Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function.

CONTEXT: The ATP-sensitive potassium (K(ATP)) channel, assembled from the inwardly rectifying potassium channel Kir6.2 and the sulfonylurea receptor 1, regulates insulin secretion in beta-cells. A loss of function of K(ATP) channels causes depolarization of beta-cells and congenital hyperinsulinism (CHI), a disease presenting with severe hypoglycemia in the newborn period. OBJECTIVE: Our objective was identification of a novel mutation in Kir6.2 in a patient with CHI and molecular and cell-biological analysis of the impact of this mutation. DESIGN AND SETTING: We combined immunohistochemistry, advanced life fluorescence imaging, and electrophysiology in HEK293T cells transiently transfected with mutant Kir6.2. PATIENT AND INTERVENTION: The patient presented with macrosomia at birth and severe hyperinsulinemic hypoglycemia. Despite medical treatment, the newborn continued to suffer from severe hypoglycemic episodes, and at 4 months of age subtotal pancreatectomy was performed. MAIN OUTCOME MEASURE: We assessed patch-clamp recordings and confocal microscopy in HEK293T cells. RESULTS: We have identified a homozygous missense mutation, H259R, in the Kir6.2 subunit of a patient with severe CHI. Coexpression of Kir6.2(H259R) with sulfonylurea receptor 1 in HEK293T cells completely abolished K(ATP) currents in electrophysiological recordings. Double immunofluorescence staining revealed that mutant Kir6.2 was partly retained in the endoplasmic reticulum (ER) causing decreased surface expression as observed with total internal reflection fluorescence. Mutation of an ER-retention signal partially rescued the trafficking defect without restoring whole-cell currents. CONCLUSION: The H259R mutation of the Kir6.2 subunit results in a channel that is partially retained in the ER and nonfunctional upon arrival at the plasma membrane.

Natural history of growth hormone deficiency in a pediatric cohort.

BACKGROUND/AIMS: Controversies still exist regarding the evaluation of growth hormone deficiency (GHD) in childhood at the end of growth. The aim of this study was to describe the natural history of GHD in a pediatric cohort. METHODS: This is a retrospective study of a cohort of pediatric patients with GHD. Cases of acquired GHD were excluded. Univariate logistic regression was used to identify predictors of GHD persisting into adulthood. RESULTS: Among 63 identified patients, 47 (75%) had partial GHD at diagnosis, while 16 (25%) had complete GHD, including 5 with multiple pituitary hormone deficiencies. At final height, 50 patients underwent repeat stimulation testing; 28 (56%) recovered and 22 (44%) remained growth hormone (GH) deficient. Predictors of persisting GHD were: complete GHD at diagnosis (OR 10.1, 95% CI 2.4-42.1), pituitary stalk defect or ectopic pituitary gland on magnetic resonance imaging (OR 6.5, 95% CI 1.1-37.1), greater height gain during GH treatment (OR 1.8, 95% CI 1.0-3.3), and IGF-1 level <-2 standard deviation scores (SDS) following treatment cessation (OR 19.3, 95% CI 3.6-103.1). In the multivariate analysis, only IGF-1 level <-2 SDS (OR 13.3, 95% CI 2.3-77.3) and complete GHD (OR 6.3, 95% CI 1.2-32.8) were associated with the outcome. CONCLUSION: At final height, 56% of adolescents with GHD had recovered. Complete GHD at diagnosis, low IGF-1 levels following retesting, and pituitary malformation were strong predictors of persistence of GHD.

[Physical exercise and bone development in chronically ill children]. / Exercice physique et développement osseux de l'enfant malade chronique.

Children with chronic diseases are at increased risk of sub-optimal bone mineral acquisition and osteoporosis, especially those who have a growth and pubertal delay, reduced physical activity, inadequate nutrition, malabsorption or take medications which may influence bone development. Weight-bearing physical activity has a beneficial effect on bone development of healthy children but little is known in children with chronic diseases. Preliminary results of our cross-sectional study in children with juvenile idiopathic arthritis (JIA) suggest that hip bone mineral density is positively related with physical fitness and muscle strength and is reduced at the more affected side. We have initiated two randomized controlled trials to determine the effects of a moderate impact exercise training program on bone mineral density of children with JIA and type 1 diabetes mellitus.