ITK – Lymphoproliferative Syndrome 1

Autosomal recessive loss‐of‐function variants in the Interleukin-2-inducible T-cell kinase (ITK) gene underlie a primary immunodeficiency marked by uncontrolled Epstein-Barr virus (EBV)–driven B-cell proliferation, designated lymphoproliferative syndrome 1 (MONDO:0013081). ITK encodes a Tec family non-receptor tyrosine kinase critical for T-cell receptor signaling and cytotoxic responses to EBV.

Clinical validity is strong: seven unrelated pediatric probands presenting with polymorphic and monomorphic EBV-positive B-cell lymphoproliferations (12 biopsies) including classic mixed-cellularity Hodgkin lymphoma, all with EBV latency type 2 (PMID:25728094); nine additional patients with massive EBV B-cell proliferation in a multi-center cohort (PMID:25339095); two consanguineous girls homozygous for ITK p.Arg335Trp who died of therapy-resistant EBV-LPD (PMID:19425169); and two further patients with R29H and D500T/F501L variants (PMID:22289921).

Genetic evidence supports autosomal recessive inheritance with segregation in multiple consanguineous families and compound heterozygotes. Over 20 probands harbor at least 15 distinct missense and five truncating or frameshift variants, including the recurrent c.1003C>T (p.Arg335Trp), demonstrating allelic heterogeneity and reaching the genetic evidence cap.

Functional assays define loss-of-function as the mechanism: ITK autophosphorylation on Y180 in the SH3 domain occurs in cis, and Y180 mutants impair kinase activity and ligand binding (PMID:17897671). The p.Arg335Trp protein is unstable in vitro, abrogating ITK signaling and NKT cell development (PMID:19425169). Patient T cells with D540N show reduced phosphorylation of ITK, PLCγ and PKC, with impaired cytotoxicity rescued by magnesium supplementation (PMID:31507602).

Additional evidence from an ITK-deficient human cohort demonstrates skewed Th17/Treg balance and reduced ILC2/ILC3 frequencies, mirroring murine Itk knockout phenotypes (PMID:31025232). These convergent data confirm haploinsufficiency is not operative; rather, biallelic LoF is required for disease.

In summary, strong genetic and moderate functional evidence establish ITK deficiency as a definitive cause of lymphoproliferative syndrome 1. Clinical genetic testing for ITK variants enables early diagnosis, informs family counseling, and highlights magnesium supplementation as a potential adjunctive therapy. Key take-home: ITK testing should be included in EBV-driven lymphoproliferation panels to guide targeted management.

References

• Histopathology • 2015 • 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. PMID:25728094
• The Journal of clinical investigation • 2009 • Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. PMID:19425169
• Leukemia • 2012 • Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. PMID:22289921
• Journal of clinical immunology • 2014 • Interleukin-2-inducible T-cell kinase (ITK) deficiency – clinical and molecular aspects. PMID:25339095
• Journal of molecular biology • 2007 • Mechanism and functional significance of Itk autophosphorylation. PMID:17897671
• Frontiers in immunology • 2019 • Magnesium Restores Activity to Peripheral Blood Cells in a Patient With Functionally Impaired Interleukin-2-Inducible T Cell Kinase. PMID:31507602
• Journal of clinical immunology • 2019 • Genetic Deficiency and Biochemical Inhibition of ITK Affect Human Th17, Treg, and Innate Lymphoid Cells. PMID:31025232

Evidence Based Scoring (AI generated)