Psychosocial, behavioral and clinical correlates of children with overweight and obesity

Background Psychological and behavioral correlates are considered important in the development and persistence of obesity in both adults and youth. This study aimed to identify such features in youth with severe obesity (BMI ≥ 120% of 95thpercentile of sex-specific BMI-for-age) compared to those with overweight or non-severe obesity. Methods Youth with BMI ≥ 85th percentile were invited to participate in a prospective research registry where data was collected on attributes such as family characteristics, eating behaviors, dietary intake, physical activity, perception of health and mental well-being, and cardiometabolic parameters. Results In a racially/ethnically diverse cohort of 105 youth (65% female, median age 16.1 years, range 4.62–25.5), 51% had severe obesity. The body fat percent increased with the higher levels of obesity. There were no differences in the self-reported frequency of intake of sugar sweetened beverages or fresh produce across the weight categories. However, the participants with severe obesity reported higher levels of emotional eating and eating when bored (p = 0.022), levels of stress (p = 0.013), engaged in fewer sports or organized activities (p = 0.044), and had suboptimal perception of health (p = 0.053). Asthma, depression and obstructive sleep apnea were more frequently reported in youth with severe obesity. The presence of abnormal HDL-C, HOMA-IR, hs-CRP and multiple cardiometabolic risk factors were more common among youth with severe obesity. Conclusions Youth with severe obesity have identifiable differences in psychosocial and behavioral attributes that can be used to develop targeted intervention strategies to improve their health

Clinical Course of Non-Functional Pituitary Microadenoma in Children: A Single Center Experience: Supplemental Table

Context: Pituitary lesions consistent with microadenomas are increasingly discovered by magnetic resonance imaging (MRI). Sparse data are available on the long-term clinical and imaging course of such lesions in children. Objective: The aim of this study was to define the clinical and imaging course of pituitary lesions representing or possibly representing non-functioning microadenomas in children to guide clinical management. Design: Retrospective observational study. Methods: The clinical data warehouse at a tertiary care academic children’s hospital was queried with the terms “pituitary” AND “microadenoma”, and “pituitary” AND “incidentaloma”. The electronic health records of the identified subjects were reviewed to extract data on the clinical and imaging course. Results: A total of 78 children with non-functioning pituitary lesions incidentally discovered during clinical care, of which 44 (56%) were reported as presumed or possible microadenomas. In the children with microadenoma (median age 15 years, IQR 2), majority (70%) underwent imaging for non-endocrine symptoms, the commonest being headache (n = 16, 36%). No significant increase in the size of the microadenoma or cysts or worsening of pituitary function was seen over the average clinical follow-up of 4.5 +/- 2.6 years. Four cases of drug-induced hyperprolactinemia resolved with discontinuation of the offending medication. Conclusions: Asymptomatic pituitary lesions representing cysts, microadenomas or possible microadenomas follow a benign course in children. In the absence of new endocrine or visual symptoms, repeat MRI may not be needed, and if performed, no sooner than a year. When possible, it is prudent to discontinue hyperprolactinemia inducing medications prior to imaging

Relationship of TSH levels with cardiometabolic risk factors in US youth aged 12-18 years and population-based reference percentiles for thyroid function tests. Supplemental data

This study examined the association of levels of Thyroid Stimulating Hormone (TSH) with cardiometabolic risk factors in youth enrolled in National Health and Nutrition Examination Survey (NHANES) over 10 years (1999-2002 and 2007-2012). We identified that higher levels of TSH were associated with abdominal obesity and insulin resistance while controlling for age, sex, race/ethnicity and level of obesity

Effect of TSH on Non-Alcoholic Fatty Liver Disease (NAFLD) independent of obesity in children of predominantly Hispanic/Latino ancestry by causal mediation analysis

Background Nonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity. Elevated TSH levels (eTSH), also associated with obesity, may contribute to the dysmetabolic state that predisposes to NAFLD. Objective To assess the relationship between TSH levels and NAFLD in children with biopsy-proven NAFLD compared to controls. Design and methods In this retrospective study of children with biopsy-proven NAFLD and age-matched controls, the association of eTSH with NAFLD was investigated and the role of TSH as a mediator between obesity and NAFLD was assessed. Results Sixty-six cases and 4067 controls (69.7 vs 59% Hispanic/Latino ancestry, p = 0.1) of the same age range seen in the same time duration at an urban Children's Hospital were studied. Children with NAFLD were more likely to be male (74.6 vs 39.4%, p < 0.001), have higher modified BMI-z scores (median 2.4 (IQR 1.7) vs 1.9 (IQR 1.7), p < 0.001), and abnormal metabolic parameters (TSH, ALT, HDL-C, non-HDL-C, and TG). Multivariate analyses controlling for age, sex and severity of obesity showed significant association between the 4(th)quartile of TSH and NAFLD. Causal mediation analysis demonstrates that TSH mediates 33.8% of the effect of modified BMI-z score on NAFLD. This comprises of 16.0% (OR = 1.1, p = 0.002) caused by the indirect effect of TSH and its interaction with modified BMI-z, and 17.7% (OR = 1.1, p = 0.05) as an autonomous effect of TSH on NAFLD. Overall, 33.8% of the effect can be eliminated by removing the mediator, TSH (p = 0.001). Conclusions The association of eTSH and biopsy-proven NAFLD is demonstrated in children of Hispanic/Latino ancestry. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity

Psychosocial, behavioral and clinical correlates of children with overweight and obesity

Abstract Background Psychological and behavioral correlates are considered important in the development and persistence of obesity in both adults and youth. This study aimed to identify such features in youth with severe obesity (BMI ≥ 120% of 95thpercentile of sex-specific BMI-for-age) compared to those with overweight or non-severe obesity. Methods Youth with BMI ≥ 85th percentile were invited to participate in a prospective research registry where data was collected on attributes such as family characteristics, eating behaviors, dietary intake, physical activity, perception of health and mental well-being, and cardiometabolic parameters. Results In a racially/ethnically diverse cohort of 105 youth (65% female, median age 16.1 years, range 4.62–25.5), 51% had severe obesity. The body fat percent increased with the higher levels of obesity. There were no differences in the self-reported frequency of intake of sugar sweetened beverages or fresh produce across the weight categories. However, the participants with severe obesity reported higher levels of emotional eating and eating when bored (p = 0.022), levels of stress (p = 0.013), engaged in fewer sports or organized activities (p = 0.044), and had suboptimal perception of health (p = 0.053). Asthma, depression and obstructive sleep apnea were more frequently reported in youth with severe obesity. The presence of abnormal HDL-C, HOMA-IR, hs-CRP and multiple cardiometabolic risk factors were more common among youth with severe obesity. Conclusions Youth with severe obesity have identifiable differences in psychosocial and behavioral attributes that can be used to develop targeted intervention strategies to improve their health.http://deepblue.lib.umich.edu/bitstream/2027.42/173638/1/12887_2020_Article_2145.pd

Hypothyroidism in Infants With Congenital Heart Disease Exposed to Excess Iodine

Thyroid hormone is critical for neonatal brain development, and even transient hypothyroidism can cause adverse neurocognitive outcomes. Infants exposed to excess iodine are at risk of developing hypothyroidism, especially those with congenital heart disease (CHD), because they are routinely exposed to excess iodine from intravenous iodinated contrast media and topical antiseptics. The aim of the present study was to identify the proportion of neonates with CHD exposed to iodine who developed hypothyroidism and to identify the associated risk factors. This was a retrospective study of neonates undergoing cardiac catheterization at Boston Children’s Hospital during a 3-year period, some of whom also underwent cardiac surgery. Hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>20 mIU/L at 24 to 96 hours of age and >15 mIU/L at >96 hours of age by heel-stick sampling and >9.1 mIU/L at 1 to 20 weeks of age by serum testing). Multivariate logistic regression was performed to predict the odds of developing hypothyroidism. Hypothyroidism was diagnosed incidentally in 46 of 183 infants (25%) with CHD after iodine exposure. Controlling for baseline cardiac risk, postnatal age, and gestational age, we found a fourfold increase in odds of developing hypothyroidism in neonates with serum creatinine >0.9 mg/dL and a fourfold increase in those who underwent more than three procedures. Hypothyroidism in neonates with CHD exposed to excess iodine is associated with multiple procedures and impaired renal function. Routine serial monitoring of thyroid function in these neonates is warranted. Future studies should examine the association between hypothyroidism and neurocognitive function in this population

Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms.

Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the OCRL gene that impacts approximately 1 in 500 000 children. Classic features include congenital cataract, cognitive/behavioural impairment and renal tubulopathy. This study is a retrospective review of clinical features reported by family based survey conducted by Lowe Syndrome Association. Frequency of non-ocular clinical feature(s) of LS and their age of onset was summarised. An LS-specific therapy effectiveness scale was used to assess the response to the administered treatment. Expression of OCRL and relevant neuropeptides was measured in postmortem human brain by qPCR. Gene expression in the mouse brain was determined by reanalysis of publicly available bulk and single cell RNA sequencing. A total of 137 individuals (1 female, 89.1% white, median age 14 years (range 0.8-56)) were included in the study. Short stature (height OCRL is expressed in human and mouse hypothalami, and in hypothalamic cell clusters expressing Ghrh, Sst, Oxt, Pomc and pituitary cells expressing Gh and Prl. There is a wide spectrum of the clinical phenotype of LS. Some of the features may be partly driven by the loss of function of OCRL in the hypothalamus and the pituitary. © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.</CopyrightInformation

OR33-07 ARNT2: a potential novel candidate gene for monogenic obesity in humans

Introduction: Aryl hydrocarbon nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH)-PAS (Per/Arnt/Sim) transcription factor shown to be critical to the development of paraventricular nucleus of the hypothalamus (PVN), key region for energy homeostasis and feeding response. In vivo and in vitro studies have shown that ARNT2 is an obligate heterodimer for SIM1, known cause of monogenic obesity. Null mutations in Arnt2 in animals are not viable, but hypomorphic mutation results in hyperphagic obesity and its associated consequences (1). Due to the critical role of ARNT2 in the development of PVN, we hypothesize that hypomorphic mutations may result in early onset obesity in humans.Methods: The Genetics of Early Childhood Obesity (GECO) study recruits children with severe obesity (BMI &gt; 120% of 95th percentile) of early onset (&lt; 6 years). Whole exome sequencing (WES) was performed in a subset of proband-parent trios. The functional validation of the mutation(s) in ARNT2 is ongoing with co-transfection of tagged Arnt2 and Sim1 in HEK293 cells, with the induction of a luciferase reporter gene under the control of 6 repeats of bHLH-PAS core binding element by the Arnt2-Sim1 complex.Results: Two adolescents from unrelated families were found to have genetic variants in ARNT2. Subject 1 has a novel de novo heterozygous coding variant in ARNT2, c.388 C&gt;G (p.P130A, CADD 25), predicted to be deleterious by 8/12 in silico algorithms. She is a 14-year old Caucasian girl with severe early onset obesity, BMI 28.1 kg/m2 (BMIz +4.72) at 2.5 years of age that has increased to 53.54 kg/m2 (BMIz + 3.25) at 14-years, and height &gt; 95th %tile. She is non-dysmorphic, has developmental delay, absence seizures, behavior abnormalities &amp; glucose intolerance/dyslipidemia secondary to obesity. Using genematcher, we identified another proband with the phenotype of obesity: an African American girl (BMIz +1.9) with biallelic inherited heterozygous variants in ARNT2, c.1228T&gt;A (p.W410R, CADD 29) and c.916G&gt;A (p.G306S, CADD 22). An only child conceived by IVF, she is non-dysmorphic and on treatment for bilateral focal epilepsy. All 3 variants are rare, with mean allele frequency &lt; 0.005 in population-based databases such as gNOMAD. Both the patients have early onset obesity and a significant neurological phenotype. ARNT2 is a highly constrained gene of 717 amino acids with a significant depletion of missense variants in the N-terminus (1-244 aa) and overall fewer loss of function variants in ~282,644 alleles sequenced in gNOMAD.CConclusions: We propose that hypomorphic mutations in ARNT2 could be a potential novel cause of monogenic obesity in humans. Future studies will investigate the molecular mechanisms causing weight dysregulation in patient specific disease relevant hypothalamic neurons.Reference: (1) Turer et al., Dis Model Mech. 2018; 11(12

Whole Exome Sequencing Identifies RAI1 Mutation in a Morbidly Obese Child Diagnosed With ROHHAD Syndrome

Context: The current obesity epidemic is attributed to complex interactions between genetic and environmental factors. However, a limited number of cases, especially those with early-onset severe obesity, are linked to single gene defects. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is one of the syndromes that presents with abrupt-onset extreme weight gain with an unknown genetic basis. Objective: To identify the underlying genetic etiology in a child with morbid early-onset obesity, hypoventilation, and autonomic and behavioral disturbances who was clinically diagnosed with ROHHAD syndrome. Design/Setting/Intervention: The index patient was evaluated at an academic medical center. Whole-exome sequencing was performed on the proband and his parents. Genetic variants were validated by Sanger sequencing. Results: We identified a novel de novo nonsense mutation, c.3265 C>T (p.R1089X), in the retinoic acid-induced 1 (RAI1) gene in the proband. Mutat..