Alagille syndrome (ALGS) is a rare condition that can cause multisystem damage. Possible complications include biliary cirrhosis, dysmorphic facies, butterfly vertebrae, and posterior embryotoxon of the eye. In addition, patients with ALGS may experience vascular anomalies. 

“Varying vascular anomalies have been described in patients with Alagille syndrome secondary to defects associated with JAG1 and NOTCH 2 gene mutations,” Kohaut and colleagues write in Hepatology. “Both central and peripheral defects have been described in Alagille syndrome including mid-aortic syndrome, aortic aneurysms, and stenosis/aneurysm of renal arteries.” 

In the case of renovascular hypertension, angiotensin receptor blockade medications are indicated to prevent vascular events and strokes, which are a leading cause of death among patients with ALGS. 


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Below is a case study of a patient with multiple arterial stenosis who was later diagnosed with Alagille syndrome, as presented by Lee and colleagues in the Journal of Genetic Medicine.

Read more about Alagille syndrome etiology 

An Incidental Discovery of Hypertension

The case details a 16-year-old female who, upon routine examination, was discovered to be hypertensive (145/67 mmHg). Investigations into the cause included an abdominal computed tomography (CT) angiography, which revealed renal artery stenosis.

Upon further history-taking, she revealed experiencing intermittent left leg weakness that was brought about by walking for a long time. These episodes occurred around 5 to 6 times per year and resolved immediately upon resting. 

Her past medical history included a ventricular septal defect discovered at birth and repaired by surgical closure. She experienced amenorrhea shortly after menarche. Her physicians at that time suspected polycystic ovary syndrome and prescribed her oral contraceptives for 1 year. 

Her family history included a younger brother who died at 8 years of age from pulmonary atresia. In addition, her father has diabetes mellitus, while her mother has hypothyroidism. 

Physical examination revealed facial features typical of ALGS—frontal bossing, deep-set eyes, bulbous tip of the nose, and a pointed chin. Chest examination revealed a grade 1 to 2 of 6 murmur at the left sternal border. 

Read more about ALGS differential diagnosis

Both liver and renal function tests were normal; however, she had elevated aldosterone (45.6 ng/dL) and renin (2.34 ng/mL/hr). Antinuclear antibodies were present at a titer of 1:160. She also had hypertriglyceridemia (triglyceride: 296 mg/dL) and insulin resistance (insulin: 23.7 μIU/mL). 

“Kidney ultrasonography showed intact renal perfusion in both kidneys and delayed acceleration time in the left renal Doppler wave, indicating left renal artery stenosis,” the authors wrote. “CT angiography revealed 25% stenosis in the right renal artery, 50% stenosis in the left renal artery, complete celiac artery occlusion, and long segmental luminal narrowing of the infrarenal abdominal aorta.” 

A brain MRI revealed steno-occlusive changes in the proximal anterior cerebral artery and left internal carotid artery. Transfemoral cerebral angiography revealed an absent left internal carotid artery, but no evidence of moyamoya disease. An echocardiogram was unremarkable.

Abdominal and renal aortography showed a completely occluded celiac artery, with stenosis at the proximal portion of the superior mesenteric artery. Balloon angioplasty performed on the left renal artery improved the stenosis from 50% to 15%. 

A whole-exome sequencing was performed that revealed a pathogenic variant in the JAG1 gene., leading to diagnosis of ALGS. Further investigations revealed a butterfly vertebrae at T7 and bilateral pigmentary retinopathy. 

She was prescribed beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers, which led to normalized blood pressure upon follow-up 9 months later. 

Arterial Anomalies in Alagille Syndrome 

Kohaut and colleagues conducted a study into the frequency of abdominal arterial and vascular anomalies in children with ALGS undergoing liver transplantation. They retrospectively analyzed patients who were seen at their institution between November 1988 and December 2013. Twenty-five children met the inclusion criteria and had preoperative imaging available for analysis. The case files of selected participants were studied for signs of arterial and vascular anomalies. 

Among the 25 patients, 12 had celiac trunk stenosis, 2 had superior mesenteric artery stenosis, and 1 had bilateral renal arterial stenosis. 

“Children with Alagille syndrome pretransplant have a high prevalence of abdominal arterial anomalies,” they concluded. 

In the case study above, the patient first presented with hypertension with a history of polycystic ovary syndrome, although the relationship between polycystic ovary syndrome and ALGS remains unclear. In addition, she had dyslipidemia, which might have aggravated her vasculopathy due to atherosclerosis. 

Aside from her genetic results, she had 4 manifestations suggestive of ALGS: hypertension with arterial stenosis, dysmorphic facies, butterfly vertebra, and congenital heart defects. Her younger brother’s death from pulmonary atresia could also be due to familial ALGS. 

Read more about Alagille syndrome complications 

As demonstrated in this case study, vasculopathy is a common complication of ALGS, meaning that noncardiac vasculopathy assessment should be conducted for patients with ALGS. In addition, vasculopathy can be progressive; therefore, regular imaging examinations should be initiated in case early studies failed to detect them. 

As there is no curative treatment for ALGS at present, physicians should focus their efforts on symptomatic relief. In the case of this patient, this meant resolving her hypertension, which was accomplished via common antihypertensive medications.

References

Lee YH, Jeon YH, Lim SH, et al. A patient with multiple arterial stenosis diagnosed with Alagille syndrome: a case report. J Genet Med. 2021;18(2):142-146. doi:10.5734/JGM.2021.18.2.142

Kohaut J, Pommier R, Guerin F, et al. Abdominal arterial anomalies in children with Alagille syndrome: surgical aspects and outcomes of liver transplantationJ Pediatr Gastroenterol Nutr. 2017;64(6):888-891. doi:10.1097/MPG.0000000000001538