Semaglutide Treatment in Two Very Young Children With Severe Early-Onset Obesity

BACKGROUND: Monogenic obesity comprises a group of rare genetic disorders characterized by severe early-onset obesity and hyperphagia. Pharmacological treatment options for severe early-onset obesity remain limited, particularly in young children. CASE PRESENTATION: We report two children younger than 6 years of age with severe early-onset obesity, including one with genetically confirmed monogenic obesity, who showed reductions in BMI-SDS during semaglutide treatment. Case-1: A 4.5-year-old girl with a homozygous ADCY3 (c.1102G>A) variant presented with severe obesity, hyperphagia, hypertension, hepatosteatosis and Blount's disease. Baseline BMI was 48.0 kg/m2 (+5.5 SDS). Semaglutide was initiated at 0.125 mg/week and titrated to 1.5 mg/week. After 18 months, BMI-SDS decreased from +5.5 to +4.1 (-25.5%), accompanied by improved in hyperphagia and resolution of left ventricular hypertrophy. No significant adverse effects were observed, and linear growth remained age appropriate. Case-2: A 3.3-year-old boy with hyperphagia, severe obesity and dyslipidaemia was diagnosed with Klinefelter syndrome (47,XXY). Clinical Exome Sequencing identified no causative variant for obesity. Baseline BMI was 32.6 kg/m2 (+5.7 SDS). Semaglutide was initiated at 0.0625 mg/week and gradually titrated to 2.0 mg/week. After 21 months, BMI-SDS decreased from +5.7 to +4.4 (-22%). Treatment was generally well tolerated, with normal linear growth. CONCLUSION: This two cases describe reductions BMI-SDS during semaglutide treatment in very young children with severe early-onset obesity, including one child with genetically confirmed ADCY3-related monogenic obesity. These findings suggest a potential clinical benefit of semaglutide in this young population, warranting evaluation in larger studies.