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Transient myeloproliferative disease occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.
Transient myeloproliferative disease involves the excessive proliferation of non-malignant megakaryoblasts. Megakaryoblasts are hematological precursor cells which mature to megakaryocytes. Megakaryocytes release platelets into the bloodstream. Platelets are critical for normal blood clotting. In consequence of this mutation, megkaryoblasts fail to mature properly, accumulate in multiple organs, may damage these organs, and may become cancerous. The diseases also causes a reduction in the maturation of erythroblasts to circulating red blood cells and, consequently, mild anemia.
Most individuals with TMD have clinical evidence of damage to various organs, particularly the liver, due to megakaryoblast infiltration, the accumulation of fluid in various tissue compartments, a bleeding tendency due to low levels of circulating platelets , anemia due to reduced production of red blood cells, and/or other signs or symptoms of the disorder. However, some individuals with transient myeloproliferative disease have a presumably small clone of rapidly proliferating megakaryoblasts with inactivating GATA1 mutations but no other signs or symptoms of the disease. This form of TMD is termed silent transient abnormal myelopoiesis. Silent TAM is of clinical significance because it, like symptomatic TMD, may progress to an acute megakaryoblastic leukemia. This progression occurs in ~10% of TMD cases at some time during the 4-5 following birth and is due to the acquisition by the rapidly proliferating megakaryoblast clones of oncogenic mutations in other genes.
Chemotherapeutic regimens are used to treat individuals with TMD but only those who have life-threatening complications of the disease. It is not known if these regimens have an impact on the development of acute megakaryoblastic leukemia. Currently, it is recommended that individuals with TMD be followed medically for signs, symptoms, or laboratory evidence of its progression to this malignant disease with the notion that its early treatment may be of clinical benefit.