Search Results (68)

Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9⁺/Fgfr3⁺ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1⁺ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5⁺ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a–Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh–PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint. Full article

Background/Objectives: Malignant transformation of bone lesions, although rare, poses a major diagnostic and clinical challenge. Common benign lesions (e.g., osteochondroma, enchondroma, fibrous dysplasia, giant cell tumor), non-tumorous conditions (e.g., chronic osteomyelitis, irradiated bone, infarction), and low-grade malignancies (e.g., low-grade osteosarcoma, chondrosarcoma) can evolve into aggressive malignancies through distinct genetic, molecular, and microenvironmental pathways. Recognizing early malignant transformation on imaging is crucial for timely diagnosis and management. Methods: This review synthesizes current imaging characteristics, pathologic mechanisms, and clinical risk factors associated with malignant transformation of benign and low-grade malignancy bone lesions. Results: Atypical imaging findings and inaccurate biopsies can delay diagnosis. Aggressive features—such as cortical destruction, heterogeneous enhancement, and loss of internal matrix—should prompt further pathologic evaluation. Advanced imaging and a multidisciplinary approach with integrated clinicoradiologic–pathologic review are essential to minimize missed diagnoses. Patients with risk factors such as genetic syndromes, prior denosumab therapy, inadequate surgery, or prior radiation therapy require close monitoring or timely intervention. Conclusions: Radiologic–pathologic correlation remains central to distinguishing benign from malignant lesions. This review article emphasizes a comprehensive imaging-pathology overview of benign and low-grade malignancy bone lesions with malignant potential, aiming to improve diagnostic accuracy and outcomes in orthopedic oncology. Full article

Background: Focal cortical dysplasia (FCD) is a prevalent cause of drug-resistant epilepsy, but a comprehensive understanding of its pathogenesis at a cellular resolution remains limited. Previous transcriptomic studies, often constrained by bulk tissue analysis, have been unable to dissect the cell-type-specific contributions to epileptogenesis. Methods: We performed scRNA-seq on cortical tissues from one surgical patient with FCD type II and one matched control. Cell clustering, annotation, and identification of differentially expressed genes (DEGs) were conducted using standard Seurat workflow. We focused on the molecular alterations in three major glial cell types: astrocytes, microglia, and oligodendrocytes. To functionally interpret the DEGs, we performed enrichment analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results: Our profiling revealed a profoundly reconstituted cellular ecosystem in the FCD cortex. We found a marked expansion of microglia (65.57% vs. 47.02%; a ~39% relative increase) and astrocytes (10.98% vs. 4.11%; a ~167% relative increase), alongside a severe depletion of oligodendrocytes (8.12% vs. 30.63%; a ~73% relative decrease). Critically, a core set of 128 differentially expressed genes (DEGs) was shared across these glial populations, featuring consistent upregulation of RAC1 and downregulation of ATP5F1D, pointing to convergent pro-inflammatory and mitochondrial dysfunction pathways. Enrichment analyses further demonstrated a coordinated engagement of neuroinflammatory pathways, most notably IL-17 signaling. Subsequent cell–cell communication inference revealed a broad attenuation of intercellular signaling, with a 35% reduction in interaction numbers, indicating a breakdown of coordinated cellular crosstalk. Conclusions: This exploratory single-cell study provides preliminary evidence of a convergent glial pathology in FCD, characterized by shared molecular disruptions in inflammation and metabolism. Our findings highlight RAC1 and IL-17 signaling as potentially actionable pathways, warranting further investigation into their therapeutic potential for mitigating epileptogenesis in FCD. Full article

Focal cortical dysplasia (FCD) is a major cause of drug-resistant epilepsy, yet its molecular basis remains poorly understood. Numerous studies have analyzed RNA, protein, and microRNA alterations, but results are often inconsistent across subtypes and methodologies. To address this gap, we conducted a systematic review integrating transcriptomic, proteomic, and microRNA data from 117 human studies of FCD subtypes I–III. Differentially expressed factors were extracted, categorized by subtype, and analyzed using pathway enrichment and network approaches. Our integrative analysis revealed convergent dysregulation of neuroinflammatory, synaptic, cytoskeletal, and metabolic pathways across FCD subtypes. Consistently altered genes, including IL1B, TLR4, BDNF, HMGCR, and ROCK2, together with dysregulated microRNAs such as hsa-miR-21-5p, hsa-miR-155-5p, and hsa-miR-132-3p, were linked to PI3K–Akt–mTOR, Toll-like receptor, and GABAergic signaling, emphasizing shared pathogenic mechanisms. Importantly, we identified overlapping transcript–protein patterns and subtype-specific molecular profiles that may refine diagnosis and inform therapeutic strategies. This review provides the first cross-omics molecular framework of FCD, demonstrating how convergent pathways unify heterogeneous findings and offering a roadmap for biomarker discovery and targeted interventions. Full article

Background: Dominantly acting variants in TUBB2B have primarily been associated with cortical dysplasia complex with other brain malformations 7 (CDCBM7), a disorder in which cortical brain abnormalities are typically linked to developmental delay/intellectual disability (DD/ID) and seizures. While the majority of TUBB2B pathogenic variants have been linked to isolated CDCBM7, only one family with CDCBM7 and congenital fibrosis of the extraocular muscles (CFEOM) has been reported so far. We describe a second individual with a severe phenotype of CFEOM combined with CDCBM7 carrying a pathogenic TUBB2B missense variant previously reported in two individuals with isolated CDCBM7. Methods: A trio-based WGS analysis was performed. The structural impact of the identified substitution was assessed by using the UCSF Chimera (v.1.17.3) software and PyMOL docking plugin DockingPie tool. Results: WGS analysis identified a de novo missense TUBB2B variant (p.Ile202Thr, NM_178012.5), previously associated with isolated CDCBM7. Structural analysis and docking simulations revealed that Ile202 contributes to establishing a proper hydrophobic environment required to stabilize GTP/GDP in the β-tubulin pocket. p.Ile202Thr was predicted to disrupt these interactions. Conclusions: Our findings broaden the mutational spectrum of TUBB2B-related CFEOM, targeting a different functional domain of the protein, and further document the occurrence of phenotypic heterogeneity. We also highlight the limitations of exome sequencing in accurately mapping TUBB2B coding exons due to its high sequence homology with TUBB2A and suggest targeted or genome analyses when clinical suspicion is strong. Full article

Introduction: Neck-preserving total hip arthroplasty (THA) has gained interest for conserving bone stock, restoring biomechanics, and facilitating revision surgery. The Nanos^® femoral stem, designed for metaphyseal fixation while preserving the femoral neck, represents a reliable alternative to conventional THA. This study reports 15-year clinical and radiographic outcomes of the Nanos implant. Materials and Methods: We retrospectively reviewed 53 patients (35 males, 18 females) who underwent THA with the Nanos stem between 2008 and 2010. Patients were stratified into two groups according to age: <50 years (n = 24) and ≥50 years (n = 29). The primary diagnosis was osteoarthritis (95%), with a few cases of avascular necrosis or dysplasia. Clinical evaluation included the Harris Hip Score (HHS) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Radiographic assessment focused on implant stability, osteolysis, and heterotopic ossifications. Kaplan–Meier survival analysis was performed with revision for any reason as the endpoint. Results: At 15 years of follow-up, both groups showed significant improvement (p < 0.001). In patients <50 years, HHS increased from 53.3 to 94.8 and WOMAC decreased from 79.9 to 3.5. In patients ≥50 years, HHS improved from 47.5 to 95.2 and WOMAC from 81.5 to 3.2. Radiographs confirmed stable fixation without osteolysis. Complications included two dislocations and one cortical perforation requiring revision. Kaplan–Meier survivorship at 15 years was 100% (<50) and 96.6% (≥50). Conclusions: The Nanos stem provided excellent long-term outcomes with low complication and revision rates. It should be considered one of several reliable short-stem options for younger, active patients, offering durable function while preserving bone stock. Full article

Purpose: Focal cortical dysplasia (FCD) is a common developmental malformation disease of the cerebral cortex. Although mounting evidence has suggested that FCD lesions have variable locations and topographies throughout the cortex, few studies have explored consistencies in structural connectivity among different lesion types. In this study, we analyzed microscopic structural changes via lesion analysis and explored structural changes in nonlesion regions across the brain. Methods: Diffusion tensor imaging (DTI) and magnetization transfer imaging were used to compare FCD lesions and contralateral normal appearing gray/white matter (cNAG/WM). Voxel-based morphometry was calculated for 28 children with FCD and 34 sex- and age-matched healthy participants. DTI indices of the FCD and healthy control groups were analyzed via the tract-based spatial statistic method to evaluate the microstructure abnormalities of WM fiber tracts in individuals with FCD. Results: In terms of FCD lesions, compared with those of the cNAG, the fractional anisotropy (FA) values were decreased, and the mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were increased; the magnetization transfer ratios were also decreased. In terms of whole-brain changes due to FCD, compared with the healthy control group, the FCD group showed a decrease in the volume of the right hippocampus and left anterior cingulate cortex. FCD patients had lower FA values, higher MD values, lower AD values, and mainly increased RD values in relation to WM microstructure. Conclusions: Microstructural abnormalities outside lesion regions may be related to injury to the epileptic network, and the identification of such abnormalities may complement diagnoses of FCD in pediatric patients. Full article

Mandible cemento-osseous dysplasia (COD) can be found mostly associated with dental roots and tooth-bearing anatomical structures. A variety of odontogenic cysts and tumors might have similar appearances. A lesion in the jaw bone not associated with dental roots with a cyst-like appearance might suggest a non-odontogenic lesion, an empty bone cavity, an osseous, fibrous, or fibro-osseous lesion, or a traumatic bone cyst (TBC). A radiolucent irregular bone cavity without clear borders always requires improved diagnostics in cone-beam computed tomography (CBCT) as well as a revision and a biopsy in some cases. When there is some bone swelling and asymmetry on radiological evaluation, followed by extra-cortical spread, and the lesion has irregular borders with thickening or atypical calcifications, a biopsy should be performed. COD and TBCs can be found mostly associated with dental roots, but sometimes they are not associated with tooth-bearing jaw structures and might cause some diagnostic problems, especially if they resemble an empty radiolucent cystic-like lesion in an atypical location. Regardless of the type of lesion, a bone revision and a biopsy are important. When a sufficient amount of a sample is removed and evaluated, this can greatly improve the final diagnosis. The authors present an interesting case of a lesion accidentally found in a routine panoramic radiograph used for screening before scheduled orthodontic treatment. Full article

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate channels that play a pivotal role in brain development and the regulation of learning and memory processes. De novo pathogenic variants in four genes encoding NMDA receptor subunits (GRIN1, GRIN2A, GRIN2B, and GRIN2D) have been implicated in a broad spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorders, epilepsy, and movement disorders. Mutations in the GRIN1 and GRIN2B genes, which encode the GluN1 and GluN2B subunits, respectively, are strongly associated with malformations of cortical development, including diffuse dysgyria, bilateral polymicrogyria, hippocampal dysplasia, corpus callosum hypoplasia, and other findings such as ventricular enlargement and basal ganglia abnormalities. Conversely, GRIN2A mutations are associated with heterogeneous and less specific neuroimaging patterns. We reviewed the existing literature on the neuroradiological features associated with GRIN gene mutations, also providing pictorial representations from our patient cohort. The analysis revealed a more consistent association of malformations of cortical development with GRIN1 and GRIN2B variants, likely reflecting the critical role of these genes in neuronal migration and proper development of cortical structures. In comparison, GRIN2A mutations are associated with milder brain abnormalities. An integrated assessment of neuroimaging patterns and GRIN gene variants provides valuable insights for differential diagnosis and supports targeted genetic screening in patients presenting with epileptic encephalopathy, global developmental delay, and autism spectrum disorders. Full article

Artificial intelligence (AI) is revolutionarily shaping the entire landscape of medicine and particularly the privileged field of radiology, since it produces a significant amount of data, namely, images. Currently, AI implementation in radiology is continuously increasing, from automating image analysis to enhancing workflow management, and specifically, pediatric neuroradiology is emerging as an expanding frontier. Pediatric neuroradiology presents unique opportunities and challenges since neonates’ and small children’s brains are continuously developing, with age-specific changes in terms of anatomy, physiology, and disease presentation. By enhancing diagnostic accuracy, reducing reporting times, and enabling earlier intervention, AI has the potential to significantly impact clinical practice and patients’ quality of life and outcomes. For instance, AI reduces MRI and CT scanner time by employing advanced deep learning (DL) algorithms to accelerate image acquisition through compressed sensing and undersampling, and to enhance image reconstruction by denoising and super-resolving low-quality datasets, thereby producing diagnostic-quality images with significantly fewer data points and in a shorter timeframe. Furthermore, as healthcare systems become increasingly burdened by rising demands and limited radiology workforce capacity, AI offers a practical solution to support clinical decision-making, particularly in institutions where pediatric neuroradiology is limited. For example, the MELD (Multicenter Epilepsy Lesion Detection) algorithm is specifically designed to help radiologists find focal cortical dysplasias (FCDs), which are a common cause of drug-resistant epilepsy. It works by analyzing a patient’s MRI scan and comparing a wide range of features—such as cortical thickness and folding patterns—to a large database of scans from both healthy individuals and epilepsy patients. By identifying subtle deviations from normal brain anatomy, the MELD graph algorithm can highlight potential lesions that are often missed by the human eye, which is a critical step in identifying patients who could benefit from life-changing epilepsy surgery. On the other hand, the integration of AI into pediatric neuroradiology faces technical and ethical challenges, such as data scarcity and ethical and legal restrictions on pediatric data sharing, that complicate the development of robust and generalizable AI models. Moreover, many radiologists remain sceptical of AI’s interpretability and reliability, and there are also important medico-legal questions around responsibility and liability when AI systems are involved in clinical decision-making. Future promising perspectives to overcome these concerns are represented by federated learning and collaborative research and AI development, which require technological innovation and multidisciplinary collaboration between neuroradiologists, data scientists, ethicists, and pediatricians. The paper aims to address: (1) current applications of AI in pediatric neuroradiology; (2) current challenges and ethical considerations related to AI implementation in pediatric neuroradiology; and (3) future opportunities in the clinical and educational pediatric neuroradiology field. AI in pediatric neuroradiology is not meant to replace neuroradiologists, but to amplify human intellect and extend our capacity to diagnose, prognosticate, and treat with unprecedented precision and speed. Full article

Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant genetic disease, mainly characterized by enlargement of the mandible, osteosclerosis, and frequent fracture of tubular bone. GDD is caused by heterozygous mutations in Anoctamin 5 (ANO5). We have previously generated an Ano5 knockout (KO) mice model and validated the phenotypes consistent with GDD patients, including enhanced bone formation and alkaline phosphatase (ALP) activity. Experiments have identified that Ano5 deficiency elevated the osteogenesis of calvaria-derived osteoblasts (mCOBs). In this study, we found that Ano5 deficiency notably inhibited miR-34c-5p expression. Krüppel-Like Factor 4 (Klf4), a target gene of miR-34c-5p confirmed by dual luciferase reporter assay, was up-regulated in Ano5^−/− mCOBs, accompanied by activated downstream canonical Wnt/β-catenin signaling and increased expression of β-catenin. Overexpression of miR-34c-5p in Ano5^−/− mCOBs inhibited osteogenic capacity by suppressing proliferative capacity, osteoblast-related factor levels, ALP activity, and matrix calcification through regulating KLF4/β-catenin signaling axis. Furthermore, miR-34c-5p adeno-associated virus (AAV) treatment in vivo rescued the abnormally thickened cortical bone and enhanced biomechanical properties in Ano5^−/− mice. Importantly, the serum level of P1NP, a marker of bone formation, was also significantly declined. We conclude that dysregulation of miR-34c-5p contributes to the enhanced osteogenesis in GDD by excessive activation of KLF4/β-catenin signaling axis under Ano5-deficient conditions. This study elucidates the pathogenesis of GDD and provides novel insights into the therapeutic strategies. Full article

mTORopathies represent a group of neurodevelopmental disorders linked to dysregulated mTOR signaling, resulting in conditions such as tuberous sclerosis complex, focal cortical dysplasia, hemimegalencephaly, and Smith–Kingsmore Syndrome. These disorders often manifest with epilepsy, cognitive impairments, and, in some cases, structural brain anomalies. The mTOR pathway, a central regulator of cell growth and metabolism, plays a crucial role in brain development, where its hyperactivation leads to abnormal neuroplasticity, tumor formation, and heightened neuronal excitability. Current treatments primarily rely on mTOR inhibitors, such as rapamycin, which reduce seizure frequency and tumor size but fail to address underlying genetic causes. Advances in gene editing, particularly via CRISPR/Cas9, offer promising avenues for precision therapies targeting the genetic mutations driving mTORopathies. New delivery systems, including viral and non-viral vectors, aim to enhance the specificity and efficacy of these therapies, potentially transforming the management of these disorders. While gene editing holds curative potential, challenges remain concerning delivery, long-term safety, and ethical considerations. Continued research into mTOR mechanisms and innovative gene therapies may pave the way for transformative, personalized treatments for patients affected by these complex neurodevelopmental conditions. Full article

Focal cortical dysplasia type III (FCDIII) is a rare and complex condition associated with drug-resistant epilepsy and often characterized by cortical lamination abnormalities, along with a variety of neoplasms and vascular abnormalities. Objectives: This study aimed to elucidate the genetic architecture underlying FCDIII through the use of whole-exome sequencing (WES) of brain and peripheral blood samples from 19 patients who had been diagnosed with FCDIII. Methods: Variants were identified through a series of machine-learning-based detection and functional prediction methods and were not previously associated with FCDIII. Mosaic fraction scores of these variants validated the variants’ pathogenicity, and in silico and gene ontology enrichment analyses demonstrated that these variants had severe destabilizing effects on protein structure. Results: We reported ten novel pathogenic somatic missense and loss of function variants across eight genes, including CNTNAP2, ACY1, SERAC1, and BRAF. Genetic alterations were linked to clinical manifestations, such as encephalopathies and intellectual disabilities, thereby emphasizing their role as molecular drivers of FCDIII. Conclusions: We demonstrated that next-generation sequencing-based mosaic variant-calling pipelines are useful for the genetic diagnosis of FCDIII, opening up avenues for targeted therapies, yet further research is required to validate these findings and examine their therapeutic implications. Full article

Objective: Focal epilepsy is the most frequent type of epilepsy in childhood, particularly after the first year of life. This study aims to analyze the clinical aspects, electrophysiological and neuroimaging findings, and genetic predispositions in pediatric focal epilepsy. Specifically, we investigate the association between these parameters and evaluate their impact on therapeutic decisions. Methods: This is a retrospective study, in which we enrolled 39 patients currently receiving follow-up in our unit, 20 male and 19 female. Using the Chi-squared test, we compared them considering several genetic traits, pre/peri/postnatal risk factors, family history, clinical and instrumental features, and treatments. Differences are considered significant with a p value < 0.005. Results: Our findings highlight the multifactorial nature of focal epilepsy, with a combination of genetic and environmental contributions. EEG demonstrated the highest sensitivity among diagnostic tools, being non-significant in only 12.8% of cases, while MRI (p < 0.001), CT (p < 0.04), and brain ultrasound had lower detection rates. MRI findings were significant in 43.6% of patients, predominantly showing vascular malformations (35.8%). MRI-negative findings were more common in temporal and occipital epilepsy, whereas MRI-positive results were observed in 100% of frontal seizures. Importantly, some MRI-negative cases may still be lesional, particularly in temporal lobe epilepsy, where focal cortical dysplasia could be present but undetected with standard imaging. Valproic acid remains the most commonly used anti-seizure medication, and, despite guideline recommendations, it was still prescribed as a first-line treatment in 34.3% of cases and is being used in 23.5% of female patients, raising concerns about its appropriateness. Conclusions: This study highlights the role of genetic and environmental risk factors in pediatric focal epilepsy. EEG showed superior diagnostic sensitivity over MRI, particularly in MRI-negative cases. While high-resolution MRI (3T or 7T) could improve lesion detection, its cost limits accessibility. Valproate was the most prescribed drug, despite its recommended use in generalized epilepsy, emphasizing the need for improved adherence to treatment guidelines. Together with other studies, these findings can contribute to optimizing diagnostic and therapeutic strategies for pediatric focal epilepsy. Full article

Background: The Notch signaling pathway is an important regulator of stem cell activity in various tissues, including the central nervous system. It has been implicated in neurodevelopmental processes, including neuronal differentiation and synaptic plasticity. Research suggests that its expression may be associated with certain epileptogenic lesions, particularly those with neurodevelopmental origin. The aim of this study was to investigate the expression of Notch-1 in brain biopsies from various cases of pharmacoresistant epilepsy. Methods: Here, we used immunohistochemistry staining to retrospectively analyze 128 developmental lesions associated with pharmacoresistant epilepsy, including 13 cases with focal cortical dysplasia (FCD) type I, 39 with FCD type II, 37 with hippocampal sclerosis (HS), 23 with FCD IIIc, 9 with mild malformations of cortical development (MCD), 4 cases with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE), and 3 with tuberous sclerosis (TS). The tissues were stained for Neurofilament protein, Vimentin, S-100 protein, NeuN, and GFAP, as well as the stem cell marker Notch-1. Tissue that stained positively for Notch-1 was further characterized. Results: A positive Notch-1 reaction was found in all cases of FCD type IIb and TS, where it appeared in balloon cells but not in dysmorphic neurons, and in a single case of meningioangiomatosis (FCD IIIc), where it stained spider-like cells. Notch-1-positive cells showed a stem-like, glio-neuronal precursor immunophenotype. No staining was observed in the remaining cases with FCD type I, type III, HS, mild MCD, and MOGHE. Conclusions: Notch-1 displays a distinct pattern of expression in some epileptogenic lesions, potentially highlighting a stem cell-like origin or neurodevelopmental abnormalities contributing to pharmacoresistant epilepsy; however, it is not a general marker of such lesions. Its differential expression may prove useful in distinguishing between different types of FCD or other cortical malformations, which could assist in both their diagnosis and potentially in the development of more targeted therapeutic approaches. Further studies with different stem cell markers are needed in this direction. Full article