RARE DISEASE
Apert syndrome
Apert syndrome
Apert syndrome
Synonyms: ACS1, Acrocephalosyndactyly type 1
Synonyms: ACS1, Acrocephalosyndactyly type 1
Synonyms: ACS1, Acrocephalosyndactyly type 1
Drug discovery
484
papers
On emerging therapies
Overview
Apert syndrome is a rare autosomal dominant disorder caused by FGFR2 mutations, characterized by bicoronal craniosynostosis, midface hypoplasia, and complex syndactyly of hands/feet. Associated features include craniofacial anomalies, dental crowding, developmental delays, and multisystem involvement (cardiovascular, respiratory, CNS). Diagnosis relies on clinical evaluation and molecular testing [1][2][7][13].
Burden
Functional impairments: Airway obstruction, vision/hearing deficits, and limited manual dexterity [2][6][13].
Requires 15–30 surgeries lifetime; 85% risk of intracranial hypertension without intervention [6][8][16].
Psychosocial impact: Chronic care needs, reduced quality of life, and familial financial/emotional strain [3][8][10].
Therapies
Surgical: Craniosynostosis repair (6–8 months), midface advancement (5–12 years), and staged syndactyly release [3][12][15].
Multidisciplinary care: Neurosurgery, orthodontics, ophthalmology, speech/occupational therapy, and psychosocial support [8][10][13].
Adjunctive interventions: CPAP for obstructive sleep apnea, prophylactic eyedrops, and early developmental interventions [14][15][16].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare surgical maxillo-facial diseases
Research Papers
484 drug discovery papers about Apert syndrome. Recent publications:
484 drug discovery papers about Apert syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-04-10 | ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells.
While Fgf and Hippo-Yap signaling are fundamental for proper development, homeostasis, and disease, their crosstalk remains largely unknown. Here, we identified that Yap and Taz, canonical Hippo effectors, function as noncanonical effectors of Fgf signaling to maintain the proper function of neural crest (NC) lineages. NC cells are a multipotent stem cell population during vertebrate embryogenesis that contribute to numerous structures and diverse cell lineages, including craniofacial and cardiac tissues, neurons, and suture mesenchymal cells (SMCs), a specified cell population required for cranial bone growth and repair. We observed that activation of Fgf signaling in NC cells and NC-derived SMCs inhibited osteogenesis while simultaneously enhancing stemness and proliferation. Interestingly, these effects were reversed by inhibition of either Yap/Taz or phosphorylated Erk1/2 (pErk1/2). Mechanistically, Fgf signaling promotes the interaction of Yap and pErk1/2, increasing the chromatin occupancy of Yap at genes regulating stemness, proliferation, and osteogenesis. We further show that pERK1/2 phosphorylates YAP at the noncanonical S128 site, enhancing YAP's nuclear localization. This mechanism is conserved across mouse and human cells and is active in Apert syndrome-associated FGF gain-of-function models, revealing a previously unrecognized FGF-YAP axis in stem cell regulation.
2026-01-01 | Molecular Genetics and Pathophysiology
Abstract This chapter discusses the genetic mutations that cause Apert syndrome, how these lead to its characteristic clinical manifestations, and how the two canonical heterozygous mutations (which encode the amino acid substitutions p.Ser252Trp and p.Pro253Arg, located in the extracellular part of the fibroblast growth factor [FGF] receptor 2 [FGFR2] protein) were discovered. The structural basis by which these substitutions differentially enhance binding affinity for specific FGF ligands is reviewed; this ligand-dependent gain-of-function mechanism explains the distinct genotype–phenotype correlations for skull and limb malformations. Rare individuals with Apert syndrome caused by distinct FGFR2 mutations are enumerated and the mechanisms underlying their phenotypic similarity to the canonical substitutions are presented. The germline rates for the two canonical mutations in FGFR2 (c.755C>G and c.758C>G) are among the highest in the human genome. The mutations arise exclusively from the unaffected father, exhibit a paternal age effect, and are attributable to “selfish” positive selection of mutant spermatogonial stem cells in the testis. The engineering of mouse mutants harboring genotypically equivalent Apert mutations helps to elucidate the developmental pathology of craniosynostosis and implicates activation of the RAS–MAP kinase pathway as a critical mediator of many clinical features of Apert syndrome. Approaches to targeted genetic or pharmacological therapies are discussed, although these will be challenging to implement given the early onset of pathogenesis in the embryo.
2025-08-22 | Generation of three human induced pluripotent stem cell lines from FGFR2-linked syndromic craniosynostosis patients.
Craniosynostosis is a multigenic congenital condition in which one or more calvarial sutures have prematurely fused during the development of the fetus. Mutation in FGFR2 are associated with the development of syndromic craniosynostosis, such as Crouzon, Apert, and Pfeifer Syndrome. Investigation of FGFR2-linked craniosynostosis is hindered by the lack of appropriate in vitro models. Patient-derived human induced pluripotent stem cell (hiPSC) in vitro disease models provide the opportunity to investigate the disease, identify molecular targets for pharmaceutical treatments, and enable the generation of autologous pluripotent stem cell catalogues. Here, we report three patient-derived hiPSC lines carrying the FGFR2 mutation C342Y, S252W, or E565G, respectively. The patient hiPSC lines express characteristic pluripotency markers, and display distinct phosphorylation profiles under unstimulated conditions. The FGFR2C342Y shows autophosphorylation in the absence of bFGF ligand, although downstream docking proteins PLCγ and FRS2α are not phosphorylated. FGFR2S252W and FGFR2E565G hiPSCs possess increased phosphorylation of docking proteins PLCγ and FRS2α while FGFR2 is not phosphorylated. These patient hiPSC lines provide molecular and cellular options to investigate FGFR2-linked craniosynostosis in the patient-specific genomic context and develop therapeutic modalities.
2025-07-24 | Silver-modified atraumatic restorative technique approach to dental and craniofacial care in Apert syndrome: a case-based perspective
Apert syndrome is a rare congenital disorder first noted by Wheaton in 1894 and more precisely described by Eugene Apert in 1906. It is primarily characterized by craniosynostosis, midfacial hypoplasia, and complex syndactyly of the hands and feet, along with various systemic and oral abnormalities. The syndrome is estimated to occur in approximately 1 in 1,60,000 live births and typically follows an autosomal dominant inheritance pattern. Most cases are associated with spontaneous mutations in the fibroblast growth factor receptor 2 (FGFR2) gene, which plays a crucial role in bone development and tissue formation. This case report details the clinical and dental management of a 4-year-old female who was diagnosed with Apert syndrome at birth. The patient presented with hallmark craniofacial features such as a high, prominent forehead, flat midface, syndactyly affecting both hands and feet, and notably delayed developmental milestones. She had a history of undergoing multiple surgical interventions, including cranial vault reconstruction to alleviate intracranial pressure and syndactyly release procedures to improve hand functionality. Intraorally, the patient showed maxillary hypoplasia, a high-arched palate, delayed eruption of primary teeth, dental crowding, and multiple carious lesions. Dental care was tailored to her special healthcare needs, utilizing the silver-modified atraumatic restorative technique (SMART), which involves the use of silver diamine fluoride and glass ionomer cement to arrest caries and restore teeth in a minimally invasive manner. A preventive oral health plan, including dietary counselling, fluoride varnish application, and regularly scheduled recall visits, was instituted to maintain long-term dental and overall well-being.
2025-04-21 | FGFR2 residence in primary cilia is necessary for epithelial cell signaling.
Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues. In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.
proteins
2021-10-04 | Effect of Fibroblast Growth Factor 2 on Extraocular Muscle Structure and Function.
Mutations in the fibroblast growth factor (FGF) receptor can result in strabismus, but little is known about how FGFs affect extraocular muscle structure and function. These were assessed after short-term and long-term exposure to exogenously applied FGF2 to determine the effect of enhanced signaling. One superior rectus muscle of adult rabbits received either a series of three injections of 500 ng, 1 µg, or 5 µg FGF2 and examined after 1 week, or received sustained treatment with FGF2 and examined after 1, 2, or 3 months. Muscles were assessed for alterations in force generation, myofiber size, and satellite cell number after each treatment. One week after the 5 µg FGF2 injections, treated muscles showed significantly increased force generation compared with naïve controls, which correlated with increased myofiber cross-sectional areas and Pax7-positive satellite cells. In contrast, 3 months of sustained FGF2 treatment resulted in decreased force generation, which correlated with decreased myofiber size and decreased satellite cells compared with naïve control and the untreated contralateral side. FGF2 had distinctly different effects when short-term and long-term treatments were compared. The decreased size and ability to generate force correlated with decreased myofiber areas seen in individuals with Apert syndrome, where there is sustained activation of FGF signaling. Knowing more about signaling pathways critical for extraocular muscle function, development, and disease will pave the way for improved treatment options for strabismus patients with FGF abnormalities in craniofacial disease, which also may be applicable to other strabismus patients.
2018-09-28 | Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse.
FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative for multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that both the activation (Fgfr2cC342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2cnull) of the FGFR2c isoform can drive suture abolishment. This study aims to address the downstream effects of pathogenic FGFR2c signalling by studying the effects of Fgfr2c overexpression. Conditional overexpression of Fgfr2c (R26RFgfr2c;βact) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2cnull and Fgfr2cC342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2cC342Y and R26RFgfr2c;βact mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2cC342Y and R26RFgfr2c;βact mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2cC342Y), in particular to the coronal suture. Our results demonstrate that Fgfr2c overexpression is sufficient to partially rescue craniosynostosis through increased proliferation and reduced osteogenic activity in E18.5 Fgfr2cC342Y embryos. This study demonstrates the intricate balance of FGF signalling required for correct calvarial bone and suture morphogenesis, and that increasing the expression of the wild-type FGFR2c isoform may be a way to prevent or delay craniosynostosis progression.
2017-06-26 | Inducible Activation of FGFR2 in Adult Mice Promotes Bone Formation After Bone Marrow Ablation
ABSTRACT Apert syndrome is one of the most severe craniosynostoses, resulting from gain-of-function mutations in fibroblast growth factor receptor 2 (FGFR2). Previous studies have shown that gain-of-function mutations of FGFR2 (S252W or P253R) cause skull malformation of human Apert syndrome by affecting both chondrogenesis and osteogenesis, underscoring the key role of FGFR2 in bone development. However, the effects of FGFR2 on bone formation at the adult stage have not been fully investigated. To investigate the role of FGFR2 in bone formation, we generated mice with tamoxifen-inducible expression of mutant FGFR2 (P253R) at the adult stage. Mechanical bone marrow ablation (BMX) was performed in both wild-type and Fgfr2 mutant (MT) mice. Changes in newly formed trabecular bone were assessed by micro-computed tomography and bone histomorphometry. We found that MT mice exhibited increased trabecular bone formation and decreased bone resorption after BMX accompanied with a remarkable increase in bone marrow stromal cell recruitment and proliferation, osteoblast proliferation and differentiation, and enhanced Wnt/β-catenin activity. Furthermore, pharmacologically inhibiting Wnt/β-catenin signaling can partially reverse the increased trabecular bone formation and decreased bone resorption in MT mice after BMX. Our data demonstrate that gain-of-function mutation in FGFR2 exerts a Wnt/β-catenin-dependent anabolic effect on trabecular bone by promoting bone formation and inhibiting bone resorption at the adult stage. © 2017 American Society for Bone and Mineral Research.
2016-08-15 | Cell Type-Dependent Nonspecific Fibroblast Growth Factor Signaling in Apert Syndrome
Apert Syndrome (AS) is one of the most severe forms of craniosynostosis. It is caused by gain-of-function mutations in the receptor fibroblast growth factor receptor 2 (FGFR2), which leads to ligand-receptor promiscuity. Here, we aimed to better understand the behavior of mesenchymal stem cells (MSCs) and of fibroblastoid cells, cellular populations that are part of the suture complex, when stimulated with different fibroblast growth factors (FGFs). We also aimed to verify whether FGFR2 specificity loss due to AS mutations would change their signaling behavior. We tested this hypothesis through cell proliferation and differentiation assays and through gene expression profiling. We found that FGF19 and FGF10 increase proliferation of fibroblastoid cells harboring the FGFR2 p.S252W mutation, but not of mutant MSCs. FGF19 and FGF10 were associated with different expression profiles in p.S252W cells. Further, in accordance to our gene expression microarray data, FGF19 decreases bone differentiation rate of mutant fibroblastoid cells and increases bone differentiation rate of MSCs. This effect in osteogenesis appears to be mediated by BMP signaling. The present data indicate that non-natural FGFR2 ligands, such as FGF10 and FGF19, are important factors in the pathophysiology of AS. Further research is needed to determine the role of modulation of MSC proliferation or use of FGF19 or anti-BMP2 as inhibitors of osteogenesis in AS subjects’ cells, and whether these findings can be used in the clinical management of AS.
2015-02-18 | Inhibited Wnt Signaling Causes Age-Dependent Abnormalities in the Bone Matrix Mineralization in the Apert Syndrome FGFR2S252W/+ Mice
Apert syndrome (AS) is a type of autosomal dominant disease characterized by premature fusion of the cranial sutures, severe syndactyly, and other abnormalities in internal organs. Approximately 70% of AS cases are caused by a single mutation, S252W, in fibroblast growth factor receptor 2 (FGFR2). Two groups have generated FGFR2 knock-in mice Fgfr2S252W/+ that exhibit features of AS. During the present study of AS using the Fgfr2S252W/+ mouse model, an age-related phenotype of bone homeostasis was discovered. The long bone mass was lower in 2 month old mutant mice than in age-matched controls but higher in 5 month old mutant mice. This unusual phenotype suggested that bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to maintain bone homeostasis, might be involved. BMSCs were isolated from Fgfr2S252W/+ mice and found that S252W mutation could impair osteogenic differentiation BMSCs but enhance mineralization of more mature osteoblasts. A microarray analysis revealed that Wnt pathway inhibitors SRFP1/2/4 were up-regulated in mutant BMSCs. This work provides evidence to show that the Wnt/β-catenin pathway is inhibited in both mutant BMSCs and osteoblasts, and differentiation defects of these cells can be ameliorated by Wnt3a treatment. The present study suggested that the bone abnormalities caused by deregulation of Wnt pathway may underlie the symptoms of AS.
cell therapies
2026-06-01 | 32. Vertical Remodeling and Cranial Growth Following Staged Endoscopic Strip Craniectomy and Posterior Vault Distraction in Syndromic Bicoronal Craniosynostosis
Background: Syndromic bicoronal craniosynostosis leads to turribrachycephaly and restricted cranial volume, posing challenges for both aesthetics and neurodevelopment. Endoscopic strip craniectomy (ESC) and posterior vault distraction osteogenesis (PVDO) have individually advanced early cranial expansion, yet outcomes following a staged ESC + PVDO approach remain poorly defined. Methods: A retrospective review (2020-2025) identified patients undergoing ESC (1-3 months) followed by PVDO (6-8 months). CT-based turricephaly index (TI; anterior-posterior/sella-vertex ratio), cephalic index (CI), and head-circumference (HC) z-scores were compared across time points (pre-ESC, post-ESC, post-PVDO) and against normative data. Results: Five patients (60 % female; 3 Apert, 1 Muenke, 1 unspecified) were included. Mean age was ~59 days at ESC and ~214 days at PVDO. TI remained stable post-ESC (1.29 → 1.28, p = 0.68) but significantly increased after PVDO (1.28 → 1.38, p = 0.05). HC z-scores improved stepwise (−0.93 → −0.69 → +0.28), with significant gain post-PVDO (Δ +0.98, p = 0.047). Median HC percentile rose 17.7 %, while CI remained stable (93.0 → 93.4, p = 0.83). Conclusion: A staged ESC + PVDO paradigm yields progressive normalization of cranial growth and vertical remodeling in syndromic bicoronal craniosynostosis. Early ESC provides limited decompression, whereas PVDO achieves significant volumetric and morphologic correction. This protocol represents a reproducible, innovation-driven framework for comprehensive, growth-adaptive cranial reconstruction.
2026-02-27 | Morphological analysis of posterior fossa in Apert and Crouzon syndromes before and after posterior cranial vault expansion.
Syndromic craniosynostosis, such as Apert and Crouzon syndromes, involve premature fusion of cranial sutures, leading to cranial deformities and potential neurological complications. Posterior cranial vault expansion (PCVE) is commonly used to address intracranial volume (ICV) anomalies in these cases, especially in the posterior fossa region. However, the morphological variation of this region between normal, Apert and Crouzon individuals remains understudied. This study aimed to carry out a detailed morphological analysis of the posterior fossa between the aforementioned groups before and after PCVE. Retrospective computed tomography (CT) data from 28 children with Apert (n = 13) and Crouzon (n = 15) syndromes, alongside 51 age-matched controls, were analyzed. Intracranial and posterior fossa volumes (ICV and PFV) were computed pre- and post-operatively. Morphometric shape analyses were conducted for posterior fossa and intracranial cavity using principal component analysis (PCA). Pre-operatively, Apert syndrome patients exhibited larger PFV and ICV compared to Crouzon syndrome patients and controls (e.g., p = 0.009 for pre-operative Apert vs. controls), while Crouzon syndrome patients showed more variability in PFV and ICV. Post-operatively, Apert patients demonstrated significant increases in both PFV and PFV/ICV ratios (e.g., post-operative vs. pre-operative PFV: p < 0.001). In contrast, Crouzon patients exhibited limited improvements in PFV, with PFV/ICV ratios often declining post-surgery (p = 0.890; median post-operative-pre-operative difference = -0.095). PCA revealed distinct intracranial and posterior fossa shape differences between Apert and Crouzon patients. While PCVE increased posterior fossa volume, it did not appear to improve posterior fossa shape in either Apert or Crouzon patients. Future studies are required to address the limitations of small sample sizes, lack of post-operative data on Chiari anomaly, and surgical variability to further explore possible correlations between the aforementioned parameters.
2026-01-01 | Management of the Posterior Vault
Abstract Traditionally, the first surgical procedure to enlarge the vault in an infant with Apert syndrome was the fronto-orbital advancement. In 2009, teams from two large craniofacial centers located in Philadelphia (USA) and Rotterdam (Netherlands) both switched to a routine posterior vault expansion with distraction. The outcomes of this procedure have significantly improved—with fewer reoperations and a lower prevalence of raised intracranial pressure and/or Chiari malformation during follow-up—while the rate of complications has remained low.
2026-01-01 | Segmental Subcranial Midface Osteotomies: Le Fort II with Zygomatic Repositioning
Abstract Unlike the midface hypoplasia associated with Crouzon syndrome, Apert facial dysmorphology has been described as an abnormal face in an abnormal position. The Apert midface deformity is characterized by a dual concavity, with more severe deficiency in both the sagittal and vertical dimensions of the central midface relative to the lateral face. En bloc Le Fort III subcranial advancement cannot correct this unique dysmorphology and moves an abnormal face into a more normal position. Segmental approaches such as Le Fort II distraction with zygomatic repositioning (LF2ZR) or bipartition frontofacial distraction are better suited to correct the Apert facial ratios. They combine the benefits of distraction osteogenesis with the directional control of traditional techniques to create differential movements. Both techniques have benefits and disadvantages, so each case of Apert syndrome should be analyzed before midface surgery to determine which approach would best treat the most dominant aspect of dysmorphology.
2025-10-22 | Positive Impact of Frontofacial Advancement on Intracranial Volumes in Patients With Syndromic Craniofaciosynostosis.
Le Fort (LF) III midface distraction osteogenesis is one of the main techniques for correcting midface deficiency encountered in craniofaciosynostosis. However, regardless of the technique used, there may be a deterioration in the result, with a recurrence of facial hypoplasia, requiring a new procedure to advance the midface. In this retrospective study, computed tomography scans before and after LF III distraction osteogenesis of 7 patients (3 boys and 2 girls with Crouzon syndrome, 1 boy with Apert syndrome, and 1 boy with Pfeiffer syndrome) were analyzed in vestibular orientation. The ages ranged from 4 to 11 years old. All patients presented with syndromic craniofaciosynostosis with class III malocclusion and proptosis. The 3 cranial fossae were segmented slice by slice, and their volumes were calculated. The total intracranial volume was calculated by summing the volumes of the 3 cranial fossae. The Wilcoxon signed-rank test was used to compare the measured values before and after LF III distraction. A P value of less than 0.05 was considered statistically significant. Total intracranial volume significantly increased (6%; P = 0.016) in the total study group. Volumes of the anterior and middle cranial fossae increased insignificantly (22.6%, P = 0.33; 4.8%, P = 0.29). The volume of the posterior cranial fossae insignificantly decreased (0.3%, P = 0.58). A significant increase in total intracranial volume after LF III advancement in syndromic craniofaciosynostosis patients was reported.
oligonucleotides
2023-07-17 | Exosome-mediated small interfering RNA delivery inhibits aberrant osteoblast differentiation in Apert syndrome model mice.
Apert syndrome, an autosomal dominant congenital disorder characterized by craniosynostosis, is caused by a missense mutation (S252W or P253R) in fibroblast growth factor receptor 2 (FGFR2). Exosomes are naturally occurring carriers that deliver nucleic acids, including small interfering RNA (siRNA), to induce gene silencing. This study aimed to develop siRNA-loaded exosomes (Ex-siRNAFgfr2S252W) to silence the Fgfr2S252W gain-of-function mutation, thereby inhibiting the increased osteoblastic differentiation caused by the constitutive activation of FGFR2 signaling in calvarial osteoblastic cells isolated from Apert syndrome model mice. Primary calvarial osteoblast-like cells were isolated from the embryonic calvarial sutures of the Apert syndrome model (Fgfr2S252W/+) and littermate wild-type mice (Ap-Ob and Wt-Ob, respectively). Exosomes were extracted from the serum of wild-type mice, validated using biomarkers, and used to encapsulate siRNAs. After exosome-mediated siRNA transfection, cells were analyzed under a fluorescence microscope to validate the delivery of Ex-siRNAFgfr2S252W, followed by western blot and real-time reverse transcription polymerase chain reaction analyses. After 24 h of Ex-siRNAFgfr2S252W delivery in both Ap-Ob and Wt-Ob, siRNA-loaded exosome delivery was validated. Moreover, p44/42 mitogen-activated protein kinase (MAPK) phosphorylation, runt-related transcription factor 2 (Runx2), and collagen type 1 alpha 1 (Col1a1) mRNA expression, and alkaline phosphatase (ALP) activity were significantly increased in Ap-Ob. The levels of phospho-p44/42 protein, Runx2, Col1a1, and ALP were significantly decreased after Ex-siRNAFgfr2S252W transfection but did not affect Wt-Ob. These results indicate that exosome-mediated delivery of siRNA targeting Fgfr2S252W is a potential non-invasive treatment for aberrant FGF/FGFR signaling.
2018-09-22 | Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model
Apert syndrome (AS), the most severe form of craniosynostosis, is caused by missense mutations including Pro253Arg(P253R) of fibroblast growth factor receptor 2 (FGFR2), which leads to enhanced FGF/FGFR2-signaling activity. Surgical correction of the deformed skull is the typical treatment for AS. Because of constant maldevelopment of sutures, the corrective surgery is often executed several times, resulting in increased patient challenge and complications. Biological therapies targeting the signaling of mutant FGFR2 allele, in combination with surgery, may bring better outcome. Here we screened and found a small interfering RNA (siRNA) specifically targeting the Fgfr2-P253R allele, and we revealed that it inhibited osteoblastic differentiation and matrix mineralization by reducing the signaling of ERK1/2 and P38 in cultured primary calvarial cells and calvarial explants from Apert mice (Fgfr2+/P253R). Furthermore, AAV9 carrying short hairpin RNA (shRNA) (AAV9-Fgfr2-shRNA) against mutant Fgfr2 was delivered to the skulls of AS mice. Results demonstrate that AAV9-Fgfr2-shRNA attenuated the premature closure of coronal suture and the decreased calvarial bone volume of AS mice. Our study provides a novel practical biological approach, which will, in combination with other therapies, including surgeries, help treat patients with AS while providing experimental clues for the biological therapies of other genetic skeletal diseases.
2013-08-16 | Smad7 Modulates TGFβ Signaling During Cranial Suture Development to Maintain Suture Patency
ABSTRACT Craniosynostosis, the premature fusion of one or more sutures between the calvarial bones, is a common birth defect. Mutations in genes encoding receptors for the transforming growth factor-beta (TGFβ) family of signaling molecules have been associated with craniosynostosis, but how TGFβ signaling is regulated during suture development is not known. In the present study, we found that expression of Smad2 and Smad3, intracellular mediators of canonical TGFβ signaling, gradually increases during early postnatal suture development in rat in both the coronal suture (CS), which remains patent throughout life, and the posterior frontal suture (PFS), which undergoes programmed closure by postnatal day 22. The amounts of phosphorylated Smad2 and Smad3 proteins showed a similar gradual increase in the PFS and CS, but in the CS, Smad2/3 activation was suppressed after neonatal day 10. The suppression of Smad2/3 activation in the CS correlated with upregulation of Smad7 expression. We demonstrate that siRNA-mediated knockdown of Smad7 caused increased phosphorylation of Smad2 and Smad3 and induced osseous obliteration of the CS from postnatal days 10 to 22. The Smad7 siRNA-induced CS closure was associated with significantly increased levels of Fgf10 and phosphorylated ERK1/2 in the suture mesenchyme. Moreover, addition of the Erk1/2 inhibitor U0126 partially blocked Smad7-siRNA–induced CS closure. These findings suggest that canonical TGFβ signaling induces suture closure at least in part through activation of FGF and ERK signaling and that Smad7 plays an important role in maintaining suture patency by suppressing canonical TGFβ signaling during suture development. © 2014 American Society for Bone and Mineral Research.
2012-05-24 | MT1-MMP Inactivates ADAM9 to Regulate FGFR2 Signaling and Calvarial Osteogenesis
MMP14 encodes a membrane-tethered metalloproteinase MT1-MMP, capable of remodeling the extracellular matrix and modulating receptors on the cell surface. Loss of MT1-MMP results in craniofacial abnormalities. Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface. In Mmp14−/− osteoblasts, FGF-induced proliferation and downstream signaling are specifically compromised, in conjunction with ADAM9 upregulation and FGFR2 shedding. The retarded parietal growth in Mmp14−/− embryos starts at 15.5 dpc, attributable to the impaired FGFR2 signaling due to increased shedding mediated by ADAM9. Adam9 depletion completely rescues the defective FGFR2 signaling and largely restores calvarial bone growth in Mmp14−/− embryos. These data reveal a regulatory paradigm for FGRF2 signaling and identify MT1-MMP as a critical negative modulator of ADAM9 activity to maintain FGFR2 signaling in calvarial osteogenesis.
2009-10-01 | Fibroblast Growth Factor 10 Plays a Causative Role in the Tracheal Cartilage Defects in a Mouse Model of Apert Syndrome
Patients with Apert syndrome (AS) display a wide range of congenital malformations including tracheal stenosis, which is a disease characterized by a uniform cartilaginous sleeve in place of a normally ribbed cartilagenous trachea. We have studied the cellular and molecular basis of this phenotype in a mouse model of AS (Fgfr2c+/Δ mice), which shows ectopic expression of Fgfr2b in mesenchymal tissues. Here we report that tracheal stenosis is associated with increased proliferation of mesenchymal cells, where the expression of Fgf10 and its upstream regulators Tbx4 and Tbx5 are abnormally elevated. We show that Fgf10 has a critical inductive role in tracheal stenosis, as genetic knockdown of Fgf10 in Fgfr2c+/Δ mice rescues this phenotype. These novel findings demonstrate a regulatory role for Fgf10 in tracheal development and shed more light on the underlying cause of tracheal defects in AS.
other
2026-02-27 | The Impact of Genetics on Craniofacial Dysplasias and Consequent Oral Malformations-Integrative Review.
Diseases affecting the craniofacial skeleton are normally associated with disturbances in the regulation of cellular differentiation, the development of bone structures, and changes in bone density and ossification. Thus, the objective of this integrative review is to evaluate the published scientific literature from the last 8 years concerning the impact of genetics on some craniofacial dysplasias. Our aim covers the identification of oral cavity alterations to those dysplasias, through the most common orofacial manifestations. Three dysplasias were selected to be part of this integrative review: cleidocranial dysplasia, ectodermal dysplasia and Apert syndrome. For this purpose, a bibliographic search was performed in the PubMed, ScienceDirect, Web of Science and Google Scholar databases with several keywords combined with each other. The research question of this review was as follows: "What is the impact of genetic factors on the development of craniofacial dysplasias and associated oral malformations?". After selecting the articles through the application of inclusion and exclusion criteria, 11 articles were selected for this review. Genetics plays a crucial role in craniofacial dysplasias and subsequent oral malformations. The main conclusion was that mutations in different genes can lead to identical phenotypes, while mutations in the same gene can present slight phenotypic differences depending on where they occur. In the future, it would be important to conduct studies with larger samples and control groups that include genetic testing to allow for a more comprehensive study on the impact of genetics on craniofacial dysplasias.
2026-02-04 | Tracheal cartilaginous sleeve prevalence in syndromic craniosynostosis: A single institution study.
This study aimed to evaluate the incidence of tracheal cartilaginous sleeve (TCS) among syndromic craniosynostosis patients, as well as describe their genetic profiles, associated co-morbidities, and operative outcomes. We performed a retrospective analysis of syndromic craniosynostosis patients (Apert, Crouzon, and Pfeiffer) at a single tertiary academic center between January 1, 2002, and February 1, 2024. 39 patients with syndromic craniosynostosis were identified, with 17 patients (17/39, 43.6%) undergoing airway evaluation. 1 patient (1/17, 5.9%) was diagnosed with TCS, but 5 patients (5/17, 29.4%) had other airway abnormalities, all reflecting abnormalities of the airway wall or some type of airway stenosis. 28 patients (28/39, 73.7%) presented with a diagnosis of OSA, and 7 patients (7/39, 17.9%) of patients presented with choanal anomaly (atresia or stenosis). 32 patients (32/39, 82.1%) had genetic sequencing information available, with the most common mutations affecting p.P253R within the FGFR2 gene in 7 patients. No patients in our cohort presented with a p.W290 mutation and 7 patients presented with a p.C342 mutation, of which 4 patients had the p.C342Y mutation. The true prevalence of TCS may be likely lower than prior reports, which may aid with alleviating some familial anxiety and provide additional context and data for medical counseling and decision-making. Nonetheless, all patients should be strongly recommended to undergo airway evaluation given the risks associated with TCS, the high prevalence of structural airway anomalies, and the overall low risk of airway evaluation.
2023-11-29 | Unraveling the Complexity of Apert Syndrome: Genetics, Clinical Insights, and Future Frontiers.
Apert syndrome (AS), also known as type I acrocephalosyndactyly, is a rare congenital condition characterized by craniosynostosis resulting from missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. This comprehensive review delves into AS, covering its clinical manifestations, genetics, diagnosis, medical management, psychosocial considerations, and future research directions. AS presents with distinct features, including a brachycephalic skull, midface hypoplasia, and limb anomalies such as syndactyly. It follows an autosomal dominant inheritance pattern with mutations in the FGFR2 gene. Prenatal diagnosis is possible through advanced imaging techniques and molecular testing. The multidisciplinary approach to AS management involves surgical interventions, orthodontics, and psychological support. Although no curative treatment exists, early interventions can significantly improve function and aesthetics. The quality of life for AS patients is influenced by psychosocial factors, necessitating comprehensive support for both patients and their families. Future research directions include gene therapy, understanding cellular responses to FGFR2 mutations, and addressing genetic heterogeneity. Collaborative efforts are vital to advancing knowledge about AS and its genetic underpinnings. Overall, this review serves as a valuable resource for healthcare professionals, educators, and researchers, contributing to a deeper understanding of AS and facilitating advancements in diagnosis and treatment.
2023-07-31 | Molecular Scalpels: The Future of Pediatric Craniofacial Surgery?
CRISPR-Cas genome editing tools are among the most substantial advances in the life sciences in modern history. Single-dose gene therapies to correct pathogenic mutations have moved quickly from bench to bedside, with several therapeutics designed by CRISPR pioneers entering various stages of clinical investigation. Applications of these genetic technologies are poised to reshape the practice of both medicine and surgery. Many of the most morbid conditions treated by craniofacial surgeons are syndromic craniosynostoses caused by mutations in fibroblast growth factor receptor genes, including Apert, Pfeiffer, Crouzon, and Muenke syndromes. The fact that pathogenic mutations in these genes are recurrent in the majority of affected families presents a unique opportunity to develop "off-the-shelf" gene editing therapies to correct these mutations in affected children. The therapeutic potential of these interventions could reshape pediatric craniofacial surgery, potentially first eliminating the need for midface advancement procedures in affected children.
2022-10-18 | The potential role for phage therapy for genetic modification of cutaneous diseases.
Antimicrobial resistance has become increasingly common across the globe, claiming more than 33,000 lives annually in Europe and 35,000 lives in the United States alone. The problem lies in trying to find potential solutions capable of tackling resistance and being able to fight infections that may resist various antimicrobials. Since Alexander Fleming's discovery in 1928, every antimicrobial synthesized in the past 70 years has developed at least one or more strains of resistant bacteria. One particular alternative to antimicrobials has brought hope to many in the scientific community: the bacteriophage. Bacteriophages are viruses that can replicate within bacteria, triggering genetic alterations and changes in pathways of protein expression by encoding a few to hundreds of genes within their genomes. The bacteriophage can hijack the cell, using the cell's genetic apparatus to replicate within the bacterium until bacterial lysis occurs. This therapy has been used in the genodermatosis Netherton syndrome, which has been associated with the increased risk of Staphylococcus aureus infections. Emerging data support the potential role of bacteriophage therapy for Cutibacterium acnes in acne vulgaris, with a potential role in genetic disorders with severe acne vulgaris, including Apert syndrome. Bacteriophages hold benefits for genodermatoses associated with recurrent cutaneous infections, that is, the immunodeficiencies with distinctive cutaneous features as well as conditions such as atopic dermatitis, in which bacterial colonization plays a strong role.
small molecules
2026-04-10 | ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells.
While Fgf and Hippo-Yap signaling are fundamental for proper development, homeostasis, and disease, their crosstalk remains largely unknown. Here, we identified that Yap and Taz, canonical Hippo effectors, function as noncanonical effectors of Fgf signaling to maintain the proper function of neural crest (NC) lineages. NC cells are a multipotent stem cell population during vertebrate embryogenesis that contribute to numerous structures and diverse cell lineages, including craniofacial and cardiac tissues, neurons, and suture mesenchymal cells (SMCs), a specified cell population required for cranial bone growth and repair. We observed that activation of Fgf signaling in NC cells and NC-derived SMCs inhibited osteogenesis while simultaneously enhancing stemness and proliferation. Interestingly, these effects were reversed by inhibition of either Yap/Taz or phosphorylated Erk1/2 (pErk1/2). Mechanistically, Fgf signaling promotes the interaction of Yap and pErk1/2, increasing the chromatin occupancy of Yap at genes regulating stemness, proliferation, and osteogenesis. We further show that pERK1/2 phosphorylates YAP at the noncanonical S128 site, enhancing YAP's nuclear localization. This mechanism is conserved across mouse and human cells and is active in Apert syndrome-associated FGF gain-of-function models, revealing a previously unrecognized FGF-YAP axis in stem cell regulation.
2026-01-01 | Molecular Genetics and Pathophysiology
Abstract This chapter discusses the genetic mutations that cause Apert syndrome, how these lead to its characteristic clinical manifestations, and how the two canonical heterozygous mutations (which encode the amino acid substitutions p.Ser252Trp and p.Pro253Arg, located in the extracellular part of the fibroblast growth factor [FGF] receptor 2 [FGFR2] protein) were discovered. The structural basis by which these substitutions differentially enhance binding affinity for specific FGF ligands is reviewed; this ligand-dependent gain-of-function mechanism explains the distinct genotype–phenotype correlations for skull and limb malformations. Rare individuals with Apert syndrome caused by distinct FGFR2 mutations are enumerated and the mechanisms underlying their phenotypic similarity to the canonical substitutions are presented. The germline rates for the two canonical mutations in FGFR2 (c.755C>G and c.758C>G) are among the highest in the human genome. The mutations arise exclusively from the unaffected father, exhibit a paternal age effect, and are attributable to “selfish” positive selection of mutant spermatogonial stem cells in the testis. The engineering of mouse mutants harboring genotypically equivalent Apert mutations helps to elucidate the developmental pathology of craniosynostosis and implicates activation of the RAS–MAP kinase pathway as a critical mediator of many clinical features of Apert syndrome. Approaches to targeted genetic or pharmacological therapies are discussed, although these will be challenging to implement given the early onset of pathogenesis in the embryo.
2025-08-22 | Generation of three human induced pluripotent stem cell lines from FGFR2-linked syndromic craniosynostosis patients.
Craniosynostosis is a multigenic congenital condition in which one or more calvarial sutures have prematurely fused during the development of the fetus. Mutation in FGFR2 are associated with the development of syndromic craniosynostosis, such as Crouzon, Apert, and Pfeifer Syndrome. Investigation of FGFR2-linked craniosynostosis is hindered by the lack of appropriate in vitro models. Patient-derived human induced pluripotent stem cell (hiPSC) in vitro disease models provide the opportunity to investigate the disease, identify molecular targets for pharmaceutical treatments, and enable the generation of autologous pluripotent stem cell catalogues. Here, we report three patient-derived hiPSC lines carrying the FGFR2 mutation C342Y, S252W, or E565G, respectively. The patient hiPSC lines express characteristic pluripotency markers, and display distinct phosphorylation profiles under unstimulated conditions. The FGFR2C342Y shows autophosphorylation in the absence of bFGF ligand, although downstream docking proteins PLCγ and FRS2α are not phosphorylated. FGFR2S252W and FGFR2E565G hiPSCs possess increased phosphorylation of docking proteins PLCγ and FRS2α while FGFR2 is not phosphorylated. These patient hiPSC lines provide molecular and cellular options to investigate FGFR2-linked craniosynostosis in the patient-specific genomic context and develop therapeutic modalities.
2025-07-24 | Silver-modified atraumatic restorative technique approach to dental and craniofacial care in Apert syndrome: a case-based perspective
Apert syndrome is a rare congenital disorder first noted by Wheaton in 1894 and more precisely described by Eugene Apert in 1906. It is primarily characterized by craniosynostosis, midfacial hypoplasia, and complex syndactyly of the hands and feet, along with various systemic and oral abnormalities. The syndrome is estimated to occur in approximately 1 in 1,60,000 live births and typically follows an autosomal dominant inheritance pattern. Most cases are associated with spontaneous mutations in the fibroblast growth factor receptor 2 (FGFR2) gene, which plays a crucial role in bone development and tissue formation. This case report details the clinical and dental management of a 4-year-old female who was diagnosed with Apert syndrome at birth. The patient presented with hallmark craniofacial features such as a high, prominent forehead, flat midface, syndactyly affecting both hands and feet, and notably delayed developmental milestones. She had a history of undergoing multiple surgical interventions, including cranial vault reconstruction to alleviate intracranial pressure and syndactyly release procedures to improve hand functionality. Intraorally, the patient showed maxillary hypoplasia, a high-arched palate, delayed eruption of primary teeth, dental crowding, and multiple carious lesions. Dental care was tailored to her special healthcare needs, utilizing the silver-modified atraumatic restorative technique (SMART), which involves the use of silver diamine fluoride and glass ionomer cement to arrest caries and restore teeth in a minimally invasive manner. A preventive oral health plan, including dietary counselling, fluoride varnish application, and regularly scheduled recall visits, was instituted to maintain long-term dental and overall well-being.
2025-04-21 | FGFR2 residence in primary cilia is necessary for epithelial cell signaling.
Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues. In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.
proteins
2021-10-04 | Effect of Fibroblast Growth Factor 2 on Extraocular Muscle Structure and Function.
Mutations in the fibroblast growth factor (FGF) receptor can result in strabismus, but little is known about how FGFs affect extraocular muscle structure and function. These were assessed after short-term and long-term exposure to exogenously applied FGF2 to determine the effect of enhanced signaling. One superior rectus muscle of adult rabbits received either a series of three injections of 500 ng, 1 µg, or 5 µg FGF2 and examined after 1 week, or received sustained treatment with FGF2 and examined after 1, 2, or 3 months. Muscles were assessed for alterations in force generation, myofiber size, and satellite cell number after each treatment. One week after the 5 µg FGF2 injections, treated muscles showed significantly increased force generation compared with naïve controls, which correlated with increased myofiber cross-sectional areas and Pax7-positive satellite cells. In contrast, 3 months of sustained FGF2 treatment resulted in decreased force generation, which correlated with decreased myofiber size and decreased satellite cells compared with naïve control and the untreated contralateral side. FGF2 had distinctly different effects when short-term and long-term treatments were compared. The decreased size and ability to generate force correlated with decreased myofiber areas seen in individuals with Apert syndrome, where there is sustained activation of FGF signaling. Knowing more about signaling pathways critical for extraocular muscle function, development, and disease will pave the way for improved treatment options for strabismus patients with FGF abnormalities in craniofacial disease, which also may be applicable to other strabismus patients.
2018-09-28 | Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse.
FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative for multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that both the activation (Fgfr2cC342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2cnull) of the FGFR2c isoform can drive suture abolishment. This study aims to address the downstream effects of pathogenic FGFR2c signalling by studying the effects of Fgfr2c overexpression. Conditional overexpression of Fgfr2c (R26RFgfr2c;βact) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2cnull and Fgfr2cC342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2cC342Y and R26RFgfr2c;βact mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2cC342Y and R26RFgfr2c;βact mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2cC342Y), in particular to the coronal suture. Our results demonstrate that Fgfr2c overexpression is sufficient to partially rescue craniosynostosis through increased proliferation and reduced osteogenic activity in E18.5 Fgfr2cC342Y embryos. This study demonstrates the intricate balance of FGF signalling required for correct calvarial bone and suture morphogenesis, and that increasing the expression of the wild-type FGFR2c isoform may be a way to prevent or delay craniosynostosis progression.
2017-06-26 | Inducible Activation of FGFR2 in Adult Mice Promotes Bone Formation After Bone Marrow Ablation
ABSTRACT Apert syndrome is one of the most severe craniosynostoses, resulting from gain-of-function mutations in fibroblast growth factor receptor 2 (FGFR2). Previous studies have shown that gain-of-function mutations of FGFR2 (S252W or P253R) cause skull malformation of human Apert syndrome by affecting both chondrogenesis and osteogenesis, underscoring the key role of FGFR2 in bone development. However, the effects of FGFR2 on bone formation at the adult stage have not been fully investigated. To investigate the role of FGFR2 in bone formation, we generated mice with tamoxifen-inducible expression of mutant FGFR2 (P253R) at the adult stage. Mechanical bone marrow ablation (BMX) was performed in both wild-type and Fgfr2 mutant (MT) mice. Changes in newly formed trabecular bone were assessed by micro-computed tomography and bone histomorphometry. We found that MT mice exhibited increased trabecular bone formation and decreased bone resorption after BMX accompanied with a remarkable increase in bone marrow stromal cell recruitment and proliferation, osteoblast proliferation and differentiation, and enhanced Wnt/β-catenin activity. Furthermore, pharmacologically inhibiting Wnt/β-catenin signaling can partially reverse the increased trabecular bone formation and decreased bone resorption in MT mice after BMX. Our data demonstrate that gain-of-function mutation in FGFR2 exerts a Wnt/β-catenin-dependent anabolic effect on trabecular bone by promoting bone formation and inhibiting bone resorption at the adult stage. © 2017 American Society for Bone and Mineral Research.
2016-08-15 | Cell Type-Dependent Nonspecific Fibroblast Growth Factor Signaling in Apert Syndrome
Apert Syndrome (AS) is one of the most severe forms of craniosynostosis. It is caused by gain-of-function mutations in the receptor fibroblast growth factor receptor 2 (FGFR2), which leads to ligand-receptor promiscuity. Here, we aimed to better understand the behavior of mesenchymal stem cells (MSCs) and of fibroblastoid cells, cellular populations that are part of the suture complex, when stimulated with different fibroblast growth factors (FGFs). We also aimed to verify whether FGFR2 specificity loss due to AS mutations would change their signaling behavior. We tested this hypothesis through cell proliferation and differentiation assays and through gene expression profiling. We found that FGF19 and FGF10 increase proliferation of fibroblastoid cells harboring the FGFR2 p.S252W mutation, but not of mutant MSCs. FGF19 and FGF10 were associated with different expression profiles in p.S252W cells. Further, in accordance to our gene expression microarray data, FGF19 decreases bone differentiation rate of mutant fibroblastoid cells and increases bone differentiation rate of MSCs. This effect in osteogenesis appears to be mediated by BMP signaling. The present data indicate that non-natural FGFR2 ligands, such as FGF10 and FGF19, are important factors in the pathophysiology of AS. Further research is needed to determine the role of modulation of MSC proliferation or use of FGF19 or anti-BMP2 as inhibitors of osteogenesis in AS subjects’ cells, and whether these findings can be used in the clinical management of AS.
2015-02-18 | Inhibited Wnt Signaling Causes Age-Dependent Abnormalities in the Bone Matrix Mineralization in the Apert Syndrome FGFR2S252W/+ Mice
Apert syndrome (AS) is a type of autosomal dominant disease characterized by premature fusion of the cranial sutures, severe syndactyly, and other abnormalities in internal organs. Approximately 70% of AS cases are caused by a single mutation, S252W, in fibroblast growth factor receptor 2 (FGFR2). Two groups have generated FGFR2 knock-in mice Fgfr2S252W/+ that exhibit features of AS. During the present study of AS using the Fgfr2S252W/+ mouse model, an age-related phenotype of bone homeostasis was discovered. The long bone mass was lower in 2 month old mutant mice than in age-matched controls but higher in 5 month old mutant mice. This unusual phenotype suggested that bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to maintain bone homeostasis, might be involved. BMSCs were isolated from Fgfr2S252W/+ mice and found that S252W mutation could impair osteogenic differentiation BMSCs but enhance mineralization of more mature osteoblasts. A microarray analysis revealed that Wnt pathway inhibitors SRFP1/2/4 were up-regulated in mutant BMSCs. This work provides evidence to show that the Wnt/β-catenin pathway is inhibited in both mutant BMSCs and osteoblasts, and differentiation defects of these cells can be ameliorated by Wnt3a treatment. The present study suggested that the bone abnormalities caused by deregulation of Wnt pathway may underlie the symptoms of AS.
cell therapies
2026-06-01 | 32. Vertical Remodeling and Cranial Growth Following Staged Endoscopic Strip Craniectomy and Posterior Vault Distraction in Syndromic Bicoronal Craniosynostosis
Background: Syndromic bicoronal craniosynostosis leads to turribrachycephaly and restricted cranial volume, posing challenges for both aesthetics and neurodevelopment. Endoscopic strip craniectomy (ESC) and posterior vault distraction osteogenesis (PVDO) have individually advanced early cranial expansion, yet outcomes following a staged ESC + PVDO approach remain poorly defined. Methods: A retrospective review (2020-2025) identified patients undergoing ESC (1-3 months) followed by PVDO (6-8 months). CT-based turricephaly index (TI; anterior-posterior/sella-vertex ratio), cephalic index (CI), and head-circumference (HC) z-scores were compared across time points (pre-ESC, post-ESC, post-PVDO) and against normative data. Results: Five patients (60 % female; 3 Apert, 1 Muenke, 1 unspecified) were included. Mean age was ~59 days at ESC and ~214 days at PVDO. TI remained stable post-ESC (1.29 → 1.28, p = 0.68) but significantly increased after PVDO (1.28 → 1.38, p = 0.05). HC z-scores improved stepwise (−0.93 → −0.69 → +0.28), with significant gain post-PVDO (Δ +0.98, p = 0.047). Median HC percentile rose 17.7 %, while CI remained stable (93.0 → 93.4, p = 0.83). Conclusion: A staged ESC + PVDO paradigm yields progressive normalization of cranial growth and vertical remodeling in syndromic bicoronal craniosynostosis. Early ESC provides limited decompression, whereas PVDO achieves significant volumetric and morphologic correction. This protocol represents a reproducible, innovation-driven framework for comprehensive, growth-adaptive cranial reconstruction.
2026-02-27 | Morphological analysis of posterior fossa in Apert and Crouzon syndromes before and after posterior cranial vault expansion.
Syndromic craniosynostosis, such as Apert and Crouzon syndromes, involve premature fusion of cranial sutures, leading to cranial deformities and potential neurological complications. Posterior cranial vault expansion (PCVE) is commonly used to address intracranial volume (ICV) anomalies in these cases, especially in the posterior fossa region. However, the morphological variation of this region between normal, Apert and Crouzon individuals remains understudied. This study aimed to carry out a detailed morphological analysis of the posterior fossa between the aforementioned groups before and after PCVE. Retrospective computed tomography (CT) data from 28 children with Apert (n = 13) and Crouzon (n = 15) syndromes, alongside 51 age-matched controls, were analyzed. Intracranial and posterior fossa volumes (ICV and PFV) were computed pre- and post-operatively. Morphometric shape analyses were conducted for posterior fossa and intracranial cavity using principal component analysis (PCA). Pre-operatively, Apert syndrome patients exhibited larger PFV and ICV compared to Crouzon syndrome patients and controls (e.g., p = 0.009 for pre-operative Apert vs. controls), while Crouzon syndrome patients showed more variability in PFV and ICV. Post-operatively, Apert patients demonstrated significant increases in both PFV and PFV/ICV ratios (e.g., post-operative vs. pre-operative PFV: p < 0.001). In contrast, Crouzon patients exhibited limited improvements in PFV, with PFV/ICV ratios often declining post-surgery (p = 0.890; median post-operative-pre-operative difference = -0.095). PCA revealed distinct intracranial and posterior fossa shape differences between Apert and Crouzon patients. While PCVE increased posterior fossa volume, it did not appear to improve posterior fossa shape in either Apert or Crouzon patients. Future studies are required to address the limitations of small sample sizes, lack of post-operative data on Chiari anomaly, and surgical variability to further explore possible correlations between the aforementioned parameters.
2026-01-01 | Management of the Posterior Vault
Abstract Traditionally, the first surgical procedure to enlarge the vault in an infant with Apert syndrome was the fronto-orbital advancement. In 2009, teams from two large craniofacial centers located in Philadelphia (USA) and Rotterdam (Netherlands) both switched to a routine posterior vault expansion with distraction. The outcomes of this procedure have significantly improved—with fewer reoperations and a lower prevalence of raised intracranial pressure and/or Chiari malformation during follow-up—while the rate of complications has remained low.
2026-01-01 | Segmental Subcranial Midface Osteotomies: Le Fort II with Zygomatic Repositioning
Abstract Unlike the midface hypoplasia associated with Crouzon syndrome, Apert facial dysmorphology has been described as an abnormal face in an abnormal position. The Apert midface deformity is characterized by a dual concavity, with more severe deficiency in both the sagittal and vertical dimensions of the central midface relative to the lateral face. En bloc Le Fort III subcranial advancement cannot correct this unique dysmorphology and moves an abnormal face into a more normal position. Segmental approaches such as Le Fort II distraction with zygomatic repositioning (LF2ZR) or bipartition frontofacial distraction are better suited to correct the Apert facial ratios. They combine the benefits of distraction osteogenesis with the directional control of traditional techniques to create differential movements. Both techniques have benefits and disadvantages, so each case of Apert syndrome should be analyzed before midface surgery to determine which approach would best treat the most dominant aspect of dysmorphology.
2025-10-22 | Positive Impact of Frontofacial Advancement on Intracranial Volumes in Patients With Syndromic Craniofaciosynostosis.
Le Fort (LF) III midface distraction osteogenesis is one of the main techniques for correcting midface deficiency encountered in craniofaciosynostosis. However, regardless of the technique used, there may be a deterioration in the result, with a recurrence of facial hypoplasia, requiring a new procedure to advance the midface. In this retrospective study, computed tomography scans before and after LF III distraction osteogenesis of 7 patients (3 boys and 2 girls with Crouzon syndrome, 1 boy with Apert syndrome, and 1 boy with Pfeiffer syndrome) were analyzed in vestibular orientation. The ages ranged from 4 to 11 years old. All patients presented with syndromic craniofaciosynostosis with class III malocclusion and proptosis. The 3 cranial fossae were segmented slice by slice, and their volumes were calculated. The total intracranial volume was calculated by summing the volumes of the 3 cranial fossae. The Wilcoxon signed-rank test was used to compare the measured values before and after LF III distraction. A P value of less than 0.05 was considered statistically significant. Total intracranial volume significantly increased (6%; P = 0.016) in the total study group. Volumes of the anterior and middle cranial fossae increased insignificantly (22.6%, P = 0.33; 4.8%, P = 0.29). The volume of the posterior cranial fossae insignificantly decreased (0.3%, P = 0.58). A significant increase in total intracranial volume after LF III advancement in syndromic craniofaciosynostosis patients was reported.
oligonucleotides
2023-07-17 | Exosome-mediated small interfering RNA delivery inhibits aberrant osteoblast differentiation in Apert syndrome model mice.
Apert syndrome, an autosomal dominant congenital disorder characterized by craniosynostosis, is caused by a missense mutation (S252W or P253R) in fibroblast growth factor receptor 2 (FGFR2). Exosomes are naturally occurring carriers that deliver nucleic acids, including small interfering RNA (siRNA), to induce gene silencing. This study aimed to develop siRNA-loaded exosomes (Ex-siRNAFgfr2S252W) to silence the Fgfr2S252W gain-of-function mutation, thereby inhibiting the increased osteoblastic differentiation caused by the constitutive activation of FGFR2 signaling in calvarial osteoblastic cells isolated from Apert syndrome model mice. Primary calvarial osteoblast-like cells were isolated from the embryonic calvarial sutures of the Apert syndrome model (Fgfr2S252W/+) and littermate wild-type mice (Ap-Ob and Wt-Ob, respectively). Exosomes were extracted from the serum of wild-type mice, validated using biomarkers, and used to encapsulate siRNAs. After exosome-mediated siRNA transfection, cells were analyzed under a fluorescence microscope to validate the delivery of Ex-siRNAFgfr2S252W, followed by western blot and real-time reverse transcription polymerase chain reaction analyses. After 24 h of Ex-siRNAFgfr2S252W delivery in both Ap-Ob and Wt-Ob, siRNA-loaded exosome delivery was validated. Moreover, p44/42 mitogen-activated protein kinase (MAPK) phosphorylation, runt-related transcription factor 2 (Runx2), and collagen type 1 alpha 1 (Col1a1) mRNA expression, and alkaline phosphatase (ALP) activity were significantly increased in Ap-Ob. The levels of phospho-p44/42 protein, Runx2, Col1a1, and ALP were significantly decreased after Ex-siRNAFgfr2S252W transfection but did not affect Wt-Ob. These results indicate that exosome-mediated delivery of siRNA targeting Fgfr2S252W is a potential non-invasive treatment for aberrant FGF/FGFR signaling.
2018-09-22 | Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model
Apert syndrome (AS), the most severe form of craniosynostosis, is caused by missense mutations including Pro253Arg(P253R) of fibroblast growth factor receptor 2 (FGFR2), which leads to enhanced FGF/FGFR2-signaling activity. Surgical correction of the deformed skull is the typical treatment for AS. Because of constant maldevelopment of sutures, the corrective surgery is often executed several times, resulting in increased patient challenge and complications. Biological therapies targeting the signaling of mutant FGFR2 allele, in combination with surgery, may bring better outcome. Here we screened and found a small interfering RNA (siRNA) specifically targeting the Fgfr2-P253R allele, and we revealed that it inhibited osteoblastic differentiation and matrix mineralization by reducing the signaling of ERK1/2 and P38 in cultured primary calvarial cells and calvarial explants from Apert mice (Fgfr2+/P253R). Furthermore, AAV9 carrying short hairpin RNA (shRNA) (AAV9-Fgfr2-shRNA) against mutant Fgfr2 was delivered to the skulls of AS mice. Results demonstrate that AAV9-Fgfr2-shRNA attenuated the premature closure of coronal suture and the decreased calvarial bone volume of AS mice. Our study provides a novel practical biological approach, which will, in combination with other therapies, including surgeries, help treat patients with AS while providing experimental clues for the biological therapies of other genetic skeletal diseases.
2013-08-16 | Smad7 Modulates TGFβ Signaling During Cranial Suture Development to Maintain Suture Patency
ABSTRACT Craniosynostosis, the premature fusion of one or more sutures between the calvarial bones, is a common birth defect. Mutations in genes encoding receptors for the transforming growth factor-beta (TGFβ) family of signaling molecules have been associated with craniosynostosis, but how TGFβ signaling is regulated during suture development is not known. In the present study, we found that expression of Smad2 and Smad3, intracellular mediators of canonical TGFβ signaling, gradually increases during early postnatal suture development in rat in both the coronal suture (CS), which remains patent throughout life, and the posterior frontal suture (PFS), which undergoes programmed closure by postnatal day 22. The amounts of phosphorylated Smad2 and Smad3 proteins showed a similar gradual increase in the PFS and CS, but in the CS, Smad2/3 activation was suppressed after neonatal day 10. The suppression of Smad2/3 activation in the CS correlated with upregulation of Smad7 expression. We demonstrate that siRNA-mediated knockdown of Smad7 caused increased phosphorylation of Smad2 and Smad3 and induced osseous obliteration of the CS from postnatal days 10 to 22. The Smad7 siRNA-induced CS closure was associated with significantly increased levels of Fgf10 and phosphorylated ERK1/2 in the suture mesenchyme. Moreover, addition of the Erk1/2 inhibitor U0126 partially blocked Smad7-siRNA–induced CS closure. These findings suggest that canonical TGFβ signaling induces suture closure at least in part through activation of FGF and ERK signaling and that Smad7 plays an important role in maintaining suture patency by suppressing canonical TGFβ signaling during suture development. © 2014 American Society for Bone and Mineral Research.
2012-05-24 | MT1-MMP Inactivates ADAM9 to Regulate FGFR2 Signaling and Calvarial Osteogenesis
MMP14 encodes a membrane-tethered metalloproteinase MT1-MMP, capable of remodeling the extracellular matrix and modulating receptors on the cell surface. Loss of MT1-MMP results in craniofacial abnormalities. Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface. In Mmp14−/− osteoblasts, FGF-induced proliferation and downstream signaling are specifically compromised, in conjunction with ADAM9 upregulation and FGFR2 shedding. The retarded parietal growth in Mmp14−/− embryos starts at 15.5 dpc, attributable to the impaired FGFR2 signaling due to increased shedding mediated by ADAM9. Adam9 depletion completely rescues the defective FGFR2 signaling and largely restores calvarial bone growth in Mmp14−/− embryos. These data reveal a regulatory paradigm for FGRF2 signaling and identify MT1-MMP as a critical negative modulator of ADAM9 activity to maintain FGFR2 signaling in calvarial osteogenesis.
2009-10-01 | Fibroblast Growth Factor 10 Plays a Causative Role in the Tracheal Cartilage Defects in a Mouse Model of Apert Syndrome
Patients with Apert syndrome (AS) display a wide range of congenital malformations including tracheal stenosis, which is a disease characterized by a uniform cartilaginous sleeve in place of a normally ribbed cartilagenous trachea. We have studied the cellular and molecular basis of this phenotype in a mouse model of AS (Fgfr2c+/Δ mice), which shows ectopic expression of Fgfr2b in mesenchymal tissues. Here we report that tracheal stenosis is associated with increased proliferation of mesenchymal cells, where the expression of Fgf10 and its upstream regulators Tbx4 and Tbx5 are abnormally elevated. We show that Fgf10 has a critical inductive role in tracheal stenosis, as genetic knockdown of Fgf10 in Fgfr2c+/Δ mice rescues this phenotype. These novel findings demonstrate a regulatory role for Fgf10 in tracheal development and shed more light on the underlying cause of tracheal defects in AS.
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2026-02-27 | The Impact of Genetics on Craniofacial Dysplasias and Consequent Oral Malformations-Integrative Review.
Diseases affecting the craniofacial skeleton are normally associated with disturbances in the regulation of cellular differentiation, the development of bone structures, and changes in bone density and ossification. Thus, the objective of this integrative review is to evaluate the published scientific literature from the last 8 years concerning the impact of genetics on some craniofacial dysplasias. Our aim covers the identification of oral cavity alterations to those dysplasias, through the most common orofacial manifestations. Three dysplasias were selected to be part of this integrative review: cleidocranial dysplasia, ectodermal dysplasia and Apert syndrome. For this purpose, a bibliographic search was performed in the PubMed, ScienceDirect, Web of Science and Google Scholar databases with several keywords combined with each other. The research question of this review was as follows: "What is the impact of genetic factors on the development of craniofacial dysplasias and associated oral malformations?". After selecting the articles through the application of inclusion and exclusion criteria, 11 articles were selected for this review. Genetics plays a crucial role in craniofacial dysplasias and subsequent oral malformations. The main conclusion was that mutations in different genes can lead to identical phenotypes, while mutations in the same gene can present slight phenotypic differences depending on where they occur. In the future, it would be important to conduct studies with larger samples and control groups that include genetic testing to allow for a more comprehensive study on the impact of genetics on craniofacial dysplasias.
2026-02-04 | Tracheal cartilaginous sleeve prevalence in syndromic craniosynostosis: A single institution study.
This study aimed to evaluate the incidence of tracheal cartilaginous sleeve (TCS) among syndromic craniosynostosis patients, as well as describe their genetic profiles, associated co-morbidities, and operative outcomes. We performed a retrospective analysis of syndromic craniosynostosis patients (Apert, Crouzon, and Pfeiffer) at a single tertiary academic center between January 1, 2002, and February 1, 2024. 39 patients with syndromic craniosynostosis were identified, with 17 patients (17/39, 43.6%) undergoing airway evaluation. 1 patient (1/17, 5.9%) was diagnosed with TCS, but 5 patients (5/17, 29.4%) had other airway abnormalities, all reflecting abnormalities of the airway wall or some type of airway stenosis. 28 patients (28/39, 73.7%) presented with a diagnosis of OSA, and 7 patients (7/39, 17.9%) of patients presented with choanal anomaly (atresia or stenosis). 32 patients (32/39, 82.1%) had genetic sequencing information available, with the most common mutations affecting p.P253R within the FGFR2 gene in 7 patients. No patients in our cohort presented with a p.W290 mutation and 7 patients presented with a p.C342 mutation, of which 4 patients had the p.C342Y mutation. The true prevalence of TCS may be likely lower than prior reports, which may aid with alleviating some familial anxiety and provide additional context and data for medical counseling and decision-making. Nonetheless, all patients should be strongly recommended to undergo airway evaluation given the risks associated with TCS, the high prevalence of structural airway anomalies, and the overall low risk of airway evaluation.
2023-11-29 | Unraveling the Complexity of Apert Syndrome: Genetics, Clinical Insights, and Future Frontiers.
Apert syndrome (AS), also known as type I acrocephalosyndactyly, is a rare congenital condition characterized by craniosynostosis resulting from missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. This comprehensive review delves into AS, covering its clinical manifestations, genetics, diagnosis, medical management, psychosocial considerations, and future research directions. AS presents with distinct features, including a brachycephalic skull, midface hypoplasia, and limb anomalies such as syndactyly. It follows an autosomal dominant inheritance pattern with mutations in the FGFR2 gene. Prenatal diagnosis is possible through advanced imaging techniques and molecular testing. The multidisciplinary approach to AS management involves surgical interventions, orthodontics, and psychological support. Although no curative treatment exists, early interventions can significantly improve function and aesthetics. The quality of life for AS patients is influenced by psychosocial factors, necessitating comprehensive support for both patients and their families. Future research directions include gene therapy, understanding cellular responses to FGFR2 mutations, and addressing genetic heterogeneity. Collaborative efforts are vital to advancing knowledge about AS and its genetic underpinnings. Overall, this review serves as a valuable resource for healthcare professionals, educators, and researchers, contributing to a deeper understanding of AS and facilitating advancements in diagnosis and treatment.
2023-07-31 | Molecular Scalpels: The Future of Pediatric Craniofacial Surgery?
CRISPR-Cas genome editing tools are among the most substantial advances in the life sciences in modern history. Single-dose gene therapies to correct pathogenic mutations have moved quickly from bench to bedside, with several therapeutics designed by CRISPR pioneers entering various stages of clinical investigation. Applications of these genetic technologies are poised to reshape the practice of both medicine and surgery. Many of the most morbid conditions treated by craniofacial surgeons are syndromic craniosynostoses caused by mutations in fibroblast growth factor receptor genes, including Apert, Pfeiffer, Crouzon, and Muenke syndromes. The fact that pathogenic mutations in these genes are recurrent in the majority of affected families presents a unique opportunity to develop "off-the-shelf" gene editing therapies to correct these mutations in affected children. The therapeutic potential of these interventions could reshape pediatric craniofacial surgery, potentially first eliminating the need for midface advancement procedures in affected children.
2022-10-18 | The potential role for phage therapy for genetic modification of cutaneous diseases.
Antimicrobial resistance has become increasingly common across the globe, claiming more than 33,000 lives annually in Europe and 35,000 lives in the United States alone. The problem lies in trying to find potential solutions capable of tackling resistance and being able to fight infections that may resist various antimicrobials. Since Alexander Fleming's discovery in 1928, every antimicrobial synthesized in the past 70 years has developed at least one or more strains of resistant bacteria. One particular alternative to antimicrobials has brought hope to many in the scientific community: the bacteriophage. Bacteriophages are viruses that can replicate within bacteria, triggering genetic alterations and changes in pathways of protein expression by encoding a few to hundreds of genes within their genomes. The bacteriophage can hijack the cell, using the cell's genetic apparatus to replicate within the bacterium until bacterial lysis occurs. This therapy has been used in the genodermatosis Netherton syndrome, which has been associated with the increased risk of Staphylococcus aureus infections. Emerging data support the potential role of bacteriophage therapy for Cutibacterium acnes in acne vulgaris, with a potential role in genetic disorders with severe acne vulgaris, including Apert syndrome. Bacteriophages hold benefits for genodermatoses associated with recurrent cutaneous infections, that is, the immunodeficiencies with distinctive cutaneous features as well as conditions such as atopic dermatitis, in which bacterial colonization plays a strong role.
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