The Experts below are selected from a list of 1545 Experts worldwide ranked by ideXlab platform
Joan T Richtsmeier - One of the best experts on this subject based on the ideXlab platform.
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from shape to cells mouse models reveal mechanisms altering palate development in Apert Syndrome
Disease Models & Mechanisms, 2013Co-Authors: Neus Martinezabadias, Yingli Wang, Ethylin Wang Jabs, Greg Holmes, Talia Pankratz, Xueyan Zhou, Joan T RichtsmeierAbstract:Apert Syndrome is a congenital disorder characterized by severe skull malformations and caused by one of two missense mutations, S252W and P253R, on fibroblast growth factor receptor 2 (FGFR2). The molecular bases underlying differential Apert Syndrome phenotypes are still poorly understood and it is unclear why cleft palate is more frequent in patients carrying the S252W mutation. Taking advantage of Apert Syndrome mouse models, we performed a novel combination of morphometric, histological and immunohistochemical analyses to precisely quantify distinct palatal phenotypes in Fgfr2+/S252W and Fgfr2+/P253R mice. We localized regions of differentially altered FGF signaling and assessed local cell patterns to establish a baseline for understanding the differential effects of these two Fgfr2 mutations. Palatal suture scoring and comparative 3D shape analysis from high resolution μCT images of 120 newborn mouse skulls showed that Fgfr2+/S252W mice display relatively more severe palate dysmorphologies, with contracted and more separated palatal shelves, a greater tendency to fuse the maxillary-palatine sutures and aberrant development of the inter-premaxillary suture. These palatal defects are associated with suture-specific patterns of abnormal cellular proliferation, differentiation and apoptosis. The posterior region of the developing palate emerges as a potential target for therapeutic strategies in clinical management of cleft palate in Apert Syndrome patients.
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fgf fgfr signaling coordinates skull development by modulating magnitude of morphological integration evidence from Apert Syndrome mouse models
PLOS ONE, 2011Co-Authors: Neus Martinezabadias, Yann Heuze, Yingli Wang, Ethylin Wang Jabs, Kristina Aldridge, Joan T RichtsmeierAbstract:The fibroblast growth factor and receptor system (FGF/FGFR) mediates cell communication and pattern formation in many tissue types (e.g., osseous, nervous, vascular). In those craniosynostosis Syndromes caused by FGFR1-3 mutations, alteration of signaling in the FGF/FGFR system leads to dysmorphology of the skull, brain and limbs, among other organs. Since this molecular pathway is widely expressed throughout head development, we explore whether and how two specific mutations on Fgfr2 causing Apert Syndrome in humans affect the pattern and level of integration between the facial skeleton and the neurocranium using inbred Apert Syndrome mouse models Fgfr2+/S252W and Fgfr2+/P253R and their non-mutant littermates at P0. Skull morphological integration (MI), which can reflect developmental interactions among traits by measuring the intensity of statistical associations among them, was assessed using data from microCT images of the skull of Apert Syndrome mouse models and 3D geometric morphometric methods. Our results show that mutant Apert Syndrome mice share the general pattern of MI with their non-mutant littermates, but the magnitude of integration between and within the facial skeleton and the neurocranium is increased, especially in Fgfr2+/S252W mice. This indicates that although Fgfr2 mutations do not disrupt skull MI, FGF/FGFR signaling is a covariance-generating process in skull development that acts as a global factor modulating the intensity of MI. As this pathway evolved early in vertebrate evolution, it may have played a significant role in establishing the patterns of skull MI and coordinating proper skull development.
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brain phenotypes in two fgfr2 mouse models for Apert Syndrome
Developmental Dynamics, 2010Co-Authors: Kristina Aldridge, Neus Martinezabadias, Yingli Wang, Ethylin Wang Jabs, Cheryl A Hill, Jordan R Austin, Christopher J Percival, Thomas Neuberger, Joan T RichtsmeierAbstract:Apert Syndrome (AS) is one of at least nine disorders considered members of the fibroblast growth factor receptor (FGFR) -1, -2, and -3-related craniosynostosis Syndromes. Nearly 100% of individuals diagnosed with AS carry one of two neighboring mutations on Fgfr2. The cranial phenotype associated with these two mutations includes coronal suture synostosis, either unilateral (unicoronal synostosis) or bilateral (bicoronal synostosis). Brain dysmorphology associated with AS is thought to be secondary to cranial vault or base alterations, but the variation in brain phenotypes within Apert Syndrome is unexplained. Here, we present novel three-dimensional data on brain phenotypes of inbred mice at postnatal day 0 each carrying one of the two Fgfr2 mutations associated with AS. Our data suggest that the brain is primarily affected, rather than secondarily responding to skull dysmorphogenesis. Our hypothesis is that the skull and brain are both primarily affected in craniosynostosis and that shared phenogenetic developmental processes affect both tissues in craniosynostosis of Apert Syndrome.
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activation of p38 mapk pathway in the skull abnormalities of Apert Syndrome fgfr2 p253r mice
BMC Developmental Biology, 2010Co-Authors: Yingli Wang, Neus Martinezabadias, Cheryl A Hill, Christopher J Percival, Xueyan Zhou, Miao Sun, Victoria L Uhlhorn, Inga Peter, Joan T RichtsmeierAbstract:Background Apert Syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert Syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation.
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abnormalities in cartilage and bone development in the Apert Syndrome fgfr2 s252w mouse
Development, 2005Co-Authors: Yingli Wang, Joan T Richtsmeier, Ran Xiao, Fan Yang, Baktiar O Karim, Anthony J Iacovelli, Juanliang Cai, Charles P Lerner, Jen M LeszlAbstract:Apert Syndrome is an autosomal dominant disorder characterized by malformations of the skull, limbs and viscera. Two-thirds of affected individuals have a S252W mutation in fibroblast growth factor receptor 2 (FGFR2). To study the pathogenesis of this condition, we generated a knock-in mouse model with this mutation. The Fgfr2(+/S252W) mutant mice have abnormalities of the skeleton, as well as of other organs including the brain, thymus, lungs, heart and intestines. In the mutant neurocranium, we found a midline sutural defect and craniosynostosis with abnormal osteoblastic proliferation and differentiation. We noted ectopic cartilage at the midline sagittal suture, and cartilage abnormalities in the basicranium, nasal turbinates and trachea. In addition, from the mutant long bones, in vitro cell cultures grown in osteogenic medium revealed chondrocytes, which were absent in the controls. Our results suggest that altered cartilage and bone development play a significant role in the pathogenesis of the Apert Syndrome phenotype.
Ethylin Wang Jabs - One of the best experts on this subject based on the ideXlab platform.
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from shape to cells mouse models reveal mechanisms altering palate development in Apert Syndrome
Disease Models & Mechanisms, 2013Co-Authors: Neus Martinezabadias, Yingli Wang, Ethylin Wang Jabs, Greg Holmes, Talia Pankratz, Xueyan Zhou, Joan T RichtsmeierAbstract:Apert Syndrome is a congenital disorder characterized by severe skull malformations and caused by one of two missense mutations, S252W and P253R, on fibroblast growth factor receptor 2 (FGFR2). The molecular bases underlying differential Apert Syndrome phenotypes are still poorly understood and it is unclear why cleft palate is more frequent in patients carrying the S252W mutation. Taking advantage of Apert Syndrome mouse models, we performed a novel combination of morphometric, histological and immunohistochemical analyses to precisely quantify distinct palatal phenotypes in Fgfr2+/S252W and Fgfr2+/P253R mice. We localized regions of differentially altered FGF signaling and assessed local cell patterns to establish a baseline for understanding the differential effects of these two Fgfr2 mutations. Palatal suture scoring and comparative 3D shape analysis from high resolution μCT images of 120 newborn mouse skulls showed that Fgfr2+/S252W mice display relatively more severe palate dysmorphologies, with contracted and more separated palatal shelves, a greater tendency to fuse the maxillary-palatine sutures and aberrant development of the inter-premaxillary suture. These palatal defects are associated with suture-specific patterns of abnormal cellular proliferation, differentiation and apoptosis. The posterior region of the developing palate emerges as a potential target for therapeutic strategies in clinical management of cleft palate in Apert Syndrome patients.
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fgf fgfr signaling coordinates skull development by modulating magnitude of morphological integration evidence from Apert Syndrome mouse models
PLOS ONE, 2011Co-Authors: Neus Martinezabadias, Yann Heuze, Yingli Wang, Ethylin Wang Jabs, Kristina Aldridge, Joan T RichtsmeierAbstract:The fibroblast growth factor and receptor system (FGF/FGFR) mediates cell communication and pattern formation in many tissue types (e.g., osseous, nervous, vascular). In those craniosynostosis Syndromes caused by FGFR1-3 mutations, alteration of signaling in the FGF/FGFR system leads to dysmorphology of the skull, brain and limbs, among other organs. Since this molecular pathway is widely expressed throughout head development, we explore whether and how two specific mutations on Fgfr2 causing Apert Syndrome in humans affect the pattern and level of integration between the facial skeleton and the neurocranium using inbred Apert Syndrome mouse models Fgfr2+/S252W and Fgfr2+/P253R and their non-mutant littermates at P0. Skull morphological integration (MI), which can reflect developmental interactions among traits by measuring the intensity of statistical associations among them, was assessed using data from microCT images of the skull of Apert Syndrome mouse models and 3D geometric morphometric methods. Our results show that mutant Apert Syndrome mice share the general pattern of MI with their non-mutant littermates, but the magnitude of integration between and within the facial skeleton and the neurocranium is increased, especially in Fgfr2+/S252W mice. This indicates that although Fgfr2 mutations do not disrupt skull MI, FGF/FGFR signaling is a covariance-generating process in skull development that acts as a global factor modulating the intensity of MI. As this pathway evolved early in vertebrate evolution, it may have played a significant role in establishing the patterns of skull MI and coordinating proper skull development.
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brain phenotypes in two fgfr2 mouse models for Apert Syndrome
Developmental Dynamics, 2010Co-Authors: Kristina Aldridge, Neus Martinezabadias, Yingli Wang, Ethylin Wang Jabs, Cheryl A Hill, Jordan R Austin, Christopher J Percival, Thomas Neuberger, Joan T RichtsmeierAbstract:Apert Syndrome (AS) is one of at least nine disorders considered members of the fibroblast growth factor receptor (FGFR) -1, -2, and -3-related craniosynostosis Syndromes. Nearly 100% of individuals diagnosed with AS carry one of two neighboring mutations on Fgfr2. The cranial phenotype associated with these two mutations includes coronal suture synostosis, either unilateral (unicoronal synostosis) or bilateral (bicoronal synostosis). Brain dysmorphology associated with AS is thought to be secondary to cranial vault or base alterations, but the variation in brain phenotypes within Apert Syndrome is unexplained. Here, we present novel three-dimensional data on brain phenotypes of inbred mice at postnatal day 0 each carrying one of the two Fgfr2 mutations associated with AS. Our data suggest that the brain is primarily affected, rather than secondarily responding to skull dysmorphogenesis. Our hypothesis is that the skull and brain are both primarily affected in craniosynostosis and that shared phenogenetic developmental processes affect both tissues in craniosynostosis of Apert Syndrome.
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second trimester molecular prenatal diagnosis of sporadic Apert Syndrome following suspicious ultrasound findings
Ultrasound in Obstetrics & Gynecology, 1999Co-Authors: Jose Ferreira, Ethylin Wang Jabs, S M Carter, P S Bernstein, J S Glickstein, Robert W Marion, Rebecca N Baergen, Susan J GrossAbstract:Apert Syndrome, an autosomal dominant disorder characterized by craniosynostosis, mid-facial malformations, symmetric bony syndactyly of hands and feet, and varying degrees of mental retardation, is most frequently caused by a de novo mutation. Two missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been found to account for the disorder in approximately 98% of affected patients. Seven cases of prenatal ultrasound diagnosis have been reported. Although one earlier diagnosis has been made in a familial case, sporadic cases have not been definitively diagnosed until the third trimester when craniosynostosis is usually detected. We report a second-trimester molecular diagnosis of a sporadic case, based on the ultrasound observation of fetal 'mitten hands' and craniosynostosis. We discuss the approach to such ultrasound features, given the current availability of molecular diagnosis for Apert Syndrome.
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prenatal ultrasonographic and molecular diagnosis of Apert Syndrome
Prenatal Diagnosis, 1997Co-Authors: Karen Filkins, Wen Jiang, Joseph F Russo, Susan Boehmer, Marianne Camous, Kelly A Przylepa, Ethylin Wang JabsAbstract:Apert Syndrome is a rare craniosynostosis Syndrome with significant bilateral syndactyly of the hands and feet. Usually it is detected by ultrasonography during the third trimester unless there is a family history. We present an interesting sporadic case with features consistent with Apert Syndrome detected as early as the first trimester. A first-trimester ultrasound evaluation prior to chorionic villus sampling (CVS) for maternal age 41 was within normal limits except for the suggestion of a 'mitten-like' hand and proximally placed thumb. Mid-trimester ultrasound was not diagnostic; however, following the development of polyhydramnios in the third trimester, the evaluation of the digits and facial features were strongly suggestive of Apert Syndrome. Amniocentesis was performed and a molecular diagnosis of Apert Syndrome was made and confirmed on cord blood.
John A. Persing - One of the best experts on this subject based on the ideXlab platform.
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does different cranial suture synostosis influence orbit volume and morphology in Apert Syndrome
International Journal of Oral and Maxillofacial Surgery, 2021Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, John A. PersingAbstract:Abstract This study was performed to compare the orbital and peri-orbital morphological variations in Apert Syndrome patients with different cranial vault suture synostosis, so as to provide an anatomic basis for individualized surgical planning. Computed tomography scans of 57 unoperated Apert Syndrome patients and 59 controls were subgrouped as follows: type I, bilateral coronal synostosis; type II, pansynostosis; type III, perpendicular combinations of cranial vault suture synostoses. Orbit bony cavity volume was significantly reduced in type I and type II, by 19% (P
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morphological basis for airway surgical intervention in Apert Syndrome
Annals of Plastic Surgery, 2020Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, Derek M Steinbacher, Kitae E Park, Omar Allam, Cristiano Tonello, John A. PersingAbstract:Objective Previous studies have explored the restricted nasopharyngeal airway in Apert Syndrome patients. This study aims to investigate the segmented airway volume changes with age and directly analyze their correlations with subcranial dimensions and angulations. Methods Ninety-seven preoperative computed tomography scans (Apert, n = 44; control, n = 53) were included in this study, and divided into 5 age-related subgroups. Computed tomography scans were measured using Mimics and 3-matics software. Results Before 6 months of age, the nasal cavity in Apert Syndrome is reduced by 47% (P = 0.002), which gradually approximates normal thereafter; however, there remained a 30% reduction, compared with controls. It is highly correlated with the anteroposterior length of subcranial space, and the position of maxilla and palate. The pharyngeal airway volume in Apert Syndrome patients, younger than 6 months, was larger than normal by 129% (P = 0.013). However, between 2 and 6 years of age, the pharyngeal airway becomes smaller than normal, with a 57% (P = 0.010) reduction in childhood and 52% (P = 0.005) in adolescence. It is closely correlated with the intercondylar and intergonial widths. Conclusions Airway compromise in Apert Syndrome patients is attributable more to the nasal cavity in infants, but in the older child, it is the pharyngeal region. The restricted nasal airway in Apert Syndrome is correlated with the subcranial space length and width, but independent of cranial base flexion. The pharyngeal airway volume in Apert Syndrome is not as highly correlated with craniofacial morphology. Rather, it is impacted by the growth of mandible, which often requires surgical intervention later in childhood.
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cranial fossa volume and morphology development in Apert Syndrome
Plastic and Reconstructive Surgery, 2020Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, Derek M Steinbacher, Alexander T Wilson, John A. PersingAbstract:Background Apert Syndrome causes normal or enlarged intracranial volume overall as patients grow. This study aimed to trace the segmental anterior, middle, and posterior cranial fossae volume and structural morphology in these patients, to help discern a more focused and individualized surgical treatment plan for patients with Apert Syndrome. Methods This study included 82 preoperative computed tomographic scans (Apert, n = 32; control, n = 50) divided into five age-related subgroups. The scans were measured using image processing and three-dimensional modeling software. Results The middle cranial fossa volume was increased and was the earliest change noted. It was increased by 45 percent (p = 0.023) compared with controls before 6 months of age and remained increased into adulthood (161 percent, p = 0.016), with gradually increasing severity. The anterior and posterior cranial fossae volumes also increased, by 35 percent (p = 0.032) and 39 percent (p = 0.007), respectively. Increased depth of cranial fossae contributed most to the increase in volumes of patients with Apert Syndrome, with correlation coefficients of 0.799, 0.908, and 0.888 for anterior, middle, and posterior cranial fossa, respectively. The intracranial volume was increased 12 percent (p = 0.098) across the entire test age range (0 to 26 years old), but only had statistical significance during the age range of 6 to 18 years (22 percent, p = 0.001). Conclusions Malformation of the middle cranial fossa is an early, perhaps the initial, pivotal cranial morphologic change in Apert Syndrome. Increased cranial fossae depth is an inherent characteristic of the maldevelopment. Normalization of cranial volume and circumference overall may not achieve a normal skull structure, as it does not correct regional craniocerebral disproportion.
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cranial fossa volume in differing subtypes of Apert Syndrome
Journal of Craniofacial Surgery, 2019Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, Derek M Steinbacher, Alexander T Wilson, John A. PersingAbstract:BACKGROUND Based on an established classification system of Apert Syndrome subtypes, detailed regional morphology and volume analysis may be useful to provide additional clarification to individual Apert cranial structure characteristics, and treatment planning. METHODS Computed tomography scans of 32 unoperated Apert Syndrome and 50 controls were included and subgrouped as: type I, bilateral coronal synostosis; type II, pansynostosis; type III, perpendicular combination synostosis. Three-dimensional analysis of craniometric points was used to define structural components using Materialise Mimics and 3-Matics software. RESULTS Occipitofrontal circumference of all subtypes of Apert Syndrome patients is normal. Intracranial volumes of types I and II were normal, but type III was 20% greater than controls. Middle cranial fossa volume was increased in all 3 types, with the greatest increase in type II (86%). Type II developed a 69% increase in anterior cranial fossa volume, whereas type III had 39% greater posterior cranial fossa volume. Increased cranial fossa depth contributed most to above increased volume. The anteroposterior lengths of middle and posterior cranial fossae were reduced in type I (15% and 17%, respectively). However, only the anterior cranial fossa was significantly shortened in type III. CONCLUSIONS Occipitofrontal circumference and overall intracranial volume is not always consistent in individual subunits of Apert Syndrome. Detailed and segmental anterior, middle, and posterior cranial fossae volumes and morphology should be analyzed to see what impact this may have related to surgical planning.
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airway analysis in Apert Syndrome
Plastic and Reconstructive Surgery, 2019Co-Authors: Antonio J Forte, Michael Alperovich, John A. Persing, Derek M Steinbacher, Peter W Hashim, Nivaldo AlonsoAbstract:Background:Apert Syndrome is frequently combined with respiratory insufficiency, because of the midfacial deformity which, in turn, is influenced by the malformation of the skull base. Respiratory impairment resulting from Apert Syndrome is caused by multilevel limitations in airway space. Therefore
Yingli Wang - One of the best experts on this subject based on the ideXlab platform.
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from shape to cells mouse models reveal mechanisms altering palate development in Apert Syndrome
Disease Models & Mechanisms, 2013Co-Authors: Neus Martinezabadias, Yingli Wang, Ethylin Wang Jabs, Greg Holmes, Talia Pankratz, Xueyan Zhou, Joan T RichtsmeierAbstract:Apert Syndrome is a congenital disorder characterized by severe skull malformations and caused by one of two missense mutations, S252W and P253R, on fibroblast growth factor receptor 2 (FGFR2). The molecular bases underlying differential Apert Syndrome phenotypes are still poorly understood and it is unclear why cleft palate is more frequent in patients carrying the S252W mutation. Taking advantage of Apert Syndrome mouse models, we performed a novel combination of morphometric, histological and immunohistochemical analyses to precisely quantify distinct palatal phenotypes in Fgfr2+/S252W and Fgfr2+/P253R mice. We localized regions of differentially altered FGF signaling and assessed local cell patterns to establish a baseline for understanding the differential effects of these two Fgfr2 mutations. Palatal suture scoring and comparative 3D shape analysis from high resolution μCT images of 120 newborn mouse skulls showed that Fgfr2+/S252W mice display relatively more severe palate dysmorphologies, with contracted and more separated palatal shelves, a greater tendency to fuse the maxillary-palatine sutures and aberrant development of the inter-premaxillary suture. These palatal defects are associated with suture-specific patterns of abnormal cellular proliferation, differentiation and apoptosis. The posterior region of the developing palate emerges as a potential target for therapeutic strategies in clinical management of cleft palate in Apert Syndrome patients.
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fgf fgfr signaling coordinates skull development by modulating magnitude of morphological integration evidence from Apert Syndrome mouse models
PLOS ONE, 2011Co-Authors: Neus Martinezabadias, Yann Heuze, Yingli Wang, Ethylin Wang Jabs, Kristina Aldridge, Joan T RichtsmeierAbstract:The fibroblast growth factor and receptor system (FGF/FGFR) mediates cell communication and pattern formation in many tissue types (e.g., osseous, nervous, vascular). In those craniosynostosis Syndromes caused by FGFR1-3 mutations, alteration of signaling in the FGF/FGFR system leads to dysmorphology of the skull, brain and limbs, among other organs. Since this molecular pathway is widely expressed throughout head development, we explore whether and how two specific mutations on Fgfr2 causing Apert Syndrome in humans affect the pattern and level of integration between the facial skeleton and the neurocranium using inbred Apert Syndrome mouse models Fgfr2+/S252W and Fgfr2+/P253R and their non-mutant littermates at P0. Skull morphological integration (MI), which can reflect developmental interactions among traits by measuring the intensity of statistical associations among them, was assessed using data from microCT images of the skull of Apert Syndrome mouse models and 3D geometric morphometric methods. Our results show that mutant Apert Syndrome mice share the general pattern of MI with their non-mutant littermates, but the magnitude of integration between and within the facial skeleton and the neurocranium is increased, especially in Fgfr2+/S252W mice. This indicates that although Fgfr2 mutations do not disrupt skull MI, FGF/FGFR signaling is a covariance-generating process in skull development that acts as a global factor modulating the intensity of MI. As this pathway evolved early in vertebrate evolution, it may have played a significant role in establishing the patterns of skull MI and coordinating proper skull development.
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brain phenotypes in two fgfr2 mouse models for Apert Syndrome
Developmental Dynamics, 2010Co-Authors: Kristina Aldridge, Neus Martinezabadias, Yingli Wang, Ethylin Wang Jabs, Cheryl A Hill, Jordan R Austin, Christopher J Percival, Thomas Neuberger, Joan T RichtsmeierAbstract:Apert Syndrome (AS) is one of at least nine disorders considered members of the fibroblast growth factor receptor (FGFR) -1, -2, and -3-related craniosynostosis Syndromes. Nearly 100% of individuals diagnosed with AS carry one of two neighboring mutations on Fgfr2. The cranial phenotype associated with these two mutations includes coronal suture synostosis, either unilateral (unicoronal synostosis) or bilateral (bicoronal synostosis). Brain dysmorphology associated with AS is thought to be secondary to cranial vault or base alterations, but the variation in brain phenotypes within Apert Syndrome is unexplained. Here, we present novel three-dimensional data on brain phenotypes of inbred mice at postnatal day 0 each carrying one of the two Fgfr2 mutations associated with AS. Our data suggest that the brain is primarily affected, rather than secondarily responding to skull dysmorphogenesis. Our hypothesis is that the skull and brain are both primarily affected in craniosynostosis and that shared phenogenetic developmental processes affect both tissues in craniosynostosis of Apert Syndrome.
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activation of p38 mapk pathway in the skull abnormalities of Apert Syndrome fgfr2 p253r mice
BMC Developmental Biology, 2010Co-Authors: Yingli Wang, Neus Martinezabadias, Cheryl A Hill, Christopher J Percival, Xueyan Zhou, Miao Sun, Victoria L Uhlhorn, Inga Peter, Joan T RichtsmeierAbstract:Background Apert Syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert Syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation.
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abnormalities in cartilage and bone development in the Apert Syndrome fgfr2 s252w mouse
Development, 2005Co-Authors: Yingli Wang, Joan T Richtsmeier, Ran Xiao, Fan Yang, Baktiar O Karim, Anthony J Iacovelli, Juanliang Cai, Charles P Lerner, Jen M LeszlAbstract:Apert Syndrome is an autosomal dominant disorder characterized by malformations of the skull, limbs and viscera. Two-thirds of affected individuals have a S252W mutation in fibroblast growth factor receptor 2 (FGFR2). To study the pathogenesis of this condition, we generated a knock-in mouse model with this mutation. The Fgfr2(+/S252W) mutant mice have abnormalities of the skeleton, as well as of other organs including the brain, thymus, lungs, heart and intestines. In the mutant neurocranium, we found a midline sutural defect and craniosynostosis with abnormal osteoblastic proliferation and differentiation. We noted ectopic cartilage at the midline sagittal suture, and cartilage abnormalities in the basicranium, nasal turbinates and trachea. In addition, from the mutant long bones, in vitro cell cultures grown in osteogenic medium revealed chondrocytes, which were absent in the controls. Our results suggest that altered cartilage and bone development play a significant role in the pathogenesis of the Apert Syndrome phenotype.
Antonio J Forte - One of the best experts on this subject based on the ideXlab platform.
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does different cranial suture synostosis influence orbit volume and morphology in Apert Syndrome
International Journal of Oral and Maxillofacial Surgery, 2021Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, John A. PersingAbstract:Abstract This study was performed to compare the orbital and peri-orbital morphological variations in Apert Syndrome patients with different cranial vault suture synostosis, so as to provide an anatomic basis for individualized surgical planning. Computed tomography scans of 57 unoperated Apert Syndrome patients and 59 controls were subgrouped as follows: type I, bilateral coronal synostosis; type II, pansynostosis; type III, perpendicular combinations of cranial vault suture synostoses. Orbit bony cavity volume was significantly reduced in type I and type II, by 19% (P
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morphological basis for airway surgical intervention in Apert Syndrome
Annals of Plastic Surgery, 2020Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, Derek M Steinbacher, Kitae E Park, Omar Allam, Cristiano Tonello, John A. PersingAbstract:Objective Previous studies have explored the restricted nasopharyngeal airway in Apert Syndrome patients. This study aims to investigate the segmented airway volume changes with age and directly analyze their correlations with subcranial dimensions and angulations. Methods Ninety-seven preoperative computed tomography scans (Apert, n = 44; control, n = 53) were included in this study, and divided into 5 age-related subgroups. Computed tomography scans were measured using Mimics and 3-matics software. Results Before 6 months of age, the nasal cavity in Apert Syndrome is reduced by 47% (P = 0.002), which gradually approximates normal thereafter; however, there remained a 30% reduction, compared with controls. It is highly correlated with the anteroposterior length of subcranial space, and the position of maxilla and palate. The pharyngeal airway volume in Apert Syndrome patients, younger than 6 months, was larger than normal by 129% (P = 0.013). However, between 2 and 6 years of age, the pharyngeal airway becomes smaller than normal, with a 57% (P = 0.010) reduction in childhood and 52% (P = 0.005) in adolescence. It is closely correlated with the intercondylar and intergonial widths. Conclusions Airway compromise in Apert Syndrome patients is attributable more to the nasal cavity in infants, but in the older child, it is the pharyngeal region. The restricted nasal airway in Apert Syndrome is correlated with the subcranial space length and width, but independent of cranial base flexion. The pharyngeal airway volume in Apert Syndrome is not as highly correlated with craniofacial morphology. Rather, it is impacted by the growth of mandible, which often requires surgical intervention later in childhood.
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cranial fossa volume and morphology development in Apert Syndrome
Plastic and Reconstructive Surgery, 2020Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, Derek M Steinbacher, Alexander T Wilson, John A. PersingAbstract:Background Apert Syndrome causes normal or enlarged intracranial volume overall as patients grow. This study aimed to trace the segmental anterior, middle, and posterior cranial fossae volume and structural morphology in these patients, to help discern a more focused and individualized surgical treatment plan for patients with Apert Syndrome. Methods This study included 82 preoperative computed tomographic scans (Apert, n = 32; control, n = 50) divided into five age-related subgroups. The scans were measured using image processing and three-dimensional modeling software. Results The middle cranial fossa volume was increased and was the earliest change noted. It was increased by 45 percent (p = 0.023) compared with controls before 6 months of age and remained increased into adulthood (161 percent, p = 0.016), with gradually increasing severity. The anterior and posterior cranial fossae volumes also increased, by 35 percent (p = 0.032) and 39 percent (p = 0.007), respectively. Increased depth of cranial fossae contributed most to the increase in volumes of patients with Apert Syndrome, with correlation coefficients of 0.799, 0.908, and 0.888 for anterior, middle, and posterior cranial fossa, respectively. The intracranial volume was increased 12 percent (p = 0.098) across the entire test age range (0 to 26 years old), but only had statistical significance during the age range of 6 to 18 years (22 percent, p = 0.001). Conclusions Malformation of the middle cranial fossa is an early, perhaps the initial, pivotal cranial morphologic change in Apert Syndrome. Increased cranial fossae depth is an inherent characteristic of the maldevelopment. Normalization of cranial volume and circumference overall may not achieve a normal skull structure, as it does not correct regional craniocerebral disproportion.
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cranial fossa volume in differing subtypes of Apert Syndrome
Journal of Craniofacial Surgery, 2019Co-Authors: Antonio J Forte, Michael Alperovich, Nivaldo Alonso, Derek M Steinbacher, Alexander T Wilson, John A. PersingAbstract:BACKGROUND Based on an established classification system of Apert Syndrome subtypes, detailed regional morphology and volume analysis may be useful to provide additional clarification to individual Apert cranial structure characteristics, and treatment planning. METHODS Computed tomography scans of 32 unoperated Apert Syndrome and 50 controls were included and subgrouped as: type I, bilateral coronal synostosis; type II, pansynostosis; type III, perpendicular combination synostosis. Three-dimensional analysis of craniometric points was used to define structural components using Materialise Mimics and 3-Matics software. RESULTS Occipitofrontal circumference of all subtypes of Apert Syndrome patients is normal. Intracranial volumes of types I and II were normal, but type III was 20% greater than controls. Middle cranial fossa volume was increased in all 3 types, with the greatest increase in type II (86%). Type II developed a 69% increase in anterior cranial fossa volume, whereas type III had 39% greater posterior cranial fossa volume. Increased cranial fossa depth contributed most to above increased volume. The anteroposterior lengths of middle and posterior cranial fossae were reduced in type I (15% and 17%, respectively). However, only the anterior cranial fossa was significantly shortened in type III. CONCLUSIONS Occipitofrontal circumference and overall intracranial volume is not always consistent in individual subunits of Apert Syndrome. Detailed and segmental anterior, middle, and posterior cranial fossae volumes and morphology should be analyzed to see what impact this may have related to surgical planning.
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airway analysis in Apert Syndrome
Plastic and Reconstructive Surgery, 2019Co-Authors: Antonio J Forte, Michael Alperovich, John A. Persing, Derek M Steinbacher, Peter W Hashim, Nivaldo AlonsoAbstract:Background:Apert Syndrome is frequently combined with respiratory insufficiency, because of the midfacial deformity which, in turn, is influenced by the malformation of the skull base. Respiratory impairment resulting from Apert Syndrome is caused by multilevel limitations in airway space. Therefore