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The expansion of newborn screening (NBS) for congenital hypothyroidism (CH) is essential to reducing the number of preventable intellectual disabilities in children. Because of logistical issues, including geographic extremes, distinct cultures, and 4.8 million births annually, Indonesia has struggled to achieve universal NBS coverage. A national cross-sectional electronic survey was conducted to explore challenges in CH NBS. Responses from 423 healthcare professionals and program administrators across 30 provinces in Indonesia were collected. The major challenges reported were refusal from families (39.2%), newborns being discharged <24 h (38.3%), and limited availability of filter paper (35.9%). The respondents considered refusal from families to be due to fear, while others did not understand the necessity of CH NBS. The vast majority of respondents believed that parents do not have sufficient understanding regarding CH NBS (96.5%). Our study found that only 38.5% of respondents had received formal CH NBS training, with pediatric endocrinologists being the only profession in which all respondents had been trained. Concerted efforts are needed to improve the access to and availability of resources, increase the capacity for sample collection and analysis, empower healthcare professionals, and develop educational resources to promote understanding and acceptance of NBS amongst families.

Context: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy., Objective: To evaluate safety and efficacy of intranasal carbetocin in PWS., Design: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up., Setting: Twenty-four ambulatory clinics at academic medical centers., Participants: A total of 130 participants with PWS aged 7 to 18 years., Interventions: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose., Main Outcome Measures: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C)., Results: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing., Conclusions: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS., Clinical Trials Registration Number: NCT03649477., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Pediatric endocrinology is a specialty that is struggling worldwide to maintain adequately trained professionals. Pediatric endocrine care in Central America and Caribbean countries is often performed by pediatricians or adult endocrinologists due to the limited number of pediatric endocrinologists. These health care providers are seldom members of endocrine societies and frequently lack formal training in the field., Objective: In this study, we describe the scope of a virtual conference in pediatric endocrinology and diabetes targeted to low- and middle-income countries to provide equal opportunities for access to medical education for health care professionals., Methods: The virtual conference was sponsored by the Pediatric Endocrine Society (North America), Asociación Costarricense de Endocrinología (previously, Asociación Nacional Pro Estudio de la Diabetes, Endocrinología y Metabolismo), and Asociacion Centroamericana y del Caribe de Endocrinologia Pediátrica. The conference was free to participants and comprised 23 sessions that were either synchronous with ability for real-time interactive sessions or asynchronous sessions, where content was available online to access at their convenience. Topics included idiopathic short stature, polycystic ovarian syndrome, diabetes mellitus, telemedicine, Turner syndrome, congenital adrenal hyperplasia, obesity, central precocious puberty, and subclinical hypothyroidism. The participants were asked to evaluate the conference after its completion with a questionnaire., Results: A total of 8 speakers from Spain, Canada, Costa Rica, and the United States delivered the virtual event to 668 health care professionals from Guatemala, Venezuela, Dominican Republic, Costa Rica, Ecuador, Peru, Uruguay, Mexico, Honduras, Argentina, the United States, Bolivia, Chile, Panama, El Salvador, Nicaragua, Paraguay, Belize, Spain, and Colombia. Name, profession, and country were fully disclosed by 410 (61.4%) of the 668 health care professionals. The profession or level of training of participants were as follows: pediatric endocrinologists (n=129, 19.3%), pediatricians (n=116, 17.4%), general practitioners (n=77, 11.5%), adult endocrinologists (n=34, 5.1%), medical students (n=23, 3.4%), residents in various specialties (n=14, 2.1%), and others (n=17, 2.6%). A total of 23 sessions were offered, most of which were bilingual (Spanish and English). Feedback from the evaluation questionnaire indicated that the content of the conference was very relevant to the participants' professional practice. Additionally, the participants reported that they were very satisfied with the organization, the web-based platform, and the sessions of the conference., Conclusions: Lack of accessibility to the latest and cutting-edge medical education in pediatric endocrinology and diabetes for medical professionals from low- and middle-income countries can be overcome with a virtual conference. Online availability, low cost, and easy-to-use technology were well received from the participants, who were overall very satisfied by the quality and the relevance of the sessions to their professional practice., (©Roberto Bogarin, Luis Elizondo, Evangelia Kalaitzoglou, Jadranka Popovic, Alan Rogol, Erick Richmond, Jean-Pierre Chanoine, Jose M Lopez-Pedrosa, Francis Ruiz Salazar, Patricia Vuguin. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 08.05.2023.)

Background: The co-presentation of severe obesity (SO) and global developmental delay (GDD) in Canadian preschool children has not been examined. However, SO and GDD may require syndromic diagnoses and unique management considerations., Objectives: To determine (1) minimum incidence; (2) age of onset and risk factors; and (3) health care utilization for co-presenting SO and GDD., Methods: Through the Canadian Paediatric Surveillance Program (CPSP), a monthly form was distributed to participants from February 2018 to January 2020 asking for reports of new cases of SO and GDD among children ≤5 years of age. We performed descriptive statistics for quantitative questions and qualitative content analysis for open-ended questions., Results: Forty-seven cases (64% male; 51% white; mean age: 3.5 ± 1.2 years) were included. Age of first weight concern was 2.5 ± 1.3 years and age of GDD diagnosis was 2.7 ± 1.4 years. Minimum incidence of SO and GDD was 3.3 cases per 100,000 for ≤5 years of age per year. Identified problems included school and/or behavioural problems (n = 17; 36%), snoring (n = 14; 30%), and asthma/recurrent wheeze (n = 10; 21%). Mothers of 32% of cases (n = 15) had obesity and 21% of cases (n = 10) received neonatal intensive care. Microarray was ordered for 57% (n = 27) of children. A variety of clinicians and services were accessed. As reported by CPSP participants, challenges faced by families and health service access were barriers to care., Conclusion: Children with SO and GDD have multiple comorbidities, and require early identification and referral to appropriate services. These cases may also benefit from additional testing to rule out known genetic obesity syndromes., Competing Interests: WTG received research funding from the Canadian Institutes of Health Reearch. AMH is a member of the Clinical Advisory Board, Setmelanotide for BBS/Alstrom’s disease, Rhythm Pharmaceuticals; Chair, Scientific Advisory Board, PWS USA and PI for clinical trials with Rhythm pharmaceuticals and Levo Therapeutics. KMM has served as a member of an advisory board for Novo Nordisk and is on a Data Safety Monitoring committee for Novartis. She has received research funding from the Canadian Institutes of Health Research and McMaster University. JH has consulted for Novo Nordisk and the Pediatric Obesity National Advisory Board. She has received funding from Mead Johnson, Levo Therapeutics, and the Foundation for Prader-Willi Research. MH holds a Fonds de la recherche du Québec – Santé (FRQS) Junior 2 Clinical Research Scholar Award and is the recipient of the 2019 Canadian Society for Endocrinology and Metabolism Young Investigator Award. She is member of Canada’s Children’s Hospitals Foundation (CCHF) and Sun Life Child and Youth Type 2 Diabetes Prevention Initiative. She has received research funding from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, Diabète Québec, the Fonds de Recherche du Québec – Santé, the Quebec Cardiometabolic Health, Diabetes and Obesity Network and the Quebec Network on Nursing Intervention Research, as well as through the Canada’s Children’s Hospitals Foundation (CCHF)/Sun Life initiative. GDCB served as a member of a national advisory board with Novo Nordisk Canada. He received research funding from the Canadian Institutes of Health Research, Public Health Agency of Canada, Alberta Health Services, Alberta Innovates, and the Women and Children’s Health Research Institute (UAlberta). All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To: (1) complete an integrative literature review of transition studies that focus on individuals with intersex traits; (2) conduct an environmental scan of the current resources (practice guidelines, policies and procedures) used by healthcare providers working with Canadians with intersex traits; (3) investigate the experiences of Canadians with intersex traits in their healthcare transitions across the lifespan and (4) assess the understanding of healthcare providers about these transitions., Design: A qualitative prospective community participation study was conducted. It used mixed methods including an environmental scan and semistructured engagement sessions., Setting: The environmental scan examined resources available throughout Canada. The engagement sessions took place in British Columbia and Ontario, Canada., Participants: Sixteen participants were recruited. These included 13 individuals with intersex traits (a heterogeneous group of congenital conditions affecting the development of sex characteristics) and three caregivers., Methods: Mixed methods included an integrated literature review, environmental scan and qualitative approaches developed in collaboration with community partners., Results: The literature review identified gaps in transition care for individuals with intersex traits. The environmental scan uncovered no specific resources used by healthcare providers working with patients with intersex traits, though several general guidelines were used. Engaging providers in the study was problematic. Thematic analysis generated three main themes that emerged from the engagement sessions: (1) transition is a lifespan activity; (2) building personal agency is valuable and (3) well-being promotion is an application of health literacy., Conclusions: Transition resources for individuals living in Canada with intersex are scarce. Transitions happen across the lifespan with ownership of thought and actions seen as acts of personal agency. Health literacy skills and knowledge change with increased age, yet the primary source of knowledge often remained important in the individual's autobiographical self., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Congenital adrenal hyperplasia (CAH), if untreated, carries high morbidity and mortality. A higher incidence of CAH is expected in countries where consanguinity is common, such as in the countries of the WHO Eastern Mediterranean Region (EMRO). CAH is managed through lifelong treatment with fludrocortisone and hydrocortisone. In this analysis, performed in the 22 EMRO countries and territories plus Algeria, we review which countries offer a neonatal screening programme for CAH and describe the barriers and opportunities to access oral fludrocortisone and oral and injectable hydrocortisone. Neonatal CAH screening was only available nationally in Qatar, Kuwait and partially in Lebanon and Saudi Arabia. We reviewed the national lists of essential medicines (NEMLs) and found that 13/23 (57%) countries included fludrocortisone and 18/23 (78%) included oral hydrocortisone. Fludrocortisone was not included by any of the low-income countries and oral hydrocortisone was only included by one low-income country. We then contacted paediatric endocrinologists in each country to assess perceived availability of these medicines. Overall, there was a relatively good consistency between inclusion of fludrocortisone and hydrocortisone in the NEML and their actual availability in a country. We propose several mechanisms to improve access, including prequalification by the WHO, a common registration process for groups of countries, pooled procurement, working with local pharmaceutical companies, special access status for medicines not yet registered in a country and compounding. We suggest that access to medicines requires a collaboration between health professionals, families of patients, health authorities, pharmaceutical companies and the WHO., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Electronic learning (e-learning) is a widely accessible, low-cost option for learning remotely in various settings that allows interaction between an instructor and a learner., Objective: We describe the development of a free and globally accessible multilingual e-learning module that provides education material on topics in pediatric endocrinology and diabetes and that is intended for first-line physicians and health workers but also trainees or medical specialists in resource-limited countries., Methods: As complements to concise chapters, interactive vignettes were constructed, exemplifying clinical issues and pitfalls, with specific attention to the 3 levels of medical health care in resource-limited countries. The module is part of a large e-learning portal, ESPE e-learning, which is based on ILIAS (Integriertes Lern-, Informations- und Arbeitskooperations-System), an open-source web-based learning management system. Following a review by global experts, the content was translated by native French, Spanish, Swahili, and Chinese-speaking colleagues into their respective languages using a commercial web-based translation tool (SDL Trados Studio)., Results: Preliminary data suggest that the module is well received, particularly in targeted parts of the world and that active promotion to inform target users is warranted., Conclusions: The e-learning module is a free globally accessible multilingual up-to-date tool for use in resource-limited countries that has been utilized thus far with success. Widespread use will require dissemination of the tool on a global scale., (©Evangelia Kalaitzoglou, Edna Majaliwa, Margaret Zacharin, Carine de Beaufort, Jean-Pierre Chanoine, Conny van Wijngaard-DeVugt, Ervin Sperla, Annemieke M Boot, Stenvert L S Drop. Originally published in JMIR Formative Research (http://formative.jmir.org), 05.11.2020.)

It is established that pediatric hematopoietic stem cell transplant (HSCT) recipients have a lower rate of chronic graft-versus-host disease (cGvHD) compared to adults. Our group has previously published immune profiles changes associated with cGvHD of clinically well-defined adult and pediatric HSCT cohorts. Since all analyses were performed by the same research group and analyzed using identical methodology, we first compared our previous immune profile analyses between adults and children. We then performed additional analyses comparing the T cell populations across age groups, and a sub-analysis of the impact of the estimated pubertal status at time of HSCT in our pediatric cohort. In all analyses, we corrected for clinical covariates including total body irradiation and time of onset of cGvHD. Three consistent findings were seen in both children and adults, including elevations of ST2 and naive helper T (Th) cells and depression of NK reg cells. However, significant differences exist between children and adults in certain cytokines, B cell, and T reg populations. In children, we saw a broad suppression of newly formed B (NF-B) cells, whereas adults exhibited an increase in T1-CD21 lo B cells and a decrease in T1-CD24 hi CD38 hi B cells. Prepubertal children had elevations of aminopeptidase N (sCD13) and ICAM-1. T reg abnormalities in children appeared to be primarily in memory T reg cells, whereas in adults the abnormalities were in naïve T reg cells. In adults, the loss of PD1 expression in naïve T reg and naïve Th cells was associated with cGvHD. We discuss the possible mechanisms for these age-related differences, and how they might theoretically impact on different therapeutic approaches to cGvHD between children and adults., (Copyright © 2020 Cuvelier, Li, Drissler, Kariminia, Abdossamadi, Rozmus, Chanoine, Ng, Mostafavi, Brinkman and Schultz.)

Pediatric specialists are often unavailable in low- and middle-income countries. As part of multiple professional associations' efforts to improve access to endocrine expertise globally, a pediatric endocrine teleconsultation network was established on a store-and-forward teleconsultation platform to facilitate focused, language-appropriate advice that can be kept for future reference while bypassing real-time video-conferencing, and obviating the need for a scheduled appointment. User information was recorded, and quality statistics on network performance and qualitative evaluation by referring physicians were analyzed. Over a 3-year period, 81 referrers (88% from Haiti) and 13 pediatric endocrinologists registered onto the network and discussed 47 pediatric endocrine cases, exchanging a total of 412 messages for a median of 7 messages (IQR 5, 11) per case. Diagnoses spanned the spectrum of pediatric endocrine disorders. According to referrers, an appropriate expert was consulted and an answer provided sufficiently quickly in 100% of cases. The answer was well-adapted to their environment in 86%, and referrers were able to follow the advice given in 72%. All but one referrer found the advice helpful, it clarified the diagnosis in 88%, assisted with management in 93%, improved patient's symptoms in 77%, improved function in 77%, and was considered cost-saving in 50%. Perceived benefits of the consultations were academic instruction, setting-adapted advice beyond the scope of guidelines or textbooks, and advancement in the diagnostic process. Pediatric endocrine remote store-and-forward consultations in low- and middle-income countries may provide a reasonable alternative to face-to-face visits, providing clinical and educational benefit, and a potential for cost-saving., (Copyright © 2019 von Oettingen, Craven, Duperval, Sine St. Surin, Eveillard, Saint Fleur, Van Vliet, Chanoine and Louis.)

Background: Paediatric obesity management remains generalised to dietary and exercise modifications with an underappreciation for the contributions of eating behaviours and appetitive traits in the development of obesity., Objectives: To determine whether treatment-seeking children and adolescents with obesity cluster into phenotypes based on known eating behaviours and appetitive traits ("eating correlates") and how socio-demographic and clinical characteristics associate with different phenotypes., Methods: A cross-sectional, multi-centre questionnaire was administered between November 2015 and March 2017 examining correlates of eating in children and adolescents attending weight-management programmes in Canada. Latent profile analysis was used to cluster participants based on seven eating correlate scores obtained from questionnaires. Analysis of variance (ANOVA) was used to determine phenotype differences on socio-demographic and clinical characteristics. Multinomial logistic regression models assessed relative risk of specific characteristics associating with a disordered eating phenotype., Results: Participants were 247 children and adolescents (45.3% male, mean BMI z-score = 3.4 ± 1.0 kg/m 2 ) from six paediatric weight management centres in Canada. Seven eating correlates clustered into three distinct phenotypes: (1) loss of control eating, emotional eating, external eating, hyperphagia, impulsivity ("Mixed-Severe"; n = 42, 17%), (2) loss of control eating, emotional eating, external eating, hyperphagia ("Mixed-Moderate"; n = 138, 55.9%), and (3) impulsivity ("Impulsive"; n = 67; 27.1%). Social functioning scores and body esteem were significantly different across groups, with the Mixed-Severe participants having the poorest social functioning and lowest body esteem. Low body esteem indicated a greater risk of being in a multi-correlate group compared to the Impulsive group, while poor social function had a greater risk of clustering in the Mixed-Severe than Impulsive phenotype., Conclusions: Distinct eating phenotypes were found in treatment-seeking children and adolescents with obesity. Empirical evidence is needed, but these data suggest that tailored treatment approaches could be informed by these classifications to improve weight-management outcomes.

Background: Previous studies suggest significant ethnic and racial differences in clitoral sizes and anogenital distances in the newborn. This study aimed to document normative data on clitoral sizes and anogenital distances of apparently normal term female infants in Sagamu., Methods: The study was a multi-center, cross-sectional descriptive research carried out among 317 female term infants within the first 72 h of life. Interviewer-based questionnaire was applied to obtain sociodemographic data, pregnancy and birth history. A sliding digital caliper was used for measurement. Data analysis was with SPSS version 20.0., Results: The mean clitoral length was 6.7 ± 1.6 mm while the mean clitoral width was 5.6 ± 0.8 mm. The mean fourchette-clitoris distance, anus-clitoris distance and anus-fourchette distance were 21.9 ± 2.1 mm, 35.5 ± 2.5 mm and 17.0 ± 2.6 mm respectively. The anus-clitoris and anus-fourchette distances significantly correlated with the anthropometric parameters while the clitoral measurements did not., Conclusion: The mean values recorded in this study were higher than observed in most previous studies. This simple, affordable and non-invasive evaluation could aid early diagnosis and treatment of female infants with potentially harmful conditions such as congenital adrenal hyperplasia., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Background: Country-specific data on outcomes of treatment with recombinant human growth hormone are lacking. We present such data for children treated with growth hormone in Canada., Methods: We describe characteristics and outcomes of 850 children (mean age at baseline 8.5 yr) treated with growth hormone constituting the Canadian cohort of the multinational phase IV prospective observational Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). The diagnosis associated with short stature was as determined by the investigator. Auxological data were evaluated yearly until near-adult height. Adverse events were assessed in all growth-hormone-treated patients., Results: The diagnosis ascribed as the cause of short stature was growth hormone deficiency in 526 children (61.9%), predominantly organic rather than idiopathic, particularly congenital pituitary abnormalities and intracranial tumours. All diagnostic groups with sufficient patients for analysis had increased height velocity standard deviation score (SDS) and height SDS during growth hormone treatment. For patients who reached near-adult height ( n = 293), the mean height SDS was within the normal range for about 80% of patients with organic growth hormone deficiency ( n = 131) or idiopathic growth hormone deficiency ( n = 50), 50% of patients with idiopathic short stature ( n = 10) and 46% of patients with Turner syndrome ( n = 79). Eleven deaths were reported, 7 in patients with organic growth hormone deficiency. Serious adverse events considered related to growth hormone treatment ( n = 19) were isolated except for medulloblastoma recurrence ( n = 2) and adenoidal hypertrophy ( n = 2)., Interpretation: Growth hormone treatment was effective and had a good safety profile in Canadian children. Growth hormone dosages were lower than in the US and global GeNeSIS cohorts, and a greater proportion of treated Canadian children had organic growth hormone deficiency., Study Registration: ClinicalTrials.gov, no. NCT01088412., Competing Interests: Competing interests: Cheri Deal has been involved with phase III and/or phase IV studies with Eli Lilly and Company, Serono, Versartis and OPKO Health, invited lectureships sponsored by Novo Nordisk, Eli Lilly and Company, Pfizer, EMD Serono and Merck Serono, ad hoc consulting with EMD Serono, Novo Nordisk, Merck Serono, Versartis, OPKO Health and Zafgen, and the Grant for Growth Innovation Scientific Advisory Board: Merck. She was a member of the Genetics and Neuroendocrinology of Short Stature International Study International Advisory Board. She has received honoraria and meeting expenses from Eli Lilly and Company. Susan Kirsch and Nan Jia are employees of Eli Lilly and Company. Jean-Pierre Chanoine has received honoraria (speaker fees and advisory board membership) from Eli Lilly and Company. Elizabeth Cummings has received grant support from Eli Lilly and Company and Sanofi. Elizabeth Rosolowsky has received grant support from Eli Lilly and Company and has served on the advisory boards for Insulet and Medtronic. Christopher Child is an employee and stockholder of Eli Lilly and Company. No other competing interests were declared., (Copyright 2018, Joule Inc. or its licensors.)

Background: There is increasing recognition of the value of "real-world evidence" in evaluating health care services. Registry-based, observational studies conducted in clinical settings represent a relevant model to achieve this directive. Starting in 2010, we undertook a longitudinal, observational study (the CANadian Pediatric Weight management Registry [CANPWR]), which is embedded in 10 multidisciplinary, pediatric weight management clinics across Canada. The objective of this paper was to share the lessons our team learned from this multi-centre project., Methods: Data sources included a retrospective review of minutes from 120 teleconferences with research staff and investigators, notes taken during clinical site visits made by project leaders, information from quality control processes to ensure data accuracy and completeness, and a study-specific survey that was sent to all sites to solicit feedback from research team members (n = 9). Through an iterative process, the writing group identified key themes that surfaced during review of these information sources and final lessons learned were developed., Results: Several key lessons emerged from our research, including the (1) value of pilot studies and central research coordination, (2) need for effective and regular communication, (3) importance of consensus on determining outcome measures, (4) challenge of embedding research within clinical practice, and (5) difficulty in recruiting and retaining participants. The sites were, in spite of these challenges, enthusiastic about the benefits of participating in multi-centre collaborative studies., Conclusion: Despite some challenges, multi-centre observational studies embedded in pediatric weight management clinics are feasible and can contribute important, practical insights into the effectiveness of health services for managing pediatric obesity in real-world settings.

Background: Few studies have evaluated the effect of adherence to a lifestyle intervention on adolescent health outcomes. The objective of this study was to determine whether adolescent and parental adherence to components of an e-health intervention resulted in change in adolescent body mass index (BMI) and waist circumference (WC) z-scores in a sample of overweight/obese adolescents., Methods: In total, 159 overweight/obese adolescents and their parents participated in an 8-month e-health lifestyle intervention. Each week, adolescents and their parents were asked to login to their respective website and to monitor their dietary, physical activity, and sedentary behaviours. We examined participation (percentage of webpages viewed [adolescents]; number of weeks logged in [parents]) and self-monitoring (number of weeks behaviors were tracked) rates. Linear mixed models and multiple regressions were used to examine change in adolescent BMI and WC z-scores and predictors of adolescent participation and self-monitoring, respectively., Results: Adolescents and parents completed 28% and 23%, respectively, of the online component of the intervention. Higher adolescent participation rate was associated with a decrease in the slope of BMI z-score but not with change in WC z-score. No association was found between self-monitoring rate and change in adolescent BMI or WC z-scores. Parent participation was not found to moderate the relationship between adolescent participation and weight outcomes., Conclusions: Developing strategies for engaging and promoting supportive interactions between adolescents and parents are needed in the e-health context. Findings demonstrate that improving adolescents' adherence to e-health lifestyle intervention can effectively alter the weight trajectory of overweight/obese adolescents.

Background: Accurately determining energy requirements is key for nutritional management of pediatric obesity. Recently, a portable handheld indirect calorimeter, MedGem (MG) has become available to measure resting energy expenditure (REE). Our work aims to determine the clinical validity and usefulness of MG to measure REE in overweight and obese adolescents., Methods: Thirty-nine overweight and obese adolescents (16 male (M): 23 female (F), 15.2 ± 1.9 y, BMI percentile: 98.6 ± 2.2%) and 15 normal weight adolescents (7M: 8F, age 15.2 ± 2.0 y, BMI percentile: 39.2 ± 20.9%) participated. REE was measured with both MG and standard indirect calorimeter (VMax) in random order., Results: MG REE (1,600 ± 372 kcal/d) was lower than VMax REE (1,727 ± 327 kcal/) in the overweight and obese adolescents. Bland Altman analysis (MG -VMax) showed a mean bias of -127 kcal/d (95% CI = -72 to -182 kcal/d, P < 0.001), and a proportional bias existed such that lower measured REE by VMax was underestimated by MG, and higher measured REE by VMax were overestimated by MG., Conclusion: MG systematically underestimates REE in the overweight and adolescent population, thus the MG portable indirect calorimeter is not recommended for routine use. Considering that it is a systematic underestimation of REE, MG may be clinically acceptable, only if used with caution.

Background: Genital measurements are a useful adjunct in the early detection of various endocrine conditions including hypopituitarism and disorders of sexual differentiation. Standards for genital sizes have been published but racial/ethnic differences exist. This study was done to establish norms for genital sizes in term Ghanaian male newborns., Methods: This was a cross-sectional study of all apparently well full-term newborns of postnatal age < 48 h and birth weight between 2.5 and 4.0 kg delivered at Komfo Anokye Teaching Hospital within the study period. Anthropometric and genital parameters were documented for study subjects as well as parental socio-demographic indices., Results: A total of 644 male newborns were recruited between May and September 2014. The mean penile length (MPL) was 3.3 ± 0.5 cm and the mean penile width (MPW) was 1.05 ± 0.1 cm. An inverse relationship was found between maternal age and MPL (correlation coefficient -0.062, 95% CI -0.121 to -0.002; p  = 0.04). MPL was also significantly different ( p  = 0.04) by mode of delivery, with babies delivered by caesarean section having the lowest MPL. MPL correlated positively with both gestational age ( p  = 0.04) and birth length ( p  < 0.001), while MPW correlated proportionally with birth weight and length ( p  < 0.001 for both)., Conclusions: Using the conventional definition of micropenis as stretched penile length (SPL) < 2.5 standard deviation (SD) below the mean and macropenis as an SPL > 2.5 SD, a Ghanaian term newborn may warrant investigation if he has an MPL < 2.1 cm or > 4.4 cm.

Background: Data on normative clitoral sizes in newborns is relatively sparse and racial/ethnic differences have also been reported. This study was performed to establish norms for clitoral size in term Ghanaian female newborns., Methods: This was a cross-sectional study of all apparently well full-term newborns of postnatal age < 48 h and birth weight between 2.5 and 4.0 kg delivered at Komfo Anokye Teaching Hospital between May and September, 2014. Anthropometric and genital parameters were documented for study subjects as well as parental socio-demographic indices., Results: In 612 newborn females studied, the mean (±SD) clitoral length (MCL) and the mean (±SD) clitoral width (MCW) were 4.13 ± 1.6 mm and 4.21 ± 1.1 mm, respectively. MCL was inversely related to birth weight ( r  = -0.62; p < 0.001 ) while MCW was inversely related to both gestational age ( r  = -0.1; p = 0.02 ) and birth weight ( r  = -0.54; p < 0.001 ). Babies with a clitoris that was completely covered by the labia majora had relatively lower clitoral sizes ( p  < 0.001) than those who had a partially covered or prominent clitoris. Neither MCL nor MCW differed significantly by birth length or maternal tribe., Conclusions: Clitoral size varies with birth weight and gestational age. Babies with a completely covered clitoris are unlikely to warrant detailed clitoral measurements for clitoromegaly.

Paediatric endocrinology and diabetes is a paediatric specialty with less common conditions and higher cost medicines. Access to medicines for our specialty in low and middle income countries remains limited. We analysed the content of the WHO (children and adults) and of all available national Model Lists of Essential Medicines (EMLs) for Mexico, the Caribbean, Central and South America from a paediatric endocrinology and diabetes standpoint. A master list of medicines deemed necessary in paediatric endocrinology and diabetes was established and compared with the WHO and national EMLs, taking into account the gross national income. The WHO EMLs, which are largely recognised as an international benchmark and drive the content of the national EMLs, included many but not all medicines present on our master list. Interestingly, several national EMLs from richer countries included medicines that were not present in the WHO EMLs. Our analysis suggests that these medicines could be considered by the WHO for inclusion in their EMLs, which may promote the adoption of more medicines by individual countries. We also propose several changes to the WHO and national EMLs that could facilitate access to medicines in our specialty: age cut-off for a child using physical maturity rather than a set age limit; greater standardisation of the formatting of the national EMLs for easier comparison and collaborations between countries; greater emphasis on age-specificity and population-specificity for some medicines; and formatting of the EMLs in a disease-focused manner rather than as individual medicines., Competing Interests: Competing interests: None declared.

Traditionally, clinical recommendations for assessing and managing paediatric obesity have relied on anthropometric measures, such as body mass index (BMI), BMI percentile and/or BMI z-score, to monitor health risks and determine weight management success. However, anthropometric measures do not always accurately and reliably identify children and youth with obesity-related health risks or comorbidities. The authors propose a new clinical staging system (the Edmonton Obesity Staging System for Pediatrics, EOSS-P), adapted from the adult-oriented EOSS. The EOSS-P is used to stratify patients according to severity of obesity-related comorbidities and barriers to weight management into four graded categories (0 to 3) within four main health domains: metabolic, mechanical, mental health and social milieu (the 4Ms). The EOSS-P is based on common clinical assessments that are widely available and routinely completed by clinicians, and has the potential to provide clinical and prognostic information to help evaluate and inform the management of paediatric obesity.

Background: A pilot study was conducted to assess the feasibility of establishing a multi-site CANadian Pediatric Weight management Registry (CANPWR) containing individual, family and weight management program information., Methods: Standardized baseline data were collected to characterize CANPWR participants (n = 310) in comparison to a sample of age-matched Canadian children measured in the nationally representative Canadian Health Measures Survey (CHMS; n = 3,788). This study compared demographic, anthropometric, cardiometabolic and lifestyle characteristics of participants (aged 6-17 years) in the CANPWR pilot study with those from the CHMS., Results: Compared to CHMS respondents, CANPWR participants had higher BMI z-score, waist circumference, blood pressure, total cholesterol, LDL cholesterol, triglycerides and fasting glucose, and lower HDL cholesterol. They reported lower sugared drink consumption, were more likely to be non-white and had parents with lower education., Conclusions: The CANPWR cohort represents a group that has biological and behavioral profiles that place them at increased health risk and who differ significantly from typical Canadians of the same age.

Background: In 2010, the WHO Growth Charts for Canada were recommended for use in Canada, while the US Centers for Disease Control and Prevention (Georgia, USA) charts remained in active use., Objective: To assess the availability, utilization of and satisfaction with growth charts in clinical practice in Canada., Methods: In October 2012, a one-time survey was sent through the Canadian Paediatric Surveillance Program (CPSP) to 2544 paediatricians and 280 family physicians with a stated interest in paediatrics., Results: The response rate was 24% (63% general paediatricians, 36% subspecialists, 1% family physicians). Of these respondents, 68% preferred the WHO charts for infants and 49% for children and youth. Regarding the WHO charts, 49.7% of respondents reported concerns with their inability to assess weight for children >10 years of age, and many believed that there were too few percentile lines between the third and 97th percentiles for infant (24%) and for child and youth measures (19%). The addition of extreme percentiles (0.1 and 99.9), shading on charts and lack of availability with electronic medical record providers were other concerns mentioned by 10% to 13% of respondents., Conclusion: There is support for the use of the WHO data for monitoring the growth of Canadian children. Concerns regarding the design of the charts were raised. These survey results lend support to the redesign of the WHO Growth Charts for Canada, as was recently completed in 2014.

Background: Many families referred to specialized health services for managing paediatric obesity do not initiate treatment; however, reasons for noninitiation are poorly understood., Objective: To understand parents' reasons for declining tertiary-level health services for paediatric weight management., Method: Interviews were conducted with 18 parents of children (10 to 17 years of age; body mass index ≥85th percentile) who were referred for weight management, but did not initiate treatment at one of three Canadian multidisciplinary weight management clinics. A semi-structured interview guide was used to elicit parents' responses about reasons for noninitiation. Interviews were audio-recorded and transcribed verbatim. Data were managed using NVivo 9 (QSR International, Australia) and analyzed thematically., Results: Most parents (mean age 44.1 years; range 34 to 55 years) were female (n=16 [89%]), obese (n=12 [66%]) and had a university degree (n=13 [71%]). Parents' reasons for not initiating health services were grouped into five themes: no perceived need for paediatric weight management (eg, perceived children did not have a weight or health problem); no perceived need for further actions (eg, perceived children already had a healthy lifestyle); no intention to initiate recommended care (eg, perceived clinical program was not efficacious); participation barriers (eg, children's lack of motivation); and situational factors (eg, weather)., Conclusion: Physicians should not only discuss the need for and value of specialized care for managing paediatric obesity, but also explore parents' intention to initiate treatment and address reasons for noninitiation that are within their control.

Background: Over recent decades, the prevalence of pediatric obesity has increased markedly in developed and developing countries, and the impact of obesity on health throughout the lifespan has led to urgent calls for action. Family-based weight management interventions that emphasize healthy lifestyle changes can lead to modest improvements in weight status of children with obesity. However, these interventions are generally short in duration, reported in the context of randomized controlled trials and there are few reports of outcomes of these treatment approaches in the clinical setting. Answering these questions is critical for improving the care of children with obesity accessing outpatient health services for weight management. In response, the CANadian Pediatric Weight management Registry (CANPWR) was designed with the following three primary aims: 1. Document changes in anthropometric, lifestyle, behavioural, and obesity-related co-morbidities in children enrolled in Canadian pediatric weight management programs over a three-year period; 2. Characterize the individual-, family-, and program-level determinants of change in anthropometric and obesity-related co-morbidities; 3. Examine the individual-, family-, and program-level determinants of program attrition., Methods/design: This prospective cohort, multi-centre study will include children (2-17 years old; body mass index ≥85(th) percentile) enrolled in one of eight Canadian pediatric weight management centres. We will recruit 1,600 study participants over a three-year period. Data collection will occur at presentation and 6-, 12-, 24-, and 36-months follow-up. The primary study outcomes are BMI z-score and change in BMI z-score over time. Secondary outcomes include anthropometric (e.g., height, waist circumference,), cardiometabolic (e.g., blood pressure, lipid profile, glycemia), lifestyle (e.g., dietary intake, physical activity, sedentary activity), and psychosocial (e.g., health-related quality of life) variables. Potential determinants of change and program attrition will include individual-, family-, and program-level variables., Discussion: This study will enable our interdisciplinary team of clinicians, researchers, and trainees to address foundational issues regarding the management of pediatric obesity in Canada. It will also serve as a harmonized, evidence-based registry and platform for conducting future intervention research, which will ultimately enhance the weight management care provided to children with obesity and their families.

Background: Discordance of monozygotic twins for thyroid dysgenesis suggests that epigenetic mechanisms may underlie defects in thyroid gland development. This prompted us to evaluate whether differentially methylated regions (DMRs) can be found between human thyroids (either eutopic or ectopic) and matched leukocytes., Methods: To compare the genome-wide methylation profile of thyroids and leukocytes, immunoprecipitated methylated DNA was interrogated on human promoter plus CpG island tiling arrays. In addition, the methylation profile of the human FOXE1, PAX8, and NKX2.1 promoter was examined using bisulfite sequencing. Finally, the functional impact of CpG methylation of the promoter on FOXE1 expression was assessed with luciferase assays., Results: Genome-wide methylation profiling and bisulfite sequencing of CpG islands of PAX8 and NKX2.1 promoters revealed no DMR between thyroid and leukocytes. However, bisulfite sequencing revealed that the methylation level of two consecutive CpG dinucleotides (CpG14 and CpG15, which were not covered by the genome-wide array) in one CpG island of the FOXE1 promoter (-1600 to -1140 from the transcription start site) is significantly higher in leukocytes than in eutopic or ectopic thyroid tissues, suggesting that methylation of this region may decrease FOXE1 gene expression. Indeed, luciferase activities were decreased when FOXE1 promoter constructs were methylated in vitro. Moreover, derepression of luciferase activity was observed when the methylation of CpG14 and CpG15 was prevented by mutations., Conclusion: We report a tissue-dependent DMR in the FOXE1 promoter. This DMR contains two consecutive CpG dinucleotides, which are epigenetic modifiers of FOXE1 expression in nontumoral tissues.

Background: Obesity in Canada is a growing concern, but little is known about the available services for managing obesity in adults. Our objectives were to (a) survey and describe programs dedicated to weight management and (b) evaluate program adherence to established recommendations for care., Methods: We conducted an online environmental scan in 2011 to identify adult weight management services throughout Canada. We examined the degree to which programs adhered to the 2006 Canadian Clinical Practice Guidelines on the Management and Prevention of Obesity in Adults and Children (CCPGO) and the analysis criteria developed by the Association pour la Santé Publique du Québec (ASPQ)., Results: A total of 83 non-surgical (34 community-based, 42 primary care-based, 7 hospital-based) and 33 surgical programs were identified. All programs encouraged patient self-management. However, few non-surgical programs adhered to the CCPGO recommendations for assessment and intervention, and there was a general lack of screening for eating disorders, depression and other psychiatric diseases across all programs. Concordance with the ASPQ criteria was best among primary care-based programs, but less common in other settings with deficits most frequently revealed in multidisciplinary health assessment/management and physical activity counselling., Conclusions: With more than 60% of Canadians overweight or obese, our findings highlight that availability of weight management services is far outstripped by need. Our observation that evidence-based recommendations are applied inconsistently across the country validates the need for knowledge translation of effective health services for managing obesity in adults.

Dysglycaemia (hyper- or hypoglycaemia) in critically ill children has been associated with poor outcome. We compared the clinical outcomes in children admitted to Pediatric Emergency Unit (PEU) at Komfo Anokye Teaching Hospital (KATH) for acute medical conditions and presenting with euglycaemia or dysglycaemia. This is a prospective case matching cohort study. Eight hundred subjects aged between 3 and 144 months were screened out of whom 430 (215 with euglycaemia and 215 with dysglycaemia) were enrolled. The median age was 24 months (range: 3-144 months). In the dysglycaemia group, 28 (13%) subjects had hypoglycemia and 187 (87%) had hyperglycemia. Overall, there were 128 complications in 116 subjects. The number of subjects with complications was significantly higher in dysglycaemia group (n = 99, 46%) compared to euglycaemia group (n = 17, 8%) (P < 0.001). Forty subjects died out of whom 30 had dysglycaemia (P = 0.001). Subjects with dysglycaemia were 3 times (95% CI: 1.5-6.0) more likely to die and 4.8 times (95% CI: 3.1-7.5) more likely to develop complications (P = 0.001). Dysglycaemia is associated with increased morbidity and mortality in children with acute medical conditions and should lead to intensive management of the underlying condition.

The Canadian Pediatric Endocrinology Group (CPEG) has produced complementary growth curves based on the 2010 'WHO Growth Charts for Canada'. In response to concerns from CPEG members and the general paediatric community regarding the presentation of the WHO data, complementary curves were generated, which the authors believe will enhance clarity, reduce potential errors in classification and enable users to better track short-term changes, particularly for weight in older children. Specifically, these curves extend weight-for-age beyond 10 years of age, restore additional percentiles within the normal range, remove extreme percentiles and harmonize the choice of body mass index percentiles with adult definitions of overweight and obesity. All modifications followed strict WHO methodology and used core data from the United States National Center for Health Statistics. The curves retain the clean appearance of the 2010 Canadian curves and are available from the CPEG website (http://cpeg-gcep.net).

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: At least two million Canadian children meet established criteria for weight management. Due to the adverse health consequences of obesity, most pediatric weight management research has examined the efficacy and effectiveness of interventions to improve lifestyle behaviors, reduce co-morbidities, and enable weight management. However, little information is available on families' decisions to initiate, continue, and terminate weight management care. This is an important knowledge gap since a substantial number of families fail to initiate care after being referred for weight management while many families who initiate care discontinue it after a brief period of time. This research aims to understand the interplay between individual, family, environmental, and systemic factors that influence families' decisions regarding the management of pediatric obesity., Methods/design: Individual interviews will be conducted with children and youth with obesity (n = 100) and their parents (n = 100) for a total number of 200 interviews with 100 families. Families will be recruited from four Canadian multi-disciplinary pediatric weight management centers in Vancouver, Edmonton, Hamilton, and Montreal. Participants will be purposefully-sampled into the following groups: (i) Non-Initiators (5 families/site): referred for weight management within the past 6 months and did not follow-up the referral; (ii) Initiators (10 families/site): referred for weight management within the past 6 months and did follow-up the referral with at least one clinic appointment; and (iii) Continuers (10 families/site): participated in a formal weight management intervention within the past 12 months and did continue with follow-up care for at least 6 months. Interviews will be digitally recorded and analyzed using an ecological framework, which will enable a multi-level evaluation of proximal and distal factors that underlie families' decisions regarding initiation, continuation, and termination of care. Demographic and anthropometric/clinical data will also be collected., Discussion: A better understanding of family involvement in pediatric weight management care will help to improve existing health services in this area. Study data will be used in future research to develop a validated survey that clinicians working in pediatric obesity management can use to understand and enhance their own health services delivery.

Context: The thyroid contains two types of cells, the thyroid follicular cells and the calcitonin-producing cells. The site of origin of the thyroid follicular cells is the median thyroid anlage, an endothelial diverticulum in the midline of the ventral pharynx between the first and the second pharyngeal pouches. The ultimobranchial bodies (UBB), a pair of transient embryonic structures evaginated from the fourth pharyngeal pouch and located symmetrically on the sides of the developing neck, are the source of calcitonin-producing cells. In human embryos, the thyroid bud starts its migration at embryonic day 24 and reaches its final location in front of the trachea at embryonic day 45-50. The UBB fuse with the primitive thyroid when thyroid migration is completed. Lingual thyroids result from the failure of the thyroid precursor cells to migrate from the primordial pharynx to the anterior part of the neck. Therefore, calcitonin-producing cells are not expected to be present in lingual thyroids., Objective: Our objective was to determine whether calcitonin-producing C cells are present in ectopic lingual thyroids., Design, Setting, Patients, and Main Outcome Measure: We performed calcitonin immunolabeling and transcript detection on four flash-frozen ectopic lingual thyroids. Additional calcitonin immunolabeling was performed on two other paraffin-embedded ectopic lingual thyroids., Results: We report evidence of calcitonin-producing cells in six independent cases of ectopic lingual thyroids., Conclusion: The UBB are not the only source of calcitonin-producing cells in humans. Interactions between calcitonin-producing and thyroid follicular cells occur earlier than previously accepted.

The objective was to conduct a program evaluation of the Centre for Healthy Weights-Shapedown BC (CHW-SB), a family-centered, multidisciplinary program for obese children, by assessing the change in weight trajectories from program intake to completion. Secondary outcomes included changes in clinical, biochemical and psychological parameters, and in physical activity (PA) levels. The CHW-SB program was evaluated over 10 weeks. Data collection included anthropometric, metabolic, PA and psychological measures. Longitudinal mixed effects regression was performed to evaluate weight change from Phase 1 (before program on waitlist) to Phase 2 (during program). 238 children <18 years of age were referred to the program of which 119 were eligible for participation. There was a significant decrease in weight trajectory in children following program entry. Participants experienced an average .89% monthly increase before program entry, compared to a .37% monthly decline afterwards, a drop of 1.26% (p < 0.0001, 95%CI 1.08 to 1.44). zBMI (2.26 ± 0.33 to 2.20 ± 0.36, p < 0.001), waist circumference (99 ± 15.7 to 97 ± 16 cm, p < 0.0001) and fasting insulin (137 ± 94.8 to 121 ± 83.4 pmol/L, p < 0.001) also decreased in participants who attended the final visit. Significant improvements were seen in all measures of PA, self-concept, and anxiety. CHW-SB, a government-funded program, is the first obesity-treatment program to be evaluated in Canada. While short-term evaluation revealed significant improvements in adiposity, PA, and psychological measures, the lack of full follow-up is a limitation in interpreting the clinical effectiveness of this program, as drop-out may be associated with lack of success in meeting program goals. These data also emphasize the need for ongoing evaluation to assess the long-term implications of this unique program and ultimately optimize utilization of governmental resources.

Context: KISS1 is a candidate gene for GnRH deficiency., Objective: Our objective was to identify deleterious mutations in KISS1., Patients and Methods: DNA sequencing and assessment of the effects of rare sequence variants (RSV) were conducted in 1025 probands with GnRH-deficient conditions., Results: Fifteen probands harbored 10 heterozygous RSV in KISS1 seen in less than 1% of control subjects. Of the variants that reside within the mature kisspeptin peptide, p.F117L (but not p.S77I, p.Q82K, p.H90D, or p.P110T) reduces inositol phosphate generation. Of the variants that lie within the coding region but outside the mature peptide, p.G35S and p.C53R (but not p.A129V) are predicted in silico to be deleterious. Of the variants that lie outside the coding region, one (g.1-3659C→T) impairs transcription in vitro, and another (c.1-7C→T) lies within the consensus Kozak sequence. Of five probands tested, four had abnormal baseline LH pulse patterns. In mice, testosterone decreases with heterozygous loss of Kiss1 and Kiss1r alleles (wild-type, 274 ± 99, to double heterozygotes, 69 ± 16 ng/dl; r(2) = 0.13; P = 0.03). Kiss1/Kiss1r double-heterozygote males have shorter anogenital distances (13.0 ± 0.2 vs. 15.6 ± 0.2 mm at P34, P < 0.001), females have longer estrous cycles (7.4 ± 0.2 vs. 5.6 ± 0.2 d, P < 0.01), and mating pairs have decreased litter frequency (0.59 ± 0.09 vs. 0.71 ± 0.06 litters/month, P < 0.04) and size (3.5 ± 0.2 vs. 5.4 ± 0.3 pups/litter, P < 0.001) compared with wild-type mice., Conclusions: Deleterious, heterozygous RSV in KISS1 exist at a low frequency in GnRH-deficient patients as well as in the general population in presumably normal individuals. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.

Question: What advice should I give parents of overweight children about physical activity? How can we encourage these children to become more physically active?, Answer: The Canadian Paediatrics Society 2002 position statement on healthy living for children and youth, which is currently being revised, recommends that physicians advise children and adolescents to increase the time they spend on physical activities by at least 30 minutes a day, with at least 10 minutes involving vigorous activities, and that goals should be reset to reach at least 90 minutes a day of total physical activity. The extent to which children and youth are physically active is influenced by a multitude of complex, interrelated factors. Addressing physical inactivity and its contribution to childhood obesity requires a comprehensive and holistic approach.

Background: Congenital hypothyroidism from thyroid dysgenesis (CHTD) is predominantly a sporadic disease characterized by defects in the differentiation, migration or growth of thyroid tissue. Of these defects, incomplete migration resulting in ectopic thyroid tissue is the most common (up to 80%). Germinal mutations in the thyroid-related transcription factors NKX2.1, FOXE1, PAX-8, and NKX2.5 have been identified in only 3% of patients with sporadic CHTD. Moreover, a survey of monozygotic twins yielded a discordance rate of 92%, suggesting that somatic events, genetic or epigenetic, probably play an important role in the etiology of CHTD., Methodology/principal Findings: To assess the role of somatic genetic or epigenetic processes in CHTD, we analyzed gene expression, genome-wide methylation, and structural genome variations in normal versus ectopic thyroid tissue. In total, 1011 genes were more than two-fold induced or repressed. Expression array was validated by quantitative real-time RT-PCR for 100 genes. After correction for differences in thyroid activation state, 19 genes were exclusively associated with thyroid ectopy, among which genes involved in embryonic development (e.g. TXNIP) and in the Wnt pathway (e.g. SFRP2 and FRZB) were observed. None of the thyroid related transcription factors (FOXE1, HHEX, NKX2.1, NKX2.5) showed decreased expression, whereas PAX8 expression was associated with thyroid activation state. Finally, the expression profile was independent of promoter and CpG island methylation and of structural genome variations., Conclusions/significance: This is the first integrative molecular analysis of ectopic thyroid tissue. Ectopic thyroids show a differential gene expression compared to that of normal thyroids, although molecular basis could not be defined. Replication of this pilot study on a larger cohort could lead to unraveling the elusive cause of defective thyroid migration during embryogenesis.

Maintenance of normal glucose homeostasis is crucial for survival during the perinatal period. Acylated ghrelin (AG) but not unacylated ghrelin (UAG) inhibits insulin release from pancreatic islets in adult rats. Circulating AG concentrations are low in the fetus and progressively increase in the postnatal period. We tested the hypothesis that AG has insulinostatic effects in vitro and in vivo during the perinatal period. In vitro, AG (10(-10)-10(-8) M) caused a 25-53% decrease in insulin secretion by islets from 5-d-old rat pups under normo- and hyperglycemic conditions, an effect that was mediated through the growth hormone secretagogue receptor (GHSR- 1a). Ghrelin (1-5) amide, [Dap3]-octanoyl, a pentapeptide that is resistant to deacylation and binds the GHSR-1a, had similar effects at 10(-8) M. In vivo, AG, UAG, or GHRP-6 [D-Lys3], a GHSR-1a antagonist, did not affect insulin or glucagon concentrations during the first 3 h of life. In 6-d-old pups, AG, UAG, or ghrelin (1-5) amide, [Dap3]-octanoyl did not affect glucose-induced insulin or C-peptide concentrations. In summary, AG has insulinostatic effects in vitro as early as during the perinatal period. These effects could not be confirmed in vivo, possibly due to the short half-life of AG in rat neonates.

Acylated (octanoylated) ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyrylcholinesterase. Acylated and desacyl ghrelin both promote adipogenesis. Ghrelin concentrations decrease with hyperglycemia and hyperinsulinism. We hypothesized that 1) acylated ghrelin increases during pregnancy, contributing positively to energy balance, but is lower in women with gestational diabetes and 2) butyrylcholinesterase activity is inversely correlated with acylated ghrelin concentrations. In a first group of subjects, using two-site sandwich ghrelin assays that specifically detect full-length forms, we investigated women with and without gestational diabetes (n = 14/group) during pregnancy and after delivery. We examined whether changes in ghrelin during a test meal were correlated with changes in pituitary growth hormone [assessed through calculation of the area under the curve (AUC) during the test meal]. In postpartum subjects, the percent of total ghrelin that is acylated was four to five times higher than previously observed using single antibody assays. During pregnancy, acylated ghrelin concentrations (mean +/- SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 +/- 0.2 vs. 10.2 +/- 1.9 ng.ml(-1).90 min(-1), P < 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated (r = 0.50, P = 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 +/- 1.9 vs. 8.6 +/- 1.2 ng.ml(-1).90 min(-1), P = 0.005). In a second group of subjects (n = 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 +/- 0.5 vs. 4.5 +/- 0.6 microg/ml, P = 0.029) and cholinesterase activity (705 +/- 33 vs. 1,013 +/- 56 U/ml, P < 0.001) were lower during pregnancy compared with the postpartum period. In conclusion, acylated ghrelin markedly decreases during pregnancy, likely because of a decrease in the acylation process. Desacyl ghrelin increases in gestational diabetes, possibly reflecting resistance to the inhibitory effect of insulin on ghrelin secretion.

The pancreas is a major source of ghrelin in the perinatal period, whereas gastric production progressively increases after birth. Loss of function of the genes for ghrelin or for the constitutively activated growth hormone secretagogue receptor (GHSR) does not affect birth weight and early postnatal growth. However, ghrl(-/-) or ghsr(-/-) mice fed a high fat diet starting soon after weaning are resistant to diet-induced obesity, suggesting that ghrelin affects the maturation of the metabolic axes involved in energy balance. In addition, animal and human studies suggest that GHSR plays a physiological role in linear growth. In mice, absence of the GHSR gene is associated with lower insulin-like growth factor 1 concentrations and lower body mass in adult animals, independently of food intake. In humans, a mutation of the GHSR gene that impairs the constitutive activity of the receptor was found in two families with short stature. Administration of acylated ghrelin to rat pups directly does not affect weight gain. In contrast, administration of ghrelin to pregnant or lactating rats results in greater fetal weight and postnatal weight gain, respectively, suggesting that maternal ghrelin may stimulate perinatal growth. These data point toward a physiological role for ghrelin and GHSR in growth and/or in the maturation of hormonal systems involved in the regulation of energy balance.

The processing of preproghrelin in the stomach by prohormone convertase (PC) 1/3 produces ghrelin and possibly obestatin. In the neonate, the pancreas is also a major source of ghrelin. We compared the ontogeny of preproghrelin, ghrelin, obestatin, and PCs in the stomach and pancreas from rat embryos (day 21) and neonates (days 1, 6, 13, 21, and 28) by immunohistochemistry. In stomach, preproghrelin positive cells were present from embryonic day 21 and were in excess of ghrelin cells. The number of ghrelin positive cells progressively increased with age. When preproghrelin cells were immunoreactive for ghrelin, they were also immunoreactive for obestatin and PC1/3. In pancreas, we only found 0 to 2 preproghrelin positive cells per islet and each of these cells was also positive for ghrelin and obestatin. None of the ghrelin positive cells stained for insulin, but we observed ghrelin positive/glucagon negative and ghrelin positive/glucagon positive cells. Ghrelin positive cells contained PC1/3 or PC2. In summary, in stomach, an excess of preproghrelin positive cells compared with ghrelin/PC1/3 positive cells suggests that PC1/3 determines preproghrelin processing to ghrelin. In pancreas, the colocalization of PC1/3 or PC2 in ghrelin positive cells points to a role for both PCs in preproghrelin processing.

Objective: Increased physical activity is an integral part of weight loss programs in adolescents. We prospectively investigated the effects of exercise on glucagon-like peptide-1 (GLP-1) concentrations and on appetite markers., Methods and Procedures: Normal weight (NW) and at risk of overweight/overweight (OW) male adolescents (n = 17/gr) underwent five consecutive days of aerobic exercise (1 h/day). A test meal was administered prior to the first exercise session and 36 hours following the last exercise session. GLP-1 and markers of appetite were assessed., Results: GLP-1 concentrations over the course of the test meal were lower in OW compared to NW boys (P < 0.05), while fasting GLP-1 concentrations tended to be lower in OW boys (0.05 < P < 0.1). Exercise caused an increase in the acute GLP-1 response to the liquid meal (from 52 to 78%, P = 0.02) that was similar in NW and OW adolescents. OW adolescents expressed greater restraint compared to NW adolescents (three-factor eating questionnaire, TFEQ) and there was a significant correlation between TFEQ for restraint score and BMI s.d. both before and after exercise intervention (P < 0.015). There was no significant correlation between markers of appetite and GLP-1 concentrations., Discussion: Lower concentrations of GLP-1, a satiety hormone, in OW compared to NW male adolescents support the theory that GLP-1 plays a role in the etiology of overweight. Whether the greater meal-induced, 0-30 min GLP-1 response following exercise is associated with increased satiety, a potentially beneficial effect of exercise, needs to be evaluated in larger studies. Obesity (2008) 16, 202-204. doi:10.1038/oby.2007.39.

Context: Increased physical activity is an integral part of weight loss programs in adolescents. We hypothesized that exercise could affect appetite-regulating hormones and the subjective desire to eat, which could partly explain the poor success rate of the existing interventions., Objective: The objective of this study was to investigate prospectively the effects of exercise on acylated ghrelin (AG) and desacyl ghrelin (DG) concentrations and on appetite., Setting: The setting for this study was a tertiary care center., Participants: Normal-weight [NW; body mass index (mean +/- se), 20.7 +/- 0.5 kg/m2] and overweight (OW; body mass index, 32.4 +/- 1.7) male adolescents (n = 17/group, age 15.3 +/- 0.2 yr) were studied., Intervention: Those studied participated in 5 consecutive days of aerobic exercise (1 h/d)., Main Outcome: Changes in AG and DG concentrations and in appetite during a test meal were studied., Results: Exercise did not significantly affect insulin sensitivity or body weight. Fasting total (AG and DG) ghrelin concentrations were lower in OW (600 +/- 33 pg/ml) compared with NW (764 +/- 33 pg/ml, P < 0.05) boys and were not affected by exercise. In contrast, there was a differential effect of exercise on both AG and DG (P

Triple A syndrome (AAAS, OMIM#231550) is an autosomal recessive condition characterized by adrenal insufficiency, achalasia, alacrima, neurodegeneration and autonomic dysfunction. Mutations in the AAAS gene on chromosome 12q13 have been reported in several subjects with AAAS. Over the last 5 years, we have evaluated six subjects with the clinical diagnosis of AAAS. Three subjects had mutations in the AAAS gene-- including one novel mutation (IVS8+1 G>A)-- and a broad spectrum of clinical presentations. However, three subjects with classic AAAS did not have mutations in the AAAS gene on both alleles. This finding supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded.

To determine whether peptide YY (PYY), ghrelin, glucose-dependent insulinotropic polypeptide (GIP), and satiety responses to food intake are impaired in anorexia or obesity, we studied 30 female adolescents with anorexia nervosa [body mass index (BMI) 16.3 kg/m2], obesity (BMI 34.3 kg/m2), or normal weight (BMI 20.2 kg/m2). PYY, ghrelin, GIP, insulin, and glucose concentrations and four markers of satiety were measured for 240 min after a mixed meal. The area under the curve for glucose was similar in obese (OB) and normal-weight control (C) subjects but was 15% lower in anorexic (AN) subjects. The area under the curve for insulin was 47% lower in AN and 87% higher in OB subjects, compared with C subjects. After the meal, PYY increased significantly in C (+41%, P < 0.05) but not in AN or OB adolescents. Ghrelin concentrations were highest in AN subjects and lowest in the OB group, compared with C subjects and fell significantly by 25% in all three groups. GIP concentrations were lower in AN subjects throughout the test and increased in all three groups after the mixed meal. AN adolescents reported being less hungry than OB and C adolescents. There was a negative correlation between fasting ghrelin (but not PYY or GIP) and BMI and insulin (r2= 0.33) and a positive correlation between the decrease in hunger 15 min after the meal and PYY concentrations at 15 min (r2= 0.20). In conclusion, the blunted PYY response to a meal in OB adolescents suggests that PYY plays a role in the pathophysiology of obesity. Ghrelin is unlikely to play a causal role in anorexia nervosa or obesity. The lower GIP observed in AN subjects despite a similar caloric intake may appropriately prevent an excessive insulin response in these patients.

Ghrelin is an orexigenic peptide secreted mainly by the stomach in adult rats. Ghrelin concentrations increase with fasting and decrease after food intake. Ghrelin is also present in the placenta and in the fetal stomach, but the role of fetal ghrelin remains unclear. In this study, we compared changes in plasma ghrelin, insulin, and glucose concentrations and in ghrelin gene expression in stomach, pancreas, and placenta in response to fasting and feeding in adult nonpregnant rats and in 20-d pregnant dams and their fetuses. Plasma total ghrelin concentrations were three times higher in the fetus than in the dam but did not increase in response to fasting. In contrast to total ghrelin, plasma active ghrelin concentrations wee 50% lower in the fetus compared with the adult pregnant rat. Ghrelin mRNA and total ghrelin were markedly elevated in the fetal pancreas and six to seven times greater than in the fetal stomach but were not affected by fasting. In contrast, fetal pancreas and stomach active ghrelin concentrations increased two to three times after maternal fasting. Ghrelin receptor mRNA was present in all fetal pancreas samples. Placenta ghrelin gene expression was detectable but low. These data raise the possibility that in the fetus, in contrast to the adult, the pancreas and not the stomach is a major source of circulating immunoreactive ghrelin. Furthermore, the presence of a strong ghrelin gene expression and of ghrelin receptor mRNA in the fetal pancreas is intriguing and suggests that ghrelin may play an important role in beta-cell development.

Ghrelin has orexigenic effects. It is present in umbilical cord plasma in full-term neonates, raising the prospect that ghrelin plays a role in fetal and neonatal energy balance. We measured ghrelin in small (SGA), appropriate (AGA), and large (LGA) for gestational age neonates and evaluated whether ghrelin levels are modulated by neonatal insulin and glucose concentrations. Plasma concentrations of ghrelin, insulin, and glucose were measured in cord blood sampled at birth in 123 SGA, AGA, and LGA neonates (gestational age, 24-41 wk) born to mothers with and without diabetes. Ghrelin was detected in samples from all infants. Its concentration was 40% higher in SGA neonates (mean +/- SD, 2436 +/- 657 pg/ml) compared with AGA (1738 +/- 380) and LGA (1723 +/- 269) neonates. There was a positive correlation between ghrelin and gestational age in AGA/LGA (r = 0.23; P < 0.05) and a negative correlation in SGA (r = -0.67; P < 0.005) neonates. Therefore, the difference in ghrelin between SGA and AGA/LGA neonates decreases with advancing gestational age. Birth weight z-score, maternal hypertension, and glucose concentrations were significant determinants of ghrelin concentrations. In conclusion, SGA neonates present with higher umbilical cord ghrelin plasma concentrations than AGA/LGA neonates. Ghrelin may play a physiological role in fetal adaptation to intrauterine malnutrition.

The leptin to fat ratio early in life could contribute to fixing the set point of leptin feedback at the hypothalamic level. Subjects from Asian and Caucasian ethnicities differ in body composition. We tested the hypothesis that anthropometric markers and their relationship to umbilical cord leptin, cortisol and cortisone, DHEAs and oestriol differed between Caucasians and Asians at birth. Birthweight, length, arm, calf and abdominal circumferences, scapular, triceps, quadriceps and abdominal skinfolds were measured in 180 healthy, full-term newborns of Asian and Caucasian ethnicities. Leptin and steroid hormone concentrations were determined in umbilical cord plasma. There was a significant difference in the slope of the regression between leptin and birthweight (p = 0.03) and calf circumference (p = 0.05) between male Caucasian and Asian neonates. In contrast, in female neonates, there was no significant difference (p = 0.099 and p = 0.07 for birthweight and calf circumference, respectively). In addition, while the slopes of the regression plots were not affected by gender in Asian newborns, there was a significant difference between male and female Caucasian newborns (p = 0.006 and p = 0.002 for birthweight and calf circumference, respectively). There was no significant correlation between cord leptin concentrations or anthropometric markers and steroid hormone concentrations. In conclusion, gender and ethnic differences in the relationship between leptin and anthropometric markers are detectable at birth between Asians and Caucasians, two ethnic groups that have been demonstrated to have different body compositions later in life. This may represent the first clinical evidence of a difference in leptin regulation between these two ethnic groups.

Objective: To establish the prevalence of celiac disease (CD) in children with type 1 diabetes in British Columbia., Patients and Methods: Two hundred thirty-three children with type 1 diabetes were prospectively screened for CD using blind testing with the current 'gold standard', immunoglobulin A endomysium antibody (EmA), and the novel immunoglobulin A tissue transglutaminase (tTG) antibody. Those children with positive results were offered small bowel biopsy; a gluten-free diet was recommended if CD was confirmed., Results: Nineteen children were positive for EmA and had an elevated tTG level. One patient from this group was already known to have CD, and the other 18 patients consented to biopsy. One biopsy was normal, three biopsies demonstrated elevated intraepithelial lymphocyte counts with normal morphology and 14 biopsies had morphological changes consistent with CD. Growth parameters were normal in all patients, and nine of 19 children who were positive for EmA were asymptomatic. Seven patients had mild elevation of tTG levels alone. Two children from this latter group had normal biopsies, and five declined biopsy., Conclusions: At least 14 new cases of CD were detected in addition to four known cases, yielding an overall biopsy-confirmed prevalence of CD of 7.7% (18 of 233). The present study confirms that CD is as prevalent in the pediatric type 1 diabetic population in British Columbia as it is in Europe. Serological screening of these children is important because many children have no symptoms or signs suggestive of CD. This study suggests that tTG serology may also be useful in monitoring response and compliance with a gluten-free diet.