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C H A P T E R 63

MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE

NEOPLASMS IN CHILDREN

Franklin O. Smith, Christopher C. Dvorak, and Benjamin S. Braun

The myelodysplastic syndromes (MDS) and myeloproliferative 5q− syndrome, an entity not seen in children. Far more common in
neoplasms (MPN) are a heterogeneous group of clonal stem cell adults is a disease characterized by the accumulation of genetic
disorders that result in ineffective hematopoiesis and an increased damage, progression to BM failure, and a high probability of develop-
risk of developing acute myeloid leukemia (AML). In children, ing AML. This form of the disease is characterized as a mutator
8
MDS and MPN are now classified into three main groups: MDS, phenotype. The primary MDS seen in children appear to share this
juvenile myelomonocytic leukemia (JMML), and transient abnormal mutator phenotype.
myelopoiesis (TAM) in children with Down syndrome. Whereas in As in adults, secondary MDS in children can also arise as sequelae
MDS, ineffective hematopoiesis results in progressive cytopenias, from exposure to chemotherapy and radiation, and from genetic
in MPN, at least initially, ineffective hematopoiesis leads to exces- conditions including monosomy 7 syndrome, Down syndrome,
sive proliferation frequently characterized by increased peripheral paroxysmal nocturnal hemoglobinuria (PNH), neurofibromatosis,
blood counts. MDS and MPN are rare in children. Chronic myeloid Bloom syndrome, and Li-Fraumeni syndrome. However, MDS in
leukemia (CML), characterized by the Philadelphia chromosome children may often result from inherited constitutional BM failure
(BCR/ABL positive) is seen in both children and adults, but other syndromes including Fanconi anemia (FA), severe congenital neutro-
forms of MPN (polycythemia vera [PV], essential thrombocythe- penia, Shwachman-Diamond syndrome, congenital amegakaryocytic
mia [ET], primary myelofibrosis, chronic neutrophilic leukemia, thrombocytopenia, dyskeratosis congenital, Diamond-Blackfan
chronic eosinophilic leukemia, chronic basophilic leukemia, chronic anemia, and MonoMAC syndrome. Unlike de novo MDS in the
myelomonocytic leukemia, systemic mastocytosis [SM], and stem elderly, the true incidence of de novo MDS in children may become
cell leukemia–lymphoma syndrome) are exceedingly rare in children. less frequently diagnosed as genetics and inherited constitutional BM
Readers interested in CML and disorders that are predominantly failure syndromes (IBMFS) causes of secondary MDS are increasingly
found in adults are referred to in Chapters 67–70. In contrast, two identified in children.
MPNs are uniquely pediatric: JMML and Down syndrome–associated Ongoing studies are now defining the molecular pathogenesis and
TAM. interrelationships among MDS, MPN, and AML. 9–11 Accumulating
data suggest that aberrant signal transduction resulting from acquired
somatic mutations encoding proteins leading to hyperactivation of
MYELODYSPLASTIC SYNDROMES the Ras pathway may stimulate proliferation without concomitant
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differentiation. This has been clearly demonstrated in CML (BCR-
The MDS are a heterogeneous group of clonal disorders characterized ABL). 12,13 A number of other putative pathogenetic mutations have
by ineffective hematopoiesis, impaired maturation of hematopoietic been identified in other myeloproliferative disorders, including JAK2
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cells, progressive cytopenias, and dysplastic changes in the bone V617F mutations in PV, ET, and primary myelofibrosis ; KIT D816V
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marrow (BM). mutations in SM ; FIPL1-PDGFRA in chronic eosinophilic
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leukemia-SM ; ZNF198-FG4FR1 mutations in stem cell leukemia–
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lymphoma syndrome ; RAS/NF1/PTPN11 mutations in JMML 18–20
Epidemiology (Fig. 63.1); and GATA1 mutations in TAM. 21
AML is the result of cooperating mutations in genes that confer
MDS is a common malignancy of adults with an incidence of 50 a proliferative and survival advantage (e.g., activating mutations in
1
cases per million in people older than the age of 60 years. In contrast, receptor tyrosine kinases [FLT3, c-kit]) and genes that impair dif-
MDS accounts for only 3%–7% of all hematologic malignancies in ferentiation and apoptosis (e.g., loss-of-function mutations in tran-
children, with an unknown true incidence, owing in part to the scription factors [CBF, AML/ETO]) (Fig. 63.2). This multistep
inclusion of children with Down syndrome in some estimates. Several model for the pathogenesis of AML is supported by murine
population-based studies have been performed with reported inci- models, 22,23 the analysis of leukemia in twins, 24–27 and the analysis of
2
dences of 4.0 cases per million in Denmark, 3.1 per million in patients with familial platelet disorder with a propensity to develop
3
British Columbia (Canada), and 1.35 per million in the United AML (FDP/AML syndrome). 28
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Kingdom. The median age of presentation is 6.8 years with an equal Recent advances in sequencing techniques and a rapidly evolving
4–6
sex distribution. However, in a study of children with advanced or understanding of the biology of epigenetics (global methylation and
high-risk MDS, the median age of presentation was older at 10.7 histone modification) and mRNA slicing machinery have transformed
years with a 2 : 1 male to female ratio. 7 our understanding of oncogenic driver mutations in adult MDS. 29–32
In adults with MDS, approximately 50% of patients have recurrent
mutations in a slicing factor (SF3B1, U2AF1, SRSF2, ZRSR2), a novel
Pathobiology class of cancer-associated genes that was only recently recognized to
be important in MDS. Similarly, the same percent of adult patients
As in adults, MDS in children can be considered as primary (de novo) have at least one mutated epigenetic regulator (TET2, ASXL1,
or secondary. In adults, two predominant patterns of primary, de DNMT3A, EZH2, IDH1, and IDH2), whereas approximately 25% of
novo MDS have been observed. In the first of these patterns, the adults will have mutations in both splicing factors and epigenetic
disease is indolent in nature and is characterized by prolonged sur- regulators. Karyotypic abnormalities (5/5q−, 7/7q−, 3q, 20q) alone
vival, little accumulated genetic damage, and a low probability of occur in approximately 5% of adults. Approximately 15% of adult
progression to AML. This group of diseases is best exemplified by the patients have mutations in other genes (without associated mutations
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