Search Results (99)

Background: Vitamin D deficiency rickets is a metabolic bone disorder caused by impaired calcium and phosphate homeostasis resulting from insufficient vitamin D. In children, severe vitamin D deficiency can disturb the mineralization of growing bones and teeth. Although the skeletal manifestations are well recognized, reports describing generalized developmental enamel defects affecting nearly all permanent teeth remain limited. Methods: A 6-year-9-month-old Japanese boy with a history of vitamin D deficiency rickets diagnosed at 2 years 5 months of age was referred to our department for evaluation of generalized discoloration and morphological abnormalities affecting multiple permanent teeth. Clinical, radiographic, and medical findings were reviewed. Results: Laboratory examination at diagnosis revealed severe vitamin D deficiency with elevated intact parathyroid hormone levels. Possible contributing factors included exclusive breastfeeding, delayed weaning, avoidance of fish and dairy products, and limited outdoor activity. Following oral alfacalcidol supplementation, skeletal and biochemical findings gradually normalized. However, clinical examination revealed generalized enamel hypoplasia affecting the permanent incisors and first molars, characterized by yellow-brown discoloration, rough enamel surfaces, morphological irregularities, and attrition, whereas the primary dentition showed no obvious abnormalities. Panoramic radiography demonstrated generalized crown malformation involving both erupted and unerupted permanent teeth, particularly the permanent incisors, first molars, and canines, while premolars and second molars were relatively unaffected. Based on the developmental timing of the affected teeth and the patient’s medical history, the enamel defects were considered to be associated with systemic mineralization disturbance during early childhood. Restorative treatment, including composite resin restorations and stainless steel crowns, was performed to improve aesthetics and occlusal function. Preventive surgical exposure followed by composite resin restoration was also performed for the permanent canines at the onset of eruption. Conclusions: Severe vitamin D deficiency during critical stages of tooth development may be associated with irreversible developmental enamel defects in the permanent dentition, even after apparent systemic recovery from rickets. Early dental assessment, long-term dental follow-up, and multidisciplinary management should be considered in children with a history of nutritional rickets. Full article

C. c. rubrofuscus is an economically important species in South China. During breeding, some individuals develop skeletal softening, but the underlying mechanisms remain unclear. In this study, five-month-old C. c. rubrofuscus were classified into a hard-bone group and a softened-bone group based on X-ray radiography. A systematic comparison was then conducted between the two groups, including analyses of external morphology, skeletal morphology, vertebral bone mineral density (BMD), calcium (Ca) and phosphorus (P) levels in serum and bone tissue, bone histology, and the expression of autophagy-related genes and proteins. The prevalence of the softened-bone phenotype was approximately 14% in the cultured population. Compared with the hard-bone group, the softened-bone group showed significantly lower vertebral BMD, significantly increased serum Ca levels, significantly decreased serum P levels, and markedly reduced Ca and P contents in bone tissue. In addition, varying degrees of deformity were observed in the ribs, caudal intermuscular spines, and urostyle. Histological examination further revealed severe skeletal malformations in the softened-bone group, characterized by irregular cortical bone thickness in the ribs and pterygiophores, together with a significantly reduced osteocyte density. Meanwhile, microtubule-associated protein 1 light chain 3 (LC3) levels were significantly increased, whereas sequestosome 1 (p62) levels were significantly decreased. The upregulated expression of autophagy-related genes suggested dysregulated autophagy, which may contribute to osteocyte loss. Collectively, these results indicate that the softened-bone phenotype in C. c. rubrofuscus is not associated with obvious changes in external body morphology. However, disrupted Ca-P homeostasis, together with altered autophagy, may impair osteocyte viability and bone mineralization, ultimately leading to bone softening and skeletal deformity. These findings provide a theoretical basis for further investigation of the mechanisms underlying bone softening and deformity in C. c. rubrofuscus and for the genetic improvement and selective breeding of cyprinid fish to reduce the occurrence of the softened-bone trait. Full article

Sox9, a pivotal transcription factor belonging to the Sox family, orchestrates critical processes throughout embryonic development, maintenance and differentiation, and exerts a profound influence on organogenesis. Its regulatory versatility stems from precise binding to defined DNA regions, often in collaboration with tissue-specific partners. The dysregulation of Sox9 during chondrogenesis leads to a skeletal malformation termed campomelic dysplasia and has emerged as a significant factor in various other human diseases, including cancer. A point mutation at position 76 (alanine to glutamic acid, A76E) of Sox9 is recognized as one of the causes of campomelic dysplasia. We have used a combination of biophysical, structural and computational techniques to characterize the Sox9 A76E mutant and compare it with the wild-type (WT) Sox9. WT and A76E Sox9 assemble as homodimers, but form predominantly monomeric complexes in the presence of Sox-specific DNA. A CD analysis shows that the A76E mutant preserves the folding as well as the overall secondary structure of Sox9. Both A76E and WT Sox9 behave similarly in the presence of Sox-specific DNA. Perturbation, with increased temperature, displays a lower melting point for A76E, relative to WT Sox9, indicating decreased stability that may arise due to the long and charged side chain of glutamic acid compared to the small hydrophobic alanine, making unfavorable intra-molecular interactions. The destabilizing effect of the A76E mutant may disturb the formation of a stable higher-order complex that is a prerequisite for normal gene expression. Full article

STT3A encodes the catalytic subunit of the oligosaccharyltransferase A (OST-A) complex and is classically linked to severe autosomal-recessive congenital disorder of glycosylation (CDG). To define the distinct autosomal-dominant disorder, we reviewed all published cases and integrated three previously unpublished individuals from the CDG natural history study. Across 21 individuals, abnormal transferrin glycosylation was present in nearly all individuals (20/21), and subtle facial dysmorphism was common (18/21). Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21). Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21). Less frequent features included congenital heart defects (5/21) and coagulation factor deficiency (5/21). Importantly, the newly reported individuals expand dominant STT3A-CDG with previously unreported features, including anorectal malformation, morbid obesity, and clinically significant bleeding diathesis with von Willebrand factor and factor VIII deficiency. Biochemical signatures ranged from classic type I transferrin patterns to subtle or atypical abnormalities, emphasizing that near-normal transferrin testing does not exclude the diagnosis. Variants clustered in conserved catalytic regions, with recurrent p.Arg405 across de novo, inherited, and mosaic cases supporting a mutational hotspot and likely dominant-negative mechanism. Full article

Prenatal exposure to aflatoxin B₁ (AFB₁) poses a significant risk to fetal development and is associated with reduced birth weight in humans. Experimental studies consistently show that AFB₁ induces fetal abnormalities, with skeletal malformations and ossification defects being the most common. However, the specific impact of AFB₁ on fetal osteogenesis remains unclear. Given this knowledge gap, this study aimed to review the existing literature concerning the pathogenesis of AFB₁ and its potential influence on bone development. The primary mechanisms implicated in AFB₁’s impact on bone include dysfunction in vitamin D and calcium metabolism, alterations in parathyroid hormone production and function, induction of inflammatory responses, and oxidative stress. Collectively, these mechanisms have the potential to impair osteoblast and osteoclast function and, consequently, compromise ossification. Based on these findings, studies should explore and elucidate the effects of AFB₁. Elucidating these mechanisms is crucial for mitigating the deleterious impacts of AFB₁ on fetal skeletal development. Full article

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: 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

Triclosan (TCS) is a widely used antimicrobial agent found in personal care products and household cleaners. While valued since the 1960s for its ability to inhibit bacterial fatty acid synthesis, its environmental persistence, ecotoxicity, and bioaccumulative potential have raised significant global concern. The increased use of disinfectants during the COVID-19 pandemic has further exacerbated its prevalence as an aquatic pollutant. In the environment, TCS is distributed through water bodies and sediments, undergoing processes such as biodegradation and photochemical degradation. Its bioaccumulation poses a substantial threat to aquatic organisms, particularly fish. A growing body of research indicates that TCS acts as an endocrine disruptor and developmental toxicant, with documented adverse effects encompassing impaired embryonic and larval development, skeletal malformations, and induction of oxidative stress, mitochondrial dysfunction, DNA damage, and inflammatory responses. Furthermore, TCS exposure is linked to reproductive toxicity, including altered sex hormone levels and diminished reproductive capacity. This review consolidates current knowledge on the chemical properties, environmental fate, biodegradation pathways, and ecotoxicological impacts of TCS, with a specific emphasis on its multifaceted health risks to fish. The synthesis aims to provide a foundation for future research, inform environmental risk assessments, and support the development of evidence-based regulatory measures. Full article

The present study aimed to assess the potential maternal toxicity of Ficus deltoidea var. kunstleri aqueous extract in pregnant rats, along with its impact on maternal hepatic drug metabolism and foetal skeletal development. Pregnant rats were divided into five groups and orally administered varying doses of F. deltoidea aqueous extract (0, 250, 500, 1000, and 2000 mg/kg body weight) from gestation day 6 to 20. Throughout the administration period, clinical observations, body weight, and food and water intake were monitored. On gestation day 21, the pregnant rats were sacrificed, and their vital organs and foetuses were collected for analysis. Gene expression related to hepatic drug metabolism was evaluated using the RT2 Profiler™ PCR array. Foetal external morphology was examined for abnormalities, and skeletal structures were stained with Alizarin Red to assess the effects of F. deltoidea aqueous extract on bone ossification during organogenesis. No maternal toxicity was observed, except for a significant increase in liver weight in the treated groups (p < 0.05). Analysis of 84 genes revealed significant changes in 15, 4, and 11 genes in the 250, 500, and 2000 mg/kg body weight groups, respectively. Notably, Gpx5 and Pkm, both phase II metabolising enzyme genes were downregulated in a dose-dependent manner. Despite some skeletal variations, the extract did not induce foetal external malformations or skeletal abnormalities. The significant increase in maternal liver weight, together with the downregulation of Gpx5 and Pkm, suggests an adaptive hepatic response to the extract rather than an adverse effect. These findings also suggest that F. deltoidea var. kunstleri aqueous extract does not cause embryo toxicity, foetal growth retardation, or developmental malformations, particularly in skeletal formation. The developmental no-observed-adverse-effect level (NOAEL) was determined to be >2000 mg/kg/day via oral administration. Further research is warranted to explore the synergistic interactions of genes involved in hepatic drug metabolism in response to the extract. Full article

Background: Lymphangiomas are rare benign malformations of the lymphatic system, most frequently affecting the head and neck region. Oral involvement is uncommon, and when the tongue is affected, particularly its anterior two-thirds, it can cause major functional and esthetic disturbances. Case Presentation: We report the case of a 13-year-old boy who had undergone total glossectomy at the age of 4 for cystic lymphangioma. During follow-up, the patient presented marked dental and craniofacial alterations, including severe maxillary and mandibular crowding and a skeletal Class III pattern. This case highlights the significant morphological and functional consequences resulting from the absence of the tongue during growth. Conclusions: This case underscores the crucial role of the tongue in craniofacial growth and occlusal development. Early total glossectomy can result in long-term dental and skeletal disturbances, emphasizing the importance of early multidisciplinary follow-up combining surgical, orthodontic, and functional rehabilitation. Further studies are needed to establish appropriate management and rehabilitation protocols for such rare cases. Full article

Background: Foetal structural abnormalities can be detected in approximately 3% of all pregnancies and frequently remain without a genetic diagnosis. This study aims to apply an integrated approach with the final goal of providing a molecular diagnosis in the challenging Italian setting of early termination of pregnancy. Methods: In a cohort of 86 foetuses, post-mortem dysmorphological examination, radiological assessments, and molecular autopsy through Whole-Exome Sequencing—WES—analysis were performed. Results: Forty-two foetuses were phenotypically classified as presenting a single major malformation (i.e., central nervous system, skeletal, urogenital, or cardiac anomalies, or fluid accumulation), while 44 foetuses presented multiple malformations and/or dysmorphic features. Overall, WES provided a diagnostic yield of 26.7%; additionally, seven Variants of Uncertain Significance (VUS) potentially liked to the foetal phenotype were identified. The highest detection rate was achieved for foetuses presenting a single major urogenital (50%) or skeletal (42.9%) malformation, followed by foetuses presenting multiple malformations (27.3%). Peculiar results of particular interest were (1) the identification of two splicing variants (within the INPPL1 and RHOA genes), functionally characterised through minigene assay, which contributed to evaluate their pathogenicity, and (2) the identification of a novel de novo missense ZNF292 variant (NM_015021.3:c.6325A>C p.(Ser2109Arg)) in a foetus affected by corpus callosum hypoplasia. The ZNF292 gene is associated with the Intellectual developmental disorder, autosomal dominant 64 and this finding represents the first report of prenatally detected anomalies of the central nervous system in a foetus carrying a ZNF292 variant. Conclusions: This study underlines the diagnostic utility of an integrated approach to achieve a precise genetic diagnosis for structural foetal abnormalities, thus providing families with precise recurrence risk estimations and detailed options about future pregnancies. Additionally, a systematic implementation of this strategy could be crucial to better characterise new variants and discover new genes involved in embryonic and foetal development. Full article

This study reports, for the first time, lanthanum oxide (La₂O₃) nanoparticles (NPs) that simultaneously suppress osteosarcoma MG63 cell proliferation and promote normal Vero cell viability, a dual effect not previously documented for La₂O₃ or similar metal oxide NPs. Physico-chemical characterization revealed a unique needle-like morphology, cubic crystallinity, and dispersion stability in DMSO without acidic dispersants, properties that can influence cellular uptake, ROS modulation, and biocompatibility. Comprehensive characterization (fluorescence spectroscopy, particle size/zeta potential, Raman, XRD, TGA, ATR-FTIR, and TEM) confirmed structural stability and surface chemistry relevant to biological interactions.La₂O₃ NPs exhibited broad-spectrum antibacterial activity (Gram-positive Streptococcus pyogenes, Bacillus cereus; Gram-negative Escherichia coli, Pseudomonas aeruginosa) and strong enzymatic/non-enzymatic antioxidant capacity, supporting potential use in implant coatings and infection control. MTT assays demonstrated dose-dependent cytotoxicity in MG63 cells, with enhanced proliferation in Vero cells. In zebrafish embryos, developmental toxicity assays yielded an LC₅₀ of 2.6 mg/mL higher (less toxic) than values reported for Ag NPs (~0.3–1 mg/mL) with normal development at lower concentrations and dose-dependent malformations (e.g., impaired somite formation and skeletal deformities) at higher doses. Collectively, these findings position La₂O₃ NPs as a multifunctional platform for oncology and regenerative medicine, uniquely combining selective anticancer activity, normal cell support, antimicrobial and antioxidant functions, and a defined developmental safety margin. Full article

Background: Unilateral lung agenesis (ULA) is a rare congenital anomaly characterized by the complete absence of one lung, often accompanied by cardiovascular, skeletal, or gastrointestinal malformations. Despite its clinical significance, evidence of prevalence, anatomical variants, and outcomes remain fragmented. This systematic review aimed to synthesize existing data on ULA’s prevalence, anatomical classifications, diagnostic approaches, and clinical implications. Methods: Following PRISMA 2020 guidelines, five databases (MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE) were searched from inception to January 2024. Inclusion criteria encompassed case reports, case series, and observational studies on ULA in humans. Risk of bias was assessed using the Joanna Briggs Institute (JBI) checklist. Narrative synthesis was performed due to methodological heterogeneity. Results: Thirty-two studies (137 participants) were included. Right-sided ULA predominated (58%), with poorer prognoses due to mediastinal distortion. Cardiovascular anomalies (40%) were the most common comorbidity. Diagnostic modalities included chest radiography (85%), CT (70%), and bronchoscopy (25%). Schneider-Boyden scale was used to classify the included studies. Risk of bias assessment revealed 65% of studies as low risk, 28% as moderate, and 7% as high risk. Conclusions: ULA necessitates multidisciplinary management, particularly in cases with associated anomalies. Left-sided ULA correlates with better outcomes, emphasizing the role of early imaging. Limitations include reliance on case reports and inconsistent reporting of anatomical variants. Future research should adopt standardized classifications and longitudinal designs to improve evidence quality. Open science framework (OSF): 10.17605/OSF.IO/XVQSP. Full article

Background: Craniofacial clefts represent the most common congenital malformation in the head and neck region. Although most patients undergo primary cleft repair in childhood, many still present midfacial growth deficiencies in adulthood. This study aimed to evaluate and compare the incidence and indications for orthognathic surgery in adult patients with cleft lip (CL), cleft lip and alveolus (CLA), cleft lip and palate (CLP), and isolated cleft palate (CP). Materials and Methods: Sixty adult cleft patients (36 males and 24 females) born with a cleft and with a mean age of 19.51 ± 1.83 years were retrospectively enrolled in this study. All patients had undergone primary lip and palate repair during childhood at the Oral and Maxillofacial Surgery Service of “Mother Teresa” University Hospital Centre in Tirana. Clinical records, orthodontic documentation, and cephalometric data were reviewed to determine the indication for orthognathic surgery. Results: The statistical analysis showed that orthognathic surgery was deemed necessary in 30% patients, including ten males (56%) and eight females (44%). The most prevalent type of cleft was CLP, accounting for 35% of all patients, and it showed the highest surgical indication rate (83.3%). Cleft patients and the need for orthognathic surgery were evaluated according to the skeletal malocclusion in three planes. The need for surgery was more prevalent in patients with skeletal class III malocclusion with maxillary hypoplasia (83.3% of surgical cases), those with anterior and posterior crossbite (21.7% of all patients), and in deep bite patients (16.7% of all patients). Additionally, all patients with facial asymmetry (15%) required orthognathic surgery, highlighting the strong association between asymmetry and surgical indication. Conclusions: Patients with craniofacial cleft, especially those with CLP and combined maxillary deficiencies, demonstrate a significantly higher need for orthognathic surgery. Quantitative assessment supports the necessity of a multidisciplinary treatment approach to address persistent skeletal discrepancies and optimize functional and aesthetic outcomes in adult cleft patients. Full article

Gestational diabetes mellitus (GDM), a prevalent metabolic disorder in pregnancy, induces maternal hyperglycemia and elevates fetal malformation risks, particularly in craniofacial development. To investigate the underlying mechanisms, we employed zebrafish as a model organism due to its conserved skeletal development pathways with humans. Zebrafish embryos were exposed to 3.5% and 4% high glucose (HG) from 10–80 h post-fertilization (hpf). Through comprehensive analyses including Alcian blue staining, confocal microscopy, and molecular assays, we demonstrated that HG exposure caused significant developmental abnormalities including growth retardation, craniofacial cartilage malformations, and impaired cranial neural crest cells (CNCCs) migration and proliferation. Mechanistically, HG induced reactive oxygen species (ROS) accumulation and oxidative stress while downregulating critical CNCCs markers (dlx2 and tfap2a). These molecular alterations correlated with histomorphological defects in pharyngeal arch cartilage, particularly in ceratohyal formation. Our findings establish that glucose disrupts craniofacial development through oxidative stress-mediated CNCCs dysfunction, providing novel mechanistic insights into GDM-associated skeletal abnormalities and potential therapeutic targets. Full article