Epidemiology

Because MDS is a disease of aging, its incidence sharply increases in patients older than 60 years of age and the median age is 70 years.
Most subtypes of MDS appear to be more common in men than women, with the most recent SEER data suggesting respective age-adjusted incidences of 6.7 versus 3.9 per 100,000. The one exception to this is MDS with isolated del(5q), which most series show to be more common in women.
The two exposures most consistently associated with subsequent development of MDS are ionizing radiation and cytotoxic chemotherapy, and therapy-related MDS is frequently characterized by TP53 mutations, multiple large-scale chromosomal abnormalities including complex karyotypes (most commonly defined as ≥3 clonal chromosomal anomalies), and frequent transformation to treatment-refractory AML.

Clinical Presentation

Typically show persistent (>6 months) unexplained cytopenias.
The vast majority of MDS patients present with anemia.
- PB shows normocytic, normochromic, or macrocytic anemia with macroovalocytes. Microcytosis can be present in rare cases of MDS (eg, cases associated with congenital or acquired alpha thalassemia).
- It is uncommon to diagnose patients with MDS because of critically symptomatic anemia, bleeding, or neutropenic fever. That said, symptoms of anemia, thrombocytopenia, fever, other constitutional symptoms, or unexplained infectious processes can lead to a diagnosis of MDS.
Patients with MDS can have gastrointestinal blood loss that may present with normal to mildly increased red cell volumes.

The cause of MDS is not known but there are strong data that suggest that MDS can be the result of toxic exposure of bone marrow stem cells.
The most frequent events are genes involved in the control of RNA splicing and epigenetic modifications.
- Mutant alternative splicing may lead to abnormal hematopoietic function and dysplastic features, particularly in the cases of SF3B1 and SRSF2 gene mutations.
- Epigenetic modifications such as DNMT3A, TET2, ASXL1, and EZH2 are critical regulators of gene expression in different cell types and tissues. Many epigenetic regulators modulating methylation patterns of critical differentiation and cell cycle regulating genes have been identified in the last decades and harbor functionally relevant mutations in myelodysplasia.

The recurrently mutated genes in myelodysplastic syndrome can be organized into a limited number of biologic categories.

A number of genetic syndromes (associated with bone marrow failure) are associated with the development of MDS.
- Diamond–Blackfan anemia, Shwachman–Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome.
- Ribosomopathies characterized by altered ribosome biogenesis and function.
- Haploinsufficiency in ribosomal genes, such as RPS14, is also implicated in the pathogenesis of the 5q-syndrome thus providing further linkage between these conditions.
- Patients with Fanconi anemia are also at increased risk of developing MDS.
- Mutations in RUNX1 have been described in MDS of patients with Fanconi anemia.
A number of rare familial syndromes can predispose to late development of a myeloid malignancy.
- Although only 1.5% of patients with a myeloid neoplasm harbor DDX41 mutations, up to 50% of these are germ line, the most common being a heterozygous frameshift mutation D140Gfs*2.