Fanconi Anemia · What It Is, Causes, Signs and Symptoms, Treatment, and More

Signs and symptoms of FA are heterogeneous and vary from individual to individual, however, the most common symptoms are congenital physical abnormalities and bone marrow failure. Signs and symptoms may include a small head (i.e., microcephaly), digit abnormalities (e.g., extra or deformed thumbs, missing or incompletely developed fingers), skeletal abnormalities (e.g., scoliosis), structural kidney problems (e.g., underdeveloped kidneys), underdeveloped gastrointestinal system (e.g., absence of an anus), light to dark brown pigmented birthmarks called cafe au lait spots, ophthalmologic abnormalities including strabismus (i.e., misalignment of the eyes), and structural cardiac abnormalities (e.g., a defect in tissues separating the heart chambers).  

Individuals with FA have progressive bone marrow failure that often presents in the first decade of life. Bone marrow failure results in pancytopenia, or low counts of red blood cells (i.e., anemia), white blood cells (i.e., leukopenia), and platelets (i.e., thrombocytopenia).  

Anemia may cause excessive fatigue, weakness, lightheadedness, shortness of breath, pale skin color, and increased heart rate. Additionally, leukopenia may increase the risk of infections, as the body has low levels of immune cells to fight infection. Thrombocytopenia may manifest as easy bruising and spontaneous bleeding from mucous membranes (e.g., gums). 

Diagnosis of FA begins with a thorough review of symptoms and medical and family history. Diagnostic delays can be common since bone marrow failure does not present until the first decade of life and congenital physical abnormalities may be subtle. Laboratory testing with a complete blood count (CBC) may reveal the presence of cytopenias (i.e., low levels of red or white blood cells or platelets). Additional imaging tests such as X-rays and ultrasound imaging can be performed to assess the extent and severity of structural abnormalities (e.g., underdeveloped bones, kidney, and gastrointestinal structural abnormalities). 
 
Several indications exist for screening a child or young adult with the following: 
(i) Persistent moderate to severe cytopenia, such that there are two or more lineages of cytopenias for more than two weeks, in the absence of malignancy, chemotherapy, active severe infection, or other known medical cause; 

(ii) At least three of the following physical abnormalities: vertebral/spinal anomalies, anal atresia, congenital heart disease, tracheoesophageal abnormalities, renal structure abnormalities, limb anomalies, short stature, cafe au lait spots, and digit abnormalities; 

(iii) A family history of FA. 

Other scenarios where screening for FA may be considered include individuals with unexplained and persistent cytopenias, young individuals (i.e., <40 years old) with myelodysplastic syndrome or blood disorders, development of squamous cell cancer of the head, neck, or anorectal region without attributable exposure, and those with prior history of chemotherapy or radiation therapy.  

A chromosome breakage test using a sample of peripheral blood is used to detect defective DNA repair that is observed in FA. If the chromosome breakage test is positive, then a next-generation sequencing test is used to identify the specific genetic mutation and to confirm the diagnosis of FA. 

Treatment of FA consists of pharmacologic and supportive care strategies aimed at addressing bone marrow failure and routine screening for early detection of malignancies. Individuals may benefit from a multidisciplinary team of specialists to ensure comprehensive care. If structural deformities are severe, surgical correction may be warranted (e.g., absence of an anus or esophagus). Androgen therapy improves blood counts in approximately half of individuals with FA. For example, red blood cell counts typically improve, as indicated by increases in hemoglobin, within the first few months of treatment. Growth factors such as granulocyte colony-stimulating factor (G-CSF) can improve white blood cell counts.  

The only established curative treatment for FA is either a stem cell transplant (i.e., transplant procedure that utilizes a healthy donor’s stem cells from the bloodstream) or a bone marrow transplant (i.e., transplant procedure that utilizes a healthy donor’s stem cells from the bone marrow). Individuals with FA can be referred to a specialized stem cell transplant center and a specialized hematologist for an initial evaluation and to discuss the risks and benefits of transplantation. Laboratory testing with CBC is used to monitor for blood count improvements. A bone marrow aspiration, which utilizes a thin needle to remove a small amount of liquid from the bone marrow, can be performed to assess cellular and chromosomal morphology, and for human leukocyte antigen-typing (i.e., used to match affected individuals and donors for bone marrow transplantation).  

Finally, individuals should follow up with a primary care physician and hematologist for routine disease monitoring and screening for early-onset malignancies. Genetic counseling is recommended for individuals and families to understand the risk of passing the genetic mutations to future generations.