Myelodysplastic syndrome in childhood: a retrospective study of 189 patients in Japan


We report a retrospective analysis of children with myelodysplastic syndrome (MDS) diagnosed between 1990 and 1997 in Japan. In total, 189 patients were enrolled: 122 cases of primary MDS (26 RA, 18 RAEB, 25 RAEBt, 53 CMML/JMML), 24 cases with constitutional predisposition to MDS, and 43 cases of therapy-related MDS (t-MDS). The frequency of pediatric MDS was estimated to be 7.7% of all leukemias. Cytogenetic abnormalities were observed in 41% of primary MDS and 90% of t-MDS cases. The 4-year survival rate, estimated by Kaplan–Meier analysis, for primary RA was 78.9%, while other types of MDS and JMML had rates lower than 40%, and t-MDS showed an even more unfavorable prognosis. In primary MDS, the survival rate of patients with cytogenetic abnormalities was significantly lower. Among prognostic variables by IPSS, only the cytogenetic pattern was useful for predicting outcome in childhood MDS. There was no apparent advantage to chemotherapy for RA, and the survival rate in patients with primary RA, JMML, or t-MDS receiving stem cell transplantation was significantly higher. More precise designs of our diagnostic and classification systems, as well as therapeutic trials in large-scale prospective studies, are necessary for further improvements in MDS outcome.


Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis, morphologic abnormalities in the bone marrow, and the probability of evolution to acute myeloblastic leukemia (AML). MDS occurs predominantly in the elderly. Although several series of MDS in childhood have been reported,1,2,3,4,5,6,7,8 epidemiological data are very limited,1,4,8 in part because pediatric MDS is relatively rare, and also because of difficulties in diagnosis and classification. The classification of MDS is based on the morphology of peripheral blood and bone marrow proposed by the French–American–British (FAB) group in 1982.9 However, the FAB criteria developed for adult MDS may need to be modified for childhood MDS because pediatric MDS is more complicated. For example, 10% of pediatric MDS have inherited predispositions such as Down's syndrome, Fanconi's anemia, severe congenital neutropenia, neurofibromatosis, or Noonan's syndrome.4,5,6 Furthermore, the terms ‘JCML’ and ‘infantile monosomy 7 syndrome’ have been used for early childhood preleukemic syndrome. The patients in these groups show clinical similarities with MDS, but do not necessarily satisfy the FAB criteria. The International Juvenile Myelomonocytic Leukemia Working Group has recently proposed the term ‘JMML’,10,11 which has been widely used in some recent publications.

The optimal treatment for childhood MDS has not been defined, but options now include cytokine therapy, immunosuppressive therapy, cytotoxic chemotherapy, and stem cell transplantation (SCT). In order to define the optimal therapy for childhood MDS, an improved classification system with strong prognostic capabilities is needed. This requires data from a large number of cases that have been well categorized to define the features, outcome, and utility of each trial treatment. Therefore, we have reviewed 189 patients with pediatric MDS collected through a nation-wide surveillance program; we retrospectively analyzed their clinical and laboratory features, associated genetic conditions, treatment, and the outcome.

Materials and methods

Data on children with MDS were retrospectively collected through pediatric hematologists/oncologists who are members of the Japan Pediatric Hematology Society at 234 institutions. Each report consisted of a list of questions on the clinical and laboratory findings on diagnosis, therapies, and clinical outcome of each patient. Sixty-two institutions reported 189 patients less than 16 years of age diagnosed with MDS between April 1990 and March 1997. The diagnosis and classification of MDS were made according to the FAB classification system in each institution; as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEBt), or CMML. JMML according to the diagnostic criteria of Niemeyre et al11 was incorporated as an additional category. Patients with previously diagnosed genetic disorders were classified as having a constitutional predisposition. MDS arising after administration of anti-neoplastic agents for malignant disease or immunosuppressive therapy for aplastic anemia was categorized as therapy-related MDS (tMDS).

Bone marrow morphology was examined at each institution. For evaluating prognosis, all patients with RA, RAEB, and RAEBt were divided into subgroups defined by blasts less than 5%, 5 to 10%, 10 to 20%, and >20%. Cytopenias were defined as a hemoglobin level less than 10 g/dl, an absolute neutrophil count less than 1500/μl, or a platelet count less than 100 000/μl. Cytogenetic analysis of marrow cells was performed in each institute, and the data were available from 178 cases. The individual cytogenetic abnormalities were classified as normal karyotype, chromosome 7 abnormalities, trisomy 8, trisomy 21, and all others. Patients were also divided into karyotypic subgroups according to the International Scoring System for prognostic evaluation:12 good = normal, del(5q) only, del(20q) only, or −Y only; intermediate = +8, single miscellaneous, or double abnormalities; poor = complex (3 anomalies) or chromosome 7 abnormalities.

Survival curves were prepared by the Kaplan–Meier method, and overall survival was defined as the time between diagnosis of MDS and death. A log-rank test was used to detect significant differences between groups. All analyses were performed using computer software JMP (SAS Institute, Cary, NC, USA).


One hundred and eighty-nine MDS patients were identified. Using the number of leukemias registered from the same institutes during the same period, the frequency of childhood MDS in Japan was estimated as 7.7% of all leukemias.

Patient profiles

The distribution of patients by FAB subgroup is shown in Table 1. The number of patients with primary MDS without constitutional predisposition was 122, comprising 26 RA, 18 RAEB, 25 RAEBt, and 53 CMML/JMML. There were 24 MDS patients with constitutional predisposition as shown in Table 2, and only one patient with RARS, who had Pearson's syndrome, was reported in this review. The most common associated diagnosis was Down's syndrome (two RA and 11 RAEB/RAEBt), and five cases of Fanconi's anemia were found in RA and RAEB. There were two cases of Pearson's syndrome (RA, RARS), two neurofibromatosis (JMML), one Diamond–Blackfan syndrome (RA), and one Noonan's syndrome (JMML). Therapy-related MDS developed in 43 patients, 24 after chemotherapy for malignant diseases with or without irradiation, and 19 after other treatment such as immunosuppressive therapy for aplastic anemia (Table 3).

Table 1 Distribution of patients by FAB subclassification
Table 2 Childhood MDS with constitutional predisposition
Table 3 Distribution of primary diseases in therapy-related MDS

Presenting features

The clinical characteristics in primary MDS according to morphologic subclassication are summarized in Table 4. Ages at diagnosis ranged from 2 months to 15 years with a median of 3.4 years, and children with JMML were the youngest. Males dominated in CMML/JMML, most pronounced in JMML. Skin rash, hepatosplenomegaly, and elevation in HbF value were commonly associated with JMML. Hepatomegaly and/or splenomegaly were also detected in some cases of RA and RAEB. Progression toward AML during the course of MDS was found in 23% of RA cases (to RAEB or AML) and 43% of RAEB/RAEBt cases (to AML).

Table 4 Clinical features of primary MDS

Table 5 lists the clinical features of tMDS. The age at diagnosis of tMDS was higher, distributed between 2 and 15 years with a median of 10.1 years. Down's syndrome was not observed in tMDS. Five patients with Fanconi's anemia presented with RA or RAEB after immunosuppressive therapies although they were not included in tMDS. They were listed in MDS with constitutional predisposition (Table 2).

Table 5 Clinical features of therapy-related MDS


Chromosomal data of bone marrow samples were available from 179 cases (95%). Of these, 68 (59%) were normal in 115 primary MDS cases, while 90% of tMDS cases had clonal abnormalities (Table 6). The most common finding was chromosome 7 abnormalities, detected in 20% of primary MDS (20 cases of monosomy 7; two cases of 7q−; and one case of 7p+) and 52% of tMDS. Trisomy 8 was shown in 5% of the primary MDS and 9% of tMDS cases. Additional chromosome 21 was presented in eight cases, including two patients with the constitutional abnormality. In 13% of primary MDS and 71% of therapy-related MDS cases, other types of cytogenetic abnormalities were found.

Table 6 Cytogenetics in childhood MDS

Outcome and treatment

Outcome data were available for 186 patients (98%); two cases of Pearson's syndrome were eliminated from these analyses because these patients died from progression of their original disease. Figure 1a shows Kaplan–Meier survival curves of each FAB subgroup with primary MDS. Estimated 4-year survivals of RA, RAEB, RAEBt, and CMML/JMML were 78.9%, 17.7%, 34.1%, and 35.7%, respectively; there was a significant difference between RA and the other groups. Patients with constitutional predisposition, especially with Down's syndrome, showed an overall better prognosis as shown in Figure 1b. The 4-year survival rates in tMDS were generally lower than in primary MDS: RA 47.8%, RAEB 26.7%, RAEBt 0%, and CMML 33.3% (Figure 1c).

Figure 1

Probability of survival in children with MDS related to FAB classification subgroups (Kaplan–Meier curves). (a) Primary MDS; (b) MDS with constitutional predisposition; (c) therapy-related MDS.

To identify risk factors in evaluating prognosis, we analyzed the correlation between survival rates of primary MDS and laboratory data, including the proportion of marrow blasts, the number of cytopenias, and cytogenetics. Based on the marrow blast percentage, patients with RA, RAEB, and RAEBt were separated into four subgroups, and their survival rates were compared (Figure 2a). Although patients with blasts >20% showed a poorer prognosis, the number of marrow blasts did not necessarily correlate with clinical outcome. Figure 2b shows survival curves related to the number of cytopenias (one, two, or three cytopenias), and there was no significant difference between these subgroups.

Figure 2

Probability of survival in children with primary MDS related to marrow blast percentage, and the number of cytopenias. (a) Patients with primary RA, RAEB, and RAEBt were divided into subgroups according to the percentage of marrow blasts as described in the Methods. Marrow blast data were lacking in five of 26 RA patients and three of 43 RAEB/RAEBt patients, and these cases were eliminated in this analysis. Hence, the number of RA became 21. There were eight RAEB/RAEBt patients who had BM blasts less than 5% and were diagnosed due to an elevated blast count in PB. (b) Patients were divided into subgroups according to 1 cytopenia, 2 cytopenia, and 3 cytopenia.

The influence of cytogenetic abnormalities on the prognosis of primary MDS was evaluated. The survival rate of patients with abnormalities was significantly lower than for those having normal karyotypes (Figure 3a). It was noted that five out of six RA patients who developed RAEB or AML had clonal abnormalities. When patients were classified into prognostic subgroups of International Scoring System, the survival rates of ‘good’, ‘intermediate’ and ‘poor’ subgroups were 83.8%, 48.9% and 6.5%, respectively, as shown in Figure 3b. The results suggest that this cytogenetic classification is useful for evaluating prognosis. In tMDS (RA+RAEB+RAEBt), the survival rate of patients with blasts >10% was significantly poorer than for those showing lesser numbers (Figure 4a). There was no difference in survival for tMDS patients with or without chromosomal abnormalities (Figure 4b).

Figure 3

Probability of survival in children with primary MDS related to cytogenetic abnormalities. (a) Patients with primary RA, RAEB, and RAEBt were divided into subgroups with and without cytogenetic abnormalities. (b) Patients were divided into cytogenetic subgroups according to the IPSS categorization.

Figure 4

Probability of survival in children with therapy-related MDS related to the percentage of marrow blasts and cytogenetic abnormalities. (a) Patients with therapy-related MDS were divided into subgroups according to the percentage of marrow blasts as described in the Methods. (b) Patients with therapy-related MDS were divided into subgroups with and without cytogenetic abnormalities.

Treatment was chosen at each institute by the attending physician associated with the diagnosis. Patients with RA were classified as (1) those who received no treatment other than blood transfusion or had therapies other than anti-neoplastic agents; (2) patients treated with anti-neoplastic agents; and (3) those who received stem cell transplantation (SCT). As shown in Figure 5a, the survival rates of patients in groups 1 and 3 were extremely high, but the chemotherapy group had the worst prognosis. The results for RAEB and RAEBt were presented together because no difference was observed in the prognosis between these subgroups. When the effect of SCT on the outcome of primary RAEB and RAEBt was evaluated, the survival curve for SCT was not significantly better than that of non-SCT patients (Figure 5b), whereas SCT did improve the survival of CMML/JMML (Figure 5c) and tMDS patients (Figure 6).

Figure 5

Survival rates in primary MDS related to treatment. Patients were divided into subgroups as described in the Results. (a) Primary RA; (b) Primary RAEB and RAEBt; (c) CMML/JMML.

Figure 6

Survival rates in patients with therapy-related MDS related to treatment. Patients were divided into subgroups as in Figure 5.


In this first nation-wide survey of childhood MDS in Japan, 204 cases were reported. Of these, 15 cases were excluded because nine did not fulfill the diagnostic criteria for MDS, and six patients with tMDS were older than 17 years at diagnosis of MDS. As a result, 189 patients were retrospectively analyzed. Although this study was not population-based, the large number of cases provides useful epidemiological data, and the frequency of pediatric MDS in Japan is comparable to that in Denmark and Canada.4,8 There was no remarkable difference in the distribution of subtypes by FAB classification when compared with reports from Denmark, the US, and the UK.4,6,7 RARS, which account for 25% of adult MDS, is rare in children, and the fact that most childhood RARS cases were observed in Pearson's syndrome suggests an association with congenital mutations of mitochondrial DNA.5

Predisposing conditions were found in 24 MDS patients, and the most common disorder was Down's syndrome. Although it is well known that children with these congenital disorders have an excess risk of developing clonal diseases, such as leukemia,13,14,15 the pathogenetic mechanisms in these patients are unknown. A recent study on NF-1 mutations in bone marrow cells supports a role for this gene in protection from JMML.14,16,17 Somatic mutations in the G-CSF receptor were observed in some cases of severe congenital neutropenia, which can be associated with progression to MDS.18,19 Hence, further investigation of MDS patients with a constitutional predisposition may help to discover genes involved in the pathogenesis of MDS. Interestingly, MDS patients with constitutional predisposition have unique clinical features; MDS in Down's syndrome showed a good prognosis in our and other studies.6,13 Certainly, these patients should be categorized as a distinct group.

CMML by the FAB system does not always correspond to the clinical features of chronic myeloproliferative disorders of childhood. Since the diagnosis and subclassification of MDS were made at different institutions, both diagnosis (CMML and JMML) were used in the survey. Of the 11 cases diagnosed as primary CMML in the reports, five cases fulfilled diagnostic criteria for JMML, three did not, and the laboratory data required for diagnosis were lacking in three cases. Hence, CMML and JMML were presented as a single subgroup in this study. A prospective evaluation is required to categorize these entities using comparative data sets.

MDS occurred in 24 patients secondary to chemotherapy, with or without irradiation, for malignant disease, and in 19 cases after treatment for non-malignant hematopoietic disorders, such as aplastic anemia. Thus, tMDS constituted 23% of all pediatric MDS. There has been no other report of a large series of tMDS in children, so the importance of this group should be noted. The prognosis of severe aplastic anemia (SAA) has improved with use of immunosuppressive agents (high-dose corticosteroids, antilymphocyte globulin, and cyclosporin A) in combination with better supportive therapies. Long-term follow-up studies of SAA have demonstrated a high incidence of MDS, PNH, and leukemia as late complications,20,21,22,23 again raising the old and unresolved question of the relationship between AA and clonal disease.24 Based on a nation-wide registry in Japan, the estimated incidence of MDS secondary to AA reached as high as 15–20% after 4 years.23 Luna-Fineman et al25 suggested two hypotheses on the association between SAA and MDS: (1) AA and MDS are two manifestations of the same fundamental injury to stem cells; (2) MDS develops in patients with AA either as a secondary effect of treatment or from continued exposure to the same agent which induced the original marrow failure. Clonal disorders frequently occur in association with congenital AA, and clonal abnormalities were found in 4% of patients with acquired AA at diagnosis.26 Our data on the development of MDS in aplastic anemia patients best support the first hypothesis, although agents modulating a developmental process towards MDS cannot be excluded.

Although 59% of primary MDS cases showed no chromosomal abnormality, cytogenetic study was important for making the diagnosis as well as for predicting prognosis. As reported previously, monosomy 7 was the most common abnormality in this study. Monosomy 7 or del(7q) are associated with childhood de novo MDS, and AML, as well as tMDS and AML in all age groups. Monosomy 7 was common in younger children with JMML or other constitutional disorders, such as Fanconi's anemia, congenital neutropenia, neurofibromatosis, all of which increase the risk of developing a malignant myeloid disorder.25 Epidemiological and cytogenetic investigations suggest that chromosome 7 deletions contribute to developing MDS/AML through loss of function of a tumor-suppressor gene.25,27,28 In many patients with monosomy 7, the presence of RAS mutations was reported,19,29 and the coexistence of these abnormalities in children with MDS may cooperate in leukemogenesis.

The outcome of childhood MDS is poor, except in RA or MDS with Down's syndrome. Choices for treatment include cytokines, immunosuppressive therapy, chemotherapy, and SCT. An improved classification system is required for making optimal treatment choices for childhood MDS. For that purpose, the FAB criteria were appropriate for childhood MDS with some modification, in part, because childhood MDS is more heterogeneous than in adults. Recent classification methods have been proposed for prognostic use in adult MDS that include clinical and laboratory variables, cytogenetic findings and morphologic FAB classification. In this study, we examined whether the IPSS system would prove useful for predicting outcome in pediatric MDS. Only the cytogenetic pattern was prognostic for childhood MDS; the IPSS was of limited value because variables such as marrow blast percentage and cytopenia did not correlate with prognosis. The survival rate of 17 cases with monosomy 7 alone was 0%, which did not coincide with a recent report by Hasle et al30 that MDS with monosomy 7 alone had a superior survival than those with other cytogenetic abnormalities. Passmore et al7 have proposed a new scoring system for pediatric MDS in which the HbF value and cytogenetics are incorporated into the modified FAB. This may be applicable to CMML/JMML but may not be helpful in other subgroups since most of the cases with high HbF value were JMML.

There does not appear to be a survival effect of toxic chemotherapy in childhood MDS,6,7 in fact, patients who only received blood transfusion, or therapies other than anti-neoplastic agents showed better survival rates in RA. Among those who survived, nine cases were disease-free, and blood transfusion was required for only two patients. All RA patients who received SCT survived. A prospective study is needed to evaluate the efficacy of immunosuppressive or cytokine therapy in RA patients, and SCT should be considered for poor prognosis RA patients, such as those with chromosome 7 abnormalities. The survival rate in patients with CMML/JMML or tMDS who received SCT was significantly higher than in those treated with chemotherapy. The European Working Group on MDS in Children has similarly reported a 58% 5-year event-free survival (EFS) in MDS patients other than CMML and 38% EFS in CMML after SCT.31,32 However, SCT did not improve the survival of primary RAEB/RAEBt patients in our study. Our transplant data must be evaluated with caution because the patients were not treated with a constant regimen, ie some underwent intensive chemotherapy prior to SCT while others did not, and various types of conditioning regimens were used. To further improve outcome, a uniform treatment protocol for chemotherapy and indications for SCT should be adopted.

In conclusion, the FAB classification for adult MDS is useful for pediatric MDS with some modifications. MDS children with constitutional predispositions should be categorized as a distinct group. CMML and JMML are best categorized as myeloproliferative diseases rather than MDS. Survival of patients with cytogenetic abnormalities was significantly lower in primary MDS. Although treatment was not uniform, there was no apparent advantage of chemotherapy for RA, but SCT did improve survival in primary RA, JMML, and t-MDS patients.

A more precise diagnosis and classification system and large-scale prospective therapeutic trials are necessary for appropriate therapeutic decisions in pediatric MDS. We began a prospective study in Japan in 1999, which includes a central review system for diagnosis and proposals for uniform treatment for each type of MDS. We expect to have useful data for further improving the prognosis of childhood MDS in the near future.


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The authors express sincere gratitude to the members of Japan Pediatric Hematology Society for their cooperation in this study. We also thank Dr Ichiro Tsukimoto for providing the data of registry on childhood leukemia and aplastic anemia.

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Correspondence to H Sasaki.

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Sasaki, H., Manabe, A., Kojima, S. et al. Myelodysplastic syndrome in childhood: a retrospective study of 189 patients in Japan. Leukemia 15, 1713–1720 (2001).

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  • myelodysplastic syndrome
  • children
  • clinical features
  • predisposing conditions
  • cytogenetics
  • prognosis

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