Abstract
Birth defects are associated with increased cancer risk in the general pediatric population, yet their impact on leukemia risk in children with Down syndrome (DS) remains uncertain. We assessed this using data from 26,660 children with DS in the Genetic Overlap Between Anomalies and Cancer in Kids Registry Linkage Study. Among them, 71.9% had at least one major birth defect, predominantly involving the cardiac (64.2%), musculoskeletal (21%), and gastrointestinal systems (6.8%). The cumulative incidence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) was comparable in children with and without co-occurring defects. Adjusted hazard ratios (aHR) for ALL and AML in children with versus without co-occurring major birth defects were 1.12 (95% confidence interval [CI]: 0.80-1.56) and 1.09 (95% CI: 0.76-1.58), respectively. Overall, no consistent patterns were seen between organ system-level defects and ALL. However, in terms of specific defects, we identified that anophthalmia/microphthalmia (aHR: 2.83, 95% CI: 1.16-6.92) was associated with ALL and tetralogy of Fallot (aHR: 2.40, 95% CI: 1.27-4.55) was associated with AML. While children with DS experience a higher prevalence of birth defects, these defects do not appear to strongly influence leukemia risk, unlike the elevated risk observed in the general pediatric population (< 18 years).