Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children

Abstract

Objective: C-type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate and plays a key role in endochondral growth. Its amino-terminal propeptide (NTproCNP) is an equimolar product of CNP biosynthesis and is easily measured in plasma. Preliminary studies suggest that NTproCNP levels correlate with height velocity in sheep and children. The objectives of the study were to correlate NTproCNP levels with height velocity and to define the reference range for plasma CNP and NTproCNP across childhood.

Design: This was a prospective, cross-sectional, observational study of healthy children.

Patients: Participants were 258 healthy children between 2 months and 20 years of age.

Measurements: Anthropometrics were obtained and CNP and NTproCNP levels were determined by radioimmunoassay.

Results: For both sexes, CNP and NTproCNP levels were high in infancy, lower in early childhood, rising during puberty, then falling to low adult levels. Levels of NTproCNP peaked at 14·1 years in boys and 11·9 years in girls, coincident with the age of peak height velocity. Levels of NTproCNP varied with pubertal status, peaking at genital Tanner stage IV in boys and III in girls. There was a highly significant correlation between NTproCNP and height velocity.

Conclusions: C-type natriuretic peptide plays an integral role in endochondral growth. We show here that CNP synthesis (as measured by NTproCNP levels in plasma) is closely related to linear growth in healthy children at all ages. We propose NTproCNP as a biomarker of linear growth.

Figure 1

CNP and NTproCNP levels vary by age. Plasma levels of CNP and NTproCNP were determined by RIA for healthy children between the age of 2 months and 19.8 years of age. Open circles, individual data points; heavy line, median; light lines, 5^th and 95^th percentiles. Top left panel, NTproCNP levels for boys (n = 209), top right panel, CNP levels for boys (n = 178). Bottom left panel, NTproCNP levels for girls (n = 143), bottom right panel, CNP levels for girls (n = 140).

Figure 2

CNP and NTproCNP levels vary by Tanner stage. Bar, median; error bars, 25^th and 75^th percentiles. For boys, penile Tanner stage was used, for girls, breast Tanner stage. Children of Tanner stage I were older than 6 years of age; Children of Tanner stage V were less than 20 years of age. Top left panel, CNP levels for boys, top right panel, CNP levels for girls. Bottom left panel, NTproCNP levels for boys, bottom right panel, NTproCNP levels for girls. For all four panels, levels differed as group by Kruskal-Wallis Test (p<0.005 for all). *, p<0.05 compared to boys of Tanner stage I, II, and V by Dunn’s Test post hoc pair-wise comparison. †, p<0.05 compared to girls of Tanner stage IV and V.

Figure 3

Correlation between height velocity and NTproCNP levels. Plasma for NTproCNP was taken at the first visit. Annualized height velocity was determined using the height at the first visit and a follow up height taken between 2 and 12 months later. Line, least mean squares linear regression line. The correlation is significant (n=139, r=0.711, p<0.0005).

Figure 4

Correlation between the NTproCNP measured by RIA and by ELISA. Plasma samples from 40 healthy children were assayed for NTproCNP both by the in house RIA and the commercially available ELISA. Line, least mean squares linear regression line. A single data point was discarded as a statistical outlier. The correlation is significant (n=39, r=0.748, p<0.0005).