Nancy H. Miller

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.

Familial idiopathic scoliosis: evidence of an X-linked susceptibility locus.

Study Design. A genomic screen and statistical linkage analysis of a large sample of families with individuals having idiopathic scoliosis was performed. Objectives. To identify an X-linked susceptibility locus involved in the expression of familial idiopathic scoliosis. Summary of Background Data. A large sample of families with individuals having idiopathic scoliosis (202 families; 1198 individuals) were diagnosed through physical examination and radiographic criteria, and genomic screening and genetic linkage analyses were performed. Methods. Model-independent linkage analysis was used to screen genotyping data from 15 X-linked markers in 202 families (1198 individuals). Families were stratified based on the ratio of the likelihood of an X-linked dominant (XLD) inheritance model relative to that of an autosomal dominant (AD) model. Both model-independent and model-dependent linkage analyses were used to identify potential candidate regions. Results. When the entire set of families were analyzed with model-independent methods, no result was significant at the 0.05 level for any of the markers. However, when the families were stratified based on the ratio of the likelihood of the X-linked dominant to autosomal dominant mode of inheritance, results from model-dependent linkage analysis of 15% of the families most likely to have X-linked dominant inheritance showed six adjacent markers with positive lod score values and a maximum lod score of 1.69 (&thgr; = 0.2) at marker GATA172D05. A lod score of 2.23 at this same marker was found in a single family with six affected individuals. Conclusion. The results suggest that a region on the X chromosome may be linked to the expression of familial idiopathic scoliosis in a subset of these families.

Identification of candidate regions for familial idiopathic scoliosis

Study Design. A genomic screen and statistical linkage analysis of 202 families with at least two individuals with idiopathic scoliosis was performed. Objectives. To identify candidate regions or the autosomal loci that may be involved in the expression of familial idiopathic scoliosis. Summary of Background Data. A large sample of families with individuals having idiopathic scoliosis (202 families; 1,198 individuals) was ascertained; diagnoses were based on physical examination and radiographic criteria. Methods. Model-independent linkage analysis of qualitative and quantitative traits (degree of lateral curvature) related to scoliosis was used to screen genotyping data from 391 markers in the 202 families. Subsets of families were determined before genotyping based on the most likely mode of inheritance for each family (autosomal dominant vs. X-linked dominant). Fine mapping results corroborated linkage in the primary candidate regions. Results. Candidate regions on chromosomes 6, 9, 16, and 17 were considered to have the strongest evidence for linkage across all subsets considered. Conclusion. Linkage analyses have identified several candidate regions, a significant step in defining the genetic etiology of this disorder.

Genetics of familial idiopathic scoliosis.

Idiopathic scoliosis in the adolescent period is a complex genetic disorder of high prevalence and extreme variability. Epidemiological approaches have confirmed the genetic basis of this disorder and have suggested multiple modes of heritability. The current challenge is to identify the genetic determinants of this condition to distinguish individuals who are at risk for severe progression. This review summarizes the literature establishing the genetic basis of this disorder. Studies focused on the identification of genes responsible for the scoliotic phenotype are reviewed, with an emphasis on recent works that have utilized contemporary strategies to isolate genes related to complex diseases. To date, molecular studies have isolated critical regions on chromosomes1,5,6,8,9,16,17,19 and X of potential importance to the etiology of scoliosis. An analysis of these works will aid in an understanding of seemingly conflicting results, and will help us determine the focus of future work. Level of Evidence: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Idiopathic Scoliosis : Identification of Candidate Regions on Chromosome 19p13

Study Design. We performed genomic screening, statistical linkage analysis, and fine mapping of 202 families with at least 2 individuals with idiopathic scoliosis. Objective. To identify regions on chromosome 19p13 statistically linked to the phenotypic expression of idiopathic scoliosis. Summary of Background Data. Idiopathic scoliosis is a common structural curvature of the spine affecting otherwise healthy children. Presently, no clear consensus exists regarding the underlying abnormality or genetic determinants of this disease. Methods. Model-independent linkage analysis of qualitative and quantitative traits related to scoliosis was used to screen genotyping data from 391 markers in 202 families (1198 individuals). Subsets of families with probands having a curve ≥30° were dichotomized based on the most likely mode of inheritance for each family (autosomal dominant or X-linked dominant). Fine mapping was performed to show linkage to candidate regions on chromosome 19. Results. When the threshold of disease was set at a curvature of ≥30°, qualitative linkage analysis revealed significant results at 2 successive markers on chromosome 19. Conclusion. The data confirm a previously reported genetic locus on chromosome 19 as potentially significant in the etiology of idiopathic scoliosis.

Comparison of dynamic versus static external fixation for pediatric femur fractures.

External fixation of pediatric femoral shaft fractures has the advantages of minimal dissection and early weight bearing. However, it is associated with slow healing and potential for refracture. Some surgeons have proposed that axial dynamization may improve the speed and strength of callus formation. to test this hypothesis, we performed a randomized controlled trial using 53 femur fractures in 52 patients between 1995 and 1999. Patients were randomized to receive dynamic or static fixation. Average time until early callus formation was 23.2 days for dynamic fixation and 24.9 days for static fixation (P = 0.627). Average time until complete radiographic healing was 70.1 days for dynamic fixation and 63.1 days for static fixation (P = 0.370). Similarly, the differences in time to fixator removal and to full weight bearing did not reach statistical significance. The conclusion was that axial dynamization of external fixation for pediatric femur fractures has no significant effect on time to healing or frequency of complications.

The role of serial casting in early-onset scoliosis (EOS).

Background: Serial casting has demonstrated efficacy for idiopathic early-onset scoliosis (EOS). Results of casting in nonidiopathic (syndromic and congenital) EOS patients have not previously been well described. Methods: A total of 53 patients underwent serial casting for EOS from 2005 to 2010 at a single institution. Deformity was classified as idiopathic or nonidiopathic. Diagnosis, time in cast, number of casts, use of bracing, complications, and outcomes were recorded. Radiographic measures included Cobb angle and thoracic height (T1-T12). Thoracic height velocity was calculated and compared with established norms. Results: A total of 36 patients, 19 idiopathic and 17 nonidiopathic (14 syndromic, 3 congenital), completed cast treatment and had >6-month follow-up and were therefore included. Of those, 17% (6/36) experienced resolution of their deformity, 53% (19/26) are currently in braces, and 31% (11/36) had undergone surgery. Surgery occurred on average at age 5.6 years and was delayed by an average of 2.1 years from time of first cast. A 19% complication was observed. There was no statistical difference in the rate of resolution of deformity between idiopathic (5/19) and nonidiopathic (1/17) patients (P=0.182), although there exists a trend toward greater curve correction in idiopathic patients. Surgery occurred in fewer patients (2/19) in the idiopathic group compared with the nonidiopathic group (9/17) (P=0.006). Significant improvements in Cobb angle was observed in the idiopathic group (12.2 degrees) during casting (P=0.003). Nonidiopathic patients did not maintain the correction gained during casting at the time of final follow-up. T1-T12 height increased across all study patients regardless of etiology during the period of casting at similar velocity to established norms of 1.4 cm/y for this age group. Conclusions: Serial casting offers modest deformity correction in idiopathic deformities compared with nonidiopathic deformities. Thoracic height growth continued throughout the casting period at normal velocity. Serial casting maintained normal longitudinal thoracic growth in all patients with EOS in this cohort. Although many required surgery, the increased thoracic height may have positive implications on ultimate pulmonary function. Level of Evidence: Therapeutic level III.

Spine update: Genetics of familial idiopathic scoliosis

The etiology et 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.

A multidisciplinary approach improves infection rates in pediatric spine surgery.

Background: Surgical site infections (SSI) associated with elective pediatric spinal surgery are a commonly reported complication, increasing hospital length of stay, readmissions, operations, and financial costs. In July 2007, a multidisciplinary task force, designated Target Zero, was created to address this issue and establish prevention protocols at our institution. Methods: A consecutive series of 394 patient charts from April 2006 to September 2008 were retrospectively reviewed to identify patients who developed an SSI secondary to elective spinal surgery. Four cohorts were evaluated; high-risk (HR) and low-risk (LR) patients who underwent surgery before (April 2006 to June 2007) and after (July 2007 to September 2008) Target Zero initiation. The definition of HR included diagnoses of cerebral palsy, spina bifida, muscle disease, paralytic deformities, and vertebral column resections. Patients were followed for 1 year to meet The Center for Disease Control-National Health Safety Network’s definition of an SSI with an implantable device. Overall infection rates were determined for each group and compared statistically. Results: A total of 192 patients (70 HR and 122 LR) underwent surgery before, and 202 patients (92 HR and 110 LR) underwent surgery after Target Zero initiation. Overall infection rates were reduced from 7.8% to 4.5% (P=0.203), 12.9% to 6.5% (P=0.183), and 4.9% to 2.7% (P=0.505) for all patients, HR patients, and LR patients, respectively. The relative risk reduction was 43.0% for all patients, 49.3% for HR patients, and 44.6% for LR patients. Conclusions: Although decreases in overall infection rates were not statistically significant, the results from Target Zero were shown to be clinically meaningful with a relative risk reduction approaching 50% overall and in defined subgroups. Based on the number needed to treat analysis, 1 infection in every 16 patients within the HR group, and 1 in 30 overall, was prevented up to 1 year postoperatively. This study is the first to document the effectiveness of a multidisciplinary team implementing protocols for decreasing infection rates in pediatric spine surgery.

Lack of association between the aggrecan gene and familial idiopathic scoliosis.

Study Design. A study was conducted to determine the potential association between a specific aggrecan gene polymorphism and familial idiopathic scoliosis (FIS). Objectives. To determine the allelic distribution of the exon 12 polymorphism within a sample of families with FIS. Summary of Background Data. FIS is a structural curvature of the spine where the underlying genetic etiology has not been established. The aggrecan locus has been linked to multiple skeletal disorders. A polymorphism, within the aggrecan gene, was previously reported to be associated with curve severity in individuals with scoliosis. Methods. Fifty-eight families with FIS were genotyped for the aggrecan exon 12 polymorphism using a polymerase chain reaction method. Model-independent sib-pair linkage analyses and tests of association were performed to analyze the genetic effects of the exon 12 polymorphism. Results. Linkage analyses of a genomic screen performed on a subgroup of 48 families with a most likely to be X-linked dominant mode of inheritance of FIS showed marginally significant results on chromosome 15q25-26 (P < 0.05). The overall distribution of the alleles was consistent with previously reported literature; no evidence of association and marginal significance of linkage was found between the polymorphism and FIS or the degree of lateral curvature. Conclusions. Despite the negative association reported here, further investigation of the gene and its potential association to FIS is required.