Search Results (150)

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

Van Maldergem Syndrome (VMS) is a rare autosomal recessive disorder caused by pathogenic variants in the atypical cadherin genes DCHS1 or FAT4 and is marked by craniofacial, skeletal, and neurodevelopmental abnormalities. Although DCHS1–FAT4 binding is mediated by their respective extracellular domains, the in vivo function of the DCHS1 intracellular domain (ICD) is poorly defined. To test its function, we generated mice in which the DCHS1 ICD was deleted and replaced with a V5 epitope tag (Dchs1^ΔICD-V5). Homozygous Dchs1^{ΔICD-V5/ΔICD-V5} mice are viable but exhibit VMS-like craniofacial flattening with enlarged fontanelles and reduced palatine/maxillary structures, along with airway cartilage abnormalities including reduced mineralization and decreased tracheal circularity. In periventricular regions, wild-type DCHS1 expression shows polarized localization, whereas mice with the ICD deletion exhibit altered cell polarization within the subventricular zone, concomitant with changes in neural cellular distribution. Neonatal brains display reduced pYAP1: YAP1 ratios and increased Ki67+ proliferation with greater Ki67–neuronal co-localization within the periventricular zone. Together, these data identify the DCHS1 ICD as a critical effector for DCHS1 signaling and a regulator of polarity-dependent growth, with associated changes in Hippo pathway activity during craniofacial and neural morphogenesis. Additionally, our data establish Dchs1^{ΔICD-V5/ΔICD-V5} mice as a model that recapitulates core features of VMS, thereby allowing new mechanistic discoveries into its pathogenesis. Full article

Introduction: Apert syndrome is a rare genetic disorder characterized by craniofacial anomalies and limb malformations, often accompanied by neurodevelopmental abnormalities that can considerably affect motor development. Aim: The aim of this study was to document the progress in motor development of a girl with Apert syndrome, with an emphasis on assessing functional needs and evaluating the effects of a multidisciplinary rehabilitation approach. Materials and Methods: Motor functions were evaluated using the Gross Motor Function Measure (GMFM-88) at 16 and 24 months of age. Rehabilitation consisted of an intensive physiotherapy program, Dynamic Movement Intervention (DMI), delivered in monthly cycles over eight months. The therapeutic approach focused on developing postural control, transitional positions, and functional mobility while stimulating sensorimotor integration and neuroplasticity. Results: The initial GMFM score was 29.00%, and the final assessment score reached 68.68%, representing a relative improvement of 136.83%. The most considerable progress was observed in sitting, crawling, and kneeling, with initial improvements in standing. Despite the limitations of this study, the results suggest a positive effect of early, intensive, and individualized rehabilitation combined with active family involvement. Conclusions: The outcomes highlight the importance of early assessment, continuous monitoring of motor development, and a multidisciplinary rehabilitation approach in children with Apert syndrome, with the GMFM serving as a valuable tool for evaluating gross motor function. Full article

Background and objective: Obstructive sleep apnea (OSA) is a common pediatric sleep disorder, most often caused by adenotonsillar hypertrophy. Although adenotonsillectomy (AT) is the standard first–line treatment, a substantial proportion of children experience residual OSA (rOSA). This systematic review aimed to synthesize current evidence on risk factors associated with rOSA in children following AT. Materials and Methods: A systematic review was conducted in accordance with PRISMA guidelines. PubMed and the Cochrane Library were searched without date restrictions using English–language terms related to rOSA, children, and adenotonsillectomy. Studies assessing postoperative persistence of OSA and associated risk factors were included. Results: Thirteen studies published between 2010 and 2024 met the inclusion criteria. The reported prevalence of rOSA varied widely (18.6–85.0%), reflecting heterogeneity in study design, patient populations, baseline disease severity, and follow–up methods. Obesity emerged as the most consistently identified risk factor, with significantly higher rOSA rates reported among children with elevated body mass index. Age also influenced outcomes, with both very young (<3 years) and older (>7 years) children demonstrating an increased likelihood of persistent disease. Comorbid conditions, particularly asthma and Down syndrome, were associated with poorer postoperative improvement. Additional contributors included craniofacial or developmental abnormalities and higher preoperative apnea–hypopnea index. Limited evidence also suggested that socioeconomic and environmental factors may affect postoperative outcomes. Conclusions: Residual OSA is common following adenotonsillectomy in children. Obesity, age, and comorbidities are key predictors, underscoring the need for comprehensive preoperative risk stratification and structured postoperative follow–up. Full article

Background: Ankylosis of the temporomandibular joint (TMJ) is a rare developmental disorder that involves fibrous or bony fusion within the joint. It is a severe structural and functional disorder. Typically, the phenotype manifests as joint immobilization and results in facial deformity and trismus. To date, ankylosis is rarely diagnosed as congenital and its occurrence mechanism has not been thoroughly understood. We observed a female patient who as a newborn showed slight facial asymmetry and impaired mandibular retraction. In addition, non-uniform occlusal fissures were noted; the lower part of the left earlobe was slightly smaller than the right earlobe. The aim of the work was the identification of pathogenic variants in the genome related to ankylosis. Ankylosis has no known causative gene yet; thus, Whole Exome Sequencing (WES) was performed. Materials and Methods: We observed a female patient with facial asymmetry and impaired mandibular retraction from birth. No phenotypic abnormalities were noted on the head or elsewhere on the body. A diagnostic computed tomography (CT) scan of the head performed at five months of age led to the diagnosis of congenital zygomatic-coronoid ankylosis. Genomic DNA samples were subjected to WES. Library preparation was carried out using the Twist Library Preparation EF Kit 2.0, followed by target enrichment with the Twist Exome 2.0 Plus Comprehensive Exome. Sequencing reads were aligned to the human reference genome (GRCh38), and variant calling was performed using standard bioinformatics workflows. Variants were subsequently filtered, annotated, and interpreted using VariantStudio. Assessment of variant pathogenicity was primarily based on comparisons with public databases, including ClinVar and VarSome, and was supported by in silico prediction tools such as SIFT and PolyPhen-2. Results: In genes responsible for disorders of the I and II pharyngeal arches, three pathogenic variants were identified: in the genes TCOF1 and POLR1B, responsible for the development of Treacher Collins syndrome (TCS), and one in the DHODH gene, responsible for Miller syndrome. Additionally, in genes that have not been linked so far with rare facial disorders, 42 variants were identified, of which 8 are listed as pathogenic. We present the first described patient with congenital ankylosis, who, although showing no phenotypic features of these syndromes, has identified pathogenic variants in genes responsible for craniofacial dysostosis. Conclusions: Variants in TCOF1, POLR1B and DHODH may represent candidate genetic factors associated with susceptibility to ankylosis. WES analysis is an appropriate method in the case of patients with congenital diseases with unknown genetic origin. In this study we provide a comprehensive list of all identified pathogenic variants. This might be useful for scientists searching for the genetic background of skeletal system issues, one of which could be bone and fibrous tissue remodeling. Full article

Objectives: This study aimed to evaluate phenotypic associations between preoperative alkaline phosphatase (ALP) levels and clinical characteristics, and explore clinical factors associated for postoperative regrowth in craniofacial fibrous dysplasia. Methods: In this retrospective cohort (2003–2024), 71 surgically treated fibrous dysplasia patients were analyzed. Relationships between preoperative ALP (using age-stratified reference ranges) and key phenotypes (age at surgery, onset age, laterality, lesion type) were assessed via nonparametric tests. Associations with postoperative regrowth were assessed using Mann–Whitney U or Kruskal–Wallis tests for non-normally distributed continuous variables and χ² or Fisher’s exact tests for categorical variables. Results: Preoperative ALP levels significantly correlated with younger surgical age (16–19 vs. ≥19 years: 244.0 vs. 107.0 U/L, p < 0.001), earlier onset (0–16 vs. >16 years: 114.0 vs. 83.0 U/L, p = 0.030), bilateral lesions (176.0 vs. 106.2 U/L, p = 0.006), and polyostotic subtype (polyostotic fibrous dysplasia vs. monostotic fibrous dysplasia: 162.0 vs. 87.5 U/L, p < 0.001). However, neither ALP levels (p = 0.061) nor abnormal ALP rates (p = 0.090) predicted regrowth. Crucially, bilateral lesions were significantly associated with regrowth (83.3% (5/6) vs. 21.5% (14/65); p = 0.005). The overall regrowth rate was 8.5% (6/71). Conclusions: Bilateral lesions demonstrate significant association with postoperative regrowth risk, potentially guiding surveillance intensity. ALP correlates with phenotypic burden but shows limited prognostic utility. These findings, interpreted considering retrospective constraints, warrant validation in larger cohorts. Full article

Peters-Plus syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the B3GLCT gene and characterized by multisystem involvement. Fewer than 100 cases have been reported to date, and only a limited number have been diagnosed prenatally. Prenatal identification is challenging due to the variable and non-specific nature of fetal findings and the frequent absence of detectable ocular anomalies during routine ultrasound. We report a prenatal diagnosis of Peters-Plus syndrome in a monochorionic diamniotic twin pregnancy, based on the progressive identification of early-onset intrauterine growth restriction, rhizomelic limb shortening, craniofacial dysmorphism, and mild central nervous system abnormalities. Standard cytogenetic and chromosomal microarray analyses were normal, prompting extended genetic testing. Prenatal exome sequencing identified a homozygous pathogenic splice-site variant (c.660+1G>A) in B3GLCT in both fetuses, confirming the diagnosis. This case highlights the importance of recognizing suggestive multisystem prenatal findings and the crucial role of advanced genetic testing in achieving an accurate prenatal diagnosis. Early molecular confirmation enables appropriate parental counseling regarding prognosis, recurrence risk, and future reproductive options. Full article

Background: Marfan syndrome is an autosomal dominant connective tissue disorder that affects multiple organ systems, with cardiovascular complications posing a major risk. With advancements in medical care and the increasing lifespan of patients with Marfan syndrome, the spectrum of medical issues has evolved. This case report highlights the complex anaesthetic management of a patient with Marfan syndrome during elective ventral hernia repair. Case presentation: A 37-year-old male with Marfan syndrome was admitted for elective open ventral hernia repair. Challenges included severe arterial hypertension, prior aortic valve replacement, scoliosis, and an anticipated difficult airway, as the patient presented with restricted mouth opening due to craniofacial abnormalities consistent with difficult laryngoscopy. Preoperative assessments included routine tests, echocardiography and chest X-ray. The anaesthetic management focused on specific patient positioning with head-up tilt, maintenance of haemodynamic stability with the insertion of an arterial line before the induction of anaesthesia and neuromuscular block (NMB) monitoring, followed by titrated doses of all medications. Lung ventilation strategies were specifically adjusted to address the patient’s underlying comorbidities. The patient was extubated and transferred to the recovery unit. The intraoperative and immediate postoperative periods were relatively uneventful. Dyspnea due to external pressure on the abdominal wall caused by a specific binder was treated with the release of pressure. Later postoperative recovery was complicated by hydrothorax and pneumonia, both treated successfully. Conclusions: This case emphasises the importance of multidisciplinary approaches and vigilant monitoring in the management of a patient with Marfan syndrome perioperatively, even for seemingly low-risk operations. Appropriate anaesthetic management helped to avoid major perioperative complications. Full article

Objectives: Global Developmental Delay (GDD) and Intellectual Disability (ID) are prevalent neurodevelopmental disorders with significant disability burden, and genetic factors play a crucial role in their etiology. This study aimed to develop and validate a clinical prediction model for identifying children with GDD/ID at high genetic risk, facilitating targeted genetic testing. Methods: We retrospectively analyzed clinical data of children with GDD/ID treated at Nanjing Children’s Hospital from January 2019 to December 2023. Children with comorbid Autism Spectrum Disorder (ASD) were excluded. The dataset was randomly split into training and validation sets (7:3 ratio). Lasso regression was used to identify potential predictive factors for positive genetic test results, followed by multivariable logistic regression to select independent predictors, which were incorporated into a nomogram. Model performance was evaluated by discrimination, calibration, and clinical utility using decision curve analysis in both sets. Results: Four independent predictors—craniofacial abnormalities, visceral abnormalities, physical growth abnormalities, and family history of ID—were identified. The resulting nomogram demonstrated an area under the curve (AUC) of 0.734., with good calibration and positive net benefit on decision curve analysis. Validation confirmed the reliability of the model. Conclusions: We developed a clinically applicable prediction model to identify high genetic risk among children with GDD/ID without ASD. This model may serve as a preliminary screening tool to assist clinicians in prioritizing genetic testing and improving diagnostic efficiency in clinical practice. Full article

Airway obstruction may lead to dentofacial dysmorphogenesis, with severity influenced by age, duration, and extent of obstruction. Aims: to evaluate long-term craniofacial changes in children with a history of mouth breathing, comparing outcomes between those treated with lymphoid tissue removal or with medication, and considering treatment age. Materials and Methods: Fifty-seven patients with a mean age of 19.09 years (range: 15.1–25.2 years) who had been evaluated in an earlier study (T1) were recalled at an average of 13 years follow-up (T2) and classified into a surgical group (n = 34), who had an adenoidectomy, and a non-surgical group (n = 23) treated with medication. Lateral cephalograms were obtained and compared with the original pre-treatment records. Control groups were included, matching the subjects in both groups for age and sex. Statistical analyses included group comparisons and associations among variables. Results: Significant improvement in both treatment groups were observed for the gonial angle (Ar-Go-Me), facial convexity (S-N-Me) and facial height (N-Gn), but T2-T1 changes in the surgical group were statistically significantly greater than in the medical therapy group. The palatal plane inclination to the horizontal (PP/H) and the mandibular plane inclination (MP/H) and to cranial base (MP/SN) were significantly improved in both groups (0.001 < p < 0.01). Conclusions: Both surgical and medical treatment of airway obstruction resulted in the reversal of the harmful effect of the obstruction. However, adenoidectomy was associated with greater improvements, possibly because the original obstruction was more severe and longer-standing. The results underline the importance of early recognition and management of airway obstruction to mitigate developmental orofacial dysmorphology. 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

Background: SPATA5L1-related neurodevelopmental disorder is a recently described condition characterized by psychomotor delay, sensorineural hearing loss, and variable motor dysfunction. Because only a few cases have been reported, the full phenotypic spectrum remains poorly defined. Expanding clinical characterization is crucial for improving early diagnosis and targeted management. Case Presentation: We report a 24-month-old female with compound heterozygous SPATA5L1 variants c.1918C>T (p.Arg640Ter) and c.2066G>T (p.Gly689Val). She presented with global psychomotor delay, bilateral sensorineural hearing loss, strabismus, and craniofacial dysmorphism. Brain MRI showed cortical and white matter atrophy, delayed myelination, and a thin corpus callosum. Vojta neurodevelopmental assessment demonstrated an 11-month motor delay, abnormal responses in all seven Vojta postural reactions, and persistent primitive reflexes. Early EEG recordings were without significant changes, whereas abnormalities emerged later in the clinical course. Genetic testing confirmed the variants in trans. Management and Outcomes: Early rehabilitation including reflex locomotion therapy was initiated. The persistence of primitive reflexes, central hypotonia, and pathological postural reactions provided a coherent neuromotor profile and indicated a high vulnerability to atypical motor development, and do not rule out the possibility of later evolution toward a spastic–dystonic motor pattern. These findings, combined with neuroimaging abnormalities, refined the patient’s neuromotor phenotype and guided individualized therapeutic planning. Conclusions: This case expands the clinical and neurodevelopmental spectrum associated with SPATA5L1 variants and highlights the diagnostic value of integrating genomic sequencing with structured motor assessments. Early, multidimensional evaluation may improve recognition of rare neurodevelopmental disorders and support more precise prognostication and rehabilitation strategies. Full article

Background: Complex cases of retinoblastoma (RB) often require integrative molecular approaches to define tumor etiology and guide clinical management. Purpose: Our aim was to evaluate the usefulness of combining aqueous humor (AH)/plasma cell-free DNA next-generation sequencing (cfDNA-NGS) and long-read–whole-genome sequencing (LR-WGS) to resolve diagnostically challenging RB cases. Case Description: We report the case of a 3-year-old Caucasian girl, conceived by heterologous assisted reproductive technology (ART), presenting with unilateral, widely infiltrative RB in the right eye. She exhibited limited verbal communication, a glabellar angioma extending to the nasal bridge and philtrum, and mild hypertelorism. Standard blood testing revealed no pathogenic SNVs, CNVs, or methylation abnormalities in the RB1 gene. Targeted cfDNA analysis using the Illumina TruSight Oncology 500 (TSO500) panel on AH and plasma identified a somatic RB1 splice-site variant (c.1498+2T>C) with a variant allele frequency (VAF) of 98.5%, consistent with biallelic inactivation. Additional gains (fold change > 1.5) were found in AH and confirmed in plasma, suggesting a germline 13q duplication. Third-generation LR-WGS, performed with Oxford Nanopore Technology (ONT), on blood confirmed a 24.6 Mb duplication on chromosome 13, compatible with the rare 13q duplication syndrome characterized by psychomotor delay, craniofacial dysmorphism, and hemangiomas. AH-cfDNA revealed additional somatic copy-number alterations, including amplifications (i.e., MDM4 and ALK) and deletions (i.e., BRCA2), indicating progressive clonal tumor evolution. Conclusions: This experience tells us that a combined approach with TSO500 Illumina NGS on cfDNA, along with LR-WGS, is able to help solve complex cases and define the appropriate treatment and surveillance strategy. Full article

Background: SATB2-associated syndrome (SAS), also known as Glass syndrome, is a neurodevelopmental disorder (NDD) characterized by intellectual disability, developmental delay, absent or limited speech, and distinctive craniofacial and dental anomalies. It is caused by autosomal dominant pathogenic variants in the SATB2 gene, which plays a crucial role in brain, dental, and jaw development. Due to its variable phenotype, clinical diagnosis can be challenging, necessitating genetic confirmation. Methods: We present six new cases of SAS with SATB2 germline variants identified through next generation sequencing (NGS) technologies, expanding the known genetic and clinical spectrum of the syndrome. Detailed clinical phenotyping was performed for all patients. Results: Our cohort exhibits a broad range of clinical manifestations consistent with SAS, encompassing severe intellectual disability, profound speech delay, various palatal and dental abnormalities. We report the oldest adult patient (56 years old) carrying an in-frame duplication, and a pediatric patient with a missense variant who presented a significant reduction in visual acuity, likely of neurological or cortical origin, in the absence of ophthalmological abnormalities. SATB2 variants include three missenses, two in-frame deletion/duplication and one frameshift variant, several of which are novel and classified as likely pathogenic or pathogenic according to ACMG guidelines. Conclusions: This report provides new clinical and genetic insights into the landscape of SAS. Our findings confirm the phenotypic heterogeneity of SAS and highlight the critical role of comprehensive genetic testing for accurate diagnosis in NDD patients. Full article

Background/Objective: POLR1A and related gene variants cause craniofacial and developmental syndromes, including Acrofacial Dysostosis-Cincinnati, Treacher-Collins types 2–4, and TWIST1-associated disorders. Using a patient case integrated with molecular analyses, we aimed to clarify shared pathogenic mechanisms and propose these conditions as part of a spectrum of RNA polymerase I (Pol I)–related ribosomopathies. Methods: A patient with a heterozygous POLR1A variant underwent clinical evaluation. Findings were integrated with a literature review of craniofacial syndromes to identify overlapping fea tures. Protein-protein and gene-gene interactions were analyzed with STRING and Pathway Commons, a structural modeling of POLR1A assessed the mutation’s impact. Results: The patient exhibited features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins types 2–4, supporting a shared spectrum. Computational analyses identified POLR1A-associated partners and pathways converging on Pol I function, ribosomal biogenesis, and nucleolar processes. Structural modeling of the Met496Ile variant suggested disruption of DNA binding and polymerase activity, linking molecular dysfunction to the clinical phenotype. Conclusion: Significant clinical and genetic overlap exists among Saethre-Chotzen, Sweeney-Cox, Treacher-Collins types 2–4, and Acrofacial Dysostosis-Cincinnati. POLR1A and related Pol I subunits provide a mechanistic basis through impaired nucleolar organization and rRNA transcription, contributing to abnormal craniofacial development. Integrative protein, gene, and structural analyses support classifying these syndromes as Pol I–related ribosomopathies, with implications for diagnosis, counseling, and future mechanistic or therapeutic studies. Full article