Genetic potential and height velocity during childhood and adolescence do not fully account for shorter stature in cystic fibrosis

Abstract

Background: Despite improved health, shorter stature is common in cystic fibrosis (CF). We aimed to describe height velocity (HV) and contribution of height-related genetic variants to height(HT) in CF. Methods: HV cohort – Standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center’s CF Foundation registry data. HV-Z was compared to population means at each age (5–17y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared to MPAH-Z. GRS cohort- HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed. Results: HV cohort: Average HV-Z was normal across ages in our cohort but was 1.5x-lower (p<0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p< 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho=0.42;R 2 =0.25) vs. PI (rho=0.27;R 2 =0.11). Conclusions: Despite shorter stature compared to peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late-childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors.

Most Short Children with Cystic Fibrosis Do Not Catch Up by Adulthood

“…In our comparisons, we did not have heights from the parents to calculate mid-parental height targets for the subjects, but given the data utilized is obtained from the national registry, one would anticipate a near mean average adult height of the parents. Additionally, the recent report by Zysman-Colman et al demonstrates that when parental heights are known, there is a reduction in obtainment of mid-parental linear growth targets in children with CF [19]. Our analysis would further suggest that CF children with evidence of poor growth early in life warrant closer attention.…”

“…This difference was most notable in pre-pubertal children, which suggests that final height is determined early in life in CF. The study cohort had below average lengths from birth that persisted into adulthood despite normal childhood and pubertal growth velocities and adequate nutrition [19].…”

Bone accrual and structural changes over one year in youth with cystic fibrosis

“…Early nutritional interventions in infants diagnosed at birth led to normal weight status at age one year, but persistent length deficits [27] . These early length deficits are likely responsible for persistent short stature in CF, as height velocity in mid- to late- childhood was found to be normal [28] .…”

The Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status

“…Early nutritional interventions in infants diagnosed with CF at birth led to normal weight status at age one year, but persistent length deficits [ 30 ]. These early length deficits are likely responsible for persistent short stature in youth with CF, as height velocity in mid- to late- childhood was found to be normal [ 65 ]. As highly effective CFTR modulators are used in younger patients, it will be important to determine if early initiation will lead to correction of intrinsic bone deficits and allow for appropriate linear growth.…”