Fanconi anemia is an inherited disorder characterized by a severe form of anemia and various other physical malformations. Patients with Fanconi anemia are susceptible to various types of cancer .
Fanconi anemia (FA) was first described in 1927 by a Swiss pediatrician named Guido Fanconi. It is a rare, inherited form of aplastic anemia. Aplastic anemia is a life-threatening condition in which a person is unable to produce adequate amounts of red blood cells, white blood cells, or platelets. Red blood cells serve to carry oxygen to all areas of the body. White blood cells help to fight infection and disease. Platelets are responsible for clotting to help to heal wounds and control bleeding. Without adequate amounts of these important blood cells, patients affected with aplastic anemia are easily fatigued and susceptible to infections. Most cases of aplastic anemia develop throughout the course of a person's lifetime. However, in FA, the aplastic anemia is inherited, or present from birth.
FA is also associated with various other findings. These include short stature, skeletal abnormalities, kidney problems, and heart defects. Additionally, people with FA experience a high incidence of leukemia and an increased incidence of other types of cancer.
The chromosomes in the cells of FA patients break and rearrange easily. Chromosomes are the information manuals of our cells. Genes are arranged on chromosomes in a linear fashion, like beads are arranged on a string. Genes tell our cells how to make proteins. These proteins perform many vital functions in the body. When chromosomes break, genes are disrupted and they do not function correctly. This leads to abnormal proteins and various health problems. The chromosome breakage in FA can be seen in the laboratory and is used to diagnose the disorder.
It has been determined that there are at least eight different genes associated with FA. A change in any one of these genes causes the disorder. As of 2001, the proteins made by these genes are not yet known and their role in FA is not yet understood.
For someone to be affected with FA, each of their parents must have a defect in the same gene . Parents that carry the defective gene do not show symptoms of FA because they have a corresponding gene on the other chromosome that produces an adequate amount of protein. Thus, they often do not know they are carriers until they have an affected child. If both parents carry the same defective gene, each pregnancy has a 25% chance of inheriting both abnormal genes and being affected with FA. Likewise, each pregnancy has a 25% chance of inheriting two functional copies of the gene and being unaffected. This leaves a 50% chance that the pregnancy will have one functional gene and one defective gene and will be an unaffected carrier of the disorder. This pattern is known as autosomal recessive inheritance .
The FA genes are designated by a letter of the alphabet. Defects in the FA-A gene account for approximately 65% of FA cases. Defects in the FA-C gene account for about 15% of FA cases. In the Ashkenazi Jewish population, however, defects in this particular gene are responsible for nearly all cases of FA.
FA occurs equally in males and females. The total number of FA patients has not been documented. It has been estimated, however, that between one in 100 and one in 600 people carry one of the defective genes. FA is found in all ethnic groups but is more frequent in the Ashkenazi Jewish population. One in every 89 people in this population carry a mutation in the FA-C gene.
Signs and symptoms
The signs and symptoms of FA generally appear between the ages of three and 12. In rare cases, symptoms do not present until adulthood. These symptoms vary in severity from case-to-case. Even within a family, siblings who are both affected may show very different signs of the disorder.
Aplastic anemia is the first sign of FA in many patients. In some cases, it may be the only sign of the disorder. In aplastic anemia, the bone marrow does not produce an adequate amount of red cells, white cells, or platelets. This can lead to several conditions. Anemia can result due to the deficiency in red blood cells, leading to weakness, fatigue, and a pale appearance. Without enough white blood cells, the patient may be vulnerable to common germs and infections. The deficiency in platelets can cause easy bruising, nosebleeds, and possible internal bleeding.
Ten to fifteen percent of patients with FA develop leukemia, specifically acute myelogenous leukemia (AML). Leukemia is a cancer of the blood system in which abnormal white blood cells grow rapidly in number and suppress the development of healthy blood cells. AML is a particularly aggressive type of leukemia and is difficult to treat successfully. Individuals with FA are very sensitive to the toxic drugs used to fight leukemia, which makes treatment even more difficult.
Among the physical defects associated with FA, short stature is very common. Additionally, an affected child may be born with missing, misshapen, or extra thumbs, or an underdeveloped or missing bone in the arm. Approximately one-fifth of patients with FA exhibit other skeletal abnormalities, such as those of the hip, spine, or rib. About 25% of individuals with FA are born with abnormalities of the kidneys. Some are born with defects of the heart, stomach, esophagus, or intestinal tract. These problems may require immediate surgery at birth.
FA is also associated with hyperpigmentation, or a darkening of the skin, in approximately 65% of patients. This darkening may be present in the form of spots or it may be more diffuse over a larger portion of the body. Additionally, the head or eyes might be smaller than average and some patients may not grow properly. Learning disabilities are thought to be fairly common in FA as well. Hearing loss has been reported in 10% of patients.
As these individuals become older, other problems may result. In males, it is common to see underdeveloped male organs and infertility. Females often have a delay in the start of their menstrual periods and a decrease in fertility. Menopause may occur as early as age 30.
People with FA, especially those over the age of 20, are at a high risk to develop cancerous tumors in the head, neck, intestines, urinary tract, liver, and esophagus. Women are also at an increased risk for cancers of the reproductive tract.
The most common test for FA is called a chromosome breakage test. White blood cells are isolated from a patient's blood sample and destructive chemicals are added to these cells. The chromosomes are then viewed under a microscope. If the person is not affected with FA, the chromosomes will appear normal. If the person is affected with FA, the chromosomes will be broken and rearranged. Skin cells can be tested in a similar fashion and will often show this chromosome breakage as well. This particular test can be completed prenatally if a family desires to know whether or not a child is affected before he or she is born. Cells obtained from the mother's placenta or cells floating in the amniotic fluid that surrounds the fetus in the womb can be used to detect chromosome breakage.
For families who have a defect in the FA-C gene, it is possible to look directly at the gene to determine whether or not a defect is present. This can detect those who carry the gene defect as well as those who are affected. Carrier testing is offered routinely to those in the Ashkenazi Jewish population since the frequency of carriers is so high.
Treatment and management
Once the diagnosis of FA has been made, several initial tests should be completed, including liver and kidney function studies, a formal hearing evaluation, a developmental assessment, and an ultrasound examination of the kidneys and urinary system.
People affected with FA should be followed closely by a physician. Their blood cell and platelet counts should be monitored frequently. Symptoms caused by anemia and low platelets, such as bleeding, fatigue, chest pain, and dizziness, can be treated with transfusions as needed. Antibiotics are often given to fight infections. At times, hospitalization may be necessary to adequately tend to these complications. As patients get older, they should be monitored for any signs of solid tumor cancers.
Due to either aplastic anemia or leukemia, many individuals with FA will eventually require a bone marrow transplant. The donor must be carefully matched to the patient. The prognosis for transplant is best for young patients who have an sibling donor with a matching tissue type.
Between 50 and 75% of individuals with FA will respond to androgens. These are artificial male hormones that can stimulate production of one or more types of blood cells. They are most effective in increasing the number of red blood cells but can increase platelets and white cells as well. These drugs prolong the lives of individuals with FA but are not a cure.
As of 2001, various hematopoetic growth factors have been studied in relation to FA. These substances are already present in the body and serve to stimulate the production of blood cells and platelets. Scientists have developed a way to manufacture these substances. They have been given to patients with FA and show promise in increasing the counts of blood cells and platelets.
FA is an unpredictable illness. The average life expectancy for an affected individual is 22 years, but any one individual can have a lifespan that is quite different from this average. Research discoveries have led to life-extending treatments and improved bone marrow transplant outcome. However, as patients live longer, they become at an increased risk to develop other types of tumors.
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Aplastic Anemia Foundation. PO Box 613, Annapolis, MD 21404-0613. (800) 747-2820. <http://www.aplastic.org>.
Fanconi Anemia Research Fund. 1801 Willamette St., Suite 200, Eugene, OR 97401-4030. (800) 828-4891. <http://www.fanconi.org>.
Leukaemia Research Fund. 43 Great Ormond St., London, WC1N 3JJ. 020-7405-3139. <http://dspace.dial.pipex.com/lrf>.
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Fanconi Anemia Research Fund. <http://www.fanconi.org>.
Mary E. Freivogel, MS