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PubMed2000

Clustering of FGFR2 gene mutations inpatients with Pfeiffer and Crouzon syndromes (FGFR2-associated craniosynostoses).

A cohort of 36 unrelated German patients with craniosynostosis syndromes of the Crouzon and Pfeiffer type were analyzed for FGFR mutations. Mutations in FGFR2 were identified in 25 Crouzon and 5 Pfeiffer syndrome patients, whereas no sequence alterations were found in the remaining patients, even after screening of the relevant parts of FGFR1, FGFR3, and TWIST. Mutations in FGFR2 clustered at two critical cysteine residues, 278 and 342, which were involved in 18 of 30 cases (60%). These two mutational hot spots, therefore, are prime targets for an efficient mutation-screening strategy. The spectrum of mutations overlapped the two syndromes and thus reflected the phenotypic similarities observed in both patient groups. In 21 families, the origin of the mutation could be traced by analyzing parents and relatives. Eleven mutations arose de novo, indicating a high mutation rate for FGFR2. In the 10 familial cases, the clinical presentation varied considerably within the pedigree, but both syndromes "bred true," i.e., a Pfeiffer syndrome phenotype was never observed in a Crouzon syndrome family and vice versa.

Acrocephalosyndactylia↗

PubMed1988

Craniofacial surgery for craniosynostosis: functional and morphological results.

The functional and morphological aspects of craniosynostoses are reviewed, based on a series of 462 operations, 350 intra-cranial pressure recordings and 300 I.Q. assessments. Increased intracranial pressure and mental impairment are linked. The frequency of intracranial hypertension is higher when more than one suture is involved, but even monosutural craniosynostoses can be affected. Increased intracranial pressure had mental deficiency are more frequent after one year of age than before. Surgery lowers the intracranial pressure and halts the mental regression. The younger the patient is at the time of surgery, the better the results. Surgery does not improve the I.Q. once it is already impaired. Morphological results of frontocranial remodeling are good and remain so with growth. Facial anomalies associated with craniosynostoses improve after early frontocranial remodeling, except for the severe midface retrusion of Crouzon's disease and Apert's syndrome that need in most cases a supplementary midface advancement.

Cephalometry↗

PubMed1995

Genetic study of nonsyndromic coronal craniosynostosis.

From a series of 1265 individuals with different craniosynostoses hospitalized between 1976 and 1993, 260 probands with nonsyndromic unilateral (181) or bilateral (79) coronal synostosis were analysed. The prevalence of craniosynostoses was estimated as 1 in 2100 children. In the group of coronal synostosis, family history was obtained on 192 probands in 180 pedigrees. The male:female ratio was 1:2. The average paternal age was 32.7 +/- 6.4 years, which is significantly higher than normal. In 26 of the 180 pedigrees, a high degree of familial aggregation was observed, giving a 14.4% figure of familial cases. The bicoronal synostoses were significantly more often familial than the unicoronal synostoses. Segregation analysis of these families leads to the conclusion that coronal synostosis is transmitted as a dominant disorder with 0.60 penetrance and 61% of sporadic cases.

Adult↗

PubMed1999

Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders.

Craniosynostoses are a heterogeneous group of disorders characterized by premature fusion of cranial sutures. Mutations in fibroblast growth factor receptors (FGFRs) have been associated with a number of such conditions. Nevertheless, the cellular mechanism(s) involved remain unknown. We analyzed cell proliferation and differentiation in osteoblasts obtained from patients with three genetically and clinically distinct craniosynostoses: Pfeiffer syndrome carrying the FGFR2 C342R substitution, Apert syndrome with FGFR2 P253R change, and a nonsyndromic craniosynostosis without FGFR canonic mutations, as compared with control osteoblasts. Osteoblasts from craniosynostotic patients exhibited a lower proliferation rate than control osteoblasts. P253R and nonsyndromic craniosynostosis osteoblasts showed a marked differentiated phenotype, characterized by high alkaline phosphatase activity, increased mineralization and expression of noncollagenous matrix proteins, associated with high expression and activation of protein kinase Calpha and protein kinase Cepsilon isoenzymes. By contrast, the low proliferation rate of C342R osteoblasts was not associated with a differentiated phenotype. Although they showed higher alkaline phosphatase activity than control, C342R osteoblasts failed to mineralize and expressed low levels of osteopontin and osteonectin and high protein kinase Czeta levels. Stimulation of proliferation and inhibition of differentiation were observed in all cultures on FGF2 treatment. Our results suggest that an anticipated proliferative/differentiative switch, associated with alterations of the FGFR transduction pathways, could be the causative common feature in craniosynostosis and that mutations in distinct FGFR2 domains are associated with an in vitro heterogeneous differentiative phenotype.

Acrocephalosyndactylia↗

PubMed2002

[Surgery for craniosynostosis: timing and technique].

Craniosynostoses are a group of diseases, the presentation of which differs markedly on account of the cranial suture involved. Their impact is cosmetic, cerebral, and ophthalmologic. Syndromic craniosynostoses associate a more or less pronounced faciostenosis, which requires surgical correction as well, because of cosmetic, ophthalmologic or airway problems. Surgical treatment depends on the type of the craniosynostosis and the patient's age; ideally, the child should be operated between 3 and 12 months. This surgery requires a perfect collaboration between neurosurgeon, plastic surgeon, and anaesthesiologist. Surgical correction allows in large measures the preservation of intellect, sight, and body image.

Anesthesia↗

PubMed1998

Studies in cranial suture biology: up-regulation of transforming growth factor-beta1 and basic fibroblast growth factor mRNA correlates with posterior frontal cranial suture fusion in the rat.

The mechanisms involved in normal cranial suture development and fusion as well as in the pathophysiology of craniosyostosis are not well understood. The purpose of this study was to investigate the expression of several cytokines--transforming growth factor-beta-1 (TGF-beta1), basic fibroblast growth factor (bFGF), and interleukin-6 (IL-6)--during cranial suture fusion. TGF-beta exists in three mammalian isoforms that are abundant in bone and stimulate calvarial bone formation when delivered locally. Other bone growth factors including basic fibroblast growth factor and the interleukins regulate bone growth and are mitogenic for bone marrow cells and osteoblasts. The involvement of growth factors in the pathophysiology of craniosynostosis is supported by recent genetics data linking fibroblast growth factor receptor mutations to syndromal craniosynostoses. In this experimental study, in situ hybridization was used to localize and quantify the gene expression of TGF-beta1, bFGF, and IL-6 during cranial suture fusion. In the Sprague-Dawley rat, the posterior frontal cranial suture normally undergoes fusion between 12 and 22 days of age, whereas all other cranial sutures remain patent. All in situ analyses of fusing posterior frontal sutures were compared with the patent, control, sagittal sutures. Posterior frontal and sagittal sutures, together with underlying dura, were harvested from rats at 8, 12, 16, and 35 days of postnatal life to analyze posterior frontal suture activity before, during, and after fusion. In situ hybridization was performed on frozen sections of these specimens using DNA probes specific for TGF-beta1, bFGF, and IL-6 mRNA. A negative control probe to IL-6 in the sense orientation was also used to validate the procedure. Cells expressing cytokine-specific mRNA were quantified (in cells positive per 10(-1) mm2) and analyzed using the unpaired Student's t test. Areas encompassing the fibrous suture and the surrounding bone plates were analyzed for cellular mRNA activity. IL-6 mRNA expression showed a minimal rise in the posterior frontal suture at days 12 and 16, with an average count of 10 and 6 cells per 10(-1) mm2, respectively. The sagittal suture remained negative for IL-6 mRNA at all time points. TGF-beta1 and bFGF analyses were most interesting, showing marked increases specifically in the posterior frontal suture during the time of active suture fusion. On postnatal day 8, a 1.5-fold increase in posterior frontal suture TGF-beta1 mRNA was found compared with sagittal sutures (p = 0.1890, unpaired Student's t test). This difference was increased 26-fold on day 12 in posterior frontal suture TGF-beta1 expression (p = 0.0005). By day 35, posterior frontal suture TGF-beta1 mRNA had nearly returned to prefusion levels, whereas TGF-beta1 mRNA levels in the sagittal suture remained low. A similar upregulation of bFGF mRNA, peaking at day 12, was observed in posterior frontal but not sagittal sutures (p = 0.0003). Furthermore, both TGF-beta1 and bFGF mRNA samples with intact dura showed an intense dural mRNA expression in the time preceding and during active posterior frontal suture fusion but not in sagittal tissues. Our data demonstrate that TGF-beta1 and bFGF mRNA are up-regulated in cranial suture fusion, possibly signaling in a paracrine fashion from dura to suture. TGF-beta1 and bFGF gene expression were dramatically increased both in and surrounding the actively fusing suture and followed the direction of fusion from endocranial to epicranial. These experimental data on bone growth factors support the recent human genetics data linking growth factor/fibroblast growth factor receptor deletions to syndromal craniosynostoses. The ultimate aim of these studies is to understand the underlying mechanisms regulating suture growth, development, and fusion so surgeons may one day manipulate the biology of premature cranial suture fusion.

Animals↗

PubMed2005

The effect of an early Le Fort III surgery on permanent molar eruption.

The purpose of this retrospective study was to evaluate the extent to which an early Le Fort III osteotomy affects the position and eruption of the permanent maxillary first and second molars. To test the null hypothesis that there are no changes in eruption patterns, 31 patients diagnosed with craniosynostoses (13 with Crouzon's syndrome, nine with Apert's syndrome, eight with Pfeiffer's syndrome, and one with Carpenter's syndrome) with a mean age at the time of surgery of 5.3 +/- 1.3 years were studied. All patients underwent a Le Fort III osteotomy performed by a single surgeon to correct the anatomical deformity for functional and psychosocial reasons. Eighteen patients with craniosynostoses who had not been operated on (11 with Crouzon's syndrome, four with Apert's syndrome, and three with Pfeiffer's syndrome) served as controls; they had a mean age of 21.2 +/- 9.5 years. First and second molar positions and eruption patterns were assessed separately on panoramic radiographs by three observers. For the patients who underwent surgery, long-term evaluation showed that although 79 percent of all first molars erupted compared with 100 percent for the control group (p < 0.001), only 18 percent of all second permanent molars erupted compared with 89 percent for the control group (p < 0.0001). The authors conclude that in a significant minority of cases, early Le Fort III osteotomy affects first molar eruption, whereas the probability of second molar eruption is significantly decreased in the majority of cases. Therefore, Le Fort III osteotomy sites should be positioned distal to the second molar tooth buds. If this is not possible, patients, parents, and dental professionals should be made aware of these early postosteotomy sequelae so that later treatment planning can be enhanced.

Adult↗

PubMed1997

Classification of previously unclassified cases of craniosynostosis.

Cases of craniosynostosis usually fall into well-demarcated categories: those related to a syndrome or those identified by a combination of suture involvement and morphological appearance. Between 1976 and 1995, 53 (3.6%) of 1474 cases in the craniofacial databank were assessed and designated as nonsyndromic but unclassifiable. The records and radiological studies obtained in these patients were retrospectively analyzed and comparisons were made with patients classified in the databank as having simple craniosynostoses. It proved possible to divide the formerly unclassifiable cases into two groups: those with "two-suture disease" (Group A) and a "complex" group (Group B) in which more than two sutures were affected. Group A consisted of 36 cases (68%) of patients presenting with clear evidence of simultaneous involvement of two sutures but with no progression over time to suggest a more diffuse pansynostosis. Suture involvement was as follows: 17 of 36 sagittal plus one coronal; seven of 36 sagittal and metopic; six of 36 sagittal plus one lambdoid; and six of 36 metopic plus one coronal. The only significant difference between the Group A cases and the cases of simple craniosynostoses was in the percentage requiring a second operation (24% vs. 5%, p < 0.0001). Group B consisted of 17 cases in which the patients presented at a slightly earlier age (mean 1 year) with severe morphological changes and multiple suture involvement. At the time of surgery, six of 17 patients showed large areas of lacunae within the cranial vault, making craniectomy the only option. In Group B, 10 of 17 patients displayed bilateral lambdoid plus sagittal suture involvement resulting in marked occipital recession posteriorly, whereas anteriorly in six of these 10 patients there was a massive frontal bone associated with posteriorly located coronal sutures. In contrast, there were also four patients in Group B with bilateral coronal plus metopic involvement resulting in a small frontal bone. There was a trend toward a lower intelligence quotient and a worse morphological outcome in the patients in Group B, but again the only result attaining statistical significance when compared to the databank was the rate of second operation (37.5 vs. 5%, p < 0.0001). "Two-suture synostosis" is a relatively straightforward condition and is treatable with standard craniosynostosis techniques. However, possibly as a result of surgical compromise when two sutures are involved, the rate of reoperation is far higher than in simple suture cases. In contrast, patients in the "complex" group presenting with severe multisuture involvement require a more tailor-made approach to their management that often entails a second procedure.

Analysis of Variance↗

PubMed1987

Craniosynostosis in two African green monkeys.

Multiple craniosynostoses were found in two infant African green monkeys. The bones of the calvariums were overlapped and fused at all the cranial sutures with resulting pressure necrosis of the cerebral cortices. The cause of the craniosynostoses is unknown, but the two infants were born within 15 days of each other and had the same father, suggesting either exposure to a teratogen or a genetic etiology. The overlapping of the cranial bones is unlike craniosynostosis in humans.

Animals↗

PubMed1994

[Development of the frontal sinus after frontocranial remodeling for craniostenosis in infancy].

General considerations about frontal sinus development are discussed. This retrospective radiological study concerns 90 craniosynostoses among 850 cases operated in the Cranio-Facial Unit (1976-88, Hôpital Necker des Enfants Malades, Paris, France). The incidence of frontal sinus development is compared between a control group and the craniosynostoses group with a mean age at surgery of 3 years and a mean follow-up of 6.5 years. Pneumatization of the frontal bone seemed to vary according to the type of surgery and the age at review, but was not linked to sex and age at surgery. A classification of fronto-cranial remodelling is suggested.

Adolescent↗

PubMed1995

Technetium-99m-HMPAO SPECT cerebral blood flow study in children with craniosynostosis.

UNLABELLED: Premature closure of cranial sutures (primary craniosynostosis) in children leads to characteristic skull deformities and prevents the constricted brain from growing normally. Although the cause remains unknown, several etiological factors have been cited. Recently, hypovascularity has been reported as a possible cause of craniosynostosis. METHODS: In a prospective study regional cerebral blood flow studies were carried out with 99mTc-HMPAO SPECT in seven children with craniosynostoses. Five preoperative and six postoperative studies were conducted and the results correlated with radiological and surgical findings. RESULTS: Preoperative studies revealed regional hypovascularity in the underlying cerebral hemisphere, corresponding to the fused sutures. Postoperative studies revealed disappearance of these perfusion defects in most cases, indicating normalization of perfusion following surgical decompression. CONCLUSION: This study establishes the presence of cerebral hypovascularity in craniosynostoses and suggests that early surgery and release of craniostenosis is essential to achieve optimum perfusion and brain development.

Brain↗

PubMed1997

Craniosynostosis.

Primary craniosynostosis, the premature closure of one or more cranial sutures, occurs in up to one in 2,500 births. Secondary causes of craniosynostosis include disorders that lead to failure of brain development and conditions that influence bone metabolism. The craniosynostoses result in skull deformities and increased intracranial pressure as the developing brain is compressed. Clinical signs and symptoms depend on which suture or combination of sutures are involved. The etiology of craniosynostosis is believed to concern genetic abnormalities in fibroblast growth factors or their receptors, and the craniosynostoses can be associated with other congenital syndromes. The most important differential diagnoses are molding that occurs during birth in young infants, and positional molding that occurs as a result of excessive time spent in the supine position in older infants. The diagnosis may be confirmed by plain films of the skull, and surgical treatment is usually indicated to prevent neurologic complications.

Adult↗

PubMed1995

Assignment of FGF8 to human chromosome 10q25-q26: mutations in FGF8 may be responsible for some types of acrocephalosyndactyly linked to this region.

Emerging evidence suggests that Fgf8, a recently identified member of the fibroblast growth factor family, plays an important role in outgrowth and patterning of the face, limbs, and central nervous system of the vertebrate embryo. We report the mapping of FGF8 to human chromosome 10q25-q26, using Southern blot analyses of genomic DNAs from rodent/human somatic cell hybrid lines. Apert, Crouzon, Jackson-Weiss, and Pfeiffer syndromes are craniosynostoses genetically linked in part to 10q25-q26 and are associated with point mutations in the extracellular domain of FGFR2. Given the assignment to the same chromosomeal band(s) as FGFR2 and the probable ligand-receptor relationship of the gene products of FGF8 and FGFR2, we hypothesize that some cases of these craniosynostoses linked to 10q25-q26 that do not have mutations in FGFR2 may involve mutations in FGF8.

Acrocephalosyndactylia↗

PubMed1997

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 students 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 not significant differences between sexes.

Age Factors↗

PubMed1978

Normal intelligence in two children with Carpenter syndrome.

Previous reports have noted a constant association between the Carpenter syndrome (acrocephalopolysyndactyly, type II) and mental retardation. We report two patients with this condition with normal intelligence. These observations indicate that mental deficiency is not necessarily a component of the Carpenter syndrome and that early surgical correction of the craniosynostoses may improve the chances of normal mentality.

Acrocephalosyndactylia↗

PubMed2005

Novel phenotype of craniosynostosis and ocular anterior chamber dysgenesis with a fibroblast growth factor receptor 2 mutation.

Fibroblast growth factor receptor 2 (FGFR2) mutations are associated with syndromic and non-syndromic craniosynostoses. More recently it has been recognized that FGFR2 may have a role in the development of the anterior chamber of the eye following the finding of a specific FGFR2 mutation (p.Ser351Cys, c.1231 C --> G) with anterior chamber dysgenesis. Affected patients had a severe craniofacial phenotype and clinical course. A child with a different FGFR2 mutation (p.Ala344Ala, c1032 G --> A heterozygote), premature fusion of the sagittal suture, and an Axenfeld-Rieger anomaly but otherwise normal clinical course is reported. The case provides further evidence that FGFR2 has a role in anterior chamber embryogenesis.

Anterior Chamber↗

PubMed1994

Ocular findings in trigonocephaly.

BACKGROUND: Trigonocephaly, caused by premature closure of the metopic suture, is a rare form of craniosynostosis. The aim of this study was to assess the visual outcome in children operated on for trigonocephaly. METHODS: We present eight cases of children with trigonocephaly surgically corrected by the same craniofacial technique. CT with 3D reconstruction was performed in all cases. Genitori defined three types of trigonocephaly according to the severity of the deformity of the skull base only types II and III were included in this study directed at evaluation of the ocular disorder. A complete eye examination was performed on all children by the same observer, with a follow-up of 2-6 years. RESULTS: 3D-CT reconstruction of the skull base showed that the frontozygomatic region was affected by the deformation. Ocular examination showed considerable astigmatism in most children with late operation. A low degree of strabismus was observed in most children. CONCLUSION: This study demonstrated that reconstructive surgery should be performed by the age of 6 months, given the immaturity of the visual system up to that time. Close cooperation between neurosurgeons, pediatricians and ophthalmologists is of paramount importance in order to prevent this bone deformation exerting an adverse effect on visual development. The ophthalmologist must possess a basic understanding of the various craniosynostoses.

Astigmatism↗

PubMed1986

Problems with lateral canthal advancement.

The technique of lateral canthal advancement for the treatment of premature coronal craniosynostoses has been employed in 12 cases. In patients with high intracranial pressure aesthetic problems after the operation were observed. The frontolateral area did not reossify and the brain bulged forward. For secondary correction in these cases the bilateral advancement of Marchac and Renier was used. A sufficient increase of intracranial volume could be achieved by complete osteotomy of the skull base. The bone segments were stabilized by miniplate osteosynthesis. The results were thereby improved.

Craniosynostoses↗