What is Fanconi anemia?

Risk Factors

Children are at risk if both parents are carriers; for each child conceived by two carriers, the risk of being affected will be one in four. The severity of congenital malformations, the age at which bone marrow failure begins, and life expectancy are uncertain. In different populations, carrier frequency may range from 1 in 600 to 1 in 100. The disease occurs in about 1 in 360,000 live births but may be as high as 1 in 40,000 births in certain groups.

Etiology and Genetics

Fanconi anemia occurs in males and females in all ethnic groups throughout the world. The inheritance pattern is usually autosomal recessive, but at least one Fanconi anemia gene is located on the X chromosome. Since the 1990s, researchers have discovered a series of Fanconi anemia genes, their chromosomal location, and their gene products. At least fifteen Fanconi anemia genes have been identified. Mutations in three of these genes—FANCA, FANCC, and FANCG—account for between 80 and 90 percent of Fanconi anemia cases.

The proteins encoded by Fanconi anemia genes form a complex involved in fundamental cellular activities, including the maintenance of genomic integrity. Mutations in Fanconi anemia genes lead to increased susceptibility to chemicals that damage DNA. Cells that carry mutated Fanconi anemia genes exhibit a high level of chromosomal aberrations. In addition to aplastic anemia, patients are at very high risk of developing acute myeloid leukemia and squamous cell cancers. The discovery of Fanconi anemia–like genes in common experimental animals, such as mice and chickens, should expedite basic research.

Symptoms

Clinical histories indicate that there is no typical Fanconi anemia patient, but certain signs and symptoms call for specific diagnostic tests. Birth defects may include malformed thumbs, skeletal abnormalities, microcephalus (small head), heart defects, kidney problems, patchy discolorations of the skin, defects of the eyes and ears, underdevelopment of the bone marrow, and abnormal red blood cells. Bone marrow failure usually appears between five and ten years of age. The lack of platelets, red blood cells, and white blood cells impairs the body’s ability to form blood clots, oxygenate tissues, and fight infection. Bone marrow failure is the main cause of death.

Screening and Diagnosis

Because Fanconi anemia is so rare, pediatricians and family doctors may be unfamiliar with the disease. Early diagnosis and referral to appropriate experts is important because of the risk of bone marrow failure. Some cases are recognized at birth, because of characteristic physical anomalies, but some patients are not diagnosed until adulthood.

Physical examinations and blood tests may detect symptoms that suggest Fanconi anemia, but specific tests are needed to visualize the disease at the cellular level. A definitive diagnosis requires studies of chromosome breakage and hypersensitivity to DNA damaging agents. A test for gene mutations is also possible. Genetic tests can be performed on embryos in affected families.

Treatment and Therapy

Improvements in therapy have increased life expectancy and improved the quality of life for most patients, but there is no definitive cure for the full spectrum of problems associated with the disease. Blood, blood products, androgens, corticosteroids, and growth factors have been used to treat early bone marrow failure. Stem-cell transplants using umbilical cord blood or bone marrow have significantly increased life expectancy. Transplants from a healthy sibling of the same tissue type are most successful, but recent developments are making it possible to use less perfectly matched donors. Successful transplants cure the aplastic anemia, but other anomalies and the high risk of cancers remain. Researchers hope that gene therapy will eventually be used to correct the genetic defect.

Prevention and Outcomes

Genetic tests make it possible to identify carriers and affected embryos. If both parents are known carriers, then a fetus with Fanconi anemia can be identified during pregnancy by testing fetal cells obtained by amniocentesis or chorionic villi sampling for sensitivity to chromosome breakage. Parents can use in vitro fertilization and preimplantation genetic diagnosis to select embryos that are free of the disease. Genetic screening with embryo diagnosis can be used to select healthy embryos that match the tissue type of an affected child in order to provide umbilical cord blood cells or bone marrow.

Studies of this rare genetic disease are providing insights into broader questions about genomic maintenance, the genesis of cancers, and the mechanism of aging.

Bibliography

Ahmad, Shamin I., and Sandra H. Kirk, eds. Molecular Mechanisms of Fanconi Anemia. New York: Springer, 2006. Print.

Alter, Blanche P., and Gary Kupfer. "Fanconi Anemia." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 7 Feb. 2013. Web. 23 July 2014.

Chang, Lixian, et al. "Whole Exome Sequencing Reveals Concomitant Mutations of Multiple FA Genes in Individual Fanconi Anemia Patients." BMC Medical Genomics 7.1 (2014): 1–17. Web. 23 July 2014.

Schindler, Detlev, and Holger Hoehn, eds. Fanconi Anemia: A Paradigmatic Disease for the Understanding of Cancer and Aging. New York: Karger, 2007. Print.

Zheng, Zhaojing, et al. "Molecular Defects Identified by Whole Exome Sequencing in a Child with Fanconi Anemia." Gene 530.2 (2013): 295–300. Print.