Von Hippel–Lindau disease

Conditions associated with VHL disease include angiomatosis, hemangioblastomas, pheochromocytoma, renal cell carcinoma, pancreatic cysts (pancreatic serous cystadenoma), endolymphatic sac tumor, and bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women).

[11] The disease is caused by mutations of the Von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26).

The condition is inherited in an autosomal dominant manner – one copy of the faulty gene is sufficient to increase the risk of developing tumours.

[14][15] Approximately 20% of cases of VHL disease are found in individuals without a family history, known as de novo mutations.

This is a subunit of a heterodimeric transcription factor that at normal cellular oxygen levels is highly regulated.

In normal physiological conditions, pVHL recognizes and binds to HIF1α only when oxygen is present due to the post translational hydroxylation of 2 proline residues within the HIF1α protein.

In individuals with a family history of VHL disease, one hemangioblastoma, pheochromocytoma or renal cell carcinoma may be sufficient to make a diagnosis.

In hereditary VHL disease, techniques such as the Southern blot and gene sequencing can be used to analyse DNA and identify mutations.

[9][18] Von Hippel-Lindau (VHL) disease is classified into two main types based on the presence or absence of pheochromocytoma (pheo).

The first involves patients with a family history of developing hemangioblastomas (HB) in the central nervous system (CNS) or retinal angiomas (RA), pheo, pancreatic tumors or cysts, or epididymal cystadenomas.

Early recognition and treatment of specific manifestations of VHL can substantially decrease complications and improve quality of life.

For this reason, individuals with VHL disease are usually screened routinely for retinal angiomas, CNS hemangioblastomas, clear-cell renal carcinomas and pheochromocytomas.

In an article appearing in the Associated Press, it has been speculated by a Vanderbilt University endocrinologist that the hostility underlying the Hatfield–McCoy feud may have been partly due to the consequences of Von Hippel–Lindau disease.

Slit lamp photograph showing retinal detachment in Von Hippel–Lindau disease
Typical distribution of hemangioblastomas in Von Hippel–Lindau disease.
Von Hippel–Lindau disease is inherited in an autosomal dominant pattern.
The regulation of HIF1α by pVHL. Under normal oxygen levels, HIF1α binds pVHL through 2 hydroxylated proline residues and is polyubiquitinated by pVHL. This leads to its degradation via the proteasome. During hypoxia, the proline residues are not hydroxylated and pVHL cannot bind. HIF1α causes the transcription of genes that contain the hypoxia response element. In VHL disease, genetic mutations cause alterations to the pVHL protein, usually to the HIF1α binding site.
Original Von Hippel's description of disease