De novo brain arteriovenous malformation formation and development: A case repor

lNTRODUCTlON

Brain arteriovenous malformation (AVM) is one of the main causes of spontaneous cerebral hemorrhage in children[1] and accounts for 30%-50% of spontaneous cerebral hemorrhage in children[1,2]. It is generally believed that AVM is a kind of congenital vascular disease[3]. The abnormality is formed in the third to fourth week of embryonic development, when the length is about 40-80 mm, during the process of cerebrovascular development and manifests as abnormal coiled and interlaced vascular clusters[4]. Arteries and veins are directly connected by malformed vascular clusters. At present, the mechanism of the occurrence and development of AVM is not clear, and there have been very few case reports that have documented the progression of abrain AVM[5-7]. Here, we have documented for the first time a case of a child with abrain AVM that progressed and ruptured twice within 6 years. We have also reported for the first time the potential role of heterozygous mutations in thegene in the pathogenesis of AVM.

CASE PRESENTATlON

Chief complaints

A 15-year-old boy was admitted to the hospital in November 2019 with complaints of an acute headache for 3 h.

The boy had normal growth and development and no history of other special diseases. In August 2011,the child presented at another hospital with complaints of a headache for more than 1 wk. At that time,magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) were performed. The scans revealed that there was no vascular abnormality,abnormal signal intensity, or any other findings suggestive of an AVM (Figure 1A-C). At that time, the doctor did not administer any treatment, and the headache was ameliorated by itself. In October 2013,the child again presented at another hospital with headache and nausea for 2 d. His MRA scan revealed a small right temporal AVM, the size of which was 6.2 mm × 1.9 mm (Figure 1C). Digital subtraction angiography revealed the presence of a suspicious lesion in the right temporal lobe (Figure 1D). The boy was treated for headaches and was not examined further. In February 2019, the boy presented at our hospital complaining of a sudden headache and vomiting for 2 h. He was conscious when he came to our hospital. His Glasgow coma scale score was 14, and National Institutes of Health Stroke Scale score was 1. Computed tomography of the head demonstrated acute intracerebral hemorrhage in the right temporal lobe. The MRA revealed a small AVM in the right temporal lobe (Figure 1E). Symptomatic treatment was given to the child during hospitalization, and gamma knife radiosurgery was suggested.Unfortunately, the child’s parents rejected radiotherapy.

History of present illness

[3] 吴拥政,何 杰,司林坡,等.义马矿区深部矿井地应力分布规律研究[J].煤炭科学技术,2018,46(10):16-21.

History of past illness

你说什么都白搭。你根本不可能说服我，一点希望也没有。西双摊开两手，说，她病了，我去看她，这件事就算完了。她以后再有什么事，都与我无关……如果你想把这顿饭吃得不痛快，你就继续劝我，我反正充耳不闻。不过，如果你能让我安安静静把这顿饭吃完，我会很感激你。

Personal and family history

通过饱和砂岩流固耦合蠕变试验，简单描述了砂岩在不同孔隙水压蠕变变形的特性及变形破坏所需时间，根据改进后Druck-Prager屈服函数求出岩石蠕变本构模型，并在此基础上进一步推导三维状态下本构方程，得到了4条结论。

Physical examination

The patient was conscious when examined at our hospital in November 2019. His Glasgow coma scale score was 15 and his National Institutes of Health Stroke Scale score was 1.

Laboratory examinations

We thank the Department of Neurosurgery and the Department of Radiology of The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University for the diagnosis and treatment of the patient.

Imaging examinations

A small AVM within the right temporal lobe was visualized in the MRA (Figure 1G), and cerebral angiogram revealed the presence of a 21.6 mm × 21.2 mm right temporal AVM, which was supplied by the inferior temporal branches of the right posterior cerebral artery. Venous drainage occurred through superficial cerebellar veins into the right sigmoid sinus. It was classified as Spetzler-Martin grade 1(Figure 1H).

In November 2019, computed tomography of the head demonstrated the presence of an acute intracerebral hemorrhage in the right temporal lobe (Figure 1I). Digital subtraction angiography displayed abnormal vascular clusters, which were slightly larger than those seen 10 mo ago. The size of these clusters was 24.3 mm × 22.8 mm. The AVM was classified as a Spetzler-Martin grade 1 (Figure 1J).

Further diagnostic work-up

After receiving consent from the child’s parents, we conducted genetic analysis for the child and his parents. We discovered a mutation that might be related to the incidence of AVM,heterozygous mutation [NM_024408.3; c.1418A＞T; p.Asp473Val]. The mutation was only found in the child.

FlNAL DlAGNOSlS

Brain AVM, Spetzler-Martin grade 1.

制定规范与流程[8] 实验室依据国家和学校相关制度制定并颁布院级仪器设备开放共享暂行办法、仪器设备开放共享收费标准、仪器设备开放预约实验指南、校内转账流程等。开放共享初期对放置在各大实验室的仪器设备强行开放共享，鼓励放在各个课题组教师实验室的10万元以上的大型仪器设备开放共享，采取自愿原则。

TREATMENT

The parents refused to conduct further interventional treatment. Supportive treatment was administered during the hospitalization period, and the boy was discharged after 10 d in good clinical condition.

The patient underwent MRI, MRA, and MRV scans in August 2011, at the age of 5 years and 2 mo for nonspecific headaches. No abnormal vascular lesions or secondary signs of brain AVM were observed.A brain AVM was first identified in October 2013. Bleeding occurred for the first time in February 2019 and occurred again in November 2019. The malformed vascular clusters progressed significantly during this period. No risk factors were associated with AVM in this case. Literature review revealed that most of the reported AVM cases had underlying pathology, and only a few of them had no cause ofAVM[5,8]. Our case report is the first to define the progression and eventual rupture within 6 years following its primary discovery. We also report for the first time that heterozygous mutations in thegene might be playing a role in the pathogenesis of AVM.

OUTCOME AND FOLLOW-UP

The clinical condition of the child was good during the final follow-up, which was performed on January 2021. The child was in good general condition at the time. After January 2021, he was lost to follow-up.

DlSCUSSlON

原因何在？我们可以从平顶山环境污染防治攻坚战领导小组办公室印发的一份通知中得到答案。该通知针对改善空气质量共提出了25项重点任务，其中涉及“科学规划营运加油站点”：要求6月底前，市内四个国控空气质量自动监测站点周边2公里范围内营运加油站完成选址搬迁……搬迁前，即日起范围内加油站营业时间改为每日19时至次日8时。

Currently, the pathogenesis of brain AVM is not clearly understood. The imbalance of some signal molecules during embryonic development is believed to be the most likely reason for no capillary formation between the arteries and veins[9]. This balance is dependent on the strict regulation of various angiogenic factors, and any interference for these automatic regulation factors may lead to the formation of AVM[10,11]. There was no high-risk factor for AVM in this case, and the only high-risk factor that may have a relation in the development of AVM was the heterozygous mutation of thegene. The NOTCH2 protein is the receptor of the Notch signaling pathway, and its activity can directly affect Notch signaling[12]. However, the Notch signaling pathway has complex and contextdependent effects on angiogenesis[13,14]. Studies have demonstrated that abnormal activation of Notch signaling in human brain AVM was associated with AVM bleeding[15]. The inhibition and activation of Notch signaling were both associated with AVM formation. The mutation in this case (p.Asp473Val)was first described by Gilbert[16]. The mutation is located in exon 8, and exon 8 encodes the epidermal growth factor-12 domain of[16,17]. Unfortunately, there has been no research on the effect of this mutation on the function of the NOTCH2 protein.

在调整粮食统计口径数据出台之前，要完成原口径粮食统计历史数据的调整工作，确保统计口径调整前后数据之间的衔接性和连续性，避免出现调整前后数据出现“断崖”。在调整过程中，要核实各省(直辖市、自治区)统计数据与国家统计数据长期存在的数据差异情况，尽量减小差异，保证国家与各省(直辖市、自治区)之间数据的衔接性。

CONCLUSlON

We report for the first time a case ofAVM formation in a child, which progressed and eventually ruptured within 6 years. Our case contests the traditional view that brain AVM is congenital, and our case once again confirms the view that brain AVM is an acquired disease that is the result of an interaction of genes, environment, and molecules.

The child presented with a sudden severe headache for 3 h with no inducing factors. He was conscious and had no history of nausea, dizziness, or fever.

ACKNOWLEDGEMENTS

Laboratory examinations showed no significant abnormality.

FOOTNOTES

Li DD was in charge of case review and preparation of the manuscript; Huang H, Wang X, Guo AN, and Li W collected clinical opinions regarding this case and drafted the manuscript; Duan RH, Fang JH, and Yin B participated in the coordinating the manuscript; Huang H and Li DD revised the manuscript; All authors read and approved the final manuscript.

the Science and Technology Program of Wenzhou, China, No. Y20190145 to Huan Huang; and the Beijing New Health Industry Development Foundation, No. XM2020-02-002 to Bo Yin.

Written informed consent was obtained from the patient’s parents.

The patient did not have any personal or family history of brain AVM.

The authors declare there are no conflicts of interest.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

一篇教育类文章中有这样一段话：“美国式的教育注重培养学生的开放型思维和质疑精神，鼓励学生质疑他们所学到的东西，但是忽略了基础知识的传授；中国学生则具备扎实的理论基础，踏实严谨的求学态度，但在开放型思维和独立思考的能力方面还有一定欠缺。”在此，我不对中美教育进行评论，也不对中国的教育进行批判，只想从自己的教育工作入手，思考一个与语文教学相关的问题：如何在语文教学中培养学生的质疑精神。

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Huan Huang 0000-0001-8842-2424; Xue Wang 0000-0001-6178-6316; An-na Guo 0000-0003-3631-1401;Wei Li 0000-0002-3401-0077; Ren-Hua Duan 0000-0003-2776-7060; Jun-Hao Fang 0000-0002-1395-0756; Bo Yin 0000-0002-5487-0197; Dan-Dong Li 0000-0003-4973-8818.

该量表由我国学者丛中、高文凤[20]编制，共16个项目，包括自我评价与自我接纳两个因子.量表总分越高,自我接纳程度越高；反之越低.自我接纳和自我评价两因子的内部一致性系数分别为0.93和0.91，重测信度为0.76.

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