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Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1 +/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.

Background: The pathophysiology of nonsyndromic craniosynostosis remains poorly understood. The authors seek to understand the cause of this condition with a specific focus on how osteoclasts may contribute to craniosynostosis. Here, the authors characterize proteins differentially expressed in patent and fused cranial sutures by comparing their respective proteomes., Methods: Fused and patent suture samples were obtained from craniosynostotic patients undergoing surgery at a single academic medical center. Extracted protein from samples was interrogated using mass spectrometry. Differential protein expression was determined using maximum likelihood-based G-test with a q-value cutoffs of 0.5 after correction for multiple hypothesis testing. Immunolocalization of lead protein candidates was performed to validate proteomic findings. In addition, quantitative polymerase chain reaction analysis of corresponding gene expression of proteins of interest was performed., Results: Proteins differentially expressed in patent versus fused sutures included collagen 6A1 (Col6A1), fibromodulin, periostin, aggrecan, adipocyte enhancer-binding protein 1, and osteomodulin (OMD). Maximum likelihood-based G-test suggested that Col6A1, fibromodulin, and adipocyte enhancer-binding protein 1 are highly expressed in patent sutures compared with fused sutures, whereas OMD is up-regulated in fused sutures compared with patent sutures. These results were corroborated by immunohistochemistry. Quantitative polymerase chain reaction data point to an inverse relationship in proteins of interest to RNA transcript levels, in prematurely fused and patent sutures that potentially describes a feedback loop mechanism., Conclusions: Proteome analysis validated by immunohistochemistry may provide insight into the mechanism of cranial suture patency and disease from an osteoclast perspective. The authors results suggest a role of inflammatory mediators in nonsyndromic craniosynostosis. Col6A1 may aid in the regulation of suture patency, and OMD may be involved in premature fusion. Additional validation studies are required.

Background: Rapid maxillary expansion (RME), indicated in the treatment of maxillary deficiency directs high forces to maxillary basal bone and to other adjacent skeletal bones. The aim of this study is to (i) evaluate stress distribution along craniofacial sutures and (ii) study the displacement of various craniofacial structures with rapid maxillary expansion therapy by using a Finite Element model., Methods: An analytical model was developed from a dried human skull of a 12 year old male. CT scan images of the skull were taken in axial direction parallel to the F-H plane at 1 mm interval, processed using Mimics software, required portion of the skull was exported into stereo-lithography model. ANSYS software was used to solve the mathematical equation. Contour plots of the displacement and stresses were obtained from the results of the analysis performed., Results: At Node 47005, maximum X-displacement was 5.073 mm corresponding to the incisal edge of the upper central incisor. At Node 3971, maximum negative Y-displacement was -0.86 mm which corresponds to the anterior zygomatic arch, indicating posterior movement of craniofacial complex. At Node 32324, maximum negative Z-displacement was -0.92 mm representing the anterior and deepest convex portion of the nasal septum; indicating downward displacement of structures medial to the area of force application., Conclusions: Pyramidal displacement of maxilla was evident. Apex of pyramid faced the nasal bone and base was located on the oral side. Posterosuperior part of nasal cavity moved minimally in lateral direction and width of nasal cavity at the floor of the nose increased, there was downward and forward movement of maxilla with a tendency toward posterior rotation. Maximum von Mises stresses were found along midpalatal, pterygomaxillary, nasomaxillary and frontomaxillary sutures.

Background: The study aimed to evaluate and compare the stress distribution and 3-dimensional displacements along the craniofacial sutures in between the Rapid maxillary Expansion (RME) and Implant supported RME (I-RME). METHODS: Finite element model of the skull and the implants were created using ANSYS software. The finite element model thus built composed of 537692 elements and 115694 nodes in RME model & 543078 elements and 117948 nodes with implants model. The forces were applied on the palatal surface of the posterior teeth to cause 5mm of transverse displacement on either side of the palatal halves, making it a total of 10mm. The stresses and the displacement values were obtained and interpreted., Results: Varying pattern of stress and the displacements with both positive and negative values were seen. The maximum displacement was seen in the case of plain RME model and that too at Pterygomaxillary suture and Mid-palatal suture in descending order. In the case of I-RME maximum displacement was seen at Zygomaticomaxillary suture followed by Pterygomaxillary suture. The displacements produced in all the three planes of space for the plain RME model were greater in comparison to the Implant Supported RME model. And the stresses remained high for all the sutures in case of an I-RME., Conclusions: There is a definite difference in the stress and the displacement pattern produced by RME and I-RME model and each can be used according to the need of the patient. The stresses generated in case of conventional RME were considerably less than that of the I-RME for all the sutures.

Craniosynostosis, the premature ossification of one or more skull sutures, is a clinically and genetically heterogeneous congenital anomaly affecting approximately one in 2,500 live births. In most cases, it occurs as an isolated congenital anomaly, that is, nonsyndromic craniosynostosis (NCS), the genetic, and environmental causes of which remain largely unknown. Recent data suggest that, at least some of the midline NCS cases may be explained by two loci inheritance. In approximately 25-30% of patients, craniosynostosis presents as a feature of a genetic syndrome due to chromosomal defects or mutations in genes within interconnected signaling pathways. The aim of this review is to provide a detailed and comprehensive update on the genetic and environmental factors associated with NCS, integrating the scientific findings achieved during the last decade. Focus on the neurodevelopmental, imaging, and treatment aspects of NCS is also provided., (© 2017 Wiley Periodicals, Inc.)

Repair of calvarial bony defects remains challenging for craniofacial surgeons. Injury experiments on animal calvarial bones are widely used to study healing mechanisms and test tissue engineering approaches. Previously, we identified Gli1+ cells within the calvarial sutures as stem cells supporting calvarial bone turnover and injury repair. In this study, we tested the regenerative capacity of the suture region compared with other areas of calvarial bone. Injuries were made to mouse sagittal sutures or other areas of the calvarial bone at varying distances from the suture. Samples were collected at different time points after injury for evaluation. MicroCT and histological analyses were conducted. EdU incorporation analysis was performed to assay cell proliferation. Gli1-Cre ERT2 ;Tdtomato flox mice were used to trace the fate of Gli1+ stem cells after injury. Calvarial sutures possess much stronger regeneration capability than the nonsuture bony areas of the calvaria. The healing rate of the calvarial bone is inversely proportional to the distance between the suture and injury site: injuries closer to the suture heal faster. After complete removal of the sagittal suture, regeneration and restoration of normal organization occur within 6 weeks. Gli1+ cells within the suture mesenchyme are the cellular source for injury repair and bone regeneration. These results demonstrate that calvarial bone healing is not an evenly distributed event on the calvarial surface. Sutures contain stem cells and are the origin of calvarial bone tissue regeneration. Therefore, current practice in calvarial surgery needs to be reevaluated and modified. These findings also necessitate the design of new approaches for repairing calvarial bony defects., Competing Interests: Author Disclosure Statement No competing financial interests exist.

Background: In this finite element (FE) study, the stress distribution and displacement pattern was evaluated in the mid-palatal area and around circum-maxillary sutures exerted by bone-borne palatal expander (BBPE) in comparison with conventional HYRAX rapid palatal expander in unilateral cleft lip and palate., Methods: Computed tomography scan images of a patient with unilateral cleft palate was used to create a FE model of the maxillary bone along with circum-maxillary sutures. A three-dimensional model of the conventional HYRAX (Hygienic Rapid Expander) expander and custom-made BBPE was created by laser scanning and programmed into the FE model., Results: With the BBPE, the maximum stress was observed at the implant insertion site, whereas with the conventional HYRAX expander, it was at the dentition level. Among the circum-maxillary sutures, the zygomaticomaxillary suture experienced maximum stress followed by the zygomaticotemporal and nasomaxillary sutures. Displacement in the X-axis (transverse) was highest on the cleft side, and in the Y-axis (antero-posterior), it was highest in the posterior region in the BBPE., Conclusions: The total displacement was observed maximum in the mid-palatal cleft area in the BBPE, and it produced true skeletal expansion at the alveolar level without any dental tipping when compared with the conventional HYRAX expander.

The morphological and mechanical properties of the pediatric skull are important in understanding pediatric head injury biomechanics. Although previous studies have analyzed the morphology of cranial sutures, none has done so in pediatric specimens nor have previous studies related the morphology to mechanical properties of human sutures. This study quantified the geometry of pediatric cranial sutures and investigated its correlation with the suture mechanical properties. First, the suture fiber alignment was quantified using histological analysis for four ages-neonate, 9 months-old, 11 months-old, and 18 months-old. For the morphometric investigation of the suture interdigitation, suture samples from a 6-year-old were scanned using micro-CT and the level of interdigitation was measured using two techniques. The first technique, the sinuosity index, was calculated by dividing the suture path along the surface of the skull by the suture distance from beginning to end. The second technique, the surface area interdigitation index, was calculated by measuring the surface area of the bone interface outlining the suture and dividing it by the cross-sectional area of the bone. The mechanical properties were obtained using methods reported in Davis et al.6. The results of the histological analysis showed a significant increase in fiber alignment in older specimen; where random fiber alignment has an average angle deviation of 45°, neonatal suture fibers have an average deviation of 32.2° and the 18-month-old fibers had an average deviation of 16.2° (p < 0.0001). For the suture index measurements, only the sinuosity was positively correlated with the ultimate strain (R (2) = 0.62, Bonferroni corrected p = 0.011) but no other measurements showed a significant relationship, including the amount of interdigitation and elastic modulus. Our results demonstrate that there is a distinct developmental progression of the suture fiber alignment at a young age, but the differences in suture interdigitation can only predict the ultimate strain and no other mechanical properties.

Introduction: In this study, we aimed to evaluate the effects of maxillary protraction using traditional labiolingual arches and implant-type protraction devices before orthopedic treatment of patients with skeletal Class III malocclusion., Methods: A 3-dimensional finite element model of the maxillofacial bones with high biologic similarity and including the sutures was constructed. Through stress and displacement calculations, a biomechanical study was performed for the maxillofacial bones, mandible, and sutures., Results: We quantified detailed changes in the sutures with 2 protraction methods to analyze their effects on the growth of the maxillofacial bones., Conclusions: (1) The labiolingual arch is suitable for skeletal Class III patients with crossbite and deep overbite. The frontomaxillary and zygomaticomaxillary sutures played major roles in the forward displacement and counterclockwise rotation of the maxilla. The temporozygomatic and pterygopalatine sutures did not change significantly. (2) The implant type of protraction device is suitable for skeletal Class III patients with crossbite and open bite. Both the frontomaxillary and zygomaticomaxillary sutures played decisive roles in the forward displacement and clockwise rotation of maxilla. The temporozygomatic and pterygopalatine sutures showed small changes. (3) The labiolingual arch caused less stimulatory growth on the maxilla, whereas the implant caused greater stimulatory growth on the maxilla. Protraction with the labiolingual arch is more suitable for early skeletal Class III patients at a younger age; protraction with an implant is applicable to skeletal Class III patients in the late mixed dentition or early permanent dentition., (Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Background/objective: The aim of this study was to investigate the effect of systemic St John's wort (Hypericum perforatum) on bone formation in the expanded premaxillary suture in rats., Materials/methods: A total of 28 rats were randomly divided into four groups of equal numbers: control (C); only expansion (OE); St John's wort extract given only during the expansion and retention period (a total of 17 days; SJW group); and St John's wort extract given during the nursery phase before expansion (a period of 40 days), and during the expansion and retention periods (a total of 57 days; N + SJW group). After the 5 day expansion period was completed, the rats in the OE, SJW, and N + SJW groups underwent 12 days of mechanical retention, following which they were killed, and their premaxilla dissected and fixed. Histological examination was performed to determine the number of osteoclasts and capillaries, as well as the number of osteoblasts, inflammatory cell infiltration, and the amount of new bone formation., Results: Statistical analysis showed that the number of osteoclasts and capillaries, and the inflammatory cell infiltration, as well as new bone formation, were higher in the SJW and N + SJW groups than in the other groups. However, statistical analysis demonstrated that among these two groups, all parameters, with the exception of the number of capillaries, were higher in the N + SJW group than the SJW group., Conclusions/implications: Although more effective in long-term usage, systemic use of St John's wort hastens new bone regeneration at the premaxillary suture and may help prevent relapse after expansion., (© The Author 2014. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study examined the mechanical properties of the adult sagittal suture compared with surrounding parietal bones using bending tests and investigated the association between the mechanical properties of the suture and age. We used the heads of 116 Japanese cadavers (76 male cadavers and 40 female cadavers) of known age and sex. A total of 1160 cranial samples, 10 from each skull, were collected. The samples were imaged using multidetector computed tomography, and the sample thickness at the center of each sample (ST) was measured. The failure stress of each sample (FS) was measured by a bending test, and the ratio of failure stress to the square of sample thickness (FS/ST(2)) was calculated. Statistical analyses revealed that the FS and FS/ST(2) values were significantly lower at all suture sites than at all bone sites regardless of sex. There were not significant but slight positive correlations between age and FS and FS/ST(2) values at any suture site in male samples. In female samples, age had significant positive correlations with FS and FS/ST(2) values at the middle suture sites, whereas there were not significant but slight positive correlations between age and FS and FS/ST(2) values at the edges of the suture. Statistical analyses also demonstrated that FS and FS/ST(2) values were significantly greater in male samples than in female samples at the middle suture sites. These findings suggest that the bending strength of the adult sagittal suture is significantly lower than that of surrounding parietal bones. Therefore, avoiding direct impact on cranial sutures may be important for preventing skull fractures and severe complications that can cause death. The results of this study also revealed that the bending strength of the middle sagittal suture significantly increases with age in only female samples, whereas the bending strength is significantly higher in male samples than in female samples at the middle suture sites, indicating the possibility of sex difference in the bony interdigitation of the sutures during childhood., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: New forms and varieties of craniosynostoses are continuously identified due to the current increased interest of clinicians and genetists especially since the introduction of microarray-based comparative genomic hybridization (Array-CGH) techniques in the diagnostic setting of patients with craniofacial anomalies., Methods: In this report, we describe the case of an infant who associated the early fusion of the metopic and both the coronal sutures. The interaction of the early fusion of the anterior group of the main cranial sutures gave the infant a particular clinical phenotypes with a Y configuration of the frontal bone and a globally reduced size of the skull. Such a deformity was observed in utero and was subsequently confirmed by the postnatal imaging of the head., Results: This phenotype was never described previously in antenatal period to our knowledge. The array-CGH showed a heterozygous 9.0 Mb deletion in the chromosomal region 7p21.1p21.3 encompassing approximately 25 other genes, spanning from THSD7A to TWIST1/FERD3L., Conclusion: This case further illustrates the variability of the clinical spectrum of craniofacial disorders associated with TWIST1 abnormalities. It is important to note that the Saethre-Chotzen syndrome caused by microdeletion is generally characterized by a mental disability. However, of interest, the postoperative psychomotor development of the child considered hereby was within the normal limits., (© 2015 Wiley Periodicals, Inc.)

Introduction: There is limited craniofacial literature on the complications of helmet therapy and controversy regarding the effects of inadequate orthotic helmet therapy. The authors present a case of inadvertently prolonged orthotic helmet therapy after endoscopic strip craniectomy for isolated sagittal synostosis., Case Presentation: A two-month-old Caucasian baby underwent uncomplicated endoscopic-assisted strip craniectomy to treat synostosis of the sagittal suture and was fitted for an orthotic helmet two weeks postoperatively. He presented to the craniofacial clinic eight weeks postoperatively with occipital flattening and increased posterior vault height, so the helmet was refitted. During the next 18 months, the helmet was used inconsistently without follow-up. Upon re-presentation, the patient had developed pansynostosis, requiring a subsequent open total cranial vault reconstruction for correction for this secondary deformity., Conclusions: Although it remains unclear whether postoperative development of pansynostosis is the result of prolonged helmeting or the consequence of progressive synostotic disease, this report highlights the importance of parent education and judicious scheduled follow-up for the avoidance of potential helmet therapy complications.

Background: Orthodontic palatal expansion appliances have been widely used with satisfactory and, most often, predictable clinical results. Recently, clinicians have successfully utilized micro-implants with palatal expander designs to work as anchors to the palate to achieve more efficient skeletal expansion and to decrease undesired dental effects. The purpose of the study was to use finite element method (FEM) to determine the stress distribution and displacement within the craniofacial complex when simulated conventional and micro-implant-assisted rapid palatal expansion (MARPE) expansion forces are applied to the maxilla. The simulated stress distribution produced within the palate and maxillary buttresses in addition to the displacement and rotation of the maxilla could then be analyzed to determine if micro-implants aid in skeletal expansion., Methods: A three-dimensional (3D) mesh model of the cranium with associated maxillary sutures was developed using computed tomography (CT) images and Mimics modeling software. To compare transverse expansion stresses in rapid palatal expansion (RPE) and MARPE, expansion forces were distributed to differing points on the maxilla and evaluated with ANSYS simulation software., Results: The stresses distributed from forces applied to the maxillary teeth are distributed mainly along the trajectories of the three maxillary buttresses. In comparison, the MARPE showed tension and compression directed to the palate, while showing less rotation, and tipping of the maxillary complex. In addition, the conventional hyrax displayed a rotation of the maxilla around the teeth as opposed to the midpalatal suture of the MARPE. This data suggests that the MARPE causes the maxilla to bend laterally, while preventing unwanted rotation of the complex., Conclusions: In conclusion, the MARPE may be beneficial for hyperdivergent patients, or those that have already experienced closure of the midpalatal suture, who require palatal expansion and would worsen from buccal tipping of the teeth or maxillary complex.

Object: Unilateral fusion of the frontoparietal suture is the most common cause of synostotic frontal plagiocephaly. Localized fusion of the frontosphenoidal suture is rare but can lead to a similar, but subtly distinct, phenotype., Methods: A retrospective chart review of the authors' craniofacial database was performed. Patients with isolated frontosphenoidal synostosis on CT imaging were included. Demographic data, as well as the clinical and radiographic findings, were recorded., Results: Three patients were identified. All patients were female and none had an identifiable syndrome. Head circumference was normal in each patient. The mean age at presentation was 4.8 months (range 2.0-9.8 months); 2 fusions were on the right side. Frontal flattening and recession of the supraorbital rim on the fused side were consistent physical findings. No patient had appreciable facial angulation or orbital dystopia, and 2 patients had anterior displacement of the ipsilateral ear. All 3 patients were initially misdiagnosed with unilateral coronal synostosis, and CT imaging at a mean age of 5.4 months (range 2.1-10.8 months) was required to secure the correct diagnosis. Computed tomography findings included patency of the frontoparietal suture, minor to no anterior cranial base angulation, and vertical flattening of the orbit without sphenoid wing elevation on the fused side. One patient underwent CT scanning at 2.1 months of age, which demonstrated a narrow, but patent, frontosphenoidal suture. The patient's condition was assumed to be a deformational process, and she underwent 6 months of unsuccessful helmet therapy. A repeat CT scan obtained at 10.7 months of age demonstrated the synostosis. All 3 patients underwent fronto-orbital correction at mean age of 12.1 months (range 7.8-16.1 months). The mean duration of postoperative follow-up was 11.7 months (range 1.9-23.9 months)., Conclusions: Isolated frontosphenoidal synostosis should be considered in the differential diagnosis of atypical frontal plagiocephaly.

Purpose: This study investigated stress distribution in maxillas that underwent surgically assisted palatal expansion (SARPE)., Materials and Methods: Five maxillary models were built: no osteotomy (M1), Le Fort I osteotomy with a step in the zygomaticomaxillary buttress (M2), Le Fort I osteotomy with a step in the zygomaticomaxillary buttress and the pterygomaxillary disjunction (M3), Le Fort I osteotomy without a step (M4), and Le Fort I osteotomy with pterygomaxillary disjunction and no step (M5). Displacement coherence and maximum stress (MS) analyses were used for all models., Results: Areas of tension spread to the maxilla and the region between the alveolar ridge and the palate and a critical point in the median suture for M2, M3, M4, and M5. In M2 and M4, MS spread farther toward and over the pterygoid process, contrary to what was found in M3 and M5. M3 had a better performance than the other models, and the tensile stress was interrupted by the posterior osteotomy, thus avoiding possible damage to the sphenoid bone or difficulties in expanding the posterior region of the maxilla., Conclusions: The steps in the zygomaticomaxillary buttress and the pterygomaxillary disjunction seem to be important to decrease the harmful dissipation of tensions during SARPE., (Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through endochondral ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable endochondral ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2(-/-) mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2(-/-) PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological endochondral ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2(-/-) PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2(-/-) PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2(-/-) PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2(-/-) PF-sutures lack physiological endochondral ossification, contain ectopic cartilage and display delayed suture closure.

Craniofacial sutures are bone growth fronts that respond and adapt to biomechanical environments. Little is known of the role sutures play in regulating the skull biomechanical environment during patency and fusion conditions, especially how delayed or premature suture fusion will impact skull biomechanics. Tgf-β3 has been shown to prevent or delay suture fusion over the short term in rat skulls, yet the long-term patency or its consequences in treated sutures is not known. It was therefore hypothesized that Tgf-β3 had a long-term impact to prevent suture fusion and thus alter the skull biomechanics. In this study, collagen gels containing 3 ng Tgf-β3 were surgically placed superficial to the posterior interfrontal suture (IFS) and deep to the periosteum in postnatal day 9 (P9) rats. At P9, P24, and P70, biting forces and strains over left parietal bone, posterior IFS, and sagittal suture were measured with masticatory muscles bilaterally stimulated, after which the rats were sacrificed and suture patency analyzed histologically. Results demonstrated that Tgf-β3 treated sutures showed less fusion over time than control groups, and strain patterns in the skulls of the Tgf-β3-treated group were different from that of the control group. Although bite force increased with age, no alterations in bite force were attributable to Tgf-β3 treatment. These findings suggest that the continued presence of patent sutures can affect strain patterns, perhaps when higher bite forces are present as in adult animals., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: This study examined early language acquisition in children with single suture craniosynostosis (SSC) and in children with deformational posterior plagiocephaly. Our purpose was to determine whether infants with SSC have normal language acquisition at the age of 3 years, and whether infants with deformational posterior plagiocephaly demonstrate parallel development when compared with children with SSC., Methods: The study population includes 61 infants. Twenty of them had synostosis of the sagittal suture, 12 synostosis of other suture and 29 deformational posterior plagiocephaly. Forty-nine of them were operated on a mean age of 10.6 months, and 12 were non-operated children with deformational posterior plagiocephaly. Language skills of participants were prospectively evaluated at the mean age of 3 years 4 months., Results: About one half of the subjects (49%) had normal linguistic development, 30% had slight developmental problems and 21% had severe disorders in speech-language-related skills. These figures showed the prevalence of severe language disorders to be three times higher in our study population when compared with the general population. Children with sagittal synostosis managed better in all language skills compared with other types of SSC. Defective language development was found in deformational posterior plagiocephaly, both operated and non-operated., Conclusions: We found a noticeable developmental risk for specific language impairment in children with nonsyndromic SSC, and that the deviant language development is observable already in early infancy. Contrary to previous beliefs, the developmental risk for defective language development in deformational posterior plagiocephaly was found in both operated and non-operated subjects.

Background: Complex craniosynostoses (i.e., multisutural, nonsyndromic) are rare and present unique treatment challenges. The authors sought to assess long-term outcomes, including postsurgical growth and development, to develop evidence-based treatment algorithms., Methods: A retrospective review of all patients identified as having multiple sutural synostosis excluding bicoronal and FGFR- and TWIST-associated synostoses was conducted. Data were summarized using descriptive statistics., Results: Over an 18-year period, 858 patients underwent craniosynostosis correction, and 31 patients (3.6 percent) satisfied inclusion criteria. Average number of affected sutures was 2.9 (lambdoid, 36 percent; sagittal, 31 percent; coronal, 18 percent; metopic, 15 percent), and 1.7 procedures were performed per patient (mean follow-up, 3.5 years). Average hospital stay was 2.3 days, 21 percent required blood transfusions, and there were no major complications. For synostosis patterns isolated to one side of the anterior sagittal suture (anterior or posterior skull halves), 93 percent were corrected with a single procedure. When the synostosis pattern crossed both skull halves, 80 percent underwent two procedures (p<0.001). Forty percent developed acquired Chiari deformations; of these, 60 percent required decompression. The incidence of Chiari deformations increased from 7 percent to 70 percent with lambdoid sutural involvement (p<0.002). Anthropometric data revealed postoperative growth impairment. Gross developmental delays were noted in 20 percent (mild, 16 percent; moderate to severe, 4 percent)., Conclusions: Complex craniosynostoses are associated with a higher incidence of acquired Chiari deformations (especially with lambdoid involvement), require multiple operative procedures, and may have more developmental delays than the isolated single sutural synostoses. The authors recommend surgical paradigms based on sutural involvement, compensatory surgical overcorrection, and routine magnetic resonance imaging monitoring for Chiari deformations., Clinical Question/level of Evidence: Therapeutic, IV.

Summary: While both intermittent and continuous forces are commonly used to expand sutures, it remains unclear which force is most effective. Using nickel-titanium (NiTi) open coil springs (50 g) and 3 mm long miniscrew implants (MSIs) for skeletal anchorage, intermittent and continuous forces were used to expand the midsagittal sutures in 18 New Zealand white juvenile male rabbits, 11 weeks of age, for 29 days. In the intermittent group, expansion forces of 50 g were delivered for 5 days (on) and paused for 1 day (off); the on/off cycles were repeated five times. Expansion forces of 50 g were delivered for 29 consecutive days in the continuous group. Longitudinal biometric and histomorphometric analyses were performed to evaluate sutural separation and bone formation using implanted tantalum bone markers and fluorescent bone labelling, respectively. Multilevel modelling procedures were undertaken to compare the groups and time intervals. Continuous forces produced significantly greater overall sutural separation (1.3 mm) than intermittent forces (0.8 mm). Although they were delivered over a period of time 86 per cent as long, intermittent forces produced only 61 per cent of the sutural separation of continuous forces. Between days 7 and 17, continuous forces resulted in significantly greater mineral apposition and bone formation rates than intermittent forces. Intermittent forces produced approximately 59 per cent as much mineral apposition and 61 per cent as much bone formation as continuous forces. Due to greater sutural separation and bone formation, continuous forces provide a more effective approach for separating sutures than intermittent forces.

Introduction: Spring cranioplasty is used in selected cases of craniosynostosis. A rabbit model was used to determine (1) if cranial biomechanics modify the expected rate of spring expansion, (2) the residual spring force in situ after cranial expansion, and (3) if the spring weakens during clinical use., Materials and Methods: Twenty-seven New Zealand white rabbits were divided into 3 groups: the treatment group that underwent posterior frontal suturectomy and spring expansion (n = 15) and the control (n = 6) and sham groups (n = 6) that underwent suturectomy and incision only, respectively. Cephalography measured cranial expansion for 7 weeks. Spring force-deflection curves were measured in a dynamometer before and after use., Results: Significant cranial expansion was observed for 8 hours (15% of the total expansion). The rate of expansion decreased significantly between 48 and 96 hours followed by a second period of rapid expansion from 96 hours to 7 days (P = 0.001). Approximately 80% of expansion was achieved by 2 weeks and 90% by 3 weeks. Initial spring force was 9.4 N (range, 7.2-10.7). Once the spring had achieved 90% of its eventual expansion, it retained 40% of its original force. At the completion of cranial expansion, the residual spring force was 2.6 N (range, 1.4-4.0) or 28% of the original spring force. All springs maintained identical load-compression curves after use., Conclusions: The craniofacial structures are mechanically complex and modify the uniform expansion curve expected as the spring force decays. Significant force is maintained within the spring at the completion of cranial expansion. This may have implications for possible relapse if the springs are removed early.

Background: Spring-assisted cranioplasty transmits forces throughout the craniofacial complex that can be measured as strain. The strain magnitude in relation to normal background physiologic strains and the distribution of these strains are currently unknown., Methods: Twenty New Zealand White rabbits were randomized into two groups: the treatment group, which included posterofrontal suture removal and spring insertion (n = 10); and the control group, which consisted of posterofrontal suture removal (n = 10). Strain gauges were placed across the interfrontal suture, both coronal sutures, and the frontal bone. Continuous strain recordings were made for 15 minutes after spring insertion., Results: Physiologic strains caused by dural pulsation and intracerebral swelling measured were higher within sutures (40 to 50 microepsilon) than in bone (10 to 20 microepsilon). Spring activation produced large increases in strain across all sutures and bone. Compared with controls, tensile strains were 20 times higher in the frontal bone (mean, 341 microepsilon; p = 0.000), 15 times higher in the interfrontal suture (539 microepsilon; p = 0.000), and 21 times higher in the coronal suture (700 microepsilon; p = 0.000). Compressive strain in the left coronal suture confirmed a shear force at these sutures (-503 microepsilon; p = 0.000). The variability of background physiologic strain was not dampened by spring loading., Conclusions: Spring-assisted cranioplasty produces supraphysiologic strain in adjacent cranial bone and suture tissue. Mechanotransduction converts these forces into the biological processes that modulate calvarial morphology. Contrary to expectations, bone lateral to the spring insertion is subjected to tensile strain on its ectocranial surface. A compressive strain on its endocranial surface is likely because of bone flexion. This has implications for subsequent calvarial morphology.

Background: The mechanical properties of the pediatric craniofacial complex allow dissipation of spring cranioplasty forces. Springs do not fully expand in situ and continue to transmit a continuous force until removal. The authors wished to investigate whether ongoing forces altered the biomechanical characteristics of cranial sutures., Methods: Thirty New Zealand White rabbits were divided into five groups: spring expansion for 4, 7, and 10 weeks; early spring removal at 4 weeks followed by monitoring for 3 weeks; and a control group (n = 6 each). Cranial expansion was monitored using cephalometry. The left coronal suture then underwent load-displacement testing in a dynamometer., Results: Relapse of cranial expansion was observed following early spring removal (mean, 6 percent; p = 0.017). Cranial suture thickness was significantly correlated to the length of spring insertion. Load displacement curves of sutures in all groups initially exhibited classic viscoelastic behavior. The treatment group developed intrasutural weakening before failure that was not observed in controls. The peak load before failure as a percentage of that observed in controls was 31 percent in the 4-week group (p = 0.001), 35 percent in the 7-week group (p = 0.000), and 45 percent in the 10-week group (p = 0.023)., Conclusions: Cranial suture compliance is modified in the presence of continuous spring cranioplasty forces. Thickening of the coronal sutures, which have been expanded in a shear-like manner, increases their three-dimensional surface area and may contribute to the relative lack of relapse observed after early spring removal.

Introduction: The aim of this study was to evaluate the density of the midpalatal suture as assessed by low-dose computed tomography (CT) before rapid maxillary expansion (RME) (T0), at the end of active expansion (T1), and after a retention period of 6 months (T2)., Methods: The study sample comprised 17 prepubertal subjects (mean age, 11.2 years) with constricted maxillary arches and unilateral or bilateral posterior crossbite. The total amount of expansion was 7 mm in all subjects. Multi-slice low-dose CT scans were taken at T0, T1, and T2. On axial CT scanned images, 4 regions of interest (ROIs) were placed along the midpalatal suture (anterior [AS ROI] and posterior [PS ROI]) and in 2 regions of palatal bone (anterior and posterior). Density was measured in Hounsfield units. The Mann-Whitney U test and Friedman analysis of variance (ANOVA) with post-hoc test were used (P <0.05)., Results: The densities in the AS and PS ROIs were significantly smaller than the reference bone densities before RME therapy. Both AS and PS ROIs showed significant decreases in density from T0 to T1, significant increases from T1 to T2, and no significant differences from T0 to T2., Conclusions: The effective opening of the midpalatal suture by RME in prepubertal subjects was associated with a significant decrease in sutural density. The sutural density after 6 months of retention post-RME indicated reorganization of the midpalatal suture, since it showed values similar to the pretreatment ones., (Copyright (c) 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Object: The authors present the results of treating infants with multiple-suture nonsyndromic craniosynostosis in whom the authors used minimally invasive endoscopy-assisted techniques and postoperative cranial molding over an 11-year period., Methods: A total of 21 patients who presented with multiple-suture (nonsyndromic) craniosynostosis were treated using minimally invasive endoscopy-assisted craniectomies. Surgery was followed by treatment with custommade cranial orthoses for up to 12 months. A total of 48 sutures were treated. The most common was the coronal suture (38 cases) and this was followed by the sagittal (11 cases), metopic (6 cases), and lambdoid (3 cases) sutures. There were 13 male and 8 female pediatric patients. Their ages ranged between 3 weeks and 9 months (mean 3.2 months, median 2.5 months). The sagittal suture was treated with a wide vertex craniotomy via 2 incisions located behind the anterior fontanel and in front of the lambda. The metopic suture underwent a suturectomy as did the coronal and lambdoid sutures., Results: The mean follow-up duration was 61 months (range 3-135 months). There were no deaths. In patients with bicoronal synostosis, brachycephaly was corrected. Patients presenting with vertical dystopia or nasal deviation had these deformities corrected as well. The mean blood loss was 42 ml (range 10-120 ml). The mean hospital length of stay was 1 day. The intraoperative transfusion rate was 0%. The results indicate that nonsyndromic multiple-suture synostosis can be safely and effectively treated using endoscopic techniques., Conclusions: Early treatment of complex multiple-suture synostosis with endoscopic techniques provides an excellent surgical alternative. The results of the present study indicate marked correction of skull base and craniofacial deformities. Endoscopy provides a safe and effective way to treat these patients.

Introduction: In this finite element study, we compared the stress patterns along the various craniofacial sutures with maxillary protraction with and without expansion., Methods: Two 3-dimensional analytic models were developed, 1 simulating maxillary protraction and the other simulating maxillary protraction with expansion. The model consisted of 108799 10 node solid 92 elements (tetrahedron), 193633 nodes, and 580899 degrees of freedom., Results: The overall stresses after maxillary protraction with maxillary expansion were significantly higher than with a facemask alone. The magnitude of stress on the craniofacial sutures with maxillary protraction alone was in the range of a few millinewtons per square millimeter, whereas, with maxillary protraction with maxillary expansion, the stresses ranged from a few newtons per square millimeter to a few hundred newtons per square millimeter. The pattern of stress distribution also differed with the 2 treatment modalities as did the sutures experiencing maximum and minimum stresses., Conclusions: The osteogenic potential of such low stresses after maxillary protraction can be questioned. High stresses generated in various craniofacial sutures after maxillary protraction with expansion are responsible for disrupting the circummaxillary sutural system and presumably facilitating the orthopedic effect of the facemask.

Introduction: The aims of this study were to develop a method for constructing a 3-dimensional finite-element model (FEM) of the maxilla and to evaluate the effects of transverse expansion on the status of various midpalatal sutures., Methods: A 3-dimensional FEM of the craniofacial complex was developed by using computed-tomography images and Bionix modeling software (version 3.0, CANTIBio, Suwon, Korea). To evaluate the differences between transverse expansion forces in the solid model (maxilla without a midpalatal suture), the fused model (maxilla with suture elements), and the patent model (maxilla without suture elements), transverse expansion forces of 100 g were applied bilaterally to the maxillary first premolars and the first molars., Results: The fused model expressed a stress pattern similar to that of the solid model, except for the decreased first principal stress concentration in the incisive foramen area. The patent model, however, had a unique stress pattern, with the stress translated superiorly to the nasal area. The anterior nasal spine and the central incisors moved downward and backward in both solid and fused models but moved primarily downward with a slight backward movement of the anterior nasal spine in the patent model., Conclusions: Clinical observations of maxillary expansion can be explained by different suture statuses. This efficient and customized FEM model can be used to predict craniofacial responses to biomechanics in patients.

Objective: To determine whether premature sagittal craniosynostosis is associated with developmental instability in the skull by analyzing fluctuating asymmetry in skull shape., Design: Cranial shape was quantified by collecting coordinate data from landmarks located on three-dimensional reconstructions of preoperative computed tomography (CT) images of 22 children with sagittal craniosynostosis and 22 age-matched controls. A fluctuating asymmetry application of Euclidean distance matrix analysis (EDMA) was used to quantify and compare asymmetry in cranial shape using these landmark data., Results: In contrast to expectations, the sagittal craniosynostosis group did not show a statistically significant increase in the overall level of fluctuating asymmetry relative to the control group. However, we discerned statistically significant localized increases in fluctuating asymmetry in the sagittal craniosynostosis group at pterion and the anterior clinoid processes (alpha = .05). We also determined a significant correlation of fluctuating asymmetry values between the two groups (r = .71)., Conclusions: We conclude that there is no evidence of a role for system-wide developmental instability in the etiology of nonsyndromic sagittal craniosynostosis. However, the localized evidence of asymmetry at the anterior clinoid processes in the sagittal synostosis group suggests an association with the tracts of dura mater that attach there.

Introduction: The goal of this study was to analyze the strains induced in the sutures of the midface and the cranial base by headgear therapy involving orthopedic forces. Does the mechanical signal induced in the sutures sufficiently account for a growth-influencing effect?, Methods: A finite element model of the viscerocranium and the neurocranium was used. It consisted of 53,555 tetrahedral elements and 97,550 nodes. The strain induced in the sutures of the cranial base and the midface when applying orthopedic headgear forces of 5 and 10 N was computed and recorded with an interactive measurement tool., Results: The magnitude and the distribution of the measured strains depended on the level and the direction of the acting force. Overall, the strain values measured at the sutures of the midface and the cranial base were moderate. The measured peak values at a load of 5 N per side were usually just below 20 microstrain irrespective of the force direction. A characteristic distribution of strain values appeared on the anatomical structures of the midface and the cranial base for each vector direction. The measurements based on the finite element method provided a good overview of the approximate magnitudes of sutural strains with orthopedic headgear therapy. The signal arriving in the sutures is apparently well below threshold, since the maximum measured strains in most sutures were about 100 fold lower than the minimal effective strain. A skeletal effect of the orthopedic headgear due to a mechanical effect on sutural growth cannot be confirmed from these results., Conclusions: The good clinical efficacy of headgear therapy with orthopedic forces is apparently based mainly on dentoalveolar effects, whereas the skeletal effect due to inhibition of sutural growth is somewhat questionable.

Objective: The goal of the study was to examine the strain in the sutures of the midface and the cranial base with maxillary protraction therapy and to clarify whether such stretching suggests a skeletal effect of the apparatus employed for that purpose., Materials and Methods: Using a finite elements model, a maxillary protraction therapy was simulated with various force levels and vectors, and the strains appearing at the sutures (in microstrain) were measured at the midface and the cranial base. The simulation model we employed consisted of 53,555 individual elements; the simulated forces were 2 x 3 N and 2 x 5 N, while the vectors of the applied forces were in the anterior and anterior caudal direction., Results: The maximum measured strains were on average below 10 microstrain, while higher values were measured only at the nasal bone and at the cranial base at the oval and spinous foramina with anterior directed force vectors (26.4 microstrain). With an anterior-caudal force vector, the measured values were usually lower., Discussion: The measured strains were on average about hundredfold lower than the Frost thresholds (2000 microstrain). It does not seem probable that the strains occurring upon maxillary protraction therapy suffice to stimulate any additional bone growth., Conclusion: The good clinical efficacy of maxillary protraction therapy is apparently based, for the most part, on dental effects, while its skeletal effects still remain doubtful.

Objective: Various causal mechanisms of familial nonsyndromic craniosynostosis have been presented. One hypothesis suggests that overproduction of bone at the suture is the primary origin of craniosynostosis, which affects brain and cranial growth secondarily through altered intracranial pressure (Primary Suture Fusion Model). Other hypotheses suggest that decreased cranial base growth or abnormal brain growth are the primary cause of craniosynostosis (Cranial Base, Brain Parenchyma Models, respectively). This study was designed to investigate which model best describes neurocranial changes associated with craniosynostosis in a rabbit model through multivariate path analysis., Design: Serial magnetic resonance imaging scans and intracranial pressure measurements were obtained at 10, 25, and 42 days of age from 18 rabbits: six controls, six with delayed-onset synostosis, and six with early-onset synostosis. Five variables were collected from each rabbit: calvarial thickness at the affected suture, cranial base length, brain volume, cerebrospinal fluid volume, and intracranial pressure. This data set was used to test causal pathway relationships generated by the proposed models. Goodness of fit was measured by experimental group for each model., Results: Primary Suture Fusion Model best explained the variables in both delayed-onset and early-onset synostotic rabbits (Goodness of fit = 93%, 97%, respectively). Cranial Base Model (Goodness of fit = 94%) best explained the data in control rabbits., Conclusion: Results suggest that the primary site of craniosynostosis in craniosynostotic rabbits is most likely the synostosed suture. Other cranial vault anomalies are most likely secondary compensatory changes. Results of the present study may provide insight regarding the causal pathway of craniosynostosis.

Objective: Crouzon syndrome is caused by mutations in fibroblast growth factor receptor 2 (FGFR2) leading to constitutive activation of receptors in the absence of ligand binding. The syndrome is characterized by premature fusion of the cranial sutures that leads to abnormal cranium shape, restricted brain growth, and increased intracranial pressure. Surgical remodeling of the cranial vault is currently used to treat affected infants. The purpose of this study was to develop a pharmacological strategy using tyrosine kinase inhibition as a novel treatment for craniosynostotic syndromes caused by constitutive FGFR activation., Methods: Characterization of cranial suture fusion in Fgfr2 mutant mice, which carry the most common Crouzon mutation, was performed using micro-computed tomographic analysis from embryogenesis through maturation. Whole calvarial cultures from wild-type and Fgfr2 mice were established and cultured for 2 weeks in the presence of dimethyl sulfoxide control or PD173074, an FGFR tyrosine kinase inhibitor. Paraffin sections were prepared to show suture morphology and calcium deposition., Results: In untreated Fgfr2 cultures, the coronal suture fused bilaterally with loss of overlap between the frontal bone and parietal bone. Calvaria treated with PD173074 (2 micromol/L) showed patency of the coronal suture and were without evidence of any synostosis., Conclusion: We report the successful use of PD173074 to prevent in vitro suture fusion in a model for Crouzon syndrome. Further studies are underway to develop an in vivo treatment protocol as a novel therapeutic modality for FGFR associated craniosynostotic syndromes.

Craniosynostosis represents a heterogeneous cluster of congenital disorders and manifests as premature ossification of one or more cranial sutures. Cranial sutures serve to enable calvarial growth and function as joints between skull bones. The mechanical properties of synostosed cranial sutures are of vital importance to their function and yet are poorly understood. The present study was designed to characterize the nanostructural and nanomechanical properties of synostosed postnatal sagittal and metopic sutures. Synostosed postnatal sagittal sutures (n = 5) and metopic sutures (n = 5) were obtained from craniosynostosis patients (aged 9.1 +/- 2.8 months). The synostosed sutural samples were prepared for imaging and indentation on both the endocranial and ectocranial surfaces with the cantilever probe of an atomic force microscopy. Analysis of the nanotopographic images indicated robust variations in sutural surface characteristics with localized peaks and valleys. In 5 x 5 mum scan sizes, the surface roughness of the synostosed metopic suture was significantly greater (223.6 +/- 93.3 nm) than the synostosed sagittal suture (142.9 +/- 80.3 nm) (P < 0.01). The Young's modulus of the synostosed sagittal suture at 0.7 +/- 0.2 MPa was significantly higher than the synostosed metopic suture at 0.5 +/- 0.1 MPa (P < 0.01). These data suggest that various synostosed cranial sutures may have different structural and mechanical characteristics.

Introduction: Exposure to reduced ambient pressure may result in decompression sickness (DCS). Headache is among the DCS symptoms encountered and is usually regarded as neurological DCS, which is traditionally classified as serious DCS. Since cranial sutures may be considered joints, it is possible that some headaches are actually joint pain and when associated with decompression sickness need not be neurological DCS., Methods: Records were individually recovered from the Davis Hyperbaric Laboratory at Brooks City-Base, TX. Information was extracted using a detailed survey instrument. Possible joint pain headache cases were identified using three criteria: headache localized at a suture, normal neurologic exam, and resolution within 30 min of hyperbaric oxygen treatment., Results: A total of 729 records documenting treatment for DCS were scrutinized. Of these, 70 cases of altitude DCS with headache were examined. Analysis, using the three criteria, showed 23% (16 cases) of altitude headache DCS symptoms could potentially be re-classified as joint pain., Conclusion: Generally, headache DCS is considered neurological DCS. However, since cranial sutures are joints, both histologically and functionally, and since DCS most commonly affects joints, headache DCS may, at times, be joint pain DCS. Indeed, retrospective data analysis suggests that this possibility exists. Such a reclassification from neurological to joint pain DCS would lessen the aeromedical impact of a DCS headache.

Introduction: This article addresses the relevance of venous hypertension to children born with, in particular, the "syndromic" forms of craniosynostosis. The development of the human cerebral venous system is summarised and the patterns of anomalous venous drainage seen in children with complex forms of craniosynostosis associated with raised intracranial pressure are described., Aetiology: The aetiology of these abnormal patterns is discussed under the general headings of "The constriction theory", "A primary role for FGFR mutations" and "Persistence of the foetal pattern of intracranial venous drainage."Venous hypertension (along with hydrocephalus, cranio-cerebral disproportion and airway obstruction) has an important role in the aetiology of raised intracranial pressure in severely affected children., Treatment: The inter-relationship between these factors is explained and then the treatment of those children whose raised intracranial pressure is considered to be due predominantly to venous hypertension is described.

Introduction: One third of patients with craniofacial dysostosis syndromes and about 15-20% of children with single suture craniostenosis have a documented increase in intracranial pressure (ICP). The early detection of intracranial hypertension is important in order to reduce the risks for brain development and visual function. However, in children with craniosynostosis, the clinical manifestations of abnormally increased ICP are difficult to detect, as the majority of patients may have neither warning signs nor symptoms for a long period of time., Review: Moreover, data from the literature suggest that neither fundoscopic nor radiological findings are necessarily related to intracranial pressure recordings in this type of pathology. In this context prolonged ICP monitoring seems actually to be the most valuable diagnostic tool. Extradural, subdural, and intraparenchymal devices have been used, and different softwares have been employed for PC storage and analysis of the data obtained. Most recent series consider mean ICP combined with plateaux waves as the most sensitive indicators in the final evaluation of the results., Conclusions: The analysis of the literature demonstrates a significant difference in the prevalence of raised ICP preoperatively between non-syndromic and syndromic patients. Among the non-syndromic children, a direct relation between the number of sutures involved and raised ICP is documented. The analysis of plateaux waves seems to be particularly important in children with borderline mean ICP values. Persistent postoperative raised ICP has been described in 6-15% of patients with craniofacial dysostosis. It must be related to the multifactorial etiology of increased ICP in these patients, which includes cerebral venous congestion, upper airway obstruction, and hydrocephalus.

Introduction: Chiari malformation (CM) is a frequent finding in multisutural and syndromic craniosynostosis, occurring in 70% of patients with Crouzon's syndrome, 75% with oxycephaly, 50% with Pfeiffer's syndrome and 100% with the Kleeblattschädel deformity. The pathogenesis of this condition and rationale for treatment are still controversial., Discussion: Since its first description in 1972, several factors have been cited to play a role in inducing CM. In the light of recent publications, the roles of premature fusion of cranial vault and cranial base sutures, of congenital anomalies of the cerebellum and brain stem, of raised intracranial pressure, of venous hypertension and of hydrocephalus are reviewed. Evaluation and management of CM are also discussed., Conclusion: Chiari malformation appears to be an acquired and progressive condition that develops in the first months of life, because of a disproportion between hindbrain growth and an abnormally small posterior fossa, a consequence of the premature fusion of lambdoid and cranial base sutures. Venous hypertension caused by stenosis of the jugular foramen can also be present in these patients, resulting in intracranial hypertension and/or hydrocephalus. Careful MRI evaluation is recommended for the forms of craniosynostosis at a high risk of developing hindbrain herniation. The selection of posterior cranial vault expansion as the first surgical procedure is advocated. In selected cases, treatment of the posterior cranial deformity by occipital vault remodelling and treatment of the Chiari-like deformity by suboccipital decompression can be carried out using the same surgical procedure.

Introduction: Ventriculo-peritoneal (VP) shunt malfunction is usually due to blockage of the ventricular catheter and this is typically apparent as enlarged ventricles on a CT scan of the brain. We describe a less common radiological finding in an infant with a blocked shunt., Case Report: A male infant presenting with hydrocephalus in the neonatal period underwent insertion of a VP shunt. He represented at 17 months of age with the clinical features of raised intracranial pressure. A CT scan of the brain revealed that the ventricles were smaller compared with his previous scan, but X-rays taken as part of the shunt series revealed diastasis of the sagittal, coronal and lambdoid sutures. The shunt was explored and the ventricular catheter was found to be blocked and was replaced. Post-operatively there was complete resolution of the symptoms and the suture diastasis., Conclusions: Suture diastasis with small ventricles on a CT scan of the brain is an unusual radiological finding in an infant with a blocked shunt. Suture diastasis in this patient suggests raised intracranial volume and this may be due to the transependymal absorption of CSF into the white matter.

Background: Unilateral coronal synostosis denotes one-sided premature fusion of the frontoparietal suture. However, this is only one component of the coronal hemi-ring that includes the contiguous frontoparietal, frontosphenoidal, and frontoethmoidal sutures. Possible fusion of the basilar sutures in unilateral coronal synostosis is poorly documented., Methods: The authors retrospectively reviewed the radiographic records of 91 patients with unilateral coronal synostosis who were evaluated in their unit between 1986 and 2003. Fifty-one computed tomography scans were of sufficient quality to adequately assess the basilar sutures. Each suture in the coronal hemi-ring (frontoparietal, frontosphenoid, and sphenoethmoid) was assessed on axial images for evidence of synostosis, extent and location of fusion, and cranial base angulation. The data were analyzed using SAS statistical software (SAS, Cary, N.C.)., Results: One frontoparietal ("coronal") suture was fused in all 50 patients. Synostosis was incomplete in 19 patients; specifically, the superior and inferior portions of the frontoparietal suture were patent. Fourteen of the 19 scans showing partial frontoparietal fusion were in infants less than 5 months of age. Scans were grouped according to extent of fusion in the basilar coronal hemi-ring: group I (n = 15), the frontosphenoidal suture was open on the affected side, whereas in group II (n = 36), there was variable synostosis in the lateral portion of the ipsilateral frontosphenoidal suture. Patients in group I were significantly younger than those in group II at the time of computed tomographic study (p < 0.001). Furthermore, group I patients were more likely to have incomplete frontoparietal fusion, as compared with group II (p < 0.001). The frontosphenoidal suture was patent in 100 percent of patients younger than 3 months, in 43 percent of those between 3 and 5 months old, and in 0 percent of patients older than 5 months at the time the scan was obtained. There was also a trend toward a larger cranial base angulation in group II, although this difference was not significant (p = 0.33). Seven patients were syndromic; however, their mean age (207 days) at the time of computed tomography was not statistically different from that of patients without a detectable mutation (188 days), nor did the cranial base angulation differ in this subgroup., Conclusions: The authors conclude that unilateral coronal fusion begins in the middle of the frontoparietal suture and extends superiorly and inferiorly. There also is age-dependent, progressive involvement of the lateral frontosphenoidal suture between 3 and 5 months of age. Nevertheless, synostotic extension into the basilar coronal hemi-ring is not associated with increased cranial base angulation.

Structural chromosome abnormalities have aided in gene identification for over three decades. Delineation of the deletion sizes and rearrangements allows for phenotype/genotype correlations and ultimately assists in gene identification. In this report, we have delineated the precise rearrangements in four subjects with deletions, duplications, and/or triplications of 1p36 and compared the regions of imbalance to two cases recently published. Fluorescence in situ hybridization (FISH) analysis revealed the size, order, and orientation of the duplicated/triplicated segments in each subject. We propose a premeiotic model for the formation of these complex rearrangements in the four newly ascertained subjects, whereby a deleted chromosome 1 undergoes a combination of multiple breakage-fusion-bridge (BFB) cycles and inversions to produce a chromosome arm with a complex rearrangement of deleted, duplicated and triplicated segments. In addition, comparing the six subjects' rearrangements revealed a region of overlap that when triplicated is associated with craniosynostosis and when deleted is associated with large, late-closing anterior fontanels. Within this region are the MMP23A and -B genes. We show MMP23 gene expression at the cranial sutures and we propose that haploinsufficiency results in large, late-closing anterior fontanels and overexpression results in craniosynostosis. These data emphasize the important role of cytogenetics in investigating and uncovering the etiologies of human genetic disease, particularly cytogenetic imbalances that reveal potentially dosage-sensitive genes.

Intracranial pressure (ICP) and skull volume are intricately related. Craniosynostosis alters skull volume, and the many forms of craniosynostosis complicate the relationship to ICP even further. Patients with single-suture synostosis are less likely to experience elevated ICP than patients in whom multiple sutures, craniofacial syndromes, or both are involved. Among patients with more than one suture involved, the multifactorial mechanisms underlying elevated ICP include cephalocranial disproportion and venous outflow obstruction. Direct monitoring of ICP for at least 24 hours can aid in the diagnosis and decision making process. The management of craniosynostotic patients is diverse and necessitates a long-term plan for follow-up.

Craniosynostosis, the premature fusion of cranial sutures, is one of the most common craniofacial anomalies, with a reported incidence of up to one in 2500 live births. Despite its prevalence, the cause of craniosynostosis remains unknown. Previously, apoptosis has been postulated to be a contributing factor in the pathogenesis of craniosynostosis, although the role of programmed cell death in cranial sutures is poorly understood. To address this problem, the authors used an established rodent model of posterior-frontal suture fusion and sagittal suture patency to globally examine apoptosis in cranial sutures. Apoptosis was evaluated by systemically coinjecting Sprague-Dawley rats with both fluorescent and technetium-99m-labeled annexin V at time points before, during, and after the period of predicted posterior-frontal suture fusion to determine the magnitude and time course of overall apoptotic activity in both fusing and patent sutures. Using these novel in situ imaging techniques, the authors observed a significant increase in the overall levels of apoptosis in both the posterior-frontal and sagittal suture complexes during the period of predicted posterior-frontal suture fusion. To further explore this increase in apoptotic activity, they used microarray technology to study apoptosis-related genes within the suture complex. Interestingly, there was activation of distinct apoptotic pathways in the posterior-frontal and sagittal sutures during the period of predicted posterior-frontal suture fusion. Whereas increased transcription of genes associated with the mitochondria-mediated apoptotic pathway occurred in the posterior-frontal suture during fusion, activation of genes associated with the death receptor-mediated apoptotic pathway predominated in the patent sagittal suture during the same time period. These data suggest that although overall apoptotic activity in rat patent and fusing sutures is similar, the pathways mediating apoptosis within each suture are distinct.

Unlabelled: Craniosynostosis, premature fusion of the skull bones at the sutures, is the second most common human birth defect in the skull. Raman microspectroscopy was used to examine the composition, relative amounts, and locations of the mineral and matrix produced in mouse skulls undergoing force-induced craniosynostosis. Raman imaging revealed decreased relative mineral content in skulls undergoing craniosynostosis compared with unloaded specimens., Introduction: Raman microspectroscopy, a nondestructive vibrational spectroscopic technique, was used to examine the composition, relative amounts, and locations of the mineral and matrix produced in mouse skulls undergoing force-induced craniosynostosis. Craniosynostosis, premature fusion of the skull bones at the sutures, is the second most common birth defect in the face and skull. The calvaria, or flat bones that comprise the top of the skull, are most often affected, and craniosynostosis is a feature of over 100 human syndromes and conditions., Materials and Methods: Raman images of the suture, the tips immediately adjacent to the suture (osteogenic fronts), and mature parietal bones of loaded and unloaded calvaria were acquired. Images were acquired at 2.6 x 2.6 microm spatial resolution and ranged in a field of view from 180 x 210 microm to 180 x 325 microm., Results and Conclusions: This study found that osteogenic fronts subjected to uniaxial compression had decreased relative mineral content compared with unloaded osteogenic fronts, presumably because of new and incomplete mineral deposition. Increased matrix production in osteogenic fronts undergoing craniosynostosis was observed. Understanding how force affects the composition, relative amounts, and location of the mineral and matrix provides insight into musculoskeletal disease in general and craniosynostosis in particular. This is the first report in which Raman microspectroscopy was used to study musculoskeletal disease. These data show how Raman microspectroscopy can be used to study subtle changes that occur in disease.

A series of experiments was performed on young monkeys, rabbits, and turtles to study gross sutural growth of bones. Radiopaque implants in conjunction with serial, direct gross, and indirect radiographic measurements were employed. Differences in growth were observed in the monkey among five facial sutures and also the same suture at different times. Growth was greatest at the zygomaticotemporal suture and least at the premaxillomaxillary suture. In the rabbit, the nasal bone side of the frontonasal suture grew about twice as fast as the frontal bone side. In the turtle shell, the midsagittal suture grew faster than the transverse suture. In all of the animals, the rate of sutural growth decreased with an increase in age. No gross regional growth disturbance was noted after resection of the frontonasal, midpalatine, or transpalatine sutures. The frontonasal suture reformed presumably because of the underlying nasomucoperiosteum, as in a cranial suture, presumably because of the underlying dura. After extirpation of the midpalatine suture with the formation of a complete cleft and despite no underlying membrane, a new suture reformed in an eccentric position in a number of instances. Bone growth at sutures is secondary or compensatory to some other factors.

Differentiation of skeletal tissues, such as bone, ligament and cartilage, is regulated by complex interaction between genetic and epigenetic factors. In the present study, we attempted to elucidate the possible role of cell-extracellular matrix (ECM) adhesion on the inhibitory regulation in chondrogenesis responding to the tension force. The midpalatal suture cartilages in rats were expanded by orthopedic force. In situ hybridization for type I and II collagens, immunohistochemical analysis for fibronectin, alpha5 and beta1 integrins, paxillin, and vinculin, and cytochemical staining for actin were used to demonstrate the phenotypic change of chondrocytes. Immunohistochemical analysis for phosphorylation and nuclear translocation of extracellular signal-regulated kinase (ERK)-1/2 was performed. The role of the cell-ECM adhesion in the response of the chondroprogenitor cells to mechanical stress and the regulation of gene expression of focal adhesion kinase (FAK) and integrins were analyzed by using an in vitro system. A fibrous suture tissue replaced the midpalatal suture cartilage by the expansive force application for 14 days. The active osteoblasts that line the surface of bone matrix in the newly formed suture tissue strongly expressed the type I collagen gene, whereas they did not express the type II collagen gene. Although the numbers of precartilaginous cells expressing alpha5 and beta1 integrin increased, the immunoreactivity of alpha5 integrin in each cell was maintained at the same level throughout the experimental period. During the early response of midpalatal suture cartilage cells to expansive stimulation, formation of stress fibers, reorganization of focal adhesion contacts immunoreactive to a vinculin-specific antibody, and phosphorylation and nuclear translocation of ERK-1/2 were observed. In vitro experiments were in agreement with the results from the in vivo study, i.e. the inhibited expression of type II collagen and upregulation in integrin expression. The arginine-glycine-aspartic acid-containing peptide completely rescued chondrogenesis from tension-mediated inhibition. Thus, we conclude that stretching activates gene expression of beta1 integrin and FAK and inhibits chondrogenesis through cell-ECM interactions of chondroprogenitor cells.