Limb disorders

Gene: NPR2

Green List (high evidence)

Comment on list classification: There are 27 individuals reported in PMID: 40424589 with heterozygous NPR2 variants and idiopathic short stature, with limb disorders being the main skeletal feature. Brachydactyly was present in 13/27 individuals. Clinodactyly and syndactyly have also been reported. Brachydactyly is also a consistent feature in recessive NPR2-related skeletal dysplasia (Acromesomelic dysplasia 1, Maroteaux type). Hence, the rating should be promoted to Green on Limb disorders at the next GMS update, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 5 Jun 2026, 2:42 p.m. | Last Modified: 5 Jun 2026, 2:45 p.m.

Panel Version: 8.9

PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 had brachydactyly; clinodactyly and syndactyly were also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).
Sources: Literature

Created: 5 Jun 2026, 2:36 p.m. | Last Modified: 5 Jun 2026, 2:36 p.m.

Panel Version: 8.8

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Short stature with nonspecific skeletal abnormalities, OMIM:616255

Publications

• 40424589