C-Type Natriuretic Peptide and Achondroplasia
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.
|Study Design:||Observational Model: Case-Only
Time Perspective: Prospective
|Official Title:||C-Type Natriuretic Peptide and Achondroplasia|
- NTproCNP level in plasma [ Time Frame: one time point ] [ Designated as safety issue: No ]Aminoterminal propeptide of CNP (NTproCNP) is measured in plasma by RIA and compared to an existing sex- and age- based reference range.
- CNP level in plasma [ Time Frame: one time point ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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.
Biospecimen Retention: Samples Without DNA
Plasma and serum samples are stored for potential future research.
|Study Start Date:||February 2012|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
achondroplasia or hypochondroplasia
Children or adults with achondroplasia or hypochondroplasia
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 children and adults with achondroplasia or hypochondroplasia. Specific aim 2 is to determine if NTproCNP levels correlate with height velocity in children with achondroplasia or hypochondroplasia.
The study is an observational, cross-sectional/partially longitudinal study of children and adults with achondroplasia or hypochondroplasia. Children will be seen as part of routine clinic visits. Children seen more than once during the study period will provide longitudinal data. Adult subjects with achondroplasia or hypochondroplasia will be studied a single time. Data collected will include anthropometrics, information on neurologic complications of achondroplasia, and blood levels of CNP, NTproCNP, and cGMP. We anticipate 100 subjects will be recruited, with about 20 being studied as many as three times during the course of the study.
By studying the potential role of the CNP system in achondroplasia and hypochondroplasia, not only will we provide further insight into the pathophysiology of these common syndromes, we will also provide greater insight into the regulation of normal linear growth.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01541306
|United States, Delaware|
|Alfred I. duPont Hospital for Children|
|Wilmington, Delaware, United States, 19803|
|Principal Investigator:||Robert Olney, MD||Nemours Children's Clinic|
|Principal Investigator:||Michael Bober, MD, PhD||Alfred I. duPont Hospital for Children|