Clinical features and outcomes in an international cohort of 731 Alagille syndrome patients from 19 countries

Abstract : Background: Alagille syndrome (ALGS) is a multisystem disorder, typically presenting with neonatal cholestasis. Prior cohort studies in ALGS largely come from tertiary center liver centers and therefore select for the most severely affected cholestatic patients. As a result, the full spectrum of ALGS liver involvement remains unclear. Furthermore, a comprehensive assessment of extrahepatic manifestations in a large cohort of patients is missing. In 2017, the Global ALagille Alliance (GALA) Study Group was established to overcome these limitations. Methods: This is a retrospective multicentre study in children and young adults with a clinically and/or genetically confirmed diagnosis of ALGS, born between January 1997-May 2019. Histopathological findings before and after 6 months were compared using chi-square test. Native liver survival (NLS) in patients presenting with neonatal cholestasis and overall survival were estimated using cox regression analysis. Results: 731 ALGS (41% female) subjects from 32 centres were included (median follow-up 4.75 yrs, IQR 2.0-10.2). Among the 76% (n=554/731) genetically-confirmed patients, 95% had a JAG1 mutation and 4% a NOTCH2mutation (70% de novo). Presence of any cardiac anomaly and characteristic facies were the most common clinical manifestations, 87% (each), followed by posterior embryotoxon, 45%, butterfly vertebrae, 43% and renal anomalies, 38%. Available MRI and CT reports (mostly performed for screening) revealed cerebral and intra-abdominal vascular anomalies in 36% (n=57/159) and 26% (n=27/105) of subjects, respectively. 79% of ALGS subjects presented with neonatal cholestasis. 299 initial liver biopsy reports were reviewed (Table 1) and revealed an increasing frequency of bile duct paucity with age and of note, bile duct plugs in 6% of biopsies