A Chinese Family With Cerebral Cavernous Malformation Caused by a Frameshift Mutation of the CCM1 Gene: A Case Report and Review of the Literature

Abstract

Background: Familial cerebral cavernous malformation (FCCM) is a vascular malformation disease closely linked to three identified genes: KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3. Over the past decade, a few cases of cerebral cavernous malformation (CCM) caused by different gene mutations have been reported in Chinese families. Herein, we introduce a Chinese family affected by FCCM due to a kind of KRIT1/CCM1 frameshift mutation. At the same time, a literature review was conducted to identify case reports of familial cerebral cavernous malformation.

Case presentation: The proband in the family in question demonstrated a series of clinical symptoms and features, including headache and bleeding. The proband was hospitalized for headache twice and, both times was examined under suspicion of CCM and received surgical treatment. Magnetic resonance imaging results showed that the proband had multiple intracranial vascular lesions, including on the brain, brainstem, and cerebellum. Genetic test results showed that the classic KRIT1 gene in the proband had a pathogenic mutation. The family members of the proband also showed typical cerebral cavernous malformation when considering clinical manifestations, magnetic resonance imaging findings and genetic test results.

Conclusions: We report a case of Chinese FCCM and its associated symptoms with CCM1-deletion mutations in China. Our findings deepen our understanding of CCM mutations and related phenotypes, the investigation results of this clinical experiment further show that the gene mutation form we reported plays an important role in human FCCM, and this trial investigation is beneficial for genetic counseling for CCM patients.

Keywords: Chinese family; KRIT1/CCM1 gene; case report; familial cerebral cavernous hemangioma; literature review.

Figure 1

Pedigree diagram of the Chinese family with familial cerebral cavernous malformation, a heterozygous frameshift mutation described as c.1362_1363del (p.Gln455fs) was found in exon 14 of CCM1. The arrows designate the index patient (proband); filled squire = affected; unfilled square = unaffected.

Figure 2

MRI findings. Cerebral MRI in subjects II-1 (1–5), II-4 (6–10), II-6 (11–16), II-8 (17–21), III-2 (22–27), III-3 (28–31), and iii-4 (32–35). 1–5 the MRI imaging showing there are multiple lesions in bilateral cerebellar hemispheres, brainstem area, left thalamus, and white matter areas in both cerebral hemispheres. 6–10 the MRI imaging showing there are multiple lesions in the brain stem and bilateral cerebral hemispheres. 11–16 the MRI imaging showing there are multiple lesions in the cerebellum, brainstem, and bilateral cerebral hemispheres, the large lesions are located in the right basal ganglia area, with a slight space–occupying effect. 17–21 the MRI imaging showing there are multiple lesions in bilateral cerebellar hemispheres, brainstem, bilateral thalamus, and bilateral cerebral hemispheres. 22–27 the MRI imaging showing there are lesions in the right cerebellar hemisphere and the right parietal lobe. 28–31 the MRI imaging showing there are multiple lesions on both sides of the brain, and the arrow points to the postoperative manifestations. 33–35 the MRI imaging showing there are multiple lesions in the brain stem and bilateral cerebral hemispheres.

Figure 3

(A) Representative sequencing results from a patient in the family. The graph shows a “c.1362_1363del” deletion mutation of exon 14 in krit1. (B) Representative sequencing results from a normal member without mutation in the family.