Metopic synostosis: Defining the temporal sequence of normal suture fusion and differentiating it from synostosis on the basis of computed tomography images

Only the metopic suture normally fuses during early childhood; all other cranial sutures normally fuse much later in life. Despite this, metopic synostosis is one of the least common forms of craniosynostosis. The temporal sequence of normal physiologic metopic suture fusion remains undefined and controversial. Therefore, diagnosis of metopic synostosis on the basis of computed tomography images alone can prove misleading. The present study sought to determine the normal sequence of metopic suture fusion and characterize both endocranial and ectocranial suture morphology. An analysis of computed tomography scans of 76 trauma patients, ranging in age from 10 days to 18 months, provided normative craniofacial data that could be compared to similar data obtained from the preoperative computed tomography scans of 30 patients who had undergone surgical treatment for metopic synostosis. Metopic suture fusion was complete by 6 to 8 months in all nonsynostotic patients, with initiation of suture fusion evident as early as 3 months of age. Fusion was found to commence at the nasion, proceed superiorly in progressive fashion, and conclude at the anterior fontanelle. Although an endocranial ridge was not commonly seen in synostotic patients, an endocranial metopic notch was virtually diagnostic of premature suture fusion and was seen in 93 percent of synostotic patients. A metopic notch was not seen in any nonsynostotic patient. The morphologic and normative craniofacial data presented permit diagnosis of metopic synostosis based on computed tomography images obtained beyond the normal fusion period.     

Preoperative anthropometric dysmorphology in metopic synostosis

Anthropometric identification of dysmorphology in craniofacial anomalies, including the craniosynostoses, provides invaluable assistance in clinical diagnosis as well as offering a technique for interpreting possible deformities in skeletal remains. Premature closure of the metopic suture is a rare form of craniosynostosis, representing about 4% of clinically diagnosed synostoses. Accompanying this closure are defects of the head and face, particularly the upper face and orbits. To identify quantitatively the craniofacial dysmorphology associated with metopic synostosis, 50 patients with a diagnosis of primary (nonsyndromal) metopic synostosis were examined using a battery of 24 anthropometric measurements from which 11 proportion indices were calculated. The data were compared to sex- and age-matched normal standards and converted to standard (Z) scores before being analyzed using Student's t-test. The data indicate a complex pattern of dysmorphology arising from the synostosis which affects the upper face and orbits as well as the cranial vault. The entire fronto-orbito-zygomatic complex is narrowed, and vertex is reduced. There is compensatory sagittal and transverse growth of the posterior neurocranium and compensatory vertical and sagittal growth of the upper face. There are statistically significant differences in the pattern of dysmorphology between patients presenting prior to 6 months of age and those older but no significant differences between sexes. Am J Phys Anthropol 103:341–351, 1997. © 1997 Wiley-Liss, Inc.     

American society of maxillofacial surgeons outcome study: preoperative and postoperative neurodevelopmental findings in single-suture craniosynostosis

The purpose of this study was to prospectively determine the neurodevelopmental effects associated with single-suture, nonsyndromic craniosynostosis before and after surgery. Children diagnosed with single-suture craniosynostosis were evaluated by a psychologist using the Bayley Scales of Infant Development-Second Edition (BSID-II) within 2 months before and again 1 year after surgical correction. The BSID-II is a widely used measure of infant cognitive and motor development. The scale consists of three parts, the Mental Developmental Index (MDI), the Psychomotor Developmental Index (PDI), and the Behavior Rating Scale. The MDI and PDI yield age-standard scores (mean, 100; SD, 16). The children ranged in age from 2.5 to 10 months at the time of the craniofacial reconstruction (average age, 5.9 months). Metopic synostosis was diagnosed in 23 percent, sagittal synostosis in 45 percent, and unilateral coronal synostosis in 32 percent of patients. Twenty-two patients were evaluated preoperatively, of whom 15 patients were evaluated postoperatively. Mean baseline BSID-II scores revealed a mild delay in mental and motor scores (MDI, 82.3; PDI, 79.5). Mean postoperative BSID-II scores still revealed a mild delay in mental scores but significantly improved motor scores (MDI, 79.3; PDI, 89.3). Of the 15 children, four (27 percent) had BSID-II evaluations that were in the average range for all scales and nine infants (60 percent) had at least one MDI or PDI score in the significantly delayed range (<70). Among children with single-suture nonsyndromic craniosynostosis, mean Bayley scores indicated mild baseline deficits in both mental and motor scores. After surgical treatment, improvement was seen in the motor scale. It appears from this sample that neurodevelopmental abnormalities may be present in children with single-suture synostosis, and some may persist at 1 year of follow-up.     

Neurodevelopment in children with single-suture craniosynostosis and plagiocephaly without synostosis.

The objective of this study was to determine whether children with nonsyndromic craniosynostosis and plagiocephaly without synostosis demonstrated cognitive and psychomotor delays when compared with a standardized population sample. This was the initial assessment of a larger prospective study, which involved 21 subjects with nonsyndromic craniosynostosis (mean age, 10.9 months) and 42 subjects with plagiocephaly without synostosis (mean age, 8.4 months). Each child was assessed using the Bayley Scales of Infant Development-II (BSID-II) for cognitive and psychomotor development before therapeutic intervention (surgery for craniosynostosis and molding-helmet therapy for plagiocephaly without synostosis). The distribution of the scores was divided into four groups: accelerated, normal, mild delay, and significant delay. The distributions of the mental developmental index (MDI) and the psychomotor developmental index (PDI) were then compared with a standardized Bayley's age-matched population, using Fisher's exact chi-square test. Within the craniosynostosis group, the PDI scores were significantly different from the standardized distribution (p < 0.001). With regard to the PDI scores, 0 percent of the subjects in the craniosynostosis group were accelerated, 43 percent were normal, 48 percent had mild delay, and 9 percent had significant delay. In contrast, the MDI scores were not statistically different (p = 0.08). Within the group with plagiocephaly without synostosis, both the PDI and MDI scores were significantly different from the normal curve distribution (p < 0.001). With regard to the PDI scores, 0 percent of the subjects in the group with plagiocephaly without synostosis were accelerated, 67 percent were normal, 20 percent had mild delay, and 13 percent had significant delay. With regard to the MDI scores, 0 percent of the subjects in this group were accelerated, 83 percent were normal, 8 percent had mild delay and 9 percent had significant delay. This study indicates that before any intervention, subjects with single-suture syndromic craniosynostosis and plagiocephaly without synostosis demonstrate delays in cognitive and psychomotor development. Continued postintervention assessments are needed to determine whether these developmental delays can be ameliorated with treatment.     

Clinical characteristics of patients with unicoronal synostosis and mutations of fibroblast growth factor receptor 3: a preliminary report.

Clinical teaching dictates that isolated unicoronal synostosis is sporadic in occurrence and is possibly related to intrauterine constraint. Despite this, isolated reports document a familial occurrence. It has previously been recognized that there may be a familial pattern of inheritance. Recently, mutations in fibroblast growth factor receptors (FGFRs) have been implicated in several syndromic craniosynostoses. At the authors' institution, mutations in FGFR3, located at chromosome 4p16, have been found to cause coronal synostosis. Two cases of unicoronal synostosis were found to have the same Pro250Arg missense mutation in FGFR3. This finding suggested that all patients with a diagnosis of unicoronal synostosis be screened for the FGFR3 mutation. Between January and December of 1996, patients with a diagnosis of plagiocephaly at the Children's Hospital of Philadelphia were evaluated for the FGFR3 mutation. Thirty-seven patients with unicoronal synostosis had mutational studies. Two additional patients were known to have the FGFR3 mutation at the onset of the study. Of the 37 patients screened, four were found to have the FGFR3 mutation, for a total of six patients with both unicoronal synostosis and the FGFR3 mutation. All patients with unicoronal synostosis were evaluated for facial dysmorphology and operative outcome. The six patients with the FGFR3 mutation had more severe cranial dysmorphology and were more likely to need surgical revision than those without the FGFR3 mutation. The occurrence of the FGFR3 mutation among patients with unicoronal synostosis provides evidence for a genetic basis of certain forms of plagiocephaly. The clinical, radiologic, and molecular findings will be an important addition to the surgical management and counseling of patients with unicoronal synostosis.     

Photographic assessment of head shape following sagittal synostosis surgery.

A photographic assessment of the head shape of infants who had undergone surgical correction of sagittal synostosis was performed to determine (a) whether this subset could be delineated from an age-matched normal subpopulation and (b) whether two operative procedures differed in achieving normalization of head shape. This retrospective study included 8 patients who underwent extended strip craniectomy, 12 patients who underwent subtotal calvarectomy and cranial vault remodeling, and 12 age-matched subjects with no calvarial abnormality, for a total of 32 subjects. Criteria for inclusion in this study included surgery for sagittal synostosis within the first year of life and postoperative photographs at ages 4 to 8 years (mean, 4.5 years). Each set of images (frontal and lateral profile) were ranked from most to least normal by five lay observers and four professional observers. The rankings were analyzed with statistics designed for ordinal data. Differences in ranking between treatment groups were examined with Kruskal-Wallis rank sums tests. Mean ranks were calculated for lay and professional observers in an attempt to produce simpler and more generalizable results; these means were also analyzed using statistics designed for ordinal data. There was no statistical difference in the ranks of infants who had undergone a surgical correction and the normal subpopulation. In the mean rankings of the lay observers, the normal groups had the highest score mean (15.6), the group with extended strip craniectomy was second (16.0), and the subtotal calvarectomy with calvarial remodeling group was last (17.8) (p = 0.84). In the mean rankings of the professional observers, the normal groups again had the highest score mean (15.8), the subtotal calvarectomy group was second (15.9), and the extended craniectomy group was last (18.6) (p = 0.77). These results suggest that children who have undergone correction of sagittal synostosis in infancy are indistinguishable from their peers, on the basis of fully haired head shape on frontal and lateral photographs, when they begin primary school, irrespective of the type of calvarial surgery.     

Correction of unilateral coronal synostosis leads to resolution of mandibular asymmetry in rabbits

Mandibular dysmorphology in unilateral coronal synostosis has been recognized clinically. In patients with unilateral coronal synostosis, the chin point deviates away from the affected side. To investigate whether this mandibular asymmetry resolves after correction of unilateral coronal synostosis, familial nonsyndromic rabbits were used. Rabbits with unilateral coronal synostosis that underwent "correction" with resection of the affected suture were compared with "uncorrected" rabbits with unilateral coronal synostosis and normal, wild-type rabbits (n = 36; three equal groups of 12). Serial lateral cephalograms obtained at 10, 25, 42, and 84 days showed no asymmetries in wild-type rabbits and progressive asymmetries in the ramal height and mandibular length in uncorrected unilateral coronal synostosis rabbits. However, in corrected unilateral coronal synostosis rabbits, existing asymmetries at 10 and 25 days improved by 42 days and were not seen by maturity, at 84 days. In dry, mature, mandibular specimens, wild-type rabbits showed equal side-to-side measurements and uncorrected unilateral coronal synostosis rabbits showed the following on the affected side: longer ramal height (15 percent), shorter ramal width (13 percent), longer body height (10 percent), and shorter body width (13 percent). By contrast, the corrected unilateral coronal synostosis specimens showed no side-to-side differences in 10 of 11. There were no asymmetries in condylar shape or condylar volume in any of the three groups. Cranial base measurements showed asymmetries of the uncorrected unilateral coronal synostosis specimens that were consistent with an anteriorly positioned glenoid fossa on the affected side. However, only one of 11 corrected unilateral coronal synostosis specimens showed similar cranial base asymmetries. The data showed that mandibular asymmetries in nonsyndromic, familial rabbits with unilateral coronal synostosis are progressive with growth but improve after correction of synostosis.     

Maxillary volume growth in craniosynostosis

Craniosynostosis, and in particular, craniofacial dysostosis, exhibits abnormalities of the nasomaxillary complex in form, position, and development. The aim of this study was to quantitatively assess the volumetric maxillary abnormality in patients at the time of initial diagnosis of craniosynostosis and to make comparisons with a "normal" reference range for maxillary volumes throughout childhood. The technique of segmentation was applied to preoperative computed tomographic head scans obtained in 31 children (14 boys, 17 girls), between 1 and 34 months of age (mean, 11.06 months), who underwent cranial expansion surgery for craniosynostosis affecting the coronal suture complex. Maxillary volumes were plotted against age for the first 3 years of life and were compared with a healthy population. There was no statistical difference between the two sexes for mean maxillary volume. The mean maxillary volumes for the entire group were statistically smaller than the norm (p = 0.046, linear regression with age as a covariable), but there was no statistical difference among the four different groups of coronal synostosis (unilateral coronal, nonsyndromic bilateral coronal, nonsyndromic complex pansynostosis, syndromic bilateral coronal synostosis) (p = 0.407, one-way analysis of variance). On graphic data analysis, the maxillary volume was smaller than the norm in craniosynostotic children who presented in the first few months of life. However, by 7 months of age in nonsyndromic bilateral coronal synostosis and by 17 months of age in syndromic bilateral coronal synostosis, the maxillary volumes had increased toward the norm. This implies that the effect of the craniosynostotic process on the midface structures is present from birth and parallels the effect on the cranial vault sutures.     

The reversal exchange technique of total calvarial reconstruction for sagittal synostosis

The role of total calvarial reconstruction in the treatment of sagittal synostosis remains controversial, especially in patients younger than 1 year of age. The purpose of this study was to prospectively evaluate the efficacy of a single surgical technique for total calvarial reconstruction (the reversal exchange technique) in patients younger than 1 year of age who had a radiographically confirmed diagnosis of sagittal synostosis. Twenty-three consecutive patients underwent the reversal exchange technique of total calvarial reconstruction at a median age of 3 months (age range, 6 weeks to 10 months). Quantitative assessments were performed on the basis of preoperative and postoperative (minimum, 6 months) measurements of the cephalic index (cranial width/cranial length x 100) taken from three-dimensional computed tomography scans, which were obtained in 18 of 23 patients. Aesthetic assessments were performed on the basis of the grading of preoperative and postoperative photographs, obtained in 17 of 23 patients, by three independent raters who were blinded as to the surgical technique. The mean preoperative cephalic index was 65.0, and the mean postoperative index was 76.4, yielding a mean improvement of 11.4 (17.5 percent). By photographic evaluation, 12 of 17 patients (70.6 percent) were classified as having a normal head shape (grade 4) and five of 17 (29.4 percent) as having minor residual deformities (grade 3). No patients were identified as having significant residual deformities (grades 1 or 2). There were two intraoperative complications and one postoperative complication, none of which resulted in permanent morbidity. It was concluded that the reversal exchange technique of total calvarial reconstruction provided significant improvement in head shape on the basis of quantitative measurements (cephalic index) and independent evaluations of aesthetic improvement.     

Coronal ring involvement in patients treated for unilateral coronal craniosynostosis

The etiopathology of the clinical entity normally referred to as unilateral coronal synostosis is commonly used to connote unilateral fusion of the frontoparietal suture. However, other sutures in the coronal ring may exhibit synostosis concomitant with or independent from frontoparietal synostosis and give rise to similar clinical phenotypes. This study retrospectively analyzes high-resolution computed tomographic data sets to determine patency of sutures within the coronal ring. Computed tomographic scan digital data from 33 infants who subsequently underwent surgical correction of unilateral coronal synostosis were assessed for sutural patency using Analyze imaging software. The frontosphenoidal suture was subdivided into intraorbital frontosphenoidal and extraorbital frontosphenoidal portions, and the patency of the frontoethmoidal suture was also assessed. Patients were sorted into two groups on the basis of the status of their frontosphenoidal sutures: group 1 had patent frontosphenoidal but synostotic frontoparietal sutures (n = 21) and group 2 had both frontosphenoidal and frontoparietal synostoses. Observer reproducibility was tested. The vertical and horizontal dimensions of the bony orbit and the endocranial base deflection angle were measured with the observer blinded with regard to sutural status group. Frontoethmoidal synostosis was not noted in any patients in either group. Two patients had no frontoparietal suture synostosis with isolated intraorbital frontosphenoidal and extraorbital frontosphenoidal suture closures. Suture diagnosis reproducibility was 99 percent. In group 1, the ipsilateral-to-contralateral vertical orbit dimension ratio averaged 1.11, whereas in group 2 it averaged 1.04 (p < 0.05). The ratio of horizontal orbit measurements was not significantly different between groups. In both groups, the endocranial base was deflected ipsilateral to the synostotic frontoparietal suture, with an average angle of 12 degrees in group 1 and 17 degrees in group 2 (p < 0.005). The extent of synostosis along the coronal sutural ring contributes to the dysmorphology of the orbit and the endocranial base deflection in patients whose clinical phenotypic diagnosis is unilateral coronal synostosis.     

Calvarial sutural abnormalities: metopic synostosis and coronal deformation--an anatomic, three-dimensional radiographic, and pathologic study

The purposes of this study were (1) to evaluate the histologic differences between synostotic versus deformational suture abnormalities and (2) to correlate these histologic findings with anatomic and three-dimensional computed tomographic (CT) scans. We examined three infants with premature metopic synostosis; one infant also had microcephaly trisomy 13 and curious overriding of the coronal sutures. The three-dimensional CT scans demonstrated obliteration of the metopic suture inferiorly. Histologic sections of this suture showed complete bony stenosis. The same pattern was found in all three infants, including the two infants with trigonocephaly who did not have trisomy 13 or microcephaly. In the trisomy 13 infant, the overlapped inferior coronal suture was obliterated on CT examination. However, histologic sections in this region showed a merging of bone; there was no synostosis. In summary, three-dimensional CT re-formation correlated with metopic suture histology. "Stenotic" fusion existed in all infants with trigonocephaly, those with normal and abnormal karyotypes, with and without microcephaly. However, three-dimensional CT re-formation of the trisomic infant showed opacification of the coronal suture in the areas of greatest overlap, whereas histology revealed a curious bone remodeling pattern, possibly a precursor to "deformational" craniosynostosis.     

Unilateral and bilateral expression of a quantitative trait: asymmetry and symmetry in coronal craniosynostosis

Bilateral symmetry in vertebrates is imperfect and mild asymmetries are found in normal growth and development. However, abnormal development is often characterized by strong asymmetries. Coronal craniosynostosis, defined here as consisting of premature suture closure and a characteristic skull shape, is a complex trait. The premature fusion of the coronal suture can occur unilaterally associated with skull asymmetry (anterior plagiocephaly) or bilaterally associated with a symmetric but brachycephalic skull. We investigated the relationship between coronal craniosynostosis and skull bilateral symmetry. Three-dimensional landmark coordinates were recorded on preoperative computed tomography images of children diagnosed with coronal nonsyndromic craniosynostosis (N = 40) and that of unaffected individuals (N = 20) and analyzed by geometric morphometrics. Our results showed that the fusion pattern of the coronal suture is similar across individuals and types of coronal craniosynostosis. Shape analysis showed that skulls of bilateral coronal craniosynostosis (BCS) and unaffected individuals display low degrees of asymmetry, whereas right and left unilateral coronal craniosynostosis (UCS) skulls are asymmetric and mirror images of one another. When premature fusion of the coronal suture (without taking into account cranial dysmorphology) is scored as a qualitative trait, the expected relationship between trait frequency and trait unilateral expression (i.e. negative correlation) is confirmed. Overall, we interpret our results as evidence that the same biological processes operate on the two sides in BCS skulls and on the affected side in UCS skulls, and that coronal craniosynostosis is a quantitative trait exhibiting a phenotypic continuum with BCS displaying more intense shape changes than UCS.     

Tracing craniosynostosis to its developmental stage through bone center displacement.

In metopic and coronal suture synostosis, the involved bone centers are abnormally situated just next to the affected suture. Bone centers are the starting point of ossification during embryogenesis from which bone growth spreads radially. In this paper, we describe a similar observation for sagittal suture synostosis, with both parietal bone centers located almost completely cranially. The (reduced) distance between the bone centers of a synostotic suture reflects the time during embryogenesis at which fusion took place. We suggest that in craniosynostosis the bone centers arise in their normal position, and initial outgrowth is undisturbed until the bone fronts meet. It is during this developmental stage that fusion occurs instead of suture formation. Due to the fusion, growth can only occur at the free bony rims from then on. The bone centers remain located at a fixed distance from one another in the middle of the fused bones, becoming relatively more displaced with time. This implies that the distance between the involved bone centers directly indicates the developmental period during which sutural growth was arrested. The same phenomenon of bone center displacement is found in types of craniosynostosis with and without fibroblast growth factor receptor (FGFR) or TWIST gene mutations.     

Inhibition of apoptosis: a potential mechanism for syndromic craniosynostosis

The biologic pathogenesis of syndromic craniosynostosis remains unknown. The purpose of this investigation was to determine whether specific biologic differences exist between normal calvarial osteoblasts and osteoblasts derived from patients with syndromic craniosynostosis. This study (1) examined the apoptotic rate and cell cycle of osteoblasts derived from patients with syndromic craniosynostosis, and (2) investigated for the presence of soluble factors released from syndrome-derived osteoblasts. Osteoblast cell lines were established from calvarial specimens of patients with clinically diagnosed syndromic synostosis and from normal controls. A co-culture technique was used to investigate for the presence of elaborated soluble factors. Apoptotic rate and cell cycle analyses were performed by using flow cytometry after staining with annexin V-fluorescein isothiocyanate and propidiumiodide, respectively. The apoptotic rate was significantly reduced in syndrome-derived osteoblasts as compared with control osteoblasts. Control osteoblasts co-cultured with syndromic osteoblasts demonstrated a dramatic reduction in their apoptotic rate as compared with those co-cultured with control osteoblasts. These results indicate that osteoblasts derived from patients with syndromic craniosynostosis display a lower apoptotic rate, a normal DNA synthetic rate, and the capability to reduce the apoptotic rate in normal calvarial osteoblasts through the elaboration of soluble factors.     

Endoscopic craniectomy for early correction of craniosynostosis

Twelve patients between 0.4 and 7.8 months of age were treated by an endoscopic approach to strip craniectomy. Nine patients had sagittal suture involvement. Two patients had a single unilateral lambdoid suture synostosis, and one patient had a combination of a right coronal synostosis and a metopic synostosis. Postoperatively, all patients were placed in cranial remodeling helmets and the results showed that the estimated blood loss ranged from 5 cc to 150 cc, with blood transfusion required in only one patient. All patients were discharged from the hospital by day 2, and all patients had an improvement in their cranial head shape. The specific technique of using the endoscope to aid in performing a strip craniectomy will be discussed. Nine endoscopically treated patients with the diagnosis of sagittal suture synostosis were compared with nine patients treated by using the Marchac remodeling techniques. The mean operative time (1.6 hours versus 3.5 hours), estimated blood loss (43 cc versus 168 cc), hospital costs ($11,671 versus $36,685), and length of stay (1.16 days versus 5.1 days) were less by using the endoscopic technique. All nine patients treated by using the Marchac technique required a blood transfusion, whereas only one patient was transfused in the endoscopically treated group.     

A genomic survey of the fish parasite Spironucleus salmonicida indicates genomic plastiCity among diplomonads and significant lateral gene transfer in eukaryote genome evolution

Background

Craniosynostosis, the premature fusion of calvarial sutures, is a common craniofacial abnormality. Causative mutations in more than 10 genes have been identified, involving fibroblast growth factor, transforming growth factor beta, and Eph/ephrin signalling pathways. Mutations affect each human calvarial suture (coronal, sagittal, metopic, and lambdoid) differently, suggesting different gene expression patterns exist in each human suture. To better understand the molecular control of human suture morphogenesis we used microarray analysis to identify genes differentially expressed during suture fusion in children with craniosynostosis. Expression differences were also analysed between each unfused suture type, between sutures from syndromic and non-syndromic craniosynostosis patients, and between unfused sutures from individuals with and without craniosynostosis.

Results

We identified genes with increased expression in unfused sutures compared to fusing/fused sutures that may be pivotal to the maintenance of suture patency or in controlling early osteoblast differentiation (i.e. RBP4, GPC3, C1QTNF3, IL11RA, PTN, POSTN). In addition, we have identified genes with increased expression in fusing/fused suture tissue that we suggest could have a role in premature suture fusion (i.e. WIF1, ANXA3, CYFIP2). Proteins of two of these genes, glypican 3 and retinol binding protein 4, were investigated by immunohistochemistry and localised to the suture mesenchyme and osteogenic fronts of developing human calvaria, respectively, suggesting novel roles for these proteins in the maintenance of suture patency or in controlling early osteoblast differentiation. We show that there is limited difference in whole genome expression between sutures isolated from patients with syndromic and non-syndromic craniosynostosis and confirmed this by quantitative RT-PCR. Furthermore, distinct expression profiles for each unfused suture type were noted, with the metopic suture being most disparate. Finally, although calvarial bones are generally thought to grow without a cartilage precursor, we show histologically and by identification of cartilage-specific gene expression that cartilage may be involved in the morphogenesis of lambdoid and posterior sagittal sutures.

Conclusion

This study has provided further insight into the complex signalling network which controls human calvarial suture morphogenesis and craniosynostosis. Identified genes are candidates for targeted therapeutic development and to screen for craniosynostosis-causing mutations.     

Craniosynostosis and altered patterns of fetal TGF-beta expression induced by intrauterine constraint

Recent work has demonstrated that fusion of the calvarial sutures is mediated by locally elaborated soluble growth factors, including the transforming growth factor-betas (TGF-betas), leading some to speculate that external biomechanical forces play little role in suture development. Clinical evidence has long suggested, however, that fetal head constraint may play a critical role in the pathogenesis of many cases of nonsyndromic craniosynostosis. The purpose of these experiments was to test the hypothesis that intrauterine constraint leads to an alteration in normal patterns of TGF-beta expression and that these alterations are associated with craniosynostosis. Fetal constraint was induced by allowing C57Bl/6 murine fetuses to grow for 2.5 days beyond the normal 20-day gestation by performing uterine cerclage on the eighteenth day. Cranial suture morphology was examined in hematoxylin and eosin-stained sections and in cleared whole-mount specimens, double stained with alizarin red S and Alcian blue. Expression patterns of TGF-beta1 and TGF-beta3 were examined by immunohistochemical techniques. Gross and microscopic examination of the cranial sutures of 17 constrained fetuses revealed changes that ranged from narrowing to complete osseous obliteration of the coronal and squamosal sutures. All sutures of 14 nonconstrained control pups remained patent. Fetal head constraint was associated with increased TGF-beta1 immunoreactivity within the new bone and the underlying dura when compared with nonconstrained age-matched controls. TGF-beta3 immunoreactivity was associated with the dura underlying patent, nonconstrained sutures, whereas constraint-induced synostosis was characterized by down-regulation of dural TGF-beta3 expression. These experiments confirm the ability of intrauterine constraint to induce premature fusion of the cranial sutures and provide evidence that intrauterine head constraint induces the expression of osteogenic growth factors in fetal calvarial bone and the underlying dura.     

Management of craniosynostosis

Learning Objectives: After studying this article, the participant should be able to: 1. Review the etiopathogenesis of craniosynostosis and craniofacial anomalies. 2. Develop a basic understanding of the clinical manifestations and diagnosis of craniofacial anomalies. 3. Describe the surgical principles of managing craniosynostosis and craniofacial anomalies.Craniosynostosis, or the premature closure of calvarial sutures, results in deformed calvaria at birth. Although the etiology of craniosynostosis is currently unknown, animal experiments and a recent interest in molecular biology point toward interplay between the dura and the underlying brain. This interaction occurs by means of a local alteration in the expression of transforming growth factor, MSX2, fibroblast growth factor receptor, and TWIST. The fused suture restricts growth of the calvaria, thus leading to a characteristic deformation, each associated with a different type of craniosynostosis. Uncorrected craniosynostosis leads to a continuing progression of the deformity, and in some cases, an elevation of intracranial pressure. Clinical examination should include not only an examination of the skull but also a general examination to rule out the craniofacial syndromes that accompany craniosynostosis. Because deformational plagiocephaly, or plagiocephaly without synostosis, occurs secondary to sleeping in the supine position during the early perinatal period, the physician should be aware of this abnormality. Treatment for deformational plagiocephaly is conservative when compared with treatment for craniosynostosis, which requires surgery. Appropriate investigations should include genetic screening, radiologic examination with a computerized tomographic scan, and neurodevelopmental analysis. Surgical intervention should be performed during infancy, preferably in the first 6 months of postnatal life, to prevent the further progression of the deformity and possible complications associated with increased intracranial pressure. The principles of surgical intervention are not only to excise the fused suture but also to attempt to normalize the calvarial shape. Long-term follow-up is critical to determine the effect of the surgical outcome.     

Simultaneous induction of apoptosis, collagen type I expression and mineralization in the developing coronal suture following FGF4 and FGF2 application

This study aimed to evaluate the disturbances in normal coronal suture development resulting in craniosynostosis, a congenital disorder in which the calvarial sutures close prematurely. Craniosynostosis syndromes can be caused by mutations in the genes encoding for the fibroblast growth factor receptors (FGFRs) 1, 2, and 3. These gain-of-function mutations cause the transcribed receptor to be constitutively activated. To mimic this genetic defect, fibroblast growth factor (FGF) 2 or 4 was administered near the developing coronal suture in normal mouse embryos through ex utero surgery. The effect on apoptosis and bone differentiation, as collagen type I expression and mineralization, within the FGF-exposed coronal suture was investigated through (immuno)histochemical staining. An increase in the number of apoptotic cells together with ectopic collagen type I expression within the suture and accelerated mineralization followed FGF application. Macroscopically, this presented as a synostotic coronal suture. These results suggest that both apoptosis and differentiation are two processes that are simultaneously implicated in synostosis of the coronal suture in case of a FGFR-related craniosynostosis.