Haematologica:诱发白血病的综合征是儿童遗传性血细胞减少症的主要原因

2022-04-09 从医路漫漫 MedSci原创

白血病诱因综合征的临床表现各不相同,可能包括孤立性血小板减少症、中性粒细胞减少症、贫血或全血细胞减少症,伴有或不伴有骨髓衰竭。

背景:长期血细胞减少是一种非特异性体征,具有广泛的鉴别诊断,包括获得性和遗传性疾病。在遗传性疾病中,白血病诱因最近成为一种重要的临床实体,对患者及其家人的随访和管理计划具有直接影响。白血病诱因综合征的临床表现各不相同,可能包括孤立性血小板减少症、中性粒细胞减少症、贫血或全血细胞减少症,伴有或不伴有骨髓衰竭。在白血病出现之前诊断这些综合征对于适当的治疗和治愈是至关重要的。

经典遗传性骨髓衰竭综合征(IBMFS)被公认为骨髓恶性肿瘤的诱因。越来越多的基因中具有致病变异的非经典IBMFS已被大量描述。 IBMFS在造血系统外先天性异常、BMF的发病年龄以及发生骨髓增生异常综合征(MDS)和急性髓系白血病(AML)的风险和年龄方面存在差异。儿童难治性血细胞减少症(RCC)是儿童MDS最常见的形式。与成人MDS相比,儿童MDS更常与遗传易感性相关。GATA 2和SAMD9L的遗传改变已成为遗传性儿童MDS的最常见原因。与MDS和白血病相关的家族性血小板障碍于1999年首次被描述,并在遗传性血小板减少症(IT)和AML家族中鉴定出有害的杂合RUNX1变异。后来, 描述了导致血小板减少症和MDS/AML易感性的其他基因,例如ETV6和ANKRD26.11 RUNX1和ETV6变异体也易患淋巴细胞恶性肿瘤。具有MDS易感性的个体中的这种表现可能包括孤立的轻度至中度血小板减少症,以及正常的血小板大小和形态; 因此与经典信息技术重叠。

对易患白血病的遗传综合征的准确诊断具有重要的治疗意义,包括对患者的强化随访;这可能需要每年进行一次骨髓检查。诊断对于确定治疗方案也至关重要,包括在发生急性白血病之前决定造血干细胞移植(HSCT ),以及选择合适的移植条件。此外,准确的分子诊断对于识别可能存在骨髓转化风险的无症状家庭成员、为受影响的患者和家庭成员提供遗传咨询以及选择未受影响的相关供体进行移植是至关重要的。

当单个基因是特定疾病的主要原因时,基因检查可以从桑格测序开始。然而,由于导致血细胞减少综合征的非特异性临床和实验室表现,下一代测序(NGS)技术所提供的无偏见诊断通常是必不可少的。事实上,几项研究已经证明了NGS技术在改善诊断方面的优势,并报告了13-54%的遗传诊断率。然而,在患者群体(仅IBMFS、仅MDS、仅IT或所有这些情况)、年龄(儿童、成人或两者)、测序方法(NGS小组或全外显子组测序(WES))、检测到的变异类型(种系变异或体细胞和种系变异)和报告的序列变异类型(仅致病性和可能致病性(P/LP))或未知意义的变异(VOUS))方面存在明显差异。因此,比较这些研究的结果具有挑战性。

目的:williamhill asia 旨在确定导致儿童持续血细胞减少症的遗传原因的类型和患病率。

方法:该研究包括患有持续性血细胞减少症、骨髓增生异常综合征、再生障碍性贫血或疑似遗传性骨髓衰竭综合征的儿童,他们在2016-2019年期间被以色列所有儿科血液中心转诊进行遗传评估。对于变异体检测,williamhill asia 使用常见突变基因的Sanger测序和定制的靶向下一代测序板,覆盖226个已知在遗传性血细胞减少症中突变的基因;少数人随后接受了全外显子组测序。

结果:总共有189名持续血细胞减少的儿童接受了基因评估。在59名患者(31.2%)中发现了致病性和可能的致病性变异,包括47名白血病易感综合征患者。后者中的大多数(32,68.1%)具有遗传性骨髓衰竭综合征,9例(19.1%)具有遗传性血小板减少症诱发白血病的倾向,各有3例(6.4%)具有骨髓增生异常综合征或先天性中性粒细胞减少症的倾向。12名患者患有未知白血病诱因的血细胞减少症,包括9名遗传性血小板减少症患儿和3名先天性中性粒细胞减少症患儿。

表 诊断遗传性骨髓衰竭综合征的患者的临床特征(通过Sanger测序法诊断)

表2 诊断为遗传性骨髓衰竭综合征的患者的临床特征(由NGS小组诊断)

表3 骨髓增生异常综合征患者的临床特征

表4 孤立性血小板减少症患者的临床特征

结论:在189名持续血细胞减少的儿童中,几乎三分之一有潜在的遗传疾病;其中79.7%具有白血病的种系易感性。对血细胞减少症患儿的准确诊断应指导随访和管理计划,并可能对疾病结果产生积极影响。

原文出处:

Gilad O,  Dgany O,  Noy-Lotan S,et al.Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children.Haematologica 2022 Mar 17

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    2022-06-23 changfy
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    2022-04-09 yangchou

    好文章,谢谢分享。

    0

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    2022-04-08 fengyi812
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    2022-04-08 zhouqu_8

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