Novel RELA Mutation Associated with Macrophage Activation Syndrome and Familial Lupus: Linking NF-κB to Monogenic SLE

Introduction RELA encodes the p65 subunit of NF-κB, a transcription factor involved in cell survival, inflammation, and immune regulation. Heterozygous RELA variants have been linked to inborn errors of immunity (IEIs) presenting with early-onset systemic lupus erythematosus (SLE), mucocutaneous ulcers, Behçet-like features, autoimmune lymphoproliferative syndrome–like symptoms and variable infectious susceptibility [1]. Clinical Case We report a 9-year-old girl with a history of recurrent infections. At age 8, she was admitted with septic shock due to necrotizing pneumococcal pneumonia. During that hospitalization, she developed Raynaud’s phenomenon, hip synovitis, pancytopenia, and SLE-associated autoantibodies (antinuclear antibody 1/640, anti–double-stranded DNA antibody, anti-Ro/La) with low C3/C4 levels, leading to a diagnosis of SLE. She received steroids, hydroxychloroquine, and mycophenolate. At age 9, she developed spontaneous pneumococcal peritonitis, which triggered macrophage activation syndrome (MAS) (hyperferritinemia >8,000 ng/mL, IL-6 >5,000 pg/mL, hypo-fibrinogenemia, cytopenias, and elevated liver enzymes and triglycerides). Despite intensive immunosuppressive therapy (steroids, cyclosporine, intravenous immunoglobulin, and cyclophosphamide), she died of multiorgan failure. Immunologic workup revealed global lymphopenia, IgG2/IgG4 subclass deficiency, and hypocomplementemia. Genetic testing identified a heterozygous RELA variant (c.1502C>G; p.T501S, variant of uncertain significance [VUS]), also found in her father, who had adult-onset SLE with nephritis and severe infections (pneumococcal sepsis, herpes zoster meningoencephalitis). Interferon signature testing is pending. Discussion This case shows the overlap between monogenic autoimmunity and IEIs. RELA mutations may exert dominant-negative or gain-of-function effects, impairing NF-κB signaling and enhancing type I interferon signature. The severity/familial segregation support a possible pathogenic role of the VUS, though functional validation is needed. Recurrent infections raise the possibility that RELA may play a role in infectious immunity, particularly in mucosas. TNF agents have shown benefit in some patients; JAKinhibs are a promising option for refractory cases. Conclusion IEIs should be suspected in children with early-onset SLE and severe infections. Functional studies are essential to determine variant pathogenicity and guide-targeted interventions.