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Children with autism and their parents face daily challenges that may be stressful for both. However, little is known about biological stress (hair cortisol concentrations [HCC]) in these families and its connection to children's health outcomes. This study investigates biological stress in children with autism and their parents and its associations with child mental health, eating behavior and BMI. Stress was measured in 102 young children with autism and their parents (101 mothers, 86 fathers) using HCC and self-reported parenting stress (OBVL). Child mental health was measured through autism symptoms (ADOS-2, SRS-2) and problem behavior (CBCL). Child eating behavior (CEBQ) and BMIz were also measured. Children with autism had higher HCC than their peers. Child HCC was not linked to mental health, eating behavior, or BMIz. Maternal stress (self-reported and HCC) was associated with child problem behavior. In fathers, self-reported parenting stress correlated with child autism symptoms (SRS-2) and behavior problems. Both parents' self-reported stress was associated with child eating behavior, specifically emotional undereating and overeating. In conclusion, higher HCC levels in children with autism in comparison to children from the general population, suggest differences in stress-regulation in children with autism. Given these findings, monitoring HCC in research and clinical practice could improve our understanding of stress-regulation in children with autism. The association between parental stress and children's mental health and eating behaviors, underscores the importance of considering family dynamics in clinical (preventive) interventions and in further research that addresses the mental and physical health of children with autism., Competing Interests: Declarations. Conflict of Interest: The authors have no conflicts of interest to declare that are relevant to the content of this article., (© 2024. The Author(s).)

Context: The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well as its constitutive activity, enhances GH secretion. Studies in knock-out mice suggest that heterozygous loss-of-function of GHSR is associated with decreased GH response to fasting, but patient observations in small case reports have been equivocal., Objective: To establish the phenotype of GHSR haploinsufficiency and their growth response to GH treatment., Methods: This case series includes 26 patients with short stature and heterozygous GHSR variants. Pathogenicity was studied in vitro using total protein levels, cell surface expression, and receptor activity in basal, stimulated and inhibited states., Results: Ten different variants were identified, of which six were novel. Variants showed either partial or complete loss-of-function, primarily through loss of constitutive activity. Patients (4.0-15.1 years) had proportionate short stature (height -2.8±0.5 SDS), failure to thrive with low appetite (n=4), a mean serum insulin growth factor I (IGF-I) of -1.6±0.7 SDS, and a normal stimulated GH response. Nine patients received GH treatment, showing a height gain of 0.9±0.4 SDS after 1 year and 1.5±0.4 SDS after 2 years (n=5)., Conclusion: This study combines phenotypical and functional data in a uniquely large group of children with short stature carrying GHSR variants, and shows their good response to GH treatment. The results strengthen the hypothesis of GHSR's role in GH secretion., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies., Competing Interests: Competing interests The development of this work was made without external financial support from industries involved in the manufacturing of therapies for BBS. Competing interests of members of the guideline development group have been recorded in writing and addressed. HD has consulted for Novartis, Rhythm Pharmaceuticals, Jansen Pharmaceutical, GenSight Biologics and Sparing Vision. JK, DL, AG, MMVH and JM have consulted for Rhythm Pharmaceuticals. EVDA’s institute was the recipient of a research grant from Rhythm Pharmaceuticals. MC is a principal investigator for the RM-IMC-901 study (a Registry of Patients with Biallelic Proopiomelanocortin (POMC), Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1), or Leptin Receptor (LEPR) Deficiency Obesity, or Bardet-Biedl Syndrome (BBS), Treated with Setmelanotide) and received payments for lectures, expert testimony and consulting fees and study support from Rhythm Pharmaceuticals; MC also received payments for lectures from Canon Medical Systems. CB is the medical and managing director of Medizinische Genetik Mainz and Limbach Genetics. BPL has consulted for Novartis, Jansen Pharmaceutical, GenSight Biologics and Sparing Vision. CP has consulted for Rhythm Pharmaceuticals and Novo Nordisk. SR has consulted for Rhythm Pharmaceuticals, Sandoz and Novo Nordisk. MRL, PM, AV, GMB, MGP, FT, MFS, FS, AG, MZ, HM, AMVE, DM, AS, DV, have no competing interests to declare., (© 2024. The Author(s).)

Background: Both the causes and consequences of childhood obesity can be complex. To provide healthcare that is suitably tailored to the specific needs of children with obesity integrated care is required. The objective of this study was to explore the perceived barriers and facilitators of healthcare professionals (HCPs) in providing integrated care for children with obesity, to support them in tailoring the healthcare approach., Methods: In this qualitative study, semi-structured in-depth interviews were conducted with 18 healthcare professionals with experience in childhood obesity care; pediatricians, youth healthcare nurses and a youth healthcare physician. A two-phased thematic content analysis was performed: an inductive analysis with open and selective coding and a deductive analysis with axial coding using the patient-centered care model by Stewart., Results: Overall, the healthcare professionals defined the etiology of obesity as complex, and experienced the integrated care as complicated. The results fit into the four theme-structure of the patient-centered care model, with the integrated care system as an additional fifth theme. The main barriers were perceived within the sub-themes of illness and healthcare experiences, and sensitivity over talking about weight-related issues. The main facilitators were perceived within the sub-themes of conducting a biomedical, psychosocial and lifestyle assessment, tailoring the approach to families' situation and investing in a family-professional relationship. Weight stigma appeared to be an underlying barrier for healthcare professionals that impacted, both explicitly and implicitly, upon all themes., Conclusions: Healthcare professionals providing integrated care for children with obesity, experience this type of care as complicated and comprising many barriers and facilitators regarding the four themes of the patient-centered care model and the fifth theme of the integrated care system. This paper demonstrates the patient-centered care model could prove helpful structuring a tailored approach within integrated care. This approach supports healthcare professionals in adopting a broad perspective towards individual and environmental factors and investing in the relationship, with respect to the sensitivity and complexity of childhood obesity., (© 2024. The Author(s).)

Context: The melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity., Objective: We have identified 17 MC4R variants in adult and pediatric patients with obesity. Here we aimed to functionally characterize these variants by analyzing 4 different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants., Materials and Methods: Cell surface expression and α-melanocyte stimulating hormone (α-MSH)- or setmelanotide-induced cAMP response, β-arrestin-2 recruitment, and ERK activation were measured in cells expressing either wild type or variant MC4R., Results: We found a large heterogeneity in the function of these variants. We identified variants with a loss of response for all studied MC4R signaling, variants with no cAMP accumulation or ERK activation but normal β-arrestin-2 recruitment, and variants with normal cAMP accumulation and ERK activation but decreased β-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms. Setmelanotide displayed a greater potency and similar efficacy as α-MSH and induced significantly increased maximal cAMP responses of several variants compared to α-MSH. Despite the heterogeneity in functional response, there was no apparent difference in the obesity phenotype in our patients., Conclusion: We show that these obesity-associated MC4R variants affect MC4R signaling differently yet lead to a comparable clinical phenotype. Our results demonstrate the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity, which may aid in improving personalized treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Partial androgen insensitivity syndrome (PAIS) is a rare condition that is reported to be commonly associated with gynecomastia in males., Objectives: To assess the management of gynecomastia in male PAIS., Materials and Methods: Retrospective review of males with PAIS over the age of 10 years in the I-DSD registry., Results: Of the 205 eligible cases, information was available for 57 from 13 centers. An androgen receptor gene variant was confirmed in 45 (79%) with a median age at first presentation of 1.0 year (range 0.1, 26.0). Of the 45 genetically confirmed cases, gynecomastia was present in 41 (91%) with a median age at the time of gynecomastia development of 13.5 years (11.0, 29.0). In the other 4 (9%) with no gynecomastia, the median age at last assessment was 15.7 years (10.6, 17.0). In 30 cases with information available, micropenis was present at the time of gynecomastia development in 23 (77%). Of the 35 with information available, 2 (6%) exhibited spontaneous resolution between the ages of 15 and 21 years and 25 (71%) had breast surgery at a median age of 15.7 years (14.0, 23.0). Of these 25, 9 (26%) had previously received medical therapy. The median clinician score of effectiveness for medical therapy was 3 (1, 8) compared to 10 (3, 10) for surgery (P < .0001). In 31 with information available, 13 (42%) had received psychology support., Conclusion: Gynecomastia is common in PAIS but not universal. Surgical management may be more effective than medical therapy, but there is a need for further standardized and systematic studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: It is unclear whether targeted monitoring of acute adrenal insufficiency (AI) related adverse events (AE) such as sick day episodes (SDEs) and hospitalization rate in congenital adrenal hyperplasia (CAH) is associated with a change in the occurrence of these events., Aim: Study temporal trends of AI related AE in the I-CAH Registry., Methods: In 2022, data on the occurrence of AI-related AE in children aged <18 years with 21-hydroxylase deficiency CAH were compared to data collected in 2019., Results: In 2022, a total of 513 children from 38 centers in 21 countries with a median of 8 children (range 1-58) per center had 2470 visits evaluated over a 3-year period (2019-2022). The median SDE per patient year in 2022 was 0 (0-2.5) compared to 0.3 (0-6) in 2019 ( P = .01). Despite adjustment for age, CAH phenotype and duration of study period, a difference in SDE rate was still apparent between the 2 cohorts. Of the 38 centers in the 2022 cohort, 21 had also participated in 2019 and a reduction in SDE rate was noted in 13 (62%), an increase was noted in 3 (14%), and in 5 (24%) the rate remained the same. Of the 474 SDEs reported in the 2022 cohort, 103 (22%) led to hospitalization compared to 299 of 1099 SDEs (27%) in the 2019 cohort ( P = .02)., Conclusion: The I-CAH Registry can be used for targeted monitoring of important clinical benchmarks in CAH. However, changes in reported benchmarks need careful interpretation and longer-term monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication., (© 2024 The Authors. Clinical Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Rare genetic obesity commonly features early-onset obesity, hyperphagia, and therapy-resistance to lifestyle interventions. Pharmacotherapy is often required to treat hyperphagia and induce weight loss. We describe clinical outcomes of glucagon-like peptide-1 analogue liraglutide or naltrexone-bupropion treatment in adults with molecularly confirmed genetic obesity (MCGO) or highly suspected for genetic obesity without definite diagnosis (HSGO)., Methods: We conducted a real-world cohort study at the Obesity Center CGG at Erasmus University Center, Rotterdam, Netherlands, between March 19, 2019, and August 14, 2023. All patients with MCGO and HSGO who were treated with either liraglutide or naltrexone-bupropion were included. Liraglutide 3 mg and naltrexone-bupropion were administered according to the manufacturer's protocol. Treatment evaluation occurred short-term, after 12 weeks on maximum or highest-tolerated dose, preceded by the 4-5 week dose escalation phase. Differences in anthropometrics, body composition, metabolic markers, self-reported appetite, eating behaviour, and quality of life (QoL) were evaluated., Findings: Ninety-eight adults were included in the analysis: 23 patients with MCGO and 75 patients with HSGO, with median BMI of 42.0 kg/m 2 (IQR 38.7-48.2) and 43.7 kg/m 2 (IQR 38.0-48.7), respectively. After liraglutide treatment, median weight at evaluation significantly decreased compared to baseline in both groups: -4.7% (IQR -6.0 to -1.5) in patients with MCGO and -5.2% (IQR -8.1 to -3.5) in patients with HSGO. Additionally, improvements were observed in appetite, fat mass, fasting glucose, and HbA1c in both patients with MCGO and with HSGO. Patients with HSGO also reported significant improvements in several domains of QoL and eating behaviour. In patients with MCGO and HSGO treated with naltrexone-bupropion, mean weight at evaluation significantly differed from baseline: -5.2% ± 5.8 in patients with MCGO and -4.4% ± 4.7 in patients with HSGO. Appetite, fat mass, and waist circumference significantly decreased in both groups. Obesity-related comorbidities improved in significant proportions of patients treated with liraglutide or naltrexone-bupropion., Interpretation: In conclusion, our short-term findings show potential of liraglutide and naltrexone-bupropion as treatment options for adults with (a clinical phenotype of) genetic obesity., Funding: MB, EvdA, and EvR are supported by the Elisabeth Foundation, a non-profit foundation supporting academic obesity research., Competing Interests: The institution of MW, CdG, EvdA, and EvR has received funding for clinical trial research from Rhythm Pharmaceuticals, Inc. The current study is not linked to this study. MB and EvR receive personal royalties for the lay book FAT the secret organ. Payment to the institution or personal for scientific and/or educational presentations have been received by EvR. All other authors declare no competing interests., (© 2024 The Author(s).)

Objective: Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity., Methods: We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients., Results: A total of 79 adults with genetic obesity (32 with MO, 47 with SO) were compared with 186 control patients with CO. Median BMI was similar among the groups: 41.2, 39.5, and 38.7 kg/m 2 for patients with MO, SO, and CO, respectively. Median age of onset of obesity was 3 (IQR: 1-6) years in patients with MO, 9 (IQR: 4-13) years in patients with SO, and 21 (IQR: 13-33) years in patients with CO (p < 0.001). Patients with genetic obesity more often reported increased appetite: 65.6%, 68.1%, and 33.9% in patients with MO, SO, and CO, respectively (p < 0.001). Intellectual deficit and autism spectrum disorder were more prevalent in patients with SO (53.2% and 21.3%) compared with those with MO (3.1% and 6.3%) and CO (both 0.0%). The ES recommendations were fulfilled in 56.3%, 29.8%, and 2.7% of patients with MO, SO, and CO, respectively (p < 0.001)., Conclusions: We found distinct phenotypes in adult genetic obesity. Additionally, we demonstrated low sensitivity for detecting genetic obesity in adults using pediatric ES recommendations, necessitating specific genetic testing recommendations in adult obesity care., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Context: Due to ethical considerations, antenatal dose finding for prednisolone and dexamethasone in pregnant women is limited, leading to a knowledge gap., Objective: In order to guide the clinician in weighing benefits vs risks, the aim is to systematically review the current literature on the side effects of antenatal predniso(lo)ne and dexamethasone use on the fetus, newborn, and (pre)pubertal child., Evidence Acquisition: The search was performed in PubMed/MEDLINE and Embase using prespecified keywords and Medical Subject Headings. This systematic review investigated studies published until August 2022, with the following inclusion criteria: studies were conducted in humans and assessed side effects of long-term antenatal predniso(lo)ne and dexamethasone use during at least one of the trimesters on the child during the fetal period, neonatal phase, and during childhood., Evidence Synthesis: In total, 328 papers in PubMed and 193 in Embase were identified. Fifteen studies were eligible for inclusion. Seven records were added through references. Antenatal predniso(lo)ne use may be associated with lower gestational age, but was not associated with miscarriages and stillbirths, congenital abnormalities, differences in blood pressure or low blood glucose levels at birth, or with low bone mass, long-term elevated cortisol and cortisone, or high blood pressure at prepubertal age. Increased risks of antenatal dexamethasone use include association with miscarriages and stillbirths, and from age 16 years, associations with disturbed insulin secretion and higher glucose and cholesterol levels., Conclusions: Based on the limited evidence found, predniso(lo)ne may have less side effects compared with dexamethasone in short- and long-term outcomes. Current literature shows minimal risk of side effects in the newborn from administration of a prenatal predniso(lo)ne dose of up to 10 mg per day., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects., Objective: To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes., Methods: Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin., Results: We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99)., Conclusion: Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Obesity is present in 8-32% of the children with Autism Spectrum Disorder (ASD). However, most studies are performed in school-aged children from the USA. The current study compares obesity rates of Dutch preschoolers with ASD with children from the Dutch general population and explores which child- and parental factors are related to obesity in children with ASD. This cross-sectional study is part of the ongoing Tandem Study (Dutch Trial register: NL7534). Seventy-eight children with ASD aged 3-7 years and their parents (77 mothers, 67 fathers) participated. Child factors are: Body Mass Index (by physical measurement), child eating behavior (Child Eating Behavior Questionnaire), child problem behavior (Child Behavior Checklist), and ASD severity (Autism Diagnostic Observation Scale 2). Parental factors are: BMI (by physical measurement), parental eating behavior (Dutch Eating Behavior Inventory), parenting stress (The Parenting Stress Questionnaire) and highest completed educational level (SES). Children with ASD were 8 times more often obese (16.8%) than children from the general population (2.0%). Child BMI correlated positively with child food approach behavior and maternal BMI, and correlated negatively with child 'Slowness in eating'. There was no correlation between child BMI and ASD severity, problem behavior, parental eating behavior, parental stress and SES. Thus, Dutch, preschool children with ASD have 8 times higher obesity rates than children from the general population. More attention to obesity risk in research and clinical care could contribute to the quality of life of individuals with ASD and their families. CLINICAL TRIAL REGISTRATION: Dutch Trial register, NL7534, https://trialsearch.who.int/Trial2.aspx?TrialID=NL7534 ., (© 2024. The Author(s).)

Background: Dexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and functional abilities. The aim of this study was to establish the effect of a dexamethasone course on sarcopenia and physical frailty in children with ALL, and to explore prognostic factors., Methods: Patients with ALL aged 3-18 years were included during maintenance therapy. Patients had a sarcopenia/frailty assessment on the first day of (T1) and on the day after (T2) a 5-day dexamethasone course. Sarcopenia was defined as low muscle strength in combination with low muscle mass. Prefrailty and frailty were defined as having two or ≥three of the following components, respectively: low muscle mass, low muscle strength, fatigue, slow walking speed, and low physical activity. Chi-squared and paired t-tests were used to assess differences between T1 and T2. Logistic regression models were estimated to explore patient- and therapy-related prognostic factors for frailty on T2., Results: We included 105 patients, 61% were boys. Median age was 5.3 years (range: 3-18.8). At T1, sarcopenia, prefrailty, and frailty were observed in respectively 2.8%, 23.5%, and 4.2% of patients. At T2, the amount of patients with frailty had increased to 17.7% (p = 0.002), whereas the number of patients with sarcopenia and prefrailty remained similar. Higher ASMM (odds ratio [OR]: 0.49, 95% CI: 0.28-0.83), stronger handgrip strength (OR: 0.41, 95% CI: 0.22-0.77) and more physical activity minutes per day (OR: 0.98, 95% CI: 0.96-0.99) decreased the risk of frailty at T2. Slower walking performance (OR: 2, 95% CI: 1.2-3.39) increased the risk. Fatigue levels at T1 were not associated with frailty at T2., Conclusion: Physical frailty increased strikingly after a 5-days dexamethasone course in children with ALL. Children with poor physical state at start of the dexamethasone course were more likely to be frail after the course., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening., Study Design: This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated., Results: We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P < .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity., Conclusions: Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities., Competing Interests: Declaration of Competing Interest Supported by the Elisabeth Foundation (project name ObesEcare), a nonprofit foundation supporting academic research. The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: During treatment for acute lymphoblastic leukaemia (ALL), children are prone to musculoskeletal deterioration. However, non-invasive tools to measure muscle mass and intramuscular alterations are limited. In this study we explored the feasibility of muscle ultrasound in children with ALL. Additionally, we analysed whether automated ultrasound outcomes of muscle size and intramuscular fat infiltration (IMAT) were associated with appendicular skeletal muscle mass (ASMM), muscle strength and physical performance., Methods: Children with ALL, aged 3-18 years were included during maintenance therapy. Bilateral images of the rectus femoris muscle were captured using a portable linear array transducer connected to a tablet. Subsequently, an automated image annotation software (MuscleSound) was used to estimate cross-sectional area, muscle thickness and IMAT. Feasibility was assessed using acceptance (percentage of children approached who were enrolled), practicality (percentage of children that completed the ultrasound measurement after enrolment) and implementation (percentage of children that had sufficient imaging to be processed and analysed by the software). Assessments of ASMM by bioimpedance analysis, muscle strength using handheld dynamometry and timed physical performance tests were administered at the same visit. Multivariable linear models were estimated to study the associations between muscle ultrasound outcomes and ASMM, strength and physical performance, adjusted for sex, age, body mass index and ALL treatment week., Results: Muscle ultrasound was performed in 60 out of 73 invited patients (76.9%), of which 37 were boys (61.7%), and median age was 6.1 years (range: 3-18.8 years). The acceptance was 98.7%, practicality 77.9% and implementation was 100%. Patients who refused the examination (n = 13) were younger (median: 3.6, range: 3-11.2 years) compared with the 60 examined children (P = 0.0009). In multivariable models, cross-sectional area was associated with ASMM (β = 0.49 Z-score, 95% confidence interval [CI]:0.3,2.4), knee-extension strength (β = 16.9 Newton [N], 95% CI: 4.8, 28.9), walking performance (β = -0.46 s, 95% CI: -0.75, -0.18) and rising from the floor (β = -1.07 s, 95% CI: -1.71, -0.42). Muscle thickness was associated with ASMM (β = 0.14 Z-score, 95% CI: 0.04, 0.24), knee-extension strength (β = 4.73 N, 95% CI: 0.99, 8.47), walking performance (β = -0.13 s, 95% CI: -0.22, -0.04) and rising from the floor (β = -0.28 s, 95% CI: -0.48, -0.08). IMAT was associated with knee-extension strength (β = -6.84 N, 95% CI: -12.26, -1.41), walking performance (β = 0.2 s, 95% CI: 0.08, 0.32) and rising from the floor (β = 0.54 s, 95% CI: 0.27, 0.8). None of the muscle ultrasound outcomes was associated with handgrip strength., Conclusions: Portable muscle ultrasound appears a feasible and useful tool to measure muscle size and intramuscular alterations in children with ALL. Validation studies using magnetic resonance imaging (gold standard) are necessary to confirm accuracy in paediatric populations., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Introduction: Clarifying the effect of music on pain endurance in an experimental design could aid in how music should be applied during both surgical and non-surgical interventions. This study aims to investigate the effect of music on pain endurance and the involvement of the sympathetic adrenomedullary axis (SAM) and the hypothalamic-pituitary-adrenocortical axis (HPA)., Materials and Methods: In this randomized controlled trial all participants received increasing electric stimuli through their non-dominant index finger. Participants were randomly assigned to the music group (M) receiving a 20-minute music intervention or control group (C) receiving a 20-minute resting period. The primary outcome was pain endurance, defined as amount milliampere tolerated. Secondary outcomes included anxiety level, SAM-axis based on heart rate variability (HRV) and salivary alpha-amylase, and HPA-axis activity based on salivary cortisol., Results: In the intention-to-treat analysis, the effect of music on pain tolerance did not statistically differ between the M and C group. A significant positive effect of music on pain endurance was noted after excluding participants with a high skin impedance (p = 0.013, CI 0.35; 2.85). Increased HRV was observed in the M-group compared to the C-group for SDNN (B/95%CI:13.80/2.22;25.39, p = 0.022), RMSSD (B/95%CI:15.97/1.64;30.31, p = 0.032), VLF (B/95%CI:212.08/60.49;363.67, p = 0.008) and HF (B/95%CI:821.15/150.78;1491.52, p = 0.0190). No statistical significance was observed in other secondary outcomes., Conclusions: The effect of the music intervention on pain endurance was not statistically significant in the intention-to-treat analysis. The subgroup analyses revealed an increase in pain endurance in the music group after correcting for skin impedance, which could be attributed to increased parasympathetic activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ACTH (adrenocorticotropic hormone) stimulation test is the gold standard for the diagnosis of adrenal insufficiency (AI), performed with ACTH high dose (HDT) or low dose (LDT). As salivary cortisol has been proposed as an alternative to serum cortisol, our aim was to evaluate the reliability of salivary cortisol compared to serum cortisol for diagnosing AI in children. Data were collected retrospectively. Salivary and serum cortisol values derived by 80 ACTH stimulation tests were obtained (39 F, 36 M; median age 11.5 years, IQR 6.9). Sampling was performed at baseline and after 30 and 60 min from ACTH administration during the HDT, and at baseline and 10, 20, 30, 40 and 60 min after the stimulation for the LDT. A serum cortisol level > 420 nmol/L ruled out AI. The correlation coefficients between serum and salivary cortisol for the HDT ( n = 24) were 0.80 at t0, 0.48 at t30 and 0.75 at t60. All patients were adrenal sufficient. In 41% of the LDT, peak serum cortisol indicated insufficient adrenal function. The correlation coefficients between serum and salivary cortisol were 0.59 at t0 and 0.33 at the peak. For a cut-off of salivary cortisol < 15 nmol/L, sensitivity was 73.9% and specificity 69.6%. Our data do not support salivary cortisol as a valid alternative to serum cortisol during LDT. Regarding the HDT, results are more encouraging, however, further studies are needed.

Background: Infants admitted to the intensive care unit experience numerous early-life stressors, which may have long-term effects on hypothalamic-pituitary-adrenal axis functioning., Aims: To determine the effects of intensive care treatment and related exposure to stress, pain, and opioids in infancy on cortisol levels in childhood and adolescence., Study Design: Cross-sectional study., Subjects: Children and adolescents aged 8 to 18 years with a history of intensive care treatment in infancy and healthy controls. The intensive care treatment cohort consisted of four subgroups with varying levels of exposure to stress, pain, and opioids in infancy. They received either mechanical ventilation, extracorporeal membrane oxygenation, major surgery, or excochleation of a giant congenital melanocytic nevus., Outcome Measures: Between-group differences in stress reactivity to a study visit consisting of pain threshold testing and an MRI examination and diurnal cortisol levels, as measured in saliva., Results: After adjustment for age, sex, and gestational age, the diurnal cortisol output (AUCg) in the overall intensive care group (N = 76) was 18 % (approximately 1000 nmol/L) (95 % CI [-31 %, -3 %], P = 0.022) lower than that in the control group (N = 67). Cortisol awakening response, diurnal decline, and stress reactivity neither differed significantly between the overall intensive care group and control group, nor between the intensive care subgroups and control group., Conclusion: Children and adolescents with a history of intensive care treatment in infancy have similar cortisol profiles to those of healthy controls, except for an 18 % lower diurnal cortisol output. The clinical relevance of this reduction is yet to be determined., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Air-Displacement-Plethysmography (ADP) by BOD POD is widely used for body fat assessment in children. Although validated in healthy subjects, studies about use in pediatric patients are lacking. We evaluated user experience and usability of ADP measurements with the BOD POD system in healthy children and pediatric and young adult patients., Methods: Using the experiences of seven cohort studies, which included healthy children and patients aged 2-22 years, we retrospectively evaluated the user experience with the User Experience Questionnaire (UEQ) (n = 13) and interviews (n = 7). Technical performance was studied using the quality control data collected by the ADP-system., Results: From 2016 to 2022, 1606 measurements were scheduled. BOD POD was mostly rated 'user-friendly', with a generally neutral evaluation on all scales of the UEQ. However, questionable reliability and validity of the results were frequently (86%) reported. We found a high technical failure-rate of the device, predominantly in stability (17%) and accuracy of the measurement (12%), especially in the 'pediatric option' for children aged <6 years. Measurement failure-rate was 38%, mostly due to subject's fear or device failure, especially in young and lean children, and in children with physical and/or intellectual disabilities., Conclusion: We conclude that ADP by BOD POD in children and young adults is non-invasive and user-friendly. However, in specific pediatric populations, BOD POD has several limitations and high (technical) failure-rates, especially in young children with aberrant body composition. We recommend caution when interpreting body composition results of pediatric patients as assessed with BOD POD using the current default settings., Competing Interests: Conflict of interest The Sophia Pluto study is an investigator-initiated cohort study, for which AHK received an independent research grant (number 120417) by Danone Nutricia Research. LEV's salary (TROMPET study) was supported by funding from the Stichting Vrienden van het Sophia (Erasmus MC Sophia Children’s Hospital, “Sporten voor Sophia” event, grant number B18-01). The ROSA study was supported by Stichting Vrienden van het Sophia (grant number B17-04A) and Stichting the Merel. The BRAVE study was supported by the Sophia Foundation for Scientific Research (SSWO) (Grant numbers: S15-13, S22-65) and an internal Erasmus MV grant of the department of Radiology and Nuclear Medicine of the Erasmus University Medical Center. The BRAVE study is also made possible by financial contribution of the Stichting Vogelgezang, which made it possible to complete the follow-up measurements. The other studies received no specific payments or services from a third party for this research. The sponsors had no role in the study design, collection, analysis or interpretation of the data, the writing of the manuscript or the decision to submit it for publication. The other research groups declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding., Methods: Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3-18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect., Results: The median age was 5.5 years (range 3.0-18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect -2.05 (95% confidence interval (CI) -6.00-1.90). Also, no benefit from hydrocortisone compared to placebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL., Conclusions: Hydrocortisone, when compared to placebo, had no additional effect in reducing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hydrocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems., Trial Registration: Netherlands Trial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017-002738-22 (https://eudract.ema.europa.eu/)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Dr. R. Pieters is editorial member of European Journal of Cancer. The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Dexamethasone, the preferred corticosteroid in most treatment protocols for pediatric acute lymphoblastic leukemia (ALL), can induce undesirable side effects. Neurobehavioral and sleep problems are frequently reported, but the interpatient variability is high. We therefore aimed to identify determinants for parent-reported dexamethasone-induced neurobehavioral and sleep problems in pediatric ALL., Methods: Our prospective study included patients with medium-risk ALL and their parents during maintenance treatment. Patients were assessed before and after one 5-day dexamethasone course. Primary end points were parent-reported dexamethasone-induced neurobehavioral and sleep problems, measured with the Strengths and Difficulties Questionnaire and Sleep Disturbance Scale for Children, respectively. Analyzed determinants included patient and parent demographics, disease and treatment characteristics, parenting stress (Parenting Stress Index and Distress Thermometer for Parents), dexamethasone pharmacokinetics, and genetic variation (candidate single-nucleotide polymorphisms rs41423247 and rs4918 ). Statistically significant determinants identified in univariable logistic regression analyses were incorporated in a multivariable model., Results: We included 105 patients: median age was 5.4 years (range, 3.0-18.8) and 61% were boys. Clinically relevant dexamethasone-induced neurobehavioral and sleep problems were reported by parents in 70 (67%) and 61 (59%) patients, respectively. In our multivariable regression models, we identified parenting stress as a significant determinant for parent-reported neurobehavioral (odds ratio [OR], 1.16; 95% CI, 1.07 to 1.26) and sleep problems (OR, 1.06; 95% CI, 1.02 to 1.10). Furthermore, parents who experienced more stress before start of a dexamethasone course reported more sleep problems in their child (OR, 1.16; 95% CI, 1.02 to 1.32)., Conclusion: We identified parenting stress, and not dexamethasone pharmacokinetics, genetic variation, patient/parent demographics, or disease/treatment characteristics, as a significant determinant for parent-reported dexamethasone-induced neurobehavioral and sleep problems. Parenting stress may be a modifiable target to reduce these problems.

Background: Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce., Methods: A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing's syndrome) that had been reported by 12 centres in 8 European countries between January 2020 and December 2021., Results: Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison's disease, 19 by congenital adrenal hyperplasia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission., Conclusion: This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.

Background: Alterations in stress regulation and function of the hypothalamic-pituitary-adrenal (HPA) axis during infancy may be a risk factor for the development of psychopathology later in life. Maternal childhood trauma, depression, anxiety and stressful life events are individually associated with HPA axis dysregulation. Less is known about their interdependent influence on maternal and infant stress regulation in at risk populations. In a sample of mothers with a history of depressive-, and/or anxiety disorders and their infants we explored if a history of maternal childhood trauma, current depressive and anxiety symptomatology, and recent life events were associated with maternal and infant long-term cortisol levels three months postpartum., Methods: Data were available of 89 mothers and 49 infants. All mothers fulfilled criteria for a lifetime depressive or anxiety disorder. Diagnosis was established with a diagnostic interview. Current depressive symptomatology was assessed with the Edinburgh Postnatal Depression Scale (EPDS), current anxiety with the State-Trait Anxiety Inventory (STAI), maternal childhood trauma with the Childhood Trauma Questionnaire (CTQ) and recent life events with the Everyday Problem Checklist (EPC). Maternal and infant hair cortisol concentrations (HCC) were quantified with liquid chromatography with tandem mass spectrometry (LC-MS/MS) three months after birth. Total scores of the CTQ and subscales, EPDS, STAI, and EPC were regressed on maternal and infant HCC using regression analyses. Differences in HCC regarding trauma history were tested with t-tests. Potential confounders were identified and adjusted for., Results: In regression analyses, a positive curvilinear relationship was found between CTQ total score and maternal HCC (n = 83, B = 0.076, SE 0.033, p = .021), but not for current depression (n = 88, B = -0.001, SE 0.011, p = .931), current anxiety (n = 88, B = 0.002, SE 0.004, p = .650) or recent life events (n = 89, B = 0.018, SE 0.032, p = .568). Analyses were adjusted for confounders. A negative linear relationship was found between maternal CTQ score and infant HCC (n = 49, β = -0.264, B = -0.006, SE 0.003, p = .052), but not for current maternal depression (n = 45, β = -0.182, B = -0.011, SE 0.008, p = .164), current maternal anxiety (n = 45, β = -0.209, B = -0.005, SE 0.003, p = .113) or recent life events (n = 46, β = -0.128, B = -0.022, SE 0.023, p = .325). Analyses were adjusted for relevant infant hair characteristics. Specifically, maternal emotional and physical neglect were related to HCC in both mothers and infants., Conclusions: Results suggest that maternal childhood trauma is more prominent in altering maternal and infant long-term cortisol levels than perinatal depressive and anxiety symptomatology or recent life stressors in mothers with a history of depressive and/or anxiety disorders, and their infants. As infants of mothers with psychopathology are at increased risk for later psychiatric disease, future studies should investigate the interplay of possible risk factors for transgenerational transmission, intra-uterine programming of the HPA axis, including (epi-)genetic phenomena, of the HPA axis, and the influence of parenting impairment., Competing Interests: None., (© 2023 The Author(s).)

Context: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids., Objective: To investigate LTL in children with CAH., Methods: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1 ± 0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z., Results: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, -0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (-0.29, P = 0.012), in overtreated than in optimally treated patients (-0.07, P = 0.002), and patients receiving prednisolone compared with hydrocortisone (-0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05)., Conclusion: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Leptin receptor (LEPR) deficiency is a rare genetic disorder that affects the body's ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life; however, little is published about this impact. We here report the experiences of a 10.5-year-old girl with leptin receptor deficiency and her family. The diagnosis of this rare genetic obesity had a deep impact on the life of the child and her family. It led to a better understanding of the cause of the impaired appetite regulation and early-onset obesity with subsequently less judgement by others and improved cooperation of their social network and school on maintaining a healthy lifestyle for this girl. A strict eating regimen and lifestyle measures resulted in the first year after diagnosis in a significantly decreased body mass index (BMI), followed by BMI stabilization, still categorized as obesity class three. However, the troublesome challenge of how to manage the disruptive behaviour due to hyperphagia remained. Eventually, due to treatment with targeted pharmacotherapy, i.e., melanocortin-4 receptor agonists, her BMI continued to decrease due to resolving hyperphagia. The daily routine of the family and the atmosphere at home positively changed as they were no longer dominated by the food-focused behaviour of the child and the adherence to the strict eating regimen. This case report demonstrates the importance and impact of a rare genetic obesity disorder diagnosis in a family. Additionally, it highlights the value of genetic testing in patients with a high suspicion of a genetic obesity disorder as it can eventually lead to personalized treatment, such as guidance by specialized healthcare professionals and educated caregivers or targeted pharmacotherapy., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Obesity is a multifactorial, chronic, progressive disease associated with decreased health-related quality of life, comorbidities, and increased mortality risk. Lifestyle interventions, focusing on dietetics, physical exercise, and behavioral therapy, are a cornerstone of therapy. Despite this very multidisciplinary treatment approach, the definition of treatment success is often based only on a weight loss of ≥ 5%. However, the heterogeneous nature of obesity may necessitate a more comprehensive approach to assessing treatment effects., Objectives: Here, we describe changes in physiological, psychological, and behavioral health after a multidisciplinary combined lifestyle intervention (CLI). Additionally, we investigated whether these changes were related to weight loss., Methods: This prospective observational longitudinal study comprised 96 adults with obesity (73 women, 81 Caucasian) participating in a CLI at the Obesity Center CGG, Erasmus University Medical Center, Rotterdam, the Netherlands. The 1.5-year intervention comprised multidisciplinary professional guidance towards a healthy diet, increased physical activity, and included cognitive behavioral therapy. Physiological health outcomes, psychological well-being, eating behavior, and physical activity were assessed after ten weeks and 1.5 years and compared to baseline., Results: An average of 5.2% weight loss (-6.0 kg) was accompanied by a mean 9.8% decrease in fat mass (-5.9 kg; both P < 0.001) and significant improvements in metabolism, hormonal status, and immune parameters (all P < 0.05). Moreover, we observed decreased psychopathology, increased quality of life, and decreased disordered eating (all P < 0.05). Weight loss correlated with most metabolic changes (all P < 0.05) but not with most psychological/behavioral changes., Conclusions: Combined lifestyle intervention in patients with obesity was accompanied by significant improvements in body weight and body composition along with cardiometabolic, endocrine, immunological, psychological, and behavioral improvements. Interestingly, most changes in psychological and behavioral health occurred independently of weight loss. Obesity treatment success should be evaluated based on a combination of physical and patient-reported outcomes rather than weight loss alone., Competing Interests: Conflict of Interests: All authors are employed by ErasmusMC Medical Center, Rotterdam, the Netherlands, (Copyright © 2022, International Journal of Endocrinology and Metabolism.)

Objective: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4)., Design: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries., Patients: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry., Measurements: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM)., Results: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m 2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R 2  = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R 2  = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m 2 /day for every 1 point increase in weight standard deviation score., Discussion: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: To explore the perspectives of healthcare professionals (HCPs) within an integrated care approach on the facilitators, barriers and needs in children with obesity and their parents in achieving a healthier lifestyle., Methods: Semi-structured interviews were conducted with eighteen HCPs working within a Dutch integrated care approach. The interviews were analyzed by performing a thematic content analysis., Results: Main facilitators identified by HCPs were support from parents and the social network. Main barriers were first and foremost family's lack of motivation, which was singled out as a precondition for starting the behavior change process. Other barriers were child's socio-emotional problems, parental personal problems, lack of parenting skills, parental lack of knowledge and skills regarding a healthier lifestyle, parental lack of problem awareness and HCP's negative attitude. To overcome these barriers, main needs that HCPs suggested were a tailored approach in healthcare and a supportive HCP., Conclusion: The HCPs identified the breadth and complexity of underlying factors of childhood obesity, of which the family's motivation was pointed out as a critical factor to address., Innovation: Understanding the patient's perspective is important for HCPs to provide the tailored care needed to address the complexity of childhood obesity., Competing Interests: All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Pediatric obesity is a multifactorial disease which can be caused by underlying medical disorders arising from disruptions in the hypothalamic 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 or without underlying medical causes., Methods: This prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic centre that evaluated endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio between measured REE (mREE) and predicted REE (Schofield equations), REE%, was calculated, with decreased mREE defined as REE% ≤90% and elevated mREE ≥110%. Additionally, the influence of fat-free-mass (FFM) on mREE was evaluated using multiple linear regression., Results: We included 292 patients (146 [50%] with body composition measurements), of which 218 (75%) patients had multifactorial obesity and 74 (25%) 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 p<0.01). In 9 children with pseudohypoparathyroidism type 1a, mean REE% was similar (100.4 ± 5.1). Across all patients, mREE was decreased in 60 (21%) patients and elevated in 69 (24%) patients. After adjustment for FFM, mREE did not differ between patients within each of the subgroups of underlying medical causes compared to multifactorial obesity (all p>0.05)., Conclusions: In this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Consistent with previous studies, almost half of patients had decreased or elevated mREE. This knowledge is important for patient-tailored treatment, e.g. personalized dietary and physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abawi, Koster, Welling, Boeters, van Rossum, van Haelst, van der Voorn, de Groot and van den Akker.)

Introduction: Transition from paediatric to adult endocrinology can be challenging for adolescents, their families and healthcare professionals. Previous studies have shown that up to 25% of young adults with endocrine disorders are lost to follow-up after moving out of paediatric care. This poses a health risk for young adults, which can lead to serious and expensive medical acute and long-term complications., Methods: In order to understand and prevent dropout, we studied electronic medical records of patients with endocrine disorders. These patients were over 15 years old when they attended the paediatric endocrine outpatient clinic (OPC) of our hospital in 2013-2014 and should have made the transfer to adult care at the time of the study., Results: Of 387 adolescents, 131 had an indication for adult follow-up within our university hospital. Thirty-three (25%) were lost to follow-up. In 24 of them (73%), the invitation for the adult OPC had never been sent. We describe the failures in logistic processes that eventually led to dropout in these patients., Conclusion: We found a 25% dropout during transfer from paediatric to adult tertiary endocrine care. Of all dropouts, 73% could be attributed to the failure of logistic steps. In order to prevent these dropouts, we provide practical recommendations for patients and paediatric and adult endocrinologists.

Context: Rare homozygous or biallelic variants in POMC , PCSK1 , and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity. In pivotal Phase 3 clinical trials, treatment with the MC4R agonist setmelanotide reduced hunger and weight in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency., Objective: To characterize the historical weight trajectory in these patients., Methods: This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). These were multicenter trials. Patients had obesity due to POMC/PCSK1 or LEPR deficiency. During the trial, patients were treated with setmelanotide. Historical data on measured weight and height were obtained during screening., Results: A total of 17 patients (POMC, n = 8; PCSK1, n = 1; LEPR, n = 8) with historical weight and height data were included in this analysis. Before setmelanotide treatment, patients with obesity due to POMC/PCSK1 or LEPR deficiency were above the 95th percentile for weight throughout childhood, demonstrated continuous weight gain, and did not show long-term weight loss upon interventions (eg, diet, surgery, exercise). Setmelanotide treatment attenuated weight and body mass index trajectories over the observation period of 1 year., Conclusion: In patients with POMC, PCSK1, or LEPR deficiency, traditional interventions for weight loss had limited impact on the trajectory of severe early-onset obesity. However, setmelanotide treatment attenuated weight and body mass index trajectories and led to weight loss associated with health benefits in most individuals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: During treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases., Objective: This study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes., Methods: This prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors., Results: Patient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed., Conclusions: This first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions., International Registered Report Identifier (irrid): DERR1-10.2196/33517., (©Emma Jacobine Verwaaijen, Annelienke van Hulst, Marta Fiocco, Annelies Hartman, Martha Grootenhuis, Saskia Pluijm, Rob Pieters, Erica van den Akker, Marry M van den Heuvel-Eibrink. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.04.2022.)

Context: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening)., Objective: We aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores., Methods: This 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies., Results: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores., Conclusion: No clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Hypothalamic obesity (HO) in children has severe health consequences. Lifestyle interventions are mostly insufficient and currently no drug treatment is approved for children with HO. Amphetamines are known for their stimulant side-effect on resting energy expenditure (REE) and suppressing of appetite. Earlier case series have shown positive effects of amphetamines on weight in children with acquired HO. We present our experiences with dextroamphetamine treatment in the, up to now, largest cohort of children with HO., Methods: A retrospective cohort evaluation was performed of children with HO treated with dextroamphetamine at two academic endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive, therapy-resistant acquired or congenital HO. Anthropometrics, REE, self-reported (hyperphagic) behavior and energy level, and side effects were assessed at start and during treatment., Results: Nineteen patients with a mean age of 12.3 ± 4.0 years had been treated with dextroamphetamine. In two patients, ΔBMI SDS could not be evaluated due to short treatment duration or the simultaneous start of extensive lifestyle treatment. Mean treatment duration of the 17 evaluated patients was 23.7 ± 12.7 months. Fourteen patients ( n = 10 with acquired HO, n = 4 with congenital HO) responded by BMI decline or BMI stabilization (mean ΔBMI SDS of -0.6 ± 0.8, after a mean period of 22.4 ± 10.5 months). In three patients, BMI SDS increased (mean ΔBMI SDS of +0.5 ± 0.1, after a mean period of 29.7 ± 22.6 months). In 11 responders, measured REE divided by predicted REE increased with +8.9%. Thirteen patients (68.4%) reported decreased hyperphagia, improvement of energy level and/or behavior during treatment. Two patients developed hypertension during treatment, which resulted in dosage adjustment or discontinuation of treatment. Twelve children continued treatment at last moment of follow-up., Conclusion: In addition to supportive lifestyle interventions, dextroamphetamine treatment may improve BMI in children with HO. Furthermore, dextroamphetamines have the potential to decrease hyperphagia and improve resting energy expenditure, behavior, and energy level. In patients with acquired HO, these effects seem to be more pronounced when compared to patients with congenital HO. Future studies are needed to support these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Schaik, Welling, de Groot, van Eck, Juriaans, Burghard, Oude Ophuis, Bakker, Tissing, Schouten-van Meeteren, van den Akker and van Santen.)

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; I 2  = 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; I 2  = 51.2%) and pooled regression coefficient 0.049 kg/m 2 per point increase in 10-log-transformed HairF (pg/mg) on LC-MS (95%CI 0.045-0.054 kg/m 2 ; 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., (© 2021 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Context: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction., Objective: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed., Methods: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action., Results: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported., Conclusions: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

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 <10 years (19/21). This was often attributed to loss of daily structure and perceived stress. Families who reported no changes (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., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Obesity is highly prevalent and comes with serious health burden. In a minority, a genetic cause is present which often results in therapy-resistant obesity. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue, which has beneficial effects on satiety and weight in common obesity. We present the effects of GLP-1 analogues in adults with a molecularly proven genetic cause of their overweight or obesity. All patients were treated with liraglutide 3.0 mg daily, in addition to intensive supportive lifestyle treatment. Anthropometrics, metabolic parameters, resting energy expenditure (REE), side effects, and subjectively reported satiety and quality of life were assessed. Two patients with 16p11.2 deletion syndrome and two patients with heterozygous pathogenic melanocortin-4 receptor variants were treated. At baseline, their age ranged between 21 and 32 years and body mass index (BMI) ranged between 28.1 and 55.7 kg/m 2 . At follow-up (ranges 43 weeks-12 years), a mean change in BMI and waist circumference was observed of -5.7 ± 3.8 kg/m 2 and -15.2 ± 21.1 cm, respectively. All patients achieved ≥5% weight loss, three of them lost ≥10% of their body weight. All patients reported improved quality of life and three of them reported ameliorated satiety. Moreover, improvement of glycaemic control and dyslipidaemia were seen. In two patients, REE before and during treatment was measured, which either increased (+26% of predicted REE) or decreased (-18% of predicted REE). Two patients experienced mild side effects for a brief period. In conclusion, our case series shows beneficial effects of GLP-1 analogues on weight, metabolic parameters and quality of life in all four patients with genetic obesity., (© 2021 The Authors. Clinical Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Peak stimulated growth hormone (GH) levels are known to decrease with increasing body mass index (BMI), possibly leading to overdiagnosis of GH deficiency (GHD) in children with overweight and obesity. However, current guidelines do not guide how to interpret the peak GH values of these children. This systematic review and meta-analysis aimed to study the effect of the BMI standard deviation score (SDS) on stimulated peak GH values in children, to identify potential moderators of this association, and to quantify the extent to which peak GH values in children with obesity are decreased. This systematic review was performed by the PRISMA guidelines. Medline, Embase, Cochrane, Web of Science, and Google Scholar databases were searched for studies reporting the impact of weight status on peak GH in children. Where possible, individual participant data was extracted and/or obtained from authors. Quality and risk of bias were evaluated using the Scottish Intercollegiate Guidelines Network (SIGN) checklists. The primary outcome was the association between peak GH values and BMI SDS. The pooled correlation coefficient r , 95% confidence interval (CI), and heterogeneity statistic I 2 were calculated under a multilevel, random-effects model. In addition, exploratory moderator analyses and meta-regressions were performed to investigate the effects of sex, pubertal status, presence of syndromic obesity, mean age and mean BMI SDS on the study level. For the individual participant dataset, linear mixed-models regression analysis was performed with BMI SDS as the predictor and ln(peak GH) as the outcome, accounting for the different studies and GH stimulation agents used. In total, 58 studies were included, providing data on n  = 5135 children (576 with individual participant data). Thirty-six (62%) studies had high, 19 (33%) medium, and 3 (5%) low risks of bias. Across all studies, a pooled r of -0.32 (95% CI -0.41 to -0.23, n  = 2434 patients from k  = 29 subcohorts, I 2 = 75.2%) was found. In meta-regressions, larger proportions of males included were associated with weaker negative correlations ( p  = 0.04). Pubertal status, presence of syndromic obesity, mean age, and mean BMI SDS did not moderate the pooled r (all p  > 0.05). Individual participant data analysis revealed a beta of -0.123 (95% CI -0.160 to -0.086, p  < 0.0001), i.e. per one-point increase in BMI SDS, peak GH decreases by 11.6% (95% CI 8.3-14.8%). To our knowledge, this is the first systematic review and meta-analysis to investigate the impact of BMI SDS on peak GH values in children. It showed a significant negative relationship. Importantly, this relationship was already present in the normal range of BMI SDS and could lead to overdiagnosis of GHD in children with overweight and obesity. With the ever-rising prevalence of pediatric obesity, there is a need for BMI (SDS)-specific cutoff values for GH stimulation tests in children. Based on the evidence from this meta-analysis, we suggest the following weight status-adjusted cutoffs for GH stimulation tests that have cutoffs for children with normal weight of 5, 7, 10, and 20 µg/L: for overweight children: 4.6, 6.5, 9.3, and 18.6 µg/L; and for children with obesity: 4.3, 6.0, 8.6, and 17.3 µg/L.

Context: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cutoffs. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false positives., Objective: We assessed the accuracy and turnaround time of the current CAH NBS algorithm in comparison with alternative algorithms by performing a second-tier 21-deoxycortisol (21-DF) pilot study., Methods: Dried blood spots (DBS) of newborns with inconclusive and positive 17-OHP (immunoassay) first HP results were sent from regional NBS laboratories to the Amsterdam UMC Endocrine Laboratory. In 2017-2019, 21-DF concentrations were analyzed by LC-MS/MS in parallel with routine NBS. Diagnoses were confirmed by mutation analysis., Results: A total of 328 DBS were analyzed; 37 newborns had confirmed classic CAH, 33 were false-positive and 258 were categorized as negative in the second HP following the current algorithm. With second-tier testing, all 37 confirmed CAH had elevated 21-DF, while all 33 false positives and 253/258 second-HP negatives had undetectable 21-DF. The elevated 21-DF of the other 5 newborns may be NBS false negatives or second-tier false positives. Adding the second-tier results to inconclusive first HPs reduced the number of false positives to 11 and prevented all 286 second HPs. Adding the second tier to both positive and inconclusive first HPs eliminated all false positives but delayed referral for 31 CAH patients (1-4 days)., Conclusion: Application of the second-tier 21-DF measurement to inconclusive first HPs improved our CAH NBS by reducing false positives, abolishing the second HP, and thereby shortening referral time., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Higher long-term glucocorticoid levels, measured in scalp hair (HairGC), are associated with obesity. This may represent the state of obesity (perhaps interrelated with chronic immune activation), but could also promote further weight gain. We studied whether hair cortisol (HairF) and hair cortisone (HairE) predict changes in body mass index (BMI) and waist circumference (WC) over time, and assessed the association between HairGC and common immune parameters., Methods: We measured HairGC in 1604 participants of the Netherlands Study of Depression and Anxiety (NESDA), and investigated their associations to BMI, WC, and immune parameters (interleukin-6 (IL-6), C-reactive protein (CRP), and leukocyte subsets). Also, we assessed whether baseline HairGC predict changes in BMI and WC at follow-up (three years later)., Results: In cross-sectional analyses, HairF and HairE were positively associated to BMI (β = 2.06 kg/m 2 , 95% confidence interval (CI)= 1.22-2.90 kg/m 2 ) and β = 2.84 kg/m 2 (95%CI 1.75-3.93 kg/m 2 ) respectively) and WC (β = 5.36 cm (95%CI 3.09-7.62 cm) and β = 8.54 cm (95%CI 5.60-11.48 cm) respectively, all p < 0.001). HairF was also positively associated to IL-6 (β = 0.15 (95%CI 0.003-0.292) p < 0.05) and leukocyte count (β = 0.57 (95%CI 0.234-0.909), p < 0.01), and HairE to IL-6 (β = 0.21 (95%CI 0.016-0.399), p < 0.05). In the longitudinal analyses, higher HairF was associated with yearly increases in BMI (β = 0.58% BMI change per year (95%CI 0.14-1.01%), p = 0.009) and higher HairE with increases in WC (β = 0.84% WC change per year (95%CI 0.02-1.69%), p = 0.049). Adjusting for baseline IL-6 or leukocytes did not change the found associations between HairGC and WC or BMI change., Conclusions: HairGC levels are positively associated to BMI, WC, IL-6 and leukocyte numbers in cross-sectional analyses, and to increases in BMI and WC in longitudinal analyses. Although causality is yet to be proven, higher long-term glucocorticoid levels could represent a relevant risk factor for the development of obesity., (Copyright © 2021. Published by Elsevier Ltd.)

Context: Biological stress is related to cardiovascular disease in adults. The associations of stress with cardiovascular and metabolic diseases may originate in childhood., Objective: This work aims to examine the associations of hair cortisol concentrations at age 6 years with cardiometabolic risk factors at ages 6 and 10 years., Methods: Cortisol concentrations were measured in hair of 6-year-old children (n = 2598) participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Main outcome measures included blood pressure, heart rate, concentrations of insulin, glucose, lipids, and C-reactive protein in blood at ages 6 and 10 years., Results: Higher hair cortisol concentrations at age 6 years were associated with higher systolic blood pressure at age 10 years (difference 0.17 SD score; 95% CI, 0.03-0.31). The association attenuated into nonsignificance after adjustment for childhood body mass index (BMI) at age 6 years. Higher hair cortisol concentrations at age 6 years were associated with an increase in total and low-density lipoprotein cholesterol between ages 6 and 10 years but not with those measurements at age 6 or 10 years. Hair cortisol concentrations were not associated with other cardiometabolic risk factors at age 6 or 10 years., Conclusion: Hair cortisol concentrations were not independent of BMI associated with cardiometabolic risk factors at 6 or 10 years. The associations of biological stress with cardiometabolic risk factors may develop at later ages., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Fetal exposure to cannabis and tobacco during pregnancy leads to adverse fetal and childhood outcomes. We hypothesized that fetal exposure to cannabis and tobacco have persistent programming effects on hypothalamic pituitary adrenal (HPA) axis functioning in childhood. Therefore, we examined the associations of parental cannabis and tobacco use during pregnancy with childhood hair cortisol and cortisone concentrations at 6 years, as biomarkers of long-term HPA-axis functioning., Method: In a population-based prospective birth cohort among 2577 mothers and their children, information of parental cannabis and tobacco use was collected by questionnaires, and maternal urine samples were additionally analyzed to detect cannabis metabolite concentrations. Cortisol and cortisone were measured in hair samples at 6 years. Linear regression analysis with adjustment for several confounders was used to test our hypothesis., Results: As compared to non-exposed children, offspring exposed to cannabis during pregnancy (in combination with tobacco) had higher childhood cortisol concentrations (log-10 transformed difference 0.16, 95 % Confidence Interval 0.04 to 0.28). This association was not mediated by birth weight. No differences in cortisone concentrations among cannabis-exposed children were observed. Maternal tobacco use during pregnancy was not associated with childhood cortisol or cortisone concentrations. Further, paternal cannabis or tobacco use was not associated with childhood cortisol or cortisone concentrations., Conclusions: Our findings suggest that maternal cannabis use, combined with tobacco, during pregnancy is associated with alterations in offspring HPA-axis functioning. Further studies need to replicate these findings, and assess the causality and long-term consequences of these associations., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Caring for an excessively crying infant (ECI) can be stressful for mothers and fathers and is associated with mental and bonding problems. Hair cortisol offers a unique measure for the biological reaction of the body to stress over time., Methods: In this case-control study, scalp hair cortisol concentrations (HCC) were measured using liquid chromatography-tandem mass spectrometry (LC-MS) in 35 mothers and 23 fathers and their ECIs. The control group consisted of 64 mothers and 63 fathers of non-ECIs of similar age. Parental stress, depression, anxiety and bonding were assessed using validated questionnaires., Results: Mean HCC were significantly lower in mothers and fathers of ECIs (2.3 pg/mg, 95% CI 1.8-2.9 and 1.6 pg/mg, 95% CI 1.3-2.0) than that in control mothers and fathers (3.2 pg/mg, 95% CI 3.0-3.7 and 2.9 pg/mg, 95% CI 2.5-3.5). In the total group of parents and within the parents of ECIs, HCC were not associated with negative feelings. In the control group, HCC showed a positive association with stress and depression (r = 0.207, p = 0.020 and r = 0.221, p = 0.013). In infants, no differences were found in mean HCC between the ECI group and the control group. No associations were found between maternal and infant HCC, paternal and infant HCC and maternal and paternal HCC., Conclusion: Parents of ECIs showed significantly lower HCC than control parents, reflecting a diminished response of the hypothalamic-pituitary-adrenal (HPA) axis. More research is needed to examine whether this decrease in response is pre-existing or caused by excessive infant crying.

Objective: Steroids play an essential role in treating pediatric acute lymphoblastic leukemia (ALL). The downside is that these drugs can cause severe side effects, such as adverse psychological reactions (APRs) and sleep problems, which can compromise health-related quality of life. This study aimed to systematically review literature to identify risk factors for steroid-induced APRs and sleep problems in children with ALL., Methods: A systematic search was performed in six databases. Titles/abstracts were independently screened by two researchers. Data from each included study was extracted based on predefined items. Risk of bias and level of evidence were assessed, using the Quality in Prognosis Studies tool and the Grading of Recommendations Assessment, Development and Evaluation tool, respectively., Results: Twenty-four articles were included. APR measurement ranged from validated questionnaires to retrospective record retrieval, sleep measurement included questionnaires or actigraphy. Overall, quality of evidence was very low. Current evidence suggests that type/dose of steroid is not related to APRs, but might be to sleep problems. Younger patients seem at risk for behavior problems and older patients for sleep problems. No studies describing parental stress or medical history were identified. Genetic susceptibility associations remain to be replicated., Conclusions: Based on the current evidence, conclusions about risk factors for steroid-induced adverse psychological reactions or sleep problems in children with ALL should be drawn cautiously, since quality of evidence is low and methods of measurement are largely heterogeneous. A standardized registration of steroid-induced APRs/sleep problems and risk factors is warranted for further studies in children with ALL., (© 2021 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)