Case Report: Genetically primed hyperinflammation: cytomegalovirus-triggered HLH-like syndrome in an adolescent with a gain-of-function STING1 (p.Arg281Trp) variant with novel autosomal dominant inheritance and atypical presentation.

We report the case of an 18-year-old previously healthy female who developed acute liver and kidney injuries with cytopenia and hyperinflammatory markers following cytomegalovirus (CMV) infection. Despite not meeting the hemophagocytic lymphohistiocytosis (HLH)-2004 or H-score criteria, her clinical and biochemical profiles suggested an HLH-like syndrome. Whole-exome sequencing revealed a heterozygous dominant stimulator of interferon genes (STING1) (c.841C>T; p. Arg281Trp) mutation. Although the patient lacked classic STING-associated vasculopathy with onset in infancy (SAVI)-associated skin or lung manifestations, immunological profiling revealed an inverted cluster of differentiation (CD)4/CD8 ratio and absolute CD4+ lymphopenia, supporting a state of underlying immune dysregulation that likely predisposed the patient to severe CMV infection. The patient showed partial clinical and biochemical improvements following antiviral and corticosteroid therapy, supporting our hypothesis of a genetically primed infection-triggered hyper-inflammatory response. This case broadens the STING1 disease spectrum and emphasizes the importance of genomic evaluation of unexplained hyperinflammation, even in apparently immunocompetent hosts.

Conclusion

This case highlights a novel STING1 (p. Arg281Trp) gain-of-function mutation with a previously unreported autosomal dominant inheritance pattern identified in both the patient and her asymptomatic father, suggesting incomplete penetrance and variable expression rather than a fully penetrant autosomal dominant pattern. The patient's presentation was atypical compared with classical SAVI, manifesting as a CMV-triggered HLH-like syndrome with acute renal and liver cell injury in an adolescent with no prior evidence of immune deficiency or family history of genetic disease. Notably, this presentation lacked the characteristic cutaneous and pulmonary involvement. This case highlights a distinct phenotypic spectrum and expands our understanding of STING1-related interferonopathies.