ESPE Yearbook of Paediatric Endocrinology

Clin Endocrinol Metab. 2021;106(2):431–441. doi: 10.1210/clinem/dgaa842. PMID: 33205215

This study aimed to describe the clinical characteristics of 6 patients with NPR2 gene mutations and the response to rhGH treatment in 2 of them.

The natriuretic peptide receptor 2 gene (NPR2) is a paracrine factor involved in the regulation of cell proliferation and differentiation as well as in the synthesis of extracellular matrix in the growth plate (1). Compound heterozygous or homozygous mutations are responsible for severe skeletal dysplasia, whereas heterozygous mutations are associated with idiopathic short stature (ISS) (2). Data on rhGH treatment response in these disorders are still scarce (3, 4).

Here, the 6 patients (3 girls and 3 boys) underwent routine examinations for short stature. The average height SDS at presentation was –3.3±1.9 (range: – 6.3 to – 1.4 SDS). Suspicion of genetic defects in osteochondral dysplasia–related genes (FGFR3, ACAN, SHOX, NPR2) was based on clinical evidence of skeletal abnormalities (shortened metacarpals/metatarsal, mesomelic limb shortening, scoliosis) and facial dysmorphic features (midface hypoplasia, flat nasal bridge, high-arched palate). Two of the 6 patients received rhGH treatment; they showed height gains of 3 and 2 cm on rhGH therapy, which was discontinued after 1.5 months and 1 month, respectively.

The authors also performed a literature review of NPR2 mutations, finding 270 NPR2 mutation cases, of which 85 cases with homozygous or compound heterozygous mutations and 185 cases with heterozygous mutations. Average height SDS at diagnosis was –6.6±2.2 in patients with homozygous or compound heterozygous mutations, and –2.7±0.9 in those with heterozygous mutations. 21 patients were treated with rhGH, starting at a mean age of 8.2±3.5 years and with a mean treatment duration of 3.8±2.6 years. A significant increase in height SDS after rhGH treatment was detected. The height gain was more pronounced in girls than in boys, and the height increase was negatively associated with age at start of treatment. Due to the short-term rhGH therapy in all patients reported to date, it is impossible to draw any conclusion yet about the efficacy of such treatment in patients with NPR2 mutations.

Reference: 1. Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006;27(1):47–72.2. Vasques GA, Arnhold IJ, Jorge AA. Role of the natriuretic peptide system in normal growth and growth disorders. Horm Res Paediatr. 2014;82(4):222–9.3. 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. Vasques GA, Hisado-Oliva A, Funari MF, Lerario AM, Quedas EP, Solberg P, et al. Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2. J Pediatr Endocrinol Metab. 2017;30(1):111–6.