Alagille Syndrome

Alagille syndrome (ALGS) is an autosomal-dominant multisystem disorder caused by pathogenic variants in the or genes that disrupt the Notch signalling pathway, which is critical for embryonic development. The syndrome occurs in approximately 1 in 30,000 to 50,000 live births, though this may underestimate true prevalence due to variable expressivity and reduced penetrance. The hallmark feature is the paucity of interlobular bile ducts, leading to chronic cholestasis. This typically presents in the first 3 months of life with jaundice, pruritus, and elevated gamma-glutamyltransferase levels. Beyond the liver, ALGS affects multiple organ systems with characteristic features including cardiac abnormalities, distinctive facial features, skeletal anomalies, ophthalmologic findings, and renal involvement. Disease severity varies dramatically even within families, ranging from asymptomatic or isolated features to severe multiorgan disease that requires intervention. While some infants with significant cholestasis may experience well-compensated liver disease later in life, an estimated 20% to 30% of patients require liver transplantation for complications, including intractable pruritus, severe growth failure, liver synthetic dysfunction, portal hypertension, or severe osteodystrophy.