Vascular Anomalies in Alagille Syndrome

Abstract

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.

Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development

“…Consistent with this finding, we have previously shown that inhibition of Notch in neural crest cells, which act as smooth muscle precursors in the pulmonary artery, results in pulmonary artery stenosis and other congenital heart defects reminiscent of those seen in Alagille syndrome (22). Defects in smooth muscle development may also be responsible for other vascular pathologies seen in patients with Alagille syndrome, such as a predisposition to intracranial bleeding (28).…”

“…One of the principal findings in Alagille syndrome is congenital heart disease, especially pulmonary artery stenosis, and vascular disease including a predisposition to intracranial bleeding (27,28). Therefore, a better understanding of the role of Jag1 in cardiovascular development promises to provide insight into the pathogenesis of Alagille syndrome and other forms of congenital heart and vascular diseases.…”

Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation

“…In mice, mutation of Jagged1 results in lethality at embryonic day 10.5 and is accompanied by abnormal vascular patterning and failure to remodel the primary vascular plexus in the yolk sac (33). In humans, Alagille syndrome, caused by a mutation in the Notch ligand Jagged1 gene, is associated with arteriopathy, most notably involving the pulmonary artery (34). Similarly, the human CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) syndrome is a heritable arteriopathy caused by a mutation in the human Notch3 gene (35).…”

Alagille syndrome case report: implications for forensic pathology and anthropology

“…In Alagille syndrome, however, death in the pediatric age range, secondary to intracranial bleeding after mild or no trauma, is common [37,41,42], since they tend also to have more vasculopathies than the normal population [41]. These range from stenosis of the internal carotid artery, intracerebral aneurysms, and non-atherosclerotic carotid artery anomalies to thin-walled vessels and moyamoya-like changes [42].…”