Alagille syndrome (AGS) is a highly variable, multisystem, autosomal dominant disorder that primarily affects the liver, heart, eyes, face, and skeleton [1–3]. There is significant variability in the extent to which each of these systems is affected in an individual, if at all [4, 5]. AGS has traditionally been diagnosed 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 [6]. It has an estimated frequency of 1 in 70,000 live births based on the presence of neonatal cholestasis. However, this is an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease.

Alagille syndrome is caused by mutations in Jagged1 (JAG1), a ligand in the Notch signaling pathway [7, 8]. JAG1 mutations are identified in more than 90% of clinically diagnosed probands [9]. Recently, mutations in Notch2 have been identified in a few patients with AGS who do not have JAG1 mutations [10]. This exciting development has enhanced our understanding of the heterogeneity of this disorder, though much remains to be understood about the tremendous variability seen in affected individuals and the likely genetic modifiers involved.

BILE DUCT PAUCITY

Bile duct paucity is present in a diverse group of metabolic, infectious, and inflammatory hepatic disorders in infancy.