ESPE Abstracts

Introduction: C-type natriuretic peptide receptor encoded by NPR2 gene stimulates chondrocyte differentiation and hypertrophy and extracellular matrix production within the growth plate. The phenotypical spectrum of NPR2 mutations is broad, from severe autosomal recessive acromesomelic dysplasia to milder autosomal dominant growth disorders. Some children with NPR2 variants are treated with growth hormone (GH), however, with the inconsistent results.

Aims: To elucidate the frequency of pathogenic NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype in detail including the GH treatment response.

Materials and Methods: A total of 112 children with FSS out of 917 children registered in the single center database of patients treated with short stature who met inclusion criteria: body height (BH) before GH therapy ≤-2 SD in both patient and shorter parent and with unknown genetic etiology of short stature, were included in our study. The Next generation sequencing methods were performed searching for NPR2 gene variants. The results were evaluated using ACMG standards and guidelines. The phenotype of children with (likely) pathogenic variants was described including the GH treatment response (growth velocity, body-height SDS increase over five years of treatment).

Results: In total of 6 children (from 5 families) out of 112 children with FSS (5.4%), the (likely) pathogenic variant in NPR2 gene was found [p.Ile558Thr (in three), p.Arg205*, p.Arg557His, p.Ser603Thr]. The mean birth weight and length of affected children was -1.2 SD (+0.9 to -2.0) and -1.9 SD (-1.2 to -3.1) respectively. Three of them were born small for gestational age (SGA). The BH before GH therapy was -3.3 SD (mean, range -2.6 to – 4.0) in all affected children and -2.7 SD (-2.1 to -3.7) in their shorter parents. Mean IGF1 level was -1.5 SD (-1.4 to -1.7), maximal stimulated GH concentration was 9.6 ug/l (4.5-17.0) in all affected children. Three of them were clinically classified as GH deficient. Five out of six children with NPR2 gene variants were treated with GH. The mean age of treatment initiation was 6.5 years, mean GH dose 0.034 mg/kg/day (0.031 to 0.038). The growth velocity after GH treatment initiation improved from 5.1 to 8.7 cm/year (P=0.0003, paired sample T-test). The height SDS increased from -3.3 to -2.1 over five years of treatment (P<0.001, linear mixed-effects model).

Conclusion: NPR2 gene variants cause a substantial part of FSS. The GH therapy should be considered in children carrying NPR2 gene variants.