Autosomal Recessive Congenital Ichthyosis

Mendelian MONDO:0017265 Pathograph 31 Show in embeddings browser inherited ichthyosis disorder of cornification

Autosomal recessive congenital ichthyosis (ARCI) is a nonsyndromic, genetically heterogeneous disorder of cornification. It is defined by biallelic pathogenic variants in genes controlling epidermal differentiation, cornified-envelope cross-linking, and lipid handling, producing abnormal skin scaling from birth or early infancy with variable erythroderma and barrier compromise.

Ask OpenScientist

Ask a research question about Autosomal Recessive Congenital Ichthyosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

👪

Inheritance

Autosomal recessive HP:0000007

ARCI is caused by biallelic pathogenic variants in multiple causative genes.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:36980989 SUPPORT Human Clinical

"ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."

Directly supports autosomal recessive inheritance through biallelic pathogenic variants.

◆

Subtypes

Lamellar Ichthyosis MONDO:0017778

67.5% in a 74-patient Italian ARCI cohort

Major ARCI phenotype with generalized large scales, typically less prominent erythroderma, and variable ectropion or palmoplantar involvement.

Show evidence (1 reference)

PMID:38588653 SUPPORT Human Clinical

"RESULTS: 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."

Supports lamellar ichthyosis as the largest major subtype in this genetically confirmed ARCI cohort.

Congenital Ichthyosiform Erythroderma MONDO:0019306

24.3% in a 74-patient Italian ARCI cohort

Major ARCI phenotype characterized by generalized scaling with more conspicuous erythroderma than classic lamellar ichthyosis.

Show evidence (1 reference)

PMID:38588653 SUPPORT Human Clinical

Supports congenital ichthyosiform erythroderma as a major ARCI subtype in a genetically confirmed cohort.

Harlequin Ichthyosis MONDO:0009443

2.7% in a 74-patient Italian ARCI cohort

Severe ARCI phenotype, most often linked to ABCA12 loss-of-function, with profound neonatal hyperkeratosis and barrier compromise. The neonate is encased in thick plate-like armour separated by deep fissures, with ectropion, eclabium and flattened ears. It is no longer invariably fatal: with modern neonatal care, reported survival is around half, and deaths concentrate in the first three months from sepsis and respiratory failure - the direct consequences of a stratum corneum that cannot function as a barrier. Survivors carry a chronic severe scaling erythroderma. Genotype tracks outcome, with homozygous loss-of-function alleles reported in all deaths in the largest series and compound heterozygosity over-represented among survivors. The reported association between early oral retinoid treatment and survival in that series is deliberately not curated here as a treatment effect: it is a retrospective, questionnaire-based comparison with no randomisation and obvious scope for confounding by indication and by era of neonatal care, and the source itself claims only that early retinoids may improve survival.

Show evidence (4 references)

PMID:36980989 SUPPORT Human Clinical

"The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12."

Supports harlequin ichthyosis as the severe ABCA12-associated ARCI phenotype.

PMID:21339420 SUPPORT Human Clinical

"Of the 45 cases, the ages of the survivors ranged from 10 months to 25 years, with an overall survival rate of 56%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% of cases."

Quantifies survival and the timing and cause of death in the largest reported harlequin ichthyosis series, establishing that the disorder is severe but not invariably fatal.

PMID:21339420 SUPPORT Human Clinical

"Mutation analysis revealed that 52% of survivors had compound heterozygous mutations, whereas all deaths were associated with homozygous mutations."

Documents the genotype-outcome relationship. Note this is an observed association in a retrospective questionnaire-based series, not a demonstrated dose-response, and is curated as such.

+ 1 more reference

ARCI1 (TGM1) MONDO:0009441

TGM1 hgnc:11777 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is TGM1. It was one of the two most frequent genotypes in the 74-patient Italian cohort, carried a significantly higher mean ichthyosis severity score than all genes other than ABCA12, and was the only genotype in which cholesterol clefts were seen on electron microscopy.

Show evidence (2 references)

PMID:36980989 SUPPORT Human Clinical

"ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."

Names TGM1 among the genes whose biallelic mutation causes ARCI.

PMID:38588653 SUPPORT Human Clinical

"Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."

Supports the ultrastructural finding that distinguishes this genotype in the cohort.

ARCI2 (ALOX12B) MONDO:0009439

ALOX12B hgnc:430 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is ALOX12B, encoding the epidermal lipoxygenase arachidonate 12-lipoxygenase, 12R type. It tied with TGM1 as the most frequent genotype in the 74-patient Italian cohort. Most patients with an ALOX12B or ALOXE3 genotype present with a mild erythrodermic ichthyosis.

Show evidence (3 references)

PMID:36980989 SUPPORT Human Clinical

"ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."

Names ALOX12B among the genes whose biallelic mutation causes ARCI.

PMID:33435499 SUPPORT Human Clinical

"The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively."

Identifies the enzyme ALOX12B encodes.

PMID:33435499 SUPPORT Human Clinical

"The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma."

Supports the typical severity of this arm in a 224-patient cohort.

ARCI3 (ALOXE3) MONDO:0011680

ALOXE3 hgnc:13743 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is ALOXE3, encoding the epidermis-type lipoxygenase-3. Deficiency of this enzyme and of the ALOX12B product disrupts epidermal barrier function and produces abnormal epidermal differentiation.

Show evidence (2 references)

PMID:36980989 SUPPORT Human Clinical

"ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."

Names ALOXE3 among the genes whose biallelic mutation causes ARCI.

PMID:33435499 SUPPORT Human Clinical

"Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation."

Supports the mechanism attributed to loss of the ALOXE3 product.

ARCI4A (ABCA12, non-harlequin) MONDO:0011026

ABCA12 hgnc:14637 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is ABCA12 and the phenotype is congenital ichthyosiform erythroderma or lamellar ichthyosis rather than harlequin ichthyosis. The split from ARCI4B tracks variant class: biallelic missense variants mainly give this presentation, while biallelic loss-of-function variants generally give harlequin ichthyosis, which this entry carries as the separate Harlequin Ichthyosis subtype.

Show evidence (1 reference)

PMID:36980989 SUPPORT Human Clinical

"Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI."

Supports the variant-class split that separates this arm from the harlequin arm.

ARCI5 (CYP4F22) MONDO:0011485

CYP4F22 hgnc:26820 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is CYP4F22. Patients with this genotype had the lowest mean ichthyosis severity score of any gene in the 74-patient Italian cohort.

Show evidence (1 reference)

PMID:38588653 SUPPORT Human Clinical

"The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients."

Supports the low-severity position of this genotype within the series.

ARCI6 (NIPAL4) MONDO:0012847

NIPAL4 hgnc:28018 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is NIPAL4. In the Italian cohort this genotype carried a distinctive combination of psoriasis-like lesions, a reticulate trunk scale pattern and striated keratoderma.

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 the phenotypic signature reported for this genotype.

ARCI8 (LIPN) MONDO:0013495

LIPN hgnc:23452 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is LIPN, epidermal lipase N. It was described as a late-onset form of recessive ichthyosis in a single large consanguineous pedigree, in which a 2 bp deletion segregated with the phenotype. LIPN is expressed exclusively in the epidermis and strongly induced during keratinocyte differentiation.

Show evidence (1 reference)

PMID:21439540 SUPPORT Human Clinical

"In the present study, we describe a late-onset form of recessive ichthyosis in a large consanguineous pedigree. By using a combination of homozygosity mapping and positional candidate-gene screening, we identified a 2 bp deletion in LIPN that segregated with the disease phenotype throughout the family."

The founding report establishing LIPN as an ARCI gene and describing the late-onset presentation.

ARCI9 (CERS3) MONDO:0014010

CERS3 hgnc:23752 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is CERS3, ceramide synthase 3. Loss of CERS3 reduces epidermis-specific very-long-chain ceramides and interferes with epidermal differentiation.

Show evidence (1 reference)

PMID:23754960 SUPPORT Human Clinical

"analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients"

Establishes CERS3 as a cause of non-syndromic ARCI.

ARCI10 (PNPLA1) MONDO:0014011

PNPLA1 hgnc:21246 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is PNPLA1. The gene was found through a spontaneous lamellar ichthyosis of the golden retriever and then confirmed in human ARCI families.

Show evidence (1 reference)

PMID:22246504 SUPPORT Human Clinical

"We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families."

The human genetic evidence establishing PNPLA1 as an ARCI gene.

ARCI12 (CASP14) MONDO:0015018

CASP14 hgnc:1502 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is CASP14, caspase-14. It is one of the thirteen genes screened on contemporary non-syndromic ARCI panels. Caspase-14 is the protease that carries out the terminal step of filaggrin catabolism, so this arm sits on a different branch of the cornification program from the lipid-pathway and transglutaminase arms.

Show evidence (1 reference)

PMID:35412663 SUPPORT BACKGROUND Human Clinical

"DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel."

Names CASP14 among the thirteen genes screened as the established non-syndromic ARCI gene set. Graded BACKGROUND because the gene list is prior knowledge the study restates in its methods rather than a result of the study.

ARCI13 (SDR9C7) MONDO:0033092

SDR9C7 hgnc:29958 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is SDR9C7, an enzyme that converts retinal into retinol. Homozygous missense variants were identified in three Lebanese families, and the locus proved to lie outside the previously mapped ARCI7 interval.

Show evidence (1 reference)

PMID:28173123 SUPPORT Human Clinical

"Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one..."

The human genetic evidence establishing SDR9C7 as an ARCI gene.

ARCI14 (SULT2B1) MONDO:0033091

SULT2B1 hgnc:11459 Autosomal recessive inheritance

Gene-defined arm of the numbered ARCI series in which the causative gene is SULT2B1, a cytosolic sulfotransferase. Loss of function abolishes cholesterol sulfate and raises cholesterol in organotypic skin cultures, placing this arm in the cholesterol rather than the acylceramide branch of epidermal lipid handling.

Show evidence (2 references)

PMID:28575648 SUPPORT Human Clinical

"Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI."

The human genetic evidence establishing SULT2B1 as an ARCI gene.

PMID:28575648 SUPPORT In Vitro

"By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1."

Supports the cholesterol-sulfate mechanism attributed to this arm.

⚙

Pathophysiology

Biallelic ARCI Gene Defects

ARCI begins with biallelic pathogenic variants in a heterogeneous set of genes involved in epidermal cornification, lipid transport, lipid metabolism, and filaggrin catabolism.

keratinocyte CL:0000312

TGM1 hgnc:11777 ABCA12 hgnc:14637 ALOX12B hgnc:430 ALOXE3 hgnc:13743 CYP4F22 hgnc:26820 NIPAL4 hgnc:28018 CERS3 hgnc:23752 PNPLA1 hgnc:21246 SDR9C7 hgnc:29958 SULT2B1 hgnc:11459 LIPN hgnc:23452 CASP14 hgnc:1502

keratinization GO:0031424 ⚠ ABNORMAL lipid metabolic process GO:0006629 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Cornified Envelope Cross-Linking Defect

Epidermal Lipid Processing and Transport Defect

Defective Filaggrin Catabolism and Natural Moisturizing Factor Generation

Show evidence (2 references)

PMID:36980989 SUPPORT Human Clinical

"ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."

Directly supports the core biallelic ARCI gene spectrum.

PMID:35412663 SUPPORT BACKGROUND Human Clinical

Extends the gene set of this node beyond the ten-gene list above to the thirteen genes screened on contemporary non-syndromic ARCI panels, which is where LIPN and CASP14 come from. Graded BACKGROUND because the gene list is prior knowledge the study restates in its methods.

Cornified Envelope Cross-Linking Defect

TGM1-associated ARCI disrupts transglutaminase-dependent cornified-envelope formation in differentiating keratinocytes; this mechanism is associated with higher severity and thick brownish scales in cohort data.

keratinocyte CL:0000312

TGM1 hgnc:11777

epidermal cell differentiation GO:0009913 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Abnormal Stratum Corneum and Barrier Phenotype

Show evidence (2 references)

PMID:38588653 SUPPORT Human Clinical

"The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients."

Supports TGM1 as a high-severity ARCI genotype.

PMID:38588653 SUPPORT Human Clinical

"Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."

Supports a genotype-informative ultrastructural abnormality in TGM1-associated ARCI.

Epidermal Lipid Processing and Transport Defect

Multiple ARCI genes affect epidermal lipid metabolism, lipid transport, or acylceramide-related barrier biology. ABCA12-associated ARCI is especially severe when both alleles cause loss of function.

keratinocyte CL:0000312

ABCA12 hgnc:14637 ALOX12B hgnc:430 ALOXE3 hgnc:13743 CYP4F22 hgnc:26820 NIPAL4 hgnc:28018 CERS3 hgnc:23752 PNPLA1 hgnc:21246 SDR9C7 hgnc:29958 SULT2B1 hgnc:11459 LIPN hgnc:23452

lipid transport GO:0006869 ⚠ ABNORMAL ceramide biosynthetic process GO:0046513 ⚠ ABNORMAL establishment of skin barrier GO:0061436 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Abnormal Stratum Corneum and Barrier Phenotype

Show evidence (4 references)

PMID:36980989 SUPPORT Human Clinical

"Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI."

Supports ABCA12 functional severity as a determinant of the ARCI phenotype.

PMID:38588653 SUPPORT Human Clinical

"Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."

Supports lamellar-body abnormalities in lipid-barrier ARCI genotypes.

PMID:21439540 SUPPORT In Vitro

"LIPN encodes one of six acid lipases known to be involved in triglyceride metabolism in mammals . LIPN was found to be exclusively expressed in the epidermis and to be strongly induced during keratinocyte differentiation."

Places LIPN on this node: an epidermis-restricted acid lipase acting in triglyceride metabolism and induced during keratinocyte differentiation.

+ 1 more reference

Defective Filaggrin Catabolism and Natural Moisturizing Factor Generation

A third branch of the ARCI cornification lesion, distinct from transglutaminase cross-linking and from epidermal lipid handling. Caspase-14 is expressed in the suprabasal epidermis and activated during keratinocyte cornification, where it performs the terminal proteolytic step that breaks filaggrin down into the free amino acids and derivatives that make up the natural moisturizing factors of the stratum corneum. Where this step fails, filaggrin fragments accumulate and natural moisturizing factors are depleted. CASP14 is the ARCI gene assigned to this branch.

keratinocyte CL:0000312

CASP14 hgnc:1502

protein catabolic process GO:0030163 ↓ DECREASED establishment of skin barrier GO:0061436 ⚠ ABNORMAL

peptidase activity GO:0008233 ↓ DECREASED

skin epidermis UBERON:0001003

Downstream

Abnormal Stratum Corneum and Barrier Phenotype Loss of the terminal filaggrin degradation step depletes the natural moisturizing factors that keep the stratum corneum hydrated.

Show evidence (3 references)

PMID:21654840 SUPPORT Model Organism

"Caspase-14 is a protease that is mainly expressed in suprabasal epidermal layers and activated during keratinocyte cornification. Caspase-14-deficient mice display reduced epidermal barrier function and increased sensitivity to UVB radiation."

Supports the cell type, the epidermal location, the peptidase activity and the barrier consequence asserted by this node.

PMID:21654840 SUPPORT Model Organism

"Consequently, we show that the defective FLG degradation in caspase-14-deficient skin results in substantial reduction in the amount of NMFs, such as urocanic acid and pyrrolidone carboxylic acid."

Supports the protein-catabolism defect and the loss of natural moisturizing factors that this node asserts.

PMID:35412663 SUPPORT BACKGROUND Human Clinical

Supports CASP14 belonging to the non-syndromic ARCI gene set, which is what places this branch inside this disease rather than beside it. Graded BACKGROUND because the gene list is prior knowledge the study restates in its methods.

Abnormal Stratum Corneum and Barrier Phenotype

Defective cornification and lipid-barrier biology converge on abnormal stratum corneum structure, generalized scaling, variable erythema, and chronic skin symptoms.

keratinocyte CL:0000312

keratinization GO:0031424 ⚠ ABNORMAL epidermis development GO:0008544 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Abnormal skin scaling Abnormal stratum corneum structure manifests clinically as generalized scaling.

Erythroderma Barrier and cornification defects can produce diffuse erythema in congenital ichthyosiform erythroderma.

Hyperkeratosis Disordered keratinization and stratum corneum architecture produce hyperkeratotic skin thickening.

Ectropion Severe congenital barrier and cornification defects can tighten periorbital skin enough to evert the eyelids.

Alopecia Severe ARCI skin involvement can extend to hair-bearing areas and produce alopecia.

Eclabium Severe congenital ichthyosis can tighten facial skin enough to evert the lips.

Pruritus and quality-of-life burden Persistent barrier disruption and scaling can drive pruritic symptom burden.

Show evidence (1 reference)

PMID:38027029 SUPPORT Human Clinical

"Autosomal recessive congenital ichthyoses (ARCI) are a skin pathology due to genetic causes characterized by a variable degree of desquamation, accompanied by erythema."

Supports the clinical consequence of abnormal scaling and erythema arising from genetic skin-barrier disease.

⬡

Pathograph

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

●

Phenotypes

Head and Neck 2

Ectropion HP:0000656

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 ectropion as a genotype-associated clinical sign in ARCI.

Eclabium Eclabion HP:0012472

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 eclabium as a genotype-associated ARCI feature.

Immune 1

Erythroderma HP:0001019

Show evidence (1 reference)

PMID:38027029 SUPPORT Human Clinical

"Autosomal recessive congenital ichthyoses (ARCI) are a skin pathology due to genetic causes characterized by a variable degree of desquamation, accompanied by erythema."

Supports erythema as a variable clinical feature accompanying desquamation in ARCI.

Integument 4

Abnormal skin scaling Very frequent Ichthyosis HP:0008064

Show evidence (1 reference)

PMID:36980989 SUPPORT Human Clinical

"Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin."

Directly supports abnormal skin scaling as a defining ARCI manifestation.

Hyperkeratosis HP:0000962

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 thick scaling, particularly in TGM1-associated ARCI.

Alopecia HP:0001596

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 feature.

Pruritus and quality-of-life burden HP:0000989

Show evidence (1 reference)

PMID:38027029 SUPPORT Human Clinical

"The degree of symptoms is variable, different altered genes are involved, and the symptoms drastically affect patients' quality of life."

Supports clinically important symptom burden but does not quantify pruritus specifically.

🧬

Genetic Associations

TGM1 (Causative)

Gene: TGM1 hgnc:11777 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

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 in the cohort.

ALOX12B (Causative)

Gene: ALOX12B hgnc:430 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:38588653 SUPPORT Human Clinical

Supports ALOX12B as a common causative ARCI gene in the cohort.

PMID:33435499 SUPPORT Human Clinical

"Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3."

The largest reported allelic series for this gene.

CYP4F22 (Causative)

Gene: CYP4F22 hgnc:26820 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (1 reference)

PMID:38588653 SUPPORT Human Clinical

"The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients."

Supports a lower-severity CYP4F22-associated ARCI pattern in this cohort.

ABCA12 (Causative)

Gene: ABCA12 hgnc:14637 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:36980989 SUPPORT Human Clinical

"The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12."

Supports ABCA12 as the gene classically associated with harlequin ichthyosis.

PMID:36980989 SUPPORT Human Clinical

"Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI."

Supports variant-class correlation for ABCA12-associated ARCI phenotypes.

Variants (2)

ABCA12 biallelic loss-of-function variants

Biallelic loss-of-function variants generally cause harlequin ichthyosis.

ABCA12 biallelic missense variants

Biallelic missense variants mainly cause congenital ichthyosiform erythroderma or lamellar ichthyosis.

ALOXE3 (Causative)

Gene: ALOXE3 hgnc:13743 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:38588653 SUPPORT Human Clinical

Supports ALOXE3 as a causative ARCI gene in the cohort.

PMID:33435499 SUPPORT Human Clinical

"To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature."

Quantifies the reported allelic spectrum for this gene relative to its sibling lipoxygenase.

NIPAL4 (Causative)

Gene: NIPAL4 hgnc:28018 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

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 distinctive NIPAL4-associated features.

LIPN (Causative)

Gene: LIPN hgnc:23452 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:21439540 SUPPORT Human Clinical

The human genetic evidence establishing LIPN as an ARCI gene.

PMID:21439540 SUPPORT In Vitro

"LIPN was found to be exclusively expressed in the epidermis and to be strongly induced during keratinocyte differentiation."

Supports the epidermis-restricted expression that makes LIPN a plausible cornification gene.

Variants (1)

LIPN 2 bp deletion

A 2 bp deletion in LIPN segregating with the disease phenotype throughout the reported consanguineous family.

CERS3 (Causative)

Gene: CERS3 hgnc:23752 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:23754960 SUPPORT Human Clinical

Establishes CERS3 as a cause of non-syndromic ARCI, separating it from the contiguous-deletion syndrome in the same families.

PMID:23754960 SUPPORT In Vitro

"Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation."

Supports the ceramide-synthesis mechanism attributed to this gene.

PNPLA1 (Causative)

Gene: PNPLA1 hgnc:21246 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:22246504 SUPPORT Human Clinical

"We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families."

The human genetic evidence establishing PNPLA1 as an ARCI gene.

PMID:22246504 SUPPORT Model Organism

"We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs."

The canine model finding that led to the human gene.

SDR9C7 (Causative)

Gene: SDR9C7 hgnc:29958 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:28173123 SUPPORT Human Clinical

The human genetic evidence establishing SDR9C7 as an ARCI gene.

PMID:28173123 SUPPORT Human Clinical

"we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus"

Supports the statement that the SDR9C7 locus is distinct from the still-unsolved ARCI7 locus.

SULT2B1 (Causative)

Gene: SULT2B1 hgnc:11459 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:28575648 SUPPORT Human Clinical

The human genetic evidence establishing SULT2B1 as an ARCI gene.

PMID:28575648 SUPPORT In Vitro

Supports the cholesterol-sulfate mechanism attributed to this gene.

CASP14 (Causative)

Gene: CASP14 hgnc:1502 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:35412663 SUPPORT BACKGROUND Human Clinical

Names CASP14 within the established non-syndromic ARCI gene set. Graded BACKGROUND because the gene list is prior knowledge the study restates in its methods rather than a result of the study.

PMID:21654840 SUPPORT Model Organism

"Consequently, we show that the defective FLG degradation in caspase-14-deficient skin results in substantial reduction in the amount of NMFs, such as urocanic acid and pyrrolidone carboxylic acid."

Supports the filaggrin-catabolism mechanism through which caspase-14 loss impairs the stratum corneum.

💊

Medical Actions

Topical emollients and keratolytic/supportive topical therapy

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Topical treatments are first-line symptomatic management for scaling and barrier dysfunction.

Target Phenotypes: ichthyosis HP:0008064

Show evidence (1 reference)

PMID:38027029 SUPPORT Human Clinical

"Topical treatments are a first-choice strategy due to their ease of application and cost; however, enteral administration of retinoids offers greater efficacy, although with certain limitations."

Supports topical therapy as first-choice symptomatic treatment and retinoids as more efficacious but limited options.

Retinoid pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: isotretinoin CHEBI:6067

Systemic or topical retinoid therapy is used to reduce scaling in severe inherited ichthyosis, with efficacy balanced against tolerability and safety limitations.

Target Phenotypes: ichthyosis HP:0008064

Show evidence (2 references)

PMID:38027029 SUPPORT Human Clinical

"Topical treatments are a first-choice strategy due to their ease of application and cost; however, enteral administration of retinoids offers greater efficacy, although with certain limitations."

Supports retinoid pharmacotherapy as a more efficacious treatment class with limitations.

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 clinical development for congenital ichthyosis including ARCI-LI.

Topical TGM1 gene therapy

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

KB105 is a topical, non-integrating HSV-1 vector expressing TGM1 under clinical investigation for TGM1-deficient ARCI.

Mechanism Target:

RESTORES Cornified Envelope Cross-Linking Defect — Topical TGM1 replacement is intended to restore deficient transglutaminase 1 expression in affected skin.

Show evidence (2 references)

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.

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 a randomized phase 2 study of KB105 in children and adults with ARCI.

IL-17A-targeting biologic therapy

Action: Pharmacotherapy NCIT:C15986

Agent: secukinumab NCIT:C152315

Secukinumab has been studied as mechanism-based anti-inflammatory therapy in ichthyoses, reflecting evidence of IL-17A pathway activation in ichthyosis skin rather than a proven ARCI-specific standard of care.

Target Phenotypes: ichthyosis HP:0008064

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 across ichthyoses, but this trial record is not ARCI-specific.

🔬

Diagnosis

Multigene molecular testing

Diagnosis is increasingly confirmed by next-generation sequencing panels or broader sequencing with CNV-aware follow-up, because overlapping phenotypes make molecular classification important.

genetic testing NCIT:C15709

Results: Biallelic pathogenic variants in an ARCI gene confirm the molecular diagnosis.

Show evidence (4 references)

PMID:39189679 SUPPORT Human Clinical

"Diagnosis of ichthyosis was confirmed with genetic testing in 33 cases, and with conventional diagnostic methods, such as clinical findings, skin biopsy and family history of ichthyoses, in 55 cases."

Supports molecular testing as a diagnostic route for congenital ichthyoses.

PMID:39189679 SUPPORT Human Clinical

"During the study period next-generation sequencing became the genetic testing method of choice providing new opportunities in diagnostics."

Supports next-generation sequencing as the current preferred genetic testing method.

PMID:30578701 SUPPORT Human Clinical

"Sequence data analysis identified biallelic mutations in 106 families out of a total of 125 (85%), most of them (102, 96.2%) being homozygous, reflecting consanguinity in these families."

Gives the diagnostic yield of a targeted ichthyosis panel in a large consanguineous ARCI cohort, and the caveat that the yield is raised by consanguinity.

+ 1 more reference

Ultrastructural skin analysis

Transmission electron microscopy can provide genotype-informative clues, including cholesterol clefts in TGM1-mutated disease and abnormal lamellar bodies in SDR9C7- or CERS3-associated disease.

Results: Genotype-informative ultrastructural features can support ARCI classification.

Show evidence (1 reference)

PMID:38588653 SUPPORT Human Clinical

"Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."

Supports ultrastructural skin analysis as a genotype-informative diagnostic adjunct.

📈

Progression

Congenital onset

Age: Birth or early neonatal period

Show evidence (1 reference)

PMID:36980989 SUPPORT Human Clinical

"Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin."

Supports congenital onset and abnormal skin scaling as defining features.

Lifelong course

Age: Lifelong

Show evidence (1 reference)

PMID:38027029 SUPPORT Human Clinical

"Despite the treatment alternatives, ARCI will persist throughout life, disabling people."

Supports persistence of ARCI across the life course.

📊

Prevalence

Genetically confirmed Italian ARCI cohort

In the 74-patient Italian cohort, lamellar ichthyosis represented 67.5%, congenital ichthyosiform erythroderma 24.3%, harlequin ichthyosis 2.7%, and other minor ARCI subtypes 5.4%.

Show evidence (1 reference)

PMID:38588653 SUPPORT Human Clinical

Provides subtype distribution in a genetically confirmed ARCI clinical cohort.

📊

Related Datasets

Proteomic Manifestations of Genetic Defects in Autosomal Recessive Congenital Ichthyosis massive:MSV000082828

Numerous genetic conditions give rise to a scaly skin phenotype as a result of impaired barrier function. Differences in appearance suggest the response of epidermal cells depends upon the basic defect. The present work characterizes the departure of afflicted corneocytes from normal as judged by their proteomic profiles in three types of autosomal recessive congenital ichthyosis arising from defects in the genes PNPLA1, SDR9C7 and TGM1. The results show that the profiles were distinctive, each displaying a set of altered protein levels, but with a subset of common alterations.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Autosomal Recessive Congenital Ichthyosis"). Retrieved 2026-08-02.

🔬

Clinical Trials

NCT04154293

Vehicle-controlled trial of topical TMB-001 isotretinoin ointment for congenital ichthyosis including ARCI-lamellar ichthyosis.

Target Phenotypes: ichthyosis HP:0008064

Show evidence (1 reference)

clinicaltrials:NCT04154293 SUPPORT Human Clinical

Supports this trial as directly relevant to ARCI-lamellar ichthyosis.

NCT04047732

Phase I/II topical KB105 intra-patient comparison trial for TGM1-deficient ARCI.

Show evidence (1 reference)

clinicaltrials:NCT04047732 SUPPORT Human Clinical

Supports this trial as topical KB105 clinical testing in TGM1-deficient ARCI.

NCT05735158

Randomized placebo-controlled topical KB105 study in children and adults with ARCI.

Show evidence (1 reference)

clinicaltrials:NCT05735158 SUPPORT Human Clinical

Supports this as a randomized ARCI KB105 trial record.

{ }

Source YAML

click to show

name: Autosomal Recessive Congenital Ichthyosis
creation_date: "2026-05-07T12:56:33Z"
category: Mendelian
description: >-
  Autosomal recessive congenital ichthyosis (ARCI) is a nonsyndromic,
  genetically heterogeneous disorder of cornification. It is defined by
  biallelic pathogenic variants in genes controlling epidermal differentiation,
  cornified-envelope cross-linking, and lipid handling, producing abnormal skin
  scaling from birth or early infancy with variable erythroderma and barrier
  compromise.
references:
- 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:
  - Autosomal_Recessive_Congenital_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: The 74-patient ARCI cohort links genotype to subtype distribution, severity, clinical signs, and ultrastructural features.
    supporting_text: >-
      The cohort included lamellar ichthyosis, congenital ichthyosiform
      erythroderma, harlequin ichthyosis, and minor ARCI subtypes with variants
      across TGM1, ALOX12B, CYP4F22, ABCA12, ALOXE3, NIPAL4, CERS3, PNPLA1,
      and SDR9C7.
- reference: DOI:10.3390/genes14030717
  title: Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis.
  found_in:
  - Autosomal_Recessive_Congenital_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: ABCA12 genotype class correlates with harlequin ichthyosis versus CIE or lamellar ichthyosis.
    supporting_text: >-
      The ABCA12 cohort supports biallelic loss-of-function variants causing
      harlequin ichthyosis and biallelic missense variants mainly causing CIE or
      lamellar ichthyosis.
- reference: DOI:10.3389/fphar.2023.1274248
  title: "Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs."
  found_in:
  - Autosomal_Recessive_Congenital_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: ARCI treatment remains symptomatic, with topical therapy first-line and retinoids more efficacious but limited.
    supporting_text: >-
      The review describes variable desquamation with erythema, quality-of-life
      burden, first-choice topical treatments, and retinoid efficacy with
      limitations.
- reference: DOI:10.1002/mgg3.70000
  title: Genetic testing and new variants in diagnosis of congenital ichthyoses.
  found_in:
  - Autosomal_Recessive_Congenital_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Next-generation sequencing has become a preferred diagnostic method for congenital ichthyoses.
    supporting_text: >-
      The register-based study reports genetic confirmation in 33 cases and
      states that next-generation sequencing became the genetic testing method
      of choice during the study period.
- reference: DOI:10.1007/s13555-024-01239-4
  title: Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.
  found_in:
  - Autosomal_Recessive_Congenital_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Gene and cell therapy development is underway for inherited ichthyosis and related congenital skin disorders.
    supporting_text: >-
      The review summarizes preclinical and clinical gene and cell therapy
      development for epidermolysis bullosa and 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:
  - Autosomal_Recessive_Congenital_Ichthyosis-deep-research-falcon.md
  findings:
  - statement: Broad molecular testing helps classify nonsyndromic ichthyosis and identifies ARCI-associated genes.
    supporting_text: >-
      The study used sequencing of more than 50 ichthyosis-related genes and
      identified ARCI associated with ALOX12B, NIPAL4, and TGM1 mutations.
- reference: PMID:20301593
  title: "Autosomal Recessive Congenital Ichthyosis."
  tags:
  - GeneReviews
- reference: PMID:35887135
  title: Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2.
  findings:
  - statement: >-
      Superficial epidermolytic ichthyosis, the KRT2 disease that MONDO files
      beneath this entry's anchor, is autosomal dominant, which is why it is not
      curated as a subtype of an autosomal recessive entry.
    supporting_text: >-
      Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant
      inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently
      shows erythroderma and widespread blistering at birth.
- reference: PMID:18843291
  title: "Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing."
  findings:
  - statement: >-
      The ST14 phenotype numbered ARCI11 is syndromic - congenital ichthyosis
      with follicular atrophoderma, hypotrichosis, hypohidrosis and woolly hair
      - which is the basis on which it is recorded but not curated as a subtype
      of this non-syndromic entry.
    supporting_text: >-
      Congenital ichthyosis encompasses a heterogeneous group of disorders of
      cornification. Isolated forms and syndromic ichthyosis can be
      differentiated. We have analyzed two consanguineous families from the
      United Arab Emirates and Turkey with an autosomal recessive syndrome of
      diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized
      and diffuse nonscarring hypotrichosis, marked hypohidrosis, and woolly
      hair (OMIM 602400).
synonyms:
- ARCI
- autosomal recessive inherited ichthyosis
- ichthyosis, congenital, autosomal recessive
disease_term:
  preferred_term: autosomal recessive congenital ichthyosis
  term:
    id: MONDO:0017265
    label: autosomal recessive congenital ichthyosis
parents:
- inherited ichthyosis
- disorder of cornification
has_subtypes:
- name: Lamellar Ichthyosis
  display_name: Lamellar Ichthyosis
  subtype_term:
    preferred_term: lamellar ichthyosis
    term:
      id: MONDO:0017778
      label: lamellar ichthyosis
  description: >-
    Major ARCI phenotype with generalized large scales, typically less prominent
    erythroderma, and variable ectropion or palmoplantar involvement.
  subtype_frequency: 67.5% in a 74-patient Italian ARCI cohort
  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: "RESULTS: 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: Supports lamellar ichthyosis as the largest major subtype in this genetically confirmed ARCI cohort.
- name: Congenital Ichthyosiform Erythroderma
  display_name: Congenital Ichthyosiform Erythroderma
  subtype_term:
    preferred_term: congenital non-bullous ichthyosiform erythroderma
    term:
      id: MONDO:0019306
      label: congenital non-bullous ichthyosiform erythroderma
  description: >-
    Major ARCI phenotype characterized by generalized scaling with more
    conspicuous erythroderma than classic lamellar ichthyosis.
  subtype_frequency: 24.3% in a 74-patient Italian ARCI cohort
  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: "RESULTS: 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: Supports congenital ichthyosiform erythroderma as a major ARCI subtype in a genetically confirmed cohort.
- name: Harlequin Ichthyosis
  display_name: Harlequin Ichthyosis
  subtype_term:
    preferred_term: harlequin ichthyosis
    term:
      id: MONDO:0009443
      label: autosomal recessive congenital ichthyosis 4B
  description: >-
    Severe ARCI phenotype, most often linked to ABCA12 loss-of-function, with
    profound neonatal hyperkeratosis and barrier compromise. The neonate is
    encased in thick plate-like armour separated by deep fissures, with
    ectropion, eclabium and flattened ears. It is no longer invariably fatal:
    with modern neonatal care, reported survival is around half, and deaths
    concentrate in the first three months from sepsis and respiratory failure -
    the direct consequences of a stratum corneum that cannot function as a
    barrier. Survivors carry a chronic severe scaling erythroderma. Genotype
    tracks outcome, with homozygous loss-of-function alleles reported in all
    deaths in the largest series and compound heterozygosity over-represented
    among survivors. The reported association between early oral retinoid
    treatment and survival in that series is deliberately not curated here as a
    treatment effect: it is a retrospective, questionnaire-based comparison with
    no randomisation and obvious scope for confounding by indication and by era
    of neonatal care, and the source itself claims only that early retinoids may
    improve survival.
  subtype_frequency: 2.7% in a 74-patient Italian ARCI cohort
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12."
    explanation: Supports harlequin ichthyosis as the severe ABCA12-associated ARCI phenotype.
  - reference: PMID:21339420
    reference_title: "Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 45 cases, the ages of the survivors ranged from 10 months to 25 years, with an overall survival rate of 56%. Death usually occurred in the first 3 months and was attributed to sepsis and/or respiratory failure in 75% of cases.
    explanation: >-
      Quantifies survival and the timing and cause of death in the largest
      reported harlequin ichthyosis series, establishing that the disorder is
      severe but not invariably fatal.
  - reference: PMID:21339420
    reference_title: "Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation analysis revealed that 52% of survivors had compound heterozygous mutations, whereas all deaths were associated with homozygous mutations.
    explanation: >-
      Documents the genotype-outcome relationship. Note this is an observed
      association in a retrospective questionnaire-based series, not a
      demonstrated dose-response, and is curated as such.
  - reference: PMID:21413658
    reference_title: "Harlequin ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had firm plaques covering his body, with fissures especially in flexural areas. Other remarkable findings included edematous hands and feet, ectropion, eclabium, and contractures (Figure).
    explanation: >-
      Documents the characteristic neonatal presentation - armour-plate scale
      with fissuring, ectropion and eclabium.
- name: ARCI1
  display_name: ARCI1 (TGM1)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 1
    term:
      id: MONDO:0009441
      label: autosomal recessive congenital ichthyosis 1
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    TGM1. It was one of the two most frequent genotypes in the 74-patient
    Italian cohort, carried a significantly higher mean ichthyosis severity
    score than all genes other than ABCA12, and was the only genotype in which
    cholesterol clefts were seen on electron microscopy.
  genes:
  - preferred_term: TGM1
    term:
      id: hgnc:11777
      label: TGM1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."
    explanation: Names TGM1 among the genes whose biallelic mutation causes ARCI.
  - 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: "Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."
    explanation: Supports the ultrastructural finding that distinguishes this genotype in the cohort.
- name: ARCI2
  display_name: ARCI2 (ALOX12B)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 2
    term:
      id: MONDO:0009439
      label: autosomal recessive congenital ichthyosis 2
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    ALOX12B, encoding the epidermal lipoxygenase arachidonate 12-lipoxygenase,
    12R type. It tied with TGM1 as the most frequent genotype in the 74-patient
    Italian cohort. Most patients with an ALOX12B or ALOXE3 genotype present
    with a mild erythrodermic ichthyosis.
  genes:
  - preferred_term: ALOX12B
    term:
      id: hgnc:430
      label: ALOX12B
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."
    explanation: Names ALOX12B among the genes whose biallelic mutation causes ARCI.
  - reference: PMID:33435499
    reference_title: Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively."
    explanation: Identifies the enzyme ALOX12B encodes.
  - reference: PMID:33435499
    reference_title: Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma."
    explanation: Supports the typical severity of this arm in a 224-patient cohort.
- name: ARCI3
  display_name: ARCI3 (ALOXE3)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 3
    term:
      id: MONDO:0011680
      label: autosomal recessive congenital ichthyosis 3
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    ALOXE3, encoding the epidermis-type lipoxygenase-3. Deficiency of this
    enzyme and of the ALOX12B product disrupts epidermal barrier function and
    produces abnormal epidermal differentiation.
  genes:
  - preferred_term: ALOXE3
    term:
      id: hgnc:13743
      label: ALOXE3
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."
    explanation: Names ALOXE3 among the genes whose biallelic mutation causes ARCI.
  - reference: PMID:33435499
    reference_title: Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation."
    explanation: Supports the mechanism attributed to loss of the ALOXE3 product.
- name: ARCI4A
  display_name: ARCI4A (ABCA12, non-harlequin)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 4A
    term:
      id: MONDO:0011026
      label: autosomal recessive congenital ichthyosis 4A
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    ABCA12 and the phenotype is congenital ichthyosiform erythroderma or
    lamellar ichthyosis rather than harlequin ichthyosis. The split from ARCI4B
    tracks variant class: biallelic missense variants mainly give this
    presentation, while biallelic loss-of-function variants generally give
    harlequin ichthyosis, which this entry carries as the separate Harlequin
    Ichthyosis subtype.
  genes:
  - preferred_term: ABCA12
    term:
      id: hgnc:14637
      label: ABCA12
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI."
    explanation: Supports the variant-class split that separates this arm from the harlequin arm.
- name: ARCI5
  display_name: ARCI5 (CYP4F22)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 5
    term:
      id: MONDO:0011485
      label: autosomal recessive congenital ichthyosis 5
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    CYP4F22. Patients with this genotype had the lowest mean ichthyosis
    severity score of any gene in the 74-patient Italian cohort.
  genes:
  - preferred_term: CYP4F22
    term:
      id: hgnc:26820
      label: CYP4F22
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  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: "The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients."
    explanation: Supports the low-severity position of this genotype within the series.
- name: ARCI6
  display_name: ARCI6 (NIPAL4)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 6
    term:
      id: MONDO:0012847
      label: autosomal recessive congenital ichthyosis 6
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    NIPAL4. In the Italian cohort this genotype carried a distinctive
    combination of psoriasis-like lesions, a reticulate trunk scale pattern and
    striated keratoderma.
  genes:
  - preferred_term: NIPAL4
    term:
      id: hgnc:28018
      label: NIPAL4
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  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 the phenotypic signature reported for this genotype.
- name: ARCI8
  display_name: ARCI8 (LIPN)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 8
    term:
      id: MONDO:0013495
      label: autosomal recessive congenital ichthyosis 8
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    LIPN, epidermal lipase N. It was described as a late-onset form of
    recessive ichthyosis in a single large consanguineous pedigree, in which a
    2 bp deletion segregated with the phenotype. LIPN is expressed exclusively
    in the epidermis and strongly induced during keratinocyte differentiation.
  genes:
  - preferred_term: LIPN
    term:
      id: hgnc:23452
      label: LIPN
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:21439540
    reference_title: "A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the present study, we describe a late-onset form of recessive ichthyosis in a large consanguineous pedigree. By using a combination of homozygosity mapping and positional candidate-gene screening, we identified a 2 bp deletion in LIPN that segregated with the disease phenotype throughout the family."
    explanation: The founding report establishing LIPN as an ARCI gene and describing the late-onset presentation.
- name: ARCI9
  display_name: ARCI9 (CERS3)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 9
    term:
      id: MONDO:0014010
      label: autosomal recessive congenital ichthyosis 9
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    CERS3, ceramide synthase 3. Loss of CERS3 reduces epidermis-specific
    very-long-chain ceramides and interferes with epidermal differentiation.
  genes:
  - preferred_term: CERS3
    term:
      id: hgnc:23752
      label: CERS3
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23754960
    reference_title: Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients"
    explanation: Establishes CERS3 as a cause of non-syndromic ARCI.
- name: ARCI10
  display_name: ARCI10 (PNPLA1)
  subtype_term:
    preferred_term: autosomal recessive congenital ichthyosis 10
    term:
      id: MONDO:0014011
      label: autosomal recessive congenital ichthyosis 10
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    PNPLA1. The gene was found through a spontaneous lamellar ichthyosis of the
    golden retriever and then confirmed in human ARCI families.
  genes:
  - preferred_term: PNPLA1
    term:
      id: hgnc:21246
      label: PNPLA1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:22246504
    reference_title: PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families."
    explanation: The human genetic evidence establishing PNPLA1 as an ARCI gene.
- name: ARCI12
  display_name: ARCI12 (CASP14)
  subtype_term:
    preferred_term: ichthyosis, congenital, autosomal recessive 12
    term:
      id: MONDO:0015018
      label: ichthyosis, congenital, autosomal recessive 12
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    CASP14, caspase-14. It is one of the thirteen genes screened on
    contemporary non-syndromic ARCI panels. Caspase-14 is the protease that
    carries out the terminal step of filaggrin catabolism, so this arm sits on
    a different branch of the cornification program from the lipid-pathway and
    transglutaminase arms.
  genes:
  - preferred_term: CASP14
    term:
      id: hgnc:1502
      label: CASP14
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35412663
    reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel."
    explanation: >-
      Names CASP14 among the thirteen genes screened as the established
      non-syndromic ARCI gene set. Graded BACKGROUND because the gene list is
      prior knowledge the study restates in its methods rather than a result of
      the study.
- name: ARCI13
  display_name: ARCI13 (SDR9C7)
  subtype_term:
    preferred_term: ichthyosis, congenital, autosomal recessive 13
    term:
      id: MONDO:0033092
      label: ichthyosis, congenital, autosomal recessive 13
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    SDR9C7, an enzyme that converts retinal into retinol. Homozygous missense
    variants were identified in three Lebanese families, and the locus proved to
    lie outside the previously mapped ARCI7 interval.
  genes:
  - preferred_term: SDR9C7
    term:
      id: hgnc:29958
      label: SDR9C7
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:28173123
    reference_title: Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp)."
    explanation: The human genetic evidence establishing SDR9C7 as an ARCI gene.
- name: ARCI14
  display_name: ARCI14 (SULT2B1)
  subtype_term:
    preferred_term: ichthyosis, congenital, autosomal recessive 14
    term:
      id: MONDO:0033091
      label: ichthyosis, congenital, autosomal recessive 14
  description: >-
    Gene-defined arm of the numbered ARCI series in which the causative gene is
    SULT2B1, a cytosolic sulfotransferase. Loss of function abolishes
    cholesterol sulfate and raises cholesterol in organotypic skin cultures,
    placing this arm in the cholesterol rather than the acylceramide branch of
    epidermal lipid handling.
  genes:
  - preferred_term: SULT2B1
    term:
      id: hgnc:11459
      label: SULT2B1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:28575648
    reference_title: Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI."
    explanation: The human genetic evidence establishing SULT2B1 as an ARCI gene.
  - reference: PMID:28575648
    reference_title: Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1."
    explanation: Supports the cholesterol-sulfate mechanism attributed to this arm.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    ARCI is caused by biallelic pathogenic variants in multiple causative genes.
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."
    explanation: Directly supports autosomal recessive inheritance through biallelic pathogenic variants.
progression:
- phase: Congenital onset
  age_range: Birth or early neonatal period
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin."
    explanation: Supports congenital onset and abnormal skin scaling as defining features.
- phase: Lifelong course
  age_range: Lifelong
  evidence:
  - reference: PMID:38027029
    reference_title: "Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the treatment alternatives, ARCI will persist throughout life, disabling people."
    explanation: Supports persistence of ARCI across the life course.
prevalence:
- population: Genetically confirmed Italian ARCI cohort
  notes: >-
    In the 74-patient Italian cohort, lamellar ichthyosis represented 67.5%,
    congenital ichthyosiform erythroderma 24.3%, harlequin ichthyosis 2.7%, and
    other minor ARCI subtypes 5.4%.
  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: "RESULTS: 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: Provides subtype distribution in a genetically confirmed ARCI clinical cohort.
phenotypes:
- category: Dermatological
  name: Abnormal skin scaling
  frequency: Very frequent
  description: >-
    Generalized scaling is the core clinical phenotype across ARCI subtypes.
  phenotype_term:
    preferred_term: ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin."
    explanation: Directly supports abnormal skin scaling as a defining ARCI manifestation.
- category: Dermatological
  name: Erythroderma
  description: >-
    Erythema accompanies scaling to a variable degree and is prominent in the
    congenital ichthyosiform erythroderma phenotype.
  phenotype_term:
    preferred_term: erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:38027029
    reference_title: "Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive congenital ichthyoses (ARCI) are a skin pathology due to genetic causes characterized by a variable degree of desquamation, accompanied by erythema."
    explanation: Supports erythema as a variable clinical feature accompanying desquamation in ARCI.
- category: Dermatological
  name: Hyperkeratosis
  description: >-
    Thickened scale and generalized hyperkeratosis are most severe in harlequin
    ichthyosis and in higher-severity TGM1- or ABCA12-associated disease.
  phenotype_term:
    preferred_term: hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  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 thick scaling, particularly in TGM1-associated ARCI.
- category: Dermatological
  name: Ectropion
  description: >-
    Eyelid eversion is associated with more severe TGM1- and ABCA12-mutated
    ARCI.
  phenotype_term:
    preferred_term: ectropion
    term:
      id: HP:0000656
      label: Ectropion
  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 ectropion as a genotype-associated clinical sign in ARCI.
- category: Dermatological
  name: Alopecia
  description: >-
    Alopecia is associated with TGM1- and ABCA12-mutated ARCI in cohort data.
  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 feature.
- category: Craniofacial
  name: Eclabium
  phenotype_term:
    preferred_term: Eclabium
    term:
      id: HP:0012472
      label: Eclabion
  description: >-
    Eversion or outward turning of the lips is associated with TGM1- and
    ABCA12-mutated ARCI in cohort data. No precise HPO term was confirmed
    locally, so this is left as preferred-term-only rather than mapped to an
    incorrect lip morphology term.
  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 eclabium as a genotype-associated ARCI feature.
- category: Dermatological
  name: Pruritus and quality-of-life burden
  description: >-
    ARCI symptoms substantially affect patient quality of life; itch is commonly
    considered in outcome measures and trials.
  phenotype_term:
    preferred_term: pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:38027029
    reference_title: "Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of symptoms is variable, different altered genes are involved, and the symptoms drastically affect patients' quality of life."
    explanation: Supports clinically important symptom burden but does not quantify pruritus specifically.
pathophysiology:
- name: Biallelic ARCI Gene Defects
  conforms_to: "epidermal_cornification_failure#Cornification Program Component Deficiency"
  description: >-
    ARCI begins with biallelic pathogenic variants in a heterogeneous set of
    genes involved in epidermal cornification, lipid transport, lipid
    metabolism, and filaggrin catabolism.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    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: CERS3
    term:
      id: hgnc:23752
      label: CERS3
  - preferred_term: PNPLA1
    term:
      id: hgnc:21246
      label: PNPLA1
  - preferred_term: SDR9C7
    term:
      id: hgnc:29958
      label: SDR9C7
  - preferred_term: SULT2B1
    term:
      id: hgnc:11459
      label: SULT2B1
  - preferred_term: LIPN
    term:
      id: hgnc:23452
      label: LIPN
  - preferred_term: CASP14
    term:
      id: hgnc:1502
      label: CASP14
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Cornified Envelope Cross-Linking Defect
  - target: Epidermal Lipid Processing and Transport Defect
  - target: Defective Filaggrin Catabolism and Natural Moisturizing Factor Generation
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1."
    explanation: Directly supports the core biallelic ARCI gene spectrum.
  - reference: PMID:35412663
    reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel."
    explanation: >-
      Extends the gene set of this node beyond the ten-gene list above to the
      thirteen genes screened on contemporary non-syndromic ARCI panels, which
      is where LIPN and CASP14 come from. Graded BACKGROUND because the gene
      list is prior knowledge the study restates in its methods.
- name: Cornified Envelope Cross-Linking Defect
  conforms_to: "epidermal_cornification_failure#Defective Cornified Envelope Assembly and Lamellar Lipid Delivery"
  description: >-
    TGM1-associated ARCI disrupts transglutaminase-dependent cornified-envelope
    formation in differentiating keratinocytes; this mechanism is associated
    with higher severity and thick brownish scales in cohort data.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: epidermal cell differentiation
    term:
      id: GO:0009913
      label: epidermal cell differentiation
    modifier: ABNORMAL
  genes:
  - preferred_term: TGM1
    term:
      id: hgnc:11777
      label: TGM1
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Abnormal Stratum Corneum and Barrier Phenotype
  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: "The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients."
    explanation: Supports TGM1 as a high-severity ARCI genotype.
  - 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: "Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."
    explanation: Supports a genotype-informative ultrastructural abnormality in TGM1-associated ARCI.
- name: Epidermal Lipid Processing and Transport Defect
  conforms_to: "epidermal_cornification_failure#Defective Cornified Envelope Assembly and Lamellar Lipid Delivery"
  description: >-
    Multiple ARCI genes affect epidermal lipid metabolism, lipid transport, or
    acylceramide-related barrier biology. ABCA12-associated ARCI is especially
    severe when both alleles cause loss of function.
  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: 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: CERS3
    term:
      id: hgnc:23752
      label: CERS3
  - preferred_term: PNPLA1
    term:
      id: hgnc:21246
      label: PNPLA1
  - preferred_term: SDR9C7
    term:
      id: hgnc:29958
      label: SDR9C7
  - preferred_term: SULT2B1
    term:
      id: hgnc:11459
      label: SULT2B1
  - preferred_term: LIPN
    term:
      id: hgnc:23452
      label: LIPN
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Abnormal Stratum Corneum and Barrier Phenotype
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI."
    explanation: Supports ABCA12 functional severity as a determinant of the ARCI phenotype.
  - 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: "Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."
    explanation: Supports lamellar-body abnormalities in lipid-barrier ARCI genotypes.
  - reference: PMID:21439540
    reference_title: "A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "LIPN encodes one of six acid lipases known to be involved in triglyceride metabolism in mammals . LIPN was found to be exclusively expressed in the epidermis and to be strongly induced during keratinocyte differentiation."
    explanation: >-
      Places LIPN on this node: an epidermis-restricted acid lipase acting in
      triglyceride metabolism and induced during keratinocyte differentiation.
  - reference: PMID:33435499
    reference_title: Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation."
    explanation: >-
      Places the two epidermal lipoxygenases on this node by naming the barrier
      and differentiation consequence of losing them.
- name: Defective Filaggrin Catabolism and Natural Moisturizing Factor Generation
  conforms_to: "epidermal_cornification_failure#Defective Cornified Envelope Assembly and Lamellar Lipid Delivery"
  biological_scale: CELLULAR
  description: >-
    A third branch of the ARCI cornification lesion, distinct from
    transglutaminase cross-linking and from epidermal lipid handling. Caspase-14
    is expressed in the suprabasal epidermis and activated during keratinocyte
    cornification, where it performs the terminal proteolytic step that breaks
    filaggrin down into the free amino acids and derivatives that make up the
    natural moisturizing factors of the stratum corneum. Where this step fails,
    filaggrin fragments accumulate and natural moisturizing factors are
    depleted. CASP14 is the ARCI gene assigned to this branch.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  molecular_functions:
  - preferred_term: peptidase activity
    term:
      id: GO:0008233
      label: peptidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein catabolic process
    term:
      id: GO:0030163
      label: protein catabolic process
    modifier: DECREASED
  - preferred_term: establishment of skin barrier
    term:
      id: GO:0061436
      label: establishment of skin barrier
    modifier: ABNORMAL
  genes:
  - preferred_term: CASP14
    term:
      id: hgnc:1502
      label: CASP14
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Abnormal Stratum Corneum and Barrier Phenotype
    causal_link_type: DIRECT
    description: >-
      Loss of the terminal filaggrin degradation step depletes the natural
      moisturizing factors that keep the stratum corneum hydrated.
  evidence:
  - reference: PMID:21654840
    reference_title: Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Caspase-14 is a protease that is mainly expressed in suprabasal epidermal layers and activated during keratinocyte cornification. Caspase-14-deficient mice display reduced epidermal barrier function and increased sensitivity to UVB radiation."
    explanation: >-
      Supports the cell type, the epidermal location, the peptidase activity and
      the barrier consequence asserted by this node.
  - reference: PMID:21654840
    reference_title: Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consequently, we show that the defective FLG degradation in caspase-14-deficient skin results in substantial reduction in the amount of NMFs, such as urocanic acid and pyrrolidone carboxylic acid."
    explanation: >-
      Supports the protein-catabolism defect and the loss of natural moisturizing
      factors that this node asserts.
  - reference: PMID:35412663
    reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel."
    explanation: >-
      Supports CASP14 belonging to the non-syndromic ARCI gene set, which is
      what places this branch inside this disease rather than beside it. Graded
      BACKGROUND because the gene list is prior knowledge the study restates in
      its methods.
- name: Abnormal Stratum Corneum and Barrier Phenotype
  conforms_to: "epidermal_cornification_failure#Stratum Corneum Permeability Barrier Failure"
  description: >-
    Defective cornification and lipid-barrier biology converge on abnormal
    stratum corneum structure, generalized scaling, variable erythema, and
    chronic skin symptoms.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  - preferred_term: epidermis development
    term:
      id: GO:0008544
      label: epidermis development
    modifier: ABNORMAL
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  downstream:
  - target: Abnormal skin scaling
    causal_link_type: DIRECT
    description: >-
      Abnormal stratum corneum structure manifests clinically as generalized
      scaling.
  - target: Erythroderma
    causal_link_type: DIRECT
    description: >-
      Barrier and cornification defects can produce diffuse erythema in
      congenital ichthyosiform erythroderma.
  - target: Hyperkeratosis
    causal_link_type: DIRECT
    description: >-
      Disordered keratinization and stratum corneum architecture produce
      hyperkeratotic skin thickening.
  - target: Ectropion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - thickened taut skin
    - eyelid eversion
    description: >-
      Severe congenital barrier and cornification defects can tighten periorbital
      skin enough to evert the eyelids.
  - target: Alopecia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - severe epidermal involvement
    - hair-bearing skin disruption
    description: >-
      Severe ARCI skin involvement can extend to hair-bearing areas and produce
      alopecia.
  - target: Eclabium
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - thickened taut skin
    - lip eversion
    description: >-
      Severe congenital ichthyosis can tighten facial skin enough to evert the
      lips.
  - target: Pruritus and quality-of-life burden
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired epidermal barrier
    - chronic skin symptoms
    description: >-
      Persistent barrier disruption and scaling can drive pruritic symptom
      burden.
  evidence:
  - reference: PMID:38027029
    reference_title: "Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive congenital ichthyoses (ARCI) are a skin pathology due to genetic causes characterized by a variable degree of desquamation, accompanied by erythema."
    explanation: Supports the clinical consequence of abnormal scaling and erythema arising from genetic skin-barrier disease.
genetic:
- name: TGM1
  gene_term:
    preferred_term: TGM1
    term:
      id: hgnc:11777
      label: TGM1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI1
  inheritance:
  - name: Autosomal recessive
  notes: >-
    TGM1 was one of the two most common mutated genes in the Italian ARCI cohort
    and was associated with higher severity, alopecia, ectropion, eclabium, and
    large thick brownish scales.
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 24.3
    cohort_size: 74
    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: Reports the TGM1 share of genetically solved cases in this cohort.
  - population: 28-patient Indian ARCI cohort
    case_fraction_percent: 21.4
    cohort_size: 28
    evidence:
    - reference: PMID:35412663
      reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each."
      explanation: Reports the TGM1 share of cases in an independent Indian cohort.
  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 in the cohort.
- name: ALOX12B
  gene_term:
    preferred_term: ALOX12B
    term:
      id: hgnc:430
      label: ALOX12B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI2
  inheritance:
  - name: Autosomal recessive
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 24.3
    cohort_size: 74
    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: Reports the ALOX12B share of genetically solved cases in this cohort.
  - population: 28-patient Indian ARCI cohort
    case_fraction_percent: 14.3
    cohort_size: 28
    evidence:
    - reference: PMID:35412663
      reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each."
      explanation: Reports the ALOX12B share of cases in an independent Indian cohort.
  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 in the cohort.
  - reference: PMID:33435499
    reference_title: Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3."
    explanation: The largest reported allelic series for this gene.
- name: CYP4F22
  gene_term:
    preferred_term: CYP4F22
    term:
      id: hgnc:26820
      label: CYP4F22
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI5
  inheritance:
  - name: Autosomal recessive
  notes: CYP4F22-mutated patients had the lowest mean severity score in the cohort.
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 16.2
    cohort_size: 74
    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: Reports the CYP4F22 share of genetically solved cases in this cohort.
  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: "The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients."
    explanation: Supports a lower-severity CYP4F22-associated ARCI pattern in this cohort.
- name: ABCA12
  gene_term:
    preferred_term: ABCA12
    term:
      id: hgnc:14637
      label: ABCA12
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI4A
  inheritance:
  - name: Autosomal recessive
  notes: >-
    ABCA12 spans two numbered arms of the series. Biallelic loss-of-function
    alleles give harlequin ichthyosis (ARCI4B), curated here as the Harlequin
    Ichthyosis subtype; biallelic missense alleles mainly give congenital
    ichthyosiform erythroderma or lamellar ichthyosis (ARCI4A), the subtype this
    record is keyed to.
  variants:
  - name: ABCA12 biallelic loss-of-function variants
    description: Biallelic loss-of-function variants generally cause harlequin ichthyosis.
  - name: ABCA12 biallelic missense variants
    description: Biallelic missense variants mainly cause congenital ichthyosiform erythroderma or lamellar ichthyosis.
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 12.2
    cohort_size: 74
    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: Reports the ABCA12 share of genetically solved cases in this cohort.
  - population: 28-patient Indian ARCI cohort
    case_fraction_percent: 3.6
    cohort_size: 28
    evidence:
    - reference: PMID:35412663
      reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each."
      explanation: Reports the ABCA12 share of cases in an independent Indian cohort.
  evidence:
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12."
    explanation: Supports ABCA12 as the gene classically associated with harlequin ichthyosis.
  - reference: PMID:36980989
    reference_title: "Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI."
    explanation: Supports variant-class correlation for ABCA12-associated ARCI phenotypes.
- name: ALOXE3
  gene_term:
    preferred_term: ALOXE3
    term:
      id: hgnc:13743
      label: ALOXE3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI3
  inheritance:
  - name: Autosomal recessive
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 9.5
    cohort_size: 74
    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: Reports the ALOXE3 share of genetically solved cases in this cohort.
  - population: 28-patient Indian ARCI cohort
    case_fraction_percent: 14.3
    cohort_size: 28
    evidence:
    - reference: PMID:35412663
      reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each."
      explanation: Reports the ALOXE3 share of cases in an independent Indian cohort.
  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 causative ARCI gene in the cohort.
  - reference: PMID:33435499
    reference_title: Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature."
    explanation: Quantifies the reported allelic spectrum for this gene relative to its sibling lipoxygenase.
- name: NIPAL4
  gene_term:
    preferred_term: NIPAL4
    term:
      id: hgnc:28018
      label: NIPAL4
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI6
  inheritance:
  - name: Autosomal recessive
  notes: >-
    NIPAL4-mutated ARCI showed psoriasis-like lesions, reticulate trunk scaling,
    and striated keratoderma in the 2024 cohort.
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 9.5
    cohort_size: 74
    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: Reports the NIPAL4 share of genetically solved cases in this cohort.
  - population: 28-patient Indian ARCI cohort
    case_fraction_percent: 10.7
    cohort_size: 28
    evidence:
    - reference: PMID:35412663
      reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each."
      explanation: Reports the NIPAL4 share of cases in an independent Indian cohort.
  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 distinctive NIPAL4-associated features.
- name: LIPN
  gene_term:
    preferred_term: LIPN
    term:
      id: hgnc:23452
      label: LIPN
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI8
  inheritance:
  - name: Autosomal recessive
  notes: >-
    LIPN encodes epidermal lipase N, one of six mammalian acid lipases acting in
    triglyceride metabolism, and is expressed only in epidermis. The founding
    report is a single large consanguineous pedigree with a late-onset
    presentation, so the allelic and phenotypic spectrum of this arm is narrower
    than that of the common ARCI genes.
  variants:
  - name: LIPN 2 bp deletion
    description: >-
      A 2 bp deletion in LIPN segregating with the disease phenotype throughout
      the reported consanguineous family.
  evidence:
  - reference: PMID:21439540
    reference_title: "A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the present study, we describe a late-onset form of recessive ichthyosis in a large consanguineous pedigree. By using a combination of homozygosity mapping and positional candidate-gene screening, we identified a 2 bp deletion in LIPN that segregated with the disease phenotype throughout the family."
    explanation: The human genetic evidence establishing LIPN as an ARCI gene.
  - reference: PMID:21439540
    reference_title: "A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "LIPN was found to be exclusively expressed in the epidermis and to be strongly induced during keratinocyte differentiation."
    explanation: Supports the epidermis-restricted expression that makes LIPN a plausible cornification gene.
- name: CERS3
  gene_term:
    preferred_term: CERS3
    term:
      id: hgnc:23752
      label: CERS3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI9
  inheritance:
  - name: Autosomal recessive
  notes: >-
    CERS3 was reached through a contiguous gene deletion at 15q26.3 that also
    removes part of ADAMTS17, so the founding families carried a syndromic
    picture; the gene-level attribution rests on a separate patient with
    non-syndromic ARCI and a homozygous CERS3 splice-site change. Abnormal
    lamellar bodies were reported for CERS3 cases in the Italian ultrastructural
    review.
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 1.4
    cohort_size: 74
    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: Reports the CERS3 share of genetically solved cases in this cohort.
  - population: 28-patient Indian ARCI cohort
    case_fraction_percent: 3.6
    cohort_size: 28
    evidence:
    - reference: PMID:35412663
      reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each."
      explanation: Reports the CERS3 share of cases in an independent Indian cohort.
  evidence:
  - reference: PMID:23754960
    reference_title: Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients"
    explanation: Establishes CERS3 as a cause of non-syndromic ARCI, separating it from the contiguous-deletion syndrome in the same families.
  - reference: PMID:23754960
    reference_title: Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation."
    explanation: Supports the ceramide-synthesis mechanism attributed to this gene.
- name: PNPLA1
  gene_term:
    preferred_term: PNPLA1
    term:
      id: hgnc:21246
      label: PNPLA1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI10
  inheritance:
  - name: Autosomal recessive
  notes: >-
    PNPLA1 was identified through a spontaneous canine model - a lamellar
    ichthyosis of the golden retriever - and then confirmed in human ARCI
    families, which is why the dog is a well-characterised natural model for
    this arm.
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 1.4
    cohort_size: 74
    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: Reports the PNPLA1 share of genetically solved cases in this cohort.
  - population: 28-patient Indian ARCI cohort
    case_fraction_percent: 10.7
    cohort_size: 28
    evidence:
    - reference: PMID:35412663
      reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each."
      explanation: Reports the PNPLA1 share of cases in an independent Indian cohort.
  evidence:
  - reference: PMID:22246504
    reference_title: PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families."
    explanation: The human genetic evidence establishing PNPLA1 as an ARCI gene.
  - reference: PMID:22246504
    reference_title: PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs."
    explanation: The canine model finding that led to the human gene.
- name: SDR9C7
  gene_term:
    preferred_term: SDR9C7
    term:
      id: hgnc:29958
      label: SDR9C7
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI13
  inheritance:
  - name: Autosomal recessive
  notes: >-
    SDR9C7 converts retinal into retinol, so this arm implicates epidermal
    vitamin A metabolism in terminal keratinocyte differentiation. Abnormal
    lamellar bodies were reported for SDR9C7 cases in the Italian
    ultrastructural review. The mapping that led to the gene fell outside the
    previously reported ARCI7 interval on chromosome 12, so SDR9C7 is not the
    ARCI7 gene.
  case_fractions:
  - population: 74-patient Italian ARCI cohort
    case_fraction_percent: 1.4
    cohort_size: 74
    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: Reports the SDR9C7 share of genetically solved cases in this cohort.
  evidence:
  - reference: PMID:28173123
    reference_title: Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp)."
    explanation: The human genetic evidence establishing SDR9C7 as an ARCI gene.
  - reference: PMID:28173123
    reference_title: Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus"
    explanation: Supports the statement that the SDR9C7 locus is distinct from the still-unsolved ARCI7 locus.
- name: SULT2B1
  gene_term:
    preferred_term: SULT2B1
    term:
      id: hgnc:11459
      label: SULT2B1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI14
  inheritance:
  - name: Autosomal recessive
  notes: >-
    SULT2B1 makes cholesterol sulfate, so this arm sits in the cholesterol
    branch of epidermal lipid handling rather than the acylceramide branch that
    most other ARCI genes occupy.
  evidence:
  - reference: PMID:28575648
    reference_title: Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI."
    explanation: The human genetic evidence establishing SULT2B1 as an ARCI gene.
  - reference: PMID:28575648
    reference_title: Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1."
    explanation: Supports the cholesterol-sulfate mechanism attributed to this gene.
- name: CASP14
  gene_term:
    preferred_term: CASP14
    term:
      id: hgnc:1502
      label: CASP14
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ARCI12
  inheritance:
  - name: Autosomal recessive
  notes: >-
    CASP14 is carried on contemporary thirteen-gene non-syndromic ARCI panels.
    The mechanistic evidence for its role in cornification is strongest in the
    caspase-14-deficient mouse, where filaggrin fragments accumulate and
    natural moisturizing factors fall; the human allelic series is small.
  evidence:
  - reference: PMID:35412663
    reference_title: Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel."
    explanation: >-
      Names CASP14 within the established non-syndromic ARCI gene set. Graded
      BACKGROUND because the gene list is prior knowledge the study restates in
      its methods rather than a result of the study.
  - reference: PMID:21654840
    reference_title: Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consequently, we show that the defective FLG degradation in caspase-14-deficient skin results in substantial reduction in the amount of NMFs, such as urocanic acid and pyrrolidone carboxylic acid."
    explanation: Supports the filaggrin-catabolism mechanism through which caspase-14 loss impairs the stratum corneum.
diagnosis:
- name: Multigene molecular testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis is increasingly confirmed by next-generation sequencing panels or
    broader sequencing with CNV-aware follow-up, because overlapping phenotypes
    make molecular classification important.
  results: Biallelic pathogenic variants in an ARCI gene confirm the molecular diagnosis.
  evidence:
  - reference: PMID:39189679
    reference_title: Genetic testing and new variants in diagnosis of congenital ichthyoses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis of ichthyosis was confirmed with genetic testing in 33 cases, and with conventional diagnostic methods, such as clinical findings, skin biopsy and family history of ichthyoses, in 55 cases."
    explanation: Supports molecular testing as a diagnostic route for congenital ichthyoses.
  - reference: PMID:39189679
    reference_title: Genetic testing and new variants in diagnosis of congenital ichthyoses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the study period next-generation sequencing became the genetic testing method of choice providing new opportunities in diagnostics."
    explanation: Supports next-generation sequencing as the current preferred genetic testing method.
  - reference: PMID:30578701
    reference_title: "Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence data analysis identified biallelic mutations in 106 families out of a total of 125 (85%), most of them (102, 96.2%) being homozygous, reflecting consanguinity in these families."
    explanation: >-
      Gives the diagnostic yield of a targeted ichthyosis panel in a large
      consanguineous ARCI cohort, and the caveat that the yield is raised by
      consanguinity.
  - reference: PMID:30578701
    reference_title: "Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotype-genotype correlations allowed assignment of specific genes in the majority of the families to a specific subtype of ARCI, lamellar ichthyosis (LI) versus congenital ichthyosiform erythroderma (CIE). Interestingly, mutations in several genes could give rise to an overlapping phenotype consistent with either LI or CIE."
    explanation: >-
      Supports the entry's two-axis subtype structure: gene and clinical
      presentation correlate but do not determine one another.
- name: Ultrastructural skin analysis
  description: >-
    Transmission electron microscopy can provide genotype-informative clues,
    including cholesterol clefts in TGM1-mutated disease and abnormal lamellar
    bodies in SDR9C7- or CERS3-associated disease.
  results: Genotype-informative ultrastructural features can support ARCI classification.
  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: "Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients."
    explanation: Supports ultrastructural skin analysis as a genotype-informative diagnostic adjunct.
treatments:
- name: Topical emollients and keratolytic/supportive topical therapy
  description: >-
    Topical treatments are first-line symptomatic management for scaling and
    barrier dysfunction.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:38027029
    reference_title: "Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical treatments are a first-choice strategy due to their ease of application and cost; however, enteral administration of retinoids offers greater efficacy, although with certain limitations."
    explanation: Supports topical therapy as first-choice symptomatic treatment and retinoids as more efficacious but limited options.
- name: Retinoid pharmacotherapy
  description: >-
    Systemic or topical retinoid therapy is used to reduce scaling in severe
    inherited ichthyosis, with efficacy balanced against tolerability and safety
    limitations.
  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: PMID:38027029
    reference_title: "Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical treatments are a first-choice strategy due to their ease of application and cost; however, enteral administration of retinoids offers greater efficacy, although with certain limitations."
    explanation: Supports retinoid pharmacotherapy as a more efficacious treatment class with limitations.
  - 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 clinical development for congenital ichthyosis including ARCI-LI.
- name: Topical TGM1 gene therapy
  description: >-
    KB105 is a topical, non-integrating HSV-1 vector expressing TGM1 under
    clinical investigation for TGM1-deficient ARCI.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Cornified Envelope Cross-Linking Defect
    treatment_effect: RESTORES
    description: Topical TGM1 replacement is intended to restore deficient transglutaminase 1 expression 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.
  - 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 a randomized phase 2 study of KB105 in children and adults with ARCI.
- name: IL-17A-targeting biologic therapy
  description: >-
    Secukinumab has been studied as mechanism-based anti-inflammatory therapy in
    ichthyoses, reflecting evidence of IL-17A pathway activation in ichthyosis
    skin rather than a proven ARCI-specific standard of care.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: secukinumab
      term:
        id: NCIT:C152315
        label: Secukinumab
  target_phenotypes:
  - preferred_term: ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  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 across ichthyoses, but this trial record is not ARCI-specific.
clinical_trials:
- name: NCT04154293
  description: >-
    Vehicle-controlled trial of topical TMB-001 isotretinoin ointment for
    congenital ichthyosis including ARCI-lamellar ichthyosis.
  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 this trial as directly relevant to ARCI-lamellar ichthyosis.
- name: NCT04047732
  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
  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 ARCI KB105 trial record.
datasets:
- accession: massive:MSV000082828
  title: Proteomic Manifestations of Genetic Defects in Autosomal Recessive Congenital Ichthyosis
  description: 'Numerous genetic conditions give rise to a scaly skin phenotype as a result of impaired barrier function. Differences in appearance suggest the response of epidermal cells depends upon the basic defect. The present work characterizes the departure of afflicted corneocytes from normal as judged by their proteomic profiles in three types of autosomal recessive congenital ichthyosis arising from defects in the genes PNPLA1, SDR9C7 and TGM1. The results show that the profiles were distinctive, each displaying a set of altered protein levels, but with a subset of common alterations.'
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Autosomal Recessive Congenital Ichthyosis"). Retrieved 2026-08-02.
notes: >-
  Two subtype axes are carried in the same has_subtypes list, and they
  cross-cut rather than nest. The first three rows are the clinical
  presentations (lamellar ichthyosis, congenital ichthyosiform erythroderma,
  harlequin ichthyosis); the rows named ARCIn are the numbered gene-defined
  arms. One gene can present as either clinical form - the 125-family
  consanguineous cohort reports that mutations in several genes can give an
  overlapping phenotype consistent with either lamellar ichthyosis or
  congenital ichthyosiform erythroderma - so a patient occupies one row on each
  axis, not one row overall.
  The gene-level share of cases sits in genetic[].case_fractions rather than on
  the gene rows, because the shares are cohort-specific and two cohorts are
  cited.

  Genes named in the numbered series but deliberately not curated here. ST14 is
  the gene of the entity OMIM and MONDO number as ARCI11 (MONDO:0011218). Its
  reported phenotype is syndromic - diffuse congenital ichthyosis together with
  patchy follicular atrophoderma, generalised non-scarring hypotrichosis,
  marked hypohidrosis and woolly hair - and MONDO's own exact synonyms for the
  term are IFAH syndrome, ichthyosis-follicular atrophoderma-hypotrichosis
  syndrome and ichthyosis-hypotrichosis syndrome. This entry is scoped to
  non-syndromic ARCI, and the thirteen-gene panel that contemporary
  non-syndromic ARCI sequencing uses does not include ST14. The MONDO
  hierarchy is faithful to the OMIM series numbering; the disagreement is
  between that numbering and the non-syndromic scoping used in the clinical
  genetics literature, so ST14 is recorded here rather than curated as a
  subtype.

  KRT2 and superficial epidermolytic ichthyosis (MONDO:0007813) are likewise
  not curated here. That disease is an autosomal dominant inherited ichthyosis
  caused by KRT2 mutations, so it cannot be a subtype of an autosomal recessive
  entry, and MONDO's own direct parents for it are keratinopathic ichthyosis
  and exfoliative ichthyosis. It reaches this entry's MONDO subtree only
  through the chain MONDO:0007813 is_a MONDO:0017339 exfoliative ichthyosis
  is_a MONDO:0017265, which places a dominant keratin disease under an
  autosomal recessive parent.

  ARCI7 (MONDO:0014009) has no curated arm because no causative gene is
  recorded for it. MONDO carries no RO:0004003 causal-gene relation on that
  term, and the SDR9C7 report states that the causative gene for ARCI7 alone
  had not been identified and that its own mapping interval fell outside the
  ARCI7 locus, so SDR9C7 does not close it.

  The thirteen-gene non-syndromic ARCI panel quoted on the pathophysiology
  trigger node names one further gene, SLC27A4, that is not curated here.
  MONDO files the SLC27A4 disease as ichthyosis prematurity syndrome
  (MONDO:0012089), a syndromic disease with no is_a path to MONDO:0017265, so
  it is a neighbouring entity rather than an arm of this one.

  No ARCI gene has a ClinGen Gene-Disease Validity assertion. Each of TGM1,
  ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7,
  SULT2B1, CASP14, ST14 and KRT2 was searched by symbol in the ClinGen
  Gene-Disease Validity download whose own header records FILE CREATED:
  2026-09-24, and none returned a row. Gene attribution here therefore rests on
  primary reports and cohort series, not on an expert-panel classification.

📚

References & Deep Research

References

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

The 74-patient ARCI cohort links genotype to subtype distribution, severity, clinical signs, and ultrastructural features.

"The cohort included lamellar ichthyosis, congenital ichthyosiform erythroderma, harlequin ichthyosis, and minor ARCI subtypes with variants across TGM1, ALOX12B, CYP4F22, ABCA12, ALOXE3, NIPAL4, CERS3, PNPLA1, and SDR9C7."

DOI:10.3390/genes14030717

Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis.

1 finding

ABCA12 genotype class correlates with harlequin ichthyosis versus CIE or lamellar ichthyosis.

"The ABCA12 cohort supports biallelic loss-of-function variants causing harlequin ichthyosis and biallelic missense variants mainly causing CIE or lamellar ichthyosis."

DOI:10.3389/fphar.2023.1274248

Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs.

1 finding

ARCI treatment remains symptomatic, with topical therapy first-line and retinoids more efficacious but limited.

"The review describes variable desquamation with erythema, quality-of-life burden, first-choice topical treatments, and retinoid efficacy with limitations."

DOI:10.1002/mgg3.70000

Genetic testing and new variants in diagnosis of congenital ichthyoses.

1 finding

Next-generation sequencing has become a preferred diagnostic method for congenital ichthyoses.

"The register-based study reports genetic confirmation in 33 cases and states that next-generation sequencing became the genetic testing method of choice during the study period."

DOI:10.1007/s13555-024-01239-4

Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.

1 finding

Gene and cell therapy development is underway for inherited ichthyosis and related congenital skin disorders.

"The review summarizes preclinical and clinical gene and cell therapy development for epidermolysis bullosa and 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

Broad molecular testing helps classify nonsyndromic ichthyosis and identifies ARCI-associated genes.

"The study used sequencing of more than 50 ichthyosis-related genes and identified ARCI associated with ALOX12B, NIPAL4, and TGM1 mutations."

PMID:20301593

Autosomal Recessive Congenital Ichthyosis.

No top-level findings curated for this source.

PMID:35887135

Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2.

1 finding

Superficial epidermolytic ichthyosis, the KRT2 disease that MONDO files beneath this entry's anchor, is autosomal dominant, which is why it is not curated as a subtype of an autosomal recessive entry.

"Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth."

PMID:18843291

Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing.

1 finding

The ST14 phenotype numbered ARCI11 is syndromic - congenital ichthyosis with follicular atrophoderma, hypotrichosis, hypohidrosis and woolly hair - which is the basis on which it is recorded but not curated as a subtype of this non-syndromic entry.

"Congenital ichthyosis encompasses a heterogeneous group of disorders of cornification. Isolated forms and syndromic ichthyosis can be differentiated. We have analyzed two consanguineous families from the United Arab Emirates and Turkey with an autosomal recessive syndrome of diffuse congenital..."

Deep Research

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 (1)

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

GitHub review issue: https://github.com/monarch-initiative/dismech/issues/3596 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: **Autosomal Recessive Congenital Ichthyosis** - Entry: `kb/disorders/Autosomal_Recessive_Congenital_Ichthyosis.yaml` - Selection basis: #128 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. Actionable baseline check: a `diagnosis` section exists, but no top-level GeneReviews tag was detected in the YAML. For this Mendelian entry, confirm whether a GeneReviews article exists and either add/tag it or record why no GeneReviews baseline applies. 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 (Lamellar Ichthyosis, Congenital Ichthyosiform Erythroderma, Harlequin 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 Biallelic ARCI Gene Defects, Cornified Envelope Cross-Linking Defect, Epidermal Lipid Processing and Transport Defect, Abnormal Stratum Corneum and Barrier Phenotype. 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:10.1159/000536366, DOI:10.3390/genes14030717, DOI:10.3389/fphar.2023.1274248, DOI:10.1002/mgg3.70000. 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: diagnosis present but should be checked against baseline sources. - 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/Autosomal_Recessive_Congenital_Ichthyosis-deep-research-falcon.md` - DOI:10.1159/000536366: https://doi.org/10.1159/000536366 - DOI:10.3390/genes14030717: https://doi.org/10.3390/genes14030717 - DOI:10.3389/fphar.2023.1274248: https://doi.org/10.3389/fphar.2023.1274248 - DOI:10.1002/mgg3.70000: https://doi.org/10.1002/mgg3.70000 No YAML files or `references_cache/*.md` files were edited for this review.

Falcon ▸

Key 2023–2024 highlights (executive summary)

Edison Scientific Literature 24 citations 2026-05-07T09:08:56.693208

1. Disease Information

1.1 What is the disease?

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic, congenital disorder of cornification characterized by generalized scaling with variable erythema and barrier dysfunction, typically presenting at birth (often as a collodion baby) and persisting lifelong. (hotz2023mutationalspectrumof pages 1-2, penacorona2023advancesinthe pages 1-2)

Direct abstract quote (treatment review): “Autosomal recessive congenital ichthyoses (ARCI) are a skin pathology due to genetic causes characterized by a variable degree of desquamation, accompanied by erythema.” (Frontiers in Pharmacology; 2023-11-09) (penacorona2023advancesinthe pages 1-2)

1.2 Key identifiers

Evidence retrieved here did not include authoritative identifier pages (OMIM/Orphanet/MONDO/MeSH/ICD-10/ICD-11). Therefore, OMIM/Orphanet/MONDO/ICD/MeSH identifiers cannot be reliably asserted from this tool run.

1.3 Common synonyms / alternative names

ARCI is often used as an umbrella for major phenotypes/subtypes including: - Lamellar ichthyosis (LI) - Congenital ichthyosiform erythroderma (CIE) - Harlequin ichthyosis (HI) (most severe) - Minor/related clinical presentations: self-healing collodion baby, bathing suit ichthyosis, and related “collodion baby” neonatal presentations. (diociaiuti2024crosssectionalstudyon pages 2-3, hotz2023mutationalspectrumof pages 1-2, penacorona2023advancesinthe pages 1-2)

2. Etiology

2.1 Disease causal factors

ARCI is a Mendelian (autosomal recessive) genetic disorder caused by biallelic pathogenic variants in multiple genes involved in cornified envelope formation and epidermal lipid processing/transport, leading to skin barrier failure. (hotz2023mutationalspectrumof pages 1-2, penacorona2023advancesinthe pages 1-2)

In a 2024 Italian ARCI cohort study (n=74), the genetic distribution was: TGM1 24.3%, ALOX12B 24.3%, CYP4F22 16.2%, ABCA12 12.2%, ALOXE3 9.5%, NIPAL4 9.5%, and CERS3/PNPLA1/SDR9C7 1.4% each. (Diociaiuti et al., Dermatology; 2024-04; https://doi.org/10.1159/000536366) (diociaiuti2024crosssectionalstudyon pages 1-2)

2.2 Risk factors

Genetic risk: family history consistent with autosomal recessive inheritance and biallelic pathogenic variants in ARCI genes (see Section 4). (hotz2023mutationalspectrumof pages 1-2, diociaiuti2024crosssectionalstudyon pages 1-2)
Consanguinity can increase likelihood of autosomal recessive disease: in the 74-patient Italian series, consanguinity was 13/73 families (17.8%). (diociaiuti2024crosssectionalstudyon pages 2-3)

Evidence retrieved here did not include robust environmental, toxin, or lifestyle risk factors for ARCI as a genetic disorder.

2.3 Protective factors

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

2.4 Gene–environment interactions

No explicit gene–environment interaction studies were identified in the retrieved sources.

3. Phenotypes

3.1 Core phenotype spectrum and frequencies (recent cohort data)

In a 2024 cross-sectional Italian series (74 genetically confirmed ARCI patients): - Subtype distribution: LI 67.5% (50/74); CIE 24.3% (18/74); HI 2.7% (2/74); other minor ARCI subtypes 5.4% (4/74). (diociaiuti2024crosssectionalstudyon pages 1-2) - Symptom/feature frequencies (reported across cohort): - Pruritus: 86.3% (63/73); mean itch VAS 5.7 ± 2.0 - Pain: 15.1% (11/73); pain VAS 5.2 ± 2.7 - Palmoplantar keratoderma (PPK): 97.3% (72/74) - Fissures: 28.4% (21/74) - Ectropion: 25.7% (19/74) - Eclabium: 14.9% (11/74) These data support high burden of itch and frequent keratoderma with variable ocular/perioral involvement. (diociaiuti2024crosssectionalstudyon pages 2-3)

3.2 Severity measurement in current research/practice

The Italian cohort operationalized severity using a SCORAD-based ichthyosis severity score incorporating body surface involvement, 10 clinical features, and VAS itch and pain. (diociaiuti2024crosssectionalstudyon pages 2-3)

3.3 Genotype-associated phenotypes (selected)

TGM1 and ABCA12 variants were associated with higher severity, and with alopecia/ectropion/eclabium. (diociaiuti2024crosssectionalstudyon pages 1-2)
CYP4F22 group had the lowest mean severity score in that cohort. (diociaiuti2024crosssectionalstudyon pages 1-2)
NIPAL4: association with psoriasis-like lesions, reticulate trunk scale, and striated keratoderma, emphasized as diagnostically relevant. (diociaiuti2024crosssectionalstudyon pages 1-2)

3.4 Quality of life impact

ARCI is described as having symptoms that “drastically affect patients’ quality of life” in a 2023 treatment review. (penacorona2023advancesinthe pages 1-2) A diagnostic-practice study also states that ichthyosis has a negative effect on QoL, citing prior literature. (salo2024genetictestingand pages 1-2)

3.5 Suggested HPO terms (examples; not exhaustive)

Ichthyosis/scaling: HP:0008064 (Ichthyosis), HP:0000969 (Generalized dry skin)
Erythroderma: HP:0001043 (Erythroderma)
Collodion baby: HP:0001012 (Collodion membrane)
Pruritus: HP:0000989 (Pruritus)
Palmoplantar keratoderma: HP:0000982 (Palmoplantar keratoderma)
Ectropion/eclabium: HP:0000656 (Ectropion), HP:0000233 (Eclabium)
Alopecia: HP:0001596 (Alopecia)

4. Genetic / Molecular Information

4.1 Causal genes and gene functions (current understanding)

ARCI is genetically heterogeneous; recent sources list core causal genes including ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, TGM1. (hotz2023mutationalspectrumof pages 1-2)

A large 2023 ABCA12 cohort paper states: “ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1.” (Genes; 2023-03; https://doi.org/10.3390/genes14030717) (hotz2023mutationalspectrumof pages 1-2)

Gene–phenotype synthesis table

Gene	Protein/function (1 phrase)	ARCI subtype associations	Key genotype–phenotype notes/statistics	Key source (include DOI and year)
TGM1	Transglutaminase-1; cornified envelope cross-linking	LI, CIE, bathing suit ichthyosis; severe ARCI	In the 74-patient Italian ARCI cohort, 18/74 (24.3%) had TGM1 variants; mean severity was among the highest across genes. Alopecia, ectropion, and eclabium were significantly associated with TGM1; large, thick, brownish scales were particularly linked to this genotype. On ultrastructure, cholesterol clefts were 100% specific for TGM1-mutated cases. TGM1 is also described as the most common cause of ARCI in review literature (diociaiuti2024crosssectionalstudyon pages 1-2, penacorona2023advancesinthe pages 1-2).	Diociaiuti 2024, DOI: 10.1159/000536366; Peña-Corona 2023, DOI: 10.3389/fphar.2023.1274248 (diociaiuti2024crosssectionalstudyon pages 1-2, penacorona2023advancesinthe pages 1-2)
ALOX12B	12R-lipoxygenase; epidermal lipid processing	LI, CIE, collodion baby/self-improving phenotypes	In the Italian cohort, 18/74 (24.3%) had ALOX12B variants, tying TGM1 as the most frequent gene. Severity was lower than TGM1/ABCA12 overall. Reviews identify ALOX12B as a major ARCI gene involved in barrier lipid metabolism; phenotypes can range from collodion baby to later generalized ichthyosis (diociaiuti2024crosssectionalstudyon pages 1-2, penacorona2023advancesinthe pages 1-2).	Diociaiuti 2024, DOI: 10.1159/000536366; Peña-Corona 2023, DOI: 10.3389/fphar.2023.1274248 (diociaiuti2024crosssectionalstudyon pages 1-2, penacorona2023advancesinthe pages 1-2)
CYP4F22	Cytochrome P450 ω-hydroxylase; acylceramide synthesis	LI/CIE spectrum, often milder ARCI	In the Italian cohort, 12/74 (16.2%) had CYP4F22 variants. This group had the lowest mean ichthyosis severity score among the common ARCI genes in that study. Founder effects are reported for some variants in prior population studies, supporting population-specific enrichment (diociaiuti2024crosssectionalstudyon pages 1-2).	Diociaiuti 2024, DOI: 10.1159/000536366 (diociaiuti2024crosssectionalstudyon pages 1-2)
ABCA12	Lipid transporter for lamellar granule cargo/glucosylceramides	HI, also LI and CIE	In the Italian cohort, 9/74 (12.2%) had ABCA12 variants; severity was among the highest and alopecia, ectropion, eclabium were significantly associated. In the dedicated 64-patient ABCA12 cohort, 34 novel variants expanded the known spectrum to 217 mutations; putative hotspots included c.4541G>A p.(Arg1514His) and c.4139A>G p.(Asn1380Ser). Strong correlation: biallelic loss-of-function usually causes HI, whereas biallelic missense variants mainly cause CIE or LI (hotz2023mutationalspectrumof pages 1-2, diociaiuti2024crosssectionalstudyon pages 1-2).	Hotz 2023, DOI: 10.3390/genes14030717; Diociaiuti 2024, DOI: 10.1159/000536366 (hotz2023mutationalspectrumof pages 1-2, diociaiuti2024crosssectionalstudyon pages 1-2)
ALOXE3	Epidermal lipoxygenase eLOX3; lipid barrier metabolism	LI/CIE spectrum	In the Italian cohort, 7/74 (9.5%) had ALOXE3 variants. Included among core ARCI genes in multiple recent reviews and diagnostic papers; phenotype overlaps with other lipid-metabolism ARCI genes, supporting need for molecular confirmation (diociaiuti2024crosssectionalstudyon pages 1-2, fioretti2024comprehensivemolecularanalysis pages 16-17).	Diociaiuti 2024, DOI: 10.1159/000536366; Fioretti 2024, DOI: 10.3390/biomedicines12051112 (diociaiuti2024crosssectionalstudyon pages 1-2, fioretti2024comprehensivemolecularanalysis pages 16-17)
NIPAL4	Ichthyin; epidermal lipid homeostasis/acylceramide pathway	LI/CIE spectrum, distinctive patterned/psoriasiform ARCI	In the Italian cohort, 7/74 (9.5%) had NIPAL4 variants. Distinctive associations included psoriasis-like lesions, reticulate trunk scale pattern, and striated keratoderma; these were highlighted as a novel phenotypic feature with possible diagnostic/therapeutic implications. Prior referenced literature also links NIPAL4 to reduced stratum corneum acylceramides (diociaiuti2024crosssectionalstudyon pages 1-2, diociaiuti2024crosssectionalstudyon pages 17-17).	Diociaiuti 2024, DOI: 10.1159/000536366 (diociaiuti2024crosssectionalstudyon pages 1-2, diociaiuti2024crosssectionalstudyon pages 17-17)
CERS3	Ceramide synthase 3; very-long-chain ceramide synthesis	Rare ARCI, LI/CIE-like phenotypes	Rare in the Italian cohort (1/74; 1.4%). Ultrastructural review showed abnormal lamellar bodies in the CERS3 case, consistent with a barrier-lipid trafficking/synthesis defect (diociaiuti2024crosssectionalstudyon pages 1-2).	Diociaiuti 2024, DOI: 10.1159/000536366 (diociaiuti2024crosssectionalstudyon pages 1-2)
PNPLA1	Patatin-like phospholipase; acylceramide biosynthesis	Rare ARCI, typically LI/CIE-like	Rare in the Italian cohort (1/74; 1.4%). Included among established ARCI genes in recent reviews and sequencing studies; contributes to defective epidermal lipid barrier formation (diociaiuti2024crosssectionalstudyon pages 1-2, hotz2023mutationalspectrumof pages 1-2).	Diociaiuti 2024, DOI: 10.1159/000536366; Hotz 2023, DOI: 10.3390/genes14030717 (diociaiuti2024crosssectionalstudyon pages 1-2, hotz2023mutationalspectrumof pages 1-2)
SDR9C7	Short-chain dehydrogenase/reductase; epidermal retinoid/vitamin A-related metabolism	Rare ARCI, LI/CIE-like	Rare in the Italian cohort (1/74; 1.4%). Ultrastructural analysis showed abnormal lamellar bodies in the SDR9C7 patient; referenced literature links SDR9C7 to impaired epidermal barrier function and vitamin A metabolism (diociaiuti2024crosssectionalstudyon pages 1-2, diociaiuti2024crosssectionalstudyon pages 17-17).	Diociaiuti 2024, DOI: 10.1159/000536366 (diociaiuti2024crosssectionalstudyon pages 1-2, diociaiuti2024crosssectionalstudyon pages 17-17)
SULT2B1	Cholesterol sulfotransferase; epidermal sterol metabolism	Rare ARCI / nonsyndromic ichthyosis	Not represented among the 74 Italian patients, but listed as an established ARCI gene in recent ABCA12-focused and multi-gene diagnostic papers. Multi-gene NGS studies support inclusion of SULT2B1 on ichthyosis panels because phenotype overlaps with other ARCI forms (hotz2023mutationalspectrumof pages 1-2, fioretti2024comprehensivemolecularanalysis pages 16-17).	Hotz 2023, DOI: 10.3390/genes14030717; Fioretti 2024, DOI: 10.3390/biomedicines12051112 (hotz2023mutationalspectrumof pages 1-2, fioretti2024comprehensivemolecularanalysis pages 16-17)

Table: This table summarizes major ARCI genes, their biological roles, subtype associations, and the most informative genotype–phenotype findings from the provided evidence. It emphasizes cohort-based frequencies from Diociaiuti 2024 and the ABCA12-specific correlations from Hotz 2023 for diagnostic and knowledge-base use.

4.2 Pathogenic variants and variant classes

ABCA12 (2023 cohort, n=64): identified 34 novel ABCA12 mutations, expanding the reported spectrum to 217 mutations and noting possible hotspots c.4541G>A p.(Arg1514His) and c.4139A>G p.(Asn1380Ser). (hotz2023mutationalspectrumof pages 1-2)
Genotype–phenotype rule (ABCA12): “Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.” (hotz2023mutationalspectrumof pages 1-2)
ARCI cohort (Italy, 2024): identified 25 previously undescribed mutations, plus structural events (microduplications in TGM1, microdeletions in CYP4F22 and NIPAL4), illustrating that CNVs are relevant in ARCI diagnostics. (diociaiuti2024crosssectionalstudyon pages 1-2)

4.3 Modifier genes

No validated modifier genes were identified in the retrieved sources.

4.4 Epigenetic information

No ARCI-specific epigenetic mechanisms were identified in the retrieved sources.

4.5 Chromosomal abnormalities

Structural variants (CNVs) were reported in ARCI genes in the 2024 Italian cohort (microduplications/microdeletions), supporting CNV-aware diagnostic pipelines. (diociaiuti2024crosssectionalstudyon pages 1-2)

5. Environmental Information

No consistent non-genetic environmental causes were identified in the retrieved sources, consistent with ARCI being primarily monogenic. Supportive care often includes environmental management (e.g., avoiding overheating due to hypohidrosis/heat intolerance), but specific external causal exposures were not established in these sources. (diociaiuti2024crosssectionalstudyon pages 2-3)

6. Mechanism / Pathophysiology

6.1 Current mechanistic model (upstream→downstream causal chain)

Upstream trigger: biallelic pathogenic variants in genes mediating cornified envelope formation (e.g., TGM1) and/or epidermal lipid transport/metabolism (e.g., ABCA12, lipoxygenases, acylceramide pathway genes). (hotz2023mutationalspectrumof pages 1-2, penacorona2023advancesinthe pages 1-2)

Intermediate biological effects: defective cornification and impaired lipid processing/transport produce an abnormal stratum corneum architecture and permeability barrier; ultrastructural signatures can be gene-informative (e.g., “cholesterol clefts” in TGM1). (diociaiuti2024crosssectionalstudyon pages 1-2)

Clinical manifestations: generalized hyperkeratosis/scaling with variable erythema, fissuring, ectropion/eclabium, pruritus and pain; severe ABCA12 loss-of-function produces harlequin ichthyosis with life-threatening neonatal complications. (diociaiuti2024crosssectionalstudyon pages 2-3, hotz2023mutationalspectrumof pages 1-2)

6.2 Inflammatory/immune involvement (emerging theme)

A 2023 treatment review frames ARCI as having an “inflammatory process” and motivates repurposing biologics based on overlapping immune signatures with psoriasis/atopic dermatitis. (penacorona2023advancesinthe pages 1-2) Clinical trial development targeting IL-17 (secukinumab) and IL-12/23 (ustekinumab) further reflects this mechanistic direction. (NCT03041038 chunk 1, penacorona2023advancesinthe pages 6-7)

6.3 Suggested ontology mappings

GO Biological Process (examples): keratinization; epidermis development; lipid metabolic process; establishment of skin barrier.
Cell types (CL): CL:0000312 keratinocyte; (optionally) differentiated keratinocytes/corneocytes.
Anatomy (UBERON): UBERON:0002097 skin of body; UBERON:0001003 epidermis; stratum corneum.

7. Anatomical Structures Affected

7.1 Organ/system level

Primary organ: skin (epidermis/stratum corneum). (hotz2023mutationalspectrumof pages 1-2, diociaiuti2024crosssectionalstudyon pages 1-2) Secondary/complication-relevant systems include eyes (ectropion), mouth/lips (eclabium), thermoregulation (hypohidrosis/heat intolerance), and infection susceptibility due to barrier compromise. (diociaiuti2024crosssectionalstudyon pages 2-3)

7.2 Tissue/cell level

Key affected tissue: keratinizing stratified squamous epithelium of the epidermis; key cell type: keratinocytes undergoing abnormal terminal differentiation/cornification. (penacorona2023advancesinthe pages 1-2)

7.3 Subcellular/cellular components (suggested)

Cornified envelope structures and lipid-processing/transport organelles (e.g., lamellar body biology) are implicated; ultrastructural abnormalities were used diagnostically (including abnormal lamellar bodies in CERS3/SDR9C7 cases). (diociaiuti2024crosssectionalstudyon pages 1-2)

8. Temporal Development

8.1 Onset

ARCI is typically congenital/early-onset; the “collodion baby” presentation is frequently described across ARCI. (hotz2023mutationalspectrumof pages 1-2, diociaiuti2024crosssectionalstudyon pages 2-3)

8.2 Progression

The 2024 cohort includes ages from infancy to adulthood (0.1–48.8 years), supporting the view that ARCI is generally chronic and lifelong, with variable severity across genotypes. (diociaiuti2024crosssectionalstudyon pages 1-2)

9. Inheritance and Population

9.1 Inheritance

Autosomal recessive inheritance is explicit in the disease definition. (hotz2023mutationalspectrumof pages 1-2)

9.2 Epidemiology (available estimates in retrieved sources)

A 2023 ARCI treatment review cites: - TGM1-related prevalence “at 1:100,000 population” (citing Vahlquist et al., 2008), and - a French epidemiologic study reporting ARCI prevalence 7:1,000,000 (citing Dreyfus et al., 2014). (penacorona2023advancesinthe pages 1-2)

Because these are secondary citations within a review, they should be treated as contextual estimates rather than definitive contemporary global prevalence.

9.3 Population structure: consanguinity

The 2024 Italian cohort reported 17.8% consanguinity (13/73 families). (diociaiuti2024crosssectionalstudyon pages 2-3)

10. Diagnostics

10.1 Clinical diagnosis and differential diagnosis

Diagnosis generally starts from clinical phenotype (LI/CIE/HI spectrum, collodion baby) and is increasingly confirmed by genetic testing. (diociaiuti2024crosssectionalstudyon pages 1-2, salo2024genetictestingand pages 1-2)

10.2 Histopathology/ultrastructure as diagnostic support

The 2024 Italian ARCI study incorporated transmission electron microscopy and reported gene-informative ultrastructural patterns (e.g., “cholesterol clefts” specific for TGM1). (diociaiuti2024crosssectionalstudyon pages 1-2)

10.3 Genetic testing: current real-world approach

A 2024 register-based Finnish study (2000–2020; n=88) describes how diagnostic practice evolved: - “Diagnosis of ichthyosis was confirmed with genetic testing in 33 cases … and with conventional diagnostic methods … in 55 cases.” (Accepted 2024-08-06; https://doi.org/10.1002/mgg3.70000) (salo2024genetictestingand pages 1-2) - “When genetic testing became available, it was offered primarily to patients with severe forms of ichthyosis. During the study period next-generation sequencing became the genetic testing method of choice…” (salo2024genetictestingand pages 1-2)

The 2024 Italian cohort used targeted NGS panels and escalation to clinical exome/other methods, plus qPCR/array CGH for CNV detection and Sanger validation. (diociaiuti2024crosssectionalstudyon pages 2-3)

10.4 Suggested testing algorithm (evidence-aligned)

1) Phenotype-driven evaluation (LI/CIE/HI; collodion baby) with assessment of extracutaneous features to exclude syndromic ichthyoses. (salo2024genetictestingand pages 1-2) 2) NGS multigene panel covering core ARCI genes; consider CNV-aware methods (microarray/MLPA/NGS CNV calling) given reported microdeletions/duplications. (diociaiuti2024crosssectionalstudyon pages 1-2, salo2024genetictestingand pages 1-2) 3) If negative/uncertain: clinical exome or genome sequencing; segregation analysis where needed. (diociaiuti2024crosssectionalstudyon pages 2-3, salo2024genetictestingand pages 1-2)

11. Outcome / Prognosis

The retrieved sources emphasize clinical heterogeneity and mention improved outcomes for severe forms with intensive neonatal care, but they do not provide cohort-level survival curves for ARCI/HI within 2023–2024 primary literature in this run. The Italian cohort supports long-term survivorship into adulthood across subtypes, while HI is highlighted as the most severe and high-burden neonatal condition. (hotz2023mutationalspectrumof pages 1-2, diociaiuti2024crosssectionalstudyon pages 1-2)

12. Treatment

12.1 Current standard management (symptom-directed)

A 2023 review states: “Topical treatments are a first-choice strategy due to their ease of application and cost; however, enteral administration of retinoids offers greater efficacy, although with certain limitations.” (Published 2023-11-09; https://doi.org/10.3389/fphar.2023.1274248) (penacorona2023advancesinthe pages 1-2)

12.2 Systemic retinoids and alternatives

The retrieved evidence establishes systemic retinoids as commonly used in severe inherited ichthyosis management (review-level statement), but does not provide ARCI-specific response rates in 2023–2024 primary trials in this run. (penacorona2023advancesinthe pages 1-2)

12.3 Recent developments and real-world implementations (prioritizing 2023–2024)

(A) Topical isotretinoin (TMB-001) — late-phase repurposing in congenital ichthyosis

Trial: NCT04154293 (Timber Pharmaceuticals; Phase 2; completed). (NCT04154293 chunk 1) - Population: age ≥9 years, genetically confirmed congenital ichthyosis including ARCI-LI and RXLI; 10–90% BSA involvement. (NCT04154293 chunk 1) - Design: randomized, double-blind, vehicle-controlled; 34 participants; 1:1:1 to 0.05% BID, 0.1% BID, or vehicle for 12 weeks. (Study start 2019-12-03; completion 2021-08-30) (NCT04154293 chunk 1) - Primary endpoint: VIIS-50 responder at Week 12 (≥50% reduction in VIIS scaling). (NCT04154293 chunk 1) - Patient-centered secondary endpoints included itch scale change and DLQI. (NCT04154293 chunk 1) URL: https://clinicaltrials.gov/study/NCT04154293 (registry-derived). (NCT04154293 chunk 1)

(B) Topical gene replacement for TGM1-deficient ARCI — KB105 (HSV-1 vector)

Gene/cell therapy review (2024) states: “Gene therapy for the most common type of ichthyosis, lamellar ichthyosis caused by biallelic pathogenic variants in TGM1, is currently being developed using an engineered herpes simplex virus type 1 vector.” (Published online 2024-08-07; https://doi.org/10.1007/s13555-024-01239-4) (koutsoukos2024highlightsofgene pages 1-3)

ClinicalTrials.gov trials: - NCT04047732 (KB105; Phase 1/2; single-group, intra-patient comparison; up to 6 adults; started 2019-08-27; primary completion estimated Oct 2022; completion estimated Mar 2025). Endpoints include safety (TEAEs) and improvement by Investigator’s Global Assessment (IGA), VIIS-L changes, and immunofluorescence measurement of TGM1 in treated skin. (NCT04047732 chunk 1) - NCT05735158 (KB105-02; Phase 2; randomized, placebo-controlled, double-blind intra-subject design; estimated 15; weekly dosing; primary endpoint Composite IGA responder at Week 9; includes systemic retinoid stability/washout rules). (Posted as 2023 trial record; sponsor Krystal Biotech) (NCT05735158 chunk 1) URLs: https://clinicaltrials.gov/study/NCT04047732 and https://clinicaltrials.gov/study/NCT05735158 (registry-derived). (NCT04047732 chunk 1, NCT05735158 chunk 1)

(C) Anti–IL-17A biologic therapy (secukinumab) — mechanism-based repositioning

Trial: NCT03041038 (Northwestern University; Phase 2; completed; results posted 2021). (NCT03041038 chunk 1) - Enrollment: 20 adults. - Dosing: secukinumab 300 mg SC weekly ×5 then monthly vs placebo with crossover/open-label phases. (NCT03041038 chunk 1) - Primary efficacy endpoint: Week 16 reduction in Ichthyosis Area Severity Index (IASI). - Primary safety endpoint: bacterial/fungal mucocutaneous infections through Week 16. (NCT03041038 chunk 1) URL: https://clinicaltrials.gov/study/NCT03041038 (registry-derived). (NCT03041038 chunk 1)

(D) Anti–IL-12/23 (ustekinumab) — trial-scale testing in ichthyoses

A 2023 ARCI repositioning review notes a trial “with 13 participants receiving injections every 8 weeks for one year” aiming to reduce severity and assess infection safety endpoints (review-level summary). (penacorona2023advancesinthe pages 6-7)

12.4 MAXO (Medical Action Ontology) suggestions (examples)

Topical emollient therapy; keratolytic therapy; systemic retinoid therapy; topical retinoid therapy; biologic anti–IL-17 therapy; biologic anti–IL-12/23 therapy; gene replacement therapy (topical viral vector).

13. Prevention

Primary prevention is genetic (not environmental): carrier testing, prenatal diagnosis, and reproductive counseling are standard concepts for autosomal recessive disorders, but explicit ARCI-specific prevention guideline statements were not retrieved in this run. Genetic counseling is emphasized as enabled by molecular diagnosis in diagnostic-practice literature. (salo2024genetictestingand pages 1-2)

14. Other Species / Natural Disease

The retrieved sources in this run do not provide primary evidence for naturally occurring ARCI-equivalent disease across species. (No species-specific evidence retrieved.)

15. Model Organisms

The retrieved sources in this run mention that gene and cell therapy development for ichthyosis is supported by preclinical work (review-level), but do not provide specific animal model identifiers or detailed phenotype recapitulation for ARCI subtypes in the captured excerpts. (koutsoukos2024highlightsofgene pages 1-3)

Key 2023–2024 highlights (executive summary)

1) Genotype–phenotype resolution is improving with large cohorts: a 2024 single-center ARCI cohort (n=74) provides gene frequencies and statistically associated clinical features and ultrastructural signatures (including itch burden and high prevalence of PPK). (diociaiuti2024crosssectionalstudyon pages 2-3, diociaiuti2024crosssectionalstudyon pages 1-2) 2) ABCA12 genotype–phenotype correlation is reinforced: biallelic loss-of-function → HI; biallelic missense → LI/CIE; 34 novel variants in a 64-patient cohort (2023). (hotz2023mutationalspectrumof pages 1-2) 3) Diagnostics are shifting to NGS as first-tier with increasing use over time and improved classification/prognosis and counseling; conventional methods remain common where testing is unavailable (2024 register study). (salo2024genetictestingand pages 1-2) 4) Therapeutic innovation is moving toward targeted biologics and gene therapy: topical HSV-1–vector TGM1 gene therapy trials are ongoing/expanding; topical isotretinoin and IL-17 blockade have been tested in controlled trial frameworks. (koutsoukos2024highlightsofgene pages 1-3, NCT04047732 chunk 1, NCT05735158 chunk 1, NCT04154293 chunk 1, NCT03041038 chunk 1)

URLs and publication dates for key cited sources

Diociaiuti et al. “Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses…” Apr 2024. DOI/URL: https://doi.org/10.1159/000536366 (diociaiuti2024crosssectionalstudyon pages 1-2)
Hotz et al. “Mutational Spectrum of the ABCA12 Gene…” Mar 2023. DOI/URL: https://doi.org/10.3390/genes14030717 (hotz2023mutationalspectrumof pages 1-2)
Peña‑Corona et al. “Advances in the treatment of autosomal recessive congenital ichthyosis…” Published 2023-11-09. DOI/URL: https://doi.org/10.3389/fphar.2023.1274248 (penacorona2023advancesinthe pages 1-2)
Salo et al. “Genetic testing and new variants in diagnosis of congenital ichthyoses” Accepted 2024-08-06. DOI/URL: https://doi.org/10.1002/mgg3.70000 (salo2024genetictestingand pages 1-2)
Koutsoukos & Bilousova “Highlights of Gene and Cell Therapy…” Published online 2024-08-07. DOI/URL: https://doi.org/10.1007/s13555-024-01239-4 (koutsoukos2024highlightsofgene pages 1-3)
ClinicalTrials.gov: NCT04154293 https://clinicaltrials.gov/study/NCT04154293 (NCT04154293 chunk 1)
ClinicalTrials.gov: NCT04047732 https://clinicaltrials.gov/study/NCT04047732 (NCT04047732 chunk 1)
ClinicalTrials.gov: NCT05735158 https://clinicaltrials.gov/study/NCT05735158 (NCT05735158 chunk 1)
ClinicalTrials.gov: NCT03041038 https://clinicaltrials.gov/study/NCT03041038 (NCT03041038 chunk 1)

References

(diociaiuti2024crosssectionalstudyon pages 2-3): 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.
(hotz2023mutationalspectrumof pages 1-2): Alrun Hotz, Julia Kopp, Emmanuelle Bourrat, Vinzenz Oji, Kira Süßmuth, Katalin Komlosi, Bakar Bouadjar, Iliana Tantcheva-Poór, Maritta Hellström Pigg, Regina Betz, Kathrin Giehl, Fiona Schedel, Lisa Weibel, Solveig Schulz, Dora Stölzl, Gianluca Tadini, Emine Demiral, Karin Berggard, Andreas Zimmer, Svenja Alter, and Judith Fischer. Mutational spectrum of the abca12 gene and genotype–phenotype correlation in a cohort of 64 patients with autosomal recessive congenital ichthyosis. Genes, 14:717, Mar 2023. URL: https://doi.org/10.3390/genes14030717, doi:10.3390/genes14030717. This article has 27 citations.
(penacorona2023advancesinthe pages 1-2): Sheila I. Peña-Corona, Stephany Celeste Gutiérrez-Ruiz, Ma de los Dolores Campos Echeverria, Hernán Cortés, Manuel González-Del Carmen, and Gerardo Leyva-Gómez. Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs. Frontiers in Pharmacology, Nov 2023. URL: https://doi.org/10.3389/fphar.2023.1274248, doi:10.3389/fphar.2023.1274248. This article has 9 citations.
(salo2024genetictestingand pages 1-2): Milja Salo, Teija Kimpimäki, Heini Huhtala, and Tanja Saarela. Genetic testing and new variants in diagnosis of congenital ichthyoses. Molecular Genetics & Genomic Medicine, Aug 2024. URL: https://doi.org/10.1002/mgg3.70000, doi:10.1002/mgg3.70000. This article has 1 citations and is from a peer-reviewed journal.
(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
(diociaiuti2024crosssectionalstudyon pages 1-2): 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.
(fioretti2024comprehensivemolecularanalysis pages 16-17): 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.
(diociaiuti2024crosssectionalstudyon pages 17-17): 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.
(NCT03041038 chunk 1): Amy Paller. The Efficacy and Safety of Secukinumab in Patients With Ichthyoses. Northwestern University. 2016. ClinicalTrials.gov Identifier: NCT03041038
(penacorona2023advancesinthe pages 6-7): Sheila I. Peña-Corona, Stephany Celeste Gutiérrez-Ruiz, Ma de los Dolores Campos Echeverria, Hernán Cortés, Manuel González-Del Carmen, and Gerardo Leyva-Gómez. Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs. Frontiers in Pharmacology, Nov 2023. URL: https://doi.org/10.3389/fphar.2023.1274248, doi:10.3389/fphar.2023.1274248. This article has 9 citations.
(NCT04154293 chunk 1): 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
(koutsoukos2024highlightsofgene pages 1-3): Stefanos A. Koutsoukos and Ganna Bilousova. Highlights of gene and cell therapy for epidermolysis bullosa and ichthyosis. Dermatology and Therapy, 14:2379-2392, Aug 2024. URL: https://doi.org/10.1007/s13555-024-01239-4, doi:10.1007/s13555-024-01239-4. This article has 5 citations.
(NCT05735158 chunk 1): Topical KB105 for the Treatment of TGM1-deficient Autosomal Recessive Congenital Ichthyosis (ARCI). Krystal Biotech, Inc.. 2023. ClinicalTrials.gov Identifier: NCT05735158

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Related Datasets

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 What is the disease?

1.2 Key identifiers

1.3 Common synonyms / alternative names

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype spectrum and frequencies (recent cohort data)

3.2 Severity measurement in current research/practice

3.3 Genotype-associated phenotypes (selected)

3.4 Quality of life impact

3.5 Suggested HPO terms (examples; not exhaustive)

4. Genetic / Molecular Information

4.1 Causal genes and gene functions (current understanding)

Gene–phenotype synthesis table

4.2 Pathogenic variants and variant classes

4.3 Modifier genes

4.4 Epigenetic information

4.5 Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Current mechanistic model (upstream→downstream causal chain)

6.2 Inflammatory/immune involvement (emerging theme)

6.3 Suggested ontology mappings

7. Anatomical Structures Affected

7.1 Organ/system level

7.2 Tissue/cell level

7.3 Subcellular/cellular components (suggested)

8. Temporal Development

8.1 Onset

8.2 Progression

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology (available estimates in retrieved sources)

9.3 Population structure: consanguinity

10. Diagnostics

10.1 Clinical diagnosis and differential diagnosis

10.2 Histopathology/ultrastructure as diagnostic support

10.3 Genetic testing: current real-world approach

10.4 Suggested testing algorithm (evidence-aligned)

11. Outcome / Prognosis

12. Treatment

12.1 Current standard management (symptom-directed)

12.2 Systemic retinoids and alternatives

12.3 Recent developments and real-world implementations (prioritizing 2023–2024)

(A) Topical isotretinoin (TMB-001) — late-phase repurposing in congenital ichthyosis

(B) Topical gene replacement for TGM1-deficient ARCI — KB105 (HSV-1 vector)

(C) Anti–IL-17A biologic therapy (secukinumab) — mechanism-based repositioning

(D) Anti–IL-12/23 (ustekinumab) — trial-scale testing in ichthyoses

12.4 MAXO (Medical Action Ontology) suggestions (examples)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key 2023–2024 highlights (executive summary)

URLs and publication dates for key cited sources