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Genetics Home Reference: your guide to understanding genetic conditions
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Cerebral cavernous malformation

Reviewed November 2012

What is cerebral cavernous malformation?

Cerebral cavernous malformations are collections of small blood vessels (capillaries) in the brain that are enlarged and irregular in structure. These capillaries have abnormally thin walls, and they lack other support tissues, such as elastic fibers, which normally make them stretchy. As a result, the blood vessels are prone to leakage, which can cause the health problems related to this condition. Cavernous malformations can occur anywhere in the body, but usually produce serious signs and symptoms only when they occur in the brain and spinal cord (which are described as cerebral).

Approximately 25 percent of individuals with cerebral cavernous malformations never experience any related health problems. Other people with this condition may experience serious signs and symptoms such as headaches, seizures, paralysis, hearing or vision loss, and bleeding in the brain (cerebral hemorrhage). Severe brain hemorrhages can result in death. The location and number of cerebral cavernous malformations determine the severity of this disorder. These malformations can change in size and number over time.

There are two forms of the condition: familial and sporadic. The familial form is passed from parent to child, and affected individuals typically have multiple cerebral cavernous malformations. The sporadic form occurs in people with no family history of the disorder. These individuals typically have only one malformation.

How common is cerebral cavernous malformation?

Cerebral cavernous malformations affect about 0.5 percent of the population worldwide.

What genes are related to cerebral cavernous malformation?

Mutations in at least three genes, KRIT1 (also known as CCM1), CCM2, and PDCD10 (also known as CCM3), cause familial cerebral cavernous malformations.

The precise functions of these genes are not fully understood. Studies show that the proteins produced from these genes are found in the junctions connecting neighboring blood vessel cells. The proteins interact with each other as part of a complex that strengthens the interactions between cells and limits leakage from the blood vessels. Mutations in any of the three genes impair the function of the protein complex, resulting in weakened cell-to-cell junctions and increased leakage from vessels as seen in cerebral cavernous malformations.

Mutations in these three genes account for 85 to 95 percent of all cases of familial cerebral cavernous malformations. The remaining 5 to 15 percent of cases may be due to mutations in unidentified genes or to other unknown causes. Mutations in the KRIT1, CCM2, and PDCD10 genes are not involved in sporadic cerebral cavernous malformations. The cause of this form of the condition is unknown.

Related Gene(s)

Changes in these genes are associated with cerebral cavernous malformation.

  • CCM2
  • KRIT1
  • PDCD10

How do people inherit cerebral cavernous malformation?

This condition has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In the familial form, an affected person inherits the mutation from one affected parent.

Most people with cerebral cavernous malformations have the sporadic form of the disorder. These cases occur in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of cerebral cavernous malformation?

These resources address the diagnosis or management of cerebral cavernous malformation and may include treatment providers.

  • Angioma Alliance: Imaging and Diagnostics (http://www.angiomaalliance.org/pages.aspx?content=67&id=57)
  • Gene Review: Familial Cerebral Cavernous Malformation (http://www.ncbi.nlm.nih.gov/books/NBK1293)
  • Genetic Testing Registry: Cerebral cavernous malformation (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1861784)
  • Genetic Testing Registry: Cerebral cavernous malformations 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/CN042719)
  • Genetic Testing Registry: Cerebral cavernous malformations 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1864041)
  • Genetic Testing Registry: Cerebral cavernous malformations 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1864040)
  • MedlinePlus Encyclopedia: Cerebral angiography (http://www.nlm.nih.gov/medlineplus/ency/article/003799.htm)

You might also find information on the diagnosis or management of cerebral cavernous malformation in Educational resources (http://www.ghr.nlm.nih.gov/condition/cerebral-cavernous-malformation/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/cerebral-cavernous-malformation/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about cerebral cavernous malformation?

You may find the following resources about cerebral cavernous malformation helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for cerebral cavernous malformation?

  • CCM
  • central nervous system cavernous hemangioma
  • cerebral cavernous hemangioma
  • familial cavernous hemangioma
  • familial cavernous malformation
  • familial cerebral cavernous angioma
  • familial cerebral cavernous malformation
  • intracerebral cavernous hemangioma

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about cerebral cavernous malformation?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding cerebral cavernous malformation?

angioma ; autosomal ; autosomal dominant ; capillaries ; cavernous ; cell ; central nervous system ; cerebral hemorrhage ; CNS ; cutaneous ; elastic ; familial ; family history ; gene ; hemangioma ; hemorrhage ; inheritance ; malformation ; mutation ; nervous system ; pattern of inheritance ; population ; protein ; retina ; sporadic

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E; Société Française de Neurochirurgie. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet. 2005 Jan;76(1):42-51. Epub 2004 Nov 12. (http://www.ncbi.nlm.nih.gov/pubmed/15543491?dopt=Abstract)
  • Dashti SR, Hoffer A, Hu YC, Selman WR. Molecular genetics of familial cerebral cavernous malformations. Neurosurg Focus. 2006 Jul 15;21(1):e2. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16859255?dopt=Abstract)
  • Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, Zerah M, Maciazek J, Tournier-Lasserve E; Société Française de Neurochirurgie. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet. 2004 Feb;74(2):326-37. Epub 2004 Jan 22. (http://www.ncbi.nlm.nih.gov/pubmed/14740320?dopt=Abstract)
  • Gault J, Sarin H, Awadallah NA, Shenkar R, Awad IA. Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance. Neurosurgery. 2004 Jul;55(1):1-16; discussion 16-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15214969?dopt=Abstract)
  • Labauge P, Krivosic V, Denier C, Tournier-Lasserve E, Gaudric A. Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas: a clinical and genetic study. Arch Ophthalmol. 2006 Jun;124(6):885-6. (http://www.ncbi.nlm.nih.gov/pubmed/16769843?dopt=Abstract)
  • Marchuk DA, Srinivasan S, Squire TL, Zawistowski JS. Vascular morphogenesis: tales of two syndromes. Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R97-112. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12668602?dopt=Abstract)
  • Plummer NW, Zawistowski JS, Marchuk DA. Genetics of cerebral cavernous malformations. Curr Neurol Neurosci Rep. 2005 Sep;5(5):391-6. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16131422?dopt=Abstract)
  • Stockton RA, Shenkar R, Awad IA, Ginsberg MH. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med. 2010 Apr 12;207(4):881-96. doi: 10.1084/jem.20091258. Epub 2010 Mar 22. (http://www.ncbi.nlm.nih.gov/pubmed/20308363?dopt=Abstract)
  • Sure U, Freman S, Bozinov O, Benes L, Siegel AM, Bertalanffy H. Biological activity of adult cavernous malformations: a study of 56 patients. J Neurosurg. 2005 Feb;102(2):342-7. (http://www.ncbi.nlm.nih.gov/pubmed/15739564?dopt=Abstract)
  • Verlaan DJ, Davenport WJ, Stefan H, Sure U, Siegel AM, Rouleau GA. Cerebral cavernous malformations: mutations in Krit1. Neurology. 2002 Mar 26;58(6):853-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11914398?dopt=Abstract)
  • Voss K, Stahl S, Schleider E, Ullrich S, Nickel J, Mueller TD, Felbor U. CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics. 2007 Nov;8(4):249-56. Epub 2007 Jul 27. (http://www.ncbi.nlm.nih.gov/pubmed/17657516?dopt=Abstract)
  • Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL, Marchuk DA. CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet. 2005 Sep 1;14(17):2521-31. Epub 2005 Jul 21. (http://www.ncbi.nlm.nih.gov/pubmed/16037064?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: November 2012
Published: December 16, 2014