Heterozygous NPR2 Variants in Idiopathic Short Stature

Abstract

Heterozygous variants in the <i>NPR2</i> gene, which encodes the B-type natriuretic peptide receptor (NPR-B), a regulator of skeletal growth, were reported in 2-6% cases of idiopathic short stature (ISS). Using next-generation sequencing (NGS), we aimed to assess the frequency of <i>NPR2</i> variants in our study cohort consisting of 150 children and adolescents with ISS, describe the <i>NPR2</i> phenotypic spectrum with a growth pattern including birth data, and study the response to growth hormone (GH) treatment. A total of ten heterozygous pathogenic/likely pathogenic <i>NPR2</i> variants and two heterozygous <i>NPR2</i> variants of uncertain significance were detected in twelve participants (frequency of causal variants: 10/150, 6.7%). During follow-up, the <i>NPR2</i> individuals presented with a growth pattern varying from low-normal to significant short stature. A clinically relevant increase in BMI (a mean gain in the BMI SDS of +1.41), a characteristic previously not reported in <i>NPR2</i> individuals, was observed. In total, 8.8% participants born small for their gestational age (SGA) carried the <i>NPR2</i> causal variant. The response to GH treatment was variable (SDS height gain ranging from -0.01 to +0.74). According to the results, <i>NPR2</i> variants present a frequent cause of ISS and familial short stature. Phenotyping variability in growth patterns and variable responses to GH treatment should be considered.