Melanocortin-4 Receptor Agonist Treatment of Hypothalamic Obesity in ROHHAD Syndrome

ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) syndrome is a rare and complex pediatric condition marked by severe, early-onset hyperphagia and life-threatening obesity. For the past 2 years, we have been treating a boy, now aged 12 years, with ROHHAD syndrome. In light of the patient's progressive weight gain, intractable appetite, ventilator dependence, metabolic dysfunction-associated steatotic liver disease and behavioral dysregulation, including aggressive outbursts posing significant risk to self and others, we initiated off-label treatment with setmelanotide, a melanocortin-4 receptor (MC4R) agonist. Setmelanotide induced meaningful improvements, including substantial weight loss (28%, from 97 to 70 kg), measurable regression of hepatic steatosis as quantified by ultrasonography-based attenuation imaging, reduced ventilatory support, and a marked improvement in behavioral disorders that permitted the tapering of antipsychotic medication. After 18 months of therapy, insurance coverage for the off-label use was refused, and treatment was discontinued, which resulted in significant weight gain within 3 months (10%, from 70 to 77 kg). This treatment of hyperphagia-associated obesity in ROHHAD syndrome with setmelanotide suggests a potential pathophysiological origin in the MC4R pathway.