Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.
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.


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.
Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pa 19104, USA.
Binita M
BM
Kamath
Nancy B
NB
Spinner
Karan M
KM
Emerick
Albert E
AE
Chudley
Carol
C
Booth
David A
DA
Piccoli
Ian D
ID
Krantz
D000015:Abnormalities, Multiple / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D000328:Adult; D016738:Alagille Syndrome / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000783:Aneurysm / Q000453:epidemiology / Q000209:etiology*; D001014:Aortic Aneurysm / Q000453:epidemiology / Q000209:etiology; D001017:Aortic Coarctation / Q000453:epidemiology / Q000209:etiology; D001808:Blood Vessels / Q000002:abnormalities* / Q000196:embryology; D002135:Calcium-Binding Proteins; D002340:Carotid Artery Diseases / Q000453:epidemiology / Q000209:etiology; D002648:Child; D015331:Cohort Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D002532:Intracranial Aneurysm / Q000453:epidemiology / Q000209:etiology; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000502:physiology; D009072:Moyamoya Disease / Q000453:epidemiology / Q000209:etiology; D018919:Neovascularization, Physiologic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch; D012078:Renal Artery Obstruction / Q000453:epidemiology / Q000209:etiology; D012189:Retrospective Studies; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins