Heterozygous TREX1 variants in a neonate with Aicardi-Goutières syndrome type 1: a case report

Abstract

Aicardi-Goutières syndrome type 1 (AGS1) is a rare autosomal recessive inflammatory disorder caused by mutations in TREX1 gene, and is frequently misdiagnosed as congenital or neonatal central nervous system infection because of its overlapping clinical manifestations. We report a 27-day-old male neonate who presented with recurrent fever, a persistent cerebrospinal fluid (CSF) pleocytosis, and poor response to broad-spectrum antimicrobial therapy. Imaging revealed diffuse white matter abnormalities and bilateral basal ganglia calcifications. Extensive microbiological investigations were negative, prompting genetic testing. Whole exome sequencing identified two compound heterozygous variants in TREX1 : c.294dup (p.Cys99MetfsTer3) and c.868_885del (p.Pro290_Ala295del), inherited from his mother and father, respectively. Based on the clinical manifestations, neuroimaging findings, and genetic results, a diagnosis of AGS1 was established. Treatment with the Janus kinase inhibitor ruxolitinib reduced the frequency and severity of febrile episodes. However, the patient developed microcephaly, neurodevelopmental delay, and motor impairment in infancy. We reported a rare case of AGS1 associated with two compound heterozygous variants, including c.294dup (p.Cys99MetfsTer3) and c.868_885del (p.Pro290_Ala295del). This case expands the genotypic and phenotypic spectrum of TREX1 -associated AGS1 and highlights the importance of considering monogenic interferonopathies in neonates presenting with sterile CSF inflammation, intracranial calcifications, and treatment-refractory fever.