Combined immunodeficiency due to partial RAG1 deficiency

Combined immunodeficiency due to partial RAG1 deficiency is a rare primary immunodeficiency disorder caused by hypomorphic (partial loss-of-function) mutations in the RAG1 gene. RAG1 (Recombination Activating Gene 1) encodes a protein essential for V(D)J recombination, the process by which T cells and B cells generate diverse antigen receptors. Unlike complete RAG1 deficiency, which causes severe combined immunodeficiency (SCID) with absent T and B cells, partial RAG1 deficiency allows some residual recombinase activity, resulting in reduced but not completely absent T and B lymphocyte development. This condition is also referred to as Omenn syndrome-like phenotype or leaky SCID when associated with partial RAG1 function, depending on the clinical presentation. Patients typically present in infancy or early childhood with recurrent and severe infections, including bacterial, viral, and opportunistic infections. The immune system is significantly compromised, with low numbers of T and B lymphocytes and impaired antibody production (hypogammaglobulinemia). Some patients may develop features of immune dysregulation, including autoimmune cytopenias, granulomatous disease, and lymphoproliferation. The clinical spectrum is broad, ranging from presentations resembling Omenn syndrome (with erythroderma, eosinophilia, elevated IgE, and lymphadenopathy) to milder combined immunodeficiency with later onset. Management depends on the severity of the immunodeficiency. Supportive care includes immunoglobulin replacement therapy, prophylactic antimicrobials, and aggressive treatment of infections. Hematopoietic stem cell transplantation (HSCT) is the definitive curative treatment and is recommended for patients with severe disease. Gene therapy approaches are under investigation. Early diagnosis through newborn screening programs that detect T-cell receptor excision circles (TRECs) has improved outcomes by enabling earlier intervention. Without treatment, patients are at significant risk of life-threatening infections and complications from immune dysregulation.

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