Familial Cerebral Cavernous Malformations

CLINICAL CHARACTERISTICS

Familial cerebral cavernous malformations (FCCM) is a disorder characterized by multiple vascular lesions in the brain and spinal cord that consist of clustered, endothelial-lined caverns ranging in diameter from a few millimeters to several centimeters. Cerebral and/or spinal cavernous malformations may increase in number over time, and individual lesions may increase or decrease in size. The number of cerebral cavernous malformations (CCMs) identified in an individual ranges from one or two to hundreds of lesions (typical number 6-20 CCMs) depending on the individual'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 of life either incidentally or associated with seizures, focal neurologic deficits, headaches, and/or cerebral hemorrhage. Cutaneous vascular lesions are found in 9% and retinal vascular lesions in almost 5% of affected individuals. Up to 50% of individuals with FCCM remain symptom free throughout their lives.

DIAGNOSIS/TESTING: The diagnosis of familial cerebral cavernous malformations (FCCM) is established in a proband with multiple CCMs, one CCM and at least one other family member with one or more CCMs, or a heterozygous germline pathogenic variant in , , or identified by molecular genetic testing.

MANAGEMENT

: Surgical removal of symptomatic lesions may be considered in individuals with acute hemorrhage and/or a mass effect presenting with focal neurologic deficit, headache, or seizure or in those with intractable seizures (with or without associated hemorrhage). Treatment of epilepsy is symptomatic. Headaches are managed symptomatically and prophylactically. Rehabilitation may aid in management of acute and chronic neurologic deficits. Brain MR imaging with susceptibility-weighted imaging (SWI) is indicated in individuals experiencing new neurologic manifestations. Caution is recommended with medications such as analgesics such as NSAIDs, antithrombotic medications such as heparin and warfarin (Coumadin), thrombolytic agents, and oral female hormones. Note: When antithrombotic and thrombolytic medications are necessary for treatment of life-threatening thrombosis, careful consideration of appropriate dosage and close monitoring are warranted. Radiation to the central nervous system may lead to new lesion formation. 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 individuals at risk of developing CCMs. Symptomatic relatives may undergo brain MRI with SWI sequences to determine presence, size, and location of lesions. Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or headaches require close monitoring during pregnancy. Seizures are the most common manifestations of CCM hemorrhage during pregnancy; exposure to anti-seizure medication during pregnancy may increase the risk for adverse fetal outcomes but is generally recommended, as the fetal risk is typically less than that associated with an untreated maternal seizure disorder. Any focal neurologic deficits or severe headaches during pregnancy should be evaluated and other neurologic causes (e.g., ischemic stroke, cerebral venous thrombosis) ruled out.

GENETIC COUNSELING

FCCM is inherited in an autosomal dominant manner. Many individuals diagnosed with FCCM have a symptomatic parent. The proportion of individuals with FCCM caused by a pathogenic variant is unknown. Each child of an individual with FCCM has a 50% chance of inheriting an FCCM-related pathogenic variant. If a pathogenic variant has been identified in an affected family member, prenatal testing of an at-risk pregnancy and preimplantation genetic testing are possible.