The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor that regulates energy homeostasis. Pathogenic MC4R variants represent the most common cause of monogenic obesity and are frequently associated with increased linear growth. However, the mechanisms linking MC4R signaling to somatic growth remain incompletely understood. We report a child with severe growth hormone deficiency (GHD) carrying a heterozygous MC4R variant (c.496G>A; p.V166I), in whom recombinant human growth hormone (rhGH) therapy triggered an unexpectedly exaggerated clinical and biochemical response, suggesting a potential pharmacogenetic interaction between MC4R signaling and the GH/IGF-1 axis. The male patient was first evaluated at 1 month of age due to micropenis and diagnosed with multiple pituitary hormone deficiencies. At 57 months of age, his height was 97.3cm (-2.56 SDS) and annual growth velocity was 4.1cm/year (<-2 SDS); rhGH (somatropin) therapy was initiated. Despite severe biochemically confirmed GHD, rhGH at 0.03mg/kg/day triggered an exaggerated response: IGF-1 levels increased from -3.35 SDS to +8.00 SDS. Concurrently, his height velocity accelerated to 16cm/year, and his bone age rapidly advanced by approximately 4 years over a 23-month period, culminating in mandibular prognathism. The coexistence of severe GHD and an MC4R variant is rarely described, and such a pronounced response to rhGH has not previously been reported. These findings suggest that MC4R p.V166I may modulate peripheral GH/IGF-1 signaling and act as a pharmacogenetic modifier of GH responsiveness. Careful rhGH dose titration with close IGF-1 monitoring may be considered in patients carrying the MC4R p.V166I variant.