ITK deficiency

IL2-inducible T-cell kinase (ITK) deficiency is a rare autosomal recessive primary immunodeficiency condition caused by biallelic pathogenic variants in the ITK gene, leading to impaired T-cell development, T-cell receptor (TCR) signalling, cytokine release and regulation of differentiation. Due to T-cell dysfunction, affected patients usually present in childhood with variable clinical symptoms of lymphoproliferation, combined immunodeficiency and Epstein-Barr virus (EBV)-related lymphoma.

Symptoms of ITK deficiency typically present in early childhood or adolescence. The main clinical features are variable, but can include:

• lymphoma, particularly (but not exclusively) EBV associated;
• EBV-associated lymphoproliferative disease (for example, enlarged lymph nodes and/or pulmonary nodules);
• haemophagocytic lymphohistiocytosis (HLH);
• recurrent bacterial and/or viral infections; and
• autoimmune manifestations.

Laboratory tests show low CD4 T cells, particularly naive T cells, and progressive hypogammaglobulinaemia. There are also absent or few invariant natural killer T (iNKT) cells.

ITK deficiency is caused by biallelic pathogenic variants in the ITK gene, which encodes IL2 inducible T cell kinase. The enzyme is recruited to the cell membrane upon TCR activation. It then activates downstream immune pathways, such as the NFkB, mTOR and MAPK/ERK pathways.

Variants are typically loss of function, including missense, nonsense and indels, and may impact critical regions of the protein, such as the kinase, SH2 and PH domains.

ITK may be diagnosed following clinical evaluation of prolonged EBV-related mononucleosis, lymphoproliferation, and autoimmune manifestations. Patients may have a family history of immunodeficiency.

Laboratory tests comprise:

• full blood count, which may show reduced lymphocyte count;
• lymphocyte subset testing, which may show reduced CD4 T-cell levels, particularly CD45RA+ CD4+ T cells and reduced iNKT cells; and
• T-cell proliferation assay, showing impaired response.

Genomic testing confirms the diagnosis and differentiates ITK deficiency with other forms of primary immunodeficiency.

For information about testing, see ‘Infant or child with severe, recurrent, persistent and/or unusual infections.’

ITK deficiency may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

ITK deficiency is caused by biallelic pathogenic variants in the ITK gene. It is inherited in an autosomal recessive pattern and is a rare primary immunodeficiency, with fewer than 50 cases described.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. De novo variants may also arise. Carriers do not appear to be affected by disease.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

ITK deficiency can present variably, and this will determine management options.

Patients often require immunosuppressive agents initially, and rituximab (anti-CD20) can provide control of lymphoproliferative complications.

Patients with HLH should be managed using standard treatment based on current HLH diagnostic and therapeutic protocols.

The primary curative treatment for ITK deficiency is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications.

ITK deficiency may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• OMIM: 613011 Lymphoproliferative syndrome

References:

• Ghosh S, Bienemann K, Boztug K and others. ‘Interleukin-2-inducible T-cell kinase (ITK) deficiency – Clinical and molecular aspects‘. Journal of Clinical Immunology 2014: volume 34, issue 8, pages 892–899. DOI: 10.1007/s10875-014-0110-8
• Henter J-I, Horne A, Aricó M and others. ‘HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis‘. Pediatric Blood & Cancer 2006: volume 48, issue 2, pages 124–131. DOI: 10.1002/pbc.21039
• Ogishi M, Yang R, Rodriguez R and others. ‘Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis‘. Journal of Experimental Medicine 2023: 220, issue 1. DOI: 10.1084/jem.20220484

For patients

• Immune Deficiency Foundation: Chapter 18: Hemophagocytic lymphohistiocytosis and EBV susceptibility
• Immunodeficiency UK