Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
Department of Neurology & Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
Curr Osteoporos Rep. 2021 Apr;19(2):123-130. doi: 10.1007/s11914-021-00658-y. Epub 2021 Feb 15.
Atypical femur fractures (AFFs) are rare subtrochanteric or diaphyseal fractures regarded as side effects of bisphosphonates (BPs), possibly with a genetic background. Here, we summarize the most recent knowledge about genetics of AFFs.
AFF has been reported in 57 patients with seven different monogenic bone disorders including hypophosphatasia and osteogenesis imperfecta; 56.1% had never used BPs, while 17.5% were diagnosed with the disorder only after the AFF. Gene mutation finding in familial and sporadic cases identified possible AFF-related variants in the GGPS1 and ATRAID genes respectively. Functional follow-up studies of mutant proteins showed possible roles in AFF. A recent small genome-wide association study on 51 AFF cases did not identify significant hits associated with AFF. Recent findings have strengthened the hypothesis that AFFs have underlying genetic components but more studies are needed in AFF families and larger cohorts of sporadic cases to confirm previous results and/or find novel gene variants involved in the pathogenesis of AFFs.
不典型股骨骨折（AFF）是罕见的转子下或骨干骨折，被认为是双膦酸盐（BPs）的副作用，可能具有遗传背景。在此，我们总结了 AFF 遗传学的最新知识。
在包括低磷酸酯酶症和成骨不全症在内的 7 种不同的单基因骨疾病的 57 名患者中报道了 AFF；56.1%的患者从未使用过 BPs，而 17.5%的患者仅在 AFF 后才被诊断出该疾病。家族性和散发性病例的基因突变发现分别在 GGPS1 和 ATRAID 基因中确定了可能与 AFF 相关的变异体。对突变蛋白的功能后续研究表明，它们可能在 AFF 中发挥作用。最近对 51 例 AFF 病例进行的全基因组关联研究未发现与 AFF 相关的显著关联。最近的发现进一步证实了 AFF 具有潜在遗传成分的假说，但需要在 AFF 家族和更大的散发性病例队列中进行更多研究，以证实先前的结果和/或发现参与 AFF 发病机制的新基因变异体。
