Fanconi anemia (FA) is a cancer-prone chromosomal instability disorder with autosomal recessive inheritance. Cells derived from FA patients are hypersensitive to chromosomal breakage by DNA cross-linking agents such as mitomycin C or diepoxybutane, which is used to confirm a clinical suspicion of FA. At least eleven genetic subtypes are distinguished. Eight of these have been connected to distinct disease genes, including the breast cancer susceptibility gene, BRCA2. Most FA genes encode orphan proteins with no known molecular function. They are supposed to act in an integrated pathway with BRCA1 and BRCA2 to maintain the integrity of the genome. Molecular diagnosis is feasible in >95% of all cytogenetically confirmed FA patients.
FA: CLINICAL ASPECTS
Fanconi anemia is a rare syndrome (ca. 10 per million newborns) with autosomal recessive inheritance. Clinical symptoms include multiple developmental abnormalities, bone marrow failure, and a high risk of malignancies (Table 1). Clinical suspicion of FA is mostly based on growth delay, skeletal abnormalities (aplastic or hypo-plastic thumbs and radii), in combination with bone marrow failure (pancytopenia), which usually starts between 5 and 10 years of age.[1,2] However, the symptoms are highly variable. Therefore, the diagnosis should always be verified using cytogenetic or molecular techniques. Hematopoietic mosaicism occurs in a proportion of patients because of genetic reversion at the disease locus in certain primitive progenitor cells, which may (partially) correct the bone marrow defect and in some cases may lead to an incorrect diagnosis. The bone marrow failure is usually progressive. Most patients die prematurely from the consequences of aplastic anemia, leukemia, or solid tumors.
Some aplastic FA patients may respond to treatment with androgens or steroids. Transplantation with bone marrow stem cells from a related or unrelated donor is currently the only way to correct the marrow failure and reduce the risk of leukemia. Because of their hypersen-
sitivity to cyclophosphamide, which is used in the conditioning regimen for transplants, transplantation centers follow an attenuated protocol for FA patients. Gene therapy trials aimed at correcting the genetic defect in hematopoietic stem cells are ongoing. Like bone marrow transplantation, this treatment could only repair the bone marrow defect and is not expected to change the risk of solid tumors.
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