Search Results (89)

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

Body stalk anomaly (BSA) is a rare and usually fatal congenital disorder involving severe malformations of the body wall, limbs, spine, and internal organs. This study presents the first documented cases of BSA in seven dogs, offering new insights into how the disorder manifests in animals. The affected fetuses consistently exhibited major anomalies, including large abdominal wall defects, structural spinal abnormalities, and a variety of limb malformations ranging from partial agenesis and meromelia to phocomelia and complete amelia. Structural urogenital anomalies and orofacial clefts were also observed, aligning with similar findings in BSA cases reported in pigs and cats. These findings support the hypothesis of a multifactorial etiology involving early embryonic disruptions, such as abnormal folding of the embryo, rupture of the amniotic membrane, and vascular compromise. The frequent occurrence of abdominal wall defects alongside umbilical cord abnormalities further suggests a shared developmental pathway. This study also highlights the value of veterinary cases in comparative embryology and the need to assess congenital anomalies as part of a broader malformation complex. By expanding the phenotypic spectrum of BSA in domestic animals, this work contributes to a deeper understanding of its pathogenesis and emphasizes the importance of further research into the genetic and environmental factors involved. Such efforts could lead to improved classification and diagnosis of complex congenital malformations, as well as facilitate cross-species comparisons. Full article

Background/Objectives: Congenital clubfoot (CC) is one of the most common congenital deformities of the lower limbs, typically presenting as a complex skeletal malformation. It is frequently associated with other congenital anomalies, although the co-occurrence with agenesis of the toes is rare. This case report describes a unique presentation of congenital clubfoot associated with agenesis of the 4th and 5th toes, focusing on clinical management and reviewing the literature on skeletal malformations linked to CC. Methods: A comprehensive literature review was conducted, focusing on studies published in the last decade regarding congenital clubfoot and its association with other skeletal malformations. A clinical analysis of a patient with congenital clubfoot and digital agenesis was performed, including diagnostic methods, treatment approach, and follow-up results. The patient was treated with the Ponseti method, followed by percutaneous Achilles tendon tenotomy due to insufficient correction. Due to persistent equinus deformity, a second intervention involving Achilles tendon lengthening and syndesmotic capsulotomy was performed. Results: The patient presented with unilateral congenital clubfoot and agenesis of the 4th and 5th toes, a rare combination. Initial correction was achieved with the Ponseti method, but further surgical intervention was needed. Follow-up at 2 years showed excellent results, with the patient able to walk without difficulty. The literature review revealed limited cases involving digital agenesis associated with clubfoot. Conclusions: This case report highlights the rare association between congenital clubfoot and agenesis of the 4th and 5th toes. While satisfactory outcomes were achieved, further studies are needed to explore potential worse outcomes in cases with associated malformations and the genetic factors involved. Full article

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that resists biological degradation and accumulates in organisms. It disrupts zebrafish embryo development, affecting their heartbeat rate and locomotion. Meanwhile, probiotics are known to enhance the development and ossification of zebrafish embryos. In this study, we examined the toxic effects of PFOA on growth and bone formation in zebrafish and the potential of the probiotic Bacillus subtilis var. natto to counteract its toxicity. Larvae were exposed to 0, 50, or 100 mg/L PFOA from hatching to 21 days post-fertilization (dpf), with or without dietary probiotic supplementation (10⁷ CFU/larva/day), and they were sampled at 7, 14, and 21 dpf. PFOA exposure reduced standard length at 21 dpf, while the co-administration of probiotics mitigated these effects. Craniofacial cartilage defects appeared in larvae exposed to 50 mg/L PFOA at 7 and 14 dpf, while 100 mg/L PFOA impaired bone development at 7 dpf. Probiotics counteracted these abnormalities. PFOA also delayed ossification, correlating with the downregulation of col10a1a, runx2b, and cyp26b1, while the probiotic treatment restored normal ossification. These findings improve our understanding of PFOA’s detrimental effects on zebrafish growth and bone formation while demonstrating the protective role of probiotics against PFOA-induced developmental toxicity. Full article

Background: This systematic review aims to evaluate the relationship between craniocervical posture and sagittal skeletal malocclusions, focusing on cervical curvature, head posture, and the influence of skeletal classification on craniofacial development. Methods: A comprehensive electronic search was conducted across PubMed, Scopus, and Web of Science for studies published between January 2015 and January 2025. Studies meeting the PICOS criteria, which assessed craniocervical posture in individuals with skeletal Class I, II, or III malocclusions, were included. A total of 12 studies were reviewed and analyzed for relevant data. Results: Significant correlations were identified between sagittal skeletal malocclusions and craniocervical posture, particularly cervical curvature. Class II malocclusion was associated with increased cervical curvature and forward head posture, whereas Class III malocclusion was linked to straighter cervical columns and a more posterior head position. Variations in cervical vertebral morphology were also observed, especially in relation to head posture and craniofacial structure. However, considerable heterogeneity was noted among studies regarding sample populations, measurement techniques, and classification criteria. Conclusions: This review highlights a strong interrelationship between craniocervical posture and sagittal skeletal classification, with potential clinical implications for orthodontic diagnosis and treatment planning. Further longitudinal studies are needed to establish causal relationships and improve orthodontic management strategies. Full article

Background: The umbilical cord normally contains two arteries and one vein. The presence of supernumerary—four or five—umbilical cord vessels is a rare phenomenon, with few cases reported in the literature. The majority of cases are detected postnatally. However, given their potential association with developmental abnormalities, primarily severe cardiac anomalies and genetic disorders, the prenatal diagnosis of supernumerary umbilical cord vessels may have clinical relevance. Methods: A review of the clinical phenomenon of the four-vessel umbilical cord and its complications was conducted using case studies and literature reviews in PubMed from 1977 to the present and in Google Scholar from 1966 to the present. Results: Among the 24 reported cases, 7 cases were associated with malformations, 8 cases were detected antenatally, and 16 cases postpartum. Among the eight antenatally diagnosed cases, only one had a congenital malformation, hydrops fetalis. Among the postnatally diagnosed cases, six had congenital abnormalities: three were cardiovascular, two were associated with hydrops, urinary, gastrointestinal, and skeletal disorders, hypoplastic corpus callosum, and dysmorphic facial features. Conclusions: Four-vessel umbilical cords are more frequent than previously thought, as they can be easily overlooked during the mandatory ultrasound examination. A review of the literature revealed a correlation between supernumerary umbilical cord vessels and major congenital malformations, underscoring the significance of prenatal diagnosis; however, the four-vessel cord may not always be indicative of a serious condition. Full article

The study of ecotoxicity induced by vanadium (V) represents an area of increasing interest due to the growing use of V in both the industrial and pharmaceutical areas. This leads to its introduction into water environments, marking a developing problem, especially since rising global temperatures appear to intensify its toxic properties. Cytotoxicological approaches carried out on whole marine embryos represent a valid research tool since they grow directly in contact with the pollutants and are equipped with highly responsive cells to stressors. Here, we discuss the detrimental impact on Paracentrotus lividus sea urchin embryos resulting from the combination of V and higher temperatures, reflecting the effects of climate variation. The results demonstrate the remodeling of embryonic architecture at the morphometric level, revealing developmental delays and anomalies. These malformations involve variations in the total skeletal mass due to the almost total absence of the skeleton, with the exception of small calcareous aggregates. Furthermore, both a modulation in total tissue remodeling enzymatic activities and a variation in the amount of three MMP-like gelatinases (MMP-2, -9, and -14) were observed. This research demonstrates that climate change significantly increases the harmful effects of V, emphasizing the necessity for comprehensive toxicity assessments in environmental evaluations. Full article

Background: Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder caused by pathogenic variants in the NF1 gene. Although genotype–phenotype correlation studies are increasing, robust clinically relevant correlations have remained limited. Methods: We conducted a retrospective analysis of data obtained from a cohort of 204 Hungarian individuals, with a mean age of 16 years (age range: 1–33 years). The data were collected over 15 years. Results: Among the cohort of 204 patients, 148 subjects fulfilled ≥2 criteria established by the National Health Institute. Genetic testing was performed in 70 patients, with an 82.8% detection rate, of which 13 patients were excluded. Among the remaining 45 pathogenic variants, 17 (37.7%) frameshift, 11 (24.4%) nonsense, 8 (17.8%) splice-site, 4 (8.9%) missense mutations, and 5 (11.11%) copy number variations (CNVs) were detected. Café-au-lait macules were present in all patients (100%). Intracranial malformations were the second most common feature (55.6%), followed by Lisch nodules (35.6%), neurofibromas (33.3%), and skeletal abnormalities (31.1%). Conclusions: In our cohort, patients with splice-site variants (8/45, 17.8%) demonstrated a notably more severe phenotype compared to findings reported in other studies, with a high prevalence of plexiform neurofibromas (37.5%), intracranial findings (62.5%), skeletal abnormalities (50%), Lisch nodules (50%), and even pseudarthrosis (25%). Correlating with the literature, missense variants represented a mild phenotype, while patients with microdeletion syndrome revealed a more severe phenotype. Full article

Background/Objectives: Abnormal development of the second heart field significantly contributes to congenital heart defects, often caused by disruptions in tightly regulated molecular pathways. Smyd1, a gene encoding a protein with SET and MYND domains, is essential for heart and skeletal muscle development. Mutations in SMYD1 result in severe cardiac malformations and misregulation of Hand2 expression in mammals. This study examines the role of Smyd1b in zebrafish cardiac morphogenesis to elucidate its function and the mechanisms underlying congenital heart defects. Methods: Smyd1b (still heart) mutant embryos were analyzed for cardiac defects, and changes in gene expression related to heart development using live imaging, in situ hybridization, quantitative PCR and immunofluorescent comparisons and analysis. Results: Smyd1b mutants displayed severe cardiac defects, including failure to loop, severe edema, and an expansion of cardiac jelly linked to increased has2 expression. Additionally, the expression of key cardiac transcription factors, such as gata4, gata5, and nkx2.5, was notably reduced, indicating disrupted transcriptional regulation. The migration of cardiac progenitors was impaired and the absence of Islet-1-positive cells in the mutant hearts suggests a failed contribution of SHF progenitor cells. Conclusions: These findings underscore the essential role of Smyd1b in regulating cardiac morphogenesis and the development of the second heart field. This study highlights the potential of Smyd1b as a key factor in understanding the genetic and molecular mechanisms underlying congenital heart defects and cardiac development. Full article

Background: The orthodontic management of pediatric patients with rare diseases, such as Ectodermal Dysplasia (ED) and Osteogenesis Imperfecta (OI), requires complex protocols due to dental anomalies in both the number and structure of teeth. These conditions necessitate a departure from traditional orthodontic approaches, as skeletal anchoring is often required because of these anomalies. Case Presentation: A patient with ED, characterized by hypodontia and malformed teeth, presented with insufficient natural teeth for anchorage. This challenge was addressed using a Maxillary Skeletal Expander (MSE) with miniscrews. Cone-beam computed tomography (CBCT) and cephalometric radiographs were used to assess bone density, which guided the creation of a customized hybrid device. A second patient with OI, a condition causing fragile bones, had malformed teeth and a high risk of fractures. Skeletal anchoring with MSE and miniscrews was chosen to avoid damaging brittle bones. The fragile nature of the patient’s bones required careful planning and close monitoring throughout the treatment process. Both patients were treated at the UOC of Pediatric Dentistry, Sapienza University of Rome, using MSE with miniscrews. Pre- and post-treatment imaging (CBCT and cephalometric radiographs) were used to evaluate bone quality and monitor progress. Skeletal anchoring successfully addressed the unique challenges in both cases, achieving outcomes comparable to those in unaffected patients. Discsussions: despite limited bone volume, MSE successfully achieved maxillary arch expansion and improved occlusion. Post-treatment radiographs showed successful maxillary expansion and alignment without complications. Conclusions: This case series highlighted the effectiveness of MSE with miniscrews in treating patients with rare diseases. It advances orthodontic management by offering reliable solutions for complex cases involving dental anomalies and compromised bone structures. Full article

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder characterized by a distinctive facial appearance, growth/cognitive retardation, developmental delay, skeletal malformation, hypertrichosis, and other abnormalities. Patients with mild CdLS have less severe phenotypes, while retaining representative facial features. Mutations in the genes NIPBL, SMC1A, SMC3, HDAC8, and RAD21 have been associated with CdLS, with mutations in NIPBL accounting for approximately 60% of cases. Herein, we present a case of CdLS accompanied by cholelithiasis and nephrolithiasis. A 9-year-old Korean boy presented with vomiting and abdominal pain. Abdominal ultrasonography revealed several gallstones and renal stones. Extracorporeal shock wave lithotripsy failed; therefore, cholecystectomy and nephrolithotomy were performed. Postoperative stone composition analysis revealed calcium oxalate as the primary component. CdLS was suspected based on the characteristic appearance and physical examination, with genetic testing confirming an NIPBL gene mutation. Simultaneous CdLS, cholelithiasis, and nephrolithiasis requires careful management and treatment tailored to each patient’s specific needs and challenges. Full article