2016-11-02T18:49:00

No abstract

Hyperinsulinism in infancy is one of the most diYcult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without diYculty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It oVers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment. (Arch Dis Child Fetal Neonatal Ed 2000;82:F98-F107)

Hyperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder that occurs in ~1 of 50,000 live births. Histologically, pancreases from HI patients can be divided into 2 major groups. In the first, diffuse HI, ␤-cell distribution is similar to that seen in normal neonatal pancreas, whereas in the second, focal HI, there is a discrete region of ␤-cell adenomatous hyperplasia. In most patients, the clinical course of the disease suggests a slow progressive loss of ␤-cell function. Using double immunostaining, we examined the proportion of ␤-cells undergoing proliferation and apoptosis during the development of the normal human pancreas and in pancreases from diffuse and focal HI patients. In the control samples, our findings show a progressive decrease in ␤-cell proliferation from 3.2 ± 0.5% between 17 and 32 weeks of gestation to 0.13 ± 0.08% after 6 months of age. In contrast, frequency of apoptosis is low (0.6 ± 0.2%) in weeks 17-32 of gestation, elevated (1.3 ± 0.3%) during the perinatal period, and again low (0.08 ± 0.3%) after 6 months of age. HI ␤-cells showed an increased frequency of proliferation, with focal lesions showing particularly high levels. Similarly, the proportion of apoptotic cells was increased in HI, although this reached statistical significance only after 3 months of age. In conclusion, we demonstrated that islet remodeling normally seen in the neonatal period may be primarily due to a wave of ␤-cell apoptosis that occurs at that time. In HI, our findings of persistently increased ␤-cell proliferation and apoptosis provide a possible mechanism to explain the histologic picture seen in diffuse disease. The slow progressive decrease in insulin secretion seen clinically in these patients suggests that the net effect of these phenomena may be loss of ␤-cell mass. Diabetes 49: 1325-1333, 2000 H yperinsulinism of infancy (HI), also known as persistent hyperinsulinemic hypoglycemia of infancy, is a rare genetic disorder, the molecular basis of which was recently elucidated. Most cases are caused by mutations in either the sulfonylurea receptor (SUR1) or the inward rectifying potassium channel (Kir6.2), 2 subunits of the ␤-cell K ATP channel (1-5). A minority of patients have glucokinase or glutamate dehydrogenase mutations, whereas in 40-50% of the patients, the genetic cause of the disease is still not known (4-7).The histologic appearance of the pancreases from affected children can be subdivided into 2 major forms: diffuse HI and focal HI (8-10). The former is more common and bears some characteristics of nesidioblastosis, a phenomenon observed in the healthy fetus and newborn but which normally evolves during the first year of life into the adult-type architecture (9,11,12). In diffuse HI, the neonatal-type ␤-cell distribution persists (8,13).Focal HI is generally easily recognized as a discrete region of adenomatous hyperplasia (8), whereas the rest of the pancreas appears normal for its age. Focal HI is caused by the somatic l...

Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K + (K ATP ) channel in the pancreatic β cell. Though most disease-causing mutations of the 2 genes encoding K ATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating K ATP mutations, we have identified and characterized 16 families with 14 different dominantly inherited K ATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a K ATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant K ATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited K ATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant K ATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy.