Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants:...

NPR2 plays a critical role in the human growth plate. Heterozygous NPR2 variants result in varying degrees of short stature. Most individuals have no specific clinical findings and are classified as idiopathic short stature.

To describe phenotypic characteristics, analyze genotype-phenotype correlations and assess response to growth hormone (GH) treatment in children with a heterozygous (likely) pathogenic NPR2 variant.

Twenty-seven children and adolescents (18 boys, 9 girls) were identified in the Dutch National Registry of GH treatment in children.

We found 18 different NPR2 variants in 27 children. Of these variants, 5 were truncating, 11 were non-truncating, and 2 were splice site. Most were located in the ligand binding domain or kinase homology domain (KHD). Median (IQR) baseline height SDS was -2.9 (-3.3 to -2.4). Mild features suggestive of a skeletal dysplasia were found in 89%, most frequently mild disproportion and dysmorphic features of the hands. Patients with a truncating NPR2 variant had a shorter height compared to children with a non-truncating variant (-3.3 vs -2.5 SDS, P = .02). Patients with a KHD variant had shorter height than those with a variant in another domain (-3.2 SDS vs -2.5 SDS, P < .01). After 2 years of GH treatment, median height gain SDS in prepubertal children was 1.2 (0.8 to 1.4) and in pubertal children 0.5 (0.3 to 0.9). Near adult height improved in 5/6 children.

The majority of patients with a heterozygous (likely) pathogenic NPR2 variant have mild features suggestive of skeletal dysplasia. We furthermore show that the majority of NPR2 patients have a significant growth response during the first 2 years of GH treatment.