Objectives: Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture, but the etiology of this disposition is unknown. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS.
Methods: This was a cross-sectional study of 10 children (9 females) ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Ultradistal tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II). Z-scores were calculated for DXA and pQCT measures. Reference data for the Xtreme CT II HR-pQCT scanner are not yet available, so these measures were descriptively compared to a sample of healthy children ages 520 years (n=247). Anthropometrics and labs were also collected.
Results: Based on one-sample t-tests, mean Z-scores for height and weight (both P<0.05), but not DXA bone measures, were negative and significantly different from zero. For pQCT bone measures, Z-scores for total bone mineral content (BMC) at the distal 3% site and cortical BMC, cortical area, and cortical thickness at the distal 38% site were negative and different from zero (all P<0.05). Compared to healthy children, those with ALGS generally had lower trabecular number, greater trabecular separation, and lower bone volume to total volume fraction despite having greater trabecular thickness (measured via HR-pQCT). Overall, bilirubin and bile acids, which are markers of hepatic cholestasis, were associated with poorer bone health. For example, bilirubin was associated with lower trabecular number (Spearmans rho=−0.86, P=0.014), greater trabecular separation (Spearmans rho=0.82, P=0.023), and greater cortical pore diameter (Spearmans rho=0.99, P<0.001) measured via HR-pQCT, and bile acids were associated with lower cortical area measured via pQCT (Spearmans rho=−0.78, P=0.041) and lower serum insulin-like growth factor 1 (Spearmans rho=−0.86, P=0.002).
Conclusions: Further investigation is needed to understand the factors contributing to ALGS-related cortical and trabecular bone inadequacies, and the manner in which these deficits contribute to increased fracture risk.
Disclosure: The authors declared no competing interests.