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case study [hematology | cytology]
Leukocytosis, Thrombocytopenia, and Hepatosplenomegaly In A Neonate
With Down Syndrome
Lugen Chen, MD, PhD,1 Qinglong Hu, MD,1
Harshad O Shah, PhD,1 Jen H Lin, MD1,2
1Departments of Pathology and Laboratory Medicine, Nassau
University Medical Center, 2The Health Science Center of the State
University of New York at Stony Brook, East Meadow, NY
Full-term male newborn.
chlamydia, and a purified protein derivative (PPD) skin
test was negative. At the time of delivery, the baby was
floppy with no spontaneous respirations. His Apgar score
was 1 at 2 minutes and 10 at 5 minutes after birth. He had
1 healthy sibling, and there was no history of familial or
genetic disorders.
Physical Examination
He was intubated, afebrile, and responsive to minimal
stimuli. He had scattered rashes over his entire body, lowset ears, epicanthic folds, hypoplastic maxilla, muscular
hypotonia, abundant neck skin, and simian creases. There
was hepatosplenomegaly with a palpable liver and spleen,
2 cm (liver) and 5 cm (spleen) below the right and left
costal margins, respectively.
Chief Complaint
Respiratory distress, meconium aspiration, and blasts in a
peripheral blood smear.
Medical History
A 2,300-gram baby boy with breach presentation and protrusion of an arm, leg, and umbilical cord in the vaginal
canal was delivered by Caesarean section at 39 weeks of
gestation. His 20-year-old G2P1 mother received routine
prenatal care, and the progression of her pregnancy
occurred normally. Her blood type was group B/Rh negative, and she received Rh immunoglobulin at 28 weeks of
gestation. The mother’s laboratory tests were negative for
human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), syphilis, gonorrhea, and
1. What are this patient’s most striking clinical and
laboratory findings?
2. How do you explain this patient’s most striking clinical
and laboratory findings?
3. Based on the cytochemical and immunocytochemical
findings, what type of blasts are present in this patient’s
peripheral blood and bone marrow?
4. What is this patient’s diagnosis?
5. Does this patient have a true leukemia?
6. Is it important to know whether or not this patient has a
true leukemia?
7. How should this patient be treated and what is the most
likely clinical course of this patient’s disease?
Principal Laboratory Findings
Patient’s Result
“Normal” Reference Range
Neonatal Age
3 wk
15 wk
3 wk
15 wk
WBC count
Blast count
Platelet count
Peripheral blood smear findings:
6.0-17.5 x 103/µL
———————150-450 x 103/µL——————————
10.0-13.0 g/dL
44 NRBCs/100 WBCs and blasts resembling lymphoblasts [I1A], occasionally demonstrating ectocytoplasmic projections [I1B]
Cytochemical characteristics of blastoid cells after staining using:
α-Naphthyl acetate esterase Positive
ASD-chloroacetate esterase Negative
Acid phosphatase Paranuclear Golgi zone staining [I1C]
Immunocytochemical findings:
Positive for CD61 [I1D]
Negative for CD3, CD10, and CD20
Bone marrow aspirate findings:
27% blasts, morphologically similar to those seen in the peripheral blood smear
Karyotype (all cells)*
*Performed on nucleated cells from culture of a peripheral blood sample from the patient with phytohemagglutinin followed by chromosome isolation and banding using the
trypsin-Giemsa method.
WBC, white blood cell; NRBCs, nucleated red blood cells; CD, cluster of differentiation.
laboratorymedicine> september 2004> number 9> volume 35
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Principal Laboratory Findings
[T1] and [I1].
Possible Answers:
1. Scattered rashes over his entire body, low-set ears, epicanthic folds, hypoplastic maxilla, muscular hypotonia,
abundant neck skin, simian creases, and
hepatosplenomegaly; increased WBC count; decreased
platelet count; increased number of nucleated red blood
cells (NRBCs) and a transiently increased number of lymphoblastoid cells in peripheral blood with similarly
appearing blast cells in a bone marrow aspirate; and abnormal karyotype (47XY+21) [T1].
3. The lineage of blasts is megakaryoblastic. Morphologically,
megakaryoblasts are usually medium to large in size (12 to 18
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2. This patient’s phenotypic clinical features (ie, low set
ears, epicanthic folds, hypoplastic maxilla, muscular hypotonia, abundant neck skin, and simian creases) are consistent with Down syndrome as confirmed by the trisomy
21 karyotype, while the transiently increased number of
peripheral blood blast cells is consistent with transient
myeloproliferative disorder (TMD).
µm in diameter) with a round or slightly indented nucleus that
displays fine chromatin and 1 to 3 conspicuous nucleoli. The
cytoplasm of these cells is basophilic, agranular, and may
show distinct blebs or pseudopods. In some cases, however,
megakaryoblasts are predominantly small with a high nuclearcytoplasmic (N/C) ratio, resembling lymphoblasts.1
Cytochemical diagnostic features of megakaryocytes are positive staining for α-naphthyl acetate esterase and negative staining using a granule-specific esterase. Characteristically, acid
phosphatase staining of these cells is strongly positive and predominantly localized in the Golgi zone.2 Immunophenotyping
of megakaryoblasts usually indicates expression of CD34, a
marker for primitive blasts, CD33 and/or CD13 (ie, myeloid
differentiated antigens), and at least 1 platelet-associated antigen (CD36, CD41a, CD41b, or CD61) with occasional aberrant expression of CD7 (a T-cell associated antigen) and
CD56.3-6 In addition, a proportion of these type of blast cells
also express glycophorin A (an erythroid marker)7 and
erythroid-specific mRNAs such as gamma-globin and
erythroid δ-aminolevulinate synthetase.8 The immunophenotypic profile tends to favor that blasts in TMD are derived
[I1] Patient’s hematological, cytochemical, and immunocytochemical peripheral blood findings illustrating (A) a typical blast cell with fine nuclear
chromatin, a high nuclear-cytoplasmic (N/C) ratio, and morphology resembling a lymphoblast; (B) a blast cell with distinct blebs or pseudopods; (C)
paranuclear Golgi zone staining of a blast cell with acid phosphatase; (D) positive staining of blast cells for CD61. All images, 1,000x magnification.
laboratorymedicine> september 2004> number 9> volume 35
from an immature megakaryocytic or a common erythroid
megakaryocytic lineage. Ultrastructurally, megakaryoblasts
typically demonstrate the presence of platelet peroxidase
(PPO) within the nuclear envelope and in the endoplasmic
reticulum but not in the granules of the cytoplasm.9 In this
case, the combination of cytochemical (ie, positive staining
for α-naphthyl acetate esterase, negative staining for ASDchloroacetate esterase, and paranuclear Golgi zone staining
with acid phosphatase) and immunocytochemical findings
(ie, positive for CD61 and negative for CD3, CD10, and
CD20 [T1]) confirms the lineage of these blast cells as
5. Yes, TMD is a true leukemia-showing clonal proliferation. The unique feature of TMD in a Down syndromeaffected individual is its spontaneous resolution. The
hypothesis to explain this phenomenon is that the TMD
clone is derived from fetal hematopoietic cells in the liver
rather than in the bone marrow; thus, spontaneous resolution occurs due to the turning off of liver hematopoiesis
shortly after birth.12 This hypothesis is consistent with the
lower blast count in the bone marrow than in the peripheral blood that is observed often in cases of TMD associated with Down syndrome. Moreover, it is well known
that neonates and infants with Down syndrome have a significant risk of developing leukemia. There is at least a
20-fold increased incidence of leukemia in Down
syndrome-affected individuals compared with cytogenetically normal individuals. In addition, TMD occurs in approximately 10% of patients with Down syndrome.
Although the majority of such TMD cases resolve spontaneously, approximately 25% of patients who recover from
TMD relapse to acute megakaryocytic leukemia (AMKL)
in the first 4 years of life.10,13 One of the most popular
models to explain the increased incidence of TMD in
Down syndrome-affected individuals is increased gene
dosage of a leukemia predisposition gene or a
hematopoiesis regulatory gene on chromosome 21 that
stimulates abnormal proliferation of hematopoietic stem
6. Yes, differentiation of TMD from AMLK and true congenital leukemia (TCL) has clinical significance due to the different prognoses and treatments for these diseases. This
differentiation is complicated by the fact TMD blasts are morphologically indistinguishable from AMKL blasts.1 However,
the main difference in the clinical presentation of these disorders is the age of onset, with TMD occurring at birth or in the
first few days of life and AMLK often developing after 1 year
of age.11 Blast cells associated with these 2 disorders share
some immunophenotypic features, including positivity for
CD38, CD33, CD36, CD45, CD34, CD41, CD61, and CD7
and negativity for CD14, CD15, and CD16. The major
immunophenotypic difference between them is the expression
of CD13 and CD11b in AMLK. Other biologic markers to
distinguish TMD and AMLK include telomerase activity
which is higher in myeloid cells from patients with malignant
AMLK and lower in cells from patients with TMD, a
relatively benign disorder.19 In contrast to AMLK and TMD,
TCL represents a distinctive category of neonatal myeloproliferative disorders. It is usually found in neonates without Down
syndrome and shows a more aggressive clinical course.
Patients with TCL usually have marked hepatosplenomegaly
and typical skin leukemic infiltrates—generalized multiple
red-blue nodules of “blueberry muffin lesions.”20 The majority
of TCL cases express monocytic or myelomonocytic CD
markers, and occasionally, biphenotypic (ie, myelocytic and
lymphocytic) markers.21 Chemotherapy is the treatment of
choice for TCL.
7. Close observation and supportive care are the
treatments of choice in this patient, since infants with this
disorder are typically healthy except for the rare presence
of erythematous skin plaques and rashes and a mild to
moderate degree of hepatosplenomegaly.22 Most cases of
TMD in patients with Down syndrome follow a self-limited benign course with spontaneous resolution of the
signs and symptoms. Even after the disappearance of
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4. Diagnosis: Down syndrome with TMD. The presence of
a large number of megakaryocytic blasts (51%) in our patient’s peripheral blood and a lesser number (27%) of similar blasts in his bone marrow, which spontaneously
disappeared from the peripheral blood 15 weeks later
without chemotherapy, is a typical course for TMD in a
neonate with Down syndrome. Moreover, TMD is a disorder found only in neonates with Down syndrome. Transient myeloproliferative disorder (TMD) is characterized
by leukocytosis with blasts expressing megakaryocytic
antigens in both the peripheral blood and bone marrow
with various degrees of thrombocytopenia, anemia, and
hepatosplenomegaly.10 The fact that a higher blast count is
seen in the peripheral blood than in the bone marrow is a
classic feature of TMD.11 In most TMD cases,
spontaneous regression of the signs and symptoms occurs
within 4 months of the initiation of supportive therapy.10
cells in infancy, frequently resulting in TMD.14 Recent
molecular studies have demonstrated that blast cells from
both TMD- and AMKL-affected individuals contain mutations in the GATA1 gene,15-17 the gene that encodes the
essential hematopoietic transcript factor, GATA1 (GATA
binding protein 1 or globin transcription factor 1). The
GATA binding protein plays a key role in the maturation
of erythroid cells and megakaryocytes. More recently, a
“multiple hit” model has been proposed to explain the
leukemogenesis of TMD and AMLK.12,18 In this model,
trisomy 21 is the initial event, which may provide a survival advantage to progenitors by increased dosage of
genes on chromosome 21, whereas GATA1 mutations contribute to leukemogenesis by blocking megakaryocytic
differentiation. Enhanced proliferation and disrupted differentiation of megakaryocytes are considered adequate
events for the induction of TMD. Additional acquired lesions (such as a p53 mutation, altered telomerase activity,
or additional genetic abnormalities) lead to overt AMLK.
blasts from the peripheral blood, a close follow-up of
these patients is recommended at least for the first 3 years
of life because of the potential for developing acute
leukemia, particularly AMKL.13 Moreover, some cases of
TMD are complicated by severe, possible lethal sequelae,
including progressive hepatic fibrosis, hydrops, and/or
cardiopulmonary failure. Low-dose Ara-C therapy has
been found to be effective in the treatment of these sequelae.23 Currently, there are 4 primary indications for using
low-dose Ara-C in patients with TMD: 1) hyperleukocytosis (ie, a leukemic blast count exceeding 100,000/µL), 2)
organ involvement with signs of impairment, 3) hydrops
faetalis at birth, and 4) the presence of a disseminated intravascular coagulopathy.12
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Patient’s Treatment and Course
On the 10th day of life, the infant’s skin rashes became
coalescent with crusty, dry, and yellowish exudates, for
which antibiotics and supportive therapy were initiated.
Three (3) weeks later, the skin rashes disappeared. The
patient had been doing well on the last clinic visit at age
27 months with unremarkable laboratory results. Thereafter, the infant was lost to follow-up.
13. Zipursky A. Transient leukaemia - A benign form of leukaemia in newborn
infants with trisomy 21. Br J Haematol. 2003;120:930-938.
14. Abe K, Kajii T, Niikawa N. Disomic homozygosity in 21-trisomic cells: A
mechanism responsible for transient myeloproliferative syndrome. Hum
Genet. 1989;82:313-316.
15. Mundschau G, Gurbuxani S, Gamis AS, et al. Mutagenesis of GATA1 is an
initiating event in Down syndrome leukemogenesis. Blood. 2003;101:42984300.
16. Hitzler JK, Cheung J, Li Y, et al. GATA1 mutations in transient leukemia
and acute megakaryoblastic leukemia of Down syndrome. Blood.
17. Xu G, Nagano M, Kanezaki R, et al. Frequent mutations in the GATA-1
gene in the transient myeloproliferative disorder of Down syndrome. Blood.
2003; 102:2960-2968.
18. Gurbuxani S, Vyas P, and Crispino JD. Recent insights into mechanisms of
myeloid leukemogenesis in Down syndrome. Blood. 2004;103:399-406.
19. Holt SE, Brown EJ, Zipursky A. Telomerase and the benign and malignant
megakaryoblastic leukemias of Down syndrome. J Pediatr Hematol Oncol.
20. Resnick KS, Brod BB. Leukemia cutis in congenital leukemia: Analysis
and review of the world literature with report of an additional case. Arch
Dermatol. 1993;129:1301-1306.
21. Brissette M. Simurdak J, Larsen R. Immunophenotyping of congenital
leukemia. Cytometry. 1995; 22:180-181.
22. de Tar MW, Bittman W, Gilbert J. Transient myeloproliferative disease of
the newborn: Case report with placental, cytogenetic, and flow cytometric
findings. Hum Pathol. 2000;31:396-398.
23. Al-Kasim F, Doyle JJ, Massey GV, et al. Incidence and treatment of
potentially lethal diseases in transient leukemia of Down syndrome:
Pediatric oncology group study. J Pediatr Hematol Oncol. 2002;24:9-13.
Keywords: transient myeloproliferative disorder, Down
syndrome, acute megakaryocytic leukemia, true congenital
leukemia, cluster of differentiation
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myeloproliferative disorder associated with Down syndrome: Morphologic,
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