Inborn errors of immunity in children with neuroinflammation

Inborn errors of immunity (IEIs), an expanding group of monogenic disorders with diverse clinical manifestations, are increasingly recognized to include neuroinflammatory disease. Examples of diseases included under this umbrella are Aicardi-Goutières syndrome, deficiency of adenosine deaminase 2, familial haemophagocytic lymphohistiocytosis, neonatal-onset multisystem inflammatory disease, and acute necrotizing encephalopathy, among others. Children with IEIs may develop encephalopathy, seizures, focal neurological deficits, aseptic meningitis, inflammatory lesions on magnetic resonance imaging, or other central or peripheral nervous system manifestations. While systemic features of autoinflammation or autoimmunity are often present and provide important clues that an underlying IEI may be present, neuroinflammation may be the presenting or sole manifestation in some children. Early recognition of neuroinflammatory presentations of IEIs is critical to prompt immunological and genetic investigations, enabling diagnosis and timely initiation of appropriate immunotherapies, and reducing the risk of long-term neurological outcomes. This review highlights paediatric-onset neuroinflammatory phenotypes associated with IEIs and provides practical frameworks for their recognition and investigation in clinical practice.