ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2020) 17 4.11 | DOI: 10.1530/ey.17.4.11

ESPEYB17 4. Growth and Growth Factors New perspectives (5 abstracts)

4.11. NPR2 Variants are frequent among children with familial short stature and respond well to growth hormone therapy

Plachy L , Dusatkova P , Maratova K , Petruzelkova L , Zemkova D , Elblova L , Kucerova P , Toni L , Kolouskova S , Snajderova M , Sumnik Z , Lebl J & Pruhova S


Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic stepanka.pruhova@fnmotol.cz


To read the full abstract: J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgaa037.

This study aimed to assess the frequency of natriuretic peptide receptor type B gene (NPR2 ) variants in 87 children with familial short stature (FSS) and evaluate their response to GH therapy. By applying whole-exome or custom-targeted NGS panel sequencing, NPR2 variants were found in 5 children (5.7%) belonging to 4 families. These variants were classified as pathogenic (n =2) or likely pathogenic (n =3) according to the American College of Medical Genetics and Genomics guidelines. Three children were born SGA and 3 were classified as GH deficient (GHD). Two children had disproportionate short stature with short limbs and one had a dysplastic middle phalanx of the fifth finger. All parents with short stature carried the same NPR2 variant as the probands. GH therapy improved growth velocity after the first year of treatment (from 3.6 to 4.2 cm/year) and the gain in height ranged from 0.33 to 0.79 S.D. after 1 year of GH therapy, 0.43 to 1.34 S.D. at 2 years, and 1.2 to 1.8 S.D. after 5 years.

C-type natriuretic peptide (CNP) is present in high concentrations in chondrocytes and regulates many types of bone cells (1). In animals, inactivating mutations of its gene cause severe dwarfism and impaired endochondral ossification (1). By contrast, high levels of natriuretic peptides due to transgenic overexpression or reduced clearance cause skeletal overgrowth (1). CNP acts by binding to NPR2, whose loss of function also leads to dwarfism in animal models (1) and whose homozygous loss of function mutations are observed in patients with a rare autosomal recessive form of short-limb dwarfism, named acromesomelic dysplasia, type Maroteaux (1). Interestingly, patients with a single mutated NPR2 allele are shorter than average and may display mild signs of bone dysplasia (2)(3). Genome-wide association studies have highlighted the CNP-NPR2 system in influencing adult height and previous studies have reported that NPR2 mutations are present in up to 6% of children classified as having idiopathic short stature (3). The importance of this pathway in regulating bone growth and shape is demonstrated by a recent trial showing that subcutaneous administration of a biologic analogue of CNP increases growth velocity in patients with achondroplasia (4).

FSS refers to a child with a stature below the third centile but within the parental target range and with at least one short parent, and the exclusion of other causes of short stature. Mild forms of FSS are likely related to a polygenic inheritance whereas monogenic traits cause more severe forms. This study shows, for the first time, that NPR2 variants could account for some cases of FSS. Although the response to GH therapy in these cases seems promising, no conclusive data about the efficacy of GH treatment can be drawn due to the small number of subjects and their surprising heterogeneity, including both SGA and GHD subjects. Furthermore, no functional study was performed to demonstrate the pathogenicity of the observed NPR2 variants.

References:

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. Wang SR, Jacobsen CM, Carmichael H, Edmund AB, Robinson JW, Olney RC, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Hum Mutat. 2015;36(4):474–81.

3. Inzaghi E, Reiter E, Cianfarani S. The Challenge of Defining and Investigating the Causes of Idiopathic Short Stature and Finding an Effective Therapy. Horm Res Paediatr. 2019;92(2):71–83.

4. Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med. 2019;381(1):25–35.

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