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Every cell in the body has 2 copies of every gene. In VHL disease one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. Tumours only form in cells where the second copy of the gene has been mutated. This is known as the [[two-hit hypothesis]]. A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop<ref>{{cite journal|last=Knudson|first=AG|title=Two genetic hits (more or less) to cancer.|journal=Nature reviews. Cancer|date=2001 Nov|volume=1|issue=2|pages=157-62|pmid=11905807}}</ref><ref name ="pmid18039096">{{cite journal|last=Kaelin|first=WG|title=Von Hippel-Lindau disease.|journal=Annual review of pathology|date=2007|volume=2|pages=145-73|pmid=18039096}}</ref>
Every cell in the body has 2 copies of every gene. In VHL disease one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. Tumours only form in cells where the second copy of the gene has been mutated. This is known as the [[two-hit hypothesis]]. A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop<ref>{{cite journal|last=Knudson|first=AG|title=Two genetic hits (more or less) to cancer.|journal=Nature reviews. Cancer|date=2001 Nov|volume=1|issue=2|pages=157-62|pmid=11905807}}</ref><ref name ="pmid18039096">{{cite journal|last=Kaelin|first=WG|title=Von Hippel-Lindau disease.|journal=Annual review of pathology|date=2007|volume=2|pages=145-73|pmid=18039096}}</ref>


Approximately 20% of cases of VHL disease are found in individuals without a family history, known as ''de novo'' mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.<ref name = "pmid21386872"/>
Approximately 20% of cases of VHL disease are found in individuals without a family history, known as ''[[de novo]]'' mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.<ref name = "pmid21386872"/>


==VHL disease subtypes==
==VHL disease subtypes==

Revision as of 19:14, 2 January 2013

Von Hippel–Lindau disease
SpecialtyMedical genetics, neurology Edit this on Wikidata
Frequency0.0021322%

Von Hippel–Lindau (VHL) disease is a rare, autosomal dominant genetic condition that predisposes individuals to benign and malignant tumours. The most common tumours found in VHL are central nervous system and retinal hemangioblastomas, clear cell renal carcinomas, pheochromocytomas, pancreatic neuroendocrine tumours, pancreatic cysts, endolymphatic sac tumors and epididymal papillary cystadenomas.[1][2] VHL results from a mutation in the von Hippel–Lindau tumor suppressor gene on chromosome 3p25.3.[3]

Epidemiology

VHL disease has an incidence of one in 36,000 births. There is over 90% penetrance by the age of 65.[4]

Signs and symptoms

Slit lamp photograph showing retinal detachment in Von Hippel-Lindau disease.

Signs and symptoms associated with VHL disease include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure. Conditions associated with VHL disease include angiomatosis, hemangioblastomas, pheochromocytoma, renal cell carcinoma, pancreatic cysts (pancreatic serous cystadenoma) and café au lait spots.[5] Angiomatosis occurs in 37.2% of patients presenting with VHL disease and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms.[3] Approximately 40% of VHL disease presents with CNS hemangioblastomas and they are present in around 60-80%. Spinal hemangioblastomas are more specific for VHL disease as 80% are found in the disease.[6][7]

Genetics

The disease is caused by mutations of the von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26).[8]

Von Hippel–Lindau disease is inherited in an autosomal dominant pattern.

Every cell in the body has 2 copies of every gene. In VHL disease one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. Tumours only form in cells where the second copy of the gene has been mutated. This is known as the two-hit hypothesis. A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop[9][10]

Approximately 20% of cases of VHL disease are found in individuals without a family history, known as de novo mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.[6]

VHL disease subtypes

VHL disease can be subdivided according to the clinical manifestations, although these groups often correlate with certain types of mutations present in the VHL gene.[11]

Type 1

Type one often has deletion or nonsense mutations. This group manifests mostly as hemangioblastomas and clear cell renal carcinomas and pheochromocytomas are rare.[11]

Type 2

Type 2 VHL disease is subdivided into Type 2A, B and C and are characterised mostly by missense mutations. Type 2A are at risk of hemangioblastomas and pheochromocytomas, but not clear cell renal carcinomas. Type 2B are at risk of all three tumours, with a higher risk of clear cell renal carcinoma. Type 2C are only at risk for pheochromocytoma.[11]

Type 3

Type 3 VHL disease has a risk of Chuvash polycythaemia.[11]

VHL protein

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.

The VHL protein (pVHL) is involved in the regulation of a protein known as hypoxia inducible factor 1α (HIF1α). This is a subunit of a heterodimeric transcription factor that at normal cellular oxygen levels is highly regulated. In normal physiological conditions, pVHL recognises and binds to HIF1α only when oxygen is present due to the post translational hydroxylation of 2 proline residues within the HIF1α protein. pVHL is an E3 ligase that ubiquitinates HIF1α and causes its degradation by the proteasome. In low oxygen conditions or in cases of VHL disease where the VHL gene is mutated, pVHL does not bind to HIF1α. This allows the subunit to dimerise with HIF1β and activate the transcription of a number of genes, including vascular endothelial growth factor, platelet-derived growth factor B, erythropoietin and genes involved in glucose upatake and metabolism.[10][12]

Diagnosis

In individuals with a family history of VHL disease, one hemangioblastoma, pheochromocytoma or renal cell carcinoma may be sufficient to make a diagnosis. As all of the tumours associated with VHL disease can be found sporadically, at least two tumours must be identified to diagnose VHL disease in a person without a family history.[6][7]

Treatment

There is no current way to reverse the presence of the VHL mutation in patients. Nonetheless, early recognition and treatment of specific manifestations of VHL disease 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. CNS hemangioblastomas are usually surgically removed if they are symptomatic. Photocoagulation and cryotherapy are usually used for the treatment of symptomatic retinal angiomas, although anti-angiogenic treatments may also be an option. Renal tumours may be removed by a partial nephrectomy or other techniques such as radiofrequency ablation.[6]

History

Original von Hippel's description of disease.

The German ophthalmologist, Eugen von Hippel first described the angiomas in the eye in 1904.[13] Arvid Lindau described the angiomas of the cerebellum and spine in 1927.[14] The term von Hippel-Lindau disease was first used in 1936, however it only became common use in the 1970s.[6]

People

Some descendants of the McCoy family (involved in the Hatfield-McCoy feud of Appalachia, USA) are presumed to have VHL. 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. The article suggests that the McCoy family was predisposed to bad tempers because many of them had a pheochromocytoma, which produced excess adrenaline and a tendency toward explosive tempers.[15]

Nomenclature

Other uncommon names are: angiomatosis retinae, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel Disease, Hippel–Lindau syndrome, HLS, VHL, Lindau disease or retinocerebellar angiomatosis.[16][17]

See also

References

  1. ^ Richard, S (2012 May 30). "Von Hippel-Lindau: How a rare disease illuminates cancer biology". Seminars in cancer biology. PMID 22659535. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ Henry, <by> Todd, James Campell <and Arthur Hawley> Sanford ed. by Israel Davidsohn <and> John Bernard (1969). Todd-Sanford clinical diagnosis by laboratory methods, edited by Israel Davidsohn [and] John Bernard Henry (14th ed. ed.). Philadelphia: Saunders. p. 555. ISBN 0-7216-2921-0. {{cite book}}: |edition= has extra text (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b Wong WT; n E; Agró Coleman HR; et al. (2007). "Genotype–phenotype correlation in von Hippel–Lindau disease with retinal angiomatosis". Archives of ophthalmology. 125 (2): 239–45. doi:10.1001/archopht.125.2.239. PMID 17296901. Retrieved 2008-10-22. {{cite journal}}: Unknown parameter |author-separator= ignored (help); Unknown parameter |month= ignored (help)
  4. ^ Kim, JJ (2010). "Von Hippel Lindau syndrome". Advances in experimental medicine and biology. 685: 228–49. PMID 20687511. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ Lindsay, Kenneth W (1991). Neurology and Neurosurgery Illustrated. United States: Churchill Livingstone. ISBN 0-443-04345-0. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ a b c d e Maher, ER (2011 Jun). "von Hippel-Lindau disease: a clinical and scientific review". European journal of human genetics : EJHG. 19 (6): 617–23. PMID 21386872. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ a b Friedrich, CA (1999 Dec 1). "Von Hippel-Lindau syndrome. A pleomorphic condition". Cancer. 86 (11 Suppl): 2478–82. PMID 10630173. {{cite journal}}: Check date values in: |date= (help)
  8. ^ Kondo, K (10 March 2001). "The von Hippel–Lindau Tumor Suppressor Gene". Experimental Cell Research. 264 (1): 117–125. doi:10.1006/excr.2000.5139.
  9. ^ Knudson, AG (2001 Nov). "Two genetic hits (more or less) to cancer". Nature reviews. Cancer. 1 (2): 157–62. PMID 11905807. {{cite journal}}: Check date values in: |date= (help)
  10. ^ a b Kaelin, WG (2007). "Von Hippel-Lindau disease". Annual review of pathology. 2: 145–73. PMID 18039096.
  11. ^ a b c d Calzada, MJ (2010 Mar). "Von Hippel-Lindau syndrome: molecular mechanisms of the disease". Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 12 (3): 160–5. PMID 20231120. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Bader, HL (2012 Jun 4). "Systemic VHL gene functions and the VHL disease". FEBS letters. 586 (11): 1562–9. PMID 22673568. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ Von Hippel E (1904). "Ueber eine sehr seltene Erkrankung der Netzhaut". Albrecht von Graefes Arch Ophthal. 59: 83–106.
  14. ^ Lindau A (1927). "Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation". Acta Ophthal. 4: 193–226.
  15. ^ "Hatfield–McCoy feud blamed on 'rage' disease". MSNBC.com. 2007-04-05. Retrieved 2007-04-05.
  16. ^ "NORD national organisation for rare disorders".
  17. ^ "MeSH (Medical Subject Headings)". Retrieved 08/11/2012. {{cite web}}: Check date values in: |accessdate= (help)

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