Lower extremity physeal fractures and post-traumatic surgical deformities; National Trauma Data Bank and institutional cohorts.

Background: Pediatric lower extremity physeal fractures carry a risk of developing deformities. Most epidemiological evidence is over 25 years old, single institution, and lacks follow-up, while recent studies report variable results. Understanding their epidemiology and deformity risk is important for patient counseling and follow-up. Methods: The National Trauma Data Bank (NTDB) from 2016 was queried to describe the modern epidemiology of physeal fractures. This was contrasted with our 10-year experience of surgically treated deformities. Basic descriptive statistics, Chi-square analysis, prevalence ratios and multivariable linear regression were used to interpret results. Results: The NTDB contained 22,048 non-physeal and 1,929 physeal fractures of the femur, tibia, and fibula. Physeal fracture prevalence rose after 8 years of age but decreased for girls 2 years sooner than boys. Salter Harris (SH) type 2 fractures predominated. Physeal fractures were more commonly associated with lower energy mechanisms of injury. Distal tibia fractures were more prevalent in the NTDB cohort, while distal femur and SH-1 fractures were more prevalent in the operative cohort. Over 10 years, only 52 (5.3%) of the deformity-correcting surgeries at our institution were for physeal fracture sequelae. Age at injury and intraarticular fractures were associated with shorter times from injury to deformity correction. Conclusion: Lower extremity physeal fractures are uncommon. Fracture pattern prevalence differs from an operative cohort. Proximal tibia physeal fractures appear to be an underappreciated source of deformity. The risk of developing deformity requiring operative intervention appears to be low and is generally treated within 2 years of initial injury.

GLP-1 receptor agonists and cardiovascular outcomes in patients with type 2 diabetes: Clinical evidence and best practice.

ABSTRACT: Cardiovascular disease (CVD) is a major cause of death and disability among people with type 2 diabetes (T2D), presenting a significant impact on longevity, patient quality of life, and health care costs. In the United States, attainment of recommended glycemic targets is low and T2D-related cardiovascular complications remain a significant burden. Many glucose-lowering treatment options are available, but glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are recommended in recent guidelines as the preferred add-on therapy to metformin to improve glycemic control. This is particularly the case for patients with T2D and established atherosclerotic CVD, at high risk of atherosclerotic CVD, and/or with chronic kidney disease. Recommendations were based on GLP-1RA and SGLT-2 inhibitor cardiovascular outcomes trials (CVOTs), which consistently showed that these agents pose no additional cardiovascular risk compared with placebo. Three GLP-1RAs (liraglutide, dulaglutide, and subcutaneous semaglutide) demonstrated significantly lower major adverse cardiovascular events versus placebo and are now approved for this indication. However, to realize improvement in outcomes in the clinical setting, organized, systematic, and coordinated approaches to patient management are also needed. For example, nurse-led diabetes self-management education and support programs have been shown to be effective. This article explores T2D management with emphasis on cardiovascular risk and CVOTs performed to date and reviews the clinical experience with GLP-1RAs for managing hyperglycemia and their impact on cardiovascular risk. In addition, practical guidance is given for key health care providers involved in the care of patients with T2D with cardiovascular risk outside of diabetes clinics/endocrinology centers.

Twelve-week standard of care protocol longer than median time to normalization among IIc hips treated with Pavlik harness.

Best treatment protocols for infants with developmental dysplasia of the hip (DDH) are poorly defined. This study estimates the time to normalization among Graf IIc hips undergoing Pavlik harness treatment. Following institutional review board approval, patients referred for DDH evaluation at a pediatric institution between 2009 and 2018 (n = 1424 hips/712 patients) were identified. We isolated all Graf IIc hips that underwent Pavlik harness treatment (n = 132 hips/n = 106 patients). Demographic and outcome measures were collected. Normalization was defined as alpha angle greater than or equal to 60° and femoral head coverage greater than or equal to 50%. Kaplan-Meier and Cox proportional hazards regression analyses modeled time to normalization and identified factors associated with earlier normalization. Median time to normalization was 7.0 weeks. At 12 weeks standard treatment, 85.8% [95% confidence interval (CI): 80.2-91.9%] had normalized. Greater femoral head coverage [hazard ratio (HR) per 1% increase: 1.03; 95% CI: 1.01-1.05; P = 0.0068] and hip stability at treatment initiation (HR unstable vs. stable: 0.64; 95% CI: 0.44-0.93; P = 0.0192) were associated with longer time to normalization. Some patients may not need 12 weeks of Pavlik bracing, particularly those with stable presentation who normalize before week 12. Shorter treatment lengths offer benefit without sacrificing long-term outcomes. Findings reinforce growing evidence that femoral head coverage should be a more significant consideration during diagnosis and instability is a concerning finding on examination.

Fassier-Duval Rod Failure: Is It Related to Positioning in the Distal Epiphysis?

BACKGROUND: The relationship between Fassier-Duval (FD) rod placement and rod failure rates has not previously been quantified. METHODS: Retrospective review was conducted on patients with osteogenesis imperfecta treated with FD rods between 2005 and 2017. Age at first surgery, sex, Sillence type of osteogenesis imperfecta, bisphosphonate treatment, location of rod (side of body and specific bone), and dates of surgeries, radiographs, and rod failures were collected. C-arm images determined rod fixation within the distal epiphysis at the time of surgery. C-arm variables included rod deviation (percent deviation from the midline of the distal epiphysis) and anatomical direction of deviation (anterior/posterior and medial/lateral). X-ray images were examined for rod failure, which was defined as bending, pulling out of the physis, protrusion out of the bone, and/or failure to telescope. Cox proportional hazards regression models were used to compare failure rates with location of placement within the distal epiphysis allowing for clustering of the data by side (left or right) and bone (femur or tibia). RESULTS: The cohort was 13 patients (11 female individuals and 2 male individuals) with a total of 66 rods and 75 surgeries. Mean time from the first surgery to the last follow-up visit was 8.9 years (SD=5 y). There was a 7% increase in hazard of failure per 1-mm increase in antero-posterior (AP) deviation [hazard ratio (HR), 1.07; 95% confidence interval (CI), 1.01-1.14; P=0.029)]. Similarly, there was a 9% increase in hazard of failure for every 1-mm increase in lateral deviation (HR, 1.09; 95% CI, 1.01-1.18; P=0.019). A 12% increase in hazard of failure per 10% increase in deviation from the midline for both AP and lateral radiograph views was also found, although this was only statistically significant for lateral deviation on the AP radiograph view (HR, 1.12; 95% CI, 1.01-1.25; P=0.030). CONCLUSIONS: FD rod placement within the distal epiphysis has significant impact on increasing rod survival. LEVEL OF EVIDENCE: Level III-therapeutic study.

Fassier-Duval Rods are Associated With Superior Probability of Survival Compared With Static Implants in a Cohort of Children With Osteogenesis Imperfecta Deformities.

BACKGROUND: The survival of Fassier-Duval (FD) telescoping rods as compared with static implants in children affected by osteogenesis imperfecta is not well characterized. The purpose of this study was to compare risk of lower extremity implant failure in FD rods versus static implants. METHODS: Data were retrospectively collected from patients with osteogenesis imperfecta who underwent surgical treatment using either FD rods or static implants (Rush rods, flexible nails, or Steinmann pins) between 1995 and 2015. The timing of implant failure was the primary outcome variable of interest. Comparisons were limited to limbs with no previous history of implants. Cox-proportional hazards regression analyses were used to compare the hazard of implant failure across implants. Negative binomial regression analyses were used to compare the incidence of surgical procedures in the 2 implant groups. RESULTS: The final cohort consisted of 64 limbs (n=21 patients). The static implant group (n=38) consisted of 24 Rush rods (63%), 14 flexible nails (37%), and 2 Steinmann pins (5%). The hazard of implant failure in the static implant group was 13.2 times [95% confidence interval (CI), 2.5-69.6; P=0.0024] the hazard of implant failure in the FD rod group. The hazard of implant failure among females was 4.8 (95% CI, 1.4-16.7; P=0.0125) times the hazard of implant failure among males. The total surgery rate in the static implant group was 7.8 (95% CI, 1.8-33.0; P=0.0056) times the total surgery rate in the FD group. CONCLUSIONS: Among surgically naive limbs, FD rods were associated with significantly improved probability of survival compared with static implants. LEVEL OF EVIDENCE: Level II-retrospective study.

A missense variant in SLC39A8 is associated with severe idiopathic scoliosis.

Genetic factors predictive of severe adolescent idiopathic scoliosis (AIS) are largely unknown. To identify genetic variation associated with severe AIS, we performed an exome-wide association study of 457 severe AIS cases and 987 controls. We find a missense SNP in SLC39A8 (p.Ala391Thr, rs13107325) associated with severe AIS (P = 1.60 × 10-7, OR = 2.01, CI = 1.54-2.62). This pleiotropic SNP was previously associated with BMI, blood pressure, cholesterol, and blood manganese level. We replicate the association in a second cohort (841 cases and 1095 controls) resulting in a combined P = 7.02 × 10-14, OR = 1.94, CI = 1.63-2.34. Clinically, the minor allele of rs13107325 is associated with greater spinal curvature, decreased height, increased BMI and lower plasma manganese in our AIS cohort. Functional studies demonstrate reduced manganese influx mediated by the SLC39A8 p.Ala391Thr variant and vertebral abnormalities, impaired growth, and decreased motor activity in slc39a8 mutant zebrafish. Our results suggest the possibility that scoliosis may be amenable to dietary intervention.

Osteosarcoma in an Adolescent with Kniest Dysplasia: A Case Report.

CASE: A 19-year-old adolescent with Kniest dysplasia was incidentally found to have osteosarcoma of the proximal aspect of the humerus after having a chest radiograph for evaluation of an upper respiratory infection. He underwent chemotherapy and resection of the tumor, and there was no evidence of metastasis at the 16-month follow-up. CONCLUSION: Patients with osteochondrodysplasias often have multiple orthopaedic symptoms. Changes in chronic pain symptoms should be investigated to rule out insidious secondary causes of musculoskeletal pain, such as osteosarcoma.

Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology.

Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.

Prevalence of Persistent Median Arteries in the Pediatric Population on Ultrasonography.

OBJECTIVES: To use real-time ultrasonography to estimate the prevalence of persistent median arteries in a cohort of pediatric orthopedic patients. METHODS: With Institutional Review Board approval, patients between the ages of 3 months and 19 years were recruited for this cross-sectional study. Variables of interest included demographics, underlying diagnoses, and the presence of a Doppler-confirmed median artery. Ultrasonographic examinations were performed on both upper extremities by a single investigator. Patient- and limb-level analyses were performed. A multivariable generalized logistic regression analysis was used to test the association between the prevalence of limb-specific persistent median arteries and age. A generalized estimating equation was used to adjust for the inclusion of multiple limbs from the same patient. RESULTS: A total of 135 patients (270 limbs) were evaluated. The patient-specific prevalence rate (persistent median arteries present in 1 or both limbs) was 26.7%. Among these patients (n = 36), a persistent median artery was present bilaterally in 55.6% (n = 20). The limb-specific prevalence rate (proportion of limbs with a persistent median artery) was 20.7%. After adjusting for race, for every 1-year increase in age, the odds of a persistent median artery decreased by 4.4%. After adjusting for age, African Americans were significantly more likely to present with a persistent median artery (odds ratio, 3.78; 95% confidence interval, 1.25-11.48). CONCLUSIONS: Ultrasonography can effectively visualize anatomic variants, such as persistent median arteries, in the pediatric population. The prevalence of persistent median arteries was higher than anticipated, especially among African American patients.

Clinical and Radiographic Outcomes After Submuscular Plating (SMP) of Pediatric Femoral Shaft Fractures.

BACKGROUND: To evaluate lower extremity strength and alignment among children who underwent submuscular plating (SMP). METHODS: Subjects who underwent SMP for a length unstable femoral fracture returned for isokinetic strength testing ≥2 years after surgery. Extensor and flexor strength deficits (percent difference) between the operative and nonoperative limbs were evaluated. Radiographic measurements of mechanical alignment [anatomic lateral distal femoral angle (aLDFA)] and qualitative measurements (The Pediatric Outcomes Data Collection Instrument, PODCI) were obtained from all subjects. The upper 97.5% confidence interval approach to establishing clinical equivalency was utilized to compare differences in strength and alignment between the operative and nonoperative limbs. An extensor strength deficit of >19% and an aLDFA discrepancy of >5 degrees were considered to be clinically significant. RESULTS: The average age at surgery of the 10 subjects included in the study was 8.7 years. The hardware was placed an average of 27.9 mm from the distal femoral physis and was removed 6.4 months postsurgery. Among all subjects, the median PODCI scores were ≥97 according to all subscales. There was no significant difference in extension torque between the operative versus nonoperative limbs at 60 degrees/s (P=0.5400), 120 degrees/s (P=0.4214), or 180 degrees/s (P=0.8166). More importantly, extension strength deficits between the operative and nonoperative limbs were not clinically significant at 60 degrees/s [upper 97.5% confidence interval (CI), 10.9%], 120 degrees/s (upper 97.5% CI, 11.0%), or 180 degrees/s (upper 97.5% CI, 10.7%). The difference in aLDFA between the operative and nonoperative limb was less than the predefined clinically significant threshold of 5 degrees for all subjects. CONCLUSIONS: SMP achieves satisfactory clinical and functional results. In this series, extensor strength deficits and/or lower extremity malalignment were not clinically meaningful. High patient satisfaction can be expected after implant removal. LEVEL OF EVIDENCE: Level IV-case series.

Outcomes of Isolated Varus Derotational Osteotomy in Children With Cerebral Palsy Hip Dysplasia and Predictors of Resubluxation.

BACKGROUND: The appropriate intervention for hip subluxation or dislocation in children affected by cerebral palsy (CP) remains controversial. The purpose of this retrospective study was to report radiographic and clinical outcomes following isolated femoral varus derotational osteotomy (VDRO) in children with CP hip dysplasia. Risk factors for resubluxation and avascular necrosis (AVN) were also examined. METHODS: A cohort of 100 patients (199 hips) with CP treated with isolated VDRO between 2003 and 2009 was reviewed. All but 1 patient received bilateral surgery. Patients were followed for an average of 5.4 years (range, 1.03 to 10.20 y). Anteroposterior pelvic radiographs were used to assess migration percentage (MP), Shenton's line, and presence of AVN. Resubluxation was defined as a postoperative break in Shenton's line. Radiographic outcomes and risk analysis was performed in the 91 subjects (179 hips) with radiographic follow-up >1 year. RESULTS: Significant improvement was observed in MP, and all hips had a reconstituted Shenton's line following surgery. Over the course of follow-up, 16% of hips were noted to have a repeat break in Shenton's line. Univariate risk analysis showed preoperative MP, Gross Motor Function Classification System (GMFCS) level, and age at surgery were risk factors for a recurrent line break. Preoperative MP and GMFCS level were found to be predictors of resubluxation in multivariate analysis. AVN was detected in 10 hips (5.7%). GMFCS level V patients were more at risk for resubluxation, but less at risk for AVN when compared with ambulatory (GMFCS I/II/II) patients and GMFCS level IV patients. CONCLUSIONS: Performing a VDRO without additional procedures provided a stable and concentrically reduced hip joint in this population of children with CP. Attention should be paid to initial ambulatory status during the postoperative period. Concomitant procedures such as pelvic osteotomy should be considered for patients of GMFCS level IV and V, as these patients were more at risk for recurrent subluxation. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

POSTURAL STABILITY AND KINETIC CHANGE IN SUBJECTS WITH PATELLOFEMORAL PAIN AFTER A NINE-WEEK HIP AND CORE STRENGTHENING INTERVENTION.

BACKGROUND: Idiopathic patellofemoral pain (PFP) has been linked to hip weakness and abnormal lower extremity mechanics. The effect of a strengthening intervention on balance has not been well studied among individuals with PFP. HYPOTHESIS/PURPOSE: The primary aim of this study was to evaluate changes in center of pressure displacement during the single limb squat following a nine-week physical therapy intervention among adolescent females with PFP. STUDY DESIGN: Interventional and cross-sectional. METHODS: Seven adolescent females with PFP (10 extremities) were included in the study. Center of Pressure (CoP) excursions during a single limb squat task were measured before and after a nine week of physical therapy intervention focused on strengthening of the hip and core. Seven asymptomatic females were matched to the PFP group on the basis of age and activity level, and were tested as a reference group. CoP trajectories were reduced into four variables: mean distance (MDIST), root-mean-square distance (RDIST), range (RANGE), and 95% confidence interval circle area (AREA-CC). Maximum knee flexion angle, peak knee power generation and absorption were also recorded. Linear mixed models were used to test for within and between group differences in CoP metrics. RESULTS: Pre-intervention, CoP range, knee power absorption and generation were significantly decreased in the PFP group relative to the reference group. Post-intervention, the PFP group reported a significant decrease in symptom severity. There was also a significant (p<0.05) increase in MDIST, RDIST, RANGE, AREA-CC, peak knee flexion angle, peak power absorption and power generation. There was no difference (p>0.05) in knee flexion, knee power or CoP displacement between the two groups after the physical therapy intervention. CONCLUSION: Hip and core-strengthening resulted in a significant decrease in symptom severity as well as significant reductions in CoP displacement. LEVEL OF EVIDENCE: 3.

Standardized Note Templates Improve Electronic Medical Record Documentation of Neurovascular Examinations for Pediatric Supracondylar Humeral Fractures.

BACKGROUND: Optimization of the electronic medical record (EMR) is essential to support the clinician and to improve the quality and efficiency of patient care. The present report describes the development and implementation of a standardized template that is embedded in the EMR and is focused on a comprehensive physical examination during the evaluation of pediatric supracondylar humeral fractures. We compared the completeness of physical examinations as well as the timing of detection and documentation of neurovascular injuries before and after implementation of the template. We hypothesized that the use of a template would increase the completeness of examinations and would lead to earlier documentation of neurovascular injuries. METHODS: A multidisciplinary quality-improvement task force was created to address neurovascular documentation practices for patients who underwent operative treatment of supracondylar humeral fractures. Following a series of formative and process evaluations, a standardized EMR template was implemented. Neurovascular examination documentation practices that were in use before (pre-template group, n = 224) and after (template group, n = 300) the implementation of the template were compared. Logistic regression analyses of the 2 groups were used to compare the likelihood of a complete neurovascular examination and the timing of neurovascular injury identification. RESULTS: There was significant improvement in the documentation of the vascular (odds ratio [OR], 70.7; 95% confidence interval [CI], 39.5 to 126.6; p < 0.0001), motor (OR, 17.6; 95% CI, 9.5 to 32.7; p < 0.0001), and sensory (OR, 23.9; 95% CI, 12.9 to 44.4; p < 0.0001) examinations in the template group. Neurological injuries were more likely to be identified preoperatively in the template group compared with the pre-template group (OR, 6.8; 95% CI, 1.7 to 27.1; p = 0.0067). CONCLUSIONS: The incorporation of a standardized template in the EMR improved the completeness and timing of documentation of neurological injury. Standardized EMR templates developed by a clinically driven multidisciplinary task force have the potential to improve the quality of clinical documentation and to ease communication among providers. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

Evaluation of IRX Genes and Conserved Noncoding Elements in a Region on 5p13.3 Linked to Families with Familial Idiopathic Scoliosis and Kyphosis.

Because of genetic heterogeneity present in idiopathic scoliosis, we previously defined clinical subsets (a priori) from a sample of families with idiopathic scoliosis to find genes involved with spinal curvature. Previous genome-wide linkage analysis of seven families with at least two individuals with kyphoscoliosis found linkage (P-value = 0.002) in a 3.5-Mb region on 5p13.3 containing only three known genes, IRX1, IRX2, and IRX4 In this study, the exons of IRX1, IRX2, and IRX4, the conserved noncoding elements in the region, and the exons of a nonprotein coding RNA, LOC285577, were sequenced. No functional sequence variants were identified. An intrafamilial test of association found several associated noncoding single nucleotide variants. The strongest association was with rs12517904 (P = 0.00004), located 6.5 kb downstream from IRX1 In one family, the genotypes of nine variants differed from the reference allele in all individuals with kyphoscoliosis, and two of three individuals with scoliosis, but did not differ from the reference allele in all other genotyped individuals. One of these variants, rs117273909, was located in a conserved noncoding region that functions as an enhancer in mice. To test whether the variant allele at rs117273909 had an effect on enhancer activity, zebrafish transgenesis was performed with overlapping fragments of 198 and 687 bp containing either the wild type or the variant allele. Our data suggests that this region acts as a regulatory element; however, its size and target gene(s) need to be identified to determine its role in idiopathic scoliosis.

Posterolaterally displaced and flexion-type supracondylar fractures are associated with a higher risk of open reduction.

To identify factors predictive of the risk of conversion from closed to open reduction. International Classification of Disease-9 codes were used to identify completely displaced pediatric supracondylar humerus fractures that were subjected to planned closed reduction and percutaneous pinning. Clinical and radiographic variables were retrospectively collected. Compared with posterior extension fractures, flexion (risk ratio: 34.1, 95% confidence interval: 8.1-143.6, P<0.0001) and posterolateral extension (risk ratio: 6.0, 95% confidence interval: 1.3-27.5, P=0.0221) fractures were significantly more likely to undergo conversion from closed to open reduction. The direction of displacement should be considered during the preoperative evaluation of supracondylar fractures.

Does Strict Adherence to the Ponseti Method Improve Isolated Clubfoot Treatment Outcomes? A Two-institution Review.

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. QUESTIONS/PURPOSES: 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? METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis.

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 non-synonymous/splice-site variants in extracellular matrix genes were significantly enriched in AIS cases compared with 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 with 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 = 3 × 10(-12), OR = 2.2, CI = 1.8-2.7) and revealed a highly significant single-gene association with COL11A2 (P = 6 × 10(-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.

Incidence of Deep Vein Thrombosis and Pulmonary Embolism in the Elective Pediatric Orthopaedic Patient.

BACKGROUND: Although venous thromboembolism (VTE) has been well studied in the pediatric trauma population, rates of VTE associated with elective pediatric orthopaedic procedures have not been addressed in current literature. The purpose of this retrospective study was to identify the incidence of VTE in the elective pediatric orthopaedic surgical population and delineate subsets of this population at greatest risk. This study may provide valuable data to begin the process of resolving the controversy surrounding deep vein thrombosis prophylaxis in the pediatric orthopaedic population. METHODS: The Pediatric Health Information System was queried for patients admitted on an ambulatory or inpatient basis, aged below 18 years, from January 2006 to March 2011 during which an elective orthopaedic surgery was the principal procedure performed. Patients with diagnoses or procedures related to infection, trauma, malignancy, or coagulopathies were excluded. Patients admitted through the emergency department or whose orthopaedic procedure was not performed on the admission date were excluded. Age, sex, ethnicity, race, admission year, and all procedures/diagnoses were recorded. The presence of VTE at the index admission or any subsequent readmission within 90 days was recorded. All criteria were coded using ICD-9-CM codes. Generalized logistic regression analyses were used to identify factors related to VTE. RESULTS: A total of 143,808 admissions (117,676 patients) matched the inclusion criteria. Thirty-three had a VTE during the index admission with an additional 41 at subsequent readmissions, for a total incidence of 0.0515% by admission and 0.0629% by patient. In the multivariable model, variables significantly (P<0.05) related to VTE included increasing age, admission type, diagnosis of metabolic conditions, obesity, and/or syndromes, and complications of implanted devices and/or surgical procedures. No procedure variables were significantly related to VTE in the multivariable model. CONCLUSIONS: The incidence of VTE in this cohort of pediatric patients undergoing elective orthopaedic surgery was 0.0515%. In children, underlying diagnosis seems to be a stronger predictor of VTE than procedures performed. Diagnosis with a metabolic condition, syndrome, and/or obesity, complications of implanted devices and/or surgical procedures, older age, and admission as an inpatient were significantly related to the development of a VTE. LEVEL OF EVIDENCE: Level IV­case series.

Sequencing of the TBX6 Gene in Families with Familial Idiopathic Scoliosis.

STUDY DESIGN: A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the TBX6 gene and Familial Idiopathic Scoliosis (FIS). OBJECTIVE: To determine if variants within exons of the TBX6 gene segregate with the FIS phenotype within a sample of families with FIS. SUMMARY OF BACKGROUND DATA: Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The TBX6 gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the TBX6 gene. METHODS: Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the TBX6 gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p. RESULTS: Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the TBX6 variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element. CONCLUSIONS: Although this study did not identify any TBX6 coding variants that segregate with FIS, we identified a variant that is located in a potential TBX6 enhancer element. Therefore, further investigation of the region is needed.

Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis.

Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype.