Neonatal diabetes due to potassium channel mutation: Response to sulfonylurea according to the genotype

Objective A precision medicine approach is used to improve treatment of patients with monogenic diabetes. Herein, we searched SU efficiency according to the genotype-phenotype correlation, dosage used, and side effects. Research Design and Methods Systematic review conducted according the PRISMA control criteria identifying relevant studies evaluating the in vivo and in vitro sensitivity of ATP-dependent potassium channels according to the characteristics of genetic mutation. Results Hundred and three selected articles with complete data in 502 cases in whom 413 (82.3%) had mutations inKCNJ11(#64) and 89 inABCC8(# 56). Successful transfer from insulin to SU was achieved in 91% and 86.5% patients, respectively, at a mean age of 36.5 months (0-63 years). Among patients withKCNJ11andABCC8mutations 64 and 46 were associated with constant success, 5 and 5 to constant failure, and 10 and 4 to variable degrees of reported success rate, respectively. The glibenclamide dosage required for each genotype ranged from 0.017 to 2.8 mg/kg/day. Comparing both the in vivo and in vitro susceptibility results, some mutations appear more sensitive than others to sulfonylurea treatment. Side effects were reported in 17/103 of the included articles: mild gastrointestinal symptoms and hypoglycaemia were the most common. One premature patient had an ulcerative necrotizing enterocolitis which association with SU is difficult to ascertain. Conclusions Sulfonylureas are an effective treatment for monogenic diabetes due toKCNJ11andABCC8genes mutations. The success of the treatment is conditioned by differences in pharmacogenetics, younger age, pharmacokinetics, compliance, and maximal dose used."Societe Francophone du diabete" (2012) European Society for Pediatric Endocrinology Societe Francophone du Diabet

Insulin gene VNTR genotype is associated with insulin sensitivity and secretion in infancy

AIMS We have previously demonstrated that insulin sensitivity and secretion at age 1 year was in part related to variation in weight and height gain during infancy. In order to determine whether genetic variation at the insulin gene could also influence these associations, we have studied the relationship between insulin gene variable number of tandem repeat (INS VNTR) genotypes, insulin secretion and early postnatal growth. METHODS We assessed fasting and dynamic insulin secretion in 99 healthy infants at age 1 year, using a short intravenous glucose tolerance test (sIVGTT). Infants were genotyped at the -23 HphI locus, as a surrogate marker for INS VNTR allele classes I and III. Anthropometric data were recorded at birth and at 1 year. Data are shown as median (interquartile range). RESULTS Fasting insulin levels were higher in III/III infants (n = 9) than in I/I infants [n = 55; 27.4 (17.6-75.6) pmol/l vs. 18.1 (10.3-25.2) pmol/l; P < 0.05]. Insulin secretion during the sIVGTT, as estimated by the serum insulin area under the curve, was also higher in III/III infants [2417 (891-4041) pmol min/l vs. 1208 (592-2284) pmol min/l; P < 0.05]. Fasting and postload plasma glucose levels were similar in both groups. Analysis of covariance showed that genotype differences in fasting insulin sensitivity and insulin secretion were independent of size at birth, postnatal growth velocity and current body mass index. CONCLUSIONS Significant associations between INS VNTR genotype and both insulin sensitivity and secretion were apparent in infancy; these might interact with childhood appetite and nutrition to impact the development of childhood obesity and insulin resistance

Reproductive hormones during pubertal transition in girls with transient Thelarche

Context Transient thelarche (TT), that is, the appearance, regression and subsequent reappearance of breast buds, is a frequent phenomenon, but little is known about pubertal transition in these girls. Objective To describe pubertal progression, growth, genotypes, reproductive hormones and growth factors in girls with TT compared to those who do not present TT (non-TT). Design Retrospective analysis of a longitudinal population-based study. Patients or Other Participants Girls (n = 508) of the Chilean Growth and Obesity cohort. Measurements Pubertal progression, reproductive hormones, follicle stimulating hormone (FSH) beta subunit/FSH receptor gene single nucleotide polymorphisms and growth. Results Thirty-seven girls (7.3%) were presented TT. These girls entered puberty by pubarche more frequently (51%) than girls with normal progression (non-TT; n = 471; 23%,P = .005). Girls with TT who were under 8 years old had lower androgens, anti-Mullerian hormone (AMH), luteinizing hormone (LH) and oestradiol (allP < .05) than older girls with TT. At the time of Tanner breast stage 2 (B2), girls with TT had higher androgens, LH, FSH, IGF1, LH, insulin and oestradiol (P < .01) than at the time of TT. TT girls were older at B2 (10.3 +/- 1.1 vs. 9.2 +/- 1.2 years,P < .001) and menarche (12.3 +/- 0.8 vs. 12.0 +/- 1.0 years,P = .040) than their counterparts (non-TT). No differences in anthropometric variables orFSHB/FSHRgenotypes were detected. Conclusion Transient thelarche is a frequent phenomenon that does not appear to be mediated by hypothalamic-pituitary-gonadal axis activation or by adiposity. Hormonal differences between earlier TT and later TT suggest that their mechanisms are different.World Cancer Research Fund International (WCRF) WCRF 2010/245 European Society for Paediatric Endocrinology Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) CONICYT FONDECYT 1140447 112032

Early Obesity: Risk Factor for Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD), defined as fat accumulation greater than 5% in hepatocytes, may progress to fibrosis or cirrhosis later in life. NAFLD prevalence in adolescents has increased significantly in direct relation with obesity prevalence. Fatty liver has become the most frequent indication for liver transplantation in adults. Objective: The aim of the study was to identify anthropometric variables during the first 10 years of life associated to the risk of developing NAFLD in adolescence. Methods: Longitudinal cohort study 'Growth and Obesity Chilean Cohort Study' (GOCS) consisting of 513 children born in 2002 to 2003, with yearly anthropometric data collected over a 10-year period. The presence of intrahepatic fat in the livers of subjects 14 to 16 years of age was determined using abdominal ultrasound. In addition, elastography was performed on all participants with ultrasound evidence of NAFLD. Results: 9.7% of the participants presented findings compatible with NAFLD. After 2 years of age, obesity significantly and progressively increased the probability of NAFLD occurrence in adolescence. Obesity at 5 years of age was associated with the highest OR for NAFLD, reaching values of 8.91 (95% CI 3.03-16.11). Among participants with NAFLD, those with altered liver elasticity (>= 7 kPa) had greater weight, BMIz-score, waist and hip circumference, and altered liver enzymes (P < 0.05). Conclusion: The risk of developing NAFLD in adolescence increases progressively with early obesity starting at age 2 years.Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) CONICYT FONDECYT N81161456 Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) N82218023

Contract Negotiations and Market Order

Artículo de publicación ISIContext: Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly. Objective: To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure. Design: Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene. Setting: An academic pediatric endocrinology clinic. Patients or Other Participants: Two adult siblings (male patient [P1] and female patient 2 [P2]) presented with a history of severe postnatal growth failure (adult heights: P1, -6.8 SD score; P2, -4 SD score), microcephaly, primary gonadal failure, and early-onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28. Intervention(s): Single nucleotide polymorphism microarray and exome sequencing. Results: Combined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect. Conclusions: In this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non-homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition.Eunice Kennedy Shriver Institute of Child Health and Human Development at the National Institutes of Health 5K23HD073351 1R01HD078592 European Community HEALTH-F2-2010-25989