Fanconi anemia (FA) is a rare, inherited condition affecting many parts of the body. It is defined by the inability of cells to properly repair damage to their DNA. This issue with DNA maintenance leads to a range of health problems, including physical abnormalities, bone marrow failure, and an increased risk for certain types of cancer. Symptoms and their severity can vary greatly, with some individuals diagnosed in early childhood and others not until adulthood.
Genetic Origins of Fanconi Anemia
The root cause of Fanconi Anemia lies within an individual’s genes. The disorder arises from mutations in one of more than 20 different genes, such as FANCA, FANCC, or FANCG, which are part of a cellular system known as the FA pathway. This pathway is responsible for repairing a specific type of DNA damage called interstrand crosslinks, where the two strands of the DNA helix are improperly stuck together. When a gene in this pathway is mutated, the repair machinery cannot function, leading to an accumulation of chromosomal damage.
This genetic condition is most commonly passed down through families in an autosomal recessive pattern. This means for a child to have FA, they must inherit one non-working copy of an FA gene from each parent. The parents, who each have one functional copy and one non-working copy, are considered carriers and do not show signs of the disorder. They have a 25% chance with each pregnancy of having a child with FA.
The specific gene that is mutated can influence the presentation and progression of the disease, although most subtypes share core characteristics. Identifying the exact gene is part of the diagnostic process and helps medical professionals understand the disorder’s potential course and inform family planning discussions.
Recognizable Signs and Symptoms
The signs of Fanconi Anemia fall into three main areas: physical characteristics, progressive bone marrow failure, and cancer susceptibility. Approximately 75% of individuals with FA are born with at least one physical abnormality. These can include:
- Skeletal issues affecting the arms and hands, such as misshapen, extra, or absent thumbs
- Short stature and a smaller-than-average head size (microcephaly)
- Distinctive facial characteristics like small eyes
- Skin pigmentation changes, such as light brown patches known as café-au-lait spots
A defining feature of FA is the gradual failure of bone marrow. This failure leads to a condition called pancytopenia, a shortage of all three types of blood cells: red blood cells, white blood cells, and platelets. A low red blood cell count (anemia) causes fatigue and shortness of breath. A deficiency of white blood cells compromises the immune system, leading to frequent or severe infections, while insufficient platelets can result in easy bruising and prolonged bleeding.
Individuals with FA face an increased lifetime risk of developing certain cancers, often at a much younger age than the general population. They are particularly vulnerable to blood cancers like acute myeloid leukemia (AML) and have a higher incidence of solid tumors affecting the head, neck, skin, and other organs. This predisposition to cancer is a direct consequence of the cells’ inability to repair DNA damage.
The Diagnostic Process
Diagnosing Fanconi Anemia involves a specific laboratory procedure called the chromosome breakage test. In this procedure, a sample of the patient’s blood is exposed to chemicals, such as diepoxybutane (DEB) or mitomycin C (MMC), which are known to cause DNA interstrand crosslinks. In cells from a person with FA, the faulty repair system is unable to cope. This results in a visibly high level of chromosomal breaks and other abnormalities when the cells are examined under a microscope, which is the hallmark cellular feature of Fanconi Anemia.
Following a positive test, genetic testing is performed. This step involves sequencing the known FA genes to pinpoint the specific mutation. Identifying the precise gene helps predict the disease’s potential severity, guides treatment decisions, and is necessary for accurate genetic counseling for the patient and their family.
Management and Treatment Strategies
Managing Fanconi Anemia is a lifelong process focused on monitoring, addressing bone marrow failure, and managing cancer risk. Surveillance involves regular blood tests to track blood cell counts and annual bone marrow examinations to watch for signs of failure or leukemia. Screening for solid tumors, including frequent physical exams and imaging, is also part of the management plan.
When bone marrow failure becomes severe, treatment is directed at managing the resulting low blood counts. Supportive care, such as blood and platelet transfusions, can temporarily alleviate symptoms. In some cases, synthetic growth factors may be used to stimulate the bone marrow to produce more of its own blood cells. The only curative treatment for bone marrow failure is a hematopoietic stem cell transplant (also known as a bone marrow transplant), which replaces the patient’s defective marrow with healthy stem cells from a donor.
Treating cancer in individuals with FA presents unique challenges. Because their cells cannot effectively repair DNA damage, patients are highly sensitive to standard doses of many chemotherapy drugs and radiation therapy. Therefore, treatment protocols must be carefully modified. Oncologists use reduced doses of these agents and avoid certain types of drugs altogether to minimize toxicity to the patient’s healthy tissues.