Introduction

The Hamann-Todd collection at the Cleveland Museum of Natural History (Cleveland, OH, USA) includes 63 paediatric skeletal specimens in varying condition and completeness. The initial data collection included representative skeletons of children aged 1–18 years. The aim of this study was to better understand the growth patterns of the paediatricspine and ribs.

Methods

Data from vertebrae and corresponding ribs were collected. Data included 46 measurements from the vertebral body and ribs at T1, T4, T7, T10, and L3. Measurements were obtained with Vernier calipers, tape measures, and photographs of each bone. Several specimens were digitised with a Next Engine 3D laser scanner. The initial analysis used caliper-derived data, with some measurements obtained from photographs. The data were analysed by age, specific bone, and morphological features. More than 2000 cross correlations were studied. Linear regressions were done on scalar measurements with SAS (version 9.1.3) and JMP (version 8.0). Although the general demographics for each child were known, specifics such as height and weight or previous trauma were not.

Introduction

Sparing of the spinal growth and scoliotic deformity control in patients with early-onset scoliosis is a challenge in spinal surgery. Loss of the surgical correction, implant breakage, and revision surgeries are the main disadvantages of present treatment methods. The purpose of this study is to investigate whether growing transpedicular instrumentation spares achieved surgical correction during patient's growth.

Methods

This is a prospective study of 12 consecutive patients with early-onset scoliosis from one clinical centre. All patients underwent anterior convex growth arrest and posterior transpedicular instrumentation with growing construct.

Spinal derotation was used for the correction of the deformity. The diagnoses were infantile idiopathic (n=10) and congenital (n=2) scoliosis (formation failure). Follow-up was 3 years. Mean age at the time of surgery was 9·1 years.

Introduction

Developments in the use of ultrasound during pregnancy for assessment of fetal spine abnormalities indicate a need for accurate information about the antenatal development of the vertebral column. The published work is deficient in this regard, with available data examining only the period of 8–26 weeks. The aims of this study are to establish antenatal spine growth curves with fetal radiographs, to establish growth velocity curves for each anatomical spinal, region and to calculate the multiplier factor during antenatal life.

Methods

75 anteroposterior spine radiographs were retrieved from the fetal pathology unit. Cases with spinal anomalies were excluded from analysis. Individual vertebral regions were measured from radiographs with the method of Bagnall and colleagues,1 with use of DICOM software. Polynomial regression analysis was applied to each measurement with PASW statistics 18 (SPSS, Chicago, IL, USA).

Introduction

There is an unresolved controversy in the published work about the effect of screws crossing the neuro-central cartilage (NCC) on spinal canal dimension in very young children and in animals. Anterior vertebral body screws with fusion can invade and damage the NCC, especially at the site of screw insertion; however, this finding has never been studied.

Methods

This study is a retrospective, clinical and radiological analysis of seven consecutive children aged 1–2 years treated with anterior vertebral instrumentation and fusion by downsized rod screw systems. The mean age at time of surgery was 2 years 4 months (range 1 year 9 months to 2 years 10 months). The average follow-up period was 3 years 3 months (2 years 6 months to 4 years 5 months). 16 screws inserted anteriorely were evaluated by a follow-up CT scan. Spinal canals were divided with known anatomical landmarks into right and left hemicanals. The relation of the anterior screws to the NCC and the spinal canal dimension were studied. All clinical and radiological complications were recorded.

Introduction

Posterior spinal arthrodesis with thoracoplasty and an open anterior approach, with respect to a posterior only fusion, have a deleterious effect on pulmonary function for up to 5 years after surgical treatment of adolescent idiopathic scoliosis. We aimed to compare two groups of adolescents surgically treated for their spinal deformity either by posterior segmental fusion alone (PSF) or by posterior spinal fusion and thoracoplasty (PSF+T). We focused on the long-term effects of thoracoplasty on pulmonary function in the surgical treatment of adolescent idiopathic scoliosis.

Methods

We compared 40 consecutive adolescent patients surgically treated between 1998 and 2001 by PSF+T with a similar cohort of 40 adolescents treated in the same period by PSF. Inclusion criteria were pedicle screw instrumentation alone and a minimum 5 years of follow-up. A radiographic analysis and a chart review were done, evaluating the pulmonary function tests (PFTs), the SRS-30 score questionnaire, and the Lenke classification system. A radiographic rib-hump (RH) assessment was also undertaken.

Introduction

Adolescent idiopathic scoliosis accounts for 80–85% of all lateral curvatures, and negatively affects pulmonary functions. The concave rib osteotomy technique is designed to provide additional mobility and flexibility of the spine, especially for rigid curves during correction. Only a few studies have investigated the effect of concave rib osteotomy on pulmonary functions.

Methods

We undertook a prospective study of 127 patients who underwent posterior spinal fusion for correction of adolescent idiopathic scoliosis. Patients were divided according to their Cobb angle into two groups: group 1 (n=78) with a Cobb angle greater than 70° who underwent an additional concave rib osteotomy (CRO); and group 2 (n=49) with a Cobb angle less than 70° who did not (NCRO). All patients received a programme of pulmonary rehabilitation immediately after the operation for 1 year. Vital capacity (VC) and peak expiratory flow rate (PEF) were measured preoperatively, at 3 months and 12 months postoperatively, and at 5 years postoperatively.

Introduction

The change of position of the distal pedicle screws with growing rods in relation to vertebral bodies was described as pedicle screws migration. Pedicle screws are subjected to serial distractive forces pushing them down with every distraction; additionally there is continuous growth of the vertebral bodies during the treatment period. These two factors can affect the change of position of the pedicle screws in relation to the vertebrae during the use of growing rods. To our knowledge, this finding has never been studied, confirmed, or quantified.

Methods

This is a retrospective review of the radiographs and operative notes of 23 consecutive cases of early-onset scoliosis treated with single growing rods. Age at index surgery ranged from 4 years 2 months to 8 years 9 months, and the number of distractions was four to 11 per patient. Measurements were done on post-index and latest follow-up true lateral radiographs. With optimum initial position of the screws in the pedicle, we calculated the distance between the upper end plate and the pedicle screw (distance superior to the screw [SS]) and the distance between the screw and lower-end plate (distance inferior to the screw [IS]). We expressed this ratio as a percentage: SS/IS x 100%. Any increase in this percentage with time denoted a more caudal position; however, a change in the percentage of less than 10% was regarded as insignificant.

Introduction

Autonomic nerve system (ANS) regulates intercostal vascular nutrition (internal mammary artery), and its pathological status leads to developmental asymmetry of the trunk and rib cage, and consequently producing scoliotic deformity of the spine. The aim of this study is to investigate the possible causation of idiopathic scoliosis in development abnormalities of ANS.

Methods

We evaluated samples taken from 12 patients with idiopathic scoliotic deformities and a control set of three patients without scoliotic deformity. We examined the samples of autonomic nerves taken from convexity and concavity of the scoliotic deformity during the patients' surgical correction by the transthoracic approach. We used the electronmicroscopic method to analyse samples, and the morphometric method for statistical evaluation.

Introduction

The potential structural effect of the sacral tilt on the development of disc wedging adjacent to lowest instrumented vertebra (LEV), and consequent postoperative coronal trunk decompensation in the surgical treatment of idiopathic scoliosis are well known. The aim of this study is firstly to establish the possible role of sacral tilt, limb length inequality, and associated pelvic girdle anomalies in the cause of idiopathic scolisosis, and secondly to determine the effect of sacral tilt on adjacent disc wedging below LEV in some idiopathic curves such as thoracolumbar/lumbar curves, and double major curves postoperatively.

Methods

Between 2006 and 2008, 159 patients with idiopathic scoliosis from outpatient clinics were included in analyses. In all patients, standing posteroanterior and lateral spinal column and Ferguson radiographs were routinely taken. If direct radiographs suggested iliac bone asymmetry, hemi-pelvis volume measurements were done with CT scan. Curve type, sacral tilt, L5 tilt, iliac asymmetry, and limb-length differences were measured. As a second part of study, 87 surgically treated patients with double major curves were examined retrospectively in terms of adjacent subjacent disc wedging below LEV and sacral tilt.

Introduction

Many methods are available for distal anchoring of spine-based and rib-based growing rod systems for early-onset scoliosis. One of these methods, pelvic S-hooks, was initially recommended for patients with spina bifida or for those with severe thoracolumbar curves. No study has yet analysed the clinical and radiographic effects of S-hooks on patients with rib-based instrumentation. The purpose of this study is to retrospectively review the results of S-hook pelvic fixation in patients with rib-based instrumentation

Methods

A multicentre, retrospective study, approved by the institutional review board, was undetaken in all patients treated with rib-based constructs using S-hooks for pelvic fixation. Preoperative and postoperative clinical variables, radiological measurements, and the incidence and management of complications were evaluated in patients with a minimum follow-up of 2 years.

Introduction

With the use of each pedicle screw for surgical correction of adolescent idiopathic scoliosis (AIS), there is an increase in instrumentation-related costs, operative time, risk of neural injury, and overall health-care expenses. As such, alternate level screw strategy (ALSS) has been reported as a potential alternative to contiguous multilevel screw strategy (CMSS). Moreover, studies have shown the importance in accounting for the flexibility of the curve based on the fulcrum bending radiograph when assessing postoperative curve correction. Therefore, this study addressed a radiographic and cost analysis comparing CMSS with ALSS for the treatment of thoracic AIS with titanium screws and rod application.

Methods

77 patients with AIS underwent surgery (range 6–15 levels). 35 patients received CMSS, which was characterised as bilateral screw fixation at every level. 42 patients underwent ALSS, which entailed bilateral screw fixation at alternate levels. Titanium rods were used in all cases. Preoperative and postoperative posteroanterior and fulcrum bending radiographic Cobb angles were obtained for all patients. The fulcrum flexibility and the fulcrum bending correction index (FBCI) were assessed. Cost analysis was also done.

Introduction

Growing rods are used in the treatment of early-onset scoliosis. The aim of this technique is to achieve deformity correction while maintaining spinal growth. Gradual stiffening or spontaneous fusion of the spine can interfere with the ability to lengthen. Furthermore, diminished acquired length with serial distraction is common and needs to be evaluated and quantified. The purpose of this prospective study was to measure the forces and amount of distraction over time in patients with early-onset scoliosis treated with growing rods.

Methods

Distraction forces were measured prospectively during 60 consecutive lengthening procedures in 26 patients. All patients had single submuscular rod constructs with side-to-side connectors. For every measurement, output from a transducer on a dedicated pair of distraction calipers was recorded at zero load status, and the force was then recorded at every 1 mm lengthening; length was obtained at each event and was recorded in millimeters.

Introduction

Our short segment anterior technique produces similar correction and better functional outcomes for patients with adolescent idiopathic scoliosis by instrumentation of fewer levels than does posterior segmental instrumentation. We present the results of the first consecutive 45 patients operated by the short segment bone-on-bone anterior scoliosis technique, with a mean follow-up of 6 years. Every patient was followed up over 2 years and none was lost to follow-up.

Methods

The patients (28 with thoracic scoliosis; 17 with thoracolumbar scoliosis) were operated between 1996 and 2004 for single curve idiopathic scoliosis. The mean age was 19 years (range 9–51); 87% of the cohort was female and the mean follow-up was 72 months (range 28–121). We operated on curves less than 75° by the short segment anterior approach with total discectomy, bone-on-bone apposition, and dual-rod instrumentation. We assessed the sagittal and coronal corrections on erect anteroposterior and lateral radiographs done preoperatively, postoperatively, and at final follow-up.

Introduction

Spinopelvic parameters describe the orientation, shape, and morphology of the spine and pelvis. These parameters change during the first 10 years of life in children without spinal deformity; however, spinopelvic parameters have yet to be defined in children with significant early-onset scoliosis (EOS). Sagittal plane alignment could affect the natural history and outcome of interventions for EOS. As a result, spinopelvic parameters are being defined for this population. On the basis of the landmarks used for measurement of these parameters, there may be inherent error in performing these measurements on the immature pelvis. The purpose of this study is to define the variability associatedwith the measurement of spinopelvic parameters in children with EOS.

Methods

Standing, lateral radiographs of 11 patients with untreated EOS were evaluated. Sagittal spinopelvic parameters (pelvic incidence [PI], pelvic tilt [PT], sacral slope [SS], and modified pelvic radius angle [PR]) were measured. To assess intraobserver reliability, these measurements were repeated 15 days apart. To define interobserver reliability, radiographs were measured by 2 independent observers.

Introduction

Spinopelvic parameters describe the orientation, shape, and morphology of the spine and pelvis. In children without spinal deformity, these parameters change during the first 10 years of life; however, spinopelvic parameters need to be defined in children with significant early-onset scoliosis (EOS). The purpose of this study is to examine the effects of EOS on sagittal spinopelvic alignment. We hypothesise that sagittal spinopelvic parameters for patients with EOS will differ from age-matched children without spinal deformity. These values will act as a baseline for future studies and may predict postoperative complications such as proximal junctional kyphosis and implant failure in children being treated with growing systems.

Methods

Standing, lateral radiographs of 82 untreated patients with EOS with Cobb angle greater than 50° were evaluated. Sagittal spine parameters (sagittal balance, thoracic kyphosis [TK], lumbar lordosis [LL]) and sagittal pelvic parameters (pelvic incidence [PI], pelvic tilt [PT], sacral slope [SS], and modified pelvic radius angle [PR]) were measured. These results were compared with those reported by Mac-Thiong and colleagues (Spine, 2004) for a group of similar aged children without spinal deformity.

Introduction

Children with early-onset scoliosis (EOS) with rib hump chest-wall distortion or fused/absent ribs have thoracic insufficiency syndrome (TIS). Commonly, respiration is adversely affected by loss of lung volume from chest-wall constriction and clinical loss of active rib cage expansion. The dynamic thoracic components of diaphragm or rib cage lung expansion during respiration is poorly characterised by radiograph or CT scan. Pulmonary function tests indicate only hemithorax performance. Dynamic lung MRI, however, can visualise both chest-wall and diaphragm motion, allowing assessment of each individual hemithorax performance, so that a dynamic classification system of the thoracic function can be developed.

Methods

Ten patients with TIS underwent dynamic lung MRI testing as part of the routine clinical preoperative work-up. Each hemithorax was graded: 1=intact motion of both chest wall and diaphragm; 2=primarily loss of chest-wall motion with minimal diaphragm abnormality; 3=substantial loss of diaphragm excursion with minimal loss or compensatory hyperkinesis of chest wall; and 4=substantial loss of both diaphragm and chest-wall motion. The grades for each hemithorax were added and averaged to form the thoracic function score. Ranges of scores were grouped into levels of clinical thoracic performance: level I (score 1–1·5); level II (>1·5–2·5); level III (>2·5–3·5); and level IV(>3·5–4·0).

Introduction

Despite extensive research, the cause of adolescent idiopathic scoliosis (AIS) is still largely unclear. Girls with AIS tend to be taller and leaner, and have a lower body-mass index (BMI) and lower bone mass, than do healthy girls. Recent MRI studies have shown the presence of relative anterior spinal overgrowth in girls with AIS. The lower bone mineral status and BMI could be related to dysfunctional central regulation pathway of growth, bodyweight, and bone metabolism. Following several interesting reports on the role of leptin in regulation of the above pathway in animals and human beings, our recent study has shown a low leptin concentration in girls with AIS girls compared with healthy adolescents. This finding leads to our new hypothesis that abnormal leptin bioavailability could be associated with the lower bodyweight, lower bone mineral density, and relatively disproportional endochondral skeletal growth in AIS. This study aimed to investigate the leptin bioavailability in girls with AIS.

Methods

53 girls with AIS and 27 healthy girls (aged 11–16 years) were recruited in this preliminary study. Clinical and anthropometric data were obtained. Blood samples were obtained for ELISA of leptin and soluble leptin receptor (sOB-R). Independent Student's t test and multivariate regression were used in group comparison.

Introduction

Calmodulin probably has a regulatory role in muscle contraction and its antagonism may decrease the magnitude and progression of scoliosis. A separate study has shown that tamoxifen (TMX), a known antagonist, is effective in altering the natural history in an avian model; however, whether the same effect is conceivable in mammals is unknown.

We aimed to analyse whether the natural course of scoliosis in mice may be altered by the administration of TMX.

Methods

60 female, 3-week-old, C57BL/6 mice underwent amputations of forelimbs and tails. 57 mice were assigned to three groups: control group, no medications; TMX group, 10 mg TMX/L drinking water; and combined group, 10 mg TMX plus 10 mg trifluoperazine (TFP)/L drinking water. PA scoliosis radiographs were taken at 20 and 40 weeks and evaluated for presence and magnitude of spinal curves.

Introduction

Elastic fibres are constructed of a central core of elastin surrounded by microfibrils that are composed mainly of fibrillin-1 and fibrillin-2. Patients with mutations in the gene encoding fibrillin-1 or fibrillin-2 develop Marfan syndrome or Beals syndrome (congenital contractural arachnodactyly), respectively. Scoliosis is one of the clinical manifestations in these patients, but how a defect in the elastic proteins could lead to a spinal deformity is not clear. On the one hand, the mutations could induce scoliosis via mechanical means as they could lead to alterations in the biomechanics of the elastic fibre system. On the other hand, elastic fibres also bind growth factors such as transforming growth factor β (TGFβ) and bone morphogenic proteins (BMPs), and the mutations could hence change patterns of spinal growth.

Methods

We have investigated the localisation of elastic proteins in different spinal tissues at different stages of curve development in mouse models and in human tissue obtained during scoliosis surgery.

Introduction

We prospectively examined the effect of pedicle screw placement at a young age (<5 years) for early-onset spinal deformity on the growth and development of pedicles and the spinal canal.

Methods

Patients with early-onset deformity who received pedicle screw placement before the age of 5 years and had preoperative and final follow-up axial imaging were included. To increase sample size, patients who had the same criteria but with no preoperative axial images were also included. Anteroposterior and transverse diameters of the canal and pedicle length were measured on axial images cutting through the middle of the pedicle (figures 1 and 2).

Introduction

Type 1 neurofibromatosis is a serious hereditary disease in which mainly skin, nervous, muscular, and bone systems are damaged. In bone systems the most common deformities are thoracic kyphosis and scoliosis. Data for morphological changes in the structural components of spine in neurofibromatosis are scarce. Thus our study aimed to investigate morphological changes in structural components of the spine in NF1 neurofibromatosis.

Methods

Growth plates, intervertebral discs, and fragments of vertebral bodies from deformed and adjacent segments of the spine were obtained from 15 patients aged 10–14 years with scoliosis (Cobb angle 90–120°) caused by neurofibromatosis. Preoperative examination included MRI study of the spine and brain to exclude intracanal masses, and radiographic study of the spine. Patients did not present any neurological symptoms. All children underwent anterior release and interbody fusion. Structural spinal components from children aged 12–14 years collected at forensic autopsy were used as controls. Tissues were investigated by conventional histochemical and ultrastructural methods. The levels of aggrecan and NF1 gene expression were studied with the PCR method.

Introduction

Monitoring of scoliosis is traditionally done with radiographs, which can be associated with an increased risk of cancer secondary to multiple exposures over many years. This study investigated whether the findings from surface topography can be used to monitor scoliosis curves and how much this method affects outcome scores in patients with scoliosis. This study therefore had two subsets: (1) to investigate whether lateral asymmetry (LA) from ISIS2 surface topography can predict radiographic Cobb angle, providing an alternative non-invasive means of monitoring patients with scoliosis (LA and Cobb subset); and (2) to establish the relationships between the magnitude of the deformity in scoliosis, measured by Cobb angle on radiograph and volumetric asymmetry (VA) with the ISIS2 surface topography, and the patient perception of self-image and mental health, measured with SRS-22 scores (Cobb, VA, and SRS subset).

Methods

In the LA and Cobb subset, 72 untreated patients with scoliosis (77 curves) with a Cobb angle of 55° or less were included in the study. They had clinical assessment, Cobb angle measurement taken from a standard radiograph, and surface topography done on the same day. A comparison of Cobb angle and LA was done. In the Cobb, VA, and SRS subset, 89 untreated patients with scoliosis were included in the study. They had clinical assessment, Cobb angle measurement of radiograph, and surface topography done on the same day along with SRS-22 questionnaires. A comparison correlation of SRS scores for function, pain, self-image, and mental health against Cobb angle and VA was undertaken. All statistical analysis was done with software R.

Introduction

Different subclinical neurological dysfunction has been reported in adolescent idiopathic scoliosis (AIS), including poor postural control and asymmetric otolith vestibulo-ocular responses when compared with normal controls. The objective of this pilot study is to establish whether abnormal MRI morphoanatomical changes arise in the CNS (brain and vestibular system), among left-thoracic versus right-thoracic AIS when compared with normal adolescent controls, with use of advanced computerised statistical morphometry techniques.

Methods

We compared nine girls with left-thoracic AIS (mean age 14 years; mean Cobb angle 19°) with 11 matched controls, and 20 girls with right-thoracic AIS (mean age 15 years, mean Cobb angle 33·8°) with 17 matched controls. The statistical brain analysis was done with validated automatic segmentation and voxel-based morphometry (VBM). The T2W-MRI data for shape analysis of the vestibular system were obtained from 20 patients with right-thoracic AIS and 20 matched controls. A best-fit plane and a best-fit circle were calculated to approximate each semicircular canal. The shape of vestibular system was measured by: (1) the angle between each pair of best-fit planes; (2) the length; and (3) angle formed between the corresponding lines connecting the centres of each pair of circles. Statistical analysis was done with one-way ANOVA.

Introduction

Horizontal gaze palsy (HGP) in association with scoliosis has been reported in both orthopaedic and ophthalmological published work. Juvenile progressive scoliosis in combination with HGP is caused by a malfunction of the normal control mechanism for equilibrium related to the lower brain stem, mostly associated with ROBO3 gene mutation.

The aim of this study is to establish the association of scoliosis and HGP.

Methods

13 cases (four families and three sporadic cases) with HGP and scoliosis were documented; other systemic and ocular associated findings were identified and genetic counselling was done. All patients had radiograph of the spine, cranial and spinal cord MRI, chromosome analysis, gene analysis, and full ophthalmological examination. Blood samples were tested for ROBO3 gene mutation at Engle Laboratory, USA.

Introduction

At the Zorab Symposium in Oxford, 2006, we showed that semicircular canal (SCC) anomalies occurring with posterior basicranium asymmetry affect the oculovestibular system in human beings. As a consequence, we proposed the hypothesis of a descending direct vestibulospinal and cognitive top-down effect on some scoliosis. We will show that some SCC anomalies detected with MRI modelling are malformations frequently found in scoliosis.

Methods

445 patients (323 women, mean age 21 years; 122 men, mean age 24 years) with instability, imbalance, and spatial disorientation were submitted to T2 MRI modelling. 95 of 445 patients had scoliosis: 57 thoracolumbar scoliosis, 24 thoracic scoliosis, and 14 lumbar deformation. We processed the data acquired with G.E.MRI (1.5T), T2- 3D Fiesta with a set of Brainvisa modules (http://brainvisa.info/).

Introduction

The Proprio-oculo-vestibular system is involved in scoliosis. In Congress ZORAB, Oxford 2006, we showed correlations between morphological semicircular canals (SCC) anomalies and vestibular dysfunctions associated with oculomotor anomalies. We will describe a set of specific anomalies in adolescent idiopathic scoliosis (AIS) in favour of an altered perception of space.

Methods

The study included 95 patients with AIS: 57 had thoracolumbar scoliosis, 24 thoracic scoliosis, and 14 lumbar deformation. Patients were submitted to a set of tests: (1) three-dimensional vestibular evaluation with semicircular canal-specific horizontal and vertical stimulations; (2) measurement of the static ocular torsion; (3) ocular smooth pursuits analyses with a new automatised programme; and (4) posturographic recording (static and dynamic tests). The tests were done before and after treatment (vestibular training and oculomotor training).

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.

Introduction

Postural and motor activities are the results of interactions of smaller inhibitory and larger facilitating structures of the central nervous system (CNS). In the case of dysbalance of inhibitory and facilitating structures during CNS evolution, the asymmetry of postural activities can appear. This asymmetry remains hidden in the early periods of evolution and becomes apparent in the periods of quick growth and increased hormonal and metabolic activities. Genetic and neural factors have proven to be significant in the cause of idiopathic scoliosis (IS), so we propose a neural developmental hypothesis of this disease.

Methods

We evaluated a cohort of 19 patients, all of whom were girls with a mean age of 14·7 years (range 13–18) with right idiopathic thoracic curve (mean Cobb angle 53·5°, range 37–72°; of the apical vertebra from T7 to T9). Heart and pulmonary functions were evaluated by heart ECHO and spiroergometry.

Introduction

One of the most complicated problems of orthopaedics is the treatment of scoliosis. More than 90% of cases are attributable to idiopathic deformation, the cause of which is unknown. We investigated the cause and pathogenesis of this disorder.

Methods

At our institution, more than 6900 patients aged 1–89 years have undergone inpatient and outpatient treatment in connection with spinal pain syndrome and different neurological disorders associated with idiopathic scoliosis. This study was undertaken between February, 1996, and February, 2010. All patients had had clinical, radiographic, and laboratory examinations.

Introduction

In patients with adolescent idiopathic scoliosis (AIS), anomalous extra-spinal left-right skeletal length asymmetries in upper limbs, periapical ribs, and ilia beg the question as to whether these bilateral asymmetries are connected in some way with pathogenesis. The upper arm and iliac length asymmetries correlate significantly with adjacent spinal curve severity respectively in thoracic and lower (thoracolumbar and lumbar) spine. In lower limbs, skeletal length asymmetries and proximo-distal disproportion are unrelated to spinal curve severity. Overall, these observations raise questions about mechanisms that determine skeletal bilateral symmetry of vertebrates in health and disorder, and whether such mechanisms are involved in the cause of this disease. We investigated upper arm length (UAL) asymmetries in two groups of right-handed girls aged 11–18 years, with right thoracic adolescent idiopathic scoliosis (RT-AIS, n=98) from preoperative and screening referrals (mean Cobb angle 45°) and healthy controls (n=240).

Methods

Right and left UAL were measured with a Harpenden anthropometer of the Holtain equipment, by one of four observers (RGB, AAC, RKP, FJP). UAL asymmetry was calculated as UAL difference, right minus left, in mm. Repeatability of the measurements was assessed by technical error of the measurement (TEM) and coefficient of reliability (R).

Introduction

Spinal deformations are a deviation of the natural arrangement of forces during growth. Environmental factors play a part in these deviations. The presence of lordosis in the thoracic spine is a causative factor in spinal deformations that needs to be addressed. Most biomechanical models of bracing have a scientific background. Has older knowledge lost its value? In living structures, all processes such as regulation of equilibrium in posture and movement use Newton's law and extended laws of Hooke for conservation of energy, momentum, and angular momentum under control of the central nervous system. Form follows function (phylogenetic and ontogenetic) in the spine as primary engine in movement in animals. The change in function in bipedals is that the coupling mechanism at the thoracolumbar joint now couples a reversed pendulum.

Methods

A literature search shows a clear gap in the evolution in science on deformities during 1914–45. In 1792, Van Gesscher postulated two concepts in Observations on Deformations of the Spine (Dutch). First, the optimalisation of the balancing forces in men needs a specific optimum curvature to keep the weight of the head and shoulders above the hips. The second concept was the role of sitting in relation to changes around the discs at the thoracolumbar spine. Girls who read or knitted while sitting developed scoliosis more easily than did others. His extending (by lordosis) corrective corset was used for more than 150 years before plaster became popular. Andry described guidance and correction of growing spines with use of the moulding capability of muscular forces, with exercises and extending corsets (for so-called weak girls). Extension and avoidance of incorrect posture during sitting became a mainstay in orthopaedics (and schools). In 1907, Wullstein described experiments in young dogs to show how forced fiexion produces all characteristics of kyphotic deformities. In 1912, Murk Jansen did a critical review of all available knowledge and his own research in The Physiologic Scoliosis and its causes. Post mortem studies showed anatomical asymmetry in the left and right crura of the diaphragm, which indicated that asymmetric rotational forces in ventilation could induce predominant lateral curves. In-vivo tests show increased thoracolumbar kyphosis if siblings are put in seated positions too frequently and too soon. The stiffening in kyphosis creates a fulcrum to cantilever the opposing rotational forces to lateral curvatures. In experiments in rabbits, lower intrathoracic pressure was shown in the right pleural cavity. Common alertness of parents and teachers was underwritten. Some of this still survives. In progressed scoliosis, Sayre's method of corrective plastering in suspension and Calot's corrections in prone position under anaesthesia and plaster shelves with lordosis in bed became popular. In the Volkmann Hueter principle, the resilience of the deformable structures in the spine were identified–eg, the discs, the apophyses, and the cartilage in joints have a role in spinal deformity. Cobb drew attention to the clinical aspects of scoliosis. Roth provided a comprehensive explanation of how growth is organised and regulated by the oldest organ of animal life: the central nervous system in vertebrates. Between 1960 and 1985, Roth developed his concepts on neurovertebral and neuro-osseous growth relations and the tension-driven incongruence of growth. Roth provided new biological knowledge about how growth seems to support older clinical observations. In animal experiments, mechanical modelling, and radiological studies in scoliosis he stressed the role that growth has in the formation of the spine. A so-called short cord can indeed cause scoliosis. Recent studies with MRI in idiopathic scoliosis confirm this hypothesis. Personal observations In 2008, a study showed that forceful restoration of thoracolumbar lordosis can correct double major scoliotic curves. A consequent thoracolumbar kyphotic curve was found, and recently reproduced. The thoracolumbar lordotic intervention brace technique showed promising results. It relied on the older techniques, leaving only the fear for lordosis brought by Dickson. In personal observations, the presence of neuromuscular tightness or tension also present in progressive scoliosis as representatives of deforming and protective forces.

Introduction

Thoracic pedicle screws have been proven to be safe and effective in the treatment of adolescent idiopathic scoliosis (AIS). However, the effect of the instrumentation alloy has not yet been investigated. We aimed to compare segmental versus non segmental thoracic pedicle screw instrumentation in patients with AIS.

Methods

A consecutive series of 143 patients with AIS (Lenke classification 1–4) surgically treated from 1998 to 2005 by means of thoracic pedicle screws were retrospectively reviewed. Considering implant density (number of fixation anchors placed per available anchors sites; segmental =60% [S], non-segmental =60% [NS]) and implant alloy used (titanium [Ti] vs stainless steel [SS]) we divided the cohort into four groups: Ti-S (48 cases); Ti-NS (34 cases); SS-S (35 cases); and SS-NS (26 cases). Groups were similar for preoperative mean age, sex distribution, Risser sign, main thoracic curve, and thoracic kyphosis. Pearson correlation coefficient and univariate analysis of variance were used.

Introduction

We aimed to determine the midterm effect of pedicle screw instrumentation on sagittal plane alignment, compared with a hybrid alignment, in the treatment of thoracic adolescent idiopathic scoliosis (AIS).

Methods

88 consecutive patients with AIS with a Lenke type 1 curve treated between 1998 and 2003 were analysed. Thoracic hooks were used in 45 patients (group Hy) and thoracic screws alone in 43 patients (group TPS). Preoperative average age (Hy 15·3 years vs TPS 16 years), sex (38 female and seven male vs 37 female and six male), Risser sign (2·9 vs 2·9), main thoracic curve (64° vs 65·5°), and thoracic kyphosis (22·6° vs 21·4°) were similar in both groups. Pearson correlation coefficient and univariate ANOVA were used.

Introduction

Distal adding-on is often accompanied by unsatisfactory clinical outcome and high risk of reoperation. However, very few studies have focused on distal adding-on and its attendant risk factors, and optimum treatment strategies remain controversial. In a retrospective study, we aimed to identify risk factors for the presence of distal adding-on in Lenke 1A scoliosis and to compare different treatment strategies.

Methods

Data for all surgically treated patients with adolescent idiopathic scoliosis (AIS) were retrieved from one institutional database. Inclusion criteria included: patients with Lenke 1A scoliosis treated with posterior pedicle screw-only constructs; and a minimum 1-year radiographic follow-up. Distal adding-on was defined as a progressive increase in the number of vertebrae included distally within the primary curve combined with either an increase of more than 5 mm in deviation of the first vertebra below instrumentation from the centre sacral vertical line (CSVL), or an increase of more than 5° in the angulation of the first disc below the instrumentation at 1 year follow-up. Wilcoxon rank-sum test, Fisher's exact test, and Spearman's correlation test were used to identify the risk factors for adding-on. A multiple logistic regression model was built to identify independent predictive factors. Risk factors included: age at surgery; preoperative Cobb angle; correction rate; the gap difference of stable vertebra (SV) and lowest instrumented vertebra (LIV), neutral vertebra (NC) and LIV, and end vertebra (EV) and LIV (gap difference means, for example, if SV is at L2 and LIV is at Th12, then the difference of SV-LIV is 2); and the preoperative deviation of LIV+1 (the first vertebra below the instrumentation) from the CSVL (the vertical line that bisects proximal sacrum). Five methods for determining LIV were compared in both the adding-on group and the no adding-on group.

Introduction

Surgical correction of spinal deformities is a challenge; segmental instrumentation controlling almost every level is the most recent approach. Correction of the deformity only through apical manipulation has many potential advantages, including little tissue disruption, less invasive intervention, preservation of spinal mobility, and vertebral growth. However, quantification of the amount of force needed to pull on the apex and its effect on translation, de-rotation, and overall correction of the curve needs to be studied. The purpose of this study is to determine the effect and amount of force needed to pull on the apex of a scoliotic deformity towards the midline, and the feasibility of use of this novel potential method of correction in the treatment of patients with adolescent idiopathic scoliosis (AIS).

Methods

Measurements were taken from 20 patients with AIS treated between June, 2009, and January, 2010. There were 16 female and 4 male patients with an average age of 14.2 years (range 11–20); the coronal preoperative Cobb angle was 67° (42–108°), decreasing on bending to 39° (8–83°), and the apex of the deformity was between T6 and L2. All patients had proximal and distal anchors spanning two levels on each end; the anchors were connected by a concave rod to which the apical vertebra was pulled. We measured the distance between the rod and the apical vertebra and the rotation of the apical vertebrae.

Introduction

How translation of different parts of spine responds to selective thoracic fusion has not been well investigated. Furthermore, how posterior pedicle-screw-only constructs affect spontaneous lumbar curve correction (SLCC) remains unknown. In a retrospective study, we aimed to investigate the balance change after selective thoracic fusion in Lenke 1C type adolescent idiopathic scoliosis (AIS) treated with posterior pedicle-screw-only constructs.

Methods

All AIS cases, surgically treated between 2002 and 2008 in our institute, were reviewed. Inclusion criteria were: patients with Lenke 1C scoliosis treated with posterior pedicle-screw-only constructs; the lowest instrumented vertebra (LIV) ended at L1 level or above; and a minimum 2-year radiographic follow-up. Standing anteroposterior (AP) and lateral digital radiographs from different timepoints (preoperative, immediately postoperative, 3 months postoperative, and final follow-up) were reviewed. In each standing AP radiograph, centre sacral vertical line (CSVL) was drawn first, followed by measurement of the translation (deviation from the CSVL) of some key vertebrae, such as the LIV, LIV+1 (the first vertebra below LIV), LIV+2 (the second vertebra below LIV), LIV+3 (the third vertebra below LIV), lumbar apical vertebra, thoracic apical vertebra, and T1. Additionally, the Cobb angles of major thoracic and lumbar curve were measured at different timepoints, and the correction rate was calculated. Furthermore, clinical photos of patients' back appearance were taken preoperatively and postoperatively.

Introduction

Genetic predisposition is a key causal factor in adolescent idiopathic scoliosis (AIS), which is the most common form of spinal deformity. However, common quantitative genetic effect estimates such as hereditability have not been fully evaluated and reported for this disorder. We aimed to determine the sibling recurrent risk and hereditability of AIS in first-degree relatives of 513 Chinese patients with this disorder.

Methods

Family members of 513 Chinese patients with AIS attending a scoliosis clinic were assessed. A diagnosis of AIS was made with the criteria of Cobb angle greater than 20°. The evaluation included clinical assessment and physical examination in a health screening centre by medical doctors with use of forward bending test. Any positive screening cases were referred to a scoliosis clinic for follow-up spinal radiograph. All radiographs were assessed by an orthopaedic surgeon in the scoliosis clinic. A population prevalence of scoliosis was obtained from the data of a territory-wide screening campaign. The prevalence of AIS among siblings of probands was measured both overall and divided by sex of siblings. The sibling recurrent risk (λs) was calculated for male and female siblings separately with reported population incidence of AIS.

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).

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.

Introduction

Kyphoscoliosis is defined by a structural lateral curvature of the spine of 10° or more and an excessive thoracic kyphotic curve of 40° or more. Genetic analyses of families in which two or more members had kyphoscoliosis identified a 3·5 Mb area on chromosome 5p containing three genes of the Iroquois (IRX) homeobox family, IRX1, IRX2, and IRX4, which were then sequenced.

Methods

Exons and highly conserved non-coding regions (HNCRs) 500 kb upstream and downstream fromIRX1, IRX2, and IRX4 were sequenced in 46 individuals from six families. Selection of these elements was based on PhastCons Placental Mammal Conserved Elements, Multiz Alignment. Single-nucleotide polymorphism (SNP) genotypes and sequence variants were obtained from all individuals. There were 431 SNPs, 61 in IRX4 regions, 80 in IRX2 regions, and 290 in IRX1 regions. 137 SNPs were novel. Mendelian inconsistencies were detected with PEDCHECK (inconsistency rate: 1·4%; missing data: 2·8%). SNPs and individuals with greater than 10% missing rate were excluded. Association analyses (ASSOC [SAGE version 6.0.1]) of the quantitative trait with patient's largest curve, were undertaken on 391 SNPs.

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.

Introduction

Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity. It occurs mainly in girls and progresses during pre-pubertal and pubertal growth, which is a crucial period for bone mass acquisition. The cause and molecular mechanisms of AIS are not clear; at present the consensus is that AIS has a multifactor cause, with many genetic factors. During the past 5 years, considerable effort has been devoted to identify a gene or genes that cause a predisposition to AIS. Many loci for this disorder have been mapped to different chromosome regions, but no genes have been clearly identified as being responsible for AIS, and, most importantly, the resulting protein defects remain to be shown. We aimed to identify the gene(s) that could be involved in AIS and to validate their involvement by both genetic and functional analyses.

Methods

A large multiplex AIS French family was chosen for this study on the basis of clinical and radiological data. Whole genome genotyping of the 20 members of this family led to the mapping of a dominant disease-causing gene to two critical genomic intervals (Edery and colleagues, Eur J Hum Genet, accepted [2011]), but the causative mutation remains to be identified. In parallel, gene expression profiling was investigated by microarray analysis in RNA samples isolated from osteoblasts derived from healthy individuals and those with AIS. RNA samples were extracted from osteoblasts, purified, fluorescently labelled, and then hybridised to gene expression microarrays with the Illumina expression BeadChips technology containing more than 46 000 probes for the human genome (HumanHT-12). Data analysis in R version 2.10.1 (Bioconductor packages oligo and limma) was done, and genes that had at least 1·5-fold change in expression were considered differentially regulated relative to controls. AIS candidate genes within the critical intervals were selected on the basis of their mRNA expression in AIS individuals and by their known functions. The coding regions of these candidate genes were then sequenced to identify potential mutations. The biological activity of mutant proteins is under evaluation by in-vivo functional studies in zebrafish.

Introduction

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity in children, and its cause is unknown. Recently, researchers have traced a defect in the gene CHD7 to AIS. CHD7 encodes for a chromodomain helicase of the DNA-binding domain protein family and is thought to have a crucial role in many basic cellular functions. However, the functional role of CHD7 in AIS is still elusive. In this study, we investigated the potential pathogenic effect of gene defects in CHD7 in vivo by evaluating their effect on spine formation and development in zebrafish.

Methods

To investigate the function of the CHD7 encoded protein, we generated an antisense morpholino oligonucleotide against the CHD7 gene to disrupt the translation of the gene transcripts and knockdown the levels of its protein. The morpholino was injected into single-cell stage zebrafish embryos. The injected fish were allowed to develop and were then assessed for distinct phenotypes reminiscent of scoliosis by histological stains.

Introduction

Previous work has shown that C57BL/6 mice develop scoliosis when rendered bipedal. Our previous work suggested that tamoxifen (TMX) might change the natural course of scoliosis when administered before scoliotic curves develop. We analysed whether the incidence of scoliosis or the magnitude of curves may be decreased by the administration of tamoxifen after curves are observed.

Methods

20 female, 3-week-old C57BL/6 mice underwent amputations of forelimbs and tails at 3 weeks, 18 of which were included in analyses. Posteroanterior scoliosis radiographs were obtained at week 20, and scoliotic curves were recorded. After week 20, all mice received 10 mg TMX per L of daily water supply for 20 weeks. The course of deformities in this group (week 20 group) was compared with that of previous study groups (receiving TMX from week 3; week 3 group).

Introduction

Several disorders have been associated with genetic variants. Copy number variations (CNVs) are documented micro DNA insertions and deletions that may be ten times more frequent than point mutations. We undertook a genome-wide scan to find CNVs associated with adolescent idiopathic scoliosis (AIS).

Methods

879 white individuals with AIS severe spine curvatures and 1486 white controls were evaluated for CNVs with the Affymetrix 6.0 HUSNP array. After implementation of quality filters, data were quantile normalised. Copy number analysis was done with Helix Tree (Golden Helix, Bozeman, MT, USA). The copy number segments were measured with the Golden Helix's univariate segmentation algorithm. Statistically different segments were extracted with mean Log2 ratio intensity for that segment to highlight deletions, neutrals, and duplications. We then undertook association analysis on those segments. A p value of less than 10–7 was regarded as significant.

Introduction

Adolescent idiopathic scoliosis (AIS) is the most common paediatric spinal deformity, affecting about 3% of school-aged children worldwide. This disorder occurs in otherwise healthy children who bear no obvious deficiencies in the components of the spinal column itself. The cause of AIS is poorly understood, as is implied by the name. Lesions of the bony composition of the vertebrae, the vertebral endplates, the paraspinous muscles, or the neurological system each have been proposed to explain disease pathogenesis. Progress has been hampered by the absence of an obvious AIS animal model. Consequently we have used genetic studies in human populations to identify factors underlying AIS susceptibility.

The complex inheritance and population frequency of AIS suggest that many genetic factors are involved in this disease. To search comprehensively for such factors we previously undertook the first genome-wide association study (GWAS) of AIS susceptibility in a cohort of 419 families in Texas, USA. We found that chromosome 3 SNPs in the proximity of the CHL1 gene yielded strongest results, which we replicated in additional cohorts (rs10510181 OR 1·49, 95% CI 1·29–173, p=2·58×10–8). CHL1 is of interest because it encodes an axon guidance protein and is functionally related to the ROBO3 gene that causes hereditary gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Here we expanded the study to 702 Texas families.

Methods

We tested more than 327 000 single-nucleotide polymorphisms (SNPs) across all human autosomes for association with disease.

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.

Introduction

From the many human studies that attempt to identify genes for adolescent idiopathic scoliosis (AIS), the view emerging is that AIS is a complex genetic disorder with many predisposing genes exhibiting complex phenotypes through environmental interactions. Although advancements in genomic technology are transforming how we undertake genetic and genomic studies, only some success has been reached in deciphering complex diseases such as AIS. Moreover, the present challenge in AIS research is to understand the causative and correlative effects of discovered genetic perturbations. An important limitation to such investigations has been the absence of a method that can easily stratify patients with AIS.

To overcome these challenges, we have developed a functional test that allows us to stratify patients with AIS into three functional subgroups, representing specific endophenotypes. Interestingly, in families with multiple cases of AIS, a specific endophenotype is shared among the affected family members, indicating that such a transmission is inherited. Moreover, increased vulnerability to AIS could be attributable to sustained exposure to osteopontin (OPN), a multifunctional cytokine that appears to be at the origin of the Gi-coupled receptor signalling dysfunction discovered in AIS. We examined the molecular expression profiles of patients with AIS and their response to OPN.

Methods

Osteoblasts isolated from patients with AIS were selected for each functional subgroup and compared with osteoblasts obtained from healthy matched controls. We used the latest gene chip human genome array Affymetrix (HuU133 Plus 2.0 array) that allows for the analysis of the expression level of 38 000 well characterised human genes. Raw data were normalised with robust multiarray analysis method. Statistical analysis was done by the EB method with FlexArray software. Selection criteria for in-depth analysis include the magnitude of change in expression (at least □} 3-fold) and 5% false discovery rate as stringency selection. Validation of selected candidate genes was done by qPCR and at the protein level by Western blot and ELISA methods. Plasma OPN concentrations were measured by ELISA on a group of 683 consecutive patients with AIS and were compared with 262 healthy controls and 178 asymptomatic offspring, born from at least one scoliotic parent, and thus considered at risk of developing the disorder. The regulation of OPN signalling pathway in normal and AIS cells were validated in vitro by cellular dielectric spectroscopy (CDS).

Introduction

The response of the intervertebral disc to asymmetric forces may accelerate degeneration through changes in the matrix. Macroscopically, the disc sustains structural changes that may play a part in the progression of a scoliotic curve. Molecularly, disc degeneration is the outcome of the action of matrix metalloproteases (MMPs), members of a family of enzymes that bring about the degradation of extracellular matrix components. In this study we measured in vivo the expression of MMPs in a rat scoliotic intervertebral disc and studied the effect of the degree of the deformity on their production.

Methods

Asymmetric forces were applied in the intervertebral disc between the ninth and tenth vertebrae at the base of a rat tail with the use of a mini Ilizarov external fixator, under anaesthesia. Animals were categorised into three groups according to the degree of the deformity. In group I, the deformity that was applied on the intervertebral disc was 10°, in group II 30°, and in group III 50°. All the animals used were female Wistar rats before adulthood, to take into account the effect of growth for the study of intervertebral disc changes. The intact intervertebral discs outside the fixator were used as controls. After the rats' death on day 35, the tails were prepared and analysed with an immunohistochemical protocol for chromogenic detection and location of MMPs 1 and 12 in tissue sections of the intervertebral discs.

Introduction

Marfan syndrome (MFS) is a common connective tissue disorder affecting one in 3300 people worldwide, and is caused by unique mutations in the 65 exon gene for fibrillin-1—an essential microfibril component of ligaments, tendons, and muscle. A recently discovered feature in the Marfan mouse model is increased concentrations of transforming growth factor β, resulting in overgrowth. 70% of patients with MFS have scoliosis of some degree. Can lessons be learned from MFS aetiology and treatment that apply to idiopathic adolescent scoliosis? We aimed to establish whether there is a relationship between the type and location of mutation, and the presence and degree of severity of scoliosis, in patients with MFS.

Methods

Of 181 consecutive patients with MFS with known causative fibrillin-1 mutations, 93 were male (51%) and 88 female (49%). 28 (15%; ten males, 18 females) of the total group had moderate to severe scoliosis, including two females and two males who had corrective surgery. Of the 16 patients with severe scoliosis (three males, 13 females), FBN1 mutations clustered in the latter half of the gene in exons 33–63. Of these 16 mutations, ten were severe (seven stop codons, three splice site mutations); the others were point mutations, three involving added cysteine and three substituted cysteine, in calcium-binding EGF-like regions.

Height A rapid adolescent growth spurt to excessive height is a documented clinical feature in MFS. The age of clinical diagnosis as an indication of severity was on average 11·3 years (range 2 days to 36 years), and ten patients were diagnosed before the age of 12 years.

Introduction

Although the association between osteoporosis and adolescent idiopathic scoliosis (AIS) has become widely accepted, the mechanism behind the development of osteoporosis and AIS remains unknown. To elucidate this relationship, we investigated the radiological and histological changes in a model of scoliosis in chickens, focusing on the cervical vertebrae that are not affected by scoliosis.

Methods

40 newly hatched broiler chickens were divided randomly into four equal groups: sham-operated chickens serving as control (CNT); pinealectomised chickens (PNX); and sham-operated (CNT+MLT) and pinealectomized chickens (PNX+MLT) that received intraperitoneal administration of MLT (8 mg/kg) at 2200 h daily. Pinealectomies were done at the age of 3 days. Before killing the chickens at 2 months of age, blood samples were collected at midnight and MLT concentrations were measured by radioimmunoassay. Post-mortem radiographs were examined for the presence of scoliosis, and microcomputed tomography (micro-CT) images were taken to assess the microstructure of the cervical vertebrae. Histological specimens of the scanned cervical vertebra were prepared, and a mid-sagittal section was stained with haematoxylin and eosin (HE) and tartrate-resistant acid phosphatase (TRAP) to assess the numbers of osteoblasts and osteoclasts, respectively.

Introduction

Forelimb and tail amputations of 3-week-old C57BL/6 mice are known to yield spinal curves similar to adolescent idiopathic scoliosis (AIS). Our previous work showed that tamoxifen produces a significant decrease in severity of these curves. Vertebral osteoporosis was thought to be related to AIS. Interestingly, a histological pilot study has shown that scoliotic mice given tamoxifen were less osteoporotic than were controls. Raloxifene is an oestrogen receptor modulator (SERM) similar to tamoxifen with a more specific effect on bone and is commonly used to treat osteoporosis. We aimed to study and compare the effects of tamoxifen and raloxifene on the rate and magnitude of scoliosis on a C57BL/6 mice model.

Methods

90 female 3-week-old C57BL/6 mice underwent amputations of forelimbs and tails. 78 were available for analysis and were grouped as control (no medications; n=24), TMX group (10 mg tamoxifen/L drinking water; n=30), and RLX group (10 mg raloxifene/L drinking water; n=241). Seven mice from each group (including scoliotic ones) were killed for histological study at week 20 after posteroanterior (PA) scoliosis radiograph examinations. The rest were killed at the end of week 40 after PA radiographs were obtained. Radiographs were assessed for presence and magnitude of spinal curves.

Introduction

Adolescent idiopathic scoliosis (AIS) is associated with low bone mineral density, which could be related to its etiopathogenesis. Apart from bone density, bone micro-architectures are equally important for better understanding of disease initiation and progression in AIS. Quantitative assessment of bone quality is hampered by the invasive nature of investigations, until recently when the high-resolution pQCT (XtremeCT) became available for revolutionary in-vivo microimaging and derivation of bone micro-architectural parameters. Our objective was to use this powerful instrument to study bone qualities in AIS and compare findings with those from healthy controls.

Methods

48 girls with AIS and 84 sex-matched healthy controls were recruited. Cobb angle was measured with standing radiographs, and imaging of the non-dominant distal radius was captured with XtremeCT according to a standard protocol.

Introduction

The main challenge in management of adolescent idiopathic scoliosis (AIS) is to predict which curve will progress so that appropriate treatment can be given. We previously reported that low bone mineral density (BMD) was one of the adverse prognostic factors for AIS. With advancement in imaging technology, quantitative ultrasound (QUS) becomes a useful method to assess bone density and bone quality. The objective of this study was to assess the role of QUS as a radiation-free method to predict curve progression in AIS.

Methods

294 girls with AIS were recruited at ages 11–16 years and followed up until skeletal maturity. 269 age-matched healthy girls were recruited as controls. They provided the normal reference for calculation of Z score for QUS parameters. QUS measurements, including BUA (broadband ultrasound attenuation), VOS (velocity of sound) and SI (stiffness index) of the calcaneum, BMD of femoral neck, menarche history, ages, and Cobb angle of the major curve were recorded at baseline as independent variables. The predictive outcome was curve progression defined as an increase of Cobb angle of 6° or more. Logistic regression model and the ROC curve were used for statistical analysis.

Introduction

Melatonin-deficient rats are known to develop scoliosis when rendered bipedal. In a previous study we have shown that melatonin-deficient bipedal mice with scoliosis had lower bone density than did mice without scoliosis. Published work suggests that children with AIS have lower bone density than do healthy children. The aim of this study is to establish whether osteoporosis causes scoliosis. We hypothesised that bipedal rats with lower bone density would have increased spinal malalignment compared with the control group.

Methods

50 female Sprague-Dawley rats were rendered bipedal at 3 weeks of age by amputation of the forelimbs and tails. Two groups were formed: control group (n=25), in which rats received no drug; and the experiment group (n=25), in which rats received daily subcutaneous 1 U/g heparin injections. Animals were kept in standard cages, and food and water was provided at the top of the cages to encourage more time standing erect. DEXA scans were done on week 4 to assess bone density. Radiographs were taken on week 40 to assess spinal alignment in both control and experiment groups.