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Ultrashort echo time (UTE) MRI can quantify the major proton pool densities in cortical bone, including total (TWPD), bound (BWPD), and pore water (PWPD) proton densities, as well as the macromolecular proton density (MMPD), associated with the collagen content, which is calculated using macromolecular fraction (MMF) from UTE magnetization transfer (UTE-MT) modeling. This study aimed to investigate the differences in water and collagen contents in tibial cortical bone, between female osteopenia (OPe) patients, osteoporosis (OPo) patients, and young participants (Young). Being postmenopausal and above 55 yr old were the inclusion criteria for OPe and OPo groups. The tibial shaft of 14 OPe (72.5 ± 6.8 yr old), 31 OPo (72.0 ± 6.4 yr old), and 31 young subjects (28.0 ± 6.1 yr old) were scanned using a knee coil on a clinical 3T scanner. Basic UTE, inversion recovery UTE, and UTE-MT sequences were performed. Investigated biomarkers were compared between groups using Kruskal-Wallis test. Spearman's correlation coefficients were calculated between the TH DXA T-score and UTE-MRI results. MMF, BWPD, and MMPD were significantly lower in OPo patients than in the young group, whereas T1, TWPD, and PWPD were significantly higher in OPo patients. The largest OPo/Young average percentage differences were found in MMF (41.9%), PWPD (103.5%), and MMPD (64.0%). PWPD was significantly higher (50.7%), while BWPD was significantly lower (16.4%) in OPe than the Young group on average. MMF was found to be significantly lower (27%) in OPo patients compared with OPe group. T1, MMF, TWPD, PWPD, and MMPD values significantly correlated with the TH DXA T-scores (provided by the patients and only available for OPe and OPo patients). DXA T-score showed the highest correlations with PWPD (R = 0.55) and MMF (R = 0.56) values. TWPD, PWPD, and MMF estimated using the UTE-MRI sequences were recommended to evaluate individuals with OPe and OPo.

Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated. In pre-clinical models of multiple myeloma, osteoclast-driven bone loss was reduced by eliglustat in a mechanistically separate manner to zoledronic acid, a bisphosphonate that prevents osteoclast-mediated bone destruction. Autophagic degradation of TNF receptor-associated factor 3 (TRAF3), a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. By altering GSL composition, eliglustat prevented lysosomal degradation whilst exogenous addition of missing GSLs rescued TRAF3 degradation to restore osteoclast formation in bone marrow cells from myeloma patients. This work highlights the clinical potential of eliglustat as a therapy for myeloma bone disease. Furthermore, using eliglustat as a lysosomal inhibitor in osteoclasts may widen its therapeutic uses to other bone disorders such as bone metastasis, osteoporosis and inflammatory bone loss.

Chronic kidney disease–mineral and bone disorder (CKD-MBD) contributes substantially to the burden of cardiovascular disease and fractures in patients with CKD. An increasing arsenal of diagnostic tools, including bone turnover markers and bone imaging, is available to support clinicians in the management of CKD-associated osteoporosis. Although not mandatory, a bone biopsy remains useful in the diagnostic workup of complex cases. In this special report, the European Renal Osteodystrophy (EUROD) initiative introduces the concept of a kidney–bone multidisciplinary team (MDT) for the diagnosis and clinical management of challenging cases of CKD-associated osteoporosis. In 2021, the EUROD initiative launched virtual clinical-pathological case conferences to discuss challenging cases of patients with CKD-associated osteoporosis, in whom a bone biopsy was useful in the diagnostic workup. Out of these, we selected four representative cases and asked a kidney–bone MDT consisting of a nephrologist, an endocrinologist and a rheumatologist to provide comments on the diagnostic and therapeutic choices. These cases covered a broad spectrum of CKD-associated osteoporosis, including bone fracture in CKD G5D, post-transplant bone disease, disturbed bone mineralization, severely suppressed bone turnover and severe hyperparathyroidism. Comments from the MDT were, in most cases, complementary to each other and additive to the presented approach in the cases. The MDT approach may thus set the stage for improved diagnostics and tailored therapies in the field of CKD-associated osteoporosis. We demonstrate the clinical utility of a kidney-bone MDT for the management of patients with CKD-MBD and recommend their establishment at local, national, and international levels. [ABSTRACT FROM AUTHOR]

RANKL and its cognate receptor RANK are crucial regulators of bone metabolism in physiological as well as in pathological conditions. Here we go through the works that unveiled the paramount role of this signaling pathway. We focus on the RANKL cytokine, whose alterations are responsible for rare and common bone diseases. We describe recent insights on the regulation of RANKL expression, which provide new hints for the pharmacological regulation of this molecule. Based on the multiple functions exerted by RANKL (within and outside the bone tissue), we advise caution regarding the potential unintended consequences of its inhibition. [ABSTRACT FROM AUTHOR]

Mastocytosis is a heterogeneous group of disorders, characterized by accumulation of clonal mast cells which can infiltrate several organs, most often spine (70%). The pathogenesis of mastocytosis bone disease is poorly understood. The main aim of the study was to investigate whether neoplastic mast cells may be the source of sclerostin and whether there is an association between sclerostin and selected bone remodeling markers with mastocytosis related bone disease. We assessed sclerostin, bioactive sclerostin, and SOST gene expression in HMC-1.2 human mast cell culture supernatants and plasma of SM patients (n = 39). We showed that human mast cells can secrete sclerostin, and after their stimulation with IL-6, there is a significant increase in SOST gene expression. We observed significantly higher levels of sclerostin in patients diagnosed with more advanced disease. We observed a statistically significant correlation between concentations of sclerostin and its bioactive form and the concentration of alkaline phosphatase (ALP), and between sclerostin and interleukin-6 (IL-6). We observed that significantly higher sclerostin concentrations are present in patients with increased sclerosis of the spongy bone. Sclerostin may serve as a marker of more advanced disease and bone disease in mastocytosis. Further studies are justified to evaluate its role in mastocytosis. [ABSTRACT FROM AUTHOR]

Autoinflammatory bone diseases (AIBDs) constitute a recently identified subset of autoinflammatory diseases. These conditions are characterized by an exaggerated inflammatory response in the bones without any apparent etiology. Inflammatory bone lesions associated with AIBDs exhibit chronic inflammation, are typically culture-negative, and do not exhibit discernible microorganisms on histopathological examination. The most common and representative AIBD is chronic non-bacterial osteomyelitis (CNO), which is also known as chronic recurrent multifocal osteomyelitis. Another variant of CNO, which is typically observed in older teenagers or adults, is known as synovitis, acne, hyperostosis, pustulosis, osteitis syndrome. This condition is distinguished by its notable skin manifestations. Advancements in genetic research have led to the identification of three novel monogenic subtypes within the category of AIBDs. These include Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome, and interleukin-1 receptor antagonist deficiency syndrome. Another monogenic AIBD, called cherubism, affects only the maxilla and mandible. Data on the diagnosis and treatment of these rare diseases are extremely limited. However, if not diagnosed and treated promptly, it can result in significant complications, including severe disability and mortality. Thus, it is imperative to maintain a high level of clinical awareness of these diseases. These rare diagnoses should be considered in patients with musculoskeletal complaints in whom no specific etiology can be identified or in patients with systemic manifestations such as cutaneous and gastrointestinal symptoms or fever. In such patients, the diagnostic process, which encompasses imaging and genetic studies, should be initiated promptly. [ABSTRACT FROM AUTHOR]

Rheumatic disorders in children include inflammatory arthritis, inflammatory bone disorders such as chronic nonbacterial osteomyelitis (CNO), connective tissue disorders, and vasculitides (juvenile dermatomyositis, scleroderma). The diagnosis in these children is based on a combination of history, clinical examination, and laboratory investigations. Radiographs play an important role in children with arthritis, who have atypical presentation or for assessment of disease-related damage and differentiation from mimics. Further, radiographs also have an ancillary role in the assessment of musculoskeletal disorders such as dermatomyositis and hemophilia. This review seeks to present a detailed analysis of the specific indications and advantages of radiographs in the situations. Further, a structured reporting format for assessment of radiographs in pediatric rheumatic disorders has also been presented for the reader's reference. [ABSTRACT FROM AUTHOR]

Osteoporosis is a metabolic bone disorder characterized by low bone mass and bone mineral density. It is the most prevalent bone disease and a common cause of fracture in aging adults. Low bone mass, as seen in osteoporosis, results from an imbalance between osteoblast and osteoclast activity. Gli1+ cells are indispensable to the maintenance of bone tissue homeostasis. These cells give rise to osteoprogenitors and are present at the osteogenic fronts of long bones in adult mice. Runx2 is a key regulator of osteogenesis and plays a crucial role in osteoblastic differentiation and maturation during development. However, its function in maintaining adult bone tissue homeostasis remains unclear. In this study, we investigated the role of Runx2 in maintaining adult bone homeostasis in the context of ovariectomy-induced estrogen deficiency, a model for postmenopausal osteoporosis. Our results show that deletion of Runx2 in the Gli1+ osteogenic progenitor population prevents loss of both cortical and trabecular bone mass and mineralization after ovariectomy. At the cellular level, loss of Runx2 leads to a decrease in osteoclast activity. Our study indicates that Runx2 is essential for maintaining adult bone tissue homeostasis by regulating osteoclast differentiation. [ABSTRACT FROM AUTHOR]

Introduction: Bisphosphonates (BPs) are widely used for osteoporosis and cancer‐induced bone diseases due to their antiresorptive properties, yet they pose risks such as medication‐related osteonecrosis of the jaw (MRONJ). Methods: We present a unique case of concurrent oral squamous cell carcinoma (SCC) and MRONJ in a 72‐year‐old female chronically treated with oral ibandronate for osteoporosis. Following a dental extraction, she developed a nonhealing wound in the maxilla. Following conservative treatment, the patient underwent a maxillectomy and extensive tissue reconstructions to control her infection and address suspicions of an underlying malignancy. Results: Histopathological examinations confirmed simultaneous osteonecrosis and well‐differentiated SCC in the maxillary sinus and surrounding tissues. Despite multiple surgeries, the patient's disease progressed rapidly. Upon examining the literature for patients with a history of BP use diagnosed with MRONJ and/or SCC, a total of 16 cases report a diagnostic dilemma between MRONJ and locoregional SCC. Three of the 16 cases report a final diagnosis of concurrent MRONJ and SCC. This report is the fourth reported case of concurrency to date. Conclusions: The patient's complex clinical course underscores the diagnostic challenges and therapeutic dilemmas in managing concurrent MRONJ and SCC, highlighting the need for vigilant monitoring and interdisciplinary collaboration in similar cases. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Subjects and Methods Results Conclusions To assess the sclerostin, β‐catenin, and tryptase expression in fibro‐osseous lesions (FOL) of the jaws.Immunohistochemistry analysis was performed for these proteins on FOL and non‐lesional bone. The sclerostin‐positive cells were scored from 0 (no expression) to 3 (high expression).We analyzed 46 FOL biopsies and selected 38 patients. Categorization showed 15 fibrous dysplasia (FD), eight juvenile trabecular ossifying fibroma (JTOF), two psammomatoid ossifying fibroma (PsOF), and 13 FOL. We found more sclerostin‐positive cells in fibrous tissue than in bone, showing a phenotype like mast cells with strong dot‐cytoplasmic positivity. The analysis of sclerostin‐positive cell lesions (scored as 2 and 3) showed also tryptase positivity in 80.9% of 21 biopsies. β‐catenin was diffusely expressed on the fibrous component, mostly with cytosol staining. Non‐lesional bone showed sclerostin expression in medullary spaces and a few osteocytes.Sclerostin‐positive cells are mostly found in the fibrous tissue of FOL, and the tryptase mast cell marker was present in most of the lesions that were positive for sclerostin. [ABSTRACT FROM AUTHOR]

Background: Emerging research indicates that gut microbiota (GM) are pivotal in the regulation of immune-mediated bone diseases. Nonunion, a bone metabolic disorder, has an unclear causal relationship with GM and immune cells. This study aims to elucidate the causal relationship between GM and nonunion using Mendelian Randomization (MR) and to explore the mediating role of immune cells. Methods: Using a two-step, two-sample Mendelian randomization approach, this study explores the causal link between GM and nonunion, as well as the mediating role of immune cells in this relationship. Data were sourced from multiple cohorts and consortiums, including the MiBioGen consortium. GM data were derived from a recently published dataset of 473 gut microbiota, and nonunion data were obtained from genome-wide association studies (GWAS). Results: MR analysis identified 12 bacterial genera with protective effects against nonunion and seven bacterial genera associated with a higher risk of nonunion, including Agathobacter sp000434275, Aureimonas, Clostridium M, Lachnospirales, Megamonas funiformis, and Peptoccia. Reverse MR analysis indicated that nonunion does not influence GM. Additionally, MR analysis identified 12 immune cell types positively associated with nonunion and 14 immune cell types negatively associated with nonunion. Building on these findings, we conducted mediation MR analysis to identify 24 crucial GM and immune cell-mediated relationships affecting nonunion. Notably, Campylobacter D, Megamonas funiformis, Agathobacter sp000434275, Lachnospirales, Clostridium E sporosphaeroides, and Clostridium M significantly regulated nonunion through multiple immune cell characteristics. Conclusions: To our knowledge, our research results are the first to emphasize a causal relationship between the gut microbiome and nonunion, potentially mediated by immune cells. The correlations and mediation effects identified in our study provide valuable insights into potential therapeutic strategies targeting the gut microbiome, informing global action plans. [ABSTRACT FROM AUTHOR]

This study aimed to provide real-world evidence on progression risk in patients with high-risk smoldering multiple myeloma (SMM). This retrospective, observational study leveraged data from the Flatiron Health database. Eligible patients had SMM and relevant measures to apply Mayo 2018, International Myeloma Working Group (IMWG) 2020, and AQUILA trial risk criteria. Time to progression to active MM (TTP), progression or death (PFS), and death or progression on first-line MM therapy (PFS2) were evaluated using Kaplan–Meier methods and multivariate Cox regression models adjusted for age, Charlson Comorbidity Index, and time from SMM diagnosis to risk classification date. Across the three risk models (Mayo 2018, IMWG 2020, and AQUILA trial), high-risk patients with SMM had 3.0–4.0 times the risk of TTP, 2.1–3.5 times the risk of PFS, and 1.7–3.2 times the risk of PFS2 versus non-high-risk patients (p < 0.001 for all comparisons). Similar results were observed when patients with early treatment, early progression, and/or bone disease were excluded. This study demonstrates that high-risk patients with SMM have worse prognoses than non-high-risk patients, regardless of the criteria used, and highlights a need for early intervention testing. [ABSTRACT FROM AUTHOR]

Osteoblasts are the functional cells capable of bone formation in the bone microenvironment and play an important role in bone growth, development, and the maintenance of bone mass. The cells cultured in vitro are derived from preosteoblasts in tissues and possess the ability to divide and proliferate. Osteoblasts form the bone matrix by secreting collagen and other matrix proteins, which provides a foundation for the deposition of minerals such as calcium and phosphorus, ultimately resulting in the formation of hard bone tissue. Bone diseases affect the quality of life and the aging of the population. Bone diseases such as osteoporosis, fractures, bone tumours, and arthritis have a significant impact on quality of life, especially among the elderly population. These realities remind us that we should pay more attention to bone and joint health. Therefore, it is particularly important to study the imaging and characterisation of mechanical properties of bone cells, which provides a basis for the research of bone diseases in human beings. [ABSTRACT FROM AUTHOR]

Background: Osteogenesis imperfecta (OI) is a rare hereditary bone disease resulting from a defect in collagen synthesis or processing, leading to bone fragility, frequent fractures and skeletal deformities. OI is associated with increased respiratory morbidity and mortality, but the mechanisms of lung involvement are poorly understood, and there are no data on the natural history of lung function. We studied lung function over time in a cohort of adult OI patients at one center. Methods: We used data from OI patients aged 15 and above followed up at the Lausanne university hospital between 2012 and 2023 with available pre-bronchodilator spirometry. Associations between spirometric measurements at first visit and clinical characteristics were studied through linear regression. Changes of spirometric variables over time were analysed through mixed linear regression. Models were adjusted for age, sex, height and OI type (Sillence classification). Results: Among 46 subjects, 24% had impaired spirometry at baseline, with similar distribution between restrictive (8.7%), obstructive (8.7%) and mixed (6.5%) ventilatory patterns. At first visit, higher age was associated with lower FEV1 (β = −0.019 l, p = 0.014) and lower FEV1/FVC (β = −0.175%, p = 0.012). A history of asthma was associated with higher FEV1 (β = 0.636 l, p = 0.028) and FVC (β = 0.834 l, p = 0.010). At first visit, FEV1 (β = −0.750 l, p = 0.006) and FVC (β = −0.859 l, p = 0.004) was lower in individuals with OI Sillence types 3, 4 or 5 compared to type 1. Over a mean follow-up of 3.4 years, smokers had a greater decline of FEV1/FVC compared to non-smokers (β = −6.592%, p = 0.007). Individuals with a mutation in the gene COL1A2 had 740 ml lower FVC compared to those with a mutation in COL1A1 (p = 0.037). After adjustment for sex, age, height and OI type, FEV1 increased by 26 ml (95% CI 8; 45) or 1.28%pred (0.51; 2.05) and FVC increased by 25 ml (95% CI 8; 43) or 0.93%pred (0.31; 1.55) per year of follow-up. Conclusions: An increase of FEV1 and FVC over time was observed in OI patients after adjustment for other variables, suggesting that the defective collagen synthesis may impact the pulmonary interstitium and lead to increased lung compliance and hyperinflation, in contrast to skeletal deformities, which reduce the thoracic volume. Lung function changes in OI thus result from the interplay of several mechanisms. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the relationship between bone mineral density (BMD) and digit ratio, with the goal of evaluating the potential of digit ratio as a marker for predicting osteoporosis-type bone diseases. The study sample included 200 patients (100 women and 100 men) who visited the Nuclear Medicine Clinic at Cumhuriyet University Research Hospital for check-ups, along with a control group of 100 healthy individuals (50 women and 50 men). Bone densitometry measurements were obtained for all participants, and the lengths of the second and fourth digits on both hands were measured using digital calipers. The results indicated a positive correlation between digit ratio and BMD, with this relationship being more pronounced in women. In men, significant positive correlations were found between the right-hand digit ratio and L BMD (r = 0.589), the right digit ratio and L T-score (r = 0.544), and the right digit ratio and L Z-score (r = 0.454). Similar positive associations were observed between the right digit ratio and femoral BMD (r = 0.608), femoral T-score (r = 0.465), and femoral Z-score (r = 0.362) (p < 0.05). For women, stronger positive correlations were identified between the right-hand digit ratio and L BMD (r = 0.707), the right digit ratio and L T-score (r = 0.815), and the right digit ratio and L Z-score (r = 0.737). Additionally, significant associations were noted between the right digit ratio and femoral BMD (r = 0.469), femoral T-score (r = 0.535), and femoral Z-score (r = 0.495) (p < 0.05). These findings suggest that the association between digit ratio and bone mineral density is stronger in women. In summary, individuals with a high digit ratio generally have higher bone density. [ABSTRACT FROM AUTHOR]

Visfatin, an adipokine secreted by various cell types, plays multifaceted pathophysiological roles in inflammatory conditions, including obesity, which is closely associated with osteoclastogenesis, a key process underlying bone loss and increased osteoporosis (OP) risk. However, the role of visfatin in osteoclastogenesis remains controversial. This study was conducted to investigate the effects of visfatin on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation from precursor cells in vitro. Our results demonstrated that although visfatin exhibited a modest osteoclast-inductive effect relative to that of RANKL, co-stimulation of bone marrow-derived macrophages (BMDMs) with visfatin and RANKL led to significantly enhanced osteoclast differentiation and activation compared to individual stimulation. Neutralization of visfatin activity using blocking antibodies before differentiation markedly suppressed RANKL-induced osteoclastogenesis, as evidenced by a near-complete absence of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts, decreased levels of nuclear factor of activated T cells cytoplasmic 1 and osteoclast-specific proteins, inhibition of nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and a decrease in resorption pit formation. Our findings underscore the critical role of visfatin in RANKL-induced osteoclastogenesis in vitro and highlight the RANKL/visfatin signaling axis as a potential therapeutic target for destructive bone loss-related diseases. [ABSTRACT FROM AUTHOR]

Organ‐on‐a‐chip, also known as "tissue chip," is an advanced platform based on microfluidic systems for constructing miniature organ models in vitro. They can replicate the complex physiological and pathological responses of human organs. In recent years, the development of bone and joint‐on‐chip platforms aims to simulate the complex physiological and pathological processes occurring in human bones and joints, including cell–cell interactions, the interplay of various biochemical factors, the effects of mechanical stimuli, and the intricate connections between multiple organs. In the future, bone and joint‐on‐chip platforms will integrate the advantages of multiple disciplines, bringing more possibilities for exploring disease mechanisms, drug screening, and personalized medicine. This review explores the construction and application of Organ‐on‐a‐chip technology in bone and joint disease research, proposes a modular construction concept, and discusses the new opportunities and future challenges in the construction and application of bone and joint‐on‐chip platforms. [ABSTRACT FROM AUTHOR]

Postmenopausal osteoporosis (PMOP) is a bone disease characterized by bone thinning and an increased risk of fractures due to estrogen deficiency. Current PMOP therapies often result in adverse side effects. The traditional medicinal plant Curculigo capitulata is commonly used to strengthen bones and support kidney function, but its role in treating PMOP is not well understood. This study aims to investigate the therapeutic effects of the total extract of Curculigo capitulata (Eocc) on PMOP and to explore the underlying mechanisms. The major components of the extract were identified using HPLC. Transcriptomics was employed to predict potential targets. An osteogenic differentiation model of MC3T3-E1 cells was used in vitro. The osteogenic potential of the Eocc was assessed through CCK-8 cell viability assays, alkaline phosphatase (ALP) staining, Alizarin Red staining, Western blotting, and qPCR. MCF-7 and HEK-293 cells were utilized to evaluate the estrogen-like activity of Eocc. Apoptosis rates were detected by flow cytometry. In vivo, a bilateral ovariectomized mouse model of PMOP was used to further validate the in vitro findings through histopathological analysis and WB results. The results demonstrated that the Eocc promoted the proliferation of MC3T3-E1 cells, increased ALP activity, and stimulated the formation of osteogenic mineralized nodules. It also upregulated the expression of osteogenic markers (Runx2, OCN, OPN, and BSP) at both the protein and mRNA levels. The Eocc induced the activation of ERα both in vitro and in vivo, initiating the Src/PI3K/AKT signaling pathway, leading to the phosphorylation of GSK3β and subsequent osteogenesis. The activation of this pathway also stimulated the phosphorylation of mTOR and p70S6K while downregulating cleaved caspase-3 and caspase-9. Additionally, the Eocc reduced apoptosis during osteogenic differentiation and promoted cell proliferation. These findings suggest that the Eocc facilitates osteoblast proliferation and differentiation, improving bone integrity in PMOP mice, and may represent a promising therapeutic candidate for managing PMOP. [ABSTRACT FROM AUTHOR]

3M syndrome is an autosomal recessive disorder characterized by short stature and skeletal developmental abnormalities. A Chinese girl with 3M syndrome and a novel OBSL1 (obscurin-like 1 gene) variant is presented. The patient is a 2-year-old girl who presented with short stature and had intrauterine growth retardation and low birth weight. Gene analysis revealed compound heterozygote mutations in the OBSL1 gene: c.458dupG (p.L154Pfs*100) and c.427dupG (p.A143Gfs*111). The c.427dupG mutation is novel. The c.458dupG mutation has been documented in five cases, occurring only in Chinese individuals, suggesting ethnic specificity. In cases of children with short stature presenting with intrauterine growth retardation, low birth weight, and skeletal developmental abnormalities, 3M syndrome should be considered. The c.458dupG mutation may be a hotspot mutation in the Chinese population. [ABSTRACT FROM AUTHOR]

Objective: Osteogenesis imperfecta (OI) consists of a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. The aim was to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients using targeted next-generation sequencing (NGS). Methods: A targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform in patients with a confirmed diagnosis of OI. Results: Fifty-six patients (female/male: 25/31) from 46 different families were included. Consanguinity was noted in 15 (32.6%) families. Based on Sillence classification 18 (33.1%) were type 1 OI, 1 (1.7%) type 2, 26 (46.4%) type 3 and 11 (19.6%) type 4. Median body weight was -1.1 (-6.8, - 2.5) standard deviation scores (SDS), and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity affected 30 (53.5%), while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected by NGS panel had not previously been reported and were also classified as pathogenic based on American College of Medical Genetics guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in any of the 13 OI genes on the panel. Conclusion: Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. Furthermore, nine new variants were identified in known OI genes which were classified as pathogenic by standard guidelines. [ABSTRACT FROM AUTHOR]

The article discusses the management of infected nonunions through the orthoplastic approach, focusing on the importance of achieving both a clean soft tissue envelope and skeletal continuity. Topics discussed include the principles of debridement, the role of plastic surgeons in soft tissue reconstruction, and strategies for assessing and planning the treatment of infected nonunions.