Alagille syndrome and a JAG1 mutation: 41 cases of experience at a single center

Abstract

Purpose: Alagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling pathway, such as in JAG1 and NOTCH2, play a key role in embryonic development. A cardiac or hepatic presentation is a critical factor for determining the prognosis.

Methods: We conducted a retrospective study of 41 patients with Alagille syndrome or a JAG1 mutation between 1983 and 2013.

Results: The first presentations were jaundice, murmur, cyanosis, and small bowel obstruction at a median age of 1.0 months (range, 0-24 months). The JAG1 mutation was found in 27 of the 28 genetically-tested patients. Cardiovascular anomalies were identified in 36 patients, chronic cholestasis was identified in 34, and liver transplantation was performed in 9. There was no significant correlation between the severity of the liver and cardiac diseases. The most common cardiovascular anomaly was peripheral pulmonary stenosis (83.3%), with 13 patients having significant hemodynamic derangement and 12 undergoing surgical repair. A total bilirubin level of >15 mg/dL with a complex surgical procedure increased the surgical mortality (P=0.022). Eight patients died after a median period of 2.67 years (range, 0.33-15 years). The groups with fetal presentation and with combined severe liver and heart disease had the poorest survival (P<0.001).

Conclusion: The group with combined severe liver and heart disease had the poorest survival, and a multidisciplinary approach is necessary to improve the outcome.

Keywords: Alagille syndrome; Cardiovascular diseases; Cholestasis; Pulmonary valve stenosis.

Fig. 1. Kaplan-Meier survival curves. (A) The survival rate was worse in patients with a cardiac anomaly that was detected via fetal ultrasonography than in those with later cardiac presentation (50% at fetal ultrasonography vs. 75.0% at 1-4 months vs. 90.5% at 0-30 days vs. 100% at >5 months, P=0.009). (B) Overall survival was worse in patients with combined severe diseases than in those with only severe liver disease or severe heart disease, or in those without severe disease (28.6% with combined severe diseases vs. 75.0% with severe liver disease vs. 100% with severe heart disease vs. 100% without severe disease, P<0.001).