IPEX syndrome

Doctors suspect IPEX in a baby boy with watery diarrhea that will not stop, diabetes early in life and eczema. A family history of affected boys on the mother’s side adds to the suspicion. But a boy can have IPEX with no known family history.

No single blood test proves IPEX. Clues include a high level of IgE, an antibody linked to allergy; extra eosinophils, a kind of white blood cell; and autoantibodies that attack the gut, pancreas or thyroid. A lab test called flow cytometry may show few T cells carrying the FOXP3 protein. But in some boys, the level of FOXP3 in these cells is normal. Routine counts of T, B and NK cells are usually normal and do not help with the diagnosis. A gut biopsy often shows a flattened gut lining (villous atrophy). This supports the diagnosis but does not prove it.

The diagnosis is confirmed by finding a disease-causing change in the FOXP3 gene. Many labs test a panel of immune genes, or the whole exome, at once. This can also find IPEX-like conditions that look similar at first. Reaching an answer can take time. In an international study of 96 patients, the median time from first symptoms to genetic diagnosis was 14 months.

The first goal is to calm the immune attack and keep the child nourished. Medicines such as sirolimus, tacrolimus or cyclosporine, often with steroids, target T cells. Many babies need nutrition through a vein until the gut can absorb food. Diabetes is treated with insulin, and thyroid, skin and infection problems are treated as they appear.

These medicines can control IPEX, but they do not cure it. They must be taken long term, and in an international study, patients on long-term medicines often had symptoms come back or developed complications. An allogeneic stem cell transplant, using blood-forming cells from a donor, gives the child working regulatory T cells and is the only treatment that may cure IPEX. There is no approved gene therapy; an early-stage clinical trial in California, begun in 2022, is testing the patient’s own T cells engineered to carry a working FOXP3 gene.

European transplant experts advise that every patient with IPEX should be considered for transplant. Results are better when it happens before serious organ damage and while inflammation is under control. Transplant cannot regrow organs that are already damaged, so a child with diabetes before transplant may still need insulin after it.

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.

For children who have a transplant, outlook depends most on how much organ damage the immune attack has done beforehand. In the largest international study, the amount of organ damage before transplant was the only factor that clearly predicted survival after it. When children were transplanted with less organ damage, symptoms usually went away, whatever their age, donor type or conditioning.

Most deaths after transplant happened in the first months, mainly from infections. On long-term immune-calming medicines alone, survival was better in the first years. Later it fell, as the disease moved on and treatment problems built up. Boys with the same gene change can have very different courses, so the gene change alone does not predict how a child will do.