Response to Tofacitinib in an Infant with Aicardi-Goutières Syndrome due to Biallelic Variants in RNU7–1

Abstract

Aicardi-Goutières syndrome (AGS) is a severe, early-onset neuroinflammatory disease characterized by leukoencephalopathy resulting in developmental delays and neurologic regression. Patients can have extracranial findings including hematologic, cutaneous, and other organ manifestations. AGS is a recognized type I interferonopathy, with evidence of interferon activation in both the central nervous system and blood, leading to attempts to modulate disease using JAnus Kinase (JAK) inhibition.We present a now 1-year-old female who had suspected AGS despite nondiagnostic clinical genetic testing at birth, done for prematurity, failure to thrive requiring enteral tube feeding, leukodystrophy, hypotonia, seizures, hearing loss, and developmental delay. She also has dysmorphisms, including neonatal teeth, rib abnormalities and microcephaly. She was sequentially diagnosed with hepatitis (biopsy findings of mild macrovesicular steatosis, mild interface hepatitis and mildly increased fibrosis), hypertrophic cardiomyopathy, hyponatremia attributed, in part, to adrenal insufficiency, and chronic lung disease from microaspirations. Evaluation at 11 months revealed unremarkable immunoglobulin levels, vaccine titers, immunophenotyping, and proliferation to mitogens and Candida but not tetanus (despite protective titers). An elevated 6-gene interferon score (19.5) was detected in the blood.Given the devastating natural history of this syndrome, she was started on the JAK inhibitor tofacitinib age 8 months. After starting tofacitinib, she had notably decreased clinical symptoms, improved tone and milestones. Her transaminitis resolved. A repeat interferon score after 4 months of treatment showed improvement (15.9). She has tolerated common viral infections on immune suppression.Under the Undiagnosed Diseases Network, clinical trio genome sequencing was re-analyzed revealing compound heterozygous variants in the non-coding RNA RNU7–1, a newly identified cause of previously genetically unexplained AGS (AGS9). This results in impairment of U7 snRNP function leading to misprocessing of pre-mRNA and driving an interferon response. The mortality of AGS9 is higher than other AGS genotypes, with cardiac and liver involvement being more common.Revelation of RNU7–1 mutations in this case underscores that diagnostic workup for genetically unexplained AGS should include targeted evaluation of RNU7–1. The impact of early initiation of JAK inhibition in patients with AGS on long-term outcomes remains to be determined, but tofacitinib, uniquely available in liquid formulation, is one option.