Search Results (206)

The reconstruction of complex orbitomaxillary defects requires biomaterials that can simultaneously provide structural stability, biocompatibility, and accurate restoration of facial volume and contour. While rigid polymers such as polyetheretherketone (PEEK) offer reliable mechanical support, they do not adequately replicate the viscoelastic behavior of soft tissues. This report presents a translational revision case employing a personalized hybrid biomaterial approach that combines a 3D-printed PEEK implant for structural orbital floor support with a patient-specific polydimethylsiloxane (PDMS) implant for malar volumetric augmentation. Reconstruction was planned using CT segmentation and contralateral mirroring. Patient-specific implants were subsequently designed using CAD/CAM techniques, combining a rigid PEEK implant for structural orbital support with a flexible PDMS implant for malar volumetric augmentation with complementary mechanical properties. Revision surgery included the removal of inadequately positioned titanium hardware, the release of incarcerated extraocular muscles, and the restoration of orbital anatomy and facial symmetry. Postoperative imaging demonstrated stable implant positioning and sustained orbitomaxillary stability. Despite successful anatomical reconstruction, residual functional sequelae, including strabismus related to the severity of the initial orbital trauma, persisted and were addressed separately in a staged manner, resulting in satisfactory ocular alignment and resolution of diplopia in primary gaze. This case underscores the complementary functional roles of rigid and elastic polymers and highlights the translational potential of PDMS as a permanent, patient-specific implant material for volumetric and contour restoration in craniofacial reconstruction. Full article

Background: RASopathies represent a clinically and genetically diverse group of syndromes resulting from germline mutations in genes regulating the RAS/mitogen-activated protein kinase (MAPK) signaling cascade. Methods: The aim of this study was to describe the clinical features and genetic variants identified in patients with genetically confirmed Noonan syndrome (NS) in a limited cohort from Romania. A total of 25 patients with positive genetic testing for NS-associated genes were included. Genetic testing was performed primarily using next-generation sequencing. Results: A total of twenty-six variants were identified in twenty-five patients, as one patient carried two pathogenic variants in the PTPN11 gene (c.188A>G and c.922A>G). Of these variants, twenty-four (92.31%) were classified as pathogenic and two (7.69%) as variants of uncertain significance (VUS). Pathogenic variants were found in different genes, including PTPN11, LZTR1, SOS1, and RAF1, with PTPN11 being the most frequently affected gene. Males predominated (17/25), with a male-to-female ratio of approximately 2:1. Two patients inherited the pathogenic variant from an affected parent. Cardiovascular involvement was present in 21 patients (84%), with pulmonary valve stenosis (PVS) being the most common finding (48%), followed by hypertrophic cardiomyopathy (16%). Additional cardiac anomalies included atrial septal defect, valvular regurgitation, dysplastic valves, coarctation of the aorta, and sinotubular junction narrowing. Short stature was observed in 64% of patients, and craniofacial dysmorphism was present in 96%. Cutaneous, ectodermal, dental, ophthalmologic, and auditory manifestations were variably observed. Conclusions: Although based on a limited cohort from Romania, this study provides insights into clinical features suggestive of NS. Our findings highlight the genetic heterogeneity of NS and emphasize the importance of comprehensive genetic testing for confirming diagnosis, guiding clinical management, and supporting family counseling. Full article

Background/Objectives: Despite the decades-old ban on lead in fuel, plumbing, consumer goods, industrial processes, and various materials, it remains a public health threat due to its persistent nature. Zebrafish (Danio rerio) are highly effective for modeling several disorders, including those affecting neurological and behavioral functions, and are well-suited for assessing the impact of environmental toxins like lead. This study aimed to investigate the neurodevelopmental effects of embryonic lead exposure using the zebrafish model system. Methods: Embryos were exposed to lead acetate (PbAc) at concentrations ranging from 0.3 to 0.7 µg/mL using an exposure window of 6 to 48 h post-fertilization (hpf). Results: PbAc exposure produced sublethal teratogenic effects in a subset of larvae across concentrations, including tail and spinal deformities, craniofacial abnormalities, and uninflated swim bladder observed at 7 dpf. At 3 days post-fertilization (dpf), spontaneous circle swimming behavior suspected to be seizure-like was observed in the lead-exposed larvae and was more pronounced under light conditions in a dose-dependent manner. Electrophysiological recordings confirmed that larvae exhibiting circle swimming behavior had heightened neural activity, indicating a potential seizure-like phenotype driven by lead exposure. Conclusions: Our findings suggest that embryonic lead exposure leads to morphological defects and seizure susceptibility, demonstrating lead’s neurotoxic potential during early development. Seizure-like behaviors occurred in a non-linear concentration-dependent manner with a photosensitive component, and elevated baseline neural excitability was confirmed by local field potential (LFP) recordings. Full article

Background/Objectives: Craniofacial malformations such as orofacial clefts affect ~1 in 700 births; 40–60% lack clear genetic etiology, and many exhibit asymmetry and variable expressivity unexplained by classical Sonic Hedgehog (SHH) morphogen gradient models. We investigated whether integrated molecular modules linking morphogen signaling with metabolic stress responses may better account for craniofacial developmental outcomes. Methods: Sequential UniProt gene set integration identified 186 candidate craniofacial regulators. STRING network analysis revealed modular architecture. Molecular docking profiled 17 compounds against SMO, CK1δ, PINK1, and TIE2 (control). Pathway reconstruction integrated the SHH–CK1δ–HIF1A–HEY1–PINK1 axis with in-silico-predicted CK1δ phosphorylation sites on SMO (S615, T593, S751), HIF1A (Ser247), and GLI1/2/3 transcription factors. A developmental decision tree mapped affinity profiles to node-specific phenotype hypotheses. Results: CK1δ and PINK1 emerged as candidate nodes coupling morphogen signaling with mitochondrial quality control. Cross-docking showed preferential binding to developmental kinases (CK1δ: −8.34 kcal/mol; PINK1: −8.80 kcal/mol) versus TIE2 control (−6.76 kcal/mol; p < 0.001). Pathway reconstruction suggested that CK1δ-mediated Ser247 phosphorylation of HIF1A disrupts ARNT dimerization, redirecting HIF1A toward ARNT-independent HEY1 induction and consequent PINK1 suppression. Based on computed profiles, node-specific associations were proposed as computational hypotheses: SMO perturbation → midline defects; CK1δ → facial asymmetry/clefting; PINK1 → mandibular hypoplasia. Multi-target compounds (e.g., purmorphamine, taladegib) generated composite phenotype predictions consistent with clinical complexity. Conclusions: This strictly in silico study identifies candidate integrated morphogenic modules whose multi-node perturbation may underlie anatomically specific craniofacial malformation patterns. Node–phenotype associations are prioritized computational hypotheses requiring experimental validation; if confirmed, the framework could inform developmental toxicity assessment, therapeutic design, and reclassification of idiopathic craniofacial anomalies. Full article

Photobiomodulation (PBM) has shown promising potential to enhance bone regeneration; however, its optimal delivery parameters and interactions with osteoconductive scaffolds remain insufficiently defined. This preclinical study is the first to incorporate a pilot dosimetry evaluation to standardize 980-nm PBM delivery and ensure that effective irradiance reached the target surface of critical-size calvarial defects in mice. The primary aim was to evaluate the effectiveness of this novel 980-nm PBM protocol delivered using either flat-top (FT) or standard Gaussian (ST) handpieces in enhancing bone regeneration in critical-size defects (CSDs), both with and without Bio-Oss^® grafting. A total of 120 adult mice were allocated into twelve experimental groups (n = 10 per group): untreated (control), Bio-Oss^® alone, PBM alone, and PBM combined with Bio-Oss^®, using either FT or ST handpieces, and evaluated at 30 and 60 days. Animals received 980 nm irradiation at 0.6 W (nominal power output–set on laser interface) in continuous-wave mode for 60 s, three times per week, for two consecutive weeks. Pilot dosimetry included power meter measurements to determine the therapeutic power reaching the defect surface area and temperature monitoring to ensure safe energy delivery. The dosimetry study demonstrated that, after accounting for the optical properties of mouse shaved skin and the Bio-Oss^® graft covered with Bio-Gide^® membrane, the effective irradiance reaching the base of the defect surface area was 1.131 W/cm² for the FT handpiece and 0.413 W/cm² for the ST handpiece. This dose was sufficient to induce significant regenerative effects. Histological, Masson’s trichrome, and immunohistochemical analyses for Runx2, OCN, GLI1, CD34, and CTSK were performed to characterize early and late osteogenic events. The combination of PBM and Bio-Oss^® significantly accelerated bone regeneration compared with PBM alone, with the FT handpiece producing the most uniform and advanced osteogenesis. PBM enhanced progenitor activation, osteoblast differentiation, angiogenesis, matrix deposition, and late-stage remodeling, demonstrating a synergistic effect with the scaffold, whereas Bio-Oss^® alone or defect alone showed limited early regenerative potential. These findings highlight the effectiveness of this novel standardized PBM dosimetry and uniform beam profile (FT), supporting their use as a foundation for future randomized controlled trials in craniofacial bone repair. Full article

Midfacial hypoplasia is a developmental defect caused by insufficient growth of the nasal placodes and maxillary prominences. While genetic studies in mice have identified key genes involved in midfacial development, the regulation of these genes during craniofacial development remains poorly understood. In this study, we demonstrate that microRNAs, short non-coding RNAs, play a crucial role in regulating genes involved in midfacial development. We identified 224 genes associated with midfacial malformations in mice. Through bioinformatics analyses, we predicted that several microRNAs, specifically miR-129-5p, miR-381-3p, miR-124-3p, miR-136-5p, miR-448-3p, miR-374, miR-96, and miR-882, could regulate the expression of these genes. Among these, we experimentally focused on the top four candidate microRNAs: miR-129-5p, miR-381-3p, miR-124-3p, and miR-136-5p. Our findings revealed that the overexpression of these microRNAs inhibited cell proliferation and osteogenesis in nasal process mesenchymal cells. These microRNAs regulated genes associated with midfacial malformations in a dose-dependent manner. Taken together, our results emphasize the significance of pathogenic microRNA–gene networks in the cause of midfacial malformations. Full article

Background: Goldenhar syndrome (oculo–auriculo–vertebral spectrum, OAVS) is a rare congenital disorder characterized by craniofacial malformations, systemic anomalies, and significant phenotypic variability. Although it is the second most common craniofacial malformation after a cleft palate, the genetic etiology of Goldenhar syndrome remains largely unexplored. This study aimed to identify genetic variants contributing to Goldenhar syndrome in a Lebanese family with three affected individuals, using whole-exome sequencing and complementary genomic approaches. Methods: Whole-exome sequencing was performed on the nuclear family to identify variants associated with the syndrome. Complementary DNA methylation and gene ontology analyses were conducted to explore epigenetic modifications. Results: A missense shared variant in the MID1 between the affected individuals [NP_000372.1): p. Ile593Phe] gene was observed in the family, while current ACMG evidence was insufficient to establish causality. Additional variants were identified, including a de novo mutation in FBXW11 and a rare frameshift alteration in NDUFAF8, with limited segregation, implicating these genes in associated phenotypes such as craniofacial anomalies and cardiac defects. DNA methylation analysis revealed hypomethylation at CpG sites within the ZC3H3 gene, suggesting an epigenetic contribution to disease variability. Conclusions: Our findings underscore the genetic and epigenetic complexity of Goldenhar syndrome, providing new insights into its molecular etiology and highlighting the challenges of variant interpretation in familial cases of rare congenital disorders. Full article

Background: Auricular defects resulting from congenital anomalies, trauma, or oncologic resection pose significant functional and psychosocial challenges. When autologous reconstruction is not feasible or not desired, implant-retained auricular prostheses represent a reliable alternative with high patient satisfaction. This study aimed to systematically evaluate the clinical performance of craniofacial implants used for auricular prosthetic rehabilitation, focusing on implant survival, prosthetic outcomes, workflow typologies, and complications. A secondary objective was to illustrate the long-term validity of a minimally invasive navigation technique through a clinical case with 6-year follow-up. Methods: A systematic review was conducted according to PRISMA guidelines. Clinical studies published between 2005 and 2025 reporting outcomes of implant-retained auricular prostheses were searched in PubMed and Scopus databases. Data were extracted on implant type, survival rates, prosthetic performance, workflow, and complications. Risk of bias was assessed using appropriate tools based on each study design. Results: A total of thirty-two studies were included, comprising fifteen case reports, fifteen case series, one cohort study, and one prospective observational study. Implant survival was consistently high across all workflow categories, with failures predominantly associated with irradiated or anatomically compromised bone. Prosthetic outcomes were favorable, showing excellent esthetics, stable retention, and high patient satisfaction irrespective of manufacturing method, although digital and navigation-assisted workflows improved reproducibility, symmetry, and planning precision. Complication rates were low and generally limited to mild peri-abutment inflammation manageable with conservative care. The clinical case confirmed these findings, showing stable osseointegration, healthy soft tissues, and uncompromised prosthetic function at 6-year follow-up. Conclusions: Implant-retained auricular prostheses show predictable long-term success, independent of whether traditional, hybrid, or fully digital workflows are employed. Digital technologies enhance surgical accuracy, minimize morbidity, and streamline prosthetic fabrication, although high-quality comparative studies remain limited. Full article

Background: Reconstruction of the maxilla and midface remains one of the most demanding challenges in craniofacial surgery, requiring precise planning and a clear understanding of defect geometry to achieve functional and esthetic restoration. Advances in computer-assisted surgery (CAS) and virtual surgical planning (VSP), based on 3D segmentation of radiologic imaging, have significantly improved the management of maxillary deformities, allowing for further knowledge of patient-specific information, including anatomy, pathology, surgical planning, and reconstructive issues. The integration of computer-aided design and manufacturing (CAD/CAM) and 3D printing has further transformed reconstruction through customized titanium meshes, implants, and surgical guides. Methods:This systematic review, conducted following PRISMA 2020 guidelines, synthesizes evidence from clinical studies on CAD/CAM-assisted reconstruction of maxillary and midfacial defects of congenital, acquired, or post-resection origin. It highlights the advantages and drawbacks of maxillary reconstruction with patient-specific implants (PSISs). Primary outcomes are represented by accuracy in VSP reproduction, while secondary outcomes included esthetic results, functions, and assessment of complications. Results: Of the 44 identified articles, 10 met inclusion criteria with a time frame from April 2013 to July 2022. The outcomes of 24 treated patients are reported. CAD/CAM-guided techniques seemed to improve osteotomy accuracy, flap contouring, and implant adaptation. Conclusions: Although current data support the efficacy and safety of CAD/CAM-based approaches, limitations persist, including high costs, technological dependency, and variable long-term outcome data. This article critically evaluates the role of PSISs in maxillofacial reconstruction and outlines future directions for its standardization and broader adoption in clinical practice. Full article

Survival rates for children treated for malignant diseases continue to improve, yet many survivors face persistent late oral complications that affect function, aesthetics, and quality of life. Oncological therapy, especially at a young age and following head and neck radiotherapy or intensive chemotherapy, can disrupt dental and craniofacial development, resulting in dental developmental disorders, enamel defects, salivary gland dysfunction, caries susceptibility, periodontal problems, trismus, and osteoradionecrosis of the jaw. Although these effects are partially known, they are frequently underrecognized in routine practice, and many children do not receive adequate long-term dental follow-up. A key challenge highlighted in the recent literature is the absence of structured, evidence-based guidelines for monitoring and managing late oral effects. The article emphasizes the need for clearer recommendations, better communication of oncological treatment histories, and stronger integration of dental professionals within survivorship care. Developing standardized follow-up protocols will be essential to ensure timely detection, consistent management, and improved oral health outcomes for childhood cancer survivors. This article is intended as a narrative review, synthesizing available evidence from key publications to highlight clinically relevant late oral complications and gaps in current survivorship care. Full article

Background/Objectives: The Fibroblast Growth Factor Receptor 1 (FGFR1, MIM*136350) is a protein member of the fibroblast growth factor receptor (FGFR) family, with various biological functions, such as the normal development control. It contains an extracellular site for the ligand (three Ig-like domains, IgI, IgII, IgIII), a single transmembrane and a cytoplasmic protein tyrosine kinase (TK) domain. Variants in this gene have been associated with a wide spectrum of genetic disorders, including the clinical entity known as FGFR1-related Hartsfield or Hartsfield syndrome (HRTFDS, MIM#615465), which is an autosomal dominant or recessive disorder characterized by the clinical association of split-hand/foot malformation (SHFM) and holoprosencephaly (HPE). Dysmorphic facies, including cleft/lip palate, genitourinary anomalies, cardiovascular defects and intellectual disability/developmental delay (ID/DD) can also be a part of the clinical picture. Methods: The malformation phenotype of HRTFDS has been reviewed in 26 previously reported patients in terms of single congenital defects, mutational spectrum, impacted protein domains and inheritance. Molecular basis, clinical management, main differential diagnoses and genetic counseling were also illustrated. Results: SHFM was identified in every patient. The other main associated features included craniofacial defects, skeletal malformation identified at radiography, genitourinary anomalies, HPE and cardiovascular disorders. FGFR1 causative variants mainly impact the TK domain and have a smaller impact on other protein sites (IgII, IgIII). Conclusions: This study extensively recapitulates the malformation phenotype associated with HRTFDS and the underlying molecular perturbations. A multidisciplinary clinical approach is fundamental, in which genetic counseling can have an important role. However, our results are partial and refer to a restricted number of patients, pointing out the necessity of other descriptions and similar research. Additional studies will expand clinical and molecular knowledge as well as further clarify the biological mechanisms. Full article

Craniofacial bone defects of critical size, caused by trauma, tumors, infections, or congenital maldevelopment, represent a major challenge in plastic and reconstructive surgery. Autologous bone grafting is considered the gold standard, but limitations such as donor site morbidity and limited availability have prompted the development of artificial bone tissue engineering scaffolds. In recent years, bioactive scaffolds have been increasingly utilized in favor of inert biomaterials due to their immunomodulation and osteoinduction capabilities. This review methodically summarizes loading strategies for the functionalization of scaffolds with bioactive components, including cell regulatory factors, drugs, ions, stem cells, exosomes, and components derived from human tissues or cells to promote bone regeneration. The following mechanisms are involved: (1) the polarization of macrophages (M1-M2 transition), (2) the dynamic regulation of bone metabolism, and (3) the coupling of osteogenesis and angiogenesis. This review focuses on innovative delivery systems, such as 3D-printed scaffolds, nanocomposites and so on, that enable spatiotemporal control of bioactive cargo release. These address key challenges, such as infection resistance, vascularization, and mechanical stability in the process of bone regeneration. In addition, the article discusses emerging technologies, including stem cells and exosome-based acellular therapies, which demonstrate potential for personalized bone regeneration. This review integrates immunology, materials science, and clinical needs, providing a roadmap for the design of next-generation bone tissue engineering scaffolds to overcome critical-sized bone defects. Full article

Background/Objectives: The Mediator (MED) complex is an essential regulator of RNA polymerase II transcription. There is increasing evidence that pathogenic variants in several MED subunits are the cause of neurodegenerative and neurodevelopmental phenotypes, collectively referred to as “MEDopathies”. This review aims to summarize current knowledge on the genetic basis, clinical manifestations, and neuroradiological features of MED-related disorders. Methods: We undertook a narrative synthesis of the literature focusing on the MED subunits most commonly associated with neurological disorders, including MED1, MED8, MED11, MED12/MED12L, MED13/MED13L, MED14, MED17, MED20, MED23, MED25, MED27, and CDK8. Sources included peer-reviewed genetic, clinical, and imaging studies, supplemented by relevant case reports and cohort analyses. In addition, representative facial phenotypes associated with selected MED variants (MED11, MED12, MED13, MED13L, MED25) were visualized for educational purposes using artificial intelligence-based image generation derived from standardized clinical descriptors. Results: All MEDopathies show converging clinical patterns: global developmental delay/intellectual disability, hypotonia, epilepsy, speech disorders, and behavioral comorbidity. Non-neurological involvement, such as craniofacial or cardiac anomalies, is subunit-specific. Neuroradiological features include callosal abnormalities (agenesis, thinning, dysmorphia), delayed or hypomyelination, progressive cerebral and cerebellar atrophy, basal ganglia signaling changes, pontine hypoplasia, and, in MED27 deficiency, a “hot cross bun” sign. Gene-specific constellations emphasize catastrophic infantile progression (MED11), X-linked syndromes with callosal defects (MED12/MED12L), language-dominant phenotypes (MED13), and syndromic intellectual disability with systemic features (MED13L). Conclusions: The growing spectrum of MEDopathies argues for their recognition as a unified nosological group with overlapping clinical and radiological signatures. Characteristic MRI constellations may serve as diagnostic clues and guide targeted molecular testing. Future directions include longitudinal imaging to describe disease progression and the integration of genomic data with curated clinical radiological datasets to refine genotype-phenotype correlations. Full article

Pharyngeal cartilage, derived from neural crest cells (NCCs), undergoes complex morphogenesis driven by signals from the pharyngeal endoderm. However, the molecular mechanisms governing NCC proliferation and differentiation in response to endoderm-derived signals remain poorly understood. Here, we investigate the role of klf5a, a zinc-finger transcription factor expressed in pharyngeal endodermal pouches, in zebrafish pharyngeal cartilage development. Knockdown of klf5a using morpholinos minimally affected cranial NCC specification and migration but significantly impaired their proliferation and differentiation in the pharyngeal region. Notably, klf5a deficiency reduced expression of fgfbp2b, a modulator of FGF signaling, in the pharyngeal endoderm. Co-injection of klf5a mRNA rescued the cartilage defects, but injection of fgfbp2b mRNA alone failed to restore normal cartilage morphogenesis, suggesting that fgfbp2b is not the sole mediator of klf5a’s effects. These findings indicate that klf5a regulates endodermal signaling to direct NCC-derived pharyngeal cartilage formation, likely through multiple downstream targets including fgfbp2b. This study provides insights into the complex molecular network underlying craniofacial development and highlights potential therapeutic targets for craniofacial disorders. Full article

The accurate reconstruction of craniofacial defects requires the precise segmentation and mirroring of healthy anatomy. Conventional workflows rely on manual interaction, making them time-consuming and subject to operator variability. This study developed and validated a fully automated digital pipeline that integrates deep learning–based segmentation with algorithmic mirroring for craniofacial reconstruction. A total of 388 cranial CT scans were used to train a three-dimensional nnU-Net model for skull and mandible segmentation. A Principal Component Analysis–Iterative Closest Point (PCA–ICP) algorithm was then applied to compute the sagittal symmetry plane and perform mirroring. Automated results were compared with expert-generated segmentations and manually defined symmetry planes using Dice Similarity Coefficient (DSC), Mean Surface Distance (MSD), Hausdorff Distance (HD), and angular deviation. The nnU-Net achieved high segmentation accuracy for both the mandible (mean DSC 0.956) and the skull (mean DSC 0.965). Mirroring results showed minimal angular deviation from expert reference planes (mandible: 1.32° ± 0.71° in defect cases, 1.58° ± 1.12° in intact cases; skull: 1.75° ± 0.84° in defect cases, 1.15° ± 0.81° in intact cases). The presence of defects did not significantly affect accuracy. This automated workflow demonstrated robust performance and clinical applicability, offering standardized, reproducible, and time-efficient planning for craniofacial reconstruction. Full article