Clinical Features and Genetic Analysis of Pediatric Patients with Alagille Syndrome Presenting Initially with Liver Function Abnormalities

Alagille syndrome （AGS） is a multisystem disorder and caused by mutations in JAG1 or NOTCH2 gene. The diagnosis of AGS is hampered by its highly variable clinical manifestations. We performed a retrospective analysis on 16 children diagnosed as having AGS in recent five years in our hospital. Cholestasis was seen in 15 patients （93.8%）, heart disease in 12 （75%）, characteristic facies in 7 （43.8%）, and butterfly vertebrae in 7 （43.8%）. Ophthalmology examination was not performed on all the patients. Further, serum biochemical parameters were compared between AGS and 16 biliary atresia （BA） patients who were confirmed by surgery. Elevated liver enzymes were seen in all the patients. Serum total cholesterol （TC） （P=0.0007）, alanine aminotransferase （ALT） （P=0.0056）, aspartate aminotransferase （AST） （P=0.0114）, gamma-glutamyl transferase （GGT） （P=0.035） and total bile acid （TBA） levels （P=0.042） were significantly elevated in AGS patients compared to those in BA cases. However, there were no significant differences in serum total bilirubin （TB）, conjugated bilirubin （CB） and albumin （ALB） between the two groups. We identified 14 different JAG1 gene variations and 1 NOTCH2 gene mutation in 16 Chinese AGS patients. Our study suggested clinical features of AGS are highly variable and not all patients meet the classical diagnostic criteria. It was suggested that hypercholesterolaemia and significantly elevated GGT, TBA and ALT may be helpful to diagnose AGS. Genetic testing is integral in the diagnosis of AGS.

Alagille syndrome associated with total anomalous pulmonary venous connection and severe xanthomas:A case report

BACKGROUND Alagille syndrome(ALGS)is an autosomal dominant genetic disorder caused by mutations in the JAG1 or NOTCH2 gene.It is characterized by decreased intrahepatic bile ducts associated with a variety of abnormalities in many other organ systems,such as the cardiovascular,skeletal,and urinary systems.CASE SUMMARY We report a rare case of ALGS.A 1-month-old male infant presented with sustained jaundice and had a rare congenital heart disease:Total anomalous pulmonary venous connection(TAPVC).Sustained jaundice,particularly with cardiac murmur,caught our attention.Laboratory tests revealed elevated levels of alanine aminotransferase,aspartate aminotransferase,gamma-glutamyl transpeptidase,total bilirubin,and total bile acids,indicating serious intrahepatic cholestasis.Imaging confirmed the presence of butterfly vertebra at the seventh thoracic vertebra.This suggested ALGS,which was confirmed by genetic testing with a c.3197dupC mutation in the JAG1 gene.Ursodiol was administered immediately after confirmation of the diagnosis,and cardiac surgery was performed when the patient was 1.5 month old.He recovered well after treatment and was discharged at the age of 3 mo.At the age of two years,the patient returned to our clinic because multiple cutaneous nodules with xanthomas appeared,and their size and number increased over time.CONCLUSION We report a unique case of ALGS associated with TAPVC and severe xanthomas.This study has enriched the clinical manifestations of ALGS and emphasized the association between JAG1 gene and TAPVC.

Pulmonary artery stent thrombosis and symptomatic pulmonary hypertension following COVID-19 infection in Alagille patient:A case report

BACKGROUND Alagille syndrome is a multisystem disease that results in various vascular anomalies,commonly involving the cardiac and pulmonary systems.To the best of our knowledge,there is no literature regarding the cardiovascular outcomes of these patients in association with coronavirus disease 2019(COVID-19).CASE SUMMARY A 34-year-old woman with a history of Alagille syndrome who underwent successful atrial septal defect with partial anomalous pulmonary veins and patent ductus arteriosus repair,as well as left pulmonary artery catheterization and stenting in childhood due to pulmonary stenosis.The patient was without any respiratory symptoms and was a dancer prior to contracting COVID-19.Several weeks after her COVID-19 infection,she developed left pulmonary artery stent thrombosis and subsequent symptomatic pulmonary hypertension.A treatment strategy of anticoagulation alongside pharmacological agents for pulmonary hypertension for 3 months followed by balloon pulmonary artery angioplasty to reopen the stenosis was unsuccessful.CONCLUSION In the era of COVID-19,patients with pulmonary vascular malformations and endovascular stents are at an increased risk for chronic thromboembolic disease.Patients may benefit from prophylactic antiplatelet or anticoagulation therapy.Stent thrombosis is a devastating phenomenon and should be treated urgently and aggressively with balloon pulmonary angioplasty,and/or a thrombolytic agent.

A 9-year-old Chinese boy with Alagille syndrome

Alagille syndrome （AGS, OMIM#118450） is a multi-system, autosomal dominant disorder with variable clinical manifestation, which primarily affects the liver, heart, eyes, face, and skeleton. The estimated incidence of AGS is 1 in 70000 births of all races worldwide; however it has been rarely reported in Chinese children. We treated a Chinese boy presenting with jaundice, pruritus and gowth failure finally who had been diagnosed as having AGS. Informed consent was obtained from the legal guardian of the child before reporting.

Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome

Background The liver manifestations of Alagille syndrome(ALGS)are highly variable,and factors affecting its prognosis are poorly understood.We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers.Methods Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age.A good prognosis was defined as survival with native liver and total bilirubin(TB)<85.5 μmol/L,while a poor prognosis was defined as either liver transplantation,death from liver failure,or TB ≥ 85.5 μmol/L at the last follow-up.Results We found that the concentrations of two poly-hydroxylated bile acids,tauro-2β,3α,7α,12α-tetrahydroxylated bile acid(THBA)and glyco-hyocholic acid(GHCA),were significantly increased in patients with good prognosis compared to those with poor prognosis[area under curve(AUC)=0.836 and 0.782,respectively]in the discovery cohort.The same trend was also observed in the molar ratios of GHCA to glyco-chenodeoxycholic acid(GCDCA)and tetrahydroxylated bile acid(THCA)to tauro-chenodeoxycholic acid(TCDCA)(both AUC=0.836).A validation cohort confirmed these findings.Notably,tauro-2β,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00%(92.31%sensitivity and 83.33%specificity);GHCA at>607.69 nmol/L was associated with native liver survival[hazard ratio:13.03,95%confidence interval(CI):(2.662-63.753),P=0.002].Conclusions We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients.Enhanced hydroxylation of bile acids may result in better clinical outcomes.

Clinical and Genetic Characteristics of Alagille Syndrome in Adults

Background and Aims:Alagille syndrome(AGS)is an autosomal dominant multisystem disorder caused by mutations in the JAG1 and NOTCH2 genes.AGS has been rarely reported in adult patients,mainly because its characteristics in adults are subtle.The study aimed to improve the understanding of adult AGS by a descriptive case series.Methods:Eight adults diagnosed with AGS at our hospital between June 2016 and June 2019 were included in the study.Clinical data,biochemical results,imaging results,liver histopathology,and genetic testing were analyzed.Results:Three female and five male patients with a median age of 24.5 years at the time of diagnosis were included in the analysis.The clinical manifestations were adult-onset(62.5%,5/8),cholestasis(50%,4/8),butterfly vertebrae(62.5%,5/8),systolic murmurs(12.5%,1/8),typical facies(12.5%,1/8),posterior embryotoxon,and renal abnormalities(0/8).Genetic sequencing showed that all patients had mutations,with four occurring in the JAG1 gene and four in the NOTCH2 gene.Six were substitution mutations,one was a deletion mutation,and one was a splicing mutation.Five had been previously reported;but the others,one JAG1 mutation and two NOTCH2 mutations were unique and are reported here for the first time.Conclusions:The clinical manifestations highlighted by the current diagnostic criteria for most adults with AGS are atypical.Those who do not meet the criteria but are highly suspicious of having AGS need further evaluation,especially genetic testing.

Neonatal cholestasis can be the first symptom of McCune–Albright syndrome:A case report

BACKGROUND McCune–Albright syndrome(MAS)is caused by postzygotic somatic mutations of the GNAS gene.It is characterized by the clinical triad of fibrous dysplasia,caféau-lait skin spots,and endocrinological dysfunction.Myriad complications in MAS,including hepatobiliary manifestations,are also reported.CASE SUMMARY This is a case of a 4-year-old boy who presented with MAS with neonatal cholestasis.He was suspected to have Alagille syndrome due to neonatal cholestasis with intrahepatic bile duct paucity in liver biopsy,peripheral pulmonary artery stenosis,and renal tubular dysfunction.By the age of 2 years,his cholestatic liver injury gradually improved,but he had repeated left femoral fractures.He did not exhibit endocrinological abnormality or café-au-lait skin spots.However,MAS was suspected due to fibrous dysplasia at the age of 4 years.No mutation was identified in the GNAS gene in the DNA isolated from the peripheral blood,but an activating point mutation(c.601C>T,p.Arg201Cys)was observed in the DNA extracted from the affected bone tissue and that extracted from the formalin-fixed paraffin-embedded liver tissue,which was obtained at the age of 1 mo.CONCLUSION MAS should be considered as a differential diagnosis for transient cholestasis in infancy.

Atypical causes of cholestasis

Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have &#x0201c;silent&#x0201d; progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.

Heritable Chronic Cholestatic Liver Diseases:A Review

Chronic cholestasis due to heritable causes is usually diagnosedin childhood.However,many cases can present andsurvive into adulthood.The time course varies considerablydepending on the underlying etiology.Laboratory data usuallyreveal elevated conjugated hyperbilirubinemia,alkalinephosphatase,and gamma-glutamyl transpeptidase.Patientsmay be asymptomatic;however,when present,the typicalsymptoms are pruritus,jaundice,fatigue,and alcoholicstools.The diagnostic methods and management requireddepend on the underlying etiology.The development of genome-wide associated studies has allowed the identificationof specific genetic mutations related to the pathophysiologyof cholestatic liver diseases.The aim of this review was tohighlight the genetics,clinical pathophysiology,presentation,diagnosis,and treatment of heritable etiologies of chroniccholestatic liver disease.

Notch signaling:Its essential roles in bone and craniofacial development

Notch is a cellecell signaling pathway that is involved in a host of activities including development,oncogenesis,skeletal homeostasis,and much more.More specifically,recent research has demonstrated the importance of Notch signaling in osteogenic differentiation,bone healing,and in the development of the skeleton.The craniofacial skeleton is complex and understanding its development has remained an important focus in biology.In this review we briefly summarize what recent research has revealed about Notch signaling and the current understanding of how the skeleton,skull,and face develop.We then discuss the crucial role that Notch plays in both craniofacial development and the skeletal system,and what importance it may play in the future.

Advanced therapies for congenital biliary tract malformation:From bench to bedside

Congenital biliary tract malformations are a series of rare but extremely serious diseases that mainly include biliary atresia and biliary hypoplasia(referred to as Alagille syndrome).The rapid progression of biliary atresia and Alagille syndrome results in jaundice,cholestatic liver disease,cirrhosis,and even liver failure.In most cases,supportive or clinically specific therapies cannot achieve satisfactory outcomes.Therefore,liver transplantation(especially living donor liver transplantation)may be required.As many studies have elucidated the role of genetic factors and the molecular mechanism of congenital biliary tract malformations,experimental therapies such as organoid transplantation,cell therapy,and immunotherapy have been proved to be feasible.These advanced methods have shown outstanding advantages,particularly in patients with end-stage biliary tract malformations,surgery failure,and other problems that cannot be solved by conventional therapies.This review article discusses the potential pathogenesis of and promising therapeutic strategies for biliary tract malformations.