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  • 1
    In: Genes, MDPI AG, Vol. 12, No. 6 ( 2021-06-07), p. 875-
    Abstract: Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C 〉 T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.
    Type of Medium: Online Resource
    ISSN: 2073-4425
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527218-4
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  • 2
    In: Journal of Medical Genetics, BMJ, Vol. 55, No. 9 ( 2018-09), p. 578-586
    Abstract: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. Methods DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m 2 ; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. Results In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. Conclusions NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    RVK:
    Language: English
    Publisher: BMJ
    Publication Date: 2018
    detail.hit.zdb_id: 2009590-9
    SSG: 12
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  • 3
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 6, No. Supplement_1 ( 2022-11-01), p. A639-A640
    Abstract: Pediatric obesity is a multifactorial disease characterized by a prolonged imbalance between energy intake and expenditure. In rare cases, it is caused by underlying medical disorders arising from disruptions in the leptin-melanocortin pathway which regulates satiety and energy expenditure. Aim To investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with and without underlying medical causes. Methods This prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic center in which endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity were evaluated. Patients in whom no underlying medical cause was identified were classified as multifactorial obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio measured REE (mREE) vs predicted REE (Schofield equations) was expressed as REE%, with decreased mREE defined as REE% ≤90% and elevated mREE as ≥110%. Additionally, the ratio mREE vs fat-free-mass (FFM) was calculated. Results We included 292 patients, of which 218 (75%) patients had multifactorial obesity and 74 (25%) had an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p & lt;0.01). Measured REE was decreased in 60 (21%) patients (corresponding to an average overprediction of daily caloric needs of 341 kcal/day) and elevated in 69 (24%) patients. Only in hypothalamic obesity, a larger proportion of patients showed a decreased REE compared to multifactorial obesity (6/10 vs 41/218, p & lt;0.01). FFM was higher in children with non-syndromic obesity compared to multifactorial obesity (+7.5kg, p & lt;0.001), but lower in syndromic obesity (-5.2kg, p=0.03), hypothalamic obesity (-12.6kg, p & lt;0.001), and similar in medication-induced obesity (+1.5kg FFM, p=0.80). Mean mREE/FFM was 46.5 ± 10.6 kcal/day/kg FFM and did not differ between patients with underlying medical causes compared to multifactorial obesity (all p & gt;0.05). Conclusion In this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Almost half of patients had decreased or elevated mREE. When relating mREE to FFM, no differences were found between children with underlying medical causes versus multifactorial obesity. Thus, our study underlines the importance of measuring REE and relating mREE to FFM in children with early-onset severe obesity with or without underlying medical causes. This knowledge is important for patient-tailored treatment, e.g. personalized dietary or physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
    detail.hit.zdb_id: 2881023-5
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  • 4
    In: Acta Ophthalmologica, Wiley, Vol. 98, No. 4 ( 2020-06), p. 390-395
    Abstract: Central serous chorioretinopathy ( CSC ), a distinct form of macular degeneration, has been associated with glucocorticoid use and possibly also with an increased endogenous activity of the hypothalamic‐pituitary‐adrenal ( HPA ) axis. To estimate long‐term glucocorticoid exposure, measurement of hair cortisol concentrations ( HCC ) has emerged. This cross‐sectional study aimed to investigate HCC , as a reflection of chronic endogenous steroid exposure, in a cohort of patients with chronic CSC ( cCSC ). Methods Hair cortisol concentrations (HCC) were determined in 48 patients with cCSC and 230 population‐based controls (Lifelines cohort study), not using exogenous corticosteroids. Results Increased HCC (defined as 〉 10.49 pg/mg) were present in 2 (4%) patients with cCSC and 13 (6%) controls. Mean HCC values were not different between patients and controls, and no difference in HCC was found between patients with active cCSC disease and patients with inactive disease. No correlation between HCC and urinary free cortisol ( UFC ) levels in patients with cCSC was found. Conclusions This study shows that HCC in patients with cCSC are not elevated compared to population‐based controls, and no association between HCC and cCSC severity was found. This finding questions the previous suggestion that cCSC is associated with increased HPA axis activity. In line, HCC do not seem useful in monitoring cCSC disease activity.
    Type of Medium: Online Resource
    ISSN: 1755-375X , 1755-3768
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2466981-7
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  • 5
    In: International Journal of Endocrinology and Metabolism, Briefland, Vol. 21, No. 1 ( 2022-12-29)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1726-913X , 1726-9148
    Language: Unknown
    Publisher: Briefland
    Publication Date: 2022
    detail.hit.zdb_id: 2744447-8
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  • 6
    In: European Journal of Endocrinology, Oxford University Press (OUP), Vol. 173, No. 4 ( 2015-10), p. 455-464
    Abstract: Excess glucocorticoids are known to cause hypertension and cardiovascular disease (CVD). The Bcl I glucocorticoid receptor (GR) polymorphism increases glucocorticoid sensitivity and is associated with adverse metabolic effects. Previous studies investigating cardiovascular implications have shown inconsistent results. Therefore, the aim of the present study was to investigate the association of the Bcl I polymorphism with blood pressure, atherosclerosis, low-grade inflammation, endothelial dysfunction, and prevalent CVD. Design Observational cohort study, combining two cohort studies designed to investigate genetic and metabolic determinants of CVD. Methods We genotyped 1228 individuals (aged 64.7 years±8.5) from the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study and Hoorn study for the Bcl I polymorphism. We measured blood pressure, ankle–brachial index (ABI), and carotid intima–media thickness (cIMT). Low-grade inflammation and endothelial dysfunction scores were computed by averaging Z -scores of six low-grade inflammation markers and four endothelial dysfunction markers respectively. Prevalent CVD was assessed with questionnaires, hospital records, ECG, and ABI. Results Homozygous carriers (GG) had higher mean arterial pressure (103.8±12.4 mmHg vs 101.6±12.2 mmHg (mean± s.d .); P 〈 0.05) compared with non-carriers (CC). Homozygous carriers had lower ABI compared with heterozygous carriers (CG) (1.08±0.13 vs 1.11±0.14; P 〈 0.05). After adjustment for all covariates in the full model, the association with ABI was no longer significant. Bcl I was not associated with systolic blood pressure, cIMT, low-grade inflammation, endothelial dysfunction, and prevalent CVD. Conclusions The Bcl I polymorphism of the GR gene may contribute to an unfavorable cardiovascular profile; however, the effects on cardiovascular variables appear to be limited and partly mediated by the metabolic phenotype exerted by Bcl I.
    Type of Medium: Online Resource
    ISSN: 0804-4643 , 1479-683X
    RVK:
    Language: Unknown
    Publisher: Oxford University Press (OUP)
    Publication Date: 2015
    detail.hit.zdb_id: 1485160-X
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  • 7
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 107, No. 9 ( 2022-08-18), p. e3699-e3704
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
    detail.hit.zdb_id: 2026217-6
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  • 8
    In: BMJ Open, BMJ, Vol. 11, No. 12 ( 2021-12), p. e054405-
    Abstract: The synthetic glucocorticoid dexamethasone can induce serious neuropsychiatric adverse effects. Dexamethasone activates the glucocorticoid receptor (GR) but, unlike endogenous cortisol, not the mineralocorticoid receptor (MR). Moreover, dexamethasone suppresses cortisol production, thereby eliminating its MR binding. Consequently, GR overactivation combined with MR underactivation may contribute to the neuropsychiatric adverse effects of dexamethasone. The DEXA-CORT trial aims to reactivate the MR using cortisol to reduce neuropsychiatric adverse effects of dexamethasone treatment. Methods and analysis The DEXA-CORT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients who undergo elective brain tumour resection treated perioperatively with high doses of dexamethasone to minimise cerebral oedema. 180 patients are randomised between treatment with either two times per day 10 mg hydrocortisone or placebo during dexamethasone treatment. The primary study outcome is the difference in proportion of patients scoring ≥3 points on at least one of the Brief Psychiatric Rating Scale (BPRS) questions 5 days postoperatively or earlier at discharge. Secondary outcomes are neuropsychiatric symptoms, quality of sleep, health-related quality of life and neurocognitive functioning at several time points postoperatively. Furthermore, neuropsychiatric history, serious adverse events, prescribed (psychiatric) medication and referrals or evaluations of psychiatrist/psychologist and laboratory measurements are assessed. Ethics and dissemination The study protocol has been approved by the Medical Research Ethics Committee of the Leiden University Medical Center, and by the Dutch competent authority, and by the Institutional Review Boards of the participating sites. It is an investigator-initiated study with financial support by The Netherlands Organisation for Health Research and Development (ZonMw) and the Dutch Brain Foundation. Results of the study will be submitted for publication in a peer-reviewed journal. Trial registration number NL6726 (Netherlands Trial Register); open for patient inclusion. EudraCT number 2017-003705-17.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2599832-8
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  • 9
    In: Obesity Reviews, Wiley, Vol. 23, No. 8 ( 2022-08)
    Abstract: Quality of life is a key outcome that is not rigorously measured in obesity treatment research due to the lack of standardization of patient‐reported outcomes (PROs) and PRO measures (PROMs). The S.Q.O.T. initiative was founded to Standardize Quality of life measurement in Obesity Treatment. A first face‐to‐face, international, multidisciplinary consensus meeting was conducted to identify the key PROs and preferred PROMs for obesity treatment research. It comprised of 35 people living with obesity (PLWO) and healthcare providers (HCPs). Formal presentations, nominal group techniques, and modified Delphi exercises were used to develop consensus‐based recommendations. The following eight PROs were considered important: self‐esteem, physical health/functioning, mental/psychological health, social health, eating, stigma, body image, and excess skin. Self‐esteem was considered the most important PRO, particularly for PLWO, while physical health was perceived to be the most important among HCPs. For each PRO, one or more PROMs were selected, except for stigma. This consensus meeting was a first step toward standardizing PROs (what to measure) and PROMs (how to measure) in obesity treatment research. It provides an overview of the key PROs and a first selection of the PROMs that can be used to evaluate these PROs.
    Type of Medium: Online Resource
    ISSN: 1467-7881 , 1467-789X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2020497-8
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  • 10
    In: Frontiers in Endocrinology, Frontiers Media SA, Vol. 13 ( 2022-7-11)
    Abstract: 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 & lt;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 & gt;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.
    Type of Medium: Online Resource
    ISSN: 1664-2392
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2592084-4
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