Inheritance pattern: Autosomal recessive
ZAP-70 deficiency is a rare autosomal recessive combined immunodeficiency. ZAP-70 plays a crucial role in T cell development and function, and is crucial for CD8 T cell selection. Peripheral T cells from individuals with ZAP-70 deficiency demonstrate defective T cell signaling and have an autoreactive phenotype. Indeed, several individuals have presented with autoimmune disorders. Some children with ZAP-70 deficiency present within the first two years of life with a history of life-threatening infections, similar to infants with SCID. However, those with ZAP-70 deficiency may present later in childhood with palpable lymph nodes, visible tonsils and thymus. While most of the mutations cause decreased ZAP-70 activity, one mutation led to increased ZAP-70 function and a unique constellation of autoimmune phenotypes including bullous pemphigoid associated with autoantibodies and ulcerative colitis. Unlike those with SCID, individuals with ZAP-70 deficiency may have Pneumocystis jirovecii pneumonia, and cytomegalovirus (CMV) pneumonitis after 6 months of age. Autoimmunity or manifestations of immune dysregulation such as ulcerative colitis and blood cytopenias are reported. Unique presentations, such as pustular skin lesions from birth, subcutaneous nodules, lymphoma, and multisystem autoantibody disease, are also seen. In addition, cases with inflammatory features like Omenn syndrome and hemophagocytic lymphohistiocytosis (HLH) have been described. Individuals with ZAP-70 deficiency may have a normal number of circulating lymphocytes. They have normal CD3 and CD4 T cells but lack CD8 T cells. Typically, their T cells display impaired proliferation in vitro. All individuals have normal B cell and NK cell numbers. They may have reduced immunoglobulin G levels. The diagnosis of ZAP-70 deficiency should be considered in infants and young children with recurrent bacterial or opportunistic infections but also in those with early-onset autoimmunity and lymphoma. Those individuals require general management like an individual with CID, including infection avoidance; vaccination with killed, but not live, vaccines; antibiotic prophylaxis; and Ig replacement therapy. Most individuals with ZAP-70 deficiency die within the first two years of life from infection if they do not undergo HSCT.