A Novel Minimally Invasive Surgical Technique for Eight-Plate Hemiepiphysiodesis: Description and Evaluation.

Background: Temporary hemiepiphysiodesis with tension band plates or eight-plates is a common surgical procedure to treat malalignment of the lower limb axis in skeletally immature patients. The objective of this study was to compare a new minimally invasive surgical procedure with the conventional procedure and evaluate its safety and effectiveness in order to reduce the risk of hypertrophic scarring, which may cause functional impairment as well as cosmetic issues. Methods: Sixty-five growth plates of either the femur or the tibia were evaluated in 33 patients treated for genu valgum or varum between 2010 and 2017. Each growth plate was considered an individual case. The modified procedure was used in 17 cases and the conventional procedure in 48 cases. The modified surgical procedure is characterized by an 8 mm incision and preparation of the epi-periosteal layer, in which the eight-plate is positioned via a guide-wire. Positioning and implantation are controlled via fluoroscopy. Skin incision length, duration of surgery, revision rate, achievement of a defined correction goal, and correction rate were analyzed. Results: Using the minimally invasive procedure, the mean skin incision length (23.94 ± 10.18 mm vs. 8.75 ± 2.14 mm, p < 0.001) could be significantly reduced. No significant difference was found in regard to the duration of surgery, revision rate, achievement of the correction goal or correction rate. Conclusions: The minimally invasive procedure results in a reduction in incision length without significant impact on the duration of surgery, revision rate, achievement of correction goal or correction rate. Consequently, the modified procedure can be regarded as equally as effective and safe as the conventional procedure.

[Stress fractures of the growth plates in the fingers of adolescent rock climbers]. / Stressfrakturen der Wachstumsfugen der Finger jugendlicher Kletterer.

BACKGROUND: Primary periphyseal stress injuries (PPSI) of the hand and fingers are a rare condition overall but are most commonly seen in adolescent rock climbers and is the most common sport-specific injury in young climbers. Early diagnosis and treatment are crucial for a good treatment outcome and to avoid chronic sport-related injury. OBJECTIVE: The aim of the study is to introduce the injury to a wider audience. Based on an analysis of the current literature, the pathophysiology is demonstrated and the diagnostic and treatment standards are analyzed. Prophylactic measures are also reported. MATERIAL AND METHODS: Based on a systematic multiple database analysis, the current literature on PPSI of the hand and fingers in climbers were collected and further analyzed in a narrative review. The pathophysiology, diagnostic and treatment concepts are presented. RESULTS: Most cases of PPSI to the hand and fingers are in young rock climbers; however, a few cases have been reported in gymnasts, baseball players and piano players. Overall, there are over 200 documented cases in the literature. Most are Salter-Harris III/Aitken II fractures but grade I, II and IV fractures have also been reported. Patients are mostly 13-15 years of age and within the main pubertal growth spurt. After diagnosis, usually by magnetic resonance imaging (MRI), treatment is often conservative, with an increasing number of cases requiring surgical revision. Surgery usually involves spot drilling of the growth plate to induce fusion. DISCUSSION: Early diagnosis and treatment are critical for a good outcome. This includes specific education and information for athletes, coaches, parents and treating physicians. Also, the frequent use of the crimp position has also been shown to increase the risk of PPSI. Preventive aspects should target this as well as overall load management.

Solving the Puzzle: A Compelling Case Study of Calcaneal Apophysitis With Achilles Tendon Calcification in a 14-Year-Old Patient.

Calcaneal apophysitis, known as Sever's disease, manifests as heel pain and is prevalent among children and adolescents, particularly during growth spurts and periods of heightened physical activity. Although Sever's disease is well-documented, its co-occurrence with other foot pathologies in pediatric patients is relatively uncommon. We present here a unique case of a 14-year-old female patient who presented with significant heel pain and discomfort associated with flat feet, impacting her daily activities and physical performance. Clinical examination revealed tenderness at the heel consistent with Sever's disease, along with symptoms suggestive of posterior tibial tendinopathy and radiographic evidence of Achilles tendon calcification. The primary diagnoses included Sever's disease, posterior tibial tendinopathy, and calcification of the Achilles tendon. Management involved a thorough assessment comprising physical examination and imaging studies to confirm the diagnoses. Pharmacological and non-pharmacological interventions such as activity modification, stretching exercises, and orthotic devices were implemented to alleviate symptoms and improve foot mechanics. Over the course of treatment, the patient showed gradual improvement in pain levels and functional abilities, indicating a positive response to therapy. Long-term follow-up aimed at preventing recurrence and optimizing foot health was recommended to ensure sustained recovery and overall well-being. In this case study, we aim to elucidate the clinical presentation, diagnostic challenges, and management approach employed in addressing these concurrent foot conditions. By exploring this case, we hope to contribute valuable insights to the understanding and management of pediatric foot pathologies, particularly in cases involving multiple co-existing conditions.

The G protein-coupled receptor ADGRG6 maintains mouse growth plate homeostasis through IHH Signaling.

The cartilage growth plate is essential for maintaining skeletal growth; however, the mechanisms governing postnatal growth plate homeostasis are still poorly understood. Using approaches of molecular mouse genetics and spatial transcriptomics applied to formalin-fixed, paraffin-embedded (FFPE) tissues, we show that ADGRG6/GPR126, a cartilage-enriched adhesion G protein-coupled receptor (GPCR), is essential for maintaining slow-cycling resting zone cells, appropriate chondrocyte proliferation and differentiation, and growth plate homeostasis in mice. Constitutive ablation of Adgrg6 in osteochondral progenitor cells with Col2a1Cre leads to a shortened resting zone, formation of cell clusters within the proliferative zone, and an elongated hypertrophic growth plate, marked by limited expression of PTHrP but increased IHH signaling throughout the growth plate. Attenuation of Smoothened (SMO)-dependent hedgehog signaling restored the Adgrg6 deficiency-induced expansion of hypertrophic chondrocytes, confirming that IHH signaling can promote chondrocyte hypertrophy in a PTHrP-independent manner. In contrast, postnatal ablation of Adgrg6 in mature chondrocytes with AcanCreERT2, induced after the formation of the resting zone, does not affect PTHrP expression but causes an overall reduction of growth plate thickness marked by increased cell death specifically in the resting zone cells and a general reduction of chondrocyte proliferation and differentiation. Spatial transcriptomics reveals that ADGRG6 is essential for maintaining chondrocyte homeostasis by regulating osteogenic and catabolic genes in all the zones of the postnatal growth plates, potentially through positive regulation of SOX9 expression. Our findings elucidate the essential role of a cartilage-enriched adhesion GPCR in regulating cell proliferation and hypertrophic differentiation by regulation of PTHrP/IHH signaling, maintenance of slow-cycle resting zone chondrocytes, and safeguarding chondrocyte homeostasis in postnatal mouse growth plates.

The cartilage growth plate is an essential structure for skeletal growth, however, the mechanisms that govern growth plate homeostasis are still poorly understood. In this study, we showed that an adhesion G protein-coupled receptor (GPCR) named ADGRG6 plays an essential role in maintaining the slow-cycling cells in the resting zone of the growth plate and directing appropriate proliferation and differentiation of the growth plate chondrocytes. Using a technique called spatial transcriptomics, we compared the gene expression profiles in control and Adgrg6 mutant growth plates and found that ADGRG6 prevents premature hypertrophic differentiation of the growth plate chondrocytes by negatively regulating Indian Hedgehog (IHH) signaling. In summary, our findings highlighted the essential role of a cartilage-enriched GPCR in maintaining growth plate homeostasis through IHH signaling.

Slipped capital femoral epiphysis: emphasis on early recognition and potential pitfalls.

Slipped capital femoral epiphysis is a shearing injury through the growth plate of the proximal femur and is the most common hip disorder in adolescence. Delays in diagnosis persist across practice settings despite ongoing innovations in imaging. Recent insights into pathomechanics highlight the importance of femoral head surface morphology and rotational microinstability centered at the epiphyseal tubercle in causing early physeal changes, which can be detected on imaging prior to frank slip. Scrutiny of physeal morphology and comparison to the contralateral hip is critical at all stages of disease progression, and improper technique may result in undue diagnostic delay. Selective use of cross-sectional imaging can be helpful for troubleshooting equivocal early slips and can inform operative technique and adjuvant therapy candidacy in more severe cases. This review provides a comprehensive approach to imaging suspected slipped capital femoral epiphysis, with an emphasis on early detection and potential pitfalls.

Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes bone length, regulates cortical and trabecular bone mass, and maintains growth plate architecture and width in a sex- and site-specific manner in mice.

Tartrate-resistant acid phosphatase (TRAP) serum levels reflect osteoclast number, bone remodeling activity, and fracture risk. Deletion or loss of function of TRAP results in short stature in mice and man. Yet, the impact and mechanisms of TRAP for the site- and sex-specific development of bone and cartilage is not well understood. Here, we use a global TRAP knockout (TRAPKO) and wildtype littermate control (WT) mice of both sexes to investigate TRAP as a possible sex- and site-specific regulator of bone and growth plate development. TRAPKO mice of both sexes weighed less and had shorter tibial length than their WT, features that were more accentuated in male than female TRAPKO mice. These changes were not associated with a general reduction in growth as not all organs displayed a proportionally lower mass, and serum IGF-1 was unchanged. Using µCT and site-specificity analysis of the cortical bone revealed wider proximal tibia, a higher trabecular thickness, and lower trabecular separation in male TRAPKO compared to WT mice, an effect not seen in female mice. Histomorphometric analysis revealed that the growth plate height as well as height of terminal hypertrophic chondrocytes were markedly increased, and the number of columns was decreased in TRAPKO mice of both sexes. These effects were more accentuated in female mice. Proliferation and differentiation of bone marrow derived macrophages into osteoclasts, as well as C-terminal cross links were normal in TRAPKO mice of both sexes. Collectively, our results show that TRAP regulates bone and cartilage development in a sex-and site-specific manner in mice.

Fibronectin isoforms promote postnatal skeletal development.

Fibronectin (FN) is a ubiquitous extracellular matrix glycoprotein essential for the development of various tissues. Mutations in FN cause a unique form of spondylometaphyseal dysplasia, emphasizing its importance in cartilage and bone development. However, the relevance and functional role of FN during skeletal development has remained elusive. To address these aspects, we have generated conditional knockout mouse models targeting the cellular FN isoform in cartilage (cFNKO), the plasma FN isoform in hepatocytes (pFNKO), and both isoforms together in a double knockout (FNdKO). We used these mice to determine the relevance of the two principal FN isoforms in skeletal development from postnatal day one to the adult stage at two months. We identified a distinct topological FN deposition pattern in the mouse limb during different gestational and postnatal skeletal development phases, with prominent levels at the resting and hypertrophic chondrocyte zones and in the trabecular bone. Cartilage-specific cFN emerged as the predominant isoform in the growth plate, whereas circulating pFN remained excluded from the growth plate and confined to the primary and secondary ossification centers. Deleting either isoform independently (cFNKO or pFNKO) yielded only relatively subtle changes in the analyzed skeletal parameters. However, the double knockout of cFN in the growth plate and pFN in the circulation of the FNdKO mice significantly reduced postnatal body weight, body length, and bone length. Micro-CT analysis of the adult bone microarchitecture in FNdKO mice exposed substantial reductions in trabecular bone parameters and bone mineral density. The mice also showed elevated bone marrow adiposity. Analysis of chondrogenesis in FNdKO mice demonstrated changes in the resting, proliferating and hypertrophic growth plate zones, consistent alterations in chondrogenic markers such as collagen type II and X, decreased apoptosis of hypertrophic chondrocytes, and downregulation of bone formation markers. Transforming growth factor-ß1 and downstream phospho-AKT levels were significantly lower in the FNdKO than in the control mice, revealing a crucial FN-mediated regulatory pathway in chondrogenesis and bone formation. In conclusion, the data demonstrate that FN is essential for chondrogenesis and bone development. Even though cFN and pFN act in different regions of the bone, both FN isoforms are required for the regulation of chondrogenesis, cartilage maturation, trabecular bone formation, and overall skeletal growth.

MiR-322-5p is involved in regulating chondrocyte proliferation and differentiation in offspring's growth plate of maternal gestational diabetes.

Pregestational diabetes mellitus (PGDM) has an impact on fetal bone formation, but the underlying mechanism is still obscure. Although miRNAs have been extensively investigated throughout bone formation, their effects on fetal bone development caused by PGDM still need clarification. This study intends to examine the mechanism by which hyperglycemia impairs the bone formation of offspring via miR-322-5p (miR-322). In this study, miR-322 was selected by systemically screening utilizing bioinformatics and subsequent validation experiments. Using streptozotocin (STZ)-induced diabetic mice and ATDC5 cell lines, we found that miR-322 was abundantly expressed in the proliferative and hypertrophic zones of the growth plate, and its expression pattern was disturbed in the presence of hyperglycemia, suggesting that miR-322 is involved in the chondrocyte proliferation and differentiation in absence/presence of hyperglycemia. This observation was proved by manipulating miR-322 expression in ATDC5 cells by transfecting mimic and inhibitor of miR-322. Furthermore, Adamts5, Col12a1, and Cbx6 were identified as the potential target genes of miR-322, verified by the co-transfection of miR-322 inhibitor and the siRNAs, respectively. The evaluation criteria are the chondrocyte proliferation and differentiation and their relevant key gene expressions (proliferation: Sox9 and PthIh; differentiation: Runx2 and Col10a1) after manipulating the gene expressions in ATDC5 cells. This study revealed the regulative role miR-322 on chondrocyte proliferation and differentiation of growth plate by targeting Adamts5, Col12a1, and Cbx6 in hyperglycemia during pregnancy. This translational potential represents a promising avenue for advancing our understanding of bone-related complications in diabetic pregnancy and mitigating bone deficiencies in diabetic pregnant individuals, improving maternal and fetal outcomes.

Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search.

Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.

Transphyseal arthroscopic anterior cruciate ligament reconstruction in children under 12 years.

BACKGROUND: The incidence of anterior cruciate ligament (ACL) injuries in children is on the rise. Despite this trend, the optimal management of these injuries remains a matter of ongoing debate. In this light, our study seeks to assess the clinical, radiological, and functional outcomes of transphyseal ACL reconstruction in preadolescent patients in the medium-term. METHODS: This prospective study included preadolescent patients aged up to 12 years who underwent ACL transphyseal reconstruction between 2010 and 2020 and had a minimum follow-up of 2 years. Clinical assessments encompassed joint stability and range of motion. Furthermore, leg length discrepancy (LLD) and femorotibial alignment were evaluated both clinically and radiologically using full-length lower limb standing radiographs. Pre- and postoperative functional outcomes were assessed using the International Knee Documentation Committee (IKDC) and Lysholm scales, and the return to normal sports activity was evaluated using the ACL-Return to Sport after Injury (ACL-RSI) scale. Complications and relevant follow-up data were also recorded. Statistical analyses were conducted to evaluate these outcomes. RESULTS: A total of 35 preadolescent patients, consisting of 24 males and 11 females, with a mean age at surgery of 11.2 ± 0.7 years (8.7-12), were included in the study. The mean follow-up was 52.3 ± 20.7 months (24.1-95.9). No significant growth disturbances or clinically relevant LLD were evidenced. All patients demonstrated clinically stable knees with full range of motion at the 2-year follow-up. There were statistically significant improvements in pre- and postoperative IKDC (39.3 ± 13.5 vs. 99.7 ± 0.8, p < 0.005) and Lysholm scores (48.2 ± 15.1 vs. 99.6 ± 1.4, p < 0.005). All but two patients were able to return to their pre-injury level of sports activity, with a mean ACL-RSI score of 93.5 ± 1.3. The analysis revealed an 8.6% rerupture rate and an 11.4% rate of contralateral ACL injuries, with 5-year survival rates of 92.3% and 88.8%, respectively. Subgroup analyses based on age, gender, surgical delay, or associated meniscal lesions did not reveal any significant differences in functional outcomes. Additionally, there was no discernible relationship between age or timing of ACL reconstruction and the risk of meniscal injuries. CONCLUSIONS: Our study reinforces the value of ACL reconstruction in skeletally immature preadolescent patients, with transphyseal technique proven to be a safe, effective, and technically simpler option, even for children under the age of 12. The findings indicate excellent functional outcomes, a high rate of successful return to sporting activities, and minimal to no incidence of growth-related complications in the medium-term. LEVEL OF EVIDENCE: Level II, prospective comparative cohort study, before and after intervention.

Intermittent mechanical loading on mouse tibia accelerates longitudinal bone growth by inducing PTHrP expression in the female tibial growth plate.

It is not clear as to whether weight bearing and ambulation may affect bone growth. Our goal was to study the role of mechanical loading (one of the components of ambulation) on endochondral ossification and longitudinal bone growth. Thus, we applied cyclical, biologically relevant strains for a prolonged time period (4 weeks) to one tibia of juvenile mice, while using the contralateral one as an internal control. By the end of the 4-week loading period, the mean tibial growth of the loaded tibiae was significantly greater than that of the unloaded tibiae. The mean height and the mean area of the loaded tibial growth plates were greater than those of the unloaded tibiae. In addition, in female mice we found a greater expression of PTHrP in the loaded tibial growth plates than in the unloaded ones. Lastly, microCT analysis revealed no difference between loaded and unloaded tibiae with respect to the fraction of bone volume relative to the total volume of the region of interest or the tibial trabecular bone volume. Thus, our findings suggest that intermittent compressive forces applied on tibiae at mild-moderate strain magnitude induce a significant and persistent longitudinal bone growth. PTHrP expressed in the growth plate appears to be one growth factor responsible for stimulating endochondral ossification and bone growth in female mice.

Transcriptome analysis reveals the pathogenesis of spontaneous tibial dyschondroplasia in broilers.

Tibial dyschondroplasia (TD) is a severe bone disease that affects fast-growing broiler chickens and causes economic loss. Despite previous studies, the regulatory mechanism of TD remains unclear and is thought to be primarily based on thiram induction, which may differ from that of naturally occurring diseases. To better understand TD, a digital X-ray machine was used in the present study to determine its incidence in four hundred yellow-feathered broiler chickens. The results showed that the incidence of TD was 22% after 6 weeks and gradually decreased after 8 and 10 weeks. The body weight of broilers with TD decreased significantly compared to that of NTD broilers. In addition, the length and density of the tibia were reduced after eight and 10 weeks, and the density of the tibia was reduced after 6 weeks compared with the NTD chickens. This study also examined tibial quality parameters from TD (n = 12) and NTD broilers (n = 12) and found that bone mineral content, bone mineral density, bone ash content, calcium content, and phosphorus content were significantly reduced in TD broilers. Transcriptome analysis revealed 849 differentially expressed genes (DEGs) in the growth plate between TD (n = 6) and NTD groups (n = 6). These genes were enriched in ECM-receptor interaction, cytokine-cytokine receptor interaction, calcium signaling pathway, and TGF-ß signaling. Genes encoding the alpha chain of type XII collagen, that is, COL1A1, COL5A1, and COL8A1) were identified as critical in the regulatory network of TD. Gene set enrichment analysis (GSEA) revealed that the pathways of cartilage development, circulatory system development, and nervous system development were changed in the growth plates of TD birds. In the blood transcriptome, 12 DEGs were found in TD (n = 4) and NTD chickens (n = 4), and GSEA revealed that the pathways from TD broilers' blood related to the phagosome, linoleic acid metabolism, monoatomic ion homeostasis, and calcium ion transport were downregulated. This study provides a comprehensive understanding of TD, including its effects on tibial quality, tibial changes, and the circulatory system, along with identifying important genes that may lead to the development of TD.

Sustained release of MAPK14-targeting siRNA from polyelectrolyte complex hydrogels mitigates MSC osteogenesis in vitro with potential application in growth plate injury.

The growth plate is a cartilage structure at the end of long bones which mediates growth in children. When fractured, the formation of bony repair tissue known as a "bony bar" can occur and cause limb deformities. There are currently no effective clinical solutions for the prevention of the bony bar formation or regeneration of healthy growth plate cartilage after a fracture. This study employs previously developed alginate/chitosan polyelectrolyte complex (PEC) hydrogels as a sustained release vehicle for the delivery of short-interfering RNA (siRNA). Specifically, the siRNA targets the p38-MAPK pathway in mesenchymal stem cells (MSCs) to prevent their osteogenic differentiation. In vitro experimental findings show sustained release of siRNA from the hydrogels for 6 months. Flow cytometry and confocal imaging indicate that the hydrogels release siRNA to effectively knockdown GFP expression over a sustained period. MAPK-14 targeting siRNA was used to knockdown the expression of MAPK-14 and correspondingly decrease the expression of other osteogenic genes in MSCs in vitro over the span of 21 days. These hydrogels were used in a rat model of growth plate injury to determine whether siMAPK-14 released from the gels could inhibit bony bar formation. No significant reduction of bony bar formation was seen in vivo at the one concentration of siRNA examined. This PEC hydrogel represents a significant advancement for siRNA sustained delivery, and presents an interesting potential therapeutic delivery system for growth plate injuries and other regenerative medicine applications.

Tibial Damage Caused by T-2 Toxin in Goslings: Bone Dysplasia, Poor Bone Quality, Hindered Chondrocyte Differentiation, and Imbalanced Bone Metabolism.

T-2 toxin, the most toxic type A trichothecene, is widely present in grain and animal feed, causing growth retardation and tissue damage in poultry. Geese are more sensitive to T-2 toxin than chickens and ducks. Although T-2 toxin has been reported to cause tibial growth plate (TGP) chondrodysplasia in chickens, tibial damage caused by T-2 toxin in geese has not been fully demonstrated. This study aims to investigate the adverse effects of T-2 toxin on tibial bone development, bone quality, chondrocyte differentiation, and bone metabolism. Here, forty-eight one-day-old male Yangzhou goslings were randomly divided into four groups and daily gavaged with T-2 toxin at concentrations of 0, 0.5, 1.0, and 2.0 mg/kg body weight for 21 days, respectively. The development of gosling body weight and size was determined by weighing and taking body measurements after exposure to different concentrations of T-2 toxin. Changes in tibial development and bone characteristics were determined by radiographic examination, phenotypic measurements, and bone quality and composition analyses. Chondrocyte differentiation in TGP and bone metabolism was characterized by cell morphology, tissue gene-specific expression, and serum marker levels. Results showed that T-2 toxin treatment resulted in a lower weight, volume, length, middle width, and middle circumference of the tibia in a dose-dependent manner (p < 0.05). Moreover, decreased bone-breaking strength, bone mineral density, and contents of ash, Ca, and P in the tibia were observed in T-2 toxin-challenged goslings (p < 0.05). In addition, T-2 toxin not only reduced TGP height (p < 0.05) but also induced TGP chondrocytes to be disorganized with reduced numbers and indistinct borders. As expected, the apoptosis-related genes (CASP9 and CASP3) were significantly up-regulated in chondrocytes challenged by T-2 toxin with a dose dependence, while cell differentiation and maturation-related genes (BMP6, BMP7, SOX9, and RUNX2) were down-regulated (p < 0.05). Considering bone metabolism, T-2 toxin dose-dependently and significantly induced a decreased number of osteoblasts and an increased number of osteoclasts in the tibia, with inhibited patterns of osteogenesis-related genes and enzymes and increased patterns of osteoclast-related genes and enzymes (p < 0.05). Similarly, the serum Ca and P concentrations and parathyroid hormone, calcitonin, and 1, 25-dihydroxycholecalciferol levels decreased under T-2 toxin exposure (p < 0.05). In summary, 2.0 mg/kg T-2 toxin significantly inhibited tibia weight, length, width, and circumference, as well as decreased bone-breaking strength, density, and composition (ash, calcium, and phosphorus) in 21-day-old goslings compared to the control and lower dose groups. Chondrocyte differentiation in TGP was delayed by 2.0 mg/kg T-2 toxin owing to cell apoptosis. In addition, 2.0 mg/kg T-2 toxin promoted bone resorption and inhibited osteogenesis in cellular morphology, gene expression, and hormonal modulation patterns. Thus, T-2 toxin significantly inhibited tibial growth and development with a dose dependence, accompanied by decreased bone geometry parameters and properties, hindered chondrocyte differentiation, and imbalanced bone metabolism.

The metalloproteinase PAPP-A is required for IGF-dependent chondrocyte differentiation and organization.

Insulin-like growth factor (IGF) signaling is required for proper growth and skeletal development in vertebrates. Consequently, its dysregulation may lead to abnormalities of growth or skeletal structures. IGF is involved in the regulation of cell proliferation and differentiation of chondrocytes. However, the availability of bioactive IGF may be controlled by antagonizing IGF binding proteins (IGFBPs) in the circulation and tissues. As the metalloproteinase PAPP-A specifically cleaves members of the IGFBP family, we hypothesized that PAPP-A activity liberates bioactive IGF in cartilage. In PAPP-A knockout mice, the femur length was reduced and the mice showed a disorganized columnar organization of growth plate chondrocytes. Similarly, zebrafish lacking pappaa showed reduced length of Meckel's cartilage and disorganized chondrocytes, reminiscent of the mouse knockout phenotype. Expression of chondrocyte differentiation markers (sox9a, ihha, and col10a1) was markedly affected in Meckel's cartilage of pappaa knockout zebrafish, indicating that differentiation of chondrocytes was compromised. Additionally, the zebrafish pappaa knockout phenotype was mimicked by pharmacological inhibition of IGF signaling, and it could be rescued by treatment with exogenous recombinant IGF-I. In conclusion, our data suggests that IGF activity in the growing cartilage, and hence IGF signaling in chondrocytes, requires the presence of PAPP-A. The absence of PAPP-A causes aberrant chondrocyte organization and compromised growth in both mice and zebrafish.

Accelerated Linear Growth during Erdafitinib Treatment: An FGFR-Related, but Growth Factor and Sex Steroid-Independent Mechanism?

INTRODUCTION: Growth acceleration during postnatal growth only occurs during puberty as a physiological event and during catch-up growth mediated by growth-promoting therapies in growth disorders. Here we report on novel observations of skeletal symptoms during treatment with erdafitinib, a tyrosine kinase inhibitor (TKI) prescribed on the basis of a compassionate-use program. METHODS: Analysis of anthropometric, biochemical, clinical, and radiographic data of patients with CNS tumors who revealed an unanticipated growth spurt with initiation of therapy with erdafitinib was performed retrospectively. RESULTS: Linear growth acceleration was independent of sex steroids and IGF1 levels, which is especially remarkable in the context of heavily pretreated pediatric neuro-oncology patients with severe growth impairment before initiation of therapy. Growth acceleration was accompanied by a distinct widening of the growth plate and enhanced metaphyseal mineralization shortly after the start of TKI therapy. CONCLUSIONS: While targeted therapies including TKIs have become an essential part of adult cancer treatment, applications in children are still limited. Off-target effects specific to the pediatric population have been observed in various organ systems; however, knowledge about the effect of TKIs on the growing skeleton is scarce. Treatment with erdafitinib inhibits FGFR3-mediated effects and thus represents a very logical hypothetical framework of growth factor and sex steroid-independent growth acceleration.

Juvenile hallux valgus: Comparison of three types of osteotomy and medium-term postoperative results.

BACKGROUND: There is no consensus on the treatment of juvenile hallux valgus (JHV). Numerous surgical techniques have been described, none of which has been proven to be superior and the mid-term results of these methods are not well known. Our objective was to compare the mid-term clinical, radiographic, and functional results of three metatarsal osteotomy techniques. METHODS: Patients under 18 years of age operated on for JHV between January 2010 and December 2019 were included in this multicenter retrospective study. Patients were excluded if they had non-idiopathic hallux valgus or if their postoperative follow-up was less than 3 years. The surgical techniques used were metatarsal osteotomies: basimetatarsal, scarf, or distal. During follow-up visits, we collected HMIS-AOFAS (Hallux Metatarsophalangeal Interphalangeal Scale-American Orthopedic Foot and Ankle Society) and Visual Analogue Scale (VAS) scores, acquired radiographs, and recorded complications and recurrences. Secondarily, the study population was stratified according to physis status (open vs. closed). RESULTS: During the study period, 18 patients (26 feet) met the inclusion criteria. The median postoperative follow-up was 6.5 (4.1) years. At the end of follow-up, the median HMIS score was 79.0 (20.0), the mean hallux valgus angle (HVA) improvement was 13.2° (16.8), and the complication and recurrence rates were 31 % and 23 %, respectively. There was no significant difference in the outcome measures between the three techniques or any difference according to physis status at the time of surgery. DISCUSSION AND CONCLUSION: The functional and radiographic results of metatarsal osteotomies are good in the medium term, regardless of the osteotomy site. Our results are comparable to those published in the literature. As our sample size was limited, it did not lead to the identification of statistically significant differences.

Imaging of sports injuries in adolescents.

Musculoskeletal injuries in adolescents tend to occur in particular locations and have distinct characteristics, as they affect an immature skeleton. Increased engagement in sports, extended training and competition periods, and early specialization in specific sports, among other factors, have contributed significantly to the rise in musculoskeletal sports injuries in adolescents. Furthermore, females show a particularly pronounced increase in sports participation, where anatomical and hormonal factors play crucial roles in the development and increased frequency of sports-related injuries. Consequently, there is a growing demand for diagnostic imaging techniques. Musculoskeletal and pediatric radiologists require a comprehensive understanding of intrinsic and extrinsic risk factors and the successive stages of skeletal development that can influence the specific characteristics of sports injuries in adolescents. These aspects are crucial for the diagnostic, prognostic, and therapeutic management of these injuries and for mitigating chronic conditions that could compromise future sports participation. This review analyzes the primary musculoskeletal injuries in adolescent athletes and highlights the pivotal role of different imaging methods in their diagnosis and management.

Cephalometric Evaluation of Children with Short Stature of Genetic Etiology: A Review.

Introduction: A plethora of biological molecules regulate chondrogenesis in the epiphyseal growth plate. Disruptions of the quantity and function of these molecules can manifest clinically as stature abnormalities of various etiologies. Traditionally, the growth hormone/insulin-like growth factor 1 (IGF1) axis represents the etiological centre of final stature attainment. Of note, little is known about the molecular events that dominate the growth of the craniofacial complex and its correlation with somatic stature. Aim: Given the paucity of relevant data, this review discusses available information regarding potential applications of lateral cephalometric radiography as a potential clinical indicator of genetic short stature in children. Materials and Methods: A literature search was conducted in the PubMed electronic database using the keywords: cephalometric analysis and short stature; cephalometric analysis and achondroplasia; cephalometric analysis and hypochondroplasia; cephalometric analysis and skeletal abnormalities; cephalometr* and SHOX; cephalometr* and CNP; cephalometr* and ACAN; cephalometr* and CNVs; cephalometr* and IHH; cephalometr* and FGFR3; cephalometr* and Noonan syndrome; cephalometr* and "Turner syndrome"; cephalometr* and achondroplasia. Results: In individuals with genetic syndromes causing short stature, linear growth of the craniofacial complex is confined, following the pattern of somatic short stature regardless of its aetiology. The angular and linear cephalometric measurements differ from the measurements of the average normal individuals and are suggestive of a posterior placement of the jaws and a vertical growth pattern of the face. Conclusions: The greater part of the existing literature regarding cephalometric measurements in short-statured children with genetic syndromes provides qualitative data. Furthermore, cephalometric data for individuals affected with specific rare genetic conditions causing short stature should be the focus of future studies. These quantitative data are required to potentially establish cut-off values for reference for genetic testing based on craniofacial phenotypes.

How to avoid genu recurvatum in leg-length discrepancy treated with tension-band plates. A volumetric magnetic resonance analysis.

Aims and objectives: Genu recurvatum deformity after treatment of leg-length discrepancy (LLD) with tension-band plating is a recognized, but poorly described phenomenon in medical literature. The aim of this study was to evaluate clinical and radiological features of patients treated with tension-band plating for LLD assessing the development of a recurvatum deformity and its relationship to plate and screw disposition in a transversal plane, thus attempting to establish optimal plate positioning. Materials and methods: Retrospective study of children with LLD treated with tension-band plating. Primary endpoints were clinical and radiological knee recurvatum and anterior and posterior physeal areas measured drawing a line spanning from the lateral to the medial tension-band plates in the transverse plane using volumetric magnetic resonance imaging (vMRI). These findings were compared between patients with and without knee recurvatum. Results: Twelve children (mean age 11.7 years) were included. Average follow-up was 2.6 years (1.5-5.0). Tension-band plating led to a significant reduction in LLD (mean, 15 mm). Six patients (50 %) developed clinical genu recurvatum (mean, 22°). According to vMRI, patients with genu recurvatum had a larger posterior to anterior physeal area ratio in both distal femur (1.6 versus 0.9, p < 0.05) and proximal tibial physes (2.2 versus 1.0, p < 0.05). Conclusion: The optimal position of the tension-band plates in distal femoral and proximal tibial physes should be in a point where a posterior to anterior physeal areas ratio is around 1.0, so as to achieve an even distribution of the physeal areas in the multidimensional physeal transverse plane. This point anatomically corresponds in the sagittal X-ray view to an imaginary line located just anterior to the posterior diaphyseal cortical bone on a true lateral radiograph for both femur and tibia.