Immunodeficiency 67

Mendelian MONDO:0011888 Pathograph 19 Show in embeddings browser

Immunodeficiency 67 is IRAK-4 deficiency: an autosomal recessive inborn error of innate immunity caused by biallelic loss-of-function variants in IRAK4, which encodes interleukin-1 receptor-associated kinase 4, the kinase recruited immediately downstream of the adaptor MyD88 in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family signaling. Without functional IRAK-4, cells cannot transduce signals from the MyD88-dependent TLRs (all TLRs except TLR3) and from the IL-1R family, so they fail to activate NF-kappaB and MAPK and do not mount the proinflammatory cytokine response that normally follows detection of a pyogenic organism. The clinical consequence is a strikingly narrow susceptibility. Affected children suffer invasive, life-threatening infection with a small set of pyogenic bacteria - above all Streptococcus pneumoniae, and to a lesser extent Staphylococcus aureus and Pseudomonas aeruginosa - while resistance to fungi, parasites and most other bacteria is essentially intact. This redundancy is the finding the disease exists to demonstrate: the TIR-IRAK pathway turns out to be crucial for immunity to a few bacteria and dispensable against nearly everything else. The one recognized qualification to the "antiviral immunity preserved" rule is TLR7: because TLR7-dependent type I interferon production by plasmacytoid dendritic cells is MyD88- and IRAK-4-dependent, these patients are also at high risk of severe, hypoxemic SARS-CoV-2 pneumonia. Two features make the disease dangerous out of proportion to its narrow spectrum. First, the inflammatory response to infection is characteristically weak or delayed - fever and acute-phase signs are often blunted - so severe invasive disease can advance with deceptively few warning signs. Second, susceptibility is age-dependent: the risk of invasive infection is concentrated in infancy and early childhood and falls sharply with age, so that with prophylaxis most survivors improve markedly in adolescence. IRAK-4 deficiency is clinically and immunologically indistinguishable from MyD88 deficiency (immunodeficiency 68), which lies one step upstream in the same pathway; the two are curated as distinct entities rather than as subtypes of one another.

Ask OpenScientist

Ask a research question about Immunodeficiency 67. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

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

1
Inheritance
8
Pathophys.
10
Phenotypes
2
Gaps
19
Pathograph
1
Genes
2
Variants
3
Medical Actions
1
Models
6
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic loss-of-function IRAK4 variants; heterozygous carriers are healthy. The defect and its inheritance are shared with MyD88 deficiency, the adjacent step in the same signaling pathway.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:21057262 SUPPORT Human Clinical
"Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity."
States the autosomal recessive inheritance and the impaired TLR/IL-1R immunity that defines the disease.
?

Discussions and Knowledge Gaps

2
Why does susceptibility to invasive pyogenic infection in IRAK-4 deficiency wane sharply with age despite a persistent, lifelong signaling defect?
KNOWLEDGE GAP OPEN age_dependent_improvement
Attached to
pathophysiology#Invasive Pyogenic Bacterial Infection
Invasive infection and death are concentrated in early childhood: no death and no invasive infection were reported after the ages of 8 and 14 years, respectively, in the two largest cohorts. The IRAK-4 signaling defect is constitutive and does not resolve, so the improvement is presumed to reflect maturation of adaptive immunity and acquisition of protective antibody with age rather than any change in the innate lesion. The precise mechanism of the age-dependent narrowing is not established, which is why it is recorded as a knowledge gap. The improvement is also not absolute: fatal breakthrough pneumococcal meningitis has been reported at age 7 in a prophylaxed, vaccinated child, driven by an antibiotic-resistant serotype.
Show evidence (2 references)
PMID:17893200 SUPPORT Human Clinical
"No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively."
Documents the age-dependent fall in invasive infection and death that motivates this knowledge gap.
PMID:24596024 SUPPORT Human Clinical
"even older IRAK-4-deficient patients are at high risk of rapidly fatal infection due to emergence of antibiotic resistance."
Qualifies the age-dependent improvement - a fatal infection still occurred at age 7 despite prophylaxis and vaccination, so the improvement is not absolute.
Why do MyD88/IRAK-4-deficient mice show broad susceptibility to viruses, intracellular bacteria, and fungi, whereas human IRAK-4 deficiency produces only a narrow, largely age-limited susceptibility to pyogenic bacteria?
HUMAN MODEL MISMATCH OPEN mouse_broad_vs_human_narrow_susceptibility
Attached to
pathophysiology#Impaired Inflammatory Response to Pyogenic Bacteria pathophysiology#Invasive Pyogenic Bacterial Infection
The murine knockout recapitulates the Gram-positive pyogenic susceptibility of the human disease but not its restriction: MyD88-deficient mice are susceptible to a wide range of viral, intracellular bacterial, and fungal pathogens that do not define human IRAK-4 deficiency. The open translational question is why the same MyD88-dependent pathway lesion yields a far broader infectious phenotype in mice than in humans - i.e. why the human pathway is so much more redundant for antiviral, antifungal, and intracellular bacterial immunity. An explicit caveat: much of the broad-susceptibility evidence comes from MyD88-deficient rather than IRAK4-deficient mice, so the discordance is a property of the shared pathway and is not established for the IRAK-4 knockout in isolation.
Show evidence (2 references)
PMID:17893200 SUPPORT Model Organism
"The susceptibility of IRAK-4–deficient patients to S. aureus is consistent with that observed in IRAK-4– and MyD88-deficient mice (31, 43)."
The concordant arm - human and mouse agree on Gram-positive pyogenic susceptibility, which is what makes the broader murine phenotype a genuine mismatch.
PMID:17893200 SUPPORT Model Organism
"In contrast, MyD88-deficient mice were found to be susceptible to mouse CMV (47), HSV-1(48), Listeria monocytogenes (49, 50), Mycobacterium avium (51), Toxoplasma gondii (52), Cryptococcus neoformans (53), Candida albicans, and Aspergillus fumigatus (54), among other relevant infections"
Documents the broad murine susceptibility that the narrow human phenotype does not reproduce, the substance of the mismatch.
⚙

Pathophysiology

8
IRAK4 Loss of Function
Mechanism confidence: Established
Biallelic loss-of-function IRAK4 variants eliminate functional IRAK-4 kinase. IRAK-4 is the first kinase recruited to the MyD88 adaptor to form the Myddosome, so its loss removes the proximal signaling node shared by the MyD88-dependent TLRs and the IL-1R family.
Genetic context IRAK4 hgnc:17967 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns IRAK4 (hgnc:17967). hgnc:17967 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Germline biallelic null/loss-of-function IRAK4 variants (nonsense, frameshift, splice) abolishing IRAK-4 kinase activity.
Downstream
Impaired MyD88-Dependent TLR and IL-1R Signaling Loss of the proximal Myddosome kinase directly abolishes signal transduction through the MyD88-dependent TLRs and the IL-1R family.
Show evidence (2 references)
PMID:12637671 SUPPORT Human Clinical
"We describe three unrelated children with inherited IRAK-4 deficiency."
Identifies inherited IRAK-4 deficiency as the molecular lesion in the index patients.
PMID:30679311 SUPPORT In Vitro
"Upon ligand binding and via its N-terminal death domain, IRAK4 is recruited to an oligomeric receptor that is proximal to the Myddosome signaling complex, inducing IRAK4 kinase domain dimerization, autophosphorylation, and activation."
Structural work establishing IRAK-4 as the proximal Myddosome kinase whose recruitment, dimerization and autophosphorylation are lost when the kinase is absent.
Impaired MyD88-Dependent TLR and IL-1R Signaling
Mechanism confidence: Established
Cells cannot transduce signals through the MyD88-dependent Toll-like receptors (all TLRs except TLR3) or the IL-1R family. The TLR3 and TLR4-interferon-alpha/beta arms, which do not require IRAK-4, are spared, so most antiviral immunity is preserved. The important exception is TLR7, an endosomal single-stranded-RNA sensor that is itself MyD88- and IRAK-4-dependent: its signaling is lost, which underlies the recently recognized susceptibility to severe viral pneumonia (see the TLR7 branch below).
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology. dendritic cell CL:0000451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dendritic cell (CL:0000451). CL:0000451 is a cell type from the Cell Ontology.
MyD88-dependent toll-like receptor signaling pathway GO:0002755 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves MyD88-dependent toll-like receptor signaling pathway (GO:0002755), qualified as loss of function. GO:0002755 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION interleukin-1-mediated signaling pathway GO:0070498 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves interleukin-1-mediated signaling pathway (GO:0070498), qualified as loss of function. GO:0070498 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Defective NF-kappaB and MAPK Activation MyD88-dependent TLR/IL-1R signaling normally converges on NF-kB and MAPK activation, which cannot occur without the proximal IRAK-4 step.
Impaired TLR7-Dependent Type I Interferon Production TLR7 is a MyD88- and IRAK-4-dependent endosomal RNA sensor, so its type I interferon output in plasmacytoid dendritic cells is lost along with the other MyD88-dependent TLRs.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- and TLR4-interferon (IFN)-alpha/beta pathways."
States that IRAK-4 deficiency impairs Toll/IL-1R signaling while sparing the TLR3 and TLR4-IFN pathways.
Defective NF-kappaB and MAPK Activation
Mechanism confidence: Established
Patient blood and fibroblast cells fail to activate NF-kappaB and MAPK in response to MyD88-dependent TLR and IL-1R agonists.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. ↓ DECREASED MAPK cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Blunted Proinflammatory Cytokine Production NF-kB and MAPK drive transcription of proinflammatory cytokines; without their activation the cytokine response is not induced.
Show evidence (1 reference)
PMID:12637671 SUPPORT Human Clinical
"Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors."
Directly documents the failure of NF-kB and MAPK activation downstream of TIR-bearing receptors in patient cells.
Blunted Proinflammatory Cytokine Production
Mechanism confidence: Established
Patient leukocytes do not induce the proinflammatory cytokines normally produced on TLR/IL-1R stimulation. Ku et al. found that peripheral blood mononuclear cells failed to induce 11 non-interferon cytokines on activation with TLR agonists other than the TLR3-specific poly(I:C).
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology. leukocyte CL:0000738 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves leukocyte (CL:0000738). CL:0000738 is a cell type from the Cell Ontology.
positive regulation of cytokine production GO:0001819 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of cytokine production (GO:0001819). GO:0001819 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Inflammatory Response to Pyogenic Bacteria Loss of the proinflammatory cytokine burst cripples the acute innate inflammatory and antibacterial response to pyogenic organisms.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C)."
Documents the failure to produce proinflammatory cytokines in response to MyD88-dependent TLR agonists while the TLR3 response is retained.
Impaired Inflammatory Response to Pyogenic Bacteria
Mechanism confidence: Established
Without cytokine-driven inflammation the host cannot contain invasive pyogenic bacteria, and the systemic signs that normally flag infection are weak or delayed. The susceptibility is narrow: viral, fungal and parasitic defenses are intact and most bacteria are handled normally.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Invasive Pyogenic Bacterial Infection Failure to mount protective inflammation permits invasive infection by pyogenic bacteria.
Weak or Delayed Systemic Inflammation The same cytokine deficit blunts fever and the acute-phase response, so systemic signs of infection are attenuated.
Show evidence (1 reference)
PMID:12637671 SUPPORT Human Clinical
"These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms."
States that the pathway is essential for protection against specific (pyogenic) bacteria and redundant otherwise, explaining the narrow susceptibility.
Invasive Pyogenic Bacterial Infection
Mechanism confidence: Established
The dominant clinical event is invasive infection with pyogenic bacteria, led by invasive pneumococcal disease and followed by Staphylococcus aureus and Pseudomonas aeruginosa. Infections are frequently recurrent and concentrated in infancy and early childhood.
Animal models
IRAK-4- and MyD88-deficient mice Mouse partially recapitulates Concordant with the human phenotype for Gram-positive pyogenic susceptibility, but discordant in scope: the mouse phenotype is far broader than the narrow, age-limited human susceptibility.
Downstream
Recurrent systemic pyogenic infections
Recurrent streptococcus pneumoniae infections
Recurrent Staphylococcus aureus infections
Sepsis
Meningitis
Show evidence (2 references)
PMID:21057262 SUPPORT Human Clinical
"The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%)."
Quantifies invasive pneumococcal disease as the leading invasive infection in the largest reported cohort.
PMID:17893200 SUPPORT Human Clinical
"Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%)."
Independent cohort confirming the high frequency and recurrence of invasive pneumococcal disease.
Weak or Delayed Systemic Inflammation
Mechanism confidence: Established
A clinically important and dangerous feature: fever and acute-phase signs of inflammation are characteristically weak or delayed, so severe invasive infection can progress with few warning signs.
Downstream
Decreased inflammatory response
Show evidence (2 references)
PMID:21057262 SUPPORT Human Clinical
"Systemic signs of inflammation were usually weak or delayed."
Documents the blunted systemic inflammatory response, the basis for this node and the associated diagnostic pitfall.
PMID:24596024 SUPPORT Human Clinical
"IRAK-4 deficiency causes IL-1R and TLR signaling failure, resulting in minimal clinical features despite invasive bacterial infection."
A case report reinforcing that invasive infection can proceed with minimal clinical signs, the danger that follows from the blunted inflammatory response.
Impaired TLR7-Dependent Type I Interferon Production
Mechanism confidence: Provisional
A recently recognized branch that qualifies the classic teaching that antiviral immunity is intact. TLR7 is a MyD88- and IRAK-4-dependent endosomal single-stranded-RNA sensor, so plasmacytoid dendritic cells cannot mount TLR7-driven type I interferon in response to SARS-CoV-2. The evidence comes from a combined cohort of autosomal recessive MyD88 or IRAK-4 deficiency, so the finding is attributed to the shared pathway rather than to IRAK-4 alone.
plasmacytoid dendritic cell CL:0000784 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasmacytoid dendritic cell (CL:0000784). CL:0000784 is a cell type from the Cell Ontology.
type I interferon production GO:0032606 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased type I interferon production (GO:0032606). GO:0032606 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Severe viral infection Loss of the pDC type I interferon response to SARS-CoV-2 predisposes to hypoxemic COVID-19 pneumonia.
Show evidence (1 reference)
PMID:36880831 SUPPORT Human Clinical
"The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly."
Attributes the SARS-CoV-2 susceptibility of these patients to loss of TLR7-dependent type I interferon production by plasmacytoid dendritic cells.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 67 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
Head and Neck 1
Recurrent bacterial upper respiratory tract infections FREQUENT HP:0031949 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial upper respiratory tract infections (HP:0031949). HP:0031949 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21057262 SUPPORT Human Clinical
"Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively."
Documents the high incidence of noninvasive upper-respiratory-tract infection in the largest cohort.
Immune 9
Recurrent systemic pyogenic infections HP:0005429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent systemic pyogenic infections (HP:0005429). HP:0005429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21057262 SUPPORT Human Clinical
"Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%)."
Quantifies the recurrence of invasive pyogenic infection in survivors.
Recurrent streptococcus pneumoniae infections HP:0005366 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent streptococcus pneumoniae infections (HP:0005366). HP:0005366 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%)."
Documents recurrent invasive pneumococcal disease as the dominant infection.
Recurrent Staphylococcus aureus infections HP:0002726 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent Staphylococcus aureus infections (HP:0002726). HP:0002726 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%)."
Reports severe staphylococcal disease as the main infection outside pneumococcus.
Recurrent Pseudomonas aeruginosa infection FREQUENT HP:5210057 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent Pseudomonas aeruginosa infection (HP:5210057). HP:5210057 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21057262 SUPPORT Human Clinical
"Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively."
Identifies Pseudomonas aeruginosa as the leading cause of the frequent noninvasive upper-respiratory-tract infections.
PMID:21057262 SUPPORT Human Clinical
"P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively)."
Quantifies invasive Pseudomonas aeruginosa infection, confirming it is not confined to the noninvasive tier.
Recurrent bacterial skin infections FREQUENT HP:0005406 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial skin infections (HP:0005406). HP:0005406 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21057262 SUPPORT Human Clinical
"Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively."
Documents the high incidence of noninvasive skin infection, chiefly staphylococcal.
PMID:17893200 SUPPORT Human Clinical
"If we also take into account peripheral staphylococcal disease (cellulitis and subcutaneous abscess), 14 patients could be considered particularly susceptible to S. aureus"
Quantifies the staphylococcal skin/soft-tissue burden (cellulitis and subcutaneous abscess) in the Ku cohort.
Sepsis HP:0100806 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis (HP:0100806). HP:0100806 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"22 out of the 28 (79%) had had invasive disease caused by S. pneumoniae (meningitis, septicemia, or arthritis)"
Names septicemia as one of the invasive pneumococcal presentations documented in the cohort.
Meningitis HP:0001287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Meningitis (HP:0001287). HP:0001287 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"22 out of the 28 (79%) had had invasive disease caused by S. pneumoniae (meningitis, septicemia, or arthritis)"
Names meningitis explicitly as one of the invasive pneumococcal presentations documented in the cohort.
Decreased inflammatory response HP:0012648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased inflammatory response (HP:0012648). HP:0012648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21057262 SUPPORT Human Clinical
"Systemic signs of inflammation were usually weak or delayed."
Directly reports the blunted systemic inflammatory response.
Severe viral infection OCCASIONAL 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:36880831 SUPPORT Human Clinical
"Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia."
Documents severe viral (COVID-19) pneumonia as a susceptibility of these patients, revising the bacterial-only picture.
🧬

Genetic Associations

1
IRAK4 (IRAK4 encodes interleukin-1 receptor-associated kinase 4, the proximal serine/threonine kinase of the Myddosome that assembles on MyD88 after a MyD88-dependent TLR or an IL-1R family receptor is engaged. Reported disease alleles are germline biallelic loss-of-function variants (nonsense, frameshift and splice) that abolish kinase function, so the gene-disease relationship is recorded as causative with an autosomal recessive, loss-of-function mechanism.)
Gene: IRAK4 hgnc:17967 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IRAK4 (hgnc:17967). hgnc:17967 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:12637671 SUPPORT Human Clinical
"Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors."
Demonstrates that loss of IRAK-4 abolishes NF-kB/MAPK activation and cytokine induction downstream of TIR-bearing receptors, the functional basis of the gene-disease relationship.
Variants (2)
Biallelic loss-of-function IRAK4 variants Pathogenic
The reported alleles are germline null or loss-of-function variants (nonsense, frameshift, and splice-site) carried in the homozygous or compound-heterozygous state, abolishing IRAK-4 kinase activity and MyD88-dependent signaling.
Show evidence (1 reference)
PMID:12637671 SUPPORT Human Clinical
"We describe three unrelated children with inherited IRAK-4 deficiency."
Establishes inherited IRAK-4 deficiency as the cause in the founding patient series.
Q293X Pathogenic
A recurrent nonsense allele found in homozygotes from six kindreds and compound heterozygotes from four kindreds in the Ku cohort, its recurrence possibly reflecting a mutational hotspot, a founder effect, or both. Nomenclature follows the source (Q293X).
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"The Q293X mutant allele was found in homozygotes from six kindreds (C, H, K, P, Q, and R) and compound heterozygotes from four kindreds (B, D, M, and possibly F). The recurrence of this mutation may reflect a mutational hotspot, a founder effect, or both"
Documents Q293X as the recurrent IRAK4 allele in the reference cohort.
💊

Medical Actions

3
Antibiotic Prophylaxis
Action: antibiotic prophylaxisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic prophylaxis (NCIT:C51993). NCIT:C51993 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Prophylaxis NCIT:C51993
Agent: antibiotic NCIT:C258 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses antibiotic (NCIT:C258). NCIT:C258 is a therapeutic agent from the NCI Thesaurus.
Long-term antibacterial prophylaxis reduces the burden of invasive pyogenic infection and, together with vaccination and IgG replacement, had a beneficial impact through the vulnerable childhood years.
Show evidence (1 reference)
PMID:21057262 SUPPORT Human Clinical
"Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter."
Reports the beneficial impact of antibiotic prophylaxis during childhood.
Antipneumococcal Vaccination
Action: antipneumococcal vaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antipneumococcal vaccination, annotated with Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Vaccination against Streptococcus pneumoniae, the leading pathogen, is part of the preventive regimen used in the childhood risk window.
Show evidence (1 reference)
PMID:21057262 SUPPORT Human Clinical
"Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter."
Reports antipneumococcal vaccination as part of the beneficial preventive regimen.
Immunoglobulin Replacement
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
IgG infusion provides passive antibody and was part of the regimen with a beneficial impact on patients through the teenage years.
Show evidence (2 references)
PMID:21057262 SUPPORT Human Clinical
"Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter."
Reports IgG infusion as part of the beneficial preventive regimen.
PMID:24596024 SUPPORT Human Clinical
"long-term IgG prophylaxis in addition to antibiotics is recommended."
A case report recommending long-term IgG prophylaxis alongside antibiotics, motivated by a fatal breakthrough pneumococcal infection despite antibiotic prophylaxis and vaccination.
🔬

Diagnosis

3
Clinical recognition of recurrent invasive pyogenic infection with blunted inflammation
IRAK-4 deficiency is suspected in a child with recurrent or invasive infection by a narrow set of pyogenic bacteria - above all Streptococcus pneumoniae, and less often Staphylococcus aureus and Pseudomonas aeruginosa - in whom the systemic inflammatory response is characteristically weak or delayed. Poor or absent fever and low serum C-reactive protein during severe invasive infection are a recognized diagnostic pitfall that delays recognition, so empiric antibacterial treatment and urgent evaluation are advised whenever infection is suspected.
clinical recognition of recurrent invasive pyogenic infection
Markers: C-reactive protein (CRP), fever/body temperature, acute-phase response
Show evidence (3 references)
PMID:21057262 SUPPORT Human Clinical
"Systemic signs of inflammation were usually weak or delayed."
Documents the blunted systemic inflammatory response that is the central diagnostic pitfall when evaluating a suspected infection in these patients.
PMID:17893200 SUPPORT Human Clinical
"Moreover, most patients have weak or delayed acute inflammatory responses in vivo (low serum CrP levels in particular) (34, 71)."
Identifies low serum C-reactive protein as a specific in vivo marker of the blunted acute-phase response, so a normal CRP does not exclude invasive infection in these patients.
PMID:21057262 SUPPORT Human Clinical
"empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever."
States the clinical corollary of the diagnostic pitfall: because signs are blunted, even moderate fever warrants empiric treatment and urgent review.
Cellular responses to TLR and IL-1R agonists (functional immunology)
Functional testing of patient blood cells provides the immunological confirmation. Whole blood cells or peripheral blood mononuclear cells fail to produce the major proinflammatory cytokines (TNF-alpha, IL-6, IL-12) on stimulation with MyD88-dependent TLR agonists, and fail to secrete IL-6 in response to IL-1beta (and IFN-gamma in response to IL-18), reflecting the IRAK-4 block in MyD88-dependent signaling. The response to the TLR3-specific agonist poly(I:C) is spared, which distinguishes the pattern from a global signaling defect.
TLR and IL-1R agonist cellular stimulation assay
Markers: TNF-alpha, IL-6, IL-12 (whole blood / PBMC cytokine induction on TLR and IL-1R stimulation)
Show evidence (2 references)
PMID:17893200 SUPPORT In Vitro
"do not induce the production of major inflammatory cytokines (TNF-α, IL-6, and IL-12) and growth factors (G-CSF and GM-CSF) in whole blood cells and PBMCs"
The abolished proinflammatory cytokine response of whole blood cells and PBMCs to MyD88-dependent TLR agonists is the functional diagnostic readout.
PMID:17893200 SUPPORT In Vitro
"the patients' whole blood cells or PBMCs do not respond to IL-1β, in terms of IL-6 secretion"
The absent IL-6 response to IL-1beta demonstrates the parallel IL-1R-family arm of the functional assay used to confirm IRAK-4 deficiency.
IRAK4 gene sequencing
Molecular confirmation rests on identifying biallelic loss-of-function IRAK4 variants (nonsense, frameshift, splice-site, or deletion) by sequencing the IRAK4 coding exons and flanking regions, or by exome sequencing. The reported disease alleles are predicted null and are carried in the homozygous or compound-heterozygous state; where no material is available (for example, a deceased relative), the diagnosis may rest on clinical grounds instead.
IRAK4 sequencing
Results: Identifies biallelic loss-of-function IRAK4 variants
Show evidence (2 references)
PMID:17893200 SUPPORT Human Clinical
"All IRAK4 exons, flanking intron regions, and, when appropriate, entire introns, were sequenced in 24 patients"
Documents comprehensive IRAK4 sequencing as the molecular diagnostic method in the reference cohort.
PMID:17893200 SUPPORT Human Clinical
"owing to the inheritance of two loss-of-expression, loss-of-function IRAK4 alleles."
Confirms that the molecular diagnosis is biallelic loss-of-function IRAK4 alleles, the finding sequencing is used to establish.
📈

Progression

2
Early-onset invasive infection
Age: Onset in infancy, before age 2 in most patients
The first invasive infection typically occurs in infancy: most IRAK-4-deficient patients in the Ku cohort had their first invasive episode before the age of 2.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"Most patients developed their first invasive infection before the age of 2 yr (20 out of 28; 71%)"
Establishes early infancy as the typical age of first invasive infection, using the IRAK-4-only figure.
Childhood mortality risk window
Age: Birth to 8 years, with most deaths before age 2
Mortality is concentrated in early childhood and, like the susceptibility to invasive infection, falls with age: in the Ku cohort all deaths occurred before age 8 and most before age 2. This age dependence is examined further in the age_dependent_improvement discussion.
Show evidence (1 reference)
PMID:17893200 SUPPORT Human Clinical
"12 patients died of invasive Gram-positive infections, all before the age of 8 yr and most before the age of 2 yr"
Documents that the deaths in the Ku cohort were concentrated in early childhood, establishing the age window of highest mortality risk.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
The largest cohort documented 48 patients with IRAK-4 deficiency from 37 kindreds in 15 countries; the disease is ultra-rare.
Show evidence (1 reference)
PMID:21057262 SUPPORT Human Clinical
"We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries."
Gives the size and geographic spread of the largest reported IRAK-4 deficiency cohort.
⚖️

Clinical Burden

High
Untreated, the disease carries substantial early mortality: 24 deaths were recorded in the combined Picard cohort, chiefly from invasive pneumococcal disease and often during the first invasive episode, and the Ku cohort lost 12 of 28 patients. The burden is heavily front-loaded in infancy and early childhood, and prophylaxis plus spontaneous improvement in adolescence reduce it markedly thereafter.
Show evidence (2 references)
PMID:21057262 SUPPORT Human Clinical
"Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease."
Quantifies the mortality burden in the largest cohort, driving the HIGH disease-level burden assessment.
PMID:17893200 SUPPORT Human Clinical
"12 patients died of invasive Gram-positive infections, all before the age of 8 yr and most before the age of 2 yr"
Independent cohort confirming high early mortality, supporting the front-loaded burden claim.
🐁

Animal Models

1
IRAK-4- and MyD88-deficient mice
Germline Irak4- and Myd88-deficient mice model the MyD88-dependent TLR/IL-1R signaling lesion. They reproduce the human susceptibility to Gram-positive pyogenic bacteria (notably Staphylococcus aureus) but, unlike human patients, show broad susceptibility to viruses, intracellular bacteria, and fungi - a discordance that is central to interpreting the model (see the HUMAN_MODEL_MISMATCH discussion).
Species
Mouse
Genotype
Irak4-null (and Myd88-null) mice
Publication
PMID:17893200
Pathograph links
Invasive Pyogenic Bacterial Infection partially recapitulates fidelity: low observes: organism Concordant with the human phenotype for Gram-positive pyogenic susceptibility, but discordant in scope: the mouse phenotype is far broader than the narrow, age-limited human susceptibility.
Limitations: Much of the broad-susceptibility evidence is drawn from MyD88-deficient rather than IRAK4-deficient mice, so the discordance is attributed to the shared pathway rather than to IRAK-4 alone; and the mouse phenotype is not age-restricted the way the human disease is.
Divergences from the human mechanism
species mismatch qualifying
MyD88/IRAK-4-deficient mice are susceptible to murine CMV, HSV-1, Listeria, Mycobacterium avium, Toxoplasma, Cryptococcus, Candida, and Aspergillus, none of which define the human disease; the human MyD88-dependent pathway is thus far more redundant for antiviral, antifungal, and intracellular bacterial immunity than the murine one.
Show evidence (2 references)
PMID:17893200 SUPPORT Model Organism
"The susceptibility of IRAK-4–deficient patients to S. aureus is consistent with that observed in IRAK-4– and MyD88-deficient mice (31, 43)."
Establishes the concordant arm - the mouse reproduces the human Gram-positive (S. aureus) susceptibility.
+ 1 more reference
Show evidence (1 reference)
PMID:17893200 SUPPORT Model Organism
"The susceptibility of IRAK-4–deficient patients to S. aureus is consistent with that observed in IRAK-4– and MyD88-deficient mice (31, 43)."
Supports treating the murine knockout as informative for the human Gram-positive pyogenic susceptibility.
{ }

Source YAML

click to show 
name: Immunodeficiency 67
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: IRAK4 deficiency
  term:
    id: MONDO:0011888
    label: immunodeficiency 67
synonyms:
- IRAK4 deficiency
- IRAK-4 deficiency
- immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency
- IRAK4D
- IPD1
- invasive pneumococcal disease, recurrent isolated, 1
description: >-
  Immunodeficiency 67 is IRAK-4 deficiency: an autosomal recessive inborn error
  of innate immunity caused by biallelic loss-of-function variants in IRAK4,
  which encodes interleukin-1 receptor-associated kinase 4, the kinase recruited
  immediately downstream of the adaptor MyD88 in Toll-like receptor (TLR) and
  interleukin-1 receptor (IL-1R) family signaling. Without functional IRAK-4,
  cells cannot transduce signals from the MyD88-dependent TLRs (all TLRs except
  TLR3) and from the IL-1R family, so they fail to activate NF-kappaB and MAPK
  and do not mount the proinflammatory cytokine response that normally follows
  detection of a pyogenic organism.

  The clinical consequence is a strikingly narrow susceptibility. Affected
  children suffer invasive, life-threatening infection with a small set of
  pyogenic bacteria - above all Streptococcus pneumoniae, and to a lesser extent
  Staphylococcus aureus and Pseudomonas aeruginosa - while resistance to fungi,
  parasites and most other bacteria is essentially intact. This redundancy is
  the finding the disease exists to demonstrate: the TIR-IRAK pathway turns out
  to be crucial for immunity to a few bacteria and dispensable against nearly
  everything else. The one recognized qualification to the "antiviral immunity
  preserved" rule is TLR7: because TLR7-dependent type I interferon production by
  plasmacytoid dendritic cells is MyD88- and IRAK-4-dependent, these patients are
  also at high risk of severe, hypoxemic SARS-CoV-2 pneumonia.

  Two features make the disease dangerous out of proportion to its narrow
  spectrum. First, the inflammatory response to infection is characteristically
  weak or delayed - fever and acute-phase signs are often blunted - so severe
  invasive disease can advance with deceptively few warning signs. Second,
  susceptibility is age-dependent: the risk of invasive infection is
  concentrated in infancy and early childhood and falls sharply with age, so
  that with prophylaxis most survivors improve markedly in adolescence.

  IRAK-4 deficiency is clinically and immunologically indistinguishable from
  MyD88 deficiency (immunodeficiency 68), which lies one step upstream in the
  same pathway; the two are curated as distinct entities rather than as subtypes
  of one another.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic loss-of-function IRAK4 variants; heterozygous
    carriers are healthy. The defect and its inheritance are shared with MyD88
    deficiency, the adjacent step in the same signaling pathway.
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4
      and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor
      (TLR)- and interleukin-1 receptor-mediated immunity."
    explanation: States the autosomal recessive inheritance and the impaired TLR/IL-1R
      immunity that defines the disease.
genetic:
- name: IRAK4
  gene_term:
    preferred_term: IRAK4
    term:
      id: hgnc:17967
      label: IRAK4
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    IRAK4 encodes interleukin-1 receptor-associated kinase 4, the proximal
    serine/threonine kinase of the Myddosome that assembles on MyD88 after a
    MyD88-dependent TLR or an IL-1R family receptor is engaged. Reported
    disease alleles are germline biallelic loss-of-function variants (nonsense,
    frameshift and splice) that abolish kinase function, so the gene-disease
    relationship is recorded as causative with an autosomal recessive,
    loss-of-function mechanism.
  variants:
  - name: Biallelic loss-of-function IRAK4 variants
    description: >-
      The reported alleles are germline null or loss-of-function variants
      (nonsense, frameshift, and splice-site) carried in the homozygous or
      compound-heterozygous state, abolishing IRAK-4 kinase activity and
      MyD88-dependent signaling.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:12637671
      reference_title: "Pyogenic bacterial infections in humans with IRAK-4 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe three unrelated children with inherited IRAK-4 deficiency."
      explanation: Establishes inherited IRAK-4 deficiency as the cause in the founding
        patient series.
  - name: Q293X
    description: >-
      A recurrent nonsense allele found in homozygotes from six kindreds and
      compound heterozygotes from four kindreds in the Ku cohort, its recurrence
      possibly reflecting a mutational hotspot, a founder effect, or both.
      Nomenclature follows the source (Q293X).
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:17893200
      reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The Q293X mutant allele was found in homozygotes from six kindreds (C,
        H, K, P, Q, and R) and compound heterozygotes from four kindreds (B, D, M, and
        possibly F). The recurrence of this mutation may reflect a mutational hotspot,
        a founder effect, or both"
      explanation: Documents Q293X as the recurrent IRAK4 allele in the reference cohort.
  evidence:
  - reference: PMID:12637671
    reference_title: "Pyogenic bacterial infections in humans with IRAK-4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their blood and fibroblast cells did not activate nuclear factor kappaB
      and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines
      in response to any of the known ligands of TIR-bearing receptors."
    explanation: Demonstrates that loss of IRAK-4 abolishes NF-kB/MAPK activation and
      cytokine induction downstream of TIR-bearing receptors, the functional basis of
      the gene-disease relationship.
pathophysiology:
- name: IRAK4 Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic loss-of-function IRAK4 variants eliminate functional IRAK-4
    kinase. IRAK-4 is the first kinase recruited to the MyD88 adaptor to form
    the Myddosome, so its loss removes the proximal signaling node shared by the
    MyD88-dependent TLRs and the IL-1R family.
  genetic_context:
    genes:
    - preferred_term: IRAK4
      term:
        id: hgnc:17967
        label: IRAK4
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Germline biallelic null/loss-of-function IRAK4 variants (nonsense,
      frameshift, splice) abolishing IRAK-4 kinase activity.
  evidence:
  - reference: PMID:12637671
    reference_title: "Pyogenic bacterial infections in humans with IRAK-4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe three unrelated children with inherited IRAK-4 deficiency."
    explanation: Identifies inherited IRAK-4 deficiency as the molecular lesion in the
      index patients.
  - reference: PMID:30679311
    reference_title: "Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Upon ligand binding and via its N-terminal death domain, IRAK4 is recruited
      to an oligomeric receptor that is proximal to the Myddosome signaling complex,
      inducing IRAK4 kinase domain dimerization, autophosphorylation, and activation."
    explanation: Structural work establishing IRAK-4 as the proximal Myddosome kinase
      whose recruitment, dimerization and autophosphorylation are lost when the kinase
      is absent.
  downstream:
  - target: Impaired MyD88-Dependent TLR and IL-1R Signaling
    causal_link_type: DIRECT
    description: >-
      Loss of the proximal Myddosome kinase directly abolishes signal
      transduction through the MyD88-dependent TLRs and the IL-1R family.
- name: Impaired MyD88-Dependent TLR and IL-1R Signaling
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Cells cannot transduce signals through the MyD88-dependent Toll-like
    receptors (all TLRs except TLR3) or the IL-1R family. The TLR3 and
    TLR4-interferon-alpha/beta arms, which do not require IRAK-4, are spared, so
    most antiviral immunity is preserved. The important exception is TLR7, an
    endosomal single-stranded-RNA sensor that is itself MyD88- and
    IRAK-4-dependent: its signaling is lost, which underlies the recently
    recognized susceptibility to severe viral pneumonia (see the TLR7 branch
    below).
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: MyD88-dependent toll-like receptor signaling pathway
    term:
      id: GO:0002755
      label: MyD88-dependent toll-like receptor signaling pathway
    modifier: LOSS_OF_FUNCTION
  - preferred_term: interleukin-1-mediated signaling pathway
    term:
      id: GO:0070498
      label: interleukin-1-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency
      is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity,
      except for the Toll-like receptor (TLR) 3- and TLR4-interferon (IFN)-alpha/beta
      pathways."
    explanation: States that IRAK-4 deficiency impairs Toll/IL-1R signaling while sparing
      the TLR3 and TLR4-IFN pathways.
  downstream:
  - target: Defective NF-kappaB and MAPK Activation
    causal_link_type: DIRECT
    description: >-
      MyD88-dependent TLR/IL-1R signaling normally converges on NF-kB and MAPK
      activation, which cannot occur without the proximal IRAK-4 step.
  - target: Impaired TLR7-Dependent Type I Interferon Production
    causal_link_type: DIRECT
    description: >-
      TLR7 is a MyD88- and IRAK-4-dependent endosomal RNA sensor, so its type I
      interferon output in plasmacytoid dendritic cells is lost along with the
      other MyD88-dependent TLRs.
- name: Defective NF-kappaB and MAPK Activation
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Patient blood and fibroblast cells fail to activate NF-kappaB and MAPK in
    response to MyD88-dependent TLR and IL-1R agonists.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: DECREASED
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: DECREASED
  evidence:
  - reference: PMID:12637671
    reference_title: "Pyogenic bacterial infections in humans with IRAK-4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their blood and fibroblast cells did not activate nuclear factor kappaB
      and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines
      in response to any of the known ligands of TIR-bearing receptors."
    explanation: Directly documents the failure of NF-kB and MAPK activation downstream
      of TIR-bearing receptors in patient cells.
  downstream:
  - target: Blunted Proinflammatory Cytokine Production
    causal_link_type: DIRECT
    description: >-
      NF-kB and MAPK drive transcription of proinflammatory cytokines; without
      their activation the cytokine response is not induced.
- name: Blunted Proinflammatory Cytokine Production
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Patient leukocytes do not induce the proinflammatory cytokines normally
    produced on TLR/IL-1R stimulation. Ku et al. found that peripheral blood
    mononuclear cells failed to induce 11 non-interferon cytokines on activation
    with TLR agonists other than the TLR3-specific poly(I:C).
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  biological_processes:
  - preferred_term: positive regulation of cytokine production
    term:
      id: GO:0001819
      label: positive regulation of cytokine production
    modifier: DECREASED
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients' peripheral blood mononuclear cells (PBMCs) did not induce
      the 11 non-IFN cytokines tested upon activation with TLR agonists other than the
      nonspecific TLR3 agonist poly(I:C)."
    explanation: Documents the failure to produce proinflammatory cytokines in response
      to MyD88-dependent TLR agonists while the TLR3 response is retained.
  downstream:
  - target: Impaired Inflammatory Response to Pyogenic Bacteria
    causal_link_type: DIRECT
    description: >-
      Loss of the proinflammatory cytokine burst cripples the acute innate
      inflammatory and antibacterial response to pyogenic organisms.
- name: Impaired Inflammatory Response to Pyogenic Bacteria
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Without cytokine-driven inflammation the host cannot contain invasive
    pyogenic bacteria, and the systemic signs that normally flag infection are
    weak or delayed. The susceptibility is narrow: viral, fungal and parasitic
    defenses are intact and most bacteria are handled normally.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: DECREASED
  evidence:
  - reference: PMID:12637671
    reference_title: "Pyogenic bacterial infections in humans with IRAK-4 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that, in humans, the TIR-IRAK signaling pathway
      is crucial for protective immunity against specific bacteria but is redundant against
      most other microorganisms."
    explanation: States that the pathway is essential for protection against specific
      (pyogenic) bacteria and redundant otherwise, explaining the narrow susceptibility.
  downstream:
  - target: Invasive Pyogenic Bacterial Infection
    causal_link_type: DIRECT
    description: >-
      Failure to mount protective inflammation permits invasive infection by
      pyogenic bacteria.
  - target: Weak or Delayed Systemic Inflammation
    causal_link_type: DIRECT
    description: >-
      The same cytokine deficit blunts fever and the acute-phase response, so
      systemic signs of infection are attenuated.
- name: Invasive Pyogenic Bacterial Infection
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The dominant clinical event is invasive infection with pyogenic bacteria,
    led by invasive pneumococcal disease and followed by Staphylococcus aureus
    and Pseudomonas aeruginosa. Infections are frequently recurrent and
    concentrated in infancy and early childhood.
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The leading threat was invasive pneumococcal disease, documented in 41
      patients (68%) and causing 72 documented invasive infections (52.2%)."
    explanation: Quantifies invasive pneumococcal disease as the leading invasive infection
      in the largest reported cohort.
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients (22 out of 28; 79%) suffered from invasive pneumococcal
      disease, which was often recurrent (13 out of 22; 59%)."
    explanation: Independent cohort confirming the high frequency and recurrence of invasive
      pneumococcal disease.
  downstream:
  - target: Recurrent systemic pyogenic infections
    causal_link_type: DIRECT
  - target: Recurrent streptococcus pneumoniae infections
    causal_link_type: DIRECT
  - target: Recurrent Staphylococcus aureus infections
    causal_link_type: DIRECT
  - target: Sepsis
    causal_link_type: DIRECT
  - target: Meningitis
    causal_link_type: DIRECT
- name: Weak or Delayed Systemic Inflammation
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    A clinically important and dangerous feature: fever and acute-phase signs
    of inflammation are characteristically weak or delayed, so severe invasive
    infection can progress with few warning signs.
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic signs of inflammation were usually weak or delayed."
    explanation: Documents the blunted systemic inflammatory response, the basis for
      this node and the associated diagnostic pitfall.
  - reference: PMID:24596024
    reference_title: "Fatal pneumococcal meningitis in a 7-year-old girl with interleukin-1 receptor activated kinase deficiency (IRAK-4) despite prophylactic antibiotic and IgG responses to Streptococcus pneumoniae vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IRAK-4 deficiency causes IL-1R and TLR signaling failure, resulting in
      minimal clinical features despite invasive bacterial infection."
    explanation: A case report reinforcing that invasive infection can proceed with
      minimal clinical signs, the danger that follows from the blunted inflammatory response.
  downstream:
  - target: Decreased inflammatory response
    causal_link_type: DIRECT
- name: Impaired TLR7-Dependent Type I Interferon Production
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    A recently recognized branch that qualifies the classic teaching that
    antiviral immunity is intact. TLR7 is a MyD88- and IRAK-4-dependent
    endosomal single-stranded-RNA sensor, so plasmacytoid dendritic cells cannot
    mount TLR7-driven type I interferon in response to SARS-CoV-2. The evidence
    comes from a combined cohort of autosomal recessive MyD88 or IRAK-4
    deficiency, so the finding is attributed to the shared pathway rather than
    to IRAK-4 alone.
  cell_types:
  - preferred_term: plasmacytoid dendritic cell
    term:
      id: CL:0000784
      label: plasmacytoid dendritic cell
  biological_processes:
  - preferred_term: type I interferon production
    term:
      id: GO:0032606
      label: type I interferon production
    modifier: DECREASED
  evidence:
  - reference: PMID:36880831
    reference_title: "Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients' susceptibility to SARS-CoV-2 can be attributed to impaired
      TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly."
    explanation: Attributes the SARS-CoV-2 susceptibility of these patients to loss of
      TLR7-dependent type I interferon production by plasmacytoid dendritic cells.
  downstream:
  - target: Severe viral infection
    causal_link_type: DIRECT
    description: >-
      Loss of the pDC type I interferon response to SARS-CoV-2 predisposes to
      hypoxemic COVID-19 pneumonia.
phenotypes:
- category: Immunological
  name: Recurrent systemic pyogenic infections
  description: >-
    Recurrent invasive infection with pyogenic bacteria is the defining clinical
    feature; multiple or recurrent invasive infections occur in most survivors.
  phenotype_term:
    preferred_term: Recurrent systemic pyogenic infections
    term:
      id: HP:0005429
      label: Recurrent systemic pyogenic infections
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple or recurrent invasive infections were observed in most survivors
      (n = 36/50, 72%)."
    explanation: Quantifies the recurrence of invasive pyogenic infection in survivors.
- category: Immunological
  name: Recurrent streptococcus pneumoniae infections
  description: >-
    Streptococcus pneumoniae is the leading invasive pathogen; invasive
    pneumococcal disease is frequently recurrent.
  phenotype_term:
    preferred_term: Recurrent streptococcus pneumoniae infections
    term:
      id: HP:0005366
      label: Recurrent streptococcus pneumoniae infections
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients (22 out of 28; 79%) suffered from invasive pneumococcal
      disease, which was often recurrent (13 out of 22; 59%)."
    explanation: Documents recurrent invasive pneumococcal disease as the dominant infection.
- category: Immunological
  name: Recurrent Staphylococcus aureus infections
  description: >-
    Staphylococcus aureus is the second most frequent culprit, causing both
    noninvasive skin infection and invasive disease.
  phenotype_term:
    preferred_term: Recurrent Staphylococcus aureus infections
    term:
      id: HP:0002726
      label: Recurrent Staphylococcus aureus infections
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other infections were rare, with the exception of severe staphylococcal
      disease (9 out of 28; 32%)."
    explanation: Reports severe staphylococcal disease as the main infection outside
      pneumococcus.
- category: Immunological
  name: Recurrent Pseudomonas aeruginosa infection
  description: >-
    Pseudomonas aeruginosa is a recurrent culprit, dominating the noninvasive
    upper-respiratory-tract burden and also causing documented invasive infection.
  phenotype_term:
    preferred_term: Recurrent Pseudomonas aeruginosa infection
    term:
      id: HP:5210057
      label: Recurrent Pseudomonas aeruginosa infection
  frequency: FREQUENT
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Noninvasive bacterial infections occurred in 52 patients, with a high
      incidence of infections of the upper respiratory tract and the skin, mostly caused
      by Pseudomonas aeruginosa and Staphylococcus aureus, respectively."
    explanation: Identifies Pseudomonas aeruginosa as the leading cause of the frequent
      noninvasive upper-respiratory-tract infections.
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P. aeruginosa and Staph. aureus documented invasive infections also occurred
      (16.7% and 16%, respectively, in 13 and 13 patients, respectively)."
    explanation: Quantifies invasive Pseudomonas aeruginosa infection, confirming it is
      not confined to the noninvasive tier.
- category: Immunological
  name: Recurrent bacterial upper respiratory tract infections
  description: >-
    Noninvasive infection of the upper respiratory tract is a frequent part of the
    infectious burden, caused chiefly by Pseudomonas aeruginosa and Staphylococcus
    aureus.
  phenotype_term:
    preferred_term: Recurrent bacterial upper respiratory tract infections
    term:
      id: HP:0031949
      label: Recurrent bacterial upper respiratory tract infections
  frequency: FREQUENT
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Noninvasive bacterial infections occurred in 52 patients, with a high
      incidence of infections of the upper respiratory tract and the skin, mostly caused
      by Pseudomonas aeruginosa and Staphylococcus aureus, respectively."
    explanation: Documents the high incidence of noninvasive upper-respiratory-tract
      infection in the largest cohort.
- category: Immunological
  name: Recurrent bacterial skin infections
  description: >-
    Recurrent noninvasive skin infection, mostly staphylococcal, is a frequent
    manifestation; counting peripheral staphylococcal disease, half of the cohort
    was particularly susceptible to S. aureus.
  phenotype_term:
    preferred_term: Recurrent bacterial skin infections
    term:
      id: HP:0005406
      label: Recurrent bacterial skin infections
  frequency: FREQUENT
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Noninvasive bacterial infections occurred in 52 patients, with a high
      incidence of infections of the upper respiratory tract and the skin, mostly caused
      by Pseudomonas aeruginosa and Staphylococcus aureus, respectively."
    explanation: Documents the high incidence of noninvasive skin infection, chiefly
      staphylococcal.
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If we also take into account peripheral staphylococcal disease (cellulitis
      and subcutaneous abscess), 14 patients could be considered particularly susceptible
      to S. aureus"
    explanation: Quantifies the staphylococcal skin/soft-tissue burden (cellulitis and
      subcutaneous abscess) in the Ku cohort.
- category: Immunological
  name: Sepsis
  description: >-
    Invasive pyogenic infection frequently manifests as life-threatening
    septicemia, most often caused by Streptococcus pneumoniae.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "22 out of the 28 (79%) had had invasive disease caused by S. pneumoniae
      (meningitis, septicemia, or arthritis)"
    explanation: Names septicemia as one of the invasive pneumococcal presentations
      documented in the cohort.
- category: Immunological
  name: Meningitis
  description: >-
    Invasive pneumococcal disease commonly presents as meningitis, one of the
    principal invasive foci in these patients.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "22 out of the 28 (79%) had had invasive disease caused by S. pneumoniae
      (meningitis, septicemia, or arthritis)"
    explanation: Names meningitis explicitly as one of the invasive pneumococcal
      presentations documented in the cohort.
- category: Immunological
  name: Decreased inflammatory response
  description: >-
    Systemic inflammatory signs, including fever and acute-phase responses, are
    characteristically weak or delayed during invasive infection.
  phenotype_term:
    preferred_term: Decreased inflammatory response
    term:
      id: HP:0012648
      label: Decreased inflammatory response
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic signs of inflammation were usually weak or delayed."
    explanation: Directly reports the blunted systemic inflammatory response.
- category: Immunological
  name: Severe viral infection
  description: >-
    Contrary to the classic picture of preserved antiviral immunity, patients
    with autosomal recessive MyD88 or IRAK-4 deficiency are at high risk of
    severe, hypoxemic SARS-CoV-2 pneumonia, reflecting the loss of the
    TLR7-dependent type I interferon response.
  phenotype_term:
    preferred_term: Severe viral infection
    term:
      id: HP:0031691
      label: Severe viral infection
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36880831
    reference_title: "Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with inherited MyD88 or IRAK-4 deficiency were long thought to
      be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic
      COVID-19 pneumonia."
    explanation: Documents severe viral (COVID-19) pneumonia as a susceptibility of
      these patients, revising the bacterial-only picture.
treatments:
- name: Antibiotic Prophylaxis
  description: >-
    Long-term antibacterial prophylaxis reduces the burden of invasive pyogenic
    infection and, together with vaccination and IgG replacement, had a
    beneficial impact through the vulnerable childhood years.
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
    therapeutic_agent:
    - preferred_term: antibiotic
      term:
        id: NCIT:C258
        label: Antibiotic
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31),
      and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients
      until the teenage years, with no seemingly detectable impact thereafter."
    explanation: Reports the beneficial impact of antibiotic prophylaxis during childhood.
- name: Antipneumococcal Vaccination
  description: >-
    Vaccination against Streptococcus pneumoniae, the leading pathogen, is part
    of the preventive regimen used in the childhood risk window.
  treatment_term:
    preferred_term: antipneumococcal vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31),
      and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients
      until the teenage years, with no seemingly detectable impact thereafter."
    explanation: Reports antipneumococcal vaccination as part of the beneficial preventive
      regimen.
- name: Immunoglobulin Replacement
  description: >-
    IgG infusion provides passive antibody and was part of the regimen with a
    beneficial impact on patients through the teenage years.
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31),
      and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients
      until the teenage years, with no seemingly detectable impact thereafter."
    explanation: Reports IgG infusion as part of the beneficial preventive regimen.
  - reference: PMID:24596024
    reference_title: "Fatal pneumococcal meningitis in a 7-year-old girl with interleukin-1 receptor activated kinase deficiency (IRAK-4) despite prophylactic antibiotic and IgG responses to Streptococcus pneumoniae vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long-term IgG prophylaxis in addition to antibiotics is recommended."
    explanation: A case report recommending long-term IgG prophylaxis alongside antibiotics,
      motivated by a fatal breakthrough pneumococcal infection despite antibiotic prophylaxis
      and vaccination.
diagnosis:
- name: Clinical recognition of recurrent invasive pyogenic infection with blunted inflammation
  description: >-
    IRAK-4 deficiency is suspected in a child with recurrent or invasive infection
    by a narrow set of pyogenic bacteria - above all Streptococcus pneumoniae, and
    less often Staphylococcus aureus and Pseudomonas aeruginosa - in whom the
    systemic inflammatory response is characteristically weak or delayed. Poor or
    absent fever and low serum C-reactive protein during severe invasive infection
    are a recognized diagnostic pitfall that delays recognition, so empiric
    antibacterial treatment and urgent evaluation are advised whenever infection is
    suspected.
  diagnosis_term:
    preferred_term: clinical recognition of recurrent invasive pyogenic infection
  markers: C-reactive protein (CRP), fever/body temperature, acute-phase response
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic signs of inflammation were usually weak or delayed."
    explanation: >-
      Documents the blunted systemic inflammatory response that is the central
      diagnostic pitfall when evaluating a suspected infection in these patients.
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, most patients have weak or delayed acute inflammatory responses in vivo (low serum CrP levels in particular) (34, 71)."
    explanation: >-
      Identifies low serum C-reactive protein as a specific in vivo marker of the
      blunted acute-phase response, so a normal CRP does not exclude invasive
      infection in these patients.
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever."
    explanation: >-
      States the clinical corollary of the diagnostic pitfall: because signs are
      blunted, even moderate fever warrants empiric treatment and urgent review.
- name: Cellular responses to TLR and IL-1R agonists (functional immunology)
  description: >-
    Functional testing of patient blood cells provides the immunological
    confirmation. Whole blood cells or peripheral blood mononuclear cells fail to
    produce the major proinflammatory cytokines (TNF-alpha, IL-6, IL-12) on
    stimulation with MyD88-dependent TLR agonists, and fail to secrete IL-6 in
    response to IL-1beta (and IFN-gamma in response to IL-18), reflecting the
    IRAK-4 block in MyD88-dependent signaling. The response to the TLR3-specific
    agonist poly(I:C) is spared, which distinguishes the pattern from a global
    signaling defect.
  diagnosis_term:
    preferred_term: TLR and IL-1R agonist cellular stimulation assay
  markers: TNF-alpha, IL-6, IL-12 (whole blood / PBMC cytokine induction on TLR and IL-1R stimulation)
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "do not induce the production of major inflammatory cytokines (TNF-α, IL-6, and IL-12) and growth factors (G-CSF and GM-CSF) in whole blood cells and PBMCs"
    explanation: >-
      The abolished proinflammatory cytokine response of whole blood cells and
      PBMCs to MyD88-dependent TLR agonists is the functional diagnostic readout.
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the patients' whole blood cells or PBMCs do not respond to IL-1β, in terms of IL-6 secretion"
    explanation: >-
      The absent IL-6 response to IL-1beta demonstrates the parallel IL-1R-family
      arm of the functional assay used to confirm IRAK-4 deficiency.
- name: IRAK4 gene sequencing
  description: >-
    Molecular confirmation rests on identifying biallelic loss-of-function IRAK4
    variants (nonsense, frameshift, splice-site, or deletion) by sequencing the
    IRAK4 coding exons and flanking regions, or by exome sequencing. The reported
    disease alleles are predicted null and are carried in the homozygous or
    compound-heterozygous state; where no material is available (for example, a
    deceased relative), the diagnosis may rest on clinical grounds instead.
  diagnosis_term:
    preferred_term: IRAK4 sequencing
  results: Identifies biallelic loss-of-function IRAK4 variants
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All IRAK4 exons, flanking intron regions, and, when appropriate, entire introns, were sequenced in 24 patients"
    explanation: >-
      Documents comprehensive IRAK4 sequencing as the molecular diagnostic method
      in the reference cohort.
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "owing to the inheritance of two loss-of-expression, loss-of-function IRAK4 alleles."
    explanation: >-
      Confirms that the molecular diagnosis is biallelic loss-of-function IRAK4
      alleles, the finding sequencing is used to establish.
animal_models:
- name: IRAK-4- and MyD88-deficient mice
  species: Mouse
  genotype: Irak4-null (and Myd88-null) mice
  publication: PMID:17893200
  description: >-
    Germline Irak4- and Myd88-deficient mice model the MyD88-dependent TLR/IL-1R
    signaling lesion. They reproduce the human susceptibility to Gram-positive
    pyogenic bacteria (notably Staphylococcus aureus) but, unlike human patients,
    show broad susceptibility to viruses, intracellular bacteria, and fungi - a
    discordance that is central to interpreting the model (see the
    HUMAN_MODEL_MISMATCH discussion).
  modeled_mechanisms:
  - target: Invasive Pyogenic Bacterial Infection
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Concordant with the human phenotype for Gram-positive pyogenic
      susceptibility, but discordant in scope: the mouse phenotype is far broader
      than the narrow, age-limited human susceptibility.
    limitations: >-
      Much of the broad-susceptibility evidence is drawn from MyD88-deficient
      rather than IRAK4-deficient mice, so the discordance is attributed to the
      shared pathway rather than to IRAK-4 alone; and the mouse phenotype is not
      age-restricted the way the human disease is.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        MyD88/IRAK-4-deficient mice are susceptible to murine CMV, HSV-1, Listeria,
        Mycobacterium avium, Toxoplasma, Cryptococcus, Candida, and Aspergillus,
        none of which define the human disease; the human MyD88-dependent pathway
        is thus far more redundant for antiviral, antifungal, and intracellular
        bacterial immunity than the murine one.
    evidence:
    - reference: PMID:17893200
      reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The susceptibility of IRAK-4–deficient patients to S. aureus is consistent
        with that observed in IRAK-4– and MyD88-deficient mice (31, 43)."
      explanation: Establishes the concordant arm - the mouse reproduces the human
        Gram-positive (S. aureus) susceptibility.
    - reference: PMID:17893200
      reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, MyD88-deficient mice were found to be susceptible to mouse
        CMV (47), HSV-1(48), Listeria monocytogenes (49, 50), Mycobacterium avium (51),
        Toxoplasma gondii (52), Cryptococcus neoformans (53), Candida albicans, and Aspergillus
        fumigatus (54), among other relevant infections"
      explanation: Establishes the discordant arm - the murine broad susceptibility that
        the narrow human phenotype does not share.
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The susceptibility of IRAK-4–deficient patients to S. aureus is consistent
      with that observed in IRAK-4– and MyD88-deficient mice (31, 43)."
    explanation: Supports treating the murine knockout as informative for the human
      Gram-positive pyogenic susceptibility.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The largest cohort documented 48 patients with IRAK-4 deficiency from 37
    kindreds in 15 countries; the disease is ultra-rare.
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We documented the clinical features and outcome of 48 patients with IRAK-4
      deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries."
    explanation: Gives the size and geographic spread of the largest reported IRAK-4
      deficiency cohort.
progression:
- phase: Early-onset invasive infection
  age_range: Onset in infancy, before age 2 in most patients
  notes: >-
    The first invasive infection typically occurs in infancy: most IRAK-4-deficient
    patients in the Ku cohort had their first invasive episode before the age of 2.
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients developed their first invasive infection before the age of
      2 yr (20 out of 28; 71%)"
    explanation: Establishes early infancy as the typical age of first invasive infection,
      using the IRAK-4-only figure.
- phase: Childhood mortality risk window
  age_range: Birth to 8 years, with most deaths before age 2
  notes: >-
    Mortality is concentrated in early childhood and, like the susceptibility to
    invasive infection, falls with age: in the Ku cohort all deaths occurred before
    age 8 and most before age 2. This age dependence is examined further in the
    age_dependent_improvement discussion.
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "12 patients died of invasive Gram-positive infections, all before the age
      of 8 yr and most before the age of 2 yr"
    explanation: Documents that the deaths in the Ku cohort were concentrated in early
      childhood, establishing the age window of highest mortality risk.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Untreated, the disease carries substantial early mortality: 24 deaths were
    recorded in the combined Picard cohort, chiefly from invasive pneumococcal
    disease and often during the first invasive episode, and the Ku cohort lost 12
    of 28 patients. The burden is heavily front-loaded in infancy and early
    childhood, and prophylaxis plus spontaneous improvement in adolescence reduce
    it markedly thereafter.
  evidence:
  - reference: PMID:21057262
    reference_title: "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical outcome was poor, with 24 deaths, in 10 cases during the first
      invasive episode and in 16 cases of invasive pneumococcal disease."
    explanation: Quantifies the mortality burden in the largest cohort, driving the
      HIGH disease-level burden assessment.
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "12 patients died of invasive Gram-positive infections, all before the age
      of 8 yr and most before the age of 2 yr"
    explanation: Independent cohort confirming high early mortality, supporting the
      front-loaded burden claim.
discussions:
- discussion_id: age_dependent_improvement
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does susceptibility to invasive pyogenic infection in IRAK-4 deficiency
    wane sharply with age despite a persistent, lifelong signaling defect?
  attaches_to:
  - pathophysiology#Invasive Pyogenic Bacterial Infection
  rationale: >-
    Invasive infection and death are concentrated in early childhood: no death
    and no invasive infection were reported after the ages of 8 and 14 years,
    respectively, in the two largest cohorts. The IRAK-4 signaling defect is
    constitutive and does not resolve, so the improvement is presumed to reflect
    maturation of adaptive immunity and acquisition of protective antibody with
    age rather than any change in the innate lesion. The precise mechanism of
    the age-dependent narrowing is not established, which is why it is recorded
    as a knowledge gap. The improvement is also not absolute: fatal breakthrough
    pneumococcal meningitis has been reported at age 7 in a prophylaxed,
    vaccinated child, driven by an antibiotic-resistant serotype.
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No death and no invasive infection occurred in patients older than 8 and
      14 yr, respectively."
    explanation: Documents the age-dependent fall in invasive infection and death that
      motivates this knowledge gap.
  - reference: PMID:24596024
    reference_title: "Fatal pneumococcal meningitis in a 7-year-old girl with interleukin-1 receptor activated kinase deficiency (IRAK-4) despite prophylactic antibiotic and IgG responses to Streptococcus pneumoniae vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "even older IRAK-4-deficient patients are at high risk of rapidly fatal
      infection due to emergence of antibiotic resistance."
    explanation: Qualifies the age-dependent improvement - a fatal infection still occurred
      at age 7 despite prophylaxis and vaccination, so the improvement is not absolute.
- discussion_id: mouse_broad_vs_human_narrow_susceptibility
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why do MyD88/IRAK-4-deficient mice show broad susceptibility to viruses,
    intracellular bacteria, and fungi, whereas human IRAK-4 deficiency produces
    only a narrow, largely age-limited susceptibility to pyogenic bacteria?
  attaches_to:
  - pathophysiology#Impaired Inflammatory Response to Pyogenic Bacteria
  - pathophysiology#Invasive Pyogenic Bacterial Infection
  rationale: >-
    The murine knockout recapitulates the Gram-positive pyogenic susceptibility of
    the human disease but not its restriction: MyD88-deficient mice are susceptible
    to a wide range of viral, intracellular bacterial, and fungal pathogens that do
    not define human IRAK-4 deficiency. The open translational question is why the
    same MyD88-dependent pathway lesion yields a far broader infectious phenotype in
    mice than in humans - i.e. why the human pathway is so much more redundant for
    antiviral, antifungal, and intracellular bacterial immunity. An explicit caveat:
    much of the broad-susceptibility evidence comes from MyD88-deficient rather than
    IRAK4-deficient mice, so the discordance is a property of the shared pathway and
    is not established for the IRAK-4 knockout in isolation.
  evidence:
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The susceptibility of IRAK-4–deficient patients to S. aureus is consistent
      with that observed in IRAK-4– and MyD88-deficient mice (31, 43)."
    explanation: The concordant arm - human and mouse agree on Gram-positive pyogenic
      susceptibility, which is what makes the broader murine phenotype a genuine mismatch.
  - reference: PMID:17893200
    reference_title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, MyD88-deficient mice were found to be susceptible to mouse
      CMV (47), HSV-1(48), Listeria monocytogenes (49, 50), Mycobacterium avium (51),
      Toxoplasma gondii (52), Cryptococcus neoformans (53), Candida albicans, and Aspergillus
      fumigatus (54), among other relevant infections"
    explanation: Documents the broad murine susceptibility that the narrow human phenotype
      does not reproduce, the substance of the mismatch.
notes: >-
  Scope. This entry is IRAK-4 deficiency (immunodeficiency 67, MONDO:0011888).
  MyD88 deficiency (immunodeficiency 68) sits one step upstream in the same
  MyD88-dependent TLR/IL-1R pathway and is clinically and immunologically
  indistinguishable, but it is a distinct gene-disease entity and is not curated
  here as a subtype. Disease-specific claims use the IRAK-4-only figures wherever
  the source disaggregates them; a few frequency figures (the noninvasive
  Pseudomonas/upper-respiratory/skin burden and the invasive P. aeruginosa share,
  all from Picard 2010) rest on pooled IRAK-4 + MyD88 cohorts because that source
  does not separate the two, which is stated transparently in each such snippet
  and explanation.

  Mechanism confidence. The molecular chain - IRAK4 loss of function, abolished
  MyD88-dependent TLR/IL-1R signaling, failed NF-kB/MAPK activation, and absent
  proinflammatory cytokine induction - is directly measured in patient cells and
  is graded established. The TLR3 and TLR4-IFN-alpha/beta arms are spared, which
  accounts for the preserved antiviral immunity.

  Evidence base. The entry rests on the founding series (Picard 2003), the
  detailed immunophenotyping cohort (Ku 2007), and the large clinical-outcome
  cohort (Picard 2010), with the structural basis of the Myddosome kinase step
  (PMID:30679311), a fatal-breakthrough case report (PMID:24596024), and the
  combined MyD88/IRAK-4 SARS-CoV-2 cohort establishing the TLR7 viral branch
  (PMID:36880831). No GeneReviews chapter for IRAK-4 deficiency was found in
  PubMed at the time of curation. A single deep-research report was run: the
  requested provider (Falcon/Edison) was out of credits (HTTP 402), so the run
  fell back to OpenScientist, whose report validated cleanly
  (18/18 references resolved, no confabulated terms) and corroborated this
  entry; its leads were verified against the primary abstracts before use.
references:
- reference: PMID:12637671
  title: Pyogenic bacterial infections in humans with IRAK-4 deficiency.
- reference: PMID:17893200
  title: "Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity."
- reference: PMID:21057262
  title: Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.
- reference: PMID:30679311
  title: Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4).
- reference: PMID:24596024
  title: Fatal pneumococcal meningitis in a 7-year-old girl with interleukin-1 receptor activated kinase deficiency (IRAK-4) despite prophylactic antibiotic and IgG responses to Streptococcus pneumoniae vaccines.
- reference: PMID:36880831
  title: Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.
📚

References & Deep Research

References

6
PMID:12637671
Pyogenic bacterial infections in humans with IRAK-4 deficiency.
No top-level findings curated for this source.
PMID:17893200
Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity.
No top-level findings curated for this source.
PMID:21057262
Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.
No top-level findings curated for this source.
PMID:30679311
Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4).
No top-level findings curated for this source.
PMID:24596024
Fatal pneumococcal meningitis in a 7-year-old girl with interleukin-1 receptor activated kinase deficiency (IRAK-4) despite prophylactic antibiotic and IgG responses to Streptococcus pneumoniae vaccines.
No top-level findings curated for this source.
PMID:36880831
Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.
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 (2)

Record notes

Scope. This entry is IRAK-4 deficiency (immunodeficiency 67, MONDO:0011888). MyD88 deficiency (immunodeficiency 68) sits one step upstream in the same MyD88-dependent TLR/IL-1R pathway and is clinically and immunologically indistinguishable, but it is a distinct gene-disease entity and is not curated here as a subtype. Disease-specific claims use the IRAK-4-only figures wherever the source disaggregates them; a few frequency figures (the noninvasive Pseudomonas/upper-respiratory/skin burden and the invasive P. aeruginosa share, all from Picard 2010) rest on pooled IRAK-4 + MyD88 cohorts because that source does not separate the two, which is stated transparently in each such snippet and explanation. Mechanism confidence. The molecular chain - IRAK4 loss of function, abolished MyD88-dependent TLR/IL-1R signaling, failed NF-kB/MAPK activation, and absent proinflammatory cytokine induction - is directly measured in patient cells and is graded established. The TLR3 and TLR4-IFN-alpha/beta arms are spared, which accounts for the preserved antiviral immunity. Evidence base. The entry rests on the founding series (Picard 2003), the detailed immunophenotyping cohort (Ku 2007), and the large clinical-outcome cohort (Picard 2010), with the structural basis of the Myddosome kinase step (PMID:30679311), a fatal-breakthrough case report (PMID:24596024), and the combined MyD88/IRAK-4 SARS-CoV-2 cohort establishing the TLR7 viral branch (PMID:36880831). No GeneReviews chapter for IRAK-4 deficiency was found in PubMed at the time of curation. A single deep-research report was run: the requested provider (Falcon/Edison) was out of credits (HTTP 402), so the run fell back to OpenScientist, whose report validated cleanly (18/18 references resolved, no confabulated terms) and corroborated this entry; its leads were verified against the primary abstracts before use.

Create: Immunodeficiency 67 (IRAK4 deficiency) · 2026-09-04T03:29:19Z · View source

De-novo creation of Immunodeficiency 67 (IRAK-4 deficiency, MONDO:0011888, gene IRAK4 hgnc:17967, autosomal recessive). Built as a causal chain: IRAK4 loss of function -> impaired MyD88-dependent TLR/IL-1R signaling (TLR3/TLR4-IFN arms spared) -> defective NF-kB/MAPK activation -> blunted proinflammatory cytokine production -> impaired inflammatory response -> invasive pyogenic bacterial infection (S. pneumoniae, S. aureus, P. aeruginosa) and weak/delayed systemic inflammation; plus a TLR7/plasmacytoid-DC/type-I-IFN branch to severe COVID-19. Phenotypes, genetic (CAUSATIVE, LOSS_OF_FUNCTION), treatments (antibiotic prophylaxis + Antibiotic agent, antipneumococcal vaccination, IVIG), prevalence (CASES_IN_LITERATURE, ULTRA_RARE), and an age-dependent-improvement knowledge-gap discussion. Deep research: EXACTLY ONE report run; requested provider Falcon (Edison) was out of credits (HTTP 402), so --fallback produced an OpenScientist report (research/Immunodeficiency_67-deep-research-openscientist.md), which validated cleanly (18/18 references resolved, no confabulated terms, needs_review flagged only for unresolvable OMIM/Orphanet/NANDO prefixes) and corroborated the entry; its leads were verified against primary abstracts before use. GeneReviews: no GeneReviews chapter for IRAK-4 deficiency found in PubMed. Validation: just validate-disorders passes; snippets 28/28 verified against cached references (PMIDs 12637671, 21057262, 17893200, 30679311, 24596024, 36880831); term/entity-ref/causal-target/qualifier/duplicate-key/enum gates all clean.

OpenScientist ▸
Key Findings
openscientist-autonomous 15 citations 2026-09-04T03:14:41.528808

Key Findings

1. Disease identity and genetic basis (F001, F010, F014)

Immunodeficiency 67 is the OMIM designation (#607676) for autosomal recessive human IRAK-4 deficiency. It is caused by biallelic loss-of-function mutations in IRAK4 (interleukin-1 receptor-associated kinase 4; gene OMIM 606883; HGNC:17967; NCBI Gene 51135; Ensembl ENSG00000198001; UniProt Q9NWZ3), located at chromosome 12q12. IRAK4 is essential for signaling downstream of most Toll-like receptors (all except TLR3) and all IL-1 receptor family members via the MyD88-dependent Myddosome complex, culminating in activation of NF-κB and MAPK. As a review states, "interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade" and "Human IRAK4 deficiency is an autosomal recessive inborn error of immunity that classically presents with blunted or delayed inflammatory response to infection and susceptibility to a narrow spectrum of pyogenic bacteria" PMID: 32532880.

Complete identifier set (from MONDO:0011888): OMIM:607676; Orphanet:70592; MeSH C563662 & C564352; UMLS C1843256; MedGen 375137; GARD 0010311; NANDO:1200361/2200762. Synonyms/alternative names: IRAK-4 deficiency; IRAK4 deficiency; IRAK4D; immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency; and the phenotype-based synonym "recurrent isolated invasive pneumococcal disease, type 1" (IPD1). ICD-11 maps to the category 4A00.1 (immunodeficiencies due to defects in innate immunity / Toll-like receptor signaling pathway defects); ICD-10 maps to D84.8/D84.9 (other/unspecified immunodeficiency).

Information for this entry is derived predominantly from aggregated disease-level resources (OMIM, Orphanet, MONDO, HPO) and from published case series and case reports rather than individual EHR data.

2. Molecular mechanism: total loss of TIR-receptor signaling (F003, F008)

In the founding report (Picard et al., Science 2003), blood and fibroblasts from IRAK-4-deficient children "did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors" PMID: 12637671. Because the children were otherwise healthy except for pyogenic bacterial infections, the authors concluded that "the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms" PMID: 12637671. This defines both the mechanism (a complete block of TIR-receptor → NF-κB/MAPK signaling) and the reason for the surprisingly narrow infection susceptibility (redundancy against viruses, fungi, parasites, and most bacteria).

Protein architecture: IRAK4 (UniProt Q9NWZ3, 460 aa) has an N-terminal death domain that mediates recruitment to the MyD88-nucleated Myddosome, and a C-terminal Ser/Thr kinase domain. "Upon ligand binding and via its N-terminal death domain, IRAK4 is recruited to an oligomeric receptor that is proximal to the Myddosome signaling complex, inducing IRAK4 kinase domain dimerization, autophosphorylation, and activation" PMID: 30679311. Pathogenic variants span nonsense, frameshift, and splice-site alleles (LoF; the most common class — e.g., p.Gln293*/c.877C>T; splice c.942-1G>A) as well as missense variants in the kinase domain — all abrogating kinase activity or protein expression.

3. Clinical spectrum and outcome (F002, F011)

The largest cohort (Picard et al. 2010; 48 IRAK-4-deficient patients from 37 kindreds in 15 countries) established the natural history:

Feature Value
Invasive pneumococcal disease 41/48 patients (68%); 52.2% of all invasive infections
Invasive P. aeruginosa / S. aureus ~16–17% each
First invasive infection before age 2 88.3%
First invasive infection in neonatal period 32.7%
Systemic inflammatory signs Usually weak or delayed
Deaths 24
Recurrent invasive infection in survivors 36/50 (72%)

Key quotes: "The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%)"; "The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients"; "Systemic signs of inflammation were usually weak or delayed"; "Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%)"; and "Clinical outcome was poor, with 24 deaths" PMID: 21057262. Deaths clustered around the first invasive episode and around invasive pneumococcal disease, but invasive infections and deaths became rare after childhood — an age-dependent improvement in outcome.

Phenotype/HPO annotations: recurrent invasive bacterial infection (HP:0002719 Recurrent infections; HP:0002718 Recurrent bacterial infections), invasive pneumococcal disease with sepsis (HP:0100806) and meningitis (HP:0001287), cutaneous/skin abscesses mainly from S. aureus (HP:0100658; HP:0032243), upper respiratory tract infection (HP:0002788), septic arthritis (HP:0001369) and osteomyelitis (HP:0002754), and lymphadenitis (HP:0002840). Laboratory hallmarks: absent/blunted fever (HP:0001945 often ABSENT), weak acute-phase response with low or paradoxically normal CRP, and transient neutropenia during sepsis (HP:0001875). Immunoglobulins and lymphocyte subsets are typically normal. Severity is greatest in infancy and improves with age; the course is episodic/recurrent.

4. Population genetics: recessive, LoF-tolerant gene (F004, F013)

gnomAD constraint metrics for IRAK4 confirm the gene is not haploinsufficient: pLI ≈ 2.5×10⁻¹³ (essentially 0), observed/expected LoF ratio (oe_lof) = 0.85 (90% CI 0.67–1.09; LOEUF ~1.09), with 44 observed vs 51.8 expected LoF variants. This LoF tolerance is fully consistent with autosomal recessive inheritance and asymptomatic heterozygous carriers.

Inheritance is autosomal recessive with complete penetrance for the immunodeficiency but highly variable expressivity (age of first infection, organ site, survival). Estimated prevalence is <1/1,000,000 (Orphanet:70592; ultra-rare); total published cases number in the low hundreds. Sex ratio ~1:1 (autosomal). Both consanguineous (homozygous) and non-consanguineous (compound heterozygous) kindreds are reported across many ethnicities — "48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries" PMID: 21057262. There is no genetic anticipation, mitochondrial inheritance, or recurrent large chromosomal abnormality. No single founder mutation dominates, though recurrent alleles (e.g., c.877C>T p.Gln293*) recur across unrelated families.

5. Extended phenotype: severe COVID-19 (F005)

An important recent extension of the phenotype: in a 22-patient series of AR MyD88 or IRAK-4 deficiency (mean age 10.9 yr) infected with SARS-CoV-2, 16/22 were hospitalized (6 moderate, 4 severe, 6 critical pneumonia, 1 death). "The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001)" PMID: 36880831. The mechanism: "The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs" PMID: 36880831. This links IRAK-4 to antiviral defense via the TLR7/plasmacytoid dendritic cell/type I interferon axis — a susceptibility not fully appreciated from the classic bacterial-only picture.

6. Human vs. mouse: a striking phenotypic contrast (F006)

Mouse Myd88/Irak4 knockouts are broadly susceptible to many pathogens, whereas humans have a narrow phenotype. von Bernuth et al. note "MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection," whereas human AR MyD88-deficient children suffered a narrow range of pyogenic bacterial infections and "these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age" PMID: 18669862. The same contrast applies to Irak4-knockout mice versus human IRAK-4 deficiency. This has major implications for model-organism interpretation (see Section 15).

7. Diagnosis and management (F007, F009, F012)

Diagnosis rests on demonstrating absent cellular responses to TLR/IL-1R (TIR) agonists — no NF-κB/MAPK activation and no cytokine (IL-6, TNF) induction in blood/fibroblasts PMID: 12637671 — confirmed by biallelic IRAK4 mutation on sequencing (WES or gene panel). Rapid functional assays include flow-cytometric measurement of IκB-α degradation after TLR stimulation (Frans et al. 2024, PMID: 37929815) and NF-κB reporter assays in IRAK4-null HEK293T cells: "We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations" PMID: 33083971. A critical diagnostic clue is severe invasive infection with characteristically low or delayed inflammatory signs — patients often lack fever and have blunted acute-phase responses (though CRP can sometimes be elevated).

Anatomical structures affected (because IRAK4 is ubiquitously expressed, disease occurs wherever pyogenic bacteria invade): bloodstream (UBERON:0000178; sepsis/bacteremia), meninges/CNS (UBERON:0002360; meningitis, brain abscess), lungs (UBERON:0002048; pneumonia/empyema), skin and soft tissue (UBERON:0002097; abscesses, cellulitis), bone and joints (UBERON:0002481; osteomyelitis, septic arthritis), lymph nodes (UBERON:0000029; lymphadenitis), and upper respiratory tract (UBERON:0001557). The Picard cohort noted infection "with a high incidence of infections of the upper respiratory tract and the skin" PMID: 21057262. Key cell types with defective TLR/IL-1R signaling: monocytes/macrophages (CL:0000576/CL:0000235), neutrophils (CL:0000775), dendritic cells including plasmacytoid DCs (CL:0000784), and non-hematopoietic cells such as fibroblasts and epithelial cells. Subcellular: the cytoplasmic Myddosome platform and endosomal TLR compartment (GO:0035325 Toll-like receptor binding; GO:0007249 canonical NF-κB signal transduction).

Management is preventive: continuous antimicrobial prophylaxis (e.g., penicillin V or trimethoprim-sulfamethoxazole), pneumococcal conjugate/polysaccharide vaccination (PCV13, PPSV23), often immunoglobulin replacement, caregiver vigilance, and immediate empiric broad-spectrum antibiotics at the first sign of infection. Yet breakthrough disease occurs: a vaccinated, prophylaxed girl "was managed with antibiotic prophylaxis (sulfa/trimethoprim/PenV, then - due to neutropenia - Cefprozil), pneumococcal vaccination (PCV-7, Pneumovax23, PCV-13) and vigilance" but died of pneumococcal (serotype 6C) meningitis at age 7 PMID: 24596024. That report emphasizes that "IRAK-4 deficiency causes IL-1R and TLR signaling failure, resulting in minimal clinical features despite invasive bacterial infection" PMID: 24596024 — the central reason vigilance and empiric treatment are essential.

Mechanistic Model / Causal Chain

Ordered causal chain from mutation to clinical manifestation:

  1. Biallelic loss-of-function mutation in IRAK4 (12q12) leads to absent or non-functional IRAK-4 kinase protein.
  2. Absence of functional IRAK-4 results in failure to assemble/activate the MyD88-nucleated Myddosome — IRAK-4 can no longer be recruited via its death domain, dimerize, autophosphorylate, and activate downstream IRAK1/IRAK2 PMID: 30679311.
  3. Myddosome failure abolishes signal transduction from all TIR-domain receptors that use MyD88 — all TLRs except TLR3 and all IL-1R family receptors (IL-1R, IL-18R, IL-33R).
  4. This results in failure to activate NF-κB and MAPK, so cells "failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors" PMID: 12637671.
  5. Loss of pro-inflammatory cytokine induction (IL-6, TNF, IL-1β) leads to a blunted/absent acute-phase response and fever — invasive infection proceeds with "minimal clinical features."
  6. Branch A (dominant — bacterial): Impaired early innate sensing of pyogenic bacteria (especially encapsulated S. pneumoniae) leads to failure to contain infection at mucosal/entry sites → invasive bacteremia, meningitis, pneumonia, abscesses. This is worst in infancy, before protective anti-pneumococcal antibody develops, and improves with age as adaptive immunity matures.
  7. Branch B (viral, inferred/emerging): Loss of TLR7-dependent type I IFN production by plasmacytoid dendritic cells results in susceptibility to severe SARS-CoV-2 pneumonia PMID: 36880831.
IRAK4 biallelic LoF
│
▼
No functional IRAK-4 kinase
│
▼
Myddosome cannot assemble/activate  ◄── death-domain recruitment + kinase dimerization lost
│
▼
All MyD88-dependent TIR receptors silenced
 (TLR1/2/4/5/6/7/8/9  +  IL-1R/IL-18R/IL-33R;  NOT TLR3)
│
▼
No NF-κB / MAPK activation → no inflammatory cytokines
│
├─────────────► Blunted fever & acute-phase response (masks infection)
│
├── Branch A ──► Failure vs pyogenic bacteria
│                (S. pneumoniae 68%, S. aureus, P. aeruginosa)
│                → sepsis, meningitis, abscess; severe in infancy,
│                  improves with age
│
└── Branch B ──► Impaired TLR7/pDC type I IFN
                 → severe COVID-19 (OR 74.7 for mechanical ventilation)

Upstream vs downstream: the IRAK4 mutation and Myddosome failure are the most upstream lesion; NF-κB/MAPK silencing is the proximal molecular consequence; blunted inflammation and impaired bacterial/viral containment are the downstream clinical manifestations. GO terms: GO:0007249 (canonical NF-κB signal transduction), GO:0002224 (Toll-like receptor signaling pathway), GO:0035325 (Toll-like receptor binding), GO:0070498 (interleukin-1-mediated signaling), GO:0045087 (innate immune response), GO:0032496 (response to lipopolysaccharide). Relevant CHEBI: lipopolysaccharide, lipopeptide, CpG oligodeoxynucleotide (TLR agonists whose signaling is lost).

Evidence Base

PMID Title (abbreviated) Evidence type How it supports findings
12637671 Pyogenic bacterial infections in humans with IRAK-4 deficiency Human clinical + in vitro Founding report. Establishes the total TIR-signaling defect (no NF-κB/MAPK, no cytokines) and the narrow-but-crucial role of the pathway.
21057262 Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency Human clinical (n=48) Largest cohort. Natural history: 68% pneumococcal, onset <2 yr in 88%, 24 deaths, weak inflammation, age-dependent improvement.
32532880 Clinical IRAK4 deficiency… Review + case Defines disease as AR inborn error with blunted inflammation and narrow pyogenic susceptibility; IRAK4's vital TLR role.
36880831 Humans with inherited MyD88 and IRAK-4 deficiencies predisposed to hypoxemic COVID-19 Human clinical (n=22) Extends phenotype to severe COVID-19 (OR 74.7 for ventilation) via impaired TLR7/pDC type I IFN.
18669862 Pyogenic bacterial infections in humans with MyD88 deficiency Human clinical + comparative Documents the human-vs-mouse contrast: broad murine susceptibility vs narrow human phenotype improving with age.
30679311 Conformational flexibility and inhibitor binding to unphosphorylated IRAK4 Structural Death-domain recruitment + kinase-domain dimerization/autophosphorylation mechanism; basis for how LoF variants disrupt function.
33083971 IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation In vitro assay + case NF-κB reporter assay in IRAK4-null HEK293T for precise variant evaluation (functional confirmation).
24596024 Fatal pneumococcal meningitis in a 7-year-old… despite prophylaxis Human case Documents standard prophylactic regimen and breakthrough fatal disease; blunted inflammation despite invasive infection.
37929815 Diagnosis of IRAK-4-deficiency by flow cytometric IκB-α degradation Diagnostic method Rapid functional diagnostic assay.
42103176 Compound het IRAK4 variants: bacterial infections, brain calcification, epilepsy Human case + functional Expands variant/phenotype spectrum (frameshift c.123dupA + missense c.543T>G); persistently elevated CRP variant; reduced protein and impaired TLR signaling.
26472314 IRAK-4 deficiency misdiagnosed as AD Hyper-IgE syndrome Human case Illustrates diagnostic pitfalls (recurrent S. aureus skin infections, elevated IgE); homozygous c.877C>T p.Gln293*.
38838930 Two novel compound het LoF mutations, fatal P. aeruginosa sepsis Human case + functional Splice/frameshift variants (c.942-1G>A) confirmed by minigene assay; fatal neonatal Pseudomonas sepsis.

Additional supporting case reports document the anatomical/clinical breadth: transcranial abscess management PMID: 25569407, anti-NMDAR encephalitis with HHV6 reactivation PMID: 33083971, CNS pseudomonal vasculopathy PMID: 39846126, Salmonella osteomyelitis PMID: 38857180, adult fatal meningitis PMID: 37103729, and delayed adult presentation PMID: 38758474. The systems-immunology study PMID: 25344726 showed that responses to purified agonists are globally abolished but "variable residual responses were present following exposure to whole pathogens," identifying "a narrow repertoire of transcriptional programs affected" — the molecular correlate of the narrow clinical phenotype.

Section-by-Section Data Compilation

Etiology

Purely genetic: biallelic (homozygous or compound heterozygous) LoF mutations in IRAK4. No environmental cause. Risk factor for expression: consanguinity (increases homozygosity). Infectious exposure to encapsulated pyogenic bacteria is the trigger for clinical events but not a cause of the underlying condition. Heterozygous carriers are unaffected (gnomAD LoF tolerance). No known protective genetic modifiers are characterized; the strongest protective factor is increasing age (maturation of adaptive/antibody immunity). Gene-environment interaction: the genetic defect determines susceptibility, while environmental pathogen exposure and vaccination status determine timing/severity of clinical events.

Environmental Information

No toxins, radiation, or occupational exposures are implicated. The relevant infectious agents are the pathogens that exploit the immune defect: Streptococcus pneumoniae (dominant), Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella (osteomyelitis case), and SARS-CoV-2 (severe COVID-19). These are downstream complications, not causes.

Temporal Development

Onset: congenital genetic defect; first invasive infection typically in infancy — before age 2 in 88.3%, neonatal in 32.7%. Pattern: episodic/recurrent invasive infections. Progression: highest morbidity and mortality in early childhood, with age-dependent improvement; invasive infections and deaths become rare after childhood. Critical period: the first few years of life (before protective anti-pneumococcal antibody develops) is the window of greatest vulnerability and the key window for prophylactic intervention.

Outcome / Prognosis

Poor in infancy — 24 deaths in the 48-patient cohort, most during the first invasive episode or from invasive pneumococcal disease. Survivors have recurrent invasive infection (72%) but progressively improving prognosis with age. No formal 5-/10-year survival figures beyond cohort mortality; life expectancy approaches normal in patients who survive childhood with good prophylaxis. Prognostic factors: age (younger = worse), pathogen (pneumococcal worst), and access to prophylaxis/vaccination/vigilant empiric therapy.

Treatment (NCIT-relevant interventions)

  • Antibiotic prophylaxis — penicillin V, trimethoprim-sulfamethoxazole (NCIT: Antibiotic Therapy).
  • Immunoglobulin replacement therapy (IVIG/SCIG; NCIT: Intravenous Immunoglobulin Therapy).
  • Pneumococcal vaccination — PCV13 conjugate, PPSV23 polysaccharide (NCIT: Vaccine Therapy); antibody responses can be satisfactory but short-lived, requiring boosting.
  • Immediate empiric broad-spectrum antibiotics at first sign of infection (essential given blunted signs).
  • Surgical drainage of abscesses (e.g., transcranial abscess, PMID: 25569407).
  • No curative pharmacotherapy; HSCT generally not indicated (prognosis improves with age); no gene/cell therapy in clinical use.

Prevention

Primary: carrier screening/genetic counseling in affected families; vaccination; prophylactic antibiotics. Secondary: cascade genetic testing of siblings, early diagnosis, vigilant monitoring. Tertiary: aggressive early treatment of infections to prevent complications. Counseling: autosomal recessive — 25% recurrence risk for siblings of a proband; asymptomatic carriers; prenatal/preimplantation testing feasible where the familial variants are known.

Other Species / Model Organisms

  • Taxonomy: disease as such is human (NCBI Taxon 9606). Orthologs: Irak4 in mouse (NCBI Taxon 10090; Gene 266632) and rat.
  • Model organisms: Irak4 and Myd88 knockout mice are the principal models. Critical limitation: murine knockouts show broad pathogen susceptibility, poorly recapitulating the narrow human phenotype PMID: 18669862 — human disease is far more restricted and improves with age. In vitro models: patient fibroblasts/blood cells (loss of NF-κB/MAPK response) and IRAK4-null HEK293T reporter lines for variant functional testing PMID: 33083971. This species discordance is itself a key scientific finding: it demonstrates greater redundancy of the TIR-IRAK4 pathway in humans than in mice.

Limitations and Knowledge Gaps

  1. Rarity limits epidemiology. With a prevalence <1/1,000,000 and only low-hundreds of published cases, prevalence/incidence estimates are imprecise and demographic/geographic patterns are anecdotal. No population-based registries provide robust survival curves.
  2. The narrow-phenotype paradox is incompletely explained. Why loss of a pathway serving nearly all TLRs and IL-1R members produces such restricted susceptibility (chiefly S. pneumoniae) remains only partly understood; residual whole-pathogen responses PMID: 25344726 and redundancy with TLR3/TRIF and other pathways are implicated but not fully mapped.
  3. Age-dependent improvement mechanism is inferred, not proven. The favorable evolution with age is attributed to maturing adaptive immunity/antibody, but the precise immunological switch has not been directly demonstrated.
  4. Viral susceptibility scope is still emerging. The COVID-19 association PMID: 36880831 and scattered viral reports (HHV6 reactivation, PMID: 33083971) suggest the antiviral phenotype (TLR7/pDC/type I IFN) is broader than the classic bacterial picture, but its full extent is undefined.
  5. No curative therapy or genotype-phenotype map. There is no gene/cell therapy, and correlation between specific IRAK4 alleles and severity is not established (variable expressivity noted but not systematically modeled).
  6. Model-organism discordance limits translational research — mouse models over-predict susceptibility breadth.

Proposed Follow-up Experiments / Actions

  1. Build a systematic IRAK4 variant–function database. Use the IRAK4-null HEK293T NF-κB reporter PMID: 33083971 and IκB-α degradation flow assay PMID: 37929815 to functionally classify all reported alleles, establishing a genotype-phenotype/severity map and ACMG-grade functional evidence.
  2. Define the antiviral phenotype prospectively. Given the COVID-19 finding, systematically assess TLR7/pDC type I IFN responses and viral infection history across the patient population to determine whether antiviral prophylaxis/vaccination guidance should change.
  3. Dissect the narrow-phenotype paradox. Use single-cell transcriptomics of patient immune cells challenged with whole S. pneumoniae vs. other pathogens to identify the MyD88-independent (e.g., TLR3/TRIF, inflammasome, complement) compensatory circuits that spare non-pneumococcal defense.
  4. Characterize the age-dependent improvement. Longitudinal profiling of anti-pneumococcal antibody repertoire and memory B/T cell maturation in surviving patients to test whether adaptive antibody accrual explains the falling infection rate — informing when prophylaxis may be safely de-escalated.
  5. Improve model systems. Develop humanized or organoid/iPSC-derived myeloid models that better recapitulate the human narrow phenotype than mouse knockouts, for preclinical testing of interventions.
  6. Newborn/cascade screening feasibility. Evaluate whether a TLR-agonist functional screen or targeted sequencing of IRAK4/MYD88 is cost-effective in high-consanguinity populations or in siblings of probands, given the very high early-childhood mortality that early prophylaxis could prevent.

Conclusion

Immunodeficiency 67 is autosomal recessive human IRAK-4 deficiency: biallelic loss-of-function IRAK4 mutations abolish MyD88/Myddosome-dependent TLR (all except TLR3) and IL-1-receptor-family signaling to NF-κB and MAPK, producing a narrow but life-threatening susceptibility to pyogenic bacteria — above all invasive pneumococcal disease — with characteristically blunted inflammation, early-childhood onset and high early mortality that improves markedly with age, plus an emerging risk of severe viral disease (COVID-19). Management is entirely preventive (antibiotic prophylaxis, pneumococcal/conjugate vaccination, immunoglobulin, and immediate empiric antibiotics), as no curative therapy exists.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 13
Quoted claims found in source 13
Quoted claims not found in source 0
References weighed for topical relevance 18
On topic 12
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 34
Resolved 30
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 6
Terms named correctly 4
Terms named as a different term 0
Terms whose name is worth a second look 2

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:

  • GO:0007249 (2 mentions) - the report calls it "canonical NF-κB signal transduction"; GO calls it canonical NF-kappaB signal transduction
  • GO:0070498 (1 mention) - the report calls it "interleukin-1-mediated signaling"; GO calls it interleukin-1-mediated signaling pathway

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: OMIM, Orphanet, NANDO.

30 of 34 terms resolved to a current term; the rest could not be looked up either way.