Pediatric Myelodysplastic Syndrome

Updated: Sep 05, 2018
  • Author: Prasad Mathew, MBBS, DCH, FAAP; Chief Editor: Jennifer Reikes Willert, MD  more...
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Myelodysplastic syndrome (MDS) in childhood encompasses a diverse group of bone marrow disorders that share a common clonal defect of stem cells and that result in ineffective hematopoiesis with dysplastic changes in the marrow. These disorders are characterized by one or more cytopenias despite a relatively hypercellular bone marrow. MDS disorders have been referred to as “preleukemias” because of their tendency to transform into acute myeloid leukemia (AML).

MDS is rare in childhood and may have a rapidly progressive course with an extremely poor prognosis without hematopoietic stem cell transplantation (HSCT). The disease can arise in a previously healthy child; in this case, it is referred to as de novo or primary MDS. MDS may develop in a child with a known predisposition (eg, previous cytotoxic chemotherapy); this is referred to as secondary MDS (see Etiology). The disease is most common in adults, especially elderly people, and the course varies, ranging from an acute, rapidly fatal illness to a chronic, indolent illness.

MDS is classified into groups according to findings on peripheral blood smears, bone marrow histology, cytogenetics, and clinical examination. Notable controversy surrounds classification based on a systematic evaluation of frequency, outcomes, and treatment difficulty. Most accepted systems are modification of the classification of adult MDS proposed by the French-American-British (FAB) group. [1] Children with MDS whose disease fit in these classes are often considered to have adult-type MDS in current studies.

Types in the FAB system are the following:

  • Refractory anemia (RA)

  • RA with ringed sideroblasts (RARS)

  • RA with excess blasts (RAEB; 5-20% marrow blasts)

  • RAEB in transition to AML (RAEBT; 20-30% marrow blasts)

  • Chronic myelomonocytic leukemia (CMML)

MDS in children and adults differs in other ways. For example, CMML is extremely rare in pediatric populations. RARS is exceedingly rare in children. Finally, constitutional abnormalities are observed in many children but few adults.

One of the criticisms of the FAB system is that it does not include the prognostic implications of cytogenetic findings or other biologic features. Of note are 5q- syndrome (5q deletion syndrome), which is extremely rare in children; monosomy 7 syndrome; and infantile monosomy 7. Monosomy 7 is most often associated with juvenile myelomonocytic leukemia (JMML), and as many as 30% of children with JMML have a deletion of all or part of chromosome 7. Although this finding imparts some prognostic value concerning morbidity, its contribution in predicting mortality is controversial.

In an attempt to better characterize these disorders and incorporate cytogenetic information, the World Health Organization (WHO) described an alternate classification scheme for MDS. [2] As described below, the WHO classification eliminated the RAEBT category and added an unclassified category. The WHO current classification is as follows:

  • RA or RARS (erythroid dysplasia only, marrow blasts < 5%)

  • RA with multilineage dysplasia (blasts < 5%)

  • 5q- syndrome (blasts < 5%, no other genetic abnormalities)

  • RAEB (blasts 5-20%)

  • MDS unclassified (does not fit into above groups)

Another classification schema directed toward MDS in childhood, mainly adapted by the European community, included MDS (refractory cytopenia, RAEB and RAEBT), JMML, and Down syndrome–specific diseases. The changing classification schemes and continuing controversies reflect a limited understanding of MDS. An adequate scheme is likely to be devised only after detailed comprehension of MDS at its genetic, biologic, and clinical levels is attained. Progress in classifying MDS and myeloproliferative disorders in children has been slow. These diseases were included for the first time in the international classification of childhood cancers in 2005. [3]

When a child presents with cytopenias associated with MDS, physicians should administer supportive care until the diagnosis is established. Many patients present with profound cytopenia and a notable risk for infection. Transfusions and broad-spectrum antibiotics may be required to treat life-threatening anemia, thrombocytopenia, and infection until definitive therapy can be started.

In MDS pediatric patients with refractory cytopenia, hematopoietic stem cell transplantation (HSCT) from a matched related or unrelated donor early in the course of the disease is the treatment of choice. (See Treatment.)



MDS is a clonal disorder. Aberration occurs in a stem cell that can give rise to multiple lineages. This event explains the presence of multiple derangements observed in the bone marrow that involve several cell lineages. Genetic abnormalities associated with MDS block differentiation of hematopoietic stem and progenitor cells.

As the affected cell lines continue to divide and to provide the marrow with dysplastic cells, bone marrow dysfunction becomes apparent. This state may persist until a clone undergoes further transformation to leukemia and the marrow becomes fibrotic and aplastic.

As an alternative, the clone may progressively deteriorate, and the appearance of marrow may return to normal as healthy stem cells repopulate it. The natural progression of MDS is, thus, a function of an abnormal clone leading to progressive loss of marrow function, transformation to AML, or spontaneous remission.

The observation of cytogenetic abnormalities, most specifically monosomy 7 and neurofibromatosis type 1 (NF1) genetic mutations, support the theory that cell dysregulation occurs in a multi-hit fashion. In monosomy 7, a genetic predisposition and a later loss of a critical region on chromosome 7 that encodes a suspected tumor suppressor gene is suggested to set the stage for proliferation of an abnormal clone. Loss of the chromosome may occur during an embryonic period in hematopoietic stem cells or may result from cytotoxic therapy.

In patients with NF1, function of the NF1 gene product, neurofibronin (a glutamyl transpeptidase [GTPase]) is decreased, resulting in the loss of negative feedback on the RAS gene. Therefore, RAS is constitutively active in NF1. Farnesyltransferase inhibitors are able to inhibit activated RAS by preventing the required farnesylation reaction from occurring. Murine experiments suggest that RAS mutations disturb hemopoietic differentiation and lead to a proliferative advantage of hematopoietic precursor cells, ineffective erythropoiesis, and anemia. [4]

Monosomy 7 occurs in approximately 30% of primary childhood MDS cases and in about 50% of therapy-related MDS cases. [5]

The 5q- syndrome is considered a distinct MDS subtype, characterized by deletion of 5q-, less than 5% bone marrow blasts, normal or elevated platelet counts, longer survival, and an increased response to therapy with lenalidomide (Revelmid). Although 5q- is occasionally reported in children, the typical 5q- syndrome has not been reported.

In a recent study from the Brazilian Cytogenetic Subcommittee of the Pediatric Myelodysplastic Syndromes Cooperative Group, clonal abnormalities were found in 36.9% of the 84 pediatric MDS cases. Monosomy 7/deletion 7q was the most frequent clonal abnormalaity (13.9% of cases), followed by trisomy 8 and 21. Clonal abnormalities were more frequent in RAEB/T (37.5%), JMML (36.4%) and secondary MDS (33.3%) than in RC (27.2%). The median OS was 31 months for the MDS group, 122 months for the subgroup with chromosome 7 abnormality, 35 months for the subgroup with abnormal karyotype without chromosomal 7 abnormality and 29 months with those with a normal karyotype. [6]



MDS may be primary or secondary. Children with primary MDS may have an underlying but unknown genetic defect that predisposes them to develop MDS at a young age. Approximately 20% of children have an underlying congenital anomaly or syndrome associated with chromosomal abnormalities.

Secondary MDS occurs in patients after chemotherapy or radiation therapy (therapy-related MDS) or in patients with inherited bone marrow failure disorders, acquired aplastic anemia, or familial MDS. Therefore, the distinction between primary MDS and secondary MDS may become arbitrary.

Not all bone marrow failure syndromes are associated with the development of MDS. For example, patients with dyskeratosis congenita develop bone marrow failure in 95% of cases, but MDS has only been reported in a few cases. [7]

MDS and acute myeloid leukemia (AML) in Down syndrome are closely linked; the biologic and clinical features are distinct from the diseases observed in children without Down syndrome. In the proposed WHO classification, MDS and AML in Down syndrome are recognized as a single specific entity, myeloid leukemia of Down syndrome (ML-DS). [2] Antecedent MDS is common in those who develop AML in this population, affecting as many as 70% of children with ML-DS. [8]

Neurofibromatosis type 1 (NF1) is associated with the development of JMML. Patients with NF1 have a 350-fold increased risk of JMML. Shwachman-Diamond syndrome is characterized by pancreatic insufficiency with neutropenia. MDS occurs in 10-25% of individuals with this syndrome. [9]

Fanconi anemia (4-7%) increases the risk of MDS and AML [10] ; 48% of patients with Fanconi anemia develop leukemia or MDS by age 40 years. It is often associated with monosomy 7 and duplication of 1q. Diagnosing refractory cytopenia in a patient with Fanconi anemia may be difficult.

Kostmann syndrome (0.6%) is also known as congenital agranulocytosis. The survival of patients with this syndrome has significantly improved with the introduction of granulocyte colony-stimulating factor (G-CSF) treatment. Studies from the severe congenital neutropenia registry have shown a 9% crude rate of MDS development and an annual progression rate of 3%. [11] Partial or complete loss of chromosome 7 is found in more than half of the patients who develop MDS, and the development of MDS is almost always preceded by acquired mutation of the G-CSF receptor gene.

MDS has occasionally been described in patients with Diamond-Blackfan anemia. However, no estimates are available, and it may be rare, given the lack of MDS cases in a study of 229 patients. [12]

As a causative factor, previous therapy with alkylating agents (2-5%) is associated with monosomy 7 and chromosome 5 deletions. These patients have poor response rates. Previous administration of a topoisomerase inhibitor is a rare contributing factor. In the rare cases involving a topoisomerase inhibitor, patients usually develop AML.

MDS develops in 10-15% of patients with acquired aplastic anemia who are not treated with stem cell transplantation; this appears to occur at the same rate in idiopathic and hepatitis-associated aplastic anemia. [13] MDS may occur in these cases within 3 years of presentation; whether prolonged treatment with G-CSF and cyclosporine is associated with MDS development is controversial. [14]

Kim et al showed that pediatric MDS patients showed a higher methylation level of CDKN2B than pediatric controls, but a lower level than adult MDS patients. Methylation level was higher in cases with greater than 5% blasts than in pediatric controls, and the level was also higher in cases with abnormal karyotype. The CDKN2B gene encodes a tumor suppressor that normally prevents uncontrolled cell proliferation by arresting the cell cycle at the G1 phase. This gene is the most commonly silenced tumor suppressor gene in MDS, mainly by promoter hypermethylation, which contributes to disease progression in adult MDS. Thus, these authors were able to show that methylation of CDKN2B is associated with the pathogenesis and prognosis in pediatric MDS. [15]



United States statistics

The distribution of FAB classifications of MDS in adult populations is as follows:

  • RA - 38.4%

  • RARS - 11.5%

  • RAEB - 15%

  • RAEBT - 3.9%

  • CMML - 31.2%

In the pediatric population, aggressive forms such as RAEB and RAEBT are more common than RA or RARS.

The epidemiologic literature on childhood MDS is sparse. Factors for this lack of information include the following:

  • A widely accepted classification is lacking

  • Patients with indolent forms of the disease may not be referred to a tertiary center; this practice may result in a bias among institution-based studies toward the aggressive forms

  • Cancer registries do not generally register patients with MDS

In one of the earliest reports, MDS or preleukemia was reported in 17% of childhood AMLs (2.9% of all children with leukemia). [16] Other studies confirmed that a preleukemic phase precedes AML in about 12-20% of children with AML. [17] These studies were based on referrals for suspected AML and did not include the less advanced cases of MDS.

International statistics

The few population-based studies have given conflicting data about the incidence of MDS. Population-based data from Denmark and Canada (British Columbia) showed that MDS and JMML represented 6% of all hematologic malignancies in children, corresponding to annual incidences of 1.8 and 1.2 cases per million children and adolescents aged 0-14 years, respectively. [18]

A similar rate of MDS and JMML (7.7% in combination with childhood leukemia) was found in Japan, where therapy-related MDS represents 23% of all cases.

In the United Kingdom, the incidence is reported to be 0.5 case per million population, which accounts for 1.1% of childhood hematologic malignancies. The exclusion of secondary MDS may only partly explain the relatively low incidence in the United Kingdom. The incidence in elderly people is 89 per 100,000 population.

Race-, sex-, and age-related demographics

Data from the Children's Cancer Group showed that 75% of patients are white, 8.5% are Hispanic, 8% are African American, 3.5% are Asian, and 5% are of unknown race or ethnicity. [19] Most studies have been conducted in countries with predominantly white populations. Therefore, results may not reflection the true racial distribution. The incidence for each race has not been reported.

Combined data from 290 patients with mainly primary MDS showed a nearly-equal sex distribution. In patients with adult-type MDS such as RA, RAEB, and RAEBT, the male-to-female ratio is 1.2:1.

MDS occurs in people of all ages. For adult-type MDS, the median age is 5-8 years. Data from about 290 children with primary MDS showed a median age of 6.8 years.



The prognosis for pediatric patients with MDS is poor without HSCT. The most common cause of death is cytopenia. Infection, rather than progression to AML, ultimately results in the demise of most patients with MDS.

One study that included adults showed that the prognosis for Japanese patients with RA was significantly more favorable than that of German patients (median survival, 175 vs 40 mo). [20] This result suggests an ethnic variation in survival between Asian and Caucasian populations. Furthermore, the cumulative risk of acute leukemia evolution was significantly lower in Japanese patients than in German patients.

Patients with Down syndrome and MDS respond best to treatment, whereas those with MDS due to previous therapy with alkylating agents fare the worst. Patients without Down syndrome who undergo allogeneic HSCT have the best outcome, despite transplant-related mortality.

Until recently, most of the prognostic factors in MDS, such as those used in the International Prognostic Scoring System (IPSS), the Bournemouth score, and others, were based on data from adult patients. In adults, factors that have had prognostic significance for survival and progression to AML include bone marrow morphology, myeloblast percentage in the bone marrow, the appearance of the bone marrow on biopsy findings, number of cytopenias, cytogenetic abnormalities in bone marrow, age, and blood lactate dehydrogenase levels.

An analysis of candidate gene mutations in adults with MDS has demonstrated that 51% of all patients had mutations in at least 1 of 18 genes, with mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 significantly associated with a poor prognosis. Such studies have not yet been completed in children with MDS. [21]

The only factor that has consistently had prognostic significance in children with MDS is cytogenetic abnormality, notably monosomy 7.

Researchers from Japan, the United Kingdom, and the European Working Group on MDS in Childhood have all concluded that the IPSS is of limited value in children. Investigators from Japan and the United Kingdom found that only the IPSS karyotype group had significant prognostic value in terms of overall survival.

In the United States, a prospective study (CCG 2891) of AML-based therapy in children with MDS found that overall survival at 6 years was 29% ±12% for patients with MDS and 31% ±26% for those with JMML. [8] These outcomes were worse than those of patients who had antecedent MDS and who were treated in the AML phase (50% ±25%) or those of patients with de novo AML (45% ±3%). Nonsignificant differences in 6-year survival were observed between patients with JMML and MDS.

In recent reports, 5-year event-free survival (EFS) rates in patients with Down syndrome and MDS and/or AML were in excess of 80%. These rates were largely because of reductions in treatment-related deaths from 30-40% in the early 1990s to around 10% in recent Berlin-Frankfurt-Münster (BFM), Nordic Society of Paediatric Haematology and Oncology (NOPHO), and Medical Research Council studies.