Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.

PhenoApt leverages clinical expertise to prioritize candidate genes via machine learning.

In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%-140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool.

Rare variant association analyses reveal the significant contribution of carbohydrate metabolic disturbance in severe adolescent idiopathic scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear. METHODS: Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS and 15 controls was served for validation. RESULTS: SLC16A8, a lactate transporter linked to retinal glucose metabolism, was identified as a novel severe AIS-associated gene (p=3.08E-06, false discovery rate=0.009). Most AIS cases with deleterious SLC16A8 variants demonstrated early onset high myopia preceding scoliosis. Pathway-based burden test also revealed a significant enrichment in multiple carbohydrate metabolism pathways, especially galactose metabolism. Patients with deleterious variants in these genes demonstrated a significantly larger spinal curve. Genes related to catabolic processes and nutrient response showed divergent expression between AIS cases and controls, reinforcing our genomic findings. CONCLUSION: This study uncovers the pivotal role of genetic variants in carbohydrate metabolism in the development of AIS, unveiling new insights into its aetiology and potential treatment.

Can the Sterilization Protocol Be Improved to Enhance the Healing of Allograft Tendons? An In Vivo Study in Rabbit Tendons.

BACKGROUND: Peracetic acid and irradiation are common sterilization methods for allograft tendons; however, under some conditions, both methods adversely affect the fiber arrangement and ultimate load of the tendon. An in vitro study showed that low-dose peracetic acid combined with irradiation may be less detrimental to allograft tendon structure and properties, possibly because the breakdown of peracetic acid can lead to an enlargement of the interstitial spaces and an increase in porosity. QUESTIONS/PURPOSES: Using a rabbit Achilles tendon model, we asked: What is the effect of peracetic acid-ethanol combined irradiation on (1) the histopathology and fiber diameter of the allograft tendon, (2) tensile creep and load-to-failure biomechanical properties of allograft tendons, and (3) healing of the treated tendon in vivo compared with fresh-frozen allograft and peracetic acid-ethanol sterilization at 4 and 8 weeks? METHODS: The Achilles tendons used in this study were sourced from euthanized 10-week-old male New Zealand White rabbits previously used for ophthalmic experiments. All allografts were divided into three groups: fresh-frozen group (control group, n = 20), peracetic acid-ethanol sterilization group (n =20), and peracetic acid-ethanol combined irradiation group (n = 20). The sterilization protocols were performed per a predetermined plan. In the peracetic acid-ethanol sterilization group, the tendon tissues were covered with the peracetic acid-ethanol sterilization solution (1% peracetic acid for 30 minutes). In the peracetic acid-ethanol combined irradiation group, the tendon tissues were covered with the peracetic acid-ethanol sterilization solution (0.2% peracetic acid for 30 minutes) and were subjected to 15 kGy gamma irradiation. Thirty 10-week-old male New Zealand White rabbits received bilateral Achilles tendon allografts surgically. Tendon samples from each group were harvested at 4 weeks (n = 30) and 8 weeks (n = 30) postoperatively. For each timepoint, eight tissues were used for histologic staining and electron microscopy, 15 tissues were used for biomechanical testing, and seven tissues were used for hydroxyproline assay and quantitative polymerase chain reaction. Histopathology was determined qualitatively by hematoxylin and eosin and Masson staining, while fiber diameter was measured quantitatively by transmission electron microscopy. Biomechanical properties were measured using cyclic loading tests and load-to-failure tests. The healing outcome was quantitatively judged through healing-related genes and proteins. RESULTS: At 4 weeks and 8 weeks postoperatively, the peracetic acid-ethanol combined irradiation group visually demonstrated the best continuity and minimal peripheral adhesions. Histologic staining showed that tendon fibers in the peracetic acid-ethanol combined irradiation group maintained consistent alignment without notable disruptions or discontinuities, and there was a qualitatively observed increase in the number of infiltrating cells compared with the control group at the 4-week timepoint (444 ± 49 /mm 2 versus 256 ± 43 /mm 2 , mean difference 188 /mm 2 [95% confidence interval 96 to 281]; p < 0.001). At 8 weeks postoperatively, the tendon fiber diameter in the peracetic acid-ethanol combined irradiation groups was similar to that of the control group (0.23 ± 0.04 µm versus 0.21 ± 0.03 µm, mean difference 0.02 µm [95% CI -0.04 to 0.08]; p = 0.56). At 8 weeks postoperatively, the peracetic acid-ethanol combined irradiation group exhibited better properties in terms of both ultimate load (129 ± 15 N versus 89 ± 20 N, mean difference 40 N [95% CI 7 to 73]; p = 0.02) and energy absorption density (17 ± 6 kJ/m 2 versus 8 ± 4 kJ/m 2 , mean difference 8 kJ/m 2 [95% CI 0.7 to 16]; p = 0.004) compared with the control group. Gene expression analysis revealed higher expression levels of COL1A1 (2.1 ± 0.8 versus 1.0 ± 0, mean difference 1.1 [95% CI 0.1 to 2.1]; p = 0.003) and MMP13 (2.0 ± 0.8 versus 1.0 ± 0, mean difference 1.0 [95% CI 0.4 to 1.6]; p = 0.03) in the peracetic acid-ethanol combined irradiation group than in the control group. There was a higher amount of collagen Type I in tendons treated with peracetic acid-ethanol combined irradiation than in the control group (0.36 ± 0.03 versus 0.31 ± 0.04, mean difference 0.05 [95% CI 0.01 to 0.09]; p = 0.02). CONCLUSION: Treatment with peracetic acid-ethanol combined irradiation did not have any discernible adverse effect on the histology, fiber diameter, enzymatic resistance, collagen content, or biomechanical strength of the allograft tendons compared with the control group. Peracetic acid-ethanol combined irradiation treatment had a positive impact on remodeling of the extracellular matrix and realignment of collagen fibers. CLINICAL RELEVANCE: This sterilization method could be helpful to expand the scope and frequency with which allogeneic materials are applied. The long-term healing effect and strength of allograft tendons must be tested before clinical use, and it is necessary to conduct comparative studies on autografts and synthetic materials that are currently widely used clinically.

Risk Factors of Wasting-Based Malnutrition in the Flood-Affected Areas of Pakistan: A Cross-Sectional Study.

The current study aimed to find the risk factors of wasting in flood-affected areas of Khyber Pakhtunkhwa, Pakistan. Sociodemographic and anthropometric data was collected. Children living in large family are 2.59 times more likely to be wasted (AOR = 2.59, 95% confidence interval (CI): 1.10, 6.10; p value = .029) and children living in medium size family are 2.23 times more likely to be wasted (AOR = 2.23, 95% CI: 1.03, 4.80; p value = .04) as compared to children in small family size. The study underscores the need for targeted interventions to address the identified risk factors and mitigate the impact of flooding on child nutrition.

Ten-year trends in surgical management of 1207 congenital scoliosis.

PURPOSE: To report and analyze development trends in the surgical treatment of congenital scoliosis (CS) in a large CS cohort over a 10-year period. METHODS: We retrospectively searched and extracted medical records of CS inpatients receiving posterior instrumented fusion surgery at our institute from January 2010 to December 2019. We analyzed information on demographics and surgical information, including the surgical approach, number of fused segments, use of osteotomy and titanium cage implantation, length of stay, intraoperative blood loss, and rates of complications and readmission. RESULTS: 1207 CS inpatients were included. In the past decade, the proportion of patients younger than 5 years increased from 15.5 to 26.9%. The average number of fused segments decreased from 9.24 to 7.48, and the proportion of patients treated with short-segment fusion increased from 13.4 to 30.3%. The proportion of patients treated with osteotomy and titanium cage implantation increased from 55.65% and 12.03% to 76.5% and 40.22%. The average length of stay and blood loss decreased from 16.5 days and 816.1 ml to 13.5 days and 501.7 ml. The complication and readmission rates also decreased during these ten years. CONCLUSION: During this ten-year period, the surgical treatment of CS at our institute showed trends toward a younger age at fusion, lower number of fused segments, higher rate of osteotomy and titanium cage implantation, reduced blood loss, shorter length of stay and lower rate complications and readmission. These results suggest performing osteotomy combined with titanium cage implantation at an earlier age can achieve fewer fused segments and complications.

Unsuspected severe tracheal stenosis and tracheomalacia after correction surgery for congenital scoliosis: A case report.

Tracheal stenosis and tracheomalacia in patients with congenital scoliosis are serious and rare conditions caused by congenital dysplasia, postintubation injury, trauma, and tracheal tumor. Anesthesia of a child with tracheal stenosis is challenging for anesthesiologists. We describe an 8-year-old female patient developed severe tracheal stenosis and tracheomalacia after growing rod implantation for congenital scoliosis. Comprehensive assessment of preoperative pulmonary function and airway morphology, which can be neglected clinically, should be performed in congenital scoliosis patients.

Correlation between supine flexibility and postoperative correction in adolescent idiopathic scoliosis.

BACKGROUND: The preoperative flexibility of the scoliotic spine is a key aspect of surgical planning, as it provides information on the rigidity of the curve, the extent of structural changes, the levels to be fused and the amount of correction. The purpose of this study was to assess whether supine flexibility can be used to predict postoperative correction in patients with adolescent idiopathic scoliosis (AIS) by determining the correlation between these two characteristics. METHODS: A total of 41 AIS patients who underwent surgical treatment between 2018 and 2020 were retrospectively enrolled for analysis. Preoperative and postoperative standing radiographs and preoperative CT images of the entire spine were collected and used to measure supine flexibility and the postoperative correction rate. T tests were used to analyse the differences in supine flexibility and postoperative correction rate between groups. Pearson's product-moment correlation analysis was performed, and regression models were established to determine the correlation between supine flexibility and postoperative correction. Thoracic curves and lumbar curves were analysed independently. RESULTS: Supine flexibility was found to be significantly lower than the correction rate but showed a strong correlation with the postoperative correction rate, with r values of 0.68 for the thoracic curve group and 0.76 for the lumbar curve group. The relationship between supine flexibility and postoperative correction rate could be expressed by linear regression models. CONCLUSION: Supine flexibility can be used to predict postoperative correction in AIS patients. In clinical practice, supine radiographs may be used in place of existing flexibility test techniques.

The incidence and interrelationship of hemivertebra and concomitant cardiac abnormalities in congenital scoliosis.

BACKGROUND: Congenital scoliosis(CS) is associated with multiple organs defect, and cardiac abnormalities have been reported commonly associated with CS. Hemivertebra is caused by the failure of vertebral formation, which is a major constitute of CS. Till now, few studies focus on the incidence and interrelationship of hemivertebra and concomitant cardiac abnormalities in congenital scoliosis. We aimed to analyze the cardiac defect in CS patients with or without hemivertebra, and further explore the incidence of cardiac defect between different types of hemivertebra. METHODS: The ultrasonic cardiography (UCG) results of surgically treated congenital scoliosis (CS) patients between 2015 and 2018 were retrospectively analyzed. Patients were divided into hemivertebra group and non-hemivertebra group according to preoperative CT. Patients with hemivertebra was further divided into sub-group by single/multiple or fully/partially/mixed segmented hemivertebra. Demographic information, radiographic data and cardiac abnormalities were statistically compared between groups. RESULTS: A total of 329 patients were analyzed, including 216 patients with hemivertebra and 113 patients without hemivertebra. UCG results were abnormal in 89 cases (27.1%), including 41 males(12.5%) and 48 females(14.6%). Hemivertebra group had comparable incidence of cardiac abnormalities with non-hemivertebra group (p = 0.517). No significant difference in the incidence of UCG abnormalities between single and multiple hemivertebra group (P = 0.246). Binary logistic regression analysis showed that female sex with multiple hemivertebra was a risk factor for abnormal UCG (P = 0.009, OR = 3.449). Cardiac abnormalities was comparable among fully, partially and mixed segmented hemivertebra group(P = 0.264). In abnormal UCG, 33 patients with hemivertebra had non-valvular abnormalities, and 48.5% (16/33) were septal defects. 28 patients had valvular abnormalities, most of them were mitral valve abnormalities, especially mitral valve redundancy, prolapse and insufficiency(82.1%, 23/28). No significant difference between the incidence of non-valvular and valvular abnormalities in patients with hemivertebra (P = 0.581). CONCLUSIONS: The incidence of abnormal UCG results was approximately 28.2% in CS patients with hemivertebra. Female patients with multiple hemivertebra had a higher risk of UCG abnormalities. Mitral valve abnormalities were the most common abnormality of UCG found in CS patients with hemivertebra. TRIAL REGISTRATION: retrospectively registered.

Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS).

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

A Review of the Methods on Cobb Angle Measurements for Spinal Curvature.

Scoliosis is a common disease of the spine and requires regular monitoring due to its progressive properties. A preferred indicator to assess scoliosis is by the Cobb angle, which is currently measured either manually by the relevant medical staff or semi-automatically, aided by a computer. These methods are not only labor-intensive but also vary in precision by the inter-observer and intra-observer. Therefore, a reliable and convenient method is urgently needed. With the development of computer vision and deep learning, it is possible to automatically calculate the Cobb angles by processing X-ray or CT/MR/US images. In this paper, the research progress of Cobb angle measurement in recent years is reviewed from the perspectives of computer vision and deep learning. By comparing the measurement effects of typical methods, their advantages and disadvantages are analyzed. Finally, the key issues and their development trends are also discussed.

Cross-sectional analysis of associated anomalies and vertebral anomaly location in 1289 surgical congenital scoliosis.

PURPOSE: This study systematically analyzed and assessed the interrelationships among vertebral anomaly location, congenital scoliosis (CS) type and associated abnormality prevalence. METHODS: We retrospectively extracted medical records of 1289 CS inpatients surgically treated in our institute from January 2010-December 2019. All patients underwent spinal X-ray, CT, MRI, echocardiogram, urogenital ultrasound and systemic physical examination. We analyzed information on demographics, CS type, associated anomalies and vertebral anomaly location. RESULTS: Cervical, thoracic and lumbar vertebral anomalies were found in 5.7%, 78.1% and 33.6% of patients, respectively. 82.7% had one region involved. 59.5% with cervical malformations had mixed defects and 61.1% with lumbar malformations exhibited failure of formation. The musculoskeletal defect prevalence was 28.4%, 19.1% and 9.0% in patients with cervical, thoracic and lumbar anomalies. The intraspinal defect prevalence was 33.4% and 20.7% for thoracic and lumbar anomalies. 86.5% of patients with cervical anomalies had more than one region involved, while 78.1% and 62.2% with thoracic and lumbar anomalies, respectively, had only one region involved. CONCLUSIONS: Cervical malformations had higher prevalence of mixed defects, musculoskeletal and intraspinal defects and multi-region involved. Thoracic malformations had higher prevalence of intraspinal and musculoskeletal defects and more involvement of only one vertebral region. Lumbar vertebral malformation patients had much lower prevalence of intraspinal and musculoskeletal defects and more involvement of only one vertebral region. Cervical malformation was a risk factor for more associated anomalies and more severe vertebral anomalies, which deserves more attention from surgeons in outpatient clinic.

Risk factors for blood transfusion in adolescent patients with scoliosis undergoing scoliosis surgery: a study of 722 cases in a single center.

BACKGROUND: To assess the risk factors for blood transfusion in a great number of adolescent cases with different types of scoliosis who received scoliosis surgery. METHODS: Data of patients who were diagnosed as scoliosis and received one-stage posterior correction and spinal fusion from January 2014 to December 2017 were prospectively collected and retrospectively analyzed. Patients' demographic characteristics, segments of spinal fusion, Cobb angle of the major curve,osteotomy pattern, preoperative and postoperative levels of hemoglobin, and allogeneic blood transfusion (ABT) were recorded and analyzed. RESULTS: In this study, 722 cases with adolescent scoliosis were included, of whom 32.8% (237/722) received ABT. Risk factors included diagnosis: neurofibromatosis (OR = 5.592), syndromic (OR = 3.029),osteotomy: Ponte osteotomy (OR = 5.997), hemivertebrae resection (OR = 29.171), pedicle subtraction osteotomy (PSO)(OR = 8.712), vertebral column resection (VCR)(OR = 32.265);fusion segments (OR = 1.224) and intraoperative blood loss (OR = 1.004). In the subgroup analysis of cases with idiopathic scoliosis, Ponte osteotomy (OR = 6.086), length of segments of spinal fusion (OR = 1.293), and intraoperative blood loss (OR = 1.001) were found as risk factors for ABT. Results of receiver operating characteristic (ROC) curve analysis revealed that length of segments of spinal fusion equal to 11.5 vertebrae was the best cutoff value for cases with idiopathic scoliosis who did not receive osteotomy in both ABT group and non-ABT group. In the subgroup analysis of congenital scoliosis, Ponte osteotomy (OR = 5.087), hemivertebra resection (OR = 5.457), PSO (OR = 4.055), VCR (OR = 6.940), and intraoperative blood loss (OR = 1.004) were risk factors for ABT. CONCLUSIONS: Method of diagnosis, osteotomy pattern, segments of spinal fusion, and intraoperative blood loss were risk factors for ABT in cases with adolescent scoliosis. In cases with idiopathic scoliosis, Ponte osteotomy and segments of spinal fusion longer than 11.5 vertebrae were risk factors for ABT. In cases with congenital scoliosis, osteotomy pattern was the main risk factor for ABT. LEVEL OF EVIDENCE: Level III.

Older fusion-surgery age in congenital scoliosis patients is a risk factor for extended length of stay, more estimated blood loss, longer fused segments and higher medical costs: a retrospective study.

BACKGROUND: Contradictory opinions about whether early correction and fusion surgeries should be performed for congenital scoliosis (CS) patients at a young age exist. The objectives of this study were to analyze the association between patient characteristics and fusion-surgery outcomes in CS patients treated with spinal correction and fusion surgeries and to report risk factors for extended length of stay (LOS), more estimated blood loss (EBL), longer fused segments and higher medical costs. METHODS: We analyzed data of 1,207 CS inpatients treated with fusion surgeries in our institute from January 2010 - December 2019. All patients underwent spinal X-ray, CT, MRI, echocardiogram and urogenital ultrasound. We analyzed demographic and clinical information and outcome measures, including LOS, EBL, fused segments and medical costs. RESULTS: Age at fusion (OR = 1.053; p < 0.001), musculoskeletal defects (OR = 1.670; p = 0.004) and thoracic deformity (OR = 1.519; p = 0.03) were risk factors for extended LOS. Age at fusion (OR = 1.117; p < 0.001), male sex (OR = 1.813; p < 0.001), mixed defects (OR = 1.662; p = 0.027) and failure of formation (OR = 1.718; p = 0.021) were risk factors for more EBL. Age at fusion (OR = 1.213; p < 0.001) was a risk factor for longer fused segments. Age at fusion (OR = 1.091; p < 0.001) and thoracic deformity (OR = 1.853; p = 0.004) were risk factors for higher medical costs. CONCLUSIONS: We found that older age at fusion in CS patients is a risk factor for extended LOS, more EBL, longer fused segments and higher medical costs with the risk increasing by 5-21 % for each year of age. Other identified risk factors include thoracic deformity for extended LOS; longer fused segments, higher medical costs, and musculoskeletal defects for extended LOS; and CS type (FF and MD) and sex (male) for more EBL.

The effect of pedicle subtraction osteotomy for the correction of severe Scheuermann thoracolumbar kyphosis on sagittal spinopelvic alignment.

PURPOSE: To analyze how pedicle subtraction osteotomy (PSO) treatment of severe Scheuermann thoracolumbar kyphosis (STLK) using pedicle screw instrumentation affects sagittal spinopelvic parameters. BACKGROUND: The medical literature on the post-surgical effects of treatments such as Ponte osteotomy is limited, but suggests few effects on spinopelvic profiles. Currently, there is no research regarding changes in sagittal spinopelvic alignment upon PSO treatment in STLK patients. METHODS: We performed a retrospective study on 11 patients with severe STLK. These patients underwent posterior-only correction surgeries with PSO and pedicle screw instrumentation between 2012 to 2017 in a single institute. Patients were measured for the following spinopelvic parameters: global kyphosis (GK), thoracic kyphosis (TK), thoracolumbar kyphosis (TL), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), pelvic tile (PT), sacral slope (SS), and administered a Scoliosis Research Society-22 questionnaire (SRS-22) pre-operation, post-operation and at final follow-up. RESULTS: GK improved from a median of 74.1° to 40.0° after surgery, achieving a correction rate of 48.8% with a median correction loss of 0.8°. TK, TL and LL all showed significant difference (P < 0.05) and SVA improved 22.7 (11.6, 30.9) mm post operation. No significant difference was found in pelvic parameters (PI, PT, SS, all P < 0.05). The absolute value of LL- PI significantly improved from a median of 26.5° pre-operation to 6.1° at the final follow-up. 72.7% in this series showed an evident trend of thoracic and lumbar apices migrating closer to ideal physiological segments after surgery. Self-reported scores of pain, self-image, and mental health from SRS-22 revealed significant improvement at final follow-up (all P < 0.05). CONCLUSIONS: PSO treatment of severe STLK with pedicle screw instrumentation can improve spine alignment and help obtain a proper alignment of the spine and the pelvis.

Factors and predictive model associated with perioperative complications after long fusion in the treatment of adult non-degenerative scoliosis.

INTRODUCTION: Adult non-degenerative scoliosis accounts for 90% of spinal deformities in young adults. However, perioperative complications and related risk factors of long posterior instrumentation and fusion for the treatment of adult non-degenerative scoliosis have not been adequately studied. METHODS: We evaluated clinical and radiographical results from 146 patients with adult non-degenerative scoliosis who underwent long posterior instrumentation and fusion. Preoperative clinical data, intraoperative variables, and perioperative radiographic parameters were collected to analyze the risk factors for perioperative complications. Potential and independent risk factors for perioperative complications were evaluated by univariate analysis and logistic regression analysis. RESULTS: One hundred forty-six adult non-degenerative scoliosis patients were included in our study. There were 23 perioperative complications for 21 (14.4%) patients, eight of which were cardiopulmonary complications, two of which were infection, six of which were neurological complications, three of which were gastrointestinal complications, and four of which were incision-related complication. The independent risk factors for development of total perioperative complications included change in Cobb angle (odds ratio [OR] = 1.085, 95% CI = 1.035 ~ 1.137, P = 0.001) and spinal osteotomy (OR = 3.565, 95% CI = 1.039 ~ 12.236, P = 0.043). The independent risk factor for minor perioperative complications is change in Cobb angle (OR = 1.092, 95% CI = 1.023 ~ 1.165, P = 0.008). The independent risk factors for major perioperative complications are spinal osteotomy (OR = 4.475, 95% CI = 1.960 ~ 20.861, P = 0.036) and change in Cobb angle (OR = 1.106, 95% CI = 1.035 ~ 1.182, P = 0.003). CONCLUSIONS: Our study indicate that change in Cobb angle and spinal osteotomy are independent risk factors for total perioperative complications after long-segment posterior instrumentation and fusion in adult non-degenerative scoliosis patients. Change in Cobb angle is an independent risk factor for minor perioperative complications. Change in Cobb angle and spinal osteotomy are independent risk factors for major perioperative complications.

Cross-sectional analysis and trend of vertebral and associated anomalies in Chinese congenital scoliosis population: a retrospective study of one thousand, two hundred and eighty nine surgical cases from 2010 to 2019.

PURPOSE: The objective of this article is to report associated anomaly incidences of a large CS cohort and analyze interrelationships among vertebral anomaly types and associated abnormalities. METHODS: We retrospectively searched and extracted medical records of 1289 CS inpatients surgically treated in our institute from January 2010 to December 2019. All patients have taken spine X-ray, CT, MRI, echocardiogram, urogenital ultrasound, and systemic physical examination. We analyzed information on demographics, CS types, and associated anomalies. RESULTS: CS type was found to be 49.1% for failure of formation (FF), 19.5% for failure of segmentation (FS), and 31.4% for mixed defects (MD). Intraspinal defects were found in 29.4% patients (16.0% for FF, 45.4% for FS, 40.5% for MD), cardiac in 13.7% (12.3% for FF, 14.3% for FS, 15.6% for MD), genitourinary in 5.8% (4.1% for FF, 6.0% for FS, 8.4% for MD), gastrointestinal in 3.6% (4.7% for FF, 1.6% for FS, 3.0% for MD), and musculoskeletal in 16.4% (10.3% for FF, 19.9% for FS, 23.7% for MD). The intraspinal and musculoskeletal defect incidences were significantly higher in patients with failure of segmentation and mixed defects. We also observed a decreasing trend for intraspinal and musculoskeletal defect incidences as well as a tendency for more failure of formation and less failure of segmentation from 2010 to 2019. CONCLUSIONS: The intraspinal and musculoskeletal defect incidences were higher in patients with failure of segmentation and mixed defects. Strong interrelationships were found between intraspinal and musculoskeletal defects and among cardiovascular, genitourinary, and gastrointestinal defects. From 2010 to 2019, the proportion of patients with failure of formation increased significantly, causing a decrease in the intraspinal and musculoskeletal defect incidences over time. Female sex, failure of segmentation, and mixed defects could be considered risk factors for more associated anomalies in CS individuals, which would help surgeons in medical management and prenatal consultation.

TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia.

BACKGROUND: Multiple epiphyseal dysplasia (MED) is a skeletal disorder characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. At least 66% of the reported autosomal dominant MED (AD-MED) cases are caused by COMP mutations. METHODS: We recruited a four-generation Chinese family with early-onset hip osteoarthritis, flatfoot, brachydactyly, and mild short stature. An assessment of the family history, detailed physical examinations, and radiographic evaluations were performed on the proband and other family members, followed by the performance of whole-exome sequencing (WES). The pathogenicity of the candidate mutation was also analyzed. RESULTS: An AD-MED family with 10 affected members and 17 unaffected members was recruited. The main radiographic findings were symmetrical changes in the dysplastic acetabulum and femoral heads, irregular contours of the epiphyses, a shortened femoral neck, and flatfoot. Lower bone density was also observed in the ankle joints, wrist joints, and knees, as well as irregular vertebral end plates. In the proband, we identified the missense mutation c.1153G > T (p. Asp385Tyr), located in exon 11 of the COMP gene. This mutation was assessed as 'pathogenic' because of its low allele frequency and its high likelihood of co-segregation with disease in the reported family. Sanger sequencing validated the novel heterozygous mutation c.1153G > T (p. Asp385Tyr) in exon 11 of COMP in all affected individuals in the family. CONCLUSIONS: Our results underlined a key role of the Asp385 amino acid in the protein function of COMP and confirmed the pathogenicity of the COMP (c.1153G > T; p. Asp385Tyr) mutation in AD-MED disease. We have therefore expanded the known mutational spectrum of COMP and revealed new phenotypic information for AD-MED.

Identification of novel FBN1 variations implicated in congenital scoliosis.

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.