Abstract
ObjectiveMutations 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.DesignWe 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.MethodsWe 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.ResultsHigher 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.ConclusionsIndividuals 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.
Highlights
MethodsWe compared the clinical features of Kir6.2 subunits of the pancreatic ATP-sensitive potassium (KATP)-hyperinsulinism and unknown hyperinsulinism cases
We studied 761 individuals with Kir6.2 subunits of the pancreatic ATP-sensitive potassium (KATP)-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age
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
Summary
We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and ROC analysis to identify the features that predict KATPhyperinsulinism. We studied 761 probands with a pathogenic or likely pathogenic mutation in ABCC8 (N=665) or KCNJ11 (N=96) identified at the Exeter Genomics Laboratory between 2002 and 2018. We reviewed 862 patients with CHI of unknown genetic aetiology who were referred to our laboratory within the same period. In all of these patients, mutations in the ABCC8 and KCNJ11 genes had been excluded by Sanger sequencing or gene panel testing. Parental samples were tested to confirm the inheritance of ABCC8/KCNJ11 variants identified in the proband. Pathogenicity of variants was assessed according to ACMG guidelines 11
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