CHILDHOOD MDS: Unlocking the old

mystery

Mohamed Elsawy MD

Definition - MDS

A heterogeneous clonal hematopoietic disorderderived from an abnormal multipotent progenitor

Characterized by cytopenias

Hyperproliferative bone marrow, dysplasia of thecellular elements, and ineffective hematopoiesis

Increased risk of progression to acute myeloidleukemia

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

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Myelodysplastic Syndromes (MDS), WHO 2008Refractory 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

• Blast count alone is insufficient to differentiateAML from MDS

• Diagnostics criteria based on:

- Comprehensive assessment of clinical features

- Natural course

- Morphology

- Immunophenotype

- Cytogenetics

Implications of the WHO 2008classification in pediatrics

Limitations of the adult MDSclassification for pediatric MDS

No categories available to account for:

Pre-existing constitutional syndromes (30% of pediatricMDS)

Pre-existing bone marrow failure syndromes

Features unique to pediatric MDS Higher incidence of fibrosis

Lack of correlation of low blast percentage with prognosis (asseen in adults)

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 MyeloproliferativeSyndromes in Children

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

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

Clinical and laboratory features inchildren with MDS

• Pancytopenia(s)

• Occasional single lineage cytopenia

• Incidental finding during a routine work-up

• Fetal hemoglobin (HbF) is frequently moderatelyelevated

• WBC counts: low to normal

• Leucocytosis is generally not seen

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

Refractory Cytopenia of Childhood

Cytogenetic features of RefractoryCytopenia of Childhood

• Majority of the patients have normal Karyotype

• Monosomy 7 is the most common cytogeneticabnormality

• Complex karyotype can also be seen

• There is NO morphological difference between thecases with and without Monosomy 7

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Differential Diagnosis for RefractoryCytopenia 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)

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 cytogeneticabnormality (25% of the patients) followed byacquired trisomy 8 and trisomy 21

IPSSSubgroups

ChildrenN=142Mediansurvival(%)(years)

AdultsN=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

Niemeyer C and Baumann I, ASH, 2011

Secondary MDS

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

Dyskeratosis congenita• Cumulative incidence of MDS/AML may be as high as in

Fanconi anemia

• Most patients carry mutations in genes encodingcomponents 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 mutationsin sibling donors –to prevent potentially fatal graft failure

Telomere Biology

Seven of these genes abnormalities (Dyskerin,TERT, TERC, NHPP2, NOP10, WDR79/TCAB1 and

TIN2) have associated with DKC

Familial MDS

• MDS occurring in patients with a first degree relativesuffering from MDS or AML without the diagnosis ofone of the known BM failure disorders

• Often show monosomy 7

• Germline mutations in RUNX1, CEBPA, GATA2 maycause familial MDS/AML

• The genetic cause remains obscure in most reportedpedigrees

Spectrum of Hematological MalignanciesAssociated with RUNX1/AML1 point mutations

Journal of Cellular BiochemistryVolume 112, Issue 2, pages 425-432, 25 JAN 2011 DOI: 10.1002/jcb.22974

Familial MDS/AML (RUNX1) Mutations

Preudhomme C et al. Blood 2009;113:5583-5587©2009 by American Society of Hematology

GATA2 Mutations and Diseases

Nature Genetics 43: 929–931, 2011

Familial MDS/AML (GATA2 mutations)

Nat Genet. 43:1012-7, 2011

Emberger Syndrome (GATA2) Autosomal dominant trait

Sensorineural deafness

Immune dysfunction

Cutaneous warts

Myelodysplasia

Monosomy 7

Nature Genetics 43: 929–931, 2011

Other GATA2 Related Syndromes

• Monocytopenia, B-cell and NK-cell lymphopenia, andmycobacterial, fungal, and viral infections isassociated with MDS/AML, cytogeneticabnormalities, and pulmonary alveolar proteinosis

• Immunodeficiency syndrome that involved loss ofdendritic cells, monocytes, and B and natural killercells (DCML) deficiency

Marked genetic heterogeneity in familialmyelodysplasia/acute myeloid leukaemia

British Journal of HaematologyVolume 158, Issue 2, pages 242-248, 26 APR 2012 DOI: 10.1111/j.1365-2141.2012.09136.x

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.

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.

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

Bone marrow aspirate smear: Megaloblastic erythropoieis

Bone marrow aspirate: Extremely limited granulopoiesis including a bilobed neutrophil

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

Cytogenetic Findings

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

clone

Consensus Diagnosis

Familial monosomy 7 syndrome associated with childhood myelodysplastic syndrome

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