ZAP70-related severe combined immunodeficiency (ZAP70-related SCID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling. Affected children usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower respiratory infections and oral moniliasis are common. Affected children usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT)
- Weight loss
- Recurrent infections
As the name indicates, this condition is caused by mutations in the ZAP70 gene (more than 12 mutations have been identified).
The ZAP70 gene provides instructions for making a protein called zeta-chain-associated protein kinase that is important for the development and function of several types of T cells (T cells identify foreign substances and defend the body against infection). Mutations in the ZAP70 gene prevent the production of zeta-chain-associated protein kinase or result in a protein that is unstable and cannot perform its function. A loss of functional zeta-chain-associated protein kinase leads to the absence of CD8+ T cells and an excess of inactive CD4+ T cells. The resulting shortage of active T cells causes people with ZAP70-related SCID to be more susceptible to infection.
- Prevention of primary manifestations: allogeneic HSCT to reconstitute the immune system, preferably within the first three months of life.
- Prevention of secondary complications: use of irradiated, cytomegalic virus (CMV)-negative blood products; deferment of immunizations until immune reconstitution.
- Genetic counseling: ZAP70-related SCID is inherited in an autosomal recessive manner. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic allelic variants in the family are known.
ZAP70-related severe combined immunodeficiency (ZAP70-related SCID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling leading to a selective absence of CD8+ T cells and normal or elevated numbers of non-functional CD4+ T cells
The diagnosis is established by lymphocyte counts (particularly of CD3, CD4, and CD8 T cells), lymphocyte function testing, ZAP-70 protein expression, and ZAP70 molecular genetic testing.
The long-term prognosis of untreated ZAP70-related SCID is death from infection. Affected children have a declining quality of life and usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT).
Short-term treatment includes immediate intravenous immunoglobulin (IVIG) and antibacterial, antifungal, and anti-protozoal prophylaxis to control and reduce the occurrence of infections.
The standard of therapy to cure SCID is allogeneic hematopoietic stem cell transplantation (HSCT). The outcome of HSCT in children with SCID is significantly improved by performing HSCT in the first three months of life.
Following a successful HSCT, the following should be monitored every six to 12 months:
- Immune status
- Liver and renal function
- Complete blood count
- Psychomotor development
Individuals with milder findings need to be monitored for worsening of immune function with at least semiannual assessment of clinical status and functional lymphocyte responsiveness.
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