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.

Germline mutation and clinical prognostic analysis of VHL gene in familial central nervous system hemangioblastoma

Objective To discuss the clinical features, pedigree performance and VHL gene mutations detection of central nervous system hemangioblastoma in ban familial. Methods The clinical data of 15 patients with hemangioblastoma （HB） （from 9 families） proved by operation and pathology were analyzed retrospectively. We evaluated the clinical characteristics of these Chinese families with multiple members suffering from VHL disease. 12 VHL patients and 15 healthy kin（from 7 families） sign the informed consent and blood samples were obtained to perform comparative analysis of the VHL gene sequence. Direct sequencing and real-time quantitative PCR with SYBR Green chemistry was carried out. Results These 15 patient present with 34 tumor （ 10 patient had multiple lesions）. Total 22 HBs were removed by operations. Four kinds of intragenie germline mutations were found in four stemmas. Partial VHL gene deletions in exon 1 were found in two of the seven families. 3 clinically asymptomatic mutation carriers were also identified. After following up,we found 2 recurrent cases and 3 new lesions belong to frameshift and splice mutation families. Through reoperation and the gamma knife on brainstem HB, treatment effect is good. Conclusions VHL related HB relapse easily, and newborn HB appear constantly. Combined application of gene sequencing and real-time quantitative PCR can improve the detection rate of VHL gene mutation. C, ene mutation analysis is helpful to diagnose asymptomatic VHL gene mutation carriers,Gene mutation of classification will be helpful to judge the prognosis of patients.