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Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 142C:149 – 157 (2006)
Clinical Manifestations of Hematologic
and Oncologic Disorders in Patients
With Down Syndrome
Hematologic abnormalities are common in individuals with Down syndrome (DS). Increased erythrocyte mean
corpuscular volume (MCV) is frequently found among DS infants and remains elevated throughout life in twothirds of patients, making interpretation of red cell indices for diagnosis of nutritional anemias or bone marrow
failure disorders more challenging. Transient myeloproliferative disorder (TMD) associated with pancytopenia,
hepatosplenomegaly, and circulating immature WBCs, is found almost exclusively in DS infants with an incidence
of approximately 10%. In most cases, TMD regresses spontaneously within the first 3 months of life, but in some
children, it can be life threatening or even fatal. Despite the high rate of spontaneous regression, TMD can be a
preleukemic disorder in 20–30% of children with DS. The types of malignancy, response to therapy, and clinical
outcome in children with DS are also unique. There is an increased risk of leukemia with an equal incidence of
lymphoid and myeloid leukemia. Acute megakaryocytic leukemia (AMKL) subtype is the most common form of
acute myeloid leukemia (AML) in this setting, and is uncommon in children without DS. Somatic mutations of the
gene encoding the hematopoetic growth factor GATA1 have been shown to be specific for TMD and AMKL in
children with DS. Myelodysplastic syndrome can precede AML. Children with DS and leukemia are more sensitive
to some chemotherapeutic agents such as methotrexate than other children which requires careful monitoring
for toxicity. Although the risk for leukemia is higher in individuals with DS, these patients have a lower risk of
developing solid tumors, with the exception of germ cell tumors, and perhaps retinoblastoma and lymphoma.
ß 2006 Wiley-Liss, Inc.
KEY WORDS: Down syndrome; chromosome 21; macrocytosis; transient myeloproliferative disorder; leukemia; solid tumor
How to cite this article: Dixon N, Kishnani PS, Zimmerman S. 2006. Clinical manifestations of
hematologic and oncologic disorders in patients with Down syndrome.
Am J Med Genet Part C Semin Med Genet 142C:149–157.
Hematologic and oncologic disorders
account for approximately 1 to 2% of the
medical complications in individuals
with Down syndrome (DS). This review
will provide an update to the already
existent literature of the hematologic
Dr. Dixon is a Pediatric Hematology–Oncology fellow at Duke University Medical Center.
Currently she is investigating the prevalence of iron deficiency anemia in children with Down
syndrome and the association between iron deficiency and behavioral problems in this patient
population. She receives salary support from a National Institutes of Health training grant at Duke
University Medical Center entitled: Research Training in Cancer Biology and Therapy. (Grant
number 2T32 CA 09307)
Dr. Kishnani is an Associate Professor in Pediatrics and Interim Chief of the Division of Medical
Genetics at Duke University Medical Center. She is Co-Director of the Duke Comprehensive
Down Syndrome clinic, established in 1995, which has an emphasis on continued care for
patients with Down syndrome via a multidisciplinary approach. She is working with the other
authors to establish the prevalence of iron deficiency anemia in Down syndrome and identify risk
factors for its occurrence.
Dr. Zimmerman is an Associate Professor of Pediatrics and Director of the Pediatric Hematology
and Sickle Cell program at Duke University Medical Center. Her clinical interests include all
aspects of non-malignant hematology, and her research focuses on the use of hydroxyurea and
the prevention of stroke in children with sickle cell disease. She is working with Dr. Dixon and
Dr. Kishnani to investigate the prevalence of iron deficiency anemia in children with Down
*Correspondence to: Natalia Dixon, M.D., Box 2916 DUMC, 222 Bell Building, Duke University
Medical Center, Durham, NC 27710. E-mail:
DOI 10.1002/ajmg.c.30096
ß 2006 Wiley-Liss, Inc.
and oncologic disorders that most commonly occur in patients with DS,
including the diagnostic challenges
based on variations in hematologic
parameters seen in the DS population.
The pathophysiology, relevant clinical
features, treatment, and anticipatory
guidelines for diagnosis and supervision
of hematologic and oncologic disorders
pertinent to individuals with DS will
also be addressed. The association of
GATA1 mutations with transient
myeloproliferative disorders (TMD)
and acute megakaryocytic leukemia
(AMKL) in DS and findings of research
on chemotherapy sensitivity in patients
with DS are presented in this overview.
Individuals with DS are more
likely than typical children to develop
hematologic disorders. Abnormalities in
any of the three hematopoietic cell lines
can be seen and some of the abnormal
hematologic findings can be associated
with other medical complications frequently seen in individuals with DS.
Polycythemia is a well-known consequence of cyanotic heart disease as a
compensatory mechanism to increase
oxygen-carrying capacity. Thrombocytopenia may also occur in the setting of
cyanotic heart disease as a result of
increased peripheral platelet destruction.
However, polycythemia, thrombocytopenia, and other abnormal hematologic
parameters such as an increased erythrocyte mean corpuscular volume (MCV)
can present without other co-morbidities in DS. The etiology of these
hematologic abnormalities is not completely understood but seems to be
related to the presence of an extra
chromosome 21.
Newborns and infants with DS
often present with hematologic abnormalities such as anemia or polycythemia,
thrombocytopenia, or thrombocytosis,
leukemoid reactions, and TMD. Both
the American Academy of Pediatrics
(AAP) and the Down Syndrome Medical Interest Group (DSMIG) recommend screening newborns with DS with
a complete blood count to evaluate for
myeloproliferative disorders, polycythemia, and thrombocytopenia [Cohen,
1999; AAP 2001].
The first year of life is a period when
blood cell production undergoes developmental changes in all infants. Fetuses
are exposed to a hypoxic environment in
utero; this low oxygen tension leads to an
increase in red blood cell production
such that infants are born relatively
polycythemic. During the first postnatal
day, the hemoglobin values are generally
16–20 g/dl, but as the newborn breathes
in a fully oxygenated environment, red
cell production drops dramatically. The
production of red blood cells drops 10fold by the end of the first week of life.
The hemoglobin and hematocrit values
tend to stabilize after this first week but
then gradually decrease to a physiologic
nadir by 6–10 weeks of life. Preterm
infants have a more rapid drop in their
red cell counts during the initial weeks
of life due to a reduced red cell survival, and often as a result of iatrogenic
blood loss.
Polycythemia, defined as a venous
hematocrit above 65%, is frequently
found among infants with DS during
the first week of life and can be present
up to the age of 2 months, regardless of
whether they have associated cyanotic
congenital heart disease [Kivivuori et al.,
1996]. It has been postulated that this
high incidence of neonatal polycythemia might be due to a chronic fetal
hypoxemia resulting in increased erythropoietin levels [Widness et al., 1994].
The natural history of polycythemia is
usually benign, and the treatment of
symptomatic polycythemia is controversial. Some infants may need an
erythrocyte partial exchange transfusion
if the hematocrit is above 70% and the
infant develops symptoms. Despite an
increased hemoglobin and hematocrit
commonly seen in the first months of
life, infants with DS show a similar
physiologic nadir compared to infants
without DS with a median hemoglobin
concentration seen at its lowest around
10 weeks of age.
In all infants, the erythrocyte MCV
averages 135 fl at 24 weeks gestation and
gradually decreases to an average of
119 fl at term. The mean corpuscular
hemoglobin (MCH) tends to be elevated
and the MCV is abnormally high in
newborns with DS. This elevated MCV
or macrocytosis persists throughout life
in about two-thirds of individuals with
DS. This high MCV has been found
regardless of the presence of heart disease
or hemoglobin and hematocrit values,
suggesting that this finding is probably
directly associated with DS [Starc, 1992].
The etiology and physiologic significance of the macrocytosis is unknown,
although several theories have been
presented for its cause, including high
cellular turnover, enzymatic abnormalities, alterations in the erythrocyte
membrane, and changes in the genetic
control of erythrocyte development due
to the extra chromosome 21 [Bartosz
and Kedziora, 1983; Akin, 1988]. A few
studies have evaluated RBC life span in
individuals with DS with contradictory
results. Two studies reported a shortened
RBC life span [Naiman et al., 1965;
Wachtel and Pueschel, 1991], and
another study found normal circulating
RBC life span [David et al., 1996].
Normal hemoglobin F, hemoglobin
electrophoresis, vitamin B12, and folate
levels have been reported in DS, suggesting that these are not factors causing
macryocytosis [Ibarra et al., 1990;
Wachtel and Pueschel, 1991; Roizen
and Amarose, 1993; David et al., 1996].
As the MCV may not appear reduced
compared to laboratory norms for the
general population, a diagnosis of microcytic anemia, such as iron deficiency
anemia, lead toxicity, or thalassemia is
problematic and can be missed in individuals with DS.
Iron deficiency (ID) is the most
common nutritional deficiency and the
leading cause of anemia worldwide. Iron
deficiency (without anemia) develops
when the iron stores are depleted and
begin to impair hemoglobin synthesis
but the child maintains a normal hemoglobin concentration. Iron deficiency
anemia (IDA) results when the iron
supply is not sufficient, resulting in a
hemoglobin concentration two standard
deviations (SD) below the mean for age
and gender. Very little is known regarding ID/IDA in the DS population. Some
investigators examined the serum iron
and total iron binding capacity (TIBC)
in a subset of patients with DS and found
no significant differences when compared to age and gender-matched normal controls [Ibarra et al., 1990]. In
another report, DS subjects with normal
or elevated hemoglobin and MCV in the
presence of low levels of serum iron,
elevated TIBC, decreased transferrin
saturation (TS), and serum ferritin,
showed improvement in these parameters after adequate iron supplementation, indicating iron deficiency [Starc,
1992]. At the present time, there are no
specific recommendations regarding
testing for IDA in patients with DS.
Current guidelines propose a hematocrit at 1 year of age, which is similar to
what is recommended for the general
population. This screening may miss
the diagnosis of ID or IDA because the
increased MCVand MCH values found
in DS can mask the microcytosis
typically associated with IDA in the
general population. Therefore, it may
not be appropriate to use reference
values for MCV and MCH levels
derived from normal populations for
individuals with DS. Additional screening tests may be necessary to make a
diagnosis of ID/IDA in individuals with
DS, including serum ferritin, serum
iron, total iron binding capacity, transferrin saturation, and erythrocyte protoporphyrins.
Early identification and treatment
of ID/IDA in DS is of great importance;
not only because it would allow for
replacement of iron and prevention of
progression of hematologic effects, but
also because iron is required for many
relevant central nervous system processes, the most well studied being
myelination and dopaminergic functioning [Beard and Connor, 2003].
Human infants with IDA scored lower
on tests of mental development administered before treatment than infants
without anemia. The performance on
developmental tests and their behavior
after a 2 to 3-month course of iron did
not show improvement in test scores,
even though they had a good hematologic response to iron therapy [Lozoff
et al., 1982]. In another study, the
children who had moderate IDA as
infants still had lower scores on tests of
mental and motor functioning after
5 years of age. These differences
remained statistically significant after
controlling for a comprehensive set of
background factors [Lozoff et al., 1991].
An ongoing prospective research study at
Duke University is investigating ID and
IDA in a cohort of children with DS
followed at the Duke Comprehensive
Down Syndrome Clinic to determine
the prevalence of ID/IDA in this
population, to define additional laboratory tests that could help make the
diagnosis and to identify risk factors for
its occurrence. Future studies will include formal neuropsychiatric evaluations
before and after iron therapy [Dixon
et al., 2006].
Isolated neonatal thrombocytopenia is a
common finding in patients with DS. In
most cases, the cause of thrombocytopenia is unclear. In the neonatal period,
thrombocytopenia may result from
either a decreased production of platelets
in the bone marrow versus increased
peripheral destruction or consumption
of platelets. In some cases, both mechanisms occur simultaneously.
Children with cyanotic congenital
heart disease have an increased incidence
of thrombocytopenia when the hematocrit level is above 65% [Wedemeyer
et al., 1972]. Congenital heart disease is
found in approximately 40–50% of
children with DS, and only a small
proportion of this is cyanotic heart
disease. The degree of thrombocytopenia correlates with the severity of the
polycythemia. Although the exact
mechanism of thrombocytopenia in this
setting is unknown, it has been postulated that hyperviscosity may lead to
tissue hypoxemia, which then triggers a
consumptive or destructive process leading to shortened platelet survival. Platelet production in the bone marrow has
been demonstrated to be normal.
Thrombocytopenia may also occur in
newborn DS patients without congenital heart disease [Hord et al., 1995]. In
most cases, the thrombocytopenia is
transient and the platelet count rises into
the normal range by 2 to 3 weeks of life.
Infants with DS can also demonstrate profound thrombocytosis from the
age of 6 weeks to the end of the first year
of life [Kivivuori et al., 1996]; however,
this elevated platelet count is not usually
clinically significant.
There are no reports of increased
predisposition for thrombosis or bleeding disorders in individuals with DS.
However, it is important to consider that
polycythemia can lead to falsely elevated
prothrombin time and activated partial
thromboplastin time measurements.
This is observed because of a relative
excess of citrate, the anticoagulant used
when the sample is collected, compared
to the amount of plasma in the sample.
Leukocyte counts tend to be slightly
depressed in one-third of patients with
DS compared to age-matched controls
without DS [Akin, 1988; Roizen and
Amarose, 1993]. Also, it has been
recognized for many years that neonates
with DS can have massive leukemoid
reactions with elevation of the total
leukocyte count greater than 50 103
cells/ml. In fact, phenotypically normal
infants who exhibit leukemoid reactions
within the first 2 months of life should
have peripheral blood chromosome
testing to rule out mosaic trisomy
21 [Weinberg et al., 1982]. These
leukemoid reactions typically remit
Despite relatively normal leukocyte
counts, there is an increased mortality
rate due to infections, primarily respiratory infections, in children with DS
compared to the general pediatric population. The highest mortality occurs
during the first year of life, but the
overall mortality rate is increased as
much as fivefold throughout the life
span of patients with DS [Ganick, 1986].
This observation has prompted investigations of the immune system in DS, but
thus far there are no consistent immune
laboratory markers to explain the
increased susceptibility to and mortality
from infection. Abnormalities in circulating granulocyte and monocyte function have been demonstrated in some
patients with DS. Neutrophils may have
a lower mean lobe count and a reduced
number of Barr bodies [Mittwoch,
1964]. In addition, peripheral blood
monocytes and neutrophils may have
reduced chemotaxis in vitro [Miller and
Cosgriff, 1983].
Humoral and cellular immune
function in children with DS includes
variation in immunoglobulin levels,
lymphocyte populations, and lymphocyte function. In children with DS who
are younger than 6 years of age, the levels
of serum immunoglobulins do not differ
from healthy controls, but after age 6,
elevated levels of IgG and IgA have been
found. IgM levels decrease during adolescence and are lower than normal in
the majority of DS adults [Burgio et al.,
1975]. Patients with DS have a normal or
slightly reduced proportion of CD4þ
T-lymphocyte helper-cells [Burgio
et al., 1983] and a marked imbalance in
the CD4þ subpopulations has been
documented. The percentage of suppressor-cytotoxic CD8þ lymphocytes is
markedly increased. Evaluation of T-cell
function in DS patients, using mitogeninduced proliferation of lymphocytes,
has shown a normal reponse to phytohemagglutinin and concavalin A in the
first decade of life and a progressive
decline thereafter [Burgio et al., 1975].
Aplastic anemia is a bone marrow failure
disorder characterized by marrow hypoplasia and peripheral pancytopenia.
There are few case reports of idiopathic
aplastic anemia in patients with DS, but
it is not clear if a true association exists.
TMD is a disorder found almost exclusively in newborns with DS, although its
true incidence is unknown. Small series
of patients have estimated an incidence
of 10%, but this estimate could be falsely
low because of the frequency
of stillbirths caused by the disorder
[Zipursky et al., 1997, 1999]. TMD
results in abnormalities of one or more
hematopoietic cell lines, and although its
etiology is unclear, there is evidence
that TMD represents a disorder of fetal
liver hematopoiesis, with the process
originating in utero. Fetuses have been
diagnosed with TMD as early as
25 weeks gestation [Robertson et al.,
2003], and there have been reports of
prenatal diagnosis of fetal hydrops and
hepatosplenomegaly in fetuses with DS
[Smrcek et al., 2001]. The majority of
patients present with TMD at birth or
within the first few weeks of life and the
time period of spontaneous remission
correlates well with the timing of the
switch from fetal liver to bone marrow
hematopoiesis [Lange, 2000; Crispino,
The pathophysiology of TMD is
characterized by an uncontrolled proliferation of a clonal population of blasts
often expressing megakaryocytic and
sometimes erythroid markers. The clinical manifestations of TMD result from
the accumulation of immature megakaryoblasts in the peripheral blood, liver,
and bone marrow. Most commonly,
infants with TMD present with anemia,
thrombocytopenia, and blasts detected
on the peripheral smear. Some infants
who appear otherwise healthy may have
hepatosplenomegaly or cutaneous infiltrates. TMD is not always benign, and
may result in fetal hydrops from pronounced anemia and tissue infiltration
by leukemic cells. This leads to serious
pericardial, pleural, or peritoneal effusions, generalized edema and hepatosplenomegaly. For patients who develop
multi-organ infiltration, particularly
hepatic infiltration with resulting severe
liver fibrosis, TMD may be life-threatening or even fatal.
TMD can be distinguished from
congenital acute leukemia primarily by
its spontaneous resolution, typically in
the first 3 months of life. The long-term
prognosis of TMD is good with complete resolution in the majority of cases.
In 20 to 30% of patients, however, TMD
is a preleukemic disorder that predisposes to the development of AMKL
within the first 4 years of life [Homans
et al., 1993; Zipursky et al., 1994; Ma
et al., 2001] suggesting that residual
TMD blasts remain at a sub-clinical level
after resolution. Currently, there are no
identifiable clinical, hematological, or
cytogenetic parameters that can predict
if patients with TMD will subsequently
develop AMKL. Infants with a history of
TMD warrant close surveillance with
blood counts every 3 to 6 months for
the first few years of life and parental
education must be provided regarding
the presentation of AMKL.
In most cases, management of
TMD is conservative, with supportive
care and no chemotherapy. Leukopheresis should be considered when the
WBC count exceeds 200,000/ml to
avoid complications from hyperleukocytosis [Nakagawa et al., 1988]. There is
considerable controversy about which
patients with TMD should be treated
with cytotoxic therapy and when such
therapy should be initiated. Some advocate that therapy should be considered
in cases with progressive or persistent
cholestatic liver disease or in patients
with severe cardiopulmonary disease
[Al-Kasim et al., 2002; Dormann et al.,
2004]. Others recommend withholding
this therapy until definitive progression
of the leukemic process is observed or
cytogenetic analysis suggests progression
to acute myeloid leukemia (AML)
[Avet-Loiseau et al., 1995]. At this point,
treatment must be individualized based
on the clinical manifestations, degree of
organ dysfunction, co-morbid conditions, and clinical progression of cytopenias and organomegaly. Low-dose
cytarabine therapy has been effective
for treating TMD in some patients and
should be considered for severe forms of
the disease.
The distribution of malignant disorders
among patients with DS shows a unique
profile with an overrepresentation of
some tumors. Malignancies that occur
more frequently include: (1) leukemia,
(2) gonadal and extragonadal germ cell
tumors, and (3) perhaps retinoblastomas.
Tumors that occur less frequently in
patients with DS than in other patients
include: (1) intracranial and peripheral
nerve tissue tumors, (2) pediatric renal
tumors, and (3) adult bronchial, nasopharyngeal, urinary, uterine, breast, and
cutaneous carcinomas.
Children with DS have a 10 to 20-fold
increased risk of developing leukemia.
This risk extends into adulthood. The
predisposition to develop leukemia is
common not only in children with
complete trisomy 21 but also in children
with mosaic trisomy 21, who may or
may not demonstrate other phenotypic
abnormalities. There is an equal incidence of lymphoid and myeloid leukemias. This increased risk of leukemia
suggests an important role of chromosome 21 in leukemogenesis. Genes
present on chromosome 21 that may be
involved, include the ETS (ETS2 and
ERG) gene family, interferon response
genes, cystathionine beta synthetase,
superoxide dismutase, and carbonyl
reductase. The AML1 gene located on
chromosome 21q22 is involved in 25%
of childhood ALL and 15% of childhood
AML cases and is a critical regulator of
normal hematopoiesis.
Most cases of AML in children with DS
occur between the age of 1 and 5 years,
with a median age at presentation of 2
years. AMKL subtype is the most
common type of AML in these children.
Children with DS are estimated to have a
500-fold increased risk of developing
AMKL. Leukemic blasts in children
with DS express the myeloid surface
antigens CD33 and/or CD13 or
CD11b, in addition to at least one
platelet-associated antigen, such as
CD41 or CD61. Cytogenetic abnormalities that commonly present in AML,
such as t(8; 21), t(15; 17), inv (16), 5q-,
or 7q-, are rarely found in DS children
with AMKL. Similarly, the t(1; 22) (p13;
q13) that occurs in AMKL in the absence
of DS is not found in DS-AMKL [Lange
et al., 1998].
DS is by far the most frequently
encountered predisposing condition in
childhood myelodysplastic syndrome
(MDS). It occurs in 25% of patients
with a morphological diagnosis of
refractory anemia (RA), RA with excess
of blasts (RAEB), or RAEB in transformation (RAEB-T) [Hasle et al., 1995,
1999, Hasle, 2001]. In 20 to 69% of
AML cases in DS, MDS occurs first
[Zipursky et al., 1992, 1997; Lange et al.,
1998]. This MDS may present with
cytopenias, most often thrombocytopenia and with increased macrocytosis. A
bone examination is indicated when
there is clinical or laboratory suspicion
of MDS. Bone marrow morphological
changes in patients with DS and
MDS include dysplastic changes in
both erythroid and megakaryoblastic
precursors and increased number of
megakaryocytes in the presence of
thrombocytopenia suggesting ineffective thrombopoiesis. Frequently, there
is significant fibrosis of the bone marrow,
making it difficult or even impossible to
obtain an adequate specimen by aspirate.
A bone marrow biopsy is thus invaluable
in assessing marrow cellularity and
morphology and may be the only means
of making a diagnosis in the presence of
marrow fibrosis. The time of progression
from MDS to AML ranges from several
months to up to few years [Creutzig
et al., 1996]. Based on morphologic
examination, it is extremely difficult to
differentiate MDS from AML in children with DS; therefore these entities are
generally considered together, although
by definition, AML requires >20% blasts
in the bone marrow. It is probably wise
to initiate therapy for MDS when
repeated platelet transfusions or erythrocyte transfusions are required to control
bleeding or to treat anemia rather than
waiting for patients to meet criteria for a
diagnosis of AML.
Recently, somatic mutations in the
gene encoding the hematopoetic
growth factor GATA1 were detected
exclusively and almost uniformly in all
cases of TMD and AMKL of DS
[Wechsler et al., 2002; Hitzler et al.,
2003; Mundschau et al., 2003; Ahmed
et al., 2004]. GATA1 encodes a transcription factor that is required for
proper development of megakaryocytes,
erythroid cells, mast cells, and eosinophils. GATA1 mutations have never
been found in samples from DS patients
with other leukemias, including ALL or
non-AMKL. However, GATA1 mutations have been reported in children
without DS who harbor trisomy 21 in
their leukemic blasts [Rainis et al.,
2003]. Some data support the theory
that these mutations occur in a hematopoietic progenitor in the fetal liver
[Crispino, 2005a,b]. Given that 20–
30% of patients with TMD eventually
develop AMKL, it has been postulated
that GATA1 mutations could be used as
a stable molecular marker to monitor for
the presence of minimal residual disease
(MRD) after resolution of TMD, and to
assess treatment response of DS-AMKL.
Some investigators have reported the use
of clone-specific GATA1 mutations and
quantitative PCR to monitor for MRD
[Pine et al., 2005]. This may become an
important clinical tool once such testing
is more readily available.
Patients with DS and AML have an
increased sensitivity to cytarabine and
daunorubicin [Taub and Ge, 2005]. DS
myeloblasts are 10 times more sensitive
to cytarabine than non-DS blasts and the
intracellular concentration of cytarabine
is significantly higher in DS myeloblasts.
Cystathionine-b-synthetase and superoxide dismutase concentrations, measured by quantitative RT-PCR, were 12
times and 4 times higher, respectively in
the blasts of patients with DS than in
non-DS individuals. The cystathionineb-synthetase transcript level correlated
with the in vitro cytarabine sensitivity
and increased cystathionine-b-synthetase activity may contribute in modulating cytarabine metabolism [Taub et al.,
1999]. Recently, decreased transcription
of the gene encoding cytidine deaminase, a cytarabine-catabolizing enzyme,
was demonstrated in blasts of individuals
with DS. Decreased intracellular metabolism of cytarabine might account at
least in part for increased drug sensitivity
of AMKL in DS [Ge et al., 2004]. It has
been postulated that GATA1 mutations
may result in differential regulation of
target genes, contributing to the
increased cytarabine sensitivity and high
event-free survival (EFS) rates of DSAMKL [Taub and Ge, 2005].
The most remarkable clinical feature of AML in DS patients is the
extremely high EFS rates and lower rates
of relapse compared to non-DS-AML.
Cooperative group trials have shown
that DS children with AML have a
higher rate of remission and chance for
EFS with lower doses of chemotherapy
than non-DS children with AML [Lange
et al., 1998]. The reason for these
observations is unclear but likely results
from biologic differences between nonDS-AML and DS-AML combined with
differences in metabolism and tolerance
of chemotherapy [Gamis, 2005]. Toxic
deaths, rather than relapse, are more
common events among patients with DS
and AML. In addition, one Children’s
Cancer Group (CCG) study demonstrated that there was no therapeutic gain
from bone marrow transplantation in
children with DS in first remission
because of increased toxicity. Stem cell
transplantation, however, can be considered for those with recurrent disease
[Lange et al., 1998].
Age has been reported to be a
prognostic factor for DS-AML. Multivariate analysis of a prior clinical trial
demonstrated that the only risk factor for
relapse and worse survival was age at
diagnosis of 2 years or older. The reason
for the poorer outcome in the DS
children older than 2 years of age was
primarily resistant disease rather than
toxicity [Gamis et al., 2003]. On the
other hand, the karyotype of the leukemic blasts or an increased WBC at
diagnosis are not prognostic factors in
DS-AML, since even patients with DSAML who had monosomy 7 in the
leukemic blasts, which is an unfavorable
prognostic factor in non-DS-AML, had
responsive disease [Lange et al., 1998;
Gamis et al., 2003]. Current studies seek
to improve the treatment of DS-AML by
maintaining the high EFS while decreasing treatment-related toxicity.
Acute lymphoblastic leukemia (ALL) in
DS presents in older children, with a
peak frequency from 3 to 6 years of age.
ALL in children with DS is not very
different from ALL in non-DS patients,
however, some clinical differences have
been observed. ALL in DS very rarely
presents prior to age 1 year. Children
with DS and ALL also have been noted
to have a modestly lower mean platelet
count at diagnosis, and are less likely to
present with splenomegaly, lymphadenopathy, a mediastinal mass, and perhaps
CNS involvement. Leukemic blasts with
a T-cell immunophenotype and hyperdiploidy greater than 50 chromosomes
have been observed less frequently in
patients with DS-ALL when compared
to non-DS-ALL [Lange, 2000; Whitlock
et al., 2005].
The most frequent cytogenetic
abnormality in childhood ALL, t(12;21)
(p13;q22), which results in TEL/AML1
rearrangement, and other common
translocations seen in non-DS-ALL such
as, t(1;19)(q23;p13), are infrequently
seen in children with DS [Pui et al.,
1993; Lanza et al., 1997; Lange, 2000].
The leukemic cells from patients with
DS have been found to lack t(9; 22) and
t(4; 11), translocations that are generally
associated with a poor prognosis in
patients with non-DS-ALL [Lange,
2000; Whitlock et al., 2005]. Alternatively, rare cytogenetic abnormalities
like t(8;14)(q11;32), and an extra X
chromosome, may be more common
in DS-ALL [Pui et al., 1993].
A unique feature of patients with
DS and ALL is the increased sensitivity
to methotrexate therapy. Methotrexate
treatment-related toxicity is more severe
in individuals with DS and manifests
primarily as mucositis and profound
bone marrow suppression. This sensitivity may derive from gene dosage
effects on chromosome 21. Three
enzymes implicated in purine metabolism map to chromosome 21 and it is
postulated that an elevated rate of purine
synthesis resulting from increased activity of these genes confer a higher demand
for tetrahydrofolates and a greater sensitivity to antifolate agents such as methotrexate [Blatt et al., 1986; Belkov et al.,
1999]. There appears to be a direct
relationship between chromosome 21
and methotrexate therapy for both DS
and non-DS-ALL patients. The reduced
folate carrier gene, localized on chromosome 21, encodes the transmembrane
protein which transports intracellularly
reduced folates including methotrexate.
Hyperdiploid acute lymphoblastic cells
with extra copies of chromosome 21,
have an increased expression of the
reduced folate carrier gene and intracellular transport of methotrexate, therefore, generating higher levels of the
active methotrexate metabolite. The high
expression of the reduced folate carrier
gene may also account for increased
methotrexate-associated toxicity of DSALL, and its expression in various body
tissues including the gastrointestinal
tract, may further contribute to the
methotrexate toxicity in patients with
DS [Taub and Ge, 2005].
In contrast to the superior outcome
of DS-AML, DS children with ALL
have a worse outcome than non-DS
children with ALL. A recently published
study demonstrated that children with
DS-ALL treated on the CCG trials had
decreased overall survival (OS), EFS, and
disease free survival (DFS) when compared with non-DS children with ALL.
In this study, the authors reported that
DS children with ALL were less likely to
attain remission by day 28 of chemotherapy [Whitlock et al., 2005]. Other
authors observed a significantly higher
risk of death during induction for DSALL patients compared with non-DSALL patients, with most deaths due to
infections [Robinson et al., 1984].
It has been recognized for years that
the prognosis of childhood ALL is better
for patients who have standard-risk ALL
(SR ALL) compared to patients who
have high-risk ALL (HR ALL). SR ALL
is defined as having an age at diagnosis
between 1 and 9 years and an initial
WBC of less than 50,000/ml, and HR
ALL as having an age at diagnosis of less
than age 1 year or older than 10 years, or
an initial WBC count greater than
50,000/ml. In recently published data,
DS children with SR ALL had a worse
outcome when compared with non-DS
with SR ALL and children with HR
ALL had similar outcomes regardless of
whether they had DS [Whitlock et al.,
Intensive therapy in patients with
HR ALL has resulted in an outcome
comparable with non-DS ALL. Delivery of intensive therapy is thus warranted
to treat HR ALL in DS patients, with
careful attention to complications such
as mucositis and infections. Dose reductions in chemotherapy agents in the DSALL population due to concerns of
toxicities may adversely affect the outcome and thus should be avoided in the
absence of chemotherapy intolerance.
New strategies need to be developed for
DS ALL patients who have standard risk
features [Whitlock et al., 2005].
Solid tumors are infrequently reported
in patients with DS. The reduced risk to
develop solid tumors in these individuals
occurs across the life-span, with no
significant change with age [Hasle et al.,
2000; Hasle, 2001].
Some solid tumors, including neuroblastomas and Wilms tumors, are
unusually rare in children with DS [Satgé
et al., 1998b]. The infrequency of
neuroblastoma in DS may be due to an
overproduction of the chromosome 21
coded S-100 b protein. This protein
induces differentiation of neural cells
and inhibition of growth of neuroblastoma cell lines in vitro [Satgé et al.,
There are case reports of patients
with DS and retinoblastoma and some
authors support an association between
DS and this type of tumor. Two large
population-based studies looked at the
standardized incidence ratio (SIR) of
cancer in individuals with DS. One
study reported higher than expected
numbers of retinoblastomas but without a statistically significant increase in
the SIR [Hasle et al., 2000]. The other
study found no cases of eye tumors
among the DS population [Patja et al.,
Some investigators have suggested
that DS may predispose to other neoplasms of the hematopoietic tissue
including lymphoma, with a predominance of Hodgkin disease [Satgé et al.,
1998b]. Other studies have found no
significant increase in cases of lymphoma
among patients with DS [Hasle et al.,
2000; Patja et al., 2006].
Breast cancer is the most common
malignancy in women; however, very
few cases have been reported in women
with DS with a frequency nearly 10-fold
less than in the general population [Satgé
and Sasco, 2002]. Women with DS
experience earlier menopause [Schuypf
et al., 1996; Roizen and Patterson,
2003], which could explain the decreased risk for breast cancer. Another reason
could be lack of systematic longitudinal
studies. Although the risk for breast
cancer is low among women with DS,
general screening guidelines for breast
cancer surveillance should be the same as
in the general population. The current
recommendation for women with DS
over 18 years of age is a yearly clinical
breast examination [Cohen, 1999].
There is no consensus on the age at
baseline mammogram screening. There
are two different recommendations: a
mammogram every other year beginning at age 40, and yearly beginning at
age 50 [Chicoine et al., 1994]; the other
recommendation is yearly mammogram
screening beginning at age 50, unless
there is a first-degree relative with breast
cancer [Heaton, 1995].
The prevalence of gynecologic
malignancies such as genital cancer
appears to be lower in women with DS
[Patja et al., 2006]. Screening guidelines
have been developed by the DSMIG
[Cohen, 1999]. Physicians who take care
of patients with DS should follow these
Testicular cancer, particularly testicular
germ cell tumors, with a predominance
of seminomas has been reported in DS.
In the general population, testicular
tumors occur at an incidence rate of 4
cases per 100,000 person-years. In one
study, the risk of testicular cancer in
individuals with DS was reported to be
approximately 50-fold higher, and
another study reported a 5-fold increase
in the risk to develop testicular cancer
than the general population [Satgé et al.,
1997; Patja et al., 2006]. Currently, the
mechanism of this increased risk is not
well understood. Cryptorchidism and
hypogonadism have been implicated as
risk factors. An excess of luteinizing
hormone and follicle-stimulating hormone gonadotropins and overexpression
of ETS2 gene through gene dosage
effect could also predispose patients with
DS to the development of testicular
germ cell tumors [Satgé et al., 1997].
Testicular tumors can occur at very early
ages and close surveillance of the gonads
of male patients with DS is critical. An
annual testicular examination is recommended [Smith, 2001]. Non-gonadal
abdominal germ cell tumors as well as
a high proportion of intracranial germ
cell tumors in patients with DS have
been reported suggesting that individuals with DS may be prone to abnormal
proliferation of germ cells in different
Some hematologic disorders are more
common in children with DS than in
other children, particularly in the first
year of life. Newborns frequently have
polycythemia or transient thrombocytopenia. Thrombocytosis can be seen
from age 6 weeks until the end of the first
year of life. WBC and neutrophil counts
are in the low normal range among
patients with DS. These variations in the
WBC, platelets, and hemoglobin should
be taken into consideration when interpreting the results of laboratory tests
performed in these individuals. When
screening children with DS for iron
deficiency anemia, it should be noted
that the baseline MCV is elevated in
two-third of these individuals, potentially masking the diagnosis of iron
deficiency and other microcytic anemias. Norms for hematologic parameters need to be established for
patients with DS at different ages.
TMD is morphologically indistinguishable from AMKL; it is often
asymptomatic, resolving spontaneously
without treatment. In 20 to 30 percent
of patients with DS and TMD, AML
may occur later in childhood. Children
who develop TMD need to be monitored very closely with complete blood
counts for several years after the onset of
the TMD.
There is an overall increased leukemia risk among patients with DS.
AMKL is the most common subtype of
AML seen in the DS population and is
frequently preceded by a history of
MDS. A bone marrow aspirate can be
difficult to obtain due to the fibrosis
commonly seen in these patients; therefore a bone marrow biopsy is invaluable
in assessing marrow cellularity and
morphology. The cytotoxic drug sensitivity in individuals with DS is increased
when compared to the general population and should be taken into consideration prior to start chemotherapy.
The recent discovery of somatic
mutations involving the gene encoding
the hematopoietic growth factor GATA1
has been a significant advance in the
understanding of the biology of TMD/
GATA1 mutations could be used as
a molecular target useful to monitor
MRD in TMD and AMKL. Prospective
studies are needed to assess the clinical
relevance of this new tool and to
compare the sensitivity between bone
marrow and peripheral blood samples.
Also, future studies will provide an
assessment of GATA1 mutations in
children with DS of all ages and with
AML subtypes.
DS is associated with an increased
risk of hematopoietic malignancies in
childhood and a marked decrease in the
risk for solid tumors at all ages with the
exception of germ-cell tumors, and
perhaps retinoblastoma and lymphoma.
More studies are needed to establish the
true link between DS and these types of
tumors. Although the reported risk for
solid tumors is lower among patients
with DS, cancer screening should follow
the same standard guidelines as used in
the general population.
There is limited information on
many aspects of hematologic and oncologic disorders in patients with DS. As
we learn more about the unique interaction between trisomy 21 and these
disorders, and further elucidate the
function of genes encoded by chromosome 21, we may better understand the
underlying etiology of these observed
differences in normal erythrocyte indices, risk for TMD, and predisposition
to MDS and malignancy. Ultimately,
improved knowledge of the pathogenesis of various clinical observations could
provide potential therapeutic interventions that would contribute to improved
quality of life and, in some cases,
survival, for individuals with DS.
We thank the Anna’s Angels Foundation
for Down Syndrome Research for support of the iron deficiency project at the
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