Combined immunodeficiency due to ZAP70 deficiency

Combined immunodeficiency due to ZAP70 deficiency (also known as ZAP-70 deficiency, selective T-cell defect, or ZAP70-related severe combined immunodeficiency) is a rare inherited disorder of the immune system caused by mutations in the ZAP70 gene, which encodes zeta-chain-associated protein kinase 70. ZAP70 is a critical signaling molecule required for normal T-cell development and activation. In this condition, the thymic selection process is disrupted, leading to a near-complete absence of CD8+ T cells in the peripheral blood, while CD4+ T cells are present but functionally defective. This results in a severe combined immunodeficiency (SCID) phenotype despite the presence of some circulating T cells. Affected infants typically present in the first year of life with recurrent, severe, and often life-threatening infections, including pneumonia, chronic diarrhea, oral candidiasis, and skin infections. Failure to thrive is common. Opportunistic infections, such as Pneumocystis jirovecii pneumonia, may occur. The immune deficiency affects both cellular and, secondarily, humoral immunity, as T-cell help is required for adequate antibody responses. Without treatment, the disease is usually fatal in early childhood. The primary curative treatment is hematopoietic stem cell transplantation (HSCT), which can reconstitute the immune system if performed early. Supportive care includes prophylactic antibiotics, antifungal agents, and immunoglobulin replacement therapy. Avoidance of live vaccines is essential. Gene therapy approaches are under investigation but are not yet standard of care. Early diagnosis through newborn screening programs that detect T-cell receptor excision circles (TRECs) may identify affected infants before the onset of severe infections, improving transplant outcomes.

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