Taichi Tsuji

A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis is a pediatric spinal deformity affecting 2–3% of school-age children worldwide. Genetic factors have been implicated in its etiology. Through a genome-wide association study (GWAS) and replication study involving a total of 1,376 Japanese females with adolescent idiopathic scoliosis and 11,297 female controls, we identified a locus at chromosome 10q24.31 associated with adolescent idiopathic scoliosis susceptibility. The most significant SNP (rs11190870; combined P = 1.24 × 10−19; odds ratio (OR) = 1.56) is located near LBX1 (encoding ladybird homeobox 1). The identification of this susceptibility locus provides new insights into the pathogenesis of adolescent idiopathic scoliosis.

Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10−10; odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein–coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10−14; OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.

Surgical outcome of ossification of the posterior longitudinal ligament (OPLL) of the thoracic spine : Implication of the type of ossification and surgical options

Objective: Ossification of the posterior longitudinal ligament (OPLL) in the thoracic spine produces myelopathy through anterior spinal cord compression that is usually progressive and unaffected by conservative treatment. Therefore, early decompressive surgery is imperative. However, decompression surgery of thoracic myelopathy is difficult, and the outcome is often poor. A retrospective study was conducted to investigate the surgical outcome of 21 patients with thoracic OPLL to evaluate which type of surgical approach is better and which type of thoracic OPLL results in a better surgical outcome. Methods: A total of 21 patients with thoracic OPLL (10 men and 11 women; mean age 54 years), who underwent surgical treatment at our department from March 1985 to October 2000, were included in the study. Seven patients exhibited the flat-type OPLL and underwent either anterior decompression and fusion (one patient), anterior decompression via a posterior approach (three patients), or expansive laminoplasty (three patients). Fourteen patients exhibited the beak-type OPLL and also underwent either anterior decompression and fusion (two patients), anterior decompression via a posterior approach (six patients), or expansive laminoplasty (six patients). Results: Regarding of operative time and blood loss, there were no marked differences between the two types of OPLL, regardless of the type of surgical procedure; anterior decompression and fusion and anterior decompression via a posterior approach yielded longer operative times and larger blood loss volumes than expansive laminoplasty. Concerning clinical outcome, there were five cases of neurologic deterioration. All of the five deteriorated cases were of the beak-type OPLL treated by a posterior approach. Two of these patients were treated with expansive laminoplasty. Conclusions: There were five instances of neurologic deterioration in our thoracic OPLL series, and all of them exhibited beak-type OPLL. In the beak-type OPLL, a subtle alteration in the spinal alignment during posterior decompression procedures may increase spinal cord compression, leading to the deterioration of symptoms. A potential increase in kyphosis following laminectomy should be avoided by fixation with a temporary rod. If intraoperative monitoring suggests spinal cord dysfunction, an anterior decompression procedure should be attempted as soon as possible.

Vertebral reconstruction with biodegradable calcium phosphate cement in the treatment of osteoporotic vertebral compression fracture using instrumentation.

Objective: To assess the efficacy of posterior instrumentation and vertebral reconstruction with biodegradable calcium phosphate cement (CPC) in the treatment of osteoporotic vertebral compression fracture with neurologic deficit. Background: Vertebroplasty consists of the injection of polymethylmethacrylate (PMMA) cement into the vertebral body. While PMMA has high mechanical strength, it cures fast and thus allows only a short handling time. Other potential problems of using PMMA injection may include damage to surrounding tissues due to the high polymerization temperature or by the toxic unreacted monomer and the lack of long-term biocompatibility. Bone mineral cements such as calcium carbonate and CPCs have a longer working time and low thermal effect. They are also biodegradable while providing good mechanical strength. However, the viscosity of injectable mineral cements is high, and the infiltration of these cements into the vertebral body has been questioned. Recently, the infiltration properties of CPC have been significantly improved, making it more suitable for injection into the vertebral bodies for vertebral reconstruction. Methods: Five patients were included in this open prospective study. Inclusion criteria were delayed collapsed vertebral compression fractures responsible for severe pain and neurologic dysfunction necessitating posterior decompression surgery. Of five patients, two were male and three were female with an average age at surgery of 80.4 years (71–85 years) and an average duration of follow-up of 2.5 years (2–3.5 years). Evaluation of clinical data was based on x-ray, Japanese Orthopaedic Association (JOA) score for low back pain (full score is 29 points), and Visual Analog Scale (VAS). Results: The levels of the delayed collapsed vertebrae were T10, L1, and L2 (for one patient each) and L4 (two patients). All patients were in poor condition, for example, renal failure, heart failure, and chronic hepatitis. The average operative time was 2 hours (1 hour 36 minutes to 2 hours 16 minutes), and intraoperative bleeding was 181 mL (85–236 mL). As for clinical symptoms, preoperative JOA score averaged 17.8 points and was improved to 26 points postoperatively, while the preoperative VAS score of 8.6 points improved to 2 points postoperatively. Morphologic evaluation showed preoperative vertebral compression ratio averaged 41% and improved to 74% immediately after the operation and finally settled at 68%. Just one of five cases experienced late vertebral collapse 3 months after the operation. Conclusion: Vertebral reconstruction with biodegradable CPC in the treatment of osteoporotic vertebral compression fracture using instrumentation was a safe and useful surgical treatment.

Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population.

Adolescent idiopathic scoliosis (AIS) is a spinal deformity most commonly arising in apparently healthy girls around puberty. AIS has a strong genetic predisposition. Several genetic associations between AIS and single nucleotide polymorphisms (SNPs) have been reported; common SNPs in the genes for matrilin 1 (MATN1), melatonin receptor 1B (MTNR1B), tryptophan hydroxylase 1 (TPH1), and insulin‐like growth factor 1 (IGF1) are reported to be associated with AIS in Chinese. However, these associations have not been replicated so far. To confirm the associations, we compared these SNPs with AIS predisposition and curve severity in a population of Japanese females consisting of 798 AIS patients and 1,239 controls. All the subjects were genotyped using the PCR‐based Invader assay. We found no association of any of the SNPs with AIS predisposition or curve severity. Considering the statistical power and sample size of the present study, we concluded that these SNPs are not associated with either AIS predisposition or curve severity in Japanese.

Replication study of the association between adolescent idiopathic scoliosis and two estrogen receptor genes.

Adolescent idiopathic scoliosis (AIS) is a common disorder with a strong genetic predisposition. Associations between AIS and common single nucleotide polymorphisms (SNPs) in estrogen receptor genes have been reported. rs9340799 in the gene for estrogen receptor α (ESR1) is reported to be associated with curve severity in Japanese and with AIS predisposition and curve severity in Chinese. In addition, rs1256120 in the gene for estrogen receptor β (ESR2) is reported to be associated with AIS predisposition and curve severity in Chinese. However, the sample sizes of these previous studies were small, and the associations of these SNPs have not been replicated. To examine the association between AIS and estrogen receptor genes, we investigated the association of rs9340799 and rs1256120 with AIS predisposition and curve severity using a large Japanese population, consisting of 798 AIS patients and 637 sex‐matched controls. We found no association of either SNP with AIS predisposition or curve severity in the Japanese population. Considering the statistical power of the present study and the limitations of the previous reports, we conclude that the associations of rs9340799 and rs1256120 with AIS predisposition and curve severity are negative.

Risk factors for complications associated with growing-rod surgery for early-onset scoliosis

Study Design. A retrospective multicenter study. Objective. To identify risk factors for postoperative complications associated with growing-rod (GR) surgery for early-onset scoliosis (EOS). Summary of Background Data. Results and complications of GR surgery for EOS have not been adequately studied. Methods. We evaluated clinical and radiographical results from 88 patients with EOS who underwent GR surgery in 12 spine centers in Japan. The mean age at the time of initial surgery was 6.5 ± 2.2 years (range, 1.5–9.8 yr) and the mean follow-up period was 3.9 ± 2.6 years (range, 2.0–12.0 yr). Risk factors for postoperative complications were analyzed using binomial multiple logistic regression analysis. We considered the potential factors of sex, age, number of rod-lengthening procedures, whether a pedicle screw foundation was used, the uppermost level of the proximal foundation and lowermost level of the distal foundation, Cobb angles of the proximal thoracic, main thoracic, and lumbar curves, and the kyphosis angles in the proximal, main thoracic, thoracolumbar, and lumbar spine. Kaplan-Meier analysis was used to determine the complication-free survival rate of GR surgery as a function of the number of surgical procedures. Results. Complications affected 50 of the patients (57%) and were associated with 119 of 538 surgical procedures, with 86 implant-related failures (72%), 19 infections (16%), 3 neurological impairments (3%), and 11 other complications. The most frequent implant-related failure was dislodged implant (71%) and 95% of the dislodgements occurred at the proximal foundation. Kaplan-Meier analysis demonstrated a linear decrease in complication-free rates as the number of rod-lengthening procedures increased. Binomial multiple logistic regression analysis found the following significant independent risk factors: 6 or more rod-lengthening procedures (odds ratio [OR], 6.534), an increase of every 20° in the proximal thoracic Cobb angle (OR, 3.091), and an increase of every 25° in the lumbar lordosis angle (OR, 2.607) in the preoperative condition. Conclusion. Increases in the upper thoracic scoliotic curve, thoracic kyphosis, and number of rod-lengthening procedures are positively associated with an increased risk of complications after GR surgery for EOS. Level of Evidence: 4

Hip-Spine Syndrome : Total Sagittal Alignment of the Spine and Clinical Symptoms in Patients With Bilateral Congenital Hip Dislocation

Study Design. The influence of the pathologic state of the hip joint on the total sagittal alignment of the spine was investigated in patients with congenital hip dislocation retrospectively Objective. The purpose of this study was to analyze the total sagittal alignment of the spine and the clinical symptoms in patients with bilateral congenital hip dislocation. Summary of Background of Data. Abnormality in the hip joint causes abnormal curvature of the sagittal alignment of the spine and induces lumbago or lower leg pain. However, there have been no reports on the influence of bilateral congenital hip dislocation on the sagittal alignment of the spine. Materials and Methods. A total of 9 patients (8 females and 1 male) were analyzed. Their average age was 57 years (range, 46–68 years). We measured the thoracic kyphosis (T1–T12), the lumbar lordosis (L1–S), the sacral inclination (SI), the femoral flexion angle (FFA), pelvic angulation (PA), and the distances from the pelvic hip axis (HA) to the C7 plumb line and from the promontorium to the C7 plumb line. To evaluate clinical symptoms, we used the Japanese Orthopedic Association (JOA) score of low back pain (full score is 29 points) and Visual Analog Scale (VAS) for lower back pain and lower leg pain, and the possible time of walking without rest. Results. The average thoracic kyphosis, lumbar lordosis, SI, and PA were 42°, −78°, 68°, and 27°, respectively. The FFA averaged 10°, leading to a duck-like posture. The distances from HA and, promontorium to the C7 plumb line averaged −2 cm and 4 cm, respectively. A posterior shift of the gravity line with respects to the hips was compensated for by lumbar hyperlordosis, which led to a posterior shift of the center of the spine. Regarding the clinical symptoms, the JOA score averaged 20 points and the VAS for lower back pain (lumbago) and lower leg pain averaged 6.4 and 3.1, respectively. The average possible walking time without rest was 20 minutes. Conclusion. The total sagittal alignment of the spine in patients with bilateral hip dislocation was compensated for by anterior angulation of the pelvis and by lumbar hyperlordosis. The main clinical symptoms were lower back pain, and not lower leg pain.

Adjacent Segment Disease After Posterior Lumbar Interbody Fusion: Based on Cases With a Minimum of 10 Years of Follow-up.

Study Design. Retrospective case-controlled study. Objective. To investigate the incidence of adjacent segment degeneration (ASD) and the associated risk factors during a period of at least 10 years after posterior lumbar interbody fusion (PLIF). Summary of Background Data. ASD is a problematic sequelae after spinal fusion surgery. Few long-term follow-up studies have investigated ASD after PLIF; thus, magnetic resonance imaging (MRI) data available for the evaluation of postoperative changes associated with ASD are limited. Method. One hundred one patients were retrospectively enrolled. The minimum follow-up was 10 years after surgery. Preoperative and postoperative (2, 5, and 10 yr after surgery) Radiographs and MRI images were evaluated. Disc height, vertebral slip, and intervertebral angle were examined on radiographical images. Disc degeneration and spinal stenosis on MRI images were evaluated. Risk factors for developing early-onset radiographical ASD were evaluated using a multivariate logistic regression analysis. Result. The degenerative changes in disc height, vertebral slip, and intervertebral angle on radiographs 10 years after surgery were found in 12, 36, and 17 cases, respectively, at the cranial-adjacent level and in 3, 6, and 11 cases, respectively, at the caudal-adjacent level. Increased disc degeneration and spinal stenosis worsening were observed in 62 and 68 cases, respectively, at the cranial-adjacent level and in 25 and 12 cases, respectively, at the caudal-adjacent level on MRI 10 years after surgery. Ten patients (9.9%) required reoperation, and 80% of revision surgeries were performed more than 5 years after the initial surgery. High pelvic incidence was a risk factor for developing early-onset radiographical ASD. Conclusion. The majority of the reoperations for ASD were performed more than 5 years after the initial lumbar fusion surgery, although the progression of radiographical ASD began in the early postoperative period. A high degree of pelvic incidence was a risk factor for developing early-onset radiographical ASD. Obtaining appropriate lumbar lordosis in PLIF is important for preventing ASD. Level of Evidence: 4

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.