Clinical,Genetic And Literature Review Of 2 Patients With Alagille Syndrome

Objective: To explore the clinical and genetic characteristics of Alagille syndrome and review the literature.Methods:Data of liver function,hepatic fiber,cholangiography,liver pathology,blood routine,cardiac ultrasonography,abdominal ultrasonography,positive and lateral X-ray of thoracic vertebra,and ophthalmological examination were collected from 2 cases of clinically diagnosed Alagille syndrome in our department from January 2015 to January 2019.Regular review to observe changes in liver function and growth and development information.DNA was extracted from the peripheral blood of 2 children and their parents,and the target gene was captured by liquid-phase capture kit(maginol,China)for high-throughput sequencing analysis.Software such as SIFT and polyphen-2 was used to predict the pathogenicity of gene mutations.Results:Both of the 2 cases started at the neonatal stage,and the main clinical manifestations were skin yellowing with increased transaminase.Liver function showed high TBIL,mainly DBIL,with the proportion of DBIL/TBIL reaching 50%-90% at the phase of 1-3 months,accompanied by increased GGT,TBA,CHOL and ALP.Case 1 showed severe biliary dysplasia on cholangiography.Liver biopsy pathology: hepatic lobule structure was unclear,hepatocyte was cholestasis and present with mild fibrosis.Chronic inflammatory cell was infiltrating in the portal area.Note t-he proliferation of bile ducts.Masson staining showed mild bridging fibrosis near portal area and fibrosis class?(Ohkuma 's classification).Color doppler ultrasound showed congenital heart disease:ventricular septal defect,tricuspid valve mild reflux.The child was presented with typical facial features,butterfly vertebrae,short stasis.JAG1 gene: spontaneous single chain heterozygous mutation c.3197delC(p.t1066kfs),a newly discovered frame-shift mutation,was not found in either parent.Case 2 showed congenital heart disease:atrial septal(defect II,5mm),by color dop-pler ultrasound.Delayed intestinal imaging with 2h hepatobiliary radionuclide scanning,magnetic resonance cholangiopancreatography(MRCP)showed no obvious dilation of the intrahepatic and extrahepatic bile ducts,and the child was presented with ALGS facial features,growth retardation.Gene test showed that JAG1 gene had spontaneous single chain heterozygous mutation c.118 el(p.l40kfs),which was a newly discovered frameshift mutation,and neither of her parents with the corresponding mutation.Liver function outcome:the DBIL of the case1 patient gradually decreased from 187 ?mol/L at two month,to 50 ?mol/L at seven month,20 ?mol/L at 1 year old,and 8.4?mol/L at 2 years old,which was nearly normal.The DBIL of cases 2 decreased from 122 ?mol/L at 1 month,35 ?mol/L at 7 months,22-26 ?mol/L at 1 year old,to 12.8 ?mol/L at 3 years old,which was closed to normal.ALT and AST were consistently higher than normal before 2-3 years of follow-up,and the values were maintained between 2-3 times of the normal reference range.GGT and TBA values decreased gradually,but were still higher than normal at 2-3 years old.CHOL was higher than normal,and showed a gradually increasing trend before the age of 1 year.At the age of 3 years,there was no significant decrease trend of CHOL.The serum albumin of case 1 was lower than normal or slightly lower than normal,while the serum albumin of case 2 was basically normal.ALP continues to be higher than normal.Conclusion:1.Children with ALGS usually develop moderate to severe cholestatic liver disease at 1-3 months after birth,during which the proportion of DBIL/TBIL can be as high as 69% to 93%,and then gradual decline,and DBIL is close to normal when they are 2-3 years old.2.ALT,AST,GGT,TBA and CHOL of ALGS children were consistently higher than normal,and serum albumin was normal or slightly lower than normal before 2-3 years old.3.Mild and moderate iron deficiency anemia may occur before the age of 1 year in children with ALGS,which can be corrected automatically with age,and there is no obvious abnormality in white blood cell count,classification and platelet count.4.ALGS manifests as congenital heart disease and butterfly vertebrae,in this study,1 patient was with short stature and congenital iris defect,and 1 patient had growth retardation.5.Hepatic pathology of ALGS at 2 months old may present small bile duct hyperplasia in the portal area,mild fibrosis and chronic inflammatory cell infiltration.Masson staining and shown to near portal area of mild bridging fibrosis and fibrosis class ?(Ohkuma 's classification).6.Single heterozygous spontaneous mutations were found respectively from JAG1 genes in the 2 ALGS children,case 1:c.3197delC(p.t1066kfs) and case 2:c.118delC(p.L40fs).Both of which were not been reported.Neither parents detected the corresponding mutation.