Novel Insights from Clinical Practice Pediatr Neurosurg 2022;57:365–370 DOI: 10.1159/000525229 Received: May 20, 2021 Accepted: April 20, 2022 Published online: May 31, 2022 Moyamoya Syndrome in a Patient with Williams Syndrome: A Case Report Taisuke Akimoto a, b Jun Suenaga b Tomoko Hayashi a Daisuke Hirokawa a Susumu Ito a Hironobu Sato a Tetsuya Yamamoto b Neurosurgery, Yokohama City University, Yokohama, Japan Established Facts • 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. Novel Insights • 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. Keywords Williams syndrome · Moyamoya syndrome · Moyamoya gene · RNF213 Abstract Introduction: Moyamoya syndrome associated with Williams syndrome is very rare but has been reported to have severe outcomes. Here, we reported a case of Williams syndrome with moyamoya syndrome that was confirmed by the presence of an RNF213 mutation. Case Presentation: A 6-year-old boy with Williams syndrome presented with right hemiparesis induced by hyperventilation. Magnetic reso- Karger@karger.com www.karger.com/pne © 2022 The Author(s). Published by S. Karger AG, Basel This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense), applicable to the online version of the article only. Usage and distribution for commercial purposes requires written permission. nance angiography and cerebral angiography showed severe stenosis of the bilateral internal carotid arteries and development of moyamoya vessels. Genetic analysis identified a heterozygous c.14576G>A (p.R4859K) mutation in RNF213. Moyamoya syndrome was diagnosed, and bilateral indirect revascularization surgery was conducted without complications and with a good postoperative course. In moyamoya syndrome associated with Williams syndrome, adequate perioperative management of both the moyamoya arteries and the cardiovascular abnormalities is important to prevent complications. Conclusion: This was the first report on a case in which moyamoya syndrome associated with Williams syndrome was confirmed by the presence of a heterozygous Correspondence to: Jun Suenaga, suenaga @ yokohama-cu.ac.jp Downloaded from http://karger.com/pne/article-pdf/57/5/365/3738407/000525229.pdf by guest on 18 April 2024 aDepartment of Neurosurgery, Kanagawa Children’s Medical Center, Yokohama, Japan; bDepartment of RNF213 mutation. Similar to the workup of moyamoya disease, confirmation of RNF213 mutation in Williams syndrome may be useful in predicting the development of moyamoya syndrome that can lead to severe complications. © 2022 The Author(s). Published by S. Karger AG, Basel Introduction Fig. 1. a MRA shows stenosis of the bilateral internal carotid arteries. b FLAIR image demonstrates the ivy sign bilaterally (arrowheads). FLAIR, fluid-attenuated inversion recovery. 366 a Pediatr Neurosurg 2022;57:365–370 DOI: 10.1159/000525229 History and Examination 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]. Operative and Postoperative Course 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 b Akimoto/Suenaga/Hayashi/Hirokawa/Ito/ Sato/Yamamoto Downloaded from http://karger.com/pne/article-pdf/57/5/365/3738407/000525229.pdf by guest on 18 April 2024 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. Case Report 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. Genetic Study 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 Fig. 2. Common carotid angiography findings. Right frontal (a) and lateral (b) views and left frontal (c) and lateral (d) views show severe stenosis, especially in the proximal portions of the bilateral middle cerebral arteries, and development of moyamoya vessels. On the basis of these findings, we classified the moyamoya syndrome as Suzuki Stage III [19]. Moyamoya Syndrome in a Patient with Williams Syndrome a b c d Pediatr Neurosurg 2022;57:365–370 DOI: 10.1159/000525229 367 Downloaded from http://karger.com/pne/article-pdf/57/5/365/3738407/000525229.pdf by guest on 18 April 2024 Discussion 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 c d e a Fig. 3. a Four months after the second surgery, MRA demonstrates collateral vessels from the bilateral deep temporal arteries (arrowheads) and superficial temporal arteries (arrows) and reduced number of moyamoya vessels. b, d Preoperatively. c, e Postoperatively. The postoperative FLAIR images show resolution of the ivy sign bilaterally (arrowheads). FLAIR, fluid-attenuated inversion recovery. Fig. 4. Schematic result of the pyrosequencing of RNF213 A p.Arg4810Lys mutation in the RNF213 c.14429G>A is observed. 368 Pediatr Neurosurg 2022;57:365–370 DOI: 10.1159/000525229 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 atheroAkimoto/Suenaga/Hayashi/Hirokawa/Ito/ Sato/Yamamoto Downloaded from http://karger.com/pne/article-pdf/57/5/365/3738407/000525229.pdf by guest on 18 April 2024 b Conclusion 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. Acknowledgments We thank Flaminia Miyamasu of the Medical English Communications Center, University of Tsukuba, for manuscript editing. Moyamoya Syndrome in a Patient with Williams Syndrome Statement of Ethics 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. Conflict of Interest Statement All authors have no conflict of interest. Funding Sources The authors did not receive any funding for this study. Author Contributions 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. Data Availability Statement All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author. References 1 Schubert C. The genomic basis of the Williams-Beuren syndrome. Cell Mol Life Sci. 2009;66(7):1178–97. 2 Kaplan P, Wang PP, Francke U. Williams (Williams Beuren) syndrome: a distinct neurobehavioral disorder. J Child Neurol. 2001; 16(3):177–90. 3 Kawai M, Nishikawa T, Tanaka M, Ando A, Kasajima T, Higa T, et al. An autopsied case of Williams syndrome complicated by moyamoya disease. Acta Paediatr Jpn. 1993; 35(1): 63–7. 4 Sim YW, Lee MS, Kim YG, Kim DH. 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