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Fanconi Anemia


What is Fanconi anemia and how is it diagnosed?

Fanconi anemia (FA), named for Swiss pediatrician, Guido Fanconi,is one of the inherited anemias that lead to bone marrow failure (aplastic anemia). It is a recessive disorder: if both parents carry a defect (mutation) in the same FA gene, each of their children has a 25% chance of inheriting the defective gene from both parents. When this happens, the child will have FA. FA occurs equally in males and females. It is found in all ethnic groups. Though considered primarily a blood disease, it may affect all systems of the body. Many patients eventually develop acute myelogenous leukemia (AML). Older patients may develop other cancers. Many patients do not reach adulthood. Fanconi anemia patients are usually smaller than average. FA usually reveals itself when children are between the ages of 3 and 12, but in rare cases no symptoms are present until adulthood. Patients may feel extreme fatigue and have frequent infections. Nosebleeds or easy bruising may be a first sign. Blood tests may reveal a low white or red cell or platelet count or other abnormalities. Sometimes myelodysplasia or AML is the first sign of FA. FA sometimes is evident at birth through a variety of physical defects. These may include any of the following:

  • Thumb and arm anomalies: misshapen or missing thumbs or an incompletely developed or missing radius (one of the forearm bones)
  • Skeletal anomalies of the hips, spine, or ribs
  • Kidney problems
  • Skin discoloration (café-au-lait spots); portions of the body may have a suntanned look
  • Small head or eyes
  • Mental retardation or learning disabilities
  • Low birth weight
  • Gastro-intestinal difficulties
  • Small reproductive organs in males
  • Defects in tissues separating chambers of the heart.

The only general definitive test for FA at the present time is a chromosome breakage test: some of the patient's blood cells are treated, in a test tube, with a chemical that crosslinks DNA. Normal cells are able to correct most of the damage, and are not severely affected, whereas FA cells show marked chromosome breakage. There are two chemicals commonly used for this test, DEB (diepoxybutane) and MMC (mitomycin C). These tests can be performed prenatally on cells from chorionic villi or from the amniotic fluid. Another test is available for selected families. There are at least five FA genes (A, B, C, D, and E), and there is evidence for as many as eight. A defect in any one of these genes causes FA. The C gene has been isolated and sequenced, and several specific mutations have been identified. Mutations in the C gene account for about 15% of FA cases worldwide. Among Ashkenazi Jews, mutations in the C gene account for nearly all cases of FA. A rapid DNA test is available to identify mutations in the C gene. This test can be performed as part of a genetic screen (for instance, for Tay-Sachs disease). Or it can be performed on members of any family known to carry a mutation in the C gene. This test can be performed on a single cell, and can be performed on a single cell from an embryo before implantation. Defects in the A gene account for most cases of FA worldwide. The A gene has now been isolated and sequenced.

Soon mutation tests will be available for families carrying defects in the A gene, as they are now for the C gene. Many cases of FA are not diagnosed at all, or not diagnosed in a timely manner. FA should be suspected and tested for in any infant born with the thumb and arm abnormalities described above. Anyone developing aplastic anemia at any age should be tested for FA, even if no other defects are present. Many FA patients show no other abnormalities. It is absolutely essential to test for FA before contemplating bone marrow transplantation for aplastic anemia. The regimen used to prepare patients for transplant is very different for FA patients! While the total number of FA patients is not documented worldwide, scientists estimate that the carrier frequency (carriers are people carrying a defect in an FA gene, whose matching FA gene is normal) for FA is somewhere between 1 in 600 and 1 in 100. The International Fanconi Anemia Registry managed by Dr. Arleen Auerbach at The Rockefeller University maintains case data on at least 3,000 patients.

How is FA treated?

Short-term therapy may include blood transfusions and antibiotics.Long-term therapies available at the present time include:

  • Androgens
  • Growth factors
  • Bone marrow transplantation
  • Gene therapy
Androgens:

About half (or more) of FA patients respond well to androgens (male hormones), which stimulate the production of red blood cells and often platelets. Sometimes white cell production is stimulated as well. This treatment may be effective for many years, but most patients eventually fail to respond. Growth factors:Hematopoietic (blood-stimulating) growth factors are being tested now. G-CSF stimulates the production of white blood cells, and seems to be effective in FA patients. Other growth factors may be effective in combination.

Bone marrow transplantation:

At the present time, this is the only long-term cure for the blood defects in FA. This treatment has many risks associated with it, and the risks are compounded in FA patients.

Gene therapy:

Clinical trials are underway for FA patients with defects in the C or A gene. Please refer to "Fanconi Anemia: a Handbook for Families and Their Physicians" for more information. Be sure to check the "FA Family Newsletter" and "Science Letter" for the latest news about growth factor trials, bone marrow transplantation, and gene therapy.

How is FA related to Leukemia and other cancers?

People with Fanconi anemia often develop leukemia and other cancers. In fact, Fanconi anemia patients have a 15,000 times greater risk of developing acute myelogenous leukemia (AML) than people without Fanconi anemia! Leukemia is a malignancy of the blood system in which the bone marrow produces vast quantities of immature white cells called "blasts." The blasts can proliferate rapidly and suppress the development of healthy blood cells needed for effective functioning of the patient's body. If untreated, leukemia results in uncontrollable infections and bleeding, and death. The TYPE of leukemia that FA patients are likely to develop, AML, is a particularly aggressive type, usually found in older people. AML is difficult to treat successfully, especially in FA patients, who are very sensitive to the toxic drugs used to suppress the leukemia. Several laboratories around the world are developing new therapies for the treatment of AML.

Fanconi anemia patients may develop cancers in areas of the body where cells normally reproduce rapidly, such as the mouth, esophagus, the intestinal and urinary tracts, and the reproductive organs. Patients who have had a successful bone marrow transplant, and thus are cured of the blood problems associated with FA, still must have regular examinations to watch for signs of cancer.There is some evidence that at least one of the normal FA genes (the C gene) may act as a tumor suppressor. When defective, the gene can no longer play this critically important role. Understanding FA may lead to the development of life-saving treatments for millions of patients, far beyond those affected by Fanconi anemia. Contact www.fanconi.org for additional information.

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