Abstract Context Congenital hyperinsulinism (HI) is a serious clinical feature of Beckwith-Wiedemann syndrome (BWS) causing severe hypoglycemia. The relationship between BWS genotypes and HI severity is not well understood. Objective Investigate the relationship between molecular determinants of patients with BWS and HI with measures of HI severity. Design Retrospective cohort study including 85 children from 2009-2024. Setting All patients evaluated at single, tertiary care center. Patients BWS genotype frequency included 41 children with pUPD11, 24 with IC2 LOM, eight with 11p15 chromosomal anomalies, six with GWpUPD, four with IC1 GOM, and two with CDKN1C. Interventions Retrospectively reviewed interventions included maximum glucose infusion rate (max GIR), diazoxide responsiveness, and surgery. Main Outcome Measures Primary outcome was association between BWS genotypes and measures of HI severity. Secondary outcomes included the relationship between pUPD11 length and presence of K-ATP variants with diazoxide responsiveness and surgical need. Results Significant differences presented among genotypes in max GIR (p = 0.004), enteral dextrose requirements (p = 0.029), and pancreatectomy (p = 0.012). Most patients with IC2 LOM, IC1 GOM or CDKN1C were diazoxide responsive and did not require surgery. Patients with pUPD11 were more likely to be diazoxide unresponsive and require surgery, especially if pUPD11 length extended into the K-ATP gene region and if a pathogenic variant in the ABCC8 or KCNJ11 was present. Conclusion Patients with pUPD11 experience more severe HI, while patients with IC2 LOM, IC1 GOM, and CDKN1C exhibit milder disease. Based on our findings, we designed a genetic testing algorithm to guide clinical management.
George et al. (2026) studied this question.