Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature.
BACKGROUND
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.


METHODS
This was a case-control study from the general community.


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


METHODS
This was an observational study.


METHODS
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.
Olney
Robert C
RC
Division of Endocrinology, Nemours Children's Clinic, Jacksonville, FL 32207, USA. rolney@nemours.org
Bükülmez
Hülya
H
Bartels
Cynthia F
CF
Prickett
Timothy C R
TC
Espiner
Eric A
EA
Potter
Lincoln R
LR
Warman
Matthew L
ML
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000886:Anthropometry; D001827:Body Height / Q000502:physiology*; D001835:Body Weight / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007118:Immunoassay; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D010641:Phenotype; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D000099242:Atrial Natriuretic Factor Receptor B
D004247:DNA; D006162:Guanylate Cyclase; D007334:Insulin-Like Growth Factor I; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B