Familial, recurrent or genetic acute necrotizing encephalopathy of childhood: a systematic review and a case report. Focus on atypical events and on the role on immunizations

BACKGROUND: Familial, recurrent or genetic acute necrotizing encephalopathy (F/R/G ANE) is triggered by infections in children with genetic susceptibility. We conducted a systematic review to characterize clinical-neuroradiological features, therapy and outcome of F/R/G ANE in children, and to evaluate vaccination implications. METHODS: A systematic literature review was conducted in PubMed, Scopus, and Web of Science, adhering to the PRISMA guidelines, and registered in PROSPERO. An institutional case was also described. RESULTS: Ninety-two patients were analysed (91 literature cases and 1 novel case) (median onset age 24 months; 62% male; RANBP2 mutations in 81% of tested individuals). In total, 142 clinical events occurred in the 92 patients: 108 definite/probable ANE events, and 34 atypical events (25 infection-triggered encehalopathy events without bithalamic involvement, 9 other acute neurological events without bithalamic involvement and encephalopathy). In 13% of patients, atypical episodes preceded a subsequent ANE event. Routine immunization was documented in 18/19 patients pre-ANE and 5/20 resumed vaccination post-ANE (no vaccine-related relapses over a median follow-up of 19 months). CONCLUSIONS: These findings highlight the central role of RANBP2 variants and the clinical-radiological variability of F/R/G ANE, including atypical pre-ANE events. Limited immunization data support the need for prospective studies to establish safe, prophylactic strategies.