Neurological Presentations in Children with Inborn Errors of Immunity: Patient-Level Etiological Classification in a Retrospective Cohort

Background/Objectives: Neurological findings in children with inborn errors of immunity (IEIs) may reflect shared syndromic phenotypes, central nervous system (CNS) complications, or unrelated conditions. We assessed their likely etiology through patient-level review. Methods: We screened 1036 children evaluated for suspected IEI between October 2023 and May 2026. This single-center retrospective cohort included 55 children aged 0–18 years with an established or probable IEI and a neurological concern. Consensus review assigned each child to one of five etiological categories: likely IEI-related; independent coexisting diagnosis; acquired, provoked, or coincidental process; no significant neurological involvement; and undetermined. Exploratory Firth regression examined associations of prematurity and consanguinity with likely IEI-related classification. Results: Among children with ascertainable data, persistent neurodevelopmental delay occurred in 29/50 (58.0%), epilepsy in 14/53 (26.4%), and brain magnetic resonance imaging abnormalities in 28/40 (70.0%). Neurological findings preceded IEI recognition in 27/53 (50.9%); 24/54 (44.4%) had a neurological first presentation. Sixteen presentations (29.1%) were classified as likely IEI-related: 13 within monogenic, syndromic, or genetically mediated phenotypes and three as CNS complications. Other categories comprised independent diagnoses (n = 10), acquired, provoked, or coincidental processes (n = 9), no significant neurological involvement (n = 6), and undetermined etiology (n = 14). Adjusted odds ratios were 3.30 (95% CI, 0.97–12.09) for prematurity and 3.06 (95% CI, 0.87–11.49) for consanguinity, with wide confidence intervals. Conclusions: Neurological presentations in children with IEI warrant careful etiological interpretation. Multidisciplinary assessment may help distinguish IEI-associated manifestations from coexisting conditions. Further studies could inform diagnostic evaluation and clinical follow-up.