Alagille syndrome due to 20p12 microdeletion

Alagille syndrome due to 20p12 microdeletion is a contiguous gene deletion syndrome caused by a chromosomal microdeletion on the short arm of chromosome 20 (20p12) that encompasses the JAG1 gene. This is one of the two genetic mechanisms underlying Alagille syndrome (ALGS), the other being point mutations within JAG1 or, less commonly, NOTCH2. Approximately 3–7% of individuals with Alagille syndrome have a cytogenetically or molecularly detectable deletion at 20p12. The JAG1 gene encodes a ligand in the Notch signaling pathway, which is critical for embryonic development of multiple organ systems. Alagille syndrome is a multisystem disorder primarily characterized by chronic cholestasis due to a paucity of intrahepatic bile ducts (bile duct hypoplasia), congenital heart defects (most commonly peripheral pulmonary stenosis), butterfly vertebrae, posterior embryotoxon or other ocular abnormalities, and characteristic facial features including a broad forehead, deep-set eyes, pointed chin, and a straight nose. Additional features may include renal anomalies (such as renal dysplasia or renal tubular acidosis), growth retardation, and, less frequently, vascular abnormalities including intracranial bleeding. Patients with larger 20p12 deletions may occasionally exhibit additional features related to the loss of neighboring genes, potentially including developmental delay or intellectual disability, though this is variable. There is no cure for Alagille syndrome. Treatment is largely supportive and symptom-directed. Management of liver disease includes ursodeoxycholic acid to improve bile flow, fat-soluble vitamin supplementation (vitamins A, D, E, and K), nutritional support with medium-chain triglyceride-enriched formulas, and treatment of pruritus with medications such as cholestyramine, rifampin, or naltrexone. The recently approved ileal bile acid transporter (IBAT) inhibitor maralixibat has shown benefit in managing cholestatic pruritus. Liver transplantation may be necessary in cases of severe liver failure or intractable pruritus. Cardiac defects may require surgical or catheter-based intervention. Regular multidisciplinary follow-up involving hepatology, cardiology, ophthalmology, nephrology, and genetics is essential.

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