Severe aplastic anemia including Fanconi's anemia and dyskeratosis congenita.

The primary pathophysiology in the majority of cases of acquired aplastic anemia remains unknown ("idiopathic"). In contrast, there have been major advances in Fanconi's anemia, the commonest of the familial aplastic anemias. The key has been complementation analysis that provides evidence for at least five complementation groups (FA-A, FA-B, FA-C, FA-D, and FA-E) and therefore five genes for Fanconi's anemia; only the FAC gene has been cloned to date. The FAC gene has an important role in normal hematopoiesis, and expression of the mutant FAC allele is associated with increased apoptosis. Increased apoptosis is also seen in patients with idiopathic aplastic anemia. Furthermore, patients with Fanconi's anemia or dyskeratosis congenita, another familial form of aplastic anemia, have a high incidence of hematopoietic clonal disorders, as do patients with idiopathic aplastic anemia. Therefore, the familial aplastic anemias are good in vivo models for studying aplastic anemia in general; some of the idiopathic aplastic anemias could prove to be due to mutations in genes characterized originally in familial aplastic anemias. Thus identification of these genes may provide insights into the pathophysiology of idiopathic aplastic anemia and suggest new treatment options, because treatment remains unsatisfactory for patients who lack HLA-identical siblings who can serve as bone marrow donors. The recent mapping of the FA-A (16q24.3), FA-D (3p22-26), and dyskeratosis congenita (Xq28) genes suggests this goal is achievable.