Alagille Syndrome

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Alagille Syndrome is an autosomal-dominant inherited disease caused by mutations in the JAG1 and NOTCH2 genes.[1] First described by its characteristic intrahepatic bile duct hypoplasia, Alagille Syndrome is now known to impact multiple organ systems2. Those that are most commonly affected are the hepatobiliary, oral maxillofacial, ophthalmic, cardiovascular, renal and musculoskeletal2. Presentation is thought to be variable in penetrance, with many family members of those diagnosed having characteristics but not meeting clinical diagnostic criteria.[2][3][4]


Mutations are much more common in JAG1, with very few cases being caused by mutation of the NOTCH2 gene.[5] These genes function in development to aide in cell differentiation in utero.[6] Thus, it is believed that mutations affecting these genes may disrupt normal differentiation and development of the many organ systems affected.

Systemic presentation

The liver is the primarily affected organ, and hepatobiliary symptoms are what tend to guide the primary physician to investigate further. Parents may notice their child developing jaundice, pruritis, and cutaneous xanthomas. Patients may also develop coagulopathy as a consequence of poor hepatic function and decreased bile-assisted digestion of fat-soluble vitamins. Upon investigation, the inspecting physician may find an indirect bilirubinemia, hepatomegaly, and imaging suggestive of biliary atresia.[7] As the disease progresses, patients may require liver transplant due to cholestasis, or due to the development of portal hypertension and fibrosis.[4][8] A total bilirubin greater than 3.8mg/dL between ages of 12-24 months, as well as the presence of xanthomas and liver fibrosis before the age of 5 years correlate with a worse prognosis.[9] Cardiac involvement is common, with presentations ranging from benign murmur to structural defects requiring surgical intervention.[4] Right-sided heart defects are more common than left in these patients.[10] More severe defects in cardiac structure correlate with greater morbidity and mortality.[4] Facial features are notable for a saddle-like nose, hypertelorism, and a high forehead with frontal bossing or flattening.[3] Patients may present with fractures and clinical signs of osteopenia. The most frequent musculoskeletal abnormality in Alagille Syndrome is a butterfly abnormality of the vertebral column.[11] Renal involvement may include renal tubular acidosis, vesicoureteral reflux, or renal dysplasia.[12] Patients are more likely to have cerebral vessel aneurysms, but many vessels extracranially can be affected by Alagille Syndrome. Although pulmonary vessels are commonly involved in disease, many other peripheral vessels are subject to possible damage. Cerebrovascular events are a significant cause of morbidity and mortality.[13]

Ophthalmic presentation

The most common presentation of the eye in patients with Alagille Syndrome is posterior embryotoxon. Anterior segment involvement includes iris abnormalities, but intraocular pressures and pupillary function tend to be normal. Posterior segment abnormalities include pathologic changes to the optic disc including hypoplasia, elevation, and irregular tilting of the disc. Chorioretinal findings are common including diffuse hypopigmentation of the choroid and retina, and irregular pigmentation of the retinal pigment epithelium. Even with these vast findings associated with Alagille Syndrome, visual acuity in these patients tends to be unaffected.[14]


Diagnosis without a confirmed genetic test can be deduced by the characteristic inclusion of at least three organ systems. With available technology in genetics, patients with clinically suspected Alagille Syndrome are able to undergo genetic testing for mutations in the JAG1 and/or NOTCH2 genes for confirmation. Up to 95% of patients with Alagille Syndrome have an identifiable mutation that will confirm the diagnosis.[15] If both genetic panels come back negative for mutations, findings should be clinically correlated with other possible diagnoses. Previously, diagnosis was confirmed with liver biopsy, with the sparsity of bile ducts being the correlating factor examined for confirmation.


Treatment of Alagille Syndrome is mainly symptomatic. Patients will most likely present with symptoms related to their lack of a mature hepatobiliary system, including pruritis, jaundice, right upper quadrant pain, and malabsorption. Patients are recommended to ingest calorie-dense food and supplement fat-soluble vitamins to ensure proper overall absorption of nutrients.[16] Medical treatment focuses primarily on increased bile secretion into the intestines. Ursodeoxycholic acid (UDCA), rifampin, cholestyramine, opioid antagonists, antihistamines and selective serotonin re-uptake inhibitors may all be trialed. UDCA is the first-line medication prescribed for pruritis in these patients.[17] Patients that fail medical therapy may opt for partial external biliary diversion as surgical intervention.[18] Up to 75% of patients require liver transplantation by age 18.[19]

Since the majority of documented cases of Alagille Syndrome report normal visual acuity, treatment by an ophthalmologist is rarely needed. Even though treatment is rarely indicated, serial examinations are important throughout childhood to assess for disease progression and to ensure continued appropriate visual development.

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