Genetic Basis of Idiopathic Scoliosis

Research & Review: Management of Cardiovascular and Orthopedic Complications Volume 1 Issue 1

S. Sreeremya Assistant Professor, Department of Biotechnology, Sree Narayana Guru College, Coimbatore, Tamil Nadu, India Email: [email protected]

Abstract Idiopathic scoliosis (IS), the most usual spinal deformity, affects otherwise healthy children and adolescents during growth. The etiology is still not quiet understood, although genetic factors are believed to be important. This review corroborates the understanding of IS as a complex disease with a polygenic background. Presumably IS can be typically due to a spectrum of genetic risk variants, ranging from very rare or even private to very common. The most promising candidate genes are highlighted.

Keywords: Idiopathic scoliosis, Genetics, Pathogenesis, Heredity

INTRODUCTION marked by phenotypic complexity Idiopathic scoliosis (IS), the most general (variations in curve morphology and form of spinal deformity, affects otherwise magnitude, age of onset, rate of healthy children and adolescents during progression), and a prognosis mainly growth (Fig: 1). It usually presents as a rib ranging from increase in curve magnitude, hump visible at forward bending, together to stabilization, or to resolution with with unlevelled shoulders and an growth [5]. Genetic factors are known to asymmetrical waist [1]. According to play a pivotal role, as observed in twin Cobb, the diagnosis is specifically studies and their observation and singleton confirmed by a standing spinal radiograph multigenerational families [6]. A recent showing a lateral curvature of the spine research of monozygotic and dizygotic exceeding 10° [2]. A main concern in IS is twins from the Swedish twin registry the absence of reliable means by which to estimated that overall genetic effects predict risk of progression, leading to accounted for 39 % of the observed frequent follow-ups, radiographs, and phenotypic variance, leaving the remaining potentially unnecessary brace treatments. 61 % to environmental influences. Genetic A furthermore understanding of the complexity in IS is further inferred from pathogenesis and genetics in IS might aid inconsistent inheritance, discordance in identifying at-risk individuals, leading among monozygotic twins, and highly to an earlier diagnosis and possibly better variable results from genetic studies. preventive and therapeutic options [3]. Genetic counsellors have a major role to play in understanding genetic deformities Idiopathic scoliosis (IS) is a ramified [7]. developmental syndrome that constitutes the largest subgroup of human spinal The standard of care for scoliosis has not curvatures [Online Mendelian Inheritance been changed significantly in the past in Man (OMIM): 181800] [4]. First three decades, from initiating observation delineated by Hippocrates in On the to bracing and to spinal fusion surgery as a Articulations (Part 47), IS has been the last resort [8]. The healthcare costs of subject of on-going research, and yet its bracing, hospitalization, surgery, and etiology remains enigmatic. IS is typically adverse back pain are substantial. An

Research & Review: Management of Cardiovascular and Orthopedic Complications Volume 1 Issue 1

understanding of the genetics underlying critical roles in androgen synthesis. In a the disorder would help lead to earlier cohort of 304 Japanese females, no diagnosis, identification of at-risk association with IS was found. Of note, individuals, and more effective preventive both forms of the estrogen receptor, ESR1 and/or therapeutic choices [9]. (also called as ERα) and ESR2 (also known as ERβ), are present in osteoblasts Genetic variants that can affect a person’s and osteoclasts, indicating that estrogen predisposition to spinal curvature and the mainly regulates osteoblast function propensity for progression to severe directly [13]. The ESR1 gene has been curvature are still unknown. Since 1993, extensively examined as it contains the over 72 studies have attempted to identify polymorphic sites PvuII (rs2234693) and genes by either genome-wide or XbaI (rs9340799). XbaI (but not PvuII) hypothesis-driven designs, using either was specifically identified as a factor in IS pedigrees (linkage analysis) or unrelated progression in a case-only study of 304 case–control population samples Japanese females; in Chinese females (202 (association studies) [10]. Of over 35 cases/174 controls), it was associated with candidate genes tested, about 18 unique curve predisposition, progression, and loci have been identified, suggesting that abnormal growth [14]. In a separate IS may be caused by multiple genes Chinese research, analysis of a small segregating differently in various cohort of patients with double-curve populations [11] patterns only (67 cases/100 controls) suggested that PvuII (but not Xba1) was associated with curvature. Using restriction site analysis, It is been evaluated and assesed that XbaI was associated with low levels of steroids in several Italian females with IS (4 out of 174 cases/104 controls), although no statistical evaluations were effected [15]. But associations with Xba1 and PvuII were not confirmed in a larger cohort of Chinese females (540 cases/260 controls) , nor was the association with Xba1 replicated in a larger Japanese study (798 case/638 control). Although ESR1 is the major estrogen receptor in bone, it has been shown that in females, the ESR2 gene can modulate the action of ESR1 [16]. In Fig: 1. Diagram Showing Scoliosis China, the ESR2 polymorphism rs1256120 was allied with curve predisposition and Puberty and growth progression (218 case/140 control), though Curve pathogenesis in scoliosis coincides the association was not confirmed in a with growth and adolescence, genes larger Japanese cohort (798 cases/637 involved in the somatotrophic and controls). Currently, the gene for the novel androgenic axes were considered potential G protein-coupled estrogen receptor GPER IS candidates [12]. The gene encoding (also known as GPR30) was found to be cytochrome P450 17α-hydroxylase associated with curve severity, but not (CYP17) was typically considered a likely curve predisposition, in a sample of Han candidate for IS progression because of its Chinese (389 cases/338 controls) [17].

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There is evidence that estrogen enhances selection of genetic markers, and adequate the growth hormone/insulin-like growth sample size [21]. factor (IGF-1) axis, in both males and females, and is the main mediator of the For case–control studies and accelerated linear growth and increases in investigations, whether they are candidate bone dimensions observed during early-to- gene or genomic association studies, the mid puberty [18]. Because accelerated case population has to be well defined and linear growth is linked to curve delineated to avoid genetic and progression, genes that define this process environmental heterogeneity that would are candidates for inclusion in IS research. decrease the power of detection and hinder Although no association was found replication results. This is of particular between IS and the gene for the growth concern in IS because curve phenotype hormone receptor (GHR) in a cohort of ostensibly derives from various underlying Chinese females (510 cases/364 controls), etiologies. Some researchers have IGF1 was demonstrably associated with attempted to refine the phenotype with curve severity in a separate cohort of clinical parameters, such as considering Chinese females (506 cases/228 controls) . only double curves or pronounced curves Neither gene, however, appeared to be (greater than 40º) [22]. The recent related to IS in a small independent identification of biochemical endo- Chinese cohort (106 cases/106 controls). phenotypes for IS may thus potentially The lack of association between IS and decrease the heterogeneity confounding IGF1 was further confirmed in a large current genetic studies. Endophenotypes as Japanese cohort (798 cases/1,238 controls) conceived by Gottesman and colleagues [19] are heritable, quantitative traits allied with an illness both epidemiologically and To summarize, associations in small conceptually, in the sense of being on the populations between the typically common putative path from genes to molecular polymorphisms of the genes encoding the biological mechanisms [23]. They are α- and β-estrogen receptors and IS were state-independent (i.e., present not only not confirmed in two larger studies. during acute illness), co-segregate within Another two researchers found no families, and may typically appear in association for GHR. Whether IGF1 or unaffected relatives of individuals with the GPER are associated with IS needs to be disorder because they represent confirmed in larger cohorts [20]. vulnerability for the disorder, but are at a higher prevalence in affected individuals Important considerations for candidate as compared with the general population. gene studies in IS For ramified phenotypes such as IS, an A successful candidate gene is one that optimal case definition will contain both demonstrates a truly significant association clinical and biologically relevant with a disease. The truth of an association information, and this definition will likely is suggested by the power of the study and change over time as more information proven by replication studies [20]. becomes available [24]. Generally, the success rate for candidate gene studies has been poor. A 2001 review It is possible that locus or allelic for human disease showed replication of heterogeneity contributes to the observed results in only 1-2 % of the studies. This variation in IS. Therefore, detection of an deprival of success is indicative of poor association would typically require a larger study design in defining the phenotype to sample size, regardless of disease be tested, the selection of controls, prevalence [25]. Most candidate gene

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studies for IS had small cohorts, so it is all the population [31]. In the trios very difficult to discern whether components (total of 82 trials in the associations were not replicated in other population), each has a daughter/son cohorts (same or different ethnic which is affected by IS and both parents, background) as a consequence of the the region of MATN1 gene was typically genetic heterogeneity or ascertainment amplified and the amplicons were bias (e.g., “winner’s curse”). Based on analyzed after which linkage analysis was estimations from Hattersley and performed [32]. They found and identified McCarthy, a study needs thousands of three microsatellite polymorphisms in the individuals to detect a common variant of gene comprising of 103 bp, 101 bp and 99 a risk allele with a low-to-moderate effect bp respectively. MATN1, is localized at [26]. For example, for an allele with a lp35 and is primarily expressed in frequency of 20 % in controls, detection of cartilage. It produces cartilage matrix a susceptibility allele at about a 0.01 level protein, which is related to cartilage of significance with 90 % power would proteoglycans, collagen-dependent and require 1,2556individuals (assuming an collagen-independent fibrils [33]. Linkage odds ratio of 1:3). Among the 35 candidate disequilibrium was detected between the gene studies reviewed here, only three allelic variant 103 bp of the microsatellite recent association studies had more than in MATN1 gene. This suggested that it is 1,000 participants, all three showing specifically located in an allelic variant, negative results. Moreover, because it is which should have been related to the well known that originally reported effect cause of mutation of the disease. This sizes are likely to be biased upward, a study encourages researchers to sequence replication study should calculate its MATN1 gene entirely to find out if the 103 estimated sample size based on the bp of the microsatellite marker is directly anticipation of an effect smaller in size involved in the progression of idiopathic than the one originally reported [27]. scoliosis [34].

Genetic Factors LBX1 The cause of scoliosis is still unknown and In 2010, a study was conducted a GWAS studies are still going on in a rapid pace. and replication study with 1,050 females Bracing and surgery are the only the with adolescent idiopathic scoliosis and treatment options. Yet recently, several 1,475 control subjects [35]. They included clinical and genetic studies suggest only female subjects because school contribution of genetic factors [28]. Many screenings in Japan have shown that have tried to identify genes connected with prevalence of AIS is almost 10 times the susceptibility to AIS. Through the use greater in females than in males [36]. They of genome-wide association studies or have identified and assessed a locus at GWAS, genetic variations were found chromosome 10q24.31 that is associated rapidly across genomes of people with adolescent idiopathic scoliosis. The associated with the disease [29]. These are single nucleotide polymorphism that as follows [30] appeared to be significant was rs11190870 and is located near LBX1, which encodes MATN1 ladybird homeobox1 [37]. Based on the An association investigation on parent- previous report, LBX1 is expressed in offspring trios was performed in 2006 vertebrates in the dorsal part of the spinal aimed specifically at examining the loci cord and hindbrain, in muscle precursor responsible for susceptibility to idiopathic cells, and in a subpopulation of cardiac scoliosis not only in single families but in neural crest4. It is being confirmed LBX1

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expression in spinal cord and skeletal should be done to confirm this result. muscle. Due to its position, expression and Given the number of all replication studies somatosensory function, it is the best in Chinese Han populations that supported candidate to explain the association of the association of SNP rs11190870 to AIS, chromosome 10q24.31 locus [38]. more research involving other ethnic groups should be done. In the United This was a study to confirm, replication States, only rs11598564 of the three SNP’s study done in an independent southern evaluated was in the top SNPs classified in Chinese population (300 AIS patients and a current large-scale GWAS. These three 788 controls) in 2012. The odd ratios they SNPs, rs11190870, rs625039 and obtained for the association between rs11598564, are also typically located in rs11190870 and AIS risk (1.85 and 1.88) the untranslated region of the RNA. Their were very close to the first study (1.56). possible roles are still not well delineated This proposed that the effect size of the though they may act as regulatory risk allele typically between the two elements for LBX1, controlling the quality different population, Japanese and and quantity of LBX1 mRNA [43] southern Chinese population is alike. Meta-analysis of the Chinese and Japanese GPR126 GWAS results implied that rs11190870 is Aside from the chromosome 10q24.31, highly significantly associated with AIS. It which has offered the much convincing was the first SNP allied with AIS that has evidence of association with AIS, been finally replicated in another Takahashi et al. found another population. susceptibility locus on chromosome 6q24.1 in 2013. Through a stepwise Another group led by Gao replicated the association research including 10,641 X- research of Takahashi in the Chinese Han chromosome SNPs and increased size of population (953: 513 patients and 440 replication cohort (1,819 cases and 25, 939 healthy controls) at the end of 2013. They controls), they found the most significantly looked at the allied between common allied SNP was located in (which encodes variants near LBX1 and AIS, not only SNP G protein-coupled receptor 126), rs11190870 but also rs625039 and rs6570507. The connections was replicated rs11598564 availing a case-control study in a further test in Han Chinese and [39]. All SNPs were found to be associated European populations in AIS predisposition [40]. Believing that disease modifier genes can be availed for GPR126 is an orphan receptor of the predicting the development of the disease adhesion GPCR family. The loss of Sox9, and would be helpful in early clinical a key regulator of chondrogenesis, was evaluation and treatment, a case-only found to reduce the expression of GPR126 study was further conducted that involved in intervertebral disc in mice [44]. Since a subgroup of AIS patients (patients who there is no investigations yet that focused had reached the endpoints of curve on the expression of GPR126 in skeletal progression without ever having been tissues of humans in relation to scoliosis, braced) [41]. In terms of the association they evaluated the expression of GPR126 between LBX1 and the severity and mRNA in various human tissues (bone, complexity of the spinal curvature, none of cartilage and intervertebral disc) using the three SNPs were found to be a disease quantitative RT-PCR [45]. They observed modifier gene [42]. Though they suggested that it was highly expressed in cartilage. In that a more conclusive research, which addition, availing in-situ hybridization, will encompass a larger sample size, they analyzed the expression of GPR126

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in mouse spine and detected GPR126 in specific expression of SOX9 or other genes proliferating chondrocytes of the vertebral [17]. Mutations on the other candidate body during the embryonic day. The locus gene, KCNJ2, mainly resulted to on chromosome 6q24.1, GPR126, is a Andersen-Tawil syndrome, a cardiodys much promising candidate for AIS rhythmic type of period paralysis[5]. This susceptibility. This is further supported by syndrome is characterized by ventricular studies on zebrafish where the knockdown arrhythmias, periodic paralysis, facial and of the gene caused delayed ossification of skeletal dysmorphism which includes the developing spine. A wide-known scoliosis [28]. It is also an important to speculation is that abnormal skeletal note that microdeletions on chromosome growth may majorly induce scoliosis. 17q24.2–q24.3 whose deletion area More studies should be done to reveal how includes KCNJ2 and rs12946942 exhibited variations in GPR126 increase the risk of skeletal abnormalities such as progressive AIS in humans [46]. scoliosis while the same as the micro- deletion syndrome, which included SOX9 and KCNJ2 KCNJ2, but not rs12946942, has not been Aside from the novel AIS susceptibility found to be associated with a scoliosis loci on chromosomes 10q24.31 and phenotype. The identified susceptibility 6q24.1, another locus on chromosome locus may comprise other candidate causal 17q24.3 was typically identified availing a genes and need to be further studied [14]. two stage association study on approximately 12,000 Japanese subjects on Melatonin Receptor 1B the same year by Miyake et al. The p- Melatonin Receptor 1B gene encodes a values on the three models (allele model, melatonin receptor, MT2 protein, one of recessive model and dominant model) the membrane allied GPCR belonging to were evaluated and rs12946942 on the rhodopsin superfamily [7]. MT2 chromosome 17q24.3 showed a significant receptor together with MT1 receptor has connection with AIS in the recessive been suggested to have a bone remodelling model [47]. The rs12946942 genotypes function. An investigation was carried out were also found to have a significant in 2011 on 11 Chinese girls with severe association to AIS severity availing 1,767 AIS and eight control subjects using AIS cases. It was followed by replication intraoptive bone biopsies [46]. An studies on Japanese and Chinese impaired response in proliferation populations, which gave the report a typically towards melatonin was observed genome-wide significance [48] on AIS osteoblasts without MT2 receptor while those with MT2 receptor showed The rs12946942 region is a gene desert. lack of response in proliferation toward Two of much closest genes include SOX9 melatonin. This is the initial investigations and KCNJ2. SOX9 gene is known to that showed a possible abnormality in mainly encode a transcription factor MT2 receptor protein in AIS patients. It is involved in chondrogeneis [43]. Mutations indicated that AIS patients include a in this gene caused campomelic dysplasia heterogeneous population with different (skeletal dysplasia featured by bowed, causes of AIS and an evidence for the role long bones, small scapula, of melatonin in the cause and development tracheobronchial narrowing, sex reversal of the disease [18]. and kyphoscoliosis). Variants in block containing rs12946942 may contribute in GENETIC BASIS scoliosis pathogenesis through the typical The genetic variants that are responsible regulation of scoliosis-related tissue- for the AIS remain poorly understood,

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despite strong evidence that the condition associated SNP influences AIS risk is not has a genetic basis. The heritability of AIS known. A subsequent investigations in the is indicated by the increased risk of same Japanese cohort identified an developing AIS in first- degree relatives of association of AIS with SNPs near the individuals with the condition (with a adhesion G protein-coupled receptor G6 prevalence of 6–12%) and by twin studies (ADGRG6; also known as GPR126) that show higher AIS concordance rates in locus51, a gene that is essential for neural, monozygotic twins (74%) compared with cardiac and aural development. dizygotic twins (37%). In addition, a Interestingly, the protein encoded by questionnaire-based study of the large ADGRG6 also controls human height and Swedish Twin Registry estimated that 39% binds to collagens, which are functions of the variance in the risk of developing that support possible roles for this protein scoliosis in general is the result of additive in spinal development or extracellular genetic effects and 63% of the variance is matrix stability. Researches of even larger the result of unique environmental effects AIS patient cohorts are likely to reveal [12]. Further support for a complex additional genetic risk factors, although it polygenic mode of AIS inheritance is is probable that most of these factors will provided by early candidate gene- based confer small-to-modest effect. The studies. These researchers focused on fundamental basis for the female bias in genes related to connective tissue AIS has not been systematically addressed, structure, bone metabolism, melatonin although large GWAS have identified a signalling pathways, puberty, growth, axon SNP that is associated with AIS in young guidance pathways and genes that encode women but not in young men. This melatonin and oestrogen receptors [23]. sexually dimorphic susceptibility locus is Although some of these genes were found near an enhancer of the paired box 1 to be allied with AIS curve severity, no (PAX1), which encodes a transcription associations were found with the initiation factor that had previously been implicated of AIS46, 47. Furthermore, many of these in the spinal abnormalities in mice. associations have not been replicated, and Intriguingly, the alleles conferring AIS none of these genes have been significant susceptibility were shown in other studies in larger GWAS. GWAS of common to be protective for male-patterned variants have yielded key insights into the baldness, which is another strongly pathogenesis of AIS. For example, GWAS sexually dimorphic trait. identified common single-nucleotide Advances in whole-genome and exome polymorphisms (SNPs) linked with AIS sequencing have made very rare variant near the cell adhesion molecule L1-like association researches possible for AIS. (CHL1) locus, which suggested a role for Given that rare coding variants often axonal guidance molecules in AIS deleteriously alter the protein function, pathogenesis, although these connections these variants have the potential to more did not reach genome-wide significance. strongly contribute to AIS risk within an In addition, large GWAS have individual than common genetic variants. demonstrated a strong association between Rare variants in fibrillin 1 (FBN1) and AIS and SNPs near the ladybird homeobox FBN2 — the genes responsible for the 1 (LBX1) locus49, and this allied was Marfan syndrome and congenital replicated in a meta-analysis. LBX1 contractural arachno- dactyly, respectively encodes a homeobox transcription factor — were found in 7.8% of patients with involved in muscle cell migration and AIS compared with 2.5% of controls and cardiac and neural tube development, were also associated with progression of although the mechanism by which the the spinal curve severity in these patients.

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Fibrillins might influence AIS RJ. An evaluation of the Adams pathogenesis through their function as forward bend test and the scoliometer extracellular matrix proteins or through in a scoliosis school screening setting. their role in transforming growth factor-β J Pediatric Orthop. 1995;15:535–8. (TGFβ) signalling 10. Gupta P, Lenke LG, Bridwell KH. Incidence of neural axis abnormalities CONCLUSION in infantile and juvenile patients with The spinal deformities occur in the brain. spinal deformity. Is a magnetic It can be majorly due to certain mechanical resonance image screening necessary? injuries invading the skeletal system. But Spine. 1998;23:206–10. in the case of scoliosis majorly dealing 11. Schwend RM, Hennrikus W, Hall JE, with the genital aspect of spinal Emans JB. Childhood scoliosis: deformities. Clinical indications for magnetic resonance imaging. J Bone Joint Surg REFERNCES Am. 1995;77:46–53. 1. Morrissy RT, Weinstein SL. Lovell 12. Barnewolt CE, Estroff JA. Sonography and Winter’s Pediatric Orthopaedics. of the fetal central nervous system. Philadelphia: Lippincott Williams & Neuroimaging Clin N Am. Wilkins; 2006. pp. 693–762. 2004;14:255–71. 2. Ramirez N, Johnston CE, Browne RH. 13. Basu PS, Elsebaie H, Noordeen MH. The prevalence of back pain in Congenital spinal deformity: A children who have idiopathic scoliosis. comprehensive assessment at J Bone Joint Surg Am. 1997;79:364–8. presentation. Spine. 2002;27:2255–9. 3. Mehta MH. Pain provoked scoliosis. 14. Beals RK, Robbins JR, Rolfe B. Observation on the evolution of the Anomalies associated with vertebral deformity. Clin Orthop Relat Res. malformations. Spine. 1993;18:1329– 1978;135:58–65. 32. 4. Baker AS, Dove J. Progressive 15. Kane WJ, Moe JH. A scoliosis- scoliosis as the presenting sign of prevalence survey in Minnesota. Clin syringomyelia. Report of a case. J Orthop Relat Res. 1970;69:216–8. Bone Joint Surg Br. 1983;65:472–3. 16. Stirling AJ, Howel D, Millner PA, 5. Citron N, Edgar MA, Sheehy J, Sadiq S, Sharples D, Dickson RA. Thomas DG. Intramedullary spinal Late-onset idiopathic scoliosis in cord tumours presenting as scoliosis. J children six to fourteen years old: A Bone Joint Surg Br. 1984;66:513–7. cross-sectional prevalence study. J 6. Little DG, Song KM, Katz D, Herring Bone Joint Surg Am. 1996;78:1330–6 JA. Relationship of peak height 17. Rogala EJ, Drummond DS, Gurr J. velocity to other maturity indicators in Scoliosis: Incidence and natural idiopathic scoliosis in girls. J Bone history. A prospective epidemiological Joint Surg Am. 2000;82:685–93. study. J Bone Joint Surg Am. 1978; 7. Wynn-Davies R. Familial (idiopathic) 60:173–6. scoliosis. A family survey. J Bone 18. Montgomery F, Willner S. The natural Joint Surg Br. 1968;50:24–30 history of idiopathic scoliosis: 8. Adams W. London: Churchill Incidence of treatment in 15 cohorts of Livingston; 1865. Lectures on children born between 1963 and 1977. Pathology and Treatment of Lateral Spine. 1997; 22:772–4. and Other Forms of Curvature of the 19. Kane WJ. Scoliosis prevalence: A call Spine. for a statement of terms. Clin Orthop 9. Grossman TW, Mazur JM, Cummings Relat Res. 1977; 126:43–6.

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20. Travell J, Simons I: Point Myofascial mobility in patients with idiopathic Pain and Dysfunction: The Trigger scoliosis. Spine. 1991, 16: 88-93. Manual. Lippincott Williams & 33. Ellenbecker T, Davies G: Closed Wilkins. 1992 Kinetic Chain Exercise A 21. Lewit K: Manual therapy in the Comprehensive Guide to Multiple rehabilitation of the motor organ Joint Exercises. Human Kinetics. 2001 diseases. Nature Publishing;. 2001 34. Białek M, M'hango A: FITS concept: 22. Białek M, Black: Possibilities of Functional Individual Therapy of utilizing manual therapy in the Scoliosis. Stud Health Technol Inform. treatment of scolioses, author's own 2008, 135: 250-261. research;. Manual medicine. 1997, 1: 35. Białek M, M'hango A: Complex 24-27. Diagnostic and Therapy of Spinal 23. Heideman M: Proprioceptive Curvatures and Scoliosis According to neuromuscular facilitation in stroke FITS Concept, on Dysfunctions of The rehabilitation. 1995, Edinburgh: Locomotor System. University of Churchill Livingstone Medical Sciences. 2010, 1: 96-109. 24. Dubousset J: Three-dimensional 36. Białek M, Kotwicki T, M'hango A, analysis of the scoliotic deformity [w:] Szulc A: Vale of trunk rotation angle The Pediatric Spine, Weinstein S.L. within the primary and compensatory 1994, Raven Press, 479-495. curves in children with idiopathic 25. Greenman P: Principles of manual scoliosis subjected to intense, medicine. 1996, New York: individual FITS kinesitherapy. Ann Williams&Wilkins Acad Med Siles. 2007, 61: 45-48. 26. Nowotny J: Physiotherapy Basics Part 37. Białek M: Possibilities of applying II. Basic methodological and technical methods of PNF in the treatment of implementation of certain treatments. scoliosis. Physiotherapy Poland. 2001, Publisher Kasper, Cracow. 2004, 375- 1 (2): 220-221. 380. 38. Bunnell WP: An objective criterion for 27. Norris C: Back Stability. Human scoliosis screening. J Bone Joint Surg. Kinetics. 2000, 61-78. 1 1984, 66A: 1381-1387. 28. Lee D: The pelvic girdle. 2004, 39. Moe's Textbook of Scoliosis and Other London: Churchill Livingstone Spinal Deformities. 1995, WB 29. Richardson C, Hodges P, Hides J: Saunders, Philadelphia Therapeutic exercise for lumbopelvic 40. Hitesh Modi, Seung-Woo Suh, Jae- stabilization. 2004, Edinburgh: Hyuk Yang, Jae-Young Hong, Churchill Livingstoner. Venkatesh KP, Nasir Muzaffar: 30. S. Sreeremya, 2018. Genetic Spontaneous regression of curve in Counselling—Review, International immature idiopathic scoliosis -does Journal of Genetic Engineering and spinal column play a role to balance? Recombination, Vol. 4(1):1-4. An observation with literature review. 31. Lehnert,Schroth K: The Schroth J Orthop Surg Res. 2010, 5: 80-10. Scoliosis Three-Dimensional 41. Horton D (2002) In: Rimoin DL, Treatment. A physiotherapy method Connor JM, Pyeritz RE, Korf BR (eds) for scoliosis, scheuermann's kyphosis Emery and Rimoin’s principles and and other related deformities of the practices of medical genetics, 5th edn. spine. Books on Demand GmbH. 2007, Churchill Livingstone Elsevier, 20-23. Amsterdam, pp 4236–4244 32. Weiss HR: The effect of an exercise 42. Andersen MO, Thomsen K, Kyvik KO program on vital capacity and rib (2007) Adolescent idiopathic scoliosis

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in twins: a population-based survey. (2004) Assessing the probability that a Spine (Phila Pa 1976) 32(8):927–930 positive report is false: an approach for 43. Hermus JP, van Rhijn LW, van Ooij A molecular epidemiology studies. J Natl (2007) Non-genetic expression of Cancer Inst 96(6):434–442 adolescent idiopathic scoliosis: a case 47. Hirschhorn JN, Lohmueller K, Byrne report and review of the literature. Eur E, Hirschhorn K (2002) A Spine J 16(Suppl 3):338–341 comprehensive review of genetic 44. Weiss HR (2007) Idiopathic Scoliosis: association studies. Genet Med how much of a genetic disorder? 4(2):45–61 Report of five pairs of monozygotic 48. Yu W, Gwinn M, Clyne M, Yesupriya twins. Dev Neurorehabil 10(1):67–73 A, Khoury MJ (2008) A navigator for 45. Fazal MA, Edgar M (2006) Detection human genome epidemiology. Nat of adolescent idiopathic scoliosis. Acta Genet 40(2):124–125 Orthop Belg 72:184–186 46. Wacholder S, Chanock S, Garcia- Closas M, El Ghormli L, Rothman N