Birth weight and diazoxide unresponsiveness strongly predict the likelihood of congenital hyperinsulinism due to a mutation in ABCC8 or KCNJ11

OBJECTIVE: Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for the clinical management of the condition. We aimed to determine the clinical features that help to identify KATP-hyperinsulinism at diagnosis. DESIGN: We studied 761 individuals with KATP-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age. All were referred as part of routine clinical care. METHODS: We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and ROCanalysis to identify the features that predict KATP-hyperinsulinism. RESULTS: Higher birth weight, diazoxide unresponsiveness and diagnosis in the first week of life were independently associated with KATP-hyperinsulinism (adjusted Odds Ratio 4.5 (95% CI, 3.4-5.9), 0.09 (0.06-0.13) and 3.3 (2.0- 5.0) respectively). Birth weight and diazoxide unresponsiveness were additive and highly discriminatory for identifying KATP-hyperinsulinism (ROC area under the curve for birth weight 0.80, diazoxide responsiveness 0.77, and together 0.88, 95% CI 0.85-0.90). 86% born large for gestation and 78% born appropriate for gestation who did not respond to diazoxide treatment had KATP-hyperinsulinism. In contrast, of those individuals born small for gestation, none who were diazoxide responsive and only 4% of those who were diazoxide unresponsive had KATP-hyperinsulinism. CONCLUSIONS: Individuals with hyperinsulinism born appropriate or large for gestation and unresponsive to diazoxide treatment are most likely to have an ABCC8 or KCNJ11 mutation. These patients should be prioritised for genetic testing for KATP channel genes.