2型神经纤维瘤病相关前庭神经鞘瘤肿瘤微环境研究进展

2型神经纤维瘤病（neurofibromatosis type 2, NF2）是一种少见的常染色体显性遗传疾病。NF2基因定位于22q12.2染色体的抑癌基因,由于该基因发生突变引起的全身性多发肿瘤综合征。双侧前庭神经鞘瘤（bilateral vestibular schwannoma,BVS）是NF2的最显著特征。较散发性的前庭神经鞘瘤（vestibule schwannoma,VS）相比,术中观察NF2-BVS血供比较丰富,并且NF2肿瘤易复发,类似于低度恶性肿瘤。所以NF2-BVS与散发的VS是否是相同肿瘤有待进一步探索。NF2-BVS多以手术治疗为主,患者大多要面临多次手术的情况,并且术后多伴有听力减退等并发症,治疗效果及生存质量远不及散发性VS。随着对于肿瘤微环境（tumor microenvironment,TME）及肿瘤相关巨噬细胞（tumor associated macrophages,TAMs）促进肿瘤生长方面研究的深入。基于TME的针对NF2-BVS的新型治疗方法探索十分有必要。文章概述NF2-BVS疾病的特点及目前治疗手段的不足,肿瘤相关巨噬细胞对于肿瘤生长的促...     

前庭神经鞘瘤中神经鞘瘤病Ⅱ型基因变异的临床表现

听神经瘤是～种起源于前庭经鞘的良性肿瘤，可发生于单侧或双侧,尽管前诊治方法报人进陕，但仍为导致面神经与听力障碍的委要原L’十人类状22条染色体上肿瘤抑制基同的突变被认为‘川U6冲外则瘤形成有关．该研究古要担子外经纤维瘤病U佚（N匕）基因突变可引起临床特＃讲大观或有特殊人达的假设。研究目的：I验证特发性单侧或家族性从侧听神经瘤患者＊乙基因突变的形式；！探讨特异性突变的类型是否与持殊的临床表现有关；9进一步明确＊又肿瘤抑制基因和临床应用的关系。从而对N匕及特发性前庭神经鞘瘤做出早期诊断和治疗．尽盯能保留面神…     

听神经瘤分子生物学研究

听神经瘤起源于前庭神经雪旺细胞。单侧与双侧听神经瘤即Ⅱ型神经纤维瘤病（neurofibromatosis type2,NF2）,其肿瘤形成机制基本相同。大量研究表明NF2基因突变是发病的主要分子机制,其编码蛋白产物的多种表达调控与肿瘤发生密切相关,有研究指出,其它肿瘤相关基因、生长调节基因、神经生长因子、细胞凋亡转录物等可能参与听神经瘤的形成。本文对听神经瘤分子生物学研究的进展加以综述。     

听神经瘤分子生物学研究

听神经瘤起源于前庭神经雪旺细胞。单侧与双侧听神经瘤即Ⅱ型神经纤维瘤病(neurofibromatosis type2,NF2),其肿瘤形成机制基本相同。大量研究表明NF2基因突变是发病的主要分子机制,其编码蛋白产物的多种表达调控与肿瘤发生密切相关,有研究指出,其它肿瘤相关基因、生长调节基因、神经生长因子、细胞凋亡转录物等可能参与听神经瘤的形成。本文对听神经瘤分子生物学研究的进展加以综述。     

神经纤维瘤病型的遗传及其特点

神经纤维瘤病(NF2)是常染色体显性遗传病。发病率大约在1/360000～1/40000之间,但实际诊断率略低于1/200000。患者主要表现为双侧前庭神经鞘膜瘤(VS),以及其它颅神经,脊神经和外周神经鞘膜瘤,其它病变包括颅内(包括原发于视神经)和椎管内脑膜瘤,以及一些中枢神经低度恶性肿瘤(室管膜瘤、神经胶质瘤)。因为NF2患者好发VS,故早期症状以耳部为主,如耳聋、耳鸣、不稳感、眩晕。NF2的诊断标准如下:双侧VS,或有NF2家族史加上以下一种情况:1单侧VS;2以下任意两者:脑膜瘤、胶质细胞瘤、神经纤维瘤、雪旺氏细胞瘤、晶状体后囊下浊斑。以下几组…     

神经纤维瘤病Ⅱ型(附1例报告)

目的：提高对神经纤维瘤病Ⅱ型（NF2）的病因、临床表现、诊断及治疗的认识。方法：结合文献复习,分析我院收治的1例NF2患者的临床资料,并对该例患者行左侧小脑桥脑角肿瘤切除术。结果：该患者患病年龄较早,出现临床症状较晚,首发症状为渐进性听力下降伴耳鸣,头颅MRI示双侧小脑桥脑角占位性病变,双侧海绵窦区及双侧颈部多发结节。组织病理性质为神经鞘膜瘤。术后左耳全聋,左侧不完全性周围性面神经麻痹,House-Brackmann分级Ⅱ级。结论：NF2为常染色体显性遗传疾病,临床上以双侧听神经瘤为主要特征。早期诊断和治疗对患者的听力和生命的保护至关重要。MRI扫描为目前诊断NF2的金标准。     

以反复眩晕为主诉的单侧多发性前庭神经鞘瘤1例报道

<正>前庭神经鞘瘤也称听神经瘤^[1],为内听道、桥小脑角区最常见的良性肿瘤。它会引起听力下降、耳鸣或眩晕;随着肿瘤的生长并向小脑脑桥角扩展,压迫脑桥、延脑,并出现脑积水、颅内高压,进而危及患者生命^[2]。2021年8月我院收治了1例以眩晕为主诉的多发性前庭神经鞘瘤患者,后转诊至301医院,成功为患者施行了右侧迷路入路肿瘤切除手术,术中证实为右耳迷路多发性前庭神经鞘瘤。现对该病例报道如下:     

双侧听神经瘤研究进展

散发的听神经瘤 (ａｃｏｕｓｔｉｃｎｅｕｒｏｍａ)即单侧听神经瘤 ,双侧听神经瘤在常染色体显性遗传的家族性肿瘤综合征即Ⅱ型神经纤维瘤病 (ｎｅｕｒｏｆｉｂｒｏｍａｔｏｓｉｓｔｙｐｅ 2 ,ＮＦ2 )中出现。位于第 2 2号染色体长臂上的ＮＦ2肿瘤抑制基因的突变是单侧和双侧听神经瘤的分子机制。其肿瘤发生机理符合“两次打击”模型。现将对目前有关双侧听神经瘤的研究进展加以综述。历史回顾　　Ｗｉｓｈａｒｔ在 182 2年报道了一个在 2 1岁时两耳听力丧失 ,经尸体解剖证实有双侧听神经瘤及多个颅内肿瘤的病例 ,被认为是第一个有记载的Ｎ…     

GJB2、SLC26A4基因致病性突变与内耳CT表型关系的研究

目的研究感音神经耳聋GJB2、SLC26A4基因致病性突变与内耳CT表型之间的关系,探讨这两种基因检测在诊断感音神经性耳聋患者是否存在内耳畸形方面的作用。方法按DNA测序的方法检测2686例感音神经性耳聋患者GJB2、SLC26A4基因致病性突变情况,以Sennaroglu分类为标准统计以上患者内耳CT表型情况,分析GJB2、SLC26A4基因型与CT表型之间的关系。结果 1、2686例患者中共检出GJB2基因致病性突变429例(双等位基因纯合突变220例、复合杂合突变207例、单等位基因显性突变2例),共检出SLC26A4基因致病性突变596例(双等位基因纯合突变169例、复合杂合突变427例)。2、2686例患者中内耳畸形873例(Mondini畸形371例、单纯大前庭水管338例、其它164例);内耳CT正常1813例。3、GJB2基因致病性突变99.30%(426/429)在内耳CT正常组中检出,SLC26A4基因致病性突变100%(596/596)在前庭水管扩大相关内耳畸形中检出。结论 GJB2基因致病性突变与内耳正常CT表型密切相关;SLC26A4基因致病性突变与前庭水管扩大相关内耳畸形密切相关。     

前庭神经鞘膜瘤囊性变的治疗策略

摘要：目的分析前庭神经鞘膜瘤囊性变治疗策略的影响。方法回顾性分析2006年1月~2013年12月收治前庭神经鞘膜瘤697例,其中根据内听道及桥小脑角增强MRI发现为前庭神经鞘膜瘤束性变患者96例,同时从剩余601例中随机抽取96例作为实体肿瘤组,比较两组患者临床特性、术中特点和手术效果。结果前庭神经鞘膜瘤囊性变的临床进展明显较实性肿瘤快速,且听力症状较实性肿瘤患者严重,突发性耳聋率较高29（30.2%）,囊性肿瘤与面神经粘连较实体肿瘤严重,术后短期两组面神经功能差异无统计学意义（P>0.05）,但术后1年随访时CVS组面神经功能良好率明显低于SVS组（30.2% vs 44.8%,P=0.037）。两组在术后并发症发生率、死亡率、复发率方面无差异。结论前庭神经鞘膜瘤囊性变应首选手术切除,对于周围薄壁型囊性肿瘤,如剥离困难无法全切除,应以保留面神经功能为先,采取近全切除等措施,提高术后患者生活质量。     

Growth Rate Characteristics of Acoustic Neuromas Associated With Neurofibromatosis Type 2

Neurofibromatosis type 2 (NF2) is a dominantly inherited disorder characterized by the occurrence of bilateral acoustic neuromas (ANs) and other central nervous system tumors. Magnetic resonance images and audiologic data on 22 patients with NF2 who underwent multiple studies at the National Institutes of Health between 1983 and 1993 were reviewed to determine the growth characteristics of ANs in these patients. The average growth rate of ANs in NF2 patients was 0.30 cm³ per year and was significantly higher in older patients (0.75 cm³ per year) than in younger ones (0.12 cm³ per year). Larger ANs were more commonly found in patients with concomitant spinal tumors or meningiomas. NF2 patients with spinal tumors but not meningiomas demonstrated faster growth rates than patients without additional tumor burden. The data from this study suggest that older patients or patients with associated spinal tumors have faster growing ANs and therefore should be followed closely and treated aggressively.     

Correlation between GJB2 mutations and audiological deficits: personal experience

Mutations in GJB2 gene are the most common cause of genetic deafness. More than 100 mutations have been described. The aim of this work is to describe the personal experience in genetic hearing loss, investigating the audiological and genetical characteristics of Cx26 deafness and correlating genotype and phenotype. We performed audiological and genetical evaluation in 154 patients affected by non-syndromic deafness of different degree. All patients showed a bilateral symmetrical sensorineural hearing loss. From the genetical analysis 127 probands resulted as negatives while 27 as positives (51.8% homozygous for 35 delG, 14.8% compound heterozygosis and 33.3% single mutation); 7.5% of patients had a mild deafness, 37% moderate, 33.3% severe and 22.2% profound. The c.35 delG mutation was detected in 66.6% of patients. Three mutations were found in compound heterozygosis with 35 delG, six different single mutations already described, and a new mutation S138G were also found. Correlation between genotype and phenotype confirmed the high variability of hearing loss.     

Cochlear implantation in the neurofibromatosis type 2 patient: long-term follow-up

OBJECTIVE: To evaluate the long-term hearing outcomes of neurofibromatosis type 2 (NF2) patients with cochlear implants. METHODS: Retrospective analysis of cochlear implant performance in NF2 patients using open- and closed-set speech perception testing. RESULTS: Patients with NF2-associated bilateral vestibular schwannomas frequently become profoundly deaf. The aim of surgical resection should be to preserve serviceable hearing in at least one ear; however, this goal can be difficult to achieve. Frequently, tumor size or poor preoperative hearing status can require a surgical approach that leaves the patient with a profound, bilateral sensorineural hearing loss. If the cochlear nerve is preserved anatomically after vestibular schwannoma surgery, and if promontory stimulation confirms the functionality of the cochlear nerve, then cochlear implantation is an excellent option to restore hearing. We present six cochlear implant patients with NF2 who attained a significant improvement in open- and closed-set speech understanding with a mean follow-up of 7.9 (range: 5-13) years after surgery. In all but one case, the hearing results did not deteriorate over the follow-up period. CONCLUSION: Early surgical intervention for vestibular schwannomas in NF2 patients when the cochlear nerve can be spared is an important consideration to allow for possible cochlear implantation. A 6- to 8-week recovery period for the anatomically intact cochlear nerve may be necessary to obtain a positive promontory stimulation response following tumor resection and should be performed prior to cochlear implantation.     

Clinical Manifestations of Mutations in the Neurofibromatosis Type 2 Gene in Vestibular Schwannomas (Acoustic Neuromas)

Vestibular schwannomas (acoustic neuromas) continue to cause significant facial nerve and hearing morbidity, despite marked improvement in diagnosis and treatment. Mutation of a tumor-suppressor gene on human chromosome 22 has been found to be associated with vestibular schwannoma formation. The central hypothesis of this study is that specific mutations in the neurofibromatosis type 2 (NF2) gene may produce specific clinical characteristics or phenotypic expressions. The purposes of this investigation are: 1. to determine what proportion of vestibular schwannomas from patients with spontaneous unilateral and familial bilateral schwannomas have mutations present within the NF2 gene; 2. to determine whether specific types of mutations are associated with a specific clinical manifestation of this disease; and 3. to further define the relationship between newly discovered mutations within the NF2 tumor-suppressor gene and possible clinical applications of this knowledge to advance diagnosis and treatment of patients with NF2 and spontaneous vestibular schwannomas. DNA from 61 schwannomas (29 unilateral vestibular schwannomas and 32 from patients with bilateral vestibular schwannomas[NF2]) were examined, and 33 unique mutations were identified. Significant differences were found in the frequency, distribution, and type of mutation between the NF2 schwannomas and the spontaneous vestibular schwannomas. Three clinical subtypes of NF2 were identified. In tumors from 28 patients, no mutations were identified. Of the 33 mutations identified in the NF2 gene, 30 were likely to result in loss of tumor-suppressor function from protein truncation; however, three milder mutations termed missense mutations were associated with milder clinical manifestations of the disease and had a slower estimated growth rate. Variable clinical presentation in patients whose tumors had severe or truncating types of mutations suggest that factors in addition to the mutation class are likely to be responsible for a portion of the clinical expression of disease. New diagnostic options are now available for NF2 that will improve the likelihood of hearing and facial nerve preservation and ultimately have significant impact on the management of vestibular schwannomas.     

The limitations of computed tomography in adult cochlear implant evaluation

Objective

To demonstrate the added value of magnetic resonance imaging (MRI) over computed tomography (CT) during adult cochlear implant evaluation.

Patients

Two adult patients are discussed in whom MRI studies diagnosed bilateral vestibular schwannomas during cochlear implant candidacy evaluation.

Interventions

Temporal bone CT and MRI.

Main outcome measure

Diagnosis of NF2.

Results

Two adult patients, ages 67 and 68 years, were evaluated for cochlear implant candidacy. Both patients experienced slowly progressive, bilateral hearing loss without complaints of vertigo, and neither patient had a family history of hearing loss or neurogenic tumors. Both patients had near-symmetric pure tone thresholds on audiometric testing. An MRI and a CT scan were performed on both patients, and bilateral vestibular schwannomas were identified on MRI.

Conclusions

Though MRI is not routinely utilized in adult cochlear implant evaluation, it may be of greater clinical value than CT in the setting of adult-onset hearing loss. MRI allows for sensitive evaluation of cochlear patency and architecture, and cochlear nerve status. As demonstrated in the two index cases, MRI also provides the added benefit of evaluating for causes of retrocochlear hearing loss. These two patients would have likely experienced a significant delay in diagnosis of NF2 without preoperative MRI, particularly given the limitations of scanning following CI magnet placement.     

Outcomes of cochlear implantation in patients with neurofibromatosis type 2

In neurofibromatosis type 2 (NF2) bilateral vestibular schwannomas (VS) or their treatment usually results in bilateral hearing loss. Cochlear implantation (CI) was traditionally not used in these patients due to concern that retrocochlear disease would render the implant ineffective. This paper describes the auditory outcomes of CI in 13 patients with NF2 and includes patients with untreated VS and patients undergoing VS removal with cochlear nerve preservation. The non-user rate was 7.7%. Of the active users, median CUNY score was 98%, median BKB score in quiet was 90% and median BKB score in noise was 68%. CI is a viable option in selected patients with NF2.     

Neurofibromatosis 2: two case reports

Our study presents two cases of neurofibromatosis 2 (NF2) that have been diagnosed at the Ear, Nose, and Throat Department of Hradec Králové (Czech Republic). The first case involved a young man with a history of sudden hearing loss accompanied by tinnitus on the left side. The diagnosis of NF2 was made, and an operation for left acoustic neuroma was performed. Looking toward the future, the acoustic neuroma on the right side should be resolved as well. The second case concerned a woman (the mother of our patient 1) examined at the same Ear, Nose, and Throat Department in 1980, after 4 years of gait instability and progressive loss of hearing and tinnitus on the right side. Computed tomography scan detected a bilateral expansion in the pontocerebellar angles, and a large tumor on the right side was removed. The patient is deaf and has facial palsy without progression of symptomatology during long-term follow-up. These two cases document the rare but serious hereditary disease of NF2. Its most frequent first presentation is acoustic neuroma; further, benign tumors of the nervous system and juvenile cortical cataract also are often detected. The variability of number, location, and biological behavior of tumors associated with NF2 require an individual patient treatment approach, long-term follow-up, and insertion of appropriate hearing aids. Important also is a genetic examination to exclude pathological NF2 genes in the first-degree relatives of the affected individuals.     

An auditory brainstem implant system

Neurofibromastosis type II (NF2) is a condition that may result in bilateral acoustic neuromas. The tumors and their removal may cause profound bilateral deafness. Because the auditory nerve is compromised, people with NF2 are unable to receive a cochlear implant to restore a sensation of hearing. Electrical stimulation of the auditory pathway can provide hearing in such people. This is possible by means of an auditory brainstem implant (ABI). This article focuses on the MED-EL high-rate multichannel ABI system. The system consists of the implanted and external components. Appropriate placement of the ABI is dependent on electrical auditory brainstem response testing performed intra-operatively. Data on a group of European patients implanted with the MED-EL ABI are presented. Results are promising and include some open-set speech ability.     

The auditory midbrain implant: a new auditory prosthesis for neural deafness-concept and device description.

The auditory midbrain implant (AMI) is a new central auditory prosthesis designed for penetrating stimulation of the human inferior colliculus. The major group of candidates for the AMI consists of neurofibromatosis type 2 (NF2) patients who develop neural deafness because of growth and/or surgical removal of bilateral acoustic neuromas. Because of the absence of a viable auditory nerve, these patients cannot benefit from cochlear implants. An alternative solution has been the auditory brainstem implant (ABI), which stimulates the cochlear nucleus. However, speech perception performance in NF2 ABI patients has been limited. The fact that the ABI is able to produce high levels of speech perception in nontumor patients (with inaccessible cochleae or posttraumatic damage to the cochlear nerve) suggests that limitations in ABI performance in NF2 patients may be associated with cochlear nucleus damage caused by the tumors or the tumor removal process. Thus, stimulation of the auditory midbrain proximal to the damaged cochlear nucleus may be a better alternative for hearing restoration in NF2 patients. We propose the central nucleus of the inferior colliculus (ICC) as the potential site. A penetrating electrode array aligned along the well-defined tonotopic gradient of the ICC should selectively activate different frequency regions, which is an important elementfor supporting good speech understanding. The goal of this article is to present the ICC as an alternative site for an auditory implant for NF2 patients and to describe the design of the first human prototype AMI. Practical considerations for implementation of the AMI will also be discussed.