STAT2 Deficiency

Mendelian MONDO:0014715 Pathograph 6 Show in embeddings browser inborn error of immunity autosomal recessive disease

STAT2 deficiency (immunodeficiency 44; IMD44; OMIM 616636) is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in STAT2. STAT2 is an essential component of the ISGF3 transcription-factor complex (STAT1-STAT2-IRF9) that mediates type I (and type III) interferon signaling. Loss of STAT2 abolishes interferon-stimulated gene factor 3-dependent induction of antiviral interferon-stimulated genes, rendering cells permissive to viral replication. Affected individuals characteristically develop severe, sometimes fatal, viral illness, including disseminated disease after live attenuated viral vaccines (e.g., measles-mumps-rubella). Penetrance for severe infection is incomplete and the course of many common childhood viral infections is unexpectedly mild, reflecting redundancy of type I interferon for protective immunity to most viruses under natural conditions. A hyperinflammatory phenotype (hemophagocytic lymphohistiocytosis, MIS-C) has also been reported. Management is largely supportive, with immunoglobulin replacement and avoidance of live viral vaccines. A second kindred with autosomal recessive STAT2 deficiency and severe viral illness (compound heterozygous c.C1528T/c.G1576A) was reported by Moens et al (PMID:28087227); that JACI letter has no structured PubMed abstract, so claims here are corroborated with abstracted, snippet-validated sources.

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1
Inheritance
2
Pathophys.
4
Phenotypes
1
Hypotheses
6
Pathograph
1
Genes
2
Medical Actions
1
References
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
IUIS Category
innate immunity defect
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:23391734 SUPPORT Human Clinical
"Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells."
A homozygous STAT2 mutation segregating in a consanguineous kindred establishes the autosomal recessive basis of STAT2 deficiency.
◈

Mechanistic Hypotheses

1
Incomplete penetrance and type I IFN redundancy
incomplete_penetrance_model
Evidence balance 2 support
Although STAT2 is essential for type I interferon signaling in vitro, the clinical phenotype shows incomplete penetrance for severe viral infection and many common childhood viral illnesses run a mild course. This is interpreted as evidence that human type I interferons are more redundant for protective antiviral immunity under natural conditions than expected, with type I IFN-independent mechanisms of cell-intrinsic antiviral immunity compensating in most infections.
Show evidence (2 references)
PMID:23391734 SUPPORT Human Clinical
"surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities."
Documents the generally healthy interval course in surviving patients, the clinical basis for the type I IFN redundancy hypothesis.
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."
Review across IFNAR1/2, STAT1, STAT2, and IRF9 deficiencies supports greater-than-anticipated redundancy of human type I IFNs for antiviral protection.
⚙

Pathophysiology

2
Defective Type I Interferon (ISGF3) Signaling
STAT2 is a required subunit of the heterotrimeric ISGF3 complex (STAT1-STAT2-IRF9) assembled downstream of the type I interferon receptor. Biallelic loss-of-function STAT2 variants abolish or cripple STAT2 protein expression and prevent ISGF3-dependent transcription, so type I interferon (IFN-alpha/beta) fails to induce its antiviral interferon-stimulated genes (e.g., MxA, ISG15, OAS1). Because type III interferon (IFN-lambda) signals through the same ISGF3 module, the mucosal IFN-lambda arm is likely impaired as well, whereas STAT1-dependent type II (IFN-gamma/GAF) signaling remains intact - distinguishing STAT2 deficiency from the broader STAT1 deficiency phenotype that also includes mycobacterial susceptibility.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Type I interferon signaling GO:0060337 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Type I interferon signaling, annotated with type I interferon-mediated signaling pathway (GO:0060337). GO:0060337 is a biological process from the Gene Ontology. Cellular response to type I interferon GO:0071357 ↓ DECREASED 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. Antiviral defense response GO:0051607 ↓ DECREASED 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.
Downstream
Permissiveness to Viral Replication Failure of ISGF3-dependent interferon-stimulated gene induction leaves cells unable to establish a type I interferon antiviral state, permitting unchecked viral replication.
Show evidence (2 references)
PMID:23391734 SUPPORT Human Clinical
"Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein."
Directly demonstrates that STAT2 loss abolishes type I interferon signaling and produces a cell-intrinsic defect permitting viral replication.
PMID:37074537 SUPPORT Human Clinical
"Functional studies showed an impaired IFN-I-induced response and a defective IFNα expression at later stages of STAT2 pathway induction."
Confirms in an independent patient that complete STAT2 deficiency impairs the type I interferon-induced response.
Permissiveness to Viral Replication
Without an inducible type I interferon antiviral program, host cells cannot restrict viral replication. Clinically this manifests as severe viral illness and, characteristically, disseminated disease following live attenuated viral vaccines such as measles-mumps-rubella. The defect is cell-intrinsic and reproducible in patient fibroblasts, which fail to be protected by exogenous IFN-alpha (but remain responsive to IFN-gamma).
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Viral defense failure GO:0051607 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Viral defense failure, annotated with defense response to virus (GO:0051607). GO:0051607 is a biological process from the Gene Ontology.
Downstream
Severe and recurrent viral infections Without ISGF3-driven interferon-stimulated gene induction, ordinary childhood viruses replicate unchecked, so infections that are self-limiting in an immunocompetent host become severe and sometimes life-threatening from infancy.
Recurrent viral infections Recurrence is a separate claim from severity and is curated separately: the defect is cell-intrinsic and permanent, so each new exposure meets the same absent antiviral response rather than an immunity built by the last one. The two phenotypes carry different HPO terms (HP:0031691 and HP:0004429) and different sources.
Disseminated infection with live viral vaccine The hallmark presentation, and the sharpest demonstration of the mechanism: an attenuated vaccine strain is attenuated only relative to a host that can mount a type I interferon response. Classically vaccine-strain measles after MMR.
Hemophagocytic lymphohistiocytosis A hyperinflammatory arm reported in this disease, drawn from the viral replication node because uncontrolled viral antigen load is the usual trigger for HLH. The intermediates are not established in STAT2 deficiency specifically, and the reports are single cases.
Show evidence (1 reference)
PMID:23391734 SUPPORT Human Clinical
"the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection."
Illustrates the severe viral illness phenotype, including disseminated live vaccine-strain measles, that follows from failed cell-intrinsic antiviral immunity.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for STAT2 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

4
Blood 1
Hemophagocytic lymphohistiocytosis 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.
Show evidence (1 reference)
PMID:37074537 SUPPORT Human Clinical
"a novel case of complete deficiency of STAT2 in a 3-year-old child that presented with typical features of HLH after mumps, measles, and rubella vaccination at the age of 12 months."
Reports HLH (with subsequent MIS-C) in a child with complete STAT2 deficiency following MMR vaccination.
Immune 3
Severe and recurrent viral infections 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:23391734 SUPPORT Human Clinical
"the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection."
Reports severe and fatal viral illness in STAT2-deficient siblings.
Recurrent viral infections HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
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."
Establishes the type I IFN deficiency context (including STAT2) in which recurrent/severe viral infections arise, while noting variable penetrance.
Disseminated infection with live viral vaccine 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 (1 reference)
PMID:23391734 SUPPORT Human Clinical
"the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection."
Documents disseminated vaccine-strain measles after routine MMR immunization, the characteristic live-vaccine complication of STAT2 deficiency.
🧬

Genetic Associations

1
STAT2 (Causal)
Gene: STAT2 hgnc:11363 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT2 (hgnc:11363). hgnc:11363 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:23391734 SUPPORT Human Clinical
"Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells."
Identifies a homozygous splice-disrupting STAT2 mutation as the molecular cause in the founder kindred.
💊

Medical Actions

2
Immunoglobulin Replacement Therapy
Action: Intravenous immunoglobulin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Intravenous immunoglobulin therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
Immunoglobulin replacement (including high-dose intravenous immunoglobulin during severe infectious episodes) has been used to provide passive immunity and anti-inflammatory effect in STAT2-deficient patients, particularly in childhood before the adaptive immune system has matured.
Avoidance of Live Attenuated Viral Vaccines
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
Because live attenuated viral vaccines (e.g., measles-mumps-rubella) can cause disseminated vaccine-strain infection in STAT2 deficiency, such vaccines should be avoided; this is a key agents/circumstances-to-avoid consideration once the diagnosis is known.
{ }

Source YAML

click to show 
name: STAT2 Deficiency
creation_date: "2026-06-27T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: STAT2 deficiency
  term:
    id: MONDO:0014715
    label: primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection
parents:
  - inborn error of immunity
  - autosomal recessive disease
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Placed with the immune disorders: a Mendelian inborn error of type I
      (and type III) interferon immunity whose clinical burden is infection
      susceptibility, following the placement of the sibling ISGF3 defect
      entry (IRF9 deficiency) and of IMD101, which reaches the same
      interferon axis from upstream — POLR3F is a subunit of RNA polymerase III,
      the cytosolic AT-rich viral DNA sensor that drives interferon induction,
      not a component of ISGF3.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A biallelic Mendelian disorder of a single gene (STAT2), so it also
      belongs in Harrison's genetics Part.
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS 2022 phenotypic classification Table 6 (defects in intrinsic and
      innate immunity), section 3 (Predisposition to Severe Viral Infection):
      the "STAT2 deficiency" row (STAT2, AR, OMIM column 600556 - the STAT2
      gene record), with severe viral infections including disseminated
      vaccine-strain measles as the associated feature.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "STAT2 deficiency STAT2 AR 600556"
      explanation: >-
        The STAT2 row of IUIS 2022 Table 6, section 3 (Predisposition to
        Severe Viral Infection). Quoted at the row-identity fragment because
        the typeset table text merges the affected-cells and affected-function
        columns mid-word immediately after it ("cellsS TAT2-dependent"),
        corrupting the remainder of the row.
references:
  - reference: PMID:28087227
    title: "A novel kindred with inherited STAT2 deficiency and severe viral illness."
description: >
  STAT2 deficiency (immunodeficiency 44; IMD44; OMIM 616636) is an autosomal
  recessive inborn error of immunity caused by biallelic loss-of-function
  variants in STAT2. STAT2 is an essential component of the ISGF3
  transcription-factor complex (STAT1-STAT2-IRF9) that mediates type I (and
  type III) interferon signaling. Loss of STAT2 abolishes interferon-stimulated
  gene factor 3-dependent induction of antiviral interferon-stimulated genes,
  rendering cells permissive to viral replication. Affected individuals
  characteristically develop severe, sometimes fatal, viral illness, including
  disseminated disease after live attenuated viral vaccines (e.g.,
  measles-mumps-rubella). Penetrance for severe infection is incomplete and the
  course of many common childhood viral infections is unexpectedly mild,
  reflecting redundancy of type I interferon for protective immunity to most
  viruses under natural conditions. A hyperinflammatory phenotype (hemophagocytic
  lymphohistiocytosis, MIS-C) has also been reported. Management is largely
  supportive, with immunoglobulin replacement and avoidance of live viral
  vaccines. A second kindred with autosomal recessive STAT2 deficiency and
  severe viral illness (compound heterozygous c.C1528T/c.G1576A) was reported by
  Moens et al (PMID:28087227); that JACI letter has no structured PubMed
  abstract, so claims here are corroborated with abstracted, snippet-validated
  sources.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23391734
    reference_title: "STAT2 deficiency and susceptibility to viral illness in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells."
    explanation: A homozygous STAT2 mutation segregating in a consanguineous kindred establishes the autosomal recessive basis of STAT2 deficiency.
pathophysiology:
- name: Defective Type I Interferon (ISGF3) Signaling
  description: >
    STAT2 is a required subunit of the heterotrimeric ISGF3 complex
    (STAT1-STAT2-IRF9) assembled downstream of the type I interferon receptor.
    Biallelic loss-of-function STAT2 variants abolish or cripple STAT2 protein
    expression and prevent ISGF3-dependent transcription, so type I
    interferon (IFN-alpha/beta) fails to induce its antiviral
    interferon-stimulated genes (e.g., MxA, ISG15, OAS1). Because type III
    interferon (IFN-lambda) signals through the same ISGF3 module, the mucosal
    IFN-lambda arm is likely impaired as well, whereas STAT1-dependent type II
    (IFN-gamma/GAF) signaling remains intact - distinguishing STAT2 deficiency
    from the broader STAT1 deficiency phenotype that also includes mycobacterial
    susceptibility.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Type I interferon 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
  - preferred_term: Antiviral defense response
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  downstream:
  - target: Permissiveness to Viral Replication
    causal_link_type: DIRECT
    description: >
      Failure of ISGF3-dependent interferon-stimulated gene induction leaves
      cells unable to establish a type I interferon antiviral state, permitting
      unchecked viral replication.
  evidence:
  - reference: PMID:23391734
    reference_title: "STAT2 deficiency and susceptibility to viral illness in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein."
    explanation: Directly demonstrates that STAT2 loss abolishes type I interferon signaling and produces a cell-intrinsic defect permitting viral replication.
  - reference: PMID:37074537
    reference_title: "Inborn Error of STAT2-Dependent IFN-I Immunity in a Patient Presented with Hemophagocytic Lymphohistiocytosis and Multisystem Inflammatory Syndrome in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional studies showed an impaired IFN-I-induced response and a defective IFNα expression at later stages of STAT2 pathway induction."
    explanation: Confirms in an independent patient that complete STAT2 deficiency impairs the type I interferon-induced response.
- name: Permissiveness to Viral Replication
  description: >
    Without an inducible type I interferon antiviral program, host cells cannot
    restrict viral replication. Clinically this manifests as severe viral
    illness and, characteristically, disseminated disease following live
    attenuated viral vaccines such as measles-mumps-rubella. The defect is
    cell-intrinsic and reproducible in patient fibroblasts, which fail to be
    protected by exogenous IFN-alpha (but remain responsive to IFN-gamma).
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Viral defense failure
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  evidence:
  - reference: PMID:23391734
    reference_title: "STAT2 deficiency and susceptibility to viral illness in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection."
    explanation: Illustrates the severe viral illness phenotype, including disseminated live vaccine-strain measles, that follows from failed cell-intrinsic antiviral immunity.
  downstream:
  - target: Severe and recurrent viral infections
    causal_link_type: DIRECT
    description: >-
      Without ISGF3-driven interferon-stimulated gene induction, ordinary
      childhood viruses replicate unchecked, so infections that are
      self-limiting in an immunocompetent host become severe and sometimes
      life-threatening from infancy.
  - target: Recurrent viral infections
    causal_link_type: DIRECT
    description: >-
      Recurrence is a separate claim from severity and is curated separately:
      the defect is cell-intrinsic and permanent, so each new exposure meets
      the same absent antiviral response rather than an immunity built by the
      last one. The two phenotypes carry different HPO terms (HP:0031691 and
      HP:0004429) and different sources.
  - target: Disseminated infection with live viral vaccine
    causal_link_type: DIRECT
    description: >-
      The hallmark presentation, and the sharpest demonstration of the
      mechanism: an attenuated vaccine strain is attenuated only relative to a
      host that can mount a type I interferon response. Classically
      vaccine-strain measles after MMR.
  - target: Hemophagocytic lymphohistiocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A hyperinflammatory arm reported in this disease, drawn from the viral
      replication node because uncontrolled viral antigen load is the usual
      trigger for HLH. The intermediates are not established in STAT2
      deficiency specifically, and the reports are single cases.
mechanistic_hypotheses:
- hypothesis_group_id: incomplete_penetrance_model
  hypothesis_label: Incomplete penetrance and type I IFN redundancy
  description: >
    Although STAT2 is essential for type I interferon signaling in vitro, the
    clinical phenotype shows incomplete penetrance for severe viral infection
    and many common childhood viral illnesses run a mild course. This is
    interpreted as evidence that human type I interferons are more redundant for
    protective antiviral immunity under natural conditions than expected, with
    type I IFN-independent mechanisms of cell-intrinsic antiviral immunity
    compensating in most infections.
  evidence:
  - reference: PMID:23391734
    reference_title: "STAT2 deficiency and susceptibility to viral illness in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities."
    explanation: Documents the generally healthy interval course in surviving patients, the clinical basis for the type I IFN redundancy hypothesis.
  - 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: Review across IFNAR1/2, STAT1, STAT2, and IRF9 deficiencies supports greater-than-anticipated redundancy of human type I IFNs for antiviral protection.
phenotypes:
- category: Immunological
  name: Severe and recurrent viral infections
  description: >
    Affected individuals are predisposed to severe, sometimes life-threatening,
    viral infections from infancy, which may be recurrent and require repeated
    hospitalization.
  phenotype_term:
    preferred_term: Severe viral infection
    term:
      id: HP:0031691
      label: Severe viral infection
  evidence:
  - reference: PMID:23391734
    reference_title: "STAT2 deficiency and susceptibility to viral illness in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection."
    explanation: Reports severe and fatal viral illness in STAT2-deficient siblings.
- category: Immunological
  name: Recurrent viral infections
  description: >
    Recurrent viral infections occur as a consequence of the cell-intrinsic
    type I interferon signaling defect.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - 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: Establishes the type I IFN deficiency context (including STAT2) in which recurrent/severe viral infections arise, while noting variable penetrance.
- category: Immunological
  name: Disseminated infection with live viral vaccine
  description: >
    A hallmark presentation is disseminated infection after live attenuated
    viral vaccination, classically vaccine-strain measles following
    measles-mumps-rubella immunization.
  phenotype_term:
    preferred_term: Disseminated infection with live vaccine virus
    term:
      id: HP:0031697
      label: Disseminated infection with live vaccine virus
  evidence:
  - reference: PMID:23391734
    reference_title: "STAT2 deficiency and susceptibility to viral illness in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection."
    explanation: Documents disseminated vaccine-strain measles after routine MMR immunization, the characteristic live-vaccine complication of STAT2 deficiency.
- category: Immunological
  name: Hemophagocytic lymphohistiocytosis
  description: >
    A hyperinflammatory phenotype, including hemophagocytic lymphohistiocytosis
    (HLH) and multisystem inflammatory syndrome in children (MIS-C), has been
    reported in complete STAT2 deficiency, implicating dysregulated interferon
    biology in hyperinflammation as well as antiviral defense.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:37074537
    reference_title: "Inborn Error of STAT2-Dependent IFN-I Immunity in a Patient Presented with Hemophagocytic Lymphohistiocytosis and Multisystem Inflammatory Syndrome in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel case of complete deficiency of STAT2 in a 3-year-old child that presented with typical features of HLH after mumps, measles, and rubella vaccination at the age of 12 months."
    explanation: Reports HLH (with subsequent MIS-C) in a child with complete STAT2 deficiency following MMR vaccination.
genetic:
- name: STAT2
  association: Causal
  gene_term:
    preferred_term: STAT2
    term:
      id: hgnc:11363
      label: STAT2
  notes: >
    Biallelic loss-of-function STAT2 variants cause this autosomal recessive
    disease. Reported lesions include a homozygous intron 4 splice-disrupting
    mutation (Hambleton et al) and compound heterozygous c.C1528T (p.R510X,
    nonsense-mediated decay) plus c.G1576A splice variants (Moens et al kindred).
    STAT1-dependent type II interferon signaling is preserved.
  evidence:
  - reference: PMID:23391734
    reference_title: "STAT2 deficiency and susceptibility to viral illness in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells."
    explanation: Identifies a homozygous splice-disrupting STAT2 mutation as the molecular cause in the founder kindred.
treatments:
- name: Immunoglobulin Replacement Therapy
  description: >
    Immunoglobulin replacement (including high-dose intravenous immunoglobulin
    during severe infectious episodes) has been used to provide passive
    immunity and anti-inflammatory effect in STAT2-deficient patients,
    particularly in childhood before the adaptive immune system has matured.
  treatment_term:
    preferred_term: Intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
- name: Avoidance of Live Attenuated Viral Vaccines
  description: >
    Because live attenuated viral vaccines (e.g., measles-mumps-rubella) can
    cause disseminated vaccine-strain infection in STAT2 deficiency, such
    vaccines should be avoided; this is a key agents/circumstances-to-avoid
    consideration once the diagnosis is known.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
📚

References & Deep Research

References

1
PMID:28087227
A novel kindred with inherited STAT2 deficiency and severe viral illness.
No top-level findings curated for this source.