Progress in the congenital dyserythropoietic anemias: Juicy but high‐hanging fruits?

In this issue of the American Journal of Hematology, Russo et al. [1] describe a large number of novel variants in SEC23B found in unrelated patients with congenital dyserythropoietic anemia (CDA) Type 2. They make an important contribution to the molecular diagnosis and to our understanding of the possible genotype–phenotype correlation in this condition. These findings add to our comprehension of the most prevalent type of CDA and are the fruit of many years’ expert collection of patient samples via the International CDA-2 Registry in Naples, Italy (led by Achille Iolascon) and European collaborations. Because of the rarity of this disorder, a brief introduction and review of the recent progress in this field seems warranted. The model of combining advances in biochemistry, genetics, and molecular cell biology with clinical investigation recently led to the Lasker Prize being awarded to Sir David J. Weatherall [2]. This strategy has been widely applied in erythropoiesis research and clinical hematology and has clearly impacted patient care. Nowadays, it is safely possible to replace red blood cells and their progenitors; thanks to the knowledge generated in the fields of transfusion medicine and hematopoietic stem cell transplantation. Furthermore, targeted therapies have become available (i.e., eculizumab for paroxysmal nocturnal hemoglobinuria [3]) and even gene therapy has been proven a successful tool (in thalassemia [4]). Although the progress in red cell biology and its clinical applications has been impressive, it has not been universal. In fact, although molecular understanding of sickle cell disease started in the 1940s [5], and putative genes and proteins were investigated since the 1950s, only recently has research on inherited conditions of erythropoiesis started to shed some light on the pathogenesis of congenital dyserythropoietic anemias. This delay is largely due to the nature of the disease (reviewed in detail in Ref. 6), which can be summarized as follows. From a clinical standpoint, the Congenital Dyserythropoietic Anemias (CDAs) were first recognized as separate entities by Crookston et al. [7], and subsequently formally described by Heimpel and Wendt in 1968 [8]. They constitute a heterogeneous group of rare inborn disorders marked by morphological abnormalities of the erythroblast, which lead to ineffective erythropoiesis by maturation block. They are distinct from other inherited bone marrow failure syndromes, as the non-erythroid hematopoietic lineages remain unaffected, and they neither seem to be associated with cytogenetic abnormalities nor a tendency to develop malignancy [6]. In their landmark paper, Heimpel and Wendt defined three major CDA subtypes (CDA-1, CDA-2, and CDA-3). Today, this classification remains valid, since the additional subgroups and variants that have been added in the meantime have rather limited value [6]. CDA-1 can be distinguished by peripheral macrocytosis, internuclear bridging, and ultrastructural defects in the chromatin, of erythroblasts. CDA-2 is marked by peripheral normocytosis, binuclearity of erythroblasts, and abnormal glycosylation of erythrocyte membrane proteins. In fact, CDA-2 was previously known as HEMPAS (Hereditary erythroblastic multinuclearity with positive acidified serum test), and the abnormal glycosylation of red cell membrane protein band3 still serves as a valuable diagnostic tool [9]. Finally, CDA3 is characterized by the multinuclearity of erythroblasts. In CDAs, the bone marrow findings can sometimes be extreme and lead to considerable anemia. However, this is the exception and not the rule. Many patients escape clinical attention as they maintain hemoglobin levels just above the threshold for symptoms or significant impairment in performance. For example, in CDA-2, jaundice from hemolysis can be the only presenting sign, and as little as 10% of patients require transfusions. In fact, generally, CDAs are an exclusion diagnosis. Hence, a long time-lapse from presentation of subtle signs of anemia/hemolysis to suspicion of CDA is common. In addition, many patients with CDA have spent years with an incorrect diagnosis (hemolytic anemia, myelodysplastic syndrome, iron-deficient anemia, thalassemia, erythrocyte membrane abnormality, or hemochromatosis) and have been exposed to potentially harmful iron supplementation, aggressive transfusion, or steroids and cocktails of vitamins. Nonspecific and sometimes confounding clinical features such as mental retardation or congenital malformations (mostly cardiovascular and skeletal), which could be pleiotropic signs of the disease, coincidental findings or by products of consanguinity, add to the diagnostic difficulty. Intuitively, basic research on the CDAs has the potential to identify critical pathways and important players in the process of erythropoiesis. Unfortunately, as with other orphan disorders, the knowledge on CDAs has long derived from an array of case reports or small series [10]. Until the late 1990s, the absence of collaborative registry data and systematic collection of biological samples at diagnosis has prevented the use of more advanced technology to identify the disorders’ molecular pathogenesis. In fact, from an ethical standpoint, research purposes might not entirely justify a bone marrow aspirate in patients with CDA and slightly abnormal hemoglobin levels. This partly explains why the collection of research material has been rather limited. Nevertheless, the first breakthrough was made in 2002, with the description of the causative gene for CDA-1 (CDAN1 on chromosome 15) in an inbred population of Is-