Fanconi anaemia (FA) is a rare inherited (genetic) disease characterised by a variety of physical defects (congenital abnormalities), progressive bone marrow failure, chromosomal fragility and cancer susceptibility.
Characteristic congenital abnormalities include:
- hand and arm anomalies (misshapen, missing or extra thumbs or abnormalities of the radius)
- skeletal anomalies of the hips, spine or ribs
- skin discolouration (café au lait spots, hyperpigmentation)
- small head or eyes
- low birth weight and subsequent short stature
- missing or misshapen (horseshoe) kidney
- heart abnormalities (“holes in the heart”)
- gastrointestinal abnormalities including abnormal developmet of the oesophagus
- undescended testes or other abnormalities of the male reproductive organs.
However, not all patients with Fanconi anaemia have these characteristic congenital abnormalities. Typically the diagnosis is made during childhood but some patients may not present until adulthood. Some patients will be diagnosed when they present with signs and symptoms of bone marrow failure (aplastic anaemia), myelodysplastic syndrome (MDS), or leukaemia and some patients may have no signs or symptoms but be diagnosed because of a family history of Fanconi anaemia.
What causes Fanconi anaemia?
Fanconi anaemia is a genetic disease inherited in an autosomal recessive fashion. This means that an affected individual must inherit one defective gene from both their mother and father.
Each parent is a “carrier”. It is thought that approximately one person in 500 in the general population is a carrier. Carriers are not affected by the disease.
However, if two carriers have a child, there is a 25% chance that the child will be affected by Fanconi anaemia, a 50% chance that the child will be a carrier and a 25% chance that the child will inherit two copies of the normal gene. Each subsequent pregnancy carries the same risks. Boys and girls are affected equally.
It is now understood that Fanconi anaemia is not caused by a single gene. At least 11 different FA genes have been identified. All of these genetic defects result in impairment in the ability to repair DNA rendering the chromosomes, which carry the body’s genetic blueprint, susceptible to damage. Researchers are currently investigating whether specific gene defects are associated with particular features of FA.
How is Fanconi anaemia diagnosed?
If a physician suspects a diagnosis of Fanconi anaemia the diagnosis is confirmed by performing a chromosomal fragility test. This involves taking a sample of blood from the patient and treating it with a chemical known as a DNA cross-linking agent. In subjects with Fanconi anaemia excessive breakage of the chromosomes is demonstrated. This test can also be performed prenatally on cells obtained by amniocentesis or chorionic villous sampling. Having identified that an individual has Fanconi anaemia it may be possible to identify the specific genetic mutation causing the disease. If it is possible to identify the specific genetic mutation this information can be used to test relatives for carrier status.
What is the treatment for Fanconi anaemia?
Currently there is no “cure” available for Fanconi anaemia. It is hoped that in the near future gene therapy will be used to cure the disease. Once a diagnosis of Fanconi anaemia has been made, patients should be monitored for the development of bone marrow failure (aplastic anaemia) which eventually occurs in the majority of FA patients. Bone marrow transplantation can restore marrow function to FA patients who develop this life threatening complication. However, bone marrow transplantation does not remove the risk of developing other malignancies, particularly of the oral cavity, and FA patients should have an individualised screening program to monitor for the development of malignancies.
FA is a very rare genetic disorder.
- Accuracy in diagnosis is crucial and requires sophisticated expertise.
- The mode of inheritance is important for further genetic testing of siblings; finding matched donors; identification of genotype for purpose of predicting onset of symptoms and consequences; family planning (including PGD); and genetic counselling to the family.
- Expertise in FA treatment is highly specialised and to date is concentrated only in a few, critically important centres. Many patients do not have access to such expertise locally, but the use of referral networks and provider cooperation should help provide adequate care. (please note, in Australia expertise in FA treatment is significantly reduced compared to the United States and experience is relatively evenly spread around the country).
FA is a complex and chronic disorder.
- Well-orchestrated multidisciplinary care across several medical and surgical specialties is typically required for adequate monitoring and treatment.
- Clinical trials or at least the collection of longitudinal data are required to inform treatment choices for patients with FA in the future.
FA must be considered a multi-system disease.
- The name of the disorder, Fanconi anaemia, may disserve patients since haematologic manifestations of FA are not the sole (or even the most important) problem for many patients.
- The FA phenotype is quite variable and leads to misdiagnosis and failure of diagnosis. Patient monitoring must include hearing evaluation, assessment of endocrine system and GI tract issues, and long-term cancer surveillance.
- For the majority of patients, haematopoietic stem cell transplantation is the ultimate therapy for marrow dysfunction. Consequently, early involvement with a major transplant centre experienced in FA transplants and with a multidisciplinary consultation team is optimal.
FA is a cancer-prone disorder.
- Close monitoring, especially for the high incidence of SCC, is a special consideration throughout the FA patient’s lifetime, even post-transplant.
- The intrinsic genetic instability of the FA patient means that exposure to ionising radiation, environmental carcinogens and chemotherapeutic agents could pose special risks. Consequently, diagnositc x-ray exposure and some otherwise routine medical tests or agents may themselves pose undesireable risks.
FA is a physchologically demanding disorder.
- The pressures on the patients, parents and siblings over an extended time can be overwhelming, particularly where there are multiple affected family members.
- Patients, families and providers must be sensitive to issues of expense, the sophistication and availablility of medical and family counseling, and the significant and continuing emotional trauma resulting from this diagnosis.