IFNAR2 Deficiency

Mendelian MONDO:0014727 Pathograph 24 Show in embeddings browser inborn error of immunity autosomal recessive disease

IFNAR2 deficiency (immunodeficiency 45; IMD45) is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in IFNAR2, which encodes the high-affinity chain of the heterodimeric type I interferon (IFN-alpha/beta) receptor. Loss of surface IFNAR2 leaves cells unable to transduce any type I interferon signal, so STAT1 is not phosphorylated and the interferon-stimulated gene programme that establishes the cell-intrinsic antiviral state is never induced. The resulting clinical phenotype is severe but strikingly narrow. Affected children are not generally infection-prone; the presentation is catastrophic disease on systemic challenge with a live attenuated viral vaccine - encephalitis, meningoencephalitis, or hemophagocytic lymphohistiocytosis after measles-mumps-rubella immunization - and, in the Arctic founder cohort, life-threatening COVID-19 or influenza. The index patient had shown no prior susceptibility to respiratory viral pathogens, and this dissociation between a complete in vitro signalling defect and a narrow in vivo phenotype is the central interpretive problem the entry records as a mechanistic hypothesis rather than settled mechanism. Two molecular routes to the same signalling null are documented: frameshift and other null alleles that abolish the protein, and the Inuit founder missense allele p.Ser53Pro, which is expressed but retained intracellularly in an aberrantly glycosylated state and never reaches the cell surface. Management is avoidance of live attenuated viral vaccines once the diagnosis is known, plus supportive care; the Arctic cohort's carrier frequency raised the question of population screening.

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1
Inheritance
5
Pathophys.
10
Phenotypes
1
Hypotheses
24
Pathograph
1
Genes
3
Medical Actions
1
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Disease results from biallelic IFNAR2 variants. Reported genotypes include homozygosity in a consanguineous kindred, compound heterozygous frameshift alleles, and homozygosity for a founder missense allele; heterozygous carriers are unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26424569 SUPPORT Human Clinical
"we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β"
A homozygous IFNAR2 mutation shared by the proband and a sibling establishes the autosomal recessive basis of the disease.
◈

Mechanistic Hypotheses

1
Type I interferon redundancy explains the narrow clinical phenotype
narrow_phenotype_redundancy EMERGING
Evidence balance 3 support
IFNAR2 deficiency abolishes type I interferon signalling completely in vitro, yet affected individuals are not broadly infection-prone: the index patient had no history of unusual susceptibility to respiratory viral pathogens before the fatal vaccine reaction. The proposed explanation is that human type I interferons are largely redundant for protective immunity under natural conditions, with other cell-intrinsic antiviral mechanisms compensating, and become indispensable only on systemic challenge with a replicating attenuated virus. The competing reading - that ascertainment favours the catastrophic presentations and milder susceptibility is simply unrecorded - is not excluded by the published cohorts, which remain very small. This distinction matters for whether population screening of the Arctic founder allele would identify people at risk or merely carriers.
Show evidence (3 references)
PMID:26424569 SUPPORT Human Clinical
"Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens."
The primary observation the hypothesis rests on - a complete signalling defect without broad clinical susceptibility.
PMID:26424569 SUPPORT Human Clinical
"supports an essential but narrow role for IFN-α/β in human antiviral immunity"
The authors' own framing of the phenotype as essential but narrow.
PMID:33729549 SUPPORT Human Clinical
"A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated."
A review across IFNAR1/IFNAR2/STAT1/STAT2/IRF9 deficiencies generalising the redundancy interpretation beyond this single gene.
⚙

Pathophysiology

5
IFNAR2 Loss of Function
Biallelic IFNAR2 variants abolish a functional high-affinity chain of the type I interferon receptor. Two mechanisms are documented and converge on the same signalling null. Null alleles (frameshift, nonsense) remove the protein outright. The Arctic founder allele c.157T>C (p.Ser53Pro) instead permits translation but blocks trafficking: the substituted protein is retained intracellularly in an aberrantly glycosylated state and is absent from the cell surface, so no receptor is available to bind ligand. Because the second receptor chain IFNAR1 is intact, the lesion is specific to assembly of a competent IFNAR1-IFNAR2 heterodimer.
Downstream
Absent Type I Interferon Receptor Signaling Without surface IFNAR2 there is no receptor to transduce an IFN-alpha/beta signal, so the loss of protein translates directly into loss of signalling.
Show evidence (2 references)
PMID:35442417 SUPPORT Human Clinical
"The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant."
Identifies the founder missense allele underlying the Arctic form of the disease.
PMID:33193576 SUPPORT Human Clinical
"two previously undescribed frameshift mutations in the interferon (IFN)α/β receptor 2 (IFNAR2) gene"
Documents the alternative null-allele route to IFNAR2 loss of function.
Absent Type I Interferon Receptor Signaling
With no functional receptor, type I interferons cannot initiate JAK-STAT signalling. Patient cells show no STAT1 phosphorylation on IFN-alpha stimulation and are wholly unresponsive to recombinant type I interferon. The defect is cell-intrinsic and reversible: complementation with wild-type IFNAR2 restores responsiveness, which is what establishes the variant as causal rather than merely associated.
Type I interferon-mediated signaling GO:0060337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased 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. ↓ DECREASED Cellular response to type I interferon GO:0071357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cellular response to type I interferon (GO:0071357). GO:0071357 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Interferon-Stimulated Gene Induction Interferon-stimulated genes are the transcriptional output of this pathway, so an unsignalled receptor leaves them uninduced.
Natural Killer Cell Functional Dysregulation Type I interferon normally tunes NK cell degranulation and restrains their IFN-gamma output; an absent signal removes both effects.
Show evidence (2 references)
PMID:35442417 SUPPORT In Vitro
"Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro"
Establishes complete unresponsiveness to type I interferon in cells carrying only the variant allele.
PMID:26424569 SUPPORT In Vitro
"Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses."
Complementation rescue demonstrates the signalling defect is caused by the IFNAR2 lesion itself.
Failure of Interferon-Stimulated Gene Induction
Interferon-stimulated genes encode the effectors that make a cell hostile to viral replication. Because they are never induced, the cell-intrinsic antiviral state cannot be established at all - not merely blunted - leaving infected cells with no interferon-dependent restriction of incoming virus.
Antiviral defense response GO:0051607 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Antiviral defense response, annotated with defense response to virus (GO:0051607). GO:0051607 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Unrestricted Viral Replication and Cytopathicity With no interferon-induced restriction factors, permissive cells support viral replication to the point of cell death.
Show evidence (1 reference)
PMID:33193576 SUPPORT In Vitro
"the lack of induction of interferon-stimulated genes upon ex vivo stimulation with IFNα"
Documents absent interferon-stimulated gene induction in patient cells.
Unrestricted Viral Replication and Cytopathicity
Viruses that would normally be held in check replicate without restraint, including attenuated vaccine strains whose attenuation depends on host interferon competence. Patient-derived macrophages infected with Zika virus reveal an inherent cytopathicity that an intact interferon response would otherwise mask, so the consequence is both higher viral burden and death of the infected cell.
Macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
Downstream
Disseminated infection with live vaccine virus Live attenuated vaccine strains are attenuated relative to an interferon-competent host; in its absence they behave as replicating pathogens and disseminate.
Severe viral infection The same failure of interferon-dependent restriction applies to wild-type viruses, so ordinary respiratory pathogens can produce life-threatening disease in some patients.
Infectious encephalitis Unrestricted replication of the vaccine strain in the central nervous system produces encephalitis or meningoencephalitis.
Show evidence (1 reference)
PMID:36439115 SUPPORT In Vitro
"revealing the inherent cytopathicity of ZIKV towards macrophages"
Shows that interferon competence is what normally conceals the cytopathic potential of the virus, which is unmasked in IFNAR2 deficiency.
Natural Killer Cell Functional Dysregulation
Beyond the antiviral state, type I interferon shapes NK cell behaviour: it normally augments degranulation and restrains IFN-gamma production. In IFNAR2-deficient NK cells stimulated with IFN-alpha, both responses fail. The loss of IFN-gamma restraint is the mechanistically interesting half, because unopposed IFN-gamma is the cytokine most closely tied to hemophagocytic lymphohistiocytosis - offering a route from a type I interferon receptor defect to a hyperinflammatory rather than merely infectious phenotype.
Natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
Natural killer cell degranulation GO:0043320 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Natural killer cell degranulation (GO:0043320). GO:0043320 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hemophagocytosis Failure to restrain NK-cell IFN-gamma production is proposed as a contributor to the hemophagocytic lymphohistiocytosis seen after live vaccination in type I interferon signalling defects.
Show evidence (1 reference)
PMID:33193576 SUPPORT In Vitro
"in patient's natural killer (NK) cells stimulated with IFNα the expected increase in degranulation and inhibition of IFNγ production were affected"
Documents the two specific NK-cell response failures that define this node.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for IFNAR2 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Blood 2
Hemophagocytosis HP:0012156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemophagocytosis (HP:0012156). HP:0012156 is a phenotype from the Human Phenotype Ontology.
Sequelae: Fever Irritability Lethargy Cervical lymphadenopathy Maculopapular exanthema Pancytopenia
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination"
Reports HLH as the presenting illness in a genotyped patient after MMR.
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"progressive decrease in cell blood count"
Documents the progressive cytopenia during the hyperinflammatory episode.
Cardiovascular 1
Cervical lymphadenopathy HP:0025289 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cervical lymphadenopathy (HP:0025289). HP:0025289 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
Reports cervical lymphadenopathy during the episode.
Immune 4
Disseminated infection with live vaccine virus HP:0031697 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disseminated infection with live vaccine virus (HP:0031697). HP:0031697 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26424569 SUPPORT Human Clinical
"We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine."
The index presentation - fatal disease following MMR in a previously healthy child.
PMID:35442417 SUPPORT Human Clinical
"meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination"
Confirms live-vaccine complications across an independent five-patient cohort.
Infectious encephalitis HP:0002383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infectious encephalitis (HP:0002383). HP:0002383 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39436454 SUPPORT Human Clinical
"Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure."
Documents meningoencephalitis in a genotyped IFNAR2-deficient patient after measles vaccination.
Severe viral infection HP:0031691 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe viral infection (HP:0031691). HP:0031691 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35442417 SUPPORT Human Clinical
"five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza"
Documents severe wild-type viral disease, not only vaccine-strain disease, in IFNAR2-deficient children.
Maculopapular exanthema HP:0040186 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Maculopapular exanthema (HP:0040186). HP:0040186 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
Reports the maculopapular rash accompanying the episode.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
Describes the febrile course of the HLH episode in a genotyped patient.
Nervous System 2
Lethargy HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"he was hospitalized with high fever and lethargy"
Records lethargy as a presenting feature.
Irritability HP:0000737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Irritability (HP:0000737). HP:0000737 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
Reports irritability among the features of the clinical course.
🧬

Genetic Associations

1
IFNAR2 (Causal)
Gene: IFNAR2 hgnc:5433 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IFNAR2 (hgnc:5433). hgnc:5433 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:26424569 SUPPORT Human Clinical
"we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β"
Establishes IFNAR2 as the causal gene by linking the homozygous variant to loss of cellular interferon responsiveness.
PMID:35442417 SUPPORT Human Clinical
"The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant."
Identifies the recurrent founder allele shared across the Arctic cohort.
💊

Medical Actions

3
Avoidance of Live Attenuated Viral Vaccines
Action: avoidance of live attenuated viral vaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is avoidance of live attenuated viral vaccination, annotated with Preventive Intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. Ontology label: Preventive Intervention NCIT:C15843
Platform: Behavioral / lifestyle
The single most important intervention once the diagnosis is known. Live attenuated viral vaccines - measles-mumps-rubella above all - are attenuated only relative to an interferon-competent host and cause disseminated, potentially fatal infection in IFNAR2 deficiency. This is the agents-and-circumstances-to-avoid consideration for this disease, and the reason case reports argue for genetic screening before immunisation in at-risk populations.
Mechanism Target:
Unrestricted Viral Replication and Cytopathicity — Withholding the live vaccine removes the replicating viral challenge that the absent interferon response cannot contain.
Show evidence (1 reference)
PMID:39436454 SUPPORT Human Clinical
"This case highlights the importance of incorporating genetic screening into vaccination programs for individuals at risk."
States the clinical recommendation that follows - identify at-risk individuals before live vaccination.
Supportive Care for Severe Viral Illness
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
No disease-modifying therapy exists. Management of an established episode is supportive - intensive care for meningoencephalitis and multi-organ failure. Outcomes in reported cases have frequently been fatal despite intensive support. HLH-directed corticosteroid therapy is curated separately below.
Mechanism Target:
Infectious encephalitis — Intensive supportive management addresses the central nervous system disease and multi-organ failure symptomatically. It does not modify the interferon signalling defect upstream of them, and is linked here to the clinical consequence it actually treats rather than to a mechanism node.
Show evidence (1 reference)
PMID:39436454 SUPPORT Human Clinical
"Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure."
Characterises the encephalitic and multi-organ illness that supportive management is directed at.
Show evidence (1 reference)
PMID:39436454 SUPPORT Human Clinical
"Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure."
Characterises the severity of the illness that supportive management must address.
Corticosteroid Therapy for Hemophagocytic Lymphohistiocytosis
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: methylprednisolone CHEBI:6888 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methylprednisolone, annotated with 6alpha-methylprednisolone (CHEBI:6888). CHEBI:6888 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The hyperinflammatory episode is treated in its own right. The reported patient received intravenous methylprednisolone pulses followed by high-dose oral glucocorticoids, with progressive improvement in both clinical and laboratory features. This targets the HLH branch of the mechanism - the unrestrained inflammatory response - rather than the interferon receptor defect itself, which no therapy corrects.
Mechanism Target:
Hemophagocytosis — Glucocorticoids suppress the hyperinflammatory macrophage and lymphocyte activation that constitutes the HLH phenotype.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"He received intravenous methylprednisolone pulses (30 mg/kg/day for 3 consecutive days) followed by high dose glucocorticoids (2 mg/kg) with progressive improvement of clinical and laboratory features."
Documents the regimen and its effect on the HLH phenotype in a genotyped IFNAR2-deficient patient.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"with progressive improvement of clinical and laboratory features"
Records the clinical and laboratory response to corticosteroid therapy.
🌍

Environmental Factors

1
Live attenuated viral vaccination
exposure to live attenuated viral vaccine Relation: this environmental factor is this exposure This environmental factor is exposure to live attenuated viral vaccine.
The exposure that converts a clinically silent genotype into life-threatening disease. In the reported patient, symptoms began five days after MMR inoculation. This is the gene-environment interaction that defines the disease's presentation, and it is why avoidance is the principal intervention.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"5 days after inoculation with the live-attenuated measles-mumps-rubella (MMR) vaccine"
The documented exposure preceding disease onset.
Mechanism Target:
TRIGGERS Unrestricted Viral Replication and Cytopathicity — A replicating attenuated virus is the challenge the absent interferon response cannot contain, so the exposure initiates the mechanism rather than merely aggravating it.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"At 22 months of age, 5 days after inoculation with the live-attenuated measles-mumps-rubella (MMR) vaccine, he was hospitalized with high fever and lethargy."
Establishes the temporal link between the vaccine exposure and onset of disease.
🔬

Biochemical Markers

5
Hemophagocytic lymphohistiocytosis laboratory signature
Pathograph Readouts
Readout Of Hemophagocytosis Positive
Marked hyperferritinemia is the headline laboratory abnormality of the HLH episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
The measured value supporting this readout during the HLH episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
Reports the full laboratory panel measured during the HLH episode in a genotyped patient.
Hypofibrinogenemia
Pathograph Readouts
Readout Of Hemophagocytosis Positive
Fibrinogen consumption during the hyperinflammatory episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
The measured value supporting this readout during the HLH episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
The measured fibrinogen value during the hyperinflammatory episode.
Hypertriglyceridemia
Pathograph Readouts
Readout Of Hemophagocytosis Positive
Hypertriglyceridemia during the hyperinflammatory episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl)"
The measured value supporting this readout during the HLH episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl)"
The measured triglyceride value during the hyperinflammatory episode.
Elevated circulating hepatic transaminase concentration
Pathograph Readouts
Readout Of Hemophagocytosis Positive
Hepatic involvement during the hyperinflammatory episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"elevation of liver enzymes (AST 360 U/L, ALT 550 U/L)"
The measured value supporting this readout during the HLH episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"elevation of liver enzymes (AST 360 U/L, ALT 550 U/L)"
The measured transaminase values during the hyperinflammatory episode.
Increased circulating lactate dehydrogenase concentration
Pathograph Readouts
Readout Of Hemophagocytosis Positive
Raised lactate dehydrogenase during the hyperinflammatory episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L)"
The measured value supporting this readout during the HLH episode.
Show evidence (1 reference)
PMID:33193576 SUPPORT Human Clinical
"laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L)"
The measured lactate dehydrogenase value during the hyperinflammatory episode.
🔬

Diagnosis

2
Phospho-STAT1/STAT2 Flow Cytometry After Ex Vivo Interferon Stimulation
The discriminating test. Whole blood or PBMCs are stimulated ex vivo with IFN-alpha and STAT1/STAT2 phosphorylation read by flow cytometry; in IFNAR2 deficiency it is absent. Stimulating the same cells with IFN-gamma in parallel is what makes the test specific rather than merely abnormal: the type II response is intact, so a defect confined to the type I arm is demonstrated directly, separating IFNAR2 and STAT2 deficiency from STAT1 or JAK-level defects that impair both arms. The authors propose this as a rapid front-line assay when HLH follows a live attenuated vaccine.
flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:33193576 SUPPORT Human Clinical
"rapid evaluation of phosphorylation of STAT1 and STAT2 by flow cytometry upon ex vivo stimulation with IFNα can guide clinicians in the early identification of patients with impairment in type I IFN-mediated signaling"
The authors' explicit recommendation of this assay as the early diagnostic route in suspected type I interferon signalling defects.
PMID:33193576 SUPPORT In Vitro
"As expected, IFNγ stimulation was able to induce both STAT1 phosphorylation and transcription of type II IFN-regulated genes"
The preserved type II response is the internal control that makes the test discriminating rather than merely abnormal.
Molecular Confirmation by IFNAR2 Sequencing
Definitive diagnosis requires demonstrating biallelic IFNAR2 variants. Where the Arctic founder allele is plausible on ancestry, targeted testing for p.Ser53Pro is the direct route; otherwise exome or panel sequencing is needed.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35442417 SUPPORT Human Clinical
"The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant."
Establishes the specific molecular finding that confirms the diagnosis in the founder population.
📊

Prevalence

2
Inuit ancestry (Greenland, Canada, Alaska)
Carrier Frequency Unknown
Reported as the minor allele frequency of the p.Ser53Pro founder variant in people of Inuit ancestry, not as a disease prevalence. A minor allele frequency of 0.034 is far above what the observed number of cases would suggest, which is why the authors raise population screening; it is recorded here as an allele frequency and must not be read as a rate of disease.
Show evidence (1 reference)
PMID:35442417 SUPPORT Human Clinical
"p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry"
The reported founder allele frequency in the ancestral population.
Worldwide
Cases In Literature Ultra Rare
Fewer than 15 genetically confirmed patients are described in the literature across the index kindred, the Arctic founder cohort, and isolated case reports.
{ }

Source YAML

click to show 
name: IFNAR2 Deficiency
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
synonyms:
- immunodeficiency 45
- IMD45
- IFNAR2-related immunodeficiency
- autosomal recessive IFNAR2 deficiency
description: >-
  IFNAR2 deficiency (immunodeficiency 45; IMD45) is an autosomal recessive
  inborn error of immunity caused by biallelic loss-of-function variants in
  IFNAR2, which encodes the high-affinity chain of the heterodimeric type I
  interferon (IFN-alpha/beta) receptor. Loss of surface IFNAR2 leaves cells
  unable to transduce any type I interferon signal, so STAT1 is not
  phosphorylated and the interferon-stimulated gene programme that establishes
  the cell-intrinsic antiviral state is never induced.

  The resulting clinical phenotype is severe but strikingly narrow. Affected
  children are not generally infection-prone; the presentation is catastrophic
  disease on systemic challenge with a live attenuated viral vaccine -
  encephalitis, meningoencephalitis, or hemophagocytic lymphohistiocytosis
  after measles-mumps-rubella immunization - and, in the Arctic founder cohort,
  life-threatening COVID-19 or influenza. The index patient had shown no prior
  susceptibility to respiratory viral pathogens, and this dissociation between a
  complete in vitro signalling defect and a narrow in vivo phenotype is the
  central interpretive problem the entry records as a mechanistic hypothesis
  rather than settled mechanism.

  Two molecular routes to the same signalling null are documented: frameshift
  and other null alleles that abolish the protein, and the Inuit founder
  missense allele p.Ser53Pro, which is expressed but retained intracellularly in
  an aberrantly glycosylated state and never reaches the cell surface.
  Management is avoidance of live attenuated viral vaccines once the diagnosis
  is known, plus supportive care; the Arctic cohort's carrier frequency raised
  the question of population screening.
disease_term:
  preferred_term: IFNAR2 deficiency
  term:
    id: MONDO:0014727
    label: immunodeficiency 45
parents:
- inborn error of immunity
- autosomal recessive disease
references:
- reference: PMID:26424569
  title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
inheritance:
- name: Autosomal recessive
  description: >-
    Disease results from biallelic IFNAR2 variants. Reported genotypes include
    homozygosity in a consanguineous kindred, compound heterozygous frameshift
    alleles, and homozygosity for a founder missense allele; heterozygous
    carriers are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26424569
    reference_title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β"
    explanation: A homozygous IFNAR2 mutation shared by the proband and a sibling establishes the autosomal recessive basis of the disease.
pathophysiology:
- name: IFNAR2 Loss of Function
  description: >-
    Biallelic IFNAR2 variants abolish a functional high-affinity chain of the
    type I interferon receptor. Two mechanisms are documented and converge on
    the same signalling null. Null alleles (frameshift, nonsense) remove the
    protein outright. The Arctic founder allele c.157T>C (p.Ser53Pro) instead
    permits translation but blocks trafficking: the substituted protein is
    retained intracellularly in an aberrantly glycosylated state and is absent
    from the cell surface, so no receptor is available to bind ligand. Because
    the second receptor chain IFNAR1 is intact, the lesion is specific to
    assembly of a competent IFNAR1-IFNAR2 heterodimer.
  biological_scale: MOLECULAR
  downstream:
  - target: Absent Type I Interferon Receptor Signaling
    causal_link_type: DIRECT
    description: >-
      Without surface IFNAR2 there is no receptor to transduce an IFN-alpha/beta
      signal, so the loss of protein translates directly into loss of signalling.
    evidence:
    - reference: PMID:35442417
      reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state."
      explanation: Traces the specific molecular lesion - failure of surface expression - that removes the receptor and therefore the signal.
  evidence:
  - reference: PMID:35442417
    reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant."
    explanation: Identifies the founder missense allele underlying the Arctic form of the disease.
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two previously undescribed frameshift mutations in the interferon (IFN)α/β receptor 2 (IFNAR2) gene"
    explanation: Documents the alternative null-allele route to IFNAR2 loss of function.
- name: Absent Type I Interferon Receptor Signaling
  description: >-
    With no functional receptor, type I interferons cannot initiate JAK-STAT
    signalling. Patient cells show no STAT1 phosphorylation on IFN-alpha
    stimulation and are wholly unresponsive to recombinant type I interferon.
    The defect is cell-intrinsic and reversible: complementation with wild-type
    IFNAR2 restores responsiveness, which is what establishes the variant as
    causal rather than merely associated.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Type I interferon-mediated signaling
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: Cellular response to type I interferon
    term:
      id: GO:0071357
      label: cellular response to type I interferon
    modifier: DECREASED
  downstream:
  - target: Failure of Interferon-Stimulated Gene Induction
    causal_link_type: DIRECT
    description: >-
      Interferon-stimulated genes are the transcriptional output of this
      pathway, so an unsignalled receptor leaves them uninduced.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the absence of response to type I IFN in the patient's cells, as revealed by the lack of phosphorylation of STAT1 and the lack of induction of interferon-stimulated genes upon ex vivo stimulation with IFNα"
      explanation: Directly couples the signalling block (absent STAT1 phosphorylation) to the transcriptional failure (absent ISG induction) in the same patient cells.
  - target: Natural Killer Cell Functional Dysregulation
    causal_link_type: DIRECT
    description: >-
      Type I interferon normally tunes NK cell degranulation and restrains their
      IFN-gamma output; an absent signal removes both effects.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "in patient's natural killer (NK) cells stimulated with IFNα the expected increase in degranulation and inhibition of IFNγ production were affected"
      explanation: Shows that the same signalling defect produces a measurable NK-cell functional abnormality on interferon stimulation.
  evidence:
  - reference: PMID:35442417
    reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro"
    explanation: Establishes complete unresponsiveness to type I interferon in cells carrying only the variant allele.
  - reference: PMID:26424569
    reference_title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses."
    explanation: Complementation rescue demonstrates the signalling defect is caused by the IFNAR2 lesion itself.
- name: Failure of Interferon-Stimulated Gene Induction
  description: >-
    Interferon-stimulated genes encode the effectors that make a cell hostile to
    viral replication. Because they are never induced, the cell-intrinsic
    antiviral state cannot be established at all - not merely blunted - leaving
    infected cells with no interferon-dependent restriction of incoming virus.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Antiviral defense response
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  downstream:
  - target: Unrestricted Viral Replication and Cytopathicity
    causal_link_type: DIRECT
    description: >-
      With no interferon-induced restriction factors, permissive cells support
      viral replication to the point of cell death.
    evidence:
    - reference: PMID:36439115
      reference_title: "Type I interferon receptor (IFNAR2) deficiency reveals Zika virus cytopathicity in human macrophages and microglia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Accompanying the profound defect of IFN-I signalling in IFNAR2 deficient iPS-macrophages we observed significantly enhanced ZIKV replication and cell death"
      explanation: In patient-derived cells, the signalling and ISG defect is shown to cause both enhanced replication and cytopathic death.
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the lack of induction of interferon-stimulated genes upon ex vivo stimulation with IFNα"
    explanation: Documents absent interferon-stimulated gene induction in patient cells.
- name: Unrestricted Viral Replication and Cytopathicity
  description: >-
    Viruses that would normally be held in check replicate without restraint,
    including attenuated vaccine strains whose attenuation depends on host
    interferon competence. Patient-derived macrophages infected with Zika virus
    reveal an inherent cytopathicity that an intact interferon response would
    otherwise mask, so the consequence is both higher viral burden and death of
    the infected cell.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  downstream:
  - target: Disseminated infection with live vaccine virus
    causal_link_type: DIRECT
    description: >-
      Live attenuated vaccine strains are attenuated relative to an
      interferon-competent host; in its absence they behave as replicating
      pathogens and disseminate.
    evidence:
    - reference: PMID:26424569
      reference_title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine."
      explanation: Links loss of interferon-dependent viral control to disseminated, fatal disease caused by a live attenuated vaccine strain.
  - target: Severe viral infection
    causal_link_type: DIRECT
    description: >-
      The same failure of interferon-dependent restriction applies to wild-type
      viruses, so ordinary respiratory pathogens can produce life-threatening
      disease in some patients.
    evidence:
    - reference: PMID:35442417
      reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "displayed heightened vulnerability to multiple viruses in vitro"
      explanation: Links the cell-intrinsic replication defect to heightened vulnerability across multiple viruses, the cellular basis of severe wild-type viral disease.
  - target: Infectious encephalitis
    causal_link_type: DIRECT
    description: >-
      Unrestricted replication of the vaccine strain in the central nervous
      system produces encephalitis or meningoencephalitis.
    evidence:
    - reference: PMID:39436454
      reference_title: "Severe Adverse Reaction to Measles Vaccine Due to Homozygous Mutation in the IFNAR2 Gene: A Case Report and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure."
      explanation: Reports the progression from vaccine-strain viremia to central nervous system disease in a genotyped patient.
  evidence:
  - reference: PMID:36439115
    reference_title: "Type I interferon receptor (IFNAR2) deficiency reveals Zika virus cytopathicity in human macrophages and microglia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "revealing the inherent cytopathicity of ZIKV towards macrophages"
    explanation: Shows that interferon competence is what normally conceals the cytopathic potential of the virus, which is unmasked in IFNAR2 deficiency.
- name: Natural Killer Cell Functional Dysregulation
  description: >-
    Beyond the antiviral state, type I interferon shapes NK cell behaviour:
    it normally augments degranulation and restrains IFN-gamma production. In
    IFNAR2-deficient NK cells stimulated with IFN-alpha, both responses fail.
    The loss of IFN-gamma restraint is the mechanistically interesting half,
    because unopposed IFN-gamma is the cytokine most closely tied to
    hemophagocytic lymphohistiocytosis - offering a route from a type I
    interferon receptor defect to a hyperinflammatory rather than merely
    infectious phenotype.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: Natural killer cell degranulation
    term:
      id: GO:0043320
      label: natural killer cell degranulation
    modifier: DECREASED
  downstream:
  - target: Hemophagocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure to restrain NK-cell IFN-gamma production is proposed as a
      contributor to the hemophagocytic lymphohistiocytosis seen after live
      vaccination in type I interferon signalling defects.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data support a role for NK cell function dysregulation and lack of inhibition of IFNγ production as contributors to the development of HLH in patients with impaired type I IFN signaling."
      explanation: The authors' own statement of the proposed causal route from NK dysregulation to HLH; the paper frames it as a contributory mechanism rather than a demonstrated one.
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in patient's natural killer (NK) cells stimulated with IFNα the expected increase in degranulation and inhibition of IFNγ production were affected"
    explanation: Documents the two specific NK-cell response failures that define this node.
mechanistic_hypotheses:
- hypothesis_group_id: narrow_phenotype_redundancy
  hypothesis_label: Type I interferon redundancy explains the narrow clinical phenotype
  status: EMERGING
  description: >-
    IFNAR2 deficiency abolishes type I interferon signalling completely in
    vitro, yet affected individuals are not broadly infection-prone: the index
    patient had no history of unusual susceptibility to respiratory viral
    pathogens before the fatal vaccine reaction. The proposed explanation is
    that human type I interferons are largely redundant for protective immunity
    under natural conditions, with other cell-intrinsic antiviral mechanisms
    compensating, and become indispensable only on systemic challenge with a
    replicating attenuated virus. The competing reading - that ascertainment
    favours the catastrophic presentations and milder susceptibility is simply
    unrecorded - is not excluded by the published cohorts, which remain very
    small. This distinction matters for whether population screening of the
    Arctic founder allele would identify people at risk or merely carriers.
  evidence:
  - reference: PMID:26424569
    reference_title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens."
    explanation: The primary observation the hypothesis rests on - a complete signalling defect without broad clinical susceptibility.
  - reference: PMID:26424569
    reference_title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "supports an essential but narrow role for IFN-α/β in human antiviral immunity"
    explanation: The authors' own framing of the phenotype as essential but narrow.
  - reference: PMID:33729549
    reference_title: "Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated."
    explanation: A review across IFNAR1/IFNAR2/STAT1/STAT2/IRF9 deficiencies generalising the redundancy interpretation beyond this single gene.
phenotypes:
- category: Immunological
  name: Disseminated infection with live vaccine virus
  description: >-
    The hallmark presentation. Systemic challenge with a live attenuated viral
    vaccine, classically measles-mumps-rubella, produces disseminated
    vaccine-strain infection rather than the intended limited immunising
    exposure.
  phenotype_term:
    preferred_term: Disseminated infection with live vaccine virus
    term:
      id: HP:0031697
      label: Disseminated infection with live vaccine virus
  evidence:
  - reference: PMID:26424569
    reference_title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine."
    explanation: The index presentation - fatal disease following MMR in a previously healthy child.
  - reference: PMID:35442417
    reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination"
    explanation: Confirms live-vaccine complications across an independent five-patient cohort.
- category: Neurological
  name: Infectious encephalitis
  description: >-
    Encephalitis or meningoencephalitis follows dissemination of the vaccine
    strain to the central nervous system, and was fatal in the index case.
  phenotype_term:
    preferred_term: Infectious encephalitis
    term:
      id: HP:0002383
      label: Infectious encephalitis
  evidence:
  - reference: PMID:39436454
    reference_title: "Severe Adverse Reaction to Measles Vaccine Due to Homozygous Mutation in the IFNAR2 Gene: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure."
    explanation: Documents meningoencephalitis in a genotyped IFNAR2-deficient patient after measles vaccination.
- category: Immunological
  name: Hemophagocytosis
  description: >-
    Hemophagocytic lymphohistiocytosis has been reported after live attenuated
    viral vaccination, both as the presenting illness and within the Arctic
    founder cohort, marking IFNAR2 deficiency as a hyperinflammatory as well as
    an infectious phenotype.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination"
    explanation: Reports HLH as the presenting illness in a genotyped patient after MMR.
  sequelae:
  - target: Fever
    description: Continuous high fever, unresponsive to antibiotics, during the hyperinflammatory episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
      explanation: Places fever within the clinical course of the HLH episode.
  - target: Irritability
    description: Irritability with myoclonic movements during the episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
      explanation: Places irritability within the clinical course of the HLH episode.
  - target: Lethargy
    description: Lethargy at presentation of the hyperinflammatory episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "he was hospitalized with high fever and lethargy"
      explanation: Places lethargy at the onset of the HLH episode.
  - target: Cervical lymphadenopathy
    description: Cervical lymphadenopathy accompanying the episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
      explanation: Places cervical lymphadenopathy within the clinical course of the HLH episode.
  - target: Maculopapular exanthema
    description: Maculopapular rash accompanying the episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
      explanation: Places the rash within the clinical course of the HLH episode.
  - target: Pancytopenia
    description: >-
      Progressive fall in blood counts during the episode; the source does not
      specify which lineages.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "progressive decrease in cell blood count"
      explanation: Places the cytopenia within the HLH episode.
- category: Immunological
  name: Severe viral infection
  description: >-
    Beyond vaccine strains, wild-type viral infection can be life-threatening.
    The Arctic cohort included life-threatening COVID-19 and influenza,
    extending the phenotype beyond live-vaccine challenge to common respiratory
    pathogens in at least some patients.
  phenotype_term:
    preferred_term: Severe viral infection
    term:
      id: HP:0031691
      label: Severe viral infection
  evidence:
  - reference: PMID:35442417
    reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza"
    explanation: Documents severe wild-type viral disease, not only vaccine-strain disease, in IFNAR2-deficient children.
- category: Constitutional
  name: Fever
  description: >-
    High fever beginning days after live attenuated vaccination, continuous and
    unresponsive to antibiotic therapy, opened the HLH episode.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
    explanation: Describes the febrile course of the HLH episode in a genotyped patient.
- category: Neurological
  name: Lethargy
  description: >-
    Lethargy at presentation, five days after MMR inoculation, alongside
    irritability and myoclonic movements.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he was hospitalized with high fever and lethargy"
    explanation: Records lethargy as a presenting feature.
- category: Neurological
  name: Irritability
  description: >-
    Irritability with myoclonic movements characterized the clinical course of
    the hyperinflammatory episode.
  phenotype_term:
    preferred_term: Irritability
    term:
      id: HP:0000737
      label: Irritability
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
    explanation: Reports irritability among the features of the clinical course.
- category: Immunological
  name: Cervical lymphadenopathy
  description: >-
    Cervical lymphadenopathy accompanied the febrile hyperinflammatory episode.
  phenotype_term:
    preferred_term: Cervical lymphadenopathy
    term:
      id: HP:0025289
      label: Cervical lymphadenopathy
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
    explanation: Reports cervical lymphadenopathy during the episode.
- category: Dermatological
  name: Maculopapular exanthema
  description: >-
    A maculopapular rash formed part of the clinical course following the
    vaccine-triggered episode.
  phenotype_term:
    preferred_term: Maculopapular exanthema
    term:
      id: HP:0040186
      label: Maculopapular exanthema
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continuous high fever, unresponsive to antibiotic therapy, irritability, myoclonic movements, cervical lymphadenopathy and maculopapular rash characterized the clinical course."
    explanation: Reports the maculopapular rash accompanying the episode.
- category: Hematological
  name: Pancytopenia
  description: >-
    A progressive decrease in blood counts accompanied the HLH episode. The
    source does not say which lineages fell - it reports only a "progressive
    decrease in cell blood count" - so the binding to Pancytopenia, which
    asserts all three, is the curator's reading of an unspecified cytopenia in
    an HLH context rather than something the text states. HPO has no plain
    "Cytopenia" term to fall back to. Note also that the relevant HLH-2004
    criterion is cytopenia affecting at least two of three lineages, not
    pancytopenia.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive decrease in cell blood count"
    explanation: Documents the progressive cytopenia during the hyperinflammatory episode.
diagnosis:
- name: Phospho-STAT1/STAT2 Flow Cytometry After Ex Vivo Interferon Stimulation
  description: >-
    The discriminating test. Whole blood or PBMCs are stimulated ex vivo with
    IFN-alpha and STAT1/STAT2 phosphorylation read by flow cytometry; in
    IFNAR2 deficiency it is absent. Stimulating the same cells with IFN-gamma
    in parallel is what makes the test specific rather than merely abnormal:
    the type II response is intact, so a defect confined to the type I arm is
    demonstrated directly, separating IFNAR2 and STAT2 deficiency from STAT1
    or JAK-level defects that impair both arms. The authors propose this as a
    rapid front-line assay when HLH follows a live attenuated vaccine.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rapid evaluation of phosphorylation of STAT1 and STAT2 by flow cytometry upon ex vivo stimulation with IFNα can guide clinicians in the early identification of patients with impairment in type I IFN-mediated signaling"
    explanation: The authors' explicit recommendation of this assay as the early diagnostic route in suspected type I interferon signalling defects.
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As expected, IFNγ stimulation was able to induce both STAT1 phosphorylation and transcription of type II IFN-regulated genes"
    explanation: The preserved type II response is the internal control that makes the test discriminating rather than merely abnormal.
- name: Molecular Confirmation by IFNAR2 Sequencing
  description: >-
    Definitive diagnosis requires demonstrating biallelic IFNAR2 variants.
    Where the Arctic founder allele is plausible on ancestry, targeted testing
    for p.Ser53Pro is the direct route; otherwise exome or panel sequencing is
    needed.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35442417
    reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant."
    explanation: Establishes the specific molecular finding that confirms the diagnosis in the founder population.
biochemical:
- name: Hemophagocytic lymphohistiocytosis laboratory signature
  notes: >-
    During an HLH episode the reported patient met the familiar HLH-2004
    laboratory picture: marked hyperferritinemia, transaminitis, raised lactate
    dehydrogenase, hypertriglyceridemia and hypofibrinogenemia, with a
    progressive fall in blood counts. These are the markers that identify the
    hyperinflammatory episode; they are not markers of the underlying
    interferon receptor defect, which is why the diagnostic section rests on
    phospho-STAT signalling rather than on these values.
  biomarker_term:
    preferred_term: Increased circulating ferritin concentration
    term:
      id: HP:0003281
      label: Increased circulating ferritin concentration
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
    explanation: Reports the full laboratory panel measured during the HLH episode in a genotyped patient.
  readouts:
  - target: Hemophagocytosis
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Marked hyperferritinemia is the headline laboratory abnormality of the HLH episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
      explanation: The measured value supporting this readout during the HLH episode.
- name: Hypofibrinogenemia
  notes: >-
    Fibrinogen fell to 92.2 mg/dl during the HLH episode, one of the HLH-2004
    diagnostic criteria.
  biomarker_term:
    preferred_term: Hypofibrinogenemia
    term:
      id: HP:0011900
      label: Hypofibrinogenemia
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
    explanation: The measured fibrinogen value during the hyperinflammatory episode.
  readouts:
  - target: Hemophagocytosis
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Fibrinogen consumption during the hyperinflammatory episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl), and hypofibrinogenemia (92.2 mg/dl)"
      explanation: The measured value supporting this readout during the HLH episode.
- name: Hypertriglyceridemia
  notes: >-
    Triglycerides rose to 338 mg/dl during the HLH episode, another HLH-2004
    criterion.
  biomarker_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl)"
    explanation: The measured triglyceride value during the hyperinflammatory episode.
  readouts:
  - target: Hemophagocytosis
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Hypertriglyceridemia during the hyperinflammatory episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L) and triglycerides (338 mg/dl)"
      explanation: The measured value supporting this readout during the HLH episode.
- name: Elevated circulating hepatic transaminase concentration
  notes: >-
    AST 360 U/L and ALT 550 U/L during the HLH episode, reflecting hepatic
    involvement.
  biomarker_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevation of liver enzymes (AST 360 U/L, ALT 550 U/L)"
    explanation: The measured transaminase values during the hyperinflammatory episode.
  readouts:
  - target: Hemophagocytosis
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Hepatic involvement during the hyperinflammatory episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "elevation of liver enzymes (AST 360 U/L, ALT 550 U/L)"
      explanation: The measured value supporting this readout during the HLH episode.
- name: Increased circulating lactate dehydrogenase concentration
  notes: >-
    Lactate dehydrogenase reached 3155 U/L during the HLH episode.
  biomarker_term:
    preferred_term: Increased circulating lactate dehydrogenase concentration
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L)"
    explanation: The measured lactate dehydrogenase value during the hyperinflammatory episode.
  readouts:
  - target: Hemophagocytosis
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: Raised lactate dehydrogenase during the hyperinflammatory episode.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "laboratory parameters were highly suggestive for HLH, with progressive decrease in cell blood count, hyperferritinemia (4008 μg/L), elevation of liver enzymes (AST 360 U/L, ALT 550 U/L), lactate dehydrogenase (3155 U/L)"
      explanation: The measured value supporting this readout during the HLH episode.
genetic:
- name: IFNAR2
  association: Causal
  gene_term:
    preferred_term: IFNAR2
    term:
      id: hgnc:5433
      label: IFNAR2
  notes: >-
    Biallelic loss-of-function IFNAR2 variants cause this autosomal recessive
    disease. Reported lesions include a homozygous mutation in the founder
    kindred (Duncan et al), two frameshift alleles in a compound heterozygote
    presenting with HLH (Passarelli et al), and the homozygous founder missense
    allele c.157T>C (p.Ser53Pro) in Inuit populations of Greenland, Canada and
    Alaska (Bastard et al). IFNAR1 and downstream JAK-STAT components are
    intact, so the defect is confined to type I interferon reception.
  evidence:
  - reference: PMID:26424569
    reference_title: "Human IFNAR2 deficiency: Lessons for antiviral immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β"
    explanation: Establishes IFNAR2 as the causal gene by linking the homozygous variant to loss of cellular interferon responsiveness.
  - reference: PMID:35442417
    reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant."
    explanation: Identifies the recurrent founder allele shared across the Arctic cohort.
prevalence:
- population: Inuit ancestry (Greenland, Canada, Alaska)
  measure_type: CARRIER_FREQUENCY
  prevalence_class: UNKNOWN
  notes: >-
    Reported as the minor allele frequency of the p.Ser53Pro founder variant in
    people of Inuit ancestry, not as a disease prevalence. A minor allele
    frequency of 0.034 is far above what the observed number of cases would
    suggest, which is why the authors raise population screening; it is recorded
    here as an allele frequency and must not be read as a rate of disease.
  evidence:
  - reference: PMID:35442417
    reference_title: "Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry"
    explanation: The reported founder allele frequency in the ancestral population.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 15 genetically confirmed patients are described in the literature
    across the index kindred, the Arctic founder cohort, and isolated case
    reports.
treatments:
- name: Avoidance of Live Attenuated Viral Vaccines
  description: >-
    The single most important intervention once the diagnosis is known. Live
    attenuated viral vaccines - measles-mumps-rubella above all - are attenuated
    only relative to an interferon-competent host and cause disseminated,
    potentially fatal infection in IFNAR2 deficiency. This is the
    agents-and-circumstances-to-avoid consideration for this disease, and the
    reason case reports argue for genetic screening before immunisation in
    at-risk populations.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of live attenuated viral vaccination
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  target_mechanisms:
  - target: Unrestricted Viral Replication and Cytopathicity
    description: >-
      Withholding the live vaccine removes the replicating viral challenge that
      the absent interferon response cannot contain.
  evidence:
  - reference: PMID:39436454
    reference_title: "Severe Adverse Reaction to Measles Vaccine Due to Homozygous Mutation in the IFNAR2 Gene: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case highlights the importance of incorporating genetic screening into vaccination programs for individuals at risk."
    explanation: States the clinical recommendation that follows - identify at-risk individuals before live vaccination.
- name: Supportive Care for Severe Viral Illness
  description: >-
    No disease-modifying therapy exists. Management of an established episode is
    supportive - intensive care for meningoencephalitis and multi-organ
    failure. Outcomes in reported cases have frequently been fatal despite
    intensive support. HLH-directed corticosteroid therapy is curated
    separately below.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Infectious encephalitis
    description: >-
      Intensive supportive management addresses the central nervous system
      disease and multi-organ failure symptomatically. It does not modify the
      interferon signalling defect upstream of them, and is linked here to the
      clinical consequence it actually treats rather than to a mechanism node.
    evidence:
    - reference: PMID:39436454
      reference_title: "Severe Adverse Reaction to Measles Vaccine Due to Homozygous Mutation in the IFNAR2 Gene: A Case Report and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure."
      explanation: Characterises the encephalitic and multi-organ illness that supportive management is directed at.
  evidence:
  - reference: PMID:39436454
    reference_title: "Severe Adverse Reaction to Measles Vaccine Due to Homozygous Mutation in the IFNAR2 Gene: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure."
    explanation: Characterises the severity of the illness that supportive management must address.
- name: Corticosteroid Therapy for Hemophagocytic Lymphohistiocytosis
  description: >-
    The hyperinflammatory episode is treated in its own right. The reported
    patient received intravenous methylprednisolone pulses followed by high-dose
    oral glucocorticoids, with progressive improvement in both clinical and
    laboratory features. This targets the HLH branch of the mechanism - the
    unrestrained inflammatory response - rather than the interferon receptor
    defect itself, which no therapy corrects.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylprednisolone
      term:
        id: CHEBI:6888
        label: 6alpha-methylprednisolone
  target_mechanisms:
  - target: Hemophagocytosis
    description: >-
      Glucocorticoids suppress the hyperinflammatory macrophage and lymphocyte
      activation that constitutes the HLH phenotype.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He received intravenous methylprednisolone pulses (30 mg/kg/day for 3 consecutive days) followed by high dose glucocorticoids (2 mg/kg) with progressive improvement of clinical and laboratory features."
      explanation: Documents the regimen and its effect on the HLH phenotype in a genotyped IFNAR2-deficient patient.
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with progressive improvement of clinical and laboratory features"
    explanation: Records the clinical and laboratory response to corticosteroid therapy.
environmental:
- name: Live attenuated viral vaccination
  description: >-
    The exposure that converts a clinically silent genotype into
    life-threatening disease. In the reported patient, symptoms began five days
    after MMR inoculation. This is the gene-environment interaction that
    defines the disease's presentation, and it is why avoidance is the principal
    intervention.
  exposure_term:
    preferred_term: exposure to live attenuated viral vaccine
  influences_mechanisms:
  - target: Unrestricted Viral Replication and Cytopathicity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A replicating attenuated virus is the challenge the absent interferon
      response cannot contain, so the exposure initiates the mechanism rather
      than merely aggravating it.
    evidence:
    - reference: PMID:33193576
      reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At 22 months of age, 5 days after inoculation with the live-attenuated measles-mumps-rubella (MMR) vaccine, he was hospitalized with high fever and lethargy."
      explanation: Establishes the temporal link between the vaccine exposure and onset of disease.
  review_notes: >-
    ECTO was searched for a suitable exposure term for live attenuated viral
    vaccination and none was found; the exposure_term is left with a free-text
    preferred_term and no binding rather than forced onto an inaccurate CURIE.
  evidence:
  - reference: PMID:33193576
    reference_title: "IFNAR2 Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "5 days after inoculation with the live-attenuated measles-mumps-rubella (MMR) vaccine"
    explanation: The documented exposure preceding disease onset.
notes: >-
  IFNAR2 deficiency has no disease-modifying therapy. Hematopoietic stem cell
  transplantation has been considered for type I interferonopathy-adjacent
  immunodeficiencies but no outcome data specific to IFNAR2 deficiency were
  found, so it is not curated as a treatment here.
📚

References & Deep Research

References

1
PMID:26424569
Human IFNAR2 deficiency: Lessons for antiviral immunity.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: IFNAR2 Deficiency (immunodeficiency 45) · 2026-09-04T01:29:50Z · View source

New Disease entry for MONDO:0014727 (immunodeficiency 45), curated as IFNAR2 Deficiency following the STAT2_Deficiency precedent for gene-defined type I interferon inborn errors. Deep research: 'just research-disorder claude_code IFNAR2_Deficiency' (report committed). Its validation sections flagged needs_review on three counts, none of which affect this entry: one quote attributed to PMID:35442417 was a paraphrase of that paper's introduction (not reused here - the PMID:35442417 snippets in this entry were taken directly from the cached abstract); HP:0025143 and HP:0025047 were reported under labels belonging to different terms (neither is bound here); and HP:0002264 did not resolve (not bound here). GeneReviews baseline: searched PubMed for an IFNAR2 GeneReviews chapter ('IFNAR2 GeneReviews[All Fields]'); none exists, so no GeneReviews baseline was available. Phenotypes were taken from the primary case literature instead. Pathophysiology is curated as a causal chain rather than a list: IFNAR2 Loss of Function -> Absent Type I Interferon Receptor Signaling -> (Failure of Interferon-Stimulated Gene Induction -> Unrestricted Viral Replication and Cytopathicity -> phenotype nodes) and -> Natural Killer Cell Functional Dysregulation -> Hemophagocytosis. The NK-to-HLH edge is typed INDIRECT_UNKNOWN_INTERMEDIATES because Passarelli et al describe the relation between HLH and defective type I IFN responses as unclear and frame NK dysregulation as a contributor rather than a demonstrated cause. Recorded as a mechanistic hypothesis (narrow_phenotype_redundancy, status EMERGING) rather than as mechanism: the dissociation between a complete in vitro signalling defect and a narrow in vivo phenotype. The entry states the competing ascertainment-bias reading explicitly rather than asserting redundancy as settled. Deliberately NOT claimed: broad or recurrent susceptibility to ordinary respiratory viruses. Duncan et al report the opposite for the index patient, so no 'Recurrent viral infections' phenotype was added despite it being the obvious enum value for an immunodeficiency; the negative observation is carried in the hypothesis instead. The Inuit p.Ser53Pro allele frequency (0.034) is recorded as measure_type CARRIER_FREQUENCY with a note warning it must not be read as a disease rate. Validation: 'just validate' passed with 28/28 snippets verified against the cached references; 'just validate-terms' passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms and check-enum-values all clean. Five references were fetched and committed (PMID:26424569, PMID:35442417, PMID:33193576, PMID:39436454, PMID:36439115); PMID:33729549 was already in the cache on main and is cited without modification. References the deep-research validator fetched incidentally but this entry does not cite were removed from the diff.

Claude Code ▸
IFNAR2 Deficiency (Immunodeficiency-45, IMD45): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 2026-09-04T01:25:12.302729

IFNAR2 Deficiency (Immunodeficiency-45, IMD45): Comprehensive Research Report

1. Disease Information

Overview

IFNAR2 deficiency is a rare, life-threatening autosomal recessive (and, per one recently described dominant-negative allele family in COVID-19, potentially oligogenic/dominant-modifying) primary immunodeficiency of the innate immune system caused by biallelic loss-of-function variants in IFNAR2, the gene encoding the high-affinity subunit of the type I interferon (IFN-α/β/ω) receptor. Loss of IFNAR2 abolishes cellular responsiveness to all type I interferons, leaving affected individuals unable to mount an antiviral interferon-stimulated gene (ISG) response. Clinically, the disorder is characterized by an essentially normal phenotype until exposure to a virus — whether wild-type (influenza, SARS-CoV-2) or live-attenuated vaccine strain (measles-mumps-rubella [MMR], yellow fever) — at which point patients can develop fulminant, often fatal, viral disease: encephalitis/meningoencephalitis, hemophagocytic lymphohistiocytosis (HLH), viscerotropic disease, or severe pneumonia (Duncan et al. 2015; Bastard et al. 2022; Hernandez et al. 2020).

"Autosomal recessive deficiency of the IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR2 deficiency in the Arctic." (Bastard et al. 2022, J Exp Med, PMID:35442417)

Key Identifiers

Resource Identifier
Gene (HGNC) IFNAR2, HGNC:5433
OMIM gene *602376 — Interferon-alpha, -beta, and -omega receptor 2
OMIM phenotype #616669 — Immunodeficiency 45 (IMD45) (note: search results also referenced #614889, which corresponds to IMD28/ISG15 deficiency — verify the correct OMIM phenotype MIM number, 616669, directly before curation; there is some inconsistency across secondary sources)
Orphanet Listed as a major genetic susceptibility factor for "Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection" (ORPHA:431166)
Gene location Chromosome 21q22.11
Inheritance Autosomal recessive (biallelic null/loss-of-function)
NCBI Gene / Ensembl IFNAR2

Synonyms

  • Type I interferon receptor 2 deficiency
  • IFN-α/β receptor subunit 2 deficiency
  • Interferon alpha/beta receptor chain 2 deficiency
  • IMD45 (Immunodeficiency 45)
  • Complete IFNAR2 deficiency (vs. the milder, common hypomorphic/partial deficiencies seen as COVID-19 severity risk variants)

Data Source Character

Nearly all clinical knowledge derives from individual patient case reports and small case series (single families, or clustered founder-variant cohorts in the Canadian/Greenlandic/Alaskan Arctic and Inuit populations), rather than large aggregated disease-level registries — this is a genuinely ultra-rare monogenic disorder. Population-level genomic data (gnomAD, biobank cohorts) contribute allele-frequency and severe-COVID-19-association evidence for common hypomorphic IFNAR2 variants, which is a related but distinct body of evidence from the complete/biallelic-null Mendelian disease.

2. Etiology

Disease Causal Factors

IFNAR2 deficiency is a monogenic, purely genetic disorder: biallelic (homozygous or compound heterozygous) loss-of-function variants in IFNAR2 that abolish or markedly impair surface expression/function of the IFNAR2 receptor chain. The disease is fundamentally one of gene-environment interaction: the genetic lesion is clinically silent until a viral trigger (wild-type virus or live-attenuated vaccine) is encountered, at which point uncontrolled viral replication precipitates the phenotype.

Genetic Risk Factors

Reported pathogenic variants include:

Variant Type Population/Case Source
Homozygous mutation (index case) rendering cells IFN-α/β-unresponsive Loss-of-function UK child, fatal post-MMR encephalitis (Duncan et al. 2015) PMID (STM 2015, 7(307):307ra154, DOI:10.1126/scitranslmed.aac4227)
c.234delT (p.Leu79Ter, rs1310889473) + c.555_559delAAAAG (p.Ile185MetfsTer12, rs1312285586) Compound heterozygous frameshift/nonsense Caucasian boy, post-MMR HLH PMID:33193576 (Hernandez et al. 2020, Front Genet)
c.157T>C, p.Ser53Pro (NM_207585.2) Homozygous missense — founder variant 5 patients, Greenland/Canada/Alaska (Inuit ancestry); MAF 0.034 in Inuit reference cohort, 0.026 (23/448 heterozygous carriers, no homozygotes) in unpublished Greenlandic WGS PMID:35442417 (Bastard et al. 2022, J Exp Med)
Homozygous missense (VUS) Missense 10-month-old female, severe post-measles-vaccine reaction, viremia/meningoencephalitis/multi-organ failure J Clin Immunol 2024/2025;45:30, DOI:10.1007/s10875-024-01814-6
c.157T>C, p.Ser53Pro (same founder allele) Homozygous 13-month-old Inuit boy, northern Quebec — post-vaccination drug-resistant infantile epileptic spasms (West syndrome) Seizure — Eur J Epilepsy 2022, PMID/DOI S1059-1311(22)00175-3
Rare stop-gain variant (NM_000874:exon9:c.C966A, p.Y322X) and other predicted LOF IFNAR2 variants Heterozygous/burden-tested COVID-19 severity cohort (ODYSSEY phase 3) PMID:34273592 / PMC8279933 (Smieszek et al. 2021)

Mechanistic consequence of key variants: The Ser53Pro substitution "prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state" (Bastard et al. 2022). The frameshift/nonsense compound-heterozygous variants are predicted to cause "complete lack of the protein" (Hernandez et al. 2020, PMID:33193576).

Common (non-Mendelian) genetic risk modifiers: Independent of the rare Mendelian disease, common IFNAR2 polymorphisms (rs2236757, rs3153, rs1051393, rs2834158) have been associated with COVID-19 mortality risk in hospitalized cohorts, and soluble IFNAR2 plasma levels differ between survivors and non-survivors (Rodrigues et al. 2022, PMID:35967349, Front Immunol). This is a distinct, quantitative-trait/complex-disease association layer, not equivalent to biallelic loss-of-function.

Environmental / Triggering Risk Factors

  • Live-attenuated viral vaccination — MMR (measles, mumps, rubella components) and yellow fever vaccine (YFV) are the dominant identified triggers, causing meningoencephalitis, HLH, or viscerotropic disease.
  • Wild-type viral infection — influenza and SARS-CoV-2 (COVID-19) have caused life-threatening disease in IFNAR2-deficient patients.
  • Bastard et al. (2022) also reported IFNAR1/IFNAR2 deficiency and neutralizing type I IFN autoantibodies together accounting for "more than half the cases of life-threatening yellow fever vaccine-associated disease" in a broader cohort (related autoantibody-mediated phenocopy — see below).

Protective Factors

No specific genetic or environmental protective factor has been documented for the rare biallelic-null disease; heterozygous carriers (parents, siblings) are consistently reported as asymptomatic, "without history of major infection or hyperinflammatory episodes, nor vaccination reactions" (Hernandez et al. 2020), consistent with recessive inheritance and adequate residual function from a single normal allele.

Gene-Environment Interactions

This disease is a paradigm case of gene-environment interaction in inborn errors of immunity: the genotype is necessary but not sufficient — clinical disease requires viral (wild-type or vaccine-strain) exposure as the precipitating "second hit." This is analogous to, and mechanistically continuous with, the broader class of "inborn errors of type I IFN immunity" (which also includes IFNAR1, STAT1, STAT2, TYK2, IRF7, IRF9 deficiencies, and autoantibody-mediated type I IFN neutralization) recognized as a unifying mechanism for severe/critical viral pneumonia including COVID-19, influenza, and adverse reactions to live vaccines (Zhang et al.; Bastard et al., multiple JEM papers 2019–2022).

3. Phenotypes

Symptoms, Signs, and Manifestations (by clinical context)

Post-live-vaccine reactions: - Fever, lethargy, irritability (HP:0025143 lethargy) - Myoclonic movements / seizures, evolving in one case to infantile epileptic spasms syndrome (West syndrome) — drug-resistant - Cervical lymphadenopathy - Maculopapular rash - Meningoencephalitis / fatal encephalitis - Multi-organ failure - Viscerotropic disease (yellow-fever vaccine): hepatic dysfunction, coagulopathy

HLH-associated laboratory/clinical findings (from the compound-heterozygous frameshift case, PMID:33193576): - Hyperferritinemia (4008 μg/L) - Transaminitis: AST 360 U/L, ALT 550 U/L - Elevated LDH: 3155 U/L - Hypertriglyceridemia: 338 mg/dL - Hypofibrinogenemia: 92.2 mg/dL - Progressive cytopenias

Wild-type viral infection: - Life-threatening/critical COVID-19 pneumonia - Life-threatening influenza

Phenotype Characteristics

  • Age of onset: Typically infancy to early childhood (10 months–2 years in the reported cases), coinciding with the standard MMR vaccination schedule (12 months) or first serious wild-type viral exposure. The disorder is otherwise clinically silent (asymptomatic at baseline).
  • Severity: Highly severe/life-threatening at presentation — several index cases were fatal (the original Duncan et al. index patient died; a sibling case was also affected).
  • Progression: Acute, fulminant onset following the triggering exposure; not a chronic progressive disease between triggering events.
  • Frequency among affected individuals: Based on the small number of reported kindreds (fewer than ~10 published families/individuals worldwide as complete biallelic deficiency, plus the Arctic founder-variant cluster of 5 patients), most reported patients present with either (a) post-live-vaccine encephalitis/HLH, or (b) life-threatening wild-type viral disease (influenza, COVID-19).

Suggested HPO Terms

  • HP:0002383 — Encephalitis (or HP:0002264 Meningoencephalitis)
  • HP:0005537 — Hemophagocytosis / HP:0001744 Splenomegaly / features of HLH
  • HP:0001945 — Fever
  • HP:0002014 — Diarrhea (nonspecific, if present)
  • HP:0002133 — Status epilepticus / HP:0032792 Infantile spasms
  • HP:0025143 — Lethargy
  • HP:0025047 — Maculopapular rash
  • HP:0002240 — Hepatomegaly
  • HP:0001945 — Recurrent/severe viral infections — consider HP:0002718 (Recurrent infections) or HP:0004429 (susceptibility to viral infections, if available in HPO)
  • HP:0011024 — Abnormality of the gastrointestinal system (viscerotropic disease)
  • HP:0011893 — Abnormal leukocyte count / cytopenias

Quality of Life Impact

Not formally studied via standardized instruments (no EQ-5D/SF-36 data identified) given disease rarity; qualitatively, survivors of severe episodes (e.g., the epileptic-spasms case) face long-term neurodevelopmental sequelae from drug-resistant epilepsy, while patients successfully treated for HLH (e.g., the compound-heterozygous case managed with corticosteroids) have been reported as developing normally at follow-up (4 years old, "in good general condition," normal growth) (PMID:33193576).

4. Genetic / Molecular Information

Causal Gene

  • IFNAR2 (HGNC:5433), chromosome 21q22.11, OMIM *602376. Encodes the high-affinity ligand-binding subunit of the type I interferon receptor.

Gene/Protein Structure

  • IFNAR2 encodes a 487-residue type II cytokine-receptor-family transmembrane protein with an N-terminal extracellular ligand-binding domain composed of two fibronectin type III (FnIII)-like subdomains (in contrast to IFNAR1's four FnIII repeats), a single transmembrane domain, and a cytoplasmic tail.
  • IFNAR2 constitutively associates with STAT2 via its cytoplasmic domain (STAT2-binding site within the C-terminal ~110 amino acids); STAT2 recruits STAT1 upon activation.

Variant Classification / Types

  • Nonsense (p.Leu79Ter), frameshift (p.Ile185MetfsTer12), and missense (p.Ser53Pro) variants have all been reported causing complete loss of IFNAR2 surface expression.
  • All confirmed pathogenic variants for the complete Mendelian disease are recessive (require biallelic hit — homozygous or compound heterozygous).
  • Population databases (gnomAD): the frameshift variants are extremely rare (allele frequencies 0.000004–0.000016); the Ser53Pro founder variant is essentially absent from global gnomAD but reaches MAF 0.026–0.034 in Arctic Inuit reference populations — a striking example of a population-specific founder allele with major clinical relevance in that population.

Functional Consequences (mechanistically demonstrated)

  • Loss of cell-surface IFNAR2 expression on patient leukocytes (flow cytometry) — confirmed across multiple case reports.
  • Abolished STAT1 phosphorylation upon IFN-α stimulation of monocytes, while IFN-γ (type II)-induced STAT1 phosphorylation remains intact — confirms selective type I IFN pathway defect with preserved type II (IFN-γ) signaling.
  • Failure to induce type I interferon-stimulated genes (ISGs) — IFI27, IFI44L, CXCL10, ISG15, RSAD2, SIGLEC1 all fail to be induced upon ex vivo IFN-α stimulation of whole blood.
  • No CXCL10 chemokine production upon IFN-α stimulation of PBMCs (IFN-γ-induced CXCL10 normal).
  • NK cell dysfunction: patient NK cells fail to upregulate CD107a degranulation marker upon IFN-α pre-incubation (~3-fold increase seen in controls/parents, absent in patient), and fail to show the normal IFN-α-mediated suppression of intracellular IFN-γ production — proposed as a mechanistic link between IFNAR2 loss and HLH development via NK cell dysregulation.
  • In vitro increased vulnerability to multiple viruses — patient cells show enhanced viral replication/susceptibility compared to controls.
  • Reconstitution of patient cells with wild-type IFNAR2 restores IFN-α/β responsiveness and antiviral control (Duncan et al. 2015), functionally confirming causality.

Modifier Genes / Related Disease Mechanisms (phenocopies)

IFNAR2 deficiency sits within a broader group of "inborn errors of type I IFN immunity" with overlapping phenotypes, useful for differential diagnosis and pathway context: - IFNAR1 deficiency (its receptor-partner subunit) — clinically near-identical phenotype (HLH, encephalitis, severe COVID-19/influenza, adverse vaccine reactions); a common Polynesian/Pacific founder loss-of-function allele has been characterized (PMC9026234). - STAT2 deficiency — complete deficiency causes similar inflammatory viral disease (PMC10266780); a distinct STAT2 gain-of-function/loss-of-negative-regulation form causes a type I interferonopathy. - STAT1, TYK2, IRF7, IRF9 deficiencies — related type I/III IFN pathway inborn errors. - Autoantibodies neutralizing type I IFN — a phenocopy mechanism (not genetic) producing an equivalent functional block, notably implicated in adult critical COVID-19 and yellow-fever-vaccine-associated disease.

Epigenetics / Chromosomal Abnormalities

No epigenetic regulation studies or chromosomal structural abnormalities (aneuploidy, translocation) have been reported specific to IFNAR2 deficiency; the gene lies in the cytokine-receptor gene cluster on 21q22.11 alongside IFNAR1, IL10RB, IFNGR2, and IL10RB, all part of the ancestral interferon-receptor cluster on chromosome 21.

5. Environmental Information

  • Live-attenuated viral vaccines (MMR, yellow fever) are the principal, well-documented environmental trigger precipitating fulminant disease in genetically susceptible individuals — this is the dominant "environmental factor" for this disorder rather than toxins or occupational exposures.
  • Wild-type respiratory/systemic viruses: influenza virus and SARS-CoV-2 are documented triggers of life-threatening disease.
  • No infectious co-trigger, toxin, or lifestyle/dietary risk factor has been reported; this is not a disease with a classical toxicological or occupational-exposure etiology axis — its "environmental" dimension is essentially virological.
  • Infectious agents directly relevant: measles virus (vaccine strain), mumps virus (vaccine strain), rubella virus (vaccine strain), yellow fever virus (vaccine strain 17D), influenza A virus, SARS-CoV-2.

6. Mechanism / Pathophysiology

Causal Chain (ordered)

  1. Biallelic loss-of-function variant in IFNAR2 (nonsense, frameshift, or a destabilizing missense such as p.Ser53Pro) leads to absent or non-functional IFNAR2 protein, either through nonsense-mediated decay/truncation or failure of the mutant protein to traffic to the cell surface (retained intracellularly in an aberrantly glycosylated state for Ser53Pro).
  2. Absent surface IFNAR2 results in failure to form a functional IFNAR1–IFNAR2 heterodimeric type I interferon receptor complex upon IFN-α/β/ω binding.
  3. Without receptor dimerization, the receptor-associated Janus kinases — TYK2 (bound to IFNAR1) and JAK1 (bound to IFNAR2) — fail to be recruited/cross-phosphorylate; because STAT2 is constitutively docked on the IFNAR2 cytoplasmic tail (via its C-terminal ~110 aa), loss of IFNAR2 specifically eliminates the STAT2 docking site required for downstream signaling. (Demonstrated experimentally: this is inferred from the receptor biology and is directly supported by loss of STAT1 phosphorylation in patient cells.)
  4. This leads to absent STAT1/STAT2 phosphorylation and failure of ISGF3 (STAT1–STAT2–IRF9) complex formation and nuclear translocation — directly demonstrated by absent STAT1 phosphorylation upon IFN-α stimulation of patient monocytes, while IFN-γ→STAT1 phosphorylation (a JAK1/JAK2, IFNGR-dependent, IFNAR-independent pathway) remains intact, confirming pathway selectivity.
  5. Failure of ISGF3 formation results in failure to transactivate interferon-stimulated response elements (ISREs), demonstrated as absent induction of ISGs (IFI27, IFI44L, CXCL10, ISG15, RSAD2, SIGLEC1) and absent CXCL10 protein secretion upon ex vivo IFN-α challenge.
  6. Loss of the cell-intrinsic antiviral ISG program leads to unrestrained viral replication in infected cells upon exposure to IFN-sensitive viruses — demonstrated in vitro as increased viral susceptibility of patient cells and functionally rescued by IFNAR2 reconstitution (Duncan et al. 2015).
  7. In parallel, loss of IFN-α signaling in NK cells specifically abolishes the normal IFN-α-induced upregulation of degranulation (CD107a) and the normal IFN-α-mediated suppression of NK-cell IFN-γ production — this dysregulated, unrestrained NK-cell IFN-γ output is proposed (branch point) to drive the macrophage-activation/hyperinflammatory state that manifests as hemophagocytic lymphohistiocytosis (HLH) in a subset of patients — this branch is mechanistically plausible and evidence-supported at the cellular level but the causal link to clinical HLH onset remains partly inferential.
  8. Unrestrained viral replication (branch A) and/or NK-cell-driven hyperinflammation (branch B) together culminate in the clinical syndromes observed: fulminant viral encephalitis/meningoencephalitis, viscerotropic disease, HLH with multi-organ dysfunction, or severe/critical viral pneumonia (influenza, COVID-19), depending on the triggering virus, tissue tropism, and host inflammatory response.

Molecular Pathways

  • Type I interferon / JAK-STAT signaling (ISGF3 pathway): IFNAR1–IFNAR2 → TYK2/JAK1 → STAT1/STAT2 → ISGF3 (with IRF9) → ISRE-driven ISG transcription. This is the central, disrupted pathway. (KEGG: hsa04630 Jak-STAT signaling pathway; Reactome: Interferon alpha/beta signaling, R-HSA-909733.)

Cellular Processes

  • Antiviral restriction-factor induction (failure)
  • NK cell cytotoxic degranulation regulation (failure of IFN-α-mediated enhancement)
  • NK cell cytokine (IFN-γ) output regulation (failure of IFN-α-mediated suppression) — implicated in HLH pathogenesis
  • Monocyte/macrophage activation — secondary hyperinflammatory state in HLH

Protein Dysfunction

  • Loss-of-function via truncation (nonsense/frameshift) or via a folding/trafficking defect that traps mutant protein intracellularly (Ser53Pro missense) — a form of "hypomorphic/complete LOF via mislocalization" rather than catalytic-site disruption, since IFNAR2 itself has no enzymatic activity but serves as a scaffold/docking subunit.

Immune System Involvement

This is fundamentally an innate antiviral immunodeficiency with a secondary hyperinflammatory (HLH-like) phenotype — an unusual combination in which immunodeficiency and immune dysregulation coexist, mediated respectively by loss of direct antiviral ISG induction and by NK-cell dysregulation.

Suggested GO Terms

  • GO:0038196 — interferon-alpha-beta receptor complex / GO:0004905 type I interferon receptor activity
  • GO:0060337 — type I interferon-mediated signaling pathway
  • GO:0060333 — interferon-gamma-mediated signaling pathway (preserved, contrast)
  • GO:0007259 — cell surface receptor signaling pathway via JAK-STAT
  • GO:0032481 — positive regulation of type I interferon production
  • GO:0002323 — natural killer cell activation involved in immune response
  • GO:0001916 — positive regulation of T cell mediated cytotoxicity (NK degranulation context — CL/GO adjacent)

Suggested CL Terms

  • CL:0000576 — monocyte
  • CL:0000623 — natural killer cell
  • CL:0000542 — lymphocyte
  • CL:0000235 — macrophage (HLH effector)

7. Anatomical Structures Affected

  • Organ level (primary): Central nervous system (encephalitis/meningoencephalitis — the dominant severe presentation), liver (transaminitis, viscerotropic hepatic involvement, hepatomegaly), spleen (HLH-associated splenomegaly, reported elsewhere in interferonopathy literature), bone marrow/hematopoietic system (cytopenias, hemophagocytosis), respiratory system (viral pneumonia in influenza/COVID-19 presentations).
  • Secondary/systemic: Multi-organ failure in severe cases (viscerotropic yellow-fever disease, fulminant HLH).
  • Body systems involved: Immune system (primary defect), nervous system, hepatobiliary system, hematologic system, respiratory system.
  • Tissue/cell level: Leukocytes broadly (monocytes, NK cells, lymphocytes) fail to express surface IFNAR2 and fail to respond to type I IFN — this is a systemic, hematopoietic-lineage-wide receptor defect, not tissue-restricted.
  • Subcellular level: Plasma membrane (absent receptor localization); for Ser53Pro, intracellular retention (likely ER/Golgi, aberrant glycosylation) rather than normal trafficking to the cell surface — GO Cellular Component: GO:0005886 (plasma membrane), GO:0005783 (endoplasmic reticulum, for the trafficking-defective mutant).
  • UBERON suggestions: UBERON:0000955 (brain), UBERON:0002107 (liver), UBERON:0002106 (spleen), UBERON:0002371 (bone marrow), UBERON:0002048 (lung).
  • Localization: No lateralization; systemic/multi-organ, virus-tropism-dependent.

8. Temporal Development

  • Onset: Infancy/early childhood, precipitated by the routine vaccination schedule (MMR typically given ~12 months) or first severe wild-type viral exposure. The disease itself is congenital (genetic), but clinical onset is event-triggered rather than present at birth.
  • Onset pattern: Acute/fulminant following the triggering exposure — days after vaccination in the classic cases (e.g., "5 days after MMR vaccination").
  • Progression: Rapid, severe deterioration once triggered (encephalitis, HLH, multi-organ failure over days).
  • Disease course pattern: Episodic/event-triggered rather than continuously progressive — between triggering viral exposures patients are reported as clinically well. However, a single severe episode can leave lasting sequelae (e.g., drug-resistant epilepsy/infantile spasms following an encephalopathic episode).
  • Critical periods: The period surrounding live-vaccine administration is a recognized critical window of vulnerability; this underlies proposals for pre-vaccination genetic screening in populations with known founder alleles (e.g., Arctic Inuit communities) or in infants with a family history of severe vaccine reactions.
  • Remission: With prompt recognition and treatment (e.g., corticosteroids for HLH), patients can recover and remain well; the compound-heterozygous HLH case was reported in good health and normally growing at 4 years follow-up, having subsequently tolerated additional infections (febrile seizure, influenza A/HSV coinfection) without HLH recurrence.

9. Inheritance and Population

Epidemiology

  • Extremely rare globally; fewer than ten published kindreds/individuals with confirmed complete biallelic IFNAR2 deficiency as of the most recent literature identified (2015–2025).
  • Notable exception — Arctic/Inuit founder effect: the p.Ser53Pro allele reaches a minor allele frequency of ~0.026–0.034 in Inuit reference populations from Greenland/Canada/Alaska, making IFNAR2 deficiency a locally non-negligible cause of severe pediatric viral/vaccine-associated disease in this population, with an estimated homozygote (affected) frequency on the order of 1 in ~1,000–2,000 in Inuit communities based on Hardy-Weinberg expectation from the reported carrier frequency (this is an approximation derived from the reported allele frequency, not a directly reported incidence figure, and should be validated against the primary source before use as a curated statistic).

Inheritance Pattern

  • Autosomal recessive for the complete/Mendelian disease (biallelic homozygous or compound heterozygous loss-of-function).
  • Common hypomorphic IFNAR2 variants associated with COVID-19 severity behave as complex-trait risk alleles (not simple recessive Mendelian disease).

Penetrance / Expressivity

  • Penetrance for severe disease is incomplete and exposure-dependent: genotype alone does not predict a clinical event; a specific viral (or live-vaccine) exposure is required to trigger disease. Among the founder-variant homozygotes ascertained through clinical presentation, expressivity varies (encephalitis vs. HLH vs. epileptic spasms vs. severe COVID-19/influenza), indicating pleiotropic/variable expressivity depending on the triggering pathogen and host factors.
  • No reported genetic anticipation, germline mosaicism, or imprinting phenomena.

Founder Effects / Consanguinity

  • Strong, well-documented founder effect for p.Ser53Pro in circumpolar Inuit populations (Greenland, Arctic Canada, Alaska).
  • Consanguinity is not specifically emphasized in the literature relative to the founder-population homozygosity mechanism, though standard recessive-disease logic (increased homozygosity risk with shared ancestry) applies.

Population Demographics

  • Affected populations: Reported cases span European/Caucasian (index UK case), and importantly Inuit/circumpolar Arctic populations (Greenland, northern Quebec/Canada, Alaska) where the founder allele is common.
  • No formal sex-ratio or age-distribution registry data exists given the rarity and case-report-based evidence base.

10. Diagnostics

Laboratory / Functional Tests

  • Flow cytometry for IFNAR2 surface expression on leukocytes (monocytes, lymphocytes) — absent or markedly reduced in affected patients; this is a key functional screening assay.
  • STAT1 phosphorylation assay (phospho-flow or immunoblot) after ex vivo IFN-α stimulation of PBMCs/monocytes — absent in patients, normal after IFN-γ stimulation (differentiates type I from type II IFN pathway defects — critical for distinguishing IFNAR1/IFNAR2/STAT2/TYK2 defects from IFNGR/STAT1-only defects).
  • ISG induction assay — qPCR for IFI27, IFI44L, CXCL10, ISG15, RSAD2, SIGLEC1 transcripts after ex vivo IFN-α stimulation of whole blood; failure to induce is diagnostic.
  • CXCL10 (IP-10) protein assay (ELISA/Luminex) after IFN-α stimulation of PBMCs.
  • NK cell functional assays: CD107a degranulation assay with/without IFN-α pre-incubation; intracellular IFN-γ staining.
  • HLH-directed labs when clinically indicated: ferritin, triglycerides, fibrinogen, soluble CD25 (sIL-2R), AST/ALT/LDH, cytopenia panel — per HLH-2004 diagnostic criteria.

Genetic Testing

  • Targeted single-gene sequencing of IFNAR2, or more commonly, ascertainment through broader gene panels for primary immunodeficiency, HLH-associated genes, or (as in the epileptic-spasms case) a "comprehensive developmental disorders gene panel."
  • Whole exome/genome sequencing — used in most reported cases, given the initially unclear differential diagnosis (encephalitis, HLH, or epilepsy of unknown cause).
  • Population/founder screening — proposed pre-vaccination genetic screening for the p.Ser53Pro allele has been suggested for Arctic Inuit populations given the relatively high carrier frequency and severe/fatal consequences of missed diagnosis before live-vaccine administration.
  • Standard variant interpretation follows ACMG/AMP criteria; the 2024 measles-vaccine case report specifically flagged its causal variant as a Variant of Uncertain Significance (VUS) pending confirmatory functional studies, illustrating that not every case yields an unambiguous ClinVar "pathogenic" classification without functional workup.

Clinical/Differential Diagnosis

  • Differential diagnosis for the acute presentation includes other inborn errors of type I/III IFN immunity (IFNAR1, STAT1, STAT2, TYK2, IRF7, IRF9 deficiencies), primary HLH (perforin pathway defects: PRF1, UNC13D, STX11, STXBP2), and autoantibody-mediated type I IFN neutralization (an important phenocopy, especially in adults with critical COVID-19 or yellow-fever vaccine-associated disease) — anti-IFN autoantibody testing should be considered as a parallel or alternative diagnostic pathway when genetic testing is negative.
  • Standard HLH-2004 clinical criteria apply for the hyperinflammatory phenotype.

Screening

  • No newborn screening program currently exists for IFNAR2 deficiency; targeted carrier/pre-vaccination screening has been proposed specifically for high-risk founder populations (Arctic Inuit) and for infants with a family history of severe vaccine reactions, paralleling published clinical guidance for the analogous IFNAR1 Oceania founder allele ("Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania," PMID cited in search but exact number should be verified against PubMed directly).

11. Outcome / Prognosis

  • Mortality: Case-fatality is substantial among reported index cases — the original 2015 index patient died of fatal encephalitis; other reported patients have died from viscerotropic yellow-fever-vaccine disease or fulminant viral disease. No formal population-level mortality rate exists given the small numbers.
  • Morbidity: Survivors can have significant long-term morbidity — e.g., drug-resistant infantile epileptic spasms/West syndrome with attendant neurodevelopmental impairment following a post-vaccination encephalopathic episode.
  • Recovery potential with treatment: Prompt recognition and immunosuppressive treatment of the HLH phenotype (e.g., high-dose corticosteroids) has achieved good outcomes in at least one reported case, with the patient healthy and developing normally at 4-year follow-up and subsequently tolerating further infections without recurrence — suggesting that outcome is highly dependent on early recognition and supportive/immunomodulatory management of the hyperinflammatory complication, even though the underlying antiviral defect is not itself correctable outside of gene/receptor reconstitution research settings.
  • Prognostic factors: Speed of diagnosis/treatment initiation for HLH; specific triggering virus and organ tropism (CNS involvement carries the worst prognosis); possibly variant type (complete null vs. partial/hypomorphic), though this has not been systematically studied given the small case numbers.

12. Treatment

  • No disease-specific curative therapy exists. Management is reactive/supportive, directed at the triggering viral infection and any resulting hyperinflammatory (HLH) complication, since IFNAR2 loss cannot currently be pharmacologically corrected.
  • HLH-directed immunosuppression: IV methylprednisolone pulse therapy (30 mg/kg/day × 3 days) followed by tapering high-dose glucocorticoids (2 mg/kg) achieved clinical improvement in the reported compound-heterozygous case (NCIT:C2977 Corticosteroid; NCIT:C15632 or NCIT:C15986 for broader HLH-directed chemo-immunotherapy such as etoposide-based HLH-94/HLH-2004 protocols in more severe cases, though etoposide use was not specifically reported in the identified cases).
  • Antimicrobial/antiviral supportive therapy for subsequent infections (e.g., standard antimicrobial therapy for febrile seizure and combined influenza A/HSV infection in the same patient, without recurrence of HLH).
  • Avoidance of live-attenuated vaccines is the central preventive/management principle once the diagnosis is established or strongly suspected (family history, founder-population ancestry) — i.e., contraindicating MMR and yellow fever vaccines, and considering alternative protection strategies (e.g., passive immunoprophylaxis, isolation/exposure precautions) for measles/rubella/mumps/yellow-fever risk.
  • No approved gene therapy, cell therapy, or receptor-reconstitution therapy exists for this condition in humans; Duncan et al. (2015) demonstrated experimental reconstitution of patient cells with wild-type IFNAR2 in vitro restores antiviral responsiveness, establishing proof-of-concept for a gene-replacement approach, but this remains a research-only finding, not a clinical therapy (NCIT:C15238 Gene Therapy would be the relevant NCIT term for any future translational approach).
  • Hematopoietic stem cell transplantation (HSCT) has been used for other severe inborn errors of type I IFN immunity/HLH-associated primary immunodeficiencies in general practice, though it was not specifically reported as used in the identified IFNAR2 case reports; it represents a plausible but unconfirmed option for refractory/recurrent cases (NCIT:C15431 Hematopoietic Cell Transplantation).
  • Genetic counseling (NCIT:C15240) is indicated for families, especially in founder populations, given the autosomal recessive inheritance and the severity of the phenotype.

13. Prevention

  • Primary prevention: The principal actionable primary-prevention strategy identified in the literature is avoidance of live-attenuated viral vaccines (MMR, yellow fever) in known or suspected IFNAR2-deficient individuals — analogous published guidance exists for IFNAR1 deficiency ("Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania").
  • Pre-vaccination genetic screening in high-risk founder populations (Arctic Inuit communities carrying p.Ser53Pro) has been explicitly proposed by the primary literature as a means to identify at-risk infants before routine MMR administration.
  • Secondary prevention: Early recognition of post-vaccination or post-infection fever/lethargy/rash in at-risk families, with rapid clinical evaluation for encephalitis/HLH, to enable prompt immunomodulatory treatment.
  • Genetic counseling for families of affected individuals and for carrier identification in founder populations.
  • No vaccine (for the disease itself, obviously not applicable) or chemoprophylactic agent exists; general public-health measures (standard infection control) apply but are not disease-specific.

14. Other Species / Natural Disease

  • No naturally occurring veterinary/companion-animal disease analog of IFNAR2 deficiency has been identified in the literature reviewed (no OMIA entries surfaced in this search).
  • Orthology: Mouse ortholog Ifnar2 (MGI:1098243), located on mouse chromosome 16, is the standard model-organism counterpart used extensively in engineered (not naturally occurring) knockout studies (see Model Organisms, below).
  • Comparative biology: The IFNAR1/IFNAR2 receptor system and downstream JAK-STAT (ISGF3) signaling pathway is deeply conserved across mammals, supporting strong translational relevance of mouse knockout data, though mice differ from humans in interferon subtype repertoire and some aspects of receptor biology.

15. Model Organisms

  • Ifnar2 knockout mice (Ifnar2⁻/⁻) are a long-established and widely used model (MGI:1098243; e.g., commercially available strains such as Cyagen's C57BL/6NCya-Ifnar2^em1/Cya). Reported phenotypes include:
  • Defects in NK cell, CD4+ and CD8+ T cell, and B cell responses to induced/transplanted tumors, viruses, and dsDNA challenge.
  • Diminished secretion of both type I and (secondarily) type II interferons.
  • Altered/differential susceptibility to post-influenza bacterial superinfection compared with Ifnar1⁻/⁻ mice, indicating that despite forming an obligate heterodimer, the two receptor chains are not perfectly functionally redundant in every downstream context — a nuance relevant to interpreting human IFNAR1 vs. IFNAR2 deficiency phenotypic overlap/differences.
  • Broadly recapitulates loss of antiviral, antiproliferative, antiangiogenic, and immunomodulatory type-I-IFN-dependent responses.
  • Humanized IFNAR mouse models: an "extracellular humanized IFNAR immunocompetent mouse model" has been developed for analysis of human IFN-α and its subtypes (PMID:37994664; PMC10810641), useful for testing human-specific interferon pharmacology and potentially for future receptor-reconstitution/gene-therapy proof-of-concept work.
  • Ifnar1⁻/Ifnar2⁻ double and single knockouts are broadly used across virology as standard "type I IFN receptor knockout" models for high-consequence/BSL3-4 pathogens (e.g., flaviviruses, alphaviruses) precisely because they phenocopy the profound susceptibility to IFN-sensitive viruses seen in human patients — directly modeling the "increased vulnerability to multiple viruses" phenotype documented in human patient cells.
  • No induced/environmental (non-genetic) animal models specific to this disease were identified; all model-organism evidence is from targeted genetic (knockout/humanized) engineering, not spontaneous natural disease.

Summary of Key Primary Literature (PMIDs / DOIs)

Citation PMID / DOI Contribution
Duncan CJA et al., Sci Transl Med 2015;7(307):307ra154 DOI:10.1126/scitranslmed.aac4227 Index human IFNAR2 deficiency report; fatal post-MMR encephalitis; functional reconstitution rescue
Hernandez N et al., Front Genet 2020 PMID:33193576 Compound heterozygous frameshift variants; HLH post-MMR; detailed STAT1/ISG/NK functional workup; corticosteroid treatment and favorable outcome
Bastard P et al., J Exp Med 2022;219(6):e20212427 PMID:35442417 Arctic/Inuit founder variant p.Ser53Pro; 5 patients; population allele-frequency data; life-threatening COVID-19/influenza/vaccine-associated disease
Seizure–Eur J Epilepsy 2022 DOI:10.1016/j.seizure.2022.06.013 (S1059-1311(22)00175-3) Same founder variant; post-vaccination drug-resistant infantile epileptic spasms
J Clin Immunol 2024/2025;45:30 DOI:10.1007/s10875-024-01814-6 Homozygous VUS; severe post-measles-vaccine reaction with viremia/meningoencephalitis/multi-organ failure; literature review
Smieszek SP et al., EBioMedicine/PMC8279933, 2021 PMID:34273592 Rare/common LOF IFNAR2 variant burden association with severe COVID-19
Rodrigues Prestes TR et al. (or similar), Front Immunol 2022 PMID:35967349 Common IFNAR2 variants and soluble IFNAR2 levels associated with COVID-19 mortality
Bastard P et al. (yellow fever vaccine cohort) (French National Reference Center series; JEM-adjacent) IFNAR1/IFNAR2 deficiency and anti-IFN autoantibodies together account for >half of life-threatening yellow-fever-vaccine-associated disease

Note on curation caveats: OMIM phenotype MIM numbering for IMD45 should be independently confirmed directly at omim.org (this session's OMIM WebFetch calls failed due to a proxy connectivity error, so identifiers above rely on secondary-source search snippets and carry residual uncertainty — particularly the #614889 vs. #616669 MIM number discrepancy, which must be resolved against the primary OMIM record before being written into a knowledge-base entry). Similarly, several PMIDs above (e.g., for the Rockefeller J Exp Med Arctic paper, PMC9026249) were resolved via secondary aggregator search snippets rather than direct primary-source fetch; both should be verified against PubMed/PMC directly during KB curation, per this repository's evidence-verification workflow (just fetch-reference, just validate-kb-references).

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 1
Quoted claims not found in source 1
References weighed for topical relevance 13
On topic 10
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:35442417: "Autosomal recessive deficiency of the IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR2 deficiency in the Arctic."
  • closest text in source: "Patients with autosomal recessive (AR) deficiency of IFNAR2 and subsequently IFNAR1 were first recognized by their susceptibility to severe viral diseases precipitated by the exposure to live-attenuated viral vaccines (LAV)—specifically, the measles, mumps, and rubella (MMR) and yellow fever vaccines (Bastard et al., 2021b; Duncan et al., 2015; Gothe et al., 2020; Hernandez et al., 2019; Passarelli et al., 2020)"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 43
Resolved 39
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 3
Terms whose name was checked 28
Terms named correctly 20
Terms named as a different term 2
Terms whose name is worth a second look 6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0025143 (2 mentions) - the report calls it "Lethargy"; HP calls it Chills
  • HP:0025047 (1 mention) - the report calls it "Maculopapular rash"; HP calls it Abnormal brain choline level by MRS

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0002264 (1 mention) - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0002383 (1 mention) - the report calls it "Encephalitis"; HP calls it Infectious encephalitis
  • HP:0002718 (1 mention) - the report calls it "Recurrent infections"; HP calls it Recurrent bacterial infections, and lists "Recurrent pyogenic infections" among its other names
  • HP:0004429 (1 mention) - the report calls it "susceptibility to viral infections, if available in HPO"; HP calls it Recurrent viral infections
  • HP:0011024 (1 mention) - the report calls it "Abnormality of the gastrointestinal system"; HP calls it Abnormality of the gastrointestinal tract
  • HP:0011893 (1 mention) - the report calls it "Abnormal leukocyte count / cytopenias"; HP calls it Abnormal leukocyte count
  • GO:0005783 (1 mention) - the report calls it "endoplasmic reticulum, for the trafficking-defective mutant"; GO calls it endoplasmic reticulum

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MGI:1098243 - called "Ifnar2", "Orthology:* Mouse ortholog Ifnar2"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.