ZAP-70 deficiency

T cells are white blood cells that find and fight germs. When a T cell spots a germ, a protein called ZAP-70 passes the alarm along inside the cell. It is part of the chain that turns T cells on and helps them grow up properly in the body.

In ZAP-70 deficiency, this protein is missing or does not work. CD8 T cells, the “killer” cells that destroy virus-infected cells, are nearly absent. CD4 T cells, the “helper” cells, are present in normal or even high numbers, but they do not respond the way they should.

Doctors call it a combined immunodeficiency, because weak T cells also weaken antibody (B-cell) defenses. Some sources call it a form of severe combined immunodeficiency (SCID). The international classification lists it as a combined immunodeficiency that is usually less severe than classic SCID. Many babies are first diagnosed with SCID before gene testing finds the cause.

It is caused by changes in both copies of the ZAP70 gene, one inherited from each parent. This is called autosomal recessive inheritance. Parents who each carry one changed copy usually have no symptoms. Each of their children has a one-in-four chance of being affected, a one-in-two chance of being a carrier, and a one-in-four chance of neither.

ZAP-70 deficiency is rare. A 2020 review found 49 people described in the medical literature. It was first found in Mennonite families, and about 3 in 10 of the reviewed patients were of Mennonite descent. It has since been reported in many other groups, including families from Turkey, Japan, Iran, Saudi Arabia and Syria. Parents in these families are often related by blood.

Rarely, a child has one changed copy that weakens ZAP-70 and one that makes it overactive. In the two siblings described with this mix, it caused early autoimmune disease rather than severe infections. The condition cannot be caught from another person.

Symptoms usually start in the first months of life. In the 2020 review, the middle (median) age when symptoms began was 4 months. The most common problems were pneumonia and other chest infections, long-lasting diarrhea, and skin rashes such as eczema-like dermatitis. Many babies did not grow well.

Viruses such as cytomegalovirus (CMV) and chickenpox virus can cause severe illness. So can fungi such as Candida and Pneumocystis. The live BCG vaccine against tuberculosis, given at birth in some countries, can also cause infection. Some children develop autoimmune problems, in which the immune system attacks the body, such as low blood counts or kidney disease. Swollen lymph nodes, an enlarged liver or spleen, and rarely lymphoma have also been reported.

How sick a child becomes varies widely, and the exact gene change does not predict it. GeneReviews says children who have severe infections in their first year usually do not live past their second year without a transplant. Some people have a milder, later form.

Doctors usually suspect it in a baby with repeated chest infections, diarrhea, skin rashes and poor growth. In the 2020 review, the median age at diagnosis was about 10 months, about 5 months after symptoms began. A family history of immune disease, or parents who are related by blood, can raise suspicion sooner.

The key blood test counts T cells by type (flow cytometry). In ZAP-70 deficiency, CD8 T cells are very low or absent, while CD4 T cells and B cells are usually present. Lab tests of T-cell function show that T cells respond poorly when stimulated. Antibody levels are often normal, but responses to vaccines are often poor. A gene test confirms the diagnosis by finding changes in both copies of ZAP70.

Once the family’s gene changes are known, GeneReviews strongly recommends testing brothers and sisters at risk. That way, an affected baby can be found and treated early. In a 2025 study from Saudi Arabia, 3 of 13 children were found as newborns through testing because of their family history.

Before transplant, care focuses on preventing and treating infections. This usually includes immunoglobulin (antibody) replacement and medicines to prevent bacterial, fungal, viral and Pneumocystis infections. Care teams usually use only irradiated, CMV-safe blood products and hold off on vaccines until the immune system is rebuilt.

An allogeneic stem cell transplant, using blood-forming cells from a donor, is the only known cure. It gives the child donor T cells that can make working ZAP-70. Some children with a matched brother or sister have had a transplant without chemotherapy first (no conditioning). This can be enough to rebuild T-cell protection, but the donor cells may not take over the whole marrow. Chemotherapy before transplant is harder on the body, but it more often leads to full, lasting replacement.

Children who stay on antibody replacement and preventive medicines alone remain at high risk of severe infections, autoimmunity and lymph-tissue problems. No gene therapy is approved for ZAP-70 deficiency.

Families often reach the diagnosis after months of chest infections, diarrhea and rashes. Until the immune system is rebuilt, care teams usually ask families to avoid crowded indoor places, sick contacts and people with cold sores. Live vaccines are avoided for the baby and for others in the home. Breast milk is usually held back until the mother’s CMV status is known.

A transplant means a long hospital stay, often in an isolation room, and months of close follow-up for infection and graft-versus-host disease. Care is usually given at a specialist center that may be far from home.

After a successful transplant, GeneReviews describes close checks during the first year, then every 6 to 12 months. These follow growth, lungs, gut, skin and how well the donor cells have taken hold. Children who had chemotherapy before transplant also need long-term checks of organ health and development. Brothers and sisters can be tested for the family’s gene changes so any affected baby is found early.

The transplant replaces the child’s blood-forming stem cells with a donor’s, so new T cells can make working ZAP-70. GeneReviews says results are best with an HLA-matched donor. A matched brother or sister is usually looked for first, after testing shows they are not affected.

If no family donor matches, specialists search national and international registries for an unrelated donor. The 2020 review counted 21 published transplants with a known donor type. Thirteen used a matched brother or sister, and 8 used a matched unrelated donor. Half-matched (haploidentical) family donors and unrelated cord blood have also been used successfully.

Experts advise transplant early, before infections and organ damage build up, which can make an unrelated donor search urgent. Joining a registry cannot promise a match for any one child, but it widens the choices families have.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

Without a transplant, the outlook for babies with severe infections is poor. GeneReviews says those who become very sick in their first year usually do not live past their second year without one. Children managed only with antibody replacement and preventive medicines remain at high risk of severe infections, autoimmune problems and lymph-tissue overgrowth.

Transplant has changed this for many families. Published groups of transplanted children are small. Results vary with the donor, the use of chemotherapy before transplant, and how sick a child is at the time. At one center in Saudi Arabia, 3 of 11 transplanted children died, from a bloodstream infection or severe lung failure. The doctors there saw more deaths after partly matched family transplants, especially in children with active infections. Experts advise transplant early, before infections and organ damage build up. Most surviving children in recent reports were free of repeated infections and had stopped antibody replacement.