ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2020;105(10):dgaa491. doi: 10.1210/clinem/dgaa510. PMID: 32816013

This study describes the clinical characteristics of an extended family with novel NPR2 mutations. The family was an Ashkenazi Jewish family with no history of consanguinity and included two sisters with compound heterozygous NPR2 missense mutations causing acromesomelic dysplasia Maroteaux type (AMDM), 6 subjects with heterozygous NPR2 mutations and short stature, and 6 relatives with wild-type NRP2 sequences and normal stature. The study finds progressive abnormalities with age in the heterozygous carriers.

The application of next-generation sequencing has revealed the molecular basis of growth failure in many children with idiopathic short stature (ISS). NPR2 encoding the transmembrane receptor atrial natriuretic peptide receptor 2 (ANPRB or NPR2) has recently emerged as a factor involved in the pathogenesis of ISS (1-3). ANPRB is a plasma membrane protein expressed in chondrocytes that produces the second messenger cyclic GMP (cGMP) upon binding with its ligand, the C-type natriuretic peptide (CNP) (4,5). This signaling pathway represents a critical regulator of longitudinal growth and skeletal development. Short stature associated with nonspecific skeletal anomalies in heterozygous carriers of NPR2 mutations has been described (2,3,6,7).

In this study, whole-exome sequencing was used to detect NPR2 mutations in parents and daughters with severe short stature. Sanger sequencing was used to confirm the mutations and functional analysis of mutations was carried out. The heterozygous relatives showed initial proportionate short stature and progressive decline of height z-scores leading to worsening of growth retardation and of adult height potential. Disproportionate short stature developed over time (reduced arm span to height ratio but normal sitting height to height ratio). Bone age was delayed in the younger children and progressively advanced over time. The phenotype characterized by progressive loss of adult height potential, advancement of bone age and appearance of disproportionate anthropometric features, represents a novel finding and a potential useful clinical flag to help clinicians identify these patients.

Reference: 1. Hachiya R, Ohashi Y, Kamei Y, Suganami T, Mochizuki H, Mitsui N, et al. Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development. J Clin Endocrinol Metab. 2007;92(10):4009–14.2. Olney RC, Bukulmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab. 2006;91(4):1229–32.3. Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Zemkova D, Elblova L, et al. NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy. J Clin Endocrinol Metab. 2020;105(3).4. Mericq V, Uyeda JA, Barnes KM, De Luca F, Baron J. Regulation of fetal rat bone growth by C-type natriuretic peptide and cGMP. Pediatr Res. 2000;47(2):189–93.5. Teixeira CC, Agoston H, Beier F. Nitric oxide, C-type natriuretic peptide and cGMP as regulators of endochondral ossification. Dev Biol. 2008;319(2):171–8.6. Ain NU, Iqbal M, Valta H, Emerling CA, Ahmed S, Makitie O, et al. Novel variants in natriuretic peptide receptor 2 in unrelated patients with acromesomelic dysplasia type Maroteaux. Eur J Med Genet. 2019;62(9):103554.7. Vasques GA, Amano N, Docko AJ, Funari MF, Quedas EP, Nishi MY, 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):E1636-44.