Kumar, Seema

ABSTRACT Bardet‐Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.

Pediatric obesity represents an urgent public health concern, with rapidly increasing prevalence across all regions. While genetic susceptibility contributes significantly to interindividual variability in weight, the significant increase in obesity prevalence over the last 30 years is driven by shifts in environmental contributors. This narrative review will summarize evidence on the major environmental determinants of childhood obesity. Environmental contributors to obesity include the food environment, physical activity and built environments, socioeconomic and community context, home and family environments, digital exposures, early life and chemical obesogens and policy drivers. These environmental factors influence activity patterns, dietary habits, sleep, and stress. Additionally, many of these contributing factors cluster within communities that are disadvantaged, thereby increasing predisposition of specific racial, ethnic and socioeconomic groups to childhood obesity. We highlight research gaps and opportunities for multisectoral interventions aligned to impact the growing prevalence of childhood obesity.

ABSTRACT Objectives To evaluate the impact of semaglutide on body mass index (BMI) and cardiometabolic markers in adolescents with obesity and genetic variants associated with monogenic or syndromic obesity. Methods A retrospective chart review was conducted in adolescents with severe obesity who underwent multigene panel testing and were treated with semaglutide. Results Twenty‐seven adolescents (mean age 15 ± 1.9 years); BMI % of the 95th percentile 158 ± 29; (70% White) were treated with semaglutide for a mean of 10 ± 4.7 months. Participants were classified into three groups: (1) Dominant or Known Risk Variants ( n = 7); (2) Carriers of Rare Variants in Recessive Genes ( n = 10); and (3) Negative or Unmatched Genetic Findings ( n = 10). All groups showed reductions in BMI, which was not different between the groups. Adolescents with dominant or known risk variants experienced a significant decrease in BMI % of the 95th percentile (−17, (IQR −26 to −10) p = 0.022) and in BMI by −9.4% ± 7% ( p = 0.035). Significant improvements in median non‐HDL cholesterol (−16 mg/dL), total cholesterol (−15 mg/dL), and HbA1c (−0.3%) were noted in children with dominant or known risk variants ( p = 0.036). Conclusions Semaglutide was associated with significant reductions in BMI and cardiometabolic markers in adolescents (majority White) with dominant or known risk variants for monogenic obesity.

Pediatric obesity is an increasingly prevalent, chronic, and multifactorial disease. Achieving successful and sustained weight reduction with current interventions remains challenging due to significant heterogeneity in treatment response. This review summarizes current evidence describing variability in outcomes across lifestyle, pharmacologic, and metabolic/bariatric surgery interventions in children and adolescents, and examines key biological, metabolic, behavioral, environmental, and psychosocial factors that influence response. In adults, recent findings on energy balance obesity phenotypes (characterized by abnormal satiation, abnormal postprandial satiety, abnormal hedonic eating, and reduced energy expenditure) have demonstrated promise in predicting weight loss outcomes and guiding tailored interventions. However, data on obesity phenotyping within children and adolescents remain limited. Addressing this gap is essential for advancing precision medicine approaches in pediatric obesity, with the potential to improve treatment selection, enhance effectiveness, and optimize long-term clinical outcomes.

Abstract Context Pharmacological options for the treatment of early severe childhood obesity are limited. Objective This retrospective case series evaluates the effect of topiramate on weight and cardiometabolic parameters in young children with severe obesity, including those with hypothalamic etiologies. Methods This is a retrospective case series including 14 children with severe obesity, who were treated with topiramate prior to age 12 years. Anthropometric and metabolic data were analyzed. Results The median age at initiation of topiramate treatment was 10.1 years (range, 7.9-11.2 years) and 64% were boys. At baseline, the median body mass index (BMI) was 149% of the 95th percentile (range, 136%-200%). The median treatment duration was 14 months (interquartile range, 9.5-24 months), with a maximum tolerated dose of 75 mg (range, 50-150 mg). There was a median decrease in BMI% of the 95th percentile of 8% (95% CI, −15 to −1.02; P = .042), and a reduction in BMI z score by 0.37 (95% CI, −0.66 to −0.05; P = .028). The most notable response was in a child with hypothalamic obesity who experienced a 35-point reduction in BMI% of the 95th percentile over 24 months. While 11 of 14 children showed reduction in BMI, 3 had no change or increase in their BMI. No significant changes were observed in cardiometabolic markers or linear growth. Conclusion Topiramate monotherapy resulted in significant BMI reductions in young children with severe obesity, including those with hypothalamic obesity. Further prospective randomized controlled trials are warranted to assess its long-term efficacy for obesity management in young children.

Abstract Disclosure: D. Hassan: None. M. Salama: None. S. Kumar: None. K. Muthusamy: None. Background: Obesity is prevalent among individuals with Bardet-Biedl Syndrome (BBS), affecting approximately 72%-86% of patients. Setmelanotide, an MC4R agonist, is approved for the treatment of obesity in patients with BBS. It reduces hyperphagia and improves quality of life. However, the high cost of setmelanotide and the need for daily injections limit its use. Affordable and effective alternative pharmacotherapies are needed for managing obesity in patients with BBS. Here, we present a case of an adult with BBS who experienced significant weight loss following treatment with a combination of topiramate and phentermine. Clinical Case: A 29-year-old Hispanic female with BBS due to a homozygous BBS2 mutation (NM_031885.3, c.717+1G>T, GT donor) was evaluated for migraine. BMI was elevated at 42.5 kg/m², and obesity was complicated by obstructive sleep apnea, chronic respiratory failure requiring supplemental oxygen with activity, impaired fasting glucose (101 mg/dL; reference range [RR]: 70-100 mg/dL), and dyslipidemia (triglycerides: 252 mg/dL [RR: 30-150 mg/dL]; very low-density lipoprotein (VLDL): 50.4 mg/dL [RR: 8-30 mg/dL]; total cholesterol: 190 mg/dL [RR: 0-200 mg/dL]; high-density lipoprotein (HDL): 40 mg/dL [RR: 40-60 mg/dL]). She had polydactyly, retinal dystrophy, developmental delay and subclinical hypothyroidism. Topiramate was initiated at 25 mg and subsequently increased to 50 mg. At 31 years of age, BMI was 40.5 kg/m², and weight had decreased by 7.5 kg after two years of therapy with topiramate and lifestyle interventions. Phentermine 30 mg daily was added. She experienced a notable appetite-suppressing effect, reduced nighttime eating, fewer sugar cravings, and decreased stress-related eating. She was able to extend the duration of exercise with improved endurance. She reported constipation as a side effect but had no other intolerances. After three months of phentermine therapy, BMI decreased to 34.96 kg/m². Repeat metabolic profile revealed fasting glucose 70 mg/dL, HbA1c 5.5% (RR: 4.5-5.6%), triglycerides 204 mg/dL, VLDL 40.8 mg/dL, total cholesterol 175 mg/dL, HDL 38 mg/dL, and low-density lipoprotein (LDL) 96 mg/dL (RR: 70-100 mg/dL). Eight months after starting phentermine, BMI further decreased to 32.31 kg/m², reflecting a 25% total weight loss. Conclusion: This case report highlights the excellent weight loss response (25% total weight loss) and significant improvement in metabolic profile with phentermine and topiramate combination therapy in a patient with BBS. The effects of this combination therapy have not been formally studied in BBS, emphasizing the need for further research to evaluate the efficacy of conventional anti-obesity medications—used alone, sequentially, or in combination with setmelanotide—to optimize weight and metabolic outcomes. Keywords: Bardet-Biedl Syndrome, obesity, topiramate, phentermine, weight loss. Presentation: Sunday, July 13, 2025

Abstract Disclosure: M. Salama: None. F. Pinto e Vairo: None. D. Hassan: None. S. Pittock: None. A. Lteif: None. O. Olson: None. A. Al Nofal: None. K. Leopold: None. S. Kumar: None. Objective: This study aimed to evaluate the effects of semaglutide on body mass index (BMI) and cardiometabolic profiles in adolescents with genetic variants associated with a likely high risk of monogenic obesity. Methods: A retrospective chart review was conducted for adolescents with severe obesity who underwent multigene panel testing for monogenic obesity and were treated with semaglutide. Results: Data from 27 adolescents were analyzed. At baseline, the median BMI percent of the 95th percentile (IQR) was 148 (135-189), with a mean age (SD) of 15.5 years (1.93) at treatment initiation and a median (IQR) treatment duration of 8 months (6-12). The median semaglutide dose (IQR) was 1.7 mg weekly (1.0- 2.4). Seven participants comprised the ‘’likely monogenic risk’’ group, characterized by predicted deleterious variants in dominant genes and/or carrying known dominant risk alleles. Twenty patients formed the “indetermined/negative “group, defined as harboring single rare variants in recessive genes or negative panel testing. In the likely monogenic risk group, weight loss was 8.5% with a median decrease in BMI % of the 95th %ile of 17 (95% CI 1.5- 22, p = 0.02). In the indetermined/negative group, weight loss was 7.6% with a median decrease in BMI % of the 95th %ile of 14 (95% CI 11.5- 27.5, p = <0.001). There was no statistically significant difference in median BMI % of the 95th % ile reduction between the two groups (p = 0.8) or BMI percent change (p = 0.89). Cardiometabolic changes in the likely monogenic risk group included reductions in HbA1c by 0.3% (95% CI: 0.15- 0.4, p = 0.03), total cholesterol by 15 mg/dL (95% CI: 7- 48, p = 0.03), and non-HDL cholesterol by 16.5 mg/dL (95% CI: 12- 40, p = 0.03). No significant changes were observed in fasting blood glucose, triglycerides, LDL cholesterol, HDL cholesterol, or ALT levels. The indetermined/negative group exhibited a significant reduction in HbA1c by 0.25% (95% CI 0.1 - 0.7| p = 0.009). Conclusion: Semaglutide treatment was associated with significant reductions in BMI and improvements in several cardiometabolic parameters in adolescents with likely high-risk monogenic obesity variants. These findings suggest semaglutide as a potentially effective therapeutic option for managing severe obesity in this population. Larger prospective studies are warranted to confirm and further assess these outcomes. Presentation: Monday, July 14, 2025

Abstract Disclosure: D. Hassan: None. M. Salama: None. K. Muthusamy: None. A.M. Haqq: None. S. Kumar: None. Introduction: Bardet-Biedl syndrome (BBS) is a rare genetic condition characterized by obesity and considerable clinical and genetic heterogeneity. While cardiometabolic and endocrine comorbidities are commonly associated with BBS, data on their prevalence, particularly in children, remain limited. Objective: To assess the prevalence of cardiometabolic and endocrine comorbidities among pediatric and adult patients with BBS. Methods: This is a retrospective chart review of pediatric and adult patients with BBS evaluated in the outpatient setting at Mayo clinic. The cohort included individuals aged 0-50 years with either a clinical or genetic diagnosis of BBS, identified from January 1, 2000, onward. Demographic, anthropometric, phenotypic, and biochemical data were reviewed. Results: The study comprised 34 patients, including 9 children (median age 8 years (IQR: 3.5-11)) and 25 adults (median age 33.5 years (IQR: 27-42)). Females constituted 56% of the cohort and White individuals accounted for 76%. The median age at diagnosis of BBS was 9 years (IQR: 3-16). Phenotypic characteristics included retinal dystrophy in 33% of children and 92% of adults, polydactyly in 78% of children and 52% of adults, and learning disabilities in 56% of children and 52% of adults. Obesity was prevalent in 56% of children and 80% of adults. Among children, their median maximum BMI % of the 95th percentile was 149% (IQR: 136-163%). Adults had a a median maximum BMI of 50 kg/m² (IQR: 43-55). There was insufficient data to determine the onset of hyperphagia; however, the median age of obesity onset for the cohort was 7 years (IQR: 4-11). No cases of diabetes or prediabetes were identified among children, whereas 40% of adults were diagnosed with type 2 diabetes. Cardiometabolic characteristics included hypertension in 11% of children and 48% of adults, kidney dysfunction in 33% of children and 56% of adults. Dyslipidemia was noted in 22% of children and 44% of adults, with median triglyceride levels 133 mg/dL (IQR: 93-153) in children and 142 mg/dL (IQR: 120-200) in adults. No cases of cardiovascular disease were identified in children, whereas 8% of adults were diagnosed with the condition. Endocrine characteristics included hypothyroidism in 11% of children and in 24% of adults. Of the 34 patients, genotype data were available for 28 individuals (82%). The most prevalent genotype was BBS1, comprising 27% of the cases. This was followed by BBS2 and BBS10, which each accounted for 15% of the cohort. Genotypes BBS4, BBS6 (MKKS2), IFT172, and SCLT1 were each observed in 3% of the cohort. Conclusion: This study highlights the significant clinical, cardiometabolic, and endocrine burden associated with BBS across children and adults. These findings underscore the importance of early and comprehensive multidisciplinary management of BBS. Keywords: Bardet-Biedl syndrome, obesity, cardiometabolic, endocrine comorbidities. Presentation: Monday, July 14, 2025

Childhood obesity has assumed epidemic proportions; it results from a complex interplay of genetic, physiological, socioeconomic, and environmental factors. It is associated with numerous short- and long-term health complications, including cardiometabolic and psychosocial consequences. While lifestyle modifications remain the cornerstone of treatment, their overall impact is modest. As a result, pharmacotherapy is increasingly recommended as an adjunct in selected pediatric patients, particularly those with severe or refractory obesity. In recent years, several anti-obesity medications, including glucagon-like peptide-1 (GLP-1) receptor agonists, have shown promise in pediatric populations, particularly adolescents. However, the pharmacologic options remain limited for younger children. This review summarizes current evidence on the efficacy and safety of available anti-obesity medications in children and adolescents, offering practical, age-based strategies to guide the appropriate clinical use of these medications as part of a comprehensive obesity-management plan.

Abstract There is limited data on the effect of antiobesity medications in individuals with Bardet-Biedl syndrome (BBS). Here, we present a case of an adult with BBS who experienced significant weight loss following treatment with a combination of topiramate and phentermine. A 31-year-old female with BBS, with homozygous pathogenic variant in the BBS2 gene, presented with obesity, dyslipidemia, and obstructive sleep apnea. At 29 years of age, her body mass index (BMI) was 43.3 kg/m2 (reference range 18.5-24.9 kg/m2), and she was initiated on 50 mg topiramate daily for migraine prophylaxis. With lifestyle modifications, BMI dropped to 40.5 kg/m2. Subsequently, phentermine 30 mg daily was added. Eight months after adding phentermine, BMI significantly decreased to 31.5 kg/m² (27% decrease in BMI), with improvement in glycemic and lipid parameters. She developed paranoia due to a social stressor prompting a brief hold of phentermine and resumption at a lower dose. This case highlights the weight loss response with phentermine and topiramate combination therapy in a patient with BBS. Further research is needed to explore the efficacy and safety of conventional antiobesity medications in isolation, as sequential or combination therapy to setmelanotide, to most effectively impact weight and metabolic burden in patients with BBS.