Clinical characteristics: ZAP70-related combined immunodeficiency (ZAP70-related CID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling. Affected children usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower-respiratory infections and oral candidiasis are common. Affected children usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT).

Diagnosis/testing: The diagnosis of ZAP70-related CID is suggested by low to absent CD8⁺ T cells in an individual with normal CD3+ and CD4+ T-cell counts. Additional supportive laboratory features include absent proliferation of CD4⁺ T cells in response to mitogens and antigens, and absent ZAP-70 protein expression. The diagnosis is established in a proband by identification of biallelic pathogenic variants in ZAP70 on molecular genetic testing.

Management: Treatment of manifestations: Supportive care includes immediate intravenous immunoglobulin (IVIG) and antibacterial, antifungal, antiviral, and Pneumocystis jiroveci prophylaxis to control and reduce the occurrence of infections.

Prevention of primary manifestations: Allogeneic HSCT to reconstitute the immune system, preferably prior to the onset of infections.

Prevention of secondary complications: Use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products; deferment of immunizations until immune reconstitution; consideration for formula feeds in place of breast feeding until CMV status of mother is known.

Surveillance: Individuals with milder findings or those who have not undergone HSCT need to be monitored for worsening of immune function with periodic assessment of clinical status and functional lymphocyte responsiveness. Following a successful HSCT, the following should be routinely monitored: growth, psychomotor development, complete blood counts, liver and renal function, immune status, donor and recipient chimerism, development of post-transplant complications.

Agents/circumstances to avoid: Non-irradiated blood products; live viral, live mycobacterial, and live bacterial vaccinations; contaminated water sources; exposure to fungus-enriched environments (e.g., construction sites, agricultural areas with active soil disruption, mulch, hay).

Evaluation of relatives at risk: Because the outcome of HSCT in children with ZAP70-related CID is significantly improved by performing HSCT prior to the onset of severe infections, early testing of at-risk sibs should be considered. In addition, any sibs considered as bone marrow donors must be evaluated for ZAP70-related CID prior to donation.

Genetic counseling: ZAP70-related CID is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.