SYMPOSIUM ON PEDIATRIC ONCOLOGY: HEMATO-ONCOLOGY

Childhood Myelodysplastic Syndrome

Tathagata Chatterjee & V. P. Choudhry
Received: 29 November 2012 / Accepted: 6 June 2013
#Dr. K C Chaudhuri Foundation 2013
Abstract Myelodysplastic syndrome (MDS) comprises of a
heterogeneous group of bone marrow disorders resulting
from a clonal stem cell defect characterised by cytopenias
despite a relatively hypercellular marrow, ineffective hema-
topoiesis, morphological dysplasia in the marrow elements,
no response to hematinics such as iron, B12 or folic acid and
risk of progression to leukemia. Myelodysplastic syndrome
in childhood is extremely rare and accounts for less than 5 %
of all hematopoietic neoplasms in children below the age of
14 y. The primary MDS in children, also known as de novo
MDS differs from secondary MDS which generally follows
congenital or acquired bone marrow (BM) failure syndromes
as well as from therapy related MDS, commonly resulting
from cytotoxic therapy. MDS associated with Down syndrome
which accounts for approximately one-fourth of cases of child-
hood MDS is now considered a unique biologic entity synon-
ymous with Down syndrome-related myeloid leukemia and is
biologically distinct from other cases of childhood MDS. Re-
fractory cytopenia of childhood (RCC) is the commonest type
of MDS. Genetic changes predisposing to MDS in childhood
remain largely obscure. Monosomy 7 is by-far the commonest
cytogenetic abnormality associated with childhood MDS;
however most cases of RCC show a normal karyotype.
Complex cytogenetic abnormalities and trisomy 8 and
trisomy 21 are also occasionally observed. The most effec-
tive and curative treatment is Hematopoietic stem cell trans-
plantation and this is particularly effective in children with
the monosomy 7 genetic defect as well as those displaying
complex karyotype abnormalities provided it is instituted
early in the course of the disease.
Keywords Childhood MDS
.
Refractory cytopenia
of childhood
.
Down syndrome associated MDS
.
Refractory anemia with excessive blasts
Introduction
Myelodysplastic syndrome (MDS) comprises of a heteroge-
neous group of clonal stem cell disorders characterised by
cytopenias despite a relatively hypercellular marrow, ineffec-
tive hematopoiesis, morphological dysplasia in the marrow
elements, no response to hematinics such as iron, B12 or folic
acid and risk of progression to leukemia. Most studies have
been conducted in countries with predominantly white popula-
tions. Therefore, results do not reflect the true racial distribu-
tion. A population based study of children aged 014 y in
British Columbia (BC), Canada revealed the diagnosis of
MDS in 31 cases; this corresponded to an annual incidence of
3.2 per million children or roughly 6 % of all leukemias. In
contrast, the incidence of acute myeloid leukemia is 6.0/million
and for chronic myeloid leukemia is 0.5/million children [1].
These disorders are characterized by one or more cytopenias
despite a relatively hypercellular bone marrow. Many of the
morphologic, immunophenotypic and genetic features of MDS
in adults are also observed in childhood forms of the disease
but there are some significant differences reported, particularly
in patients who do not have increased blasts in their peripheral
blood (PB) or bone marrow (BM) [2] (Table 1).
Refractory anemia with excess blasts (RAEB) is charac-
terized by the presence of 219 % blasts in PB or 519 %
blasts in BM. It is further classified as RAEB-1&2 based on
the presence of 519 % blasts in BM/24 % blasts in PB and
1019 %blasts in BM/519 %blasts in PBrespectively. This
is a useful classification in Adult MDS. There are no data at
T. Chatterjee (*)
Department of Immunohematology and Transfusion Medicine,
AFMC, Pune 411040, India
e-mail: ctathagat@hotmail.com
V. P. Choudhry
Centre for Blood Disorders, Sunflag Hospital, Faridabad,
Haryana, India
V. P. Choudhry
Department of Hematology, Paras Hospital,
Gurgaon, India
Indian J Pediatr
DOI 10.1007/s12098-013-1130-8
present to distinguish the prognostic significance of Refrac-
tory anemia with excess blasts (RAEB-1 and RAEB-2) in
children as compared to adults. Children with RAEB gener-
ally have stable peripheral blood counts for weeks or months.
Some cases diagnosed in children with AML with 2029 %
blasts in the peripheral blood (PB) and/or bone marrow (BM)
that have myelodysplasia- related changes in peripheral
blood and bone marrow including myelodysplasia related
cytogenetic abnormalities may also have slowly progressive
disease. These cases considered as Refractory anemia with
excessive blasts in transformation (RAEB-t) by the French-
American-British cooperative classification, may lack the
clinical features of acute leukemia and behave more like
MDS than AML. They also do-not respond to AML like
therapy. Hence RAEB-t has been retained in Childhood
MDS as compared to Adult MDS where it is no longer
retained in the present WHO classification [3, 4]. Follow-
up of PB and BM studies are therefore necessary to monitor
the pace of the disease in such cases. It is important to note
that children having recurrent translocation cytogenetic ab-
normalities like t(8;21)(q22;q22), inv(16)(p13.1q22) or
t(16;16)(p13.1;q22) or t(15;17)(q22;q12) should be consid-
ered to have AML regardless of the blast count [4].
Monosomy 7 is the commonest cytogenetic abnormality
in childhood MDS and is seen in up to one-third of such
cases. Trisomy 8 and trisomy 21 are the second most com-
mon chromosomal numerical abnormalities. Presence of a
complex karyotype (up to or more than 3 chromosomal
abnormalities including at least one structural aberration) is
considered the most important prognostic marker as far as
outcome of the cases is concerned [5].
Classification
There was a need for a pediatric approach to the diagnosis
and management of MDS in children and adolescents due to
dramatic biologic differences from the Adult MDS. Progress
in classifying MDS in children has been slow. These diseases
were included for the first time in the international classification
of childhood cancers in 2005 [6].
MDS is basically classified as primary or secondary.
About one-fifth of children with primary MDS may have
an underlying genetic defect that predisposes them to develop
MDS at a young age.
Secondary MDS occurs in patients after chemotherapy or
radiation therapy; in such cases it is known as therapy-related
MDS or (t-MDS). It may also occur in patients with inherited
bone marrow failure disorders, acquired aplastic anemia, or
familial MDS. Among the inherited BM failure disorders, 4
7 % of Fanconi anemia patients progress to MDS and AML
and 1025 % of patients with Scwachman-Diamond syn-
drome progress to MDS. However patients of Dyskeratosis
congenita hardly ever progress to MDS. Genetic disorders like
Down syndrome, Noonan syndrome and Neurofibromatosis
can also lead to secondary MDS [6, 7].
In therapy related MDS (t-MDS) marked trilineage dys-
plasia is noted even when there is no increase in blasts.
Hypocellularity and reticulin fibrosis are also more common-
ly seen in this category than in de novo MDS, with a higher
rate of leukemic transformation [6].
The World Health Organization (WHO) Classification
System [35]
1. MDS
Refractory cytopenia of childhood
RAEB (Refractory anemia with excess blasts)
RAEB-t (Refractory anemia with excess blasts in
transformation)
2. JMML (Juvenile myelomonocytic leukemia)
3. Down syndrome specific diseases
MDS and acute myeloid leukemia (AML) in Down syn-
drome are extremely closely linked; the biologic and clinical
Table 1 Difference between adult and pediatric MDS
Adult MDS Pediatric MDS
1. Refractory anemia with ring sideroblasts common. 1. Refractory anemia with ring sideroblasts extremely rare.
2. MDS associated with isolated del (5q) chromosome abnormality are
common with good prognosis.
2. MDS associated with isolated del (5q) chromosome abnormality are
very rare.
3. Isolated anemia is the major presentation in Refractory anemia (RA) in
adults.
3. Isolated anemia, is an uncommon presentation. Common presentations
are thrombocytopenia and neutropenia.
4. Bone marrow is mostly hypercellular. 4. Hypocellularity of bone marrow is more commonly seen.
5. RAEB-t (Refractory anemia with excess blasts in transformation) has
not been retained in Adult MDS in the present WHO classifications as
these cases behave like AML.
5. RAEB-t has been retained in Childhood MDS. Children with RAEB-t
have stable peripheral blood counts for weeks or months and do not
behave as AML.
6. RAEB 1&2 (Refractory anemia with excess blasts); distinction based
on blast percentage in PB/BM has useful prognostic significance.
6. RAEB 1&2 (Refractory anemia with excess blasts); distinction based
on blast percentage in PB/BM has no prognostic significance.
Indian J Pediatr
features are totally different from the diseases observed in
children without Down syndrome including response to
chemotherapy. In the proposed WHO classification, MDS
and AML in Down syndrome are recognized as a single
specific entity and are grouped together and named my-
eloid leukemia of Down syndrome (ML-DS). MDS de-
velops very commonly in those who develop AML in
this population and affects almost two-third of children
with ML-DS (Table 2).
MDS
Refractory Cytopenia of Childhood (RCC) [5]
RCC is the most common subtype of MDS in children and
adolescents, accounting for approximately half of all MDS
cases. It affect boys and girls with equal frequency. Throm-
bocytopenia and neutropenia are more frequently observed
than anemia in children.
Clinical Features
Blood and bone marrow are always affected; spleen, liver
and lymph nodes are generally not affected [4, 5]. The most
common symptoms are malaise, bleeding, infection and
fever. Hepatosplenomegaly is not a feature. In up to 20 %
of cases there are no clinical signs or symptoms. Majority of
patients present with thrombocytopenia, while anemia and
neutropenia are noted in 50 % and 25 % cases respectively.
Morphological Features
The PB smear shows red cell anisopoikilocytosis and macro-
cytosis. Anisochromia is present. Neutropenia may be severe in
25 % cases with pseudo-Pelger-Huet nuclei and/or
hypogranularity of neutrophil cytoplasm. Blasts are absent or
account for <2 % of the white cells. Platelets display
anisocytosis and giant platelets may be noted and counts are
generally <15010
9
/L.
BM aspirate shows dysplastic changes which may be
present in two different myeloid cell lineages, or exceed
10 % in one single cell line [7]. Erythroid abnormalities
include nuclear budding, multinuclearity, karyorrhexis and
internuclear bridging along with megaloblastoid changes. It is
important to note that Ring sideroblasts are generally not found
[4]. Cells of granulocytic series reveal hyposegmentation
with pseudo-Pelger-Huet nuclei, hypogranularity of cytoplasm,
giant band forms and <5 % blasts. Megakaryocytes are low in
number; detection of micromegakaryocytes favours the
diagnosis of RCC [4, 5].
About 75 % of children with RCC show considerable
hypocellularity of the BM [7]. Cellularity may be as low as
510 % of the normal age matched value. There is a
moderate increase in erythropoiesis with accumulation of
immature precursors, mainly proerythroblasts [5, 8]. In-
creased numbers of mitoses indicate ineffective erythro-
poiesis. Granulopoiesis is decreased with <5 % blasts,
which is verified by CD34 staining. Megakaryocytes are
decreased in number but may be normal also. Dysplastic
changes include non-lobulated nuclei, micromegakaryocytes
and abnormally separated nuclear lobes. There is no increase
in reticulin fibres. Multiple sections prepared from the biopsy
are helpful in identification of abnormal megakaryocytes and
immunohistochemistry to identify micromegakaryocytes is
obligatory. This is achieved by the expression of platelets
glycoprotein like CD61 (GP 111a), CD 41(GP11b/111a) or
von Willebrand factor.
Fatty tissue between the areas of hematopoiesis can mimic
aplastic anemia and therefore, at least two biopsies at least
two weeks apart are recommended to facilitate the detection
of representative BM spaces containing foci of erythropoiesis
[5] (Table 3).
Various disorders may present with morphological fea-
tures indistinguishable from RCC. All have to excluded by
medical history, physical examination and appropriate labo-
ratory and molecular studies before a definite diagnosis of
RCC can be made (Table 4).
Prognosis and Predictive Factors
Most cases of RCC show a normal karyotype irrespective of
BM cellularity, though monosomy 7 is the commonest cyto-
genetic abnormality. Other cytogenetic abnormalities includ-
ing complex karyotypes may also be observed [8].
Karyotype is the most important factor for progression to
advanced MDS. Patients with monosomy 7 have a significantly
higher probability of progression than patients with other chro-
mosomal abnormalities or normal karyotype. Patients with
Table 2 Subtypes of
myelodysplastic syndromes
(MDS) in children
MDS Subtype % Blasts in
Peripheral Blood
% Blasts in
Bone Marrow
Refractory Cytopenia (RC) <2 % <5 %
Refractory Anemia with Excess Blasts (RAEB) 219 % 519 %
Refractory Anemia with Excess Blasts in Transformation (RAEB-t) 2029 % 2029 %
Indian J Pediatr
trisomy 8 or normal karyotype may experience a long stable
course [5].
Management
Hematopoietic stem cell transplantation (HSCT) is the only
curative therapy and is the treatment of choice with monosomy
7 or complex karyotype early in the course of their disease. An
expectant approach with careful observation may be reasonable
for patients in the absence of transfusion requirements, severe
cytopenia or infections. Immunosuppressive therapy can
be a successful therapy strategy for improving outlook
in some children with RCC since early BM failure in
such cases can be partly mediated by T-cell immuno-
suppression of hematopoiesis [5].
Preliminary data have shown a few long lasting responses
in children with RC treated with anti-thymocyte globulin.
Whether immuno-suppressive therapy can result in sustained
responses in childhood RC is not known [11, 12].
Primary MDS with Increased Blasts (Refractory Cytopenia
with Excess Blasts and Excess Blasts in Transformation;
RAEB and RAEB-t)
RAEB in children have similar morphological and
immunophenotypic features to adult MDS. However chil-
dren with RAEB have stable counts for months unlike the
adult MDS. To allow for the interface between MDS and
de novo AML, RAEB-t was retained in the pediatric classi-
fication more so since these children do not benefit from
AML like therapy [4]. The relationship between MDS and
de novo AML is better defined by biological and clinical
behavior rather than by blast count. Thus, myeloid disease
with low blast count and cytogenetic abnormalities typically
associated with de novo AML is classified as AML. As
stated earlier, monosomy 7 is the only chromosomal abnor-
mality strongly suggestive of MDS and therefore, children
presenting with a low blast count and other chromosomal
aberrations or normal karyotype have to be followed closely
before a diagnosis of MDS can be established.
The most appropriate therapy for children with RAEB or
RAEB-T is unknown. Although most investigators agree
that Hematopoietic stem cell transplantation (HSCT) can
improve survival, the importance of cytoreductive therapy
prior to grafting remains controversial. Data from the Euro-
pean Working Group of MDS in Childhood (EWOG-MDS)
indicate that intensive chemotherapy prior to HSCT will not
improve survival. In this study of advanced primary MDS,
the probability of survival was about 50 % and not
influenced by marrow blast percentage at the time of trans-
plantation. Hopefully, well controlled international clinical
trials will resolve the issues on pre-HSCT remission induction
therapy, optimal preparative regimen and stem cell source in
the future [13].
Table 3 Morphological differences between refractory cytopenia of childhood (RCC) and aplastic anemia in childhood (AA) [4, 5]
RCC AA
1. BM biopsy shows patchy distribution of erythropoiesis and increased
mitoses with maturation arrest and increased proerythroblasts among
at least 20 erythroid precursors
1. BM biopsy may not reveal erythropoiesis or show a single focus with
less than 10 cells with maturation to late erythroid stages with no
dysplastic changes
2. Decreased granulopoiesis with marked dysplastic changes 2. Decreased granulopoiesis with maturation and no dysplasia
3. Decreased megakaryopoiesis with dysplasia and presence of
micromegakaryocytes in BM biopsy
3. Hardly any megakaryocytes in BM biopsy without any dysplasia.
No micromegakaryocytes
4. CD34 positive blasts may be seen in the BM biopsy 4. Blasts are not present in the biopsy specimen
Table 4 Disorders (differential
diagnosis) which may present
with morphological features
indistinguishable from refractory
cytopenia of childhood [4]
Infections (cytomegalovirus, herpes virus, parvovirus B19, visceral leishmaniasis
Vitamin deficiency (B12, folate, vitamin E)
Metabolic disorders (mevalonate kinase deficiency)
Rheumatic disease
Autoimmune lymphoproliferative disorder
Mitochondrial deletions (Pearson syndrome)
Inherited BM failure syndrome (Fanconi anemia, Dyskeratosis congenita [9], Shwachmann-Diamond
syndrome [10], amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii, radioulnar
synostosis (Seckel syndrome)
PNH (rare in childhood)
Acquired aplastic anemia during hematological recovery.
Indian J Pediatr
Categories of Myelodysplastic and Myeloproliferative
Diseases in Children [4, 14]
I. Myelodysplastic/Myeloproliferative disease
Juvenile myelomonocytic leukemia (JMML)
II. Down Syndrome (DS) disease
Transient abnormal myelopoiesis (TAM)
Myeloid leukemia of DS (ML-DS)
III. Myelodysplastic Syndrome (MDS)
Refractory cytopenia (RC) (PB blasts <2 % and BM
blasts <5 %)
Refractory anemia with excess blasts (RAEB) (PB
blasts 219 % or BM blasts 519 %)
RAEB in transformation (RAEB-t) (PB or BM
blasts 2029 %)
Juvenile Myelomonocytic Leukemia (JMML)
JMML is a uniquely pediatric clonal disorder of the
hematopoietic stem cell and is the most common form
of myeloproliferative syndrome in childhood. It was pre-
viously referred to as JCML (Juvenile chronic monocytic
leukemia) or CMML (Chronic myelomonocytic leukemia).
The incidence is approximately 1.2 per million, comprising
23 % of all childhood leukemias but 40 % of childhood
MDS [4, 15].
Clinical Features
Majority of cases of JMML occur in children under 3 y of age
and twice commonly in boys than girls. Most patients present
with evidence of infection, marked hepatosplenomegaly, lym-
phoid and tonsillar enlargement and also skin rash. As a result
of its association with neurofibromatosis, patients may also
have caf-au-lait spots [16].
Laboratory Features
There is elevated white blood cell count with absolute
monocytosis, anemia and thrombocytopenia. Monocytes ap-
pear dysplastic both in circulation as well as in the marrow.
Blood filmappearance is characteristic and often more helpful
in the diagnosis than BM smear. The peripheral smear shows
leucoerythroblastic changes with evidence of circulating nu-
cleated red blood cells. There is hypergammaglobulinemia
and elevated Hb F. Peripheral blood blasts are generally
<5 % of all cells. Majority of the cells are monocytes, neutro-
phils and myeloid precursors. The marrow is hypercellular
with less than 20 % blasts, along with evidence of
micromegakaryocytes [17].
Differential Diagnosis
Making a diagnosis of JMML is not easy as its clinical and
laboratory features can also be associated with other myelo-
proliferative neoplasms, infection (Epstein-Barr virus, cyto-
megalovirus, human herpes virus 6, histoplasmosis, myco-
bacterium and toxoplasmosis), Langerhans cell histiocytosis,
hemophagocytic lymphohistiocytosis (HLH), Fanconi ane-
mia, Kostmann syndrome and Downs syndrome [17, 18]
(Table 5).
Poor prognostic markers include low platelet count, age
above 2 y, high hemoglobin F and high bone marrow blast
counts at diagnosis are the main factors predicting a short
survival [16, 17].
Pathophysiology
Mutation in the RAS gene is seen in 20 %, PTPN11 gene in
35 %, NF1 gene in 15 % and clinical NF1 in another 15 %.
Molecular genetics has therefore become very helpful in
diagnosing JMML. JMML includes patients with monosomy
7, previously considered to represent a distinct hematological
disorder described as the monosomy 7 syndrome. There are
no major clinical differences between JMML in children with
and without monosomy 7.
Management
JMML is a rapidly fatal disorder if left untreated. Non-
transplanted children presenting with a low platelet
count (<3310
9
/L) die within a year from diagnosis. Blastic
transformation is infrequent with JMML and most untreated
patients die from organ failure due to infiltration of the
Table 5 Diagnostic criteria of JMML [1417]
1. Required laboratory criteria (all three required)
No Philadelphia chromosome/no bcr/abl re-arrangement
Peripheral blood monocyte count >110
9
/L
Bone marrow blasts <20 %
2. Suggestive clinical features
Hepatomegaly
Splenomegaly
Pallor
Fever
Skin rash
3. Additional criteria (minimum of two required)
Increased Hb F(age corrected)
Myeloid precursors in peripheral blood
White blood cell count >10
9
/L
Clonal abnormalities, including monosomy 7
GM-CSF hypersensitivity of myeloid progenitors in vitro
Indian J Pediatr
leukemic cells. Intensive chemotherapy is mostly unsuccessful
in JMML because of an increased risk of treatment related
death, a low rate of true remissions and long-term survival of
less than 10 %. Allogeneic stem cell transplant (SCT) is the
only curative approach for JMML resulting in long-term sur-
vival in more than half the patients [19]. If no family donor is
available, a matched unrelated donor stemcell transplant (SCT)
is recommended. Generally, SCT shortly after diagnosis is
advocated, and younger age at SCT may predict for improved
survival. A conditioning regimen of total body irradiation
(TBI) and cyclophosphamide has often been used. In a retro-
spective analysis of the European Working Group on MDS in
Childhood (EWOG-MDS), busulfan-based myeloablative
therapy offered a greater anti-leukemic efficacy than TBI [13,
19]. The current study of EWOG-MDS, use of a preparative
regimen with busulfan, cyclophosphamide and melphalan has
produced event-free survival of around 50 %with no difference
between related and unrelated donor [13]. Disease recurrence
remains the major cause of treatment failure.
Non SCT treatment includes AML-like therapy, low dose
chemotherapy, interferon alpha and 13-cis retinoic acid.
Tipifarnib, a farnesyl transferase inhibitor has also been tried
[16]. The efficacy of chemotherapy, is however, limited.
Transient Myeloproliferative Disorder (TMD)/Transient
Abnormal Myelopoiesis (TAM)/Downs Syndrome
Transient Leukemia (DS-TL) [16, 17]
This is an intriguing syndrome which is generally diagnosed in
up to 10 % of neonates with Downs syndrome, usually during
the first week of life. TAM cannot be readily distinguished
from congenital AML. Blasts in TAM have now been proved
to be clonal in origin.
Clinical features of TAM include highly elevated
leucocyte counts with circulating blasts which may be
megakaryoblasts as well as erythroblasts, hepatosplenomegaly,
and an increased percentage of blasts in the bone marrow.
Additional manifestations of DS-TL include cutaneous in-
volvement, hyperviscosity, myelofibrosis, cardiopulmonary
failure, splenomegaly, and spleen necrosis.
Prognosis
There is complete clinical and hematological recovery in
more than 70 % of these neonates within weeks to a
maximum of 3 mo of life without therapy. Unfortunately
there is a small subgroup of infants with TAM who die
from liver failure and multiorgan failure due to
megakaryoblastic infiltration of the liver and hepatic fibrosis.
Early death in 17 %, is associated with high WBCs at diag-
nosis, increased bilirubin and liver enzymes and failure to
normalize WBC
Almost 30 % of infants with TMD/TAM eventually
develop AML (mostly AML M7) before 4 y of age. There is
usually a prodrome of several months in which there is evi-
dence of persistent thrombocytopenia and BM myelofibrosis
with dysplastic megakaryocytes. Mutations in GATA-1 gene
(an erythroid/megakaryocytic transcription factor) are present
in the blasts in infants with TMD as well as patients with
Downs syndrome with AML.
Treatment of TAM
Majority of infants with TAM never require therapy in the
first month of life; these infants should be observed and
given supportive therapy. A small group of infants with liver
failure warrant a course of low-dose cytarabine. Table 6
shows the difference between TAM and congenital
leukemia.
Myeloid Leukemia of Down Syndrome (ML-DS)
Children with trisomy 21 or Downs syndrome (DS) have an
approximately 1020-fold increased risk for developing
Table 6 Differences between TAM and congenital leukemia
TAM Congenital leukemia
1. Usual subtype is Acute megakaryoblastic leukemia 1. Usual subtypes are Acute monoblastic leukemia and Acute megakaryoblastic leukemia
2. Prognosis is excellent and majority recover within
3 mo of life
2. Prognosis extremely poor and majority succumb to the disease
3. Majority do not require treatment except close
follow-up
3. High dose chemotherapy followed by HSCT is the only option
4. Always presents in the first week of life 4. Presents at birth or within first month of life
5. Nearly all cases have GATA-1 mutations 5. Majority display MLL gene translocation at 11q23
6. Blasts are highly sensitive to chemotherapy,
particularly to cytarabine and daunorubicin
6. Blasts are generally resistant to chemotherapy due to MLL gene mutations
7. Commonly presents with hepatosplenomegaly and
occasionally cutaneous involvement
7. Twenty five to 30 % of infants have specific cutaneous infiltrates (leukemia cutis) which
usually appear as firm blue or red nodules (Blueberry Muffin)
Indian J Pediatr
acute leukemia compared with children without Downs
syndrome [16]. More than half of these cases are acute
myeloid leukemias and this trend persists till about the fourth
year of age. Among the myeloid leukemias, the incidence of
acute megakaryocytic leukemia (AML M7) from birth till
the fourth year of age remains the highest. In fact the inci-
dence of AML M7 is up to 500-fold greater in children with
Downs syndrome till the age of 4 y compared to the general
pediatric population. Interestingly, the ratio of ALL to AML
reverts to that of the general pediatric population once the
child completes 5 y of age. Majority of these acute myeloid
leukemias often present with features of MDS and almost
uniform presence of GATA1 mutation.
Some neonates with Downs syndrome or trisomy 21
mosaicism may manifest a transient myeloproliferative dis-
order (TMD) [17]. Surprisingly there is a high cure rate of
AML in Downs syndrome. This may be due to an increased
in vitro sensitivity of myeloblasts to cytarabine as a result of
generation of ara-C triphosphate. Blasts are also sensitive
to daunorubicin. The myeloid leukemia seen in young
children with DS is unique and classified under the uni-
fying term myeloid leukemia of DS (ML-DS). ML-DS is
preferred to acute megakaryoblastic leukemia because
other phenotypes are observed, sharing the same biologic
and clinical characteristics.
Indian Data
Limited Indian data exists for MDS.
The study by Chatterjee et al. [20] classified 21 patients of
Pediatric MDS as per the WHO proposed classification of
2003 [2]. The median age was 9 y with male predominance.
Pallor was the presenting feature in all the patients with
bleeding diathesis and fever in 50 % of cases. There were
8 cases of refractory cytopenia, three cases of RAEB, 5 cases
of RAEB-T, 4 cases of JMML and only 1 case of AML in
Down syndrome. Three patients of RAEB-T progressed to
AML within 34 mo. Refractory cytopenia had the best
prognosis and all were alive during the 3 y follow-up period
in the study concerned. All the three cases of RAEB had no
progression during the 3 y period and the solitary case of
AML-DS died within 2 mo of diagnosis. Of the four cases of
JMML, one died within 6 mo of diagnosis and one had
progressed with increasing blast count. None of the four
cases were doing well during the study period.
In the study by Choudhry et al. 23 males and one female
patient in the age range 218 (mean 9.1) y ware included in
the study [21]. There were eight patients of refractory anemia
(RA), 12 of refractory anemia with excess blasts (RAEB),
three of refractory anemia with excess blasts in transforma-
tion (RAEB-t) and one of juvenile chronic myelomonocytic
leukemia (JCML).
Grewal et al. in 1993 published the clinical and hemato-
logical characteristics of ten children with myelodysplastic
syndromes diagnosed and followed up over a 3 y period [22].
All of them had anemia and a low platelet count whilst the
white blood cell count was variable. Presentation with bilat-
eral proptosis and acute febrile neutrophilic dermatosis
(Sweets syndrome) were unique features observed in one
case each. None of these cases could afford specific therapy
and thus serve to illustrate the natural history of the disease in
pediatric practice.
A study of 16 cases of Pediatric MDS by Nair et al. in
1992 revealed all such cases to be high grade MDS and not a
single case belonged to RCC category. The mean duration of
survival was roughly 6 mo.
Agarwal et al. in 1994 analysed hematological features of 29
children, under the age of 12 y, with primary myelodysplasia.
There were 24 males and 5 females aged 4 mo to 12 y
(median 2.5 y) with marked male preponderance. Childhood
myelodysplasia constituted 16 % of all hematological malig-
nancies and 36.7 % of acute myeloid leukemia. The median
duration of symptoms prior to diagnosis was 3 mo. There were
15 cases of refractory anemia, one of refractory anemia with
excess blasts, 3 of refractory anemia with excess blasts in
transformation and 10 cases of chronic myelomonocytic leu-
kemia. Five patients evolved to acute myeloid and 4 to acute
lymphatic leukemia. The median duration of preleukaemic
phase in these patients was 7 mo (range 429 mo). The overall
mean survival was short (59 mo) in all the subgroups. Besides
supportive therapy in most patients, two patients were treated
with etoposide, one with alpha interferon 2b and one with high
dose methylprednisolone (Table 7).
Table 7 Indian data
Author Number of
patients
Year of
study
WHO subtypes Median
age
Chatterjee et al. [20] 21 2003 RC(8), RAEB(3), RAEB-t(5), JMML(4),
DS-M(1)
9 y
Choudhry et al. [21] 24 2000 RC(8), RAEB(12), RAEB-t(3), JMML(1) 9 y
Grewal et al. [22] 10 1993 RCC(4), RAEB(2), RAEB-t(4), JMML(1) 9 y
Nair et al. [23] 16 1992 RAEB(7), RAEB-t(6), JMML(3) 10 y
Agarwal et al. [24] 29 1994 RA(15),RAEB(1), RAEB-t(3), CMML(10) 2.5 y
Indian J Pediatr
Conclusions
MDS in children is rare condition, and there is still much to be
learned about the biology of the disease [25]. As our knowl-
edge increases, so will the ways in which we treat them.
For now, a stem cell transplant can cure more than half of
these young patients; other treatment options are considered
when HLA matched donor is not available. Results are,
however, poor.
Conflict of Interest None.
Role of Funding Source None.
References
1. Hasle H, Wadsworth LD, Massing BG, McBride M, Schultz
KR. A population-based study of childhood myelodysplastic
syndrome in British Columbia, Canada. Br J Haematol. 1999;106:
102732.
2. Proytcheva MA. Diagnostic Paediatric Haematopathology. New
York: Cambridge University Press; 2011. pp. 25460.
3. Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM,
Kerndrup G, et al. A paediatric approach to the WHO classification
of myelodysplastic and myeloproliferative diseases. Leukemia.
2003;17:27782.
4. Steven H, Harris NL, Jaffe ES, Brunning RD, Vardiman JW, Thiele J.
Childhood MDS in WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues. 4th ed. France: Lyon; 2008.
pp. 1047.
5. Niemeyer CM, Baumann I. Classification of Childhood Aplastic
Anaemias and MDS. ASH Educ Book. 2011;2011:849.
6. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International
classification of childhood cancer, third edition. Cancer. 2005;
103:145767.
7. Paediatric Myelodysplastic Syndrome. Prasad Mathew SIOP Edu-
cation Book 2006, International society of Paediatric Oncology,
38th Congress of the International Society of Paediatric Oncology
Geneva, SwitzerlandSeptember 1721, 2006.
8. Niemeyer CM, Baumann I. Myelodysplastic syndrome in children
and adolescents. Semin Hematol. 2008;45:6070.
9. Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol.
2000;110:76879.
10. Smith OP. Shwachman-diamond syndrome. Semin Hematol.
2002;39:95102.
11. Strahm B, Locatelli F, Bader P, Ehlert K, Kremens B, Zintl F, et al.
Reduced intensity conditioning in unrelated donor transplantation
for refractory cytopenia in childhood. Bone Marrow Transplant.
2007;40:32933.
12. Yoshida N, Yagasaki H, Hama A, Takahashi Y, Kosaka Y,
Kobayashi R, et al. Predicting response to immunosuppressive
therapy in childhood aplastic anaemia. Haematologica. 2011;
96:7714.
13. The European Working Group of MDS and JMML in Childhood.
Proceedings of the 6th International Symposium on Childhood
MDS and Bone Marrow Failure syndromes. Prague: Czech Repub-
lic; 79 November 2012.
14. McKenna RW. Myelodysplasia and myeloproliferative disorders in
children. Am J Clin Pathol. 2004;122:S5869.
15. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA,
Gralnick H, et al. The chronic myeloid leukaemia: Guidelines for
distinguishing chronic granulocytic, atypical chronic myeloid and
chronic myelomonocytic leukaemia. Proposals by the French-
American-British Cooperative Leukaemia Group. Br J Haematol.
1994;87:74654.
16. Hoffman R, Furie B, McGlave P, Silberstein LE, Shattil SJ, Benz
EJ, et al. Haematology: Basic Principles and Practice. 5th ed.
Philadelphia: Churchill Livingstone; 2009.
17. Hoffbrand VA, Catovsky D, Tuddenham EGD, Green AR. Post-
graduate Haematology. 6th ed. New Jersey: Wiley-Blackwell;
2011.
18. Niemeyer CM, Fenu S, Hasle H, Mann G, Stary J, van Wering E.
Differentiating juvenile myelomonocytic leukemia from infectious
diseases. Blood. 1998;91:3657.
19. Locatelli F, Nllke P, Zecca M, Korthof E, Lanino E, Peters C, et al;
European Working Group on Childhood MDS; European Blood
and Marrow Transplantation Group. Hematopoietic stem cell trans-
plantation (HSCT) in children with juvenile myelomonocytic leu-
kemia (JMML): Results of the EWOG-MDS/EBMT trial. Blood.
2005;105:4109. Epub 2004 Sep 7.
20. Chatterjee T, Mahapatra M, Dixit A, Naithani R, Tyagi S, Mishra P,
et al. Primary myelodysplastic syndrome in childrenclinical,
haematological and histomorphological profile from a tertiary care
centre in India. Hematology. 2005;10:4959.
21. Singh ZN, Kashyap R, Pati HP, Choudhry VP. Myelodysplastic
syndromes in childhood and adolescence: Clinical and hematological
profile. Indian Pediatr. 2001;38:716.
22. Garewal G, Marwaha RK, Roy R, Marwaha N. Clinicohaematological
profile and natural history of childhood myelodysplastic syndromes.
Indian J Pediatr. 1993;60:57381.
23. Nair R, Athale UA, Iyer RS, Nair CN, Pai SK, Kurkure PA, et al.
Childhood myelodysplastic syndromes: Clinical features, cytoge-
netics and prognosis. Indian J Pediatr. 1992;59:4438.
24. Agarwal BR, Currimbhoy ZE. Childhood myelodysplasia. Indian
Pediatr. 1994;31:797806.
25. Luna-Fineman S, Shannon KM, Atwater SK, Davis J,
Masterson M, Ortega J, et al. Myelodysplastic and myelopro-
liferative disorders of childhood: A study of 167 patients.
Blood. 1999;93:45966.
Indian J Pediatr