Significance of Bone Marrow Karyotypes in Patients with

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)和比较基因组杂交(CGH)。对患者进行了长达四年的跟踪调查。在12例FA患者中有5例(42%)检测到克隆性染色体异常，在14例DBA患者中没有发现克隆性染色体异常(0%)，在2例SDS患者中检测到2例克隆染色体异常(100%)，在3例DC患者中检测到2例克隆染色体异常(67%)。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。除了两名FA患者中的7号单体外，这些异常类型与新发MDS患者中常见的不同。1例骨髓核型正常的FA患者发展为形态MDS。在五名FA患者中，有三名患者的异常克隆先于临床显著的MDS。此外，在两名FA患者中，异常克隆在大小上有变大变小，甚至消失。这些初步数据表明，IBMFS患者的异常骨髓核型可能不同于其他新生MDS患者，并支持大型协作数据库的必要性，以便单独确定细胞遗传学在这些罕见疾病中的预后意义，并结合骨髓形态和临床评估。

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), and comparative genomic hybridization (CGH). Patients have been followed for up to four years. Clonal chromosome abnormalities have been detected in five of 12 (42 percent) patients with FA, none of 14 (0 percent) patients with DBA, two of two (100 percent) patients with SDS, and two of three (67 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. With the exception of monosomy 7 in two patients with FA, the types of abnormalities differ from those commonly seen in patients with de novo MDS. One FA patient with a normal marrow karyotype has developed morphologic MDS. Abnormal clones preceded clinically significant MDS in three of the five patients with FA. Furthermore, the abnormal clones have waxed and waned in size, and even disappeared, in two of the FA patients. These preliminary data suggest that abnormal marrow karyotypes in patients with IBMFS may differ from other patients with de novo MDS, and support the need for large collaborative databases in order to determine the prognostic significance of cytogenetics alone, and combined with marrow morphology and clinical assessment, in these rare disorders.