Myelodysplastic neoplasms with ring sideroblasts without SF3B1 mutations in adults: enrichment of germline variants in congenital sideroblastic anemia genes

Abstract

Ring sideroblasts (RS) are erythroid precursors with pathological, iron-laden mitochondria, exposed by Prussian blue staining as a perinuclear ring of blue granules [1]. RS can be seen in non-clonal (toxic or metabolic) and clonal disorders (congenital sideroblastic anemias and acquired myeloid neoplasms) [2]. Myelodysplastic neoplasms (MDS) account for the majority of RS cases, and their presence has been a defining feature of MDS in the World Health Organization (WHO) classification since 2002 [3]. In 2011, a high proportion of MDS-RS patients were found to be somatically mutated in SF3B1 [4]. However, approximately 20% of cases lack the SF3B1 mutation (SF3B1^wt MDS-RS) without clear evidence regarding the molecular driver event [5,6,7].

On the other hand, congenital forms of sideroblastic anemia (CSA) are uncommon, with variable inheritance patterns and causative genes involved in heme biosynthesis [2]. They are diagnosed usually within the first two decades of life. Nevertheless, a “second hit”, such as acquired skewed X-chromosome inactivation, can lead to diagnoses in mid to late adulthood in women carrying mutations in the erythroid-specific isoform of aminolevulinic acid synthase 2 (ALAS2), causing the most common CSA, the X-linked sideroblastic anemia (XLSA). These cases encompass one-quarter of clinically affected XLSA probands and have led to what have been considered SF3B1^wt MDS-RS misdiagnoses [8,9,10].