[Show abstract][Hide abstract] ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS cases and 843 controls of European ancestry were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level then by Gene Ontology terms. Novel nonsynonymous/splice-site variants in extracellular matrix genes were significantly enriched in AIS cases compared to controls (P=6×10(-9), OR=1.7, CI=1.4-2.0). Specifically, novel variants in musculoskeletal collagen genes were present in 32% (126/391) of AIS cases compared to 17% (146/843) of in-house controls and 18% (780/4300) of EVS controls (P=1×10(-9), OR=1.9, CI=1.6-2.4). Targeted resequencing of six collagen genes replicated this association in combined 919 AIS cases (P=3x10(-12), OR=2.2, CI=1.8-2.7) and revealed a highly significant single-gene association with COL11A2 (P=6x10(-9), OR=3.8, CI=2.6-7.2). Importantly, AIS cases harbor mainly non-glycine missense mutations and lack the clinical features of monogenic musculoskeletal collagenopathies. Overall, our study reveals a complex genetic architecture of AIS in which a polygenic burden of rare variants across extracellular matrix genes contributes strongly to risk.
Human Molecular Genetics 11/2015; DOI:10.1093/hmg/ddv463 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Despite being recognized as the gold standard in isolated clubfoot treatment, the Ponseti casting method has yielded variable results. Few studies have directly compared common predictors of treatment failure between institutions with high versus low failure rates.
We asked: (1) is the provider's rigid adherence to the Ponseti method associated with a lower likelihood of unplanned clubfoot surgery, and (2) at the institution that did not adhere rigidly to Ponseti's principles, are any demographic or treatment-related factors associated with increased likelihood of unplanned clubfoot surgery?
After institutional review board approval, a consecutive series of patients with a diagnosis of isolated clubfoot who underwent treatment between January 2003 and December 2007 were identified. At Institution 1, 91 of 133 patients met the eligibility criteria and were followed for a minimum of 2 years compared with 58 of 58 patients at Institution 2. At Institution 1, 16 providers managed care using a conservative casting approach based on the Ponseti method. However, treatment was adapted by the provider(s). At Institution 2, one orthopaedic surgeon managed care with strict adherence to the Ponseti method. Surgical indications at both institutions included the presence of a persistent equinovarus foot position while standing. A chart review was used to collect data related to proportion of patients undergoing unplanned additional treatment for deformity recurrences after Ponseti casting, demographics, and treatment patterns.
The proportion of subjects who underwent unplanned major surgical intervention was greater (odds ratio [OR], 51.1; 95% CI, 6.8-384.0; p < 0.001) at Institution 1 (60 of 131, 47%) compared with Institution 2 (two of 91, 2%). There was no difference (p = 0.200) in the proportion of patients who underwent additional casting, repeat tendo Achilles lengthening, and/or anterior tibialis tendon transfer only (minor recurrence) at Institution 1 (nine of 131, 7%) compared with Institution 2 (11 of 91, 13%). At Institution 1, an increase in the number of revision casts (multiple vs no casts, hazard ratio [HR] = 3.9; 95% CI, 2.0-7.6; p < 0.001) and an increase in the number of cast-related complications (multiple vs no complications, HR = 2.8; 95% CI, 1.2-6.7; p = 0.019) were associated with increased risk of major surgery in the multivariate analysis.
Rigid commitment to the Ponseti method in the conservative treatment of patients with isolated clubfoot was associated with a lower risk of subsequent unplanned surgical intervention. In addition, clubfoot treatment programs that use a care model that prioritizes continuity in care and dedication to the Ponseti method may decrease the proportion of patients who undergo unplanned surgical intervention.
Level of evidence:
Level III, therapeutic study.
Clinical Orthopaedics and Related Research 09/2015; DOI:10.1007/s11999-015-4559-4 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Scoliosis is a feature of several genetic disorders that are also associated with aortic aneurysm, including Marfan syndrome, Loeys-Dietz syndrome, and type-IV Ehlers-Danlos syndrome. Life-threatening complications of aortic aneurysm can be decreased through early diagnosis. Genetic screening for mutations in populations at risk, such as patients with adolescent idiopathic scoliosis, may improve recognition of these disorders.
Methods: The coding regions of five clinically actionable genes associated with scoliosis (COL3A1, FBN1, TGFBR1, TGFBR2, and SMAD3) and aortic aneurysm were sequenced in 343 adolescent idiopathic scoliosis cases. Gene variants that had minor allele frequencies of <0.0001 or were present in human disease mutation databases were identified. Variants were classified as pathogenic, likely pathogenic, or variants of unknown significance.
Results: Pathogenic or likely pathogenic mutations were identified in 0.9% (three) of 343 adolescent idiopathic scoliosis cases. Two patients had pathogenic SMAD3 nonsense mutations consistent with type-III Loeys-Dietz syndrome and one patient had a pathogenic FBN1 mutation with subsequent confirmation of Marfan syndrome. Variants of unknown significance in COL3A1 and FBN1 were identified in 5.0% (seventeen) of 343 adolescent idiopathic scoliosis cases. Six FBN1 variants were previously reported in patients with Marfan syndrome, yet were considered variants of unknown significance based on the level of evidence. Variants of unknown significance occurred most frequently in FBN1 and were associated with greater curve severity, systemic features of Marfan syndrome, and joint hypermobility.
Conclusions: Clinically actionable pathogenic mutations in genes associated with adolescent idiopathic scoliosis and aortic aneurysm are rare in patients with adolescent idiopathic scoliosis who are not suspected of having these disorders, although variants of unknown significance are relatively common. Clinical
Relevance: Routine genetic screening of all patients with adolescent idiopathic scoliosis for mutations in clinically actionable aortic aneurysm disease genes is not recommended on the basis of the high frequency of variants of unknown significance. Clinical evaluation and family history should heighten indications for genetic referral and testing.
The Journal of Bone and Joint Surgery 04/2015; 97(97):1411-7. DOI:10.2106/JBJS.O.00290 · 5.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients ask two main questions when considering an orthopaedic reconstruction: (1) Does it work? And (2) will it last? We have devoted a great deal of space on the Editorial and Spotlight pages of Clinical Orthopaedics and Related Research® to the question of efficacy, and we have considered its importance in many areas.How big of a difference is a patient likely to detect ?Have we overlooked women as we design laboratory and clinical research studies ?And what is the difference between efficacy and safety?By comparison, the question of durability may have gotten short shrift. For decades now, our specialty—and our Journal—have relied on the now-ubiquitous Kaplan-Meier method of estimating survivorship . This approach is superior to crude survivorship calculations since the Kaplan-Meier estimator adjusts for patients whose status cannot be determined because they have not failed as of the end of the study, or because they have been lost to followup. Two generations (or mor ...
Clinical Orthopaedics and Related Research 02/2015; 473(4). DOI:10.1007/s11999-015-4182-4 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adolescent idiopathic scoliosis (AIS) is the most common form of structural spinal deformities that have a radiological lateral Cobb angle — a measure of spinal curvature — of ≥10o. AIS affects between 1% and 4% of adolescents in the early stages of puberty and is more common in young women than in young men. The condition occurs in otherwise healthy individuals and currently has no recognizable cause. In the past few decades, considerable progress has been made towards understanding the clinical patterns and the three-dimensional pathoanatomy of AIS. Advances in biomechanics and technology and their clinical application, supported by limited evidence-based research, have led to improvements in the safety and outcomes of surgical and non-surgical treatments. However, the definite aetiology and aetiopathogenetic mechanisms that underlie AIS are still unclear. Thus, at present, both the prevention of AIS and the treatment of its direct underlying cause are not possible.
[Show abstract][Hide abstract] ABSTRACT: Clubfoot treatment commonly fails and often results in impaired quality of life. An understanding of the soft-tissue abnormalities associated with both treatment-responsive and treatment-resistant clubfoot is important to improving the diagnosis of clubfoot, the prognosis for patients, and treatment.
The Journal of Bone and Joint Surgery 08/2014; 96(15):1249-1256. DOI:10.2106/JBJS.M.01257 · 5.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder that causes spinal deformity in approximately 3% of the population. Candidate gene, linkage, and genome-wide association studies have sought to identify genetic variation that predisposes individuals to AIS, but the genetic basis remains unclear. Copy number variants are associated with several isolated skeletal phenotypes, but their role in AIS, to our knowledge, has not been assessed. We determined the frequency of recurrent copy number rearrangements, chromosome aneuploidy, and rare copy number variants in patients with AIS. Between January 2010 and August 2014, we evaluated 150 patients with isolated AIS and spinal curvatures measuring 10A degrees or greater, and 148 agreed to participate. Genomic copy number analysis was performed on patients and 1079 control subjects using the Affymetrix(A (R)) Genome-wide Human SNP Array 6.0. After removing poor quality samples, 143 (97%) patients with AIS were evaluated for copy number variation. We identified a duplication of chromosome 1q21.1 in 2.1% (N = 3/143) of patients with AIS, which was enriched compared with 0.09% (N = 1/1079) of control subjects (p = 0.0057) and 0.07% (N = 6/8329) of a large published control cohort (p = 0.0004). Other notable findings include trisomy X, which was identified in 1.8% (N = 2/114) of female patients with AIS, and rearrangements of chromosome 15q11.2 and 16p11.2 that previously have been associated with spinal phenotypes. Finally, we report rare copy number variants that will be useful in future studies investigating candidate genes for AIS. Copy number variation and chromosomal aneuploidy may contribute to the pathogenesis of adolescent idiopathic scoliosis. Chromosomal microarray may reveal clinically useful abnormalities in some patients with AIS.
Clinical Orthopaedics and Related Research 07/2014; 472(10). DOI:10.1007/s11999-014-3766-8 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this report is to explore assessment and serial casting intervention for painful rigid flatfoot deformities with vertical talus in an adolescent girl with hereditary spastic paraplegia who was nonambulatory.
The participant's right foot underwent 2 phases of casting with correction first toward hindfoot inversion and then dorsiflexion. Because of a vertical talus, her left foot required an intermediate casting toward plantar flexion, inversion, and forefoot adduction prior to casting toward dorsiflexion.
The patient improved despite the underlying progressive neuromuscular disorder. Pain ameliorated and she returned to supported standing and transfers. Spasticity decreased bilaterally and the flexibility of her foot deformities improved to allow orthotic fabrication in subtalar neutral. Results were maintained at 12 and 16 months.
Individualized multiphase serial casting requires further investigation with patients such as those with hereditary spastic paraplegia.
Pediatric physical therapy: the official publication of the Section on Pediatrics of the American Physical Therapy Association 06/2014; 26(2):253-64. DOI:10.1097/PEP.0000000000000023 · 1.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. Despite a strong genetic basis, few genes
have been associated with AIS and the pathogenesis remains poorly understood. In a genome-wide rare variant burden analysis
using exome sequence data, we identified fibrillin-1 (FBN1) as the most significantly associated gene with AIS. Based on these results, FBN1 and a related gene, fibrillin-2 (FBN2), were sequenced in a total of 852 AIS cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10−4) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10−6). Scoliosis severity in AIS cases was associated with FBN1 and FBN2 rare variants (P = 0.0012) and replicated in an independent Han Chinese cohort (P = 0.0376), suggesting that rare variants may be useful as predictors of curve progression. Clinical evaluations revealed
that the majority of AIS cases with rare FBN1 variants do not meet diagnostic criteria for Marfan syndrome, though variants are associated with tall stature (P = 0.0035) and upregulation of the transforming growth factor beta pathway. Overall, these results expand our definition of
fibrillin-related disorders to include AIS and open up new strategies for diagnosing and treating severe AIS.
Human Molecular Genetics 05/2014; 23(19). DOI:10.1093/hmg/ddu224 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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).
Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts.
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.
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.
Journal of Medical Genetics 04/2014; 51(6). DOI:10.1136/jmedgenet-2013-102067 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clubfoot is a common congenital birth defect with complex inheritance patterns. Currently, the genetic and morphological basis of clubfoot is poorly understood. To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of common genetic variants.
The DNA of 396 isolated clubfoot patients and 1000 controls of European descent was genotyped for >600 000 single nucleotide polymorphisms (SNP) using the Affymetrix 6.0 array. Replication was performed with an independent cohort of 370 isolated clubfoot cases and 363 controls of European descent.
Strongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 between NCOR2 and ZNF664 (rs7969148, OR=0.58, p=1.25×10(-5)) that was significant on replication (combined OR=0.63, p=1.90×10(-7)). Additional suggestive SNPs were identified near FOXN3, SORCS1 and MMP7/TMEM123 that also confirmed on replication.
Our study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.
Journal of Medical Genetics 03/2014; 51(5). DOI:10.1136/jmedgenet-2014-102303 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The role of bracing in patients with adolescent idiopathic scoliosis who are at risk for curve progression and eventual surgery is controversial. Methods
We conducted a multicenter study that included patients with typical indications for bracing due to their age, skeletal immaturity, and degree of scoliosis. Both a randomized cohort and a preference cohort were enrolled. Of 242 patients included in the analysis, 116 were randomly assigned to bracing or observation, and 126 chose between bracing and observation. Patients in the bracing group were instructed to wear the brace at least 18 hours per day. The primary outcomes were curve progression to 50 degrees or more (treatment failure) and skeletal maturity without this degree of curve progression (treatment success). ResultsThe trial was stopped early owing to the efficacy of bracing. In an analysis that included both the randomized and preference cohorts, the rate of treatment success was 72% after bracing, as compared with 48% after observation (propensity-score-adjusted odds ratio for treatment success, 1.93; 95% confidence interval [CI], 1.08 to 3.46). In the intention-to-treat analysis, the rate of treatment success was 75% among patients randomly assigned to bracing, as compared with 42% among those randomly assigned to observation (odds ratio, 4.11; 95% CI, 1.85 to 9.16). There was a significant positive association between hours of brace wear and rate of treatment success (P<0.001). Conclusions
Bracing significantly decreased the progression of high-risk curves to the threshold for surgery in patients with adolescent idiopathic scoliosis. The benefit increased with longer hours of brace wear. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and others; BRAIST ClinicalTrials.gov number, NCT00448448.)
New England Journal of Medicine 09/2013; 369(16). DOI:10.1056/NEJMoa1307337 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Study Design. Descriptive.Objective. To describe the design and development of BrAIST.Summary of Background Data. Bracing has remained the standard of care for the non-operative treatment of adolescent idiopathic scoliosis (AIS) since the introduction of the Milwaukee brace in the late 1940s, but it has never been subjected to a rigorous evaluation of either its efficacy or its effectiveness. The Bracing in Adolescent Idiopathic Scoliosis Trial (BrAIST) was designed to address the primary question: Do braces (specifically a thoracolumbosacral orthosis, or TLSO) lower the risk of curve progression to a surgical threshold (≥50 degrees) in patients with AIS relative to watchful waiting alone?Methods. The authors describe the rationale for BRAIST, including the limitations of the current literature evaluating bracing for AIS. Second, the authors describe the preliminary work, including the preparation of the NIH clinical trials planning grant. Lastly, the authors describe the trial design in detail.Results. BrAIST was conducted in 25 sites in North America. Subjects were treated either with a TLSO or watchful waiting and followed every six months until they reached skeletal maturity or the surgical threshold of 50 degrees Cobb angle.Conclusions. Clinical decision making will be improved by translation of the BrAIST results into evidence-based prognosis and estimates of how the prognosis, specifically the risk of progressing to surgery, may be altered by the use of bracing.
[Show abstract][Hide abstract] ABSTRACT: Myosin binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome (LCCS4). Because MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of theses mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared to overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.
Human Molecular Genetics 07/2013; 22(24). DOI:10.1093/hmg/ddt344 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The authors’ current experience in the surgical treatment strategy of stable slipped capital femoral epiphysis deformities was reviewed. From this, a treatment algorithm was developed that could be utilized as a guide in the evaluation and treatment of future patients with slipped capital femoral epiphysis. The clinical parameters of patients’ histories of symptoms, physical examinations, and radiographic assessments of slip severity were used in formulating the algorithm. The intent was to prepare a comprehensive algorithm providing necessary alternate treatment pathways for the variable slip deformity in accordance with the surgical experience/expertise of the treating surgeon.