4.4Epidemiology

•The incidence is not known because of the rarity of the disease and because oligo – and asymptomatic forms – may remain unidentified for a long time. Thus, the incidence of MDS may be underestimated

•Three percent of hematologic malignancies of childhood are suspected to be MDS. If MDS is considered as an initial stage of AML, the incidence increases to 12–20%. JMML is estimated to account for 2.5–3% of leukemia in childhood (Germing et al 2008)

•Incidence should be interpreted cautiously according to the various classification systems

4.5Predisposing Factors

•Familial MDS is more frequently seen than familial leukemia

•Patterns of inheritance are not identifiable

•Both children and adults are affected; however, MDS is largely a disease of the elderly: incidence rises with increasing age

•Risk of first-degree relatives of adults with MDS is approximately 15 times higher than in the general population

•Although children with familial MDS do not exhibit specific morphological forms of MDS, monosomy 7 is frequently observed

Predisposing factors for pediatric MDS

•Constitutional chromosomal aberrations

–Trisomy 8 mosaicism

–Trisomy 21 mosaicism, Down syndrome

–Klinefelter syndrome

–t(2;11), t(7;16), t(13;14), ins(16), fragile X syndrome, Turner syndrome

•Syndromes associated with disturbed DNA repair

–Fanconi anemia

–Ataxia telangiectasia

–Bloom syndrome

–Xeroderma pigmentosum

•Neurofibromatosis

•Constitutional p53 mutation (Li-Fraumeni syndrome)

•Aplastic anemia

•Congenital neutropenia (Shwachman syndrome)

•Pearson syndrome

•First-degree relatives of patients with MDS

•Alkylating agents and/or radiotherapy

•Miscellaneous conditions

–Werner syndrome

–Pierre Robin syndrome

40 T. Kühne

– Adams-Oliver syndrome

– Congenital vitium

– Hypospadias

– Endocrine dysfunctions

– Platelet storage-pool disorders

– Miscellaneous physical and psychological disorders

4.6 Etiology

• Like other malignant tumors, a process with multiple steps is suspected, with the accumulation of genetic lesions

• The initial and subsequent mutations have yet to be elucidated

• Several recurrent genetic aberrations known (e.g., mutations of the RAS protooncogene family and their influence with the tumor suppressor gene NF1)

4.7 Clinical Manifestations

•There are no specific disorders associated with the described morphological categories

•Occasionally abnormalities in blood counts are observed

•Clinical manifestations explained by degree of bone marrow failure

•Paleness, skin hemorrhages

•Sometimes hepato-/splenomegaly, particularly in refractory anemia with excess blasts (RAEB) and in patients with RAEB in transformation (RAEB-T)

•MDS associated with constitutional genetic aberrations is often seen in infants and young children

4.8Laboratory Findings

•Differentiation between MDS and AML may be difficult

•Clinical, morphological, immunephenotypical, and genetic criteria

•Morphology is based on peripheral blood analysis, bone marrow aspiration, and biopsy, interpreted by experienced reference laboratory staff

•The bone marrow is usually hypercellular; reduced marrow cellularity in 15% of patients only (“hypoplastic MDS”). Hypoplastic MDS is a diagnostic challenge (differential diagnosis: acquired aplastic anemia)

•Consider MDS if maturation abnormalities are associated with dysplasia or if one or more cell lines are present

•Red cell abnormalities and megaloblastic maturation are common; nuclear– cytoplasmic asynchrony (maturation of cytoplasm reflected by hemoglobin and nuclear development). Development of multiple nuclei and nuclear fragmentation (Howell–Jolly bodies)

•Immature myeloid cells could be increased and exhibit dysplastic signs (e.g., hypogranular granulocytes). Pelger–Huët nuclear anomaly. Percentage of myeloblasts is important for the FAB and WHO classification

•Megakaryocytic abnormalities include micromegakaryocytes, increased ratio of nucleus to cytoplasm, various cell sizes, increased or decreased cytoplasmic granules

•Other laboratory investigations: cytogenetics (abnormal karyotype in more than 70% of patients), molecular biology (single-gene mutations, clonal hematopoietic defects), cell culture analysis (often leukemic pattern of the precursor cells, particularly with many micro – and macroclusters)

4.9Differential Diagnosis

•Diagnosis based on history, physical examination, complete blood count, bone marrow cytology and histology, with interpretation by a reference laboratory

•Differentiation from acute leukemia and myelodysplastic/myeloproliferative neoplasms according to FAB or WHO classification

•Vitamin B12 and folate deficiency, as well as pyridoxine and riboflavin deficiencies, are usually well differentiated from MDS

4.10Treatment

•Remains highly controversial

•Many different multiagent chemotherapies have been tried, particularly AML induction chemotherapy

•Conventional chemotherapy is not curative

•Myeloablative therapy and allogeneic hematopoietic stem cell transplantation appear to be most effective. It is the treatment of choice in high-grade MDS

•Long-term survival of children with MDS after stem cell transplantation is in the range of 40%

•The International Prognosis Scoring System (IPSS) for MDS in adults is of limited value in children who are mainly treated with allogeneic hematopoietic stem cell transplantation for advanced MDS

References

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Bennett JM, Catovsky D, Daniel MT et al (1994) The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic

leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87:746–754

Germing U, Aul C, Niemeyer C, Haas R, Bennett JM (2008) Epidemiology, classification and prognosis of adults and children with myelodysplastic syndromes. Ann Hematol 87:691–699 Hasle H (1994) Myelodysplastic syndromes in childhood – classification, epidemiology, and treat-

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Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) (2001) World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC, Lyon Swerdlow SH et al (2008) WHO classification of tumours of haematopoietic and lymphoid tissues.

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Vardiman JW (2010) The World Health Organization (WHO) classification of tumors of the hematiopoietic and lymphoid tissues: an overview with emphasis on the myeloid neoplasms. Chem Biol Interact 184:16–20

Yin CC, Medeiros LJ, Bueso-Ramos CE (2010) Recent advances in the diagnosis and classification of myeloid neoplasms – comments on the 2008 WHO classification. Int J Lab Hematol 32:461–476