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 five years. Clonal chromosome abnormalities have been detected in six of 13 (46 percent) patients with FA, none of 14 (0 percent) patients with DBA, two of four (50 percent) patients with SDS, and two of six (33 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.
