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

Abstract

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.

Keywords

Alagille syndrome / cholestasis / biochemical characteristics / gene / infant

References

[1] AlagilleD, EstradaA, HadchouelM, et al.. Syndromic paucity of interlobularbile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr, 1987, 110(2): 195-200

[2] EmerickKM, RandEB, GoldmuntzE, et al.. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology, 1999, 29(3): 822-829

[3] TurnpennyPD, EllardS. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet, 2012, 20(3): 251-257

[4] KamathBM, PiccoliDA, MageeJC, et al.. Pancreatic insufficiency is not a prevalent problem in Alagille syndrome. J Pediatr Gastroenterol Nutr, 2012, 55(5): 612-614

[5] SalemJE, BruguiereE, IserinL, et al.. Hypertension and aortorenal disease in Alagille syndrome. J Hypertens, 2012, 30(7): 1300-1306

[6] KamathBM, BasonL, PiccoliDA, et al.. Consequences of JAG1 mutations. J Med Genet, 2003, 40(12): 891-895

[7] SubramaniamP, KniselyA, PortmannB, et al.. Diagnosis of Alagille syndrome 25 years of experience at King’s College Hospital. J Pediatr Gastroenterol Nutr, 2011, 52(1): 84-89

[8] Quiros-TejeiraRE, AmentME, HeymanMB, et al.. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr, 1999, 29(4): 431-437

[9] LykavierisP, HadchouelM, ChardotC, et al.. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut, 2001, 49(3): 431-435

[10] LiL, KrantzID, DengY, et al.. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet, 1997, 16(3): 243-251

[11] OdaT, ElkahlounAG, PikeBL, et al.. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet, 1997, 16(3): 235-242

[12] McDaniellR, WarthenDM, Sanchez-LaraPA, et al.. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am J Hum Genet, 2006, 79(1): 169-173

[13] BulkFP, MavierP, ZafraniES, et al.. Mechanism of gamma-glutamyl transpeptidase release in serum during intrahepatic and extrahepatic cholestasis in the rat: a histochemical, biochemical and molecular approach. Hepatology, 1990, 11(4): 545-550

[14] BalistreriWF, BezerraJA, JansenP, et al.. Intrahepatic cholestasis: summary of an American Association for the Study of Liver Diseases single-topic conference. Hepatology, 2005, 42(1): 222-235

[15] JurkiewiczD, GliwiczD, CiaraE, et al.. Spectrum of JAG1 gene mutations in Polish patients with Alagille syndrome. J Appl Genet, 2014, 55(3): 329-336

[16] GarciaMA1, RamonetM, CioccaM, et al.. Alagille syndrome: cutaneous manifestations in 38 children. Pediatr Dermatol, 2005, 22(1): 11-14

[17] RielyCA, CotlierE, JensenPS, et al.. Arteriohepatic dysplasia; A benign syndrome of intrahepatic cholestasis with multiple organ involvement. Am Intern Med, 1979, 91(4): 520-527

[18] ShahI, BhatnagarS, DhabeH. Clinical and biochemical factors associated with biliary atresia. Trop Gastroenterol, 2012, 33(3): 214-217

[19] Rendón-MacíasME, Villasís-KeeverMA, Castañeda-MuciñoG, et al.. Improvement in accuracy of gammaglutamyl transferase for differential diagnosis of biliary atresia by correlation with age. Turk J Pediatr, 2008, 50(3): 253-259

[20] KamathBM, et al.. SuchyFJ, SokalRJ, BalistreriWF, et al.. Alagille syndrome. Liver Disease in Children, 2007, New York, Cambridge University Press: 326-345

[21] GueganK, StalsK, DayM, et al.. JAG1 mutations are found in approximately one third of patients presenting with only one or two clinical features of Alagille syndrome. Clin Genet, 2012, 82(1): 33-40

[22] SpinnerNB, CollitonRP, CrosnierC, et al.. Jagged1 mutations in alagille syndrome. Hum Mutat, 2001, 17(1): 18-33