Familial cerebral cavernous malformation

Familial cerebral cavernous malformation

• A rare, capillary-venous malformations characterized by closely clustered irregular dilated capillaries that can be asymptomatic or that can cause variable neurological manifestations such as seizures, non-specific headaches, progressive or transient focal neurologic deficits, and/or cerebral hemorrhages.

Epidemiology

The total prevalence of CCMs is estimated between 1/200 and 1/1,000 people. Familial cerebral cavernous malformation (FCCM), representing approximately 20% of all CCM cases, has an estimated occurrence rate of 1/5,000 – 1/10,000, making it uncommon compared to the more frequent sporadic CCMs. Hispanic-American CCM families demonstrate a notable founder effect.

Clinical description

Approximately 60% of FCCM patients exhibit symptoms. While FCCM typically emerges between ages 20 and 30, symptoms can develop at any life stage. Common manifestations include seizures (40-70%), general headaches (10-30%), temporary or progressive focal neurological deficits (35-50%), and cerebral bleeding (41%). FCCM patients typically develop multiple lesions, varying from millimeter to centimeter scale. While FCCMs predominantly affect the brain, they can also manifest in the spinal cord, retina (5% of cases), and skin.

Etiology

Currently, three genes have been identified as causative factors in familial CCM: KRIT1, CCM2, and PDCD10, positioned on chromosomes 7q21.2, 7p13, and 3q26.1 respectively. These genes encode proteins that, among other functions, regulate the formation of junctions between vascular endothelial cells.

Diagnostic methods

Cerebral MRI remains the definitive diagnostic tool for CCM detection, with T2 gradient echo sequence being particularly effective in detecting hemosiderin. Unlike sporadic cases with single lesions, FCCM patients typically show multiple lesions on MRI, strongly indicating genetic origin. While molecular screening of FCCM genes can confirm diagnosis in cases with atypical MRI findings, it’s primarily used for genetic counseling purposes.

Differential diagnosis

For cases showing unusual hemorrhagic MRI patterns, FCCM must be distinguished from multiple hemorrhagic metastases or hereditary cerebral hemorrhage with amyloidosis.

Antenatal diagnosis

While prenatal testing is available, it’s rarely requested except in families with severe CCM cases affecting the basal ganglia, spinal cord, or pons.

Genetic counseling

FCCM exhibits an autosomal dominant inheritance pattern with variable penetrance. Affected families should receive comprehensive genetic counseling, highlighting the 50% probability of gene mutation transmission to offspring. When evaluating genetic predisposition to CCMs, healthcare providers consider multiple factors, including the quantity of lesions detected through MRI brain scans, familial CCM history and manifestations, and the age when symptoms first appeared.

Management and treatment

Following CCM discovery, patients require consistent monitoring, typically through annual MRI scans, as new asymptomatic lesions may develop over time. In cases without intervening symptoms, scan intervals may be extended to once every 5 years. Treatment focuses on managing symptoms like seizures and headaches. Surgical intervention becomes necessary for lesions causing severe seizures, significant neurological deficits, or cerebral hemorrhages, provided the location permits removal. Patients should avoid blood-thinning medications such as acetylsalicylic acid, heparin, and warfarin, as these may elevate hemorrhage risk.

Prognosis

FCCM progresses over time, showing a strong relationship between patient age and lesion quantity. Each lesion carries a 2-5% annual risk of hemorrhage. Patient outcomes largely depend on lesion location, with those affecting the brainstem and basal ganglia typically having poorer prognoses. However, long-term outlook remains generally positive, with 80% of patients maintaining independence.

What are the symptoms of Familial cerebral cavernous malformation?

Always Present Symptoms

• Cerebral cavernous malformation

Very Frequent Symptoms

• Cerebral hemorrhage
• Headache
• Seizure

Frequent Symptoms

• Cavernous hemangioma
• Focal T2 hyperintense brainstem lesion
• Focal T2 hypointense brainstem lesion
• Hemangioma
• Hypoesthesia
• Increased intracranial pressure
• Muscle weakness
• Neuroma
• Paresthesia
• Scoliosis

Occasional Symptoms

• Choroidal hemangioma
• Cognitive impairment
• Episodic vomiting
• Retinal cavernous angioma
• Spinal cord lesion
• Vascular skin abnormality
• Venous malformation

Rare Symptoms

• Adrenal calcification
• Astrocytoma
• Meningioma
• Vestibular schwannoma