Introduction. Idiopathic scoliosis is a spine disorder of unknown origin with a prevalence of 1·5-3% in the general population. Apart from the large multifactorial form sample of idiopathic scoliosis, there is a good evidence for the existence of a monogenic subgroup in which the disease is inherited in a dominant manner. However, results from published work suggest a strong heterogeneity in locations of the mutated genes. Methods. With a high resolution genome-wide scan, we undertook linkage analyses in three large multigenerational families with idiopathic scoliosis compatible with dominant inheritance, including 11–12 affected members or obligate carriers. Results. In two of these families, our results suggested intrafamilial genetic heterogeneity, whereas in the other we recorded a perfect marker disease co-segregation in two distinct chromosomal regions. We can state that one of these two locations is a novel idiopathic scoliosis disease gene locus, since the probability of having by chance this perfect co-segregation twice in the genome is very low (p=0·001). Lastly, in all three families studied, we excluded compatibility with linkage to the previously mapped dominant idiopathic scoliosis loci on chromosomes 19p13.3, 17p11.2, 9q34, 17q25, and 18q. Conclusions. Our findings confirm that there is a high genetic heterogeneity within the subgroup of dominant forms of idiopathic scoliosis

Introduction. Clinical studies have shown distinct differences in later-onset idiopathic scoliosis (IS) between men and women, including curve severity, stiffness, and ease of operative intervention. Therefore, significant scoliosis in men was used as criteria to create a phenotypical subset of families with IS. The goal of this study is to identify genetic determinants that relate specifically to men with a scoliotic curvature of 30° or more. Methods. We identified 25 families (208 individuals) in which a male was diagnosed with 30° or more IS curvature in adolescence. 123 individuals were affected (48 male; 75 female), and 85 were unaffected (45 male; 40 female). Initially, a genomic screen was done with a modified CHLC (version 9) marker set. After initial linkage analyses, the group underwent finemapping with a custom single-nucleotide polymorphism (SNP) panel and ABI Taqman methodology on an ABI 377 platform. The initial genome-wide screen and subsequent analyses were analysed by model-independent linkage analysis with SIBPAL (SAGE, version 5). Results. Genomic screen analyses revealed significant results (=two adjacent STRP markers p<0·005) on chromosome 22 spanning approximately 13 Mb. Subsequent finemapping SNPs were statistically significant in single and multipoint analyses; rs8140312 (-log(p)=8·0 and 2·29, respectively) and rs240597 (-log(p)=5·96 and 1·76; figure). Significant SNPs lie mainly in the introns of the LARGE gene, which is integral to the development and maintenance of skeletal muscle, and SFI1 gene, which is responsible for the integrity of the chromosomal centromere complex. Conclusions. A subset of families was identified within a cohort of familial idiopathic scoliosis (FIS) families that contained male patients with severe scoliosis, facilitating the study of genetic determinants. Data show a highly significant correlation with a locus containing the LARGE and SFI1 genes on chromosome 22. Future goals include association and sequencing analyses of this region. FIS is a complex genetic disorder. Use of clinical criteria may help to decrease the heterogeneity of any one study population, and enhance the successful identification of specific genes that bring about this disorder. The identification of a genetic locus is of major clinical and therapeutic interest and might improve understanding of spinal growth and stability

Introduction. Idiopathic scoliosis (IS) has been associated with several genetic loci in varying study populations, reflecting the disorder's genetic complexity. One region of interest is on chromosome 17, flanking regions linked to neurofibromatosis type 1 (NF1). This region is of particular relevance because the most common osseous manifestation in NF1 is scoliosis (10–30% of patients). This alludes to a potential genetic correlation within this region affecting spinal development or stability. The objective of this research is to identify candidate genes within this region that are statistically linked to IS. Methods. An initial population of IS families recruited through approval by the institutional review board (202 families; 1198 individuals) had DNA harvested from blood, and underwent genomic screening, finemapping, and statistical analyses. We identified a specific familial subset: families with males having undergone surgery for scoliosis (17 families, 147 individuals). The initial genome-wide scan indicated that this subset was linked to chromosome 17q.11.2. The most prominent marker, D17s975, (p=0·0003) at 25.12 Mb is adjacent to the NF1 deletional region. We then analysed a custom panel of single-nucleotide polymorphisms (SNPs) extending from 18·30–31·47 Mb for linkage through Taqman SNP assay protocol. With allele specific fluorescent tags, allelic discrimination was done with real-time PCR. Results. Findings show two regions with two or more contiguous SNPs of significance (p<0·05), confirming significant linkage adjacent to the NF1 locus (table). The most significant results lie within the serotonin transporter gene SLC6A4, whose product is a modulator of serotonin (5-HT) activity. Conclusions. IS is a disorder of variable phenotypic expression that has been related to several regions on the genome. Although NF1 has been definitively associated with a region on chromosome 17, the phenotypic expression is not understood at the molecular level. The elucidation of shared genetic variations within this region by two disorders marked by scoliosis has significance for the molecular understanding of the pathogenesis of scoliosis and axial development. The specific gene, SLC6A4, is of particular interest in that as a modulator of serotonin transport, bone mineral content, density, and mechanical strength can be altered. Both NF1 and IS in some patients have been associated with decreased bone mineral density. Future work will focus on replication of these findings and targeted genetic sequencing

Aims

Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease.

Introduction. The cause of adolescent idiopathic scoliosis (AIS) is still not known. Although several candidate gene studies and linkage analyses have been done, no causal relationship has yet been established. To our knowledge, we report the first case-control based genome-wide association study (GWAS) for this trait. Methods. The study was undertaken in a set of 196 cases with a specific AIS phenotype (based on Lenke's classification) in southern China, and in 401 controls without radiological evidence of scoliosis. Results. Two single-nucleotide polymorphisms (SNPs) on one particular chromosome showed marginal significant association (snp1: p=1·32×10–6, odds ratio=0·52; snp2: p=1·23×10–5, odds ratio=0·55). Imputation results suggested that three more SNPs in this region showed significant association (snp3: p=2·47×10–7, odds ratio=0·49; snp4 and snp5: p=1·68×10–6, odds ratio=0·53). Conclusions. Despite the small number of cases and controls, the strength of this study is in the use of a specific phenotype and that all controls were mature individuals with radiological confirmation of straight spines. We believe that these factors have contributed to the success of the GWAS. Our findings offer the potential to explore the pathogenesis of AIS with GWAS

Introduction. Studies of the vestibular system in patients with idiopathic scoliosis (IS) have shown abnormalities in the semicircular canals (SCC) and the basicranium. Rousie (2008) revealed a statistically increased incidence of structural anomalies in the SCCs with three-dimensional computer generated modelling. Some of these findings were replicated in a small population by Cheng (2010). The primary goals of this investigation are verification of SCC abnormalities of patients with IS versus controls with use of three-dimensional modelling with subsequent development of a unique phenotypical classification. Our long-term goal is to provide new direction for hypothesis directed identification and characterisation of genes causally related to IS. Methods. 20 patients with IS and 20 controls matched for age and sex will be identified through the clinic with approval from the institutional review board. Power analyses were done to detect the difference in distributions as the proportion of fisher tests with p values less than 0·05. A sample size of 20 per group gives 86–99% power to realise results under conservative assumptions. IS patients and controls undergo vestibular system examination via T2 MRI imaging. Extracted data are evaluated by a team including Dr Rousie, ENT, radiology, and orthopaedic surgery. DNA is extracted with Gentra Puregene kits from Qiagen (Valencia, CA, USA). Developmental genes related to SCC and axial somatogenesis are being identified through a bioinformatics approach, targeting known IS genomic loci. Custom single-nucleotide polymorphism panels, statistical linkage, and association will identify genes of significance for sequencing. Results. To date, 11 patients with IS and four controls have been recruited. Preliminary data are indicative of a significant percentage of abnormalities within the SCC system in children with IS. Analyses of preliminary findings continue according to the protocol. Conclusions. Research into genetic factors predicting IS progression and/or magnitudes of curvature have been inconclusive. Whether these abnormalities are primary or secondary to a larger systemic issue is speculative; however, they demonstrate a potential new phenotypical classification. Our initial findings show evidence of SCC abnormalities in patients with IS in a well defined patient population compared with healthy controls. Ultimately, our goal for this project is to pursue investigations of genes, pseudogenes, and conserved sequences shown to be related to vestibular structural formation during embryogenesis and development. The identification of a subset of individuals with IS and vestibular abnormalities will allow for the study of genes involved concomitantly in the embryological development of both systems, thus providing insight into the inter-relationship of these deformities

The aim of this study was to determine whether obesity affects pain, surgical and functional outcomes following lumbar spinal fusion for low back pain (LBP).

A systematic literature review and meta-analysis was made of those studies that compared the outcome of lumbar spinal fusion for LBP in obese and non-obese patients. A total of 17 studies were included in the meta-analysis. There was no difference in the pain and functional outcomes. Lumbar spinal fusion in the obese patient resulted in a statistically significantly greater intra-operative blood loss (weighted mean difference: 54.04 ml; 95% confidence interval (CI) 15.08 to 93.00; n = 112; p = 0.007) more complications (odds ratio: 1.91; 95% CI 1.68 to 2.18; n = 43858; p < 0.001) and longer duration of surgery (25.75 mins; 95% CI 15.61 to 35.90; n = 258; p < 0.001). Obese patients have greater intra-operative blood loss, more complications and longer duration of surgery but pain and functional outcome are similar to non-obese patients. Based on these results, obesity is not a contraindication to lumbar spinal fusion.

Cite this article: Bone Joint J 2015;97-B:1395–1404.

We reviewed 31 consecutive patients with Friedreich’s ataxia and scoliosis. There were 24 males and seven females with a mean age at presentation of 15.5 years (8.6 to 30.8) and a mean curve of 51° (13° to 140°). A total of 12 patients had thoracic curvatures, 11 had thoracolumbar and eight had double thoracic/lumbar. Two patients had long thoracolumbar collapsing scoliosis with pelvic obliquity and four had hyperkyphosis. Left-sided thoracic curves in nine patients (45%) and increased thoracic kyphosis differentiated these deformities from adolescent idiopathic scoliosis. There were 17 patients who underwent a posterior instrumented spinal fusion at mean age of 13.35 years, which achieved and maintained good correction of the deformity. Post-operative complications included one death due to cardiorespiratory failure, one revision to address nonunion and four patients with proximal junctional kyphosis who did not need extension of the fusion. There were no neurological complications and no wound infections. The rate of progression of the scoliosis in children kept under simple observation and those treated with bracing was less for lumbar curves during bracing and similar for thoracic curves. The scoliosis progressed in seven of nine children initially treated with a brace who later required surgery. Two patients presented after skeletal maturity with balanced curves not requiring correction. Three patients with severe deformities who would benefit from corrective surgery had significant cardiac co-morbidities.

We describe the results of a prospective case series of patients with spondylolysis, evaluating a technique of direct stabilisation of the pars interarticularis with a construct that consists of a pair of pedicle screws connected by a U-shaped modular link passing beneath the spinous process. Tightening the link to the screws compresses bone graft in the defect in the pars, providing rigid intrasegmental fixation. We have carried out this procedure on 20 patients aged between nine and 21 years with a defect of the pars at L5, confirmed on CT. The mean age of the patients was 13.9 years (9 to 21). They had a grade I or less spondylolisthesis and no evidence of intervertebral degeneration on MRI. The mean follow-up was four years (2.3 to 7.3). The patients were assessed by the Oswestry Disability Index (ODI) and a visual analogue scale (VAS). At the latest follow-up, 18 patients had an excellent clinical outcome, with a significant (p < 0.001) improvement in their ODI and VAS scores. The mean ODI score at final follow-up was 8%. Assessment of the defect by CT showed a rate of union of 80%. There were no complications involving the internal fixation.

The strength of the construct removes the need for post-operative immobilisation.

Low bone mass and osteopenia have been described in the axial and peripheral skeleton of patients with adolescent idiopathic scoliosis (AIS). Recently, many studies have shown that gene polymorphism is related to osteoporosis. However, no studies have linked the association between IL6 gene polymorphism and bone mass in AIS. This study examined the association between bone mass and IL6 gene polymorphism in 198 girls with AIS. The polymorphisms of IL6-597 G→A, IL6-572 G→C and IL6-174 G→A and the bone mineral density in the lumbar spine and femoral neck were analysed and compared with their levels in healthy controls. The mean bone mineral density at both sites in patients with AIS was decreased compared with controls (p = 0.0022 and p = 0.0013, respectively). Comparison of genotype frequencies between AIS and healthy controls revealed a statistically significant difference in IL6-572 G→C polymorphism (p = 0.0305). There was a significant association between the IL6-572 G→C polymorphism and bone mineral density in the lumbar spine, with the CC genotype significantly higher with the GC (p = 0.0124) or GG (p = 0.0066) genotypes.

These results suggest that the IL6-572 G→C polymorphism is associated with bone mineral density in the lumbar spine in Korean girls with AIS.

We have treated 175 patients with a chordoma over a ten-year period. Only two had a family history of the condition and we describe these in this paper. In one patient the tumour was at the craniocervical junction and in the other the lesion affected the sacrum. We have undertaken a literature review of familial chordoma and have identified chromosomal abnormalities associated with the condition.