Introducing and Reviewing a Novel Mutation of ROBO3 in Horizontal Gaze Palsy with Progressive Scoliosis from a Chinese Family.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder caused by ROBO3 gene mutations. To date, the number of confirmed HGPPS cases caused by gene mutations is estimated at 76. However, HGPPS caused by ROBO3 gene mutation has not been reported in the Chinese population. In this study, the clinical data, brain imaging features, somatosensory evoked potentials (SEP), and ROBO3 gene mutations were obtained for two Chinese patients with HGPPS. The proband was an 11-year-old boy. He developed horizontal eye movement disorder at the age of 1 year and scoliosis at the age of 11 years. Two eyeballs fixed in the midline position were revealed by neurological examination. A dorsal cleft in the pons and a butterfly-shaped medulla were shown by brain magnetic resonance imaging. Again, most corticospinal bundles did not cross in the brainstem, as revealed by diffusion tensor imaging. SEP confirmed that most somatosensory projections were uncrossed. The proband's 7-year-old brother exhibited similar clinical manifestations and imaging features. The brothers had compound heterozygous mutations c.3165G>A (p.W1055X) and c.955G>A (p.E319K) of the ROBO3 gene. The c.3165G>A mutation is a novel nonsense mutation that has not been previously reported. This study reports the first two cases of HGPPS carrying a novel ROBO3 gene mutation in patients from a Chinese family, thereby expanding the disease spectrum. Reports from the literature show that missense mutation is the most common mutational type in the ROBO3 gene. Early ROBO3 gene detection is required for patients exhibiting early-onset eyeball movement disorder to confirm HGPPS disease.

The first case report of Kyphoscoliotic Ehlers-Danlos syndrome of chinese origin with a novel PLOD1 gene mutation.

BACKGROUND: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by progressive kyphoscoliosis, congenital muscular hypotonia, marked joint hypermobility, and severe skin hyperextensibility and fragility. Deficiency of lysyl hydroxylase 1 (LH1) due to mutations of PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) gene has been identified as the pathogenic cause of kEDS (kEDS-PLOD1). Up to now, kEDS-PLOD1 has not been reported among Chinese population. CASE PRESENTATION: A 17-year-old Chinese male patient presenting with hypotonia, joint hypermobility and scoliosis was referred to our hospital. After birth, he was found to have severe hypotonia leading to delayed motor development. Subsequently, joint hypermobility, kyphoscoliosis and amblyopia were found. Inguinal hernia was found at age 5 years and closed by surgery. At the same time, he presented with hyperextensible and bruisable velvety skin with widened atrophic scarring after minor trauma. Dislocation of elbow joint was noted at age of 6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. His family history was unremarkable. Physical examination revealed elevated blood pressure. Slight facial dysmorphologies including high palate, epicanthal folds, and down-slanting palpebral fissures were found. He also had blue sclerae with normal hearing. X-rays revealed severe degree of scoliosis and osteopenia. The Echocardiography findings were normal. Laboratory examination revealed a slightly elevated bone turnover. Based on the clinical manifestations presented by our patient, kEDS was suspected. Genetic analysis revealed a novel homozygous missense mutation of PLOD1 (c.1697 G > A, p.C566Y), confirming the diagnosis of kEDS-PLOD1. The patient was treated with alfacalcidol and nifedipine. Improved physical strength and normal blood pressure were reported after 12-month follow-up. CONCLUSIONS: This is the first case of kEDS-PLOD1 of Chinese origin. We identified one novel mutation of PLOD1, extending the mutation spectrum of PLOD1. Diagnosis of kEDS-PLOD1 should be considered in patients with congenital hypotonia, progressive kyphoscoliosis, joint hypermobility, and skin hyperextensibility and confirmed by mutation analysis of PLOD1.

Healthcare disparities in adolescent idiopathic scoliosis: the impact of socioeconomic factors on Cobb angle.

STUDY DESIGN: Retrospective chart review. OBJECTIVES: The aim of this study is to assess the role of insurance type, geographic socioeconomic status, and ethnicity in AIS disease severity in a state with mandated scoliosis screenings. Early detection of adolescent idiopathic scoliosis (AIS) is associated with reduced curve progression, surgical treatment, and long-term sequelae. Type of insurance, ethnicity, and socioeconomic status are important determinants in healthcare access. METHODS: Data were obtained for 561 AIS patients aged 10-18 years, living within a single county, and presenting to a single healthcare system for initial evaluation of AIS between 2010 and 2016 that met inclusion criteria. Demographic data including gender, age, self-reported ethnicity, insurance, and zip code were collected. Outcome measures included Cobb angle, curve severity, and referral delay. A single fellowship-trained pediatric orthopedic surgeon calculated presenting Cobb angle for each case. Zip code was used as a proxy for household income level. Independent sample t tests, analysis of variance and covariance, and χ2 analysis were used to determine the significant differences and correlations. RESULTS: Female patients (n = 326, CA = 22.4°) had significantly greater Cobb angle measurements compared with male patients (n = 117, CA = 18.1°). Patients with government-supported insurance had significantly higher Cobb angles (CA = 22.1°) than privately insured patients (CA = 19.2°) but were both classified within the "mild" range clinically, and are likely not clinically significant. There was no correlation between income level and Cobb angle. Referral delay and Cobb angle severity did not vary by age, income, or insurance. A χ2 analysis showed no association between Cobb angle and race. CONCLUSIONS: Cobb angle severity was not influenced by SES factors, including ethnicity and household income. LEVEL OF EVIDENCE: Level-II.

Validation of the Korean Version of the Body Image Disturbance Questionnaire-Scoliosis.

STUDY DESIGN: Cross-cultural adaptation and validation of the Body Image Disturbance Questionnaire-Scoliosis OBJECTIVE.: The purpose of this study was to evaluate the reliability and validity of an adapted Korean version of the Body Image Disturbance Questionnaire-Scoliosis version (BIDQ-S). SUMMARY OF BACKGROUND DATA: A modified version of the BIDQ instrument has been validated in adolescent idiopathic scoliosis (AIS) to assess the perception of spinal appearance and psychological disturbance. However, there is no culturally adapted, reliable, and validated BIDQ-S for the Korean population. METHODS: Translation/retranslation of the English version of the BIDQ-S was conducted, and all steps of the cross-cultural adaptation process were performed. The Korean version of the BIDQ-S (K-BIDQ-S) and the previously validated appearance domain of the Korean version of the Scoliosis Research Society-22 Outcomes questionnaire (K-SRS-22) and Spinal Appearance Questionnaire (K-SAQ) were mailed to 152 patients with AIS. Reliability assessments were conducted using κ statistics to assess item agreements, and intraclass correlation coefficients (ICCs) and Cronbach α values were calculated. Convergent validity was evaluated by comparing the scores of the K-BIDQ-S, K-SAQ, and K-SRS-22 appearance domain and discriminant validity by analyzing relationships between K-BIDQ-S score and patient characteristics. RESULTS: All items of the K-BIDQ-S had κ values of agreement >0.6. The K-BIDQ-S showed excellent test/retest reliability with an ICC of 0.912. Internal consistency of the K-BIDQ-S was found to be very good (α = 0.880). Convergent validity testing demonstrated good correlations between the K-BIDQ-S and K-SAQ (r = 0.617), and between the K-BIDQ-S and K-SRS-22 (r = -651). The correlation between the K-BIDQ-S and major curve magnitude was significant (r = 0.688). Discriminant validity was confirmed by significant differences in K-BIDQ-S scores among patients requiring observation, bracing, or surgery. CONCLUSION: The K-BIDQ-S showed satisfactory reliability and validity, and thus, is considered suitable for the evaluation of spinal deformity appearance in Korean-speaking patients with AIS. LEVEL OF EVIDENCE: 3.

Association between ladybird homeobox 1 gene polymorphisms and adolescent idiopathic scoliosis: A MOOSE-compliant meta-analysis.

The Ladybird Homeobox 1 (LBX1) gene has been implicated in the etiology of adolescent idiopathic scoliosis (AIS). The association between LBX1 gene polymorphisms and AIS has been investigated in several studies. However, these findings have yield contradictory results rather than conclusive evidence.This study is to provide a meta-analysis of the published case-control studies on the association between LBX1 gene polymorphisms and AIS in Asian and Caucasian populations.This meta-analysis conformed to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We conducted a literature research on PubMed, Embase, Web of Science, and Cochrane Library until February 10, 2018. We included all case-control or cohort studies about association between LBX1 gene polymorphisms and AIS. The Risk Of Bias In Non-randomised Studies-of Interventions and Critical Appraisal Skills Programme were used to evaluate the risk of bias and study quality. We assessed the strength of association by pooled odds ratios (ORs) and 95% confidence intervals (CIs) in all genetic models under a fixed-effect model or random-effect model. We further performed subgroup analysis by ethnicity and sex. Sensitivity analysis and publication bias were also undertaken.A total of 10 studies (11,411 cases and 26,609 controls) were included in this meta-analysis. The pooled results showed a statistically significant association between LBX1 gene polymorphisms and AIS (for rs11190870, T vs C, OR = 1.54, 95% CI = 1.48-1.61, P < .00001; for rs625039, G vs A, OR = 1.50, 95% CI: 1.38-1.62; P < .00001; for rs678741, G vs A, OR = 0.74, 95% CI: 0.63-0.86; P < .0001; for rs11598564, G vs A, OR = 1.41, 95% CI: 1.31-1.51; P < .0001). For stratified analyses by ethnicity and sex, robust significant associations were detected in Asian and Caucasian populations, and in women and men under all genetic models.T allele of rs11190870 and G alleles of rs625039 and rs11598564 represent risk factors for AIS, but G allele of rs678741 may play a protective role in the occurrence of AIS. Further research is needed to confirm this finding and to understand its implications.

Cultural Variations in the Minimum Clinically Important Difference Thresholds for SRS-22R After Surgery for Adult Spinal Deformity.

STUDY DESIGN: Longitudinal cohort. OBJECTIVE: To calculate the minimum clinically important difference (MCID) threshold values for the Scoliosis Research Society-22R (SRS-22R) in Japanese patients with adult spinal deformity (ASD) and to compare the results with previously reported values in a North American population. SUMMARY OF BACKGROUND DATA: The SRS-22R has been shown to be reliable, valid, and responsive to change in patients with ASD undergoing surgery. The MCID quantifies a threshold value of improvement that is clinically relevant to the patient. We hypothesize that MCID threshold values of SRS-22R differ between different cultural groups. METHODS: We identified ASD patients who completed the SRS-22R preoperatively and the SRS-30 at minimum two years after surgery. Answers to the last seven questions of the SRS-30 were used as anchors to determine the MCID for the SRS-22R Activity, Pain, Appearance, Mental domains, and Total score using receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 122 (16 male, 106 female) patients were included in the analysis. There was a statistically significant improvement in all domain scores from preoperation to two years postoperation. There was a statistically significant difference in change in domain score among the responses to the anchors (p < .05). The ROC curve analysis yielded MCID values of 0.90 for Activity (area under the curve [AUC] = 0.766), 0.85 for Pain (AUC = 0.637), 1.05 for Appearance (AUC = 0.764), and 0.70 for Mental (AUC = 0.641) domain, 1.05 for Total score (AUC = 0.670). Except for Appearance, these MCID thresholds were higher compared with values reported in patients from North America (Activity = 0.60, Pain = 0.40, Appearance = 1.23, Total = 0.71). CONCLUSIONS: Results of this study showed that cultural variations exist for MCID threshold values for SRS-22 Activity, Pain, Mental domains, and Total score after surgical treatment of ASD.

Functional variants of hepatocyte growth factor identified in patients with adolescent idiopathic scoliosis.

The genetic etiology of adolescent idiopathic scoliosis (AIS) remains obscure. Whole-genome sequencing was performed in four members of one family. Then, we performed a rigorous computational analysis to determine the deleterious effects of the identified variants. Furthermore, the structural differences between the native hepatocyte growth factor (HGF) protein and a protein encoded by an HGF variant containing one mutation (p.T596M) were analyzed using molecular dynamic stimulation. A novel heterozygous mutation (p.T596M) within the HGF gene was identified and found to cosegregate with scoliosis phenotypes in three affected family members. Subsequent modeling and structure-based analyses supported the theory that this mutation is functionally deleterious. Functional analyses demonstrated that the HGF p.T596 M mutation changed the ability of the HGF protein to be secreted and impaired migration and invasion in HEK293T cells. Furthermore, an HGF knockdown zebrafish model exhibited a curly tailed phenotype. Mutation in HGF is associated with an autosomal dominant pattern of inheritance of AIS. This finding increases our understanding of the genetic heterogeneity of AIS.

A multiethnic meta-analysis defined the association of rs12946942 with severe adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis. Controlling its curve progression is the most important clinical task. Although recent genome-wide association studies (GWASs) identified several susceptibility loci associated with the development of AIS, the etiology of curve progression has been still unknown. Our previous GWAS has identified that rs12946942 showed significant association with severe AIS. To confirm the association, we conducted an international meta-analysis using four cohorts with different ethnicity. We analyzed 2272 severe AIS cases and 13,859 controls in total, and found the replication of significant association of rs12946942 (combined P = 7.23×10-13; odds ratio = 1.36, 95% confidence interval = 1.25-1.49). In silico analyses suggested that SOX9 is the most likely susceptibility gene for AIS curve progression in the locus.

Validation of the Korean version of the Brace Questionnaire.

OBJECTIVE: To evaluate the reliability and validity of an adapted Korean version of the Brace Questionnaire (K-BrQ). METHODS: The Greek version of the BrQ was translated/retranslated, and all steps of the cross-cultural adaptation process were performed. The K-BrQ and the previously validated Korean version of the Scoliosis Research Society-22 Outcomes questionnaire (K-SRS-22) were mailed to 120 patients with adolescent idiopathic scoliosis (AIS). Reliability assessments were conducted using kappa statistics to assess item agreements, and intraclass correlation coefficients (ICC) and Cronbach's α values were calculated. Convergent validity was evaluated by comparing the K-BrQ and K-SRS-22 scores and discriminant validity by analyzing relationships between the K-BrQ scores and patient characteristics. RESULTS: 103 patients filled in questionnaires twice. All items of the K-BrQ had kappa values of agreement of >0.6. The K-BrQ showed an excellent test/re-test reliability with an ICC of 0.913. The internal consistency of the K-BrQ was found to be very good (α = 0.872). The convergent validity testing demonstrated a strong correlation between the K-BrQ and K-SRS-22 (r = 712). The correlation between the K-BrQ and major curve magnitude was significant (r = -0.302). CONCLUSION: The adapted K-BrQ showed satisfactory reliability and validity and is thus considered suitable for monitoring the quality of life of Korean-speaking patients with AIS during brace treatment.

A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine.

OBJECTIVE: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. METHODS: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. RESULTS: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. CONCLUSION: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.

The association of rs11190870 near LBX1 with the susceptibility and severity of AIS, a meta-analysis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common structural deformity of the spine. Genetics constitute largely to AIS, and the rs11190870 polymorphism has the potential for use in public health and clinical settings as a predictor of AIS risk. The aim of the present meta-analysis was to provide exhaustive evidence to evaluate the association of rs11190870 with the susceptibility and severity of adolescent idiopathic scoliosis (AIS) in multiple ethnic groups and different genders. MATERIALS AND METHODS: The professional databases, including PubMed, Embase, Social Sciences Citation Index, CINAHL, and International Bibliography of the Social Sciences, were searched from 1966 to October 2015. No language restriction was applied. Reference lists of all the selected articles were hand-searched for any additional studies. Three authors independently extracted data from all eligible studies. The data were analyzed by meta-analysis using fixed-effects or random-effects models with mean differences and risk ratios for continuous and dichotomous variables, respectively. RESULTS: Eight studies were included, and the pooled analysis suggested that the T genotype of SNP rs11190870 leads to a higher risk of AIS in multiple ethnic groups regardless of gender (Total:OR, 1.66, 95% CI 1.53, 1.79; I2 = 37.3%, P = 0.000, Female: OR, 1.62, 95% CI 1.50, 1.73; I2 = 26.7%, P = 0.000, Male: OR, 1.79, 95% CI 1.38, 2.20; I2 = 0.00%, P = 0.000). Additionally, the TT and TC genotype had a larger Cobb angle than those with the CC genotype in the overall and female Asian populations. CONCLUSION: A significant association of rs11190870 with AIS was observed in multiple ethnic groups regardless of gender. Additionally, a significant association was found between rs11190870 and curve severity in the overall and female Asian populations. Due to the limited data and clinical heterogeneity, further studies with large sample sizes are required.

Association of vitamin D receptor BsmI rs1544410 and ApaI rs7975232 polymorphisms with susceptibility to adolescent idiopathic scoliosis: A systematic review and meta-analysis.

BACKGROUND: AIS is the most common spinal deformity disease, yet its etiology remains uncertain. Significant associations have been found between AIS risk and vitamin D receptor (VDR) gene polymorphisms; however, some of these results are controversial. The aim of this study was to determine whether VDR BsmI rs1544410 and ApaI rs7975232 polymorphisms are correlated with AIS. METHODS: Databases, including PubMed, EMBASE, Web of Science, the Cochrane Library, the Chinese Biomedical Literature Database, and the Wanfang Database, were systematically searched, and eligible case-control studies that explored the association of VDR (BsmI and ApaI) and the susceptibility to AIS were selected. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the associations, and subgroup meta-analyses were performed according to the ethnicity of the study population. RESULTS: A total of 5 studies with 717 cases and 554 controls fulfilled the inclusion criteria after assessment by 2 reviewers. Generally, significant correlations were found between the BsmI polymorphism and AIS risk in overall populations and in Asian populations (overall population: B vs b: OR = 2.12, 95% CI = 1.21-3.75, P = .009; BB vs bb: OR = 3.38, 95% CI = 1.08-10.57, P = .036; Bb vs bb: OR = 2.50, 95% CI = 1.29-4.82, P = .006; BB/Bb vs bb: OR = 2.71, 95% CI = 1.31-5.63, P = .007; Asian population: B vs b: OR = 2.42, 95% CI = 1.27-4.61, P = .007; BB vs bb: OR = 4.09, 95% CI = 1.03-16.22, P = .045; Bb vs bb: OR =  2.94, 95% CI = 1.42-6.10, P = .004; BB/Bb vs bb: OR = 3.23, 95% CI = 1.42-7.35, P = .005). There was no significant association observed in Caucasian populations (all P > .05). With regard to the ApaI polymorphism, we found that it significantly decreased the risk of AIS (Aa vs AA: OR = 0.43, 95% CI = 0.24-0.77, P = .004; Aa/aa vs AA: OR = 0.52, 95% CI = 0.30-0.91, P = .023); however, we could not draw a definitive conclusion for Caucasian populations, as no studies have been conducted in this group to determine the role of the VDR ApaI polymorphism in AIS etiology and development. CONCLUSION: VDR BsmI was significantly associated with AIS susceptibility in the overall and Asian populations, while the VDR ApaI polymorphism only played a key role in AIS etiology and development in Asian populations.

Ethnic Variation in Satisfaction and Appearance Concerns in Adolescents With Idiopathic Scoliosis Undergoing Posterior Spinal Fusion With Instrumentation.

STUDY DESIGN: Cohort analysis. OBJECTIVE: Document satisfaction with management and appearance concerns in children of different ethnicity who underwent spinal fusion/instrumentation for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Scoliosis Research Society Questionnaire (SRS-30) outcomes in AIS indicate a link between appearance and satisfaction as well as ethnic variation in appearance domain. Exploration of these findings in the Scoliosis Appearance Questionnaire (SAQ) will allow better understanding of ethnic variation in appearance concerns. METHODS: Children with AIS who underwent posterior-only operations and completed the SAQ's question 31 were identified. Univariate logistic regression of SAQ questions 12-30 was used to assess relationships with ethnicity. RESULTS: 1,977 children [boys: 281, girls: 1,290, unspecified: 406; average age 15.1 ± 2.0 years preoperatively and 817 children (boys: 113, girls: 569, unspecified: 135; average age 15.1 ± 2.0 years) at 2 years' follow-up met inclusion criteria. The majority were Caucasian (57.3%). Few were Hispanic (3.4%). Preoperatively, the largest percentage of patients in each ethnic group answered "very true" to "wanting to be more even." Preoperatively, Asians were least likely to be concerned about evenness of shoulders, hips, waist, ribs, and chest in back (p < .05); however, they expressed greatest concern about height (p < .05). African Americans and Hispanics were more likely to be concerned about breast evenness and anterior chest and looking better in clothes (p < .05). African Americans were most concerned about overall evenness and evenness of shoulders, hips, waist, ribs, posterior chest, leg length, and looking more attractive (p < .05). Surgical scar was most important postoperatively for all ethnicities. African Americans and Hispanics were more self-conscious about scar (p < .05). African Americans were most likely to want to be more even and have more even shoulders, hips, waist, leg lengths, ribs, breasts, and chest postoperatively. CONCLUSIONS: Ethnicity influenced appearance concerns in pre- and postoperative SAQ evaluation. Ethnic variation in appearance concerns should be taken into account and differentiated when counseling patients about AIS and surgical correction. LEVEL OF EVIDENCE: Level III.

Genetic polymorphisms of GPR126 are functionally associated with PUMC classifications of adolescent idiopathic scoliosis in a Northern Han population.

GPR126 has been identified to be associated with AIS (Adolescent Idiopathic Scoliosis) in different populations, but data on the northern Chinese population are unavailable. Additionally, it is important to know the exact clinical phenotypes associated with specific genetic polymorphisms. Fourteen SNP (single nucleotide polymorphism) loci in GPR126 were genotyped in 480 northern Chinese Han AIS patients and 841 controls. These patients were classified into three types based on the PUMC classification system. Luciferase assays were used to investigate their regulation of GPR126 transcription activity. Combined and stratified genotype-phenotype association analyses were conducted. The alleles rs225694, rs7774095 and rs2294773 were significantly associated with AIS (P = 0.021, 0.048 and 0.023, respectively). rs225694 and rs7774095 potentially have regulatory functions for the GRP126 gene. Correlation analysis revealed that allele A of rs225694 was a risk allele only for PUMC type II AIS (P = 0.036) and allele G of rs2294773 was a risk allele only for PUMC type I AIS (P = 0.018). In summary, rs225694, rs7774095 and rs2294773 are significantly associated with disease in northern Chinese Han AIS patients. The SNPs rs225694 and rs2294773 are associated with different AIS PUMC classifications.

VANGL1 Is Not Associated With the Susceptibility of Adolescent Idiopathic Scoliosis in the Chinese Population.

STUDY DESIGN: A case-control study. OBJECTIVE: To replicate the association between the VANGL1 gene and the susceptibility of AIS in the Chinese population. SUMMARY OF BACKGROUND DATA: The mutations of VANGL1 gene were recently reported to be associated with AIS in the Danish population. However, there is a lack of replication in other populations. Further analysis of the functional role of VANGL1 in AIS was warranted. METHODS: A total of 1481 female AIS patients and 1372 age-matched healthy controls were included in this study. single nucleotide variant (SNV)s c.407T > A and c.1318T > G were genotyped using allelic-specific multiple ligase detection reactions. single nucleotide polymorphism (SNP)s covering VANGL1 gene were selected using Haploview (v2.6). The associations between theses SNPs and AIS were investigated through Cochran-Armitage trend test by PLINK (v1.90). Relative mRNA expression of VANGL1 in the paraspinal muscles was analyzed for 30 patients and 24 age-matched controls. The difference of mRNA expression level between the two groups was analyzed with the Student t test. RESULTS: There was no case of mutation for all the subjects. A total of 22 SNPs covering VANGL1 were analyzed. All the SNPs were found to have comparable distribution of genotype and allele frequency in the cases and the controls. Moreover, there was no significant difference regarding the mRNA expression of VANGL1 in the two groups. CONCLUSION: VANGL1 gene is not associated with AIS in the Chinese population. Replication studies in other ethnic groups are warranted to further clarify the role of the VANGL1 gene in AIS. LEVEL OF EVIDENCE: 4.

The Risk of Curve Progression and Surgery in African Americans With Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Retrospective clinical cohort study. OBJECTIVE: To determine if certain risk factors (age, curve magnitude, skeletal maturity, gender, and curve pattern) traditionally associated with curve progression and surgical intervention in the general population apply equally to African Americans. SUMMARY OF BACKGROUND DATA: Currently, information is limited on the role that a patient's race plays in the risk of curve progression of adolescent idiopathic scoliosis (AIS), and existing studies have conflicting results. METHODS: Retrospective search of records identified patients who were African American, had been diagnosed with AIS, had a major curve Cobb angle of 10 degrees or more, and had at least two clinical visits with spinal radiographs at least 90 days apart to determine the risk factors for surgical treatment, and 2 years apart to determine the risk factors for curve progression. Patients with a medical condition likely to cause scoliosis were excluded. RESULTS: Of 738 African American patients with AIS, 223 were assessed for surgical risk factors, and 72 were assessed for curve progression risk factors. Fifty-six (29.17%) had progression of the major coronal curve, and 38 (17.04%) underwent surgery. Age at presentation and curve magnitude at presentation were significant risk factors for surgical intervention. Curve magnitude at presentation was a significant risk factor for curve progression. No significant relationships were found for gender or curve type as they relate to surgical intervention or curve progression. CONCLUSION: Age and curve magnitude at presentation were significantly associated with surgery, as is true in other scoliosis populations. Curve magnitude at presentation was associated with curve progression. In contrast to studies in other populations, however, no significant association was observed between curve progression and age at presentation, curve type, or gender, or between surgery and curve type or gender. LEVEL OF EVIDENCE: Level III, prognostic cohort study.

Genetic Polymorphism of LBX1 Is Associated With Adolescent Idiopathic Scoliosis in Northern Chinese Han Population.

STUDY DESIGN: A case-control association study was performed to investigate the relationship between ladybird homeobox (LBX1) and adolescent idiopathic scoliosis (AIS) in northern Chinese Han population. OBJECTIVE: To explore the prevalence and functional importance of LBX1 polymorphisms in patients with AIS within the northern Chinese Han population. SUMMARY OF BACKGROUND DATA: AIS is the most common subtype of idiopathic scoliosis. Genetic factors such as LBX1 polymorphisms have been recently proved to be associated with AIS in some populations. In this study we explored the prevalence and functional importance of the polymorphisms around LBX1 in patients with AIS within the northern Chinese Han population. METHODS: Five tag single nucleotide polymorphisms (SNPs) around or in LBX1 were genotyped in 180 patients with AIS and 182 controls. And the luciferase assay was performed to explore the functional importance of the most significant SNPs. RESULTS: We replicated that rs11190870, previously reported as the most significantly associated SNP, was enriched in our AIS cohort. In addition, we found that the T allele of rs1322331 was associated with a novel risk allele (odds ratio = 3.349, 95% confidence interval 1.742-6.436). In the following luciferase assay, the TT-type promoter showed significantly reduced transcription activity in vitro. CONCLUSION: Two SNPs around LBX1, rs11190870 and rs1322331 are associated with AIS in northern Chinese Han population. The T allele of rs1322331 is a novel risk allele. We hypothesize that rs1322331 might increase patients' susceptibility to AIS by reducing LBX1-AS1 transcription and thus upregulating the function of LBX1. LEVEL OF EVIDENCE: 3.

Association between IGF1 gene single nucleotide polymorphism (rs5742612) and adolescent idiopathic scoliosis: a meta-analysis.

PURPOSE: Insulin-like growth factor 1 (IGF1) gene single nucleotide polymorphism (rs5742612) has been associated with adolescent idiopathic scoliosis (AIS) in several studies with limited sample size and inconsistent outcomes. So we perform this meta-analysis to assess the precise association between IGF1 gene single nucleotide polymorphism (rs5742612) and AIS. METHODS: We systematically searched Pubmed, Embase, Web of Science and Cochrane Library up to January 19, 2016 to obtain relevant studies using our research strategy. Four articles all belonging to case-control studies were included in our meta-analysis. RESULTS: A total of four studies containing 763 cases and 559 controls satisfied the inclusion criteria after judgment by two reviewers. No significant associations were detected between IGF1 gene single nucleotide polymorphism (rs5742612) and AIS (T vs. C, OR = 1.10, 95 % CI 0.91-1.34, p = 0.32; TT vs. CC: OR = 1.28, 95 % CI 0.82-2.02, p = 0.28; TC vs. CC: OR = 1.29, 95 % CI 0.82-2.06, p = 0.27; TT/TC vs. CC: OR = 1.28, 95 % CI 0.83-1.98, p = 0.27; TT vs. TC/CC: OR = 1.06, 95 % CI 0.82-1.36, p = 0.66). CONCLUSIONS: IGF1 gene single nucleotide polymorphism (rs5742612) is not significant associated with susceptibility to AIS in either Asian or Caucasian populations. However, IGF1 gene rs5742612 may be associated with severity of AIS. Further studies with larger sample size and different population groups involving the relationship are required to confirm the potential association.

Association of IL-6 and MMP-3 gene polymorphisms with susceptibility to adolescent idiopathic scoliosis: a meta-analysis.

Recently, several institutions have investigated the associations of MMP-3-1171 5A/6A and IL-6-174-G/C gene polymorphisms with adolescent idiopathic scoliosis (AIS), while reports from different institutions are not consistent. Therefore, we, comprehensively and systematically performed this meta-analysis to detect whether the two gene polymorphisms are correlated with AIS. From January 1994 to October 2015, all case-control studies focussed on the relationship between the two aforementioned gene polymorphisms and the susceptibility to AIS were retrieved from bibliographic databases. A total of 16 articles were found, of which five consisted of 944 cases and 1177 controls, were finally included after being assessed by two reviewers. We calculated the pooled odds ratio (OR) with 95% confidence interval (95% CI) to assess the associations. The pooled data analyses were based on allele contrast, homozygote, heterozygote, dominant and recessive models. Overall, there was no significant association of IL-6-174-G/C gene polymorphism with AIS risk. Significant association was observed in homozygote model of MMP-3-1171-5A/6A gene polymorphism (5A5A versus 6A6A: OR = 1.69, 95% CI = 1.11-2.58, P = 0.02). When stratified into Caucasian and Asian populations, positive association was found in Caucasian population (5A versus 6A: OR = 1.43, 95% CI = 1.11-1.84, P = 0.006; 5A5A versus 6A6A: OR = 1.90, 95% CI = 1.13-3.19, P = 0.015); however, there was no significant association in Asian population. The present study concluded that 5A5A genotype of MMP-3-1171 5A/6A gene polymorphism was associated with AIS, especially in Caucasian population. However, no significant association was detected between IL-6-174-G/C gene polymorphism and AIS.

Reliability and Validity of the Adapted Spanish Version of the Early-onset Scoliosis-24 Questionnaire.

STUDY DESIGN: Translation and validation of the Early Onset Scoliosis-24 Questionnaire (EOSQ-24). OBJECTIVE: To cross-culturally adapt the American English version of the EOSQ-24 into Spanish language, and to assess its reliability and discriminative validity. SUMMARY OF BACKGROUND DATA: Treatment of early-onset scoliosis (EOS) seeks to improve natural history and health-related quality of life in children, but radiographic parameters are insufficient to evaluate the severity and efficacy of treatment in these patients. EOSQ-24 was developed to assess the health-related quality of life of EOS children; however, it has not been transculturally adapted and validated for Spanish subjects. METHODS: Translation and cross-cultural adaptation of the original EOSQ-24 was performed according to published guidelines by an expert committee. The Spanish version of the EOSQ-24 was applied to 44 EOS patients. Reliability was assessed by internal consistency using Cronbach α, item-total correlations, and inter-item correlations. Data quality was assessed by mean, median, percentage of missing data, and ceiling and floor effects. For discriminative validity, comparisons between categorical variables were made by using non-parametric (Kruskal-Wallis and/or Mann Whitney U) tests, and Spearman correlation coefficients were used for continuous variables. RESULTS: In our study, all items and domains showed very good global internal consistencies (Cronbach α 0.897 and 0.836, respectively). Corrected item-total correlations were good for all domains (>0.3). Two of 24 items showed low corrected item-total correlations (r = 0.179 and r = 0.254), but Cronbach α did not increase when these items were removed. Inter-item correlations were acceptable (>0.2). EOSQ-24 was found capable to discriminate patients with different curves severity (P = 0.001), diagnosis (P = 0.006), and ambulatory status (P = 0.053). CONCLUSION: The Spanish version of the EOSQ-24 is reliable and a valid tool for the psychometric assessment of children with EOS, and can be applied in routine clinical practice and for research purposes. LEVEL OF EVIDENCE: 2.