Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy

Genetic factors are believed to play an important role in the etiology of adolescent idiopathic scoliosis (AIS). Discordant findings for monozygotic (MZ) twins with AIS show that environmental factors including different intrauterine environments are important in etiology, but what these environmental factors may be is unknown. Recent evidence for common chronic non-communicable diseases suggests epigenetic differences may underlie MZ twin discordance, and be the link between environmental factors and phenotypic differences. DNA methylation is one important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life. The word exposome refers to the totality of environmental exposures from conception onwards, comprising factors in external and internal environments. The word exposome is used here also in relation to physiologic and etiopathogenetic factors that affect normal spinal growth and may induce the deformity of AIS. In normal postnatal spinal growth we propose a new term and concept, physiologic growth-plate exposome for the normal processes particularly of the internal environments that may have epigenetic effects on growth plates of vertebrae. In AIS, we propose a new term and concept pathophysiologic scoliogenic exposome for the abnormal processes in molecular pathways particularly of the internal environment currently expressed as etiopathogenetic hypotheses; these are suggested to have deforming effects on the growth plates of vertebrae at cell, tissue, structure and/or organ levels that are considered to be epigenetic. New research is required for chromatin modifications including DNA methylation in AIS subjects and vertebral growth plates excised at surgery. In addition, consideration is needed for a possible network approach to etiopathogenesis by constructing AIS diseasomes. These approaches may lead through screening, genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS. The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis

Relatively lower body mass index is associated with an excess of severe truncal asymmetry in healthy adolescents: Do white adipose tissue, leptin, hypothalamus and sympathetic nervous system influence truncal growth asymmetry?

<p>Abstract</p> <p>Background</p> <p>In healthy adolescents normal back shape asymmetry, here termed truncal asymmetry (TA), is evaluated by higher and lower subsets of BMI. The study was initiated after research on girls with adolescent idiopathic scoliosis (AIS) showed that higher and lower BMI subsets discriminated patterns of skeletal maturation and asymmetry unexplained by existing theories of pathogenesis leading to a new interpretation which has therapeutic implications <it>(double neuro-osseous theory)</it>.</p> <p>Methods</p> <p>5953 adolescents age 11–17 years (boys 2939, girls 3014) were examined in a school screening program in two standard positions, standing forward bending (FB) and sitting FB. The sitting FB position is thought to reveal intrinsic TA free from back humps induced by any leg-length inequality. TA was measured in both positions using a Pruijs scoliometer as angle of trunk inclinations (ATIs) across the back at each of three spinal regions, thoracic, thoracolumbar and lumbar. Abnormality of ATIs was defined as being outside 2 standard deviations for each age group, gender, position and spinal region, and termed <it>severe </it>TA.</p> <p>Results</p> <p>In the sitting FB position after correcting for age,<it>relatively lower BMIs </it>are statistically associated with a greater number of severe TAs than with relatively higher BMIs in both girls (thoracolumbar region) and boys (thoracolumbar and lumbar regions).</p> <p>The relative frequency of severe TAs is significantly higher in girls than boys for each of the right thoracic (56.76%) and thoracolumbar (58.82%) regions (p = 0.006, 0.006, respectively). After correcting for age, smaller BMIs are associated with more <it>severe TAs </it>in boys and girls.</p> <p>Discussion</p> <p>BMI is a surrogate measure for body fat and circulating leptin levels. The finding that girls with relatively lower BMI have significantly later menarche, and a significant excess of TAs, suggests a relation to energy homeostasis through the hypothalamus. The hypothesis we suggest for the pathogenesis of severe TA in girls and boys has the same mechanism as that proposed recently for AIS girls, namely: severe TAs are initiated by a <it>genetically-determined selectively </it>increased hypothalamic sensitivity (up-regulation, i.e. increased sensitivity) to leptin with asymmetry as an adverse response to stress (hormesis), mediated bilaterally mainly to the growing trunk via the sympathetic nervous system <it>(leptin-hypothalamic-sympathetic nervous system (LHS) concept)</it>. The putative autonomic dysfunction is thought to be increased by any lower circulating leptin levels associated with relatively lower BMIs. Sympathetic nervous system activation with asymmetry leads to asymmetries in ribs and/or vertebrae producing severe TA when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion of the trunk. A test of this hypothesis testing skin sympathetic responses, as in the Rett syndrome, is suggested.</p

The International Research Society of Spinal Deformities (IRSSD) and its contribution to science

From the time of its initial, informal meetings starting in 1980 to its formal creation in 1990, the IRSSD has met on a bi-annual basis to discuss all aspects of the spine and associated deformities. It has encouraged open discussion on all topics and, in particular, has tried to be the seed-bed for new ideas. The members are spread around the world and include people from all areas of academia as well as the most important people, the patients themselves. Most notably, application of the ideas and results of the research has always been at the forefront of the discussions. This paper was conceived with the idea of evaluating the impact made by the IRSSD over the last 30 years in the various areas and is intended to create discussion for the upcoming meeting in Montreal regarding future focus: "We are lost over the Atlantic Ocean but we are making good time.

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans

A segmental radiological study of the spine and rib – cage in children with progressive Infantile Idiopathic Scoliosis

BACKGROUND: The role of rib cage in the development of progressive infantile idiopathic scoliosis (IIS) has not been studied previously. No report was found for rib growth in children with IIS. These findings caused us to undertake a segmental radiological study of the spine and rib-cage in children with progressive IIS. The aim of the present study is to present a new method for assessing the thoracic shape in scoliotics and in control subjects and to compare the findings between the two groups. MATERIALS AND METHODS: In the posteroanterior (PA) spinal radiographs of 24 patients with progressive IIS, with a mean age of 4.1 years old, the Thoracic Ratios (TRs) (segmental convex and concave TRs), the Cobb angle, the segmental vertebral rotation and vertebral tilt were measured. In 233 subjects, with a mean age of 5.1 years old, who were used as a control group, the segmental left and right TRs and the total width of the chest (left plus right TRs) were measured in PA chest radiographs. Statistical analysis included Mann-Whitney, Spearman correlation coefficient, multiple linear regression analysis and ANOVA. RESULTS: The comparison shows that the scoliotic thorax is significantly narrower than that of the controls at all spinal levels. The upper chest in IIS is funnel-shaped and the vertebral rotation at T4 early in management correlates significantly with the apical vertebral rotation at follow up. CONCLUSION: The IIS thorax is narrower than that of the controls, the upper chest is funnel-shaped and there is a predictive value of vertebral rotation at the upper limit of the thoracic curve of IIS, which reflects, impaired rib control of spinal rotation possibly due to neuromuscular factors, which contribute also to the funnel-shaped chest

Biomechanical spinal growth modulation and progressive adolescent scoliosis – a test of the 'vicious cycle' pathogenetic hypothesis: Summary of an electronic focus group debate of the IBSE

There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr Ian A Stokes. It evaluates the hypothesis that in progressive scoliosis vertebral body wedging during adolescent growth results from asymmetric muscular loading in a "vicious cycle" (vicious cycle hypothesis of pathogenesis) by affecting vertebral body growth plates (endplate physes). A frontal plane mathematical simulation tested whether the calculated loading asymmetry created by muscles in a scoliotic spine could explain the observed rate of scoliosis increase by measuring the vertebral growth modulation by altered compression. The model deals only with vertebral (not disc) wedging. It assumes that a pre-existing scoliosis curve initiates the mechanically-modulated alteration of vertebral body growth that in turn causes worsening of the scoliosis, while everything else is anatomically and physiologically 'normal' The results provide quantitative data consistent with the vicious cycle hypothesis. Dr Stokes' biomechanical research engenders controversy. A new speculative concept is proposed of vertebral symphyseal dysplasia with implications for Dr Stokes' research and the etiology of AIS. What is not controversial is the need to test this hypothesis using additional factors in his current model and in three-dimensional quantitative models that incorporate intervertebral discs and simulate thoracic as well as lumbar scoliosis. The growth modulation process in the vertebral body can be viewed as one type of the biologic phenomenon of mechanotransduction. In certain connective tissues this involves the effects of mechanical strain on chondrocytic metabolism a possible target for novel therapeutic intervention

Idiopathic and normal lateral lumbar curves: muscle effects interpreted by 12th rib length asymmetry with pathomechanic implications for lumbar idiopathic scoliosis

Abstract Background The historical view of scoliosis as a primary rotation deformity led to debate about the pathomechanic role of paravertebral muscles; particularly multifidus, thought by some to be scoliogenic, counteracting, uncertain, or unimportant. Here, we address lateral lumbar curves (LLC) and suggest a pathomechanic role for quadrates lumborum, (QL) in the light of a new finding, namely of 12th rib bilateral length asymmetry associated with idiopathic and small non-scoliosis LLC. Methods Group 1: The postero-anterior spinal radiographs of 14 children (girls 9, boys 5) aged 9–18, median age 13 years, with right lumbar idiopathic scoliosis (IS) and right LLC less that 10°, were studied. The mean Cobb angle was 12° (range 5–22°). Group 2: In 28 children (girls 17, boys 11) with straight spines, postero-anterior spinal radiographs were evaluated similarly to the children with the LLC, aged 8–17, median age 13 years. The ratio of the right/left 12th rib lengths and it’s reliability was calculated. The difference of the ratio between the two groups was tested; and the correlation between the ratio and the Cobb angle estimated. Statistical analysis was done using the SPSS package. Results The ratio’s reliability study showed intra-observer +/−0,036 and the inter-observer error +/−0,042 respectively in terms of 95 % confidence limit of the error of measurements. The 12th rib was longer on the side of the curve convexity in 12 children with LLC and equal in two patients with lumbar scoliosis. The 12th rib ratios of the children with lumbar curve were statistically significantly greater than in those with straight spines. The correlation of the 12th rib ratio with Cobb angle was statistically significant. The 12th thoracic vertebrae show no axial rotation (or minimal) in the LLC and no rotation in the straight spine group. Conclusions It is not possible, at present, to determine whether the 12th convex rib lengthening is congenitally lengthened, induced mechanically, or both. Several small muscles are attached to the 12th ribs. We focus attention here on the largest of these muscles namely, QL. It has attachments to the pelvis, 12th ribs and transverse processes of lumbar vertebrae as origins and as insertions. Given increased muscle activity on the lumbar curve convexity and similar to the interpretations of earlier workers outlined above, we suggest two hypotheses, relatively increased activity of the right QL muscle causes the LLCs (first hypothesis); or counteracts the lumbar curvature as part of the body’s attempt to compensate for the curvature (second hypothesis). These hypotheses may be tested by electrical stimulation studies of QL muscles in subjects with lumbar IS by revealing respectively curve worsening or correction. We suggest that one mechanism leading to relatively increased length of the right 12 ribs is mechanotransduction in accordance with Wolff’s and Pauwels Laws