The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.

Acute Compartment Syndrome in Pediatric Patients on Extracorporeal Membrane Oxygenation Support.

BACKGROUND: When acute compartment syndrome (ACS) occurs in pediatric patients requiring venoarterial extracorporeal membrane oxygen (VA ECMO) support, there is little data to guide surgeons on appropriate management. The purpose of this study is to characterize the presentation, diagnosis, timeline, and outcomes of patients who developed this complication. METHODS: This is a single-center retrospective case series of children below 19 years old on VA ECMO support who subsequently developed extremity ACS between January 2016 and December 2022. Outcomes included fasciotomy findings, amputation, mortality, and documented function at the last follow-up. RESULTS: Of 343 patients on VA ECMO support, 18 (5.2%) were diagnosed with ACS a median 29 hours after starting ECMO. Initial cannulation sites included 8 femoral, 6 neck, and 4 central. Femoral artery cannulation was associated with an increased risk of ACS [odds ratio=6.0 (CI: 2.2 to 15), P <0.0001]. In the hospital, the mortality rate was 56% (10/18). Fourteen (78%) patients received fasciotomies a median of 1.2 hours after ACS diagnosis. Only 4 (29%) patients had all healthy muscles at initial fasciotomy, while 9 (64%) had poor muscular findings in at least 1 compartment. Patients with worse findings at fasciotomy had a significantly longer duration between ischemia onset and ACS diagnosis. Patients required a median of 1.5 additional procedures after fasciotomy, and only 1 (7%) developed a surgical site infection. Of the 7 surviving fasciotomy patients, 2 required amputations, 3 developed an equinus contracture, 1 developed foot drop, and 3 had no ACS-related deficits. Four patients did not receive fasciotomies: 3 were deemed too ill and later died, and 1 was diagnosed too late to benefit. The only surviving nonfasciotomy patient required bilateral amputations. CONCLUSIONS: Pediatric ECMO-associated ACS is not exclusive to patients with femoral artery cannulation. The majority of fasciotomy patients were diagnosed with ACS after muscle necrosis had already started. We were unable to definitively conclude whether fasciotomies provide better outcomes. There is a need for increased awareness and earlier recognition of this rare yet potentially devastating complication. LEVEL OF EVIDENCE: Level IV-retrospective case series.

Half-pin Breakage in Multiplanar External Fixators Used for Pediatric Deformity Correction.

BACKGROUND: Pediatric patients with leg length discrepancies and complex deformities may require multiplanar external fixators for correction. We have encountered 4 cases of half-pin breakage with the Orthex hexapod frame. The purpose of this study is to report factors associated with half-pin breakage and compare various deformity correction characteristics between 2 hexapod frames - Taylor Spatial Frame (TSF) and Orthex. METHODS: Pediatric patients with lower extremity deformities treated with an Orthex or TSF at a single tertiary children's hospital between 2012 and 2022 were included for retrospective review. Variables compared between frame groups include frame configuration, half-pin/wire fixation, length achieved, angular correction, and frame time. RESULTS: There were 23 Orthex frames (23 patients) and 36 TSF (33 patients) included. Four Orthex and zero TSF had proximal half-pin breakage. The Orthex group was younger on average (10 vs. 12 y, P =.04*) at the time of frame placement. The majority (52%) of Orthex frames were used for simultaneous lengthening and angular correction, while the majority (61%) of TSF was used for only angular correction. Orthex had more half-pins used for proximal fixation (median 3 vs. 2, P <0.0001*) and more frames with nonstandard configuration (7 (30%) vs. 1 (3%), P =0.004*). Orthex group had a longer total frame time (median 189 vs. 146 days, P =0.012*) and longer time required for regenerate healing (117 vs. 89 d, P =0.02*). There were no significant differences in length gained, angular correction, or healing index between Orthex and TSF. Nonstandard configuration, increased number of proximal half-pins, younger age at index surgery, and increased lengthening were associated with pin breakage. CONCLUSIONS: This is the first study to report half-pin breakage while using multiplanar frames in pediatric lower extremity deformity correction. The Orthex and TSF groups consisted of significantly different patients and frame configurations, making it difficult to identify any specific cause for pin breakage. This study shows that pin breakage is likely caused by multiple factors and is associated with the increased complexity of deformity correction. LEVEL OF EVIDENCE: Level III-Retrospective Comparison Study.

Early Postoperative Infections After Closed Reduction and Percutaneous Pinning in Type II and Type III Pediatric Supracondylar Humerus Fractures.

BACKGROUND: Supracondylar humerus fractures (SCHF) are the most common elbow fracture type in children, and one of the most common pediatric fracture types overall. Excellent outcomes are generally reported with closed reduction and pinning (CRPP), but the technique involves leaving the pins outside the skin. External pins can act as a nidus for infection. We characterize the infection complications from SCHF treatment at a single-centre tertiary children's hospital over 10 years. This is the largest series on infectious outcomes after CRPP of SCHF reported to date. METHODS: Pediatric patients undergoing CRPP for a type II or type III SCHF from 2011 to 2021 with postsurgical infections within 90 days were identified. Demographic and clinical data were retrieved from medical records. Descriptive statistics were estimated and reported as means or medians with range values or counts with percentages. RESULTS: A total of 18 patients met inclusion criteria, 10 and 8 with type II and III SCHF, respectively. The average age at diagnosis of fracture was 4.7 (2 to 9) years. The average operating time for the index surgery was 29 minutes (12 to 42). The average number of postoperative days until pin removal was 29.8 (18 to 52), and the average number of postoperative days until readmission or visit with symptoms was 38.9 (18 to 77). There was a documented history of a wet cast in 6 patients (33%). Ten (56%) patients presented with fever, and the most common positive culture was methicillin-sensitive Staphylococcus aureus (9, 50%). Thirteen (72%) patients returned to the operating room for incision and drainage. There were no cases with continued complications after the original infection after a median follow-up of 63 days (8 to 559). Infection after CRPP of SCHF is a rare adverse event. In our series, it was most often associated with common pathogens and wet casts. The necessity of return to the operating room will vary with the presentation, but if efficaciously treated afterwards with oral antibiotics, there is a low chance of recurrence or subsequent complications. Patients should be carefully instructed in cast care and demonstrate understanding of risks and complications, and to contact their orthopaedist if their cast demonstrates lack of integrity. LEVEL OF EVIDENCE: Prognostic level IV.

All-epiphyseal versus trans-epiphyseal screw fixation for tillaux fractures: Does it matter?

BACKGROUND: Tillaux fractures occur primarily in adolescents due to the pattern of physeal closure and are classified as Salter-Harris type III physeal fractures. Operative management with screw fixation is recommended for more than 2 mm of displacement or more than 1 mm of translation. However, the efficacy and complications of trans-physeal vs all-physeal screw fixation have not been investigated extensively. AIM: To compare the clinical and functional outcomes of trans-physeal (oblique) and all-epiphyseal (parallel) screw fixation in management of Tillaux fractures among pediatric patients. METHODS: This was an ethics board approved retrospective review of pediatric patients who presented to our tertiary children's care facility with Tillaux fractures. We included patients who had surgical fixation of a Tillaux fracture over a 10 year period. Data analysis included demographics, mode of injury, management protocols, and functional outcomes. The patients were divided into group 1 (oblique fixation) and group 2 (parallel fixation). Baseline patient characteristics and functional outcomes were compared between groups. Statistical tests to evaluate differences included Fisher's Exact or Chi-squared and independent samples t or Mann Whitney tests for categorical and continuous variables, respectively. RESULTS: A total of 42 patients (28 females and 14 males) were included. There were no significant differences in body mass index, sex, age, or time to surgery between the groups [IK2]. Sports injuries accounted for 61.9% of the cases, particularly non-contact (57.1%) and skating (28.6%) injuries. Computed Tomography (CT) scan was ordered for 28 patients (66.7%), leading to diagnosis confirmation in 17 patients and change in management plan in 11 patients. [GRC3] Groups 1 and 2 consisted of 17 and 25 patients, respectively. For mid to long-term functional outcomes, there were 14 and 10 patients in groups 1 and 2, respectively. Statistical analysis revealed no significant differences in the functional outcomes, pain scores, or satisfaction between groups. No infections, non-unions, physeal arrest, or post-operative ankle deformities were reported. Two (4.8%) patients had difficulty returning to sports post-surgery due to pain. One was a dancer, and the other patient had pain while running, which led to hardware removal. Both patients had parallel fixation. Hardware removal for groups 1 and 2 were 4 (23.5%) and 5 (20.0%) patients, respectively. The reasons for removal was pain in 2 patients, and parental preference in the remaining. CONCLUSION: This is the largest reported series of pediatric patients with Tillaux fractures comparing functional outcomes of different methods of screw fixation orientation to the physis, which showed no difference regarding functional outcomes.

Targeting TGF-ß for treatment of osteogenesis imperfecta.

BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-ß signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-ß signaling in children with OI and conducted a phase I clinical trial of TGF-ß inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-ß neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-ß pathway as the top activated signaling pathway, and IPA showed that TGF-ß1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-ß signaling is a driver pathogenic mechanism in OI. Anti-TGF-ß therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Does the stabilization of the calcaneocuboid joint with Steinmann pin in Evans osteotomy affect its incidence of arthritis?

PURPOSE: This study aims to determine the effect of retaining a Steinmann pin in the calcaneocuboid joint on its rates of arthritis following Evans calcaneal osteotomy lengthening procedure. The study hypothesized that leaving the pin across the calcaneocuboid joint post-operatively would lead to higher rates of arthritis. METHODS: This is a retrospective review of patients under 18 years of age who underwent Evans osteotomy at our hospital from January 2015 to May 2020. The Patients were stratified into 2 groups: Group 1 (pin was left post-operatively across the joint and removed on follow-up) and Group 2 (pin was removed during surgery). Demographic data were recorded, including age, sex, and body mass index. Calcaneocuboid arthritis was determined by radiographic imaging at least one-year follow-up. Time to pin removal, size of the pin and graft, and subluxation were analyzed as possible risk factors for arthritis. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated. RESULTS: 39 patients were included in the study: 24 patients had the pin removed post-operatively, and 15 had the pin removed intra-operatively. There were no significant differences between the 2 groups regarding body mass index, age, sex, or laterality. Calcaneocuboid arthritis rates were significantly higher in the Group 1 than Group 2 (12(50%) vs. 2(13.3%), respectively; p = 0.02). On multivariate regression, both age (OR, 1.305 [95%CI: 1.009-1.696]; p = 0.044) and leaving the pin in the joint postoperatively (OR, 7.661 [95%CI: 1.208-48.570]; p = 0.031) were found as risk factors for arthritis at follow-up. The mean time to pin removal, the size of the pin, and the size of the graft were not found to be significant predictors of arthritis (p > 0.05). CONCLUSIONS: This study shows that leaving the Steinmann pin in the calcaneocuboid joint in children post-operatively is associated with an increased risk of developing early radiographic signs of calcaneocuboid joint arthritis.

Spica MRI predictors for epiphyseal osteonecrosis after closed reduction treatment of dysplasia of the hip.

Spica MRI with intravenous gadolinium contrast after closed reduction for developmental dysplasia of the hip (DDH) helps to determine successful reduction and attempts to identify patients at risk for epiphyseal osteonecrosis. The objective of our study was to evaluate spica MRI predictors for epiphyseal osteonecrosis after closed reduction. This was a retrospective study of all patients undergoing closed reduction for DDH followed by gadolinium-enhanced spica MRI between July 2011 and November 2014. Patient demographics and clinical follow-up through 2017, including the development of epiphyseal osteonecrosis and need for reintervention after the initial reduction, were recorded. MRI data included hip abduction angles and quantifying the percentage of femoral head enhancement. Twenty-five hips in 21 patients (16 girls, five boys, mean age: 0.99 years, range: 0.4-3.1 years) were included in our study. The mean follow-up period was 3 ± 1.5 years (range: 0.65-6.1 years). Eight (32%) of 25 hips went on to develop osteonecrosis. Epiphyseal osteonecrosis was more likely with less than 80% enhancement (sensitivity 87.5%, specificity 88.25%, positive predictive value 78%, negative predictive value 94%). The mean contrast enhancement for patients developing osteonecrosis compared with those who did not was 37.5 and 86.5%, respectively; P = 0.001. Immediate postspica MRI with gadolinium is a useful prognostic tool for determining future risk for epiphyseal osteonecrosis in children treated for DDH. Our data complement existing literature and suggest that even in cases with partial epiphyseal enhancement, osteonecrosis may still develop. When the epiphyseal enhancement is less than 80%, it is recommended that spica cast revision is considered.

Utility of immediate postoperative hip MRI in developmental hip dysplasia: closed vs. open reduction.

BACKGROUND: Magnetic resonance imaging (MRI) of the hips is being increasingly used to confirm hip reduction after surgery and spica cast placement for developmental dysplasia of the hip (DDH). OBJECTIVE: To review a single institutional experience with post-spica MRI in children undergoing closed or open hip reduction and describe the utility of MRI in directing the need for re-intervention. MATERIALS AND METHODS: Seventy-four patients (52 female, 22 male) who underwent post-spica hip MRI over a 6-year period were retrospectively reviewed. One hundred and seven hips were included. Data reviewed included age at intervention, gender, type of intervention performed, MRI findings, the need for re-intervention and the interval between interventions. Gender was compared between the closed and open reduction groups via the Fisher exact test. Age at the first procedure was compared via the Wilcoxon rank test. Rates of re-intervention after closed and open reduction were calculated and the reasons for re-intervention were reviewed. RESULTS: The mean age at the time of the first intervention was 16.4 months (range: 4 to 63 months). Mean age for the closed reduction group was 10.5 months (range: 4-24 months) and for the open reduction group was 23.7 months (range: 5-63 months), which was significant (P-value <0.0001). Of the 52 hips that underwent closed reduction, 16 (31%) needed re-intervention. Of the 55 hips that underwent open reduction, MRI was useful in deciding re-intervention in only 1 (2%). This patient had prior multiple failed closed and open reductions at an outside institute. CONCLUSION: Post intervention hip spica MRI is useful in determining the need for re-intervention after closed hip reduction, but its role after open reduction is questionable.

Chronic Osteomyelitis Caused by Haemophilus parainfluenzae: A Case Report.

CASE: A 14-year-old boy presented with a pathologic fracture of the distal aspect of the tibia and a remote history of a dog bite near the injury site. Imaging studies, biopsy, and presentation corroborated the diagnosis of chronic osteomyelitis. Multiple diagnostic methods were negative until an open biopsy identified Haemophilus parainfluenzae, a fastidious oropharyngeal bacterium, with polymerase chain reaction analysis. The patient underwent extensive debridement, placement of external fixation, and a year-long antibiotic therapy regimen. He subsequently required a tibial-fibular osteotomy at a second site with placement of an intramedullary nail for correction of a leg-length discrepancy. CONCLUSION: This case report illustrates the complex management of chronic osteomyelitis in pediatric patients, its sequelae, and the importance of considering treatment of atypical pathogens.