Definition
Von Hippel-Lindau syndrome (SGS, OMIM #193300) is a genetic disease caused by mutations in the VHL gene. It is characterized by hemangioblastomas (HB) of the brain, the spinal cord, and the retina and by a predisposition to clear cell renal cell carcinomas (RCC) and renal cysts, pheochromocytomas (PHEO), pancreatic cysts, and neuroendocrine tumors (NET), endolymphatic sac tumors (ELST), and cysts of the epididymis and adnexa.
Key Data
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| Synonym | |
| Gene | VHL |
| Gene product | pVHL (Von Hippel-Lindau tumor suppressor) |
| Function | Tumor suppressor; the absence or a mutated form of pVHL results in the accumulation of HIF1α due to the inability of HIF to bind to pVHL and thereby leads to cell proliferation and neovascularization of tumors. |
| Heredity | Autosomal dominant, around 20% de novo mutations |
| Prevalence | The incidence is around 1:36.000 |
| Genotype-phenotype correlation | VHL is subdivided into 5 types, which are associated with different mutations:
|
| Penetrance | 100% at the age of 75 |
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Diagnosis
Suspected Diagnosis
Genetic diagnostics is indicated for all first-grade relatives of a person with a VHL mutation. Furthermore, Von Hippel-Lindau syndrome is suspected in individuals presenting with the following findings:
Retinal angioma (hemangioblastoma), predominantly in younger patients
Hemangioblastoma of the CNS
Clear cell renal cell carcinoma
Pheochromocytoma or paraganglioma
Endolymphatic sac tumor (ELST)
Papillary cystadenomas of the adnexa or of the epididymis
Multiple pancreatic cysts or pancreatic neuroendocrine tumors (NET)
Multiple renal cysts
Diagnostic Criteria
The diagnosis of “Von Hippel-Lindau syndrome” is considered to be confirmed by the detection of a heterozygous VHL mutation and/or
For patients with at least two of the following findings when there is no concomitant family history:
≥ 2 hemangioblastomas of the retina, the spinal cord, or the brain, or a single hemangioblastoma in association with a visceral manifestation (e.g. multiple renal or pancreatic cysts)
Renal cell carcinoma
Adrenal or extra-adrenal pheochromocytoma
ELST, papillary cystadenoma of the adnexa/epididymis, or pancreatic NET
For patients with at least one of the following findings when there is a concomitant family history:
Retinal angioma
Hemangioblastoma of the spinal cord or cerebellum
Adrenal or extra-adrenal pheochromocytoma
Renal cell carcinoma
Multiple renal and pancreatic cysts
Genetic Diagnostics
The diagnosis of “Von Hippel-Lindau syndrome” is confirmed by the detection of a heterozygous germline mutation in the VHL gene by sequence analysis or deletion/duplication analysis. The use of panel examinations consisting of multiple genes together with exome or genome sequencing may also be helpful.
Differential Diagnoses
Isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma
TMEM127-associated predisposition to pheochromocytoma
Birt-Hogg-Dubé (BHD) syndrome
Ménière’s disease
Clinical Presentation
The clinical presentation depends on the underlying VHL mutation (see the genotype-phenotype correlation) and varies greatly both within a family and between families, even when the same mutation is involved.
Hemangioblastomas
Hemangioblastomas occur in the CNS and the retina and usually grow in spurts. Depending on where they are located, they can cause different neurological symptoms, such as headaches, vomiting, ataxia, gait impairment, sensory or motor failure symptoms, and pain, if they occur in the retina, they may lead to loss of visual field and impaired vision. However, they may also progress without symptoms, in which case they are commonly identified during the course of early-detection examinations. In the CNS, 20% of hemangioblastomas occur in the spinal cord and 80% in the brain, most of which are infratentorial.
Manifestations
| Tumor | Risk | Youngest/Average Age at Diagnosis (Years) |
|---|---|---|
| CNS HB
Cerebellum |
60% – 80% 44% – 72% |
09 / 30 09 / 31 |
| Retinal angioma / HB | 25% – 60% | 00 / 25 |
| Kidney
Cysts |
25% – 75% 42% |
12 / 39 12 / 37 |
| PHEO | 10% – 25% | 02 / 27 |
| ELST | 10% – 15% | 06 / 22 |
| Pancreas
Cysts |
35% – 75% 21% |
05 / 36 05 / 33 |
| Papillary cystadenoma
Epididymis |
25% – 60% 10% |
17 / 24 16 / unknown |
Therapeutic Considerations
CNS Hemangioblastomas
Complete surgical removal of symptomatic HB
The surgical removal of asymptomatic HB is controversial.
Spinal cord cysts should be surgically removed.
Arterial embolization prior to surgery may be helpful.
Retinal Hemangioblastomas
Prospective treatment of retinal (not optic nerve) angiomas is favored.
Therapeutic options include diathermia, xenon, laser coagulation, and cryocoagulation – with varying success depending on the location, size, and number of lesions concerned.
External beam radiotherapy is another option if standard therapy is unsuccessful.
Renal Cell Carcinoma
Early surgical treatment:
- Preserving the kidneys or as a partial nephrectomy if possible
- Adrenal glands should remain in situ.
Cryoablation or radiofrequency ablation are options for small tumors (< 3 cm).
Kidney transplant if a bilateral nephrectomy is necessary
Pheochromocytomas
Surgical treatment
α and β-adrenergic blocking is helpful even if there is no hypertension.
A partial adrenalectomy is the treatment of choice for children and can also be considered for adults.
Pancreatic Cysts and NET
Cysts generally do not require surgically removal.
Surgical treatment should be performed on tumors ≥ 3 cm, when there is a mutation in exon 3, or with a doubling time of < 500 days
Endolymphatic Sac Tumors
Early surgical treatment, taking into account the potential for postoperative deafness
Papillary Cystadenomas
Surgical treatment is generally not necessary if they are not causing symptoms or threatening fertility.
Surveillance Recommendations
Surveillance Recommendations
Regardless of age, every individual suffering from Von Hippel-Lindau syndrome should undergo annual clinical examinations which include blood pressure checks, neurological examinations, and evaluations to detect visual or auditory deterioration. In addition, people with VHL should be informed about the symptoms and signs of the disease. It would be ideal for all VHL patients to be treated by a physician who is familiar with Von Hippel-Lindau syndrome and has access to a multidisciplinary team.
Concerning the individual manifestations as part of VHL, the American Association for Cancer Research (AACR) makes the following surveillance recommendations:
Retinal Hemangioblastomas
Annual ophthalmological examination, including retinal diagnostics starting at birth
Pheochromocytomas
Blood pressure checks at every medical checkup starting at 2 years of age
Annual free plasma metanephrine levels (PFM) or fractionated metanephrines in 24-hour urine starting from 2 years of age:
- If the PFM ≥ 4x the reference value: Reconcile with PHEO, imaging to determine the location should follow.
- If the PFM 2x-4x the reference value: Repeat the examination in 2 months.
- If the PFM increases marginally: Repeat the examination in 6 months (or conduct a clonidine suppression test to rule out false positives).
Endolymphatic Sac Tumors
Every two years, with an audiogram starting at 5 years of age
CNS Hemangioblastomas
Every two years (or annually for adults if necessary), a cranial MRI with and without contrast agent and thin-layer images of the internal auditory canal should be performed from 8 years of age
Every two years (or annually for adults if necessary), a spinal MRI with contrast agent should be performed from 8 years of age
Renal Cell Carcinoma
Annual abdominal MRI from 10 years of age (may be conducted together with screening for pancreatic NET)
Pancreatic Neuroendocrine Tumors
Annual abdominal MRI from 10 years of age (may be conducted together with screening for renal cell carcinomas)
Additional Information
Open Clinical Trials / Registries
There are currently no open clinical trials/registries for patients with Von Hippel-Lindau syndrome that we can recommend to you for more information.