Familial Cerebral Cavernous Malformations : A Clinical Series and Literature Review

Abstract

Objective: Familial cerebral cavernous malformation (FCCM) is a genetically inherited condition involving the collection of abnormal slow-flow venous capillaries with no cerebral parenchyma in between. In this case series, we review the clinical, radiological, pathological, and genetic findings of seven blood relatives diagnosed with FCCM and discuss their treatment in light of the different presentations.

Methods: The patients with FCCMs were assessed in our neurosurgery clinic between April 2016 and October 2024. All patients underwent detailed clinical evaluation, radiological imaging, histopathological examination, and genetic testing. Functional outcomes were evaluated using the Karnofsky performance scale (KPS).

Results: Five of the seven patients were symptomatic, while the remaining two were asymptomatic carriers. On radiological examination, hemorrhagic type I lesions were detected in symptomatic cases, whereas the asymptomatic carriers had non-hemorrhagic type 4 lesions. Genetic testing revealed a heterozygous pathogenic mutation in the CCM1 gene in one of the symptomatic patients. The three symptomatic cases underwent surgery for complete resection of the lesions; no additional neurological deficit or residual lesion was detected postoperatively (postoperative KPS score, 100). Histopathological examination revealed benign cavernous angioma in all cases. Over the postoperative follow-up, no seizures were detected in patients who underwent surgery due to refractory epilepsy.

Conclusion: Advances in molecular genetic testing have allowed for prompt diagnosis and timely management of patients with FCCMs. Surgical treatment is an effective option in symptomatic cases with progressive neurological deficits and refractory epilepsy. Regular neurological monitoring and radiological assessment are recommended in symptomatic cases and asymptomatic carriers.

Keywords: Cerebral cavernous malformation; Cerebral cavernous malformations 1 protein; Family characteristics.

Fig. 1.

Case 1. A : A cerebral cavernoma measuring 2.7×2.6 cm located in the left frontal region visualized on the T1-weighted image. B : Multiple, adjacent, cavernous capillaries in the neuroglial tissue seen on histopathological examination (×5).

Fig. 2.

A : Case 2. Cavernous angioma (arrow) visualized on the cranial susceptibility weighted imaging. B : Case 3. Multiple millimetric cavernomas located in both cerebral and cerebellar hemispheres and the central region of pons (arrows). C : Case 4. Susceptibility-weighted imaging of the spinal cord showed millimetric cavernoma in the central region of the spinal cord at the C2-C3 level (arrow) and on the right side at the C4-C5 level.

Fig. 3.

Case 5. A : A cavernoma (3.5×3.4 cm) with lobulated contours containing blood products at varying ages can be seen in the left occipital lobe. B : A cutaneous cavernoma was observed on the posterolateral region of the left thigh. C : Gross appearance of the cavernoma excised during a left occipital craniotomy. D : The 3-month postoperative T2-weighted magnetic resonance imaging shows total excision of the cavernoma.

Fig. 4.

Case 6. Cranial magnetic resonance imaging showing a small residual cavernoma (10 mm in diameter) with minor bleeding in the ventral pons following radiotherapy.

Fig. 5.

Case 7. A : A hemorrhagic type I cavernoma (4×3 cm) seen in the left frontal lobe on cranial magnetic resonance imaging. B : Histopathological examination of the specimen showing multiple, adjacent, cavernous capillaries in the neuroglial tissue (left lower rim) (Hematoxylin and Eosin, original magnification : ×40).