Search Results (194)

Background: Craniofacial growth is regulated by a complex interaction of genetic, functional, and systemic metabolic factors. Mechanical loading generated during mastication plays a fundamental role in mandibular development through bone modeling and remodeling mechanisms. In contrast, Type I diabetes mellitus is associated with impaired bone metabolism, which may compromise skeletal growth. Although the independent effects of functional loading and metabolic disorders on bone tissue have been widely investigated, their combined influence on mandibular development remains insufficiently understood. Objective: This study primarily aimed to evaluate the effect of Type I diabetes mellitus on mandibular growth in growing rats and, secondarily, to assess the impact of dietary consistency (hard versus soft food) on mandibular development under diabetic and non-diabetic conditions, as well as determine whether diabetes modifies the mandibular adaptive response to increased masticatory loading. Materials and Methods: An experimental animal study was conducted using twenty-four male Wistar rats aged one month. The animals were randomly allocated into four groups according to metabolic status (control or diabetic) and dietary consistency (hard or soft diet). Type I diabetes mellitus was experimentally induced in the relevant groups using streptozotocin. All animals underwent cone beam computed tomography (CBCT) scanning at baseline (Day 1) and at the end of the experimental period (Day 28). Linear measurements were obtained using specialized software following euthanasia. Two-way ANOVA was used to evaluate the effects of diabetes, diet, and their interaction, using appropriate post hoc tests for multiple comparisons. Categorical variables were analyzed using the chi-square test. A p-value < 0.05 was considered statistically significant. Results: Longitudinal morphometric analysis demonstrated that Type I diabetes mellitus significantly impaired mandibular growth. Diabetic animals exhibited reduced growth rates and smaller final mandibular dimensions compared with controls. Hard diet intake significantly enhanced mandibular development in control animals, reflecting a strong adaptive response to increased functional loading. However, this osteogenic response was markedly attenuated in diabetic rats. Under soft-diet conditions, differences between control and diabetic groups were diminished, indicating that reduced mechanical stimulation limits adaptive growth responses. Significant interaction effects between diabetes and dietary consistency were observed in several morphometric parameters, particularly those related to mandibular body length, ramus height, and condylar position. Conclusions: Type I diabetes mellitus exerts a detrimental effect on mandibular growth in growing rats and compromises the adaptive response of craniofacial structures to mechanical loading. Although a hard diet functions as a potent osteogenic stimulus, its growth-promoting effect is substantially reduced in the presence of metabolic dysfunction. Full article

Wilson–Turner syndrome (WTS) is an X-linked developmental disorder associated with variants in the LAS1L gene, which plays a role in ribosome biogenesis. We report a 6-year-and-5-month-old boy presenting with growth retardation, early developmental delay, and mild scoliosis. Exome sequencing analysis identified a novel hemizygous LAS1L frameshift variant, c.2082dup (p.Leu697ProfsTer59), inherited from his asymptomatic mother that was absent from population databases. Functional analysis in HEK-293T cells suggested reduced protein expression with a partial loss of function effect, while structural modeling indicated potential alteration of the C-terminal region. The patient lacked classical WTS features, including craniofacial dysmorphism, truncal obesity, hypogonadism, and neuromuscular involvement. This case expands the phenotypic spectrum of LAS1L-related disorders and highlights the consideration of LAS1L variants in children with unexplained growth failure, scoliosis, or developmental delay, even in the absence of classical WTS features. Full article

Background: Pycnodysostosis is a rare autosomal recessive skeletal disorder caused by biallelic pathogenic variants in CTSK, which encodes cathepsin K, a lysosomal cysteine protease required for osteoclast-mediated degradation of bone matrix. Case Report: We describe a girl with short stature, skeletal deformities, osteosclerosis, craniofacial features, clavicular dysplasia, and radiological evidence of fractures. Clinical exome sequencing identified two heterozygous CTSK variants, c.85T > C (p.Trp29Arg) and c.679A>T (p.Ile227Phe), both currently classified as variants of uncertain significance. Segregation analysis showed that the variants were inherited in trans. Computational modeling and in silico prediction tools supported a possible deleterious effect on cathepsin K structure or function. Serum cathepsin K was higher in the patient than in two age-matched controls; this result is reported as an exploratory observation only. Increased serum cathepsin K may reflect altered expression, secretion, clearance, or accumulation of dysfunctional protein, but cannot be interpreted as proof of compensatory upregulation. Conclusions: The patient’s clinical and radiographic features, the biallelic trans configuration of the CTSK variants, their rarity in population databases, and computational predictions support p.Trp29Arg and p.Ile227Phe as strong candidate disease-associated variants. Functional studies are required to confirm their effect on cathepsin K expression, maturation, and enzymatic activity. Full article

Background/Objectives: Arthrochalasia Ehlers–Danlos syndrome (aEDS) is a rare connective tissue disorder characterized by severe joint hypermobility, congenital hip dislocation, skin hyperextensibility, and muscle hypotonia. It is typically caused by heterozygous splice-site variants in COL1A1 or COL1A2, leading to exon 6 skipping. Autosomal recessive forms are extremely rare and have been reported predominantly in families from Saudi Arabia carrying the homozygous COL1A1 missense variant c.2050G>A, p.(Glu684Lys), with clinical presentations ranging from severe to mild. Methods: Clinical and molecular genetic evaluation of the patient was performed. Whole-exome sequencing was carried out, followed by confirmatory Sanger sequencing in the proband and both parents. Results: A 10-month-old boy presented with severe congenital hypotonia, bilateral hip dislocation, generalized joint hypermobility, skin hyperextensibility and craniofacial dysmorphism. A homozygous likely pathogenic variant NM_000088.4:c.2050G>A, p.(Glu684Lys) was identified in exon 31 of COL1A1; both healthy parents were confirmed to be heterozygous carriers of this variant. To our knowledge this is the first reported case in the Russian population and one of the few cases described worldwide of an autosomal recessive arthrochalasia-like EDS phenotype. Conclusions: This case further refines the phenotypic characterization associated with the recurrent homozygous COL1A1 p.(Glu684Lys) variant, demonstrating an arthrochalasia-like EDS phenotype of intermediate severity between the severe neonatal form with respiratory distress and recurrent fractures and the classical EDS. It further highlights the importance of considering collagenopathies in the differential diagnosis of congenital hypotonia, particularly in cases initially suggestive of neuromuscular disorders. Full article

Arthrogryposis multiplex congenita (AMC) is a diverse group of conditions characterized by multiple joint contractures. Although individually rare, these disorders are estimated to affect 1 in 3000–5000 live births. Their common pathophysiological mechanism is fetal akinesia, a sustained reduction of fetal movement that may arise from intrinsic disturbances—such as central nervous system malformations, motor neuronopathies, neuropathies, neuromuscular junction defects, congenital myopathies, muscular dystrophies, or metabolic diseases—or from extrinsic factors including uterine constraint, maternal illness, infections, or toxic exposures. Reduced fetal motion leads to relatively uniform clinical manifestations, known as the fetal akinesia deformation sequence (FADS), which is characterized by craniofacial anomalies, pulmonary hypoplasia, growth restriction, and contractures. Currently, AMC is classified by clinical features, such as distal arthrogryposis or lethal congenital contracture syndromes. However, advances in molecular genetics have shown wide variability among conditions classified into the same category. Prognosis is widely variable, ranging from lethal perinatal forms to non-progressive mild conditions. This review discusses AMC etiologies from a topographic standpoint, considering the different levels of the motor system involved, by combining current clinical, genetic, and pathophysiological information. Full article

Background/Objectives: Orofacial myofunctional therapy (OMT) is a system of targeted neuromuscular exercises and behavioral retraining intended to optimize tongue, lip, jaw, and airway function during rest, breathing, swallowing, and sleep. Historically associated with tongue thrust and abnormal swallowing, OMT is now applied across an expanding range of clinical contexts, including sleep-disordered breathing (SDB), tongue-tie rehabilitation, orthodontic stability, and perioperative functional recovery. As its use has broadened, persistent questions have followed: what is myofunctional therapy, where did it originate, and how did a set of oral exercises evolve into an intervention increasingly integrated with airway health, sleep medicine, and surgical care? Methods: This article presents a narrative historical review with a perspective component, synthesizing foundational literature, interdisciplinary contributions, and selected contemporary evidence to examine the evolution of OMT from ancient functional practices to modern clinical science. It is written to trace recurring clinical observations, shifts in educational frameworks, and key inflection points that shaped how OMT has been taught and applied over time. Results: OMT did not emerge from randomized controlled trials or standardized protocols. It arose from repeated clinical encounters with patients with atypical craniofacial development, relapse of structural correction, persistent mouth breathing, and/or unresolved swallowing and speech dysfunction despite technically successful treatment. These patterns suggested that anatomy alone could not account for outcome variability. Over time, clinical attention expanded beyond isolated tongue function to include breathing patterns, posture, neuromuscular tone, and airway behavior. In the past two decades, controlled trials, cohort studies, and systematic reviews have supported selected applications of OMT, particularly in SDB and adjunctive airway care, while also revealing ongoing challenges related to training variability, terminology, scope of practice, and standardization. Conclusions: OMT has historically been described as a system of targeted neuromuscular and behavioral interventions aimed at modifying orofacial rest posture and function. Over time, the field has expanded beyond localized muscle retraining toward a broader functional framework that integrates airway physiology, craniofacial growth, sleep, and interdisciplinary rehabilitation. Full article

Noonan syndrome (NS) is a paradigmatic rare, genetically heterogeneous, multisystem disorder belonging to the RASopathies family, caused by dysregulated RAS/MAPK signaling. It is characterized by distinctive craniofacial features, postnatal short stature, and a high prevalence of congenital cardiac defects, with pulmonary valve stenosis (PS) and hypertrophic cardiomyopathy (HCM) being the hallmark lesions. First described by Dr. Jacqueline Noonan in 1968, the molecular era began with the discovery of PTPN11 mutations in 2001, revolutionizing diagnosis, risk stratification, and understanding of pathogenesis. Strong genotype–phenotype correlations now guide prognosis and personalized management; for instance, RAF1 and RIT1 variants confer a high risk of severe, early-onset HCM, while PTPN11 is strongly linked to dysplastic PS. Cardiac involvement remains the central determinant of long-term outcomes, requiring continuous surveillance from the prenatal period through adulthood. Management is inherently multidisciplinary, addressing endocrine, hematologic, neurodevelopmental, and oncologic aspects. Recent consensus statements emphasize the critical need for structured transition from pediatric to adult care. Novelty arises from the potential of MEK inhibitors as targeted therapies for severe HCM and lymphatic complications. This review provides a comprehensive update on NS, integrating foundational clinical knowledge with contemporary molecular insights, advanced cardiologic management, and emerging frontiers in therapy and diagnostics, underscoring the necessity of a proactive, lifelong, and personalized care approach. Full article

This study reports a previously unreported heterozygous MYCN missense variant, c.454G>A (p.Ala152Thr), identified in a child and two affected relatives, with clinical findings consistent with Feingold syndrome type 1, an autosomal dominant developmental disorder most commonly caused by loss-of-function variants in MYCN. The proband presented with a cleft palate, craniofacial dysmorphism, feeding difficulties, hypotonia, and characteristic digital anomalies. Similar features were observed in the father and sibling. Clinical exome sequencing revealed the novel MYCN variant, which was confirmed by Sanger sequencing and demonstrated co-segregation with the phenotype. Although most pathogenic MYCN variants leading to FS1 truncate the protein, this missense change lies within the N-terminal transactivation domain, a region involved in transcriptional regulation and protein stability. The physicochemical alteration introduced at residue Ala152 may plausibly affect MYCN function, consistent with haploinsufficiency as the established disease mechanism. According to the 2024 ACGS Best Practice Guidelines, the variant was classified as a variant of uncertain significance leaning toward pathogenicity. This report expands the mutational spectrum of MYCN, supports the potential clinical relevance of N-terminal missense variation in MYCN, and highlights intrafamilial phenotypic variability in FS1. Full article

Mulibrey nanism is a rare autosomal recessive multisystem disorder caused by biallelic loss of function variants in TRIM37 encoding a peroxisomal E3 ubiquitin ligase. Initially described in Finland, where it remains most prevalent due to a founder mutation, the condition is now recognized worldwide and is characterized by severe prenatal-onset growth failure, distinctive craniofacial features, radiological abnormalities, ocular findings, and hepatopathy. Although its clinical spectrum extends far beyond these core manifestations, the major determinant of morbidity and mortality is progressive cardiovascular disease, including constrictive pericarditis and restrictive cardiomyopathy. Additional features include metabolic dysfunction such as insulin resistance and type 2 diabetes, gonadal insufficiency, skeletal abnormalities including fibrous dysplasia, and an increased risk of benign and malignant tumours. The clinical course evolves across the lifespan from early growth and developmental abnormalities to progressive multisystem disease in adolescence and adulthood. Recent advances have expanded understanding of TRIM37 function, linking it to mTORC1 TFEB signalling autophagy, centrosome integrity, extracellular matrix regulation, and immune cell function, providing mechanistic insights into tumour predisposition, skeletal pathology, and immune dysregulation. Management remains supportive and requires multidisciplinary care with emphasis on early recognition and treatment of cardiac disease, metabolic complications, and malignancy risk. Prognosis is variable but improves with early diagnosis and appropriate surveillance. This review summarises the clinical spectrum molecular mechanisms and current management of Mulibrey nanism and highlights priorities for future research. Full article

Background/Objectives: Sleep-disordered breathing (SDB), including obstructive sleep apnea, is common in children and is associated with mouth breathing, snoring, and neurobehavioral disturbances. In pediatric orthodontic patients, oral habits and craniofacial imbalances may contribute to airway dysfunction, making orthodontic evaluation a potential setting for early identification of SDB. This study aimed to estimate the prevalence of SDB and to evaluate its associations with parent-reported behavioral symptom profiles in a cohort of pediatric orthodontic patients. Methods: A multicenter cross-sectional study was conducted in 186 children aged 7–13 years attending orthodontic clinics in Oradea and Târgu Mureș, Romania. Parents completed a structured questionnaire on oral habits, the 22-item Pediatric Sleep Questionnaire (PSQ), with SDB defined as 8 or more positive responses, and a parent-reported behavioral screening form assessing ADHD symptom subtypes, oppositional-defiant disorder (ODD), conduct disorder, and anxiety/depression. These behavioral outcomes were based on screening measures and were not intended as clinical psychiatric diagnoses. Associations were analyzed using chi-square or Fisher’s exact tests, and multivariable logistic regression analyses were performed adjusting for age, sex, and weight status. Results: Mouth breathing was reported in 61.8% of participants, snoring in 26.9%, and SDB in 13.4%. Positive screens for ADHD-inattentive (p < 0.001), ADHD-hyperactive/impulsive (p < 0.001), ADHD-combined (p < 0.001), ODD (p < 0.001), and anxiety/depression (p < 0.001) were significantly more frequent among children with SDB. In multivariable analysis, SDB remained independently associated with ADHD-combined subtype (OR = 6.22), ADHD-hyperactive/impulsive symptoms (OR = 5.84), oppositional-defiant disorder (OR = 4.91), and anxiety/depression (OR = 4.38). Conclusions: SDB was identified in a meaningful proportion of pediatric orthodontic patients and was significantly associated with multiple screening-defined behavioral symptom domains. These findings support consideration of brief airway- and sleep-oriented screening during orthodontic assessment, particularly in school-aged children presenting with mouth breathing, snoring, or behavioral concerns. Given the cross-sectional and questionnaire-based design, the findings should be interpreted as associative and warrant confirmation in prospective studies using objective sleep measures. Full article

Craniofacial and corneal neuropathic pain are disabling conditions characterized by persistent pain that is frequently refractory to conventional pharmacologic and interventional therapies. These disorders arise from complex interactions between peripheral nerve injury, neuroinflammation, and maladaptive central sensitization within trigeminal pathways, features that span neuropathic and nociplastic pain mechanisms as defined by the International Association for the Study of Pain, thus emphasizing the need for mechanism-based, patient-stratified treatment strategies. Regenerative medicine offers a paradigm shift from symptom suppression toward structural nerve repair and functional restoration. This narrative review examines the pathophysiological mechanisms underlying craniofacial and corneal neuropathic pain and critically evaluates emerging regenerative therapies, including autologous biologics (autologous serum tears and platelet-rich plasma), mesenchymal stem cells and their derivatives, exosomes and extracellular vesicles, and neurotrophic peptides. Particular emphasis is placed on corneal neuropathic pain as a translational model, given the cornea’s dense sensory innervation and the ability to non-invasively quantify nerve regeneration using in vivo confocal microscopy as an objective biomarker of treatment response. Clinical evidence across regenerative modalities varies by indication: cenegermin has demonstrated robust efficacy and regulatory approval for neurotrophic keratitis, while platelet-rich plasma shows growing evidence in temporomandibular disorders, myofascial pain, and occipital neuralgia. Cell-based and cell-free therapies demonstrate strong preclinical promise but remain limited by heterogeneous protocols and a paucity of large-scale randomized trials. Key barriers to translation include regulatory uncertainty, lack of standardized outcome measures, and workforce and implementation challenges. Advancing regenerative therapies for craniofacial and corneal neuropathic pain will require rigorous clinical trials, biomarker-driven patient selection, and multidisciplinary collaboration. Sex as a biological variable remains underexplored across all regenerative modalities and represents a priority for future research. Full article

Background/Objectives: Bainbridge–Ropers syndrome (BRPS) is a rare neurodevelopmental disorder caused by truncating and splicing pathogenic variants in the additional sex combs-like 3 (ASXL3) gene. It is primarily characterized by neurodevelopmental delay and craniofacial dysmorphism. Most reported cases involve de novo mutations in the ASXL3 gene, whereas inherited mutations have been rarely described. The present report aims to describe the clinical and molecular presentation of a familial case of BRPS and to highlight the potential role of parental mosaicism. Methods: We describe the clinical and molecular presentation of a 12-year-old boy and his 20-month-old half-brother, both affected by Bainbridge–Ropers syndrome. Trio-exome sequencing (ES) was performed in the family to identify variants in the ASXL3 gene, and targeted Sanger sequencing was also performed for segregation analysis. Results: Genetic analysis identified a previously unreported heterozygous frameshift variant in the ASXL3 gene (c.1648_1649del; p.Met550Aspfs*5) shared by both siblings. The variant was inherited from their clinically unaffected mother, who carries the mutation in the mosaic state with a variant allele fraction of approximately 15% in peripheral blood DNA. Conclusions: This observation highlights parental mosaicism as a potential mechanism underlying the familial recurrence of BRPS and emphasizes the importance of considering mosaic variants during the genetic evaluation and counseling of affected families. 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

Fetal MRI has been increasingly used in diagnosis and assessment of congenital anomalies and conditions by providing detailed structural information. However, such information is only part of the whole landscape of these genetic disorders. Given that genetic disorders are associated with significant morbidity and mortality in infants, multidisciplinary team management is essential for perinatal management and parental counseling. In the past two decades, there are advances in both fetal MRI and genetic testing for prenatal diagnosis of genetic disorders. This narrative review consolidates the current literature and aims to provide a systematic overview of fetal MRI applications in genetic disorders affecting the central nervous system, craniofacial structures, skeletal system, lungs, and urinary system. Understanding embryological and genetic basis as well as imaging phenotypes of genetic disorders are important in improving perinatal diagnosis and management. 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