Introduction
Background
Grouped as a hereditary phakomatosis, von Hippel-Lindau syndrome (VHL) is an autosomal dominant, inherited, neurocutaneous dysplasia complex with an 80-100% penetrance and variable delayed expressivity. Sex distributions are equal, and 20% of cases are familial.
VHL is characterized by a predisposition to bilateral and multicentric retinal angiomas, central nervous system (CNS) hemangioblastomas; renal cell carcinomas; pheochromocytoma s; islet cell tumors of the pancreas; endolymphatic sac tumors; and renal, pancreatic, and epididymal cysts. CNS hemangioblastoma (Lindau tumor) is the most commonly recognized manifestation of VHL and occurs in 40% of patients.1
Symptoms often begin in the second to third decades of life. Patients may present with ocular signs and/or symptoms due to retinal hemorrhage, retinal detachment, glaucoma, or uveitis. Funduscopic examination may reveal tortuous aneurysms of the retinal vessels, exudates on the fundus, and subretinal yellowish spots. Patients may present with neurologic symptoms such as headaches, ataxia, and blindness. The exact neurologic deficit depends on the site of the primary lesion.
Pathophysiology
VHL has an autosomal dominant transmission with variable penetrance and delayed expression. It has been reported in identical twins. The gene has been located on chromosome bands 3p25-26, and flanking markers have been identified. As many as 20% of cases can be familial. DNA polymorphism analysis is useful in distinguishing gene carriers from healthy siblings.2,3,4,5
Germ-line mutations of the VHL gene in humans cause a hereditary cancer syndrome characterized by the development of retinal and CNS hemangioblastomas.2,3 Other tumors associated with VHL are renal cell carcinoma and pheochromocytoma. Precancerous renal lesions have been described as a part of VHL in which the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type renal cell carcinoma is well documented. In the genesis of papillary renal cell carcinoma, an adenoma-carcinoma sequence is also recognized.6
Pheochromocytomas associated with VHL and multiple endocrine neoplasia type 2 (MEN 2) display distinct biochemical and clinical phenotypes.7 These distinct changes are related to underlying differences in the expression of tyrosine hydroxylase, rate-limiting enzymes in catecholamine synthesis, and phenylethanolamine N- methyltransferase, the enzyme that converts norepinephrine to epinephrine.8
Compared with other patients, those with MEN 2 with adrenal pheochromocytoma are more symptomatic; they have higher incidence of paroxysmal hypertension; and they have higher plasma concentrations of metanephrine. Paradoxically, they also have lower total plasma concentrations of catecholamine than do patients with VHL. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis underlie the different clinical presentations of pheochromocytoma in patients with MEN 2 and VHL.
Criteria for the diagnosis of VHL include the following: (1) more than 1 hemangioblastoma in the CNS, (2) 1 CNS hemangioblastoma and visceral manifestations of VHL, or (3) 1 manifestation and a known family history of VHL.
Systemic manifestations of VHL are as follows:
- Retina - Hemangioblastoma and retinal angiomatosis (45%), multiple in 66% and bilateral in 50%9
- Central nervous system - Hemangioblastoma, cerebellum (65%), cerebrum, medulla oblongata (20%), spinal cord (15%), multiple hemangioblastoma (10-15%), syringomyelia, meningioma, arteriovenous malformation of the cervical cord and posterior fossa epidermoid, and miliary spinal hemangioblastomas
- Labyrinth - Endolymphatic sac neoplasm (7%)1,10,11
- Lung - Cyst
- Heart - Rhabdomyoma
- Kidney - Hemangioblastoma, renal cell adenoma, renal cell carcinoma (20-45%), multicentric 87%, bilateral 10-75%, renal hemangioma, cortical renal cyst (75%), and renal cell carcinoma (may arise from cyst wall)12
- Bladder - Hemangioblastoma
- Epididymis/testis - Cysts of the epididymis, clear cell papillary cystadenoma of the epididymis, hypernephroid tumor of the epididymis, and testicular germ cell tumor
- Broad ligament - Papillary cystadenoma
- Adrenal gland - Pheochromocytoma cyst (10-17%, bilateral in 40%)
- Pancreas - Hemangioblastoma, cysts (30% of patients; 72% incidence in autopsy series), cystadenoma, islet cell adenoma, and islet cell carcinoma. Pancreatic lesions, including cysts, islet cell tumors, and microcystic cystic adenomas, may be the only abdominal manifestations of VHL and may precede other manifestations by several years5,13,14
- Liver - Cyst, adenoma, angioma, and carcinoid of the common bile duct
- Spleen - Angioma and cyst
- Skin - Nevus and café au lait spot
- Bone - Cyst and hemangioma
- Miscellaneous - Omental and mesenteric cysts and paraganglioma
Frequency
United States
VHL occurs with an approximate frequency of 1 case per 36,000 live births.4
Mortality/Morbidity
- Blindness and permanent brain damage were once the eventual outcome in patients with VHL. Surgical outcomes for patients with CNS hemangioblastomas are favorable. However, the treatment of hemangioblastomas associated with VHL is more difficult and is a prolonged endeavor for patients.
- The most common causes of morbidity and mortality are associated with frequent tumor recurrence and frequent surgical intervention. Renal cell carcinoma is the cause of death in 30-50% of patients.
- In patients with VHL, neurologic screening enables the identification of lesions before patients become symptomatic. Because patients with VHL are at risk of developing new lesions, they require lifelong follow-up care.
Sex
The male-to-female ratio is 1:1.
Age
Patients with VHL most commonly present in the second to third decades of life.
Presentation
Symptoms caused by VHL depend on the organ involved. Patients with involvement of the CNS at presentation are usually aged 25-35 years. Again, depending on the site of CNS involvement, patients may present with a variety of symptoms.
Cerebellar symptoms include dysdiadochokinesia, dysmetria, and a positive Romberg sign. Signs of increased intracranial pressure due to tumor mass effect may be evident. Spinal cord symptoms are uncommon and may include proprioception and sensory loss. Ocular symptoms may dominate, ranging from retinal hemorrhage, retinal detachment, glaucoma, or uveitis to decreasing visual acuity. Neoplasms of the endolymphatic sac may cause sensorineural hearing loss. Polycythemia may develop as a consequence of renal hemangioblastoma or a renal cell carcinoma, whereas hypertension may be the presenting feature of a renal tumor or a neuroblastoma.15,16
Islet cell tumors of the pancreas may cause gastrointestinal tract or metabolic upset, depending on the type of islet cell tumor. Pancreatic cysts and islet cell tumors may be the only manifestations of VHL, and these may precede any other manifestation of the disease by several years. Rarely, pancreatic masses may cause bile duct obstruction.
The Cambridge protocol was devised by Maher et al for screening patients with VHL disease or at-risk relatives. The protocol is as follows17 :
- Affected asymptomatic patient
- Annual physical examination and urine test
- Annual direct and indirect ophthalmoscopy
- Annual fluorescein angiography or angiography
- Annual renal ultrasonographic examination
- MRI or CT scan of the brain every 3 years to age 50 years then every 5 years thereafter
- Abdominal CT scanning every 3 years (more often if multiple renal cysts are present)
- Annual 24-hour urine collection for vanillylmandelic acid (VMA) levels
- At-risk relatives - The same protocol is followed as for asymptomatic patients, apart from age limits, which are as follows:
- Annual direct and indirect ophthalmoscopy from age 5 years
- Annual fluorescein angiography or angiography from age 10 years until age 60 years
- MRI or CT scanning of the brain every 3 years from ages 15-40 years, then every 5 years until age 60 years
- Abdominal CT scanning every 3 years from ages 20-65 years
Preferred Examination
Tumors at various sites are demonstrable by using different imaging modalities, including ultrasonography, CT, MRI, radionuclide studies, and angiography. The preferred examination depends on the site or organ involved. CT and MRI best depict intracranial lesions, but MRI is more appropriate for examining spinal lesions. Although retinal tumors are visualized best on sonograms, the kidneys and pancreas can be imaged by using MRI sonograms and/or CT scans.15,18
When asymptomatic patients and at-risk relatives are screened, noninvasive techniques should be emphasized. Preferably, those not involving ionizing radiation, such as ultrasonography and MRI, should be used.
Limitations of Techniques
The limitation of various techniques depends on the size of the tumor and on problems with atypia. CT is an excellent modality for detecting tumors anywhere in the body, but it has the disadvantage of ionizing radiation, which may become problematic in screening asymptomatic patients and at-risk relatives.
Differential Diagnoses
| Arachnoid Cyst | Hemangioblastoma, Spine |
| Astrocytoma, Brain | Meningioma, Brain |
| Brain, Colloid Cyst | Multiple arteriovenous malformations in vascular
neurocutaneous syndromes |
| Craniopharyngioma | Pancreas, Islet Cell Tumors |
| Disseminated hemangioblastomas without Von
Hippel Lindau | Renal Cell Carcinoma |
| Epidermoid, Brain | Vascular metastasis |
| Hemangioblastoma, Brain |
Other Problems to Be Considered
Angioreticuloma (spinal hemangioblastoma)
Endolymphatic sac tumor
Pilocytic astrocytoma
Cystic meningioma
Ganglion cell tumors
Craniopharyngioma
Nonneoplastic cysts, such as arachnoid, colloid, dermoid, and epidermoid cystsRenal lesions Renal adenoma
Renal cell carcinoma
Renal cystsPancreatic lesions Pancreatic islet cell tumors
Multiple endocrine neoplasia type 2Adrenal gland lesions Other adrenal massesDifferential diagnosis of retinal angiomatosis VHL Eales disease
Coats disease
Leber disease
Capillary angiectasis
More on Von Hippel-Lindau Syndrome |
 Overview: Von Hippel-Lindau Syndrome |
| Imaging: Von Hippel-Lindau Syndrome |
| Follow-up: Von Hippel-Lindau Syndrome |
| Multimedia: Von Hippel-Lindau Syndrome |
| References |
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References
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Further Reading
Keywords
angiomatosis retinae, cerebelloretinal angiomatosis, hemangioblastomatosis cerebelloretinae, Hippel's syndrome, Hippel-Czermak syndrome, Lindau-von Hippel syndrome, retinocerebellar angiomatosis, inherited neurocutaneous dysplasia complex, angioreticuloma, spinal hemangioblastoma, endolymphatic sac tumor, cerebellopontine angle ceruminoma, external choroid plexus, extradural choroid plexus papilloma, Lindau tumor
