Clinical Guidance

KRIT1. A higher prevalence (estimated between 9% and 20%) and a different predominant morphologic subtype of cutaneous vascular malformations were observed in individuals from northern Mexico and the southwestern United States with this founder variant compared to other FCCM cohorts .

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"

Penetrance

KRIT1. Among 64 families with 202 individuals who were heterozygous for a KRIT1 pathogenic variant :

• Sixty-two percent were symptomatic;

• Fifty-eight percent of those who were at least age 50 years had symptoms related to CCM;

• Forty-five of 53 symptom-free individuals had lesions on MRI (three had indications of a type 4 lesion; see ) 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 KRIT1 . Penetrance in individuals with pathogenic variants in CCM2 is not known.

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"

Diagnostic Criteria

No consensus clinical diagnostic criteria for familial cerebral cavernous malformations (FCCM) have been published.

Suggestive Findings

FCCM should be suspected in individuals with the following clinical findings, brain and/or spinal cord imaging findings, and family history.

Clinical findings

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"

Differential Diagnosis

Sporadic cerebral cavernous malformations (CCMs). Histologically, familial CCMs (FCCM) and sporadic CCMs are similar. However, sporadic CCM is typically characterized by a single cavernous malformation and often associated with a developmental venous anomaly (DVA); multiple cavernous malformations can occur in the sporadic form, but they are always situated around or near a DVA. Limited evidence suggests that a DVA is an anatomic and genetic primer of sporadic CCM . Some series indicate that up to 30% of sporadic CCMs are associated with a DVA. In a study using 7 Tesla MRI imaging, 100% of individuals with sporadic CCMs were found to have abnormal venous output from the cavernous malformation. Of note, DVAs are rarely seen in individuals with FCCM.

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"

Management Guidelines

The management of cerebral cavernous malformations (CCMs) is largely based on epidemiologic, non-randomized surgical and radiosurgical studies, as well as expert opinion. In 2017, The Alliance to Cure Cavernous Malformation (Formerly Angioma Alliance) Scientific Committee published guidelines for the management of CCMs including familial CCM (FCCM) . Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with FCCM, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Familial Cerebral Cavernous Malformations: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"

Clinical Guidance

Analgesics

• There is limited data regarding the use of non-aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs). One study reported a reduction in hemorrhage risk in individuals with sporadic or familial CCM taking NSAIDs ; however, the dose and duration of medication use is not known. In general, it is best to avoid NSAIDs; however, in asymptomatic individuals it is not absolutely contraindicated.

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

Antithrombotic medications include anticoagulants (e.g., heparin, warfarin [Coumadin®], direct oral anticoagulants) and antiplatelet agents (e.g., aspirin, clopidogrel, ticagrelor). In general, it is recommended to avoid antithrombotic agents in individuals with FCCM unless they are necessary for the treatment of life-threatening thrombosis with close monitoring by the medical team. Recent data suggest that antithrombotics may lower the risk of cerebral hemorrhage, possibly by reducing thrombosis within the cavernous malformation .

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"

Therapies Under Investigation

Stereotactic radiosurgery. There are no published randomized clinical trials of radiosurgery versus observation in individuals with CCM. In general, data are derived mainly from single centers with limited follow up. Data suggest that the risk of hemorrhage from a CCM can be reduced to 1%-2% per year, but that effect is not seen for up to two years. The risk of treatment complications has been estimated at approximately 2%-4% . Since natural history studies similarly show a decline in hemorrhage rate after two years , there is debate on the efficacy of this therapy for CCM. This has led to the Cavernomas: A Randomized Effectiveness (CARE) trial comparing neurosurgery or stereotactic radiosurgery to conservative management in the United Kingdom (NIHR128694).

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 5. Familial Cerebral Cavernous Malformations: Recommended Surveillance

Source: GeneReviews — "Familial Cerebral Cavernous Malformations"