Introduction: Childhood obesity is a global concern and has both nutritional and genetic causative factors. One of the most common monogenic causes of obesity is heterozygous mutations in the Melanocortin 4 receptor (MC4R), which are found in 5.7–8.6% of individuals with early-onset obesity. We report, the effect of semaglutide, a long-acting glucagon-like peptide (GLP-1) analogue, in the treatment of severe obesity in an adolescent boy with a heterozygous mutation in MC4R. Case Presentation: A 13-year-old boy with a history of excessive weight gain since infancy was referred to the specialised weight management team. He was born at full term with a birth weight of 3.57 kg (50th centile), but his weight consistently exceeded the 99.6th percentile after the age of 1 year. At the age of 5 years, he was diagnosed with autism spectrum disorder (ASD). Diagnostic investigations revealed insulin resistance and dyslipidaemia, while genetic testing confirmed a heterozygous mutation in MC4R (E61K), inherited from his mother. Managing his condition was challenging due to his rapid weight gain, needle phobia, and behavioural difficulties. Despite intense multidisciplinary lifestyle interventions, he continued to gain weight, reaching a peak weight of 187.5 kg (+16.65 standard deviation score [SDS]), body mass index (BMI) of 56.9 kg/m2 (+4.19 SDS), and body fat of 63.9% at the age of 13 years. Due to severe ASD and needle phobia, he was not keen on daily GLP-1 injections. He was commenced on semaglutide subcutaneous injection at a dose of 0.25 mg weekly, gradually increasing to the maximum dose of 1 mg weekly. Over the course of 12 weeks, his BMI decreased to 52.2 kg/m2 (+4.08 SDS) and weight dropped to 176.8 kg (+14.76 SDS, body fat: 52.7%). At the 3-month and 12-month reviews post-treatment, he achieved weight loss of 5.7% and 11%, respectively. The quality of life questionnaire showed improved scores from 35.95 to 60.36 at 12-month review, indicating enhanced well-being. The continuous glucose monitor demonstrated an improvement in time in range. Conclusion: Semaglutide was approved by the US Food and Drug Administration (FDA) for weight management in adolescents aged 12 years and above in December 2022. A recent case series underscored the benefits of therapy with liraglutide, a short-acting GLP-1 analogue, in rare genetic cases of early-onset obesity. To our knowledge, this is the first case report to highlight the efficacy and safety of semaglutide in an adolescent with heterozygous MC4R mutation. Semaglutide could be a potential treatment option for monogenic obesity and will benefit from further research.

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