Significance of Marrow Karyotypes in Inherited Bone Marrow Failure Syndromes

遗传性骨髓衰竭综合征(IBMFS)是一组罕见的异质性遗传病，具有独特的表型和实验室异常。IBMFS患者，包括Fanconi贫血(FA)、钻石-Blackfan贫血(DBA)、Shwachman-Diamond综合征(SDS)和先天性角化不良(DC)，患再生障碍性贫血(AA)、骨髓增生异常综合征(MDS)和急性髓系白血病(AML)的风险增加。为了确定IBMFS患者骨髓染色体异常的发生率、类型和可能的临床意义，我们对骨髓进行了前瞻性、系列性、常规性和分子细胞遗传学分析。我们假设，在没有其他MDS(显著的细胞减少或形态异常)证据的情况下，异常的骨髓核型可能不能预测不良结果。分析包括中央审查的骨髓形态、G显带核型分析、荧光原位杂交(FISH)、比较基因组杂交(CGH)和光谱核型分析(SKY)。对患者进行了长达九年的跟踪调查。19例FA患者中有9例(47%)、26例DBA患者中无一例(0%)、5例SDS患者中有3例(60%)、27例DC中有3例(11%)有克隆性染色体异常。G显带是检测异常克隆的最好方法，FISH提供了额外的信息；CGH是最不敏感的方法。在我们记录的IBMFS患者中，大约有一半的克隆异常与散发性MDS或AML患者中常见的不同。在临床稳定且无形态MDS的IBMFS患者中发现了异常克隆。此外，这些克隆中的一些已经随着时间的推移而兴衰。这些数据表明，IBMFS的细胞遗传学改变的临床和可能的生物学意义可能不同于其他新发骨髓衰竭或MDS患者。我们目前正在完成和验证我们的临床、细胞遗传学和骨髓形态数据库，为进行横断面和纵向分析做准备，并在这一独特的患者队列中公布研究结果。

The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of rare genetic disorders with distinctive phenotypic and laboratory abnormalities. Patients with IBMFS, including Fanconi Anemia (FA), Diamond-Blackfan Anemia (DBA), Shwachman-Diamond Syndrome (SDS), and Dyskeratosis Congenita (DC), have an increased risk of developing aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). To determine the incidence, types, and possible clinical significance of abnormal bone marrow karyotypes among patients with IBMFS, we are conducting prospective, serial, routine and molecular cytogenetic analyses of marrow. We hypothesize that abnormal marrow karyotypes, without other evidence of MDS (significant cytopenias or morphologic dyspoiesis), may not predict an adverse outcome. Analyses have included centrally-reviewed marrow morphology, G-banded karyotype analysis, fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH) and spectral karyotyping (SKY). Patients have been followed for up to nine years. Clonal chromosome abnormalities have been detected in nine of 19 (47 percent) patients with FA, none of 26 (0 percent) patients with DBA, three of five (60 percent) patients with SDS, and three of 27 (11 percent) patients with DC. G-banding is the best method for detecting abnormal clones, and FISH provides additional information; CGH is the least sensitive method. Approximately half of the clonal abnormalities documented among our patients with IBMFS are different from those commonly found in patients with sporadic MDS or AML. Abnormal clones have been found in IBMFS patients who are clinically stable and do not have morphologic MDS. Furthermore, some of these clones have waxed and waned over time. These data suggest the clinical, and possibly biological, significance of cytogenetic changes in IBMFS may be different from other patients with de novo bone marrow failure or MDS. We are currently completing and verifying our clinical, cytogenetic, and marrow morphology databases in preparation for running cross-sectional and longitudinal analyses and publishing the findings in this unique cohort of patients.