ZAP70-Related Combined Immunodeficiency D81.8

ZAP70-Related Combined Immunodeficiency ( ZAP=Zeta-associated protein 70) is a very rare autosomal recessive cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling. Affected children usually suffer from recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive during the first year of life. Severe lower respiratory tract infections and oral candidiasis are common. Affected children usually do not survive more than two years without hematopoietic stem cell transplantation (HSCT).

The diagnosis of ZAP70-related CID is made by low to absent CD8+ T cells in a person with normal CD3+ and CD4+ T cell counts. Furthermore: lack of proliferation of CD4+ T cells in response to mitogens and antigens and lack of expression of ZAP-70 protein. Diagnosis is made in one subject by identifying biallelic pathogenic variants of ZAP70 in a molecular genetic assay.

Combined immunodeficiency (CID) characterized by the selective absence of circulating CD8 T cells in the presence of low, normal or elevated CD4 T cells in peripheral blood.

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

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

ZAP70-related CID is inherited in an autosomal recessive manner. At conception, each sibling of an affected person 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. If the pathogenic variants are known in the family, carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible.

Prevention of secondary complications: use of irradiated, leukoreduced, cytomegalovirus (CMV)-safe blood products; vaccination with live viral, mycobacterial, and bacterial vaccines; contaminated water sources; contact with fungus-laden environments (e.g., construction sites, agricultural fields with active soil scarification, mulch, hay). Consider formula feeding in lieu of breastfeeding until the mother's CMV status is known.

To date, 14 unique mutations in the ZAP70 gene have been identified in patients with ZAP-70-related CID.

ZAP-70 deficiency should be considered in infants and young children with recurrent bacterial infections, even if the lymph nodes are palpable, the thymic shadow is conspicuous, and the total lymphocyte count is normal.

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2. Akar HH et al (2017) Silent brain infarcts in two patients with zeta chain-associated protein 70 kDa (ZAP70) deficiency. Clin Immunol 158: 88-91.
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