Modeling of levothyroxine in newborns and infants with congenital hypothyroidism: challenges and opportunities of a rare disease multi-center study.

Modeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from several decades measured with different assays. Here we present a retrospective pharmacometrics (PMX) based data analysis of the rare disease congenital hypothyroidism (CH) in newborns and infants. Our overall aim is to develop a model that can be applied to optimize dosing in this pediatric patient population since suboptimal treatment of CH during the first 2 years of life is associated with a reduced intelligence quotient between 10 and 14 years. The first goal is to describe a retrospectively collected dataset consisting of 61 newborns and infants with CH up to 2 years of age. Overall, 505 measurements of free thyroxine (FT4) and 510 measurements of thyrotropin or thyroid-stimulating hormone were available from patients receiving substitution treatment with levothyroxine (LT4). The second goal is to introduce a scale/location-scale normalization method to merge available FT4 measurements since 34 different postnatal age- and assay-specific laboratory reference ranges were applied. This method takes into account the change of the distribution of FT4 values over time, i.e. a transformation from right-skewed towards normality during LT4 treatment. The third goal is to develop a practical and useful PMX model for LT4 treatment to characterize FT4 measurements, which is applicable within a clinical setting. In summary, a time-dependent normalization method and a practical PMX model are presented. Since there is no on-going or planned development of new pharmacological approaches for CH, PMX based modeling and simulation can be leveraged to personalize dosing with the goal to enhance longer-term neurological outcome in children with the rare disease CH.

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.

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.

Slowing of Peripheral Nerve Conduction Velocity in Children and Adolescents With Type 1 Diabetes Is Predicted by Glucose Fluctuations.

Nerve conduction velocity (NCV) abnormalities are the forerunners of diabetic peripheral neuropathy (DPN). Therefore, this study aimed to analyze the effect of glucose profile quality on NCV in children and young adults with type 1 diabetes. Fifty-three children age 5 to 23 years with type 1 diabetes were recruited to participate in the study, which was conducted prospectively at the Children's Hospital of Eastern Switzerland from 2016 to 2022. Glycemic targets were recorded, and a cross-sectional nerve conduction study analyzing the peroneal, tibial, median motor, and median sensory nerves was performed. Data were compared with those of a control group of 50 healthy children. In the age- and height-matched diabetes subgroup aged 10-16 years, all four nerves showed significantly slower NCV, most pronounced for the peroneal nerve. Because height has a retarding effect on peroneal NCV, NCV was adjusted for height (dNCV). Peroneal dNCV correlated negatively with long-term glycated hemoglobin and highly significantly with glucose variability. Because high glucose variability clearly increases the risk of neuropathy, together with but also independently of the mean glucose level, this aspect of glycemic control should be given more attention in the care of individuals with diabetes. ARTICLE HIGHLIGHTS: There is a strong need for the better identification of early subclinical manifestations of microvascular complications, such as diabetic peripheral neuropathy, in young individuals with diabetes. To identify peripheral neuropathy and contributing factors at an asymptomatic disease stage, and to exclude height as a known modifying factor, we performed association studies of height-adjusted nerve conduction velocity. We identified high glucose variability, especially the SD of mean glucose, as an unexpectedly strong predictor of slowed nerve conduction velocity. More attention should be paid to the goal of low glucose variability in the care of individuals with diabetes.

Home visits to identify the roles lifestyle and stress play in families of children with obesity.

One-sixth of Swiss children are affected by overweight, and despite the implementation of an evidence-based multiprofessional approach, there has only been moderate therapeutic success. An unfavourable home environment and psychosocial stresses on the family may impede lifestyle changes. This longitudinal observational study included children with obesity (body mass index [BMI] ≥97th percentile [P.]) or overweight (BMI ≥ 90th P.) with a comorbidity, and who were participating in a regional 12-month multiprofessional group programme (MGP). Two health professionals routinely visited the family home at baseline (T0) to identify obesogenic environmental factors and psychosocial stress using an observation and question checklist and the Heidelberger stress scale (HSS). At T0 and after an 8-month intensive intervention phase (T1), the BMI standard deviation score (BMI-SDS) and its associations with the environmental and psychosocial factors were assessed. Twenty-eight children (17 male) met the criteria for participation in the MGP. At T0, age was 11.2 ± 1.71 years, BMI 28.1 ± 4.7 kg/m2 and BMI-SDS 2.9 ± 0.8, means ±SD. By T1, the mean BMI-SDS had decreased significantly, by -0.11 (p < .05). The stress scores (30.46 ± 17.8) were elevated and the subcategories of financial and social stress showed a trend towards predicting BMI or BMI-SDS at T0 and T1, but none of the other supposed obesogenic risk factors significantly predicted weight status. Conducting home visits allowed health professionals to identify obesity-promoting home conditions and, more importantly, otherwise undisclosed high psychosocial stress and resource limitations in families that impacted the children's obesity before and after the MGP intervention.

Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease.

Objectives: Graves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy. Methods: Retrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis. Results: Data from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity. Discussion: We present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases.

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.

Association between foot growth and musculoskeletal loading in children with Prader-Willi syndrome before and during growth hormone treatment.

OBJECTIVE: To explore how foot growth relates to musculoskeletal loading in children with Prader-Willi syndrome (PWS). STUDY DESIGN: In 37 children with PWS, foot length (FL) before and after 6 years of growth hormone therapy (GHT) was retrospectively evaluated with parental and sibling's FL, height, and factors reflecting musculoskeletal loading, such as weight for height (WfH), lean body mass (LBM; dual energy X-ray absorptiometry, deuterium labeled water), physical activity (accellerometry), and walk age. Because of the typically biphasic evolution of body mass and the late walk age in PWS, 2 age groups were separated (group 1, >2.5 years; group 2, < or =2.5 years). RESULTS: Children with PWS normalized height, but not FL after 6 years of GHT. Parental FL correlation with PWS's FL was lower than with sibling's FL. In group 1, FL positively correlated with WfH, LBM, and physical activity. In group 2, FL negatively correlated with age at onset of independent ambulation. Foot catch-up growth with GHT was slower in group 2 compared with group 1. CONCLUSION: In PWS, FL is positively associated with musculoskeletal loading. Small feet in children with PWS before and during long-term GHT may be more than just another dysmorphic feature, but may possibly reflect decreased musculoskeletal loading influencing foot growth and genetic and endocrine factors.

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.

Evaluating a childhood obesity program with the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework.

Primary care providers can use behavioral lifestyle interventions to effectively treat children with overweight and obesity, but implementing these interventions is challenging. Most childhood obesity intervention evaluation studies focus on effectiveness. Few studies describe implementation. Our goal was to evaluate critical components of a childhood obesity intervention in primary care. We conducted a pilot implementation study of an existing structured lifestyle intervention in the Canton of Bern, Switzerland from 2013 to 2015. The intervention consisted of 10 sessions, led by a primary care physician. It included children aged 6-8 years old, with BMI over the 90th age-adjusted percentile. We used the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) evaluation framework to describe the pilot implementation study. We stratified description of RE-AIM components at the patient- and physician-level. For Reach: 864 children were screened; 65 were overweight; 394 physicians were invited to participate in the study. For Effectiveness: BMI z-score significantly decreased (-5.6%, p = 0.01). For Adoption: 14 participating physicians treated 26 patients. Implementation: the mean number of consultations was 8. For Maintenance: 9 (35%) children discontinued the intervention; 7 (50%) of physicians continued to apply at least one component of the intervention. The summarized components of the program within the RE-AIM framework suggest the program was successful. Stakeholders can use our results if they intend to disseminate and evaluate similar interventions in different settings.

Developmental profiles in young children with Prader-Labhart-Willi syndrome: effects of weight and therapy with growth hormone or coenzyme Q10.

Muscle hypotonia and failure to thrive are key symptoms of Prader-Willi syndrome (PWS) allowing diagnosis during infancy already. Improved general care as well as Coenzyme Q(10) (CoQ(10)) and growth hormone (GH) are administered to improve PWS children's outcome. This study aims to investigate psychomotor development of young PWS children in relation to body weight and body composition at baseline as well as to the effects of GH or CoQ(10) therapy. Twenty-six young children (age 1.0 +/- 0.1 years, mean +/- SEM) with PWS genetically proven at age 0.1 +/- 0.1 years (17 deletions, 8 maternal disomy) were divided into three groups: Group 1 on GH therapy (started in 1994-1996, 6 mg/kg/week) tolerating low body weight (<50th centile), group 2 on GH (1997-2000) and group 3 on CoQ(10) (2001-2002, 2.5 mg/kg/day orally), both combined with active early weight management to achieve weight >50th centile. Anthropometry, body composition and Griffith's developmental scores (DQs) were assessed before therapy and after 12 months. DQs were not related to infants' weight, lean mass or genetic background. DQs improved significantly with chronological age and were best in the most recently diagnosed group. Improved psychomotor development, mainly due to progress in locomotor development, did not differ between GH and CoQ(10) treated groups. In conclusion, while only GH has significant effects on growth and body composition, GH and CoQ(10) therapy act equally on psychomotor development of PWS infants. However, improving psychomotor development may merely reflect an age-related phenomenon additionally depending on early diagnosis and introduction of appropriate care.

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. DESIGN: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. METHODS: Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). RESULTS: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10-11) or controls (18%, P = 5.5 × 10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10-7). CONCLUSIONS: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

Serum retinol-binding protein 4 concentration and its ratio to serum retinol are associated with obesity and metabolic syndrome components in children.

CONTEXT: Although retinol-binding protein (RBP)-4 concentrations are elevated in animal models of obesity and insulin resistance (IR), the link between RBP4 and IR in humans is less clear. There are few published data on RBP4 levels in overweight children, and most previous studies did not control for vitamin A (VA) status and/or subclinical inflammation. OBJECTIVE: The objective of the study was to measure serum RBP4, serum retinol (SR), the RBP4-to-SR molar ratio, and dietary VA intakes in normal-weight and overweight children and investigate the relationship of these variables to IR, subclinical inflammation, and the metabolic syndrome in this age group. DESIGN: This was a cross-sectional study. SETTING: The study was conducted in Northern Switzerland. PATIENTS: Patients included 6- to 14-yr-old normal-weight, overweight, and obese children (n = 79). MAIN OUTCOME MEASURES: Body mass index, body fat percentage, waist-to-hip ratio, dietary VA intakes, serum RBP4, and SR were determined. IR was assessed using fasting insulin and the quantitative insulin sensitivity check index, and components of the metabolic syndrome and indices of subclinical inflammation were measured. RESULTS: Only 3% of children had low VA status. Independent of age, VA intakes, and C-reactive protein, body mass index, body fat percentage, and waist-to-hip ratio were significant predictors of RBP4, SR, and RBP4/SR. Independent of adiposity, RBP4 and RBP4/SR were significantly correlated with serum triglycerides, and RBP4/SR was correlated with fasting insulin. The RBP4-to-SR ratio more strongly correlated with components of the metabolic syndrome than serum RBP4. CONCLUSION: Independent of subclinical inflammation and vitamin A intakes, serum RBP4 and the RBP4-to-SR ratio are correlated with obesity, central obesity, and components of the metabolic syndrome in prepubertal and early pubertal children.

Fructose intake is a predictor of LDL particle size in overweight schoolchildren.

BACKGROUND: High amounts of dietary fructose may contribute to dyslipidemia in adults, but there are few data in children. Childhood adiposity is associated with smaller LDL particle size, but the dietary predictors of LDL size in overweight children have not been studied. OBJECTIVES: We aimed to determine whether LDL particle size is associated with dietary factors and specifically with fructose intake in normal-weight and overweight children. DESIGN: In a cross-sectional study of normal-weight and overweight 6-14 y-old Swiss children (n = 74), dietary intakes were assessed by using two 24-h-recalls and a 1-d dietary record. Body mass index (BMI) and waist-hip ratio (WHR) were measured, and plasma lipid profile and LDL particle size were determined. RESULTS: Compared with the normal-weight group, overweight children had significantly higher plasma triacylglycerol concentrations, lower HDL-cholesterol concentrations, and smaller LDL particle size (P < 0.05). LDL particle size was inversely correlated to BMI SD scores and WHR (P = 0.007). Although there were no significant differences in total fructose intake, the overweight children consumed a significantly (P < 0.05) higher percentage of fructose from sweets and sweetened drinks than did the normal-weight children. After control for adiposity, the only dietary factor that was a significant predictor of LDL particle size was total fructose intake (P = 0.024). CONCLUSIONS: In school-age children, greater total and central adiposity are associated with smaller LDL particle size and lower HDL cholesterol. Overweight children consume more fructose from sweets and sweetened drinks than do normal-weight children, and higher fructose intake predicts smaller LDL particle size.

Clinical effects of treatment for hypogonadism in male adolescents with Prader-Labhart-Willi syndrome.

BACKGROUND: In boys with Prader-Labhart-Willi syndrome (PWS), hypogonadism causes pubertal arrest and reduces pubertal muscle growth. Formerly, it was assumed that therapy with gonadal hormones accentuates behaviour abnormalities in PWS. Our aim was to assess the clinical effects of human chorionic gonadotropin (hCG) therapy on pubertal development, muscle mass and behaviour in adolescents with PWS. METHODS: 6 peripubertal boys with PWS undergoing long-term treatment with growth hormone were examined 6-monthly for at least 2 years before and after pubertal arrest (13.5 +/- 0.3 years, mean +/- SEM) and the beginning of hCG therapy (500-1,500 IU twice weekly, intramuscularly). Height, weight, pubertal stage, bone age, body composition (by dual-energy X-ray absorptiometry), testosterone levels and behaviour abnormalities (obtained from parents) were assessed. RESULTS: Testicular volume and lean mass were reduced in pubertal boys with PWS. During hCG therapy, testosterone levels and lean mass significantly increased (at the beginning and after 2 years of hCG therapy: 2.3 +/- 0.9 and 10.7 +/- 1.3 nmol/l, -3.1 +/- 0.3 and -1.4 +/- 0.6 SD, respectively), and fat mass stabilized at 38%. The characteristically observed PWS-associated problems, mood instability, aggressiveness and difficulties in social interaction, did not deteriorate during therapy. CONCLUSION: In the present study, timely application of hCG to treat hypogonadism in boys with PWS promoted virilization and normalized muscle mass without detrimental effects on behaviour. Larger studies comparing hCG therapy with testosterone replacement would be useful.

Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart- Willi syndrome.

CONTEXT: The specific form of hypogonadism in Prader-Labhart-Willi syndrome (PWS), central or peripheral, remains unexplained. OBJECTIVES: The objectives of this study were to investigate the cause of hypogonadism in PWS and determine whether human chorionic gonadotropin (hCG) treatment can restore pubertal development. DESIGN: This was a clinical follow-up study, divided into two samples, over a duration of 1.5 and 4.5 yr. PATIENTS: Eight male infants and six peripubertal boys (age at start of observation, 0.06-0.93 and 8.1-10.8 yr, respectively) with genetically confirmed PWS were studied. INTERVENTION: hCG (500-1500 U twice weekly) was given from age 13.5 yr to the present. MAIN OUTCOME MEASURES: Serum FSH, LH, inhibin B, and testosterone levels and pubertal development were the main outcome measures. RESULTS: Infants with PWS presented normal LH (2.3 +/- 0.7 U/liter) and testosterone (2.5 +/- 0.9 nmol/liter) levels (mean +/- sem at 5 months) compared with the reference range. However, two thirds of the boys displayed cryptorchidism. Inhibin B levels were at the lowest level of the normal range and decreased significantly between infancy and puberty (at 13 yr, 72 +/- 17 pg/ml), whereas FSH secretion increased (9.9 +/- 2.6 U/liter). Pubertal maturation stopped at an average bone age of 13.9 yr. hCG therapy increased testosterone (11 +/- 2 nmol/liter) and reduced FSH (at 16 yr, 1.1 +/- 0.9 U/liter) levels. Testicular volume (5.6 +/- 1 ml) and inhibin B (26.5 +/- 11.9 pg/ml) remained low. CONCLUSION: Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (low inhibin B and high FSH) hypogonadism, suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss. hCG therapy stimulates testosterone production and virilization.

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.

A daily comprehensive muscle training programme increases lean mass and spontaneous activity in children with Prader-Willi syndrome after 6 months.

UNLABELLED: The reduction of spontaneous physical activity (PA) and of muscle tissue are thought to be major causes of fat accretion and metabolic deterioration in Prader-Labhart-Willi syndrome (PWS). We investigated whether a generalized physical training programme in a home setting improves these parameters. The prospective study included 11 prepubertal children (mean age 8.7 years, range 5.9-11.8) with documented PWS and under continuous growth hormone treatment for at least 2.8 years. Seven children were enrolled in a training programme for several muscle groups during 4-10 minutes daily. Twelve matched children with PWS served as controls (average age 8.8 years, 6.1-11.3). Before and after training, at 6 months, PA was assessed by measuring walking distance by pedometer registration and by an activity score, and body composition by DEXA expressed as standard deviation scores (SDS) related to height. After training, lean mass (LM) increased from -1.83 to -1.48 SDS, p <0.05, whereas the controls showed no change. In the training group, walking distance and PA increased from 4.2 to 4.7 km/d and from 255 to 266 points, respectively, and these rises significantly exceeded those observed in controls. CONCLUSION: Children with PWS can be motivated by their families to follow a short daily training, which has general effects on PA and does increase, but not normalize LM.

Non-Virilizing Congenital Adrenal Hyperplasia in a Female Patient with a Novel HSD3B2 Mutation.

Classic 3ß-hydroxysteroid dehydrogenase type 2 (3ß-HSD II) deficiency causes congenital adrenal hyperplasia with glucocorticoid, mineralocorticoid, and sex steroid deficiency. We present a female patient with congenital adrenal hyperplasia detected in newborn screening due to elevated 17OH-progesterone. Female external genitalia and non-measurable androgen levels elicited the suspicion of a defect early in the steroid cascade. Two loss-of-function HSD3B2 mutations (1 novel) were detected and confirmed in silico. We argue that in a girl with glucocorticoid and mineralocorticoid deficiency without virilization, 3ß-HSD II deficiency is an important differential diagnosis. 17OH-progesterone may initially be elevated due to placental and peripheral activity of 3ß-HSD I, whereas dehydroepiandrosterone may not be increased.