Caesarean section and phaeochromocytoma resection in a patient with Von Hippel Lindau disease

This report describes the anaesthetic management of a women with a term gestation, Von Hippel Lindau disease (VHLD), and a phaeochromocytoma, scheduled for a combined phaeochromocytoma resection and Caesarean section. Von Hippel Lindau disease is characterized by diffuse haemangioblastomas of the central nervous system (CNS) and viscera. It is also associated with phaeochromocytomas and renal cell carcinomas. Patients frequently have asymptomatic spinal cord and intracranial pathology. The patient and her fetus presented a challenge because of the anaesthetic restrictions imposed by VHLD, and her pregnancy. She was also at risk of developing malignant hypertension from the phaeochromocytoma. The patient was not a candidate for regional anaesthesia because of the possibility of spinal cord haemangioblastomas. She had received adrenergic blockade with phentolamine (total 30 mg a day) and propranolol (total 40 mg a day) since the 27th wk of gestation in order to control hypertension secondary to the phaeochromocytoma. General anaesthesia was administered with aggressive management of hypertension with adrenergic blockers (labetalol 1.0 mg · kg^?1 and esmolol 0.75 mg · kg^?1) and sodium nitroprusside 1.5 μg · kg^?1 (total). Before delivery of the baby, opioids, which could have resulted in a fetus with CNS depression, were avoided. After delivery, opioids (sufentanil 0.4 ng · kg^?1 hr^?1) were used to limit the use of inhalational anaesthesia which may contribute to uterine atony. Postoperative pain was managed with an intravenous narcotic infusion. Both patients had uneventful postoperative courses.     

Elevated ocular levels of vascular endothelial growth factor in patients with von Hippel-Lindau disease

Background: Von Hippel–Lindau disease (VHL) is a rare autosomal dominant inherited disorder characterized by highly vascularized tumors in various organs. The abundant presence of endothelial cells in VHL tumors strongly suggest a role of the VHL tumor suppressor gene in the regulation of angiogenesis. Recently, in vitro studies have shown that the VHL tumor suppressor gene regulates the expression of vascular endothelial growth factor (VEGF). We investigated whether VHL patiens have increased levels of VEGF in their body fluids.Patients and methods: The concentration of VEGF was measured in fluid of the anterior chamber of the eye, serum, urine, and fluid from renal cysts of VHL patients and unaffected individuals by ELISA. In addition, levels of basic fibroblast growth factor (bFGF), interleukin-8 (IL-8) and endothelin-1 (ET-1) were measured in urine and serum of VHL patients and control subjects.Results: In 80% of the VHL patients VEGF was detectable in aqueous fluid of the anterior chamber of their eyes. A strong positive correlation (r = 0.90) was found between the age of VHL patients and ocular VEGF concentrations. At comparable age, VEGF levels in ocular fluid of VHL patients were significantly higher (P < 0.001) than in unaffected subjects. No correlation was found between VEGF concentration and the presence of retinal angiomas. A 10 and 16 fold increase of VEGF concentration was seen in fluid from two independent VHL-related cysts as compared with VEGF serum levels of the same patient. The mean concentration of VEGF in serum of VHL patients (n = 15) (319 ± 84 pg/ml) was higher than in matched controls (238 ± 68 pg/ml; P = NS). The mean concentration of VEGF in urine of VHL patients (128 ± 36 pg/ml) was lower than in matched controls (183 ± 25 pg/ml; P = NS). Concentrations of VEGF did not correlate with the presence of VHL-related tumors. No differences were observed between concentrations of bFGF, IL-8 and ET-1 in serum and urine of VHL patients and matched controls.Conclusions: These findings support a role for the VHL tumor suppressor gene in the in vivo regulation of VEGF.     

Germline mutations in the VHL gene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

Von Hippel–Lindau (VHL) disease is a rare autosomal dominant inherited cancer syndrome that is characterized by hemangioblastomas in the central nervous system and retina, renal cell carcinoma and cysts, pancreatic tumors and cysts, and pheochromocytoma. The underlying gene in this disease is the VHL tumor suppressor gene. We characterized a family with 2 affected siblings. The brother and sister displayed VHL type 2B and type 2A features, respectively. Renal lesions in the brother exhibited 3 different phenotypes, including simple renal cysts, multilocular cystic renal cell carcinoma and clear cell renal cell carcinoma. The phenotypes of the 3 concurrent renal lesions were first reported in this study. Mutation detection of the VHL gene revealed 2 recurrent mutations, namely c.256C>T (p.P86S) and c.340 + 5G > C. The former was predicted to be deleterious and to destabilize the hydrophobic core and lead to VHL dysfunction; however, the latter was predicted to be a benign variant. Our findings provided new data for the genotype-phenotype of VHL diseases and elucidated the pathogenic mechanism with in silico analysis.     

VHL-deficient vasculogenesis in hemangioblastoma

Hemangioblasts are capable of differentiation into vascular structures and blood. Patients with von Hippel–Lindau (VHL) disease develop hemangioblastomas which are composed of VHL-deficient tumor cells with protracted hemangioblastic differentiation potential. In a subset of these tumors, hemangioblastic differentiation is characterized by different stages of red blood cell formation. It has remained controversial, however, whether VHL-deficient hemangioblastic cells are similarly capable of differentiating into vascular cells and functioning vascular structures in vivo.     

肾癌患者血清VHL和HIF-1α与HIF-2α的表达及其与预后的相关性

【摘要】目的 探讨肾癌患者血清希佩尔 林道基因(VHL)、缺氧诱导因子 1(HIF 1α)和缺氧诱导因子 2(HIF 2α)的表达及与预后的相关性分析。 方法 选取2015年3月~2016年3月我院收治的82例肾癌患者为肾癌组,同时选取51例健康者为对照组。利用酶联免疫吸附法(ELISA)测定两组的VHL、HIF 1α及HIF 2α水平。结果 肾癌组患者VHL水平比对照组明显降低,HIF 1α、HIF 2α水平比对照组明显升高（P＜005）;Ⅰ/Ⅱ、Ⅲ期肾癌患者术后VHL水平均高于术前,且Ⅰ/Ⅱ期高于Ⅲ期（P＜005）;Ⅰ/Ⅱ、Ⅲ期肾癌患者术后HIF 1α、HIF 2α水平均低于术前,且Ⅰ/Ⅱ期低于Ⅲ期（P＜005）;肾癌患者血清VHL、HIF 1α及HIF 2α表达水平与年龄、性别无关(均P＞005),与病灶直径、淋巴结转移、病理分级、TNM分期相关(均P＜005);肾癌患者3年生存率与患者年龄、性别无关(均P＞005),患者VHL高表达的3年生存率明显高于VHL低表达(P＜005),患者HIF 1α、HIF 2α高表达的3年生存率明显低于HIF 1α、HIF 2α低表达(均P＜005);血清VHL低表达、血清HIF 1α、HIF 1α高表达是肾癌患者术后肾衰竭的独立危险因素;患者VHL水平与发生肾癌呈负相关,HIF 1α、HIF 2α水平与发生肾癌呈正相关（P＜005）;血清VHL、HIF 1α、HIF 2α预测肾癌患者的最佳截值分别为37978、771、095,三者联合预测的AUC大于VHL（Z=8268,P＜005）,HIF 1α（Z=8268,P＜005）,HIF 2α（Z=8268,P＜005）。结论 血清VHL、HIF 1α和HIF 2α对肾癌患者具有较好的预后预测价值,可作为肾癌患者发生、发展的重要指标及预后预测的分子标志物,三者联合应用能提高其预后预测能力。     

Ophthalmological manifestations in VHL and NF 1: pathological and diagnostic implications

Von Hippel–Lindau disease (VHL) and neurofibromatosis type 1 (NF 1) are hereditary multitumor syndromes that show associated ocular manifestations. Capillary retinal angioma, a benign vascular tumor, is the classical ocular lesion in VHL. It often appears as the first manifestation of the disease and may thus lead to the diagnosis of VHL. Since small angiomas can be treated easily by laser photocoagulation, a regular ocular screening of VHL patients is recommended. Ocular manifestations of NF 1 are more diverse as compared to VHL. Lisch nodules of the iris are an important diagnostic criteria of NF 1 since they can be found in almost every affected patient. Optic glioma can occur both intraorbitally and intracranially. The intraorbital form causes progressive protrusion of the globe and eventually blindness. Extension of the tumor beyond the chiasm worsens the prognosis quoad vitam. The hallmark of NF 1, namely cutaneous neurofibroma can cause visual impairment when affecting the skin of the eyelids. The rare intraorbital pexiform neurofibroma is associated with abnormal development of the orbital bones and infantile glaucoma. It may result in orbital mass effects and therefore may need surgical excision.     

Central nervous system manifestations in VHL: genetics,pathology and clinical phenotypic features

This review focuses on CNS hemangioblastomas in von Hippel–Lindau (VHL) disease. The pathogenesis of these lesions remains unclear to date; however, biallelic inactivation of the VHL tumor suppressor gene is thought to be an important step. These benign tumors occur frequently in patients with VHL disease and produce symptoms by mass effect either by the tumor itself or an accompanying cyst or edema. Furthermore, cases of spontaneous hemorrhage have been described. Genetic testing for VHL germline mutations is recommended in all patients with hemangioblastoma and yearly screening, including MRI of the brain and spine, is recommended for all VHL disease patients. Treatment of these tumors is mainly surgical. In general, surgery is indicated in symptomatic hemangioblastomas and eventually also in asymptomatic tumors that exhibit radiographic progression. However, since most VHL disease patients harbor multiple lesions, a careful individual decision must be made in each case. The tumors can usually be completely removed by dissection in the plane between tumor and CNS tissue and coagulating and cutting of the numerous feeding vessels with low power. As long as consequent yearly surveillance is performed and lesions are adequately treated in time, the prognosis of CNS hemangioblastomas in VHL disease is good. Preoperative neurological deficit, however, will not improve after surgery in most patients. Local tumor recurrences are rare.     

Intracranial haemorrhage associated with phaeochromocytoma

INTRODUCTION: Pheochromocytoma is rarely disclosed by intracranial hemorrhage. We report two cases. OBSERVATION: The first 26-year-old patient developed subarachnoid hemorrhage due to a ruptured aneurysm of the middle cerebral artery. The second patient, aged 44 years, had a temporal hematoma. Diagnosis was suggested in both patients by hypertension and elevated urinary catecholamines and confirmed by imaging and MIBG scintigraphy. Adrenal gland tumors, on both glands in the first patient and on the right gland in the second were successfully removed; cranial hypertension totally regressed. Von Hippel Lindau disease was diagnosed by molecular genetics in the first patient. Paroxysmal hypertension could explain the brain hemorrhage in the first patient and may have favored aneurysmal rupture in the second. CONCLUSION: The relationships between pheochromocytoma and cerebral aneurysm are discussed.     

Solid haemangioblastomas of the CNS: a review of 17 consecutive cases

A retrospective study on solid central nervous system haemangioblastomas was performed to characterize clinical features, treatment strategies and outcome in these rare lesions. Between 1993 and 2006 23, solid haemangioblastomas were surgically removed in 17 patients. Eight lesions were located within pons Varolii and medulla oblongata, six within the cerebellar hemispheres and three in the cerebellopontine angle. Three haemangioblastomas were located supratentorially and three within the spinal cord. All patients except two underwent pre-operative magnetic resonance imaging (MRI). Post-operative digital subtraction angiography and/or MRI was performed in all surviving patients. Except for spinal cord lesions, rather unsystematic clinical symptoms were observed. Twenty-two tumours could be resected completely. Two patients with brainstem lesions died within 10 weeks after surgery from infectious complications. Persistent new neurological deficits occurred in two patients. Three patients underwent radiosurgery prior to or following the surgical procedure. Solid haemangioblastomas represent a surgical challenge due to their arteriovenous malformation-like vascularisation and their frequent location in eloquent areas. Surgery is the therapy of choice. Circumferential dissection with devascularization and en bloc removal yields good functional results. A location within the brainstem carries the most unfavourable prognosis.