MON-697 The Impact of MC4R Agonist Therapy for Obesity in Bardet-Biedl Syndrome: A Case Study of Puerto Rican Siblings

Abstract Disclosure: L.Z. Salgado-Romero: None. A.C. Cotto-Vazquez: None. K. Yelton-Torres: None. D. Perez-Gonzalez: None. O. Mora-Osoria: None. L. Rodriguez-Franco: None. J. Aleman-Ortiz: None. A. Figueroa-Cruz: None. Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy caused by mutations in over 20 genes, affecting signaling pathways. Primary features include retinal dystrophy, polydactyly, obesity, intellectual disability, renal dysfunction, and male hypogonadism. Secondary features include hepatic fibrosis, endocrinological complications (such as dyslipidemia, diabetes mellitus, and reproductive abnormalities), and developmental delays. Diagnosis requires at least four primary features or three primary and two secondary, confirmed by genetic testing. Early diagnosis is crucial for timely interventions to improve quality of life and slow progression. MC4R agonist therapy (Setmelanotide) offers a novel treatment for hyperphagia and obesity, reducing cardiometabolic risk. We present two sibling patients diagnosed with BBS in their third decade of life with progressive vision loss as the primary symptom. Both struggled with severe obesity since childhood despite lifestyle modifications. Genetic testing confirmed BBS, with the first patient having both BBS1 and PDE6A gene variants and the second having BBS1. The first patient, a 44-year-old male with history of obesity, legal blindness, retinitis pigmentosa, prediabetes, obstructive sleep apnea (OSA), and dyslipidemia was started on Setmelanotide in May 2024. He lost 41 lbs (250 to 209), with waist circumference reduced from 45 to 39 inches by January 2025. His HbA1c improved from 5.8% to 5.5%, with skin hyperpigmentation as the main side effect. The second patient, a 38-year-old female with history of obesity, retinitis pigmentosa, hypertension, proteinuria, gastroparesis, and OSA, was started on Setmelanotide in February 2024. She lost 71 lbs (414 lbs to 343 lbs), with waist circumference reduced from 62 to 54 inches by January 2025. Both patients received nutritional counseling and lifestyle modifications, resulting in substantial weight loss, improved metabolic health and quality of life.BBS-related obesity is linked to melanocortin-4 receptor (MC4R) pathway dysfunction, which regulates hunger and metabolism. MC4R agonist, restores this function reducing hyperphagia and promoting weight loss. While side effects as skin hyperpigmentation, gastrointestinal disturbances, and mood changes can occur, the benefits for managing BBS obesity are significant. These cases highlight the heterogeneous presentation of BBS, which often leads to delayed diagnosis. Raising awareness of BBS and its metabolic challenges is essential for early intervention. MC4R agonist therapy is a significant advancement in treating BBS-related obesity by targeting the underlying neuroendocrine dysfunction. Although BBS management requires a multidisciplinary approach, endocrinologists play a crucial role in managing hormonal imbalances, metabolic disorders, and cardiovascular risks, improving patient outcomes.div> Presentation: Monday, July 14, 2025