35: The Myelodysplastic Syndrome

Key Points

  • Disease summary:

    • The myelodysplastic syndrome (MDS), a primary bone marrow failure state, represents a heterogeneous hematopoietic stem cell disorder, which results in abnormal cellular maturation and peripheral blood cytopenias. Greater than 50% of patients with MDS have clonal cytogenetic abnormalities, which help to stratify the disease into poor, intermediate, and good prognostic groups. The identification of recurrent mutations in MDS has led to insights into the pathophysiology of the disease.

    • MDS is primarily a disease of older individuals with a median age of diagnosis over 70 years. It is more common in males than females.

    • Although the clinical presentation is nonspecific, symptoms are primarily related to the cytopenias. The most common cytopenia is anemia; therefore, patients often present with fatigue, weakness, dyspnea on exertion, and angina pectoris.

    • MDS is characterized by progressive bone marrow failure, and the most common causes of death in higher-risk patients are infection and bleeding.

    • Approximately 35% to 40% of patients with MDS progress to acute myeloid leukemia (AML), which confers a poor prognosis.

  • Differential diagnosis:

    • Infections (including HIV, Epstein-Barr virus [EBV], cytomegalovirus [CMV], parvovirus B19), nutritional deficiencies (B12 or folate), drug-induced myelosuppression, myeloproliferative neoplasms, and other hematologic malignancies affecting the bone marrow, such as lymphoma, leukemia, multiple myeloma, and paroxysmal nocturnal hemoglobinuria (PNH)

  • Monogenic forms:

    • No single gene cause of MDS is known to exist.

  • Family history:

    • There is no evidence that family members who have first-degree relatives with MDS are at higher risk of developing the disease. While the majority of MDS is sporadic, rare inherited bone marrow failure syndromes may predispose patients to myeloid malignancies, including MDS and AML. These include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan syndrome.

  • Twin studies:

    • No increased risk in monozygotic twins has been reported in the literature.

  • Environmental factors:

    • Although the etiologic agent cannot be identified in the majority of patients, exposure to ionizing radiation, chemicals, chemotherapy agents (particularly alkylating agents and topoisomerase II inhibitors), and other environmental agents can be implicated. Benzene exposure, in particular, has a strong association with the development of MDS and AML. In addition, there may be an increased risk of MDS with the use of permanent hair dyes and cigarette smoking.

  • Genome-wide associations:

    • Genes involved in the regulation of histone function and DNA methylation are recurrently mutated in MDS, suggesting an important link between genetic and epigenetic mechanisms in this disease (Table 35-1). The mechanism by which these mutations contribute to disease pathogenesis and progression is currently under study. Testing for these mutations is not part of routine clinical practice at this time.

  • Pharmacogenomics:

    • When available, testing for gene mutations can help to assess the prognosis of an individual patient’s disease and guide in treatment approaches.

Table 35-1   Genetic Abnormalities in MDS 

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for MDS

Diagnostic evaluation should include

  • Complete blood count with differential and reticulocyte count.

  • Examination of the peripheral blood smear.

  • A bone marrow aspirate and biopsy, including studies for flow cytometry and cytogenetics. The diagnosis of MDS is based primarily on morphologic manifestations of dysplasia and aberrant maturation in the peripheral blood and bone marrow lineages. These include but are not limited to megaloblastoid erythropoiesis, nucleocytoplasmic asynchrony in the myeloid and erythroid precursors, and dysmorphic megakaryocytes.

  • Iron studies, B12 or folate levels, serum erythropoietin level.

  • Thyroid-stimulating hormone (TSH), T3 and T4 to rule out hypothyroidism.

  • Documentation of transfusion history.

Clinical Characteristics

The clinical presentation is variable. Symptoms often correlate with a patient’s cytopenias, with those associated with anemia being the most common. These include fatigue, weakness, dyspnea, angina, and cardiac dysfunction. Fatigue may be disproportionate to the degree of anemia. Patients may also present with signs and symptoms related to neutropenia, including bacterial infections, or thrombocytopenia, including easy bruising, ecchymosis, petechiae, epistaxis, gingival bleeding, or gastrointestinal bleeding. Physical findings are also nonspecific. Organomegaly is infrequently observed. Lymphadenopathy and skin infiltration may occur but are uncommon. The classic laboratory findings include peripheral blood cytopenias, anemia with macrocytosis, and functional abnormalities involving one or more cell lines. In most patients, the bone marrow is hypercellular, and there are dysplastic features in the progenitor cells.

Screening and Counseling


Family members of patients with MDS are not routinely screened. There is no known genetic predisposition to development of the disease.


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Jun 2, 2016 | Posted by in HUMAN BIOLOGY & GENETICS | Comments Off on 35: The Myelodysplastic Syndrome

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