Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference >10°) and 2 concordant (Cobb angle difference ≤2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Morphological changes of intervertebral disc in relation with curve severity of patients with Adolescent Idiopathic Scoliosis – a T2-weighted MRI study

The purpose of this study was to evaluate the morphological changes of intervertebral discs (IVD) and vertebral bodies (VB) in AIS girls according to the subgroups with different curve severity by magnetic resonance imaging (MRI). This study included 33 age-matched female controls and 76 AIS girls with a right-sided thoracic curvature. Wedge angle, height ratio and distance ratio of VB and IVD were measured on the best midline coronal and sagittal planes from reformatted MRI spine. Volumes of VB, IVD and nucleus pulposus (NP) were evaluated on volumetric images. One-way ANOVA with Bonferroni correction was used. There was significant difference in wedge angle and height ratio of VB and IVD between AIS and controls. In severe-AIS, the position of NP was significantly shifted to the convexity when compared with non-severe AIS and controls. Whereas, the volume of IVD and NP in severe-AIS was found to be significantly smaller. On top of coronal wedging of VB and IVD, there was significantly reduced volume of IVD and NP in severe-AIS patients, despite T2 signal of IVD was preserved. The current findings indicate that early mechanical effects on the discs and vertebrae in adolescent scoliotic spine is evident on quantitative imaging. Importantly, these patients may be vulnerable to disc degeneration if no operative treatment is prescribed.

Genetic variant of MIR4300HG is associated with progression of adolescent idiopathic scoliosis in a Chinese population

Background A recent genome-wide association study identified a susceptible locus in MIR4300HG gene that was associated with curve progression of adolescent idiopathic scoliosis (AIS) in the Japanese population. However, the association between the gene and curve progression in other populations remains unclear. Methods A cohort of 1952 AIS patients and 2495 healthy controls were included in the case-control analysis. In the case-only analysis, 747 patients were assigned to the progression group and 520 patients were assigned to the non-progression group, respectively. Rs35333564 was genotyped for all the subjects. Paraspinal muscles of 76 patients were collected for the analysis of gene expression. Chi-square test and ANOVA test were used for the intergroup comparison. Pearson correlation analysis was performed to investigate the relationship between the gene expression and curve magnitude. Results Variant rs35333564 was significantly associated with the curve severity of AIS (p = 0.025), but not the development of AIS (p = 0.418). Genotype GG was indicated by remarkably lower expression of MIR4300 (p = 0.020) which was significantly correlated with curve magnitude (p = 0.010). As a predicted target gene of MIR4300, the expression of CRTC1 was negatively correlated with MIR4300 expression (p = 0.012, r = −0.287) and positively correlated with curve severity (p = 0.025, r = 0.257). Conclusions The association between rs35333564 and curve progression was successfully replicated in a Chinese AIS population. CRTC1 may be the target gene of MIR4300 that plays a role in the curve progression of AIS.

Associations between curve severity and revised Scoliosis Research Society-22 and scoliosis Japanese Questionnaire-27 scores in female patients with adolescent idiopathic scoliosis: a multicenter, cross-sectional study

Background Patient-reported outcome measures are widely utilized to assess health-related quality of life (HRQOL) in patients with adolescent idiopathic scoliosis (AIS). However, the association between HRQOL and curve severity is mostly unknown. The aim of this study is to clarify the association between HRQOL and curve severity, and to determine the optimal cutoff values of patient-reported outcomes for major curve severity in female patients with AIS. Methods Female patients with AIS treated conservatively were recruited. The patients’ HRQOL outcomes were examined using the revised Scoliosis Research Society-22 (SRS-22r) and the Scoliosis Japanese Questionnaire-27 (SJ-27). The correlations of the SRS-22r and SJ-27 scores with the major Cobb angle were assessed using Spearman’s correlation coefficient analysis. The association between HRQOL issues in the SJ-27 and the major Cobb angle was evaluated by calculating Akaike’s Information Criterion (AIC). Furthermore, the optimal cutoff values of the SRS-22r and SJ-27 scores for the major Cobb angle were determined by AIC analysis. Results The study cohort comprised 306 female patients with AIS. The SRS-22r and SJ-27 scores were significantly correlated with the major Cobb angle. Questions in the SJ-27 regarding discomfort when wearing clothes showed a lower AIC value in patients with severe scoliosis. The optimal cutoff values were a SRS-22r score of 3.2 for the discrimination of severe scoliosis (Cobb angle ≥48°), and a SJ-27 score of 32 for the discrimination of moderate scoliosis (Cobb angle ≥33°). Conclusion Discomfort when wearing clothes was the most important HRQOL problem caused by severe scoliosis. The SRS-22r and SJ-27 scores are useful for the discrimination of clinical status in female patients with severe scoliosis or moderate scoliosis.

The importance of curve severity, type and instrumentation strategy in the surgical correction of adolescent idiopathic scoliosis: an in silico clinical trial on 64 cases

Adolescent idiopathic scoliosis is a three-dimensional deformity of the spine which is frequently corrected with the implantation of instrumentation with generally good or excellent clinical results; mechanical post-operative complications such as implant loosening and breakage are however relatively frequent. The rate of complications is associated with a lack of consensus about the surgical decision-making process; choices about the instrumentation length, the anchoring implants and the degree of correction are indeed mostly based on personal views and previous experience of the surgeon. In this work, we performed an in silico clinical trial on a large number of subjects in order to clarify which factors have the highest importance in determining the risk of complications by quantitatively analysing the mechanical stresses and loads in the instrumentation after the correction maneuvers. The results of the simulations highlighted the fundamental role of the curve severity, also in its three-dimensional aspect, and of the instrumentation strategy, whereas the length of the fixation had a lower importance.

Intervention versus Observation in Mild Idiopathic Scoliosis in Skeletally Immature Patients

Introduction: Observation is the treatment of choice for idiopathic scoliosis with Cobb angles between 15 degrees - 20 degrees in growing children. This passive approach does not address the anxiety of the patient and the stress of the parents. In this paper, we attempt to identify skeletally immature patients with mild scoliosis curvatures that are more at risk of progression and propose possible intervention for this group of subjects. Methods: The literature was searched in Pubmed, and additional references were searched manually in the literature. Results: Many studies have shown that low serum 25[OH]D level, bone mineral density (BMD), and body mass index (BMI) are related to the curve severity or progression of the curve. We suggest that skeletally immature patients (< Risser 2) with mild curves be divided into two groups, viz. Group O (observation) with a lower risk of progression, and Group I (intervention) with a higher risk of curvature progression. We propose early intervention for the latter group. It is suggested that pre-menarcheal, skeletally immature patients with mild idiopathic scoliosis, and low vitamin D, BMD, and BMI should be treated. Also, asymmetric foot biomechanics should be addressed, although nutrition and foot orthoses are regarded to have no role in the management of idiopathic scoliosis. The outcome of early intervention may be utterly different from late treatment when the curvature becomes more structural, and the patient more skeletally mature. Conclusion: Research is required to prove if the intervention is clinically indicated.

Association between Bone Turnover Markers, Leptin, and Nutritional Status in Girls with Adolescent Idiopathic Scoliosis (AIS)

The link between scoliotic deformity and bone metabolism in adolescent idiopathic scoliosis (AIS) has not been well researched. Moreover, the data concerning the cross-talk between fat tissue content/hormonal activity and bone markers in this group of patients are lacking. The aim of the study was to assess whether there exists a significant relationship between the severity of AIS and bone turnover markers and leptin levels. The study group was consisted of 77 AIS girls, aged 14.7 ± 2.17 years. Scoliotic curve severity assessed by Cobb’s angle was categorized as mild (10–19°), moderate (20–39°), or severe (≥40°). Corrected height, weight, and waist and hip circumferences were measured and body mass index (BMI), corrected height Z-score, BMI Z-score, and waist/height ratio (WHtR) were calculated for the entire group. Body composition parameters: fat mass (FAT), fat-free mass (FFM), and predicted muscle mass (PMM) were determined using a bioelectrical impedance analyzer. Bone turnover markers (osteocalcin (OC) and amino terminal of collagen cross-links (NTx) and leptin levels were assessed in serum. Multiple regression analysis showed that, OC, NTx (negatively with p < 0.05), and leptin (positively with p < 0.01) were significantly associated with curve severity in AIS girls. Moreover, Cobb’s angle was positively correlated with W/HtR (p < 0.01) and FAT (p < 0.05). One-way analysis of variance (ANOVA) revealed significant differences in leptin (p < 0.05 vs. mild only), OC (p < 0.05 vs. mild and moderate), and W/HtR (p < 0.01 and p < 0.05 vs. mild and moderate, respectively) between the three AIS severity subgroups. OC was significantly lower in the severe AIS subgroup, while leptin and W/HtR were significantly higher. Significant correlations between leptin and anthropometrical parameters as BMI z-score and W/HtR were shown. Leptin level correlated also significantly with BMI z score (p < 0.001), W/HtR (p < 0.0001), and body composition parameters (p < 0.000001). Moreover, there was a significant negative correlation between NTx and leptin level (p < 0.05). Bone metabolism in AIS girls seems to be altered and significantly related to the scoliotic curve severity. Leptin may be a crucial link in the cross-talk between bone turnover and body composition in this group of patients. Further studies concerning interrelationship between nutritional status and bone metabolism in patients with AIS are warranted.

The importance of curve severity, type and instrumentation strategy in the surgical correction of adolescent idiopathic scoliosis: an in silico clinical trial on 64 cases

Adolescent idiopathic scoliosis is a three-dimensional deformity of the spine which is frequently corrected with the implantation of instrumentation with generally good or excellent clinical results; mechanical post-operative complications such as implant loosening and breakage are however relatively frequent. The rate of complications is associated with a lack of consensus about the surgical decision-making process; choices about the instrumentation length, the anchoring implants and the degree of correction are indeed mostly based on personal views and previous experience of the surgeon. In this work, we performed an in silico clinical trial on a large number of subjects in order to clarify which factors have the highest importance in determining the risk of post-operative complications by quantitatively analysing the mechanical stresses and loads in the instrumentation after the correction maneuvers. The results of the simulations highlighted the fundamental role of the curve severity, also in its three-dimensional aspect, and of the instrumentation strategy, whereas the length of the fixation had a lower importance.