LAUSR

Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML) (OMIM #601399) is an autosomal dominant disorder characterized by quantitative and qualitative platelet defects and an increased risk of AML. FPD/AML shares phenotypic similarities with Jacobsen syndrome; platelet counts show mild to moderate reductions but are variable between individuals with the same genetic etiology of disease, and a reduction in dense granule secretion is often observed as a secondary qualitative abnormality [1]. The major clinical complication of this disorder, however, is not the bleeding tendency experienced by some patients, but the propensity for a proportion of patients to develop myelodysplasia or leukemia [2]. The molecular genetic cause of FPD/AML was first elucidated by linkage studies which mapped the underlying genetic defect to a region on human chromosome 21q [3]. Contained within this region is the gene encoding the master regulator of hematopoiesis, Runt-related transcription factor 1 (RUNX1). Variants have been identified throughout the coding region of RUNX1 but those clustered within the region encoding the Runt homology domain (RHD), which mediates DNA binding and heterodimerization with core binding factor beta (CBF-β) [4], and are most likely to be detrimental [5]. RUNX1 mutation can result in haploinsufficiency of RUNX1, or reduced RUNX1 function as a result of a dominant-negative effect, that disrupts the formation of complexes with CBF-β, thereby disturbing the regulation of genes necessary for hematopoietic stem cell (HSC) maintenance, maturation, and differentiation [6,7]. Over 40 RUNX1 mutations associated with FPD/AML have been reported in patients to date (Table I, Figure 1). However, the prevalence of RUNX1 defects is believed to be underestimated and as sequencing technologies improve an increasing number of patients are being reported [8,9]. The mutations reported are predominantly missense and phenotypically platelets from patients present with dense granule secretion defects and persistence of MYH10 expression which can be used as a biomarker of genetic variation [1,10]. It has been suggested that the risk of malignancy is reduced in those cases having RUNX1 defects that cause haploinsufficiency when compared to those patients with dominant-negative RUNX1 defects. Due to the associated predisposition to myeloid malignancy with some variants in RUNX1, it is critical to establish diagnosis as early as possible to aid in patient management and guidance.