gene FLG (1q21.3; founder alleles R501X and 2282del4), with biallelic carriers showing more severe disease. Filaggrin deficiency impairs keratin-filament aggregation and abolishes filaggrin-derived natural moisturizing factor, producing xerosis, fine scaling with flexural sparing, keratosis pilaris and palmoplantar hyperlinearity (histologic hallmark: reduced/absent granular layer), while the same barrier defect drives atopic dermatitis, asthma and contact sensitization. It is a chronic, lifelong, non-life-threatening condition managed symptomatically with hydration, emollients and keratolytics (acitretin for severe cases); there is no cure.
Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 32 |
| Resolved | 32 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 2 |
| Quoted claims found in source | 2 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 32 |
| On topic | 23 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 25 |
| Resolved | 22 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 21 |
| Terms named correctly | 9 |
| Terms named as a different term | 10 |
| Terms whose name is worth a second look | 2 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0007810 (5 mentions) - the report calls it "if available"; MONDO calls it autosomal dominant ichthyosis vulgarisHP:0000958 (2 mentions) - the report calls it "Dry skin/xerosis", "Near-universal; variable"; HP calls it Dry skinHP:0100792 (2 mentions) - the report calls it "Ichthyosis/scaling"; HP calls it AcantholysisHP:0032152 (2 mentions) - the report calls it "Keratosis pilaris", "Common"; HP calls it Keratosis pilarisHP:0007598 (2 mentions) - the report calls it "Palmoplantar hyperlinearity", "Sens 46–72% for FLG"; HP calls it Bilateral single transverse palmar creasesHP:0100512 (2 mentions) - the report calls it "Vitamin D deficiency", "Highly prevalent"; HP calls it Decreased circulating vitamin D concentrationNCIT:C1516 (1 mention) - the report calls it "Emollient agent"; NCIT calls it LisofyllineNCIT:C29736 (1 mention) - the report calls it "Urea"; NCIT calls it Stress-Induced ProteinNCIT:C1214 (1 mention) - the report calls it "Salicylic acid"; NCIT calls it ResiniferatoxinNCIT:C1878 (1 mention) - the report calls it "Acitretin"; NCIT calls it Darbepoetin AlfaThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
NCIT:C177 (1 mention), reported as "Retinoid" - NCIT does not contain this termThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
UBERON:0001003 (2 mentions) - the report calls it "epidermis"; UBERON calls it skin epidermis, and lists "epidermis" among its other namesUBERON:0002027 (2 mentions) - the report calls it "stratum corneum region", "stratum corneum"; UBERON calls it stratum corneum of epidermis, and lists "stratum corneum" among its other namesThe report gives these identifiers more than one name of its own:
HP:0000958 - called "Dry skin/xerosis", "Near-universal; variable"HP:0032152 - called "Keratosis pilaris", "Common"HP:0007598 - called "Palmoplantar hyperlinearity", "Sens 46–72% for FLG"HP:0100512 - called "Vitamin D deficiency", "Highly prevalent"UBERON:0002027 - called "stratum corneum region", "stratum corneum"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.