Congenital bone marrow failure syndromes associated with protean developmental defects and leukemia

Congenital bone marrow failure syndromes are associated with a number of congenital abnormalities affecting a wide range of organ systems. The underlying molecular abnormalities that cause these disorders affect normal embryonic development during the critical organogenesis phase (weeks 4 to 8). These syndromes predispose patients to leukemia and other malignancies, and these genetic disorders may represent the first hit of at least two hits necessary for malignant transformation. The molecular defects underlying these diseases are just beginning to be understood; mechanisms suggested by recent research include DNA repair (FA-A, FA-G); abnormalities of the ribosomes (DBA, DC); to disorders of electron transport (FA-C, Pearson's syndrome, Barth's syndrome). Understanding these molecular mechanisms provides the knowledge necessary to develop better therapy, possibly including gene therapy, offering for the first time the potential for curing the hematologic manifestations of these illnesses.