无血管瘤的vonHippel—Lindau病二例报告并文献复习

Diagnosis and treatment of von Hippel-Lindau disease without angioma： two cases reports and literature review

目的探讨无血管瘤的yonHippel—Lindau（VHL）病的基因诊断及治疗方法。方法回顾性分析2例VHL病患者的临床资料并复习文献。2009年9月收治1例VHL患者（例1），男，30岁。实验室检查24h尿香草扁桃酸：166．27μmol／24h。MRI检查示右肾上腺占位，考虑为嗜铬细胞瘤；右肾多发小囊肿；双侧附睾多发结节；胰腺多发囊肿。经充分术前准备后，全麻下行右侧肾上腺肿瘤切除术，术中发现右肾多发肿物，术中冷冻病理检查诊断为右肾透明细胞癌，遂行根治性右肾切除术。术后病理诊断为右肾上腺嗜铬细胞瘤；右肾透明细胞癌。术后给予干扰素及白细胞介素-2治疗。因双侧附睾结节行双侧附睾结节切除术，术后病理诊断为附睾乳头状囊腺瘤。结合临床诊断为Ⅱ型VHL病。对患者有血缘关系的家庭成员进行临床检查，发现其弟（例2）为双肾多发肿瘤、双肾囊肿、胰腺多发囊肿，因其右肾肿瘤为多发且较大，行根治性右肾切除术；左肾肿瘤较小，未手术治疗。术后病理诊断为透明细胞癌。予干扰素及白细胞介素-2治疗。因例1为Ⅱ型VHL病，故例2诊断为Ⅱ型VHL病。抽取2例患者及例1患者儿子的外周血，提取基因组DNA对3个外显子翻译区及剪接区扩增，扩增产物经纯化后直接测序。将所得突变类型与人类基因突变数据库比较。结果2例患者视网膜及中枢神经系统均无血管瘤，但均有多发性肾囊肿、肾肿瘤、胰腺多发性囊肿、双侧睾丸多发囊实性病变。3例基因测序均见VHL基因第452位核苷酸发生G—T突变，导致第78位编码氨基酸由天冬氨酸转变为丝氨酸，家系的基因突变位点均位于第1外显子，且均为点突变。结论无血管瘤的VHL病可通过基因突变检测明确诊断；因为病变常为双侧性，治疗上在应尽量保留肾脏，对不具备保肾条件的患者可行根治性治疗。

Objective To study the genetic diagnosis and treatment of von Hippel-Lindau disease without angioma. Methods We retrospectively analyzed clinical data of two cases with VHL and review the related literature. On September 2009, we treated one 30 years old male patient with VHL. Laboratory tests showed that the 24h urine VMA was 166. 27 μmol/24h. MRI examinations showed a right adrenal mass, which was considered as pheochromocytoma; multiple small cysts kidney; bilateral epididymal multiple nodules; multiple pancreatic cysts. After careful preoperative preparation, the patient underwent right adrenal tumor resection under general anesthesia. During surgery, multiple kidney tumors were noticed, which the freezing pathological diagnosis was clear cell carcinoma. Then, the right radical nephrectomy was performed. The final pathological diagnosis was right adrenal pheochromocytoma and right renal cell carcinoma. Interferon and interleukin-2 therapy were given to the patient after surgery. The patient underwent bilateral epididymal nodule resection, which the pathological diagnosis was papillary cystadenoma. According to those results, a type Ⅱ VHL disease was considered. The patients＇ family members were further reviewed and accepted the related clinical examinations. We found that his brother had multiple renal tumors and cysts, multiple pancreatic cysts. Because his brother suffered from type Ⅱ VHL disease, the second patient was diagnosed Ⅱ type VHL disease, as well. Since the patient＇s right kidney tumors were multiple and larger than the left one, he received radical right nephroectomy. Due to the small size of left renal tumor, no additional surgery was further performed. The tumor was diagnosed clear cell carcinoma after surgery. We treated him with interferon and interleukin-2. To move forward a single step, we extracted peripheral blood from two cases and son of one case. We extracted genome DNA,using the meliorated method to amplify three exons located in the translating and splicing region, sequence directly them after purifying and compare with the human mutation database. Results There are no angioma tendency in the retina and central nervous system of the two patients who have polycystic kidney disease, kidney cancer, the pancreas multiple cysts and bilateral testicular multiple cystic lesions. In the gene sequencing of three patients, the 452th nucleotide guanine of the VHL gene was substituted by thymine, resulting in the 78th encode ASP substituted by Ser. The genetic mutations sites in the dendrogram locate in the exon 1 which are all point mutations. Conclusions The character of the sporadic example without angioma correspond with VHL. We can make a explicit diagnosis by genetic mutations examination. In the treatment, it should be adopted by the radical excision on the base of protecting the kidney.