ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab 2025 May 27:dgaf309. PMID: 40424589. doi: 10.1210/clinem/dgaf309

Brief Summary: This study evaluated the response to GH treatment in 27 children with heterozygous NPR2 variants, which encode natriuretic peptide receptor-B (NPR-B), a key regulator of endochondral bone growth. These variants are recognized as an important cause of short stature, often diagnosed as idiopathic short stature (ISS). Most patients (89%) exhibited mild skeletal dysplasia features, most commonly dysmorphic hand findings such as brachydactyly (48%) identified through physical and/or radiological assessment. Careful clinical examination, particularly of the hands, proved valuable in raising suspicion for NPR2-related short stature.

Children with truncating NPR2 variants had shorter stature (median −3.3 SDS) than those with non-truncating variants (median −2.5 SDS). Variants located in the Kinase Homology Domain (KHD) were also associated with more severe short stature (median −3.2 SDS) relative to variants in other domains (median −2.5 SDS). Prepubertal children (n=15) showed a median height gain of +1.2 SDS over two years of GH treatment, whereas pubertal children (n=12) demonstrated a median height gain of +0.5 SDS. Among 6 pubertal children who reached near-adult height, 5 achieved an improvement in final stature, in some cases surpassing −2 SDS or exceeding the height of their affected parent. GH therapy was generally well tolerated; transient elevations in IGF-1 normalized either spontaneously or after dose adjustment.

This study reinforces that heterozygous pathogenic NPR2 variants commonly present with subtle skeletal dysplasia features, underlining the diagnostic importance of detailed clinical assessment, especially of the hands. GH treatment produced a meaningful growth response in both prepubertal and pubertal patients, with encouraging improvements in near-adult height. Notably, this research nearly doubles the number of NPR2-deficient children and adolescents with reported GH treatment outcomes, and uniquely includes real-world data on near-adult height. However, findings should be interpreted in light of limitations, including potential selection bias, concomitant treatments, and the inherent difficulty of conducting randomized controlled trials in rare conditions.

References: 1. Wang SR, Jacobsen CM, Carmichael H, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Hum Mutat. 2015;36(4):474-481.2. Andrade NLM, Funari MFA, Malaquias AC, et al. Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature. Endocr Connect. 2022;11(12):e220214.3. Toni L, Plachy L, Dusatkova P, et al. The genetic landscape of children born small for gestational age with persistent short stature. Horm Res Paediatr. 2024;97(1):40-52.4. Vasques GA, Amano N, Docko AJ, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. J Clin Endocrinol Metab. 2013;98(10):E1636-E1644.