Alagille syndrome due to a NOTCH2 point mutation

Alagille syndrome due to a NOTCH2 point mutation (also known as Alagille syndrome type 2, or ALGS2) is a rare multisystem disorder caused by pathogenic variants in the NOTCH2 gene, as opposed to the more common form caused by JAG1 mutations. Alagille syndrome is a dominantly inherited condition that primarily affects the liver, heart, skeleton, eyes, kidneys, and facial features. The hallmark feature is a paucity (reduced number) of interlobular bile ducts in the liver, which leads to chronic cholestasis — a condition where bile cannot flow properly from the liver. This results in jaundice, intense itching (pruritus), elevated cholesterol with xanthomas (fatty deposits under the skin), and poor growth in affected children. Key clinical features include congenital heart defects, most commonly peripheral pulmonary artery stenosis, as well as butterfly vertebrae (an abnormal shape of the spinal bones seen on X-ray), posterior embryotoxon (an eye finding visible on slit-lamp examination), and a characteristic facial appearance with a broad forehead, deep-set eyes, pointed chin, and a straight nose. Renal abnormalities, including structural kidney anomalies and renal tubular dysfunction, may also occur. The severity of the condition is highly variable, even within the same family, ranging from mild subclinical findings to severe liver disease requiring transplantation. Treatment for Alagille syndrome type 2 is largely supportive and symptom-directed. Management of cholestasis may include ursodeoxycholic acid, fat-soluble vitamin supplementation (vitamins A, D, E, and K), nutritional support, and medications to manage pruritus. Ileal bile acid transporter (IBAT) inhibitors such as maralixibat and odevixibat have been approved or investigated for cholestatic pruritus in Alagille syndrome. In cases of severe liver disease with intractable pruritus or liver failure, liver transplantation may be necessary. Cardiac defects may require surgical or catheter-based intervention. Long-term multidisciplinary follow-up involving hepatology, cardiology, ophthalmology, nephrology, and nutrition is essential.

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