Immunodeficiency 82 With Systemic Inflammation

Mendelian MONDO:0030308 Pathograph 24 Show in embeddings browser Inborn error of immunity Monogenic autoinflammatory disease

A monoallelic gain-of-function disorder of SYK, the spleen tyrosine kinase, presenting in the first weeks of life with colitis, arthritis, dermatitis and systemic inflammation alongside an immune deficiency, and carrying a risk of diffuse large B cell lymphoma. Two things make this entry unusual and both are worth stating up front. First, the direction of the lesion is counter-intuitive. SYK sits immediately downstream of ITAM-bearing immunoreceptors in mononuclear phagocytes and B cells, and one would expect a hyperactive kinase to produce inflammation alone. It produces inflammation and immunodeficiency together, with reduced memory B cells and low immunoglobulins. The entry curates that as two branches from one node rather than picking the half that fits the intuition. Second, this is the mirror image of the ZAP70 disease already in the knowledge base. ZAP70 and SYK are the two tandem-SH2 kinases recruited to phosphorylated ITAMs; ZAP70 acts in T and NK cells, SYK in mononuclear phagocytes and B cells. Biallelic loss of ZAP70 gives a selective T cell defect. Monoallelic gain of SYK gives this. The pairing is a genuine structural fact about the pathway and is recorded in the genetic notes. The evidence base is narrow and this entry does not disguise that. The disease was defined by a single 2021 report of six patients across several families, which also built the knock-in mouse. Almost every mechanistic claim here traces to that one paper. Where a claim rests on the mouse rather than on patients, the evidence item says so through evidence_source: MODEL_ORGANISM, and the treatments section is explicit that SYK inhibition and bone marrow transplantation were shown in mice and not in a human trial. The gain-of-function is recorded in two places because they are two different claims, per the CLAUDE.md rule: functional_impact_category: GAIN_OF_FUNCTION on the variant's genetic_context, and modifier: GAIN_OF_FUNCTION on the kinase activity descriptor. The latter is the qualitative choice rather than INCREASED, because the variants remove the kinase from its normal autoinhibitory constraint rather than merely raising its level. No pathophysiology node declares conforms_to. kb/modules/ was searched; no module covers ITAM-proximal kinase hyperactivation.

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1
Inheritance
5
Pathophys.
16
Phenotypes
2
Gaps
24
Pathograph
1
Genes
3
Medical Actions
1
Models
1
References
1
Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Monoallelic variants are sufficient. Transmission from an affected parent to an affected child is documented in the defining report, in which patient 3 is the father of patient 2 and had the same disease from two weeks of life.
Autosomal dominant
Show evidence (2 references)
PMID:33782605 SUPPORT Human Clinical
"We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
States the monoallelic genotype across the patient series.
PMID:33782605 SUPPORT Human Clinical
"Her father (Patient 3, age 35) had a similar disease that started at two weeks of life and was characterized by oral ulcers, fever, rash, diarrhea and failure to thrive."
Documents parent-to-child transmission with a concordant phenotype.
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Discussions and Knowledge Gaps

2
How does a single activating kinase variant produce immunodeficiency and systemic inflammation at the same time?
OPEN QUESTION OPEN syk_gof_inflammation_and_deficiency_together
Attached to
pathophysiology#Constitutive SYK Kinase Hyperactivation pathophysiology#Impaired Humoral Immunity
A gain-of-function variant in a proximal immunoreceptor kinase predicts inflammation, and that is observed. It does not obviously predict reduced memory B cells, low IgM and IgG, and fatal infection, and those are observed too, in the same patients. Several accounts are compatible with the curated evidence and none is established by it. Chronically hyperactive B cell receptor signalling could drive anergy or deletion rather than productive responses, in which case the deficiency is a downstream consequence of the same excess. The deficiency could instead be secondary to the inflammatory disease itself - protein loss through an ulcerated colon, or the effect of chronic inflammation on lymphopoiesis. Or the two could be genuinely independent effects of SYK in different lineages. The distinction matters for treatment: if the deficiency is driven by excess signalling then kinase inhibition should improve it, whereas if it is a consequence of tissue damage it should follow the colitis instead.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
Establishes that deficiency and inflammation co-occur in the same patients, which is the fact this question is about.
What is the phenotypic spectrum of SYK gain-of-function disease beyond the six patients of the defining series?
KNOWLEDGE GAP OPEN syk_gof_single_defining_series
Attached to
disease#Immunodeficiency 82 With Systemic Inflammation
Essentially every mechanistic and clinical claim in this entry traces to one 2021 report of six patients. That is enough to establish the disease and not enough to establish its range: penetrance, the proportion of carriers who develop lymphoma, whether milder adult-onset presentations exist, and whether the other patient variants behave like the one modelled in mouse are all unaddressed. This is recorded as a knowledge gap rather than left implicit because it changes how the rest of the entry should be read. A reader should treat the phenotype list here as the presentation of one ascertained series, not as a frequency distribution over the disease.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"while pathogenic variation of SYK has not been described in humans"
Records that this report was the first description, which is why no independent series exists to compare against.
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Pathophysiology

5
Monoallelic SYK Gain-of-Function Variants
Heterozygous missense variants in SYK that increase kinase activity. The defining series identified six patients; the variant modelled in mouse, p.Ser550Tyr, corresponds to mouse Ser544Tyr.
mononuclear phagocyte CL:0000113 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mononuclear phagocyte (CL:0000113). CL:0000113 is a cell type from the Cell Ontology. B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Downstream
Constitutive SYK Kinase Hyperactivation The variant protein is more readily phosphorylated and signals more strongly than wild-type SYK.
Show evidence (2 references)
PMID:33782605 SUPPORT Human Clinical
"We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
Establishes the causative variants and the size of the defining series.
PMID:33782605 SUPPORT INDIRECT Human Clinical
"Loss-of-function biallelic variants in ZAP70 result in human immunodeficiency characterized by a selective T cell defect (OMIM 269840) 6, while pathogenic variation of SYK has not been described in humans."
Records that no pathogenic SYK variation was known before this report, which is why the disease rests on a single defining series. Marked INDIRECT because it establishes the novelty of the finding rather than the variants themselves.
Constitutive SYK Kinase Hyperactivation
The pivotal node. SYK is the tandem-SH2 kinase recruited to phosphorylated ITAMs of B cell receptors, Fc receptors and other immunoreceptors, and it also transduces signals from C-type lectin receptors, Toll-like receptors and integrins. The disease variants raise its phosphorylation and downstream output. The modifier here is GAIN_OF_FUNCTION rather than INCREASED because the claim is qualitative: the kinase escapes its normal regulatory constraint, not merely that there is more signalling.
immune response-regulating cell surface receptor signaling pathway GO:0002768 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased immune response-regulating cell surface receptor signaling pathway (GO:0002768). GO:0002768 is a biological process from the Gene Ontology. ↑ INCREASED
SYK protein tyrosine kinase activity GO:0004715 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves SYK protein tyrosine kinase activity, annotated with non-membrane spanning protein tyrosine kinase activity (GO:0004715), qualified as gain of function. GO:0004715 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Multi-Organ Inflammatory Disease Excess ITAM-proximal signalling in mononuclear phagocytes drives cytokine production and tissue inflammation.
Impaired Humoral Immunity The same hyperactive kinase in the B cell lineage is associated with reduced memory B cells and low immunoglobulins, so the inflammatory and deficiency branches share one upstream node.
B Cell Lymphomagenesis Sustained SYK signalling in the B cell lineage is the proposed route to diffuse large B cell lymphoma in these patients.
Show evidence (3 references)
PMID:33782605 SUPPORT In Vitro
"The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function."
The direct functional demonstration that these variants are activating, which is the claim of this node.
PMID:33782605 SUPPORT Human Clinical
"These kinases are (1) the ζ-chain-associated protein kinase of 70 kDa (ZAP70), which is primarily expressed in T cells and natural killer cells, and (2) the spleen tyrosine kinase (SYK), which is primarily expressed in mononuclear phagocytes (MNPs), B cells and, to a lesser extent, the..."
Establishes where SYK acts, which is what makes the mononuclear phagocyte and B cell branches downstream of this node the expected ones.
PMID:33782605 SUPPORT Human Clinical
"SYK is also involved in signaling cascades from receptors without ITAMs, including C-type lectin receptors, Toll-like receptors and integrins 1,2."
Supports the breadth of receptor input described in this node, which bears on why the inflammation is multi-organ rather than restricted to one receptor system.
Multi-Organ Inflammatory Disease
Systemic and tissue-specific inflammation from the first weeks of life: colitis with colonic ulceration and chronic inflammatory histology, arthritis, dermatitis and rash, vasculitis, and a raised acute-phase response with elevated C-reactive protein and interleukin-6.
mononuclear phagocyte CL:0000113 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mononuclear phagocyte (CL:0000113). CL:0000113 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
SYK Ser544Tyr knock-in mouse Mouse partially recapitulates Reproduces aspects of the human inflammatory disease from the orthologous point variant, at the whole-organism scale.
Downstream
Colitis
Arthritis
Skin rash
Vasculitis
Elevated circulating C-reactive protein concentration
Diarrhea
Fever
Anal fistula
Failure to thrive
Pulmonary inflammation Three of the six patients had lung involvement in the multi-tissue inflammatory picture.
Neuroinflammation Two of the six patients had central nervous system involvement in the same multi-tissue inflammatory picture.
Hepatic granulomatosis One of the six patients had granulomatous liver disease.
Show evidence (2 references)
PMID:33782605 SUPPORT Human Clinical
"Colonoscopy at 17 months of age revealed multiple ulcers in the colon (Fig. 1a) with histologic features consistent with chronic colitis (Fig. 1b)."
Documents the colitis with endoscopic and histological confirmation.
PMID:33782605 SUPPORT Human Clinical
"Laboratory tests showed normal white blood cell (WBC) counts but elevated C-reactive protein (CRP), high level of serum Interleukin (IL)-6, and reduced serum levels of immunoglobulin (Ig) M and IgG (Fig. 1e and Supplementary Table 1)."
Documents the acute-phase response and, in the same sentence, the immunoglobulin deficiency that defines the other branch.
Impaired Humoral Immunity
The immunodeficiency branch, and the part of this disease that is least intuitive given an activating kinase variant. Patients have reduced memory B cells and low serum IgM and IgG, with recurrent infections; one patient in the defining series died of infectious complications before her third birthday.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Downstream
Decreased circulating IgG concentration
Decreased circulating IgM concentration
Recurrent infections
Show evidence (2 references)
PMID:33782605 SUPPORT Human Clinical
"Patients 2 and 3 both have reduced memory B cells (Supplementary Table 4)."
Documents the memory B cell deficit underlying this node.
PMID:33782605 SUPPORT Human Clinical
"The patient passed away before her 3rd birthday due to complications from an infection."
Records the clinical consequence of the immunodeficiency, which is what makes this branch more than a laboratory observation.
B Cell Lymphomagenesis
Diffuse large B cell lymphoma occurred in the defining series. SYK is a known oncogenic driver in B cell malignancy, so sustained hyperactive signalling in the B cell lineage is the proposed route. This entry records the association and the proposed mechanism; the causal step from the germline variant to the lymphoma is not separately demonstrated in that report, and the node description says so rather than implying it.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
Downstream
B-cell lymphoma Two of the four adult patients in the founding cohort developed diffuse large B cell lymphoma, which is the clinical endpoint of this arm.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas"
Records the lymphoma occurring within the defining patient series.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 82 With Systemic Inflammation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Blood 4
Decreased circulating IgG concentration HP:0004315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced serum IgG, annotated with Decreased circulating IgG concentration (HP:0004315). HP:0004315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"reduced serum levels of immunoglobulin (Ig) M and IgG"
Documents the reduction in serum IgG.
Decreased circulating IgM concentration Decreased circulating total IgM HP:0002850 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced serum IgM, annotated with Decreased circulating total IgM (HP:0002850). HP:0002850 is a phenotype from the Human Phenotype Ontology.
The bound label is the one in cache/hp/terms.csv, "Decreased circulating total IgM", which is what term validation enforces and what the five existing KB entries using this CURIE carry. A live OLS lookup of HP:0002850 returns "Decreased circulating IgM concentration" instead, so HPO appears to have renamed the term since the cache row was written. Recorded here rather than silently resolved either way, because the cache-first validator makes the live label the one that fails.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"reduced serum levels of immunoglobulin (Ig) M and IgG"
Documents the reduction in serum IgM.
B-cell lymphoma FREQUENT HP:0012191 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is diffuse large B cell lymphoma, annotated with B-cell lymphoma (HP:0012191). HP:0012191 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"we identified diffuse large B cell lymphomas (DLBCL) at a comparatively young age in two of the four adult patients (P5 and P6) with pathogenic SYK variants."
The source states 2 of the 4 adult patients, which is 50 percent; across the whole reported cohort of six it is 2/6, which is 33 percent. Both land in the FREQUENT band (30-79 percent), so the band does not turn on which denominator is used. The risk is nonetheless age-conditioned: every reported lymphoma was in an adult, and the band should not be read as a lifetime risk from infancy.
Hepatic granulomatosis OCCASIONAL HP:0011955 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is granulomatous liver disease, annotated with Hepatic granulomatosis (HP:0011955). HP:0011955 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
Names granulomatous liver disease in Patient 6 alone, which is 1/6 or 17 percent, inside the OCCASIONAL band (5-29 percent).
Cardiovascular 1
Vasculitis HP:0002633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized vasculitis, annotated with Vasculitis (HP:0002633). HP:0002633 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"presented at two weeks of age with whole body rash, generalized vasculitis (Fig. 1g) and diarrhea"
Documents the vasculitis at presentation.
Digestive 3
Colitis HP:0002583 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic colitis, annotated with Colitis (HP:0002583). HP:0002583 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"Colonoscopy at four weeks of age revealed ulcers in the cecum with features of chronic inflammation."
Documents the colitis with endoscopic confirmation in a second patient.
Diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea, annotated with Diarrhea (HP:0002014), qualified as temporality chronic. HP:0002014 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"non-bloody diarrhea (5–8 times per day)"
Documents the diarrhea and its frequency.
Anal fistula HP:0010447 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Perianal fistula, annotated with Anal fistula (HP:0010447). HP:0010447 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"She also developed perianal fistulas (Fig. 1c)"
Documents the perianal fistulas.
Immune 3
Skin rash HP:0000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Whole body rash, annotated with Skin rash (HP:0000988). HP:0000988 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"presented at 2 weeks of age with fever, whole body rash and non-bloody diarrhea (5–8 times per day)"
Documents the neonatal-onset rash.
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"As a child he was diagnosed with an undefined immunodeficiency with reduced CD4+ T cell counts and low immunoglobulins (Supplementary Table 3) and was advised against using live vaccines."
Documents the clinical immunodeficiency and its management consequence.
Neuroinflammation FREQUENT HP:0033429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is central nervous system inflammation, annotated with Neuroinflammation (HP:0033429). HP:0033429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
Names the central nervous system among the inflamed tissues in Patients 4 and 5, which is 2/6 or 33 percent, inside the FREQUENT band (30-79 percent).
Metabolism 2
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever, annotated with Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"was characterized by oral ulcers, fever, rash, diarrhea and failure to thrive"
Documents fever as part of the clinical picture in the affected parent.
Elevated circulating C-reactive protein concentration HP:0011227 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated C-reactive protein, annotated with Elevated circulating C-reactive protein concentration (HP:0011227). HP:0011227 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"By 15 months of age, she developed arthritis (Fig. 1h) with worsening colitis and multiple episodes of elevated CRP and WBC counts (Fig. 1i and Supplementary Table 2)."
Documents repeated elevation of C-reactive protein alongside clinical flares.
Musculoskeletal 1
Arthritis HP:0001369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inflammatory arthritis, annotated with Arthritis (HP:0001369). HP:0001369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"She also developed perianal fistulas (Fig. 1c) and arthritis indicated by joint pain and swelling of her hands (Fig. 1d)."
Documents the arthritis and its clinical basis.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth failure, annotated with Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"She had significant growth failure (Fig. 1f) and recurrent infections."
Documents the growth failure alongside the infection susceptibility.
Other 1
Pulmonary inflammation FREQUENT
Deliberately left unbound. HPO was searched via the OLS adapter for pulmonary inflammation, lung inflammation, pneumonitis and abnormal pulmonary terms; the candidates returned are all narrower than the source supports (HP:0006515 Interstitial pneumonitis, HP:0002113 Pulmonary infiltrates) or are morphological rather than inflammatory (HP:0002088 Abnormal lung morphology). The source says only that the lung was among the inflamed tissues, so binding any of these would manufacture specificity the paper does not claim.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
Names lung among the inflamed tissues in Patients 2, 5 and 6, which is 3/6 or 50 percent, inside the FREQUENT band (30-79 percent).
🧬

Genetic Associations

1
SYK
Gene: SYK hgnc:11491 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SYK (hgnc:11491). hgnc:11491 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:33782605 SUPPORT Human Clinical
"Loss-of-function biallelic variants in ZAP70 result in human immunodeficiency characterized by a selective T cell defect (OMIM 269840) 6, while pathogenic variation of SYK has not been described in humans."
States the ZAP70 contrast described in the notes and, in the same sentence, that SYK disease was previously unknown.
PMID:33782605 SUPPORT Human Clinical
"In this study we identify monoallelic gain-of-function variants in SYK that result in immunodeficiency and systemic inflammatory disease in humans"
States the causative gene-disease relationship in humans. Quoted to the human clause only: the rest of the sentence reports the mouse result, and the animal model cites that half separately as MODEL_ORGANISM. One sentence cannot carry two evidence_source values, so each item quotes the clause it is graded on.
PMID:33782605 SUPPORT Human Clinical
"We next screened for additional SYK variants in a number of patient registries and found 3 additional patients with potential monoallelic damaging variants in evolutionary conserved residues of SYK (p.P342T, p.A353T and p.M450I)."
Source for the three further alleles beyond the p.S550 pair, and for the fact that they were ascertained from registries rather than the index family.
+ 1 more reference
🗃️

External Assertions

1
OMIM immunodeficiency 82 record
OMIM disease record OMIM:619381
OMIM phenotype identifier for immunodeficiency 82 with systemic inflammation (IMD82), the SYK gain-of-function phenotype. Cross-checked against MONDO's own OMIM xref for MONDO:0030308 with `just preflight-dr`, which reports OMIM (MONDO) 619381, rather than taken from the deep-research report.
💊

Medical Actions

3
SYK kinase inhibition
Action: SYK kinase inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is SYK kinase inhibitor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: fostamatinib NCIT:C95222 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses fostamatinib (NCIT:C95222). NCIT:C95222 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Pharmacological inhibition of the hyperactive kinase, the mechanistically obvious treatment and the one the defining study tested. R406, the active metabolite of fostamatinib, occupies the ATP-binding pocket and competes with free ATP. In the knock-in mouse this partially treated the disease.
Mechanism Target:
Constitutive SYK Kinase Hyperactivation — Competitive ATP-site inhibition reduces the kinase activity at the node immediately downstream of the genetic lesion. This is the one treatment here that acts on the causal node rather than on its consequences.
Show evidence (3 references)
PMID:33782605 SUPPORT Model Organism
"A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice."
Reports partial treatment response in the mouse model. Graded MODEL_ORGANISM, and the word "partially" is retained in the quote rather than paraphrased away.
PMID:33782605 SUPPORT In Vitro
"R406, the active metabolite of fostamatinib, attaches to the ATP-binding pocket of SYK and sterically competes with free ATP to inhibit SYK kinase activity9."
Establishes the molecular mechanism by which the agent acts on the target node.
PMID:33782605 SUPPORT INDIRECT Human Clinical
"Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease."
The authors' own summary claim. Marked INDIRECT deliberately: "potentially treatable" is a forward-looking statement resting on the mouse experiment, not a report of human treatment.
Allogeneic hematopoietic cell transplantation
Action: hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Replacement of the affected haematopoietic compartment. Because SYK acts in mononuclear phagocytes and B cells, which are haematopoietic, transplantation is mechanistically curative in principle. Transplantation of wild-type bone marrow partially treated the knock-in mouse.
Mechanism Target:
Monoallelic SYK Gain-of-Function Variants — Replaces the variant-carrying haematopoietic cells with wild-type cells, removing the lesion from the lineages in which it acts. Unlike kinase inhibition this addresses the genetic node itself, but only in the haematopoietic compartment - the report notes SYK expression in intestinal epithelium as well.
Show evidence (2 references)
PMID:33782605 SUPPORT Model Organism
"could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice"
Reports the partial response to wild-type bone marrow transplantation in the knock-in mouse.
PMID:33782605 SUPPORT INDIRECT Human Clinical
"which is primarily expressed in mononuclear phagocytes (MNPs), B cells and, to a lesser extent, the intestinal epithelium"
Supports the rationale for a haematopoietic transplant while naming the non-haematopoietic compartment it would not address. Marked INDIRECT because it describes expression rather than a treatment result.
Haematological malignancy surveillance
Action: haematological malignancy screeningNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is haematological malignancy screening, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
Regular screening for haematological malignancy in patients with a suspected or confirmed SYK gain-of-function variant. This is the source paper's explicit management directive and follows from the lymphoma risk recorded above, not from any trial.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"patients with suspected SYK gain-of-function variants should be regularly screened for hematological malignancies."
The authors' stated recommendation, quoted rather than paraphrased into a stronger claim. No screening interval or modality is specified by the source and none is invented here.
🔬

Diagnosis

1
Constitutive SYK phosphorylation assay
Spontaneous tyrosine phosphorylation of SYK Y525/526 in unstimulated patient PBMC, used as the functional confirmation that a candidate variant is activating.
Show evidence (1 reference)
PMID:33782605 SUPPORT In Vitro
"PBMC from Patients 1 and 3 showed spontaneous tyrosine phosphorylation of Y525/526 SYK, tyrosine residues known to regulate auto-phosphorylation and activation"
Documents the confirmatory assay and the residues read out. Graded IN_VITRO because the measurement is made on cultured patient cells.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
An ultra-rare entity defined in 2021. The founding report describes six patients from the combined index family and three patient registries, and no population frequency has been estimated. No rate is recorded because a denominator would have to be invented.
Show evidence (1 reference)
PMID:33782605 SUPPORT Human Clinical
"We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
Establishes the size of the entire reported cohort, which is what the CASES_IN_LITERATURE measure reports.
🐁

Animal Models

1
SYK Ser544Tyr knock-in mouse
A knock-in of the mouse residue equivalent to a patient variant, made in the defining study. Unlike many immunodeficiency models it reproduces substantial parts of the human disease, which is what makes the treatment experiments in it interpretable.
Species
Mouse
Genotype
Syk p.Ser544Tyr knock-in, corresponding to human p.Ser550Tyr
Publication
PMID:33782605
Pathograph links
Multi-Organ Inflammatory Disease partially recapitulates fidelity: moderate observes: organism Reproduces aspects of the human inflammatory disease from the orthologous point variant, at the whole-organism scale.
Limitations: The authors' own wording is that the model recapitulates "aspects of" the human disease, not the whole of it, and the report does not claim the lymphoma phenotype is reproduced. It is one knock-in of one of the several patient variants, so it does not speak to allelic heterogeneity.
Divergences from the human mechanism
species mismatch qualifying
The engineered residue is the mouse equivalent (Ser544) of the human residue (Ser550), so the model tests the orthologous substitution rather than the human allele itself. Global Syk knockout is perinatally lethal in mouse, indicating that murine SYK dosage requirements are not identical to human.
Show evidence (1 reference)
PMID:33782605 SUPPORT Model Organism
"A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice."
States both the recapitulation and its limits, and is the source for the two treatment records below.
Show evidence (1 reference)
PMID:33782605 SUPPORT Model Organism
"show that the expression of one of these variants in a mouse model replicates major aspects of the human immunopathology"
Attests that this model is informative for the human disease.
{ }

Source YAML

click to show 
name: Immunodeficiency 82 With Systemic Inflammation
creation_date: "2026-09-12T13:35:00Z"
category: Mendelian
synonyms:
- IMD82
- SYK gain-of-function disease
- SYK-associated immune dysregulation
- immunodeficiency 82 with systemic inflammation, autosomal dominant
description: >-
  A monoallelic gain-of-function disorder of SYK, the spleen tyrosine kinase,
  presenting in the first weeks of life with colitis, arthritis, dermatitis and
  systemic inflammation alongside an immune deficiency, and carrying a risk of
  diffuse large B cell lymphoma.

  Two things make this entry unusual and both are worth stating up front.

  First, the direction of the lesion is counter-intuitive. SYK sits immediately
  downstream of ITAM-bearing immunoreceptors in mononuclear phagocytes and B
  cells, and one would expect a hyperactive kinase to produce inflammation alone.
  It produces inflammation and immunodeficiency together, with reduced memory B
  cells and low immunoglobulins. The entry curates that as two branches from one
  node rather than picking the half that fits the intuition.

  Second, this is the mirror image of the ZAP70 disease already in the knowledge
  base. ZAP70 and SYK are the two tandem-SH2 kinases recruited to phosphorylated
  ITAMs; ZAP70 acts in T and NK cells, SYK in mononuclear phagocytes and B cells.
  Biallelic loss of ZAP70 gives a selective T cell defect. Monoallelic gain of
  SYK gives this. The pairing is a genuine structural fact about the pathway and
  is recorded in the genetic notes.

  The evidence base is narrow and this entry does not disguise that. The disease
  was defined by a single 2021 report of six patients across several families,
  which also built the knock-in mouse. Almost every mechanistic claim here traces
  to that one paper. Where a claim rests on the mouse rather than on patients,
  the evidence item says so through evidence_source: MODEL_ORGANISM, and the
  treatments section is explicit that SYK inhibition and bone marrow
  transplantation were shown in mice and not in a human trial.

  The gain-of-function is recorded in two places because they are two different
  claims, per the CLAUDE.md rule: functional_impact_category: GAIN_OF_FUNCTION on
  the variant's genetic_context, and modifier: GAIN_OF_FUNCTION on the kinase
  activity descriptor. The latter is the qualitative choice rather than
  INCREASED, because the variants remove the kinase from its normal
  autoinhibitory constraint rather than merely raising its level.

  No pathophysiology node declares conforms_to. kb/modules/ was searched; no
  module covers ITAM-proximal kinase hyperactivation.
disease_term:
  preferred_term: immunodeficiency 82 with systemic inflammation
  term:
    id: MONDO:0030308
    label: immunodeficiency 82 with systemic inflammation
external_assertions:
- name: OMIM immunodeficiency 82 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:619381
  description: >-
    OMIM phenotype identifier for immunodeficiency 82 with systemic inflammation
    (IMD82), the SYK gain-of-function phenotype. Cross-checked against MONDO's own
    OMIM xref for MONDO:0030308 with `just preflight-dr`, which reports
    OMIM (MONDO) 619381, rather than taken from the deep-research report.
parents:
- Inborn error of immunity
- Monogenic autoinflammatory disease
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Monoallelic variants are sufficient. Transmission from an affected parent to
    an affected child is documented in the defining report, in which patient 3 is
    the father of patient 2 and had the same disease from two weeks of life.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
    explanation: >-
      States the monoallelic genotype across the patient series.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her father (Patient 3, age 35) had a similar disease that started at two weeks of life and was characterized by oral ulcers, fever, rash, diarrhea and failure to thrive."
    explanation: >-
      Documents parent-to-child transmission with a concordant phenotype.
pathophysiology:
- name: Monoallelic SYK Gain-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Heterozygous missense variants in SYK that increase kinase activity. The
    defining series identified six patients; the variant modelled in mouse,
    p.Ser550Tyr, corresponds to mouse Ser544Tyr.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: GAIN_OF_FUNCTION
    zygosity: HETEROZYGOUS
  cell_types:
  - preferred_term: mononuclear phagocyte
    term:
      id: CL:0000113
      label: mononuclear phagocyte
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Constitutive SYK Kinase Hyperactivation
    description: >-
      The variant protein is more readily phosphorylated and signals more
      strongly than wild-type SYK.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
    explanation: >-
      Establishes the causative variants and the size of the defining series.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function biallelic variants in ZAP70 result in human immunodeficiency characterized by a selective T cell defect (OMIM 269840) 6, while pathogenic variation of SYK has not been described in humans."
    explanation: >-
      Records that no pathogenic SYK variation was known before this report, which
      is why the disease rests on a single defining series. Marked INDIRECT
      because it establishes the novelty of the finding rather than the variants
      themselves.
- name: Constitutive SYK Kinase Hyperactivation
  biological_scale: MOLECULAR
  description: >-
    The pivotal node. SYK is the tandem-SH2 kinase recruited to phosphorylated
    ITAMs of B cell receptors, Fc receptors and other immunoreceptors, and it also
    transduces signals from C-type lectin receptors, Toll-like receptors and
    integrins. The disease variants raise its phosphorylation and downstream
    output. The modifier here is GAIN_OF_FUNCTION rather than INCREASED because
    the claim is qualitative: the kinase escapes its normal regulatory constraint,
    not merely that there is more signalling.
  molecular_functions:
  - preferred_term: SYK protein tyrosine kinase activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004715
      label: non-membrane spanning protein tyrosine kinase activity
  biological_processes:
  - preferred_term: immune response-regulating cell surface receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0002768
      label: immune response-regulating cell surface receptor signaling pathway
  downstream:
  - target: Multi-Organ Inflammatory Disease
    description: >-
      Excess ITAM-proximal signalling in mononuclear phagocytes drives cytokine
      production and tissue inflammation.
  - target: Impaired Humoral Immunity
    description: >-
      The same hyperactive kinase in the B cell lineage is associated with reduced
      memory B cells and low immunoglobulins, so the inflammatory and deficiency
      branches share one upstream node.
  - target: B Cell Lymphomagenesis
    description: >-
      Sustained SYK signalling in the B cell lineage is the proposed route to
      diffuse large B cell lymphoma in these patients.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function."
    explanation: >-
      The direct functional demonstration that these variants are activating,
      which is the claim of this node.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These kinases are (1) the ζ-chain-associated protein kinase of 70 kDa (ZAP70), which is primarily expressed in T cells and natural killer cells, and (2) the spleen tyrosine kinase (SYK), which is primarily expressed in mononuclear phagocytes (MNPs), B cells and, to a lesser extent, the intestinal epithelium."
    explanation: >-
      Establishes where SYK acts, which is what makes the mononuclear phagocyte
      and B cell branches downstream of this node the expected ones.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SYK is also involved in signaling cascades from receptors without ITAMs, including C-type lectin receptors, Toll-like receptors and integrins 1,2."
    explanation: >-
      Supports the breadth of receptor input described in this node, which bears
      on why the inflammation is multi-organ rather than restricted to one
      receptor system.
- name: Multi-Organ Inflammatory Disease
  biological_scale: ORGANISM
  description: >-
    Systemic and tissue-specific inflammation from the first weeks of life: colitis
    with colonic ulceration and chronic inflammatory histology, arthritis,
    dermatitis and rash, vasculitis, and a raised acute-phase response with
    elevated C-reactive protein and interleukin-6.
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  cell_types:
  - preferred_term: mononuclear phagocyte
    term:
      id: CL:0000113
      label: mononuclear phagocyte
  downstream:
  - target: Colitis
  - target: Arthritis
  - target: Skin rash
  - target: Vasculitis
  - target: Elevated circulating C-reactive protein concentration
  - target: Diarrhea
  - target: Fever
  - target: Anal fistula
  - target: Failure to thrive
  - target: Pulmonary inflammation
    description: >-
      Three of the six patients had lung involvement in the multi-tissue
      inflammatory picture.
    evidence:
    - reference: PMID:33782605
      reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
      explanation: Names lung among the inflamed tissues and lists the affected patients.
  - target: Neuroinflammation
    description: >-
      Two of the six patients had central nervous system involvement in the same
      multi-tissue inflammatory picture.
    evidence:
    - reference: PMID:33782605
      reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
      explanation: Names the central nervous system among the inflamed tissues.
  - target: Hepatic granulomatosis
    description: >-
      One of the six patients had granulomatous liver disease.
    evidence:
    - reference: PMID:33782605
      reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
      explanation: Names granulomatous liver disease and the single affected patient.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colonoscopy at 17 months of age revealed multiple ulcers in the colon (Fig. 1a) with histologic features consistent with chronic colitis (Fig. 1b)."
    explanation: >-
      Documents the colitis with endoscopic and histological confirmation.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory tests showed normal white blood cell (WBC) counts but elevated C-reactive protein (CRP), high level of serum Interleukin (IL)-6, and reduced serum levels of immunoglobulin (Ig) M and IgG (Fig. 1e and Supplementary Table 1)."
    explanation: >-
      Documents the acute-phase response and, in the same sentence, the
      immunoglobulin deficiency that defines the other branch.
- name: Impaired Humoral Immunity
  biological_scale: ORGANISM
  description: >-
    The immunodeficiency branch, and the part of this disease that is least
    intuitive given an activating kinase variant. Patients have reduced memory B
    cells and low serum IgM and IgG, with recurrent infections; one patient in the
    defining series died of infectious complications before her third birthday.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Decreased circulating IgG concentration
  - target: Decreased circulating IgM concentration
  - target: Recurrent infections
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 2 and 3 both have reduced memory B cells (Supplementary Table 4)."
    explanation: >-
      Documents the memory B cell deficit underlying this node.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient passed away before her 3rd birthday due to complications from an infection."
    explanation: >-
      Records the clinical consequence of the immunodeficiency, which is what
      makes this branch more than a laboratory observation.
- name: B Cell Lymphomagenesis
  biological_scale: CELLULAR
  description: >-
    Diffuse large B cell lymphoma occurred in the defining series. SYK is a
    known oncogenic driver in B cell malignancy, so sustained hyperactive
    signalling in the B cell lineage is the proposed route. This entry records the
    association and the proposed mechanism; the causal step from the germline
    variant to the lymphoma is not separately demonstrated in that report, and the
    node description says so rather than implying it.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas"
    explanation: >-
      Records the lymphoma occurring within the defining patient series.
  downstream:
  - target: B-cell lymphoma
    description: >-
      Two of the four adult patients in the founding cohort developed diffuse large
      B cell lymphoma, which is the clinical endpoint of this arm.
    evidence:
    - reference: PMID:33782605
      reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we identified diffuse large B cell lymphomas (DLBCL) at a comparatively young age in two of the four adult patients (P5 and P6) with pathogenic SYK variants."
      explanation: >-
        Reports the lymphoma outcome in the cohort, which is what connects this
        node to its phenotype.

phenotypes:
- category: Gastrointestinal
  name: Colitis
  description: >-
    Very-early-onset colitis with colonic ulceration and chronic inflammatory
    histology, presenting within the first weeks to months of life.
  phenotype_term:
    preferred_term: Chronic colitis
    term:
      id: HP:0002583
      label: Colitis
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colonoscopy at four weeks of age revealed ulcers in the cecum with features of chronic inflammation."
    explanation: >-
      Documents the colitis with endoscopic confirmation in a second patient.
- category: Musculoskeletal
  name: Arthritis
  description: >-
    Inflammatory arthritis with joint pain and swelling, developing in infancy and
    persisting into adulthood in the affected parent.
  phenotype_term:
    preferred_term: Inflammatory arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also developed perianal fistulas (Fig. 1c) and arthritis indicated by joint pain and swelling of her hands (Fig. 1d)."
    explanation: >-
      Documents the arthritis and its clinical basis.
- category: Dermatologic
  name: Skin rash
  description: >-
    Whole-body rash from the neonatal period, part of the dermatitis reported
    across the series.
  phenotype_term:
    preferred_term: Whole body rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented at 2 weeks of age with fever, whole body rash and non-bloody diarrhea (5–8 times per day)"
    explanation: >-
      Documents the neonatal-onset rash.
- category: Vascular
  name: Vasculitis
  description: >-
    Generalized vasculitis reported in the neonatal presentation of one patient.
  phenotype_term:
    preferred_term: Generalized vasculitis
    term:
      id: HP:0002633
      label: Vasculitis
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented at two weeks of age with whole body rash, generalized vasculitis (Fig. 1g) and diarrhea"
    explanation: >-
      Documents the vasculitis at presentation.
- category: Gastrointestinal
  name: Diarrhea
  description: >-
    Non-bloody diarrhea from the neonatal period, a presenting feature in several
    patients.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "non-bloody diarrhea (5–8 times per day)"
    explanation: >-
      Documents the diarrhea and its frequency.
- category: Constitutional
  name: Fever
  description: >-
    Recurrent fever as part of the systemic inflammatory presentation.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was characterized by oral ulcers, fever, rash, diarrhea and failure to thrive"
    explanation: >-
      Documents fever as part of the clinical picture in the affected parent.
- category: Gastrointestinal
  name: Anal fistula
  description: >-
    Perianal fistulas, a fistulising complication of the colitis.
  phenotype_term:
    preferred_term: Perianal fistula
    term:
      id: HP:0010447
      label: Anal fistula
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also developed perianal fistulas (Fig. 1c)"
    explanation: >-
      Documents the perianal fistulas.
- category: Constitutional
  name: Failure to thrive
  description: >-
    Significant growth failure, reported in the index patient and in the affected
    parent as a child.
  phenotype_term:
    preferred_term: Growth failure
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had significant growth failure (Fig. 1f) and recurrent infections."
    explanation: >-
      Documents the growth failure alongside the infection susceptibility.
- category: Laboratory
  name: Elevated circulating C-reactive protein concentration
  description: >-
    Raised acute-phase response, with elevated C-reactive protein recorded
    repeatedly and accompanied by high serum interleukin-6.
  phenotype_term:
    preferred_term: Elevated C-reactive protein
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  reports_on:
  - target: Multi-Organ Inflammatory Disease
    relationship: READOUT_OF
    description: >-
      The acute-phase response is a systemic laboratory readout of the
      inflammatory node rather than a separate disease consequence.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By 15 months of age, she developed arthritis (Fig. 1h) with worsening colitis and multiple episodes of elevated CRP and WBC counts (Fig. 1i and Supplementary Table 2)."
    explanation: >-
      Documents repeated elevation of C-reactive protein alongside clinical
      flares.
- category: Immunologic
  name: Decreased circulating IgG concentration
  description: >-
    Reduced serum IgG, part of the humoral deficiency that coexists with the
    inflammation.
  phenotype_term:
    preferred_term: Reduced serum IgG
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  reports_on:
  - target: Impaired Humoral Immunity
    relationship: READOUT_OF
    description: >-
      Serum immunoglobulin measurement is the laboratory readout of the humoral
      deficiency node.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduced serum levels of immunoglobulin (Ig) M and IgG"
    explanation: >-
      Documents the reduction in serum IgG.
- category: Immunologic
  name: Decreased circulating IgM concentration
  description: >-
    Reduced serum IgM, measured alongside the IgG deficiency.
  phenotype_term:
    preferred_term: Reduced serum IgM
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  reports_on:
  - target: Impaired Humoral Immunity
    relationship: READOUT_OF
    description: >-
      Serum immunoglobulin measurement is the laboratory readout of the humoral
      deficiency node.
  notes: >-
    The bound label is the one in cache/hp/terms.csv, "Decreased circulating total
    IgM", which is what term validation enforces and what the five existing KB
    entries using this CURIE carry. A live OLS lookup of HP:0002850 returns
    "Decreased circulating IgM concentration" instead, so HPO appears to have
    renamed the term since the cache row was written. Recorded here rather than
    silently resolved either way, because the cache-first validator makes the
    live label the one that fails.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduced serum levels of immunoglobulin (Ig) M and IgG"
    explanation: >-
      Documents the reduction in serum IgM.
- category: Immunologic
  name: Recurrent infections
  description: >-
    Susceptibility to infection, fatal in the index patient. The affected parent
    was diagnosed as a child with an undefined immunodeficiency and advised
    against live vaccines.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As a child he was diagnosed with an undefined immunodeficiency with reduced CD4+ T cell counts and low immunoglobulins (Supplementary Table 3) and was advised against using live vaccines."
    explanation: >-
      Documents the clinical immunodeficiency and its management consequence.
- category: Neoplasm
  name: B-cell lymphoma
  description: >-
    Diffuse large B cell lymphoma at unusually young age. This is the name-defining
    malignancy risk of SYK gain of function and the reason the source paper
    recommends haematological surveillance.
  phenotype_term:
    preferred_term: diffuse large B cell lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  frequency: FREQUENT
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified diffuse large B cell lymphomas (DLBCL) at a comparatively young age in two of the four adult patients (P5 and P6) with pathogenic SYK variants."
    explanation: >-
      The source states 2 of the 4 adult patients, which is 50 percent; across the
      whole reported cohort of six it is 2/6, which is 33 percent. Both land in the
      FREQUENT band (30-79 percent), so the band does not turn on which denominator
      is used. The risk is nonetheless age-conditioned: every reported lymphoma was
      in an adult, and the band should not be read as a lifetime risk from infancy.
- category: Respiratory
  name: Pulmonary inflammation
  description: >-
    Lung involvement as part of the multi-tissue inflammatory disease, reported in
    three of the six patients. The source names the organ without characterising the
    pattern radiologically or histologically.
  phenotype_term:
    preferred_term: pulmonary inflammation
  frequency: FREQUENT
  notes: >-
    Deliberately left unbound. HPO was searched via the OLS adapter for pulmonary
    inflammation, lung inflammation, pneumonitis and abnormal pulmonary terms; the
    candidates returned are all narrower than the source supports
    (HP:0006515 Interstitial pneumonitis, HP:0002113 Pulmonary infiltrates) or are
    morphological rather than inflammatory (HP:0002088 Abnormal lung morphology).
    The source says only that the lung was among the inflamed tissues, so binding any
    of these would manufacture specificity the paper does not claim.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
    explanation: >-
      Names lung among the inflamed tissues in Patients 2, 5 and 6, which is 3/6 or
      50 percent, inside the FREQUENT band (30-79 percent).
- category: Neurologic
  name: Neuroinflammation
  description: >-
    Central nervous system involvement as part of the multi-tissue inflammatory
    disease, reported in two of the six patients.
  phenotype_term:
    preferred_term: central nervous system inflammation
    term:
      id: HP:0033429
      label: Neuroinflammation
  frequency: FREQUENT
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
    explanation: >-
      Names the central nervous system among the inflamed tissues in Patients 4 and
      5, which is 2/6 or 33 percent, inside the FREQUENT band (30-79 percent).
- category: Hepatic
  name: Hepatic granulomatosis
  description: >-
    Granulomatous liver disease, reported in one of the six patients.
  phenotype_term:
    preferred_term: granulomatous liver disease
    term:
      id: HP:0011955
      label: Hepatic granulomatosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All Patients had inflammation in multiple tissues including bowel (Patients 1–6), skin (Patients 1–5), joints (Patients 1–3 and 6), lung (Patients 2, 5, 6), central nervous system (Patients 4 and 5) and granulomatous liver disease (Patient 6)."
    explanation: >-
      Names granulomatous liver disease in Patient 6 alone, which is 1/6 or 17
      percent, inside the OCCASIONAL band (5-29 percent).

genetic:
- name: SYK
  gene_term:
    preferred_term: SYK
    term:
      id: hgnc:11491
      label: SYK
  relationship_type: CAUSATIVE
  notes: >-
    SYK and ZAP70 are the two tandem-SH2 kinases recruited to phosphorylated ITAMs
    and are functionally paired: ZAP70 acts principally in T and NK cells, SYK in
    mononuclear phagocytes and B cells. The two diseases are mirror images -
    biallelic ZAP70 loss of function gives a selective T cell defect, monoallelic
    SYK gain of function gives this disorder. dismech already carries a
    ZAP70_Deficiency entry; the pairing is why this entry's cell types are
    phagocyte and B cell rather than T cell.

    The variant modelled in mouse is the human p.Ser550Tyr, corresponding to mouse
    Ser544Tyr.

    Allelic series across the six reported patients: p.S550Y (Patient 1, de novo),
    p.S550F (Patients 2 and 3), p.P342T (Patient 4, de novo), p.A353T (Patient 5)
    and p.M450I (Patient 6). The positions group into three structural classes that
    the source distinguishes: p.S550 sits close to the two activation-loop tyrosines
    and away from the ATP pocket; p.M450 sits close to the ATP-binding pocket; and
    p.P342T and p.A353T sit in the interdomain B linker that holds SYK
    auto-inhibited. All are novel or very rare and carry CADD scores above 25.
    ClinVar accessions SCV001450452 to SCV001450456 are cited by the source.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function biallelic variants in ZAP70 result in human immunodeficiency characterized by a selective T cell defect (OMIM 269840) 6, while pathogenic variation of SYK has not been described in humans."
    explanation: >-
      States the ZAP70 contrast described in the notes and, in the same sentence,
      that SYK disease was previously unknown.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study we identify monoallelic gain-of-function variants in SYK that result in immunodeficiency and systemic inflammatory disease in humans"
    explanation: >-
      States the causative gene-disease relationship in humans. Quoted to the human
      clause only: the rest of the sentence reports the mouse result, and the animal
      model cites that half separately as MODEL_ORGANISM. One sentence cannot carry
      two evidence_source values, so each item quotes the clause it is graded on.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We next screened for additional SYK variants in a number of patient registries and found 3 additional patients with potential monoallelic damaging variants in evolutionary conserved residues of SYK (p.P342T, p.A353T and p.M450I)."
    explanation: >-
      Source for the three further alleles beyond the p.S550 pair, and for the fact
      that they were ascertained from registries rather than the index family.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The p.P342T and p.A353T variants are located in the linker region (interdomain B) that maintains SYK in an auto-inhibited conformation"
    explanation: >-
      Source for the structural rationale recorded in the notes: these two alleles
      act by releasing autoinhibition rather than at the ATP pocket or activation
      loop. Graded IN_VITRO because the claim rests on the paper's structural and
      biochemical characterisation rather than on a patient observation.
animal_models:
- name: SYK Ser544Tyr knock-in mouse
  species: Mouse
  genotype: Syk p.Ser544Tyr knock-in, corresponding to human p.Ser550Tyr
  publication: PMID:33782605
  description: >-
    A knock-in of the mouse residue equivalent to a patient variant, made in the
    defining study. Unlike many immunodeficiency models it reproduces substantial
    parts of the human disease, which is what makes the treatment experiments in
    it interpretable.
  modeled_mechanisms:
  - target: Multi-Organ Inflammatory Disease
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces aspects of the human inflammatory disease from the orthologous
      point variant, at the whole-organism scale.
    limitations: >-
      The authors' own wording is that the model recapitulates "aspects of" the
      human disease, not the whole of it, and the report does not claim the
      lymphoma phenotype is reproduced. It is one knock-in of one of the several
      patient variants, so it does not speak to allelic heterogeneity.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The engineered residue is the mouse equivalent (Ser544) of the human
        residue (Ser550), so the model tests the orthologous substitution rather
        than the human allele itself. Global Syk knockout is perinatally lethal in
        mouse, indicating that murine SYK dosage requirements are not identical to
        human.
    evidence:
    - reference: PMID:33782605
      reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice."
      explanation: >-
        States both the recapitulation and its limits, and is the source for the
        two treatment records below.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "show that the expression of one of these variants in a mouse model replicates major aspects of the human immunopathology"
    explanation: >-
      Attests that this model is informative for the human disease.
treatments:
- name: SYK kinase inhibition
  description: >-
    Pharmacological inhibition of the hyperactive kinase, the mechanistically
    obvious treatment and the one the defining study tested. R406, the active
    metabolite of fostamatinib, occupies the ATP-binding pocket and competes with
    free ATP. In the knock-in mouse this partially treated the disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: SYK kinase inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fostamatinib
      term:
        id: NCIT:C95222
        label: Fostamatinib
  target_mechanisms:
  - target: Constitutive SYK Kinase Hyperactivation
    description: >-
      Competitive ATP-site inhibition reduces the kinase activity at the node
      immediately downstream of the genetic lesion. This is the one treatment here
      that acts on the causal node rather than on its consequences.
  notes: >-
    Efficacy is demonstrated in the knock-in mouse and was partial there. This
    entry records no human trial evidence, because the defining report describes
    none. The phrase "potentially treatable" is the authors' own and is quoted
    below rather than upgraded.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice."
    explanation: >-
      Reports partial treatment response in the mouse model. Graded
      MODEL_ORGANISM, and the word "partially" is retained in the quote rather
      than paraphrased away.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "R406, the active metabolite of fostamatinib, attaches to the ATP-binding pocket of SYK and sterically competes with free ATP to inhibit SYK kinase activity9."
    explanation: >-
      Establishes the molecular mechanism by which the agent acts on the target
      node.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease."
    explanation: >-
      The authors' own summary claim. Marked INDIRECT deliberately: "potentially
      treatable" is a forward-looking statement resting on the mouse experiment,
      not a report of human treatment.
- name: Allogeneic hematopoietic cell transplantation
  description: >-
    Replacement of the affected haematopoietic compartment. Because SYK acts in
    mononuclear phagocytes and B cells, which are haematopoietic, transplantation
    is mechanistically curative in principle. Transplantation of wild-type bone
    marrow partially treated the knock-in mouse.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Monoallelic SYK Gain-of-Function Variants
    description: >-
      Replaces the variant-carrying haematopoietic cells with wild-type cells,
      removing the lesion from the lineages in which it acts. Unlike kinase
      inhibition this addresses the genetic node itself, but only in the
      haematopoietic compartment - the report notes SYK expression in intestinal
      epithelium as well.
  notes: >-
    Shown in the mouse model, not in a reported human series. The mechanistic
    caveat above is real: the same report records SYK expression in intestinal
    epithelium, which a haematopoietic transplant would not replace.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice"
    explanation: >-
      Reports the partial response to wild-type bone marrow transplantation in the
      knock-in mouse.
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "which is primarily expressed in mononuclear phagocytes (MNPs), B cells and, to a lesser extent, the intestinal epithelium"
    explanation: >-
      Supports the rationale for a haematopoietic transplant while naming the
      non-haematopoietic compartment it would not address. Marked INDIRECT because
      it describes expression rather than a treatment result.
- name: Haematological malignancy surveillance
  description: >-
    Regular screening for haematological malignancy in patients with a suspected or
    confirmed SYK gain-of-function variant. This is the source paper's explicit
    management directive and follows from the lymphoma risk recorded above, not from
    any trial.
  treatment_term:
    preferred_term: haematological malignancy screening
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with suspected SYK gain-of-function variants should be regularly screened for hematological malignancies."
    explanation: >-
      The authors' stated recommendation, quoted rather than paraphrased into a
      stronger claim. No screening interval or modality is specified by the source
      and none is invented here.
  notes: >-
    Recorded as a surveillance recommendation, not an intervention with an outcome.
    No study evaluates whether screening changes outcome in this disease.

diagnosis:
- name: Constitutive SYK phosphorylation assay
  description: >-
    Spontaneous tyrosine phosphorylation of SYK Y525/526 in unstimulated patient
    PBMC, used as the functional confirmation that a candidate variant is activating.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PBMC from Patients 1 and 3 showed spontaneous tyrosine phosphorylation of Y525/526 SYK, tyrosine residues known to regulate auto-phosphorylation and activation"
    explanation: >-
      Documents the confirmatory assay and the residues read out. Graded IN_VITRO
      because the measurement is made on cultured patient cells.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    An ultra-rare entity defined in 2021. The founding report describes six patients
    from the combined index family and three patient registries, and no population
    frequency has been estimated. No rate is recorded because a denominator would
    have to be invented.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
    explanation: >-
      Establishes the size of the entire reported cohort, which is what the
      CASES_IN_LITERATURE measure reports.

references:
- reference: PMID:33782605
  title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."

discussions:
- discussion_id: syk_gof_inflammation_and_deficiency_together
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    How does a single activating kinase variant produce immunodeficiency and
    systemic inflammation at the same time?
  attaches_to:
  - pathophysiology#Constitutive SYK Kinase Hyperactivation
  - pathophysiology#Impaired Humoral Immunity
  rationale: >-
    A gain-of-function variant in a proximal immunoreceptor kinase predicts
    inflammation, and that is observed. It does not obviously predict reduced
    memory B cells, low IgM and IgG, and fatal infection, and those are observed
    too, in the same patients.

    Several accounts are compatible with the curated evidence and none is
    established by it. Chronically hyperactive B cell receptor signalling could
    drive anergy or deletion rather than productive responses, in which case the
    deficiency is a downstream consequence of the same excess. The deficiency
    could instead be secondary to the inflammatory disease itself - protein loss
    through an ulcerated colon, or the effect of chronic inflammation on
    lymphopoiesis. Or the two could be genuinely independent effects of SYK in
    different lineages. The distinction matters for treatment: if the deficiency
    is driven by excess signalling then kinase inhibition should improve it,
    whereas if it is a consequence of tissue damage it should follow the colitis
    instead.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas."
    explanation: >-
      Establishes that deficiency and inflammation co-occur in the same patients,
      which is the fact this question is about.
- discussion_id: syk_gof_single_defining_series
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the phenotypic spectrum of SYK gain-of-function disease beyond the six
    patients of the defining series?
  attaches_to:
  - disease#Immunodeficiency 82 With Systemic Inflammation
  rationale: >-
    Essentially every mechanistic and clinical claim in this entry traces to one
    2021 report of six patients. That is enough to establish the disease and not
    enough to establish its range: penetrance, the proportion of carriers who
    develop lymphoma, whether milder adult-onset presentations exist, and whether
    the other patient variants behave like the one modelled in mouse are all
    unaddressed.

    This is recorded as a knowledge gap rather than left implicit because it
    changes how the rest of the entry should be read. A reader should treat the
    phenotype list here as the presentation of one ascertained series, not as a
    frequency distribution over the disease.
  evidence:
  - reference: PMID:33782605
    reference_title: "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while pathogenic variation of SYK has not been described in humans"
    explanation: >-
      Records that this report was the first description, which is why no
      independent series exists to compare against.
📚

References & Deep Research

References

1
PMID:33782605
Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Immunodeficiency 82 With Systemic Inflammation (SYK, MONDO:0030308) · 2026-09-12T14:11:22Z · View source

De novo curation of IMD82, monoallelic SYK gain-of-function disease, from claim issue #11740. The entry models one upstream node, constitutive SYK kinase hyperactivation, branching into three: multi-organ inflammatory disease, impaired humoral immunity, and B cell lymphomagenesis. The second branch is the counter-intuitive one and is curated rather than dropped: an activating variant in a proximal immunoreceptor kinase predicts inflammation, and these patients also have reduced memory B cells, low IgM and IgG, and fatal infection. An OPEN_QUESTION discussion sets out the candidate explanations and says none is established by the curated evidence. Gain of function is recorded in both places the CLAUDE.md rule requires, because they are two claims: functional_impact_category GAIN_OF_FUNCTION on the variant genetic_context, and modifier GAIN_OF_FUNCTION on the kinase activity descriptor. The modifier is the qualitative value rather than INCREASED because the variants remove the kinase from normal autoinhibitory constraint rather than merely raising its level. Evidence base. Essentially the whole entry rests on one 2021 report of six patients. That is recorded as a KNOWLEDGE_GAP rather than left implicit, because it changes how the phenotype list should be read: it is the presentation of one ascertained series, not a frequency distribution. Both treatments carry evidence_source MODEL_ORGANISM and notes stating that efficacy was shown in the knock-in mouse and was partial there, with no human trial reported. The authors' phrase potentially treatable is quoted rather than upgraded, and is marked directness INDIRECT because it is a forward-looking claim resting on the mouse. Deep research required two runs and the first was discarded. The first openscientist report for this disease contained zero mentions of SYK and fifty of RIPK1: an entirely different disease. just preflight-dr returned FAIL and correctly said to discard it rather than cherry-pick. Re-running returned the identical report from the local deep-research cache in 0.01 seconds with cached true, because the cache is keyed on the query and the query was correct; the provider had simply answered the wrong question. Recovery required evicting the specific cache entry by hand, after which the re-run produced a correct report with 98 SYK mentions, zero RIPK1, a preflight PASS, and an OMIM number matching MONDO. Both the provider failure and the absence of a supported cache-bust path are filed as issue #11748; the off-target report and its cache entry are preserved outside the repository. The corrected report was read and deliberately not mined for additional citations. Its reference list is padded with general SYK biology that is not about this disease: mantle cell lymphoma BCR signalling, a SYK chemical-genetics mouse. Adding those would have inflated the apparent evidence base of an entry whose honest state is one source, which is the opposite of what the KNOWLEDGE_GAP records. One binding correction during curation: cache/hp/terms.csv holds HP:0002850 as Decreased circulating total IgM while a live OLS lookup returns Decreased circulating IgM concentration. Term validation is cache-first, so the live label failed. The cached label was used, matching the five existing KB entries that bind this CURIE, and the discrepancy is recorded in the phenotype notes and filed as issue #11750. Validation: just validate passed with 35/35 snippets verified; just validate-terms passed; check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms and check-snippet-length all clean.

OpenScientist ▸
Immunodeficiency 82 With Systemic Inflammation (IMD82) — Comprehensive Disease Characterization Report
openscientist-autonomous 18 citations 2026-09-12T13:55:39.771523

Immunodeficiency 82 With Systemic Inflammation (IMD82) — Comprehensive Disease Characterization Report

Target Disease: Immunodeficiency 82 With Systemic Inflammation OMIM: #619381 · MONDO: MONDO:0030308 · Causal gene: SYK (HGNC:11491) Category: Mendelian (monogenic inborn error of immunity)

Summary

Immunodeficiency 82 with systemic inflammation (IMD82) is an ultra-rare, autosomal dominant inborn error of immunity (IEI) caused by germline heterozygous gain-of-function (GOF) missense variants in SYK (spleen tyrosine kinase). The disease was defined in 2021 by Wang and colleagues, who identified damaging monoallelic SYK variants in six patients presenting with a distinctive triad: immune deficiency, multi-organ inflammatory disease (colitis, arthritis, dermatitis), and diffuse large B-cell lymphoma (DLBCL) (PMID: 33782605). The variants increase SYK phosphorylation and enhance downstream signaling, establishing a gain-of-function mechanism.

Mechanistically, SYK is normally held in an autoinhibited conformation in which its tandem SH2 (tSH2) domain and interdomain linkers constrain the kinase domain. Binding of phosphorylated immunoreceptor tyrosine-based activation motifs (pITAMs) plus autophosphorylation switches SYK to its active state (PMID: 23154170). IMD82 variants bias SYK toward the active conformation, producing constitutive ITAM-based signaling through PLCγ2, PI3K–AKT, MAPK/ERK, and NF-κB. This single hyperactive-kinase lesion simultaneously drives the inflammatory arm (excess cytokine/immune-cell activation) and the malignant arm (sustained pro-survival BCR/PI3K signaling that predisposes B cells to lymphoma).

Because the driver is a druggable, hematopoietically restricted kinase, IMD82 is potentially treatable. A knock-in Syk-Ser544Tyr mouse (modeling the patient variant p.Ser550Tyr) recapitulated key disease features that could be partially corrected either with a SYK inhibitor or with transplantation of wild-type bone marrow (PMID: 33782605). Fostamatinib, an FDA-approved oral SYK inhibitor (approved for chronic immune thrombocytopenia), provides a clinically available agent whose mechanism directly matches the disease lesion. Diagnosis relies on next-generation sequencing (whole-exome/whole-genome sequencing or IEI gene panels) with confirmatory functional testing of elevated SYK phosphorylation/downstream signaling. Only ~6 patients have been reported worldwide, so much of the clinical natural history remains to be defined.

Key Findings

Finding 1 — IMD82 is caused by monoallelic gain-of-function variants in SYK

Wang et al. (2021, Nature Genetics) identified damaging monoallelic (heterozygous) SYK variants in six patients. Functional assays demonstrated that the variants increased SYK phosphorylation and enhanced downstream signaling, formally establishing a gain-of-function (rather than loss-of-function) mechanism and an autosomal dominant mode of inheritance. This is the defining genetic feature of the disease and is catalogued as OMIM #619381 / MONDO:0030308.

"We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function." — PMID: 33782605

This finding is notable because most SYK-related disease hypotheses historically concerned loss of function; IMD82 is a rare instance where a kinase gain-of-function drives a combined immunodeficiency-plus-autoinflammation syndrome.

Finding 2 — SYK is normally autoinhibited; GOF variants disrupt the activation switch

Crystal structures of full-length SYK reveal an autoinhibited conformation in which the tandem SH2 (tSH2) domain and interdomain linkers restrain kinase activity. Binding of phosphorylated ITAMs to the tSH2 domain, together with autophosphorylation of interdomain-A tyrosines (e.g., Y348/Y352), switches SYK to the active conformation and strongly stimulates in vitro autophosphorylation (PMID: 23154170). IMD82 patient variants (e.g., p.Ser550Tyr, and residues in the interdomain-A/kinase regions) constitutively bias this switch toward the active state, producing elevated basal phosphorylation and downstream signaling.

"Here, we present the first crystal structures of full-length Syk (fl-Syk) as wild type and as Y348F,Y352F mutant forms in complex with AMP-PNP revealing an autoinhibited conformation." — PMID: 23154170

"The functional relevance of pITAM binding to fl-Syk was confirmed by a strong stimulation of in vitro autophosphorylation." — PMID: 23154170

This provides a clear structural rationale for the disease: the GOF variants relieve the molecular brake that normally couples SYK activation to receptor engagement.

Finding 3 — Constitutive SYK signaling links the inflammatory and lymphoma-predisposition arms

SYK is the proximal kinase that transduces signals from the B-cell receptor (BCR) and Fc/C-type-lectin receptors into downstream PI3K–AKT, PLCγ2, MAPK/ERK, and NF-κB cascades (PMID: 35398488; PMID: 38503806). Sustained/tonic PI3K-pathway signaling downstream of SYK promotes B-cell survival rather than negative selection, and high SYK/BCR signaling activity predicts aggressive B-cell lymphoma behavior. This mechanistically unifies the two seemingly disparate arms of IMD82 — chronic multi-organ inflammation and predisposition to DLBCL — under a single constitutively active kinase.

"ZAP70 diverts SYK from activation of NFAT towards tonic PI3K-signaling, which promotes survival instead of cell death" — PMID: 35398488

In mantle cell lymphoma, higher BCR/SYK signaling responses correlate with shorter progression-free and overall survival, underscoring that SYK signaling intensity is a determinant of malignant aggressiveness (PMID: 38503806).

Finding 4 — Clinical phenotype: pediatric-onset immunodeficiency + multi-organ autoinflammation + DLBCL

In the defining cohort of six patients, the phenotype combined immune deficiency with multi-organ inflammatory disease — colitis (HP:0002583), arthritis (HP:0001369), and dermatitis (HP:0011123) — plus diffuse large B-cell lymphoma (HP:0004297) (PMID: 33782605). Onset is typically in childhood, frequently as a very-early-onset inflammatory-bowel-disease-like presentation. IMD82/SYK is incorporated into the formal IUIS Inborn Errors of Immunity classification framework used for diagnosis (PMID: 41608114).

"immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas" — PMID: 33782605

"This report provides an updated classification of inborn errors of immunity (IEIs) involving 508 different genes and 17 phenocopies." — PMID: 41608114

Finding 5 — Ultra-rare autosomal dominant disorder diagnosed by exome/genome sequencing

Only ~6 patients were reported in the defining publication, and no population prevalence/incidence estimates exist (ultra-rare). Inheritance is autosomal dominant (monoallelic/heterozygous variants), consistent with both de novo and inherited transmission. Diagnosis relies on next-generation sequencing (WES/WGS or IEI gene panels), as used across monogenic VEO-IBD and IEI cohorts, with confirmatory functional assays demonstrating elevated SYK phosphorylation/downstream signaling (PMID: 33782605).

"We identified damaging monoallelic SYK variants in six patients" — PMID: 33782605

Finding 6 — The disease is potentially treatable with SYK inhibition or bone-marrow transplant

A knock-in Syk-Ser544Tyr mouse (modeling patient variant p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or with transplantation of wild-type bone marrow (PMID: 33782605). Fostamatinib is an FDA-approved oral SYK inhibitor (approved for chronic ITP), making targeted pharmacotherapy immediately plausible.

"A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice." — PMID: 33782605

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A germline heterozygous gain-of-function missense variant in SYK (e.g., p.Ser550Tyr) arises de novo or is inherited (autosomal dominant). — demonstrated (PMID: 33782605)
  2. The variant disrupts SYK's autoinhibited conformation — normally maintained by the tSH2 domain and interdomain-A linkers — biasing the kinase toward its active state. — inferred from structure (PMID: 23154170)
  3. This relieves the requirement for pITAM engagement/autophosphorylation, so SYK exhibits elevated basal (constitutive) kinase activity and enhanced phosphorylation independent of full receptor input. — demonstrated (increased pSYK) (PMID: 33782605)
  4. Constitutive SYK activity hyper-transduces ITAM-coupled receptor signals (BCR, Fc receptors, C-type lectin receptors) into downstream cascades: PLCγ2, PI3K–AKT, MAPK/ERK, and NF-κB. — demonstrated/inferred (PMID: 35398488)
  5. The mechanism then branches:
  6. Branch A (autoinflammation/immune dysregulation): Excess NF-κB/MAPK-driven cytokine production and immune-cell activation in myeloid and lymphoid compartments → multi-organ inflammation (colitis, arthritis, dermatitis). Paradoxical immune deficiency co-exists, reflecting dysregulated rather than simply amplified immunity. — demonstrated clinically (PMID: 33782605)
  7. Branch B (lymphomagenesis): Sustained tonic PI3K–AKT survival signaling downstream of SYK promotes B-cell survival over negative selection, permitting accumulation of transformation-prone clones → diffuse large B-cell lymphoma. — inferred from lymphoma biology (PMID: 35398488; PMID: 38503806)
  8. Because the lesion is a hematopoietically restricted, druggable kinase, SYK inhibition (pharmacologic) or replacement of the mutant hematopoietic compartment (WT bone-marrow transplant) partially reverses disease. — demonstrated in mouse (PMID: 33782605)

Schematic

  SYK GOF variant (e.g. p.Ser550Tyr)
      │  disrupts
      ▼
  Autoinhibited SYK  ──X──►  Constitutively ACTIVE SYK
   (tSH2 brake)                    │ hyper-signaling
                   ▼
┌──────────── ITAM-coupled receptor cascades ────────────┐
│      PLCγ2 · PI3K–AKT · MAPK/ERK · NF-κB                 │
└──────────────┬───────────────────────┬──────────────────┘
       │                        │
     BRANCH A (inflammation)     BRANCH B (survival)
     cytokines, immune            tonic PI3K–AKT →
     dysregulation                B-cell survival
       │                        │
       ▼                        ▼
Colitis, arthritis,            Diffuse large B-cell
dermatitis + immune            lymphoma (DLBCL)
deficiency
       │                        │
       └──── TREATABLE via ─────┘
     SYK inhibitor (fostamatinib) │ WT BMT/HSCT

Upstream vs downstream

  • Upstream (initiating): the SYK GOF variant and loss of autoinhibition.
  • Midstream (amplifying): constitutive PLCγ2/PI3K–AKT/MAPK/NF-κB signaling.
  • Downstream (manifesting): organ inflammation and B-cell lymphomagenesis.

Suggested ontology terms

  • Gene/protein: SYK (HGNC:11491); GO:0004715 (non-membrane spanning protein tyrosine kinase activity); GO:0050853 (B cell receptor signaling pathway); GO:0038094 (Fc receptor signaling); GO:0002250 (adaptive immune response); GO:0006954 (inflammatory response); GO:0043066 (negative regulation of apoptotic process).
  • Cell types (CL): CL:0000236 (B cell), CL:0000235 (macrophage), CL:0000775 (neutrophil), CL:0000542 (lymphocyte).
  • Subcellular (GO CC): GO:0005829 (cytosol), GO:0005886 (plasma membrane / receptor-proximal).
  • Anatomy (UBERON): UBERON:0000160 (intestine) — colitis; joint/synovium — arthritis; UBERON:0002097 (skin) — dermatitis; UBERON:0002509 (lymphoid tissue) — lymphoma.
  • Chemical (CHEBI): fostamatinib / R788 (SYK inhibitor prodrug); ATP-competitive kinase inhibition.
  • Disease: MONDO:0030308; Phenotypes (HPO): HP:0002583 (colitis), HP:0001369 (arthritis), HP:0011123 (inflammatory abnormality of the skin / dermatitis), HP:0004297 (neoplasm of the immune system / lymphoma), HP:0002715 (abnormality of the immune system / immunodeficiency).

Section-by-Section Report

1. Disease Information

IMD82 is a Mendelian inborn error of immunity in which a single hyperactive kinase produces a combined phenotype of immunodeficiency, systemic autoinflammation, and B-cell lymphoma predisposition. - Key identifiers: OMIM #619381; MONDO:0030308; causal gene SYK (HGNC:11491). Orphanet, ICD-10/ICD-11, and MeSH-specific codes are not clearly established for this ultra-rare 2021-defined entity; it maps within IEI/combined immunodeficiency-with-associated-features categories. - Synonyms: "Immunodeficiency 82 with systemic inflammation"; "SYK gain-of-function disease"; "SYK-GOF immune dysregulation." - Information source: Aggregated disease-level resources (OMIM, IUIS classification) built from an individual-patient case series (n≈6) rather than large EHR datasets.

2. Etiology

  • Causal factor: Genetic — germline heterozygous GOF missense variants in SYK (monogenic, autosomal dominant) (PMID: 33782605).
  • Genetic risk factors: The causal SYK variant itself is necessary and sufficient. Modifier genes are not defined given the tiny cohort. ZAP70 (SYK's paralog) shapes SYK signaling output in principle (PMID: 35398488).
  • Environmental risk factors: No established environmental triggers; inflammatory flares plausibly modulated by microbial/antigenic exposure via ITAM-coupled receptors (inferred, not demonstrated).
  • Protective factors: None defined. By mechanistic logic, reduced SYK signaling (pharmacologic inhibition) is protective against manifestations.
  • Gene–environment interactions: Not characterized; the ITAM-receptor biology implies antigen/microbe exposure could amplify constitutive signaling.

3. Phenotypes

Phenotype Type HPO Onset Frequency (n≈6 cohort)
Colitis / IBD-like enteropathy Clinical sign HP:0002583 Childhood/very-early-onset Core feature
Arthritis Clinical sign HP:0001369 Childhood Core feature
Dermatitis Physical manifestation HP:0011123 Childhood Core feature
Immunodeficiency (infection susceptibility) Clinical/lab HP:0002715 Childhood Core feature
Diffuse large B-cell lymphoma Neoplasm HP:0004297 Childhood–young adult Reported in cohort

Severity is variable and can be severe/refractory; progression includes both chronic inflammation and episodic flares plus a serious oncologic complication (DLBCL). Quality-of-life impact is substantial (chronic multi-organ inflammation, malignancy risk, treatment burden), though formal EQ-5D/SF-36 data are unavailable for this ultra-rare disease (PMID: 33782605).

4. Genetic / Molecular Information

  • Causal gene: SYK (spleen tyrosine kinase), chromosome 9q22, HGNC:11491; encodes a cytoplasmic non-receptor tyrosine kinase with tandem SH2 domains + kinase domain.
  • Variant classification/type: Pathogenic/likely pathogenic missense variants (e.g., p.Ser550Tyr) affecting the activation switch (interdomain-A/kinase regions) (PMID: 33782605).
  • Functional consequence: Gain of function — increased phosphorylation and enhanced downstream signaling.
  • Allele frequency: Effectively absent from population databases (gnomAD) given pathogenicity and rarity.
  • Origin: Germline (monoallelic); both de novo and inherited transmission consistent with AD inheritance. (Note: a distinct somatic ETV6–SYK fusion drives chronic eosinophilic leukemia — a separate entity, not IMD82 — PMID: 42005114.)
  • Modifier genes / epigenetics / chromosomal abnormalities: Not defined for this disorder.

5. Environmental Information

No established environmental, lifestyle, or infectious causes. The disease is monogenic. Because SYK sits downstream of pattern-recognition and Fc/C-type-lectin receptors, microbial and antigenic exposures are plausible amplifiers of inflammation but are not demonstrated drivers.

6. Mechanism / Pathophysiology

Presented above as the ordered causal chain and schematic. In brief: a SYK GOF variant disrupts kinase autoinhibition → constitutive ITAM-coupled signaling (PLCγ2, PI3K–AKT, MAPK/ERK, NF-κB) → branches into (A) multi-organ autoinflammation with paradoxical immunodeficiency and (B) tonic PI3K–AKT survival signaling predisposing to DLBCL. Key molecular pathways: B-cell receptor signaling (Reactome/KEGG), Fc receptor signaling, PI3K–AKT, MAPK, NF-κB. Cellular processes: inflammation, dysregulated lymphocyte/myeloid activation, and suppressed apoptosis/enhanced survival of B cells. Immune involvement spans both immunodeficiency and chronic inflammation — a hallmark of immune-dysregulation IEIs.

7. Anatomical Structures Affected

  • Primary organs/systems: Gastrointestinal tract (colon — colitis; UBERON:0000160), joints (arthritis; synovium), skin (dermatitis; UBERON:0002097), and the immune/lymphoid system (UBERON:0002509).
  • Secondary/complication: Lymphoid tissues affected by DLBCL; systemic effects of chronic inflammation.
  • Cell populations: B lymphocytes (CL:0000236) central; macrophages (CL:0000235), neutrophils (CL:0000775), and other ITAM-receptor-bearing hematopoietic cells contribute.
  • Subcellular: Cytosolic/plasma-membrane-proximal signaling compartments (GO:0005829, GO:0005886).
  • Laterality: Systemic/bilateral (not a lateralized disease).

8. Temporal Development

  • Onset: Pediatric/childhood, often very-early-onset (VEO-IBD-like presentation); course is chronic with episodic inflammatory flares.
  • Progression: Variable; chronic multi-organ inflammation punctuated by the serious late complication of DLBCL.
  • Critical windows: Early SYK-targeted intervention is mechanistically attractive to blunt both inflammation and lymphoma risk (inferred from mouse rescue data, PMID: 33782605).

9. Inheritance and Population

  • Epidemiology: Ultra-rare; ~6 reported patients; no prevalence/incidence estimates.
  • Inheritance: Autosomal dominant (monoallelic/heterozygous). Penetrance/expressivity not quantifiable in so small a cohort; both de novo and inherited variants are consistent with the genetics.
  • Founder effects/consanguinity/carrier frequency: Not applicable (dominant, ultra-rare).
  • Demographics: No described ethnic, geographic, or sex predilection.

10. Diagnostics

  • Recommended approach: Next-generation sequencing — whole-exome or whole-genome sequencing, or IEI/VEO-IBD gene panels including SYK — is the diagnostic backbone (PMID: 33782605; cohorts in PMID: 42494428, PMID: 42724325).
  • Confirmatory functional testing: Phospho-specific assays demonstrating elevated basal/inducible SYK phosphorylation (pSYK) and enhanced downstream signaling distinguish GOF variants from benign or LOF variants — a key step because SYK variant interpretation requires functional context.
  • Supportive workup: Immunophenotyping/immunoglobulin levels (immunodeficiency evaluation), inflammatory markers, endoscopy/biopsy for colitis, and oncologic staging if lymphoma is suspected.
  • Differential diagnosis: Other monogenic immune-dysregulation/VEO-IBD disorders (e.g., CTLA4 haploinsufficiency — PMID: 42577265), other IEIs with autoimmunity/lymphoproliferation (PMID: 42625995). Functional pSYK testing plus the specific SYK variant distinguishes IMD82.

11. Outcome / Prognosis

No formal survival statistics exist for this ultra-rare entity. Prognosis is shaped by (a) severity/refractoriness of multi-organ inflammation and (b) the serious complication of DLBCL, which historically carries substantial mortality. The identification of a druggable, hematopoietically restricted target materially improves the outlook, since SYK inhibition or HSCT can address the root cause (mouse-model rescue, PMID: 33782605). Prognostic biomarkers plausibly include SYK/BCR signaling intensity, given its correlation with aggressive B-cell lymphoma behavior (PMID: 38503806).

12. Treatment

  • Targeted pharmacotherapy (NCIT: spleen tyrosine kinase inhibitor): Fostamatinib (R788), an FDA-approved oral SYK inhibitor (approved for chronic ITP), mechanistically matches the lesion; mouse data show a SYK inhibitor partially treats the disease (PMID: 33782605). Fostamatinib's efficacy in other SYK-driven immune disorders (ITP, warm AIHA, TRAF3-deficient autoimmunity) supports the class rationale (PMID: 40903253; PMID: 42026764). Safety note: fostamatinib carries potential vascular/thrombotic and off-target concerns (e.g., a reported aortic-dissection case, PMID: 40962713).
  • Cell therapy (NCIT: hematopoietic stem cell transplantation): Allogeneic HSCT / wild-type bone-marrow transplant is curative in the mouse model and is a rational option because the disease is hematopoietically restricted (PMID: 33782605).
  • Supportive/anti-inflammatory therapy: Standard IEI/IBD management (immunoglobulin replacement for immunodeficiency; anti-inflammatory/biologic/JAK-inhibitor strategies for colitis/arthritis/dermatitis, extrapolated from VEO-IBD practice, PMID: 42499735).
  • Lymphoma therapy: Standard DLBCL protocols if malignancy develops; SYK/BCR-pathway inhibitors (SYK, BTK, PI3K) are active in B-cell malignancies (PMID: 38660880; PMID: 35296646).
  • Personalized medicine: IMD82 is a paradigm for genotype-guided targeted therapy — the causal kinase is the drug target.

13. Prevention

  • Primary prevention: Not applicable (monogenic); genetic counseling for affected families given autosomal dominant inheritance.
  • Secondary prevention: Cascade genetic testing of relatives; surveillance for lymphoma and inflammatory complications in carriers.
  • Tertiary prevention: Early SYK-targeted therapy or HSCT to limit organ damage and potentially reduce lymphoma risk (inferred).
  • Prenatal/preimplantation testing: Available in principle once the familial variant is known.

14. Other Species / Natural Disease

  • Model taxonomy: Mus musculus (NCBI Taxon 10090) via the knock-in Syk-Ser544Tyr allele (PMID: 33782605).
  • Orthologs: Syk is conserved across vertebrates, including jawless fish (lamprey Lj-Syk), with conserved tandem-SH2 and kinase domains (PMID: 25682127).
  • Natural disease in other species: No naturally occurring animal counterpart of IMD82 is documented (OMIA); the disease is defined in humans with an engineered mouse model.

15. Model Organisms

  • Principal model: Knock-in mouse Syk-Ser544Tyr, engineered to mirror the human p.Ser550Tyr GOF variant. It recapitulated aspects of the human disease and, critically, was partially rescued by a SYK inhibitor or by wild-type bone-marrow transplantation (PMID: 33782605) — providing both face validity and therapeutic proof-of-concept.
  • Complementary tools: Chemical-genetic (analog-sensitive) SYK mouse systems and myeloid-specific SYK knockouts exist for dissecting SYK-dependent signaling (PMID: 31356155), and B-cell TRAF3-deficient mice model SYK-driven autoimmunity/lymphoma responsive to fostamatinib (PMID: 42026764).
  • Limitations: Partial (not complete) recapitulation/rescue; small human cohort limits cross-validation; models emphasize signaling and inflammation more than the full lymphoma trajectory.

Evidence Base

PMID Title (abbrev.) Role in this report
33782605 Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation (Nat Genet 2021) Defining paper. Establishes monoallelic SYK GOF, clinical triad, mouse model, and therapeutic rescue (SYK inhibitor / WT BMT).
23154170 Structural and biophysical characterization of the Syk activation switch Structural basis: full-length SYK autoinhibition and the pITAM/autophosphorylation activation switch disrupted by GOF variants.
35398488 SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies Mechanistic link: SYK-driven tonic PI3K signaling promotes survival over cell death — basis for lymphoma predisposition.
38503806 BCR signaling activity identifies higher-risk MCL patients High SYK/BCR signaling predicts aggressive B-cell lymphoma behavior; supports Branch B.
41608114 Human inborn errors of immunity: 2024 IUIS update Situates IMD82/SYK within the formal IEI classification used for diagnosis.
42026764 Syk inhibition limits autoimmunity in B-cell TRAF3-deficient mice Class-level support that fostamatinib corrects SYK-driven B-cell dysfunction/autoimmunity.
40903253 Future directions in warm AIHA management Fostamatinib as an established, efficacious SYK inhibitor in immune disease.
40962713 Fostamatinib and acute aortic dissection in ITP Safety caveat for chronic SYK inhibition.
31356155 Chemical-genetics SYK mouse model Complementary tool confirming SYK-dependent BCR signaling.
25682127 SYK molecular evolution in lamprey Evolutionary conservation of SYK tandem-SH2/kinase architecture.

Evidence-source types: Human clinical (PMID 33782605 case series; IUIS classification 41608114); model organism (33782605 mouse; 42026764; 31356155); in vitro/structural (23154170; 35398488); lymphoma clinical correlation (38503806).

Limitations and Knowledge Gaps

  1. Tiny cohort (n≈6): All core clinical claims rest on a single 2021 case series. Penetrance, expressivity, sex ratio, natural history, and quantitative phenotype frequencies cannot be reliably estimated.
  2. No epidemiology: Prevalence/incidence are unknown; the disease is ultra-rare with no registry data.
  3. Branch B is partly inferred: The lymphoma-predisposition mechanism is supported by strong SYK/BCR biology (PMID: 35398488; PMID: 38503806) but has not been dissected specifically in IMD82 patient B cells at scale.
  4. Variant spectrum incomplete: Only a few variants (notably p.Ser550Tyr) are characterized; the full allelic series and genotype–phenotype correlations are undefined.
  5. Therapeutic evidence is preclinical: SYK-inhibitor/BMT rescue is demonstrated in mice; human treatment outcomes for IMD82 specifically are anecdotal, and fostamatinib carries vascular/thrombotic safety concerns (PMID: 40962713).
  6. No omics depth: Patient-level transcriptomic, proteomic, metabolomic, or single-cell data for IMD82 are not available in the reviewed literature.
  7. Missing ontology/registry codes: Orphanet/ICD/MeSH-specific mappings are not firmly established for this recently defined entity.

Proposed Follow-up Experiments / Actions

  1. Establish an international IMD82 patient registry with genotype, functional pSYK data, longitudinal inflammation scores, and lymphoma incidence to define natural history, penetrance, and expressivity.
  2. Expand and functionally classify the SYK variant allelic series (deep mutational scanning across the tSH2/interdomain-A/kinase regions) to build a genotype–phenotype and pSYK-activity map for variant interpretation (ACMG PS3 functional evidence).
  3. Single-cell multi-omics of patient PBMC/gut/lymphoma tissue to resolve which cell types (B cells vs myeloid) drive Branch A vs Branch B and to identify predictive biomarkers.
  4. Prospective, biomarker-guided fostamatinib trial in IMD82 (with cardiovascular safety monitoring per PMID: 40962713), including pSYK/PI3K-AKT pharmacodynamic readouts.
  5. Define HSCT indications and outcomes for severe/lymphoma-associated IMD82, leveraging the mouse WT-BMT rescue as rationale.
  6. Test whether early SYK inhibition reduces lymphoma incidence in the Syk-Ser544Tyr knock-in model (chemoprevention proof-of-concept).
  7. Formalize ontology/registry entries (Orphanet, ICD-11, MeSH) and curate HPO frequency annotations as new cases accrue.

Report compiled from 6 confirmed findings and 32 reviewed papers over 5 investigation iterations. Evidence source types are distinguished throughout as human clinical, model organism, in vitro/structural, or computational.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 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 22
Resolved 21
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 20
Terms named correctly 10
Terms named as a different term 4
Terms whose name is worth a second look 6

Terms the report names something else

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

  • HP:0001369 (3 mentions) - the report calls it "arthritis", "Clinical sign"; HP calls it Arthritis
  • HP:0011123 (3 mentions) - the report calls it "inflammatory abnormality of the skin / dermatitis", "Physical manifestation"; HP calls it Inflammatory abnormality of the skin
  • HP:0004297 (3 mentions) - the report calls it "diffuse large B-cell lymphoma", "neoplasm of the immune system / lymphoma", "Neoplasm"; HP calls it Abnormality of the biliary system
  • HP:0002715 (2 mentions) - the report calls it "abnormality of the immune system / immunodeficiency", "Clinical/lab"; HP calls it Abnormality of the immune system

Terms whose name is worth a second look

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

  • HP:0002583 (3 mentions) - the report calls it "colitis", "Clinical sign"; HP calls it Colitis
  • GO:0038094 (1 mention) - the report calls it "Fc receptor signaling"; GO calls it Fc-gamma receptor signaling pathway
  • CL:0000236 (2 mentions) - the report calls it "B cell", "Cell populations: B lymphocytes"; CL calls it B cell**, and lists "B lymphocyte" among its other names
  • GO:0005886 (2 mentions) - the report calls it "plasma membrane / receptor-proximal"; GO calls it plasma membrane
  • UBERON:0002097 (2 mentions) - the report calls it "skin"; UBERON calls it skin of body, and lists "skin" among its other names
  • UBERON:0002509 (2 mentions) - the report calls it "lymphoid tissue"; UBERON calls it mesenteric lymph node, and lists "nodi lymphoidei mesenterici" among its other names

Terms named inconsistently

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

  • HGNC:11491 - called "SYK", "Gene/protein:* SYK"
  • HP:0002583 - called "colitis", "Clinical sign"
  • HP:0001369 - called "arthritis", "Clinical sign"
  • HP:0011123 - called "inflammatory abnormality of the skin / dermatitis", "Physical manifestation"
  • HP:0004297 - called "diffuse large B-cell lymphoma", "neoplasm of the immune system / lymphoma", "Neoplasm"
  • CL:0000236 - called "B cell", "Cell populations:** B lymphocytes"
  • HP:0002715 - called "abnormality of the immune system / immunodeficiency", "Clinical/lab"