Clinical characteristics: Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability; this variability is seen even among individuals from the same family. The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects (primarily involving the pulmonary arteries), butterfly vertebrae, ophthalmologic abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Renal abnormalities, growth failure, behavioral differences, splenomegaly, retinal changes, and vascular abnormalities may also occur.

Diagnosis/testing: The diagnosis of ALGS is established in a proband who meets clinical diagnostic criteria and/or has a heterozygous pathogenic variant in JAG1 or NOTCH2 identified by molecular genetic testing.

Management: Targeted therapy: Ileal bile acid transporter inhibitors (maralixabat and odevixibat) to increase excretion of bile acids.

Supportive care: Management by a multidisciplinary team according to clinical manifestations (clinical genetics, gastroenterology/hepatology, nutrition, cardiology, ophthalmology, nephrology, transplant hepatology, and child development); choleretic agents (ursodeoxycholic acid), other medications (cholestyramine, rifampin, naltrexone) for pruritus and xanthomas; liver transplantation for refractory cholestasis and/or end-stage liver disease; optimized nutrition and replacement of fat-soluble vitamins as needed; treatment of cardiovascular manifestations in a center with experience with ALGS; low vision services as needed; standard treatment for hepatocellular carcinoma and renal and neurologic involvement.

Surveillance: Monitor liver function per gastroenterologist/hepatologist; serum alpha-fetoprotein and liver ultrasound every six months; at each visit, assess growth, blood pressure, and for recurrent fractures; nutrition assessment as needed; assessment for vascular manifestations per cardiologist; vision assessment per ophthalmologist; basic metabolic panel every six months; assess developmental progress and for attention and executive function impairment annually.

Agents/circumstances to avoid: Contact sports; alcohol consumption if liver disease is present.

Genetic counseling: ALGS is inherited in an autosomal dominant manner. Approximately 40% of individuals have an inherited pathogenic variant and about 60% have a de novo pathogenic variant. Parental somatic/germline mosaicism has been reported. Offspring of an individual with ALGS have a 50% chance of inheriting the JAG1 or NOTCH2 pathogenic variant. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible if the causative genetic alteration has been identified in an affected family member. Because ALGS is associated with highly variable expressivity with clinical features ranging from subclinical to severe, clinical manifestations cannot be predicted by molecular genetic prenatal testing.