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PubMed1994

Development of the frontal sinus and glabellar morphology after frontocranial remodeling for craniosynostosis in infancy.

General considerations about frontal sinus development are first discussed. We include retrospective clinical and radiographical studies dealing with 90 craniosynostoses among 850 patients operated in the Craniofacial Unit of Necker's Hospital for Sick Children (1976-1988; Paris, France). The incidence of frontal sinus development is analyzed: The pneumatization of the frontal bone seemed to develop according to the type of surgery and to the age at which review was realized, but was not linked to the age at which surgery was performed. The surgery consisted of fronto-orbital remodeling after supraorbital bar mobilization. The median age at surgery was approximately 3 years, and the median length of the postoperative follow-up was 6.5 years, depending on the type of pathology. The correlation between frontal sinus development and glabellar morphology are also analyzed: When there was a significant advancement of the supraorbital bar, the projection of the glabella was satisfactory without any frontal sinus. When no significant advancement was performed, pneumatization of the frontal bone was as frequent as in the general population and was dependent on the underlying frontal sinus. A classification of the different type of frontal advancement is proposed.

Adolescent↗

PubMed2002

Distinct craniofacial-skeletal-dermatological dysplasia in a patient with W290C mutation in FGFR2.

Mutations in the fibroblast growth factor receptor genes (FGFR) have been known to be associated with many craniosynostosis syndromes with overlapping phenotypes. We studied a 15-year-old Thai boy with an unspecified craniosynostosis syndrome characterized by multiple suture craniosynostoses, a persistent anterior fontanel, corneal scleralization, choanal stenosis, atresia of the auditory meatus, broad thumbs and great toes, severe scoliosis, acanthosis nigricans, hydrocephalus, and mental retardation. Radiography revealed bony ankyloses of vertebral bodies of T9-12, humero-radio-ulnar joints, intercarpal joints, distal interphalangeal joints of fifth fingers, fibulo-tibial joints, intertarsal joints, and distal interphalangeal joints of the first toes. The patient was a heterozygous for a 870G --> T change resulting in a W290C amino acid substitution in the extracellular domain of the fibroblast growth factor receptor 2 gene (FGFR2). This mutation has previously been reported in a patient with severe Pfeiffer syndrome type 2 that is distinct from the craniosynostosis in our patient. These findings emphasize locus, allelic, and phenotypic heterogeneity of craniofacial-skeletal-dermatological syndrome due to FGFR2 mutations.

Abnormalities, Multiple↗

PubMed1989

Functional and anatomic aspects of the orbitotomy in craniofacial surgery.

The orbitotomy has a central importance in craniofacial surgery. It is indicated for premature craniosynostoses, malformations and tumor surgery. The aim of the treatment is to correct functional disturbances and aesthetic impairments. Anatomical structures must be respected. Functional and anatomical aspects of the orbitotomy in craniofacial surgery are described.

Humans↗

PubMed1997

Osteoglophonic dysplasia: appearance and progression of multiple nonossifying fibromata.

The appearance and gradual enlargement of fibrous cortical defects and multiple nonossifying fibromata are documented in this report of a 2-year-old boy with a very rare skeletal dysplasia known as osteoglophonic dysplasia, characterized by multiple and recurrent craniosynostoses, platyspondyly, short tubular bones, and epiphyseal dysplasia.

Bone Diseases, Developmental↗

PubMed1994

Molecular basis and diagnosis of neurogenetic disorders.

Over the past few years, molecular neurogenetics has developed into one of the most promising and active research fields. The new discipline applies modern molecular genetic techniques to the investigation of classical neurological disorders. In the following article, a definition of neurogenetic disease is introduced, the molecular basis of four groups of neurogenetic disorders is described and recent diagnostic developments are presented. The first group of diseases is caused by trinucleotide expansions. "Expanding" trinucleotide repeats were not known to occur in any species until about three years ago. Today, disorders such as Huntington's disease, spinocerebellar ataxia type 1, fragile X mental retardation, spinobulbar muscular atrophy and myotonic dystrophy are all known to be caused by the expansion of trinucleotides. The second group is characterized by chromosomal deletions or uniparental disomies. Lissencephaly and the Miller-Dieker syndrome, Prader-Willi and Angelman syndromes and Duchenne and Becker muscular dystrophies belong to this category. The third group includes those neurogenetic disorders that are mainly caused by point mutations such as the X-linked leukodystrophies, including Pelizaeus-Merzbacher disease and adrenoleukodystrophy, Charcot-Marie-Tooth syndrome type 1, familial forms of amyotrophic lateral sclerosis, several types of craniosynostoses and some CNS tumor syndromes. Finally, Alzheimer's and Parkinson's disease are discussed as representatives of group four, i.e. genetically heterogeneous neurological disorders.

Animals↗

PubMed2006

Piezosurgery--a new safe technique in cranial osteoplasty?

All surgical interventions on the neurocranium bear the risk of injury of the dura mater and development of a cerebrospinal fluid fistula. Therefore, despite careful preparation, damage to the dura mater cannot always be omitted. Especially after surgery and in patients with increased intracranial pressure (craniosynostoses) there is a high risk of perforating the dura. In this article a new surgical technique for osteotomy (Piezosurgery) that avoids perforation of the dura is presented. Ultrasonic microvibrations allow a selective cut of only mineralized structures without damage to the soft tissue. Even in case of accidental contact the dura remains undamaged. This advantage is also useful for bone splitting, to separate the tabula externa from the tabula interna in situ, without any risk of dura perforation even in case of the very thin bones in an infantile skull. The present work shows the applicability of piezoelectric surgery in high-risk patients after osteotomy, avoiding perforation of the dura mater.

Brain Injuries↗

PubMed1998

Pre-surgical CT/FEA for craniofacial distraction: I. Methodology, development, and validation of the cranial finite element model.

Recently, surgeons have begun to treat serious congenital craniofacial deformities including craniosynostoses with mechanical devices that gradually distract the skull. As a prospective means of treatment planning for such complex deformities, FE models derived from routine preoperative CT scans (CT/FEA) would provide ideal patient specific engineering analyses. The purpose of this study was to assess the dimensional and predictive accuracy of the CT/FEA process through the development of a 3D model of a dry human calvarium subjected to two-point distraction ex vivo. Comparative skull measurements revealed that CT/FEA construction error did not exceed 1% for transcranial dimensions, and the thickness error did not exceed 8.66% or 0.31 mm. CT/FEA strain predictions for the central region of the skull, between the distraction posts, were not statistically different from homologous gage values at P < 0.05. Peripherally, however, the strain fields were less well behaved and the FE predictions showed only general qualitative agreement with gage recordings.

Biomechanical Phenomena↗

PubMed2003

Fgfr mRNA isoforms in craniofacial bone development.

Mutations in genes encoding for fibroblast growth factor receptors (FGFRs) have been identified as causes of both chondrodysplasias and craniosynostoses, both of which cause abnormalities in the growth and development of the craniofacial region. FGFRs form mRNA splicing isoforms, each with distinct ligand binding specificity and tissue distribution. These confer specific biological functions on these isoforms. Although it is known that FGFRs are expressed at numerous locations during early mouse development, including the craniofacial area, relatively little is known about the expression of the splicing isoforms during craniofacial bone development. To address this, we have performed a detailed survey to detect these genes in the developing mouse craniofacial region. We have analyzed the developing mouse mandible, calvaria, and cranial base, in particular the spheno-occipital synchondrosis, a key centre of craniofacial growth. Fgfr1c was detected weakly in osteoblastic cells in both the developing calvarial and mandibular bones. Fgfr3b and Fgfr3c were found chiefly in proliferating chondrocytes of the cranial base synchondroses and the mandibular condyle. Fgfr2b transcripts were most notably detected in the perichondria of the mandibular condyle and the cranial base. Fgfr2c transcripts were detected with high intensity in differentiating osteoblasts at the sutural osteogenic fronts of the calvarial bones. In addition, Fgfr2c was also expressed in the perichondria of the mandibular condyle and the cranial base. These expression patterns suggest both differing and similar functions for -b and -c isoforms. The former is exemplified by Fgfr1 transcripts, which show distinct differences in their distribution, being mutually exclusive. Similar functions are suggested by the overlapping expression patterns of the -b and -c isoforms of both Fgfr2 and Fgfr3. Fgfr4 transcripts were found in developing muscles. These data help to explain the disturbances in craniofacial growth exhibited by both patients and the growing number of transgenic mice carrying mutations in genes encoding FGFRs/Fgfrs.

Animals↗

PubMed2003

A Ser252Trp [corrected] substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis.

Apert syndrome (AS) is one of the most severe craniosynostoses and is characterized by premature fusion of craniofacial sutures. Mutations of either Ser252Trp or Pro253Arg in fibroblast growth factor receptor 2 (FGFR2) are responsible for nearly all known cases of AS. Here we show that mutant mice carrying the activation mutation, Ser252Trp [corrected] which corresponds to Ser252Trp in human FGFR2, have malformations mimicking the skull abnormalities found in AS patients. Mutant mice (Fgfr2(250/+)) are smaller in body size with brachycephaly and exhibit distorted skulls with widely spaced eyes. Unexpectedly, the premature closure of the coronal suture is accompanied by decreased, rather than increased, bone formation. We demonstrate that the Fgfr2-Ser252Trp [corrected] mutation does not cause obvious alterations in cell proliferation and differentiation; however, it results in increased Bax expression and apoptosis of osteogenic cells in mutant coronal suture. The accelerated cell death possibly reduces the space between osteogenic fronts of flat bones and results in the physical contact of these bones. Thus, our data reveal that dysregulated apoptosis plays an important role in the pathogenesis of AS related phenotypes.

Acrocephalosyndactylia↗

PubMed1995

Receptors for fibroblast growth factors.

The recent discovery of the involvement of heparan sulfate proteoglycans (HSPG) in the activation of fibroblast growth factor receptors (FGFR) has led to an intensification of study of this field. It appears that the HSPG act as low affinity receptors to which the fibroblast growth factors (FGF) must bind in order to successfully activate the high affinity FGFR. Heparan sulfate chains consisting of alternately arranged N-acetylated or N-sulfated glucosamine and uronic acid disaccharide regions, covalently attached to a core protein are found in two major families of cell surface HSPG, the syndecans and glypicans. A high affinity bFGF binding region has been isolated from fibroblast HS. There are four basic members of the FGFR family (FGFR 1-4), as well as a wealth of splice variants. The alternative forms of the basic receptors can have altered ligand binding or signalling qualities, depending on the region of the gene which is spliced. Investigations with null FGFR, incapable of signalling, have demonstrated the requirement for FGF in the organization of mammalian tissues and in embryonic patterning. Mutation of the FGFR genes has been recognized recently in human craniosynostoses where a single base pair mutation in the FGFR gene results in skeletal malformations specific to each syndrome. One suggestion is that the interaction of the mutant FGFR with the HSPG/FGF complex somehow contributes to the disease phenotype.

Binding Sites↗

PubMed1997

Mutations of the TWIST gene in the Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome (acrocephalo-syndactyly type III, ACS III) is an autosomal dominant craniosynostosis with brachydactyly, soft tissue syndactyly and facial dysmorphism including ptosis, facial asymmetry and prominent ear crura. ACS III has been mapped to chromosome 7p21-22. Of interest, TWIST, the human counterpart of the murine Twist gene, has been localized on chromosome 7p21 as well. The Twist gene product is a transcription factor containing a basic helix-loop-helix (b-HLH) domain, required in head mesenchyme for cranial neural tube morphogenesis in mice. The co-localisation of ACS III and TWIST prompted us to screen ACS III patients for TWIST gene mutations especially as mice heterozygous for Twist null mutations displayed skull defects and duplication of hind leg digits. Here, we report 21-bp insertions and nonsense mutations of the TWIST gene (S127X, E130X) in seven ACS III probands and describe impairment of head mesenchyme induction by TWIST as a novel pathophysiological mechanism in human craniosynostoses.

Acrocephalosyndactylia↗

PubMed2001

New Zealand Maori family with the pro250arg fibroblast growth factor receptor 3 mutation associated with craniosynostosis.

Background: A large New Zealand Maori family has non-syndromic coronal craniosynostosis, which is inherited as an autosomal dominant mutation with variable expression. The aim of the study is to determine whether the family has the pro250 arg mutation in the gene for fibroblast growth factor receptor 3 (FGFR3), a mutation found in patients with various types of craniosynostosis. Patients: Fourteen members of a New Zealand Maori family were evaluated, of whom five have coronal synostosis. A family pedigree tracing six generations was recorded. Methods: Blood samples were drawn for genomic DNA analysis from 14 family members. Polymerase chain reaction, restriction-enzyme digestion and DNA sequencing was performed to identify the pro250arg mutation in FGFR3. Results: Seven family members were heterozygous for the pro250arg mutation in FGFR3. The mutation showed autosomal dominance with reduced penetrance and variable expressivity. Conclusion: Our data and those of other investigators suggest that we should begin integrating molecular diagnosis with phenotypic diagnosis of craniosynostoses. Copyright 2001 European Association for Cranio-Maxillofacial Surgery.

Journal Article↗

PubMed2003

[The treatment of hydrocephalus in infants and children using hydrostatic valves].

Complications of CSF-shunt systems may not only prolong hospitalization, but also influence dramatically the neurological and mental outcome of patients, especially of premature newborns. Shunt complications may be caused by mechanical problems such as shunt occlusion or dysfunction of the valve itself. Another cause of shunt complications is the overdrainage and, lastly, shunt infection. The choice of the specific shunt system seems to play an important role in avoiding the above mentioned complications. In this study 32 children with hydrocephali due to different etiologies were treated with hydrostatic valves, the so called Pädi GAV (pediatric hydrostatic valve) valves developed by Miethke. In addition to mechanical occlusions and shunt infections, the overdrainage related complications, such as subdural hematomas/ fluid collections, slit ventricles and secondary craniosynostoses were taken into consideration. None of the patients showed these complications. On the contrary, postoperative MRI or the ultrasound demonstrated prominent ventricles comparing these with those of non-hydrocephalic children as measured by the Evans-Index and FOR (fronto-to-occipital ratio). Whether the overdrainage-related complications actually reduced using Pädi GAV valves will be shown by further long-term follow ups. This study aims to evaluate the initial experience with the Pädi GAV shunt system, particularly with respect to the overdrainage-related problems.

Cerebrospinal Fluid Shunts↗

PubMed2004

[Surgery of craniofacial deformities].

Most craniofacial abnormalities are craniosynostoses due to premature fusion of one or more craniofacial sutures. The typical cranial deformities result from growth inhibition perpendicular to the affected sutures. Functional impairment is caused either directly by the pathological growth pattern or indirectly by the increased intracranial pressure. Craniosynostosis is frequently accompanied by dysmorphia or dystopia of the orbits, resulting in possible functional problems. The indications for operation are to increase the intracranial volume and to correct aesthetic impairments. The planning of the surgical procedures has to consider the orbital problems. This review describes the different disease patterns of premature craniosynostosis and specific surgical approaches for their correction.

Craniofacial Abnormalities↗

PubMed2006

[Malposition of the orbita from the surgical point of view].

The individual appearance of a person is mainly determined by the head and, in particular, by the eyes. The orbita exerts a decisive influence on the harmony of the face. Anomalies of the neuro- and viscerocranium have varying impact on the orbits as well as on the structures of the bulb, resulting in dysmorphia or dystopia of the orbits which, in turn, lead to corresponding functional impairments. Premature craniosynostoses, representing the most frequent craniofacial malformation, may have an influence on the region of the orbita in different manner. Symptomatics depend on localisation, number and severity of the synostoses. Main symptoms are uni- or bilateral exophthalmus as well as hypo- or hypertelorism. The deformation of the patients is not only a "cosmetic problem" but often also a barrier to social communication with all consequent impairments of the patient's development. Sometimes it is even the only reason for a mental retardation of the child. Apart from augmentation of the intracranial volume, the main aim of corrective surgery, therefore, is normalisation of the patient's appearance. There are various surgical procedures for operative correction. However, therapy is not only directed towards the orbita but has to be integrated into the overall concept for therapy of the disease. In this article we show the surgical approaches for the treatment of orbital malformations caused by various craniofacial malformations, using clinical examples.

Eye Abnormalities↗

PubMed2001

A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes.

Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon 9 (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients.

Acrocephalosyndactylia↗

PubMed2002

SNT1/FRS2 mediates germinal vesicle breakdown induced by an activated FGF receptor1 in Xenopus oocytes.

The docking protein SNT1/FRS2 (fibroblast growth factor receptor substrate 2) is implicated in the transmission of extracellular signals from the fibroblast growth factor receptor (FGFR), which plays vital roles during embryogenesis. Activating FGFR mutations cause several craniosynostoses and dwarfism syndromes in humans. Here we show that the Xenopus homolog of mammalian FRS-2 (XFRS2) is essential for the induction of oocyte maturation by an XFGFR1 harboring an activating mutation (XFGFR1act). Using a dominant-negative form of kinase suppressor of Ras, we show the Mek activity is required for germinal vesicle breakdown (GVBD) induced by co-expression of XFGFR1act and XFRS2, but this activity is not required for progesterone-induced GVBD. Furthermore, Mek/MAPK activity is critical for the induction and/or maintenance of H1 kinase activity at metaphase of meiosis II in progesterone-treated oocytes. An activated XFGFR1 containing a mutation in the phospholipase Cgamma binding site (XFGFR1actY672F) displayed a reduced ability to induce cell-cycle progression in oocytes, suggesting phospholipase Cgamma may not be necessary but that it augments XFGFR signaling in this system. Oocytes co-expressing XFGFR1act and XFRS2 showed substantial H1 kinase activity, but this activity was blocked when the oocytes were treated with the phosphatidylinositol 3-kinase inhibitor LY294002. Although phosphatidylinositol 3-kinase activity is essential for XFGFR1act/XFRS2-induced oocyte maturation, this activity is not required for maturation induced by progesterone. Finally, ectopic expression of Xspry2, a negative regulator of XFGFR signaling, greatly reduced MAPK activation and GVBD induced by the expression of either XFGFR1act plus XFRS2 or activated Ras (H-RasV12). In contrast, Xspry2 did not prevent GVBD induced by an activated form of Raf1, suggesting that Xspry2 exerts its inhibitory function upstream or parallel to Raf and downstream of Ras.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Spring mediated dynamic craniofacial reshaping. Case report.

A new technique of using implantable springs as an adjunct after corrective surgery for craniofacial malformations is presented. A 6-month-old boy with multiple premature craniosynostoses and extreme turricephaly underwent surgery of limited extensiveness but supplemented with a set of indwelling springs for gradual postoperative skull reshaping. At spring removal three months later the skull was normalised both clinically and on cephalogram. A 5-year-old boy with Apert syndrome, severe midface retrusion, exorbitism, and sleep apnoea underwent a monobloc full face disjunction without repositioning, but was fitted with two springs for postoperative facial advancement. Three months postoperatively cephalometric analysis revealed 14 mm advancement at incisor level and at least 16 mm in the frontal region. There was no more exorbitism or clinically noticeable midface retrusion. Sleep studies revealed that the sleep apnoea was significantly improved, meaning complete cure except when sleeping flat on the back. It was concluded from these first clinical applications of spring assisted craniofacial distraction that springs hold significant promise for the future in many respects.

Acrocephalosyndactylia↗