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ZAP-70 deficiency

Related gene: ZAP-70

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 in 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, and visible tonsils and thymus. While most of variants cause decreased ZAP-70 activity, one variant 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 have impaired proliferation. 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 combined immunodeficiency, including infection avoidance; vaccination with killed, but not live, vaccines; antibiotic prophylaxis; and immunoglobulin (Ig) replacement therapy. Most individuals with ZAP-70 deficiency die within the first two years of life from infection if they do not undergo a hematopoietic stem cell transplant (HSCT).

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This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA