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Familial cerebral cavernous malformation

ORPHA221061
Synonym(s) Familial brain cavernous angioma
Familial brain cavernous hemangioma
Familial cerebral cavernoma
Hereditary brain cavernous angioma
Hereditary brain cavernous hemangioma
Hereditary cerebral cavernoma
Hereditary cerebral cavernous malformation
Prevalence 1-5 / 10 000
Inheritance Autosomal dominant
Age of onset All ages
ICD-10
  • Q28.3
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Familial cerebral cavernous malformation (FCCM) is a rare evolutive vascular malformation disorder 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.

The overall prevalence of all CCMs has been estimated at 1/200 to 1/1,000 individuals. FCCM represents about 20% of all CCM cases with an estimated prevalence of 1/5,000 -1/10,000 and is therefore rare, contrarily to sporadic CCMs which are not. A strong founder effect has been found in Hispanic-American CCM families.

Close to 60 % of FCCM patients are symptomatic. FCCM usually manifests between 20 to 30 years of age, but clinical manifestations can occur at any age. Symptoms include seizures (40-70%), non-specific headaches (10-30%), progressive or transient focal neurologic deficits (35-50%), and/or cerebral hemorrhages (41%). FCCM patients most often present with multiple lesions, ranging from a few millimeters to a few centimeters in size. FCCMs occur predominantly in the brain, but have also been reported in the spinal cord, retina (5% of FCCM patients) and skin.

To date, mutations in three genes have been demonstrated to cause familial CCM; KRIT1, CCM2 and PDCD10, located on chromosome 7q21.2, 7p13, and 3q26.1 respectively, which encode proteins that, among their various functions, modulate junction formation between vascular endothelial cells.

Cerebral magnetic resonance imaging (MRI) revealing the CCM(s) is the gold standard investigation to diagnose FCCM and should include a T2 gradient echo sequence which is highly sensitive for hemosiderin. Molecular screening of FCCM genes is sometimes useful to ascertain the diagnosis in patients showing atypical MRI lesions; however, in most cases, it is used for genetic counseling.

In cases presenting with atypical hemorrhagic MRI lesions, the differential diagnosis of FCCM includes multiple hemorrhagic metastases or hereditary cerebral hemorrhage with amyloidosis (see this term).

Prenatal diagnosis is possible. However, in practice, very few prenatal diagnoses are requested in this disease (mostly in families where several patients have been severely affected with CCMs in the basal ganglia or spinal cord or pons).

FCCM is transmitted as an autosomal dominant trait with incomplete penetrance. Genetic counseling should be offered to the affected families informing them of the 50% risk of inheriting the mutated gene. Other important considerations in evaluating the genetic predisposition of CCMs include the number of lesions on the MRI brain scan, family history of CCM clinical characteristics, and the age of onset.

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. Treatment of seizures and headaches is symptomatic. Lesions causing severe disabling seizures and/or focal neurologic deficits call for surgical removal of lesions whenever possible. Acetylsalicylic acid, heparin and warfarin may increase the risk of hemorrhage.

FCCM is an evolving condition with a strong correlation between the patient's age and the number of CCM lesions. The hemorrhagic event rate is estimated at 2-5 % per lesion per year. Functional outcome is mostly conditioned by the location of CCM lesions, with brainstem and basal ganglia lesions having a worse prognosis. Available data suggest that in most patients the long-term prognosis is quite favorable with a preserved autonomy in 80% of cases.

Expert reviewer(s)

  • Pr Elisabeth TOURNIER-LASSERVE

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Clinical genetics review
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