Genetic predisposition syndromes: when should they be considered in the work-up of MDS?

Abstract

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute myeloid leukemia (AML). While sporadic MDS is primarily a disease of the elderly, MDS in children and young and middle-aged adults is frequently associated with underlying genetic predisposition syndromes. In addition to the classic hereditary bone marrow failure syndromes (BMFS) such as Fanconi Anemia and Dyskeratosis Congenita, in recent years there has been an increased awareness of non-syndromic familial MDS/AML predisposition syndromes such as those caused by mutations in GATA2, RUNX1, CEBPA, and SRP72 genes. Here, we will discuss the importance of recognizing an underlying genetic predisposition syndrome a patient with MDS, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common BMFS and familial MDS/AML syndromes which may be encountered in adult patients with MDS.

Keywords: CEBPA; Congenital Amegakaryocytic Thrombocytopenia; Diamond-Blackfan Anemia; Dyskeratosis Congenita; Emberger Syndrome; FPD/AML; Fanconi Anemia; GATA2; MDS; MonoMac; RUNX1; SRP72; Severe Congenital Neutropenia; Shwachman-Diamond Syndrome; bone marrow failure syndromes; familial MDS; familial leukemia; genetic predisposition; myelodysplastic syndromes.

Figure 1. Primary and Secondary Myelodysplastic Syndromes

Figure 2. A Schematic Diagram of Relative Incidence of Primary MDS and MDS Secondary to Genetic Predisposition Syndromes

Primary MDS (dashed line, gray bar), the most common type of MDS diagnosed in the elderly, is thought to be multifactorial and to arise due to the cumulative age-related genetic damage. In contrast, in children and younger adults, MDS is strongly associated with cytotoxic exposures (not shown), and genetic predisposition syndromes (solid line, black bar), including the classic hereditary BMFS and the nonsyndromic familial MDS/AML syndromes.

Figure 3. Proposed Algorithm for Evaluation of Genetic Predisposition Syndromes in a Patient with MDS

Because of a risk of life-threatening toxicities with inappropriate therapy, all pediatric and younger adult patients presenting with MDS should be systematically evaluated for an underlying predisposition syndrome. We recommend that Fanconi Anemia, Dyskeratosis Congenita and GATA2 haploinsufficiency should be ruled out in all MDS patients under the age of 50 years who do not have a history of cytotoxic chemotherapy. Clinical history suggestive of an underlying genetic predisposition syndrome includes congenital anomalies and associated clinical conditions, suggestive family history, and classic cytogenetic and molecular findings. Genetic syndromes that are more likely to be encountered as a new diagnosis in an adult patient with MDS including Fanconi Anemia, Dyskeratosis Congenita and familial MDS/AML syndromes—GATA2 haploinsufficiency, RUNX1-associated FAP/AML, familial AML with mutated CEBPA, and familial aplastic anemia/MDS with SRP72 mutation. Although isolated cases of adult presentations of Congenital Amegakaryocytic Thrombocytopenia (CAMT), Diamond-Blackfan Anemia (DBA), Severe Congenital Neutropenia (SCN) and Shwachman-Diamond Syndrome (SDS) have been reported, a new presentation of these syndromes in adult patients is highly unusual.