Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management

摘要

Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in children,which if unrecognized may lead to development delays and permanent neurologicdamage. Prompt recognition and appropriate treatment of HI are essential toavoid these sequelae. Major advances have been made over the past two decades inunderstanding the molecular basis of hyperinsulinism and mutations in nine genesare currently known to cause HI. Inactivating KATP channel mutationscause the most common and severe type of HI, which occurs in both a focal and adiffuse form. Activating mutations of glutamate dehydrogenase (GDH) lead tohyperinsulinism/hyperammonemia syndrome, while activating mutations ofglucokinase (GK), the “glucose sensor” of the beta cell, causeshyperinsulinism with a variable clinical phenotype. More recently identifiedgenetic causes include mutations in the genes encoding short-chain3-hydroxyacyl-CoA (SCHAD), uncoupling protein 2 (UCP2), hepatocyte nuclearfactor 4-alpha (HNF-4α), hepatocyte nuclear factor 1-alpha (HNF-1α),and monocarboyxlate transporter 1 (MCT-1), which results in a very rare form ofHI triggered by exercise. For a timely diagnosis, a critical sample and aglucagon stimulation test should be done when plasma glucose is < 50 mg/dL.A failure to respond to a trial of diazoxide, a KATP channel agonist,suggests a KATP defect, which frequently requires pancreatectomy.Surgery is palliative for children with diffuse KATPHI, but childrenwith focal KATPHI are cured with a limited pancreatectomy. Therefore,distinguishing between diffuse and focal disease and localizing the focal lesionin the pancreas are crucial aspects of HI management. Since 2003,18 F-DOPA PET scans have been used to differentiate diffuse andfocal disease and localize focal lesions with higher sensitivity and specificitythan more invasive interventional radiology techniques. Hyperinsulinism remainsa challenging disorder, but recent advances in the understanding of its geneticbasis and breakthroughs in management should lead to improved outcomes for thesechildren.