ZAP-70 (zeta-associated protein 70) deficiency is an immunodeficiency disorder involving impaired T-cell activation caused by a signaling defect. Diagnosis is by detecting lymphopenia, absence or a very low number of T cells, and impaired lymphocyte proliferative responses to mitogens. Definitive treatment is hematopoietic stem cell transplantation.
(See also Overview of Immunodeficiency Disorders and Approach to the Patient With an Immunodeficiency Disorder.)
ZAP-70 deficiency is a primary immunodeficiency disorder that involves cellular immunity deficiencies. Inheritance is autosomal recessive.
ZAP-70 is important in T-cell signaling and in T-cell selection in the thymus. ZAP-70 deficiency causes T-cell activation defects.
Patients who have ZAP-70 deficiency present during infancy or early childhood with recurrent infections similar to those in severe combined immunodeficiency (SCID); however, they live longer, and the deficiency may not be diagnosed until they are several years old.
Diagnosis of ZAP-70 Deficiency
Routine neonatal screening using the T-cell receptor excision circle (TREC) test
White blood cell (WBC) count
Mitogen and vaccine antigen stimulation assays
Serum immunoglobulin levels
Flow cytometry for T cell and B cells
Diagnosis of ZAP-70 deficiency is similar to diagnosis of SCID.
ZAP-70 deficiency may be suspected in older children with a history of recurrent infections or other characteristic manifestations. Complete blood count, including absolute WBC count and differential, is done; immunoglobulin levels are measured. Responses to mitogens and to standard vaccine antigens are determined to evaluate WBC and antibody function.
The disorder is considered in patients with the following:
Lymphopenia
A low number of or no T cells
Absent lymphocyte proliferative responses to mitogens
Other tests may be done, including flow cytometry to determine T cell, B cell, and natural killer cell counts. Adenosine deaminase (ADA) and purine nucleoside phosphorylase levels in WBCs, red blood cells, and fibroblasts are measured.
Patients have normal, low, or elevated serum immunoglobulin levels and normal or elevated numbers of circulating CD4 T cells but essentially no CD8 T cells.
Their CD4 T cells do not respond to mitogens or allogeneic cells in vitro and do not produce CD8 cytotoxic T cells. In contrast, activity of natural killer cells, which are mostly CD16 or CD56 cells, is normal.
Testing of family members can be considered if they have clinical symptoms suggestive for disease.
Treatment of ZAP-70 Deficiency
Hematopoietic stem cell transplantation
Treatment of ZAP-70 deficiency generally involves preventing infection, managing acute infection, and replacing missing immune globulins with immunoglobulin replacement therapy.
The ZAP-70 deficiency is fatal unless treated by hematopoietic stem cell transplantation, which is potentially curative.
