To date, research on hereditary cerebral hemorrhage in China and other countries has focused primarily on cerebral amyloidosis. In the present study, the genetic characteristics of two cases of familial cavernous hemangioma and one case of hereditary cerebral hemorrhage with amyloidosis were described in detail. The clinical features of these diseases were compared, and the finding differed from those of previous reports on monogenic hereditary cerebral hemorrhage.
Cerebral cavernous hemangioma occurs more commonly in young adults and rarely in the elderly (6). Most cases are sporadic, and single lesions are commonly seen in the brain. In addition, multiple lesions are common in patients with autosomal dominant familial cerebral cavernous malformation (CCMs). Anthropological analyses in recent decades reported higher incidence rates of CCMs in Hispanic and Chinese populations (7, 8).
Most hemorrhaging from CCMs occurs via an intracranial cavernous hemangioma. The risk of bleeding differs depending on the location of the cavernous hemangioma. The risk of bleeding recurrence is approximately 5–60% per year (9), and short-term recurrent bleeding is also often reported (10). Therefore, immediate treatment should be given upon the first bleeding event. Amongst the family members of our three cases, four had a history of cerebral hemorrhage (3 male patients and 1 female patient), and none had a history of spinal cord hemorrhage. In fact, the coexistence of cerebral and spinal cord hemorrhage in patients with CCMs is extremely rare (11). Notably, Sirvente et al. reported that cutaneous vascular malformations appear only in patients with a CCM1 gene mutation and are not seen in patients with CCM2 and CCM3 gene mutations (12). In the study by Labauge et al, approximately 75% of patients with CCMs were found to have an isolated cerebral cavernous hemangioma on head MRI (13). Overall, about 60% of patients with CCMs who carry a gene mutation will have symptoms such as complex partial seizures, focal neurologic deficits, headaches and cerebral hemorrhage (9). Therefore, by investigating the gene mutations in the present cases, this study aimed to identify carriers of disease-causing genes within the patients’ families for guidance of early treatment intervention or symptom relief.
was diagnosed with cerebral cavernous hemangioma, and the patient’s clinical symptoms as well as imaging results fulfilled the diagnostic criteria for CCM. The patient’s condition was further confirmed via pathologic examination. The patient’s mother and younger sister were also diagnosed with CCM based on pathological examination. Unfortunately, no genetic testing was performed for the patient or her family members. However, through a survey of her family, it was concluded that the patient had familial cerebral cavernous hemangioma.
Hereditary cerebral hemorrhage with amyloidosis is an autosomal dominant genetic disease. Its pathological changes are similar to those of cerebral amyloid angiopathy (CAA) and include deposition of amyloid beta in cerebral blood vessels. Therefore, hereditary cerebral hemorrhage with amyloidosis is classified as familial CAA, and the three main types for which mutations have been identified are known as the Dutch, Italian and Icelandic types. The first two types (Dutch and Italian) are caused by mutations in the amyloid precursor protein (APP), with mutation sites for the Dutch-type and Italian-type at E693Q and E693K, respectively. The Icelandic-type is caused by mutant cystatin C (CST3). Hereditary cerebral hemorrhage with amyloidosis is clinically characterized by recurrent cerebral hemorrhage, dementia, etc., and the symptoms of cerebral hemorrhage usually appear around 50 years of age, with lobar hemorrhage being most common. As the disease progresses, brain imaging shows more changes related to leukoaraiosis, cerebral microbleed, and infarction (14).
of this study was diagnosed with hereditary cerebral hemorrhage with amyloidosis, Finnish type (Finnish gelsolin amyloidosis, FGA), which an autosomal dominant genetic disorder, caused by a frameshift mutation in the GSN gene. This is different from the more common pathogenic genes of hereditary cerebral hemorrhage with amyloidosis. The classic clinical manifestations of FGA are convulsions, multiple cerebrovascular malformations, and multiple hemorrhagic foci (15), which were seen in the proband. Genetic testing confirmed a heterozygous G duplicate mutation in exon 1 of the GSN gene, which was the cause of the disease. The proband’s mother and daughter also were carriers of the genetic mutation, but they had no history of related clinical manifestations. It is possible that the gene mutation varies among different patients, resulting in variation in the pathogenesis and clinical manifestations (16). Notably, the proband was male, whereas his non-symptomatic, mutation-carrying family members were female, suggesting the possibility that the clinical manifestations of FGA are associated with gender.
A previous study of mutations of the GSN gene reported a single nucleotide substitution of G for A or T at position 654 (17), and the pathogenic locus of the mutation in Case 3 was not reported. No genetic mutation was observed in the younger brother of the proband, indicating that the mother was a heterozygous carrier of GSN gene mutation, as was confirmed by gene sequencing.