Partial RAG1/2 deficiency
Related genes: RAG1, RAG2
Inheritance pattern: Autosomal recessive
Recombination activating genes 1 and 2 (RAG1 and 2) are important for the generation of T cell receptors on T cells and immunoglobulin on B cells. This process is essential for adequate immune response to the vast majority of infectious microorganisms.
Severe variants in RAG1 and RAG2 can cause severe combined immunodeficiency (SCID). However, "leaky" variants with residual protein function and T cell production, also known as hypomorphic variants, can have a variable presentation, including Omenn syndrome in the newborn with T cells that infiltrate the skin, liver, and spleen, but also combined immunodeficiency (CID) manifesting later in life with granulomatous disease and/or autoimmunity. Granulomas may affect the skin and multiple organs, while autoimmune disease includes autoimmune cytopenias and multi-organ autoimmunity. Disseminated infection with viruses like varicella and nontuberculous mycobacteria can also be present.
Individuals with RAG deficiencies sometimes can have isolated low T cell counts with delayed onset of infections, or manifest as a hyper IgM syndrome, common variable immune deficiency (CVID), or sterile chronic multifocal osteomyelitis (CRMO). Presentation can be beyond early childhood with autoimmune and autoinflammatory complications, with or without chronic recurrent sinopulmonary infections. Most individuals require immunoglobulin (Ig) replacement therapy and antibiotic prophylaxis as standard treatment but immunosuppressive therapy may also be indicated to control granulomas and autoimmunity. Hematopoietic stem cell transplant (HSCT) has been curative and should be considered in these cases.