Significance of Marrow Karyotypes in Inherited Bone Marrow Failure Syndromes

遗传性骨髓衰竭综合征（IBMFS）是一组罕见的遗传性疾病，具有独特的表型和实验室异常。患有IBMFS的患者，包括范可尼贫血（FA）、Diamond-Blackfan贫血（DBA）、Shwachman-Diamond综合征（SDS）和先天性角化不良（DC），发生再生障碍性贫血（AA）、骨髓增生异常综合征（MDS）和急性髓性白血病（AML）的风险增加。为了确定IBMFS患者骨髓核型异常的发生率、类型和可能的临床意义，我们对骨髓进行了前瞻性、系列、常规和分子细胞遗传学分析。我们假设骨髓核型异常，没有其他MDS的证据（显著的血细胞减少或形态发育不良），可能不能预测不良结局。分析包括集中审查的骨髓形态学、G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）。患者已随访长达10年。在39例FA患者中有19例（49%）、46例DBA患者中有3例（7%）、12例SDS患者中有4例（33%）和40例DC患者中有4例（10%）检测到克隆性染色体异常。G显带是检测异常克隆的最佳方法，FISH提供了额外的信息; CGH是最不敏感的方法。在我们的IBMFS患者中记录的克隆异常中，约有一半与散发性MDS或AML患者中常见的克隆异常不同。在临床稳定且没有形态学MDS的IBMFS患者中发现了异常克隆。此外，随着时间的推移，这些克隆中的一些已经成熟和衰退。这些数据表明，IBMFS的细胞遗传学变化的临床意义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。我们目前正在完成并验证我们的临床、细胞遗传学和骨髓形态学数据库，为进行横断面和纵向分析做准备，并发表这一独特患者队列的研究结果。

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 ten years. Clonal chromosome abnormalities have been detected in 19 (49%) of 39 patients with FA, three (7%) of 46 patients with DBA, four (33%) of 12 patients with SDS, and four (10%) of 40 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.