Von Hipple-Lindau Syndrome
Von Hippel-Lindau (VHL) is a syndrome which was first recognized by Eugen von Hippel who described cases of ocular angiomas in 1904 and Arvid Lindau who described cases of cerebellar angiomas in 1927. It is an autosomal dominant syndrome that is associated with several tumors including retinal, cerebellum, and spinal hemangioblastomas as well as tumors or cysts in the viscera. Von Hippel named these retinal hemangioblastomas as "angiomatosis retina". Lindau was credited with making the association between retinal hemangioblastomas and cerebellar hemangioblastomas.[5] Hypernephroma, renal cell carcinoma, benign cysts of the kidney, pancreas, and epididymis all represent extra CNS manifestations of this condition. The von Hippel-Lindau syndrome arises from germ line mutation to a tumor suppressor gene protein located on chromosome 3p.[1] Under normal condition, the gene produces two proteins which go back and forth between the cytoplasm and the nucleus. Some of the functions of the protein includes: Polyubiquitination which mark substrates for degradation, regulation of hypoxia-inducible factors which are degraded by the protein in the presence of oxygen, interaction with the extracellular matrix, and involvement with cell cycle control. Genetic testing is about 80% sensitive. Prevalence of the disease is around 1 in 40,000 to 100,000 individuals.[2] The diagnosis is often missed because the lesions, other than cerebellar hemangioblasomas, are often asymptomatic and that this disease is often not considered in patient found to have hemangioblastomas.
Patients may present with a variety of different clinical manifestations. As in our patient's case, her first symptoms were a result of her renal cell carcinoma, which was discovered first. Later, the patient became symptomatic from cerebellar involvement of her disease. This patient did not display the most common initial pattern of presentation which includes retinal along with CNS hemangioblastomas, and pancreatic cyst. She did, however, present early on in her disease with pontine hemangioblastoma which usually presents in the second decade of life.[2] Hemangioblastomas are slow growing and are either discovered incidentally or as a result of mass effect. These tumors are highly vascular and can occasionally bleed causing cerebellar hemorrhage. In this case, most of her symptoms were initially attributed to her alcohol consumption which confounded the actual pathology of a slow growing hemangioblastoma near her cerebellum. After treatment, she developed significant edema in the area of her hemangioblastoma which exacerbated her symptoms. Cerebellar hemangioblastomas are more frequent than cerebral hemangioblastomas, and most of the cerebellar hemangioblastomas are found in the hemisphere rather than the vermis.[2] Early symptoms of cerebellar hemangiolastomas include headache, ataxia, nausea/vomiting, and nystagmus in the order of most common presenting symptom. The best imaging technique is brain MRI with contrast for visualization of hemangioblastoma. The incidence of cerebellar hemangioblastoma increases with age among VHL patients. It is estimated that 84% of VHL patients will have a cerebellar hemangioblastoma by age of 60. About 5% of VHL patients will present with cerebral hemangioblastomas as well. Other locations include the brainstem and spinal cord.[2] Spinal cord hemangioblastomas are often associated with a syringomyelic cavity in as many as 80% of these cases.[4]
Cerebellar hemangioblastomas have been histological and radiographically classified into four types. Type 1 is a simple cyst without macroscopic nodule. Type 2 is a cyst with a mural nodule. Type 3 is a solid tumor. Type 4 is solid tumor with small internal cysts. Type 2 tumors make up the majority. Several studies have shown the clinical progression of cerebellar hemangioblastomas. Slater et al. [8] documented that the most common progression occurs from nodular to nodular with an enlarging cyst. Once a hemangioblastoma has progressed to a cystic component, then surgery may be necessary to avoid compressive effects of tumor. The clinician should utilize clinical signs and symptoms to determine when this CNS lesion has reached the point of surgical intervention. In this patient, her original MRI from 2002 showed a small solitary nodule, read as a small vascular malformation. By 2006, a large cyst with a mural nodule had evolved during the interval. The cystic component measured 2.7 cm at its maximum diameter. The was a slight decrease following radiation therapy in 2006, but an MRI in 2007 showed enlargement of the solitary tumor from 1.5 to 1.9 cm and the cystic component from 2.8 to 3.6 cm. There was significant mass effect and compression of the fourth ventricle which ultimately caused worsening of her neurological condition and required a ventriculo-peritoneal shunt for decompression.
Features outside of the CNS are also equally devastating. The most common being renal cell carcinoma which develops in about 70% of patients.[2] This is the leading cause of death in patients with VHL and it is not uncommon to have multiple tumors in the same patient. Other manifestations include pheochromocytoma with its constellation of symptoms including hypertension, stroke, myocardial infarction, headache, and diaphoresis.
Retinal hemangioblastomas are usually one of the early manifestations of this disease. They usually present in childhood but can present much later in life. Retinal disease in patients with VHL can be divided into three stages. The first being a pinkish/red red vascular lesion with visible feeders located in mid-peripheral retina. This lesion can have a variable amount of exudates. The second stage is marked by appearance of a pale grey lesion, which the feeders are visualized by fluorescein angiography. Finally, the third stage demonstrates retinal vascular lesions similar to diabetic micro aneurysms but without retinal vascular connections. These lesions may or may not result in visual impairment.[5]
Treatment for this disease is very limited. Family screening is a very important component of the work-up for patients with VHL. All first degree relatives should be screened for VHL if a proband presents with VHL or pheocromacytoma. Occasionally the cerebellar hemangioblastomas can be surgically resected or treated with radiation therapy as in our case.[4] There is a high incidence of recurrence if these tumors are resected. Retinal lesions are treated with either cryocoagulation or photocoagulation. Renal disease is most appropriately treated with partial or complete nephrectomy and hemodialysis in appropriate patients.[5]
A formal diagnosis of VHL can be made based on clinical presentation alone. Supplementary genetic testing is available for VHL and is done by Southern blots and PCR single-stranded conformation polymorphism (SSCP) analysis. One study found mutations in 8 of 16 patients (50%) with clinically confirmed VHL.[7] Screening was done by PCR of the three VHL genes using SSCP. The study concludes that a positive genetic test result supports an initial VHL impression made on clinical grounds. A negative genetic test result, however, does not preclude the VHL diagnosis. Furthermore, the study advises that genetic counseling of families should be limited to those in which a proband has been established. The test is very costly, and the benefit must be weighed against the financial obligation to the patient.
Unfortunately, our patient continued to decline. Despite numerous attempts with radiation therapy, ventricular-peritoneal shunt placement, and multiple admissions in which she received intravenous methylprednisolone for her hemangioblastoma, the mass effects from her lesion worsened. As a result of diffuse pontine swelling, her ataxia and dysmetria continued to progress to the extent that she could no longer ambulate without assistance. She was admitted to the VA with worsening of mentation, dyspnea, and headache. She was found to have a pontine hemorrhage in the area of her hemangioblastoma. She refused surgical intervention and elected for hospice care. She died a short time after being placed in hospice care.
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