Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome.
The diseases also causes a reduction in the maturation of erythroblasts to circulating red blood cells and, consequently, mild anemia.
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.
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.
Features in a review of 39 reported fetal cases include: reduced platelet production often accompanied by significantly reduced levels of circulating platelets; reduced red blood cell production sometimes accompanied by mild anemia; increased levels of circulating megakaryoblasts and white blood cells; grossly enlarged liver and liver dysfunction due to an excessive accumulation of platelet precursor cells; enlarged spleen presumed due mostly to the portal hypertension accompanying liver disease with extramedullary hematopoiesis possibly contributing to the enlargement; accumulation of excessive fluid in bodily compartments such as the pericardial, pleural, abdominal spaces; hydrops fetalis, i.e. the accumulation of excessive fluid in two or more bodily compartments; cardiomegaly and other cardiac abnormalities resulting form atrial septal defects, small ventricular septal defects, and/or, possibly, accumulation of megakaryocytes and secondary cardiac fibrosis.
[6] Clinical features in a review of 3 studies reporting on a total of 329 cases of symptomatic TMD include: premature birth (33-47%); enlarged liver (55-62%); evidence of liver dysfunction (13-63%); enlarged spleen (36-44%); heart disease (47-71%); gastrointestinal abnormalities (1-25%); and fluid accumulations in lung, heart, and/or abdomen (16-21%).
The incidence of all these features except for low levels of blood platelets are appreciably higher in TMD than in Down syndrome individuals that lack inactivating GATA1 mutations.
Silent TAM nonetheless carries the threat of progressing to AMKL with an incidence similar to that occurring in TMD.
[7] These genetic changes do occur in rare cases of individuals who do not have Down syndrome but nonetheless develop transient myeloproliferative disease[8] due to the presence of extra copies of key genes normally found on chromosome 21 genes caused by mosaic, Robertsonian translocation, partial trisomy 21, isochromosome formation, or duplication.
[2] It is hypothesized that trisomy 21 induces genome instability and stress, contributing to the development of somatic mutations associated with progression to leukemia.
However, the original mutations are again detected in the acute megakaryoblastic leukemia cells indicating that the GATA1 mutations causing TMD decrease to undetectable levels as TMD resolves but, at least in cases that progress to AMKL, persist in a tiny clone of megakaryoblasts that evolve into the malignant cells of AMKL.
[15] The development and progression of TMD result from collaborations between various genes: 1) during fetal development, an immature megakaryoblast which has extra copies of key genes located on chromosome 21 (e.g. ERG, DYKR1A, and/or RUNX1) acquires an inactivating mutation in GATA1 that causes it to make only GATA1-S; 2) this cell(s) grows into a genetically identical group, i.e. a clone, of non-malignant megakaryoblasts which proliferate excessively, fail to mature normally, and over-populate fetal blood-forming organisms, particularly the liver and bone marrow, thereby establishing TMD; 3) most cells in this clone are still genetically programmed to die during the ensuing fetal and early postnatal period thereby resolving TMD; 4) some cells in this GATA1-mutant clone escape the death program although their numbers are too low for detection by current methods; 5) in ~10% of TMD cases, the surviving cells from the GATA1 mutant clone undergo an evolution to cancer, i.e. they acquire mutations in other genes (see preceding section) which causes at least one of them to be malignant, immortal, and rapidly proliferating thereby founding a clone of megakaryoblasts that have the original GATA1 mutation, extra chromosome 21 genes, and one or more one of the newly acquired oncogenic gene mutations; and 6) the cells in this malignant clone infiltrate, accumulate in, and injure various organs and tissues thereby establishing AMKL.
[2] The liver of TMD-individuals accumulate abnormally high numbers of platelet and -to a lesser extent- red blood cell precursors.
Notably, cohesin mutations alter chromatin accessibility at ERG, RUNX1, and GATA transcription factor motifs.
Also like TMD, these Down syndrome (no GATA1 mutation) individuals exhibit hepatomegaly, abnormal liver function tests, and jaundice.
Furthermore, enlarged spleen, fluid accumulations in body cavities, and leukemia cutis (i.e. a rash due to the infiltration of platelet precursor cells into the skin) occur in ~30, 9, and 5%, respectively, of TMD cases but are rarely observed in individuals with Down syndrome (no GATA1 mutation).
[5] In all individuals suspected of having the symptomatic or silent disease, the diagnosis of TMD requires demonstrating the presence, in the platelet precursor cells of blood, bone marrow, or liver, of GATA1 mutations that are projected to cause the gene to make GATA1-S but not GATA1 transcription factors.
[1] Since 80 to 90% of newborns with transient myeloproliferative disease recover within ~3 months (organ enlargement make take longer to resolve), treatment is generally restricted to cases with life-threatening complications.
These complications include severe: a) hydrops fetalis; b) increases in circulating white blood cells (e.g. >10-fold elevations) that can lead to a blood disorder termed the hyperviscosity syndrome; c) bleeding due to disseminated intravascular coagulation or, less commonly, reduced levels of circulating platelet; d) liver dysfunction; or e) cardiac dysfunction.
[1] Experts suggest that individuals with symptomatic or silent TMD be followed medically for signs and/or symptoms of the disease's progression to AMKL.
[2] A complex drug regimen that includes high dose cytarabine[20] has shown good results in treating AMKL.
Risk factors that increased mortality in TMD were prematurity, extremely elevated circulating blast and/or white blood cells, hepatic dysfunction, ascites (i.e. fluid in the abdominal cavity), excessive bleeding and/or blood clotting, and kidney dysfunction.