CNS hemangioblastomas

• CNS hemangiobalstomas is the second most common presenting feature of VHL disease. It commonly occurs at the cerebellum, brain stem or spinal cord in 60-80% of VHL disease patients [23] [24] [25]. The clinical presentation varies and usually reflects the mass effect of the tumor. For example, hemangioblastomas in the cerebellum present with limb or truncal ataxia. Cyst-containing hemangioblastomas present with symptomats earlier than non-cystic types [25].

Retinal angiomas

• Retinal angiomas are actually hemangioblastomas found in the eye. It is the most common presenting feature of VHL disease. 50% of cases are multiple and bilateral [26].
• Retinal angiomas should be detected as soon as possible to prevent complications such as exudation, retinal traction, or haemorrhage. These complications are associated with late detection of angiomas and can cause visual loss.

Renal cysts and RCC

• Renal cysts commonly occur in VHL disease patients. The cysts rarely disrupt renal function; however, these cysts have very high malignancy potential to progress to clear cell RCC. RCC is usually detected while doing annual renal screening procedure in most patients. Asymptomatic tumors are usually detected at a mean age of 16 years old [27] [28].

Pheochromocytoma

• The risk varies according to the clinical subtype. Type 1 VHL disease does not involve pheochromocytoma. VHL commonly involves adrenal-related pheochromocytoma. An extra-adrenal pheochromocytoma raises the probability of a familial gene mutation isolated from VHL disease [8].

Pancreatic cysts

• Cysts and tumours are relatively common features of VHL disease. Multiple cysts are the most frequent pancreatic manifestation and are present in most elderly patients. Nonetheless, pancreatic cysts rarely impair pancreatic function [29].

Endolymphatic sac tumors (ELST)

• ELSTs are often asymptomatic and bilateral. The most common presentation is hearing loss but tinnitus and vertigo can also be complaints.

Epididymal cystadenomas

• Epididymal cystadenomas are asymptomatic and bilateral [31]. Even though they affect 60% of male cases, this type of cystadenomas does not warrant treatment.

• Swelling

  Swelling of face and conjunctival chemosis on the dependent side of face is not uncommon. The issue of cerebral edema and raised intra-ocular pressure as well as airway edema is less due to lateral position in partial nephrectomy. [apicareonline.com]

  People with this syndrome should watch closely for general signs or symptoms that could signal tumors: Aches, pains, lumps or swelling that cannot be explained Headaches, vomiting, changes in vision or nerve function that do not go away Hearing loss, [stjude.org]

  Brain and Spinal Hemangioblastomas Symptoms related to hemangioblastomas in the brain and spinal cord depend on tumor location, size, and the presence of associated swelling or cysts. Symptomatic lesions grow more rapidly than asymptomatic lesions. [rarediseases.org]

  They can occur anywhere along the brain/spine areas, and swelling or cysts are often associated. The most common locations for CNS hemangioblastomas are in the spinal cord and cerebellum. [encyclopedia.com]

• Collapse

  Once the lesion has been removed, the cyst will collapse. If any portion of the tumor is left in place, the cyst will re-fill. [rarediseases.org]

• Hypertension

  Reminder of important clinical lesson Unsuspected Von Hippel-Lindau syndrome in acute-onset resistant hypertension Gavasker A Sivaskandarajah, http://orcid.org/0000-0002-5793-7713Terra G Arnason Department of Medicine, University of Saskatchewan College [casereports.bmj.com]

  The classic presentation of pheochromocytoma is episodic hypertension, headaches, palpitations, and diaphoresis. In the pediatric population, 40% of pheochromocytomas have a hereditary basis. [ncbi.nlm.nih.gov]

  Screening for phaeochromocytoma is essential in patients undergoing surgery (because of the risk of hypertensive crisis). [patient.info]

  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. [accessanesthesiology.mhmedical.com]

• Palpitations

  The classic presentation of pheochromocytoma is episodic hypertension, headaches, palpitations, and diaphoresis. In the pediatric population, 40% of pheochromocytomas have a hereditary basis. [ncbi.nlm.nih.gov]

  Phaeochromocytomas are usually benign but may cause symptoms such as headaches, palpitations and episodes of shock-like signs. RCC and cysts affect up to 60% of patients and are usually asymptomatic. [news-medical.net]

  Symptoms can include anxiety and panic attacks, extremely high blood pressure, palpitations, headache, and excessive sweating. Kidney cysts: Symptoms can include blood in the urine, tiredness, and low back pain. [verywellhealth.com]

  Pheo surges may be interpreted as panic attacks, palpitations, or in some cases anger or rage. *** Note too that the use of psychotropic drugs or other drugs, including marijuana and cocaine, may cause a false positive. [web.archive.org]

  Symptoms include: High blood pressure Rapid pulse Heart palpitations Headache Nausea Clammy skin Tremor Anxiety Endolymphatic sac tumors: Endolymphatic sac tumors are malignant tumors of the inner ear. [hopkinsmedicine.org]

• Tachycardia

  Pheochromocytomas can cause hypertension, tachycardia, and sweating[5]. Differential diagnosis The differential diagnosis of VHL contains the various VHL-associated tumors seen in isolation[5]. [eyewiki.aao.org]

  Since pheochromocytomas can have low activity, the classical symptoms (such as tachycardia, diaphoresis, postural hypotension, tachypnea, cold and clammy skin, severe headache, angina, palpitations, nausea, vomiting, or epigastric pain) may be missing [hindawi.com]

• Osteoporosis

  Manilay, Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies, Current Osteoporosis Reports, 10.1007/s11914-019-00503-3, (2019). [doi.org]

  Glomerulonephritis Goodpasture’s syndrome Laryngitis Lead poisoning Legionellosis Leishmaniasis Leprosy Leptospirosis Listeriosis Leukemia Lice Loiasis Lung cancer Lupus erythematosus Lyme disease Lymphogranuloma venereum Lympho Obesity Osteoarthritis Osteoporosis [play.google.com]

• Tinnitus

  Panel A shows a contrast-enhanced scan from 2000 with no evidence of an endolymphatic-sac tumor, despite the patient's report of left tinnitus. By 2002, worsening tinnitus, acute hearing loss in the left ear, and vertigo had developed. [nejm.org]

  In 1960, a 24-year-old woman presented with unilateral hearing loss, pulsatile tinnitus and a mass visible on otoscopy. The patient underwent surgical biopsy, which was complicated by haemorrhage, and ultimately resulted in death. [ncbi.nlm.nih.gov]

  Endolymphatic sac tumors are benign by can erode the bone in the inner ear, leading to tinnitus, vertigo or hearing loss. Epididymal cystadenomas are usually asymptomatic and found with ultrasound imaging, without the need for treatment. [news-medical.net]

• Night Sweats

  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. [accessanesthesiology.mhmedical.com]

  The following symptoms may occur with tumors: Fever or chills Fatigue Loss of appetite Night sweats Weight loss Pain Exams and Tests Your health care provider might see a tumor, such as skin cancer. [mountsinai.org]

• Increased Sweating

  Increased sweating Profuse sweating Sweating Sweating profusely Sweating, increased [ more ] 0000975 Hypertension 0000822 Increased intracranial pressure Rise in pressure inside skull 0002516 Multiple renal cysts Multiple kidney cysts 0005562 Neoplasm [rarediseases.info.nih.gov]

• Headache

  He had never had a similar headache before, but he did have occasional severe headaches that were accompanied by blurred vision. He had no family history of migraines. He denied fever, chills, sweats, and neck pain and stiffness. [consultant360.com]

  Hemangioblastomas that develop in the brain and spinal cord can cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia). [medlineplus.gov]

  Symptoms may include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, deafness in one ear, and high blood pressure. [ninds.nih.gov]

  The classic presentation of pheochromocytoma is episodic hypertension, headaches, palpitations, and diaphoresis. In the pediatric population, 40% of pheochromocytomas have a hereditary basis. [ncbi.nlm.nih.gov]

• Nystagmus

  0100659 Aplasia/Hypoplasia of the cerebellum Absent/small cerebellum Absent/underdeveloped cerebellum [ more ] 0007360 Arteriovenous malformation 0100026 Neurological speech impairment Speech disorder Speech impairment Speech impediment [ more ] 0002167 Nystagmus [rarediseases.info.nih.gov]

  […] have VHL disease may experience tumors and/or cysts in up to ten parts of the body, including the brain, spine, eyes, kidneys, pancreas, adrenal glands, inner ears, reproductive tract, liver and lung: Brain/Spinal Hemangioblastoma Headaches, ataxia, nystagmus [rarediseases.org]

  Affiliated tissues include kidney, testes and adrenal gland, and related phenotypes are nystagmus and neurological speech impairment Genetics Home Reference : 26 Von Hippel-Lindau syndrome is an inherited disorder characterized by the formation of tumors [malacards.org]

  However, these cerebellar neoplasms more often present with cerebellar signs and symptoms as headache, nausea and vomiting, dizziness, blurred vision, nystagmus, ataxia, intention tremors, coordination deficits and at a later stage herniation of the cerebellum [wjso.biomedcentral.com]

• Insomnia

  Approximately 1 month after surgery, the patient complained about general fatigue, poor concentration, loss of appetite, and insomnia. The patient was examined by a physician, but laboratory testing revealed no abnormalities. [hindawi.com]

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 [32].

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.

• Retinal angiomas

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.

• CNS Hemangioblastomas

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.

• RCC

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 [33]. 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.

• Pheochromocytoma

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 [34] even in the absence of hypertensive episodes.

• ELST

Screening includes the use of auditory questionnaire and audiogram. MRI will follow if both tests are positive.

Renal Cell Carcinoma

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 [35] until they reach a size of 3 mm in diameter. A partial nephrectomy or conservative radiofrequency ablation is then performed [27]. In cases approached with partial nephrectomy, smaller lesions are also removed to retard the need for another operation.

Retinal angiomas

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 [36] [37].

Pheochromocytoma

Endoscopic adrenalectomy can be done for the management of pheochromocytoma [38]. ACTH test must be done to detect mineralo- and glucocorticosteroid adequacy [39].

CNS hemangioblastomas

• CNS hemangioblastomas are benign, slow-growing tumors. As a result, there is no indication for removal of asymptomatic lesions. 
• The success of surgical removal hinges on the number and location of the hemangiobalstomas. Lesions found at the periphery of the cerebellum yields an excellent surgical outcome. Multiple lesions at the center , brain stem, and spine do not guarantee the same outcome and necessitates a surgeon who has specialised training in VHL disease [15] [16].

Retinal angiomas

• The risk of visual loss is approximately 35% in carriers of the mutant VHL gene and 55% of patients aged 50 years old and above [17].
• Potential visual loss-threatening complications such as exudation, retinal traction or haemorrhage tend to be associated with larger angiomas. Hence management is directed towards identifying asymptomatic angiomas to prevent further complications.

RCC

• Clear cell RCC is the most common cause of death in VHL disease. Types 1 and 2B are the most common types to develop RCC from renal cysts. The risk of acquiring RCC in the lifetime of a VHL disease patient is up to 70% [18].

Pheochromocytoma

• The risk of malignancy stemming from pheochromocytoma is less than 5% in VHL disease.

Pancreatic Tumor

• Pancreatic tumors are usually solid and non-secretory islet cell tumors. Tumors can also possess cystic components called miscorcystic cystadenomas [19]. These tumors occur in about 5-10% of patients. The surgical removal of tumors is not recommended unless it is more than 3 cm in size [20] [21]. 

Epididymal cystadenomas

• They are usually asymptomatic and do not require treatment.

Life expectancy

• Screening protocols and treatment have increased the average life expectancy of patients from 50 to 67 years old [22].

Autosomal Dominant

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.

Sporadic

One-fifth [4] 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

•  A finding of a single VHL disease-related tumor is sufficient to establish a diagnosis.

Examples of VHL disease-related tumor are:

• CNS hemangioblastoma
• Retinal angioma
• Clear cell RCC
• Pheochromocytoma
• Endolymphatic Sac tumor
• Visceral cysts (e.g. renal, pancreatic, or epididymal cyst)

No family history of VHL disease

• Two VHL-disease related tumors must be present to establish a diagnosis. For example, two different types of hemangiomas found in the cerebellum and brain stem is necessary for diagnosis.

The male-to-female ratio of VHL disease case is 1:1.

• VHL disease in an autosomal dominant disorder. A parent that has the defective gene has an equal (50%) chance of passing it on to his son or daughter. Therefore, males and females have an equal chance of acquiring the disease. 

The chance of seeing a VHL disease is 1 in every 36,000 persons [5] [6].

The mutation of the VHL tumor suppressor gene is responsible for causing [7] [8] [9]:

• 33% of CNS hemangioblastoma cases
•  > 50% of retinal angioma cases
• 50% of isolated familial pheochromocytoma
• 11% of sporadic pheochromocytoma
• 1% of patients with RCC 

The diagnosis of VHL is earlier in familial than sporadic types.

• Familial VHL disease is diagnosed at a mean age of 29 years old compared to a mean age of 48 years old for the sporadic type [10].
• The discrepancy is most likely attributable to the two-hit model hypothesis. Only one mutation is needed to trigger VHL for a person who inherited a defective VHL gene. A person with no family history of the disease needs two instances of mutation for VHL disease to commence.

20% of VHL disease patients constitute the sporadic type [4].

• These individuals do not have a family history of VHL disease. Instead, the mutation is a result of de novo synthesis with 2 separate incidences of VHL tumor suppression gene mutation.

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 [11] in the event of hypoxia. In addition, HIF-2 appears to play a role in directly promoting VHL gene mutation [12] [13]. 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) [14].

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

• Presence of either CNS hemangioblastomas, retinal angioma, or RCC
• Absence of pheochromocytoma 

Type 2A VHL disease

• Pheochromocytoma , haemangioblastomas, and a lower risk of RCC [1] [2] [3].

Type 2B VHL disease

• Pheochromocytoma,haemangioblastomas,and/or RCC

Type 2C VHL disease

• Pheochromocytoma only

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.

Symptoms
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.

• Tumors located in the brain will be felt as headache, nausea, and dizziness.
• Eye tumors may present with visual changes such as blurring of vision.
• Ear tumors can manifest with hearing loss or rotatory dizziness.
• Adrenal tumors will often present with high blood pressure.

Screening
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:

• Yearly monitoring of blood pressure.
• Eye check-up every year starting preferably at infancy.
• Yearly MRI of the abdomen starting at 16 years old.
• MRI of the head and spine at adolescence every 1-3 years.

Treatment

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[22].
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.

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