Significance of Marrow Karyotypes in Inherited Bone Marrow Failure Syndromes

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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.