Pharmacogenetic hypersensitivity to somatropin in a child with severe growth hormone deficiency and MC4R p.V166I variant.

In a child with severe GHD and an MC4R variant, rhGH therapy led to an unexpected increase in IGF-1 and height velocity, suggesting a need for careful dosing and monitoring.

Summary and findings

This study reports a child with severe growth hormone deficiency (GHD) carrying a heterozygous MC4R variant who exhibited an exaggerated response to recombinant human growth hormone (rhGH) therapy. The patient received rhGH at a dose of 0.03 mg/kg/day, resulting in significant increases in IGF-1 levels and height velocity. The findings suggest a potential pharmacogenetic interaction affecting GH responsiveness.

Abstract

<h4>Objectives</h4>The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor that regulates energy homeostasis. Pathogenic <i>MC4R</i> 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 <i>MC4R</i> 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.<h4>Case presentation</h4>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 97.3 cm (-2.56 SDS) and annual growth velocity was 4.1 cm/year (<-2 SDS); rhGH (somatropin) therapy was initiated. Despite severe biochemically confirmed GHD, rhGH at 0.03 mg/kg/day triggered an exaggerated response: IGF-1 levels increased from -3.35 SDS to +8.00 SDS. Concurrently, his height velocity accelerated to 16 cm/year, and his bone age rapidly advanced by approximately 4 years over a 23-month period, culminating in mandibular prognathism.<h4>Conclusions</h4>The coexistence of severe GHD and an <i>MC4R</i> variant is rarely described, and such a pronounced response to rhGH has not previously been reported. These findings suggest that <i>MC4R</i> 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 <i>MC4R</i> p.V166I variant.

Limitations

Not reported in abstract.

Elsewhere in the HGH (Somatropin) corpus