Partial RAG deficiency in a patient with varicella infection, autoimmune cytopenia, and anticytokine antibodies

RAG gene defects at the verge of immunodeficiency and immune dysregulation

“…Circulating B cells are present in variable number; immunoglobulin serum levels are often normal but may also be low or high, and specific antibody responses may be variably affected . Finally, these patients produce a broad spectrum of autoantibodies; neutralizing anti‐cytokine antibodies directed against interferon‐α and IFN‐ω has been reported, especially in patients with a history of varicella zoster virus infection …”

“…3 Finally, these patients produce a broad spectrum of autoantibodies; neutralizing anti-cytokine antibodies directed against interferonα and IFNω has been reported, especially in patients with a history of varicella zoster virus infection. 60,62 Moreover, patients with hypomorphic RAG mutations may initially be given other diagnoses, including idiopathic CD4 + lymphopenia, 63 common variable immunodeficiency, 64,65 IgA deficiency, 66 selective deficiency of polysaccharide-specific antibodies, 67 hyper-IgM syndrome, 68 and autoimmune lymphoproliferative syndrome. 69 Although at least in some of these cases, the clinical and laboratory data were clearly suggestive of a combined immunodeficiency, the fact remains that these clinical examples have taught us how diverse is the clinical and immunological phenotype associated with hypomorphic RAG mutations.…”

Asymptomatic Infant With Atypical SCID and Novel Hypomorphic RAG Variant Identified by Newborn Screening: A Diagnostic and Treatment Dilemma

“…Lastly, autoantibody testing targeting IFNα, IFNω, and IL-12 was performed by ELISA, as presence of these autoantibodies have been associated with immune dysregulation in partial RAG deficiency (12,21). These anti-cytokine antibodies were not detected in our patient.…”

“…Early diagnosis of patients with RAG deficiency is of high importance. If left undiagnosed and untreated, these patients develop severe and often fatal complications of immune dysregulation and/or infections (21,28,29). However, there are also reports of the same compound heterozygous RAG variants resulting in variable phenotype and disease severity.…”

“…Patients with partial RAG deficiency including atypical SCID and CID phenotype are increasingly recognized in young children and adults after severe infections (13,14,21). As with SCID, multiple classification systems for primary CID disorders exist, complicating diagnostic and management decisions.…”