Alagille Syndrome

Excerpt

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, developmental delays, splenomegaly, 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: Treatment of manifestations: Management by a multidisciplinary team according to clinical manifestations (clinical genetics, gastroenterology, nutrition, cardiology, ophthalmology, nephrology, transplant hepatology, and child development); choloretic agents (ursodeoxycholic acid), other medications (cholestyramine, rifampin, naltrexone); liver transplantation for end-stage liver disease; standard treatment for cardiac, renal, and neurologic involvement.

Surveillance: Regular monitoring by cardiology, gastroenterology, and nutrition specialists.

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

Genetic counseling: ALGS is inherited in an autosomal dominant manner. Approximately 30%-50% of individuals have an inherited pathogenic variant and about 50%-70% have a de novo pathogenic variant. Parental somatic/germline mosaicism has been reported. Each child of an affected individual is at a 50% risk of inheriting the ALGS-related genetic alteration and developing signs of ALGS. 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.