Neonatal Aicardi–Goutières syndrome presenting with macrophage activation syndrome-like hyperinflammation and severe congenital glaucoma: a case report

Neonatal-onset Aicardi–Goutières syndrome (AGS) is a rare monogenic type I interferonopathy that may mimic congenital infection and can present with severe multisystem inflammation. The distinction between primary hemophagocytic lymphohistiocytosis (HLH) and AGS-associated macrophage activation syndrome (MAS)-like hyperinflammation can be challenging in neonates. We report a term neonate presenting with cholestatic jaundice, a generalized blueberry muffin-like ecchymotic-purpuric rash, cytopenias, hyperferritinemia, hepatosplenomegaly, intracranial calcifications, and severe bilateral ocular disease including cataract, congenital glaucoma, corneal perforation, and endophthalmitis. Extensive infectious evaluation was negative. The patient fulfilled five of eight HLH-2004 criteria, consistent with a severe MAS-like hyperinflammatory phenotype. Dexamethasone and intravenous immunoglobulin had been initiated at the referring centre for presumed virus-associated HLH but were not continued after transfer to our unit. With persistent disease activity, negative microbiological studies, and neuroimaging strongly suggestive of a type I interferonopathy, ruxolitinib was initiated on day of life (DOL) 34 before molecular confirmation. Exome sequencing subsequently identified homozygous pathogenic variants in RNASEH2B and CYP1B1, supporting AGS type 2 and primary congenital glaucoma (glaucoma 3 A), respectively. Serial laboratory data showed sustained improvement after initiation of JAK1/2 inhibition, although the observational nature of a single case and other immunomodulatory exposures limit causal attribution. This case illustrates the clinical overlap between neonatal AGS and MAS-like hyperinflammation, the potential role of early mechanism-based therapy in selected critically ill neonates with suspected interferonopathy, and the importance of comprehensive genomic evaluation when severe ocular disease accompanies AGS. The CYP1B1 variant provides a strong molecular explanation for the congenital glaucoma, while the broader ocular phenotype may have been multifactorial.