Alagille Syndrome — Pediatric

Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused most commonly by mutations in JAG1 (over 90 percent) or NOTCH2 genes, with highly variable expression even within the same family.

The clinical hallmarks include chronic cholestasis from intrahepatic bile duct paucity, congenital cardiac disease (most often peripheral pulmonic stenosis, sometimes tetralogy of Fallot), butterfly vertebrae, posterior embryotoxon of the eye and characteristic facial features (broad forehead, deep-set eyes, pointed chin).

Children typically present in infancy with prolonged neonatal jaundice, severe pruritus from elevated bile acids, xanthomas, growth failure, fat malabsorption with fat-soluble vitamin deficiencies and hypercholesterolemia.

Diagnostic criteria require bile duct paucity on liver biopsy plus three of five major features (cholestasis, cardiac, vertebral, ophthalmologic, facial); genetic testing of JAG1 and NOTCH2 confirms diagnosis when paucity is borderline.

Management is multidisciplinary including ursodeoxycholic acid, ileal bile acid transporter (IBAT) inhibitors such as maralixibat or odevixibat for refractory pruritus, fat-soluble vitamin supplementation, growth and nutrition support, cardiology surveillance and liver transplantation in patients with intractable pruritus, end-stage liver disease or growth failure.