Von Hippel Lindau Syndrome

This syndrome is characterized by multiple clear cell neoplasms in various organs including the retina, central nervous system (CNS) hemangioblastomas (most frequently cerebellar and spinal), renal cell carcinomas, pheochromocytomas, pancreatic endocrine tumors, and cysts.

Neumann and Wiesler have classified this entity into two different types based on the presence or absence of a pheochromocytoma. Type I (without pheochromocytoma) and type II (with pheochromocytoma). In 1995, Brauch et al. subdivided type II into IIA (with pheochromocytoma) and type IIB (with pheochromocytoma and renal cell carcinoma). Recently, a type IIC was described when patients affected with von Hippel Lindau had an isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma

The estimated birth incidence in East Anglia, Norfolk, UK, is believed to be 1:36,000 live births and an estimated prevalence of heterozygotes to be 1 in 53,000. Direct and indirect estimates of the mutation rate were 4.4 per million gametes per generation and 2.32 per million gametes per generation, respectively. There are no significant associations between parental age or birth order and new mutations. In the Freiburg district of Germany, the prevalence has been calculated for this disorder to be 1 in 38,951. In the northwest of England, 83 affected persons were reported in 1996 and the calculated prevalence for this disease was estimated (heterozygotes) in the region to be 1 in 85,000 persons, with an estimated birth incidence of 1 in 45,500 live births. The incidence of the most common lesions are as follows: retinal angiomatosis (57%), cerebellar (55%), medullary (6%), and spinal (14%) hemangioblastomas; pheochromocytoma (19%), renal cysts (14%), renal cell carcinoma (24%), epididymal cystadenoma (17%), pancreatic cysts (14%), pancreatic malignancy (4%).

The gene is a putative tumor suppressor gene responsible for von Hippel Lindau, an autosomal dominant multitumor syndrome. It is also implicated in the development of sporadic tumors including clear cell renal carcinoma and CNS hemangioblastoma. The gene has recently been isolated by positional cloning and the cDNA encodes 852 nucleotides in 3 exons. The von Hippel Lindau (VHL) gene seems to be unrelated to any known gene families.

Interfamilial differences in predisposition to pheochromocytoma in VHL reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma.

The presence of visceral cysts of the kidney, pancreas, and epididymis occurs not only as features of VHL but also in the general population; however, the association of those cysts with retinal, CNS hemangioblastoma may represent a more significant association for the disease. The use of markers as presymptomatic diagnosis of VHL in patients with epididymal cysts has been demonstrated to be not suitable as a diagnostic criterion. Similarly, the genetic studies suggested that VHL with or without pheochromocytomas is caused by defects within the same gene may be misleading. Renal cell carcinoma occurs as part of VHL; a second more proximal region of chromosome 3, 3p14.2, is responsible for “pure familial renal cell carcinoma.” It has been suggested that the likelihood of VHL being present in an individual showing a single ocular angioma is conditional upon the age of presentation, results of DNA analysis, family history of VHL, and results of systemic screening. The presence of a positive VHL family history can lead to the diagnosis in a patient with at least 1 typical VHL tumor. Typical VHL tumors are retinal, spinal, and cerebellar hemangioblastoma; renal cell carcinoma; and pheochromocytoma. Endolymphatic sac tumors and multiple pancreatic cysts suggest a positive carriership in the presence of a positive VHL family history because they are uncommon in the general population. In contrast, renal and epididymal cysts occur very frequently in the general population and are, as sole manifestations, not reliable indicators for VHL disease. In patients with a negative family history of VHL-associated tumors, a diagnosis of VHL disease can also be made on the basis of two or more hemangioblastomas or a single hemangioblastoma in association with a visceral manifestation (e.g., pheochromocytoma or renal cell carcinoma). The suspicion for VHL can also be raised in a patient with classic VHL disease (meeting clinical diagnostic criteria) and/or first-degree family members; and/or a person from a family in which a germline VHL gene mutation has been identified (presymptomatic test). Also, a VHL-suspected patient, i.e., one with multicentric tumors in one organ, bilateral tumors, two organ systems affected, or one VHL-associated tumor at a young age (less than 50 years for hemangioblastoma and pheochromocytoma or less than 30 years for renal cell carcinoma); or a patient from a family with hemangioblastoma, renal cell carcinoma, or pheochromocytoma only can also be diagnosed.

The cardinal features of von Hippel Lindau syndrome are angiomata of the retina and hemangioblastoma of the cerebellum and/or spinal cord. Hemangioma of the spinal cord has also been reported. Pheochromocytoma occurs in some patients and will help in the classification. The combination of hypertension with angioma may lead to subarachnoid hemorrhage and the consequences associated with this clinical presentation. Hypernephroma-like renal tumors occur in some patients. Polycythemia may be due to either the hemangioblastoma of the cerebellum or the hypernephroma. Hemangiomas of the adrenals, lungs, and liver, and multiple cysts of the pancreas and kidneys have been observed in some instances.

The possibility of an association with a pheochromocytoma must be eliminated. A complete history providing information about symptomatology with this vascular disease should include: symptoms of dysrhythmia or ventricular dysfunction, sudden and severe headaches, palpitations, night sweating. Catecholamine-induced cardiomyopathy may be present. A complete evaluation of the cardiovascular system must include: ECG, echocardiography, stress test if the patient is old enough. Start alpha blockade. Competitive alpha antagonists (e.g., phentolamine, prazosin) have been used but do not give the same stability as noncompetitive blockade (phenoxybenzamine). Beta blockade may be started after alpha blockade to control dysrhythmias. The minimum duration for alpha blockade is 36 hours, although the optimal period is not defined. End points used for adequate blockade have included a 5% drop in hematocrit or the maximum dose of phenoxybenzamine at which the side effects are tolerated by the individuals. Respiratory assessment: chest radiograph to exclude pulmonary congestion. Renal function: Check renal function, hypertensive nephropathy may be present and nephrectomy is occasionally necessary to achieve tumor excision. Metabolic factors: blood glucose (insulin rarely needed), exclude hypercalcemia. The presence of intracranial hemangiomas must also be evaluated. Raised intracranial pressure must be eliminated. Spinal cord tumors will also require an evaluation, and the use of sensory evoked potential conductivity should be considered prior to anesthesia.

In the presence of a pheochromocytoma, the anesthesia management should include a premedication, unless the level of consciousness and/or intracranial pressure prevents its administration. Invasive monitoring, central venous pressure (CVP), arterial blood pressure (BP) are mandatory. Induction of anesthesia and intubation can be a period of major cardiovascular instability. Prepare a vasodilator such as sodium nitroprusside to control surges in blood pressure during tumor manipulation. According to the local team experience other vasodilators may be used (phentolamine, calcium antagonists such as nicardipine, magnesium sulfate). Esmolol is probably the beta blockade of choice to control dysrhythmias. Hypotension following tumor excision or clamping of its venous drainage should initially be treated with volume loading but a transient infusion of the catecholamine secreted by the removed tumor is sometimes necessary. Patients with intracranial involvement may have raised intracranial pressure and caution should be taken to avoid further increases in pressure. The presence of spinal cord tumor in the cervical region may be of significant consideration during laryngoscopy and tracheal intubation since compression of the neural tissue may be caused by extension or flexion of the neck. Careful attention to patient positioning. Epidural catheter anesthesia can be used but special attention must be provided when advancing the catheter in place. This technique has been used successfully for cesarean section and neurosurgery, contributing to limit the vasodilatory effects of general anesthetics. Supplementation of general anesthesia is reported but is probably only of use for postoperative analgesia, as its intraoperative use may complicate the anesthetic. Postoperatively monitor for hypotension, hypertension, and hypoglycemia in a critical care setting.

The pharmacological implications will be dictated by the presence or absence of a pheochromocytoma. For instance, pharmacological agents favoring release of catecholamines, histamines, and/or vasoactive agents (e.g., serotonin) must be avoided. Desflurane is contraindicated in VHL. Atropine should be used with caution.

Pheochromocytoma: Tumor of chromaffin tissue (neuro-ectodermal origin), most commonly affecting the adrenal medulla (90%) but may occur in any tissue derived embryologically from the neuro-ectoderm, including any sympathetic ganglia, the gastrointestinal tract, bladder, and thorax. Catecholamine-secreting tumor.

Multiple Endocrine Neoplasia (MEN): Familial multiple endocrine tumors in parathyroid, thyroid, pancreas and or surrenals. MEN type II is the most probable because of its association with pheochromocytoma.