Published Online
on March 1, 2004

A more recent version of this article appeared on March 23, 2004

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Submitted on October 7, 2003
Revised on December 10, 2003
Accepted on January 5, 2004

Vascular Anomalies in Alagille Syndrome. A Significant Cause of Morbidity and Mortality

Binita M. Kamath MBBChir, Nancy B. Spinner PhD, Karan M. Emerick MD, Albert E. Chudley MD, Carol Booth MD, David A. Piccoli MD, and Ian D. Krantz MD^*

From the Divisions of Gastroenterology and Nutrition (B.M.K., D.A.P.) and Human Genetics and Molecular Biology (N.B.S., I.D.K.), The Children’s Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pa; the Division of Gastroenterology and Nutrition, Northwestern University Medical School, Children’s Memorial Hospital, Chicago, Ill (K.M.E.); Children’s Hospital and University of Manitoba, Winnipeg, Canada (A.E.C.); and Lutheran General Children’s Hospital, Park Ridge, Ill (C.B.).

^* To whom correspondence should be addressed. E-mail: ian2{at}mail.med.upenn.edu.

Background--Alagille syndrome (AGS) is a dominantly inherited multisystem disorder involving the liver, heart, eyes, face, and skeleton, caused by mutations in Jagged1. Intracranial bleeding is a recognized complication and cause of mortality in AGS. There are multiple case reports of intracranial vessel abnormalities and other vascular anomalies in AGS. The objective of this study was to characterize the nature and spectrum of vascular anomalies in AGS.

Methods and Results--Retrospective chart review of 268 individuals with AGS was performed. Twenty-five patients (9%) had noncardiac vascular anomalies or events. Sixteen patients had documented structural vascular abnormalities. Two had basilar artery aneurysms, 7 had internal carotid artery anomalies, and another had a middle cerebral artery aneurysm. Moyamoya disease was described in 1 patient. Three of the 16 patients had aortic aneurysms, and 2 had aortic coarctations. One of the patients with a basilar artery aneurysm also had coarctation of the aorta. One of the individuals with an internal carotid artery anomaly also had renal artery stenosis. Nine more patients had intracranial events without documented vessel abnormalities. Vascular accidents accounted for 34% of the mortality in this cohort.

Conclusions--The vascular anomalies described in our cohort of AGS individuals identify an underrecognized and potentially devastating complication of this disorder. It is a major cause of morbidity and mortality in this population, accounting for 34% of the mortality. We have also reviewed the body of evidence supporting a role for Jagged1 and the Notch signaling pathway in vascular development.

Key words: aneurysm • angiogenesis • cerebrovascular disorders • vasculature

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