Endocrine Abstracts

JOINT3545

Background: Hypothalamic obesity (HO) is a severe and treatment-resistant form of obesity resulting from hypothalamic damage, often following brain injury. Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has shown promise in managing genetic and HO. However, its use in very young children remains limited. We present a case of a 22-month-old boy with severe HO, who demonstrated positive metabolic and neurodevelopmental responses to Setmelanotide therapy.

Case Presentation: A 22-month-old boy with a history of fulminant E. coli sepsis and meningoencephalitis, complicated by a brain abscess on day six of life, developed hypothalamic dysfunction leading to severe obesity, alongside global developmental delay, adrenal insufficiency, and central diabetes insipidus. His weight trajectory was uncontrolled despite dietary interventions, reaching 35.8 kg at 22 months with a disproportionately high weight-for-length ratio (SD +11.60). Severe obesity significantly impacted his quality of life, leading to an inability to sleep flat, requiring a seated position due to severe gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA). Excess adiposity in the limbs and brain injury resulted in complete immobility, with no head control, inability to sit, turn in bed, or achieve any developmental milestones. He also developed deep skin folds with recurrent infections. His immunological workup revealed lymphopenia and heterozygous variants of uncertain significance in the TLR3 gene, with a recommendation to avoid live vaccines. Liver enzymes remained elevated (ALT: 221 IU/l, AST: 170 IU/l), secondary to fatty liver disease. Cholesterol levels were also elevated, indicating dyslipidemia as an additional metabolic concern. Given the severity of his HO, he was started on Setmelanotide {add dose and titration) at 22 months of age. Following initiation, weight stabilization was achieved with a reduction in the rate of weight gain and a drop in the weight-for-length SD (+11.11). Additionally, he exhibited markedly significant motor and social development improvements, including increased arm and hand movements, head-turning, vocalization, emotional expression, and greater interaction with family members. Biochemical improvements were also observed, with a decline in liver enzyme levels (ALT and AST) and a reduction in cholesterol levels, indicating improved metabolic health. No side effects were observed except for mild skin pigmentation.

Conclusion: This case highlights the potential role of Setmelanotide in the early treatment of severe debilitating HO, particularly in very young children. The observed metabolic stabilization, coupled with neurodevelopmental improvements, underscores the need for further studies on the early use of MC4R agonists in pediatric patients with early-onset HO.