NORD gratefully acknowledges David Brouch, NORD Intern from the University of Notre Dame, Jakub Tolar, MD, PhD, Executive Vice Dean, Medical School, Distinguished McKnight University Professor, Department of Pediatrics, Division of Blood and Marrow Transplantation, Director, Stem Cell Institute, Edmund Wallace Tulloch and Anna Marie Tulloch Chair in Stem Cell Biology, Genetics and Genomics, 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 at least 18 different genes. Most of the subtypes share the characteristic symptoms and findings. Fanconi anemia is not the same as Fanconi syndrome, a rare kidney function disorder.
The symptoms of FA vary from person to person. 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 occurs in 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 18 genes can cause FA. The proteins encoded by these genes work together in a common pathway called the FA pathway that 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 two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Mutations in the following genes also cause FA and are inherited in an autosomal recessive manner: BRCA2, BRIP1, FANCB, FANCD2, FANCE, FANCF, FANCI, ERCC4, FANCL, FANCM, PALB2, RAD51C, SLX4, and UBE2T.
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 genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his 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.
Mutations in the RAD51 gene cause autosomal dominant FA. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. To date, all affected individuals with FA due to a RAD51 gene mutation have a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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.
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 18 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 2014 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.
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.
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
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
The following resources are available for researchers:
FA Cell Repository and the FA Antibody Project
Fanconi Anemia Research Fund, Inc.
Oregon Health & Science University
School of Medicine/Human Genetics Initiative
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