Alagille综合征诊断治疗进展

Alagille 综合征(Alagille syndrome, ALGS)又称为动脉-肝脏发育不良,是一种常染色体显性遗传的多系统疾病.该病患者JAG1 基因(1 型ALGS)或者NOTCH2 基因突变(2 型ALGS)导致Notch 信号通路缺陷,从而影响肝脏、心脏、眼睛、脊椎和面部等多个器官或系统.其主要的临床特征有慢性胆汁淤积、先天性心脏病、轻微椎体分割异常、特征性面容、角膜后胚胎环,以及肾脏发育不良等.该文从ALGS 的病因、发病机制、诊断和治疗等方面的进展作一综述.     

20p12.2缺失致Alagille综合征患儿临床和肝脏病理分析

目的分析20p12缺失致Alagille综合征(ALGS)患儿的临床表现和肝脏病理。方法回顾分析1例20p12微缺失致ALGS患儿的临床资料。结果患儿,男,1月龄起病,以胆汁淤积为首发表现,伴特殊面容,蝶形椎,肾脏和心脏病变;肝脏穿刺术病理学检测提示肝脏淤胆改变,肝细胞中度损害(G2S3),无胆管减少表现。采集患儿及父母血标本,采用二代基因测序检测发现chr20p12.2:(9288462-10654178)处1.36 Mb的杂合缺失,缺失片段中包含JAG1基因,为新发突变。确诊后予以对症支持治疗,随访半年,患儿生长发育无异常,黄疸仍迁延不退,远期预后有待进一步随访。结论ALGS是一种常染色体显性遗传病,临床表现多样,基因检测和肝活检有助于诊断。     

1个Alagille综合征家系中JAG1基因新突变的识别

Alagille综合征 （ALGS）是一种主要由JAG1基因突变导致的常染色体显性遗传病,可累及肝脏、心脏、骨骼、眼和面部等多器官。本文报道1例ALGS患儿的临床和遗传学特征。患儿,男,2岁9个月,因发现肝功能异常及心脏杂音2年余就诊。查体：发育营养稍差,皮肤巩膜无黄染。前额突起,左眼内斜视,鼻梁低平,小下颌。双肺呼吸音清,胸骨左缘2~3肋间可闻及2/6级收缩期杂音,肝脾不大。血生化发现胆汁酸、胆红素、转氨酶等均升高。心脏彩超提示房间隔缺损 （静脉窦型）和左肺动脉狭窄;脊柱正位片发现第6、8胸椎蝴蝶椎畸形。患儿明显左眼内斜,眼科诊断眼球后退综合征。因此,该患儿符合ALGS在肝脏、心脏、脊柱和面部的特殊表现,且DNA直接测序发现JAG1基因存在一个新突变c.2419delG （p.Glu807AsnfsX819）,ALGS诊断明确。确诊后予以对症支持治疗。目前已随访至4岁2个月,病情平稳,但面部畸形、左眼内斜视、心脏杂音和肝功能异常持续存在,其远期预后有待观察。     

Alagille综合征患儿1例临床和遗传学分析:一个包含JAG1基因的染色体新中间缺失的识别

Alagille综合征(ALGS)是一种常染色体显性遗传病,可累及肝脏、心脏、骨骼、眼睛、肾脏、颜面等多个系统。本文报道1例ALGS患儿的临床和遗传学特征。患儿为3个月10d男婴,因发现皮肤、巩膜黄染3个月就诊。体格检查示:宽额头,小下颌;胸骨左缘第2、3肋间可闻及3~4/6级收缩期杂音;腹部膨隆,肝右肋下3cm可触及,质地中等。生化结果示肝功能明显异常,胆红素升高,且以结合胆红素升高为主,伴总胆汁酸和γ-谷氨酰转肽酶显著升高。心脏彩超示房间隔缺损、肺动脉狭窄。二代测序发现该患儿JAG1基因整体杂合缺失,而染色体微阵列分析在患儿20号染色体p12.3p12.2处检出约3.0Mb缺失,该范围包含ALGS致病基因JAG1。该患儿具备特殊面容、心脏畸形和胆汁淤积等临床表现,结合遗传学分析结果,诊断ALGS明确。确诊后给予对症支持治疗,现已随访至生后11个月,胆红素较治疗前明显下降,但总胆汁酸和γ-谷氨酰转肽酶等指标仍明显升高,其远期预后仍有待随访观察。本研究扩展了JAG1基因突变谱,同时为患儿诊断、治疗及家系遗传咨询和产前诊断提供了实验室依据。     

活体肝移植治疗Alagille综合征

目的 探讨Alagille综合征(AGS)的临床表现特点及活体肝移植治疗AGS的手术疗效和预后.方法 2013年7月到2015年5月期间7例诊断为AGS的患儿(5男2女)在我中心接受了活体肝移植手术,供肝均来自患儿父母.患儿术前Child分级:B级4名,C级3名,均因终末期肝病接受活体肝移植手术.患儿中位年龄5岁(10个月至13岁1个月),术后中位随访时间11个月(5～23个月).结果 7例患儿中,所有患儿均存在慢性胆汁淤积和特殊面容的临床表现,6例患儿存在先天性心脏结构异常,6例患儿存在特征性肝内胆管稀少的表现.所有病例供、受体均手术成功,5例患儿存活至今,其术后胆汁淤积表现均得以纠正,肝功能在随访期间始终维持正常,黄色瘤体积逐渐减小,生长发育速度明显提高,术后1年患儿身高体重达到正常同龄儿水平.1例患儿移植术前接受胆囊结肠造瘘减黄手术,移植术后12d因结肠吻合口感染导致全身感染而死亡.1例患儿术后第三天因肺动脉破裂出血导致失血性休克伴多脏器功能衰竭死亡.结论 活体肝移植是治疗AGS的有效方式,仔细的体格检查和影像学检查并借助肝脏活检结果是诊断AGS最可靠的手段,准确的临床诊断对AGS患儿的预后有着重要的意义,而术前评估中排除患儿可能存在的内脏和颅内血管畸形可以有效避免围手术期意外的出现.     

有关婴儿期肾病综合征的一些进展

发生于婴儿期的肾病综合征 (ＮＳ)在病因、发病机理、病理改变、临床表现及预后方面有其特点。近年随着分子生物学、分子遗传学的进展 ,对此期的ＮＳ特别是先天肾病综合征 (ＣＮＳ ,特指生后３个月内发病者 )有了更深入的了解。为提高临床诊治水平 ,对某些进展介绍如下。一、先天性和婴儿期起病的ＮＳ此可由多种病因致成［１］,见表１。二、芬兰型先天肾病综合征 (ＣＮＦ)首先由Ｈａｌｌｍａｎ等于１９５６年报告 ［２］。多见于芬兰 ,其发生率于芬兰为 (１．０～１．２)／万新生儿 ,但除芬兰外其他国家包括我国亦有报告。１．病因及发病机…     

Alagille 综合征2例临床特征及 JAGI 基因分析北大核心CSCD

目的：对慢性胆汁淤积症患儿开展 JAGI 基因检测,以提高对 Alagille 综合征临床特征的认识和诊断水平。方法选取2例慢性胆汁淤积症伴多器官受累患儿为研究对象,收集其临床资料、实验室检查结果。抽取患儿外周静脉肝素抗凝血2 mL,采用聚合酶链反应和基因测序技术对 JAGI 基因26个外显子及其侧翼序列进行突变基因检测。结果1例患儿临床表现为慢性胆汁淤积、心脏杂音和特殊面容,肝穿刺病理检查显示胆管上皮缺乏,JAGI 基因检测6号外显子新 c.809809delG（p. G270Dfs＊142）杂合突变,为异常氨基酸代替 JAG1蛋白,导致 JAG1蛋白截断,表皮生长因子（EGF）样重复序列部分丢失以及富含半胱氨酸区完全丢失;1例患儿典型的临床表现仅包括慢性胆汁淤积和特殊面容,JAGI 基因检测第20内含子剪切位点已知 IVS20-25delTAAG 杂合突变,导致剪切位点改变。结论发现1种尚未报道的 JAGI 基因新突变 c.809809delG（p. G270Dfs＊142）。对慢性胆汁淤积症伴多器官受累患儿开展 Notch 信号通路 JAGI 致病基因筛查,有助于临床 Alagille 综合征的诊断。     

Rett综合征的诊断与治疗

Rett综合征（RS）作为一种严重影响儿童精神运动发育的非神经系统退化性疾病，自发现以来得到了国际医学领域的广泛关注。由于临床表型及其严重性具有显著异质性，且无特异性检测指标，RS的诊断与治疗仍有一定难度。现对RS的发病机制、临床表现及其诊断标准的变化与治疗作一简要介绍，以期加深临床医师对RS诊断标准及治疗方案的认识。     

噬血细胞综合征的研究进展

噬血细胞综合征(HPS)又称噬血细胞性淋巴组织增生症(HLH),是一种反应性单核吞噬系统疾病,常见于小儿,临床酷似恶性组织细胞增生症,易误诊。本病分为原发性和继发性两种,两者临床经过及预后均不同。本文就近年来此病的研究进展综述如下。     

噬血细胞综合征研究新进展

噬血细胞综合征（HPS）是一种罕见的良性单核巨噬细胞系统反应增生性疾病。临床以高热、肝脾肿大、全血细胞减少和凝血障碍为主要表现。未及时诊断和治疗病死率很高。其病因分为原发性和继发性两大类，前者主要与遗传有关，后者与基础疾病密切相关。HPS的发病机制仍未明确，但多认为免疫调节系统异常起主要作用。目前，对于原HPS行骨髓移植是根本性治疗，而对于继发性HPS的治疗应该基础疾病与HPS并重，否则预后很差。病毒相关性HPS，尤其是EB病毒相关性HPS的患者病死率相对较高。     

Alagille syndrome and nephroblastoma: Unusual coincidence of two rare disorders

Alagille syndrome is a rare developmental disorder combining bile duct paucity, congenital cardiopathy, facial dysmorphy, vertebrae defects, and ocular abnormalities, and frequent renal abnormalities. It does not usually predispose to malignancies. Nephroblastoma has been observed in many developmental disorders, but never in Alagille syndrome. We report two original cases of nephroblastoma associated to Alagille syndrome. We identified a new V136G JAG1 missense mutation in one patient and a constitutional deletion of 20p12 in the other. In one nephroblastoma an additional somatic 1p36 deletion was present. The link between Alagille syndrome, JAG1 alterations and nephroblastoma is discussed.     

Alagille syndrome

Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interiobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect; posterior embryotoxon and peculiar facies. AGS has long been said to have a relative good prognosis but overall survival at twenty years averages 70%. Complex congenital heart disease and hepatic disease with or without liver transplantation contribute significantly to mortality.JAGGED1 has been identified as a responsible gene by demonstration of mutations in AGS patients. Studies ofJAGGED1 expression pattern demonstrate that minor features and almost all the elements in the long list of manifestations described in AGS patients are not coincidental. This suggests that Alagille syndrome definition may be revisited in the light ofJAGGED1 mutations.     

Alagille syndrome

Alagille syndrome (AGS) was described more than 35 years ago as a genetic entity characterised by five major features: chronic cholestasis owing to paucity of interlobular bile ducts; peripheral pulmonary stenosis; butterfly like vertebral arch defect; posterior embryotoxon and peculiar facies. AGS has long been said to have a relative good prognosis but overall survival at twenty years averages 70%. Complex congenital heart disease and hepatic disease with or without liver transplantation contribute significantly to mortality. JAGGED1 has been identified as a responsible gene by demonstration of mutations in AGS patients. Studies of JAGGED1 expression pattern demonstrate that minor features and almost all the elements in the long list of manifestations described in AGS patients are not coincidental. This suggests that Alagille syndrome definition may be revisited in the light of JAGGED1 mutations.     

Proliferation to Paucity: Evolution of Bile Duct Abnormalities in a Case of Alagille Syndrome

Alagille syndrome is an autosomal dominant disorder characterized by abnormalities in multiple organ systems, including the liver, and is caused by mutations in JAG1. Chronic cholestasis secondary to paucity of interlobular bile ducts is traditionally both a clinical and a pathologic hallmark of this disease at diagnosis. We describe the biliary changes on serial liver biopsies in a patient who presented with jaundice and extrahepatic stigmata of Alagille syndrome. Her initial specimens at 6 and 10 months of age demonstrated interlobular bile duct proliferation and cholestasis, suggestive of distal biliary obstruction. A specimen at 2 years of age showed near-total absence of interlobular bile ducts, with the classic histologic appearance of bile duct paucity. We present this case to underscore the potential pitfalls in interpreting cholestatic liver morphology in the absence of clinical information. The progression of bile duct abnormalities is discussed in the context of the role postulated for JAG1 in postnatal liver growth and development.     

Investigation of serum bile acids; seven patients with Alagille syndrome

To clarify whether an abnormal bile acid pattern has a role in the pathogenesis of Alagille syndrome, we compared serum bile acid patterns in seven with Alagille syndrome with those of patients with congenital biliary atresia (CBA), neonatal hepatitis (NH) and normal infants.Of the seven patients with Alagille syndrome, four patients were younger and three were older than 1 year. The mean total serum bile acid level in the infants was higher than in older subjects. There was a dissociation between the levels of serum total bile acid and bilirubin in three of the seven cases. The mean total bile acid levels in serum were in the following decreasing order: CBA, Alagille syndrome, NH and controls.The ratio of cholate to chenodeoxycholate in the younger patients with Alagille syndrome was significantly higher than CBA (P<0.001). However, no specific bile acid pattern was found in Alagille syndrome by high-performance liquid chromatography (HPLC).Abbreviations TBA total bile acids - FBA free bile acids - conj-BA conjugated bile acids - C/CDC ratio of cholate to chenodeoxycholate - G/T ratio of glycine conjugates to taurine conjugates - GPT glutamic pyruvic transaminase - CBA congenital biliary atresia - NH neonatal hepatitis - HPLC high performance liquid chromatography - GCA glycocholate - TCA taurocholate - GCDCA glycochenodeoxycholate - TCDCA taurochenodeoxycholate