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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

Initial Posting: ; Last Update: August 4, 2016.

Summary

Clinical 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 FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%.

Diagnosis/testing.

The diagnosis of familial cerebral cavernous malformation (FCCM) is established in a proband with either or both of the following:

Management.

Treatment of manifestations: Surgical removal of lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect may be considered. Treatment of seizures and epilepsy is symptomatic. Headaches are managed symptomatically and prophylactically. Acute and chronic neurologic deficits may be managed through rehabilitation.

Surveillance: Brain MRI imaging with gradient echo (GRE) or susceptibility-weighted imaging (SWI) is indicated in individuals experiencing new neurologic symptoms.

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. Radiation to the central nervous system may lead to new lesion formation.

Evaluation of relatives at risk: Asymptomatic at-risk relatives of all ages may be evaluated by molecular genetic testing (if the family-specific pathogenic variant 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.

Pregnancy management: Baseline MRI one year prior to delivery is recommended to determine lesion locations; pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine require closer monitoring during pregnancy; individulas with FCCM are at a higher risk for symptomatic cerebral hemorrhage during pregnancy than those with sporadic CCM; seizure is the most common symptom of CCM hemorrhage during pregnancy; exposure to antiepileptic medication during pregnancy may increase the risk for adverse fetal outcome but is generally recommended because the fetal risk is typically less than that associated with fetal exposure to an untreated maternal seizure disorder.

Genetic counseling.

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

Diagnosis

Suggestive Findings

Familial cerebral cavernous malformation (FCCM) should be suspected in individuals with the following clinical findings, brain imaging, histopathology, and family history.

Clinical findings

  • Seizure disorder with onset at any age, but most typically between the second and fifth decades
  • Focal neurologic deficits
  • Nonspecific headaches
  • Cerebral hemorrhage
  • Vascular skin lesions (capillary malformations, hyperkeratotic cutaneous capillary venous malformations, venous malformations, red macules, and/or nodular venous malformations)
  • Retinal cavernomas and rare choroidal hemangiomas

Brain imaging. Brain MRI using either gradient echo (GRE) or susceptibility-weighted imaging (SWI) demonstrating one or more cerebral cavernous malformations [Bulut et al 2014]:

Note: Intravenous gadolinium contrast administration is not needed for identification of cavernous malformations, but is useful in identifying complex vascular malformations with arterial and venous components (which on rare occasion are associated with CCMs) and other types of vascular brain malformations including telangiectasias, arteriovenous malformations, and aneurysms.

Histopathology

  • Closely clustered enlarged capillary channels (caverns) ranging from two to 55 mm (mean: 8 mm) with a single layer of endothelium without normal mature vessel wall elements or intervening brain parenchyma
  • Thrombosis and intra- and extralesional hemorrhage. Edema may surround lesions with recent hemorrhage.

Family history. Two or more family members (including the proband) with cerebral cavernous malformations (CCM). 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 (FCCM).

Establishing the Diagnosis

The diagnosis of familial cerebral cavernous malformation (FCCM) is established in a proband with either or both of the following:

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and genomic testing.

Serial single-gene testing. Sequence analysis of KRIT1, CCM2, and PDCD10 is performed first (either sequentially or concurrently) followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

Several founder pathogenic variants that are useful for stratifying genetic testing in specific populations have been identified:

A multi-gene panel that includes KRIT1, CCM2, and PDCD10 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

Table 1.

Molecular Genetic Testing Used in Familial Cerebral Cavernous Malformation

Gene 1Proportion of FCCM Attributed to Pathogenic Variants in This Gene 2Proportion of Pathogenic Variants 3 Detected by Test Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
KRIT153%-65%85%-95% 65%-15% 6
CCM220%40%-70% 630%-60% 6, 7
PDCD1010%-16%80%-90% 60%-10% 6
Unknown 8NA
1.
2.

Following stringent inclusion criteria for familial CCM (multiple lesions and/or family history), a causative heterozygous pathogenic variant in either KRIT1, CCM2, or PDCD10 is detected in at least 75% of affected families [Denier et al 2006, Liquori et al 2007, D’Angelo et al 2011, Riant et al 2013, Spiegler et al 2014], with some authors reporting 97% detection rates [Cigoli et al 2014].

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Pathogenic alleles detected by Riant et al [2013] by gene and methodology: KRIT: 68/80 alleles by sequencing and 12/80 alleles by del/dup; CCM2: 16/23 alleles by sequencing and 7/23 alleles by del/dup; PDCD10: 16/19 by sequencing and 3/19 alleles by del/dup. Pathogenic alleles detected by Liquori et al [2007] by gene and methodology: KRIT: 23/24 alleles by sequencing and 1/24 alleles by del/dup; CCM2: 10/24 alleles by sequencing and 14/24 alleles by del/dup; PDCD10: 4/4 by sequencing and 0/24 alleles by del/dup.

7.

Variability in the detection rate of deletion/duplication testing results from the high prevalence of a founder CCM2 deletion (exons 2-10) in the US. This deletion was rare in an Italian population [Liquori et al 2007, Liquori et al 2008].

8.

Based on exclusion of a PDCD10 (CCM3 locus) pathogenic variant in a large family whose phenotype is linked to the CCM3 locus but not to the CCM1 (KRIT1) or CCM2 (CCM2) loci, Liquori et al [2006] proposed a putative CCM4 locus at 3q26.3-q27.2. However, with high rates of pathogenic variant detection in affected individuals the existence of a CCM4 locus is unlikely.

Clinical Characteristics

Clinical Description

Neurologic findings. In familial CCM, up to 50% of individuals with a heterozygous pathogenic variant in either KRIT1, CCM2, or PDCD10 are clinically asymptomatic, although at least half of these individuals have identifiable CCM lesions on head imaging [Battistini et al 2007, Fischer et al 2013]. However, based on CCMs ascertained on autopsy, approximately 90% of individuals with either sporadic CCM or FCCM were asymptomatic [Otten et al 1989].

Cerebral cavernous malformation (CCM) has been reported in infants and children, but the majority of individuals with FCCM 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]. A more recent study of affected individuals found that 20% were younger than age ten years and 33% younger than age 18 years at the time of referral for genetic testing; the age of symptom onset was not cited [Spiegler et al 2014].

Clinically affected individuals most often present with seizures (40%-70%), focal neurologic deficits (35%-50%), nonspecific headaches (10%-30%), and cerebral hemorrhage (32%) [Denier et al 2004b]. Five percent of individuals with intractable temporal lobe epilepsy have CCM [Spencer et al 1984], although it is unknown how many of these individuals have FCCM.

Central nervous system hemorrhages may be intralesional or extend beyond the lesion [Al-Shahi Salman et al 2008]. In children, hemorrhage and an aggressive presentation were thought to be more likely than in adults [Lee et al 2008]; however, Al-Holou et al [2012] evaluated hemorrhage risk in affected individuals younger than age 25 years and found that it was similar to the rates in adults. In general, symptom onset in children with FCCM is earlier than 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].

Brain MRI. Either gradient echo (GRE) or susceptibility-weighted imaging (SWI) is the imaging modality of choice. While larger, complex lesions are visible on routine T1- and T2- weighted MRI sequences, GRE MRI sequences reveal up to triple the number of lesions and SWI MRI sequences reveal 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].

Four characteristic types of lesions have been described [Zabramski et al 1994] by MRI and histology (see Table 2). Dividing CCM into these radiologic and histologic types is clinically useful in predicting hemorrhage risk [Nikoubashman et al 2015].

Table 2.

Classification of CCM by MRI and Histopathology

LesionMR SignalHistopathologyClinical Correlation
Type 1
  • SE T1: hyperintense core
  • SE T2: hyperintense core or hypointense core
Subacute hemorrhageAcute hemorrhage; high frequency of bleeding relapse
Type 2
  • SE T1: reticulated mixed signal core
  • SE T2: reticulated mixed signal core w/surrounding hypointense rim
Lesions w/hemorrhages & thromboses of varying ages
Type 3
  • SE T1: iso- or hypointensity
  • SE T2: hypointense lesion w/hypointense rim magnifying size of lesion
Chronic hemorrhage w/hemosiderin staining in & around lesion
Type 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

Specific MRI sequences and programs:

SE = spin echo MRI

GRE = gradient echo MRI

SWI = susceptibility-weighted imaging MRI

The medical significance of small lesions (classified as type 4) seen on MRI (sometimes referred to as cerebral dot-like cavernomas or black spot lesions) is unclear. For these lesions, a mean bleeding rate of 0.7% per lesion–year was found over a period of 5.5 years in 18 children with either an inherited or a de novo heterozygous pathogenic variant in KRIT1 or PDCD10. Of the ten inidividuals who had hemorrhages, only two were symptomatic [Nikoubashman et al 2013, Nikoubashman et al 2015].

FCCM is a dynamic disease on neuroimaging studies. 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. In both FCCM and sporadic CCM lesions may change in size and signal characteristics over time.

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 heterozygous KRIT1 pathogenic variant, Denier et al [2004b] found that 26 (20%) appeared to have only one lesion when evaluated with T2-weighted MRI sequences. Further examination with 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 heterozygous KRIT1 pathogenic variant 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. Since lesions are more readily identifiable using SWI, the number of clinically asymptomatic affected individuals is likely to increase as longitudinal studies using SWI are published.

Some studies have identified an increasing number of lesions in families by generation: five to 12 lesions in children and adolescents; 20 lesions in parents; and more than 100 lesions in grandparents [Horowitz & Kondziolka 1995]. This is likely related to ascertainment bias; it has not been borne out by subsequent studies.

Brunereau et al [2000] and Labauge et al [2001] determined that in familial CCM 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].

Spinal cord lesions are considered rare, reportedly occurring in fewer than 5% of affected individuals [Deutsch et al 2000, Badhiwala et al 2014]. In one large family with a known heterozygous KRIT1 pathogenic variant, spinal cavernous angiomas, either alone or associated with vertebral hemangiomas, were found in five of eight individuals studied using spinal MRI [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; however, multiplicity of spinal cord cavernous malformations are strongly suggestive of FCCM.

Other. Vascular lesions found outside of the central nervous system have been reported in association with multiple intracranial cavernomas (cavernous malformations) with and without confirmed heterozygous pathogenic variants in KRIT1, CCM2, or PDCD10.

Phenotype Correlations by Gene

The clinical course of FCCM varies within and between families; therefore, the following are generalizations.

KRIT1. Individuals with a heterozygous pathogenic variant in KRIT1 may have a less severe clinical phenotype than those with a heterozygous pathogenic variant in either CCM2 or PDCD10 [Gault et al 2006].

CCM2. Individuals with a heterozygous pathogenic variant in CCM2 have fewer brain lesions on GRE MRI, and the rate of lesion development is slower than in individuals with a heterozygous pathogenic variant in KRIT1 [Denier et al 2006].

PDCD10. Individuals with a heterozygous pathogenic variant in PDCD10 are most likely to present with hemorrhage and to have symptom onset before age 15 years [Denier et al 2006, Shenkar et al 2015].

  • Individuals with pathogenic variants in this gene generally have the most severe clinical phenotype [Riant et al 2013, Shenkar et al 2015], including a higher risk of the following:
    • Lesion burden
    • Skin lesions
    • Scoliosis
    • Brain tumors (meningioma, astrycytoma, acoustic neuroma)
    • Cognitive disability unrelated to lesion burden or hemorrhage

Penetrance

KRIT1. Among 64 families with 202 individuals who were heterozygous for a KRIT1 pathogenic variant [Denier et al 2004b]:

  • 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 4 lesion; see Table 2) 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.

PDCD10. Penetrance may be decreased in families with a heterozygous pathogenic variant in PDCD10 compared to families with a heterozygous pathogenic variant in KRIT1 [Denier et al 2006]. Penetrance may be specific to the pathogenic variant [Gianfrancesco et al 2007].

Prevalence

Based on autopsy studies, approximately 0.4%-0.5% of the general population have either sporadic CCM or FCCM [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].

There is a high incidence of FCCM in individuals of Mexican descent who have the pathogenic p.Gln455Ter variant in KRIT1 – a finding that could be attributable to inheritance from a common ancestor [Johnson et al 1995, Gunel et al 1996].

Differential Diagnosis

CCMs represent 5%-15% of all cerebral vascular malformations [Rigamonti et al 1988]. Other vascular malformations occurring in the brain that should be distinguishable from CCM by neuroimaging and clinical manifestations:

The finding of developmental venous anomalies (DVA) in association with CCM decreases the likelihood that an individual has FCCM [Petersen et al 2010].

The following acquired conditions may lead to brain imaging findings similar to those seen in individuals with CCM:

  • Hypertensive angiopathy
  • Trauma
  • Multiple hemorrhagic metastases
  • Myloid angiopathy (with lacunar stroke)
  • Pneumocephalus [Palma et al 2009]
  • Cysticercosis

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with familial cerebral cavernous malformation (FCCM), the following evaluations are recommended:

  • MRI imaging of the brain and/or spinal cord if not already performed
    • Cerebral angiography may be considered to better define a complex lesion with arterial or venous components identified on brain MRI; however, caution should be used as cerebral angiography carries a small but appreciable risk of stroke.
  • In those with epilepsy:
    • Electoencephalogram (EEG) and/or video-EEG
    • Wada testing (to determine which hemisphere is language dominant)
    • Magnetoencephalography to confirm the localization of the epilepsy and to exclude other epileptogenic lesions
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Recurrent hemorrhage or mass effect. Surgical removal of lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect has traditionally been recommended [Heros & Heros 2000, Selman et al 2000, Folkersma & Mooij 2001]; however, a recent large prospective study in Scotland reported that surgical excision increased the overall risk of short-term neurologic disability, symptomatic intracranial hemorrhage, and new focal neurosurgical deficits [Moultrie et al 2014], calling this practice into question.

  • Neuropsychological testing may be considered prior to any neurosurgical procedure.
  • Microsurgical techniques rely on intraoperative examination for precise localization.
  • 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 the 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, radiosurgery may be an option [Monaco et al 2010].

  • In a group of individuals with symptomatic cavernous malformations studied in Japan, radiosurgery using varying doses of radiation for deep lesions was compared with conservative (nonsurgical) management. Doses less than 15 Gray (Gy) were associated with the lowest level of complications. Complications were also lower when the lesions were of smaller size, with overall hemorrhage rates reduced initially but reverting to a rate similar to that of the natural history after the first two years post-radiosurgery [Kida et al 2015].
  • A study that carefully reviewed post-radiosurgery changes in individuals with CCM or AVM found that more than 30% developed radiation necrosis [Blamek et al 2010].

Seizures. Standard treatment for focal seizures using antiepileptic medication with early evaluation for surgical resection is appropriate (see Recurrent hemorrhage or mass effect).

Headaches. Standard treatment and management of headaches is indicated unless the headache is severe, prolonged, or progressive, or associated with new or worsening neurologic deficits. In this circumstance, urgent brain imaging could lead to surgical management.

Neurologic deficits. Rehabilitation is indicated for those with temporary or permanent neurologic deficits.

Surveillance

Brain MRI imaging with GRE or SWI 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 affected individual’s medical team [Schneble et al 2012, Flemming et al 2013, Erdur et al 2014].

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.

Radiation to the central nervous system is associated with de novo lesion formation in FCCM [Larson et al 1998, Nimjee et al 2006, Golden et al 2015]. The pathology of these lesions appears to be histologically different from the cavernomas found prior to radiation [Cha et al 2015].

Evaluation of Relatives at Risk

It is appropriate to evaluate both symptomatic and apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of screening and preventive measures.

Evaluations can include:

  • Molecular genetic testing if the pathogenic variant in the family is known.
  • Brain and/or spinal cord MRI imaging including GRE or SWI if the pathogenic variant in the family is not known

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

Pregnancy Management

Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine will require closer observation during pregnancy. Baseline MRI one year prior to delivery is recommended to determine lesion locations [De Jong et al 2012, Witiw et al 2012, Yamada et al 2013].

Simonazzi et al [2014] reported six women with CCM who had symptoms such as seizure or focal neurologic deficit during pregnancy or within six weeks post-delivery. Reviewing the literature they found ten further cases in which pregnancy outcome was published. Of the 16 women, hemorrhage occured in ten. Preterm delivery occurred in four of six cases, one because of neurologic symptoms at 30 weeks. Cæsarean (C-)section was performed in nine cases, eight of which were for concern over CCM.

Affected women and obstetricians are frequently concerned that the risk of increased blood pressure and intrathoracic pressure during stage 3 labor (pushing phase) could lead to CCM hemorrhage. However, in a study of 168 pregnancies (64 women), 28 with sporadic CCM and 36 with FCCM, only five symptomatic cerebral hemorrhages were reported, most commonly manifesting as seizures. Nineteen deliveries in this study were by C-section, mostly due to fear of possible intracranial hemorrhage. The risk of CCM hemorrhage was higher in the familial cases (3.6% compared with 1.8% in sporadic cases) [Kalani & Zabramski 2013].

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

To access further information on medication use during pregnancy, visit MotherToBaby.

Therapies Under Investigation

Recent advances in the understanding of the pathobiology and molecular signaling of the CCM proteins (see Molecular Genetics) has identified several pathways which may be amenable to drug targeting. These are being investigation in in vitro assays and in live animal models.

Fasudil, a specific Rho kinase inhibitor, has been demonstrated in Krit1(+/-) and Ccm2 (+/-) mouse models of FCCM to reduce both lesion size and number, as well as to lesson hemorrhage, proliferation, and inflammation [Stockton et al 2010, McDonald et al 2012]. Fasudil is approved in Japan for treatment of vasodilation; it is not currently available with FDA approval in the United States.

Statin medications are nonspecific Rho kinase inhibitors and may be suitable for repurposing to treat CCM lesions. Strong in vitro data [Whitehead et al 2009] led to simvastatin being studied in people with CCM who are eligible to take this medication for other indications such as hyperlipidemia. This trial is in the final data collection and analysis phase (ClinicalTrials.gov identifier: NCT01764451). However, a Ccm2 knockout mouse model treated with simvastatin did not show a significant decrease in lesion burden, raising questions about dosing and efficacy of statin drug therapy [Gibson et al 2015]. A further proof-of-concept human trial is planned for atorvastatin therapy (ClinicalTrials.gov identifier: NCT02603328).

The chemotherapeutic drug sorafenib [Wüstehube et al 2010] has been investigated in murine models of FCCM caused by mutation of KRIT1 with the finding of reduced capillary sprouting.

Loss of function of KRIT1 leads to an increase in signaling of the TGFβ pathway leading to an inappropriate endothelial-to-mesenchymal cellular transition (EndMT): endothelial cells change to become more proliferative, with increased invasiveness and sprouting. Chemical inhibition of TGFβ decreases both the size and number of CCM lesions in mouse models [Maddaluno et al 2013]. Furthermore, inhibition of upstream Wnt/B-Catenin signaling related to EndMT with the drug sulindac restores junctional integrity between endothelia, and also reduces number and size of CCM lesions in a Pdcd10 knockout mouse model [Bravi et al 2015]. Sulindac is used clinically in humans for other indications, including for the treatment of colon cancer.

A repurposing drug screen identified vitamin D3 (cholecalciferol) and tempol (a superoxide scavenger) as potential therapeutic drugs for CCM. Both of these molecules reduced lesion number in mouse models of CCM [Gibson et al 2015]. Vitamin D3 inhibits the signaling activation of RHOA, while tempol targets superoxide, suggesting a role for oxidative stress in CCM disease pathogenesis.

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].
  • A proband with FCCM may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant 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 pathogenic variant – most commmonly in PDCD10 – have been reported [Lucas et al 2001, Denier et al 2004b, Liquori et al 2008, Stahl et al 2008, Shenkar et al 2015].
  • If the pathogenic variant 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 pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant 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.
  • The family history of some individuals diagnosed with FCCM 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 pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (i.e., molecular genetic testing if the pathogenic variant has been identified in the proband and/or brain MRI including GRE or SWI) has been performed on the parents of the proband.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the proband's parents:
    • If a parent of the proband is affected or has the pathogenic variant with no clinical symptoms, the risk to each sib of inheriting the pathogenic variant is 50%.
    • If the KRIT1, CCM2, or PDCD10 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of 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 pathogenic variant 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 brain MRI with GRE and/or SWI.

Offspring of a proband. Each child of an individual with FCCM has a 50% chance of inheriting the pathogenic variant.

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 pathogenic variant, his or her family members may be 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 pathogenic variant. When neither parent of a proband with FCCM has the pathogenic variant or clinical evidence of the disorder, the KRIT1, CCM2, or PDCD10 pathogenic variant is likely de novo. However, other 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 (see angiomaalliance.org).

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the KRIT1, CCM2, or PDCD10 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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

Overview

A single inherited pathogenic variant in one of three genes – KRIT1 (CCM1), CCM2, or PDCD10 (CCM3) – is sufficient to cause familial cerebral cavernous malformation (FCCM); however, the precise molecular mechanisms that leads to the formation of CCM lesions remains unclear. It is known that the proteins encoded by these genes are essential for blood vessel growth and development. Additionally, these molecules serve a variety of roles within cells related to maintaining proper cellular shape, integrity, and behavior. A better understanding of the function of these genes has identified and will continue to identify druggable pathways that can be targeted for clinical research. Several promising drug candidates are currently under investigation in mice.

KRIT1

Gene structure. KRIT1, previously known as CCM1, comprises 16 coding exons. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic allelic variants. More than 100 pathogenic variants that predict loss of function have been published to date [Cavé-Riant et al 2002, Verlaan et al 2002a, Denier et al 2004a, Revencu & Vikkula 2006, Guarnieri et al 2007, Kuhn et al 2009, Riant et al 2013]; 50% are frameshifts, 24% are nonsense, and 24% are changes in the invariant splice junctions. The pathogenic variants are evenly distributed across the entire gene, with no evidence of hot spots.

CCM cohorts who had no detectable KRIT1, CCM2, or PDCD10 pathogenic variant by sequence analysis had (multi)exonic deletions of KRIT1 at a frequency of 5% in the US, 4% in France, and 50% in Italy [Liquori et al 2008, Riant et al 2013].

Two founder pathogenic variants have been identified:

  • p.Gln455Ter, referred to as the "common Hispanic variant," was identified in about 70% of affected families of Hispanic heritage descending from the original settlers of the American southwest (16/21 individuals) [Sahoo et al 1999].
  • p.Cys329Ter was identified in four families in Sardinia [Cau et al 2009].

Consistent with loss-of-function pathogenic variants, four pathogenic missense variants 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].

Table 3.

KRIT1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.987C>Ap.Cys329TerNM_194456​.1
NP_919438​.1
c.1363C>Tp.Gln455Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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 anchor protein has been demonstrated to have a role in regulating cell structure and responding to shear stress through the integrin signaling pathway [Zawistowski et al 2002, Macek Jilkova et al 2014], maintaining homeostasis of intracellular reactive oxygen species [Goitre et al 2010, Goitre et al 2014], and regulating autophagy by activating the mTOR pathway [Marchi et al 2015].

Within human endothelium, KRIT1 regulates endothelial cell-cell junctions to maintain junctional stability and control of vascular permeability in response to inflammation [Glading et al 2007, Borikova et al 2010, Corr et al 2012]. KRIT1 can activate angiogenesis through Delta-Notch signaling [Wüstehube et al 2010, DiStefano et al 2014].

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

Loss of KRIT1 function leads to CCM lesion genesis. Loss of KRIT1 alters cellular signaling and changes cellular behavior. In the absence of KRIT1, endothelial cells become more stem cell-like, proliferative, and invasive [Maddaluno et al 2013].

Understanding pathways involved in KRIT1 signaling may lead to potentially druggable targets to develop therapeutics to prevent bleeding from and genesis of CCM lesions.

CCM2

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

Pathogenic allelic variants. The majority of CCM2 pathogenic variants predict inactivation of the gene or the protein product. Most pathogenic variants are single-base changes or small indels that are readily identifiable by sequence analysis. However, a 77.6-kb deletion that includes exons 2-10 is a common founder deletion in the US population (see Table 1, footnote 7) is not identifiable by sequence analysis.

Among affected individuals in whom no pathogenic variant was detected by sequence analysis of KRIT1, CCM2, and PDCD10, a CCM2 exon or multiexon deletion was detected in 95% of those in the US and in 40% of Italians [Liquori et al 2008].

Table 4.

CCM2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.30+5_30+6delGCinsTT--NM_031443​.3
NP_113631​.1
77.6-kb deletion--

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Cerebral cavernous malformations 2 protein, a protein with a PTB (phospho-tyrosine binding) domain encoded by CCM2, binds to and regulates the localization of KRIT1. Cerebral cavernous malformations 2 protein is a scaffold protein for multiple signaling cascades including the p38 mitogen-activated protein kinase (MAPK) signaling [Uhlik et al 2003, Fisher et al 2015] and Rho kinase signaling for maintenance of proper vascular integrity [Whitehead et al 2009, Borikova et al 2010, Stockton et al 2010].

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

PDCD10

Gene structure. PDCD10, formerly known as CCM3, has ten exons; the coding region starts with exon 4. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic allelic variants. Bergametti et al [2005] originally described seven distinct pathogenic variants in eight families: one deletion of the entire gene, one abnormal splicing of exon 5, three pathogenic nonsense variants, and two pathogenic splice site variants. Consistent with this allelic series, all other identified PDCD10 pathogenic variants result in or predict loss-of-function alleles. CCM cohorts that had no detectable KRTI1, CCM2, or PDCD10 pathogenic variant by sequence analysis had exon or multiexon deletions at a frequency of 0% in the US vs 10% in Italy [Liquori et al 2008].

Normal gene product. PDCD10 encodes a 212-amino acid adaptor protein, programmed cell death 10 (PDCD10), with no known functional domains. PDCD10 plays a role in apoptosis; PDCD10 overexpression leads to activation of caspase 3 and increased cell death [Wang et al 1999, Guclu et al 2005].

PDCD10 is involved in a wide variety of cellular signaling processes and has been shown to be part of the macromolecular complex including KRIT1 and cerebral cavernous malformations 2 protein [Hilder et al 2007, Voss et al 2007]. Within the vasculature, PDCD10 plays a critical role in vascular development (through VEGF signaling) and regulation of angiogenesis (through DLL4-Notch signaling) [He et al 2010, You et al 2013].

Abnormal gene product. The nature of the pathogenic variants detected to date (loss-of-function alleles) suggests a role for haploinsufficiency or somatic loss of heterozygosity [Akers et al 2009, Pagenstecher et al 2009].

References

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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

  • 4 August 2016 (ma) Comprehensive update posted live
  • 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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