FP20-4 Children and Adults with Achondroplasia Have Resistance to C-Type Natriuretic Peptide

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP20-Growth: Clinical Trials & Observational Studies
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:00 AM
Room 122 (Moscone Center)

Poster Board SUN-627
Robert Caldwell Olney*1, William MacKenzie2, Timothy C Prickett3, Angela Duker2, Colleen Ditro2, Eric A Espiner3 and Michael Bober2
1Nemours Children's Clinic, Jacksonville, FL, 2Nemours/Alfred I. duPont Hospital for Children, 3Christchurch School of Medicine, Christchurch, New Zealand
Achondroplasia (Ach) is the most common form of human dwarfism and is caused by activating mutations of the fibroblast growth factor receptor-3 gene (FGFR3). The downstream activation of MAP kinase pathways triggered by the FGFR3 mutations reduces the proliferation and differentiation of growth plate chondrocytes. In contrast, CNP, acting through its receptor natriuretic peptide receptor-B (NPR-B) promotes chondrocyte differentiation and linear growth. In murine models of Ach, CNP can rescue the skeletal phenotype. Disruption of CNP signaling causes acromesomelic dysplasia, Maroteaux type, another form of short-limbed dwarfism which is often associated with more significant short stature than Ach. In vitrostudies have shown that activation of MAP kinase pathways inhibits NPR-B signal transduction, causing CNP resistance. Accordingly, we hypothesized that plasma CNP and the bioinactive aminoterminal proCNP (NTproCNP) are elevated in people with Ach as a result of CNP resistance.

Fifty-eight people with Ach were studied, 42 children under 18 years (20 girls, 22 boys) and 16 adults (10 women, 6 men). Plasma samples were assayed for CNP and NTproCNP by radioimmunoassay and standard deviation (SD) scores were calculated using published reference ranges (1,2). For the children, CNP SD scores were elevated at 0.78±0.85 (mean±SD), compared to age- and sex-matched controls (0±1, P<0.00001). NTproCNP SD scores (a measure of CNP biosynthesis) were elevated at 1.15±1.00. The ratio of CNP-to-NTproCNP SD score (a measure of CNP clearance) was -0.16±0.89 and was not different from the reference population. For the adults, CNP SD scores were 1.39±1.28 (P<0.001) and NTproCNP SD scores were 0.44±0.64 (P<0.05).

In healthy children, plasma NTproCNP is strongly correlated with height velocity (1). Height velocity data were available on 36 of the children with Ach (16 girls, 20 boys). For each subject, a height velocity-matched control was selected from a database of 139 healthy children without Ach. Height velocities were well matched at 4.3 cm/y (3.8–5.5 cm/y)[median (25%ile – 75%ile)] vs. 4.1 cm/y (3.8–5.5 cm/y) for controls. However, the ages of the children with Ach were considerably lower, 4.7 y (2.9–6.9 y) vs. 10.5 y (8.0–12.8 y)(P<0.0005 by Wilcoxon Signed-Rank test). CNP levels were higher in the children with Ach, 2.1 pmol/L (1.8–2.3 pmol/L) vs. 1.4 (1.3–1.8 pmol/L) in controls, as was NTproCNP, 54.5 pmol/L (46.0–61.5 pmol/L) vs. 34.6 (31.5–36.4 pmol/L)(P<0.0005 for both). For children growing at the same height velocity, CNP and NTproCNP levels were significantly higher in children with Ach.

Plasma CNP and NTproCNP concentrations are raised in Ach, demonstrating CNP resistance in vivo at the intracellular level. Whether CNP resistance contributes to the Ach phenotype, and the extent to which resistance can be overcome by exogenous CNP therapy, remain to be determined.

(1) Olney RC et al., Clin Endocrinol (Oxf) 2012; 77:416. (2) Prickett T et al., Clin Endocrinol (Oxf) 2012; Sep 11 [Epub ahead of print].

Nothing to Disclose: RCO, WM, TCP, AD, CD, EAE, MB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Nemours Research