Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis -expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.

In the anterior foregut (AFG) of mouse embryos, the transcription factor SOX2 is expressed in the epithelia of the esophagus and proximal branches of respiratory organs comprising the trachea and bronchi, whereas NKX2.1 is expressed only in the epithelia of respiratory organs. Previous studies using hypomorphic Sox2 alleles have indicated that reduced SOX2 expression causes the esophageal epithelium to display some respiratory organ characteristics. In the present study, we produced mouse embryos with AFG-specific SOX2 deficiency. In the absence of SOX2 expression, a single NKX2.1expressing epithelial tube connected the pharynx and the stomach, and a pair of bronchi developed in the middle of the tube. Expression patterns of NKX2.1 and SOX9 revealed that the anterior and posterior halves of SOX2-deficient AFG epithelial tubes assumed the characteristics of the trachea and bronchus, respectively. In addition, we found that mesenchymal tissues surrounding the SOX2-deficient NKX2.1-expressing epithelial tube changed to those surrounding the trachea and bronchi in the anterior and posterior halves, as indicated by the arrangement of smooth muscle cells and SOX9expressing cells and by the expression of Wnt4 (esophagus specific), Tbx4 (respiratory organ specific), and Hoxb6 (distal bronchus specific). The impact of mesenchyme-derived signaling on the early stage of AFG epithelial specification has been indicated. Our study demonstrated an opposite trend where epithelial tissue specification causes concordant changes in mesenchymal tissues, indicating a reciprocity of epithelial-mesenchymal interactions.

A LFNG mutation is reported in a case of spondylocostal dysostosis (SCD), a skeletal dysplasia with severe malformations of vertebra and rib. The CS patient with LFNG mutations had multiple vertebral malformations including hemivertebrae, butterfly vertebrae, and block vertebrae, and rib malformations. LFNG mutations may cause a spectrum of phenotypes including CS and SCD. The current list of known disease genes could explain only a small fraction of genetic cause of CS.

Study Design: This study was a post hoc analysis of prospective data. Objective: The objective of this study was to investigate whether K-line (–) in the neck-flexion position [f-K-line (–)] affects patient-reported outcome measures after cervical laminoplasty for patients with ossification of the posterior longitudinal ligament (OPLL). Summary of Background and Data: The f-K-line was recently proposed as a predictor of poor outcomes after laminoplasty for patients with OPLL. However, its impact on patient-reported outcome measures remains to be elucidated. Patients and Methods: We analyzed prospectively collected data from 68 patients with cervical myelopathy due to OPLL who underwent double-door laminoplasty between 2008 and 2015. Patients were categorized into f-K-line (–) and f-K-line (+) groups on a baseline neck-flexion radiograph. Outcome measures included the Japanese Orthopaedic Association score, EuroQol 5-Dimensional Questionnaire, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, and 11-point Numerical Rating Scale for pain. The degree of satisfaction with the outcome was assessed at the 2-year follow-up using a 7-point Numerical Rating Scale. Results: Of the 68 patients, 22 (32%) and 46 (68%) were grouped into the f-K-line (–) and f-K-line (+) groups, respectively. The 2 groups showed no significant difference in baseline functions. The f-K-line (–) group showed a significantly lower recovery rate of the Japanese Orthopaedic Association score and a significantly lower gain in EuroQol 5-Dimensional Questionnaire score than compared with the f-K-line (+) group at the 2-year follow-up. Among the 5 domains of the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, cervical function, and upper extremity function were significantly lower in the f-K-line (–) group than in the f-K-line (+) group. Patients in the f-K-line (–) group also reported a significantly higher pain intensity in the upper and lower extremities and a significantly lower degree of satisfaction compared with those in the f-K-line (+) group. Conclusion: The f-K-line (–) was significantly associated with poorer functional recovery, higher pain intensity in the extremities, and lower patient satisfaction after cervical laminoplasty for patients with OPLL.

on behalf of the Japan Spinal Deformity Institute Study Group Study Design. A retrospective multicenter study. Objective. To determine the surgical site infection (SSI) rate, associated risk factors, and causative pathogens in pediatric patients with spinal deformity. Summary of Background Data.There have been no extensive investigations of the risk factors for SSI in Japan. Methods. Demographic data, radiographic findings, and the incidence of SSI were retrospectively analyzed in 1449 pediatric patients who underwent primary definitive fusion surgery for spinal deformity at any of 15 institutions from 2015 to 2017. SSI was defined according to the US Centers for Disease Control and Prevention guideline. Results. The incidence of all SSIs was 1.4% and that of deep SSIs was 0.76%. The most common pathogenic microbes were methicillin-resistant staphylococci (n ¼ 5) followed by gram-negative rods (n ¼ 4), methicillin-sensitive staphylococci (n ¼ 1), and others (n ¼ 10). In univariate analysis, younger age, male sex, a diagnosis of kyphosis, type of scoliosis, American Society of Anesthesiologists (ASA) class !3, mental retardation urinary incontinence, combined anterior-posterior fusion, greater magnitude of kyphosis, three-column osteotomy, use of blood transfusion, and number of antibiotic administration were associated with the likelihood of SSI (all P < 0.05). Multivariate logistic regression analysis identified the following independent risk factors for SSI: syndromic scoliosis etiology (vs. idiopathic scoliosis; adjusted odds ratio [OR] 16.106; 95% confidence interval [CI] 2. neuromuscular scoliosis etiology (vs. idiopathic scoliosis; adjusted OR 11.814; ASA class 3 (vs. class 2; adjusted OR 15.231;, and administration of antibiotic therapy twice daily (vs. three times daily; adjusted OR 6.121; 95% CI 1.261-29.718). Conclusion.The overall infection rate was low. The most common causative bacteria were methicillin-resistant followed by gram-negative rods. Independent risk factors for SSI in pediatric patients undergoing spinal deformity surgery were scoliosis etiology, ASA class 3, and administration of antibiotic therapy twice daily.

BackgroundCongenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity.MethodsWe recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments.ResultsWe identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype.ConclusionsOur study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

Introduction The Japanese Scoliosis Society (JSS) planned to make a longitudinal survey of the mortality and morbidity (M&M) of spinal deformity surgery and established the M&M Committee in 2012. We reported the analysis of the surgical complication (M&M) survey in 2012. Methods A request to participate in this survey was mailed to all JSS members. Questionnaires were sent by email to members who agreed to cooperate, and their answers were obtained. Diagnosis was grouped into idiopathic scoliosis, congenital scoliosis, neuromuscular scoliosis, spondylolisthesis, pediatric kyphosis, and adult spinal deformity. Complications were grouped into death, blindness, neurological deficit, infection, massive bleeding, hematoma, pneumonia, cardiac failure, DVT/PE, gastrointestinal perforation, and instrumentation failure. Results A total of 2,906 patients were reported from sixty-eight hospitals: idiopathic 488, congenital 91, neuromuscular 82, others 214, spondylolisthesis 1,241, pediatric kyphosis 41, and adult spinal deformity 749. Complications were death in 3, neurological deficit in 49, early infection in 37, late infection in 14, massive bleeding in 91, hematoma in 18, pneumonia in 6, cardiac failure in 1, DVT/PE in 9, gastrointestinal perforation in 2, and instrumentation failure in 73. The complication rate of having a neurological deficit, massive bleeding, and instrumentation failure was 4.88%, 7.32%, and 4.88% respectively in patients with pediatric kyphosis, and 3.07%, 8.01%, and 5.21% respectively in patients with an adult spinal deformity. The complication rate of early infection was 4.88% in the patients with pediatric kyphosis. Conclusions The complication rates of pediatric kyphosis and adult spinal deformity were high.

Adolescent idiopathic scoliosis (AIS) is a common disease causing three‐dimensional spinal deformity in as many as 3% of adolescents. Development of a method that can accurately predict the onset and progression of AIS is an immediate need for clinical practice. Because the heritability of AIS is estimated as high as 87.5% in twin studies, prediction of its onset and progression based on genetic data is a promising option. We show the usefulness of polygenic risk score (PRS) for the prediction of onset and progression of AIS. We used AIS genomewide association study (GWAS) data comprising 79,211 subjects in three cohorts and constructed a PRS based on association statistics in a discovery set including 31,999 female subjects. After calibration using a validation data set, we applied the PRS to a test data set. By integrating functional annotations showing heritability enrichment in the selection of variants, the PRS demonstrated an association with AIS susceptibility (p = 3.5 × 10−40 with area under the receiver‐operating characteristic [AUROC] = 0.674, sensitivity = 0.644, and specificity = 0.622). The decile with the highest PRS showed an odds ratio of as high as 3.36 (p = 1.4 × 10−10) to develop AIS compared with the fifth in decile. The addition of a predictive model with only a single clinical parameter (body mass index) improved predictive ability for development of AIS (AUROC = 0.722, net reclassification improvement [NRI] 0.505 ± 0.054, p = 1.6 × 10−8), potentiating clinical use of the prediction model. Furthermore, we found the Cobb angle (CA), the severity measurement of AIS, to be a polygenic trait that showed a significant genetic correlation with AIS susceptibility (rg = 0.6, p = 3.0 × 10−4). The AIS PRS demonstrated a significant association with CA. These results indicate a shared polygenic architecture between onset and progression of AIS and the potential usefulness of PRS in clinical settings as a predictor to promote early intervention of AIS and avoid invasive surgery. © 2021 American Society for Bone and Mineral Research (ASBMR).