Pediatric MDS

Pediatric myelodysplastic syndrome (MDS) is a rare disorder with an annual incidence of only 2-4 per million children. It comprises a heterogeneous group of clonal stem cell disorders characterized by peripheral blood cytopenias, and ineffective and dysplastic hematopoiesis. MDS can be classified as primary de novo MDS and secondary MDS following congenital or acquired bone marrow failure (BMF) syndromes, radiation therapy, or cytotoxic therapies for both malignant and non-malignant conditions.


The hallmark of MDS is dysplasia that can be observed in the bone marrow and peripheral blood of affected patients.

In 2008, the World Health Organization (WHO) classification of neoplastic diseases of the hematopoietic and lymphoid tissue revised the MDS classification system and acknowledged that pediatric MDS has some distinct differences from adult MDS. Therefore, the WHO added a separate category for childhood MDS. The following disease entities are described:

  • Refractory cytopenia of childhood (RCC)
  • Refractory anemia with excess blasts (RAEB)
  • RAEB in transformation (RAEB-T)

The specific subtype of childhood MDS is mostly defined based on the number of blasts observed in the peripheral blood and bone marrow. While RAEB is defined by 2-19% of blast in the peripheral blood and 5-19% of blast in the bone marrow, RAEB-T shows 20-29% of blasts in the blood or bone marrow. In these cases, children are often diagnosed with Acute Myeloid Leukemia (AML) where the marrow demonstrates myelodysplastic changes and often shows cytogentic changes associated with MDS.

In 2004, the European Working Group on childhood MDS (EWOG-MDS) published their findings on prospective studies of pediatric MDS and showed that about 54% of all childhood MDS are classified as Refractory Cytopenia (RC), whereas RAEB and RAEB-T only contribute 26% and 20% respectively. RC is diagnosed in all age groups and affects boys and girls with equal frequency.

MDS associated with Down syndrome is now considered a completely separate disease entity. In addition, the pediatric overlap syndromes between MDS and myeloproliferative disorders (MPD), in particular Juvenile Myelomonocytic Leukemia (JMML), are now also considered distinct disease entities and are no longer grouped together with MDS.

As of 2008, the World Health Organization (WHO) classification of neoplastic diseases of the hematopoietic and lymphoid tissue, incorporating both morphology and genetic changes, describes the following six subtypes of adult MDS:

Classification of MDS in adults according to the WHO classification of neoplastic diseases of the hematopoietic and lymphoid tissue (2008).

Many of the morphologic, immunophenotypic and genetic features observed in adults are similar to those found in pediatric MDS patients, but there are some significant differences reported.

For example, ringed sideroblasts are rarely seen in children, the importance of multilineage dysplasia is unknown in children, and the clinically distinctive 5q-syndrome has not been described in pediatric patients.

In contrast with adults, children often present with a hypocellular marrow as opposed to a hypercellular marrow. Monosomy 7 appears to be a distinctive entity in the pediatric group and differs from the 7q phenotype observed in adults. For example, children with monosomy 7 tend to present with hypocellular bone marrows often accompanied by marrow fibrosis, which is usually not seen in adults. Furthermore, the clinical presentation varies from the adult counterpart as well.

Anemia, which is often the only presenting sign in the adult leading to refractory anemia (RA), is uncommon in children, who usually present with neutropenia and thrombocytopenia. Therefore, the term “refractory cytopenia” (RC) was felt to be more appropriate and a pediatric modification of the WHO classification for MDS was developed and revised in 2008.

The most common clinical symptoms are usually malaise, bleeding or infection and occur secondary to cytopenia. The majority of pediatric patients have thrombocytopenia (about 75 percent), while anemia and neutropenia occur less frequently (in 50 percent and 25 percent of patients respectively). Macrocytosis is present in most patients. Reactive lymphadenopathy because of a local infection can also be observed. Hepatosplenomegaly is infrequent and usually not seen with Refractory Cytopenia (RC).

The hallmark of MDS is dysplasia, which and can be observed in the peripheral blood and bone marrow of patients with MDS. Therefore, the diagnostic work up of patients with suspected MDS includes a careful evaluation of the peripheral blood and a bone marrow aspirate and biopsy. The peripheral blood smear of a patient with MDS will often show anisopoikilocytosis and macrocytosis of the red cells. Platelets may display anisocytosis including occasional giant platelets. The neutrophils often display pseudo-Pelget-Huet nuclei and hypogranularity of the cytoplasm.

Both a bone marrow aspirate and biopsy are mandatory to make an accurate diagnosis of MDS. The aspirate allows for assessment of the cytologic detail to determine the degree of dysplastic features in each cell line. The bone marrow biopsy is critical in evaluating cellularity, bone marrow architecture, clustering of immature erythroid forms with increased mitosis, and other associated features such as marrow fibrosis. Assessment of the cellularity is particularly important since about half of the cases present with a hypocellular marrow, which can make the differential diagnosis in particular to aplastic anemia (AA) challenging.

In addition, inherited bone marrow failure (BMF) disorders such as Fanconi anemia, dykeratosis congenita, Schwachman-Diamond syndrome and others can show overlapping features with pediatric MDS, particular with RC. Therefore, an accurate bone marrow diagnosis requires an experienced hematopathologist with particular expertise in pediatric hematopathlogy. In addition, inherited bone marrow failure disorders also need to be excluded by medical history, physical examination, and laboratory and molecular studies.

Another disease to be considered in the differential diagnosis is paroxysmal noctural hemoglobinuria (PNH). While the full clinical picture of PNH with hemolysis and thrombosis is rare in childhood, PNH clones have been observed in children with RC.

Lastly, a variety of non-hematologic conditions such as viral infections, nutritional deficiencies (vitamin M12, folate and vitamin E), metabolic disorders, rheumatologic conditions and others can give rise to dysplastic features and need to be carefully evaluated and excluded.

To date, hematopoietic stem cell transplantation (HSCT) is the only curative therapy for pediatric patients with MDS and is the treatment of choice for almost all patients. In rare circumstances, careful observation might be an acceptable alternative in a small subgroup of patients, who have mild cytopenias, no transfusion requirements or infections and do not have a complex cytogentic abnormality or monosomy 7. There is some suggestion in the literature that immunosuppressive therapy might be helpful in some of these patients. However, larger systematic clinical trials are needed to evaluate this further.

Supportive care, including transfusions and broad-spectrum antibiotics in the setting of fever and neutropenia, is essential to prevent and treat the complications of the disease.

Karyotype is the most important predictive factor for progression to advanced MDS. Patients with monosomy 7 have a significantly higher probability of progression than patients with other chromosomal abnormalities or a normal karyotype. Other important positive prognostic factors are the presence of primary versus secondary MDS, the availability of a suitable bone marrow donor and the overall health of the patient.