Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and

Automated summary

Patients with hypomorphic mutations in the RAG1 or RAG2 gene can present with various clinical phenotypes, such as Omenn syndrome or atypical combined immunodeficiency. Hematopoietic stem cell transplantation (HSCT) is a potential cure for these patients, but information about its outcomes is limited. We report on a global cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, with 78% experiencing infections (29% active at HSCT), 72% developing autoimmunity, and 18% having granulomas before transplantation. These complications often lead to organ damage. Eight individuals (13%) were diagnosed through newborn screening or family history. HSCT was performed at a median age of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and...