Autoinflammation, immune dysregulation, and eosinophilia

Mendelian MONDO:0033558 Pathograph 32 Show in embeddings browser hereditary disease Primary Immunodeficiency

Autoinflammation, immune dysregulation, and eosinophilia (AIIDE; OMIM 618999) is a very rare immune-dysregulation disorder caused by activating JAK1 variants. The prototypic heterozygous germline c.1901C>A (p.A634D) variant in the regulatory pseudokinase domain causes severe early-onset atopy, eosinophilia, growth failure, gastrointestinal and hepatic involvement, and autoimmunity. A post-zygotic mosaic p.S703I variant caused a severe autoinflammatory, gastrointestinal, and renal phenotype. Additional heterozygous variants across the FERM, SH2, pseudokinase, and kinase domains have been associated with a broader JAK1-associated autoimmunity, atopy, colitis, and dermatitis (JAACD) spectrum. These later variants show functional gain of signaling but variable expressivity and reduced penetrance, so they should not all be interpreted as equivalent to the fully penetrant p.A634D syndrome. Hyperactive baseline and cytokine-induced STAT phosphorylation is the shared molecular readout. Published patient-level responses to ruxolitinib, tofacitinib, baricitinib, and upadacitinib support pathway-directed therapy, but evidence remains limited to a family, individual cases, and a small genotype-first series rather than controlled trials.

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1
Inheritance
5
Pathophys.
17
Phenotypes
32
Pathograph
6
Variants
4
Medical Actions
3
Differentials
1
Datasets
2
Models
4
References
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous germline JAK1 gain-of-function variants segregate with disease in an autosomal dominant pattern. In the index family the variant arose de novo in the mother and was transmitted to both of her affected sons; it was absent in the unaffected maternal grandparents. Across the broader cohort, activating JAK1 variants are heterozygous, and one reported patient carried a post-zygotic mosaic variant.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:28111307 SUPPORT Human Clinical
"JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
The disease-defining report establishes germline JAK1 gain-of-function as the cause of an autosomal dominant immune dysregulatory and hypereosinophilic syndrome; de novo origin in the mother and transmission to both sons is described in the article text and pedigree (Fig 1, A).
PMID:38563820 SUPPORT Human Clinical
"Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants."
A 59-individual cohort confirms that disease-associated JAK1 GoF variants are heterozygous, consistent with dominant action.
PMID:32750333 SUPPORT Human Clinical
"We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
Post-zygotic mosaic JAK1 gain-of-function is a documented non-germline occurrence.
⚙

Pathophysiology

5
JAK1 gain-of-function and loss of autoinhibition
The prototypic JAK1 p.A634D substitution lies in the inhibitory pseudokinase (JH2) domain, at a residue highly conserved across species and within the aC helix. In the resting state the JH2 domain restrains the adjacent kinase (JH1) domain; the A634D change relieves this autoinhibition and yields constitutively active JAK1 without altering JAK1 mRNA or protein expression. The same residue is recurrently mutated as a somatic gain-of-function event in lymphoid malignancy, independently establishing its activating nature. Activating germline variants are not confined to the pseudokinase domain: a post-zygotic mosaic pseudokinase variant (S703I) and germline variants spanning all four JAK1 domains (FERM E139K, SH2 R506C, pseudokinase S700N, kinase V985I) are also gain-of-function, indicating multiple routes to constitutive JAK1 activation.
JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
positive regulation of JAK-STAT signaling GO:0046427 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of JAK-STAT signaling, annotated with positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427). GO:0046427 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Constitutive JAK-STAT pathway activation Loss of pseudokinase-domain autoinhibition drives ligand-independent and ligand-amplified activation of downstream JAK-STAT signaling.
Show evidence (5 references)
PMID:28111307 SUPPORT Human Clinical
"JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
The report attributes the syndrome to a germline JAK1 gain-of-function variant; functional assays in the article localize the p.A634D change to the inhibitory pseudokinase domain and show increased baseline and stimulated JAK1/STAT activation.
PMID:18362173 SUPPORT In Vitro
"Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3-independent growth in Ba/F3 cells"
Somatic JAK1 pseudokinase-domain mutations are functionally validated as gain-of-function, supporting an activating mechanism for the analogous germline p.A634D allele cited by the index report.
PMID:32750333 SUPPORT Human Clinical
"We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
Extends the activating-variant spectrum to a post-zygotic mosaic pseudokinase-domain variant (S703I) causing early-onset multi-organ immune dysregulation.
+ 2 more references
Constitutive JAK-STAT pathway activation
Hyperactive JAK1 increases phosphorylation of STAT1 and STAT3 both at baseline and after cytokine stimulation. Patient-derived B cells show increased IFN-alpha-induced STAT1 phosphorylation, and primary CD3+ T cells show enhanced IL-6-induced STAT3 phosphorylation in a time- and dose-dependent manner. Across the broader JAK1-variant cohort, the variants confer hyperactive baseline and cytokine-induced STAT phosphorylation and elevated baseline interferon-stimulated gene (ISG) expression, acting predominantly through cis-activation; the mosaic S703I variant is in addition neomorphic, transactivating partner JAKs independent of its own catalytic domain. Transcriptomic analysis converges on IL-4, IL-13, and interferon signaling as the dysregulated core, driving a Th2-skewed immune phenotype. Pharmacologic JAK inhibition reduces this excess STAT phosphorylation.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. T-helper 2 cell CL:0000546 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 2 cell (CL:0000546). CL:0000546 is a cell type from the Cell Ontology.
JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
JAK-STAT signaling GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased JAK-STAT signaling, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↑ INCREASED tyrosine phosphorylation of STAT protein GO:0007260 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased tyrosine phosphorylation of STAT protein (GO:0007260). GO:0007260 is a biological process from the Gene Ontology. ↑ INCREASED type I interferon-mediated signaling GO:0060337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased type I interferon-mediated signaling, annotated with type I interferon-mediated signaling pathway (GO:0060337). GO:0060337 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Eosinophil expansion and tissue infiltration Sustained JAK-STAT signaling promotes eosinophil expansion and accumulation despite normal levels of the canonical eosinophilopoietic cytokines IL-3, IL-5, and GM-CSF.
Skin barrier disruption and atopic inflammation Hyperactive JAK1-STAT signaling in skin drives a Th2-biased inflammatory, pruritic dermatitis phenotype.
Multiorgan inflammatory tissue injury Cytokine hypersignaling and immune dysregulation are associated with gastrointestinal, renal, hepatic, endocrine, and systemic injury, but the organ-specific intermediates are incompletely resolved.
Show evidence (4 references)
PMID:25587654 SUPPORT Other
"Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions."
Establishes that the JAK-STAT pathway is a conserved cytokine-signaling system whose dysregulating mutations cause immune-related human disease, providing the mechanistic context for constitutive JAK1-STAT activation.
PMID:38563820 SUPPORT In Vitro
"In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1."
Directly demonstrates that JAK1 GoF variants elevate both baseline and cytokine-induced STAT phosphorylation and ISG expression relative to wild-type.
PMID:32750333 SUPPORT In Vitro
"Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1."
Establishes that an activating JAK1 variant increases JAK1 activity and can act neomorphically by transactivating partner JAKs, broadening the mechanistic model beyond simple cis-hyperactivation.
+ 1 more reference
Eosinophil expansion and tissue infiltration
Patients develop marked peripheral eosinophilia and eosinophilic precursors, with tissue infiltration reported in the liver and gastrointestinal tract. Modeling p.A634D in zebrafish and human iPSCs reveals enhanced myelopoiesis, linking the activating lesion to expansion of the myeloid/eosinophil lineage. Ruxolitinib markedly decreases eosinophil counts, although residual elevation can persist.
eosinophil CL:0000771 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves eosinophil (CL:0000771). CL:0000771 is a cell type from the Cell Ontology.
JAK-STAT signaling GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased JAK-STAT signaling, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↑ INCREASED eosinophil differentiation GO:0030222 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased eosinophil differentiation (GO:0030222). GO:0030222 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hypereosinophilia Expansion of eosinophils and their precursors produces persistent peripheral hypereosinophilia.
Hepatosplenomegaly Eosinophilic and inflammatory organ infiltration accompanies enlargement of liver and spleen.
Colonic eosinophilia Eosinophilic tissue infiltration can involve the colon.
Eosinophilic liver infiltration The classic syndrome includes eosinophilic infiltration of hepatic tissue.
Show evidence (2 references)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"revealed increased eosinophils and eosinophilic precursors"
Bone-marrow studies in the affected children demonstrate expansion of eosinophils and their precursors.
PMID:36546480 SUPPORT Model Organism
"Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis."
Zebrafish and iPSC models of the p.A634D variant show enhanced myelopoiesis, supporting a cell-intrinsic driver of eosinophil/myeloid expansion.
Skin barrier disruption and atopic inflammation
Severe, treatment-resistant atopic dermatitis-like skin inflammation with intractable pruritus is a hallmark, present in the mother since birth. Mouse models carrying a Jak1 gain-of-function substitution recapitulate the phenotype: JAK1 hyperactivation drives skin serine-protease overexpression, skin-barrier disruption, and a Th2-biased pruritic dermatitis that is delayed by pharmacologic JAK1 inhibition, mirroring the JAK-inhibitor response in patients.
positive regulation of JAK-STAT signaling GO:0046427 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of JAK-STAT signaling, annotated with positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427). GO:0046427 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Atopic dermatitis Barrier disruption and cutaneous inflammation manifest as atopic dermatitis.
Pruritus The inflammatory dermatitis produces severe itch.
Asthma Systemic atopic inflammation can involve the airways.
Food allergy Systemic atopic immune dysregulation includes food hypersensitivity.
Show evidence (2 references)
PMID:27111231 SUPPORT Model Organism
"These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function."
A Jak1 gain-of-function mouse model reproduces the skin-barrier defect and pruritic dermatitis seen in patients, supporting JAK1 hyperactivation as the driver of the cutaneous phenotype.
PMID:27111231 SUPPORT Model Organism
"Pharmacological inhibition of JAK1 also delayed disease onset."
Pharmacologic JAK1 inhibition mitigates the dermatitis in the model, paralleling the clinical resolution of dermatitis with JAK inhibitors.
Multiorgan inflammatory tissue injury
JAK1 cytokine hypersignaling is associated with gastrointestinal inflammation, renal immune injury, autoimmune endocrine disease, hepatic abnormalities, infection susceptibility, and impaired growth. The organ-specific cellular intermediates vary across variants and remain less resolved than the proximal JAK-STAT defect.
JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Hepatic cysts Prenatal hepatic cysts are part of severe developmental p.A634D disease, although the tissue mechanism is unresolved.
Colitis Intestinal immune dysregulation can manifest as colitis or very-early-onset inflammatory bowel disease.
Hypothyroidism Immune dysregulation can target the thyroid.
Autoimmunity Persistent cytokine hypersignaling is associated with systemic and organ-specific autoimmune disease.
Failure to thrive Chronic multisystem disease and altered inflammatory signaling impair weight and linear growth.
Short stature Sustained disease activity can impair linear growth.
Membranous nephropathy Renal immune injury in the mosaic p.S703I case manifested as membranous nephropathy.
Nephrotic syndrome Membranous renal injury produced proteinuria, edema, and a nephrotic presentation.
Recurrent viral infections Some affected individuals have recurrent viral infection susceptibility.
Show evidence (1 reference)
PMID:32750333 SUPPORT Human Clinical
"We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
The mosaic case establishes a multisystem inflammatory phenotype arising from JAK1 gain-of-function.
⬡

Pathograph

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

17
Blood 1
Hypereosinophilia Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased total eosinophil count (HP:0001880), qualified as course stable. HP:0001880 is a phenotype from the Human Phenotype Ontology.
Course: STABLE
Show evidence (2 references)
PMID:28111307 SUPPORT Human Clinical
"JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
The syndrome is defined as hypereosinophilic; the article reports sustained eosinophil counts above the hypereosinophilia threshold.
PMID:36546480 SUPPORT Human Clinical
"Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia."
Independent report confirming eosinophilia as a core consequence of germline JAK1 GoF.
Cardiovascular 1
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558 SUPPORT Other
""subject":"MONDO:0033558","object":"HP:0001433""
The HPO/OMIM-derived association records hepatosplenomegaly for AIIDE with PMID:28111307 as its publication.
Digestive 2
Hepatic cysts HP:0001407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prenatal liver cysts, annotated with Hepatic cysts (HP:0001407), qualified as antenatal onset. HP:0001407 is a phenotype from the Human Phenotype Ontology.
Onset: ANTENATAL
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"poor intrauterine growth, hepatic cysts, respiratory distress at birth"
The longitudinal p.A634D report explicitly identifies hepatic cysts as a fetal manifestation.
Colitis HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colitis (HP:0002583). HP:0002583 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38563820 SUPPORT Human Clinical
"increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
EHR-based cohort analysis links JAK1 variants to colitis as part of the JAACD syndrome.
Endocrine 1
Hypothyroidism HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Both patients were also diagnosed with hypothyroidism, eosinophilic gastrointestinal disease (EGID), and possible liver fibrosis."
Both affected children in the p.A634D family had hypothyroidism.
Immune 3
Atopic dermatitis HP:0001047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atopic dermatitis (HP:0001047), qualified as severity severe. HP:0001047 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (2 references)
PMID:38563820 SUPPORT Human Clinical
"increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
Cohort-level EHR analysis links JAK1 variants to atopy and dermatitis.
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Ruxolitinib treatment initiated at ages 6 years (III-1) and 20 months (III-2) rapidly improved pruritus and atopic dermatitis symptoms, so that topical corticosteroids were discontinued."
Both affected children had rapidly treatment-responsive atopic dermatitis symptoms.
Autoimmunity HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38563820 SUPPORT Human Clinical
"increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
Cohort analysis links JAK1 variants to autoimmunity as a core JAACD feature.
Food allergy HP:0500093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Food allergy (HP:0500093). HP:0500093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Similar to III-1 and III-2, their mother (patient II-2) suffers from severe allergic inflammation, including eosinophilia, atopic dermatitis, asthma, allergic rhinitis, and food and drug allergy."
Food allergy is explicitly reported in the p.A634D family.
Integument 1
Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Ruxolitinib treatment initiated at ages 6 years (III-1) and 20 months (III-2) rapidly improved pruritus and atopic dermatitis symptoms, so that topical corticosteroids were discontinued."
Pruritus was a treatment-responsive component of the p.A634D cutaneous phenotype.
Growth 2
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"In 2017, an IEI was discovered in a family with severe atopic dermatitis, asthma, food allergy, failure to thrive, autoimmune thyroiditis, and markedly elevated peripheral blood eosinophil counts"
Failure to thrive is explicitly part of the p.A634D family phenotype.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558 SUPPORT Other
""subject":"MONDO:0033558","object":"HP:0004322""
The HPO/OMIM-derived association records short stature for AIIDE with PMID:28111307 as its publication.
Other 6
Colonic eosinophilia HP:0031813 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colonic eosinophilia (HP:0031813). HP:0031813 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML SUPPORT Human Clinical
"Eosinophilic infiltration of the colon was consistently noted."
Serial biopsies in the mosaic p.S703I case consistently demonstrated colonic eosinophilia.
Eosinophilic liver infiltration HP:0032021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eosinophilic infiltration of the liver, annotated with Eosinophilic liver infiltration (HP:0032021). HP:0032021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558 SUPPORT Other
""subject":"MONDO:0033558","object":"HP:0032021""
The HPO/OMIM-derived association records eosinophilic liver infiltration for AIIDE with PMID:28111307 as its publication.
Asthma HP:0002099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthma (HP:0002099). HP:0002099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Similar to III-1 and III-2, their mother (patient II-2) suffers from severe allergic inflammation, including eosinophilia, atopic dermatitis, asthma, allergic rhinitis, and food and drug allergy."
Asthma is explicitly reported in the p.A634D family.
Membranous nephropathy HP:0012578 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Membranous nephropathy (HP:0012578). HP:0012578 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML SUPPORT Human Clinical
"which was refractory to treatment with corticosteroids, and later, cyclosporine and tacrolimus."
Renal biopsy established membranous nephropathy in the mosaic p.S703I patient.
Nephrotic syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML SUPPORT Human Clinical
"At 3 years of age, she developed rapid weight gain, edema, and proteinuria."
Edema and proteinuria document the nephrotic presentation in the p.S703I case.
Recurrent viral infections HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558 SUPPORT Other
""subject":"MONDO:0033558","object":"HP:0004429""
The HPO/OMIM-derived association records recurrent viral infections for AIIDE with PMID:28111307 as its publication.
🔬

Variants

6
c.1901C>A (p.A634D) Pathogenic
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous germline JAK1 missense variant (alanine to aspartate at codon 634) in the regulatory pseudokinase domain. It produces gain of JAK1 signaling and segregated with severe disease in the original family.
Show evidence (2 references)
PMID:28111307 SUPPORT Human Clinical
"JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
The report identifies a germline JAK1 gain-of-function variant (p.A634D) as causal for the syndrome and validates increased JAK1/STAT activation in patient and transfected cells.
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Whole exome sequencing revealed a heterozygous gain-of-function (GOF) variant in the regulatory pseudokinase domain"
The longitudinal family report confirms the variant class, zygosity, and regulatory-domain location.
p.S703I (mosaic) Pathogenic
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Post-zygotic mosaic JAK1 pseudokinase-domain gain-of-function variant (c.2108G>T) reported in a patient with early-onset multi-organ immune dysregulation. It is hypermorphic and neomorphic, transactivating partner JAKs independently of its own catalytic domain.
Show evidence (1 reference)
PMID:32750333 SUPPORT Human Clinical
"We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
Reports the mosaic S703I pseudokinase-domain variant as the cause of early-onset multi-organ immune dysregulation.
p.E139K (FERM domain) Uncertain Significance
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous germline JAK1 FERM-domain gain-of-function variant (c.415C>T) reported in the JAACD cohort; the carrier (patient P3) had severe atopic dermatitis that responded to baricitinib. Functional gain of signaling is established, but formal variant-level pathogenic classification remains limited by the small number of carriers.
Show evidence (2 references)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT In Vitro
"these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
One of four JAACD JAK1 variants functionally validated as gain-of-function (FERM-domain E139K, confirmed in the article full text).
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT Human Clinical
"Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
The reported spectrum supports caution about equating this allele with classic severe AIIDE.
p.R506C (SH2 domain) Uncertain Significance
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous germline JAK1 SH2-domain gain-of-function variant (c.1516C>T) reported in the JAACD cohort. Genotype-first ascertainment and unaffected or mildly affected carriers indicate incomplete penetrance; functional hyperactivity alone is insufficient for a pathogenic assertion.
Show evidence (2 references)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT In Vitro
"these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
One of four JAACD JAK1 variants functionally validated as gain-of-function (SH2-domain R506C, confirmed in the article full text).
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT Human Clinical
"Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
The reported spectrum supports incomplete penetrance and variable clinical severity for this allele.
p.S700N (pseudokinase domain) Uncertain Significance
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous germline JAK1 pseudokinase-domain gain-of-function variant (c.2099G>A) reported in the JAACD cohort. The functional phenotype supports gain of signaling, but the clinical evidence remains limited.
Show evidence (2 references)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT In Vitro
"these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
One of four JAACD JAK1 variants functionally validated as gain-of-function (pseudokinase-domain S700N, confirmed in the article full text).
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT Human Clinical
"Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
The reported spectrum supports caution because gain of signaling need not imply severe or early clinical disease.
p.V985I (kinase domain) Uncertain Significance
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous germline JAK1 kinase-domain gain-of-function variant (c.2953G>A) reported in the JAACD cohort. Genotype-first ascertainment and variable expressivity support caution in assigning individual-carrier causality despite the functional signaling phenotype.
Show evidence (2 references)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT In Vitro
"these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
One of four JAACD JAK1 variants functionally validated as gain-of-function (kinase-domain V985I, confirmed in the article full text).
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT Human Clinical
"Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
The reported spectrum supports incomplete penetrance and variable clinical severity for this allele.
💊

Medical Actions

4
Ruxolitinib
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ruxolitinib CHEBI:66919 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ruxolitinib (CHEBI:66919). CHEBI:66919 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral JAK1/2 inhibitor used as precision therapy targeting the exaggerated JAK1 signaling. Long-term treatment of the two affected children produced rapid improvement in pruritus and dermatitis and sustained improvement in growth, gastrointestinal symptoms, liver markers, and eosinophilia. Residual eosinophilia and airway disease can persist. Dose-dependent anemia improved with dose adjustment.
Mechanism Target:
INHIBITS Constitutive JAK-STAT pathway activation — Ruxolitinib inhibits the hyperactive JAK1/2-STAT signaling that drives the disorder.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"patients experienced rapid and sustained improvements in growth and allergic immune dysregulation on ruxolitinib."
Clinical improvement after direct pathway inhibition supports excess JAK-STAT signaling as the therapeutic target.
Target Phenotypes: Increased total eosinophil count HP:0001880 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Increased total eosinophil count (HP:0001880). HP:0001880 is a phenotype from the Human Phenotype Ontology. Atopic dermatitis HP:0001047 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atopic dermatitis (HP:0001047). HP:0001047 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36546480 SUPPORT Human Clinical
"long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation."
Longer-term follow-up of the index children documents sustained improvement in growth, eosinophilia, and allergic inflammation on ruxolitinib.
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Ruxolitinib therapy dramatically improved eosinophil counts; however, they remained above the normal upper limit"
The full follow-up documents a marked but incomplete eosinophil response.
PMID:27111231 SUPPORT Model Organism
"Pharmacological inhibition of JAK1 also delayed disease onset."
JAK1 inhibition ameliorates the JAK1-driven dermatitis in a model system, providing mechanistic support for the ruxolitinib response in patients.
Tofacitinib
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tofacitinib CHEBI:71200 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tofacitinib (CHEBI:71200). CHEBI:71200 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral JAK inhibitor used as precision therapy in a patient with the mosaic S703I JAK1 gain-of-function variant, leading to rapid resolution of clinical disease.
Mechanism Target:
INHIBITS Constitutive JAK-STAT pathway activation — Tofacitinib suppresses the excessive cytokine signaling produced by mosaic JAK1 p.S703I.
Show evidence (1 reference)
PMID:32750333 SUPPORT Human Clinical
"the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease."
Rapid disease resolution after JAK inhibition supports pathway suppression as the treatment mechanism.
Show evidence (1 reference)
PMID:32750333 SUPPORT Human Clinical
"the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease."
Demonstrates a precision-medicine JAK-inhibitor response in a JAK1 GoF (S703I) patient.
Baricitinib
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: baricitinib CHEBI:95341 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses baricitinib (CHEBI:95341). CHEBI:95341 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral JAK1/2-selective inhibitor used in a JAK1 E139K patient with severe atopic dermatitis, producing clinically significant improvement (SCORAD 60 to 16 over 30 days) and normalization of STAT phosphorylation.
Mechanism Target:
INHIBITS Constitutive JAK-STAT pathway activation — Baricitinib inhibits JAK1/JAK2 and reduced the hyperphosphorylated STAT readout in the treated patient.
Show evidence (1 reference)
PMID:38563820 SUPPORT Human Clinical
"treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement."
Response to a JAK1/JAK2-selective inhibitor supports suppression of proximal pathway hyperactivity.
Target Phenotypes: Atopic dermatitis HP:0001047 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atopic dermatitis (HP:0001047). HP:0001047 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38563820 SUPPORT Human Clinical
"treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement."
Confirms JAK-inhibitor efficacy (baricitinib) in a JAK1 GoF patient with severe atopic dermatitis.
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT Human Clinical
"reducing from SCORAD = 60 at treatment initiation to SCORAD = 16 after 30 days"
The full report quantifies the rapid dermatitis improvement in the treated E139K carrier.
Upadacitinib
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Selective JAK1 inhibition improved pruritus and dermatitis in the affected adult p.A634D carrier. Rosacea and weight gain were reported, and this single-patient partial response does not establish comparative efficacy.
Mechanism Target:
INHIBITS Constitutive JAK-STAT pathway activation — Selective JAK1 blockade targets the proximal gain-of-function signaling defect.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Treatment with a selective JAK1 inhibitor upadacitinib at a dose of 15 mg/day improved the patient’s pruritis and dermatitis"
Symptom improvement after selective JAK1 inhibition supports the proximal signaling defect as the target.
Target Phenotypes: Atopic dermatitis HP:0001047 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atopic dermatitis (HP:0001047). HP:0001047 is a phenotype from the Human Phenotype Ontology. Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Treatment with a selective JAK1 inhibitor upadacitinib at a dose of 15 mg/day improved the patient’s pruritis and dermatitis"
Documents a clinical response to upadacitinib in the affected adult p.A634D carrier.
🔬

Diagnosis

2
Molecular identification of an activating JAK1 variant
Sequence JAK1 in patients with otherwise unexplained early-onset eosinophilia plus multisystem atopy, autoinflammation, colitis, renal disease, or autoimmunity. Analysis should allow detection of constitutional heterozygous variants and lower-allele-fraction post-zygotic mosaic variants.
Results: A clinically concordant activating JAK1 variant; p.A634D and mosaic p.S703I have the strongest case-level causal evidence.
Show evidence (2 references)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"Whole exome sequencing revealed a heterozygous gain-of-function (GOF) variant in the regulatory pseudokinase domain"
Exome sequencing identified the causal p.A634D variant in the affected family.
PMID:32750333 SUPPORT Human Clinical
"We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
A mosaic-aware diagnostic approach is required because a pathogenic post-zygotic variant has been reported.
Functional JAK-STAT signaling assessment
Baseline and cytokine-stimulated STAT phosphorylation and interferon-stimulated gene expression can provide functional support for a candidate variant, but results must be interpreted with segregation, phenotype, frequency, and penetrance data.
Results: Hyperactive baseline or cytokine-induced STAT phosphorylation relative to wild-type controls
Functional gain of signaling does not by itself prove full clinical penetrance or justify upgrading a population-observed variant to pathogenic.
Show evidence (1 reference)
PMID:38563820 SUPPORT In Vitro
"In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1."
This defines the shared functional readout used to evaluate the four broader JAACD variants.
📈

Progression

2
Antenatal to early childhood onset
Age: Antenatal to early childhood
Severe p.A634D disease can begin with poor intrauterine growth and hepatic cysts, followed in infancy or childhood by dermatitis, eosinophilia, gastrointestinal disease, hypothyroidism, and growth failure. The mosaic p.S703I case had a pustular rash at birth and gastrointestinal inflammation from approximately one year of age.
Show evidence (2 references)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"poor intrauterine growth, hepatic cysts, respiratory distress at birth"
Longitudinal follow-up documents antenatal and neonatal manifestations in the p.A634D family.
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML SUPPORT Human Clinical
"At birth, the patient was noted to have a widespread pustular rash in a linear pattern that predominantly affected the left side of the body"
The mosaic p.S703I phenotype was clinically apparent at birth.
Persistent multisystem disease with treatment-modifiable activity
Age: Childhood through adulthood
Untreated disease can remain active across skin, blood, gastrointestinal, endocrine, hepatic, and renal systems. Targeted JAK inhibition can produce rapid and sustained improvement, although residual eosinophilia or other manifestations may persist.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"patients experienced rapid and sustained improvements in growth and allergic immune dysregulation on ruxolitinib."
Long-term follow-up shows that the course is substantially modified by pathway-directed therapy.
🌍

Epidemiology

1
Reported-case frequency
Population prevalence has not been established. The literature began with one three-member p.A634D family and one patient with mosaic p.S703I. A later forward- and reverse-genetics study described 59 heterozygous variant carriers, but ascertainment included genotype-first biobank participants and does not mean that all 59 had clinically penetrant AIIDE.
The disorder is best treated as ultra-rare; no incidence or population prevalence estimate is available.
Show evidence (1 reference)
PMID:38563820 SUPPORT Human Clinical
"Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants."
This is the largest reported variant-carrier series, but its combined phenotype-first and genotype-first design precludes using 59 as a count of clinically affected classic AIIDE cases.
⚖️

Clinical Burden

High
Classic and mosaic severe JAK1 gain-of-function disease causes congenital or early-childhood multisystem inflammation, growth failure, severe dermatitis, tissue eosinophilia, and potentially organ failure. The p.S703I case developed refractory membranous nephropathy requiring transplantation and later hemodialysis. Burden is more variable in the broader JAACD spectrum.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML SUPPORT Human Clinical
"Kidney transplantation was performed at age 11, but MN recurred within 1 year, followed by antibody-mediated rejection, requiring subsequent hemodialysis."
The mosaic case demonstrates major irreversible renal morbidity and intensive long-term care burden.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autoinflammation, immune dysregulation, and eosinophilia:

Reactive or clonal hypereosinophilic disorders
Overlapping Features Infection, drug reaction, allergic disease, eosinophilic neoplasia, and other reactive or clonal hypereosinophilic syndromes can resemble AIIDE.
Distinguishing Features
  • A pathogenic or clinically concordant activating JAK1 variant favors AIIDE.
  • Congenital or early multisystem atopy, autoimmunity, growth failure, and JAK-STAT hyperphosphorylation support AIIDE over isolated reactive eosinophilia.
Show evidence (1 reference)
PMID:36546480 SUPPORT Human Clinical
"Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia."
The defining genetic cause distinguishes AIIDE from acquired and clonal eosinophilic conditions.
Severe atopic dermatitis or eosinophilic gastrointestinal disease
Overlapping Features Organ-limited atopy and eosinophilic gastrointestinal disease overlap with the cutaneous, allergic, and gastrointestinal manifestations of AIIDE.
Distinguishing Features
  • Multisystem autoimmunity, growth failure, renal or hepatic disease, and marked JAK-STAT hyperactivation favor AIIDE.
  • Molecular evidence of an activating JAK1 variant supports a syndromic diagnosis.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Human Clinical
"In 2017, an IEI was discovered in a family with severe atopic dermatitis, asthma, food allergy, failure to thrive, autoimmune thyroiditis, and markedly elevated peripheral blood eosinophil counts"
The combination of atopy with growth, endocrine, and hematologic findings demonstrates the syndromic pattern.
Other inborn errors of immunity with immune dysregulation
Overlapping Features Combined variable immune deficiency, STAT gain-of-function disorders, and other monogenic immune-dysregulation syndromes can present with infection, enteropathy, autoimmunity, eczema, and poor growth.
Distinguishing Features
  • Gene-panel or exome analysis differentiates JAK1 gain-of-function from other monogenic immune disorders.
  • Variant-specific STAT phosphorylation patterns and segregation can support interpretation.
Show evidence (1 reference)
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML SUPPORT Human Clinical
"presented in adulthood with nonspecific colitis, recurrent respiratory infections, autoimmune thrombocytopenia, and autoimmune hepatitis, suggesting a diagnosis of combined variable immune deficiency (CVID)."
A JAACD proband initially resembled CVID, documenting this clinically relevant overlap.
📊

Related Datasets

1
A Zebrafish JAK1-A634D Gain-of-Function Model Provides New Insights into the Pathogenesis of Familial Hypereosinophilia geo:GSE142599
Bulk RNA sequencing of casper, human JAK1-WT, and human JAK1-A634D transgenic zebrafish embryos at 28 and 36 hours post-fertilization.
zebrafish BULK RNA SEQ n=18 Ion Torrent Proton
Conditions: casper embryos at 28 and 36 hours post-fertilization JAK1-WT transgenic embryos at 28 and 36 hours post-fertilization JAK1-A634D transgenic embryos at 28 and 36 hours post-fertilization
PMID:36546480
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE142599 SUPPORT Other
"Total RNA from casper, JAK1-WT and JAK1-A634D zebrafish embryos at 28 and 36 hours post-fertilization was extracted to characterize the transcriptomic effects of the JAK1-A634D gain-of-function mutation"
The GEO record states the model groups, time points, and transcriptomic study design.
url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML SUPPORT Model Organism
"The zebrafish RNA-Seq data are available under"
The primary publication identifies the public accession for the zebrafish RNA-seq data.
🐁

Animal Models

2
Transgenic human JAK1 p.A634D gain-of-function compared with JAK1 wild-type and uninjected casper embryos zebrafish (Danio rerio) Transgenic gain-of-function model
Transgenic embryos expressing human JAK1 p.A634D show enhanced myelopoiesis, abnormal development, and a conserved IL-4/IL-13 and interferon transcriptomic signature. Ruxolitinib rescues developmental abnormalities, providing in vivo pharmacologic support for pathway dependence.
Enhanced myelopoiesis Abnormal embryonic development Dysregulated IL-4, IL-13, and interferon signaling
Species
zebrafish (Danio rerio)
Genotype
Transgenic human JAK1 p.A634D gain-of-function compared with JAK1 wild-type and uninjected casper embryos
Genes
JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:36546480 SUPPORT Model Organism
"Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis."
The study directly validates the zebrafish p.A634D model and its myelopoietic phenotype.
Spade Jak1 gain-of-function missense model mouse (Mus musculus) Spontaneous gain-of-function model
Jak1-hyperactive mice develop progressive pruritic dermatitis through skin serine-protease overexpression, barrier disruption, and a subsequent Th2-biased response. JAK1 inhibition delays disease onset.
Pruritic dermatitis Skin barrier disruption Th2-biased inflammation
Species
mouse (Mus musculus)
Genotype
Spade Jak1 gain-of-function missense model
Genes
JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:27111231 SUPPORT Model Organism
"Here, we have described a mutant mouse that spontaneously develops pruritic dermatitis as the result of an initial defect in skin homeostasis that is followed by induction of a Th2-biased immune response."
The model recapitulates the barrier-first pruritic dermatitis mechanism associated with JAK1 hyperactivation.
{ }

Source YAML

click to show 
name: Autoinflammation, immune dysregulation, and eosinophilia
creation_date: "2026-06-27T00:00:00Z"
category: Mendelian
synonyms:
- AIIDE
- JAK1 gain-of-function syndrome
- JAACD syndrome
- JAK1-associated autoimmunity, atopy, colitis, and dermatitis syndrome
- Autosomal dominant immune dysregulatory and hypereosinophilic syndrome
- Germline JAK1 gain-of-function disorder
disease_term:
  preferred_term: Autoinflammation, immune dysregulation, and eosinophilia
  term:
    id: MONDO:0033558
    label: autoinflammation, immune dysregulation, and eosinophilia
parents:
- hereditary disease
- Primary Immunodeficiency
description: >-
  Autoinflammation, immune dysregulation, and eosinophilia (AIIDE; OMIM 618999)
  is a very rare immune-dysregulation disorder caused by activating JAK1
  variants. The prototypic heterozygous germline c.1901C>A (p.A634D) variant in
  the regulatory pseudokinase domain causes severe early-onset atopy,
  eosinophilia, growth failure, gastrointestinal and hepatic involvement, and
  autoimmunity. A post-zygotic mosaic p.S703I variant caused a severe
  autoinflammatory, gastrointestinal, and renal phenotype. Additional
  heterozygous variants across the FERM, SH2, pseudokinase, and kinase domains
  have been associated with a broader JAK1-associated autoimmunity, atopy,
  colitis, and dermatitis (JAACD) spectrum. These later variants show functional
  gain of signaling but variable expressivity and reduced penetrance, so they
  should not all be interpreted as equivalent to the fully penetrant p.A634D
  syndrome. Hyperactive baseline and cytokine-induced STAT phosphorylation is
  the shared molecular readout. Published patient-level responses to
  ruxolitinib, tofacitinib, baricitinib, and upadacitinib support pathway-directed
  therapy, but evidence remains limited to a family, individual cases, and a
  small genotype-first series rather than controlled trials.
references:
- reference: PMID:28111307
  title: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome."
- reference: PMID:36546480
  title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
- reference: PMID:32750333
  title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
- reference: PMID:38563820
  title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
epidemiology:
- name: Reported-case frequency
  description: >-
    Population prevalence has not been established. The literature began with
    one three-member p.A634D family and one patient with mosaic p.S703I. A later
    forward- and reverse-genetics study described 59 heterozygous variant
    carriers, but ascertainment included genotype-first biobank participants
    and does not mean that all 59 had clinically penetrant AIIDE.
  notes: >-
    The disorder is best treated as ultra-rare; no incidence or population
    prevalence estimate is available.
  evidence:
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants."
    explanation: >-
      This is the largest reported variant-carrier series, but its combined
      phenotype-first and genotype-first design precludes using 59 as a count of
      clinically affected classic AIIDE cases.
progression:
- phase: Antenatal to early childhood onset
  age_range: Antenatal to early childhood
  notes: >-
    Severe p.A634D disease can begin with poor intrauterine growth and hepatic
    cysts, followed in infancy or childhood by dermatitis, eosinophilia,
    gastrointestinal disease, hypothyroidism, and growth failure. The mosaic
    p.S703I case had a pustular rash at birth and gastrointestinal inflammation
    from approximately one year of age.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor intrauterine growth, hepatic cysts, respiratory distress at birth"
    explanation: Longitudinal follow-up documents antenatal and neonatal manifestations in the p.A634D family.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At birth, the patient was noted to have a widespread pustular rash in a linear pattern that predominantly affected the left side of the body"
    explanation: The mosaic p.S703I phenotype was clinically apparent at birth.
- phase: Persistent multisystem disease with treatment-modifiable activity
  age_range: Childhood through adulthood
  notes: >-
    Untreated disease can remain active across skin, blood, gastrointestinal,
    endocrine, hepatic, and renal systems. Targeted JAK inhibition can produce
    rapid and sustained improvement, although residual eosinophilia or other
    manifestations may persist.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients experienced rapid and sustained improvements in growth and allergic immune dysregulation on ruxolitinib."
    explanation: Long-term follow-up shows that the course is substantially modified by pathway-directed therapy.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Classic and mosaic severe JAK1 gain-of-function disease causes congenital or
    early-childhood multisystem inflammation, growth failure, severe dermatitis,
    tissue eosinophilia, and potentially organ failure. The p.S703I case
    developed refractory membranous nephropathy requiring transplantation and
    later hemodialysis. Burden is more variable in the broader JAACD spectrum.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney transplantation was performed at age 11, but MN recurred within 1 year, followed by antibody-mediated rejection, requiring subsequent hemodialysis."
    explanation: The mosaic case demonstrates major irreversible renal morbidity and intensive long-term care burden.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous germline JAK1 gain-of-function variants segregate with disease
    in an autosomal dominant pattern. In the index family the variant arose de
    novo in the mother and was transmitted to both of her affected sons; it was
    absent in the unaffected maternal grandparents. Across the broader cohort,
    activating JAK1 variants are heterozygous, and one reported patient carried
    a post-zygotic mosaic variant.
  evidence:
  - reference: PMID:28111307
    reference_title: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
    explanation: >-
      The disease-defining report establishes germline JAK1 gain-of-function as
      the cause of an autosomal dominant immune dysregulatory and
      hypereosinophilic syndrome; de novo origin in the mother and transmission
      to both sons is described in the article text and pedigree (Fig 1, A).
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants."
    explanation: >-
      A 59-individual cohort confirms that disease-associated JAK1 GoF variants
      are heterozygous, consistent with dominant action.
  - reference: PMID:32750333
    reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
    explanation: Post-zygotic mosaic JAK1 gain-of-function is a documented non-germline occurrence.
pathophysiology:
- name: JAK1 gain-of-function and loss of autoinhibition
  conforms_to: "jak_stat_pathway_activation#Constitutive JAK Kinase Activation"
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The prototypic JAK1 p.A634D substitution lies in the inhibitory pseudokinase
    (JH2) domain, at a residue highly conserved across species and within the aC
    helix. In the resting state the JH2 domain restrains the adjacent kinase
    (JH1) domain; the A634D change relieves this autoinhibition and yields
    constitutively active JAK1 without altering JAK1 mRNA or protein expression.
    The same residue is recurrently mutated as a somatic gain-of-function event
    in lymphoid malignancy, independently establishing its activating nature.
    Activating germline variants are not confined to the pseudokinase domain: a
    post-zygotic mosaic pseudokinase variant (S703I) and germline variants
    spanning all four JAK1 domains (FERM E139K, SH2 R506C, pseudokinase S700N,
    kinase V985I) are also gain-of-function, indicating multiple routes to
    constitutive JAK1 activation.
  genes:
  - preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  biological_processes:
  - preferred_term: positive regulation of JAK-STAT signaling
    term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  evidence:
  - reference: PMID:28111307
    reference_title: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
    explanation: >-
      The report attributes the syndrome to a germline JAK1 gain-of-function
      variant; functional assays in the article localize the p.A634D change to
      the inhibitory pseudokinase domain and show increased baseline and
      stimulated JAK1/STAT activation.
  - reference: PMID:18362173
    reference_title: "Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3-independent growth in Ba/F3 cells"
    explanation: >-
      Somatic JAK1 pseudokinase-domain mutations are functionally validated as
      gain-of-function, supporting an activating mechanism for the analogous
      germline p.A634D allele cited by the index report.
  - reference: PMID:32750333
    reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
    explanation: >-
      Extends the activating-variant spectrum to a post-zygotic mosaic
      pseudokinase-domain variant (S703I) causing early-onset multi-organ immune
      dysregulation.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing revealed a heterozygous gain-of-function (GOF) variant in the regulatory pseudokinase domain"
    explanation: The longitudinal family study identifies the prototypic variant and its regulatory-domain location.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
    explanation: The expanded study functionally defines gain-of-signaling variants across all four JAK1 domains.
  downstream:
  - target: Constitutive JAK-STAT pathway activation
    causal_link_type: DIRECT
    description: >-
      Loss of pseudokinase-domain autoinhibition drives ligand-independent and
      ligand-amplified activation of downstream JAK-STAT signaling.
    evidence:
    - reference: PMID:38563820
      reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1."
      explanation: Functional assays directly link activating JAK1 variants to excess STAT phosphorylation and ISG expression.
- name: Constitutive JAK-STAT pathway activation
  conforms_to: "jak_stat_pathway_activation#Constitutive STAT Activation and Nuclear Translocation"
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Hyperactive JAK1 increases phosphorylation of STAT1 and STAT3 both at
    baseline and after cytokine stimulation. Patient-derived B cells show
    increased IFN-alpha-induced STAT1 phosphorylation, and primary CD3+ T cells
    show enhanced IL-6-induced STAT3 phosphorylation in a time- and
    dose-dependent manner. Across the broader JAK1-variant cohort, the variants
    confer hyperactive baseline and cytokine-induced STAT phosphorylation and
    elevated baseline interferon-stimulated gene (ISG) expression, acting
    predominantly through cis-activation; the mosaic S703I variant is in
    addition neomorphic, transactivating partner JAKs independent of its own
    catalytic domain. Transcriptomic analysis converges on IL-4, IL-13, and
    interferon signaling as the dysregulated core, driving a Th2-skewed immune
    phenotype. Pharmacologic JAK inhibition reduces this excess STAT
    phosphorylation.
  genes:
  - preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  biological_processes:
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  - preferred_term: tyrosine phosphorylation of STAT protein
    term:
      id: GO:0007260
      label: tyrosine phosphorylation of STAT protein
    modifier: INCREASED
  - preferred_term: type I interferon-mediated signaling
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:25587654
    reference_title: "The JAK-STAT pathway: impact on human disease and therapeutic intervention."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions."
    explanation: >-
      Establishes that the JAK-STAT pathway is a conserved cytokine-signaling
      system whose dysregulating mutations cause immune-related human disease,
      providing the mechanistic context for constitutive JAK1-STAT activation.
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1."
    explanation: >-
      Directly demonstrates that JAK1 GoF variants elevate both baseline and
      cytokine-induced STAT phosphorylation and ISG expression relative to
      wild-type.
  - reference: PMID:32750333
    reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1."
    explanation: >-
      Establishes that an activating JAK1 variant increases JAK1 activity and
      can act neomorphically by transactivating partner JAKs, broadening the
      mechanistic model beyond simple cis-hyperactivation.
  - reference: PMID:36546480
    reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling."
    explanation: >-
      Cross-model transcriptomics anchored on patient whole blood identifies
      IL-4, IL-13, and interferon signaling as the convergent dysregulated
      core downstream of JAK1 GoF.
  downstream:
  - target: Eosinophil expansion and tissue infiltration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained JAK-STAT signaling promotes eosinophil expansion and
      accumulation despite normal levels of the canonical eosinophilopoietic
      cytokines IL-3, IL-5, and GM-CSF.
    evidence:
    - reference: PMID:36546480
      reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis."
      explanation: Cross-species models link the activating variant to enhanced myeloid production.
  - target: Skin barrier disruption and atopic inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Hyperactive JAK1-STAT signaling in skin drives a Th2-biased inflammatory,
      pruritic dermatitis phenotype.
    evidence:
    - reference: PMID:27111231
      reference_title: "Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function."
      explanation: A Jak1 gain-of-function mouse provides an experimental link from kinase hyperactivation to barrier disruption and dermatitis.
  - target: Multiorgan inflammatory tissue injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cytokine hypersignaling and immune dysregulation are associated with
      gastrointestinal, renal, hepatic, endocrine, and systemic injury, but the
      organ-specific intermediates are incompletely resolved.
    evidence:
    - reference: PMID:32750333
      reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
      explanation: The p.S703I case directly associates JAK1 gain-of-function with early-onset multiorgan immune dysregulation.
- name: Eosinophil expansion and tissue infiltration
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Patients develop marked peripheral eosinophilia and eosinophilic precursors,
    with tissue infiltration reported in the liver and gastrointestinal tract.
    Modeling p.A634D in zebrafish and human iPSCs reveals enhanced myelopoiesis,
    linking the activating lesion to expansion of the myeloid/eosinophil
    lineage. Ruxolitinib markedly decreases eosinophil counts, although residual
    elevation can persist.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  - preferred_term: eosinophil differentiation
    term:
      id: GO:0030222
      label: eosinophil differentiation
    modifier: INCREASED
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed increased eosinophils and eosinophilic precursors"
    explanation: >-
      Bone-marrow studies in the affected children demonstrate expansion of
      eosinophils and their precursors.
  - reference: PMID:36546480
    reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis."
    explanation: >-
      Zebrafish and iPSC models of the p.A634D variant show enhanced
      myelopoiesis, supporting a cell-intrinsic driver of eosinophil/myeloid
      expansion.
  downstream:
  - target: Hypereosinophilia
    causal_link_type: DIRECT
    description: Expansion of eosinophils and their precursors produces persistent peripheral hypereosinophilia.
    evidence:
    - reference: PMID:36546480
      reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia."
      explanation: The follow-up study directly identifies eosinophilia as a consequence of germline JAK1 gain-of-function.
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Eosinophilic and inflammatory organ infiltration accompanies enlargement of liver and spleen.
    evidence:
    - reference: url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558
      reference_title: "https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"subject":"MONDO:0033558","object":"HP:0001433"'
      explanation: The HPO/OMIM-derived Monarch association links AIIDE to hepatosplenomegaly and cites PMID:28111307.
  - target: Colonic eosinophilia
    causal_link_type: DIRECT
    description: Eosinophilic tissue infiltration can involve the colon.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eosinophilic infiltration of the colon was consistently noted."
      explanation: Repeated biopsies in the mosaic p.S703I case consistently demonstrated colonic eosinophilia.
  - target: Eosinophilic liver infiltration
    causal_link_type: DIRECT
    description: The classic syndrome includes eosinophilic infiltration of hepatic tissue.
    evidence:
    - reference: url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558
      reference_title: "https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"subject":"MONDO:0033558","object":"HP:0032021"'
      explanation: The HPO/OMIM-derived Monarch association links AIIDE to eosinophilic liver infiltration and cites PMID:28111307.
- name: Skin barrier disruption and atopic inflammation
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Severe, treatment-resistant atopic dermatitis-like skin inflammation with
    intractable pruritus is a hallmark, present in the mother since birth.
    Mouse models carrying a Jak1 gain-of-function substitution recapitulate the
    phenotype: JAK1 hyperactivation drives skin serine-protease overexpression,
    skin-barrier disruption, and a Th2-biased pruritic dermatitis that is delayed
    by pharmacologic JAK1 inhibition, mirroring the JAK-inhibitor response in
    patients.
  biological_processes:
  - preferred_term: positive regulation of JAK-STAT signaling
    term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  evidence:
  - reference: PMID:27111231
    reference_title: "Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function."
    explanation: >-
      A Jak1 gain-of-function mouse model reproduces the skin-barrier defect and
      pruritic dermatitis seen in patients, supporting JAK1 hyperactivation as
      the driver of the cutaneous phenotype.
  - reference: PMID:27111231
    reference_title: "Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pharmacological inhibition of JAK1 also delayed disease onset."
    explanation: >-
      Pharmacologic JAK1 inhibition mitigates the dermatitis in the model,
      paralleling the clinical resolution of dermatitis with JAK inhibitors.
  downstream:
  - target: Atopic dermatitis
    causal_link_type: DIRECT
    description: Barrier disruption and cutaneous inflammation manifest as atopic dermatitis.
    evidence:
    - reference: PMID:27111231
      reference_title: "Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function."
      explanation: The Jak1 gain-of-function mouse directly links kinase hyperactivation, barrier disruption, and dermatitis.
  - target: Pruritus
    causal_link_type: DIRECT
    description: The inflammatory dermatitis produces severe itch.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ruxolitinib treatment initiated at ages 6 years (III-1) and 20 months (III-2) rapidly improved pruritus and atopic dermatitis symptoms, so that topical corticosteroids were discontinued."
      explanation: Parallel rapid improvement of itch and dermatitis after pathway inhibition supports their shared mechanism.
  - target: Asthma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Systemic atopic inflammation can involve the airways.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Similar to III-1 and III-2, their mother (patient II-2) suffers from severe allergic inflammation, including eosinophilia, atopic dermatitis, asthma, allergic rhinitis, and food and drug allergy."
      explanation: Asthma occurs within the severe allergic-inflammatory phenotype of the p.A634D family.
  - target: Food allergy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Systemic atopic immune dysregulation includes food hypersensitivity.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Similar to III-1 and III-2, their mother (patient II-2) suffers from severe allergic inflammation, including eosinophilia, atopic dermatitis, asthma, allergic rhinitis, and food and drug allergy."
      explanation: Food allergy is explicitly reported as part of the p.A634D allergic-inflammatory phenotype.
- name: Multiorgan inflammatory tissue injury
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    JAK1 cytokine hypersignaling is associated with gastrointestinal
    inflammation, renal immune injury, autoimmune endocrine disease, hepatic
    abnormalities, infection susceptibility, and impaired growth. The
    organ-specific cellular intermediates vary across variants and remain less
    resolved than the proximal JAK-STAT defect.
  genes:
  - preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  evidence:
  - reference: PMID:32750333
    reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
    explanation: The mosaic case establishes a multisystem inflammatory phenotype arising from JAK1 gain-of-function.
  downstream:
  - target: Hepatic cysts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Prenatal hepatic cysts are part of severe developmental p.A634D disease, although the tissue mechanism is unresolved.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "poor intrauterine growth, hepatic cysts, respiratory distress at birth"
      explanation: Hepatic cysts are explicitly described among fetal manifestations of JAK1 gain-of-function.
  - target: Colitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Intestinal immune dysregulation can manifest as colitis or very-early-onset inflammatory bowel disease.
    evidence:
    - reference: PMID:38563820
      reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
      explanation: The expanded cohort identifies colitis as part of the JAACD phenotype spectrum.
  - target: Hypothyroidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Immune dysregulation can target the thyroid.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients were also diagnosed with hypothyroidism, eosinophilic gastrointestinal disease (EGID), and possible liver fibrosis."
      explanation: Hypothyroidism was present in both affected children in the p.A634D family.
  - target: Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Persistent cytokine hypersignaling is associated with systemic and organ-specific autoimmune disease.
    evidence:
    - reference: PMID:38563820
      reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
      explanation: Genotype-first analysis supports an association between JAK1 variants and autoimmune presentations.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic multisystem disease and altered inflammatory signaling impair weight and linear growth.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 2017, an IEI was discovered in a family with severe atopic dermatitis, asthma, food allergy, failure to thrive, autoimmune thyroiditis, and markedly elevated peripheral blood eosinophil counts"
      explanation: Failure to thrive is part of the reported p.A634D clinical constellation.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Sustained disease activity can impair linear growth.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Over this time, she also experienced asthma, food and environmental allergies, severely stunted growth with leg length discrepancy, and poor weight gain"
      explanation: Severe growth impairment occurred during the multisystem course of the mosaic p.S703I case.
  - target: Membranous nephropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Renal immune injury in the mosaic p.S703I case manifested as membranous nephropathy.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "which was refractory to treatment with corticosteroids, and later, cyclosporine and tacrolimus."
      explanation: Biopsy confirmed severe treatment-refractory membranous nephropathy in the p.S703I patient.
  - target: Nephrotic syndrome
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Membranous renal injury produced proteinuria, edema, and a nephrotic presentation.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At 3 years of age, she developed rapid weight gain, edema, and proteinuria."
      explanation: The mosaic case developed the defining clinical features of nephrotic syndrome before renal biopsy.
  - target: Recurrent viral infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Some affected individuals have recurrent viral infection susceptibility.
    evidence:
    - reference: url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558
      reference_title: "https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"subject":"MONDO:0033558","object":"HP:0004429"'
      explanation: The HPO/OMIM-derived Monarch association links AIIDE to recurrent viral infections and cites PMID:28111307.
phenotypes:
- category: Hematologic
  name: Hypereosinophilia
  description: >-
    Marked, persistent peripheral blood eosinophilia, with eosinophilic tissue
    infiltration in severe disease.
  phenotype_term:
    preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
    clinical_course: STABLE
  evidence:
  - reference: PMID:28111307
    reference_title: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
    explanation: >-
      The syndrome is defined as hypereosinophilic; the article reports
      sustained eosinophil counts above the hypereosinophilia threshold.
  - reference: PMID:36546480
    reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia."
    explanation: >-
      Independent report confirming eosinophilia as a core consequence of
      germline JAK1 GoF.
- category: Dermatologic
  name: Atopic dermatitis
  description: >-
    Severe, early-onset, treatment-resistant atopic dermatitis-like eczema with
    intractable pruritus.
  phenotype_term:
    preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
    severity: SEVERE
  evidence:
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
    explanation: >-
      Cohort-level EHR analysis links JAK1 variants to atopy and dermatitis.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ruxolitinib treatment initiated at ages 6 years (III-1) and 20 months (III-2) rapidly improved pruritus and atopic dermatitis symptoms, so that topical corticosteroids were discontinued."
    explanation: Both affected children had rapidly treatment-responsive atopic dermatitis symptoms.
- category: Dermatologic
  name: Pruritus
  description: Intractable itch accompanying the dermatitis; improved rapidly with ruxolitinib.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ruxolitinib treatment initiated at ages 6 years (III-1) and 20 months (III-2) rapidly improved pruritus and atopic dermatitis symptoms, so that topical corticosteroids were discontinued."
    explanation: Pruritus was a treatment-responsive component of the p.A634D cutaneous phenotype.
- category: Gastrointestinal
  name: Hepatosplenomegaly
  description: >-
    Enlargement of the liver and spleen occurs in the classic syndrome and can
    accompany eosinophilic hepatic infiltration.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558
    reference_title: "https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"subject":"MONDO:0033558","object":"HP:0001433"'
    explanation: The HPO/OMIM-derived association records hepatosplenomegaly for AIIDE with PMID:28111307 as its publication.
- category: Gastrointestinal
  name: Hepatic cysts
  description: Liver cysts noted on prenatal ultrasound in the affected children.
  phenotype_term:
    preferred_term: Prenatal liver cysts
    term:
      id: HP:0001407
      label: Hepatic cysts
    onset:
      onset_category: ANTENATAL
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor intrauterine growth, hepatic cysts, respiratory distress at birth"
    explanation: The longitudinal p.A634D report explicitly identifies hepatic cysts as a fetal manifestation.
- category: Gastrointestinal
  name: Colonic eosinophilia
  description: Repeated intestinal biopsies can show eosinophilic infiltration of the colon.
  phenotype_term:
    preferred_term: Colonic eosinophilia
    term:
      id: HP:0031813
      label: Colonic eosinophilia
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eosinophilic infiltration of the colon was consistently noted."
    explanation: Serial biopsies in the mosaic p.S703I case consistently demonstrated colonic eosinophilia.
- category: Gastrointestinal
  name: Eosinophilic liver infiltration
  description: Eosinophilic infiltration of hepatic tissue is part of classic AIIDE.
  phenotype_term:
    preferred_term: Eosinophilic infiltration of the liver
    term:
      id: HP:0032021
      label: Eosinophilic liver infiltration
  evidence:
  - reference: url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558
    reference_title: "https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"subject":"MONDO:0033558","object":"HP:0032021"'
    explanation: The HPO/OMIM-derived association records eosinophilic liver infiltration for AIIDE with PMID:28111307 as its publication.
- category: Gastrointestinal
  name: Colitis
  description: >-
    Colitis, including very-early-onset inflammatory bowel disease, is part of
    the broader JAK1-variant (JAACD) spectrum.
  phenotype_term:
    preferred_term: Colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
    explanation: >-
      EHR-based cohort analysis links JAK1 variants to colitis as part of the
      JAACD syndrome.
- category: Endocrine
  name: Hypothyroidism
  description: Hypothyroidism, including autoimmune thyroiditis in the classic family.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients were also diagnosed with hypothyroidism, eosinophilic gastrointestinal disease (EGID), and possible liver fibrosis."
    explanation: Both affected children in the p.A634D family had hypothyroidism.
- category: Immunologic
  name: Autoimmunity
  description: Autoimmune disease, manifesting as autoimmune thyroid disease in the index family and enriched broadly across the JAACD spectrum.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals"
    explanation: >-
      Cohort analysis links JAK1 variants to autoimmunity as a core JAACD feature.
- category: Respiratory
  name: Asthma
  description: Asthma as part of the atopic spectrum in affected individuals.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to III-1 and III-2, their mother (patient II-2) suffers from severe allergic inflammation, including eosinophilia, atopic dermatitis, asthma, allergic rhinitis, and food and drug allergy."
    explanation: Asthma is explicitly reported in the p.A634D family.
- category: Immunologic
  name: Food allergy
  description: Food allergy and environmental allergies within the atopic phenotype.
  phenotype_term:
    preferred_term: Food allergy
    term:
      id: HP:0500093
      label: Food allergy
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to III-1 and III-2, their mother (patient II-2) suffers from severe allergic inflammation, including eosinophilia, atopic dermatitis, asthma, allergic rhinitis, and food and drug allergy."
    explanation: Food allergy is explicitly reported in the p.A634D family.
- category: Constitutional
  name: Failure to thrive
  description: >-
    Profound failure of linear growth and weight gain in the affected children,
    improving after starting ruxolitinib. Growth failure can begin in utero.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2017, an IEI was discovered in a family with severe atopic dermatitis, asthma, food allergy, failure to thrive, autoimmune thyroiditis, and markedly elevated peripheral blood eosinophil counts"
    explanation: Failure to thrive is explicitly part of the p.A634D family phenotype.
- category: Constitutional
  name: Short stature
  description: Moderate short stature in the affected adult (mother).
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558
    reference_title: "https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"subject":"MONDO:0033558","object":"HP:0004322"'
    explanation: The HPO/OMIM-derived association records short stature for AIIDE with PMID:28111307 as its publication.
- category: Renal
  name: Membranous nephropathy
  description: >-
    The mosaic p.S703I case developed biopsy-proven membranous nephropathy that
    was refractory to corticosteroids and calcineurin inhibitors and recurred
    after kidney transplantation.
  phenotype_term:
    preferred_term: Membranous nephropathy
    term:
      id: HP:0012578
      label: Membranous nephropathy
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which was refractory to treatment with corticosteroids, and later, cyclosporine and tacrolimus."
    explanation: Renal biopsy established membranous nephropathy in the mosaic p.S703I patient.
- category: Renal
  name: Nephrotic syndrome
  description: Proteinuria and edema accompanied the membranous nephropathy in the mosaic p.S703I case.
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC7398039/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 3 years of age, she developed rapid weight gain, edema, and proteinuria."
    explanation: Edema and proteinuria document the nephrotic presentation in the p.S703I case.
- category: Immunologic
  name: Recurrent viral infections
  description: Recurrent viral infections have been annotated in the classic AIIDE phenotype.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: url:https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558
    reference_title: "https://api.monarchinitiative.org/v3/api/association?subject=MONDO%3A0033558"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"subject":"MONDO:0033558","object":"HP:0004429"'
    explanation: The HPO/OMIM-derived association records recurrent viral infections for AIIDE with PMID:28111307 as its publication.
treatments:
- name: Ruxolitinib
  description: >-
    Oral JAK1/2 inhibitor used as precision therapy targeting the exaggerated
    JAK1 signaling. Long-term treatment of the two affected children produced
    rapid improvement in pruritus and dermatitis and sustained improvement in
    growth, gastrointestinal symptoms, liver markers, and eosinophilia. Residual
    eosinophilia and airway disease can persist. Dose-dependent anemia improved
    with dose adjustment.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
  target_phenotypes:
  - preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  - preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  target_mechanisms:
  - target: Constitutive JAK-STAT pathway activation
    treatment_effect: INHIBITS
    description: Ruxolitinib inhibits the hyperactive JAK1/2-STAT signaling that drives the disorder.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "patients experienced rapid and sustained improvements in growth and allergic immune dysregulation on ruxolitinib."
      explanation: Clinical improvement after direct pathway inhibition supports excess JAK-STAT signaling as the therapeutic target.
  evidence:
  - reference: PMID:36546480
    reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation."
    explanation: >-
      Longer-term follow-up of the index children documents sustained
      improvement in growth, eosinophilia, and allergic inflammation on
      ruxolitinib.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ruxolitinib therapy dramatically improved eosinophil counts; however, they remained above the normal upper limit"
    explanation: The full follow-up documents a marked but incomplete eosinophil response.
  - reference: PMID:27111231
    reference_title: "Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pharmacological inhibition of JAK1 also delayed disease onset."
    explanation: >-
      JAK1 inhibition ameliorates the JAK1-driven dermatitis in a model system,
      providing mechanistic support for the ruxolitinib response in patients.
  notes: >-
    Evidence is from two related children. Eosinophils improved but could remain
    above the reference range; anemia improved with dose adjustment.
- name: Tofacitinib
  description: >-
    Oral JAK inhibitor used as precision therapy in a patient with the mosaic
    S703I JAK1 gain-of-function variant, leading to rapid resolution of clinical
    disease.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tofacitinib
      term:
        id: CHEBI:71200
        label: tofacitinib
  target_mechanisms:
  - target: Constitutive JAK-STAT pathway activation
    treatment_effect: INHIBITS
    description: Tofacitinib suppresses the excessive cytokine signaling produced by mosaic JAK1 p.S703I.
    evidence:
    - reference: PMID:32750333
      reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease."
      explanation: Rapid disease resolution after JAK inhibition supports pathway suppression as the treatment mechanism.
  evidence:
  - reference: PMID:32750333
    reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease."
    explanation: >-
      Demonstrates a precision-medicine JAK-inhibitor response in a JAK1 GoF
      (S703I) patient.
  notes: Evidence is limited to one patient with mosaic p.S703I.
- name: Baricitinib
  description: >-
    Oral JAK1/2-selective inhibitor used in a JAK1 E139K patient with severe
    atopic dermatitis, producing clinically significant improvement (SCORAD
    60 to 16 over 30 days) and normalization of STAT phosphorylation.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baricitinib
      term:
        id: CHEBI:95341
        label: baricitinib
  target_phenotypes:
  - preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  target_mechanisms:
  - target: Constitutive JAK-STAT pathway activation
    treatment_effect: INHIBITS
    description: Baricitinib inhibits JAK1/JAK2 and reduced the hyperphosphorylated STAT readout in the treated patient.
    evidence:
    - reference: PMID:38563820
      reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement."
      explanation: Response to a JAK1/JAK2-selective inhibitor supports suppression of proximal pathway hyperactivity.
  evidence:
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement."
    explanation: >-
      Confirms JAK-inhibitor efficacy (baricitinib) in a JAK1 GoF patient with
      severe atopic dermatitis.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reducing from SCORAD = 60 at treatment initiation to SCORAD = 16 after 30 days"
    explanation: The full report quantifies the rapid dermatitis improvement in the treated E139K carrier.
  notes: Evidence is limited to one treated individual.
- name: Upadacitinib
  description: >-
    Selective JAK1 inhibition improved pruritus and dermatitis in the affected
    adult p.A634D carrier. Rosacea and weight gain were reported, and this
    single-patient partial response does not establish comparative efficacy.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Atopic dermatitis
    term:
      id: HP:0001047
      label: Atopic dermatitis
  - preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  target_mechanisms:
  - target: Constitutive JAK-STAT pathway activation
    treatment_effect: INHIBITS
    description: Selective JAK1 blockade targets the proximal gain-of-function signaling defect.
    evidence:
    - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
      reference_title: "Abstract"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment with a selective JAK1 inhibitor upadacitinib at a dose of 15 mg/day improved the patient’s pruritis and dermatitis"
      explanation: Symptom improvement after selective JAK1 inhibition supports the proximal signaling defect as the target.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with a selective JAK1 inhibitor upadacitinib at a dose of 15 mg/day improved the patient’s pruritis and dermatitis"
    explanation: Documents a clinical response to upadacitinib in the affected adult p.A634D carrier.
variants:
- name: c.1901C>A (p.A634D)
  description: >-
    Heterozygous germline JAK1 missense variant (alanine to aspartate at codon
    634) in the regulatory pseudokinase domain. It produces gain of JAK1
    signaling and segregated with severe disease in the original family.
  gene:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:28111307
    reference_title: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
    explanation: >-
      The report identifies a germline JAK1 gain-of-function variant (p.A634D)
      as causal for the syndrome and validates increased JAK1/STAT activation in
      patient and transfected cells.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing revealed a heterozygous gain-of-function (GOF) variant in the regulatory pseudokinase domain"
    explanation: The longitudinal family report confirms the variant class, zygosity, and regulatory-domain location.
- name: p.S703I (mosaic)
  description: >-
    Post-zygotic mosaic JAK1 pseudokinase-domain gain-of-function variant
    (c.2108G>T) reported in a patient with early-onset multi-organ immune
    dysregulation. It is hypermorphic and neomorphic, transactivating partner
    JAKs independently of its own catalytic domain.
  gene:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:32750333
    reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
    explanation: >-
      Reports the mosaic S703I pseudokinase-domain variant as the cause of
      early-onset multi-organ immune dysregulation.
- name: p.E139K (FERM domain)
  description: >-
    Heterozygous germline JAK1 FERM-domain gain-of-function variant
    (c.415C>T) reported in the JAACD cohort; the carrier (patient P3) had severe
    atopic dermatitis that responded to baricitinib. Functional gain of signaling
    is established, but formal variant-level pathogenic classification remains
    limited by the small number of carriers.
  gene:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
    explanation: >-
      One of four JAACD JAK1 variants functionally validated as gain-of-function
      (FERM-domain E139K, confirmed in the article full text).
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
    explanation: The reported spectrum supports caution about equating this allele with classic severe AIIDE.
- name: p.R506C (SH2 domain)
  description: >-
    Heterozygous germline JAK1 SH2-domain gain-of-function variant (c.1516C>T)
    reported in the JAACD cohort. Genotype-first ascertainment and unaffected or
    mildly affected carriers indicate incomplete penetrance; functional
    hyperactivity alone is insufficient for a pathogenic assertion.
  gene:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
    explanation: >-
      One of four JAACD JAK1 variants functionally validated as gain-of-function
      (SH2-domain R506C, confirmed in the article full text).
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
    explanation: The reported spectrum supports incomplete penetrance and variable clinical severity for this allele.
- name: p.S700N (pseudokinase domain)
  description: >-
    Heterozygous germline JAK1 pseudokinase-domain gain-of-function variant
    (c.2099G>A) reported in the JAACD cohort. The functional phenotype supports
    gain of signaling, but the clinical evidence remains limited.
  gene:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
    explanation: >-
      One of four JAACD JAK1 variants functionally validated as gain-of-function
      (pseudokinase-domain S700N, confirmed in the article full text).
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
    explanation: The reported spectrum supports caution because gain of signaling need not imply severe or early clinical disease.
- name: p.V985I (kinase domain)
  description: >-
    Heterozygous germline JAK1 kinase-domain gain-of-function variant
    (c.2953G>A) reported in the JAACD cohort. Genotype-first ascertainment and
    variable expressivity support caution in assigning individual-carrier
    causality despite the functional signaling phenotype.
  gene:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "these findings define, at least in vitro, JAK1 E139K, R506C, S700N, and V985I as clear GoF variants"
    explanation: >-
      One of four JAACD JAK1 variants functionally validated as gain-of-function
      (kinase-domain V985I, confirmed in the article full text).
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare-to-common JAK1 GoF variants lie on a correlated frequency and phenotype spectrum with JAACD syndrome accounting for more common presentations that are often less severe and later onset."
    explanation: The reported spectrum supports incomplete penetrance and variable clinical severity for this allele.
diagnosis:
- name: Molecular identification of an activating JAK1 variant
  description: >-
    Sequence JAK1 in patients with otherwise unexplained early-onset
    eosinophilia plus multisystem atopy, autoinflammation, colitis, renal disease,
    or autoimmunity. Analysis should allow detection of constitutional
    heterozygous variants and lower-allele-fraction post-zygotic mosaic variants.
  results: >-
    A clinically concordant activating JAK1 variant; p.A634D and mosaic p.S703I
    have the strongest case-level causal evidence.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing revealed a heterozygous gain-of-function (GOF) variant in the regulatory pseudokinase domain"
    explanation: Exome sequencing identified the causal p.A634D variant in the affected family.
  - reference: PMID:32750333
    reference_title: "Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines."
    explanation: A mosaic-aware diagnostic approach is required because a pathogenic post-zygotic variant has been reported.
- name: Functional JAK-STAT signaling assessment
  description: >-
    Baseline and cytokine-stimulated STAT phosphorylation and interferon-stimulated
    gene expression can provide functional support for a candidate variant, but
    results must be interpreted with segregation, phenotype, frequency, and
    penetrance data.
  results: Hyperactive baseline or cytokine-induced STAT phosphorylation relative to wild-type controls
  evidence:
  - reference: PMID:38563820
    reference_title: "Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1."
    explanation: This defines the shared functional readout used to evaluate the four broader JAACD variants.
  notes: >-
    Functional gain of signaling does not by itself prove full clinical
    penetrance or justify upgrading a population-observed variant to pathogenic.
differential_diagnoses:
- name: Reactive or clonal hypereosinophilic disorders
  description: >-
    Infection, drug reaction, allergic disease, eosinophilic neoplasia, and other
    reactive or clonal hypereosinophilic syndromes can resemble AIIDE.
  distinguishing_features:
  - A pathogenic or clinically concordant activating JAK1 variant favors AIIDE.
  - Congenital or early multisystem atopy, autoimmunity, growth failure, and JAK-STAT hyperphosphorylation support AIIDE over isolated reactive eosinophilia.
  evidence:
  - reference: PMID:36546480
    reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia."
    explanation: The defining genetic cause distinguishes AIIDE from acquired and clonal eosinophilic conditions.
- name: Severe atopic dermatitis or eosinophilic gastrointestinal disease
  description: >-
    Organ-limited atopy and eosinophilic gastrointestinal disease overlap with
    the cutaneous, allergic, and gastrointestinal manifestations of AIIDE.
  distinguishing_features:
  - Multisystem autoimmunity, growth failure, renal or hepatic disease, and marked JAK-STAT hyperactivation favor AIIDE.
  - Molecular evidence of an activating JAK1 variant supports a syndromic diagnosis.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2017, an IEI was discovered in a family with severe atopic dermatitis, asthma, food allergy, failure to thrive, autoimmune thyroiditis, and markedly elevated peripheral blood eosinophil counts"
    explanation: The combination of atopy with growth, endocrine, and hematologic findings demonstrates the syndromic pattern.
- name: Other inborn errors of immunity with immune dysregulation
  description: >-
    Combined variable immune deficiency, STAT gain-of-function disorders, and
    other monogenic immune-dysregulation syndromes can present with infection,
    enteropathy, autoimmunity, eczema, and poor growth.
  distinguishing_features:
  - Gene-panel or exome analysis differentiates JAK1 gain-of-function from other monogenic immune disorders.
  - Variant-specific STAT phosphorylation patterns and segregation can support interpretation.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC10986756/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in adulthood with nonspecific colitis, recurrent respiratory infections, autoimmune thrombocytopenia, and autoimmune hepatitis, suggesting a diagnosis of combined variable immune deficiency (CVID)."
    explanation: A JAACD proband initially resembled CVID, documenting this clinically relevant overlap.
animal_models:
- species: zebrafish (Danio rerio)
  genotype: Transgenic human JAK1 p.A634D gain-of-function compared with JAK1 wild-type and uninjected casper embryos
  category: Transgenic gain-of-function model
  genes:
  - preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  description: >-
    Transgenic embryos expressing human JAK1 p.A634D show enhanced myelopoiesis,
    abnormal development, and a conserved IL-4/IL-13 and interferon transcriptomic
    signature. Ruxolitinib rescues developmental abnormalities, providing in vivo
    pharmacologic support for pathway dependence.
  associated_phenotypes:
  - Enhanced myelopoiesis
  - Abnormal embryonic development
  - Dysregulated IL-4, IL-13, and interferon signaling
  evidence:
  - reference: PMID:36546480
    reference_title: "Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis."
    explanation: The study directly validates the zebrafish p.A634D model and its myelopoietic phenotype.
- species: mouse (Mus musculus)
  genotype: Spade Jak1 gain-of-function missense model
  category: Spontaneous gain-of-function model
  genes:
  - preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  description: >-
    Jak1-hyperactive mice develop progressive pruritic dermatitis through skin
    serine-protease overexpression, barrier disruption, and a subsequent
    Th2-biased response. JAK1 inhibition delays disease onset.
  associated_phenotypes:
  - Pruritic dermatitis
  - Skin barrier disruption
  - Th2-biased inflammation
  evidence:
  - reference: PMID:27111231
    reference_title: "Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we have described a mutant mouse that spontaneously develops pruritic dermatitis as the result of an initial defect in skin homeostasis that is followed by induction of a Th2-biased immune response."
    explanation: The model recapitulates the barrier-first pruritic dermatitis mechanism associated with JAK1 hyperactivation.
clinical_trials: []
datasets:
- accession: geo:GSE142599
  title: A Zebrafish JAK1-A634D Gain-of-Function Model Provides New Insights into the Pathogenesis of Familial Hypereosinophilia
  description: >-
    Bulk RNA sequencing of casper, human JAK1-WT, and human JAK1-A634D
    transgenic zebrafish embryos at 28 and 36 hours post-fertilization.
  organism:
    preferred_term: zebrafish
    term:
      id: NCBITaxon:7955
      label: Danio rerio
  data_type: BULK_RNA_SEQ
  sample_count: 18
  conditions:
  - casper embryos at 28 and 36 hours post-fertilization
  - JAK1-WT transgenic embryos at 28 and 36 hours post-fertilization
  - JAK1-A634D transgenic embryos at 28 and 36 hours post-fertilization
  platform: Ion Torrent Proton
  publication: PMID:36546480
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE142599
    reference_title: "GEO Accession viewer"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Total RNA from casper, JAK1-WT and JAK1-A634D zebrafish embryos at 28 and 36 hours post-fertilization was extracted to characterize the transcriptomic effects of the JAK1-A634D gain-of-function mutation"
    explanation: The GEO record states the model groups, time points, and transcriptomic study design.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC9869972/fullTextXML
    reference_title: "Abstract"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The zebrafish RNA-Seq data are available under"
    explanation: The primary publication identifies the public accession for the zebrafish RNA-seq data.
notes: >-
  Classic AIIDE caused by p.A634D and the severe mosaic p.S703I case should be
  distinguished from the broader JAACD association spectrum. The E139K, R506C,
  S700N, and V985I variants show increased signaling in experimental systems,
  but population frequency, genotype-first ascertainment, variable expressivity,
  and reduced penetrance require variant-level caution. Published JAK-inhibitor
  outcomes are uncontrolled and patient-specific. Systemic corticosteroids and
  other immunosuppressants were ineffective for important manifestations in the
  severe reported cases, but this does not establish universal treatment failure.
review_notes: >-
  Full review completed 2026-07-21. Primary-source evidence was checked for the
  p.A634D family, mosaic p.S703I case, and JAACD cohort. ClinicalTrials.gov
  searches for JAK1 gain-of-function, JAK1-associated autoimmunity, AIIDE, and
  JAACD returned no registered disease-specific studies, so clinical_trials is
  explicitly empty. Population prevalence and formal diagnostic criteria remain
  unavailable. GSE142599 is the only clearly public disease-specific omics
  accession identified; protected or on-request human data were not represented
  as public datasets.
📚

References & Deep Research

References

4
PMID:28111307
JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome.
No top-level findings curated for this source.
PMID:36546480
Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation.
No top-level findings curated for this source.
PMID:32750333
Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function.
No top-level findings curated for this source.
PMID:38563820
Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.
No top-level findings curated for this source.