Pediatric Myelodysplastic Syndrome Workup

Updated: Sep 05, 2018
  • Author: Prasad Mathew, MBBS, DCH, FAAP; Chief Editor: Jennifer Reikes Willert, MD  more...
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Workup

Approach Considerations

Diagnostic studies for myelodysplastic syndrome center on a complete blood count (CBC) with differential, peripheral blood smears, bone marrow aspiration and biopsy. On the CBC, patients often have anemia with high mean cellular volume and RBC distribution width. Neutropenia and thrombocytopenia may be found.

In juvenile myelomonocytic leukemia (JMML), marked monocytosis may be present. Other diagnostic criteria for JMML include myeloid precursors in blood smears, clonal abnormality, granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors, and hemoglobin F levels above the reference range for age.

Other studies include the following:

  • Hemoglobin electrophoresis

  • Studies for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) to exclude marrow suppression due to a viral etiology

  • Folate and vitamin B-12 studies to evaluate for possible defects or deficiencies

  • Tissue typing of the patient and the family in anticipation of hematopoietic stem cell rescue

  • Testing for hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF)

Chromosomal analysis

Look for constitutional abnormalities if the patient has manifestations of Down syndrome (trisomy 21). Trisomy 21 with mosaicism occurs in 2-3% of cases in which 2 populations of cell types are present: a normal cell line with 46 chromosomes and a second cell line with trisomy 21. These children may appear phenotypically normal.

Order chromosomal fragility studies, including diepoxybutane (DEB) and mitomycin C (MCC) tests for Fanconi anemia.

Children with complex chromosomal aberrations combined with a low platelet count and/or elevated hemoglobin F levels have a notably worsened outcome.

The presence of monosomy 7 should prompt an evaluation of family members.

Bone marrow studies

Performing a bone marrow aspiration and biopsy is essential in establishing diagnosis and classification. In MDS, bone marrow findings reveal evidence of morphologic myelodysplasia in at least 2 different myeloid cell lines or dysplasia that exceeds 10% in one single cell line, with evidence of a clonal cytogenetic abnormality in hematopoietic cells. Dysplastic cells of various stages of differentiation with hypercellular findings may be evident.

Gene expression profile (GEP) analysis of bone marrow specimens has proved to be a powerful tool for the identification of gene signatures associated with distinct leukemia subtypes and has helped to stratify patients into different risk classes, as well as to identify deregulated genes involved in leukemia development. In 32 pediatric bone marrow specimens from MDS patients, GEP analysis was able to identify at diagnosis, patients with high risk to progress into AML. All MDS patients who evolved into AML showed AML-like signatures, while none of the MDS patients with a non AML-like signature showed evolution to AML. [22]

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Histologic Findings

On peripheral smears, dysplastic shapes and cells with odd-appearing nuclear and cytoplasmic ratios (eg, anisocytosis, macrocytosis, microcytosis, poikilocytosis) are apparent. Although macrocytosis can indicate megaloblastic anemia (vitamin B-12 or folate deficiency), it is often observed in most bone marrow failure syndromes, including MDS. RBCs are often dimorphic (both hypochromic and normochromic). The number of reticulocytes is reduced in relation to the degree of anemia.

Depending on the class, variable granulocytic abnormalities are present. Pseudo–Pelger-Huët anomalies (eg, hyposegmented mature neutrophils, hypogranulation of cytoplasm) are characteristic of dysgranulopoiesis observed with MDS.

As additional immature elements are observed in periphery, these elements often appear bizarre with abnormal nucleus-to-cytoplasm ratios and are often oddly shaped. In addition, the number of eosinophils and basophils may increase in patients with adult-type MDS. On smears, platelets markedly vary in size.

Myelodysplasia most commonly presents with a hypercellular marrow. In refractory anemia (RA), the ratio of erythroid to myeloid cells is abnormal, and the marrow appears similar to that of patients with megaloblastic anemia due to folate or vitamin B-12 deficiency. Erythroblasts are often large, with clumped chromatin and a large nucleolus.

In refractory anemia with excess blasts (RAEB), the myeloid component of marrow increases. Small myeloblasts and promyelocytes predominate in the marrow. These cells are often dysmorphic with abnormal nucleus-to-cytoplasm ratios.

Abnormal megakaryocytes may appear small (micromegakaryocytes) or large. They may have a variable number of nuclei in the same marrow sample.

The minimal diagnostic criteria for MDS includes at least 2 of the following:

  • Sustained, unexplained cytopenia (neutropenia, thrombocytopenia, or anemia)

  • At least bilineage morphologic dysplasia

  • Acquired clonal cytogenetic abnormality in hematopoietic cells

In the prospective study of the European Working Group on MDS in Childhood, more than half of the patients with refractory cytopenia had a normal karyotype, followed in frequency by monosomy 7, trisomy 8, and other abnormalities. [23] Loss of the long arm of chromosome 5 (5q-), the most frequent chromosomal aberration in adults with RA, is rare in childhood.

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