RARE DISEASE
Crouzon syndrome
Crouzon syndrome
Crouzon syndrome
Synonyms: Crouzon craniofacial dysostosis
Synonyms: Crouzon craniofacial dysostosis
Synonyms: Crouzon craniofacial dysostosis
Drug discovery
788
papers
On emerging therapies
Overview
Crouzon syndrome is an autosomal dominant craniosynostosis syndrome caused by FGFR2/FGFR3 mutations, characterized by premature cranial suture fusion, midface hypoplasia, ocular proptosis, and craniofacial dysmorphism. Affected individuals face risks of increased intracranial pressure (30% incidence), obstructive sleep apnea, and vision/hearing impairments. Diagnosis combines clinical evaluation with genetic testing (80% FGFR2 IgIII domain mutations). Unlike Apert syndrome, it lacks limb anomalies [1][2][10].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders
Research Papers
788 drug discovery papers about Crouzon syndrome. Recent publications:
788 drug discovery papers about Crouzon syndrome. Recent publications:
categories:
Small molecules
small molecules
2025-07-31 | Mechanistic Role of PIEZO1 in Crouzon Syndrome: Osteogenic Regulation By FGFR2-Mutated Periosteal Progenitors at the Ossification Interface.
Crouzon syndrome represents an autosomal dominant genetic disorder primarily characterized by craniofacial malformations. Recent advancements have enabled the successful derivation of periosteal stem cells from the periosteum, a critical reservoir of osteogenic progenitor cells. This investigation employs periosteal stem cells transfected with the C361Y-FGFR2 point mutation in conjunction with an in vitro mechanical tensile stress model to elucidate the aberrant osteogenic differentiation patterns under mechanical stimulation. The study identifies PIEZO1, a mechanosensitive ion channel protein, as a pivotal mediator in transducing extracellular mechanical signals. Through integrated analysis of PIEZO1-modulated HIPPO/YAP and BMP2/SMAD2 signaling cascades, the authors systematically evaluate the expression patterns of key regulatory nodes within these pathways. These findings establish a molecular framework for understanding defective osteogenic differentiation mechanisms in periosteal stem cells derived from Crouzon syndrome models, offering novel insights into potential therapeutic targets.
2025-04-14 | Current Understanding of Crouzon Syndrome Pathophysiology and New Therapeutic Approaches.
Crouzon syndrome (CS) is a rare genetic disorder characterized by the premature fusion of cranial sutures, leading to craniofacial abnormalities and potential neurological complications. CS is caused primarily by gain-of-function mutations in the FGFR2 gene and, less commonly, by mutations in the FGFR3 gene (specifically associated with CS with acanthosis nigricans). Managing CS requires a multidisciplinary approach, combining early and later surgical interventions to prevent intracranial hypertension and correct craniofacial deformities, along with ongoing care to address associated complications. Recent advancements in CS classification on the basis of cranial suture involvement have refined phenotype-genotype correlations, improving personalized therapeutic strategies. This review aims to provide a comprehensive and updated overview of CS, including detailed insights into molecular genetics and biological mechanisms underlying its pathophysiology, and a depiction of the clinical features, diagnosis, and surgical aspects of CS. In addition, we delve into innovative theranostic views, where molecular genetic testing allows the design of personalized noninvasive therapeutic approaches based on innovative biotechnologies, including RNA-interference molecules, pharmacological modulation of FGFR signaling pathways, and recombinant proteins. These advancements underscore the importance of integrating molecular studies into diagnostic and therapeutic protocols to increase the precision and effectiveness of nonsurgical treatments for CS.
2025-02-24 | Structural and functional stenosis of the upper airway in Crouzon syndrome patients: A computational fluid dynamics analysis.
This study aimed to simulate the aerodynamics and to identify the spatial correlation between anatomical and functional stenoses in Crouzon syndrome patients. Six patients of Crouzon syndrome were included. Computational fluid dynamics (CFD) was utilized to simulate airflow dynamics, and characteristics, including the velocity, pressure intensity, wall shear stress, airflow resistance and streamline, were extracted for quantitative analysis both in overall and regionally. Structural stenosis was defined at the minimum cross-sectional area, while functional stenosis was identified at the point of maximum airflow velocity. The spatial distances between the Frankfurt plane and structural/functional stenosis were calculated and compared. Structural stenosis occurred in the palatopharynx, while the highest inspiratory resistance and peak airflow velocity during expiration identified the glossopharynx as the functional stenosis site. A steep increase in negative pressure and a significant increase in wall shear stress could be observed surrounding the functional stenosis. The intensity and diffusion range of wall shear stress are positively correlated with age. Notably, the functional stenosis was consistently 5 mm below the structural stenosis (P < 0.05). CFD effectively visualized both overall and regional aerodynamics of Crouzon syndrome, providing a novel method for functional airway evaluation. The spatial distributions of structural and functional stenoses did not strictly correspond; the structural stenosis was located on the palatopharynx, while the functional stenosis was on the glossopharynx. The wall shear stress worsens pathologically with age, aggravating functional stenosis to structural stenosis. Therefore, functional stenosis should also be addressed in airway management to ensure therapeutic effectiveness.
2025-01-22 | FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia.
Gain-of-function mutations in fibroblast growth factor receptor (FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3-activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome (Crz) and hypochondroplasia (Hch). Bone mineralization of the calluses was abnormally high in Crz mice and abnormally low in Hch mice. The latter model presented pseudarthrosis and impaired chondrocyte differentiation. Spatial transcriptomic analyses of the Hch callus revealed abnormally low expression of Col11, Col1a, Dmp1 genes in mature chondrocytes. We found that the expression of genes involved in autophagy and apoptosis (Smad1, Comp, Birc2) was significantly perturbed and that the Dusp3, Dusp9, and Socs3 genes controlling the mitogen-activated protein kinase pathway were overexpressed. Lastly, we found that treatment with a tyrosine kinase inhibitor (BGJ398, infigratinib) or a C-type natriuretic peptide (BMN111, vosoritide) fully rescued the defective endochondral bone repair observed in Hch mice. Taken as a whole, our findings show that FGFR3 is a critical orchestrator of bone repair and provide a rationale for the development of potential treatments for patients with FGFR3-osteochondrodysplasia.
2023-04-27 | Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration
ETS2 repressor factor (ERF) insufficiency causes craniosynostosis (CRS4) in humans and mice. ERF is an ETS domain transcriptional repressor regulated by Erk1/2 phosphorylation via nucleo-cytoplasmic shuttling. Here, we analyze the onset and development of the craniosynostosis phenotype in an Erf-insufficient mouse model and evaluate the potential of the residual Erf activity augmented by pharmacological compounds to ameliorate the disease. Erf insufficiency appears to cause an initially compromised frontal bone formation and subsequent multisuture synostosis, reflecting distinct roles of Erf on the cells that give rise to skull and facial bones. We treated animals with Mek1/2 and nuclear export inhibitors, U0126 and KPT-330, respectively, to increase Erf activity by two independent pathways. We implemented both a low dosage locally over the calvaria and a systemic drug administration scheme to evaluate the possible indirect effects from other systems and minimize toxicity. The treatment of mice with either the inhibitors or the administration scheme alleviated the synostosis phenotype with minimal adverse effects. Our data suggest that the ERF level is an important regulator of cranial bone development and that pharmacological modulation of its activity may represent a valid intervention approach both in CRS4 and in other syndromic forms of craniosynostosis mediated by the FGFR-RAS-ERK-ERF pathway.
cell therapies
2026-07-24 | Auricular Cartilage Grafting for Lower-Eyelid Entropion in Syndromic Craniosynostosis: A Case Series
Patients with syndromic craniosynostosis, including Crouzon and Pfeiffer syndromes, may develop lower-eyelid malposition, including retraction and secondary entropion, associated with complex midfacial and orbital anatomical abnormalities. Progressive midface hypoplasia, shallow orbits, and postoperative anatomical changes following craniofacial surgery may contribute to imbalance between the anterior and posterior lamellae, relative posterior lamellar insufficiency, and persistent eyelash-corneal contact. We report a retrospective case series of 3 patients who underwent posterior lamellar lengthening using autologous auricular cartilage grafts via a transconjunctival approach. The harvested cartilage was secured to the tarsal plate to increase posterior lamellar height and correct lower-eyelid entropion. All patients experienced improvement in cilia-corneal touch and symptomatic relief, with satisfactory functional and aesthetic outcomes. No recurrence or major complications were observed during follow-up. Auricular cartilage grafting may represent a useful surgical option for selected patients with lower-eyelid entropion associated with syndromic craniosynostosis, particularly in patients with severe midface hypoplasia or previous midface advancement procedures.
2026-04-15 | Mechanical bone loading effects on morphology and mechanobiology in the coronal suture of Crouzon mice.
Craniosynostosis is a congenital condition characterized by the premature fusion of the craniofacial sutures. The Crouzon mouse (Fgfr2cC342Y/+) is a well-established model of this condition which shows premature fusion of the coronal suture. Our group has recently shown that postnatal, cyclic loading can potentially rescue the coronal suture and normalize skull morphology in Crouzon mice. This study aimed to investigate the underlying biological mechanism of the treatment. Wild-type (WT) and Crouzon (MUT) mice underwent in vivo loading sessions. Loading did not significantly affect skull shape. The patency across the coronal suture did not change between treated and untreated MUT animals. Orientation and coherence of the coronal suture collagen fibres were statistically different when comparing WT untreated with MUT untreated and WT treated with MUT treated. Treatment increases the number of proliferative cells in both the WT and MUT sutures compared to their untreated counterparts. The mechanobiological mechanisms driving the differences need further investigation into molecular mechanotransduction pathways. Understanding the biological principles affected during bone loading, a more refined cyclical bone loading protocol can be developed and refined for potential clinical use.
2024-08-02 | Optic nerve elongation during fronto-facial surgery for Crouzon syndrome: 3D quantification and clinical implications.
Fronto-facial monobloc advancement with internal distraction (FFMBA) is a key procedure in the management of syndromic craniosynostoses. FFMBA involves circumferential dissection and linear enlargement of the orbit, potentially leading to mechanical stress on the optic nerve (ON). Several reports of transient vision loss during the distraction process led us to investigate ON shape modifications during facial advancement, with the aim to potentially refine current clinical guidelines on postoperative management and the distraction schedule. Twenty-six patients with Crouzon syndrome were included in this study. ONs were segmented on pre- and postoperative CT scans. Distraction amplitudes, linear and curved lengths, and cross-section diameters of the ON were assessed along the main axis of the nerve. A two-level hierarchical multivariate linear model was used to screen for factors associated with ON morphology. The mean age at FFMBA was 4.4 ± 3.8 years. Two patients presented with transient impaired vision during distraction. The final mean fronto-orbital and temporo-zygomatic distraction amplitudes were 18 ± 4 mm and 18 ± 6 mm, respectively. At the end of distraction, ONs were elongated (+1.8 mm for curved lengths, p = 0.013), and their mean cross-section was reduced (-1.9 mm2, p < 0.001) in the proximal intraorbital portion (first 15 mm). In the 2 patients with visual symptoms, functional impairment was associated with ON area reduction (OR 0.487, p < 0.001) and increased temporo-zygomatic distraction amplitude (OR 2.240, p < 0.001). ON was elongated during FFMBA, with proximal diameter reduction. Transient visual impairment with normal fundus examination during distraction seemed to have a morphological basis, based on 2 cases. These results suggest the importance of vision monitoring associated with fundus examination during distraction, and advocate for early extubation after FFMBA to allow clinical follow-up.
2024-07-24 | Apert syndrome: neurosurgical outcomes and complications following posterior vault distraction osteogenesis.
Posterior vault distraction osteogenesis (PVDO) has been utilized during the past 15 years to treat a variety of clinical features commonly presented by patients with Apert syndrome. The objective of this study is to determine the efficacy of PVDO in addressing both elevated intracranial pressure (ICP) and ectopia of the cerebellar tonsils (ECT) in young Apert patients. In addition, we aimed to determine the prevalence of hydrocephalus in Apert syndrome patients who underwent PVDO. A retrospective study was made with a cohort of 40 consecutive patients with syndromic craniosynostosis (SC), previously diagnosed with Apert syndrome, who underwent PVDO between 2012 and 2022, and thereafter received at least 1 year of follow-up care. Demographic data and diagnosis, along with surgical and outcome data, were verified using medical records, clinical photographs, radiologic examination, and interviews with the parents of all cohort patients. The average patient age when PVDO was performed was 12.91 ± 10 months. The average posterior advancement distance achieved per patient was 22.68 ± 5.26 mm. The average hospital stay per patient was 3.56 ± 2.44 days. The average absolute and relative blood transfusion volumes were 98.47 ml and 17.63 ml/kg, respectively. Although five patients (14%) presented ECT preoperatively, this condition was completely resolved by PVDO in three of these five patients. One of the three patients whose ECT had completely resolved presented syringomyelia postoperatively, requiring subsequent extra dural foramen magnum decompression. All of the remaining four patients were asymptomatic for ECT for at least 1 year of follow-up, and none of these four patients required any additional treatments to address ECT. Two patients presented hydrocephalus requiring ventriculoperitoneal shunt placement. This study demonstrates that PVDO both reduces diagnosed elevated ICP symptoms and is partially effective in treating ECT in Apert syndrome patients. Hydrocephalus in Apert syndrome is an uncommon feature. The effectiveness of PVDO in addressing hydrocephalus is uncertain.
2024-06-21 | Early posterior vault distraction osteogenesis changes the syndromic craniosynostosis treatment paradigm: long-term outcomes of a 23-year cohort study
Abstract Background Early surgical management of syndromic craniosynostosis varies widely between centers, with patients typically undergoing multiple intracranial procedures through childhood. This study evaluates the long-term impact of early posterior vault distraction osteogenesis (PVDO) versus conventional treatment paradigms on the number and timing of subsequent craniofacial procedures. Methods We retrospectively analyzed the longitudinal operative patterns of patients with syndromic craniosynostosis treated from 2000 to 2023 with greater than five years of follow-up. Outcomes of patients who underwent early PVDO and conventional vault reconstruction were compared. Results Fifty-five patients met the inclusion criteria (30 PVDO and 25 conventional). Age at initial vault surgery was similar between the PVDO and conventional cohorts (7.6 vs. 8.8 months), as were baseline craniometrics ( p > 0.05). Multiple fronto-orbital advancement (FOA) procedures were performed in only 1/30 (3%) PVDO-treated patient versus 12/25 (48%) conventionally-treated patients ( p < 0.001). Twelve (40%) PVDO-treated patients did not undergo FOA at all. Among patients with Apert and Crouzon syndromes, fewer PVDO-treated patients required FOA prior to midface surgery (33% vs. 92%, p = 0.004) or repeat FOA (6% vs. 50%, p = 0.005) compared to conventionally-treated patients. Among patients with Muenke and Saethre–Chotzen syndromes, a similar proportion of patients required FOA in the PVDO and conventional cohorts (91% vs. 100%, p = 0.353), though no PVDO-treated patients required repeat FOA (0% vs. 44%, p = 0.018). Conclusions Early PVDO is associated with a reduction in the high burden of both FOA and, critically, revisionary frontal procedures which are commonly seen in conventionally-treated patients with syndromic craniosynostosis.
proteins
2024-06-27 | Unexpected massive bleeding during the modified LeFort III advancement surgery for Crouzon syndrome: A case report.
Vigilant monitoring for postoperative complications, including bleeding and dysrhythmia, is crucial in patients with craniosynostosis syndromes like Crouzon syndrome undergoing craniofacial surgery, with a thorough evaluation, including coagulation tests, assisting in diagnosing underlying conditions such as von Willebrand disease subtype 1 to inform appropriate management strategies. Crouzon syndrome is a rare genetic disorder affecting craniofacial structures. Its etiology is the premature fusion of cranial sutures. The LeFort III advancement surgery is a commonly used approach to correct malformations related to midface hypoplasia. Complications following surgical treatment of craniosynostosis and craniofacial syndromes can include both intracranial and extracranial problems. Reporting of this syndrome and the surgery complications, in addition to consideration of other differential diagnoses, can help improve the treatment plan and surgery outcomes. The aim of the article is to report a 14-year-old female with Crouzon syndrome who underwent the modified LeFort III osteotomy and developed unexpected massive bleeding during the surgery. Post-surgery, she experienced complications including dysrhythmia, hypothermia, and cyanosis. Treatment included fluid therapy, blood transfusions, and antibiotic therapy for suspected septic shock. Differential diagnosis was disseminated intravascular coagulation but was ruled out. Post-discharge, coagulation tests suggested von Willebrand disease subtype 1 as the diagnosis. Excessive bleeding during surgery for craniosynostosis syndromes is a significant and concerning issue in the surgical management of Crouzon syndrome. For patients with von Willebrand disease who are candidates for elective surgeries, von Willebrand factor concentrates or recombinant von Willebrand factor can be used.
2024-03-20 | Noggin promotes osteogenesis in human adipose-derived mesenchymal stem cells via FGFR2/Src/Akt and ERK signaling pathway
Abstract The balance between Noggin and bone morphogenetic proteins (BMPs) is important during early development and skeletal regenerative therapies. Noggin binds BMPs in the extracellular space, thereby preventing BMP signaling. However, Noggin may affect cell response not necessarily through the modulation of BMP signaling, raising the possibility of direct Noggin signaling through yet unspecified receptors. Here we show that in osteogenic cultures of adipose-derived stem cells (ASCs), Noggin activates fibroblast growth factor receptors (FGFRs), Src/Akt and ERK kinases, and it stabilizes TAZ proteins in the presence of dexamethasone. Overall, this leads ASCs to increased expression of osteogenic markers and robust mineral deposition. Our results also indicate that Noggin can induce osteogenic genes expression in normal human bone marrow stem cells and alkaline phosphatase activity in normal human dental pulp stem cells. Besides, Noggin can specifically activate FGFR2 in osteosarcoma cells. We believe our findings open new research avenues to further explore the involvement of Noggin in cell fate modulation by FGFR2/Src/Akt/ERK signaling and potential applications of Noggin in bone regenerative therapies.
2022-09-01 | The Effect of Yes-Associated Protein on the Interaction Between the MEK/Extracellular Signal-Regulated Kinase and Hippo Pathways in Osteoblasts Co-Cultured With Fibroblast Growth Factor Receptor 2-Mutated Dura Cells.
C342Y (Cys342Tyr) point mutation of FGFR2 (fibroblast growth factor receptor 2) is closely associated with the pathogenesis of Crouzon syndrome. The dura mater plays an important role in mediating the closure of cranial sutures. However, the underlying mechanisms of these pathological processes have been rarely investigated. in this study, the authors analyzed the effects of dura cells with FGFR2 mutations on the biological function of osteoblasts. Dura cells and cranial osteoblasts from C57BL/6 mice were extracted and cultured. C342Y-FGFR2 mutant constructs were established via lentivirus and applied to infect dura cells. A co-cultured trans-well system with dura cells and osteoblasts was established. Three experimental groups were set up: oste group, Oste + Dura-vector group, and Oste + Dura-C342Y group. The expression levels of key factors in MEK (Mitogen-activated protein kinase kinase, MAPKK)/extracellular signal-regulated kinase (ERK) and Hippo pathway were detected by western blot and RT-qPCR (Real Time Quantitative PCR). Finally, a rescue experiment was carried out with small interference RUA. The proliferation level of osteoblasts in Oste + Dura- C342Y group was significantly up-regulated. Our studies indicated that the activation of MEK/ERK pathway in Oste + Dura-C342Y group could inhibit the Hippo pathway, lead to down-regulation of large tumor suppressor 1 and promote the activation and nuclear localization of yes-associated protein, and the results of rescue experiments showed a reverse expression trend, further confirming the effects of C342Y-FGFR2 mutation in dura cells on osteoblasts and its potential mechanism. This study suggested that the C342Y-FGFR2 mutation in dura cells could promote osteoblastic proliferation, and shown the crosstalk between MEK/ERK and Hippo pathways. As the regulatory machinery center, yes-associated protein might play a bridging role in these pathways, and might influence the pathogenesis of craniosynostosis by activating downstream transcriptional factors.
2020-08-17 | Viral delivery of tissue nonspecific alkaline phosphatase diminishes craniosynostosis in one of two FGFR2C342Y/+ mouse models of Crouzon syndrome.
Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro CT. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p<0.02) and the incidence of malocclusion from 82.4% to 34.7% (p<0.03), with no effect on cranial bone in C57BL/6 FGFR2C342Y/+ mice. In contrast, treatment with TNAP increased cranial bone volume (p< 0.01), density (p< 0.01) and mineral content (p< 0.01) as compared to vehicle treated controls, but had no effect on craniosynostosis or malocclusion in BALB/c FGFR2C342Y/+ mice. These results indicate that postnatal recombinant TNAP enzyme therapy diminishes craniosynostosis severity in the C57BL/6 FGFR2C342Y/+ neonatal onset mouse model of Crouzon syndrome, and that effects of exogenous TNAP are genetic background dependent.
2019-08-01 | <p>Titania nanotube-based protein delivery system to inhibit cranial bone regeneration in Crouzon model of craniosynostosis</p>
Craniosynostosis is a developmental disorder characterized by the premature fusion of skull sutures, necessitating repetitive, high-risk neurosurgical interventions throughout infancy. This study used protein-releasing Titania nanotubular implant (TNT/Ti) loaded with glypican 3 (GPC3) in the cranial critical-sized defects (CSDs) in Crouzon murine model (Fgfr2c342y/+ knock-in mutation) to address a key challenge of delaying post-operative bone regeneration in craniosynostosis.A 3 mm wide circular CSD was created in two murine models of Crouzon syndrome: (i) surgical control (CSDs without TNT/Ti or any protein, n=6) and (ii) experimental groups with TNT/Ti loaded with GPC3, further subdivided into the presence or absence of chitosan coating (on nanotubes) (n=12 in each group). The bone volume percentage in CSDs was assessed 90 days post-implantation using micro-computed tomography (micro-CT) and histological analysis.Nano-implants retrieved after 90 days post-operatively depicted well-adhered, hexagonally arranged, and densely packed nanotubes with average diameter of 120±10 nm. The nanotubular architecture was generally well-preserved. Compared with the control bone volume percentage data (without GPC3), GPC3-loaded TNT/Ti without chitosan coating displayed a significantly lower volume percent in cranial CSDs (P<0.001). Histological assessment showed relatively less bone regeneration (healing) in GPC3-loaded CSDs than control CSDs.The finding of inhibition of cranial bone regeneration by GPC3-loaded TNT/Ti in vivo is an important advance in the novel field of minimally-invasive craniosynostosis therapy and holds the prospect of altering the whole paradigm of treatment for affected children. Future animal studies on a larger sample are indicated to refine the dosage and duration of drug delivery across different ages and both sexes with the view to undertake human clinical trials.
gene therapies
2026-08-31 | Crouzon Syndrome and Craniosynostosis - A Review for the Twenty-First Century.
Crouzon syndrome (CS) is a syndromic craniosynostosis most often caused by heterozygous activating variants in fibroblast growth factor receptor 2, leading to premature fusion of cranial sutures and progressive craniofacial dysmorphology. Premature suture fusion alters cranial growth patterns and modifies cranial base anatomy, increasing the risk of raised intracranial pressure, ventriculomegaly or hydrocephalus, and hindbrain crowding; shallow orbits cause ocular proptosis with exposure keratopathy, strabismus and amblyopia; midface (maxillary) hypoplasia results in class III malocclusion and nasopharyngeal narrowing, contributing to sleep-disordered breathing; and middle ear disease and external canal stenosis contribute to conductive or mixed hearing loss. This narrative review aims to highlight clinical features and treatment for patients with CS. This narrative review was formulated by critically evaluating and synthesising a range of existing literature, particularly focusing on review articles published between 2007 and 2026. Diagnosis is based on clinical and radiological assessment, confirmed by molecular testing. Management is staged and multidisciplinary: cranial vault expansion - posterior and/or fronto-orbital - is usually performed in late infancy to protect the brain and vision; midface advancement during later childhood or adolescence addresses ocular exposure, airway obstruction and malocclusion; ongoing ophthalmological, audiological, orthodontic and sleep-medicine management aims to reduce functional impairment. A rarer variant, CS with acanthosis nigricans, results from pathogenic variants in fibroblast growth factor receptor 3 and is characterised by distinctive skin findings and a higher risk of choanal anomalies. With timely diagnosis, structured surveillance and coordinated reconstruction within specialist craniofacial centres, long-term functional outcomes and life expectancy are generally positive.
2026-05-05 | The Clinical and Molecular Spectrum of Turkish Patients with Syndromic Craniosynostosis: A Single Center Study.
Syndromic craniosynostosis is caused by pathogenic variants in genes regulating suture development. This study aims to investigate clinical and molecular characteristics in syndromic craniosynostosis. This retrospective descriptive study included 53 patients from 40 families with syndromic craniosynostosis. Molecular testing was performed in 22 families. The study included Saethre-Chotzen (n=14), Apert (n=12), Crouzon (n=11), Pfeiffer (n=4), Muenke (n=4), and Carpenter (n=1) syndromes, Crouzon syndrome with acanthosis nigricans (n=2), craniosynostosis with dental anomalies (n=2), craniosynostosis type 4 (n=2), and hypochondroplasia with craniosynostosis (n=1). Genetic etiology was identified in 20 families involving six genes: FGFR1 (Pfeiffer), FGFR2 (Apert, Crouzon, Pfeiffer), FGFR3 (Crouzon with acanthosis nigricans, Muenke), TWIST1 (Saethre-Chotzen), ERF (Craniosynostosis type 4), and IL11RA (Craniosynostosis with dental anomaly). Additionally, a FGFR3 variant causing hypochondroplasia was identified in a patient with multisuture synostosis. Familial inheritance was identified in 25%, but not in Apert syndrome. Brachycephaly (28.3%) was the most common cranial abnormality, followed by plagiocephaly (22.6%). Apert syndrome was characterized by frequent cardiac anomalies, cleft palate, developmental delay, and a higher rate of surgical intervention. In contrast, Crouzon, Pfeiffer, Saethre-Chotzen, and Muenke syndromes showed favorable outcomes, although a fatal course was observed in a patient with Crouzon syndrome with acanthosis nigricans. Rare etiologies included ERF-related craniosynostosis with mild craniofacial findings and IL11RA-related craniosynostosis with intrafamilial phenotypic heterogeneity. This study describes clinical features of well-defined syndromes such as Apert, Crouzon, and Pfeiffer; reports craniosynostosis in hypochondroplasia; and documents rare ERF- and IL11RA-related forms, highlighting the importance of combining clinical and molecular diagnostics.
2026-03-30 | Predictors of Epilepsy in Syndromic Craniosynostosis
BACKGROUND: Epilepsy is rarely observed in patients with craniofacial syndromes, with few reports in the literature devoted to identifying epilepsy predictors for this patient population. This study aims to determine potential predictors of epilepsy in syndromic craniosynostosis. METHODS: This retrospective study analyzed data from 476 patients with Apert, Crouzon, or Pfeiffer syndromes treated at 2 craniofacial centers between 2007 and 2022. Patients were divided into 2 groups: those diagnosed with epilepsy (group A) and those without (group B). Independent variables included age, number of surgeries, previous surgery performed elsewhere, neurosurgical complication during craniofacial surgery, Chiari malformation type I, meningitis, systemic complication, encephalomalacia, hydrocephalus, placement of a ventriculoperitoneal shunt, and family history of epilepsy. These variables were compared between groups. Statistical analyses were conducted using logistic regression models to identify significant epilepsy predictors. RESULTS: Epilepsy was diagnosed in 24 patients, resulting in a prevalence of 5%. Significant predictors of epilepsy included previous surgeries performed elsewhere and neurosurgical complications during craniofacial surgery, with odds ratios of 853 and 902, respectively. These factors suggest that epilepsy in this population is primarily acquired rather than congenital. CONCLUSION: The study identified a higher prevalence of epilepsy among children with syndromic craniosynostosis compared with the general population. Intracranial complications, particularly those associated with surgeries performed outside specialized centers, are key predictors of epilepsy. These findings emphasize the importance of specialized surgical care to mitigate epilepsy risk in this patient population.
2026-01-01 | A Case of Atypical Sagittal Synostosis with Notable Digital Impressions, Hydrocephalus, Posterior Nasal Stenosis, and Tight Posterior Fossa Caused by a Pathogenic Variant in the Fibroblast Growth Factor Receptor 2 Gene
Sagittal synostosis is the most common type of craniosynostosis and frequently manifests as an isolated anomaly without genetic mutations. However, progression to complex conditions has been reported, suggesting that sagittal synostosis may be an early sign of a syndromic condition. We report an atypical sagittal synostosis characterized by notable digital impressions, saddle-shaped deformity, tight posterior fossa, hydrocephalus, and posterior nasal stenosis. At 6 months of age, the patient underwent wider suturectomy; however, he subsequently developed hydrocephalus, fusion of the coronal and lambdoid sutures, and increased digital impressions, necessitating ventriculoperitoneal shunting and posterior vault distraction osteogenesis. Genetic testing identified a pathogenic fibroblast growth factor receptor 2 (FGFR2) variant (p.Cys342Tyr), previously reported in Crouzon and Pfeiffer syndromes, as well as other FGFR2-related craniosynostosis syndromes. Although this case initially presented as atypical sagittal synostosis, it evolved into complex pansynostosis. When atypical findings are observed in sagittal synostosis, syndromic conditions should be considered and early genetic testing performed.
2025-09-09 | The Patient with Crouzon Syndrome Underwent Living Donor Liver Transplantation Because of Biliary Atresia
IntroductionCrouzon syndrome (CS) is characterized by craniosynostosis and facial dysostosis with an incidence of 16.5/1000,000.1 It’s considered the most common craniosynostosis syndrome. Besides the coronal craniosynostosis, brachycephaly, hypertelorism, frontal bossing, strabismus, orbital proptosis, maxillary hypoplasia, hearing loss, hydrocephalus, tonsillar herniation sacrococcygeal tail can be seen .1,2 As the main issue in CS is to achieve eye protection against orbital proptosis and to prevent obstructive sleep apnea related complications, several ophthalmological assessments, surgical procedures have been performed .3 In the molecular studies, it was found that CS is related to multiple fibroblast growth factor receptor 2 (FGFR2) mutations .4 FGFR consists of three extracellular immunoglobulin like domain, a single transmembrane segment and a split tyrosine kinase domain .5 Although mutations of FGFR2 are related to CS, a number of well-characterized mutations of FGFR2 have also been identified that affect cell proliferation, such as in osteoblasts and chondrocytes.Biliary atresia (BA) is a disease characterized by dysplasia of extrahepatic tree. It’s found that BA results from prenatal injury and post-inflammatory fibrous obliteration of the extrahepatic biliary tree.6 Various signaling pathways, such as transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP), and fibroblast growth factor (FGF), are involved in embryonic development. FGFR2 also plays a critical role in modeling of hepatic gene activation in intrauterine life. 7 Mutations in FGFR2 may also underlie the pathogenesis of cholangiocarcinoma. 8Although there’s similar genetic similarities between CS and liver embryogenesis, there’s no CS and BA in the literature. Here we want to present CS patient who underwent Living Donor Liver Transplantation because of biliary atresia.
other
2022-02-14 | Complex Airway Management in Patients with Tracheal Cartilaginous Sleeves.
A tracheal cartilaginous sleeve (TCS) is a rare anomaly characterized by anterior fusion of tracheal cartilages. TCS is associated with syndromic craniosynostoses including Apert, Crouzon and Pfeiffer syndromes and FGFR2, FGFR3, and TWIST1 variants. This study presents a 30-year review of patients with syndromic craniosynostosis and TCS and describes diagnostic methods, genetic variants, surgical interventions, and long-term outcomes. Retrospective, single-institution review. This review included patients with syndromic craniosynostosis and TCS treated at Seattle Children's Hospital from 1990 to 2020. Tracheostomy, genetic variants, and additional surgery were primary measures. Fisher's exact test compared need for tracheostomy in patients with proposed high-risk (FGFR2 p.W290 or FGFR2 p.C342) versus low-risk genetic variants. Thirty patients with TCS were identified. Average age at diagnosis was 12 months (range 2-weeks to 7.9-years; standard deviation 19.8 months). Syndromes included Pfeiffer (37%), Apert (37%), and Crouzon (26%). Severe obstructive sleep apnea was present in 76% of patients. Tracheostomy was performed in 17 patients (57%); five were successfully decannulated. Additional interventions included adenotonsillectomy (57%), nasal (20%), laryngeal (17%), and craniofacial skeletal surgery (87%). All patients with Pfeiffer syndrome and FGFR2 p.W290C variants and 83% of patients with FGFR2 p.C342 variants required tracheostomy, differing from other variants (P = .02, odds ratio 33, 95% confidence interval 1.56-697.96). One patient (3%) died. TCS contributes to multilevel airway obstruction in patients with syndromic craniosynostosis. Genetic testing in patients with FGFR2-related syndromic craniosynostoses may identify those at risk of TCS and facilitate early intervention. A better understanding of this patient population may foster individualized airway management strategies and improve outcomes. 4 Laryngoscope, 132:215-221, 2022.
2007-05-01 | Potential role of PC‐1 expression and pyrophosphate elaboration in the molecular etiology of the FGFR‐associated craniosynostosis syndromes
Fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling is associated with the aberrant mineralization phenotype of the craniosynostosis syndromes. One critical aspect of mineralization involves the elaboration and transport of pyrophosphate into the extracellular matrix with subsequent enzymatic hydrolysis into phosphate. We have previously shown that FGF2 up-regulates expression of the pyrophosphate generating enzyme, PC-1, and the pyrophosphate channel, ANK, while down-regulating expression of the pyrophosphate hydrolyzing enzyme, tissue non-specific alkaline phosphatase in pre-osteoblastic, MC3T3E1(C4) cells. These results suggest that FGF/FGFR signaling may affect mineralization via changes in the elaboration and metabolism of pyrophosphate.We are currently conducting experiments towards a more systematic analysis of PC-1 expression in osteoblastic cells, in order to more clearly elucidate the significance of pyrophosphate elaboration in the process of normal bone mineralization and in the molecular etiology of the FGFR-associated craniosynostosis syndromes.Towards this goal we have constructed a PC-1 gene promoter/firefly luciferase reporter construct, in order to more directly investigate the regulation of PC-1 by FGF/FGFR signaling in osteoblastic and non-osteoblastic cells.Preliminary results confirm that FGF/FGFR signaling, either via treatment with FGF2 or via expression of a Crouzon syndrome-associated mutant FGFR2, induces PC-1 promoter activity in osteoblastic cells in culture. This appears to be a cell type specific phenomenon. These results suggest that the expression of PC-1 downstream of FGF signaling is an integral aspect of osteoblastic function, and that pyrophosphate elaboration may play a significant role in the pathology of craniosynostosis.
2003-05-01 | Delivery of Transforming Growth Factor-β2-Perturbing Antibody in a Collagen Vehicle Inhibits Cranial Suture Fusion in Calvarial Organ Culture
Objective To determine whether antibody perturbation of Tgf-β, delivered in a collagen gel, could inhibit cranial suture fusion. Design Attachment and proliferation of osteoblasts cultured on a collagen gel with or without anti-Tgf-β2 antibody were determined by AlamarBlue dye assay and cell morphology by toluidine-blue staining. In rat calvarial organ culture, collagen gel with and without anti-Tgf-β2 antibody was injected subperiosteally over the posterior frontal suture of postnatal day 15 rat calvariae. A quantitative analysis of suture fusion was used to measure suture bridging in histological serial sections at various time points. Results Attachment and proliferation for cells cultured on collagen gel with anti-Tgf-β2 antibody were similar to collagen gel controls. Although proliferation was lower than on tissue culture plastic, cells treated with anti-Tgf-β2 antibody maintained an osteoblastic morphology. After 7, 10, and 15 days in organ culture, anti-Tgf-β2 antibody treatment caused a reduction in the percent bridging of posterior frontal sutures, compared with controls. Sutures exposed to anti-Tgf-β2 antibody and fibroblast growth factor-2 concurrently did not show an inhibition of bony bridging. Conclusions These results support previous reports suggesting a role for Tgf-β2 in cranial suture fusion. In cell culture the collagen gel, both with and without anti-Tgf-β2 antibody, promoted similar osteoblast attachment, proliferation, and osteoblastic morphology. In organ culture anti-Tgf-β2 antibody was delivered in a bioactive state via a collagen gel to inhibit cranial suture fusion. Also, the results suggest that the inductive effect of fibroblast growth factor-2 is not dependent on Tgf-β2 activity. Together, these results provide further support for the role of Tgf-β2 in cranial suture fusion.
2002-03-01 | Blocking Endogenous FGF-2 Activity Prevents Cranial Osteogenesis
Normal growth and morphogenesis of the cranial vault reflect a balance between cell proliferation in the sutures and osteogenesis at the margins of the cranial bones. In the clinical condition craniosynostosis, the sutures fuse prematurely as a result of precocious osteogenic differentiation and craniofacial malformation results. Mutations in several fibroblast growth factor receptor (FGFR) genes have now been identified as being responsible for the major craniosynostotic syndromes. We have used a grafting technique to manipulate the levels of endogenous FGF-2 ligand in embryonic chick cranial vaults and thereby perturb morphogenesis. Implantation of beads loaded with FGF-2 did not affect normal cranial development at physiological concentrations, although they elicited a morphogenetic response in the limb. Implantation of beads loaded with a neutralising antibody to FGF-2 generated a concentration-dependent response. When a single bead was implanted, the grafts grew to a massive size as a result of increased cell division in the tissue. With greater inactivation of FGF-2 protein (two to three beads implanted), all further bone differentiation and cell proliferation was blocked. These data further support the emerging idea that the intensity of FGF-mediated signalling determines the developmental fate of the skeletogenic cells in the cranial vault. High and low levels correlate with differentiation and proliferation, respectively. A balance between the two ensures normal cranial vault morphogenesis. This is consistent with the observation that several FGFR mutations causing craniosynostosis result in constitutive activation of the receptor.
small molecules
2025-07-31 | Mechanistic Role of PIEZO1 in Crouzon Syndrome: Osteogenic Regulation By FGFR2-Mutated Periosteal Progenitors at the Ossification Interface.
Crouzon syndrome represents an autosomal dominant genetic disorder primarily characterized by craniofacial malformations. Recent advancements have enabled the successful derivation of periosteal stem cells from the periosteum, a critical reservoir of osteogenic progenitor cells. This investigation employs periosteal stem cells transfected with the C361Y-FGFR2 point mutation in conjunction with an in vitro mechanical tensile stress model to elucidate the aberrant osteogenic differentiation patterns under mechanical stimulation. The study identifies PIEZO1, a mechanosensitive ion channel protein, as a pivotal mediator in transducing extracellular mechanical signals. Through integrated analysis of PIEZO1-modulated HIPPO/YAP and BMP2/SMAD2 signaling cascades, the authors systematically evaluate the expression patterns of key regulatory nodes within these pathways. These findings establish a molecular framework for understanding defective osteogenic differentiation mechanisms in periosteal stem cells derived from Crouzon syndrome models, offering novel insights into potential therapeutic targets.
2025-04-14 | Current Understanding of Crouzon Syndrome Pathophysiology and New Therapeutic Approaches.
Crouzon syndrome (CS) is a rare genetic disorder characterized by the premature fusion of cranial sutures, leading to craniofacial abnormalities and potential neurological complications. CS is caused primarily by gain-of-function mutations in the FGFR2 gene and, less commonly, by mutations in the FGFR3 gene (specifically associated with CS with acanthosis nigricans). Managing CS requires a multidisciplinary approach, combining early and later surgical interventions to prevent intracranial hypertension and correct craniofacial deformities, along with ongoing care to address associated complications. Recent advancements in CS classification on the basis of cranial suture involvement have refined phenotype-genotype correlations, improving personalized therapeutic strategies. This review aims to provide a comprehensive and updated overview of CS, including detailed insights into molecular genetics and biological mechanisms underlying its pathophysiology, and a depiction of the clinical features, diagnosis, and surgical aspects of CS. In addition, we delve into innovative theranostic views, where molecular genetic testing allows the design of personalized noninvasive therapeutic approaches based on innovative biotechnologies, including RNA-interference molecules, pharmacological modulation of FGFR signaling pathways, and recombinant proteins. These advancements underscore the importance of integrating molecular studies into diagnostic and therapeutic protocols to increase the precision and effectiveness of nonsurgical treatments for CS.
2025-02-24 | Structural and functional stenosis of the upper airway in Crouzon syndrome patients: A computational fluid dynamics analysis.
This study aimed to simulate the aerodynamics and to identify the spatial correlation between anatomical and functional stenoses in Crouzon syndrome patients. Six patients of Crouzon syndrome were included. Computational fluid dynamics (CFD) was utilized to simulate airflow dynamics, and characteristics, including the velocity, pressure intensity, wall shear stress, airflow resistance and streamline, were extracted for quantitative analysis both in overall and regionally. Structural stenosis was defined at the minimum cross-sectional area, while functional stenosis was identified at the point of maximum airflow velocity. The spatial distances between the Frankfurt plane and structural/functional stenosis were calculated and compared. Structural stenosis occurred in the palatopharynx, while the highest inspiratory resistance and peak airflow velocity during expiration identified the glossopharynx as the functional stenosis site. A steep increase in negative pressure and a significant increase in wall shear stress could be observed surrounding the functional stenosis. The intensity and diffusion range of wall shear stress are positively correlated with age. Notably, the functional stenosis was consistently 5 mm below the structural stenosis (P < 0.05). CFD effectively visualized both overall and regional aerodynamics of Crouzon syndrome, providing a novel method for functional airway evaluation. The spatial distributions of structural and functional stenoses did not strictly correspond; the structural stenosis was located on the palatopharynx, while the functional stenosis was on the glossopharynx. The wall shear stress worsens pathologically with age, aggravating functional stenosis to structural stenosis. Therefore, functional stenosis should also be addressed in airway management to ensure therapeutic effectiveness.
2025-01-22 | FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia.
Gain-of-function mutations in fibroblast growth factor receptor (FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3-activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome (Crz) and hypochondroplasia (Hch). Bone mineralization of the calluses was abnormally high in Crz mice and abnormally low in Hch mice. The latter model presented pseudarthrosis and impaired chondrocyte differentiation. Spatial transcriptomic analyses of the Hch callus revealed abnormally low expression of Col11, Col1a, Dmp1 genes in mature chondrocytes. We found that the expression of genes involved in autophagy and apoptosis (Smad1, Comp, Birc2) was significantly perturbed and that the Dusp3, Dusp9, and Socs3 genes controlling the mitogen-activated protein kinase pathway were overexpressed. Lastly, we found that treatment with a tyrosine kinase inhibitor (BGJ398, infigratinib) or a C-type natriuretic peptide (BMN111, vosoritide) fully rescued the defective endochondral bone repair observed in Hch mice. Taken as a whole, our findings show that FGFR3 is a critical orchestrator of bone repair and provide a rationale for the development of potential treatments for patients with FGFR3-osteochondrodysplasia.
2023-04-27 | Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration
ETS2 repressor factor (ERF) insufficiency causes craniosynostosis (CRS4) in humans and mice. ERF is an ETS domain transcriptional repressor regulated by Erk1/2 phosphorylation via nucleo-cytoplasmic shuttling. Here, we analyze the onset and development of the craniosynostosis phenotype in an Erf-insufficient mouse model and evaluate the potential of the residual Erf activity augmented by pharmacological compounds to ameliorate the disease. Erf insufficiency appears to cause an initially compromised frontal bone formation and subsequent multisuture synostosis, reflecting distinct roles of Erf on the cells that give rise to skull and facial bones. We treated animals with Mek1/2 and nuclear export inhibitors, U0126 and KPT-330, respectively, to increase Erf activity by two independent pathways. We implemented both a low dosage locally over the calvaria and a systemic drug administration scheme to evaluate the possible indirect effects from other systems and minimize toxicity. The treatment of mice with either the inhibitors or the administration scheme alleviated the synostosis phenotype with minimal adverse effects. Our data suggest that the ERF level is an important regulator of cranial bone development and that pharmacological modulation of its activity may represent a valid intervention approach both in CRS4 and in other syndromic forms of craniosynostosis mediated by the FGFR-RAS-ERK-ERF pathway.
cell therapies
2026-07-24 | Auricular Cartilage Grafting for Lower-Eyelid Entropion in Syndromic Craniosynostosis: A Case Series
Patients with syndromic craniosynostosis, including Crouzon and Pfeiffer syndromes, may develop lower-eyelid malposition, including retraction and secondary entropion, associated with complex midfacial and orbital anatomical abnormalities. Progressive midface hypoplasia, shallow orbits, and postoperative anatomical changes following craniofacial surgery may contribute to imbalance between the anterior and posterior lamellae, relative posterior lamellar insufficiency, and persistent eyelash-corneal contact. We report a retrospective case series of 3 patients who underwent posterior lamellar lengthening using autologous auricular cartilage grafts via a transconjunctival approach. The harvested cartilage was secured to the tarsal plate to increase posterior lamellar height and correct lower-eyelid entropion. All patients experienced improvement in cilia-corneal touch and symptomatic relief, with satisfactory functional and aesthetic outcomes. No recurrence or major complications were observed during follow-up. Auricular cartilage grafting may represent a useful surgical option for selected patients with lower-eyelid entropion associated with syndromic craniosynostosis, particularly in patients with severe midface hypoplasia or previous midface advancement procedures.
2026-04-15 | Mechanical bone loading effects on morphology and mechanobiology in the coronal suture of Crouzon mice.
Craniosynostosis is a congenital condition characterized by the premature fusion of the craniofacial sutures. The Crouzon mouse (Fgfr2cC342Y/+) is a well-established model of this condition which shows premature fusion of the coronal suture. Our group has recently shown that postnatal, cyclic loading can potentially rescue the coronal suture and normalize skull morphology in Crouzon mice. This study aimed to investigate the underlying biological mechanism of the treatment. Wild-type (WT) and Crouzon (MUT) mice underwent in vivo loading sessions. Loading did not significantly affect skull shape. The patency across the coronal suture did not change between treated and untreated MUT animals. Orientation and coherence of the coronal suture collagen fibres were statistically different when comparing WT untreated with MUT untreated and WT treated with MUT treated. Treatment increases the number of proliferative cells in both the WT and MUT sutures compared to their untreated counterparts. The mechanobiological mechanisms driving the differences need further investigation into molecular mechanotransduction pathways. Understanding the biological principles affected during bone loading, a more refined cyclical bone loading protocol can be developed and refined for potential clinical use.
2024-08-02 | Optic nerve elongation during fronto-facial surgery for Crouzon syndrome: 3D quantification and clinical implications.
Fronto-facial monobloc advancement with internal distraction (FFMBA) is a key procedure in the management of syndromic craniosynostoses. FFMBA involves circumferential dissection and linear enlargement of the orbit, potentially leading to mechanical stress on the optic nerve (ON). Several reports of transient vision loss during the distraction process led us to investigate ON shape modifications during facial advancement, with the aim to potentially refine current clinical guidelines on postoperative management and the distraction schedule. Twenty-six patients with Crouzon syndrome were included in this study. ONs were segmented on pre- and postoperative CT scans. Distraction amplitudes, linear and curved lengths, and cross-section diameters of the ON were assessed along the main axis of the nerve. A two-level hierarchical multivariate linear model was used to screen for factors associated with ON morphology. The mean age at FFMBA was 4.4 ± 3.8 years. Two patients presented with transient impaired vision during distraction. The final mean fronto-orbital and temporo-zygomatic distraction amplitudes were 18 ± 4 mm and 18 ± 6 mm, respectively. At the end of distraction, ONs were elongated (+1.8 mm for curved lengths, p = 0.013), and their mean cross-section was reduced (-1.9 mm2, p < 0.001) in the proximal intraorbital portion (first 15 mm). In the 2 patients with visual symptoms, functional impairment was associated with ON area reduction (OR 0.487, p < 0.001) and increased temporo-zygomatic distraction amplitude (OR 2.240, p < 0.001). ON was elongated during FFMBA, with proximal diameter reduction. Transient visual impairment with normal fundus examination during distraction seemed to have a morphological basis, based on 2 cases. These results suggest the importance of vision monitoring associated with fundus examination during distraction, and advocate for early extubation after FFMBA to allow clinical follow-up.
2024-07-24 | Apert syndrome: neurosurgical outcomes and complications following posterior vault distraction osteogenesis.
Posterior vault distraction osteogenesis (PVDO) has been utilized during the past 15 years to treat a variety of clinical features commonly presented by patients with Apert syndrome. The objective of this study is to determine the efficacy of PVDO in addressing both elevated intracranial pressure (ICP) and ectopia of the cerebellar tonsils (ECT) in young Apert patients. In addition, we aimed to determine the prevalence of hydrocephalus in Apert syndrome patients who underwent PVDO. A retrospective study was made with a cohort of 40 consecutive patients with syndromic craniosynostosis (SC), previously diagnosed with Apert syndrome, who underwent PVDO between 2012 and 2022, and thereafter received at least 1 year of follow-up care. Demographic data and diagnosis, along with surgical and outcome data, were verified using medical records, clinical photographs, radiologic examination, and interviews with the parents of all cohort patients. The average patient age when PVDO was performed was 12.91 ± 10 months. The average posterior advancement distance achieved per patient was 22.68 ± 5.26 mm. The average hospital stay per patient was 3.56 ± 2.44 days. The average absolute and relative blood transfusion volumes were 98.47 ml and 17.63 ml/kg, respectively. Although five patients (14%) presented ECT preoperatively, this condition was completely resolved by PVDO in three of these five patients. One of the three patients whose ECT had completely resolved presented syringomyelia postoperatively, requiring subsequent extra dural foramen magnum decompression. All of the remaining four patients were asymptomatic for ECT for at least 1 year of follow-up, and none of these four patients required any additional treatments to address ECT. Two patients presented hydrocephalus requiring ventriculoperitoneal shunt placement. This study demonstrates that PVDO both reduces diagnosed elevated ICP symptoms and is partially effective in treating ECT in Apert syndrome patients. Hydrocephalus in Apert syndrome is an uncommon feature. The effectiveness of PVDO in addressing hydrocephalus is uncertain.
2024-06-21 | Early posterior vault distraction osteogenesis changes the syndromic craniosynostosis treatment paradigm: long-term outcomes of a 23-year cohort study
Abstract Background Early surgical management of syndromic craniosynostosis varies widely between centers, with patients typically undergoing multiple intracranial procedures through childhood. This study evaluates the long-term impact of early posterior vault distraction osteogenesis (PVDO) versus conventional treatment paradigms on the number and timing of subsequent craniofacial procedures. Methods We retrospectively analyzed the longitudinal operative patterns of patients with syndromic craniosynostosis treated from 2000 to 2023 with greater than five years of follow-up. Outcomes of patients who underwent early PVDO and conventional vault reconstruction were compared. Results Fifty-five patients met the inclusion criteria (30 PVDO and 25 conventional). Age at initial vault surgery was similar between the PVDO and conventional cohorts (7.6 vs. 8.8 months), as were baseline craniometrics ( p > 0.05). Multiple fronto-orbital advancement (FOA) procedures were performed in only 1/30 (3%) PVDO-treated patient versus 12/25 (48%) conventionally-treated patients ( p < 0.001). Twelve (40%) PVDO-treated patients did not undergo FOA at all. Among patients with Apert and Crouzon syndromes, fewer PVDO-treated patients required FOA prior to midface surgery (33% vs. 92%, p = 0.004) or repeat FOA (6% vs. 50%, p = 0.005) compared to conventionally-treated patients. Among patients with Muenke and Saethre–Chotzen syndromes, a similar proportion of patients required FOA in the PVDO and conventional cohorts (91% vs. 100%, p = 0.353), though no PVDO-treated patients required repeat FOA (0% vs. 44%, p = 0.018). Conclusions Early PVDO is associated with a reduction in the high burden of both FOA and, critically, revisionary frontal procedures which are commonly seen in conventionally-treated patients with syndromic craniosynostosis.
proteins
2024-06-27 | Unexpected massive bleeding during the modified LeFort III advancement surgery for Crouzon syndrome: A case report.
Vigilant monitoring for postoperative complications, including bleeding and dysrhythmia, is crucial in patients with craniosynostosis syndromes like Crouzon syndrome undergoing craniofacial surgery, with a thorough evaluation, including coagulation tests, assisting in diagnosing underlying conditions such as von Willebrand disease subtype 1 to inform appropriate management strategies. Crouzon syndrome is a rare genetic disorder affecting craniofacial structures. Its etiology is the premature fusion of cranial sutures. The LeFort III advancement surgery is a commonly used approach to correct malformations related to midface hypoplasia. Complications following surgical treatment of craniosynostosis and craniofacial syndromes can include both intracranial and extracranial problems. Reporting of this syndrome and the surgery complications, in addition to consideration of other differential diagnoses, can help improve the treatment plan and surgery outcomes. The aim of the article is to report a 14-year-old female with Crouzon syndrome who underwent the modified LeFort III osteotomy and developed unexpected massive bleeding during the surgery. Post-surgery, she experienced complications including dysrhythmia, hypothermia, and cyanosis. Treatment included fluid therapy, blood transfusions, and antibiotic therapy for suspected septic shock. Differential diagnosis was disseminated intravascular coagulation but was ruled out. Post-discharge, coagulation tests suggested von Willebrand disease subtype 1 as the diagnosis. Excessive bleeding during surgery for craniosynostosis syndromes is a significant and concerning issue in the surgical management of Crouzon syndrome. For patients with von Willebrand disease who are candidates for elective surgeries, von Willebrand factor concentrates or recombinant von Willebrand factor can be used.
2024-03-20 | Noggin promotes osteogenesis in human adipose-derived mesenchymal stem cells via FGFR2/Src/Akt and ERK signaling pathway
Abstract The balance between Noggin and bone morphogenetic proteins (BMPs) is important during early development and skeletal regenerative therapies. Noggin binds BMPs in the extracellular space, thereby preventing BMP signaling. However, Noggin may affect cell response not necessarily through the modulation of BMP signaling, raising the possibility of direct Noggin signaling through yet unspecified receptors. Here we show that in osteogenic cultures of adipose-derived stem cells (ASCs), Noggin activates fibroblast growth factor receptors (FGFRs), Src/Akt and ERK kinases, and it stabilizes TAZ proteins in the presence of dexamethasone. Overall, this leads ASCs to increased expression of osteogenic markers and robust mineral deposition. Our results also indicate that Noggin can induce osteogenic genes expression in normal human bone marrow stem cells and alkaline phosphatase activity in normal human dental pulp stem cells. Besides, Noggin can specifically activate FGFR2 in osteosarcoma cells. We believe our findings open new research avenues to further explore the involvement of Noggin in cell fate modulation by FGFR2/Src/Akt/ERK signaling and potential applications of Noggin in bone regenerative therapies.
2022-09-01 | The Effect of Yes-Associated Protein on the Interaction Between the MEK/Extracellular Signal-Regulated Kinase and Hippo Pathways in Osteoblasts Co-Cultured With Fibroblast Growth Factor Receptor 2-Mutated Dura Cells.
C342Y (Cys342Tyr) point mutation of FGFR2 (fibroblast growth factor receptor 2) is closely associated with the pathogenesis of Crouzon syndrome. The dura mater plays an important role in mediating the closure of cranial sutures. However, the underlying mechanisms of these pathological processes have been rarely investigated. in this study, the authors analyzed the effects of dura cells with FGFR2 mutations on the biological function of osteoblasts. Dura cells and cranial osteoblasts from C57BL/6 mice were extracted and cultured. C342Y-FGFR2 mutant constructs were established via lentivirus and applied to infect dura cells. A co-cultured trans-well system with dura cells and osteoblasts was established. Three experimental groups were set up: oste group, Oste + Dura-vector group, and Oste + Dura-C342Y group. The expression levels of key factors in MEK (Mitogen-activated protein kinase kinase, MAPKK)/extracellular signal-regulated kinase (ERK) and Hippo pathway were detected by western blot and RT-qPCR (Real Time Quantitative PCR). Finally, a rescue experiment was carried out with small interference RUA. The proliferation level of osteoblasts in Oste + Dura- C342Y group was significantly up-regulated. Our studies indicated that the activation of MEK/ERK pathway in Oste + Dura-C342Y group could inhibit the Hippo pathway, lead to down-regulation of large tumor suppressor 1 and promote the activation and nuclear localization of yes-associated protein, and the results of rescue experiments showed a reverse expression trend, further confirming the effects of C342Y-FGFR2 mutation in dura cells on osteoblasts and its potential mechanism. This study suggested that the C342Y-FGFR2 mutation in dura cells could promote osteoblastic proliferation, and shown the crosstalk between MEK/ERK and Hippo pathways. As the regulatory machinery center, yes-associated protein might play a bridging role in these pathways, and might influence the pathogenesis of craniosynostosis by activating downstream transcriptional factors.
2020-08-17 | Viral delivery of tissue nonspecific alkaline phosphatase diminishes craniosynostosis in one of two FGFR2C342Y/+ mouse models of Crouzon syndrome.
Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro CT. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p<0.02) and the incidence of malocclusion from 82.4% to 34.7% (p<0.03), with no effect on cranial bone in C57BL/6 FGFR2C342Y/+ mice. In contrast, treatment with TNAP increased cranial bone volume (p< 0.01), density (p< 0.01) and mineral content (p< 0.01) as compared to vehicle treated controls, but had no effect on craniosynostosis or malocclusion in BALB/c FGFR2C342Y/+ mice. These results indicate that postnatal recombinant TNAP enzyme therapy diminishes craniosynostosis severity in the C57BL/6 FGFR2C342Y/+ neonatal onset mouse model of Crouzon syndrome, and that effects of exogenous TNAP are genetic background dependent.
2019-08-01 | <p>Titania nanotube-based protein delivery system to inhibit cranial bone regeneration in Crouzon model of craniosynostosis</p>
Craniosynostosis is a developmental disorder characterized by the premature fusion of skull sutures, necessitating repetitive, high-risk neurosurgical interventions throughout infancy. This study used protein-releasing Titania nanotubular implant (TNT/Ti) loaded with glypican 3 (GPC3) in the cranial critical-sized defects (CSDs) in Crouzon murine model (Fgfr2c342y/+ knock-in mutation) to address a key challenge of delaying post-operative bone regeneration in craniosynostosis.A 3 mm wide circular CSD was created in two murine models of Crouzon syndrome: (i) surgical control (CSDs without TNT/Ti or any protein, n=6) and (ii) experimental groups with TNT/Ti loaded with GPC3, further subdivided into the presence or absence of chitosan coating (on nanotubes) (n=12 in each group). The bone volume percentage in CSDs was assessed 90 days post-implantation using micro-computed tomography (micro-CT) and histological analysis.Nano-implants retrieved after 90 days post-operatively depicted well-adhered, hexagonally arranged, and densely packed nanotubes with average diameter of 120±10 nm. The nanotubular architecture was generally well-preserved. Compared with the control bone volume percentage data (without GPC3), GPC3-loaded TNT/Ti without chitosan coating displayed a significantly lower volume percent in cranial CSDs (P<0.001). Histological assessment showed relatively less bone regeneration (healing) in GPC3-loaded CSDs than control CSDs.The finding of inhibition of cranial bone regeneration by GPC3-loaded TNT/Ti in vivo is an important advance in the novel field of minimally-invasive craniosynostosis therapy and holds the prospect of altering the whole paradigm of treatment for affected children. Future animal studies on a larger sample are indicated to refine the dosage and duration of drug delivery across different ages and both sexes with the view to undertake human clinical trials.
gene therapies
2026-08-31 | Crouzon Syndrome and Craniosynostosis - A Review for the Twenty-First Century.
Crouzon syndrome (CS) is a syndromic craniosynostosis most often caused by heterozygous activating variants in fibroblast growth factor receptor 2, leading to premature fusion of cranial sutures and progressive craniofacial dysmorphology. Premature suture fusion alters cranial growth patterns and modifies cranial base anatomy, increasing the risk of raised intracranial pressure, ventriculomegaly or hydrocephalus, and hindbrain crowding; shallow orbits cause ocular proptosis with exposure keratopathy, strabismus and amblyopia; midface (maxillary) hypoplasia results in class III malocclusion and nasopharyngeal narrowing, contributing to sleep-disordered breathing; and middle ear disease and external canal stenosis contribute to conductive or mixed hearing loss. This narrative review aims to highlight clinical features and treatment for patients with CS. This narrative review was formulated by critically evaluating and synthesising a range of existing literature, particularly focusing on review articles published between 2007 and 2026. Diagnosis is based on clinical and radiological assessment, confirmed by molecular testing. Management is staged and multidisciplinary: cranial vault expansion - posterior and/or fronto-orbital - is usually performed in late infancy to protect the brain and vision; midface advancement during later childhood or adolescence addresses ocular exposure, airway obstruction and malocclusion; ongoing ophthalmological, audiological, orthodontic and sleep-medicine management aims to reduce functional impairment. A rarer variant, CS with acanthosis nigricans, results from pathogenic variants in fibroblast growth factor receptor 3 and is characterised by distinctive skin findings and a higher risk of choanal anomalies. With timely diagnosis, structured surveillance and coordinated reconstruction within specialist craniofacial centres, long-term functional outcomes and life expectancy are generally positive.
2026-05-05 | The Clinical and Molecular Spectrum of Turkish Patients with Syndromic Craniosynostosis: A Single Center Study.
Syndromic craniosynostosis is caused by pathogenic variants in genes regulating suture development. This study aims to investigate clinical and molecular characteristics in syndromic craniosynostosis. This retrospective descriptive study included 53 patients from 40 families with syndromic craniosynostosis. Molecular testing was performed in 22 families. The study included Saethre-Chotzen (n=14), Apert (n=12), Crouzon (n=11), Pfeiffer (n=4), Muenke (n=4), and Carpenter (n=1) syndromes, Crouzon syndrome with acanthosis nigricans (n=2), craniosynostosis with dental anomalies (n=2), craniosynostosis type 4 (n=2), and hypochondroplasia with craniosynostosis (n=1). Genetic etiology was identified in 20 families involving six genes: FGFR1 (Pfeiffer), FGFR2 (Apert, Crouzon, Pfeiffer), FGFR3 (Crouzon with acanthosis nigricans, Muenke), TWIST1 (Saethre-Chotzen), ERF (Craniosynostosis type 4), and IL11RA (Craniosynostosis with dental anomaly). Additionally, a FGFR3 variant causing hypochondroplasia was identified in a patient with multisuture synostosis. Familial inheritance was identified in 25%, but not in Apert syndrome. Brachycephaly (28.3%) was the most common cranial abnormality, followed by plagiocephaly (22.6%). Apert syndrome was characterized by frequent cardiac anomalies, cleft palate, developmental delay, and a higher rate of surgical intervention. In contrast, Crouzon, Pfeiffer, Saethre-Chotzen, and Muenke syndromes showed favorable outcomes, although a fatal course was observed in a patient with Crouzon syndrome with acanthosis nigricans. Rare etiologies included ERF-related craniosynostosis with mild craniofacial findings and IL11RA-related craniosynostosis with intrafamilial phenotypic heterogeneity. This study describes clinical features of well-defined syndromes such as Apert, Crouzon, and Pfeiffer; reports craniosynostosis in hypochondroplasia; and documents rare ERF- and IL11RA-related forms, highlighting the importance of combining clinical and molecular diagnostics.
2026-03-30 | Predictors of Epilepsy in Syndromic Craniosynostosis
BACKGROUND: Epilepsy is rarely observed in patients with craniofacial syndromes, with few reports in the literature devoted to identifying epilepsy predictors for this patient population. This study aims to determine potential predictors of epilepsy in syndromic craniosynostosis. METHODS: This retrospective study analyzed data from 476 patients with Apert, Crouzon, or Pfeiffer syndromes treated at 2 craniofacial centers between 2007 and 2022. Patients were divided into 2 groups: those diagnosed with epilepsy (group A) and those without (group B). Independent variables included age, number of surgeries, previous surgery performed elsewhere, neurosurgical complication during craniofacial surgery, Chiari malformation type I, meningitis, systemic complication, encephalomalacia, hydrocephalus, placement of a ventriculoperitoneal shunt, and family history of epilepsy. These variables were compared between groups. Statistical analyses were conducted using logistic regression models to identify significant epilepsy predictors. RESULTS: Epilepsy was diagnosed in 24 patients, resulting in a prevalence of 5%. Significant predictors of epilepsy included previous surgeries performed elsewhere and neurosurgical complications during craniofacial surgery, with odds ratios of 853 and 902, respectively. These factors suggest that epilepsy in this population is primarily acquired rather than congenital. CONCLUSION: The study identified a higher prevalence of epilepsy among children with syndromic craniosynostosis compared with the general population. Intracranial complications, particularly those associated with surgeries performed outside specialized centers, are key predictors of epilepsy. These findings emphasize the importance of specialized surgical care to mitigate epilepsy risk in this patient population.
2026-01-01 | A Case of Atypical Sagittal Synostosis with Notable Digital Impressions, Hydrocephalus, Posterior Nasal Stenosis, and Tight Posterior Fossa Caused by a Pathogenic Variant in the Fibroblast Growth Factor Receptor 2 Gene
Sagittal synostosis is the most common type of craniosynostosis and frequently manifests as an isolated anomaly without genetic mutations. However, progression to complex conditions has been reported, suggesting that sagittal synostosis may be an early sign of a syndromic condition. We report an atypical sagittal synostosis characterized by notable digital impressions, saddle-shaped deformity, tight posterior fossa, hydrocephalus, and posterior nasal stenosis. At 6 months of age, the patient underwent wider suturectomy; however, he subsequently developed hydrocephalus, fusion of the coronal and lambdoid sutures, and increased digital impressions, necessitating ventriculoperitoneal shunting and posterior vault distraction osteogenesis. Genetic testing identified a pathogenic fibroblast growth factor receptor 2 (FGFR2) variant (p.Cys342Tyr), previously reported in Crouzon and Pfeiffer syndromes, as well as other FGFR2-related craniosynostosis syndromes. Although this case initially presented as atypical sagittal synostosis, it evolved into complex pansynostosis. When atypical findings are observed in sagittal synostosis, syndromic conditions should be considered and early genetic testing performed.
2025-09-09 | The Patient with Crouzon Syndrome Underwent Living Donor Liver Transplantation Because of Biliary Atresia
IntroductionCrouzon syndrome (CS) is characterized by craniosynostosis and facial dysostosis with an incidence of 16.5/1000,000.1 It’s considered the most common craniosynostosis syndrome. Besides the coronal craniosynostosis, brachycephaly, hypertelorism, frontal bossing, strabismus, orbital proptosis, maxillary hypoplasia, hearing loss, hydrocephalus, tonsillar herniation sacrococcygeal tail can be seen .1,2 As the main issue in CS is to achieve eye protection against orbital proptosis and to prevent obstructive sleep apnea related complications, several ophthalmological assessments, surgical procedures have been performed .3 In the molecular studies, it was found that CS is related to multiple fibroblast growth factor receptor 2 (FGFR2) mutations .4 FGFR consists of three extracellular immunoglobulin like domain, a single transmembrane segment and a split tyrosine kinase domain .5 Although mutations of FGFR2 are related to CS, a number of well-characterized mutations of FGFR2 have also been identified that affect cell proliferation, such as in osteoblasts and chondrocytes.Biliary atresia (BA) is a disease characterized by dysplasia of extrahepatic tree. It’s found that BA results from prenatal injury and post-inflammatory fibrous obliteration of the extrahepatic biliary tree.6 Various signaling pathways, such as transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP), and fibroblast growth factor (FGF), are involved in embryonic development. FGFR2 also plays a critical role in modeling of hepatic gene activation in intrauterine life. 7 Mutations in FGFR2 may also underlie the pathogenesis of cholangiocarcinoma. 8Although there’s similar genetic similarities between CS and liver embryogenesis, there’s no CS and BA in the literature. Here we want to present CS patient who underwent Living Donor Liver Transplantation because of biliary atresia.
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2022-02-14 | Complex Airway Management in Patients with Tracheal Cartilaginous Sleeves.
A tracheal cartilaginous sleeve (TCS) is a rare anomaly characterized by anterior fusion of tracheal cartilages. TCS is associated with syndromic craniosynostoses including Apert, Crouzon and Pfeiffer syndromes and FGFR2, FGFR3, and TWIST1 variants. This study presents a 30-year review of patients with syndromic craniosynostosis and TCS and describes diagnostic methods, genetic variants, surgical interventions, and long-term outcomes. Retrospective, single-institution review. This review included patients with syndromic craniosynostosis and TCS treated at Seattle Children's Hospital from 1990 to 2020. Tracheostomy, genetic variants, and additional surgery were primary measures. Fisher's exact test compared need for tracheostomy in patients with proposed high-risk (FGFR2 p.W290 or FGFR2 p.C342) versus low-risk genetic variants. Thirty patients with TCS were identified. Average age at diagnosis was 12 months (range 2-weeks to 7.9-years; standard deviation 19.8 months). Syndromes included Pfeiffer (37%), Apert (37%), and Crouzon (26%). Severe obstructive sleep apnea was present in 76% of patients. Tracheostomy was performed in 17 patients (57%); five were successfully decannulated. Additional interventions included adenotonsillectomy (57%), nasal (20%), laryngeal (17%), and craniofacial skeletal surgery (87%). All patients with Pfeiffer syndrome and FGFR2 p.W290C variants and 83% of patients with FGFR2 p.C342 variants required tracheostomy, differing from other variants (P = .02, odds ratio 33, 95% confidence interval 1.56-697.96). One patient (3%) died. TCS contributes to multilevel airway obstruction in patients with syndromic craniosynostosis. Genetic testing in patients with FGFR2-related syndromic craniosynostoses may identify those at risk of TCS and facilitate early intervention. A better understanding of this patient population may foster individualized airway management strategies and improve outcomes. 4 Laryngoscope, 132:215-221, 2022.
2007-05-01 | Potential role of PC‐1 expression and pyrophosphate elaboration in the molecular etiology of the FGFR‐associated craniosynostosis syndromes
Fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling is associated with the aberrant mineralization phenotype of the craniosynostosis syndromes. One critical aspect of mineralization involves the elaboration and transport of pyrophosphate into the extracellular matrix with subsequent enzymatic hydrolysis into phosphate. We have previously shown that FGF2 up-regulates expression of the pyrophosphate generating enzyme, PC-1, and the pyrophosphate channel, ANK, while down-regulating expression of the pyrophosphate hydrolyzing enzyme, tissue non-specific alkaline phosphatase in pre-osteoblastic, MC3T3E1(C4) cells. These results suggest that FGF/FGFR signaling may affect mineralization via changes in the elaboration and metabolism of pyrophosphate.We are currently conducting experiments towards a more systematic analysis of PC-1 expression in osteoblastic cells, in order to more clearly elucidate the significance of pyrophosphate elaboration in the process of normal bone mineralization and in the molecular etiology of the FGFR-associated craniosynostosis syndromes.Towards this goal we have constructed a PC-1 gene promoter/firefly luciferase reporter construct, in order to more directly investigate the regulation of PC-1 by FGF/FGFR signaling in osteoblastic and non-osteoblastic cells.Preliminary results confirm that FGF/FGFR signaling, either via treatment with FGF2 or via expression of a Crouzon syndrome-associated mutant FGFR2, induces PC-1 promoter activity in osteoblastic cells in culture. This appears to be a cell type specific phenomenon. These results suggest that the expression of PC-1 downstream of FGF signaling is an integral aspect of osteoblastic function, and that pyrophosphate elaboration may play a significant role in the pathology of craniosynostosis.
2003-05-01 | Delivery of Transforming Growth Factor-β2-Perturbing Antibody in a Collagen Vehicle Inhibits Cranial Suture Fusion in Calvarial Organ Culture
Objective To determine whether antibody perturbation of Tgf-β, delivered in a collagen gel, could inhibit cranial suture fusion. Design Attachment and proliferation of osteoblasts cultured on a collagen gel with or without anti-Tgf-β2 antibody were determined by AlamarBlue dye assay and cell morphology by toluidine-blue staining. In rat calvarial organ culture, collagen gel with and without anti-Tgf-β2 antibody was injected subperiosteally over the posterior frontal suture of postnatal day 15 rat calvariae. A quantitative analysis of suture fusion was used to measure suture bridging in histological serial sections at various time points. Results Attachment and proliferation for cells cultured on collagen gel with anti-Tgf-β2 antibody were similar to collagen gel controls. Although proliferation was lower than on tissue culture plastic, cells treated with anti-Tgf-β2 antibody maintained an osteoblastic morphology. After 7, 10, and 15 days in organ culture, anti-Tgf-β2 antibody treatment caused a reduction in the percent bridging of posterior frontal sutures, compared with controls. Sutures exposed to anti-Tgf-β2 antibody and fibroblast growth factor-2 concurrently did not show an inhibition of bony bridging. Conclusions These results support previous reports suggesting a role for Tgf-β2 in cranial suture fusion. In cell culture the collagen gel, both with and without anti-Tgf-β2 antibody, promoted similar osteoblast attachment, proliferation, and osteoblastic morphology. In organ culture anti-Tgf-β2 antibody was delivered in a bioactive state via a collagen gel to inhibit cranial suture fusion. Also, the results suggest that the inductive effect of fibroblast growth factor-2 is not dependent on Tgf-β2 activity. Together, these results provide further support for the role of Tgf-β2 in cranial suture fusion.
2002-03-01 | Blocking Endogenous FGF-2 Activity Prevents Cranial Osteogenesis
Normal growth and morphogenesis of the cranial vault reflect a balance between cell proliferation in the sutures and osteogenesis at the margins of the cranial bones. In the clinical condition craniosynostosis, the sutures fuse prematurely as a result of precocious osteogenic differentiation and craniofacial malformation results. Mutations in several fibroblast growth factor receptor (FGFR) genes have now been identified as being responsible for the major craniosynostotic syndromes. We have used a grafting technique to manipulate the levels of endogenous FGF-2 ligand in embryonic chick cranial vaults and thereby perturb morphogenesis. Implantation of beads loaded with FGF-2 did not affect normal cranial development at physiological concentrations, although they elicited a morphogenetic response in the limb. Implantation of beads loaded with a neutralising antibody to FGF-2 generated a concentration-dependent response. When a single bead was implanted, the grafts grew to a massive size as a result of increased cell division in the tissue. With greater inactivation of FGF-2 protein (two to three beads implanted), all further bone differentiation and cell proliferation was blocked. These data further support the emerging idea that the intensity of FGF-mediated signalling determines the developmental fate of the skeletogenic cells in the cranial vault. High and low levels correlate with differentiation and proliferation, respectively. A balance between the two ensures normal cranial vault morphogenesis. This is consistent with the observation that several FGFR mutations causing craniosynostosis result in constitutive activation of the receptor.
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