2型婴儿肝功能衰竭综合征发病机制及治疗研究进展

2型婴儿肝功能衰竭综合征(infantile liver failure syndrome-2,ILFS2)是一种罕见的由神经母细胞瘤扩增序列(neuroblastoma amplified sequence,NBAS)基因突变引起的常染色体隐性遗传性疾病,主要表现为反复发生与发热/感染相关的急性肝功能衰竭(acute liver failure,ALF),首次发作多见于婴儿期或幼儿期(8月龄~3岁)。该病最大的特点是两次肝功能衰竭发作间歇期肝功能可完全恢复,基因检测有助于确诊。目前ILFS2的发病机制尚未完全了解,临床上主要以个体化的对症支持治疗为主,当疾病发展到终末期,肝移植是唯一的治疗方法。该文就ILFS2的发病机制及治疗现况进行综述。     

NBAS基因变异所致疾病研究进展

NBAS(GenBank: NM_015909.3;OMIM 608025)基因变异目前被发现可导致两种疾病.2010年Maksimova等[1]通过对俄罗斯东部31个雅库特家庭中的34例患者研究分析后,首次发现并报告了NBAS基因变异会导致SOPH综合征(OMIM 614800),主要表现为矮小、视神经萎缩和Pelg...     

肝移植治疗NBAS基因缺陷病急性肝衰竭3例并文献复习

目的探讨肝移植治疗儿童NBAS基因缺陷病急性肝衰竭的临床疗效和预后。方法回顾性病例总结2013年1月至2022年6月就诊于复旦大学附属儿科医院并行肝移植手术的3例NBAS基因缺陷病患儿的临床资料, 并分别以"NBAS""neuroblastoma amplified sequence recurrent""acute liver failure""SOPH syndrome""short stature with optic nerve atrophy and Pelger-Hu?t anomaly""发热相关肝衰竭""急性肝衰竭"为关键词检索PubMed、万方数据库、中国知网数据库建库至2022年6月关于NBAS基因缺陷病肝移植的病例报道, 总结其临床疗效和预后。结果 3例NBAS基因缺陷病患儿行肝移植治疗, 男2例, 女1例。3例患儿临床表型为发热相关的反复急性肝衰竭, 基因结果为NBAS基因复合杂合致病变异。肝移植前急性肝衰竭次数分别为11、2和4次, 手术年龄分别为3.5、2.3和2.0岁。肝移植时, 例1为肝衰竭恢复期, 例2为肝衰竭急性期肝性脑病Ⅴ期和呼吸衰竭, 例3可能为...     

Reye’s综合征的临床特征和预后

作者报告1979～1982年间北爱尔兰23例散发的Reye’s综合征,其诊断标准为:(1)有上呼吸道或胃肠道症状,伴有发热或水痘;(2)以血氨和/或血清转氨酶3倍升高,凝血酶原时间明显延长(与正常对照比较<40%)为特征的肝功能衰竭;(3)突然发生中枢神经系统紊乱,表现意识改变(伴有其他异常);(4)排除有类似临床特征的其他疾病。按Lovejoy分级方案对患儿的意识状态进行分级。17     

NBAS 基因缺陷症一家系报告及文献复习

目的探讨NBAS基因缺陷症的发病机制及其诊断和治疗。方法回顾分析一家系2例NBAS基因缺陷症患儿的临床资料。结果先证者为14岁6月龄男性患儿,其妹妹7岁11月龄,2例患儿均有早老面容、视神经萎缩、色盲、身材矮小、肝功能异常等。血涂片均有Pelger-Hu?t细胞。基因检测示2例患儿均存在NBAS基因变异c.5752AC和c.1599+1GC,分别来自其父母。其中c.5752AC变异已有文献报道,c.1599+1GC变异为新剪切突变。随着年龄增长,未经特殊治疗,兄妹的肝功能均有明显好转。结论 NBAS基因缺陷症主要累及视神经、肝脏、骨骼等,确诊需依靠基因检测,目前无特异治疗方法。     

40例婴儿肝炎综合征病原学研究

婴儿肝炎综合征是指1岁以内婴儿(其中包括新生儿)因各种原因引起的黄疸、肝功能损害和肝脾肿大等临床症候群,其中部分是病毒陸肝炎,如巨细胞病毒(CMV)、风疹病毒、单纯疱疹病毒(HSV_1、HSV_2)EB病毒、乙型肝炎病毒(HB-     

婴儿与儿童出血性休克和脑病综合征

出血性休克、脑病综合征(HSE)为一病因未明,见于婴儿和儿童的疾病。以高热、凝血病变、脑病、肾、肝功能障碍为主要表现的综合征。1983年6月 Levin 等首次报道了10例主要表现为     

婴儿肝炎综合征,先心病血浆心钠素水平

本文用放射免疫法测定婴儿肝炎综合征、先心病患儿血浆心钠素(ANP),结果提示婴儿肝炎综合征血浆ANP明显高于先心病血浆ANP(P<0.01)。先心病中血浆ANP水平,室间隔缺损(VSD)高于房间隔缺损(ASD)和动脉导管未闭(PDA)(P<0.01)。增高的原因可能与婴儿肝炎综合征肝功能不良、VSD左心房扩大有关。     

促肝细胞生长素治疗婴儿肝炎综合征

目的探讨促肝细胞生长素治疗婴儿肝炎综合征的临床疗效及安全性。方法选择2002年3月～2003年2月住院的婴儿肝炎综合征患儿61例,静脉滴注促肝细胞生长素,进行前瞻性研究;选取2001年3月～2002年2月住院的婴儿肝炎综合征患儿54例为对照组,治疗2周后观察患儿总胆红素(TBIL)、ALT、AST等,判断药物疗效。结果疗程结束后婴儿肝炎综合征治疗组TBIL、ALT下降明显,优于对照组(P<0.05);治疗组和对照组总有效率分别为78 69%和61.11%,治疗组优于对照组(P<0.05)。结论促肝细胞生长素有助婴儿肝炎综合征肝功能恢复,无明显不良反应。     

新生儿行为测定对婴儿发育的预测

根据Barry M等研究,将足月儿和早产儿在孕40、42和44周时新生儿行为估价评分(NBAS)项目群绘成曲线,其参数和18个月时贝来评分(Baylety Scale)的精神发育分数有密切关系,初步显示NBAS重复测试结果对婴儿发育有预测性。我们亦进     

Genetics of the Berardinelli-Seip syndrome (congenital generalized lipodystrophy) in Norway: epidemiology and gene mapping

Five of the six families with the Berardinelli Seip syndrome in Norway cluster in six adjacent rural municipalities of south-western Norway. The six patients from this area were born between 1951 and 1973, none between 1974 and 1995. The absence of new cases may be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogical investigations show that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural East Norwegian population. A genetic linkage study of all six families revealed fresh crossovers versus the disease allele in nine DNA marker systems and the absence of recombination in three (maximum lod score + 1.3). None of the last showed allelic association. These families are included in an international effort to map the CLBS locus. The patients have been included in the homozygosity testing of totally 28 patients in an international collaborative study. The three patients, assumed identical in descent from both parents, were jointly homozygous in none of the 250 dinucleotide markers tested. A heterochromatic 9qh + segregated from one parent in two families.     

无脑回畸形儿1例报告并文献复习

目的探讨无脑回畸形的临床特征及其致病基因LIS1基因的检测特点。方法回顾性分析1例无脑回畸形患儿的临床、实验室检查及基因检测结果,同时复习相关文献。结果女性,5月龄,确诊癫痫20 d,3 d内再次抽搐发作30余次入院,抽搐发作表现为双眼凝视、上翻,口唇、面色发绀,口吐白沫,四肢强直,意识丧失,约2~3 min自行缓解。外周血白细胞计数13.67×109/L,血红蛋白108 g/L,红细胞计数3.90×1012/L,淋巴细胞10.26×109/L;心肌酶谱、肝肾功能均正常;血氨23μmol/L,乳酸2.11 mmol/L;长程视频脑电图显示高度失律,频繁部分性发作,有时继发全身阵挛发作。头部MRI提示无脑回畸形。口服左乙拉西坦片,约27 mg/(kg·d),托吡酯片约6.5 mg/(kg·d),目前暂无发作。患儿LIS1基因检测发现c.232del G杂合突变,导致蛋白移码突变(p.E78Nfs X25);患儿父母均未见突变。结论无脑回畸形患儿可合并癫痫,可能由LIS1基因突变所致,该基因c.232del G位点突变在国内外未见报道。     

软骨发育不全家系FGFR3基因突变分析与产前基因诊断

目的 通过对一个软骨发育不全(achondroplasia,ACH)家系成员成纤维细胞生长因子受体(fibroblast growth factor receptor 3,FGFR3)基因突变的靶向检测与产前基因诊断,以达到优生的目的.方法 应用变性高效液相色谱技术(denaturing high performance liquid chromatography,DHPLC),PCR产物限制性片段多态分析(PCR-restricted fragment length polymorphism,PCR-RFLP)与PCR产物直接测序的方法,对ACH家系中4个表型正常个体、2个ACH患者与胎儿的FGFR3基因第10外显子中可导致G380R与G375C改变的3个热点突变进行检测.结果 ACH家系中患者均为G1138A突变杂合子,而表型正常者与胎儿在该位点为GG纯合子.胎儿娩出后脐血基因分析结果与产前检查一致,且随后1年中生长发育正常.结论 软骨发育不全是一种少见的常染色体显性遗传病,随着致病基因FGFR3的定位克隆,该病的临床基因检测与产前基因诊断成为可能,但仍需完善中国人ACH基因突变谱,以不断提高对该病的分子诊断水平.     

过度惊吓反应症临床及遗传学特征（附６例报告）

目的　分析6例过度惊吓反应症患儿的临床及遗传学特征。 方法　对2011年6月至2018年5月于北京大学第一医院诊断的6例过度惊吓反应症患儿的临床表现、诊治过程、脑电图（EEG）及神经影像学、遗传学结果等进行分析。 结果　6例中男5例、女1例。6例均为新生儿早期起病,均可因不经意的听觉或触觉刺激诱发过度惊跳反应和全身僵硬症状,3例曾出现短暂窒息发作,1例曾惊吓后摔倒致外伤。6例点鼻反射均阳性,4例合并疝。EEG示1例正常,5例为不典型放电或一过性异常。4例曾行头颅磁共振检查未见明显异常。经遗传学分析,6例中3例携带GLRA1基因杂合突变,2例携带GLRB基因复合杂合突变,1例经全外显子测序未发现基因突变。6例给予氯硝西泮治疗, 1例全身僵硬及过度惊吓反应均基本消失, 5例全身僵硬症状消失、偶有惊跳反应。6例智力发育均正常,2例存在宽基底步态状行走姿势。1例有相同症状而窒息死亡的明确家族史。 结论　过度惊吓反应症具有典型临床表现,点鼻反射阳性,可行基因诊断确诊。该病对氯硝西泮有良好的治疗反应。早期经临床诊断及基因确诊,及时、恰当治疗,对于改善预后至关重要。     

5 例低磷酸酯酶症患儿临床及遗传学分析

目的总结低磷酸酯酶症(HPP)的临床及遗传学特点。方法回顾分析5 例HPP患儿的临床资料,以及患儿及其亲属的外周血高通量测序及Sanger验证结果。结果 5例患儿均有骨骼矿化不良以及血清碱性磷酸酶降低,3例伴有惊厥等神经系统症状。5例HPP患儿高通量测序共发现ALPL6个突变位点,c.346GA(p.A116T)、c.1097至c.1099del CCT复合杂合突变(p.T366_S367deli)、c.1014至c.1015ins G(p.H338fs)、c.1446CA(p.482HQ)复合杂合突变、c.920CT(p.P307L)、c.883AG(p.M295V),其中c.1014_c.1015ins G、c.1097_c.1099del CCT、c.1446CA为首次报道,蛋白质结构预测均为可能有害,ACMG评级为可能致病。结论确诊5例HPP患儿,发现 3种新型突变,丰富了人类ALPL基因突变数据库。     

111 例未通过听力筛查新生儿常见耳聋基因突变位点分析

目的了解未通过听力筛查新生儿耳聋基因突变情况。方法随机选取听力筛查未通过、经听觉脑干诱发电位(ABR)测试为感音神经性耳聋患儿111例,收集足跟血血片,提取基因组DNA后,检测GJB2、SLC26A4和线粒体12 Sr RNA基因中的11个热点的突变,分析听力损失程度与突变的关联。结果 111例新生儿中,共检出携带耳聋基因突变24例(21.6%)。其中,GJB 2基因突变14例(12.6%),包括235 del C单杂合突变5例,235 del C和299_300 del AT复合杂合突变5例,以及235del C纯合突变、299_300del AT单杂合突变、176_191del16和235del C复合杂合突变、299_300del AT和508_511 dup AACG复合杂合突变各1例;SLC 26 A 4基因突变10例(9.0%),包括IVS 7-2 AG单杂合突变2例,1226 GA单杂合突变3例,2168 AG单杂合突变2例,IVS7-2AG和2168 AG复合杂合突变3例。本组耳聋患儿中未检出线粒体基因突变。结论未通过听力筛查新生儿中,超过1/5检测到聋基因突变,并以GJB2基因突变最常见,实施热点致聋基因检测可以提高耳聋的病因诊断率。     

高IgE综合征研究进展

正高IgE综合征(hyper-IgE syndrome,HIES)是一种罕见的原发性免疫缺陷病,临床表现为嗜酸性粒细胞及血清Ig E水平增高,反复细菌、病毒或真菌感染,特应性皮炎,特殊面容及过敏反应等。从1996年第1例因STAT3基因突变导致的HIES报道以来,目前已发现多种基因突变均可导致HIES,但其发病机制、遗传学特征及临床表型差异很大,现就HIES发病机制及临床最新进展做一综述。     

Inherited risk factors for thrombophilia in children with nephrotic syndrome

A hereditary tendency to venous thrombosis rarely results in a spontaneous thrombotic episode before puberty. The acquired hypercoagulability associated with nephrotic syndrome (NS) could, however, coincide with underlying inherited thrombophilia, thereby resulting in a thrombotic event. In order to determine the contribution of inherited prothrombotic conditions to thrombosis in children with NS, we analysed DNA from a cohort of patients with NS for the common genetic risk factors of vascular disease. We evaluated 53 children with NS and 41 paediatric controls for prevalence of the factor V mutation Arg506→Gln (factor V Leiden), the prothrombin variant (20210G→A), and homozigosity for Ala677→Val in the methylenetetrahydrofolate reductase gene (MTHFR). Eight thrombo-embolic events were identified in 6 out of 53 (11%) children. Three thrombotic events occurred during NS activity and were associated with systemic infections in two and an arterial puncture in one. An inherited risk factor was identified in seven children, all without thrombosis (two heterozygous for the prothrombin variant and five homozygous for the MTHFR-T). None of the studied inherited risk factors were identified among those with thrombosis. Conclusions These data suggest that inherited thrombophilia is not a strong risk factor for the development of non recurrent thrombosis in children with NS. Received: 21 October 1997 / Accepted in revised form: 12 April 1998     

Studies of the RB7 Gene and the p53 Gene in Human Osteosarcomas

We analyzed 14 native osteosarcoma tissue samples for alterations of the tumor suppressor genes RB1 and p53 on the DNA level, and as far as possible, the RNA level. Southern blot analyses concerning both tumor suppressor genes were carried out in all osteosarcomas. In two cases we could demonstrate a deletion within the RB1 gene. DNA analysis of a third osteosarcoma patient revealed a rearrangement of the p53 gene.

We had the opportunity of performing corresponding northern analyses in eight native osteosarcoma specimens. The RB1 gene expression was significantly decreased or completely absent in six tumor samples. In two of these tissue probes the expression of both tumor suppressor genes was missing. We determined coexistence of decreased expression of both tumor suppressor genes in one additional case.

In summary, 7/14 or 6/8 cases of osteosarcomas (including only those cases which allowed both analyses) showed RB1 gene alteration. In 3/14 or 3/8 osteosarcomas we could determine p53 gene abnormalities. This may indicate that either loss of p53 function is etiologically important only for the development of some osteosarcomas, or a major part of p53 gene mutations are subtle ones and their detection requires more sophisticated techniques, which are currently under development.