Moyamoya Syndrome in a Patient with Williams Syndrome: A Case Report Open Access

• Moyamoya syndrome associated with Williams syndrome is very rare.

• The prognoses of moyamoya syndrome with Williams syndrome cases were severe.

• RNF213 c.14576G>A is known to be significantly associated with definite moyamoya disease.

• This was the first reported case of a Williams syndrome with moyamoya syndrome that was confirmed by the presence of an RNF213 mutation.

• In moyamoya syndrome associated with Williams syndrome, adequate perioperative management of both the moyamoya arteries and the cardiovascular abnormalities is important to prevent complications.

Williams syndrome is a genetic disorder characterized by cardiovascular problems, such as supravalvular aortic and pulmonary artery stenoses, mental retardation, and an elfin face. The disorder is caused by deletions of multiple contiguous genes, including the ELN gene, that code for the protein elastin, on the long arm of chromosome 7 [1, 2]. Because elastin is related within the formation of blood vessels, lack of the protein causes the circulatory system abnormalities of this syndrome.

Moyamoya syndrome in patients with Williams syndrome is very rare; in fact, a PubMed search uncovered only a few reports on such association [3, 4], and the prognoses of these cases were severe [3, 4]. Moreover, there was only one extremely rare case of indirect revascularization for Williams syndrome and moyamoya disease. In this present report, we showed the case of a 6-year-old boy with Williams syndrome associated with moyamoya syndrome that was confirmed by the presence of a c.14576G>A (p.R4859K) mutation in RNF213 and was successfully treated with cerebral revascularization surgery. In Williams syndrome, both the cardiovascular and cerebrovascular complications are major causes of death; therefore, evaluation of the moyamoya syndrome by magnetic resonance imaging or the presence of an RNF213 mutation, in addition to the cardiac function, may be necessary.

The patient presented at the age of 6 years with right hemiparesis induced by hyperventilation. In addition to transient right hemiparesis, he sometimes cried while his head was being held, suggesting headache. At the age of 2 years, he had been diagnosed with Williams syndrome, which was confirmed by the deletion of 7q11.23 on fluorescence in-situ hybridization. There was no history of trauma or any preceding infection, such as varicella-zoster. The patient had no history of moyamoya disease.

Although he had mild pulmonary artery bifurcation stenosis (i.e., about 2 m/s on both sides with pressure difference 10–15 mm Hg), the echocardiography results showed normal cardiac function, as follows: left ventricular internal dimension in diastole of 28 mm, fractional shortening of 40%, ejection fraction of 70%, and no supravalvular aortic stenosis. Specialists from the cardiology department assessed and anticipated no problems during angiography or surgery. Magnetic resonance angiography (MRA) showed severe stenosis of the bilateral internal carotid arteries, and the fluid-attenuated inversion recovery image demonstrated the ivy sign bilaterally (Fig. 1). Likewise, cerebral angiography showed severe stenosis, especially in the proximal portions of the bilateral middle cerebral arteries, as well as development of moyamoya vessels (Fig. 2). The presence of bilateral stenosis of the internal carotid arteries without obvious dissecting vessels on MRA and cerebral angiography ruled out focal cerebral arteriopathy, based on its new classification, and was consistent with moyamoya syndrome, which we classified as Suzuki stage III [5, 6].

The patient underwent left-sided indirect cerebral revascularization surgery using superficial temporal artery, temporal muscle, and periosteum tissues from a donor. Two months after the first operation, there was left hemiparesis induced by crying. Therefore, we performed the same procedure on the right side. In both perioperative periods, normocapnia, normotension, and adequate hematocrit level were strictly maintained, in addition to pain control with fentanyl and dehydrobenzperidol. After the second operation, the patient recovered well and had no cerebral ischemic event. Postoperative MRA demonstrated collateral vessels from the bilateral superficial and deep temporal arteries and reduced number of moyamoya vessels (Fig. 3). Moreover, the postoperative fluid-attenuated inversion recovery images showed resolution of the bilateral ivy sign (Fig. 3). Five years after the operation, he had no hemiparesis or ischemic events.

DNA analysis showed a p.Arg4810Lys mutation in the ring finger protein (RNF) 213 c.14429G>A (Fig. 4). We extracted gDNA samples from the blood and analyzed the genome sequence by pyrosequencing. An RNF213 NM_001256071.1 c.14429G>A pArg4810Lys heterozygous mutation was found in exon 60 of RNF213. A mutation, in which the arginine at the 4,810th position was replaced with a lysine, was observed by changing the base from G to A at the 14,429th position. The mutation was registered in the dbSNP database as rs112735431.

Williams syndrome is causative of moyamoya syndrome, but only 2 cases have been reported so far [3, 4]; in both cases, the disease was fatal. One case was that of an 18-year-old patient with Williams syndrome and died of intracerebral hemorrhage secondary to moyamoya syndrome, based on autopsy [3]. The other case was that of a 9-year-old boy from who unexpectedly developed global cerebral infarction after revascularization surgery for moyamoya disease, which led to brain death [4]. In that case from Korea, the patient’s pupils dilated suddenly on the third postoperative day and diffuse hypodense areas in the bilateral cerebral hemispheres were seen on brain computed tomography 1 h after. Two months before his operation, the patient had undergone a second surgery for coarctation of the aorta.

The reports that we found on such cases had poor prognosis; therefore, we were concerned that this would be a high-risk operation. In Williams syndrome, cardiovascular problems and cerebrovascular complications are the major cause of death. In fact, the risk of sudden death was 25–100 times greater than that for an age-matched normal population [7]. Decreased cardiac output, myocardial ischemia, and arrhythmias are the presumed mechanisms of death. In this present case, the patient only had mild pulmonary stenosis in the cardiovascular system, which fortunately allowed us to perform indirect revascularization surgery.

Moyamoya syndrome refers to a condition in which a stenosis or occlusion is found in the terminal portion of the internal carotid artery, anterior cerebral artery, and proximal portion of the middle cerebral artery. It is accompanied by an abnormal vascular network, which is similar to the findings in definite moyamoya disease, but moyamoya syndrome has an underlying genetic or autoimmune disease [8]. The treatment for moyamoya syndrome is similar to that of definite moyamoya disease. For moyamoya syndrome associated with Recklinghausen’s disease, Down syndrome, or irradiation, direct and indirect revascularization has been demonstrated to be effective [9-11]. However, owing to the few number of reports, the value and efficacy of revascularization for Williams syndrome were unclear. In patients with moyamoya syndrome, unilateral involvement may progress to bilateral disease [12], and the nature of the underlying disease influences the prognosis [13]. This present case was a symptomatic and bilaterally progressive moyamoya syndrome associated with Williams syndrome, and indirect revascularization surgery could be done without complication.

RNF213 c.14576G>A is known to be significantly associated with definite moyamoya disease. The variant is involved in vascular development and in the function of vascular endothelial cells [14-16]. Although its exact function is unknown, the presence of RNF213 c.14576G>A may act as a pathologic condition that triggers the atherogenic development of the end of the internal carotid artery in definite moyamoya disease. On the other hand, in moyamoya syndrome, various baseline diseases could trigger the pathologic condition. For example, the RNF213 variant might be a risk factor for development of moyamoya syndrome in NF-1 populations [17]; however, this association is weaker compared with the robust contributions of the RNF213 c.14576G>A variant to sporadic/familial moyamoya disease [17]. In patients with Down Syndrome, reports have shown a relatively early age of onset (i.e., 2 years) of moyamoya syndrome, owing to the presence of the RNF213 variant. This finding suggested that the Down syndrome and RNF213 variants contribute to the development of moyamoya vasculopathy [18]. In a study on Japanese patients with moyamoya disease, homozygous individuals had relatively early onset and severe presentation [19]. Therefore, the disease severity is possibly related with a combination of the number and type of variants present, as well as with other modifiers affected by genetic/environmental factors [19, 20].

Based on this report, we suggest that the RNF213 c.14576G>A mutation may be a modifier of the phenotypic features of Williams syndrome. More clinical data are needed to further elucidate the frequency and importance of the RNF213 mutation in Williams syndrome, especially in patients with intracranial artery anomalies and moyamoya vessels. Williams syndrome is associated with a high incidence of sudden death and risk of intracranial vascular stenosis (i.e., moyamoya syndrome); therefore, intracranial arterial evaluation and the presence of the RNF213 gene mutation should be noted.

We reported a rare case of moyamoya syndrome in a patient with Williams syndrome that was successfully treated with indirect revascularization with superficial temporal artery, temporal muscle, and periosteum tissues. In Williams syndrome, cardiovascular problems (such as obstructive left-heart lesions and/or coronary artery stenosis) and cerebrovascular complications are a major cause of death. Confirming the presence of RNF213 mutations may be necessary in cases of Williams syndrome.

We thank Flaminia Miyamasu of the Medical English Communications Center, University of Tsukuba, for manuscript editing.

The authors affirm that the parents of the patient gave written informed consent for publication of data and images. Ethical approval was not required for this study in accordance with national guidelines.

All authors have no conflict of interest.

The authors did not receive any funding for this study.

Taisuke Akimoto and Jun Suenaga conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Taisuke Akimoto drafted the manuscript, analyzed the data, and reviewed the literature. Taisuke Akimoto, Jun Suenaga, Tomoko Hayashi, Daisuke Hirokawa, Susumu Ito, Hironobu Sato, and Tetsuya Yamamoto critically reviewed the manuscript, approved the final manuscript to be submitted, and agreed to be accountable for all aspects of the work.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.