Severe Antenatal Presentation of a Novel Dnase2 Mutation in a Preterm Omani Neonate: Expanding the Clinical Spectrum of an Ultra-Rare Interferonopathy.

Dnase2 deficiency is an ultra-rare type I interferonopathy resulting from impaired intracellular DNA degradation, leading to neonatal cytopenias and systemic inflammation. Whole-exome sequencing enables definitive diagnosis, and Janus kinase inhibitors have emerged as targeted immunomodulatory therapy. This report describes a preterm infant with an early and severe presentation of DNASE2 deficiency, manifesting antenatally with fetal hydrops, intrauterine growth restriction, and cardiomyopathy. Postnatally, the infant developed persistent pancytopenia, hepatosplenomegaly, cholestatic jaundice, and hemophagocytic lymphohistiocytosis-like features, including marked hyperferritinemia. Whole-exome sequencing identified two novel heterozygous pathogenic variants in the DNASE2 gene. Initiation of Janus kinase inhibitor therapy (ruxolitinib) was challenging due to the patient's young age and low body weight; however, targeted treatment was associated with significant clinical improvement, including improved growth parameters and normalization of inflammatory and hemophagocytic lymphohistiocytosis (HLH)-associated markers during outpatient follow-up. This review underscores the severe antenatal and early postnatal manifestations of a novel Dnase2 deficiency, including fetal anemia, hydrops fetalis, and HLH-like inflammation in a preterm neonate. The observed clinical improvement following Janus kinase inhibitor therapy suggests that early targeted intervention may improve outcomes in this ultra-rare interferonopathy.