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

Abstract

BACKGROUND: 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. CASE PRESENTATION: 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 congenital glaucoma. 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 center 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. CONCLUSIONS: This case illustrates the clinical overlap between neonatal AGS and MAS-like hyperinflammation, underscores the potential role of early mechanism-based therapy in selected critically ill neonates with suspected interferonopathy, and emphasizes the importance of comprehensive genomic evaluation when severe ocular disease accompanies AGS. The identified CYP1B1 variant provides a strong molecular explanation for the patient's congenital glaucoma.