Last year, pediatric gastroenterologist Subra Kugathasan gave an “old fashioned” grand rounds talk at Children’s Healthcare of Atlanta’s Egleston hospital, describing a family’s struggle with a multifaceted problem of autoimmunity.

Subra Kugathasan, MD

Now the Journal of Pediatric Gastroenterology and Nutrition paper, on how the genetic alteration underlying the family’s struggles was identified, is published. Kugathasan reports that the young man at the center of the paper is scheduled for allogeneic bone marrow transplant in the United States (but not in Atlanta) in the next couple months.

The list of troubles the members of the family had to deal with is long: gastrointestinal issues and food allergies, skin irritation, bacterial + yeast infections, and arthritis. The mother and her brother were affected to some degree, as well as all three of the kids (see tree diagram). The youngest brother is the “proband”, a geneticist’s term for starting point.

As determined by whole exome sequencing, the gene responsible is FOXP3, which controls the development of regulatory T cells. These are cells that restrain the rest of the immune system; if they aren’t functioning correctly, the immune system is at war with the rest of the body, like in this family.

The genetic variant identified was new — that’s why whole exome sequencing was necessary to find it. The authors conclude:

Supporting the utility of WES [whole exome sequencing] in familial clusters of atypical IBD [inflammatory bowel disease], this approach led to a definitive diagnosis in this case, resulting in a justifiable treatment strategy of allogeneic bone marrow transplantation, the treatment of choice for IPEX [Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome].

Bone marrow transplant is a big deal; doctors are essentially wiping out the immune system then bringing it back, with several associated risks. So the decision to go ahead is not taken lightly. In general, whether bone marrow transplant — either autologous (patient donates back to self) or allogeneic (the donor is someone else) — is appropriate as a treatment for inflammatory bowel disease is still being investigated. Here, since a genetic origin is clear and there are autoimmune effects beyond the digestive system, it becomes the treatment of choice.