Context: C-type natriuretic peptide (CNP) is an important regulator of skeletal growth. Loss-of-function mutations affecting the CNP receptor natriuretic peptide receptor-B (gene NPR2) cause the autosomal recessive skeletal dysplasia, acromesomelic dysplasia, Maroteaux type (AMDM). The phenotype of heterozygous carriers of NPR2 mutations is less clear.

Objective: The objective of the study was to determine the phenotypic features of heterozygous carriers of NPR2 mutations.

Design and Setting: This was a case-control study from the general community.

Subjects: Thirty-nine members of a family in which one member has AMDM were studied.

Intervention: This was an observational study.

Main Outcome Measure: The primary measure was stature, with the hypothesis that carriers have reduced stature compared with noncarriers.

Results: Sixteen family members were NPR2 mutation carriers. Height z-scores of these carriers were −1.8 ± 1.1 (mean ± sd), which was significantly less than the 23 noncarrier family members (−0.4 ± 0.8, P < 0.0005) and the general population (P < 0.0005). However, there was no difference in body proportion between carriers and noncarriers. The proband with AMDM had low IGF-I levels and evidence of GH resistance, as well as very high plasma levels of CNP and its amino-terminal propeptide. Levels of these peptides were normal in the heterozygous carriers.

Conclusions: We have shown that heterozygous mutations in NPR2 are associated with short stature. Assuming one in 700 people unknowingly carry an NPR2 mutation, our data suggest that approximately one in 30 individuals with idiopathic short stature are carriers of NPR2 mutations.