Outcomes for nighttime bracing in adolescent idiopathic scoliosis based on brace wear adherence.

BACKGROUND: This study determined brace wear adherence for patients treated with nighttime braces and evaluated the effect of brace adherence on curve progression. METHODS: One hundred twenty-two patients with AIS ages 10-16 years, Risser stages 0-2, major curves 20°-40° treated with Providence nighttime braces prescribed to be worn at least 8 h per night were prospectively enrolled and followed until skeletal maturity or surgery. Brace adherence was measured using iButton temperature sensors after 3 months of brace initiation and at brace discharge. RESULTS: Curve types were single thoracolumbar/lumbar (62%, n = 76), double (36%, n = 44), and single thoracic (2%, n = 2). Brace adherence averaged 7.8 ± 2.3 h after 3 months (98% adherence) and 6.7 ± 2.6 h at brace discharge (84% adherence). Curves that progressed ≥ 6° had decreased brace adherence than non-progressive curves after 3 months (7.0 h vs. 8.1 h, p = 0.010) and at brace discharge (5.9 h vs. 7.1 h, p = 0.017). Multivariate logistic regression analysis showed that increased hours of brace wear [odds ratio (OR) 1.23, 95% confidence interval (CI) 1.06-1.46], single curves (OR 3.11, 95% CI 1.35-7.53), and curves < 25° (OR 2.61, 95% CI 1.12-6.44) were associated with non-progression at brace discharge. CONCLUSIONS: Patients treated with nighttime bracing have a high rate of brace adherence. Lack of curve progression is associated with increased brace wear. Nighttime bracing is effective at limiting curve progression in AIS single thoracolumbar/lumbar and double curves. LEVEL OF EVIDENCE: Prognostic Level 2.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E-11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.

Adolescent idiopathic scoliosis (AIS) is a twisting deformity of the spine that occurs during periods of rapid growth in children worldwide. Children with severe cases of AIS require surgery to stop it from getting worse, presenting a significant financial burden to health systems and families. Although AIS is known to cluster in families, its genetic causes and its inheritance pattern have remained elusive. Additionally, AIS is known to be more prevalent in females, a bias that has not been explained. Advances in techniques to study the genetics underlying diseases have revealed that certain variations that increase the risk of AIS affect cartilage and connective tissue. In humans, one such variation is near a gene called Pax1, and it is female-specific. The extracellular matrix is a network of proteins and other molecules in the space between cells that help connect tissues together, and it is particularly important in cartilage and other connective tissues. One of the main components of the extracellular matrix is collagen. Yu, Kanshour, Ushiki et al. hypothesized that changes in the extracellular matrix could affect the cartilage and connective tissues of the spine, leading to AIS. To show this, the scientists screened over 100,000 individuals and found that AIS is associated with variants in two genes coding for extracellular matrix proteins. One of these variants was found in a gene called Col11a1, which codes for one of the proteins that makes up collagen. To understand the relationship between Pax1 and Col11a1, Yu, Kanshour, Ushiki et al. genetically modified mice so that they would lack the Pax1 gene. In these mice, the activation of Col11a1 was reduced in the mouse spine. They also found that the form of Col11a1 associated with AIS could not suppress the activation of a gene called Mmp3 in mouse cartilage cells as effectively as unmutated Col11a1. Going one step further, the researchers found that lowering the levels of an estrogen receptor altered the activation patterns of Pax1, Col11a1, and Mmp3 in mouse cartilage cells. These findings suggest a possible mechanism for AIS, particularly in females. The findings of Yu, Kanshour, Ushiki et al. highlight that cartilage cells in the spine are particularly relevant in AIS. The results also point to specific molecules within the extracellular matrix as important for maintaining proper alignment in the spine when children are growing rapidly. This information may guide future therapies aimed at maintaining healthy spinal cells in adolescent children, particularly girls.

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study.

Introduction: Adolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated. Material and methods: Mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese. Results: Significant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI. Conclusions: Our Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); P=7.07e-11, OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2, or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1-Col11a1-Mmp3 signaling axis in spinal chondrocytes.

Skeletal Maturity in Legg-Calve-Perthes Disease: Significant Discrepancy Present Between the Hand and the Hip.

BACKGROUND: The concept of delayed skeletal maturity in Legg-Calve-Perthes Disease (LCPD) has been well identified with the Greulich and Pyle (GP) atlas showing 1 to 2 years delay. Recently the optimized Oxford hip skeletal age (Optimized Oxford) system has been developed and shown to have similar accuracy as the GP atlas for assessing skeletal maturity. However, this system has not been used to assess skeletal maturity in LCPD. METHODS: A retrospective review of a prospective, multicenter study of patients with LCPD treated from 1984 to 1991 and followed to skeletal maturity was performed. We identified all patients who had a left-hand radiograph at the time of presentation with an accompanying anteroposterior pelvis radiograph including the contralateral hip. Patients were excluded if their age at presentation fell outside the validated range for the Optimized Oxford system. GP atlas was used to determine bone age using left-hand radiographs and the nonaffected hip radiographs were used to calculate the Optimized Oxford bone age. Skeletal maturity indices were compared with chronological age (CA) to determine the discrepancy between methodologies. RESULTS: A total of 71 patients met inclusion criteria (mean 9.5 ± 1.2 y at presentation, 42.2% females). The mean GP bone age was 1.4 years younger than CA (95% CI: 1.01-1.76 y), with the discrepancy being greater for boys than girls (1.8 vs 0.86 y, P = 0.02). The mean Optimized Oxford bone age was 0.31 years older than CA (95% CI: 0.24-0.38 y) and correlated significantly with CA ( R = 0.97, P < 0.001). There were no sex differences in the Optimized Oxford bone age relative to CA ( P = 0.32). The GP bone age was a mean of 1.7 years younger than the Optimized Oxford bone age (95% CI: 1.35-2.05 y). CONCLUSION: Skeletal maturity assessment in children with LCPD varies according to the utilized maturity system. The Optimized Oxford bone age more closely mirrors the patient's CA and does not correlate with the GP bone age, which reveals a delayed maturation.

The Clinical Significance of Infolded Limbus on Postreduction Arthrogram in Developmental Dysplasia of the Hip.

BACKGROUND: The purpose of this study was to investigate whether presence of an infolded limbus on hip arthrogram at index closed reduction was associated with increased residual dysplasia or secondary surgery. METHODS: We retrospectively reviewed all patients who underwent closed reduction for dysplasia of the hip with a minimum 2-year follow-up between 1980 and 2016. Demographic data was obtained including the age at reduction and severity of dislocation based on the International Hip Dysplasia Institute (IHDI) classification. Arthrograms performed at time of closed reduction were separately reviewed by 3 fellowship-trained pediatric orthopaedic surgeons to evaluate for an infolded limbus. The primary radiographic outcome was acetabular indices at 2 and 4 years postreduction. We also assessed the presence of avascular necrosis and rate of secondary reconstructive surgery for residual dysplasia. RESULTS: A total of 182 hips in 165 patients underwent closed reduction at a mean age of 9.8±4.5 mo and were followed a mean of 9.0±4.9 y. An infolded limbus was identified in 20.3% (37/182) hips with substantial agreement among the 3 graders (Fleiss κ=0.75). The frequency of labral infolding increased with the severity of dislocation (8.8%% of IHDI II, 26.7% IHDI III, and 25.0% of IHDI IV hips; P=0.03). Hips with infolded limbus were older at reduction (12.4±5.3 vs. 9.2±5.8 mo, P=0.001). The mean acetabular index was higher in hips with infolded limbus than hips without at 2 years postreduction (34.8±4.8 vs. 32.6±5.8 degrees, respectively; P=0.04). However, multivariate analysis revealed that only the severity of dislocation predicted dysplasia at 2 years postreduction. No significant difference in acetabular index was seen at 4 years postreduction (27.2±7.4 vs. 25.4±6.5 degrees, P=0.24). There was no difference in avascular necrosis between groups (P=0.74). There was no difference in rate of secondary surgery between hips with labral infolding and those without (35% vs. 30%, respectively; P=0.52). CONCLUSIONS: An infolded limbus was more common in older patients with more severe dislocations. However, it is not associated with increased residual dysplasia or secondary surgery and may have limited utility in decision-making during closed reduction. LEVEL OF EVIDENCE: Level II-prognostic study.

Comparison of Outcomes by Reconstructive Strategy in Patients with Prostheses for Proximal Femoral Focal Deficiency.

BACKGROUND: The present study compares prosthetic treatment options for proximal femoral focal deficiency in terms of gait analysis, oxygen consumption, and patient-reported outcomes. METHODS: Twenty-three patients who had been managed with a prosthesis for unilateral proximal femoral focal deficiency underwent gait analysis; this group included 7 patients who had received an equinus prosthesis, 6 who had received a rotationplasty prosthesis, and 10 who had undergone Syme amputation and had received an above-the-knee prosthesis. Cadence parameters, kinematic and kinetic data, and oxygen consumption were measured, and the Gait Deviation Index (GDI) was calculated. Medical records and radiographs were reviewed. The Pediatric Outcomes Data Collection Instrument (PODCI) was completed by the child's parent. RESULTS: Patients underwent gait analysis at a mean age of 11.6 years (range, 4 to 19 years). Proximal femoral focal deficiency classification was not predictive of the chosen treatment. Patients in the rotationplasty group had undergone more procedures than those in the Syme amputation and equinus groups (mean, 3.3, 1.8, and 0.7 procedures, respectively) (p = 0.001). Oxygen cost did not differ between groups; however, all required greater energy expenditure than normal (170%, 144%, and 159%, in the equinus, rotationplasty, and Syme amputation groups, respectively) (p = 0.427). Likewise, hip power, abductor impulse, and GDI did not differ, but all groups had GDI scores >3 standard deviations below normative values. Patients in the equinus group walked faster (97% of normal for age) than those in the rotationplasty (84%) and Syme amputation groups (83%) (p = 0.018), whereas those in the Syme amputation group had superior knee range of motion (55° from the prosthetic knee) than those in the equinus (20°) and rotationplasty groups (15° generated from the ankle) (p = 0.003). There were no differences in terms of the PODCI subscales for pain, sport/physical function, happiness, or global function. Transfer/basic mobility improved with age (r = 0.516, p = 0.017), but no other associations were found between gait variables and PODCI scores. CONCLUSIONS: Rotationplasty provided no patient-reported benefit and no functional benefit in terms of gait parameters or oxygen consumption, despite requiring more surgical procedures compared with other prosthetic options. Patients with an equinus prosthesis walked the fastest, whereas treatment with a Syme amputation and prosthetic knee yielded equivalent gait parameters and oxygen consumption as compared with those for patients using an equinus prosthesis. These findings contradict those of previous reports that rotationplasty provides superior function over other proximal femoral focal deficiency prosthetic treatment options. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Complications: Second Victim.

INTRODUCTION: Physicians and surgeons in all specialties encounter and manage complications throughout their careers. Little attention has been given to a surgeon's emotional experience and reaction to the stresses of managing complications. METHODS: The author has reviewed relevant literature and added observations from 4 decades of experience with a pediatric orthopedic faculty. The author also reviewed the types of complications and principles of successful management of surgical complications. RESULTS AND DISCUSSION: A small number of published articles dealing with the issues of physician and surgeon responses to stressful occurrences were found. Proper management of complications will markedly reduce the stress upon the surgeon. Analysis of the complications with colleagues is essential to the reduction of feelings of guilt, and are useful in preventing future events. Discussions of the accompanying stress between the surgeon and colleagues, family, and occasionally counselors are helpful in achieving resolution and emotional healing. CONCLUSIONS: Greater attention to emotional stress issues affecting caregivers, and especially surgeons, is needed. This should happen at all levels of education from medical school through postgraduate training, and in the everyday practice of surgery. Research to clarify the effectiveness of various interventions is needed.

Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci.

Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.

A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females.

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10(-9)) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10(-10), OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). METHODS: Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. RESULTS: We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. CONCLUSIONS: Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.

Female patients with late-onset legg-calvé-perthes disease are frequently gymnasts: is there a mechanical etiology for this subset of patients?

BACKGROUND: The cause of Legg-Calvé-Perthes disease (LCPD) is unknown. We have observed a relatively high prevalence of female gymnasts presenting with LCPD. The purpose of this study was to determine: (1) the percentage of LCPD patients exposed to high-level gymnastics training, (2) the demographics of this subset of patients, and (3) their clinical outcomes. METHODS: Several adolescent female gymnasts presented to our clinic with recent-onset LCPD. We reviewed our cases to discern the prevalence and treatment of the disorder in this patient cohort. From 1999 to 2010, 572 patients were evaluated for a diagnosis of LCPD at our tertiary referral center. Clinical records were retrospectively reviewed. Of those, 13 patients had a history of gymnastics participation with 8 patients (all females) having competitive participation. RESULTS: For females aged 10 years and older presenting with LCPD, 7 of 9 patients (78%) were involved in high-level competitive gymnastics. These patients had disease onset between 10 and 12 years of age (mean, 11 y). Competitive gymnasts represented 6.6% (8 of 120) of females with LCPD and 1.4% (8 of 572) of all patients evaluated with LCPD during the study period. Only 1 of 111 females below 10 years with LCPD participated in competitive gymnastics (χ, P<0.0001).Patients underwent a variety of treatments. Two patients underwent nonoperative treatment, and the remainder underwent surgical management. All 7 gymnasts had a Stulberg IV result. In the nongymnast group of females 10 years and older, there were 1 Stulberg III result and 1 Stulberg IV result. CONCLUSIONS: At our center, competitive gymnasts comprise >75% of the female patients over the age of 10 who presented with late-onset LCPD. Results in general were poor. Further studies are needed to explore the association between the physical demands of advanced gymnastic training and the development of LCPD in this subset of patients. LEVEL OF EVIDENCE: IV, case series.

MR perfusion index as a quantitative method of evaluating epiphyseal perfusion in Legg-Calve-Perthes disease and correlation with short-term radiographic outcome: a preliminary study.

BACKGROUND: Current radiographic prognosticators of the outcome of Perthes disease can only be applied after femoral head deformity has occurred. Quantification of femoral head perfusion using the gadolinium-enhanced subtraction magnetic resonance imaging (MRI) technique may serve as an early prognosticator of outcome. The purposes of this study were 2-fold: (1) to develop a reliable method to quantify femoral head perfusion using this MRI technique; and (2) to determine whether the perfusion at early stages of Perthes disease correlates with radiographic deformity after a 2-year follow-up. METHODS: A total of 20 patients meeting the following inclusion criteria were studied: radiographs and MRI obtained of femoral heads predeformity, age between 5 and 13 years, and unilateral disease. MR perfusion index, a measure of perfusion in the epiphysis, was obtained using digital image analysis of subtraction gadolinium-enhanced MRI. Intraobserver and interobserver agreement of this index was assessed by 2 independent observers. MR perfusion index was correlated with a radiographic deformity index (a measure of femoral head deformity) obtained after a minimum of 2 years. RESULTS: The intraobserver agreement assessed by the intraclass correlation coefficient was 0.96 for observer 1 and 0.97 for observer 2. The interobserver agreement of the MR perfusion index was 0.90 for trials 1 and 2. MR perfusion index in the early stages of Perthes disease was highly variable, ranging from 0 to 0.70. After a minimum of 2 years following MRI acquisition, radiographs were obtained and evaluated using the deformity index, a continuous measure of femoral head deformity, by 2 blinded observers. Deformity index at 2-year follow-up showed moderate correlation with predeformity MR perfusion index (r=-0.56, P=0.01, R=0.31). In those patients who were treated nonoperatively, the correlation was stronger (r=-0.79, P=0.006, R=0.63). CONCLUSIONS: MR perfusion index obtained from gadolinium-enhanced subtraction MR images showed a high interobserver agreement. MR perfusion index is highly variable at early stages of Perthes disease, and a lower MR perfusion index correlated with greater radiographic deformity at the 2-year follow-up. This pilot study shows the promise of predeformity MR perfusion index as a possible early prognosticator of outcome in Perthes disease. LEVELS OF EVIDENCE: Prognostic level II.

Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10(-10); odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10(-14); OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.

A novel method for analyzing genetic association with longitudinal phenotypes.

Knowledge of genes influencing longitudinal patterns may offer information about predicting disease progression. We developed a systematic procedure for testing association between SNP genotypes and longitudinal phenotypes. We evaluated false positive rates and statistical power to localize genes for disease progression. We used genome-wide SNP data from the Framingham Heart Study. With longitudinal data from two real studies unrelated to Framingham, we estimated three trajectory curves from each study. We performed simulations by randomly selecting 500 individuals. In each simulation replicate, we assigned each individual to one of the three trajectory groups based on the underlying hypothesis (null or alternative), and generated corresponding longitudinal data. Individual Bayesian posterior probabilities (BPPs) for belonging to a specific trajectory curve were estimated. These BPPs were treated as a quantitative trait and tested (using the Wald test) for genome-wide association. Empirical false positive rates and power were calculated. Our method maintained the expected false positive rate for all simulation models. Also, our method achieved high empirical power for most simulations. Our work presents a method for disease progression gene mapping. This method is potentially clinically significant as it may allow doctors to predict disease progression based on genotype and determine treatment accordingly.

Pathophysiology, classifications, and natural history of Perthes disease.

Since the original reports of Legg-Calvé-Perthes disease (LCPD), much research effort has been undertaken to improve understanding of this idiopathic hip disorder. This article focuses on the current knowledge of the pathophysiology, classifications, and natural history of LCPD. Although the cause of LCPD remains largely unknown, some insight has been gained on its pathophysiology through experimental studies using animal models of ischemic necrosis. The few available clinical studies on the natural history of LCPD suggest that femoral head deformity is well tolerated in short and intermediate terms, but 50% of patients develop disabling arthritis in the sixth decade of life.