The myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS), which represent between 5% and 10% of all myeloid malignancies in children, are a heterogeneous group of disorders with the former usually presenting with cytopenias and the latter with increased peripheral white blood cell, red blood cell, or platelet counts. MDS is characterized by ineffective hematopoiesis and increased cell death, while MPS is associated with increased progenitor proliferation and survival. Because they both represent disorders of very primitive, multipotential hematopoietic stem cells, curative therapeutic approaches nearly always require allogeneic hematopoietic stem cell transplantation.
Patients usually present with signs of cytopenias, including pallor, infection, or bruising. The bone marrow is usually characterized by hypercellularity and dysplastic changes in myeloid precursors. Clonal evolution eventually can lead to the development of acute myeloid leukemia (AML). The percentage of abnormal blasts is less than 20%. The less common, hypocellular MDS, can be distinguished from aplastic anemia in part by its marked dysplasia, clonal nature, and higher percentage of CD34-positive precursors.[1,2]
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Although the etiology of MDS has not been elucidated, clues have begun to be defined. For instance, approximately 20% of malignant myeloid disorders, including MDS, in adults have been shown to have mutations in the TET2 gene. Other genes shown to be mutated in MDS include EZH2, DNMT3A, ASXL1, IDH1/2, RUNX1, ETV6-TEL, and TP53. Most of these genes are key elements of epigenetic regulation of the genome and affect DNA methylation and/or histone modification.[3,4,5] Mutations in proteins involved in RNA splicing have been described in 45% to 85% of MDS and appear to occur early in the course of the disease. MDS in both adults and children has been shown to have aberrant DNA methylation patterns and approximately one-half of cases are characterized by hypermethylation of the promoters for the CDKN2B and CALC genes, both of which play roles in cell cycle regulation.[7,8]
Patients with inherited disorders, such as Fanconi anemia, due to germline mutations in DNA repair genes, or dyskeratosis congenita, due to mutations in genes regulating telomere length, have significantly increased risk of developing MDS. Additional bone marrow failure syndromes may also evolve into MDS, including those due to mutations in genes encoding ribosome-associated proteins, such as Shwachman-Diamond syndrome and Diamond-Blackfan anemia. The 15-year cumulative risk of MDS in patients with severe congenital neutropenia, also known as Kostmann syndrome, which is due to mutations in the gene encoding elastase, has been estimated to be 15% with an annual risk of MDS/AML of 2% to 3%; how mutations affecting this protein and what role the chronic exposure of granulocyte-colony stimulating factor (G-CSF) contribute to the development of MDS is unclear.[10,11] Inherited mutations in the RUNX1 or CEPBA genes have also been shown to be associated with familial MDS/AML and congenital amegakaryocytic thrombocytopenia.[12,13]