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Cavernous Angiomas: Screening Of A Family Over Three Generations

Cavernous angiomas belong to a group of intracranial vascular malformations that are developmental malformations of the vascular bed. These congenital abnormal vascular connections frequently enlarge over time. The lesions can occur on a familial basis. Patients may be asymptomatic, although they often present with headaches, seizures, or small parenchymal hemorrhages.

In most patients, cavernous angiomas are solitary and asymptomatic. In recent times, increasing MRI has detected several such asymptomatic cases and has prompted a study into the genetics and natural history of this condition.

It is now known that cavernous angiomas have a genetic basis. Familial forms of cavernous angiomas are associated with a set of genes called CCM genes (cerebral cavernous angioma). This is a case report describing the phenotypic expression of a familial form of cavernous angioma.

CASE REPORT

A 54-year-old man was referred for an MRI of the brain with complaints of headache and seizures. A cranial CT scan revealed few hyperdense lesions. A subsequent cranial MRI scan revealed several lesions with features representing cavernous angiomas.

The patient was offered counseling and was treated conservatively. Genetic testing was not possible due to the high prohibitive cost. However, screening of the family members by MRI was recommended.

Cranial MRI of the immediate family members was performed. Four brothers of the patient and his mother were found to have multiple cavernous angiomas. The father, youngest brother, and his younger sister were found not to have any such lesion. Both children of the patient were also found to be free of these lesions. Incidentally, a meningioma was found in the father of the patient.

DISCUSSION

Cavernous angiomas are typically discrete multilobulated lesions that contain hemorrhage in various stages of evolution. Because they are lobulated and dark red to blue, the lesions grossly resemble small mulberries. They are said to be vascular hamartomas made up of endothelium lined sinusoids not sepertated by neural tissue. Several theories have been proposed to explain their pathogenesis, however, none has proven to be wholly accurate.

Cavernous angiomas may occur anywhere in the central nervous sytem, but the most common site is the supreatentorial neuroparenchyma (about 80 percent).

A genetic basis for this disease has been established. The three genes associated with familial CCM are CCM1 (KRIT1), CCM2 — both of which have been located on chromosome 7q — and CCM3 (PDCD10), which has been located on chromosome 3 (1,2). Familial CCM is inherited in an autosomal dominant manner. The occurrence of asymptomatic vascular lesions may prevent recognition of an autosomal dominant pattern of inheritance in a family. The proportion of cases caused by de novo gene mutations is unknown. Each child of an individual with CCM has a 50 percent chance of inheriting the mutation.

Molecular genetic testing and prenatal testing is available at certain centers.

Familial cerebral cavernous malformation is defined as the occurrence of CCMs in at least two family members, and/or the presence of a disease-causing mutation in one of the genes associated with CCM and/or the presence of multiple CCMs (gene CCM).

Diagnosis of cerebral cavernous angiomas is difficult. Most patients are asymptomatic and diagnosis is incidental. The common presenting symptoms include seizures, focal neurological deficits, chronic headaches, and intracranial hemorrhage (3).

MRI is the imaging technique of choice as of today. Both spin echo and gradient recall echo sequences are useful in demonstrating cavernous angiomas. However, gradient echo images have proven to be better than spin echo images (3). In the screening of family described above, the Gradient echo T2W images revealed more angiomas than the spin echo sequences. Contrast injection is usually not required.

MRI findings of cerebral cavernous angiomas are quite typical (4,5,6). On MRI they appear as popcorn-like, smoothly-circumscribed, well-delineated complex lesions. The core is formed by multiple foci of mixed signal intensities, which represents hemorrhage in various stages of evolution (7). A low-signal intensity hemosiderin ring that completely surrounds the lesion is a common finding. The low-signal intensity is more prominent or “blooms” on T2-weighted and gradient echo images.

The interspersed fibrous-containing elements demonstrate mild hypointensity on both T1- and T2-weighted images because they contain a combination of calcification and hemosiderin.

When multiple cavernous malformations are identified in one patient, a detailed neurologic family history should be sought to identify the mode of inheritance (3). MRI can then pick up such lesions in asymptomatic relatives during family screening. It is important to counsel the family members who are found to have these angiomas regarding the risk of hemorrhage and advise changes in their lifestyle.

At least the adult siblings may be screened by Axial GRE sequence to detect the angiomas.

Screening asymptomatic family members may raise cost issues. The insurance companies and government agencies may not reimburse these costs. This scenario would be different in different countries. However, if these siblings are screened only using Axial GRE, the cost and the time required in the MRI scanner may be minimized. This cost of screening may be worthwhile if asymptomatic carriers of the angiomas are detected.

REFERENCES

  1. Liquori CL, Berg MJ, Siegel AM, et al. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformationsAm J Hum Genet Dec 2003;73(6):1459-64.
  2. Craig HD, Gunel M, Cepeda O, et al. Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27Hum Mol Genet Nov 1998;7(12):1851-8.
  3. Brunereau L, Labauge P, Tournier-Lasserve, Laberge S, Levy C, Houtteville, J. Familial Form of Intracranial Cavernous Angioma: MR Imaging Findings in 51 Families. Radiology Jan 2000;214:209-216.
  4. Hallam DK, Russell EJ. Imaging of angiographically occult cerebral vascular malformationsNeuroimaging Clin N Am May 1998;8(2):323-47.
  5. Hauck EF, Barnett SL, White JA, Samson D. Symptomatic brainstem cavernomasNeurosurgery Jan 2009;64(1):61-70; discussion 70-1.
  6. Ide C, De Coene B, Baudrez V. MR features of cavernous angioma. JBR-BTR Dec 2000;83(6):320.
  7. Novak V, Chowdhary A, Abduljalil A, et al. Venous cavernoma at 8 Tesla MRIMagn Reson Imaging Nov 2003;21(9):1087-9.

*This blog post was originally published at AJNR Blog*


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