RAG1 deficiency

Every T cell and B cell carries a receptor that fits one particular germ, like a key made for one lock. To make millions of different receptors, developing cells cut and rejoin pieces of their own DNA. The RAG1 protein, working as a pair with RAG2, makes those cuts. When RAG1 does not work, T and B cells cannot develop normally.

RAG1 deficiency is a range of illnesses, not a single one. When the protein does not work at all, a baby has SCID, with almost no T or B cells. When some activity remains, the result can be Omenn syndrome, “atypical” or “leaky” SCID, or a combined immune deficiency that appears later. Natural killer (NK) cells, another kind of infection-fighting white blood cell, are usually present in every form.

The condition is caused by changes in both copies of the RAG1 gene. It is inherited in an autosomal recessive pattern: parents usually each carry one changed copy and have no symptoms. When both parents are carriers, each pregnancy has a 1 in 4 chance of an affected child.

How much RAG1 activity is left helps explain how severe the illness is. Changes that leave no working protein tend to cause SCID, and changes that leave some activity tend to cause Omenn syndrome or milder, later forms. The link is not exact, and relatives with the same gene changes can be affected differently. RAG deficiency is more common in communities where parents are often related by blood.

Babies with RAG1 SCID usually look well at birth, then develop severe infections, ongoing diarrhea and poor growth in the first months. Omenn syndrome also starts in the first weeks of life, with a red rash over much of the body, hair loss, swollen lymph nodes and an enlarged liver and spleen. In Omenn syndrome, the child’s T cells are nearly all alike, and they attack the skin, gut and other organs. Live vaccines such as rotavirus and BCG can cause serious illness in these babies.

Milder forms can first appear later in childhood or even in adulthood. People may have repeated sinus and lung infections, and severe infections with herpes-family viruses such as chickenpox. Some have autoimmune problems, in which the immune system attacks blood cells or other organs. Some develop granulomas, clumps of inflamed immune cells in the skin, lungs or elsewhere. These forms are often diagnosed late, sometimes after organ damage has begun.

Where newborn screening for SCID is offered, a heel-prick blood test can flag many babies with severe RAG1 deficiency before they get sick. The test looks for low levels of new T cells. A flagged result needs urgent follow-up with an immune specialist. Later-onset forms are usually recognized only after years of symptoms.

Before a transplant, care focuses on preventing infection. This usually means immunoglobulin, which is antibodies from donated plasma, medicines to prevent pneumonia and fungal infections, and keeping the baby away from sick people and crowds. Children with Omenn syndrome often also need medicines that calm the immune system, to control the rash and gut inflammation before transplant.

A transplant in infancy usually means a long hospital stay, then months of close checkups and protection from germs at home. Doctors follow how well T and B cells recover. Some children need immunoglobulin for a long time if their B cells do not fully return.

People with later-onset forms may live for years with infections, lung damage and autoimmune disease before the cause is found. Their care often involves several specialists and careful balancing of medicines that calm the immune system against the risk of infection.

Most children with severe RAG1 deficiency need blood-forming stem cells from another person. A brother or sister with a matching HLA type gives the best results. When there is no matched relative, doctors search the registries for a matched unrelated donor, or use a half-matched (haploidentical) parent or cord blood. Siblings are also checked for the family’s gene change, not only for their HLA match.

Timing makes the search urgent. European transplant guidelines say a donor should be sought as soon as SCID is diagnosed. If an unrelated donor cannot be found in time, a half-matched family member or a cord blood unit is preferred.

Every registry volunteer adds to the pool a search draws from. Joining cannot promise a match for any one child, and the transplant team chooses the safest suitable donor available at the time.