Von Hippel-Lindau (VHL) disease is a rare genetic disorder predisposing to a variety of malignant and benign neoplasms.
Renal cysts and RCC
Endolymphatic sac tumors (ELST)
Genetic identification of VHL mutation
Selected hospitals carry out genetic testing for deletions or alterations in the VHL tumor suppressor gene. Gene identification is more beneficial to people who have a family history of VHL disease. Sporadic cases can be tested yet receive false negative results due to assortment of defective and normal genes.
Complete blood count
HIF proteins are the main regulator of erythropoietin (EPO) synthesis. Therefore, VHL disease will allow accumulation of HIF and excessive EPO. Polycythemia may present as the earliest sign of VHL disease in the absence of VHL disease-related tumors .
Early screening procedures
Early screening protocol must be done for people diagnosed or at risk for VHL disease. Relatives are encouraged to participate since there is a 50% probability of inheriting the disease.
Early detection of retinal angiomas will prevent onset of complications such as visual loss.
Annual ophthalmologic examinations with direct and indirect ophthalmoscopy starting in infancy or early childhood should be done. Fluoroscein angiography is an option for children 5 years and older.
Though they are slow-growing tumors, removal of CNS hemangioblastomas yield excellent results if there is only one lesion present. An early detection will help improve surgical success.
MRI scans of the head and spine should be done every 1-3 years once VHL disease patients or candidates reach adolescence.
Renal cysts have a high potential to develop into malignant tumors.
Renal surveillance annually starting at 16 years of age help detect tumors before they produce symptoms.
Abdominal computed tomography (CT) scan possesses the highest sensitivity for detecting the presence of renal cysts . Clinicians still prefer ultrasound or MRI though to avoid a cumulative exposure to radiation. Abdominal ultrasound or MRI also helps detect the presence of pancreatic tumors.
High risk individuals for VHL disease should begin early screening at the age of 8 years old.
Blood pressure monitoring and the measurement of catcheloamine urinary metabolites such as vanillylmandelic acid (VMA) are part of screening procedures.
Plasma catecholamine level measurement is the most sensitive for pheochromocytoma in VHL disease  even in the absence of hypertensive episodes.
Screening includes the use of auditory questionnaire and audiogram. MRI will follow if both tests are positive.
The consensus management of small renal tumors is to preserve renal function by a nephron-sparing approach. Asymptomatic small tumors are under annual watchful observation and do not require intervention  until they reach a size of 3 mm in diameter. A partial nephrectomy or conservative radiofrequency ablation is then performed . In cases approached with partial nephrectomy, smaller lesions are also removed to retard the need for another operation.
Majority of retinal angiomas can be treated with laser photocoagulation or cryotherapy.
Damage to the optic nerve may ensue with optic disc angioma treatment. Therefore, they are usually placed under watchful observation unless there is progression  .
Endoscopic adrenalectomy can be done for the management of pheochromocytoma . ACTH test must be done to detect mineralo- and glucocorticosteroid adequacy .
Though the presentation of VHL disease varies, the cause of all subtypes is frequently an autosomal dominant mutation in the VHL gene. The VHL gene is a tumor suppressor gene that inactivates hypoxia-inducible factor (HIF) protein. HIF plays a role in rapid cellular proliferation of blood vessels and cystic formation in the event of hypoxia or unsuppressed activity. VHL keeps HIF from building-up by rapidly degrading the protein in conditions of adequate oxygenation.
The autosomal dominant mutation imparts one defective allele of the VHL gene. According to Alfred Knudson’s two-hit hypothesis, another mutation will cause a biallelic inactivation of the VHL tumor suppressor gene. This causes HIF build-up and subsequent growth of tumors and cysts.
One-fifth  of cases are sporadic in origin. There is no family history of VHL disease to raise a clinical index of suspicion.
The proposed explanation for sporadic development of VHL disease is the two-hit hypothesis as well. Two different incidences of mutation, caused by variable factors (e.g. aging, unhealthy lifestyle), is necessary to trigger the inactivation of the VHL gene compared to a familial type’s one mutation.
The non-familial occurrence of the disease paved the way for the experts to establish the newer VHL disease standard diagnostic criteria.
The VHL diagnostic criteria:
With family history of VHL disease
Examples of VHL disease-related tumor are:
No family history of VHL disease
The male-to-female ratio of VHL disease case is 1:1.
The chance of seeing a VHL disease is 1 in every 36,000 persons  .
The mutation of the VHL tumor suppressor gene is responsible for causing   :
The diagnosis of VHL is earlier in familial than sporadic types.
20% of VHL disease patients constitute the sporadic type .
The VHL protein is an integral part of the VBC-CUL2 complex, a regulatory protein complex. The VBC-CUL2 complex includes VHL, Elongin B and C, Cullin 2, and Rbx1. Elongin B functions as a stabilizing link between VHL and Elongin C. Elongin C in turn bridges the union of VHL-Elongin B and CUL2/Rbx1. The congregation of the proteins produces a powerful regulatory complex whose main role is degradation of target proteins. One of the main targets is the alpha subunits of Hypoxia-Inducible Factor (HIF) proteins 1 and 2. The HIF proteins are involved in multiple cellular processes such as angiogenesis and erythropoiesis and release of vascular endothelial growth factor (VEGF) and glucose tansporter-1 (GLUT-1) proliferation, apoptosis and metabolism  in the event of hypoxia. In addition, HIF-2 appears to play a role in directly promoting VHL gene mutation  . In conditions where oxygen supply is adequate for normal function, the VHL complex rapidly renders the HIF inactive by protein degradation. This function of the VHL gives its classification as a tumor suppressor gene.
VHL disease sets in when the VHL protein undergoes mutation; thus, it becomes inactive. The HIF proteins become free to proliferate even under normal oxygenation. HIF promotes inappropriate cellular growth that leads to hemangioblastoma of the cerebellum, brain stem or spinal cord, angioma of the retina, and cystic formation in the kidney, pancreas, epididymis, ear,broad ligament, and other organs. The aforementioned body parts are sites of predilection since VHL is strongly expressed in these areas during the first 4-10th weeks age of gestation (AOG) .
There is no clear cut method of prevention for acquiring VHL disease.
Von-Hippel Lindau (VHL) disease is a rare cluster of tumors including but not limited to CNS hemangioblastomas, retinal angiomas, pheochromocytoma, and cysts in the kindneys, pancreas, ears, and epididymis. The renal cysts are of high malignancy potential and may progress to renal cell carcinoma (RCC) clear cell type. The presence of tumors varies from person to person which prompted experts to make a subtype classification for VHL disease.
The 4 different subtypes of VHL disease are:
Type 1 VHL disease
Type 2A VHL disease
Type 2B VHL disease
Type 2C VHL disease
Von Hippel Lindau (VHL) disease is commonly an inherited disorder presenting with a cluster of tumors all over the body. It can occur in a person with no line of VHL disease in 20% of cases. It stems from a mutation in the VHL gene that causes development of tumors of the blood vessels in the brain, spinal cord and eye. Cancer of the ear, pancreas and kidneys also occur.
The symptoms felt are dependent on the location of tumors. Most tumors start out small and grow slowly. Therefore, they do not cause symptoms until they grow larger to compress involved structures.
Gene detection can now be done in specialized centers for VHL disease. It is highly recommended for children and adults who have relatives diagnosed with VHL disease.
Yearly screening must be done for VHL disease candidates to detect the onset of early tumors. This includes the following:
Early detection of the presence of VHL disease-related tumors is the key to management and increase in life expectancy of diagnosed patients. The annual screening protocol has increased the life expectancy of VHL disease patients by 17 years.
Surgical removal is warranted only when the tumors are large enough to cause symptoms. Kidney cysts are monitored carefully because they have the highest potential to develop into malignancy.