Fanconi anemia (Fanconi anaemia, FA) is a very rare genetic disease with an incidence estimated at 1 per 130,000 births (or around 31 per year in the USA), with a slightly higher frequency in Ashkenazi Jews in Israel and Afrikaners in South Africa.
FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair. As a result, the majority of FA patients develop cancer, most often acute myelogenous leukemia, and 90% develop bone marrow failure (the inability to produce blood cells) by age 40. About 60–75% of FA patients have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% of FA patients have some form of endocrine problem, with varying degrees of severity. Median age of death was 30 years in 2000.
Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is bone marrow transplant if a donor is available.
Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer by DNA crosslinking, such as mitomycin C.
The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. It should not be confused with Fanconi syndrome, a kidney disorder also named after Fanconi.
During childhood, short stature and skin pigmentation, including café au lait spots, may become apparent. The first sign of a hematologic problem is usually petechiae and bruises, with later onset of pale appearance, feeling tired, and infections. Because macrocytosis usually precedes a low platelet count, patients with typical congenital anomalies associated with FA should be evaluated for an elevated red blood cell mean corpuscular volume.
FA is primarily an autosomal recessive genetic disorder. This means that two mutated alleles (one from each parent) are required to cause the disease. There is a 25% risk that each subsequent child will have FA. About 2% of FA cases are X-linked recessive, which means that if the mother carries one mutated Fanconi anemia allele on one X chromosome, there is a 50% chance that male offspring will present with Fanconi anemia.
Scientists have identified 17 FA or FA-like genes: FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL,FANCM, FANCN (PALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF. FANCB is the one exception to FA being autosomal recessive, as this gene is on the X chromosome.
The carrier frequency in the Ashkenazi Jewish population is about 1/90. Genetic counseling and genetic testing is recommended for families that may be carriers of Fanconi anemia.
Because of the failure of hematologic components to develop — white blood cells, red blood cells and platelets — the body's capabilities to fight infection, deliver oxygen, and form clots are all diminished.
Fanconi anemia is an inherited disorder, and little can be done to prevent the disease. Families with this condition can have genetic counseling to better understand their risk. Vaccination can prevent some complications, such as pneumococcal pneumonia, hepatitis, and varicella infections.
People with this disorder should avoid things that cause cancer (carcinogens) and have regular screenings to find cancer early.
Common tests for Fanconi anemia include:
- Complete blood count (CBC)
- Bone marrow biopsy
- Drugs added to a blood sample to check for damage to chromosomes (clastogenic stress-induced chromosomal breakage analysis)
- HLA tissue typing (to find matching bone-marrow donors)
- Hand x-ray and other imaging studies (CT scan, MRI)
- Hearing test
- Developmental tests
- Ultrasound of the kidneys
- Amniocentesis or chorionic villous sampling (in pregnancy)
Many patients eventually develop acute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood.
The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects, such as microcephaly (small head)
The first line of therapy is androgens and hematopoietic growth factors, but only 50-75% of patients respond. A more permanent cure is hematopoietic stem cell transplantation. If no potential donors exist, a savior sibling can be conceived by preimplantation genetic diagnosis (PGD) to match the recipient's HLA type.