Clinical Factors Associated with Genetically Confirmed Inborn Errors of Immunity in Children Presenting with Immune Dysregulation.

BACKGROUND: Inborn errors of immunity (IEI) are increasingly recognized as important underlying causes of immune dysregulation in children. While recurrent infections remain a classical hallmark of IEI, non-infectious manifestations such as autoimmunity, lymphoproliferation, and autoinflammation are often the dominant or presenting features, posing diagnostic challenges. OBJECTIVE: To identify clinical features associated with IEI in children presenting with manifestations of immune dysregulation. METHODS: We conducted a multicenter retrospective–prospective cohort study including 106 children with manifestations of immune dysregulation evaluated at tertiary centers. Patients were stratified according to the presence or absence of genetically confirmed IEI. RESULTS: The group with genetically confirmed IEI comprised 67 patients, whereas the group with immune dysregulation without confirmed IEI comprised 39 patients. Several clinical features were significantly associated with genetic confirmation of IEI, including multilineage cytopenia (OR 6.27, 95% CI 1.74–22.59), Evans syndrome (OR 8.29, 95% CI 1.03–66.47), and lymphoproliferation (OR 4.20, 95% CI 1.55–11.35). Combined immune dysregulation phenotypes, such as autoimmunity with lymphoproliferation (OR 2.88, 95% CI 1.05–7.86) and autoimmunity with infections (OR 2.82, 95% CI 1.24–6.38), were also associated with genetic confirmation of IEI. Among genetically confirmed cases, disorders of immune dysregulation represented the largest subgroup (37.3%), followed by predominantly antibody deficiencies (31.3%) and syndromic or combined immunodeficiencies (16.4%). CONCLUSIONS: Specific patterns of immune dysregulation, particularly multilineage cytopenias, Evans syndrome, lymphoproliferation, and combined autoimmune phenotypes, were associated with genetically confirmed IEI in this cohort. Recognition of these clinical features may support earlier consideration of underlying IEI and help refine diagnostic decision-making in children presenting with immune dysregulation.