Clinical Trial: C-Type Natriuretic Peptide and Achondroplasia

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

Official Title: C-Type Natriuretic Peptide and Achondroplasia

Brief Summary: Achondroplasia and hypochondroplasia are the most common forms of dwarfism. Recent studies have shown that a small hormone called C-type natriuretic peptide (CNP) is an important regulator of linear growth. The investigators believe that genetic abnormality that causes achondroplasia and hypochondroplasia also disrupts CNP signaling, which may contribute to the growth problem. The investigators propose to look at levels of this and other closely related hormones in children and adults with achondroplasia or hypochondroplasia to see if they are different from levels in healthy people. The investigators hypothesis is that CNP levels are elevated in children with achondroplasia or hypochondroplasia, compared the healthy population. Another hypothesis is that CNP levels are not elevated in adults with achondroplasia or hypochondroplasia, since adults have no growth-plate cartilage. By studying the potential role of the CNP system in achondroplasia and hypochondroplasia, not only will the investigators provide further insight into the pathophysiology of these common syndromes, the investigators will also provide greater insight into the regulation of normal linear growth.

Detailed Summary:

Achondroplasia is the most common form of dwarfism and is characterized by short limbs with the thighs and upper arms being the most affected. Achondroplasia is also associated with a narrowing of the foramen magnum and spinal stenosis. Hypochondroplasia is a related, but less severe form of dwarfism that does not have the neurologic problems. Achondroplasia and hypochondroplasia are caused by mutations in the fibroblast growth factor receptor-3 (FGFR-3) gene that causes constitutive activation of the receptor. FGFR-3 signals primarily through the MAP kinase pathway, which is overactivated in growth plate chondrocytes in achondroplasia. C-type natriuretic peptide (CNP) is a hormone that is produced and acts in the growth plate as a potent positive regulator of linear growth. CNP signals through natriuretic peptide receptor-B (NPR-B), generating cGMP. Studies in mice show that activation of the MAP kinase pathway inhibits signaling through NPR-B. Hence the achondroplasia phenotype may be due in part to inhibition of CNP signaling. Conversely, CNP intracellular signaling inhibits the MAP kinase pathway and CNP analogs are being studied as a potential specific therapy for achondroplasia. The objective of this project is to define the state of the CNP system in children and adults with achondroplasia or hypochondroplasia. Our hypotheses are 1) blood levels of CNP and its aminoterminal propeptide (NTproCNP) are elevated and blood levels of cGMP are reduced in children with achondroplasia or hypochondroplasia, due to inhibition of NPR-B; 2) CNP and NTproCNP levels are normal in adults with achondroplasia and hypochondroplasia, due to their lack of growth plate cartilage; and 3) as in healthy children, NTproCNP levels predict height velocity in children with achondroplasia or hypochondroplasia. These hypotheses will be addressed with two specific aims. Specific aim 1 is to determine plasma levels of CNP, NTproCNP, and cGMP in c
Sponsor: Nemours Children's Clinic

Current Primary Outcome: NTproCNP level in plasma [ Time Frame: one time point ]

Aminoterminal propeptide of CNP (NTproCNP) is measured in plasma by RIA and compared to an existing sex- and age- based reference range.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • CNP level in plasma [ Time Frame: one time point ]
    C-type natriuretic peptide is measured in plasma by RIA and compared to an existing sex- and age- based reference range.
  • cGMP level in plasma [ Time Frame: one time point ]
    Cyclic GMP levels are measured in plasma by RIA and compared to existing age- and sex- matched control samples.
  • Correlation between NTproCNP level and height velocity in children [ Time Frame: Every six months over a period of a minumum of six months to a maximum of 2 years ]
    NTproCNP levels at baseline will be correlated with hieght velocity determined at subsequent visits. Measurements for determination of height velocity will be at least 6 months apart, but no more than 2 years apart. For subjects with multiple subsequent visits, the visit closest to 1 year after the baseline visit will be used for height velocity determination.


Original Secondary Outcome: Same as current

Information By: Nemours Children's Clinic

Dates:
Date Received: February 13, 2012
Date Started: February 2012
Date Completion:
Last Updated: April 13, 2015
Last Verified: April 2015