MDS in pediatrics

1. CHILDHOOD MDS:
Unlocking the old
mystery
Mohamed Elsawy MD

2. Definition - MDS
 A heterogeneous clonal hematopoietic disorder
derived from an abnormal multipotent progenitor
 Characterized by cytopenias
 Hyperproliferative bone marrow, dysplasia of the
cellular elements, and ineffective hematopoiesis
 Increased risk of progression to acute myeloid
leukemia

3. Epling-Burnett and List. Curr Opin Hematol 2009;16:70

6. •
•
•
•
•
•
•
Myelodysplastic Syndromes (MDS), WHO 2008
Refractory cytopenia with unilineage dysplasia
- Refractory anemia
- Refractory neutropenia
- Refractory thrombocytopenia
Refractory anemia with ring sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory anemia with excess of blasts
Myelodysplastic syndrome with isolated del(5q)
Myelodysplastic syndrome, unclassifiable
Childhood myelodysplastic syndrome
- Refractory Cytopenia of Childhood (RCC)—Provisional entity

9. • Blast count alone is insufficient to differentiate
AML from MDS
• Diagnostics criteria based on:
- Comprehensive assessment of clinical features
- Natural course
- Morphology
- Immunophenotype
- Cytogenetics
Implications of the WHO 2008
classification in pediatrics

10. Limitations of the adult MDS
classification for pediatric MDS
No categories available to account for:
 Pre-existing constitutional syndromes (30% of pediatric
MDS)
 Pre-existing bone marrow failure syndromes
 Features unique to pediatric MDS
 Higher incidence of fibrosis
 Lack of correlation of low blast percentage with prognosis (as
seen in adults)

11. Three main groups:
• Childhood Myelodysplastic Syndromes
− Refractory cytopenia of childhood
− Refractory anemia with excess of blasts (RAEB)
− Refractory anemia with excess of blasts (RAEB-T)
• Juvenile Myelomonocytic Leukemia (JMML)
• Myeloid Disorders of Down syndrome
Myelodysplastic and Myeloproliferative
Syndromes in Children

13. Types of Pediatric MDS
• De novo or Primary
- previously healthy child
- without a known predisposing condition
• Secondary
- In patients who received chemo- or radiation
(therapy-related MDS)
• Constitutional BM failure disorders
- Familial MDS

19. Disease No. %
Incidence
6
/10
AcuteLymphoblastic 815 79 38.5
AcuteMyeloid 115 11 5.4
Myelodysplasia 38 4 1.8
JMML 25 2 1.2
DownSyndrome+AML 19 2 0.9
ChronicMyeloid 13 1 0.6
Other 6 <1 0.2
Incidence
Hasle H et al. Leukemia 17: 277-282, 2003

20. Clinical and laboratory features in
children with MDS
• Pancytopenia(s)
• Occasional single lineage cytopenia
• Incidental finding during a routine work-up
• Fetal hemoglobin (HbF) is frequently moderately
elevated
• WBC counts: low to normal
• Leucocytosis is generally not seen

21. Refractory Cytopenia of Childhood (RCC)
Clinical features:
•Malaise, bleeding, fever and infection
•Lymphadenomegaly, secondary to infection
•Hepatosplenomegaly is rare
•Asymptomatic, up to 20% of patients
•Platelet < 150x109/L, 3/4 of the cases
•Anemia, Hb < 10g/dL, < 1/2 of the cases
•Severe neutropenia, noted in 25% of the patients

22. Refractory Cytopenia of Childhood

23. Cytogenetic features of Refractory
Cytopenia of Childhood
• Majority of the patients have normal Karyotype
• Monosomy 7 is the most common cytogenetic
abnormality
• Complex karyotype can also be seen
• There is NO morphological difference between the
cases with and without Monosomy 7

24. •
•
•
•
•
•
•
Differential Diagnosis for Refractory
Cytopenia of Childhood
Infections ( CMV, HSV, PV B19, Leishmaniais)
Vitamin deficiency ( B12, folate, Vit E)
Metabolic disorders (eg. Mevalonate kinase Def.)
Rheumatic disease
Autoimmune lymphoproliferative disorders
Inherited BM failure (Fanconi anemia, Dyskeratosis
congenita, Schwachmann-Diamond Syndrome, etc…)
PNH (paroxysmal nocturnal hemoglubinuria)

25. RAEB and RAEB-T
(Advanced Myelodysplastic Syndrome)
• Abnormal karyotype
- 55% of children with advanced primary MDS
- 76% with secondary advanced MDS
• Monosomy 7 is the most common cytogenetic
abnormality (25% of the patients) followed by
acquired trisomy 8 and trisomy 21

26. IPSS
Subgroups
Children
N=142Mediansurvival
(%)(years)
Adults
N=816Mediansurvival
(%)(years)
Low 7 >10 33 5.7
Intermediate1 47 9.7 38 3.5
Intermediate2 25 4.5 22 1.2
High 21 2.2 7 0.4
Prognosis Adult vs. Pediatric MDS

27. Niemeyer C and Baumann I, ASH, 2011
Secondary MDS

28. Constitutional bone marrow failure
• Increased risk of MDS/AML
• The risk varies greatly
• Highest risk
• Fanconi anemia
• Dyskeratosis congenita
• Severe congenital neutropenia (Kostmann)
• Shwachman-Diamond syndrome

29. Dyskeratosis congenita
• Cumulative incidence of MDS/AML may be as high as in
Fanconi anemia
• Most patients carry mutations in genes encoding
components of the telomerase complex—DKC1,
TERC,TERT, TINF2
- impairing telomerase activity
- causing excessive telomere shortening
- inducing cellular senescence and apoptosis
• Screening of telomere length and telomerase mutations
in sibling donors –to prevent potentially fatal graft failure

30. Telomere Biology
Seven of these genes abnormalities (Dyskerin,
TERT, TERC, NHPP2, NOP10, WDR79/TCAB1 and
TIN2) have associated with DKC

31. Familial MDS
• MDS occurring in patients with a first degree relative
suffering from MDS or AML without the diagnosis of
one of the known BM failure disorders
• Often show monosomy 7
• Germline mutations in RUNX1, CEBPA, GATA2 may
cause familial MDS/AML
• The genetic cause remains obscure in most reported
pedigrees

32. Spectrum of Hematological Malignancies
Associated with RUNX1/AML1 point mutations
Journal of Cellular Biochemistry
Volume 112, Issue 2, pages 425-432, 25 JAN 2011 DOI: 10.1002/jcb.22974

33. Familial MDS/AML (RUNX1) Mutations
Preudhomme C et al. Blood 2009;113:5583-5587©2009 by American Society of Hematology

34. GATA2 Mutations and Diseases
Nature Genetics 43: 929–931, 2011

35. Familial MDS/AML (GATA2 mutations)
Nat Genet. 43:1012-7, 2011

36. Emberger Syndrome (GATA2)
 Autosomal dominant trait
 Sensorineural deafness
 Immune dysfunction
 Cutaneous warts
 Myelodysplasia
 Monosomy 7
Nature Genetics 43: 929–931, 2011

37. Other GATA2 Related Syndromes
• Monocytopenia, B-cell and NK-cell lymphopenia, and
mycobacterial, fungal, and viral infections is
associated with MDS/AML, cytogenetic
abnormalities, and pulmonary alveolar proteinosis
• Immunodeficiency syndrome that involved loss of
dendritic cells, monocytes, and B and natural killer
cells (DCML) deficiency

38. Marked genetic heterogeneity in familial
myelodysplasia/acute myeloid leukaemia
British Journal of Haematology
Volume 158, Issue 2, pages 242-248, 26 APR 2012 DOI: 10.1111/j.1365-2141.2012.09136.x

67. History
A previously healthy 12 year-old African
American male presents with several days of
cough, vomiting and high fevers and was found
to be pancytopenic: WBC 1.3 K/dL, Hgb 6.4 g/dL,
MCV 94.4 fL, Plt 69 K/dL. His family history is
significant for a half-sister who was diagnosed
with monosomy 7 associated acute myeloid
leukemia 2 years previously.

68. Details
Bone marrow aspirate and clot section:
Hypocellular marrow with increased and highly
dysplastic megakaryocytes forming clusters,
decreased myeloid lineage, no increase in blasts
but limited dysplastic maturation to segmented
neutrophils and decreased erythroid lineage
with megaloblastic maturation and occasional
irregular budding.

69. Bone marrow aspirate: Numerous small and/or mononuclear
megakaryocytes, few erythoid precursors and virtually no myeloid

70. Bone marrow aspirate smear: Megaloblastic
erythropoieis

71. Bone marrow aspirate: Extremely limited granulopoiesis
including a bilobed neutrophil

72. Bone marrow clot section: Hypocellular marrow with increased, clustered and
dysplastic megakaryocytes, reduced erythropoiesis and virtually no
myelopoiesis.

73. Cytogenetic Findings
• 45,XY,-7[8]/90,XXYY,-7,-7[1]/46,XY[11]
• FISH analysis confirmed the monosomy 7
clone

74. Consensus Diagnosis
Familial monosomy 7 syndrome associated
with childhood myelodysplastic syndrome

75. Interesting Features
Familial monosomy 7 syndrome associated with
myeloid neoplasm is extremely rare, with only
14 kindreds reported. It follows an autosomal
dominant inheritance pattern with variable
penetrance. The precise molecular mechanism
of this disease is uncertain at this time. In this
case, since the siblings did not share the same
father, the mother is an obligate carrier