A Novel Heterozygous OAS1 Variant in a Child with Systemic Inflammation, Epilepsy, and Urticaria: Expanding the Spectrum of Type I Interferonopathies

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Background Variants in genes involved in the type I interferon pathway, such as OAS1, can lead to autoinflammatory disorders with neurological and systemic manifestations. We report a pediatric patient with a novel heterozygous OAS1 variant and a complex clinical phenotype. Case Presentation We report the case of a 1-year-8-month-old female, born to non-consanguineous parents, who presented with failure to thrive, gastrointestinal symptoms characterized by alternating constipation and diarrhea associated to food allergies refractory to dietary restrictions. She had a prior diagnosis of epilepsy and showed signs of global developmental delay and sensorineural hearing loss. Dermatologic examination revealed livedo reticularis. Laboratory evaluation revealed normal immunoglobulin levels but reduced post-switched memory B cells. However, interferon-related biomarkers were elevated: the IFN score was 9.81 (mean control 6.8), and IL-18 mRNA expression was 52.2 copies/ng (mean control 35). During follow-up, she developed recurrent febrile episodes accompanied by systemic inflammation and exacerbations of chronic urticaria. Exome sequencing identified a heterozygous OAS1 variant (c.199G>A, p.Gly67Ser), classified as a variant of uncertain significance due to its absence from population databases and location in a conserved region involved in double-stranded RNA sensing. Discussion Although the IFN signature was elevated, it did not reach the diagnostic range for monogenic interferonopathies. The clinical features and molecular data suggest a possible dysregulation of the interferon response. The variant has not been functionally validated, and parental segregation is pending. Based on clinical severity and molecular findings, empirical treatment with JAK inhibitors is being considered. Conclusion This case supports the involvement of OAS1 variants in early-onset inflammatory syndromes with neurologic and cutaneous features. Functional studies are required to confirm pathogenicity and elucidate the mechanism of disease.

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