Mutations in NPR2 gene linked to idiopathic short stature

Approximately one in 30 with short stature may be carriers of mutation.

Issue: May 2006

A case-control study found that heterozygous mutations in natriuretic peptide receptor-B are associated with idiopathic short stature.

Animal research has shown that C-type natriuretic peptide (CNP) is an important regulator of skeletal growth. The natriuretic peptides bind to three different receptors, natriuretic peptide receptors (NPR) –A, –B and –C, and NPR-B is the primary receptor for CNP. Individuals with loss-of-function mutations in both alleles of the NPR-B gene (NPR2) have acromesomelic dysplasia, Maroteaux type.

“This autosomal recessive skeletal dysplasia has characteristic radiological changes and results in extreme, disproportionate short stature,” investigators wrote in the Journal of Clinical Endocrinology and Metabolism. “Patients … are near normal-sized at birth with the growth abnormalities becoming apparent postnatally. [It] is not associated with impaired intelligence or other phenotypic features.”

Kindred study

Robert Olney, MD, director of the Pediatric Endocrinology Training Program at the Nemours Children’s Clinic in Jacksonville, Fla., and colleagues conducted a study of a large family in which multiple individuals carry a mutation in the NPR2 gene. “This enables accurate comparisons to be made between carriers and noncarriers,” the researchers wrote.

The family was identified through a proband diagnosed with acromesomelic dysplasia, Maroteaux type at 1-year old; she was found to be homozygous for a mutation in the NPR2 gene, whereas both her parents were found to be heterozygous for the mutation. The proband had a height z score of -8.5 at eight years of age, whereas her father and mother had height z-scores of -2.0 and -3.6, respectively.

Notably, the proband “appeared to have an abnormality in the GH/IGF-I system, characterized by low IGF-I levels, high GH levels, and lack of growth response to GH treatment,” investigators wrote. “These data imply an interaction between the CNP/NPR-B and the GH/IGF-I pathways during postnatal growth.”

Carriers vs. noncarriers

Researchers obtained data on 39 family members from four generations; relatives by marriage only were omitted from the analysis. Sixteen of these individuals are heterozygous carriers of the mutation, whereas 23 are not. Carriers of the mutation had a mean height z score of -1.8 vs. -0.4 for the noncarriers (P<.0005); the carriers also had lower z-scores than the general population (P<.0005). Carriers of the mutation also had significantly higher BMI than both noncarriers and the general population (P<.05 and P<.005, respectively).

“People who are heterozygous for mutations in this gene have idiopathic short stature,” Olney told Endocrine Today. “Given the calculated prevalence of mutations in this gene in the general population, this may be the cause in a small percentage of people with idiopathic short stature.” Researchers calculated that approximately one in 700 people are heterozygous carriers of the mutation, meaning that one person in 30 with idiopathic short stature (height z-score <-2.25) will be a carrier of the mutation.

Olney noted that this study could not conclusively determine the causality of this relationship. “In this single-family study, it is theoretically possible that it was just coincidence that the family members carrying the mutation were shorter than other family members,” he said. “More families in which mutations in this gene are found will need to be studied to confirm our findings.”

Clinical value

Although these results are promising, Olney said they are too preliminary to have clinical utility. “However, if we are able to confirm our findings, and we find that carriers respond differently to growth hormone therapy, it may be useful in the future to include NPR2 sequencing in the evaluation of children presenting with short stature. This information could then be used to help make the decision of whether to start growth hormone.”

In an accompanying editorial, Sara A. DiVall, MD and Sally Radovick, MD, of Johns Hopkins University, further emphasized the possible clinical implications of this study. “Children with idiopathic short stature very often respond to treatment with GH,” they wrote. “However, GH therapy for these children is shrouded in ethical and economic controversies. One source for this controversy is our lack of knowledge about the cellular and molecular mechanisms responsible for stature.”

Studies such as this one will advance our knowledge of these mechanisms and their relation to the GH-IGF axis, and can eventually help predict the determinants for responsiveness to therapy. “This knowledge would allow clinicians to tailor GH treatment and dosing to an individual’s molecular diagnosis,” DiVall and Radovick wrote. – by Dave Levitan

For more information:

Olney RC, Bukulmez H, Bartels CF, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab. 2006;91:1229-1232.

DiVall SA, Radovick S. Deciphering the genetics of stature – another piece of the puzzle. J Clin Endocrinol Metab. 2006;91:1218-1219.