Autoinflammation, immune dysregulation, and eosinophilia (AIIDE; OMIM 618999) is a rare autosomal dominant immune dysregulatory disorder caused by germline gain-of-function (GoF) variants in JAK1, the Janus kinase that transduces signaling from numerous cytokine and growth-factor receptors. The first affected family carried a heterozygous JAK1 c.1901C>A (p.A634D) substitution in the inhibitory pseudokinase (JH2) domain, which relieves autoinhibition and produces constitutive JAK1 kinase activity with exaggerated STAT1 and STAT3 phosphorylation. Patients present with profound blood and tissue hypereosinophilia, severe treatment-resistant atopic dermatitis-like skin inflammation, hepatosplenomegaly with eosinophilic infiltration of the liver and gastrointestinal tract, autoimmune thyroid disease, and failure to thrive or short stature. Serum IgE and the eosinophilopoietic cytokines IL-3, IL-5, and GM-CSF are not elevated, distinguishing the disorder from typical atopic disease and reactive eosinophilia. The activating-variant spectrum has since broadened beyond A634D to a post-zygotic mosaic pseudokinase-domain variant (S703I) and to additional germline variants distributed across all four JAK1 domains (E139K in FERM, R506C in SH2, S700N in pseudokinase, V985I in kinase), which collectively define a wider, often milder JAK1-associated autoimmunity, atopy, colitis, and dermatitis (JAACD) syndrome. Because the phenotype is driven by excessive JAK1 signaling, JAK inhibitors are effective precision therapies — ruxolitinib, tofacitinib, and baricitinib have each produced marked clinical responses — whereas systemic corticosteroids are largely ineffective.
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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 rare autosomal dominant immune dysregulatory disorder caused by germline
gain-of-function (GoF) variants in JAK1, the Janus kinase that transduces
signaling from numerous cytokine and growth-factor receptors. The first
affected family carried a heterozygous JAK1 c.1901C>A (p.A634D) substitution
in the inhibitory pseudokinase (JH2) domain, which relieves autoinhibition and
produces constitutive JAK1 kinase activity with exaggerated STAT1 and STAT3
phosphorylation. Patients present with profound blood and tissue
hypereosinophilia, severe treatment-resistant atopic dermatitis-like skin
inflammation, hepatosplenomegaly with eosinophilic infiltration of the liver
and gastrointestinal tract, autoimmune thyroid disease, and failure to thrive
or short stature. Serum IgE and the eosinophilopoietic cytokines IL-3, IL-5,
and GM-CSF are not elevated, distinguishing the disorder from typical atopic
disease and reactive eosinophilia. The activating-variant spectrum has since
broadened beyond A634D to a post-zygotic mosaic pseudokinase-domain variant
(S703I) and to additional germline variants distributed across all four JAK1
domains (E139K in FERM, R506C in SH2, S700N in pseudokinase, V985I in kinase),
which collectively define a wider, often milder JAK1-associated autoimmunity,
atopy, colitis, and dermatitis (JAACD) syndrome. Because the phenotype is
driven by excessive JAK1 signaling, JAK inhibitors are effective precision
therapies — ruxolitinib, tofacitinib, and baricitinib have each produced
marked clinical responses — whereas systemic corticosteroids are largely
ineffective.
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."
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
- classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant
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.
pathophysiology:
- name: JAK1 pseudokinase domain gain-of-function
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.
downstream:
- target: Constitutive JAK-STAT pathway activation
description: >-
Loss of pseudokinase-domain autoinhibition drives ligand-independent and
ligand-amplified activation of downstream JAK-STAT signaling.
- name: Constitutive JAK-STAT pathway activation
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
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.
- target: Skin barrier disruption and atopic inflammation
description: >-
Hyperactive JAK1-STAT signaling in skin drives a Th2-biased inflammatory,
pruritic dermatitis phenotype.
- name: Eosinophil expansion and tissue infiltration
description: >-
Patients develop profound peripheral blood hypereosinophilia together with
eosinophilic infiltration of the liver and gastrointestinal tract and
massive hepatosplenomegaly. All other causes of eosinophilia (infection,
drug reaction, malignancy including PDGFRA/PDGFRB/FGFR1-associated clonal
eosinophilia) were excluded, and serum IL-3, IL-5, and GM-CSF were not
different from healthy controls, indicating a cell-intrinsic JAK1-driven
process rather than cytokine-driven reactive eosinophilia. Modeling the
JAK1 GoF variant in zebrafish and iPSCs reveals enhanced myelopoiesis,
linking the activating lesion to expansion of the myeloid/eosinophil
lineage. The eosinophilia is corticosteroid-resistant but responds to
ruxolitinib.
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: 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: >-
Hypereosinophilia is the defining hematologic feature of the syndrome; the
article documents eosinophil counts well above the hypereosinophilia
threshold with eosinophilic organ infiltration and normal IL-3/IL-5/GM-CSF.
- 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.
- name: Skin barrier disruption and atopic inflammation
description: >-
Severe, treatment-resistant atopic dermatitis-like skin inflammation with
intractable pruritus is a hallmark, present in the mother since birth.
Serum IgE is normal, distinguishing it from typical IgE-driven atopic
dermatitis. 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.
phenotypes:
- category: Hematologic
name: Hypereosinophilia
description: >-
Profound, persistent peripheral blood eosinophilia (e.g., maternal range
2.87-3.29 x 10^9/L; normal <0.5 x 10^9/L) meeting the hypereosinophilia
threshold, with eosinophilic tissue infiltration.
phenotype_term:
preferred_term: Hypereosinophilia
term:
id: HP:0032061
label: Severely 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, in the setting of normal serum IgE.
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.
notes: >-
Documented in all three affected family members (Del Bel et al 2017,
PMID:28111307, Table E1); dermatitis resolved on ruxolitinib.
- category: Dermatologic
name: Pruritus
description: Intractable itch accompanying the dermatitis; improved within 2 weeks of ruxolitinib.
phenotype_term:
preferred_term: Pruritus
term:
id: HP:0000989
label: Pruritus
notes: Reported in the index family (PMID:28111307); subjective improvement on ruxolitinib.
- category: Gastrointestinal
name: Hepatosplenomegaly
description: >-
Massive hepatosplenomegaly with eosinophilic infiltration of the liver;
regressed with ruxolitinib therapy.
phenotype_term:
preferred_term: Hepatosplenomegaly
term:
id: HP:0001433
label: Hepatosplenomegaly
notes: Reported in the index family (PMID:28111307, Table E1).
- 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
notes: Prenatal finding listed in Table E1 (PMID:28111307).
- category: Gastrointestinal
name: Eosinophilic gastrointestinal infiltration
description: Eosinophilic infiltration of the gastrointestinal tract.
phenotype_term:
preferred_term: Eosinophilic infiltration of the gastrointestinal tract
term:
id: HP:0004386
label: Gastrointestinal inflammation
notes: Listed in Table E1 (PMID:28111307).
- 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: Autoimmune hypothyroidism
description: Autoimmune thyroid disease (autoimmune hypothyroidism).
phenotype_term:
preferred_term: Autoimmune hypothyroidism
term:
id: HP:0000872
label: Hashimoto thyroiditis
notes: Autoimmune hypothyroidism listed under autoimmunity in Table E1 (PMID:28111307); Hashimoto thyroiditis enriched across the JAACD cohort (PMID:38563820).
- 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
notes: Reported in the affected mother (PMID:28111307, Table E1).
- 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
notes: Atopy features (food and environmental allergies) listed in Table E1 (PMID:28111307).
- category: Constitutional
name: Failure to thrive
description: >-
Profound failure of linear growth and weight gain in the affected children,
markedly below the third percentile, improving rapidly after starting
ruxolitinib. Growth failure can begin in utero and is accompanied by low
IGF-1 that normalizes on JAK inhibition.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
notes: Pediatric failure to thrive (PMID:28111307, Fig 1D and Table E1); growth/IGF-1 improvement on long-term ruxolitinib (PMID:36546480).
- 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
notes: Adult short stature listed in Table E1 (PMID:28111307).
treatments:
- name: Ruxolitinib
description: >-
Oral JAK1/2 inhibitor used as precision therapy targeting the exaggerated
JAK1 signaling. In the index family ruxolitinib (50 mg/m^2/dose twice daily)
produced improvement in pruritus, appetite, and sleep within 2 weeks and,
after 1 month, weight gain, markedly reduced eosinophilia, and resolution of
dermatitis and hepatosplenomegaly, with significantly decreased IL-6-induced
STAT3 phosphorylation. Long-term treatment of the two affected children gave
sustained improvement in growth and eosinophilia. Reversible myelosuppression
(anemia normalizing after dose reduction) is an expected on-target effect.
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: Hypereosinophilia
term:
id: HP:0032061
label: Severely increased total eosinophil count
- preferred_term: Atopic dermatitis
term:
id: HP:0001047
label: Atopic dermatitis
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: 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.
- 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.
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
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.
- 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.
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
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.
- name: Systemic corticosteroids
description: >-
Systemic corticosteroids (e.g., oral prednisone 2 mg/kg/day) were largely
ineffective for the dermatitis and peripheral eosinophilia, in contrast to
the favorable JAK-inhibitor response.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: corticosteroid
term:
id: CHEBI:50858
label: corticosteroid
evidence:
- reference: PMID:28111307
reference_title: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome"
explanation: >-
The disease report documents that the dermatitis and eosinophilia were
unresponsive to systemic corticosteroid therapy, motivating the switch to
targeted JAK inhibition.
variants:
- name: c.1901C>A (p.A634D)
description: >-
Heterozygous germline JAK1 missense variant (alanine to aspartate at codon
634) located in the inhibitory pseudokinase (JH2) domain within the aC
helix. It relieves pseudokinase autoinhibition to produce constitutive JAK1
activity, was de novo in the index mother and transmitted to both sons, and
was absent from the Exome Aggregation Consortium. It does not alter JAK1
mRNA or protein expression. The same residue is recurrently mutated as a
somatic gain-of-function event in lymphoid malignancy.
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.
- 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.
gene:
preferred_term: JAK1
term:
id: hgnc:6190
label: JAK1
clinical_significance: LIKELY_PATHOGENIC
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: >-
One of four JAACD JAK1 variants functionally validated as gain-of-function
(FERM-domain E139K, confirmed in the article full text).
- name: p.R506C (SH2 domain)
description: >-
Heterozygous germline JAK1 SH2-domain gain-of-function variant (c.1516C>T)
reported in the JAACD cohort.
gene:
preferred_term: JAK1
term:
id: hgnc:6190
label: JAK1
clinical_significance: LIKELY_PATHOGENIC
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: >-
One of four JAACD JAK1 variants functionally validated as gain-of-function
(SH2-domain R506C, confirmed in the article full text).
- name: p.S700N (pseudokinase domain)
description: >-
Heterozygous germline JAK1 pseudokinase-domain gain-of-function variant
(c.2099G>A) reported in the JAACD cohort.
gene:
preferred_term: JAK1
term:
id: hgnc:6190
label: JAK1
clinical_significance: LIKELY_PATHOGENIC
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: >-
One of four JAACD JAK1 variants functionally validated as gain-of-function
(pseudokinase-domain S700N, confirmed in the article full text).
- name: p.V985I (kinase domain)
description: >-
Heterozygous germline JAK1 kinase-domain gain-of-function variant
(c.2953G>A) reported in the JAACD cohort.
gene:
preferred_term: JAK1
term:
id: hgnc:6190
label: JAK1
clinical_significance: LIKELY_PATHOGENIC
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: >-
One of four JAACD JAK1 variants functionally validated as gain-of-function
(kinase-domain V985I, confirmed in the article full text).
mechanistic_hypotheses:
- hypothesis_group_id: jak1_gof_canonical
hypothesis_label: JAK1 pseudokinase-domain gain-of-function drives cytokine hypersensitivity
status: CANONICAL
description: >-
Loss of JH2 pseudokinase-domain autoinhibition produces constitutively
active JAK1, lowering the threshold for and amplifying cytokine-receptor
(e.g., IFN-alpha/STAT1, IL-6/STAT3) signaling. This single upstream lesion
accounts for the convergent multisystem phenotype—hypereosinophilia, atopic
skin inflammation, eosinophilic organ infiltration, autoimmunity, and growth
failure—and predicts responsiveness to JAK inhibition.
- hypothesis_group_id: jaacd_multidomain_spectrum
hypothesis_label: Activating JAK1 variants across all four domains define a graded JAACD spectrum
status: EMERGING
description: >-
Beyond the prototypic pseudokinase lesion, gain-of-function variants in the
FERM, SH2, pseudokinase, and kinase domains all elevate baseline and
cytokine-induced STAT phosphorylation and interferon-stimulated gene
expression, predominantly via cis-activation (with the mosaic S703I variant
additionally neomorphic, transactivating partner JAKs). Individually rare,
these variants underlie a broader and often milder syndrome (JAK1-associated
autoimmunity, atopy, colitis, and dermatitis; JAACD) in which severe
A634D-type disease sits at the extreme end. The shared signaling readout
predicts that affected individuals across the spectrum benefit from JAK
inhibition.