Omenn syndrome is a rare form of severe combined immunodeficiency characterized by immune dysregulation, recurrent infections, erythroderma, eosinophilia, and failure to thrive. Hematopoietic stem cell transplantation (HSCT) remains the definitive treatment; however, outcomes are particularly challenging in patients with active severe infections before transplantation. Here, we report the case of a female infant who presented with persistent diarrhea and recurrent otitis media at 2 months of age and was diagnosed at 3 months with genetically confirmed Omenn syndrome caused by a homozygous pathogenic RAG1 variant (c.1187G>A; p.Arg396His). Her clinical course was complicated by recurrent multidrug-resistant bacterial bloodstream infections, Candida auris fungemia, acute kidney injury, disseminated intravascular coagulation, and respiratory failure requiring pediatric intensive care admission. Because she was clinically unstable for conventional conditioning chemotherapy, she underwent unconditioned matched unrelated donor peripheral blood stem cell transplantation at 8 months of age. Despite persistent mixed donor chimerism and absent Bcell engraftment, she demonstrated progressive donor-derived T-cell recovery, normalization of CD4/CD8 ratio, resolution of recurrent infections, and sustained clinical stability. To our knowledge, reports describing unconditioned matched unrelated donor HSCT in genetically confirmed Omenn syndrome complicated by multidrug-resistant bacterial infections and Candida auris fungemia remain extremely limited. This case highlights that unconditioned HSCT may provide clinically meaningful immune reconstitution when standard conditioning is not feasible.
