You are here: Home / Rare Disease Information / Rare Disease Database

Search Rare Diseases

Enter a disease name or synonym to search NORD's database of reports.

0-9 - A - B - C - D - E - F - G - H - I - J - K - L - M - N - O - P - Q - R - S - T - U - V - W - X - Y - Z

Cavernous Malformation

NORD is very grateful to Amy Akers, PhD, Chief Scientific Officer, Angioma Alliance, for assistance in the preparation of this report.

Synonyms of Cavernous Malformation

  • cavernoma
  • cavernous angioma
  • cavernous hemangioma
  • cerebral cavernous malformation (CCM)

Disorder Subdivisions

  • familial cavernous malformation
  • sporadic cavernous malformation

General Discussion

Vascular malformations are localized collections of blood vessels that are abnormal in structure or number, lead to altered blood flow, and are not cancerous (nonneoplastic). While it was originally believed that most vascular malformations are present at birth (congential), cavernous malformation lesions may develop throughout the lifetime of the affected individual. Other vascular malformations are not congenital, but are caused by trauma, radiation, or other injury to the spinal cord. Vascular malformations are typically classified by size, location, and type of change, with the four most common being capillary telangiectasias, cavernous malformations, venous malformations, and arteriovenous malformations.

Cavernous malformations are dilated blood vessels that are characterized by multiple distended "caverns" of blood-filled vasculature through which the blood flows very slowly. Vessels of a cavernous malformation lesion have a tendency to leak because they lack the proper junctions between neighboring cells as well as the necessary structural support from smooth muscle and stretchable material (elastin). Leakage (bleeding) from these vascular lesions is the underlying cause of clinical symptoms associated with the illness. Cavernous malformations are primarily located in the brain, but can also be found in the spinal cord, on the skin, and more rarely in the retina.

Cerebral cavernous malformations (CCMs) are usually located in the white matter (cortex) of the brain. CCM do not have brain tissue within the malformation like other lesions such as arteriovenous malformations, and they usually do not have defined borders (are not encapsulated). CCM are dynamic structures, changing in size and number over time and they can range in size from a few millimeters to several centimeters.

CCM are present in up to 0.5% of the general population, and they account for a large proportion (8-15%) of all brain and spinal vascular malformations. While the prevalence of individuals with at least one CCM lesion is quite high, as many as 40% of affected individual may never experience symptoms or become diagnosed with cavernous malformation. A majority of these cases are individuals with only a single lesion and no family history of the disease. (These cases are termed 'sporadic' and are not caused by an inherited genetic mutation). Individuals with the familial (genetic) form of cavernous malformation are likely to have multiple lesions and may be more likely to experience symptoms associated with the disorder. While adults are most often diagnosed with CCM, people of all ages may be affected by cavernous malformations, and approximately 25% of all diagnosed cavernous malformations are found in children.

CCM lesions are commonly associated with developmental venous anomalies (DVA) also called, venous malformations or venous angiomas. A DVA is a type of vascular malformation that, on its own, does not cause any clinical symptoms. However, when found in combination with a CCM lesion, the DVA complicates the option for surgical intervention because disturbing the DVA during surgery could cause dangerous bleeding. Association of CCMs with DVAs is uncommon in familial cavernous malformation; however, at least 40% of sporadic cavernous malformations may develop within the vicinity of a DVA. Rarely, multiple sporadic cavernous malformations are found nearby an associated DVA. The significance of DVA association with sporadic lesions is currently under investigation; perhaps this observation may suggest a difference in developmental mechanisms between sporadic and familial cavernous malformations.

Symptoms

Individuals with cerebral cavernous malformations present with a wide variety of symptoms; some affected individuals may have no symptoms at all while others may experience headaches or neurological deficits including weakness in the arms or legs, problems with memory or balance, or difficulties with vision or speech. Hemorrhagic stroke and seizures are the most severe symptoms caused by cavernous malformations. Manifestation of symptoms varies by the individual and is dependent on the location of the lesion and on its propensity to bleed.

A person who suffers from seizures is said to have epilepsy. Seizures tend to worsen with age and frequency. Most cases of epilepsy can be controlled with medications. However, for some individuals, surgical removal of the cavernous malformation may be necessary. As a complicating factor, if a person has seizures and more than one cavernous malformation, it may be difficult to pinpoint which cavernous malformation is the cause of the seizures.

Causes

Individuals with only one CCM and no affected relatives most likely have the sporadic type. Those with multiple CCMs are much more likely to have the familial type due to a genetic mutation in CCM1, CCM2 or CCM3.

Determining the normal function of these genes has been a major research focus since each was identified in 1999, 2003 and 2005 respectively. Researchers have learned that these genes each have very important functions in the development and maintenance of blood vessels. When a genetic mutation is inherited that causes one of these genes not to function properly, the blood vessels of the brain may become malformed and lead to the onset of cavernous malformation. In a small percentage of families, no mutation may be identified in one of the known genes. This may be due to technology limits of genetic testing, or there may be another gene that causes cavernous malformations, but has yet to be discovered.

Familial CCM accounts for at least 20% of all cases and follows autosomal dominant inheritance. Individuals with familial CCM have a 50% chance of passing the illness to each child because a child must only inherit one mutated copy of one CCM disease-gene in order to be affected by cavernous malformation. Families with the genetic form of CCM typically have several affected individuals in more than one consecutive generation. Individuals with familial CCM have a much greater likelihood of developing multiple CCMs.
Sporadic CCM, however, is not caused by mutations in the CCM genes. Therefore, individuals with sporadic CCM do not have a greater chance of having a child with CCM than anyone in the general population. Similarly, genetic testing may not be recommended for someone with sporadic CCM as this test would most likely yield a negative result and not provide the family with any additional information. This is because sporadic CCMs are not caused by mutations that are detectable in the blood.

Individuals with sporadic CCM typically have only one cavernous malformation lesion and have no family members with CCM. However, from time to time, individuals with sporadic CCM may have multiple lesions in close association with a DVA. The biologic cause of sporadic CCM lesion development remains unknown, and is a primary focuses for many CCM researchers.

Affected Populations

In general, cavernous malformations can develop at any age and are present in males and females in equal numbers. Importantly, any ethnic population is susceptible to the development of a CCM.

The greatest density of individuals affected by cavernous malformation is in New Mexico, USA. This is because of a specific genetic mutation in the CCM1 gene, termed the common Hispanic mutation. This mutation arose hundreds of years ago and has been passed through at least 17 generations of Americans descended from the original Spanish settlers of the Southwest.

Related Disorders

Cerebral arteriovenous malformations (AVMs) are comprised of blood vessels where arteries and veins meet directly, without the capillaries that are normally found between the veins and arteries. Without capillaries, the high pressure arteries have no way of reducing pressure before blood reaches the weaker veins, so the vessels get distended with blood and possibly burst. AVMs may cause headaches, seizures, strokes, or bleeding into the brain, similar to CCMs. However, there are several detectable differences between cerebral cavernous malformations and arteriovenous malformations. AVMs are high-flow lesions with rapid blood movement, while CCM lesions are low-flow lesions. The low-flow nature of CCMs makes them angiographically occult and they are only visually detectable using magnetic resonance imaging (MRI). Brain AVMs are a feature of another complex vascular disorder called hereditary hemorrhagic telangiectasia (HHT). (For more information on these disorders, choose arteriovenous "malformation" and "hereditary hemorrhagic telangiectasis" as your search term in the Rare Disease Database.)

Von Hippel-Lindau disease is an autosomal dominant condition characterized by multiple localized tissue malformations called hemangioblastomas and angiomas. These growths may be found in the retina, brain, kidneys, adrenal glands, and other organs. Symptoms may include headaches, dizziness and difficulty coordinating muscle movement (ataxia). Chronic high blood pressure (hypertension) can also occur. The disorder may begin during young adulthood or may develop during early childhood. Aneurysms (bulges in blood vessels) may develop and form an angioma (nodule) that resembles a balloon. Benign tumors (pheochromocytomas) of the adrenal glands may be present as well, causing chronic high blood pressure, pounding heartbeat, headache, cold hands and feet, and excessive sweating. This condition is found equally in males and females and all ethnic groups. (For more information on this disorder, choose "Von Hippel-Lindau" as your search term in the Rare Disease Database.)

Moyamoya disease is a progressive disease causing constriction of the cerebral blood vessels, particularly the connection of blood vessels called the Circle of Willis and the surrounding arteries that feed it. Moyamoya means "puff of smoke" in Japanese, which is how the angiography appears, due to the constriction of the vessels that usually occur on both sides (bilaterally). No one knows the exact cause of Moyamoya, but it may have both genetic and environmental components. Some infections may lead to the condition (leptospirosis and tuberculosis), and several genetic conditions have Moyamoya disease in association, including Fanconi anemia, sickle cell anemia, Apert syndrome, Down syndrome, Marfan syndrome, tuberous sclerosis, Turner syndrome, and neurofibromatosis. This condition is more common in females (ratio of females to males is 1.8:1) and occurs primarily in Asians (but has been found in Caucasians, African Americans, Haitians, and Hispanics). (For more information on this disorder, choose "moyamoya" as your search term in the Rare Disease Database.)

Blue rubber bleb nevus syndrome is a rare disorder, characterized by soft elevated blue, blue-black, or purplish-red swellings on or under the skin and on internal organs. On the skin, they are usually located on the upper arms or trunk, and internally they can be found in many locations, including the lungs, liver, spleen, gallbladder, kidney and skeletal muscles. When found in the gastrointestinal tract, they can cause severe anemia through uncontrolled bleeding. In the brain, hemorrhage or swelling of the brain (increased intracranial pressure) can occur. This condition occurs equally in males and females and is found in all ethnic groups. (For more information on this disorder, choose "blue rubber bleb nevus" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
Magnetic resonance imaging (MRI) is now the standard of care for diagnosing cavernous malformations. Unless an individual has had a recent bleed, CCM lesions are not readily detected by CT scans or angiography. Molecular genetic testing for mutations in the KRIT1 (CCM1), CCM2, and PDCD10 (CCM3) genes is available to confirm the diagnosis.

Treatment
Currently there is no available drug treatment for CCM. Most cavernous malformations are initially observed for change in appearance, recent hemorrhage or clinical symptoms. Medications are available to treat seizures and headaches caused by cavernous malformations. Surgery is typically assessed on a case-by-case basis and may be advocated for cavernous malformations with recent hemorrhage, and/or those that are causing seizures. Radiosurgery, by gamma knife, linear accelerator or new shaped beam techniques, is a controversial treatment option that has been used on cavernous malformations that are too dangerous to reach through traditional surgery. Radiosurgery is not recommended for individuals with familial CCM and/or multiple lesions.

In all age groups, management decisions need to be based on the risk of keeping a cavernous malformation versus the risk of surgery. When a CCM is found unexpectedly, surgery is not always necessary, especially when it is not in a dangerous area. However, clinical and MRI follow-up is necessary due to the risk of growth and hemorrhage. Choices of therapy should take into account age, location of the lesion, effects on seizures, and risk factors for severe, potentially life-threatening hemorrhage.

Risks of any surgery, including cavernous malformation resection, include stroke, paralysis, coma or death, although these complications are rare with modern surgery performed by expert neurosurgeons. Surgery on cavernous malformation in the brain stem and spinal cord is more risky, but these cavernous malformations are more dangerous if left alone. While recovery is different for everyone, many patients leave the hospital within a few days and resume normal life within a few weeks of surgery. However, people with neurological deficits may require a prolonged period of rehabilitation.

Investigational Therapies

Researchers are working hard to develop a non-surgical treatment for cavernous malformations. Two potential therapeutics, simvastatin and Fasudil, are currently being studied in cell and animal-based models of the illness.

If you are interested in participating in research studies or future clinical trials, you may sign up for the International Cavernous Angioma Patient Registry. This registry is a web-based communication tool to provided interested persons with information about current research studies and opportunities for participation. For more information, please visit: www.angioma.org/registry.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Contact for additional information about cavernous malformation:

Amy Akers, PhD
Chief Scientific Officer
Angioma Alliance
Web: www.angioma.org
Email: Amy.Akers@angioma.org

Cavernous Malformation Resources

Organizations:

References

TEXTBOOKS
Vascular Malformations of the Central Nervous System: Jafar J. Jafar, Issam A. Awad, Robert H. Rosenwasser; Lippincott Williams and Wilkens: Philadelphia, 1999.

Hemangiomas and Vascular Malformations of the Head and Neck: Milton Waner and James Suen; Wiley-Liss: New York, 1999.

JOURNAL ARTICLES
McDonald, Dave et al. Fasudil decreases lesion burden in murine model of cerebral cavernous malformation disease, Stroke. 2012;43(2):571-1.

Batra, Sachin et al. Management of hemorrhage from cavernous malformations, Curr Atheroscler Rep. 2012;14(4):360-5.

Stockton, Rebecca et al. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity, J Exp Med. 2010;207(4):881-96.

Peterson, Tina A. et al. Familial versus Sporadic Cavernous Malformations: Differences in Developmental Venous Anomaly Association and Lesion Phenotype. AJNR Am J Neuroradiol. 2010;31(2):377-82.

Whitehead, Kevin et al. The cerebral cavernous malformations pathway promotes vascular integrity via Rho GTPases, Nat Med. 2009;15(2):177-84.

Batra, Sachin et al. Cavernous malformations: natural history, diagnosis and treatment, Nature Reviews Neurology. 2009;5: 659-670.

Glading, Angela et al. KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions, J Cell Biol. 2007;179(2):247-54.

Liquori, Christina et al. Low Frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus, Hum Mutat. 2006;27(1):118.

Bergametti, F. et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations, American Journal of Human Genetics. 2005;76(1): 42-51.

Liquori, Christina L. et al. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations, American Journal of Human Genetics. 2003;73(6):1459-1464.

Sahoo, Trilochan et al. Computational and Experimental Analyses Reveal Previously Undetected Coding Exons of the KRIT1 (CCM1) Gene, Genomics. 2001;71.

Sahoo, Trilochan et al. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1), Human Molecular Genetics. 1999;8(12): 2325-2333.

Moriarity, John et al. The Natural History of Carvernous Malformations, Neurosurgery Clinics of North America. 1999;10(3): 411-417.

Craig, Holly D et al. Multilocus linkage identifies two new loci for a Mendelian form of stroke, cerebral cavernous malformation, at 7p15 and 3q25-227, Human Molecular Genetics. 1998;7(12):1851-1858.

Labauge, Pierre et al. Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families, The Lancet. 1998;352:1892-1897.

Zabramski, Joseph et al. The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg. 1994;80(3):422-32.

INTERNET
Morrison L and Akers A. (Updated May 31, 2011). Cerebral Cavernous Malformation, Familial. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org Accessed:February 26, 2013.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD:The Johns Hopkins University; Entry No.116860; Last Update:5/15/12. Available at: http://omim.org/entry/116860 Accessed:February 21, 2013.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2013/02/27 00:00:00 GMT+0

0-9 - A - B - C - D - E - F - G - H - I - J - K - L - M - N - O - P - Q - R - S - T - U - V - W - X - Y - Z

NORD's Rare Disease Information Database is copyrighted and may not be published without the written consent of NORD.

 
Copyright ©2014 NORD - National Organization for Rare Disorders, Inc. All rights reserved.
The following trademarks/registered service marks are owned by NORD: NORD, National Organization for Rare Disorders, the NORD logo, RareConnect. .