RAG2 deficiency

T and B cells recognize germs using receptors on their surface. Each developing cell builds its own receptor by cutting and rejoining pieces of its DNA, which is how the body makes millions of different ones. RAG2 is one half of the protein pair that makes the cuts; RAG1 is the other half. Without enough working RAG2, the cuts are not made and T and B cells stall early in their development.

Because RAG2 can fail completely or only partly, the illness varies. Complete loss usually causes SCID, with almost no T or B cells. Partial loss can cause Omenn syndrome, “atypical” or “leaky” SCID, or a later-onset combined immune deficiency. Natural killer (NK) cells, another kind of infection-fighting white blood cell, are usually still present.

RAG2 deficiency is caused by changes in both copies of the RAG2 gene. It follows an autosomal recessive pattern. Parents usually each carry one changed copy and are healthy, and when both are carriers each pregnancy has a 1 in 4 chance of an affected child.

In general, gene changes that leave less working RAG protein cause more severe, earlier illness, though the match is not exact. Children in the same family can even show different forms. RAG deficiency is seen more often in communities where parents are commonly related by blood, and genetic counseling can help relatives understand their own risks.

In its severe forms, RAG2 deficiency causes life-threatening infections from the first months of life, often with long-lasting diarrhea, thrush and poor growth. Babies with Omenn syndrome also develop a widespread red rash, hair loss, swollen lymph nodes and an enlarged liver and spleen. This happens because their T cells, nearly all alike, attack the baby’s own tissues. A leaky skin and gut barrier raises the risk of serious bacterial infections. Live vaccines, including rotavirus and BCG, can be dangerous for these babies.

Later-onset forms may not cause serious illness in early childhood. Instead, people can have repeated sinus and chest infections that damage the lungs. Severe infections with viruses such as chickenpox, cytomegalovirus (CMV) or Epstein–Barr virus are common, as is autoimmune disease, most often attacking blood cells. Some develop granulomas, lumps of inflamed immune cells in the skin, lungs or other organs.

Where SCID newborn screening is offered, a heel-prick blood test for new T cells can flag many babies with severe RAG2 deficiency before symptoms start. A flagged result needs urgent specialist follow-up. Later-onset forms often take years to diagnose, and the delay can allow organ damage.

Families of a baby with severe RAG2 deficiency usually keep the child away from crowds and anyone who is sick. The baby receives immunoglobulin, antibodies collected from donated plasma, along with medicines to prevent pneumonia and fungal infections. If a blood transfusion is needed, the blood is specially treated and chosen to be free of CMV, a common virus.

Transplant brings a long hospital stay and then months of close follow-up while new T and B cells grow. Some children need immunoglobulin for a long time afterward if B cells are slow to recover or do not return.

For teenagers and adults with later-onset RAG2 deficiency, the path to a diagnosis can be long and frustrating. Life may involve regular infusions, lung care and treatment for autoimmune problems, often across several specialist clinics.

Children with severe RAG2 deficiency usually need blood-forming stem cells from a donor. A matched brother or sister is the first choice, and siblings are checked for the family’s gene changes as well as their HLA type. Without a matched relative, a matched unrelated donor from the registries is the next option, and a half-matched (haploidentical) parent or cord blood can also be used.

Because SCID is an emergency, European transplant guidelines advise starting the donor search as soon as the diagnosis is made. If a matched unrelated donor cannot be found in time, a half-matched family member or cord blood is preferred over waiting.

Registry volunteers make those unrelated searches possible. No single registration can promise a match for a particular child, and the transplant team decides which donor is safest.