RESUMO
The skull roof, or calvaria, is comprised of interlocking plates of bones that encase the brain. Separating these bones are fibrous sutures that permit growth. Currently, we do not understand the instructions for directional growth of the calvaria, a process which is error-prone and can lead to skeletal deficiencies or premature suture fusion (craniosynostosis, CS). Here, we identify graded expression of fibronectin (FN1) in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvaria. Conditional deletion of Fn1 or Wasl leads to diminished frontal bone expansion by altering cell shape and focal actin enrichment, respectively, suggesting defective migration of calvarial progenitors. Interestingly, Fn1 mutants have premature fusion of coronal sutures. Consistently, syndromic forms of CS in humans exhibit dysregulated FN1 expression, and we also find FN1 expression altered in a mouse CS model of Apert syndrome. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies.
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Fibronectinas , Nascimento Prematuro , Crânio , Animais , Feminino , Humanos , Camundongos , Sinais (Psicologia) , Modelos Animais de Doenças , Fibronectinas/metabolismo , Osteoblastos , Crânio/citologia , Crânio/crescimento & desenvolvimento , Crânio/metabolismo , SuturasRESUMO
Craniosynostosis (CS) is the most common congenital cranial anomaly. Several Mendelian forms of syndromic CS are well described, but a genetic etiology remains elusive in a substantial fraction of probands. Analysis of exome sequence data from 526 proband-parent trios with syndromic CS identified a marked excess (observed 98, expected 33, p = 4.83 × 10-20) of damaging de novo variants (DNVs) in genes highly intolerant to loss-of-function variation (probability of LoF intolerance > 0.9). 30 probands harbored damaging DNVs in 21 genes that were not previously implicated in CS but are involved in chromatin modification and remodeling (4.7-fold enrichment, p = 1.1 × 10-11). 17 genes had multiple damaging DNVs, and 13 genes (CDK13, NFIX, ADNP, KMT5B, SON, ARID1B, CASK, CHD7, MED13L, PSMD12, POLR2A, CHD3, and SETBP1) surpassed thresholds for genome-wide significance. A recurrent gain-of-function DNV in the retinoic acid receptor alpha (RARA; c.865G>A [p.Gly289Arg]) was identified in two probands with similar CS phenotypes. CS risk genes overlap with those identified for autism and other neurodevelopmental disorders, are highly expressed in cranial neural crest cells, and converge in networks that regulate chromatin modification, gene transcription, and osteoblast differentiation. Our results identify several CS loci and have major implications for genetic testing and counseling.
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Craniossinostoses , Tretinoína , Humanos , Mutação , Craniossinostoses/genética , Regulação da Expressão Gênica , Cromatina , Predisposição Genética para DoençaRESUMO
Skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. We now show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals, suggesting they are compensating for vessel loss in dorsal networks. Injecting a molecular tracer into cerebrospinal fluid reveals significantly less drainage to the deep cervical lymph nodes, which is indicative of impaired lymphatic function. Collectively, our results show that meningeal lymphatic networks are affected in craniosynostosis, suggesting that the clearance of ß-amyloid and waste from the central nervous system may be impeded.
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Craniossinostoses/patologia , Vasos Linfáticos/anormalidades , Meninges/irrigação sanguínea , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Craniossinostoses/líquido cefalorraquidiano , Craniossinostoses/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Repressoras/genética , Proteína 1 Relacionada a Twist/genéticaRESUMO
A major feature of Saethre-Chotzen syndrome is coronal craniosynostosis, the fusion of the frontal and parietal bones at the coronal suture. It is caused by heterozygous loss-of-function mutations in either of the bHLH transcription factors TWIST1 and TCF12. Although compound heterozygous Tcf12; Twist1 mice display severe coronal synostosis, the individual role of Tcf12 had remained unexplored. Here, we show that Tcf12 controls several key processes in calvarial development, including the rate of frontal and parietal bone growth, and the boundary between sutural and osteogenic cells. Genetic analysis supports an embryonic requirement for Tcf12 in suture formation, as combined deletion of Tcf12 in embryonic neural crest and mesoderm, but not in postnatal suture mesenchyme, disrupts the coronal suture. We also detected asymmetric distribution of mesenchymal cells on opposing sides of the wild-type frontal and parietal bones, which prefigures later bone overlap at the sutures. In Tcf12 mutants, reduced asymmetry is associated with bones meeting end-on-end, possibly contributing to synostosis. Our results support embryonic requirements of Tcf12 in proper formation of the overlapping coronal suture.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Craniossinostoses/metabolismo , Osteogênese , Crânio/embriologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Craniossinostoses/embriologia , Craniossinostoses/genética , Células-Tronco Mesenquimais/metabolismo , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Crista Neural/metabolismo , Crânio/metabolismoRESUMO
Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathways that crosstalk to coordinate the growth and patterning of the skull with surrounding tissues. Recent insights into these signaling pathways and previously uncharacterized progenitor cell populations have refined our understanding of skull patterning, bone mineralization and tissue homeostasis. Here, we touch upon classical studies and recent advances with an emphasis on developmental and signaling mechanisms that regulate the osteoblast lineage for the calvaria, which forms the roof of the skull. We highlight studies that illustrate the roles of osteoprogenitor cells and cranial suture-derived stem cells for proper calvarial growth and homeostasis. We also discuss genes and signaling pathways that control suture patency and highlight how perturbing the molecular regulation of these pathways leads to craniosynostosis. Finally, we discuss the recently discovered tissue and signaling interactions that integrate skull and cerebrovascular development, and the potential implications for both cerebrospinal fluid hydrodynamics and brain waste clearance in craniosynostosis.
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Craniossinostoses , Crânio , Humanos , Crânio/metabolismo , Suturas Cranianas/metabolismo , Craniossinostoses/genética , Craniossinostoses/metabolismo , Homeostase , Transdução de SinaisRESUMO
Latent transforming growth factor ß (TGFß)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFß in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGFß growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFß levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.
Assuntos
Colágeno/metabolismo , Cútis Laxa/etiologia , Variação Genética , Proteínas de Ligação a TGF-beta Latente/genética , Adolescente , Alelos , Animais , Células Cultivadas , Criança , Pré-Escolar , Cútis Laxa/patologia , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lactente , Masculino , Linhagem , Pele/metabolismo , Pele/patologia , Peixe-ZebraRESUMO
PURPOSE: To determine the sensitivity, specificity, and cutoff of macular ganglion cell layer (GCL) volume consistent with optic atrophy in children with syndromic craniosynostosis and to investigate factors independently associated with reduction in GCL volume. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Patients with syndromic craniosynostosis evaluated at Boston Children's Hospital (2010-2022) with reliable macular OCT scans. METHODS: The latest ophthalmic examination that included OCT macula scans was identified. Age at examination, sex, ethnicity, best-corrected logarithm of the minimum angle of resolution (logMAR) visual acuity, cycloplegic refraction, and funduscopic optic nerve appearance were recorded in addition to history of primary or recurrent elevation in intracranial pressure (ICP), Chiari malformation, and obstructive sleep apnea (OSA). Spectral-domain OCT software quantified segmentation of macula retinal layers and was checked manually. MAIN OUTCOME MEASURES: The primary outcome was determining sensitivity, specificity, and optimal cutoff of GCL volume consistent with optic atrophy. The secondary outcome was determining whether previously elevated ICP, OSA, Chiari malformation, craniosynostosis diagnosis, logMAR visual acuity, age, or sex were independently associated with lower GCL volume. RESULTS: Median age at examination was 11.9 years (interquartile range, 8.5-14.8 years). Fifty-eight of 61 patients (112 eyes) had reliable macula scans, 74% were female, and syndromes represented were Apert (n = 14), Crouzon (n = 17), Muenke (n = 6), Pfeiffer (n = 6), and Saethre-Chotzen (n = 15). Optimal cutoff identifying optic atrophy was a GCL volume < 1.02 mm3 with a sensitivity of 83% and specificity of 77%. Univariate analysis demonstrated that significantly lower macular GCL volume was associated with optic atrophy on fundus examination (P < 0.001), Apert syndrome (P < 0.001), history of elevated ICP (P = 0.015), Chiari malformation (P = 0.001), OSA (P < 0.001), male sex (P = 0.027), and worse logMAR visual acuity (P < 0.001). Multivariable median regression analysis confirmed that only OSA (P = 0.005), optic atrophy on fundus examination (P = 0.003), and worse logMAR visual acuity (P = 0.042) were independently associated with lower GCL volume. CONCLUSIONS: Surveillance for optic atrophy by GCL volume may be useful in a population where cognitive skills can limit acquisition of other key ophthalmic measures. It is noteworthy that OSA is also associated with lower GLC volume in this population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Craniossinostoses , Hipertensão Intracraniana , Atrofia Óptica , Apneia Obstrutiva do Sono , Criança , Humanos , Masculino , Feminino , Adolescente , Células Ganglionares da Retina , Estudos Transversais , Estudos Retrospectivos , Atrofia Óptica/diagnóstico , Tomografia de Coerência ÓpticaRESUMO
RASopathies represent a distinct class of neurodevelopmental syndromes caused by germline variants in the Ras/MAPK pathways. Recently, a novel disease-gene association was implicated in MAPK kinase kinase kinase 4 (MAP4K4), which regulates the upstream signals of the MAPK pathways. However, to our knowledge, only two studies have reported the genotype-phenotype relationships in the MAP4K4-related disorder. This study reports on a Korean boy harboring a novel de novo missense variant in MAP4K4 (NM_001242559:c.569G>T, p.Gly190Val), revealed by trio exome sequencing, and located in the hotspot of the protein kinase domain. The patient exhibited various clinical features, including craniofacial dysmorphism, language delay, congenital heart defects, genitourinary anomalies, and sagittal craniosynostosis. Our study expands the phenotypic association of the MAP4K4-related disorder to include syndromic craniosynostosis, thereby providing further insights into the role of the RAS/MAPK pathways in the development of premature fusion of calvarial sutures.
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Craniossinostoses , Estudos de Associação Genética , Mutação de Sentido Incorreto , Humanos , Masculino , Craniossinostoses/genética , Craniossinostoses/patologia , Sequenciamento do Exoma , Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Mutação de Sentido Incorreto/genética , Fenótipo , Proteínas Serina-Treonina Quinases/genética , SíndromeRESUMO
Crouzon syndrome is a congenital craniofacial disorder caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2). It is characterized by the premature fusion of cranial sutures, leading to a brachycephalic head shape, and midfacial hypoplasia. The aim of this study was to investigate the effect of the FGFR2 mutation on the microarchitecture of cranial bones at different stages of postnatal skull development, using the FGFR2C342Y mouse model. Apart from craniosynostosis, this model shows cranial bone abnormalities. High-resolution synchrotron microtomography images of the frontal and parietal bone were acquired for both FGFR2C342Y/+ (Crouzon, heterozygous mutant) and FGFR2+/+ (control, wild-type) mice at five ages (postnatal days 1, 3, 7, 14 and 21, n = 6 each). Morphometric measurements were determined for cortical bone porosity: osteocyte lacunae and canals. General linear model to assess the effect of age, anatomical location and genotype was carried out for each morphometric measurement. Histological analysis was performed to validate the findings. In both groups (Crouzon and wild-type), statistical difference in bone volume fraction, average canal volume, lacunar number density, lacunar volume density and canal volume density was found at most age points, with the frontal bone generally showing higher porosity and fewer lacunae. Frontal bone showed differences between the Crouzon and wild-type groups in terms of lacunar morphometry (average lacunar volume, lacunar number density and lacunar volume density) with larger, less dense lacunae around the postnatal age of P7-P14. Histological analysis of bone showed marked differences in frontal bone only. These findings provide a better understanding of the pathogenesis of Crouzon syndrome and will contribute to computational models that predict postoperative changes with the aim to improve surgical outcome.
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Metopic synostosis patients are at risk for neurodevelopmental disorders despite a negligible risk of intracranial hypertension. To gain insight into the underlying pathophysiology of metopic synostosis and associated neurodevelopmental disorders, we aimed to investigate brain volumes of non-syndromic metopic synostosis patients using preoperative MRI brain scans. MRI brain scans were processed with HyperDenseNet to calculate total intracranial volume (TIV), total brain volume (TBV), total grey matter volume (TGMV), total white matter volume (TWMV) and total cerebrospinal fluid volume (TCBFV). We compared global brain volumes of patients with controls corrected for age and sex using linear regression. Lobe-specific grey matter volumes were assessed in secondary analyses. We included 45 metopic synostosis patients and 14 controls (median age at MRI 0.56 years [IQR 0.36] and 1.1 years [IQR 0.47], respectively). We found no significant differences in TIV, TBV, TGMV or TCBFV in patients compared to controls. TWMV was significantly smaller in patients (-62,233 mm3 [95% CI = -96,968; -27,498], Holm-corrected p = 0.004), and raw data show an accelerated growth pattern of white matter in metopic synostosis patients. Grey matter volume analyses per lobe indicated increased cingulate (1378 mm3 [95% CI = 402; 2355]) and temporal grey matter (4747 [95% CI = 178; 9317]) volumes in patients compared to controls. To conclude, we found smaller TWMV with an accelerated white matter growth pattern in metopic synostosis patients, similar to white matter growth patterns seen in autism. TIV, TBV, TGMV and TCBFV were comparable in patients and controls. Secondary analyses suggest larger cingulate and temporal lobe volumes. These findings suggest a generalized intrinsic brain anomaly in the pathophysiology of neurodevelopmental disorders associated with metopic synostosis.
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The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23-Glu-Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).
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BACKGROUND: Craniosynostosis, a congenital condition characterized by the premature fusion of cranial sutures, necessitates objective methods for evaluating cranial morphology to enhance patient treatment. Current subjective assessments often lead to inconsistent outcomes. This study introduces a novel, quantitative approach to classify craniosynostosis and measure its severity. METHODS: An artificial neural network was trained to classify normocephalic, trigonocephalic, and scaphocephalic head shapes based on a publicly available dataset of synthetic 3D head models. Each 3D model was converted into a low-dimensional shape representation based on the distribution of normal vectors, which served as the input for the neural network, ensuring complete patient anonymity and invariance to geometric size and orientation. Explainable AI methods were utilized to highlight significant features when making predictions. Additionally, the Feature Prominence (FP) score was introduced, a novel metric that captures the prominence of distinct shape characteristics associated with a given class. Its relationship with clinical severity scores was examined using the Spearman Rank Correlation Coefficient. RESULTS: The final model achieved excellent test accuracy in classifying the different cranial shapes from their low-dimensional representation. Attention maps indicated that the network's attention was predominantly directed toward the parietal and temporal regions, as well as toward the region signifying vertex depression in scaphocephaly. In trigonocephaly, features around the temples were most pronounced. The FP score showed a strong positive monotonic relationship with clinical severity scores in both scaphocephalic (ρ = 0.83, p < 0.001) and trigonocephalic (ρ = 0.64, p < 0.001) models. Visual assessments further confirmed that as FP values rose, phenotypic severity became increasingly evident. CONCLUSION: This study presents an innovative and accessible AI-based method for quantifying cranial shape that mitigates the need for adjustments due to age-specific size variations or differences in the spatial orientation of the 3D images, while ensuring complete patient privacy. The proposed FP score strongly correlates with clinical severity scores and has the potential to aid in clinical decision-making and facilitate multi-center collaborations. Future work will focus on validating the model with larger patient datasets and exploring the potential of the FP score for broader applications. The publicly available source code facilitates easy implementation, aiming to advance craniofacial care and research.
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X-ray Computed Tomography (CT) images are widely used in various fields of natural, physical, and biological sciences. 3D reconstruction of the images involves segmentation of the structures of interest. Manual segmentation has been widely used in the field of biological sciences for complex structures composed of several sub-parts and can be a time-consuming process. Many tools have been developed to automate the segmentation process, all with various limitations and advantages, however, multipart segmentation remains a largely manual process. The aim of this study was to develop an open-access and user-friendly tool for the automatic segmentation of calcified tissues, specifically focusing on craniofacial bones. Here we describe BounTI, a novel segmentation algorithm which preserves boundaries between separate segments through iterative thresholding. This study outlines the working principles behind this algorithm, investigates the effect of several input parameters on its outcome, and then tests its versatility on CT images of the craniofacial system from different species (e.g. a snake, a lizard, an amphibian, a mouse and a human skull) with various scan qualities. The case studies demonstrate that this algorithm can be effectively used to segment the craniofacial system of a range of species automatically. High-resolution microCT images resulted in more accurate boundary-preserved segmentation, nonetheless significantly lower-quality clinical images could still be segmented using the proposed algorithm. Methods for manual intervention are included in this tool when the scan quality is insufficient to achieve the desired segmentation results. While the focus here was on the craniofacial system, BounTI can be used to automatically segment any hard tissue. The tool presented here is available as an Avizo/Amira add-on, a stand-alone Windows executable, and a Python library. We believe this accessible and user-friendly segmentation tool can benefit the wider anatomical community.
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Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal-onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.
Assuntos
Craniossinostoses , Cardiopatias Congênitas , Síndrome de Noonan , Recém-Nascido , Feminino , Humanos , Gravidez , Proteínas Proto-Oncogênicas p21(ras)/genética , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Ultrassonografia Pré-NatalRESUMO
Kabuki syndrome (KS) is characterized by growth impairment, psychomotor delay, congenital heart disease, and distinctive facial features. KMT2D and KDM6A have been identified as the causative genes of KS. Craniosynostosis (CS) has been reported in individuals with KS; however, its prevalence and clinical implications remain unclear. In this retrospective study, we investigated the occurrence of CS in individuals with genetically diagnosed KS and examined its clinical significance. Among 42 individuals with genetically diagnosed KS, 21 (50%) exhibited CS, with 10 individuals requiring cranioplasty. No significant differences were observed based on sex, causative gene, and molecular consequence among individuals with KS who exhibited CS. Both individuals who underwent evaluation with three-dimensional computed tomography (3DCT) and those who required surgery tended to exhibit cranial dysmorphology. Notably, in several individuals, CS was diagnosed before KS, suggesting that CS could be one of the clinical features by which clinicians can diagnose KS. This study highlights that CS is one of the noteworthy complications in KS, emphasizing the importance of monitoring cranial deformities in the health management of individuals with KS. The findings suggest that in individuals where CS is a concern, conducting 3DCT evaluations for CS and digital impressions are crucial.
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Anormalidades Múltiplas , Craniossinostoses , Face/anormalidades , Doenças Hematológicas , Doenças Vestibulares , Humanos , Estudos Retrospectivos , Prevalência , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Doenças Hematológicas/complicações , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/epidemiologia , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/epidemiologia , Doenças Vestibulares/genética , Craniossinostoses/complicações , Craniossinostoses/diagnóstico , Craniossinostoses/epidemiologia , Histona Desmetilases/genética , MutaçãoRESUMO
Noonan syndrome is a so-called "RASopathy," that is characterized by short stature, distinctive facial features, congenital heart defects, and developmental delay. Of individuals with a clinical diagnosis of Noonan syndrome, 80%-90% have pathogenic variants in the known genes implicated in the disorder, but the molecular mechanism is unknown in the remaining cases. Heterozygous pathogenic variants of ETS2 repressor factor (ERF), which functions as a repressor in the RAS/MAPK signaling pathway, cause syndromic craniosynostosis. Here, we report an ERF frameshift variant cosegregating with a Noonan syndrome-like phenotype in a family. The proband was a 3-year-old female who presented with dysmorphic facial features, including proptosis, hypertelorism, slightly down slanted palpebral fissures, low-set posteriorly rotated ears, depressed nasal bridge, short stature, and developmental delay. Exome sequencing of the proband identified a heterozygous ERF variant [NM_006494.4: c.185del p.(Glu62Glyfs*15)]. Her mother and sister showed a similar phenotype and had the same heterozygous ERF variant. A large proportion of the previously reported patients with syndromic craniosynostosis and pathogenic ERF variants also showed characteristic features that overlap with those of Noonan syndrome. The present finding supports an association between heterozygous ERF variants and a Noonan syndrome-like phenotype.
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Mutação da Fase de Leitura , Síndrome de Noonan , Proteínas Repressoras , Pré-Escolar , Feminino , Humanos , Craniossinostoses/genética , Craniossinostoses/patologia , Craniossinostoses/diagnóstico , Sequenciamento do Exoma , Heterozigoto , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Síndrome de Noonan/diagnóstico , Linhagem , Fenótipo , Proteínas Repressoras/genética , CriançaRESUMO
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 46th Annual Meeting at Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio on October 10th-12th, 2023. On the first day of the meeting, Drs. Sally Moody and Justin Cotney were each honored with the SCGDB Distinguished Scientist Awards for their exceptional contributions to the field of craniofacial biology. The following two days of the meeting featured five sessions that highlighted new discoveries in signaling and genomic mechanisms regulating craniofacial development, human genetics, translational and regenerative approaches, and clinical management of craniofacial differences. Interactive workshops on spatial transcriptomics and scientific communication, as well as a poster session facilitated meaningful interactions among the 122 attendees representing diverse career stages and research backgrounds in developmental biology and genetics, strengthened the SCGDB community.
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Anormalidades Craniofaciais , Biologia do Desenvolvimento , Humanos , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologiaRESUMO
Recent trio-based whole-exome sequencing studies of congenital hydrocephalus and nonsyndromic craniosynostosis have identified multiple novel disease genes that have illuminated the pathogenesis of these disorders and shed new insight into the genetic regulation of human brain and skull development. Continued study of these and other historically understudied developmental anomalies has the potential to replace the current antiquated, anatomically based disease classification systems with a molecular nomenclature that may increase precision for genetic counseling, prognostication, and surgical treatment stratification-including when not to operate. Data will also inform future clinical trials, catalyze the development of targeted therapies, and generate infrastructure and publicly available data sets relevant for other related nonsurgical neurodevelopmental and neuropsychiatric diseases.
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Craniossinostoses , Crânio , Humanos , Craniossinostoses/genética , Craniossinostoses/cirurgia , Previsões , Biologia MolecularRESUMO
BACKGROUND: Obstructive sleep apnea (OSA) is common in children with syndromic craniosynostosis (SC). However, objective data on the treatment of OSA in children with SC remain inadequate. This study aimed to explore the efficacy of continuous positive airway pressure (CPAP) in the management of OSA in children with SC. METHODS: A retrospective study was performed in children with SC and OSA diagnosed by polysomnography (PSG), which was defined as an apnea hypopnea index (AHI) ≥ 1. Patients were included if they were treated with CPAP and had baseline PSG and follow-up sleep studies. Clinical and demographic data were collected from all enrolled subjects. RESULTS: A total of 45 children with SC and OSA were identified, with an average age of 6.8 ± 4.7 years. Among them, 36 cases had moderate to severe OSA (22 with severe OSA) and received CPAP therapy followed by post-treatment sleep studies. Notably, there was a significant reduction in the AHI observed after CPAP treatment (3.0 [IQR: 1.7, 4.6] versus 38.6 [IQR: 18.2, 53.3] events/h; P < 0.001). CONCLUSIONS: CPAP is effective and acceptable in treating severe OSA in children with SC.
Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Craniossinostoses , Polissonografia , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/terapia , Masculino , Feminino , Craniossinostoses/terapia , Craniossinostoses/complicações , Estudos Retrospectivos , Criança , Pré-Escolar , Resultado do TratamentoRESUMO
Craniosynostosis constitutes one of the most common congenital cranial malformations, affecting approximately 6/10,0000 live births. A genetic etiology has long been known for several forms of syndromic craniosynostosis, including pathogenic variants in TWIST1 and FGFR3 in children with Saethre-Chotzen and Muenke syndrome. Over the last decade, reports of genetic aberrations in TCF12 in children with craniosynostosis have emerged, in particular in cases with premature closure of the coronal suture(s). In this study, we, therefore, systematically reviewed the rapidly growing knowledge of TCF12-related coronal craniosynostosis, clearly illustrating its high degree of genotype and phenotype variability. With the two novel cases presented, at least 113 cases of TCF12-related coronal craniosynostosis have currently been reported. By pooling data from several prospectively collected undifferentiated craniosynostosis cohorts (ntotal = 770), we estimate a prevalence of pathogenic TCF12 variants of at least 2%. Overall, pathogenic germline variants in TCF12 are relatively frequent in children with coronal craniosynostosis, accounting for â¼10-20% of TWIST1- and FGFR1/2/3-negative cases, with even higher rates for bicoronal and syndromic cases. Genetic counseling is recommended for all children with craniosynostosis, and involvement of the coronal suture(s) should precipitate TCF12 testing.