American Journal of Medical Genetics 33:89-91 (1989)

Alagille Syndrome Associated With Moyamoya Disease
Avinoam Rachmel, Avraham Zeharia, Margalit Neuman-Levin, Raphael Weitz, Raanan Shamir, and
Gabriel Dinari
Departments of Pediatrics A (A.R., A.Z., R.S.) and Radiology (M.N.L.), Pediatric Gastroenterology Unit (G.D.), and
Pediatric Neurology Unit (R. W.),Beilinson Medical Center, Petah Tiqua, and Sackler School of Medicine, Tel Aviu University,
Tel Auiu, Israel
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A 22-month-old girl with the typical manifestations of Alagille syndrome presented with
acute right hemiparesis. Cerebral angiographic studies demonstrated the presence of
complete occlusion of both internal carotid arteries with the formation of a collateral network of vessels compatible with the diagnosis
of Moyamoya disease. This rare association
has not been reported previously.

four of the five major abnormalities are present [Alagille
e t al., 19871.
We describe a child with Alagille syndrome who developed acute hemiparesis because of occlusion of both
internal carotid arteries at the level of their terminal
bifurcation, with the formation of a telangiectatic network of vessels, which had the distinct radiologic appearance of Moyamoya disease. This rare association has not
been described previously.

KEY WORDS: hemiplegia, intrahepatic cholestasis, arterio hepatic dysplasia, cerebral artery diseases

CLINICAL REPORT

A 22-month-old girl was admitted with a sudden onset
of right hemiparesis. She was the second child of unrelated parents of Sephardic Jewish origin, born after uncomplicated gestation and delivery.
She was diagnosed as having Alagille syndrome on the
INTRODUCTION
basis of prolonged neonatal cholestatic jaundice with
Arteriohepatic dysplasia or Alagille syndrome is a syn- patent extrahepatic bile ducts, characteristic face, vertedrome of intrahepatic cholestasis caused by paucity of bral arch anomalies, peripheral pulmonic stenosis, and
interlobular bile ducts and cardiovascular and other mor- patent ductus arteriosus. Infectious and metabolic causes
phologic anomalies. The syndrome is an autosomal dom- were excluded by appropriate tests. She continued to
inant trait with variable penetrance and expressivity have mild cholestasis and was treated with cholestyramine and vitamin supplementation. The patient’s mother
[Alagille et al., 1975; Watson and Miller, 19731.
The major abnormalities seen in this syndrome include and sister have facial characteristics compatible with
chronic cholestasis, characteristic face, cardiovascular Alagille syndrome. Her sister was diagnosed as having
abnormalities, (mainly peripheral pulmonic stenosis), peripheral pulmonic stenosis, and the mother has an
vertebral arch defects, and posterior embryo-toxon. Less undiagnosed systolic murmur; however, neither has signs
frequently associated anomalies are growth retardation, of hepatic dysfunction.
On her present admission the girl appeared well nourglomerular changes in the form of mesangiolipidosis,
mental retardation, and other skeletal abnormalities [Al- ished and alert. She was afebrile, and her vital signs were
agille et al., 19871. Rarely have kidney abnormalities such normal. She had moderate right hemiparesis, with mild
as infantile polycystic kidney [Greenwood et al., 19761, right facial weakness. The function of other cranial
nephronophthisis [Hyams, 19831, single kidney [Oes- nerves was intact, deep tendon reflexes were symmetritreich et al., 19831, and arterial hypertension caused by cally absent, and there was a bilateral flexor plantar
renal artery stenosis [Labrecque et al., 19821 been re- response. All peripheral arterial pulses were palpable,
ported in this syndrome. Alagille has suggested that a and no murmurs or bruits were found over the carotid
mild form of the syndrome occurs when only three or arteries or the skull. Her head circumference was 45 cm
(below the 3rd centile).
Results of laboratory examinations, including complete blood count, erythrocyte sedimentation rate, urinalysis, coagulation studies, serum glucose, electrolytes,
Received for publication July 14, 1988; revision received Novemcalcium, magnesium, phosphorus, and albumin levels
ber 28, 1988.
Address reprint requests to A. Rachmel, M.D., Dept. of Pediatrics were normal. Serum alanin aminotransferase was 154 i.u.
(2.57 pkat/L), alkaline phosphatase was 753 i.u. (12.6
A, Beilinson Medical Center, Petah Tiqva 49100, Israel.

0 1989 Alan R. Liss, Inc.

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Rachmel et al.

pkat/L), cholesterol was 424 mg% (10.96 mmol/L), and
triglycerides were 68 mg% (0.77 mmol/L). Total and
conjugated serum bilirubin were 1.5 mg% (25 pmol/L)
and 0.9 mg % (15 pmol/L), respectively. Vitamin E level
was 1.3 pg/ml (3.0 pmol/L). The electroencephalogram
demonstrated slow wave activity over the entire left
hemisphere.
Cranial computerized tomography demonstrated a lowdensity area with small calcified foci in the left frontal

Fig. 1. Localized area of brain atrophy is demonstrated by C T scan
(coronal section). A low-density area with calcifications is seen (arrow).
The white square shows dilatation of the left lateral ventricle.

lobe. Mild dilatation of the left lateral ventricle and
widening of the sulci were also noted. The findings were
compatible with an old hemorrhage (Fig. 1). Transfemoral cerebral arteriography demonstrated complete bilateral occlusion of the internal carotid arteries at the level
of the carotid syphon. A network of tiny collaterals
extending from the external carotid circulation was demonstrated at the level of the ophthalmic arteries, the
basal ganglia, and dural branches, with retrograde filling
of the anterior cerebral arteries and part of the middle
cerebral branches. The vertebral and basilar arteries had
a normal appearance (Fig. 2). These angiographic
changes were compatible with the diagnosis of “Moyamoya” disease. The girl’s neurologic status improved
gradually with intensive physiotherapy. Four months
after the initial episode she had only very mild weakness
of her right limbs. Encephalo-myosynangiosis as a palliative surgical procedure was considered, but the parents
did not give consent for this procedure.
DISCUSSION
Moyamoya is a Japanese term that means “something
hazy like a puff of cigarette smoke drifting in the air.” It
is applied to a peculiar angiographic picture consisting of
abnormal net-like vessels at the base of the brain [Suzuki
and Kodama, 19831. There is usually bilateral stenosis or
occlusion of the internal carotid artery at the level of its
bifurcation, together with abnormalities of the anterior
and middle cerebral arteries. In its more common, congenital form, the abnormality has been related to an
arterial dysplastic process often associated with other
systemic vascular anomalies such as renal artery stenosis,
neurofibromatosis [Tomsick et al., 19761, and Down syndrome [Schrager et al., 19771. An acquired form of the
disease has been described in adults with sickle cell
anemia [Stockman et al., 19721, tuberculous meningitis

Fig. 2. R t carotid angiography. Left: Early phase. Note the site of occlusion of the internal carotid
artery (arrow). Right: Late phase. Collateral circulation in the form of a telangiectatic network of
communication vessels between the extracranial arteries and the intracranial circulation is demonstrated
(arrows).

Moyamoya in Alagille Syndrome
[ Mathew et al., 19701, connective tissue abnormalities
[Richman et al., 19771, in association with Fanconi’s
anemia [Cohen et al., 19801, and following brain irradiation [Rajakulasingam et al., 19791.
The main cardiovascular anomalies in Alagille syndrome are well defined and consist of peripheral pulmonic
stenosis, patent ductus arteriosus, ventricular septal defect, and atrial septal defect [Greenwood et al., 19761. In
a recent review of 80 patients [Alagille et al., 19871,
cerebral vascular complication was mentioned as the
cause of death of a 3-year-old patient, but no further
details are given. Common carotid artery anomalies were
found in two of seven autopsies in another series [Watson
and Miller, 19731,but anomalies of cerebral arteries such
as those found in our patient have not been described
previously in this syndrome.
Low serum levels of vitamin E because of chronic
cholestasis have been considered to be a cause for thrombocytosis and hypercoagulability state. However, our patient’s thrombocytes were normal, and there were no
signs of hypercoagulability. Moreover, recent review of
vitamin E deficiency did not support previous concepts
of its role in the development of vascular occlusion [Bieri
et al., 19831.
Recently, evidence was presented for a vascular basis
for neural and nonneural malformations, which were not
previously related to vascular anomalies [Hoyme et al.,
1981; Stevenson et al., 19871. Thus, it is conceivable that
the hepatic lesion in Alagille syndrome is also related to
some early developmental vascular compromise, which
might also cause vascular malformation at other sites,
such as the heart, the great vessels, and the cerebral
arteries. However, the rarity of this association prevents
any substantiation of this hypothesis at the present time.

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