Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include one or more of the following: short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ears (and decreased hearing), heart, gastrointestinal system, central nervous system; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 50 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-30%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%.
The diagnosis of FA rests upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of at least 15 genes, which are responsible for the known FA complementation groups (A, B, C, D1 [BRCA2], D2, E, F, G, I, J [BRIP1], L, M, N [PALB2], O [RAD51C], and P [SLX4]). The latter two genes are still thought of as tentative as they do not fall within a very easily characterized compartment biologically and have very few representative individuals. If the relevant complementation group is identified, molecular genetic testing can be directed to the appropriate gene. Molecular genetic testing is clinically available for most of the genes.
Abnormalities of Fanconi anemia (FA) genes are inherited in an autosomal recessive manner except for mutations in FANCB, which are inherited in an X-linked manner. Autosomal recessive FA: Each sibling of an affected individual has a 25% chance of inheriting both mutations and being affected, a 50% chance of inheriting one mutated gene and being a carrier, and a 25% chance of inheriting both normal genes and not being a carrier. Carriers (heterozygotes) for autosomal recessive FA are asymptomatic. X-linked FA: For carrier females the chance of transmitting the mutation in each pregnancy is 50%; males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. For both autosomal recessive and X-linked FA: Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for all known genes if the disease-causing mutations in the family are known.