Overlap of Syndromes Associated with Myelodysplasia and Leukemia

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are heterogeneous hematopoietic stem cell clonal disorders characterized by defective hematopoiesis and premature mortality in many patients. The majority of MDS and AML cases are sporadic but there are also rare cases where two or more affected individuals are found within the same family - “familial myelodysplasia and leukemia.” These familial cases represent a high-risk group of patients who require a unique management approach; they also provide an excellent opportunity for the identification of genetic changes that drive the disease. Over the last 15 years several genetic subtypes of familial MDS/AML have been identified and characterized. This includes families with constitutional heterozygous mutations in RUNX1, CEBPA, TERC, TERT, GATA2, and SRP72. The spectrum of mutations associated with familial MDS/AML implicates different biological pathways in the development of the disease, including transcription regulation (RUNX1, CEBPA and GATA2), telomere maintenance (TERC and TERT) and signal recognition (SRP72). It is notable that somatic mutations in RUNX1, CEBPA, and GATA2 are found in patients with sporadic MDS and AML. These discoveries demonstrate that familial MDS/AML is very heterogeneous and that the genetic characterization of the uncharacterized families will offer further insight into the primary pathophysiology of MDS/AML. Analysis of the MDS/AML families demonstrates considerable variability in the spectrum of features seen in these six genetic categories. There is heterogeneity even within each genetic subtype. The diverse range of different mutations in the disease gene in part explains the phenotypic difference between families. However, there are also differences amongst members of the same family (for example, in RUNX1 families some individuals only have a platelet abnormality and yet others have AML), suggesting that additional factors contribute to the phenotype. The mechanisms that underlie the development of progression to leukemia remain to be characterized. In families with CEBPA mutations there appears to be a near complete penetrance to developing AML. This is in contrast to the very diverse phenotypes associated with constitutional TERC and TERT mutations, ranging from dyskeratosis congenita (DC) to aplastic anemia, MDS, and AML. A similar situation has been observed with constitutional heterozygous GATA2 mutations. Here again affected individuals can display a wide range of phenotypes including MDS, AML, Emberger syndrome (primary lymphoedema with MDS/AML), MonoMAC syndrome (monocytopenia and Mycobacterium infection; the phenotype may also include Natural Killer cell and B-cell lymphopenia). It is notable that Natural Killer and B-cell deficiencies are also observed in DC. This highlights the overlap of features between the different genetic subtypes in addition to MDS/AML. Recognition of familial MDS/AML is important in guiding management. This includes appropriate genetic counselling of family members as well as careful selection of family donors regarding hematopoietic stem cell transplantation (HSCT). It also enables other specific modifications in the management. For example, patients with significant lymphopenia (be at secondary to TERC or GATA2 mutation) benefit from appropriate antimicrobial prophylaxis. Equally, patients with TERC and TERT mutations require low intensity Fludarabine-based HSCT (due to the abnormal/delayed healing of tissues as a consequence of the telomere deficiency) whereas patients with RUNX1 mutations appear to tolerate standard conditioning regimens. Further understanding of the biology and the associated phenotypic diversity will help to improve management of this group of patients. It is also likely to have relevance for sporadic MDS and AML.