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NORD is very grateful to David Brouch, NORD Intern from the University of Notre Dame, and Blanche P Alter, MD, MPH, FAAP, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, for assistance in the preparation of this report.
Fanconi anemia (FA) is a rare genetic disorder, in the category of inherited bone marrow failure syndromes. Half the patients are diagnosed prior to age 10, while about 10 % are diagnosed as adults. Early diagnoses are facilitated in patients with birth defects, such as small size, abnormal thumbs and/or radial bones, skin pigmentation, small heads, small eyes, abnormal kidney structures, and cardiac and skeletal anomalies. The disorder is often associated with a progressive deficiency of all bone marrow production of blood cells, red blood cells, white blood cells, and platelets. Affected individuals have an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML), or tumors of the head, neck, skin, gastrointestinal system, or genital tract. FA occurs equally in males and females, and is found in all ethnic groups. It is usually inherited as an autosomal recessive genetic disorder, but X-linked inheritance has also been reported.
There are several subtypes of FA that result from the inheritance of two gene mutations in each of 15 different genes. Most of the subtypes share the characteristic symptoms and findings.
FA is not related to the same as Fanconi syndrome, a rare kidney functional disorder.
The symptoms of FA vary from case to case. Identified symptoms include a variety of physical abnormalities, bone marrow failure, and an increased risk of malignancy. Physical abnormalities normally reveal themselves in early childhood, but in rare cases diagnoses are made in adulthood. Blood production problems often develop between 6 to 8 years of age. Bone marrow failure eventually affects of the majority of affected individuals, although the progression and age of onset vary. Patients who live into adulthood are likely to develop head and neck, gynecologic, and/or gastrointestinal cancer at a much earlier age than the general population, whether or not they had earlier blood problems.
At least 60% of individuals affected with FA are born with at least one physical anomaly. This may include any of the following:
-thumb and arm anomalies: an extra or misshaped or missing thumbs and fingers or an incompletely developed or missing radius (one of the forearm bones)
-skeletal anomalies of the hips, spine, or ribs
-kidney structural problems
-skin pigmentation (called café au lait spots)
-small, crossed, or widely spaced eyes
-low birth weight
-small reproductive organs in males
-defects in tissues separating chambers of the heart
Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing, and cardiac symptoms.
There may be excessive bruising following minimal injury and spontaneous bleeding from the mucous membranes, especially those of the gums and nose.
Bone Marrow Failure
Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding.
Progressive bone marrow failure typically presents by the age of 10 and is usually accompanied with low platelet levels or low white blood cells. By age 40 to 50 years, the estimated incidence of bone marrow failure as the first serious event is more than 50%.
Affected individuals develop low levels of all the cellular elements of the bone marrow- red and white blood cells and platelets- which can lead to the following:
-low level of circulating red blood cells - anemia
-low level of white blood cells - leukopenia
-low level of neutrophils (a type of white blood cell) - neutropenia
-low level of platelets - thrombocytopenia
Increased Risk of Malignancy
Individuals with FA have a higher risk than the general population of developing certain forms of cancer including acute myeloid leukemia and specific solid tumors. Affected individuals may are at extremely high risk of developing cancer affecting the head and neck region, gastrointestinal tract, esophagus or gynecologic regions. Most of these are a specific form of cancer, known as squamous cell carcinoma. FA patients whose bone marrow failure is treated with male hormones (called "androgens") have in increased risk of liver tumors.
In approximately 30 percent of cases associated with cancer, the development of malignancy precedes a diagnosis of FA.
The chromosomes within the cells of individuals with FA are unable to repair deoxyribonucleic acid (DNA) damage, and thus break and rearrange easily (chromosome instability). DNA is the carrier of the genetic code and damage to DNA is a normal daily occurrence. In most people, damage to DNA is repaired. However, in individuals with FA, breaks and rearrangements occur more often and their bodies are slow or fail to repair the damage.
Mutations in at least 15 genes can cause FA. The proteins encoded by these genes work together in a common pathway called the FA pathway which goes into operation when DNA damage occurs. The FA pathway sends certain proteins to the area of damage so DNA can be repaired and DNA can continue to be copied (replicated). Eight proteins form a complex known as the FA core complex, which activates two genes to make proteins, called FANCD2 and FANCI. The activation of these two proteins brings DNA repair proteins to the area of DNA damage.
Eighty to 90 percent of cases of FA are due to mutations in one of three genes, FANCA, FANCC, and FANCG. These genes provide instructions for producing components of the FA core complex. Mutations in any of the many genes associated with the FA core complex will cause the complex to be nonfunctional and disrupt the entire FA pathway. Disruption of this pathway results in a build-up of DNA damage that can lead to abnormal cell death or abnormal cell growth. The death of cells results in a decrease in blood cells and physical abnormalities associated with FA. Uncontrolled cell growth can lead to the development of acute myeloid leukemia or other cancers.
Most cases of FA are inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits the same abnormal gene from each parent (although the abnormalities in the genes may be different). If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass a defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
The FANCB gene is located on the X chromosome, and causes less than 1 percent of all cases of FA. This FA gene is inherited as an X-linked recessive trait.
X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is 'turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son.
Certain chemicals may increase the risk of chromosomal breakage in individuals with FA and should be avoided whenever possible. These chemicals include tobacco smoke, formaldehyde, herbicides, and organic solvents such as gasoline or paint thinner.
The incidence rate of FA is estimated to be about 1 in 136,000 births. This condition is more common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans.
Symptoms of the following disorders may be similar to those of FA. Comparisons may be useful for a differential diagnosis.
Chromosome instability syndromes: autosomal recessive inherited disorders that are associated with increased chromosomal breakage and genetic instability. These chromosomal abnormalities place affected individuals at a higher than average risk for developing certain cancers, especially leukemia. Additional abnormalities are present in most cases. Chromosomal instability syndromes include Bloom syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, and xeroderma pigmentosum. (For more information on these disorders choose the specific disorder name as your search terms in the Rare Disease Database.)
Acquired aplastic anemia: a rare disorder caused by profound, almost complete bone marrow failure. Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells eventually results in low levels of red and white blood cells and platelets (pancytopenia). Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infections, dizziness, weakness, headaches, and episodes of excessive bleeding. Although some cases of acquired aplastic anemia occur secondary to other disorders, researchers now believe that many cases result from a disorder of the patient's immune system, in which the immune system mistakenly targets the bone marrow (autoimmunity). This is based on the response of approximately half of patients to immunotherapy, whether it is ATG, cyclosporine, high-dose steroids or cyclophosphamide. (For more information on this disorder, choose "aplastic anemia" as your search term in the Rare Disease Database.)
Thrombocytopenia-absent radius (TAR) syndrome: a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhaging) primarily during infancy. Other characteristic findings include absence (aplasia) of the bone on the thumb side of the forearms (radii) and sometimes underdevelopment (hypoplasia) or absence of the bone on the "pinky" side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or mental retardation that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "thrombocytopenia-absent radius" as your search term in the Rare Disease Database.)
Dyskeratosis congenita, also known as Zinsser-Cole-Engman syndrome: a rare genetic disorder characterized by darkening and/or unusual absence of skin color (hyper/hypopigmentation), abnormal changes in the nails (dystrophy), and progressive degenerative changes of the mucous membranes (leukoplakia) in the mouth, and rarely the anus or urethra. Many patients have eye problems, including tearing due to narrowing of the ducts that drain tears. Additional symptoms may include the reduction of red and white blood cells and platelets in the blood (pancytopenia), resulting in bone marrow failure. Affected individuals may also have thickening of skin on the palms of the hands and soles of the feet, excessive sweating of the palms and soles, sparse or absent hair, fragile bones, underdeveloped testes, and dental abnormalities. This disorder may be inherited or occur sporadically. X-linked recessive is the most common inheritance pattern, but autosomal dominant (a parent with a mutated gene passes it to their child) is common, and autosomal recessive is rare. (For more information on this disorder, choose "dyskeratosis congenita" as your search term in the Rare Disease Database.)
VACTERL association: a nonrandom association of birth defects that affects multiple organ systems. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children: (V) = vertebral abnormalities; (A) = anal atresia; (C) = cardiac (heart) defects; (T) = tracheoesophageal fistula; (E) = esophageal atresia; (R) = renal (kidney) abnormalities; (L) = limb abnormalities (including thumbs and radii). In addition to the above mentioned features, affected children may also exhibit less frequent abnormalities including growth deficiencies and failure to gain weight and grow at the expected rate (failure to thrive). In some cases, the acronym VATER association is used. Mental functioning and intelligence are usually unaffected. Most cases occur randomly, for no apparent reason (sporadic). However, at least 5 % of FA patients have this association. (For more information on this disorder, choose "VACTERL" as your search term in the Rare Disease Database.)
The following disorders may be associated with FA as secondary complications. They are not necessary for a differential diagnosis.
Myelodysplastic syndromes (MDS): a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some cases, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. The exact cause of MDS is unknown. There are no certain environmental risk factors. (For more information on this disorder, choose "myelodysplastic syndrome" as your search term in the Rare Disease Database.)
Acute myeloid leukemia (AML): a rare form of blood cancer that begins in cells that normally develop into certain types of white blood cells. The transition to leukemia is accompanied by worsening marrow function and the accumulation, first in the marrow and subsequently in the blood, of undeveloped "immature" cells called blasts which suppress any remaining marrow cell production. As a consequence, the complications from anemia, bleeding, and infection become life-threatening. The abnormal (leukemic) cells may eventually spread via the bloodstream to other organ systems of the body. (For more information on this disorder, choose "acute myeloid leukemia" as your search term in the Rare Disease Database.)
A diagnosis of FA is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of specialized tests.
The 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.
Blood tests may be performed to determine the levels of red and white blood cells and platelets. X-ray examinations may reveal the presence and extent of skeletal malformations and internal structural abnormalities.
Many cases of FA are not diagnosed at all or are not diagnosed in a timely manner. FA should be suspected and tested for in any infant born with the thumb and arm abnormalities described previously. Anyone developing aplastic anemia at any age should be tested for FA, even if no other defects are present. Any patient who develops squamous cell carcinoma of the head and neck, gastrointestinal or gynecologic system at an early age with or without a history of tobacco or alcohol use, should be tested for FA. Many FA patients show no other abnormalities. It is essential to test for FA before contemplating stem cell transplantation for aplastic anemia or treatment for cancer, as standard chemotherapy and radiation protocols may prove toxic to FA patients.
Molecular genetic testing is available for all 15 genes associated with FA. Complementation testing is usually done first in order to identify which FA gene is mutated. Sequence analysis of the appropriate gene can then be done to determine the specific mutation in that gene. If a mutation is not identified, deletion/duplication analysis is available clinically for the genes associated with FA.
Targeted mutation analysis is available for the common Ashkenazi Jewish FANCC mutation.
Clinical Testing/ Work Up
To establish the extent of disease in an individual diagnosed with FA, the following evaluations are recommended as needed:
-Ultrasound examination of the kidneys and urinary tract
-Formal hearing test
-Developmental assessment (particularly important for toddlers and school-age children)
-Referral to an ophthalmologist, otolaryngologist, endocrinologist, hand surgeon, gynecologist (for females as indicated), gastroenterologist, urologist, dermatologist, ENT surgeon, genetic counselor
-Evaluation by a hematologist, to include complete blood count, fetal hemoglobin, and bone marrow aspirate for cell morphology and chromosome study (cytogenetics), as well as biopsy for cellularity
-HLA typing of the affected individual, siblings, and parents for consideration of hematopoietic stem cell transplantation
-Full blood typing
-Blood chemistries (assessing liver, kidney, thyroid, lipids, and iron status)
The treatment of FA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, kidney specialists (nephrologists), urologists, gastroenterologists, specialists who assess and treat hearing problems (audiologists and otolaryngologists), eye specialists and other health care professionals may need to systematically and comprehensively plan an affected individual’s treatment.
Recommendations for treatment were agreed upon at a 2008 consensus conference:
-Androgen (male hormone) administration: Androgens improve the blood counts in approximately 50% of individuals with FA. The earliest response is seen in red cells, with increase in hemoglobin generally occurring within the first month or two of treatment. Responses in the white cell count and platelet count are variable. Platelet responses are generally incomplete and may not be seen before several months of therapy. Improvement is generally greatest for the red cell count. Resistance to therapy may develop over time.
-Hematopoietic growth factors: Granulocyte colony-stimulating factor (G-CSF) may improve the neutrophil count in some individuals. It is usually used only for support during intercurrent illnesses.
-Hematopoietic stem cell transplantation (HSCT): the only curative therapy for the hematologic manifestations of FA. Donor stem cells may be obtained from bone marrow, peripheral blood, or cord blood.
-Cancer treatment: Treatment of malignancies is challenging secondary to the increased toxicity associated with chemotherapy and radiation in FA. Care should be obtained from centers experienced in the treatment of FA patients.
Surgery may be necessary to correct skeletal malformations such as those affecting the thumbs and forearm bones, cardiac defects, and gastrointestinal abnormalities such as tracheoesophageal fistula or esophageal atresia, as well as anal atresia.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Currently there are numerous clinical trials listed as "Recruiting" on www.clinicaltrials.gov which examine several treatment aspects of Fanconi anemia.
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about this condition:
The following resources are available for researchers:
NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
National Cancer Institute
Fanconi Anemia Cell Repository
Department of Medical and Molecular Genetics
3181 Southwest Sam Jackson Park Road L103
Oregon Health & Science University
Portland OR 97201
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FA Fact Sheet. Fanconi Anemia Research Fund, Inc, http://www.fanconi.org/index.php/learn_more/fact_sheet Revised May 2012.
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Report last updated: 2013/01/14 00:00:00 GMT+0