BACKGROUND Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI. METHODS Histology 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-β 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. RESULTS OI 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-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 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. CONCLUSION Increased TGF-β signaling is a driver pathogenic mechanism in OI. Anti–TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION ClinicalTrials.gov NCT03064074. FUNDING Brittle 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.

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.

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.

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.

This case report illustrates the complex management of chronic osteomyelitis in pediatric patients, its sequelae, and the importance of considering treatment of atypical pathogens.