Association between genetic polymorphisms and risk of adolescent idiopathic scoliosis in case-control studies: a systematic review.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a structural lateral spinal curvature of ≥10° with rotation. Approximately 2%-3% of children across populations are affected with AIS, and this condition is responsible for ~$3 billion in costs within the USA. Although AIS is believed to have a strong genetic contribution, clinical translation of identified genetic variants has stalled. METHODS: The databases MEDLINE (via PubMed), Embase, Google Scholar and Ovid MEDLINE were searched and limited to articles in English. Title and abstract, full-text and data extraction screening was conducted through Covidence, followed by data transfer to a custom REDCap database. Studies containing variant-level data using genome-wide methodology as well as validation studies of genome-wide methods were considered. Quality assessment was conducted using Q-Genie. RESULTS: 33 studies were included, including 9 genome-wide association studies, 4 whole exome sequencing and 20 validation studies. Combined, these studies included data from >35,000 cases and >67,000 controls, not including validation cohorts. Additionally, results from six meta-analyses containing novel cohorts were also reported. All included study cohorts were from populations of primarily East Asian or Caucasian descent. Quality assessment found that overall study quality was high and control group selection was moderate. The highest number of reported associations were in single nucleotide polymorphisms (SNPs) in or near LBX1, LBX1-AS1, GPR126/ADGRG6 or BNC2. CONCLUSION: AIS risk may be influenced by specific SNPs, particularly those in/near LBX1 and GPR126. Translatability of study findings is unknown due to an underrepresentation of most ethnic groups as well as few identified genome-wide studies. Further studies may benefit from increased cohort diversity and thorough evaluation of control cohort groups.

Prediction of Late Dysplasia Based on Ultrasound and Plain X-Ray at 6 Months.

BACKGROUND: Developmental dysplasia of the hip represents a spectrum of deformity. Residual dysplasia at 2 years of age is associated with an increased risk for osteoarthritis and functional limitations. We compared the prognostic value of 6-month imaging modalities and aimed to identify optimal diagnostic metrics for the prediction of residual dysplasia. METHODS: After IRB approval, patients who underwent Pavlik treatment between 2009 and 2018 with 2-year follow-up were identified. Sonographs [ultrasound (US)] and radiographs (x-ray) were obtained at 6-month and 2-year-old visits. Dysplasia at 2 years was defined as an acetabular index (AI) >24 degrees. Receiver operating characteristic curves were constructed to quantitatively compare the prognostic ability of US and x-ray-based measures at 6 months. Youden's index [(YI) (values range from 0 (poor test) to 1 (perfect test)] was used to evaluate existing cutoffs at 6 months of age (normal measurements: alpha angle (AA) ≥60 degrees, femoral head coverage (FHC) ≥50%, and AI <30 degrees) relative to newly proposed limits. RESULTS: Fifty-nine patients were included, of which 28.8% of patients (95% CI: 17.3 to 40.4%) had acetabular dysplasia at 2 years. After adjusting for sex, AA [Area under the Curve (AUC): 80] and AI (AUC: 79) at 6 months of age were better tests than FHC (AUC: 0.77). Current diagnostic cutoffs for AA (YI: 0.08), AI (YI: 0.0), and FHC (YI: 0.06) at 6 months had poor ability to predict dysplasia at 2 years. A composite test of all measures based on proposed cutoffs (AA ≥73 degrees, FHC > 62% and AI ≤24 degrees) was a better predictor of dysplasia at 2 years (Youden's index (YI): 0.63) than any single metric. CONCLUSIONS: The rate of residual dysplasia remains concerning. The 6-month x-ray and US both play a role in the ongoing management of the developmental dysplasia of the hip. The prediction of dysplasia is maximized when all metrics are considered collectively. Existing parameters were not accurate; We recommend the following cutoffs: AA ≥73 degrees, FHC > 62%, and AI ≤24 degrees. These cutoffs must be validated. LEVEL OF EVIDENCE: Prognostic Level II.

Application of Accepted Use Criteria for the Treatment of Developmental Dysplasia of the Hip Decreases the Number of Infants Treated With a Pavlik Harness.

BACKGROUND: This analysis examined how the application of the American Academy of Orthopedic Surgeons appropriate use criteria (AUC) for developmental dysplasia of the hip in infants would change treatment patterns and outcomes for Graf IIA hips at a single quaternary pediatric hospital. METHODS: After Institutional Review Board approval, patient medical records were reviewed and data were collected. Graf IIa hips were defined as alpha angle (AA) 50 to 59 degrees. AA and femoral head coverage (FHC) were measured from initial and 6-month ultrasounds and acetabular index (AI) was measured from radiographs at 6 months of age. Instability (positive Ortolani and Barlow tests) was noted. On the basis of the American Academy of Orthopedic Surgeons AUC for managing developmental dysplasia of the hip, hips were further categorized as normal (FHC ≥45%), borderline (FHC 35% to 44%), or dysplastic (FHC <35%). RESULTS: Overall, 13% (49/371) of Graf IIa hips (AA 50 to 59 degrees) were dysplastic (FHC <35%). Total 24% (89/371) were clinically unstable. Total 42% (37/89) of unstable Graf IIa hips were dysplastic. Only 4% of stable Graf IIa hips were dysplastic (12/282). Out of 371 Graf IIa hips, 256 were treated with Pavlik harness (n=250) or Rhino brace (n=6). Among stable, nondysplastic (SND) hips (those with normal and borderline FHC≥35%), 33% (52/158) were treated because of a more severe contralateral side. If the AUC had been applied, 67% (106/158) of SND Graf IIa hips would not have been treated. Among the n=162 hips that returned for a 6-month radiograph, there was no difference in AI in the 115 treated and 47 untreated SND hips (mean difference treatment vs. no treatment: -1.5, 95% CI, -3.1 to 0.2, P =0.0808). CONCLUSIONS: Using AUC recommendations, our center could reduce the number of SND Graf IIa hips we treat by 67%. Although 24% of Graf IIa hips were clinically unstable and 13% were dysplastic based on FHC, most Graf IIa hips had normal or borderline FHC per the AUC and may do well with observation and follow-up ultrasound at 12 weeks old. LEVEL OF EVIDENCE: Level III-diagnostic study.

Mutations in KIF7 implicated in idiopathic scoliosis in humans and axial curvatures in zebrafish.

Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within extracellular matrix, cilia, and actin networks, but the genetic architecture and underlying mechanisms remain unresolved. Here, we used whole-exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (minor allele frequency < 0.05). Genotyping of additional family members identified a candidate heterozygous variant (H1115Q, G>C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of the second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR-Cas9. kif7co63/co63 zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7co63/co63 embryos, although alterations were seen in Hh pathway gene expression. This study suggests defects in KIF7-dependent Hh signaling, which may drive pathogenesis in a subset of individuals with IS.

Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16-18, 2017, Dallas, Texas.

Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10° or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). "Congenital" scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is evidence that both conditions are etiologically related. A 2-day conference entitled "Genomic Approaches to Understanding and Treating Scoliosis" was held at Scottish Rite Hospital for Children in Dallas, Texas, to synergize research in this field. This first combined, multidisciplinary conference featured international scoliosis researchers in basic and clinical sciences. A major outcome of the conference advancing scoliosis research was the proposal and subsequent vote in favor of merging the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) and International Consortium for Scoliosis Genetics (ICSG) into a single entity called International Consortium for Spinal Genetics, Development, and Disease (ICSGDD). The ICSGDD is proposed to meet annually as a forum to synergize multidisciplinary spine deformity research.

Operative versus nonoperative treatment of displaced proximal humeral physeal fractures: a matched cohort.

BACKGROUND: Displaced proximal humeral physeal fractures (PHPF) are rare injuries. Because of the lack of comparative studies, treatment has historically been based on surgeon preference. The purpose of this study was to compare treatment outcomes among skeletally immature patients who underwent operative versus nonoperative treatment for Neer-Horwitz (NH) III or IV PHPF. METHODS: Skeletally immature patients who underwent treatment for a displaced PHPF from 2003 to 2012 were identified. Eligible subjects were invited to complete a validated shoulder outcome instrument (QuickDASH) and a phone survey. A propensity score matching approach was utilized to match subjects who underwent operative treatment to subjects who underwent nonoperative treatment on the basis of age at injury and NH classification. RESULTS: Seventy patients were identified with a NH III or IV PHPF, of whom 32 subjects completed the study. There was also no difference (P=0.5637) in the proportion of subjects who developed a less than desirable treatment outcome in operative group (57.14%, 4/7) as compared with the nonoperative group (42.86%, 3/7). There was also no difference (P=0.5637) in the proportion of subjects who developed a less than desirable treatment outcome in operative group (57.14%, 4/7) as compared with the nonoperative group. Differences in rate of return to preinjury level of activity (P>0.9999), or cosmetic appearance scores (P>0.999) were not significantly different. QuickDASH scores were 1.9 points (95% CI, 3.0-6.9; P=0.3699) higher overall in the nonoperative group as opposed to the operative group. A less than desirable treatment outcome was noted in 4/23 (17.4%) subjects who underwent nonoperative treatment. Subgroup analysis of the nonoperative cases showed that, for every 1 year increase in age at initial injury, the odds of less than desirable outcome increased by a factor of 3.81 (95% CI, 1.31-21.0). CONCLUSIONS: In a matched cohort of patients with proximal humerus physeal fractures, there was no difference in occurrence of complications, rate of return to activity, or cosmetic satisfaction. Functional outcomes were also nonsignificant, but tended to be higher among fractures that underwent nonoperative treatment. Among nonoperatively treated fractures, less than desirable outcomes were more common in older patients, particularly those older than 12 years of age. LEVEL OF EVIDENCE: Level III-therapeutic.

Intra-articular Radial Head Fractures In the Skeletally Immature Patient: Complications and Management.

BACKGROUND: Intra-articular (IARH) and extra-articular (EARH) radial head fractures in skeletally immature patients are rare injuries that have not been well studied. The objective of this study was to investigate the rate of complications associated with IARH fractures relative to EARH fractures in pediatric patients treated at a tertiary referral children's hospital. METHODS: With IRB approval, Current-Procedural Terminology codes were used to identify all patients who underwent management of radial head and/or neck fractures between 2005 and 2012. A retrospective chart review was used to collect variables related to: demographics, fracture type, treatment method(s), complications, need for physical/occupational therapy, and the need for subsequent surgery. Mid-P exact tests and logistic regression analyses were used to compare differences in the incidence of complications, need for physical therapy (PT), and need for revision surgery between the IARH and EARH fracture groups. RESULTS: Among the 311 patients included in the cohort, 12 (3.86%) were affected by IARH fractures and 299 (96.14%) were affected by EARH fractures. The mean age at the time of injury was 11.46 (±3.09) years and 8.32 (±3.31) years in the IARH and EARH group, respectively. The estimated incidence of complications was significantly (P<0.0001) higher in the IARH group (50 per 100) compared with the EARH group (1.34 per 100). A significantly (P<0.0001) greater proportion of the subjects with IARH fractures also required revision surgery (25% IARH vs. 0% EARH) and PT (50% IARH vs. 19.59% EARH). CONCLUSIONS: Compared with EARH fractures, IARH fractures were associated with a significantly higher rate of complications, greater need for PT, and greater need for surgical intervention. The significant complication rate associated with pediatric IARH fractures necessitates an increased awareness of this fracture pattern and prompt, aggressive diagnostic and treatment modalities. LEVEL OF EVIDENCE: Therapeutic studies: Level III.

Outcomes of Simultaneous Lengthening and ACL Reconstruction in Fibular Hemimelia: A Retrospective Case Series.

Background: Fibular hemimelia is the most common congenital long bone deficiency. It is often associated with femoral and tibial deficiencies which result in a clinically evident leg length discrepancy. The primary soft tissue concern is ACL/PCL deficiency. If treatment includes bony lengthening, joint stability is imperative to avoid complications. In this study, we detail a novel technique for long bone lengthening and ACL reconstruction in a single, cohesive surgery. This consolidates the need for multiple procedures and offers improved limb length symmetry and knee stability for this patient population. Clinical outcomes of pediatric patients with hemimelia who underwent either femoral or tibial lengthening with PRECICE® nail and concomitant ACL reconstruction are presented. Methods: After IRB approval, we identified five patients with complex fibular hemimelia who underwent ACL reconstruction and concomitant lengthening with at least two years of follow-up. Two patients (40%) presented with congenital short femur, and three (60%) with congenital short tibia. In each case, ACL reconstruction and either femoral or tibial guided growth via PRECICE® nail were performed. Operative techniques involving both soft tissue and bony methodology are described in detail. Results: All patients had objective improvement in knee stability as assessed both intra and post operatively, as well as successful intermedullary lengthening without complications related to joint stability. Three patients had minor complications unrelated to joint stability that did not interfere with overall result. Conclusion: Fibular hemimelia associated with hypoplasia of bony and soft tissue structures can be successfully addressed with concomitant ligamentous reconstruction at the time of implantation of lengthening devices. This addresses knee instability and reduces both number of operative procedures and potential complications related to joint instability while pursuing bony lengthening. Level of Evidence: V.

Pediatric and Adult Fracture Incidence: A Decreasing Trend With Increasing Hospital Admissions.

Large-scale studies examining fracture trends and epidemiological data are lacking. The purpose of this study was to evaluate the incidence of fractures presenting to US emergency departments using the National Electronic Injury Surveillance System. A total of 7,109,078 pediatric and 13,592,548 adult patients presenting to US emergency departments with a fracture between 2008 and 2017 were analyzed for patterns. Fractures accounted for 13.9% of pediatric injuries and 15% of adult injuries. Among children, fracture incidence was highest in the group 10 to 14 years old and most frequently involved the forearm (19.0%). Fracture incidence was highest in adults 80 years and older and most frequently involved the lower trunk (16.2%). On average, the rate of pediatric fractures decreased by 2.34% per year (95% CI, 0.25% increase to 4.88% decrease; P=.0757). Among adults, fracture incidence increased 0.33% per year (95% CI, 2.34% decrease to 2.85% increase; P=.7892). This change was significantly different between the pediatric and adult populations (P=.0152). There was an increase in the annual proportion of adults with fractures who were admitted (odds ratio per 1-year increase, 1.05; 95% CI, 1.03-1.07; P<.0001). There was no change in the proportion of pediatric patients with fractures who were admitted (odds ratio, 1.02; 95% CI, 0.99-1.05; P=.0606). The incidence of fractures decreased in pediatric patients yet was relatively stable in adult patients. Conversely, the proportion of patients with fractures who were admitted increased, particularly among adults. These findings may suggest that less severe fractures are presenting elsewhere, falsely inflating the observed rise in admissions. [Orthopedics. 2023;46(6):e369-e375.].

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction.

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere's disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere's disease, and 38 European-American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere's disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease.

Cytoskeletal Keratins Are Overexpressed in a Zebrafish Model of Idiopathic Scoliosis.

Idiopathic scoliosis (IS) is a three-dimensional rotation of the spine >10 degrees with an unknown etiology. Our laboratory established a late-onset IS model in zebrafish (Danio rerio) containing a deletion in kif7. A total of 25% of kif7co63/co63 zebrafish develop spinal curvatures and are otherwise developmentally normal, although the molecular mechanisms underlying the scoliosis are unknown. To define transcripts associated with scoliosis in this model, we performed bulk mRNA sequencing on 6 weeks past fertilization (wpf) kif7co63/co63 zebrafish with and without scoliosis. Additionally, we sequenced kif7co63/co63, kif7co63/+, and AB zebrafish (n = 3 per genotype). Sequencing reads were aligned to the GRCz11 genome and FPKM values were calculated. Differences between groups were calculated for each transcript by the t-test. Principal component analysis showed that transcriptomes clustered by sample age and genotype. kif7 mRNA was mildly reduced in both homozygous and heterozygous zebrafish compared to AB. Sonic hedgehog target genes were upregulated in kif7co63/co63 zebrafish over AB, but no difference was detected between scoliotic and non-scoliotic mutants. The top upregulated genes in scoliotic zebrafish were cytoskeletal keratins. Pankeratin staining of 6 wpf scoliotic and non-scoliotic kif7co63/co63 zebrafish showed increased keratin levels within the zebrafish musculature and intervertebral disc (IVD). Keratins are major components of the embryonic notochord, and aberrant keratin expression has been associated with intervertebral disc degeneration (IVDD) in both zebrafish and humans. The role of increased keratin accumulation as a molecular mechanism associated with the onset of scoliosis warrants further study.

Overview of Gene Special Issue "Genetic Conditions Affecting the Skeleton: Congenital, Idiopathic Scoliosis and Arthrogryposis".

In this Special Issue of Genes entitled "Genetic Conditions Affecting the Skeleton: Congenital, Idiopathic Scoliosis and Arthrogryposis", evidence is presented which suggests that congenital, idiopathic scoliosis, and arthrogryposis share similar overlapping, but also distinct etiopathogenic mechanisms, including connective tissue and neuromuscular mechanisms [...].

Genetic variants associated with the occurrence and progression of adolescent idiopathic scoliosis: a systematic review protocol.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a structural lateral spinal curvature of ≥ 10° with rotation. Approximately 2-3% of children in most populations are affected with AIS, and this condition is responsible for approximately $1.1 billion in surgical costs to the US healthcare system. Although a genetic factor for AIS has been demonstrated for decades, with multiple potentially contributory loci identified across populations, treatment options have remained limited to bracing and surgery. METHODS: The databases MEDLINE (via PubMed), Embase, Google Scholar, and Ovid MEDLINE will be searched and limited to articles in English. We will conduct title and abstract, full-text, and data extraction screening through Covidence, followed by data transfer to a custom REDCap database. Quality assessment will be confirmed by multiple reviewers. Studies containing variant-level data (i.e., GWAS, exome sequencing) for AIS subjects and controls will be considered. Outcomes of interest will include presence/absence of AIS, scoliosis curve severity, scoliosis curve progression, and presence/absence of nucleotide-level variants. Analyses will include odds ratios and relative risk assessments, and subgroup analysis (i.e., males vs. females, age groups) may be applied. Quality assessment tools will include GRADE and Q-Genie for genetic studies. DISCUSSION: In this systematic review, we seek to evaluate the quality of genetic evidence for AIS to better inform research efforts, to ultimately improve the quality of patient care and diagnosis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration #CRD42021243253.

Multi-day delay to care identified in pediatric trauma cases during COVID-19.

This study aims to establish how pediatric fracture patterns were altered at a level 1 trauma center in a state that implemented a shutdown during the initial height of COVID-19. After IRB approval, we identified 2017 patients treated at a pediatric institution for definitive management of a fracture between 26 March and 31 May 2018, 2019, or 2020. Dates were chosen based on statewide stay-at-home orders for Colorado. Patients were excluded for treatment at another institution (n = 148), no fracture noted in clinic (n = 18), or other (n = 13). Data were retrospectively collected from the remaining 1838 patients regarding demographics, fracture injury, mechanism, and treatment. Odds ratios (ORs) were calculated for each variable during COVID-19 relative to prior years. The number of fractures during 2020 decreased by 26% relative to 2019 and 23% to 2018. A larger proportion of patients experienced at least a 5-day delay to definitive treatment [OR: 1.55, confidence interval (CI): 1.23-1.96, P = 0.0002]. Rates of non-accidental trauma (NAT) increased non-significantly (OR: 2.67, CI: 0.86-8.32, P = 0.0900) during 2020 (1.2%) relative to 2018 (0.6%) and 2019 (0.3%). Fractures occurring at home increased to 79.9% (OR: 6.44, CI: 5.04-8.22, P < 0.0001). Despite less overall trauma during shelter-in-place orders, greater fracture numbers were seen among younger children and severe fractures were likely among older children. Patients may hesitate to seek care during 2020. Rates of NAT doubled during 2020. As communities prepare for future waves, treatment centers should warn against common fracture mechanisms and raise awareness of NAT.

Genetic animal modeling for idiopathic scoliosis research: history and considerations.

PURPOSE: Idiopathic scoliosis (IS) is defined as a structural lateral spinal curvature ≥ 10° in otherwise healthy children and is the most common pediatric spinal deformity. IS is known to have a strong genetic component; however, the underlying etiology is still largely unknown. Animal models have been used historically to both understand and develop treatments for human disease, including within the context of IS. This intended audience for this review is clinicians in the fields of musculoskeletal surgery and research. METHODS: In this review article, we synthesize current literature of genetic animal models of IS and introduce considerations for researchers. RESULTS: Due to complex genetic and unique biomechanical factors (i.e., bipedalism) hypothesized to contribute to IS in humans, scoliosis is a difficult condition to replicate in model organisms. CONCLUSION: We advocate careful selection of animal models based on the scientific question and introduce gaps and limitations in the current literature. We advocate future research efforts to include animal models with multiple characterized genetic or environmental perturbations to reflect current understanding of the human condition.

The heterogeneous mechanical properties of adolescent growth plate cartilage: A study in rabbit.

The growth plate is a cartilaginous tissue that functions to lengthen bones in children. When fractured, however, the growth plate can lose this critical function. Our understanding of growth plate fracture and mechanobiology is currently hindered by sparse information on the growth plate's microscale spatial gradients in mechanical properties. In this study, we performed microindentation across the proximal tibia growth plate of 9-week-old New Zealand White rabbits (n = 15) to characterize spatial variations in mechanical properties using linear elastic and nonlinear poroelastic material models. Mean indentation results for Hertz reduced modulus ranged from 380 to 690 kPa, with a peak in the upper hypertrophic zone and significant differences (p < 0.05) between neighboring zones. Using a subset of these animals (n = 7), we characterized zonal structure and extracellular matrix content of the growth plate through confocal fluorescent microscopy and Raman spectroscopy mapping. Comparison between mechanical properties and matrix content across the growth plate showed that proteoglycan content correlated with compressive modulus. This study is the first to measure poroelastic mechanical properties from microindentation across growth plate cartilage and to discern differing mechanical properties between the upper and lower hypertrophic zones. This latter finding may explain the location of typical growth plate fractures. The spatial variation in our reported mechanical properties emphasize the heterogeneous structure of the growth plate which is important to inform future regenerative implant design and mechanobiological models.

Analysis of Physeal Fractures from the United States National Trauma Data Bank.

BACKGROUND: Pediatric long-bone physeal fractures can lead to growth deformities. Previous studies have reported that physeal fractures make up 18-30% of total fractures. This study aimed to characterize physeal fractures with respect to sex, age, anatomic location, and Salter-Harris (SH) classification from a current multicenter national database. METHODS: A retrospective cohort study was performed using the 2016 United States National Trauma Data Bank (NTDB). Patients ≤ 18 years of age with a fracture of the humerus, radius, ulna, femur, tibia, or fibula were included. RESULTS: The NTDB captured 132,018 patients and 58,015 total fractures. Physeal fractures made up 5.7% (3291) of all long-bone fractures, with males accounting for 71.0% (2338). Lower extremity physeal injuries comprised 58.6% (1929) of all physeal fractures. The most common site of physeal injury was the tibia comprising 31.8% (1047), 73.9% (774) of which were distal tibia fractures. Physeal fractures were greatest at 11 years of age for females and 14 years of age for males. Most fractures were SH Type II fractures. DISCUSSION AND CONCLUSIONS: Our analysis indicates that 5.7% of pediatric long-bone fractures involved the physis, with the distal tibia being the most common. These findings suggest a lower incidence of physeal fractures than previous studies and warrant further investigation.

Respiratory manifestations of Marfan syndrome: a narrative review.

OBJECTIVE: The prevalence of Marfan syndrome (MFS) is estimated to be 1 in 10,000 to 15,000 individuals, but the phenotype of MFS may not be apparent and hence its diagnosis may not be considered by clinicians. Furthermore, the effects of MFS on the lungs and breathing are underrecognized despite the high morbidity that can occur. The objective of this Narrative Review is to delineate the molecular consequences of a defective fibrillin-1 protein and the skeletal and lung abnormalities in MFS that may contribute to respiratory compromise. It is important for clinicians to be cognizant of these MFS-associated respiratory conditions, and a contemporaneous review is needed. BACKGROUND: MFS is an autosomal dominant, connective tissue disorder caused by mutations in the FIBRILLIN-1 (FBN1) gene, resulting in abnormal elastic fibers as well as increased tissue availability of transforming growth factor-beta (TGFß), both of which lead to the protean clinical abnormalities. While these clinical characteristics are most often recognized in the cardiovascular, skeletal, and ocular systems, MFS may also cause significant impairment on the lungs and breathing. METHODS: We searched PubMed for the key words of "Marfan syndrome," "pectus excavatum," and "scoliosis" with that of "lung disease," "breathing", or "respiratory disease." The bibliographies of identified articles were further searched for relevant articles not previously identified. Each relevant article was reviewed by one or more of the authors and a narrative review was composed. CONCLUSIONS: Though the classic manifestations of MFS are cardiovascular, skeletal, and ocular, FBN1 gene mutation can induce a variety of effects on the respiratory system, inducing substantial morbidity and potentially increased mortality. These respiratory effects may include chest wall and spinal deformities, emphysema, pneumothorax, sleep apnea, and potentially increased incidence of asthma, bronchiectasis, and interstitial lung disease. Further research into approaches to prevent respiratory complications is needed, but improved recognition of the respiratory complications of MFS is necessary before this research is likely to occur.

A Decade in Review after Idiopathic Scoliosis Was First Called a Complex Trait-A Tribute to the Late Dr. Yves Cotrel for His Support in Studies of Etiology of Scoliosis.

Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings. It is now over a decade since the first proposal of the complex trait genetic model for AIS. Here, we review in detail the vast information about the genetic and environmental factors in AIS pathogenesis gathered to date. More importantly, new insights into AIS etiology were brought to us through new research data under the perspective of a complex trait. Hopefully, future research directions may lead to better management of AIS, which has a tremendous impact on affected adolescents in terms of both physical growth and psychological development.

Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis.

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.