Transient myeloproliferative disease
Transient myeloproliferative disease | |
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Other names | Transient abnormal myelopoiesis (TAM), transient leukemia, myeloid leukemia of Down syndrome |
Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the
Transient myeloproliferative disease involves the excessive proliferation of non-malignant
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 (i.e. thrombocytopenia), anemia due to reduced production of red blood cells, and/or other signs or symptoms of the disorder.[5] 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 (i.e. silent TAM). 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.[2]
Signs and symptoms
Before birth
Transient myeloproliferative disease develops and may be of concern in fetuses. 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
After birth
Symptomatic disease
Clinical features in a review of 3 studies reporting on a total of 329 cases of symptomatic TMD include:
Silent disease
Silent TAM lacks almost all of the clinical features of TMD, i.e. newborns with this disease exhibit no signs or symptoms that differ from those found in Down syndrome individuals who lack inactivating GATA1 mutations. Silent TAM nonetheless carries the threat of progressing to AMKL with an incidence similar to that occurring in TMD.[2]
Genetics
Down syndrome
Down syndrome is caused be the presence of an extra
Down syndrome by itself (i.e. in the absence of GATA1 gene mutations) is a cause for numerous hematological abnormalities which are similar to those seen in TMD. These Down syndrome-related abnormalities include increased numbers of stem cell precursors to platelets and red blood cells, impaired maturation of these precursors to platelets and red blood cells, thrombocytopenia, abnormal bleeding, anemia, leukocytosis, and serious liver damage. Since TMD is restricted to individuals with Down syndrome or otherwise have an excess of key chromosome 21 genes, it is suggested that certain chromosome 21 genes that are in triplicate and cause these hematological disorders in Down syndrome are essential for the development of GATA1 inactivating mutations and thereby TMD. These genes include ERG, a potentially cancer-causing oncogene that codes for a transcription factor; DYRK1A, which codes for a protein kinase type of enzyme involved in promoting cellular proliferation; and RUNX1, which codes for a transcription factor that regulates the maturation of hematological stem cells and, when mutated, is involved in the development of various myeloid neoplasms.[2]
Transient myeloproliferative disease
The human GATA1 gene is located on the short (i.e. "p") arm of the
The GATA1 mutations in Down syndrome cause TMD. They occur in exon 2 or 3 of the gene and are truncating mutations that result in the gene's exclusive formation of GATA1-S, i.e. the gene makes no GATA1.
The GATA1 gene also regulates the maturation of
Acute megakaryoblastic leukemia
TMD may be followed within weeks to ~5 years by a subtype of
Pathophysiology
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
The severity of transient myeloproliferative disease appears to depend on the size of the GATA1 mutant clone. It is likely, for example, that the lack of clinical features in silent TAM is a reflection of the small size of its mutant GATA1 clone.[2]
The liver of TMD-individuals accumulate abnormally high numbers of platelet and -to a lesser extent- red blood cell precursors. The liver, it is suggested, may be the primary site for excessive proliferation of the GATA1 mutant clone(s) of platelet precursor cells, primarily megakaryobllasts and the accumulation of these precursor cells along to red blood cell precursor cells appears to be an important cause of the liver enlargement and dysfunction occurring in TMD.[14]
TMD is associated with
Diagnosis
Fetuses
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. Since these mutations are limited to a clone(s) of platelet precursor cells which may represent only a small fraction of all platelet precursor cells, high-throughput DNA sequencing methods are required to detect many cases of the disease, particularly in silent TAM cases which may have only a small number of platelet precursors with the mutation.[2] The in utero diagnosis of fetal TMD depends on medical ultrasound scanning to detect fluid accumulations in body cavities, cardiac abnormalities (particularly atrial septal defects), organ enlargements (particularly of the liver, spleen, or heart), fetal size, and fetal movements. Blood samples are obtained from the fetal umbilical cord to determine blood cell counts, measure blood enzymes to evaluate liver function, and the presence in circulating platelet precursor cells of GATA1 mutations that are associated with TMD.[1]
Treatment
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)
Experts suggest that individuals with symptomatic or silent TMD be followed medically for signs and/or symptoms of the disease's progression to AMKL. This includes physical examinations to measure liver and spleen size as well as complete blood counts to measure the levels of circulating platelets, erythrocytes, white blood cells, and platelet precursor cells. Recommendations for the frequency of these measurements vary from every 3 to 12 months.[2] A complex drug regimen that includes high dose cytarabine[18] has shown good results in treating AMKL.[2]
Prognosis
Overall mortality during the first year as reported in three studies (all of which included individuals treated for their TMD), range between 15 and 21% in TMD and between 4 and 12% in Down syndrome (no GATA1 mutation). Virtually all of the deaths occurring in TMD happened within the first 6 months. 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.[5] About 10% of all TMD cases, including those with silent disease, will progress to AMKL at some time during the first 5 years after birth. AMKL associated with Down syndrome is far less severe a disease that AMKL not associated with the syndrome. Event free survival and overall survival (studies include chemotherapy-treated cases) during the 5 years following its diagnosis in Down syndrome children with AMKL is ~80%; it is 43% and 49%, respectively, in children with AMKL who do not have Down syndrome. Median survival in adult AMKL is only 10.4 months.[4]
History
TMD was first described and termed congenial leukemia by Bernard and colleagues in a 1951 publication.[19] It was defined to be limited to individuals with Down Syndrome and to be spontaneously regressing in 1954,[20] and thereafter reported to progress to a leukemia in two reports, the first published in 1957[21] and the second published in 1964.[22] Respective reports by D. Lewis in 1981[23] and Bennett et al in 1985[24] indicated that the blast cells involved in TMD and its leukemic sequel were platelet precursor cells. Studies by J.D. Crispino and colleagues in 2002[25] and 2003[26] showed that GATA1 mutations were respectively involved in TMD and AMKL.
See also
References
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