Distinctive phenotypes in two children with novel germlineRUNX1mutations-one with myeloid malignancy and increased fetal hemoglobin
Distinctive phenotypes in two children with novel germlineRUNX1mutations-one with myeloid malignancy and increased fetal hemoglobin
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DOI：
10.1080/08880018.2020.1814463
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发表时间：
2020-09-28
影响因子：
1.7
通讯作者：
Ravindranath, Yaddanapudi
中科院分区：
文献类型：
--
作者：
Bagla, Shruti;Regling, Katherine A.;Ravindranath, Yaddanapudi
RUNX1相关性家族性血小板紊乱(FPD)是一种罕见的常染色体显性遗传性血液病，以血小板减少和/或血小板功能改变为特征。急性髓系白血病、骨髓增生性肿瘤或骨髓增生异常综合征常伴有其他基因的继发性体细胞变异，因此发生髓系恶性肿瘤的倾向增加。到目前为止，全世界已报告23例FPD-MM儿科病例。在这里，我们提出了两个新的家族具有新的RUNX1致病变异，其中儿童是先证者。第一个家系是一个女儿/母亲双胞胎，共享RUNX1基因的杂合移码突变(c.501delT p.Ser167Argfs*9)。女儿，13岁，表现为类似幼年粒单核细胞白血病的特征-严重贫血、血小板减少、原始细胞高白细胞计数、单核细胞增多、有核红细胞增多，并在CUX1、PHF6和SH2B3基因上有高等位基因负荷的体细胞突变。她还增加了胎儿血红蛋白和LIN28B的表达。这位母亲有很长的再生障碍性贫血病史，她有不同的体细胞突变-CUX1的一个非编码突变，但PHF6或SH2B3没有。她的胎儿血红蛋白和LIN28B表达正常。在第二个家族中，先证者现在4岁，患有单独的血小板减少症，在3个月大的时候进行了持续的新生儿大血小板减少症的调查。分子检测发现了RUNX1中包含外显子5的杂合性基因内缺失。众所周知，他的父亲多年来一直在增加瘀伤，但无法进行检测。这两个病例说明了继发性突变在RUNX1-FPD向MM的发展和进展中的重要性。
RUNX1associated familial platelet disorder (FPD) is a rare autosomal dominant hematologic disorder characterized by thrombocytopenia and/or altered platelet function. There is an increased propensity to develop myeloid malignancy (MM) - acute myeloid leukemia, myeloproliferative neoplasms or myelodysplastic syndrome often in association with secondary somatic variants in other genes. To date, 23 FPD-MM pediatric cases have been reported worldwide. Here, we present two new kindreds with novelRUNX1pathogenic variants in which children are probands. The first family is a daughter/mother diad, sharing a heterozygous frameshift variant inRUNX1gene (c.501delT p.Ser167Argfs*9). The daughter, age 13 years, presented with features resembling juvenile myelomonocytic leukemia - severe anemia, thrombocytopenia, high white cell count with blast cells, monocytosis, increased nucleated red cells and had somatic mutations with high allele burden inCUX1, PHF6, andSH2B3genes. She also had increased fetal hemoglobin and increasedLIN28Bexpression. The mother, who had a long history of hypoplastic anemia, had different somatic mutations- a non-coding mutation inCUX1but none inPHF6orSH2B3. Her fetal hemoglobin andLIN28Bexpression were normal. In the second kindred, the proband, now 4 years old with thrombocytopenia alone, was investigated at 3 months of age for persistent neonatal thrombocytopenia with large platelets. Molecular testing identified a heterozygous intragenic deletion inRUNX1encompassing exon 5. His father is known to have increased bruising for several years but is unavailable for testing. These two cases illustrate the significance of secondary mutations in the development and progression of RUNX1-FPD to MM.