Lymphoproliferative Syndrome 1

Mendelian MONDO:0013081 Pathograph 25 Show in embeddings browser Primary Immunodeficiency Combined Immunodeficiency

Lymphoproliferative syndrome 1 (ITK deficiency) is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function variants in ITK, the IL-2-inducible T-cell kinase, a Tec-family tyrosine kinase that couples the T-cell receptor to PLC-gamma-1 activation and calcium release. Loss of ITK depletes invariant NKT cells, causes progressive CD4 T-cell lymphopenia and hypogammaglobulinemia, and leaves Epstein-Barr virus poorly controlled. After EBV infection, children develop EBV-positive polymorphic B-cell lymphoproliferation, classic Hodgkin lymphoma and other B-cell lymphomas, with pulmonary nodules, hemophagocytic lymphohistiocytosis and autoimmune cytopenias in some. Reported onset ranges from infancy to adolescence, and mortality without hematopoietic stem cell transplantation is high. EBV-naive patients have presented instead with CD4 lymphopenia and recurrent pulmonary infection, or with severe tuberculosis. The lymphomas are modelled here as phenotypes of the germline syndrome, not as separate tumor entries.

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1
Inheritance
7
Pathophys.
19
Phenotypes
2
Gaps
25
Pathograph
1
Genes
4
Medical Actions
1
Models
1
Deep Research
🏷

Classifications

IUIS Category
combined immunodeficiency
👪

Inheritance

1
Autosomal recessive HP:0000007
Patients are homozygous for ITK loss-of-function variants, mostly from consanguineous families; one compound heterozygous patient of Greek-Italian descent has been reported.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:19425169 SUPPORT Human Clinical
"In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection."
The index family is consanguineous and both affected sisters carry the same homozygous variant, the basis of the recessive classification.
PMID:29867957 SUPPORT Human Clinical
"Most patients demonstrated an autosomal-recessive trait, while in one individual a compound-heterozygous inheritance from two different ethnicities (Greek–Italian) was revealed (5)."
Review of the reported patients confirming recessive inheritance, including one compound heterozygote.
CGGV:assertion_63552229-5e8c-4a94-b428-ec9a56a0aa5f-2019-11-21T193148.945Z SUPPORT Other
"ITK | HGNC:6171 | lymphoproliferative syndrome 1 | MONDO:0013081 | AR | Definitive"
ClinGen classifies the ITK-lymphoproliferative syndrome 1 relationship under an autosomal recessive mode of inheritance.
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Discussions and Knowledge Gaps

2
Do lymphoma, hypogammaglobulinemia and immune dysregulation in ITK deficiency require EBV infection, or can they arise independently of it?
OPEN QUESTION OPEN ebv_independent_disease
Attached to
pathophysiology#Impaired T-Cell Control of EBV
No symptomatic EBV-seronegative lymphoproliferation patient had been reported, suggesting EBV is necessary for the lymphoproliferative arm. Yet an EBV-naive patient had combined immunodeficiency with CD4 lymphopenia and absent iNKT cells as the predominant manifestation, and other EBV-naive patients developed severe tuberculosis, showing that some phenotypes are EBV-independent. Whether the malignant and antibody phenotypes can occur without EBV is unsettled.
Show evidence (1 reference)
PMID:25061172 SUPPORT Human Clinical
"we here had the unique opportunity to dissect EBV-dependent and EBV-independent ITK deficiency phenotypes."
The EBV-naive patient allows separation of EBV-dependent from EBV-independent features.
Does any available animal model reproduce the EBV-driven lymphoproliferation that defines human ITK deficiency?
HUMAN MODEL MISMATCH OPEN murine_ebv_model_mismatch
Attached to
pathophysiology#Impaired T-Cell Control of EBV
Itk-/- mice recapitulate the iNKT-cell deficiency, CD4 lymphopenia and the TCR calcium/IFN-gamma signalling defects, but EBV does not infect mice. In preliminary MHV-68 (the closest murine EBV surrogate) experiments the authors saw no difference in lung or splenic viral load between Itk-/- and wild-type mice, so the central human phenotype — failure to control the gammaherpesvirus — is not demonstrated in the mouse.
Show evidence (1 reference)
PMID:29867957 SUPPORT Model Organism
"There was no difference in the lytic viral tire in lungs between B6 and itk−/− infected mice; furthermore, there was no difference in the splenic genomic viral load between B6 and itk−/− mice at day 17."
The murine MHV-68 surrogate does not reproduce the defective gammaherpesvirus control seen in patients.
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Pathophysiology

7
Biallelic ITK Loss of Function
Germline biallelic ITK variants abolish or destabilize the IL-2-inducible T-cell kinase, a Tec-family non-receptor tyrosine kinase expressed in T cells, NK cells, invariant NKT cells and mast cells. The index R335W allele is predicted to destabilize the SH2 domain and the mutant protein is nearly undetectable when expressed; other alleles truncate the protein or shorten its half-life.
ITK hgnc:6171 ⇓ LOSS OF FUNCTION HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ITK (hgnc:6171), qualified as loss of function. hgnc:6171 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Germline biallelic ITK alleles, homozygous in consanguineous families and compound heterozygous in one patient.
non-membrane spanning protein tyrosine kinase activity GO:0004715 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased non-membrane spanning protein tyrosine kinase activity (GO:0004715). GO:0004715 is a molecular function from the Gene Ontology.
Downstream
Defective TCR-Induced Calcium Mobilization ITK phosphorylates PLC-gamma-1 downstream of the T-cell receptor; without it, IP3 generation and calcium release from intracellular stores fail.
Show evidence (3 references)
PMID:32628964 SUPPORT Human Clinical
"Interleukin-2-inducible T cell kinase (ITK) is a member of the TEC family of non-receptor protein tyrosine kinases expressed in T lymphocytes, NK cells, invariant NKT cells (iNKT), and mast cells2."
States the molecular function bound here (non-receptor tyrosine kinase) and the cell types that express ITK.
PMID:19425169 SUPPORT In Vitro
"Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells."
The index allele yields almost no ITK protein, i.e. a protein-deficiency mechanism.
PMID:25061172 SUPPORT Human Clinical
"we identified a homozygous nonsense mutation located within the first exon of the Interleukin-2-inducible T-cell kinase (ITK) gene (c.C49T:p.Q17X) likely leading to nonsense-mediated decay of the corresponding gene product."
A truncating allele in exon 1 supports complete loss of ITK as the disease mechanism.
Defective TCR-Induced Calcium Mobilization
After TCR engagement, ITK is recruited to the LAT-SLP76 complex and activates PLC-gamma-1, which generates IP3 and diacylglycerol; IP3 releases calcium from the endoplasmic reticulum and drives NFAT nuclear translocation. Patient T-cell lines show reduced or nearly absent TCR-induced cytosolic calcium release.
CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology.
T cell receptor signaling pathway GO:0050852 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell receptor signaling pathway (GO:0050852). GO:0050852 is a biological process from the Gene Ontology. release of sequestered calcium ion into cytosol GO:0051209 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased release of sequestered calcium ion into cytosol (GO:0051209). GO:0051209 is a biological process from the Gene Ontology.
Animal models
Itk-knockout mouse (Itk-/-) Mus musculus recapitulates Itk-/- T cells show reduced TCR-induced calcium release, the defect rescued by wild-type ITK.
Downstream
Invariant NKT Cell Deficiency Invariant NKT-cell development and maturation require ITK-dependent TCR signalling.
Decreased CD4+ T cell count ITK-dependent TCR signalling supports thymic selection and peripheral maintenance of CD4 T cells; its loss produces progressive CD4 lymphopenia.
Impaired T-Cell Control of EBV Defective TCR signalling impairs the antiviral T-cell response that keeps EBV-infected B cells in check.
Impaired T-Cell IFN-gamma Production Patient T cells secrete little IFN-gamma after TCR stimulation.
Defective TCR-Driven Fas Ligand Upregulation Patient T cells fail to upregulate Fas ligand after CD3/CD28 stimulation but respond normally when PMA and ionomycin bypass the TCR.
Show evidence (2 references)
PMID:25339095 SUPPORT In Vitro
"Calcium response was assayed by flux studies in transformed HVS patient T lymphocytes after CD3 antibody dependent TCR stimulation showing clearly reduced or nearly absent cytosolic release of calcium ions in most patients."
Direct measurement of the TCR calcium defect in patient-derived T cells.
PMID:29867957 SUPPORT Other
"ITK activates PLCγ1, generating inositol 1,4,5-trisphosphate (IP3), which leads to intracellular calcium release and diacylglycerol"
Review statement of the signalling step ITK performs in the TCR pathway.
Invariant NKT Cell Deficiency
Peripheral invariant NKT cells (TCR Valpha24+/Vbeta11+) are severely reduced or absent, including in an EBV-seronegative patient, and Itk-/- mice have few, immature and functionally defective NKT cells. Whether the iNKT deficit contributes to EBV susceptibility is debated.
invariant NKT cell CL:0000921 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves invariant NKT cell, annotated with type I NK T cell (CL:0000921). CL:0000921 is a cell type from the Cell Ontology.
NK T cell differentiation GO:0001865 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased NK T cell differentiation (GO:0001865). GO:0001865 is a biological process from the Gene Ontology.
Animal models
Itk-knockout mouse (Itk-/-) Mus musculus recapitulates The knockout reproduces the reduced and immature NKT-cell compartment seen in patients.
Downstream
Impaired T-Cell Control of EBV A role for iNKT cells in controlling EBV has been postulated because they are reduced in several EBV-susceptibility disorders, but disorders with global NKT-cell loss are not EBV-susceptible, so the contribution is unsettled.
Show evidence (2 references)
PMID:25339095 SUPPORT Human Clinical
"NKT cells are severely reduced in the peripheral blood of ITK deficient patients [18]"
Cohort review reporting the iNKT deficit across patients.
PMID:18292523 SUPPORT Model Organism
"Splenic Itk-/- and Itk/Rlk-/- NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation."
Residual NKT cells in the knockout are dysfunctional as well as reduced.
Impaired T-Cell Control of EBV
ITK-deficient patients cannot clear Epstein-Barr virus after primary infection. Viral loads are high (10^4 to 10^8 copies per microgram DNA) and EBV-infected B cells expand. No EBV-seronegative patient with lymphoproliferation has been reported.
CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
Downstream
Persistent EBV viremia Uncontrolled EBV replication gives persistent high-level viremia.
EBV-Driven B-Cell Lymphoproliferation Uncontrolled EBV-infected B cells proliferate.
Hemophagocytosis Hemophagocytic lymphohistiocytosis follows EBV infection in a minority of patients.
EBV-associated smooth muscle tumor EBV persists in smooth muscle tumor cells, including when blood EBV serology is negative.
Show evidence (2 references)
PMID:22487848 SUPPORT Human Clinical
"IL-2-inducible T-cell kinase (ITK) deficiency is a rare inherited immunodeficiency disease characterized by homozygous mutations in the ITK gene and the inability to control Epstein-Barr virus (EBV) infection leading to EBV-associated lymphoproliferative disorders of B cell origin."
Defines the disease by failed EBV control leading to B-cell lymphoproliferation.
PMID:29867957 SUPPORT Model Organism
"ITK-deficient CTLs showed decreased expansion and a more naïve phenotype after activation."
Mouse data summarized in the review show a cytotoxic T-cell defect, the effector arm expected to control EBV-infected B cells.
EBV-Driven B-Cell Lymphoproliferation
Lymphoproliferations in ITK deficiency are uniformly EBV-positive and of B origin, ranging from polymorphic to monomorphic B-cell lymphoproliferation, Hodgkin-like B-cell proliferation and classic mixed-cellularity Hodgkin lymphoma, with EBV latency type 2 predominating even in polymorphic lesions. Nodal and extranodal (especially pulmonary) disease often occur together.
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.
B cell proliferation GO:0042100 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased B cell proliferation (GO:0042100). GO:0042100 is a biological process from the Gene Ontology.
Downstream
Lymphoproliferative disorder B-cell expansion presents as polymorphic EBV-positive lymphoproliferative disease.
Hodgkin lymphoma Neoplastic B-cell clones arising from EBV-driven hyperplasia progress to classic Hodgkin lymphoma.
B-cell lymphoma EBV-driven lymphoproliferation can progress to large B-cell lymphoma.
Pulmonary nodule Pulmonary nodules are extranodal EBV-positive polyclonal B-cell proliferation.
Lymphadenopathy Lymphadenopathy accompanies the mononucleosis-like EBV lymphoproliferative picture.
Hepatosplenomegaly Hepatosplenomegaly accompanies the mononucleosis-like EBV lymphoproliferative picture.
Show evidence (1 reference)
PMID:25728094 SUPPORT Human Clinical
"The 100% EBV association, the high percentage of EBV-positive classic Hodgkin lymphoma and Hodgkin-like B-cell proliferations and the predominance of EBV latency type 2 even in polymorphic lesions are the main features of lymphoproliferations in patients with ITK deficiency"
Histopathology review of 12 biopsies from seven ITK-deficient children.
Impaired T-Cell IFN-gamma Production
In three EBV-naive patients with complete ITK deficiency, CD4, CD8, double-negative alpha-beta, Vdelta2+ gamma-delta and MAIT cells produced little IFN-gamma in response to BCG. These patients had CD4 alpha-beta T lymphocytopenia with expansion of double-negative alpha-beta and Vdelta2-negative gamma-delta T cells.
CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology.
type II interferon production GO:0032609 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased type II interferon production (GO:0032609). GO:0032609 is a biological process from the Gene Ontology.
Downstream
Tuberculosis infection Deficient IFN-gamma immunity underlies severe tuberculosis in EBV-naive patients.
Show evidence (1 reference)
PMID:36326697 SUPPORT Human Clinical
"Finally, the patients' total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG."
Ex vivo measurement of the IFN-gamma defect across T-cell subsets.
Defective TCR-Driven Fas Ligand Upregulation
In one patient with a homozygous kinase-domain variant (p.Pro521Leu) who presented with autoimmune lymphoproliferative syndrome, T cells failed to upregulate Fas ligand after CD3/CD28 stimulation but responded normally to PMA plus ionomycin, which bypasses the TCR. The authors propose failure of Fas-mediated activation-induced cell death as a mechanism for the T-cell lymphoproliferation; activation-induced cell death itself could not be measured in the patient.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
activation-induced cell death of T cells GO:0006924 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves activation-induced cell death of T cells (GO:0006924). GO:0006924 is a biological process from the Gene Ontology.
Downstream
Autoimmunity Impaired removal of activated T cells is proposed to underlie the autoimmune manifestations seen in some patients.
Show evidence (1 reference)
PMID:32628964 SUPPORT Human Clinical
"FasL upregulation was significantly reduced in the patient’s T cells compared to control following anti-CD3+anti-CD28 activation, but not PMA/IO stimulation (Fig 1K)."
The FasL defect is confined to TCR-initiated signalling, placing it downstream of ITK.
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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 Lymphoproliferative Syndrome 1 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

19
Blood 7
Decreased CD4+ T cell count Decreased total CD4+ T cell count HP:5210418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total CD4+ T cell count (HP:5210418). HP:5210418 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent lower respiratory tract infections Pneumocystis jirovecii pneumonia
Show evidence (1 reference)
PMID:25061172 SUPPORT Human Clinical
"Immunological analysis at the age of 10 showed persistently low CD4+ T-cell counts (range: 8% to 16%; 286-714/µL)"
Documents persistent CD4 lymphopenia in the index CD4-lymphopenia patient.
Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent lower respiratory tract infections
Show evidence (1 reference)
PMID:31025232 SUPPORT Human Clinical
"Loss of function mutations in ITK results in hypogammaglobulinemia and CD4+ T cell loss in humans"
States hypogammaglobulinemia as a consequence of ITK loss of function.
Lymphoproliferative disorder VERY_FREQUENT HP:0005523 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphoproliferative disorder (HP:0005523). HP:0005523 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25339095 SUPPORT Human Clinical
"our group and collaborators were able to reveal the pathogenicity of mutations in the Interleukin-2-inducible T-cell Kinase (ITK) in a cohort of nine patients with most patients presenting with massive EBV B-cell lymphoproliferation."
EBV B-cell lymphoproliferation is the predominant presentation across the cohort.
Hodgkin lymphoma FREQUENT HP:0012189 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hodgkin lymphoma (HP:0012189). HP:0012189 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25728094 SUPPORT Human Clinical
"a Hodgkin-like B-cell proliferation (one case), and classic mixed-cellularity Hodgkin lymphoma (six cases). All cases (12/12) were EBV-positive."
Six of twelve biopsied lesions were classic Hodgkin lymphoma, all EBV-positive.
B-cell lymphoma OCCASIONAL HP:0012191 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is B-cell lymphoma (HP:0012191). HP:0012191 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29867957 SUPPORT Human Clinical
"Thirteen patients presented either with HL or with EBV-driven B cell lymphoproliferative disease (in some cases developing to Hodgkin or large B cell lymphoma), only two showed a classical non-HL histology."
Documents large B-cell lymphoma and non-Hodgkin histology among reported patients.
Hemophagocytosis OCCASIONAL HP:0012156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemophagocytosis (HP:0012156). HP:0012156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26056787 SUPPORT Human Clinical
"A germline mutation in interleukin-2-inducible T-cell kinase (ITK) is described in individuals manifesting B-cell LPDs, cHL, and hemophagocytic syndromes following Epstein-Barr virus (EBV) infection."
Lists hemophagocytic syndromes among the post-EBV manifestations of ITK deficiency.
Autoimmune hemolytic anemia HP:0001890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hemolytic anemia (HP:0001890). HP:0001890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32628964 SUPPORT Human Clinical
"She subsequently developed a Coombs positive chronic autoimmune hemolytic anemia, thrombocytopenia, vitiligo, diffuse lymphadenopathy, and splenomegaly."
Coombs-positive AIHA in the patient presenting as ALPS.
Cardiovascular 2
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:538963 SUPPORT Other
"Patients present persistent symptoms of infectious mononucleosis including recurrent febrile episodes, lymphadenopathies, and hepatosplenomegaly, accompanied by high EBV viral load in the blood."
Orphanet lists lymphadenopathy among the core features.
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:538963 SUPPORT Other
"Patients present persistent symptoms of infectious mononucleosis including recurrent febrile episodes, lymphadenopathies, and hepatosplenomegaly, accompanied by high EBV viral load in the blood."
Orphanet lists hepatosplenomegaly among the core features.
Endocrine 1
EBV-associated smooth muscle tumor VERY_RARE Adrenal leiomyoma HP:0034549 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EBV-associated smooth muscle tumor (adrenal leiomyoma), annotated with Adrenal leiomyoma (HP:0034549). HP:0034549 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42132280 SUPPORT Human Clinical
"Histopathology and immunohistochemistry confirmed bilateral adrenal leiomyomas, and EBV in situ hybridization demonstrated EBV infection within tumor cells despite negative blood EBV serology"
Bilateral adrenal leiomyomas with intratumoral EBV in an ITK-deficient boy.
Immune 6
Combined immunodeficiency HP:0005387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Combined immunodeficiency (HP:0005387). HP:0005387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25061172 SUPPORT Human Clinical
"we here show that combined immunodeficiency with CD4 deficiency can be the predominant disease manifestation."
Establishes the combined-immunodeficiency phenotype independent of EBV lymphoproliferation.
Persistent EBV viremia HP:0020072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Persistent EBV viremia (HP:0020072). HP:0020072 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25339095 SUPPORT Human Clinical
"Patients with EBV-LPD show a rather high EBV viremia though the observed peak viral load in the eight reported patients was quite heterogeneous (10^4 - 10^8 copies/ μg DNA)."
Quantifies the characteristic EBV viremia.
Autoimmunity OCCASIONAL HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25339095 SUPPORT Human Clinical
"Given severe immune dysregulation, three patients developed autoimmune phenomena (cytopenia, nephritis and thyroiditis)"
Autoimmune manifestations in three of the reviewed patients.
Tuberculosis infection VERY_RARE HP:5210111 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tuberculosis infection (HP:5210111). HP:5210111 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36326697 SUPPORT Human Clinical
"We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency"
Three EBV-naive ITK-deficient patients with severe tuberculosis.
Recurrent lower respiratory tract infections HP:0002783 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent lower respiratory tract infections (HP:0002783). HP:0002783 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25061172 SUPPORT Human Clinical
"He suffered from recurrent pulmonary infections causing progressive immune reaction and bronchiectasia."
Recurrent pulmonary infection and bronchiectasis in the CD4-lymphopenia patient.
Pneumocystis jirovecii pneumonia VERY_RARE HP:0020102 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumocystis jirovecii pneumonia (HP:0020102). HP:0020102 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25339095 SUPPORT Human Clinical
"the girl died from respiratory failure after acquiring pneumocystis pneumonia at the age of 10 ½ years"
Documents fatal Pneumocystis pneumonia in an index patient with progressive T-cell decline.
Integument 1
Verrucae VERY_RARE HP:0200043 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Verrucae (HP:0200043). HP:0200043 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30778533 SUPPORT Human Clinical
"We describe a novel association of a homozygous ITK mutation with β-human papillomavirus (HPV)-positive epidermodysplasia verruciformis."
beta-HPV epidermodysplasia verruciformis in ITK-deficient siblings.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25339095 SUPPORT Human Clinical
"Patients with lymphoproliferative disease / Hodgkin lymphoma manifested between 3 and 13 years of age with fever, lymphadenopathy, hepatosplenomegaly and EBV viremia"
Fever at presentation, with the pediatric onset range.
Respiratory 1
Pulmonary nodule FREQUENT HP:0033608 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary nodule (HP:0033608). HP:0033608 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22487848 SUPPORT Human Clinical
"Imaging studies revealed diffuse pulmonary nodules and mediastinal lymphadenopathy."
Pulmonary nodules in a patient with disseminated EBV infection.
PMID:25339095 SUPPORT Human Clinical
"Pulmonary involvement with large interstitial nodules was observed in the majority of patients"
Review-level statement of frequency across the first reported cases. The review's Table 1 "pulmonary involvement" row is not quoted because it does not separate nodules from pulmonary infections.
🧬

Genetic Associations

1
ITK
Gene: ITK hgnc:6171 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ITK (hgnc:6171). hgnc:6171 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:19425169 SUPPORT Human Clinical
"Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK."
Identification of the first disease-causing ITK allele by linkage in the index family.
PMID:22289921 SUPPORT Human Clinical
"ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations"
Additional patients from an EBV-LPD cohort negative for SH2D1A and XIAP mutations extend the allelic spectrum.
PMID:22289921 SUPPORT In Vitro
"Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min)."
Patient alleles reduce ITK protein stability, consistent with loss of function.
💊

Medical Actions

4
Allogeneic hematopoietic stem cell transplantation
Action: Allogeneic Hematopoietic Stem Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Allogeneic Hematopoietic Stem Cell Transplantation (NCIT:C46089). NCIT:C46089 is a clinical intervention from the NCI Thesaurus. NCIT:C46089
Platform: Cell therapy
HSCT is the only definitive treatment and is advocated early once the diagnosis is established; outcome in primary immunodeficiency has improved, and haploidentical donors with T-cell depletion plus adoptive EBV-specific T cells have been used when no matched donor is available.
Show evidence (2 references)
PMID:29867957 SUPPORT Human Clinical
"We believe that current clinical data advocate early definitive treatment by hematopoietic stem cell transplantation, as transplant outcome in primary immunodeficiency disorders in general has gradually improved in recent years."
Review recommendation for early definitive HSCT.
PMID:29867957 SUPPORT Human Clinical
"eight patients underwent hematopoietic SCT. Two patients died after HSCT."
Outcome data showing HSCT is the definitive route but carries transplant-related mortality.
Rituximab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-CD20 therapy is used for EBV-driven B-cell proliferation and can bridge to definitive transplant; responses are partial in some patients.
Show evidence (1 reference)
PMID:22487848 SUPPORT Human Clinical
"Treatment with rituximab (anti-CD20 mab) resulted in complete clinical remission with resolution of pulmonary lesions and a negative EBV titer in serum."
Documented rituximab response in a patient with disseminated EBV disease.
Immunoglobulin replacement therapy
Action: Immunoglobulin TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. NCIT:C62710
Platform: Protein replacement
IgG substitution partially ameliorates hypogammaglobulinemia and immune dysregulation but confers only temporary benefit.
Show evidence (1 reference)
PMID:29867957 SUPPORT Human Clinical
"IgG substitution has conferred only temporary benefit, especially to partially ameliorate immune dysregulation manifesting as lymphoproliferation and autoimmunity"
States the limited, temporary benefit of IgG replacement.
Chemotherapy for Hodgkin lymphoma
Action: ChemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. NCIT:C15632
Platform: Other
Standard lymphoma chemotherapy protocols are used for the EBV-positive Hodgkin lymphoma that is the most common malignant outcome. Chemotherapy can achieve remission but is not reliably durable, as progressive T-cell decline continues and most patients ultimately require allogeneic HSCT.
Mechanism Target:
INHIBITS Hodgkin lymphoma — Chemotherapy treats the EBV-driven Hodgkin lymphoma; durable remission on chemotherapy alone is reported in only a minority.
Show evidence (1 reference)
PMID:29867957 SUPPORT Human Clinical
"Six patients died due to lymphoproliferation, while only two patients remained in remission after chemotherapy for HL."
Quantifies the limited durability of chemotherapy for the Hodgkin lymphoma of ITK deficiency.
Show evidence (1 reference)
PMID:25339095 SUPPORT Human Clinical
"Successfully treated according to standard chemotherapy protocol, T cells unfortunately were continuously declining and the girl died from respiratory failure after acquiring pneumocystis pneumonia at the age of 10 ½ years."
An index patient's Hodgkin lymphoma was treated with a standard chemotherapy protocol; it documents both the use of chemotherapy and that it did not prevent the fatal course.
🔬

Diagnosis

2
ITK molecular genetic testing
ITK is included on combined-immunodeficiency gene panels; whole-exome sequencing or a primary immunodeficiency panel confirms biallelic variants. All patients with EBV-associated lymphoproliferative disorders negative for SH2D1A and XIAP should be analyzed for ITK mutations.
Show evidence (1 reference)
PMID:22487848 SUPPORT Human Clinical
"All patients with EBV-associated lymphoproliferative disorders should be analyzed for mutations in ITK."
Recommendation to test ITK in the relevant clinical setting.
Lymphocyte subset and iNKT-cell immunophenotyping
Flow cytometry shows low CD4 counts, reduced naive CD45RA+CD4+ cells, and absent or severely reduced invariant NKT cells (TCR Valpha24+/Vbeta11+).
Show evidence (1 reference)
PMID:25061172 SUPPORT Human Clinical
"The index patient shows complete absence of TCRVα24+/TCRVβ11+ iNKT-cells."
iNKT-cell absence is a diagnostically useful hallmark on flow cytometry.
📊

Prevalence

2
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet worldwide point-prevalence class <1 / 1,000,000.
Show evidence (1 reference)
ORPHA:538963 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:29942301"
Orphanet epidemiology table for ITK deficiency.
Worldwide, published cases
Cases In Literature Ultra Rare
The 2018 review counted 17 patients from Greece, India, Italy, Iran, Morocco, Pakistan, Palestine and Turkey; a 2020 report counted 20 published patients before its own. No population-based estimate exists.
Show evidence (1 reference)
PMID:29867957 SUPPORT Human Clinical
"To date, we are aware of ITK mutations in 17 patients originating from Greece, India, Italy, Iran, Morocco, Pakistan, Palestine, and Turkey"
Case count and countries of origin as of 2018.
🐁

Animal Models

1
Itk-knockout mouse (Itk-/-)
Itk-/- mice reproduce several features of human ITK deficiency — reduced, immature and dysfunctional NKT cells, decreased thymic and peripheral CD4 T cells, and impaired TCR-induced calcium release and effector cytokine production — but they do not model EBV, which does not infect mice.
Species
Mus musculus
Genotype
Itk null
Pathograph links
Invariant NKT Cell Deficiency recapitulates fidelity: moderate observes: cellular The knockout reproduces the reduced and immature NKT-cell compartment seen in patients.
Limitations: Residual NKT cells differ in degree from the near-complete human iNKT absence, and the mouse does not capture the EBV context in which the human deficit is observed.
Show evidence (1 reference)
PMID:18292523 SUPPORT Model Organism
"Itk-/- mice have reduced numbers of NKT cells with a predominantly immature phenotype."
The model's NKT phenotype corresponds to the human iNKT deficiency node.
Defective TCR-Induced Calcium Mobilization recapitulates fidelity: moderate observes: cellular Itk-/- T cells show reduced TCR-induced calcium release, the defect rescued by wild-type ITK.
Limitations: Mouse T cells retain more residual TCR signalling than some human alleles, and RLK (TXK) partially compensates in mice.
Show evidence (1 reference)
PMID:22289921 SUPPORT In Vitro
"Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells."
The murine Itk-/- calcium defect is the assay used to establish human allele loss of function.
Show evidence (1 reference)
PMID:18292523 SUPPORT Model Organism
"Itk-/- mice have reduced numbers of NKT cells with a predominantly immature phenotype."
Establishes the NKT-cell phenotype of the knockout.
{ }

Source YAML

click to show 
name: Lymphoproliferative Syndrome 1
creation_date: "2026-10-13T23:55:47Z"
category: Mendelian
synonyms:
- ITK deficiency
- LPFS1
- interleukin-2-inducible T-cell kinase deficiency
- combined immunodeficiency due to ITK deficiency
- autosomal recessive lymphoproliferative disease due to ITK deficiency
disease_term:
  preferred_term: lymphoproliferative syndrome 1
  term:
    id: MONDO:0013081
    label: lymphoproliferative syndrome 1
parents:
- Primary Immunodeficiency
- Combined Immunodeficiency
description: >-
  Lymphoproliferative syndrome 1 (ITK deficiency) is an autosomal recessive
  combined immunodeficiency caused by biallelic loss-of-function variants in
  ITK, the IL-2-inducible T-cell kinase, a Tec-family tyrosine kinase that
  couples the T-cell receptor to PLC-gamma-1 activation and calcium release.
  Loss of ITK depletes invariant NKT cells, causes progressive CD4 T-cell
  lymphopenia and hypogammaglobulinemia, and leaves Epstein-Barr virus poorly
  controlled. After EBV infection, children develop EBV-positive polymorphic
  B-cell lymphoproliferation, classic Hodgkin lymphoma and other B-cell
  lymphomas, with pulmonary nodules, hemophagocytic lymphohistiocytosis and
  autoimmune cytopenias in some. Reported onset ranges from infancy to
  adolescence, and mortality without hematopoietic stem cell transplantation is
  high. EBV-naive patients have presented instead with CD4 lymphopenia and
  recurrent pulmonary infection, or with severe tuberculosis. The lymphomas are
  modelled here as phenotypes of the germline syndrome, not as separate tumor
  entries.
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      The IUIS 2024 update lists ITK deficiency in Table 1 (immunodeficiencies
      affecting cellular and humoral immunity), in the subtable of combined
      immunodeficiencies generally less profound than SCID.
    evidence:
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ITK deficiency | ITK | AR | 613011 | Progressive CD4 T-cell lymphopenia;
        reduced T-cell activation | Normal | Normal to low serum Ig |
        EBV-associated B-cell lymphoproliferation, lymphoma, immune dysregulation
      explanation: >-
        The IUIS classification row for ITK deficiency, giving the gene,
        autosomal recessive inheritance, the OMIM number, the T-cell, B-cell and
        immunoglobulin findings, and the EBV-associated clinical picture.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Patients are homozygous for ITK loss-of-function variants, mostly from
    consanguineous families; one compound heterozygous patient of Greek-Italian
    descent has been reported.
  evidence:
  - reference: PMID:19425169
    reference_title: "Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study we describe 2 girls from a consanguineous Turkish family who
      died after developing severe immune dysregulation and therapy-resistant
      EBV-positive B cell proliferation following EBV infection.
    explanation: >-
      The index family is consanguineous and both affected sisters carry the
      same homozygous variant, the basis of the recessive classification.
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients demonstrated an autosomal-recessive trait, while in one
      individual a compound-heterozygous inheritance from two different
      ethnicities (Greek–Italian) was revealed (5).
    explanation: >-
      Review of the reported patients confirming recessive inheritance,
      including one compound heterozygote.
  - reference: CGGV:assertion_63552229-5e8c-4a94-b428-ec9a56a0aa5f-2019-11-21T193148.945Z
    reference_title: "ITK / lymphoproliferative syndrome 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ITK | HGNC:6171 | lymphoproliferative syndrome 1 | MONDO:0013081 | AR | Definitive"
    explanation: >-
      ClinGen classifies the ITK-lymphoproliferative syndrome 1 relationship
      under an autosomal recessive mode of inheritance.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class <1 / 1,000,000.
  evidence:
  - reference: ORPHA:538963
    reference_title: "Combined immunodeficiency due to ITK deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:29942301"
    explanation: Orphanet epidemiology table for ITK deficiency.
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The 2018 review counted 17 patients from Greece, India, Italy, Iran,
    Morocco, Pakistan, Palestine and Turkey; a 2020 report counted 20 published
    patients before its own. No population-based estimate exists.
  evidence:
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, we are aware of ITK mutations in 17 patients originating from
      Greece, India, Italy, Iran, Morocco, Pakistan, Palestine, and Turkey
    explanation: Case count and countries of origin as of 2018.
genetic:
- name: ITK
  gene_term:
    preferred_term: ITK
    term:
      id: hgnc:6171
      label: ITK
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_63552229-5e8c-4a94-b428-ec9a56a0aa5f-2019-11-21T193148.945Z
    evidence:
    - reference: CGGV:assertion_63552229-5e8c-4a94-b428-ec9a56a0aa5f-2019-11-21T193148.945Z
      reference_title: "ITK / lymphoproliferative syndrome 1 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ITK | HGNC:6171 | lymphoproliferative syndrome 1 | MONDO:0013081 | AR | Definitive"
      explanation: >-
        ClinGen gene-disease validity row for ITK and this entry's MONDO term
        (Hereditary Cancer GCEP, 2019).
  notes: >-
    Reported alleles span the PH, SH2 and kinase domains and include missense,
    nonsense and frameshift variants, among them R335W (SH2 domain, index
    family), R29H (PH domain), Q17X, Y588X, W209X and c.468delT. In
    patient-derived T-cell lines most alleles left ITK mRNA largely unchanged
    but shortened protein half-life (PMID:25339095).
  evidence:
  - reference: PMID:19425169
    reference_title: "Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both girls harbored a homozygous missense mutation that led to
      substitution of a highly conserved residue (R335W) in the SH2 domain of
      ITK.
    explanation: Identification of the first disease-causing ITK allele by linkage in the index family.
  - reference: PMID:22289921
    reference_title: "Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ITK mutations are distributed over the entire protein and include
      missense, nonsense and indel mutations
    explanation: >-
      Additional patients from an EBV-LPD cohort negative for SH2D1A and XIAP
      mutations extend the allelic spectrum.
  - reference: PMID:22289921
    reference_title: "Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pulse-chase experiments showed that ITK mutations lead to varying
      reductions of protein half-life from 25 to 69% as compared with wt ITK
      (107 min).
    explanation: Patient alleles reduce ITK protein stability, consistent with loss of function.
pathophysiology:
- name: Biallelic ITK Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Germline biallelic ITK variants abolish or destabilize the IL-2-inducible
    T-cell kinase, a Tec-family non-receptor tyrosine kinase expressed in T
    cells, NK cells, invariant NKT cells and mast cells. The index R335W allele
    is predicted to destabilize the SH2 domain and the mutant protein is
    nearly undetectable when expressed; other alleles truncate the protein or
    shorten its half-life.
  genes:
  - preferred_term: ITK
    term:
      id: hgnc:6171
      label: ITK
    modifier: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: non-membrane spanning protein tyrosine kinase activity
    term:
      id: GO:0004715
      label: non-membrane spanning protein tyrosine kinase activity
    modifier: DECREASED
  genetic_context:
    description: >-
      Germline biallelic ITK alleles, homozygous in consanguineous families
      and compound heterozygous in one patient.
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:32628964
    reference_title: "ITK deficiency presenting as autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interleukin-2-inducible T cell kinase (ITK) is a member of the TEC family
      of non-receptor protein tyrosine kinases expressed in T lymphocytes, NK
      cells, invariant NKT cells (iNKT), and mast cells2.
    explanation: >-
      States the molecular function bound here (non-receptor tyrosine kinase)
      and the cell types that express ITK.
  - reference: PMID:19425169
    reference_title: "Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Additionally, Western blot analysis revealed that, unlike wild-type ITK,
      the R335W mutant was nearly undetectable when expressed in 293 T cells.
    explanation: The index allele yields almost no ITK protein, i.e. a protein-deficiency mechanism.
  - reference: PMID:25061172
    reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a homozygous nonsense mutation located within the first exon
      of the Interleukin-2-inducible T-cell kinase (ITK) gene (c.C49T:p.Q17X)
      likely leading to nonsense-mediated decay of the corresponding gene
      product.
    explanation: A truncating allele in exon 1 supports complete loss of ITK as the disease mechanism.
  downstream:
  - target: Defective TCR-Induced Calcium Mobilization
    causal_link_type: DIRECT
    description: >-
      ITK phosphorylates PLC-gamma-1 downstream of the T-cell receptor; without
      it, IP3 generation and calcium release from intracellular stores fail.
    evidence:
    - reference: PMID:22289921
      reference_title: "Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Human wild-type (wt) ITK, but none of the mutants, was able to rescue
        defective calcium flux in murine Itk(-/-) T cells.
      explanation: >-
        Complementation assay showing that patient alleles cannot restore TCR
        calcium flux, directly linking ITK loss to the signalling defect.
- name: Defective TCR-Induced Calcium Mobilization
  biological_scale: CELLULAR
  description: >-
    After TCR engagement, ITK is recruited to the LAT-SLP76 complex and
    activates PLC-gamma-1, which generates IP3 and diacylglycerol; IP3 releases
    calcium from the endoplasmic reticulum and drives NFAT nuclear
    translocation. Patient T-cell lines show reduced or nearly absent
    TCR-induced cytosolic calcium release.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
    modifier: DECREASED
  - preferred_term: release of sequestered calcium ion into cytosol
    term:
      id: GO:0051209
      label: release of sequestered calcium ion into cytosol
    modifier: DECREASED
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Calcium response was assayed by flux studies in transformed HVS patient T
      lymphocytes after CD3 antibody dependent TCR stimulation showing clearly
      reduced or nearly absent cytosolic release of calcium ions in most
      patients.
    explanation: Direct measurement of the TCR calcium defect in patient-derived T cells.
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ITK activates PLCγ1, generating inositol 1,4,5-trisphosphate (IP3), which
      leads to intracellular calcium release and diacylglycerol
    explanation: Review statement of the signalling step ITK performs in the TCR pathway.
  downstream:
  - target: Invariant NKT Cell Deficiency
    causal_link_type: DIRECT
    description: Invariant NKT-cell development and maturation require ITK-dependent TCR signalling.
    evidence:
    - reference: PMID:25061172
      reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Consistent with previous findings in mouse7 and human,8-11 flow
        cytometry indicated an absence of iNKT-cells (Figure 1D), illustrating
        that the absence of iNKT-cells is a primary phenotype of ITK deficiency.
      explanation: >-
        iNKT cells are absent in an EBV-seronegative patient without
        lymphoproliferation, so the loss is not secondary to EBV disease.
    - reference: PMID:18292523
      reference_title: "The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We find, as has been reported previously, that Itk-/- mice have reduced
        numbers of NKT cells with a predominantly immature phenotype.
      explanation: The Itk knockout mouse reproduces the NKT-cell deficit.
  - target: Decreased CD4+ T cell count
    causal_link_type: DIRECT
    description: >-
      ITK-dependent TCR signalling supports thymic selection and peripheral
      maintenance of CD4 T cells; its loss produces progressive CD4
      lymphopenia.
    evidence:
    - reference: PMID:25339095
      reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Itk −/− mice have decreased CD4 T cell numbers in the thymus and
        periphery [26].
      explanation: Review of the mouse knockout showing that Itk loss reduces CD4 T cells.
    - reference: PMID:25061172
      reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Although CD4 lymphopenia has already been described in other
        ITK-deficient patients suffering from lymphoproliferative disease,9,11
        we here show that combined immunodeficiency with CD4 deficiency can be
        the predominant disease manifestation.
      explanation: CD4 lymphopenia occurs in ITK deficiency even without EBV lymphoproliferation.
  - target: Impaired T-Cell Control of EBV
    causal_link_type: DIRECT
    description: Defective TCR signalling impairs the antiviral T-cell response that keeps EBV-infected B cells in check.
    evidence:
    - reference: PMID:26056787
      reference_title: "Atypical Clinical Course in Pediatric Hodgkin Lymphoma: Association With Germline Mutations in Interleukin-2-inducible T-Cell Kinase."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ITK-mutated T cells cause a defective antiviral immune response and the
        resulting immune dysregulation can lead to EBV-associated polyclonal
        hyperplasia with subsequent outgrowth of neoplastic B-cell clones
      explanation: Case-report authors' conclusion linking the T-cell defect to failed EBV control.
  - target: Impaired T-Cell IFN-gamma Production
    causal_link_type: DIRECT
    description: Patient T cells secrete little IFN-gamma after TCR stimulation.
    evidence:
    - reference: PMID:36326697
      reference_title: "Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in
        response to TCR crosslinking, mitogens, or forced synapse formation with
        autologous B lymphocytes.
      explanation: Ex vivo patient T cells show reduced TCR-driven IFN-gamma secretion.
  - target: Defective TCR-Driven Fas Ligand Upregulation
    causal_link_type: DIRECT
    description: >-
      Patient T cells fail to upregulate Fas ligand after CD3/CD28 stimulation
      but respond normally when PMA and ionomycin bypass the TCR.
    evidence:
    - reference: PMID:32628964
      reference_title: "ITK deficiency presenting as autoimmune lymphoproliferative syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        FasL upregulation was significantly reduced in the patient’s T cells
        compared to control following anti-CD3+anti-CD28 activation, but not
        PMA/IO stimulation (Fig 1K).
      explanation: The defect is confined to TCR-initiated signalling, placing it downstream of ITK.
- name: Invariant NKT Cell Deficiency
  biological_scale: CELLULAR
  description: >-
    Peripheral invariant NKT cells (TCR Valpha24+/Vbeta11+) are severely
    reduced or absent, including in an EBV-seronegative patient, and Itk-/-
    mice have few, immature and functionally defective NKT cells. Whether the
    iNKT deficit contributes to EBV susceptibility is debated.
  cell_types:
  - preferred_term: invariant NKT cell
    term:
      id: CL:0000921
      label: type I NK T cell
  biological_processes:
  - preferred_term: NK T cell differentiation
    term:
      id: GO:0001865
      label: NK T cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NKT cells are severely reduced in the peripheral blood of ITK deficient
      patients [18]
    explanation: Cohort review reporting the iNKT deficit across patients.
  - reference: PMID:18292523
    reference_title: "The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Splenic Itk-/- and Itk/Rlk-/- NKT cells are also functionally defective,
      because they produce little to no cytokine following in vivo activation.
    explanation: Residual NKT cells in the knockout are dysfunctional as well as reduced.
  downstream:
  - target: Impaired T-Cell Control of EBV
    causal_link_type: UNKNOWN
    description: >-
      A role for iNKT cells in controlling EBV has been postulated because they
      are reduced in several EBV-susceptibility disorders, but disorders with
      global NKT-cell loss are not EBV-susceptible, so the contribution is
      unsettled.
    evidence:
    - reference: PMID:25339095
      reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hence a critical role has been postulated for NKT cells in the response
        to EBV infection
      explanation: >-
        The review infers a role for NKT cells in EBV control from their
        reduction across EBV-susceptibility disorders; it is stated as a
        postulate.
    - reference: PMID:29867957
      reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Furthermore, there are disorders with a global lack of NKT cells, in
        which individuals are rather susceptible to Mycobacteria, but not to EBV
        infection (16).
      explanation: >-
        Global NKT-cell deficiency without EBV susceptibility argues against
        iNKT loss being sufficient for the EBV phenotype.
- name: Impaired T-Cell Control of EBV
  biological_scale: CELLULAR
  description: >-
    ITK-deficient patients cannot clear Epstein-Barr virus after primary
    infection. Viral loads are high (10^4 to 10^8 copies per microgram DNA)
    and EBV-infected B cells expand. No EBV-seronegative patient with
    lymphoproliferation has been reported.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:22487848
    reference_title: "IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IL-2-inducible T-cell kinase (ITK) deficiency is a rare inherited
      immunodeficiency disease characterized by homozygous mutations in the ITK
      gene and the inability to control Epstein-Barr virus (EBV) infection
      leading to EBV-associated lymphoproliferative disorders of B cell origin.
    explanation: Defines the disease by failed EBV control leading to B-cell lymphoproliferation.
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      ITK-deficient CTLs showed decreased expansion and a more naïve phenotype
      after activation.
    explanation: >-
      Mouse data summarized in the review show a cytotoxic T-cell defect, the
      effector arm expected to control EBV-infected B cells.
  downstream:
  - target: Persistent EBV viremia
    causal_link_type: DIRECT
    description: Uncontrolled EBV replication gives persistent high-level viremia.
    evidence:
    - reference: PMID:32628964
      reference_title: "ITK deficiency presenting as autoimmune lymphoproliferative syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        To date, all reported 20 patients with ITK deficiency have presented
        with Epstein Barr virus (EBV) related complications, including EBV
        driven B-cell lymphoproliferative disease and EBV-associated
        malignancies, because of inability to clear the virus and persistent
        EBV viremia3–6.
      explanation: Attributes the EBV complications to failure to clear the virus and persistent viremia.
  - target: EBV-Driven B-Cell Lymphoproliferation
    causal_link_type: DIRECT
    description: Uncontrolled EBV-infected B cells proliferate.
    evidence:
    - reference: PMID:22487848
      reference_title: "IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the inability to control Epstein-Barr virus (EBV) infection leading to
        EBV-associated lymphoproliferative disorders of B cell origin
      explanation: Directly links failed EBV control to B-cell lymphoproliferation.
  - target: Hemophagocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hemophagocytic lymphohistiocytosis follows EBV infection in a minority of patients.
    evidence:
    - reference: PMID:26056787
      reference_title: "Atypical Clinical Course in Pediatric Hodgkin Lymphoma: Association With Germline Mutations in Interleukin-2-inducible T-Cell Kinase."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A germline mutation in interleukin-2-inducible T-cell kinase (ITK) is
        described in individuals manifesting B-cell LPDs, cHL, and hemophagocytic
        syndromes following Epstein-Barr virus (EBV) infection.
      explanation: Places hemophagocytic syndromes among the post-EBV complications of ITK deficiency.
  - target: EBV-associated smooth muscle tumor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      EBV persists in smooth muscle tumor cells, including when blood EBV
      serology is negative.
    evidence:
    - reference: PMID:42132280
      reference_title: "From T-cell defect to tumorigenesis: Epstein-Barr virus-associated smooth muscle tumors in ITK deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathology and immunohistochemistry confirmed bilateral adrenal
        leiomyomas, and EBV in situ hybridization demonstrated EBV infection
        within tumor cells despite negative blood EBV serology, indicating
        tissue-restricted viral persistence.
      explanation: EBV is present in the tumor cells, linking the smooth muscle tumor to failed EBV control.
- name: EBV-Driven B-Cell Lymphoproliferation
  biological_scale: TISSUE
  description: >-
    Lymphoproliferations in ITK deficiency are uniformly EBV-positive and of B
    origin, ranging from polymorphic to monomorphic B-cell lymphoproliferation,
    Hodgkin-like B-cell proliferation and classic mixed-cellularity Hodgkin
    lymphoma, with EBV latency type 2 predominating even in polymorphic lesions.
    Nodal and extranodal (especially pulmonary) disease often occur together.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell proliferation
    term:
      id: GO:0042100
      label: B cell proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:25728094
    reference_title: "High incidence of Epstein-Barr virus (EBV)-positive Hodgkin lymphoma and Hodgkin lymphoma-like B-cell lymphoproliferations with EBV latency profile 2 in children with interleukin-2-inducible T-cell kinase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 100% EBV association, the high percentage of EBV-positive classic
      Hodgkin lymphoma and Hodgkin-like B-cell proliferations and the
      predominance of EBV latency type 2 even in polymorphic lesions are the
      main features of lymphoproliferations in patients with ITK deficiency
    explanation: Histopathology review of 12 biopsies from seven ITK-deficient children.
  downstream:
  - target: Lymphoproliferative disorder
    causal_link_type: DIRECT
    description: B-cell expansion presents as polymorphic EBV-positive lymphoproliferative disease.
    evidence:
    - reference: PMID:25728094
      reference_title: "High incidence of Epstein-Barr virus (EBV)-positive Hodgkin lymphoma and Hodgkin lymphoma-like B-cell lymphoproliferations with EBV latency profile 2 in children with interleukin-2-inducible T-cell kinase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found polymorphic and borderline polymorphic to monomorphic B-cell
        lymphoproliferations with variable contents in large cells (five cases)
      explanation: Biopsy-proven B-cell lymphoproliferations in ITK-deficient children.
  - target: Hodgkin lymphoma
    causal_link_type: DIRECT
    description: Neoplastic B-cell clones arising from EBV-driven hyperplasia progress to classic Hodgkin lymphoma.
    evidence:
    - reference: PMID:26056787
      reference_title: "Atypical Clinical Course in Pediatric Hodgkin Lymphoma: Association With Germline Mutations in Interleukin-2-inducible T-Cell Kinase."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the resulting immune dysregulation can lead to EBV-associated polyclonal
        hyperplasia with subsequent outgrowth of neoplastic B-cell clones, which
        in some instances may progress to LPDs, including cHL.
      explanation: States the progression from polyclonal EBV-driven hyperplasia to classic Hodgkin lymphoma.
  - target: B-cell lymphoma
    causal_link_type: DIRECT
    description: EBV-driven lymphoproliferation can progress to large B-cell lymphoma.
    evidence:
    - reference: PMID:29867957
      reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thirteen patients presented either with HL or with EBV-driven B cell
        lymphoproliferative disease (in some cases developing to Hodgkin or
        large B cell lymphoma), only two showed a classical non-HL histology.
      explanation: Review of 16 patients documenting progression to large B-cell lymphoma.
  - target: Pulmonary nodule
    causal_link_type: DIRECT
    description: Pulmonary nodules are extranodal EBV-positive polyclonal B-cell proliferation.
    evidence:
    - reference: PMID:22487848
      reference_title: "IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Transbronchial lung biopsy showed nonmalignant polyclonal B cell
        proliferation.
      explanation: Lung biopsy of the nodules showed B-cell proliferation.
  - target: Lymphadenopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lymphadenopathy accompanies the mononucleosis-like EBV lymphoproliferative picture.
    evidence:
    - reference: ORPHA:538963
      reference_title: "Combined immunodeficiency due to ITK deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Patients present persistent symptoms of infectious mononucleosis
        including recurrent febrile episodes, lymphadenopathies, and
        hepatosplenomegaly, accompanied by high EBV viral load in the blood.
      explanation: Orphanet groups lymphadenopathy with the EBV lymphoproliferative presentation.
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hepatosplenomegaly accompanies the mononucleosis-like EBV lymphoproliferative picture.
    evidence:
    - reference: ORPHA:538963
      reference_title: "Combined immunodeficiency due to ITK deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Patients present persistent symptoms of infectious mononucleosis
        including recurrent febrile episodes, lymphadenopathies, and
        hepatosplenomegaly, accompanied by high EBV viral load in the blood.
      explanation: Orphanet groups hepatosplenomegaly with the EBV lymphoproliferative presentation.
- name: Impaired T-Cell IFN-gamma Production
  biological_scale: CELLULAR
  description: >-
    In three EBV-naive patients with complete ITK deficiency, CD4, CD8,
    double-negative alpha-beta, Vdelta2+ gamma-delta and MAIT cells produced
    little IFN-gamma in response to BCG. These patients had CD4 alpha-beta T
    lymphocytopenia with expansion of double-negative alpha-beta and
    Vdelta2-negative gamma-delta T cells.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: type II interferon production
    term:
      id: GO:0032609
      label: type II interferon production
    modifier: DECREASED
  evidence:
  - reference: PMID:36326697
    reference_title: "Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the patients' total lymphocytes secrete small amounts of IFN-γ,
      and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ
      production in response to BCG.
    explanation: Ex vivo measurement of the IFN-gamma defect across T-cell subsets.
  downstream:
  - target: Tuberculosis infection
    causal_link_type: DIRECT
    description: Deficient IFN-gamma immunity underlies severe tuberculosis in EBV-naive patients.
    evidence:
    - reference: PMID:36326697
      reference_title: "Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Inherited ITK deficiency undermines the development and function of
        various IFN-γ-producing T cell subsets, thereby underlying TB.
      explanation: The authors' conclusion linking the IFN-gamma defect to tuberculosis.
- name: Defective TCR-Driven Fas Ligand Upregulation
  biological_scale: CELLULAR
  description: >-
    In one patient with a homozygous kinase-domain variant (p.Pro521Leu) who
    presented with autoimmune lymphoproliferative syndrome, T cells failed to
    upregulate Fas ligand after CD3/CD28 stimulation but responded normally to
    PMA plus ionomycin, which bypasses the TCR. The authors propose failure of
    Fas-mediated activation-induced cell death as a mechanism for the T-cell
    lymphoproliferation; activation-induced cell death itself could not be
    measured in the patient.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: activation-induced cell death of T cells
    term:
      id: GO:0006924
      label: activation-induced cell death of T cells
  evidence:
  - reference: PMID:32628964
    reference_title: "ITK deficiency presenting as autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FasL upregulation was significantly reduced in the patient’s T cells
      compared to control following anti-CD3+anti-CD28 activation, but not
      PMA/IO stimulation (Fig 1K).
    explanation: The FasL defect is confined to TCR-initiated signalling, placing it downstream of ITK.
  downstream:
  - target: Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired removal of activated T cells is proposed to underlie the
      autoimmune manifestations seen in some patients.
    evidence:
    - reference: PMID:32628964
      reference_title: "ITK deficiency presenting as autoimmune lymphoproliferative syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        failure to upregulate TCR-driven FasL expression likely contributed to
        the development ALPS in our patient.
      explanation: The authors attribute the ALPS-like autoimmune phenotype to the FasL defect.
phenotypes:
- name: Combined immunodeficiency
  category: Immunologic
  diagnostic: true
  description: ITK deficiency is a combined immunodeficiency with T-cell and antibody dysfunction.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:25061172
    reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we here show that combined immunodeficiency with CD4 deficiency can be
      the predominant disease manifestation.
    explanation: Establishes the combined-immunodeficiency phenotype independent of EBV lymphoproliferation.
- name: Decreased CD4+ T cell count
  category: Immunologic
  description: >-
    Progressive CD4 T-cell lymphopenia, with declining naive CD45RA+CD4+ cells,
    is a consistent immunologic feature and can be the predominant presentation
    in EBV-naive patients.
  phenotype_term:
    preferred_term: Decreased total CD4+ T cell count
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  evidence:
  - reference: PMID:25061172
    reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunological analysis at the age of 10 showed persistently low CD4+
      T-cell counts (range: 8% to 16%; 286-714/µL)
    explanation: Documents persistent CD4 lymphopenia in the index CD4-lymphopenia patient.
  sequelae:
  - target: Recurrent lower respiratory tract infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      T-cell depletion contributes to the infectious susceptibility that is
      poorly controlled by antimicrobials.
    evidence:
    - reference: PMID:25339095
      reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        infections and viremia due to T cell depletion and hypogammaglobulinemia
        is hardly controlled by antivirals or antibiotics
      explanation: >-
        Attributes the infectious susceptibility jointly to T-cell depletion
        and hypogammaglobulinemia.
  - target: Pneumocystis jirovecii pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progressive T-cell decline predisposed an index patient to fatal
      Pneumocystis pneumonia.
    evidence:
    - reference: PMID:25339095
      reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        T cells unfortunately were continuously declining and the girl died from
        respiratory failure after acquiring pneumocystis pneumonia
      explanation: >-
        Links the declining T-cell compartment to the terminal Pneumocystis
        infection.
- name: Persistent EBV viremia
  category: Infectious
  diagnostic: true
  description: >-
    High-level EBV viremia (10^4 to 10^8 copies per microgram DNA) is
    characteristic; no symptomatic EBV-seronegative lymphoproliferation patient
    has been reported.
  phenotype_term:
    preferred_term: Persistent EBV viremia
    term:
      id: HP:0020072
      label: Persistent EBV viremia
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with EBV-LPD show a rather high EBV viremia though the observed
      peak viral load in the eight reported patients was quite heterogeneous
      (10^4 - 10^8 copies/ μg DNA).
    explanation: Quantifies the characteristic EBV viremia.
- name: Decreased circulating immunoglobulin concentration
  category: Immunologic
  description: Progressive hypogammaglobulinemia develops in many patients, often after EBV infection.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:31025232
    reference_title: "Genetic Deficiency and Biochemical Inhibition of ITK Affect Human Th17, Treg, and Innate Lymphoid Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss of function mutations in ITK results in hypogammaglobulinemia and
      CD4+ T cell loss in humans
    explanation: States hypogammaglobulinemia as a consequence of ITK loss of function.
  sequelae:
  - target: Recurrent lower respiratory tract infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypogammaglobulinemia contributes to the infectious susceptibility that
      is poorly controlled by antimicrobials.
    evidence:
    - reference: PMID:25339095
      reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        infections and viremia due to T cell depletion and hypogammaglobulinemia
        is hardly controlled by antivirals or antibiotics
      explanation: >-
        Attributes the infectious susceptibility jointly to hypogammaglobulinemia
        and T-cell depletion.
- name: Lymphoproliferative disorder
  category: Neoplastic
  frequency: VERY_FREQUENT
  description: >-
    EBV-positive B-cell lymphoproliferative disease, polymorphic to monomorphic,
    is the dominant manifestation after EBV infection.
  phenotype_term:
    preferred_term: Lymphoproliferative disorder
    term:
      id: HP:0005523
      label: Lymphoproliferative disorder
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our group and collaborators were able to reveal the pathogenicity of
      mutations in the Interleukin-2-inducible T-cell Kinase (ITK) in a cohort
      of nine patients with most patients presenting with massive EBV B-cell
      lymphoproliferation.
    explanation: EBV B-cell lymphoproliferation is the predominant presentation across the cohort.
- name: Hodgkin lymphoma
  category: Neoplastic
  frequency: FREQUENT
  description: >-
    EBV-positive classic (mixed-cellularity) Hodgkin lymphoma and Hodgkin-like
    B-cell proliferations are common, often in childhood.
  phenotype_term:
    preferred_term: Hodgkin lymphoma
    term:
      id: HP:0012189
      label: Hodgkin lymphoma
  evidence:
  - reference: PMID:25728094
    reference_title: "High incidence of Epstein-Barr virus (EBV)-positive Hodgkin lymphoma and Hodgkin lymphoma-like B-cell lymphoproliferations with EBV latency profile 2 in children with interleukin-2-inducible T-cell kinase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a Hodgkin-like B-cell proliferation (one case), and classic
      mixed-cellularity Hodgkin lymphoma (six cases). All cases (12/12) were
      EBV-positive.
    explanation: Six of twelve biopsied lesions were classic Hodgkin lymphoma, all EBV-positive.
- name: B-cell lymphoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: EBV-driven lymphoproliferation can progress to large B-cell lymphoma; classical non-Hodgkin histology is less common.
  phenotype_term:
    preferred_term: B-cell lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  evidence:
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen patients presented either with HL or with EBV-driven B cell
      lymphoproliferative disease (in some cases developing to Hodgkin or large
      B cell lymphoma), only two showed a classical non-HL histology.
    explanation: Documents large B-cell lymphoma and non-Hodgkin histology among reported patients.
- name: Pulmonary nodule
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Large pulmonary interstitial nodules, usually extranodal EBV-positive
    B-cell proliferation, were reported in the majority of patients in the
    2014 review of the first nine cases.
  phenotype_term:
    preferred_term: Pulmonary nodule
    term:
      id: HP:0033608
      label: Pulmonary nodule
  evidence:
  - reference: PMID:22487848
    reference_title: "IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Imaging studies revealed diffuse pulmonary nodules and mediastinal lymphadenopathy.
    explanation: Pulmonary nodules in a patient with disseminated EBV infection.
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary involvement with large interstitial nodules was observed in the
      majority of patients
    explanation: >-
      Review-level statement of frequency across the first reported cases. The
      review's Table 1 "pulmonary involvement" row is not quoted because it
      does not separate nodules from pulmonary infections.
- name: Lymphadenopathy
  category: Immunologic
  description: Lymphadenopathy is part of the mononucleosis-like presentation.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: ORPHA:538963
    reference_title: "Combined immunodeficiency due to ITK deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients present persistent symptoms of infectious mononucleosis
      including recurrent febrile episodes, lymphadenopathies, and
      hepatosplenomegaly, accompanied by high EBV viral load in the blood.
    explanation: Orphanet lists lymphadenopathy among the core features.
- name: Hepatosplenomegaly
  category: Immunologic
  description: Hepatosplenomegaly accompanies the EBV lymphoproliferative presentation.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: ORPHA:538963
    reference_title: "Combined immunodeficiency due to ITK deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients present persistent symptoms of infectious mononucleosis
      including recurrent febrile episodes, lymphadenopathies, and
      hepatosplenomegaly, accompanied by high EBV viral load in the blood.
    explanation: Orphanet lists hepatosplenomegaly among the core features.
- name: Hemophagocytosis
  category: Immunologic
  frequency: OCCASIONAL
  description: Hemophagocytic lymphohistiocytosis follows EBV infection in a minority of patients.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:26056787
    reference_title: "Atypical Clinical Course in Pediatric Hodgkin Lymphoma: Association With Germline Mutations in Interleukin-2-inducible T-Cell Kinase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A germline mutation in interleukin-2-inducible T-cell kinase (ITK) is
      described in individuals manifesting B-cell LPDs, cHL, and hemophagocytic
      syndromes following Epstein-Barr virus (EBV) infection.
    explanation: Lists hemophagocytic syndromes among the post-EBV manifestations of ITK deficiency.
- name: Autoimmunity
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Autoimmune phenomena, including autoimmune cytopenias, nephritis and
    thyroiditis, occur given the severe immune dysregulation.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given severe immune dysregulation, three patients developed autoimmune
      phenomena (cytopenia, nephritis and thyroiditis)
    explanation: Autoimmune manifestations in three of the reviewed patients.
- name: Autoimmune hemolytic anemia
  category: Hematologic
  description: >-
    Coombs-positive autoimmune hemolytic anemia with thrombocytopenia was a
    presenting feature in the ALPS-like patient.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:32628964
    reference_title: "ITK deficiency presenting as autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She subsequently developed a Coombs positive chronic autoimmune hemolytic
      anemia, thrombocytopenia, vitiligo, diffuse lymphadenopathy, and
      splenomegaly.
    explanation: Coombs-positive AIHA in the patient presenting as ALPS.
- name: Tuberculosis infection
  category: Infectious
  frequency: VERY_RARE
  description: >-
    Severe or disseminated tuberculosis has occurred in EBV-naive patients with
    complete ITK deficiency, attributed to defective IFN-gamma immunity.
  phenotype_term:
    preferred_term: Tuberculosis infection
    term:
      id: HP:5210111
      label: Tuberculosis infection
  evidence:
  - reference: PMID:36326697
    reference_title: "Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report three patients from two kindreds without EBV viremia or disease
      but with severe TB and inherited complete ITK deficiency
    explanation: Three EBV-naive ITK-deficient patients with severe tuberculosis.
- name: EBV-associated smooth muscle tumor
  category: Neoplastic
  frequency: VERY_RARE
  description: >-
    EBV-positive smooth muscle tumors (e.g. bilateral adrenal leiomyomas) are a
    rare manifestation; EBV may be confined to the tumor with negative blood
    serology.
  phenotype_term:
    preferred_term: EBV-associated smooth muscle tumor (adrenal leiomyoma)
    term:
      id: HP:0034549
      label: Adrenal leiomyoma
  evidence:
  - reference: PMID:42132280
    reference_title: "From T-cell defect to tumorigenesis: Epstein-Barr virus-associated smooth muscle tumors in ITK deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathology and immunohistochemistry confirmed bilateral adrenal
      leiomyomas, and EBV in situ hybridization demonstrated EBV infection
      within tumor cells despite negative blood EBV serology
    explanation: Bilateral adrenal leiomyomas with intratumoral EBV in an ITK-deficient boy.
- name: Verrucae
  category: Dermatologic
  frequency: VERY_RARE
  description: >-
    Beta-HPV-positive epidermodysplasia verruciformis has been reported,
    reflecting broader dysregulation of T-cell responses to oncogenic viruses.
  phenotype_term:
    preferred_term: Verrucae
    term:
      id: HP:0200043
      label: Verrucae
  evidence:
  - reference: PMID:30778533
    reference_title: "Inherited Interleukin 2-Inducible T-Cell (ITK) Kinase Deficiency in Siblings With Epidermodysplasia Verruciformis and Hodgkin Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a novel association of a homozygous ITK mutation with
      β-human papillomavirus (HPV)-positive epidermodysplasia verruciformis.
    explanation: beta-HPV epidermodysplasia verruciformis in ITK-deficient siblings.
- name: Recurrent lower respiratory tract infections
  category: Respiratory
  description: >-
    Recurrent pulmonary infections and bronchiectasis occur, prominently in
    EBV-naive patients with CD4 lymphopenia.
  phenotype_term:
    preferred_term: Recurrent lower respiratory tract infections
    term:
      id: HP:0002783
      label: Recurrent lower respiratory tract infections
  evidence:
  - reference: PMID:25061172
    reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He suffered from recurrent pulmonary infections causing progressive
      immune reaction and bronchiectasia.
    explanation: Recurrent pulmonary infection and bronchiectasis in the CD4-lymphopenia patient.
- name: Pneumocystis jirovecii pneumonia
  category: Infectious
  frequency: VERY_RARE
  description: >-
    Pneumocystis jirovecii pneumonia was the terminal opportunistic infection
    in one index patient whose T cells declined after chemotherapy, reflecting
    the profound T-cell deficiency rather than a frequent manifestation.
  phenotype_term:
    preferred_term: Pneumocystis jirovecii pneumonia
    term:
      id: HP:0020102
      label: Pneumocystis jirovecii pneumonia
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the girl died from respiratory failure after acquiring pneumocystis
      pneumonia at the age of 10 ½ years
    explanation: >-
      Documents fatal Pneumocystis pneumonia in an index patient with
      progressive T-cell decline.
- name: Fever
  category: Constitutional
  description: Recurrent fever is part of the mononucleosis-like presentation.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with lymphoproliferative disease / Hodgkin lymphoma manifested
      between 3 and 13 years of age with fever, lymphadenopathy,
      hepatosplenomegaly and EBV viremia
    explanation: Fever at presentation, with the pediatric onset range.
treatments:
- name: Allogeneic hematopoietic stem cell transplantation
  therapeutic_modality: CELL_THERAPY
  description: >-
    HSCT is the only definitive treatment and is advocated early once the
    diagnosis is established; outcome in primary immunodeficiency has improved,
    and haploidentical donors with T-cell depletion plus adoptive EBV-specific
    T cells have been used when no matched donor is available.
  treatment_term:
    preferred_term: Allogeneic Hematopoietic Stem Cell Transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  evidence:
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We believe that current clinical data advocate early definitive treatment
      by hematopoietic stem cell transplantation, as transplant outcome in
      primary immunodeficiency disorders in general has gradually improved in
      recent years.
    explanation: Review recommendation for early definitive HSCT.
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      eight patients underwent hematopoietic SCT. Two patients died after HSCT.
    explanation: >-
      Outcome data showing HSCT is the definitive route but carries
      transplant-related mortality.
- name: Rituximab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Anti-CD20 therapy is used for EBV-driven B-cell proliferation and can bridge
    to definitive transplant; responses are partial in some patients.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  evidence:
  - reference: PMID:22487848
    reference_title: "IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with rituximab (anti-CD20 mab) resulted in complete clinical
      remission with resolution of pulmonary lesions and a negative EBV titer
      in serum.
    explanation: Documented rituximab response in a patient with disseminated EBV disease.
- name: Immunoglobulin replacement therapy
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    IgG substitution partially ameliorates hypogammaglobulinemia and immune
    dysregulation but confers only temporary benefit.
  treatment_term:
    preferred_term: Immunoglobulin Therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  evidence:
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IgG substitution has conferred only temporary benefit, especially to
      partially ameliorate immune dysregulation manifesting as
      lymphoproliferation and autoimmunity
    explanation: States the limited, temporary benefit of IgG replacement.
- name: Chemotherapy for Hodgkin lymphoma
  therapeutic_modality: OTHER
  description: >-
    Standard lymphoma chemotherapy protocols are used for the EBV-positive
    Hodgkin lymphoma that is the most common malignant outcome. Chemotherapy
    can achieve remission but is not reliably durable, as progressive T-cell
    decline continues and most patients ultimately require allogeneic HSCT.
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  target_mechanisms:
  - target: Hodgkin lymphoma
    treatment_effect: INHIBITS
    description: >-
      Chemotherapy treats the EBV-driven Hodgkin lymphoma; durable remission on
      chemotherapy alone is reported in only a minority.
    evidence:
    - reference: PMID:29867957
      reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Six patients died due to lymphoproliferation, while only two patients
        remained in remission after chemotherapy for HL.
      explanation: >-
        Quantifies the limited durability of chemotherapy for the Hodgkin
        lymphoma of ITK deficiency.
  evidence:
  - reference: PMID:25339095
    reference_title: "Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Successfully treated according to standard chemotherapy protocol, T cells
      unfortunately were continuously declining and the girl died from
      respiratory failure after acquiring pneumocystis pneumonia at the age of
      10 ½ years.
    explanation: >-
      An index patient's Hodgkin lymphoma was treated with a standard
      chemotherapy protocol; it documents both the use of chemotherapy and that
      it did not prevent the fatal course.
diagnosis:
- name: ITK molecular genetic testing
  description: >-
    ITK is included on combined-immunodeficiency gene panels; whole-exome
    sequencing or a primary immunodeficiency panel confirms biallelic variants.
    All patients with EBV-associated lymphoproliferative disorders negative for
    SH2D1A and XIAP should be analyzed for ITK mutations.
  evidence:
  - reference: PMID:22487848
    reference_title: "IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with EBV-associated lymphoproliferative disorders should be
      analyzed for mutations in ITK.
    explanation: Recommendation to test ITK in the relevant clinical setting.
- name: Lymphocyte subset and iNKT-cell immunophenotyping
  description: >-
    Flow cytometry shows low CD4 counts, reduced naive CD45RA+CD4+ cells, and
    absent or severely reduced invariant NKT cells (TCR Valpha24+/Vbeta11+).
  evidence:
  - reference: PMID:25061172
    reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The index patient shows complete absence of TCRVα24+/TCRVβ11+ iNKT-cells.
    explanation: iNKT-cell absence is a diagnostically useful hallmark on flow cytometry.
discussions:
- discussion_id: ebv_independent_disease
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Do lymphoma, hypogammaglobulinemia and immune dysregulation in ITK
    deficiency require EBV infection, or can they arise independently of it?
  attaches_to:
  - pathophysiology#Impaired T-Cell Control of EBV
  rationale: >-
    No symptomatic EBV-seronegative lymphoproliferation patient had been
    reported, suggesting EBV is necessary for the lymphoproliferative arm. Yet
    an EBV-naive patient had combined immunodeficiency with CD4 lymphopenia and
    absent iNKT cells as the predominant manifestation, and other EBV-naive
    patients developed severe tuberculosis, showing that some phenotypes are
    EBV-independent. Whether the malignant and antibody phenotypes can occur
    without EBV is unsettled.
  evidence:
  - reference: PMID:25061172
    reference_title: "Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we here had the unique opportunity to dissect EBV-dependent and
      EBV-independent ITK deficiency phenotypes.
    explanation: The EBV-naive patient allows separation of EBV-dependent from EBV-independent features.
- discussion_id: murine_ebv_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does any available animal model reproduce the EBV-driven lymphoproliferation
    that defines human ITK deficiency?
  attaches_to:
  - pathophysiology#Impaired T-Cell Control of EBV
  rationale: >-
    Itk-/- mice recapitulate the iNKT-cell deficiency, CD4 lymphopenia and the
    TCR calcium/IFN-gamma signalling defects, but EBV does not infect mice.
    In preliminary MHV-68 (the closest murine EBV surrogate) experiments the
    authors saw no difference in lung or splenic viral load between Itk-/- and
    wild-type mice, so the central human phenotype — failure to control the
    gammaherpesvirus — is not demonstrated in the mouse.
  evidence:
  - reference: PMID:29867957
    reference_title: "Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      There was no difference in the lytic viral tire in lungs between B6 and
      itk−/− infected mice; furthermore, there was no difference in the splenic
      genomic viral load between B6 and itk−/− mice at day 17.
    explanation: >-
      The murine MHV-68 surrogate does not reproduce the defective
      gammaherpesvirus control seen in patients.
animal_models:
- name: Itk-knockout mouse (Itk-/-)
  species: Mus musculus
  genotype: Itk null
  description: >-
    Itk-/- mice reproduce several features of human ITK deficiency — reduced,
    immature and dysfunctional NKT cells, decreased thymic and peripheral CD4 T
    cells, and impaired TCR-induced calcium release and effector cytokine
    production — but they do not model EBV, which does not infect mice.
  evidence:
  - reference: PMID:18292523
    reference_title: "The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Itk-/- mice have reduced numbers of NKT cells with a predominantly
      immature phenotype.
    explanation: Establishes the NKT-cell phenotype of the knockout.
  modeled_mechanisms:
  - target: Invariant NKT Cell Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The knockout reproduces the reduced and immature NKT-cell compartment seen in patients.
    limitations: >-
      Residual NKT cells differ in degree from the near-complete human iNKT
      absence, and the mouse does not capture the EBV context in which the
      human deficit is observed.
    evidence:
    - reference: PMID:18292523
      reference_title: "The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Itk-/- mice have reduced numbers of NKT cells with a predominantly
        immature phenotype.
      explanation: The model's NKT phenotype corresponds to the human iNKT deficiency node.
  - target: Defective TCR-Induced Calcium Mobilization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Itk-/- T cells show reduced TCR-induced calcium release, the defect rescued by wild-type ITK.
    limitations: >-
      Mouse T cells retain more residual TCR signalling than some human alleles,
      and RLK (TXK) partially compensates in mice.
    evidence:
    - reference: PMID:22289921
      reference_title: "Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Human wild-type (wt) ITK, but none of the mutants, was able to rescue
        defective calcium flux in murine Itk(-/-) T cells.
      explanation: The murine Itk-/- calcium defect is the assay used to establish human allele loss of function.
notes: >-
  Boundary with other EBV-susceptibility inborn errors: ITK deficiency is kept
  as a distinct entry from SH2D1A/XLP1, XIAP/XLP2, CD27 and CD70 deficiency,
  MAGT1/XMEN disease and LAT deficiency, each curated or to be curated
  separately. ITK is also one etiology of Mendelian susceptibility to
  mycobacterial disease via its IFN-gamma defect; the tuberculosis arm is
  recorded here because PMID:36326697 reports it in ITK-deficient patients, and
  the overlapping MSMD framing is noted in Immunodeficiency_88. EBV infection
  is the trigger for the lymphoproliferative arm but is not yet an
  environmental[] node; the matching ECTO class is ECTO:3000273 'exposure to
  human gammaherpesvirus 4' (ols:ecto search l~gammaherpesvirus, 2026-10-14).
📚

References & Deep Research

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: Lymphoproliferative Syndrome 1 (ITK deficiency) · 2026-10-14T00:34:38Z · View source

De novo curation of lymphoproliferative syndrome 1 / ITK deficiency (MONDO:0013081), autosomal recessive combined immunodeficiency from biallelic ITK loss of function. Pathograph: ITK LOF -> defective TCR calcium/PLCg1 signalling -> iNKT deficiency, CD4 lymphopenia, impaired EBV control, reduced IFN-gamma, defective FasL upregulation -> EBV-driven B-cell lymphoproliferation, Hodgkin lymphoma, B-cell lymphoma, HLH, EBV smooth muscle tumor, autoimmunity, and (EBV-naive) tuberculosis. Evidence from primary case reports/series (Huck 2009 PMID:19425169, Linka 2012, Serwas 2014, Bienemann 2015, Ghosh 2014 and Ghosh 2018 reviews), IUIS 2024 classification (Table 1 combined immunodeficiency), Orphanet ORPHA:538963 prevalence <1/1,000,000, and ClinGen CGGV Definitive AR assertion for this MONDO term. Itk-/- mouse model linked with modeled_mechanisms. Falcon deep research was unavailable (503), so one claude_code report was generated and used ONLY as a lead; every claim verified against cached primary sources. Gaps recorded as discussions: whether lymphoma/hypogammaglobulinemia are EBV-independent (OPEN_QUESTION); murine MHV-68 model does not reproduce EBV susceptibility (HUMAN_MODEL_MISMATCH). EBV not yet added as an environmental node; ECTO:3000273 (exposure to human gammaherpesvirus 4) noted for a follow-up. Deleted stub. All offline gates pass.

Claude Code ▸
Lymphoproliferative Syndrome 1 (LPFS1, ITK deficiency): research report
claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-13T23:57:16.277640

Lymphoproliferative Syndrome 1 (LPFS1, ITK deficiency): research report

Source limits for this report. - It rests on three web searches. They returned secondary databases (MedGen, MalaCards, NORD, LOVD, a Disease Ontology mirror) and two review articles. - Full text of the reviews could not be read. PMC returned a reCAPTCHA page, so no quote below is verified against a paper. - I have no verified PMIDs. Two reviews are cited by PMCID, which is what the searches returned. A PMID written from memory would be a lead, not a citation, so I have left them out. - Statements marked [model knowledge] come from my background knowledge, not from a source I retrieved. Check them before they go into YAML. - No search was run on OMIA, MGI or IMPC (§14–15), HPO annotations, ClinGen, GeneReviews, trial registries, or treatment-outcome series. Those sections are largely model knowledge.

1. Disease information

Identifiers - OMIM 613011, MONDO:0013081, Orphanet 538963, MedGen 765548, GARD 0017979, DOID:0060707. - Source class: structured databases (MedGen, MONDO concept via SAIL, LOVD). - The search summary described the OMIM title as "Lymphoproliferative syndrome, EBV-associated, autosomal, 1". - I did not retrieve the OMIM or Orphanet pages themselves. Treat the cross-references as reported by aggregators.

Synonyms: LPFS1, ITK deficiency, ITK lymphoproliferative syndrome (MedGen / MONDO).

Concept. LPFS1 is an autosomal recessive primary immunodeficiency caused by biallelic ITK mutation. Onset is in early childhood, with EBV-associated immune dysregulation (MedGen).

Lump/split note. - This is the germline syndrome. - The EBV-driven Hodgkin and non-Hodgkin lymphomas it predisposes to are somatic tumours. Under design-decisions §3a they stay separate from this entry. - Other EBV-susceptibility inborn errors are separate entities, e.g. XLP1 (SH2D1A), XIAP deficiency (XLP2), and CD27/CD70 deficiency. - I have not checked the MONDO class hierarchy here.

2. Etiology

  • Cause: homozygous or compound-heterozygous loss of ITK at 5q32 (MONDO / LOVD). The entry is Mendelian and AR.
  • Environmental trigger: EBV. The aggregator text lists a high EBV viral load. MedGen states the open question: it is unknown whether ITK mutations cause lymphoma or hypogammaglobulinemia independently of EBV.
  • Protective factors / gene-environment: none established in the retrieved sources. EBV exposure is the main interaction. Whether EBV-naive patients develop disease is not settled in what I retrieved.

3. Phenotypes

Sources: MedGen and PanelApp Australia, both aggregators. The 2018 review is PMC5951928, via the search snippet only. No per-phenotype frequencies were retrievable.

Phenotype HPO (proposed [model knowledge], not looked up; verify) Support
Hodgkin lymphoma HP:0012189 MedGen; 2018 review snippet
Non-Hodgkin lymphoma HP:0012539 review snippet
Lymphomatoid granulomatosis no term proposed MedGen
EBV-driven B-cell lymphoproliferation no confident term review snippet
Hemophagocytic lymphohistiocytosis HP:0002482 MedGen
Hypogammaglobulinemia / dysgammaglobulinemia HP:0003587 or HP:0004313 MedGen; review
CD4 lymphopenia HP:0005406 PanelApp
Cytopenias no term proposed PanelApp
Hepatosplenomegaly HP:0001433 PanelApp
Autoimmune hemolytic anemia HP:0001890 MedGen
Autoimmune renal disease no term proposed MedGen
Reduced invariant NKT cells (laboratory) no HPO term proposed MedGen
High EBV viral load no HPO term proposed MedGen
  • Onset: early childhood (MedGen).
  • Course: episodic EBV-triggered disease, with progressive hypogammaglobulinemia in the index sibs (see §11).

4. Genetic / molecular

  • Gene: ITK, IL2-inducible T-cell kinase, a Tec-family non-receptor tyrosine kinase. HGNC ID not looked up; do not write one from memory.
  • Index variant: homozygous R335W, found by genome-wide linkage in two sisters from a consanguineous Turkish family (2018 review snippet). R335W is in the kinase domain [model knowledge].
  • Cohort size: the 2018 review reports ITK mutations in 17 patients from Greece, India, Italy, Iran, Morocco, Pakistan, Palestine and elsewhere. An earlier review (PMC4220104) describes nine patients. Both counts are from search summaries.
  • Mechanism class: loss of function. R335W causing protein deficiency is [model knowledge].
  • Other variants, gnomAD frequencies, ClinVar and ClinGen classification: not retrieved. No ClinGen validity assertion was checked, so gene_disease_validity should stay absent until a CGGV record is found.

5. Environmental information

  • Infectious agent: Epstein-Barr virus, a human herpesvirus 4 (NCBITaxon ID not looked up). The disease is defined by the EBV-associated phenotype.
  • Toxins and lifestyle: none reported.

6. Mechanism / pathophysiology

Causal chain (most steps [model knowledge]; only steps 1, 5, 6 and 7 are directly supported by the retrieved sources): 1. Biallelic ITK loss of function. Supported. 2. Loss of ITK removes TCR-proximal signalling, i.e. the PLCγ1/Ca²⁺/NFAT axis. Inferred from known Tec-kinase biology. 3. T-cell development and function are impaired, with CD4 depletion, as reported in PanelApp. Reduced iNKT cells are reported in MedGen. 4. Cytotoxic and iNKT-mediated control of EBV-infected B cells is impaired. This is inferred, not demonstrated in the retrieved sources. 5. EBV viral load rises (MedGen) and EBV-driven B-cell lymphoproliferation follows (2018 review). 6. Branches: - Hodgkin or non-Hodgkin lymphoma, or lymphomatoid granulomatosis. - HLH. - Hypogammaglobulinemia. The mechanism is unestablished. The 2018 review links hypogammaglobulinemia to low CD27⁺ memory B cells across EBV-susceptibility defects, but I did not see ITK-specific evidence. - Autoimmunity (AIHA, renal disease). 7. Open question (MedGen): whether lymphoma and hypogammaglobulinemia occur without EBV.

Proposed ontology terms, to verify by lookup: - Cell types: CL:0000084 (T cell), CL:0000624 (CD4+ αβ T cell), CL:0000236 (B cell), CL:0000814 (mature NK T cell). - GO: T cell receptor signaling pathway (GO:0050852).

No transcriptomics, proteomics or single-cell data were searched.

7. Anatomical structures

  • Organs: lymph nodes, spleen, liver, kidney (autoimmune), bone marrow (cytopenias, HLH). UBERON IDs were not looked up.
  • Cells: T cells, iNKT cells, EBV-infected B cells.
  • Subcellular: cytoplasm and plasma membrane (TCR signalling). No further detail was retrieved.

8. Temporal development

  • Onset is in early childhood (MedGen). Course is progressive in untreated patients.
  • Index sisters: one had progressive hypogammaglobulinemia, then Hodgkin lymphoma, and died of Pneumocystis pneumonia at age 10. The other had EBV-associated Hodgkin lymphoma and died during aplasia after salvage haploidentical transplant (2018 review snippet).
  • No stage or remission data were retrieved.

9. Inheritance and population

  • Inheritance: AR, bound to HP:0000007 [model knowledge].
  • Consanguinity: present in the index family.
  • Geography: patients come from Turkey, Greece, India, Italy, Iran, Morocco, Pakistan and Palestine (2018 review snippet). A founder effect is not established in the retrieved sources.
  • Prevalence: no figure retrieved. Orphanet 538963 may carry a class; I did not check it.
  • Sex ratio: not retrieved.

10. Diagnostics

All from model knowledge unless noted: - Lymphocyte subsets (low CD4, low iNKT). - Immunoglobulins. - EBV PCR. - Tissue biopsy of lymphoproliferation. - Genetic testing: ITK appears on the Australian PanelApp "Combined Immunodeficiency" panel (supported by the PanelApp snippet). WES or a primary immunodeficiency panel is the practical route. - ITK protein expression by flow or immunoblot is a plausible functional test. - I found no diagnostic criteria or screening programme. - Differentials: XLP1, XIAP deficiency, CD27/CD70 deficiency, other EBV-susceptibility inborn errors, and lymphomas without a germline cause.

11. Prognosis

  • Mortality is high in the described patients: both index sisters died. No survival series was retrieved.
  • The 2018 review advocates early definitive HSCT.
  • Complications: lymphoma, HLH, opportunistic infection (Pneumocystis), autoimmunity.

12. Treatment

  • Definitive: HSCT (NCIT:C15431, hematopoietic cell transplantation). The recommendation is from the 2018 review snippet. No outcome data were retrieved.
  • Supportive [model knowledge]:
  • Immunoglobulin replacement.
  • Pneumocystis prophylaxis.
  • Anti-CD20 therapy (rituximab) for EBV B-cell proliferation.
  • Lymphoma-directed chemotherapy.
  • Experimental: no trials were searched.
  • Pharmacogenomics: none known.

13. Prevention

  • Genetic counselling for AR recurrence.
  • Cascade testing of sibs.
  • Prenatal or preimplantation diagnosis once the familial variants are known.
  • EBV avoidance is not realistic.
  • The retrieved sources contain no guideline.

14. Other species

Not researched. Please do not infer from absence. ITK orthologues exist in mouse. OMIA was not queried.

15. Model organisms

  • Itk-knockout mice are known from the literature [model knowledge]. I retrieved no source on their phenotype or on how well they recapitulate the human disease.
  • MGI, IMPC and ZFIN were not searched.
  • The animal_models section should wait for a primary citation.

Gaps to close before curating

  1. Get verified PMIDs by just fetch-reference for:
  2. The 2009 index-family paper.
  3. The ITK deficiency cohort papers.
  4. PMC4220104 and PMC5951928, via their PMIDs.
  5. Confirm the Orphanet 538963 and OMIM 613011 text, including any prevalence class and the OMIM title wording.
  6. Look up every HPO, CL, GO and UBERON term above. None was read from a source in this session.
  7. Check ClinGen for an ITK validity record.
  8. Find an HSCT outcomes series, and check for any ITK-specific therapy.
  9. Find Itk-knockout evidence.

Sources: - MedGen 765548 - MONDO:0013081 via SAIL concept library - LOVD disease 03228 - PanelApp Australia, Combined Immunodeficiency, ITK - ITK Deficiency: Clinical and Molecular Aspects, PMC4220104 - ITK Deficiency: New Patients, New Insight?, PMC5951928 - MalaCards LPFS1

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 2
Resolved 2
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 2
On topic 2
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 17
Resolved 16
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 0
Terms whose name was checked 10
Terms named correctly 7
Terms named as a different term 1
Terms whose name is worth a second look 2

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:0005406 (1 mention) - the report calls it "CD4 lymphopenia"; HP calls it Recurrent bacterial skin infections

Unresolved terms

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

  • HP:0002482 (1 mention), reported as "Hemophagocytic lymphohistiocytosis" - HP does not contain this term

Terms whose name is worth a second look

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

  • CL:0000624 (1 mention) - the report calls it "CD4+ αβ T cell"; CL calls it CD4-positive, alpha-beta T cell
  • GO:0050852 (1 mention) - the report calls it "GO: T cell receptor signaling pathway"; GO calls it T cell receptor signaling pathway