Analysis Of Clinical Characteristics Of Hereditary Hemorrhagic Cerebrovascular Disease

Objective:In this study,the cases of hereditary hemorrhagic cerebrovascular diseases in 3families were analyzed and compared with the literature to discuss their clinical,imaging and genetic features,so as to provide some help for early diagnosis,disease assessment and genetic counseling of such diseases.Methods:Three probands and their family members who were hospitalized and diagnosed as hereditary hemorrhagic cerebrovascular disease in our hospital from 2014 to 2018 were selected as subjects in this study.According to Synopsis of guidelines for the clinical management of cerebral cavernous malformations in 2017 and Chinese guidelines for prevention and treatment of Cerebrovascular Diseases in 2019,the patients were divided into familial cerebral cavernous malformations(FCCM)group and hereditary cerebral hemorrhage with amyloidosis(HCHWA)group.We will retrospectively summarize pedigree investigation,clinical data,laboratorial examination,imaging data and genetic polymorphism of the probands,and compare them with the literature reports to explore the differences of clinical,imaging and genetic characteristics between FCCM and HCHWA patients.Results:1.Family 1 and family 2 were diagnosed as FCCM,and family 3 was diagnosed as HCHWA(Finnish type)confirmed by pathology or genetics.2.There were 7 people in FCCM group and 3 people in HCHWA group respectively participating in the clinical data survey,and the ratio of male to female was 3:4 and 1:2,respectively.The average age of diagnosis in the FCCM group was about 39.6 years,while that in the HCHWA group was 42 years.There was only one patient with hyperlipidemia in HCHWA group,and no other risk factors of cerebrovascular disease were found in the other two groups.3.In the FCCM group,4 patients(4/7,57.1%)showed intracerebral hemorrhage(ICH),2 patients(2/7,28.6%)showed varying degrees of epilepsy,2 patients(2/7,28.6%)were asymptomatic and 1 patient(1/7,14.3%)showed headache。In the HCHWA group,2 patients(2/3,66.67%)were asymptomatic,and 1 patient(1/3,33.3%)showed epilepsy and ICH.4.4 patients in the FCCM group and 3 patients in the HCHWA group participated in imaging examination.In the FCCM group,multiple lesions were found in all cases(4/4,100%),4 cases(4/4,100%)in cerebral hemisphere,3 cases(3/4,75%)in cerebellar hemisphere,2 cases(2/4,50%)in brainstem and thalamus or basal ganglion region.In the HCHWA group,there were 2 cases(2/3,66.7%)with multiple lesions,2cases(2/3,66.7%)in the cerebral hemisphere,1 case(1/3,33.3%)in the cerebellar hemisphere,and 1 case(1/3,33.3%)in the thalamus or basal ganglia.5.According to the literature,we searched the pedigree of hereditary hemorrhagic cerebrovascular disease in recent 20 years and counted FCCM and HCHWA patients with imaging data,184 and 227 patients were included in this study,respectively.We found that in FCCM patients,there were 122 cases in the cerebral hemisphere,41cases(41/184,22.28%)in cerebellar hemisphere,35 cases(35/184,19.02%)in brainstem,21 cases(21/184,11.41%)in thalamus or basal ganglion region,and 21cases(21/184,11.41%)in the spinal cord.And there were 146 cases of multiple lesions and 17 cases of single lesions.No patients with spinal cord lesions were found in this case report,and the common sites of the lesions were similar to those mentioned above,all of which were multiple.ICH was most common in HCHWA group,of which 132 cases(132/227,58.15%)were located in cerebral hemisphere,23cases(23/227,10.13%)in thalamus or basal ganglia,no lesions in cerebellar hemisphere and brain stem,followed by 28 cases(28/227,12.33%)of cerebral microbleeds(CMBS),17 cases(17/227,7.49%)of white matter hyperintensity(WMH),and 14 cases(14/227,6.17%)of occipital cortex calcification.In this case report,there were 2 cases(2/3,66.67%)in the cerebral hemisphere,1 case(1/3,33.33%)in the cerebellar hemisphere,and 1 case(1/3,33.33%)in the thalamus.One case(1/3,33.33%)showed CMBs,and no WMH and occipital cortex calcification were found.6.In this study,we summarized the FCCM cases with genetic information in China in the past 20 years,A total of 111 patients were enrolled,including 65 males and 46 females.The average age of onset was about 33.8 years old.Among them,there were 95 cases of CCM1(97/111,87.39%),8 cases of CCM2(8/111,7.21%),1case of CCM3(1/111,0.90%),5 cases of unknown genetic data(5/111,4.50%).Among the FCCM gene carriers,there were 29 asymptomatic cases(29/111,26.13%),30 cases of epilepsy(30/111,27.03%),22 cases(22/111,19.82%)of headache,17 cases(17/111,15.32%)of ICH and 18 cases(18/111,16.22%)of focal neurological deficit(FND).There were 103 cases(103/111,92.79%)of cavernous malformations(CM)in the head,3 cases(3/111,2.70%)of CM in the spinal cord.There were 19 cases(19/111,17.12%)with skin CMs,of which 18(18/19,94.75%)were CCM1 gene carriers.Conclusions:1.The average age of diagnosis in patients with FCCM is slightly earlier than that in patients with HCHWA.They are not accompanied by hypertension,diabetes,hyperlipidemia and other cerebrovascular disease risk factors.2.FCCM and HCHWA have similar clinical manifestations,including ICH,epilepsy,headache,and FND.The proportion of ICH in FCCM patients was higher than that in HCHWA patients,although the majority of patients in HCHWA are asymptomatic.3.Neuroimaging studies of FCCM and HCHWA showed that both lesions were characterized by multiple lesions,and the lesion sites were commonly found in the cerebral hemisphere(lobes).WMH,CMBs and occipital cortex calcification on head magnetic resonance imaging(MRI)are of great value in the diagnosis of HCHWA.4.CCM1 is the pathogenic gene of FCCM family in this study,which is consistent with the main pathogenic genotype of FCCM in Chinese population.Skin CM is highly specific to the CCM1 genotype.Epilepsy is the most common clinical symptom of FCCM.