Pediatric Myelodysplastic Syndrome

Updated: Jun 03, 2022
  • Author: Meena Kadapakkam, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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Myelodysplastic syndrome (MDS) in childhood is a diverse group of clonal bone marrow disorders characterized by peripheral cytopenia, dysplastic changes in the bone marrow, and ineffective hematopoiesis. MDS disorders have been referred to as “preleukemias” because of their tendency to transform into acute myeloid leukemia (AML). Because of this risk, they are most commonly treated with bone marrow transplantation.

MDS is rare in childhood, with an incidence of 1-4 cases per 1 million children affected. The disease is more common in adults, especially elderly people, and the course varies, ranging from an acute, rapidly fatal illness to a chronic, indolent disease. MDS in children is a distinct entity from that seen in adults. Childhood MDS is more commonly associated with inherited bone marrow failure syndromes and other genetic disorders.  

Diagnosis of MDS is made based upon evaluation of blood and bone marrow, cytogenetic abnormalities, and blast percentage. MDS is considered transformed to AML once the bone marrow blast percentage rises above 20-30%. Diagnostic criteria for MDS include two of the following four criteria:

  • Sustained unexplained cytopenia
  • Bilineage morphological myelodysplasia (10% of at least one myeloid cell line with confirmed dysplasia)
  • Acquired clonal cytogenetic abnormality
  • Increased blasts (>5%)

Childhood MDS rarely presents with anemia alone; often, neutropenia or thrombocytopenia accompanies anemia. [1]

Childhood MDS is categorized based on the 2008 WHO Classification of Childhood Myelodysplastic Syndromes, as described below.

MDSs are characterized as follows:

  • Refractory cytopenia of childhood (RCC): Blood blasts less than 2%, bone marrow blasts less than 5%
  • Refractory anemia with excessive blasts (RAEB): Blood blasts greater than 2%, bone marrow blasts 5-19%
  • Refractory anemia with excess blasts in transformation (RAEB-T): Bone marrow blasts 20-29%, or acute myelogenous leukemia with MDS-related changes (peripheral blood or blood blast >20%)

Myelodysplastic/myeloproliferative disease is characterized as follows:

  • Juvenile myelomonocytic leukemia (JMML)

Down syndrome disease is characterized as follows:

  • Transient abnormal myelopoiesis
  • Myeloid leukemia of Down syndrome

Classification of adult MDS is based upon the French-American-British (FAB) classification of MDS (1982) and consists of five categories: (1) refractory anemia, (2) refractory anemia with ring sideroblasts (RARS), (3) RAEB, (4) RAEB-T, and (5) and myelomonocytic leukemia. RARS is exceedingly rare in childhood, leading to its omission from the childhood WHO classification. Other cytogenetic differences between adult and childhood MDS include very low occurrence of 5q- aberration in childhood MDS and increased occurrence of monosomy 7 in childhood MDS (30% vs 10%). Driver mutations have also been noted to be distinct between adult and childhood MDS (see Pathophysiology). [2]

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.

For pediatric patients with refractory cytopenia, certain cytogenetic abnormalities, or malignant transformation, 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 of myeloid stem cells. 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. [2]

Monosomy 7 occurs in approximately 30% of primary childhood MDS cases and in about 50% of therapy-related MDS cases. [3]

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 (Revlimid). Although 5q- is occasionally reported in children, the typical 5q- syndrome has not been reported.

In a 2013 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. [4] Monosomy 7/deletion 7q was the most frequent clonal abnormality (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 refractory cytopenis (27.2%). The median overall survival 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.

A 2017 publication on the genomic landscape of pediatric MDS showed that the genomic landscape is distinct from adult MDS. [2] Mutations in the Ras/MAPK pathway are more common in pediatric MDS (45%). SAMD9/SAMD9L mutations were detected in 17% of primary MDS samples and represented a new MDS predisposing mutation. Mutations in RNA splicing genes and epigenetic pathways are commonly seen in adult MDS, but are rare (< 2%) in childhood. Mutations in transcription factors such as GATA2, RUNX1, ETV6, SRP72, and CEBPA have been shown to lead to familial MDS/AML. GATA2 mutations are found in 7% of childhood MDS cases and are associated with a higher risk of malignant transformation. Similarly, patients with monosomy 7 also have a higher risk of developing MDS/AML.



Myelodysplastic syndrome (MDS) may be primary or secondary. Children with primary MDS may have an underlying genetic defect that predisposes them to develop MDS at a young age. Approximately 30-50% of children with MDS have an underlying congenital anomaly or syndrome associated with chromosomal abnormalities. Monosomy 7 is the most common of these chromosomal abnormalities, occurring in 30% of childhood MDS cases.

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. [5]

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). [6]  Antecedent MDS is common in those who develop AML in this population, affecting as many as 70% of children with ML-DS. [7]

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. [8]

Fanconi anemia (4-7%) increases the risk of MDS and AML [9] ; 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%. [10]  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. [11]

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. [12]  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. [13]

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. [14]



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). [15] Other studies confirmed that a preleukemic phase precedes AML in about 12-20% of children with AML. [16] 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. [17]

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. [18] 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). [19] 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. [20]

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. [7] 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.

The Center of International Blood and Marrow Transplant Research showed an 8-year disease-free survival rate of 40–65% for RCC and 28-48% for RAEB/RAEB-T. In another study, the European Working Group of Myelodysplastic Syndromes in Childhood reported outcomes for children with advanced MDS, with a 5-year overall survival of 63%. Outcome rates are worse for patients with treatment-related MDS, ranging from 10-35%. [21]