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Morphology Corner

Acute Megakaryoblastic Leukemia Leading to the Diagnosis of Germline Trisomy 21 Mosaicism

Savla, Dipal MD*; Del Campo, Miguel MD, PhD; Masser-Frye, Diane MS, MSW; Kuo, Dennis John MD, MS§

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Journal of Pediatric Hematology/Oncology: May 2020 - Volume 42 - Issue 4 - p 299-301
doi: 10.1097/MPH.0000000000001753
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A 2-year-old girl presented with malaise, lethargy, tachycardia, pallor, and purpura. Laboratory evaluation was notable for pancytopenia with white blood cell count 7.6 TH/µL, absolute neutrophil count 608/µL, hemoglobin 5.8 g/dL, platelets 129 TH/µL, and reticulocyte count 0.6%. Because of the concern for acute leukemia, a bone marrow aspiration and biopsy were performed. Pathologic evaluation revealed the diagnosis of acute megakaryoblastic leukemia (AMKL) and she started induction chemotherapy on a protocol for de novo acute myeloid leukemia (AML).

Fluorescent in situ hybridization (FISH) of her diagnostic bone marrow revealed trisomy 21 in 13% of cells and tetrasomy 21 in 9% of cells. There was no evidence of ETO-RUNX1 fusion. Tetrasomy 21, without trisomy 21, was found in her karyotype (Fig. 1). The patient had a mild expressive speech delay, but no physical features of Down syndrome on examination by a consulting geneticist aside from minimally upslanting palpebral fissures (Fig. 2). Because of concerns for germline mosaicism, FISH for RUNX1, a gene on chromosome 21, was performed at the end of induction (Fig. 3). This demonstrated a persistent gain of RUNX1 in 11% of cells, consistent with germline mosaicism of trisomy 21, despite her being in remission, suggesting that the trisomy 21 population was not part of the malignant clone. No cells with 4 copies of RUNX1 were noted in the remission marrow. The diagnosis of the trisomy 21 mosaicism was confirmed with FISH on a skin fibroblast culture from a skin biopsy which showed nuc ish(D21S341x3)[86]/(D21S341x2)[14]. The relative proportion of the cells in the skin biopsy with trisomy 21 was 86% and disomy 21 was 14%. The patient remained in remission and repeat FISH testing of a bone marrow aspiration for RUNX1 6 months later at the end of therapy, revealed persistence of Trisomy 21 mosaicism in 14% of cells.

The diagnostic bone marrow chromosomal analysis reported 48,XX,+21,+21[2]/46,XX[18], demonstrating tetrasomy 21 was observed in 10% of the analyzed metaphases. Trisomy 21 was not noted in this karyotype study.
Patient at 4 years of age, 1 year after the completion of therapy. Minimal upslanting of the palpebral fissures is noted.
Fluorescence in situ hybridization (FISH) showed 3 signals for the RUNX1 locus in 11% of the interphase cells scored when the patient was in remission, which was suggestive of a persistent nonmalignant trisomy 21 population. In the photograph, the red signals correspond to the RUNX1 locus (21q22) (3 signals in both cells) and the green signals correspond to the ETV6 locus (12p13) (2 signals in both cells).


Children under the age of 5 years with Down syndrome have a 150-fold increased risk of myeloid leukemia (ML-DS, which includes AML and MDS occurring in young children with Down syndrome) when compared with children without Down syndrome.1 While aneuploidy of chromosome 21 can be an acquired, somatic mutation in AML, underlying germline mosaicism of trisomy 21 needs to be considered when such findings in the leukemic clone are discovered at diagnosis because patients with trisomy 21 mosaicism may have no physical signs of Down syndrome.2,3 Somatic trisomy 21 has been discovered in 5% of AML patients with an aberrant karyotype, with the somatic acquisition of trisomy 21 having been reported in 1% of AML cases as the sole aberration.4 The only somatically acquired trisomy more common in AML than trisomy 21 is trisomy 8.4 The diagnosis of mosaicism of trisomy 21 had significant impacts in this patient’s oncologic and general pediatric care. She was switched to a less intense chemotherapy regimen better suited for patients with Down syndrome. She is currently in remission twelve months after having completed therapy. With more detailed evaluation, she was found to have more deficits in receptive and expressive language, and receives speech therapy.

AMKL is uncommon, representing 4% to 15% of all childhood AML.5 Among children with germline trisomy 21, the incidence of AMKL is 500-fold higher, accounting for the majority of cases of ML-DS.1,4 It is estimated that for each patient with germline trisomy 21 who develops AMKL, 4 times as many had self-resolved, transient myeloproliferative disease in infancy. While the diagnosis of Down syndrome associated myeloid disorders such as transient myeloproliferative disease and ML-DS generally occurs in patients who have an established diagnosis of Down syndrome, there have been several case reports of patients incidentally found to have trisomy 21 germline mosaicism after being diagnosed with transient myeloproliferative disease, myelodysplastic syndrome, and acute myelogenous leukemia.6–9

While there was a tetrasomy 21 clone discovered in the diagnostic leukemic bone marrow, germline tetrasomy 21, which can share many phenotypic features with trisomy 21, is very rare and has been identified in only a few case reports ( The prevalence is estimated to be <1/1,000,000. Patients with tetrasomy 21 have a significantly increased incidence of hematologic malignancy, and often have early malignancies. In this case, the tetrasomy 21 population was eliminated with treatment suggesting that this mutation was only present in the leukemic clone.

Clarifying the underlying germline genetic diagnosis is important as patients with trisomy 21 often experience increased risks of toxicities with intensive chemotherapy and have a form of AML that is more likely to be cured with less intense chemotherapy.1 There are not standardized guidelines for the clinical testing for trisomy 21 generally in patients with AMKL at this time. However, standard cytogenetics on the blast population at diagnosis can reveal somatic trisomy 21, as in this case, which should be an indicator of the need to reconsider the possibility of a diagnosis of trisomy 21 mosaicism at the time of remission.


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6. Zubizarreta P, Muriel FS, Fernández Barbieri MA. Transient myeloproliferative disorder associated with trisomy 21, a wide range syndrome: report of two cases with trisomy 21 mosaicism. Med Pediatr Oncol. 1995;25:60–64.
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8. Hu J, Shekhter-Levin S, Shaw PH, et al. A case of myelodysplastic syndrome with acquired monosomy 7 in a child with a constitutional t(1;19) and a mosaicism for trisomy 21. Cancer Genet Cytogenet. 2005;156:62–67.
9. Reinhardt D, Reinhardt K, Neuhoff C, et al. GATA1-mutation associated leukemia in children with trisomy 21 mosaic. Klin Padiatr. 2012;224:153–155.

acute myeloid leukemia; acute megakaryoblastic leukemia; down syndrome; mosaicism

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