Spine update: genetics of familial idiopathic scoliosis

The etiology of familial idiopathic scoliosis remains in question. The role of genetic factors in the development of this disorder has been well-documented; however, reports of the specific mode of genetic inheritance are inconclusive. These facts, combined with the phenotypic variability of this disorder, suggest that the genetic expression if idiopathic scoliosis may be dependent upon multiple factors and genetic interactions. Strategies to resolve the complex nature of this condition include genome-wide scanning of one extensive family or, alternatively, a well-characterized population of families affected with idiopathic scoliosis.     

Current theories on the etiology of idiopathic scoliosis

Review of the literature shows that the cause of idiopathic scoliosis remains unknown, although research has possibly eliminated some hypothetical causes. Abnormalities of disc, bone, muscle, and collagen do not appear to be etiological factors but, rather, reflect the effects of scoliosis on normal tissues. Although most patients with idiopathic scoliosis are thought of as tall and slender, it has not yet been proven that growth in this condition differs from normal. It is possible that idiopathic scoliosis is caused by multiple factors rather than a single factor. Perhaps there are different factors for curve initiation and curve progression. It appears that a brain stem or equilibrium abnormality does exist in patients with idiopathic scoliosis, although more research is needed to confirm and define the problem. There also may be a genetic basis for idiopathic scoliosis, as it does seem to occur within patients' families more frequently than in the general population. Whether these two factors form the basis for a multifactorial etiology of idiopathic scoliosis remains to be proven.     

Idiopathic scoliosis: etiological concepts and hypotheses

Scoliosis is diagnosed as idiopathic in 70 % of structural deformities affecting the spine in children and adolescents, probably reflecting our current misunderstanding of this disease. By definition, a structural scoliosis should be the result of some primary disorder. The goal of this article is to give a comprehensive overview of the currently proposed etiological concepts in idiopathic scoliosis regarding genetics, molecular biology, biomechanics, and neurology, with particular emphasis on adolescent idiopathic scoliosis (AIS). Despite the fact that numerous potential etiologies for idiopathic scoliosis have been formulated, the primary etiology of AIS remains unknown. Beyond etiology, identification of prognostic factors of AIS progression would probably be more relevant in our daily practice, with the hope of reducing repetitive exposure to radiation, unnecessary brace treatments, psychological implications, and costs-of-care related to follow-up in low-risk patients.     

Changing curve pattern in infantile idiopathic scoliosis: family report with a follow-up of 15 years

STUDY DESIGN: The authors monitored a father and his six children, all of whom had idiopathic scoliosis for more than 13 years. OBJECTIVE: To analyze the similarities and differences in curve pattern between the family members. SUMMARY OF BACKGROUND DATA: The etiology and pathogenesis of idiopathic scoliosis are not well understood. Genetic factors play an important role, as is shown by the high concordance in monozygotic twins. METHODS: Radiographs from all family members were analyzed. Location and direction of the curve, Cobb angle, location of the apex, and rib-vertebra angle difference were compared. RESULTS: A father and his six children had idiopathic scoliosis. The curves differed within the family and changed during follow-up. The father had a left convex thoracic scoliosis of 42 degrees. Only three of the children had a curve of similar severity, and only four children had a left convex thoracic scoliosis. In three children the curve pattern changed during follow-up. CONCLUSIONS: This report of idiopathic scoliosis in a father and six children supports the present theories on a genetic origin of the disorder but also stresses the importance of dynamic processes in the development of scoliosis.     

Genetic analysis of structural elastic fiber and collagen genes in familial adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis is a genetic disorder of unknown etiology. Scoliosis is a clinical feature of inherited connective-tissue disorders including Marfan syndrome. Mutations within the gene of FBN1 (fibrillin 15), a component of the extracellular matrix, are now linked to Marfan syndrome and similar clinical phenotypes. This study investigated the potential association of structural genes encoding for extracellular matrix components of FBN1, elastin, and one of the polypeptides of type-I collagen (COL1A2) with familial adolescent idiopathic scoliosis. Eleven pedigrees, including 96 individuals, were identified in which adolescent idiopathic scoliosis segregated in an apparent autosomal dominant pattern. Fifty-two individuals were determined to be affected with scoliosis. Genomic DNA was analyzed by genetic linkage utilizing four intragenic markers for the structural genes FBN1, elastin, and COL1A2. Collectively, our results exclude the structural genes of FBN1. elstin, and COL1A2 as candidate genes within these families. However, when viewed individually, specific markers cannot be excluded within all of the families. This information complements previously reported data that fibrillin production and matrix incorporation from scoliotic fibroblasts in vitro are normal in more than 80% of patients studied.     

Melatonin and adolescent idiopathic scoliosis: The present evidence

IntroductionAdolescent idiopathic scoliosis (AIS) is a multifactorial condition with genetic predisposing factors, and several causes have been put forward for its aetiopathogenesis, including possible hormonal dysfunction. Melatonin seems to play significant role in AIS.MethodsA systematic search in different database, to July 2021, was performed to define the role of melatonin in the pathophysiology of adolescent idiopathic scoliosis. Eight suitable studies were identified.ResultsThe concentration and rhythm of melatonin secretion can play an important role by influencing the pathogenesis of adolescent idiopathic scoliosis.ConclusionsAlthough there are many alterations of melatonin in subjects with adolescent idiopathic scoliosis, the many variables present do not allow to establish a direct cause–effect relationship.Level of evidenceLevel IV.     

Curve characteristics in monozygotic twins with adolescent idiopathic scoliosis: 3 new twin pairs and a review of the literature

Most authors state that there is strong evidence for a genetic origin of adolescent idiopathic scoliosis (AIS). This conclusion is mainly based on the fact that the rate of concordance for AIS in monozygotic twins is significantly higher than that in dizygotic twins. However, it is of interest to determine whether all elements of scoliosis formation are genetically predetermined. If this were the case, there would perhaps be less place for closed treatment. We surveyed the literature for monozygotic twin pairs in which both members suffered from idiopathic scoliosis and added 3 pairs from our own patient group. The total group consisted of 32 twin pairs. We found that gender, direction of the convexity, the level of the apex and the kyphotic angle were determined more by genetic factors than the lateral Cobb angle of the scoliotic curve. This suggests that variations in the environment may affect the curve patterns in monozygotic twins.     

Curve characteristics in monozygotic twins with adolescent idiopathic scoliosis: 3 new twin pairs and a review of the literature

Most authors state that there is strong evidence for a genetic origin of adolescent idiopathic scoliosis (AIS). This conclusion is mainly based on the fact that the rate of concordance for AIS in monozygotic twins is significantly higher than that in dizygotic twins. However, it is of interest to determine whether all elements of scoliosis formation are genetically predetermined. If this were the case, there would perhaps be less place for closed treatment. We surveyed the literature for monozygotic twin pairs in which both members suffered from idiopathic scoliosis and added 3 pairs from our own patient group. The total group consisted of 32 twin pairs. We found that gender, direction of the convexity, the level of the apex and the kyphotic angle were determined more by genetic factors than the lateral Cobb angle of the scoliotic curve. This suggests that variations in the environment may affect the curve patterns in monozygotic twins.     

Etiology of idiopathic scoliosis: current trends in research

Current population studies characterize idiopathic scoliosis as a single-gene disorder that follows the patterns of mendelian genetics, including variable penetrance and heterogeneity. The role of melatonin and calmodulin in the development of idiopathic scoliosis is likely secondary, with indirect effects on growth mechanisms. Reported abnormalities of connective tissue, skeletal muscle, platelets, the spinal column, and the rib cage are all thought to be secondary to the deformity itself. Although no consistent neurological abnormalities have been identified in patients with idiopathic scoliosis, it is possible that a defect in processing by the central nervous system affects the growing spine. The true etiology of idiopathic scoliosis remains unknown; however, it appears to be multifactorial.     

Infantile idiopathic scoliosis. Causative factors, particularly in the first six months of life.

An attempt has been made to determine the aetiological factors in infantile idiopathic scoliosis from a clinical, genetic and epidemiological survey of 134 infants, ninety-seven of whom developed a curve in the first six months of life. Plagiocephaly was present in all cases; mental retardation occurred in 13 per cent of males with progressive scoliosis; congenital dislocation of the hip occurred in 3-5 per cent of cases and congenital heart disease in 2-5 per cent; and inguinal hernia was found in 7-4 per cent of males. Approximately 3 per cent of parents and 3 per cent of sibs had the same deformity, thirty times the general population frequency for the Edinburgh area. Other positive findings included an excess of breech presentations and of premature, low birthweight males, and a preponderance of curves developing in the winter months. Infants with progressive scoliosis tended to have older mothers and to come from poorer families. Only three children all with resolving scoliosis, habitually lay prone in early infancy, in marked contrast to North American infants where this posture is usual. The almost complete absence of infantile idiopathic scoliosis in North America is noted and it is thought that the two facts may be related. The aetiology is likely to be multifactorial, with a genetic tendency to the deformity which is either "triggered off" or prevented by external factors.     

Idiopathic scoliosis in families of children with congenital scoliosis

Although most cases of congenital scoliosis are thought to be of sporadic etiology, it is not known whether other types of spinal deformity occur in families of individuals with this type of scoliosis. Children with congenital scoliosis were identified through a review of health records and radiographic report databases. Of 237 children with congenital scoliosis investigated, 49 (20.7%) reported a family history of spinal deformity. Detailed pedigrees were done, which showed a history of idiopathic scoliosis in 17.3% of the 237 families. This is a higher than expected rate of spinal deformity in families of children with congenital scoliosis, and the strong association of idiopathic scoliosis in families of children with congenital scoliosis has not been reported previously. Although this finding could be related to the chance occurrence of multiple genetic abnormalities or sporadic events in these families, it does raise the possibility that one genetic defect at least predisposes these families to having different types of spinal deformity develop.     

Curve characteristics in monozygotic twins with adolescent idiopathic scoliosis: 3 new twin pairs and a review of the literature

Most authors state that there is strong evidence for a genetic origin of adolescent idiopathic scoliosis (AIS). This conclusion is mainly based on the fact that the rate of concordance for AIS in monozygotic twins is significantly higher than that in dizygotic twins. However, it is of interest to determine whether all elements of scoliosis formation are genetically predetermined. If this were the case, there would perhaps be less place for closed treatment.

We surveyed the literature for monozygotic twin pairs in which both members suffered from idiopathic scoliosis and added 3 pairs from our own patient group. The total group consisted of 32 twin pairs.

We found that gender, direction of the convexity, the level of the apex and the kyphotic angle were determined more by genetic factors than the lateral Cobb angle of the scoliotic curve. This suggests that variations in the environment may affect the curve patterns in monozygotic twins.     

Non-genetic expression of adolescent idiopathic scoliosis: a case report and review of the literature

Treating children with idiopathic scoliosis can amaze someone at the many different ways in which the deformity can present. Most authors state that genetics stipulates the course of adolescent idiopathic scoliosis. This is mainly based on the high concordance in monozygotic twins. However, there is indication that environmental factors have influences on adolescent idiopathic scoliosis. This is the first report in which a monozygotic twin pair is described concordant for idiopathic scoliosis but with different apical levels, magnitudes and age at detection of scoliosis which stresses the importance of environmental factors.

     

Factors affecting curve flexibility in skeletally immature and mature idiopathic scoliosis

Background  

The determination of factors affecting curve flexibility is important in idiopathic scoliosis patients with regard to the Risser sign. The objective of this retrospective study was to identify factors affecting curve flexibility in patients with skeletally immature and mature idiopathic scoliosis.     

Studies on skin fibroblasts of patients with idiopathic scoliosis

Previous examinations of skin biopsies suggested that connective tissue may be abnormal in patients with idiopathic scoliosis. The fibroblast culture system has proven a powerful technique for approaching many diseases of known connective origin, and therefore, seemed an appropriate method with which to study scoliosis. Present observations on collagen synthesis, skin collagen extractability, and glycosaminoglycan (GAG) synthesis and degradation appear normal. Idiopathic scoliosis does not prove to be a generalized connective tissue disorder. While factors other than collagen and GAG metabolism seem not to be at fault, other possibilities seem not to be taken into consideration by basic research on the spinal column: genetics, biochemistry, and physiology.     

A study of postural equilibrium in idiopathic scoliosis

The relationship between upright static and dynamic equilibrium function and idiopathic scoliosis was investigated using a seven-part postural equilibrium test battery. Twenty-three normal subjects and 31 subjects with differing degrees of idiopathic scoliosis participated in the study. No significant difference was found among any of the subtest scores of the normal and scoliotic groups. Subtest scores were not significantly correlated with curve measurements. Curve measurements and subjects' ages proved to have some effect on subtest scores, but other unknown factors accounted for a greater percentage of score variance. The existence of a clinically measurable deficit in upright static and dynamic equilibrium in idiopathic scoliosis could not be proven. Further investigation is suggested to identify the factors that affect equilibrium scores. If these factors could be identified, the test battery might serve as a tool for the examination of female patients with idiopathic scoliosis.     

Correlation between curve severity, somatosensory evoked potentials, and magnetic resonance imaging in adolescent idiopathic scoliosis.

STUDY DESIGN: A prospective study in patients with adolescent idiopathic scoliosis of different clinical severity using whole-spine magnetic resonance imaging and somatosensory evoked potentials. OBJECTIVES: To correlate the presence of magnetic resonance imaging structural abnormalities with somatosensory evoked potential-detected functional disorders in the hind brain and spinal cord and the Cobb's angle in patients with adolescent idiopathic scoliosis and to compare the result with those in healthy matched control subjects. SUMMARY OF BACKGROUND DATA: Many different types of neurologic dysfunction have been reported in scoliosis. With the advent of magnetic resonance imaging, there are increased reports on the association of idiopathic scoliosis and syringomyelia, Chiari I malformation, or tonsillar ectopia. The actual link between structural and functional disorder in idiopathic scoliosis is, however, unclear. METHODS: Posterior tibial nerve evoked potentials and whole-spine magnetic resonance imaging were performed in 36 healthy control subjects, 135 patients with adolescent idiopathic scoliosis with Cobb's angle less than 45 degrees, and 29 patients with Cobb's angle more than 45 degrees. RESULTS: Tonsillar ectopia or syringomyelia, detected by magnetic resonance imaging, or functional disturbance in the somatosensory pathway, detected by somatosensory evoked potentials, was found to be significantly more frequent in the group of patients with severe scoliosis curvature, with an incidence of 31% and 27.6%, respectively. Incidence of tonsillar ectopia was 33.3% in patients with abnormal somatosensory evoked potentials in contrast to the much lower incidence of 2.9% in patients with normal somatosensory evoked potentials. There was a significant structural and functional link. The incidence of syringomyelia in patients with and without tonsillar ectopia was 33.3% and 0.7%, respectively. CONCLUSIONS: In patients with adolescent idiopathic scoliosis with severe curve, the significant association with tonsillar ectopia and abnormal somatosensory function points to a neural origin. Disorders in the somatosensory function may be one of the mechanisms linking tonsillar ectopia to scoliosis. Somatosensory evoked potentials and magnetic resonance imaging may have important diagnostic and predictive value and may help in the management of adolescent idiopathic scoliosis.     

Stature and idiopathic scoliosis. A prospective study

A study of 130 scoliotic children with curves measuring 10 degrees or more has been performed in order to elucidate the importance of stature, growth and development. Girls with adolescent idiopathic curves measuring 15 degrees or more were taller than girls with smaller idiopathic curves and taller than those whose scoliosis was secondary to leg-length inequality (pelvic tilt scoliosis). No differences were observed as regards growth velocity or development. The increased standing height may be genetic but the uncoiling effect of the normal kyphosis to give a flat lateral profile is a more likely cause. The familial trend in idiopathic scoliosis may therefore be explained by the genetically determined shape of the spine in the median (sagittal) plane.     

Molekulare und genetische Aspekte der idiopathischen Skoliose

Spinal deformities, and particularly scoliosis, are the most frequent forms of orthopedic deformities in children and adolescents. About 1–6% of the population has scoliosis. This disorder leads to severe spinal deformities and predominantly affects adolescent girls. Although the multifactorial origin of adolescent idiopathic scoliosis (AIS) is broadly recognized, the genetic causes of AIS are still largely unknown. Our previous studies suggested a generalized dysfunction of melatonin transduction (the hormone that is primarily produced in the brain and epiphysis). In the meantime we have demonstrated that such a defect of signal transduction is caused by chemical alterations, which inactivate the function of the inhibitory G protein-coupled melatonin receptors. This discovery has led to the development of the first blood test to detect children without symptoms who are at risk of developing scoliosis. Since a single function (cellular reaction to melatonin) is determined, the unique advantage of this test is that it can be performed without knowledge of mutations in defective genes that could provoke the onset of AIS.     

Prevalence of cardiac dysfunction and abnormalities in patients with adolescent idiopathic scoliosis requiring surgery

The prevalence of cardiac abnormalities in patients with adolescent idiopathic scoliosis in an Asian population has not been reported. A retrospective study was conducted to evaluate the incidence of cardiac abnormalities in these patients. From January 2007 to April 2009, echocardiography and pulmonary function tests were performed in 80 adolescent idiopathic scoliosis patients who required surgical intervention. A thorough analysis of cardiopulmonary functions and cardiac structures was performed. The risk factors, types of cardiac abnormalities, and associations between severity of scoliosis or pulmonary function and cardiac abnormalities were assessed. Cardiac abnormalities were detected by echocardiogram in 25 patients, including 14 with structural abnormalities and 11 with functional abnormalities. The most common functional abnormality was tricuspid regurgitation (9 of 80; 11.3%), whereas atrial septal defect was the most common structural abnormality (7 of 80). Altered hemodynamics occurred in 5 patients, including 3 with ventricular septal defect and 2 with mitral valve dysplasia. Abnormal electrocardiographic findings presented in only 9 of the 25 patients with cardiac abnormalities. No significant associations were found between severity of scoliosis or pulmonary function and cardiac abnormalities. A high incidence of cardiac abnormality exists in patients with adolescent idiopathic scoliosis in this region. Although most patients tolerated surgery, some patients were at risk of decompensation postoperatively. Electrocardiography is of limited value for detecting cardiac problems in patients with adolescent idiopathic scoliosis, we recommend echocardiography as a routine modality in the preoperative evaluation of patients with adolescent idiopathic scoliosis.