Research Of Several Genetic Causes In Children With Chronic Jaundice

Aim:To investigate the significance of uridine-diphosphoglucuronosyltransferase1A1（UGT1A1） gene variations in prolonged unconjugated hyperbilirubinemia beyond neonatal period.Methods:Fifteen infants with prolonged unconjugated hyperbilirubinemia between the ages of1and3months who were referred to pediatric liver disease clinics of Children’s Hospital of Fudan University from May2009to January2011were enrolled. The medical history was recorded, including the feeding history, sex, ages and liver function tests, etc. Whole blood cell count, reticulocyte count, and thyroid function tests were performed. The promoter area and all5coding exons of UGT1A1gene were amplified and sequenced directly.Results:None of15infants had evidence of hemolysis, infection and hypothyroidism. UGT1A1gene variations were detected in13of the15infants, including2of3bottle-fed infants. Four variations were detected, included G71R, P364L, A（TA）6/（TA）7TAA and P229Q, the variation rates were73.3%,20.0%,13.3%and6.7%respectively. The variation rates in control group were26.0%,4.0%,20.0%and2.0%. The prevalence of G71R was much higher in case group than that in normal control group （p=0.001）Conclusion:Whether breast-feed or bottle-feed, UGT1A1deficiency is the most common cause of prolonged unconjugated hyperbilirubinemia beyond neonatal period. G71R was the most common variation. Aims:To investigate the significance of uridine-diphosphoglucuronosyltransferase1A1（UGT1A1） gene mutations in Children with chronic non-hemolytic unconjugated hyperbilirubinemia and its characteristics of mutations.Methods:Twelve children with chronic non-hemolytic unconjugated hyperbilirubinemia who were referred to pediatric liver disease clinics of Children’s Hospital of Fudan University from August2007to April2011were enrolled. The medical history was recorded, including the family history, sex, ages and response to phenobarbital. Whole blood cell count, reticulocyte count and liver function tests were performed routinely in all patients. The promoter area and all5coding exons of UGT1A1gene were amplified and sequenced directly.Results:Jaundice resolved rapidly in all patients after administrating with Phenobarbital, except one case. All patients are in normal growth and development. All12patients had at least one mutation of the UGT1A1, including2homozygous,7compound heterozygous and3heterozygous. Twelve mutations were detected, six were reported previous, including P229Q, R341X, P364L, Q357X, P451L, Y486D; and the other six mutations were novel, including G96E, L255Q, S343X, T371I, S381N and c.1047de1G All11mutations were detected in one case, except Y486D, wich was identified in eight cases, including two homozygotes and six heterozygotes. Besides, two common SNPs, such as A（TA）6/（TA）7TAA （3heterozygotes）and G71R （1homozygote and6heterozygotes） were identified.Conclusion:UGT1A1gene mutation is the most important cause of children with chronic non-hemolytic unconjugated hyperbilirubinemia. Y486D is probably a hot mutation in children with Crigler-Najjar and Gilbert syndrome in Mainland China. Aim:To study the significance of ABCB4gene mutations in mainland Chinese children with chronic intrahepatic cholestasis, its clinical features and response to ursodeoxycholic acid （UDCA） therapy.Methods:Thirteen patients with chronic intrahepatic cholestasis and elevated gamma-glutamyl-transpeptidase （GGT） of unknown cause after exclusion of other main causes of cholestasis from March2004to October2009were enrolled in a single pediatric center. All encoding exons and flanking areas of the ABCB4gene were sequenced. The clinical features, biochemical parameters and response to therapy were compared with patients with or without ABCB4mutation（s）.Results:Six mutations were identified in three patients with compound heterozygous ABCB4gene mutations. Apart from R47X, all were novel mutations, including IVS5+2₊3insT, D459G, R582Q, P693HfsX698, M1276WfsX1308. The serum total bile acid （TBA） levels were higher in patients with ABCB4mutations than those in patients without ABCB4mutations （P=7.32E-05）. There was no difference in other biochemical parameters between patients with and without ABCB4mutations. After oral UDCA administration in three patients with ABCB4mutations, pruritus significantly diminished or disappeared and serum aminotransferases levels declined.Conclusions:Some cases of chronic intrahepatic cholestasis with high GGT could be attributed to ABCB4mutations in China. Serum TBA level seems a promising indicator in differentiating progressive familial intrahepatic cholestasis type3from other causes. UDCA administration could partially improve clinical symptoms and liver function. Background and aims:Patients with deficiency of3β-hydroxy-C27-steroid dehydrogenase （3β-HSD） are rare. Though cholic acid （CA） could improve the prognosis, it is not universally available. Here we report two Chinese patients with genetic confirmed3β-HSD deficiency, and their successfully management with high-dose ursodeoxycholic acid （UDCA）.Methods:Two infants with neonatal onset cholestasis, normal serum gamma glutamyl transpeptidase （GGT） and total bile acid （TBA） were selected. All6coding exons and at least100bp adjacent intronic regions of the HSD3B7gene were amplified and sequenced directly. Varying doses of UDCA was administrated to these two patients.Results:Both of them were identified HSD3B7mutations. First case harbored a homozygous mutation c.1031A>G, p. Y344C. Second case harbored compound heterozygous mutations c.45₄6delAG, p.G17LfsX45å'Œc.988₉90del ACC, p.T330del. Carrier state was detected in both parents. Afterward blood and urinary bile acid spectrum analysis was consisting with the diagnosis. With various dose of UDCA oral administration, two patients responded well in50mg per kilogram per day with cholestasis resolved rapidly, serum transaminases normalized and clinical manifestation of cirrhosis disappeared..Conclusions:3β-HSD deficiency is an important cause of bile acid synthetic deficit in Chinese infants. High-dose UDCA administration is an alternative choice for the successfully management of3β-HSD deficiency patients. Overview1. Some chronic jaundice had genetic cause, genetic testing could help us to definite the diagnoses, treatment and prognosis.2. UGT1A1deficiecy is the most common cause of children with non-hemolytic unconjugated hyperbilirubinemia.3. ABCB4mutation is the important cause of chronic intrhepatic chlostais with high GGT in China. Serum TBA level seems a promising indicator in differentiating progressive familial intrahepatic cholestasis type3from other causes.4. Congenital bile acid synthesis defect exists in Mainland China.3(3-HSD deficiency is the most common cause in chronic intrahepatic cholestasis with low GGT and TBA. High-dose UDCA dministration is an alternative choice for the successfully management of3β-HSD deficiency patients.