Diamond-Blackfan贫血(DBA)是以红系发育不全为特征的遗传性骨髓衰竭综合征之一。核糖体蛋白(RP)基因的潜在变异占病例的80%,从而将DBA分类为核糖体病。除了RP基因,非RP基因中极其罕见的变异,包括GATA1,红细胞生成的主要转录因子,近年来有DBA样表型患者的报道。随后,通过研究表明RP单倍体功能不全下游GATA1mRNA翻译受损,确定了GATA-1在DBA病理生理学中的关键作用.这里,我们从荷兰DBA登记处报道了一名患者,其中我们在GATA1中发现了一个新的半合子变体(c.220+2T>C),和一名伊朗患者,先前报道的GATA1起始密码子中有变异(c.2T>C)。尽管临床特征与DBA一致,两名患者的骨髓形态对于DBA均不典型,显示中度红细胞生成活性,伴有红细胞生成异常和巨核细胞生成异常的迹象。这促使我们重新评估以前报道的病例的临床特征,这导致了18例2外显子遗传性GATA-1缺陷患者的综合特征,这在本病例系列中出现。此外,我们重新调查了先前发表的一例的骨髓穿刺液.总之,我们的观察表明,由GATA1缺陷引起的DBA具有独特的表型特征,包括红细胞生成异常和巨核细胞生成异常,因此代表了DBA疾病谱中的一个独特的表型,这可能需要具体的临床管理。
Diamond−Blackfan anemia (DBA) is one of the inherited bone marrow failure syndromes marked by erythroid hypoplasia. Underlying variants in ribosomal protein (RP) genes account for 80% of cases, thereby classifying DBA as a ribosomopathy. In addition to RP genes, extremely rare variants in non-RP genes, including GATA1, the master transcription factor in erythropoiesis, have been reported in recent years in patients with a DBA-like phenotype. Subsequently, a pivotal role for GATA-1 in DBA pathophysiology was established by studies showing the impaired translation of GATA1 mRNA downstream of the RP haploinsufficiency. Here, we report on a patient from the Dutch DBA registry, in which we found a novel hemizygous variant in GATA1 (c.220+2T>C), and an Iranian patient with a previously reported variant in the initiation codon of GATA1 (c.2T>C). Although clinical features were concordant with DBA, the bone marrow morphology in both patients was not typical for DBA, showing moderate erythropoietic activity with signs of
dyserythropoiesis and dysmegakaryopoiesis. This motivated us to re-evaluate the clinical characteristics of previously reported cases, which resulted in the comprehensive characterization of 18 patients with an inherited GATA-1 defect in exon 2 that is presented in this case-series. In addition, we re-investigated the bone marrow aspirate of one of the previously published cases. Altogether, our observations suggest that DBA caused by GATA1 defects is characterized by distinct phenotypic characteristics, including
dyserythropoiesis and dysmegakaryopoiesis, and therefore represents a distinct phenotype within the DBA disease spectrum, which might need specific clinical management.