Syndrome-associated myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis resulting in cytopenias, and an increased risk of developing acute myeloid leukemia (AML). MDS is predominantly a sporadic disease that affects the elderly, with a median age of diagnosis of over 70 years, and generally carries a poor prognosis. Significant progress has been made in delineating the molecular pathophysiology of MDS and AML. Ineffective apoptosis and disordered cell differentiation arise from the acquisition of genetic insults by a hematopoietic stem cell. These genetic lesions may be inherited or acquired, but their exact nature is poorly understood for most patients. The presence of an initiating event is required to increase the susceptibility of the affected progenitor cell to further DNA damage, leading to an accumulation of secondary genetic aberrations that ultimately results in the development of overt MDS/AML. These can include structural chromosomal abnormalities, gene mutations, and epigenetic changes, and may be influenced by immune dysregulation and the marrow microenvironment. A history of prior chemotherapy or environmental/occupational exposure to radiation or toxins such as benzene may be associated with MDS development. This risk may be increased in subjects who have mutations of the carcinogen detoxifying enzyme NAD(P)H:quinone oxidoreductase. While the majority of MDS cases are sporadic, rare familial cases have been described. These familial cases are a precious resource as they have allowed key initiating germline mutations to be identified. The most clearly defined of the familial MDS syndromes is familial platelet disorder with propensity to myeloid malignancy (FPD/AML). Multiple new pedigrees have been recently described and further clarify the clinical presentation and outcome of this disease. The pathogenesis and presentation of recognized familial MDS syndromes will be reviewed here.