Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6

In humans, congenital spinal defects occur with an incidence of 0.5-1 per 1000 live births. One of the most severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade, the genetic basis of several forms of autosomal recessive SCD cases has been solved with the identification of four causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been reported, but to date no genetic etiology has been described for these. Here, we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. We show that this mutation has a deleterious effect on the transcriptional activation activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the patterning of the vertebral precursor tissues, somites; thus, mutation of TBX6 is likely to be causative of SCD in this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases even in small families with few affected individuals.

Estrogen receptor α regulates area-adjusted bone mineral content in late pubertal girls

Context: Whether the action of estrogen in skeletal development depends on estrogen receptor α as encoded by the ESR1 gene is unknown. Objectives: The aim of this study was to establish whether the gain in area-adjusted bone mineral content (ABMC) in girls occurs in late puberty and to examine whether the magnitude of this gain is related to ESR1 polymorphisms. Design: We conducted a cross-sectional analysis. Setting: The study involved the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based prospective study. Participants: Participants included 3097 11-yr-olds with DNA samples, dual x-ray absorptiometry measurements, and pubertal stage information. Outcomes: Outcome measures included separate prespecified analyses in boys and girls of the relationship between ABMC derived from total body dual x-ray absorptiometry scans and Tanner stage and of the interaction between ABMC, Tanner stage, and ESR1 polymorphisms. Results: Total body less head and spinal ABMC were higher in girls in Tanner stages 4 and 5, compared with those in Tanner stages 1, 2, and 3. In contrast, height increased throughout puberty. No differences were observed in ABMC according to Tanner stage in boys. For rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms, differences in spinal ABMC in late puberty were 2-fold greater in girls who were homozygous for the C and G alleles, respectively (P = 0.001). For rs7757956, the difference in total body less head ABMC in late puberty was 50% less in individuals homozygous or heterozygous for the A allele (P = 0.006). Conclusions: Gains in ABMC in late pubertal girls are strongly associated with ESR1 polymorphisms, suggesting that estrogen contributes to this process via an estrogen receptor α-dependent pathway.

Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis

Objective. Ankylosing spondylitis (AS) is a debilitating chronic inflammatory condition with a high degree of familiality (λs=82) and heritability (>90%) that primarily affects spinal and sacroiliac joints. Whole genome scans for linkage to AS phenotypes have been conducted, although results have been inconsistent between studies and all have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis. Methods: The International Genetics of Ankylosing Spondylitis Consortium combined data from three whole genome linkage scans for AS (n=3744 subjects) to determine chromosomal markers that show evidence of linkage with disease. Linkage markers typed in different centres were integrated into a consensus map to facilitate effective data pooling. We performed a weighted meta-analysis to combine the linkage results, and compared them with the three individual scans and a combined pooled scan. Results: In addition to the expected region surrounding the HLA-B27 gene on chromosome 6, we determined that several marker regions showed significant evidence of linkage with disease status. Regions on chromosome 10q and 16q achieved 'suggestive' evidence of linkage, and regions on chromosomes 1q, 3q, 5q, 6q, 9q, 17q and 19q showed at least nominal linkage in two or more scans and in the weighted meta-analysis. Regions previously associated with AS on chromosome 2q (the IL-1 gene cluster) and 22q (CYP2D6) exhibited nominal linkage in the meta-analysis, providing further statistical support for their involvement in susceptibility to AS. Conclusion: These findings provide a useful guide for future studies aiming to identify the genes involved in this highly heritable condition. . Published by on behalf of the British Society for Rheumatology.

Genetic studies of disorders of calcium crystal deposition

In summary, although many factors are likely to be involved in regulating calcification and ossification processes, studies of the causation of articular chondrocalcinosis and disorders of spinal ossification, such as DISH and OPLL, implicate control over inorganic pyrophosphate levels as being one of the most important factors in their aetiopathogenesis. The findings of these studies may prove relevant to other rheumatic diseases in which ectopic ossification occurs, such as AS.

Partial intervertebral fusion secures successful outcomes after thoracoscopic anterior scoliosis correction: A low-dose computed tomography study

Study Design Retrospective review of prospectively collected data. Objectives To analyze intervertebral (IV) fusion after thoracoscopic anterior spinal fusion (TASF) and explore the relationship between fusion scores and key clinical variables. Summary of Background Information TASF provides comparable correction with some advantages over posterior approaches but reported mechanical complications, and their relationship to non-union and graft material is unclear. Similarly, the optimal combination of graft type and implant stiffness for effecting successful radiologic union remains undetermined. Methods A subset of patients from a large single-center series who had TASF for progressive scoliosis underwent low-dose computed tomographic scans 2 years after surgery. The IV fusion mass in the disc space was assessed using the 4-point Sucato scale, where 1 indicates <50% and 4 indicates 100% bony fusion of the disc space. The effects of rod diameter, rod material, graft type, fusion level, and mechanical complications on fusion scores were assessed. Results Forty-three patients with right thoracic major curves (mean age 14.9 years) participated in the study. Mean fusion scores for patient subgroups ranged from 1.0 (IV levels with rod fractures) to 2.2 (4.5-mm rod with allograft), with scores tending to decrease with increasing rod size and stiffness. Graft type (autograft vs. allograft) did not affect fusion scores. Fusion scores were highest in the middle levels of the rod construct (mean 2.52), dropping off by 20% to 30% toward the upper and lower extremities of the rod. IV levels where a rod fractured had lower overall mean fusion scores compared to levels without a fracture. Mean total Scoliosis Research Society (SRS) questionnaire scores were 98.9 from a possible total of 120, indicating a good level of patient satisfaction. Conclusions Results suggest that 100% radiologic fusion of the entire disc space is not necessary for successful clinical outcomes following thoracoscopic anterior selective thoracic fusion.

CBCT-guided radiotherapy for locally advanced head and cancer: dosimetric impact of weight loss on VMAT and IMRT plans for selected organs at risk structures (OARs)

Purpose: It is common for head and neck patients to be affected by time trend errors as a result of weight loss during a course of radiation treatment. The objective of this planning study was to investigate the impact of weight loss on Volumetric Modulated Arc Therapy (VMAT) as well as Intensity modulated radiation therapy (IMRT) for locally advanced head and neck cancer using automatic co-registration of the CBCT. Methods and Materials: A retrospective analysis of previously treated IMRT plans for 10 patients with locally advanced head and neck cancer patients was done. A VMAT plan was also produced for all patients. We calculated the dose–volume histograms (DVH) indices for spinal cord planning at risk volumes (PRVs), the brainstem PRVs (SC+0.5cm and BS+0.5cm, respectively) as well as mean dose to the parotid glands. Results: The results show that the mean difference in dose to the SC+0.5cm was 1.03% and 1.27% for the IMRT and VMAT plans, respectively. As for dose to the BS+0.5, the percentage difference was 0.63% for the IMRT plans and 0.61% for the VMAT plans. The analysis of the parotid gland doses shows that the percentage change in mean dose to left parotid was -8.0% whereas that of the right parotid was -6.4% for the IMRT treatment plans. In the VMAT plans, the percentages change for the left and the right parotid glands were -6.6% and -6.7% respectively. Conclusions: This study shows a clinically significant impact of weight loss on DVH indices analysed in head and neck organs at risk. It highlights the importance of adaptive radiotherapy in head and neck patients if organ at risk sparing is to be maintained.

Understanding how axial loads on the spine influence segmental biomechanics for idiopathic scoliosis patients: A magnetic resonance imaging study

Background Segmental biomechanics of the scoliotic spine are important since the overall spinal deformity is comprised of the cumulative coronal and axial rotations of individual joints. This study investigates the coronal plane segmental biomechanics for adolescent idiopathic scoliosis patients in response to physiologically relevant axial compression. Methods Individual spinal joint compliance in the coronal plane was measured for a series of 15 idiopathic scoliosis patients using axially loaded magnetic resonance imaging. Each patient was first imaged in the supine position with no axial load, and then again following application of an axial compressive load. Coronal plane disc wedge angles in the unloaded and loaded configurations were measured. Joint moments exerted by the axial compressive load were used to derive estimates of individual joint compliance. Findings The mean standing major Cobb angle for this patient series was 46°. Mean intra-observer measurement error for endplate inclination was 1.6°. Following loading, initially highly wedged discs demonstrated a smaller change in wedge angle, than less wedged discs for certain spinal levels (+ 2,+1,− 2 relative to the apex, (p < 0.05)). Highly wedged discs were observed near the apex of the curve, which corresponded to lower joint compliance in the apical region. Interpretation While individual patients exhibit substantial variability in disc wedge angles and joint compliance, overall there is a pattern of increased disc wedging near the curve apex, and reduced joint compliance in this region. Approaches such as this can provide valuable biomechanical data on in vivo spinal biomechanics of the scoliotic spine, for analysis of deformity progression and surgical planning.

Inter-lamellar shear resistance confers compressive stiffness in the intervertebral disc: An image-based modelling study on the bovine caudal disc

The intervertebral disc withstands large compressive loads (up to nine times bodyweight in humans) while providing flexibility to the spinal column. At a microstructural level, the outer sheath of the disc (the annulus fibrosus) comprises 12–20 annular layers of alternately crisscrossed collagen fibres embedded in a soft ground matrix. The centre of the disc (the nucleus pulposus) consists of a hydrated gel rich in proteoglycans. The disc is the largest avascular structure in the body and is of much interest biomechanically due to the high societal burden of disc degeneration and back pain. Although the disc has been well characterized at the whole joint scale, it is not clear how the disc tissue microstructure confers its overall mechanical properties. In particular, there have been conflicting reports regarding the level of attachment between adjacent lamellae in the annulus, and the importance of these interfaces to the overall integrity of the disc is unknown. We used a polarized light micrograph of the bovine tail disc in transverse cross-section to develop an image-based finite element model incorporating sliding and separation between layers of the annulus, and subjected the model to axial compressive loading. Validation experiments were also performed on four bovine caudal discs. Interlamellar shear resistance had a strong effect on disc compressive stiffness, with a 40% drop in stiffness when the interface shear resistance was changed from fully bonded to freely sliding. By contrast, interlamellar cohesion had no appreciable effect on overall disc mechanics. We conclude that shear resistance between lamellae confers disc mechanical resistance to compression, and degradation of the interlamellar interface structure may be a precursor to macroscopic disc degeneration.

Gravity-induced coronal plane joint moments in adolescent idiopathic scoliosis

Background Adolescent Idiopathic Scoliosis is the most common type of spinal deformity, and whilst the risk of progression appears to be biomechanically mediated (larger deformities are more likely to progress), the detailed biomechanical mechanisms driving progression are not well understood. Gravitational forces in the upright position are the primary sustained loads experienced by the spine. In scoliosis they are asymmetrical, generating moments about the spinal joints which may promote asymmetrical growth and deformity progression. Using 3D imaging modalities to estimate segmental torso masses allows the gravitational loading on the scoliotic spine to be determined. The resulting distribution of joint moments aids understanding of the mechanics of scoliosis progression. Methods Existing low-dose CT scans were used to estimate torso segment masses and joint moments for 20 female scoliosis patients. Intervertebral joint moments at each vertebral level were found by summing the moments of each of the torso segment masses above the required joint. Results The patients’ mean age was 15.3 years (SD 2.3; range 11.9 – 22.3 years); mean thoracic major Cobb angle 52° (SD 5.9°; range 42°-63°) and mean weight 57.5 kg (SD 11.5 kg; range 41 – 84.7 kg). Joint moments of up to 7 Nm were estimated at the apical level. No significant correlation was found between the patients’ major Cobb angles and apical joint moments. Conclusions Patients with larger Cobb angles do not necessarily have higher joint moments, and curve shape is an important determinant of joint moment distribution. These findings may help to explain the variations in progression between individual patients. This study suggests that substantial corrective forces are required of either internal instrumentation or orthoses to effectively counter the gravity-induced moments acting to deform the spinal joints of idiopathic scoliosis patients.

Surgical fusion of early onset severe scoliosis increases survival in Rett syndrome: A cohort study

Aim Scoliosis is a common co-morbidity in Rett syndrome and spinal fusion may be recommended if severe. We investigated the impact of spinal fusion on survival and risk of severe lower respiratory tract infection in Rett syndrome. Method Data were ascertained from hospital medical records, the Australian Rett Syndrome Database, a longitudinal and population-based registry, and from the Australian Institute of Health and Welfare National Death Index database. Cox regression and generalized estimating equation models were used to estimate the effects of spinal surgery on survival and severe respiratory infection respectively in 140 females who developed severe scoliosis (Cobb angle ≥45°) before adulthood. Results After adjusting for mutation type and age of scoliosis onset, the rate of death was lower in the surgery group (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.12–0.74; p=0.009) compared to those without surgery. Rate of death was particularly reduced for those with early onset scoliosis (HR 0.17, 95% CI 0.06–0.52; p=0.002). There was some evidence to suggest that spinal fusion was associated with a reduction in risk of severe respiratory infection among those with early onset scoliosis (risk ratio 0.41, 95% CI 0.16–1.03; p=0.06). Interpretation With appropriate cautions, spinal fusion confers an advantage to life expectancy in Rett syndrome.

Analysis and prevention of extreme vibration in high speed craft - A research framework

Extreme vibration has been reported for small, high speed craft in the maritime sector, with performance and health threatening effects on boat operators and crew. Musculoskeletal injuries are an enduring problem for high speed craft passengers. Spinal or joint injuries and neurological disorders may occur from repetitive pounding over rough water, continued vibration and single impact events. The risk from whole body vibration (WBV) induced through the small vessels mainly depends on time spent on the craft, which can’t be changed in a military scenario; as well as the number of shocks and jolts, and their magnitude and frequency. In the European Union for example, physical agents directives require all employers to control exposure to a number of physical agents including noise and vibration. The EC Vibration Directive 2002/44/EC then sets out regulations for the control of health and safety risks from the exposure of workers to hand arm vibration (HAV) and WBV in the workplace. Australia has exposure standards relating to WBV, AS 2670.1-2001 – Evaluation of human exposure to whole body vibration. This standard is identical to the ISO 2631-1:1997, Mechanical vibration and shock – Evaluation of human exposure to whole-body vibration. Currently, none of the jurisdictions in Australia have specific regulations for vibration exposures in workplaces. However vibration is mentioned to varying degrees in their general regulations, codes of practice and guidance material. WBV on high speed craft is normally caused by “continuous 'hammering' from short steep seas or wind against tide conditions. Shock on High Speed Craft is usually caused by random impacts. Military organisations need the knowledge to make informed decisions regarding their marine operations, compliance with legislation and potentially harmful health effects, and develop and implement appropriate counter-measures. Marine case studies in the UK such as published MAIB (Marine Accident Investigation Branch) reports show injuries that have occurred in operation, and subsequent MCA (Maritime Coastguard Agency) guidance is provided (MGN 436 (M+F), WHOLE-BODY VIBRATION: Guidance on Mitigating Against the Effects of Shocks and Impacts on Small Vessels. MCA, 2011). This paper proposes a research framework to study the origin, impact and pathways for prevention of WBV in small, high speed craft in a maritime environment.

Development, reliability and validity of the queensland evaluation of wheelchair skills (QEWS)

- Objectives To develop and test a valid and reliable assessment of wheelchair skills for individuals with spinal cord injuries (SCI); the Queensland Evaluation of Wheelchair Skills (QEWS). - Setting Hospital, Australia. - Methods Phase 1: Four Delphi panel rounds with clinical experts were used to develop the QEWS. Phase 2: Intra-rater and inter-rater reliability of the QEWS items were examined in 100 people with SCI. Phase 3a: Concurrent validity was investigated by examining the association between QEWS total scores and physiotherapists’ global ratings of wheelchair skill performance. Phase 3b: Construct validity was tested in 20 people with recent SCI by examining change in QEWS total scores between when they first mobilised in a wheelchair and scores obtained 10 weeks later. - Results Phase 1: The QEWS was developed. Phase 2: The intra-class correlation coefficients reflecting the intra-rater reliability and the inter-rater reliability for the QEWS total score were 1.00 and 0.98, with scores being within one point of each other 96 and 91% of the time, respectively. Phase 3a: The QEWS total scores were comparable with the global rating of wheelchair skill performance (r2=0.93). Phase 3b: The QEWS scores changed by a median (interquartile range (IQR)) of 4 (1 to 6) points over the 10-week period following first wheelchair mobilisation. - Conclusion The QEWS is a valid and reliable tool for measuring wheelchair skills in individuals with SCI. The QEWS is efficient and practical to administer and does not require specialised equipment.

Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: Sequential not parallel processes

Background Ankylosing spondylitis (AS) is an immune-mediated arthritis particularly targeting the spine and pelvis and is characterised by inflammation, osteoproliferation and frequently ankylosis. Current treatments that predominately target inflammatory pathways have disappointing efficacy in slowing disease progression. Thus, a better understanding of the causal association and pathological progression from inflammation to bone formation, particularly whether inflammation directly initiates osteoproliferation, is required. Methods The proteoglycan-induced spondylitis (PGISp) mouse model of AS was used to histopathologically map the progressive axial disease events, assess molecular changes during disease progression and define disease progression using unbiased clustering of semi-quantitative histology. PGISp mice were followed over a 24-week time course. Spinal disease was assessed using a novel semi-quantitative histological scoring system that independently evaluated the breadth of pathological features associated with PGISp axial disease, including inflammation, joint destruction and excessive tissue formation (osteoproliferation). Matrix components were identified using immunohistochemistry. Results Disease initiated with inflammation at the periphery of the intervertebral disc (IVD) adjacent to the longitudinal ligament, reminiscent of enthesitis, and was associated with upregulated tumor necrosis factor and metalloproteinases. After a lag phase, established inflammation was temporospatially associated with destruction of IVDs, cartilage and bone. At later time points, advanced disease was characterised by substantially reduced inflammation, excessive tissue formation and ectopic chondrocyte expansion. These distinct features differentiated affected mice into early, intermediate and advanced disease stages. Excessive tissue formation was observed in vertebral joints only if the IVD was destroyed as a consequence of the early inflammation. Ectopic excessive tissue was predominantly chondroidal with chondrocyte-like cells embedded within collagen type II- and X-rich matrix. This corresponded with upregulation of mRNA for cartilage markers Col2a1, sox9 and Comp. Osteophytes, though infrequent, were more prevalent in later disease. Conclusions The inflammation-driven IVD destruction was shown to be a prerequisite for axial disease progression to osteoproliferation in the PGISp mouse. Osteoproliferation led to vertebral body deformity and fusion but was never seen concurrent with persistent inflammation, suggesting a sequential process. The findings support that early intervention with anti-inflammatory therapies will be needed to limit destructive processes and consequently prevent progression of AS.

Genetics of ankylosing spondylitis - Insights into pathogenesis

Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B*27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B*27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B*27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.