Bloom综合征一家系的临床特征与BLM基因变异分析

Clinical and molecular analysis of two Chinese siblings with Bloom syndrome

目的 分析Bloom综合征患儿的临床特征及基因变异.方法 分析归纳2009年1月至2017年6月期间在上海交通大学医学院附属上海儿童医学中心随访的2例Bloom综合征同胞姐弟的临床特点,2015年提取患儿及其父母亲外周血全基因组DNA,用Illumina测序平台进行高通量测序,检测基因变异位点.结果 患儿为同胞两姐弟,因“身材矮小,身高增长缓慢”就诊,足月顺产,母孕产史无异常,均有喂养困难,营养不良.体格检查：匀称型身材矮小,反应迟钝,有长脸、小下颌、颧骨高的特殊面容.先证者8岁3月龄初次就诊,身高99.7 cm,体质指数12.07 kg/m^2,头围45.5 cm,出生体重1.6 kg,反复呼吸道感染及中耳炎病史.先证者胞弟3岁11月龄初次就诊,身高86.6 cm,体质指数14 kg/m^2,出生体重1.95 kg,16月龄因“头围36 cm”诊断为小头畸形,有反复呼吸道感染及鼻窦炎病史.随访8年,均未发现蝶形红斑样皮疹,均未发现肿瘤的临床征象.基因分析提示先证者及同胞弟弟的BLM基因均携带c.772_773delCT（p.Leu258Glufs＊7）和c.959＋2T＞A复合杂合变异,分别遗传自其父母,搜索文献及数据库无c.959＋2T＞A变异的报道.结论 Bloom综合征主要表现为身材矮小、小头畸形、特殊面容,喂养困难,免疫功能低下,可无蝶形红斑样皮肤改变.BLM基因c.959＋2T＞A为新发现的致病性变异.

Objective To expand the knowledge of the clinical and molecular characteristics of the children with Bloom syndrome.Methods Clinical data of two siblings with classic Bloom syndrome of Shanghai Children＇s Medical Center from January 2009 to June 2017 were obtained and analyzed.The DNA of peripheral blood was collected from two Bloom syndrome siblings and their parents during 2015.The mutations were detected with high-throughput sequencing by Illumina sequencing platform.Results The two siblings （probands） visited our department for short stature and growth retardation,they had full-term normal delivery after normal pregnancy of their mother.Both cases presented with feeding difficulties,malnutrition,microcephaly and mental retardation,repeated infection,symmetrical short stature and special faces.At first,the proband was an 8-year-3-month old girl,her height was 99.7 cm,body mass index （BMI）12.07 kg/m^2,head circumference was 45.5 cm,and birth weight was 1.6 kg.Her younger brother was 3-year-11-month old,his height was 86.6 cm,BMI was 14 kg/m^2,birth weight was 1.95 kg,and the head circumference reached 36 cm at 16 months.No evidence of cancer and characteristic rash was detected at 8-year follow-up.Pathogenic complex heterozygous mutations c.772_773delCT,p.Leu258Glufs＊7 and c.959＋2T〉A in BLM gene were detected in both siblings,which were separately inherited from their unaffected parents.Besides,c.959 ＋ 2T〉A has not been reported previously.Conclusions Children with Bloom syndrome are characterized by short stature,microcephaly,special faces,feeding difficulties,and immunodeficiency.And butterfly erythematous rash may be absent.The c.959＋2T〉A mutation detected in our patients maybe a novel pathogenic mutation.