Introduction

Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder which was first described in 1969 by Daniel Alagille as a constellation of clinical features in five different organ systems [1]. The diagnosis was based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac disease (most often peripheral pulmonary stenosis), skeletal abnormalities (typically butterfly vertebrae), ocular abnormalities (primarily posterior embryotoxon), and characteristic facial features. Advances in molecular diagnostics have enabled an appreciation of the broader disease phenotype with recognition of renal and vascular involvement [2,3]. There is significant variability in the extent to which each of these systems is affected in an individual, if at all [4,5]. It was originally estimated that ALGS had a frequency of 1 in 70000 live births, although this was based on the presence of neonatal cholestasis. However, this is clearly an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease and the true frequency is likely closer to 1 in 30000 [5].

Alagille syndrome is caused by mutations in JAGGED1 (JAG1), encoding a ligand Jagged1 in the Notch signaling pathway [6,7]. Mutations in JAG1 are identified in 94% of clinically defined probands [8]. Recently, mutations in NOTCH2 have been identified in a few patients with ALGS who do not have JAG1 mutations [9]. This exciting development has enhanced our understanding of the heterogeneity of this disorder, although much remains to be understood about the tremendous variability seen in affected individuals and the likely genetic modifiers involved.