Novel NPR2 c.553G>A variant linked to familial short stature shows variable rhGH response

Genetic factors play a significant role in short stature, with variants in the Natriuretic Peptide Receptor 2 (NPR2) gene accounting for 2-6% of idiopathic short stature cases. NPR2 is crucial for endochondral ossification in the growth plate, a process essential for bone lengthening. Current standard-of-care often involves recombinant human growth hormone (rhGH), but its efficacy can vary widely, especially in genetically defined conditions. Understanding the specific impact of NPR2 variants on rhGH response is vital for predicting treatment outcomes and individualizing care for children with familial short stature.

This case report details a large family with 18 subjects exhibiting short stature. The proband, a 5.2-year-old boy with proportionate short stature, delayed bone age, and other clinical features, underwent whole-exome sequencing. This revealed a novel heterozygous c.553G>A variant in the NPR2 gene, leading to a missense variant in the extracellular ligand-binding domain. Six children from the family with this NPR2 mutation received recombinant human growth hormone (rhGH) therapy. The treatment duration averaged 4.68 ± 2.68 years, with height standard deviation score (SDS) as the primary endpoint.

All family members carrying the novel NPR2 c.553G>A variant demonstrated marked short stature, though phenotypes varied. Before rhGH treatment, the average height SDS for the six treated children ranged from -4.01 to -1.20, with a mean of -2.59 ± 1.16. The difference between bone age and chronological age in these children ranged from -2.3 to 0 years.

After an average of 4.68 ± 2.68 years of rhGH therapy, the height SDS of the treated children improved significantly by 1.54 ± 0.78. This improvement confirms a therapeutic response to rhGH in individuals with this specific NPR2 variant, despite the observed variability in clinical features and treatment outcomes even within the same family.