NORD gratefully acknowledges Amy Akers, PhD, Chief Scientific Officer, Angioma Alliance, for assistance in the preparation of this report.
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. CCMs 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). CCMs are dynamic structures, changing in size and number over time and they can range in size from a few millimeters to several centimeters.
CCMs 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 individuals 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 typically develop 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 clustered nearby an associated DVA. The significance of DVA association with sporadic lesions is not understood.
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.
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 one of three genes, 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.
Furthermore, these genes are responsible to maintaining structural integrity between blood vessel cells, such the blood does not leak into the brain.
Familial CCM accounts for at least 20% of all cases and follows autosomal dominant inheritance. This means that the illness will be present in every generation of a family (does not skip generation like recessive diseases) and is not selective for males or females. Individuals with familial CCM have a 50% chance of passing the illness to each child. Furthermore, inheritance of only one mutated copy of one CCM disease-gene is necessary to be affected by cavernous malformation. Families with the genetic form of CCM typically have several affected individuals in more than one consecutive generation and have a much greater likelihood of developing multiple CCMs.
CCM3 gene mutations cause the most aggressive form of the illness and also lead to distinct features that warrant special consideration. Individuals affected by CCM3 gene mutations are more likely to be diagnosed as children, hemorrhage at an early age and may also experience scoliosis, cognitive disability, benign brain tumors and/or skin lesions. However, as with all familial CCM, clinical course varies within and between families.
Sporadic CCM is not caused by heritable 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. Recent evidence suggests that the cause of sporadic CCM lesion development is quite similar to familial CCM lesions. Researchers have found that there are genetic mutations of the CCM genes that occur only with the blood vessels of the sporadic CCM lesion. These mutations are not heritable. This data suggests that all forms of CCM lesions develop following a similar mechanism and therefore may be treated with the same therapeutic drug in the future.
In general, cavernous malformations can develop at any age and are present in males and females in equal numbers. Importantly, all ethnic populations are 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. Being Hispanic does not predispose individuals to CCM. Instead, the large Hispanic population affected by the Common Hispanic Mutation is due to relatedness and passing the mutation from generation to generation for several hundred years.
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.
Genetic testing may be recommended for individuals with a family history and/or multiple CCM lesions. By identifying your genetic mutation, other family members can undergo targeted genetic testing to see whether or not they also carry your family’s specific disease-causing mutation. Genetic screening of family members can provide them with a definitive diagnosis or with relief, if they don’t have a mutation.
Genetic testing typically identifies a causative mutation in those with the familial form of the illness. However, 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.
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 patient-by-patient 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.
Researchers are working hard to develop a non-surgical treatment for cavernous malformations. Recent advances related to the pathobiology and molecular signaling of the CCM proteins has identified several druggable pathways that are currently under investigation. The following drugs are being analyzed in cell-based and live animal models.
Fasudil, is a drug that has been demonstrated in CCM1 and CCM2 mouse models to reduce lesion size, lesion number, and hemorrhage rate. Fasudil is an approved drug in Japan to treat vasodilation; it is not available with FDA approval in the United States.
Statin Medications also under investigation to treat CCM lesions and target the same molecular signal as Fasudil. Simvastatin being studied in a small trial focused on people with CCM who are eligible to take this medication for cholesterol management. This trial is in the final data collection and analysis phase, ClinicalTrials.gov identifier: NCT01764451. Another human trial is planned for Atorvastatin therapy, but has not yet begun recruitment ClinicalTrials.gov identifier: NCT02603328.
The chemotherapeutic, sorafenib, has been investigated in mouse models of CCM1.
The drug Sulindac, has been shown to repair defective structure of blood vessel cells that make up CCM lesions. Furthermore, this drug also reduces number and size of CCM lesions in CCM3 mice. Sulindac is used clinically for other indications including colon cancer.
Vitamin D3 (cholecalciferol) and Tempol have both recently been identified as potential therapeutics for CCM. These molecules reduced lesion number in mouse 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
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about cavernous malformation:
Amy Akers, PhD
Chief Scientific Officer
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.
Bravi L, Rudini N, Cuttano R, Giampietro C, Maddaluno L, Ferrarini L, Adams RH, Corada M, Boulday G, Tournier-Lasserve E, Dejana E, Lampugnani MG. Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice, Proc Natl Acad Sci USA. 2015 Jul 7;112(27):8421-6. doi:10.1073/pnas.1501352112.Epub 2015 Jun 24.
Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, Marcondes de Souza J, Lee C, Marchuk DA, Awad IAExceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations, Genet Med. 2015 March;17(3):188-96.doi: 10.1038/gim.2014.97.Epub 2014 Aug 14.
McDonald DA, Shi C, Shenkar R, Gallione CJ, Akers AL, Li S, De Castro N, Berg MJ, Corcoran DL, Awad IA, Marchuk DA. Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis, Hum Mol Genet. 2014 Aug 15;23(16):4357-70. Doi:10.1093/hmg/ddu153. Epub 2014 April 3.
Spiegler S, Najm J, Liu J, Gkalympoudis S, Schröder W, Borck G, Brockmann K, Elbracht M, Fauth C, Ferbert A, Freudenberg L, Grasshoff U, Hellenbroich Y, Henn W, Hoffjan S, Hüning I, Korenke GC, Kroisel PM, Kunstmann E, Mair M, Munk-Schulenburg S, Nikoubashman O, Pauli S, Rudnik-Schöneborn S, Sudholt I, Sure U, Tinschert S, Wiednig M, Zoll B, Ginsberg MH, Felbor U.High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors, Mol Genet Genomic Med. 2014 Mar;2(2):176-85. doi: 10.1002/mgg3.60. Epub 2014 Jan 14.
Stockton Ra, Shenkar R, Awad IA, Ginsberg MH. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular intergrity, J Exp Med. 2010 Apr 12;207(4):881-96. Doi:10.1084/jem.20091258. Epub 2010 March 22.
Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling, Proc Natl Acad Sci USA. 2010 Jul 13;107(28):12640-5. Doi:10.1073/pnas.1000132107. Epub 2010 Jun 24.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.
Morrison L, Akers A. Cerebral Cavernous Malformation, Familial. 2003 Feb 24 [Updated 2011 May 31]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.Available from: http://www.ncbi.nlm.nih.gov/books/NBK1293/. Accessed March 21, 2016.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD:The Johns Hopkins University; Entry No.116860; Last Update:09/03/2013. Available at: http://omim.org/entry/116860 Accessed March 21, 2016.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100