Definition of ZAP-70 Deficiency
The zeta-associated protein of 70 kDa (ZAP-70) is recruited to phosphorylated CD3 chains following TCR ligation, and participates in intracellular signaling. Mutations of ZAP-70 result in a rare form of SCID, with inability to support positive selection of CD8+ lymphocytes in the thymus, whereas development of CD4+ T cells is unaffected.101,108,109
Clinical and Laboratory Features
Patients present with clinical features of SCID, with early onset and severe infections. However, lymph nodes are palpable, and a thymic shadow can be visualized by chest radiography. Although the number of circulating CD8+ T cells is severely reduced in patients with ZAP-70 deficiency, the absolute lymphocyte count is normal or can even be elevated. The in vitro response to mitogens is markedly reduced, indicating that CD4+ lymphocytes are functionally defective. Profound hypogammaglobulinemia has been demonstrated in some patients, but normal antibody responses to immunization antigens have been recorded in others.
Differential diagnosis includes major histocompatibility complex (MHC) class I deficiency and CD8 deficiency, two conditions characterized by a severe reduction of CD8+ lymphocytes. Patients with CD8 deficiency have an unusual population of CD3+ TCR + CD4– CD8– cells that have a normal proliferative responses and usually survive to adulthood, although a late death from infections has been reported.110,111
ZAP-70 Deficiency Treatment is allogeneic hematopoietic stem cell transplantation.
The only curative treatment of ZAP-70 deficiency is allogeneic hematopoietic stem cell transplantation.