Alagille syndrome

Alagille syndrome
Synonyms	Alagille–Watson syndrome (ALGS), hepatic ductular hypoplasia
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Alagille syndrome is a genetic disorder that affects multiple organ systems, primarily the liver, heart, eyes, skeleton, and kidneys. It is characterized by a paucity of intrahepatic bile ducts, leading to cholestasis and other systemic manifestations.

Etiology

Alagille syndrome is primarily caused by mutations in the JAG1 gene, which encodes a ligand in the Notch signaling pathway. In some cases, mutations in the NOTCH2 gene are also implicated. These mutations are typically inherited in an autosomal dominant pattern, although de novo mutations can occur.

Pathophysiology

The Notch signaling pathway plays a crucial role in cell differentiation and organ development. Mutations in JAG1 or NOTCH2 disrupt this pathway, leading to the characteristic features of Alagille syndrome. The paucity of bile ducts results in impaired bile flow, causing cholestasis and subsequent liver damage.

Clinical Features

Hepatic Manifestations

The most prominent feature of Alagille syndrome is cholestasis, which often presents in infancy. Patients may exhibit jaundice, pruritus, and xanthomas. Progressive liver disease can lead to cirrhosis and liver failure.

Cardiac Anomalies

Congenital heart defects are common, with pulmonary artery stenosis being the most frequent. Other possible anomalies include tetralogy of Fallot and ventricular septal defect.

Skeletal Abnormalities

Characteristic skeletal findings include butterfly vertebrae, which are often asymptomatic but can be detected on X-ray.

Ocular Features

Patients may have posterior embryotoxon, a thickened and anteriorly displaced Schwalbe's line visible on slit-lamp examination.

Renal Involvement

Renal abnormalities can include renal tubular acidosis and other structural anomalies.

Diagnosis

Diagnosis of Alagille syndrome is based on clinical criteria and confirmed by genetic testing. A liver biopsy may show bile duct paucity, supporting the diagnosis. Genetic testing can identify mutations in JAG1 or NOTCH2.

Management

Management of Alagille syndrome is primarily supportive and symptomatic. Treatment options include:

• Ursodeoxycholic acid to improve bile flow.
• Cholestyramine or rifampicin for pruritus.
• Nutritional support, including fat-soluble vitamin supplementation.
• Liver transplantation in cases of end-stage liver disease.

Prognosis

The prognosis of Alagille syndrome varies depending on the severity of organ involvement. Liver disease is a major determinant of outcome, and some patients may require liver transplantation. Cardiac anomalies may also impact prognosis.

Epidemiology

Alagille syndrome occurs in approximately 1 in 30,000 to 45,000 live births. It affects both males and females equally.

See Also

• Cholestasis
• Congenital heart defect
• Genetic disorder

References

• Kamath BM, et al. "Alagille syndrome: diagnosis and management." Clin Liver Dis. 2018.
• McDaniell R, et al. "NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway." Am J Hum Genet. 2006.

Classification	ICD-10: Q44.7 (EUROCAT Q44.71) OMIM: 118450 MeSH: D016738 DiseasesDB: 29085
External resources	eMedicine: ped/60

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