Pathology of Myeloid Proliferations Related to Down Syndrome

Updated: Feb 28, 2018
  • Author: Angie Duong, MD; Chief Editor: Christine G Roth, MD  more...
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Transient abnormal myelopoiesis (TAM) and acute myeloid leukemia of Down syndrome (AML-DS) are disorders associated with trisomy 21; these conditions almost always develop before the age of 5 years. In individuals with Down syndrome (DS), the risk of developing AML-DS is increased 150 to 500 fold, [1] compared to a 30-fold increase of developing acute lymphoblastic leukemia (ALL). Approximately 1%-2% of children with DS develop acute myeloid leukemia, with a large majority of cases (70%) being acute megakaryoblastic leukemia (AML French-American-British [FAB] classification: M7). Although rare, there have been reports of patients with Down syndrome and a history of AML who also developed ALL. [2]

TAM is a disorder that predominantly occurs in newborns with Down syndrome. It is characterized by an increase in the number of circulating blasts that have acquired mutations in the transcription factor gene GATA1. [3] The circulating blasts in TAM generally have the morphologic and immunophenotypic features of megakaryoblasts. [4, 5]

Although 10% of newborns with DS develop TAM with clinical signs and more than 10% blasts, [6]  an additional 10%-15% of newborns with DS have clinically silent disease with a low number of circulating blasts that have acquired a GATA1 mutation(s). [7, 8]  Whereas TAM is most often associated with newborns with Down syndrome, this condition is occasionally found in phenotypically normal neonates. [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]  A subset of these neonates are found to be mosaic for trisomy 21. [10, 11, 12, 13, 14, 15, 16]

A majority of TAM cases resolve spontaneously; however, a significant percentage persist (ie, 20%-30%) and progress to acute megakaryoblastic leukemia within 1-3 years. As mentioned above, AML-DS is most often of the acute megakaryoblastic type, AML-FAB M7. It should be recognized that both myelodysplastic syndrome associated with Down syndrome (MDS-DS) and AML-DS are classified as myeloid leukemia associated with Down syndrome. [22]

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Clinical and Morphologic Features

Patients with transient abnormal myelopoiesis (TAM) have a variable presentation, ranging from clinically silent to extremely ill. Commonly, babies with clinically detectable TAM will have at least one sign or symptom, such as thrombocytopenia, leukocytosis, organomegaly, jaundice, and/or rash. Patients with a severe presentation can have severe liver dysfunction, indicating hepatic infiltration by blasts. Additionally, the hepatic dysfunction can result in abnormal coaugulation studies and liver function tests. There is no blast threshold for establishing a diagnosis of TAM, and the percentage of blasts in the peripheral blood (PB) may exceed the percentage of blasts in the bone marrow.

The morphologic and immunophenotypic features of TAM are often identical to those of the majority of cases of acute myeloid leukemia of Down syndrome (AML-DS) (see the following image). TAM is characterized by megakaryoblasts that have cytoplasmic blebs and coarse basophilic granules. There may be an associated peripheral blood basophilia. In addition, erythroid and megakaryocytic dysplasia may be present in the bone marrow specimen. 

Blasts from the peripheral blood of a 1-day-old in Blasts from the peripheral blood of a 1-day-old infant with trisomy 21 and transient abnormal myelopoiesis.

In myelodysplastic syndrome associated with Down syndrome (MDS-DS), the blasts represent fewer than 20% of the bone marrow cells. Dyserythropoiesis associated with macrocytic erythroid cells is often present.

AML-DS may sometimes be associated with a leukoerythroblastic picture. The blasts are often similar to those described in TAM. There is often an associated dyserythropoiesis, as well as dysgranulopoiesis and dysmegakaryopoiesis. Bone marrow fibrosis may also be present. Cases of acute megakaryoblastic leukemia (AML, FAB M7) may show increased clusters of dysplastic megakaryocytes and micromegakaryocytes, and an increased number of megakaryoblasts, as shown in the following image.

Multiple megakaryoblasts with cytoplasmic blebbing Multiple megakaryoblasts with cytoplasmic blebbing are seen in this image.

Immunophenotypic Features

The blasts of transient abnormal myelopoiesis (TAM) most commonly are positive for CD4 (dim), CD7, CD13, CD33, CD34, CD36, CD41, CD42, CD56, CD61, CD71, CD117, and HLA-DR (variable). They are negative for CD14, CD15, myeloperoxidse, and glycophorin A. [23] Most often, these markers are analyzed by flow cytometric analysis, but immunohistochemistry for CD41 and CD61 can also be performed.

The leukemic blasts in acute myeloid leukemia of Down syndrome (AML-DS) display an immunophenotype similar to that of TAM—with the exception that CD34 is expressed in only half of cases. Additionally, CD56 and CD41 are absent in up to 30% of cases.

The blasts of all TAM and AML-DS are positive for thrombopoietin receptor (TPO-R) and interleukin (IL)-3R, whereas erythropoietin receptor (EPO-R) and IL-6R are absent. The absence of EPO-R on the blasts is likely due to high expression of mutated and less active GATA1. [23]

The loss of full-length GATA1 (GATA1F) expression on megakaryocytes appears to be a sensitive and specific immunohistochemical marker for myeloid proliferative disorders associated with Down syndrome. [24]

Monocyte chemoattractant protein-1 (MCP-1) may have potential as a noninvasive biomarker of liver fibrosis associated with transient myeloproliferative disorder in Down syndrome. [25]

In the other AML subtypes that arise in Down syndrome, the blasts display the characteristic immunophenotypic features of that particular subtype of AML.


Molecular/Genetic Features

In addition to the constitutional trisomy 21, the blasts of transient abnormal myelopoiesis (TAM) and acute myeloid leukemia of Down syndrome (AML-DS) contain acquired GATA1 mutations; such mutations are considered pathognomonic of these disorders. [26, 27, 28, 29]

Along with abnormalities of chromosome 21, some patients with TAM have other clonal chromosomal abnormalities at presentation. [9, 20, 30, 31, 32, 33, 34] These abnormalities usually disappear at remission. [35] Trisomy 8 is another common cytogenetic abnormality in AML-DS, occurring in approximately in 13%-44% of cases. [36, 37]

Microarray transcript profiling is able to distinguish TAM from acute megakaryoblastic leukemia in patients with Down syndrome. [38] Among the significant differences, CDKN2C, the effector of GATA1 -mediated cell cycle arrest, is increased in AML-DS but not in TAM. In contrast, n-MYC is expressed in TAM at a significantly greater level than in AML-DS.




Transient abnormal myelopoiesis (TAM) usually resolves spontaneously [3]  within the first 3 months of life (80% of patients). Cases in which there are fewer than 20% blasts in the bone marrow tend to follow a more indolent course, although no factors have been shown to reliably predict progression. Previous studies have shown that the risk of progression from TAM to acute myeloid leukemia of Down syndrome (AML-DS) is between 20% and 30%. With more sensitive molecular studies for GATA1, more cases of so-called "silent TAM" have been identified, which may overall decrease the risk of progression. [7]  

The prognosis for children with AML-DS is better than the prognosis for children with AML not associated with Down syndrome. [39, 40] Long-term survival ranges from 74% to 91%; however, the prognosis for older children (ie, those with GATA1 mutations) is more poor in comparison to pediatric AML that is not associated with DS. Those with disease relapse also have a poor prognosis, [41, 42] with an overall 3-year survival of only 21%-26%. [7, 43, 44, 45, 46]  Other poor prognostic factors in AML-DS include minimal residual disease following induction therapy, trisomy 8, non-M7 morphology, older age at diagnosis, and disease relapse. [1, 47]