The Genetic Basis of Fanconi Anemia

Abstract

eventy-five years ago, Dr. Guido Fanconi reported three siblings who exhibited both congenital defects and aplastic anemia. Since then, we have learned that Fanconi anemia (FA) is a rare multigenic disorder (a prevalence of 1-5 per million"^), that predisposes children and adults to life-threatening bone marrow failure, myelodysplasia,^ acute nonlymphocytic leukemia (AML), and certain epithelial malignancies. '^ So far, the sine qua non of this disease is cytogenetic instability in vitro after exposure of FA cells to biftinctional alkylating agents. ' Indeed, the current diagnostic test for Fanconi anemia, quantification of chromosomal breakage responses to alkylating agents, is based on this feature (reviewed in ref. 10). Classic clinical features such as growth retardation, small head size, cafi-au-lait spotSy and radial ray defects can be strong diagnostic clues, but FA can occur in patients without con­genital defects and can be clinically ascertained in adulthood. In fact, some patients with very minimal blood count abnormalities have been identified only because they were siblings of known FA patients and were tested for that reason. Consequendy, there is substantial pheno-typic heterogeneity in FA and while some of it can be explained by genetic heterogeneity, certain of the clinical consequences are the result of gene-environment interactions.