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:

  • Type I: truncating mutations, exon deletions
    • Retinal angioma, CNS hemangioblastoma (HB), renal cell carcinoma (RCC)
    • Pancreatic neuroendocrine tumors (NET)
    • Low risk of pheochromocytomas (PHEO)
  • Type IB: deletions throughout the VHL gene
    • Retinal angioma, CNS HB, pancreatic NET
    • Low risk of PHEO and RCC
  • Type IIA: missense variants (e.g. p.Y98H, p.Y112H, p.V116F)
    • PHEO, retinal angioma, CNS HB
    • Low risk of RCC
  • Type IIB: missense variants (e.g. p.R167Q, p.R167W)
    • PHEO, retinal angioma, CNS HB, pancreatic cysts, pancreatic NET, RCC
  • Type IIC: missense variants (e.g. p.V84L, p.L188V)
    • PHEO, CNS HB, pancreatic NET (rare)
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

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
Brain stem
Spinal

60% – 80%

44% – 72%
10% – 25%
13% – 50%

09 / 30

09 / 31
12 / 32
08 / 33

Retinal angioma / HB 25% – 60% 00 / 25
Kidney

Cysts
RCC

25% – 75%

42%
17% – 70%

12 / 39

12 / 37
13 / 44

PHEO 10% – 25% 02 / 27
ELST 10% – 15% 06 / 22
Pancreas

Cysts
NET

35% – 75%

21%
10% – 17%

05 / 36

05 / 33
16 / 35

Papillary cystadenoma

Epididymis
Adnexa

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.

Support Groups