Fanconi anemia (FA) is a rare autosomal recessive disease characterized by progressive bone marrow failure, congenital anomalies, and predisposition to cancer. At least 8 complementation groups for FA are known (A, B, C, D1, D2, E, F, G), and 7 FA genes have been cloned. FA cells are highly sensitive to the DNA crosslinking agents, mitomycin C (MMC) or diepoxybutane (DEB), thus providing the basis for the clinically certified diagnostic MMC/DEB test.1 FA subtyping is generally considered to be a research tool, and it is not clinically certified. At present, FA subtyping is performed only rarely, in the setting of FA gene therapy, prenatal diagnosis, or preimplantation genetic diagnosis (PGD).
FA patients display a wide range of clinical variability. Recent studies indicate that this variability may be accounted for, at least in part, by their specific FA subtype. FA-A patients, for example, may follow a milder disease course, with later onset of bone marrow failure.2 FA-G and FA-C patients, in contrast, often have more severe disease, with earlier onset of bone marrow failure and hematologic malignancy. FA-D1 patients, who have biallelic mutations in the FANCD/BRCA2 gene, may have even earlier onset of malignancies, such as brain tumors3 (A.S. and A.D.D., unpublished observation, May 2003), and these tumors appear to precede their aplastic anemia. Moreover, FANCD1/BRCA2 (+/-) heterozygote carriers have an increased risk of developing breast, ovarian, or other cancers.4 Other genetic diseases, such as the Nijmegen Breakage Syndrome (NBS), have partial clinical overlap with FA and some cellular sensitivity to DEB, further confounding the diagnosis of NBS.5 Compared with FA patients, NBS patients have a predisposition to lymphoma.
Routine subtyping of FA patients will therefore have a signifi-cant impact on clinical management. As the relationship between genotype and phenotype is established, identification of patients likely to benefit from earlier institution of curative hematopoietic stem cell transplantation for marrow failure may be feasible. FA-D1 patients may benefit from further reductions in radiation and chemotherapy, due to their enhanced sensitivity to these agents, compared with other FA subtypes (A.S. and A.D.D., unpublished observations, July 2003). Furthermore, BRCA2 carrier status testing of family members of all FA-D1 patients would allow assessment of their own cancer risk. Appropriate counseling and cancer surveillance could be initiated for affected family members. Additional clinical benefits for FA patients and families, derived from FA subtyping, are summarized in Table 1.
Moreover, FA subtyping is relatively straightforward, entailing the systematic use of retroviral complementation, immunoblotting of FA proteins, and direct gene sequencing.6,7 For FA patients of particular ethnic backgrounds, more direct tests for specific FANC alleles (ie, the FANCC IVS4+4 A to T allele in Ashkenazi Jews8 ) may be used. Although Fanconi anemia subtyping is not currently clinically certified, once the affected gene is identified from the pool of 8 possible Fanconi genes, mutations can be confirmed via gene sequencing in a Clinical Laboratory Improvement Amendment (CLIA)–certified laboratory. Taken together, the recent advances in FA research now make FA subtyping a straightforward and important element of the clinical management of the FA patient.
