Fanconi anemia

Related Terms

Acute myelogenous leukemia, abnormal ears, abnormal hearing, AML, anemia, aplastic, aplastic anemia, blood cells, bone marrow, bone marrow failure, BRCA2 gene, bruises, bruising, caf?-au-lait spots, cancer, chromosomal instability, clotting, constitutional aplastic anemia, developmental delay, Estren Dameshek Fanconi anemia, FA, Fanconi's anemia, fatigue, genitourinary problems, hepatoma, infections, inherited bone marrow failure syndrome, leukemia, liver adenoma, low birth weight, MDS, missing thumb, myelodysplastic syndromes, pallor, pancytopenia, petechiae, platelets, poor growth, radial ray anomalies, skin pigmentation, short stature, structural renal defects, thumb anomalies.

Background

Fanconi anemia is a rare inherited disease characterized by bone marrow failure and a broad variety of birth defects. Bone marrow is the soft inner part of bones that makes blood cells. Because of defects in the bone marrow, individuals with Fanconi anemia have lower than normal numbers of red and white blood cells and platelets. The lack of white blood cells predisposes the patient to infections, while the lack of red blood cells can lead to anemia. Anemia can cause fatigue as a result of low levels of oxygen being delivered throughout the body. Low platelet levels in Fanconi anemia may cause problems with blood clotting, which is necessary to stop bleeding and repair the site of injury or surgical incision.
A Swiss pediatrician named Guido Fanconi reported the first case of Fanconi anemia in 1927. It is important to note that Fanconi anemia is different from Fanconi syndrome, which was also named after Dr. Fanconi. Conversely, Fanconi syndrome is a rare kidney disorder in which an individual loses nutrients through the urine.
Although Fanconi anemia is considered primarily a blood disease, it can affect all systems of the body. It has been reported that approximately 75% of individuals with Fanconi anemia have birth defects. In the remaining 25%, symptoms appear slowly throughout childhood and often lead to complete bone marrow failure.
Fanconi anemia is generally diagnosed when a patient is two to 15 years of age. In rare cases, individuals do not have symptoms until adulthood. Patients who have Fanconi anemia are usually smaller in stature than average, feel extremely fatigued, and frequently have infections. Nosebleeds or easy bruising may be the first sign of the disease. Fanconi anemia should be suspected and tested for in any infant born with malformed thumbs and arms. Anyone developing aplastic anemia, despite the individual's age or lack of visible defects, should be tested for Fanconi anemia.
The main complications of Fanconi anemia are myelodysplastic syndromes (MDS), which is a mild form of leukemia, acute myeloid leukemia (AML), and other types of cancer. Although many patients are of short stature and have skeletal anomalies, intelligence is usually normal, and education and career planning should be encouraged.
Fanconi anemia is caused by an inherited genetic defect (mutation). Mutations in at least 13 genes are known to cause Fanconi anemia. These genes include FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN. It is still not clear exactly how these mutations cause birth defects, bone marrow failure, or cancer predisposition in Fanconi anemia.
Treatment of Fanconi anemia includes the use of medications, blood transfusions, and bone marrow transplantation. Bone marrow transplantation is the most effective treatment. Even with a bone marrow transplant, however, patients face an increased risk of developing cancer and other serious health problems throughout their lifetime. Cancer prevention and screening, frequent blood count checks, and yearly bone marrow exams are necessary. Transfusions or antibiotics can treat symptoms caused by low blood counts, such as bleeding, infections, or anemia. Individuals who develop a fever in addition to low white blood cell counts are generally treated by intravenous antibiotics under hospital supervision.
Because Fanconi anemia is inherited, there is currently no known way to prevent this condition. With proper treatment, a patient with Fanconi anemia can live to age 30 or beyond.

Signs and symptoms

General: Although Fanconi anemia is considered primarily to be a blood disease, it can affect all systems of the body. About 75% of people with Fanconi anemia have birth defects. In the remaining 25%, symptoms appear slowly throughout childhood and often lead to complete bone marrow failure.
Aplastic anemia: Aplastic anemia is a type of anemia caused by bone marrow failure. Anemia occurs when there are not enough red blood cells or when there is a lack of hemoglobin. Hemoglobin is a protein found in red blood cells that makes the blood red and carries the oxygen in the bloodstream. People with anemia do not get enough oxygen delivered to their tissues by the blood. Without oxygen, the organs and tissues cannot work as well as they should. Anemic individuals are often tired and may faint or have pallor (change in facial complexion associated with illness). It is estimated that 25% of all cases of aplastic anemia are caused by Fanconi anemia.
Birth defects: About 75% of patients with Fanconi anemia have birth defects. Patients with mutations in the FANCD1 or FANCJ genes have the most severe birth defects. Birth defects that are associated with Fanconi anemia include short stature, small head, and delicate facial features. Patients may also have abnormal eye shape or function that may cause blindness and abnormal ear shape or function that may cause deafness. Both males and females may have abnormal or absent genitals that may lead to infertility in some cases. Many skeletal abnormalities may occur, including missing, extra, or distorted thumbs; small or missing arm or hand bones; and extra, missing, or deformed fingers or toes. Of all Jewish children born with Fanconi anemia, 90% do not have thumbs. Other skeletal abnormalities may affect the ribs, spine, hip, or leg. Skin abnormalities may include patches of dark skin called cafe-au-lait spots, irregular light patches of skin called vitiligo, bruises, or small red spots called petechiae caused by small broken blood vessels. More serious birth defects may include a malformed kidney, heart, or lungs, or problems with the digestive tract.
Blood abnormalities: Blood abnormalities that may occur with Fanconi anemia include macrocytosis, pancytopenia, neutropenia, and thrombocytopenia. Macrocytosis, also called megaloblastic anemia, consists of unusually large red blood cells, usually occurs before age 7, and may be the first symptom leading to a diagnosis of Fanconi anemia. Pancytopenia, which is a blood abnormality that affects more than one blood cell type, is usually noted before age 15. Neutropenia, or low neutrophil count, can increase the risk of infection. Neutrophils are white blood cells that fight infections. Thrombocytopenia refers to a low platelet count. Patients with a low platelet count cannot properly form blood clots to heal wounds, which may result in petechiae (small bruises caused by tiny broken blood vessels), bruising, and hemorrhage (major bleeding event that can be life threatening).
Cognitive problems: Patients with Fanconi anemia may have an intellectual disability or learning disabilities associated with improperly formed nerve connections in the brain.
Developmental problems: Individuals who have Fanconi anemia are often smaller in stature, have a low birth weight, grow at a slower rate than normal, and take longer than normal to develop skills, such as walking and reading.
Infections: Because they may have decreased numbers of white blood cells (neutrophils) or a lack of platelets, people with Fanconi anemia may be prone to infection. Neutrophils are blood cells that fight infections. Platelets are necessary for broken blood vessels to properly heal and for cuts to form clots and close up.

Diagnosis

General: Generally, Fanconi anemia is diagnosed when an individual is two to15 years old. In rare cases a patient may not show symptoms until adulthood. Diagnosis is usually made based on the presence of aplastic anemia (low red blood cell counts) and in many cases, birth defects. Any individual diagnosed with aplastic anemia, despite age or lack of symptoms, should be tested for Fanconi anemia.
Fanconi anemia patients are usually smaller than average, feel extreme fatigue, and have frequent infections. Nosebleeds or easy bruising may be other signs of the disease. Fanconi anemia should be suspected and tested for in any infant born with malformed thumbs and arms. Patients with Fanconi anemia are at high risk for developing acute myeloid leukemia (AML) and certain solid tumors and may even have these cancers at the time of diagnosis.
Blood tests: Blood tests may reveal a low white blood cell, red blood cell, or platelet count. A complete blood count (CBC) may reveal that more than one type of blood cell is present at lower than normal levels (pancytopenia) or may show only macrocytic (abnormally large) red blood cells. The mean corpuscular volume, a measure of the average red blood cell size, is elevated in patients with Fanconi anemia. The CBC may also show low levels of platelets (thrombocytopenia) or white blood cells (leucopenia). In an adult, a normal platelet count is about 150,000-450,000 platelets per microliter. A normal white blood cell count is 4,100-10,900 per microliter. A normal red blood cell count in men is 4,300,000-6,200,000 per microliter, and in women and children 3,800,000-5,000,000 per microliter.
Bone marrow biopsy: A bone marrow biopsy removes a sample of bone with the marrow inside. In patients with Fanconi anemia, a bone marrow biopsy may reveal abnormally low numbers of cells for the marrow to use in making red and white blood cells and platelets. In the case of Fanconi anemia patients who have developed leukemia, there may be a buildup of dysfunctional white blood cells. While this procedure is generally safe, there is a risk of infection.
Chromosome breakage test: The best test for diagnosing Fanconi anemia is the chromosome breakage test. In this test, a blood sample is mixed 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 cells from Fanconi anemia patients show obvious chromosome breakage under a microscope. The two chemicals commonly used for this test are DEB (diepoxybutane) and MMC (mitomycin C). These tests can be performed prenatally on cells from chorionic villi or from the amniotic fluid.
Developmental tests: Because poor vision and hearing are associated with Fanconi anemia, people suspected to have this disorder will need to have their vision and hearing tested. Other tests may be performed in children to determine whether they have learning disabilities.
Flow cytometry: Flow cytometry is a technique for counting, examining, and sorting microscopic particles suspended in a stream of fluid. Blood cells from patients are collected and labeled with a fluorescent dye. Depending on how well the cells replicate, they will behave differently in the flow cytometer. In patients with Fanconi anemia, blood cells do not replicate fast enough, while other types of cells may replicate too quickly, causing tumor formation.
Genetic testing: In some cases, it is possible to test for mutation in the genes associated with Fanconi anemia. These tests are generally performed only in research laboratories, with the exception of a relatively common mutation found in Ashkenazi Jews.
Physical exam: A physical exam may identify birth defects associated with Fanconi anemia. Approximately 75% of patients with Fanconi anemia have birth defects, which may include short stature, small head, and delicate facial features. Patients may also have abnormal eye shape or function that may cause blindness and abnormal ear shape or function that may cause deafness. Both males and females may have abnormal or absent genitals. Many skeletal abnormalities may occur, including missing, extra, or misshapen thumbs; small or missing arm or hand bones; and extra, missing, or deformed fingers or toes. Of Jewish children born with Fanconi anemia, 90% do not have thumbs. Other skeletal abnormalities may affect the ribs, spine, hip, or leg. Skin abnormalities may include patches of dark skin called cafe-au-lait spots, irregular light patches of skin called vitiligo, bruises, or small red spots called petechiae that are caused by small broken blood vessels.
Prenatal diagnosis: Prenatal diagnosis of Fanconi anemia can be done by performing the chromosome breakage test on cells obtained from chronic villus sampling, from amniocentesis, or from blood collected from the umbilical cord. Another method of prenatal diagnosis is to look for mutations associated with Fanconi anemia in DNA extracted from fetal cells. Any prenatal test carries a risk of miscarriage.
Preimplantation genetic diagnosis can be performed using methods that allow implantation of an embryo that is known to be free of mutations associated with Fanconi anemia.
Ultrasound: Ultrasound uses sound waves to image organs inside the body. Ultrasound may be used to identify common problems associated with Fanconi anemia in the kidneys, heart, brain, and liver. Ultrasound can also be used to monitor for solid tumors.
X-ray: X-rays may be used to check for common birth defects seen in Fanconi anemia, including skeletal abnormalities such as missing, extra, or distorted thumbs; small or missing arm or hand bones; and extra, missing, or deformed fingers or toes. Other skeletal abnormalities may be found in the ribs, spine, hip, or leg.

Complications

General: The main complications of Fanconi anemia are myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and other types of cancer, usually developed in that order. The risk of developing either MDS or AML is 27% before 20 years of age, 43% by 30 years of age, and 52% by 40 years of age. Even after a successful bone marrow transplant, about 25% of Fanconi anemia patients die from complications within two years of the transplant.
Acute myeloid leukemia: Many patients who have Fanconi anemia also develop acute myeloid leukemia (AML) during childhood. The risk of developing AML increases with the onset of bone marrow failure. AML is characterized as a cancer of the blood and bone marrow in which the bone marrow makes abnormal white blood cell precursors (myeloblasts), red blood cells, or platelets. In AML patients, there is uncontrolled accumulation of white blood cells (leukocytes). Under normal circumstances, the blood-forming cells of the bone marrow make leukocytes from myeloblasts to defend the body against infectious organisms, such as viruses and bacteria. White blood cells also produce, transport, and distribute antibodies as part of the body's immune response. Antibodies identify foreign objects, such as a bacteria or virus. If some leukocytes are damaged and remain in an immature form, they become poor infection fighters that multiply excessively and do not die off as they should.
All of the many subtypes of AML can occur in Fanconi anemia with the exception of promyelocytic, which is caused by an abnormal accumulation of blood cells called promyelocytes. It is different from other types of AML because it can be treated with all-trans-retinoic acid (ATRA) therapy. However, myelomonocytic and acute monocytic are the most common subtypes observed.
Bone marrow failure: Bone marrow failure results in inadequate blood cell production caused when the stem cells in the bone marrow fail to reproduce and subsequently die. In patients with Fanconi anemia, bone marrow failure usually leads to MDS and then to AML.
Cancer: People with Fanconi anemia are extremely likely to develop head and neck, esophageal, gynecological, or gastrointestinal cancers at a young age. Even after receiving bone marrow transplants, people with Fanconi anemia are still likely to develop several types of cancers, including leukemia, oral, and liver cancers. Patients who have had a successful bone marrow transplant must still have regular examinations to watch for signs of cancer.
Fanconi anemia patients with mutations in the FANCD1 and FANCN genes have especially high rates of AML, brain tumors, and Wilms tumors. These types of cancers are found in 95% of patients by age five. In approximately 25% of patients with Fanconi anemia who have cancer, the diagnosis of leukemia or a tumor precedes the diagnosis of Fanconi anemia.
Fertility: Men with Fanconi anemia have decreased fertility, although a small number have fathered children. Depending on the severity of symptoms, both males and females may have abnormal or absent genitals.
Myelodysplastic syndromes (MDS): MDS, formerly known as preleukemia, are a group of bone marrow disorders that are similar to AML. In MDS, however, the percentage of precursors to certain blood cells found in the bone marrow (called blast cells) is less than 20% of normal levels. When left untreated, MDS will lead to AML in about 30% of cases. MDS has been reported in about 6% of Fanconi anemia patients, primarily in teens and young adults.
Pancytopenia: Pancytopenia is defined as blood abnormalities in multiple blood cell types. More than 90% of patients with Fanconi anemia develop pancytopenia caused by aplastic anemia, which is often fatal.
Pregnancy: Women with Fanconi anemia who become pregnant should be monitored carefully by a doctor. They often need blood transfusions throughout pregnancy.

Treatment

General: People with Fanconi anemia are usually treated by a team of doctors, including a blood disorder specialist (hematologist), a doctor who treats diseases related to glands (endocrinologist), and an eye doctor (ophthalmologist). Depending on the symptoms, a bone doctor (orthopedist), a doctor specializing in female reproduction (gynecologist), or kidney disease specialist (nephrologist) may also be necessary.
Treatment of Fanconi anemia with medications, blood transfusions, and stem cell transplantation increases life expectancy beyond the average of approximately age 30 years. Cancer prevention and screening are also necessary to identify cancers at an early stage, when they are most treatable.
Patients with Fanconi anemia require frequent blood count checks and yearly bone marrow exams. Transfusions or antibiotics can treat symptoms caused by low blood counts, such as bleeding, infections, or anemia.
Bone marrow transplantation: Bone marrow transplantation is the only long-term cure for the blood defects in Fanconi anemia. In this surgical procedure, bone marrow is taken while the donor is under general anesthesia. Some of the donor's bone marrow is removed from the top of the hip bone. The bone marrow is then filtered, treated, and transplanted into the patient through a vein and is naturally carried into the bone cavities where it grows to replace the old bone marrow.This treatment is usually most successful in children. Bone marrow transplantation has many risks associated with it, especially because Fanconi anemia patients are extremely sensitive to radiation and cancer drugs (chemotherapy). Fanconi anemia patients are at very high risk for organ toxicity, graft-versus-host disease, in which the patient's body rejects the donor's bone marrow, and development of glucose intolerance, with most patients requiring insulin therapy. Therefore, bone marrow transplants should be done at a hospital that specializes in this type of procedure.
A bone marrow transplant in a person with Fanconi anemia has a relatively low success rate when the donor is unrelated and a higher success rate when the donor is a sibling with a matching HLA (human leukocyte antigen) immunity type. HLA types are used by the body to recognize "self" vs. "nonself." Other sources are blood cells from the umbilical cord and bone marrow from an unrelated person. Even though a successful bone marrow transplant can cure the bone marrow complications from Fanconi anemia, people with this condition must be regularly screened for cancers.
Lifestyle adjustments: Patients with thrombocytopenia should avoid trauma, such as that resulting from contact sports, and should use helmets and padding if participating in such activities. Those with anemia should participate in strenuous activities only under supervision and only as tolerated. Those with severe neutropenia need to avoid exposure to people with active infections.
Medications: Before bone marrow transplantation was available for Fanconi anemia patients, the standard treatment was androgen (male hormone) therapy combined with low doses of steroids such as hydrocortisone and prednisone. This approach is still used in people who do not have or are waiting for a bone marrow donor.
About half of Fanconi anemia patients respond well to androgens, which stimulate the production of red blood cells and platelets. Sometimes white cell production is stimulated as well. This treatment may be effective for many years, but most patients fail to respond in the long term and eventually need a bone marrow transplant. Many side effects are associated with androgen use. The most common are high blood pressure and elevated cholesterol levels. Corticosteroids, such as cortisol, may be used to improve blood vessel integrity and reduce bleeding.
Hematopoietic (blood-stimulating) growth factors are also used. Granulocyte colony-stimulating factor (G-CSF) stimulates the production of white blood cells. Other growth factors may be effective in combination. In the short term, taking growth factors, such as erythropoietin, G-CSF, and GM-CSF, can improve blood counts. Symptomatic neutropenia usually responds to G-CSF. While most Fanconi anemia patients are initially responsive to androgen and growth factor therapy, these have been shown to promote leukemia and can have severe side effects, in particular liver cancer.
Surgery: Surgery and splinting may be done on malformed thumbs and other bones. Hand surgery should be performed early in life to ensure maximal function. Heart defects, digestive tract problems, and solid tumors associated with cancers may also be treated surgically. Because of potential complications, all surgeries should be performed only in consultation with hematologists and oncologists who have experience with Fanconi anemia.

Integrative therapies

Currently, there are limited scientific data on the use of integrative therapies for the treatment or prevention of Fanconi anemia.

Prevention

Because Fanconi anemia is an inherited condition, there is currently no known way to prevent it.
Vaccinations: Vaccination can prevent some complications, such as pneumococcal pneumonia, hepatitis, and varicella infections.
Cancer prevention: Patients with this disorder should avoid cancer-causing substances (carcinogens) and participate in regular screenings to ensure early diagnosis, while the cancer is more likely to be treatable. Additional ways to reduce cancer risk include eating a diet rich in fruits and vegetables, exercising regularly, wearing sunscreen, avoiding tobacco use, and avoiding alcohol consumption.
Genetic counseling: Individuals who have Fanconi anemia may meet with a genetic counselor before having children to discuss the risk of having a child with Fanconi anemia. Carriers of defective genes associated with Fanconi anemia can be determined through detailed family histories. If it is known that a variation of one of the mutations associate with Fanconi anemia is common in a certain family, genetic testing may be available in some cases. Families with this condition can have genetic counseling to better understand their risk.
Prenatal diagnosis: Prenatal diagnosis of Fanconi anemia can be done by performing the chromosome breakage test on cells obtained from chorionic villus sampling, from amniocentesis, or from blood collected from the umbilical cord. Another method of prenatal diagnosis is to look for mutations associated with Fanconi anemia in the DNA extracted from fetal cells. Genetic counselors are available to guide individuals in deciding whether to terminate a pregnancy or to carry the pregnancy to term. In vitro fertilization and preimplantation genetic diagnosis can be used to identify a fetus that does not have Fanconi anemia. All prenatal tests are associated with a risk of miscarriage.

Author information

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

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Causes

General: Fanconi anemia is caused by an inherited genetic defect (mutation). Mutations in at least 13 genes are known to cause Fanconi anemia. These genes include FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN. The specific role of mutations in these genes in causing birth defects, bone marrow failure, or cancer predisposition is not yet clear.
It has been extremely difficult for researchers to define the precise functions of the proteins that are encoded by the genes associated with Fanconi anemia because these proteins have multiple functions. They form large complexes with other proteins in the cell and interact with a variety of signaling molecules. When one of the proteins in the complex has a mutation, the signaling molecules malfunction. This can cause many problems in the cell, including problems fixing damaged DNA, chromosomal instability (where large complexes of DNA and protein are not properly organized), dilemmas concerning the removal of toxic substances called free radicals that damage DNA, and an inability to control how fast cells replicate. Cells that reproduce too quickly may become tumor cells.
Mutations in the genes associated with Fanconi anemia have been observed in a wide variety of human cancers in the general population. Specifically, mutations in the FANCD1 gene are associated with mutations in another gene called BRCA2 that has been linked to breast cancer. It is not clear whether mutations in one gene lead to mutations in another.
Many of the proteins associated with Fanconi anemia are important for recognition and repair of damaged DNA and also for cellular replication. When cellular replication is not carefully controlled, tissues, such as those in the bone marrow, may stop reproducing and die. Successful cellular replication is very important during fetal development, which may explain some of the birth defects commonly seen in Fanconi anemia patients.
Inheritance: Fanconi anemia is inherited in an autosomal recessive manner. Genes are inherited on alleles, or genetic variants of a specific gene. Individuals receive two copies of most genes, one from the mother and one from the father. Because Fanconi anemia is an autosomal recessive disorder, an individual must inherit two mutated alleles to have the disease. However, individuals who possess only one mutated allele do not experience symptoms but are referred to as "carriers" because they have the ability to pass the mutated gene on to their offspring. If only one parent is a carrier, then there is a 50% chance with each birth that the child will become a carrier but a 0% chance that the child will actually inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, a 50% chance that each child will be a carrier, and a 25% chance that each child will not inherit either mutant allele.

Risk factors

General: Because Fanconi anemia is inherited, the only known risk factor is a family history of the disorder. Men and women are affected in equal numbers. Approximately 1,000 people worldwide presently have the disease. Fanconi anemia affects approximately one out of 360,000 people.
Autosomal recessive inheritance: Fanconi anemia is inherited in an autosomal recessive manner. Genes are inherited on alleles, or genetic variants of a specific gene. Individuals receive two copies of most genes, one from the mother and one from the father. Because Fanconi anemia is an autosomal recessive disorder, an individual must inherit two mutated alleles to have the disease. Individuals who possess only one mutated allele do not experience symptoms but are referred to as "carriers" because they have the ability to pass the mutated gene on to their children. If only one parent is a carrier, then there is a 50% chance with each birth that the child will become a carrier but a 0% chance that the child will actually inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, a 50% chance that each child will be a carrier, and a 25% chance that each child will not inherit either mutant allele. If both parents have the disease, there is a 100% chance that their offspring will have the disease. Approximately one in every 300 individuals is a carrier.
Ethnicity: Although Fanconi anemia is a rare disorder, it is more likely to occur in certain populations. Among Ashkenazi Jews, approximately one out of every 90 people is a carrier and approximately one out of every 30,000 people has the disease. In the following populations, approximately one out of every 40,000 people currently has the disease: South African Afrikaners, sub-Saharan Africans, and certain populations in Spain.