Fanconi anemia is a disorder characterized by physical abnormalities, organ defects, bone marrow failure and an increased risk of certain cancers. This disorder occurs due to the inhibited function of a group of proteins necessary for maintaining the integrity of the genome, leading to DNA instability and chromosomal changes.
What are the Symptoms of Fanconi Anemia?
Physical abnormalities are present in 60%-75% of individuals with Fanconi anemia and include one or more of the following characteristics: short stature, developmental delays, abnormal skin pigmentation, malformation of the eyes or ears, problems in the skeletal, heart or gastrointestinal systems, defects in the kidney and urinary tract, and absent or reduced function of the gonads causing reduced fertility. Other signs include abnormalities of the brain and the spinal cord (central nervous system), including increased fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly).
Most people with Fanconi anemia have impaired bone marrow function and produce decreased levels of all blood cells (aplastic anemia). Red blood cells are important for carrying oxygen around the body and reduced levels (anemia) cause extreme tiredness. Reduced levels of white blood cells (leukopenia) lead to frequent infections. Lower platelet numbers (thrombocytopenia) cause bleeding problems. Progressive bone marrow failure presents in the first decade, initially with thrombocytopenia or leukopenia, and the risk of bone marrow failure is up to 90% by age of 40-50 years.
Individuals with Fanconi anemia are also more susceptible to developing certain types of cancers. The relative risk of developing cancers of blood-forming cells, such as acute myeloid leukemia, can be as high as 500-fold higher than normal. Most of these cases will occur between the ages of 15 and 35 years. Fanconi anemia patients may also develop myelodysplastic syndrome, when immature blood cells fail to develop normally. The risk of developing either acute myeloid leukemia or myelodysplastic syndrome before the age of 20 is 27%, which increases to 43% by the age of 30 and 52% by the age of 40. The risk of developing solid tumors of the head, neck, skin, esophagus and gynecologic area is also increased up to 30% by the age of 50. These cancers are difficult to treat because Fanconi anemia patients are sensitive to DNA damaging agents present in radiation and chemotherapy.
What Causes Fanconi Anemia Group C?
The Fanconi anemia pathway is essential to repair damaged DNA, which can occur during DNA replication. Mutations in at least 15 genes, encoding components of this pathway, cause Fanconi anemia. About 80%-90% of Fanconi anemia cases are due to mutations in three of these genes – FANCA, FANCC and FANCG. Fanconi anemia group C is the most common form found in people of Ashkenazi Jewish descent and is caused by mutations in FANCC. Mutations in this gene disrupt the Fanconi anemia pathway and any DNA damage is not properly repaired during DNA replication. Cells that divide faster, like the bone marrow cells, are particularly affected, leading to many of the physical abnormalities that are characteristic of Fanconi anemia. Two mutations in FANCC, IVS4+4A>T (also known as c.456+4A>T) and 322delG (a.k.a. c.67delG), are tested in this panel. The IVS4+4A>T mutation occurs in approximately 85% of Ashkenazi Jewish cases and causes a more severe disease, characterized by an earlier onset of blood-related abnormalities and more birth defects.
How is Fanconi Anemia Group C Diagnosed?
Recommended guidelines for Fanconi anemia diagnosis were established in 2008 and can be found on the Fanconi Anemia Research Fund website. Diagnosis often relies on detection of chromosomal aberrations, followed by molecular genetic testing for the presence of genetic changes in FANCC.
Cytogenetic testing involves chromosome breakage studies and abnormal bone marrow characteristics. Defects in the Fanconi anemia pathway often result in a type of DNA damage known as interstrand cross-links. These occur when two DNA building blocks (nucleotides) on opposite strands of DNA abnormally attached together stopping DNA replication. These cytogenetic tests look for increased chromosome breakage or rearrangements caused by these abnormal cross-links. Carriers of Fanconi anemia, who only have one defective copy of FANCC cannot be identified using this test.
Two other tests are immunoblot assays for FANCD2 protein monoubiquitination and cell cycle arrest. FANCD2 is a protein involved in the Fanconi anemia pathway and monoubiquitination is essential for its function. In the absence of functional FANCC, FANCD2 will not be ubiquitinated and this can be identified using an immunoblot. This assay distinguishes Fanconi anemia from other diseases causing bone marrow failure and chromosome breakages.
Cell cycle analysis makes use of the sensitivity of Fanconi anemia-affected cells to mitomycin c. The normal cell cycle contains four stages known as G1, S, G2 and M. DNA is replicated (copied) in the S phase and DNA damage at this stage will cause replication to stop and cells to accumulate in the G2 phase. Mitomycin c causes increased levels of DNA damage in primary skin fibroblast cells from Fanconi anemia patients, so a larger fraction will accumulate in the G2 phase. The stages of the cell cycle can be determined using flow cytometry, a technique used to separate cells based on physical characteristics.
Although these test results are specific to Fanconi anemia, they do not distinguish between the 15 different subtypes or complementation groups of Fanconi anemia, nor do they identify carriers of Fanconi anemia. Molecular genetic analysis of the FANCC gene is the only way to definitively diagnose Fanconi anemia group C and to identify carriers of Fanconi anemia group C. Two mutations in FANCC, IVS4+4A>T (also known as c.456+4A>T) and 322delG (a.k.a. c.67delG), cause the majority of cases in Ashkenazi Jewish individuals, and both are identified in this Jewish disease panel.
How is Fanconi Anemia Group C Treated?
Treatment options for Fanconi anemia group C disease depend on the age of a patient and the severity of symptoms. These options focus on surveillance and treatment of symptoms, including physical abnormalities, bone marrow failure, leukemia and solid tumors. Recommended guidelines for treatment and management can be found on the Fanconi Anemia Research Fund website.
Androgen therapy is used to improve blood counts and is effective for approximately 50% of the individuals with Fanconi anemia. Improvement is generally greatest for red blood cells, whereas increases in white cell counts and platelet counts can be variable. Standard recommended androgen is oxymetholone at a starting oral dose of 2.5mg/kg/day. These doses are then tapered to minimally effective doses with careful monitoring to circumvent resistance to therapy that may develop over time (usually years). Side effects of androgen therapy include liver toxicity, cholestasis, peliosis hepatis (vascular lesion with multiple blood-filled cysts) and hepatic tumors. Hematopoietic growth factors such as granulocyte colony-stimulating factor are generally given subcutaneously to improve neutrophil counts.
Hematopoietic stem cell transplantation (bone marrow, cord blood, or peripheral blood stem cells) will cure the anemia and prevent leukemia or myelodysplatic syndrome. However, this should be only considered for individuals with an HLA-matched sibling donor that increases the survival rate to >80%. Ideally these should be done prior to onset of myelodysplatic syndrome or leukemia, and before multiple transfusions are given for hematopoietic support. Transplants should be performed at centers with expertise in hematopoietic stem cell transplantation for Fanconi anemia patients, because patients are extremely sensitive to the toxicity of chemotherapy and radiation used in preparation for bone marrow transplantations. Individuals whose hematologic manifestations are successfully treated with transplantation appear to be at an increased risk for solid tumors, particularly tongue squamous cell carcinoma.
Surgical care may be provided to correct physical abnormalities such as with thumb and radial anomalies, congenital heart defects and gastrointestinal anomalies.
Cancer treatment should be obtained from centers experienced in the treatment of patients with Fanconi anemia, as the disease presents challenges involved with increased toxicity associated with chemotherapy and radiation. Detection and surgical removal of early-stage cancers remain the main form of treatment.
Monitoring of blood counts are recommended at least every 2-3 months. A bone marrow aspirate/biopsy is also recommended at least annually. Individuals who are receiving androgen therapy require liver chemistry profile monitoring and ultrasound examination of the liver every 6-12 months for androgen-related changes including tumors. Management options for cancer include annual gynecologic exams and Pap smears, frequent dental and oropharyngeal exams and an annual eosophageal endoscopy. Patients with anemia should only participate in strenuous activities under proper supervision. Those with neutropenia (low white blood count) should avoid people with infections and those with thrombocytopenia (low platelets) should avoid trauma, such as contact sports and should use protective equipment.
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