Severe pediatric obesity:Diagnostic aspects

Severe pediatric obesity is a complex, chronic endocrine disease caused by genetic, environmental, behavioral, socioeconomic and cultural factors. In a minority of children with severe obesity, the obesity phenotype is caused by a singular underlying medical cause interfering with the function of the brain areas that regulate satiety and energy expenditure. Current guidelines define the following underlying medical causes: (1) genetic obesity disorders, (2) hypothalamic obesity, (3) endocrine obesity, and (4) medication-induced obesity. This thesis investigated several important diagnostic aspects of severe pediatric obesity. For example, the yield of the systematic diagnostic workup of Obesity Center CGG is described. A singular underlying medical cause was identified in 19% of patients, most of which (13%) were genetic obesity disorders (13% of patients). This shows that an extensive diagnostic approach is needed to identify the underlying medical causes. Furthermore, this thesis shows that the reported prevalence of a specific genetic obesity disorder, leptin receptor deficiency deficiency in Europe is only 2% of predicted prevalence, suggesting underreporting, underdiagnosis, early mortality, or a combination of these factors. This suggests that genetic screening should be performed in all cases with early-onset severe obesity and hyperphagia. This thesis also describes BMI trajectories of patients with genetic obesity and controls with obesity from a population-based cohort study. The presented BMI trajectories can thereby guide clinicians’ decision to perform genetic testing. Finally, a general discussion in the context of current literature is provided, including recommendations, future perspectives and implications

Genetic Obesity Disorders:Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population

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 &lt; .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.</p

Severe pediatric obesity:Diagnostic aspects

Severe pediatric obesity is a complex, chronic endocrine disease caused by genetic, environmental, behavioral, socioeconomic and cultural factors. In a minority of children with severe obesity, the obesity phenotype is caused by a singular underlying medical cause interfering with the function of the brain areas that regulate satiety and energy expenditure. Current guidelines define the following underlying medical causes: (1) genetic obesity disorders, (2) hypothalamic obesity, (3) endocrine obesity, and (4) medication-induced obesity. This thesis investigated several important diagnostic aspects of severe pediatric obesity. For example, the yield of the systematic diagnostic workup of Obesity Center CGG is described. A singular underlying medical cause was identified in 19% of patients, most of which (13%) were genetic obesity disorders (13% of patients). This shows that an extensive diagnostic approach is needed to identify the underlying medical causes. Furthermore, this thesis shows that the reported prevalence of a specific genetic obesity disorder, leptin receptor deficiency deficiency in Europe is only 2% of predicted prevalence, suggesting underreporting, underdiagnosis, early mortality, or a combination of these factors. This suggests that genetic screening should be performed in all cases with early-onset severe obesity and hyperphagia. This thesis also describes BMI trajectories of patients with genetic obesity and controls with obesity from a population-based cohort study. The presented BMI trajectories can thereby guide clinicians’ decision to perform genetic testing. Finally, a general discussion in the context of current literature is provided, including recommendations, future perspectives and implications

Impact of body mass index on growth hormone stimulation tests in children and adolescents: A systematic review and meta-analysis

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

Impact of body mass index on growth hormone stimulation tests in children and adolescents

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

Leukocyte Telomere Length in Children with Congenital Adrenal Hyperplasia.

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. DESIGN Prospective observational cohort study. Patients were followed-up at two visits (mean 4.1 ± 0.7 months apart). SETTING Four academic Pediatric Endocrinology Outpatient Clinics. PATIENTS Children aged 0-18 years with genetically confirmed CAH. MAIN OUTCOME MEASURES 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 -0.12-1.43). LTL was shorter in patients with classic compared to non-classic 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  0.05). CONCLUSIONS LTL is shorter in patients with classic than non-classic CAH, as well as 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

Second case of Bardet–Biedl syndrome caused by biallelic variants in IFT74

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive disorder of the cilia, often resulting in a phenotype of obesity, rod-cone dystrophy, a variable degree of intellectual disability, polydactyly, renal problems, and/or hypogonadism in males or genital abnormalities in females. We here report the case of an 11-year-old girl who presented with postaxial polydactyly, retinal dystrophy, and childhood obesity, suggesting Bardet–Biedl syndrome. She had no renal problems, developmental delay, or intellectual disability. Genetic testing revealed compound heterozygous variants in the IFT74 gene (c.371_372del p.Gln124Argfs*9 and c.16850–1G>T p.?). We here report the second patient with Bardet–Biedl syndrome due to biallelic IFT74 variants. Both patients have obesity, polydactyly, retinal dystrophy, and no renal abnormalities. The present case however, has normal intellect, whereas the other patient has intellectual disability. We hereby confirm IFT74 as a BBS gene and encourage diagnostic genetic testing laboratories to add IFT74 to their BBS gene panels