SUMMARY
1. Zeta assotiated protein (ZAP) 70 deficiency results in an autosomal recessive form of SCID that is characterized by a selective absence of CD8 T cells.
2. Patients present early in life with a SCID phenotype: FTT, chronic diarrhea, invasive infections, and opportunistic infections (PJP, candidiasis, CMV). Patients presenting with a milder phenotype or Omenn syndrome have also been described.
3. Laboratory findings include the following:
-Normal or elevated absolute lymphocyte count
-CD3 T cell, CD4 T cell, B cell, and NK cell numbers are normal
-CD8 T cell numbers are either absent or markedly reduced
-In vitro T cell proliferation to mitogens (PHA, PWM, ConA) are reduced
-Despite normal B cell numbers, IgG levels are low
-Specific antibody responses to vaccine antigens are greatly reduced
4. ZAP70 is an early T cell signaling molecule that transmits signals from the TCR/CD3 complex and triggers calcium signaling and MAPK pathway activation leading to gene transcription. ZAP70 is also required for normal thymic differentiation of CD8 T cells but not CD4 T cells.
5. The diagnosis should be suspected in patients presenting with a severe combined immunodeficiency phenotype and selective deficiency of CD8 T cells. Sequencing of the ZAP70 gene can confirm the diagnosis.
6. In addition to the treatment of acute infections, the following immediate management steps must be implemented:
-Avoid all live viral vaccines
-Only irradiated, CMV negative blood products should be used (to prevent GVHD and infections)
-Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole
-IVIG replacement therapy
-Start HLA-typing for the patient and any siblings for possible hematopoietic stem cell transplantation (HSCT).
7. Even with supportive therapies, patients with SCID will not survive without a HSCT. Patients who are transplanted earlier (before they have suffered end organ damage from infections) have a higher success rate.
OVERVIEW
Zeta assotiated protein (ZAP) 70 deficiency results in an autosomal recessive form of SCID that is characterized by a selective absence of CD8 T cells.
Patients present early in life with a SCID phenotype: FTT, chronic diarrhea, invasive infections, and opportunistic infections (PJP, candidiasis, CMV). Patients presenting with a milder phenotype or Omenn syndrome have also been described.
Laboratory findings include the following:
-Normal or elevated absolute lymphocyte count
-CD3 T cell, CD4 T cell, B cell, and NK cell numbers are normal
-CD8 T cell numbers are either absent or markedly reduced
-In vitro T cell proliferation to mitogens (PHA, PWM, ConA) are reduced
-Despite normal B cell numbers, IgG levels are low
-Specific antibody responses to vaccine antigens are greatly reduced
PATHOGENESIS
T cells are activated by antigen binding to the TCR. The CD3 complex consisting of the gamma, delta, epsilon, and zeta chains transmit an intracytoplasmic signal via ITAM motifs that are phosphorylated by src kinases leading to the recruitment and activation of ZAP70. ZAP70 phosphorylates a number of different substrates including phospholipase C gamma which leads to calcium signaling pathway and MAPK pathway activation. These signals trigger key transcription factor activation leading to an immune response. ZAP70 is also required for normal thymic differentiation of CD8 T cells but not CD4 T cells.
EVALUATION
The diagnosis should be suspected in patients presenting with a severe combined immunodeficiency phenotype and selective deficiency of CD8 T cells.
STEP 1: Immune Evaluation
-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-T-cell proliferation to Mitogens (PHA)
-IgG, IgA, IgM, levels
-Specific Antibody levels (if older than 6 months)
-Chest X-Ray
-Unlike typical SCID, the absolute lymphocyte count is normal in ZAP70 deficiency.
-CD3 and CD4 T cell numbers are normal but CD8 T cell are markedly reduced or absent. B cell and NK cell numbers are normal.
-In vitro T cell proliferation to mitogens is profoundly decreased.
-IgG levels are very low. IgA and IgM levels may be normal.
-Specific antibody responses to vaccine antigens are very low.
-Unlike typical SCID, a CXR reveals the presence of thymic tissue.
STEP 2: Genetic Testing
-ZAP70 gene sequencing
-Genetic testing for ZAP70 is commercially available through correlagen diagnostics.
MANAGEMENT
Pending the completion of an immunologic evaluation for suspected Omenn syndrome, it is critical to initiate certain measures to prevent life-threatening complications for patients. The following precautions should be implemented immediately:
1. Avoid all live viral vaccines (rotavirus, varicella, MMR, BCG)
Severe vaccine strain disease can occur if SCID patients receive these vaccines.
2. Only irradiated, CMV negative blood products should be used
Leukocytes from non-irradiated blood can cause graft versus host disease and CMV can cause severe infections.
3. Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole
4-6mg/kg/day of Trimethoprim component divided twice daily 3 days per week
4. IVIG replacement therapy
5. High resolution HLA-typing for the patient and any siblings
For possible Hematopoietic Stem Cell Transplantation (HSCT)
Even with supportive therapies, patients with SCID will not survive without a HSCT. Patients who are transplanted earlier (before they have suffered end organ damage from infections) have a higher success rate. A fully matched sibling donor (if available) is the preferred source for hematopoietic stem cells.
RESOURCES
Diagnostic Resources
SPECIFIC ZAP 70 Deficiency Testing:
Correlagen Genetic Testing for ZAP70
The following tests resources are accessible on the SCID overview diagostic resources page:
1. Lymphocyte Subsets by Flow Cytometry for T-cell (CD3, CD4, CD8), B-cell
(CD19), and NK cell (CD16/56).
2. Naïve (CD45 RA) and Memory (CD45 RO) T cells by Flow Cytometry
3. T-cell proliferation to Mitogens and Specific Antigens (candida, tetanus)
4. TREC (T-cell receptor excision circle) Analysis
5. T-cell Receptor Gene Rearrangement (TCR Spectratyping)