Fanconi Anemia

Excerpt

Fanconi anemia is the most common cause of inherited bone marrow failure due to a rare autosomal recessive genetic disorder involving all 3 blood cell lines in which homozygous or heterozygous mutations result in pathogenic alleles, including point mutations, duplications, splicing defects, and deletions. These genetic mutations of Fanconi anemia genes cause an accruement of chromosomal damage due to the cell's inability to conduct repairs. Typically, Fanconi anemia proteins maintain genomic integrity and replicative capacity through DNA interstrand crosslinks (ICLs) repair. ICLs prevent DNA strand separation and maintain DNA integrity. These genetic mutations in the Fanconi anemia pathway lead to cells that cannot properly repair DNA damage, resulting in genomic instability, subsequent pancytopenia, and an increased susceptibility to cytotoxic agents, ultraviolet radiation, spontaneous deformation, and predisposition to malignancies. Additionally, Fanconi anemia affects almost all organs of the body.

Fanconi anemia is also thought of as an inherited form of aplastic anemia. Extensive studies of other bone marrow failure syndromes and chromosome fragility diseases have enhanced the scientific understanding of bone marrow failure in Fanconi anemia. Common clinical symptoms of Fanconi anemia include shortness of breath, chest pain, dizziness, and fatigue. Additionally, a clinical history of epistaxis, petechiae, and excessive bleeding from a wound site is common due to thrombocytopenia. The condition is mainly associated with other congenital deformities and is usually more common during childhood, with the average age of diagnosis being 7 years. Structural extremity abnormalities are more commonly observed on physical exams in patients with Fanconi anemia. The disorder may also predispose patients to the development of hematologic and solid tumors. Pancytopenia characteristic of Fanconi anemia is usually evident in serum laboratory studies demonstrating a decrease in all 3 blood cell lines, including red blood cells (RBCs), platelets, and leukocytes.

Fanconi anemia should be evaluated in patients presenting with signs and symptoms of pancytopenia with or without characteristic malformations and in patients with a family history of bone marrow failure or unbalanced translocations identified during a diagnostic leukemia evaluation. Furthermore, Fanconi anemia should be considered in patients with early-onset tumors or excessive toxicity after standard-dose chemotherapy. A Fanconi anemia diagnosis is typically confirmed with a chromosomal fragility test, which remains the gold standard. Management of Fanconi anemia primarily includes supportive therapy, hematopoeitic stem cell transplantation, and androgen treatment.