Background: Congenital hyperinsulinism of infancy represents a group of heterogeneous disorders characterized by over-secretion of insulin from pancreatic β cells causing severe hypoglycemia. Genetically, congenital hyperinsulinism is caused by defects in key genes regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, and non-constantly HNF1A). The aim of our project was to perform molecular genetic analysis of Czech patients with congenital hyperinsulinism.
Methods: Since 2012 we have systematically collected clinical information and DNA samples from 38 Czech patients with the diagnosis of congenital hyperinsulinism (12 females, median age of diagnosis 2 months (06 months)). The DNA was investigated by direct sequencing of the above mentioned genes.
Results: Out of 38 patients, 19 patients have been found to carry a causal mutation in genes associated with congenital hyperinsulinism. We found 11 mutations in ABCC8 (seven novel), two novel mutations in KCNJ11 (one patient carries heterozygote mutations in ABCC8 and in KCNJ11 simultaneously), one mutation in GCK, two novel mutations in HNF4A and four mutations in HNF1A - G31D, L254Q, R272H, and E508K (mutation L254Q is novel, mutations G31D, R272H and E508K have been described in connection with HNF1A-MODY diabetes). Clinically congenital hyperinsulinism caused by mutations in HNF1A gene is usually milder, manifests in the first weeks of life (second day, first week, third week respectively), presents with fetal macrosomy and is diazoxide-responsive. The patients are expected to develop HNF1A-MODY diabetes later in life.
Conclusion: In comparison with other genetic studies of larger patient cohorts, the incidence of mutations in HNF1A gene in our Czech study is much higher. This confirms the role of HNF1A in pathogenesis of congenital hyperinsulinism and emphasizes the importance of molecular genetic testing of HNF1A gene in patients presenting with congenital hyperinsulinism.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology