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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.

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.)

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.

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.

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.

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.

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.

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.

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.

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: 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.

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.

Recent studies have implicated the transforming growth factor (TGF)-beta family in the regulation of pathological sporadic cranial suture fusion. In addition, these studies have shown that TGF-beta is highly expressed by the dura mater underlying fusing murine cranial sutures. The purpose of the present experiments was to analyze the effects of disrupting TGF-beta signaling during programmed mouse cranial suture fusion. Using recombinant DNA technology, a replication-deficient adenovirus encoding a defective TGF-beta receptor (Ad.DN-TbetaRII) capable of blocking TGF-beta biological activity was constructed. Mouse posterior frontal sutures were harvested before the initiation of suture fusion (postnatal day 25), and the dura mater underlying the suture was infected with vehicle, Ad.DN-TbetaRII, or control virus (Ad.LacZ; n = 10 each). Sutures were cultured for 14 or 30 days in an organ culture system and analyzed macroscopically and histologically.X-gal staining of Ad.LacZ-infected sutures 14 days after culture revealed strong staining of cells localized to the dura mater. Macroscopic analysis revealed complete sutural fusion in vehicle and Ad.LacZ-infected sutures. In contrast, Ad.DN-TBRII-infected sutures demonstrated nearly complete patency. Histological analysis confirmed our macroscopic observations with sutural fusion in 81.3 +/- 10 percent and 74.5 +/- 9 percent of vehicle and Ad.LacZ-infected sutures, respectively, versus 38.1 +/- 12 percent (p < 0.001) in Ad.DN-TbetaRII-infected sutures. In addition, transfection with the Ad.DN-TbetaRII virus resulted in a significant attenuation of anterior-to-posterior suture fusion, with the majority of fused sections localized to anterior sections. These data strongly implicate TGF-beta biological activity in the dura mater underlying the posterior frontal suture in the regulation of programmed sutural fusion. In addition, this study demonstrates the utility of adenovirus-mediated gene transfer in preventing programmed sutural fusion.

Although the etiology of nonsyndromic forms of craniosynostosis remains uncertain, recent experiments from our laboratory have demonstrated that fetal head constraint induces cranial suture fusion in mice through a process associated with altered patterns of transforming growth factor beta (TGF-beta) isoform expression. Other recent studies have highlighted the role of secreted signaling molecules, including members of the TGF-beta superfamily and the fibroblast growth factors (FGFs), as well as their receptors, in regulating suture development and fusion. The purpose of these experiments was to examine the potential role of TGF-beta receptors and FGF receptor 2 (FGFR2) in nonsyndromic craniosynostosis by determining their temporospatial patterns of expression during development complicated by intrauterine head constraint. This study consisted of two groups of C57BI/6J mice: an experimental group subjected to intrauterine constraint and a control unconstrained group. Fetal head constraint was induced by performing uterine cerclage on day 17.5 of gestation and allowing intrauterine fetal growth to continue 24 and 48 hours beyond the normal gestational period. Control animals underwent hysterotomy on day 17.5 and the nonconstrained pups were allowed to continue intra-abdominal fetal growth 48 hours beyond normal gestation. Expression of TGF-beta receptor types I and II, and FGFR2 in the calvarial tissue was determined by immunohistochemical analysis. In the unconstrained control animals, there was minimal immunoreactivity for both TGF-beta receptors and FGFR2 within the coronal suture. After 24 hours of constraint, however, there was a marked increase in immunoreactivity of TGF-beta receptors and FGFR2 in the osteoblasts along the osteogenic fronts and in the dural cells. After 48 hours, there was continued expression of both type I and type II receptors and FGFR2 within the midsutural mesenchyme of the coronal suture, in the osteoblasts, and in the dura. The authors demonstrated substantial upregulation of TGF-beta receptor types I and II and FGFR2 in coronal sutures subjected to in utero constraint. These results suggest an important role for TGF-beta/TGF-beta receptor, and FGF/FGFR signaling in the pathogenesis of constraint-induced craniosynostosis.

Purpose: To report a case in which strabismus surgery did not eliminate the abnormal head posture although it did improve the vertical strabismus; and to consider the causes of this situation., Case Report: The patient had a right eso-hypertropia and ocular torticollis to the left shoulder as a result of a right superior oblique mechanical deficiency, secondary to her craniosynostosis. A myectomy of the right inferior oblique muscle and a tucking procedure of the right superior oblique muscle were performed. Postoperatively, the abnormal head posture persisted, although strabismus surgery improved the vertical deviation. However, improvement of the abnormal head posture upon patching the deviated eye only indicated that the origin of the persistent abnormal head posture must be ocular. Further tests revealed that an anomalous retinal correspondence (ARC) with eccentric fixation was responsible., Conclusions: In patients with ocular torticollis, ARC with eccentric fixation must be ruled out prior to surgery as these may negatively affect the outcome.

Craniosynostoses have been known for at least 20 centuries, but their etiopathogeneses are still unclear. There are three main theories to explain the etiology of craniosynostosis, Moss's theory being the most popular. According to Moss, the development of the neurocranial form is viewed as an integration of the growth of the skull base, the calvarial bones, the meninges, and the enclosed brain. Experimental studies, however, are generally focused on cranial vault suture synostosis. This study aims to demonstrate the effects of cranial base synostosis by performing fronto-parieto-squamosal suture fusion. This fusion affected the whole cranial configuration. These effects were more prominent closer to the cranial vault, increasing at the anterior facial height and the lower facial length, reflected by ventral dislocation of the total face, and increasing of the kyphosis at the cranial base. It has also been demonstrated that synostosis of a junction point near the cranial base affects the vault and the base simultaneously. Any approach that tries to treat the cause, and not the symptom, of synostosis must, then, be based on an understanding of how cranial growth occurs and of how sutural growth processes are related to the totality of cranial growth.

A longitudinal growth analysis of a patient with premature closure of the left coronal suture is presented. The resultant facial asymmetry of patients with unilateral synostosis of the coronal suture is accompanied by diagnostic facial characteristics and radiographic skull distortions. The midfacial structures distort and grow toward the site of synostosis while the lower face grows away from the site of synostosis. Unilateral craniosynostosis of the coronal suture results in distortions and compensations within the cranial vault and the cranial base. Therefore, with growth of the contiguous facial structures, the facial distortions are magnified.