Craniofacial sutures: morphology, growth, and in vivo masticatory strains. (1/66)

The growth and morphology of craniofacial sutures are thought to reflect their functional environment. However, little is known about in vivo sutural mechanics. The present study investigates the strains experienced by the internasal, nasofrontal, and anterior interfrontal sutures during masticatory activity in 4-6-month-old miniature swine (Sus scrofa). Measurements of the bony/fibrous arrangements and growth rates of these sutures were then examined in the context of their mechanical environment. Large tensile strains were measured in the interfrontal suture (1,036 microepsilon +/- 400 SD), whereas the posterior internasal suture was under moderate compression (-440 microepsilon +/- 238) and the nasofrontal suture experienced large compression (-1,583 microepsilon +/- 506). Sutural interdigitation was associated with compressive strain. The collagen fibers of the internasal and interfrontal sutures were clearly arranged to resist compression and tension, respectively, whereas those of the nasofrontal suture could not be readily characterized as either compression or tension resisting. The average linear rate of growth over a 1-week period at the nasofrontal suture (133.8 micrometer, +/- 50.9 S.D) was significantly greater than that of both the internasal and interfrontal sutures (39.2 micrometer +/- 11.4 and 65. 5 micrometer +/- 14.0, respectively). Histological observations suggest that the nasofrontal suture contains chondroid tissue, which may explain the unexpected combination of high compressive loading and rapid growth in this suture.  (+info)

Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. (2/66)

Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used. ARMS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles. A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families. Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome). Eleven different mutations in the 22 families were detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P=2. 4x10-7; 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34. 50+/-7.65 years vs. 30.45+/-1.28 years, P<.01). Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations.  (+info)

Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. (3/66)

Fibroblast growth factors (FGF) play a critical role in bone growth and development affecting both chondrogenesis and osteogenesis. During the process of intramembranous ossification, which leads to the formation of the flat bones of the skull, unregulated FGF signaling can produce premature suture closure or craniosynostosis and other craniofacial deformities. Indeed, many human craniosynostosis disorders have been linked to activating mutations in FGF receptors (FGFR) 1 and 2, but the precise effects of FGF on the proliferation, maturation and differentiation of the target osteoblastic cells are still unclear. In this report, we studied the effects of FGF treatment on primary murine calvarial osteoblast, and on OB1, a newly established osteoblastic cell line. We show that FGF signaling has a dual effect on osteoblast proliferation and differentiation. FGFs activate the endogenous FGFRs leading to the formation of a Grb2/FRS2/Shp2 complex and activation of MAP kinase. However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis. When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. To study the effect of craniosynostosis-linked mutations in osteoblasts, we introduced FGFR2 carrying either the C342Y (Crouzon syndrome) or the S252W (Apert syndrome) mutation in OB1 cells. Both mutations inhibited differentiation, while dramatically inducing apoptosis. Furthermore, we could also show that overexpression of FGF2 in transgenic mice leads to increased apoptosis in their calvaria. These data provide the first biochemical analysis of FGF signaling in osteoblasts, and show that FGF can act as a cell death inducer with distinct effects in proliferating and differentiating osteoblasts.  (+info)

New surgical concepts resulting from cranio-orbito-facial surgery. (4/66)

The authors have defined the subspecialty of craniofacial surgery and described the organization of the multi-disciplinary team required to care for such patients. Common features of the craniofacial patient have been summarized and three major categories of patients have been proposed. These are: I. Syndromes associated with hypertelorism; II. Syndromes associated with premature synostoses or growth arrests; III. Syndromes associated with primarily mid- and lower face anomalies. Growing out of an experience with 242 operations on 106 patients, the authors have listed 9 relatively new surgical "principles." Each has led to a current surgical approach that is now being employed by the craniofacial team at The University of Virginia. A number of examples are given to show ways in which the lessons learned from the craniofacial patients are now being applied, with improved results, to patients with neoplasms, traumatic injuries, or other conditions.  (+info)

Prominent basal emissary foramina in syndromic craniosynostosis: correlation with phenotypic and molecular diagnoses. (5/66)

BACKGROUND AND PURPOSE: Jugular foraminal stenosis (JFS) or atresia (JFA) with collateral emissary veins (EV) has been documented in syndromic craniosynostosis. Disruption of EV during surgery can produce massive hemorrhage. Our purpose was to describe the prevalence of prominent basal emissary foramina (EF), which transmit enlarged EV, in syndromic craniosynostosis. Our findings were correlated with phenotypic and molecular diagnoses. METHODS: We reviewed the medical records and imaging examinations of 33 patients with syndromic craniosynostosis and known fibroblast growth factor receptor (FGFR) mutations. All patients underwent CT and 14 MR imaging. The cranial base was assessed for size of occipitomastoid EF and jugular foramina (JF). Vascular imaging studies were available from 12 patients. A control group (n = 76) was used to establish normal size criteria for JF and EF. RESULTS: Phenotypic classification included Crouzon syndrome (n = 10), crouzonoid features with acanthosis nigricans (n = 3), Apert syndrome (n = 10), Pfeiffer syndrome (n = 4), and clinically unclassifiable bilateral coronal synostosis (n = 6). EF > or = 3 mm in diameter and JFS or JFA were identified in 23 patients with various molecular diagnoses. Vascular imaging in patients with JFS or JFA and enlarged EF revealed atresia or stenosis of the jugular veins and enlarged basal EV. JFA was seen in all patients with the FGFR3 mutation with crouzonoid features and acanthosis nigricans. Four patients had prominent EF without JFS. Six patients had normal JF and lacked enlarged EF. CONCLUSION: Enlarged basal EF are common in syndromic craniosynostosis and are usually associated with JFS or JFA. Bilateral basilar venous atresia is most common in patients with the FGFR3 ala391glu mutation and crouzonoid features with acanthosis nigricans, but may be found in patients with FGFR2 mutations. Skull base vascular imaging should be obtained in patients with syndromic craniosynostosis with enlarged EF.  (+info)

Role of the extracellular matrix and growth factors in skull morphogenesis and in the pathogenesis of craniosynostosis. (6/66)

The complex and largely obscure regulatory processes that underlie ossification and fusion of the sutures during skull morphogenesis are dependent on the conditions of the extracellular microenvironment. The concept that growth factors are involved in the pathophysiology of craniosynostosis due to premature fusion of skull bone sutures, is supported by recent genetic data. Crouzon and Apert syndromes, for example, are characterized by point mutations in the extracellular or transmembrane domains of fibroblast growth factor-2 receptor. In primary cultures of periosteal fibroblasts and osteoblasts obtained from Apert and Crouzon patients, we observed that Crouzon and Apert cells behaved differently with respect to normal cells as regards the expression of cytokines and extracellular matrix (ECM) macromolecule accumulation. Further modulation of ECM components observed after the addition of cytokines provides support for an autocrine involvement of these cytokines in Crouzon and Apert phenotype. Changes in ECM composition could explain the altered osteogenic process and account for pathological variations in cranial development. We suggest that a correlation exists between in vitro phenotype, clinical features and genotype in the two craniosynostotic syndromes. New research into signal transduction pathways should establish further connections between the mutated genotype and the molecular biology of the cellular phenotype.  (+info)

The prenatal diagnosis of Binder syndrome before 24 weeks of gestation: case report. (7/66)

A case of Binder syndrome was diagnosed at 21 weeks of gestation using two-dimensional and three-dimensional ultrasound. The first indication of any abnormality was a flattened fetal nose demonstrated in the mid-sagittal plane. Further ultrasound imaging showed the virtual absence of the naso-frontal angle, giving the impression of a flat forehead and small fetal nose. Suspected mild hypertelorism was also seen using transverse and coronal planes. Differential diagnosis of this condition is discussed.  (+info)

Stenosis of the cervical canal in craniodiaphyseal dysplasia. (8/66)

Craniodiaphyseal dysplasia (CDD) is a rare sclerosing bone disorder, the severity of which depends on its phenotypic expression. Hyperostosis can cause progressive foraminal stenosis leading to palsy of cranial nerves, epilepsy and mental retardation. We report the only case of CDD in an adult, with stenosis of the cervical canal leading to quadriparesis as a late complication of hyperostosis, and describe the problems associated with its treatment. Although the syndrome is rare, its pathophysiological and therapeutic considerations may be applicable to the management of stenosis of the spinal canal in other hyperostotic bone disorders.  (+info)