Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders.
Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders.
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DOI：
10.1186/s13023-016-0432-0
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发表时间：
2016-04-26
影响因子：
3.7
通讯作者：
Favier R
中科院分区：
文献类型：
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作者：
Latger-Cannard V;Philippe C;Bouquet A;Baccini V;Alessi MC;Ankri A;Bauters A;Bayart S;Cornillet-Lefebvre P;Daliphard S;Mozziconacci MJ;Renneville A;Ballerini P;Leverger G;Sobol H;Jonveaux P;Preudhomme C;Nurden P;Lecompte T;Favier R
截至目前，报告的FPD/AML（OMIM 601309）患者不到50例，可能存在低估。本研究的目的是描述的自然史，血液学特征和基因型-表型相关性的这个实体，以便，首先，更好地和更早地筛选它，白血病发生之前，其次，优化适当的监测和治疗，特别是当家族性干细胞移植被认为是。我们调查了41名RUNX 1变异携带者，他们来自9个不相关的FPD/AML法国家庭和2名综合征患者，这些患者在2005年至2015年期间在法国罕见血小板疾病网络中注册。5个错义突变，1个无义突变，3个移码突变和2个大的缺失，涉及几个基因，包括RUNX 1被证明。家族性白血病史提示FPD/AML在7个家系，而常染色体显性遗传模式的终身血小板减少症的临床表现的两个。其他综合征的特点是两个大的零星缺失。出血倾向为轻度，血小板减少症为中度（>50 x109/L），血小板体积正常。在10例患者中发现了与δ颗粒释放缺陷一致的功能性血小板缺陷，无论RUNX 1改变的类型如何。当突变的RUNX 1等位基因可能引起显性负效应时（19/34），血液系统恶性肿瘤的发生率高于功能缺失等位基因（3/9）。血小板计数正常并不排除FPD/AML的诊断，因为在三名突变受试者中发现血小板计数正常，这一特征在异基因造血干细胞移植的情况下对寻找相关供体有直接影响。提示δ颗粒释放缺陷的血小板功能障碍可能对PPD/AML的诊断有价值，特别是当临床表现为常染色体显性血小板减少症且血小板大小正常且无家族性恶性肿瘤时。基因型-表型相关性可能有助于遗传咨询和适当的最佳治疗管理。
Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered. We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015. Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x109/L), with normal platelet volume. A functional platelet defect consistent with a δ-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation. Platelet dysfunction suggestive of defective δ-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management.