VHL基因与家族性血管母细胞瘤研究进展

希佩尔-林道病(von Hippel-Lindau disease,VHL)是一种常染色体显性遗传病,以发生多器官肿瘤为特征,家族性血管母细胞瘤是其在中枢神经系统的一种表现形式,它是由于VHL基因的突变引起的。VHL基因是一种重要的抑癌基因,它通过VHL蛋白(pVHL)对elonginABC的抑制作用来发挥对相关细胞生长基因的调控。VHL基因突变在家族性血管母细胞瘤中有很高的检出率,因而针对VHL基因的研究可能为家族性血管母细胞瘤的治疗带来新的思路及方法。     

家族性髓母细胞瘤一例报告并文献复习

目的 报告家族性髓母细胞瘤1例并对文献进行回顾,探讨其可能病因.方法 该家族中共有4名患者,其中少年儿童3例,成人1例;男3例,女1例,有2名患者为同胞姐弟,表现为颅高压症状,均接受手术治疗.结果 4名患者病理证实髓母细胞瘤,其中1例于术后次日死亡,2例因肿瘤复发已死亡,1例现存活良好.结论 家族性髓母细胞瘤罕见,家族性髓母细胞瘤的发病可能与家族遗传易感性有关,但确切的发病机制及遗传学仍不明了,需进一步深入研究.     

血管母细胞瘤复发相关因素的临床病理分析

为了探讨与血管母细胞瘤（ＨＢ）复发密切相关的因素，为临床评估病人术后复发的可能性及预后提供参考依据，我们对５７例ＨＢ病人作了术后长期随访和临床病理资料分析。结果发现，其中１６例（２８．１％）在术后３￣１３２个月复发，复发组首次发病年龄小、术前病程短、肿瘤体积小、常呈家庭性发病、肿瘤呈多灶性、肿瘤中毛细血管白细胞附壁少或缺如，主要含毛玻璃样间质细胞和肿瘤中出现较多异型核间质细胞，与未复发组比较差异均     

家族性同一部位血管母细胞瘤的诊断治疗(附两个家系报告)

目的 探讨家族性同一部位血管母细胞瘤(HB)的诊断和治疗.方法 回顾分析两个家系2例小脑HB、3例脑干HB的临床资料和手术疗效,结合文献进行讨论.结果 两个家系均确诊为希佩尔-林道病(VHL).5例肿瘤全部切除,随访6-48个月,5例KPS评分均≥90分.结论 HB诊断主要依靠MRI,基因检测对VHL病的诊断有重要价值.显微手术技巧可显著提高本病的疗效;术后控制正常灌注压突破综合征、及时发现和处理相关并发症对本病的预后有重要意义.

Abstract：

Objective To study the diagnosis and treatment of familical hemangioblastoma with the same parts of central nervous system.Methods The clinical presentation, surgical treatment and outcomes in two families of two cerebellar hemangioblastoma and three hemangioblastoma of brainstem were analyzed retrospectively and literature review was performed.Results Family A was suspected to be VHL, family B was confirmed to be VHL.Five tumors were removed completely.The KPS of all patients were more than 90 during follow - up period ( from 6 months to 48 months ).Conclusion MRI and DSA may be the most important methods for the diagnosis of HBs.Genetic testing bears great value in the diagnosis of VHL.Microsurgical technique play a key role in the curative effect of hemangioblastoma.NPPB could be controlled in the perioperative period and management of complications is important for prognosis.     

家族性中枢神经系统血管母细胞瘤VHL基因突变与临床预后分析

目的 探讨汉族人家族性中枢神经系统血管母细胞瘤（HB）的临床特点及家系表现和VHL基因突变的关系.方法 回顾性分析9个家族15例经手术和病理证实的HB患者进行临床分析.对长期随访的7个家族中的12例患者和15例相关家族成员抽取外周血进行VHL基因测序.对于测序阴性的患者,对其DNA进行三个外显子实时定量PCR测定.结果 本组15例HBs中,多发性肿瘤10例,共34个肿瘤.进行开颅和脊髓手术17次,共切除HB22个.基因测序发现在4种点突变.通过实时定量PCR发现2个家族外显子1大片段缺失.在未发病家族成员中检出携带者3例.随访期间发现2例复发和3例新生的HB,主要集中在移码突变和拼接错误的家族中.通过再次手术和对脑干HB进行γ刀治疗,效果较好.结论 VHL相关的HB易复发,并不断有新生HB出现.基因测序和实时定量PCR联合应用可以提高VHL基因突变的检出率.基因突变分析可有助于未发病基因突变携带者确诊,基因突变的分型有助于对患者的预后进行判断.     

血管母细胞瘤35例临床分析

目的 通过对颅内血管母细胞瘤(HBs)的影像学、病理和治疗分析,探讨HBs的诊断、形成原因和疗效. 方法 皖南医学院弋矶山医院神经外科自2005年1月至2010年1月应用肿瘤切除术治疗35例颅内HBs患者,根据影像学表现分为大囊小结节型、小囊大结节型和完全实质型.分析患者的临床资料,对肿瘤标本行HE染色和免疫组化染色检测NSE和CD34的表达. 结果 本组肿瘤全切除34例,次全切除1例,术后无死亡.出院后28例获得随访,随访时间3个月至3年.其中1例复发(大囊小结节型)行伽玛刀治疗.HE染色显示纤细血管相互吻合成网状,分隔脂质胞浆;免疫组化染色显示不同类型肿瘤CD34阳性细胞数比较差异无统计学意义(P＞0.05).大囊小结节型肿瘤NSE阳性细胞数最多,小囊大结节型其次,实质型最少,差异均有统计学意义(P＜0.05). 结论 HBs无特殊临床表现,影像学表现是主要诊断方法.治疗首选手术切除,手术全切除是降低复发的关键.HBs囊腔的形成与肿瘤间质细胞密切相关.     

血管母细胞瘤

血管母细胞瘤（HGB）为起源于脑膜的中枢神经系统肿瘤,WHO I级,占颅内肿瘤的1％～2％、颅后窝肿瘤的7％。好发于成年人：可分为散发性和家族性两种类掣。前着约占75％,于中老年发病．多见于小脑半球;     

中枢神经系统血管母细胞瘤的年龄分层分析

目的 探讨不同年龄段的中枢神经系统（CNS）血管母细胞瘤（HB）的临床特征、预后及其影响因素。方法 回顾性分析2016年1月至2022年1月手术治疗的86例CNS-HB的临床资料。根据初次手术年龄分为四个年龄段（≤20岁、21~40岁、41~60岁和≥61岁）,分析不同年龄段临床特征、预后差异。结果 CNS-HB以颅内压增高症状为主,其次是小脑症状。肿瘤主要位于幕下,其中小脑占65.6%、脑干占17.7%,其次是脊髓（11.5%）,幕上极少（5.2%）;实性肿瘤43例（44.8%）,囊性肿瘤53例（55.2%）。年龄≤20岁组病程[（1.68±1.87）个月]较年龄≥61岁组[（26.50±50.66）个月]明显缩短（P<0.05）。年龄≤40岁病人VHL病发生率较年龄>40岁病人明显增高（P<0.05）。不同年龄段病人的肿瘤部位、肿瘤性质均无明显差异（P>0.05）。术后41例（42.7%）出现坠积性肺炎,年龄越大,发生肺炎的几率越高（P<0.001）。术后15例（15.6%）出现颅内并发症,实性肿瘤及脑干肿瘤病人术后颅内并发症发生率明显高于囊性肿瘤或肿瘤位于其他部位病人（P<0.05）。末次随访,预后良好78例（81.3%）,预后不良8例（18.7%）。多因素logistic回归分析显示男性、肿瘤位于脑干以及实性肿瘤是CNS-HB预后不良的独立危险因素（P<0.001）。结论 年轻HB病人的病程较短,而老年HB病人术后并发症发生率较高,但是年龄不是HB病人预后不良的危险因素,肿瘤部位及肿瘤性质与HB病人不良预后有关。40岁以下病人VHL病发病率较高,建议年轻病人积极进行VHL病的筛查。     

家族性中枢神经系统海绵状血管畸形致病基因的研究进展

本文首先简要介绍家族性中枢神经系统海绵状血管畸形 (Familial cerebral cavernous malformation，FCCM)发病特点及临床治疗,然后主要从分子遗传学的角度，介绍该病致病基因CCM1/ Krit-1、CCM2/MGC4607和CCM3/PDCD10的研究概况，特别是CCM2/MGC4607和CCM3/PDCD10这两个基因的近些年最新研究成果，从而使读者了解到该领域的分子遗传学的最新研究进展,由于基因是该病明确的致病因素，可见对其深入的研究可以为病因学﹑分子病理学以及基因诊断学奠定坚实的基础，同时为今后的临床治疗乃至基因治疗提供新的治疗方法与手段。     

家族性与散发性精神分裂症临床对照分析

Marrty(1985 )提出家族性与散发性精神分裂症概念 [1 ] ,发现两者临床症状、疗效、预后有所不同。我们对此进行研究 ,以探讨家族史与精神分裂症临床特征的关系。1　对象与方法收集 1996年 1～ 10月所有首次住院符合 CCMD- 2 - R精神分裂症诊断标准的病例资料 ,共 2 77例。根据家族性与散发性精神分裂症的界定标准分为家族性组及散发性组。以简明精神病评定量表 (BPRS)评定症状。 1999年 10月进行信访 ,了解其出院 3年中的康复情况。统计采用 SPSS(8.0 )软件包进行χ2 检验。2　结果家族性组 88例 ,男 48例 ,女 40例 ;平均年龄 (30 .6…     

两家系家族性颅内血管网状细胞瘤的临床特征及诊疗分析

目的 分析2个家系5名家族性血管网状细胞瘤患者的临床表现及诊断治疗方法.方法 湖北省襄阳市中心医院肿瘤科自2005年9月至2011年5月共收治2个家系共5名家族性血管网状细胞瘤患者,回顾性分析患者的临床资料、影像学特征、诊断与治疗方法. 结果 头颅MRI检查显示家系1中3例患者有2例为囊实性肿瘤,1例为实性肿瘤;家系2中2例患者均为囊实性肿瘤.5例患者均存在突变,均可诊断为Von Hippel-Lindau(VHL)病.所有患者均未合并肝脏等其他部位的病变.镜下全切或近全切肿瘤后均行定期随访1年,无复发、无死亡病例. 结论 头颅磁共振检查仍是目前家族性血管网状细胞瘤最主要的诊断及随访方法,手术仍是最主要的治疗手段.     

家族性血管网状细胞瘤临床分析(附一家系报告)

目的 分析1个家族性血管网状细胞瘤家系3名患者的临床特点、影像学表现及诊断治疗方法 及预后.方法 通过调查、收集自2004年10月至2010年5月期间我院收治的1个家族性血管网状细胞瘤家系3名患者的病史、临床表现、影像资料,并检测其他部位的病变情况,探讨本病的诊断和治疗情况,综合分析其临床特点.结果 3名患者均未合并其他部位病变,头颅MRI显示2例为囊实性肿瘤,1例为实质性肿瘤,手术镜下全切后均给予定期随访,至今未见复发.结论 对于家族性血管网状细胞瘤,头颅MRI检查是主要的诊断及随访方法 ,手术切除是主要治疗手段.鉴于家族性血管网状细胞瘤易合并其他部位病变、复发率高、手术难度大,应加强对家族性血管网状细胞瘤的早期诊断和治疗认识.     

家族性ALS的临床特征及基因分析

目的探讨肌萎缩侧索硬化症(ALS)家系的临床特点及SOD1基因突变规律。方法详细分析一个FALS大家系的临床特征、肌电图改变、遗传方式,用PCR-SSCP法检测SOD1基因的突变。结果该家系有6代、237人,其中13人患病,8人死于ALS,具典型ALS症状,但起病前有较长一段时间肌肉纤颤期。PCR-SSCP法检测SOD1基因未发现突变,为非SOD1基因突变的ALS家系。结论(1)对于家族性肌跳的患者,宜动态观察其肌电图的改变,注重临床随访;(2)该家系可能存在一个非SOD1基因的、新的FALS致病基因。     

家族性双侧腕管综合征一家系分析并文献复习

目的分析家族性腕管综合征的临床表现、电生理、影像学及分子遗传学特点,尤其是遗传学的研究进展。方法收集家族性腕管综合征一家系中先证者的临床资料、实验室结果、电生理和影像学资料,同时对先证者、先证者之子以及家系中其他患病成员围绕周围神经病行基因学检测。结果家系中患病者均早年即出现典型的双侧腕管综合征,呈常染色体显性遗传模式。通过基因检测排除了合并有遗传性压力易感性周围神经病和家族性淀粉样变性的可能,同时发现了INF2、KIF1B、TRPV4、SCN9A这4个基因存在点突变。结论原发性家族性腕管综合征可能为其他基因异常引起的一种独立的疾病,然而其致病基因是未知的,仍有待我们进一步探索。     

Pathological findings in a patient with alpha-synuclein p.A53T and familial Parkinson's disease

The present report documents a patient harboring an alpha-synuclein p.A53T variant from a family presenting with autosomal dominant inheritance, including four patients clinically diagnosed with Parkinson's disease (PD) and two with dementia. The alpha-synuclein p.A53T variant is linked to young- or middle-aged onset parkinsonism and cognitive decline. Our patient had a different haplotype from that of a patient with a p.A53T variant from an Italian family. The proband presented at 42 years of age with progressive parkinsonism and good response to levodopa in the early stages of the disease. At 46 years of age, he developed delusions and cognitive decline. Brain magnetic resonance imaging showed bilateral atrophic changes in the hippocampus and temporal lobes. He died of pneumonia at the age of 52 years. Neuropathological examination revealed severe neuronal loss in the substantia nigra, locus coeruleus, and dorsal nucleus of the vagus nerve, as well as widespread Lewy pathology including Lewy bodies and neurites, corresponding to Braak stage 6, and diffuse neocortical-type PD. There was mild appearance of tau pathology and glial cytoplasmic inclusion, in the absence of TDP-43 pathology. Alpha-synuclein p.A53T characteristically cause the Lewy body pathology and the symptoms, that resembled those of the reported patients with p.A53T.     

延髓背侧血管母细胞瘤的显微外科治疗(10例报告)

目的探讨延髓背侧血管母细胞瘤的影像学特征、显微外科手术技巧以及并发症的防治。方法回顺性分析10例经手术和病理证实的延髓背侧血管母细胞瘤的临床资料和手术疗效。结果8例肿瘤全部切除,随访3～45个月,正常工作学习7例、生活自理1例,2例次全切除者于术后25 d、半年因呼吸衰竭及顽固性消化道出血死亡。结论头部MR、DSA对本病的诊断具有重要的价值,正确的手术处理原则及娴熟的显微外科手术技巧可提高本病的疗效,术前早期给予制酸剂、术后早期置胃管、气管切开对及时发现和治疗并发症具有重要意义。     

Sequence analysis and bioinformatics analysis of chromosome 17q25 in familial moyamoya disease

Objects The pathogenesis of moyamoya disease is still unknown. The present study aimed to find out the responsible genes that are located in the 17q25 locus.Methods Considering the function, we selected nine genes as candidates from a total of 65 genes identified in the 9-cM region of D17S785–D17S836 in chromosome 17q25, and performed sequence analysis on the DNA samples obtained from a pedigree of familial moyamoya disease, which showed a complete linkage to the region by a haplotype analysis. Also, we attempted to identify candidate genes that have not been known but might be functionally relevant to the disease among a total of 2,100 expressed sequence tag (EST) sequences using bioinformatics techniques.Results and conclusion The sequence analysis could detect no mutation in the nine genes. Nor could we identify a novel candidate gene by the EST analysis. Further studies using alternative approaches are warranted to clarify the pathogenesis of moyamoya disease.     

Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma

Cell-cell and cell-matrix interactions are essential for many basic functions, including differentiation and development. In pathological conditions such as inflammation and tumorigenesis adhesive events also play a major role. Cellular adhesion is mediated by specific molecules expressed by both normal and neoplastic tissues. Capillary hemangioblastoma is a tumor of controversial origin, characterized by two major components, vacuolated stromal cells and a capillary network. In order to shed light on the differentiation of the stromal cells and the interactions between the two major components of hemangioblastoma we studied the expression of several adhesion molecules by immunocytochemistry. The endothelium-associated adhesion molecules (ICAM-1, ICAM-2, VCAM-1, PECAM-1 and ELAM-1) were expressed by endothelial cells within the tumors, but not by stromal cells. In contrast, the stromal cells showed strong neuronal cell adhesion molecule (NCAM/CD56) expression, further distinguishing them from endothelial cells. In addition, the stromal cells expressed CD44, which is of interest, as this membrane protein is linked to ezrin, a cytoskeleton-associated protein also expressed by stromal cells. We conclude that the stromal cells and endothelial cells of capillary hemangioblastoma exhibit quite divergent expression patterns of adhesion molecules. The NCAM expression in stromal cells suggests neuroectodermal or mesenchymal differentiation of this tumor. In addition, the NCAM expression could contribute to the sometimes problematic differential diagnosis between capillary hemangioblastoma and metastatic renal cell carcinoma of the central nervous system. Received: 17 December 1995 / Revised, accepted: 13 May 1996     

Mesial temporal lobe epilepsy: clinical and neuropathologic findings of familial and sporadic forms

Purpose: To evaluate the clinical and hippocampal histological features of patients with mesial temporal lobe epilepsy (MTLE) in both familial (FMTLE) and sporadic (SMTLE) forms.
Methods: Patients with FMTLE (n = 20) and SMTLE (n = 39) who underwent surgical treatment for refractory seizures were studied at the University of São Paulo School of Medicine at Ribeirão Preto. FMTLE was defined when at least two individuals in a family had clinical diagnosis of MTLE. Hippocampi from all patients were processed for Nissl/HE and Timm's stainings. Both groups were compared for clinical variables, hippocampal cell densities, and intensity of supragranular mossy fiber staining.
Results: There were no significant differences between FMTLE and SMTLE groups in the following: age at the surgery, age of first usual epileptic seizure, history of initial precipitating injury (IPI), age of IPI, latent period, ictal and interictal video-EEG patterns, presence of hippocampal atrophy and signal changes at MRI, and postoperative outcome. In addition, no differences were found in cell densities in hippocampal cornu ammonis subfields (CA1, CA2, CA3, CA4), fascia dentata, polymorphic region, subiculum, prosubiculum, and presubiculum. However, patients with SMTLE had greater intensity of mossy fiber Timm's staining in the fascia dentata-inner molecular layer (p< 0.05).
Discussion: Patients with intractable FMTLE present a clinical profile and most histological findings comparable to patients with SMTLE. Interestingly, mossy fiber sprouting was less pronounced in patients with FMTLE, suggesting that, when compared to SMTLE, patients with FMTLE respond differently to plastic changes plausibly induced by cell loss, neuronal deafferentation, or epileptic seizures.