Supplemental data from: Determinants of hyperinsulinism severity in children with Beckwith-Wiedemann Syndrome

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.