| Chapter 1 A Promoter Polymorphism of Neurotrophin 3 (NTF3) Gene Is Associated With Curve Severity and Bracing Effectiveness in Adolescent Idiopathic ScoliosisObjective To explore whether the NTF3 gene polymorphisms are associated with the susceptibility, curve severity or bracing effectiveness of adolescent idiopathic scoliosis (AIS).Methods A total of 362 AIS patients and 377 age-matched healthy controls were recruited. Two single nucleotide polymorphisms(SNPs) were selected based on the Chinese data from the HapMap project and Genotyping was carried out by PCR-RFLP for each SNP respectively. Case-control study and case-only study were performed to define the contribution of NTF3 gene polymorphisms to predisposition and disease severity of AIS. Another subgroup of 120 skeletally immature AIS patients who received continuous brace treatment for minimal 2 years was genotyped and bracing effectiveness was assessed to determine its association with NTF3 gene polymorphisms.Results The genotype and allele frequency distribution were similar between AIS and normal control for these two SNPs (χ2 test:p>0.05). For SNP rs11063714 in the promoter region of NTF3 gene, AIS patients with AA genotype showed significantly lower mean maximum Cobb angle than the patients with AG or GG genotypes(ANOVA:p=0.008). In addition, skeletally immature bracing AIS patients with AA genotype possessed significantly higher successful ratio of brace treatment compared with GG genotype(χ2 test:p=0.043). For SNP rs1805149, no significant association with predisposition or curve severity was detected.Conclusion The NTF3 gene polymorphisms are not associated with the occurrence of AIS, but the promoter polymorphism (rs11063714) is associated with the curve severity, implicating an alleviating role of NTF3 in the curve progression of AIS. In addition, the promoter polymorphism is also associated with brace-responsiveness. These findings indicated that NTF3 gene might be a disease-modifying gene of AIS.Chapter 2 (section1) An Updated Analysis of Pubertal Linear GrowthCharacteristics and Age at Menarche in Ethnic ChineseObjective Concerns regarding change in the onset and tempo of pubertal growth in ethnic Chinese have posed a need for current information on growth characteristics. This study is to update the normative data of pubertal linear growth characteristics and distribution of age at menarche in healthy Chinese adolescents.Methods Through a randomized multistage stratified cluster sampling investigation based on age and sex, a total of 15204 healthy boys and 13047 healthy girls aged 8-17 years were recruited from primary and middle schools in the rural and urban area of Changzhou, China. Standard anthropometric measurements were performed including standing height, sitting height and arm span. Menarche data were available for 6476 of the 13047 female participants. Applying the PB1 mathematical model which fits the pubertal growth spurt well, growth charts and height velocity curves (HVC) were constructed using SPSS 13.0 statistical package and MATLAB7.3 software. Ages at menarche were estimated through probit analysis at the ages at which 10%,25%,50%, 75%, and 90% of the girls attained menarche.Results The averaged standing height in each age group was 132.1 ±5.9 cm, 136.6±6.4 cm,141.5±6.9 cm,148.1±8.1 cm,155.4±8.7 cm,161.4±8.4 cm,166.6±7.4 cm,170.6±6.4 cm,172.5±5.8 cm,173.6±5.6 cm in boys and 131.2±5.7 cm,136.2±6.7 cm,142.3±7.4cm,149.1±7.6 cm,154.3±6.7 cm,157.2±6.2cm,159.1±5.6 cm, 161.1±5.4 cm,160.3±5.2 cm,160.9±5.2 cm,161.1±5.4 cm in girls. The peak growth age (PGA) was 12.6 years for boys and 10.6 years for girls, and the peak height velocity (PHV) was 6.91 cm/yr in boys and 6.69 cm/yr in girls. Age at takeoff was estimated to be 9.3 years of age in boys and 8.0 years of age in girls. The mean contribution of pubertal growth to final height is 35.7 cm in boys, accounting for 20.4% of the final height, and 29.1cm in girls, accounting for 18.0%of the final height. Less than 10% of Chinese girls experience onset of menses before 11.38 years, and approximately 90% of all Chinese girls are menstruating by 13.88 years, with a median age of 12.63 years.Conclusion The current study showed an advancing trend in PGA in both Chinese boys and girls. Decreasing menarche age was also observed for Chinese girls. These updated data would serve as useful reference for interpretation of endocrine and growth status and growth disorders in Chinese during peripubertal period.Chapter 2 (section 2) Timing and correlates of peak height velocity in adolescent idiopathic scoliosisObejective To determine the timing and magnitude of PHV(Peak height velocity) in Chinese idiopathic scoliosis (IS) through construction of growth velocity curves. The predictive value of several maturity indicators in its association with the timing of the PHV will also be investigated. Moreover, the PHV and other maturity indicators will be evaluated for their correlation with curve progression during brace treatment, so as to optimize the treatment strategy.Methods This prospective longitudinal cohort study will be incorporated in the usual care of patients with adolescent idiopathic scoliosis. New female IS patients aged 9-12yrs and male IS patients aged 10-13 yrs with open triradiate cartilage will be recruited in this study. Follow up will take place every 6 months, with each patient be followed through the pubertal growth spurt. Several maturity indicators are evaluated including different body length dimensions (standing height and arm span), secondary sexual characteristics, skeletal age in hand and wrist, the Risser sign, the status of the triradiate cartilage. Timing and magnitude of PHV in IS will be determined through construction of growth velocity curves. Correlations of all dimensions of maturity indicators will be investigated in their relationship to the timing of the pubertal growth spurt, and to the progression of the scoliotic curve.Results 21 female and 8 male IS patients were recruited in this study. The averaged PHV was 9.54±1.26 cm/y in girls and 11.48±1.77 cm/y in boys, while the averaged PGA was 11.24±0.77 yrs in girls and 13.21±0.98 yrs in boys. PHV occurred at an averaged DSA score of 416.00±26.76 in boys and 338.88±22.62 in girls. Within the period of PHV, Tanner Whitehouse stage G occupied 83.7%in girls and 85.2%in boys; stage 1 and 2 of the triradiate cartilage occupied 28.6% and 66.7% in girls,25% and 75% in boys, respectively. The Risser 0 and 1 took up of 80.9%and 19.1% in girls,100% and 0% in boys. Tanner stage 2 and 3 in girls accounted for 42.6%and 52.3% for breast and pubic hair, respectively, while Tanner stage 2 and 3 in boys accounted for 62.5%and 37.5%,50.0% and 25.0%for penis and scrotum and pubic hair, respectively. Brace treatment through the pubertal growth spurt demonstrated a failure rate of 57.1%in girls and 62.5% in boys, with the peak angular velocity averaged 11.69±4.25°/y in girls and 13.97±3.87°/y in boys. All but three cases experienced this marked curve acceleration phase at or half a year post-PHV. The corresponding Risser sign for this phase is Risser 0 with semi-closed or closed triradiate cartilage and Risser 1. The DSA score averaged 431.83±33.64 for girls and 382.00+62.71 for boys during this curve acceleration phase.Conclusions Delayed onset of pubertal growth spurt was observed in idiopathic scoliotic individuals, with relatively larger growth velocity observed in our study. The DSA score, Tanner Whitehouse stage G, semi-closed triradiate cartilage, Tanner stage 2 and 3 of secondary sexual characteristics are all good predictors for timing of peak height velocity. Timing of PHV (onset or half a year post-PHV), Risser 0 with semi-closed or closed triradiate cartilage and Risser 1 are highly associated with the curve accelaration phase in IS, and IS patients are prone to be resistent to brace treatment despite strictly braced during this phase.Chapter 2 (section 3) Timing of menarche in Chinese girls with and without adolescent idiopathic scoliosis:current results and review of the literatureObejective To estimate the distribution of age at menarche for AIS girls and normal controls with large sample size, and subsequently to explore the potential menarche age difference and elucidate it through literature reviewing, so as to investigate the possible role of menarche in AIS.Methods Subjects for normal control girls were selected from a large cross-sectional anthropometric survey conducted in 2008, which aimed to investigate pubertal linear growth in East China. Menstrual status data were collected by inquiring of female participants or their guardians about the age when their periods or menstrual cycles started.6376 of the 13047 female participants experienced onset of menses by the time of investigation, with their menarche data available.2196 AIS girls prescribed with conservative treatment (follow-up at periodic interval or bracing treatment) or correction surgery in our hospital since 2002 were recruited, with their menarche data recorded either at their initial clinical visit or in the follow-up period. Statistical analysis was performed using the SPSS statistical software (version 13.0, Chicago, USA). Probit analysis was used to calculate the median menarche age and estimate ages at menarche at which 10%,25%,50%,75%, and 90% of the girls attained menarche. The fiducial limits of these estimates were computed to indicate the level of precision for these estimated ages from the probit analysis. Probit plots for age at menarche were made for AIS affected girls and normal controls, respectively. Independent-Sample T test was used to explore the difference of menarche age between AIS girls and normal controls. Proportion of girls starting to menstruate after 14yrs was also compared through x2 test among AIS and normal controls. Moreover mean menarche age of AIS affected girls with Cobb angle<40°,40°-60°,>60° were compared to investigate its association with curve severity by Independent-Sample T test.Results We notice that less than 10% of healthy Chinese girls experienced onset of menses before 11.38yrs, and approximately 90% of healthy Chinese girls were menstruating by 13.88yrs, with a median age of 12.63yrs. As for AIS girls, less than 10% started to menstruate before 11.27 yrs, and approximately 90% were menstruating by 14.38 yrs, with a median age of 12.83 yrs. Average menarche age in AIS (12.83 ±1.22yrs) was significantly later than that of normal control girls (12.63 ±0.98yrs) (p<0.001). Age at menarche for AIS affected girls was significantly later than that of normal control girls at 75%,90% of those who had attained menarche (p=0.001, p<0.001). Proportion of girls starting to menstruate after 14yrs was significantly higher in AIS population compared with normal controls (16.3%vs. 8.1%, p<0.001). In addition, AIS girls with Cobb angle>60° experienced onset of menses at an average age of 13.25yrs, which was significant later than AIS girls with Cobb angle<40°(12.81yrs, p<0.05) and marginally significant later than AIS girls with Cobb angle between 40°-60°(12.86yrs, p=0.053).Conclusion A tendency of delayed onset of menarche was observed in Chinese idiopathic scoliotic girls in this large sample study, especially for girls with Cobb angle>60°, which is supported by multiple previously established positive linkages on AIS etiology studies. Accordingly it is believed that late menarche may contribute importantly to abnormal pubertal growth and subsequently modulate curve behavior in AIS. |
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