Clinically Meaningful Outcomes after 1 Year of Treatment with Setmelanotide in an Adult Patient with a Variant in SH2B1.

INTRODUCTION: Monogenic obesity is caused by a unique genetic dysfunction, often appears in childhood, and can be accompanied by neuroendocrine, skeletal, developmental, and behavioral disorders, among other manifestations. Some variants in the SH2B1 gene have been suggested as strong candidates for the development of autosomal dominant obesity. CASE PRESENTATION: We describe here the clinical response after 1 year of setmelanotide treatment in a 22-year-old patient with an SH2B1 variant. After 3 months of treatment, our patient lost 5.4% of body weight. This period was followed by a 3-month period of noncompliance, in which the patient gained 4% body weight. After reinstating daily drug administration, the patient showed a 19.5% reduction in body weight and a clear improvement in all hunger scales after 1 year of treatment. CONCLUSION: These results indicate that the changes seen are drug dependent and provide positive evidence for the administration of setmelanotide in adult patients with heterozygous variants in the SH2B1 gene.

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 < .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.

SH2B1 variants as potential causes of non-syndromic monogenic obesity in a Brazilian cohort.

PURPOSE: SH2B1 gene encodes an important adaptor protein to receptor tyrosine kinases or cytokine receptors associated with Janus kinases. This gene has been associated with the structural and functional modulation of neurons and other cells, and impacts on energy and glucose homeostasis. Several studies suggested that alterations in this gene are strong candidates for the development of obesity. However, only a few studies have screened SH2B1 point variants in individuals with obesity. Therefore, the aim of this study was to investigate the prevalence of SH2B1 variants in a Brazilian cohort of patients with severe obesity and candidates to bariatric surgery. METHODS: The cohort comprised 122 individuals with severe obesity, who developed this phenotype during childhood. As controls, 100 normal-weight individuals were included. The coding region of SH2B1 gene was screened by Sanger sequencing. RESULTS: A total of eight variants were identified in SH2B1, of which p.(Val345Met) and p.(Arg630Gln) variants were rare and predicted as potentially pathogenic by the in the silico algorithms used in this study. The p.(Val345Met) was not found in either the control group or in publicly available databases. This variant was identified in a female patient with severe obesity, metabolic syndrome and hyperglycemia. The p.(Arg630Gln) was also absent in our control group, but it was reported in gnomAD with an extremely low frequency. This variant was observed in a female patient with morbid obesity, metabolic syndrome, hypertension and severe binge-eating disorder. CONCLUSION: Our study reported for the first time two rare and potentially pathogenic variants in Brazilian patients with severe obesity. Further functional studies will be necessary to confirm and elucidate the impact of these variants on SH2B1 protein function and stability, and their impact on energetic metabolism. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.

When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin.

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

Identification of a Rare and Potential Pathogenic MC4R Variant in a Brazilian Patient With Adulthood-Onset Severe Obesity.

BACKGROUND: The melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor (MC4R) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity. METHODS: This study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m2, stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0-11 years), 19 patients in the adolescence/youth-onset group (12-21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject's DNA was assessed using automated Sanger sequencing. RESULTS: Significant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity. CONCLUSION: This study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity.