Background: DNASE2 deficiency is a rare autosomal recessive type I interferonopathy. Since its first description in 2017 1, only four patients have been reported worldwide 1–2. These cases typically presented with pancytopenias, hepatosplenomegaly, liver dysfunction, and progressive autoinflammatory features that mimic hemophagocytic lymphohistiocytosis (HLH) 1–3. Clinical responses to corticosteroids, Methotrexate and anti-TNF-alpha have been partial 1 compared to Janus Kinase inhibitor (JAK). Objective: To describe the first reported Omani preterm neonate with DNASE2 deficiency presenting antenatally with intrauterine growth restriction (IUGR) and fetal anemia, thereby broadening the recognized phenotypic spectrum of this disorder. Case Presentation: A female Omani infant delivered at 30 weeks’ gestation to non-consanguineous parents (Figure: 1) after attempted intrauterine transfusion for severe fetal anemia. Antenatal ultrasound showed symmetric IUGR and cardiomegaly. Shortly after delivery, the neonate developed apnea and bradycardia requiring initial non-invasive support and subsequently invasive ventilation. Physical exam revealed deep jaundice, hepatosplenomegaly, with no distinctive facial features. Laboratory studies demonstrated pancytopenia with profound neutropenia, conjugated hyperbilirubinemia, cholestatic liver dysfunction, high ferritin and low fibrinogen. All infectious work up including TORCH screen were negative. The neonate required multiple blood product transfusions. Genetic testing confirmed a novel compound heterozygous mutation in the DNASE2 gene (c. 141₁42del and c. 2T>c). Initiation of JAK inhibitor therapy posed a significant challenge due to the patient’s extreme prematurity, low birth weight, and absence of prior data supporting use in an infant of this age. Consequently, treatment was deferred until she reached 3 months of age and weight of 2. 4 Kg. Discussion: A similar presentation has been described previously in patients with anemia, hepatosplenomegaly, cytopenias, and cholestasis, however, this presentation is unique in its severity and onset in utero. Previous cases reported variants with reduced DNase II activity presenting in infancy or childhood; one adolescent patient responded to a JAK inhibitor. Our neonates expand the disease spectrum to include preterm and antenatal manifestations associated with severe fetal anemia and IUGR. Recognition of this phenotype is crucial to guide management, genetic counseling, and timely referral to advanced therapies. Conclusion: DNASE2 deficiencies can manifest early antenatally with fetal anemia and IUGR, and can postnatally can mimic pictures of HLH with pancytopenia, hepatosplenomegaly, or cholestatic jaundice. Starting JAK inhibitors is extremely difficult given the age of the patient with a low birth weight.
Barumi et al. (Thu,) studied this question.