Syndromic Forms Of Obesity Research Articles

Genetic Contributors to Obesity

Genetic forms of obesity contribute to ∼7% of severe obesity in children and adolescents. The exact global prevalence of monogenic and syndromic forms of obesity is not well established, most likely due to missed or delayed diagnosis. The challenge in determining the prevalence can be attributed to the lack of consensus on identifying and evaluating symptoms of genetic defects in a timely manner and hence a vastly undertested patient population. Further large-scale and long-term studies are needed to advance the understanding of this unique phenotype of obesity and effective treatment options."

Biallelic Mutations in P4HTM Cause Syndromic Obesity.

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

Obesity is rarely curable: individual concepts and therapy programs for children and adolescents

Obesity in children has an increased risk to persist in adulthood. In most cases, obesity starts to develop in children at school age. Lower social economic status and migration background are severe risk factors for obesity. Additionally, genetic predisposition for the development of obesity plays an especially important role in children and adolescents. However, the individual cause for obesity is heterogeneous and complex. This is the reason why only asystematic analysis of individually existing problems is necessary for adifferentiated and realistic planning of the treatment. Long-lasting therapy concepts need to be based on current available evidence.The treatment of childhood obesity should rely on multiprofessional lifestyle programs. An exception might be rare monogenic or syndromic forms of obesity, because defects within the central regulatory pathways of body weight regulation could be present. In general, akey component of the treatment strategy should include an improvement of nutrition, physical exercise and self-esteem combined with areduction of stress. Moreover, the inclusion of parents into the treatment strategy has shown to be beneficial and necessary. Long-term follow-up studies on the development of associated comorbidities are rare. Unfortunately, patient groups at risk are currently not necessarily reached with available treatment programs.Amultiprofessional analysis of individual problems and differentiated treatment planning with aparticipative approach (acknowledging the cultural background and involving members of the family) should lead to long-lasting improvement of the therapeutic outcome. The individual main treatment aim should also include - apart from the reduction of body weight - the improvement of associated comorbidities and quality of life, especially by avoiding any stigmatization. Ahealth-promoting environment is desirable for this salutogenetic approach.

Outcomes in morbidly obese adolescent patients undergoing laparoscopic sleeve gastrectomy in the Indian subcontinent: A retrospective review

Introduction:There is a worldwide increase in the prevalence of obesity among the adolescent population in India from 16.3% in 2001 to 19.3% in 2010. Recent evidence suggests that bariatric surgery leads to resolution of comorbidities and associated long-term complications in adolescent patients with morbid obesity.Aim:The aim of this study is to determine the impact of bariatric surgery on the weight loss and comorbidities of morbidly obese adolescents.Materials and Methods:A retrospective review of the data of 10 adolescent patients, who underwent Laparoscopic Sleeve Gastrectomy at our institute (tertiary care hospital), from July 2009 to July 2016 was carried out.Results:Of the 10 patients, 4 patients had syndromic forms of obesity. The median age was 16.54 years. The median pre-operative weight and height were 112 kg and 154 cm, respectively, with a body mass index of 47.2 kg/m2. There was no intra-operative or post-operative complication except for suspected methylene blue toxicity in one patient which was treated conservatively. Median follow-up period was 1 year (0–5 years). The patients had an increase in excess weight loss (EWL) of 54.5% until the end of 1 year. There was a regain of weight between the 1st and 2nd year, followed by a sustained weight loss achieving 44.8% EWL at 3 years and 60% at the end of 5 years (only two patients followed up at 5 years). Similar results were found in syndromic patients. Among the four diabetic patients, three had complete resolution and one had improvement in diabetes status. Among the three patients with obstructive sleep apnoea, two patients had complete resolution, while one patient had improvement in symptoms. One patient with hypocortisolism improved after surgery with a decrease in the steroid requirement. Among the hypothyroid patients, one patient had a complete resolution, one patient had improvement in hypothyroid status while two patients had no change.Conclusion:Bariatric surgery is effective for morbidly obese adolescents, leading to significant resolutions of comorbid illness.

A261 - CAN CHILDREN WITH GENETIC SYNDROME BE OFFERED BARIATRIC SURGERY?

Background: Obesity-related complication is one of the leading causes of mortality in children with genetic syndrome. Most syndromic forms of obesity are associated with mild to severe cognitive deficits and unusual behaviors. While many other syndromes affecting cognition such as Down syndrome are also associated with a higher incidence of obesity.

Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity

BackgroundSyndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype.ResultsPathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the GNB3 gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility loci. We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (CHAMP1), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. PTBP2, TMEM18, MYT1L, POU3F2, SIM1, SH2B1), and also identified other potentially relevant candidates including TAS1R3, ALOX5AP, and GAS6.ConclusionUnderstanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.

Cytokine Responses to Acute Intermittent Aerobic Exercise in Children With Prader-Willi Syndrome and Nonsyndromic Obesity.

Prader-Willi Syndrome (PWS), the best characterized form of syndromic obesity, presents with abnormally high fat mass. In children, obesity presents with low-grade systemic inflammation. This study evaluated if PWS and/or nonsyndromic obesity affected cytokine responses to intermittent aerobic exercise in children. Eleven children with PWS (11 ± 2 y, 45.4 ± 9.5% body fat), 12 children with obesity (OB) (9 ± 1 y, 39.9 ± 6.8% body fat), and 12 lean (LN) children (9 ± 1 y, 17.5 ± 4.6% body fat) participated. Children completed 10 2-min cycling bouts of vigorous intensity, separated by 1-min rest. Blood samples were collected preexercise (PRE), immediately postexercise (IP), and 15, 30, and 60 min into recovery to analyze possible changes in cytokines. In all groups, IL-6 and IL-8 concentrations were greater during recovery compared with PRE. PWS and OB exhibited higher IL-6 area under the curve (AUC) than LN (p < .01 for both). PWS demonstrated higher IL-8 AUC than LN (p < .04). IL-10, TNF-α, and IFN-γ did not change with exercise (p > .05 for all). Results indicate that children with PWS respond with increased Il-6 and IL-8 concentrations to acute exercise similarly to controls. Excess adiposity and epigenetic modifications may explain the greater integrated IL-6 and IL-8 responses in PWS compared with controls.

Bariatric surgery in monogenic and syndromic forms of obesity

Currently, no topic is more controversial in bariatric surgery than performing these procedures on children with monogenic and syndromic forms of obesity. The medical community and the caregivers of those patients are struggling to find a solution that can alleviate their suffering and save their life. In all forms of obesity, dieting and physical activity do not result in significant weight loss and is associated with a high rate of weight regain. Additionally, effective medical therapy is not available yet. While there is significant debate about the risks and benefits of bariatric surgery in the adolescent population, there is an increasing number of studies that demonstrate the success of this option for the appropriate patients. Similarly, our experience demonstrated the same success not only in normal children and adolescents but also in those with monogenic and syndromic form of obesity.

Obesity with associated developmental delay and/or learning disability in patients exhibiting additional features: Report of novel pathogenic copy number variants

Obesity is a major threat to public health worldwide, and there is now mounting evidence favoring a role for the central nervous system (CNS) in weight control. A causal relationship has been recognized in both monogenic (e.g., BDNF, TRKB, and SIM1 deficiencies) and syndromic forms of obesity [e.g., Prader-Willi syndrome (PWS)]. Syndromic obesity arising from chromosomal abnormalities, that typically also affect learning and development, are often associated with congenital malformations and behavioral characteristics. We report on nine unrelated patients with a diagnosis of learning disability and/or developmental delay (DD) in addition to obesity that were found to have copy number variants (CNVs) by single nucleotide polymorphism array-based analysis. Each patient also had a distinct and complex phenotype, and most had hypotonia and other neuroendocrine issues, such as hyperphagia and hypogonadism. Molecular and clinical characterization of these patients enabled us to determine with confidence that the CNVs we observed were pathogenic or likely to be pathogenic. Overall, the CNVs reported here encompassed a candidate gene or region (e.g., SIM1) that has been reported in patients associating obesity and DD and/or intellectual disability (ID) and novel candidate genes and regions.

Heritability of body weight: Moving beyond genetics

Obesity is a complex disease, arising from the interaction between several genetic and environmental factors. Until recently, the genetic basis of complex diseases in general, and of obesity in particular, were poorly characterized. While the relatively rare monogenic and syndromic forms of obesity clearly recognize a genetic origin, the actual worldwide epidemics of obesity represent a challenge for the identification of the genetic factors involved, being likely the effect of several loci each having a subtle influence on the phenotypic expression. Progress in DNA analysis techniques and in computational tools, and the increasing level of characterization of the variability of the human genome has recently allowed to study comprehensively the association between genetic variants and obesity. To date, well-conducted and powered genome-wide association studies allowed to consistently identify genomic regions – lying on different chromosomes and affecting different metabolic pathways – influencing the predisposition to the accumulation of body fat, ultimately leading to overweight and obesity. However, the population attributable risk for obesity linked to the most statistically significant loci, like FTO and MC4R, remains discouragingly low, explaining only small fractions of the overall variance of body weight. In the last few years, the role of the complex interaction between genetic determinants and environmental factors in the rapid global increase of obesity has been further challenged by the entry of new players, that is the transcriptional and post-transcriptional regulation, summarized under the emerging discipline of epigenetics. The key challenge now is to move from the identification of causal genes and variants to the integration of different “omics” disciplines, finally allowing the molecular understanding of obesity and related conditions.