Fanconi anemia is a highly penetrant cancer susceptibility syndrome.

F irst described by Guido Fanconi in 1927, Fanconi anemia (FA) is now one of the best defined inherited bone marrow failure syndromes. It is usually inherited as an autosomal recessive trait, but in a small subset of FA cases it can be an X-linked recessive disorder. FA patients show marked clinical heterogeneity. Characteristic features include the progressive development of bone marrow failure (BMF) and an increased predisposition to malignancy. 1-3 Affected individuals may also have one or more congenital/developmental abnormalities including abnormal skin pigmentation (e.g. café au lait spots), skeletal (e.g. radial ray anomalies), genitourinary (e.g. horseshoe kidney), and gas-trointestinal (e.g. duodenal atresia) abnormalities. A significant subset (~30%) of FA patients have no apparent somatic abnormalities. The majority of patients present towards the end of the first decade of life. However, an increasing number of patients are being diagnosed for the first time in adulthood. At the same time, many patients diagnosed in childhood are now surviving into adulthood. This means that awareness of this disorder on the part of both adult and pediatric physicians is becoming increasingly important. Over the last 20 years, major advances have been made in our understanding of the biology of FA. FA cells characteristically display a high frequency of spontaneous chromosomal breakage and hypersensitivity to DNA cross-linking agents, such as diepoxybutane (DEB). This genomic instability led to the development of a diagnostic test (i.e. increased chromosomal breakage in FA cells compared with normal controls after exposure to DEB) over two decades ago and this is still a useful test today. This FA cell hallmark has also facilitated many advances in our understanding of FA, including clarification of the complex genetics of this disease with 13 subtypes/complementation groups identified at present. and FANCN) responsible for these subtypes have all been identified. Studies from many research groups around the world have demonstrated that the proteins encoded by the FA genes participate in a complicated network which is important for DNA repair. 5 Specifically, eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM) interact with each other and form a nuclear complex called the FA core complex (Figure 1). The FA core complex is required for the activation of the FANCD2 protein to a monoubiquitinated isoform (FANCD2-Ub). In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to chromatin containing the DNA damage (e.g. DNA cross-link). …