• Disease Overview
  • Synonyms
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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  • Complete Report

Cavernous Malformation

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Last updated: April 06, 2020
Years published: 1989, 1995, 1998, 2003, 2010, 2013, 2016, 2020


Acknowledgment

NORD gratefully acknowledges Amy Akers, PhD, Chief Scientific Officer, Angioma Alliance, for assistance in the preparation of this report.


Disease Overview

Vascular malformations are localized collections of blood vessels that are abnormal in structure or number. Vascular malformations lead to altered blood flow and are not cancerous (nonneoplastic). In the past, researchers believed that most vascular malformations are present at birth (congenital). However, we now know that cavernous malformation lesions display some cancer-like qualities and can develop throughout the lifetime of the affected individual. The four most common types of vascular malformations are capillary telangiectasias, cavernous malformations, venous malformations, and arteriovenous malformations.

Cavernous malformations are lesions made of dilated blood vessels and characterized by multiple distended “caverns” of blood-filled vasculature through which the blood flows very slowly. Vessels of a cavernous malformation lesion lack the proper junctions between neighboring cells as well as the necessary structural support from smooth muscle and stretchable material (elastin). These properties cause cavernous malformations to leak. Leakage (bleeding) from these vascular lesions is an underlying cause of clinical symptoms associated with the illness. Most often located in the brain, cavernous malformations can also present in the spinal cord, on the skin, and more rarely in the retina.

Cerebral cavernous malformations (CCMs) usually develop in the white matter (cortex) of the brain. CCM lesions lack intervening brain tissue within the malformation. 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 approximately 0.2% 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, a significant number of affected individuals will remain undiagnosed for their entire lives. As many as 40% of affected individuals may never experience symptoms or become diagnosed with cavernous malformation. A majority of these individuals have only a single lesion, no family history of the disease, and no inherited mutation. These cases are termed ‘sporadic.’ 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. People of all ages may be affected by cavernous malformations. Children represent approximately 25% of all diagnosed individuals.

In sporadic cases, it is common for CCM lesions to develop close to an abnormal vein. Developmental venous anomalies (DVA), also called venous malformations or venous angiomas, are a type of vascular malformation that, on its own, do 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. With the application of better imaging technologies in recent years, there is consensus among the research and clinical communities that all sporadic lesions form near an abnormal vein or within the vicinity of a DVA. Rarely, multiple sporadic cavernous malformations develop in a cluster near an associated DVA. The significance of DVA in association with sporadic lesions is not entirely understood.

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Synonyms

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

  • familial cavernous malformation
  • sporadic cavernous malformation
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Signs & 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. Clinical symptoms vary by individual and are dependent on the location of the lesion(s) and on the propensity to bleed. Spinal cord cavernous malformations can cause numbness, weakness, paralysis, tingling, burning, or itching. Cavernous malformations of the spinal cord can also cause problems with bladder and bowel control.

Seizures are one of the most common symptoms of cavernous malformations. A person who experiences more than one seizure is said to have epilepsy. Seizures tend to worsen with age and frequency. Anti-seizure medications control many cases of epilepsy. However, for some individuals for whom medication is ineffective for seizure control, surgical removal of the cavernous malformation may be necessary. Even if seizures are well controlled with medication, surgery may be recommended to avoid a lifetime of exposure to anti-epilepsy medications. 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.

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Causes

Individuals with only one CCM and no affected relatives most likely have the sporadic (non-inherited) form of the illness. Those with multiple CCMs and/or a family history of the cavernous malformations are much more likely to have the familial type due to a change (mutation) in one of three genes, CCM1 (KRIT1), CCM2, or CCM3 (PDCD10).

Determining the normal function of these CCM genes has been a research focus since each gene was identified in 1999, 2003, and 2005, respectively. Researchers have learned that these genes each have necessary functions related to maintaining structural integrity between blood vessel cells and ensuring that the blood does not leak into the brain. When a genetic mutation is inherited that causes one of these genes not to function correctly, the blood vessels of the brain can become malformed and lead to the onset of cavernous malformation.

Familial CCM accounts for at least 20% of all cases. An inherited mutation of the CCM1, CCM2, or CCM3 gene causes familial cavernous malformation. The illness follows autosomal dominant inheritance. It will be present in every generation of a family (does not skip generation like recessive diseases) and is not selective for males or females. Each child of an individual with familial CCM has a 50% chance of inheriting the illness. Families with the genetic form of CCM typically have several affected individuals in more than one consecutive generation. Lesions develop when a second somatic (randomly acquired and not heritable) mutation occurs within brain blood vessel cells that completely destroys the function of one of the CCM genes. Multiple lesions are typical of those with familial CCM.

A mutation in any of the three CCM genes will likely result in lesion development. However, CCM3 gene mutations cause the most aggressive form of the illness and 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, develop high numbers of lesions, and may also experience scoliosis, cognitive disability, benign brain tumors and/or skin lesions. Even considering these unique features of CCM3, as with all familial CCM, the clinical course varies within and between families.

In contrast to familial CCM, inherited mutations do not cause the sporadic form of the illness. Therefore, individuals with sporadic CCM do not have a higher chance of having a child with CCM than anyone in the general population, and the illness will not run in their family. Furthermore, experts do not recommend genetic testing for someone with sporadic CCM because mutations will not be detectable in the blood or saliva.

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, but that these mutations occur only with the blood vessels of the sporadic CCM lesion. These mutations are not heritable; they are randomly acquired within brain blood vessels and cause a CCM lesion to form. This data suggests that all forms of CCM lesions develop following a similar mechanism (a complete loss of function of one of the CCM genes within the brain blood vessel cells). Because of this biological similarity, there is optimism that the same therapeutic drug may treat all forms of CCM in the future.

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Affected populations

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 highest known density of individuals affected by cavernous malformation is in New Mexico, USA. The disproportionate number of affected individuals is because of a specific genetic mutation in the CCM1 gene, termed the common Hispanic mutation. This mutation is known as a founder mutation; it arose hundreds of years ago and has been passed through at least 14 generations of Americans descended from the original Spanish settlers of the Southwest. Being Hispanic does not predispose individuals to CCM. Instead, the large population affected by the common Hispanic mutation is due to family relatedness and passing the mutation from generation to generation for several hundred years. In recent years, researchers identified two additional CCM2 gene founder mutations. One of the founder mutations runs in the Ashkenazi Jewish population, and another, a large deletion in the CCM2 gene, traces its ancestry to an originating family born in the southern United States in the 1700s. The genealogy for all of the founder mutations is still a work in progress.

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Diagnosis

Magnetic resonance imaging (MRI) is now the standard of care for diagnosing cavernous malformations. Unless an individual has had a recent bleed, CT scans or angiography will not detect CCM lesions. For familial cases, molecular genetic testing for mutations in the CCM1, CCM2, and CCM3 genes is commercially available to confirm the diagnosis and is less expensive than MRI.

Experts recommend genetic testing for individuals with a family history and/or multiple CCM lesions. By identifying the affected individual’s genetic mutation, other family members can undergo targeted genetic testing to see whether or not they also carry the family’s specific disease-causing mutation. Genetic screening of family members can provide them with a definitive diagnosis without the need to undergo a MRI, or with relief if they do not have a mutation.

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Standard Therapies

Treatment

Currently, there is no available drug treatment for CCM. Most cavernous malformations are conservatively managed by observing for change in appearance, recent hemorrhage, or clinical symptoms. Medications are available to treat symptoms like seizures and headaches caused by cavernous malformations. Assessment of the risk and possible benefit of surgery is unique to each patient. Neurosurgeons may recommend lesion removal by craniotomy for cavernous malformations with recent hemorrhage, or those that are causing seizures.

Radiosurgery, by gamma knife, linear accelerator, or shaped beam techniques, is a controversial treatment option that has been used on cavernous malformations that are solitary, symptomatic, and too dangerous to reach through traditional surgery. Expert consensus recommends not using radiosurgery for asymptomatic or surgically accessible lesions. Additionally, radiosurgery is not recommended for those individuals with familial CCM, as the radiation may contribute to the development of additional lesions.
In all age groups, management decisions need to weigh the risk of keeping a cavernous malformation versus the risk of surgery. Surgery is often not recommended when a CCM is found unexpectedly (incidental finding). However, clinical and MRI follow-up is recommended to monitor growth and hemorrhage events of all lesions, including those found incidentally.

Researchers are working to develop a technique to predict future and diagnose past hemorrhage that does not require imaging. Prognostic and diagnostic biomarkers are tools that measure inflammatory markers in the blood as a surrogate measure of hemorrhage. Validation of these biomarkers is currently underway. The goal is to use these tools in the clinic to estimate future risk of hemorrhage and diagnose past hemorrhage.

The therapeutic approach decided upon by the patient and physician 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 poses an additional risk, 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.

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Clinical Trials and Studies

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: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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/

Education and Patient Support

Angioma Alliance is the patient organization for those affected by cavernous malformations (cavernous angioma). Angioma Alliance supports research, offers genetic testing, recognizes Clinical Centers of Excellence, and manages a patient registry. The Cavernous Angioma Patient Registry is a web-based communication tool designed to provide interested persons with information about current research studies and opportunities for participation. To join the registry, please visit www.AngiomaRegistry.org For more information about Angioma Alliance or to learn more about our programming, please visit www.Angioma.org

Contact for additional information about cavernous malformation:
Amy Akers, PhD
Chief Scientific Officer
Angioma Alliance
Web: www.angioma.org
Email: [email protected]

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References

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Choi JP, Wang R, Yang X, Wang X, Wang L, Ting KK, Foley M, Cogger V, Yang Z, Liu F, Han Z, Liu R, Daell J, Zheng X. Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations. Sci Adv. 2018. Nov 7;4(11):eaau0731.

Akers A, Al-Shahi Salman R, Awad I, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whitehead K. Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery. 2017 May 1;8(5):665-680.

Tang AT, Choi JP, Kotzin JJ, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Vosa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Hennao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017; 545(7654):305-310.

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.

Gibson CC, Zhu W, Davis CT, Bowman-Kirigin JA, Chan AC, Ling J, Walker AE, Goitre L, Delle Monache S, Retta SF, Shiu YT, Grossmann AH, Thomas KR, Donato AJ, Lesniewski LA, Whitehead KJ, Li DY. Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulations. 2015 Jan 20;131(3):289-99.

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.

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 IA. Exceptional 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.

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.

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

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

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.

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.

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.

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

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

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

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):118Bergametti, 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.

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

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.

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, Akers A. Cerebral Cavernous Malformation, Familial. 2003 Feb 24 [Updated 2016 Aug 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1293/ Accessed Feb 6, 2020.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD:The Johns Hopkins University; Entry No.116860; Last Update: 03/27/2019. Available at: http://omim.org/entry/116860 Accessed Feb 6, 2020.

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