MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia
MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia
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DOI：
10.1182/bloodadvances.2018016501
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发表时间：
2018-03-27
期刊：
影响因子：
7.5
通讯作者：
Ballmaier, Matthias
中科院分区：
文献类型：
--
作者：
Germeshausen, Manuela;Ancliff, Phil;Ballmaier, Matthias
据报道，Mecom(MDS1和EVI1复合基因)杂合突变是先天性无核细胞血小板减少症和放射状尺骨融合的罕见关联的原因。我们报告了12例由Mecom突变(包括10个新突变)引起的先天性低巨核细胞减少症。这些突变影响了EVI1蛋白的不同功能域。前3例患者的表型谱比最初报道的要广泛得多；我们发现有家族性和散发性病例，临床谱系从孤立的无血液学或轻度血液学损害的放射尺骨合着病到没有明显骨骼异常的严重骨髓衰竭。临床表现包括尺放射骨融合、骨髓衰竭、斜指畸形、心脏和肾脏畸形、B细胞缺陷和老年前期听力损失。在所有受Mecom突变影响的患者中没有发现单一的临床表现。只有在EVI1的C-末端锌指结构域发生突变的患者中，才能观察到放射状尺骨融合和B细胞缺陷。我们建议将这种异质性遗传病称为Mecom相关综合征，并将Mecom测序纳入先天性骨髓衰竭的诊断工作中。
Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of MECOM sequencing in the diagnostic workup of congenital bone marrow failure.