ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism

• Published in: Journal of medical genetics Vol. 47; no. 11; pp. 752 - 759
• Main Authors: Bellanné-Chantelot, C, Saint-Martin, C, Ribeiro, M-J, Vaury, C, Verkarre, V, Arnoux, J-B, Valayannopoulos, V, Gobrecht, S, Sempoux, C, Rahier, J, Fournet, J-C, Jaubert, F, Aigrain, Y, Nihoul-Fékété, C, de Lonlay, P
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.11.2010; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: ABCC8; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; congenital hyperinsulinism; Congenital Hyperinsulinism - diagnosis; Congenital Hyperinsulinism - drug therapy; Congenital Hyperinsulinism - genetics; Dehydrogenases; diazoxide; Diazoxide - therapeutic use; DNA Mutational Analysis; Drug Resistance; Endocrinopathies; Female; Genetics; Genotype; Humans; Infant; Infant, Newborn; KCNJ11; Life Sciences; Male; Medical sciences; Mutation; potassium channel; Potassium Channels, Inwardly Rectifying - genetics; Receptors, Drug - genetics; Sulfonylurea Receptors; Surgery; Vasodilator Agents - therapeutic use; Endocrinopathy; Human; Hyperinsulinemia; Genetic determinism; Congenital disease; Molecular genetics; Metabolic disorders
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmg.2009.075416

BackgroundCongenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic β-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (KATP) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients.MethodsABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed.ResultsABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single KATP channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole KATP channel mutation.ConclusionsThe identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single KATP channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.