特殊面容、反复高甘油三酯1年余

患儿,女,1岁9个月,新生儿期即发现高甘油三酯血症,伴逐渐出现的特殊面容和体征：全身皮肤黝黑、皮下脂肪消失,颈部黑棘皮,毛发增多、浓密,面部呈空双颊,四肢肌肉肥大,肝脏肿大,以及中性粒细胞缺乏。单基因病全外显子组测序发现患儿存在已报道的先天性全身脂肪营养不良（CGL）的BSCL2基因突变：c.974（外显子7）_c.975（外显子7）insG纯合突变,其父母均为该位点的杂合子。确诊CGL,但不能明确中性粒细胞缺乏与CGL的关系。予低脂及高碳水化合物饮食控制后甘油三酯可维持正常,体征无明显变化。CGL为罕见的常染色体隐性遗传的系统性疾病,表现为新生儿期出现的全身皮下脂肪消失、四肢肌肉肥大和代谢紊乱：如高甘油三酯、高胰岛素血症、高血糖等,95%的CGL由AGPAT2或BSCL2突变导致。     

BSCL2 基因突变致先天性全身脂肪营养不良症1 例报告并文献复习

目的探讨先天性全身脂肪营养不良症(CGL)的临床及基因特点。方法回顾分析1例BSCL2基因突变致CGL患儿的临床资料,并进行文献复习。结果女性患儿,2岁9个月,临床表现为全身脂肪组织消失,黑棘皮征,肝脾大,轻度智力低下;实验室检查示高三酰甘油血症、高胰岛素血症和心肌病变。提取患儿及父母外周血,对AGPAT2、BSCL2、CAV1和PTRF 4个基因行Sanger测序显示,患儿存在BSCL2基因杂合突变,分别为母源移码突变(c.567-568del GA,p.E 189 Efs X 12)及父源无义突变(c.565 GT,p.E 189 X),均为致病突变。回顾文献,BSCL2基因突变是亚洲CGL最常见的病因,BSCL2突变的CGL患儿常见临床表现为全身脂肪组织消失、黑棘皮征和肝脾大,心肌病变和智力低下发生率分别为40%和30%。结论 BSCL2基因突变引起的CGL主要临床表现为自幼全身脂肪组织消失及代谢紊乱,常伴有心肌病变和智力低下,对疑似患儿应尽早行基因分析确诊。     

AGPAT2 基因变异致先天性全身脂肪营养不良症1 例报告并文献复习

目的分析AGPAT2基因变异致先天性全身脂肪不良症(CGL)的诊断和治疗。方法回顾分析1例AGPAT2基因变异致CGL患儿的临床资料、实验室检查及基因测序结果,并结合国内外文献进行分析总结。结果女性患儿,12岁,多饮多尿伴体质量下降1个月。患儿三角面容,皮下脂肪极少,肌肉发达,腋下黑棘皮症。实验室检查提示糖尿病、高脂血症以及脂肪肝。基因检测提示患儿AGPAT2基因复合杂合变异,c.379GC源自父亲,c.317-10TA源自母亲。根据美国医学遗传学与基因组学学会指南分析,c.379GC变异为疑似致病变异,c.317-10TA变异临床意义未明。患儿经皮下胰岛素注射及口服二甲双胍治疗后血糖控制可。结论该例为国内报道的第2例AGPAT2基因变异致CGL,且为新发现的基因变异。     

多发性线粒体功能障碍综合征6 型1 例报告并文献复习

目的探讨PMPCB基因变异导致多发性线粒体功能障碍综合征6型(MMDS6)的临床表型和基因变异特点。方法回顾分析1例MMDS6患儿的临床资料,并结合文献进行复习。结果患儿,男,5月龄。表现为体质量不增、喂养困难、运动发育倒退、四肢肌张力低,伴高乳酸血症、心力衰竭。心脏彩超示肺动脉高压。全外显子和线粒体基因测序显示PMPCB基因c.524GA纯合核苷酸变异,父母均为杂合子,该纯合变异尚未见文献报道。结论 PMPCB基因c.524GA纯合核苷酸变异是MMDS6的致病变异。二代基因测序有助于基因型诊断。     

POLG 基因变异致线粒体病一家系分析

目的分析POLG基因变异致线粒体病的临床表型及基因变异。方法回顾分析于2019年5月就诊,并经采集外周血DNA进行医学外显子、外显子-内含子交界区靶向二代测序和一代验证,1个确诊为POLG基因变异致线粒体病家系的临床资料。结果先证者,男,10岁,与其同卵双胎哥哥均有相同的体征,深感觉受损、腱反射消失、肌肉可疑萎缩。先证者3个兄姐先后于1岁多夭折。提取患儿及其父母的外周血,先证者及同卵双胎哥哥POLG基因均存在G.2558A(p.R853Q)、c.2890T(p.R964C)复合杂合变异,分别来源于患儿父母亲。结论 POLG基因复合杂合变异线粒体病家系成员有不同的表型;POLG相关疾病,即使同种基因变异,其临床异质性也较大。     

Menkes病二家系遗传学分析

目的分析Menkes病基因变异特征。方法回顾分析2例Menkes病患儿的临床资料以及ATP7A基因检测结果。结果例1患儿为男性,2月龄,ATP7A基因第21外显子存在c.4077dupT的纯合变异。例2患儿为男性,4月龄,ATP7A基因第10外显子存在c.2354delC的纯合变异,2例患儿家系验证父母均为野生型。这2种变异在HGMD数据库中均未报道,根据ACMG指南划分为致病变异。结论对2例患儿家系的遗传学分析丰富了中国人ATP7A基因的变异谱,也为临床医师早期诊断和遗传咨询提供帮助。     

甲状腺球蛋白增高的先天性甲状腺功能减退症1 例报告并文献复习

目的探讨甲状腺球蛋白(TG)增高的先天性甲状腺功能减退症(CH)家系的临床特征及TG基因变异特征。方法回顾分析1个TG增高的CH家系的临床及TG基因检测结果,并复习相关国内外文献。结果先证者,女,45日龄,生后黄疸消褪延迟伴便秘。甲状腺功能检测提示为CH,同时发现TG水平增高。基因检测结果显示患儿TG基因存在c.2149 C>T和c.5401+113 A>G的复合杂合变异;Sanger测序验证c.2149 C>T来源于父亲,c.5401+113 A>G来源于母亲,其哥哥携带c.5401+113A>G杂合变异。患儿哥哥及父母表型正常。c.2149C>T及c.5401+113A>G变异尚未见文献报道,根据美国遗传变异分类标准与指南分别为疑似致病变异及临床意义未明变异。结论确诊TG基因变异引起CH患者TG水平增高,并发现2个新的TG基因变异位点。     

儿童重型遗传性血管性血友病2 例临床分析

目的分析儿童重型遗传性血管性血友病(VWD)的临床特征及基因变异。方法回顾分析2例VWD患儿的临床资料,采用免疫比浊法检测血管性血友病因子(VWF)活性。采集患者及其父母的外周血,通过高通量基因测序,分析F7、F8、F9、F11、VWF基因全部外显子编码区和剪接区的变异情况。采用PCR结合Sanger测序的方法,分析VWF基因位点的变异情况。结果 2例男性患儿,分别为1岁和2岁,临床表现以皮肤黏膜出血为主,血管性血友病因子活性(VWF:Act)分别为5.0%及2.8%。例1血浆因子Ⅷ凝血活性(FⅧ:C)1.9%、血浆因子ⅩⅡ凝血活性(FⅩⅡ:C)43.2%;例2 FⅧ:C 23%。例1 VWF基因检测到c.813CG(p.Tyr271Ter)纯合变异;父母均为杂合变异。例2 VWF基因检测到c.55GA(p.Gly19 Arg)和c.1200 CA(Asp400Glu)杂合变异,分别来自其父亲、母亲。c.813CG(p.Tyr271Ter)变异与3型VWD相关;c.55GA(p.Gly19 Arg)变异率极低,与1型VWD相关;c.1200 CA(Asp400Glu)变异未见报道,SIFT、Polyphen和MutationTaster均预测其有致病性。2例患儿经止血及替代治疗后,病情均有所好转。结论经基因检测确诊重型1型和3型VWD各1例,并发现VWF基因c.1200 CA(Asp400Glu)新发变异。     

Bardet-Biedl 综合征1 例报告并文献复习

目的提高对Bardet-Biedl综合征临床表现和致病基因特点的认识。方法回顾性分析1例确诊为BardetBiedl综合征患儿临床、实验室资料及基因检测结果,并复习相关文献。结果患儿,男,13岁,临床表现有多趾畸形、视网膜色素变性、性腺发育不全、肥胖、智力发育迟缓、肾囊性发育不全、慢性肾功能不全、糖耐量异常、尿道下裂、脂肪肝、贫血、矮小症。高通量测序分析发现患儿BBS2基因存在纯合突变(c.1148_1149dup TC,p.His384Serfs*34),其父母该位点均为杂合子。结论借助于高通量测序技术,有助于得到明确的Bardet-Biedl综合征分子诊断。该患儿BBS2基因的变异未在HGMD、Ex AC及Clin Var数据库中收录,为国内外首次报道。     

新生儿CHARGE综合征5例临床及基因变异分析

目的 分析5例诊断为新生儿CHARGE综合征患儿的临床特征及基因变异特点,明确死亡患儿的遗传学病因。方法 收集5例患儿的临床资料,应用高通量测序技术对5例疑诊CHARGE综合征患儿进行检测,利用Sanger测序技术对可疑位点和核心家系成员进行验证。结果 5例患儿均存在结构畸形合并喂养困难(均排除鼻后孔闭锁),其中2例出现歪嘴哭。3例患儿合并鼻腔狭窄或者上气道塌陷综合征,因治疗效果差,不能撤离呼吸机最终死亡;1例患儿因家属放弃治疗死于家中;1例目前随访中。家系1为CHD 7基因c. 478 del(Y 160 Tfs*51)移码变异,家系2为CHD 7基因c. 5428 C>T(P.R 1810*)无义变异,家系3为CHD 7基因c. 6292 C>T(P.R 2098*)无义变异,家系4为CHD 7基因c.4317delA(p.Q1440S fs*3)移码变异,家系5为CHD7基因c.469C>T(P.R157*)无义变异。5个家系的父母均未携带相应的变异,均为新发变异。其中家系4的CHD7基因c.4317delA为未报道的新变异。结论 CHD7基因变异可能为5例患儿...     

CFHR家族基因变异致儿童非典型溶血尿毒综合征1例报告并文献复习

目的 分析CFHR家族基因变异导致的儿童非典型溶血尿毒综合征(aHUS)的临床特征.方法 回顾分析1例aHUS患儿的临床资料,以及采用二代测序技术进行的相关基因变异分析结果.结果 女性患儿,8岁,呼吸道感染后出现面色苍黄、肉眼血尿.实验室检查示溶血性贫血、血小板减少、急性肾衰竭、低补体C3血症、补体C4无异常;肾脏病理...     

Allgrove syndrome with features of familial dysautonomia: a novel mutation in the AAAS gene

Allgrove syndrome (or triple-A syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency (glucocorticoid in the majority of cases) and autonomic/neurological abnormalities. This disease is now known to be caused by mutation in the AAAS gene located on chromosome 12q13. Diagnosis should be readily available when the full-blown features are there, but it becomes less apparent when presentation is atypical or in the evolving process. We present a brother and sister (12 and 19 y old, respectively) born to consanguineous parents of Palestinian origin with Allgrove syndrome. The index patient was erroneously diagnosed to be a case of familial dysautonomia before the diagnosis of adrenal insufficiency was made at the age of 7.5 y, while his elder sister had only alacrima from birth and developed achalasia at the age of 15 y. She started to develop early evidence of adrenal disease at the age of 19 y. Both of them had neuroautonomic dysfunction. The diagnosis of Allgrove syndrome was confirmed in these two patients by studying the gene mutation in the family. The sequencing of the AAAS gene in the two patients identified a novel homozygous mutation within intron 5 (IVS5+1G-->A). Both parents as well as all three other children were heterozygous for the same mutation. CONCLUSION: These two cases illustrate the heterogenous nature and the intrafamilial phenotypic variability of Allgrove syndrome.     

KCNT2基因变异致遗传性癫痫伴热性惊厥附加症一家系分析并文献复习

目的:总结 KCNT2基因突变所致遗传性癫痫伴热性惊厥附加症(GEFS ＋)一家系的临床特点及治疗情况,并进行文献复习。 方法:收集2019年5月在广州市妇女儿童医疗中心神经内科就诊的GEFS ＋患儿及其家族成员的临床资料;提取患儿及其父母、哥哥、外祖父母的外周血DNA,采...     

66日龄婴儿发现多发皮下结节1月余

患儿,男,66?d,因发现皮下结节46?d,腹胀10?d入院。患儿主要临床表现为全身脂肪组织减少,皮下结节,胰岛素抵抗型糖尿病,高三酰甘油血症,肝脂肪变性,最终确诊为先天性全身性脂肪代谢障碍1型。经改用含中链脂肪酸比例高的配方奶及先后予胰岛素注射、二甲双胍口服后病情好转。基因检测显示AGPAT2基因存在c.646A > T纯合突变,其父母均为该突变的携带者。该病例为国内报道的起病年龄最小、且以多发皮下结节为首发症状的先天性全身性脂肪代谢障碍1型患儿。     

Langerhans cell histiocytosis in non‐twin siblings

Langerhans cell histiocytosis (LCH), which has unknown pathogenesis, can manifest as many kinds of signs and symptoms at any age. Although its genetic background has not been exactly identified, the familial clustering of this disease has been described in some reports. It is very uncommon, however, in siblings who are not monozygotic or dizygotic twins. Reported herein is a case of LCH in non‐twin siblings (younger sister and elder brother) who were diagnosed at 3.3 and 14.5 years of age, respectively, and successfully treated with chemotherapy, with BRAF V600E mutation status, and a brief review of the literature.     

丙酮酸脱氢酶缺乏症PDHA1基因的一个新突变及其致病性鉴定

目的研究丙酮酸脱氢酶缺乏症发病分子遗传学机制,从基因水平诊断丙酮酸脱氢酶缺乏症,为遗传咨询和产前基因诊断提供依据。方法对临床表现及实验室检查符合丙酮酸脱氢酶缺乏症的1例患儿采用PCR法对PDHA1基因的11个外显子及外显子交界区进行扩增,并通过对扩增产物直接测序检测突变。采用生物信息学方法对新突变进行氨基酸保守型分析,预测蛋白二、三级结构,鉴定其致病性。结果先症者PDHA1基因第11外显子出现小片段重复突变,即c.1111_1158dup48bp,为新发突变。50例正常对照直接测序均未检测到c.1111_1158dup48bp突变。蛋白质二级、三级结构预测结果显示:新突变c.1111_1158dup48bp引起Ser371_Phe386的16个氨基酸重复,导致蛋白质二、三级结构发生明显变化,而正常对照无此变化。结论 PDHA1基因c.1111_1158dup48bp重复突变不是多态性变异,可能是一种新的致病性突变,导致丙酮酸脱氢酶缺乏症的发病。     

1例常染色体隐性痉挛性截瘫55型的临床特点和C12orf65基因突变分析

该文报道1例常染色体隐性痉挛性截瘫55型患儿的临床特征及C12orf65基因突变特点。患儿女,8岁,5岁起病,以视神经萎缩为主要临床表现,伴有蹲起缓慢和轻度鸭形步态。提取患儿及其父母和哥哥外周血DNA标本,对患儿进行全外显子组和线粒体基因组测序,并进行Sanger测序验证。结果显示患儿C12orf65基因存在c.394C > T和c.447_449delGGAinsGT的复合杂合突变,前者来自父亲,为已知致病突变;后者来自母亲,是一个未见文献报道的新突变。该研究扩展了C12orf65基因突变谱,为患儿病因诊断及该家系的遗传咨询提供了分子依据。     

Danon�����·ʺ����ļ���LAMP2������ͻ�����

??Abstracts?? Objectives To investigate the clinical features and LAMP2 gene mutation a case with hypertrophic cardiomyopathy due to Danon disease.Methods A boy (proband) of hypertrophic cardiomyopathy due to Danon disease was hospitalized in the Department of Pediatrics of Peking University First Hospital on October, 2013. He was the first child of non-consanguineous Chinese couples. Gene analysis was performed by direct sequencing. Results The patient had not any symptoms with normal intelligence and physical development. Elevated serum alanine aminotransferase had been noticed in a medical examination for entry to kindergarten. His serum alanine aminotransferase, glutamic-oxaloacetic transaminase, creatine phosphokinase, creatine kinase-MB, lactate dehydrogenase, and hydroxybutyrate dehydrogenase were elevated. Electrocardiograph showed left ventricular high voltage, prolonged Q-T interval. Ultrasonic cardiogram showed ventricular septum and left ventricular wall thickening, left ventricular enlargement, increased trabecular of left ventricular apex, and mitral inadequacy, supporting the diagnosis of hypertrophic cardiomyopathy. A homozygous mutation, c.973-974insC (p.L325fs) was detected on LAMP2 gene of the patient. His mother had unexplained hypertrophic cardiomyopathy. She carries a heterozygous mutation c.973-974insC. His father is healthy without any mutation on LAMP2. c.973-974insC was a novel mutation, leading to frameshift mutation and a premature termination codon. Conclusions Danon disease is a rare fatal genetic cardiomyopathy without effective treatment. In this study, a Chinese boy and his mother with Danon disease were firstly diagnosed by gene analysis. LAMP2 gene study is important for the diagnosis of Danon disease and genetic counseling of the family.