X-linked severe combined immunodeficiency (X-SCID)

SCID stands for severe combined immunodeficiency. It is a group of rare genetic conditions in which a baby is born without a working immune system. X-linked SCID is the most common type. The Immune Deficiency Foundation estimates it causes nearly 3 in 10 cases. In U.S. newborn screening from 2008 to 2013, it was about 1 in 5 cases, likely because screening every baby finds more of the other types.

Babies with X-linked SCID have almost no T cells and very few natural killer (NK) cells, which attack cells infected by viruses. They usually do have B cells, the cells that make antibodies. But without T cells to guide them, those B cells cannot protect the baby. Doctors call this pattern T-B+NK- SCID.

Some changes in the same gene cause a milder, “atypical” form. It can show up in the first years of life or later, with repeated chest infections, warts, skin problems, autoimmune disease or a rare, overactive immune state called Omenn syndrome. Newborn screening usually does not find this form.

X-linked SCID is caused by changes in a gene called IL2RG. This gene makes a protein called the common gamma chain. It is a shared part of several receptors on immune cells, and these receptors pass on the signals the cells need to grow and mature.

The IL2RG gene is on the X chromosome. Boys have only one X chromosome, so one changed copy causes the condition, while a mother who carries it usually has no symptoms. In each pregnancy, a carrier mother has a 1 in 2 chance of passing on the change: a son who inherits it will be affected, and a daughter who inherits it will be a carrier. A man with X-linked SCID passes the change to all of his daughters and none of his sons.

Once the family’s gene change is known, relatives can be tested, and a pregnancy can be tested before birth. A baby boy known to be at risk can be protected from germs from the day he is born and tested right away. A genetic counselor can explain what the result means for each person in the family.

Babies with X-linked SCID look healthy at birth. Without treatment, they get infections that keep coming back, do not clear, or are caused by germs that rarely harm other babies. Problems include thrush (a yeast infection in the mouth) that will not go away, ongoing diarrhea, poor growth, skin rashes and a dangerous pneumonia called Pneumocystis pneumonia.

In the United States, newborn screening for SCID began in 2008 and reached every state by the end of 2018. A heel-prick blood test called TREC checks for signs that the baby is making new T cells. Today, most US babies with typical X-linked SCID are found this way while they still seem well. Before screening, most babies were found only after infections started, usually between 3 and 6 months of age.

An abnormal screen is not a diagnosis, but it needs urgent attention from an immunology team. Speed matters: in a large study in the United States and Canada, babies who had an active infection when they were transplanted were less likely to survive.

The weeks between diagnosis and transplant can be frightening. Families are usually asked to keep the baby at home or in hospital, away from crowds, daycare and anyone who is sick, even with a cold. Brothers and sisters who go to school or daycare can bring germs home, so daily routines often change for the whole family.

Treatment means a stay at a specialist children’s hospital, sometimes far from home. Afterward, checkups continue for years. They look at how well the donor cells have taken hold and at growth, lungs, gut and skin. Children who had conditioning also need long-term checks of organ health and development.

Preventive medicines and antibody replacement are stopped only when the new immune system is working well. Vaccines are given after that, on the team’s schedule. Some children need antibody replacement for life. Talking with other SCID families and with the hospital’s social workers can help with the stress, the isolation and the practical costs.

A transplant for X-linked SCID uses blood-forming stem cells from a donor whose IL2RG gene works normally. A brother or sister who is a full HLA match is the first choice, because it gives the best chance of full immune recovery. But each full sibling has only about a 1 in 4 chance of being a match, and a brother may have the condition himself, so many children do not have one.

Without a matched sibling, teams look for a fully matched unrelated donor through the registries. If that search would take too long for the baby’s safety, or no match exists, a half-matched family member, usually a parent (a haploidentical donor), or a cord blood unit is used instead. In a large study in the United States and Canada, survival was high with every donor type when babies were transplanted young or before infections set in.

This is why registry volunteers matter for SCID, and why speed matters. A baby is waiting in protective isolation, so a matched volunteer who is ready to donate quickly can make an unrelated transplant possible. Joining a registry cannot promise a match for any one child, and many children are treated with a parent’s cells instead.