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 of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. 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 (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n=247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p<0.05), were significantly less than zero. DXA bone Z-scores were not significantly different from zero, but were highly variable. For pQCT bone measures, Z-scores for total bone mineral content at the distal 3% site and cortical bone mineral content, cortical area, and cortical thickness at the distal 38% site were significantly less than zero (all p<0.05). There was good correspondence between pQCT measures of cortical thickness Z-scores and DXA Z-scores for aBMD at the whole body less head, 1/3 radius, and femoral neck (all p<0.05). Compared to healthy children, those with ALGS generally had lower trabecular number and greater trabecular separation despite having greater trabecular thickness (measured via HR-pQCT). Bilirubin and bile acids, markers of hepatic cholestasis, were associated with poorer bone measures. For example, greater bilirubin was associated with lower trabecular number (Spearman's rho [ρ]=-0.82, p=0.023) and greater trabecular separation (ρ=0.82, p=0.023) measured via HR-pQCT, and greater bile acids were associated with lower cortical area measured via pQCT (ρ=-0.78, p=0.041) and lower serum insulin-like growth factor-1 (ρ=-0.86, p=0.002). In summary, deficits in cortical bone size and trabecular bone microarchitecture were evident in children with ALGS. Further investigation is needed to understand the factors contributing to these skeletal inadequacies, and the manner in which these deficits contribute to increased fracture risk.

中文翻译：

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Alagille 综合征儿童的骨几何结构和微结构缺陷

Alagille 综合征 (ALGS) 是一种常染色体显性遗传疾病，归因于 Notch 信号通路中的突变。患有 ALGS 的儿童发生未知病因的脆性骨折的风险增加。我们的目标是表征 ALGS 儿童的骨量、几何形状和微结构。这是一项横断面研究，对 10 名 8-18 岁的儿童（9 名女性）进行了横断面研究，临床诊断为 ALGS。通过 DXA (Hologic Discovery A) 在几个骨骼区域评估骨密度。胫骨小梁和皮质骨分别通过 pQCT (Stratec XCT 2000) 在远端 3% 和 38% 部位进行评估。胫骨骨微结构通过 HR-pQCT (Scanco XtremeCT II) 在位于胫骨长度 4% 的超远侧部位和胫骨长度的 30% 处的皮质部位进行评估。计算 DXA 和 pQCT 测量的 Z 分数。在缺乏 XtremeCT II HR-pQCT 参考数据的情况下，将这些结果指标与 5-20 岁健康儿童样本（n=247）进行了描述性比较。还收集了人体测量学和实验室。基于单样本 t 检验，身高和体重的平均 Z 分数（均 p<0.05）显着小于零。DXA 骨骼 Z 分数与零没有显着差异，但变化很大。对于 pQCT 骨测量，远端 3% 部位的总骨矿物质含量和远端 38% 部位的皮质骨矿物质含量、皮质面积和皮质厚度的 Z 分数显着小于零（所有 p<0.05）。pQCT 测量的皮质厚度 Z 分数和 DXA Z 分数在全身少头、1/3 半径和股骨颈的 aBMD 之间存在良好的对应关系（所有 p<0.05）。与健康儿童相比，尽管小梁厚度较大（通过 HR-pQCT 测量），但患有 ALGS 的儿童通常具有较低的小梁数量和较大的小梁分离。胆红素和胆汁酸是肝胆汁淤积的标志物，与较差的骨骼指标有关。例如，通过 HR-pQCT 测量，较高的胆红素与较低的小梁数量（Spearman's rho [ρ]=-0.82，p=0.023）和较大的小梁分离（ρ=0.82，p=0.023）相关，并且与较高的胆汁酸相关通过 pQCT 测量的皮质面积较低（ρ=-0.78，p=0.041）和较低的血清胰岛素样生长因子-1（ρ=-0.86，p=0.002）。总之，ALGS 儿童的皮质骨大小和骨小梁微结构缺陷很明显。