Whole-Exome Sequencing Analysis Of Familial Chiari Malformation Type ? And Clinical/radiographic Study Of Chiari Malformation Type ?/scoliosis

Chapter 1 Whole-Exome Sequencing Identifying Genetic Etiology of Familial Chiari malformation Type ?Objective.The aim was to perform a molecular genetics study to identify the pathogenic gene of Chiari I malformation(CMI)using the whole exome sequencing(WES).Method.From June 2012 to October 2015,family with inherited CMI(Chiari Family)were identified and enrolled in our study.Genomic DNA was draw from the whole peripheral blood of these participants.The WES and statistical analysis were used to identify CMI-related genetic mutations in these cases.Result.12 Chiari family were finally enrolled in this study.After knowledge-based data mining,two candidate mutations IRX6 and Syne-1,were identified.Conclusion.IRX6 and Syne-1 may play an important role in the development of CMI.Our study also proved WES as a new and cost-effective analysis strategy for the genetic study in small pedigree.Chapter 2(sectionl)Morphometric features of posterior cranial fossa are different between Chiari I malformation with and without syringomyeliaPurpose.To investigate whether the posterior cranial fossa(PCF)morphology in Chiari I malformation without syringomyelia(also called syrinx)(CMI-only)is different from that in Chiari I malformation with syrinx(CMI-S).Methods.Nineteen CMI-patients without syrinx constituted the CMI-only group,whereas 48 CMI-patients with syrinx were assigned to the CMI-S group.Another cohort of 40 age-matched asymptomatic adolescents was enrolled to serve as the control group.Six measurements were evaluated and compared between these three groups from T1-weighted magnetic resonance(MR)imaging,including the length of the clivus(AB),the anteroposterior diameter of the foramen magnum(BC),the length of the supraocciput(CD),the anteroposterior diameter of the posterior fossa(DA),the posterior fossa height(BE)and the clivus gradient(??).The posterior cranial fossa morphology in relation to syrinx severity was also investigated.Results.Compared to the normal controls,the AB,CD,DA,BE and ?? were significantly larger in the CMI-S group.Similar changes in AB,CD,DA and BE were also demonstrated in the CMI-only group,while the clivus gradient(??)was found to be normal when compared with the control group.A significantly decreased clivus gradient was observed in the CMI-S group as compared to CMI-only group.In addition,the clivus was significantly flattened in patients with a distended-syrinx in comparison to those with a non-distended syrinx.Conclusions.Small size of the posterior fossa was detected both in CMI cases with and without syrinx.The clivus gradient served as the only morphologic difference in the PCF between CMI-S and CMI-only patients and was correlated with the severity of the syrinx,may support the theory that the restricted circulation of cerebrospinal fluid at the anterior paramedial subarachnoid space contributes to the formation of a syrinx.Chapter 2(section2)Morphometric analysis of the posterior possa in adolescents with idiopathic syringomyeliaObjective.To investigate the morphometric characteristics of the posterior fossa in adolescents with idiopathic syringomyelia(IS)and to elucidate their clinical significances.Methods.A retrospective radiographic review was performed on 25 adolescents who were diagnosed with IS and treated at our clinic between Januarary 2008 and October 2011.Another cohort of normal adolescents and CMI-S patients,matched with the IS patients by age and gender,were recruited to serve as the control group.six parameters were assessed on mid-sagittal MR images,including the linear parameters(the length of the clivus,the anteroposterior diameter of the foramen magnum,the length of supraocciput,the anteroposterior diameter of the posterior fossa,the posterior fossa height)and the angular parameter(the clivus gradient).Results.In the IS group,the length of the clivus ranged from 25.4mm to 48.7mm(mean 38.3mm),the anteroposterior diameter of the foramen magnum ranged from 27.2mm to 44.2mm(mean 33.6mm),the length of supraocciput ranged from 23.6 mm to 48.2mm(mean:36.7mm),the anteroposterior diameter of the posterior fossa ranged from 62.9 mm to 88.4mm(mean 74.3mm),the posterior fossa height ranged from 18.51mm to 43.9mm(mean 31.3mm)and the clivus gradient ranged from 30.0°to 77.0°(mean 56.7°).Significant differences were observed in all six morphometric parameters when comparing the IS group and CMI-S group with the normal group respectively.Additionally,all parameters were similar between the IS and CMI-S groups expect for the clivus gradient,which was significantly larger in the IS group(56.69±10.6°)(P<0.05).Conclusion.The posterior fossa in patients with IS,sharing the similar characteristcs with that in patients with CMI-S,is indeed smaller than normal.A steeper clivus is observed in patients with IS when comparing with that in patients with CMI-S.Chapter 2(section3)Diffusion tensor imaging in cervical syringomyelia secondary to Chiari ? malformation:implications for understanding the neurological deficits resulting from the syrinx cavityObjective.Syringomyelia is a common finding in CMI patients.Conventional imaging techniques frequently fail to assist clinicians in quantitatively assessing the neural damage in these patients.The aim was to perform a quantitative analysis of the neuronal status in cervical syringomyelia secondary to Chiari ? malformation(CMI-SM)using diffusion tensor imaging(DTI).Methods.Twenty-three CMI-SM patients(8-25 years)were prospectively enrolled from April 2012 to August 2013.Sensitivity encoding single-shot echo-planar imaging was used for the sagittal DTI.Fractional anisotropy(FA)values in the spinal cord were compared between the patients and normal volunteers and further evaluated with respect to syrinx severity and neurological signs/symptoms.Results.Compared to the normal controls,the FA values were significantly decreased within the area of syrinx(0.423±0.011 vs.0.533±0.007;p<0.001),while no significant decreased FA value was measured in the tissue rostral and caudal to the syrinx.Concerning patients with different size of the syrinx,significantly decreased FA values within the area of the syrinx were observed in patients with a distended syrinx in comparison to those with a non-distended syrinx(0.397±0.013 vs.0.480 ±0.018;p=0.0007).Moreover,the FA value within the area of the syrinx was both significantly decreased in the symptomatic and non-symptomatic groups when compared with the control groups and there was also a significant difference between the two CMI-S groups(0.371 ±0.018 vs.0.479±0.011;P=0.003).Conclusions.Decreased FA value of syringomyelia may provide quantitative information of increased microstructural damage within the spinal cord at this area and changes in this DTI parameter are significantly related to syrinx size and to the appearance of neurological signs/symptoms.Chapter 3(sectionl)Prospective observational study exploring spinal column osteotomies for correction of complicated adult kyphoscoliosisObjective.To evaluate the safety and clinical outcomes of spinal column osteotomies utilized in complicated adult kyphoscoliosis.Methods.A prospective study was conducted for the adult patients,with complicated kyphoscoliosis,who had spinal osteotomies from September 2011 to September 2012.The coronal parameters including Cobb angle and distance between C7 plumb line and center sacral vertical line(C7PL-CSVL),as well as the sagittal parameters including global kyphosis(GK)and sagittal vertical axis(SVA)were measured pre-operatively,post-operatively and at last follow-up.The Scoliosis Research Society-22 questionnaire(SRS-22),the MOS item short from health survey(SF-36),visual analogue scale(VAS),Oswestry Disability Index(ODI)and American Spinal Injury Association score(ASIA)were fullfilled at pre-operation and each follow-up.The paired t-test was used to analyze the differences among pre-operation,post-operation and last follow-up.Results.Seventeen patients(7 males and 10 females)with an average age of 34.6±10.9(18?55 yrs)years were finally included in this study.The average follow-up period was 24.3±1.8 months.The pre-operative the average Cobb angle and GK angle were 78.50± 13.1°(51°?97°)and 71.8°±19.8°(50°?112°).The post-operative the average Cobb angle and GK angle were 37.7°±17.7° and 25.0°±16.4°.The correction rate of the Cobb angle and GK angle were 51.9%± 18.7%and 67.2%±20.3%.At the last followup,the average Cobb angle and GK angle was 39.5°±16.6° and 26.2°±17.6° with no significant loss of correction.The pre-operative,post-operative and last follow-up C7PL-CSVL were 58.4±21.3 mm,18.0±9.4 mm and 22.1±15.4 mm,respectively.Significant post-operative improvement was observed while there was no change at last follow-up.SVA decreased significantly from 56.4±51.2 mm to 27.6± 16.9 mm.The average SVA at last follow-up were 30.4±17.1 mm and no loss of correction was found.In addition,significant post-operative improvement were observed in SF36,VAS,ODI,SRS-22 and there was no change at last follow-up.Compared with preoperative baseline,no significant reduction in AISA scale was found in these patients.Moreover,no death or paralysis were observed in this study.The incidence of complications was 52.9%,including temporarily hypoaesthesia in 5 cases,anterior vertebral body fracture in 1 case,pedicle screw malposition in 1 case,implant complications in 2 cases.Conclusion.The spinal column osteotomy is a safe and effect surgical technique for managing complicated kyphoscoliosis in adult patients,although the procedure is exhaustingly lengthy and blood loss,and was associated with a variety of complications.Chapter 3(section2)Comparative research of Kirschner wire technique and electric drill-assisted pedicle screw installation in lumbar scoliosisObjective.To evaluate the accuracy and safety of the "electric drill-assisted" technique in placing Lumbar pedicle screw(LPS)as compared with the conventional "freehand"technique.Methods.A total of 157 patients with lumbar scoliosis who underwent posterior instrument were included in the study.The patients were divided into Kirschner wire(free hand)group and electric drill-assisted group according to methods of canal preparation,Post-operative computed tomography(CT)were acquired to determine the distribution of cortical perforation and distance between screw tip and cortical.?2 test were performed to compare the differences of two groups and convex side and concave side.Results.1118 lumbar pedicle screws were inserted in 157 patients with scoliosis.The incidence of cortical perforation was 9.3%.64 of 642 screws(10.0%)perforated cortices in free hand group,40 of 476 screws(8.4%)perforated cortices in electric drillassisted group.No significant difference of perforation rate was found between the two groups(P=0.373).In electric drill-assisted group,the incidence of cortical perforation was 9.7%(23/236)in convex side and 7.1%(17/240)in concave side.There was no significantly statistical difference between these two groups(convex:P=0.714,concave:P=0.108).Moreover,no neurologic,vascular,or visceral complications caused by LPS placement was occurred in both groups.Conclusion.The electric drill-assisted technique shows similar accuracy and safety in placing Lumbar pedicle screw(LPS)as compared with the conventional Kirschner wire technique.