Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: KRIT1, CCM2, PDCD10
Condition: Cerebral cavernous malformations 1, 2, and 3
GENEDISEASE PAIRS: KRIT1116860 CCM2603284 PDCD10603285
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The overall prevalence of all cerebral cavernous malformations (CCMs) has been estimated at 1/200 to 1/1,000 individuals. Familial CCM (FCCM) represents about 20% of all CCM cases with an estimated prevalence of 1/5,000 to 1/10,000. The fairly common occurrence of asymptomatic vascular lesions in individuals with FCCM suggests that the population incidence of FCCM has been routinely underestimated. A strong founder effect has been found in Hispanic-American families, resulting in a high incidence of FCCM.
1 2 3
Clinical Features
(Signs / symptoms)
FCCM is a vascular malformation disorder characterized by closely clustered irregular dilated capillaries (caverns) that can be asymptomatic or can cause variable neurological manifestations such as seizures, nonspecific headaches, progressive or transient focal neurologic deficits, and/or cerebral hemorrhages. The number of lesions can vary from none to hundreds, depending on age and the quality and type of brain imaging. The diameter of CCMs can range from a few millimeters to several centimeters. CCMs typically occur in the brain, but have also been reported in the spinal cord and outside of the central nervous system, including the skin, retina, and liver.
1 2 3
Natural History
(Important subgroups & survival / recovery)
FCCM is a dynamic disease, with CCM size increasing or decreasing over time and new lesions estimated to appear at a rate of 0.2 to 0.4 lesions per patient per year. Although CCMs have been reported in infants and children, the majority of cases become evident between the second and fifth decades. An estimated 50-60% of individuals with FCCM are clinically asymptomatic, although at least half of these individuals have identifiable CCM lesions on head imaging. Clinically affected individuals most often present with seizures (40%-70%), focal neurologic deficits (35%-50%), nonspecific headaches (10%-30%), and cerebral hemorrhage (32-41%). The hemorrhagic event rate is estimated at 2-5% per lesion per year and the new onset seizure rate is 2.4%. Functional outcome is mostly conditioned by the location of CCM, with brainstem and basal ganglia lesions having a worse prognosis. The long-term prognosis of FCCM is not well known, but an estimated 80% of cases have preserved autonomy. CCMs can lead to death from intracranial hemorrhage or from complications of surgery, particularly when found in the brainstem.
 
The clinical course can vary by genotype. Individuals with a pathogenic variant in PDCD10 in general have the most severe clinical phenotype and are most likely to present with hemorrhage and have symptom onset before age 15 years. While individuals with a heterozygous pathogenic variant in CCM2 typically have fewer brain lesions and slower lesion development compared to individuals with a pathogenic variant in KRIT1, some studies indicate that individuals with a heterozygous pathogenic variant in KRIT1 may have a less severe clinical phenotype than those with a pathogenic variant in CCM2.
1 2 3
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
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
 
• Consultation with a clinical geneticist and/or genetic counselor
 
• In those with epilepsy: electroencephalogram (EEG), Wada testing to determine which hemisphere is language dominant, and magnetoencephalography to confirm the localization of the epilepsy and to exclude other epileptogenic lesions. (Tier 4)
3
Guidelines for the treatment of CCMs do not distinguish between the surgical and medical treatment of sporadic CCMs and those due to germline mutations. In addition, seizures and headache due to CCM are treated with standard approaches.
4
• Surgical removal of CCMs has traditionally been indicated for lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect.
 
- A retrospective study reported clinical outcomes of neurosurgical intervention in 13 patients with CCMs (7 with epilepsy and 6 with focal neurological deficits; unspecified as sporadic or familial CCMs) with 1-6 years (mean=3.3 years) of follow-up. Patients with epilepsy had reduction in seizure frequency, with 4 becoming seizure-free. Patients with neurological deficits due to intracerebral hemorrhage (5 patients) or mass effect (1 patient) showed improvements with 2 making full recoveries. There was no mortality or morbidity resulting from the surgery, and no patients required re-operation during the follow-up period. There was no comparison group that received conservative management.
 
- A prospective, non-randomized, population-based study reported outcomes among 134 adults with CCM who underwent surgical or conservative management concluded that excision may worsen neurological outcomes. The 25 patients who underwent CCM excision were more likely to be younger and to present with symptomatic intracranial hemorrhage or focal neurologic deficit than those managed conservatively (non-surgically) (48% vs 26%). During 5 years of follow-up, surgical CCM excision was associated with worse neurological outcomes and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (HR=3.60, 95% CI: 1.29–10.03).
 
- A study reported outcomes in 298 symptomatic patients with CCM who had been treated with gamma knife surgery (mean time from presentation was 33 months with mean follow-up time of 68 months). Among those who presented with seizures (n=35) and had sufficient follow-up time (n=27), 48% were seizure free after treatment. Among those who had presented with hemorrhage (n=255), the hemorrhage rate went from 28.7% from the first symptomatic episode to radiosurgery to 4.8% after radiosurgery. New or recurrent bleeding occurred in 61 (24%) with 3 (1%) dying from rebleeding. Radiation-induced edema occurred in 7% of patients. Cases treated with doses below 15 Gy were associated with fewer complications as were smaller lesions. However it is unclear how this evidence applies to symptomatic or incidentally discovered lesions as the natural history between symptomatic and asymptomatic lesions are very different. Asymptomatic lesions have been associated with bleeding rates of 0.6% for individuals without a previous hemorrhage. (Tier 3)
3
• Certain medications (e.g., simvastatin, fasudil) can be used to stabilize CCM lesions by improving vascular integrity. Preventing progression of CCM lesions could be reached by using sorafenib. Trials on the use of these medications are ongoing. Current evidence is limited to in vitro data and animal models. (Tier 3)
2
• Standard treatment for focal seizures using antiepileptic medication with early evaluation for surgical resection is appropriate. (Tier 4)
3
• 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. (Tier 4)
3
There is no contraindication for pregnancy and normal delivery in patients with identified small lesions, without recent clinical signs of hemorrhage. Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine require closer monitoring during pregnancy. Baseline MRI one year prior to delivery is recommended to determine lesion locations. 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. One review of 16 women with symptomatic CCMs (number of familial cases not reported) reported that hemorrhage occurred in 10, 2 patients opted for pregnancy termination, preterm delivery occurred in 4 cases with 1 case due to neurological symptoms at 30 weeks' gestation, and 9 women had a Caesarean section with a concern over CCM as the indication in 8 of these cases. 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 5 symptomatic cerebral hemorrhages were reported, most commonly manifesting as seizures. Nineteen deliveries in this study were by Caesarean 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). (Tier 3)
3
Surveillance
Regular check-ups, generally with an MRI once a year, are recommended after the discovery of a CCM, as additional asymptomatic lesions may appear with time. (Tier 4)
1 3
MRI is recommended in individuals experiencing new neurologic symptoms; however, interpretation can be difficult because new hemorrhages may be asymptomatic. (Tier 4)
3
Family Management
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 and brain and/or spinal cord MRI imaging if the pathogenic variant in the family is not known. (Tier 4)
3
Circumstances to Avoid
Patients should avoid agents that increase risk of hemorrhage; however, evidence cited for this recommendation indicates that these agents likely do not precipitate hemorrhage on patients with known CCMs. This recommendation includes 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. One prospective study of 16 patients with CCMs, with no history of CCM hemorrhage, and taking antithrombotic therapy for the treatment of concurrent cardiovascular disease, including 5 taking warfarin and 11 using antiplatelet therapy by either aspirin (n=9) or clopidogrel (n=2), reported that none had a CCM hemorrhage during follow-up (mean period of 3.9 years). In a separate study, 40 patients with CCMs, 5 who presented with hemorrhage, were placed on antiplatelets alone (n=32), anticoagulants alone (n=6), or both (n=2) for the treatment of cardiovascular disease. One patient developed a prospective hemorrhage over the 258 person-years of follow-up (prospective hemorrhage rate 0.41% per person-year). Within a hospital thrombolysis registry, 1 of 9 patients with CCM versus 11 of 341 without CCM had a symptomatic intracerebral hemorrhage (p=0.27). Parenchymal hemorrhage occurred in 2 of the 9 patients with CCM versus 27 of 341 patients without CCM (p=0.17). (Tier 3)
2 3
Radiation to the central nervous system is associated with de novo lesion formation in FCCM. The pathology of these lesions appears to be histologically different from the cavernomas found prior to radiation. A case study of 2 patients with FCCM reported that, following therapeutic radiation, both patients developed very high numbers of CCMs within the radiation ports, supporting radiation as an accelerator of lesion formation and suggesting implications for risks of radiation in this disease. (Tier 3)
3
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
The exact prevalence of pathogenic variants that lead to FCCM is unknown, though 40%-65% of cases of FCCM are attributable to pathogenic variants in KRIT1, 15-20% of cases are attributable to CCM2, and approximately 10-40% are attributable to PDCD10. (Tier 4)
2 3
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
It is estimated that up to 50% of persons with FCCM caused by a heterozygous pathogenic variant in KRIT1, CCM2, or PDCD10 are clinically asymptomatic, although at least least half of these asymptomatic individuals having identifiable CCM lesions on head imaging. (Tier 3)
3
One study of 64 probands and 138 relatives (mean age 42 years) who were heterozygous for a KRIT1 pathogenic variant reported a mean age of clinical onset of 30 years. Of all 202 individuals, 62% were symptomatic with the most common presenting events being seizure (55%) and cerebral hemorrhage (32%). Among the 138 non-proband relatives, 62 (45%) were asymptomatic; however, upon imaging 85% of asymptomatic relatives who underwent MRI were found to have CCM lesions. In all, 58% of those who were at least age 50 years had symptoms related to CCM. (Tier 3)
3
Vascular skin lesions have been reported in 9% of individuals with a heterozygous pathogenic variant in KRIT1. (Tier 3)
3
Spinal cord lesions are considered rare, reportedly occurring in fewer than 5% of affected
 
Individuals. (Tier 3)
3
Retinal vascular lesions have been reported in 5% of FCCM individuals. (Tier 3)
3
Information on relative risk was not available.
 
 
Expressivity
The clinical course of FCCM varies within and between families. (Tier 4)
3
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions included in this report include regular MRI surveillance, surgical excision of CCMs, enhanced pregnancy monitoring, avoidance of antithrombotic and certain analgesic medications, and avoidance of radiation.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Most CCMs are detected incidentally or suspected when symptoms become evident. Up to 41% of cases with symptoms present with cerebral hemorrhage. (Tier 3)
1 2 3
However, general guidelines recommend EEG and neuroimaging following unprovoked seizures to identify structural abnormalities that may cause certain epilepsies, thus CCMs that lead to epilepsy are likely to be detected at this point. (Tier 5)
5
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Hemorrhage / Medication (simvastatin, fasudil)
2
2C
0D
3
7CD
Hemorrhage / MRI
2
2C
0C
3
7CC
Hemorrhage / Delivery management
2
2C
1C
3
8CC
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Familial cerebral cavernous malformation. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=221061
2. Haasdijk RA, Cheng C, Maat-Kievit AJ, Duckers HJ. Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management. Eur J Hum Genet. (2012) 20(2):134-40.
3. L Morrison, A Akers. Cerebral cavernous malformation, familial. 2003 Feb 24 [Updated 2016 Aug 04]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1293
4. Samarasekera, N., Poorthuis, M., Kontoh, K., Stuart, I., Respinger, C., Berg, J., Kitchen, N., Salman, R.A.. Guidelines for the management of cerebral cavernous malformations in adults.. Publisher: Cavernoma Alliance UK, Genetic Alliance UK. (2012) Accessed: 2016-11-21. Website: https://www.cavernoma.org.uk/wp-content/uploads/2015/03/final-CCM-guidelines.pdf
5. National Institute for Health and Clinical Excellence (NICE). The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. clinical guideline no. 137. (2012) Accessed: 2016-12-15. Website: https://www.nice.org.uk/guidance/cg137
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