Improving the diagnosis of hyperphagia in melanocortin-4 receptor pathway diseases

Characteristics of hyperphagia include heightened and prolonged hunger, longer time to satiation, shorter duration of satiety, severe preoccupation with food (i.e., hyperphagic drive), abnormal food-seeking behaviors, and distress or functional impairment when food is unavailable. Patients with melanocortin-4 receptor (MC4R) pathway diseases including those caused by variants in one of multiple key genes of the pathway often present with hyperphagia that results in early-onset, severe obesity because this pathway plays a critical role in regulation of hunger/satiation and energy balance. Patients with syndromic obesity (e.g., Bardet-Biedl syndrome) may also have hyperphagia as a result of neurodevelopmental disruptions in the MC4R pathway. Genetic testing is suggested in patients with early-onset, severe obesity and clinical features of genetic obesity (e.g., hyperphagia, neurodevelopmental differences, dysmorphic features); however, only a small percentage of individuals who meet these criteria undergo testing, potentially owing to limited availability, overlapping symptoms with other obesity types, and infrequent use of genetic testing during diagnosis. Diagnosing hyperphagia may be challenging, as no guidelines have been established for individuals with MC4R pathway diseases. Identifying these individuals is crucial to addressing the challenges of hyperphagia and associated obesity, which often limit quality of life and place overwhelming burdens on patients and families.