NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice.

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1. The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1-deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1-deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

Linear stapled gastrojejunostomy results in fewer strictures compared to circular stapled gastrojejunostomy in laparoscopic gastric bypass surgery.

PURPOSE: Currently, there are two laparoscopic stapling techniques to perform the gastrojejunostomy in gastric bypass surgery: the linear stapling and circular stapling techniques. The aim of the study was to compare the two techniques regarding postoperative morbidity and weight loss at an accredited bariatric reference center in Switzerland. METHODS: We compared two consecutive cohorts at a single institution between November 2012 and June 2014 undergoing laparoscopic gastric bypass surgery. The frequency of complications and weight loss at 1 year was assessed in 109 patients with the 21-mm circular stapling technique (CSA) and 134 patients with the linear stapling technique (LSA). RESULTS: Postoperative complications were more frequent in the CSA group with 23.9 versus 4.5% in the LSA group (p = <0.0001). The main difference was the frequency of strictures, which occurred in 15.6% in the CSA group versus 0% in the LSA group. As a result, endoscopic dilation was required at least once in 15 patients. There was no statistically significant difference in percentage of excessive weight loss (EWL) in both groups; EWL was 74% in the CSA group and 73% in the LSA group (p = 0.68). CONCLUSION: Linear stapled laparoscopic gastric bypass had fewer stenotic strictures with similar weight loss at 1 year compared to circular stapling technique.

Health-Related Quality of Life of Young Adults Treated with Recombinant Human Growth Hormone during Childhood.

BACKGROUND: Since recombinant human growth hormone (rhGH) became available in 1985, the spectrum of indications has broadened and the number of treated patients increased. However, long-term health-related quality of life (HRQoL) after childhood rhGH treatment has rarely been documented. We assessed HRQoL and its determinants in young adults treated with rhGH during childhood. METHODOLOGY/PRINCIPAL FINDINGS: For this study, we retrospectively identified former rhGH patients in 11 centers of paediatric endocrinology, including university hospitals and private practices. We sent a questionnaire to all patients treated with rhGH for any diagnosis, who were older than 18 years, and who resided in Switzerland at time of the survey. Three hundred participants (58% of 514 eligible) returned the questionnaire. Mean age was 23 years; 56% were women; 43% had isolated growth hormone deficiency, or idiopathic short stature; 43% had associated diseases or syndromes, and 14% had growth hormone deficiency after childhood cancer. Swiss siblings of childhood cancer survivors and the German norm population served as comparison groups. HRQoL was assessed using the Short Form-36. We found that the Physical Component Summary of healthy patients with isolated growth hormone deficiency or idiopathic short stature resembled that of the control group (53.8 vs. 54.9). Patients with associated diseases or syndromes scored slightly lower (52.5), and former cancer patients scored lowest (42.6). The Mental Component Summary was similar for all groups. Lower Physical Component Summary was associated with lower educational level (coeff. -1.9). Final height was not associated with HRQoL. CONCLUSIONS/SIGNIFICANCE: In conclusion, HRQoL after treatment with rhGH in childhood depended mainly on the underlying indication for rhGH treatment. Patients with isolated growth hormone deficiency/idiopathic short stature or patients with associated diseases or syndromes had HRQoL comparable to peers. Patients with growth hormone deficiency after childhood cancer were at high risk for lower HRQoL. This reflects the general impaired health of this vulnerable group, which needs long-term follow-up.

Insulinoma: only in adults?-case reports and literature review.

Insulinomas first presenting as refractory seizure disorders are well documented in adulthood but rarely found in children. Only a few cases of childhood insulinoma have been reported so far. We report on two adolescents with hyperinsulinaemic hypoglycaemia, initially misdiagnosed as epilepsy and migraine accompagnée, and compare those to other cases published. Localization of insulinoma was challenging and, in one patient, angiography with selective arterial calcium stimulation and hepatic venous sampling in addition to CT and MRI was necessary. In these patients, long-term recovery was achieved by laparoscopic distal pancreatic resection in one and by conventional enucleation in the pancreatic head in the second patient. In contrast to adults, macrosomy and a decrease in school performance were the main symptoms and, during fasting, impaired cognitive function occurred after a relatively short period and at a higher glucose threshold or lower insulin/glucose ratio, respectively. Neuroglycopenic signs may be attributed to behaviour abnormalities or seizure disorders but in children and adolescents may already be caused by insulinoma. In these cases, timely diagnosis as well as tumour resection ensure long-term cure.

[Options and limits in the treatment of overweight children and adolescents and their families in primary care]. / Behandlung von übergewichtigen Kindern und Jugendlichen mit ihren Familien in der Grundversorgung - Möglichkeiten und Grenzen.

The general practitioner or pediatrician mostly is the first point of contact for overweight children and may recognize adiposity early enough in order to start therapy of obesity or comorbidity or to initiate measures of prevention. Interventions against overweight are most efficient before age 7 in terms of short-and long-term results and should not be delayed. As obesity requires care of the entire family, close or recurring contact with the overweight child and its family is important as well as the treatment nearby their residence. In preschoolers, targeting parents exclusively for obesity therapy is highly effective. Changing cherished habits and style of education is the biggest challenge to parents. Therefore, various techniques of treatment of alcohol or tobacco addiction can be used and recommendations for improvement of self-worth as well as healthy eating behavior and exercise are presented. First feasible objectives include modest lifestyle changes and reduction of comorbidities; if an extreme obesity with a BMI above 99.5th percentile or mental disorders are present or if it becomes apparent within the first 6 months that the patient cannot achieve his own goals for changes in lifestyle and body weight, a referral to a specialized center is indicated. There, a multi-professional treatment of the child and his family is performed in common by specialists for nutrition, exercise and psychology. Childhood obesity is a chronic disease that requires a very long-term treatment and usually persists into adulthood.

A new phenotype of nongoitrous and nonautoimmune hyperthyroidism caused by a heterozygous thyrotropin receptor mutation in transmembrane helix 6.

CONTEXT: Activating mutations in the TSHR gene were found in patients suffering from nonautoimmune hyperthyroidism. In the past, it was assumed that thyroid hyperplasia is due to constitutive activation of the Gs/adenylyl cyclase signaling pathway; however, the physiological role of the Gq/11 pathway in this context remains unclear. OBJECTIVE: In this study, we investigated molecular details of the TSHR in a patient with nonautoimmune and nongoitrous hyperthyroidism. RESULTS: We detected a heterozygous mutation in exon 10 of the TSHR gene leading to an exchange of a cysteine residue for tryptophan at amino acid position 636 in transmembrane helix 6. Functional characterization of the mutant receptor revealed a slight reduction of the cell surface expression and TSH induced cAMP accumulation compared to the wild type. Additional observations included a constitutive activation of the Gs-mediated signaling pathway and a simultaneous nearly complete loss-of-function for the Gq/11 pathway after bovine TSH stimulation. Studies on TSHR models suggest significant changes of important amino acid interactions and the overall helix arrangement caused by mutation C636W. CONCLUSION: We report a patient in whom a TSHR mutation leads to nonautoimmune hyperthyroidism due to a mutation that constitutively activates the Gs signaling pathway but additionally completely inhibits the Gq/11 pathway. The absence of goiter in the patient suggests that the Gq/11 pathway is related to thyroid growth and that different signaling pathways are mediated and regulated by TSH. These functional data could be confirmed by reproducible findings of two siblings with a constitutive activation for both pathways.

Diet determines features of the metabolic syndrome in 6- to 14-year-old children.

BACKGROUND/OBJECTIVES: Insulin resistance (IR) and hypertension are common in overweight children, and the adipocyte-derived hormones resistin, adiponectin, and leptin may modulate IR and blood pressure (BP). Few data exist in children on dietary determinants of IR, BP, or leptin, and no data exist on dietary determinants of resistin and adiponectin. Therefore, the objective of this study was to investigate dietary determinants of IR, BP, resistin, adiponectin, and leptin concentrations, as well as the interrelationship among these variables, in normal and overweight children. SUBJECTS/METHODS: In 6- to 14-year-old Swiss children (n=79), nutritional intake was assessed using two 24-hour-recalls and a one-day dietary record. Body mass index (BMI), body fat percentage (BF%), waist/hip ratio (W/H ratio), BP, glucose, insulin, resistin, adiponectin, and leptin were determined. IR was calculated using the quantitative insulin sensitivity check index (QUICKI). RESULTS: BMI, BF%, and W/H ratio were significant predictors of leptin and insulin, QUICKI, and systolic BP, but not resistin or adiponectin. Of the overweight and obese children, 40% were diagnosed pre-hypertensive or hypertensive. Total energy, fat, saturated fat, and protein intakes were significant predictors of fasting insulin and QUICKI, and total fat, saturated fat, and monounsaturated fat intakes were significant predictors of systolic BP, independent of BMI standard deviation score (BMI-SDS) and age. There were no associations between these dietary factors and leptin, adiponectin, or resistin. CONCLUSION: In children, dietary macronutrient composition is a predictor of IR and systolic BP, but not resistin, adiponectin, or leptin concentrations. Resistin and adiponectin concentrations are not correlated with IR or BP in this age range.

Two-year follow-up in 21,784 overweight children and adolescents with lifestyle intervention.

Although randomized controlled trials demonstrated the long-term efficacy of lifestyle interventions in overweight children, the effects of these interventions in clinical practice under real-life conditions are largely unknown. One hundred twenty-nine centers specialized in outpatient pediatric obesity care participated in this quality assessment. All patients presenting before the year 2006 for lifestyle intervention of at least 6 months duration in these institutions were analyzed in a 2-year follow-up. A total of 21,784 (45% male) overweight children and adolescents aged 2-20 years (mean BMI 30.4 kg/m2, mean SDS-BMI 2.51, mean age 12.6 years) were included in the analysis. Based on an intention-to-treat analysis with variables set back to baseline in lost of follow-up, 22% of the children reduced their SDS-BMI after 6 months, 15% after 12 months, and 7% after 24 months, but only in 24, 17, and 8% of children, respectively, complete data were available. In the five treatment centers with the best outcome (518 patients), 83% of the children reduced their overweight after 6 months, 67% after 12 months, and 51% after 24 months. Under real-life conditions, most treatment centers cannot prove the long-term efficacy of their interventions due to high drop-out rate or lack of documentation. Conversely, some institutions achieved a reduction of overweight in nearly the half of their patients 24 months after baseline demonstrating the great heterogeneity in outcome. To improve the effectiveness of lifestyle interventions in real-life studying, the process and structure quality as well as their long-term results is urgently needed.

Dietary intakes of fat and antioxidant vitamins are predictors of subclinical inflammation in overweight Swiss children.

BACKGROUND: In obese children, subclinical inflammation is often present and is correlated with the metabolic syndrome. Dietary factors, such as fatty acids and antioxidants, potentially modulate the association between adiposity and subclinical inflammation, but few data are available in children. OBJECTIVE: The aim of the study was to determine whether dietary fat or antioxidant intakes influence circulating tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), C-reactive protein (CRP), and leptin concentrations in overweight children. DESIGN: In a cross-sectional study of 6-14-y-old normal-weight (n = 33), overweight (n = 19), and obese (n = 27) Swiss children, nutritional intakes were assessed from two 24-h dietary recalls and a 1-d dietary record. Percentage body fat from skinfold thicknesses, waist-hip ratio, and blood pressure were measured. Fasting blood samples were collected for the measurement of insulin, glucose, HDL-cholesterol, triacylglycerol, CRP, IL-6, TNF-alpha, and leptin concentrations. RESULTS: CRP, IL-6, and leptin increased significantly (P < 0.02) with increasing adiposity, independent of age; TNF-alpha did not increase. Total dietary fat and the percentage of energy from fat were significant predictors of CRP concentration, independent of body mass index (P < 0.05). Meat intake was a significant predictor of IL-6 and leptin, independent of body mass index (P < 0.05). Intakes of antioxidant vitamins (vitamins E and C and beta-carotene) were significant predictors of leptin (P < 0.05) but not of CRP, IL-6, or TNF-alpha. CONCLUSIONS: Overweight Swiss children as young as 6 y have elevated concentrations of inflammatory markers. Intakes of total fat and antioxidant vitamins are determinants of subclinical inflammation in this age group.