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Little is known about the prevalence of negative weight-biased attitudes among Dutch healthcare professionals (HCPs) when treating children and adolescents with obesity and whether interdisciplinary differences are present. Accordingly, we asked Dutch HCPs that treat pediatric patients with obesity to complete a validated 22-item self-report questionnaire about their weight-biased attitudes. In total, 555 HCPs participated from seven different disciplines: 41 general practitioners (GPs), 40 pediatricians, 132 youth healthcare physicians, 223 youth healthcare nurses, 40 physiotherapists, 40 dieticians, and 39 mental health professionals. HCPs from all disciplines reported to experience negative weight-biased attitudes among themselves. Pediatricians and GPs scored highest on negative weight-biased attitudes, including frustrations in treating children with obesity, and feeling less confident and prepared to treat children with obesity. Dieticians scored the least negative weight-biased attitudes. Participants from all groups perceived weight bias expressed by their colleagues, toward children with obesity. These findings are comparable to results reported by adult HCPs from other countries. Interdisciplinary differences were found and underscore the need for more research on contributing factors that impact explicit weight bias among pediatric HCPs.

Background It is unknown whether weight class is associated with impairment of health-related quality of life (HRQOL) for children in the Netherlands. The aim of this study was to explore generic and weight-specific HRQOL in a clinical cohort of children with overweight, obesity or severe obesity aged 4–19 years in the Netherlands. Methods 803 children from three clinical cohorts participated: mean age 11.5 (SD 2.9) years, 61.1% girls. The influence of weight class was explored in a subgroup of 425 children (25.2% with overweight, 32.5% obesity and 42.3% severe obesity), of whom the exact International Obesity Task Force (IOTF) BMI class was known. Generic HRQOL was measured by the PedsQL child report. Weight-specific HRQOL was measured by the IWQOL-Kids child or parent report. Average total, subscale and item scores were reported and the influence of the IOTF BMI class analyzed by multiple linear regression, corrected for age and sex. Results Children with severe obesity had lower generic and weight-specific HRQOL scores than those with obesity or overweight. IOTF BMI class was negatively associated with item scores from all subscales, especially physical, social and emotional problems. Children with overweight reported similar HRQOL total, subscale and item scores to children with obesity.

Objective Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin–stimulating hormone (α-MSH) and desacetyl-α-melanocortin–stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. Methods We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. Results The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. Conclusion The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control.

Background Pediatric obesity is a multifactorial disease characterized by a prolonged imbalance between energy intake and expenditure. In rare cases, it is caused by underlying medical disorders arising from disruptions in the leptin-melanocortin pathway which regulates satiety and energy expenditure. Aim To investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with and without underlying medical causes. Methods This prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic center in which endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity were evaluated. Patients in whom no underlying medical cause was identified were classified as multifactorial obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio measured REE (mREE) vs predicted REE (Schofield equations) was expressed as REE%, with decreased mREE defined as REE% ≤90% and elevated mREE as ≥110%. Additionally, the ratio mREE vs fat-free-mass (FFM) was calculated. Results We included 292 patients, of which 218 (75%) patients had multifactorial obesity and 74 (25%) had an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p0.05). Conclusion In this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Almost half of patients had decreased or elevated mREE. When relating mREE to FFM, no differences were found between children with underlying medical causes versus multifactorial obesity. Thus, our study underlines the importance of measuring REE and relating mREE to FFM in children with early-onset severe obesity with or without underlying medical causes. This knowledge is important for patient-tailored treatment, e.g. personalized dietary or physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m.

Objective Sex differences in disease susceptibility might be explained by sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. However, studies conducted thus far lacked an assessment of Tanner pubertal stage. This study aimed to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism. Methods Participants (n = 218) were enrolled from a population-based Netherlands Twin Register. At the ages of 9, 12 and 17 years, Tanner pubertal stage was assessed and early morning urine samples were collected. Cortisol metabolites were measured with GC-MS/MS and ratios were calculated, representing cortisol metabolism enzyme activities, such as A-ring reductases, 11β-HSDs and CYP3A4. Cortisol production and metabolism parameters were compared between sexes for pre-pubertal (Tanner stage 1), early pubertal (Tanner stage 2–3) and late-pubertal (Tanner stage 4–5) stages. Results Cortisol metabolite excretion rate decreased with pubertal maturation in both sexes, but did not significantly differ between sexes at any pubertal stage, although in girls a considerable decrease was observed between early and late-pubertal stage (P < 0.001). A-ring reductase activity was similar between sexes at pre- and early pubertal stages and was lower in girls than in boys at late-pubertal stage. Activities of 11β-HSDs were similar between sexes at pre-pubertal stage and favored cortisone in girls at early and late-pubertal stages. Cytochrome P450 3A4 activity did not differ between sexes. Conclusions Prepubertally, sexes were similar in cortisol parameters. During puberty, as compared to boys, in girls the activities of A-ring reductases declined and the balance between 11β-HSDs progressively favored cortisone. In addition, girls showed a considerable decrease in cortisol metabolite excretion rate between early and late-pubertal stages. Our findings suggest that the sexual dimorphism in cortisol may either be explained by rising concentrations of sex steroids or by puberty-induced changes in body composition.

Background: Many healthcare professionals (HCPs) feel uncomfortable and incompetent to talk about weight with children with overweight and obesity and their parents. To optimally target interventions that can improve obesity care for children, we assessed the self-efficacy (SE) and perceived barriers (PBs) of Dutch HCPs in regard to talking about weight and lifestyle when treating children with overweight or obesity. In addition, we analyzed interdisciplinary differences.Methods: A newly developed, practice- and literature-based questionnaire was completed by 578 HCPs of 7 different professions. Kruskal-Wallis, t-tests and chi-square tests were used to analyze interdisciplinary differences on SE, PBs and the effort to discuss weight and lifestyle despite barriers. Results: On average for the total group, the reported strength of SE was 7.2 (range 3-10; scale 1-10), and the median number of different PBs was 4.0 (range 0-12; out of 17). The majority of HCPs (94.6%) reported that they perceived one or more barriers.HCPs who perceived too many barriers to discuss the weight and lifestyle of the child in the majority of cases (9.6%), reported a lower SE (mean 6.3), as compared to professionals who were likely to discuss these topics (mean SE 7.3 p < 0.01), although a similar number of PBs. In total, 14.2% (n = 82) of all HCPs either rated their SE below 5 or reported that they did not address weight and lifestyle due to PBs in the majority of cases.Conclusions: Although on average Dutch HCPs rated their self-efficacy fairly good, for a subgroup major improvements are necessary to lower perceived barriers and improve their self-efficacy, aiming to improve the quality of care for Dutch children with obesity.

Introduction: Corticosteroids are widely prescribed and their use has been linked to adverse cardiometabolic outcomes. A pivotal role in the action of corticosteroids is reserved for the glucocorticoid receptor (GR). Here, we assessed the relationship of glucocorticoid sensitivity-altering GR polymorphisms with anthropometrics and metabolic syndrome (MetS) in corticosteroid users. Methods: In this population-based cohort study (Lifelines), we genotyped 10,621 adult participants for GR hypersensitive (1/2 copies BclI and/or N363S) and GR resistant (1/2 copies ER22/23EK and/or 9β) variants. We assessed the relationship between functional GR polymorphisms with BMI, waist circumference (WC), and MetS in users of corticosteroids. Results: Overall corticosteroid use was associated with a significantly higher BMI and WC in GR wild-type (WT) users (BMI, +0.63 kg/m2 [0.09–1.16], p = 0.022; WC, +2.03 cm [0.61–3.44], p = 0.005) and GR hypersensitive (BMI, +0.66 kg/m2 [95% CI, 0.31–1.01]; WC, +2.06 cm [1.13–2.98], both p < 0.001) but not in GR resistant users. Significantly higher WC in GR resistant carriers was observed only for inhaled corticosteroid users. With respect to MetS, again only GR WT users (odds ratio [OR] 1.44 [1.07–1.94], p = 0.017) and GR hypersensitives (OR 1.23 [95% CI, 1.00–1.50], p = 0.046) were more likely to have MetS; even more pronounced in only inhaled corticosteroid users (GR WT users, OR 1.64 [1.06–2.55], p = 0.027; GR hypersensitive users, OR 1.43 [1.08–1.91], p = 0.013). Conclusions: Polymorphisms associated with increased GR sensitivity and WT GR are related to increased BMI, WC, and an increased MetS presence in corticosteroid users, especially of the inhaled types, when compared to nonusers. The adverse effects of corticosteroid use are less pronounced in users harboring GR resistant polymorphisms.

BACKGROUND: Long-term glucocorticoids (HairGC) measured in scalp hair have been associated with body mass index (BMI), waist circumference (WC), and waist-hip-ratio (WHR) in several cross-sectional studies. We aimed to investigate the magnitude, strength, and clinical relevance of these relations across all ages.METHODS: We performed a systematic review and meta-analysis (PROSPERO registration CRD42020205187) searching for articles relating HairGC to measures of obesity. Main outcomes were bivariate correlation coefficients and unadjusted simple linear regression coefficients relating hair cortisol (HairF) and hair cortisone (HairE) to BMI, WC, and WHR.RESULTS: We included k = 146 cohorts (n = 34,342 individuals). HairGC were positively related to all anthropometric measurements. The strongest correlation and largest effect size were seen for HairE-WC: pooled correlation 0.18 (95%CI 0.11-0.24; k = 7; n = 3,158; I2 = 45.7%) and pooled regression coefficient 11.0 cm increase in WC per point increase in 10-log-transformed HairE (pg/mg) on liquid-chromatography-(tandem) mass spectrometry (LC-MS) (95%CI 10.1-11.9 cm; k = 6; n = 3,102). Pooled correlation for HairF-BMI was 0.10 (95%CI 0.08-0.13; k = 122; n = 26,527; I2 = 51.2%) and pooled regression coefficient 0.049 kg/m2 per point increase in 10-log-transformed HairF (pg/mg) on LC-MS (95%CI 0.045-0.054 kg/m2 ; k = 26; n = 11,635).DISCUSSION: There is a consistent positive association between HairGC and BMI, WC, and WHR, most prominently and clinically relevant for HairE-WC. These findings overall suggest an altered setpoint of the hypothalamic-pituitary-adrenal axis with increasing central adiposity.

Introduction Early-onset obesity is a cardinal feature of rare genetic obesity disorders. According to the Endocrine Society guideline, genetic screening is indicated in selected cases with age of onset (AoO) of severe obesity (grade ≥2) Aims To present the detailed BMI characteristics of children and adolescents with rare genetic obesity disorders; to evaluate whether the following growth chart characteristics can aid in assessing which children should be screened for genetic obesity disorders: AoO of obesity, AoO of severe obesity, BMI standard deviation scores (SDS) at yearly age intervals. Methods In this prospective observational study, children with non-syndromic and syndromic genetic obesity disorders treated at our tertiary obesity center were included. Growth measurements from birth onwards were collected. Children with obesity from a population-based cohort study with follow-up until age 10 years were included as an unselected reference cohort. Diagnostic performance (sensitivity [sens], specificity [spec], positive likelihood ratio [LR+], area-under-the-curve [AUC]) for AoO of obesity and severe obesity and for BMI-SDS at yearly age intervals was calculated. Results We included 64 children with genetic obesity disorders (32 non-syndromic, 32 syndromic) and 298 control children with obesity. At intake, median age of children with genetic obesity was 10.5 years (IQR 7.0–14.7) and mean BMI-SDS +3.1 ± 1.1. Median AoO of obesity was 1.2 years (IQR 0.6–3.7) in non-syndromic genetic obesity, 2.1 years (IQR 0.9–4.2) in syndromic genetic obesity, and 3.8 years (IQR 2.3–6.2) in the control population. For non-syndromic genetic obesity, optimal cut-off value for AoO of obesity was ≤1.5 years: sens 0.60, spec 0.88, LR+ 5.22, AUC 0.79 (p Conclusion This study shows that growth charts characteristics such as BMI-SDS and AoO of obesity (grade 1), but not AoO of severe obesity (grade ≥2), could be useful to distinguish between children with genetic obesity disorders and children with obesity from a population-based cohort study. However, all investigated growth charts characteristics showed misclassification, especially in syndromic genetic obesity, indicating that additional clinical features should be present to warrant genetic testing in these children. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

Introduction: COVID-19 lockdown measures have large impact on lifestyle behaviors and well-being of children. The aim of this mixed-methods study was to investigate the impact of COVID-19 lockdown measures on eating styles and behaviors, physical activity (PA), screen time, and health-related quality of life (HRQoL) in children (0–18 years) with severe obesity. Methods: During the first COVID-19 wave (April 2020), validated questionnaires were completed and semi-structured telephone interviews were conducted with parents of children with severe obesity (adult body mass index [BMI]-equivalent ≥35 kg/m2) and/or with the children themselves. Changes in pre-pandemic versus lockdown scores of the Dutch Eating Behavior Questionnaire Children, Pediatric Quality of Life Inventory, and Dutch PA Questionnaire were assessed. Qualitative analyses were performed according to the Grounded Theory. Results: Ninety families were approached of which 83 families were included. Characteristics of the included children were: mean age 11.2 ± 4.6 years, 52% female, mean BMI SD-score +3.8 ± 1.0. Emotional, restrained, and external eating styles, HRQoL, and (noneducational) screen time did not change on group level (all p > 0.05). However, weekly PA decreased (mean difference −1.9 h/week, p = 0.02) mostly in adolescents. In the majority of children, mean weekly PA decreased to ≤2 h/week. Children with high emotional or external eating scores during lockdown or pre-existent psychosocial problems had the lowest HRQoL (p < 0.01). Qualitative analyses revealed an increased demand for food in a significant proportion of children (n = 21), mostly in children n = 15) or improved eating behaviors (n = 11) attributed this to already existing strict eating schemes that they kept adhering to during lockdown. Conclusion: This study shows differing responses to COVID-19 lockdown measures in children with severe obesity. On group level, PA significantly decreased and in substantial minorities eating styles and HRQoL deteriorated. Children with pre-existent psychosocial problems or pre-pandemic high external or emotional eating scores were most at risk. These children and their families should be targeted by health care professionals to minimize negative physical and mental health consequences.

Background Maternal psychopathology during pregnancy is associated with negative outcomes in offspring. Increased placental transfer of maternal cortisol may contribute to mediate this association. Hair cortisol concentrations (HCCs) appear to be a good biomarker of long-term prenatal stress exposure. Little is known about the associations between severe maternal psychopathology and perinatal infant HCCs. Aims We assessed HCCs in the perinatal period in mother–infant dyads with and without severe psychiatric disorders. Method We examined group differences in HCCs of mother–infant dyads (n = 18) subjected to severe maternal psychiatric disorders versus healthy control dyads (n = 27). We assessed the correlation of HCCs between mother and infant within both groups, and the association between current maternal symptoms and HCCs in patient dyads. Results Median (interquartile range) and distribution of HCC differed in patients compared with control mothers (U = 468.5, P = 0.03). HCCs in infants of patients did not differ from control infants (U = 250.0, P = 0.67). Subsequently, we found that HCCs within healthy control dyads were correlated (n = 27, r 0.55 (0.14), P = 0.003), but were not within patient dyads (n = 18, r 0.082 (0.13), P = 0.746). HCCs in infants of patients showed a positive correlation with maternal symptoms (n = 16, r = 0.63 (0.06), P = 0.008). Conclusions These preliminary findings suggest that infant HCC reflect perinatal stress exposure. In infants, these early differences could influence lifetime hypothalamic–pituitary–adrenal axis functioning, which might be associated with increased susceptibility to later disease.

Objective Sex-specific differences in hypothalamic–pituitary–adrenal axis activity might explain why male preterm infants are at higher risk of neonatal mortality and morbidity than their female counterparts. We examined whether male and female preterm infants differed in cortisol production and metabolism at 10 days post-partum. Design and methods This prospective study included 36 preterm born infants (18 boys) with a very low birth weight (VLBW) ( Results No differences between sexes were found for cortisol excretion rate, corticosteroid excretion rate or 11B-HSD activity. Interaction was observed between: sex and SNAPPE II score on 11B-HSD activity (P = 0.04) and sex and BPD on cortisol excretion rate (P = 0.04). Conclusion This study did not provide evidence for sex-specific differences in adrenocortical function in preterm VLBW infants on a group level. However, in an interaction model, sex differences became manifest under stressful circumstances. These patterns might provide clues for the male disadvantage in neonatal mortality and morbidity following preterm birth. However, due to the small sample size, the data should be seen as hypothesis generating.

Summary Recent studies report negative mental health effects of the COVID‐19 related lockdown measures in general paediatric cohorts. Since obesity is a risk factor for COVID‐19 in adults, children (including adolescents) with obesity might perceive themselves to be vulnerable. Using a combined quantitative and qualitative approach, we explored COVID‐19 related anxiety in paediatric patients with severe obesity in the Netherlands using semi‐structured telephone interviews and the Paediatric Quality of Life Inventory (PedsQL) questionnaire, which had also been completed by the study population at baseline in the year prior to the COVID‐19 outbreak. In total, 75 families participated in the semi‐structured telephone interviews during the lockdown, April 2020. Characteristics of included patients were: median age 10.5 years (interquartile range = 7.6‐15.2); 52% female; mean BMI standard deviation score 3.8 (SD = 1.0). COVID‐19 related anxiety was reported for 24/75 (32%) children. The mean decrease in PedsQL score between baseline visit and COVID‐19 outbreak did not differ between children for whom anxiety was reported vs those for whom it was not (mean change −10.3 ± 36.5 vs −3.3 ± 24.4, P = .54). Self‐imposed strict quarantine measures were taken by 19/75 (25%) families. During follow‐up, several families reported that the previous contact alleviated their anxiety. In conclusion, healthcare professionals should address possible COVID‐19 related anxiety in children with severe obesity. Addressing COVID‐19 related anxiety could mitigate its potential negative effects.

Purpose In previous studies, associations between breast-milk cortisol levels obtained on one occasion and infant neurodevelopment were demonstrated. However, more recent evidence indicates that breast-milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis, peaking in the early morning and with a nadir at midnight. We studied associations between breast-milk glucocorticoid (GC) rhythmicity, and infant behavior and sleep. Methods We included 59 mothers, and their infants, of whom 17 had consulted an expert center during pregnancy for an increased risk of psychological distress. At 1 month postpartum, breast milk was sampled (on average six times) over a 24 h period for assessment of cortisol and cortisone using LC-MS/MS, and experienced maternal distress was assessed using the Hospital Anxiety and Depression Scale questionnaire. Three months after birth, infant behavior was assessed with the Infant Behavior Questionnaire, and infant sleep pattern was quantified by questionnaire. Associations between breast-milk GC rhythm parameters (maximum, delta, and Area Under the Curve increase and ground) and infant behavior and sleep were tested with linear regression analyses. Results No consistent associations between breast-milk GC rhythm parameters and infant behavior or sleep were found. Conclusions Breast-milk GC rhythmicity at 1 month postpartum was not associated with infant behavior or sleep at the age of 3 months. Findings from previous studies linking breast-milk cortisol to infant neurodevelopment might be biased by the lack of GC measurements across the full diurnal cycle, and should therefore be interpreted with caution.

Context The hypothalamus-pituitary-adrenal (HPA) axis displays a diurnal rhythm. However, little is known about its development in early life. Objective To describe HPA-axis activity and study possible influencing factors in 1-month-old infants. Design Observational. Setting Amsterdam University Medical Center, location VU University Medical Center (VUMC), and Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam. Participants Fifty-five mother-infant pairs. Interventions Collection of breast milk and infants’ saliva 1 month postpartum for analysis of glucocorticoids (GCs; ie, cortisol and cortisone) using liquid chromatography– tandem mass spectrometry. Main Outcome Measure GC rhythm in infants’ saliva and associations with vulnerability for maternal psychological distress (increased Hospital Anxiety and Depression Scale [HADS] score) or consultation at the Psychiatric Obstetric Pediatric (POP clinic), season at sampling, sex, and breast milk GC rhythmicity analyzed with SigmaPlot 14.0 software (Systat Software, San Jose, CA, USA) and regression analyses. Results A significant biphasic GC rhythm was detected in infants, with mean peaks [standard error of the mean, SEM] at 6:53 am [1:01] and 18:36 pm [1:49] for cortisol, and at 8:50 am [1:11] and 19:57 pm [1:13] for cortisone. HADS score, POP consultation, season at sampling, and sex were not associated with the infants’ GC rhythm. Breast milk cortisol maximum was positively associated with infants’ cortisol area-under-the-curve (AUC) increase and maximum. Higher breast milk cortisone AUC increase, AUC ground, and maximum were associated with an earlier maximum in infants. Breast milk and infant GC concentrations were associated between 6:00 am and 9:00 am. Conclusions A biphasic GC rhythm, peaking in the morning and evening, was seen in 1-month-old infants at a group level. Breast milk GC parameters might be associated with the infants’ GC rhythm, possibly caused by a signaling effect of breast milk GCs, or as an associative effect of increased mother-infant synchrony. These results contribute to an increased understanding of early life HPA-axis development.

Context Obesity and cardiometabolic diseases are associated with higher long-term glucocorticoid levels, measured as scalp hair cortisol (HairF) and cortisone (HairE). Cardiometabolic diseases have also been associated with copeptin, a stable surrogate marker for the arginine-vasopressin (AVP) system. Since AVP is, together with corticotropin-releasing hormone (CRH) an important regulator of the hypothalamic-pituitary adrenal axis (HPA axis), we hypothesize that AVP contributes to chronic hypercortisolism in obesity. Objective To investigate whether copeptin levels are associated with Higher HairF and HairE levels in obesity. Design A cross-sectional study in 51 adults with obesity (BMI ≥30 kg/m2). Methods Associations and interactions between copeptin, HairF, HairE, and cardiometabolic parameters were cross-sectionally analyzed. Results Copeptin was strongly associated with BMI and waist circumference (WC) (rho = 0.364 and 0.530, P = 0.008 and Conclusion In patients with obesity, AVP seems not a major contributor to the frequently observed high cortisol levels. Other factors which stimulate the HPA axis or affect cortisol synthesis or breakdown may be more important than the influence of AVP on long-term glucocorticoid levels in obesity.

BackgroundUnderlying medical causes of obesity (endocrine disorders, genetic obesity disorders, cerebral or medication-induced obesities) are thought to be rare. Even in specialized pediatric endocrinology clinics, low diagnostic yield is reported, but evidence is limited. Identifying these causes is vital for patient-tailored treatment.ObjectivesTo present the results of a systematic diagnostic workup in children and adolescents referred to a specialized pediatric obesity center.MethodsThis is a prospective observational study. Prevalence of underlying medical causes was determined after a multidisciplinary, systematic diagnostic workup including growth charts analysis, extensive biochemical and hormonal assessment and genetic testing in all patients.ResultsThe diagnostic workup was completed in n = 282 patients. Median age was 10.8 years (IQR 7.7-14.1); median BMI +3.7SDS (IQR +3.3-+4.3). In 54 (19%) patients, a singular underlying medical cause was identified: in 37 patients genetic obesity, in 8 patients cerebral and in 9 patients medication-induced obesities. In total, thirteen different genetic obesity disorders were diagnosed. Obesity onset ConclusionsTo our knowledge, this is the first study to report the results of a systematic diagnostic workup aimed at identifying endocrine, genetic, cerebral or medication-induced causes of pediatric obesity. We found that a variety of singular underlying causes were identified in 19% of the patients with severe childhood obesity. Because of this heterogeneity, an extensive diagnostic approach is needed to establish the underlying medical causes and to facilitate disease-specific, patient-tailored treatment.

Introduction: During the COVID-19 pandemic, lockdown measures were implemented with large impact on lifestyle behaviors and well-being of children (including adolescents). The impact on children with severe obesity, who plausibly are at even larger risk, has not yet been described. Aim of this study was to investigate the impact of COVID-19 lockdown on eating behaviors, physical activity, screen time and quality of life (QoL) of children with severe obesity. Methods: In this mixed-methods study, questionnaires and semi-structured telephone interviews were used to investigate impact of COVID-19 during the first wave in the Netherlands (April 2020) on children with severe obesity (adult BMI-equivalent ≥35kg/m2) treated at our obesity center. The Dutch Eating Behavior Questionnaire - Child, Pediatric Quality of Life Inventory, and Dutch Physical Activity Questionnaire were filled out by their families pre-pandemic and during lockdown. Changes over time in percentile scores, weekly physical activity and screen time were assessed. Qualitative analyses were performed according to the Grounded Theory. Results: We included 83 families, of which 75 participated in the interviews. Their children’s characteristics were mean age 11.5years (SD 4.6), 52% female, mean BMI SD score 3.8 (SD 1.0), indicating severe obesity. On group level, no changes in scores for emotional, restrained, external eating, and QoL nor in screen time were observed (Δ scores +9.2, +3.9, +0.3; and +3.0, respectively; -0.3 hr/wk; all p>0.05). Weekly physical activity decreased (Δ -1.9 hr/wk, p=0.02). Age, pre-existent psychosocial problems and pre-pandemic questionnaire scores were associated with improved or deteriorated questionnaire scores in specific subgroups. For example, children who did not fulfill WHO physical activity criteria pre-pandemic showed a further decline from 2.8 to 0.7 h/wk (p=0.001). Children with high emotional and external eating during lockdown had the lowest QoL scores (p-values Conclusion: This study shows differential response profiles to COVID-19 lockdown in children with severe obesity. Although on group level lifestyle scores averaged out, a substantial part of families reported deterioration in physical activity and eating behaviors. Children with pre-existent psychosocial problems, high external or emotional eating scores were most at risk. Health care professionals should target these vulnerable children to minimize short- and long-term negative physical and mental health consequences.

Introduction: Hypothalamic obesity (HO) in children can be either genetic or acquired, as a result of a suprasellar tumor or its treatment. HO, resulting from hyperphagia and/or a decreased resting energy expenditure (REE), may have devastating consequences for the child and its family. Currently, no effective drug treatment is yet available for HO. Amphetamines – commonly used in children with attention-deficit/hyperactivity disorder – are known for their stimulant effect on REE and inhibitory effect on appetite. We here present our experiences of dextroamphetamine treatment in children and adolescents with acquired or genetic HO. Methods: A retrospective cohort evaluation was performed of patients (n = 18) treated with dextroamphetamine at 2 endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive therapy resistant acquired HO (n = 13) and in patients with genetic obesity (n = 5). Initial treatment dosing was once or twice daily 5mg. This dose was weekly increased with 5 mg/day depending on the patient’ wellbeing and the presence of side effects, to a maximum of 0.5 mg/kg/day. Anthropometrics and REE at start and during follow-up, changes in (hyperphagic) behavior, and side effects were assessed. Results: At start of treatment, mean age was 12.8 years ± 3.4 [range 7.1–17.9] and mean REE was 69.5%± 18.5 (n = 15). At follow-up, mean treatment duration was 18.3 months ± 14.7. Ten out of eighteen children (55.6%) showed clinically relevant weight loss. In 10/13 patients with acquired HO, weight loss was observed (mean ΔBMI SDS -1.09 ± 1.00), in one patient BMI stabilization (ΔBMI SDS +0.03), and in two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.32 ± 0.05). Of nine children with acquired HO and measurement of REE before and during treatment, a mean REE increase of +15.3% ± 10.5 was observed. In three out of five patients with genetic obesity, initially weight loss was observed resulting in BMI stabilization at end of follow-up due to weight regain (mean ΔBMI SDS -0.08 ± 0.19). In these patients, no difference in REE before and during treatment was observed. In two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.29 ± 0.25). However, one patient discontinued treatment after one month, due to hypertension. Thirteen out of 18 children (72.2%) reported improvement of either their hyperphagia, energy level, and/or behavior. No serious side effects were reported. Conclusion: In children and adolescents with acquired HO, treatment with dextroamphetamine may significantly lower BMI, reduce hyperphagia and improve activity level. In genetic HO, these effects were less pronounced. Future studies in a larger cohort and with randomized controlled designs are needed to support these results.

Introduction: Obesity is highly prevalent, comes with serious health burden and is difficult to treat. In a minority, there is a genetic cause for the obesity. In these patients, therapy-resistant obesity is often observed despite intensive lifestyle treatment. Moreover, it is still unclear whether bariatric surgery is less successful in genetic obesity. Liraglutide is a Glucagon-Like-Peptide-1 (GLP-1) receptor agonist or GLP-1 analogue, showing positive effects on metabolic parameters, satiety and weight loss in lifestyle-induced obesity. We present our experiences of GLP-1 analogue treatment in patients with genetic obesity disorders. Methods: Adults with overweight or severe obesity and a molecularly proven genetic cause were treated with liraglutide 3,0 mg daily, in addition to ongoing intensive supportive lifestyle treatment. Anthropometrics, metabolic parameters, resting energy expenditure (REE), side effects, and subjectively reported satiety and quality of life were assessed. Results: Two patients with a heterozygous pathogenic melanocortin 4 recepter variant and two patients with 16p11.2 deletion syndrome, ranging in age between 21 and 32 years and in BMI between 28.1 and 55.7 kg/m2 at baseline, were treated. At end of follow-up, ranging between 33 weeks and 12 years, a mean change in BMI and waist circumference was observed of -5.7 ± 3.8 kg/m2 and -15.2 ± 21.1 cm, respectively. All patients reported better quality of life, three of them also reported improved satiety. Moreover, improvement of metabolic parameters was seen. No clear effect on REE was observed. Two patients experienced mild side effects, e.g. nausea and stomach pain, for a brief period. Conclusion: We here show beneficial effects of GLP-1 analogues on weight, metabolic parameters, and quality of life in four patients with genetic obesity. Satiety improved in three of the four patients. All patient achieved at least the clinically relevant 5–10% weight loss. Our findings suggest that GLP-1 analogue treatment might be an effective treatment option, in addition to a healthy lifestyle, for patients with genetic obesity.

Background Glucocorticoids (GCs) measured in neonatal hair might reflect intrauterine as well as postpartum GC regulation. We aimed to identify factors associated with neonatal hair GC levels in early life, and their correlation with maternal hair GCs. Methods In a single-center observational study, mother–infant pairs (n = 107) admitted for >72 h at the maternity ward of a general hospital were included. At birth and an outpatient visit (OPV, n = 72, 44 ± 11 days postpartum), maternal and neonatal hair was analyzed for cortisol and cortisone levels by LC–MS/MS. Data were analyzed regarding: (1) neonatal GC levels postpartum and at the OPV, (2) associations of neonatal GC levels with maternal GC levels and (3) with other perinatal factors. Results (1) Neonatal GC levels were >5 times higher than maternal levels, with a decrease in ±50% between birth and the OPV for cortisol. (2) Maternal and neonatal cortisol, but not cortisone, levels were correlated both at postpartum and at the OPV. (3) Gestational age was associated with neonatal GC postpartum (log-transformed β (95% CI): cortisol 0.07 (0.04–0.10); cortisone 0.04 (0.01–0.06)) and at the OPV (cortisol 0.08 (0.04–0.12); cortisone 0.00 (−0.04 to 0.04)), while weaker associations were found between neonatal GCs and other perinatal and maternal factors. Conclusions Neonatal hair GCs mainly reflect the third trimester increase in cortisol, which might be caused by the positive feedback loop, a placenta-driven phenomenon, represented by the positive association with GA. Between birth and 1.5 months postpartum, neonatal hair cortisol concentrations decrease sharply, but still appear to reflect both intra- and extrauterine periods.

Vertical transmission of glucocorticoids via breast milk might pose a mechanism through which lactating women could prepare their infants for the postnatal environment. The primary source of breast milk glucocorticoids is probably the systemic circulation. Research from our group showed that milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis activity, with a higher abundance of cortisone compared to cortisol. Measurement of breast-milk glucocorticoid concentrations is challenging due to possible cross-reactivity with progestagens and sex steroids, which are severely elevated during pregnancy and after parturition. This requires precise methods that are not hindered by cross reactivity, such as LC-MS/MS. There are some data suggesting that breast-milk glucocorticoids could promote intestinal maturation, either locally or after absorption into the systemic circulation. Breast-milk glucocorticoids might also have an effect on the intestinal microbiome, although this has not been studied thus far. Findings from studies investigating the systemic effects of breast-milk glucocorticoids are difficult to interpret, since none took the diurnal rhythm of glucocorticoids in breast milk into consideration, and various analytical methods were used. Nevertheless, glucocorticoids in breast milk might offer a novel potential pathway for signal transmission from mothers to their infants. (C) 2017 Elsevier Ltd. All rights reserved

Background: Many very preterm (i.e., Summary: Studies suggested that very preterm newborns have impairments along multiple levels of the hypothalamus-pituitary-adrenal (HPA) axis. Among the impairment were defects in: (1) the pituitary responsiveness to exogenous corticotropin-releasing hormone, (2) 11β-hydroxylase activity, and (3) the interconversion between cortisol and inert cortisone. There is some evidence suggesting that later in life these infants have an increased basal secretion rate of cortisol and adrenal hyperandrogenism. However, the response to acute (psychosocial) stress was blunted rather than enhanced in them. The mechanisms explaining this switch in HPA axis activity are complex and not yet fully understood. Key Messages: Very preterm newborns have several impairments along the HPA axis that could impede an adequate adrenocortical response to stress or illness. Later in life, these infants are predisposed to increased HPA axis activity, which could partially explain their phenotype.

Objective: Glucocorticoids (GCs) in breastmilk have previously been associated with infant body growth and body composition. However, the diurnal rhythm of breastmilk GCs was not taken into account, and we therefore aimed to assess the associations between breastmilk GC rhythmicity at 1 month and growth and body composition at 3 months in infants. Methods: At 1 month postpartum, breastmilk GCs were collected over a 24-h period and analyzed by LC-MS/MS. Body composition was measured using air-displacement plethysmography at 3 months. Length and weight were collected at 1, 2, and 3 months. Results: In total, 42 healthy mother&ndash, infant pairs were included. No associations were found between breastmilk GC rhythmicity (area-under-the-curve increase and ground, maximum, and delta) and infant growth trajectories or body composition (fat and fat free mass index, fat%) at 3 months. Conclusions: This study did not find an association between breastmilk GC rhythmicity at 1 month and infant&rsquo, s growth or body composition at 3 months. Therefore, this study suggests that previous observations linking breastmilk cortisol to changes in infant weight might be flawed by the lack of serial cortisol measurements and detailed information on body composition.

Finding new ways to reach sustainable weight reduction, which are suitable for daily practice, is important. In this commentary we discuss the article by Astbury et al. suggesting that a total diet replacement (TDR) programme in a primary care setting is safe and effective. We raise some important questions about the limited duration of the study, lack of clarity about additionally provided behavioural coaching and/or exercise in the intervention group vs the usual care control group, as well as the potential effects of low calorie dieting on muscle mass. Although other studies using meal replacements do not show an additional benefit compared to interventions based on a balanced diet with behavioural therapy, the results after this 52-week study are promising. However, longer-term follow-up and external validation is needed. Moreover, the large variation in results between participating centres shows that it is not a matter of "one size fits all" when it comes to successful dieting.

Background: Long-term glucocorticoid levels measured in scalp hair (HairGC) are positively correlated to obesity in cross-sectional studies, however it is unclear whether this reflects a state of obesity or an actual maintaining or contributing factor to obesity. Objectives: To investigate whether hair cortisol (HairF) and hair cortisone (HairE) predict changes in body mass index (BMI) and waist circumference (WC) over time, and to assess whether HairGC are linked to immune parameters. Methods: We measured HairGC in 1604 participants of the Netherlands Study of Depression and Anxiety (NESDA), and correlated these to BMI, WC, and immune parameters (interleukin-6 (IL-6), high-sensitive C-reactive protein (CRP), total leukocyte, monocyte and lymphocyte counts and the neutrophil-to-lymphocyte ratio). Also, we assessed whether baseline HairGC predict changes in BMI and WC at the follow-up visit, three years later, and whether immune parameters influenced this correlation. Results: In cross-sectional analyses, HairF and HairE were positively correlated to BMI (β=2.06 and β=2.84kg/m2 respectively) and WC (β=5.36 and β= 8.54cm respectively, all p

Very preterm (i.e.

BACKGROUND Very preterm infants often receive donor milk from mothers who deliver at term, but its composition differs from that of their own mother's milk. Because breast-milk glucocorticoids can support developing neonates, we explored concentration variability within and between mothers. OBJECTIVE We hypothesized that breast-milk glucocorticoid concentrations would be higher after very preterm delivery [gestational age (GA)

Preterm survivors exhibit neurodevelopmental impairments. Whether this association is influenced by antenatal glucocorticoid treatment and glucocorticoid sensitivity is unknown.This study aimed to study the effects of antenatal glucocorticoid treatment and glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) polymorphisms on behavior and intelligence quotient (IQ).This study was part of the 19-year follow-up of the Project On Preterm and Small-for-gestational-age birth cohort.Multicenter study.Three hundred forty-four 19-year-olds born very preterm (gestational age32 wk), of whom 71 had received betamethasone antenatally.Single antenatal treatment course of betamethasone.Behavior (Young Adult Self Report and Young Adult Behavior Checklist for parents) and IQ (digital Multicultural Capacity Test-intermediate level). Data were analyzed by linear regression and presented as regression coefficient (95% confidence interval [CI]).Sex ratio, GR (R23K; N363S) and MR (-2G/C; I180V) genotypes were equally distributed between treated and nontreated subjects. Independent of treatment, R23K carriers had improved IQ scores (β 9.3; 95% CI, 3.4 to 15.1) and a tendency toward more favorable total problem behavior scores (β -8.5; 95% CI, -17.3 to 0.2) ; -2G/C CC carriers had poorer IQ scores (β -6.2; 95% CI, -10.5 to -1.9); I180V carriers had more favorable internalizing behavior scores (β -2.0; 95% CI, -3.9 to -0.1). Antenatal glucocorticoid treatment was associated with more unfavorable behavior scores, especially internalizing behavior (β 2.4; 95% CI, 0.3 to 4.5). Interaction between GR and MR polymorphisms and antenatal glucocorticoid treatment was observed, with poorer IQ scores for exposed N363S carriers; poorer intellectual subdomain scores for exposed I180V-carriers; more favorable total problem behavior scores for exposed R23K carriers.Genetic variations in glucocorticoid sensitivity and antenatal glucocorticoid treatment are associated with IQ and behavior in young adult preterm survivors.

Background Preterm birth has been associated with altered hypothalamic-pituitary-adrenal (HPA-) axis activity as well as cardiometabolic diseases and neurodevelopmental impairments later in life. We assessed cortisol from term age to age 8 y in children born preterm, to explore the development of HPA-axis activity in association with intrauterine and early-postnatal growth until 6 mo. corrected age. Methods In 152 children born at a gestational age ≤32 wks. and/or with a birth weight ≤1,500 g, random serum cortisol was assessed at term age (n = 150), 3 mo. (n = 145) and 6 mo. corrected age (n = 144), and age 8 y (n = 59). Salivary cortisol was assessed at age 8 y (n = 75): prior to bedtime, at awakening, 15 min after awakening, and before lunch. Cortisol was analyzed in association with birth weight-standard deviation score (SDS), being born small for gestational age (SGA), and combinations of intrauterine and postnatal growth: appropriate for gestational age (AGA) with or without growth restriction (AGA GR+ or AGA GR−) at 6 mo. corrected age, and SGA with or without catch-up growth (SGA CUG+ or SGA CUG−) at 6 mo. corrected age. Cross-sectional associations at all time points were analyzed using linear regression, and longitudinal associations were analyzed using generalized estimating equations. Results Longitudinally, birth weight-SDS was associated with cortisol (β [95%CI]): lower cortisol over time was seen in infants with a birth weight ≤−2 SDS (−50.69 [−94.27; −7.11], p = 0.02), infants born SGA (−29.70 [−60.58; 1.19], p = 0.06), AGA GR+ infants (−55.10 [−106.02; −4.17], p = 0.03) and SGA CUG− infants (−61.91 [−104.73; −19.10], p = 0.01). In cross-sectional analyses at age 8 y, no associations were found between either serum or salivary cortisol and birth weight-SDS, SGA-status, or growth from birth to 6 mo. corrected age. Conclusion In children born preterm, poor intrauterine and postnatal growth were associated with lower cortisol in early infancy, but not at age 8 y. Even though HPA-axis activity no longer differed between groups at age 8 y, or differences could not be confirmed due to attrition, it is unknown whether the differences found in early infancy could attribute to increased health risks later in life.

Background In adults, hypothalamus–pituitary–adrenal (HPA) axis activity shows sexual dimorphism, and this is thought to be a mechanism underlying sex-specific disease incidence. Evidence is scarce on whether these sex differences are also present in childhood. In a meta-analysis, we recently found that basal (non-stimulated) cortisol in saliva and free cortisol in 24-h urine follow sex-specific patterns. We explored whether these findings could be extended with sex differences in HPA axis reactivity. Methods From inception to January 2016, PubMed and EMBASE.com were searched for studies that assessed HPA axis reactivity in healthy girls and boys aged ≤18 years. Articles were systematically assessed and reported in the categories: (1) diurnal rhythm, (2) cortisol awakening response (CAR), (3) protocolled social stress tests similar or equal to the Trier Social Stress Test for children (TSST-C), (4) pharmacological (ACTH and CRH) stress tests, and (5) miscellaneous stress tests. Results Two independent assessors selected 109 out of 6158 records for full-text screening, of which 81 studies (with a total of 14,591 subjects) were included. Studies showed that girls had a tendency towards a more variable diurnal rhythm (12 out of 29 studies), a higher CAR (8 out of 18 studies), and a stronger cortisol response to social stress tests (9 out of 21 studies). We found no evidence for sex differences in cortisol response after a pharmacological challenge or to miscellaneous stress tests. Discussion Sex differences in HPA axis reactivity appear to be present in childhood, although evidence is not unequivocal. For a better evaluation of sex differences in HPA axis reactivity, standardization of protocols and reports of stress tests is warranted. Electronic supplementary material The online version of this article (doi:10.1186/s13293-017-0144-8) contains supplementary material, which is available to authorized users.