Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients
Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients
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DOI：
10.3324/haematol.2017.181909
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发表时间：
2018-07-31
期刊：
影响因子：
10.1
通讯作者：
Pasquet, Marlene
中科院分区：
文献类型：
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作者：
Donadieu, Jean;Lamant, Marie;Pasquet, Marlene
杂合子种系GATA2突变强烈倾向于白血病、免疫缺陷和/或淋巴水肿。我们描述了自2011年以来诊断的79例患者（53个家庭），由法国和比利时的所有患者组成，随访2249例患者/年。首次出现临床症状的中位年龄为18.6岁（范围0-61岁）。严重传染病（分枝杆菌、真菌和人乳头瘤病毒）和血液系统恶性肿瘤是最常见的首发表现。到40岁时，仍无症状的概率为8%。53例先证者中，错义突变24例，包括4个复发等位基因，无义或移码突变21例，全基因缺失4例，剪接缺陷2例，复杂突变2例。错义突变患者（34例中有14例）的白血病病例明显多于无义或移码突变患者（28例中有2例）。我们还确定了该疾病的新特征：急性淋巴细胞白血病、少年髓细胞白血病、与JC病毒相关的致命性进行性多灶性白质脑病和免疫/炎症性疾病。修订后的国际预后评分系统（IPSS）评分允许区分稳定疾病和血液学转化。化疗疗效有限，毒性高，并伴有严重的感染并发症。由于我们的队列死亡率很高（40岁时高达35%），造血干细胞移植（HSCT）仍然是避免严重感染和/或血液学并发症的最佳治疗选择。HSCT的时机仍然难以确定，但越早进行，结果越好。
Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.