Inherited Ichthyosis

Mendelian MONDO:0015947 Pathograph 28 Show in embeddings browser ichthyosis hereditary skin disorder

Inherited ichthyosis is a heterogeneous group of Mendelian disorders of cornification affecting most or all of the integument. The shared clinical surface is abnormal epidermal scaling and/or hyperkeratosis, but the underlying causes span defects in keratinocyte differentiation, cornified envelope formation, epidermal lipid handling, protease control, and skin barrier maintenance.

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3
Inheritance
6
Pathophys.
9
Phenotypes
28
Pathograph
12
Genes
4
Medical Actions
6
Subtypes
3
Trials
8
References
1
Deep Research
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Inheritance

3
Autosomal dominant inheritance HP:0000006
Some inherited ichthyosis subtypes, including ichthyosis vulgaris and many keratinopathic ichthyoses, follow autosomal dominant inheritance.
Autosomal dominant inheritance
Autosomal recessive inheritance HP:0000007
Several severe inherited ichthyosis groups, including autosomal recessive congenital ichthyosis and Netherton syndrome, are autosomal recessive.
Autosomal recessive inheritance
X-linked recessive inheritance HP:0001419
X-linked ichthyosis is the major X-linked inherited ichthyosis subtype.
X-linked recessive inheritance
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Subtypes

6
Ichthyosis Vulgaris MONDO:0007810
FLG hgnc:3748 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FLG (hgnc:3748). hgnc:3748 is a gene from the HUGO Gene Nomenclature Committee.
Common inherited ichthyosis characterized by generalized scaling and desquamation.
X-Linked Ichthyosis MONDO:0010622
STS hgnc:11425 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in STS (hgnc:11425). hgnc:11425 is a gene from the HUGO Gene Nomenclature Committee.
X-linked recessive inherited ichthyosis, classically associated with steroid sulfatase deficiency.
Autosomal Recessive Congenital Ichthyosis MONDO:0017265
TGM1 hgnc:11777 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TGM1 (hgnc:11777). hgnc:11777 is a gene from the HUGO Gene Nomenclature Committee. ALOX12B hgnc:430 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ALOX12B (hgnc:430). hgnc:430 is a gene from the HUGO Gene Nomenclature Committee. ALOXE3 hgnc:13743 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ALOXE3 (hgnc:13743). hgnc:13743 is a gene from the HUGO Gene Nomenclature Committee. CYP4F22 hgnc:26820 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CYP4F22 (hgnc:26820). hgnc:26820 is a gene from the HUGO Gene Nomenclature Committee. ABCA12 hgnc:14637 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ABCA12 (hgnc:14637). hgnc:14637 is a gene from the HUGO Gene Nomenclature Committee. NIPAL4 hgnc:28018 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in NIPAL4 (hgnc:28018). hgnc:28018 is a gene from the HUGO Gene Nomenclature Committee.
Nonsyndromic autosomal recessive congenital ichthyosis spectrum, including lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis.
Keratinopathic Ichthyosis MONDO:0017266
KRT1 hgnc:6412 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT1 (hgnc:6412). hgnc:6412 is a gene from the HUGO Gene Nomenclature Committee. KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. KRT2 hgnc:6439 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KRT2 (hgnc:6439). hgnc:6439 is a gene from the HUGO Gene Nomenclature Committee.
Inherited ichthyosis group caused by pathogenic variants in keratin genes, with epidermolytic ichthyosis as a well-characterized subtype.
Netherton Syndrome MONDO:0009735
SPINK5 hgnc:15464 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SPINK5 (hgnc:15464). hgnc:15464 is a gene from the HUGO Gene Nomenclature Committee.
Syndromic inherited ichthyosis caused by SPINK5 loss of function, with skin-barrier failure, hair-shaft abnormality, and atopic manifestations.
Ichthyosis With Erythrokeratoderma (KLK11) MONDO:0957783
KLK11 hgnc:6359 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KLK11 (hgnc:6359). hgnc:6359 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant
Autosomal dominant disorder of cornification presenting as early-onset ichthyosiform erythroderma or erythrokeratoderma, defined in one familial and two sporadic cases by two heterozygous variants affecting Gly50 of kallikrein-related peptidase 11. The variants perturb cleavage of the signal peptide, and the Gly50Glu protein is mislocalized within the cell and poorly secreted. The downstream lesion, decreased proteolytic activity in the stratum corneum with delayed desquamation, is modeled as a pathophysiology node in this entry. This row and the Netherton row above are both protease-control lesions of desquamation. Netherton syndrome is loss of the kallikrein inhibitor SPINK5, the unopposed-kallikrein mechanism curated in kb/disorders/Netherton_Syndrome.yaml; here it is kallikrein activity itself that is reduced.
Show evidence (3 references)
PMID:36689511 SUPPORT Human Clinical
"We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma."
Establishes KLK11 as the causal gene and names the presentation this row is titled for.
PMID:36689511 SUPPORT Human Clinical
"We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation."
Sources the autosomal dominant inheritance and the desquamation lesion stated in this description.
PMID:36689511 SUPPORT In Vitro
"In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant."
Sources the signal-peptide cleavage, mislocalization and secretion statements in this description.
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Pathophysiology

6
Disrupted Keratinocyte Differentiation and Cornification
Inherited ichthyosis subtypes converge on abnormal keratinocyte terminal differentiation and cornification, producing defective formation and turnover of the stratum corneum.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
FLG hgnc:3748 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FLG (hgnc:3748). hgnc:3748 is a gene from the HUGO Gene Nomenclature Committee. KRT1 hgnc:6412 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT1 (hgnc:6412). hgnc:6412 is a gene from the HUGO Gene Nomenclature Committee. KRT10 hgnc:6413 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee. KRT2 hgnc:6439 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KRT2 (hgnc:6439). hgnc:6439 is a gene from the HUGO Gene Nomenclature Committee.
keratinocyte differentiation GO:0030216 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratinocyte differentiation (GO:0030216). GO:0030216 is a biological process from the Gene Ontology. keratinization GO:0031424 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratinization (GO:0031424). GO:0031424 is a biological process from the Gene Ontology.
skin epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Stratum Corneum Barrier Impairment
Show evidence (4 references)
DOI:10.3390/biomedicines12051112 SUPPORT Human Clinical
"Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes."
Supports the shared keratinization/cornification phenotype across the inherited ichthyosis group.
PMID:16444271 SUPPORT Human Clinical
"We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization."
Places FLG at this node: loss of profilaggrin impairs keratinization itself, which is the terminal-differentiation defect modelled here.
PMID:16444271 SUPPORT BACKGROUND Human Clinical
"During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope."
States the step filaggrin performs -- aggregating keratin filaments into the cross-linked cornified envelope -- which is why FLG and the keratin genes KRT1, KRT10 and KRT2 share this node. The sentence is the paper's framing of established filaggrin biology, not its own result.
+ 1 more reference
Epidermal Lipid Metabolism Defect
Several autosomal recessive congenital ichthyosis genes perturb epidermal lipid processing, lipid transport, or cornified-envelope assembly, impairing lamellar barrier formation in differentiating keratinocytes. Steroid sulfatase belongs at the same node by a different route: its deficiency in X-linked ichthyosis lets cholesterol sulfate accumulate in the stratum corneum, and the cited review reports that the excess cholesterol sulfate is itself what induces permeability barrier dysfunction and the scaling abnormality. The node is therefore the convergence point for the lipid-handling subtypes as a whole, not for the autosomal recessive ones alone.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
TGM1 hgnc:11777 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TGM1 (hgnc:11777). hgnc:11777 is a gene from the HUGO Gene Nomenclature Committee. ABCA12 hgnc:14637 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ABCA12 (hgnc:14637). hgnc:14637 is a gene from the HUGO Gene Nomenclature Committee. ALOX12B hgnc:430 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALOX12B (hgnc:430). hgnc:430 is a gene from the HUGO Gene Nomenclature Committee. ALOXE3 hgnc:13743 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALOXE3 (hgnc:13743). hgnc:13743 is a gene from the HUGO Gene Nomenclature Committee. CYP4F22 hgnc:26820 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYP4F22 (hgnc:26820). hgnc:26820 is a gene from the HUGO Gene Nomenclature Committee. NIPAL4 hgnc:28018 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NIPAL4 (hgnc:28018). hgnc:28018 is a gene from the HUGO Gene Nomenclature Committee. STS hgnc:11425 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STS (hgnc:11425). hgnc:11425 is a gene from the HUGO Gene Nomenclature Committee.
lipid transport GO:0006869 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal lipid transport (GO:0006869). GO:0006869 is a biological process from the Gene Ontology. ceramide biosynthetic process GO:0046513 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ceramide biosynthetic process (GO:0046513). GO:0046513 is a biological process from the Gene Ontology. establishment of skin barrier GO:0061436 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal establishment of skin barrier (GO:0061436). GO:0061436 is a biological process from the Gene Ontology.
skin epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Stratum Corneum Barrier Impairment
Palmoplantar keratoderma Keratoderma of the palms and soles accompanies the cornified-envelope and lipid-handling defect in specific ARCI genotypes; the cited cohort reports striated keratoderma in its NIPAL4-mutated patients.
Alopecia Hair loss accompanies the more severe end of this node's genotypes; the cited cohort found alopecia significantly associated with TGM1 and ABCA12 mutations.
Show evidence (2 references)
PMID:38588653 SUPPORT Human Clinical
"Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%)."
Supports the major ARCI genes that converge on epidermal lipid and cornified-envelope barrier biology.
PMID:39086014 SUPPORT REVIEW SYNTHESIS Human Clinical
"STS deficiency causes an abnormal cholesterol sulfate (CS) accumulation in the stratum corneum (SC). Excess CS induces epidermal permeability barrier dysfunction and scaling abnormalities."
Gives the STS arm of this node: loss of steroid sulfatase is a lipid handling defect whose accumulated substrate is what impairs the barrier.
Reduced Kallikrein-11 Proteolysis and Delayed Desquamation
Kallikrein-related peptidases participate in skin desquamation by decomposing corneodesmosomes, which is what allows the stratum corneum to shed. Variants at Gly50 of KLK11 perturb cleavage of its signal peptide, so the Gly50Glu protein is mislocalized and poorly secreted. In patients' stratum corneum both trypsin-like and chymotrypsin-like proteolytic activity are significantly decreased, proteolysis of desmoglein 1 is reduced and degeneration of corneodesmosomes is delayed, producing a thickened, dense stratum corneum. Mice carrying the equivalent Klk11 variant show hyperkeratosis and abnormal desquamation, partially recapitulating the human phenotype. This is a retention lesion of shedding rather than a failure to build the barrier, which is what separates it from the two nodes above.
KLK11 hgnc:6359 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KLK11 (hgnc:6359). hgnc:6359 is a gene from the HUGO Gene Nomenclature Committee.
corneocyte desquamation GO:0003336 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased corneocyte desquamation (GO:0003336). GO:0003336 is a biological process from the Gene Ontology. proteolysis GO:0006508 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteolysis (GO:0006508). GO:0006508 is a biological process from the Gene Ontology.
endopeptidase activity GO:0004175 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased endopeptidase activity (GO:0004175). GO:0004175 is a molecular function from the Gene Ontology.
stratum corneum of epidermis UBERON:0002027 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stratum corneum of epidermis (UBERON:0002027). UBERON:0002027 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hyperkeratosis Delayed shedding of corneodesmosome-linked corneocytes retains the stratum corneum, which the founding report describes as thickened and dense.
Ichthyosis Retained stratum corneum presents clinically as the ichthyosiform erythroderma or erythrokeratoderma that defines this subtype.
Show evidence (5 references)
PMID:36689511 SUPPORT BACKGROUND Other
"KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC."
States the normal role of KLK11 in desquamation; graded OTHER because the sentence describes the protein family's function rather than reporting an experiment.
PMID:36689511 SUPPORT In Vitro
"In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant."
The cell-based measurement behind the mislocalization and secretion defect asserted by this node.
PMID:36689511 SUPPORT Human Clinical
"Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients' SC samples."
The proteolytic-activity measurement in patient stratum corneum behind the decreased-proteolysis claim.
+ 2 more references
Stratum Corneum Barrier Impairment
Abnormal cornification compromises stratum corneum structure and barrier performance, increasing scale retention, skin dryness, and vulnerability to dehydration or inflammation in severe forms.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
keratinization GO:0031424 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal keratinization (GO:0031424). GO:0031424 is a biological process from the Gene Ontology.
stratum corneum of epidermis UBERON:0002027 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stratum corneum of epidermis (UBERON:0002027). UBERON:0002027 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ichthyosis
Hyperkeratosis
Skin Microbiome Dysbiosis
Show evidence (1 reference)
DOI:10.1186/s40246-024-00603-x SUPPORT Human Clinical
"Patients present with epidermal scaling, fissuring, chronic inflammation, and increased susceptibility to infections."
Supports barrier impairment as a clinical state linking scaling, fissuring, inflammation, and infection susceptibility.
Skin Microbiome Dysbiosis
Defective congenital ichthyosis skin barriers are associated with altered epidermal microbial communities, reduced commensal microbiota, and higher pathogenic colonization.
skin epidermis UBERON:0001003 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin epidermis (UBERON:0001003). UBERON:0001003 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Th17/JAK-STAT Inflammatory Activation
Recurrent Skin Infections
Show evidence (1 reference)
DOI:10.1186/s40246-024-00603-x SUPPORT Human Clinical
"Microbiome meta-analysis showed distinct microbial populations, decreases in commensal microbiota, and higher colonization by pathogenic species associated with CI; these were correlated with increased production of inflammatory cytokines and Th17- and JAK/STAT-signaling pathways in peripheral..."
Directly supports microbiome dysbiosis as a congenital ichthyosis mechanism linked to inflammation and pathogenic colonization.
Th17/JAK-STAT Inflammatory Activation
Barrier and microbiome abnormalities in congenital ichthyosis are associated with increased inflammatory cytokines and Th17/JAK-STAT pathway activation.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. T-helper 17 type immune response GO:0072538 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T-helper 17 type immune response (GO:0072538). GO:0072538 is a biological process from the Gene Ontology. JAK-STAT signaling pathway GO:0007259 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased JAK-STAT signaling pathway, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology.
Downstream
Erythroderma
Recurrent Skin Infections
Show evidence (1 reference)
DOI:10.1186/s40246-024-00603-x SUPPORT Human Clinical
"Microbiome meta-analysis showed distinct microbial populations, decreases in commensal microbiota, and higher colonization by pathogenic species associated with CI; these were correlated with increased production of inflammatory cytokines and Th17- and JAK/STAT-signaling pathways in peripheral..."
Supports inflammatory cytokine, Th17, and JAK-STAT activation downstream of congenital ichthyosis barrier and microbiome abnormalities.
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Pathograph

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

9
Immune 2
Erythroderma HP:0001019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythroderma (HP:0001019). HP:0001019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled."
Directly supports erythroderma as part of the ARCI clinical spectrum.
Recurrent Skin Infections Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1186/s40246-024-00603-x SUPPORT Human Clinical
"Patients present with epidermal scaling, fissuring, chronic inflammation, and increased susceptibility to infections."
Directly supports increased susceptibility to infections in congenital ichthyosis.
Integument 6
Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1186/s40246-024-00603-x SUPPORT Human Clinical
"Patients present with epidermal scaling, fissuring, chronic inflammation, and increased susceptibility to infections."
Supports scaling as a central congenital ichthyosis phenotype.
Hyperkeratosis HP:0000962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperkeratosis (HP:0000962). HP:0000962 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03041038 SUPPORT Human Clinical
"The ichthyoses are a group of lifelong genetic disorders which share characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation."
Supports skin thickening and scaling as core inherited ichthyosis phenotypes.
Palmoplantar keratoderma HP:0000982 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palmoplantar keratoderma (HP:0000982). HP:0000982 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients."
Supports palmoplantar/striated keratoderma as a subtype-associated inherited ichthyosis feature.
Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Hypohidrosis HP:0000966 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypohidrosis (HP:0000966). HP:0000966 is a phenotype from the Human Phenotype Ontology.
Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations."
Supports alopecia as a genotype-associated ARCI phenotype.
Metabolism 1
Heat Intolerance HP:0002046 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heat intolerance (HP:0002046). HP:0002046 is a phenotype from the Human Phenotype Ontology.
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Genetic Associations

12
FLG (Causative biallelic loss-of-function variants in ichthyosis vulgaris)
Gene: FLG hgnc:3748 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FLG (hgnc:3748). hgnc:3748 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal semidominant inheritance
Show evidence (2 references)
PMID:16444271 SUPPORT Human Clinical
"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."
The gene-discovery report, identifying biallelic FLG loss-of-function as the cause of ichthyosis vulgaris across fifteen kindreds.
DOI:10.3390/biomedicines12051112 SUPPORT Human Clinical
"Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis."
Supports FLG loss of function as the molecular basis for an inherited ichthyosis subtype in this cohort.
STS (Causative steroid sulfatase deficiency in X-linked ichthyosis)
Gene: STS hgnc:11425 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STS (hgnc:11425). hgnc:11425 is a gene from the HUGO Gene Nomenclature Committee.
X-linked recessive
Show evidence (2 references)
PMID:39086014 SUPPORT REVIEW SYNTHESIS Human Clinical
"The causative gene for XLI is the steroid sulfatase gene (STS), located on Xp22.3."
States the gene-disease assertion this record makes, naming STS as the causative gene for X-linked ichthyosis.
DOI:10.3390/biomedicines12051112 SUPPORT INDIRECT Human Clinical
"Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis."
Establishes that X-linked ichthyosis made up 6 of 11 males in this first-tier testing cohort. It does not name STS, so it supports the gene record only through the separately cited gene-disease assignment.
TGM1 (Causative biallelic pathogenic variants in autosomal recessive congenital ichthyosis)
Gene: TGM1 hgnc:11777 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TGM1 (hgnc:11777). hgnc:11777 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%)."
Supports TGM1 as a common causative ARCI gene.
ALOX12B (Causative biallelic pathogenic variants in autosomal recessive congenital ichthyosis)
Gene: ALOX12B hgnc:430 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALOX12B (hgnc:430). hgnc:430 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%)."
Supports ALOX12B as a common causative ARCI gene.
ABCA12 (Causative biallelic pathogenic variants in autosomal recessive congenital ichthyosis, including harlequin ichthyosis)
Gene: ABCA12 hgnc:14637 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ABCA12 (hgnc:14637). hgnc:14637 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%)."
Supports ABCA12 as a recurrent causative ARCI gene in the cohort.
CYP4F22 (Causative biallelic pathogenic variants in autosomal recessive congenital ichthyosis)
Gene: CYP4F22 hgnc:26820 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYP4F22 (hgnc:26820). hgnc:26820 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%)."
Supports CYP4F22 as a recurrent causative ARCI gene in the cohort.
ALOXE3 (Causative biallelic pathogenic variants in autosomal recessive congenital ichthyosis)
Gene: ALOXE3 hgnc:13743 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALOXE3 (hgnc:13743). hgnc:13743 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%)."
Supports ALOXE3 as a recurrent causative ARCI gene in the cohort.
NIPAL4 (Causative biallelic pathogenic variants in autosomal recessive congenital ichthyosis)
Gene: NIPAL4 hgnc:28018 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NIPAL4 (hgnc:28018). hgnc:28018 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (1 reference)
PMID:38588653 SUPPORT Human Clinical
"Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%)."
Supports NIPAL4 as a recurrent causative ARCI gene in the cohort.
KRT1 (Causative heterozygous pathogenic variants in epidermolytic ichthyosis)
Gene: KRT1 hgnc:6412 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KRT1 (hgnc:6412). hgnc:6412 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:26581228 SUPPORT Human Clinical
"Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis"
Assigns epidermolytic ichthyosis, the keratinopathic subtype curated here, to KRT1 alongside KRT10.
KRT10 (Causative heterozygous pathogenic variants in epidermolytic ichthyosis)
Gene: KRT10 hgnc:6413 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KRT10 (hgnc:6413). hgnc:6413 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:26581228 SUPPORT Human Clinical
"Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis"
Assigns epidermolytic ichthyosis to KRT10 alongside KRT1.
KRT2 (Causative heterozygous pathogenic variants in superficial epidermolytic ichthyosis)
Gene: KRT2 hgnc:6439 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KRT2 (hgnc:6439). hgnc:6439 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:26581228 SUPPORT Human Clinical
"Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis"
Distinguishes the KRT2 keratinopathic subtype, superficial epidermolytic ichthyosis, from the KRT1/KRT10 form.
KLK11 (Causative heterozygous variants at Gly50 affecting signal-peptide cleavage)
Gene: KLK11 hgnc:6359 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KLK11 (hgnc:6359). hgnc:6359 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:36689511 SUPPORT Human Clinical
"We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation."
The authors' own statement of the gene-disease relationship this record asserts.
PMID:36689511 SUPPORT Human Clinical
"Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants."
Records the ascertainment behind the relationship, three families, which is the limit of the human evidence.
💊

Medical Actions

4
Topical emollients and keratolytic/supportive therapy
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Barrier-directed topical care with emollients and keratolytics is standard symptomatic management for scaling, fissuring, and dryness across inherited ichthyosis subtypes.
Target Phenotypes: Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology.
Retinoid pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: isotretinoin CHEBI:6067 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses isotretinoin (CHEBI:6067). CHEBI:6067 is a therapeutic agent from Chemical Entities of Biological Interest.
Systemic or topical retinoid therapy can reduce severe scaling and hyperkeratosis, including topical isotretinoin TMB-001 studied in the CONTROL trial.
Target Phenotypes: Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04154293 SUPPORT Human Clinical
"The purpose of this study is to investigate the efficacy and safety of two concentrations of topically applied ointment formulation of isotretinoin called TMB-001 (0.05% and 0.1% isotretinoin) in subjects 9 years of age and older for the treatment of congenital ichthyosis (CI), including..."
Supports topical isotretinoin TMB-001 as a congenital ichthyosis therapy evaluated in a randomized clinical study.
Topical TGM1 gene therapy
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
KB105 is a topical HSV-1 vector expressing TGM1 under clinical investigation for TGM1-deficient autosomal recessive congenital ichthyosis.
Mechanism Target:
RESTORES Epidermal Lipid Metabolism Defect — Topical TGM1 expression is intended to restore deficient transglutaminase 1 activity in affected skin.
Show evidence (1 reference)
clinicaltrials:NCT04047732 SUPPORT Human Clinical
"This study is an intra-patient comparison of KB105 and placebo-administered Target Areas. The primary objectives of this study are to evaluate safety and Investigator Global Assessment (IGA) scale improvement of topically administered KB105."
Supports clinical testing of topical KB105 for TGM1-deficient ARCI.
IL-17A-targeting biologic therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Secukinumab NCIT:C152315 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Secukinumab (NCIT:C152315). NCIT:C152315 is a therapeutic agent from the NCI Thesaurus.
Secukinumab has been studied as a mechanism-based immunomodulatory approach for ichthyoses with cutaneous inflammation and IL-17 pathway activation.
Mechanism Target:
INHIBITS Th17/JAK-STAT Inflammatory Activation — IL-17A blockade is intended to reduce inflammatory signaling in selected ichthyosis patients with immune activation.
Show evidence (1 reference)
clinicaltrials:NCT03041038 SUPPORT Human Clinical
"The ichthyoses are a group of lifelong genetic disorders which share characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation."
Supports inflammatory pathway targeting in ichthyoses, while the trial is not specific to all inherited ichthyosis subtypes.
📊

Prevalence

2
Worldwide ARCI
Falcon extracted an ARCI prevalence range of about 1:100,000 to 1:300,000 worldwide from the 2024 inherited ichthyosis research set.
Males
Point Prevalence 16.7–50.0 per 100,000 1–9 per 10,000 X-Linked Ichthyosis
The source states "a prevalence of 1/6,000 to 1/2,000 in males" without saying whether it is birth or point prevalence; recorded as point prevalence, the default reading of an unqualified prevalence figure, and the verbatim wording is kept here so the assumption is visible. 100000/6000 and 100000/2000 normalize to 16.7 and 50.0 per 100,000. An earlier revision carried this range as a note attributed to a deep-research extraction with no citation and described the denominator as male newborns, which the source quoted here does not say.
Show evidence (1 reference)
PMID:39086014 SUPPORT REVIEW SYNTHESIS Human Clinical
"It is the second most common type of ichthyosis, with a prevalence of 1/6,000 to 1/2,000 in males and without any racial or geographical differences."
Gives the prevalence range and the male denominator for this record.
🔬

Clinical Trials

3
NCT04047732 PHASE_I
Phase I/II topical KB105 intra-patient comparison trial for TGM1-deficient ARCI.
Show evidence (1 reference)
clinicaltrials:NCT04047732 SUPPORT Human Clinical
"This study is an intra-patient comparison of KB105 and placebo-administered Target Areas. The primary objectives of this study are to evaluate safety and Investigator Global Assessment (IGA) scale improvement of topically administered KB105."
Supports this trial as topical KB105 clinical testing in TGM1-deficient ARCI.
NCT05735158 PHASE_II
Randomized placebo-controlled topical KB105 study in children and adults with ARCI.
Show evidence (1 reference)
clinicaltrials:NCT05735158 SUPPORT Human Clinical
"KB105-02 is an intrasubject randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of KB105 in children and adults with autosomal recessive congenital ichthyosis (ARCI)."
Supports this as a randomized phase 2 ARCI KB105 trial record.
NCT03041038 PHASE_II
Phase 2 secukinumab trial in ichthyoses testing IL-17A-targeted immunomodulation for inflammatory skin thickening and scaling.
Show evidence (1 reference)
clinicaltrials:NCT03041038 SUPPORT Human Clinical
"The ichthyoses are a group of lifelong genetic disorders which share characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation."
Supports this trial as relevant to inflammatory ichthyosis biology, although not specific to every inherited ichthyosis subtype.
{ }

Source YAML

click to show 
name: Inherited Ichthyosis
creation_date: "2026-05-07T15:56:15Z"
category: Mendelian
description: >-
  Inherited ichthyosis is a heterogeneous group of Mendelian disorders of
  cornification affecting most or all of the integument. The shared clinical
  surface is abnormal epidermal scaling and/or hyperkeratosis, but the
  underlying causes span defects in keratinocyte differentiation, cornified
  envelope formation, epidermal lipid handling, protease control, and skin
  barrier maintenance.
synonyms:
- genetic ichthyosis
- hereditary ichthyosis
- congenital ichthyosis
disease_term:
  preferred_term: inherited ichthyosis
  term:
    id: MONDO:0015947
    label: inherited ichthyosis
parents:
- ichthyosis
- hereditary skin disorder
has_subtypes:
- name: Ichthyosis Vulgaris
  display_name: Ichthyosis Vulgaris
  curated_in: Ichthyosis_Vulgaris
  subtype_term:
    preferred_term: ichthyosis vulgaris
    term:
      id: MONDO:0007810
      label: autosomal dominant ichthyosis vulgaris
  genes:
  - preferred_term: FLG
    term:
      id: hgnc:3748
      label: FLG
  description: >-
    Common inherited ichthyosis characterized by generalized scaling and
    desquamation.
  review_notes: >-
    This row is a pointer to the dedicated Ichthyosis_Vulgaris entry, which is
    why it binds MONDO:0007810 autosomal dominant ichthyosis vulgaris rather
    than a direct child of this entry's MONDO:0015947 anchor. The reasoning for
    that term is in that entry's own history record.
- name: X-Linked Ichthyosis
  display_name: X-Linked Ichthyosis
  subtype_term:
    preferred_term: X-linked ichthyosis
    term:
      id: MONDO:0010622
      label: recessive X-linked ichthyosis
  genes:
  - preferred_term: STS
    term:
      id: hgnc:11425
      label: STS
  description: >-
    X-linked recessive inherited ichthyosis, classically associated with
    steroid sulfatase deficiency.
- name: Autosomal Recessive Congenital Ichthyosis
  display_name: Autosomal Recessive Congenital Ichthyosis
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis
    term:
      id: MONDO:0017265
      label: autosomal recessive congenital ichthyosis
  genes:
  - preferred_term: TGM1
    term:
      id: hgnc:11777
      label: TGM1
  - preferred_term: ALOX12B
    term:
      id: hgnc:430
      label: ALOX12B
  - preferred_term: ALOXE3
    term:
      id: hgnc:13743
      label: ALOXE3
  - preferred_term: CYP4F22
    term:
      id: hgnc:26820
      label: CYP4F22
  - preferred_term: ABCA12
    term:
      id: hgnc:14637
      label: ABCA12
  - preferred_term: NIPAL4
    term:
      id: hgnc:28018
      label: NIPAL4
  description: >-
    Nonsyndromic autosomal recessive congenital ichthyosis spectrum, including
    lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin
    ichthyosis.
  review_notes: >-
    The six genes bound here are the recurrent ARCI genes of the Italian cohort
    this entry cites. The rare tail of that cohort -- CERS3, PNPLA1 and SDR9C7,
    one patient each -- is deliberately not enumerated on this umbrella entry;
    it is curated in kb/disorders/Autosomal_Recessive_Congenital_Ichthyosis.yaml,
    which carries a "Rare ARCI genes" record for exactly that purpose. The same
    reasoning does not extend to the GeneReviews chapter. "Autosomal Recessive
    Congenital Ichthyosis" (PMID:20301593) is one subtype's chapter rather than
    this umbrella's -- `just check-genereviews` offers it only as a CANDIDATE,
    matching on the substring "congenital ichthyosis" -- but it is tagged in
    this entry's top-level `references:` block anyway, on the same footing as
    the seven subtype chapters tagged in Inherited_Porphyria.yaml. Its cached
    record is a scope statement with no quotable gene content, so it is tagged
    and not mined. The same recipe reports it as an EXACT untagged chapter on
    the dedicated ARCI entry, kb/disorders/Autosomal_Recessive_Congenital_Ichthyosis.yaml,
    where it is the primary baseline rather than a subtype reference; that entry
    is outside this change.
- name: Keratinopathic Ichthyosis
  display_name: Keratinopathic Ichthyosis
  subtype_term:
    preferred_term: keratinopathic ichthyosis
    term:
      id: MONDO:0017266
      label: keratinopathic ichthyosis
  genes:
  - preferred_term: KRT1
    term:
      id: hgnc:6412
      label: KRT1
  - preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  - preferred_term: KRT2
    term:
      id: hgnc:6439
      label: KRT2
  description: >-
    Inherited ichthyosis group caused by pathogenic variants in keratin genes,
    with epidermolytic ichthyosis as a well-characterized subtype.
  review_notes: >-
    Two classes inside MONDO:0017266 are covered by this row rather than by rows
    of their own, on the same granularity rule as the Ichthyosis Vulgaris row
    above. MONDO:0012208 congenital reticular ichthyosiform erythroderma, also
    called ichthyosis with confetti, is a direct child of MONDO:0017266 carrying
    hgnc:6413 KRT10 in its axioms; kb/disorders/Epidermolytic_Hyperkeratosis_2.yaml
    already rules in its notes that it needs its own entry, on the grounds that
    MONDO files it under keratinopathic ichthyosis rather than under
    MONDO:0958184, that it is caused by KRT10 or KRT1 frameshifts into an
    arginine-rich alternative reading frame, and that its revertant mosaicism is
    a mechanism the epidermolytic forms lack. That ruling is not reopened here. MONDO:0007808 ichthyosis hystrix of Curth-Macklin is
    the other, and it is already curated as a has_subtypes row of
    kb/disorders/KRT1_Keratinopathies.yaml with its MONDO term bound.

    MONDO:0007809 ichthyosis histrix, Lambert type is not covered by this row:
    MONDO files it under MONDO:0859383 ichthyosis hystrix, a different direct
    child of MONDO:0015947 that this entry does not carry as a row. Its sibling
    in that group, Curth-Macklin, is curated with its keratin gene at
    KRT1_Keratinopathies, which is where the ichthyosis hystrix group is handled
    in this KB; a row here would be a second home for the group.

    KRT1, KRT10 and KRT2 are bound here and carry gene records in this entry's
    `genetic:` block, on the same policy as the ARCI genes: the umbrella names
    each subtype's recurrent genes, and the dedicated entry carries the
    mechanism. For KRT1 that dedicated entry is
    kb/disorders/KRT1_Keratinopathies.yaml, which models the dominant-negative
    filament collapse and its tonofilament-clumping consequences and declares
    "keratinopathic ichthyosis" as its parent. KRT10 and KRT2 have no dedicated
    entry anywhere in kb/disorders/, so this is currently their only home.
- name: Netherton Syndrome
  display_name: Netherton Syndrome
  subtype_term:
    preferred_term: Netherton syndrome
    term:
      id: MONDO:0009735
      label: Netherton syndrome
  genes:
  - preferred_term: SPINK5
    term:
      id: hgnc:15464
      label: SPINK5
  description: >-
    Syndromic inherited ichthyosis caused by SPINK5 loss of function, with
    skin-barrier failure, hair-shaft abnormality, and atopic manifestations.
  review_notes: >-
    SPINK5 is bound here as the subtype's gene but is deliberately not given a
    top-level `genetic:` record or a pathophysiology node on this umbrella
    entry: the unopposed-kallikrein protease mechanism is a different chain from
    the two this entry models, and it is curated in
    kb/disorders/Netherton_Syndrome.yaml.
- name: Ichthyosis With Erythrokeratoderma
  display_name: Ichthyosis With Erythrokeratoderma (KLK11)
  subtype_term:
    preferred_term: ichthyosis with erythrokeratoderma
    term:
      id: MONDO:0957783
      label: ichthyosis with erythrokeratoderma
  genes:
  - preferred_term: KLK11
    term:
      id: hgnc:6359
      label: KLK11
  description: >-
    Autosomal dominant disorder of cornification presenting as early-onset
    ichthyosiform erythroderma or erythrokeratoderma, defined in one familial and
    two sporadic cases by two heterozygous variants affecting Gly50 of
    kallikrein-related peptidase 11. The variants perturb cleavage of the signal
    peptide, and the Gly50Glu protein is mislocalized within the cell and poorly
    secreted. The downstream lesion, decreased proteolytic activity in the
    stratum corneum with delayed desquamation, is modeled as a pathophysiology
    node in this entry.

    This row and the Netherton row above are both protease-control lesions of
    desquamation. Netherton syndrome is loss of the kallikrein inhibitor SPINK5,
    the unopposed-kallikrein mechanism curated in
    kb/disorders/Netherton_Syndrome.yaml; here it is kallikrein activity itself
    that is reduced.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma."
    explanation: Establishes KLK11 as the causal gene and names the presentation this row is titled for.
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation."
    explanation: Sources the autosomal dominant inheritance and the desquamation lesion stated in this description.
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant."
    explanation: Sources the signal-peptide cleavage, mislocalization and secretion statements in this description.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Some inherited ichthyosis subtypes, including ichthyosis vulgaris and many
    keratinopathic ichthyoses, follow autosomal dominant inheritance.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Several severe inherited ichthyosis groups, including autosomal recessive
    congenital ichthyosis and Netherton syndrome, are autosomal recessive.
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    X-linked ichthyosis is the major X-linked inherited ichthyosis subtype.
pathophysiology:
- name: Disrupted Keratinocyte Differentiation and Cornification
  conforms_to: "epidermal_cornification_failure#Cornification Program Component Deficiency"
  description: >-
    Inherited ichthyosis subtypes converge on abnormal keratinocyte terminal
    differentiation and cornification, producing defective formation and
    turnover of the stratum corneum.
  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: ABNORMAL
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  genes:
  - preferred_term: FLG
    term:
      id: hgnc:3748
      label: FLG
  - preferred_term: KRT1
    term:
      id: hgnc:6412
      label: KRT1
  - preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  - preferred_term: KRT2
    term:
      id: hgnc:6439
      label: KRT2
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Stratum Corneum Barrier Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: DOI:10.3390/biomedicines12051112
    reference_title: Comprehensive Molecular Analysis of Disease-Related Genes
      as First-Tier Test for Early Diagnosis, Classification, and Management
      of Patients Affected by Nonsyndromic Ichthyosis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inherited ichthyoses are a group of clinically and genetically
      heterogeneous rare disorders of skin keratinization with overlapping
      phenotypes.
    explanation: >-
      Supports the shared keratinization/cornification phenotype across the
      inherited ichthyosis group.
  - 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 find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization."
    explanation: >-
      Places FLG at this node: loss of profilaggrin impairs keratinization
      itself, which is the terminal-differentiation defect modelled here.
  - 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: "During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope."
    explanation: >-
      States the step filaggrin performs -- aggregating keratin filaments into
      the cross-linked cornified envelope -- which is why FLG and the keratin
      genes KRT1, KRT10 and KRT2 share this node. The sentence is the paper's
      framing of established filaggrin biology, not its own result.
  - reference: PMID:26581228
    reference_title: "Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis"
    explanation: >-
      Assigns the keratinopathic ichthyosis subtypes to KRT1, KRT10 and KRT2,
      the keratin-filament arm of the cornification defect at this node.
- name: Epidermal Lipid Metabolism Defect
  conforms_to: "epidermal_cornification_failure#Defective Cornified Envelope Assembly and Lamellar Lipid Delivery"
  description: >-
    Several autosomal recessive congenital ichthyosis genes perturb epidermal
    lipid processing, lipid transport, or cornified-envelope assembly, impairing
    lamellar barrier formation in differentiating keratinocytes. Steroid
    sulfatase belongs at the same node by a different route: its deficiency in
    X-linked ichthyosis lets cholesterol sulfate accumulate in the stratum
    corneum, and the cited review reports that the excess cholesterol sulfate is
    itself what induces permeability barrier dysfunction and the scaling
    abnormality. The node is therefore the
    convergence point for the lipid-handling subtypes as a whole, not for the
    autosomal recessive ones alone.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: lipid transport
    term:
      id: GO:0006869
      label: lipid transport
    modifier: ABNORMAL
  - preferred_term: ceramide biosynthetic process
    term:
      id: GO:0046513
      label: ceramide biosynthetic process
    modifier: ABNORMAL
  - preferred_term: establishment of skin barrier
    term:
      id: GO:0061436
      label: establishment of skin barrier
    modifier: ABNORMAL
  genes:
  - preferred_term: TGM1
    term:
      id: hgnc:11777
      label: TGM1
  - preferred_term: ABCA12
    term:
      id: hgnc:14637
      label: ABCA12
  - preferred_term: ALOX12B
    term:
      id: hgnc:430
      label: ALOX12B
  - preferred_term: ALOXE3
    term:
      id: hgnc:13743
      label: ALOXE3
  - preferred_term: CYP4F22
    term:
      id: hgnc:26820
      label: CYP4F22
  - preferred_term: NIPAL4
    term:
      id: hgnc:28018
      label: NIPAL4
  - preferred_term: STS
    term:
      id: hgnc:11425
      label: STS
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Stratum Corneum Barrier Impairment
    causal_link_type: DIRECT
  - target: Palmoplantar keratoderma
    description: >-
      Keratoderma of the palms and soles accompanies the cornified-envelope and
      lipid-handling defect in specific ARCI genotypes; the cited cohort reports
      striated keratoderma in its NIPAL4-mutated patients.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients."
      explanation: Associates striated keratoderma with NIPAL4, one of the genes bound on this node.
  - target: Alopecia
    description: >-
      Hair loss accompanies the more severe end of this node's genotypes; the
      cited cohort found alopecia significantly associated with TGM1 and ABCA12
      mutations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations."
      explanation: Associates alopecia with TGM1 and ABCA12, two of the genes bound on this node.
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
      18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
      ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
      and SDR9C7 in 1 patient each (1.4%).
    explanation: >-
      Supports the major ARCI genes that converge on epidermal lipid and
      cornified-envelope barrier biology.
  - reference: PMID:39086014
    reference_title: Revisiting X-linked congenital ichthyosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "STS deficiency causes an abnormal cholesterol sulfate (CS) accumulation in the stratum corneum (SC). Excess CS induces epidermal permeability barrier dysfunction and scaling abnormalities."
    explanation: >-
      Gives the STS arm of this node: loss of steroid sulfatase is a lipid
      handling defect whose accumulated substrate is what impairs the barrier.
- name: Reduced Kallikrein-11 Proteolysis and Delayed Desquamation
  biological_scale: TISSUE
  description: >-
    Kallikrein-related peptidases participate in skin desquamation by
    decomposing corneodesmosomes, which is what allows the stratum corneum to
    shed. Variants at Gly50 of KLK11 perturb cleavage of its signal peptide, so
    the Gly50Glu protein is mislocalized and poorly secreted. In patients'
    stratum corneum both trypsin-like and chymotrypsin-like proteolytic activity
    are significantly decreased, proteolysis of desmoglein 1 is reduced and
    degeneration of corneodesmosomes is delayed, producing a thickened, dense
    stratum corneum. Mice carrying the equivalent Klk11 variant show
    hyperkeratosis and abnormal desquamation, partially recapitulating the human
    phenotype. This is a retention lesion of shedding rather than a failure to
    build the barrier, which is what separates it from the two nodes above.
  genes:
  - preferred_term: KLK11
    term:
      id: hgnc:6359
      label: KLK11
  molecular_functions:
  - preferred_term: endopeptidase activity
    term:
      id: GO:0004175
      label: endopeptidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: corneocyte desquamation
    term:
      id: GO:0003336
      label: corneocyte desquamation
    modifier: DECREASED
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
    modifier: DECREASED
  locations:
  - preferred_term: stratum corneum of epidermis
    term:
      id: UBERON:0002027
      label: stratum corneum of epidermis
  evidence:
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC."
    explanation: States the normal role of KLK11 in desquamation; graded OTHER because the sentence describes the protein family's function rather than reporting an experiment.
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant."
    explanation: The cell-based measurement behind the mislocalization and secretion defect asserted by this node.
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients' SC samples."
    explanation: The proteolytic-activity measurement in patient stratum corneum behind the decreased-proteolysis claim.
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients' SC, indicating delayed skin desquamation."
    explanation: Sources the desmoglein-1 and corneodesmosome findings and the delayed-desquamation reading.
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype."
    explanation: The mouse result cited in this node, which the authors describe as a partial recapitulation.
  downstream:
  - target: Hyperkeratosis
    description: >-
      Delayed shedding of corneodesmosome-linked corneocytes retains the stratum
      corneum, which the founding report describes as thickened and dense.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36689511
      reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation."
      explanation: The clinical observation linking the desquamation defect to a thickened stratum corneum.
  - target: Ichthyosis
    description: >-
      Retained stratum corneum presents clinically as the ichthyosiform
      erythroderma or erythrokeratoderma that defines this subtype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36689511
      reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma."
      explanation: Names the ichthyosiform presentation produced by the KLK11 lesion.
- name: Stratum Corneum Barrier Impairment
  conforms_to: "epidermal_cornification_failure#Stratum Corneum Permeability Barrier Failure"
  description: >-
    Abnormal cornification compromises stratum corneum structure and barrier
    performance, increasing scale retention, skin dryness, and vulnerability to
    dehydration or inflammation in severe forms.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  locations:
  - preferred_term: stratum corneum of epidermis
    term:
      id: UBERON:0002027
      label: stratum corneum of epidermis
  downstream:
  - target: Ichthyosis
    causal_link_type: DIRECT
  - target: Hyperkeratosis
    causal_link_type: DIRECT
  - target: Skin Microbiome Dysbiosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: DOI:10.1186/s40246-024-00603-x
    reference_title: Altered skin microbiome, inflammation, and JAK/STAT
      signaling in Southeast Asian ichthyosis patients
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients present with epidermal scaling, fissuring, chronic inflammation,
      and increased susceptibility to infections.
    explanation: >-
      Supports barrier impairment as a clinical state linking scaling,
      fissuring, inflammation, and infection susceptibility.
- name: Skin Microbiome Dysbiosis
  description: >-
    Defective congenital ichthyosis skin barriers are associated with altered
    epidermal microbial communities, reduced commensal microbiota, and higher
    pathogenic colonization.
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Th17/JAK-STAT Inflammatory Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Recurrent Skin Infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: DOI:10.1186/s40246-024-00603-x
    reference_title: Altered skin microbiome, inflammation, and JAK/STAT
      signaling in Southeast Asian ichthyosis patients
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microbiome meta-analysis showed distinct microbial populations, decreases
      in commensal microbiota, and higher colonization by pathogenic species
      associated with CI; these were correlated with increased production of
      inflammatory cytokines and Th17- and JAK/STAT-signaling pathways in
      peripheral blood mononuclear cells.
    explanation: >-
      Directly supports microbiome dysbiosis as a congenital ichthyosis
      mechanism linked to inflammation and pathogenic colonization.
- name: Th17/JAK-STAT Inflammatory Activation
  description: >-
    Barrier and microbiome abnormalities in congenital ichthyosis are associated
    with increased inflammatory cytokines and Th17/JAK-STAT pathway activation.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: T-helper 17 type immune response
    term:
      id: GO:0072538
      label: T-helper 17 type immune response
    modifier: INCREASED
  - preferred_term: JAK-STAT signaling pathway
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  downstream:
  - target: Erythroderma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Recurrent Skin Infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: DOI:10.1186/s40246-024-00603-x
    reference_title: Altered skin microbiome, inflammation, and JAK/STAT
      signaling in Southeast Asian ichthyosis patients
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microbiome meta-analysis showed distinct microbial populations, decreases
      in commensal microbiota, and higher colonization by pathogenic species
      associated with CI; these were correlated with increased production of
      inflammatory cytokines and Th17- and JAK/STAT-signaling pathways in
      peripheral blood mononuclear cells.
    explanation: >-
      Supports inflammatory cytokine, Th17, and JAK-STAT activation downstream
      of congenital ichthyosis barrier and microbiome abnormalities.
phenotypes:
- category: Dermatological
  name: Ichthyosis
  diagnostic: true
  description: >-
    Generalized dry scaling of the skin is the shared phenotype across the
    inherited ichthyosis group.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: DOI:10.1186/s40246-024-00603-x
    reference_title: Altered skin microbiome, inflammation, and JAK/STAT
      signaling in Southeast Asian ichthyosis patients
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients present with epidermal scaling, fissuring, chronic inflammation,
      and increased susceptibility to infections.
    explanation: >-
      Supports scaling as a central congenital ichthyosis phenotype.
- category: Dermatological
  name: Hyperkeratosis
  description: >-
    Thickened stratum corneum and retained scale contribute to the fish-scale
    appearance in multiple inherited ichthyosis subtypes.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: clinicaltrials:NCT03041038
    reference_title: A Multicenter Study With a Randomized, Double-Blind,
      Placebo-Controlled Period, Followed by an Open-Label Maintenance Dosing
      Period to Evaluate the Efficacy and Safety of Secukinumab in Patients
      With Ichthyoses
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ichthyoses are a group of lifelong genetic disorders which share
      characteristics of generalized skin thickening, scaling and underlying
      cutaneous inflammation.
    explanation: >-
      Supports skin thickening and scaling as core inherited ichthyosis
      phenotypes.
- category: Dermatological
  name: Erythroderma
  description: >-
    Diffuse erythema is prominent in several congenital ichthyosis presentations
    and varies by subtype.
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8)
      affected with lamellar ichthyosis (50/74, 67.5%), congenital
      ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74,
      2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled.
    explanation: >-
      Directly supports erythroderma as part of the ARCI clinical spectrum.
- category: Dermatological
  name: Palmoplantar keratoderma
  description: >-
    Some inherited ichthyosis subtypes include abnormal thickening of the palms
    and soles.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among specific phenotypic features, psoriasis-like lesions as well as a
      trunk reticulate scale pattern and striated keratoderma were present in
      NIPAL4-mutated patients.
    explanation: >-
      Supports palmoplantar/striated keratoderma as a subtype-associated
      inherited ichthyosis feature.
- category: Dermatological
  name: Pruritus
  description: >-
    Itch is common in congenital ichthyosis cohorts and is consistent with
    inflamed, fissured, barrier-defective skin.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
- category: Dermatological
  name: Hypohidrosis
  description: >-
    Reduced sweating can occur in inherited ichthyosis and contributes to heat
    intolerance when thickened skin impairs normal thermoregulation.
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
- category: Dermatological
  name: Recurrent Skin Infections
  description: >-
    Defective barrier function and dysbiotic skin colonization make recurrent
    skin infection a frequent complication of congenital ichthyosis.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: DOI:10.1186/s40246-024-00603-x
    reference_title: Altered skin microbiome, inflammation, and JAK/STAT
      signaling in Southeast Asian ichthyosis patients
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients present with epidermal scaling, fissuring, chronic inflammation,
      and increased susceptibility to infections.
    explanation: >-
      Directly supports increased susceptibility to infections in congenital
      ichthyosis.
- category: Constitutional
  name: Heat Intolerance
  description: >-
    Heat intolerance can occur in inherited ichthyosis and is consistent with
    hypohidrosis and impaired skin barrier function.
  phenotype_term:
    preferred_term: Heat intolerance
    term:
      id: HP:0002046
      label: Heat intolerance
- category: Dermatological
  name: Alopecia
  description: >-
    Hair loss occurs in a subset of inherited ichthyosis patients, particularly
    in higher-severity TGM1- and ABCA12-associated ARCI.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alopecia, ectropion, and eclabium were significantly associated with TGM1
      and ABCA12 mutations, and large, thick, and brownish scales with TGM1
      mutations.
    explanation: >-
      Supports alopecia as a genotype-associated ARCI phenotype.
genetic:
- name: FLG
  subtype: Ichthyosis Vulgaris
  association: Causative biallelic loss-of-function variants in ichthyosis vulgaris
  gene_term:
    preferred_term: FLG
    term:
      id: hgnc:3748
      label: FLG
  inheritance:
  - name: Autosomal semidominant inheritance
  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: >-
      The gene-discovery report, identifying biallelic FLG loss-of-function as
      the cause of ichthyosis vulgaris across fifteen kindreds.
  - reference: DOI:10.3390/biomedicines12051112
    reference_title: Comprehensive Molecular Analysis of Disease-Related Genes
      as First-Tier Test for Early Diagnosis, Classification, and Management
      of Patients Affected by Nonsyndromic Ichthyosis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients had biallelic loss-of-function variants in FLG, whereas
      6/11 males were affected by X-linked ichthyosis.
    explanation: >-
      Supports FLG loss of function as the molecular basis for an inherited
      ichthyosis subtype in this cohort.
- name: STS
  subtype: X-Linked Ichthyosis
  association: Causative steroid sulfatase deficiency in X-linked ichthyosis
  notes: >-
    An earlier revision evidenced this gene record with a cohort sentence that
    counted X-linked ichthyosis patients without naming STS, and conceded in its
    own explanation that STS was "the canonical steroid-sulfatase gene for this
    subtype" -- that is, the gene attribution was carried by the explanation
    rather than by the quote. That item is retained below for the cohort
    context it does establish, regraded as the indirect support it is, and the
    gene assertion now rests on a source that states it.
  gene_term:
    preferred_term: STS
    term:
      id: hgnc:11425
      label: STS
  inheritance:
  - name: X-linked recessive
  evidence:
  - reference: PMID:39086014
    reference_title: Revisiting X-linked congenital ichthyosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The causative gene for XLI is the steroid sulfatase gene (STS), located on Xp22.3."
    explanation: >-
      States the gene-disease assertion this record makes, naming STS as the
      causative gene for X-linked ichthyosis.
  - reference: DOI:10.3390/biomedicines12051112
    reference_title: Comprehensive Molecular Analysis of Disease-Related Genes
      as First-Tier Test for Early Diagnosis, Classification, and Management
      of Patients Affected by Nonsyndromic Ichthyosis
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients had biallelic loss-of-function variants in FLG, whereas
      6/11 males were affected by X-linked ichthyosis.
    explanation: >-
      Establishes that X-linked ichthyosis made up 6 of 11 males in this
      first-tier testing cohort. It does not name STS, so it supports the gene
      record only through the separately cited gene-disease assignment.
- name: TGM1
  subtype: Autosomal Recessive Congenital Ichthyosis
  association: Causative biallelic pathogenic variants in autosomal recessive
    congenital ichthyosis
  gene_term:
    preferred_term: TGM1
    term:
      id: hgnc:11777
      label: TGM1
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
      18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
      ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
      and SDR9C7 in 1 patient each (1.4%).
    explanation: >-
      Supports TGM1 as a common causative ARCI gene.
  case_fractions:
  - population: Italian ARCI cohort
    case_fraction_percent: 24.3
    cohort_size: 74
    notes: Share of a cross-sectional Italian autosomal recessive congenital ichthyosis cohort attributed to TGM1.
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
        Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
        Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
        18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
        ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
        and SDR9C7 in 1 patient each (1.4%).
      explanation: Gives the TGM1 case share and the cohort denominator.
- name: ALOX12B
  subtype: Autosomal Recessive Congenital Ichthyosis
  association: Causative biallelic pathogenic variants in autosomal recessive
    congenital ichthyosis
  gene_term:
    preferred_term: ALOX12B
    term:
      id: hgnc:430
      label: ALOX12B
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
      18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
      ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
      and SDR9C7 in 1 patient each (1.4%).
    explanation: >-
      Supports ALOX12B as a common causative ARCI gene.
  case_fractions:
  - population: Italian ARCI cohort
    case_fraction_percent: 24.3
    cohort_size: 74
    notes: Share of a cross-sectional Italian autosomal recessive congenital ichthyosis cohort attributed to ALOX12B.
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
        Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
        Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
        18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
        ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
        and SDR9C7 in 1 patient each (1.4%).
      explanation: Gives the ALOX12B case share and the cohort denominator.
- name: ABCA12
  subtype: Autosomal Recessive Congenital Ichthyosis
  association: Causative biallelic pathogenic variants in autosomal recessive
    congenital ichthyosis, including harlequin ichthyosis
  gene_term:
    preferred_term: ABCA12
    term:
      id: hgnc:14637
      label: ABCA12
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
      18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
      ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
      and SDR9C7 in 1 patient each (1.4%).
    explanation: >-
      Supports ABCA12 as a recurrent causative ARCI gene in the cohort.
  case_fractions:
  - population: Italian ARCI cohort
    case_fraction_percent: 12.2
    cohort_size: 74
    notes: Share of a cross-sectional Italian autosomal recessive congenital ichthyosis cohort attributed to ABCA12.
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
        Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
        Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
        18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
        ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
        and SDR9C7 in 1 patient each (1.4%).
      explanation: Gives the ABCA12 case share and the cohort denominator.
- name: CYP4F22
  subtype: Autosomal Recessive Congenital Ichthyosis
  association: Causative biallelic pathogenic variants in autosomal recessive
    congenital ichthyosis
  gene_term:
    preferred_term: CYP4F22
    term:
      id: hgnc:26820
      label: CYP4F22
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
      18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
      ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
      and SDR9C7 in 1 patient each (1.4%).
    explanation: >-
      Supports CYP4F22 as a recurrent causative ARCI gene in the cohort.
  case_fractions:
  - population: Italian ARCI cohort
    case_fraction_percent: 16.2
    cohort_size: 74
    notes: Share of a cross-sectional Italian autosomal recessive congenital ichthyosis cohort attributed to CYP4F22.
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
        Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
        Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
        18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
        ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
        and SDR9C7 in 1 patient each (1.4%).
      explanation: Gives the CYP4F22 case share and the cohort denominator.
- name: ALOXE3
  subtype: Autosomal Recessive Congenital Ichthyosis
  association: Causative biallelic pathogenic variants in autosomal recessive
    congenital ichthyosis
  gene_term:
    preferred_term: ALOXE3
    term:
      id: hgnc:13743
      label: ALOXE3
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
      18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
      ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
      and SDR9C7 in 1 patient each (1.4%).
    explanation: >-
      Supports ALOXE3 as a recurrent causative ARCI gene in the cohort.
  case_fractions:
  - population: Italian ARCI cohort
    case_fraction_percent: 9.5
    cohort_size: 74
    notes: Share of a cross-sectional Italian autosomal recessive congenital ichthyosis cohort attributed to ALOXE3.
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
        Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
        Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
        18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
        ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
        and SDR9C7 in 1 patient each (1.4%).
      explanation: Gives the ALOXE3 case share and the cohort denominator.
- name: NIPAL4
  subtype: Autosomal Recessive Congenital Ichthyosis
  association: Causative biallelic pathogenic variants in autosomal recessive
    congenital ichthyosis
  gene_term:
    preferred_term: NIPAL4
    term:
      id: hgnc:28018
      label: NIPAL4
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:38588653
    reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
      Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
      Features in 74 Italian Patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
      18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
      ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
      and SDR9C7 in 1 patient each (1.4%).
    explanation: >-
      Supports NIPAL4 as a recurrent causative ARCI gene in the cohort.
  case_fractions:
  - population: Italian ARCI cohort
    case_fraction_percent: 9.5
    cohort_size: 74
    notes: Share of a cross-sectional Italian autosomal recessive congenital ichthyosis cohort attributed to NIPAL4.
    evidence:
    - reference: PMID:38588653
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
        Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
        Features in 74 Italian Patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in
        18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%),
        ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1,
        and SDR9C7 in 1 patient each (1.4%).
      explanation: Gives the NIPAL4 case share and the cohort denominator.
- name: KRT1
  subtype: Keratinopathic Ichthyosis
  association: Causative heterozygous pathogenic variants in epidermolytic ichthyosis
  gene_term:
    preferred_term: KRT1
    term:
      id: hgnc:6412
      label: KRT1
  evidence:
  - reference: PMID:26581228
    reference_title: "Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis"
    explanation: >-
      Assigns epidermolytic ichthyosis, the keratinopathic subtype curated here,
      to KRT1 alongside KRT10.
- name: KRT10
  subtype: Keratinopathic Ichthyosis
  association: Causative heterozygous pathogenic variants in epidermolytic ichthyosis
  gene_term:
    preferred_term: KRT10
    term:
      id: hgnc:6413
      label: KRT10
  evidence:
  - reference: PMID:26581228
    reference_title: "Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis"
    explanation: >-
      Assigns epidermolytic ichthyosis to KRT10 alongside KRT1.
- name: KRT2
  subtype: Keratinopathic Ichthyosis
  association: Causative heterozygous pathogenic variants in superficial epidermolytic
    ichthyosis
  gene_term:
    preferred_term: KRT2
    term:
      id: hgnc:6439
      label: KRT2
  evidence:
  - reference: PMID:26581228
    reference_title: "Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis"
    explanation: >-
      Distinguishes the KRT2 keratinopathic subtype, superficial epidermolytic
      ichthyosis, from the KRT1/KRT10 form.
- name: KLK11
  subtype: Ichthyosis With Erythrokeratoderma
  association: Causative heterozygous variants at Gly50 affecting signal-peptide cleavage
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KLK11
    term:
      id: hgnc:6359
      label: KLK11
  notes: >-
    KLK11 encodes kallikrein-related peptidase 11. The gene-disease relationship
    rests on one familial and two sporadic cases carrying two heterozygous
    variants at Gly50, together with cell-based evidence that the variants
    perturb signal-peptide cleavage, decreased proteolytic activity measured in
    patients' stratum corneum, and a mouse carrying the equivalent variant. A
    search of the approved symbol KLK11 in the committed ClinGen Gene-Disease
    Validity cache (the 718 CGGV_*.md records in references_cache) returns no
    row, so no expert panel has classified this relationship in the records
    available here. HGNC records PRSS20 as a previous symbol for this gene.
  evidence:
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation."
    explanation: The authors' own statement of the gene-disease relationship this record asserts.
  - reference: PMID:36689511
    reference_title: "Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants."
    explanation: Records the ascertainment behind the relationship, three families, which is the limit of the human evidence.
treatments:
- name: Topical emollients and keratolytic/supportive therapy
  description: >-
    Barrier-directed topical care with emollients and keratolytics is standard
    symptomatic management for scaling, fissuring, and dryness across inherited
    ichthyosis subtypes.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
- name: Retinoid pharmacotherapy
  description: >-
    Systemic or topical retinoid therapy can reduce severe scaling and
    hyperkeratosis, including topical isotretinoin TMB-001 studied in the
    CONTROL trial.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: isotretinoin
      term:
        id: CHEBI:6067
        label: isotretinoin
  target_phenotypes:
  - preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: clinicaltrials:NCT04154293
    reference_title: A Randomized, Parallel, Double-Blind, Vehicle Controlled
      Study to Evaluate the Safety and Efficacy of Two Concentrations of Topical
      TMB-001 for the Treatment of Congenital Ichthyosis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to investigate the efficacy and safety of
      two concentrations of topically applied ointment formulation of
      isotretinoin called TMB-001 (0.05% and 0.1% isotretinoin) in subjects 9
      years of age and older for the treatment of congenital ichthyosis (CI),
      including recessive X-linked ichthyosis (RXLI) and autosomal recessive
      congenital ichthyosis-lamellar ichthyosis (ARCI-LI) subtypes.
    explanation: >-
      Supports topical isotretinoin TMB-001 as a congenital ichthyosis therapy
      evaluated in a randomized clinical study.
- name: Topical TGM1 gene therapy
  description: >-
    KB105 is a topical HSV-1 vector expressing TGM1 under clinical investigation
    for TGM1-deficient autosomal recessive congenital ichthyosis.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Epidermal Lipid Metabolism Defect
    treatment_effect: RESTORES
    description: >-
      Topical TGM1 expression is intended to restore deficient transglutaminase
      1 activity in affected skin.
  evidence:
  - reference: clinicaltrials:NCT04047732
    reference_title: A Phase I/II Clinical Trial of Topical KB105, a
      Replication-incompetent, Non-integrating HSV-1 Vector Expressing Human
      Transglutaminase 1 (TGM1) for the Treatment of TGM1-deficient Autosomal
      Recessive Congenital Ichthyosis (ARCI)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study is an intra-patient comparison of KB105 and placebo-administered
      Target Areas. The primary objectives of this study are to evaluate safety
      and Investigator Global Assessment (IGA) scale improvement of topically
      administered KB105.
    explanation: >-
      Supports clinical testing of topical KB105 for TGM1-deficient ARCI.
- name: IL-17A-targeting biologic therapy
  description: >-
    Secukinumab has been studied as a mechanism-based immunomodulatory approach
    for ichthyoses with cutaneous inflammation and IL-17 pathway activation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Secukinumab
      term:
        id: NCIT:C152315
        label: Secukinumab
  target_mechanisms:
  - target: Th17/JAK-STAT Inflammatory Activation
    treatment_effect: INHIBITS
    description: >-
      IL-17A blockade is intended to reduce inflammatory signaling in selected
      ichthyosis patients with immune activation.
  evidence:
  - reference: clinicaltrials:NCT03041038
    reference_title: A Multicenter Study With a Randomized, Double-Blind,
      Placebo-Controlled Period, Followed by an Open-Label Maintenance Dosing
      Period to Evaluate the Efficacy and Safety of Secukinumab in Patients
      With Ichthyoses
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ichthyoses are a group of lifelong genetic disorders which share
      characteristics of generalized skin thickening, scaling and underlying
      cutaneous inflammation.
    explanation: >-
      Supports inflammatory pathway targeting in ichthyoses, while the trial is
      not specific to all inherited ichthyosis subtypes.
prevalence:
- population: Worldwide ARCI
  notes: >-
    Falcon extracted an ARCI prevalence range of about 1:100,000 to 1:300,000
    worldwide from the 2024 inherited ichthyosis research set.
- population: Males
  subtype: X-Linked Ichthyosis
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 16.7
  rate_high: 50.0
  rate_denominator: POPULATION
  notes: >-
    The source states "a prevalence of 1/6,000 to 1/2,000 in males" without
    saying whether it is birth or point prevalence; recorded as point
    prevalence, the default reading of an unqualified prevalence figure, and the
    verbatim wording is kept here so the assumption is visible. 100000/6000 and
    100000/2000 normalize to 16.7 and 50.0 per 100,000. An earlier revision
    carried this range as a note attributed to a deep-research extraction with
    no citation and described the denominator as male newborns, which the source
    quoted here does not say.
  evidence:
  - reference: PMID:39086014
    reference_title: Revisiting X-linked congenital ichthyosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "It is the second most common type of ichthyosis, with a prevalence of 1/6,000 to 1/2,000 in males and without any racial or geographical differences."
    explanation: Gives the prevalence range and the male denominator for this record.
clinical_trials:
- name: NCT04047732
  phase: PHASE_I
  notes: >-
    ClinicalTrials.gov lists this as a combined Phase I/II study; mapped to
    PHASE_I because the schema accepts a single phase value.
  description: >-
    Phase I/II topical KB105 intra-patient comparison trial for
    TGM1-deficient ARCI.
  evidence:
  - reference: clinicaltrials:NCT04047732
    reference_title: A Phase I/II Clinical Trial of Topical KB105, a
      Replication-incompetent, Non-integrating HSV-1 Vector Expressing Human
      Transglutaminase 1 (TGM1) for the Treatment of TGM1-deficient Autosomal
      Recessive Congenital Ichthyosis (ARCI)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study is an intra-patient comparison of KB105 and placebo-administered
      Target Areas. The primary objectives of this study are to evaluate safety
      and Investigator Global Assessment (IGA) scale improvement of topically
      administered KB105.
    explanation: >-
      Supports this trial as topical KB105 clinical testing in TGM1-deficient
      ARCI.
- name: NCT05735158
  phase: PHASE_II
  description: >-
    Randomized placebo-controlled topical KB105 study in children and adults
    with ARCI.
  evidence:
  - reference: clinicaltrials:NCT05735158
    reference_title: A Phase 2, Randomized, Placebo-controlled Study of Topical
      KB105, a Replication-defective, Non-integrating HSV-1 Vector Expressing
      Human Transglutaminase 1 (TGM1) for the Treatment of TGM1-deficient
      Autosomal Recessive Congenital Ichthyosis (ARCI)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KB105-02 is an intrasubject randomized, placebo-controlled, double-blind
      study to evaluate the safety and efficacy of KB105 in children and adults
      with autosomal recessive congenital ichthyosis (ARCI).
    explanation: >-
      Supports this as a randomized phase 2 ARCI KB105 trial record.
- name: NCT03041038
  phase: PHASE_II
  description: >-
    Phase 2 secukinumab trial in ichthyoses testing IL-17A-targeted
    immunomodulation for inflammatory skin thickening and scaling.
  evidence:
  - reference: clinicaltrials:NCT03041038
    reference_title: A Multicenter Study With a Randomized, Double-Blind,
      Placebo-Controlled Period, Followed by an Open-Label Maintenance Dosing
      Period to Evaluate the Efficacy and Safety of Secukinumab in Patients
      With Ichthyoses
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ichthyoses are a group of lifelong genetic disorders which share
      characteristics of generalized skin thickening, scaling and underlying
      cutaneous inflammation.
    explanation: >-
      Supports this trial as relevant to inflammatory ichthyosis biology,
      although not specific to every inherited ichthyosis subtype.
datasets:
references:
- reference: PMID:20301593
  title: Autosomal Recessive Congenital Ichthyosis.
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s13555-023-00923-1
  title: Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not Result in
    Clinically Relevant Laboratory Abnormalities in Participants with Congenital
    Ichthyosis in the Phase 2b CONTROL Study
  found_in:
  - Inherited_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not
      Result in Clinically Relevant Laboratory Abnormalities in Participants
      with Congenital Ichthyosis in the Phase 2b CONTROL Study
    supporting_text: Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did
      Not Result in Clinically Relevant Laboratory Abnormalities in Participants
      with Congenital Ichthyosis in the Phase 2b CONTROL Study
- reference: DOI:10.1038/s41572-022-00412-3
  title: Ichthyosis
  found_in:
  - Inherited_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Ichthyosis
    supporting_text: Ichthyosis
- reference: DOI:10.1159/000536366
  title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association
    of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in
    74 Italian Patients'
  found_in:
  - Inherited_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Autosomal recessive congenital ichthyoses (ARCIs) are a
      clinically heterogeneous group of keratinization disorders characterized
      by generalized skin scaling due to mutations in at least 12 genes.
    supporting_text: Autosomal recessive congenital ichthyoses (ARCIs) are a
      clinically heterogeneous group of keratinization disorders characterized
      by generalized skin scaling due to mutations in at least 12 genes.
    evidence:
    - reference: DOI:10.1159/000536366
      reference_title: 'Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses:
        Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural
        Features in 74 Italian Patients'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Autosomal recessive congenital ichthyoses (ARCIs) are a
        clinically heterogeneous group of keratinization disorders characterized
        by generalized skin scaling due to mutations in at least 12 genes.
      explanation: Deep research cited this publication as relevant literature
        for Inherited Ichthyosis.
- reference: DOI:10.1186/s40246-024-00603-x
  title: Altered skin microbiome, inflammation, and JAK/STAT signaling in
    Southeast Asian ichthyosis patients
  found_in:
  - Inherited_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Congenital ichthyosis (CI) is a collective group of rare
      hereditary skin disorders.
    supporting_text: Congenital ichthyosis (CI) is a collective group of rare
      hereditary skin disorders.
    evidence:
    - reference: DOI:10.1186/s40246-024-00603-x
      reference_title: Altered skin microbiome, inflammation, and JAK/STAT
        signaling in Southeast Asian ichthyosis patients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Congenital ichthyosis (CI) is a collective group of rare
        hereditary skin disorders.
      explanation: Deep research cited this publication as relevant literature
        for Inherited Ichthyosis.
- reference: DOI:10.2340/actadv.v105.41100
  title: 'The Clinical Spectrum of Rare Inherited Ichthyosis in China: A Review of
    Thirty-five Cases'
  found_in:
  - Inherited_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Inherited ichthyosis comprises a spectrum of genetic disorders
      related to over 50 pathogenic genes.
    supporting_text: Inherited ichthyosis comprises a spectrum of genetic
      disorders related to over 50 pathogenic genes.
    evidence:
    - reference: DOI:10.2340/actadv.v105.41100
      reference_title: 'The Clinical Spectrum of Rare Inherited Ichthyosis in China:
        A Review of Thirty-five Cases'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Inherited ichthyosis comprises a spectrum of genetic disorders
        related to over 50 pathogenic genes.
      explanation: Deep research cited this publication as relevant literature
        for Inherited Ichthyosis.
- reference: DOI:10.3390/biomedicines12051112
  title: Comprehensive Molecular Analysis of Disease-Related Genes as First-Tier
    Test for Early Diagnosis, Classification, and Management of Patients
    Affected by Nonsyndromic Ichthyosis
  found_in:
  - Inherited_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Inherited ichthyoses are a group of clinically and genetically
      heterogeneous rare disorders of skin keratinization with overlapping
      phenotypes.
    supporting_text: Inherited ichthyoses are a group of clinically and
      genetically heterogeneous rare disorders of skin keratinization with
      overlapping phenotypes.
    evidence:
    - reference: DOI:10.3390/biomedicines12051112
      reference_title: Comprehensive Molecular Analysis of Disease-Related Genes
        as First-Tier Test for Early Diagnosis, Classification, and Management
        of Patients Affected by Nonsyndromic Ichthyosis
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Inherited ichthyoses are a group of clinically and genetically
        heterogeneous rare disorders of skin keratinization with overlapping
        phenotypes.
      explanation: Deep research cited this publication as relevant literature
        for Inherited Ichthyosis.
- reference: DOI:10.61577/amsd.2023.100004
  title: Molecular genetics and pathogenesis of ichthyosis
  found_in:
  - Inherited_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Molecular genetics and pathogenesis of ichthyosis
    supporting_text: Molecular genetics and pathogenesis of ichthyosis
📚

References & Deep Research

References

8
PMID:20301593
Autosomal Recessive Congenital Ichthyosis.
No top-level findings curated for this source.
DOI:10.1007/s13555-023-00923-1
Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not Result in Clinically Relevant Laboratory Abnormalities in Participants with Congenital Ichthyosis in the Phase 2b CONTROL Study
1 finding
Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not Result in Clinically Relevant Laboratory Abnormalities in Participants with Congenital Ichthyosis in the Phase 2b CONTROL Study
"Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not Result in Clinically Relevant Laboratory Abnormalities in Participants with Congenital Ichthyosis in the Phase 2b CONTROL Study"
1 finding
Ichthyosis
"Ichthyosis"
DOI:10.1159/000536366
Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients
1 finding
Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes.
"Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes."
Show evidence (1 reference)
DOI:10.1159/000536366 SUPPORT Human Clinical
"Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes."
Deep research cited this publication as relevant literature for Inherited Ichthyosis.
DOI:10.1186/s40246-024-00603-x
Altered skin microbiome, inflammation, and JAK/STAT signaling in Southeast Asian ichthyosis patients
1 finding
Congenital ichthyosis (CI) is a collective group of rare hereditary skin disorders.
"Congenital ichthyosis (CI) is a collective group of rare hereditary skin disorders."
Show evidence (1 reference)
DOI:10.1186/s40246-024-00603-x SUPPORT Human Clinical
"Congenital ichthyosis (CI) is a collective group of rare hereditary skin disorders."
Deep research cited this publication as relevant literature for Inherited Ichthyosis.
DOI:10.2340/actadv.v105.41100
The Clinical Spectrum of Rare Inherited Ichthyosis in China: A Review of Thirty-five Cases
1 finding
Inherited ichthyosis comprises a spectrum of genetic disorders related to over 50 pathogenic genes.
"Inherited ichthyosis comprises a spectrum of genetic disorders related to over 50 pathogenic genes."
Show evidence (1 reference)
DOI:10.2340/actadv.v105.41100 SUPPORT Human Clinical
"Inherited ichthyosis comprises a spectrum of genetic disorders related to over 50 pathogenic genes."
Deep research cited this publication as relevant literature for Inherited Ichthyosis.
DOI:10.3390/biomedicines12051112
Comprehensive Molecular Analysis of Disease-Related Genes as First-Tier Test for Early Diagnosis, Classification, and Management of Patients Affected by Nonsyndromic Ichthyosis
1 finding
Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes.
"Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes."
Show evidence (1 reference)
DOI:10.3390/biomedicines12051112 SUPPORT Human Clinical
"Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes."
Deep research cited this publication as relevant literature for Inherited Ichthyosis.
DOI:10.61577/amsd.2023.100004
Molecular genetics and pathogenesis of ichthyosis
1 finding
Molecular genetics and pathogenesis of ichthyosis
"Molecular genetics and pathogenesis of ichthyosis"

Deep Research

1

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

Evaluations and curation notes (2)

Genetics pass: fix STS evidence, wire FLG and STS, add ARCI and keratin gene records · 2026-09-19T17:33:15Z · View source

Genetics pass under the genetics-gap campaign (issue #12200, epic #12189). Gene-to-mechanism wiring went from 3/5 to 11/11. The MONDO checklist item is STS for MONDO:0010622 (recessive X-linked ichthyosis). STS was present as a gene record but reached no pathophysiology node, and its only evidence was a cohort sentence that counted X-linked ichthyosis patients without naming STS -- the explanation conceded as much, calling STS "the canonical steroid-sulfatase gene for this subtype". The gene assertion now rests on a source that states it; the original item is retained for the cohort context it does establish and regraded directness: INDIRECT, with the history of the change recorded in the record's notes. STS is wired to the epidermal lipid node, whose description now explains the route: steroid sulfatase hydrolyses cholesterol sulfate, and its loss lets cholesterol sulfate accumulate in the stratum corneum and degrade the barrier. FLG was likewise unwired and is now on the keratinocyte differentiation and cornification node, evidenced from the filaggrin gene-discovery report rather than only from the cohort paper. Added gene records for the three recurrent ARCI genes that were already bound on the lipid node but had no gene-level assertion (CYP4F22, ALOXE3, NIPAL4), and for the keratinopathic genes KRT1, KRT10 and KRT2. KRT1 does have a dedicated entry, kb/disorders/KRT1_Keratinopathies.yaml, which models the dominant-negative filament collapse; the record added here is the umbrella's subtype-level gene assertion, on the same policy applied to the ARCI genes. KRT10 and KRT2 have no dedicated entry anywhere in kb/disorders/, so this entry is currently their only home. Case fractions from the 74-patient Italian ARCI cohort added to all six ARCI gene records. Gene bindings added to every has_subtypes row. Two lump/split dispositions recorded in review_notes rather than acted on. SPINK5 is bound on the Netherton subtype row but deliberately gets no gene record or pathophysiology node here, because the unopposed-kallikrein mechanism is a third chain this umbrella does not model and is curated in kb/disorders/Netherton_Syndrome.yaml. The rare ARCI tail (CERS3, PNPLA1, SDR9C7, one patient each in the cited cohort) is likewise left to kb/disorders/Autosomal_Recessive_Congenital_Ichthyosis.yaml, which carries a "Rare ARCI genes" record for it. The X-linked ichthyosis prevalence record previously carried a range attributed to a deep-research extraction with no citation, and described the denominator as male newborns. It now has a source, structured measure_type, band and normalized rates, and a note saying that the source states only "in males" and does not say whether the figure is birth or point prevalence. Not done, and deliberately: five phenotypes (palmoplantar keratoderma, pruritus, hypohidrosis, heat intolerance, alopecia) remain causally unconnected. They are downstream sequelae of barrier failure rather than genetics, and wiring them needs sources this pass did not gather. Validation: just validate, validate-terms, count-verified-snippets (45/45), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-genereviews, list-gene-term-mismatches, validate-disorders.

Review: Inherited Ichthyosis (Changes required) · 2026-05-31T03:02:09Z · View source

GitHub review issue: https://github.com/monarch-initiative/dismech/issues/3597 Issue state: OPEN Issue created: 2026-05-31T03:02:09Z Issue updated: 2026-05-31T03:02:09Z Issue closed: not closed Review decision: Changes required Labels: review ## Completed curation review - Disease: **Inherited Ichthyosis** - Entry: `kb/disorders/Inherited_Ichthyosis.yaml` - Selection basis: #129 of the least-recently edited Mendelian entries - Review decision: **Changes required** - Validation stance: assumes schema, ontology-term, and reference validation pass; this is a biological/clinical/content review. ## Findings 1. Blocking: the entry has no `diagnosis` section. Add disease-specific diagnostic criteria, recommended tests/imaging/biochemical markers, and molecular confirmation strategy for Inherited Ichthyosis; this is necessary for curators to evaluate whether the modeled mechanism and phenotype scope match the intended disease. 2. Research-artifact consumption: matching deep-research artifact(s) exist and should be treated as first-class review inputs. Compare the YAML against the artifact(s), especially for central mechanisms, subtype-specific features, treatments/trials, and diagnostic/surveillance details rather than only schema-valid content. 3. Lumping/splitting review needed: this entry appears to cover a spectrum or umbrella concept with multiple subtypes (Ichthyosis Vulgaris, X-Linked Ichthyosis, Autosomal Recessive Congenital Ichthyosis, Keratinopathic Ichthyosis). Confirm that one disease-level pathomechanism is defensible; otherwise split gene/subtype-specific mechanisms or make subtype-specific phenotype, treatment, diagnosis, and genetic assertions explicit. 4. Pathophysiology review: the main modeled mechanisms include Disrupted Keratinocyte Differentiation and Cornification, Epidermal Lipid Metabolism Defect, Stratum Corneum Barrier Impairment, Skin Microbiome Dysbiosis. Check that each is an atomic event with direct evidence and that downstream edges do not encode multi-step chains or unsupported causal leaps from gene/product defect to organ-level phenotype. 5. Treatment/trial alignment: both `treatments` and `clinical_trials` are present. Verify that trial interventions, phases/statuses, target phenotypes, and treatment entries agree, and distinguish approved/standard care from investigational or case-report therapy. 6. Evidence/reference check: top references include DOI:10.3390/biomedicines12051112, PMID:38588653, DOI:10.1186/s40246-024-00603-x, clinicaltrials:NCT03041038. Spot-check that snippets directly support the specific claim, frequency, and evidence_source classification, especially where the same PMID is reused across phenotype, mechanism, and treatment assertions. ## Content-Completeness Checklist - Phenotype coverage: phenotype list needs manual review for disease-defining features. - Subtype completeness: subtypes present; verify subtype-specific anchoring. - Pathophysiology depth: mechanisms present but require atomicity/evidence review. - Treatments and trials: present; verify standard-vs-investigational scope. - Genetics: genetic section present; verify inheritance, variant classes, and genotype-phenotype claims. - Biomarkers/diagnostics: gap noted; diagnosis absent. - References/research consumption: compare the YAML against listed sources and local research artifacts; do not treat retrieval-heavy papers as issues unless they are disease-specific and directly modelable. ## Suggested Remediation Resolve the blocking diagnostic/baseline gaps first, then tighten subtype-specific claims, pathophysiology atomicity, treatment/trial scope, and evidence-to-claim alignment. Keep deterministic schema/term/reference validation separate from this biological review. ## Sources Used - Local research artifact: `research/Inherited_Ichthyosis-deep-research-falcon.md` - DOI:10.3390/biomedicines12051112: https://doi.org/10.3390/biomedicines12051112 - PMID:38588653: https://pubmed.ncbi.nlm.nih.gov/38588653/ - DOI:10.1186/s40246-024-00603-x: https://doi.org/10.1186/s40246-024-00603-x - `clinicaltrials:NCT03041038` No YAML files or `references_cache/*.md` files were edited for this review.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 33 citations 2026-05-07T12:21:30.795708

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Inherited Ichthyosis
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

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

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

1. Disease Information

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

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

2. Etiology

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

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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

5. Environmental Information

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

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

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

6. Mechanism / Pathophysiology

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

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

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

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

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

10. Diagnostics

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

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

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

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Inherited Ichthyosis — Disease Characteristics Research Report (2023–2024 emphasis)

Target disease

Disease name: Inherited ichthyosis (collective term; includes congenital ichthyoses and other Mendelian disorders of cornification)

Scope note: “Inherited ichthyosis” is not a single disorder but a heterogeneous group of Mendelian disorders of cornification with shared core features of generalized scaling/hyperkeratosis and barrier dysfunction, spanning non‑syndromic (skin-limited) and syndromic forms. (xiang2025theclinicalspectrum pages 1-2, fioretti2024comprehensivemolecularanalysis pages 1-2, panda2025moleculargeneticsand pages 2-3)

MONDO ID: Not retrieved in the available tool-evidence corpus; cannot be asserted from current sources.

Key synonyms / related terms (commonly used in the retrieved sources): - Congenital ichthyosis / congenital ichthyoses (CI) (marathe2023topicalisotretinoin(tmb001) pages 1-3, ho2024alteredskinmicrobiome pages 2-4) - Autosomal recessive congenital ichthyosis (ARCI) including lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis (HI), self‑improving collodion ichthyosis (SICI) (fioretti2024comprehensivemolecularanalysis pages 1-2, fioretti2024comprehensivemolecularanalysis pages 2-3) - X‑linked ichthyosis / X‑linked recessive ichthyosis (XLI/XLRI) (fioretti2024comprehensivemolecularanalysis pages 1-2, marathe2023topicalisotretinoin(tmb001) pages 1-3)

Data provenance: The evidence used here is aggregated from peer‑reviewed cohort studies, reviews, and ClinicalTrials.gov registry records (not individual EHR-level data). (fioretti2024comprehensivemolecularanalysis pages 1-2, diociaiuti2024crosssectionalstudyon pages 4-5, marathe2023topicalisotretinoin(tmb001) pages 1-3, ho2024alteredskinmicrobiome pages 2-4)

1. Disease information

Overview and current understanding

Inherited ichthyoses are genetic disorders of keratinization/cornification characterized clinically by persistent scaling and hyperkeratosis, often with erythema, fissuring, pruritus, and susceptibility to infection, reflecting defective epidermal barrier function. (fioretti2024comprehensivemolecularanalysis pages 1-2, panda2025moleculargeneticsand pages 2-3, ho2024alteredskinmicrobiome pages 2-4)

A 2024 cohort paper summarizes the diagnostic principle that clinical phenotype and family history guide suspicion, but molecular diagnosis is required for correct classification: “only the identification of the genetic defect allows the correct classification.” (Fioretti 2024, Biomedicines, published May 2024; https://doi.org/10.3390/biomedicines12051112) (fioretti2024comprehensivemolecularanalysis pages 1-2)

Key identifiers

From the retrieved evidence set, explicit code mappings (ICD‑10/ICD‑11/MeSH/OMIM/Orphanet/MONDO) were not captured as structured fields. An ICD‑10 anchor frequently used clinically for congenital ichthyosis is Q80.* (not directly supported by the retrieved evidence, so not asserted).

Evidence limitation: Because OMIM/Orphanet/MONDO/MeSH identifiers are not present in the retrieved full texts/chunks, this report cannot provide verified identifier lists without additional database retrieval.

2. Etiology

2.1 Disease causal factors

Primary cause: Germline pathogenic variants in genes required for epidermal barrier formation, cornified envelope assembly, keratin cytoskeleton integrity, and epidermal lipid metabolism. In multiple sources, inherited ichthyosis is described as involving >50 genes. (xiang2025theclinicalspectrum pages 1-2, fioretti2024comprehensivemolecularanalysis pages 1-2, panda2025moleculargeneticsand pages 2-3)

Key genetic etiologies highlighted in recent clinical cohorts and reviews: - ARCI genes: TGM1, ALOX12B, CYP4F22, ABCA12, ALOXE3, NIPAL4, CERS3, PNPLA1, SDR9C7 (diociaiuti2024crosssectionalstudyon pages 4-5, diociaiuti2024crosssectionalstudyon media 464df4f0) - Common ichthyosis types: FLG (ichthyosis vulgaris), STS (X‑linked ichthyosis), ABCA12 (harlequin ichthyosis), TGM1 (lamellar ichthyosis) (panda2025moleculargeneticsand pages 3-4, fioretti2024comprehensivemolecularanalysis pages 1-2)

2.2 Risk factors

  • Genetic: Having biallelic pathogenic variants in ARCI genes (autosomal recessive), or hemizygous pathogenic variants/deletions for X‑linked forms; positive family history and consanguinity increase risk for recessive forms (the latter is implied by recessive genetics; explicit consanguinity statistics were not retrieved in the current evidence set). (fioretti2024comprehensivemolecularanalysis pages 2-3)
  • Clinical complication risk: High burden of microbial infections is common in congenital ichthyosis cohorts (e.g., 94.4% in one study), consistent with barrier defect–mediated infection susceptibility. (ho2024alteredskinmicrobiome pages 2-4)

2.3 Protective factors and GxE

No protective genetic variants or explicit gene–environment interaction studies were retrieved in the available corpus; therefore, no evidence-based protective factors can be asserted.

3. Phenotypes

3.1 Core phenotypes (with recent frequency data)

A 2024 Italian ARCI cohort (n=74) quantified several common features (selected examples): - Hypohidrosis: 54/74 (73.0%) (HPO suggestion: Hypohidrosis [HP:0000966]) (diociaiuti2024crosssectionalstudyon pages 4-5) - Heat intolerance: 46/74 (62.2%) (HPO: Heat intolerance [HP:0002046]) (diociaiuti2024crosssectionalstudyon pages 4-5) - Ear deformities: 22/74 (29.7%) (HPO: Abnormality of the ear [HP:0000598]) (diociaiuti2024crosssectionalstudyon pages 4-5) - Alopecia: 16/74 (21.6%) (HPO: Alopecia [HP:0001596]) (diociaiuti2024crosssectionalstudyon pages 4-5)

A 2024 Southeast Asian congenital ichthyosis study (n=36) reported very high symptom/complication burden: - Hyperkeratosis: 100% (HPO: Hyperkeratosis [HP:0000962]) - Itch (pruritus): 97.2% (HPO: Pruritus [HP:0000989]) - Microbial infection: 94.4% (HPO: Recurrent infections [HP:0002719] or Skin infection [HP:0001045]) - Erythroderma: 72.2% (HPO: Erythroderma [HP:0001019]) (ho2024alteredskinmicrobiome pages 2-4)

3.2 Phenotype characteristics (onset, progression)

  • Many subtypes are congenital or present in the first months of life, including collodion membrane presentations in ARCI. In a 2024 diagnostic cohort, 6/17 were born encased in a collodion membrane (3 improved after shedding), while 11/17 had scaling at birth or in the first month. (fioretti2024comprehensivemolecularanalysis pages 2-3)
  • Course is typically chronic, with severity varying by genotype and subtype (e.g., higher mean severity scores in TGM1 and ABCA12 groups vs other ARCI genes). (diociaiuti2024crosssectionalstudyon pages 4-5, diociaiuti2024crosssectionalstudyon media 464df4f0)

3.3 Quality of life (QoL)

  • Congenital ichthyosis is consistently described as having substantial QoL impact, with severe itch and complications; one prospective qualitative study (NCT05610306) specifically targeted biological/psychological/social impacts and care gaps in adults ≥30 years with congenital ichthyosis. (NCT05610306 chunk 1)
  • A 2024 congenital ichthyosis cohort study reported mental health difficulty in 53% (19/36) of patients, emphasizing psychosocial burden. (ho2024alteredskinmicrobiome pages 2-4)

4. Genetic / molecular information

4.1 Causal genes (high-confidence examples from recent cohorts)

ARCI (example gene distribution in a 2024 Italian cohort, n=74): - TGM1: 18/74 (24.3%) - ALOX12B: 18/74 (24.3%) - CYP4F22: 12/74 (16.2%) - ABCA12: 9/74 (12.2%) - ALOXE3: 7/74 (9.5%) - NIPAL4: 7/74 (9.5%) - CERS3 / PNPLA1 / SDR9C7: 1/74 each (1.4%) (diociaiuti2024crosssectionalstudyon pages 4-5, diociaiuti2024crosssectionalstudyon media 464df4f0)

Visual evidence (gene frequencies and severity scores): (diociaiuti2024crosssectionalstudyon media 464df4f0)

4.2 Pathogenic variant classes and consequences

Across cohorts, variant classes include SNVs/indels and structural variants (e.g., microduplications in TGM1 and microdeletions affecting CYP4F22 and NIPAL4 in the Italian ARCI study). (diociaiuti2024crosssectionalstudyon pages 4-5)

Mechanistic consequence examples (review-level): - X‑linked ichthyosis: STS deficiency leading to cholesterol sulfate accumulation and barrier disruption (review summary). (panda2025moleculargeneticsand pages 1-2, panda2025moleculargeneticsand pages 2-3)

Direct mechanistic quote (review-level framing): “The disturbance in the epidermal barrier function is at the core of ichthyosis pathogenesis.” (panda2025moleculargeneticsand pages 2-3)

4.3 Modifier genes, epigenetics

No modifier-gene or epigenetic datasets specific to inherited ichthyosis were retrieved in the current corpus.

5. Environmental information

Inherited ichthyosis is primarily genetic. Environmental factors in the retrieved sources are mainly relevant to complications and management (e.g., infection risk and wound care). A detailed toxin/lifestyle exposure literature was not retrieved; thus no evidence-based environmental risk factor list is provided.

6. Mechanism / pathophysiology

6.1 Barrier defect → inflammation → infection susceptibility

A mechanistic chain supported by 2024 data: 1) Germline variants in barrier/cornification genes and lipid metabolism genes → 2) Altered epidermal structure and barrier permeability → 3) Dysbiosis with reduced commensals and increased pathogenic colonization → 4) Systemic and cutaneous immune activation (Th17/Th2 and JAK/STAT signatures) → 5) Clinical manifestations: scaling/hyperkeratosis, pruritus, infections, impaired wound healing.

The 2024 Southeast Asian study explicitly links microbiome changes and immune signaling: “Microbiome meta-analysis revealed distinct microbial populations, reduced commensal microbiota, and higher colonization by pathogenic species. This correlated with increased production of inflammatory cytokines, including Th17 and JAK/STAT signaling, in peripheral blood mononuclear cells.” (Ho 2024, Human Genomics, Apr 2024; https://doi.org/10.1186/s40246-024-00603-x) (ho2024alteredskinmicrobiome pages 1-2)

Additional quantitative immuno-microbiome findings include elevated neutrophils across congenital ichthyosis clusters and increased STAT3 phosphorylation (pY705) in several dysbiosis clusters, consistent with JAK/STAT pathway activation. (ho2024alteredskinmicrobiome pages 10-13)

6.2 Cell types (CL) and GO terms (suggestions)

Based on inflammation and barrier biology reported: - Cell types (CL term suggestions): - Keratinocyte (CL:0000312) - Neutrophil (CL:0000775) - CD4-positive, alpha-beta T cell (CL:0000624) including Th17 and Th2 subsets - Peripheral blood mononuclear cell (broad category; not a single CL type)

  • GO biological process term suggestions:
  • Keratinization (GO:0031424)
  • Epidermis development (GO:0008544)
  • Skin barrier establishment (GO:0061436)
  • Defense response to bacterium (GO:0042742)
  • IL‑17 signaling pathway (GO:0038111)
  • JAK‑STAT cascade (GO:0007259)

6.3 Model organism / experimental mechanism note

A review source notes that SMS2 knockout in mice produced an ichthyotic phenotype with epidermal hyperplasia and hyperkeratosis, supporting lipid pathway involvement in barrier integrity. (panda2025moleculargeneticsand pages 2-3)

7. Anatomical structures affected

Organ/tissue level

  • Primary: skin/epidermis (UBERON suggestion: skin UBERON:0002097; epidermis UBERON:0001003).
  • Common secondary involvement in cohorts includes wounds/infections and complications such as sepsis in severe subtypes. In the 2024 congenital ichthyosis cohort, lethal infant sepsis occurred in 6 cases (4 HI, 1 LI, 1 EI). (ho2024alteredskinmicrobiome pages 2-4)

Subcellular/cellular compartments (GO cellular component suggestions)

  • Cornified envelope (GO:0001533)
  • Keratin filament (GO:0045095)
  • Lamellar body (GO:0042599) (suggested by ARCI ultrastructural discussion context; direct GO mapping not explicitly provided in the evidence corpus)

8. Temporal development

  • Onset: Many forms are congenital/early infancy, including collodion membrane presentations in ARCI (see diagnostic cohort description). (fioretti2024comprehensivemolecularanalysis pages 2-3)
  • Course: Chronic lifelong disease with variable severity, influenced by genotype; a 2024 ARCI cohort demonstrated gene-associated severity differences (e.g., higher mean severity in TGM1 vs CYP4F22). (diociaiuti2024crosssectionalstudyon pages 4-5, diociaiuti2024crosssectionalstudyon media 464df4f0)

9. Inheritance and population

Inheritance patterns

  • ARCI is typically autosomal recessive with biallelic variants in barrier/lipid pathway genes (e.g., TGM1, ALOX12B). (diociaiuti2024crosssectionalstudyon pages 4-5, fioretti2024comprehensivemolecularanalysis pages 2-3)
  • X‑linked ichthyosis affects males with X‑linked STS involvement (XLI/XLRI). (fioretti2024comprehensivemolecularanalysis pages 1-2, marathe2023topicalisotretinoin(tmb001) pages 1-3)

Epidemiology (recently cited quantitative estimates)

A 2024 molecular diagnostic paper cited global frequency estimates: - ARCI prevalence: ~1:100,000–300,000 worldwide - X‑linked ichthyosis incidence: ~1:2000–1:6000 male newborns (fioretti2024comprehensivemolecularanalysis pages 1-2)

A 2023 review excerpt (from Nature Reviews Disease Primers) includes country-level prevalence figures presented in mixed formats; for example, it lists the United States as 200,000 patients (61 per 100,000). (gutierrezcerrajero2023ichthyosis pages 11-13)

Evidence caveat: The extracted 2023 primer chunks available in this tool run are not the full article and include tabulated prevalence figures without full definitional context; therefore, these values should be treated as secondary/compiled epidemiology rather than primary incidence studies. (gutierrezcerrajero2023ichthyosis pages 11-13)

10. Diagnostics

10.1 Clinical evaluation and pathology

Clinical evaluation plus family history guides initial classification, but phenotypic overlap and evolution can make subtyping difficult. The 2024 NGS study emphasizes that definitive classification requires DNA analysis. (fioretti2024comprehensivemolecularanalysis pages 2-3)

Review-level sources note that confirmation may include skin biopsy histology and electron microscopy in selected settings. (panda2025moleculargeneticsand pages 1-2)

10.2 Genetic testing (current real-world implementation)

Multi-gene NGS panels / WES/WGS: - A 2024 Italian series used targeted filtering across 54 ichthyosis/erythrokeratoderma genes in a high‑coverage NGS workflow and achieved molecular diagnosis in all 17/17 patients. (fioretti2024comprehensivemolecularanalysis pages 2-3) - The authors conclude comprehensive molecular testing can function as a first-tier diagnostic classifier for nonsyndromic ichthyosis. (fioretti2024comprehensivemolecularanalysis pages 1-2)

Direct quote (diagnostic rationale): “only the identification of the genetic defect allows the correct classification.” (fioretti2024comprehensivemolecularanalysis pages 1-2)

10.3 Differential diagnosis

Not systematically extractable from this evidence corpus; however, the diagnostic cohorts emphasize overlap across ichthyosis subtypes and the need for genetic confirmation. (fioretti2024comprehensivemolecularanalysis pages 2-3)

11. Outcome / prognosis

Severity and complications vary strongly by subtype and genotype.

Infection/sepsis outcomes (2024 congenital ichthyosis cohort): - 6 lethal infant sepsis cases (4 HI, 1 LI, 1 EI) - 10 treatable childhood sepsis cases (HI 3/8; IV 7/15) (ho2024alteredskinmicrobiome pages 2-4)

Evidence limitation: Survival/life expectancy estimates for specific inherited ichthyosis subtypes were not comprehensively retrieved (outside this cohort’s sepsis outcomes).

12. Treatment

12.1 Standard-of-care (symptomatic) therapy (general)

Symptom-directed care typically includes emollients/humectants/keratolytics and, in more severe disease, systemic retinoids; however, this report emphasizes recent targeted therapeutics and trial evidence because detailed guideline text was not available in the retrieved corpus. (panda2025moleculargeneticsand pages 2-3)

12.2 Recent developments (2023–2024): topical retinoid formulation (TMB‑001)

Topical isotretinoin (TMB‑001), Phase 2b CONTROL study (published May 2023): - Population: participants ≥9 years with confirmed XLRI or ARCI‑lamellar ichthyosis; n=33 randomized 1:1:1. (marathe2023topicalisotretinoin(tmb001) pages 1-3) - Efficacy responders reported in excerpt: VIIS‑50 achieved by 64% / 40% / 33% (TMB‑001 0.05% / 0.1% / vehicle) and IGA success by 55% / 40% / 8%, with mean baseline BSA affected 74%. (marathe2023topicalisotretinoin(tmb001) pages 3-4) - Safety: “Topical isotretinoin (tmb-001) treatment for 12 weeks did not result in clinically relevant laboratory abnormalities…” (Marathe 2023, Dermatology and Therapy, May 2023; https://doi.org/10.1007/s13555-023-00923-1). (marathe2023topicalisotretinoin(tmb001) pages 1-3)

Application/implementation: The study highlights a potential path to retinoid efficacy with reduced systemic laboratory toxicity compared with oral retinoids, which are known to cause clinically significant lab changes. (marathe2023topicalisotretinoin(tmb001) pages 1-3)

MAXO suggestions: topical retinoid therapy; topical keratolytic therapy (ontology IDs not retrieved in corpus).

12.3 Recent developments: topical gene therapy for TGM1-deficient ARCI (KB105)

KB105 (HSV‑1 vector expressing human TGM1; topical gel): - Phase I/II registry (NCT04047732; first posted 2019): intra‑patient comparison; up to 6 adults with genetically confirmed TGM1-deficient ARCI (null mutation) and lamellar ichthyosis; includes immunofluorescence measurement of TG1 in treated skin. (https://clinicaltrials.gov/study/NCT04047732) (NCT04047732 chunk 1) - Phase 2 registry (NCT05735158; posted 2023): intrasubject randomized, placebo-controlled, triple-masked study; enrollment 15; includes participants ≥6 months with genetically confirmed TGM1-deficient ARCI and lamellar ichthyosis; weekly application; primary endpoint composite IGA responder at Week 9. (https://clinicaltrials.gov/study/NCT05735158) (NCT05735158 chunk 1)

Expert/authoritative interpretation: These trials operationalize a pathogenesis‑based approach (gene replacement in skin) enabled by localized topical delivery, aligning with review-level framing that gene therapy is emerging for ichthyosis. (panda2025moleculargeneticsand pages 1-2)

MAXO suggestions: gene therapy; topical gene delivery (IDs not retrieved in corpus).

12.4 Biologics / immune-phenotype–guided therapy

Secukinumab (anti‑IL‑17A) in ichthyoses, Phase 2 trial: - NCT03041038: randomized, crossover, quadruple‑masked Phase 2; n=20; included ARCI (LI/CIE), epidermolytic ichthyosis, and Netherton syndrome; primary efficacy outcome reduction at Week 16 in Ichthyosis Area Severity Index (IASI). (NCT03041038 chunk 1)

Dupilumab repurposing trial for pruritic genetic inflammatory skin disorders (includes genetic skin disorders; ichthyosis may be included depending on phenotype): - NCT05649098: open-label pilot; n=30; primary goal is improvement in itch, targeting ≥50% of patients achieving ≥2‑point Worst Itch NRS reduction. (NCT05649098 chunk 1)

Mechanism–application link: The observed Th17/JAK/STAT activation and infection susceptibility in congenital ichthyosis supports the clinical rationale for immunomodulatory trials in selected immune-phenotypes. (ho2024alteredskinmicrobiome pages 1-2, NCT03041038 chunk 1)

13. Prevention

Primary prevention of inherited ichthyosis is limited (genetic disorders), but secondary prevention is feasible via early genetic diagnosis and counseling; diagnostic studies emphasize that NGS enables precise diagnosis and genetic counseling. (fioretti2024comprehensivemolecularanalysis pages 1-2, fioretti2024comprehensivemolecularanalysis pages 2-3)

14. Other species / natural disease

No OMIA/veterinary natural disease evidence was retrieved in this tool run; cannot be asserted.

15. Model organisms

Evidence in this corpus is limited; one review reports an ichthyosis-like phenotype in SMS2 knockout mice, supporting sphingomyelin/lipid pathway contributions to epidermal homeostasis. (panda2025moleculargeneticsand pages 2-3)

Recent quantitative findings summary (for knowledge base ingestion)

The table below consolidates key 2023–2024 quantitative findings across genetics, cohorts, mechanistic studies, and therapeutic trials.

Study / dataset Year Population / design Key quantitative findings URL Citations
Diociaiuti et al., Italian ARCI cohort 2024 Cross-sectional single-center cohort of 74 genetically diagnosed ARCI patients Subtypes: lamellar ichthyosis 50/74 (67.5%), CIE 18/74 (24.3%), harlequin ichthyosis 2/74 (2.7%), other ARCI 4/74 (5.4%). Mutated genes: TGM1 18/74 (24.3%), mean severity score 40.3 ± 14.1; ALOX12B 18/74 (24.3%), 23.2 ± 11.3; CYP4F22 12/74 (16.2%), 17.9 ± 5.1; ABCA12 9/74 (12.2%; higher severity than most other genes); ALOXE3 7/74 (9.5%); NIPAL4 7/74 (9.5%); CERS3, PNPLA1, SDR9C7 1/74 each (1.4%). 83 distinct sequence variants, including 25 previously undescribed; 2 microduplications in TGM1 and 2 microdeletions affecting CYP4F22/NIPAL4. Frequent features: hypohidrosis 54/74 (73.0%), heat intolerance 46/74 (62.2%), ear deformities 22/74 (29.7%), alopecia 16/74 (21.6%). https://doi.org/10.1159/000536366 (diociaiuti2024crosssectionalstudyon pages 4-5, diociaiuti2024crosssectionalstudyon media 464df4f0)
Fioretti et al., NGS first-tier molecular testing 2024 17 unrelated Italian patients with nonsyndromic ichthyosis; massively parallel sequencing of >50 ichthyosis-related genes; unaffected comparison set n=300 Molecular cause identified in 17/17 (100%). Diagnoses: 8/17 ARCI (ALOX12B, NIPAL4, TGM1), 3/17 with biallelic FLG loss-of-function, 6/11 males with X-linked ichthyosis. 24 disease-causing alleles detected, including 8 novel variants; included a synonymous TGM1 variant causing a splicing defect. Study supports multigene NGS as an effective first-tier diagnostic/classification test. https://doi.org/10.3390/biomedicines12051112 (fioretti2024comprehensivemolecularanalysis pages 1-2, fioretti2024comprehensivemolecularanalysis pages 2-3)
Marathe et al., TMB-001 CONTROL Phase 2b 2023 Randomized, double-blind, vehicle-controlled phase 2b trial; participants ≥9 years with genetically confirmed XLRI or ARCI-lamellar ichthyosis 33 enrolled: TMB-001 0.05% n=11, TMB-001 0.1% n=10, vehicle n=12; subtype split 52% ARCI-LI / 48% XLRI. Key efficacy: VIIS-50 achieved by 64% / 40% / 33% (0.05% / 0.1% / vehicle); IGA success by 55% / 40% / 8%. Mean baseline BSA affected 74%. Safety: 3/33 (9%) withdrew due to treatment-emergent AEs; no serious AEs or deaths; laboratory abnormalities were isolated/asymptomatic and authors reported no clinically significant laboratory changes through 12 weeks. https://doi.org/10.1007/s13555-023-00923-1 (marathe2023topicalisotretinoin(tmb001) pages 3-4, marathe2023topicalisotretinoin(tmb001) pages 1-3, NCT04154293 chunk 2)
Ho et al., microbiome / inflammation / JAK-STAT study 2024 Southeast Asian case-control study with congenital ichthyosis patients and healthy controls; WES plus skin metagenomics and immune profiling Cohort: 36 CI patients + 15 controls (total 51); mean age 10.2 years, median follow-up 4.3 years. Subtypes: IV 15, HI 8, LI 3, EI 4, TTD 3, ARC 1, SLS 2. Clinical burden: hyperkeratosis 100%, itch 97.2%, microbial infection 94.4%, erythroderma 72.2%, mental health difficulty 53% (19/36). Sepsis: 6 lethal infant cases (4 HI, 1 LI, 1 EI) plus 10 treatable childhood sepsis cases (HI 3/8; IV 7/15). Genetics: 20 novel + 31 recurrent/pathogenic variants. Mechanistic findings: reduced commensals, increased pathogenic colonization, elevated Th17 and JAK/STAT signaling; all CI clusters showed elevated neutrophils, eosinophils elevated in one cluster, and STAT3 pY705 increased in P2/P3/P4. https://doi.org/10.1186/s40246-024-00603-x (ho2024alteredskinmicrobiome pages 10-13, ho2024alteredskinmicrobiome pages 1-2, ho2024alteredskinmicrobiome pages 2-4)
KB105 topical gene therapy, NCT04047732 2019 registry record Phase I/II intra-patient topical gene therapy trial for TGM1-deficient ARCI Planned enrollment up to 6 adults. KB105 is a replication-incompetent, non-integrating HSV-1 vector expressing human TGM1 in topical gel. Key inclusion: genetically confirmed TGM1-deficient ARCI with a null TGM1 mutation, clinical diagnosis of lamellar ichthyosis, age ≥18 years, target-area IGA 3–4. Primary focus: safety/tolerability and IGA improvement over ~12 weeks. https://clinicaltrials.gov/study/NCT04047732 (NCT04047732 chunk 1)
KB105 topical gene therapy, NCT05735158 2023 registry record Phase 2, intrasubject randomized, placebo-controlled, triple-masked study of topical KB105 Planned enrollment 15 children/adults. Weekly topical KB105 vs matched placebo on paired target areas, with optional open-label area. Key inclusion: age ≥6 months, genetically confirmed TGM1-deficient ARCI, clinical diagnosis of lamellar ichthyosis, paired target areas with same scaling severity and severity ≥3. Primary endpoint: composite IGA responder at Week 9. https://clinicaltrials.gov/study/NCT05735158 (NCT05735158 chunk 1)

Table: This table compiles recent quantitative findings across genetics, clinical cohorts, immune/microbiome studies, and therapeutic trials in inherited ichthyosis. It highlights sample sizes, subtype distributions, gene frequencies, severity metrics, and design features most useful for a disease knowledge base.

Evidence gaps (what is not currently supported by the retrieved corpus)

  • Verified MONDO/Orphanet/OMIM/MeSH/ICD mappings for the umbrella term “inherited ichthyosis”.
  • Comprehensive modifier gene / epigenetic associations.
  • Systematic environmental risk/protective factors.
  • Detailed guideline algorithms for treatment stratified by subtype (a 2024 guideline update appears in search results but was unobtainable in this run).

References

  1. (xiang2025theclinicalspectrum pages 1-2): Ruiyu Xiang, Xin Huang, Yihe Liu, Shuya Sun, Di Hua, Ran Mo, Yong Yang, and Zhiming Chen. The clinical spectrum of rare inherited ichthyosis in china: a review of thirty-five cases. Acta Dermato-Venereologica, Jul 2025. URL: https://doi.org/10.2340/actadv.v105.41100, doi:10.2340/actadv.v105.41100. This article has 1 citations and is from a domain leading peer-reviewed journal.

  2. (fioretti2024comprehensivemolecularanalysis pages 1-2): Tiziana Fioretti, Fabrizio Martora, Ilaria De Maggio, Adelaide Ambrosio, Carmelo Piscopo, Sabrina Vallone, Felice Amato, Diego Passaro, Fabio Acquaviva, Francesca Gaudiello, Daniela Di Girolamo, Valeria Maiolo, Federica Zarrilli, Speranza Esposito, Giuseppina Vitiello, Luigi Auricchio, Elena Sammarco, Daniele De Brasi, Roberta Petillo, Antonella Gambale, Fabio Cattaneo, Rosario Ammendola, Paola Nappa, and Gabriella Esposito. Comprehensive molecular analysis of disease-related genes as first-tier test for early diagnosis, classification, and management of patients affected by nonsyndromic ichthyosis. Biomedicines, 12:1112, May 2024. URL: https://doi.org/10.3390/biomedicines12051112, doi:10.3390/biomedicines12051112. This article has 2 citations.

  3. (panda2025moleculargeneticsand pages 2-3): Suman Panda. Molecular genetics and pathogenesis of ichthyosis. Annals of Medical and Surgical Dermatology, Jan 2025. URL: https://doi.org/10.61577/amsd.2023.100004, doi:10.61577/amsd.2023.100004. This article has 1 citations.

  4. (marathe2023topicalisotretinoin(tmb001) pages 1-3): Kalyani Marathe, Joyce M. C. Teng, Scott Guenthner, Christopher G. Bunick, Steven Kempers, Kimmie Eads, Leslie Castelo-Soccio, Alan M. Mendelsohn, Jessica Raiz, and Dédée F. Murrell. Topical isotretinoin (tmb-001) treatment for 12 weeks did not result in clinically relevant laboratory abnormalities in participants with congenital ichthyosis in the phase 2b control study. Dermatology and Therapy, 13:1255-1264, May 2023. URL: https://doi.org/10.1007/s13555-023-00923-1, doi:10.1007/s13555-023-00923-1. This article has 6 citations.

  5. (ho2024alteredskinmicrobiome pages 2-4): Minh Ho, Huynh-Nga Nguyen, Minh Van Hoang, Tien Thuy Thi Bui, Bao-Quoc Vu, Truc Huong Thi Dinh, Hoa Thi My Vo, Diana C. Blaydon, Sherif A. Eldirany, Christopher G. Bunick, and Chi-Bao Bui. Altered skin microbiome, inflammation, and jak/stat signaling in southeast asian ichthyosis patients. Human Genomics, Apr 2024. URL: https://doi.org/10.1186/s40246-024-00603-x, doi:10.1186/s40246-024-00603-x. This article has 14 citations and is from a peer-reviewed journal.

  6. (fioretti2024comprehensivemolecularanalysis pages 2-3): Tiziana Fioretti, Fabrizio Martora, Ilaria De Maggio, Adelaide Ambrosio, Carmelo Piscopo, Sabrina Vallone, Felice Amato, Diego Passaro, Fabio Acquaviva, Francesca Gaudiello, Daniela Di Girolamo, Valeria Maiolo, Federica Zarrilli, Speranza Esposito, Giuseppina Vitiello, Luigi Auricchio, Elena Sammarco, Daniele De Brasi, Roberta Petillo, Antonella Gambale, Fabio Cattaneo, Rosario Ammendola, Paola Nappa, and Gabriella Esposito. Comprehensive molecular analysis of disease-related genes as first-tier test for early diagnosis, classification, and management of patients affected by nonsyndromic ichthyosis. Biomedicines, 12:1112, May 2024. URL: https://doi.org/10.3390/biomedicines12051112, doi:10.3390/biomedicines12051112. This article has 2 citations.

  7. (diociaiuti2024crosssectionalstudyon pages 4-5): Andrea Diociaiuti, Marialuisa Corbeddu, Sabrina Rossi, Elisa Pisaneschi, Claudia Cesario, Angelo Giuseppe Condorelli, Tonia Samela, Simona Giancristoforo, Adriano Angioni, Giovanna Zambruno, Antonio Novelli, Rita Alaggio, Damiano Abeni, and May El Hachem. Cross-sectional study on autosomal recessive congenital ichthyoses: association of genotype with disease severity, phenotypic, and ultrastructural features in 74 italian patients. Dermatology (Basel, Switzerland), 240:397-413, Apr 2024. URL: https://doi.org/10.1159/000536366, doi:10.1159/000536366. This article has 10 citations.

  8. (diociaiuti2024crosssectionalstudyon media 464df4f0): Andrea Diociaiuti, Marialuisa Corbeddu, Sabrina Rossi, Elisa Pisaneschi, Claudia Cesario, Angelo Giuseppe Condorelli, Tonia Samela, Simona Giancristoforo, Adriano Angioni, Giovanna Zambruno, Antonio Novelli, Rita Alaggio, Damiano Abeni, and May El Hachem. Cross-sectional study on autosomal recessive congenital ichthyoses: association of genotype with disease severity, phenotypic, and ultrastructural features in 74 italian patients. Dermatology (Basel, Switzerland), 240:397-413, Apr 2024. URL: https://doi.org/10.1159/000536366, doi:10.1159/000536366. This article has 10 citations.

  9. (panda2025moleculargeneticsand pages 3-4): Suman Panda. Molecular genetics and pathogenesis of ichthyosis. Annals of Medical and Surgical Dermatology, Jan 2025. URL: https://doi.org/10.61577/amsd.2023.100004, doi:10.61577/amsd.2023.100004. This article has 1 citations.

  10. (NCT05610306 chunk 1): Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis. Maastricht University Medical Center. 2022. ClinicalTrials.gov Identifier: NCT05610306

  11. (panda2025moleculargeneticsand pages 1-2): Suman Panda. Molecular genetics and pathogenesis of ichthyosis. Annals of Medical and Surgical Dermatology, Jan 2025. URL: https://doi.org/10.61577/amsd.2023.100004, doi:10.61577/amsd.2023.100004. This article has 1 citations.

  12. (ho2024alteredskinmicrobiome pages 1-2): Minh Ho, Huynh-Nga Nguyen, Minh Van Hoang, Tien Thuy Thi Bui, Bao-Quoc Vu, Truc Huong Thi Dinh, Hoa Thi My Vo, Diana C. Blaydon, Sherif A. Eldirany, Christopher G. Bunick, and Chi-Bao Bui. Altered skin microbiome, inflammation, and jak/stat signaling in southeast asian ichthyosis patients. Human Genomics, Apr 2024. URL: https://doi.org/10.1186/s40246-024-00603-x, doi:10.1186/s40246-024-00603-x. This article has 14 citations and is from a peer-reviewed journal.

  13. (ho2024alteredskinmicrobiome pages 10-13): Minh Ho, Huynh-Nga Nguyen, Minh Van Hoang, Tien Thuy Thi Bui, Bao-Quoc Vu, Truc Huong Thi Dinh, Hoa Thi My Vo, Diana C. Blaydon, Sherif A. Eldirany, Christopher G. Bunick, and Chi-Bao Bui. Altered skin microbiome, inflammation, and jak/stat signaling in southeast asian ichthyosis patients. Human Genomics, Apr 2024. URL: https://doi.org/10.1186/s40246-024-00603-x, doi:10.1186/s40246-024-00603-x. This article has 14 citations and is from a peer-reviewed journal.

  14. (gutierrezcerrajero2023ichthyosis pages 11-13): Carlos Gutiérrez-Cerrajero, Eli Sprecher, Amy S. Paller, Masashi Akiyama, Juliette Mazereeuw-Hautier, Angela Hernández-Martín, and Rogelio González-Sarmiento. Ichthyosis. Nature Reviews Disease Primers, 9:1-23, Jan 2023. URL: https://doi.org/10.1038/s41572-022-00412-3, doi:10.1038/s41572-022-00412-3. This article has 93 citations.

  15. (marathe2023topicalisotretinoin(tmb001) pages 3-4): Kalyani Marathe, Joyce M. C. Teng, Scott Guenthner, Christopher G. Bunick, Steven Kempers, Kimmie Eads, Leslie Castelo-Soccio, Alan M. Mendelsohn, Jessica Raiz, and Dédée F. Murrell. Topical isotretinoin (tmb-001) treatment for 12 weeks did not result in clinically relevant laboratory abnormalities in participants with congenital ichthyosis in the phase 2b control study. Dermatology and Therapy, 13:1255-1264, May 2023. URL: https://doi.org/10.1007/s13555-023-00923-1, doi:10.1007/s13555-023-00923-1. This article has 6 citations.

  16. (NCT04047732 chunk 1): Topical KB105 Gene Therapy for the Treatment of TGM1-deficient Autosomal Recessive Congenital Ichthyosis (ARCI). Krystal Biotech, Inc.. 2019. ClinicalTrials.gov Identifier: NCT04047732

  17. (NCT05735158 chunk 1): Topical KB105 for the Treatment of TGM1-deficient Autosomal Recessive Congenital Ichthyosis (ARCI). Krystal Biotech, Inc.. 2023. ClinicalTrials.gov Identifier: NCT05735158

  18. (NCT03041038 chunk 1): Amy Paller. The Efficacy and Safety of Secukinumab in Patients With Ichthyoses. Northwestern University. 2016. ClinicalTrials.gov Identifier: NCT03041038

  19. (NCT05649098 chunk 1): Amy Paller. Repurposing Dupilumab for Management of Pruritic Genetic Inflammatory Skin Disorders. Northwestern University. 2023. ClinicalTrials.gov Identifier: NCT05649098

  20. (NCT04154293 chunk 2): A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis. Timber Pharmaceuticals Inc.. 2019. ClinicalTrials.gov Identifier: NCT04154293