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Cerebral Cavernous Malformation, Familial

Synonyms: Familial Cavernous Hemangioma, Familial Cerebral Cavernous Angioma, Familial Cerebral Cavernous Malformation

, MD and , PhD.

Author Information
, MD
Departments of Neurology and Pediatrics
University of New Mexico
Albuquerque, New Mexico
, PhD
Angioma Alliance

Initial Posting: ; Last Update: May 31, 2011.

Summary

Disease characteristics. Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person’s age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with CCM remain symptom free throughout their lives. Familial cerebral cavernous malformation (FCCM) is defined as the occurrence of CCMs in at least two family members and/or the presence of multiple CCMs and/or the presence of a disease-causing mutation in one of the three genes in which mutations are known to cause familial CCM. Cutaneous vascular lesions are found in 9% of those with FCCM and retinal vascular lesions in almost 5%.

Diagnosis/testing. FCCM is diagnosed by clinical history and family history; physical examination including neurologic, cutaneous and retinal; brain and/or spinal cord MRI; and when available, histopathologic examination of tissue specimens. The diagnosis of FCCM can be confirmed by molecular genetic testing of the following three genes in which mutations are known to cause FCCM: KRIT1 (locus name CCM1), CCM2 (locus CCM2), and PDCD10 (locus CCM3).

Management. Treatment of manifestations: Treatment of seizures and epilepsy is symptomatic, unless a surgically accessible specific lesion is responsible for seizures that are disabling. Headaches are managed symptomatically and prophylactically. Acute and chronic neurologic deficits may be managed through rehabilitation.

Surveillance: Some clinicians advocate spinal cord MRI at the time of diagnosis to serve as a baseline. Some clinicians advocate annual brain gradient echo (GRE) or susceptibility-weighted imaging (SWI). Because hemorrhage has been described in neonates and infants born into families with CCM, it is recommended that they undergo imaging with GRE or SWI.

Agents/circumstances to avoid: Agents that increase risk of hemorrhage: aspirin, NSAIDs, heparin, and sodium warfarin (Coumadin®). Note: When these medications are necessary for treatment of life-threatening thrombosis, careful consideration and close medical monitoring of dosage are warranted.

Evaluation of relatives at risk: Asymptomatic at-risk relatives of all ages may be evaluated by molecular genetic testing (if the family-specific mutation is known) to allow early diagnosis and monitoring of those at high risk of developing CCMs. Symptomatic relatives may undergo brain MRI with special sequences (GRE or SWI) to determine presence, size, and location of lesions.

Genetic counseling. Familial CCM is inherited in an autosomal dominant manner. The proportion of affected individuals with a de novo mutation is unknown. Each child of an individual with CCM has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

Familial cerebral cavernous malformation (FCCM) is diagnosed by clinical history and family history; physical examination including neurologic, cutaneous, and retinal; brain and/or spinal cord MRI; and when available, histopathologic examination of tissue specimens. The diagnosis of FCCM can be confirmed by molecular genetic testing (Table 1).

Familial cerebral cavernous malformation is defined as the occurrence of CCMs in at least two family members [Verlaan et al 2002a] and/or the presence of multiple CCMs [Denier et al 2004b, Verlaan et al 2004] and/or the presence of a disease-causing mutation in one of the three genes in which mutations are known to cause FCCM.

Note: Individuals with a single CCM may have familial CCM; therefore, the presence of a single CCM in an individual with no family history of CCM (i.e., a simplex case) does not exclude the diagnosis of familial CCM.

MRI with either gradient echo (GRE) or susceptibility-weighted imaging (SWI) is the imaging modality of choice in the diagnosis of CCM. While larger, complex lesions are visible on routine T1 and T2 MRI sequences, GRE MRI sequences reveal up to triple the number of lesions and SWI MRI sequences reveal yet an additional doubling or tripling [Cooper et al 2008, de Souza et al 2008]. Use of these sensitive imaging techniques may reveal hundreds of lesions [Petersen et al 2010].

Note: Magnetic resonance angiogram (MRA), performed with or without an intravenous contrast injection, may help distinguish CCM from other types of vascular brain malformations such as telangiectasias, arteriovenous malformations, and aneurysms.

Depending on the type and strength of MRI, lesions may appear as black dots, mixed signal intensity, or with rims of hemosiderin, fresh hemorrhage, or edema [Al-Shahi Salman et al 2008, de Souza et al 2008]. The characteristic lesion of mixed signal intensity with a central reticulated core surrounded by a dark ring is presumed to be hemosiderin deposition from prior hemorrhage [Rigamonti et al 1987].

The medical significance of the small lesions seen on MRI remains unknown, but detection of multiple lesions is helpful in distinguishing between familial CCMs and a sporadic (i.e., nonfamilial) CCM. Of note, younger persons with FCCM may appear to have only a single lesion at the time of first imaging; therefore, use of the more sensitive methods of MRI with GRE or SWI at that time could identify additional lesions and, thus, confirm the diagnosis of FCCM.

Note: Intravenous gadolinium contrast administration is not necessary to identify cavernous malformations, but is useful in identifying complex vascular malformations with arterial and venous components which on rare occasion are associated with CCM’s. Note: Surgical resection of these complex vascular lesions must preserve the venous drainage.

Cerebral angiography, performed by injecting intravenous contrast directly into the cerebral arteries, may reveal persistent opacification of irregular sinusoidal channels; however, cavernous malformations are rarely visualized on angiography because of the small size of the afferent vessels, the presence of thrombosis, and the relatively low flow in these lesions [Selman et al 2000].

Note: Because of the small but significant risk of stroke with cerebral angiography, it is usually only performed, as needed, to better define a complex lesion with arterial or venous components identified on initial brain MRI.

Table 1. Classification of CCM Type by MRI and Histopathology

TypeMR SignalHistopathologyClinical Correlation
1
  • SE T1: hyperintense core
  • SE T2: hyperintense core or hypointense core
Subacute hemorrhageAcute hemorrhage; high frequency of bleeding relapse
2
  • SE T1: reticulated mixed signal core
  • SE T2: reticulated mixed signal core with surrounding hypointense rim
Lesions with hemorrhages and thromboses of varying ages
3
  • SE T1: iso- or hypointensity
  • SE T2: hypointense lesion with hypointense rim magnifying the size of the lesion
Chronic hemorrhage with hemosiderin staining within and around the lesion
4
  • SE T1: not seen
  • SE T2: not seen
  • GRE: punctate hypointense lesion
  • SWI: punctuate hypointense lesion
Tiny CCM or telangiectasiaPossibly represent true new lesions

Zabramski et al [1994], de Souza et al [2008]

Specific MRI sequences and programs:

SE = spin echo MRI

GRE = gradient echo MRI

SWI = susceptibility-weighted imaging MRI

Histopathology. Cerebral cavernous malformations (CCMs) are vascular malformations consisting of closely clustered enlarged capillary channels (caverns) with a single layer of endothelium without normal mature vessel wall elements or intervening brain parenchyma. The diameters range from two to 55 millimeters (mean: 8 mm) [Rigamonti et al 1987, Zabramski et al 1994, Brunereau et al 2000]. Thrombosis and intra- and extra-lesional hemorrhage may be found in CCM specimens. Edema may surround lesions with recent hemorrhage.

Molecular Genetic Testing

Genes. Mutation of any one of three genes (KRIT1, CCM2, and PDCD10) is known to cause familial cerebral cavernous malformation (Table 2 and Table A).

Possible locus heterogeneity. In multiple cohorts from the United States, France, and Italy, 85% to 95% of persons with suspected FCCM have a detectable mutation in one of the three genes included in Table 2 [Denier et al 2006, Liquori et al 2007, D’Angelo et al 2011]; however, in a fraction of individuals with FCCM, mutations are not detected in any of the three genes. Based on exclusion of a PDCD10 mutation in a large family whose phenotype is linked to the CCM3 locus but not to the CCM1 or CCM2 loci, Liquori et al [2006] proposed a putative CCM4 locus at 3q26.3-q27.2.

Table 2. Summary of Molecular Genetic Testing Used in Familial Cerebral Cavernous Malformation

Gene 1 / Locus NameProportion of FCCM Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
KRIT1 / CCM153%Sequence analysis 4 / mutation scanning 5Sequence variants
Targeted mutation analysisc.1363C>T, p.Gln455Ter (see Details – a)
Duplication/deletion analysis 6Exonic or whole-gene deletions (see Details – b)
CCM2 / CCM215% Sequence analysis 4 Sequence variants
Duplication/deletion analysis 6Exonic or whole-gene deletions (see Details – b)
Targeted mutation analysisDeletion of 77.6 kb including exons 2-10 (see Details – c)
PDCD10 / CCM310%Sequence analysis 4 Sequence variants
Duplication/deletion analysis 6Exonic or whole-gene deletions (see Details – b)

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. In non-Hispanic individuals with a positive family history and/or multiple CCMs [Riant et al 2010 and references therein].

3. See Molecular Genetics for information on allelic variants.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Details - Table 2 mutation data

a.

The c.1363C>T (p.Gln455Ter) KRIT1 mutation, referred to as the "common Hispanic mutation," was identified in:

b.

Exonic or whole-gene deletions. In probands with FCCM who had no identifiable mutation by sequence analysis, the frequency of exonic or multiexonic deletions in KRIT, CCM2, and PDCD10 varied considerably in CCM cohorts from the US versus Italy [Liquori et al 2008]:

  • KRIT
    • US cohort 1/20
    • Italian cohort 5/10
  • CCM2
    • US cohort 19/20
    • Italian cohort 4/10
  • PDCD10
    • US cohort 0/20
    • Italian cohort 1/10
c.

Deletion of 77.6 kb including exons 2-10. Found in up to 22% of individuals with FCCM in the US, the deletion is specific to the US population as a result of a founder effect [Liquori et al 2007, Stahl et al 2008].

Testing Strategy

To confirm/establish the diagnosis in a proband

Brain MRI is performed with a magnet strength of at least 1.5 Tesla and at least GRE and/or SWI to identify a single lesion or multiple hypointense or mixed signal (hyper- and hypointense) lesions.

Molecular genetic testing is likely to identify a germline mutation in individuals who either have EITHER:

1.

A known family history of CCM and either a single lesion or multiple lesions

OR

2.

Multiple lesions without a known family history of CCM. Note: 45% to 67% of simplex cases (i.e., a single occurrence in a family) with multiple lesions were found to have a de novo mutation [Denier et al 2006].

For individuals meeting either criteria (1 or 2) the molecular genetic testing strategy is as follows:

  • Persons of Hispanic ancestry. First evaluate for the common KRIT1 mutation, 1363C>T. If the common mutation in KRIT1 is not identified, continue with the analysis sequence (or steps) below.
  • Persons not of Hispanic ancestry. Molecular genetic testing in the following order:

Evaluation of a young person with a single CCM who appears to be a simplex case (i.e., a single occurrence in a family) warrants:

  • Evaluation of the family history for individuals with CCM and related neurologic findings
  • Consideration of
    • Evaluation of the parents
    • Molecular genetic testing

Molecular genetic testing is unlikely to identify a germline mutation in individuals with a single CCM who are simplex cases (i.e., a single occurrence of CCM in a family) [Riant et al 2010 and references therein].

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Cerebral cavernous malformation (CCM) has been reported in infants and children, but the majority of individuals present with symptoms between the second and fifth decades. In one study, 9% of individuals were symptomatic before age ten years, 62%-72% between ages ten and 40 years, and 19% after age 40 years [Gunel et al 1996].

Brunereau et al [2000] and Labauge et al [2001] determined that new lesions appear at a rate of between 0.2 and 0.4 lesions per patient-year. They and others [Zabramski et al 1999] emphasized the dynamic nature of CCM. Other evidence of change observed on MRI over time includes appearance of acute, often asymptomatic, hemorrhages (0.7%/lesion/year) that increase in size and change in signal intensity over time. Hemorrhages may be intralesional or extend beyond the lesion [Al-Shahi Salman et al 2008].

It had been assumed that individuals with familial CCM generally have multiple lesions while individuals who represent simplex cases (i.e., a single occurrence of a CCM in a family) have a single lesion; however, in a study of 138 individuals (62 symptomatic and 76 asymptomatic) with a KRIT1 mutation, Denier et al [2004b] found that 26 (20%) appeared to have only one lesion when evaluated with T2-weighted MRI sequences. Further examination with gradient-echo (GRE) sequence MRI of 12 of the apparently symptom-free individuals revealed multiple lesions in eight (66%) and a single detectable lesion in four (33%). Additionally, eight of the symptom-free individuals showed no lesion at all. Thus, approximately 13% of individuals with a KRIT1 mutation had only one lesion detected when examined with T2-weighted MRI and about 2% had only one lesion detected when examined with GRE sequence MRI.

Others have identified an increasing number of lesions in families by generation: 5-12 lesions in children and adolescents; 20 lesions in parents; and more than 100 lesions in grandparents [Horowitz & Kondziolka 1995, Siegel et al 1998].

Brunereau et al [2000] and Labauge et al [2001] determined that 76%-86% of lesions were supratentorial and 16%-24% infratentorial. Of the infratentorial lesions, almost half occurred in the brain stem. Brain stem lesions are frequently associated with symptoms [Fritschi et al 1994]. Lesions occasionally occur in the spinal cord.

Up to 25%-50% of individuals with CCM remain symptom free throughout their lives [Siegel 1998]. This percentage may be an underestimate because many asymptomatic persons go unrecognized. Otten et al [1989] reported absence of symptoms in 90% of individuals with CCMs ascertained on autopsy.

Approximately 50%-75% of persons with CCM become symptomatic. Affected individuals most often present with seizures (40%-70%), focal neurologic deficits (35%-50%), nonspecific headaches (10%-30%), and cerebral hemorrhage. Denier et al [2004b] found seizures in 55%, focal neurologic deficits in 9%, nonspecific headaches in 4%, and cerebral hemorrhage in 32%. Five percent of individuals with intractable temporal lobe epilepsy have CCM [Spencer et al 1984]. In children, hemorrhage and an aggressive presentation may be more likely than in adults [Lee et al 2008]; presentation in children with FCCM is earlier than presentation in children with sporadic (i.e., non-genetic) CCM [Acciarri et al 2009].

Cavernous malformation can lead to death from intracranial hemorrhage or from complications of surgery [Acciarri et al 2009] particularly when found in the brain stem [Bhardwaj et al 2009, Abla et al 2010]. Of note, severe hemorrhage from CCM is less common than hemorrhage from arteriovenous malformations (AVM) [Selman et al 2000].

Spinal cord lesions are rare, occurring in fewer than 5% of affected individuals [Deutsch et al 2000]; In one large CCM1 family, spinal cavernous angiomas were found in five of eight individuals studied with spinal MRI, either alone or associated with vertebral hemangiomas [Toldo et al 2009]. Cohen-Gadol et al [2006] found that 40% of persons presenting with a spinal CM had a similar intracranial lesion (CCM). In this same study 40% of persons with both spinal and intracranial CMs were simplex cases. Molecular genetic testing was not done in this study.

Retinal, skin, and liver lesions and atrial myxoma have occasionally been reported [Dobyns et al 1987, Labauge et al 1999, Eerola et al 2000, Chen et al 2002, Ardeshiri et al 2008].

Vascular skin lesions have been reported in 9% of persons with CCM1 and less commonly in those with CCM2 and CCM3 [Eerola et al 2000, Zlotoff et al 2007, Sirvente et al 2009, Toldo et al 2009]. In the 38 individuals with FCCM and cutaneous vascular malformations reported by Sirvente et al [2009], the skin lesions were classified as capillary malformations (13); hyperkeratotic cutaneous capillary venous malformation (15), venous malformations (8), and unclassified (2).

Retinal vascular lesions, reported in 5% of affected individuals, are seen in all three familial forms of CCM [Labauge et al 2006]. Most studies of individuals with CCM have not included information on retinal findings.

Genotype-Phenotype Correlations

The lack of reported individuals homozygous for a KRIT1 mutation suggests the possibility of homozygote lethality. Homozygosity in animal models is embryonic lethal in all three genetic subtypes.

CCM1 (KRIT1) may have a less severe clinical phenotype than CCM2 (CCM2) and CCM3 (PDCD10) [Gault et al 2006]. Approximately 50% of persons with CCM1 become symptomatic by age 25 years. Skin lesions may be more common in persons with a KRIT1 mutation [Sirvente et al 2009]; however, skin findings are not reported in most studies and thus, this observation has yet to be confirmed [Author, personal observation].

CCM2 has fewer brain lesions on GRE MRI, and the rate of lesion development is slower than in CCM1 [Denier et al 2006].

CCM3 is most likely to present with hemorrhage and to have symptom onset before age 15 years [Denier et al 2006].

Penetrance

KRIT1. Denier et al [2004b] found that of individuals with a KRIT1 mutation:

  • 62% were symptomatic;
  • 58% of those who were at least age 50 years had symptoms related to CCM;
  • 45 of 53 symptom-free individuals had lesions on MRI (3 had indications of a type IV lesion; see Table 1) and five had no clinical or MRI findings of CCM.

    Note: SWI MRI, the most sensitive imaging technique for identifying CCMs, was not performed in this study.

CCM3. Denier et al found evidence that penetrance may be decreased in families with CCM3 compared with families with CCM1 [Denier et al 2006].

Penetrance may be mutation specific [Gianfrancesco et al 2007].

Anticipation

Anticipation has not been observed [Kuhn et al 2009].

Prevalence

CCMs occur in 0.4%-0.5% of the general population based on autopsy studies [Otten et al 1989, Del Curling et al 1991, Robinson et al 1991]. The fairly common occurrence of asymptomatic vascular lesions in individuals with FCCM suggests that the population incidence of FCCM has been routinely underestimated [Verlaan et al 2002a, Johnson et al 2004].

A particularly high incidence of FCCM in individuals of Mexican descent has been noted. In the state of New Mexico alone, thousands of cases are suspected with confirmation of at least 1300 [Morrison, personal observation]. Linkage studies revealed that familial and nonfamilial occurrences in this population could be attributed to inheritance of the same mutation from a common ancestor [Johnson et al 1995, Gunel et al 1996].

Differential Diagnosis

Hypertensive angiopathy, trauma, multiple hemorrhagic metastases, amyloid angiopathy (with lacunar stroke), and pneumocephalus [Palma et al 2009] are in the differential diagnosis for CCM because they may have similar findings on brain imaging.

Of all cerebral vascular malformations, CCMs represent 5%-15% [Rigamonti et al 1988]. Other vascular malformations occurring in the brain that should be distinguishable from CCM by neuroimaging and clinical manifestations include arteriovenous malformations, venous malformations, telangiectases, vascular tumors such as hemangioblastomas (including those seen in Von Hippel-Lindau syndrome), and the vascular malformations of Sturge-Weber disorder [Mohr & Pile-Spellman 2005].

Cavernous malformations may result from a germline mutation in one of the genes known to be associated with familial CCM or may be of unknown cause. The presence of multiple CCMs is diagnostic of the familial form of CCM; however, the presence of only a single lesion can be seen in individuals with familial (genetic) CCM as well as in individuals with a sporadic (non-genetic) CCM. In addition to molecular genetic testing, another possible way to distinguish between a single CCM in a simplex case that is genetic and one that is sporadic (non-genetic) is to determine if other brain vascular malformations are present, especially developmental venous anomalies (DVA). An association of CCM and DVA (an apparent combined vascular lesion) was observed in eight (44%) of 18 simplex cases and only one of 81 familial cases in which a total of 2176 CCMs were observed [Petersen et al 2010].

Radiation to the central nervous system is associated with de novo lesion formation in both FCCM and the sporadic forms of disease [Larson et al 1998, Nimjee et al 2006].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with FCCM, the following evaluations are recommended:

  • MRI imaging of the brain and/or spinal cord if they have not yet been imaged.
  • Detailed family history with emphasis on stroke and epilepsy.
  • Genetic consultation

Treatment of Manifestations

Persons with epilepsy secondary to CCM may require evaluation with an electoencephalogram (EEG), video-EEG, and/or other tests such as Wada testing (to determine which hemisphere is language dominant) and/or magnetoencephalography to confirm the localization of the epilepsy and to exclude other lesions that may be epileptogenic.

Neuropsychological testing is a common part of the evaluation of patients with epilepsy requiring a neurosurgical procedure.

Surgical removal of lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect [Heros & Heros 2000, Selman et al 2000, Folkersma & Mooij 2001]. Microsurgical techniques rely upon intraoperative examination for precise localization. Thirteen individuals, seven with seizures and six with progressive focal neurologic deficits, improved postoperatively; none required reoperation [Folkersma & Mooij 2001]. Even when a large number of lesions are present, a surgical approach may be justified.

Gamma knife surgery or radiosurgery, while effective, appears to increase risk of recurrent hemorrhage and remains unproven [Wang et al 2010, Steiner et al 2010]. Very large single lesions can be difficult to ablate, especially in the brain stem. In these instances, radiotherapy may be an option [Monaco et al 2010].

Other

  • Treatment of seizures
  • Treatment and management of headaches
  • Rehabilitation for those with temporary or permanent neurologic deficits

Surveillance

MRI is indicated in individuals experiencing new neurologic symptoms. Interpretation can be difficult because new hemorrhages may be asymptomatic.

Agents/Circumstances to Avoid

Limited evidence suggests an increased risk of hemorrhage with certain analgesic medications such as nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) and aspirin. Individuals with headaches and other pain should avoid these medications if suitable substitutes are available.

Other medications that increase risk of hemorrhage (e.g., heparin, sodium warfarin [Coumadin®]) should be avoided or, when such medications are necessary for treatment of life-threatening thrombosis, should be closely monitored by the patient’s medical team.

The use of narcotic pain medications is also discouraged in chronic pain conditions because of the potential for addiction and because of their association with rebound headaches.

Evaluation of Relatives at Risk

Symptomatic relatives may undergo periodic brain MRI to determine presence, size, and location of lesions, regardless of molecular genetic confirmation. The exact frequency of repeat MRIs has not been established but many authors suggest every one to two years. Since many new lesions are asymptomatic these repeat MRIs can been psychologically unsettling to patients and some authors advise repeat MRI only with new symptoms.

Asymptomatic at-risk relatives of all ages may be evaluated by molecular genetic testing (if the family-specific mutation is known) to allow early diagnosis and monitoring of those at high risk of developing disease manifestations.

Asymptomatic family members (including parents and offspring of a proband) who have been identified by MRI as having lesions consistent with CCM or by molecular genetic testing as having the family-specific mutation may be evaluated with repeat MRI in special circumstances [Sürücü et al 2006].

Note: Although it has been recommended that asymptomatic adults and children who are known to have the family-specific disease-causing mutation or who are at risk for CCM based on family history undergo surveillance with MRI examination at regular intervals based on the observation that new lesions form over time [Kattapong et al 1995], asymptomatic lesions are rarely treated. Therefore, the clinical utility of such routine screening has yet to be determined.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Simvastatin is being studied in people with CCM who are eligible to take this medication for other indications such as hyperlipidemia.

Simvastatin [Whitehead et al 2009], fasudil [Stockton et al 2010], and sorafenib [Wüstehube et al 2010] have been investigated in murine models.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial cerebral cavernous malformation (FCCM) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with familial CCM have a symptomatic parent. However, the fairly common occurrence of asymptomatic vascular lesions may prevent recognition of an autosomal dominant pattern of inheritance in a family [Denier et al 2004b].
  • If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The proportion of cases caused by a de novo mutation is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic testing data are insufficient. Individuals with a de novo germline mutation have been reported [Lucas et al 2001, Denier et al 2004b, Liquori et al 2008, Stahl et al 2008].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing and/or brain MRI including GRE or SWI. Family history may help to determine which parent is most likely to require laboratory/diagnostic examination.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although many individuals diagnosed with CCM have a symptomatic parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance in the parent with the disease-causing mutation.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or to have the disease-causing mutation, the risk to sibs of inheriting the mutation is 50%.
  • If the disease-causing mutation cannot be detected in the DNA of the either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Since more than 5% of individuals with multiple lesions and /or a family history of CCMs do not have an identifiable mutation in any of the three genes known to be associated with FCCM, the assumption of a familial form must be made and sibs and parents offered high-quality brain MRI with GRE and/or SWI.

Offspring of a proband. Each child of an individual with CCM has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Angioma Alliance
    520 West 21st Street
    Suite G2-411
    Norfolk VA 23517-1950
    Phone: 866-432-5226 (toll-free); 757-623-0615
    Fax: 757-623-0616
    Email: info@angioma.org
  • National Library of Medicine Genetics Home Reference
  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org
  • International Cavernous Angioma Patient Registry
    This registry is developed and supported by Angioma Alliance.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Familial Cerebral Cavernous Malformation: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Familial Cerebral Cavernous Malformation (View All in OMIM)

116860CEREBRAL CAVERNOUS MALFORMATIONS; CCM
603284CEREBRAL CAVERNOUS MALFORMATIONS 2; CCM2
603285CEREBRAL CAVERNOUS MALFORMATIONS 3; CCM3
604214KREV INTERACTION TRAPPED 1; KRIT1
607929CCM2 GENE; CCM2
609118PROGRAMMED CELL DEATH 10; PDCD10

KRIT1

Gene structure. KRIT1 comprises 16 coding exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 100 loss-of-function mutations have been published to date [Cave-Riant et al 2002, Verlaan et al 2002a, Denier et al 2004a, Revencu & Vikkula 2006, Guarnieri et al 2007, Kuhn et al 2009]. Fifty percent are frameshifts, 24% are nonsense, 24% are changes in the invariant splice junctions. The mutations are evenly distributed across the entire gene, without any mutational hotspots. CCM cohorts who had no detectable KRIT1 mutation by sequence analysis had (multi)exonic deletions at a frequency of 5% in the US vs 50% in Italy [Liquori et al 2008].

Two founder mutations have been identified:

  • c.1363C>T, p.Gln455Ter, referred to as the "common Hispanic mutation," was identified in about 70% of affected families of Hispanic heritage (16/21 individuals) [Sahoo et al 1999].
  • c.Cys329Ter, a founder KRIT mutation, was identified in four families in Sardinia [Cau et al 2009].

Consistent with the loss-of-function allelic series of mutations, four missense mutations activate cryptic splice sites with aberrant splicing of KRIT1 mRNA and frameshift with a premature stop codon [Sahoo et al 1999, Verlaan et al 2002b, Riant et al 2010].

Normal gene product. The KRIT1 protein is 736 amino acids in length. KRIT1 has a variety of functions within the vascular system and throughout the body. This protein has been demonstrated to have roles in regulating cell structure through the integrin signaling pathway [Zawistowski et al 2002], maintaining homeostasis of intracellular reactive oxygen species [Goitre et al 2010], and the worm ortholog of KRIT1 is involved in non-automomous cell death [Ito et al 2010]. Within human endothelium, recent biochemical studies with KRIT1 have shown it to be a RAP1 effector that regulates endothelial cell-cell junctions [Glading et al 2007, Borikova et al 2010]. Through this function, KRIT1 is an essential component to maintaining endothelial junctional stability. Additionally, recent evidence suggests that KRIT1 activates the DELTA-NOTCH signaling cascade to activate angiogenesis [Wüstehube et al 2010].

In a Krit1 murine knock out, Whitehead et al [2004] found ubiquitous expression in early embryogenesis and evidence for homozygous lethality. Their studies suggest that KRIT1 exerts its effect primarily in vascular tissue rather than in the supporting neuronal tissue. This was confirmed in further studies on somatic mosaicism [Gault et al 2005, Akers et al 2009, Gault et al 2009, Pagenstecher et al 2009].

Abnormal gene product. Mutations in this gene predict a premature termination of translation, which supports a loss-of-function mechanism [Verlaan et al 2002a].

CCM2

Gene structure. CCM2 has ten coding exons, with an alternatively spliced exon 1B. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The majority of CCM2 mutations predict inactivation of the gene or the protein product. A 77.6-kb deletion that includes exons 2-10 is a common founder mutation in the US population (see Table 2). CCM cohorts who had no detectable CCM2 mutation by sequence analysis had exon or multiexon deletions at a frequency of 95% in US vs 40% in Italy [Liquori et al 2008].

Normal gene product. Malcavernin (MGC4607), a protein with a PTB (phospho-tyrosine binding) domain is utilized to bind to and regulate the localization of KRIT1. The CCM2 protein malcavernin functions as a scaffold protein for multiple signaling cascades including the p38 mitogen activated protein kinase (MAPK) signaling [Uhlik et al 2003] and is an essential component for Rho Kinase signaling for maintenance of proper vascular integrity [Whitehead et al 2009, Borikova et al 2010, Stockton et al 2010].

Abnormal gene product. Mutations in CCM2 result, or predict, loss of function. Animal models and molecular studies support the mode of action for CCM2 mutations to follow a two-hit genetic mechanism [Akers et al 2009, Pagenstecher et al 2009, Whitehead et al 2009].

PDCD10

Gene structure. PDCD10 has ten exons; the coding region starts with exon 4. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Bergametti et al [2005] originally described seven distinct mutations in eight families: one deletion of the entire gene, one abnormal splicing of exon 5, three nonsense mutations, and two splice-site mutations. Consistent with this allelic series, all other identified PDCD10 mutations result in, or predict, loss of function alleles. CCM cohorts who had no detectable PDCD10 mutation by sequence analysis had exonic or multiexonic deletions at a frequency of 0% in the US vs 10% in Italy [Liquori et al 2008].

Normal gene product. The gene encodes a 212-amino acid protein, programmed cell death 10 (PDCD10), with no known functional domains. PDCD10 is reported to increase expression in a human myeloid cell line while undergoing apoptosis [Wang et al 1999]. While the precise function of CCM3 remains elusive, it has been shown that the PDCD10 protein is also part of the macromolecular complex including KRIT1 and malcavernin [Hilder et al 2007, Voss et al 2007]. Additionally, recent studies have corroborated the role of PDCD10 in apoptosis, as cell culture studies show that PDCD10 overexpression leads to activation of caspase 3 and increased cell death [Guclu et al 2005]. PDCD10 plays a critical role in vascular development through the stabilization of VEGF signaling [He et al 2010]. The function of PDCD10 is also required for cell orientation and migration as the protein has also been identified as part of a larger protein complex that includes the germinal center kinase III (GSKIII) family of kinases [Fidalgo et al 2010].

Abnormal gene product. The nature of the mutations detected to date suggests a role for haploinsufficiency or somatic loss of heterozygosity [Akers et al 2009, Pagenstecher et al 2009].

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Chapter Notes

Author Notes

NIH Funding- 454RD

Scientific Advisory Board, Angioma Alliance

Author History

Amy Akers, PhD (2011-present)
Leslie Morrison, MD (2011-present)
Eric W Johnson, PhD; Barrow Neurological Institute (2003-2011)

Revision History

  • 31 May 2011 (me) Comprehensive update posted live
  • 13 July 2006 (ej) Revision: additional information on CCM4; prenatal testing available for KRIT1, CCM2, and PDCD10
  • 31 May 2005 (me) Comprehensive update posted to live Web site
  • 1 September 2004 (ej) Revision: change in testing
  • 18 March 2004 (ej) Revision: identification of CCM2 gene
  • 24 February 2003 (me) Review posted to live Web site
  • 5 February 2002 (ej) Original submission
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