Alagille syndrome

Alagille syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. A high proportion of probands carry a de novo pathogenic variant (approximately 60%). Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis rests on consensus criteria. Meeting these criteria establishes the clinical diagnosis of Alagille syndrome. Suggestive features include cholestasis, congenital heart disease (most commonly peripheral pulmonic stenosis), butterfly vertebrae, posterior embryotoxon, and the characteristic facies. Liver biopsy demonstrating bile duct paucity is the most important and constant histologic feature, identified in approximately 65% of biopsies performed within the first three months of life and in approximately 95% of individuals eventually. AP chest radiographs identify butterfly vertebrae, and slit-lamp examination identifies posterior embryotoxon.

Main differential diagnoses include:

• Biliary atresia: most common identifiable cause of neonatal cholestasis; a progressive fibro-obliterative cholangiopathy of the extrahepatic bile ducts requiring early surgical intervention (Kasai portoenterostomy); non-Mendelian, no causative gene
• Axenfeld-Rieger syndrome: anterior segment dysgenesis with posterior embryotoxon plus iris and iridocorneal angle anomalies, dental hypoplasia, and redundant periumbilical skin, without the cholestatic liver disease characteristic of ALGS; FOXC1, PITX2
• 22q11.2 deletion syndrome: conotruncal cardiac defects (including TOF and VSD) with thymic/parathyroid hypoplasia, palatal abnormalities, and characteristic neurodevelopmental profile; butterfly vertebrae and poor growth may overlap, but liver disease is not a feature; 22q11.2 contiguous-gene deletion (TBX1)

• Establishing the molecular diagnosis through identification of the causative pathogenic variant.
• Enabling specific and individualised surveillance, including for hepatocellular carcinoma and for hepatic, cardiac, ophthalmologic, renal, growth/nutritional, skeletal, and developmental manifestations, and providing the prerequisite for targeted medical care, the details of which are determined by the treating physicians in consultation with the affected individual.
• Allowing predictive testing of at-risk family members once the familial pathogenic variant has been identified.

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• Vandriel SM, Li LT, She H, Wang JS, Gilbert MA, Jankowska I, et al. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from the GALA study. Hepatology. 2023;77(2):512-529. PMID: .
• Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, Chao G, McEldrew D, et al. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40(12):2197-2220. PMID: .
• Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet. 2003;40(12):891-895. PMID: .