Alagille Syndrome

The paucity of intrahepatic bile ducts on liver biopsy reported for the infant in the vignette suggests the diagnosis of Alagille syndrome, which is associated with systolic heart murmurs. Alagille is a familial form of chronic intrahepatic cholestatis typically presenting with neonatal cholestasis (direct hyperbilirubinemia) in the first 3 months after birth. Physical examination demonstrates a thin, jaundiced infant.

An autosomal dominant (variable penetrance and expressivity) genetic condition characterized by five principal features:

• paucity of the intrahepatic (interlobular) bile ducts (as opposed to Biliary Atresia)
• cardiac defects (especially peripheral pulmonic stenosis)
• posterior embryotoxon
• vertebral anomalies (especially hemivertebrae)
• elfin facies (hypertelorism, pointed chin)

Infants usually are both short and underweight. Affected children are either cognitively normal or have mild developmental delay. Patients may experience more severe involvement of the same organ systems (eg, pulmonary arterial hypoplasia, tetralogy of Fallot, glaucoma).

Other conditions reported in Alagille syndrome include

• renal abnormalities (horseshoe kidney, tubular dysfunction)
• ear abnormalities (otitis media, deafness).

Most cases of Alagille syndrome result from mutations in the JAGGED1 gene on chromosome 20. JAGGED1 is a ligand for NOTCH receptor, a gene important in cell differentiation, and mice that have the JAGGED1 mutation experience defects in embryogenesis.

Workup

• labs: increased direct bilirubin, alkaline phosphatase and gamma-glutamyl transpeptidase.
• echo
• Ophthalmologic examination is needed to demonstrate the posterior embryotoxon, which is a thickening of Schwalbe line (where the corneal endothelium and  uveal trabecular meshwork meet).
• CXR: hemivertebrae.
• Liver biopsy often is necessary to differentiate Alagille syndrome from other causes of neonatal cholestasis (eg, biliary atresia, alpha-1-antitrypsin deficiency).

Prognosis

• highly variable
• usually reflects the severity of the liver and cardiac disease
• Approximately 20% to 25% of patients develop progressive severe liver disease that may require liver transplantation.

Management

• primarily supportive and involves aggressive nutritional supplementation in infants who are not growing; monitoring of fat-soluble vitamin levels; and supplementation with vitamins A, D, E, and K.

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the corpus callosum associated with relapsing hypothermia: a
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Root AW. Precocious puberty. Pediatr Rev. 2000;21:10-19.
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