Cerebellar gliomas in children with NF1: pathology and surgery

Cerebellar gliomas associated with NF1 (CGNF1) are rarely reported in the literature, and they are considered to be malignant in a high proportion of cases. In an attempt to improve the definition of this disease and clarify its management, we reviewed our patients with CGNF1 and compared their tumors with sporadic cerebellar gliomas (SGC). We operated on six children with CGNF1, all but one of whom were asymptomatic. They represented one-tenth of all pediatric cerebellar gliomas, and one third of NF1- associated gliomas seen in our institution. CGNF1 appeared at a later age than SCG. They are seated near the roof of the IV ventricle and are not related to white matter hypersignal hamartomas. Most of these tumors showed radiological progression. They were four pilocytic astrocytomas, one ganglioglioma, and one malignant astrocytoma. One patient had tumor recurrence after 8 years, and the others are still disease free. The overall outcome appeared to be better for GCNF1 than for SCG. On account of the regular growth, uncertain pathology, and good surgical outcome, we advocate systematic resection of these tumors. Received: 7 February 2000     

中国人Ⅰ型神经纤维瘤病基因突变分析

目的对中国人Ⅰ型神经纤维瘤病（NF1）基因20、28、29、39号外显子进行基因突变分析及评价聚合酶链反应-单链构象多态／异源双链（PCR-SSCP／HA）技术在NFl基因诊断中的价值。方法应用PCR—SSCP／HA技术，结合DNA测序，筛查56例患者NF1基因20、28、29、39号外显子的突变或多态性。结果在20号外显子发现一个家系父子3人的SSCP／HA出现泳动异常，DNA测序证实为20号外显子上T—G的杂合突变即Leul 141Arg错义突变；发现1例患者28号外显子的SSCP／HA检测有泳动异常，测序证实为28号外显子5’端上游的第28位核苷酸G—T杂合；29、39号外显子未检测到泳动异常的条带。结论联合应用SSCP／HA的方法可提高基因突变检测敏感度及检出率，NF1基因20、28、29、39号外显子不是突变热点或突变率相对较高的区域。     

A novel mutation in NF1 is associated with diverse intra-familial phenotypic variation and astrocytoma in a Chinese family

Neurofibromatosis type 1 (NF1) is a dysregulated neurocutaneous disorder, characterized by neurofibromas and café-au-lait spots. NF1 is caused by mutations in the NF1 gene, encoding neurofibromin. Here, we present a clinical molecular study of a three-generation Chinese family with NF1. The proband was a male patient who showed café-au-lait spots and multiple subcutaneous neurofibromas over the whole body, but his siblings only had regional lesions. The man’s daughter presented with severe headache and vomiting. Neurological examination revealed an intracranial space occupying lesion. Surgery was undertaken and the histopathological examination showed a grade I-II astrocytoma. Next-Generation sequencing (Illumina HiSeq2500 Analyzers; Illumina, San Diego, CA, USA) and Sanger sequencing (ABI PRISM 3730 automated sequencer; Applied Biosystems, Foster City, CA, USA) identified the c.227delA mutation in the NF1 gene in the man. The mutation is co-segregated with the disease phenotypes among the affected members of this family and was absent in 100 healthy controls. This novel mutation results in a frameshift (p.Asn78IlefsX7) as well as truncation of neurofibromin by formation of a premature stop codon. Our results not only extended the mutational and phenotypic spectra of the gene and the disease, but also highlight the importance of the other genetic or environmental factors in the development and severity of the disease.     

Ⅰ型神经纤维瘤病基因28及31号外显子突变的检测

目的　探讨国人Ⅰ型神经纤维瘤病 (NF1)基因突变的热点。方法　用PCR SSCP方法检查NF1基因 2 8和 3 1号外显子共约 10 60bp ,约占NF1基因全部编码区的 6 95 %。结果　在 2 7个家系中 ,发现 4个家系 (14 82 % )、13例病人(2 3 64 % )存在NF1基因突变。结论　提示本组病例 2 8和 3 1号外显子可能为突变热点。对突变性质的定论有赖于DNA序列分析。     

1077例胶质瘤的临床和病理学分析

目的总结胶质瘤发病规律,探索其流行病学特点,以指导临床诊断及手术治疗。方法从性别、年龄、肿瘤发生部位及组织学病理类型等方面,对2002～2008年经手术后病理学证实的1077例胶质瘤患者的临床资料进行回顾性分析。结果胶质瘤的高发年龄为30～49岁,男性略多于女性,肿瘤发生部位以额、颞叶最多见。组织学病理类型依次为星形细胞性肿瘤(81.5%)、胚胎性肿瘤(7.4%)、室管膜肿瘤(5.4%)、少突胶质肿瘤(3.5%)及其它类型胶质瘤,其中星形细胞性肿瘤占81.5%,明显高于国内其他文献资料。结论胶质瘤在发病年龄、性别及组织病理学类型和肿瘤发生部位等方面均具有一定的规律性,掌握其规律,有助于术前诊断及手术治疗。     

NF1患者大脑活动特征的PET-CT研究

目的采用正电子发射断层扫描/X射线计算机断层成像（PET-CT）检测Ⅰ型神经纤维瘤病（NF1）成年患者大脑代谢活动特征变化情况，探讨该疾病稳定状态下的特异脑活动异常情况。 方法利用PET-CT技术，结合脑内葡萄糖代谢特征分析方法，对自2018年1月至7月就诊于首都医科大学附属北京天坛医院神经外科的11例病情稳定的NF1患者（NF1组）和10例健康对照组进行全脑数据分析，运用基于Matlab的SPM软件比较NF1组与健康对照组在全脑水平上大脑各区域活动的变化。 结果NF1组与健康对照组在额叶、颞叶等区域存在不同的代谢特征。全脑分析结果显示NF1在右侧颞上回后部、中央区、额上回、额中回，双侧的颞叶内侧面、顶叶视觉区等脑区出现了与健康对照组不同的脑代谢表现，特别是在双侧丘脑区域出现了显著异常，差异具有统计学意义（P<0.05），主要表现为双侧丘脑区域的葡萄糖摄取减低，提示该区域的脑活动减弱。 结论非中枢系统病变或疾病自身基因突变引起大脑的功能代谢变化，可能为NF1患者的一项重要临床特征，也将为该类疾病以及具有同类型脑部疾病患者的康复及治疗提供前瞻指导。     

Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation

The hallmark of neurofibromatosis type 1 (NF1) are multiple dermal neurofibromas. They show high inter- and intrafamilial variability for which the influence of modifying genes is discussed. NF1 patients presenting microdeletions spanning NF1 and several contiguous genes have an earlier onset and higher number of dermal neurofibromas than classical NF1 patients, pointing to one of the deleted genes as modifier. Expression analysis of 13 genes of the microdeletion region in dermal neurofibromas and other tissues revealed four candidates for the modification of neurofibroma formation: CENTA2, RAB11FIP4, C17orf79, and UTP6.     

Brain gliomas,hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1

PurposeTo evaluate the incidence and clinical importance of brain gliomas – optic pathway gliomas (OPGs) and especially gliomas outside the optic pathway (GOOP) for children with neurofibromatosis type 1 (NF1), additionally, to assess the causes of obstructive hydrocephalus in NF1 children with an emphasis on cases caused by idiopathic aqueduct stenosis.Subjects and methodsWe analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery.ResultsWe have found OPGs in 77/285 (27%) children and GOOPs in 29/285 (10,2%) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30,5%). GOOPs were significantly more often treated than OPGs (p > 0.01). OPGs contain clinically important subgroup of 14/285 (4.9%) spreading to hypothalamus. Spontaneous regression was documented in 4/285 (1.4%) gliomas and the same number of NF1 children died due to gliomas.Obstructive hydrocephalus was found in 22/285 (7.7%) patients and 14/22 cases were due to glioma. Idiopathic aqueduct stenosis caused hydrocephalus in 6/22 cases and was found in 2.1% of NF1 children. Two had other cause.ConclusionsThe total brain glioma number (OPGs and only GOOPs together) better reflected the overall brain tumour risk for NF1 children. However, GOOPs occur less frequently than OPGs, they are more clinically relevant. The obstructive hydrocephalus was severe and featuring frequent complication, especially those with GOOP. Idiopathic aqueduct stenosis shows an unpredictable cause of hydrocephalus in comparison with glioma and is another reason for careful neurologic follow up.     

促肾上腺皮质激素释放因子受体1在人脑胶质瘤中表达及其临床意义

目的探讨促肾上腺皮质激素释放因子受体1(CRFR1)在人脑胶质瘤中表达及其临床意义。方法随机收集35例临床手术切除胶质瘤组织标本及培养人类胶质母细胞瘤株U87,进行CRFR1免疫组化染色,以5例泌乳素垂体腺瘤组织标本作为阳性对照。检测胶质瘤组织中增殖细胞核抗原(PCNA)表达。同时,分析CRFR1表达与临床病理因素之间的相关性。结果 CRFR1着色于肿瘤细胞膜,在不同类型、级别的脑胶质瘤中均有着色,且随肿瘤病理级别增高而表达增高,差异有统计学意义(P<0.05);胶质母细胞瘤中存在U87、CRFR1和PCNA高表达;CRFR1表达与患者KPS评分及PCNA表达有关。结论 CRFR1在胶质瘤细胞发生、增殖及侵袭性生长过程中可能扮演了重要角色,对胶质瘤恶性生物学特性的作用机制需要进一步探讨。     

B细胞易位基因1在脑胶质瘤组织中的表达及意义

目的探讨B细胞易位基因1(BTG1)和人10号染色体磷酸酶张力蛋白样同源物(PTEN)在脑胶质瘤组织中的表达及其与肿瘤分级的关系和意义。方法采用免疫组织化学染色(EnVision法)分别检测80例脑胶质瘤及25例正常脑组织中BTG1和PTEN的表达,并采用Western blot检测随机抽取的4例脑胶质瘤及4例正常脑组织中二者的表达。结果 BTG1在胶质瘤和正常脑组织中的阳性表达率分别为73.8%、96.0%,PTEN在脑胶质瘤的表达率分别为77.5%、100%,差异均具有统计学意义(P0.05);二者的表达与世界卫生组织(WHO)胶质瘤组织学分级呈负相关(P0.05),但与患者性别及肿瘤直径无关(P0.05)。结论 BTG1和PTEN在胶质瘤的发生及发展过程中起重要作用,二者表达检测可为肿瘤的组织学分级提供参考,也提示BTG1和PTEN作为新型抑癌基因可能成为胶质瘤基因治疗的新靶点。     

人脑胶质瘤 IDH1基因突变与临床病理类别的关系

目的探究不同病理类型和级别的胶质瘤患者中异柠檬酸脱氢酶1（IDH1）基因突变情况及其临床意义。 方法选取厦门大学附属第一医院神经外科自2014年1月至2017年9月收治并实施手术的胶质瘤患者76例,通过免疫组化检测并鉴定各病理组织样本中IDH1基因突变情况,分析不同病理类型、不同WHO级别和不同年龄患者IDH1基因突变率。 结果76例胶质瘤标本中,共检出37例IDH1基因突变,总突变率48.68%。各种病理类型突变率由高至低分别为：弥漫性星形细胞瘤（71.43%）、间变型少突星形细胞瘤（71.43%）、少突胶质瘤（66.67%）、少突星形细胞瘤（66.67%）、间变型星形细胞瘤（63.64%）、胶质母细胞瘤（34.62%）。IDH1基因突变型的年龄普遍较野生型更小,其中,弥漫性星形细胞瘤、少突星形细胞瘤、间变型星形细胞瘤、间变型少突星形细胞瘤及胶质母细胞瘤样本中,IDH1基因突变型患者平均年龄均低于野生型患者,差异具有统计学意义（P<0.05）。 结论IDH1基因突变在WHOⅡ、Ⅲ级胶质瘤中的发生率较高,并在胶质瘤的发生、发展过程中起重要作用。     

人脑胶质瘤中CCND1基因的转录与表达

目的检测和分析人脑胶质瘤中CCND1基因的转录与表达,及其对肿瘤发生、发展的生物学意义.方法采用免疫组化、原位杂交法检测52例人脑胶质瘤及8例正常人脑组织中Cyclin D1 mRNA蛋白以及增殖细胞核抗原(PCNA)的表达水平.结果脑胶质瘤中CD1蛋白及mRNA呈过度表达,其标记指数和阳性率随肿瘤的恶性程度增高而增加.两者的标记指数之间、以及与PCNA标记指数之间均为显著正性相关.结论人脑胶质瘤中CCND1过度转录和表达,随胶质瘤临床病理分级增加而增高,同时与肿瘤细胞增殖状态密切相关,提示CCND1基因的异常转录和表达在胶质瘤的发生与发展中起着重要的促进作用.     

Infantile spasms in patients with neurofibromatosis type 1

The authors report two patients with neurofibromatosis type 1 who were affected by infantile spasms. The infantile spasms were severe and unresponsive to anticonvulsant treatment. The authors maintain that infantile spasms may belong to the clinical features of neurofibromatosis type 1.     

Spinal neurofibromatosis in a family with classical neurofibromatosis type 1 and a novel NF1 gene mutation

Familial spinal neurofibromatosis (FSNF) is a rare form of neurofibromatosis type 1 (NF1) characterized by multiple, histologically proven neurofibromas of the spinal roots leaving no intact segments and associated neurofibromas of major peripheral nerves. It is sometimes associated with other NF1 stigmata. Most patients have NF1 gene mutations. We describe a patient who fulfilled the diagnostic criteria for spinal neurofibromatosis and belonged to a family in which other affected members exhibited classical NF1 stigmata. A novel missense (c.7109 T > A; p.Val2370Asp) mutation in exon 39 of the NF1 gene was present in the affected family members. The family displayed extreme phenotypic variability in the spectrum of NF1. To our knowledge, this is the first patient with spinal neurofibromatosis in the context of classical NF1 with an NF1 gene mutation. The term FSNF is inaccurate as this condition simply reflects the typical autosomal dominant pattern of NF1 inheritance with phenotypoc variability and does not encompass patients with sporadic disease or those in the context of a classical NF1 phenotype as reported in the present family. The term could be replaced by “spinal neurofibromatosis”.     

Glioblastoma in adults with neurofibromatosis type I: A report of two cases

Neurofibromatosis type I (NF1) is a familial tumor syndrome with an autosomal‐dominant inheritance. NF1‐associated tumors often include neurofibromas, malignant peripheral nerve sheath tumors and pilocytic astrocytomas of the optic nerve. The presentation of NF1 patients with glioblastoma is a rare occurrence, with only a handful of cases reported in the literature. We report two cases of glioblastomas occurring in adults with NF1 and briefly review the relevant literature.     

MCT1CD147在人胶质瘤中的表达与预后的相关性

目的 探讨MCT1、CD147在人胶质瘤中的表达及其与预后的相关性,分析其作为胶质瘤预后判断指标及药物治疗靶点的可能性.方法 本文采用实时荧光定量PCR和western blotting方法 检测MCT1和CD147在不同级别胶质瘤及正常组织中的表达情况,并利用生存曲线对患者的生存预后进行分析.结果 MCT1和CD47在人胶质瘤患者组织中均高表达,且高级别胶质瘤患者MCT1和CD147表达与低级别胶质瘤患者差异有统计学意义（P〈0.05）,低级别胶质瘤患者MCT1和CD147与正常组织表达差异统计学意义（P〈0.05）.不同级别胶质瘤患者与正常对照组MCT1和CD147表达生存相关曲线差异有统计学意义（P〈0.05）.结论 MCT1和CD47是神经胶质瘤恶性程度的重要标志物,且二者可以作为胶质瘤预后判断的指标参考及药物治疗的靶点.     

Unusual association of neurofibromatosis Type 1 and idiopathic syringomyelia—bulbia—pontia

Since the association of syringomyelia and neurofibromatosis is mostly related to intramedullary tumors, syringomyelia in neurofibromatosis type 1 (NF-1) is much rarer than in neurofibromatosis type 2 (NF-2). In this paper, we present a case of NF-1 associated with an idiopathic syringomyelia extending from conus medullaris to the upper pons and discuss the relationship between neurofibromatosis and syringomyelia.