Shohei Minami

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.

MECHANICAL STABILITY OF THE PEDICLE SCREW FIXATION SYSTEMS FOR THE LUMBAR SPINE

Five different pedicle screw systems: AO Fixator Interne, VSP Steffee plate, Luque ISF, modified Zielke, and Chibatype plate screw system (experimental device), were evaluated for biomechanical strength. A fatigue test for the screw, compressive, and torsional tests for the pedicle screw systems and a pull-out test of the pedicle screw were done. Even the Schanz screw, which showed the highest endurance limit, may be broken under the continuous loading condition in the body. The AO Fixator Interne and Steffee plate system themselves are rigid and are indicated for injuries that need reduction. The Luque ISF, modified Zielke, and Chiba-type plate screw systems, however, are indicated for degenerative lumbar disease requiring in situ fusion. There was a linear positive correlation between the bone mineral density of the vertebral body and the pull-out strength of the pedicle screw (correlation coefficient, 0.68). The fixation strength of the pedicle screw to the bone decreased remarkably in osteoporosis.

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.

Preoperative MRI analysis of patients with idiopathic scoliosis. A prospective study

Study Design. A prospective trial of preoperative MRI study in patients with “idiopathic” scoliosis. Objectives. To investigate the prevalence of neural axis malformations and the clinical relevance of MRI in the evaluation of patients with idiopathic scoliosis undergoing surgical intervention. Summary of Background Data. With the development of MRI, neural axis abnormalities such as syringomyelia or Chiari malformations are increasingly being found in patients with “idiopathic” scoliosis. The risk of neurologic complications during correction of scoliosis without prior decompression surgery for syringomyelia has been documented; however, there have been no prospective studies for identifying the risk of neurologic complications as a result of scoliosis surgery in patients with asymptomatic neural axis malformations. Methods. A total of 250 patients who were classified as having “idiopathic” scoliosis at first presentation and admitted for spinal surgery were evaluated. All patients were examined for neural axis abnormalities using MRI. The presence of neurologic symptoms and abnormal neurologic signs was also examined before and after surgical intervention. Neurologic complications during scoliosis surgery were reviewed in patients with neural axis abnormalities. Results. There were 44 (18%) patients (13 males and 31 females) who had neural axis abnormalities on MRI, including syringomyelia with Chiari malformations in 22 patients, syringomyelia with tonsillar ectopia in 2, Chiari malformations in 13, tonsillar ectopia in 6, and low conus medullaris in 1. On clinical examination, 44 (18%) patients had abnormal neurologic signs and 26 (7%) patients complained of headache or back pain. There were significant differences between patients with and without neural axis abnormalities regarding the age at first visit, gender, curve pattern, sagittal profile of thoracic spine, presence of neurologic deficit, and complaint of pain. Only 12 of 44 patients needed neurosurgical treatment for foramen magnum decompression before correction of scoliosis. Neurologic status temporarily worsened in 3 patients, including 2 patients with neurosurgical treatment and 1 patient without neurosurgical treatment; however, there were no permanent neurologic complications as a result of scoliosis surgery. All patients without neurologic deficits or complaints of pain did not receive neurosurgical treatment, while they had no permanent neurologic complications. Conclusions. Foramen magnum decompression for neural axis malformations could prevent permanent neurologic complications during scoliosis surgery. There is little risk of neurologic complications in patients with “idiopathic” scoliosis whose neurologic status is normal, even if these patients have a neural axis malformation on MRI.

Idiopathic scoliosis in twins studied by DNA fingerprinting: THE INCIDENCE AND TYPE OF SCOLIOSIS

We investigated 21 pairs of twins for zygosity and idiopathic scoliosis. DNA fingerprinting confirmed that 13 pairs were monozygotic and eight were dizygotic. There was concordance for idiopathic scoliosis in 92.3% of monozygotic and 62.5% of dizygotic twins. Of the 12 pairs of monozygotic twins concordant for idiopathic scoliosis, six showed discordant curve patterns but eight had differences in Cobb angle of less than 10 degrees. Seven of the ten pairs of monozygotic twins had similar back shapes. Our findings suggest that there is a genetic factor in the aetiology of idiopathic scoliosis; they also indicate that there is a genetic factor in both the severity of the curve and the general shape of the back.

Natural history of scoliosis in children with syringomyelia

We performed a retrospective review of 27 scoliotic patients with syringomyelia using MRI. Their mean age at the first MRI examination was 10.9 years, and at the final review 15.8 years. The mean ratio of the diameter of the syrinx to the cord on the midsagittal MRI (S/C ratio) decreased from 0.49 to 0.24; 14 patients showed a decrease of 50% or more (reduction group). In this reduction group, the cerebellar tonsillar herniation decreased from a mean of 11.3 mm to 6.0 mm, and some improvement in dissociated sensory disturbance was seen in nine of 13 patients. The scoliosis improved by 5 degrees or more in six patients in the reduction group. Our results indicate that spontaneous shrinkage of syringomyelia in children is not unusual and is associated with improvement in the tonsillar herniation, the scoliosis and the neurological deficit.

School screening for scoliosis by the Chiba university medical school screening program-results of 1.24 million students over an 8-year period

The screening program for scoliosis started by Chiba University in 1979 consists of using moiré topography, low-dose roentgenography and a final ordinary x-ray examination. The number of children screened through this Chiba University Medical School (CUMS) screening program to 1986 amounted to 1,246,798. The incidence of scoliosis of more than 15 degrees increased linearly according to age from the fifth grade primary school children (0.07% in boys, 0.44% in girls) to the second grade junior high school students (0.25% in boys, 1.77% in girls). The female predominance of scoliosis cases with curvatures of more than 20 degrees detected during the total period was 10:1 and this female predominance was the same for primary school children and junior high school students. According to a study of the incidence of scoliosis by districts, (areas were divided according to population density and urbanization) there were no significant differences in the fifth grade primary school children between the sparsely and densely populated areas. In the cases of children beyond the fifth grade primary school level, however, the incidence in the densely populated areas were significantly higher than those in the sparsely populated districts. The incidence of scoliosis of more than 20 degrees decreased significantly every year among junior high school students, because they were screened periodically in school and the scoliotic students who had already been detected were left out of the next screening. This study establishes that screening for scoliosis by the CUMS screening program is cost-effective with a low risk of radiation hazards.

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