Nguyen Hanh H, van de Laarschot Denise M, Verkerk Annemieke JMH, Milat Frances, Zillikens M Carola, Ebeling Peter R
Department of Medicine School of Clinical Sciences Monash University Clayton Australia.
Department of Endocrinology Monash Health Clayton Australia.
JBMR Plus. 2018 Jan 3;2(1):1-11. doi: 10.1002/jbm4.10024. eCollection 2018 Jan.
Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long-term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate-naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand-searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (): osteogenesis imperfecta (), pycnodysostosis (), hypophosphatasia (), X-linked osteoporosis (), osteopetrosis, X-linked hypophosphatemia (), and osteoporosis pseudoglioma syndrome (). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate-naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X-linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole-exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted gene sequencing, an heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in . Targeted sequencing of , , , and genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well-phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition.
非典型股骨骨折（AFFs）并不常见，尤其与长期抗吸收治疗有关，包括双膦酸盐类药物。尽管AFFs的发病机制尚不清楚，但在未使用过双膦酸盐的个体以及单基因骨病患者中发现了此类骨折，这引发了一种假说，即遗传因素使个体易患AFFs。我们的目的是回顾和总结AFF患者中遗传因素的证据。我们对与AFF相关的关键词进行了结构化文献检索，并人工查阅了会议摘要/参考文献列表，共识别出2566条引用文献。两名研究人员独立审查了以下两类文献：（i）单基因骨病中的AFF病例；（ii）AFF患者的遗传学研究。在患有以下7种单基因骨病的23名患者中报告了AFFs：成骨不全症、致密性骨发育不全、低磷酸酯酶症、X连锁骨质疏松症、骨硬化症、X连锁低磷血症和骨质疏松假性神经胶质瘤综合征。在8例（35%）患者中，单基因骨病是在AFF发生后才被发现的。在致密性骨发育不全、低磷酸酯酶症、骨硬化症、X连锁低磷血症和骨质疏松假性神经胶质瘤综合征患者中报告了未使用过双膦酸盐的AFF病例。一项针对13例AFF患者和268名对照的初步研究通过外显子阵列分析发现，AFF病例中罕见变异的数量更多。一项对3例患有AFFs的姐妹进行的全外显子测序研究显示，在37个共享的遗传变异中，甲羟戊酸途径中对破骨细胞功能至关重要的 基因存在p.Asp188Tyr突变，而双膦酸盐类药物也会抑制该途径。两项研究完成了靶向 基因测序，在一组11例AFF患者中的1例发现了 杂合突变，而第二项包含10例AFF病例的研究未在 基因中发现突变。对5例AFF患者的 基因、 基因、 基因和 基因进行靶向测序，在1例患者的COL1A2基因中发现了一个变异。这些发现表明AFFs存在遗传易感性。需要开展一项针对表型明确的AFF病例和对照的大型多中心合作研究，以了解遗传学在这种罕见病症中的作用。
