Moyamoya Syndrome in Children With Alagille Syndrome: Additional Evidence of a Vasculopathy (1999)

Alagille syndrome (arteriohepatic dysplasia) is a congenital disorder that can affect the liver, heart, eye, skeleton, and facial appearance.1,2 It is associated with bile duct paucity and is an important cause of neonatal jaundice and cholestasis in older children.3 The most common cardiac malformation associated with Alagille syndrome is peripheral pulmonary stenosis.4 This syndrome has an autosomal dominant inheritance with variable penetrance, although sporadic cases are common.3We present two children with sporadic Alagille syndrome who also suffered from moyamoya syndrome, a rare idiopathic intracranial vasculopathy. We hypothesize that this cerebrovascular abnormality may be part of a spectrum of vascular disease that can occur in Alagille syndrome.A 2-month-old Caucasian girl was diagnosed with Alagille syndrome when she presented with jaundice, pruritis, and failure to thrive. A liver biopsy demonstrated a paucity of bile ducts. Echocardiography revealed pulmonary valvular and pulmonary artery stenosis with right ventricular hypertrophy. Other characteristic features of Alagille syndrome included posterior embryotoxon on eye examination (thickened Schwalbe's ring in the anterior chamber) and butterfly vertebrae (T4 and T7) on spine films.At 1 year of age, the patient underwent a balloon angioplasty of the left pulmonary artery because of severe stenosis. Postoperatively, she was noted to have right arm and leg weakness. Head computed tomography (CT) performed the following day showed decreased attenuation of periventricular white matter in the left frontal lobe. It was thought that she had had an embolic ischemic event affecting the left hemisphere. She regained good function of the right side within weeks.At 21 months of age, the patient developed sudden weakness of the right arm. Magnetic resonance imaging (MRI) demonstrated increased T2-weighted signal intensities in the cortical gyri of the left frontal and parietal lobes associated with enlargement of the left lateral ventricle (Fig 1, A). On diffusion-weighted images, there were increased signal intensities in the left frontoparietal cortex (Fig 1, B), which was associated with reduced signal on the apparent diffusion coefficient map (consistent with an acute infarction). Magnetic resonance angiography (MRA) demonstrated severe stenosis of the left supraclinoid internal carotid artery (ICA) and reduced flow in the left anterior and middle cerebral arteries (ACA, MCA) (Fig 1, C). The right ICA was normal. Cerebral angiography showed a minimally narrowed left ICA in the cavernous portion, with high-grade stenosis of the supraclinoid segment, just distal to the take-off of the ophthalmic artery (Fig 1, D). Irregular serpentine vessels were seen in the basal ganglia and distally within the MCA territory. The left common carotid and bifurcation were normal. The patient's deficits resolved within 2 days. She was started on intravenous heparin, then changed to warfarin.Repeat cerebral angiography performed at 2½ years of age revealed an occlusion of the left supraclinoid ICA with proliferation of lenticulostriate vessels, characteristic of moyamoya syndrome. In addition, there was an 80% stenosis of theright ICA in the midcervical segment. However, distally theright ICA, MCA, and ACA all were normal, and there were no moyamoya changes. The right carotid artery stenosis was dilated successfully by balloon angioplasty. At 3 years of age, the patient remains on aspirin, and she has had no additional stroke-like episodes.Laboratory results have shown consistently elevated cholesterol levels up to 2715 mg/dL (70.32 mmol/L; normal, <170 mg/dL or 4.40 mmol/L) and triglyceride levels up to 296 mg/dL (3.34 mmol/L; normal, <125 mg/dL or 1.41 mmol/L). These levels have improved with the addition of atorvastatin.A 2-year-old previously healthy Caucasian girl was admitted after sudden onset of left hemiparesis. On general examination, she had frontal bossing, deep-set eyes, a small nose with broad nasal root, and low-set ears. On neurologic examination, she was alert and interactive. On the left, she had facial weakness, flaccid hemiplegia, hyperreflexia, and an extensor plantar response. These deficits resolved within 24 hours, but she had another episode of transient left hemiplegia 2 days later. Subsequent CT demonstrated a large right hemispheric infarction (Fig 2, A). Echocardiography revealed a hypoplasia of the left pulmonary artery and its distal branches. Cerebral angiography demonstrated moderate bilateral (right greater than left) distal intracranial ICA stenosis with early moyamoya changes in the lenticulostriate arteries (Fig 2, B). A lipid profile was moderately abnormal, with a cholesterol of 264 mg/dL (6.84 mmol/L; normal, <170 mg/dL or 4.40 mmol/L) and triglycerides of 128 mg/dL (1.45 mmol/L; normal, <125 mg/dL or 1.41 mmol/L). The patient was treated with aspirin.One month later, the patient had another episode of transient left hemiplegia. Repeat angiography demonstrated increased stenosis of the right supraclinoid ICA. The patient underwent a right encephaloduroarteriosynangiosis (EDAS, a procedure that involves transplanting a scalp artery to a dural opening) followed by a left EDAS. A liver biopsy revealed a reduced number of bile ducts. No butterfly vertebrae were present, and the ophthalmologic examination was normal. However, the diagnosis of incomplete Alagille syndrome was made based on the presence of typical facies, peripheral pulmonary stenosis, and cholestatic liver dysfunction associated with a reduced number of bile ducts on liver biopsy.Over the next 3 years, the patient had one left hemispheric and three right hemispheric infarctions. Follow-up angiography failed to demonstrate collateral development from either EDAS site. Therefore, the patient underwent a right extracranial–intracranial bypass (direct superficial temporal artery–MCA anastomosis). Currently at 8 years of age, she has not experienced additional transient ischemic attacks or strokes.To our knowledge, the association of Alagille syndrome with moyamoya syndrome has been reported previously only once—in a 22-month-old girl who presented with a left hemispheric stroke.5 In another report, common carotid stenosis was found in 2 patients who had autopsies, although pathologic details were not reported.6 Furthermore, in addition to peripheral pulmonary stenosis, which occurs in a majority of patients with Alagille,2 vascular stenosis also has been described in the renal artery and midaorta.7 Thus, it is likely that a propensity to develop vascular lesions exists in patients with Alagille.Moyamoya disease is an idiopathic chronic progressive arterial occlusive disease that affects the distal intracranial carotid arteries and the vessels arising from the circle of Willis.8 It is classified as definite if bilateral and probable if unilateral.8 Although first described in the Japanese population, the disease has a worldwide prevalence. The disease typically presents with cerebral ischemic symptoms in children and brain hemorrhage in adults.9 Moyamoya means “hazy puff of smoke” in Japanese and refers to the angiographic appearance of the abnormal network of vessels that develop at the base of the brain and basal ganglia to supply a collateral route of blood flow.10 The etiology of moyamoya disease is unknown. Pathologically, the cerebral vessels in moyamoya disease are abnormal and frequently have enlarged or duplicated elastic lamina and attenuation of the media without inflammatory changes.11Recently, an increase in elastin gene expression has been identified, suggesting the importance of overproduction of elastin in the pathophysiology.12Secondary causes of distal ICA occlusion such as atherosclerosis, vasculitis, and cardiogenic embolus may cause a similar syndrome (moyamoya syndrome). This syndrome also has been associated with neurofibromatosis, sickle cell disease, meningitis, and cranial radiation.Modern neuroimaging techniques are useful for the diagnosis of moyamoya syndrome. Often, distal ICA stenosis can be detected noninvasively with MRI and MRA. The confirmation of moyamoya syndrome usually requires cerebral angiography, which should demonstrate stenosis of the intracranial arteries near the circle of Willis and abnormal proliferation of the lenticulostriate vessels. The serial neuroimaging studies and angiograms in our patients clearly showed progressive cerebrovascular changes consistent with moyamoya syndrome.It is unknown why patients with Alagille syndrome develop vascular lesions. Hyperlipidemia is common in patients with liver disease, including Alagille syndrome13; however, hyperlipidemia alone is not adequate to explain the severe vascular abnormalities in Alagille syndrome. In typical atherosclerosis, the extracranial carotid artery usually is affected before lesions occur intracranially, and either irregular narrowing or plaque is often visualized with angiography.14 Although our 2 patients have hyperlipidemia, the angiographic morphology of the stenotic lesions do not resemble atherosclerosis. Furthermore, stenotic pulmonary arteries in patients with Alagille syndrome do not exhibit abnormalities on pathologic examination.6 We suspect that unidentified genetic factors predispose Alagille patients to develop vasculopathy.In conclusion, we report the association of Alagille syndrome with moyamoya syndrome. Patients with Alagille syndrome who present with focal cerebral ischemic symptoms should be evaluated for moyamoya syndrome or more proximal carotid lesions. In addition, because patients with Alagille syndrome often undergo cardiac catheterization or surgical procedures that may predispose them to cerebral ischemic events, it is important to consider the possibility of preexisting carotid disease. MRI and MRA offer noninvasive techniques for identification of significant cerebrovascular abnormalities in patients with Alagille syndrome. We speculate that cerebrovascular disease, with anatomic features typical of moyamoya syndrome, is one manifestation of an inherent predisposition toward vasculopathy in Alagille syndrome.