分子遗传学检查诊断Crigler-Najjar综合征域Ⅱ型3例

目的探讨采用分子遗传学检查诊断Crigler-Najjar综合征Ⅱ型的方法。方法在本科收治的3例高间接胆红素血症患者,抽取外周静脉血,提取基因组DNA,应用PCR法扩增尿苷二磷酸葡萄糖醛酸转移酶1A1基因(UGT1A1)所含5个外显子及其侧翼序列,进行DNA直接测序。结果 3例患者均检出UGT1A1基因5号外显子存在c.1456 TG(p.Y486D)纯合突变;Y486D位于第5外显子上,使1456位胸腺嘧啶(T)突变为鸟嘌呤(G),导致486位氨基酸由酪氨酸(Tyr)变为天冬氨酸(Asp)。结论当临床上高度怀疑Crigler-Najjar综合征Ⅱ型时,应尽早行分子遗传学检查,确定其基因突变位点,以明确诊断。     

Gilbert综合征患者血UGT1A1基因检测及临床意义

目的 观察Gilbert综合征（GS）患者血UGT1A1基因遗传变异情况,并探讨其意义.方法 采用Sanger 双脱氧链终止法对4例GS患者（包括1家系）进行外周血UGT1A1基因检测,检测内容包括UGT1A1基因的启动子TATA盒、c-3279位点及全部5个外显子核酸序列.结果 1例UGT1A1第5号外显子存在Tyr486Asp纯合突变;1例UGT1A1启动子TATA盒TA插入杂合变异,且c-3279T＞G杂合突变;1例UGT1 A1基因无遗传变异;1例家系中先证者为UGT1A1启动子TATA盒TA插入纯合变异,患者父亲、母亲为A（TA）6TAA/A （TA） 7TAA杂合基因型.结论 GS属染色体隐性遗传疾病,其UGT1A1基因遗传变异包括启动子TATA盒TA插入变异、c-3279T＞G以及外显子碱基突变,在GS诊断中有重要意义.     

利用多重荧光定量PCR协助诊断Crigler-Najjar综合征Ⅱ型及Gilbert综合征

目的尝试建立一个多重荧光定量PCR反应体系对Crigler-Najjar综合征Ⅱ型(Crigler-Najjar syndromeⅡ,CNSⅡ)及Gilbert综合征(Gilbert syndrome,GS)患者的尿苷二磷酸葡糖醛酸基转移酶1A1(uridine diphosphate glucuronosyltransferase 1A1,UGT1A1)基因突变进行检测,以运用于协助以上疾病的临床诊断。方法选取国内外目前报道较多UGT1A1基因常见突变的4个位点[A(TA)7TAA、Gly71Arg、Pro229Gln及Try486Asp],利用多重荧光定量PCR Tapman探针法对96例临床诊断为GS或CNSⅡ患者及100名健康体检者全血基因组进行检测,利用T-A克隆法对扩增产物进行测序验证。结果多重荧光定量PCR反应体系可有效检测出实验样本中所存在的以上4种基因突变。A(TA)7TAA、Gly71Arg、Pro229Gln及Try486Asp在试验组测得的阳性率高于对照组,差异有统计学意义(P0.05)。PCR产物电泳及测序结果与其基因检测表型完全一致。结论利用多重荧光定量PCR技术可以更简便、快捷、有效地对GS或CNSⅡ患者中的UGT1A1基因突变进行检测,为临床诊断提供有用信息。     

Gilbert综合征与Crigler-Najjar综合征Ⅱ型患者 UGT1A1基因多态性分析

目的 分析Gilbert综合征（GS）与Crigler-Najjar综合征Ⅱ型（CN-2）患者UGT1A1基因突变位点、单倍型及双倍型的差异。方法 回顾性分析2010年1月1日—2019年12月31日就诊于首都医科大学附属北京佑安医院的138例GS与CN-2患者临床资料，其中GS组109例,CN-2组29例，分析两种表型在突变位点上的差异。计量资料两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ²检验或Fisher精确检验。使用SNPStats软件对突变位点进行连锁不平衡（LD）分析及单倍型分析。强LD被定义为|D′|和r²均>0.8,中度LD被定义为|D′|>0.8且r²>0.4。结果 138例患者均进行了UGT1A1基因检测，突变主要发生在启动子上游苯巴比妥反应增强元件（PBREM）区域-3279T>G突变（104例,75.36%）、-3152G>A突变（82例,59.42%）和启动子TATA 盒TA插入突变（88例,63.77%）,以及编码区1号外显子上的c.2...     

Gilbert综合征和Crigler-Najjar综合征相关尿苷二磷酸葡糖醛酸转移酶A1基因突变位点特征分析

目的探讨Gilbert综合征(GS)和Crigler-Najjar综合征(CNS)相关尿苷二磷酸葡糖醛酸转移酶A1(UGT1A1)基因的突变特征及与临床的相关性。方法通过检索PubMed和人类基因突变数据库归纳UGT1A1基因突变位点的特征并分析其临床相关性。结果截至2018年11月16日,共发现UGT1A1基因163个突变位点,上述位点存在以下规律:(1)GS或CNS表型相关的UGT1A1的不同外显子发生的基因突变个数,均与外显子长度呈正相关;(2)无义点突变主要发生在CNS I型;(3)GS、CNS II型的复合杂合突变位点的组合和分布存在一定规律,其中GS的4种复合杂合组成中,均有-3279T>G突变;(4)亚洲地区报道的UGT1A1基因突变位点在c.211-c.558有明显的聚集性。结论UGT1A1基因突变位点不同、报道地区不同及人群不同,其突变特征及临床相关性也不同。本研究对GS和CNS的基础研究和临床诊疗有参考价值。     

七例Brugada综合征患者SCN5A基因突变检测

目的 对7例Brugada综合征患者进行SCN5A基因突变检测,分析其分子遗传学特征. 方法 提取7例Brugada综合征患者外周血DNA样本,设计41对引物进行多聚核苷酸聚合酶链式反应,扩增SCN5A基因28对外显子,并采用双脱氧链终止法进行直接测序. 结果 SCN5A基因外显子部分未发现新的突变位点. 结论 Brugada综合征可能存在除SCN5A基因之外的其他相关基因突变.     

MENⅡA综合征家系的RET原癌基因突变及其临床意义

目的筛查1个MEN-ⅡA综合征家系的RET原癌基因突变位点,用于指导临床。方法对1个MEN-ⅡA综合征家系的5个成员外周血提取DNA,采用聚合酶链反应和DNA直接测序方法进行RET基因热点突变的第10、11外显子检测,并讨论MEN—ⅡA家系基因突变早期检测对预防性选择外科治疗的指导意义。结果第11外显子634密码子存在TGC→CGC突变,编码的氨基酸由Cys（半胱氨酸）变为Arg（精氨酸）。结论MEN—ⅡA综合征的早期基因诊断意义较大。     

胰蛋白酶原基因新突变与胰腺先天分裂异常的相关性研究

目的研究胰腺先天分裂异常（pancreas divisum，PD）患者胰蛋白酶原基因（cationic trypsinogen gene，PRSSI）1～4号外显子区的异常情况以及相应临床特征。方法应用PCR法扩增15例胰腺先天分裂异常患者以及60名健康体检者的PRSSI基闪1～4号外显子，产物纯化后直接测序，同时收集患者的一般资料。结果在15例患者中发现6例患者的PRSS1基因4号外显子存在c．486C〉T多态，其中1例患者除了携带SNP-c．486C〉T（p．D162D）外，还存在c．111C〉A（p．Y37X）突变，经NCBI网站比对，得知p．Y37X是新发现的突变形式，临床表现为胰腺先天分裂异常并发慢性胰腺炎；SNP-c.486 C〉T同时存在于12例健康对照者中，经X^2检验，基因型频率在两组分布差异有统计学意义（OR=1．79，X^2=5．047，P=0．028）。结论PRSS1基因4号外显子SNP—c．486C〉T与胰腺先天分裂异常存在一定的关系；p．Y37X为新发现的突变形式，可能与胰腺先天分裂异常的临床表型存在相关性。     

Brugada综合征SCN5A基因的三个新突变

目的 研究Brugada综合征相关基因SCN5A突变情况。方法 以4例Brugada综合征患者和9例临床可疑Brugada综合征患者为研究对象,采用聚合酶链反应和双脱氧末端终止测序法对所有患者进行SCNSA基因扫描。对阳性结果者进行家系中其他成员的筛查。结果 在1个Brugada综合征家系发现两个杂合突变,即SCN5A基因第3外显子上发现一错义突变（G283A）,导致代表缬氨酸残基的第95位密码子突变为异亮氨酸残基（V95I）,第28外显子上也发现一错义突变（CA946T）,导致代表丙氨酸的第1649位密码子突变为缬氨酸（A1649V）。在1个临床可疑Brugada综合征家系发现一杂合突变,即SCN5A基因第28外显子缺失3个碱基（TCT）,导致代表苯丙氨酸残基的第1617位密码子缺失（delF1617）。结论 在Brugada综合征患者发现了3个SCN5A基因新突变（V95I、A1649V、delF1617）。     

一个Ⅱa型多内分泌腺瘤病家系的RET原癌基因突变研究

目的 检测一个Ⅱa型多内分泌腺瘤（MEN-Ⅱa)病家系中RET原癌基因的突变情况。方法 提取9名家系成员外周血基因组DNA，对RET原癌基因第10和第11外显子进行聚合酶链反应（PCR），PCR产物进行直接DNA测序。结果 家系中2例经病理确诊的患者存在RET原癌基因第11外显子Cys(TGC)634Gly(GGC)错义突变，另筛查出4名成员为该突变基因携带者，其中2例经B超检查发现甲状腺有新生物，1例双侧甲状腺及双侧肾上腺有新生物。1例15岁的突变基因携带者无临床表现。结论 对MEN-Ⅱa家系的基因分析证实RET原癌基因第11外显子在密码子634存在TGC→GGC突变，对MEN-Ⅱa能在基因水平作出诊断，对MEN-Ⅱa家系成员作分子遗传学分析有助于判断患MEN-Ⅱa的危险性和临床上作进一步处理。     

Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes

BACKGROUND AND OBJECTIVE: Crigler-Najjar syndromes type I and II and Gilbert's syndrome are familial unconjugated hyperbilirubinemias caused by genetic lesions involving a single complex locus encoding for bilirubin-UDP-glucuronosyltransferase which is involved in the detoxification of bilirubin by conjugation with glucuronic acid. Over the last few years a number of different mutations affecting this gene have been characterized. The aim of this work is to review the molecular pathology of Crigler-Najjar and Gilbert's syndromes, to discuss its impact on the clinical and genetic classification of these conditions, and on the diagnostic evaluation of clinical pictures associated with unconjugated hyperbilirubinemia. EVIDENCE AND INFORMATION SOURCES: The authors of the present review are involved in the clinical management of patients with familial unconjugated hyperbilirubinemia as well as in the characterization of its molecular bases. Evidence from journal articles covered by the Science Citation Index and Medline has been reviewed and collated with personal data and experience. STATE OF THE ART AND PERSPECTIVES: It has been known for many years that mild to severe deficiency of bilirubin UDP-glucuronosyltransferase in the liver is the cause of two types of familial unconjugated hyperbilirubinemia, Crigler-Najjar syndromes I and II, and Gilbert's syndrome. Since the characterization of the gene encoding for bilirubin UDP-glucuronosyltransferase, a number of mutations affecting the expression of this gene have been identified. These mutations can be classified into three groups: mutations which result in a reduced production of a normal enzyme; mutations which give rise to the synthesis of a structurally abnormal and dysfunctional enzyme; mutations which completely abolish the expression of the affected allele. The combination of mutations affecting the coding region of the gene and of promoter mutations which reduce the expression of the gene accounts for the wide clinical spectrum of familial unconjugated hyperbilirubinemias, ranging from the clinically negligible Gilbert's syndrome to the severe and often fatal Crigler-Najjar type I syndrome. A better understanding of the genetics of these conditions and the availability of molecular diagnosis will improve the diagnostic efficiency and afford better informed genetic counseling, not only for Crigler-Najjar and Gilbert's syndromes, but also for several acquired conditions characterized by unconjugated hyperbilirubinemia.     

Fenofibrate treatment in two adults with Crigler-Najjar syndrome type II.

Crigler-Najjar syndrome type II is a rare familial disorder of bilirubin conjugation with consecutive life-long unconjugated hyperbilirubinemia. In the presence of severe hyperbilirubinemia, a fetus or an adult is at risk for neurological defects in this syndrome. This paper is the first report emphasizing details about this disorder in two patients from Turkey. The diagnosis was made on the basis of history and laboratory findings excluding other causes of unconjugated hyperbilirubinemia. Phenobarbital loading test and C bile analysis also supported the diagnosis. There was a study in the literature in which treatment with chlofibrate had been recommended in this syndrome. Based on the results of that study, we administered fenofibrate treatment to our patients for one month and analyzed serum bilirubin levels before and after this procedure. No improvement in bilirubin levels was observed in either case.     

A homozygous mutation in a Chinese man with Crigler-Najjar syndrome type II and a family genetic analysis

OBJECTIVE: To investigate the family genetic background of a 22-year-old man with Crigler-Najjar syndrome type II (CN-II). METHODS: After the proband (patient) with CN-II was diagnosed by liver function tests, a low calorie intake test and an oral phenobarbital enzyme-induction trial, blood samples were collected from 11 family members for identifying DNA gene groups. Exons 1-5 of the UGT1A1 gene were amplified by polymerase chain reaction (PCR) and mutations of the UGT1A1 gene were screened by a direct DNA sequencing. RESULTS: The serum unconjugated bilirubin increased in the proband from 156.4 micromol/L to 243.5 micromol/L after he started a low calorie intake, and it decreased to 51.8 micromol/L within a month of taking oral phenobarbital daily. Both functional tests and ultrasonographic images of the liver were normal except for the unconjugated hyperbilirubinemia. A missense mutation of Tyr486Asp at exon 5 in the UGT1A1 gene and a homozygous mutation were confirmed in the proband. Heterozygous mutations were found in his parents, his younger sister and three great-uncles, while no mutation of the UGT1A1 gene was detected in the remaining four family members. CONCLUSION: A missense mutation of Tyr486Asp is considered to be the cause of the CN-II in this patient. It is a recessive trait that is autosomally inherited in this family. No influence of the mutation was found on the response elements for phenobarbital in the promoter region.     

Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect

Gilbert syndrome is a common genetic disorder associated with mild unconjugated hyperbilirubinemia and no clinical illness. In contrast, Crigler-Najjar syndrome types I and II are rare genetic disorders associated with severe unconjugated hyperbilirubinemia and a life-long risk of kernicterus. Patients with Gilbert syndrome have low levels of a normal form of uridinediphosphoglucuronate glucuronosyltransferase because of a defect in the promoter region of both alleles, whereas patients with Crigler-Najjar syndrome are homozygous for a defect that yields an abnormal form of the enzyme that has limited or no activity. This case report describes a young adult with Crigler-Najjar syndrome type II in whom kernicterus developed after a laparoscopic cholecystectomy. The development of kernicterus was the result of a largely preventable series of events that lead to an increase in the free fraction of his serum bilirubin. Analysis of his genetic defect showed that he was homozygous for the mutation associated with Gilbert syndrome and heterozygous for a second mutation in the open reading frame of one allele of the bilirubin uridinediphosphoglucuronate glucuronosyltransferase gene. The combined defect leads to severe hyperbilirubinemia and shows how seemingly benign genetic defects, when combined, can cause serious clinical disease. (Gastroenterology 1997 Jun;112(6):2099-103)     

Relationships between serum bilirubins and production and conjugation of bilirubin. Studies in Gilbert's syndrome, Crigler-Najjar disease, hemolytic disorders, and rat models

The pattern of serum bilirubins was determined in serum of humans and rats with unconjugated hyperbilirubinemia due to increased pigment load or defective hepatic conjugation. Bilirubin ester conjugates were present in all serum samples tested and were identified as bilirubin 1-O-acyl glucuronides. In Gilbert's syndrome, the concentration of total conjugates was comparable to the values in healthy control subjects. Because the concentration of unconjugated pigment was increased, the fraction of conjugated relative to total bilirubins was markedly decreased. Sera from patients with Crigler-Najjar disease differed from those with Gilbert's syndrome by the higher unconjugated bilirubin levels and the undetectability of diconjugated bilirubins. A striking finding was that in hemolytic disease, the concentration of both monoconjugates and diconjugates was enhanced in parallel with the increase of unconjugated pigment. Therefore, the fraction of conjugated relative to total bilirubins remained within the normal range. As in Gilbert's syndrome, heterozygote R/APfd-j/+ rats with impaired hepatic bilirubin conjugation exhibit an increased unconjugated bilirubin level in serum, whereas the concentration of total conjugates was comparable to the values in normal rats. In serum of normal rats loaded intraperitoneally with unconjugated bilirubin, both unconjugated and mono- and diconjugated bilirubins were increased in parallel so that the ratio of unconjugated to esterified pigment remained unaffected. Decreased hepatic conjugation or increased bilirubin load was associated with a lower percentage of diconjugates relative to total conjugates both in human and rat serum. The present results are consistent with a compartmental model in which there is bidirectional transfer across the sinusoidal membrane for unconjugated bilirubin as well as for the bilirubin glucuronides. Because typical patterns of serum bilirubins are found in Gilbert's syndrome and patients with hemolytic hyperbilirubinemia, determination of esterified bilirubins in serum is of value to study the pathophysiology and the differential diagnosis of unconjugated hyperbilirubinemia.     

Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects

BACKGROUND AND AIM: Numerous mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with familial unconjugated hyperbilirubinemia. The UGT1A1 mutation appears to be considerably different among ethnic groups. To clarify the incidence of this gene mutation in the Japanese population, the presence of UGT1A1 mutation was investigated in a group of Japanese patients with Crigler-Najjar syndrome type 2 (CNS2) and Gilbert's syndrome (GS), as well as in healthy anicteric subjects. METHODS: Four patients with CNS2, 63 patients with GS, and 71 healthy subjects were enrolled in the study. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. The PCR products were directly sequenced by a dye terminating method. The UGT1A1 enzyme activity was determined in COS7 cells transfected with wild or P364L (1091 C > T) mutant DNA. RESULTS: Homozygous Y486D was observed in all four patients with CNS2. The GS patients had UGT1A1 mutations with 13 different genotypes in the promoter and coding region. Homozygous TA insertion in the TATA box (TA7) of the promoter region (TA7/7; 33%), homozygous G71R (9%), and combination of TA7/6 and heterozygous G71R (17%) were the most frequent findings in GS patients. Homozygous or heterozygous Y486D (8%) and P229Q (8%) were also observed in GS. A novel mutation, heterozygous P364L, was also identified in a GS patient. In addition to GS patients, homozygous or heterozygous TA7, G71R, and heterozygous Y486D were also observed in healthy subjects. The allele frequency of G71R and TA7 was 0.183 and 0.113 in healthy subjects, respectively. The P364L UGT1A1 enzyme activity was 64.4% lower than the wild-type enzyme activity. CONCLUSIONS: Polymorphisms in the coding region of UGT1A1 were commonly observed in Japanese patients with GS and in healthy subjects. The genetic basis of hyperbilirubinemia appears to be different between the Japanese and Caucasian populations.     

Etiology and Incidence of Unconjugated Hyperbilirubinemia after Orthotopic Liver Transplantation

Obfectives: Gilbert's syndrome, or slow bilirubin glucuronidation phenotype, is a common cause of benign hyperbilirubinemia in the general population. There have heen only two previously reported cases of Gilbert's syndrome occurring in patients after liver transplantation. This study was conducted to determine the frequency of Gilbert's syndrome in liver transplant recipients. Methods: The charts of all patients followed by the Mayo Liver Transplant Clinic for 1 yr or more after transplantation, as of June 1992, were reviewed to identify all patients with a consistent pattern of unconjugated hyperbiliruhinemia greater than two times the upper limits of normal and with a normal conjugated bilirubin level. These patients were further evaluated to exclude all other causes of hyperbilirubinemia, including biliary obstruction, rejection, viral infection, cholestatic liver disease, and hemolysis. Resutts: Five of 229 patients (2.2%) had a consistent pattern of unconjugated hyperbiliruhinemia. Only three patients (1.3%) had no other identifiable cause of hyperbilirubinemia. Conclusions: This study was performed to determine the incidence of unconjugated hyperbilirubinemia and particularly to determine the incidence of Gilbert's disease in liver transplant recipients. The apparently low frequency of Gilbert's after liver transplantation may reflect the masking of the diagnosis by other transplant-associated pathology or donor selection bias because of unexplained hyperbilirubinemia. Post-transplant patients who fit the Gilbert's syndrome profile of unconjugated hyperbilirubinemia should have a postprandial bilirubin drawn as a first step. The awareness of this syndrome may avoid a costly and invasive evaluation in the liver transplant recipient.     

几种主要的先天性胆红素代谢障碍性肝病的临床及病理研究

目的回顾性研究并分析几种主要的先天性胆红素代谢障碍性肝病的临床及病理学特点。方法收集我院2000年以来7036例患者的活体肝组织穿刺病理学诊断（肝穿）资料,其中主要的几种先天性胆红素代谢障碍性肝病病例155例,包括Gilbert综合征115例,Dubin—Johnson综合征33例,Crigler-Najjar综合征5例,Roter综合征2例,并结合其临床资料、生化检查进行统计学比较分析;采用常规HE染色及胆色素、铁、铜、网状纤维和胶原纤维等特殊染色,结合部分免疫组织化学染色,探讨其临床及病理学特点。结果该组155例先天性胆红素代谢障碍性肝病病例占总肝穿病例的2．2％,男女比例为5：1。年龄2～49岁;病史1个月～39年;临床主要以眼黄、尿黄和皮肤黄染为主（60．0％）,其次为乏力和纳差（20．6％）、脾大（21．9％）及肝大（17．4％）、胆红素升高（16．1％）。实验室比较分析,Gilbert综合征和Crigler—Najjar综合征以间接胆红素（IBIL）增高为主,Dubin-Johnson综合征和Roter综合征以直接胆红素（DBIL）增高为主,其中有3例Dubin—Johnson综合征患者在发病过程中动态监测始终以IBIL增高为主;主要病理改变为：肝组织内小叶结构均基本完整,中央区周围／区域肝细胞浆内在Gilbert综合征和Crigler—Najjar综合征可见较细的棕褐色色素颗粒沉积,在Dubin—Johnson综合征可见较粗糙的棕黑色色素颗粒沉积,而Roter综合征几乎难觅色素颗粒;部分肝细胞轻度水样变性或脂肪变性,Kupffer细胞内无吞噬色素颗粒现象;小叶间胆管轻度增生,无纤维组织增生及界面炎改变。结论先天性胆红素代谢障碍性肝病病例以男性为主,发病年龄以青少年居多,临床表现及实验室检查具有一定特点,病史从几个月到十几年不等,未见慢性化病理改变,组织检查均显示其特殊的病理特征,但?     

Hepatic transport of serum bilirubin,bromsulfophthalein, and indocyanine green in patients with congenital non-hemolytic hyperbilirubinemia and patients with constitutional indocyanine green excretory defect

We carried out a retrospective study of 71 patients with congenital non-hemolytic hyperbilirubinemia who had been treated at our institution over the 25 years from 1965 to 1990. Twenty patients had Gilbert's syndrome, 1 had Crigler-Najjar syndrome, 1 had new type unconjugated hyperbilirubinemia, 21 had Dubin-Johnson syndrome, and 28 had Rotor's syndrome. We also reviewed 20 patients with constitutional indocyanine green (ICG) excretory defect. The study focused on the hepatic transport of serum bilirubin, bromsulfophthalein (BSP), and ICG. In Dubin-Johnson syndrome, a defect appeared in late-stage transport, while uptake and storage capacity were normal. In Rotor's syndrome, defects were found in the early stage, and storage capacity was reduced, while excretion into bile was slightly suppressed. A secondary rise in serum ICG was seen in 5 of the 10 patients with Dubin-Johnson syndrome. The transport defect in Gilbert's syndrome was unclear. It could not be considered to be homogeneous, but it may exist at multiple sites, from the conjugation with serum proteins to excretion into bile. Following phenobarbital administration, the ICG secondary rise in the 5 patients with Dubin-Johnson syndrome disappeared, and ICG was rapidly cleared from blood. However, in patients with Dubin-Johnson syndrome, BSP clearance in serum did not show any change before and after phenobarbital administration. ICG excretion in patients with constitutional ICG excretory defect was due only to the impairment o ICG transport, and the defect was suggested to be hepatic uptake. These results indicate that studies of the hepatic transport of bilirubin, BSP, and ICG are useful for determining the etiological factors involved in congenital hyperbilirubinemia and constitutional ICG excretory defect.     

Successful photo-and phenobarbital therapy during pregnancy in a woman with Crigler-Najjar syndrome type II

Severe hyperbilirubinemia in a pregnant mother suffering from Crigler-Najjar syndrome type II is a threat to the unborn child and may result in brain injury. We report the case of a Gly71-->Arg/Tyr486-->Asp homozygous mother of East Asian descent, who was treated with phototherapy during embryogenesis and with phenobarbital during the rest of the pregnancy. This resulted in significantly reduced bilirubin levels in the mother, who gave birth to a healthy boy. A neonatal hyperbilirubinemia resolved spontaneously.