Down syndrome is a common congenital disorder affecting 1/1000 live births. Newborns and children with Down syndrome may present
with many hematological problems. In addition, benign and malignant abnormalities of the blood count and blood film, which may
manifest at any age
Down syndrome, hematological manifestation of DS neutrophilia ,polycythemia Thrombocytopenia Transient
myeloproliferative disorder ML-DS
Down syndrome is a chromosomal condition that is associated
with intellectual disability, a characteristic facial appearance, and
weak muscle tone (hypotonia)in infancy. All affected individuals
experience cognitive delays, but the intellectual disability is
usually mild to moderate.in addition to that newborn and children
of down syndrome my develop many haematological abnormality
varied from benign hematological abnormality of blood count and
blood film, which can present at any age.
in neonatal period patient with down syndrome can present
with Transit abnormal mylopoiesis (TAM) ,nonspecific
changes associated with intrauterine growth restrictions and
trisomeise :neutropenia ,thrombocytopenia ,erythroblastosis and
polycythemia and subtle mylodysplastic feature :abnormal myloid
cell granulation, and giant platelet .
as child with DS growing up the risk of malignancy going higher
in population-based and cancer registries and clinical trials suggest
~12-fold increased risk of acute leukaemia in children younger
than 5 years of down syndrome such as myeloid leukaemia of
down syndrome ( ML-DS) ,myelodysplasia and acute myeloid
leukaemia .deaths from leukaemia, in part , accounts for excess
mortality associated with down syndrome(8) many other non
–malignant hematological abnormalities have been reported but
their clinical important remain to be defined such as polycythemia
due to cardiac disease , reduced number of B lymphocytes and
benign hematology manifestation in down syndrome
There is various haematological abnormalities have been reported
in neonate of down syndrome like .Thrombocytopenia ,
Thrombocytosis , Polycythemia ,and , Neutrophilia
in in an Intermountain Healthcare (IHC) hospital with a date of
birth between January 1, 2001 and December 31, 2005.
CBCs done during the first week after birth on all neonates with
Down syndrome ,
During this period, 145,522 live births were recorded at 18
hospitals. Down syndrome was recognized in 226 (1 in 644),
One hundred fifty-eight (70%) of these had one or more CBCs
obtained before the seventh day (144 hr).
Neonates who did versus did not have a CBC in the first week had
a similar gestational age, birth weight, percentage who were LGA
and SGA, and length of stay
Neutrophilia was the most common hematological abnormality
detected, with 80% of absolute neutrophil counts above the upper
limit of normal for age.
The next most commonly detected abnormality was
thrombocytopenia, with 66% of platelet counts <150,000/μl, and
with 6% of counts <50,000/μl.
Polycythemia was the next most common hematological
abnormality detected, with 33% of hematocrit values above 65%
or hemoglobin concentrations above 22 g/dl.
One had neutropenia associated with an infection after bowel
Neutrophilia, thrombocytopenia, and polycythemia were the most
common hematological abnormalities observed among neonates
with Down syndrome. Anemia, thrombocytosis, and neutropenia
were not more common than among neonates who do not have
Down syndrome. (25-26)
Transit Abnormal Myelopoiesis (TAM) also called Transient
myloprolifereative disorder which can be confined to newborns
with trisomy 21, present in fetal life or in neonatal period and can
be found in non-Down syndrome who have acquired trisomy 21
to hematopoietic cell(5) .similar disorder can be found with other
syndrome like Noonan syndrome but the true TMA is strictly
association with trisomy 21 .its potential to transform into an acute
leukemia ,known as myeloid leukemia of down syndrome (ML-
DS) .which is estimated to occur in ~20-30%of babies with TAM,
the frequency of it is not known and it can be consider as leukemia
or pre leukemic syndrome ( 6)
Blasts from the peripheral blood of 1-day-old patient with trisomy 21 and transient abnormal
clinical finding of TAM is variable presentation (6) it mostly present
after birth but during gestation it may present with hydropsfetalis,
and anemia with hepatosplenomegaly and myocardial infiltration
with blast cell which is carry poor prognosis if it compere with
TAM presented after birth .
TAM after birth ,can be diagnosed basis of circulating blast cell
with or without mild leukocytosis ,10% of neonate with DS are
said to developed TAM and 10 %of fetus with DS die in utero
,possibly due to TAM (8)
Clinically TAM is conventionally defined by combination of
clinical features such as pericardial effusion ,Ascites ,pulmonary
odemahepatosplenomegaly, hepatic fibrosis ,liver failure,
obstructive jaundice andhematological feature such as leukocytosis
,persistence peripheral blood blast cell ,abnormal platelet count
:often reduced or raised but may be normal
Molecular genetic studies have shown that neonates with TAM
have mutations in the N-terminal truncating mutations of key
megakaryocyte transcription factor GATA1 (9)
10-15% of neonate with down syndrome diagnosed with different
acquired mutation of GATA1 with <10% circulating blast may
have silent haematological and clinical presentation ,
In most of cases of TAM and silent TAM, the GATA1 mutant clone
goes into complete and permanent remission without the need for
10–20 % of neonates with TAM and silent TAM subsequently
develop ML-DS in the first 5 years of life when persistent GATA1
mutant cells acquire additional oncogenic mutations, most often in
cohesin or epigenetic regulator genes( 10)
in patients with a sever TAM ,the main cause of death in early
life are progressive hepatic fibrosis,cardio pulmonary failure ,and
disseminated intravasculer coagulation and that may related to
blast of visceral infiltration .(21)
As TAM blasts appear to be sensitive to Cytarabine The Berlin-
Frankfurt-Münster and s recommended treatment with Cytarabine
with dose of (0.5–1.5 mg/kg for 3–12 days) subcutaneously or
intravenously and in COG group for 7 days .
Although TAM resolves in the majority of DS infants, 20-30 %
may developed ML-DS
Figure 1: Natural history and pathogenesis of TAM and ML-DS. Schematic representation of molecular, biological and clinical data, indicating that transient abnormal myelopoiesis (TAM) and myeloid leukaemia of down syndrome(ML-DS) are initiated before birth whwen fetal liver hematopoietic stem and progenitor cells(HSPC) triomic for chromosome 21 demonstratrte perturbed haematapoiesis with an expansion of megakaryocyte-crythroid progenitors (MEP) and megakaryocytes. these cells subsequently acquire N-terminal truncaating GATA1 mutations ressulting in TAM in late fetal or early neonatal life. Although most cases of TAM spontaneously and permanentaly remit(~90%)by the age of 6 months, in ~10% of cases, additional genetic/epigenetic events lead to further clonal expansion resulting in ML-DS before the age of 5years.
ML-DS is classified as subtype of AML in WHO classification its present in the first 2y and rare after 4 y of age and usually proceed
neonatal TAM (12-13) that may be because of inappropriate diagnostic test for TAM in early life
GATA1 mutations are found neonates with ML-DS even in the absence of an antecedent history of TAM( 14)ML-DS presented with
progressive pancytopenia with low percentage of circulating blasts for many months before the development of ML-DS (12-15-16)
. bone marrow aspiration is essential of the diagnosis as the circulating blast is low and the aspiration often associated with dry tap
secondary to marked bone marrow fibrosis and bone marrow biopsy is necessary to confirm ML-DS(10)
the blast cell similar to those in TAM with a typical megakaryoblatic morphology and co-operation of stem cell marker
(CD34,CD117), MYLOID (CD33), megakaryocytic (CD42b and CD41) and erythroid markers (CD36 and glycophorinA) as well as
the cytogenattic differences between DS and non-DS AML including absence of taranslocation t(1:22) ,and instead ,the presence of
trisomies involving chromosomes 8 and 1, as well as monosomy 7 . (19-20)
the conventional treatment oF ML-DS has been associated with excessive treatment mortality ,cardiac toxicity due to anthracyclines
and serious infections( 21)
Several collaborative study groups have adapted their standard AML protocol for ML-DS by reducing the dose of drugs (Table 1)( 21)
AML99 DS protocol consisted of pirarubicin (25 mg/m2/d, on
days 1 and 2), which was estimated to be equivalent as 25mg/m2/d
of daunomycin (DNR), cytarabine (100 mg/m2/d on day 1 through
7), and etoposide (150 mg/m2/d on day 3 through 5).
A total of 70 of the 72 patients (97.2%) achieved a CR. The 4-year
EFS was 83.3% plus or minus 9.1% and the 4-year OS was 83.7%
plus or minus 9.5%. The regimen related toxicities were relatively
Only one patient died as a result of pneumonia in the second
course of intensification. The 3-year EFS in the five patients
with monosomy 7 was significantly worse than in the 65 patients
without monosomy 7 (40,0% plus or minus 26.3% v 86.2% plus or
minus 8.8%)(21) in the
ALL in DS: “DS-ALL”
this type of leukaemia is common in non- down syndrome and its
driven from lymphoid they are B-cell lymphoblastic leukaemia(
B-ALL) ,T-cell lymphoblastic leukaemia (T-ALL)
and mixed phenotype acute leukemia (MPAL) (22).
The prognostic factors and outcome of DS-ALL patients treated in
contemporary protocols are uncertain.
Children with DS-ALL have an inferior outcome compared with
non-DS patients because of both higher treatment-related mortality
(TRM) and a higher relapse rate.(23)
- Int J ClinExpPathol. 2008; 1(5): 387–395.
Published online 2008 Jan 1. Prepublished online 2007 Dec 31.
- Blood 2011 118:6752-6759
- Richards M, Welch J, Watmore A, et al. Trisomy 21 associated
myeloproliferation in the absence of Down’s syndrome. Arch Dis
Child Fetal Neonatal Ed 1998;79:F215–7.
- Zipursky A. Transient leukaemia—a benign form of leukaemia
infants with trisomy 21. Br J Haematol 2003;120:930–8.
- Neonatal Ed 1998;79:F215–7.
- Haematology of Down syndrome
David Webb, Irene Roberts, PareshVyas
Arch Dis Child Fetal Neonatal Ed 2007;92:F503–F507. doi: .1136/
- Wechsler J, Greene M, McDevitt MA, et al. Acquired mutations
in GATA1 in the
megakaryoblastic leukemia of Down syndrome. Nat Genet
- CurrHematolMalig Rep (2016) 11:333–341 DOI 10.1007/
- Zwaan C, Kaspers G, Pieters R, Hahlen K, Janka-Schaub G,
van Zantwijk C, et al. Different drug sensitivity profiles of acute
myeloid and lymphoblastic leukemia and normal peripheral blood
mononuclear cells in children with and without Down syndrome.
- Creutzig U, Zimmermann M, Ritter J, Reinhardt D, Hermann
J, Henze G, et al. Treatment strategies and long-term results in
paediatric pa- tients treated in four consecutive AML-BFM trials.
- Hasle H, Abrahamsson J, Arola M, Karow A, et al. Myeloid
leukemia in children 4 years or older with Down syndrome often
lacks GATA1 mutation and cytogenetics and risk of relapse are
more akin to sporadic
- Ahmed M, Sternberg A, Hall G, Thomas A, Smith O,
O’Marcaigh A, et al. Natural history of GATA1 mutations in Down
syndrome. Blood. 2004;103:2480–9.
- Rao A, Hills R, Stiller C, Gibson B, et al. Treatment for myeloid
leukaemia of Down syndrome: population-based experience in the
UK and results from the Medical Research Council AML 10 and
AML 12 trials. Br J Haematol. 2006;132:576–83.
- Webb D, Roberts I, Vyas P. Haematology of Down syndrome.
Arch Dis Child Fetal Neonatal Ed. 2007;92:503–7
- Karandikar NJ, Aquino DB, McKenna RW, Kroft SH. Transient
my- eloproliferative disorder and acute myeloid leukemia in Down
syn- drome. An immunophenotypic analysis. Am J ClinPathol.
- Langerbrake C, Creutzig U, Reinhardt D. Immunophenotype
of Down syndrome acute myeloid leukemia and transient
myeloproliferative disease differs significantly from other diseases
with morphologically identical or similar blasts. KlinPadiatr.
- Kudo K, Kojima S, Tabuchi K, Yabe H, Tawa A, Imaizumi M,
Hanada R, Hamamoto K, Kobayashi R, Morimoto A, Nakayama
H, Tsuchida M, Horibe K, Kigasawa H, Tsukimoto I. Prospective
study of a pirarubicin, intermediate-dose cytarabine, and etoposide
regimen in children with Down syndrome and acute myeloid
leukemia: the Japanese Childhood AML Cooperative Study Group.
J ClinOncol. 2007 Dec 1; 25(34):5442–7. [PubMed: 18048827]
- Forestier E, Izraeli S, Beverloo B, Haas O, Pession A,
Michalova K, Stark B, Harrison CJ, Teigler- Schlegel A, Johansson
B. Cytogenetic features of acute lymphoblastic and myeloid
leukemias in pediatric patients with Down syndrome: an iBFM-SG
study. Blood. 2008 Feb 1; 111(3):1575–83. [PubMed: 17971484]
- ©2013 Kudo; licensee InTech. This is an open access article
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License (http://creativecommons.org/licenses/by/3.0), which
permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
- Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of
the World Health Organization (WHO) classification of myeloid
neoplasms and acute leukemia: rationale and important changes.
- .Acute lymphoblastic leukemia in children with Down
syndrome: a retrospective analysis from the Ponte di Legno study
Blood 2014 123:70-77; doi: https://doi.org/10.1182/
- Dördelmann M, Schrappe M, Reiter A, et al; Berlin-
Frankfurt-Münster Group. Down’s syndrome in childhood acute
lymphoblastic leukemia: clinical characteristics and treatment
outcome in four consecutive BFM trials. Leukemia 1998;12(5):645-
651.CrossRefPubMedWeb of ScienceGoogle Scholar
- Int J ClinExpPathol. 2008; 1(5): 387–395.
Published online 2008 Jan 1. Prepublished online 2007 Dec 31.
- zm J Med Genet A. 2007 Jan 1;143A(1):42-50.
Hematological abnormalities during the first week of life among
neonates with Down syndrome: data from a multihospital
Henry E1, Walker D, Wiedmeier SE, Christensen RD.