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

in European Journal of Endocrinology
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  • 1 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
  • | 2 Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK
  • | 3 Royal Devon and Exeter Foundation Hospital, Exeter, UK
  • | 4 National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK

Correspondence should be addressed to K A Patel Email k.a.patel@exeter.ac.uk

(S E Flanagan and K A Patel contributed equally to this research as senior authors)

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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 receiver operator characteristic (ROC) analysis 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). In this study, 86% born large for gestation and 78% born appropriate for gestation and 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 of KATP channel genes.

Supplementary Materials

    • Supplementary Table 1 – Characteristics of individuals with congenital hyperinsulinism caused by mutations in ABCC8 and KCNJ11. Categorical data are shown as n (%) whereas continuous data are shown as mean (SD). *P values are above the Bonferroni corrected threshold for multiple comparison (0.05/8 = 0.006). Number of patients [n] is shown In square brackets where it differs from the total number in the cohort.
    • Supplementary Table 2 - Sensitivity analysis showing the utility of clinical features to discriminate between KATP CHI and CHI of an unknown aetiology in the two countries and institutes with the most referrals. ROC AUC = Receiver Operating Characteristic Area Under the Curve

 

     European Society of Endocrinology

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