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  Oct 09, 2018

Von Hippel-Lindau Syndrome Screening and Diagnosis

Von Hippel-Lindau (VHL) syndrome is a rare genetic disorder inherited in an autosomal dominant manner. The disease is characterized by hemangioblastomas or slow-growing vascular tumors of the brain, spinal cord, and retina; pancreatic neuroendocrine tumors; pheochromocytomas or benign tumors of the adrenal gland; epididymal and broad ligament cysts; kidney cysts and clear cell renal cell carcinoma; and endolymphatic sac tumors.

The pathogenesis of VHL syndrome is associated with the germline mutation in VHL gene, which is a tumor suppressor gene involved in cell growth regulation and degradation of hypoxia-inducible factor. Mutation of this gene causes abnormal cell division and tumor formation.

As an autosomal dominant disease, a mutation in only one copy of the gene in each cell is sufficient to increase the risk of disease onset. Offspring of an affected parent has 50% chance of inheriting the mutation.  

Screening and Diagnosis

The disease usually developes at the early stage of life because of inheritance disease transmission.  VHL screening and diagnosis is difficult at an early stage due to a wide range of clinical symptoms. Familial history, if established  clinically for VHL syndrome then genetic consultation is recommended. But most of the countries have ethical issues to perform genetic mutation screening for minor, which is one of the barriers to early diagnosis of VHL syndrome.

The prognosis of VHL syndrome depends on the location and number of tumors. With early detection and treatment, disease outcome can be managed significantly. If left untreated, it may result in blindness or permanent brain damage.

The diagnosis of VHL syndrome can be established based on specific clinical features or by genetic testing. Depending upon the clinical features, VHL syndrome is classified as Type 1 (renal carcinoma is the primary clinical feature with less scope to develop pheochromocytoma); Type 2a, 2b and 2c ( Both 2a and 2b have higher scope to develop both renal carcinoma and pheochromocytoma, whereas clinical features of 2c consists of pheochromocytoma; clinical features of 2c has higher scope of developing Chuvash polycythemia).   Laboratory examinations that are generally used to determine the clinical features include spinal cord and brain MRI, MRI or ultrasound analysis of the abdomen, fundoscopy or examination of the retina, and detection of blood and urinary catecholamine metabolites. In case of indecisive clinical features, genetic testing is conducted for identification of a heterozygote gamete VHL pathogenic variant.



An individual with a family history of VHL syndrome can be diagnosed with the disease if characterized by one or more of the following clinical features:

  • Retinal angioma
  • Hemangioblastoma of the central nervous system
  • Renal cell carcinoma
  • Multiple kidney or pancreatic cysts
  • Adrenal tumors

In individuals with de novo mutation, i.e. individuals with a newly acquired mutation without any family history of the disease, presence of two or more of the following features can meet the clinical criteria of the diagnosis of VHL syndrome:

  • Two or more hemangioblastomas of the brain, spinal cord, or retina
  • A single hemangioblastoma along with multiple kidney or pancreatic cysts
  • Renal cell carcinoma
  • Adrenal tumors
  • Epididymal and broad ligament cysts, endolymphatic sac tumors, or neuroendocrine tumors of the pancreas

The molecular genetic testing employed for detecting a heterozygous pathogenic germline mutation of VHL gene include:

  • Single gene testing - Sequence analysis of VHL gene. This test may be followed by a gene-targeted copy number analysis if no pathogenic variant is detected after initial analysis.
  • Multi-gene panel testing – Sequence analysis of VHL gene along with other genes that may be associated with the disease phenotype.
  • Exome sequencing
  • Genome sequencing
  • Mitochondrial DNA sequencing

Differential Diagnosis

The clinical sensitivity of these genetic testing approaches is very important to rule out the diagnosis of VHL disease in patients with isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma who share extremely similar clinical features. In addition, germline mutations and specific missense mutations in VHL gene can be detected in patients with familial non-syndromic pheochromocytomas and autosomal recessive form of polycythaemia, respectively, without any manifestation of VHL syndrome. Similarly, endolymphatic sac tumors in patients with VHL syndrome is often misdiagnosed with the Menière disease, an inner ear disorder associated with vertigo.

Overall, the pathogenic variant of VHL gene is highly penetrant. Almost all individuals with pathogenic mutations in this gene are expected to have disease phenotype by the age of 65 years.

Reviewed by Nita Sharma Das, PhD, ND